What is Ginkgo Biloba? What is Ginkgo Biloba Extract or GBE?

Ginkgo Biloba Research Update.:

A-Ginkgo Biloba:Property with Gut,Intestine,Stomach,Gastrointestinal,Bladder Research:

1.The effect of Ginkgo biloba on the activity of catalase and lipid peroxidation in experimental strangulation ileus.:

Int J Clin Lab Res. 1998;28(1):69-71.PMID: 9594365
This study was designed to assess the therapeutic effect of Ginkgo biloba extract (EGb 761) in experimental strangulation ileus. Rats were divided into control (n = 7), placebo (n = 11), and EGb-treated (n = 11) groups. No surgical procedure was carried out on the control group. Strangulation ileus was produced in the placebo and EGb groups for 2.5 h. At the end of this period, 100 mg/kg EGb in 1 ml of saline was injected intraperitoneally to the EGb-treated group. In the placebo group, animals received an equivalent amount of saline intraperitoneally; 24 h later, repeat laparotomies were performed to take blood and intestinal tissue samples. The EGb treatment decreased tissue malondialdehyde levels and increased catalase activities compared with the placebo group (P < 0.05 for both). Serum creatine kinase and phosphorus levels were also determined in all groups. In the placebo group these were significantly higher than in the control group (P < 0.01 and P < 0.05, respectively). In the EGb group these were not different from controls and the increase in creatine kinase activity in the EGb group was not as high as in the placebo group (P < 0.05). Our results suggest that EGb could be preventive against the effects of strangulation ileus in a rat model.

2.Histopathological assessment of the prophylactic effect of gingko-biloba extract on intestinal ischemia-reperfusion injury.:

Acta Gastroenterol Belg. 1999 Oct-Dec;62(4):386-9.PMID: 10692767
In this experimental study, the prophylactic effects of Gingko-Biloba Extract (GBE) were examined after experimental ischemia on intestinal wall damage. 50 Wistar-Albino rats (2.5 month old) were gathered and separated into 5 groups (n:10). Group 1 was subjected to a laparotomy (sham-operated group) whereas all other experimental groups were subjected to an occlusion of their superior mesenteric arteries for 30 minutes and a period of 20 minutes reperfusion following occlusion. Group 2 was not given any prophylactic agent during the experiment (untreated control group). GBE was administered in a dosage of 50 mg/kg (i.v.) as a prophylactic agent to Group 3 one hour prior to laparotomy whereas Group 4 was given GBE at 50 mg/kg (i.v.) just before ischemia. Group 5 was given GBE in the same dosage just before reperfusion. Immediately after reperfusion, a biopsy was taken from the ileum (10 cm proximity to ileocaecal valve) for histopathological assessment. A significant prophylactic effect of GBE was observed in Group 5 in which GBE was administered just before reperfusion.

3.Protective effects of Ginkgo biloba extract on gastric mucosa.:

Acta Pharmacol Sin. 2000 Dec;21(12):1153-6.PMID: 11603292
AIM: To study the protective effects of Ginkgo biloba extract (GbE) on gastric mucosa.METHODS: By means of restaint-cold stress (RCS) in rats and 100% ethanol gavage in mice, the index of gastric mucosal injury was evaluated. The gastric juice was collected using pyloric ligation, and the volume and acidity of juice, and activity of pepsin were determined. The content of malondialdehyde (MDA) was measured by thiobarbituric acid (TBA) method.RESULTS: GbE (25, 50, and 100 mg/kg, bid x 5 d, ig) inhibited dose-dependently the gastric mucosal injury induced by RCS and 100% ethanol gavage. The index of gastric mucosal injury after RCS in groups pretreated with GbE was 58%, 43%, and 31% of control group respectively. The index of gastric mucosal injury induced by ethanol in groups pretreated with GbE was 62%, 36%, and 26% of the control group, respectively. And GbE enhanced the protective effects of cimetidine (Cim) on gastric mucosa. But it did not obviously influence the volume and acidity of gastric juice as well as the activity of pepsin. One hour after the administration of ig 100% ethanol, the contents of MDA in gastric mucosa and serum in mice increased (P < 0.01) vs the control group. But pretreatment with GbE (25, 50, and 100 mg/kg, ig) could inhibit this increase of MDA both in gastric mucosa and in serum.CONCLUSION: GbE had protective effects on gastric mucosa and GbE plus Cim possessed the synergism in the treatment of acute gastric mucosal lesions.

4.An assessment of the effect of Ginkgo Biloba EGb 761 on ischemia reperfusion injury of intestine.:

Hepatogastroenterology. 2002 Jan-Feb;49(43):201-4.PMID: 11941954
BACKGROUND/AIMS: The aim of this study was to determine the effect of Ginkgo Biloba (EGb 761) on reperfusion injury of the small bowel.METHODOLOGY: Forty-eight male 200-250 g Spraque-Dawley rats in six groups were used to determine the biochemical and histopathological changes after a 30-min ischemia and 30-min reperfusion. Pre-treatment with 50 mg/kg EGb 761 (Tebofortan, Karlsruhe-Germany) or 10-mL/kg saline was administered intravenously in the treatment and control groups. The superior mesenteric artery was occluded distal to the right colic artery and collateral arcades were ligated to provide complete ischemia. Ischemia was determined by the existence of pulseless or pale color of the small intestine. The return of the pulses and the reestablishment of the pink color were assumed to be the reperfusion of the intestine. Rats that were administered Egb 761 and saline were subjected to laparotomy, ischemia, or ischemia-reperfusion procedures. Mucosal lesions were graded from 0 to 5 in histopathological examination. Malondialdehyde and myeloperoxidase levels of the intestinal mucosa were measured.RESULTS: No significant difference was noted between the control and treatment groups regarding the histopathological changes. Although malonyldialdehyde and myeloperoxidase levels of the reperfusion + EGb 761 group were slightly higher than the laparotomy + saline group, they were significantly lower than the reperfusion + saline group.CONCLUSIONS: We concluded that EGb 761 pre-treatment before ischemia-reperfusion decreased malondialdehyde and myeloperoxidase levels and attenuated the mucosal damage.

5.Effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.:

World J Gastroenterol. 2004 Feb 15;10(4):560-6.PMID: 14966917
AIM: To investigate the effects of Ginkgo biloba extract on cytoprotective factors in rats with duodenal ulcer.METHODS: Sprague-Dawley rats were randomly divided into four groups: sham operation without ginkgo, sham operation with ginkgo, duodenal ulcer without ginkgo, and duodenal ulcer with ginkgo. Rats with duodenal ulcer were induced by 500 mL/L acetic acid. Rats with ginkgo were intravenously injected with Ginkgo biloba extract from the tail at a dose of 0.5 mg/(kg/d) for 7 and 14 days.RESULTS: Pathological result showed that duodenal ulcer rats with ginkgo improved mucosal healing and inflammation compared with those without ginkgo after 7 d treatment. After 14 d treatment, duodenal ulcer rats with ginkgo significantly increased weight gain (34.0+/-4.5 g versus 24.5+/-9.5 g, P<0.05) compared with those without ginkgo. Duodenal ulcer rats significantly increased cell proliferation (27.4+/-4.0 and 27.8+/-2.3 BrdU-labeled cells in duodenal ulcer rats with and without ginkgo versus 22.4+/-3.5 and 20.8+/-0.5 BrdU-labeled cells in sham operation rats with and without ginkgo, P<0.05) compared with sham operation rats. Mucosal prostaglandin E(2) concentration significantly increased by 129% (P<0.05) in duodenal ulcer rats with ginkgo compared with that in those without ginkgo. Duodenal ulcer rats without ginkgo significantly decreased superoxide dismutase activity in the duodenal mucosa and erythrocytes (19.4+/-6.7 U/mg protein versus 38.1+/-18.9 U/mg protein in the duodenal mucosa, and 4.87+/-1.49 U/mg protein versus 7.78+/-2.16 U/mg protein in erythrocytes, P<0.05) compared with sham operation rats without ginkgo. However, duodenal ulcer rats with ginkgo significantly increased erythrocyte superoxide dismutase activity (8.22+/-1.92 U/mg protein versus 4.87+/-1.49 U/mg protein, P<0.05) compared with those without ginkgo. Duodenal ulcer rats without ginkgo significantly increased plasma lipid peroxides (4.18+/-1.12 micromol/mL versus 1.60+/-1.10 micromol/mL and 1.80+/-0.73 micromol/mL, P<0.05) compared with sham operation rats without ginkgo and duodenal ulcer rats with ginkgo during the experimental period.CONCLUSION: Ginkgo biloba extract can improve weight gain and mucosal healing in duodenal ulcer rats by the actions of cytoprotection and antioxidation.

6.In vitro susceptibility of Helicobacter pylori to botanical extracts used traditionally for the treatment of gastrointestinal disorders.:

Phytother Res. 2005 Nov;19(11):988-91.PMID: 16317658
The gram-negative bacterium Helicobacter pylori (HP), identified in 1982, is now recognized as the primary etiological factor associated with the development of gastritis and peptic ulcer disease. In addition, HP infections are also associated with chronic gastritis, gastric carcinoma and primary gastric B-cell lymphoma. For centuries, herbals have been used in traditional medicine to treat a wide range of ailments, including gastrointestinal (GI) disorders such as dyspepsia, gastritis and peptic ulcer disease (PUD). However, the mechanism of action by which these botanicals exert their therapeutic effects has not been completely elucidated. As part of an ongoing screening program, the study assessed the in vitro susceptibility of 15 HP strains to botanical extracts, which have a history of traditional use in the treatment of GI disorders. Methanol extracts of Myristica fragrans (seed) had a MIC of 12.5 microg/mL; Zingiber officinale (ginger rhizome/root) and Rosmarinus officinalis (rosemary leaf) had an MIC of 25 microg/mL. Methanol extracts of botanicals with a MIC of 50 microg/mL included Achillea millefolium, Foeniculum vulgare (seed), Passiflora incarnata (herb), Origanum majorana (herb) and a (1:1) combination of Curcuma longa (root) and ginger rhizome. Botanical extracts with a MIC of 100 microg/mL included Carum carvi (seed), Elettaria cardamomum (seed), Gentiana lutea (roots), Juniper communis (berry), Lavandula angustifolia (flowers), Melissa officinalis (leaves), Mentha piperita (leaves) and Pimpinella anisum (seed). Methanol extracts of Matricaria recutita (flowers) and Ginkgo biloba (leaves) had a MIC > 100 microg/mL.

7.Ginkgo biloba attenuates mucosal damage in a rat model of ulcerative colitis.:

Pharmacol Res. 2006 Apr;53(4):324-30. Epub 2006 Feb 3.PMID: 16458529
Intestinal inflammatory states, regardless of specific initiating events, share common immunologically mediated pathways of tissue injury and repair. The efficacy of various drugs used to treat ulcerative colitis (UC) was investigated. The aim of the present study is to evaluate the effects of ginkgo biloba extract on the extent and severity of UC caused by intracolonic administration of acetic acid in rats. The inflammatory response was assessed by histology and measurement of myeloperoxidase activity (MPO), reduced glutathione (GSH), tumor necrosis factor (TNF-alpha) and interleukin-1beta (IL-1beta) levels in colon mucosa. Oral pretreatment with Ginkgo biloba in doses of (30, 60, 120 mg kg(-1) body weight) and sulfasalazine in a dose of (500 mg kg(-1) body weight used as reference) for 2 days before induction of colitis and continued for 5 consecutive days, significantly decreased colonic MPO activity, TNF-alpha, and IL-1beta levels and increased GSH concentration. Moreover, Ginkgo biloba attenuated the macroscopic colonic damage and the histopathological changes-induced by acetic acid. These results suggest that Ginkgo biloba may be effective in the treatment of UC through its scavenging effect on oxygen-derived free radicals.

8.The effects of Gingko biloba extract on acetic acid-induced colitis in rats.:

Turk J Gastroenterol. 2006 Sep;17(3):177-82.PMID: 16941250
BACKGROUND/AIMS: Gingko biloba is an antioxidant substance which has antagonistic activity on platelet-activating factor. We aimed to investigate the antioxidant effect and the histopathologic changes caused by Gingko biloba on acetic acid-induced colitis.METHODS: Totally 22 rats were divided into three groups. Group 1 (n=7) served as the control group. Group 2 (n=7) and Group 3 (n=8) were given 2 ml/day of 4% acetic acid by intracolonic instillation for three days. Gingko biloba (100 mg/kg) was then given only to Group 3 intraperitoneally for three days. Oxidative stress was assessed by determinate tissue and serum malondialdehyde (MDA) levels, and colonic damage was assessed by histologic examination.RESULTS: Depth of necrosis, extent of necrosis, degree of inflammation, extent of inflammation, fibrosis and total histologic scores in Group 2 were significantly higher than in the control group (p<0.05). The same parameters were lower in Group 3 versus Group 2, but the difference was not significant. Tissue and serum MDA levels in Group 2 were significantly higher than Group 1 (p<0.01 and 0.05, respectively). Again, the same parameters in Group 3 were lower than in Group 2, but the difference was not significant statistically.CONCLUSIONS: Gingko biloba did not significantly affect histopathological and oxidative stress parameters in experimental colitis.

9.Preventive effects of Ginkgo biloba extract on ischemia-reperfusion injury in rat bladder.:

Urol Int. 2007;78(2):167-72.PMID: 17293659
AIMS: The aim of this experimental study was to evaluate the effects of Ginkgo biloba (EGb 761) on ischemia-reperfusion (I-R) injury in the rat bladder.METHODS: A bladder I-R injury was induced by abdominal aorta occlusion by ischemia for 30 min, followed by 45 min reperfusion in rats. The rats were divided into four groups of 7 rats each; the control, I-R, and I-R groups were pretreated intraperitoneally with 50 or 100 mg/kg G. biloba 60 min before ischemia induction. Contractile responses to carbachol through isolated organ bath studies were recorded, histological sections were evaluated by light microscopy, and TUNEL staining was performed for the evaluation of apoptosis.RESULTS: In the I-R group, the contractile responses of the bladder strips were lower than those of the control group (p < 0.01-0.001) and were restored by pretreatment with 100 mg/kg G. biloba (p < 0.05-0.001). Decreased polymorphonuclear leukocyte infiltration was detected in the G. biloba pretreatment groups when compared to the I-R group during histological evaluation. The ratio of TUNEL-positive nuclei was 1.84% in the I-R group, whereas it was decreased in both of the G. biloba pretreatment groups (p < 0.01, p < 0.01).CONCLUSION: Our data indicated that G. biloba has a preventive effect on I-R injury in rat urinary bladder.

10.The effect of ginkgo biloba extract (EGb 761) pretreatment on intestinal epithelial apoptosis induced by intestinal ischemia/reperfusion in rats: role of ceramide.:

Am J Chin Med. 2007;35(5):805-19.PMID: 17963320
Apoptosis was demonstrated to be a major mode of intestinal epithelial cell death caused by intestinal ischemia/reperfusion (II/R). Ceramide has been proposed as a messenger for apoptosis. The present study was aimed to investigate the effect of Ginkgo biloba extract 761 (EGb 761) pretreatment on II/R-induced intestinal mucosal epithelial apoptosis in rats and the mechanism related to ceramide. The rat model of II/R injury was produced by clamping superior mesenteric artery for 60 min followed by reperfusion for 180 min. Twenty four rats were randomly allocated into Sham, II/R and EGb + II/R groups. In EGb + II/R group, EGb 761 (100 mg/kg per day) was administered intragastrically for 7 days before the surgery. Animals in II/R and sham groups were treated with equal volume of normal saline solution. Intestinal mucosal epithelial apoptosis was detected via electron microscopy and TUNEL method. Lipid peroxidation in intestinal mucosa was determined by detecting the malondialdehyde level and the activities of superoxide dismutase and peroxidase glutathione. The ceramide generation and sphingomyelinase (SMase) mRNA expression in intestinal mucosa were determined by high performance, thin layer chromatography, and RT-PCR, respectively. II/R caused intestinal mucosal epithelial apoptosis and over-production of the ceramide accompanied by up-regulation of SMase mRNA expression and increases of lipid peroxidation. EGb 761 pretreatment significantly decreased apoptosis index, and concurrently reduced the ceramide generation accompanied by down-regulation of SMase expression and inhibition of lipid peroxidation. The findings indicate that EGb 761 pretreatment attenuates II/R-induced intestinal epithelial apoptosis, which might be attributable to its antioxidant action of mediating ceramide pathway.

11.Ginkgo biloba (EGb 761) extract: effects on the myenteric plexus of the large intestine in Wistar rats.:

Dig Dis Sci. 2009 Feb;54(2):232-7. Epub 2008 Jul 9.PMID: 18612823
The objective of this study was to evaluate the effect of the purified extract of the Ginkgo biloba (EGb 761) plant on the myenteric plexus in the proximal and distal colon of Wistar rats for a period of 120 days. The experimental rats were divided into two age groups: a young group, sacrificed at age 90 days, and an adult group, sacrificed at age 210 days. We observed a significant reduction in the number of neurons in the myenteric plexus of the adult group compared to the young group in both of the segments studied (P < 0.01). The adult group treated with Ginkgo biloba showed a significant increase in neuronal profile area in both the segments studied (P < 0.001). It can be concluded from these results that treatment with the purified Ginkgo biloba (EGb 761) plant extract at a dose of 50 mg/kg body weight has neurotrophic effect on the myenteric plexus in the proximal and distal colon of rats after 120 days of treatment.

B-Ginkgo Biloba:Cell/Organism Protection,Anti-Radiation Research:

1.Effects of Ginkgo biloba extract on the morphological preservation of vestibular sensory epithelia in mice:

Presse Med. 1986 Sep 25;15(31):1484-7.PMID: 2947086
Oral or parenteral Ginkgo biloba extract seems to uniformly improve the ultrastructural qualities of vestibular sensorial epithelia when fixed by vascular perfusions. The improvements observed may be consequential to the effects of Ginkgo biloba extract on capillary permeability and general microcirculation, which would accelerate penetration of the fixator into vestibular tissues, and/or to more complex processes associated with cellular metabolism and membrane protective systems.

2.Radiation-induced clastogenic factors: anticlastogenic effect of Ginkgo biloba extract.:

Free Radic Biol Med. 1995 Jun;18(6):985-91.PMID: 7628734
Clastogenic factors (CFs) were first described in the blood of persons irradiated accidentally or for therapeutic reasons. Work of our laboratory has shown that they occur also under other circumstances, which are characterized by oxidative stress, and that CF-induced chromosome damage is regularly prevented by superoxide dismutase (SOD). Recently we found CFs in a high percentage of salvage personnel of the Chernobyl reactor accident. These liquidators represent a high-risk population and might benefit from cancer chemoprevention by antioxidants. SOD would have to be injected and is not appropriate for long-term prophylactic treatment. In the present study, we therefore evaluated the anticlastogenic effect of the Ginkgo biloba extract EGb 761, which is known for its superoxide scavenging properties. EGb 761 was tested on CF-treated blood cultures of healthy donors. After establishing the optimal protective EGb concentration, using CFs produced by irradiation of whole blood from healthy volunteers, the extract was tested on cultures exposed to CFs from plasma of persons irradiated as liquidators. The anticlastogenic effect could be confirmed for a final concentration of 100 micrograms/ml. In 12 consecutive experiments, CFs induced an average of 18.00 +/- 4.41 aberrations/100 cells. This was reduced to 7.33 +/- 3.08 in the parallel cultures receiving 100 micrograms/ml EGb 761 (p < .001). SOD was anticlastogenic in the same system at concentrations of 30 cytochrome C units/ml (approximately 10 micrograms/ml). Preliminary results obtained in a small series of liquidators showed regression or complete disappearance of CFs in the plasma after 2 months of treatment with EGb 761 (3 x 40 mg/d).

3.Clastogenic factors in the plasma of Chernobyl accident recovery workers: anticlastogenic effect of Ginkgo biloba extract.:

Radiat Res. 1995 Nov;144(2):198-205.PMID: 7480646
Clastogenic factors are found in the plasma of persons irradiated accidentally or therapeutically. They persisted in the plasma of A-bomb survivors over 30 years. Clastogenic factors were found in 33 of 47 Chernobyl accident recovery workers (often referred to as liquidators) in a previous study (I. Emerit et al., J. Cancer Res. Clin. Oncol. 120, 558-561, 1994). In the present study, we show that there is a positive correlation between clastogenic activity and dose and that these biomarkers of oxidative stress can be influenced successfully by appropriate antioxidant treatment. With the authorization of the Armenian Ministry of Health, 30 workers were treated with antioxidants from Ginkgo biloba leaves. The extract EGb 761 containing flavonoids and terpenoids was given at a daily dose of 3 x 40 mg (Tanakan, IPSEN, France) during 2 months. The clastogenic activity of the plasma was reduced to control levels on the first day after the end of the treatment. A 1-year follow-up showed that the benefit of the treatment persisted for at least 7 months. One-third of the workers again had clastogenic factors after 1 year, demonstrating that the process which produced clastogenic factors continued. However, the observation that antioxidants do not have to be given continuously is encouraging for intervention trials on a large-scale basis. These appear justified, since clastogenic factors are thought to be risk factors for the development of late effects of irradiation.

4.Enhancement of radiation effect by Ginkgo biloba extract in C3H mouse fibrosarcoma.:

Radiother Oncol. 1996 Nov;41(2):163-7.PMID: 9004360
BACKGROUND AND PURPOSE: Ginkgo biloba leaf extract (GBE) is known to increase peripheral blood circulation. The hypothesis that GBE may be able to enhance radiosensitivity of tumor by improving tumor blood flow and thus decreasing hypoxic fraction was tested.MATERIALS AND METHODS: Fibrosarcoma (FSaII) growing in C3H mouse leg muscle was used as a tumor model. GBE was given i.p. 1 h before irradiation with or without priming dose given 1 day earlier. Effect on tumor and normal tissue radiation reaction was investigated.RESULTS: Tumor growth delay by radiation was more elongated after two doses (1-day interval) of GBE than after a single dose. Radiation dose for 3-day tumor growth delay was decreased from 12.45 (10.97-13.93) Gy to 6.06 (3.89-8.22) Gy by two doses of GBE [enhancement ratio = 2.06 (1.32-2.79)]. Hypoxic cell fraction was 10.6% (6.3-18.2%) for control, 7.2% (3.8-14.0%) after a single dose (P = 0.18) and 2.7% (1.5-5.0%) after two doses (P < 0.001). Radiation effect on normal tissue, estimated by acute skin reaction and jejunal crypt assay, was not affected by GBE.CONCLUSION: Ginkgo biloba extract enhances radiation effect on tumor without increasing acute normal tissue radiation damage in this model system probably by increasing tumor blood flow and further investigation for this possible radiosensitizer is needed.

5.Induction of superoxide dismutase and catalase activity in different rat tissues and protection from UVB irradiation after topical application of Ginkgo biloba extracts.:

Methods Find Exp Clin Pharmacol. 1997 Jul-Aug;19(6):367-71.PMID: 9385585
Ginkgo biloba extract (GBE) prepared from the leaves of Ginkgo biloba with 50% diluted alcohol was found to locally induce superoxide dismutase (SOD) and catalase (CAT) enzyme activity in epidermis after topical application, and also to systemically increase the activity of both enzymes in the liver, heart and kidney of Sprague Dawley rats. Skin pretreated with 50% diluted alcohol-extracted liquid formulation was protected from exacerbation of UVB damage. Changes in the lipid structure of the skin of rats determined by ATR/FT-IR spectroscopy demonstrated penetration of active components from GBE dosage formulations.

6.A Ginkgo biloba extract (EGb 761) prevents mitochondrial aging by protecting against oxidative stress.:

Free Radic Biol Med. 1998 Jan 15;24(2):298-304.PMID: 9433905
The effect of aging on indices of oxidative damage in rat mitochondria and the protective effect of the Ginkgo biloba extract EGb 761 was investigated. Mitochondrial DNA from brain and liver of old rats exhibited oxidative damage that is significantly higher than that from young rats. Mitochondrial glutathione is also more oxidized in old than in young rats. Peroxide formation in mitochondria from old animals was higher than in those from young ones. According to morphological parameters (size and complexity), there are two populations of mitochondria. One is composed of large, highly complex mitochondria, and the other population is smaller and less complex. Brain and liver from old animals had a higher proportion of the large, highly complex mitochondria than seen in organs from young animals. Treatment with the Ginkgo biloba extract EGb 761 partially prevented these morphological changes as well as the indices of oxidative damage observed in brain and liver mitochondria from old animals.

7.Functional protection of photoreceptors from light-induced damage by dimethylthiourea and Ginkgo biloba extract.:

Invest Ophthalmol Vis Sci. 1999 May;40(6):1191-9.PMID: 10235553
PURPOSE: To investigate the functional protective effect of a synthetic (dimethylthiourea, DMTU) and a natural antioxidant (Ginkgo biloba extract, EGb 761) against light-induced retinal degeneration.METHODS: Wistar rats were exposed for 24 hours to 1700-lux light after treatment with DMTU or EGb 761. Electroretinograms were recorded before and on day (D)1, D3, D8, D15, D22, and D29 after light exposure. The b-wave amplitude was plotted against log L (ganzfeld luminance), providing the b-wave sensitivity curve. The Naka-Rushton function fitted to the sensitivity curve enabled derivation of the parameters Bmax (saturated amplitude) and K (luminance-inducing Bmax/2). In addition, rats from each group were killed for retinal morphometric analyses.RESULTS: In the untreated group, light exposure caused collapse of the b-wave sensitivity curves. Bmax was reduced by 51% at D1 without subsequent recovery. K increased temporarily, reverting to normal values 8 days later. The outer nuclear layer thicknesses decreased markedly in the superior retina. In the treated groups, light exposure had a weaker effect on sensitivity curves. The values of Bmax were not significantly different from those in the unexposed-untreated group, although K increased temporarily. Retinal morphometry was preserved.CONCLUSIONS: Dimethylthiourea and EGb 761 afford functional protection against light-induced retinal damage.

8.Protective effects of Ginkgo biloba extract against lysophosphatidylcholine-induced vascular endothelial cell damage.:

Zhongguo Yao Li Xue Bao. 1998 Jul;19(4):359-63.PMID: 10375785
AIM: To study the protective effects of Ginkgo biloba extract (GbE) against endothelial cell damage induced by lysophosphatidylcholine (LPC).METHODS: The vasorelaxation response to acetylcholine (ACh) were investigated in the isolated rabbit thoracic aorta. Lipid peroxidation products were determined by measuring thiobarbituric acid reactive substance.RESULTS: GbE attenuated the inhibition of vasorelaxation response to ACh and prevented the LPC-induced increase of malondialdehyde (MDA) content both in thoracic aortae. GbE prevented the leakage of LDH and the increase of MDA content in cultured endothelial cells in a concentration-dependent manner. GbE also markedly increased epoprostenol level in cultured endothelial cells treated with LPC.CONCLUSION: GbE protected endothelial cells against LPC-induced damage due to reduction in lipid peroxidation and facilitation of synthesis and/or release of epoprostenol.

9.Protection of mitochondrial respiration activity by bilobalide.:

Biochem Pharmacol. 1999 Jul 1;58(1):109-19.PMID: 10403524
Mitochondria alteration is an early event in ischemia-induced damage, and its prevention improves tissue survival upon reperfusion. Adenine translocase and complex I activities are rapidly affected by ischemia. Ginkgo biloba extract demonstrates anti-ischemic properties attributable to the terpenoid fraction, mainly due to the presence of bilobalide. The mechanism of the protection afforded by bilobalide is not yet known. In this work, the effects of bilobalide on mitochondrial respiration were investigated. Mitochondria isolated from rats treated with bilobalide (2 to 8 mg/kg) showed a dose-dependent increase in the respiratory control ratio, due to a lower oxygen consumption during state 4. Bilobalide also decreased the sensitivity of oxygen consumption to inhibition of complex I by Amytal or to inhibition of complex III by antimycin A or myxothiazol. There was no protection of complexes IV and V. It also increased the activity of complex I but not of adenine translocase. Similar effects were also obtained in vitro when control mitochondria were preincubated for 1 hr with 0.8 microg/mL bilobalide. Treatment of the rats with 8 mg/kg bilobalide also prevented the ischemia-induced decrease in state 3 of the mitochondrial respiration and thus the decrease in RCR. The protective effect of bilobalide on cellular ATP content observed under ischemic conditions can be correlated with the above observations. By protecting complex I and III activities, bilobalide allows mitochondria to maintain their respiratory activity under ischemic conditions as long as some oxygen is present, thus delaying the onset of ischemia-induced damage. This mechanism provides a possible explanation for the anti-ischemic properties of bilobalide and of Ginkgo biloba extract in therapeutic interventions.

10.Anticlastogenic effects of Ginkgo biloba extract (EGb 761) and some of its constituents in irradiated rats.:

Mutat Res. 1999 Sep 15;445(1):99-104.PMID: 10521695
In a previous study we reported that radiation-induced clastogenic factors (CF) are found in the plasma of Chernobyl accident recovery workers and that their chromosome damaging effects are inhibited by antioxidant treatment with a Ginkgo biloba extract (EGb761). In the present study, we induced CF in rats with a radiation dose of 4.5 Gy. The protective effects of the complete extract were compared to those obtained with the extract devoid of its terpene fraction (CP205), with isolated ginkgolides A+B and bilobalide at the concentrations present in EGb761. The pretreatment samples were taken at day 22 postirradiation, the posttreatment samples the day following arrest of the 3-week treatment. The adjusted clastogenic score (ACS) were reduced from 11.71+/-3.55 to 2.00+/-2.83 after treatment with 100 mg/kg and from 13.43+/-2.23 to 4.29+/-2.14 with 50 mg/kg of the complete extract (p<0.0001). Similar protective effects were observed with CP205, ginkgolides and bilobalide (p<0. 001), while the reduction of ACS in placebo-treated rats was not statistically significant (12.80+/-1.79 and 9.20+/-2.68). However, if the efficacy of the treatment was compared to placebo, only the complete extract was significantly protective. While all components exerted anticlastogenic effects at the concentrations present in the complete extract, the comparison of the different groups by analysis of variance did not reveal significant differences. This may be due to to the small number of animals available in each treatment group. The complete extract reduced the ACS by 83% at the dose of 100 mg/kg, while the lower dose of 50 mg/kg and the three components reached only 66%-68% reduction. The better protection provided by the complete extract is due to synergistic rather than to additive effects.

11.Mitochondria, oxidative stress and aging.:

Free Radic Res. 2000 Mar;32(3):189-98.PMID: 10730818
In the eighties, Miquel and Fleming suggested that mitochondria play a key role in cellular aging. Mitochondria, and specially mitochondrial DNA (mtDNA), are major targets of free radical attack. At present, it is well established that mitochondrial deficits accumulate upon aging due to oxidative damage. Thus, oxidative lesions to mtDNA accumulate with age in human and rodent tissues. Furthermore, levels of oxidative damage to mtDNA are several times higher than those of nuclear DNA. Mitochondrial size increases whereas mitochondrial membrane potential decreases with age in brain and liver. Recently, we have shown that treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and oxidation of mitochondrial glutathione. Moreover, the extract EGb 761 also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver. Thus, mitochondrial aging may be prevented by antioxidants. Furthermore, late onset administration of certain antioxidants is also able to prevent the impairment in physiological performance, particularly motor co-ordination, that occurs upon aging.

12.Effect of Ginkgo biloba extract (EGb 761) on rats in an experimental model of acute encephalopathy after total body irradiation:

Cancer Radiother. 2000 May-Jun;4(3):202-6.PMID: 10897763
PURPOSE: To define the therapeutic effect of Ginkgo biloba extract (EGb 761) in an experimental model of acute encephalopathy following total body irradiation in rats.MATERIAL AND METHODS: Ninety four-month-old rats received 4.5 Gy total body irradiation (TBI) at day 1 while 15 rats received sham irradiation. A behavioural study based on a conditioning test of negative reinforcement, the one-way avoidance test, was performed test, was performed after irradiation. Orally treatment was started one day (study A) or twenty two days (study B) after irradiation and repeated daily for twelve days. In the irradiated group, three subgroups were defined according to the treatment received: EGb 761 (50 mg/kg), EGb 761 (100 mg/kg), water.RESULTS: This work comprised two consecutive studies. In study A (45 rats) the one-way avoidance test was administered daily from day 7 to day 14. In study B (45 rats) the behavioural test was performed from day 28 to day 35. Study A (three groups of 15 rats): following TBI, irradiated rats treated with water demonstrated a significant delay in a learning the one-way avoidance test in comparison with sham-irradiated rats (P < 0.0002) or irradiated rats treated with EGb 761 (50 mg/kg; P < 0.0017) or EGb 761 (100 mg/kg; P < 0.0002). The irradiated rats, treated with EGb 761 (50 or 100 mg/kg) did not differ from the sham-irradiated controls. Study B (three groups of 15 rats): the irradiated rats, treated with water or EGb 761 (50 or 100 mg/kg) did not differ from the sham-irradiated controls.CONCLUSION: This study indicates that a relatively low dose of total body irradiation induces a substantial acute learning dysfunction in the rat, which persists fourteen days after TBI. This effect is prevented by the administration of EGb 761 (50 or 100 mg/kg) started twenty-four hours after irradiation.

13.Mitochondrial oxidative stress plays a key role in aging and apoptosis.:

IUBMB Life. 2000 May;49(5):427-35.PMID: 10902575
Harman first suggested in 1972 that mitochondria might be the biological clock in aging, noting that the rate of oxygen consumption should determine the rate of accumulation of mitochondrial damage produced by free radical reactions. Later in 1980 Miquel and coworkers proposed the mitochondrial theory of cell aging. Mitochondria from postmitotic cells use O2 at a high rate, hence releasing oxygen radicals that exceed the cellular antioxidant defences. The key role of mitochondria in cell aging has been outlined by the degeneration induced in cells microinjected with mitochondria isolated from fibroblasts of old rats, especially by the inverse relationship reported between the rate of mitochondrial production of hydroperoxide and the maximum life span of species. An important change in mitochondrial lipid composition is the age-related decrease found in cardiolipin content. The concurrent enhancement of lipid peroxidation and oxidative modification of proteins in mitochondria further increases mutations and oxidative damage to mitochondrial DNA (mtDNA) in the aging process. The respiratory enzymes containing the defective mtDNA-encoded protein subunits may increase the production of reactive oxygen species, which in turn would aggravate the oxidative damage to mitochondria. Moreover, superoxide radicals produced during mitochondrial respiration react with nitric oxide inside mitochondria to yield damaging peroxynitrite. Treatment with certain antioxidants, such as sulphur-containing antioxidants, vitamins C and E, or the Ginkgo biloba extract EGb 761, protects against the age-associated oxidative damage to mtDNA and the oxidation of mitochondrial glutathione. Moreover, the EGb 761 extract also prevents changes in mitochondrial morphology and function associated with aging of the brain and liver.

14.Mitochondria of retinal Müller (glial) cells: the effects of aging and of application of free radical scavengers.:

Ophthalmic Res. 2000 Sep-Oct;32(5):229-36.PMID: 10971185
Age-related changes of mitochondria were studied in Müller (retinal glial) cells from guinea pigs fed with or without externally applied Ginkgo biloba extract EGb 761, an established radical scavenger. When Müller cell mitochondria from aged animals were compared with those from young adults, they displayed (1) a diminished number of well-defined cristae at the ultrastructural level, (2) a reduced membrane potential, as revealed by fluorimetry using the voltage-sensitive dye tetramethyl rhodamine methylester, and (3) a slightly reduced index of vitality assayed by tetrazolium salt colorimetry. Müller cell mitochondria were also studied in aged guinea pigs which had been fed daily by EGb 761 during the last 2 months before they were sacrificed. Such mitochondria displayed (1) many well-defined cristae at the ultrastructural level, and, compared with mitochondria from untreated aged animals, (2) a significantly enhanced membrane potential and (3) a significantly enhanced index of vitality. No age- or drug-related changes were observed in the mitochondrial content of GABA transaminase, as revealed by immunocytochemistry/densitometry. These results suggest that many but not all structural and functional parameters of aging Müller cell mitochondria are impaired by accumulating oxidative damage, and that externally applied radical scavengers may protect the organelles from the damaging actions of free radicals. As it has been shown earlier that EGb 761 treatment enhances the intrinsic glutathione content of aged guinea pig Müller cells, the protective radical-scavenging effect of the drug may be mediated both directly and indirectly.

15.Protective effects of bilobalide on amyloid beta-peptide 25-35-induced PC12 cell cytotoxicity.:

Acta Pharmacol Sin. 2000 Jan;21(1):75-9.PMID: 11263252
AIM: To study the effect of bilobalide, a terpene extracted from the leaves of Ginkgo biloba, on beta-amyloid peptide fragment 25-35 (A beta 25-35)-induced PC12 cell cytotoxicity.METHODS: 3-[4,5-Dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide and lactate dehydrogenase assay were used to measure the viability of PC12 cells. Thiobarbituric acid-reactive substances were measured to determine lipid peroxidation of cells. Antioxidant enzymes in PC12 cells were detected.RESULTS: Treatment of PC12 cells with A beta 25-35 (100 mumol.L-1) for 24 h caused a great decrease in cell viability (P < 0.01 compared with control). Bilobalide 25-100 mumol.L-1 dose-dependently attenuated the cytotoxic effect of A beta 25-35. Bilobalide also inhibited A beta 25-35 (100 mumol.L-1)-induced elevation of lipid peroxidation and decline of antioxidant enzyme activities.CONCLUSION: Bilobalide protected PC12 cells from A beta 25-35-induced cytotoxicity.

16.Chemopreventive effect of Ginkgo biloba extract against benzo(a)pyrene-induced forestomach carcinogenesis in mice: amelioration of doxorubicin cardiotoxicity.:

J Exp Clin Cancer Res. 2001 Mar;20(1):39-50.PMID: 11370828
Ginkgo biloba extract (EGb) is a natural product that possesses antioxidant and anticlastogenic properties. The current study was conducted to investigate the effect of EGb on benzo(a)pyrene (BP)-induced forestomach neoplasia, and to explore its possible beneficial effects against doxorubicin (Dox)-induced cardiotoxicity. Tumor was induced in female Swiss albino mice by oral administration of 1 mg BP, twice weekly for four weeks. EGb was given, at a daily oral dose of 150 mg kg(-1), two weeks before and during BP administration. Dox was given ip at a dose of 1.5 mg kg(-1), once weekly, for four weeks, during BP administration. EGb and Dox were given as combined or monotherapies. Results of the present investigation revealed that EGb blunted forestomach tumor multiplicity, as compared to control tumor bearing group. It also exhibited high activity to induce cytosolic glutathione S-transferase and glucose-6-phosphate dehydrogenase (G6PDH) in liver, as well as replenished hepatic glutathione that have been inhibited or depleted by tumorigenesis. Furthermore, it normalized nitric oxide (NO) serum level, without any observed alteration in neither the activity of liver microsomal NADPH-cytochrome P-450 reductase nor serum level of tumor necrosis factor-alpha (TNFalpha). Similar results have been obtained with Dox, but it failed to affect G6PDH activity, while increased serum TNFalpha and NO levels. The combined therapy did not add further to the anticarcinogenic effect of Dox, however it succeeded in ameliorating the deleterious effects of Dox on the heart; as evidenced by the reduction of cardiac lipoperoxidation, with modulation of Dox-induced pathological changes. Therefore, EGb confers a beneficial chemopreventive effect against BP-induced gastric carcinogenesis in mice, and possesses a salutary ameliorating potential on the cardiotoxic effects of Dox.

17.Changes in zinc levels and superoxide dismutase activities in the skin of acute, ultraviolet-B-irradiated mice after treatment with ginkgo biloba extract.:

Biol Trace Elem Res. 2001 May;80(2):175-9.PMID: 11437182
Acute ultraviolet-B (UV-B) irradiation is known to act as an initiator in the formation of reactive oxygen species. These oxygen products are highly reactive and they are able to cause irreversible damage to cellular components. Oxygen free radicals are normally neutralized by very efficient systems in the body. These include antioxidant enzymes like superoxide dismutase (SOD). In a healthy subject, there is a balance between free radicals and the levels of antioxidants. In some pathological conditions such as oxidative stress, the level of antioxidants is significantly reduced. The skin contains relatively high levels of zinc (Zn), an essential element known to be a cofactor in some metabolic pathways. Zinc has also been reported to have antioxidant properties. In the present study, we investigated the effect of ginkgo biloba extract (Gbe), a potent free-radical scavenger, on UV-B-irradiated skin by measuring SOD activity and Zn levels in the skin, before and after treatment. The SOD activity was decreased after UV-B exposure, in comparison with the control group (p < 0.05). After Gbe treatment, the SOD activity increased (p < 0.05) as compared with the untreated UV-B irradiated group. The Zn levels changed in the same pattern as the SOD activity values.

18.Effect of biflavones of Ginkgo biloba against UVB-induced cytotoxicity in vitro.:

J Dermatol. 2001 Apr;28(4):193-9.PMID: 11449670
The effect of Ginkgo biloba extract on Ultraviolet B (UVB) irradiated fibroblasts was examined by using a neutral red dye uptake assay and a lactic dehydrogenase (LDH) release assay. Crude extract along with individual components, including flavone-glycosides and biflavones, were applied to cultured normal human skin fibroblasts for 12 hours, and 0, 20, 40 and 80 mJ/cm2 of UVB were irradiated. Two synthetic flavonoids, quercetin and rutin, which have polyphenol structures close to the flavonoids in Ginkgo biloba extract, were used to compare any structure-related activity under the same conditions. At the concentrations (from 0.25 to 2 mg/ml) treated with biflavone components (isoginkgetin/ginkgetin, sciadopitysin) and quercetin, high neutral red dye uptake was detected with gradual increases in UVB irradiation. The time-course release of LDH was determined as the cytotoxicity index (%) during 24 hours following a high dose UVB irradiation (200 mJ/cm2), and the pattern of this cytotoxicity index was similar to that of the neutral red dye uptake results. Sciadopitysin, isoginkgetin/ginkgetin and quercetin treatments lowered cytotoxicity indices to 50.81, 67.81 and 62.19%, respectively, compared to 95.38% for the untreated control. The antioxidant potential of biflavones of Ginkgo biloba could be explained on the basis of structure-related activity; hydroxy- and methyl-substitutions on the basic structure of these flavonoids played a role, as other reports have suggested.

19.Age-related increase of oxidative stress-induced apoptosis in mice prevention by Ginkgo biloba extract (EGb761).:

J Neural Transm. 2001;108(8-9):969-78.PMID: 11716149
Enhanced apoptosis and elevated levels of reactive oxygen species (ROS) play a major role in aging. In addition, several neurodegenerative diseases are associated with increased oxidative stress and apoptosis in neuronal tissue. Antioxidative treatment has neuro-protective effects. The aim of the present study was to evaluate changes of susceptibility to apoptotic cell death by oxidative stress in aging and its inhibition by the antioxidant Ginkgo biloba extract EGb761. We investigated basal and ROS-induced levels of apoptotic lymphocytes derived from the spleen in young (3 months) and old (24 months) mice. ROS were induced by 2-deoxy-D-ribose (dRib) that depletes the intracellular pool of reduced glutathione. Lymphocytes from aged mice accumulate apoptotic cells to a significantly higher extent under basal conditions compared to cells from young mice. Treatment with dRib enhanced this difference, implicating a higher sensitivity to ROS in aging. Apoptosis can be reduced in vitro by treatment with EGb761. In addition, mice were treated daily with 100 mg/kg EGb761 per os over a period of two weeks. ROS-induced apoptosis was significantly reduced in the EGb761 group. Interestingly, this effect seemed to be more pronounced in old mice.

20.Experimental study on suppressive effect of ginkgo extract on adhesion of vascular endothelial cell to monocyte induced by minimally modified low density lipoprotein:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000 Dec;20(12):917-9.PMID: 11938864
OBJECTIVE: To observe the effect of Ginkgo extract on the interaction between minimally modified low density lipoprotein (MM-LDL) induced human umbilical vein endothelial cell (HUVEC) and U937 monocyte-like cell line.METHODS: The adhesive percentage between HUVEC and U937 by counting and the expression of VCAM-1, ICAM-1, P-selectin by ELISA.RESULTS: Treatment of HUVEC with MM-LDL (75 micrograms/ml) for 4 hrs could significantly increase the adhesion of U937 to HUVEC (P < 0.01) and Ginkgo extract could suppress the adhesion in dose-dependent manner. The surface expression of VCAM-1, ICAM-1, P-selectin was not induced by MM-LDL, while recombination tumor necrosis factor-alpha 5.0 ng/ml, as a positive control, could do.CONCLUSION: Ginkgo extract afforded protection against HUVEC damage induced by MM-LDL and the adhesion of monocytes to endothelial cells induced by MM-LDL is not mediated by VCAM-1, ICAM-1 and P-selectin.

21.Mitochondrial damage in aging and apoptosis.:

Ann N Y Acad Sci. 2002 Apr;959:448-51.PMID: 11976217
Mitochondria are essential to cellular aging, and free radical production by mitochondria is increased with aging. The rate of oxidant production by mitochondria correlates inversely with maximal life span of species. In many species, females live longer than males. We report that mitochondrial oxidant production by females is significantly lower than that of males. However, mitochondria from ovariectomized females have a similar oxidant production as those of males. Thus, gender difference in life span can be explained, at least in part, by different oxidant generation by mitochondria. Administration of antioxidants, such as vitamins C and E, or a Ginkgo biloba extract, protects against age-associated oxidative damage to mitochondrial DNA, oxidation of glutathione, and other signs of oxidative damage to mitochondria.

22.The effects of EGb 761 on lipid peroxide levels and superoxide dismutase activity in sunburn.:

Photodermatol Photoimmunol Photomed. 2002 Jun;18(3):117-20.PMID: 12207673
BACKGROUND/PURPOSE: Free oxygen radicals are involved in inflammatory skin reactions induced by ultraviolet B (UVB). In this study, the effect of a herbal antioxidant Ginkgo biloba extract (EGb 761) was investigated in UVB irradiated mice skin.METHODS: The study was carried out on four groups of mice (n = 6 in each group). The first group was a control group (G1). The second group (G2) was only exposed to acute UVB irradiation. The third group (G3) received 100 mg/kg/day of EGb 761 orally for 5 days before UVB irradiation and the fourth group (G4) was given only a single dose of EGb 761 immediately after UVB irradiation. Eighteen hours after exposing to UVB, lipid peroxide levels, and superoxide dismutase (SOD) activities were studied and UVB damage was evaluated histopathologically according to "sun-burn cell count".RESULTS: The SOD activities and Malondialdehyde (MDA) levels in G2, G3 and G4 were found to be decreased significantly when compared with G1 (P < 0.05). The SOD activities of G3 and G4 were higher when compared with G2 (P < 0.05). The number of sunburn cells (SBCs) was the highest in G2.CONCLUSIONS: Our results suggest that EGb 761 may have an important effect, both as a protective and therapeutic agent, in sunburn after UVB irradiation.

23.Ginkgo biloba extract EGb 761 protects against mitochondrial aging in the brain and in the liver.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):685-92.PMID: 12396080
According to the free radical theory of aging, oxygen-derived free radicals causes the age-associated impairment at the cellular and tissue levels. The mitochondrial theory of aging points to mitochondria, and specially mitochondrial DNA, as the major targets of free radical attack upon aging. Thus, oxidative damage to mtDNA accumulate with age in human and rodent tissues and also is inversely related to maximum life span of mammals. Mitochondrial deficits, such as a decrease in mitochondrial membrane potential, occur upon aging due to oxidative damage. The age-related mitochondrial oxidative stress may be prevented by late onset administration of certain antioxidants, such as Ginkgo biloba extract EGb 761. These antioxidants may also delay the physiological impairment associated with aging.

24.Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress.:

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S15-23.PMID: 13130384
As major sources of reactive oxygen species (ROS), mitochondrial structures are exposed to high concentrations of ROS and may therefore be particularly susceptible to oxidative damage. Mitochondrial damage could play a pivotal role in the cell death decision. A decrease in mitochondrial energy charge and redox state, loss of transmembrane potential (depolarization), mitochondrial respiratory chain impairment, and release of substances such as calcium and cytochrome c all contribute to apoptosis. These mitochondrial abnormalities may constitute a part of the spectrum of chronic oxidative stress in Alzheimer's disease. Accumulation of amyloid beta (Abeta) in form of senile plaques is also thought to play a central role in the pathogenesis of Alzheimer's disease mediated by oxidative stress. In addition, increasing evidence shows that Abeta generates free radicals in vitro, which mediate the toxicity of this peptide. In our study, PC12 cells were used to examine the protective features of EGb 761(definition see editorial) on mitochondria stressed with hydrogen peroxide and antimycin, an inhibitor of complex III. In addition, we investigated the efficacy of EGb 761 in Abeta-induced MTT reduction in PC12 cells. Moreover, we examined the effects of EGb 761 on ROS levels and ROS-induced apoptosis in lymphocytes from aged mice after in vivo administration. Here, we will report that EGb 761 was able to protect mitochondria from the attack of hydrogen peroxide, antimycin and Abeta. Furthermore, EGb 761 reduced ROS levels and ROS-induced apoptosis in lymphocytes from aged mice treated orally with EGb 761 for 2 weeks. Our data further emphasize neuroprotective properties of EGb 761, such as protection against Abeta-toxicity, and antiapoptotic properties, which are probably due to its preventive effects on mitochondria.

25.Effects of EGb 761 Ginkgo biloba extract on mitochondrial function and oxidative stress.:

26.Cell culture protection and in vivo neuroprotective capacity of flavonoids.:

Neurotox Res. 2003;5(6):425-32.PMID: 14715446
Flavonoids are an important group of recognized antioxidants ubiquitous in fruits, vegetables and herbs. There are epidemiological evidences for the stroke-protecting capacity of flavonoids and while the neuroprotective power of complex extracts rich in flavonoids like those of Ginkgo biloba, green tea or lyophilized red wine have been demonstrated in several studies, neuroprotection by individual flavonoids has been poorly studied in vivo. The neuroprotective capacity of individual flavonoids was studied in PC12 cells in culture and in a model of permanent focal ischemia (permanent Middle Cerebral Artery Occlusion - pMCAO). In the in vivo experiments, flavonoids were administered in lecithin preparations to facilitate the crossing of the blood brain barrier. The simultaneous incubation of PC12 cells with 200 micro M hydrogen peroxide (H2O2) and different flavonoids for 30 min resulted in a conspicuous profile: quercetin, fisetin, luteolin and myricetin significantly increased cell survival while catechin, kaempherol and taxifolin did not. Quercetin was detected in brain tissue 30 min and 1 h after intraperitoneal administration. When one of the protective flavonoids (quercetin) and one of those that failed to increase PC12 cell survival (catechin) were assessed for their protective capacity in the pMCAO model, administered i.p. 30 min after vessel occlusion, quercetin significantly decreased the brain ischemic lesion while catechin did not. It is concluded that when administered in liposomal preparations, flavonoids structurally related to quercetin could become leads for the development of a new generation of molecules to be clinically effective in human brain ischemia.

27.Effects of Ginkgo biloba extract on number and activity of endothelial progenitor cells from peripheral blood.:

J Cardiovasc Pharmacol. 2004 Mar;43(3):347-52.PMID: 15076217
The aim of this study is to investigate whether Ginkgo biloba extract can augment endothelial progenitor cells numbers, and promote the cells' proliferative, migratory, adhesive, and in vitro vasculogenesis capacity. Total mononuclear cells were isolated from peripheral blood by Ficoll density gradient centrifugation, and then the cells were plated on fibronectin-coated culture dishes. After 7 days culture, attached cells were stimulated with Ginkgo biloba extract (to make a series of final concentrations: 10 mg/L, 25 mg/L, and 50 mg/L) or vehicle control for the respective time points (6 hours, 12 hours, 24 hours, and 48 h). Endothelial progenitor cells were characterized as adherent cells double positive for DiLDL-uptake and lectin binding by direct fluorescent staining under a laser scanning confocal microscope. They were further documented by demonstrating the expression of KDR, VEGFR-2, and AC133 with flow cytometry. Endothelial progenitor cells proliferation, migration, and in vitro vasculogenesis activity were assayed with 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay, modified Boyden chamber assay, and in vitro vasculogenesis kit, respectively. Endothelial progenitor cells adhesion assay was performed by replating those on fibronectin-coated dishes, and then counting adherent cells. Incubation of isolated human mononuclear cells with Ginkgo biloba extract dose- and time-dependently increased the number of endothelial progenitor cells, maximum at 25 mg/L, 24 hours (approximately 1-fold increase, P < 0.01). In addition, Ginkgo biloba extract also dose- and time-dependently promoted endothelial progenitor cells proliferative, migratory, adhesive, and in vitro vasculogenesis capacity. The results of the present study defined a novel functional effect of Ginkgo biloba extract: the augmentation of endothelial progenitor cells with enhanced functional activity.

28.Effect of Ginkgo biloba extract on the rat heart mitochondrial function.:

J Ethnopharmacol. 2007 May 22;111(3):512-6. Epub 2006 Dec 28.PMID: 17258877
Ginkgo biloba L. (Ginkgoaceae) originated from China, first introduced to Europe in the 18th century, it is now distributed all over the world. The leaves of Ginkgo biloba include a rich complex of active compounds responsible for various pharmacological properties. Ginkgo biloba extract improves blood circulation, protects against oxidative cell damage, blocks platelet aggregation that could be important for prevention of cardiovascular diseases. Therefore the fluid extract from Ginkgo biloba leaves was prepared and tested for it is effect on rat mitochondrial function. Our data showed that 0.5 microl/ml of GE (containing 0.57 ng/ml of rutin, 0.23 ng/ml of quercitrin, 0.105 ng/ml of hyperosid and 0.02 ng/ml of quercetin) had no effect on the State 2 respiration rate of mitochondria with all used substrates: pyruvate+malate, succinate and palmitoyl-L-carnitine. Further increase in GE concentration (2 and 4 microl/ml), increased the State 2 respiration rate with all respiratory substrates in a dose-dependent manner (by 35-116%). The State 3 respiration rate was not affected by GE. In order to identify which compounds of GE could be responsible for the observed effects, we measured the effect of pure flavonoids: rutin, quercetin, hyperosid and quercitrin on mitochondrial respiration. All flavonoids (except of hyperosid) at maximal used concentration, comparable/identical to that in GE, stimulated the State 2 respiration rate only by 8-20%, i.e. less effectively as compared to GE. Therefore, for the explanation of the GE-induced uncoupling of oxidative phosphorylation, other biologically active compounds of GE have to be taken into account in future studies.

29.Anticlastogenic effect of Ginkgo biloba extract in Graves' disease patients receiving radioiodine therapy.:

J Clin Endocrinol Metab. 2007 Nov;92(11):4286-9. Epub 2007 Aug 21.PMID: 17711926
BACKGROUND: Chromosomal damage, as assessed by clastogenic factors (CFs) and micronuclei (MN) appearance, after radioiodine therapy of Graves' disease has been reported.OBJECTIVE AND METHODS: Our objective was to evaluate the effect of Ginkgo biloba extract (EGb 761) supplementation on the time course (up to 120 d) of CFs and MN appearance in lymphocytes from patients with Graves' disease after iodine-131 ((131)I) therapy. Patients were randomly assigned to EGb 761 or placebo, in a blinded manner.RESULTS: In the placebo group, MN increased early (P < 0.001) after (131)I, peaking at the 21st day (P = 0.0003) and declining thereafter. In EGb 761-treated patients, MN increased early (P < 0.05), while returning toward baseline value thereafter. Therefore, mean MN increment was significantly higher in the placebo group as compared with EGb 761-treated patients (P < 0.01). Moreover, an early (P < 0.0001) and sustained (up to 35 d; P < 0.001) MN increase induced by CFs was observed in the placebo group. Conversely, in EGb 761-treated patients, MN increase induced by CFs never reached the statistical significance; therefore, the mean of the MN increments was significantly lower than in placebo (P < 0.05). A significant positive correlation between MN maximum increment and the bone marrow dose was observed in the placebo group only (P = 0.03). No significant difference was observed in clinical outcome between the two groups.CONCLUSIONS: EGb 761 supplementation neutralized genotoxic damage induced by radioiodine treatment, without affecting the clinical outcome. Although (131)I therapy is generally safe, our data suggest that Gingko biloba extracts may prevent genetic effects of radioiodine therapy for hyperthyroid Graves' disease.

30.Dual effects of Ginkgo biloba leaf extract on human red blood cells.:

Basic Clin Pharmacol Toxicol. 2009 Feb;104(2):138-44. Epub 2008 Dec 18.PMID: 19143753
Extracts from the leaves of Ginkgo biloba have been used in Chinese medicine for thousands of years. Today, various standardized preparations from G. biloba leaf extract have been developed. G. biloba leaf extract, which contains flavonoids and terpenoids as the major biologically active components, has become one of the most popular and commonly used herbal remedies due to its wide spectrum of beneficial effects on health. In this study, we investigated the effects of G. biloba leaf extract on the properties of human red blood cells in the presence and absence of amyloid peptide (Abeta25-35), peroxide and hypotonic stress. The results suggest that G. biloba leaf extract has a dual action, both protective and disruptive, on red blood cells, depending on whether an exogenous stress is present. G. biloba leaf extract has a protective role on red blood cells against Abeta- and hypotonic pressure-induced haemolysis, peroxide-induced lipoperoxidation, as well as glutathione consumption and methaemoglobin formation. On the other hand, G. biloba leaf extract also exhibited damage to red blood cells by increasing cell fragility, changing cellular morphology and inducing glutathione consumption and methaemoglobin formation, especially when applied at high doses. These anti- and pro-oxidative activities of polyphenolic substances are thought to be involved in the dual function of G. biloba leaf extract. The results of this study suggest that high doses of herbal remedies and dietary supplements can be toxic to cells.

31.Experimental study on effect of total flavone of Ginkgo biloba on delaying cell senescence(aging):

Zhong Yao Cai. 2009 Jan;32(1):100-2.PMID: 19445133
OBJECTIVE: To investigate the mechanism of delaying the senescence of human diploid fibroblast (2BS) by total flavone of Ginkgo biloba (FG).METHODS: The drug sera of FG was used to treat the 2BS. The population doublings of 2BS cells were observed, the mRNA expression of P16 gene was determined by fluorescence real-time quantitative PCR.RESULTS: FG significantly extended the population doublings of 2BS cells, and decreased the expression of P16 mRNA.CONCLUSION: FG can delay the senescence of cells by inhibiting the P16 gene expression.

32.Ginkgo biloba extract EGb761 protects against aging-associated mitochondrial dysfunction in platelets and hippocampi of SAMP8 mice.:

Platelets. 2010;21(5):373-9.PMID: 20459350
Standardized Ginkgo biloba extract, EGb761, has been shown to possess polyvalent properties, such as anti-oxidation, anti-apoptosis and anti-inflammation. Recently, it has also been proposed to have direct protective effects on mitochondria. The effects of EGb761 make it a potential anti-aging drug. Despite that, the 'anti-aging' effect of EGb761, particularly its effect on the central nervous system, is still inconclusive. Using two age groups (3-week-old and 40-week-old) of SAMP8 mice (a senescence-accelerated strain of mice), the effects of EGb761 on mitochondrial function in platelets and hippocampi were investigated in this study. It was found that mitochondrial functions, evaluated as cytochrome c oxidase (COX) activity, mitochondrial ATP (adenosine-5'-triphosphate) content and mitochondrial glutathione (GSH) content, decreased with age. EGb761 protected against mitochondrial dysfunction in platelets of young and old mice, suggesting a peripheral effect of this herb in the prevention and treatment of age-associated degeneration. In contrast, in hippocampi, protective effects of EGb761 were observed only in the old mice, probably due to an age-associated increase in the permeability of the blood brain barrier (BBB). Therefore, while EGb761 has a potential anti-aging effect, its central effect can be affected by in vivo factors such as the BBB permeability. A better understanding of the in vivo pharmacological actions of EGb761 may contribute to a better understanding of the effectiveness and complexity of this drug.

C-Ginkgo Biloba:Antioxidant,Antiradical Research:

1.Antiradical properties of Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1475-9.PMID: 2947084
The anti-radical properties of Ginkgo biloba extract have been determined on several in vitro models. The products is as effective as uric acid, an anti-radical agent known to entrap the hydroxyl and diphenylpicrylhydrazyl radicals. In addition, it inactivates the formation of radicals, such as adriamycyl, which escape uric acid activity. It also inhibits membrane lipid peroxidation and owes to its anti-radical activity exerts a stimulant effect on the biosynthesis of prostanoids.

2.Ginkgo biloba extract inhibits oxygen species production generated by phorbol myristate acetate stimulated human leukocytes.:

Experientia. 1987 Feb 15;43(2):181-4.PMID: 3028858
A Ginkgo biloba extract (Gbe) containing flavonoids, among other compounds, was tested for the release of activated oxygen species (O-2, H2O2, OH.) during the stimulation of human neutrophils (PMNs) by a soluble agonist. The extract slows down O2 consumption (respiratory burst) of stimulated cells by its inhibitory action on NADPH-oxidase, the enzyme responsible for the reduction of O2 to O-2. Consequently, superoxide anion (O-.2) and hydrogen peroxide (H2O2) production is significantly decreased when the PMNs stimulation is done in the presence of the extract at concentrations of 500, 250 and 125 micrograms/ml. Moreover, the hydroxyl radical generation (OH.) is very much decreased at concentrations as low as 15.6 micrograms Gbe/ml, which indicates that the extract also has free radical scavenging activity. Gbe is able at least to reduce very severely the activity of myeloperoxidase contained in neutrophils. This enzyme, secreted into the intra and extracellular medium, catalyzes the oxidation of chloride (Cl-) by H2O2 to yield strong oxidants (HOCl, chloramines) which are implicated in inflammatory processes.

3.Free radical-mediated effects in reperfusion injury: a histologic study with superoxide dismutase and EGB 761 in rat retina.:

Ophthalmic Res. 1991;23(4):225-34.PMID: 1945294
In Sprague-Dawley rats, retinal ischemia was induced by occlusion of the central retinal artery, while reperfusion was initiated by unclamping and removing the occluder. Ninety minutes of regional ischemia followed by 24 h of reperfusion resulted in a development of retinal edema in the inner plexiform layer and a migration of neutrophils into the retinal tissue. Oxygen free radicals have been implicated as inducers of cell damage in different tissues. This finding has led us to speculate that, if oxygen free radicals play an important role in the development of reperfusion injury, superoxide dismutase (SOD) and EGB 761 (Tanakan, extract of Ginkgo biloba, IPSEN) should be protective against reperfusion-induced injury. Under our experimental conditions, SOD dose-dependently reduced the development of edema formation (which was expressed in micrometers, measuring the thickness of the inner plexiform layer). Thus, 3,750, 7,500 and 15,000 U/kg of SOD reduced the reperfusion-induced edema formation from its drug-free ischemic value of 112 +/- 4 to 107 +/- 7, 91 +/- 6 (p less than 0.05) and 85 + 4 microns (p less than 0.001), respectively. Furthermore, SOD significantly reduced the migration of neutrophils which can also contribute to the development of reperfusion-induced injury. The same protective effect was observed, concerning the edema formation and neutrophil migration, in the EGB 761-treated groups. Our results indicate that free radicals play an important role in the development of reperfusion-induced injury, and the treatment of ischemic and reperfused retina with free radical scavengers may reduce the severity of reperfusion damage.

4.Influences of Ginkgo biloba on cyclosporin A induced lipid peroxidation in human liver microsomes in comparison to vitamin E, glutathione and N-acetylcysteine:

Biochem Pharmacol. 1991 May 15;41(10):1521-6.PMID: 2018556
The in vitro effect of cyclosporin A (CsA) on lipid peroxidation in human liver microsomes was investigated, and efforts were made to prevent the resulting toxic effect of CsA. Microsomes were prepared from human liver resection material and incubated with CsA (0, 10, 30, 100, 300, 1000 micrograms/mL) for one hour (pH 7.4, 37 degrees, 95% O2, 5% CO2). Subsequently the resulting concentrations of malondialdehyde equivalents (MDA) were determined, a breakdown product of lipid peroxidation. Furthermore the duration of incubation was varied (0, 15, 30, 60, 90 min) using a CsA concentration of 300 micrograms/mL. CsA was shown to stimulate MDA-formation to up to 10-fold of the control value in both a time and concentration dependent manner. The dosage dependent experiment stated above was repeated, adding alpha-tocopherol (vitamin E, 1 mM), reduced glutathione (GSH, 1 mM), N-acetylcysteine (0.1, 0.3, 1, 3 mM), and Ginkgo biloba extract (Gbe, 15, 50, 150 micrograms/mL), respectively, to the medium of incubation. Vitamin E, a potent radical scavenger, proved to inhibit lipid peroxidation almost totally. Both GSH and N-acetylcysteine were also able to prevent lipid peroxidation, suggesting that the antioxidant effect of GSH might be caused by its thiol group and does not depend on the integrity of the whole molecule. Gbe inhibited CsA induced lipid peroxidation in a concentration dependent manner. This effect of Gbe was diminished yet not totally abolished when FeCl3 was added to the medium of incubation, whereas N-acetylcysteine even slightly enhanced CsA stimulated lipid peroxidation in the presence of iron. These results suggest that Gbe might be able to prevent radical mediated damage to human membranes caused by CsA.

5.Effects of an extract of Gingko biloba on bromethalin-induced cerebral lipid peroxidation and edema in rats.:

Am J Vet Res. 1992 Jan;53(1):138-42.PMID: 1539906
The effects of administration of a commercially available extract of Gingko biloba (EGB) on bromethalin-induced brain lipid peroxidation and cerebral edema in adult male Sprague-Dawley rats was determined. Gingko biloba extract was given (100 mg/kg) by gavage immediately after bromethalin (1.0 mg/kg) administration. Rats were euthanatized at 24 hours after dosing. Brain lipid peroxidation was determined by measurement of brain malonaldehyde-thiobarbituric acid chromophore (MDA-TBA) concentration, brain sodium concentration, and brain water content. Treatment of bromethalin-dosed rats (10/group) with EGB was associated with a statistically significant (P less than 0.05) decrease in clinical sign severity, compared with bromethalin-dosed saline solution-treated rats. All rats given bromethalin and saline solution developed clinical signs of toxicosis including CNS depression, hind limb weakness, ataxia, paralysis, and coma. Some rats given bromethalin and EGB developed clinical signs, however, none developed hind limb paralysis. The brain MDA-TBA concentration (2.4 +/- 0.5 delta MDA-TBA concentration/mg of protein), percentage of water in brain tissue (80.3 +/- 0.30%), and brain sodium concentration (6.68 +/- 0.21 mg/g of dry weight) were significantly increased in rats given bromethalin and saline solution, compared with control rats given saline solution (1.0 +/- 0.1 delta MDA-TBA concentration/mg of protein; 78.1 +/- 0.33% water in brain tissue; 4.83 +/- 0.30 mg of brain Na+/g of dry weight) and rats given bromethalin and EGB (1.6 +/- 0.2 delta MDA-TBA concentration/mg of protein; 79.3 +/- 0.31% water in brain tissue; 5.37 +/- 0.34 mg of brain Na+/g of dry weight).

6.Protection from uv-light-induced oxidative stress by nutritional radical scavengers:

Z Gesamte Inn Med. 1992 Nov;47(11):518-22.PMID: 1462677
Two series of examinations were carried out in two voluntary test groups for the purpose of elucidating the correlation between ultraviolet light load and oxidative stress as well as the way it is influenced by nutritive radical scavengers. After a 6 to 7-hour impact of sunshine on the whole body (sunbathing beach) at n = 8 a continuous progredient increase of thiobarbituric acid reactive substances could be identified in the serum (from 5.56 +/- 0.98 to 8.91 +/- 0.99 mumol/l, p < 0.001), which after new exposure to sunshine reached 11.3 +/- 2.4 mumol/l. Likewise, a 15-minute exposure to ultraviolet light at n = 24 induced increases of TBRS concentrations lasting from 1-2 days. After 14-day supplementation with beta-carotene (n = 6), D-alpha-tocopherol (n = 6), selenium (n = 6), and ginkgo biloba extract (n = 6) the extent of the oxidative stress could be inhibited during a second exposure to ultraviolet light up to the following efficiency: Se > Ginkgo > beta-carotene > vitamin E. The clastogenous effect of sunshine and ultraviolet light must be regarded as a factor for initiating and promoting cancerogenesis in the total organism. Concerning the aetiopathogenesis of malignant melanoma the paramagnetic properties of free radicals with their nonenergetic effects of the magnetic field have to be considered more carefully in scientific examinations.

7.Ca(2+)-induced increase in oxidative metabolism of dissociated mammalian brain neurons: effect of extract of ginkgo biloba leaves.:

Jpn J Pharmacol. 1993 Apr;61(4):367-70.PMID: 8320882
Effect of an extract of Ginkgo biloba leaves (EGb) on oxidative metabolism was studied using rat brain neurons and 2',7'-dichlorofluorescin fluorescence. Ionomycin (100 nM to 1 microM), a Ca(2+)-ionophore, dose-dependently augmented the 2',7'-dichlorofluorescin fluorescence in the presence of external Ca2+, but not under the external Ca(2+)-free condition. Preincubation of neurons with EGb (3 micrograms/ml) greatly reduced the ionomycin-induced increase in 2',7'-dichlorofluorescin fluorescence. Results suggest that EGb may reduce the Ca(2+)-induced increase in the oxidative metabolism of brain neurons.

8.Myricetin and quercetin, the flavonoid constituents of Ginkgo biloba extract, greatly reduce oxidative metabolism in both resting and Ca(2+)-loaded brain neurons.:

Brain Res. 1994 Jan 28;635(1-2):125-9.PMID: 8173947
The antioxidant action of myricetin and quercetin, the flavonoid constituents of the extract of Ginkgo biloba (EGb), on oxidative metabolism of brain neurons dissociated from the rats was examined using 2',7'-dichlorofluorescin (DCFH) which is retained within the neuron and then is oxidized by cellular hydrogen peroxide to be highly fluorescent. Incubation with myricetin or quercetin reduced the oxidation of DCFH in resting brain neurons, more profoundly than EGb. Myricetin decreased the oxidative metabolism at concentrations of 3 nM or more. It was 10 nM or more for the case of quercetin. Incubation with each flavonoid constituent also reduced the Ca(2+)-induced increase in the oxidative metabolism without affecting the cellular content of DCFH or the intracellular concentrations of Ca2+. Such an antioxidant action of myricetin or quercetin may be responsible for a part of the beneficial effects of EGb on brain neurons subject to ischemia.

9.Effects of natural antioxidant ginkgo biloba extract (EGB 761) on myocardial ischemia-reperfusion injury.:

Free Radic Biol Med. 1994 Jun;16(6):789-94.PMID: 8070682
Recently, it was reported that Ginkgo biloba extract (EGb 761), which is known to have antioxidant properties, also has antiarrhythmic effects on cardiac reperfusion-induced arrhythmias. In the present study, effects of EGb 761 on cardiac ischemia-reperfusion injury were investigated from the point of view of recovery of mechanical function as well as the endogenous antioxidant status of ascorbate. Isolated rat hearts were perfused using the Langendorff technique, and 40 min of global ischemia were followed by 20 min of reperfusion. EGb 761 improved cardiac mechanical recovery and suppressed the leakage of lactate dehydrogenase (LDH) during reperfusion. Furthermore, EGb 761 diminished the decrease of myocardial ascorbate content after 40 min of ischemia and 20 min of reperfusion. Interestingly, EGb 761 also suppressed the increase of dehydroascorbate. These results indicate that EGb 761 protects against cardiac ischemia-reperfusion injury and suggest that the protective effects of EGb 761 depend on its antioxidant properties.

10.The nitric oxide-scavenging properties of Ginkgo biloba extract EGb 761.:

Biochem Biophys Res Commun. 1994 Jun 15;201(2):748-55.PMID: 8003011
Ginkgo biloba extract EGb 761 was found to be a scavenger of nitric oxide in in vitro acellular systems, under physiological conditions. EGb 761 competed with oxyhemoglobin for reaction with nitric oxide generated during the interaction of hydroxylamine with Complex I of catalase. An EGb 761 dose-dependent decrease in the amount of nitrite formed in the reaction of oxygen with nitric oxide produced from solution of 5 mM sodium nitroprusside was also observed. These data implicate it as a potential therapeutic agent in conditions of altered production of nitric oxide.

11.Inhibition of preretinal proliferation by free radical scavengers in an experimental model of tractional retinal detachment.:

Exp Eye Res. 1994 Dec;59(6):697-706.PMID: 7698262
An original model of experimental proliferative vitreoretinopathy consisting of an intravitreal injection of 10(7) human platelets and 1 IU of hyaluronidase was developed in pigmented rabbits. One group of 11 eyes served as non-treated controls. Two other groups of 11 eyes each received Ginkgo Biloba extracts which are known free radical scavengers (EGb761, Ipsen, France), given orally in two doses, 50 mg kg-1 day-1 and 100 mg kg-1 day-1 respectively, from the day after the platelet injection to the end of the first month. The fourth group (11 eyes) was intravenously injected with a unique dose of 15000 U kg-1 of superoxide dismutase the day after platelet injection. All animals were ophthalmoscopically examined in a masked fashion twice a week for 1 month and killed at the end of the experiment for histological analysis. Vitreoretinal proliferation was graded according to a six-stage classification. The non-treated eyes showed a high rate of retinal detachment (11/11 eyes), with a mean final score of 3.91 +/- 0.94. Histologic examinations consistently showed retinal retraction by fibrocellular preretinal membranes spreading to both surfaces of the retina as well as preretinal neovascularization. Many cells positively reacted with anti-cytokeratin or anti-vimentin monoclonal antibodies. All three groups of treated eyes showed significantly lower scores of vitreoretinal proliferation at almost each time point of examination. At the end of the study, five retinal detachments were found in the EGb761 group at 50 mg kg-1 day-1 (mean final score 2.45 +/- 1.37), only one in the group receiving 100 mg kg-1 day-1 (mean score 1.64 +/- 1.03), and one in the SOD treated eyes. The lowest mean score found at day 28 was observed in the group receiving SOD (1.36 +/- 1.43), although this group presented during the first 3 weeks with an intense vitreous and sometimes anterior chamber inflammation. Statistical comparison between treatments did not show significant differences at most time points of the study. These results demonstrate that antioxidants may efficiently prevent preretinal proliferation, in clinicopathological entities where free radicals had not yet been shown to play a direct pathogenetic role. They are also among the first attempts for inhibiting preretinal proliferations with non-cytotoxic agents and using a non-ocular route.

12.Modification of cisplatin-induced renal p-aminohippurate uptake alteration and lipid peroxidation by thiols, Ginkgo biloba extract, deferoxamine and torbafylline.:

Nephron. 1995;70(4):425-9.PMID: 7477647
To determine whether inhibition of lipid peroxidation modifies cisplatin-induced changes of renal p-aminohippurate (PAH) uptake, we examined the effects of various radical scavengers and torbafylline on cisplatin-induced lipid peroxidation and PAH accumulation changes in rat renal cortical slices. Renal cortical slices were incubated with different cisplatin concentrations (0.3, 0.6, 1.0 mg/ml) in the presence of either glutathione, N-acetylcysteine, the iron chelator deferoxamine, Ginkgo biloba extract or the xanthine derivate torbafylline. Lipid peroxidation monitored as the production of malondialdehyde (MDA) was stimulated by increasing cisplatin concentrations in a dose-related manner. At a cisplatin concentration of 1.0 mg/ml, MDA production was twofold compared to controls (0.69 +/- 0.06 vs. 1.36 +/- 0.07 nmol/mg; p < 0.05). In turn, cisplatin decreased PAH uptake of kidney slices dose-dependently from 13.3 +/- 1.3 to 2.6 +/- 0.2 (p < 0.01). All agents tested inhibited cisplatin-induced lipid peroxidation; however, at a cisplatin concentration of 1.0 mg/ml, none of them prevented the decline of cisplatin-induced PAH uptake. Of the agents tested, deferoxamine proved to be the most effective antioxidant, completely inhibiting cisplatin-induced lipid peroxidation but in contrast preventing the decrease in PAH uptake only at a cisplatin concentration of 0.3 mg/ml. No strict association between lipid peroxidation and decline of PAH uptake was found, suggesting that lipid peroxidation may only in part participate in cisplatin-induced alterations of PAH uptake.

13.Lipoperoxidation induced by hydrogen peroxide in human erythrocyte membranes. 1. Protective effect of Ginkgo biloba extract (EGb 761).:

J Int Med Res. 1995 Jan-Feb;23(1):1-8.PMID: 7774754
The antioxidant potential of Ginkgo biloba extract (EGb 761) on healthy human erythrocyte membranes was investigated. Lipoperoxidation was induced in erythrocyte suspensions using hydrogen peroxide, in the presence of EGb 761 at 37 degrees C; malondialdehyde production was determined as the indicator of lipoperoxidation during the incubation period. The results for EGb 761 at concentrations of 0, 25, 50, 125, 250 and 500 micrograms/ml suggest that the antioxidant potential of EGb 761 in erythrocyte membranes increases with dose. Similarly, using different incubation periods (0, 15, 30, 45 or 60 min) indicated that the antioxidant effect of EGb 761 increased by the incubation time.

14.Lipoperoxidation induced by hydrogen peroxide in human erythrocyte membranes. 2. Comparison of the antioxidant effect of Ginkgo biloba extract (EGb 761) with those of water-soluble and lipid-soluble antioxidants.:

J Int Med Res. 1995 Jan-Feb;23(1):9-18.PMID: 7774762
An in vitro model using healthy human erythrocyte suspensions was used to compare the antioxidant effect of standardized Ginkgo biloba extract (EGb 761) with those of water-soluble (ascorbic acid, glutathione and uric acid) and lipid-soluble (alpha-tocopherol and retinol acetate) antioxidants. Lipid peroxidation was induced by hydrogen peroxide in the absence (control) and presence of antioxidants at low (25 micrograms/ml) and high (250 micrograms/ml) concentrations. Malondialdehyde production was determined as the indicator of lipid peroxidation during the incubation period. The results suggest that all of the antioxidants, except ascorbic acid, have antioxidant potential in this system in a concentration-dependent manner. When the antioxidants were compared, EGb 761 was found to be more effective than water-soluble antioxidants, and as effective as lipid-soluble antioxidants. Among the lipid-soluble antioxidants there was no significant difference in potency between alpha-tocopherol and retinol acetate, but uric acid was the most potent of the water-soluble antioxidants. The antioxidant potency of EGb 761 appears to be comparable with that of the well-known antioxidants alpha-tocopherol and retinol acetate.

15.Antioxidant effect of a Ginkgo biloba extract (EGb 761) on the retina.:

Int J Tissue React. 1995;17(3):93-100.PMID: 8867648
Several investigations have recently shown that the retina is very sensitive to oxygenated free radicals (O2-, OH.) at the origin of the membrane phospholipids peroxidation. Peroxy radical (ROO.) release is responsible for the induction of electrophysiological disturbances leading to retinopathy development. As Ginkgo biloba extract (EGb 761, IPSEN, France) was reported to scavenge primary (O2-, OH.) and secondary (ROO.) free radicals, we evaluated its antioxidant effect on retinas of albino rats submitted to different types of aggressors. On isolated rat retina, EGb 761 given orally significantly protected against lipoperoxidation induced by a mixture of ferrous sulfate and sodium ascorbate added to the perfusion solution. With EGb 761, the decrease of the b-wave ERG amplitude was less pronounced and the retina survival was increased. EGb 761 was also effective against ischaemia-reperfusion disorders due to occlusion of the central retinal artery or by intraocular hypertony. Like other antioxidants such as superoxide dismutase tested on these models, EGb 761 significantly attenuated, according to a dose-response effect, the free-radical injury. EGb 761 reduces the decrease of the b-wave amplitude, the oedema, necrosis and ion homeostasis disturbances. Xenobiotics are also responsible for the retinotoxicity partly due to free radicals and PAF release. We noted an EGb 761 dose-dependent protective effect against acute and chronic chloroquine toxicity to the retina. The deleterious effect of chloroquine was characterized by a delayed b-wave and an asymmetry of the signal with slow declining b-wave. After EGb 761 treatment, the ERG aspect was partially normal. In conclusion, EGb 761, by its general free-radical scavenger properties, is an antioxidant that inhibits or reduces the functional and morphological retina impairments observed after lipoperoxide release.

16.Protection of polyunsaturated fatty acids against iron-dependent lipid peroxidation by a Ginkgo biloba extract (EGb 761).:

Methods Find Exp Clin Pharmacol. 1995 Mar;17(2):83-8.PMID: 7674702
Iron can induce a peroxidative degradation of the membrane polyunsaturated fatty acids by the well-known Fenton reaction. Chelated iron can also form a complex with oxygen, called perferryl ion, which is able to induce lipoperoxidation without a detectable production of hydroxyl radicals. The antioxidant properties of a titrated and standardized extract of Ginkgo biloba leaves (EGb 761) against iron-dependent peroxidative degradation of the membrane polyunsaturated fatty acids were studied. Rat liver microsomes were exposed to a mixture of NADPH, ADP and FeCl3 hypothesized to produce iron-oxygen complexes. The results of the analysis of the microsomal polyunsaturated fatty acids by gas chromatography show that the susceptibility to peroxidation of the different polyunsaturated fatty acids increases with their unsaturation level, and that EGb 761 protects these membrane polyunsaturated fatty acids regardless of their susceptibility to peroxidation. This protective effect is correlated with the decrease in the thiobarbituric acid-reactive substances concentration, but the calculation of the antioxidant potency of EGb 761 as an IC50 value using results of the thiobarbituric acid reaction leads to an underestimated evaluation when the reaction is carried out in the presence of iron ions.

17.Peroxyl radical scavenging activity of Ginkgo biloba extract EGb 761.:

Biochem Pharmacol. 1995 May 26;49(11):1649-55.PMID: 7786306
Antioxidant mechanisms have been proposed to underlie the beneficial pharmacological effects of EGb 761, an extract from Ginkgo biloba leaves used for treating peripheral vascular diseases and cerebrovascular insufficiency in the elderly. In vitro evidence has been reported that EGb 761 scavenges various reactive oxygen species, i.e. nitric oxide, and the superoxide, hydroxyl, and oxoferryl radicals. However, the ability of EGb 761 to scavenge peroxyl radicals (reactive species mainly involved in the propagation step of lipid peroxidation) has not been investigated. To characterize further the antioxidant action of EGb 761, we measured the protective effects of EGb 761 during: (1) the oxidation of B-phycoerythrin by peroxyl radicals generated in aqueous solution by 2,2'-azobis (2-amidinopropane) hydrochloride (AAPH); and (2) the reaction of luminol or cis-parinaric acid with peroxyl radicals generated from 2,2'-azobis (2,4-dimethylvaleronitrile) (AMVN) in liposomes or in human low density lipoprotein (LDL), respectively. To evaluate the peroxyl radical scavenging activity of EGb 761 in a more physiologically relevant model of damage to lipid-containing systems, we also analyzed the effect of the extract on the oxidation of human LDL exposed to the azo-initiators in terms of: (1) accumulation of cholesterol linoleate ester hydroperoxides, (2) depletion of alpha-tocopherol and beta-carotene, and (3) changes in intrinsic tryptophan fluorescence. EGb 761 afforded protection against oxidative damage in all the systems we analyzed; thus, it is an efficient scavenger of peroxyl radicals. This result extends the oxygen radical scavenging properties of the extract and supports the hypothesis of an antioxidant therapeutic action of EGb 761.

18.Ginkgo biloba extract (EGb 761) protects human low density lipoproteins against oxidative modification mediated by copper:

Biochem Biophys Res Commun. 1995 Jul 17;212(2):360-6.PMID: 7626049
The antioxidant effects of Ginkgo biloba extract (EGb 761) on copper-mediated human low density lipoprotein (LDL) oxidative modification were evaluated by several techniques. Human LDL (0.5 mg/ml) in phosphate buffered saline, pH 7.4, was incubated with 10 microM cupric sulfate at 37 degrees C under air for 8 hours and 24 hours in the presence of varying concentrations of EGb 761. Increases in LDL apoB carbonylation, lipid peroxidation, apoB electrophoretic mobility and LDL fluorescence were all inhibited when the incubation mixture contained EGb 761 at concentrations less than 100 micrograms/ml. This inhibition was EGb 761-concentration-dependent. Thus, EGb 761 has powerful antioxidant effects on copper-mediated LDL oxidative modification.

19.Ginkgo biloba attenuates oxidative stress in macrophages and endothelial cells.:

Free Radic Biol Med. 1996;20(1):121-7.PMID: 8903688
The action of Ginkgo biloba extract (GBE) as an antioxidant was studied using various models of oxidative stress in macrophages and vascular endothelial cells. GBE was incubated with murine macrophages (J774) at 37 degrees C and 5% CO2 for 1 h; oxidative burst was triggered by zymosan. The intensity of fluorescence was measured directly in 96-well plates using a computerized microplate fluorometer at 485 nm excitation and 530 nm emission. GBE exhibited both time- and concentration-dependent suppression of oxidative burst. Confluent monolayers of bovine pulmonary artery endothelial cells (PAEC) were preincubated with different concentrations of GBE for 16 h, washed, and then exposed to an organic oxidant tert-butyl hydroperoxide (tBHP) for 2 h. Lipid peroxidation products of PAEC were determined by measuring thiobarbituric acid-reactive substances (TBARS). Cell injury was assessed by measuring the release of intracellular lactate dehydrogenase (LDH), and cell viability was determined by the methylthiazol tetrazolium (MTT) assay. tBHP increased production of TBARS in PAEC. Preincubation with GBE inhibited the increase of TBARS induced by tBHP. GBE protected biomembranes from oxidative injury by decreasing intracellular LDH leakage from PAEC. MTT assay showed that GBE minimized loss of cell viability induced by oxidative injury. The extensive antioxidant effect of GBE may be valuable to the prevention and treatment of various disorders related to free radical-induced pathology.

20.Ginkgo biloba extract (EGb 761) pretreatment limits free radical-induced oxidative stress in patients undergoing coronary bypass surgery.:

Cardiovasc Drugs Ther. 1997 Apr;11(2):121-31.PMID: 9140689
A growing body of evidence supports the trigger role of free radicals in the delayed functional and metabolic myocardial recovery following cardiopulmonary bypass (CPB) in humans, thus opening the field to specific therapies. This clinical study was designed to evaluate, in 15 patients undergoing aortic valve replacement, whether the extent of CPB- and reperfusion-induced lipid peroxidation, ascorbate depletion, tissue necrosis, and cardiac dysfunction is reduced by orally administered EGb 761, a Ginkgo biloba extract with potent in vitro antiradical properties. Patients received either EGb 761 (Tanakan, 320 mg/day, n = 8) or a matching placebo (n = 7) for 5 days before surgical intervention. Plasma samples were obtained from the peripheral circulation and the coronary sinus at crucial stages of the operation (i.e., before incision, during ischemia, and within the first 30 minutes post-unclamping), and up to 8 days postoperatively. Upon aortic unclamping, EGb 761 inhibited the transcardiac release of thiobarbituric acid-reactive species (p < 0.05), as assessed by high-performance liquid chromatography, and attenuated the early (5-10 minute) decrease in dimethylsulfoxide/ascorbyl free radical levels, an electron spin resonance index of the plasma ascorbate pool (p < 0.05). EGb 761 also significantly reduced the more delayed leakage of myoglobin (p = 0.007) and had an almost significant effect on ventricular myosin leakage (p = 0.053, 6 days postoperatively). The clinical outcome of recovery of treated patients was improved, but not significantly, compared with untreated patients. Our results demonstrate the usefulness of adjuvant EGb 761 therapy in limiting oxidative stress in cardiovascular surgery and suggest the possible role of highly bioavailable terpene constituents of the drug.

21.Ginkgo biloba extract (EGb 761) as an antioxidant factor of exogenous origin:

Rev Med Chir Soc Med Nat Iasi. 1997 Jul-Dec;101(3-4):192-6.PMID: 10756797
Extracted from Ginkgo biloba leaves, the EGb 761 has a great number of therapeutical properties and anti-stress effects, for example the antioxidant one. We estimated in our experiment the influence of a chronic treatment with EGb 761 on the concentration of the main product of lipidic degradation--malondialdehyde (MDA), in cerebral cortex, in diencephalon, thymus and gastric mucosa. The experiment was performed on Wistar rats, male, young. The MDA estimation was performed by the spectrocalorimetry. We have determined that the stress raised the MDA concentration in all examined structures with approximately 100% and 80% of animals manifested stress ulcer. The treatment with EGb 761 before a stress inhibits the post-stress growth of MDA concentration and the process of stress ulcer formation.

22.Antioxidative activity of ginkgolides against superoxide in an aprotic environment.:

Chem Biol Interact. 1997 Oct 24;106(3):183-90.PMID: 9413545
The terpene lactones ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J and bilobalide, which are components of a standardized extract (EGb 761) from leaves of Ginkgo biloba, as well as ginkgolide M from roots of G. biloba were studied regarding their reaction against superoxide (O2-) and hydroperoxyl radicals (HO2) in dimethyl sulfoxide as an aprotic solvent. It was found that the ginkgolides B, C, J, M as well as bilobalide react with superoxide and its protonated form as demonstrated by EPR and UV/VIS spectroscopy. The initial reaction rate with these oxygen-derived radicals is in the order of 100 M-1/s and below. Ginkgolide A does not react with superoxide under these conditions. From these findings it can be suggested that the superoxide scavenging effect of the ginkgolides B, C, J, M and bilobalide contributes to the antioxidant properties of G. biloba.

23.In vitro antioxidant effect of Ginkgo biloba extract (EGb 761) on lipoperoxidation induced by hydrogen peroxide in erythrocytes of Behçet's patients.:

Jpn J Pharmacol. 1997 Nov;75(3):253-8.PMID: 9434256
Excessive superoxide radical production and an impaired antioxidant mechanism in both the neutrophils and plasma of patients with Behçet's disease (BD) have been reported. To provide clinical support for the earlier data, erythrocyte membrane integrity was investigated by measuring malondialdehyde (MDA, a marker of lipid peroxidation) levels in the erythrocytes of BD patients. In addition, the antioxidant effect of Ginkgo biloba extract (EGb 761) at 25 and 250 microg/ml concentrations on lipoperoxidation induced by hydrogen peroxide (H2O2) in erythrocyte obtained from BD patients was examined in in vitro conditions. When compared to healthy controls, basal erythrocyte MDA levels were found to be higher in BD patients. In the in vitro study, there was also a significant increase in H2O2-induced MDA production in the medium containing no EGb 761 in the patient group, whereas significant decreases in MDA levels were observed in the mediums containing EGb 761 both in the patient and control groups. The decrease in MDA production was found to be related to EGb 761 concentration. These data indicate that an oxidative damage is present in erythrocytes obtained from Behçet's patients, and EGb 761, which may strengthen the antioxidant defense system, may contribute to the treatment of BD.

24.Stoichiometric and kinetic studies on Ginkgo biloba extract and related antioxidants.:

Lipids. 1998 Apr;33(4):365-70.PMID: 9590623
Owing to increasing evidence showing the importance of lipid peroxidation in oxidative stress in vivo, the role and evaluation of antioxidants have received much attention. Ginkgo biloba extract (GBE), well-known as an efficient drug against diseases induced by free radicals, has been suggested to exert its effect by antioxidant action. A method was established to determine the activity of GBE as a hydrogen donor by stoichiometric and kinetic studies, and GBE was compared with several other antioxidants such as alpha-tocopherol, propyl gallate, and two kinds of flavonoids which are found in GBE, quercetin, and kaempferol. It was found that there were 6.62 x 10(19) active hydrogens in 1 g of GBE. Stoichiometric studies showed that one molecule of alpha-tocopherol reacted with one molecule of galvinoxyl radical. For quercetin, kaempferol and propyl gallate, the experimental stoichiometric numbers were 4.0, 1.9, and 3.1, respectively. The rates of reaction of antioxidants with galvinoxyl in ethanol were determined spectrophotometrically, using a stopped-flow technique. The second-order rate constant, k2, obtained at 25 degrees C was 0.13 (g/L)(-1)s(-1) for GBE and 5.9 x 10(3), 2.1 x 10(3), 1.2 x 10(4), and 2.4 x 10(3) M(-1)s(-1) for quercetin, kaempferol, propyl gallate, and alpha-tocopherol, respectively. The second-order rate constant, k2', on the molar basis of active hydroxyl groups in the tested substances obtained at 25 degrees C decreased in the order of propyl gallate > alpha-tocopherol > quercetin > GBE approximately kaempferol. This is the first study on GBE as an antioxidant which reports both stoichiometric and kinetic results.

25.Effects of EGb 761 on nitric oxide and oxygen free radicals, myocardial damage and arrhythmia in ischemia-reperfusion injury in vivo.:

Biochim Biophys Acta. 1998 Apr 28;1406(3):228-36.PMID: 9630646
The cardioprotective effects of EGb 761 on the release of nitric oxide (NO), the concentration of serum thiobarbituric acid reaction substance (TBARS), the activity of creatine kinase (CK) and the incidence of ventricular arrhythmias were investigated in myocardial ischemia-reperfusion injury in vivo. Using sodium nitrite (NaNO2) as standard source of nitric oxide (NO), we compared the correlation coefficients of the three measuring methods used currently in the determination of NOFe2+(DETC)2 complex with that of the measuring method suggested in this study. The result showed that measuring the whole height of three splitting signals is the best linear correlation to the concentration of NO comparing with other methods in this system. Using this method, we observed the effects of EGb 761 on NOFe2+(DETC)2 complex in myocardial ischemia-reperfusion injury in vivo. The hearts of the Wistar rats were subjected to 30 min of ischemia and 10 min of reperfusion in vivo. Different doses of EGb 761 (25, 50, 100, 200 mg/kg i.p.), superoxide dismutase (SOD, 10(4) U/kg), l-arginine (50 mg/kg i.p.) and nitric oxide synthase (NOS) inhibitor NG-nitro-l-arginine (NNA, 50 mg/kg i.p.) were administered to the ischemia-reperfusion rats. EGb 761 under the dose of 100 mg/kg increased the signal intensity of NOFe2+(DETC)2 complex, while EGb 761 at 200 mg/kg showed an effect of decreasing the signal intensity of NOFe2+(DETC)2 complex. EGb 761 inhibited the formation of TBARS, the release of CK, and mitigated the incidence of ventricular arrhythmias in a dose dependent way. Both l-arginine and SOD increased the signal intensity of NOFe2+(DETC)2 complex and inhibited the formation of TBARS, the leakage of CK and the incidence of ventricular arrhythmia. NNA not only had no protective effects on myocardial injury, but also increased the incidence of reperfusion-induced arrhythmia. In conclusion, EGb 761 has cardiovascular protective effects by means of adjusting the level of NO and inhibiting oxygen free radicals induced lipid peroxidation in myocardial ischemia-reperfusion injury in vivo.

26.The protection of the retina from ischemic injury by the free radical scavenger EGb 761 and zinc in the cat retina.:

Ophthalmologica. 1998;212(4):268-74.PMID: 9672217
We investigated the effects of a free radical scavenger (EGb 761) and zinc in experimentally induced ischemic injury in the cat retina. Total retinal ischemia for 90 min was produced in the left eyes of 40 cats by raising intraocular pressure. In group 1, 10 cats were used as control. The free radical scavenger (EGb 761, 100 mg/kg) in group 2 (10 cats) and zinc chloride (250 microg/kg) in group 3 (10 cats) were administered intravenously at the end of ischemia. In group 4, both EGb 761 (100 mg/kg) and zinc chloride (250 microg/kg) were injected into 10 cats. ERG and a histologic study were performed 1 h, 1 day, 3 days, 1 week and 2 weeks after ischemia. The amplitude of the ERG b-wave was 62.73+/-0.32, 84.31+/-6.10, 83.65+/-12.23 and 102.4+/-14.27%, and the summed amplitude of oscillatory potentials was 66.16+/-16.42, 99.44+/-14.92, 95.45+/-6.42 and 99.62+/-12.32% in each group 2 weeks after ischemia. There was no significant effect in animals that received zinc alone (group 3) by the end of 1 week but some additive effect in combining EGb 761 and zinc chloride (group 4) 1 h after ischemia. These findings suggest that the free radical scavenger EGb 761 may efficiently protect the retina from ischemic injury and zinc may have an additive effect when combined with a radical scavenger.

27.The effect of meclofenoxate with ginkgo biloba extract or zinc on lipid peroxide, some free radical scavengers and the cardiovascular system of aged rats.:

Pharmacol Res. 1998 Jul;38(1):65-72.PMID: 9697157
Aged rats are highly prone to many physiological changes such as blood pressure and heart rate. These changes could be due to modification in membrane phospholipid composition of their blood vessels. Lipid peroxide in vivo has been identified as a basic deteriorative reaction in cellular mechanisms of aging in human. The effect of a nootropic drug, meclofenoxate (MF) or its combination with extract of ginkgo biloba (EGb-761) or zinc (Zn) on malondialdehyde (MDA) product as an index of endogenous lipid peroxidation; phospholipid; glutathione (GSH) and protein thiols (PrSHs) contents as well as superoxide dismutase (SOD) activity in blood, brain, heart and liver of 24-month-old male rats was investigated. Aged rats were treated with MF once daily at oral doses of 100 mg kg-1 body wt. alone or with either EGb at a dose of 150 mg kg-1 body wt. or Zn at 10.5 mg kg-1 body wt. for 4 weeks. This study showed that aging caused a higher increment in MDA level of brain and heart than liver and plasma accompanied with reduction in brain and heart phospholipid contents as well as alteration of the antioxidant systems as compared to 4-month-old rats. Treatment of aged rats with MF alone or combined with either EGb or Zn caused improvement in the measured free radical scavengers especially in brain and heart tissues. Our results also showed that both EGb and Zn induced a significant potential effect of MF action on blood pressure and heart rate. The results were explained in the light of the antioxidant properties of EGb and Zn. Thus it is concluded that EGb and Zn have a beneficial role with MF in diminishing cumulative oxidative changes in aging.

28.Superoxide scavenging effect of Ginkgo biloba extract on serotonin-induced mitogenesis.:

Biochem Pharmacol. 1998 Aug 15;56(4):527-33.PMID: 9763230
We have reported previously that serotonin (5-HT) stimulates the mitogenesis of bovine pulmonary artery smooth muscle cells (SMCs) through active transport of 5-HT and cellular signaling that includes elevation of superoxide (O2.-) and enhancement of protein tyrosine phosphorylation. Ginkgo biloba extract 501 (EGb 501), which has been demonstrated to act as an antioxidant, was found to block both the elevated O2.- and the proliferative and hypertrophic influences of 5-HT on SMCs, but not to directly inhibit the associated activation of NAD(P)H oxidase or the stimulation of phosphorylation of GTPase-activating protein (GAP). A similar effect of Ginkgo biloba extract 501 occurred on Chinese hamster lung fibroblasts (CCL-39), where 5-HT receptor, as opposed to transporter, action has been associated with mitogenesis. We conclude from these studies that Ginkgo biloba extract 501 quenches O2.- formation by 5-HT, thereby blocking its mitogenic effect. Stimulation of protein tyrosine phosphorylation of GAP by 5-HT appears to precede the elevation of O2.-.

29.Effects of EGb761 and superoxide dismutase in an experimental model of retinopathy generated by intravitreal production of superoxide anion radical.:

Graefes Arch Clin Exp Ophthalmol. 1999 Jan;237(1):58-66.PMID: 9951643
BACKGROUND: A study was carried out to investigate the effect of two antioxidants--Ginkgo biloba extract (EGb761) and superoxide dismutase (SOD)--in an experimental model of vitreoretinopathy obtained by direct production of oxygen free radicals in the vitreous cavity.METHODS: Twenty-eight pigmented rabbits were used. Vitreoretinopathy was induced by intravitreal injection of 50 microliters of a mixture composed of 40 nmol of xanthine and 0.001 IU of xanthine oxidase. Rabbits were randomly distributed into four groups: Group 1 (n = 8) did not receive any treatment and served as a positive control. Groups 2 (n = 8) and 3 (n = 8) received for 1 month EGb761 given orally at a dose of 100 mg/kg/day, respectively 1 day after and 1 week before induction of retinopathy. Group 4 (n = 4) was treated by three intramuscular injections of 15,000 IU/kg of SOD, 24 h before induction and 24 and 48 h thereafter. Clinical evaluations and electroretinograms (ERG) were repeatedly performed until the animals were killed at day 28. Histological examinations and immunohistological procedures were performed to ascertain the origin and characteristics of the cellular proliferation and to compare vitreoretinal structures in the four groups.RESULTS: Intravitreal injection of xanthine-xanthine oxidase produced a strong inflammatory response with vitreous infiltrates and epiretinal membrane formation, inconstantly associated with retinal detachment. ERG showed a decrease of the a-, b- and c-waves beginning within a few hours after injection. Histologic evaluation found an intravitreal and epiretinal infiltration by leukocytes and epithelial-derived cells, dense vitreoretinal membranes and retinal detachments with occasional neovascularization. In the treated groups (groups 2-4), all clinical, electric and histologic data were significantly improved compared to the control group. However, no difference could be found among the three treated groups.CONCLUSION: This study demonstrates the strong pathologic effects of free radical production on the retina and the close relationships between free radicals, inflammatory pathways and vitreoretinal proliferative disorders. It also confirms the pharmacological interest of prevention by antioxidants and free radical scavengers.

30.Additional information to the in vitro antioxidant activity of Ginkgo biloba L.:

Phytother Res. 1999 Mar;13(2):160-2.PMID: 10190193
The in vitro antioxidant and free radical scavenging activity of the ethanol extract from Ginkgo biloba L. was examined in different systems. The extract showed hydrogen-donating ability, reducing power, copper-binding property, free radical scavenging activity in a H2O2/.OH-luminol system and it could prevent the autoxidation of linoleic acid. All these properties are involved in the overall antioxidant activity of Ginkgo biloba which makes it suitable for the prevention of human disease in which free radicals play an important role.

31.Different effects of the constituents of EGb761 on apoptosis in rat cerebellar granule cells induced by hydroxyl radicals.:

Biochem Mol Biol Int. 1999 Mar;47(3):397-405.PMID: 10204076
The present study was conducted to evaluate the different effects of the constituents of EGb761 (Ginkgo biloba Extract) on apoptosis in cerebellar granule cells induced by hydroxyl radicals. The total flavonoid component of EGb761, two pure EGb761 components (rutin and quercetin), and a mixture of flavonoids and terpenes protected cerebellar granule cells from oxidative damage and apoptosis induced by hydroxyl radicals. ESR(electron spin resonance) results showed that the IC50 of the flavonoids for scavenging hydroxyl radicals was almost the same as that of EGb761, even though flavonoids make up only 24% of EGb761, implying that other constituents of EGb761 besides flavonoids can scavenge hydroxyl radicals. Total terpenes of EGb761 did not protect against apoptosis. Flavonoids and terpenes did not show a synergistic effect in this regard. Terpenes did not scavenge hydroxyl radicals directly, which might be related to their "cage-like" structures.

32.The effects of free oxygen radical scavenger and platelet-activating factor antagonist agents in experimental acute pancreatitis.:

Pancreas. 1999 Aug;19(2):143-9.PMID: 10438161
This study was done to evaluate the possible preventive effects of reactive oxygen species (ROS) scavenger agent desferrioxamine (DFX) and platelet-activating factor (PAF) antagonist agent ginkgo biloba (GB) in an experimental acute pancreatitis model. Seventy-eight CD-1 mice were divided into six groups consisting of 10-13 mice. Induction of pancreatitis was achieved by cerulein injection in groups 2-5. The first group was control, whereas DFX and GB were used alone or in combinations as preventive agents in groups 3-5. DFX or GB were injected to the mice in groups 6 and 7 to evaluate any toxic effect. The assessment of the pancreatic edema and inflammation, the measurement of the amylase and the pancreatic weight and the measurement of the pancreatic tissue oxidative capacity by chemiluminescence method were the parameters to evaluate pancreatitis. Although the results indicate DFX and GB alone or in combinations have significant preventive roles, this was not a complete prevention.

33.Oxidative damage and protection by antioxidants in the frontal cortex of Alzheimer's disease is related to the apolipoprotein E genotype.:

Free Radic Biol Med. 1999 Sep;27(5-6):544-53.PMID: 10490274
A great number of epidemiological studies have demonstrated that the frequency of the epsilon4 allele of the apolipoprotein E gene (APOE) is markedly higher in sporadic and in familial late onset Alzheimer disease (AD). In the frontal cortex of AD patients, oxidative damage is elevated. We address the hypothesis that the APOE genotype and reactive oxygen-mediated damage are linked in the frontal cortex of AD patients. We have related the APOE genotype to the levels of lipid oxidation (LPO) and to the antioxidant status, in frontal cortex tissues from age-matched control and AD cases with different APOE genotypes. LPO levels were significantly elevated in tissues from Alzheimer's cases which are homozygous for the epsilon4 allele of APOE, compared to AD epsilon3/epsilon3 cases and controls. Activities of enzymatic antioxidants, such as catalase and glutathione peroxidase (GSH-PX), were also higher in AD cases with at least one epsilon4 allele of APOE, while superoxide dismutase (SOD) activity was unchanged. In the frontal cortex, the concentration of apoE protein was not different between controls and AD cases, and was genotype independent. The Ginkgo biloba extract (EGb 761), the neurosteroid dehydroepiandrosterone (DHEA) and human recombinant apoE3 (hapoE3rec) were able to protect control, AD epsilon3/epsilon3 and epsilon3/epsilon4 cases against hydrogen peroxide/iron-induced LPO, while hapoE4rec was completely ineffective. Moreover, EGb 761 and DHEA had no effect in homozygous epsilon4 cases. These results demonstrate that oxidative stress-induced injury and protection by antioxidants in the frontal cortex of AD cases are related to the APOE genotype.

34.Inhibitory effect of Ginkgo biloba extract on the expression of inducible nitric oxide synthase in endothelial cells.:

Biochem Pharmacol. 1999 Nov 15;58(10):1665-73.PMID: 10535759
Excessive production of nitric oxide (NO) may have cytotoxic effects through the formation of peroxynitrite with superoxide. The extract of Ginkgo biloba leaves (EGb) has been demonstrated to be a potent scavenger of free radicals. Although EGb has been shown recently to inhibit NO production in macrophages, its effect on NO production in endothelial cells is largely unknown. The objective of this study was to elucidate the mechanism by which EGb affects NO production in a human endothelial cell line (ECV304). After cells were incubated with EGb (10-100 microg/mL) for 2 or 4 hr, the amounts of NO metabolites released by the cells were quantitated, and cellular NOS activities were determined following the conversion of [3H]arginine to [3H]citrulline. NOS protein expression was determined by western immunoblotting analysis. mRNA levels were examined by reverse transcription-polymerase chain reaction (RT-PCR) analysis. EGb (50 microg/mL) caused a 30% reduction of NO metabolites released by endothelial cells. Following EGb treatment, cellular inducible NO synthase (iNOS) activity was reduced by 28% with a concomitant reduction in the levels of iNOS protein mass and mRNA. There was no change in the activity or protein mass of constitutive NO synthase in these cells. EGb inhibited NO production by attenuating the level of iNOS mRNA in ECV304 cells. Selective inhibition of iNOS by EGb may be therapeutically relevant in modulating NO production in endothelial cells.

35.Antioxidants and herbal extracts protect HT-4 neuronal cells against glutamate-induced cytotoxicity.:

Free Radic Res. 2000 Feb;32(2):115-24.PMID: 10653482
Antioxidant therapy has been shown to be beneficial in neurological disorders including Alzheimer's disease and cerebral ischemia. Glutamate-induced cytotoxicity in HT-4 neuronal cells has been previously demonstrated to be due to oxidative stress caused by depletion of cellular glutathione (GSH). The present study demonstrates that a wide variety of antioxidants inhibit glutamate-induced cytotoxicity in HT-4 neuronal cells. Low concentrations of alpha-tocopherol and its analogs were highly effective in protecting neuronal cells against cytotoxicity. Purified flavonoids and herbal extracts of Gingko biloba (EGb 761) and French maritime pine bark (Pycnogenol) were also effective. We have previously shown that pro-glutathione agents can spare GSH and protect cells from glutamate insult in a C6 glial cell model. The protective effects of nonthiol-based antioxidants tested in the HT-4 line were not mediated via GSH level modulation. In contrast, protective effects of thiol-based pro-glutathione agents alpha-lipoic acid (LA) and N-acetyl cysteine (NAC) corresponded with a sparing effect on GSH levels in glutamate-treated HT-4 cells. Glutamate-induced cytotoxicity in HT-4 cells is a useful model system for testing compounds or mixtures for antioxidant activity.

36.Protective and rescuing abilities of IGF-I and some putative free radical scavengers against beta-amyloid-inducing toxicity in neurons.:

Ann N Y Acad Sci. 1999;890:356-64.PMID: 10668442
beta-Amyloid (A beta) peptides are most likely involved in the neurodegenerative process occurring in Alzheimer's Disease (AD) and are enriched in senile plaques. The mechanisms of A beta toxicity are not clear but likely involve free radicals and apoptosis. Much interest is currently aiming at developing effective approaches to block A beta toxicity in order to slow down disease progression. In that context, we are particularly interested in studying the role of insulin-like growth factors, particularly IGF-I and purported free radical scavengers including a Gingko biloba extract (EGb761) as blocker of A beta toxicity in a simple in vitro model of hippocampal primary cultures. We observed that both IGF-I and EGb761 are unique in that they are able not only to protect but even to rescue neurons against A beta toxicity. These results are summarized here and possible mechanisms of action are discussed to explain the protective properties of these two classes of agents.

37.In-vivo and in-vitro assessment of the free-radical-scavenger activity of Ginkgo flavone glycosides at high concentration.:

J Pharm Pharmacol. 1999 Dec;51(12):1435-40.PMID: 10678500
Free radicals are involved in numerous skin diseases, especially inflammatory reactions and photosenescence. To identify possible free-radical scavenging by an original terpene-free Ginkgo biloba extract containing 33% Ginkgo flavone glycosides, mostly quercetin and kaempferol derivatives, we studied its activity by means of in-vitro and in-vivo experiments, using superoxide dismutase (SOD) as a positive control. By means of an in-vitro electron-spin resonance (ESR) assay we compared the activity of the Ginkgo extract with that of its two aglycones, quercetin and kaempferol. Quercetin and Ginkgo extract had significant antioxidant properties without pro-oxidant effect. In contrast, kaempferol, above an optimum antioxidant concentration, behaved as a pro-oxidant. The in-vivo experiments were conducted on an anti-inflammatory model. The cutaneous blood flux which reflects the skin inflammatory level was recorded by means of a laser Doppler perfusion imager. The data confirmed the free-radical-scavenging property of both Ginkgo extract and SOD. The Ginkgo extract significantly inhibited (37%) cutaneous blood flux to the same extent as SOD. These data confirmed the antioxidant property of Ginkgo extract. A complementary spin-trapping technique would enable identification of the free radicals involved. This Ginkgo extract should be useful for protection of the skin against free radicals.

38.Hydrogen peroxide-induced oxidative damage and apoptosis in cerebellar granule cells: protection by Ginkgo biloba extract.:

Pharmacol Res. 2000 Apr;41(4):427-33.PMID: 10704267
The ability of oxidative stress to induce apoptosis and the protective effects of Ginkgo biloba extract (EGb761) against this induction were studied in cultures of rat cerebellar granule cells. Cells were exposed to oxidative stress by treatment with 50 microm hydrogen peroxide+100 microm ferrous sulphate which generates hydroxyl radicals by Fenton reaction. Both morphological observation and biochemical analysis revealed that H(2)O(2)/FeSO(4)treatment induced apoptotic cell death in cerebellar granule cells, which was characterized by chromatin condensation and DNA fragmentation. During this process, the fluidity of the cell membrane decreased markedly, and the conformation of membrane proteins altered significantly. Pretreating cerebellar granule cells with the antioxidant EGb761 (Ginkgo biloba extract) effectively attenuated oxidative damage induced by H(2)O(2)/FeSO(4), and prevented cells from apoptotic cell death. The results suggested that EGb761 might be used as a potential drug for neuronal diseases associated with the excessive production of reactive oxygen species.

39.The Ginkgo biloba extract (EGb 761) protects and rescues hippocampal cells against nitric oxide-induced toxicity: involvement of its flavonoid constituents and protein kinase C.:

J Neurochem. 2000 Jun;74(6):2268-77.PMID: 10820186
An excess of the free radical nitric oxide (NO) is viewed as a deleterious factor involved in various CNS disorders. Numerous studies have shown that the Ginkgo biloba extract EGb 761 is a NO scavenger with neuroprotective properties. However, the mechanisms underlying its neuroprotective ability remain to be fully established. Thus, we investigated the effect of different constituents of EGb 761, i.e., flavonoids and terpenoids, against toxicity induced by NO generators on cells of the hippocampus, a brain area particularly susceptible to neurodegenerative damage. Exposure of rat primary mixed hippocampal cell cultures to either sodium nitroprusside (SNP; 100 microM) or 3-morpholinosydnonimine resulted in both a decrease in cell survival and an increase in free radical accumulation. These SNP-induced events were blocked by either EGb 761 (10-100 microg/ml) or its flavonoid fraction CP 205 (25 microg/ml), as well as by inhibitors of protein kinase C (PKC; chelerythrine) and L-type calcium channels (nitrendipine). In contrast, the terpenoid constituents of EGb 761, known as bilobalide and ginkgolide B, as well as inhibitors of phospholipases A [3-[(4-octadecyl)benzoyl]acrylic acid (OBAA)] and C (U-73122), failed to display any significant effects. Moreover, EGb 761 (50 microm) CP 205 (25 microg/ml), and chelerythrine were also able to rescue hippocampal cells preexposed to SNP (up to 1 mM). Finally, EGb 761 (100 microg/ml) was shown to block the activation of PKC induced by SNP (100 microM). These data suggest that the protective and rescuing abilities of EGb 761 are not only attributable to the antioxidant properties of its flavonoid constituents but also via their ability to inhibit NO-stimulated PKC activity.

40.Mitochondrial oxidative stress plays a key role in aging and apoptosis.:

41.Mechanisms of apoptosis in rat cerebellar granule cells induced by hydroxyl radicals and the effects of EGb761 and its constituents.:

Toxicology. 2000 Aug 7;148(2-3):103-10.PMID: 10962128
In this study investigation is made on whether oxidative stress produced by treatment with hydroxyl radicals can induce apoptosis in rat cerebellar granule cells. The protective effects of Ginkgo biloba extract (EGb761) and its active constituents against apoptosis are also examined. The results show that hydroxyl radicals generated by the Fenton reaction induced apoptosis in cerebellar granule cells, which was associated with the decrease in the Bcl-2 mRNA level and the increase in the protein levels of the transcription factors Fos and Jun. Moreover, hydroxyl radicals induced time-dependent lipid peroxidation in cells and caused the changes in the sulfhydryl group binding sites on the membrane proteins. Hydroxyl radicals may induce apoptosis via different signaling pathways. EGb761 attenuated these changes and its different constituents showed different effects. The total flavonoid component of EGb761 and a mixture of flavonoids and terpenes protected cerebellar granule cells from oxidative damage and apoptosis induced by hydroxyl radicals. Total terpenes of EGb761 did not protect against apoptosis. Flavonoids and terpenes did not show a synergistic effect in this regard.

42.Effect of the extract of Ginkgo biloba (EGb 761) on the circulating and cellular profiles of polyunsaturated fatty acids: correlation with the anti-oxidant properties of the extract.:

Prostaglandins Leukot Essent Fatty Acids. 2000 Nov;63(5):293-300.PMID: 11090256
Ginkgo biloba extract (EGb 761) has beneficial effects on cognitive functions in aging patients, and on various pathologies, including cardiovascular diseases. Although the extract is known to have antioxidant properties and improve membrane fluidity, the cellular mechanisms underlying these effects have not been determined. Here, we examined the in vivo effects of EGb 761 on circulating and cellular lipids. EGb 761 treatment induced significant increases in the levels of circulating polyunsaturated fatty acids (PUFAs), and a decrease in the saturation index SI (saturated/polyunsaturated species). Plasma triglycerides and cholesterol were not affected, while phospholipids were slightly increased at the higher dose of EGb 761. EGb 761 treatment also induced a significant increase in the levels of PUFAs in erythrocyte membranes, especially for the eicosapentaenoic acid (EPA omega 3), and a decrease in the saturation index. Moreover, the response of erythrocytes to oxidative stress was improved in EGb 761-treated animals (H(2)O(2)-induced cell lysis decreased by 50%). Considering that PUFAs are known to improve membrane fluidity and response to oxidative damage, and are precursors of signaling molecules such as prostaglandins, the effects of EGb 761 on circulating and cellular PUFAs may explain some of the pharmacological properties of Ginkgo biloba.

43.Induction of heme oxygenase-1 by Ginkgo biloba extract but not its terpenoids partially mediated its protective effect against lysophosphatidylcholine-induced damage.:

Pharmacol Res. 2001 Jan;43(1):63-9.PMID: 11207067
In this study, we examined whether Ginkgo Biloba Extract and its terpenoid constituents protect against oxidative stress through actions on heme oxygenase (HO) gene expression and activity. HO-1 and glutathione peroxidase (GPx) gene expressions were examined by reverse transcription polymerase chain reaction (RT-PCR) analysis, HO activity and GPx enzyme activity were analysed by spectrophotometric assay. Pretreatment of H9c2 myocytes with 100-500 microgml(-1)Ginkgo Biloba Extract caused induction of HO-1 gene expression and a significant increase in HO activity; 30 microgml(-1)ginkgolide B and 30 microgml(-1)bilobalide had little effect. Treatment with Ginkgo Biloba Extract for 24 h also significantly increased GPx gene expression and GPx enzyme activity. Pretreatment with Ginkgo Biloba Extract, ginkgolide B and bilobalide protected myocytes against lysophosphatidylcholine (LPC)-induced damage. The protective effect of Ginkgo Biloba Extract against LPC-induced damage was partially suppressed by a HO inhibitor, Zinc protoporphyrin-IX (ZnPP-IX), while ZnPP-IX did not suppress the protective effect of ginkgolide B or bilobalide. Furthermore, pretreatment with hemin, biliverdin or bilirubin reduced cytotoxicity induced by LPC. These results suggest that induction of HO-1 by Ginkgo Biloba Extract but not its terpenoid constituents may play a beneficial role in oxidative stress. The mechanism of Ginkgo Biloba Extract-induced HO-1 gene expression and the increase in HO activity may be related to alteration of intracellular glutathione levels.

44.Inhibition by ginkgolides and bilobalide of the production of nitric oxide in macrophages (THP-1) but not in endothelial cells (HUVEC).:

Biochem Pharmacol. 2001 Feb 15;61(4):503-10.PMID: 11226385
Nitric oxide (NO) is a principal mediator in many physiological and pathological processes. NO produced by constitutive nitric oxide synthase in endothelial cells (eNOS) acts as a vasodilator, whereas excess NO production due to elevated expression of inducible nitric oxide synthase (iNOS) may produce cytotoxic effects to cells in the vascular wall. We demonstrated in our previous work that the extract of Ginkgo biloba leaves (EGb) inhibits iNOS-mediated NO production. The objective of the present study was to investigate the effects of several active EGb components on iNOS-mediated NO production in macrophages derived from a human monocytic cell line (THP-1), as well as on eNOS-mediated NO production in human umbilical vein endothelial cells (HUVEC). Ginkgolide A, ginkgolide B, or bilobalide (0.25 to 1.0 microg/mL) caused a 30-65% reduction in the levels of NO metabolites released by THP-1 macrophages after 4 hr of incubation, with a corresponding decrease in iNOS activity. Western immunoblotting analysis coupled with a nuclease protection assay and reverse transcription-polymerase chain reaction revealed a concomitant reduction in the levels of iNOS protein mass and mRNA in ginkgolide A-, ginkgolide B-, or bilobalide-treated macrophages. On the other hand, these compounds did not affect eNOS-mediated NO production or the expression of eNOS protein and mRNA in HUVEC. Taken together, these results suggest that ginkgolide A, ginkgolide B, and bilobalide may contribute to the selective inhibitory effect of EGb on iNOS expression without affecting eNOS-mediated NO production.

45.Ginkgo biloba leaf extract: review of biological actions and clinical applications.:

Antioxid Redox Signal. 1999 Winter;1(4):469-80.PMID: 11233145
The number of studies on Ginkgo biloba leaves is rapidly increasing. A variety of effects of Ginkgo biloba leaf extract (GBLE) have been identified. GBLE contains many different flavone glycosides and terpenoides. GBLE has an antioxidant action as a free radical scavenger, a relaxing effect on vascular walls, an antagonistic action on platelet-activating factor, an improving effect on blood flow or microcirculation, and a stimulating effect on neurotransmitters. Besides a direct scavenging action on active oxygen species, GBLE exerts an anti-inflammatory effect on inflammatory cells by suppressing the production of active oxygen and nitrogen species. GBLE inhibited the increase in the products of the oxidative decomposition low-density lipoprotein (LDL), reduced the cell death in various types of neuropathy, and prevented the oxidative damage to mitochondria, suggesting that GBLE exhibits beneficial effects on neuron degenerative diseases by preventing chronic oxidative damage. The study using a model of ischemia-reperfusion injury has also demonstrated the protective effect of GBLE on cardiac muscle and its antioxidative action in vivo. Favorable results have been obtained in double-blind, placebo-controlled, comparative trials of patients with memory disorders, obstructive arteriosclerosis, and dementia. We review the recent studies on GBLE with respect to its various pharmacological actions, such as a scavenging activity on free radicals and an inhibitory action on lipid peroxidation. GBLE shows a very strong scavenging action on free radicals, and is thus considered to be useful for the treatment of diseases related to the production of free radicals, such as ischemic heart disease, cerebral infarction, chronic inflammation, and aging.

46.The effect of ginkgo biloba extract on free radical production in hypoxic rats.:

Biol Pharm Bull. 2001 Jun;24(6):710-2.PMID: 11411566
In the present study, we assayed the antioxidant properties of Ginkgo biloba (Gb) extract on rats submitted to 21 d of chronic hypoxia. Doses of 25 and 50 mg/kg were examined. Oxygenated free radical production measured by the chemiluminescence technique was significantly decreased in treated rats compared to control rats placed in similar experimental conditions, and this effect was more significant at the 50 mg/kg dose. On the other hand, no antioxidant enzyme activities of the drug were observed towards red blood cells. These results suggest that ginkgo biloba extract has a free radical scavenging action. These antioxidant properties could explain the beneficial hematological properties of Gb extract.

47.The antioxidant activity of standardized extract of Ginkgo biloba (EGb 761) in rats.:

Phytother Res. 2001 Aug;15(5):449-51.PMID: 11507743
The standardized extract of Ginkgo biloba (EGb 761) has been widely employed for its significant benefit in neurodegenerative disorders. Although antioxidative actions have been attributed to this extract, the mechanisms of the multiple principles involved in this pharmacological activity are not completely established. Parkinson's and Alzheimer's diseases are frequently associated with oxidative stress and defects in the cellular protective mechanisms. In this study, the lipid peroxidation (LPO) and the activity of the antioxidant enzymes, catalase (CAT) and superoxide dismutase (SOD) were evaluated in the hippocampus, striatum and substantia nigra (SN) of rats treated with EGb 761. An increase in the CAT and SOD activities in the hippocampus, striatum and SN, and a decrease of the LPO in the hippocampus were observed. These data are additional to the antioxidant properties of EGb 761 reported in the literature and indicate a possible role for the extract in the treatment of diseases involving free radicals and oxidative damage.

48.Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced release of nitric oxide.:

Chem Biol Interact. 2001 Jul 31;137(1):43-58.PMID: 11518563
Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages is known to induce the production of nitric oxide (NO) from inducible nitric oxide synthase (iNOS). Here we show that pre-treatment with Ginkgo biloba extract (EGb 761) suppresses the in vivo production of NO (measured by the Griess reaction) after challenge with LPS. In order to begin to understand the mechanism of this inhibition, we evaluated in vitro effects of EGb 761 and its flavonoid component, quercetin, on LPS-treated RAW 264.7 macrophages. Pre-treatment with EGb 761 or quercetin dose-dependently inhibited NO release. Both substances scavenged NO generated from the decomposition of sodium nitroprusside. Western analysis showed that EGb 761 and quercetin inhibited LPS-induced levels of iNOS protein. Northern blotting demonstrated that EGb 761 and quercetin decreased LPS-induced iNOS mRNA levels without altering the half-life. Activation of mitogen activated protein kinases (MAPKs) and the redox-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1) are key events in the signal transduction pathways mediating iNOS induction. In our studies, both EGb 761 and quercetin inhibited p38 MAPK activity, which is necessary for iNOS expression in LPS-stimulated RAW 264.7 macrophages. However, differences in the response of NF-kappaB, AP-1, and Jun N-terminal kinase/stress activated protein kinase (JNK/SAPK) and its downstream substrates to EGb 761 and quercetin suggest that quercetin is not the sole component responsible for the in vivo inhibition of LPS-induced iNOS activation by EGb 761.

49.Protective effects of extract of Ginkgo biloba (EGb) on lysophosphatidylcholine induced damages of vascular endothelial cells in vitro:

Yao Xue Xue Bao. 1997 Oct;32(10):735-9.PMID: 11596214
Effects of EGb on cultured bovine aortic endothelial cells (BAEC) damaged by lysophosphatidylcholine (LPC) were investigated. When endothelial cells were incubated with LPC (2.5 micrograms.ml-1) for 24 h, the endothelial cells turned round pyknotic, exfoliated and broken, and the contents of malondialdehyde (MDA), lactate dehydrogenase (LDH) and plasminogen activator inhibitor (PAI) were markedly increased and the superoxide dismutase (SOD) activity was inhibited. Treatment with EGb at concentrations of 125 and 250 micrograms.ml-1, caused a reduction in MDA, LDH and PAI contents, while the SOD activity in the medium was increased and the morphologically damaged BAECs were alleviated. These results suggest that EGb afforded protection against BAECs damages induced by LPC and that the protective effect of EGb may be due to anti-lipid peroxidation via free-radical scavenging activity.

50.Antioxidant activity and phenolic compounds in selected herbs.:

J Agric Food Chem. 2001 Nov;49(11):5165-70.PMID: 11714298
The antioxidant capacities (oxygen radical absorbance capacity, ORAC) and total phenolic contents in extracts of 27 culinary herbs and 12 medicinal herbs were determined. The ORAC values and total phenolic contents for the medicinal herbs ranged from 1.88 to 22.30 micromol of Trolox equivalents (TE)/g of fresh weight and 0.23 to 2.85 mg of gallic acid equivalents (GAE)/g of fresh weight, respectively. Origanum x majoricum, O. vulgare ssp. hirtum, and Poliomintha longiflora have higher ORAC and phenolic contents as compared to other culinary herbs. The ORAC values and total phenolic content for the culinary herbs ranged from 2.35 to 92.18 micromol of TE/g of fresh weight and 0.26 to 17.51 mg of GAE/g of fresh weight, respectively. These also were much higher than values found in the medicinal herbs. The medicinal herbs with the highest ORAC values were Catharanthus roseus, Thymus vulgaris, Hypericum perforatum, and Artemisia annua. A linear relationship existed between ORAC values and total phenolic contents of the medicinal herbs (R = 0.919) and culinary herbs (R = 0.986). High-performance liquid chromatography (HPLC) coupled with diode-array detection was used to identify and quantify the phenolic compounds in selected herbs. Among the identified phenolic compounds, rosmarinic acid was the predominant phenolic compound in Salvia officinalis, Thymus vulgaris, Origanum x majoricum, and P. longiflora, whereas quercetin-3-O-rhamnosyl-(1 --> 2)-rhamnosyl-(1 --> 6)-glucoside and kaempferol-3-O-rhamnosyl-(1 --> 2)-rhamnosyl-(1 --> 6)-glucoside were predominant phenolic compounds in Ginkgo biloba leaves.

51.EGb761 blocks MPP+-induced lipid peroxidation in mouse corpus striatum.:

Neurochem Res. 2001 Nov;26(11):1245-51.PMID: 11874207
EGb761 has been suggested to be an antioxidant and free radical scavenger. Excess generation of free radicals, leading to lipid peroxidation (LP), has been proposed to play a role in the damage to striatal neurons induced by 1-methyl-4-phenylpyridinium (MPP+). We investigated the effects of EGb761 pretreatment on MPP+ neurotoxicity. C-57 black mice were pretreated with EGb761 for 17 days at different doses (0.63, 1.25, 2.5, 5 or 10 mg/kg) followed by administration of MPP+, (0.18, 0.36 or 0.72 mg/kg). LP was analyzed in corpus striatum at 30 min, 1 h, 2 h and 24 h after MPP+ administration. Striatal dopamine content was analyzed by HPLC at the highest EGb761 dose at 2 h and 24 h after MPP+ administration. MPP+-induced LP was blocked (100%) by EGb761 (10 mg/kg). Pretreatment with EGb761 partially prevented (32%) the dopamine-depleting effect of MPP+ at 24 h. These results suggest that supplements of EGb761 may be effective at preventing MPP+-induced oxidative stress.

52.Ginkgo biloba extracts EGb 761 and bilobalide increase NADH dehydrogenase mRNA level and mitochondrial respiratory control ratio in PC12 cells.:

Neurochem Res. 2002 Apr;27(4):319-23.PMID: 11958534
In the present study, we investigated the effect of Ginkgo biloba extract, EGb 761, and one of its components, bilobalide, on gene expression of subunit 1 of mitochondrial NADH dehydrogenase (ND1) in PC12 cells. By Northern blot analysis we found a approximately 2-fold significant increase in NDI mRNA level, after 48 and 72 h exposure to 100 microg/ml EGb 761 and to 10 microg/ml bilobalide. We also evaluated, by oxygraphy measurements, mitochondrial respiration during state 3 and state 4. In cells treated with EGb 761 and bilobalide for 48 and 72 h, state 4 respiration was significantly decreased, and the respiratory control ratio was increased. These results provide evidence that EGb 761 and bilobalide exert their protective effects by up-regulating mitochondrial ND1 gene expression and by decreasing state 4 respiration, whose increase is thought to be responsible for oxidative damage.

53.Bioflavonoid-rich botanical extracts show antioxidant and gene regulatory activity.:

Ann N Y Acad Sci. 2002 May;957:70-7.PMID: 12074962
Reactive oxygen and nitrogen metabolites are obligatory and essential products of metabolism. Unregulated increase in their production is associated with a number of chronic illnesses. Diets rich in fruits, vegetables, and wines are implicated in the prevention of chronic diseases. Molecular mechanisms by which fruits and vegetables confer their disease-preventive actions are poorly defined. However, recent developments in the fields of genomics and bioinformatics provide powerful tools to investigate the mechanisms by which botanicals affect cellular functions. This monograph illustrates the potential of large-scale messenger RNA analysis to unravel the role of transcription in mediating the effects of botanical extracts with antioxidant properties. The application of microarrays and oligonucleotide arrays shows multiple effects of antioxidant extracts on the expression of a broad spectrum of genes.

54.Induction of heme oxygenase 1 by Ginkgo biloba in neuronal cultures and potential implications in ischemia.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):647-53.PMID: 12396075
Ginkgo biloba extract (EGb 761) is a standardized extract originating in traditional Chinese medicine. Ginkgo biloba dried leaves have been used for centuries to treat various neurological conditions. The constituents from the extract are likely to have synergistic effects that have been shown to be protective against oxidative stress injury. However, the cellular mechanisms of protection afforded by Ginkgo biloba are still unclear. The cascade leading to neuronal cell death in acute and chronic neurodegenerative conditions, such as cerebral ischemia and Alzheimer's disease, has been postulated to be mediated by free radical damage. We tested the hypothesis that the neuroprotective action of EGb 761 could be due partially to an induction of heme oxygenase I (HO1). We and others have previously reported that modulation of HO total activity may well have direct physiological implications in stroke and in Alzheimer's disease. Heme oxygenase acts as an antioxidant enzyme by degrading heme into iron, carbon monoxide, and biliverdin which is rapidly converted into bilirubin. Through the use of primary neuronal cultures, we demonstrated that EGb 761 induces HO1 in a dose-dependent manner (0, 10, 50, 100 and 500 microg/ml) and time-dependent manner with a maximal induction at 8 hr. We are proposing that several of the protective effects of EGb 761 in ischemia could be mediated through beneficial actions of heme degradation and its metabolites.

55.Protective effect of ginkgo biloba extract on endothelial cell against damage induced by oxidative stress.:

J Cardiovasc Pharmacol. 2002 Dec;40(6):809-14.PMID: 12451313
The viability of bovine aortic endothelial cells (BAECs) treated with 0.1 m H O was decreased by 39.8%, and 100 mg/l EGb761 increased the viability by 20.6%. Exposure BAECs to H O for 6 min resulted in a significant elevation in the intracellular free Ca. Pretreatment of BAECs with 10 mg/l and 100 mg/l EGb761 for 10 min showed a decrease in the intracellular free Ca, 4.5% and 20.6%, respectively. The apoptotic rate of BAECs measured by propidium iodide (PI) staining was (38.1 +/- 2%) after 18 h of treatment with H O. Pretreatment of BAECs with 100 mg/l EGb761 for 1 h reduced the apoptotic rate to 27 +/- 1%. In addition, there were about 5-7% of cells stained positive measured by TUNEL assay. When BAECs were exposed to 0.1 m H O for 18 h, the number of TUNEL-positive cells increased to 37-44%. When 10 mg/l EGb761 and 100 mg/l EGb761 were used, the TUNEL-positive cells decreased to 26.5 +/- 3.1% and 17.5 +/- 1.7%, respectively. Furthermore, EGb761 also inhibited caspase-3 activity induced by H O. It is concluded that EGb761 has protective effect on bovine vascular endothelial cells against damage induced by H O. Further studies are needed to clarify the mechanisms of action of EGb761.

56.Standardized extracts of flavonoids increase the viability of PC12 cells treated with hydrogen peroxide: effects on oxidative injury.:

Arch Toxicol. 2003 Jan;77(1):22-9. Epub 2002 Oct 16.PMID: 12491037
Oxidative stress plays an important role in cell death associated with many diseases. In the present study, concentration-dependence of hydrogen peroxide on rat pheochromocytoma (PC12) cell viability was studied. Preventive effects of antioxidants on the viability of these cells treated with 2 mM hydrogen peroxide were compared. Trolox and Stobadine, as chain-breaking antioxidants were studied in comparison with standardized extracts of flavonoids of Ginkgo biloba and Pycnogenol, known as agents effective in several diseases. All antioxidants increased the viability of hydrogen peroxide-treated PC12 cells. Flavonoid extracts were more effective than Trolox and Stobadine. Antioxidants were most effective if present after the oxidative treatment. As expected, the preloading with antioxidants was without effect on cell viability. Correlations between viability increase induced by antioxidants, and content of oxidation products of proteins and lipids were studied at concentrations of antioxidants mostly effective in preventing cell death: Trolox (10 microM), Stobadine (30 microM), Ginkgo biloba (160 microg/ml), Pycnogenol (100 microg/ml). In these concentrations, antioxidants did not statistically significantly decrease the content of protein carbonyls, with exception of Stobadine, which had no effect. Ginkgo biloba, Trolox and Stobadine intensively decreased the content of malondialdehyde, a product of lipid peroxidation. Pycnogenol was without any preventive effect. Concentrations of antioxidants with a large effect on viability of PC12 cells were not effective in preventing oxygen radical-induced injury of proteins. Antioxidants prevented the oxidative injury of lipids more effectively than that of proteins.

57.Effect of folium ginkgo extract on the erythrocyte immunity function and serum lipid peroxide in asphyxia neonate:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2002 Apr;22(4):267-9.PMID: 12584787
OBJECTIVE: To observe the changes of erythrocyte immunity and serum lipid peroxide in asphyxia neonate, and to study the effect of Folium Ginkgo extract (FGE) on them.METHODS: Thirty asphyxia neonates were randomly divided into 2 groups, the treated group and the control group, 15 in each group. Erythrocyte C3b receptor rosette rate (E-C3bRR), erythrocyte immune complex rosette rate (E-ICR), blood superoxide dismutase (SOD) activity and serum lipid peroxide (LPO) level were determined at 24 hrs after birth. Conventional treatment was given to both groups and FGE (15 mg/kg.d) was given to the treated group additionally for 7-8 days, then the above-mentioned parameters were re-examined and neonatal behavioral neurological assessment (NBNA) was measured as well.RESULTS: E-C3bRR and SOD lowered, E-ICR and serum LPO increased in the asphyxia neonate significantly (P < 0.05). After treatment, comparison between the two groups showed that E-C3bRR and SOD were higher, E-ICR and serum LPO were lower in the treated group than those in the control group, and NBNA scoring was obviously higher in the former than that in the latter (all P < 0.05).CONCLUSION: Decrease of erythrocyte immunity in asphyxia neonate is related to the declined anti-oxidation ability and lipid peroxidase injury. FGE could suppress the free radical production, scavenge free radicals, antagonize the lipid peroxidation injury of cell membrane and up-regulate erythrocyte immunity. It displays the effects of nerve tissue protection and hypoxia-ischemic brain injury alleviation

58.Investigation of the free radical scavenging activity of Ginkgo biloba L. leaves.:

Fitoterapia. 2003 Feb;74(1-2):1-6.PMID: 12628386
The free radical scavenging activity of methanolic, ethanolic and aqueous extracts from Ginkgo biloba leaves, has been determined by EPR (electron paramagnetic resonance) using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical scavenging method. The investigation has also included selected constituents of G. biloba leaves, protocatechuic and p-coumaric acids, quercetin, rutin, isoginkgetin and (+)-catechin.

59.Comparison study on total flavonoid content and anti-free redical activity of the leaves of bamboo, phyllostachys nigra, and Ginkgo bilabo:

Zhongguo Zhong Yao Za Zhi. 2002 Apr;27(4):254-7, 320.PMID: 12774365
OBJECTIVE: To investigate the differences of total flavonoid (TF) content and antifree radical activity between the-leaves of bamboo and Gingo biloba, as well as their seasonal changes.METHOD: Spectrophotometery and Chemiluminescence methods were adopted to determine TF and half inhibiting concentration (IC50) on active oxygen free radicals of the leaves of bamboo, phyllostachys nigra (Lodd. ex. Lindl.) Munro, and Ginkgo biloba. Two kinds of leaves were picked in the same plot at the same time monthly.RESULT: The TF of bamboo leaf varied in the range of 0.67%-1.71% (in dry basis of leaf, below as same) throughout a year, the minimum apparing in June and the maximum in July, then going down obviously, and remaining at a much high lever during November to next April. However, the TF of Ginkgo bilabo leaf varied in 1.48%-2.49% during whole growing period, early April to late November. It ascended with the growth of leaf, reaching the top during June and July, the going down slowly, and finally another peak appeared before defoliation. The average IC50 values on O2-. and .OH of bamboo leaf were at 11.0 micrograms.mL-1 and 5.3 mg.mL-1, and Ginkgo biloba at 19.0 micrograms.mL-1 and 3.6 mg.mL-1, respectively.CONCLUSION: The TF content and anti-free radical activity the bamboo leaf are comparable with the leaf of ginkgo biloba, which is a kind of potential resources for natural antioxidant and free radical scavenger.

60.Effects of estradiol, phytoestrogens, and Ginkgo biloba extracts against 1-methyl-4-phenyl-pyridine-induced oxidative stress.:

Endocrine. 2003 Jun;21(1):89-95.PMID: 12777708
Oxidative stress has been recently considered as a mediator of nerve cell death in several neurodegenerative diseases. We studied the effect of the parkinsonism-inducing toxine 1-methyl-4-phenyl-pyridine (MPP+) on several parameters of cell distress using native and neuronal PC12 cells. Then, since estrogens have been reported to prevent neuronal degeneration caused by oxidative damage, we investigated the ability of 17beta- estradiol (E2); two Ginkgo biloba extracts, EGb 761 and Cp 202; as well as two flavonoids, quercetin and kaempferol, to rescue PC12 cells submitted to MPP+- induced oxidative stress. Our results consistently show that both Ginkgo biloba extracts could prevent cell death in native and neuronal PC12 cells, while in neuronal PC12 cells also quercetin and E2 could reverse MPP+ neurotoxic effet. Western blot analysis demonstrated that MPP+ injuries might modulate dopamine transporter (DAT) protein expression but not estrogen receptor beta (ERbeta) protein expression. EGb 761 and Cp 202 also modulate DAT and ERbeta protein expression in neuronal cells. From these studies, we outline the importance of testing estrogen-like plant-derived molecules as potent antioxidants and examine their effect on protein expression.

61.Comparison of antioxidant activity in commercial Ginkgo biloba preparations.:

J Altern Complement Med. 2003 Oct;9(5):625-9.PMID: 14629840
AIM: To compare the relative levels of antioxidant activity in vitro in Ginkgo biloba samples (in tablet or capsule form) from different commercial suppliers, to determine whether some brands may be more efficacious in their potential to increase endogenous antioxidant activity, and thereby counter oxidative stress related disorders.DESIGN: Antioxidant activity of the above sample extracts was determined in vitro against the ABTS.(+) (2-2'-amino-bis-3-ethylbenzthiazoline-6-sulfonic acid) radical, relative to Trolox (water-soluble vitamin E analogue) antioxidant standards, using an established assay procedure.OUTCOME MEASURES: The relative antioxidant activity of G. biloba sample extracts was expressed in terms of millimoles per liter of Trolox equivalent (TE) for the initial extract, micromol TE per whole tablet, nmol TE per mg tablet, and nmol TE per mg ginkgo content.RESULTS: Data (as mean +/- standard deviation (SD) from 4 separate estimations) obtained in this study showed a considerable variation (approximately 50-fold) in the level of antioxidant activity in preparations from different suppliers, particularly when compared on an equivalent (i.e., nmol TE/mg ginkgo) basis. Of the 18 products investigated, the highest level of antioxidant activity (whether expressed as micromol TE per whole tablet or nmol TE/mg ginkgo) was obtained for Pharma Nord Bio-Biloba (Pharma Nord, Morpeth, UK) tablets (p < 0.05, Dunnett's statistical test).CONCLUSIONS: Some of the apparent variation in antioxidant activity of the various products investigated can be accounted for in terms of the physical nature of the G. biloba (i.e., dried leaf powder or standardized concentrated extract) used in tablet formulation. However, even when comparing products based on concentrated extract, the data demonstrated that there is still a considerable variation in antioxidant activity. Presumably this may result from differences in the manufacturing process between suppliers, which in turn may limit the efficacy of these preparations in the prevention or treatment of disease.

62.Ginkgo biloba prevents mobile phone-induced oxidative stress in rat brain.:

Clin Chim Acta. 2004 Feb;340(1-2):153-62.PMID: 14734207
BACKGROUND: The widespread use of mobile phones (MP) in recent years has raised the research activities in many countries to determine the consequences of exposure to the low-intensity electromagnetic radiation (EMR) of mobile phones. Since several experimental studies suggest a role of reactive oxygen species (ROS) in EMR-induced oxidative damage in tissues, in this study, we investigated the effect of Ginkgo biloba (Gb) on MP-induced oxidative damage in brain tissue of rats.METHODS: Rats (EMR+) were exposed to 900 MHz EMR from MP for 7 days (1 h/day). In the EMR+Gb groups, rats were exposed to EMR and pretreated with Gb. Control and Gb-administrated groups were produced by turning off the mobile phone while the animals were in the same exposure conditions. Subsequently, oxidative stress markers and pathological changes in brain tissue were examined for each groups.RESULTS: Oxidative damage was evident by the: (i) increase in malondialdehyde (MDA) and nitric oxide (NO) levels in brain tissue, (ii) decrease in brain superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activities and (iii) increase in brain xanthine oxidase (XO) and adenosine deaminase (ADA) activities. These alterations were prevented by Gb treatment. Furthermore, Gb prevented the MP-induced cellular injury in brain tissue histopathologically.CONCLUSION: Reactive oxygen species may play a role in the mechanism that has been proposed to explain the biological side effects of MP, and Gb prevents the MP-induced oxidative stress to preserve antioxidant enzymes activity in brain tissue.

63.Experimental studies of Panax notoginseng saponines and Ginkgo biloba extracts on preventing acute oxygen toxicity:

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2004 May;20(2):201-4.PMID: 21166216
AIM: To investigate the preventive effects of Panax notoginseng saponines (PNS) and Ginkgo biloba extracts (GbE) on acute oxygen toxicity and the possible mechanisms.METHODS: Mice were injected intraperitoneally with PNS and GbE for 5 days, then were exposed to 500 kPa hyperbaric oxygen (HBO) for 60 min, the convulsion latency, times and interval were observed. Moreover, reactive oxygen (RO) unit, MDA, NO, GSH levels and GSH-Px, CAT, MAO activities of mice brain were determined after they were exposed to HBO for 15 min.RESULTS: PNS and GbE could markedly prolong the convulsion latency and interval, reduce convulsion times, decrease contents of MDA and NO in mice brain, keep RO unit, GSH and GSH-Px at higher levels, but had no effects on CAT and MAO activities.CONCLUSION: PNS and GbE could effectively prevent acute oxygen toxicity, which were related to their antioxidant activities.

64.The leaf extract of Ginkgo Biloba L. suppresses oxidized LDL-stimulated fibronectin production through an antioxidant action in rat mesangial cells.:

Br J Pharmacol. 2004 Jun;142(3):419-24. Epub 2004 May 17.PMID: 15148252
1 The leaf extract of Ginkgo Biloba L. exhibits a variety of pharmacological effects through an antioxidant action. We examined the effects of the leaf extract (Ginkgolon-24) on the production of fibronectin induced by oxidized low-density lipoprotein (oxLDL) in rat mesangial cells. 2 Stimulation with oxLDL accelerated the production of fibronectin with the preceding generation of reactive oxygen species (ROS). Pretreatment with Ginkgolon-24 inhibited the oxLDL-induced fibronectin production as well as ROS generation. 3 oxLDL also elicited the activation of SP-1, nuclear factor-kappaB, and cAMP response element-binding protein, which are transcription factors involved in the fibronectin production. Among these activated transcription factors, Ginkgolon-24 inhibited the activation of SP-1 only. 4 Furthermore, 7-ketocholesterol, an oxidized lipid in oxLDL particles, induced the production of fibronectin and the activation of SP-1, which were also suppressed by Ginkgolon-24. 5 These results suggest that the leaf extract of Ginkgo Biloba L. inhibits the oxLDL-induced production of fibronectin probably through inhibitory effects on ROS generation and SP-1 activation in rat mesangial cells.

65.The evaluation of nitric oxide scavenging activity of certain herbal formulations in vitro: a preliminary study.:

Phytother Res. 2004 Jul;18(7):561-5.PMID: 15305317
The nitric oxide (NO) scavenging activities of traditional polyherbal drugs like abana, chyavanaprasha, geriforte, septilin, mentat and triphala were examined using sodium nitroprusside as a NO donor in vitro. All the drugs tested demonstrated direct scavenging of NO and were superior to Gingko biloba, which was used as a positive control. The extracts of various polyherbal drugs exhibited dose-dependent NO scavenging activities and the potency was in the following order: abana > chyavanaprasha > triphala > geriforte > septilin > mentat > Gingko biloba. The present results suggest that the traditional Indian polyherbal crude drugs may be potent and novel therapeutic agents for scavenging of NO, and thereby inhibit the pathological conditions caused by excessive generation of NO and its oxidation product, peroxynitrite. These findings may also help to explain, at least in part, the pharmacological activities like rejuvenating, adaptogenic, anti-infection, anti-inflammatory, cardioprotective and neuroprotective activities of these traditional, clinically used non toxic drugs.

66.Effect of Ginkgo biloba L leaves on oxidation of human low density lipoproteins in vitro:

Wei Sheng Yan Jiu. 2004 Jul;33(4):453-4, 2 p following 520.PMID: 15461274
OBJECTIVE: To study the effects of Ginkgo biloba L leave on oxidation of human low density lipoproteins (LDL) induced by Fe2+ or Cu2+ in vitro.METHODS: LDL was oxidized by Fe2+ or Cu2+ for 1, 2, 4, 6h, while it was protected by extracts from leaves of Ginkgo biloba L. ( EGB761), ginkgo flavonids(GF) and ginkgo terpenlactones (GT). Lipofusion (LF), malondialdehyde (MDA) and vitamin E (VitE) were measured as the index of the oxidation of LDL by means of Fluorescence spectroscopy methods.RESULTS: Each extract can inhibit the oxidation of LDL, the inhibition of each extract is increasing during the first 4 hours and subsequently decrease, after 6 hours all the inhibitor have almost lost their ability on antioxidation.CONCLUSION: EGB761, GF and GT are effective antioxidant and the anti-oxidation vary with time.

67.Antioxidant effect of EGb 761 on hydrogen peroxide-induced lipoperoxidation of G-6-PD deficient erythrocytes.:

Phytother Res. 2004 Oct;18(10):837-40.PMID: 15551377
In order to reduce the haemolytic susceptibility of glucose-6-phosphate dehydrogenase (G-6-PD) deficient erythrocytes, Ginkgo biloba extract (EGb 761) and vitamin E (vit E) were used as antioxidant agents and their effects compared. The erythrocyte suspensions from control and G-6-PD deficient patients were subjected to hydrogen peroxide (H2O2) incubation for 1 h. The produced thiobarbituric acid reactive substance (TBARS) levels measured as nmol/g Hb were compared with those of the erythrocytes administered 250 microg/mL EGb 761 or vit E previously or concomitantly with H2O2. Preincubation with EGb 761 reduced the TBARS levels from 317.14 +/- 25.27 to 160.09 +/- 21.97 nmol/g Hb in controls and from 348.24 +/- 7.79 to 205.60 +/- 14.22 nmol/g Hb in deficient erythrocytes. Concomitant application of EGb 761 with H2O2 resulted in similar but less reduction. The antioxidative effects of vitamin E were comparable to those of EGb 761. Contrary to the results obtained from oxidant conditions, the antioxidant characteristics of EGb 761 and vitamin E were not observed when they were applied directly to the erythrocytes without oxidative stress. The findings demonstrate that irrespective of administration time, EGb 761 significantly reduced TBARS levels in the erythrocytes of control and G-6-PD deficient patients subjected to oxidative stress.

68.Effect of nitric oxide and plant antioxidants on microsomal content of lipid radicals.:

Biol Res. 2000;33(2):159-65.PMID: 15693283
The antioxidant ability of nitric oxide (NO) generated by a chemical donor and of commercially available antioxidant preparations was assayed. SNAP (S-Nitroso-N-acetylpenicilamine) was used as the NO donor, and Ginkgo biloba, wheat and alfalfa preparations were tested. Lipid peroxidation was assayed by EPR employing a reaction system consisting of rat liver microsomes, ADP, FeCl3, NADPH and POBN in phosphate buffer, pH=7.4. In vitro NO exposure decreased microsomal lipid peroxidation in a dose-dependent manner. The dose responsible for inhibiting the microsomal content of lipid radical adducts by 50% (LD50) for SNAP was 550 microM (NO generation rate 0.1 microM/min). The addition of 50 microM hemoglobin to the incubation media prevented NO effect on lipid peroxidation. The addition of an amount of the antioxidant preparations equivalent to the LD50 doses inhibited lipid peroxidation by 21, 15, and 33% for wheat, alfalfa, ginkgo biloba preparations respectively in the presence of 550 microM SNAP. We detected a decrease in the content of lipid radical adducts after simultaneous supplementation, although it was less than 50%, even when LD50 doses of the products were added. This suggests that NO and the natural antioxidants inhibit lipid peroxidation by a mechanism that has both common and non-shared features.

69.Comparison study on inhibitory effect of extracts from leaves of Ginkgo biloba L. on the oxidation of human low density lipoproteins:

Zhong Yao Cai. 2004 Sep;27(9):654-6.PMID: 15704584
OBJECTIVE: To compare the effects of extracts from leaves of Ginkgo biloba L. (EGB761), ginkgo flavonoids (GF) and ginkgo terpenlactones (GT) on the oxidation of human plasma low density lipoproteins (LDL) induced by Fe2+ or Cu2+.METHOD: LDL was pretreated with EGB761, GF and GT, then was oxidized by CuSO4 or FeSO4 6 micromol/L for 4 h. Fluorescence Spectroscopy methods were adopted to determine the contents of lipofusion (LF), malondialdehyde (MDA) and vitamin E (VitE) of LDL oxidized by Fe2+ or Cu2+ and protected by EGB761, GF or GT.RESULT: After the oxidation of LDL induced by Fe2+ or Cu2+, VitE was exhausted, while MDA and LF were markedly increased. EGB761, GF and GT prevented the decrease of VitE and increases of MDA and LF in the ox-LDL. The inhibitory effect was GF > EGB761 > GT.CONCLUSION: GF played the main role in anti-oxidation.

70.Assays of physical stability and antioxidant activity of a topical formulation added with different plant extracts.:

J Pharm Biomed Anal. 2005 Feb 23;37(2):287-95.PMID: 15708669
In the present investigation the changes on physical stability (pH, viscosity, flow index and tixotropy) of topical formulations were evaluated following inclusion of different plant extracts containing flavonoids. Also, the antioxidant effect of these plant extracts alone and after addition in the formulation was evaluated using chemiluminescence and the stable free radical 1,1-diphenyl-2-picrylhydrazyl (DPPH(.-)) assays, as well as the inhibition of lipid peroxidation. Formulation added with dl-alpha-tocopherol was used to compare the physical stability and antioxidant activity. Formulations with plant extracts showed pseudoplastic behavior with decreasing on viscosity and tixotropy. The Glycyrrhiza glabra (GG) and Ginkgo biloba (GB) extracts alone and the formulations containing these extracts showed great antioxidant and free radical scavenging activities while the other extracts studied (mixture of Glycyrrhiza glabra, Symphytum officinale L and Arctium majus root, Nelumbium speciosum and soybean) showed lower activity. The results suggest that GG and GB extracts may be used in topical formulations in order to protect skin against damage caused by free radical and reactive oxygen species.

71.The significance of free radicals and antioxidants due to the load induced by sport activity:

Cesk Fysiol. 2004;53(2):76-9.PMID: 15709642
Sport performance is followed by a high production of free radicals. The main reasons are reperfusion after the previous imbalance between the increased need of the organism and the ability of blood supply by oxygen, increased production of ATP, decomposition of the cells particularly white blood cells, oxidation of the purin basis from DNA, stress, output of epinephrine release of free iron, increased temperature in the muscle and its inflammation, and the reception of free radicals from external environment. Peroxidation of lipids, proteins, DNA and other compounds follows the previous biochemical steps. Antioxidants are consumed by free radicals, antioxidative enzymes are released into blood plasma, intracellular calcium is increased, the production of nitric oxide rises, the levels of hydrogen peroxide and hypochlorous acid increase. These penetrate through the membranes and oxidatively damage the tissues. Training improves the ability of the organism to balance the increased load of free radicals. The damage can be lowered by the application of a mixture of antioxidants, the most important are vitamin C, A, E, glutathione, selenium, carnosine, eventually bioflavonoids and ginkgo biloba. The lack of antioxidants can significantly diminish the sport performance and therefore the supplementation with antioxidants is for top sportsmen but also for aged people advisable.

72.Effect of flavonoids of ginkgo biloba on anti-oxidizing system of mice after acute alcohol administration:

Wei Sheng Yan Jiu. 2005 May;34(3):303-6.PMID: 16111036
OBJECTIVE: To investigate the protective effects of flavonoids of ginkgo biloba on anti-oxidizing system damaged by acute alcohol administration.METHODS: Adult male Kunming mice were employed and divided into randomly flavonoid intervention group, normal control and ethanol control group according to body weight. After pretreated with flavonoids of ginkgo biloba (96mg/kg bw), the mice in flavonoid intervention group ingested alcohol (ethanol 4.8g/kg bw) via i.g. and were decapitated after 0.5, 1, 2, 4, 6, 9, and 15 h of ethanol administration. The same treatment was carried out on ethanol control group except that physiological saline was applied instead of flavonoid of ginkgo biloba. Meanwhile, the normal control group was established.RESULTS: The concentration of glutathione (GSH), malondialdehyde (MDA) and the activity of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) in the serum and liver were determined. The experiment displays that the content of GSH and the activities of GSH-Px and SOD decreased rapidly after 1 h of treatment with alcohol and dropped to the lowest level at 4h of treatment. After 6h of treatment, these indexes came to the normal level rapidly. The level of MDA of serum and liver increased rapidly after 1 h of treatment and reached the climax at 4h and 6h respectively. It went back to the normal concentration until 15h and 9 h respectively. On a whole, there were similar curves between flavonoids intervention group and alcohol control group on the indexes. However, to some extent, the supplement of flavonoid of ginkgo biloba can prohibit the rise of MDA level and the decline of GSH-Px, SOD, GSH which were induced by acute alcohol intakes.CONCLUSION: Flavonoid of ginkgo biloba have some protective effects on the damage of anti-oxidizing system of mice induced by acute alcohol adminstration.

73.Ginkgo biloba extract regulates differentially the cell death induced by hydrogen peroxide and simvastatin.:

Neurotoxicology. 2006 Mar;27(2):158-63. Epub 2005 Sep 26.PMID: 16185767
Several human diseases have been associated with the overproduction of reactive oxygen species (ROS) and subsequently various antioxidants emerged as potential therapeutic agents that scavenge ROS. As an oxidative stress model of human disease, we used hydrogen peroxide (H2O2) to study effect of ROS on C6 glioma cells as a surrogate for astrocytes. H2O2 induced dose- and time-dependent apoptotic cell death which was preceded by growth arrest, and transiently activated the signalling proteins ATF-2, ERK1/2 and AKT in C6 glioma cells. While several antioxidants failed to block H2O2-induced apoptosis of these cells, Ginkgo biloba extract (EGb) totally prevented the cell death and growth inhibition induced by H2O2. Interestingly, EGb did not prevent the activation of ATF-2, ERK1/2 and AKT induced by H2O2 excluding the role of these factors in the pro-apoptotic effect of H2O2. We have previously shown that the lipid-lowering drug, simvastatin, causes apoptotic cell death in C6 glioma cells [Koyuturk M, Ersoz M, Altiok N. Simvastatin induces proliferation inhibition and apoptosis in C6 glioma cells via c-jun N-terminal kinase. Neurosci Lett 2004;370(2-3):212-7]. However, in parallel experiments with H2O2, EGb was unable to prevent cell death induced by simvastatin suggesting the involvement of separate signalling pathways between H2O2 and simvastatin. Thus, EGb and other plant flavonoids might have potential as protective agents against apoptosis through scavenging ROS upon cerebral or myocardial diseases associated with free radical generation.

74.Ginkgo biloba extract improves oxidative organ damage in a rat model of thermal trauma.:

J Burn Care Rehabil. 2005 Nov-Dec;26(6):515-24.PMID: 16278567
This study was designed to determine the possible protective effect of Ginkgo biloba extract (EGb) against oxidative organ damage distant from the original burn wound. Under brief ether anesthesia, the shaved dorsum of the rats was exposed to 90 degrees C (burn group) or 25 degrees C (control group) water bath for 10 seconds. EGb (50 mg/kg/day) or saline was administered intraperitoneally immediately and at 12 hours after the burn injury. Rats were decapitated 24 hours after burn injury and tissue samples from the liver and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity, and collagen contents. Formation of reactive oxygen species in the tissue samples was monitored by the chemiluminescence technique. Tissues also were examined microscopically. Blood urea nitrogen, creatinine, alanine aminotransferase, and aspartate aminotransferase levels and tumor necrosis factor- and lactate dehydrogenase activity were assayed in serum samples. Severe skin scald injury (30% TBSA) caused a significant decrease in GSH levels and significant increases in MDA levels, MPO activity, and collagen content of hepatic and renal tissues. Treatment of rats with EGb significantly increased the GSH level and decreased the MDA level, MPO activity, and collagen contents. Similarly, serum alanine aminotransferase, aspartate aminotransferase, and blood urea nitrogen levels, as well as lactate dehydrogenase and tumor necrosis factor-, were increased in the burn group as compared with the control group. However, treatment with EGb reversed all these biochemical indices, as well as histopathological alterations that were induced by thermal trauma. Our results show that thermal trauma-induced oxidative damage in hepatic and renal tissues is protected by the administration of EGb, with its antioxidant effects. Therefore, its therapeutic role as a "tissue injury-limiting agent" must be further elucidated in oxidant-induced tissue damage.

75.Protective effects of extract of Ginkgo biloba against ethanol-induced oxidative injury in rat testes:

Wei Sheng Yan Jiu. 2005 Sep;34(5):559-62.PMID: 16329596
OBJECTIVE: This study was designed to investigate whether EGB protect against ethanol-induced oxidative injury in rat testes.METHODS: The rats were pretreated with EGB (4.8,9.6 mg/100g bw per day) before 30% ethanol administration (2.37g/kg bw by gastric incubation). Ninety days later, the rats were killed in order to measure the activities of Superoxide Dismutase (SOD), Glutathione Reductase (GST), Glutathione Peroxidase (GSH-Px), Catalase (CAT) and the contents of Glutathione (GSH), Reactive Oxygen Species (ROS), Malondialdehyde (MDA)in rat testes. The microsomal fractions were obtained by the method of differential centrifugation, and HO-1 (Heme Oxygenase-1) activity in testicular microsomal was measured. To examine the expression of HO-1 mRNA by reverse transcription polymerase chain reaction (RT-PCR).RESULTS: Compared with ethanol group, ROS, and MDA contents significantly decreased in EGB group testes, respectively (P < 0.05). GST, GSH-Px, CAT, SOD activities, and GSH content in EGB group testes elevated markedly (P <0.05). EGB could enhance HO-1 mRNA expression remarkably.CONCLUSION: It is suggested that EGB as a preventive antioxidant can protect against ethanol-induced testicular injury, which may be associated with HO-1 activity enhancement, free radicals elimination, lipid per-oxidation reaction inhibition.

76.Ginkgo biloba extract protects against ionizing radiation-induced oxidative organ damage in rats.:

Pharmacol Res. 2006 Mar;53(3):241-52. Epub 2006 Jan 10.PMID: 16412663
The present study was designed to determine the possible protective effects of Ginkgo biloba extract (EGb) against oxidative organ damage induced by irradiation (IR). Sprague-Dawley rats were exposed to whole-body IR (800 cGy) after a 15-day pretreatment with either saline or EGb (50 mg/kg/day), intraperitoneally, and treatments were repeated immediately after the IR. Then the rats were decapitated at either 6 h or 72 h after IR, where EGb or saline injections were repeated once daily. Lung, liver, kidney and ileum samples were obtained for the determination of malondialdehyde, glutathione levels, myeloperoxidase activity and collagen contents, while oxidant-induced DNA fragmentation was evaluated in the ileal tissues. All tissues were also examined microscopically and assayed for the production of reactive oxidants using chemiluminescence (CL). Lactate dehydrogenase (LDH)-an indicator of tissue damage and TNF-alpha were assayed in serum samples. In the saline-treated irradiation groups, glutathione levels were decreased significantly, while the malondialdehyde levels, myeloperoxidase activity and collagen content were increased in the tissues (p < 0.01-0.001), which were in parallel with the increases in luminol and lucigenin CL values. In the EGb treated-IR groups, all of these oxidant responses were prevented significantly (p < 0.05-0.01). LDH and TNF-alpha levels, which were increased significantly (p < 0.01-0.001) following IR, were decreased (p < 0.05-0.001) with EGb treatment. In conclusion, the present data demonstrate that EGb, through its free radical scavenging and antioxidant properties, attenuates irradiation-induced oxidative organ injury, suggesting that EGb may have a potential benefit in enhancing the success of radiotherapy.

77.Effects of Ginkgo biloba on plasma oxidant injury induced by bleomycin in rats.:

Toxicol Ind Health. 2006 Feb;22(1):47-52.PMID: 16572711
Bleomycin is an anti-neoplastic agent and its clinical usage is limited by its toxicity, which is mostly induced by oxygen radicals. The aim of this study was to investigate the effect of Ginkgo biloba on plasma indices of oxidants induced by bleomycin in rats. Male Sprague-Dawley rats were divided into five groups: none medicated or 0.9% NaCl injected or only Ginkgo biloba (orally, 100 mg/kg per day for 14 days) or only a single dose of bleomycin (intratracheal, 2.5 U/kg) or Gingko biloba and bleomycin-treated groups. After 14 days, blood was taken before the rats were sacrificed. The plasma was removed and stored at -85 degrees C until the study day. Plasma superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and xanthine oxidase (XO) enzyme activities with malondialdehyde and nitric oxide (NO) levels were studied. The levels of malondialdehyde and NO with activity of XO were higher in plasma of bleomycin group than the other groups (P <0.05). The activities of SOD and GSH-Px were increased in the bleomycin plus Gingko biloba group in comparison with the bleomycin group (P <0.05). There was a positive correlation between malondialdehyde and NO levels in the bleomycin group (r =0.859, P <0.05). There were positive correlations between SOD and GSH-Px activities (r =0.760, P <0.05) and between XO activity and malondialdehyde level (r =0.822, P <0.05) in the bleomycin plus Gingko biloba group. In conclusion, it was thought that bleomycin induced oxidative stress can be prevented by Gingko biloba treatment via high anti-oxidant enzyme activity together with decreased radical production from XO.

78.Evaluation of antioxidant activity of Ginkgo biloba phytosomes in rat brain.:

Phytother Res. 2006 Nov;20(11):1013-6.PMID: 16909446
Ginkgo biloba from the traditional Chinese system of medicine has been found to possess neurocognitive enhancing effects. The mechanism of action of Ginkgo seems to be related to its antioxidant properties. In the present study, Ginkgo biloba phytosomes were administered to Wistar rats at 50 mg/kg and 100 mg/kg for 7 and 14 days. Chemical hypoxia was induced by administration of sodium nitrite (75 mg/kg) 1 h after the last administration of treatment. Thirty minutes after sodium nitrite administration, the animals were killed and the cerebral cortex, cerebellum, hippocampus and striatum were isolated and homogenized. The supernatants were used for the estimation of the antioxidant enzymes superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase. Ginkgo biloba phytosome treatment was found to increase superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase activities in all the brain regions compared with those treated only with sodium nitrite. The prevention of depletion of the antioxidant enzymes by sodium nitrite in the presence of Ginkgo biloba phytosomes may be correlated to its antioxidant activity.

79.Comparison of antioxidant activities between salvianolic acid B and Ginkgo biloba extract (EGb 761).:

Acta Pharmacol Sin. 2006 Sep;27(9):1137-45.PMID: 16923333
AIM: To investigate and compare the antioxidant activities of salvianolic acid B (SalB) and Ginkgo biloba extract (EGb 761) in aqueous solution, rat microsomes and the cellular system.METHODS: Superoxide anion (O2-.) was generated using xanthine/xanthine oxidase system and phenazine methosulate/NADH system, and the effects of SalB and EGb 761 on the generation of O2-.were achieved by spectrophotometric measurement of the product formed on reduction of nitro blue tetrazolium. Two different methods were used to assess the scavenging effects of the extracts on hydroxyl radical (. OH): HPLC method was used for quantitation of . OH by oxy-radical trapping of 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) to form DMPO-OH adducts in Fe2+-EDTA-H2O2 system. To confirm the HPLC data, .OH was also measured by spectrophotometry using a commercial detection kit. The anti-lipid peroxidation effects of the extracts in microsomes of rat brain, liver and kidney induced by ascorbate-NADPH were determined by thiobarbituric acid (TBA) method. The protective effects of the extracts on peroxide hydrogen (H2O2)-induced oxidative damage in SH-SY5Y cells were investigated by assessing cell viability assay, the level of lipid peroxidation, and the lactate dehydrogenase(LDH) release.RESULTS: Both SalB and EGb 761 were able to scavenge O2-. and . OH, inhibit lipid peroxidation of microsomes, and protect SH-SY5Y cells against H2O2-induced oxidative damage. However, the concentration of SalB was far lower than that of EGb 761 when a similar effect was obtained.CONCLUSION: The antioxidant efficiency of SalB was greater than that of EGb 761. These results suggest that SalB, like EGb 761, has promising potential in treating oxidative damage-derived neurodegenerative disorders.

80.Ginkgo biloba leaf extract reverses amyloid beta-peptide-induced isoprostane production in rat brain in vitro.:

Planta Med. 2006 Nov;72(14):1296-9. Epub 2006 Oct 4.PMID: 17022004
Isoprostanes are prostaglandin (PG) isomers generated from oxygen radical peroxidation of arachidonic acid, which are reliable markers of membrane oxidative damage. Aging is characterized by an imbalance between the generation of reactive oxygen species and antioxidant detoxification pathways. Ginkgo biloba leaf extract is reputed as a neuroprotective antioxidant agent. We have tested the effects of a Ginkgo biloba extract {containing 24.1 % flavonoids and 181 % terpene lactones [bilobalide (0.542 %), ginkgolide A (0.570 %), ginkgolide B (0.293 %), ginkgolide C (0.263 %), and ginkgolide J (0.138 %)]} on the production of 8-iso-PGF2alpha from rat brain synaptosomes obtained from young (3 months old) or aged (12 and 24 months old) rats, both in the basal state and after oxidative stress induced by either hydrogen peroxide or amyloid beta-peptide. Our findings show that Ginkgo biloba extract pretreatment is able to completely reverse both basal and hydrogen peroxide-stimulated isoprostane production (IC50 of 81.92 microM and 31.89 microM, respectively). Amyloid beta-peptide-induced isoprostane production was also inhibited, both in young and aged rats, to a level even lower than that in unstimulated synaptosomes. This suggests that the oxygen radical scavenging properties of the Ginkgo biloba extract are fully effective in young, as well as in old rats, showing a greater inhibition of isoprostane production in the latter.

81.Protective effects of Ginkgo biloba extract against mercury(II)-induced cardiovascular oxidative damage in rats.:

Phytother Res. 2007 Jan;21(1):26-31.PMID: 17072828
This study was designed to determine the possible protective effect of Ginkgo biloba extract (EGb) against Hg II-induced oxidative damage and also thromboplastic activity in the aorta and heart tissues. Wistar albino rats of either sex (200-250 g) were divided into four groups. Rats were injected intraperitoneally with (1) control (C) group: 0.9% NaCl; (2) EGb group: Ginkgo biloba extract (Abdi Ibrahim Pharmaceutical Company, Istanbul, Turkey) at a dose of 50 mg/kg/day; (3) Hg group: a single dose of 5 mg/kg mercuric chloride (HgCl(2)); and (4) Hg + EGb group: First day EGb at a dose of 50 mg/kg/day, i.p., 1 hour after HgCl(2) (5 mg/kg) injection; following four days EGb at a dose 50 mg/kg/day, i.p. After decapitation of the rats, trunk blood was obtained and serum tumor necrosis factor-alpha (TNF-alpha), lactate dehydrogenase (LDH) activity, and malondialdehyde (MDA) and glutathione (GSH) levels were analysed. In the aorta and heart tissues total protein, MDA, GSH levels and thromboplastic activity were determined. The results revealed that HgCl(2) induced oxidative tissue damage, as evidenced by increases in MDA levels and decreased GSH levels both in serum and tissue samples. Thromboplastic activity was increased significantly following Hg administration, which verifies the cardiotoxic effects of HgCl(2). Serum LDH and TNF-alpha were elevated in the Hg group compared with the control group. Since EGb treatment reversed these responses, it seems likely that Ginkgo biloba extract can protect the cardiovascular tissues against HgCl(2)-induced oxidative damage.

82.Ginkgo biloba extract reduces naphthalene-induced oxidative damage in mice.:

Phytother Res. 2007 Jan;21(1):72-7.PMID: 17094175
This investigation elucidated the role of free radicals in naphthalene-induced toxicity and protection by Ginkgo biloba extract (EGb). BALB-c mice of either sex were administered with naphthalene (100 mg/kg; i.p.) for 30 days, along with either saline or EGb (150 mg/kg, orally). At the end of the experiment, following decapitation, lung, liver and kidney tissue samples were taken for histological examination or determination of malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO) activity and collagen contents. In addition, proinflammatory cytokines (TNF-alpha and IL-beta) and total antioxidant capacity (AOC) were assayed in the plasma, while lactate dehydrogenase (LDH) activity was assayed in serum samples. The results revealed that naphthalene caused a significant decrease in GSH level, and significant increases in MDA level, MPO activity and collagen content of tissues. Similarly, plasma cytokines, as well as serum LDH activity, were elevated while AOC was decreased in the naphthalene group compared with the control group. On the other hand, EGb treatment reversed all these biochemical indices. The results demonstrate that EGb extract, by balancing the oxidant-antioxidant status and inhibiting the generation of proinflammatory cytokines and neutrophil infiltration, protects against naphthalene-induced oxidative organ injury.

83.Ginkgo biloba extract protects against mercury(II)-induced oxidative tissue damage in rats.:

Food Chem Toxicol. 2007 Apr;45(4):543-50. Epub 2006 Aug 30.PMID: 17267089
Mercury(II) is a highly toxic metal which induces oxidative stress in the body. In this study we aimed to investigate the possible protective effect of Ginkgo biloba (EGb), an antioxidant agent, against experimental mercury toxicity in rat model. Following a single dose of 5mg/kg mercuric chloride (HgCl(2); Hg group) either saline or EGb (150mg/kg) was administered for 5days. After decapitation of the rats trunk blood was obtained and the tissue samples from the brain, lung, liver, and kidney were taken for the determination of malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen contents. Formation of reactive oxygen species in the tissue samples was monitored by chemiluminescence (CL) technique. BUN, creatinin, ALT, and AST levels and tumor necrosis factor-alpha (TNF-alpha) and lactate dehydrogenase (LDH) activity were assayed in serum samples. The results revealed that HgCl(2) induced oxidative damage caused significant decrease in GSH level, significant increase in MDA level, MPO activity and collagen content of the tissues. Treatment of rats with EGb significantly increased the GSH level and decreased the MDA level, MPO activity, and collagen contents. Similarly, serum ALT, AST and BUN levels, as well as LDH and TNF-alpha, were elevated in the Hg group as compared to control group. On the other hand, EGb treatment reversed all these biochemical indices. Our results implicate that mercury-induced oxidative damage in brain, lung, liver, and kidney tissues protected by G. biloba extract, with its antioxidant effects.

84.Antioxidative activity of Ginkgo, Echinacea, and Ginseng tinctures.:

Medicina (Kaunas). 2007;43(4):306-9.PMID: 17485958
The aim of this study was to determine the amount of phenol compounds in tinctures prepared from Ginkgo leaves, Echinacea plant, and Ginseng roots and to evaluate the antioxidative activity of these preparations. We studied the antioxidative activity using the standard 2,2-diphenyl-1-picrylhydrazyl (DPPH.) radical cation scavenging and tyrosine nitration inhibition tests. The obtained findings showed that the amount of phenol compounds in the studied tinctures differed and ranged between 114 to 340+/-29 gallic acid equivalents (GAE) mg/100 mL. We found that the amount of phenol compounds in Ginkgo tincture was statistically significantly greater than that in Echinacea or Ginseng tinctures. The effectiveness of Ginkgo tincture was by 52.7% (P<0.01) lower (from 1343+/-11 mumol catechin/100 mL solution to 637+/-64 catechin/100 mL solution), compared to Echinacea tincture. Ginseng tincture was the weakest scavenger of free radicals--only 8+/-1 micromol catechin/100 mL solution. The inhibition of tyrosine nitration was by 34% (P<0.01) greater in Echinacea tincture, compared to Ginkgo tincture (from 892+/-36 micromol catechin/100 mL solution to 588+/-17 micromol catechin/100 mL solution). Ginseng tincture was the weakest inhibitor of tyrosine nitration--only 20+/-8 micromol catechin/100 mL solution, which was by 44.6 times less, compared to Echinacea tincture. Tests on DPPH. radical cation scavenging and inhibition of nitration showed that the antioxidative activity of Echinacea tincture was statistically significantly greater compared to that of Ginkgo or Ginseng tinctures. This allows us to conclude that antioxidative activity is determined not only by phenol compounds, but also by a complex of other components of medicinal raw material.

85.Effects of Gingko Extract (EGb761) on oxidative damage under different conditions of serum supply.:

J Bioenerg Biomembr. 2009 Feb;41(1):61-9. Epub 2009 Feb 11.PMID: 19205855
Standardized Ginkgo biloba extract EGb761 is known to have multivalent properties such as anti-oxidation and anti-apoptosis. In this study, we determined in rat pheochromocytoma (PC12) cells effects of EGb761 treatment on oxidative damage under three different conditions of serum supply: normal growth medium (NGM), serum deprivation (SE) and serum deprivation followed by re-supply (SERS). It was found that, under the condition of serum deprivation, oxidative damage induced less cell death than the condition of serum supply. This appears to be related to inhibition of mitochondrial metabolism. Moreover, after serum deprivation, serum re-supply exacerbated cell necrosis, possibly through enhancement of oxidative damage. EGb761 could attenuate oxidative damage under the condition of serum supply whereas no protective effect on serum-depleted cells was observed. These results suggest that, there is a synergistic effect between trophic factors and EGb761. EGb761 treatment may protect cells from possible oxidative damage induced by the trophic factors. On the other hand, trophic factors appear to strengthen the protective effect of EGb761. To fully understand the synergistic interaction between antioxidants and trophic factors will help to sort out rational use of drugs in clinic practice.

86.Comparison of the antioxidant activity amongst Gingko biloba extract and its main components.:

Zhong Yao Cai. 2009 May;32(5):736-40.PMID: 19771849
OBJECTIVE: To compare the antioxidant activity amongst the extract of Ginkgo biloba (EGb) and its main components, flavonoids and terpenoids.METHODS: The induction of EGb, flavonoids and terpenoids on a typical antioxidant enzyme, glutamate cysteine ligase catalytic subunit (GCLC), in cell lines was detected by Western-blot. The effects of EGb, flavonoids and terpenoids on superoxide anion radical (O2*(-)), hydroxyl radical (OH*), rat erythrocyte hemolysis and lipid peroxidation of rat liver homogenate were determined by respective activity.RESULTS: EGb and flavonoids but not terpenoids were demonstrated significantly to induce the antioxidant enzyme (GCLC), directly scavenge O2*(-), OH* and inhibit rat erythrocyte hemolysis and lipid peroxidation of rat liver homogenate. Compared these antioxidant activities between EGb and flavonoids, the activities of flavonoids were weaker than those of EGb, which contains similar dose of flavonoids.CONCLUSION: EGb has stronger antioxidant activities than flavonoids, but terpenoids did not show antioxidant activity in this research.

87.Structure characterization and antioxidant activity of a novel polysaccharide isolated from Ginkgo biloba.:

Int J Biol Macromol. 2010 May 1;46(4):436-9. Epub 2010 Feb 11.PMID: 20153363
A novel polysaccharide (GBP50S2) with antioxidant activity was isolated from Ginkgo biloba. The structure of GBP50S2 was elucidated on the basis of physico-chemical and instrumental analyses, and its average molecular weight (Mw=2.30x10(5)) was determined by gel permeation chromatography. The backbone of GBP50S2 was composed of (1-->4)-linked alpha-d-mannopyranosyl residues which branched at O-3. The three branches consisted of beta-l-rhamnopyranosyl residues, (1-->4)-linked alpha-d-galactopyranosyl terminated with beta-l-rhamnopyranosyl residues, and (1-->3,4)-linked alpha-d-mannopyranosyl terminated with beta-l-rhamnopyranosyl residues, respectively. In the in vitro antioxidant assay, GBP50S2 was found to possess DPPH radical-scavenging activity and hydroxyl radical-scavenging activity with an IC(50) value of 0.412 mg/mL and 0.482 mg/mL, respectively.

88.Ginkgo biloba leaf extract action in scavenging free radicals and reducing mutagenicity and toxicity of cigarette smoke in vivo.:

J Environ Sci Health A Tox Hazard Subst Environ Eng. 2010;45(4):498-505.PMID: 20390896
In this study, ginkgo biloba leaf extract (GBE) was added to sample cigarettes, including in the filter (0.8 mg/cigarette) and/or the cut filler (0.8 mg/cigarette). The effects of GBE in scavenging free radicals and reducing mutagenicity and toxicity of cigarette smoke in vivo were investigated. Smoke analysis results indicated that GBE eliminated up to 30% of free radicals. Biological experiments, conducted for both GBE cigarettes and control samples, included the Ames test, acute toxicity, neutral red cytotoxicity assay and chronic toxicity. Results showed that the mutagenicity and toxicity of the GBE cigarettes were lower than for the control cigarettes. A possible mechanism of GBE in scavenging free radicals is discussed in this article.

D-Ginkgo Biloba:Anti-Cancer,Anti-Tumor,Anti-Edema,Canceration Prevention Research:

1.Idiopathic cyclic edema. The role of capillary hyperpermeability and its correction by Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1550-3.PMID: 2947096
Idiopathic cyclic oedema is a frequent and often unrecognized condition in young women. It is characterized by water and sodium retention with secondary hyperaldosteronism due to capillary hyperpermeability. Treatment is not easy. It includes spironolactone, sometimes sympathomimetics and hygienic-dietetic measures. Thiazide diuretics and laxatives must be avoided. Correcting the capillary defect is of paramount importance. This defect is detected and measured by Landis' labelled albumin test. The authors have tried Ginkgo biloba extract administered either orally or by intravenous infusion. Full correction of the biological anomaly was obtained in 10 cases in which Landis' test was performed before and after oral treatment, and in the 5 cases treated by intravenous infusion.

2.Development of a model to study the anti-edema properties of Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1575-6.PMID: 2947104
The vasogenic edema observed after irradiation of the brain constitutes a new and interesting model to study the anti-oedema properties of drugs. We have just completed a first pharmaco-clinical study of Ginkgo biloba extract with the dual purpose of assessing the feasibility of a therapeutic protocol and of deciding on simple and non-invasive criteria that would quantity cerebral oedema. The results of this pilot study have encouraged us to pursue our investigations under strict methodological conditions, in view of their therapeutic but also epidemiological interest.

3.Edematous syndromes caused by capillary hyperpermeability. Diffuse angioedema:

J Mal Vasc. 1989;14(3):231-5.PMID: 2778397
Edema due to increased capillary permeability (ICP) may be diffuse or localized. Local edemas (Quincke edema, angioneurotic edema) are most often allergic or very rarely due to a defect in C1-inhibitor. Generalized edemas due to ICP share the following clinical features: Fluid retention (subcutaneous edema and diffused swelling) is predominant in lower limbs; it is worsened by orthostatism and warmth and alleviated by decubitus and cold, with important weight variations between morning and evening. It is associated with enhanced thirst, hypotension, oliguria, headaches and blood volume reduction; secondary hyperaldosteronism is the main mechanism. These troubles are due to ICP, associated with lymphatic drainage abnormalities; ICP is measured by the isotopic Landis Test. This abnormality is present in several diseases. Idiopathic orthostatic edema (IOE) is frequent and often unrecognized, occurring mainly in women, often associated with luteal insufficiency. Iatrogenic complications (diuretic and laxative abuses) are frequently superimposed. ICP may be corrected by vitamins P (rutin, anthocyanosides, diosmin, Ginkgo biloba extracts...) Cyclic shock due to ICP is rare. It is characterized by cyclic edema and shock with hypovolemia, hypoproteinemia; the mechanism of shock is a severe loss of fluid and protein from the vascular bed. It is often associated with monoclonal gammapathy and complement activation. In our personal case, the trouble in CP was present all along the disease with permanent edema and low blood pressure (especially in orthostatism). Vit "P" and Ginkgo biloba extracts were able to partially improve CP and the clinical troubles. However, in spite of this treatment a fatal shock occurred after ten years follow-up. Episodic angioedema associated with eosinophilia was first described by Gleich.

4.A quantitative structure-activity relationship for antitumor activity of long-chain phenols from Ginkgo biloba L.:

Chem Pharm Bull (Tokyo). 1989 Jun;37(6):1619-21.PMID: 2776245
With the aim of obtaining compounds with strong antitumor activity, a quantitative structure-activity relationship (QSAR) of antitumor phenolic compounds (long-chain phenols) was derived using the Hansch-Fujita equation. The ED50 values against Chinese hamster V-79 cells were analyzed in terms of log P as the hydrophobic parameter and the energy of the lowest unoccupied molecular orbital (ELUMO) calculated by using the modified neglect of differential overlap (MNDO) method as the electronic parameter, by means of multiple regression analysis. It was found that the activities mainly depended on log P (an optimum log P of 8.3) and a low-lying ELUMO value. 4-Undecylcatechol, selected on the basis of the above results, exhibited strong antitumor activity against Sarcoma 180 ascites and P-388 lymphocytic leukemia.

5.Phospholipase Cgamma1 inhibitory principles from the sarcotestas of Ginkgo biloba.:

J Nat Prod. 1998 Jul;61(7):867-71.PMID: 9677265
Ten phenolic compounds were isolated from the CHCl3 extract of Ginkgo biloba sarcotestas (Ginkgoaceae) as a new class of phosphatidylinositol-specific phospholipase Cgamma1 (PI-PLCgamma1) inhibitors. The substances without the long chain were ineffective. On the other hand, the activities of these compounds were dramatically decreased by acetylation of aromatic hydroxyl groups of cardanol, phenolic acid, and bilobol and by methylation of the aromatic carboxyl group of phenolic acid. The unsaturated long chain as well as the aromatic hydroxyl and carboxyl groups might play a key role for the PI-PLCgamma1 inhibitory activity. These compounds also inhibited the growth of a number of human cancer cell lines, but were less cytotoxic against a human normal colon cell line.

6.Traditional Chinese medicine, acupuncture, and other alternative medicines for prostate cancer: an introduction and the need for more research.:

Semin Urol Oncol. 1999 May;17(2):103-10.PMID: 10332924
There are several other alternative medicines apart from vitamins and minerals that the clinician should be aware of because they have grown in popularity in other fields of medicine. In time, these therapies should impact the arena of urologic oncology. Traditional Chinese Medicine, which includes acupuncture, is an area that has received some attention. The theory behind it can be quite daunting because it is so different from the theory behind Western Medical Science. In addition, exactly how acupuncture can be applied to a patient and its potential use in prostate cancer need to be addressed. Other herbal therapies for the patient experiencing symptoms related to a localized cancer diagnosis also need to be evaluated. St John's Wort for depression and Kava for anxiety are two examples of herbal alternatives that some prostate patients are inquiring about. Finally, Ginkgo biloba has received a great deal of attention in the media for erectile dysfunction, but there is a dearth of evidence in this area and the information that already exists can be misleading until further studies are conducted. Also, it is imperative that additional studies be performed in all of the above subjects as they relate to prostate cancer, but a general survey on alternative medicine use in urologic diseases is needed first before an adequate review of the most popular therapies can be published.

7.Experimental studies of the protective effect of ginkgo biloba extract (GBE) on cisplatin-induced toxicity in rats:

Nippon Jibiinkoka Gakkai Kaiho. 1999 Jul;102(7):907-17.PMID: 10459293
Cisplatin (CDDP) is an effective antineoplastic agent in the treatment of solid malignant tumors. Its clinical use, however, is limited because of various side effects including sensorineural hearing loss. Several agents have been proposed to reduce these side effects. GBE has recently been reported to scavenge superoxide and hydroxyl radicals, resulting in a reduction of lipid peroxidation. GBE is expected to protect against CDDP-induced toxicity because its generative mechanism is thought to be associated with free-radical formation. The purpose of the present study was to evaluate GBE's efficacy as a protective agent against cisplatin-induced ototoxicity. Fisher rats were used in this study and were divided into three treatment groups: 1) animals administered 1.0 mg of CDDP per kg for 10 days (Group I), 2) animals receiving 100 mg of GBE per kg 90 min before administration 1.0 mg of CDDP per kg (Group II) and 3) a vehicle control (Group III). First, the protective effect of GBE on CDDP-induced ototoxicity was investigated. The auditory threshold was evaluated by means of the compound action potential (CAP) recording. After CAP recordings, cochlear sensory epithelia were observed throughout the cochlea by scanning electron microscopy. In Group II, the elevation of CAP thresholds at 12 kHz, 16 kHz, 20 kHz and the missing rate for the outer hair cells were significantly reduced as compared to those in Group I. These data suggest that GBE is effective for otoprotection against CDDP. Second, the protective effect of GBE on CDDP-induced nephrotoxicity was evaluated. Nephrotoxicity was evaluated by means of measurement of serum BUN and creatinine and histopathological examination of the kidney. These were significant differences in serum BUN and creatinine levels between Group I and Group II. Third, the influence of GBE against the antitumor effect of CDDP was researched in the rats inoculated subcutaneously with SCC-158 squamous cell carcinoma cells. There was no difference in tumor growth rate (TGR) between Group I and Group II. The result suggested that the combined administration had no influence on the antitumor activity of CDDP. In conclusion, the co-administration of CDDP with GBE is beneficial to ameliorate CDDP-induced toxicity without attenuation of CDDP antitumor activity.

8.Phase II study with 5-fluorouracil and ginkgo biloba extract (GBE 761 ONC) in patients with pancreatic cancer.:

Arzneimittelforschung. 1999 Dec;49(12):1030-4.PMID: 10635450
The aim of the study was to evaluate the efficacy and tolerability of as well as the quality of life under treatment with 5-fluorouracil (CAS 51-21-8, 5-FU) combined with parenteral GBE 761 ONC (i.e. the ginkgo biloba special extract EGb 761) in patients with pancreatic cancer. Forty-eight patients with locally or metastatic advanced pancreatic cancer were treated within a phase II study. The treatment was repeated every three weeks until progression. Response to therapy was evaluated after 2 and 4 treatment courses. Thirty-two patients were evaluable for response. Progressive disease was observed in 22 (68.8%) patients, no change in 7 (21.9%) patients and partial response in 3 (9.4%) patients (overall response = 9.4%). GBE 761 ONC was well tolerated. Adverse events which occurred during the study consisted mainly of myelosuppression and gastrointestinal symptoms and were judged as 5-FU-related or consisted of liver toxicity, respectively, and were judged as tumour-related. These results suggest a good benefit-risk ratio of the combination of 5-FU and GBE 761 ONC in the treatment of pancreatic cancer. In comparison with the results of studies with either 5-FU or gemcitabine as single agents the combination of 5-FU/GBE 761 ONC shows comparable response rates. The toxicity of the 5-FU/GBE 761 ONC combination was low. This combination therapy therefore warrants further clinical investigation, such as a controlled clinical trial against 5-FU or gemcitabine monotherapy.

9.Antagonistic effects of Ginkgo biloba extract on adhesion of monocytes and neutrophils to cultured cerebral microvascular endothelial cells.:

Zhongguo Yao Li Xue Bao. 1999 May;20(5):423-5.PMID: 10678089
AIM: To study the action of Ginkgo biloba extract (GbE) on tumor necrosis factor (TNF-alpha)-induced adhesion of monocytes (Mon) and neutrophils (Neu) to cultured cerebral microvascular endothelial cells.METHODS: TNF-alpha-induced endothelial adhesivity toward Mon and Neu was studied using bovine cerebral microvascular endothelial cells (BCMEC) in vitro. The number of Mon and Neu adhering to the BCMEC monolayers was determined by flow cytometry.RESULTS: Pretreatment of BCMEC with TNF-alpha increased Mon and Neu adhesion to BCMEC from 12.5% +/- 0.2% to 31.3% +/- 0.5% and from 13.8% +/- 0.4% to 32.1% +/- 0.5%, respectively. GbE (1-100 mg.L-1) inhibited the effect of TNF-alpha in a concentration-dependent manner. E-selectin mAb (1 mg.L-1) blocked Mon and Neu adhesion to BCMEC induced by TNF-alpha.CONCLUSION: The inhibition of GbE on Mon and Neu adhesion to BCMEC was mediated through the suppression of E-selection expression.

10.Antioxidant compounds EGB-761 and BN-520 21 attenuate heat shock protein (HSP 72 kD) response, edema and cell changes following hyperthermic brain injury. An experimental study using immunohistochemistry in the rat.:

Amino Acids. 2000;19(1):339-50.PMID: 11026505
Influence of the extract of Gingko biloba (EGB-761) and one of its constituent Gingkolide B (BN-52021) on hyperthermia induced cellular damage and heat shock protein (HSP 72kD) response was examined in a rat model. Rats subjected to 4h heat stress at 38 degrees C in a biological oxygen demand (BOD) incubator (relative humidity 50-55%, wind velocity 20-25cm/sec) resulted in profound edema and cell injury in many parts of the cerebral cortex, hippocampus, cerebellum, thalamus, hypothalamus and brain stem. Immunostaining of HSP 72 kD showed marked upregulation in the damaged and distorted neurons located within the edematous area. Pretreatment with EGB-761 (50mg/kg/day, p.o.) and BN-520 21 (2mg/kg, p.o.) per day for 5 days significantly reduced HSP expression and attenuated cell damage. Our results show that EGB-761 and its component Gingkolide B (BN-52021) has the capacity to reduce edema and cell injury following hyperthermia and this effect of the compound is somehow associated with a reduction in cellular stress response as evidenced with a reduction in HSP expression.

11.Drug-induced inhibition of the peripheral-type benzodiazepine receptor expression and cell proliferation in human breast cancer cells.:

Anticancer Res. 2000 Sep-Oct;20(5A):2835-47.PMID: 11062691
The peripheral-type benzodiazepine receptor (PBR) expression and localization correlate with human breast cancer cell proliferation and aggressive phenotype expression. The standardized extract of Ginkgo biloba leaves (EGb 761) and isolated ginkgolide B (GKB) were shown to decrease PBR mRNA expression in adrenal cells. We examined the effect of EGb 761 and GKB on PBR expression and cell proliferation in human breast cancer cells. EGb 761 and GKB decreased in a time- and dose-dependent manner PBR expression and cell proliferation in the highly aggressive, rich in PBR, human breast cancer cell line MDA-231 whereas they did not affect the proliferation of the non-aggressive human breast cancer cell line MCF-7, which contains very low PBR levels. This effect was reversible and not due to the antioxidant properties of the compounds tested. Using a human cDNA expression array we determined that EGb 761 treatment altered, in addition to PBR, the expression of 36 gene products involved in various pathways regulating cell proliferation. These in vitro data were further validated in an in vivo model where EGb 761 and GKB significantly inhibited the nuclear PBR expression and growth of MDA-231 cell xenografts in nude mice. Taken together, these data suggest that the manipulation of PBR expression could be used to control tumor growth and that EGb 761 and GKB, under the conditions used, exert cytostatic properties.

12.Phase II study of combined 5-fluorouracil/ Ginkgo biloba extract (GBE 761 ONC) therapy in 5-fluorouracil pretreated patients with advanced colorectal cancer.:

Phytother Res. 2001 Feb;15(1):34-8.PMID: 11180520
The aim of the study was to evaluate the efficacy, tolerability and quality of life in 5-fluorouracil (5-FU) pretreated colorectal cancer patients after combined 5-FU and Ginkgo biloba extract GBE 761 ONC (i.e. the Ginkgo biloba special extract EGb 761(R)) therapy. Following conventional 5-FU therapy, 44 patients (32 evaluable for response) with advanced progressive colorectal cancer were treated every 3 weeks with courses of 350 mg GBE 761 ONC as a 30 min i.v. infusion on days 1-6 followed by 500 mg/m(2)/d 5-FU as a 30 min i.v. infusion on days 2-6. The response to therapy was evaluated after the second and fourth course of treatment. The data of 32 patients could be evaluated for efficacy. We observed a progression of disease in 22 patients, no change in 8 patients and a partial response in 2 patients (overall response = 6.3%). Seventeen of 22 patients with observed progressive disease showed further progression after two cycles, two after three cycles and three after four cycles. The median survival time was 9.5 months (7.7-11.5 months). GBE 761 ONC was well tolerated. Adverse events that occurred during the study were mainly myelosuppression and gastrointestinal symptoms and were judged to be 5-FU related or consistent with liver toxicity and thus tumour related. Our results suggest a good benefit-risk ratio of the combined 5-FU and GBE 761 ONC therapy as second line treatment in metastatic colorectal cancer. The survival time was similar to that known from second line treatment according to the Ardalan scheme. Since an improvement was observed in some patients despite the failure of the conventional 5-FU pretreatment, it would be interesting to evaluate whether the application of 5-FU plus GBE 761 ONC as a first line treatment is of benefit.

13.mRNA expression profile of a human cancer cell line in response to Ginkgo biloba extract: induction of antioxidant response and the Golgi system.:

Free Radic Res. 2000 Dec;33(6):831-49.PMID: 11237105
Supplementation of diets with plant extracts for health and prevention of degenerative diseases is popular. However the molecular basis of their therapeutic potentials are poorly defined. We hypothesized that in vitro assays that enable quantitative analysis of the gene expression profiles combined with targeted biochemical analysis can identify the potential effects of phytochemicals. The hypothesis was tested by application of GeneChips to define mRNA expressions of a human bladder cancer cell line incubated with a flavonoid containing extract of Ginkgo biloba leaves. The analysis of the transcriptional response revealed a net activation of transcription. Functional classification of the affected mRNAs showed the largest changes in the abundance of mRNAs for intracellular vesicular transport, mitochondria, transcription and antioxidants. The transcripts for hemeoxygenase-1, mitochondrial superoxide dismutase and the regulatory subunit of gamma-glutamyl-cysteinyl synthetase and their encoded proteins were elevated. The extract also increased intracellular glutathione, the transcripts for DNA repair and synthesis, and decreased 3H-thymidine incorporation. These results demonstrate that a flavonoid containing extract initiates an adaptive transcriptional response that augments the "antioxidant status" of the cells and inhibits DNA damage. These in vitro studies using GeneChips demonstrated a promising strategy for identifying nutritional supplement induced cellular responses that may have a role in counteracting chronic human diseases.

14.Effects of Ginkgo biloba extract (EGb 761) and quercetin on lipopolysaccharide-induced signaling pathways involved in the release of tumor necrosis factor-alpha.:

Biochem Pharmacol. 2001 Oct 1;62(7):963-74.PMID: 11543732
Administration of bacterial lipopolysaccharide (LPS) to laboratory animals and cultured macrophages induces tumor necrosis factor-alpha (TNF-alpha), a pro-inflammatory cytokine. Pretreatment with Ginkgo biloba extract (EGb 761) inhibited the in vivo production of TNF-alpha (measured by ELISA) after challenge with LPS. To begin to understand the mechanism of this inhibition, we evaluated the in vitro effects of EGb 761 and its flavonoid component, quercetin, on LPS-treated RAW 264.7 macrophages. Pretreatment with EGb 761 or quercetin concentration-dependently inhibited TNF-alpha release, as measured by the L929 fibroblast assay. Northern blotting demonstrated that quercetin inhibited LPS-induced TNF-alpha mRNA, but did not alter its half-life. Activation of mitogen-activated protein kinases (MAPKs) and the redox-sensitive transcription factors, nuclear factor-kappaB (NF-kappaB) and activator protein 1 (AP-1), are key events in the signal transduction pathways mediating TNF-alpha induction. Phosphorylation of extracellular signal-related kinases 1 and 2 (ERK 1/2), p38 MAPK, and Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK), members of the MAPK family, was analyzed by western blotting. Our results suggest that quercetin is unique in its ability to inhibit TNF-alpha transcription by inhibiting the phosphorylation and activation of JNK/SAPK and, therefore, suppressing AP-1-DNA binding [assessed by electrophoretic mobility shift analysis (EMSA)]. Results from western analysis, EMSA, and transient transfections suggest that EGb 761 diminishes LPS-induced NF-kappaB but has no effect on LPS-induced TNF-alpha transcription. Both EGb 761 and quercetin inhibited ERK1/2 phosphorylation and p38 MAPK activity, which are important in the post-transcriptional regulation of TNF-alpha mRNA.

15.In vitro evaluation of the cytotoxic potential of alkylphenols from Ginkgo biloba L.:

Toxicology. 2002 Aug 15;177(2-3):167-77.PMID: 12135620
Extracts from the leaves of Ginkgo biloba L. belong to the most widely used phytopharmaceuticals. In crude Ginkgo extracts, ginkgolic acids (GA) and related alkylphenols (e.g. cardanols and cardols) have been recognized as hazardous compounds with suspected cytotoxic, allergenic, mutagenic and carcinogenic properties. To further assess the cytotoxic potential of GA, their effect on the human keratinocyte cell line HaCaT and the rhesus monkey kidney tubular epithelial cell line LLC-MK(2) was investigated. The action of a defined mixture of GA on cell growth, viability and integrity was evaluated by the neutral red uptake assay as well as the release of lactate dehydrogenase (LDH) and acid phosphatase (ACP). Cell morphology was examined by electron microscopy. For comparison, the effect of the standardized Ginkgo extract EGb 761, which contains less than 5 ppm GA, was also investigated. Following incubation of cells with EGb 761, neutral red uptake was half-maximally inhibited at concentrations of 900 mg/l (HaCaT) and 1480 mg/ml (LLC-MK(2)). The corresponding IC(50)-values for the mixture of GA ranged between 22 mg/l (HaCaT) and 4.6 mg/l (LLC-MK(2)), respectively. In parallel to the inhibition of neutral red uptake, a concentration dependent release of LDH was observed when cells were incubated in the presence of GA (1-100 mg/l). In contrast, even at a concentration of 1800 mg/l EGb 761 did not cause release of LDH above controls. Since GA interacted with the assay for ACP, no index of lysosomal damage could be established by this method. Incubation of HaCaT cells with GA for 18 h increased the proportion of apoptotic cells from about 6% (control) to nearly 80% at concentrations of >or=30 mg/l. Electron microscopic analysis of HaCaT cells revealed a drug induced formation of myelinosomes possibly due to the inhibition of lysosomal enzymes, while morphological evaluation of LLC-MK(2) cells indicated that the cytotoxic activity of GA in these cells is primarily mediated by transformation of mitochondria, which is probably induced by uncoupling of oxidative phosphorylation.

16.Apoptosis of hepatoma cells SMMC-7721 induced by Ginkgo biloba seed polysaccharide.:

World J Gastroenterol. 2002 Oct;8(5):832-6.PMID: 12378625
AIM: To study the apoptosis of hepatoma cells SMMC-7721 induced by polysaccharide isolated from Ginkgo biloba seed.METHODS: Ginkgo biloba seed polysaccharide (GBSP) was isolated by ethanol fractionation of Ginkgo biloba seed and purified by Sephadex G-200 chromatography. The purity of GBSP was verified by reaction with iodine-potassium iodide and ninhydrin and confirmed by UV spectrophotometer, cellulose acetate membrane electrophoresis and Sepharose 4B gel filtration chromatography. The Scanning Electron Microscope (SEM) and Flow Cytometry (FCM) were used to examine the SMMC-7721 cells with and without GBSP treatment at 500 mg/ml for 36 h.RESULTS: GBSP product obtained was of high purity with the average molecular weight of 1.86 X 10(5). Quantitative analysis of SMMC-7721 cells in vitro with FCM showed that the percentages of G(2)-M cells without and with GBSP treatment were 17.01+/-1.28 % and 11.77+/-1.50% (P<0.05), the debris ratio of the cells were 0.46+/-0.12 % and 0.06+/-0.06 % (P<0.01), and the apoptosis ratio of cells was 3.84+/-0.55 % and 9.13+/-1.48 % (P<0.01) respectively. Following GBSP treatment, microvilli of SMMC-7721 cells appeared thinner and the number of spherical cells increased markedly. Most significantly, the apoptosis bodies were formed on and around the spherical cells treated with GBSP.CONCLUSION: GBSP could potentially induce the apoptosis of SMMC-7721 cells.

17.Common gene targets of Ginkgo biloba extract (EGb 761) in human tumor cells: relation to cell growth.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):655-62.PMID: 12396076
The standardized extract of Ginkgo biloba leaves (EGb 761) has been shown to inhibit aggressive human breast cancer cell proliferation both in vitro and in vivo. These results were extended to human glioma and hepatoma cells in vitro suggesting that EGb 761 may have a more widespread application for tumor growth control. To understand the mechanism by which EGb 761 acts to inhibit cell proliferation, we investigated the effects of EGb 761 on human breast cancer, glioma and hepatoma cell transcriptomes by means of various large-scale DNA array techniques. The data presented focus on genes regulated by EGb 761 that are common to the three tumor cell types and for which the data were verified by two different types of DNA microarray and/or RNA (Northern) blot analysis and real-time quantitative PCR. These results could therefore help elucidate the mechanism of cytostatic action of EGb 761 and identify genes important for tumor growth.

18.Ginkgo biloba extracts and cancer: a research area in its infancy.:

Fundam Clin Pharmacol. 2003 Aug;17(4):405-17.PMID: 12914542
Recent studies conducted with various molecular, cellular and whole animal models have revealed that leaf extracts of Ginkgo biloba may have anticancer (chemopreventive) properties that are related to their antioxidant, anti-angiogenic and gene-regulatory actions. The antioxidant and associated anti-lipoperoxidative effects of Ginkgo extracts appear to involve both their flavonoid and terpenoid constituents. The anti-angiogenic activity of the extracts may involve their antioxidant activity and their ability to inhibit both inducible and endothelial forms of nitric oxide synthase. With regard to gene expression, a Ginkgo extract and one of its terpenoid constituents, ginkgolide B, inhibited the proliferation of a highly aggressive human breast cancer cell line and xenografts of this cell line in nude mice. cDNA microarray analyses have shown that exposure of human breast cancer cells to a Ginkgo extract altered the expression of genes that are involved in the regulation of cell proliferation, cell differentiation or apoptosis, and that exposure of human bladder cancer cells to a Ginkgo extract produced an adaptive transcriptional response that augments antioxidant status and inhibits DNA damage. In humans, Ginkgo extracts inhibit the formation of radiation-induced (chromosome-damaging) clastogenic factors and ultraviolet light-induced oxidative stress - effects that may also be associated with anticancer activity. Flavonoid and terpenoid constituents of Ginkgo extracts may act in a complementary manner to inhibit several carcinogenesis-related processes, and therefore the total extracts may be required for producing optimal effects.

19.Therapeutic mechanism of ginkgo biloba exocarp polysaccharides on gastric cancer.:

World J Gastroenterol. 2003 Nov;9(11):2424-7.PMID: 14606069
AIM: To study the therapeutic mechanism of Ginkgo biloba exocarp polysaccharides (GBEP) on gastric cancer.METHODS: Thirty patients with gastric cancer were treated with oral GBEP capsules. The area of tumors was measured by electron gastroscope before and after treatment, then the inhibitory and effective rates were calculated. The ultrastructures of tumor cells were examined by transmissional electron microscope. Cell culture, MTT, flow cytometry were performed to observe proliferation, apoptosis and changes of relevant gene expression of human gastric cancer SGC-7901 cells.RESULTS: Compared with the statement before treatment, GBEP capsules could reduce the area of tumors, and the effective rate was 73.4%. Ultrastructural changes of the cells indicated that GBEP could induce apoptosis and differentiation in tumor cells of patients with gastric cancer. GBEP could inhibit the growth of human gastric cancer SGC-7901 cells following 24-72 h treatment in vitro at 10-320 mg/L, which was dose- and time-dependent. GBEP was able to elevate the apoptosis rate and expression of c-fos gene, but reduce the expression of c-myc and bcl-2 genes also in a dose-dependent manner.CONCLUSION: The therapeutic mechanism of GBEP on human gastric cancer may relate to its effects on the expression of c-myc, bcl-2 and c-fos genes, which can inhibit proliferation and induce apoptosis and differentiation of tumor cells.

20.Ginkgo biloba extract inhibits tumor necrosis factor-alpha-induced reactive oxygen species generation, transcription factor activation, and cell adhesion molecule expression in human aortic endothelial cells.:

Arterioscler Thromb Vasc Biol. 2003 Sep 1;23(9):1559-66. Epub 2003 Jul 31.PMID: 12893683
OBJECTIVE: This study was conducted to examination whether Ginkgo biloba extract (GBE), a Chinese herb with antioxidant activity, could reduce cytokine-induced monocyte/human aortic endothelial cell (HAEC) interaction, a pivotal early event in atherogenesis.METHODS AND RESULTS: Pretreatment of HAECs with GBE (50 and 100 microg/mL for 18 hours) significantly suppressed cellular binding between the human monocytic cell line U937 and tumor necrosis factor-alpha (TNF-alpha)-stimulated HAECs by using in vitro binding assay (68.7% and 60.1% inhibitions, respectively). Cell enzyme-linked immunosorbent assay and immunoblot analysis showed that GBE (50 microg/mL for 18 hours) significantly attenuated TNF-alpha-induced cell surface and total protein expression of vascular cellular adhesion molecule-1 and intracellular adhesion molecule-1 (63.5% and 69.2%, respectively; P<0.05). However, pretreatment with probucol (5 micromol/L for 18 hours) reduced the expression of vascular cellular adhesion molecule-1 but not intracellular adhesion molecule-1. Preincubation of HAECs with GBE or probucol significantly reduced intracellular reactive oxygen species formation induced by TNF-alpha (76.8% and 68.2% inhibitions, respectively; P<0.05). Electrophoretic mobility shift assay demonstrated that both GBE and probucol inhibited transcription factor nuclear factor-kappaB activation in TNF-alpha-stimulated HAECs (55.2% and 65.6% inhibitions, respectively) but only GBE could inhibit the TNF-alpha-stimulated activator protein 1 activation (45.1% inhibition, P<0.05).CONCLUSIONS: GBE could reduce cytokine-stimulated endothelial adhesiveness by downregulating intracellular reactive oxygen species formation, nuclear factor-kappaB and activator protein 1 activation, and adhesion molecule expression in HAECs, supporting the notion that the natural compound Ginkgo biloba may have potential implications in clinical atherosclerosis disease.

21.Ginkgo biloba extracts and cancer: a research area in its infancy.:

22.Effects of Ginkgo biloba extract on cell proliferation and cytotoxicity in human hepatocellular carcinoma cells.:

World J Gastroenterol. 2004 Jan;10(1):37-41.PMID: 14695765
AIM: To study the effect of Ginkgo biloba extract (EGb 761) containing 22-27% flavonoids (ginkgo-flavone glycosides) and 5-7% terpenoids (ginkgolides and bilobalides) on cell proliferation and cytotoxicity in human hepatocellular carcinoma (HCC) cells.METHODS: Human HCC cell lines (HepG2 and Hep3B) were incubated with various concentrations (0-1 000 mg/L) of EGb 761 solution. After 24 h incubation, cell proliferation and cytotoxicity were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay and lactate dehydrogenase (LDH) release, respectively. After 48 h incubation, the expression of proliferating cell nuclear antigen (PCNA) and p53 protein was measured by Western blotting.RESULTS: The results showed that EGb 761 (50-1 000 mg/L) significantly suppressed cell proliferation and increased LDH release (P<0.05) in HepG2 and Hep3B cells compared with the control group. The cell proliferation of HepG2 and Hep3B cells treated with EGb 761 (1 000 mg/L) was 45% and 39% of the control group (P<0.05), respectively. LDH release of HepG2 cells without and with EGb 761 (1 000 mg/L) treatment was 6.7% and 37.7%, respectively, and that of Hep3B cells without and with EGb 761 (1 000 mg/L) treatment was 7.2% and 40.3%, respectively. The expression of PCNA and p53 protein in HepG2 cells treated with EGb 761 (1 000 mg/L) was 85% and 174% of the control group, respectively.CONCLUSION: Ginkgo biloba extract significantly can suppress proliferation and increase cytotoxicity in HepG2 and Hep3B cells. Additionally, Ginkgo biloba extract can decrease PCNA and increase p53 expression in HepG2 cells.

23.Antioxidant compounds EGB-761 and BN-52021 attenuate brain edema formation and hemeoxygenase expression following hyperthermic brain injury in the rat.:

Acta Neurochir Suppl. 2003;86:313-9.PMID: 14753460
Role of carbon monoxide (CO) in hyperthermic brain injury induced brain pathology was examined in a rat model using immunohistochemistry of the hemeoxygenase-2 (HO-2) enzyme. Exposure of rats to 4 h heat stress at 38 degrees C resulted in profound hyperthermia, breakdown of the blood-brain barrier (BBB), brain edema formation, cell damage and expression of HO-2 in several brain regions. Pretreatment with potent antioxidant compounds EGB-761 and BN-52021 markedly reduced the HO-2 expression, BBB breakdown, brain edema formation and cell damage without attenuating the hyperthermic response. This effect was most marked in animals treated with EGB-761. These observations suggest that upregulation of HO-2 representing generation of CO plays important roles in hyperthermic brain injury, and oxidative stress seems to be one of the most important signals in inducing HO-2 expression in hyperthermia, not reported earlier.

24.Preventive effects of extract of leaves of ginkgo (Ginkgo biloba) and its component bilobalide on azoxymethane-induced colonic aberrant crypt foci in rats.:

Cancer Lett. 2004 Jul 16;210(2):159-69.PMID: 15183531
The modifying effects of dietary feeding of extract of leaves of ginkgo (Ginkgo biloba) (EGb) and bilobalide isolated from EGb on the development of azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF) were investigated in male F344 rats. We also assessed the effects of EGb and bilobalide on proliferating cell nuclear antigen (PCNA) index in 'normal-appearing' crypts and activities of detoxifying enzymes of cytochrome P450 (CYP), glutathione S-transferase (GST) and quinine reductase (QR) activity in the liver. To induce ACF, rats were given two weekly subcutaneous injections of AOM (20 mg/kg body wt). They also received the experimental diets containing EGb (50 or 500 ppm) and bilobalide (15 or 150 ppm) for 4 weeks, starting 1 week before the first dosing of AOM. AOM exposure produced a substantial number of ACF (106 +/- 10) at the end of the study (week 4). Dietary administration of EGb and bilobalide caused significant reduction in the frequency of ACF: 50 ppm EGb, 73 +/- 17 (31% reduction, P < 0.001); 500 ppm EGb, 56 +/- 13 (47% reduction, P < 0.001); 15 ppm bilobalide, 79 +/- 17 (25% reduction, P < 0.001); and 150 ppm bilobalide, 71 +/- 30 (33% reduction, P < 0.01). Immunohistochemically, EGb or bilobalide administration significantly lowered PCNA index in normal-appearing crypts. Feeding with EGb or bilobalide increased activities of CYP as well as GST and QR in the liver. These findings might suggest possible chemopreventive ability of EGb or bilobalide, through alterations in cryptal cell proliferation activity and drug metabolizing enzymes' activities, in colon tumorigenesis.

25.Clinical study on treatment of patients with upper digestive tract malignant tumors of middle and late stage with Ginkgo biloba exocarp polysaccharides capsule preparation.:

Zhong Xi Yi Jie He Xue Bao. 2003 Sep;1(3):189-91.PMID: 15339558
OBJECTIVE: To observe the clinical efficacy of Ginkgo biloba exocarp polysaccharides (GBEP) capsule preparation in treating upper digestive tract malignant tumors of middle and late stage.METHODS: Eighty-six patients of the upper digestive tract malignant tumors were treated with GBEP capsule preparation taken orally. The clinical symptoms and the qualities of life of the patients with single GBEP and combined with operation, radiotherapy or intervention chemotherapy were observed. The tumor size was measured by electronic gastroscope before and after treatment with single GBEP. Objective response rate (RR) of the tumor was calculated. The survival period of patient was observed. The changes of blood routine examination in the patients treated with radiotherapy were observed.RESULTS: GBEP preparation could markedly improve the patients'clinical symptoms. Karnofsky scoring of the patients markedly increased after treatment. There were 2 CR (complete response, 6.3%), 22 PR (partial response, 68.8%)and 5 SD (stable disease, 15.6%) of 32 cases with single GBEP preparation. The survival periods of the 32 cases were markedly prolonged. The preparation could relieve the inhibited hematopietic function and the weight loss due to radiotherapy.CONCLUSION: GBEP capsule preparation has some definite therapeutic effects on upper digestive tract malignant tumors of middle and late stage.

26.Ginkgo biloba extract prevents high altitude pulmonary edema in rats.:

High Alt Med Biol. 2004 Winter;5(4):429-34.PMID: 15671632
Ginkgo biloba reduces the severity of acute mountain sickness in humans, but protection against high altitude pulmonary edema (HAPE) has not been reported. This study was conducted to determine if G. biloba would prevent early HAPE in rats. Six rats (ginkgo group) received G. biloba (200 mg/kg body weight in drinking water and an equal amount in peanut butter) for 2 days before and during high altitude exposure (380 mmHg pressure for 24 h). Six other rats (control group) received water and peanut butter alone. Protein concentrations in bronchoalveolar lavage fluid (BALF) were increased in control rats (19.8 +/- 2.6 mg/dL) compared to ginkgo rats (11.6 +/- 0.9 mg/dL; p = 0.014), demonstrating that untreated (control) rats developed mild HAPE following high altitude exposure. For comparison, BALF protein concentrations in sea-level rats (air group) given peanut butter were 12.6 +/- 0.8 mg/dL (n = 6). Although pleural effusions did not develop in any rats, the protein concentrations of pleural fluid were also increased in control rats (4.9 +/- 0.16 g/dL) compared to ginkgo rats (4.0 +/- 0.13; p = 0.001); air group: 3.5 +/- 0.08 g/dL. There were no differences in wet/dry lung weight ratios between groups, but wet left lung weights/preexposure body weight were increased in control rats (1.26 +/- 0.02 g/kg) compared to the ginkgo group (1.17 +/- 0.01 g/kg; p = 0.002); air group: 1.11 +/- 0.03 g/kg. In conclusion, the data show that G. biloba prevents the development of early HAPE in rats.

27.Ginkgo biloba extract (EGb 761) induces apoptosis by the activation of caspase-3 in oral cavity cancer cells.:

Oral Oncol. 2005 Apr;41(4):383-9.PMID: 15792610
We have investigated whether Ginkgo biloba extract (EGb 761) induces apoptosis of oral cavity cancer cells and attempted to characterize the apoptotic pathway activated by EGb 761. The inhibition of SCC 1483 oral cavity cancer cells proliferation was noted from 250 micro/ml of EGb 761. Apoptosis was observed after 24 h of incubation with 250 microg/ml EGb 761 and occurred in a time- and dose-dependent manner. Apoptosis was confirmed by DNA fragmentation and PARP cleavage. Co-treatment with the caspase inhibitor (z-VAD-fmk) inhibited apoptosis and PARP cleavage induced by EGb 761. Caspase-3 activity was upregulated by EGb 761 but reduced to the control level by co-treating with z-VAD-fmk. In summary, EGb 761 induces apoptosis of oral cavity cancer cells and caspase-3 is activated in this apoptosis. Therefore, EGb 761 may be considered as a possible chemopreventive agent against oral cavity cancer.

28.Ginkgolides induce apoptosis and decrease cell numbers in mouse blastocysts.:

Biochem Biophys Res Commun. 2005 Dec 16;338(2):1263-7. Epub 2005 Oct 24.PMID: 16259949
In this report, we examine the cytotoxic effect of ginkgolides, the major components of Ginkgo biloba extracts, on the blastocyst stage of mouse embryos and on subsequent early postimplantation embryonic development in vitro. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay revealed that blastocysts treated with 5 or 10muM ginkgolide A or ginkgolide B showed increased apoptosis versus untreated controls. This could be correlated with the observation that ginkgolide-treated blastocysts showed a significant reduction in the average number of total cells in the blastocyst and trophectoderm/inner cell mass lineage versus controls. In addition, ginkgolide-pretreated blastocysts showed normal levels of implantation on culture dishes in vitro, but significantly fewer embryos reached the later stages of embryonic development in the treatment groups versus the controls, instead dying at relatively early stages of development. Our results collectively indicate that ginkgolide treatment of mouse blastocysts induces apoptosis, decreases cell numbers, retards early postimplantation blastocyst development, and increases early-stage blastocyst death. These novel findings provide important new insights into the effect of Ginkgo biloba extracts on mouse blastocysts.

29.Cancer-related overexpression of the peripheral-type benzodiazepine receptor and cytostatic anticancer effects of Ginkgo biloba extract (EGb 761).:

Anticancer Res. 2006 Jan-Feb;26(1A):9-22.PMID: 16475673
The peripheral-type benzodiazepine receptor (PBR) is an 18-kDa high affinity drug- and cholesterol-binding protein that is involved in various cell functions, including cell proliferation and apoptosis. PBR was shown to be overexpressed in certain types of malignant human tumors and cancer cell lines, correlating with enhanced tumorigenicity and cell proliferation rates. The present study was conducted in order to further define the role of PBR in cancer and to extend our recent findings regarding the possible anticancer effects of the standardized Ginkgo biloba extract EGb 761. Treatment with EGb 761 decreased PBR mRNA levels and inhibited the proliferation of breast, glioma and hepatocarcinoma cell lines, further corroborating our previous contention that its mechanism of action is through the modification of PBR expression. In vivo treatment with Ginkgo biloba extract led to dose-dependent decreases in xenograft growth of both MDA-MB-231 breast cancer and U-87 glioma cell lines in nude mice, although the effects were not maintained after 50 days of treatment in the latter. The results obtained in MDA-MB-231 xenografts indicated pronounced inhibition of tumor growth, verified by MRI imaging. These results were obtained using a modified experimental protocol where the animals were treated with the extract before cell inoculation. Although an exact role for PBR in relation to the initiation and progression of various types of cancer remains to be defined, our results indicate that PBR overexpression in certain cancer cells is related to an aggressive phenotype. Since EGb 761 treatment opposes this aggressive phenotype by decreasing PBR overexpression, it could be useful in preventing or treating cancer invasiveness and metastasis.

30.An adjunctive preventive treatment for cancer: ultraviolet light and ginkgo biloba, together with other antioxidants, are a safe and powerful, but largely ignored, treatment option for the prevention of cancer.:

Med Hypotheses. 2006;66(6):1152-6. Epub 2006 Feb 17.PMID: 16483725
Cancer has surpassed heart disease as the leading cause of death in the United States. The mortality rate for cancer is high (roughly 42%), and it increases dramatically with increasing age, especially in patients between the ages of 40 and 60 years old. Currently, the efforts at cancer prevention have been minimal. The drugs developed so far are expensive and have serious side effects. There are at least 18 vitamin D-sensitive cancers. Ultraviolet light, and specifically ultraviolet B (UVB), could reduce cancer by the limited exposure of suitable skin areas to UVB of an intensity and duration insufficient to produce skin cancer. An irrational fear of skin cancer is preventing this idea from being implemented. Though skin cancer incidence is significant, mortality from skin cancer is relatively rare. Roughly 1,000,000 Americans will be affected by skin cancer but only 10,000 deaths are expected in 2005 (a 1% mortality rate). Skin cancer is easily detected and often cured by excisional biopsy alone. Current practice among practicing clinicians is to use a prescription drug substitute for UV light, calcitriol (1-25 dihydroxycholcalciferol). However, high levels of (calcitriol) are dangerous, and there is no consensus on just what a high dose or a safe dose is. Apart from skin cancer, UV light exposure possesses few risks. Additionally, a number of botanical agents such as ginkgo biloba, vitamins E and C, carotenoids, selenium and proanthocyanidins can prevent the risk of skin cancer. Ginkgo biloba also possess the following additional cancer chemopreventive qualities: (1) promoting apoptosis of cancer cells; (2) an anti-clastogenic effect on chromosomes by repairing and reconstituting broken and damaged chromosomes; (3) a powerful therapeutic effect on the treatment of fibrosis-related cancer; (4) a therapeutic effect on free radical-induced cancer; (5) a therapeutic effect on the treatment of cancer incident to the result of numerous carcinogens; (6) a therapeutic effect on preventing free radical-induced cancer; (7) an enhancing effect on radiation therapy in the treatment of cancer; and (8) a therapeutic effect on reducing the size of cancer tumors. Ginkgo biloba is widely-used and has few adverse effects. The proposed preventive treatment for cancer consists of short intermittent exposure of the least sensitive areas of the body to sunlight and/or artificial ultraviolet light. The routine testing of plasma vitamin D levels help monitor the effectiveness of the treatment and periodic checkups with a dermatologist help monitor the safety.

31.Targeting angiogenesis with integrative cancer therapies.:

Integr Cancer Ther. 2006 Mar;5(1):9-29.PMID: 16484711
An integrative approach for managing a patient with cancer should target the multiple biochemical and physiological pathways that support tumor development while minimizing normal tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The authors will focus on natural health products (NHPs) that have a high degree of antiangiogenic activity but also describe some of their many other interactions that can inhibit tumor progression and reduce the risk of metastasis. NHPs target various molecular pathways besides angiogenesis, including epidermal growth factor receptor (EGFR), the HER-2/neu gene, the cyclooxygenase-2 enzyme, the NF-kB transcription factor, the protein kinases, Bcl-2 protein, and coagulation pathways. The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are confirming the knowledge that is already documented in traditional texts. The following herbs are traditionally used for anticancer treatment and are antiangiogenic through multiple interdependent processes that include effects on gene expression, signal processing, and enzyme activities: Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (turmeric), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinale (ginger), Panax ginseng, Rabdosia rubescens (rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking on clinical trials. More data are required on dose response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as biological response modifiers and adaptogens, potentially enhancing the efficacy of the so-called conventional therapies. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials might be preferred, smaller studies with appropriate end points and surrogate markers for antiangiogenic response could help prioritize agents for the larger resource-intensive phase 3 trials.

32.Bilobalide prevents ischemia-induced edema formation in vitro and in vivo.:

Neuroscience. 2007 Jan 5;144(1):217-22. Epub 2006 Oct 2.PMID: 17014966
EGb761, a standardized extract of Ginkgo biloba, has neuroprotective properties in animal models of ischemia, an activity that is partially attributed to its constituent, bilobalide. EGb761 has also been reported to inhibit edema formation induced by toxins such as triethyltin. The goal of this study was to test the activity of pure bilobalide to prevent edema formation in models of ischemia. Oxygen-glucose deprivation (OGD) in rat hippocampal slices served as a model of in vitro-ischemia. OGD caused cellular edema formation as indicated by an increase of slice water contents in 30 min. Bilobalide (1-10 microM) reduced slice water contents in ischemic slices in a concentration-dependent manner. As a model of in vivo-ischemia, we performed middle cerebral artery occlusion (MCAO) in mice. Permanent MCAO caused cell death and swelling of the ischemic hemisphere within 24 h. Pretreatment of the mice with bilobalide (10 mg/kg i.p.) reduced infarct area by 43% (as judged by 2,3,5-triphenyl-tetrazolium chloride (TTC) staining) and edema formation by 70% (as judged by hemispheric enlargement). In parallel experiments, pretreatment with bilobalide also reduced forebrain water contents in the ischemic hemisphere by 57%. As an alternative model of brain edema formation, we used water intoxication to increase brain water content; bilobalide, was, however, inactive in this model. We conclude that bilobalide strongly and specifically attenuates edema formation in models of brain ischemia in vitro and in vivo. Bilobalide may be therapeutically effective in brain edema which occurs secondarily to large hemispheric stroke and traumatic brain injury in humans.

33.Ginkgo biloba and ovarian cancer prevention: epidemiological and biological evidence.:

Cancer Lett. 2007 Jun 18;251(1):43-52. Epub 2006 Dec 27.PMID: 17194528
There is considerable interest in herbal therapies for cancer prevention but often with little scientific evidence to support their use. In this study, we examined epidemiological data regarding effects of commonly used herbal supplements on risk for ovarian cancer and sought supporting biological evidence. 4.2% of 721 controls compared to 1.6% of 668 cases regularly used Ginkgo biloba for an estimated relative risk (and 95% confidence interval) of 0.41 (0.20,0.84) (p=0.01); and the effect was most apparent in women with non-mucinous types of ovarian cancer, RR=0.33 (0.15,0.74) (p=0.007). In vitro experiments with normal and ovarian cancer cells showed that Ginkgo extract and its components, quercetin and ginkgolide A and B, have significant anti-proliferative effects ( approximately 40%) in serous ovarian cancer cells, but little effect in mucinous (RMUG-L) cells. For the ginkgolides, the inhibitory effect appeared to be cell cycle blockage at G0/G1 to S phase. This combined epidemiological and biological data provide supportive evidence for further studies of the chemopreventive or therapeutic effects of Ginkgo and ginkgolides on ovarian cancer.

34.Dosage effects of ginkgolide B on ethanol-induced cell death in human hepatoma G2 cells.:

Ann N Y Acad Sci. 2007 Jan;1095:388-98.PMID: 17404051
Ginkgolide B is a major active component of Ginkgo biloba extracts, which has been shown to confer anticancer effects by inducing apoptosis or inhibiting oxidative stress generation. Ethanol induces a wide range of cellular toxicities, many of which have been linked to free radical generation. To further elucidate the cellular effects of ginkgolide B, we examined the dose-response effect of ginkgolide B on ethanol-induced toxicity in human Hep G2 cells. TUNEL and MTT assays revealed that ethanol (50-400 mM) induced apoptotic cell death in human Hep G2 cells, and that this effect was inhibited by low (5-25 microM) doses of ginkgolide B, but enhanced by high (50-100 microM) doses of ginkgolide B. Additional experiments revealed that ethanol treatment directly increased intracellular oxidative stress; this effect was enhanced by high doses of ginkgolide B but decreased following treatment with low concentrations of ginkgolide B. The dose-response effects of ginkgolide B on reactive oxygen species (ROS) generation were directly correlated with cell apoptotic biochemical changes including c-Jun N-terminal kinase (JNK) activation, caspase-3 activation, and DNA fragmentation. These results indicate that treatment dosage may determine the effect of ginkgolide B on ethanol-induced ROS generation and cell apoptosis, and support the notion that an appropriate dosage of ginkgolide B may aid in decreasing the toxic effects of ethanol.

35.Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 1.:

Curr Oncol. 2006 Feb;13(1):14-26.PMID: 17576437
An integrative approach for managing a patient with cancer should target the multiple biochemical and physiologic pathways that support tumour development and minimize normal-tissue toxicity. Angiogenesis is a key process in the promotion of cancer. Many natural health products that inhibit angiogenesis also manifest other anticancer activities. The present article focuses on products that have a high degree of anti-angiogenic activity, but it also describes some of the many other actions of these agents that can inhibit tumour progression and reduce the risk of metastasis. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclooxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. The herbs that are traditionally used for anticancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy, they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies.

36.Natural health products that inhibit angiogenesis: a potential source for investigational new agents to treat cancer-Part 2.:

Curr Oncol. 2006 Jun;13(3):99-107.PMID: 17576449
The herbalist has access to hundreds of years of observational data on the anticancer activity of many herbs. Laboratory studies are expanding the clinical knowledge that is already documented in traditional texts. The herbs that are traditionally used for anti-cancer treatment and that are anti-angiogenic through multiple interdependent processes (including effects on gene expression, signal processing, and enzyme activities) include Artemisia annua (Chinese wormwood), Viscum album (European mistletoe), Curcuma longa (curcumin), Scutellaria baicalensis (Chinese skullcap), resveratrol and proanthocyanidin (grape seed extract), Magnolia officinalis (Chinese magnolia tree), Camellia sinensis (green tea), Ginkgo biloba, quercetin, Poria cocos, Zingiber officinalis (ginger), Panax ginseng, Rabdosia rubescens hora (Rabdosia), and Chinese destagnation herbs. Natural health products target molecular pathways other than angiogenesis, including epidermal growth factor receptor, the HER2/neu gene, the cyclo-oxygenase-2 enzyme, the nuclear factor kappa-B transcription factor, the protein kinases, the Bcl-2 protein, and coagulation pathways. Quality assurance of appropriate extracts is essential prior to embarking upon clinical trials. More data are required on dose-response, appropriate combinations, and potential toxicities. Given the multiple effects of these agents, their future use for cancer therapy probably lies in synergistic combinations. During active cancer therapy they should generally be evaluated in combination with chemotherapy and radiation. In this role, they act as modifiers of biologic response or as adaptogens, potentially enhancing the efficacy of the conventional therapies or reducing toxicity. Their effectiveness may be increased when multiple agents are used in optimal combinations. New designs for trials to demonstrate activity in human subjects are required. Although controlled trials may be preferable, smaller studies with appropriate endpoints and surrogate markers for anti-angiogenic response could help to prioritize agents for larger, resource-intensive phase iii trials.

37.Antimutagenic in vitro activity of plant polyphenols: Pycnogenol and Ginkgo biloba extract (EGb 761).:

Phytother Res. 2008 Mar;22(3):384-8.PMID: 18167041
Ofloxacin (15 microg/mL) and acridine orange (5 microg/mL) induce mutagenicity by different mechanisms in the photosynthetic flagellate Euglena gracilis. The present study examined whether Pycnogenol (PYC; 5-100 microg/mL) or Ginkgo biloba extract (EGb 761; 5-100 microg/mL) could protect against the mutagenic effects of each of the mutagens and the potential mechanisms underlying such protection. The highest concentration of PYC and EGb 761 effectively reduced the mutagenic activity of both ofloxacin and acridine orange by more than 99% (p < 0.001). Using luminol-dependent photochemical methodology it was demonstrated that EGb 761 and PYC were effective antioxidants. In addition, as determined by spectrophotometry, PYC and EGb 761 bound acridine orange. Both PYC and EGb 761 have been shown to produce dual antimutagenic effects, as evidenced by both antioxidant and physicochemical properties. The findings suggest that EGb 761 and PYC would thus be suitable for future study, not only as antioxidants, but also as antimutagenic agents.

38.Effect of extract of Ginkgo biloba on doxorubicin-associated cardiotoxicity in patients with breast cancer:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2008 Jan;28(1):68-70.PMID: 18418975
OBJECTIVE: To study the effect of extract of Ginkgo biloba (Egb761) on doxorubicin-associated cardiotoxicity in patients with breast cancer (BC).METHODS: Sixty BC patients in stage IV were randomly assigned to two groups, the control group was treated with chemotherapy, using 4 cycles of PA protocol alone and the treated group with the same chemotherapy and Egb761. Changes in electrocardiogram (ECG), myocardial enzyme spectrum (MES) and ultrasono-cardiogram (USCG) before and after treatment were observed.RESULTS: After treatment, the incidence of abnormal ECG was lower in the treated group than in the control group (6.7% vs 30.0%); significant differences were found between the two groups in the parameters of MES (P< 0.05); USCG showed significant difference between the two groups in left ventricular diastolic diameter (LVDd), left ventricular systolic diameter (LVDs), ratio of early and late diastolic transmitral peak flow velocity (E/A) and fractional shortening (FS), while there was no significant difference in ejection fraction (EF).CONCLUSION: Egb761 is an ideal drug for preventing and reducing the acute doxorbincin-induced cardiotoxicity; it could also be helpful for alleviating the chronic cardiotoxicity.

39.Ginkgo biloba extract kaempferol inhibits cell proliferation and induces apoptosis in pancreatic cancer cells.:

J Surg Res. 2008 Jul;148(1):17-23. Epub 2008 Mar 26.PMID: 18570926
BACKGROUND: Kaempferol is one of the most important constituents in ginkgo flavonoids. Recent studies indicate kaempferol may have antitumor activities. The objective of this study was to determine the effect and mechanisms of kaempferol on pancreatic cancer cell proliferation and apoptosis.MATERIALS AND METHODS: Pancreatic cancer cell lines MIA PaCa-2 and Panc-1 were treated with kaempferol, and the inhibitory effects of kaempferol on pancreatic cancer cell proliferation were examined by direct cell counting, 3H-thymidine incorporation, and MTS assay. Lactate dehydrogenase release from cells was determined as an index of cytotoxicity. Apoptosis was analyzed by terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay.RESULTS: Upon the treatment with 70 microm kaempferol for 4 days, MIA PaCa-2 cell proliferation was significantly inhibited by 79% and 45.7% as determined by direct cell counting and MTS assay, respectively, compared with control cells (P < 0.05). Similarly, the treatment with kaempferol significantly inhibited Panc-1 cell proliferation. Kaempferol treatment also significantly reduced 3H-thymidine incorporation in both MIA PaCa-2 and Panc-1 cells. Combination treatment of low concentrations of kaempferol and 5-fluorouracil showed an additive effect on the inhibition of MIA PaCa-2 cell proliferation. Furthermore, kaempferol had significantly less cytotoxicity than 5-fluorouracil in normal human pancreatic ductal epithelial cells (P = 0.029). In both MIA PaCa-2 and Panc-1 cells, apoptotic cell population was increased when treated with kaempferol in a concentration-dependent manner.CONCLUSIONS: Ginkgo biloba extract kaempferol effectively inhibits pancreatic cancer cell proliferation and induces cancer cell apoptosis, which may sensitize pancreatic tumor cells to chemotherapy. Kaempferol may have clinical applications as adjuvant therapy in the treatment of pancreatic cancer.

40.Ginkgo biloba extract EGb 761 exerts anti-angiogenic effects via activation of tyrosine phosphatases.:

J Cell Mol Med. 2009 Aug;13(8B):2122-30. Epub 2008 Oct 23.PMID: 19175691
The standardised Ginkgo biloba extract EGb 761 (Dr. Willmar Schwabe Pharmaceuticals, Karlsruhe, Germany) is one of the most widely used herbal remedies. Indications for this extract range from dementia to peripheral vascular disease, based on well-documented vascular effects. Surprisingly, the actions of EGb 761 on angiogenesis as a function of vascular cells have not been investigated to date. The anti-cancer activity of EGb 761 in vitro and epidemiological data showing reduced risk for ovarian cancer in regular users have prompted us to investigate this issue. We show an anti-angiogenic profile of EGb 761 in vitro (inhibited proliferation, migration and tube formation of endothelial cells) and in vivo in the chicken chorio-allantoic membrane (CAM) assay. An analysis of the underlying mechanisms indicates inhibition of growth factor-induced extracellular signal-regulated kinase (ERK) phosphorylation by EGb 761. Inhibitory effects of EGb 761 on ERK as well as of the upstream kinases map-erk-kinase (MEK) and rapidly growing fibrosarcoma (Raf)-1 could be completely reversed by pre-treatment with sodium vanadate (inhibitor of tyrosine phosphatases). Sodium vanadate also reversed the EGb 761-induced inhibition of endothelial cell migration. Focusing on tyrosine phosphatases upstream of the Raf-MEK-ERK cascade, we identified the tyrosine phosphatase Src homology-2 domain-containing phosphatase 1 (SHP-1) as one target of EGb 761. SHP-1 was rapidly activated by EGb 761, and silencing SHP-1 (siRNA) abrogated reduction of endothelial proliferation by EGb 761. In summary, we identify EGb 761 as a potent anti-angiogenic drug. The underlying mechanism is the activation of protein tyrosine phosphatases, leading to inhibition of the Raf-MEK-ERK pathway. These findings provide a rational basis for using EGb 761 for an additional therapeutic indication: anti-angiogenesis-based tumour prevention and adjuvant therapy.

41.Comparative anticancer and antioxidant activities of different ingredients of Ginkgo biloba extract (EGb 761).:

Planta Med. 2009 Jun;75(8):792-6. Epub 2009 Mar 13.PMID: 19288403
Flavonoid glycosides are the major constituents of Ginkgo biloba extract (EGb 761) and are well known to be an antioxidant for inhibiting tumor growth. Because it contains several flavonoid glycosides and other bioactive substances, the activities of EGb 761 against cancer in vivo and in vitro remain poorly understood. This situation prompted interest in the compounds for experimental study. We have investigated the anticancer effects of three analogues of EGb 761 samples on sarcoma 108 (S180)-bearing mice and leukemic 1210 (L1210) cell lines. We have also evaluated the changes of endogeneous antioxidant scavenging enzymes, including superoxide dismutase (SOD), glutathione (GST), lipid peroxidation (LPx), and catalase (CAT), in the blood of the S180-bearing mice. The EGb 761, EGb 761-H (containing mainly flavonoid aglycones and terpene trilactones), and EGb 761-DT-H (containing mainly flavonoid aglycones) samples exhibited cytotoxicity and inhibitory activity with IC (50) values of 46.36 +/- 2.43 microM, 10.27 +/- 0.88 microM, and 14.93 +/- 0.73 microM in L1210 cell-based assays, respectively. This resulted in 41.74 %, 60.72 %, and 63.76 % reductions in tumor weight after 10 days of treatment, respectively. In summary, the anticancer activity of EGb 761 can be improved by increasing the concentration of the aglycone form of the flavonoid. Terpene trilactones cannot exert the anticancer effects of flavonoids in vivo. Raising the levels of the free radical scavenger enzymes GST, SOD and CAT may be one of the involved anticancer mechanisms.

42.Antimutagenicity protection of Ginkgo biloba extract (Egb 761) against mitomycin C and cyclophosphamide in mouse bone marrow.:

Genet Mol Res. 2009 Mar 24;8(1):328-33.PMID: 19440968
Ginkgo biloba (Egb 761) extract, the most prescribed phytomedicine in Europe for the treatment of cerebral insufficiency and vascular diseases, was tested for its possible protective effects against mitomycin C (MMC)- and cyclophosphamide (CP)-induced mutagenicity using the micronucleus test in mouse bone marrow. The extract was co-administered to mice at doses of 50, 100 and 200 mg/kg (po) with 4 mg/kg (ip) MMC or 24 mg/kg (ip) CP. All doses of Egb 761 were significantly (P < 0.05) effective in reducing the frequency of micronucleated polychromatic erythrocytes, when compared with MMC or CP alone. Based on these results, we suggest that Egb 761 possesses both direct and indirect antimutagenic potential.

43.Ginkgo biloba extracts (EGb761) inhibits aflatoxin B1-induced hepatocarcinogenesis in Wistar rats:

Zhong Yao Cai. 2009 Jan;32(1):92-6.PMID: 19445131
OBJECTIVE: To investigate the effect of Ginkgo biloba extracts (EGb761) on aflatoxin B1 (AFB1)-induced hepatocarcinogenesis and its antioxidant activity in Wistar rats.METHODS: 71 Wistar rats were randomly divided into three groups: AFB1 (group A); AFB1 +EGb761 (group B), Control (group C). Rats in gurop A and B were injected with AFB, through abdomen and the doses were 100-200 microg/kg, one to three times a week. Liver biopsy were performed in all rats during 14th w, 28th w, 42th w and 55th w, and were executed at 64th w. Gammaglutamyl transpeptidase-positive hyperplastic cell foci (gamma-GT foci) and histopathology of the liver tissue were observed. The levels of malondialdehyde (MDA), as well as the activity of Glutathione peroxidase (GSH-Px) was examined.RESULTS: At 42th w and 55th w, the gamma-GT focus area (mm2/focus) and general area of foci (mm2/cm2) of group B were significantly smaller than that in group A (P = 0.000). The incidence of hepatocelluiar carcinoma (HCC) in group B (26.92%) was significantly lower than that in group A(76%) (P = 0.000). Group C didnt have HCC development. EGb 761 markedly increased GSH-Px activity, reduced MDA levels (P < 0.05).CONCLUSION: EGB761 shows effective inhibition to hepatocarcinogenesis induced by AFB1 in rats, which may be related to its antioxidant activity.

44.Gingko biloba leaf extract induces oxidative stress in carcinoma HSC-2 cells.:

Toxicol In Vitro. 2009 Sep;23(6):992-9. Epub 2009 Jun 25.PMID: 19560534
The antiproliferative effects of a Gingko biloba leaf extract to cells from tissues of the human oral cavity were studied. Toxicity to carcinoma HSC-2 cells was correlated with the prooxidative nature of the extract. G. biloba leaf extract generated reactive oxygen species (ROS) in cell culture medium and, albeit to a lesser extent, in buffer, with higher levels detected at alkaline pH. Lowered levels of ROS were detected in culture medium coamended with the extract and with either catalase or superoxide dismutase, indicating the generation of hydrogen peroxide and superoxide anion, respectively. Biological activity of the extract was through oxidative stress. Toxicity to the HSC-2 cells was lessened by the ROS scavengers, divalent cobalt and pyruvate, by catalase, and by the antioxidant, N-acetyl-L-cysteine, and was potentiated by the glutathione depleters, DL-buthionine-[S,R]-sulfoximine, 1-chloro-2,4-dinitrobenzene, and bis(2-chloroethyl)-N-nitrosourea. G. biloba reacted directly with authentic glutathione and lowered the intracellular glutathione content in HSC-2 cells. Induction of apoptosis upon exposure of HSC-2 cells to G. biloba extract was noted by apoptotic cell morphologies, by TUNEL staining, and by PARP cleavage. The data strongly suggest that the prooxidative nature of the G. biloba extract was the cause of apoptotic cell death.

45.Kaempferol and quercetin, components of Ginkgo biloba extract (EGb 761), induce caspase-3-dependent apoptosis in oral cavity cancer cells.:

Phytother Res. 2010 Jan;24 Suppl 1:S77-82.PMID: 19585476
EGb 761, extracted from Ginkgo biloba leaves, has been proven to induce caspase-3-dependent apoptosis in oral cavity cancer cells. Since EGb 761 is a composition of various components, it is important to identify which components are responsible for its anticancer effects to reduce the total dosage and to avoid toxicity. Therefore, the study aimed to determine the effective compounds of EGb 761 that induce apoptosis in oral cavity cancer cells and to identify whether caspase-3 was involved in apoptosis of oral cancer cells by EGb 761 components. The results of cell proliferation assays on oral cavity cancer cells showed that kaempferol and quercetin significantly inhibited cellular proliferation at a concentration of 40 microM. Flow cytometry showed that the antiproliferative effects of each component were due to increased apoptosis. Kaempferol and quercetin induced apoptosis in various oral cancer cell lines (SCC-1483, SCC-25 and SCC-QLL1) and showed cleavage of poly (ADP-ribose) polymerase (PARP). Caspase-3 activity assay revealed that induction of apoptosis by kaempferol and quercetin was caspase-3-dependent. In conclusion, the results suggest that kaempferol and quercetin, two components of EGb 761, effectively induce caspase-3-dependent apoptosis of oral cavity cancer cells and can be considered as possible anti-oral cavity cancer agents.

46.Interventional effect of Ginkgo biloba extract on the progression of gastric precancerous lesions in rats.:

J Dig Dis. 2009 Nov;10(4):293-9.PMID: 19906108
OBJECTIVE: To investigate the effect of Ginkgo biloba extract on gastric precancerous lesions in rats.METHODS: 80 4-week-old Wistar rats were randomly divided into four groups: a control group, a model group, a low and a high dose Ginkgo biloba extract intervention group; 20 in each group. Gastric precancerous lesions were induced by giving them 100 mg/L N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) solution to drink ad libitum for 20 weeks. In addition to the MNNG, the intervention groups were lavaged with Ginkgo biloba extract (0.5 mg/kg/d in the low dose group, 1.5 mg/kg/d in the high dose group) for 20 weeks. Starting from week 21 all the rats were fed with normal rat chow and tap water. At the end of week 30 the rats were killed. The histopathological changes of their gastric mucosa, ISA, NGI, the serum and gastric mucosal SOD/MDA and the expressions of oncogenes were studied.RESULTS: The incidence of mild to severe intestinal metaplasia and dysplasia were significantly lower in the intervention groups than those in the model group (P < 0.01). The ISA and NGI in the intervention groups were significantly lower than those in the model group (P < 0.01). In the intervention groups the activity of SOD was increased and the concentration of MDA was decreased (P < 0.01). Expressions of Bcl-2, c-myc and FasL decreased in the intervention groups, whereas the expression of Fas increased. When compared with the model group, the differences were statistically significant (P < 0.01, P < 0.05, respectively).CONCLUSION: Ginkgo biloba extract can increase anti-oxidative activity and inhibit the progression of gastric precancerous lesions via the regulation of cell proliferation and apoptosis.

47.Ginkgo biloba and risk of cancer: secondary analysis of the Ginkgo Evaluation of Memory (GEM) Study.:

Pharmacoepidemiol Drug Saf. 2010 Jul;19(7):694-8.PMID: 20582906
PURPOSE: Evidence from in vitro and in vivo studies suggests that Ginkgo biloba has cancer chemopreventive properties, but epidemiological evidence is sparse. We analyzed cancer as a secondary endpoint in the Ginkgo Evaluation of Memory (GEM) Study, the largest randomized, double-blind, placebo-controlled clinical trial of Ginkgo supplementation to date.METHODS: A total of 3069 GEM participants 75+ years of age were randomized to twice-daily doses of either 120 mg Ginkgo extract (EGb 761) or placebo and followed for a median 6.1 years. We identified hospitalizations for invasive cancer by reviewing hospital admission and discharge records for all reported hospitalizations over follow-up. Using an intention-to-treat approach, we compared the risk of cancer hospitalization between participants assigned to treatment and those assigned to placebo.RESULTS: During the intervention, there were 148 cancer hospitalizations in the placebo group and 162 in the EGb 761 group (Hazard ratio (HR), 1.09; 95% confidence interval (CI), 0.87-1.36; p = 0.46). Among the site-specific cancers analyzed, we observed an increased risk of breast (HR, 2.15; 95%CI, 0.97-4.80; p = 0.06) and colorectal (HR, 1.62; 95%CI, 0.92-2.87; p = 0.10) cancer, and a reduced risk of prostate cancer (HR, 0.71; 95%CI, 0.43-1.17; p = 0.18).CONCLUSIONS: Overall, these results do not support the hypothesis that regular use of Ginkgo biloba reduces the risk of cancer.

48.Antitumor effects of ginkgolic acid in human cancer cell occur via cell cycle arrest and decrease the Bcl-2/Bax ratio to induce apoptosis.:

Chemotherapy. 2010;56(5):393-402. Epub 2010 Oct 15.PMID: 20948210
BACKGROUND: Ginkgolic acids (GAs), extracted from the seed coat of Ginkgo biloba L. Our previous study has shown that GA monomer could inhibit the growth of Hep-2 significantly and induce the fragmentation of the chromosomal DNA. To further assess the antitumor potential and turn it into a candidate new antitumor drug, the antitumor mechanism of GA was investigated.METHOD: The cytotoxicity and antitumor effect of GA monomer were assayed by MTT colorimetric assay with nontumorogenic MC-3T3-E1 as well as tumorogenic Hep-2 and Tac8113 cell lines. The effect of GA monomer on the proliferation of tumor cell lines was analyzed with MTT colorimetric and CFSE labeled assay. Cell cycle distribution and measurement of the percentage of apoptotic cells were performed by flow cytometry following stained with propidium iodide, annexin V-FITC. The expression of apoptotic proteins Bcl-2, Bax and caspase-3 was analyzed with Western blot.RESULT: GA only inhibited the growth of tumorogenic cell lines in a both dose- and time-dependent manner. Tumor cells were treated with GA for 72 h, 70.53 ± 4.54% Hep-2 and 63.5 ± 7.2% Tca8113 cells were retarded at GO/G1 phase, and the percentage of apoptosis was 40.4 ± 1.58 and 38.4 ± 1.7%, respectively. GA-treated activated caspase-3 downregulated the expression of anti-apoptotic Bcl-2 protein and upregulated the expression of pro-apoptotic Bax protein, eventually leading to a decrease in the Bcl-2/Bax ratio in tumor cells.CONCLUSIONS: The antitumor action of GA was due to inhibiting the proliferation in a manner of inhibiting division, retarding the progress of cell cycle and inducing apoptosis, making GA a candidate as new antitumor drug.

E-Ginkgo Biloba:Inflammatory,Anti-inflammatory,Sepsis,Toxins,Ulcer Research:

1.Ginkgo biloba extract (EGb 761): inhibitory effect on nitric oxide production in the macrophage cell line RAW 264.7.:

Biochem Pharmacol. 1997 Mar 21;53(6):897-903.PMID: 9113109
The present study was conducted to evaluate the effect of Ginkgo biloba extract (EGb 761) on the synthesis of nitric oxide (NO) induced by lipopolysaccharide (LPS) plus interferon-gamma (IFN-gamma) in the mouse macrophage cell line RAW 264.7. EGb 761 inhibited nitrite and nitrate production, taken as an index for NO, in a concentration-dependent fashion. The IC50 for inhibition of nitrite production by activated macrophages was about 100 micrograms/mL EGb 761. The inducible NO synthase (iNOS) enzyme activity of cytosolic preparations from activated RAW 264.7 cells was inhibited by treatment with EGb 761. In addition, reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that the expression of iNOS mRNA in activated macrophages was suppressed by high concentrations of EGb 761. However, NF-kappa B DNA binding activity induced by activation with LPS/IFN-gamma was not inhibited by EGb 761. These findings indicate that not only does EGb 761 directly act as an NO scavenger but also that it inhibits NO production in LPS/IFN-gamma-activated macrophages by concomitant inhibition of induction of iNOS mRNA and the enzyme activity of iNOS. Thus, EGb 761 may act as a potent inhibitor of NO production under tissue-damaging inflammatory conditions.

2.The effects of prostaglandin E2 indomethacin & Ginkgo biloba extract on resistance to experimental sepsis.:

Indian J Med Res. 1998 Sep;108:88-92.PMID: 9798334
We investigated the effect of 16,16-dimethyl prostaglandin E2 indomethacin and Ginkgo biloba extract on the survival in two experimental sepsis models in rats due to administration of 1 x 10(7) cfu and 1 x 10(9) cfu Escherichia coli. Animals in each model were then randomly divided (10/group) into four groups, administered saline, indomethacin, G. biloba extract and prostaglandin E2 respectively. When compared, there was no significant difference in the survival period between the two sepsis models (P > 0.05). The best survival rate was observed in the PGE2-administered animals in the first major model (P < 0.05). Indomethacin appeared not to decrease the mortality rates. There was no significant difference in PGE2 levels between two sepsis models (P > 0.05). Our results suggest that elevated prostaglandin E2 levels following major trauma are not responsible for the postinjury increased susceptibility to infectious complications. Our observations should also discourage aggressive use of cyclo-oxygenase inhibitors for protection against infectious complications after major trauma.

3.Inhibition of rat adjuvant-induced arthritis by ginkgetin, a biflavone from ginkgo biloba leaves.:

Planta Med. 1999 Jun;65(5):465-7.PMID: 10418340
Ginkgetin, a biflavone isolated from Ginkgo biloba leaves, was previously reported as an inhibitor of group II phospholipase A2. In this study, ginkgetin was evaluated for in vivo antiarthritic and analgesic activities. Ginkgetin (10-20 mg/kg/day) strongly reduced arthritic inflammation in an animal model of rat adjuvant-induced arthritis (86% inhibition at 16 days at a dose of 20 mg/kg/day) via intraperitoneal injection, while prednisolone (5 mg/kg/day) showed 79% reduction. Histological examination of the knee joints confirmed our findings. When analgesic activity was measured, ginkgetin showed a dose-dependent inhibition in an animal model of acetic acid-induced writhing. ED50 values for ginkgetin and indomethacin were 8.9 and 3.8 mg/kg, respectively. All these results indicate that ginkgetin may be a potential antiarthritic agent having analgesic activity.

4.The effects of two new antagonists of secretory PLA2 on TNF, iNOS, and COX-2 expression in activated macrophages.:

Shock. 1999 Dec;12(6):473-8.PMID: 10588517
Phospholipase A2 (PLA2) regulates eicosanoid and platelet-activating factor production. It also plays an important role in the regulation of critical mediators in inflammatory diseases in which PLA2 activity is significantly enhanced during sepsis and multiple organ failure. Therefore, inhibitors of PLA2 activity offer themselves as target substances in the development of anti-inflammatory drugs. We identified 2 biflavonoids, bilobetin and ginkgetin, that can inhibit PLA2 activity. In experiments using 2-linol-[1-14C]PE as substrate both substances potently inhibited several kinds of type II 14-kDa PLA2 while inhibiting type I 14-kDa PLA2 to a lesser extent. We tested these PLA2 inhibitors for their ability to inhibit the production of tumor necrosis factor alpha (TNFalpha) and 2 enzymes, inducible nitric oxide synthase (iNOS) and inducible cyclooxygenase (COX-2) in an assay system using lipopolysaccharide (LPS)-stimulated Raw264.7 macrophages. In Raw264.7cells, bacterial LPS induced the production of COX-2 and iNOS proteins as well as TNFalpha. The inhibitors consistently inhibited the production of TNFalpha in a dose-dependent manner. Moreover, treatment of the macrophages with bilobetin and ginkgetin shut down the production of nitrite, one of the stable end products of NO released into the culture supernatant. The decrease in NO products was accompanied by a decrease in iNOS protein level as assessed by Western blot probed with specific anti-iNOS antibody. Both inhibitors also reduced the expression of COX-2 protein in the LPS-stimulated cells, which coincided with the reduction in iNOS protein. These results, therefore, suggest that these two sPLA2 inhibitors may be useful for inhibiting the production of inflammatory cytokine and NO production in inflammatory diseases.

5.Generalized convulsions after consuming a large amount of gingko nuts.:

Epilepsia. 2001 Feb;42(2):280-1.PMID: 11240603
We report a 36-year-old woman, without any past or family histories of epilepsy, who presented frequent vomiting and generalized convulsions. About 4 h before the convulsion, she had consumed approximately 70-80 gingko nuts, seeds of Gingko biloba, in an attempt to improve her health. It is important to know that convulsion may be induced if a large amount of gingko nuts is consumed. The neurotoxicity of gingko nuts, particularly their convulsion-inducing effect, should be recognized.

6.Protective effect of Gingko biloba extract against doxorubicin-induced cardiotoxicity in mice.:

Indian J Exp Biol. 2002 Aug;40(8):894-900.PMID: 12597018
Doxorubicin (DXR) causes dose dependent cardiotoxicity in experimental animals and in humans. In chronic doxorubicin cardiotoxicity model mice, the role of G. biloba extract (Gbe) which has an antioxidant property, was investigated. Doxorubicin treated animals showed higher mortality (68%), increased ascites, marked bradycardia, prolongation of ST and QT intervals and widening of QRS complex. Myocardial SOD and glutathione peroxidase activity were decreased and lipid peroxidation was increased. Ultrastructure of heart of DXR treated animals showed loss of myofibrils, swelling of mitochondria, vacuolization of mitochondria. G. biloba extract significantly protected the mice from cardiotoxic effects of doxorubicin as evidenced by lowered mortality, ascites, myocardial lipid peroxidation, normalization of antioxidant enzymes, reversal of ECG changes and minimal ultrastructural damage of the heart. The results indicate that administration of G. biloba extract protected mice from doxorubicin-induced cardiotoxicity.

7.Evaluation of the anti-inflammatory, anti-nociceptive and gastric effects of Ginkgo biloba in the rat.:

Pharmacol Res. 2004 Feb;49(2):133-42.PMID: 14643693
Ginkgo biloba extract (GbE) was assessed in models of acute inflammation induced by carrageenan, formalin or capsaicin in the rat, in models of nociceptive pain, such as hot-plate (55 degrees C) latency, tail-electric stimulation assay and capsaicin-induced paw licking and in the model of acute gastric damage induced by indomethacin. The agent showed marked anti-inflammatory activity in the carrageenan model of paw oedema. When given subcutaneously (s.c.) (25 and 50 mg kg(-1)) 30 min before challenge, GbE inhibited paw oedema with a maximal effect of 43.7 and 56.9%, respectively, at 2h post-carrageenan. Significant inhibition of oedema was also observed when GbE (50 mg kg(-1), s.c.) was given 30 min after carrageenan challenge. The agent was also active p.o. in acute inflammation caused by carrageenan. The administration of GbE with indomethacin, rofecoxib, celecoxib, dexamethasone or melatonin resulted in an additive effect. GbE (50 mg kg(-1), s.c.) caused significant inhibition of formalin-induced paw oedema, but did not reduce the capsaicin-induced paw oedema. In tests of nociception, GbE (25, 50 or 100 mg kg(-1)) decreased in dose-dependent manner the capsaicin-induced hind paw licking time and was similarly effective in the hot-plate assay of nociception. In contrast, when assessed in the tail-electric stimulation test, GbE was only effective in the highest dose (100 mg kg(-1)). In pylorus-ligated rats, GbE (25 or 50 mg kg(-1)) increased gastric acid secretion, but reduced gastric mucosal damage caused by IND. Results suggest that GbE may be of clinical value as an anti-inflammatory and analgesic drug alone or in conjunction with NSAIDs.

8.The effects of Ginkgo biloba extract on lipopolysaccharide-induced inflammation in vitro and in vivo.:

Exp Eye Res. 2004 Aug;79(2):181-7.PMID: 15325565
PURPOSE: Ginkgo biloba extract (GBE) contains many different flavone glycosides and terpenoides. Several previous studies have demonstrated that GBE exhibits a wide variety of biological activities, including an antioxidant action, on which we focused our attention. The aim of the present study was to investigate the efficacy of GBE on endotoxin induced uveitis in rats. The anti-inflammatory potency of GBE in vivo was compared with that of prednisolone. In addition, we also investigated nitric oxide (NO), prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and the expression of iNOS in a mouse macrophage cell line (RAW 264.7) treated with GBE in vitro to clarify the anti-inflammatory effect.METHODS: EIU was induced in male Lewis rats by a footpad injection of lipopolysaccharide (LPS). Immediately after the LPS inoculation, either 1, 10 or 100 microg of GBE were injected intravenously. 24hr later, the aqueous humor was collected from both eyes, and the number of infiltrating cells, protein concentration and NO level in the aqueous humor was determined. The RAW 264.7 cells were pretreated with various concentrations of GBE for 24hr and subsequently incubated with LPS for 24hr. Levels of NO, PGE2 and TNF-alpha were determined by enzyme-linked immunosorbent assay. The expression of iNOS protein was analyzed by Western blotting method.RESULTS: GBE treatment in vivo decreased the concentrations of protein and NO in the aqueous humor of EIU rats. The anti-inflammatory effect of 1 mg GBE was as strong as that of same dose prednisolone. It also significantly reduced the concentration of PGE2, TNF-alpha and NO production in the medium of RAW 264.7 cells compared to that of the LPS group in vitro. The expression of iNOS protein in the 1000 microg ml(-1) of GBE treated cells decreased significantly.CONCLUSION: The present results indicate GBE suppresses the inflammation of EIU by blocking the iNOS protein expression and its anti-inflammatory effect on eye is comparable with the effect of prednisolone used in similar doses.

9.Change of peripheral blood monocytes derived macrophage scavenger receptors activity in patients with coronary heart disease, and the intervention effect of ginkgo biloba extract:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2004 Dec;24(12):1069-72.PMID: 15658646
OBJECTIVE: To observe the activity of peripheral blood monocytes (PBMs) derived macrophage scavenger receptors (MSR) and changes of serum inflammatory factor in peripheral blood in patients with coronary heart disease (CHD), and to evaluate the effect of Ginkgo biloba extract (GBE) on the MSR activity, to explore the relationship between inflammatory factor and scavenger receptors activity as well as the possible mechanism of GBE in stabilizing the atheromatous plaque.METHODS: Ninety-seven CHD patients with normal blood lipids were classified into the stable angina group, the unstable angina group and the acute myocardial infarction group, and 29 healthy persons were taken as control. Levels of C-reactive protein (CRP), soluble intercellular adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in all subjects were determined. And their PBMs were isolated, cultured in vitro, and transferred into macrophage to observe the effect of GBE on the expression of scavenger receptors.RESULTS: The levels of MSR activity, CRP, sICAM-1 and sVCAM-1 in patients with acute myocardial infarction > unstable angina > stable angina > control.CONCLUSION: GBE could down-regulate the MSR activity in CHD patients, which was positively correlated with levels of CRP, sICAM-1 and sVCAM-1. MSR activity could be taken as a monitoring criteria for active degree of vulnerable atherosclerosis plaque. GBE has the effect of suppressing MSR activity.

10.Ginkgo terpene component has an anti-inflammatory effect on Candida albicans-caused arthritic inflammation.:

Int Immunopharmacol. 2005 Jun;5(6):1049-56.PMID: 15829420
The Ginkgo biloba extract, EGb 761, contains flavonoid glycosides and unique terpene lactones as major active components. In this study, we determined the anti-inflammatory effect of the water-soluble portion (GH415) of the EGb 761 on the inflammation caused by Candida albicans, a major ethiological agent that causes fungal arthritis. For inflammatory induction, an emulsified mixture of C. albicans cell wall and Complete Freund's Adjuvant (CACW/CFA) was injected into BALB/c mice by the hind footpad route once a day for 3 days. Twenty-four hours after the final injection, mice having the swollen footpad were given the GH415 (2 mg/dose) intraperitoneally to the mice once every 3 days for 15 days. The footpad-swelling of these mice was measured during the entire observation period. Results showed that the GH415 treatment reduced the swelling. In the same animal model, this effect was enhanced by treatment with the GH415 entrapped within liposome (Lipo-GH: 200 micro/dose). Further analysis revealed that terpene, not flavone portion, was responsible for such therapeutic anti-inflammatory effect. Treatment with the terpene (7.4 microg/dose) by liposomal delivery method had similar effects as the treatment with indomethacin at 30 microg/dose. Addition of the terpene to lipopolysaccharide-treated macrophages showed suppression of nitric oxide (NO) production. These results suggest that blockage of the NO production from the macrophages that infiltrated to the inflamed site may be a possible mechanism for the therapeutic anti-inflammatory effect.

11.Expression of pro-inflammatory and anti-inflammatory cytokines in brain of atherosclerotic rats and effects of Ginkgo biloba extract.:

Acta Pharmacol Sin. 2005 Jul;26(7):835-9.PMID: 15960890
AIM: To study the protein and mRNA expressions of pro-inflammatory and anti-inflammatory cytokines in the brain of rats with atherosclerosis (AS) and the effects of Ginkgo biloba extract (GbE) on expressions of cytokines.METHODS: The experimental model of AS in rats were established by intraperitioneal injection of vitamin D3 with high fat/cholesterol diet. GbE 100 mg/kg was administered to rats by ig. After 8 weeks, the expressions of IL-1beta, TNF-alpha, IL-10, and IL-10R in the brain tissues of AS rats were detected by enzyme-linked immunosorbant assay, immunohistochemistry, Western blotting, and reverse transcriptase polymerase chain reaction.RESULTS: The protein and mRNA expressions of IL-1beta, TNF-alpha, and IL-10 in the brains were markedly higher in AS groups than that in control groups (6.11+/-0.15, 1.55+/-0.14, 0.54+/-0.04 ng/g wet weight vs 0.80+/-0.14, 0.33+/-0.09, and 0.33+/-0.02 ng/g wet weight, respectively). The protein and mRNA expressions of IL-1beta and TNF-alpha in the brains were markedly lower in GbE groups (3.82+/-0.54, 0.95+/-0.08 ng/g wet weight) than that in AS groups, the protein and mRNA expressions of IL-10 and IL-10R in the brains were markedly higher in GbE groups (0.85+/-0.06 ng/g wet weight) than that in AS groups.CONCLUSION: GbE inhibited production of pro-inflammatory cytokines IL-1beta and TNF-alpha, but up-regulated the production of anti-inflammatory cytokines, IL-10 and IL-10R in brain, which might be related with its anti-AS actions.

12.Protective effects of Ginkgo biloba extract on the ethanol-induced gastric ulcer in rats.:

World J Gastroenterol. 2005 Jun 28;11(24):3746-50.PMID: 15968732
AIM: To evaluate the preventive effect of Ginkgo biloba extract (GbE) on ethanol-induced gastric mucosal injuries in rats.METHODS: Female Wistar albino rats were used for the studies. We randomly divided the rats for each study into five subgroups: normal control, experimental control, and three experimental groups. The gastric ulcers were induced by instilling 1 mL 50% ethanol into the stomach. We gave GbE 8.75, 17.5, 26.25 mg/kg intravenously to the experimental groups respectively 30 min prior to the ulcerative challenge. We removed the stomachs 45 min later. The gastric ulcers, gastric mucus and the content of non-protein sulfhydryl groups (NP-SH), malondialdehyde (MDA), c-Jun kinase (JNK) activity in gastric mucosa were evaluated. The amount of gastric juice and its acidity were also measured.RESULTS: The findings of our study are as follows: (1) GbE pretreatment was found to provide a dose-dependent protection against the ethanol-induced gastric ulcers in rats; (2) the GbE pretreatment afforded a dose-dependent inhibition of ethanol-induced depletion of stomach wall mucus, NP-SH contents and increase in the lipid peroxidation (increase MDA) in gastric tissue; (3) gastric ulcer induced by ethanol produced an increase in JNK activity in gastric mucosa which also significantly inhibited by pretreatment with GbE; and (4) GbE alone had no inhibitory effect on gastric secretion in pylorus-ligated rats.CONCLUSION: The finding of this study showed that GbE significantly inhibited the ethanol-induced gastric lesions in rats. We suggest that the preventive effect of GbE may be mediated through: (1) inhibition of lipid peroxidation; (2) preservation of gastric mucus and NP-SH; and (3) blockade of cell apoptosis.

13.Effects of Ginkgo biloba on haemostatic factors and inflammation in chronic peritoneal dialysis patients:

Phytother Res. 2005 Jun;19(6):546-8.PMID: 16114087
Ginkgo biloba extract decreased plasma D-dimer concentration, a marker of intravascular coagulation, in chronic peritoneal dialysis patients. Blood levels of fibrinogen, von Willebrand factor, hs-CRP, albumin and liver enzyme levels were not significantly changed. No bleeding episode was reported. These results suggest that Ginkgo biloba extract was effective in partially reversing the thrombogenic coagulation profile without increasing the risk of bleeding.

14.Effect of Ginkgo biloba extract on carrageenan-induced acute local inflammation in gamma irradiated rats.:

Pharmazie. 2005 Aug;60(8):614-9.PMID: 16124406
The effect of low dose whole-body gamma irradiation on inflammation and its possible modulation by Ginkgo biloba extract (GbE) was studied in the carrageenan-induced paw oedema model. Rats were subjected to two doses of gamma radiation (2 Gy or intermittent radiation at 2 Gy increment delivered daily up to cumulative dose of 4 Gy), 4 h before unilateral subplantar injection of carrageenan. The effect of GbE (25 or 50 mg/kg) administered subcutaneously daily for 3 days was also studied. Local oedema (days 1-3), the content of gamma glutamyl transpeptidase (GTT), malondialdehyde (MDA) and glutathione (GSH) in paw (72 h), were determined. In rats subjected to 4 Gy fraction, paw oedema was significantly reduced 1-4 h post-carrageenan injection (-26.2 to -16.2% vs control group). Moreover, at 24, 48 and 72 h after carrageenan, paw oedema was much reduced in the 2 Gy (-33.6, -46.4, -40%) or 4 Gy (-55, -56, -71.8%) irradiated groups compared to carrageenan unirradiated control. In addition, in irradiated rats, the carrageenan oedema was further significantly reduced by the administration of GbE, the effect of the agent being more marked in those irradiated with 2 Gy fraction. Changes in paw oedema were matched by a reduction in GGT and MDA paw tissue levels, while GSH content decreased in inflamed paw tissue 72 h post-treatment. These results indicate that exposure to 4 Gy fraction decreased the carrageenan-induced paw oedema and that the administration of GbE further lessened the severity of this inflammatory response in irradiated rats. The effects observed may be related in part to the inhibition of GGT activity and MDA production, and partly to augmentation of GSH content in the inflamed paw tissue.

15.Ginkgetin, a Biflavone from Ginko biloba leaves, inhibits cyclooxygenases-2 and 5-lipoxygenase in mouse bone marrow-derived mast cells.:

Biol Pharm Bull. 2005 Dec;28(12):2181-4.PMID: 16327145
Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A(2) inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase-2 (COX-2) in vitro effect. Ginkgetin inhibits COX-2 dependent phases of prostaglandin D(2) (PGD(2)) generation in bone marrow-derived mast cells (BMMC) in a concentration-dependent manner with IC(50) values of 0.75 microM. Western blotting probed with specific anti-COX-2 antibodies showed that the decrease in quantity of the PGD(2) product was accompanied by a decrease in the COX-2 protein level. In addition, this compound consistently inhibited the production of leukotriene C(4) (LTC(4)) in a dose dependent manner, with an IC(50) value of 0.33 microM. These results demonstrate that ginkgetin has a dual cyclooxygenase-2/5-lipoxygenase inhibitory activity. Furthermore, this compound also inhibited degranulation reaction in a dose dependent manner, with an IC(50) value of 6.52 microM. Therefore, this compound might provide a basis for novel anti-inflammatory agents.

16.Protective effects of ginkgo biloba against acetaminophen-induced toxicity in mice.:

Mol Cell Biochem. 2006 Feb;283(1-2):39-45.PMID: 16444584
BACKGROUND: The analgesic acetaminophen (AAP) causes a potentially fatal, hepatic centrilobular necrosis when taken in overdose. It was reported that these toxic effects of AAP are due to oxidative reactions that take place during its metabolism.OBJECTIVE: In this study, we aimed to investigate the possible beneficial effect of Ginkgo biloba (EGb), an antioxidant agent, against AAP toxicity in mice.METHODS: Balb/c mice were injected i.p. with: (1) vehicle, control (C) group; (2) a single dose of 50 mg/kg Ginkgo biloba extract, EGb group; (3) a single dose of 900 mg/kg i.p. acetaminophen, AAP group, and (4) EGb, in a dose of 50 mg/kg after AAP injection, AAP + EGb group. Serum ALT, AST, and tumor necrosis factor-alpha (TNF-alpha) levels in blood and glutathione (GSH), malondialdehyde (MDA) levels, myeloperoxidase (MPO) activity, and collagen contents in liver tissues were measured. Formation of reactive oxygen species in hepatic tissue samples was monitored by using chemiluminescence (CL) technique with luminol and lusigenin probe. Tissues were also examined microscopically.RESULTS: ALT, AST levels, and TNF-alpha were increased significantly (p < 0.001) after AAP treatment, and reduced with EGb. Acetaminophen caused a significant (p < 0.05-0.001) decrease in GSH levels while MDA levels and MPO activity were increased (p < 0.001) in liver tissues. These changes were reversed by EGb treatment. Furthermore, luminol and lusigenin CL levels in the AAP group increased dramatically compared to control and reduced by EGb treatment (p < 0.01).CONCLUSION: Our results implicate that AAP causes oxidative damage in hepatic tissues and Ginkgo biloba extract, by its antioxidant effects protects the tissues. Therefore, its therapeutic role as a "tissue injury-limiting agent" must be further elucidated in drug-induced oxidative damage.

17.Preventive effect of Ginkgo biloba extract (GBB) on the lipopolysaccharide-induced expressions of inducible nitric oxide synthase and cyclooxygenase-2 via suppression of nuclear factor-kappaB in RAW 264.7 cells.:

Biol Pharm Bull. 2006 May;29(5):985-90.PMID: 16651732
During our ongoing efforts to identify bioactive natural products with anti-inflammatory activity, we produced an extract from Ginkgo biloba (GBB) which contains higher levels of the active principles terpene and biflavonoid than EGb, the standard commercially available extract. In the present study, we examined and compared the effects of these two extracts on lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production by the RAW 264.7 macrophage cell line. Our data indicate that GBB is a more potent inhibitor of NO and PGE2 production than EGb 761, and it also significantly decreased tumor necrosis factor (TNF)-alpha release. Consistent with these observations, the protein and mRNA expression levels of inducible NO synthase (iNOS) and cyclooxygenase-2 (COX-2) were found to be inhibited by GBB in a dose-dependent manner. Furthermore, GBB inhibited the LPS-induced DNA binding activity of nuclear factor-kappaB (NF-kappaB), which was associated with the prevention of IkappaB degradation, and subsequently with decreased p65 protein level in the nucleus. These results suggest that GBB inhibits LPS-induced iNOS, COX-2 and TNF-alpha expressions through the down-regulation of NF-kappaB-DNA binding activity.

18.Effects of anti-inflammatory biflavonoid, ginkgetin, on chronic skin inflammation.:

Biol Pharm Bull. 2006 May;29(5):1046-9.PMID: 16651744
Ginkgetin, a biflavonoid from Ginkgo biloba leaves (Ginkgoaceae), was previously demonstrated to inhibit phospholipase A2 and to suppress proinflammatory gene expression such as cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase. In this study, the effects of ginkgetin were examined on an animal model of chronic skin inflammation and proinflammatory gene expression. When topically applied to ICR mouse ear, ginkgetin (20-80 microg/ear/treatment) inhibited ear edema (22.8-30.5%) and prostaglandin E2 production (30.2-31.1%) induced by multiple treatment of 12-O-tetradecanoylphorbol-13-acetate (TPA) for 7 consecutive days. By histological comparison, ginkgetin was also found to reduce epidermal hyperplasia. The expression of proinflammatory gene, interleukin-1beta, was suppressed by ginkgetin. From the results, it is suggested that ginkgetin may be beneficial against chronic skin inflammatory disorders like atopic dermatitis.

19.Ginkgolide A contributes to the potentiation of acetaminophen toxicity by Ginkgo biloba extract in primary cultures of rat hepatocytes.:

Toxicol Appl Pharmacol. 2006 Dec 1;217(2):225-33. Epub 2006 Sep 12.PMID: 17045319
The present cell culture study investigated the effect of Ginkgo biloba extract pretreatment on acetaminophen toxicity and assessed the role of ginkgolide A and cytochrome P450 3A (CYP3A) in hepatocytes isolated from adult male Long-Evans rats provided ad libitum with a standard diet. Acetaminophen (7.5-25 mM for 24 h) conferred hepatocyte toxicity, as determined by the lactate dehydrogenase (LDH) assay. G. biloba extract alone increased LDH leakage in hepatocytes at concentrations > or =75 mug/ml and > or =750 mug/ml after a 72 h and 24 h treatment period, respectively. G. biloba extract (25 or 50 mug/ml once every 24 h for 72 h) potentiated LDH leakage by acetaminophen (10 mM for 24 h; added at 48 h after initiation of extract pretreatment). The effect was confirmed by a decrease in [(14)C]-leucine incorporation. At the level present in a modulating concentration (50 mug/ml) of the extract, ginkgolide A (0.55 mug/ml), which increased CYP3A23 mRNA levels and CYP3A-mediated enzyme activity, accounted for part but not all of the potentiating effect of the extract on acetaminophen toxicity. This occurred as a result of CYP3A induction by ginkgolide A because triacetyloleandomycin (TAO), a specific inhibitor of CYP3A catalytic activity, completely blocked the effect of ginkgolide A. Ginkgolide B, ginkgolide C, ginkgolide J, quercetin, kaempferol, isorhamnetin, and isorhamnetin-3-O-rutinoside did not alter the extent of LDH leakage by acetaminophen. In summary, G. biloba pretreatment potentiated acetaminophen toxicity in cultured rat hepatocytes and ginkgolide A contributed to this novel effect of the extract by inducing CYP3A.

20.Oral administration of Ginkgo biloba extract, EGb-761 inhibits thermal hyperalgesia in rodent models of inflammatory and post-surgical pain.:

Br J Pharmacol. 2007 May;151(2):285-91. Epub 2007 Mar 20.PMID: 17375081
BACKGROUND AND PURPOSE: Studies in vitro suggest that the standardised extract of Ginkgo biloba, EGb-761 has anti-inflammatory properties and modulatory effects on key pain-related molecules. This study investigated the analgesic and anti-inflammatory effects of EGb-761 on carrageenan-induced inflammatory and hindpaw incisional pain.EXPERIMENTAL APPROACH: Adult male Wistar rats (n=6-10/group; 250-420 g) were injected intradermally with carrageenan into the left hindpaw or anaesthetised with isoflurane (2%) and a longitudinal 1 cm incision was made through the skin, fascia and plantaris muscle of the hindpaw. EGb-761 (3, 10, 30, 100 or 300 mg kg(-1)), diclofenac (5 mg kg(-1)) or drug-vehicle was administered 3 h post-carrageenan/post-surgery. Hindpaw withdrawal latency (in seconds) to thermal stimulation, response threshold (in grams) to mechanical stimulation and paw volume were measured.KEY RESULTS: Carrageenan induced significant mechanical allodynia, thermal hyperalgesia and paw oedema at 6 h post-carrageenan, while paw incision surgery induced significant mechanical allodynia and thermal hyperalgesia at 6 and 24 h post-surgery. Administration of EGb-761 dose-dependently inhibited thermal hyperalgesia and was equally effective as diclofenac (5 mg kg(-1)) in both the carrageenan and hindpaw incision model. EGb-761 had no effect on carrageenan- or incision-induced mechanical allodynia or paw oedema. Diclofenac significantly reduced mechanical allodynia in both models and carrageenan-induced paw oedema.CONCLUSIONS AND IMPLICATIONS: EGb-761 dose-dependently alleviates acute inflammatory and surgically induced thermal hyperalgesia and is comparable to diclofenac, a commonly prescribed non-steroidal anti-inflammatory drug. This indicates that EGb-761 has analgesic potential in acute inflammatory pain.

21.Ginkgo biloba extract EGb 761 has anti-inflammatory properties and ameliorates colitis in mice by driving effector T cell apoptosis.:

Carcinogenesis. 2008 Sep;29(9):1799-806. Epub 2008 Jun 20.PMID: 18567620
Ulcerative colitis is a dynamic, chronic inflammatory condition of the colon associated with an increased colon cancer risk. Ginkgo biloba is a putative antioxidant and has been used for thousands of years to treat a variety of ailments. The aim of this study was to test whether the standardized G.biloba extract, EGb 761, is an antioxidant that can be used to prevent and treat colitis in mice. Here, we show that EGb 761 suppresses the activation of macrophages and can be used to both prevent and treat mouse colitis. Markers of inflammation (iNOS, Cox-2 and tumor necrosis factor-alpha) and inflammatory stress (p53 and p53-phospho-serine 15) are also downregulated by EGb 761. Furthermore, we show that EGb 761 reduces the numbers of CD4+/CD25-/Foxp3- effector T cells in the colon. Interestingly, EGb 761 drives CD4+ effector T cell apoptosis in vitro and in vivo, providing a mechanistic explanation to the reduction in numbers of this cell type in the colon. This current study is in agreement with previous studies supporting a use of EGb 761 as a complementary and alternative strategy to abate colitis and associated colon cancer.

22.Effect of total flavonoid in leaves of Ginkgo biloba on the apoptosis of eosinophil in broncho alveloar lavage fluid:

Yao Xue Xue Bao. 2008 May;43(5):480-3.PMID: 18717334
This study was to investigate the effect of total flavonoid in leaves of Ginkgo biloba (total flavonoid in leaves of Ginkgo biloba, FG) on the apoptosis of eosinophils (EOS) in broncho alveloar lavage fluid (BALF) of asthma mice. Mouse asthma model was established by ovalbumin (OVA) challenge methods. After atomizing therapy for two weeks, differential count in BALF, morphological change and proportion of apoptosis were detected by AO/EB stain and Annexin V-FITC/PI. The number of total leucocytes and eosinophils in BALF decreased obviously after FG treatment. Compared with model group, the number and proportion of EOS apoptosis increased significantly after FG treatment. The results indicated that one of the anti-inflammation mechanisms of FG might be promoting apoptosis of eosinophils.

F-Ginkgo Biloba:ED/FSD treatment,Anti-Estrogenic Research:

1.An experimental study of the effect of ginkgo biloba extract on the human and rabbit corpus cavernosum tissue.:

J Urol. 1996 Nov;156(5):1876-80.PMID: 8863636
PURPOSE: To investigate the effect of subfractions of extract from the ginkgo on human and rabbit corpus cavernosal tissue and their possible use for the treatment of impotence.MATERIALS AND METHODS: Among the fractions of ginkgo biloba extract (GBE), nonginkgolide nonflavonoid fraction (NGF) has the most potent relaxing effect on vascular smooth muscle. We subfractionated NGF and speculated that some of the subfractions might have a very potent relaxing effect on corpus cavernosal tissue. Thereafter we have studied their effect on human and rabbit corpus cavernosum using organ bath and electrical field stimulation experiments.RESULTS: In the tissue precontracted by norepinephrine (10(-5)M.), corpus cavernosal tissue of human and rabbit showed relaxation in response to subfractions of NGF in a dose-dependent manner. 304U-1 showed the most potent relaxing effect (ED50 = 0.74 mg./ml. in human, ED50 = 0.66 mg./ml. in rabbit). 304U-1 elicits pharmacological actions on corpus cavernosum smooth muscle via the signal transduction pathway whereby relaxation induced by 304U-1 is mediated by intracellular cAMP and perhaps partially by antagonizing of the adrenergic nervous system. A hyperpolarizing effect via potassium channel opening might also be related to this relaxing effect.CONCLUSION: The subfractions of NGF, especially 304U-1, have a relaxing effect on corpus cavernosum tissue. 304U-1, which showed the most potent relaxing effect, can possibly be used as a drug for intracavernosal injection therapy. Considering the fact that the value of ED50 is too high, further fractionation and in vivo study are needed before clinical use in an oral form.

2.Ginkgo biloba for antidepressant-induced sexual dysfunction.:

J Sex Marital Ther. 1998 Apr-Jun;24(2):139-43.PMID: 9611693
In an open trial ginkgo biloba, an extract derived from the leaf of the Chinese ginkgo tree and noted for its cerebral enhancing effects, was found to be 84% effective in treating antidepressant-induced sexual dysfunction predominately caused by selective serotonin reuptake inhibitors (SSRIs, N = 63). Women (n = 33) were more responsive to the sexually enhancing effects of ginkgo biloba than men (N = 30), with relative success rates of 91% versus 76%. Ginkgo biloba generally had a positive effect on all 4 phases of the sexual response cycle: desire, excitement (erection and lubrication), orgasm, and resolution (afterglow). This study originated from the observation that a geriatric patient on ginkgo biloba for memory enhancement noted improved erections. Patients exhibited sexual dysfunction secondary to a variety of antidepressant medications including selective serotonin reuptake inhibitor (SSRIs), serotonin and nonrepinephrine reuptake inhibitor (SNRIs) monoamine oxidase inhibitor (MAOIs), and tricyclics. Dosages of ginkgo biloba extract ranged from 60 mg qd to 120 mg bid (average = 209mg/d). The common side effects were gastrointestinal disturbances, headache, and general central nervous system activation. The article includes a discussion of presumed pharmacologic mechanisms, including effects on platelet activating factor, prostaglandins, peripheral vasodilatation, and central serotonin and norepinephrine receptor factor modulation.

3.An alternative medicine study of herbal effects on the penetration of zona-free hamster oocytes and the integrity of sperm deoxyribonucleic acid.:

Fertil Steril. 1999 Mar;71(3):517-22.PMID: 10065791
OBJECTIVE: To analyze the effects of certain herbs on sperm DNA and on the fertilization process.DESIGN: Prospective comparative study.SETTING: Clinical and academic research environment.PATIENT(S): Donor sperm specimens.INTERVENTION(S): Zona-free hamster oocytes were incubated for 1 hour in saw palmetto (Serenoa repens), echinacea purpura, ginkgo biloba, St. John's wort (Hypericum perforatum), or control medium before sperm-oocyte interaction. The DNA of herb-treated sperm was analyzed with denaturing gradient gel electrophoresis.MAIN OUTCOME MEASURE(S): Oocyte penetration and integrity of the sperm BRCAI exon 11 gene.RESULT(S): Pretreatment of oocytes with 0.6 mg/mL of St. John's wort resulted in zero penetration. A lower concentration (0.06 mg/mL) had no effect. High concentrations of echinacea and ginkgo also resulted in reduced oocyte penetration. Exposure of sperm to echinacea purpura and St. John's wort resulted in DNA denaturation. In contrast, saw palmetto and ginkgo had no effect. Sperm exposed to 0.6 mg/mL of St. John's wort showed mutation of the BRCA1 exon 11 gene.CONCLUSION(S): High concentrations of St. John's wort, echinacea, and ginkgo had adverse effects on oocytes. Saw palmetto had no effect. The data suggested that St. John's wort, ginkgo, and echinacea at high concentrations damage reproductive cells. St. John's wort was mutagenic to sperm cells.

4.Inhibition of human sperm motility by specific herbs used in alternative medicine.:

J Assist Reprod Genet. 1999 Feb;16(2):87-91.PMID: 10079411
PURPOSE: Our purpose was to analyze sperm motility parameters in the presence of herbs.METHODS: Washed sperm were incubated in either saw-palmetto (Serenoa repens, Permixon Sabal serrulatum), echinacea purpura, ginkgo biloba, St. John's wort (Hypericum perforatum), or control medium. Parameters were measured on a Hamilton-Thorn analyzer after 1, 4, 24, and 48 hr at 37 degrees C.RESULTS: Sperm motility was inhibited at the high concentration (0.6 mg/mL) of St. John's wort. Curvilinear velocities and beat cross frequencies also decreased, but not hyperactivation. High-concentration saw-palmetto, echinacea, or gikgo inhibited motility at 24 and 48 hr.CONCLUSIONS: A potent inhibition of sperm motility was seen in St. John's wort unrelated to changes in pH. Furthermore, sperm viability was compromised in St. John's wort, suggesting a spermicidal effect. Metabolic changes were observed in saw-palmetto-treated sperm. High-concentration echinacea purpura interfered with sperm enzymes. Ginkgo did not have an antioxidant effect on sperm motility.

5.Phytochemicals and the breakthrough of traditional herbs in the management of sexual dysfunctions.:

Int J Androl. 2000;23 Suppl 2:82-4.PMID: 10849504
Traditional herbs have been a revolutionary breakthrough in the management of erectile dysfunction and have become known world-wide as an 'instant' treatment. The modern view of the management of erectile dysfunction subscribes to a single etiology, i.e. the mechanism of erection. A large number of pharmacological agents are orally consumed and vasoactive agents inserted intraurethrally or injected intrapenially to regain good erection. Modern phytochemicals have developed from traditional herbs. Phytochemicals focus their mechanism of healing action to the root cause, i.e. the inability to control the proper function of the whole body system. Hence phytochemicals manage erectile dysfunction in the frame of sexual dysfunction as a whole entity. Protodioscin is a phytochemical agent derived from Tribulus terrestris L plant, which has been clinically proven to improve sexual desire and enhance erection via the conversion of protodioscine to DHEA (De-Hydro-Epi-Androsterone). Preliminary observations suggest that Tribulus terrestris L grown on different soils does not consistently produce the active component Protodioscin. Further photochemical studies of many other herbal plants are needed to explain the inconsistent results found with other herbal plants, such as in diversities of Ginseng, Eurycoma longifolia, Pimpinella pruacen, Muara puama, Ginkgo biloba, Yohimbe etc.

6.A placebo-controlled, double-blind trial of Ginkgo biloba for antidepressant-induced sexual dysfunction.:

Hum Psychopharmacol. 2002 Aug;17(6):279-84.PMID: 12404672
The aim of this study was to examine the effect of Ginkgo biloba on antidepressant-induced sexual dysfunction. The Ginkgo biloba (n=19) and the placebo groups (n=18) were divided; each to be administered with Ginkgo biloba and placebo respectively for 2 months by means of a randomized placebo-controlled, double-blind study. The results of this 2 month trial were: (1) there was no statistical significant difference from the placebo at weeks 2, 4 and 8 after medication; (2) in comparison with baseline, both the Ginkgo biloba group and the placebo group showed improvement in some part of the sexual function, which is suggestive of the importance of the placebo effect in assessing sexual function. This study did not replicate a prior positive finding supporting the use of Ginkgo biloba for antidepressant, especially SSRI, induced sexual dysfunction.

7.A review of plant-derived and herbal approaches to the treatment of sexual dysfunctions.:

J Sex Marital Ther. 2003 May-Jun;29(3):185-205.PMID: 12851124
Despite the increasing availability of effective conventional medical treatments, plant-derived and herbal remedies continue to provide a popular alternative for men and women seeking to improve their sex life. Nevertheless, the efficacy of most herbal agents in treating sexual problems remains uncertain. Therapists and consumers alike would benefit from an increased understanding of commonly used herbal agents on the market, their purported or supported effects, and their potential side effects. To this end, we cataloged the major prosexual herbal agents currently sold in several representative health food stores. We also specify the sexual problem purportedly ameliorated by each herbal agent. Finally, we evaluate eight herbal agents commonly promoted for the treatment of sexual problems. This evaluation includes a review of the research supporting the use, efficacy, dose, adverse effects, contraindications, and possible mechanism of action of each. We conclude by commenting on the quality of current research, pointing out gaps in our knowledge, and noting the need for rigorous research and product control to adequately address questions regarding the efficacy of these agents.

8.Nutrients and botanicals for erectile dysfunction: examining the evidence.:

Altern Med Rev. 2004 Mar;9(1):4-16.PMID: 15005641
Erectile dysfunction affects 50 percent of men ages 40-70 in the United States and is considered an important public health problem by the National Institutes of Health. Consumers are exposed to a plethora of natural products claiming to restore erection and sexual vitality. A review of the available empirical evidence reveals most naturally occurring compounds lack adequate clinical trials to support efficacy. However, arginine, yohimbine, Panax ginseng, Maca, and Ginkgo biloba all have some degree of evidence they may be helpful for erectile dysfunction. Improvements in penile endothelial L-arginine-nitric oxide activity appear to be a unifying explanation for the actions of these naturally occurring agents.

9.Prevention and treatment of erectile dysfunction using lifestyle changes and dietary supplements: what works and what is worthless, part II.:

Urol Clin North Am. 2004 May;31(2):259-73.PMID: 15123406
It seems naïve to believe that some plants or herbs do not contain specific compounds that could benefit patients with ED. Many supplements have not been investigated in a laboratory or clinical research setting before commercial sale, however,which creates a complex situation. If efficacy is or is not demonstrated through adequate research, then the benefit or lack thereof cannot be mentioned on the label. Furthermore, clinicians and the public cannot be made aware of which compounds or supplements are effective because no general standards for sale exist under the current guidelines. Dietary supplements have received a tremendous amount of publicity. The large and growing market for ED treatment seems to have contributed partly to the promotion of numerous supplements and their apparent benefits. Whether these dietary supplements have merit is questionable. Some supplements may produce results opposite to those advertised. Other supplements may be enjoying the benefits of the placebo effect. Because a placebo response of 25% to 50% has been recorded in clinical trials with effective agents, it is understandable that some supplements enjoy financial success despite the limited research espousing their use. If one to two of four individuals or one of three individuals who try a dietary supplement gain some benefit for their ED, the market for these supplements will remain extraordinary. On a larger scale, of 100,000 men who try a supplement, approximately 25,000 to 50,000 will claim some success. The challenge for clinicians is to discuss the placebo response properly and the need for good research before any intervention, especially supplements, can be advocated for general use. Table 2 summarizes some popular ED supplements and general conclusions that can be drawn from clinical investigations. Some dietary supplements may have an active ingredient that benefits patients with certain types of ED. An exciting area of future dietary supplement research is the ability of certain agents to have a synergistic effect with prescription agents for ED, thereby improving response rates in men that have failed approved ED therapy initially, especially with oral agents. Randomized clinical trials are the best method of determining which dietary supplements will become a part of conventional medicine. Therefore, more randomized trials for dietary supplements are needed so that they may have the opportunity to become a part of the mainstream milieu, which means that more funding needs to be made available for ED research. The coming years of research should bring enormous excitement and objectivity to this area of medicine.

10.Triple-blind, placebo-controlled trial of Ginkgo biloba in sexual dysfunction due to antidepressant drugs.:

Hum Psychopharmacol. 2004 Dec;19(8):545-8.PMID: 15378664
A triple-blind (investigator, patient, statistician), randomized, placebo-controlled, trial of Ginkgo biloba 240 mg daily was carried out. Following a 1-week control, it was given to 24 patients with sexual impairment due to antidepressant drugs. Efficacy analysis was carried out on eight males and five females on placebo and six males and five females on Ginkgo, completing the full 12 weeks of treatment. Not included were three subjects who dropped out after 6 weeks. A validated, sex (gender)-orientated questionnaire was recorded at - 1, 0, 1, 3, 6, 9 and 12 weeks, and a non-blind follow-up for a further 6-weeks on Ginkgo. Hamilton anxiety and depression ratings were made at 0, 6 and 12 weeks and simple global assessments of alertness and memory. There were some spectacular individual responses in both groups, but no statistically significant differences, and no differences in side-effects.

11.Inhibition of cGMP-phosphodiesterase-5 by biflavones of Ginkgo biloba.:

Planta Med. 2006 Apr;72(5):468-70.PMID: 16557462
Ginkgo biloba dimeric flavonoids (GBDF) were shown to inhibit cAMP phosphodiesterase activity and to promote vasorelaxation. In particular, amentoflavone exhibited endothelium-dependent relaxation of rat aorta rings via enhanced generation and/or increased biological activity of nitric oxide, leading to elevated cGMP levels. The aim of this study was to investigate whether GBDF were able to inhibit cGMP-specific phosphodiesterase-5 (PDE5) as well. Human recombinant PDE5A1 was prepared by expression of the full-length cDNA of PDE5A1 in COS-7 cells. The PDE activity was determined in the presence of biflavones at 0.1-100 microM. All biflavones inhibited PDE5A1 in a concentration-dependent fashion, ginkgetin being the most potent (IC50 = 0.59 microM). The ability to inhibit the enzyme followed this order: ginkgetin > bilobetin > sciadopitysin > amentoflavone > sequoiaflavone. These data suggest that GBDF could exert a vasodilating effect through a mechanism independent of NO release.

12.Ginkgo biloba extract enhances male copulatory behavior and reduces serum prolactin levels in rats.:

Horm Behav. 2008 Jan;53(1):225-31. Epub 2007 Oct 10.PMID: 18001735
The aim of this study was to investigate the effects of Ginkgo biloba extract (EGb 761) on male copulatory behavior in rats. EGb 761 (1 mg/ml) induced significant production of testosterone (T) in rat Leydig cells in vitro. Its effects on sexual behavior were then tested in Long-Evans male rats after 7, 14, 21, or 28 days of oral gavage of vehicle (distilled water) or EGb 761 at doses of 10, 50, or 100 mg/kg. Administration of 50 mg/kg of EGb 761 for 28 days and of 100 mg/kg for 14 or 21 days significantly increased intromission frequency compared to controls on the same day. An increase in ejaculation frequency was seen after treatment with 50 mg/kg of EGb 761 for 14, 21, or 28 days when compared to either the control group on the same day or the same group on day 0. A reduction in ejaculation latency was only seen after administration of 50 mg/kg of EGb 761 for 14 days compared to the vehicle-treated group. After treatment for 28 days, no significant difference was seen in mount latency, intromission latency, serum T levels, reproductive organ weight, sperm number, or levels of the metabolite of dopamine, 3,4-dihydroxyphenylacetic acid in the brain with any dose of EGb 761, but significantly reduced serum prolactin levels and increased dopamine levels in the medial preoptic area and arcuate nucleus were seen at the dose of 50 mg/kg. These findings show that EGb 761 (especially at the dose of 50 mg/kg) enhances the copulatory behavior of male rats and suggest that the dopaminergic system, which regulates prolactin secretion, may be involved in the facilitatory effect of EGb 761.

13.Ginkgo biloba (EGb 761) usage attenuates testicular injury induced by testicular ischemia/reperfusion in rats.:

Int Urol Nephrol. 2008;40(3):685-90. Epub 2007 Nov 15.PMID: 18004670
INTRODUCTION: We investigated the effect of ginkgo biloba on testicular ischemia-reperfusion (IR) injury.MATERIALS AND METHODS: Thirty-two Wistar Albino rats were randomly assigned into four groups. Torsion/detorsion (T/D) performed to the rats in group 1, group 2 received ginkgo biloba (50 mg/day) for a month before T/D, group 3 received only gingko biloba (50 mg/day) for a month and group 4 was defined as sham group. After 1 month the testes were removed.RESULTS: Mean testicular malondialdehyde, nitrate and nitrite levels were significantly increased in group 1 compared to groups 2, 3 and 4 (P<0.05). The rats in group 3 provided basal histological appearance. In group 1, edema, congestion and hemorrhage between seminiferous tubules were predominant. In group 2, histopathologic features were markedly less than group 1.CONCLUSIONS: Malondialdehyde, nitrate and nitrite levels were increased after unilateral testicular torsion. EGb 761 has a protective effect on testicular injury induced by IR.

14.Pharmacologic treatment options for hypoactive sexual desire disorder.:

Womens Health (Lond Engl). 2005 Sep;1(2):263-77.PMID: 19803843
Hypoactive sexual desire disorder is the most common cause of sexual dysfunction in women. According to a national survey, approximately a third of all women experience low sexual desire. The etiology of the disorder is often multifactorial. Research in treatment options for hypoactive sexual desire disorder is limited. In this article, treatment options including sex therapy, hormone therapy (estrogen, testosterone, dehydroepiandrosterone, tibolone), non-hormonal medical therapies (buproprion, buspirone, phosphodiesterase-5 inhibitors, amantadine and apomorphine) and herbal therapies (Avlimil(R), Arginmax(R), Zestra(R), yohimbine and Ginkgo biloba) are reviewed.

15.Sildenafil in the treatment of female sexual dysfunction induced by selective serotonin reuptake inhibitors.:

J Reprod Med. 1999 Jun;44(6):535-42.PMID: 10394548
OBJECTIVE: To review the literature describing female orgasmic disorder and impaired sexual desire disorder by selective serotonin reuptake inhibitors (SSRIs) and their treatment, including the use of sildenafil.STUDY DESIGN: Literature reviews of all available published articles on this topic from 1989 to 1996 were done. This paper also includes a sample case of a 38-year old woman who suffers from fluoxetine-induced arousal and orgasmic disturbance.RESULTS: Treatment approaches include the use of "antidotes," such as cyproheptadine, yohimbine, amantadine, granisetron and ginkgo biloba. This article also reports a case of successful female use of sildenafil, which was released by the Food and Drug Administration in March 1998 for erectile dysfunction in men.CONCLUSION: Sildenafil is beneficial in reversing female sexual dysfunction induced by SSRIs. This paper also discusses sildenafil's action in the background of nitric oxide and cyclic guaninosine monophosphate in penile/clitoral erection.

16.Effects of Herbal vX on libido and sexual activity in premenopausal and postmenopausal women.:

Adv Ther. 2000 Sep-Oct;17(5):255-62.PMID: 11186145
This study investigated the possibility of an alternative to chemical medication in the treatment of sexual dysfunction in healthy women. The efficacy of a unique herbal formulation of Muira puama and Ginkgo biloba (Herbal vX) was assessed in 202 healthy women complaining of low sex drive. Various aspects of their sex life were rated before and after 1 month of treatment. Responses to self-assessment questionnaires showed significantly higher average total scores from baseline in 65% of the sample after taking the supplement. Statistically significant improvements occurred in frequency of sexual desires, sexual intercourse, and sexual fantasies, as well as in satisfaction with sex life, intensity of sexual desires, excitement of fantasies, ability to reach orgasm, and intensity of orgasm. Reported compliance and tolerability were good. These initial findings support the strong anecdotal evidence for the benefits of Herbal vX on the female sex drive. A double-blind study is planned to further research these results.

17.Short- and long-term effects of Ginkgo biloba extract on sexual dysfunction in women.:

Arch Sex Behav. 2008 Aug;37(4):530-47. Epub 2008 Feb 15.PMID: 18274887
Ginkgo biloba extract (GBE) facilitates blood flow, influences nitric oxide systems, and has a relaxant effect on smooth muscle tissue. These processes are important to the sexual response in women and, hence, it is feasible that GBE may have a therapeutic effect. The present study was the first to provide an empirical examination of the effects of both short- and long-term GBE administration on subjective and physiological (vaginal photoplethysmography) measures of sexual function in women with Sexual Arousal Disorder. A single dose of 300 mg GBE had a small but significant facilitatory effect on physiological, but not subjective, sexual arousal compared to placebo in 99 sexually dysfunctional women. The long-term effects of GBE on sexual function were assessed in 68 sexually dysfunctional women who were randomly assigned to 8 weeks treatment of either (1) GBE (300 mg/daily), (2) placebo, (3) sex therapy which focused on training women to attend to genital sensations, or (4) sex therapy plus GBE. When combined with sex therapy, but not alone, long-term GBE treatment significantly increased sexual desire and contentment beyond placebo. Sex therapy alone significantly enhanced orgasm function compared with placebo. Long-term GBE administration did not significantly enhance arousal responses beyond placebo. It was concluded that (1) neither short- or long-term administration of GBE alone substantially impacts sexual function in women, (2) a substantial placebo effect on sexual function exists in women with sexual concerns, and (3) teaching women to focus on genital sensations during sex enhances certain aspects of women's sexual functioning.

18.Medicinal plants as alternative treatments for female sexual dysfunction: utopian vision or possible treatment in climacteric women?:

J Sex Med. 2010 Nov;7(11):3695-714. doi: 10.1111/j.1743-6109.2010.01987.x. Epub 2010 Aug 16.PMID: 20722793
INTRODUCTION: Female sexual dysfunction (FSD) is a complex and multifactorial condition. An increased incidence of FSD is especially associated with the decline of estrogen. Thus, menopause is a critical phase for FSD complaints. In this context, medicinal plants may be a therapeutic option.AIM: To identify and describe the popular and clinical uses of medicinal plants for FSD treatment in climacteric women. We highlighted the majority of the plants commonly involved with the female reproductive system including: Angelica sinensis, Cimicifuga racemosa, Ferula hermonis, Ginkgo biloba, Humulus lupulus, Lepidium meyenii, Tribulus terrestris, Trifolium pratense, and Vitex agnus-castus.METHODS: This study is a narrative review of studies of plants that are possible alternative treatments for FSD. The species described have clinical and popular uses in different cultures as well as medical indications for female reproductive disturbances, mainly in climacteric women. We have also analyzed the evidence level of clinical studies.MAIN OUTCOME MEASURES: The main outcome assessed is the efficacy of plants in improving the symptoms of FSD.RESULTS: There is little evidence from the literature to recommend the use of medicinal plants when treating FSD. The majority of studies with a strong level of evidence are associated with the treatment of the vasomotor symptoms of menopause. Ferula hermonis, Angelica sinensis, and Gingko biloba may be suggested for arousal disorder studies. Cimicifuga racemosa, Trifolium pratense, and Vitex agnus-castus may be recommended for several FSD. Humulus lupulus and Tribulus terrestris may help with desire disorder studies. Lepidium meyenii should be studied further.CONCLUSIONS: Studies of these plants indicate that they may be useful as a possible alternative and/or complementary approach for studies aimed at the treatment of FSD. At this time, however, this review cannot recommend a plant that has a strong enough level of evidence for treatment of FSD. Thus, there is a need for clinical (double-blinded and randomized) studies to evaluate the efficacy and safety of several plants that can exert a positive effect on the management of FSD.

19.Antiestrogenic activities of Ginkgo biloba extracts.:

J Steroid Biochem Mol Biol. 2006 Aug;100(4-5):167-76. Epub 2006 Jul 13.PMID: 16842996
Most climacteric and postmenopausal women appear to have vasomotor symptoms as well as a high risk of osteoporosis and cardiovascular disease. Although exogenous estrogens can reduce these symptoms, women are reluctant to use hormone replacement therapy (HRT) due to its undesirable side effects, such as irregular bleeding and an increased risk of breast cancer. A previous study suggested that Ginkgo biloba extracts (GBE) have estrogenic activity and might be suitable as an alternative to HRT. However, there are no reports of the preventive effect of GBE on breast cancer, which is the side effect of classical HRT. In this study, it was confirmed that GBE exhibits estrogenic and antiestrogenic activity depending on the E2 and GBE concentration, via estrogen receptor (ER)-dependent and ER-independent pathways. In addition, GBE reduced the E2 levels by stimulating the E2 metabolism and inhibiting E2 synthesis, which indicates that GBE can induce antiestrogenic activity via the depletion of E2. Furthermore, GBE might have similar action to selective arylhydrocarbon receptor modulators (SAhRMs), which induce antiestrogenic activity through cross-talk between the arylhydrocarbon receptor (AhR) and ER. In conclusion, GBE has a biphasic effect on estrogen, and can be considered as a potential alternative to HRT with chemopreventive effects on breast cancer. However, further studies on animals and humans will be required.

20.Ginkgo biloba extract enhances testosterone synthesis of Leydig cells in type 2 diabetic rats:

Zhonghua Nan Ke Xue. 2008 Apr;14(4):371-6.PMID: 18481435
OBJECTIVE: To investigate the effects of Ginkgo biloba extract (EGB) on the testosterone synthesis in the Leydig cells of type 2 diabetic rats.METHODS: Thirty male SD rats were equally randomised into a normal control, a type 2 diabetic and an EGB group. Morphological changes of Leydig cells were observed by light microscopy (LM) and transmission electron microscopy (TEM), concentrations of serum luteinizing hormone (LH) and testosterone (T) were determined by enzyme linked immunosorbent assay (ELISA), and the mRNA levels in the steroidogenic acute regulatory protein (StAR), cytochrome P450 side chain cleavage (P450scc), cytochrome P450 17a-hydroxylase (P450c17), 17beta-hydroxysteroid dehydrogenase 3 (17beta-HSD3) and 3beta-hydroxysteroid dehydrogenase (3beta-HSD1) from the Leydig cells were examined by RT-PCR.RESULTS: Compared with the normal control, there was a significant decrease in the number and volume of Leydig cells, the levels of serum LH and T and the expression of mRNA in StAR, P450scc, 17beta-HSD3 and 3beta-HSD1 in the type 2 diabetes group. And the expression of the P450c17 gene showed a tendency of descending, but with no significance. Compared with the type 2 diabetes group, 12 weeks of EGB treatment caused very slight pathological changes in the Leydig cells, significantly increased the concentrations of blood LH and T, markedly elevated the levels of mRNA in StAR and P450scc and induced an ascending tendency of the expressions of P450c17, 17beta-HSD3 and 3beta-HSD1.CONCLUSION: EGB enhances testosterone synthesis and secretion of Leydig cells by reducing the impairment of the testis in type 2 diabetic rats.

G-Ginkgo Biloba:Premenstrual Syndrome,Postmenopausal,Estrogenic Activities Research:

1.Value of standardized Ginkgo biloba extract (EGb 761) in the management of congestive symptoms of premenstrual syndrome:

Rev Fr Gynecol Obstet. 1993 Jul-Sep;88(7-9):447-57.PMID: 8235261
The efficacy of standardized Ginkgo biloba extract (EGb 761) in treating congestive symptoms of premenstrual syndrome (PMS) was evaluated in a controlled multicentric double blind study versus placebo. The population studied was a group of 165 women aged between 18 to 45, in genital activity period, suffering since 3 cycles from congestive premenstrual troubles during at least 7 days per cycle. The characteristics of patients and PMS were the same in both groups (EGb 761 and placebo). The observation of one menstrual cycle confirmed the diagnosis of PMS. Then, during the 2 following cycles, each patient received either EGb 761 or placebo from the 16th day of the first cycle till the 5th day of the next cycle. A double evaluation of the symptoms was realized by the patient using a daily rating scale (auto-evaluation), by the practitioner during visits at the premenstrual phase before and after the two cycles treatment. From 165 patients included, 143 observations were available. With a good acceptability, EGb 761 was effective against the congestive symptoms of PMS, particularly breast symptoms with a statistical significance between EGb 761 and placebo. Neuropsychological symptoms were also improved. EGb 761 is an alternative of interest to therapeutics already used in treating PMS or can be associated without any inconvenience.

2.Effects on cognition and mood in postmenopausal women of 1-week treatment with Ginkgo biloba.:

Pharmacol Biochem Behav. 2003 Jun;75(3):711-20.PMID: 12895689
In a double-blind, placebo-controlled study, postmenopausal women (53-65 years old) were randomly assigned to 7-day treatment with Ginkgo (120 mg/day, n=15) or matched placebo (n=16). They were given a battery of cognitive tests and measurements of mood and menopausal symptoms at baseline (before treatment began) and at the end of 7 days. The group treated with Ginkgo was significantly better than the placebo group in a matching-to-sample test of nonverbal memory, but the groups did not differ in immediate or delayed paragraph recall or in delayed recall of pictures. In a test of frontal lobe function (rule shifting) and in the Paced Auditory Serial Addition Test (PASAT) (which measures sustained attention but also involves frontal lobe function), the group treated with Ginkgo performed significantly better than the placebo group. However, the groups did not differ in a test of planning. The treatments did not differ in their effects on the volunteers' ratings of menopausal symptoms, sleepiness, bodily symptoms or aggression. The benefits of Ginkgo on memory and frontal lobe function found in this study are modest but are unlikely to be secondary to major mood changes.

3.Estrogenic activities of Ginkgo biloba extracts.:

Life Sci. 2004 Jan 30;74(11):1325-35.PMID: 14706564
Ginkgo biloba extracts (GBE) are extracted from the leaves of Ginkgo biloba tree. GBE contains 24% of phytoestrogens, which is kaempferol, quercetin, and isorhamnetin. It has been reported that phytoestrogens could be a part of SERMs (Selective estrogen receptor modulators) and possibly the alternative HRT (Hormone replacement therapy) for postmenopausal women. The goal of this study was to investigate the potencies of GBE and its major components (quercetin, kaempferol, isorhamnetin) for estrogenic effect, which confirms the capacity as an alternative HRP. It was found that GBE and its major components exerted a dual action on ER-alpha and ER-beta in competitive binding assay. The binding affinity of these chemicals to ER-beta was higher than to ER-alpha. In the E-screen assay, these chemicals induced cell proliferation in ER-positive MCF-7 cell, but not in ER-negative MDA-MB-231 cells. The cell proliferation induced by these chemicals was blocked by tamoxifen. Also, GBE and its major components induced pS2 and PR (progesterone receptor) transcription in MCF-7 cells. Therefore these results indicated that GBE and its major components had the weak estrogenic activities through the estrogen response pathway by an interaction with the ER. In conclusion, we provided the evidence of potential estrogenic activities of GBE, which could be useful as an alternative HRP. However, further studies are required to assess the physiological significance of GBE in animals and humans.

4.Limited cognitive benefits in Stage +2 postmenopausal women after 6 weeks of treatment with Ginkgo biloba.:

J Psychopharmacol. 2005 Mar;19(2):173-81.PMID: 15728439
Gingko biloba has cognitive benefits both in populations suffering from dementia and after acute treatment in healthy volunteers, with some evidence indicating that those with poorer cognitive performance show greater benefit. We have previously found that 1 week of treatment with ginkgo improved attention, memory and mental flexibility in post-menopausal women, but the evidence for any beneficial effects of longer treatment is less well-established. The present study aimed to determine whether cognitive benefits, similar to those previously found after 1 week of treatment, would persist after 6 weeks of treatment, and whether those with poorer cognitive performance would benefit more. In a placebo-controlled, double-blind study, postmenopausal women (aged 51-67 years) were randomly allocated to receive a standardized extract of ginkgo (LI 1370, Lichtwer Pharma, Marlow, UK) (one capsule/day of 120 mg, n = 45) or matching placebo (n = 42) for 6 weeks. According to an established reproductive staging system, subjects were divided into those in the early (Stage +1; mean age 55 years) and late (Stage +2: mean age 61 years) stages of menopause. At baseline and after 6 weeks of treatment, subjects completed tests of mental flexibility, planning, memory and sustained attention, and ratings of mood, sleepiness, bodily and menopausal symptoms. The only significant effects of ginkgo were in the test of mental flexibility, in which there were significant menopausal stage-ginkgo interactions. This was because subjects in Stage +2 required fewer trials to complete the task and made fewer errors after ginkgo treatment, whereas those in Stage +1 showed no benefits. Subjects in Stage +2 had poorer performance at baseline compared to those in Stage +1 both in this task and the test of planning ability. The beneficial effects of ginkgo were limited to the test of mental flexibility and to those with poorer performance.

5.A randomized, placebo-controlled trial of Ginkgo biloba L. in treatment of premenstrual syndrome.:

J Altern Complement Med. 2009 Aug;15(8):845-51.PMID: 19678774
BACKGROUND AND OBJECTIVES: During the reproductive years, most of menstruating women experience symptoms of premenstrual syndrome (PMS), which is incapacitating in up to 10% of cases. According to complicated etiology, various therapeutic approaches have been proposed. Because PMS is a chronic situation, special attention should be paid to the side-effects of pharmacological interventions. Herbal medicine is a recent favorable therapeutic approach owing to fewer side-effects. We aimed to determine the effect of Ginkgo biloba L. on the symptoms of PMS.METHODS: This was a single-blind, randomized, placebo-controlled trial conducted from November 2007 to April 2008. The students with PMS, living in dormitories of a medical university (Tehran), who met the inclusion criteria entered the study. The students filled out the daily symptom rating forms in two consecutive menstrual cycles. After we verified the PMS diagnosis in 90 students, the participants were randomly assigned to experiment and placebo groups and took G. biloba L. tablets (containing 40 mg leaf extracts) or placebo three times a day from the 16th day of the menstrual cycle to the 5th day of the next cycle. Data were collected using daily symptom rating forms.RESULTS: Eighty-five (85, 94.4%) participants completed the study. The two groups were similar in terms of demographic characteristics and baseline overall severity of symptoms. After the intervention, there was a significant decrease in the overall severity of symptoms and physical and psychologic symptoms in both Ginkgo (23.68%) and placebo (8.74%) groups (p < 0.001). However, the mean decrease in the severity of symptoms was significantly more in the Ginkgo group compared to the placebo group (p < 0.001).CONCLUSIONS: G. biloba L. can reduce the severity of PMS symptoms. Further research on active ingredients and also the efficacy and safety of various doses and treatment durations of Ginkgo are required.

H-Ginkgo Biloba:Liver Problems,Hepatitis,Liver Fibrosis,Liver Injury Protection related:

1.Preliminary study on early fibrosis of chronic hepatitis B treated with Ginkgo biloba Composita:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 1995 Oct;15(10):593-5.PMID: 8704423
The purpose of this paper was to study the effect of Ginkgo biloba Composita (GBC) on liver collagen fibrosis. The 86 patients were suffering from chronic persistent and active hepatitis B with early fibrosis confirmed by liver biopsy. Serum pro-collagen-III-peptide (PIIIP), laminin (LN), superoxide dismutase (SOD), malonyldialdehyde (MDA) were determined and some patients' biopsies examined with light and electron microscope before and after treatment were observed. By the end of 3 months, the results showed that PIIIP, LN, SOD, MDA were significantly decreased after GBC treatment (P < 0.01) and liver fibrosis of patients was partly reabsorbed and had remission. It was suggested that GBC was effective in arresting the development of liver fibrosis of chronic hepatitis.

2.The protective effect of Ginkgo biloba extract on CCl4-induced hepatic damage.:

Acta Physiol Hung. 1997-1998;85(3):277-85.PMID: 10101542
The aim of this study was to evaluate the protective effect of Ginkgo biloba extract on CCl4-induced hepatic damage in rats. Hepatic malondialdehyde, glutathione and hydroxyproline levels and histopathologic alterations in liver specimens were assessed. 200 mg/kg/day Ginkgo biloba extract were given orally to the animals for 10 days, then a single dose of 2 ml/kg b.w. carbon tetrachloride was, administered intraperitoneally. Ginkgo biloba extract treatment reduced hepatic malondialdehyde levels significantly (p < 0.05), but did not alter glutathione (p > 0.05) and hydroxyproline levels (p > 0.05). The light and electron microscopic findings showed that Ginkgo biloba extract limited the CCl4-induced hepatocyte necrosis and atrophy. These results suggest that this extract may protect the hepatocytes from carbon tetrachloride-induced liver injury.

3.The protective effects of traditional Chinese medicine prescription, han-dan-gan-le, on CCl4-induced liver fibrosis in rats.:

Am J Chin Med. 1998;26(3-4):325-32.PMID: 9862020
Han-Dan-Gan-Le, a Chinese medicine preparation composed of Salvia miltorrhiza, Radix paeoniae, Astragalus membranaceus, Stephania tetrandra, and dried leaves of Ginkgo biloba, has been used successfully to treat human liver fibrosis and cirrhosis for years. This study was designed to examine the mechanisms of the protection. Male Wistar rats were given CCl4 (1.2 ml/kg, 2 times/week), 20% fat diet, and 30% alcohol in drinking water (every other day) for 6 weeks. Han-Dan-Gan-Le (0.5 and 1.0 g/kg, p.o., daily for 6 weeks) was administered to rats simultaneously to examine the protective effects against CCl4-induced liver fibrosis. The experimentally-induced liver fibrosis and other morphological alterations were significantly ameliorated by Han-Dan-Gan-Le. Han-Dan-Gan-Le treatments decreased CCl4-induced hepatic collagen accumulation by more than 50%, and significantly increased urinary excretion of hydroxyproline. The CCl4-induced lipid peroxidation in liver and serum was ameliorated as a result of Han-Dan-Gan-Le treatment, possibly by restoring the activity of superoxide dismutase activity in liver and erythrocytes, In conclusion, Han-Dan-Gan-Le is effective in protecting against liver fibrosis. The mechanisms of the protection appear to be due to its antioxidant properties and the modulation of hepatic collagen metabolism.

4.EGb 761 protects liver mitochondria against injury induced by in vitro anoxia/reoxygenation.:

Free Radic Biol Med. 1999 Sep;27(5-6):596-604.PMID: 10490280
The present study investigated the protective effects of Ginkgo biloba extract (EGb 761) on rat liver mitochondrial damage induced by in vitro anoxia/reoxygenation. Anoxia/reoxygenation was known to impair respiratory activities and mitochondrial oxidative phosphorylation efficiency. ADP/O (2.57 +/- 0.11) decreased after anoxia/reoxygenation (1.75 +/- 0.09, p < .01), as well as state 3 and uncoupled respiration (-20%, p < .01), but state 4 respiration increased (p < .01). EGb 761 (50-200 microg/ml) had no effect on mitochondrial functions before anoxia, but had a specific dose-dependent protective effect after anoxia/reoxygenation. When mitochondria were incubated with 200 microg/ml EGb 761, they showed an increase in ADP/O (2.09 +/- 0.14, p < .05) and a decrease in state 4 respiration (-22%) after anoxia/reoxygenation. In EPR spin-trapping measurement, EGb 761 decreased the EPR signal of superoxide anion produced during reoxygenation. In conclusion, EGb 761 specially protects mitochondrial ATP synthesis against anoxia/reoxygenation injury by scavenging the superoxide anion generated by mitochondria.

5.Effects of extract of Ginkgo biloba leaves and its constituents on carcinogen-metabolizing enzyme activities and glutathione levels in mouse liver.:

Life Sci. 2002 Feb 22;70(14):1657-67.PMID: 11991253
The effects of a standardized extract of Ginkgo biloba L. leaves (EGb) and its terpene constituents, bilobalide and ginkgolides, on the activities of detoxification enzymes, i.e., glutathione S-transferases (GSTs) and DT-diaphorase, and glutathione contents, were investigated in the mouse liver. Oral treatment with EGb (100-1,000 mg/kg) and bilobalide (10-30 mg/kg) once a day for 4 days caused a dose-dependent elevation in GST activity. Ginkgolide A (30 mg/kg, for 4 days) also significantly elevated GST activity, whereas ginkgolide B and ginkgolide C at the same dose had no effects. EGb significantly increased the protein level of GST pi, and bilobalide significantly increased those of GST alpha and GST mu Moreover, EGb-treatment and bilobalide-treatment caused significant elevations in DT-diaphorase activity and in hepatic glutathione contents.

6.Evaluation of hepatoprotective activity of Ginkgo biloba in rats.:

Indian J Physiol Pharmacol. 2002 Apr;46(2):167-74.PMID: 12500491
The mechanism of hepatoprotective effects of Ginkgo biloba (GB), an herbal preparation with wide variety of therapeutic application, on paracetamol (Pcml) induced hepatic damage in rats has been investigated. GB treatment restored the marker enzyme levels indicating the in vivo protective effects against Pcml induced liver damage both in preventive and curative aspects. GB also reversed the increased TBARS levels, and elevated the GSH content of the liver. The results obtained from the study indicate hepatoprotective nature of GB, which might be due to its ability to prevent lipid peroxidation and replenishing the gllutathione level. The effects of GB were comparable to that of silymarin.

7.Hepatic injury induced by acute lung injury in aging rats:

Zhonghua Jie He He Hu Xi Za Zhi. 2002 Dec;25(12):744-7.PMID: 12622895
OBJECTIVE: To investigate the induction of hepatic function damage by acute lung injury (ALI) in aging rats and the effect of Ginkgo Biloba extract (GBE) on this process.METHODS: Thirty male Wistar rats were used to produce the aging animal model. Aging rats were randomly divided into three groups: the control group, the lipopolysaccharide (LPS, intravenous injection) group, and the GBE + LPS group (GBE given 7 days before experiment, once a day, via the esophagus). Samples from the blood, the lung and the liver were collected 2 and 6 h after LPS or saline administration.RESULTS: ALI was induced by intravenous injection of LPS in aging rats. Compared with the aging control, the total bilirubin content and the glutamic pyruvic transaminase (GPT) activity in serum did not change at 2 h after LPS administration. But at 6 h, they were increased, respectively from (10.9 +/- 0.6) mg/L and (26 +/- 3) U in the control group to (30.1 +/- 2.1) mg/L and (88 +/- 12) U in the LPS group (P < 0.001). MDA content increased in the blood and the lung tissue at 2 has compared to the control group, from (15.9 +/- 1.8) micro mol/L and (18.8 +/- 2.1) nmol/mg protein to (22.1 +/- 1.9) micro mol/L and (28.8 +/- 3.1) nmol/mg protein (all P < 0.001), respectively. SOD activity in the lung tissue was decreased significantly, from (25.5 +/- 2.6) mU/L and (36.1 +/- 2.4) U/mg protein to (20.6 +/- 1.9) mU/L and (32.0 +/- 2.7) U/mg protein, respectively (P < 0.05, P < 0.001). The GSH-P(X) activity and the Na(+)-K(+)-ATPase activity in the lung tissue at 2 hours after LPS administration were decreased markedly, from (28.2 +/- 2.8) U/mg protein and (4.9 +/- 0.5) micromol Pi x mg(-1) protein x h(-1). to (21.1 +/- 2.7) U/mg protein and (3.1 +/- 0.3) micromol Pi x mg(-1) protein x h(-1). These changes lasted 6 h after LPS administration. These parameters did not change significantly in the hepatic tissue at 2 h after LPS administration. But after 6 h, MDA content was increased from (7.9 +/- 0.9) nmol/mg protein to (10.9 +/- 0.7) nmol/mg protein; while the GSH-P(X) and the Na(+)-K(+)-ATPase activities were decreased markedly, from (59.0 +/- 3.9) U/mg protein and (0.87 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) to (49.2 +/- 3.0) U/mg protein and (0.77 +/- 0.04) micromol Pi x mg(-1) protein x h(-1) (P < 0.001, P < 0.01). There was no obvious change in the SOD activity. All the changes were significantly attenuated in the GBE + LPS group (P < 0.05, P < 0.01).CONCLUSION: Hepatic function damage could be induced by ALI in aging rats. GBE showed a protective effect on ALI and hepatic function damage in this animal model.

8.Effect of Ginkgo biloba extract on rat hepatic microsomal CYP1A activity: role of ginkgolides, bilobalide, and flavonols.:

Can J Physiol Pharmacol. 2004 Jan;82(1):57-64.PMID: 15052306
The present study investigated the in vitro effect of Ginkgo biloba extracts and some of the individual constituents (ginkgolides, bilobalide, and flavonols such as kaempferol, quercetin, isorhamnetin, and their glycosides) on CYP1A-mediated 7-ethoxyresorufin O-dealkylation in hepatic microsomes isolated from rats induced with beta-naphthoflavone. G. biloba extract competitively inhibited CYP1A activity, with an apparent Ki value of 1.6 +/- 0.4 microg/mL (mean +/- SE). At the concentrations present in the G. biloba extracts, ginkgolides A, B, C, and J and bilobalide did not affect CYP1A activity, whereas kaempferol (IC50 = 0.006 +/- 0.001 microg/mL, mean +/- SE), isorhamnetin (0.007 +/- 0.001 microg/mL), and quercetin (0.050 +/- 0.003 microg/mL) decreased this activity. The monoglycosides (1 and 10 microg/mL) and diglycosides (10 microg/mL) of kaempferol and quercetin but not those of isorhamnetin also inhibited CYP1A activity. The order of inhibitory potency was kaempferol approximately equal to isorhamnetin > quercetin, and for each of these flavonols the order of potency was aglycone >> monoglycoside > diglycoside. In summary, G. biloba extract competitively inhibited rat hepatic microsomal CYP1A activity, but the effect was not due to ginkgolides A, B, C, or J, bilobalide, kaempferol, quercetin, isorhamnetin, or the respective flavonol monoglycosides or diglycosides.

9.Ginkgo biloba extract reverses CCl4-induced liver fibrosis in rats.:

World J Gastroenterol. 2004 Apr 1;10(7):1037-42.PMID: 15052689
AIM: To study the reversing effect of Ginkgo biloba extract (GbE) on established liver fibrosis in rats.METHODS: Following confirmation of CCl(4)-induced liver fibrosis, GbE or saline was administrated to the rats for 4 weeks. The remaining rats received neither CCl(4) nor GbE as normal control. The four groups were compared in terms of serum enzymes, tissue damage, expression of alphaSMA and tissue inhibitor-1 of metalloproteinase (TIMP-1) and metalloproteinase-1 (MMP-1).RESULTS: Compared with saline-treated group, liver fibrosis rats treated with GbE had decreased serum total bilirubin (P<0.01) and aminotransferase levels (P<0.01) and increased levels of serum albumin (P<0.01). Microscopic studies revealed that the livers of rats receiving GbE showed alleviation in fibrosis (P<0.05) as well as expression of alphaSMA (P<0.01). The liver collagen and reticulum contents were lower in rats treated with GbE than saline-treated group (P<0.01). RT-PCR revealed that the level of TIMP-1 decreased while the level of MMP-1 increased in GbE group.CONCLUSION: Administration of GbE improved CCl(4)-induced liver fibrosis. It is possibly attributed to its effect of inhibiting the expression of TIMP-1 and promoting the apoptosis of hepatic stellate cells.

10.The effect of Ginkgo biloba extract (EGb 761) on hepatic sinusoidal endothelial cells and hepatic microcirculation in CCl4 rats.:

Am J Chin Med. 2004;32(1):21-31.PMID: 15154282
It has been shown that Ginkgo biloba Extract (EGb 761) increases peripheral and cerebral blood flow and microcirculation and improves myocardial ischemia reperfusion injury. This study was designed to investigate the effect of EGb 761 on hepatic endothelial cells and hepatic microcirculation. Sixty male Wister rats were divided into normal, carbon tetrachloride (CCl4) and EGb groups, and were given normal saline, CCl4 and CCl4 plus EGb 761, respectively, for 10 weeks. Samples were taken from the medial lobe of the rat livers ten weeks later. Hepatic sinusoidal endothelial cells and other parameters of hepatic microcirculation were observed under transmission electron microscopy (TEM). The amount of malondialdehyde (MDA), endothelin (ET-1), platelet-activating factor (PAF) and nitric oxide (NO) in liver tissue was determined by spectrophotometry and radioimmunoassay, respectively. Compared with the CCl4 group, aggregation of blood cell or micro thrombosis in hepatic sinusoids, deposition of collagen in hepatic sinusoids and space of Disse, injury of endothelial cells and capillization of hepatic sinusoid was significantly reduced in the EGb group. The amount of MDA, ET-1 and PAF was markedly reduced in the EGb group than in the CCl4 group, while no significant difference in the amount of NO was observed between the two groups. The results demonstrate that EGb 761 has protective effect on hepatic endothelial cells and hepatic microcirculation in rats with chronic liver injury induced by CCl4. The mechanisms may involve its inhibition on ET-1, PAF and lipid peroxidation.

11.Effect of ginkgo biloba extract on livers in aged rats.:

World J Gastroenterol. 2005 Jan 7;11(1):132-5.PMID: 15609412
AIM: To investigate the protective effect of ginkgo biloba extract (GBE) on livers of aged rats and the associated mechanisms.METHODS: Two-mo- and 20-mo-old rats were treated with GBE/saline for 3 mo. Liver tissue samples from 5-mo-old rats treated with saline (group Y) and 23-mo-old rats treated with GBE (group E) or saline (group N) were used for histopathological examinations (hematoxylin-eosin and Masson staining, Lipofuscin staining-Schmorl staining) and determination of expression of tissue inhibitor-1 of metalloproteinase (TIMP-1) and the level of malondialdehyde (MDA), glutathione peroxidase (GPx) and superoxide dismutase (SOD). Blood samples were collected for determination of alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL) and albumin.RESULTS: Microscopic studies with Masson staining revealed mild liver fibrosis in aged rats (group N), while the livers of aged rats receiving GBE (group E) showed amelioration in fibrosis (2.2+/-0.1 vs 2.8+/-0.1, P<0.01) and deposition of lipofuscin (33.7+/-5.3 vs 62.8+/-5.7, P<0.01). The expression of TIMP-1 and the level of liver MDA (1.0+/-0.1 vs 1.2+/-0.2, P<0.05) also decreased but the activity of GPx (97.1+/-15.3 vs 61.8+/-14.5, P<0.01) increased in group E. Compared with group Y, the level of liver MDA (0.8+/-0.1 vs 1.2+/-0.2, P<0.01), lipofuscin (32.4+/-6.0 vs 62.8+/-5.7, P<0.01) and TIMP-1 expression were increased, while the activity of GPx (103.2+/-17.6 vs 61.8+/-14.5, P<0.01) and SOD (16.7+/-4.4 vs 11.8+/-3.9, P<0.05) was decreased in group N. There was no difference in liver function among these three groups.CONCLUSION: GBE has protective effects on aging liver. The possible mechanisms might be its antioxidant activity and inhibition of TIMP-1 expression.

12.Ginkgo biloba extract alleviates liver fibrosis induced by CCl in rats.:

Liver Int. 2005 Dec;25(6):1224-32.PMID: 16343076
AIMS: To investigate the protective effect of Ginkgo biloba extract (GbE) on liver fibrosis induced by carbon tetrachloride (CCl4) in rats and expressions of transforming growth factor beta1 (TGF-beta1) and collagen I during this period.METHODS: The effect of GbE on liver fibrogenesis was detected by hematoxylin and eosin staining (H&E staining), Masson's trichrome staining, and electron microscope study. Blood samples were collected for measurement of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin. Malondialdehyde (MDA) in liver tissue was detected by the thiobarbituric acid (TBA) method. Immunohistochemistry assay and RT-PCR were used to examine the protein expressions and mRNA levels of TGF-beta1 and collagen I, respectively.RESULTS: H&E, Masson's trichrome stainings and electron microscope study showed liver fibrosis in rats was greatly alleviated when treated with GbE. Additionally, there was a remarkable improvement of serum ALT, AST, albumin and MDA in the GbE-treated group. Immunohistochemistry and RT-PCR results showed GbE intervention significantly inhibited TGF-beta1 and collagen I expressions in rat liver. No side effects of GbE were found during these experiments. But GbE could not reverse the pathological changes of liver fibrosis completely when compared with normal control.CONCLUSION: GbE can partially protect rat liver from the fibrogenesis induced by CCl4. The mechanism may lie in its effect of inhibiting oxidative stress caused by liver injury and expressions of signal molecules such as TGF-beta1. GbE may thus be of potential help as a medicament or food additive for alleviation of liver fibrogenesis.

13.Effects of nuclear factor kappaB and transforming growth factor beta1 in the anti-liver fibrosis process using Ginkgo biloba extract:

Zhonghua Gan Zang Bing Za Zhi. 2005 Dec;13(12):903-7.PMID: 16381635
OBJECTIVE: To evaluate the effects of Ginkgo biloba extract (EGB) on CCl(4)-induced liver fibrosis and to investigate the underlying mechanisms.METHODS: Rats were divided into the following groups: normal control group, CCl(4) model group, low dose EGB group, moderate dose EGB group and high dose EGB group. The rat liver fibrosis model was induced by intraperitoneal injection of CCl(4) twice a week for 8 weeks. The model rats of the three EGB treated groups were given 0.25 g/kg, 0.5 g/kg, 1.0 g/kg of EGB by stomach tubes every day. At the end of the eighth week, the blood and liver specimens were obtained. The expressions of nuclear factor kappaB (NF-kappaB) P65, and alpha-smooth muscle actin (alpha-SMA) were detected by immunohistochemistry. Radioimmunoassay was exploited to evaluate serum hyaluronic acid (HA) and laminin (LN) levels. Electrophoretic mobility shift assay (EMSA) was used to confirm the nuclear translocation activity of NF-kappaB in liver tissues. The mRNA expression of transforming growth factor-beta1 (TGFbeta1) and collagen I was determined by RT-PCR. Malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) in liver tissues and alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the sera were also examined.RESULTS: CCl(4) administration induced liver fibrosis, which was inhibited by EGB in a dose-dependent manner. The histopathologic scores of liver fibrosis, the levels of serum ALT, AST, HA and LN were significantly lower in the rats treated with EGB compared with those not treated (P <0.01 or P <0.05). SOD and GSH-Px activities were notably elevated and MDA content was significantly lower in the rats treated with EGB (P <0.01 or P <0.05), indicating reduced oxidative stress. Immunohistochemical staining demonstrated inhibition of hepatic stellate cell (HSC) activation (in terms of alpha-SMA expression) and NF-kappaB P65 expression in the livers of the EGB-treated rats. As determined by EMSA and RT-PCR, activation of NF-kappaB, the mRNA expression of TGFbeta1 and collagen I were significantly higher in model group rats, but obviously lower in EGB treated rats.CONCLUSION: EGB is able to ameliorate liver injury and prevent rats from CCl(4)-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the expression of TGFbeta1 and the induction of NF-kappaB on HSC activation.

14.Therapeutic effects and molecular mechanisms of Ginkgo biloba extract on liver fibrosis in rats.:

Am J Chin Med. 2006;34(1):99-114.PMID: 16437743
Oxidative stress can be implicated as a cause of liver fibrosis. In this sense, Ginkgo Biloba Extract (EGB), an antioxidant, may be beneficial in restraining liver fibrosis. The aim of this study was to evaluate the effects of EGB on experimental liver fibrosis. Rat liver fibrosis was induced by intraperitoneal injection of carbon tetrachloride (CCl4) twice a week for 8 weeks. Three groups of rats received EGB (0.25, 0.5 and 1.0 g/kg, respectively) by stomach everyday. CCl4 administration induced liver fibrosis, which was inhibited by EGB in a dose-dependent manner. The histopathologic score of fibrosis, liver function and the levels of plasma hyaluronic acid (HA) and laminin (LN) were significantly improved in rats treated with CCl4 + EGB, compared with those treated with CCl4 only (p < 0.01 or p < 0.05). The activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) were notably elevated, while malondialdehyde (MDA) content was significantly decreased in the rats treated with CCl4 + EGB (p < 0.01 or p < 0.05). Inhibition of hepatic stellate cell (HSC) activation and nuclear factor kappaBP65 (NF-kappaBP65) expression was demonstrated in the livers of EGB-treated rats. The activation of NF-kappaB was significantly suppressed in EGB-treated rats determined by electrophoretic mobility shift assay (EMSA). Furthermore, EGB reduced expressions of transforming growth factor-beta1 (TGF-beta1) and collagen I mRNA. In conclusion, EGB is able to ameliorate liver injury and prevent rats from CCl4-induced liver fibrosis by suppressing oxidative stress. This process may be related to inhibiting the induction of NF-kappaB on HSC activation and the expression of TGF-beta1.

15.Effects of extract from Ginkgo biloba on carbon tetrachloride-induced liver injury in rats.:

World J Gastroenterol. 2006 Jun 28;12(24):3924-8.PMID: 16804984
AIM: To study the effects of extract from Ginkgo biloba (EGb) containing 22% flavonoid and 5% terpenoid on chronic liver injury and liver fibrosis of rats induced by carbon tetrachloride (CCl(4)).METHODS: All rats were randomly divided into control group, CCl(4)-treated group, colchicine-treated group and EGb-protected group. Chronic liver injury was induced in experimental groups by subcutaneous injection of CCl(4) and fed with chows premixed with 79.5% corn powder, 20% lard and 0.5% cholesterol (v/v). EGb-protected group was treated with EGb (0.5 g/kg body weight per day) for 7 wk. At the end of wk 8, all the rats were killed. Liver function, liver fibrosis, oxidative stress and expression of transforming growth factor beta1 (TGF-beta1), a-smooth muscle actin (alpha-SMA) and type I collagens in liver were determined. In addition, pathology changes of liver tissue were observed under light microscope.RESULTS: The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and albumin (Alb) in EGb-protected group were notably improved as compared with the CCl(4)-treated group (P < 0.01). The contents of serum hyaluronic acid (HA), type III procollagen (PCIII), type IV collagen (CIV) and the expression of hepatic tissue TGF-beta1, alpha-SMA and type I collagen in EGb-protected group were significantly lower than those in CCl(4)-treated groups (P < 0.05, P < 0.01). The degrees of liver fibrosis in EGb-protected groups were lower than those in CCl(4)-treated groups (6.58 +/- 1.25 vs 9.52 +/- 2.06, P < 0.05). Compared to the CCl(4)-treated group, the levels of plasma glutathoine peroxidase (Se-GSH-Px), superoxide dismutase (SOD) and malondialdehyde (MDA) were strikingly improved also in EGb-protected group (P < 0.05, P < 0.01).CONCLUSION: EGb resists oxidative stress and thereby reduces chronic liver injury and liver fibrosis in rats with liver injury induced by CCl(4).

16.Effects of Ginkgo biloba extract on cell proliferation, cytokines and extracellular matrix of hepatic stellate cells.:

Liver Int. 2006 Dec;26(10):1283-90.PMID: 17105595
BACKGROUND/AIMS: Hepatic fibrosis is the common wound-healing response to chronic liver injury. Ginkgo biloba extract (GbE) has been indicated to reverse hepatic fibrosis and exhibit therapeutic effects both in vitro and in vivo. This study aimed to investigate the underlying mechanism of GbE using HSC-T6 cells, a subline of hepatic stellate cells (HSC) as a model.METHODS: HSC-T6 cells were seeded into six-well plates and allowed to attach overnight. After exposure to different concentrations of GbE761 for 24 or 48 h, cell cycle analysis, semiquantitative RT-PCR, Western blotting analysis and analysis of ECM secretion were performed.RESULTS: It was revealed that GbE (1, 10, 100, 500 mg/l) suppressed HSC proliferation and caused G0/G1 phase arrest in a concentration-dependent manner. RT-PCR and Western blot assays were applied to detect the decline of transforming growth factor beta1(TGF-beta1) and connective tissue growth factor (CTGF) in both mRNA and protein levels after GbE treatment in HSC-T6 cells for 24 or 48 h. Meanwhile, GbE inhibited the synthesis of type I and type III collagens. Secretion of some extracellular matrix (ECM) proteins, such as type III procollagen (PC III), type IV collagen (collagen IV), laminin (LN), hyaluronic acid (HA), were all decreased in supernatant of GbE treated HSC cells.CONCLUSIONS: Our results suggest that GbE confers its anti-fibrosis effects through inhibiting HSC proliferation, reducing TGF-beta1 and CTGF expression and consequently suppressing the collagen production and ECM secretion.

17.Ginkgo biloba extract protects against alcohol-induced liver injury in rats.:

Phytother Res. 2007 Mar;21(3):234-8.PMID: 17154234
Ginkgo biloba extract has been shown to be hepatoprotective. However, its benefits when used in alcoholic liver injury have not been demonstrated. This study investigated the effects of Ginkgo biloba extract on alcohol-induced liver injury in a chronic alcohol plus fish oil gavage model in rats. Liver injury was evaluated histologically and by serum alanine aminotransferase (ALT). Liver tumor necrosis factor-alpha (TNF-alpha) protein levels, malondialdehyde (MDA) and glutathione (GSH) contents were determined. TNF-alpha mRNA expression in the liver was analysed by reverse transcriptase-polymerase chain reaction (RT-PCR). Rats given fish oil plus alcohol developed macrovesicular and microvesicular steatosis, spotty necrosis and mild inflammation in the liver and elevated serum ALT levels, which were accompanied by increased MDA contents, reduced GSH contents and elevated TNF-alpha protein and mRNA expressions in the liver. Supplementation with Ginkgo biloba extract (200 mg/kg, orally) improved the liver injury, blunted the rises of MDA contents and TNF-alpha expression, and restored the GSH content in the liver. Ginkgo biloba extract protects against alcohol-induced liver injury, and the mechanism may involve a reduction of lipid peroxidation, prevention of GSH depletion and inhibition of TNF-alpha expression in the liver.

18.Protective effects of Gingko biloba on thioacetamide-induced fulminant hepatic failure in rats.:

Hum Exp Toxicol. 2006 Dec;25(12):705-13.PMID: 17286148
Gingko biloba (GB) has antioxidant and platelet-activating factor (PAF) antagonistic effects. We investigated the protective effects of GB on thioacetamide (TAA)-induced fulminant hepatic failure in rats. Fulminant hepatic failure was induced in treatment groups by three intraperitoneal (ip) injections of TAA (350 mg/kg) at 24-hour intervals. Treatments with GB (100 mg/kg per day, orally) and N-acetylcysteine (20 mg/kg twice daily, sc) were initiated 48 hours prior to TAA administration. The liver was removed for histopathological examinations. Serum and liver thiobarbituric acid-reactive substance (TBARS) levels were measured for assessment of oxidative stress. Liver necrosis and inflammation scores and serum and liver TBARS levels were significantly higher in the TAA group compared to the control group (P < 0.001, < 0.001, 0.001, < 0.001, respectively). Liver necrosis and inflammation scores and liver TBARS levels were significantly lower in the GB group compared to the TAA group (P < 0.001, < 0.001 and 0.01, respectively). GB ameliorated hepatic damage in TAA-induced fulminant hepatic failure. This may be due to the free radical-scavenging effects of GB.

19.Antioxidant and hepatoprotective effects of Ginkgo biloba phytosomes in carbon tetrachloride-induced liver injury in rodents.:

Liver Int. 2007 Apr;27(3):393-9.PMID: 17355462
AIM: The protective effects of Ginkgo biloba phytosomes (GBP) on carbon tetrachloride (CCl4)-induced hepatotoxicity and the probable mechanism(s) involved in this protection were investigated in rats.METHODS: Liver damage was induced in Wistar rats by administering a 1:1 (v/v) mixture of CCl4 and olive oil (1 ml/kg, i.p.) once daily for 7 days. GBP at 25 mg/kg and 50 mg/kg, i.p. and reference drug silymarin (200 mg/kg, p.o.) were administered for 10 days to CCl4-treated rats, this treatment beginning 3 days prior to the commencement of CCl4 administration. The degree of protection was evaluated by determining the marker enzymes (SGOT, SGPT and SALP), albumin (Alb) and total proteins (TP). Further, the effects of GBP on lipid peroxidation (LPO), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione reductase (GR) were estimated in liver homogenates to evaluate antioxidant activity.RESULTS: GBP (25 and 50 mg/kg) and silymarin elicited significant hepatoprotective activity by decreasing the activities of serum marker enzymes and lipid peroxidation and elevated the levels of GSH, SOD, CAT, GPX, GR, Alb and TP in a dose-dependent manner.CONCLUSION: The present findings indicate that the hepatoprotective effects of GBP against CCl4-induced oxidative damage may be due to its antioxidant and free radical-scavenging activity.

20.The effect of Ginkgo biloba extract on portal hypertension and hepatic microcirculation in rat:

Zhonghua Gan Zang Bing Za Zhi. 2007 Apr;15(4):245-8.PMID: 17456308
OBJECTIVE: To evaluate the effect of Ginkgo biloba extract (EGb) on hepatic microcirculation and portal hypertension in CCl4 treated rats.METHODS: Twenty-five male Wistar rats were divided into a blank, a CCl4 treated and a CCl4 plus EGb treated group, and all were treated for 10 weeks. The free portal vein pressures were measured through catheterizations. Hepatic sinusoidal endothelial cells and other parameters of hepatic microcirculation were studied with transmission electron microscopy. The amounts of malondialdehyde (MDA), endothelin (ET-1), platelet-activating factor (PAF), nitric oxide (NO), cNOS and iNOS in the liver tissues were determined.RESULTS: The portal vein pressure of the CCl4 plus EGb treated group was (7.4 +/- 0.6) mm Hg while the pressure of the CCl4 treated group was (8.7 +/- 0.8) mm Hg. Aggregation of blood cells or microthrombosis in hepatic sinusoids, deposition of collagen in hepatic sinusoids and spaces of Disse, injury of endothelial cells and capillarization of hepatic sinusoid were significantly milder in the EGb group. The amounts of MDA, ET-1, PAF, NO and iNOS were markedly lower in the CCl4 plus EGb treated group than in the CCl4 treated group.CONCLUSION: The results demonstrated that EGb can decrease the portal vein pressure and improve hepatic microcirculation in CCl4 treated rats. The mechanisms of this effect may involve its inhibition on ET-1, PAF, lipid peroxidation, and down regulation of the hepatic iNOS and NO expressions

21.Heme oxygenase-1 upregulated by Ginkgo biloba extract: potential protection against ethanol-induced oxidative liver damage.:

Food Chem Toxicol. 2007 Aug;45(8):1333-42. Epub 2007 Jan 31.PMID: 17467134
Oxidative stress plays a pivotal role in the pathogenesis and progression of alcoholic liver disease (ALD) and HO-1 induction is suggested to protect hepatocytes from ethanol hepatotoxicity. Here, we present the data to explore the hepatoprotective effect and underlying mechanism(s) of Ginkgo biloba extract (EGB), a naturally occurring HO-1 inducer, against ethanol-induced oxidative damage. Ethanol-fed (2.4 g/kg) male rats were pretreated by EGB (48 or 96 mg/kg) for 90 days. Liver damage was evaluated by histopathology and serum aminotransferase assay. Hepatic redox parameters were measured by spectrophotometry. Heme oxygenase-1 (HO-1) expression was determined by RT-PCR and flow cytometry on mRNA and protein level, respectively. Our results showed that EGB, especially at high dose, ameliorated ethanol-induced macrovesicular steatosis and parenchymatous degeneration in hepatocytes, and decreased serum aminotransferases level. Furthermore, EGB reduced ethanol-derived glutathione depletion and lipid peroxidation, and inhibited the inactivation of superoxide dismutase, glutathione peroxidase and catalase, although EGB itself had no influence on such parameters. Importantly, EGB induced hepatic microsomal HO-1 on mRNA, protein expression and enzymatic activity, which is paralleled to the EGB-derived hepatoprotective effect. Hence, HO-1 upregulation by EGB may enhance the antioxidative capacity against the ethanol-induced oxidative stress and maintain the cellular redox balance.

22.Effect of Ginkgo biloba extract on oxidative metabolism of valproic acid in hepatic microsomes from donors with the CYP2C91/1 genotype.:

Can J Physiol Pharmacol. 2007 Sep;85(9):848-55.PMID: 18066130
We investigated the effect of Ginkgo biloba extracts and some of its individual constituents on the oxidative metabolism of valproic acid (VPA) in hepatic microsomes from donors with the CYP2C9*1/*1 genotype. G. biloba extract decreased 4-ene-VPA, 3-OH-VPA, 4-OH-VPA, and 5-OH-VPA formation with mean (+/- SE) IC50 values of 340 +/- 40 microg/mL, 370 +/- 100 microg/mL, 180 +/- 30 microg/mL, and 210 +/- 20 microg/mL, respectively. This was associated with inhibition of not only CYP2C9*1, but also CYP2A6 and CYP2B6. Bilobalide, ginkgolide A, ginkgolide B, ginkgolide C, ginkgolide J, quercetin-3-O-rutinoside, kaempferol-3-O-rutinoside, and isorhamnetin-3-O-rutinoside were not responsible for the inhibition of VPA metabolism by the extract. When analyzed as the sum of the aglycone and total glycosides present in the extract, quercetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 76%, 51%, and 70%, respectively, kaempferol decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 65%, 46%, and 49%, respectively, and isorhamnetin decreased 4-ene-VPA, 4-OH-VPA, and 5-OH-VPA formation by 29%, 26%, and 31%, respectively. The 3 aglycones did not affect 3-OH-VPA formation. In summary, G. biloba extract decreased hepatic microsomal formation of 4-ene-VPA, 4-OH-VPA, 5-OH-VPA, and 3-OH-VPA, but the effect was not due to the terpene trilactones or flavonol glycosides investigated in our study.

23.Protective effects of Ginkgo biloba, Panax ginseng, and Schizandra chinensis extract on liver injury in rats.:

Am J Chin Med. 2007;35(6):995-1009.PMID: 18186586
This study investigated the effects of the combined extracts of Ginkgo biloba, Panax ginseng, and Schizandra chinensis at different doses on hepatic antioxidant status and fibrosis in rats with carbon tetrachloride (CCl4)-induced liver injury. Male Sprague-Dawley rats (n = 8-12 per group) were divided into the control, CCl4, CCl4 + silymarin (0.35%), CCl4 + low-dose herbal extract (0.24% of Ginkgo biloba, Panax ginseng, and Schizandra chinensis extract at 1:1:1; LE), and CCl4 + high-dose herbal extract (1.20% of the same herbal extract; HE) groups. Silymarin or herbal extract was orally given to rats a week before chronic intraperitoneal injection with CCl4 for 6 weeks. The pathological results showed that herbal extract suppressed hepatic bile duct proliferation, and low-dose herbal extract inhibited liver fibrosis. Hepatic superoxide dismutase (SOD) activity was lower in the CCl4 group, but there was no difference in the silymarin or herbal extract treated groups compared to the control group. Hepatic catalase activity and the ratio of reduced to oxidized glutathione were significantly higher (p < 0.05) in the HE group than those in the CCl4 group. Silymarin and herbal extract reversed the impaired hepatic total antioxidant status (p < 0.05). Herbal extract partially reduced the elevated hepatic lipid peroxides. Hepatic transforming growth factor-beta1 (TGF-beta1) level decreased significantly (p < 0.05) in the LE group. Therefore, high-dose herbal extract improved hepatic antioxidant capacity through enhancing catalase activity and glutathione redox status, whereas low-dose herbal extract inhibited liver fibrosis through decreasing hepatic TGF-beta1 level in rats with CCl4-induced liver injury.

24.Protective effects of N-acetylcysteine and Ginkgo biloba extract on ischaemia-reperfusion-induced hepatic DNA damage in rats.:

Clin Exp Med. 2008 Dec;8(4):193-8. Epub 2008 Sep 23.PMID: 18810589
Hepatic ischaemia-reperfusion injury is a serious problem that occurs during various surgical operations such as liver transplantation, surgical revascularization, and partial organ resection. Different pharmacological agents have been used for the protection of organ function and for extending the tolerable ischaemic interval after the ischaemic insult. We aimed to determine the presence of 8-hydroxydeoxyguanosine (8-OHdG) in the DNA from liver undergoing ischaemia-reperfusion, and also to evaluate the protective effects of N-acetylcysteine (NAC) and EGb761 (Ginkgo biloba extract) against hepatic oxidative DNA damage. A total of 40 rats were divided into four groups of 10 animals each (sham-operation group, control group, NAC group, and EGb761 group). Oxidative damage to DNA was evaluated by measuring the increase in 8-OHdG formation in liver tissue and also the effects of NAC and EGb761 pretreatment. Hepatic ischaemia for 90 min followed by reperfusion caused a marked increase in tissue levels of 8-OHdG, thiobarbituric acid-reactive substance, serum ALT, AST and LDH activities compared to sham-operated group. Pretreatment with both NAC and EGb761 clearly diminished 8-OHdG formation and lipid peroxidation. These findings suggest that antioxidant molecules such as NAC and EGb761 may be useful in preventing postischaemic reperfusion injury in hepatic tissue.

25.Protective role of Ginkgo biloba against hepatotoxicity and nephrotoxicity in uranium-treated mice.:

J Med Food. 2010 Feb;13(1):179-88.PMID: 20136453
The aim of the present study was to investigate the protective role of Ginkgo biloba leaf extract against uranium (U)-induced toxicity in Swiss albino mice. The mice were randomly divided into six groups, each consisting of six animals: Group I (control) received tap water alone, Group II received U at a dose of 5 mg/kg of body weight, Group III received G. biloba at a dose of 50 mg/kg of body weight, Group IV received G. biloba at a dose of 150 mg/kg of body weight, Group V received G. biloba (50 mg/kg of body weight) and U (5 mg/kg of body weight), and Group VI received G. biloba (150 mg/kg of body weight) and U (5 mg/kg of body weight) by oral gavage for 5 days. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), blood urea nitrogen (BUN), and creatinine levels were determined to assess liver and kidney function, respectively. Also, liver and kidney samples were taken for the determination of tissue malondialdehyde (MDA) and reduced glutathione (GSH) levels, and histopathological changes in liver and kidneys were investigated. The results indicated that there was a significant increase (P < .05) in selected serum parameters. Serum AST, ALT, BUN, and creatinine levels significantly increased in mice treated with U alone when compared to the other groups. Moreover, U-induced oxidative damage caused a significant decrease in GSH levels and a significant increase in MDA levels of liver and kidney tissues. Treatment with G. biloba produced amelioration in biochemical indices of hepatotoxicity and nephrotoxicity according to Group II. Each dose of G. biloba provided significant protection against U-induced toxicity, and its strongest effect was observed at a dose of 150 mg/kg of body weight. In vivo results showed that G. biloba extract is a potent protector against U-induced toxicity, and its protective role is dose-dependent.

26.Protective effect of Ginkgo biloba extract on liver damage by a single dose of CCl 4 in male rats.:

Hum Exp Toxicol. 2011 Mar;30(3):209-16. Epub 2010 Jun 22.PMID: 20571138
Functional and morphological alterations were generated by p.o. (per os) administration of a single oral dose of carbon tetrachloride (CCl(4); 0.125 mL/kg b.w., equivalent to 293 mg/kg) to adult male Wistar rats. CCl(4) significantly increased (p < 0.05) the serum activities of alanine aminotransferase (ALT; 7478 ± 1044%) and aspartate aminotransferase (AST; 6964 ± 833%), compared to control rats; CCl(4) also significantly decreased serum concentration of albumin (23 ± 5.5%) and increased the concentration of malondialhdeyde (MDA) in liver (300 ± 33%). Furthermore, CCl( 4) down-regulated the mRNA steady-state level of tumor necrosis factor a(TNF-a). CCl(4) produced necrosis in the central lobe area, extended to the periphery, nuclear alterations (pycnosis, karyolysis and karyorrhexis), and cytoplasmic acidophilia. The pretreatment with 4 mg/kg (p.o.) of Ginkgo biloba extract (GbE), for 5 days, prevented most of the damage caused by CCl(4): significantly decreased the serum activities of ALT and AST (54 and 65%, respectively), compared to CCl(4)-treated rats; GbE partially prevented the increase of liver MDA (55 ± 14%) and the decrease of albumin concentration to 12 ± 0.2%. This pretreatment prevented the down-regulation of TNF-a and up-regulated the interleukine 6 (IL-6) mRNA steady-state level. Moreover, the GbE reduced the amount of necrotic areas in the central lobe area, compared to CCl(4)-treated rats.

27.Antioxidant and hepatoprotective effects of extract of ginkgo biloba in rats of non-alcoholic steatohepatitis.:

Saudi Med J. 2010 Oct;31(10):1114-8.PMID: 20953526
OBJECTIVE: To evaluate the therapeutic effect and mechanism of extract of ginkgo biloba (EGB) in treatment of diet-induced non-alcoholic steatohepatitis (NASH) in rats.METHODS: The experiment was conducted in the Laboratory, Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, China from June 2009 to December 2009. In this study, the rat model of NASH was produced by feeding high-fat diet. Sixty rats were randomly divided into 3 groups: Normal group: normal diet, drinking water; Model group: high-fat diet, single-distilled water 10 ml/kg gavage once a day for 12 weeks; and Treated group: high-fat diet, EGB 6 mg/kg gavage once a day for 12 weeks. At the end of 12 weeks, all rats were killed. The serum biochemical, fibrosis markers, superoxide dismutase (SOD), malondialdehyde (MDA), the pathological changes, and the expression levels of nuclear factor KB (NF-κB)p65 protein in the liver were observed.RESULTS: The contents of serum alanine transaminase aspartate aminotransferase, fibrosis markers, and pathological grading of liver fibrosis and the staining intensity of NF-κBp65 protein in the liver of rats in treated group were significantly lower than those in the model group. Activities of superoxide dismutase were elevated, but levels of malondialdehyde were decreased in the treated group as compared with the model group.CONCLUSION: Extract of ginkgo biloba has antioxidant and hepatoprotective effects and can inhibit liver fibrosis in rat of NAHS.

I-Ginkgo Biloba:Immune response,Immunity,Immune System:

1.Effect of the EGb 761 (Ginkgo bilboa extract) on primary immune response in experimental chronic stress.:

Rev Med Chir Soc Med Nat Iasi. 1995 Jan-Jun;99(1-2):154-9.PMID: 9524674
The effect of a chronic stress upon the primary immune response on mice was evaluated by using the plaque-forming cells (PFC)-direct technique, which allowed us to record a serious suppression of the immune response in the exposed animals. In the next phase of the experiment a second group was initially treated with Tanakan (EGb 761--Ginkgo biloba extract) and then it was submitted to the same chronic stress: this procedure did not bring about the increase of the number of lymphocytes but it significantly improved the function of these cells.

2.Evidence for immunotoxic effects of crude Ginkgo biloba L. leaf extracts using the popliteal lymph node assay in the mouse.:

Int J Immunopharmacol. 2000 Mar;22(3):229-36.PMID: 10685005
Allergic reactions due to contact with different parts of the ancient tree Ginkgo biloba L. have repeatedly been reported. Provocation tests in patients and animal experiments have identified alkylphenols such as ginkgolic acids as causative constituents. Leaf extracts from Ginkgo are widely used to treat peripheral or cerebral circulatory disorders and Alzheimer's disease. Since alkylphenols are also present in leaves, potential allergic and other immunological hazards of such preparations have to be carefully controlled. Thus, we have evaluated if the popliteal lymph node assay (PLNA) in the mouse may represent a suitable model for the detection of constituents with immunotoxic properties in a complex mixture of biologically active agents such as plant extracts. Subplantar injection (2 mg) of a crude aqueous-ethanolic extract from Ginkgo leaves caused a significant lymphoproliferative reaction (LPR) in the ipsilateral popliteal lymph node. PLNA-active compounds in this extract could be enriched in the lipophilic phase by liquid-liquid partition between heptane and water. Chemical analysis of the heptane extract revealed the presence of a high concentration of alkylphenols (approx. 30%) and further subfractionation indicated that the enlargement of the popliteal lymph node was mainly due to the content of ginkgolic acids. This presumption was corroborated by observing a similar LPR following injection of a purified mixture of ginkgolic or hydroginkgolic acids. Thus, our experiments confirm that Ginkgo leaf extracts may contain constituents with immunotoxic properties, underlining the need to apply adequate production procedures to guarantee the completest possible removal of these compounds. The PLNA appears to represent a simple test model for the detection, characterisation and control of ingredients with potential immunotoxic side effects in complex herbal drugs.

3.IgE immune response to Ginkgo biloba pollen.:

Ann Allergy Asthma Immunol. 2000 Oct;85(4):298-302.PMID: 11061473
BACKGROUND: The ginkgo (Ginkgo biloba L.) continues to be planted as a shade tree in preference to other species in Seoul, Korea. The proportion of ginkgo to total shade trees was 43.2% in 1998, but the allergenic characteristics of ginkgo pollen has not been elucidated.OBJECTIVES: This study was undertaken to obtain information regarding the skin reactivity rate to ginkgo pollen in a population of Korean subjects with respiratory allergy. Possible ginkgo pollen allergens and the cross-reactivity of ginkgo pollen with other prevalent pollens were also examined.METHODS: Four hundred and forty-seven patients with asthma and/or allergic rhinitis were skin prick tested with extract of ginkgo pollen (1:20 wt/vol). Of these patients, positive skin responders (A/H ratio > or =2+) were selected for ELISA and immunoblot experiments.RESULTS: A total of 21 patients (4.7%) showed skin reactivity (A/H ratio > or =2+) to ginkgo pollen in the skin prick test. They were also cosensitized to many other tree, grass, and weed pollens. Sixteen (76%) of the 21 positive skin responders showed specific IgE responses to ginkgo pollen in ELISA. In inhibitory ELISA, IgE binding to ginkgo pollen was inhibited by more than 80% by oak, ryegrass, mugwort, and ragweed; and 34% by hop Japanese; and 10% by rBet v 2 at 10 microg/mL. In immunoblot, 10 out of 21 sera (48%) reacted to the 15-kD protein of ginkgo pollen, 9 (43%) to 33-35 kD, and 8 (38%) to 36-38 kD. In inhibitory immunoblot, IgE binding to ginkgo pollen proteins was almost completely inhibited by oak, ryegrass, mugwort and ragweed, but only partially by hop Japanese and rBet v 2.CONCLUSION: The skin reactivity rate to ginkgo pollen is approximately 4.7% in a population of Korean subjects with respiratory allergy. Since ginkgo pollen has a high cross-reactivity with other prevalent pollens, it could cause clinical symptoms during its pollen season by cross-reacting with the IgE produced in response to other pollens in patients sensitized to multiple pollens.

4.Sensitization of human neutrophil defense activities through activation of platelet-activating factor receptors by ginkgolide B, a bioactive component of the Ginkgo biloba extract EGB 761.:

Biochem Pharmacol. 2002 Apr 1;63(7):1241-9.PMID: 11960600
Ginkgolide B (GKB, BN 52021) was described as a platelet-activating factor (Paf) receptor antagonist. However, it is not known whether all GKB biological effects are mediated through Paf receptor antagonism only. To gain insight into the drug mode of action, we investigated here the effects of GKB per se on functional and signaling activities in human polymorphonuclear leukocytes (PMN). Treatment of PMN with GKB (0.5-12 microM) stimulates a rapid and weak production of reactive oxygen species determined by chemiluminescence. ROS production required the activation of protein kinase C (PKC), tyrosine kinases and p38 mitogen-activated protein kinase as indicated by inhibitory effects of, respectively, GF 109203X (IC(50) of 0.5 microM), genistein (IC(50) of 0.5 microM) and SB 203580 (IC(50) of 0.2 microM) or SB 202190 (IC(50) of 1.1 microM). GKB stimulated a Pertussis toxin-sensitive PLD activity assessed by the formation of tritiated phosphatidic acid and choline. By contrast, GKB did prevent the Paf-mediated PLD activity and CL response (IC(50) of 2 microM). Interestingly, both GKB and Paf-induced CL response were prevented by selective Paf antagonists such as CV 6209 or WEB 2086 indicating that GKB may directly activate Paf receptors. Finally, GKB potentiated the CL response induced by fMet-Leu-Phe and zymosan. These results show that GKB is the first partial agonist of the Paf receptor described so far capable of priming the polymorphonuclear leukocyte function.

5.Comparative study of two Ginkgo biloba extracts on the phagocytic activity and DTH response of healthy mice.:

Phytother Res. 2002 May;16(3):253-5.PMID: 12164271
The phagocytic activity and delayed-type Hypersensitivity (DTH) response to dinitrofluorobenzene (DNFB) of healthy BALB/c mice treated orally (100 mg/kg/day for 7 days) using two Ginkgo biloba extracts were studied. The phytopharmaceuticals Gb 30 (Alban Muller International, France) and EGb 761 (Schwabe, Germany) administered orally stimulated the phagocytic activity of peritoneal and alveolar macrophages. Likewise, the DTH response was found to be increased only with Gb 30 treatment. These results suggest that Ginkgo biloba possesses immunological activity in addition to the biological activity reported. The different chemical concentration of the components of the Ginkgo biloba extracts mentioned above may be responsible for the differences in the observed findings

6.Effect of Ginkgo biloba extract, EGb 761, on the cellular immune response in a hypothalamic-pituitary-adrenal axis activation model in the rat.:

Int Immunopharmacol. 2003 Jan;3(1):75-80.PMID: 12538036
We evaluated the effects of Ginkgo biloba extract (EGb 761) on the cellular immune response of rats with immunosuppression induced by activation of the hypothalamic-pituitary-adrenal (HPA) axis. Groups of five rats were subjected to chronic stress by the application of daily electric shocks (ES) over 7 days. This stress produced a significant decrement in the delayed-type hypersensitivity response (DTH) to dinitrofluorobenzene (DNFB), and a decrease in the proliferation index of splenocytes. Treatment with oral doses of the phytopharmaceutical EGb 761 (100 mg/kg per day over 7 days) restored both the DTH response to DNFB and the proliferation index. EGb 761 has stress-alleviating properties through its moderation of corticosterone levels. It also possesses antioxidant activity that may contribute to its effects on the immune response. Our observations indicate that the phytopharmaceutical EGb 761 possesses immunostimulatory properties.

7.Effects of Ginkgo biloba extract (EGb 761) on hydroxyl radical-induced thymocyte apoptosis and on age-related thymic atrophy and peripheral immune dysfunctions in mice.:

Mech Ageing Dev. 2003 Aug-Sep;124(8-9):977-83.PMID: 14499503
In this study, the effect of EGb 761, a standard extract of Ginkgo biloba leaf, on thymocyte apoptosis and age-related thymic atrophy and on peripheral immune dysfunctions was investigated in mice. When primary culture of thymocytes was preincubated with 100 microg/ml EGb 761 before their exposure to hydroxyl radicals (*OH) generated by Fe(2+)-mediated Fenton reaction, apoptotic cell death induced by *OH was distinctly prevented as determined by DNA laddering, the TUNEL assay and flow cytometric analysis. Furthermore, oral EGb 761 administration (about 1.5 mg/day/mouse) for 60 consecutive days led to a significant thymic regrowth in 22-month-old mice as revealed by the increment of thymus weight and total numbers of thymocytes. Partial recovery of peripheral immune capacities such as mitogen responsiveness and NK cell activity were also found in the old mice after 60 days of EGb 761 supplementation. Taken together, our study indicates that in addition to its protective and rescuing abilities on neurodegenerative disorders and cardiovascular diseases, EGb 761 was also found active in the rejuvenation of degenerated thymus and accordingly the strengthening of the immune system. These beneficial effects of EGb 761 on immune system are based on its antioxidant properties as well as the cell proliferation-stimulating effect.

8.Down-regulation of c-jun N-terminal kinase-activator protein-1 signaling pathway by Ginkgo biloba extract in human peripheral blood T cells.:

Biochem Pharmacol. 2003 Aug 15;66(4):679-89.PMID: 12906932
The activation of T lymphocytes contributes to inflammatory process of cardiovascular and cerebrovascular diseases. We investigated the effects of the extract of Ginkgo biloba (EGb), an ancient plant preserving antioxidant property, on phorbol 12-myristate 13-acetate+ionomycin or anti-CD3+anti-CD28 monoclonal antibodies-activated T cells. Human peripheral blood T cells were negatively selected from whole blood. Cytokines were measured by ELISA, cell surface markers by flow cytometry and the activities of transcription factors and kinases were determined by electrophoresis mobility shift assays, kinase assays and transfection assays. We showed that EGb inhibited several cytokines, including tumor necrosis factor-alpha, interleukin (IL)-2, IL-4 and interferon-gamma production from activated T cells. Electrophoresis mobility shift assay analysis indicated that EGb down-regulated activator protein-1 (AP-1) but not nuclear factor kappa B DNA-binding activity. In addition, EGb inhibited c-jun N-terminal kinase but not extracellular signal regulated protein kinase activity. The inhibitory specificity on AP-1 by EGb was also demonstrated in transfection assays. The inhibition of AP-1 signaling pathway in T cells by EGb provides a support for its efficacy in cardiovascular and cerebrovascular diseases and raises a therapeutic potential for this drug in activated T cell-mediated pathologies.

9.Effect of Ginkgo biloba extract EGb 761 on the nonspecific and humoral immune responses in a hypothalamic-pituitary-adrenal axis activation model.:

Int Immunopharmacol. 2004 Sep;4(9):1217-22.
We evaluated the immune response of healthy control and stressed Wistar rats submitted to hypothalamic-pituitary-adrenal (HPA) axis activation. Rats were treated with Ginkgo biloba extract (EGb 761) orally (100 mg/kg per day for 7 days). EGb 761 stimulated the digestion index of peritoneal and alveolar macrophages (PM and AM) of stressed rats. Likewise, the cellular immune response measured using the delayed-type hypersensitivity response to sheep red blood cells (SRBC) and the humoral immune response (measured through an anti-SRBC response), were also restored in stressed rats. Thus, this G. biloba extract possesses immunostimulatory activity in addition to its broad spectrum of pharmacological effects.

10.Protective effect of ginkgo biloba against gossypol-induced apoptosis in human lymphocytes.:

Cell Biol Int. 2005 Aug;29(8):717-20.PMID: 15949956
Ginkgo biloba (EGb 761) is a well-defined plant extract that directly scavenges hydroxyl radicals. It is a potent antioxidant that inhibits apoptosis in cultured cells and is effective in treating mild-to-moderate dementia in Alzheimer patients. Apoptosis is an active process of cell destruction and it plays an important role in pathological processes. The aim of this study is to investigate the anti-apoptotic effect of EGb 761 in gossypol-treated human lymphocytes. Pretreatment of lymphocytes with 10 microg/ml EGb 761 for 30 min or 1h decreased the percentage of apoptosis to 17.5% and 20%, respectively. EGb 761 treatment (25-150 microg/ml) decreased the level of apoptosis to a plateau between 8 and 10% of the control values. We conclude that EGb 761 reduces gossypol-induced apoptosis in human lymphocytes.

11.Ginkgolide B stimulates signaling events in neutrophils and primes defense activities.:

Biochem Biophys Res Commun. 2005 Oct 7;335(4):1149-54.PMID: 16122706
Ginkgolide B (GKB) is a bioactive component of the standardized extract from the leaves of the Ginkgo biloba tree (EGb 761), which is used in Chinese and in occidental medicine. GKB is known as a platelet-activating factor receptor antagonist. Here, we provide evidence that GKB per se (0.25-5 microM) stimulated tyrosine phosphorylation of proteins, phospholipase D activation, calcium transients, and activation of p38 but not p44/42 Map kinases in human polymorphonuclear leukocytes (PMN). These stimulatory effects remained relatively weak and primed PMN for subsequent stimulation of respiratory burst (RB) or directed locomotion by the chemoattractant fMet-Leu-Phe (fMLP) or complement-derived factor C5a. A similar RB priming was observed with rat exudate PMN after in vivo administration of EGb 761 (25 and 50 mg/kg) to rats before pleurisy induction. Thus, GKB primarily induces activation of intracellular signaling events and has the potential to prime cellular functions such as PMN defense activities.

12.Inhibitory effect of Ginkgo biloba extract on human platelet aggregation.:

Platelets. 1999;10(5):298-305.PMID: 16801106
The effect of pure flavonoids and Gingko biloba extract (GBE) on human platelet aggregation was investigated. Most of the flavonoids and vitamin E did not affect platelet aggregation in platelet-rich plasma (PRP); however some of these flavonoids inhibited platelet aggregation in gel-filtered platelets (GFP). GBE inhibited both ADP- and collagen-induced platelet aggregation in PRP, GFP and in whole blood in a dose-dependent manner. GBE at very low concentrations inhibited whole blood aggregation induced by ADP compared with those used for PRP or GFP. Flavonoids and GBE decreased the production of TxA(2) induced by collagen and ADP in PRP. However, no correlation was observed between the inhibition of platelet aggregation and the decrease of TxA(2) synthesis. GBE and flavonoids did not affect platelet membrane fluidity. However, the incubation of PRP with GBE increased cAMP levels in platelets, which is known to inhibit platelet activation by lowering intracellular Ca2+ levels. GBE is a mixture of many compounds, including flavonoids and gingkoglides, which affect metabolism of cAMP, TxA(2) and Ca2+ in platelets. It is effective in the inhibition of platelet aggregation, both in PRP and whole blood, and thus may be potentially used as an effective oral anti-platelet therapeutic agent.

13.Ginkgolide C inhibits platelet aggregation in cAMP- and cGMP-dependent manner by activating MMP-9:

Biol Pharm Bull. 2007 Dec;30(12):2340-4.PMID: 18057723
In this report, we investigated the effect of ginkgolide C (GC) from Ginkgo biloba leaves in collagen (10 mug/ml)-stimulated platelet aggregation. It has been known that matrix metalloproteinase-9 (MMP-9) is released from human platelets, and that it significantly inhibited platelet aggregation stimulated by collagen. Zymographic analysis confirmed that pro-MMP-9 (92-kDa) was activated by GC to form an activated MMP-9 (86-kDa) on gelatinolytic activities. And then, GC dose-dependently inhibited platelet aggregation, intracellular Ca(2+) mobilization, and thromboxane A(2) (TXA(2)) formation in collagen-stimulated platelets. In addition, GC significantly increased the formation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have an anti-platelet function in both resting and collagen-stimulated platelets. Therefore, we demonstrate that the inhibitory effect of GC on platelet aggregation might be involved into the following pathways. GC may increase intracellular cAMP and cGMP production and MMP-9 activity, inhibit intracellular Ca(2+) mobilization and TXA(2) production, thereby leading to inhibition of platelet aggregation. These results strongly indicate that GC is a potent inhibitor of collagen-stimulated platelet aggregation. It may be a suitable tool for a negative regulator during platelet activation.

J-Ginkgo Biloba:Parasite,Microbio,Bacteria,Anti-fungi:

1.Activity of bilobalide, a sesquiterpene from Ginkgo biloba, on Pneumocystis carinii.:

Antimicrob Agents Chemother. 1993 Jul;37(7):1492-6.PMID: 8363381
The sesquiterpene bilobalide, extracted from Ginkgo biloba leaves, was tested in vitro and in vivo for the ability to inhibit Pneumocystis carinii growth. Bilobalide was inhibitory to trophozoites cultured on human embryonic lung fibroblasts (HEL 299) at approximately the same concentration as trimethoprim plus sulfamethoxazole (lowest effective concentration, 50 micrograms of bilobalide per ml versus 9/45 microgram of trimethoprim-sulfamethoxazole per ml), inducing microscopically detectable morphological changes in the cytoplasm of the parasite. In pharmacologically immunosuppressed Sprague-Dawley rats transtracheally infected with a suspension of about 5 x 10(6) P. carinii trophozoites per ml, the daily intraperitoneal administration of bilobalide (10 mg/kg of body weight for 8 days) lowered the number of organisms by approximately 2 logs (that is, about 99%). There was no apparent toxicity either in uninfected HEL 299 feeder cells or in infected and uninfected animals. These studies suggest that the sesquiterpene bilobalide might be useful for therapy of and prophylaxis against P. carinii infections in humans.

2.Antimicrobial investigation of semipurified fractions of Ginkgo biloba leaves.:

J Ethnopharmacol. 2000 Jul;71(1-2):83-8.PMID: 10904149
A total methanolic extract of Ginkgo biloba leaves was fractionated by solvent partition using ethyl acetate (fraction A), n-butanol (fraction B) and water (fraction C). The antimicrobial activity of the three fractions was evaluated using a number of Gram-positive and -negative bacteria and yeasts. The apolar fraction A appeared to be the most interesting because of its activity against several microorganisms; this fraction was further separated by high performance liquid chromatography, and shown to contain substances with strong inhibitory activity against Enterococcus faecalis 31, different from the major known chemical components of G. biloba leaves.

3.Characteristics and antifungal activity of a chitin binding protein from Ginkgo biloba.:

FEBS Lett. 2000 Jul 28;478(1-2):123-6.PMID: 10922482
An antifungal peptide from leaves of Ginkgo biloba, designated GAFP, has been isolated. Its molecular mass of 4244.0 Da was determined by mass spectrometry. The complete amino acid sequence was obtained from automated Edman degradation. GAFP exhibited antifungal activity towards Pellicularia sasakii Ito, Alternaria alternata (Fries) Keissler, Fusarium graminearum Schw. and Fusarium moniliforme. Its activities differed among various fungi. GAFP could also cause increased hyphal membrane permeabilization and a rapid alkalization of the medium when applied at 100 microgram/ml to Pellicularia sasakii Ito hyphae. The amino acid sequence of GAFP shows characteristics of the cysteine/glycine-rich chitin binding domain of many chitin binding proteins. The cysteine residues are well conserved.

4.Ginkbilobin, a novel antifungal protein from Ginkgo biloba seeds with sequence similarity to embryo-abundant protein:

Biochem Biophys Res Commun. 2000 Dec 20;279(2):407-11.PMID: 11118300
A novel single-chained antifungal protein with a molecular weight of 13 kDa displaying an N-terminal sequence with marked similarity to embryo-abundant protein from the white spruce was isolated from the seeds of Ginkgo biloba using ion exchange chromatography on DEAE-cellulose, affinity chromatography on Affi-gel blue gel, ion exchange chromatography on SP-Sepharose, and then gel filtration on Superdex 75. The protein, designated ginkbilobin, exerted potent antifungal activity against a variety of fungi, including Botrytis cinerea, Mycosphaerella arachidicola, Fusarium oxysporum, Rhizoctonia solani, and Coprinus comatus. Ginkbilobin exhibited a moderate antibacterial action against Staphylococcus aureus, Pseudomonas aeruginosa, and Escherichia coli. It suppressed the activity of HIV-1 reverse transcriptase and the proliferation of murine splenocytes.

5.Selective responses of three Ginkgo biloba leaf-derived constituents on human intestinal bacteria.:

J Agric Food Chem. 2002 Mar 27;50(7):1840-4.PMID: 11902921
The selective responses of Ginkgo biloba leaf-derived materials against six intestinal bacteria was examined using an impregnated paper disk method and compared with that of bilobalide, ginkgolides A and B, kaempferol, and quercetin. The components of G. biloba leaves were characterized as kaempferol 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside), kaempferol 3-O-(2' '-O-beta-D-glucopyranosyl)-alpha-L-rhamnopyranoside, and quercetin 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside) by spectroscopic analysis. The growth responses varied with each bacterial strain tested. At 2 mg/disk, kaempferol 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside) and quercetin 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside) revealed potent inhibition against Clostridium perfringens, and kaempferol 3-O-(2' '-O-beta-D-glucopyranosyl)-alpha-L-rhamnopyranoside showed a clear inhibitory effect on Escherichia coli. At 0.5 mg/disk, quercetin 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside) showed a strong activity against C. perfringens, but weak activity was exhibited by kaempferol 3-O-alpha-(6' "-p-coumaroylglucosyl-beta-1,4-rhamnoside) against C. perfringens and kaempferol 3-O-(2' '-O-beta-D-glucopyranosyl)-alpha-L-rhamnopyranoside against E. coli. No inhibition was observed from treatments conducted with bilobalide, ginkgolides A and B, kaempferol, or quercetin. Furthermore, these isolated compounds did not inhibit Bifidobacterium bifidum, B. longum, B. adolescentis, or Lactobacillus acidophilus.

6.Antifungal activity of biflavones from Taxus baccata and Ginkgo biloba.:

Z Naturforsch C. 2003 Jan-Feb;58(1-2):65-9.PMID: 12622229
Bilobetin and 4'''-O-methylamentoflavone were isolated and identified in the needles of Taxus baccata, for the first time in this species. The antifungal activity of biflavones from T. baccata and Ginkgo biloba, namely amentoflavone, 7-O-methylamentoflavone, bilobetin, ginkgetin, sciadopitysin and 2,3-dihydrosciadopitysin towards the fungi Alternaria alternata, Fusarium culmorum, Cladosporium oxysporum was determined employing computer-aided image analysis couplet to a microscope. Bilobetin exhibited a significant antifungal activity with values of ED50 14, 11 and 17 microM respectively. This compound completely inhibited the growth of germinating tubes of Cladosporium oxysporum and Fusarium culmorum at a concentration 100 microM. Activity of ginkgetin and 7-O-methylamentoflavone towards Alternaria alternata was stronger than that of bilobetin. Moreover, slight structural changes in the cell wall of Alternaria alternata exposed to ginkgetin at concentration of 200 microM were observed.

7.Study on anti-bacterium activity of ginkgolic acids and their momomers:

Zhong Yao Cai. 2004 Sep;27(9):661-3.PMID: 15704587
OBJECTIVE: Ginkgolic acids and their three monomers were separated from ginkgo sarcotestas. The anti-bacterium activity of ginkgolic acids were tested. The relation between the anti-bacterium activity and side chain of ginkgolic acid were studied.METHOD: The MIC of ginkgolic acids and their three monomers and salicylic acid were tested.RESULTS: Ginkgolic acid has strong inhibitive effect on G+-bacterium. Salicylic acid has no side chain, so no anti-bacterial activity. When the length of gingkolic acid side chain is C13:0, it has the strongest anti-bacterial activity in three monomers.CONCLUSION: The side chain of ginkgolic acid is the key functional group that possessed anti-bacterial activity. The length of Ginkgolic acid was the main effective factor of anti-bacterial activity.

8.Biological activities of Ginkgo extracts.:

Phytomedicine. 2005 Apr;12(4):318-23.PMID: 15898710
The biological activity of methanolic the extracts of leaves, roots, leaf-derived callus, root-derived callus, ginkolide A, ginkgolide B, bilobalide and a commercial Ginkgo product (Tanakan) was assessed. Bioassays consisted of the Agrobacterium tumefaciens-induced potato tumor assay and a Kirby-Bauer microbial sensitivity assay with pure strains of Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes. Methanolic extracts of leaves, leaf-derived callus, root-derived callus, bilobalide and Tanakan inhibited tumor formation significantly, but more weakly than the positive control, camptothecin. No activity against E. coli was detected, but extracts from both callus types inhibited the growth of K. pneumonia, P. aeruginosa, S. aureus, S. epidermidis and S. pyogenes. All extracts and reference compounds inhibited the growth of S. pyogenes. Leaf and root tissues contained the highest levels of ginkgolide A, as compared to the callus tissues; leaf tissue contained more of all three marker compounds than the callus tissues.

9.The effects of Gingko biloba, vitamin E and melatonin on bacterial translocation in thioacetamide-induced fulminant hepatic failure in rats.:

Acta Gastroenterol Belg. 2006 Jul-Sep;69(3):268-75.PMID: 17168122
BACKGROUND AND STUDY AIMS: Bacterial translocation (BT) has been implicated in the development of infectious complications in many serious clinical conditions such as fulminant hepatic failure (FHF). We aimed to investigate the effects of Gingko biloba (GB), vitamin E (Vit E) and melatonin on intestinal oxidative damage and BT in thioacetamide (TAA)-induced FHF in rats.MATERIALS AND METHODS: A total of 42 rats were divided into five groups. Group 1 (n = 8) was the control group. Group 2 (n = 10) was the TAA group, in which rats received 350 mg/kg TAA daily by the intraperitoneal (ip) route for 3 days. Oral 100 mg/kg GB per day was administered to group 3 (n = 8), oral 200 mg/kg Vit E per day to group 4 (n = 8) and ip 3 mg/kg melatonin per day to group 5 (n = 8) 48 h prior to the first TAA injection and was continued for 5 consecutive days.RESULTS: When compared with the control group, serious hepatic and intestinal oxidative damage, increased Escherichia coli counts in ileal aspirates and high BT frequencies were observed in the TAA group (all p < 0.0001). Only GB treatment attenuated hepatic oxidative damage (p < 0.0001). There was no difference in intestinal oxidative damage, E. coli counts in ileal aspirates and BT frequency between TAA and the other antioxidant treatment groups (p > 0.05).CONCLUSION: Our results suggest that intestinal oxidative damage plays a major role in the development of BT by disrupting the barrier function of intestinal mucosa.

K-Ginkgo Biloba:Broad Spectrum of Pathologies Research:

1.Global gene expression analysis identifies cell and tissue specific actions of Ginkgo biloba extract, EGb 761.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):625-31.PMID: 12396072
Clinical and pre-clinical uses of Ginkgo biloba extract encompass a broad spectrum of pathologies that include peripheral arterial disorders, cardiovascular and neuronal dysfunctions and resolution of ischemia-reperfusion injuries. Many of these pathologies develop over time and recruit multiple cell types and molecular pathways that alter the cellular a nd molecular profiles of the failing targetorgans. Transcriptional processes are important determinants of the pathogenesis of these chronic disease states. Therefore the potential therapeutic and preventive actions of a standardized Ginkgo biloba extract, EGb 761, may be affected through modulation of transcriptional processes. We have used various techniques for large-scale mRNA expression analysis, including differential display of mRNAs, cDNA arrays and high-density oligonucleotide arrays, to evaluate the actions of EGb 761 on the activities of the genomes in vitro and in vivo. The results show broad but cell specific actions of Ginkgo biloba extract that may enhance antioxidant defenses in vitro in cancer cells and modulate neuronal functions in cortex and hippocampus in brain in vivo. The large scale analysis of mRNAs in response to Ginkgo biloba extract in vitro and in vivo show that the standardized extract affects the activities of the mammalian genome. The data provide some support for the concept that the actions of EGb 761 are mediated through it effects on the process of gene transcription which plays a causative role in chronic diseases.

2.Clinical efficacy of a Ginkgo biloba extract in the topical treatment of allergic conjunctivitis.:

Eur J Ophthalmol. 2009 May-Jun;19(3):331-6.PMID: 19396774
PURPOSE: To investigate the clinical efficacy of a Ginkgo biloba extract associated with hyaluronic acid ophthalmic solution (GB-HA, Trium, SOOFT, Italy), compared to hyaluronic acid ophthalmic solution (HA) alone, in seasonal allergic conjunctivitis (AC).METHODS: A total of 60 patients with symptomatic AC were enrolled and randomly assigned to the two treatment regimens. After a washout period of 15 days, the treatment with GB-HA eyedrops or HA ophthalmic solution alone was initiated and continued for 1 month. The clinical symptoms such as conjunctival hyperemia, conjunctival discharge, and chemosis, and subjective signs as itching, photophobia, stinging, and lacrimation, were evaluated before and after the treatment. A 0-4 score was used by an independent clinical observer to quantify the above parameters.RESULTS: Patients treated with GB-HA, compared to patients treated with HA alone, showed a significant decrease in the appearance of conjunctival hyperemia, conjunctival discharge, and chemosis. Furthermore, all patients treated with GB-HA showed a significant improvement of subjective symptoms, compared to HA patients. Compared to their baseline values, patients treated with HA alone showed a small but not significant improvement in only some of the clinical and subjective symptoms.CONCLUSIONS: The results suggest that Ginkgo biloba extract may exert therapeutic activity in the treatment of seasonal allergic conjunctivitis. Hyaluronic acid did not exert any valuable effect on this pathology.

L-Ginkgo Biloba:Subject Hair,Bone Research:

1.Effect of leaves of Ginkgo biloba on hair regrowth in C3H strain mice:

Yakugaku Zasshi. 1993 Oct;113(10):718-24.PMID: 8254481
Effects of 70% ethanolic extract from leaves of Ginkgo biloba (GBE) on the hair regrowth in normal and high butter diet-pretreated C3H strain mice which posterior hair we shaved were investigated. GBE showed a promoting effect on the hair regrowth. GBE had the inhibitory effects on blood platelet aggregation, thrombin activity and fibrinolysis. GBE inhibited the increase of serum the triglyceride level in high cholesterol diet-treated rats. These results suggested that GBE promotes the hair regrowth and could be used as a hair tonic.

2.Effects of Egb 761 on bone mineral density, bone microstructure, and osteoblast function: Possible roles of quercetin and kaempferol.:

Mol Cell Endocrinol. 2009 Apr 10;302(1):86-91. Epub 2009 Jan 22.PMID: 19356626
The effects of standardized and concentrated extract of Ginkgo biloba, Egb 761, were studied on estrogen deficiency-induced bone loss in ovariectomized (OVx) rats rendered osteopenic. Upon osteopenia development, Egb 761 was administered at a dose of 100mgkg(?1)day(?1) by oral gavage to OVx rats whereas control group received vehicle. Following 5 weeks of treatment, the OVx+Egb 761 group (n=12) of rats exhibited significantly higher whole body BMD and lower bone turnover markers (serum alkaline phosphatase and osteocalcin) than OVx rats that were given vehicle (n=12). BMD levels in excised bones were also found to be higher in both trabecular (most robustly in lumbar vertebrae) and cortical bones of OVx+Egb 761 compared with OVx+vehicle group. Egb 761 did not exhibit estrogen agonistic activity at the uterine level. Microcomputed tomography demonstrated that OVx+Egb 761 group had better bone microarchitectural parameters compared with OVx+vehicle group. Moreover, OVx+Egb 761 group had higher femoral mRNA levels of osterix, type I collagen and osteocalcin compared with OVx+vehicle group. Determination of levels of three flavonoids of Egb 761, that are known to have bone conserving property, in serum and bone marrow suggests that kaempferol and quercetin, and not rutin, likely mediate the beneficial actions observed with Egb 761 treatment. These results show for the first time that oral administration of Egb 761 restores bone mass in aged OVx rats.

M-Ginkgo Biloba:Lipid parameters,Dietary,Cellulite etc:

1.Limitation of the deterioration of lipid parameters by a standardized garlic-ginkgo combination product. A multicenter placebo-controlled double-blind study.:

Arzneimittelforschung. 1993 Sep;43(9):978-81.PMID: 8240462
The efficacy of a garlic-ginkgo combination product (Allium plus) was analyzed in a randomized placebo-controlled double-blind study under extreme dietary conditions. The Christmas/New Year's season was chosen for this 2 months lasting investigation analyzing whether the known cholesterol lowering effect of garlic was even effective during the period of the year with the most cholesterol-rich meals. 43 patients with elevated total cholesterol levels ranging between 230-390 mg/dl completed the study. There were no significant changes of the total cholesterol values in both treatment groups. Nevertheless the analysis of improvement or deterioration of total cholesterol values revealed a clear difference between verum and placebo. 20% of the patients in the placebo group showed an improvement of their total cholesterol level, while there was a significant greater improvement rate of 35% in the verum group (p < 0.05). The responders of the verum group showed a reduction in the total cholesterol values from 298.5 +/- 53.8 to 293.0 +/- 56.4 mg/dl after 1 month and a total reduction of 10.4% after 2 months to 267.6 +/- 44.4 mg/dl. The difference after 2 months of treatment was significantly different from the starting value (p < 0.05). After the 2 months treatment phase there was a 2 weeks wash-out period. During this period the total cholesterol value returned to 293.5 +/- 90.1 mg/dl showing the effectiveness of garlic treatment, but indicating the need for a continuous long-term therapy.

2.Inhibition of cAMP-phosphodiesterase by biflavones of Ginkgo biloba in rat adipose tissue.:

J Nat Prod. 1998 Nov;61(11):1386-7.PMID: 9834158
This work compares the inhibition of cAMP-phosphodiesterase in rat adipose tissue by a mixture of Ginkgo biloba biflavones with the effect of individual dimeric flavonoids. The degree of enzyme inhibition by G. biloba biflavones was amentoflavone > bilobetin > sequoiaflavone > ginkgetin = isoginkgetin. Sciadopitysin was almost inactive.

3.Parallel placebo-controlled clinical study of a mixture of herbs sold as a remedy for cellulite.:

Phytother Res. 1999 Nov;13(7):627-9.PMID: 10548762
Cellasene, a product containing Ginkgo biloba, sweet clover, sea-weed, grape seed oil, lecithins and evening primrose oil, has been marketed all over the world as a miracle cure for cellulite. As the efficacy of the product was in doubt, a parallel placebo-controlled clinical study was undertaken in a group of women to see whether the product had any effect on cellulite, or on the body weight, fat content, circumference of thighs, hips, etc. No significant changes were found in these parameters compared with the starting values, nor compared with the placebo control after a 2 month course of Cellasene, except for an increase in the cellulite, assessed by the author, compared with that initially. Seven of 11 women taking Cellasene gained weight, as did eight in the placebo control group, taking Colonease, where significance was achieved. The weight gain in both groups was apparent after the first 2 weeks, and all women had to reduce their food consumption. Only three of the women in the Cellasene group thought that their cellulite had slightly improved against two women in the control group.

4.Transcriptome profiling analysis reveals multiple modulatory effects of Ginkgo biloba extract in the liver of rats on a high-fat diet.:

FEBS J. 2009 Mar;276(5):1450-8.PMID: 19187224
Leaf extract of Ginkgo biloba (GBE) is increasingly used as a herbal medicine for the treatment of neurodegenerative, cardiovascular and cerebrovascular diseases. Several studies have demonstrated many protective effects of GBE in neurons, the endothelium and liver. In this study, we investigated the molecular mechanisms underlying the effects of GBE in disorders induced by long-term exposure to a high-fat diet (HFD). Rats were fed an HFD with or without the GBE product GBE50 for 19 weeks. We found that GBE50 reduced the development of fatty liver induced by an HFD and inhibited the commonly observed elevation of serum cholesterol and lactate dehydrogenase levels. Transcriptome profiling analysis showed that several genes were modulated by GBE50 in liver, including those involved in lipid metabolism, carbohydrate metabolism, vascular constriction, ion transportation, neuronal systems and drug metabolism. Notably, a number of genes coding for proteins involved in cholesterol metabolism were repressed, and some were upregulated. Fatty acid biosynthesis appeared to be repressed, whereas fatty acid metabolism appeared to be enhanced. In conclusion, using transcriptome profiling analysis, we demonstrated the molecular basis for the pleiotropic effects of GBE50, particularly those involved in lipid metabolism. This study provided new clues for further pharmacological study of GBEs.

N-Ginkgo Biloba:Stress-induced polydipsia Research:

1.EGb 761 inhibits stress-induced polydipsia in rats.:

Physiol Behav. 1993 May;53(5):1001-2.PMID: 8511192
The effect of daily treatments with Ginkgo biloba extract (EGb 761, IPSEN, France) on body weight and water intake of rats was followed for 15 days. During this period, two groups of rats, under slight ether anesthesia, were intubated and fed either EGb 761 (100 mg/kg b.wt. in 5% ethanol) or, for sham controls, 5% ethanol alone (6.6 ml/kg b.wt.). The increase in body weight was similar for the control and experimental groups. However, during the same period of time, the water intake, ml water/g b.wt./24 h, increased 37% in the controls. In EGb 761-treated rats, water intake remained unchanged. This suggests that EGb 761 treatment inhibits the development of polydipsia due to the stress of daily handling and intubation.

0-Ginkgo Biloba:Glucose transport and Glycogen synthesis Research:

1.Effects of Ginkgo biloba extract on glucose transport and glycogen synthesis of cultured smooth muscle cells from pig aorta.:

Pharmacol Res. 1989 Jul-Aug;21(4):421-9.PMID: 2771861
We have examined the effect of an extract of Ginkgo biloba (Gbe) on glucose uptake and on glycogen synthesis in cultured smooth muscle cells (SMC) from pig aorta. Initial rates of glucose transport were determined by measurements of 2-deoxy-D-glucose (2-DG) uptake. From kinetic analyses apparent KM and Vmax values of facilitated glucose transport in cultured SMC were evaluated at 2.2 mM and 9.1 nmol/min/10(6) cells respectively. Gbe stimulated glucose transport in a dose-dependent manner; the maximum effect was reached at a Gbe concentration of 0.25 micrograms/ml and represented an increase of 35 +/- 4% above basal activity. This stimulation mainly occurred on facilitated glucose transport. The passive diffusion measured when cells were treated with cytochalasin B represented 15 +/- 3% of glucose total transport activity either in the absence or the presence of Gbe. The effect of Gbe on glycogen synthesis in cultured SMC was then tested by the incorporation of U14C-glucose into cellular glycogen. This process was enhanced by Gbe, the maximal effect was observed at a Gbe concentration of 0.25 micrograms/ml, and represented a 41 +r4% increase above basal activity. These data argue for a direct effect of Gbe upon glucose transport and glucose utilization in cultured SMC thus allowing a better nutriment disposal in the vascular wall.

2.Effect of Ginkgo biloba extract (EGb761) on glucose metabolism-related markers in streptozotocin-damaged rat brain.:

J Neural Transm. 2001;108(12):1457-74.PMID: 11810408
To reveal whether an extract of Ginkgo biloba (EGb761) may affect streptozotocin (STZ)-induced impairments in brain glucose metabolism, autoradiographies of [3H]cytochalasin-B binding to the total population of glucose transporters, [125I]insulin binding to insulin receptors, [3H]glyburide binding to sulfonylurea receptors, and radioactive in situ hybridization for GLUT3 mRNA were carried out in hippocampal brain sections of adult rats that have additionally been divided into good performers (GP) and poor performers (PP) by behavioural tests before the experiments. The STZ-induced increases in hippocampal [3H]cytochalasin-B binding to (total) glucose transporters returned to almost normal values following EGb761 treatment, regardless of the experimental animal group (GP or PP) tested. Similarly, the STZ-mediated enhancements in hippocampal insulin receptor binding of GP rats were partially compensated by the treatment with EGb761. The data suggest beneficial effects of EGb671 on impaired brain glucose metabolism, at least under the experimental conditions used in the study presented.

P-Ginkgo Biloba:Kidney/Renal Problems,Diabetic,Kidney protection:

1.The course of color vision in early diabetic retinopathy treated with Ginkgo biloba extract. A preliminary double-blind versus placebo study:

J Fr Ophtalmol. 1988;11(10):671-4.PMID: 3072365
The therapeutic efficiency of the Ginkgo biloba extract was estimated in a double-blind trial, during a 6 months period, in 29 diabetic subjects with an early diabetic retinopathy evidenced by angiography, and associated with a blue-yellow dyschromatopsia. The functional criterion was the color vision evolution, studied by the Desaturated Panel D-15 and the 100-Hue Farnsworth test at the beginning of the trial and 6 months later. An improvement tendency was evidenced in subjects treated by Ginkgo biloba extract, and an aggravation in subjects with placebo, this improvement being statistically significative with the Desaturated Panel D-15 among subjects without retinal ischemia. These clinical results on visual function corroborate the pharmacological actions of Ginkgo biloba extract on diabetic retina.

2.The effects of oxygenated free radicals on VEP spectral components in experimental diabetes.:

Int J Neurosci. 1993 Nov;73(1-2):129-37.PMID: 8132413
In this experimental research, 33 Swiss albino rats were studied. They were divided into three equal groups as control, alloxan-diabetic (diabetic group) and alloxan-diabetic rats treated with ginkgo biloba extract (diabetic-GbE group). After two months of diabetes and before ophthalmoscopically visible diabetic retinopathy, flash VEPs of three groups were recorded and spectral analysis of VEPs was computed by Fast Fourier Transform (FFT) algorithm. Comparing the results of diabetic and diabetic-GbE groups with control group, we observed a significant increase in the amplitude (dB) of 5 Hz frequency for the left and right responses of rats. At some frequencies, we also found important differences between diabetic-GbE and control groups.

3.Effects of repeated treatments with an extract of Ginkgo biloba (EGb 761), bilobalide and ginkgolide B on the electrical activity of pancreatic beta cells of normal or alloxan-diabetic mice: an ex vivo study with intracellular microelectrodes.:

Gen Pharmacol. 1994 Jan;25(1):31-46.PMID: 8026711
1. The effects of repeated (5-day) treatments with an extract of Ginkgo biloba leaves (EGb 761), bilobalide, and ginkgolide B on the in vitro electrical activity of insulin-secreting pancreatic beta cells of mice have been examined using intracellular microelectrodes. 2. EGb 761 (200 mg/kg/day, p.o.) protected beta cells against the toxic effects of alloxan (50 mg/kg, i.v.), an effect characterized by a restoration of membrane potential (Vr) and an increase in spike frequency (Fs/30), an indicator of insulin secretion. 3. Treatment of non-diabetic mice with EGb 761 (200 mg/kg/day, p.o.) increased Fs/30 of their beta cells, as tested by in vitro exposure of the cells to 11.1 mM glucose, an effect that also occurred with bilobalide (8 mg/kg/day, i.p.) but not with ginkgolide B (4 mg/kg/day, i.p.). 4. Since bilobalide and ginkgolide B caused opposite effects on the sensitivity of beta cells to glucose, the stimulatory effect of EGb 761 on Fs/30 may be attributed to its content of bilobalide. 5. In contrast to its ex vivo effect, the direct in vitro effect of EGb 761 (10 and 25 micrograms/ml) on beta cells favors a decrease in electrical activity, indicating that its in vivo action might be indirect (e.g. via the formation of an active metabolite).

4.The effect of ginkgo biloba extract on EEG spectra in experimental diabetes: no relation to lipid peroxidation.:

Int J Neurosci. 1994 Jun;76(3-4):259-66.PMID: 7960482
Forty four Swiss albino rats aged two months, weighing 180-250 g, were used in the experiment. They were divided into four equal groups as control, alloxan-diabetic, diabetic + GbE and control + GbE. After the onset of experimental period, diabetic + GbE and control + GbE groups received ginkgo biloba extract and the other groups were given saline solution for ten weeks. Diabetic and diabetic + GbE groups were made diabetic by injecting alloxan on 16th day. Spectral analysis of EEGs recorded from parietal lobes of all groups of rats were computed by Fast Fourier Transform (FFT) algorithm. Their amplitude maxima were found to occupy the frequency bands of 1-2, 2-4, 4-6, 6-8, 8-16 and 16-30 Hz. Significant amplitude increase was found in 1-2 and 2-4 Hz frequency bands in diabetic + GbE group compared with control, but no differences were found for other groups.

5.EGb 761 and the recovery of ion imbalance in ischemic reperfused diabetic rat retina.:

Ophthalmic Res. 1995 Mar-Apr;27(2):102-9.PMID: 8538982
We studied the effects of a free-radical scavenger, EGb 761, on electrolyte shifts (Na+, Ca2+, and K+) induced by ischemia and reperfusion in the retinas obtained from streptozotocin-induced diabetic rats. Eyes were subjected to 90 min ischemia followed by 24 h of reperfusion by clamping and releasing the central retinal artery. Ten days before the induction of ischemia and reperfusion, diabetic rats received a daily dose of 25, 50, and 100 mg/kg p.o. of EGb 761, respectively (n = 12 in each group). In the drug-free diabetic control group, 90 min ischemia followed by 24 h of reperfusion resulted in an increase in retinal Na+ and Ca2+ (measured by atomic absorption spectrophotometry) compared to nonischemic control values of 73 +/- 4 and 2.6 +/- 0.3 mumol/g dry weight to 113 +/- 5 (p < 0.05) and 5.3 +/- 0.3 mumol/g dry weight (p < 0.05), respectively. Tissue K+ content was significantly reduced compared to its nonischemic diabetic control value of 268 +/- 7 to 213 +/- 6 mumol/g dry weight (p < 0.05). EGb 761 dose-dependently reduced reperfusion-induced ion imbalance, improving the recovery of ion content in diabetic rat retina. EGb 761 did not reduce blood glucose in streptozotocin-induced diabetic rats. Therefore we may conclude that these protective effects of EGb 761 are independent of blood glucose content or of the severity of diabetes and protect against electrolyte shifts directly in retinal cells.

6.Effects of Ginkgo biloba extract and preconditioning on the diabetic rat myocardium.:

Diabetologia. 1996 Nov;39(11):1255-62.PMID: 8932989
Effects of preconditioning and Ginkgo biloba extract (EGb 761) were studied in isolated nondiabetic and diabetic ischaemic and re-perfused rat hearts. Hearts were randomly divided into five groups in both the age-matched non-diabetic and the 8-week streptozotocin-induced diabetic groups: Group I, hearts were subjected to 30 min of global ischaemia followed by 30 min of re-perfusion; Group II, one cycle of preconditioning consisting of 5 min ischaemia and 10 min re-perfusion before the induction of 30 min of ischaemia and 30 min of re-perfusion; Group III, two cycles of preconditioning; Group IV, three cycles; and Group V, four cycles before the onset of 30 min ischaemia followed by 30 min of re-perfusion. Four cycles of ischaemic preconditioning resulted in a reduction of arrhythmias in non-diabetic rats. Thus, in non-diabetics, the incidence of ventricular fibrillation and tachycardia fell from 92% and 100% (no preconditioning) to 33% (p < 0.05) and 42% (p < 0.05), respectively. Four cycles of preconditioning failed to reduce the incidence of re-perfusion arrhythmias in diabetic subjects. Preconditioning reduced the formation of oxygen free radicals measured by electron spin resonance spectroscopy, but the recovery of cardiac function was low in all non-diabetic and diabetic preconditioned groups. EGb 761 at 25 and 50 mg/kg improved cardiac function in non-preconditioned and preconditioned non-diabetic and diabetic hearts. During re-perfusion in the four-cycle preconditioned non-diabetic and diabetic groups, the amount of free radicals was reduced approximately by 50 and 70% using 25 and 50 mg/kg of EGb 761, respectively. EGb 761 improved cardiac function after ischaemia in both non-preconditioned and preconditioned non-diabetic and diabetic rats. Our data suggest that diabetes could abolish the precondition-induced protection.

7.The correlation of cytophotometrically and biochemically measured enzyme activities: changes in the myocardium of diabetic and hypoxic diabetic rats, with and without Ginkgo biloba extract treatment.:

Acta Histochem. 1997 Aug;99(3):291-9.PMID: 9381912
Changes of enzyme activities in the myocardium of rats from 6 different experimental groups (normal rats, diabetic rats, hypoxic diabetic rats, each with and without Ginkgo biloba extract treatment) were measured by using both cytophotometric and biochemical methods. The activity of succinate dehydrogenase, a marker of oxidative capacity, and of menadione-dependent glycerol-3-phosphate dehydrogenase and total lactate dehydrogenase, both markers of glycolytic capacity were measured to characterize changes of the metabolic profile in myocardium. A strong correlation between cytophotometric and biochemical data were found by linear regression analysis, justifying the use of cytophotometrical enzyme activity measurements in cells of organized tissue, where biochemistry cannot provide topographical information. The comparison of the results obtained from the different groups revealed the following: Enzyme activities in the myocardium of rats with streptozotocin-induced diabetes were significantly increased by 10-30% as compared to the normal myocardium. This effect was interpreted as a metabolic compensation of the diabetic heart with reduced performance. When diabetic rats were exposed to acute hypoxia of 20 min duration, enzyme activities decreased under the normal level, to 56% of the succinate dehydrogenase activity, to 87% of glycerol-3-phosphate dehydrogenase activity and to 69% of lactate dehydrogenase activity. Treatment of rats with the oxygen radical scavenger Ginkgo biloba extract (EGb 761) over 3 months resulted primarily in an increase by 10% of oxidative capacity and in a decrease by 30% of glycolytic capacity. Under diabetic conditions a shift to more glycolytic metabolism was observed by increasing the glycolytic activity by 39% and remaining the oxidative activity.

8.Effects on skeletal muscle fibres of diabetes and Ginkgo biloba extract treatment.:

Acta Histochem. 1999 Feb;101(1):53-69.PMID: 10093642
Combined cytophotometric and morphometric analysis of muscle fibre properties and myosin heavy chain electrophoresis were performed on extensor digitorum longus and soleus muscles from healthy rats and rats with streptozotocin-induced diabetes. Moreover, the protective effect of Ginkgo biloba extract, a potent oxygen radical scavenger, on diabetic muscles was investigated. Changes in fibre type-related enzyme activities, fibre type distribution, fibre cross areas and myosin isoforms were found. In muscles of diabetic rats, a metabolic shift was measured mainly in fibres with oxidative metabolism. Fast-oxidative glycolytic fibres showed a shift to more glycolytic metabolism and about a third transformed into fast-glycolytic fibres. Slow-oxidative fibres became more oxidative. Fibre atrophy was measured in diabetic muscles dependent on fibre type and muscle. Different fibre types atrophied to a different degree. Therefore, a decreased area percentage of slow fibres and an increased area percentage of fast fibres of the whole muscle cross section in both muscles were found. This is supported by reduced slow and increased fast myosin heavy chain isoforms. These alterations of diabetic muscle fibres could be due to less motion of diabetic rats and diabetic neuropathy. After treatment with Ginkgo biloba extract, enzyme activities were increased mainly in oxidative fibres of diabetic muscles, which was interpreted as protective effect. Generally, the soleus muscle with predominant oxidative metabolism was more vulnerable to diabetic alterations and Ginkgo biloba extract treatment than the extensor digitorum longus muscle with predominant glycolytic metabolism.

9.Protective effects of Gingko biloba extract EGb 761 on myocardium of experimentally diabetic rats. I: ultrastructural and biochemical investigation on cardiomyocytes.:

Exp Toxicol Pathol. 1999 May;51(3):189-98.PMID: 10334457
Chronic diabetes in man and animal models develops cardiomyopathic alterations which cannot be absolutely avoided by insuline therapy. Since diabetic damage is partly attributed to oxidative stress antioxidative treatment could be able to reduce the alterations. Aim of this study was to investigate the cardioprotective effects of EGb 761, known as a radical scavenger, against diabetic alterations in rats. The diabetes was induced by i.p. injection of 60 mg/kg body weight streptozotocin. Duration of diabetes was 4 months, the protected group received 100 mg/kg body weight EGb 761 with the drinking water over 3 months. Electron and light microscopic morphometry of left-ventricular samples revealed typical diabetic alterations consisting in decrease of volume fraction of myofibrils, SR and t-tubules and diminishing of cardiomyocyte diameter, increase of interstitial volume, mitochondrial size and volume fraction, and of vacuoles and of lipid drops. EGb treatment could gradually prevent the loss of myofibrils and reduction of myocyte diameter but has only little influence on interstitial and mitochondria volume. The diabetic-induced increase of lipid and vacuoles and the decrease of SR and t-tubules were not influenced. Biochemical parameters of oxidative stress: malondialdehyde (MDA) was only insignificantly altered by diabetes and EGb. The superoxide dismutase (SOD) activity was increased by diabetes and more increased by EGb treatment. Creatine kinase (CK) activity was diminished by diabetes but slightly increased by EGb. The polymerase chain reaction (PCR) of i-NOS was not different between the diabetic and protected diabetic groups.

10.Protective effects of Ginkgo biloba extract EGb 761 on the myocardium of experimentally diabetic rats. II. Ultrastructural and immunohistochemical investigation on microvessels and interstitium.:

Exp Toxicol Pathol. 1999 May;51(3):213-22.PMID: 10334461
Interstitial and microvascular disorders are known as a characteristic part of the diabetic cardiomyopathy and to resist partly insulin therapy. Aim of this study was to demonstrate structure-protecting effects of Ginkgo Extract EGb 761 known as a natural radical scavenger in streptozotocin-diabetic rats on the microvascular compartment. Wistar rats (n = 5) were made diabetical by i.p. injection of 60 mg/kg body mass streptozotocin for 4 months. Rats of the protected group (n = 5) received daily 100 mg/kg body mass EGb 761 for 3 months, starting 1 month after induction of diabetes. 5 age-matched rats served as control. The volume fraction of interstitium was slightly but significantly increased only in the unprotected diabetic group. Diminishing of the capillary to the myocyte ratio was seen in the diabetic but not in the protected group. Immunostaining of collagen revealed a slight increase of type III, type IV, and type VI fibres in the interstitium, more expressed in the unprotected group. Ultrastuctural morphometry revealed significant thickening of endothelial and muscular basement membranes in diabetic animals, less expressed in the EGb- protected group. The capillary diameter was slightly increased in the diabetic and slightly decreased in the protected group. The number of plasmalemmal vesicles was tendentially more decreased, that of lysosomes more increased in the diabetic than in the protected group. It is concluded that EGb 761 can diminish partly interstitial fibrosis and reduce endothelial and muscular basement membrane thickening of the diabetic myocardium. It may contribute to prevent late diabetic complications.

11.The effect of 3-month ingestion of Ginkgo biloba extract on pancreatic beta-cell function in response to glucose loading in normal glucose tolerant individuals.:

J Clin Pharmacol. 2000 Jun;40(6):647-54.PMID: 10868316
Ginkgo biloba extract is ingested on a chronic basis for enhancing mental focus and improving cognitive function in the elderly. This study was undertaken to determine the effect of Ginkgo biloba extract on glucose-stimulated pancreatic beta-cell function in normal glucose-tolerant individuals. Twenty individuals (14 females and 6 males, ages 21-57 years) underwent a 2-hour 75 g oral glucose tolerance test (OGTT) before and after ingestion of Ginkgo biloba extract (120 mg/day at bedtime) for 3 months. Ginkgo biloba extract ingestion caused a decrease in systolic blood pressure from 125 +/- 15 to 118 +/- 12 mmHg (p < 0.05) and in diastolic blood pressure from 86 +/- 10 to 68 +/- 10 (p < 0.01). Fasting plasma insulin and C-peptide were increased, and the insulin and C-peptide areas under the curve during the OGTT changed from 136 +/- 55 to 162 +/- 94 microU/ml/h (p = 0.1232) and 9.67 +/- 5.34 to 16.88 +/- 5.20 ng/ml/h (p < 0.001), respectively. The observed dissimilar insulin/C-peptide response curves may be due to Ginkgo biloba-induced increase of the rate of insulin metabolic clearance.

12.Ginkgo biloba extract ameliorates gentamicin-induced nephrotoxicity in rats.:

Phytomedicine. 2000 Jun;7(3):191-7.PMID: 11185729
The effect of Ginkgo biloba (EGb), a plant extract with an antioxidant effect, has been studied on gentamicin-induced nephrotoxicity in male wistar rats. Ginkgo biloba extract (300 mg/kg BW) was administered orally 2 days before and 8 days concurrently with gentamicin (80 mg/kg BW). Saline treated animals served as control. Estimations of urine creatinine, glucose, blood urea, serum creatinine, plasma and kidney tissue MDA were carried out after 8 days of gentamicin treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 896% and 461% respectively, with gentamicin, compared to saline treated group. Creatinine clearance was significantly decreased with gentamicin. Ginkgo biloba extract protected rats from gentamicin-induced nephrotoxicity. Changes in blood urea, serum creatinine and creatinine clearance induced by gentamicin were significantly prevented by Ginkgo biloba extract. There was a 177% and 374% rise in plasma and kidney tissue MDA with gentamicin, which were significantly reduced to normal with Ginkgo biloba extract. Histomorphology showed necrosis and desquamation of tubular epithelial cells in renal cortex with gentamicin, while it was normal and comparable to control with Ginkgo biloba extract. These data suggest that supplementation of Ginkgo biloba extract may be helpful to reduce gentamicin nephrotoxicity.

13.The effect of 3-month ingestion of Ginkgo biloba extract (EGb 761) on pancreatic beta-cell function in response to glucose loading in individuals with non-insulin-dependent diabetes mellitus.:

J Clin Pharmacol. 2001 Jun;41(6):600-11.PMID: 11402628
In the first report (Journal of Clinical Pharmacology 2000; 40:647-654), it was shown that ingestion of 120 mg of Ginkgo biloba extract (EGb 761) daily for 3 months by normal glucose-tolerant individuals caused a significant increase in pancreatic beta-cell insulin and C-peptide response, measured as the area under the curve (AUC0-->120) during a 2-hour standard (75 g) oral glucose tolerance test (OGTT). This follow-up study was designed to determine the effect of the same Ginkgo biloba treatment on glucose-stimulated pancreatic beta-cell function in non-insulin-dependent diabetes mellitus (NIDDM) subjects. In diet-controlled subjects (fasting plasma glucose [FPG], 117 +/- 16 mg/dl; fasting plasma insulin [FPI], 29 +/- 8 microU/ml; n = 6), ingestion of Ginkgo biloba produced no significant effect on the insulin AUC0-->120 (193 +/- 53 vs. 182 +/- 58 microU/ml/h, before and after ingesting Ginkgo biloba, respectively). In hyperinsulinemic NIDDM subjects taking oral hypoglycemic medications (n = 6) (FPG 143 +/- 48 mg/dl; FPI 46 +/- 13 microU/ml), ingestion of Ginkgo biloba caused blunted plasma insulin levels from 30 to 120 minutes during the OGTT, leading to a reduction of the insulin AUC0-->120 (199 +/- 33 vs. 147 +/- 58 microU/ml/h, before and after Ginkgo biloba, respectively). The C-peptide levels increased, and so the AUC0-->120 did not parallel the insulin AUC0-->120, creating a dissimilar insulin/C-peptide ratio indicative of an enhanced hepatic extraction of insulin relative to C-peptide. Thus, in pancreatic beta-cells that are already maximally stimulated, ingestion of Ginkgo biloba may cause a reduction in plasma insulin levels. Only in NIDDM subjects with pancreatic exhaustion (FPG 152 +/- 46 mg/dl; FPI 16 +/- 8 microU/ml; n = 8), who also took oral hypoglycemic agents, did Ginkgo biloba ingestion significantly increase pancreatic beta-cell function in response to glucose loading (insulin AUC0-->120 increased from 51 +/- 29 to 98 +/- 20 microU/ml/h, p < 0.0001), paralleled by a C-peptide AUC0-->120 increase from 7.2 +/- 2.8 to 13.7 +/- 6.8 (p < 0.0001). Whether this increase is due to "resuscitation" of previously exhausted islets or increased activity of only the remaining functional islets is unclear. However, not even in this group did increased pancreatic beta-cell activity cause a reduction of blood glucose during the OGTT. It is concluded that ingestion of Ginkgo biloba extract by an NIDDM subject may increase the hepatic metabolic clearance rate of not only insulin but also the hypoglycemic agents. The result is reduced insulin-mediated glucose metabolism and elevated blood glucose.

14.Nitric oxide synthase isoforms I, III and protein kinase-Ctheta in skeletal muscle fibres of normal and streptozotocin-induced diabetic rats with and without Ginkgo biloba extract treatment.:

Histochem J. 2001 Apr;33(4):213-9.PMID: 11550802
The expression of nitric oxide synthase (NOS) isoforms I, III and protein kinase-Ctheta (PKCtheta) in rat vastus lateralis muscle was demonstrated immunohistochemically and then correlated to the physiological metabolic fibre types: SO (slow-oxidative), FOGI, FOGII (fast-oxidative glycolytic; I more glycolytic, II more oxidative), and FG (fast-glycolytic). NOS expression in muscles from different experimental groups (normal and diabetic rats, with and without Ginkgo biloba extract treatment) was assayed by Western blotting. Generally, NOS I and PKCtheta were co-expressed in fibres with predominantly oxidative metabolism (SO, FOGII). This suggests an interplay of PKCtheta and NOS I in nitric oxide production by oxidative fibres. NOS III was more highly expressed in fibres with predominantly glycolytic metabolism (FOGI, FG). A somewhat lower NOS I immunoreactivity was also found in NOS III positive fibres suggesting that NOS III and NOS I are co-expressed in these fibres. Western blotting revealed that NOS I as well as NOS III expression in the vastus lateralis muscle was down-regulated in diabetes and increased after Ginkgo biloba extract treatment. These effects may be associated with a diminished glucose uptake by myocytes of diabetic musclesand with an improved muscle function after Ginkgo biloba treatment.

15.Importance of biologically active components and plants in the prevention of complications of diabetes mellitus:

Medicina (Kaunas). 2002;38(10):970-5.PMID: 12532704
Diabetes complications, especially late (chronic) ones, are the main reasons of invalidity and early mortality. The most threatening diabetes complications are vascular and metabolic complications (diabetic neuropathy, angiopathy, cataract, glaucoma, optic neuropathy, retinopathy, diabetic nephropathy). Good diabetes control is very important, because in early stages these changes are reversible. In order to decrease the number of diabetes complications and to postpone their development, the use of biologic active components and plants is recommended. The most important biologic active substances for this purpose are vitamins and minerals, proteins, polysaccharides, lectins, saponins and flavonoids. According the scientific data, the mostly used plants are: Ginkgo biloba, Allium sativum, Silybum marianum, Panax Ginseng, Carica papaya, Vaccinium myrtillus, Phaseolus vulgaris. Some of them are proposed for treatment of symptoms related to venous and lymphatic vessel insufficiency, for the prophylaxis and treatment of liver damage caused by metabolic toxins, in chronic degenerative liver conditions, for the therapy of digestive disorders, to increase in the unspecific way the resistance of the organism to various environmental influences, and to stabilize membranes through antioxidant and radical scavenging actions.

16.Effect of the ingestion of Ginkgo biloba extract on platelet aggregation and urinary prostanoid excretion in healthy and Type 2 diabetic subjects.:

Thromb Res. 2002 Nov 1;108(2-3):151-60.PMID: 12590952
Enhanced platelet function, particularly in response to collagen, is a common occurrence in diabetes that increases the risk of cardiovascular disease. Ginkgo biloba extract is ingested primarily to improve mental focus but it possesses a blood-thinning potential, which has not been well characterized. This study was designed to compare the effect of ingesting G. biloba extract on platelet aggregation in platelet-rich plasma (PRP) and prostanoid urinary excretion in healthy volunteers and subjects with Type 2 diabetes mellitus (T2DM). Before and after ingesting 120 mg of standardized G. biloba extract for 3 months, platelet aggregation was studied in PRP and urinary metabolites of thromboxane B(2) (TXB(2)) and prostacyclin (PGI(2)) were measured. In healthy volunteers (age, 42+/-11 years; BMI, 28.4+/-4.8 kg/m(2); n=28), the ingestion of G. biloba extract significantly increased fasting insulin and C-peptide (10+/-4 vs. 12+/-6 microU/ml, p<0.007 and 1.3+/-0.8 vs. 2.1+/-1.1 ng/ml, p<0.001, respectively) and significantly reduced collagen but not PAF-mediated platelet aggregation, converting 21 of 28 subjects with [COL+/EPI+] platelets to the [COL-/EPI+] phenotype. This was accompanied by a reduction of 11-dehydro-TXB(2) from 12.4+/-6.1 to 10.3+/-6.1 ng/mg Cr (p<0.04) and PGI(2) metabolites (2,3-dinor-6-keto-PGF(1alpha) and 6-keto-PGF(1alpha)) from 2.2+/-0.8 to 1.8+/-0.8 ng/mg Cr (p<0.05). In the T2DM subjects (age, 54+/-8; BMI, 36.6+/-7.9 kg/m(2); n=19), G. biloba ingestion did not affect pancreatic beta-cell function but significantly reduced platelet aggregation, converting 16 of 19 [COL+/EPI+] platelets to the [COL-/EPI+] phenotype. Unlike the healthy volunteers, this was not accompanied by a reduced urinary prostanoid excretion. G. biloba-induced reduction of both classes of prostanoid metabolites in healthy volunteers, but not in T2DM subjects, may suggest a nonselective inhibition of COX-1-mediated TXA(2) in platelets and COX-2-mediated PGI(2) production by the endothelial cells and perhaps platelet-enriched levels of arachidonic acid or COX-1 activity, or both, in T2DM subjects.

17.Improved haemorrheological properties by Ginkgo biloba extract (Egb 761) in type 2 diabetes mellitus complicated with retinopathy.:

Clin Nutr. 2004 Aug;23(4):615-21.PMID: 15297098
BACKGROUND & AIMS: Abnormal haemorrheological property changes in erythrocyte deformability, plasma and blood viscosity, and blood viscoelasticity may play very important roles in the development of microangiopathies in diabetes mellitus (DM). In this study, we demonstrate the improvement in abnormal haemorrheological parameters in DM with ingestion of Ginkgo biloba extract 761 (Egb 761).METHODS: Haemorrheological parameters before and 3 months after Egb 761 oral ingestion were determined in 25 type 2 DM patients with retinopathy. These parameters included lipid peroxidation stress of erythrocytes, erythrocyte deformability, plasma and blood viscosity, blood viscoelasticity, and retinal capillary blood flow velocity.RESULTS: After taking Egb 761 orally for 3 months, the blood viscosity was significantly reduced at different shear rates, by 0.44 +/- 0.10 (gamma = 400), 0.52 +/- 0.09 (gamma = 150) and 2.88 +/- 0.57 (gamma = 5). Viscoelasticity was significantly reduced in diabetic patients by 3.08 +/- 0.78 (0.1 Hz). The level of erythrocyte malondialdehyde (MDA) was reduced by 30%; however, the deformability of erythrocyte was increased by 20%. And lastly, retinal capillary blood flow rate was increased from 3.23 +/- 0.12 to 3.67 +/- 0.24 cm min(-1).CONCLUSION: In this preliminary clinical study, 3 months of oral administration of Egb 761 significantly reduced MDA levels of erythrocytes membranes, decreased fibrinogen levels, promoted erythrocytes deformability, and improved blood viscosity and viscoelasticity, which may facilitate blood perfusion. Furthermore, it effectively improved retinal capillary blood flow rate in type 2 diabetic patients with retinopathy.

18.Protection of endotoxin-induced oxidative renal tissue damage of rats by vitamin E or/and EGb 761 treatment.:

J Appl Toxicol. 2005 Jan-Feb;25(1):8-12.PMID: 15669049
The aim of the present study was to evaluate the possible protective effects of vitamin E and EGb 761 treatments, alone or in combination, against oxidative renal tissue damage in experimentally induced endotoxaemic rats. Fifty healthy male Wistar albino rats, weighing 150-250 g and averaging 12 weeks old, were allotted randomly into one of five experimental groups: A (untreated), B (endotoxaemic), C (endotoxaemic + vitamin E treated), D (endotoaxemic + EGb 761 treated) and E (endotoxaemic + vitamin E and EGb 761 treated), each containing ten animals. Group A received only an intraperitoneal (i.p.) injection of 2 ml of normal saline solution and served as the control. Groups B, C, D and E were administrated a single i.p. injection of 0.5 ml of endotoxin solution. In addition, groups C, D and E received i.p. injections of 600 mg kg(-1) body mt. of vitamin E and oral extract of 50 mg kg(-1) body wt. of EGb 761, alone or in combination, immediately after the endotoxin injection. The experiment lasted for 24 h. At the end of the experiment blood and tissue samples were obtained for biochemical and histopathological investigation. Endotoxin injection produced renal damage, increased lipid peroxidation and decreased antioxidant enzyme activity. Vitamin E or/and EGb 761 treatment decreased lipid peroxidation, increased antioxidant enzyme activity and also prevented renal tissue damage in experimentally induced endotoxaemic rats. In conclusion, vitamin E and EGb 761 treatment, alone or in combination, appears to be beneficial in preventing endotoxin-induced oxidative renal tissue damage and therefore shows potential for clinical use.

19.Short-term oral ingestion of Ginkgo biloba extract (EGb 761) reduces malondialdehyde levels in washed platelets of type 2 diabetic subjects.:

Diabetes Res Clin Pract. 2005 Apr;68(1):29-38.PMID: 15811563
We have recently reported that ingestion of Ginkgo biloba extract (EGb 761) (a) significantly reduced collagen-induced platelet aggregation and thromboxane B2 (TXB2) production in both non-diabetic individuals as well as those with type 2 diabetes mellitus (T2DM), (b) significantly reduced platelet malondialdehyde (MDA), an index of lipid peroxidation, in non-diabetic subjects. In the present study we report that ingestion of EGb 761 (120 mg daily for 3 months), significantly decreased platelet MDA-thiobarbituric acid reacting substances (TBARS) (41 +/- 9 pmol/10(7) platelets versus 30 +/- 11 pmol/10(7) platelets) (p < 0.005) in T2DM subjects with normal cholesterol levels (total cholesterol, 164 +/- 22 mg/dl; age, 54 +/- 9 years; BMI, 35.0 +/- 8.8 kg/m2, n = 12). In T2DM subjects with high cholesterol (total cholesterol, 218 +/- 15 mg/dl; age, 52 +/- 5 years; BMI, 36.2 +/- 6.6 kg/m2, n = 7), EGb 761 ingestion reduced the platelet TBARS from 29 +/- 9 to 22 +/- 9 pmol/10(7) platelets (p < 0.04). Because ingestion of EGb 761 did not alter platelet counts it is concluded that EGb 761, probably due to the flavonoid fraction, reduced the TBARS by inhibiting cyclooxygenase (COX)-1-mediated arachidonic acid oxygenation or by reducing the arachidonic acid pool. This is likely to lead to a reduction of platelet hyperactivity, a significant contributor to the development of cardiovascular disease in T2DM patients. Because of other reported beneficial properties of EGb 761, such as stimulation of pancreatic beta-cell function in T2DM subjects with pancreatic exhaustion, it appears that T2DM subjects might benefit from ingesting EGb 761 as a dietary supplement.

20.Ginkgo biloba extract ameliorates ischemia reperfusion-induced renal injury in rats.:

Pharmacol Res. 2005 Sep;52(3):216-22.PMID: 15896977
There is increasing evidence to suggest that reactive oxygen metabolites (ROMs) play a role in the pathogenesis of ischemia/reperfusion injury (I/R) in the kidney. This study was designed to determine the possible protective effect of Ginkgo biloba extract (EGb) on renal ischemia/reperfusion (I/R) injury. Wistar albino rats were unilaterally nephrectomized, and 15 days later they were subjected to 45 min of renal pedicle occlusion followed by 6 h of reperfusion. Ginkgo biloba extract (EGb) (50 mg kg(-1) day(-1)) or saline was administered twice, 15 min prior to ischemia and immediately before the reperfusion period. At the end of the treatment period, all rats were decapitated. Kidney samples were taken for histological examination or determination of the renal malondialdehyde (MDA) and glutathione (GSH) levels, myeloperoxidase (MPO) activity and collagen content. Production of reactive oxidants was monitored by chemiluminescence (CL) assay. Creatinine and urea concentrations in blood were measured for the evaluation of renal function. Tumor necrosis factor-alpha (TNF-alpha) and lactate dehydrogenase (LDH) were also assayed in serum samples. Ischemia/reperfusion caused a significant decrease in GSH level, which was accompanied with significant increases in MDA level, MPO activity and collagen content of kidney tissues. Similarly, serum BUN and creatinine levels, as well as LDH and TNF-alpha, were elevated in the I/R group as compared to control group. On the other hand, EGb treatment reversed all these biochemical indices, as well as histopathological alterations, which were induced by I/R. The findings imply that ROMs play a causal role in I/R-induced renal injury and EGb exerts renoprotective effects probably by the radical scavenging and antioxidant activities.

21.Clinical observation of Gingko biloba extract injection in treating early diabetic nephropathy:

Chin J Integr Med. 2005 Sep;11(3):226-8.PMID: 16181540
OBJECTIVE: To observe the effect of Ginkgo biloba extract injection (GB) in treating early diabetic nephropathy (DN).METHODS: Sixty DN patients were divided into two groups, the treated group were treated by GB and Western medicine, and the control group were given Western medicine alone. The study lasted for 4 weeks. Fasting plasma glucose (FPG), blood pressure, 24 h urinary albumin excretion (UAE), endogenous creatinine clearance rate (Ccr), blood lipids and hemorheology indices were examined before and after the study.RESULTS: Compared with the control group, UAE were significantly decreased (P < 0.01); Ccr, blood lipids and hemorheology indices were all improved after treatment in the treated group (P < 0.05 or P < 0.01). But in FPG and blood pressure there was no significant change between the treated group and the control group (P > 0.05).CONCLUSION: GB is effective in treating early DN through decreasing urinary albumin excretion rate, regulating blood lipids, improving renal function and hemorheology.

22.Effect of extract of ginkgo bilboa leaf on early diabetic nephropathy:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005 Oct;25(10):889-91.PMID: 16313110
OBJECTIVE: To study the effect of extract of Ginkgo bilboa leaf (EGB) on renal lesions of early diabetic nephropathy (DN).METHODS: Sixty-eight patients with early DN were randomly divided into two groups, the control group (34 patients) and the treated group (34 patients). Patients in both groups received conventional therapy, while additional 9.6 mg EGB was orally taken by patients in the treated group, three times per day. The therapeutic course for both groups was three months. Indexes such as urinary microalbumin (mALB), alpha1-microglobulin (alpha1-MG), immunoglobulin (IgG), transferrin (TF), retinal binding protein (RBP) and N-acety-beta-D-glucosaminidase (NAG) before and after treatment between the two groups were compared respectively.RESULTS: Compared with before treatment, mALB, alpha1-MG, IgG, TF, RBP and NAG obviously decreased with significant difference in the treated group after treatment (P < 0.05). However, no significant decrease in the above-mentioned indexes in the control group (P > 0.05).CONCLUSION: EGB has the protective action on early DN.

23.Study on the effect of Ginkgo biloba extract on the tension of diabetic rat artery:

Zhong Yao Cai. 2005 Aug;28(8):690-3.PMID: 16379425
OBJECTIVE: To investigate the effect and possible mechanism of Ginkgo biloba extract EGB50 on vascular tension of type II diabetes mellitus (DM) induced by hyperglycemia and hyperlipidemia.METHODS: Rats were randomly divided into normal control rats (Control), diabetic rats (DM), diabetic rats oral-treated with higher dose Ginkgo biloba extract EGB50 (H) and diabetic rats treated with lower dose EGB50 (L). The serum levels of Advanced Glycosylation end-products (AGEs), cholesterol (CHOL), triglyceride (TRIG) and superior mesenteric artery tension were quantified and measured.RESULTS: After 5 weeks' oral-treatment, serum CHOL, TRIG and AGEs increased, sustained phase of contractile response in high K+ solution and PD2 of phenylephine decreased in diabetic arteries. The biochemical indexes and the tension of vascular function had less significance in L group, but improved distinctly in EGB50 H group (decreasing rate in high K+ solution: 22.52 +/- 5.48%, vs DM:44. 19 +/- 11.03%, P < 0.05) (PD2 of PE: 6.15 +/- 0.22 vs DM: 6.62 +/- 0.13, P < 0.05).CONCLUSION: EGB50 is capable of reducing serum hyperlipidemia,the concentration of AGEs, thus it can reduce the impairment of the oxidants to endothelium cells of vessels and improve pathological and functional change of artery of diabetes.

24.Experimental study about the protective effect of Ginkgo biloba extract on renal acute ischemia-reperfusion injury in rats:

Zhongguo Zhong Yao Za Zhi. 2005 Dec;30(23):1859-62.PMID: 16499028
OBJECTIVE: To study the protective effect of Ginkgo biloba extract(EGb) on the kidney in the case of ischemia-reperfusion injury.METHOD: The model of renal ischemia-reperfusion injury in male rats was made by ligation of left renal artery for 45 min and 4 h of reperfusion. The rats with pretreament were fed with EGb prior to operation. The change of MDA, SOD, Na+-K+-ATPase, Ca2+-ATPase in kidney and BUN, Cr in plasma were determined. The renal pathologic changes were observed.RESULT: After ischemia-reperfusion, the content of MDA in renal cortex and the levels of BUN, Cr in plasma were increased,the activity of SOD,Na+-K+-ATPase, Ca2+-ATPase in renal cortex were decreased, and the phathological changes induced by ischemia-reperfusion in renal tissues were observed clearly. The pretreatment of rats with EGb coued significantly prevente the reduction of SOD, Na+-K+-ATPase, Ca2+-ATPase activity in renal cortex and the increase of MDA content in renal cortex, decrease the concenration of BUN, Cr in plasma. The pathological changes of proximal tubular cells in rats kidneys induced by ischemia-reperfusion were also prevented by the pretreatment with EGb.CONCLUSION: EGb can protect rats from renal injuries caused by ischemia-reperfusion.

25.The effects of ginkgo biloba extract on tissue adenosine deaminase, xanthine oxidase, myeloperoxidase, malondialdehyde, and nitric oxide in cisplatin-induced nephrotoxicity.:

Toxicol Ind Health. 2006 Apr;22(3):125-30.PMID: 16716042
This study was carried out to determine if Ginkgo Biloba Extract (GBE or Egb 761) exerts a beneficial effect against cisplatin-induced renal failure in rats. Sprague Dawley rats were divided into four groups. The first group (control) received orally 1 mL/kg/day of 0.9% saline by an oral carrier vehicle on days 1 to 10. The second group was injected with 7 mg/kg cisplatin intraperitoneally (i.p.) on the fourth day, once only. The third group (vit E+cisplatin) was administered 10 mg/kg/day i.p. vit E on 1 to 10 days with one dose of i.p. cisplatin (7 mg/kg) injection on the fourth day. The fourth group (GBE+cisplatin) was given GBE orally at 100 mg/mL/kg started on the first day up to the tenth day with one dose of cisplatin (7 mg/kg) injection on the fourth day. Cisplatin was found to lead a statistically significant increase in plasma BUN and creatinine levels, as well as urine micro total protein (MTP) levels, leading to acute renal failure (ARF) in rats. Renal xanthine oxidase (XO) activities increased in all groups (statistically significant in cisplatin + GBE-treated rats; P < 0.001). Adenosine deaminase (AD) activities were increased in cisplatin-treated rats, and decreased in cisplatin+GBE-treated (P < 0.041) and cisplatin+vit E-treated (P < 0.005) rats, compared to controls. Malondialdehyde (MDA), nitric oxide (NO) levels and myeloperoxidase (MPO) activities were increased in the kidney tissue of cisplatin-treated rats. Vit E improved plasma creatinine and urine MTP levels, together with tissue MDA, NO levels, and MPO activities. But GBE had no statistically significant effect on those parameters. These results indicate that increased XO, AD and MPO activities, as well as MDA and NO levels play a critical role in cisplatin nephrotoxicity. GBE has been shown to protect against cisplatin-induced nephrotoxicity.

26.Ginkgo biloba extract protects rat kidney from diabetic and hypoxic damage.:

Phytomedicine. 2007 Feb;14(2-3):196-203. Epub 2006 Jun 16.PMID: 16781853
Ginkgo biloba extract EGb 761 was studied for its nephroprotective effects in experimentally diabetic and hypoxic rats. Duration of streptozotocin-induced diabetes was 4 months, that of respiratoric hypoxia of the diabetic group 20 min. The daily dose of 100 mg EGb/kg bodyweight started 1 month after induction of the diabetes. EGb reduced diabetes-induced morphological alterations of the kidney such as increase in volume of glomeruli, capillary tufts, urinary space, and thickening of Bowman's capsule basement membrane. Diabetically increased immunostaining of interstitial collagenes of types I, III, and VI was diminished by the EGb extract. EGb reduced the relative total SOD activity from 163% in diabetic kidney to 46%. Additional hypoxia-induced ultrastructural damage was also diminished.

27.Ginkgo biloba leaf extract (EGb 761) diminishes adriamycin-induced hyperlipidaemic nephrotoxicity in rats: association with nitric oxide production.:

Biotechnol Appl Biochem. 2007 Jan;46(Pt 1):35-40.PMID: 16848766
The aim of this experimental study was to investigate the effect of a standardized preparation of Ginkgo biloba extract (EGb 761) on the hyperlipidaemic nephrotoxicity and oxidative stress induced by a single intravenous injection (5 mg/kg) of adriamycin. EGb 761 was received daily thereafter by a gavage at the dose of 100 mg/kg for 35 consecutive days. EGb 761 administration significantly attenuated adriamycin-induced renal dysfunction, as assessed by measuring serum lipid profile, serum total protein, serum urea and Ccr (creatinine clearance). Furthermore, urinary excretions of protein and NAG (N-acetyl-beta-D-glucosaminidase; a marker of renal tubular injury) were significantly inhibited following EGb 761 administration. EGb 761 supplementation significantly prevented the generation of TBARS (thiobarbituric acid-reacting substances) with a marked improvement in terms of GSH content and activity of antioxidant enzymes in the kidney homogenate. Moreover, EGb 761 treatment significantly reduced both renal-tissue and urine total NO (nitric oxide) levels. The results suggest that the protective potential of EGb 761 in the prevention of adriamycin-induced hyperlipidaemic nephrotoxicity in rats was associated with the decrease in the oxidative stress and the total NO levels of renal tissues. Likewise, the present study demonstrates the ability of EGb 761 to reduce the hyperlipidaemia and proteinuria associated with this nephropathy, which might be beneficial to enhance the therapeutic index of adriamycin.

28.Effects of Ginkgo biloba on prevention of development of experimental diabetic nephropathy in rats.:

Acta Pharmacol Sin. 2007 Jun;28(6):818-28.PMID: 17506941
AIM: To observe the preventive and therapeutic effects of Ginkgo biloba extract (GbE) on early experimental diabetic nephropathy (DN) in rats.METHODS: After an early DN model was induced by streptozotocin, rats were administered GbE at 3 doses for 12 weeks. Fasting blood glucose, creatinine (Cr), blood urea nitrogen (BUN), urine protein, kidney index, anti-oxidase, advanced glycosylation end products (AGE), collagen IV and laminin, matrix metalloproteinases-2 (MMP-2) and the tissue inhibitor of metalloproteinase-2 (TIMP-2), connective tissue growth factor (CTGF), and transforming growth factor-beta1 (TGF-beta1) mRNA were measured by different methods. The ultrastructural morphology and the thickness of glomerular base membrane (GBM) were observed by a transmission electron microscope.RESULTS: For the GbE-treated DN rats, when compared with the vehicle-treated DN rats, the fasting blood glucose level, Cr, BUN, urine protein level, and the intensity of oxidative stress were significantly decreased. The expression of MMP-2 greatly increased, and TIMP-2 decreased. Also, AGE, either in serum or in renal, the collagen IV, laminin, CTGF levels, and TGF-beta1 mRNA were reduced. Furthermore, both relative grades of mesangium hyperplasia by microscopical observation and the thickness of GBM by electron microscope measurement decreased significantly.CONCLUSION: GbE has protective effects on several pharmacological targets in the progress of DN and is a potential drug for the prevention of early DN.

29.Therapeutic effect of Ginkgo biloba leaf extract on hypercholestrolemia in children with nephrotic syndrome:

Nan Fang Yi Ke Da Xue Xue Bao. 2007 May;27(5):682-4.PMID: 17545089
OBJECTIVE: To explore the therapeutic effects of the extract of Ginkgo biloba leaf on hypercholestrolemia in children with primary nephritic syndrome (NS).METHODS: Thirty-five children with NS were randomized into 2 groups for treatment with prednisone plus Ginkgo biloba leaf extract (18 cases) or with prednisone plus dipyridamole (17 cases) for 8 weeks. After completion of the treatments, the therapeutic effects were evaluated and the changes in the blood biochemical markers assayed.RESULTS: The 8-week treatment with the extract significantly ameliorated the clinical symptoms and blood biochemistry as compared with prednisone plus dipyridamole group (P<0.01). The levels of urinic protein and blood lipid in Ginkgo leaf group were significantly lower than those in prednisome plus dipyridamole group (P<0.05).CONCLUSION: The extract from Ginkgo biloba leaf can lower blood lipid levels and urinic protein in children with NS and improve their clinical syptoms and the renal function, therefore has much clinical value as an adjuvant treatment of steroid therapy in such children.

30.New phytotherapical opportunity in the prevention and treatment of 2-type of diabetes mellitus:

Acta Pharm Hung. 2006;76(4):200-7.PMID: 17575800
The authors report their preclinical and clinical test results of an infusion (Diabole) made of dill (Anethum graveolens), nettle (Urtica dioica) and gingko (Gingko biloba) herbal mixture and accordingly, this preparation given in right dosages could be suitable for reducing blood sugar level significantly in II. type of diabetes mellitus.

31.Effect of extract of Gingko biloba on soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 in patients with early diabetic nephropathy:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2007 May;27(5):412-4.PMID: 17650793
OBJECTIVE: To investigate the effect of extract of Gingko biloba (EGb) on soluble intercellular cell adhesion molecule-1 (sICAM-1) and soluble vascular cell adhesion molecule-1 (sVCAM-1) in patients with early diabetic nephropathy (DN).METHODS: Sixty-three patients with DN in early stage were randomly assigned to the control group (29 cases) and the treatment group (34 cases). Both groups were treated by routine treatment, and with EGb given to the treatment group additionally. The treatment course was 2 months. Serum sICAM-1 and sVCAM-1 were determined with ELISA before and after treatment, and urinary albumin excretion rate (UAER), fasting plasma glucose (FPG), serum creatinine (SCr) and blood lipids, etc. were examined as well.RESULTS: The levels of serum sICAM-1 and sVCAM-1 were significantly lower in both groups after treatment than those before treatment (P < 0.05 or P < 0.01), and the decrement in the treatment group was more significant than that in the control group (P < 0.01). And the levels of UAER, SCr and blood lipids decreased in the treatment group after treatment (P < 0.05 or P < 0.01).CONCLUSION: EGb could retard the development of early DN through decreasing the levels of serum sICAM-1 and sVCAM-1.

32.Effect of Ginkgo biloba on the reproductive outcome and oxidative stress biomarkers of streptozotocin-induced diabetic rats.:

Braz J Med Biol Res. 2007 Aug;40(8):1095-9.PMID: 17665046
The aim of the present study was to evaluate the effect of Ginkgo biloba treatment (EGb 761, 200 mg kg-1 day-1) administered from day 0 to 20 of pregnancy on maternal reproductive performance and on the maternal and fetal liver antioxidant systems of streptozotocin-induced diabetic Wistar rats. On day 21 of pregnancy, the adult rats (weighing approximately 250 +/- 50 g, minimum number = 13/group) were anesthetized to obtain maternal and fetal liver samples for superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GSH-Px), and total glutathione (GSH-t) determinations. The uterus was weighed with its contents. The diabetic (G3) and treated diabetic (G4) groups of rats presented significant maternal hyperglycemia, reduced term pregnancy rate, impaired maternal reproductive outcome and fetal-placental development, decreased GSH-Px (G3 = G4 = 0.6 +/- 0.2) and SOD (G3 = 223.0 +/- 84.7; G4 = 146.1 +/- 40.8), and decreased fetal CAT activity (G3 = 22.4 +/- 10.6; G4 = 34.4 +/- 14.1) and GSH-t (G3 = G4 = 0.3 +/- 0.2), compared to the non-diabetic groups (G1, untreated control; G2, treated). For G1, maternal GSH-Px = 0.9 +/- 0.2 and SOD = 274.1 +/- 80.3; fetal CAT = 92.6 +/- 82.7 and GSH-t = 0.6 +/- 0.5. For G2, G. biloba treatment caused no toxicity and did not modify maternal or fetal-placental data. EGb 761 at the nontoxic dose used (200 mg kg-1 day-1), failed to modify the diabetes-associated increase in maternal glycemia, decrease in pregnancy rate, decrease in antioxidant enzymes, and impaired fetal development when the rats were treated throughout pregnancy (21 days).

33.Cardiac ischemia and reperfusion in spontaneously diabetic rats with and without application of EGb 761: I. cardiomyocytes.:

Histol Histopathol. 2008 Jul;23(7):807-17.PMID: 18437679
Diabetic cardiomyopathy is known to result in increased mortality after ischemic events. Permanently increased oxidative stress with formation of oxygen-free radicals plays a key role in the development of specific heart muscle disease. Associated lesions include structural alterations to cardiomyocytes. Antioxidative treatment in addition to the usual insulin substitution would seem sensible in preventing or delaying long-term diabetic complications and protecting the myocardium against acute ischemic events. We investigated the effects of radical scavenger Ginkgo biloba extract EGb 761 against diabetes-induced damage to cardiomyocytes and additional ischemia/reperfusion injury in spontaneously diabetic BioBreeding/Ottawa Karlsburg (BB/OK) rats, as a model of diabetic myocardium infarction. Morphological and morphometric parameters of heart muscles were analyzed by light and electron-microscopic techniques. We used immunohistochemistry to evaluate parameters of oxidative stress (superoxide dismutase [SOD]) and inducible nitric oxide synthase (iNOS) protein expression. Our results indicated that A) Diabetic myocardium appears more vulnerable to ischemia/reperfusion damage concerning ultrastructure of cardiomyocytes (sarcomeres, vacuoles, mitochondria), expression of antioxidative enzymes (CuZnSOD, MnSOD), and iNOS than normal myocardium; B) Pre-treatment of diabetic myocardium with EGb and additional ischemia/reperfusion leads to a relative improvement in myocardial ultrastructure compared to unprotected myocardium. In summary, EGb appears to be promising as an adjuvant therapeutic drug in diabetics with respect to ischemic myocardium injury. It may contribute to the prevention of late diabetic complications in diabetic cardiomyopathy.

34.Ginkgo biloba extract prevents against apoptosis induced by high glucose in human lens epithelial cells.:

Acta Pharmacol Sin. 2008 Sep;29(9):1042-50.PMID: 18718173
AIM: To investigate the protective effects of Ginkgo biloba extract (GBE) on high glucose-induced apoptosis of human lens epithelial cells (HLEC) and the possible molecular mechanisms.METHODS: The cultured HLEC were allotted into 6 groups: normal group, high glucose group, low-, moderate-, and high-dose GBE group, and the bendazac lysine group. Cell viability, cell apoptosis, the activities of cell antioxidases, aldose reductase, caspase-3, the levels of cell antioxidants, and the expressions of Bcl-2 and Bax were assessed by different methods.RESULTS: After being incubated with high glucose for 24 h, HLEC underwent apoptosis and exhibited significant oxidative stress. In the presence of GBE at different doses, the rate of HLEC apoptosis was lower and the oxidative stress state was significantly ameliorated. The increased ratio of Bax to Bcl-2 was significantly reduced and the activation of caspase-3 was suppressed by GBE in a dose-dependent manner.CONCLUSION: GBE prevents HLEC from high glucose-induced apoptosis through inhibiting oxidative stress, reducing the ratio of Bax to Bcl-2, and decreasing the activity of caspase-3. Therefore, GBE has a potential protective effect against diabetic cataract formation.

35.Effect of Ginkgo leaf extract on vascular endothelial function in patients with early stage diabetic nephropathy.:

Chin J Integr Med. 2009 Feb;15(1):26-9. Epub 2009 Mar 7.PMID: 19271166
OBJECTIVE: To explore the effect of ginkgo leaf extract (GLE) on vascular endothelial function (VEF) in patients with early stage diabetic nephropathy (DN).METHODS: Sixty-four patients were randomized equally by a randomzing digital table into two groups, the treated group and the control group. They were all treated for 8 weeks with conventional therapy for diabetes, but GLE tablets were given to the treated group additionally. Changes in VEF were estimated before and after treatment by ultrasonic examination of the brachial artery. In the meantime, changes in plasma levels of the von Willebrand factor (vWF), nitric oxide (NO) and endothelin-1 (ET-1) were observed as well.RESULTS: The brachial arterial endothelium dependent dilating function in the treated group increased from 4.91+/-2.31% before treatment to 6.78+/-3.89% after treatment (P<0.05), while the level of vWF decreased from 182.05+/-64.13% to 128.56+/-48.98%, and that of NO increased from 50.16+/-24.64 micromol/L to 70.65+/-28.71 micromol/L (P<0.01). However, these indexes were not significantly changed in the control group after treatment (P>0.05).CONCLUSION: GLE could decrease the plasma level of vWF, raise the plasma NO level and improve the endothelium dependent vascular dilating function in DN patients.

36.Effect of Ginkgo biloba extract on glucose uptake of diaphragm in diabetic rats:

Zhongguo Zhong Yao Za Zhi. 2010 Feb;35(3):356-9.PMID: 20423005
OBJECTIVE: To investigate the effects of Ginkgo biloba extract (GbE) on the glucose uptake rate and gene expression of glucose transporter 4 (GLUT4) in diaphragm of diabetic rats.METHOD: Forty SD male rats were randomly divided into normal control group (n=10) and model group (n=30). Diabetic models were induced by feeding with high-sucrose-high-fat diet and intraperitoneal injecting 25 mg X kg(-1) streptozotocin. 20 successful models were rearranged to two groups: diabetic group and GbE treatment group, 10 rats in each. Then the saline and 8 mg X kg(-1) x d(-1) of GbE were respectively intraperitoneal injected, once a day continuously for 8 weeks. The contents of fasting blood glucose (FBG), fasting insulin (FINS) were detected, respectively. The glucose uptake rate and gene expression of GLUT4 in diaphragm were determinated and the varieties of diaphragm ultrastructure were observed.RESULT: Compared with control group, levels of FBG and FINS obviously increased in diabetic rats (P < 0.01), but the glucose uptake rate and expression of GLUT4 mRNA in diaphragm decreased significantly (P < 0.05, P < 0.01). The ultrastructure in diabetic group under electron microscope indicated that diaphragm mitochondrion swelled and degenerated. The above changes were inhibited by GbE.CONCLUSION: GbE can improve the glucose metabolism in diabetic rats and reduce the diabetes-induced diaphragm damage. The action mechanism of the drug may be related to promote the mRNA expression of GLUT4 in diaphragm and improve the uptake and metabolism of blood glucose.

37.Effects of ginkgo biloba extraction on contraction capacity of diaphragm from type 2 diabetic rats:

Zhongguo Ying Yong Sheng Li Xue Za Zhi. 2010 May;26(2):249-51.PMID: 20684294
OBJECTIVE: To investigate the effects of Ginkgo biloba extract (GbE) on the activities of energy metabolism enzymes and contraction capacity of diaphragm from type 2 diabetic rats.METHODS: Forty SD male rats were randomly divided into normal control group (n=10) and model group (n=30). Type 2 diabetes models were induced by feeding with high-sucrose-high-fat diet and intraperitoneal injecting 25 mg/kg streptozotocin. 20 successful models were rearranged to two groups: diabetic group and GbE treatment group, 10 rats in each. Then the saline and 8 mg/(kg x d) of GbE were respectively intraperitoneal injected, once a day continuously for 8 weeks. Then diaphragm contractility was assessed using Peak twitch tension (Pt), Maximum tetanic tension (P0) and fatigue index (FI) in vitro diaphragm strip preparations. Cytochrome oxidase (CCO), lactate dehydrogenase (LDH) and succinate dehydrogenase (SDH) in diaphragm were detected and the varieties of diaphragm ultrastructure were observed.RESULTS: Compared with control group, Pt, P0 and FI in diabetic group decreased significantly (P < 0.01); the activity of CCO, LDH and SDH in the tissues was more obviously reduced than those in control group (P < 0.01). The ultrastructure in diabetic group under electron microscope indicated that diaphragm mitochondrions swelled and degenerated. The above changes were inhibited by GbE.CONCLUSION: GbE can enhance contraction capacity of diaphragm from type 2 diabetic rats by increasing the aerobic oxidation capacity, glycolytic capacity and the function of respiratory chain.

38.Ginkgo biloba extract enhances glucose tolerance in hyperinsulinism-induced hepatic cells.:

J Nat Med. 2011 Jan;65(1):50-6. Epub 2010 Sep 3.PMID: 20814756
Ginkgo biloba, an herbal medication, is capable of lowering glucose, fat, and lipid peroxide in diabetic patients. In the current study, we tested the hypothesis that Ginkgo biloba extract (GBE) prevented hyperinsulinism-induced glucose intolerance in hepatocytes. We investigated the effects of GBE on glucose consumption, glucokinase activity, and mRNA levels of key genes in glucose metabolism and the insulin signaling pathway. To better show its efficacy, we included a control group that was treated with rosiglitazone, a type of thiazolidinedione (TZD). The data indicated that GBE repressed glucose uptake under normal conditions, while it dramatically improved glucose tolerance under insulin-resistant conditions. Furthermore, after analyzing gene expression, we suggest that GBE chiefly exerts its effects by stimulating IRS-2 transcription. It should be noted that, unlike rosiglitazone, GBE did not stimulate excessive glucose uptake as it improved glucose tolerance. It is said that GBE treatment could avoid drug-induced obesity. Our data suggest that GBE has the potential to prevent insulin resistance and is a promising anti-diabetic drug.

39.Cardiovascular autonomic neuropathy in spontaneously diabetic rats with and without application of EGb 761.:

Histol Histopathol. 2010 Dec;25(12):1581-90.PMID: 20886438
Cardiovascular autonomic neuropathy causes abnormalities in the diabetic heart with various clinical sequelae, including exercise intolerance, arrhythmias and painless myocardial infarction. Little is known about (ultra)structural alterations of the myocardial nervous network. On the assumption that this diabetes-specific neuropathy develops due to permanently increased oxidative stress by liberation of oxygen-free radicals, adjuvant application of antioxidative therapeutics appears promising in preventing or delaying long-term diabetic complications. We have investigated the effects of Ginkgo biloba extract (EGb 761), a radical scavenger, against diabetes-induced myocardial nervous damage in spontaneously diabetic BioBreeding/Ottawa Karlsburg (BB/OK) rats. Morphological and morphometric parameters were evaluated by electron microscopy. We used immunohistochemistry to investigate protein expression of protein gene product 9.5, S100 protein, and thyroxin hydroxylase as a neuronal marker. Alterations of cardiac sympathetic activity were measured using the in vivo 123I-metaiodobenzyl-guanidine imaging, and the immunofluorescent labeling of beta1-adrenergic receptors and adenylate cyclase. Our results revealed that A) Diabetes results in slight to moderate ultrastructural alterations (hydrops, disintegration of substructure) of autonomic nerve fibers and related Schwann cells in untreated BB diabetic rats; B) Cardiac sympathetic integrity and activity is impaired due to alterations in the presynaptic nerve terminals and the postsynaptic ß1-AR-AC coupling system; C) Pre-treatment of diabetic myocardium with EGb results in an improvement of most of these parameters compared to unprotected myocardium. In conclusion, EGb may act as a potent therapeutic adjuvant in diabetics with respect to cardiovascular autonomic neuropathy, which may contribute to the prevention of late complications in diabetes.

Q-Ginkgo Biloba:Respiratory System,Lung,Asthma,Antiemetic Research:

1.Inhibition of antigen-induced lung anaphylaxis in the guinea-pig by BN 52021 a new specific paf-acether receptor antagonist isolated from Ginkgo biloba:

Agents Actions. 1986 Jan;17(3-4):371-2.PMID: 3754380
Paf-acether appears to be a potent mediator released in response to allergen exposure in sensitized animals and it could contribute to clinical manifestations of allergic asthma. In order to ascertain this assumption the inhibition of antigen-induced lung anaphylaxis in guinea-pig by BN 52021, a new highly specific paf-acether antagonist, was studied. Ovalbumin injected into passively sensitized guinea-pig induced a large bronchoconstriction which was accompanied by thrombocytopenia and leukopenia. Treatment of animals with BN 52021 i.v., five minutes before challenge, strongly (at the doses of 1 and 2 mg/kg) or totally (at 0.1 mg/kg) inhibited the bronchoconstriction and partially reduced the thrombocytopenia and leukopenia the thrombocytopenia occurring after challenge. These results confirm that paf-acether and platelets might play a key role in asthma. BN 52021 and other paf-acether antagonist could provide a new group of potent prophylactic anti-asthma drugs.

2.Blockade of lithium chloride-induced conditioned place aversion as a test for antiemetic agents: comparison of metoclopramide with combined extracts of Zingiber officinale and Ginkgo biloba.:

Pharmacol Biochem Behav. 1995 Oct;52(2):321-7.PMID: 8577797
The present study tests the hypothesis that the blockade of lithium chloride-induced conditioned place aversion might be a suitable model to assess antiemetic properties of drugs, especially in species that do not vomit, like rats. The effects of the known antiemetic compound metoclopramide were compared with those of zingicomb, a combination preparation of extracts of Ginkgo biloba and Zingiber officinale, also presumed to have antiemetic properties. Place conditioning was performed using a conventional three-compartment test procedure. On three successive conditioning trials, rats received an intraperitoneal (i.p.) injection of lithium chloride (125 mg/kg) and were placed into the compartment that they had preferred over three baseline trials. During the test, rats treated with lithium chloride (LiCl) spent less time in the treatment compartment, indicative of a conditioned place aversion (CPA). In the first experiment, metoclopramide (MCP) was administered intragastrically (IG) in doses of 2 or 10 mg/kg 60 min prior to LiCl injection. The pretreatment with 50 and 100 mg/kg zingicomb attenuated the LiCl-produced CPA, whereas a dosage of 10 mg/kg had no effect. These findings suggest that LiCl-induced CPA is a viable procedure with which to assess the antiemetic properties of metoclopramide. Furthermore, the data confirm the hypothesis that the phytopharmacon zingicomb might have antiemetic properties that are comparable to those of metoclopramide

3.Effects of ginkgo leave concentrated oral liquor in treating asthma:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997 Apr;17(4):216-8.PMID: 9863095
OBJECTIVE: To determine the effects of Ginkgo leave concentrated oral liquor (GLC) on airway inflammation.METHODS: Airway hyperreactivity and clinical symptoms and pulmonary functions of asthma patients were determined.RESULTS: In contrast to placebo group, GLC significantly reduced airway hyperreactivity (P < 0.05) and improved clinical symptoms (P < 0.05), pulmonary functions (P < 0.05) of the asthmatic patients.CONCLUSION: GLC is an effective drug of anti airway inflammation.

4.In vitro effects of Ginkgolide B on lymphocyte activation in atopic asthma: comparison with cyclosporin A.:

Jpn J Pharmacol. 2000 Jul;83(3):241-5.PMID: 10952073
The effects of Ginkgolide B (BN52021) on in vitro activation responses of human peripheral blood mononuclear cells (PBMC) from asthmatic patients was measured using 2-channel flow cytometric analysis of activation-associated cell surface antigens or ELISA assays for cytokines known to be expressed by PBMC during T1 or T2 immunological activation. BN52021 is an anti-inflammatory extract of Ginkgo biloba and has been used therapeutically. It is a known inhibitor of platelet activating factor (PAF), which is important in the pathogenesis of asthma, and may synergise with cyclosporin A (CyA) to inhibit pathogenic immune activation in asthmatics. We compared the inhibitory effects of BN52021 and CyA (1 microM each) on activation of PBMC of asthmatic patients stimulated by phorbol myristate acetate and calcium ionophore. Inhibition of production of the cytokines IL-4 and IL-5 by BN52021 was insignificant compared to CyA. However, BN52021 significantly reversed the increase in activation-associated CD45RA expression, with a trend towards decreased expression of HLA-DR. Lymphocyte activation markers were not significantly altered by CyA. Since they appear to have differing effects on activated cells, the anti-inflammatory effects of CyA and BN52021 in atopic asthma is potentially additive. The present approach may be useful for preliminary evaluation of novel therapeutic modalities for asthma treatment.

5.Experimental study on effect of folium Ginkgo biloba in treating pulmonary interstitial fibrosis in rats:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000 Jun;20(6):441-3.PMID: 11789230
OBJECTIVE: To evaluate the therapeutic effect and mechanism of folium Ginkgo biloba (FGB) in treating pulmonary interstitial fibrosis (PIF) induced by bleomycin in rats.METHODS: PIF models of bleomycin-A5-induced pulmonary fibrosis were established in rats, they were treated by Bailuda, a preparation of FGB, and the pathological changes, collagen protein level, nuclear factor kB(NF-kB) activity, transforming growth factor beta (TGF-beta) mRNA expression and protein level of the lung tissue were measured.RESULTS: In the Bailuda treated group after treatment, amelioration of the pulmonary alveolitis and fibrosis were shown in pathological section (P < 0.05) and collagen protein content was lesser (P < 0.01) as compared with those in the model control group. After 1 week of Bailuda treatment, the NF-kB activity of pulmonary alveola macrophage lowered by 47.3%, and levels of TGF-beta mRNA expression and protein were all decreased (P < 0.05).CONCLUSIONS: Bailuda has definite effect in treating PIF. The mechanism may be through inhibiting the activity of NF-kB, decreasing TGF-beta mRNA expression and protein, so as to ameliorate the inflammation and fibrosis.

6.Ginkgo biloba extract (EGb 761) modulates bleomycin-induced acute lung injury in rats.:

Tumori. 2001 Nov-Dec;87(6):417-22.PMID: 11989597
The effect of Ginkgo biloba extract (EGb 761) on bleomycin (BLM)-induced acute lung injury was studied in rats. The responsiveness of isolated pulmonary arterial rings to 5-hydroxytryptamine (5-HT) as well as the levels of some relevant biochemical markers in the lung tissue were taken as evidence for the acute lung injury. BLM was given intraperitoneally at a dose of 15 mg/kg/day for five consecutive days. It was found that BLM treatment attenuated the vasoconstrictor effect of 5-HT on the isolated pulmonary arteries. In lung tissues BLM also elevated the level of lipid peroxides and enhanced the activity of glutathione peroxidase. On the other hand, the level of glutathione and the activity of alkaline phosphatase were reduced. Body weight, lung weight and tissue glutathione-S-transferase activity were, however, not altered. Oral administration of EGb 761 at a dose of 100 mg/kg/day for five consecutive days did not alter any of the chosen biochemical parameters in the lung tissue except for a slight reduction in alkaline phosphatase activity. However, treatment with EGb 761 reduced the responsiveness of the pulmonary artery to 5-HT. Administration of EGb 761 (100 mg/kg/day; po) two hours prior to BLM (15 mg/kg/day; ip), for five consecutive days blunted the occurrence of further reduction in the vasoconstrictor response of the pulmonary artery to 5-HT. Furthermore, EGb 761 tended to normalize BLM-induced alterations in the measured biochemical markers in the lung tissue. The apparent modulatory influence of EGb 761 on BLM-induced acute lung injury stems, at least in part, from its beneficial free radical scavenging properties that provide the extract with antioxidant activity.

7.Protective effect of Ginkgo biloba extract on acute lung injury induced by lipopolysaccharide in D-galactose aging rats:

Zhonghua Jie He He Hu Xi Za Zhi. 2002 Jun;25(6):352-5.PMID: 12126560
OBJECTIVE: To investigate the effect of Ginkgo biloba extract (GBE) on acute lung injury(ALI) induced by lipopolysaccharide (LPS) in aging rats.METHODS: The rats were randomly divided into two parts: six rats served as normal controls; 18 rats were used for producing the aging animal model ( D-gal 50 mg/kg body weight was injected intraperitoneally, once a day for 6 weeks). The aging rats were then randomly divided into 3 groups: 6 rats as the aging control group; another 6 as the LPS treated aging group (LPS,5 mg/kg body weight intravenous injection); and the third as the GBE+LPS group (6 rats, GBE was started 7 days before the experiment,given once a day via the esophagus, the amount of flavone glycosides administered being 8 mg/kg body weight, and on the day of experiment, one dose of GBE was given 2 hours before LPS administration ). The samples were collected 2 hours after LPS or saline administration.RESULTS: Compared with normal controls, the SOD activity in red cells and the Na(+) -K(+) -ATPase activity in the lung tissue decreased markedly (all P < 0.05), but the LDH activity increased (P < 0.05) in the aging rats. ALI was observed in the aging rats 2 hours after LPS administration. Compared with the aging control, in the LPS treated rats, there were more inflammatory cells in the lung tissue; protein content in bronchial alveolar lavage fluid (BALF) and the pulmonary permeability index (PPI) increased significantly (all P < 0.001); LD, MDA, NO(2) (-)/NO(3)(-), ET-1 and TNF-alpha content and LDH activity in blood, and MPO activity in lung tissue all increased significantly. On the contrary, SOD activity in red cells and Na(+) -K(+) -ATPase activity in lung tissue decreased markedly (P < 0.05, P < 0.01). These changes, except SOD, were markedly attenuated in the GBE+LPS rats.CONCLUSIONS: The anti-oxidant activity was decreased in D-gal-induced aging rats. Intravenous administration of LPS caused acute lung injury in aging rats. GBE had protective effect on ALI induced by LPS.

8.Effects of L-carnitine and ginkgo biloba extract (EG b 761) in experimental bleomycin-induced lung fibrosis.:

Pharmacol Res. 2002 Jun;45(6):461-7.PMID: 12162946
The effects of Ginkgo biloba extract (EGb 761) and L-carnitine on bleomycin (BLM)-induced lung fibrosis were studied in rats. BLM (cumulative dose of 180 mgkg(-1)) was given intraperitoneally (i.p.) three times weekly for 4 consecutive weeks. Treatment with BLM enhanced the responsiveness of isolated pulmonary arterial rings to serotonin (5-HT), significantly increased the normal serum level of tumour necrosis factor (TNF-alpha) by approximately 105% and markedly elevated the level of lipid peroxide (LPO) and collagen content in the lung homogenates by 34 and 83%, respectively. EGb 761 (100 mgkg(-1) ), given in drinking water for the whole study period, totally abolished the BLM-induced alterations in the measured biochemical and pharmacological parameters. Meanwhile, L-carnitine (500 mg kg(-1) ), administered in drinking water, significantly decreased the BLM-induced elevations of serum TNF-alpha, LPO level in lung tissues and the enhanced responsiveness of pulmonary arterial rings to 5-HT. However,L-carnitine did not reduce the increase in the collagen content produced by BLM. The results of the present study indicate the beneficial effects of EGb 761 and L-carnitine against lung toxicity induced by BLM treatment. Furthermore, the present data shows the advantageous use of EGb 761 as a protective agent in BLM-induced lung fibrosis under the experimental circumstances.

9.Clinical study on treatment of pulmonary interstitial fibrosis with ginkgo extract:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2005 Mar;25(3):222-4.PMID: 15842142
OBJECTIVE: To observe the effect of ginkgo extract on pulmonary interstitial fibrosis.METHODS: Forty-five patients with pulmonary interstitial fibrosis were randomly divided into two groups, the treated group (n = 30) received ginkgo biloba extract 1 g, three times a day; the control group received prednisone 30 mg, once a day, the therapeutic course for both groups was 3 months. Changes of clinical symptoms, pulmonary function, arterial partial pressure of oxygen, computerized tomography (CT), interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor-alpha(TNF-alpha) in the two groups were observed before and after treatment.RESULTS: The efficacy of treatment in the two groups showed insignificant difference, clinical symptoms, pulmonary function, arterial partial pressure of oxygen were improved after treatment (P < 0.05), and the levels of IL-6, IL-8 and TNF-alpha significantly decreased after treatment as compared with those before treatment in the two groups. The occurrence of pulmonary infection was less in the treated group than that in the control group (P <0.05).CONCLUSION: Ginkgo is effective in treating pulmonary interstitial fibrosis.

10.Ginkgo biloba inhibits bleomycin-induced lung fibrosis in rats.:

Pharmacol Res. 2006 Mar;53(3):310-6. Epub 2006 Feb 3.PMID: 16459098
Oxidative stress has been implicated in the pathogenesis of bleomycin-induced lung fibrosis and many antioxidant agents have been studied for prevention and treatment of the disease in animals and humans. We therefore examined whether Ginkgo biloba (Gb), a flavonoid-rich antioxidant, inhibits bleomycin-induced lung fibrosis in rats. Male Sprague-Dawley rats were given a single dose of bleomycin (2.5 mg/kg, intratracheally) in pulmonary fibrosis groups and saline in controls. First dose of Gb was given a day before the bleomycin injection and continued until sacrifice. At day 14, fibrotic changes in lung were estimated to occur by Aschoft's criteria and lung hydroxyproline content. Bleomycin challenge provoked severe pulmonary fibrosis with marked increase in hydroxyproline content of lung tissue and typical histological findings, which is prevented by Gb. Hydroxyproline level was significantly higher (13.51+/-0.87 mg/g dried tissue) in bleomycin treated rats than controls (9.2+/-1.33), and its level was remained to the control levels (7.38+/-0.76) in rats treated with prophylactic Gb. On the other hand, bleomycin injection significantly reduced activities of glutathione peroxidase, superoxide dismutase and catalase in lung tissue which is prevented by Gb. Also, bleomycin injection resulted in a marked increase of malondialdehyde and nitrite level which is attenuated by Gb. The data suggest that Gb has a potent antioxidant activity in the model of bleomycin-induced lung fibrosis in rats, and therefore has a potent antifibrotic activity against bleomycin-induced lung fibrosis model in rats.

11.Ginkgo biloba extract (EGb 761) attenuates lung injury induced by intestinal ischemia/reperfusion in rats: roles of oxidative stress and nitric oxide.:

World J Gastroenterol. 2007 Jan 14;13(2):299-305.PMID: 17226913
AIM: To investigate the effect of ginkgo biloba extract (EGb 761) on lung injury induced by intestinal ischemia/reperfusion (II/R).METHODS: The rat model of II/R injury was produced by clamping the superior mesenteric artery for 60 min followed by reperfusion for 180 min. The rats were randomly allocated into sham, II/R, and EGb + II/R groups. In EGb + II/R group, EGb 761 (100 mg/kg per day) was given via a gastric tube for 7 consecutive days prior to surgery. Rats in II/R and sham groups were treated with equal volumes of the vehicle of EGb 761. Lung injury was assessed by light microscopy, wet-to-dry lung weight ratio (W/D) and pulmonary permeability index (PPI). The levels of malondialdehyde (MDA) and nitrite/nitrate (NO2(-)/NO3(-)), as well as the activities of superoxide dismutase (SOD) and myeloperoxidase (MPO) were examined. Western blot was used to determine the expression of inducible nitric oxide synthase (iNOS).RESULTS: EGb 761 markedly improved mean arterial pressure and attenuated lung injury, manifested by the improvement of histological changes and significant decreases of pulmonary W/D and PPI (P < 0.05 or 0.01). Moreover, EGb 761 markedly increased SOD activity, reduced MDA levels and MPO activity, and suppressed NO generation accompanied by down-regulation of iNOS expression (P < 0.05 or 0.01).CONCLUSION: The results indicate that EGb 761 has a protective effect on lung injury induced by II/R, which may be related to its antioxidant property and suppressions of neutrophil accumulation and iNOS-induced NO generation. EGb 761 seems to be an effective therapeutic agent for critically ill patients with respiratory failure related to II/R.

12.Effects of Ginkgo biloba extract on proliferation and apoptosis of T lymphocytes in vitro in rats with asthma:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006 Jun;26 Suppl:47-50.PMID: 17569345
OBJECTIVE: To explore the partial therapeutic mechanism of Ginkgo Biloba extract (GBE) in treating asthma.METHODS: Fourteen SD rats were randomly divided into two groups, 7 rats were sensitized as the asthmatic model group and the others taken as the healthy control group. T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) of the rats, and were cultured in vitro with Ginkgolide B (BN-52021 group) or Ginkgo Biloba extract 761 (EGb761 group) in different concentrations or without any of them (control group). T lymphocytes proliferation in groups were measured by using MTT assay and the effect of BN-52021 on T lymphocytes apoptosis was analyzed by flow cytometry at various times.RESULTS: Compared with the control group, BN-52021 could significantly inhibit the proliferation of T lymphocytes in both healthy and asthmatic rats in vitro (P <0. 05). The effects were enhanced as the concentration increasing and the time prolonging, the effects to the latter were higher than those to the former, showing significant difference between them ( P <0.05 ). However, the effect of EGb761 was varied with the concentrations. EGb761 could promote T lymphocytes proliferation at low concentration but inhibit it at high concentration, there was a significant difference as compared with that in the control group ( all P < 0. 05). The apoptotic rate of T lymphocytes rose as the concentration of BN-52021 increasing (P < 0. 01).CONCLUSION: GBE has different effects on T lymphocytes proliferation since the different ingredients and the concentrations in vitro, and it also has different effects between healthy and asthmatic rats. Ginkgolide B is the main active ingredient among them, it can not only inhibit T lymphocytes proliferation but also increase the apoptotic rate.

13.Effects of Ginkgo biloba on airway histology in a mouse model of chronic asthma.:

Allergy Asthma Proc. 2009 Mar-Apr;30(2):186-91. Epub 2008 Dec 31.PMID: 19118503
Platelet-activating factor (PAF) is an inflammatory mediator involved in the pathophysiology of asthma, suggesting a therapy antagonizing its effects may play a role in the disease treatment. The aim of the study was to determine the effects of Ginkgo biloba, a PAF antagonist, on lung histology. Thirty-five BALB/c mice were divided into five groups; A, B, C, D, and the control. All mice except controls were sensitized and challenged with ovalbumin. Mice in group A (placebo) received saline; group B received G. biloba, 100 mg/kg; group C received G. biloba, 150 mg/kg; and group D received dexamethasone, 1 mg/kg via orogastric gavage for 7 consecutive days. Chronic structural changes and airway remodeling were evaluated by using light and electron microscopy in all groups. Evaluation of lung histology indicated that the number of goblet cells, mast cells, thicknesses of epithelium, and basement membrane were significantly improved in groups B and C when compared with group A. There was no statistically significant difference in thicknesses of subepithelial smooth muscle between groups A, B, and C. When doses of G. biloba were compared with each other, only the number of goblet cells was significantly lower in group C than in group B. When G. biloba and dexamethasone groups were compared with each other, thicknesses of basement membrane and subepithelial smooth muscle were found to be lower in group D than in groups B and C. G. biloba alleviates all established chronic histological changes of lung except smooth muscle thickness in a mouse model of asthma.

R-Ginkgo Biloba:Endocrine system,Pancreatitis:

1.Effect of Ginkgo biloba extract on biological endocrine parameters:

Presse Med. 1986 Sep 25;15(31):1573-4.PMID: 2947103
In order to find out whether Ginkgo biloba extract has an influence on endocrine balance, 7 male volunteers (mean age: 26.1 years) received twice the usual dose of the drug for 8 weeks. Different hormonal assays and stimulation tests with LHRH and TRH were performed before, and 4 and 8 weeks after treatment. No significant change or tendency to change was observed. The other, usual blood tests also were unmodified.

2.The effects of gingko biloba extract (EGb 761) on experimental acute pancreatitis.:

J Surg Res. 2003 Dec;115(2):286-93.PMID: 14697296
BACKGROUND AND OBJECTIVE: Acute pancreatitis is an important and fatal disease with high mortality and morbidity. Although the pathogenesis of acute pancreatitis is poorly understood, there are many studies that suggest the role for oxygen free radicals (OFRs) in the development of pancreatitis and its complications and show beneficial effects of scavenger treatment. In the present study, we aimed to investigate whether Egb761, the standardized extract of gingko biloba, restrains the generation of OFRs and ameliorates the histopathologic findings of acute pancreatitis.MATERIALS AND METHODS: Sixty male Sprague Dawley rats were randomly assigned to one of the following experimental groups. In early and late pancreatitis and treatment groups, acute pancreatitis was induced by retrograde infusion of 3% sodium taurocholate. In treatment groups, 100 mg/kg Egb 761 was given intraperitoneally (IP) 24 h and immediately before induction of pancreatitis. Sham-operated rats received isotonic saline instead of sodium taurocholate. After observation times of 3.5 and 12 h, the pancreas was removed for light microscopy and determination of malondialdehyde (MDA) levels as a marker for OFRs-induced lipid peroxidation. Serum samples also were obtained for amylase and lipase levels.RESULTS: There was no significant difference in control and sham-operated groups in terms of histopathologic findings and serum enzyme levels. The tissue concentrations of MDA and serum enzyme levels were significantly elevated in early and late treatment groups as compared with the control group. The treatment with Egb 761 caused significant decrease in serum amylase and lipase levels and histopathologic scores as compared with early and late pancreatitis groups.CONCLUSIONS: Prophylactic application of Egb761 exerts highly beneficial influence on the course of acute pancreatitis, and this seems to be related to the oxygen radical scavenger effect of Egb761.

S-Ginkgo Biloba:Allergic problems,Skin problems Research:

1.Allergic contact dermatitis to Ginkgo biloba L.: relationship with urushiol.:

Arch Dermatol Res. 1989;281(4):227-30.PMID: 2774654
A Ginkgo biloba L. fruit extract was prepared and purified. Three groups of guinea pigs were sensitized to the crude extract, anacardic acids 1, and cardanols 2 respectively, using the FCAT method, and the fourth group to urushiol using the epicutaneous route. Each group was tested for reaction to the primary sensitizer and to the different main aromatic compounds isolated from Ginkgo fruits. Anacardic acids were found to be good sensitizers, while cardanols failed to induce allergic contact dermatitis (ACD). No cross-reactions were observed among the compounds tested. Ginkgolic acids 1 seem to be the main allergens of Ginkgo biloba L. and the hypothesis of a biotransformation of 1 into catechol 4 is not supported by experiment.

2.Effects of flavonoids of Ginkgo biloba on proliferation of human skin fibroblast.:

Skin Pharmacol. 1997;10(4):200-5.PMID: 9413894
Ginkgo biloba studies have focused on the anti-inflammatory effects of the major components, ginkgolide and bilobalide, whereas little is known about their effect on fibroblasts. This study demonstrated the enhancing effects of Ginkgo L. extracts, especially the flavonoid fractions: quercetin, kaempferol, sciadopitysin, ginkgetin, isoginkgetin, on the proliferation of normal human skin fibroblast in vitro measured by MTT (3-[4,5-dimethylthiazole-2-yl]-2,5-diphenyl-tetrazolium bromide) assay and direct hemocytometer cell count. Furthermore, increased production of collagen and extracellular fibronectin were documented by radioisotope (2,3-3H-proline) incorporated collagen assay, procollagen type I C-peptide assay and by immunoturbidimetric assay. These proliferative effects suggest another useful pharmacologic application of Ginkgo L. extracts in addition to their well-known anti-inflammatory effect.

3.Pretreatment of skin with a Ginkgo biloba extract/sodium carboxymethyl-beta-1,3-glucan formulation appears to inhibit the elicitation of allergic contact dermatitis in man.:

Contact Dermatitis. 1998 Mar;38(3):123-6.PMID: 9536401
The clinical efficiency of mitigating contact dermatitis with a Ginkgo biloba extract and carboxymethyl-beta-1,3-glucan formulation was investigated in a double-blind versus placebo study using 22 subjects (Caucasian women aged 22-55 years) with allergic contact dermatitis from various substances in the European standard series. The formulation was applied to intact skin 2X a day for 2 weeks ("in use" application) prior to a single application of a selected contact allergen under a Finn Chamber for 24 h. Readings were carried out in a blind study by a dermatologist 2 and 3 days after patch removal. Representative photographs were taken of treated, placebo and untreated test areas. 68.2% of the panelists showed significantly reduced skin reactivity (p = 0.037*) on the treated site 2 days after patch removal, versus untreated and/or placebo sites. This finding indicates that the Ginkgo biloba/carboxymethyl-beta-1,3-glucan formulation can mitigate against allergic contact dermatitis.

4.Prevention of adriamycin-induced skin necrosis with various free radical scavengers.:

J Surg Res. 1998 Feb 15;75(1):61-5.PMID: 9614858
Infiltration of antitumor agents into subcutaneous tissues may either result in a local area of self-resolving inflammation or progress to full-thickness loss of skin and underlying vital structures. Inadvertent extravasation of adriamycin can result in severe tissue necrosis. The mechanism of this tissue damage is believed to be release of oxygen free radicals into the tissue. After adriamycin extravasation, the treatment groups were made up according to drugs used, EGb 761, pentoxifylline, alpha-tocopherol acetate, and alpha-tocopherol succinate in rats. To prevent the necrosis and to decrease the tissue malondialdehyde levels, the most effective agent was found to be EGb 761, and pentoxifylline was also effective (P < 0.001). No difference was found between topical lanoline and saline (P > 0.05). The maximum ulcer diameter was obtained in 2 weeks. The maximum tissue malondialdehyde levels were obtained in 24 h, and in comparison to the control group the treatment groups showed lower levels. Our aim is to show the role of free radicals in the formation of skin necrosis as a cause of adriamycin extravasation and to prevent or decrease the skin necrosis using various free radical scavengers.

5.The effect of Gingko biloba extract (Egb 761) as a free radical scavenger on the survival of skin flaps in rats. A comparative study.:

Scand J Plast Reconstr Surg Hand Surg. 1998 Jun;32(2):135-9.PMID: 9646361
Free radicals may have a role in pedicle flap necrosis. We undertook this study to compare the effect of various antioxidants and scavengers of free radicals such as vitamin E, vitamin C, deferoxamine, and Gingko biloba extract (Egb 761) on McFarlane caudal-based dorsal rat flaps. Fifty rats were divided into five groups of 10 animals each. One group served as a control (saline) group. The remaining four groups were given vitamin C 340 mg/kg, deferoxamine 150 mg/kg, Egb 761 100 mg/kg, and vitamin E 20 mg/kg. The necrosed area of flap was significantly reduced in the deferoxamine (p < 0.001), Egb 761 (p < 0.001), and vitamin C (p < 0.05) groups compared with the control group. Vitamin E had no effect on distal flap necrosis (p = 0.20).

6.Effects of Ginkgetin from Ginkgo biloba Leaves on cyclooxygenases and in vivo skin inflammation.:

Planta Med. 2002 Apr;68(4):316-21.PMID: 11988854
Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase (COX)-1 and -2 including an in vivo effect. Ginkgetin (1 - 10 microM) and the biflavonoid mixture (10 - 50 microg/ml), mainly a 1 : 1 mixture of ginkgetin and isoginkgetin, from G. biloba leaves, inhibited production of prostaglandin E2 from lipopolysaccharide-induced RAW 264.7 cells. This inhibition was mediated, at least in part, by down-regulation of COX-2 expression, but not by direct inhibition of COX-1 or COX-2 activity. Down-regulation of COX-2 by ginkgetin was also proved in the dorsal skin of ICR mouse treated by 12-O-tetradecanoylphorbol 13-acetate (TPA). At total doses of 1,000 microg/site on the dorsal skin (15 mm x 15 mm), ginkgetin inhibited prostaglandin E2 production by 65.6 % along with a marked suppression of COX-2 induction. In addition, ginkgetin and the biflavonoid mixture (100 - 1,000 microg/ear) dose-dependently inhibited skin inflammation of croton oil induced ear edema in mice by topical application. The present study suggests that ginkgetin from G. biloba leaves down-regulates COX-2 induction in vivo and this down-regulating potential is associated with an anti-inflammatory activity against skin inflammatory responses.

7.Evidence of the regulatory effect of Ginkgo biloba extract on skin blood flow and study of its effects on urinary metabolites in healthy humans.:

Planta Med. 2004 Nov;70(11):1052-7.PMID: 15549661
Ginkgo biloba extract has been advocated for the improvement of blood circulation in circulatory disorders. This study investigated the effect of the Gingko biloba extract EGb 761 on skin blood flow in healthy volunteers and accompanying changes in urinary metabolites. Twenty-seven healthy middle-aged subjects participated in a randomized, double-blind, placebo-controlled, crossover study. Subjects received 240 mg/d EGb 761 or placebo for periods of 3 weeks. Skin blood flow was measured on the forefoot using laser Doppler flowmetry and changes in urinary metabolites were identified by a combination of nuclear magnetic resonance (NMR) spectroscopy and multivariate data analysis (MVDA). These measurements were performed on 24-h urine samples collected at the end of the intervention periods. Following EGb 761 treatment, overall mean skin blood flow was significantly reduced as compared with placebo. Remarkably, the change of skin blood flow after EGb 761 intervention was proportionally related to blood flow after placebo treatment: subjects showed either an increased, decreased or unaltered skin blood flow. NMR/MDVA analyses showed that urinary metabolic patterns differed depending on the change in baseline blood flow after treatment with EGb 761. The present findings substantiate that EGb 761 has a multi-directional modulating action on blood flow in healthy subjects and support findings of a vasoregulatory role of this extract. Moreover, the results indicate that metabolic fingerprinting provides a powerful means to identify biochemical markers that are associated with functional changes.

8.Effects of anti-inflammatory biflavonoid, ginkgetin, on chronic skin inflammation.:

9.Inhibition of chronic skin inflammation by topical anti-inflammatory flavonoid preparation, Ato Formula.:

Arch Pharm Res. 2006 Jun;29(6):503-7.PMID: 16833019
Flavonoids are known as natural anti-inflammatory agents. In this investigation, an anti-inflammatory potential of new topical preparation (SK Ato Formula) containing flavonoid mixtures from Scutellaria baicalensis Georgi roots and Ginkgo biloba L. leaves with an extract of Gentiana scabra Bunge roots was evaluated in an animal model of chronic skin inflammation. Multiple 12-O-tetradecanoylphorbol-13-acetate treatments for 7 consecutive days on ICR mouse ear provoked a chronic type of skin inflammation: dermal edema, epidermal hyperplasia and infiltration of inflammatory cells. When topically applied in this model, this new formulation (5-20 microL/ear/treatment) reduced these responses. Furthermore, it inhibited prostaglandin E2 generation (17.1-33.3%) and suppressed the expression of proinflammatory genes, cyclooxygenase-2 and interleulin-1beta in the skin lesion. Although the potency of inhibition was lower than that of prednisolone, all these results suggest that Ato Formula may be beneficial for treating chronic skin inflammatory disorders such as atopic dermatitis.

10.Skin penetration of epigallocatechin-3-gallate and quercetin from green tea and Ginkgo biloba extracts vehiculated in cosmetic formulations.:

Skin Pharmacol Physiol. 2009;22(6):299-304. Epub 2009 Sep 25.PMID: 19786823
Green tea (Camellia sinensis) and Ginkgo biloba extracts in cosmetic formulations have been suggested to protect the skin against UV-induced damage and skin ageing. Thus, it is very important to assess the human skin penetration of their major flavonoids to verify if they penetrate and remain in the skin to exert their proposed effects. The aim of this study was to evaluate the human skin penetration of epigallocatechin-3-gallate (EGCG) and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations. This study was conducted with fresh dermatomed human Caucasian skin from abdominal surgery mounted on static Franz diffusion cells. Skin samples were mounted between two diffusion half-cells and 10 mg/cm(2) of formulations supplemented with 6% of green tea or G. biloba extract were applied on the skin surface. The receptor fluid was removed after 6 and 24 h and analyzed by high-performance liquid chromatography for the quantification of the flavonoids. The stratum corneum was removed by tape stripping and immersed in methanol and the epidermis was mechanically separated from the dermis and triturated in methanol to extract EGCG and quercetin. The results showed that the flavonoids under study penetrated into the skin, without reaching the receptor fluid. The majority of EGCG was quantified in the stratum corneum (0.87 microg/cm(2)), which was statistically higher than the EGCG concentrations found in viable epidermis (0.54 microg/cm(2)) and in the dermis (0.38 microg/cm(2)). The majority of quercetin was quantified in the viable epidermis (0.23 microg/cm(2)), which was statistically higher than the EGCG concentration found in the stratum corneum layer (0.17 microg/cm(2)). Finally, it can be concluded that EGCG and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations presented good skin penetration and retention, which can favor their skin effects.

11.Effectiveness of oral Ginkgo biloba in treating limited, slowly spreading vitiligo.:

Clin Exp Dermatol. 2003 May;28(3):285-7.PMID: 12780716
For effective treatment of vitiligo, it is as important to arrest the progression of the disease as it is to induce repigmentation. Recently, oxidative stress has been shown to play an important role in the pathogenesis of vitiligo. Ginkgo biloba extract has been shown to have antioxidant and immunomodulatory properties. In a double-blind placebo-controlled trial, we evaluated the efficacy of G. biloba extract in controlling the activity of the disease process in patients with limited and slow-spreading vitiligo and in inducing repigmentation of vitiliginous areas. Fifty-two patients were assigned to two treatment groups (A and B) in a double-blind fashion, but only 47 patients could be evaluated, because one patient in group A and four patients in group B withdrew for reasons unrelated to the study. Patients in group A were given G. biloba extract 40 mg three times daily whereas patients in group B received placebo in similar doses. A statistically significant cessation of active progression of depigmentation was noted in patients treated with G. biloba (P = 0.006). Marked to complete repigmentation was seen in 10 patients in group A, whereas only two patients in group B showed similar repigmentation. The G. biloba extract was well tolerated. G. biloba extract seems to be a simple, safe and fairly effective therapy for arresting the progression of the disease.

12.Protective effects of Ginkgo biloba leaf extracts on trichloroethylene-induced human keratinocyte cytotoxicity and apoptosis.:

Skin Pharmacol Physiol. 2005 Jul-Aug;18(4):160-9. Epub 2005 May 25.PMID: 15920354
The objective of this study was to assess the protective effects of Ginkgo biloba leaf extracts (EGb) on trichloroethylene (TCE)-induced cytotoxicity and apoptosis in normal human epidermal keratinocytes (NHEK). Cytotoxicity was determined by neutral red uptake, and lipid peroxidation of the cells was assessed by malondialdehyde (MDA) and superoxide dismutase (SOD). Electron microscopy and flow cytometry were used to evaluate NHEK apoptosis. Treatment of NHEK with various concentrations of TCE caused a substantial decrease in cell viability. NR(50 )from the cytotoxicity assay was found to be 4.53 mM. TCE caused an increase in MDA, while an inhibition of SOD activity, in a concentration-dependent manner. Electron microscopic examination revealed typical morphologic changes of apoptosis in cells treated with TCE. Incubation of NHEK with TCE (0, 0.125, 0.5, 2.0 mM) for 4 h increased the proportion of apoptotic cells from control of 19.23% to nearly 44.35%. Pretreatment of EGb at 10-200 mg/l dose-dependently attenuated the cytotoxic effect of TCE, prevented TCE-induced elevation of lipid peroxidation and decline of antioxidant enzyme activities. Similar inhibition by EGb on TCE-mediated NHEK apoptosis was also observed. These results suggest that EGb can protect NHEK from TCE-induced cytotoxicity and apoptosis, which may be associated with the superoxide scavenging effect and enhancement of antioxidant enzyme activities.

13.Changes of nitric oxide after trichloroethylene irritation in hairless mice skin and protection of ginkgo biloba extract and vitamin E:

Zhonghua Lao Dong Wei Sheng Zhi Ye Bing Za Zhi. 2009 Apr;27(4):207-10.PMID: 19493483
OBJECTIVE: To study the changes of nitric oxide (NO) in the BALB/c hairless mice skin after trichloroethylene (TCE) irritation and the protection of ginkgo biloba extract (GbE) and vitamin E (VE).METHODS: 132 BALB/c hairless mice were randomly divided into blank control group, solvent group (olive oil), TCE groups (20%TCE, 40%TCE, 80%TCE and 100%TCE), GbE groups (0.1%GbE, 1%GbE and 10%GbE) and VE groups (5%VE, 10% VE and 20% VE), with 11 animals in each group, 5 for acute irritation test and 6 for the cumulative irritation test. The skin irritation was observed, and the levels of NO in the dorsal skin of BALB/C hairless mice were detected. The kit of NO was used to detect the levels of NO in the dorsal skin of BALB/c hairless mice.RESULTS: (1) The skin presented erythema and edema after TCE irritation both in acute irritation and cumulative irritation test and the skin inflammation showed time-dose effect relationship; the mice skin was protected in GbE or VE groups. (2) In the acute stimulation test, the levels of NO in 80%TCE group (69.895 +/- 9.605 micromol/mg pro) and 100%TCE group (77.273 +/- 9.290 micromol/mg pro) were significantly different compared with blank control group and solvent control group (P < 0.05 or P < 0.01). In the protection group, the NO level were reduced, with the statistically significant differences. (3) In acute irritation test, the levels of NO in 80%TCE group (60.362 +/- 9.817 micromol/mg pro) and 100%TCE group (68.027 +/- 9.354 micromol/mg pro) were significantly different compared with blank control group and solvent control group, (P < 0.05 or P < 0.01); In the protection group, 1% GbE, 10% GbE, 10% VE and 20%VE could reduce the levels of NO, with statistically significant differences.CONCLUSION: TCE can produce the irritation on the dorsal skin of BALB/c hairless mice and induce the significant increase of the NO levels. GbE and VE can protect the skin from TCE irritation damage.

T-Ginkgo Biloba:Body balance problems,Equilibrium disorders,Endurance ability,Mountain problems:

1.Treatment of equilibrium disorders with Ginkgo biloba extract. A multicenter double-blind drug vs. placebo study:

Presse Med. 1986 Sep 25;15(31):1569-72.PMID: 2947102
This study, conducted in 3 centres, included 70 patients with vertiginous syndrome of recent onset and undetermined origin. In a double-blind trial extending over a 3-month period they were given either Ginkgo biloba extract or a placebo. The effectiveness of Ginkgo biloba extract on the intensity, frequency and duration of the disorder was statistically significant. At the end of the trial, 47% of the patients treated were rid of their symptoms as against 18% of those who received the placebo.

2.Plasticity mechanisms in vestibular compensation in the cat are improved by an extract of Ginkgo biloba (EGb 761).:

Pharmacol Biochem Behav. 1991 Oct;40(2):367-79.PMID: 1805241
The effects of administration of an extract of Ginkgo biloba (EGb 761) on vestibular compensation was studied in unilateral vestibular neurectomized cats. This experimental model of CNS plasticity was investigated by using behavioral tests (postural disorders compensation, locomotor balance recovery), electrophysiological (spontaneous and evoked neck muscle activity) and neurophysiological (spontaneous firing rate recovery of deafferented vestibular cells) recordings, and immunocytochemical methods (synaptic loss and synaptic reoccupation within the deafferented vestibular nuclei). In all experiments, EGb 761 was administered over 30 days at daily doses of 50 mg/kg IP. The results showed a faster recovery in the EGb-treated group of cats as compared to an untreated control group. EGb administration strongly accelerated postural and locomotor balance recovery. Concomitantly, spontaneous neck muscle activity, vestibulo-collic reflexes and spontaneous firing rate of vestibular units located on the lesioned side were restored earlier. Morphological correlates characterized by a more rapid synaptic reoccupation were found in the deafferented medial vestibular nucleus by means of immunoreactive labelling using an antibody against a synaptic vesicle-associated protein (synaptophysin), but they displayed a longer time-constant in comparison with the behavioral and neurophysiological data. These results clearly demonstrate that EGb 761 acts on recovery mechanisms considered as key processes in vestibular compensation. They suggest that this substance would possess neurotrophic and/or neuritogenic properties improving functional recovery after CNS injury.

3.Gingko biloba extract EGb 761 and pentoxifylline in intermittent claudication. Secondary analysis of the clinical effectiveness:

Vasa. 1992;21(4):403-10.PMID: 1485476
Clinical trials on the efficacy of EGb 761 and pentoxifylline are summarized in the context of their methods and results and compared with each other. All placebo-controlled, randomized and double-blind studies with the major target objective of "pain-free walking distance" were selected. The pentoxifylline studies were adopted from a survey of the existing literature in the English language, which has been brought up to date via DIMDI research. The studies on both active substances are fraught with similar difficulties as to method, and are not different as regards their quality. The increase in walking distance is highly variable, especially in the pentoxifylline studies. On average through each and all of the studies on both preparations, an increase of 45% (EGb 761) or 57% (pentoxifylline) in relation to initial values is here found. No differences in the documentation of efficacy and the clinical efficacy were discovered between the two substances, both of which are registered as effective substances in the treatment of peripheral arterial occlusion (pAO) in accordance with the Federal German Drugs Law (Arzneimittelgesetz, AMG) of 1976

4.Pharmacological activity of the Ginkgo biloba extract (EGb 761) on equilibrium function recovery in the unilateral vestibular neurectomized cat.:

J Vestib Res. 1995 May-Jun;5(3):187-200.PMID: 7627378
Locomotor balance recovery after unilateral vestibular neurectomy has been found strongly accelerated in the cat when the animals received a postoperative treatment with Ginkgo biloba Extract (EGb 761:50 mg/kg/d, i.p.), a result due to the improvement of plasticity mechanisms involved in vestibular compensation. The aim of this study was to determine which of the two main biochemical components (terpenes vs. flavonoids) contained in the extract was the most active in the recovery process, to test the influence of the route of administration, and to look for dose-dependent effects. Experiments were performed in six experimental groups of cats that were compared with each other and with three control groups. Comparisons were done on the recovery profile and time course of equilibrium function restoration, as quantified by the rotating beam test. Four experimental groups were treated with the standardized extract EGb 761 given orally (p.o.:2 groups; 40 mg and 80 mg/kg) or intraperitoneally (i.p.: 2 groups; 50 mg and 25 mg/kg), whereas the two others received only a special extract that did not contain the terpenes (i.p. administration: 25 mg and 10 mg/kg). Treatment was always given until complete recovery of locomotor balance function. The control groups received either no treatment (untreated cats), an oral vehicle (placebo cats), or a sham i.p. injection (sham cats). Results showed that locomotor balance recovery was significantly improved in all the experimental groups as compared to the control groups of cats, which recovered similarly and more slowly. Efficacy of the special extract without the terpenes was comparable to that of the total extract, indicating that the nonterpenic fraction was the most active biochemical constituent in this experimental model of central nervous system (CNS) plasticity. Pharmacological activity of the extract was also significantly better when given i.p. as compared to the p.o. route of administration, and dose-dependent effects were evidenced with the i.p. administration of the special extract without the terpenes, with a lower efficacy for the lowest dose (10 mg/kg). These data confirm that EGb 761 treatment serves as useful therapy in supporting brain functional recovery in this animal model of vestibular compensation and lead to a more precise understanding of the biochemical component that is active in this recovery process.

5.Placebo-controlled double-blind study of the effectiveness of Ginkgo biloba special extract EGb 761 in trained patients with intermittent claudication:

Vasa. 1996;25(3):265-74.PMID: 8967154
This monocenter, randomized, placebo-controlled double-blind study with parallel-group comparison was carried out in order to demonstrate the efficacy of Ginkgo biloba special extract EGb 761 on objective and subjective parameters of the walking performance in trained patients suffering from peripheral arterial occlusive disease in Fontaine stage IIb. In total 60 patients were recruited (42 men; aged 47-82 years) with angiographically proven peripheral arterial occlusive disease of the lower extremities and an intermittent claudication existing for at least 6 months. No improvement had been shown despite consistent walking training and a maximum pain-free walking distance on the treadmill of less than 150 m was recorded at the beginning of the study. The therapeutic groups were treated with either Ginkgo biloba special extract EGb 761 at a dose of 3 times 1 film-coated tablet of 40 mg per day by oral route or placebo over a duration of 24 weeks following a two-week placebo run-in phase. The main outcome measure was the difference of the walking distance between the start of treatment and after 8, 16 and 24 weeks of treatment as measured on the treadmill (walking speed 3 km/h and slope of 12%). As secondary parameters the corresponding differences for the maximum walking distance, the relative increase of the pain-free walking distance, the Doppler index and the subjective evaluation of the patients were analyzed. The absolute changes in the pain-free walking distance in treatment weeks 8, 16 and 24 as against the treatment beginning (median values with 95% confidence interval) led to the following values for the patients treated with Ginkgo biloba special extract EGb 761:19 m (14, 33), 34 m (18, 50) and 41 m (26, 64). The corresponding values in the placebo group were as follows: 7 m (-4, 12), 12 m (5, 22) and 8 m (-1, 21). The advantage of the EGb 761-treated group as compared to the placebo group could be verified statistically at the 3 time points with p < 0.0001, p = 0.0003 and p < 0.0001. The test for the presence of a clinically relevant difference of 20% between EGb 761 and placebo also produced a statistically significant result (p = 0.008). The Doppler index remained unchanged in both therapeutic groups: A corresponding statistically significant advantage for the EGb 761 group was observed on a descriptive level for the other parameters tested. The tolerance of the treatment was very good. The results of this placebo-controlled study show that treatment with Ginkgo biloba special extract EGb 761 produces a statistically highly significant and clinically relevant improvement of the walking performance in trained patients suffering from intermittent claudication with very good tolerance of the study preparation.

6.Ginkgo biloba in treatment of intermittent claudication. A systematic research based on controlled studies in the literature:

Fortschr Med. 1996 Mar 20;114(8):85-7.PMID: 8647571
The aim of this systematic review was to evaluate the effectiveness of ginkgo biloba in the treatment of intermittent claudication. A Medline-search identified ten controlled trials on the subject. These were heterogeneous in all respects and, with only few exceptions, of poor methodological quality. All the studies implied that ginkgo biloba is an effective therapy for intermittent claudication. This hypothesis should be confirmed in further trials employing meticulous methodology. Furthermore it would also be important to determine whether oral ginkgo biloba can be usefully combined with walking exercise.

7.EGb 761 in control of acute mountain sickness and vascular reactivity to cold exposure.:

Aviat Space Environ Med. 1996 May;67(5):445-52.PMID: 8725471
METHOD: We recruited 44 subjects to participate in a study of the preventive effect of Ginko biloba extract (EGb 761) on acute mountain sickness (AMS) and vasomotor changes of the extremities during a Himalayan expedition. After giving their written informed consent, the subjects were randomized to two groups. One group received 160 mg of EGb 761 per day in two divided doses and the other group received placebo. Assessment was based on the course of the Environmental Symptom Questionnaire (ESQ) score and the cold gradient measured by photoplethysmography.RESULTS: The prophylactic efficacy of treatment with EGb 761 was clearly demonstrated in this study. In terms of factor 1 (AMS-Cerebral), no subject in the EGb 761 group developed acute mountain sickness versus 40.9% of subjects in the placebo group; this difference was very significant (p < or = 1.4 x 10(-3)). In terms of factor 2 (AMS-Respiratory), 3 subjects (13.6%) in the EGb 761 group developed acute mountain sickness versus 18 (81.8%) in the placebo group; this difference was very significant (p = 1.2 x 10(-5)).CONCLUSION: Due to its multiple pharmacological actions, EGb 761 provides an interesting response to the prevention of mountain sickness for moderate altitude (5400 m) with gradual exposure. It also decreased vasomotor disorders of the extremities, as demonstrated by plethysmography (p < 10(-8)) and a specific questionnaire (p < 10(-9)).

8.Motor function in young and aged hemiplegic rats: effects of a Ginkgo biloba extract.:

Neurobiol Aging. 1997 Mar-Apr;18(2):219-27.PMID: 9258900
We have previously shown beneficial effects of a Ginkgo biloba extract (EGb761-IPSEN) in accelerating functional recovery from hemiplegia induced by unilateral motor cortex ablation. Here, we report the behavioral and histological effects of various dose regimes of EGb761. In young rats (3 months), 10 mg/kg/day for 7 days produced an improvement in motor performance, relative to untreated controls, on the last day of treatment. Applying a priming (P)-maintenance (M) dose regime (P-7 = 7 days, M-21 = 21 days), a P-7 of 50 (all doses expressed in mg/kg/day) and a M-21 of 10 promoted recovery from the second day after surgery. However, in aged rats (26-28 months old) this treatment ameliorated motor performance only after the 10th day of treatment. A P-7 of 100 or 200 and a M-21 of 50 or 100 produced an acceleration of behavioral recovery in aged animals. Improvement was evident by the fifth day of treatment and was maintained after the treatment regimen. These two groups also demonstrated reduced glial fibrillary acid protein (GFAP) immunostaining and ex vacuo hydrocephalus. Thus, the confirmed efficacy of EGb in hemiplegic rats can be enhanced by an appropriate posology.

9.The sensitizing capacity of ginkgolic acids in guinea pigs.:

Am J Contact Dermat. 1998 Sep;9(3):146-8.PMID: 9744906
BACKGROUND: Ginkgo biloba possesses fruits that have caused numerous cases of allergic contact dermatitis. Low amounts of the ginkgolic acids occur in the leaves as well.OBJECTIVE: Leaf extracts are used to treat cerebrovascular and peripheral vascular disorders. The question arises whether skin hypersensitivity reactions may be adverse effects because the pharmaceutical preparations contain low amounts of ginkgolic acids.METHODS: Guinea pigs were sensitized experimentally with pure ginkgolic acids as well as with leaf extracts containing approximately 1,000 ppm of ginkgolic acids.RESULTS: The guinea pigs could be sensitized successfully with the pure ginkgolic acids. The animals could not be sensitized with the leaf extract.CONCLUSION: Leaf extracts of Ginkgo biloba taken orally or given by infusion to treat diffuse cerebral disturbances can be considered safe, even when they might contain up to 1,000 ppm of the sensitizing ginkgolic acids.

10.Ginkgo biloba (EGb 761) in the treatment of equilibrium disorders.:

Adv Ther. 1998 Sep-Oct;15(5):291-304.PMID: 10345150
In an open, controlled study, 44 patients complaining of vertigo, dizziness, or both, caused by vascular vestibular disorders were randomly treated with extract of Ginkgo biloba (EGb 761) 80 mg twice daily or with betahistine dihydrochloride (BI) 16 mg twice daily for 3 months. A complete neuro-otologic and equilibrimetric examination was performed at baseline and after 3 months of treatment, with evaluation of clinical findings. In the first month of therapy, vertigo and dizziness improved in 64.7% of patients treated with BI and in 65% of those who received EGb 761. Compared to baseline, no statistically significant changes were observed in cranial scans for patients with a "central" cranial pattern. Likewise, no changes versus baseline were observed in both groups for the equilibrium score. The comprehensive test battery showed the following findings: EGb 761 induced a slight decrease of saccadic delay and considerably increased saccadic velocities; BI improved saccadic accuracy but did not modify delay; EGb 761 improved smooth pursuit gain at 0.4 Hz 40 degrees/s three times more than BI; both drugs asymmetrically reduced nystagmus maximum velocity at 40 degrees/s; both drugs asymmetrically improved the sinusoidal vestibulo-ocular reflex; BI considerably reduced--whereas EGb 761 considerably improved--visuovestibular ocular reflex. No side effects were recorded during the trial except for transient mild headache and gastric upset in 2 patients receiving EGb 761 and transient cyanosis of nails and lips in 1 patient given BI. These results suggest that EGb 761 and BI operate at different equilibrium receptor sites and show that EGb 761 can considerably improve oculomotor and visuovestibular function.

11.Evidence that the ginkgo biloba extract, EGb 761, neither accelerates nor enhances the rapid compensation of the static symptoms of unilateral vestibular deafferentation in guinea pig.:

J Vestib Res. 1999;9(2):111-8.PMID: 10378182
The concentrated Ginkgo biloba extract, EGb 761, has previously been reported to enhance and accelerate vestibular compensation following unilateral vestibular deafferentation (UVD), in particular, compensation of the dynamic postural symptoms such as locomotor dysequilibrium. However, many of these studies have not included a complete analysis of the static symptoms of UVD, such as spontaneous nystagmus (SN), yaw head tilt (YHT), and roll head tilt (RHT), nor have they included a dose-response analysis or vehicle controls for EGb 761. The aim of the present study was to examine the effects of the EGb 761 extract on static vestibular compensation in guinea pig, using a dose-response analysis and both vehicle and saline controls. Analysis of variance showed that there was a significant decrease in SN frequency (P < 0.05) and a significant change in the rate of SN compensation (P < 0.05), using 3 i.p. injections of EGb 761 (25, 50, or 100 mg/kg), or vehicle, or saline, at 0, 25, and 40 h post-UVD. However, post-hoc testing revealed that this was due entirely to significant differences between the saline and vehicle groups at 35, 40, and 50 h post-UVD (P < 0.05 in all cases) and between the saline and the 100 mg/kg and 25 mg/kg EGb 761 groups at 35 and 50 h post-UVD, respectively (P < 0.05 for both comparisons); there were no significant differences between the vehicle and drug groups at any time. YHT and RHT were not significantly different between the drug, saline, and vehicle groups. In a second set of experiments, the 50 and 100 mg/kg EGb 761 i.p. injection frequencies were doubled. However, once again, neither SN nor YHT were significantly different between the EGb 761 groups and the vehicle controls. These results suggest that 1) EGb 761 does not significantly enhance or accelerate compensation of the static symptoms of UVD in guinea pig and 2) the EGb 761 vehicle may exert some effects on its own. Therefore, EGb 761 may be of limited use in the treatment of acute vestibular dysfunction in humans.

12.Ginkgo biloba extract for the treatment of intermittent claudication: a meta-analysis of randomized trials.:

Am J Med. 2000 Mar;108(4):276-81.PMID: 11014719
PURPOSE: The optimal treatment of intermittent claudication has not yet been identified. Ginkgo biloba extract has been reported to have beneficial effects. We performed a meta-analysis of the efficacy of Ginkgo biloba extract for intermittent claudication based on the results of randomized, placebo-controlled, double-blind trials.METHODS: Literature searches of MEDLINE, EMBASE, BIOSIS, AMED, CISCOM, and the Cochrane Library were performed to identify studies on the topic. Manufacturers of commercial Ginkgo biloba products and authors of original publications and reviews were contacted to provide additional information. No language restrictions were imposed.RESULTS: Eight randomized, placebo-controlled, double-blind trials were included. Meta-analysis found a significant difference in the increase in pain-free walking distance in favor of Ginkgo biloba (weighted mean difference: 34 meters, 95% confidence interval [CI]: 26 to 43 meters). In studies using similar methodological features (ergometer speed: 3 km/h, inclination: 12%) this difference was 33 meters in favor of Ginkgo biloba (95% CI: 22 to 43 meters). Adverse effects were rare, mild, and transient.CONCLUSIONS: These results suggest that Ginkgo biloba extract is superior to placebo in the symptomatic treatment of intermittent claudication. However, the size of the overall treatment effect is modest and of uncertain clinical relevance.

13.Therapeutic efficacy of EGb761 (Gingko biloba extract) in a transgenic mouse model of amyotrophic lateral sclerosis.:

J Mol Neurosci. 2001 Aug;17(1):89-96.PMID: 11665866
EGb761 is a standardized extract of green Gingko biloba, which exerts protective effects against mitochondrial damage and oxidative stress. We examined whether oral administration of 0.022% or 0.045% EGb761 in the diet could impart neuroprotective effects in a transgenic mouse model (G93A) of amyotrophic lateral sclerosis (ALS). EGb761 significantly improved motor performance and survival, and protected against a loss of spinal-cord anterior motor horn neurons in male G93A mutant transgenic ALS mice, but not in littermate female mutant transgene mice. While EGb761 extended survival in littermate female G93A mice, significance was not reached. EGb761, however, significantly improved weight loss in both male and female transgenic ALS mice. These findings provide evidence for a gender-specific neuroprotective effect of EGb761 in a transgenic model of ALS and suggest that EGb761 may be a potential effective treatment in patients with ALS.

14.Chronic fatigue syndrome: oxidative stress and dietary modifications.:

Altern Med Rev. 2001 Oct;6(5):450-9.PMID: 11703165
Chronic fatigue syndrome (CFS) is an illness characterized by persistent and relapsing fatigue, often accompanied by numerous symptoms involving various body systems. The etiology of CFS remains unclear; however, a number of recent studies have shown oxidative stress may be involved in its pathogenesis. The role of oxidative stress in CFS is an important area for current and future research as it suggests the use of antioxidants in the management of CFS. Specifically, the dietary supplements glutathione, N-acetylcysteine, alpha-lipoic acid, oligomeric proanthocyanidins, Ginkgo biloba, and Vaccinium myrtillus (bilberry) may be beneficial. In addition, research on food intolerance is discussed, since food intolerance may be involved in CFS symptom presentation and in oxidation via cytokine induction. Finally, recent evidence suggests celiac disease can present with neurological symptoms in the absence of gastrointestinal symptoms; therefore, celiac disease should be included in the differential diagnosis of CFS.

15.Biflavones of Ginkgo biloba stimulate lipolysis in 3T3-L1 adipocytes.:

Planta Med. 2002 Jan;68(1):76-9.PMID: 11842336
Ginkgo biloba L. biflavones were shown to increase cAMP phosphodiesterase activity and to stimulate skin microcirculation. The aim of this study was to investigate whether biflavones were able to stimulate lipolysis in adipocytes. Lipolysis was assayed in fully differentiated 3T3-L1 fat cells in the presence of biflavones at 0.005 - 100 microM. Cell viability was evaluated at 0.5 -100 microM. Theophylline and caffeine were used as reference compounds. Lipolytic activity in untreated cells was 0.62 +/- 0.15 micromoles glycerol/mg DNA/h. All biflavones except sciadopitysin stimulated lipolysis in a concentration-dependent fashion. Maximal stimulation was observed at 0.1 - 0.5 microM. At higher concentrations the effect diminished progressively and was lost at 100 microM. Only a partial loss of cell viability was observed with biflavones at 10 - 100 microM.

16.An open, pilot study to evaluate the potential benefits of coenzyme Q10 combined with Ginkgo biloba extract in fibromyalgia syndrome.:

J Int Med Res. 2002 Mar-Apr;30(2):195-9.PMID: 12025528
An open, uncontrolled study was undertaken to measure the subjective effects of coenzyme Q10 combined with a Ginkgo biloba extract in volunteer subjects with clinically diagnosed fibromyalgia syndrome. Anecdotal reports from patients with fibromyalgia syndrome have claimed benefits from the use of these supplements. The aim of this study was to determine if these reports could be substantiated in a pilot clinical trial. Patient questioning had determined that poor quality of life was a major factor in the condition and a quality-of-life questionnaire was used to measure potential benefit. Subjects were given oral doses of 200 mg coenzyme Q10 and 200 mg Ginkgo biloba extract daily for 84 days. Quality of life was measured, using the well-validated Dartmouth Primary Care Cooperative Information Project/World Organization of Family Doctors (COOP/WONCA) questionnaire that measures seven different subjective responses, at 0-, 4-, 8-, and 12-week intervals. The subjects were asked for an overall self-rating at the end of the study. A progressive improvement in the quality-of-life scores was observed over the study period and at the end, the scores showed a significant difference from those at the start. This was matched by an improvement in self-rating with 64% claiming to be better and only 9% claiming to feel worse. Adverse effects were minor. A controlled study is now planned.

17.Results of combined treatment for vestibular receptor impairment with physical therapy and Ginkgo biloba extract (Egb 761):

Otolaryngol Pol. 2002;56(1):83-8.PMID: 12053674
Vestibular receptor impairment causes symptoms called vestibular organ peripheral lesion syndrome. Subjective and objective symptoms of vestibular lesion diminish gradually in the process of vestibular compensation. Stimulating a patient to action is a basic factor that influences on the compensation process. The aim of our studies was an evaluation of treatment results in patients with vertigo of peripheral origin with the use of gingko biloba extract together with kinezytherapy. Ginkgo biloba extract shows vasoactive, rheologic, metabolic and neural effects. We have examined 45 persons aged between 35 and 48 years (38 on average, 35 female, 13 male) with clinical symptoms of peripheral vestibular lesion. In each case we performed as follows: ORL physical examination, pure tone audiometry, suprathreshold audiometry, electronystagmography (eyes open and closed nystagmus, cervical tests, caloric tests according to Hallpike), static and dynamic posturography. In all of the cases vestibular rehabilitation originally programmed in our Clinic was applied. N 23 cases (17 female and 6 male) chosen at random, kinezytherapy together with gingko biloba in tablet was applied: 2 tablets twice a day for 3 months. Control examination were performed on 30, 60 and 90 days of treatment. Treatment results evaluation was based on anamnesis, electronystagmography, static and dynamic posturography. CONCLUSIONS: 1. In almost all of the cases with peripheral lesion of vestibular organ, after 30 days of application of gingko biloba extract together with kinezytherapy and without gingko biloba there was vestibular compensation confirmed in electronystagmography but there were disturbances in static and dynamic posturography. 2. Control examination in the course of treatment revealed gradual improvement in vestibular tests in both group (with and without biloba extract). But in patients treated with gingko biloba extract the improvement was more clear and faster an dynamic posturography. It implies central effect of gingko biloba extract that allows to gain full vestibular compensation sooner.

18.The use of Ginkgo biloba in Raynaud's disease: a double-blind placebo-controlled trial.:

Vasc Med. 2002;7(4):265-7.PMID: 12710841
Raynaud's phenomenon (RP) is a common and painful condition characterized by episodic digital ischaemia produced by emotion and cold. Treatment of RP is notoriously difficult because of the high incidence of side effects. The aim of our study was to investigate the clinical efficacy of a standardized Ginkgo biloba extract (Seredrin) in the treatment of RP in patients with no apparent, associated condition such as systemic sclerosis. A two-week assessment period was done during which patients were asked to record frequency, severity and duration of attacks in diaries. Subjects were then randomized independently of the study centre to receive either active or placebo treatment for 10 weeks, during which time the same data were recorded in their diaries. Patients were seen after two and four weeks of treatment and at the end of the 10-week treatment phase. Blood samples pre- and post-treatment were taken for haemorrheology. Only in the number of attacks per day was there a significant effect of treatment over placebo. The number of attacks per week prior to treatment with Seredrin was 13.2 +/- 16.5 reducing to 5.8 +/- 8.3, a reduction of 56%, whereas placebo reduced the number by only 27% (p < or = 0.00001). There were no significant differences in haamorrheology between the two groups. Ginkgo biloba phytosome may be effective in reducing the number of Raynaud's attacks per week in patients suffering from Raynaud's disease.

20.Drug treatment of intermittent claudication.:

Drugs. 2004;64(15):1657-70.PMID: 15257627
The US FDA has approved two drugs for the management of intermittent claudication: pentoxifylline and cilostazol. The mechanism of action that provides symptom relief with pentoxifylline is poorly understood but is thought to involve red blood cell deformability as well as a reduction in fibrinogen concentration, platelet adhesiveness and whole blood viscosity. The recommended dose of pentoxifylline is 400 mg three times daily with meals. Cilostazol is a potent, reversible, phosphodiesterase III inhibitor. The inhibition of phosphodiesterase allows for the increased availability of cyclic adenosine monophosphate (cAMP). cAMP mediates many agonist-induced platelet inhibitory, vasodilatory and vascular antiproliferative responses. Cilostazol, at a dose of 100 mg twice daily, is recommended to be taken 30 minutes before or 2 hours after breakfast and dinner. In addition to pentoxifylline and cilostazol, clinical trials indicate many other drugs may relieve the symptoms of intermittent claudication. Ginkgo biloba, available as an over-the-counter extract, provides symptom relief comparable to pentoxifylline. Two European agents, naftidrofuryl and buflomedil, also have efficacy that is reported to be similar to pentoxifylline. Policosanol is a mixture of fatty alcohols derived from honeybee wax which, according to very limited data, reduces symptoms of claudication. Amino acids, certain peptides and prostaglandins may have a therapeutic role. Finally, novel approaches including angiogenesis mediated by growth factors, are currently under investigation.

21.Effects of Ginkgo biloba on exhaled nasal nitric oxide during normobaric hypoxia in humans.:

High Alt Med Biol. 2004 Winter;5(4):445-9.PMID: 15671634
Ginkgo biloba, an extract of the ginkgo tree, may prevent or lessen symptoms of acute mountain sickness in humans. The mechanism of this effect is poorly understood. One hypothesis is that ginkgo alters nitric oxide (NO) metabolism, possibly by scavenging NO or altering nitric oxide synthase expression and thereby lessening the vasodilatory effects of NO. To date, an effect of Ginkgo biloba on NO metabolism has not been demonstrated in humans. We measured exhaled nasal NO output in humans (n = 9) during normoxia and then during acute normobaric hypoxia (goal oxyhemoglobin saturation 75% to 85%) before and after administration of a standardized extract of Ginkgo biloba (120 mg twice daily for 5 days). Oxygen saturation, heart rate, and minute ventilation were similar before and after Ginkgo biloba administration. Exhaled nasal NO output was increased during normoxia following ginkgo (p < 0.02) and reduced during normobaric hypoxia both before (p < 0.02) and following (p < 0.003) ginkgo. Exhaled nasal NO output during normobaric hypoxia was lowest following ginkgo (p < 0.003). We conclude that Ginkgo biloba increases exhaled nasal NO output during normoxia and enhances reduced exhaled nasal NO output during normobaric hypoxia. Our results suggest that Ginkgo biloba may act to reduce AMS through an effect on NO metabolism.

22.Ginkgo biloba and acetazolamide prophylaxis for acute mountain sickness: a randomized, placebo-controlled trial.:

Arch Intern Med. 2005 Feb 14;165(3):296-301.PMID: 15710792
BACKGROUND: Acute mountain sickness (AMS) commonly occurs when unacclimatized individuals ascend to altitudes above 2000 m. Acetazolamide and Ginkgo biloba have both been recommended for AMS prophylaxis; however, there is conflicting evidence regarding the efficacy of Ginkgo biloba use. We performed a randomized, placebo-controlled trial of acetazolamide vs Ginkgo biloba for AMS prophylaxis.METHODS: We randomized unacclimatized adults to receive acetazolamide, Ginkgo biloba, or placebo in double-blind fashion and took them to an elevation of 3800 m for 24 hours. We graded AMS symptoms using the Lake Louise Acute Mountain Sickness Scoring System (LLS) and compared the incidence of AMS (defined as LLS score > or =3 and headache).RESULTS: Fifty-seven subjects completed the trial (20 received acetazolamide; 17, Ginkgo biloba, and 20, placebo). The LLS scores were significantly different between groups; the median score of the acetazolamide group was significantly lower than that of the placebo group (P=.01; effect size, 2; and 95% confidence interval [CI], 0 to 3), unlike that of the Ginkgo biloba group (P=.89; effect size, 0; and 95% CI, -2 to 2). Acute mountain sickness occurred less frequently in the acetazolamide group than in the placebo group (effect size, 30%; 95% CI, 61% to -15%), and the frequency of occurrence was similar between the Ginkgo biloba group and the placebo group (effect size, -5%; 95% CI, -37% to 28%).CONCLUSIONS: In this study, prophylactic acetazolamide therapy decreased the symptoms of AMS and trended toward reducing its incidence. We found no evidence of similar efficacy for Ginkgo biloba.

24.Stevens-Johnson syndrome/toxic epidermal necrolysis treated with intravenous immunoglobulins:

Actas Dermosifiliogr. 2005 Nov;96(9):589-92.PMID: 16476303
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are part of the same disease spectrum, but are differentiated by the degree of skin detachment. In TEN, more than 30 % of the body's surface area is affected; thus, it is a serious process, whose frequency is estimated at 1.2-6 cases per million population/year. We describe the case of a 75-year-old male who suffered from SJS which evolved into TEN, probably because of the ingestion of ginkgo biloba extract. He was treated with intravenous immunoglobulins (Ig IV) at a dose of 0.5 g/kg/day for five consecutive days, with favorable progress and no significant side effects. It is evident that isolated cases do not justify the systematic use of this treatment, but they may help build up experience.

25.Reduction of behavioural disturbances in elderly dogs supplemented with a standardised Ginkgo leaf extract.:

Schweiz Arch Tierheilkd. 2006 May;148(5):257-63.PMID: 16739899
In this open clinical trial conducted in 10 veterinary practices, Ginkgo leaf extract was administered as a dietary supplement to 42 elderly dogs (mean age 11.4 years) at a daily dose of 40 mg/ 10 kg body weight for 8 weeks. The "severity of the geriatric condition" in dogs with a history of geriatric behavioural disturbances (mean duration 12 months), was significantly reduced after 8 weeks of treatment (P = 0.0002). The positive effect was already apparent after 4 weeks. Thirty-six % of the dogs were completely free of clinical signs at study end. Overall efficacy of treatment as judged by the investigator was good or very good in 79% of the dogs. Five of six clinical sign scores (disorientation, sleep/activity changes, behavioural changes, general behaviour and general physical condition/vitality) also showed a significant decrease over the treatment period. In conclusion, these findings provide promising results that could increase the quality of life in the elderly dog and, as a consequence, that of the pet owner. The Ginkgo leaf extract appears to be an efficacious agent that provides a safe dietary supplement for the elderly dog with age-related behavioural disturbances.

26.Effects of Ginkgo biloba administered after spatial learning on water maze and radial arm maze performance in young adult rats.:

Pharmacol Biochem Behav. 2006 May;84(1):17-25. Epub 2006 Jun 5.PMID: 16740301
Ginkgo biloba is reported to improve learning and memory in animals. However, many studies do not directly test the effects of Ginkgo on memory because the drug is administered during the learning phase of the experiments. In this study, we examined the effect of 10 mg/kg, 20 mg/kg, or 40 mg/kg G. biloba extract on spatial memory by administering the drug in the interval between training and testing. Rats were tested for long-term reference memory retention in the radial arm maze and in the Morris water maze during daily probe trials in which the hidden platform was removed. G. biloba had no effect on reference memory in either the water maze or radial arm maze. To test short-term working spatial memory using the radial arm maze, animals were removed after receiving the reward from 4 of the 8 arms and were returned to complete the maze 2 h later. While Ginkgo had no effect on working memory, over time animals exposed to Ginkgo learned task better than control animals. Thus, Ginkgo appears to enhance neither short-term working memory nor long-term reference memory, but it may promote learning of spatial information.

27.Ginkgo biloba decreases acute mountain sickness in people ascending to high altitude at Ollagüe (3696 m) in northern Chile.:

Wilderness Environ Med. 2007 Winter;18(4):251-7.PMID: 18076292
OBJECTIVE: To determine the prophylactic effect of Ginkgo biloba (doses 80 mg/12 h, 24 h before high-altitude ascension and with continued treatment) in preventing acute mountain sickness (AMS) at 3696 m in participants without high-altitude experience.METHODS: Thirty-six participants who reside at sea level were transported to an altitude of 3696 m (Ollagüe). The participants were divided into 3 groups and received G biloba (n=12) 80 mg/12 h, acetazolamide (n=12) 250 mg/12 h, or placebo (n=12) 24 hours before ascending and during their 3-day stay at high altitude. The Lake Louise Questionnaire constituted the primary outcome measurement at sea level and at 3696 m. A Lake Louise Self-Report Score greater than 3 was indicative of AMS. Oxygen saturation, heart rate, and arterial pressure were taken with each evaluation for AMS.RESULTS: A significant reduction in AMS was observed in the group that received G biloba (0%, P<.05) comparison with the groups receiving acetazolamide (36%, P<.05) or placebo (54%). No difference was observed in arterial oxygen saturation in the G biloba (92+/-2) vs the acetazolamide (89+/-2) groups. However, a marked increased saturation in arterial oxygen was seen in comparison with the placebo group (84+/-3, P<.05). No statistically significant differences were observed in mean arterial pressure or heart rate.CONCLUSIONS: This study provides evidence supporting the use of G biloba in the prevention of AMS, demonstrating that 24 hours of pretreatment with G biloba and subsequent maintenance during exposure to high altitude are sufficient to reduce the incidence of AMS in participants with no previous high-altitude experience

28.Ginkgo biloba for prevention of acute mountain sickness: does it work?:

High Alt Med Biol. 2009 Spring;10(1):33-43.PMID: 19278351
Tissot van Patot, Martha, Linda E. Keyes, Guy Leadbetter III, and Peter H. Hackett. Ginkgo biloba for the prevention of acute mountain sickness: does it work? High Alt. Med. Biol. 10:00-00, 2009.-We review the current literature regarding the prophylactic use of Ginkgo biloba extract (GBE) in acute mountain sickness (AMS). We compare studies with regard to GBE dose, composition, study design, altitude reached, ascent rate, exercise, and risk of AMS. We then review what is known about the active components of GBE and their biological effects and apply this knowledge to interpret the results of AMS prevention trials. Overall, the literature suggests that due to the complexity of GBE the standardization of the product is inadequate, which likely explains the disparate clinical results. The variability in commercially available GBE products makes it impossible to determine whether GBE is truly effective for preventing or ameliorating AMS. However, investigating the roles of specific active components of GBE in the prevention of AMS could yield rewards both clinically and in our understanding of the pathophysiology of AMS.

29.Ginkgo biloba does--and does not--prevent acute mountain sickness.:

Wilderness Environ Med. 2009 Spring;20(1):66-71.PMID: 19364166
OBJECTIVE: To determine the efficacy of 2 different sources of Ginkgo biloba extract (GBE) in reducing the incidence and severity of acute mountain sickness (AMS) following rapid ascent to high altitude.METHODS: Two randomized, double-blind, placebo-controlled cohort studies were conducted in which participants were treated with GBE (240 mg x d(-1)) or placebo prior to and including the day of ascent from 1600 m to 4300 m (ascent in 2 hours by car). Acute mountain sickness was diagnosed if the Environmental Symptom Questionnaire III acute mountain sickness-cerebral (AMS-C) score was > or =0.7 and the Lake Louise Symptom (LLS) score was > or =3 and the participant reported a headache. Symptom severity was also determined by these scores.RESULTS: Results were conflicting: Ginkgo biloba reduced the incidence and severity of AMS compared to placebo in the first but not the second study. In the first study, GBE reduced AMS incidence (7/21) vs placebo (13/19) (P = .027, number needed to treat = 3), and it also reduced severity (AMS-C = 0.77 +/- 0.26 vs 1.59 +/- 0.27, P = .029). In the second study, GBE did not reduce incidence or severity of AMS (GBE 4/15 vs placebo 10/22, P = .247; AMS-C = 0.48 +/- 0.13 vs 0.58 +/- 0.11, P = .272). The primary difference between the 2 studies was the source of GBE.CONCLUSIONS: The source and composition of GBE products may determine the effectiveness of GBE for prophylaxis of AMS.

30.Demonstration of the efficacy of ginkgo biloba special extract EGb 761 on intermittent claudication--a placebo-controlled, double-blind multicenter trial.:

Vasa. 1998 May;27(2):106-10.PMID: 9612115
BACKGROUND: A multicentric, randomized, placebo-controlled double-blind study on ginkgo biloba special extract EGb 761 (Tebonin forte) in patients suffering from peripheral occlusive arterial disease (POAD) in Fontaine stage II b was carried out in order to prove its clinical efficacy in this indication according to guidelines of European Community authorities and the German Angiological Society and to confirm the results of former clinical studies with EGb 761.PATIENTS AND METHODS: In total, 111 patients with angiographically proven POAD in Fontaine stage II b and intermittent claudication (pain-free walking distance < 150 m on the treadmill) were recruited in 5 centers and treated with either EGb 761 or placebo at a daily dose of 3 times 1 film-coated tablet over a duration of 24 weeks following a 2-week placebo run-in period. The primary response variable was the difference of the pain-free walking distance between the start of treatment and after 8, 16 and 24 weeks as measured on the treadmill (walking speed 3 km/h and slope of 12%) under standardized conditions.RESULTS: At the start of the treatment period, the mean pain-free walking distances were very similar with 108.5 m in the EGb 761 group and 105.2 m in the placebo group. At the end of the treatment period these values increased to 153.2 m and 126.6 m, respectively. The group differences were statistically significant at all three control visits with p = 0.017, p = 0.007, and p = 0.016. The differences for the maximum walking distance and the relative increases of the pain-free walking distance and the maximum distance were also significantly higher in the EGb 761 group with p-values < 0.05 each. In both groups Doppler indices remained nearly unchanged during therapy. The subjective assessment of the patients demonstrated an amelioration of complaints in both groups. Tolerability was very good with no adverse events under EGb 761 and one case of heartburn and gastric pain in the placebo group.CONCLUSIONS: It can be concluded from the results of this study that treatment with EGb 761 in POAD patients with Fontaine stage II b is very safe and causes a significant and therapeutically relevant prolongation of the patients' walking distance.

U-Ginkgo Biloba:Ear,Acoustic system/Sound damage,Eyes Benefit,Nose Research:

1.Multicenter randomized double-blind drug vs. placebo study of the treatment of tinnitus with Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1562-4.PMID: 2947100
This important multicenter study of 103 tinnitus out-patients during a 13-month treatment period was carried out by ten E.N.T. specialists, using the double blind, drug versus placebo method. The results were conclusive as regards the effectiveness of Ginkgo biloba extract and made it possible to determine the prognostic value of different parameters. Of special importance among these parameters were site and periodicity of the disease. However, the Ginkgo biloba extract treatment improved the condition of all the tinnitus patients, irrespective of the prognostic factor.

2.Effect of Gingko biloba extract (EGb 761) on chloroquine induced retinal alterations.:

Lens Eye Toxic Res. 1992;9(3-4):521-8.PMID: 1301800
Electroretinography was used to investigate the preventive action of Ginkgo biloba extract (EGb 761) in experimental chloroquine-induced retinopathy in rats. EGb 761 contains flavones and anthocyanosides known for their oxygenated radical scavenging properties. Chronic administration of chloroquine (20 days) caused an overall lengthening of the duration of the ERG b-wave, together with delayed peaking. These anomalies became more marked with increased duration of treatment. In rats treated simultaneously with chloroquine and EGb 761 no such modification of the electroretinogram (ERG) was observed. These results suggest that retinal toxicity may be related to a localized inflammation releasing oxygenated free radicals and/or PAF. EGb 761 may thus afford a useful preventive treatment for chloroquine-induced retinopathy, and generally for xenobiotic retinotoxicities.

3.Ginkgo extract EGb 761 (tenobin)/HAES versus naftidrofuryl (Dusodril)/HAES. A randomized study of therapy of sudden deafness:

Laryngorhinootologie. 1994 Mar;73(3):149-52.PMID: 7513516
80 patients with idiopathic sudden hearing loss existing no longer than 10 days were included in a randomised reference-controlled study. The therapeutic value of Ginkgo EGb 761 (Tebonin) + HAES was compared to that of Naftidrofuryl (Dusodril)+HAES. The main mechanisms of action of EGb 761 are a vasoregulating activity (increased blood flow), the platelet activating factor antagonism and a prevention of membrane damage caused by free radicals. Naftidrofuryl has antiserotonergic and therefore vasodilatory properties. The statistical analysis of the audiometric data was performed in measuring the relative hearing gain as described by Eibach 1979. After one week of observation, 40% of the patients in each group showed a complete remission of hearing loss. This was also observed by other authors who had compared other drugs. Therefore, in these cases, it is most likely that spontaneous recovery is the most important factor. After two and three weeks of observation, measuring the relative hearing gain, there was a significant borderline benefit of EGb 761 (p = 0.06) without any side effects. Some patients of the reference group developed side effects such as orthostatic dysregulation or headache or sleep disturbances. Minimising side effects should be one of the most important goals in therapy of sudden hearing loss until the efficiency of infusion therapy is proved.

4.Hearing disorders after Bungee jumping?:

Laryngorhinootologie. 1994 Mar;73(3):146-8.PMID: 8172635
Acceleration forces in bungee jumping acting on the head are different in nature and extent from those in merry-go-round, looping and scooter rides. They act mainly in the vertical plane, horizontal accelerations may develop only during uncontrollable vibrations in different directions after slowing down. According to our present knowledge the risks for injuries of the cervical spine and functional disorders of the inner ear in bungee jumping are lower than in merry-go-round, looping and scooter rides. They seem to be enhanced, however, in individuals suffering from diseases of the cervical spine and disorders of the heart and the blood circulation.

5.Ginkgo biloba extract for the treatment of tinnitus.:

Audiology. 1994 Mar-Apr;33(2):85-92.PMID: 8179518
Previous studies have shown contradictory results of Ginkgo biloba extract (GBE) treatment of tinnitus. The present study was divided into two parts: first an open part, without placebo control (n = 80), followed by a double-blind placebo-controlled study (n = 20). The patients included in the open study were patients who had been referred to the Department of Audiology, Sahlgren's Hospital, G?teborg, Sweden, due to persistent severe tinnitus. Patients reporting a positive effect on tinnitus in the open study were included in the double-blind placebo-controlled study (20 out of 21 patients participated). 7 patients preferred GBE to placebo, 7 placebo to GBE and 6 patients had no preference. Statistical group analysis gives no support to the hypothesis that GBE has any effect on tinnitus, although it is possible that GBE has an effect on some patients due to several reasons, e.g. the diverse etiology of tinnitus. Since there is no objective method to measure the symptom, the search for an effective drug can only be made on an individual basis.

6.Attenuation of salicylate-induced tinnitus by Ginkgo biloba extract in rats.:

Audiol Neurootol. 1997 Jul-Aug;2(4):197-212.PMID: 9390833
The effects of an extract from Ginkgo biloba, EGb 761, on tinnitus were tested using an animal model of tinnitus. Daily oral administration of EGb 761 in doses from 10 to 100 mg/ kg/day began 2 weeks before behavioral procedures and continued until the end of the experiment. Tinnitus was induced by daily administration of 321 mg/kg sodium salicylate s.c. (corresponding to 275 mg/kg/day of salicylate acid) in fourteen groups of pigmented rats, 6 animals/group. The results from salicylate- and EGb-761-treated animals were compared to control groups receiving either salicylate, saline, or EGb 761 only in doses of 100 mg/kg. Administration of EGb 761 resulted in a statistically significant decrease of the behavioral manifestation of tinnitus for doses of 25, 50 and 100 mg/kg/ day.

7.Effects of Ginkgo biloba extract on the cochlear damage induced by local gentamicin installation in guinea pigs.:

J Korean Med Sci. 1998 Oct;13(5):525-8.PMID: 9811183
Investigations evaluating the protective effect of Ginkgo biloba extract (EGb) on gentamicin (GM) ototoxicity were undertaken. Guinea pigs treated with 5 mg/kg gentamicin sulfate on the round window niche (RWN) showed acute changes on electrocochleogram and hair cell or microvilli damage on scanning electron microscopy (SEM). There was accumulation of GM in the whole cochlea, especially in the organ of Corti, stria vascularis, and type III fibrocyte on immunohistochemical study. However, the guinea pigs pretreated with local or systemic EGb revealed no significant changes by local GM installation. From these results, we concluded that EGb has a protective effect on the development of GM ototoxicity in the cochlea.

8.The effect of blood flow promoting drugs on cochlear blood flow, perilymphatic pO(2) and auditory function in the normal and noise-damaged hypoxic and ischemic guinea pig inner ear.:

Hear Res. 2000 Mar;141(1-2):199-219.PMID: 10713508
The effect of blood flow promoting drugs, such as hydroxyethyl starch (HES) either of low or high molecular weight (HES 70, HES 200), pentoxifylline, ginkgo biloba, naftidrofuryl and betahistine, and various combinations of the drugs was studied in unexposed and noise-exposed (broad-band noise, bandwidth 1-12 kHz, 106 dB SPL, 30 min) guinea pigs. The results were compared without therapy and placebo (isotonic saline, NaCl). The cochlear blood flow (CoBF) and the partial pressure of oxygen in the perilymph (PL-pO(2)) were continuously and simultaneously recorded over a period of 210 min. In addition, cochlear microphonics (CMs), compound action potentials of the auditory nerve (CAPs) and auditory brain stem responses (ABRs) were registered. Noise-induced hearing loss (NIHL) paralleled a decrease of PL-pO(2). Both were found to occur before evidence of reduced CoBF. PL-pO(2) and CoBF declined progressively post-exposure, while CMs, CAPs and ABRs showed no further deterioration or signs of recovery up to 180 min after cessation of noise. Treatment started 60 min post-exposure, respectively after 90 min, without manipulation in unexposed animals, and was then studied for a further 120 min. In unexposed animals, CoBF increased significantly during infusion of HES 70, HES 200, pentoxifylline and betahistine. NaCl, ginkgo biloba and naftidrofuryl did not alter CoBF. PL-pO(2) decreased significantly during infusion of all administered drugs and combinations, except for NaCl. CMs, CAPs and ABRs remained constant, with the exception of increased ABRs after infusion of HES 70 and HES 200. In noise-exposed animals, a sustained therapeutic effect on cochlear ischemia was achieved only by HES 200 and pentoxifylline. HES 70, betahistine and ginkgo biloba compensated cochlear ischemia only during infusion; however, 30-60 min after termination of therapy, no significant difference of values for CoBF was observed compared to the untreated noise-exposed groups. NaCl and naftidrofuryl showed no effect on CoBF. None of the applied drugs had a sustained compensatory effect on cochlear hypoxia. CMs, CAPs and ABRs improved significantly after HES 70, HES 200 and betahistine, resulting in partial recovery of CMs, and partial (betahistine) or even full (HES 70 and HES 200) recovery of CAPs and ABRs. In contrast, NaCl, pentoxifylline, ginkgo biloba and naftidrofuryl had no therapeutic effect on NIHL.

9.Potential role for Ginkgo biloba extract in the treatment of glaucoma.:

Med Hypotheses. 2000 Feb;54(2):221-35.PMID: 10790757
Glaucoma is becoming recognized as a condition for which not only elevated intraocular pressure, but also non-pressure-dependent risk factors are responsible. New avenues of treatment into which investigations are being initiated include agents which could possibly improve blood flow to the eye and neuroprotective drugs. Only calcium channel blockers are presently available for such treatment in glaucoma, and these have not been widely adopted, in contrast to clinical trials involving a number of neuroprotectants in other neurologic disorders. Ginkgo biloba extract is freely available and has several biological actions which combine to make it a potentially important agent in the treatment of glaucoma: improvement of central and peripheral blood flow, reduction of vasospasm, reduction of serum viscosity, antioxidant activity, platelet activating factor inhibitory activity, inhibition of apoptosis, and inhibition of excitotoxicity. The effect of Ginkgo biloba extract as a potential antiglaucoma therapy deserves intensive scrutiny.

10.Ginkgo biloba extract for age-related macular degeneration.:

Cochrane Database Syst Rev. 2000;(2):CD001775.PMID: 10796819
BACKGROUND: Ginkgo is used in the treatment of peripheral vascular disease and 'cerebral insufficiency'. It is thought to have several potential mechanisms of action including increased blood flow, platelet activating factor antagonism and prevention of membrane damage caused by free radicals. Vascular factors and oxidative damage are thought to be two potential mechanisms in the pathology of age-related macular degeneration.OBJECTIVES: The objective of this review is to determine the effect of Ginkgo biloba extract on the progression of age-related macular degeneration.SEARCH STRATEGY: The Cochrane Eyes and Vision Group specialised register, the Cochrane Controlled Trials Register - Central, MEDLINE, reference lists of identified trial reports, and the Science Citation Index were searched. The reviewer contacted Investigators of included studies for additional information. The most recent searches were performed in February 2000.SELECTION CRITERIA: All randomised trials where Ginkgo biloba extract had been compared to control in people with age-related macular degeneration were included.DATA COLLECTION AND ANALYSIS: The reviewer extracted data using a standardised form. The data were verified with the trial investigator.MAIN RESULTS: One published trial was identified. Although a beneficial effect was observed, as only 20 people were enrolled in the trial, and assessment of outcome was not masked, its results must be considered equivocal. Adverse effects and quality of life for people with age-related macular degeneration have not been addressed. One unpublished trial is awaiting translation and assessment.REVIEWER'S CONCLUSIONS: The question as to whether people with age-related macular degeneration should take Ginkgo biloba extract to prevent progression of the disease has not been answered by research to date.

11.Effectiveness of Ginkgo biloba in treating tinnitus: double blind, placebo controlled trial.:

BMJ. 2001 Jan 13;322(7278):73.PMID: 11154618
OBJECTIVE: To determine whether Ginkgo biloba is effective in treating tinnitus.DESIGN: Double blind, placebo controlled trial using postal questionnaires.PARTICIPANTS: 1121 healthy people aged between 18 and 70 years with tinnitus that was comparatively stable; 978 participants were matched (489 pairs). Intervention: 12 weeks' treatment with either 50 mg Ginkgo biloba extract LI 1370 three times daily or placebo.MAIN OUTCOME MEASURES: Participants' assessment of tinnitus before, during, and after treatment. Questionnaires included items assessing perception of how loud and how troublesome tinnitus was. Changes in loudness were rated on a six point scale. Changes in how troublesome were rated on a five point scale.RESULTS: There were no significant differences in primary or secondary outcome measures between the groups. 34 of 360 participants receiving active treatment reported that their tinnitus was less troublesome after 12 weeks of treatment compared with 35 of 360 participants who took placebo.CONCLUSIONS: 50 mg Ginkgo biloba extract LI 1370 given 3 times daily for 12 weeks is no more effective than placebo in treating tinnitus.

12.Tinnitus program at Brasília University Medical School.:

Int Tinnitus J. 1999;5(2):141-3.PMID: 10753434
Over the last 6 months, all patients seen at the otologic clinic of Brasília University Medical School answered a questionnaire designed to identify and describe the symptom of tinnitus. A total of 500 patients reported and described this symptom. They underwent physical examination, laboratory tests and audiological evaluation. In their order of frequency, presbycusis, chronic otitis media, otosclerosis, acoustic trauma, Menière's disease, ototoxicity, and vestibular schwannoma were found. Tinnitus was rated as minor in 81%, moderate in 18%, and severely disabling in 1%. Those who requested treatment for tinnitus were treated medically. Central vasodilators, vestibular suppressants, calcium channel blockers, anticholinergic drugs, anticonvulsant drugs, and gingko biloba were used with variable results. Tinnitus maskers were not used, but hearing prostheses were fitted when indicated. Treatment failed in the 1% with severe disabling tinnitus, and they were entered in a double-blind, randomized protocol for intratympanic dexamethasone injection. Under topical anesthesia, 0.2 ml of a 4-mg/ml dexamethasone solution (0.8 mg per injection) or 0.2 ml of normal saline was injected just posterior to the umbo. Patients remained supine for 20 minutes with the injected ear up and received four injections at 1-week intervals. Preliminary results are reported. Tinnitus is a very frequent symptom among our otologic patients, but most of them would not mention the symptom spontaneously, probably because for 81% it was mild. Curiously, the 5% of the severely disabling type tend to exhibit no clear cause, whereas the mild and moderate cases usually have an identifiable etiology.

13.Ginkgo special extract EGb 761 in tinnitus therapy. An overview of results of completed clinical trials:

Fortschr Med Orig. 2001 Jan 11;118(4):157-64.PMID: 11217680
In a systematic search of the literature 19 clinical trials investigating the effects of tinnitus treatment with Ginkgo biloba special extract EGb 761 were identified and evaluated. The results of eight controlled studies on tinnitus due to cerebrovascular insufficiency or labyrinthine disorders of varying genesis for the most part show a statistically significant superiority of treatment with the Ginkgo biloba special extract EGb 761 as compared with placebo or reference drugs applied of periods of one to three months. Open studies, too, some involving large numbers of patients, revealed appreciable improvements under ginkgo treatment. Therapeutic success was not directly correlated with either the genesis or the duration of tinnitus. However, investigations of prognostic factors revealed that short-standing disorders have a better prognosis, so that better results can be expected from early-onset treatment. The tolerability of Ginkgo biloba special extract EGb 761 was excellent, and in this respect the controlled clinical trials revealed little difference between drug-treated and control groups.

14.Effect of treatment with Ginkgo biloba extract EGb 761 (oral) on unilateral idiopathic sudden hearing loss in a prospective randomized double-blind study of 106 outpatients.:

Eur Arch Otorhinolaryngol. 2001 Jul;258(5):213-9.PMID: 11548897
OBJECTIVE: Test of dose-response relationship for Ginkgo biloba extract EGb 761 (oral) in outpatients with acute idiopathic sudden sensorineural hearing loss (ISSHL) of at least 15 dB at one frequency within the speech range occurring less than 10 days before study inclusion.DESIGN: Multicentre, randomized, double-blind phase III study comparing dosages of 120 mg twice daily and 12 mg twice daily over 8 weeks. MAIN ENDPOINT: Recovery (in dB) of the auditory threshold from the initial measurement to the value on the last day of treatment, averaged over those frequencies from 0.25, 0.5, 1, 2, and 3 kHz for which the initial hearing loss amounted to 15 dB or more compared to the level on the opposite side.PATIENTS: 106 patients with an average age of 44+/-16 years and with hearing loss at affected frequencies 26 dB +/- 9 dB included between December 1995 and July 1997.RESULTS: Large majorities of both treatment groups recovered completely. In exploratory analyses of the 96 patients included according to the protocol, patients given the higher dose had less risk of not recovering well (< or =10 dB residual hearing loss) (one-sided Fisher test: P = 0.0061), especially if they had no tinnitus (n = 44, P = 0.00702).CONCLUSION: A higher dosage of EGb 761 (oral) appears to speed up and secure the recovery of ISSHL patients, with a good chance that they will recover completely, even with little treatment. This was already observed after one week of treatment. We find it justified to treat patients who have unilateral ISSHL of less than 75 dB and neither tinnitus nor vertigo with 120 mg oral EGb 761 twice daily.

15.Ginkgo biloba extract EGb 761 or pentoxifylline for the treatment of sudden deafness: a randomized, reference-controlled, double-blind study.:

Acta Otolaryngol. 2001 Jul;121(5):579-84.PMID: 11583389
In a randomized, prospective, double-blind study involving 72 patients, the therapeutic efficacy of ginkgo extract EGb 761 (n = 37) was compared to that of pentoxifylline (n = 35) for the treatment of sudden deafness. The two therapeutic schedules were equally well tolerated and showed a statistically significant equivalence in improvement or in return to normal of the auditory thresholds in the two patient groups. Furthermore, no differences were found between the treatment groups with regard to the criteria for a return to normal of speech discrimination and reduction of the tinnitus which arose at the same time as the sudden hearing loss. The patient's subjective assessment of the treatment with regard to improvement in hearing and reduction in tinnitus suggested that Ginkgo biloba extract was more beneficial than pentoxifylline. In summary, it was shown that treatment of sudden deafness with ginkgo special extract EGb 761 was as effective as treatment with pentoxifylline.

16.The efficacy of Ginkgo special extract EGb 761 in patients with tinnitus.:

Int J Clin Pharmacol Ther. 2002 May;40(5):188-97.PMID: 12051570
OBJECTIVE: The objective of the present study in 60 patients with chronic tinnitus aurium was to confirm the efficacy of oral treatment with 2 x 80 mg Ginkgo special extract EGb 761 per day subsequent to 10-day EGb 761 infusion treatment.METHODS: Patients with chronic tinnitus aurium underwent 10 days of in-patient infusion treatment with 200 mg/day EGb 761, after which they were randomized to double-blind, oral out-patient treatment with either 2 x 80 mg/day EGb 761 or placebo, given over a scheduled treatment period of 12 weeks. The primary outcome measure was the change in tinnitus volume in the more severely affected ear during randomized treatment.RESULTS: Fifty-two of 60 patients (89.7%) completed the infusion treatment; complete sets of data were available for 40 (66.7%), 30 (50.0%) and 22 (36.7%) patients after 4, 8 and 12 weeks of randomized treatment, respectively. For the primary outcome measure, significant superiority of EGb 761 over placebo was demonstrated in the intention-to-treat analysis data set after 4, 8 and 12 weeks of out-patient treatment (p < 0.05, 1-tailed), although the absolute treatment group difference was moderate. The results were supported by the secondary outcome measures for efficacy (e.g. decreased hearing loss, improved self-assessment of subjective impairment). During out-patient treatment, there were no attributable adverse events under EGb 761.CONCLUSIONS: A combination of infusion therapy followed by oral administration of Ginkgo special extract EGb 761 appears to be effective and safe in alleviating the symptoms associated with tinnitus aurium.

17.Adaptational behaviour of peripheral and central acoustic responses in guinea pigs under the influence of various fractions of an extract from Gingko biloba (author's transl:

Arzneimittelforschung. 1976;26(3):367-74.
Experimental studies on 114 guinea pigs proved definitely the influence of an extract from Ginkgo biloba batch no. 02 on the acoustic system. Experiments with animals ensured that the adaptation of excitation of the organ of Corti is significantly influenced. This result is shown by registrations of the acoustic nerve potentials in the adapted and nonadapted state. The relation of excitation to adaptation is significantly changed. Under adaptation of excitation an influence on the metabolism of involution is probable. The slow evoked potentials of the acoustic cortex showed no additional influence on the central auditory pathways. With the Ginkgo biloba extract it is probably possible to diminish sound damages caused by white noise. Further experiments on animals are necessary to ensure the application of this pharmaceutical preparation for clinical use.

18.Molecular and cellular assessment of ginkgo biloba extract as a possible ophthalmic drug.:

Exp Eye Res. 2002 Oct;75(4):421-30.PMID: 12387790
We have investigated the biochemical and cell biological basis of the reported beneficiary effects of the leaf extracts of the plant Ginkgo biloba, which has been used as a possible ophthalmic drug. The antioxidant, antimicrobial, anti-apoptotic and cytoprotective properties of the standardized extract called EGb761 were assayed. Chemical stresses were induced in cells using alloxan or dexamethasone, and the effect of EGb761 on them was studied using the MTT and TUNEL assays. Its ability to modulate the activities of some antioxidant enzymes was tested in vitro. In addition, cataract was induced in rats through selenite injection, and the effect of EGb761 administration on the progression of cataract was studied using slit lamp examination. Ginkgo biloba was found to be an excellent antioxidant. It readily scavenges reactive oxygen and nitrogen radicals and inhibits oxidative modifications that occur to proteins in vitro. It enters intact cells and protects them from alloxan-mediated and light-mediated stress, and the nuclear DNA from single strand breaks. It also effectively inhibits chemically induced apoptosis. It does not modulate the activities of endogenous antioxidant enzymes, nor does it have any significant antimicrobial activity. Unlike some other plant extracts, it is not phototoxic. In experiments wherein selenite cataract was induced in laboratory rats, treatment with the extract significantly retards the progression of lens opacification in vivo. Ginkgo biloba's inherent antioxidant, antiapoptotic and cytoprotective action and potential anticataract ability appear to be some of the factors responsible for its beneficial effects.

19.Effect of Ginkgo biloba extract on preexisting visual field damage in normal tension glaucoma.:

Ophthalmology. 2003 Feb;110(2):359-62; discussion 362-4.PMID: 12578781
OBJECTIVE: To evaluate the effect of Ginkgo biloba extract (GBE) on preexisting visual field damage in patients with normal tension glaucoma (NTG).DESIGN: Prospective, randomized, placebo-controlled, double-masked cross-over trial.PARTICIPANTS: Twenty-seven patients with bilateral visual field damage resulting from NTG.INTERVENTION: Patients received 40 mg GBE, administered orally, three times daily for 4 weeks, followed by a wash-out period of 8 weeks, then 4 weeks of placebo treatment (identical capsules filled with 40 mg fructose). Other patients underwent the same regimen, but took the placebo first and the GBE last. Visual field tests, performed at baseline and at the end of each phase of the study, were evaluated for changes.MAIN OUTCOME MEASURES: Change in visual field and any ocular or systemic complications.RESULTS: After GBE treatment, a significant improvement in visual fields indices was recorded: mean deviation (MD) at baseline versus MD after GBE treatment, 11.40 +/- 3.27 dB versus 8.78 +/- 2.56 dB (t = 8.86, P = 0.0001, chi-square test); corrected pattern standard deviation (CPSD) at baseline versus CPSD after GBE treatment, 10.93 +/- 2.12 dB versus 8.13 +/- 2.12 dB (t = 9.89, P = 0.0001, chi-square test). No significant changes were found in intraocular pressure, blood pressure, or heart rate after placebo or GBE treatment. Any ocular and systemic side effects were recorded for the duration of the trial.CONCLUSIONS: Ginkgo biloba extract administration appears to improve preexisting visual field damage in some patients with NTG.

20.Gingko biloba (Rökan) therapy in tinnitus patients and measurable interactions between tinnitus and vestibular disturbances:

Int Tinnitus J. 2000;6(1):56-62.PMID: 14689620
Tinnitus is one of the most important symptoms in neurootology after vertigo, nausea, and hearing loss. In most cases, the origin of the tinnitus remains inexplicable. Well-known, however, is that tinnitus may arise in any part of the hearing pathway (i.e., both within the cochlea receptor and in the temporal lobe and projections). Tinnitus also is associated frequently with vertigo, nausea and hearing loss. An age predominance exists, with tinnitus more common among those older than 40 years. From this starting point, a great demand exists today for new ideas and developments in the diagnosis and treatment of tinnitus.

21.The Ginkgo biloba extract (EGb 761) provides a neuroprotective effect on retinal ganglion cells in a rat model of chronic glaucoma.:

Curr Eye Res. 2004 Mar;28(3):153-7.PMID: 14977516
PURPOSE: To investigate the effect of Ginkgo biloba extract (EGb 761) against neurotoxicity of retinal ganglion cells of rats with chronic moderately elevated intraocular pressure (IOP).METHODS: Unilateral chronic moderately elevated IOP was produced in rats by cautery of three episcleral vessels. Secondary degeneration was measured with and without EGb 761 for 5 months. At 5 months, retinal ganglion cells were labeled with a fast blue tracer applied to both superior colliculi. Densities of surviving retinal ganglion cells were estimated by counting fast blue labeled cells in whole mounted retinas.RESULTS: When compared with their contralateral control eyes with normal IOP, in the peripheral retina, retinal ganglion cell loss in eyes with chronic, moderately elevated IOP was 29.8 +/- 1.5% (n=5) at 5 months in untreated animals and 4.6 +/- 4.5% (n=5) at 5 months in treated animals with EGb 761.CONCLUSIONS: Pretreatment and early posttreatment with EGb 761 is an effective neuroprotectant in a rat model of chronic glaucoma.

22.Ginkgo biloba for tinnitus.:

Cochrane Database Syst Rev. 2004;(2):CD003852.PMID: 15106224
BACKGROUND: Tinnitus can be described as the perception of sound in the absence of external acoustic stimulation. At present no specific therapy for tinnitus is acknowledged to be satisfactory in all patients. There are a number of reports in the literature suggesting that Ginkgo biloba may be effective in the management of tinnitus. However, there also appears to be a strong placebo effect in tinnitus management.OBJECTIVES: To assess the effect of Ginkgo biloba in patients who are troubled by tinnitus.SEARCH STRATEGY: The Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Library Issue 4 2003), MEDLINE (1966 - 2003), EMBASE (1974 - 2003), and reference lists of identified publications. Date of the most recent search was December 2003.SELECTION CRITERIA: Adults (18 years and over) complaining of tinnitus. Adults with a primary complaint of cerebral insufficiency where tinnitus forms part of the syndrome.DATA COLLECTION AND ANALYSIS: Both reviewers independently extracted data and assessed trials for quality.MAIN RESULTS: Twelve trials were identified from the search as being relevant to the review. Ten trials were excluded on methodological grounds. No trials of tinnitus in cerebral insufficiency reached a satisfactory standard for inclusion in the review. There was no evidence that Ginkgo biloba was effective for the primary complaint of tinnitus. The incidence of side effects was small.REVIEWERS' CONCLUSIONS: The limited evidence did not demonstrate that Ginkgo biloba was effective for tinnitus which is a primary complaint. There was no reliable evidence to address the question of Ginkgo biloba for tinnitus associated with cerebral insufficiency.

23.Induction and recovery of hepatic drug metabolizing enzymes in rats treated with Ginkgo biloba extract.:

Food Chem Toxicol. 2004 Jun;42(6):953-7.PMID: 15110104
Herb-drug interactions, especially cytochrome P450 (CYP)-mediated interactions, cause an enhancement or attenuation in efficacy of co-administered drugs. In a previous study, we reported that repeated oral ingestion of Ginkgo biloba extract (GBE) markedly induced hepatic drug metabolizing enzymes in rats. In this study, we focused on the recovery of GBE-induced hepatic drug metabolizing enzymes after the discontinuation of GBE in rats. Feeding of a 0.5% GBE diet to rats for 1 week markedly increased liver weight, content of total CYP, activities of 6 CYP subtypes and glutathione S-transferase (GST). The content and activities of CYP enzymes were recovered to almost basal levels within 1 week after the discontinuation of GBE, while the activity of GST gradually decreased and recovered to the control level after 3 weeks. These results indicated that GBE-induced hepatic drug metabolizing enzymes in rats, especially CYPs, were rapidly recovered by discontinuation of GBE in rats even after excess treatment, and suggested that interactions of GBE with drugs could be avoided by discontinuation of GBE.

24.Ginkgo biloba does not benefit patients with tinnitus: a randomized placebo-controlled double-blind trial and meta-analysis of randomized trials.:

Clin Otolaryngol Allied Sci. 2004 Jun;29(3):226-31.PMID: 15142066
The objective was to ascertain if Ginkgo biloba benefits patients with tinnitus. The study design was: 1. Randomized double blind trial of Ginkgo biloba versus placebo; 2. A meta-analysis of randomized placebo controlled double blind trials. Participants included 66 adult patients with tinnitus and six (including our study) randomized placebo controlled double blind trials were meta-analysed. The main outcome measures were the Tinnitus Handicap Inventory (THI), Glasgow Health Status Inventory (GHSI) and average of hearing threshold at 0.5, 1, 2, 4 kHz. In the meta-analysis the proportion of patients gaining benefit and an overall odds ratio were determined. The results showed the mean difference in change of the THI, GHSI and hearing between Ginkgo biloba (n = 31) and placebo group (n = 29) was 2.51 (CI -10.1, 5.1, P = 0.51), 0.58 (CI-4.8, 3.6, P = 0.38) and 0.68 db (CI -4.13, 2.8, P = 0.69). Meta-analysis revealed 21.6% of Ginkgo biloba treated patients (n = 107/552) gained benefit versus 18.4% (n = 87/504) of placebo treated patients with an odds ratio of 1.24 (CI 0.89, 1.71). In conclusion, Ginkgo biloba does not benefit patients with tinnitus.

25.Ginkgo biloba extracts for tinnitus: More hype than hope?:

J Ethnopharmacol. 2005 Aug 22;100(1-2):95-9.PMID: 15998570
The investigation into the effects of Ginkgo biloba extracts on tinnitus has suffered from a dearth of effective animal models as well as systematic clinical trials employing double-blind and placebo-controlled designs. Some clinical trials have yielded positive results, however, these studies are few and have been limited either by design flaws, the small size of the significant effects, or else the results have not been published in peer-reviewed journals and therefore the quality of the research is not assured. By contrast, the two most systematic clinical trials, both double-blind and placebo controlled, and published in respected peer-reviewed journals, have yielded negative results and suggest that Ginkgo biloba extracts are of little more use in the treatment of tinnitus than a placebo. Treatments for tinnitus that do not have therapeutic efficacy not only waste money but can potentially prevent patients from seeking therapy that is efficacious. Furthermore, the unsupervised use of Ginkgo biloba extracts with other medications could lead to adverse side effects which are unnecessary and not justified in terms of therapeutic benefit.

26.Electrophysiological analysis of the effects of ginkgo biloba on visual processing in older healthy adults.:

J Gerontol A Biol Sci Med Sci. 2005 Oct;60(10):1246-51.PMID: 16282555
Several studies have tested the efficacy of ginkgo biloba using compromised visual systems and have found improvement in vision. We measured functional changes in the visual system of older, healthy adults to see if ginkgo extract EGb 761 would increase performance in the normal visual system. Two electrophysiological measures were taken during baseline, placebo, and treatment conditions: visual evoked potentials were used to assess changes in low-level functioning of the visual pathways, and P300 recognition responses were measured to assess higher order processing. No significant effect was found in the lower level visual pathways. However, when using regression analysis across age to assess higher order functioning, an improvement was found. The results suggest that the higher order processing stages, which may be influenced by cognition, decline more rapidly than do lower level processing stages in healthy adults as a function of age, and that the use of ginkgo biloba extract may improve the functioning of this system.

27.Complementary therapy for the treatment of glaucoma: a perspective.:

Ophthalmol Clin North Am. 2005 Dec;18(4):597-609.PMID: 16314222
Although neuroprotective strategies and pharmaceutical agents have been initiated in the treatment of numerous disorders of the central and peripheral nervous systems, including trauma, epilepsy, stroke, Huntington disease, amyotrophic lateral sclerosis,and AIDS dementia, none have yet been applied to the treatment of glaucoma. A prospective, placebo-controlled, multi-institutional trial of memantine is underway. One would not expect the treatment modalities that form the bases of nonpharmaceutical, traditional medical systems to be used to lower IOP. Glaucoma was unknown when these medicinal treatments were developed over the centuries. Their primary use is in improving the cardiovascular and immune systems and in what is now called neuro-protection. Rather than single compounds that target a specific receptor and have demarcated side effects in other systems, plant products are a blend of many compounds and, according to those most versed in them, they achieve a balanced therapy, helping in specific symptomatic complexes while reducing side effects through ameliorating effects in other areas. It is not insignificant that, now that the rain forests are rapidly dwindling, together with their inhabitants and the knowledge of medicinal plants (especially in South America), the pharmaceutical companies are spending large amounts of money in a sudden, almost frantic attempt to gather the knowledge about rainforest plants before all has been completely lost. Proof of effects clinically in a chronic disease such as glaucoma remains largely lacking, and controlled trials are unlikely to be initiated, except perhaps through the National Institutes of Health, because these compounds have been in the public domain for many years. Perhaps those as yet unknown or un-recorded are patentable and perhaps these include drugs known only to small surviving communities of hunter-gatherers, which explains the pharmaceutical interest in these areas. When more accurate and rapid means of assessment of progression of glaucomatous damage than perimetry and optic nerve head photography are eventually developed and trials can be reduced in time, number of subjects, or even the use of nonhuman subjects for the bulk of studies, studies could be done for verification of effect of various compounds and also comparative studies. At the present time, GBE is the best documented of all the complementary medicinal agents and seems to have the greatest potential value. Ginkgo biloba extract has numerous properties that theoretically should be beneficial in treating non-IOP-dependent mechanisms in glaucoma. Its multi-ple beneficial actions, including increased ocular blood flow, antioxidant activity, platelet activating factor inhibitory activity, nitric oxide inhibition, and neuroprotective activity, combine to suggest that GBE could prove to be of major therapeutic value in the treatment of glaucoma.

28.Ginkgo biloba in glaucoma:

Oftalmologia. 2007;51(4):30-3.PMID: 18543670
The two principal directions in the therapy of the primary open angle glaucoma (POAG) are lowering intraocular pressure medication and the surgical way. None of these two therapeutic modalities act on independent pressure risk-factors Thinking in this direction the neuro-protection concept should be in our minds all the time in the treatment of this disorder.

29.Effect of ginkgo biloba and dexamethasone in the treatment of 3-methylindole-induced anosmia mouse model.:

Am J Rhinol. 2008 May-Jun;22(3):292-6.PMID: 18588762
BACKGROUND: Olfactory loss is a challenging disease. Although glucocorticoid is sometimes used for the treatment of anosmia, it has been reported that it potentiated neural damage in the early phase of treatment. This study is designed to identify the effect of ginkgo biloba, an antioxidant that acts as a free radical scavenger, in the treatment of olfactory injury aggravated by dexamethasone.METHODS: Anosmia mouse model was induced by i.p. injection of 3-methylindole (3-MI). Twenty-five mice were divided into one control group without anosmia and four anosmia treatment groups (given treatments of dexamethasone and/or ginkgo biloba). The effects of treatment were evaluated by behavioral test, Western blot, and immunohistochemistry 2 weeks after 3-MI injection.RESULTS: Induction of anosmia was confirmed by behavioral tests. The thickness and cell number of olfactory neuroepithelium were decreased more significantly in the dexamethasone treatment group than in the combination treatment group. The expression of olfactory marker protein (OMP) in olfactory epithelium was more decreased also in the dexamethasone treatment group than in the combination treatment group. The expression of OMP was decreased significantly in the olfactory bulbs of anosmia groups but there were no differences between the anosmia treatment groups.CONCLUSION: Dexamethasone treatment was associated with further deterioration of olfactory injury by 3-MI and it was recovered by combination treatment of dexamethasone and ginkgo biloba. The antioxidant effect of ginkgo biloba might play a role in restoration of olfactory loss and it was effective only when oxidative stress is maximized by dexamethasone.

30.The effect of Ginkgo biloba on the expression of intermediate-early antigen (c-fos) in the experimentally induced anosmic mouse.:

Auris Nasus Larynx. 2009 Jun;36(3):287-91. Epub 2008 Nov 17.PMID: 19010624
OBJECTIVE: Treatment of olfactory dysfunction is very difficult and has limited modality. Treatment with steroids has been used in patients with olfactory dysfunction but the side effects of steroid need to be weighed against its potential benefits. In the present study, the effect of systemic administration of dexamethasone and EGb 761 on damage to olfactory mucosa produced by zinc sulfate was examined. Expression of the immediate-early antigen (IEG), c-fos, in the olfactory bulb and piriform cortex was used to determine the effects of treatment.METHODS: Young adult CD1 mice (6 to 8 weeks old, male) were used. After anosmic mice were made by bilateral intranasal irrigation with 0.2 ml of 5% (0.17 M) zinc sulfate, anosmia was confirmed by a food finding test. Four groups of anosmic mice were studied: a steroid group (steroid injection group, n=12), an EGb group (EGb injection group, n=12), a steroid-EGb group (steroid and EGb injection group, n=12), and a control group (anosmic mice and no Tx. n=12). The olfactory bulb and piriform cortex of four mice in each group were obtained at 1, 2, and 3 weeks after instillation of zinc sulfate by cardiac perfusion, and immunohistochemical staining for c-fos was also performed to evaluate brain activity. In approximately 10 well-defined glomeruli of the olfactory bulb and in one side of the piriform cortex, c-fos (+) cells were counted. Statistical analyses were performed by Kruskal-Wallis one-way analysis of variance (ANOVA) by rank.RESULTS: In all experimental groups, c-fos (+) cells increased in a time-dependent manner. The combination treatment of steroid and EGb was the most effective and the no-treatment group the least effective 1 week later after zinc sulfate irrigation. However, 3 weeks later after zinc sulfate irrigation, there was no statistically significant differences in the number of c-fos positive cells among all 4 groups (3 treatment groups and the control group).CONCLUSION: The combination treatment of EGb and steroid enhanced the regeneration of the olfactory pathway after olfactory mucosal injury by zinc sulfate. Our study suggests that EGb could be an effective treatment option for olfactory dysfunction.

31.Improvement of auditory discrimination learning by Ginkgo biloba extract EGb 761.:

Neurosci Lett. 2009 Oct 9;463(3):219-22. Epub 2009 Aug 4.PMID: 19660527
The effect of oral application of Ginkgo biloba extract EGb 761 on auditory discrimination learning in Mongolian gerbils was investigated using discrimination tasks with three different degrees of difficulty and two protocols for administration starting 2 weeks prior to or at the beginning of training. In comparison to placebo-treated controls we observed significant improvement of learning performance in EGb 761 treated gerbils in discrimination tasks of all degrees of difficulty, from the easiest to the most demanding. EGb 761 has been reported to increase the extracellular concentration of dopamine in prefrontal cortex of rats which plays a major role in the type of discrimination learning used in the present study. We, therefore, suppose that EGb 761 improves discrimination learning through its effect on the dopaminergic system.

32.The association between self-reported glaucoma and ginkgo biloba use.:

J Glaucoma. 2009 Sep;18(7):543-5.PMID: 19745669
PURPOSE: To assess the association between Ginkgo biloba extract (GBE) use and glaucoma.METHODS: Self-reported data on the past 12 months of GBE use and the presence of glaucoma were obtained from the 2002 National Health Interview Survey, a nationally-representative population-based sample. Crude and adjusted associations between GBE use and glaucoma were estimated.RESULTS: Those who reported having glaucoma were 26% less likely to report GBE use; however, this was not statistically significant. After adjustment for potentially confounding demographic and medical characteristics, there was no difference in GBE use among those who did and did not report having glaucoma.CONCLUSIONS: The results of this study fail to support a significant relationship between GBE use over the past 12 months and having glaucoma, though this finding requires replication in a prospective study. Moreover, whether GBE is efficacious in treating glaucoma patients remains an issue for future research.

33.Simvastatin and Ginkgo biloba in the treatment of subacute tinnitus: a retrospective study of 94 patients.:

Am J Otolaryngol. 2011 Jan-Feb;32(1):19-23. Epub 2009 Oct 31.PMID: 20015810
OBJECTIVES: Studies suggest that hypercholesterolemia promotes the development of inner ear disorders such as tinnitus. However, the underlying pathomechanisms are still not clearly defined.METHODS: A retrospective study was performed to assess whether a reduction of serum cholesterol by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors may result in a relief of subacute tinnitus. Remission rates of 58 patients were investigated after 4 months of treatment with simvastatin (40 mg). Results were compared to treatment with Ginkgo biloba (120 mg; n = 36) as control group. Differences between tinnitus score at the day of first treatment and after 4 months were used as main outcome measure.RESULTS: After treatment with simvastatin or G biloba, tinnitus score decreased from 41.3 ± 10.4 to 37.4 ± 17.3 and from 44.7 ± 11.2 to 41.2 ± 8.7, respectively. However, independently of the treatment regimen, differences of tinnitus scores were considered not significant.CONCLUSIONS: After administration of simvastatin over 4 months, this retrospective study has shown no significant efficacy in treatment of subacute tinnitus. For a more conclusive answer, further prospective, double-blind, and placebo-controlled studies with a larger number of patients are needed.

34.The influence on sound damages by an extract of ginkgo biloba (author's transl:

Arch Otorhinolaryngol. 1975 Jul 8;209(3):203-15.
A fraction of Ginkgo biloba, used in experiments with animals ensured significantly the diminution of sound damages caused by white noise or by a pure tone of 4.5 kHz. Higher amplitudes of the acoustic nerve potentials show the protective effect of this fraction of Ginkgo biloba at acute sound damages. It is moreover possible to hold physiologically the adaptation of excitation of the hair cells of the organ of Corti by the fraction of Ginkgo biloba before and after sound damage caused by white noise or during a pure tone of 4.5 kHz. The influence of the fraction of Ginkgo biloba can be seen by a significantly slower recovery of the noise damaged evoked potentials of the acoustic cortex. An efferent protective influence on the neurons of the acoustic cortex is discussed. The fraction of Ginkgo biloba in this form of solution has not been tested for clinical use but it seems to be rich in meaning.

35.Experimental retinopathy of prematurity: angiostatic inhibition by nimodipine, ginkgo-biloba, and dipyridamole, and response to different growth factors.:

Eur J Ophthalmol. 2000 Jan-Mar;10(1):51-9.PMID: 10744206
PURPOSE: To investigate whether commonly used vasodilating drugs ameliorate angiogenesis in experimental retinopathy of prematurity (ROP), and to study the response of these drugs to different growth factors.METHODS: We used a rat and mouse model of oxygen-induced ischemic retinopathy. Animals were treated with nimodipine, gingko-biloba and dipyridamole intraperitoneally starting the day before exposure to room air (day 1). Controls were injected with vehicle solution only. Eyes were processed histopathologically with serial sections and neovascularization was measured by counting the nuclei within the retinal internal limiting membrane, by a masked observer. Retinal and vitreous tissues were assayed by ELISA for VEGF, PDGF and TGFbeta2.RESULTS: Nimodipine significantly inhibited the growth of new vessels in rats. The number of nuclei was 310 +/- 69 in the control group (n:14) and 121 +/- 53 in the treated ones (n:14), (p<0.0005). Similar results were found with ginkgo-biloba extracts: 344 +/- 53 (n:15) in controls, and 136 +/- 29 (n:11) in treated ones (p<0.0005), and with dipyridamole: 303 +/- 69 (n:13) in controls, and 131 +/- 48.5 in treated rats (p<0.0005). Results were similar in mice. 186 +/- 45 (n:7) nuclei counted in controls against 90 +/- 25 (n:6) for dipyridamole treated (p<0.0005); and 81 +/- 21 for ginkgo-biloba treated animals (p<0.0005). A gradual, very significant increase in VEGF values in response to relative hypoxia (room air) contrasted with the significant inhibition noted both with ginkgo-biloba extracts and dipyridamole. TGFbeta2 and PDGF both showed a gradual increase in relative hypoxia at days 2 and 4 of room air (p<0.0005). Treated animals showed marked inhibition of the three growth factors.CONCLUSIONS: All three drugs markedly inhibited angiogenesis in experimental ROP. Growth factors were elevated in hypoxic conditions. Treated animals showed significant decreases of PDGF, VEGF, and TGFbeta2 in retinal and vitreous tissues.

V-Ginkgo Biloba:Cardiovascular Research:

1.Thrombus induction by endogenic paf-acether and its inhibition by Ginkgo Biloba extracts in the guinea pig.:

Prostaglandins. 1986 Jul;32(1):142-4.PMID: 3763943
The anti-thrombotic effects of specific paf-acether antagonist BN 52021 were compared to the effects of Ginkgo Biloba extracts A, B, (A + B), and C. Local superfusion of BN 52021 over an experimentally injured arterial segment embolizes an existent paf-acether induced platelet thrombus. When applied before paf-acether, BN 52021 prevents local thromboformation in this model. Applied intravenously, BN 52021 reduces local thromboformation in a significant way. As compared to this BN 52021 standard, only Ginkgo Biloba B and the (A + B)-mixture present major thromboreductive activity.

2.Effects of Ginkgo biloba extract on 2 models of experimental myocardial ischemia:

Presse Med. 1986 Sep 25;15(31):1516-9.PMID: 2947091
Ginkgo biloba extract, a free radical scavenger containing kaempferol and quercetin esters, which are potent radical scavengers, was studied on various models of cardiac ischaemia, both in vitro and in vivo. On the two in vitro models of ischaemia-reperfusion described (rat and guinea-pig hearts) Ginkgo biloba extract was without effect on cardiac functional parameters. However, it induced a significant decrease in the intensity of ventricular fibrillation during the reperfusion stage. On normal or hypertrophied heart in vivo, Ginkgo biloba extract provided effective protection against the electrocardiographic disorders induced by ischaemia. On the different models of global or localized ischaemia (followed or not by reperfusion), a decrease of arrhythmia without change in cardiovascular parameters was regularly noted.

3.Pharmacological bases of the vascular impact of Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1524-8.PMID: 2947093
The preferential tissue irrigatory effect of Ginkgo biloba extract in ischaemic areas is largely explained by the direct impact of this product on both arteries and veins. The adrenergic vasoregulatory system and the vascular endothelium are the preferential targets for arterial impact. Ginkgo biloba extract reinforces the physiological vasoregulation of the sympathetic nervous system directly, by acting on neuromediator release, and indirectly, by inhibiting their extraneuronal degradation by catechol-orthomethyltransferase (C.O.M.T.) In the arterial endothelium Ginkgo biloba extract stimulates the release of endogenous relaxing factors, such as endothelium-derived relaxing factor, (EDRF) and prostacyclin. The action of Ginkgo biloba extract on the venous system has been shown to have a venoconstrictor component that maintains the degree of parietal tonus essential to the dynamic clearing of toxic metabolites accumulated during tissue ischaemia. The originality of the vascular impact mechanisms of Ginkgo biloba extract is due to the fact that the product can at the same time combat the phenomena resulting from vascular spasm and with the same efficiency restore circulation in areas subject to vasomotor paralysis.

4.From the body to the cell membrane: the different levels of pharmacological action of Ginkgo biloba extract:

Presse Med. 1986 Sep 25;15(31):1529-38.PMID: 2947094
The pharmacological study of Ginkgo biloba extract has required numerous experiments over several years: different pathological models of cerebral ischaemia to evaluate its effects, and experiments at both cellular and molecular levels to determine its mechanisms of action. In experimental models of ischaemia, oedema and hypoxia, Ginkgo biloba extract reduced vascular, tissular and metabolic disturbances as well as their neurological and behavioural consequences. The pharmacological effects of Ginkgo biloba extract concern vascular, rheological and metabolic processes. Several membrane mechanisms seem to be involved: protection of the membrane ultrastructure against free radicals, modulation of some enzymatic systems and ionic pumps. The originality of the pharmacological properties of Ginkgo biloba extract lies in preferential focusing of its effects on ischaemic areas.

5.Ginkgo biloba extract in the treatment of arteriopathy of the lower extremities. A 65-week trial:

Presse Med. 1986 Sep 25;15(31):1546-9.PMID: 2947095
Thirty-six patients with arteritis were treated with Ginkgo biloba extract for sixty-five weeks. For the first six months of the treatment period, these patients participated in a double-blind randomised comparison with 35 well matched patients taking placebo. Subsequently, those patients taking Ginkgo biloba extract were given the option to continue treatment on an open basis with follow-up at regular three-monthly intervals. Ginkgo biloba extract therapy gave significantly greater pain relief and walking tolerance than the placebo after 6 months of treatment, and this improvement continued throughout the whole duration of the study. This symptomatic and measurable improvement was combined with excellent tolerance of the drug.

6.Effect of ginkgolide PAF-acether antagonists on arterial thrombosis.:

Adv Prostaglandin Thromboxane Leukot Res. 1987;17B:815-7.PMID: 2960196
Topical superfusion by PAF-acether over a branch of the mesenteric artery of the guinea pig invariably results in the formation of a platelet thrombus, adhering onto a denuded area of the vessel wall, or at sites where local retraction of the endothelial cells has occurred. It is demonstrated that the application of exogenous PAF-acether triggers a process of local autogeneration and release of endogenous PAF-acether (or PAF-like substances), maintaining a long phase of sequential regrowth and embolization of thrombi, eventually leading to a complete occlusion of the arterial lumen. Extracts of Ginkgo biloba, administered intravenously or in topical superfusion, inhibit both exogenous- and endogenous-induced thromboformation.

7.Inhibition of the metabolism of platelet activating factor (PAF-acether) by three specific antagonists from Ginkgo biloba.:

Biochem Pharmacol. 1987 Sep 1;36(17):2749-52.PMID: 2820421
Washed rabbit platelet suspensions were incubated in the presence of 1-[3H]O-alkyl-2-acetyl-sn-glycero-3-phosphocholine ([3H] PAF-acether), which was metabolized into 1-[3H]O-alkyl-2-acyl-sn-glycero-3-phosphocholine (alkylacyl-GPC) through the sequential action of cytosolic acetylhydrolase and membrane transacylase. Within 60 min at 37 degrees, percentage of [3H] PAF-acether metabolized was 50.3 +/- 5.2% (9 experiments). This conversion was inhibited in a dose-dependent manner by various concentrations of ginkgolides A, B and C (BN 52020, 52021, 52022) known as specific antagonists of PAF-acether. The three compounds displayed the following order of potency: BN 52021 (IC50 = 3.6 X 10(-6) M) greater than BN 52020 (IC50 = 9.7 X 10(-6) M) greater than BN 52022 (IC50 = 37.6 X 10(-6) M). As this order is the same as that previously defined for inhibition of platelet aggregation to PAF-acether or for inhibition of PAF-acether binding to platelets, our data bring further support to the view that PAF-acether metabolism in platelets involves in some way its binding to its membrane receptor.

8.Efficacy of an extract of Ginkgo biloba in the treatment of chronic obliterating arteriopathies of the lower limbs in stage III of Fontaine's classification:

J Mal Vasc. 1989;14(3):177-82.PMID: 2674312
A controlled trial of Ginkgo biloba extract in injectable form (Tanakan 50 mg, a lyophilizate for parenteral use) was carried out versus a placebo as a preoperative medical treatment of stage III (Fontaine classification) chronic occlusive arterial disease of the lower limbs (with pain in decubitus). The 64 men and women patients in this multicenter study (32 in each group) were over 18 years of age and had a cultural and intellectual level as well as a physical condition allowing them to play an active role in the experiment (self-evaluation of pain). During 8 days they received two daily infusions of 500 cc of normal saline solution containing either 100 mg of Ginkgo biloba extract or a placebo of identical appearance. During this period, anticoagulants were authorized; hemodilution, vasoactive drugs and platelet anti-aggregates were forbidden; pentazocine (Fortal, 50-mg tablets) was allowed at the patient's request. Pain was rated according to a visual scale, with each patient marking a point between two extremes ("maximum imaginable pain" and "total absence of pain") 100 mm apart. A questionnaire based on that of Melzack (McGill Pain Questionnaire) completed this qualitative as well as quantitative self-evaluation of pain. The results of these questionnaires were assessed on the basis of 4 scores, each determined by the patient's choice among 3 evaluation figures. The chi square, Student and Wilcoxon tests were used for statistical analysis. Results: The two randomly-composed groups with Ginkgo biloba extract and a placebo were comparable (Table I). Analysis was based on 55 observations (26 in the extract group and 29 in the placebo group).

9.Collagen-induced thrombocyte aggregation in parenteral therapy using Ginkgo biloba:

Wien Med Wochenschr. 1989 Mar 15;139(5):92-4.PMID: 2658335
24 patients suffering from arteriosclerotic disorders were divided into 2 groups. One half received 250 ml NaCl with 25 ml Ginkgo-biloba-extract the other 12 were treated with 250 ml NaCl without this substance. The collagen induced platelet aggregation was determined before, immediately after infusion and on the next day. The platelet aggregation increased in both collectives after infusion. In the group treated with Ginkgo-biloba-extract after 1 day values returned into normal range while the aggregation remained increased in the NaCl-group.

10.Effect of Ginkgo biloba on fluidity of blood and peripheral microcirculation in volunteers.:

Arzneimittelforschung. 1990 May;40(5):589-93.PMID: 2383302
In a randomized placebo controlled single-blind cross-over study of n = 10 apparently healthy subjects the influence of Ginkgo biloba (Kaveri) on blood fluidity and cutaneous microcirculation was studied. Microcirculation was measured before and every 30 min for 4 h after administration of Ginkgo biloba; fluidity of blood was determined before and after 1, 2 and 4 h. Significant changes in blood pressure or heart rate were found neither during Ginkgo phase nor placebo phase. Haematocrit, plasma viscosity, erythrocyte rigidity, thrombocyte and leukocyte count as well as thrombocyte aggregation and the number of circulating thrombocyte aggregates were also not influenced by the Ginkgo nor the placebo solution. In contrast a remarkable influence on the erythrocyte aggregation was observed: comparing two samples a significant decrease by 15.6% (p less than 0.001) with regard to the initial value was observed after 2 h. The blood flow in the nail fold capillaries also increased significantly by about 57% (p less than 0.004) 1 h after administration.

11.Effects of SOD, catalase, and a novel antiarrhythmic drug, EGB 761, on reperfusion-induced arrhythmias in isolated rat hearts.:

Free Radic Biol Med. 1993 Apr;14(4):361-70.PMID: 8385645
Effects of superoxide dismutase (SOD), catalase, EGB 761 (Tanakan), and their combination on reperfusion-induced ventricular fibrillation (VF), tachycardia (VT), and the formation of oxygen free radicals were studied after 30 min of global ischemia followed by reperfusion in isolated rat hearts. In the first series of studies, rats received a daily dose of 10(4), 2 x 10(4), or 5 x 10(4) U/kg of SOD (i.v.); 2.5 x 10(4), 5 x 10(4), or 10(5) U/kg of catalase (i.v.); and 25, 50, 100, or 200 mg/kg of EGB 761 (per os), respectively, for 10 d (chronic administration). Neither SOD nor catalase alone reduced the incidence of reperfusion arrhythmias, but EGB 761 dose-dependently reduced the incidence of such arrhythmias. The coadministration of SOD (5 x 10(4) U/kg) with catalase (5 x 10(4) U/kg) significantly reduced the incidence of VF and VT. The same reduction in the incidence of VF and VT was observed when SOD (5 x 10(4) U/kg) was given in combination with EGB 761 (50 mg/kg). In the second series of studies, hearts were isolated and perfused with 5 x 10(4) U/l of SOD plus 5 x 10(4) U/l of catalase (acute treatment), and the incidence of reperfusion-induced VF and VT was significantly reduced. The combination of SOD (5 x 10(4) U/l) with EGB 761 (50 mg/l) also reduced the incidence of VF and VT. In these experiments, we studied the time course of oxygen radical formation using 5,5-dimethyl-pyrroline-N-oxide (DMPO), a spin trap, and it was found that EGB 761 (200 mg/l) or the coadministration of EGB 761 (50 mg/l) with SOD (5 x 10(4) U/l) almost completely abolished the formation of oxygen radicals during reperfusion measured by electron spin resonance (ESR) spectroscopy. Although SOD or catalase alone significantly reduced the formation of oxygen radicals, these drugs failed to prevent the development of reperfusion arrhythmias, while their combination significantly attenuated both the formation of free radicals and the incidence of reperfusion-induced arrhythmias. Our results indicate that the combination therapy may synergistically reduce the formation of free radicals and the incidence of reperfusion-induced VF and VT.

12.Hemorheologic effects of ginkgo biloba extract EGb 761. Dose-dependent effect of EGb 761 on microcirculation and viscoelasticity of blood:

Fortschr Med. 1993 Apr 10;111(10):170-2.PMID: 8491438
Method: In a randomized open clinical trial involving 42 patients with pathological visco-elasticity values, the effect of a single intravenous injection of 50, 100, 150 or 200 mg of the Ginkgo biloba extract EGb 761, commercially available as Tebonin p.i. on the microcirculation of the skin (Doppler flowmetry) and the visco-elasticity of whole blood was investigated. Results: A dose-dependent significant increase in the microcirculation was found. In the case of visco-elasticity, this dose-dependence was less marked. The present study thus confirms the positive effect of EGb 761 on the microcirculation and whole-blood visco-elasticity in patients with pathological visco-elasticity values, already found in earlier studies, and shows it to be dependent on the dose employed.

13.Ginkgo biloba extract (EGb 761) improves postischemic function in isolated preconditioned working rat hearts.:

Coron Artery Dis. 1994 May;5(5):443-50.PMID: 7921376
BACKGROUND: We studied the effect of preconditioning and Gikgo biloba extract (EGb 761) in relation to the recovery of contractile function after global ischemia in the isolated working rat heart.METHODS: Hearts (n = 12 in each group) were randomly divided into five groups: In group I, hearts were subjected to 30 min of normothermic global ischemia followed by 30 min of reperfusion; in group II, they were subjected to one cycle of preconditioning consisting of 5 min ischemia and 10 min reperfusion before the induction of 30 min of ischemia and 30 min of reperfusion; group III hearts underwent two cycles of preconditioning; group IV hearts underwent three cycles of preconditioning; and group hearts underwent four cycles of preconditioning before the onset of 30 min ischemia followed by 30 min of reperfusion.RESULTS: Ventricular fibrillation (total) and ventricular tachycardia (no preconditioning) both fell from 100% to 50% (P < 0.05) after four cycles of preconditioning. In relation to ventricular fibrillation, preconditioning significantly reduced the formation of oxygen free radicals, measured by electron spin resonance spectroscopy (ESR), but recovery of cardiac function was low in all preconditioned groups. Because of the relatively low incidence of arrhythmias (50% ventricular fibrillation and 50% ventricular tachycardia) and relatively low cardiac function in Group V, EGb 761, a free-radical scavenger, was chosen to improve myocardial contractile function in preconditioned hearts. Fifty and 100 mg/kg of EGb 761 (per os) significantly improved coronary flow, aortic flow, left ventricular developed pressure (LVDP), and the first derivative of LVDP (LVDdP/dtmax) in the four-cycle preconditioned group. Thus, after 30 min of reperfusion, aortic flow was improved from 11.6 +/- 0.9 ml/min to 19.7 +/- 1.2 ml/min (P < 0.05) with a dose of 50 mg/kg of EGb 761 and to 22.0 +/- 1.5 ml/min (P < 0.05) with a dose 100 mg/kg of EGb 761, in the four-cycle preconditioned group. During reperfusion, the formation of free radicals was reduced by approximately 50 and 60% using 50 mg/kg and 100 mg/kg of EGb 761, respectively, when compared with the four-cycle preconditioned drug-free control group.CONCLUSION: We have demonstrated that EGb 761 can improve contractile function after global ischemia in the isolated working rat heart by reducing the formation of oxygen free radicals, and we have shown that this protection is additive to that of ischemia-induced preconditioning.

14.Effect of EGb 761, a ginkgo biloba extract, on early arrhythmia induced by coronary occlusion and reperfusion in dogs.:

J Formos Med Assoc. 1994 Jul;93(7):592-7.PMID: 7866057
EGb 761 is a preparation of Ginkgo biloba extract, which has complex biologic actions including free radical scavenging activity. To examine the anti-arrhythmic effect of EGb 761, a canine preparation of coronary artery occlusion-reperfusion was tested. Under intravenous anesthesia and open chest conditions, 32 dogs were subjected to 30 min of coronary occlusion, followed by reperfusion. Twelve received EGb 761 by intravenous injection, 1 mg/kg five minutes before coronary occlusion, followed by a continuous infusion of 0.1 mg/kg/min until five minutes after reperfusion. Immediately prior to reperfusion, an additional bolus dose of EGb 761 (1 mg/kg) was again injected (group A). The remaining 20 dogs received saline injection, and served as the control (group B). The electrocardiographic changes were recorded during the whole experimental course. The results showed that, during coronary occlusion, group A dogs had a lower count of ventricular premature beats than group B dogs. However, there was no difference in the incidence of ventricular tachycardia (VT) between the two groups. The duration of VT of the treated dogs was similar to that of the control dogs. The incidence of ventricular fibrillation (VF) was also similar. Upon reperfusion, the treated dogs were shown to be protected from VF. The duration of VT was also shorter in the treated group, although the incidence of VT was not different between the two groups. EGb 761 is effective in preventing early VF induced by coronary reperfusion while ineffective in protecting the ischemic VT and VF.

15.Inhibition of lymphocyte-induced angiogenesis by free radical scavengers.:

Free Radic Biol Med. 1994 Sep;17(3):259-66.
Solid tumors induce an angiogenic response by the host blood vessels to form a new vascular network for the supply of fresh nutrients and oxygen responsible for tumor growth. Furthermore, tumor growth and metastatic spread is abrogated or markedly reduced in the absence of neovascularization. Spleen T lymphocytes from tumor-bearing mice elicit a strong neovascular response. It is well known that certain T cell responses require the presence of active oxygen radicals. Because these metabolites are produced during tumor growth, we studied whether oxygen free radicals play a role in the angiogenesis induction by lymphocytes. In this study, we demonstrated that the administration of a free radical scavenger (EGb-761) to tumor-bearing mice, blocked the angiogenic response and decreased the lung metastatic incidence. On the other hand, when normal lymphocytes were incubated with the xanthine-xanthine oxidase system (X-XO), a known superoxide anion generator, this elicited a dose-response positive angiogenic reaction in normal recipient mice. No angiogenic response was observed in the absence of X-XO, or when EGb-761 or superoxide dismutase (SOD) plus catalase (CAT) were added to the incubation medium. These results suggest that free radicals are involved in some step of the angiogenic process, and that the EGb-761 treatments block this response due to the free radical scavenging activity of this compound.

16.Efficiency of Ginkgo biloba extract (EGb 761) in antioxidant protection against myocardial ischemia and reperfusion injury.:

Biochem Mol Biol Int. 1995 Jan;35(1):125-34.PMID: 7735127
The cardio-protective mechanisms of EGb 761, an extract of Ginkgo biloba leaves, on myocardial ischemia-reperfusion injury were investigated using rabbits subjected to 30 minutes of regional cardiac ischemia and 120 min of reperfusion under anesthesia. Compared to the saline perfused group, EGb 761 treatment (10 mg/kg, injected into the coronary artery) significantly inhibited the increase in lipid peroxidation and maintained total and CuZn-SOD levels in both plasma and tissue during and at the end of reperfusion. Both the decrease in tissue type plasminogen activator (t-PA) and the increase in plasminogen activator inhibitor-1 (PAI-1) caused by ischemia-reperfusion were also significantly suppressed by EGb 761 treatment. Furthermore, the ultrastructure of the myocytes of the EGb 761 treated heart was slightly damaged after ischemia-reperfusion, while the control ischemic-reperfused hearts demonstrated severe histological damages such as swelling and vacuolization of the mitochondria. These results suggest that EGb 761 protects hearts by its antioxidant properties and by its ability to adjust fibrinolytic activity.

17.Changes of enzyme activities in the rat myocardium caused by experimental hypoxia with and without ginkgo biloba extract EGb 761 pretreatment. A cytophotometrical study.:

Acta Histochem. 1995 Jan;97(1):67-79.PMID: 7771185
Using cytophotometry activity changes of succinate dehydrogenase, glycerol-3-phosphate dehydrogenase and myofibrillar adenosine triphosphatase, were measured in the rat myocardium under normal and different experimental conditions. After hypoxia all enzyme activities were significantly decreased in comparison to the normal situation, and the alterations differed in both ventricles. Ginkgo biloba extract treatment over three months before exposition to hypoxia resulted in a lower inhibition of succinate dehydrogenase, a higher inhibition of glycerol-3-phosphate dehydrogenase and an unchanged activity of adenosine triphosphatase after hypoxia of 20 min. These results were interpreted as a protective effect of the Ginkgo biloba extract on the hypoxic myocardium.

18.Protection of hypoxia-induced ATP decrease in endothelial cells by ginkgo biloba extract and bilobalide.:

Biochem Pharmacol. 1995 Sep 28;50(7):991-9.PMID: 7575684
Due to their localization at the interface between blood and tissue, endothelial cells are the first target of any change occurring within the blood, and alterations of their functions can seriously impair organs. During hypoxia, which mimics in vivo ischemia, a cascade of events occurs in the endothelial cells, starting with a decrease in ATP content and leading to their activation and release of inflammatory mediators. EGb 761 and one of its constituents, bilobalide, were shown to inhibit the hypoxia-induced decrease in ATP content in endothelial cells in vitro. Under these conditions, glycolysis was activated, as evidenced by increased glucose transport, as well as increased lactate production. Bilobalide was found to increase glucose transport under normoxic but not hypoxic conditions. In addition, EGb and bilobalide prevented the increase in total lactate production observed after 60 min of hypoxia. However, after 120 min of hypoxia, the total lactate production was similar under normoxic and hypoxic conditions, and both compounds increased this production. These results indicate that glycolysis slowed down between the 60th and 120th minute of hypoxia, while EGb and bilobalide delayed the onset of glycolysis activation. In another experimental model, both compounds were shown to increase the respiratory control ratio of mitochondria isolated from liver of rats treated orally. Since ischemia is known to uncouple mitochondria, the protection of ATP content and the delay in glycolysis activation observed during hypoxia in the presence of EGb 761 or bilobalide is best explained by a protection of mitochondrial respiratory activity, at least during the first 60 min of hypoxia incubation. Both products retain the ability to form ATP, thereby reducing the cell's need to induce glycolysis, probably by preserving ATP regeneration by mitochondria as long as oxygen is available.

19.Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. I. Protection of cardiomyocytes.:

Exp Toxicol Pathol. 1996 Jan;48(1):33-9.PMID: 8919269
Ginkgo biloba extract EGb 761 was used in hypoxia experiments with old rats to investigate its ultrastructure-preserving effects on the myocardium. Hypoxia was performed by means of a hypoxia chamber combined with a commercial narcosis apparatus. N2O/O2-mixture was applied with O2 at 5 vol.% for 20 minutes under normobaric conditions. Ultrastructural-morphometric analysis revealed that EGb 761-pretreatment was able to diminish hypoxic damage at mitochondrial cristae and matrix and also distension of the sarcoplasmic reticulum during acute hypoxic stress. Whereas formation of vacuoles was depressed below the level of controls, the accumulation of lipid drops was not prevented. The preservation of mitochondrial cristae was confirmed by independent secondary morphometric parameters and by cytophotometrically measured activities of mitochondrial enzymes.

20.Myocardium-protective effects of Ginkgo biloba extract (EGb 761) in old rats against acute isobaric hypoxia. An electron microscopic morphometric study. II. Protection of microvascular endothelium.:

Exp Toxicol Pathol. 1996 Jan;48(1):81-6.PMID: 8919274
Aim of this electron microscopic morphometric study was to demonstrate ultrastructure protective properties of Ginkgo biloba extract EGb 761 on myocardial microvessels of old rats during acute hypoxic stress. Hypoxia of 20 minutes duration with N2O/O2 mixture (5 vol% O2) was performed using a hypoxia chamber combined with a commercial narcosis apparatus. EGb 761-pretreatment diminished significantly the percentage of endothelial cells exhibiting edema, luminal blebs and of capillaries surrounded by pericapillary debris. Hypoxia-related decrease in plasmalemmal vesicle frequency was prevented by EGb 761, formation of vacuoles non significantly diminished against the hypoxic group. Volume density of mitochondrial cristae was significantly less diminished, the volume fraction of degenerated areas less increased in the EGb 761-protected group. The results give some evidence that EGb 761 protects endothelial cell ultrastructure of myocardial microvasculature against hypoxic alterations, probably by its radical scavenging properties.

21.Effects of Ginkgo biloba extract (EGb 761) on cochlear vasculature in the guinea pig: morphometric measurements and laser Doppler flowmetry.:

Eur Arch Otorhinolaryngol. 1996;253(1-2):25-30.PMID: 8932425
Ginkgo biloba extract (EGb 761) was administered orally for 4 or 6 weeks to healthy adult guinea pigs. Animals were then decapitated under deep ketamine anesthesia. Post-mortem morphometric measurements of cochlear vessels in the spiral lamina revealed a vasodilating effect of the extract in four of ten animals following 6 weeks of treatment. In vivo testing of the effect of 4 or 6 weeks of treatment with EGb 761 was monitored with laser Doppler flowmetry of the cochlear blood flow under pathological conditions. Results demonstrated that EGb 761 partly counteracted sodium salicylate-induced decreases in cochlear blood flow (CBF) and enhanced CBF increases induced by hypoxia. These findings indicate that EGb 761 may help to improve oxygenation in cochleas with compromised blood flow.

22.Effects of Ginkgo biloba extract (EGb 761) on arteriolar spasm in a rat cremaster muscle preparation.:

Int J Microcirc Clin Exp. 1996 Mar-Apr;16(2):98-104.PMID: 8737713
The effects of an extract of Ginkgo biloba (EGb 761) on arteriolar spasm were confirmed using a preparation of rat cremaster muscle. When vasospasm was induced by rat serum, arteriolar constriction reached 25-30% of the initial diameter after 10 min. Intravenous injection of EGb 761 (30 mg/kg) 5 min after inducing spasm inhibited about 80% of this serum-induced vasoconstriction. As previous studies have shown that EGb 761 has an antiaggregatory effect on platelets, thrombin, serotonin (platelet-derived compounds that are present in the serum) and a thromboxane analogue (U46619) were also used to induce vasospasm. Administration of EGb 761 (30 mg/kg) 5 min after exposure of the preparation to serotonin (10(-3) M) or 10 min after exposure to thrombin (20 units) did not affect vasospasm induced by these agents. In contrast, treatment with this same dose of EGb 761 5 min after exposure of the preparation to U46619 (10(-4) M) abolished the arteriolar constriction induced by this agent in 15 min. The thromboxane/prostaglandin H2 receptor antagonist SQ29548 antagonized serum-induced vasospasm, indicating an involvement of thromboxane. Other experiments indicated that the effects of EGb 761 of counteracting vasospasm may be mediated in part by ginkgolide B, a triterpene constituent of the extract that is an antagonist of platelet-activating factor and in part by an 'NO-like' action of its proanthocyanidin constituents. Taken together, these results have revealed that EGb 761 treatment can antagonize the vasoconstrictor effect of thromboxane on arterioles. As thromboxane is implicated in many cardiovascular disorders, this property of EGb 761 may explain some of its beneficial clinical effects in such pathologies.

23.The effect of Ginkgo biloba extract in patients with intermittent claudication:

Ugeskr Laeger. 1996 Jul 1;158(27):3928-31.PMID: 8701508
Eighteen patients with stable intermittent claudication were randomized in a double blind cross-over study comparing the effects of the Ginkgo biloba extract GB-8 at a dose of 120 mg o.d. with placebo. All patients were treated for three months with the active extract and three months with placebo. The effects of treatment on arterial insufficiency were quantified by measurements of systemic and peripheral systolic blood pressures, and pain-free and maximal walking distances on a tread-mill. Questionnaires based on visual analogue scales were used to quantify the severity of leg pain, impairment of concentration, and inability to remember. Short-term memory was objectively assessed. We did not find any significant changes in either peripheral blood pressures, walking distances or the severity of leg pain. Systemic blood pressure was reduced both by placebo and GB-8. The impairment of concentration and the inability to remember were both reduced, when comparing results during active treatment to placebo. Short-term memory did not change significantly. In conclusion, our study has shown that treatment with the Ginkgo biloba extract GB-8 improves some cognitive functions in elderly patients with moderate arterial insufficiency, whereas the extract did not change signs and symptoms of vascular disease in the patients.

24.Cardioprotective and anti-oxidant effects of the terpenoid constituents of Ginkgo biloba extract (EGb 761).:

J Mol Cell Cardiol. 1997 Feb;29(2):733-42.PMID: 9140830
Hemodynamic and electron spin resonance analyses were used to assess the in vivo and in vitro cardioprotective and antioxidant effects of therapeutically relevant doses of Ginkgo biloba extract (EGb 761) and its terpenoid constituents (ginkgolides A and B, bilobalide) in the rat. Significant anti-ischemic effects, indicating improved myocardial functional recovery, were observed after repeated (15-day) oral treatments with both EGb 761 (60 mg/kg/day) and ginkgolide A (4 mg/kg/day), as compared to placebo. In vitro pre- and post-ischemic perfusion of hearts in the presence of the ginkgolides A and B (both at 0.05 microgram/ml) or bilobalide (0.15 microgram/ml), but not EGb 761 (5 micrograms/ml), significantly improved all hemodynamic parameters. Post-ischemic levels of the 5,5-dimethyl-1-pyrroline N-oxide (DMPO)/hydroxyl radical spin-adduct (DMPO-OH) in coronary effluents were significantly decreased after in vivo oral treatments or after in vitro perfusion with EGb 761 or the terpenes, the most effective compound being ginkgolide A. As the presence of the terpenes did not influence the formation of the superoxide/DMPO adduct or DMPO-OH in acellular tests with superoxide and hydroxyl radical generators, their cardioprotective effects appear to involve an inhibition of free radical formation rather than direct free radical scavenging.

25.Effect of Ginkgo biloba extract (EGb 761) on the vasospastic response of mouse cutaneous arterioles to platelet activation.:

Int J Microcirc Clin Exp. 1997 Mar-Apr;17(2):61-6.PMID: 9253682
The effect of intravenously administered Ginkbo biloba extract (EGb 761) on the vasospastic response to platelet activation has been assessed using a cutaneous flap preparation in anaesthetized mice. Arterioles of the axillary artery were observed by intravital microscopy, and platelets were activated by topical application of ADP under two steady state conditions: normothermia (37 degrees C) and hypothermia (24 degrees C). Responses of the cutaneous arterioles to stimulation by topical application of a thromboxane agonist (U46619) were also compared in animals treated intravenously with EGb 761 or with a thromboxane synthesis inhibitor (U63557). ADP induced a 34% constriction of the arterioles in control animals. However, no arteriolar constriction occurred in response to ADP in platelet-depleted animals (collagen-induced thrombocytopenia) or in animals treated with EGb 761 (60 mg/kg, i.v.). Exposure of the arterioles to hypothermia (24 degrees C) for 10 min induced constriction of 7-12% in all experimental groups of animals. Under these hypothermic conditions, either EGb 761 or thrombocytopenia abolished ADP-induced arteriolar constriction which was substituted by arteriolar dilation, indicating that EGb 761 can inhibit the vasospasm that is produced by platelet activation. As topically applied U46619 (10(-5) M) induced arterioles constriction (about 22%) that was abolished by intravenous treatment with EGb 761, the extract appears to act directly rather than as a thromboxane synthase inhibitor. Collectively, these findings indicate that platelet factors can play a significant role in cutaneous vasospasm, and that EGb 761, via an action on the thromboxane pathway, could be useful in treating Raynaud's phenomenon and other vascular disorders which involve increased thromboxane production.

26.Ex vivo regulation of adrenal cortical cell steroid and protein synthesis, in response to adrenocorticotropic hormone stimulation, by the Ginkgo biloba extract EGb 761 and isolated ginkgolide B.:

Endocrinology. 1997 Dec;138(12):5415-26.PMID: 9389527
We previously demonstrated that repeated treatment of rats with the standardized extract of Ginkgo biloba leaves, EGb 761, and its bioactive component ginkgolide B (GKB), specifically reduces the ligand binding, and protein and messenger RNA expression of the adrenal mitochondrial peripheral benzodiazepine receptor (PBR), a key element in the regulation of cholesterol transport, resulting in decreased circulating corticosterone levels. Adrenocortical cells were isolated from rats treated with EGb 761 or GKB and cultured for 2 and 12 days. The effect of ACTH on normal and metabolically labeled cells was examined. Corticosterone levels were measured by RIA, and protein synthesis was analyzed by two-dimensional gel electrophoresis. Ex vivo treatment with EGb 761 and GKB resulted, respectively, in 50% and 80% reductions of ACTH-stimulated corticosterone production by adrenocortical cells cultured for 2 days compared with that by cells isolated from saline-treated rats. Two-dimensional gel electrophoresis analysis revealed that in cells from both control and drug-treated animals, ACTH induced the synthesis, at the same level, of a 29-kDa and pI 6.4-6.7 protein identified as the adrenal steroidogenic acute regulatory protein (StAR). In addition, treatment with EGb 761 and GKB specifically altered the synthesis of seven proteins, including inhibition of synthesis of a 17-kDa, identified as PBR. After 12 days in culture, ACTH-stimulated adrenocortical cell steroid synthesis was maintained, and it was identical among the cells isolated from animals treated with GKB or saline. Under the same conditions, the expression of PBR was recovered, whereas no effect of ACTH on the 29-kDa and 6.4-6.7 pI protein (StAR) or other protein synthesis could be seen. A comparative analysis of the effects of GKB and EGb 761 on adrenocortical steroidogenesis and protein synthesis identified, in addition to the 17-kDa PBR, target proteins of 32 kDa (pI 6.7) and 40 kDa (pI 5.7-6.0) as potential mediators of the effect of EGb 761 and GKB on ACTH-stimulated glucocorticoid synthesis. In conclusion, these results 1) validate and extend our previous in vivo findings on the effect of EGb 761 and GKB on ACTH-stimulated adrenocortical steroidogenesis, 2) demonstrate the specificity and reversibility of EGb 761 and GKB treatment, 3) question the role of the 29-kDa, 6.4-6.7 pI protein (mature StAR) as the sole mediator of ACTH-stimulated steroid production, and 4) demonstrate the obligatory role of PBR in hormone-regulated steroidogenesis.

27.Inhibition of type 4 phosphodiesterase by rolipram and Ginkgo biloba extract (EGb 761) decreases agonist-induced rises in internal calcium in human endothelial cells.:

Arterioscler Thromb Vasc Biol. 2000 Sep;20(9):E34-40.PMID: 10978267
The effects of Gingko biloba extract EGb 761 on 5 isolated, vascular, cyclic nucleotide phosphodiesterase (PDE) isoforms were evaluated. EGb 761 preferentially inhibited PDE4 (IC(50)=25.1 mg/L), the isoform that is mainly present in endothelial cells, in a competitive manner (K:(i)=12.5 mg/L). Because changes in cyclic nucleotide levels may affect intracellular calcium ([Ca(2+)](i)) levels in endothelial cells, we examined the effects of EGb 761 on both resting [Ca(2+)](i) levels and agonist-induced rises in [Ca(2+)](i) in single human umbilical vein endothelial cells (HUVECs) in culture. The effects of EGb 761 were compared with those of rolipram, a selective PDE4 inhibitor that increases cellular cAMP levels, and the cAMP analogue dibutyryl cAMP (db-cAMP). EGb 761 (20 and 100 mg/L), rolipram (50 micromol/L), and db-cAMP (100 micromol/L) significantly inhibited histamine-, ATP-, and thrombin-induced [Ca(2+)](i) increases in HUVECs without modifying resting [Ca(2+)](i) levels. Similar results were obtained by using a Ca(2+)-free bath solution. EGb 761 (100 mg/L), but not rolipram (50 micromol/L) or db-cAMP (100 micromol/L), also inhibited Ca(2+) influx into cells having thapsigargin-depleted internal Ca(2+) stores and bathed in a Ca(2+)-free external solution. Our results are consistent with an inhibition of PDE activity that causes a reduction of agonist-induced increases in [Ca(2+)](i) in HUVECs, mainly by inhibition of Ca(2+) mobilization from internal stores. It thus may be that the cardiovascular effects of EGb 761 involve inhibition of PDE4 activity and subsequent modification of Ca(2+) signaling in endothelial cells.

28.Antiplatelet and antithrombotic effects of a combination of ticlopidine and ginkgo biloba ext (EGb 761).:

Thromb Res. 1998 Jul 1;91(1):33-8.PMID: 9700851
The antiplatelet and antithrombotic effects of the oral combination treatment of ticlopidine and Ginkgo biloba extract (EGb 761) were studied in normal and thrombosis-induced rats. The ex vivo inhibitory effect on ADP-induced platelet aggregation of a small dose of ticlopidine (50 mg/kg/day) in combination with EGb 761 (40 mg/kg/day) was comparable to a larger dose of only ticlopidine (200 mg/kg/day). Bleeding time was also prolonged by 150%. Thrombus weight was also consistently decreased by a combination of ticlopidine and EGb 761 in an arterio-venous shunt model at two doses of ticlopidine (50 mg/kg) plus EGb 761 (20 mg/kg) and ticlopidine (50 mg/kg) plus EGb 761 (40 mg/kg). A combinatory treatment in acute thrombosis model in mice also showed a higher recovery than a single treatment.

29.Inhibitory effect of the leaf extract of Ginkgo biloba L. on oxidative stress-induced platelet aggregation.:

Biochem Mol Biol Int. 1998 Dec;46(6):1243-8.PMID: 9891858
The effect of the leaf extract of Ginkgo biloba L. on platelet aggregation induced by oxidative stress was studied. The extract caused a dose-dependent inhibition of platelet aggregation stimulated with tert-butyl hydroperoxide (t-BHP) and Fe2+. Similar inhibitory activity was observed when platelets were exposed to H2O2 and Fe2+. Synergistic aggregation induced by a combination of t-BHP and Fe2+ or H2O2 and Fe2+ in association with suboptimal concentration of collagen or U46619, was prevented by the extract. However, the extract failed to inhibit aggregation in response to collagen, thrombin or U46619. Ginkgolides A, B and C inhibited platelet-activating factor-induced aggregation, but not oxidant-induced aggregation. These data suggest that the suppressive effect of the extract is specific on platelet aggregation stimulated by oxidative stress, and that this effect is involved in the mechanism related to its protective effect upon cerebral or myocardial injuries.

30.Hemorheology and walking of peripheral arterial occlusive diseases patients during treatment with Ginkgo biloba extract.:

Zhongguo Yao Li Xue Bao. 1998 Sep;19(5):417-21.PMID: 10375799
AIM: To study the effects of Ginkgo biloba extract 761 (GbE) from the points of view of hemorheology for patients of peripheral arterial occlusive diseases (PAOD).METHODS: The treatment with GbE (240 mg.d-1, po) and the pain-free walking distance (PFWD) were carried out for 24 PAOD patients (12 nondiabetic, ND and 12 diabetic, D) over 48 wk. The parameters erythrocyte stiffness (ES) and relaxation time (RT), the blood plasma viscosity (eta), the plasma fibrinogen concentration (Cf) and the blood sedimentation rate (BSR), the PFWD, and maximal walking distance (MWD) were determined at 6 wk before treatment (-6), at the beginning of the treatment (0), and after 6, 11, 16, and 48 wk of treatment.RESULTS: At wk -6, ES and RT of both the ND- and D-group were not significantly different from a healthy control group. At wk 0, stiffness and RT were significantly higher than healthy control, and the mean PFWD was only 111 m. The eta value was significantly elevated and Cf and BSR were enhanced. Throughout 11 wk of treatment ES, RT, eta, and Cf decreased gradually and PFWD improved. Between 16 and 48 wk, ES, and RT were no longer significantly different from the controls, whereas eta and Cf decreased gradually but remained higher than normal, BSR decreased, and the PFWD improved by a factor of 3.8 times (D) and 3.3 times (ND).CONCLUSION: GbE gives therapeutic effects in PAOD patients.

31.Ginkgo biloba extract increases ocular blood flow velocity.:

J Ocul Pharmacol Ther. 1999 Jun;15(3):233-40.PMID: 10385132
We evaluated a possible therapeutic effect of Ginkgo biloba extract (GBE) on glaucoma patients that may benefit from improvements in ocular blood flow. A Phase I cross-over trial of GBE with placebo control in 11 healthy volunteers (8 women, 3 men: Age; 34 +/- 3 years, mean +/- SE) was performed. Patients were treated with either GBE 40 mg or placebo three times daily orally, for 2 days. Color Doppler imaging (Siemens Quantum 2000) was used to measure ocular blood flow before and after treatment. There was a two week washout period between GBE and placebo treatment. Ginkgo biloba extract significantly increased end diastolic velocity (EDV) in the ophthalmic artery (OA) (baseline vs GBE-treatment; 6.5 +/- 0.5 vs 7.7 +/- 0.5 cm/sec, 23% change, p=0.023), with no change seen in placebo (baseline vs GBE-treatment; 7.2 +/- 0.6 vs 7.1 +/- 0.5 cm/sec, 3% change, p=0.892). No side effects related to GBE were found. Ginkgo biloba extract did not alter arterial blood pressure, heart rate, or IOP. Ginkgo biloba extract significantly increased EDV in the OA and deserves further investigation in ocular blood flow and neuroprotection for possible application to the treatment of glaucomatous optic neuropathy as well as other ischemic ocular diseases.

32.The evaluation by video capillaroscopy of the efficacy of a Ginkgo biloba extract with L-arginine and magnesium in the treatment of trophic lesions in patients with stage-IV chronic obliterating arteriopathy:

Minerva Cardioangiol. 1999 Jun;47(6):223-30.PMID: 10522149
BACKGROUND AND AIMS: This study aimed to evaluate the influence of Ginkgo biloba extract with arginine and magnesium used for the treatment of trophic lesions in the lower limbs caused by both diabetic and non-diabetic microangiopathy.METHODS: A comparative study was carried out in 20 patients who were divided into two groups: 10 were treated with ASA plus Ginkgo biloba extract with arginine and magnesium and 10 with ASA plus conventional hemorheology. The observation time was extended to 6 months, taking into consideration patients with trophic lesions to the lower limbs suffering from diabetic and non-diabetic peripheral arterial occlusive disease. The evaluation was performed by clinical, ultrasonographic and perilesional video capillaroscopy monitoring. Ultrasonographic and video capillaroscopy instrumental methods were used because they provide a full picture of macro and microcirculatory conditions around lesions.RESULTS: The study showed the undoubted efficacy of Ginkgo biloba extract with magnesium and arginine in relation to the following points: reduced healing times for the trophic lesion compared to the control group, improved painful symptoms, increased perilesional neoangiogenesis. No significant differences were observed from a Doppler ultrasonographic point of view or with regard to the claudication free interval.CONCLUSIONS: Ginkgo biloba extract with arginine and magnesium can improve the dynamics of cutaneous trophism in lesions caused by diabetic and non-diabetic microangiopathy.

33.Ginkgo biloba inhibits hydrogen peroxide-induced activation of nuclear factor kappa B in vascular endothelial cells.:

Gen Pharmacol. 1999 Nov;33(5):369-75.PMID: 10553877
The present study determined the effects of Ginkgo biloba extract (GBE) on the activation of nuclear factor kappa B (NF-kappaB) and the level of hydrogen peroxide (H2O2) in bovine pulmonary artery endothelial cells (PAEC). H2O2 showed a concentration-dependent activation of NF-kappaB. GBE demonstrated a concentration-dependent suppression of NF-kappaB activated by H2O2. GBE directly scavenged H2O2 in a cell-free system; it also decreased H2O2 levels in PAEC. These results suggest that the inhibitory effect of GBE on H2O2-induced NF-kappaB activation may be caused by its scavenging and suppression of H2O2. Our experiments demonstrate that GBE can inhibit NF-kappaB activation induced by H2O2 and may thus be effective for the prevention or treatment of atherosclerosis and other disorders related to NF-kappaB activation.

34.Comparison of two dosages of ginkgo biloba extract EGb 761 in patients with peripheral arterial occlusive disease Fontaine's stage IIb. A randomised, double-blind, multicentric clinical trial.:

Arzneimittelforschung. 1999 Nov;49(11):900-4.PMID: 10604042
BACKGROUND: Rheologically-active drugs are widely used in the therapy of peripheral arterial occlusive disease (pAOD) Fontaine's stage II. Several clinical trials have demonstrated the efficacy of Ginkgo biloba extract in the treatment of pAOD Fontaine's stage II. A pilot study indicated the superiority of 240 mg Ginkgo biloba extract daily compared with the standard dosage of 120 mg to 160 mg daily. This trial was conducted to confirm the superiority of the higher dosage of Ginkgo biloba extract in patients with pAOD Fontaine's stage IIb statistically.PATIENTS AND METHODS: 74 patients were analysed. Thirty-eight patients received the standard dosage (EGb 761 120 mg/d), and 36 patients received 240 mg EGb 761 daily. The primary efficacy criterion was the difference of the pain-free walking distance between the start of treatment and after 24 weeks measured on a treadmill under standardized conditions.RESULTS: The pain-free walking distance improved in both groups. There was a mean increase of 60.6 m in the group of patients who received 120 mg Ginkgo biloba extract daily and a statistically significant higher (p = 0.0253) mean increase of 107.0 m in the group of patients who were treated with the higher dosage.CONCLUSION: Both dosage regimens investigated in this trial led to a clinically relevant improvement of the pain-free walking distance after 24 weeks of treatment. The superiority of the higher dosage over the standard dosage was statistically significant. Both treatment variations were safe and well tolerated.

35.Cardioprotective effects of the calcineurin inhibitor FK506 and the PAF receptor antagonist and free radical scavenger, EGb 761, in isolated ischemic/reperfused rat hearts.:

J Cardiovasc Pharmacol. 2000 Jan;35(1):37-44.PMID: 10630731
Effects of the calcineurin inhibitor FK506, the platelet-activating factor (PAF) antagonist, and free radical scavenger Ginkgo biloba extract, EGb 761, and their combination on reperfusion-induced ventricular fibrillation (VF), ventricular tachycardia (VT), and recovery of cardiac function were studied after 30 min of global ischemia followed by 2 h of reperfusion in isolated rat hearts. In the first series of studies, rats received a daily (oral) dose of 0, 1, 5, 10, 20, or 40 mg/kg/day FK506 for 10 days. FK506 dose-dependently reduced the incidence of reperfusion-induced total (irreversible plus reversible) VF from a value of 92% for untreated animals to 92% (NS), 83% (NS), 67% (NS), 33% (p<0.05), and 25% (p<0.05), for doses of 1-40 mg/kg/day, respectively, with effects on incidence of VT showing the same pattern. FK506, between 20 and 40 mg/kg/day, also resulted in significant recovery of postischemic cardiac function. In the second series of studies, rats were treated with EGb 761 alone or in combination with FK506. Whereas no significant reduction in arrhythmias or improvement in cardiac function resulted from a single intervention of EGb 761 at 25 mg/kg/day, combined treatment of rats with 25 mg/kg/day of EGb 761 and 1 or 5 mg/kg/day of FK506 resulted in a reduction in total and irreversible VF of 92% and 92% to 42% (p<0.05) and 33% (p<0.05), 25% (p<0.05) and 8% (p<0.05), respectively, versus untreated control animals, paralleled by similar effects on the incidence of VT and accompanied by significant improvements in postischemic cardiac function. Our results demonstrate a novel cardioprotective characteristic of FK506 and suggest that combination therapy by using FK506 plus EGb 761 synergistically improves postischemic cardiac function, while reducing the incidence of reperfusion-induced VF and VT, which may expand the clinical utility of FK506 and allow therapy with FK506 at lower doses than are currently useful.

36.The Effect of Ginkgo biloba Extract on Mitochondrial Oxidative Phosphorylation in the Normal and Ischemic Rat Heart.:

Phytother Res. 2011 Jan 24. doi: 10.1002/ptr.3399.PMID: 21259351
Free radical-induced myocardial damage and impairment of vascular endothelium-dependent relaxation are amongst the most important mechanisms responsible for ischemic heart injury. Ginkgo biloba leaf extract (GE) has been reported to improve blood circulation in the brain and have a beneficial impact on the cardiovascular system but its cardioprotective effects have not been elucidated yet. Therefore, this study investigated the influence of GE in 70% ethanol (1:5) administered orally to rats on the functions of isolated heart mitochondria under normal and ischemic conditions. Wistar rats were given GE or ethanol (solvent control) at a dosage of 0.32 mL/kg in drinking water for 10 and 18 days, while the control animals received untreated drinking water. Mitochondrial respiration rates were determined oxygraphically. Pyruvate and malate, succinate or palmitoyl-l-carnitine and malate were used as substrates. The GE treatment partially uncoupled mitochondrial oxidation from phosphorylation, reduced the generation of free radicals in the mitochondria, diminished the ischemia-induced V(3) decrease and the degree of respiration stimulation by exogenous cytochrome c. Thus, these results indicate that GE exerts cardioprotective effects reducing ischemia-caused impairment of the functions of heart mitochondria.

37.Ginkgo biloba extract attenuates the development of hypertension in deoxycorticosterone acetate-salt hypertensive rats.:

Clin Exp Pharmacol Physiol. 2000 Apr;27(4):277-82.PMID: 10779125
1. We examined the effects of Ginkgo biloba extract (GBE) on the development of hypertension, platelet activation and renal dysfunction in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Both DOCA-salt hypertensive rats and normotensive rats were fed a 2% GBE diet for 20 days. Blood pressure (BP) was measured by two methods, namely by the tail-cuff and telemetry methods. 2. Development of hypertension was attenuated in rats fed a 2% GBE diet. In addition, an increase in heart weight, an indicator of sustained high BP, was inhibited significantly by feeding of the GBE diet. 3. Decreases in 5-hydroxytryptamine content in platelets, a marker of platelet activation in vivo associated with hypertension, were also prevented by feeding of the GBE diet. Ginkgo biloba extract itself did not inhibit ADP- and collagen-induced platelet aggregation examined in vitro. Feeding of the GBE diet tended to inhibit increases in plasma urea nitrogen due to hypertension. 4. The telemetry study demonstrated that BP and heart rate (HR) showed a clear circadian rhythm and the antihypertensive effect of GBE was prominent in the daytime, a resting period for rats. This anti-hypertensive effect of GBE was not detected in normotensive rats. In contrast, the inhibitory effect of GBE on HR was independent of time and was observed in both normotensive and hypertensive rats. 5. These results indicate that GBE has an anti-hypertensive and bradycardiac action, which are time dependent and independent, respectively. Thus, it appears that the chronopharmacological action of GBE may be ascribed not to pharmacokinetic factors, but rather to a circadian susceptibility rhythm to GBE in DOCA-salt hypertensive rats.

38.Protective effects of Ginkgo biloba extract on cultured rat cardiomyocytes damaged by H2O2.:

Zhongguo Yao Li Xue Bao. 1999 Jul;20(7):635-8.PMID: 10678129
AIM: To investigate the influence of Ginkgo biloba extract (GbE) on cardiomyocytes damaged by H2O2.METHODS: Cultured rat cardiomyocytes were divided into 3 groups randomly: control group; H2O2 (2.5 mmol.L-1) group; H2O2 2.5 mmol.L-1 + GbE 150 mg.L-1 group. The cardiomyocytes were cultured in MEM (Eagle's) at 37 degrees C in the presence of 5% CO2 for 4 h. Lactate dehydrogenase (LDH) was assayed by colorimetric method. Lipid peroxidation was determined by measuring thiobarbituric acid-reactive substances. Ultrastructure was viewed under transmission electron microscope.RESULTS: Compared with the control group, LDH leakage and malondialdehyde (MDA) content increased in H2O2 group, LDH increased from (2166 +/- 247) U.L-1 to (5180 +/- 648) U.L-1, MDA increased from (3.5 +/- 0.2) nmol/10(6) cells to (7.2 +/- 0.4) nmol/10(6) cells (P < 0.01). The ultrastructure was damaged seriously. GbE inhibited the increase of LDH leakage and MDA content induced by H2O2. In this group, LDH decreased from (5180 +/- 648) U.L-1 to (3496 +/- 386) U.L-1, MDA decreased from (7.2 +/- 0.4) nmol/10(6) cells to (4.8 +/- 0.9) nmol/10(6) cells (P < 0.01). Ultrastructure of cells was also protected by GbE.CONCLUSION: GbE protected the cardiomyocyte against H2O2 injury, the protective action was attributed to its antiperoxidative effect.

39.Cardiovascular protective effects and NO-mediated cerebrovasorelaxant effects of extract of ginkgo biloba leaves:

Zhonghua Yi Xue Za Zhi. 1998 Sep;78(9):692-5.PMID: 11038795
OBJECTIVE: To examine the anti-free radical related cardiovascular protective effects and NO-mediated cerebrovasorelaxant effects of extract of the leaves of Ginkgo biloba(EGb) in isolated preparations.METHODS: Experiments on the anti-free radical related cardiovascular protective effects were performed in rabbit Langendorff heart and isolated aortic rings damaged by diphenyl-picryl hydyazyl(DPPH). Protective effects of EGb were determined by comparing the results of EGb pretreated group with the DPPH-injured controls. Cerebrovasorelaxant effects of EGb were examined in ring preparations of isolated porcine basilar artery in vitro using tissue bath techniques.RESULTS: EGb protected the isolated rabbit heart from the DPPH-injury to the cardiac contractility and the aortic endothelium from DPPH-attenuated ACh-induced relaxation. EGb concentrationde dependently relaxed the basilar artery and this effect was more significant in endothelium intact rings than those endothelium denuded rings. EGb enhanced the TNS-induced relaxation in basilar artery and this effect was abolished by pretreatment of N-nitro-L-arginine or tetrodotoxin.CONCLUSIONS: EGb exerts cardiovascular protection against DPPH-impaired cardiac contraction in rabbit isolated heart and endothelium-dependent relaxation in the aortic ring of rabbit in vitro. EGb relaxes porcine basilar artery and enhances the TNS-induced relaxation via a NO pathway.

40.The influence of hypoxia on the myocardium of experimentally diabetic rats with and without protection by Ginkgo biloba extract. I. Ultrastructural and biochemical investigations on cardiomyocytes.:

Exp Toxicol Pathol. 2000 Oct;52(5):419-30.PMID: 11089893
The influence of acute respiratoric hypoxia in streptozotocin-diabetic rats and protective effects of Ginkgo biloba extract (EGb 761)-pretreatment were investigated by the means of ultrastructural morphometry, biochemical parameters of oxidative stress and iNOS transcription and expression. Ultrastructural parameters revealed that acute hypoxia deteriorated the morphologic condition of the diabetic cardiomyocytes: volume fractions of sarcoplasm, t-tubules, mitochondria, cytoplasmic vacuoles, and degenerative intramitochondrial areas increased after hypoxia, those of myofibrils and mitochondrial cristae decreased. Since these alterations are more striking than after hypoxia of non-diabetic animals as demonstrated in preceding studies, we regard them as indicative for reduced hypoxia tolerance of the diabetic myocardium. EGb-treatment of the diabetic animals could improve the above mentioned parameters thus indicating a gradual improvement of the hypoxia tolerance. The biochemical parameters of oxidative stress (malondialdehyde, superoxide dismutase) were decreased after hypoxia in the diabetic myocardium but increased after EGb-pretreatment. The ultrastructural damage by hypoxia and its prevention by EGb should be regarded rather as a consequence of ATP--and energy deficiency and breakdown of membrane functions and--structure resp. as membrane stabilizing and enzyme-regulating effects of EGb than as radical-related events. The hypoxia-induced deprivation of creatine kinase activity of the diabetic myocardium was not prevented by EGb-treatment. Immunohistochemical demonstration of iNOS expression was strongest in the unprotected diabetic myocardium, absent after additional hypoxia and in the controls, and very weak in the protected hypoxic specimens. Transcription of iNOS as demonstrated by RT-PCR was present in few diabetic, some of the hypoxic diabetic, in most of the EGb-treated hypoxic diabetic, and in all control animals. EGb-treatment seems to improve the hypoxia tolerance of diabetic myocardium concerning ultratructural parameters. The partly conflicting immunohistochemical and biochemical results require further investigations.

41.Complementary cardioprotective effects of flavonoid metabolites and terpenoid constituents of Ginkgo biloba extract (EGb 761) during ischemia and reperfusion.:

Basic Res Cardiol. 2000 Oct;95(5):368-77.PMID: 11099163
Hemodynamic and electron spin resonance (ESR) analyses were performed on isolated ischemic and reperfused rat hearts to assess the cardioprotective and antioxidant effects of therapeutically relevant concentrations of Ginkgo biloba extract (EGb 761; 5, 50 or 200 microg/ml), its terpenoid constituents (ginkgolide A; 0.05 microg/ml and ginkgolide B; 0.05, 0.25 or 0.50 microg/ml), and a terpene-free fraction of EGb 761 (CP 205; 5 or 50 microg/ml). Hearts underwent 10 min of low-flow ischemia, 30 min of no-flow global ischemia, and 60 min of reperfusion. Test substances were added to the perfusion fluid during the last 10 min of control perfusion, low-flow ischemia and the first 10 min of reperfusion. A separate group of rats was treated with CP 205 (60 mg/kg/day; p.o.) for 15 days, after which the hearts were perfused with plain buffer. In ESR experiments, the spin-trap 5,5-dimethyl-1-pyrroline N-oxide (DMPO) was added to the perfusate to determine the effects of treatments on post-ischemic myocardial free radical generation. Results showed that in vitro exposure of hearts to EGb 761 (5 or 50 microg/ml) or to ginkgolides A and B (both at 0.05 microg/ml), or in vivo pretreatment of the rats with CP 205 delayed the onset of contracture during ischemia. The strong reperfusion-induced elevation of left ventricular end-diastolic pressure observed in untreated hearts was significantly reduced by in vitro exposure to the lowest concentrations of EGb 761, by ginkgolide A, and to a lesser extent by ginkgolide B, or by prior oral treatment with CP 205. Post-ischemic functional recovery.was significantly improved by in vivo administration of CP 205, by perfusion with 5 microg/ml of EGb 761 or with both terpenoids as compared to untreated group but in vitro CP 205 was not effective. ESR analyses revealed that DMPO-OH (the DMPO/hydroxyl radical spin-adduct) concentrations in coronary effluents were markedly decreased by all treatments, except for the lowest concentration of ginkgolide B. Perfusing 5 microg/ml EGb 761 resulted in a better inhibition of baseline DMPO-OH concentration than 5 microg/ml CP 205 (-70 % and -48 % vs. control, respectively), indicating that both terpenoid and flavonoid constituents of EGb 761 are required to produce this effect. CP 205 was significantly more efficient in reducing DMPO-OH concentration when administered in vivo than when applied in vitro, indicating that the antioxidant effect of flavonoid metabolites (formed in vivo) is superior to that of intact flavonol glycosides (present in vitro). Collectively, these findings provide the first evidence that part of the cardioprotection afforded by EGb 761 is due to a specific action of its terpenoid constituents and that this effect involves a mechanism independent of direct free radical-scavenging. Thus, the terpenoid constituents of EGb 761 and the flavonoid metabolites that are formed after in vivo administration of the extract act in a complementary manner to protect against myocardial ischemia-reperfusion injury.

42.Experimental hypoxia of STZ-diabetic rat myocardium and protective effects of Ginkgo biloba extract. II. Ultrastructural investigation of microvascular endothelium.:

Exp Toxicol Pathol. 2001 Feb;52(6):503-12.PMID: 11256752
Four months after induction of diabetes by intraperitonal injection of 60 mg streptozotocin/kg body weight wistar rats were exposed to an acute respiratoric hypoxia of 20 min duration. One group of the rats received daily Ginkgo biloba extract EGb 761 (100 mg/kg body weight). By means of qualitative and quantitative electron microscopic analysis we compared the hypoxia-induced ultrastructural alterations of the myocardial microvascular endothelium in normal, diabetic, and EGb-protected rats. Aim of the study was to compare the hypoxia tolerance of myocardial microvessels of normal and diabetic rats and to test the possibility of antioxidative protection. The results revealed that only some ultrastructural microvascular parameters of diabetic rats were stronger altered after acute hypoxia than normal ones, e.g. capillary dilatation, number of lysosomes, frequency of vesicles and fused vesicles, endothelial swelling, and structural state of mitochondria. Other parameters exhibited less severe alterations than in healthy rats, as luminal blebbing and protrusions, endothelial vacuoles, mitochondrial swelling, and pericapillary debris. Protective effects of EGb could be demonstrated on endothelial swelling, blebbing, vesiculation and vesicular fusioning, partly on vacuolization, but not on mitochondrial parameters. The results were discussed on pathobiochemical background. EGb 761 was estimated to be protective against hypoxic damage on myocardial microvessels also in diabetic condition, but the study should be completed by inclusion of a reoxygenation interval.

43.The influence of hypoxia on the myocardium of experimentally diabetic rats with and without protection by Ginkgo biloba extract. III: Ultrastructural investigations on mitochondria.:

Exp Toxicol Pathol. 2001 Feb;52(6):557-68.PMID: 11256759
Completing our preceding ultrastructural studies on diabetes and additional acute hypoxia of rat myocardium and the protective effect of Ginkgo extract (EGb) we investigated specific ultrastructural-morphometric parameters of corresponding mitochondria. Aim of the study was to answer the question whether mitochondria of diabetic myocardium are more sensitive to hypoxia than in normal condition, and whether antioxidative protection by EGb is effective. Further we compared the ultrastructural reactions of mitochondria of different intracellular locations. Voluminal parameters of mitochondria indicated a moderate swelling after diabetes and a further slight swelling after additional hypoxia, which was slightly reduced after EGb pretreatment. Decrease of volume density of mitochondrial cristae was less expressed after diabetes and much stronger after additional hypoxia; slight protection by EGb was only visible after diabetes. Degenerative intramitochondrial areas increased significantly after diabetes and after hypoxia; EGb was protective only after additional hypoxia. The relative number of ATPase particles (F1-coupling factors) at the inner mitochondrial membranes was slightly but significantly reduced after diabetes and stronger reduced after additional hypoxia; only in the latter condition Ginkgo extract was slightly protective. The product of volume density of mitochondria x volume density of cristae x relative number of ATPase particles at the inner mitochondrial membrane (as structural equivalent of the myocardial capacity for ATP production) indicated better than single parameters the increasing mitochondrial damage after diabetes of 4 months duration and subsequent acute hypoxia of 20 min duration. After hypoxia this capacity amounted only to 46% of the normal and was improved by EGb to 53%.

44.The effect of ginkgo biloba on hypoxic pulmonary hypertension and the role of protein kinase C:

Zhonghua Jie He He Hu Xi Za Zhi. 2000 Oct;23(10):602-5.PMID: 11372384
OBJECTIVE: To elucidate whether the mechanism of relieving hypoxic hypertension by ginkgo biloba involves attenuation of the function of protein kinase C(PKC) signal channel.METHODS: 1. Wistar rats were randomly divided into control(C), hypoxic(H) and ginkgo biloba treatment(GB + H) (200 mg.kg-1.d-1, orally) groups (n = 7). Each rat was first measured mean pulmonary arterial pressure (mPAP), mean systemic arterial pressure (mSAP) and the ratio of the weight of right ventricle to that of left ventricle plus septum [RV/(LV + S)], than two main pulmonary artery rings were isolated to exposed to PDBu(a specific activator of PKC) to observe the time-response curve and the dose-response curve in response to 500 nmol/L PDBu and 10-11,000 nmol/L PDBu respectively to evaluate the function of protein kinase C signal channel. 2. Intrapulmonary artery rings of human(IARH) from pneumolobectomy were randomly divided into PDBu, RO318220 (inhibitor of PKC) + PDBu and ginkgolide B(BN52021) + PDBu groups(n = 6), the IARH of three groups were exposed to 1-25 nmol/L PDBu to achieve dose-response curves respectively.RESULTS: (1) mPAP, RV/(LV + S) of the H group were greater than those of C and GB + H groups respectively (P < 0.05). mPAP of GB + H group was greater than that of C group (P < 0.05). In PA experiments, the function of protein kinase C of H group was higher than those of C and GB + H groups respectively(P < 0.05). (2) In IARH experiments, the function of protein kinase C of PDBu group was higher than those of RO318220 + PDBu and BN52021 + PDBu groups respectively(P < 0.05).CONCLUSIONS: Ginkgo biloba can reduce chronic hypoxic pulmonary hypertension and relieve the hypertrophy of right ventricle, which is partly related to attenuation of the function of PKC signal channel.

45.K(Ca) channel-opening activity of Ginkgo Biloba extracts and ginsenosides in cultured endothelial cells.:

Clin Exp Pharmacol Physiol. 2001 May-Jun;28(5-6):441-5.PMID: 11380519
1. Extracts of Ginkgo biloba (EGb) and ginsenosides (GS) have been reported to induce vasorelaxation. In the present study, the role of K+ channels in the action of EGb and GS to activate nitric oxide synthase (NOS) activity was investigated in cultured endothelial cells. 2. Nitric oxide synthase activity of cultured endothelial cells detected by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) histochemistry method was significantly increased after treatment with 20 microg/mL EGb or 40 microg/mL GS plus 10 mmol/L L-arginine. The effect was completely abolished by the addition of 0.5 micromol/L Nomega-nitro-L-arginine, an inhibitor of NOS, to the incubation medium and partially inhibited by 10 micromol/L tetraethylammonium (TEA), an inhibitor of Ca2+-activated K+ (KCa) channels. 3. Application of EGb to the intracellular surface of excised inside-out patches activated K+ channels in a concentration-dependent manner in the concentration range 1-100 microg/mL. Channel activity was also activated by application of GS at concentrations ranging from 1 to 300 microg/mL. The modulation of channel activity was inhibited by 0.5 mmol/L TEA but not by 0.5 mmol/L glibenclamide, an inhibitor of ATP-sensitive K+ channels. 4. Thus, in cultured endothelial cells, the increase in NOS activity induced by EGb or GS depends on the activity of KCa channels. These compounds may regulate nitric oxide release by changing the cell membrane potential in vascular endothelial cells.

46.Myocardial damage and change of mitochondrial Mn-superoxide dismutase activity in craniocerebral injured rats and the interventing effect of ginkgo biloba extract:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2010 Mar;30(3):299-302.PMID: 20535932
OBJECTIVE: To investigate the myocardial damage and changes of myocardial mitochondrial Mn-superoxide dismutase (Mn-SOD) activity in craniocerebral injured rats and the effect of Ginkgo biloba extract (GBE) on them.METHODS: Craniocerebral injured rats model was established by fluid-percussion and treated with GBE. The dynamical changes of electrocardiograph (ECG) in 24 h were monitored, the serum level of MB isoenzyme of creatine kinase (CK-MB) and the change of myocardial mitochondrial Mn-SOD activity as well as the pathologic changes of myocardium (HE staining) were observed.RESULTS: The occurrence of ECG abnormality obviously increased in the injured rats, accompanied with increased serum CK-MB (P<0.05) and decreased myocardial Mn-SOD levels (P<0.05), and the Mn-SOD activity was negatively correlated with the level of CK-MB (r=-0.997, P<0.05). Pretreatment of GBE resulted in the decrease of ECG abnormality occurrence (P<0.01), serum CK-MB level (P<0.05), and degree of myocardial damage, as well as the increase of Mn-SOD activity in post-craniocerebral injured rats.CONCLUSIONS: Craniocerebral injury can result in distinct myocardial damage, which is possibly correlated with the lowering of anti-oxidation stress level of myocardial cellular mitochondria. GBE possesses the protective effect on myocardial damage after craniocerebral injury.

47.Complexation of Ginkgo biloba extract with phosphatidylcholine improves cardioprotective activity and increases the plasma antioxidant capacity in the rat.:

Planta Med. 2001 Jun;67(4):326-30.PMID: 11458448
The aim of this work was to compare in the rat the cardioprotective efficacy and the total plasma antioxidant activity of a standardised Ginkgo biloba L. extract (GB) as such (300 mg/kg/day) or complexed with phosphatidylcholine (GB-PC; 1:2 w/w), after a 5 days oral administration. At the end of the treatment, the total plasma antioxidant defence was determined by the TRAP and FRAP assays, and the hearts from all groups of animals subjected to moderate ischemia (flow reduction to 1 ml/min for 20 min) and reperfusion (15 ml/min for 30 min). The recovery of left ventricular developed pressure (LVDP) at the end of reperfusion was 35-40% of the preischemic values in both control and vehicle rats, 50.2% in the GB group and 72.5% in the GB-PC pre-treated animals. Creatine kinase (CK) outflow in the perfusate from the hearts of GB and GB-PC treated animals were restrained to a different extent vs. controls (by 71% GB-PC; by 22% GB); the rate of prostacyclin (6-keto-PGF1 alpha) release was far greater in GB-PC than in GB hearts. In parallel, the GB extract significantly increased the total antioxidant plasma capacity (by 24.5% TRAP; 27.9% FRAP) only when complexed with phospholipids. This indicates an increased bioavailability of phenolic antioxidants when suitably embedded within a lipophilic carrier. The results of this study demonstrate that complexation of Ginkgo biloba with phospholipids induces in the rat, even after a short treatment a greater resistance of the heart to ischemia/reperfusion damage in respect to the native extract, due to an increased plasma antioxidant activity.

48.The effect of EGb 761 on the doxorubicin cardiomyopathy.:

Res Commun Mol Pathol Pharmacol. 1999;106(3):181-92.PMID: 11485048
Doxorubicin (Dx) is used to treat a number of types of cancer. The drug produces many toxic reactions and cardiomyopathy. Many drugs have been used to prevent this myocardial damage caused by peroxidative alterations. EGb 761 is being used to prevent arrhythmias in ischemic myocardium. We decided to establish the tissue protective effect of EGb 761 against myocardial toxic effects of Dx in three groups of rats. Cardiotoxicity signs of Dx were found to be dose-related, beginning at 30 mg/kg dose and being apparent at 45 mg/kg dose. 48 hr after a single i.v. injection, myocardial tissues showed a marked edema, vacuolization and fragmentation. We compared the changes in heart tissue biochemically and histopathologically among the control, Dx treated and EGb 761 (100 mg/kg/d.x 4, i.p.) + Dx treated groups. Biochemical results of CK-MB and MDA values showed a significant decrease in Dx + EGb 761 group when compared with Dx treated group. Histopathologically, myocardial tissues of Dx + EGb 761 treated group were found to have diminished vacuolization and fragmentation. These results suggest that EGb 761 might have the same therapeutic potential in Dx related cardiomyopathy.

49.Effects of the leaf of Ginkgo biloba L. extract on blood rheology in animals:

Zhongguo Zhong Yao Za Zhi. 1998 Oct;23(10):622-3, 640- inside back cover.PMID: 11599364
OBJECTIVE: To observe the effects of the leaf of Ginkgo biloba extract(GBE) on viscosity and elasticity, coagulation of blood and aggregation of blood platelets.METHOD: The viscosity and elasticity of the whole blood in rats was determined using an in vitro method. The half inhibitory concentration of the drug inhibiting rabbit platelet aggregation was also determined using ADP as an inducer. The blood coagulation in mice was recorded with a coagulation analyser after GBE was administered by vein injection.RESULT: GBE significantly lengthened the recalcium time, lowered the increase ratios of viscosity and elasticity, and reduced the maximum viscosity and elasticity. At doses of 100 and 200 mg/kg administrated by vein injection GBE lengthened the coagulation time, reduced the fibriogenesis and clot retraction ratio significantly in mice. GBE can also inhibit rabbit platelet aggregation induced by ADP and promote the disband of the aggregated platelets.CONCLUSION: GBE is helpful in reducing viscosity and elasticity of the whole blood, slowing blood coagulation and inhibiting platelet aggregation.

50.Ginkgo biloba extract-induced relaxation of rat aorta is associated with increase in endothelial intracellular calcium level.:

Life Sci. 2001 Oct 5;69(20):2327-36.PMID: 11681620
Ginkgo biloba extract (GBE) has been used clinically for improving peripheral vascular diseases in France and Germany. In the present study, to clarify the pharmacological properties of vasodilation produced by GBE, we examined the effect of GBE and quercetin, one of the ingredients in GBE, on the thoracic aorta isolated from Wistar rats. GBE produced a dose-dependent relaxation in the aortic ring precontracted with noradrenaline, and the relaxation was abolished by L-N(G)-nitro arginine methyl ester (L-NAME). Quercetin produced a similar relaxation, which was also abolished by L-NAME. We then examined the effects of GBE and quercetin on the intracellular calcium level ([Ca2+]i) of cultured aortic endothelial cells using a fluorescent confocal microscopic imaging system. Both GBE and quercetin produced significant increases in [Ca2+]i in the endothelial cells. The increase in [Ca2+]i by quercetin (10(-6) M) was abolished by removing the extracellular Ca2+, but was not affected by thapsigargin, a calcium pump inhibitor. These findings suggest that a principal ingredient of GBE producing vasodilation is quercetin, which can activate nitric oxide synthesis and release by increasing [Ca2+]i in vascular endothelial cells.

51.A preliminary investigation of Tanakan in the treatment of hypertensive arteriosclerosis and stroke in rats.:

Chin Med J (Engl). 2000 May;113(5):425-8.PMID: 11776097
OBJECTIVE: To observe the changes in hypertensive cerebral arteriosclerosis and the incidence of stroke in rats following treatment with Tanakan, a preparation of Ginkgo Biloba (GB).METHODS: Using two-kidney, two clip renovascular hypertensive rats (RHRs) as animal models--we investigated changes in these hypertensive arteriosclerosis-associated factors: A I, A II, ALD, ET, SOD and cGMP. Blood levels were observed after oral administration of GB, at both early and late stages of hypertension.RESULTS: The degree of arteriosclerosis was more severe in both RHRs control and the later treated group than in the early treated group, with blood levels of A I, A II, ALD and ET in the former two groups significantly elevated. The degree of arteriosclerosis in the early treated group decreased and the blood levels of A I, A II, ALD and ET in this group decreased nearly to normal levels. The blood levels of SOD and cGMP were also elevated in the early treated group.CONCLUSIONS: These results reveal that it is important to treat hypertension as soon as possible, in order to reduce the occurrence of stroke.

52.Effects of Ginkgo biloba extract on the proliferation of vascular smooth muscle cells in vitro and on intimal thickening and interleukin-1beta expression after balloon injury in cholesterol-fed rabbits in vivo.:

J Cell Biochem. 2002;85(3):572-82.PMID: 11967997
Restenosis may develop in response to cytokine activation and smooth muscle cell proliferation. Ginkgo biloba extract (EGb) has been used to treat cardiovascular and cerebrovascular diseases. In the present study, the effects of EGb on the growth of cultured vascular smooth muscle cells (VSMC), as well as on the expression of interleukin-1beta (IL-1beta) and the intimal response in balloon-injured arteries of cholesterol-fed rabbits, were investigated. Using bromodeoxyuridine incorporation as an index of cell proliferation, EGb was found to inhibit serum-induced mitogenesis of cultured rat aorta VSMC in a dose-dependent manner. In vivo, EGb and probucol ( positive control) reduced the atheroma area in thoracic aortas of male New Zealand white rabbits fed a 2% cholesterol diet for 6 weeks with balloon denudation of the abdominal aorta being performed at the end of the third week. Intimal hyperplasia, expressed as the intimal/medial area ratio, in the abdominal aortas was significantly inhibited in the both the EGb group (0.61 +/- 0.06) and the probucol group (0.55 +/- 0.03) compared to the C group (0.87 +/- 0.02). In the balloon-injured abdominal aorta, both EGb and probucol significantly reduced IL-1beta mRNA and protein expression and the percentage of proliferating cells. The inhibitory effects of EGb on the intimal response might be attributed to its antioxidant capacity. EGb may have therapeutic potential for the prevention of restenosis after angioplasty.

53.Protective effects of Ginkgo biloba extract on focal cerebral ischemia and thrombogenesis of carotid artery in rats:

Yao Xue Xue Bao. 1998 Dec;33(12):901-5.PMID: 12016854
Rat focal cerebral ischemia induced by occlusion and thrombogenesis of middle cerebral artery(MCAO) was used as experimental model to study the effects of extract of Ginkgo biloba (EGb) and the positive control drugs were urokinase and nimodipine on cerebral infarct size and neurological deficits. The results showed that cerebral ischemia and neurological deficits appeared in rat focal cerebral ischemic models, and the degree was of cerebral ischemia larger in occlusion model than in thrombogenesis model. The cerebral infarct size was significantly smaller and neurological deficits greatly improved at large dose of EGb(200 mg.kg-1, i.v.), the preventive effect appeared to be better than the treatment effect. The positive control drugs urokinase and nimodipine were also shown to distinctly decrease the cerebral infarct size and improve the neurological deficits in the models. Small dose of EGb(100 mg.kg-1, i.v.) was found to decrease the cerebral infarct size of thrombogenesis model, and improve neurological deficits of both thrombogenesis and occlusion model. EGb was also shown to inhibit the thrombogensis of rat common carotid artery stimulated by electrical current in dose-dependent manner. This experiment indicates that EGb might have beneficial effects on prevention and treatment of ischemic stroke and thrombogenesis.

54.Inhibition of intracellular calcium elevation and blunting of vasopressor response due to serotonin by ginkgolide B.:

Planta Med. 2002 Jun;68(6):501-4.PMID: 12094291
The vascular effects of each individual composition in the extract of Ginkgo biloba have not been clarified. In this work, we have investigated whether ginkgolide B (GKB), a terpene lactone component from Ginkgo biloba, modulates intracellular calcium ([Ca (2+)] i) of vascular smooth muscle cells (smc) and how it influences the vasopressor response in vitro caused by serotonin (5-HT). GKB (3.2 - 9.6 microM) selectively decreased serotonin-induced [Ca (2+)] i elevations in cultured smc from bovine aorta in dose-dependent manner, while it had no effects on both resting [Ca (2+)] i and potassium-elicited [Ca (2+)] i elevations. On the other hand, GKB in a concentration of 3.2 - 9.6 microM moderately decreased the maximal pressor efficacy of serotonin by 14 - 45 % in rat mesenteric vascular beds, and the EC50 remained unchanged. The comparison study also showed GKB had no effects on noradrenaline-elicited pressor reactions. These results implicate that GKB may selectively inhibit serotonin-mediated [Ca (2+)] i mobilization in vascular smc and non-competitively alleviate the vasopressor effect of serotonin in vitro.

55.Phytotherapy in cardiovascular medicine:

Ther Umsch. 2002 Jun;59(6):301-6.PMID: 12125179
There is widespread use of herbal medicine in patients suffering from cardiovascular diseases. The discussion about the benefit of these drugs is still controversial because of lack of scientific evidence. Ginkgo biloba, Crataegus and Garlic are often recommended substances for patients with cardiovascular diseases. For these substances there is a lot of data available from experimental and clinical studies, unfortunately not always adhering to the criteria of evidence based medicine. Extracts from ginkgo biloba contain several active constituents, mainly flavonoids and terpens, which have antioxidative properties and an inhibitory effect on platelet aggregation by inhibiting platelet activation factor PAF. Ginkgo is mainly used in vascular dementia and peripheral vascular disease. Garlic shows a modest lipid-lowering effect in the same range as a low-cholesterol diet. Effect on blood pressure seems to be at best minor. Crataegus is often used in patients with heart failure because of its positive inotropic effect. Additionally, crataegus acts as an antiarrhythmic substance by prolonging refractory period of the action potential.

56.Effects of Ginkgo biloba extract (EGb 761) on cerebral thrombosis and blood pressure in stroke-prone spontaneously hypertensive rats.:

Clin Exp Pharmacol Physiol. 2002 Nov;29(11):963-7.PMID: 12366386
1. An extract of Ginkgo biloba (EGb 761) has been reported to alleviate cerebrovascular problems. In the present study, we investigated the antithrombotic effects of EGb 761 in cerebral blood vessels of stroke-prone spontaneously hypertensive rats (SHRSP/Izm). 2. In the present study, EGb 761 was administered orally to SHRSP/Izm at 60 and 120 mg/kg each day for 3 weeks from the age of 7 weeks. The age-related increase in blood pressure observed in SHRSP was suppressed significantly by EGb 761 at both doses 3 weeks after treatment. 3. Thrombotic potential was assessed in vivo using a He-Ne laser-induced thrombosis model and was significantly suppressed by EGb 761. 4. The anti-oxidant effects of EGb 761 were determined by measurement of urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG). At 120 mg/kg, EGb 761 decreased 8-OHdG significantly compared with control animals. 5. Urinary nitrite/nitrate, nitric oxide (NO) metabolites, were increased significantly after administration of EGb 761. Expression of endothelial NO synthase (eNOS) mRNA was measured using a real-time quantitative reverse transcription-polymerase chain reaction method. The expression of eNOS mRNA in the EGb 761 group (120 mg/kg) was significantly higher than in the control group. 6. The results indicate that EGb 761 decreases blood pressure and mediates strong antithrombotic and anti-oxidant effects in SHRSP. These pharmacological activities may contribute to the beneficial properties of EGb 761 observed in clinical practice.

57.Reduction of rise in blood pressure and cortisol release during stress by Ginkgo biloba extract (EGb 761) in healthy volunteers.:

J Physiol Pharmacol. 2002 Sep;53(3):337-48.PMID: 12369732
The standardized extract of Ginkgo biloba (EGb 761) was found not only to improve memory and aging associated cognitive deficits but also to exert beneficial effects on mood. An antistress action of the extract has been suggested but not directly proven. The present study was aimed to evaluate the effects of EGb 761 on salivary cortisol and blood pressure responses during stress in healthy young volunteers (n = 70) in a double blind placebo controlled design. A stress model involving a combination of static exercise (handgrip) and mental stimuli was used. Single treatment with EGb 761 (120 mg) reduced stress-induced rise in blood pressure without affecting the heart rate. Salivary cortisol responses showed differences with respect to the gender and the time of day of the stress exposure, with the activation only in male subjects in the afternoon. This activation was absent if they were treated with EGb 761. The performance in a short memory test with higher scores achieved by women remained unaffected by EGb 761 treatment. Thus, this study provides evidence that EGb 761 has an inhibitory action on blood pressure and it may influence cortisol release in response to some stress stimuli.

58.Ginkgo biloba extract EGb 761 attenuates myocardial stunning in the pig heart.:

Basic Res Cardiol. 2003 Feb;98(1):59-68.PMID: 12494270
Myocardial stunning, a transient contractile dysfunction that appears following a brief period of ischemia, is at least partly due to the production of oxygen-derived free radicals. The objective of the present study was to determine whether the Ginkgo biloba extract EGb761, which has antioxidant properties in vitro, can attenuate myocardial stunning in vivo. Forty-seven anesthetized open-chest farm pigs underwent 10 min of occlusion of the left anterior descending coronary artery (LAD), followed by 3 hours of reperfusion. They were pretreated with either physiological saline, 100 mg or 300 mg of EGb 761 (Protocol I) or 3 mg or 9 mg of ginkgolide B (GkB) (Protocol II). Contractile function was assessed by sonomicrometry. Both doses of EGb 761 significantly improved recovery of contractile function in the reperfused myocardium with segment shortening averaging 23 +/- 5 % of baseline values at 3 hours post-reflow in controls versus 81 +/- 10 % and 57 +/- 12 % in the EGb100 and EGb300 groups, respectively (p < 0.05 vs control in both cases). In contrast, neither dose of GkB improved functional recovery during reperfusion. ESR experiments revealed that EGb761 resulted in a 59 % decrease in myocardial spin-adduct release during reperfusion (p < 0.05 versus control and GkB groups). A significant 28 % decrease (p < 0.05 vs control group) was also obtained in GkB-treated animals. These results indicate that EGb 761 can attenuate myocardial stunning following a brief ischemic insult in the in situ pig heart by an effect that involves a decrease in the formation of free radicals. As the effect of EGb 761 on functional recovery cannot be explained by the presence of GkB, the beneficial action of the extract on myocardial stunning likely involves complementary effects of both its non-ginkgolide and ginkgolide constituents.

59.Ginkgo biloba-induced frequent ventricular arrhythmia.:

Ital Heart J. 2002 Nov;3(11):689-91.PMID: 12506530
The use of herbal medications is becoming ever more widespread, but data for them are not yet as robust as for conventional drugs. The available safety information indicates that potential side effects of such use can be due to allergic reactions and bleeding. In this report, a case of frequent ventricular arrhythmias probably due to Ginkgo biloba is presented. The patient complained of palpitations twice in a month and on both occasions symptoms and electrocardiographic evidence of ventricular arrhythmias resolved with discontinuation of Ginkgo biloba. This case underlines that continuing research is needed to elucidate the pharmacological activities of the many herbal remedies now being used.

60.Effects of an extract of Ginkgo biloba on the blood flow of brains and back legs of dogs:

Zhong Yao Cai. 2000 Dec;23(12):764-6.PMID: 12575271
After injecting the injection of an extract of Ginkgo biloba, the cerebral blood flow of dogs wrer increased (P < 0.05-0.001). So were the back legs. And the cerebrovascular resistance was decreased (P < 0.05-0.001).

61.Ginkgo biloba for the prevention and treatment of cardiovascular disease: a review of the literature.:

J Cardiovasc Nurs. 2002 Jul;16(4):21-32.PMID: 12597260
Results from clinical trials demonstrate that standardized leaf extracts of Ginkgo biloba (SGB extract) reduce the symptoms of age-associated memory impairment and dementia, including Alzheimer's disease, and may be of benefit in treating intermittent claudication. In addition, preliminary results suggest that SGB extract may be useful in preventing and treating cardiovascular disease (CVD). particularly ischemic cardiac syndrome. Since many patients with cardiovascular disease are already taking anticoagulants and antiplatelet drugs, self-medication with SGB extract is not recommended without the advice of their physician. Although SGB extracts look promising for preventing and treating CVD, well-controlled clinical trials are needed before clinical recommendations can be made.

62.Homocysteine stimulates inducible nitric oxide synthase expression in macrophages: antagonizing effect of ginkgolides and bilobalide.:

Mol Cell Biochem. 2003 Jan;243(1-2):37-47.PMID: 12619887
Hyperhomocysteinemia is an independent risk factor for atherosclerotic diseases. Inducible nitric oxide synthase (iNOS) is mainly expressed in macrophages upon stimulation. Overproduction of nitric oxide (NO) by iNOS can exacerbate the development of atherosclerosis. Our previous studies demonstrated that the extract of ginkgo biloba leaves (EGb) inhibited the iNOS-mediated NO production in monocyte-derived macrophage. We also reported that homocysteine could stimulate monocyte chemoattractant protein-1 (MCP-1) expression in vascular cells causing enhanced monocyte chemotaxis. The objective of the present study was to investigate the effect of homocysteine on iNOS-mediated NO production in macrophages and the antagonizing effect of EGb. Human monocytic cell (THP-1)-derived macrophages were incubated with homocysteine for various time periods. Homocysteine at concentrations of 0.05-0.1 mM significantly stimulated NO production and iNOS activity in macrophages via increased expression of iNOS mRNA and protein. The increased iNOS expression was associated with activation of nuclear factor-kappa B (NF-kappaB) arising from reduced expression of inhibitor protein (IkappaB alpha) mRNA as well as increased phosphorylation of IkappaB alpha protein in homocysteine-treated cells. EGb and its terpenoids (ginkgolide A, ginkgolide B and bilobalide) could antagonize the homocysteine effect on iNOS expression in macrophages via their antioxidant effect resulting in attenuation of NF-kappaB activation. Taken together, our results have demonstrated that homocysteine, at pathophysiological concentrations, stimulates iNOS-mediated NO production in macrophages. EGb and its terpenoids can antagonize such stimulatory effect via antioxidation and attenuation of NF-kappaB activation.

63.Hemodynamic and electrocardiographic effects of short-term Ginkgo biloba.:

Ann Pharmacother. 2003 Mar;37(3):345-9.PMID: 12639160
OBJECTIVE: To evaluate the immediate and short-term hemodynamic and electrocardiographic effects of Ginkgo biloba (ginkgo).METHODS: Healthy volunteers were randomized to receive ginkgo 120 mg or placebo twice daily for 7 days in this prospective, double blind trial. After at least a 7-day washout period, subjects were crossed over to an additional 7 days of alternate therapy. Blood pressure, heart rate, and 12-lead electrocardiograms were evaluated immediately before (baseline), and at 1, 3, and 5 hours after observed ingestion of study drug on days 1 and 7 of therapy. Electrocardiographic parameters (P wave and QRS complex duration; PR, QT, and QTc intervals) were measured in lead II by a blinded investigator.RESULTS: Ginkgo had no effect on any of the evaluated electrocardiographic parameters at any time point on days 1 or 7. Additionally, no changes in heart rate or systolic and diastolic blood pressure were found between the groups at any time point on any evaluative day.CONCLUSIONS: Commonly used doses of Ginkgo biloba do not have any immediate or short-term effects on blood pressure, heart rate, or electrocardiographic variables in young, healthy volunteers.

64.Down-regulation of c-jun N-terminal kinase-activator protein-1 signaling pathway by Ginkgo biloba extract in human peripheral blood T cells.:

65.Clinical use and molecular mechanisms of action of extract of Ginkgo biloba leaves in cardiovascular diseases.:

Cardiovasc Drug Rev. 2004 Winter;22(4):309-19.PMID: 15592576
Ginkgo biloba is one of the oldest living tree species that has been referred to as a living fossil. Extract from Ginkgo biloba leaves (GBE) is among the most commonly used herbal drugs and is popularized for its alleged tonic effect and possible curative and restorative properties. There is an increasing evidence of the potential role of GBE in treating cardiovascular diseases. We examined the history of GBE usage and reviewed the literature on its effects on the cardiovascular system. In the extensive studies involving cell cultures and animal models, GBE has been shown to exert its action through diverse mechanisms. GBE has been reported to have antioxidatant properties, to modify vasomotor function, to reduce adhesion of blood cells to endothelium, to inhibit activation of platelets and smooth muscle cells, to affect ion channels, and to alter signal transduction. In addition, relevant clinical trials with CBE are being carried out, particularly in the treatment of arterial and venous insufficiency and in the prevention of thrombosis. Finally, the controversial clinical findings and the possible adverse interactions between GBE and other drugs are discussed. This review underscores the potential benefits of Ginkgo biloba in cardiovascular diseases, highlights the gaps in our current research, and suggests the necessity for more rigorous systematic investigation of cardiovascular properties of CBE.

66.Protection by bilobalide of the ischaemia-induced alterations of the mitochondrial respiratory activity.:

Fundam Clin Pharmacol. 2000 May-Jun;14(3):193-201.PMID: 15602795
Ischaemia is a common feature of most vascular diseases. There is evidence from experimental and clinical studies that Ginkgo biloba extract protects tissues from ischaemia/reperfusion damages. Bilobalide seems to be responsible, at least in part, for this activity. However, the mechanism of the protection afforded by bilobalide is not yet known. In this work, the effects of bilobalide on mitochondrial respiration were investigated during liver and brain ischaemia, since mitochondria alteration is an early event in ischaemia-induced damage. Bilobalide could prevent the decrease in respiratory activity induced by ischaemia in liver and in brain, both when glutamate/malate or succinate was used as substrate. Ischaemia decreased state 3 respiration rate and bilobalide prevented this decrease. While bilobalide was not able to prevent the decrease in adenine translocase activity, it protected complex I activity. Bilobalide allows mitochondria to maintain their respiratory activity in ischaemic conditions by protecting complex I and probably complex III activities. Hence, the energetic pool of tissues is preserved during the ischaemic period as well as its viability. This mechanism provides, a possible explanation for the anti-ischaemic properties of bilobalide and of Ginkgo biloba extract in therapeutic interventions.

67.Age-related changes in the vasodilating actions of Ginkgo biloba extract and its main constituent, bilobalide, in rat aorta.:

Clin Chim Acta. 2005 Apr;354(1-2):141-6. Epub 2005 Jan 19.PMID: 15748610
BACKGROUND: Age-related modulation in vasodilating actions induced by Ginkgo biloba extract (GBE) and bilobalide, a main constituent of GBE, were examined using rat aorta ring strips.METHODS: Wistar rats from 5 to 25 weeks old were used, and the isolated aorta ring strips were fixed in Krebs-Henseleit solution.RESULTS: GBE and bilobalide concentration-dependently dilated norepinephrine (NE)-induced vasoconstriction in all aged rats. The vasodilating actions generally decreased in accordance with aging. GBE at 1 mg/ml decreased from 28.4+/-3.8% (n=5) in 5-week-old rats to 23.7+/-7.1 (n=7) in 25-week-old rats, but not significantly. GBE (3 mg/ml)-induced vasodilation was maximum by 73.7+/-2.1% (n=4, P<0.001) in 10-week-old rats. GBE had the marked vasodilation at younger ages and further decreased it with developing ages. In the rats older than 20 weeks, however, GBE tended to rather increase the strength of vasodilating action. On the other hand, the vasorelaxation induced by 30 micromol/l bilobalide significantly decreased from 11.8+/-1.4% (n=4) in 5-week-old rats to 2.3+/-1.5% (n=5, P<0.01) in 25-week-old rats, and by 100 micromol/l from 20.2+/-3.4% (n=4) to 5.6+/-2.5% (n=5, P<0.01), respectively. Bilobalide had the similar age-related actions. The age-dependent attenuation was produced milder by bilobalide than by GBE. At lower concentrations, however, bilobalide caused the weak vasocontriction in 20- and 25-week-old rats.CONCLUSION: GBE and bilobalide possess a similar characteristic for age-related modification, clinically suggesting the more effective actions of GBE for elder persons.

68.Effects of Ginkgo biloba extract on blood pressure and vascular endothelial response by acetylcholine in spontaneously hypertensive rats.:

J Pharm Pharmacol. 2006 Feb;58(2):243-9.PMID: 16451753
We previously demonstrated that Ginkgo biloba extract (Ginkgo) produced vasodilation via the nitric oxide pathway in aortic segments isolated from Wistar rats. In this study, we have analysed the effects of daily long-term oral Ginkgo treatment on blood pressure, vascular tone, and calcium mobilization to evaluate the clinical availability. Spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were fed either a control diet or a diet containing 0.05%-0.5% Ginkgo for 30 days. Administration of Ginkgo did not change systolic blood pressure in WKY, but significantly decreased systolic blood pressure in SHR. In thoracic aortic preparations isolated from SHR, diminished relaxation in response to acetylcholine was improved by a Ginkgo-containing diet. This diet significantly decreased the EC50 value and significantly increased maximum relaxation in response to acetylcholine in SHR. In aortic segments isolated from WKY, acetylcholine-induced relaxation was not affected by a Ginkgo-containing diet. Sodium nitroprusside-induced relaxation was unchanged by a Ginkgo-containing diet in SHR and WKY. We also examined the effects of a Ginkgo-containing diet on the intracellular calcium level of aortic endothelium using a fluorescent confocal microscopic imaging system. Calcium Green 1/AM preloading indicated that acetylcholine significantly increased the endothelial intracellular calcium level. The Ginkgo-containing diet significantly enhanced this increase in the aortic endothelium of SHR, but did not change that of WKY. The results suggested that Ginkgo enhanced endothelium-dependent vasodilation and elevation of the endothelial intracellular Ca(2+) level in SHR, resulting in hypotension. This accelerative effect of Ginkgo on Ca(2+) mobilization seemed to be associated with restoration of impaired dilatory function induced by acetylcholine in endothelial cells.

69.Effect of ginkgo biloba extract and dipyridamole on transcription and translation of inducible NO synthbase in rabbits after myocardial ischemia-reperfusion injury:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006 Mar;26(3):240-3.PMID: 16613271
OBJECTIVE: To investigate the effects of Egb761, an extract of ginkgo biloba , and dipyridamole on inducible NO synthase (iNOS) in rabbits after myocardial ischemia-reperfusion injury.METHODS: After being established into ischemia-reperfusion injury model, 35 rabbits were divided randomly into 5 groups: Group A (the sham group), Group B (the model group), Group C (treated with dipyridamole 0.8 mg/kg), Group D (treated with Egb761, 40 mg/kg), and Group E (treated with Egb761 40 mg/kg combined with dipyridamole 0.8 mg/kg), all the medications were administered by intravenous injection 30 min after reperfusion. After administration, myocardial iNOS mRNA expression was detected by RT-PCR and western blot.RESULTS: Myocardial iNOS mRNA transcriptive expression in the 5 groups were A 0, B 157.11 +/- 17.73, C 202.6 +/- 21.84, D 356.13 +/- 24.18 and E 562.34 +/- 35.19 respectively, showing significant difference between the treated groups and group B (P <0.01). The translative expression of myocardial iNOS in the 5 groups were A 34.24 +/- 15.78, B 75.70 +/- 13.71, C 116.89 +/- 22.57, D 143.75 +/- 16.05 and E 195.09 +/- 22.25 respectively, showing significant difference between the treated groups and group B as well (P < 0.05, P < 0.01).CONCLUSION: Both Egb761 and dipyridamole could increase myocardial iNOS expression in transcriptive and translative levels in rabbits after myocardial ischemia-reperfusion injury, and the combined treatment of them shows a more significant effect

70.Effects of Ginkgo biloba extract 50 preconditioning on contents of inflammation-related cytokines in myocardium of rats with ischemia-reperfusion injury:

Zhong Xi Yi Jie He Xue Bao. 2010 Apr;8(4):373-8.PMID: 20388480
OBJECTIVE: To investigate the effects of Ginkgo biloba extract 50 (GBE50) preconditioning on contents of inflammation-related cytokines in rats with myocardial ischemia-reperfusion.METHODS: Fifty-eight SD rats were divided into sham-operated group, untreated group, Salviae miltiorrhizae (SM) injection group and low-, medium- and high-dose GBE50 groups. After intragastric administration for 7 d, the left anterior descending (LAD) coronary artery was occluded for 30 min followed by 60-min reperfusion to induce ischemia-reperfuion injury. Myocardium histopathologic change was observed by HE staining under a light microscope; myeloperoxidase (MPO) activity in myocardium was measured by colorimetric detection; tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and IL-8 were detected by radioimmunoassay; IL-4 and IL-10 were tested by enzyme-linked immunosorbent assay (ELISA).RESULTS: Compared with untreated group, rats in medium-dose GBE50 group had lower inflammatory reaction and MPO activity (P<0.01). GBE50 also decreased the content of IL-6 (P<0.05, P<0.01) and increased the content of IL-4 in myocardium (P<0.05, P<0.01) as compared with the untreated group. The content of TNF-alpha in myocardium in the medium-dose GBE50 group was lower and IL-10 was higher than those in the untreated group, but without significant differences.CONCLUSION: GBE50 can decrease the content of IL-6 and increase the content of IL-4 in myocardium after ischemia-reperfusion injury. It suggests that GBE50 can regulate the inflammatory reaction after ischemia-reperfusion injury via inhibiting inflammatory cytokines and promoting anti-inflammatory cytokines.

71.Ginkgolide A attenuates homocysteine-induced endothelial dysfunction in porcine coronary arteries.:

J Vasc Surg. 2006 Oct;44(4):853-62.PMID: 17012008
BACKGROUND: Homocysteine is an independent risk factor for atherosclerosis. The objective of this study was to investigate whether ginkgolide A (GA), a major constituent of Ginkgo biloba, could block homocysteine-induced endothelial dysfunction in porcine coronary arteries.METHODS: Porcine coronary artery rings were assigned to six treatment groups: control; homocysteine (50 micromol/L); low-dose (50 micromol/L) or high-dose (100 micromol/L) GA; and homocysteine plus low-dose or high-dose GA. After 24 hours' incubation, the rings were analyzed for vasomotor function in response to a thromboxane A2 analogue (U46619), bradykinin, and sodium nitroprusside. Endothelial nitric oxide synthase (eNOS) was studied by using real-time polymerase chain reaction and immunohistochemistry analysis. Superoxide anion production was assessed by chemoluminescence analysis.RESULTS: Endothelium-dependent relaxation (bradykinin) was significantly reduced in ring segments treated with homocysteine as compared with the control (P < .05). When homocysteine was combined with either low-dose or high-dose GA, endothelium-dependent relaxation was markedly recovered. There was no significant difference in maximal contraction (U46619) or endothelium-independent relaxation (sodium nitroprusside) among all groups. In addition, superoxide anion production was increased by 113% in the homocysteine-treated group, whereas there was no statistically significant difference between the control and GA/homocysteine groups. Furthermore, eNOS messenger RNA and protein levels were substantially reduced in the homocysteine-treated group (P < .05), but not in the GA/homocysteine combined groups.CONCLUSIONS: Homocysteine significantly impairs endothelium-dependent vasorelaxation through oxidative stress and downregulation of eNOS in porcine coronary arteries. GA effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores the potential clinical benefits and applications of GA in controlling homocysteine-associated vascular injury and cardiovascular disease.CLINICAL RELEVANCE: Homocysteine is an independent risk factor for atherosclerosis. This study showed that ginkgolide A, a major constituent of Ginkgo biloba, effectively prevents homocysteine-induced endothelial dysfunction and molecular changes in porcine coronary arteries. This study underscores potential clinical benefits and applications of ginkgolide A in controlling homocysteine-associated vascular injury and cardiovascular disease.

72.Reduction of atherosclerotic nanoplaque formation and size by Ginkgo biloba (EGb 761) in cardiovascular high-risk patients.:

Atherosclerosis. 2007 Jun;192(2):438-44. Epub 2007 Mar 29.PMID: 17397850
Coating a silica surface with the isolated lipoprotein receptor proteoheparan sulfate (HS-PG) from arterial endothelium and vascular matrices and adding both the atherogenic VLDL/IDL/LDL lipid fraction in its native composition and Ca(2+) ions, we could observe in vitro the earliest stages of atherosclerotic plaque development by ellipsometric techniques (patent EP 0 946 876). This so-called nanoplaque formation is represented by the ternary aggregational complex of the HS-PG receptor, lipoprotein particles and calcium ions. The model was validated in several clinical studies on statins in cardiovascular high-risk patients. In eight patients who had undergone an aortocoronary bypass operation, the reduction of atherosclerotic nanoplaque formation amounted to 11.9+/-2.5% (p<0.0078) and of nanoplaque size to 24.4+/-8.1% (p<0.0234), respectively, after a 2-month therapy with Ginkgo biloba extract (2x 120 mg daily, EGb 761). Additionally, superoxide dismutase (SOD) activity was upregulated by 15.7+/-7.0% (p<0.0391), the quotient oxLDL/LDL lowered by 17.0+/-5.5% (p<0.0234) and lipoprotein(a) concentration decreased by 23.4+/-7.9% (p<0.0234) in the patients' blood. The concentration of the vasodilating substances cAMP and cGMP was augmented by 37.5+/-9.1% (p<0.0078) and 27.7+/-8.3% (p<0.0156), respectively. A multiple regression analysis between the patients' VLDL/IDL/LDL lipoprotein fraction applied in the ellipsometry measurements as well as the further risk factors oxLDL/LDL and Lp(a) on the one hand and changes in nanoplaque formation on the other hand reveals a basis for a mechanistic explanation of nanoplaque reduction under ginkgo treatment. The atherosclerosis inhibiting effect is possibly due to an upregulation in the body's own radical scavenging enzymes and an attenuation of the risk factors oxLDL/LDL and Lp(a).

73.Ginkgo biloba extract EGb 761 increases endothelial nitric oxide production in vitro and in vivo.:

Cell Mol Life Sci. 2007 Jul;64(13):1715-22.PMID: 17497242
Beneficial effects of Ginkgo biloba on peripheral arterial occlusive disease have been repeatedly shown in clinical trials, especially after use of EGb 761, a standardized special extract. Since the underlying mechanisms are widely unknown, we aimed to elucidate the molecular basis on which EGb 761 protects against endothelial dysfunction in vitro and in vivo. Application of therapeutically feasible doses of EGb 761 for 48 h caused endothelial nitric oxide (NO) production by increasing endothelial nitric oxide synthase (eNOS) promoter activity and eNOS expression in vitro. Phosphorylation of eNOS at a site typical for Akt (Ser 1177) was acutely enhanced by treatment with EGb 761, as was Akt phosphorylation at Ser 478. Furthermore, the extract caused acute relaxation of isolated aortic rings and NO-dependent reduction of blood pressure in vivo in rats. These influences on eNOS represent a putative molecular basis for the protective cardiovascular properties of EGb 761.

74.Gender- and age-related variations in blood viscosity in normal volunteers: a study of the effects of extract of Allium sativum and Ginkgo biloba.:

Phytomedicine. 2007 Aug;14(7-8):447-51. Epub 2007 Jul 6.PMID: 17618098
This study sought to compare the effects of age and gender on blood viscosity and to appraise the effectiveness of Ginkgo biloba and Allium sativum extracts in reducing blood viscosity. Stage 1: Our sample consisted of 80 male volunteers (40 aged 18-60 and 40 aged 61 and over) and 80 females with the same age profile. Stage 2: We studied 60 male volunteers allocated in groups: placebo, G. biloba, and A. sativum. Stage 3: We studied 25 male volunteers and in the initial, intermediate, and final evaluations, the measures of blood viscosity were repeated. Volunteers were given a clinical evaluation and submitted to laboratory tests. G. biloba led to the highest reduction in blood viscosity compared with placebo and A. sativum. In relation to the use of the two substances, G. biloba and A. sativum, dry extract of G. biloba proved to be more effective in reducing blood viscosity.

75.Supervised exercise training combined with ginkgo biloba treatment for patients with peripheral arterial disease.:

Clin Rehabil. 2007 Jul;21(7):579-86.PMID: 17702699
OBJECTIVES: To evaluate whether a combination of supervised exercise training and ginkgo biloba treatment is a better treatment than exercise training alone for patients with peripheral arterial disease.DESIGN: A 24-week double-blind, placebo-controlled ginkgo biloba trial with the first 12-week period as a non-exercise control stage and the second 12-week period as an exercise training stage.SETTING: Exercise physiology laboratory.SUBJECTS: Twenty-two subjects with peripheral arterial disease.INTERVENTIONS: The subjects were randomly allocated into a ginkgo or a placebo group. During the first stage, the ginkgo group ingested standardized ginkgo biloba tablets with a daily dosage of 240 mg, while the placebo group received placebo tablets. During the second stage, all subjects engaged in a supervised treadmill-walking programme while continuing to take the same dosage of ginkgo biloba or placebo tablets.MAIN MEASURES: Walking capacity on treadmill, oxygen consumption during exercise, peripheral haemodynamics and blood viscosity were measured at baseline, and after the first and the second stages of treatment.RESULTS: The ginkgo group did not show significant changes in most of the measured variables after each stage of treatment, except that the maximal walking time was significantly increased after the combined treatment (from 236 +/- 112 seconds to 557 +/- 130 seconds, P < 0.001). However, similar response was also found in the placebo group after exercise training (from 384 +/- 125 seconds to 820 +/- 146 seconds, P < 0.001).CONCLUSION: Supervised exercise training combined with ginkgo biloba treatment did not produce greater beneficial effects than exercise training alone in patients with peripheral arterial disease.

76.Ginkgo biloba (EGb 761) in arteriosclerosis prophylaxis.:

Wien Med Wochenschr. 2007;157(13-14):288-94.PMID: 17704974
The prevention or deceleration of atherogenesis is one of the most significant anti-aging objectives since this is a matter of avoidance of myocardial infarction and stroke. To approach this prophylactic aim, phytochemical nutrition counteracting peroxidation of blood lipids based on their scavenger qualities for reactive oxygen species (ROS) can possibly serve. For example, oxidized LDL particles are highly atherogenic. Against this background, we investigated in a pilot study the effect of Ginkgo biloba (EGb 761: Rökan novo), the free oxygen radical scavenging properties of which are well-documented, on the atherosclerotic nanoplaque formation in cardiovascular high-risk patients. In eight patients who had undergone an aortocoronary bypass operation, the reduction of atherosclerotic nanoplaque formation amounted to 11.9 +/- 2.5% (p < 0.0078) and of nanoplaque size to 24.4 +/- 8.1% (p < 0.0234), respectively, after a 2-month therapy with Ginkgo biloba extract (EGb 761, 2 x 120 mg daily, Rökan novo, Spitzner Arzneimittel, Ettlingen, Germany). Additionally, superoxide dismutase (SOD) activity was upregulated by 15.7 +/- 7.0% (p < 0.0391), the quotient oxLDL/LDL lowered by 17.0 +/- 5.5% (p < 0.0234) and lipoprotein(a) concentration decreased by 23.4 +/- 7.9% (p < 0.0234) in the patients' blood after the 2-month medication regimen. The concentration of the vasodilating substances cAMP and cGMP was augmented by 37.5 +/- 9.1% (p < 0.0078) and 27.7 +/- 8.3% (p < 0.0156), respectively. A multimodal regression analysis reveals a basis for a mechanistic explanation of nanoplaque reduction under ginkgo treatment. The atherosclerosis inhibiting effect is due to an upregulation in the body's own radical scavenging enzymes and an attenuation of the risk factors oxLDL/LDL and Lp(a). Furthermore, the significant increase in the vasodilator cAMP and cGMP concentration powerfully supports the maintenance of an open bypass.

77.Ginkgo biloba extract prevents ethanol induced dyslipidemia:

Am J Chin Med. 2007;35(4):643-52.
Ginkgo biloba extract (EGB) functions as a natural substantial antioxidant and hypolipidemic. Chronic alcohol abuse leads to sustained dyslipidemia characterized by hyperlipidemia and lipid peroxidation. Thus, the present study investigates the effect of EGB on lipid disorders induced by ethanol in rats. Male Sprague-Dawley rats were fed with ethanol (2.4 g/kg), and pretreated with a daily dose of low or high EGB (48 or 96 mg/kg, respectively). During the experiment, serum was collected on day 30, 60, and 90. Serum lipid profile, including lipid peroxidation, was determined by colorimetric methods. Our data showed that ethanol intake resulted in a time-dependent increase in serum levels of triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and malondialdehyde (MDA), and a decrease of the ratio of high-density lipoprotein cholesterol (HDL-C) against TC. EGB prophylactic medication (48 and 96 mg/kg), especially at the high dose, significantly increased HDL-C content, and normalized the abnormal lipid profile and peroxidation in comparison to ethanol-fed only rats. These results suggest that ethanol results in time-dependent hypercholesterolemia, hypertriglyceridemia and promotes serum lipid peroxidation. EGB pretreatment prevents hyperlipidemia and ameliorates lipid peroxidation induced by ethanol.

78.Inhibitory effect of ginkgolide B on platelet aggregation in a cAMP- and cGMP-dependent manner by activated MMP-9.:

J Biochem Mol Biol. 2007 Sep 30;40(5):678-83.PMID: 17927900
Extracts from the leaves of the Ginkgo biloba are becoming increasingly popular as a treatment that is claimed to reduce atherosclerosis, coronary artery disease, and thrombosis. In this study, the effect of ginkgolide B (GB) from Ginkgo biloba leaves in collagen (10 microg/ml)- stimulated platelet aggregation was investigated. It has been known that human platelets release matrix metalloproteinase- 9 (MMP-9), and that it significantly inhibited platelet aggregation stimulated by collagen. Zymographic analysis confirmed that pro-MMP-9 (92-kDa) was activated by GB to form an MMP-9 (86-kDa) on gelatinolytic activities. And then, activated MMP-9 by GB dose-dependently inhibited platelet aggregation, intracellular Ca2+ mobilization, and thromboxane A2 (TXA2) formation in collagen-stimulated platelets. Activated MMP-9 by GB directly affects down-regulations of cyclooxygenase-1 (COX-1) or TXA2 synthase in a cell free system. In addition, activated MMP-9 significantly increased the formation of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), which have the anti-platelet function in resting and collagen-stimulated platelets. Therefore, we suggest that activated MMP-9 by GB may increase the intracellular cAMP and cGMP production, inhibit the intracellular Ca2+ mobilization and TXA2 production, thereby leading to inhibition of platelet aggregation. These results strongly indicate that activated MMP-9 is a potent inhibitor of collagen-stimulated platelet aggregation. It may act a crucial role as a negative regulator during platelet activation.

79.Suppression of oxidized LDL-induced PDGF receptor beta activation by ginkgo biloba extract reduces MMP-1 production in coronary smooth muscle cells.:

J Atheroscler Thromb. 2007 Oct;14(5):219-25. Epub 2007 Oct 12.PMID: 17938538
AIM: An extract of Ginkgo Biloba L. was shown to have preventive effects on cardiovascular disorders, but the molecular mechanisms of its actions remain to be elucidated. Since matrix metalloproteinases (MMPs) are implicated in the rupture of atherosclerotic plaques and the subsequent occurrence of acute coronary syndrome, we examined the effects of a leaf extract (Ginkgolon-24) on the production of MMP-1 in human coronary smooth muscle cells stimulated with oxidized low-density lipoprotein (oxLDL) and 4-hydroxynonenal, which are factors proposed to play a pivotal role in atherogenesis.METHODS: The production of MMP-1 and phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 were estimated by immunoblotting. The tyrosine-phosphorylated form of platelet-derived growth factor receptor beta (PDGFR-beta) was analyzed by immunoprecipitation of the receptor followed by immunoblotting.RESULTS: oxLDL and 4-hydroxynonenal accelerated the production of MMP-1 with the preceding phosphorylation of ERK1/2 and PDGFR-beta;. Pretreatment with Ginkgolon-24 inhibited the production of MMP-1 and phosphorylation of ERK1/2 induced by oxLDL and 4-hydroxynonenal, but did not affect the production and phosphorylation induced by phorbol ester. Furthermore, Ginkgolon-24 prevented tyrosine phosphorylation of the receptor induced by oxLDL and 4-hydroxynonenal.CONCLUSION: These results suggest that Ginkgo Biloba extract suppresses the oxLDL- and 4-hydroxynonenal-induced production of MMP-1, probably through the inhibition of PDGFR-beta activation in human coronary smooth muscle cells.

80.Effect of Ginkgo biloba (EGb 761) and aspirin on platelet aggregation and platelet function analysis among older adults at risk of cardiovascular disease: a randomized clinical trial.:

Blood Coagul Fibrinolysis. 2007 Dec;18(8):787-93.PMID: 17982321
Several case reports have implicated Ginkgo biloba in clinically adverse bleeding disorders. Ginkgo biloba has been reported to increase pain-free walking distance among patients with peripheral artery disease (PAD). Standard PAD therapy includes 325 mg/day aspirin. The objective of this study was to examine potential adverse effects of concomitant aspirin and Ginkgo biloba on platelet function. Ginkgo biloba (EGb 761, 300 mg/day) was compared with placebo for effects on measures of platelet aggregation among adults consuming 325 mg/day aspirin in a randomized, double-blind, placebo-controlled, parallel design trial of 4-week duration. Participants were adults, age 69 +/- 10 years, with PAD or risk factors for cardiovascular disease. Outcome measures included platelet function analysis (PFA-100 analyzer) using ADP as an agonist (n = 26 placebo; n = 29 ginkgo), and platelet aggregation using ADP, epinephrine, collagen and ristocetin as agonists (n = 21 placebo; n = 23 ginkgo). Participants kept daily logs of bleeding or bruising episodes. There were no clinically or statistically significant differences between treatment groups for any agonists, for either PFA-100 analysis or platelet aggregation. Reports of bleeding or bruising were infrequent and similar for both study groups. In conclusion, in older adults with PAD or cardiovascular disease risk, a relatively high dose of Ginkgo biloba combined with 325 mg/day daily aspirin did not have a clinically or statistically detectable impact on indices of coagulation examined over 4 weeks, compared with the effect of aspirin alone. No adverse bleeding events were observed, although the trial was limited to a small sample size.

81.Long-term feeding of Ginkgo biloba extract impairs peripheral circulation and hepatic function in aged spontaneously hypertensive rats.:

Biol Pharm Bull. 2008 Jan;31(1):68-72.PMID: 18175944
We previously demonstrated that Ginkgo biloba extract (GBE) produces an anti-hypertensive effect via enhanced vasodilation responses in young spontaneously hypertensive rats (SHR) and hepatic hypertrophy occurs with increased cytochrome P450 (CYP) mRNA expression in young rats. In the present study, to clarify whether these actions of GBE are observed in older rats, we investigated cardiovascular functions and hepatic CYP protein expressions in aged SHR fed a control diet or a diet containing 0.5% GBE for 4 weeks. In aged SHR, GBE feeding significantly increased liver weight per 100 g body weight without changing the body weight. Furthermore, significant increases in alanine aminotransferase level in serum and marked increase in CYP2B protein expression in the liver were observed in aged SHR fed GBE. On the other hand, GBE feeding did not affect blood pressure, but significantly reduced heart rate and blood flow velocity in tail arteries of aged SHR. Furthermore, GBE feeding did not affect contractile response to phenylephrine, relaxation responses to not only sodium nitroprusside but also acetylcholine, and protein levels of endothelium nitric oxide synthase and soluble guanylate cyclase in aortas of aged SHR. These results suggested that long-term GBE feeding impairs peripheral circulation due to bradycardia and hepatic function in aged SHR. Thus, in the elderly population with hypertension, the use of GBE may need to be assessed for effects on heart rate and liver function.

82.Ginkgo biloba extract improves coronary blood flow in healthy elderly adults: role of endothelium-dependent vasodilation.:

Phytomedicine. 2008 Mar;15(3):164-9. Epub 2008 Feb 6.PMID: 18258419
Advancing age decreases endothelial function; accordingly, it alters the physiological regulation of coronary blood flow. Ginkgo biloba extract (GBE) has well-documented anti-ageing effects. However, little is yet known about the pharmacological actions of GBE on endothelial dysfunction and coronary blood flow in healthy elderly adults. We designed the study to test the effects of GBE on distal left anterior descending coronary artery (LAD) blood flow and endothelium-dependent brachial artery flow-mediated dilation (FMD) in healthy elderly adults. Sixty healthy elderly adults were randomly assigned to either GBE or control groups. LAD blood flow and brachial artery FMD were measured non-invasively using high-resolution ultrasound before and after intravenous administration of GBE or saline. GBE significantly increased LAD blood flow in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with the placebo group (19.16+/-13.91% vs. 0.30+/-2.55%, 17.76+/-14.56% vs. 0.53+/-2.32%, and 21.73+/-16.13% vs. 0.81+/-2.33%, MDPV, MSPV, and DTVI improvement from baseline, respectively, p<0.01). Brachial artery FMD was also increased by 56.03% (from 7.21+/-2.52% to 11.28+/-3.95%, p<0.01). A linear correlation was found between the percentage change in MDPV, MSPV, or DTVI of LAD blood flow and the percentage change in brachial artery FMD following treatment with GBE (r=0.538, 0.366, or 0.573, respectively, p<0.01, p<0.05, or p<0.01). Our data demonstrate that GBE treatment in healthy elderly adults leads to the increase of LAD blood flow in MDPV, MSPV and DTVI, and the increased response might relate to the improved endothelium-dependent vasodilatory capacity. This study implies an important future therapeutic strategy of using GBE to counteract the detrimental effects of ageing.

83.Ginkgo biloba extract improves coronary artery circulation in patients with coronary artery disease: contribution of plasma nitric oxide and endothelin-1.:

Phytother Res. 2008 Jun;22(6):734-9.PMID: 18446847
In patients with coronary artery disease (CAD), coronary blood flow is usually impaired due to imbalanced vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). The study was designed to test the effects of Ginkgo biloba extract (GBE) on the distal left anterior descending coronary artery (LAD) blood flow and plasma NO and ET-1 levels. Eighty CAD patients were randomly assigned to GBE (n = 42) and control (n = 38) groups. The LAD blood flow was assessed non-invasively using Doppler echocardiography at baseline and after 2 weeks. GBE treatment demonstrated a significant improvement in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with controls (14.61 +/- 4.51% vs 0.67 +/- 2.66%, 9.03 +/- 4.81% vs 0.34 +/- 2.67% and 14.69 +/- 5.08% vs 0.68 +/- 3.00%, respectively, p < 0.01). NO was increased by 12.42% (p < 0.01), whereas ET-1 was decreased by 5.82% (p < 0.01). The NO/ET-1 ratio was increased by 19.47% (p < 0.01). A linear correlation was confirmed between the percentage change in LAD blood flow and in NO, ET-1 or NO/ET-1 ratio following GBE treatment. The results suggest that GBE treatment in CAD patients led to an increase of LAD blood flow, which might at least be related partly to the restoration of the delicate equilibrium between NO and ET-1.

84.Investigation of the dose-dependent antivasospasmic effect of Ginkgo biloba extract (EGb 761) in experimental subarachnoid hemorrhage.:

J Clin Neurosci. 2008 Dec;15(12):1382-6. Epub 2008 Oct 31.PMID: 18951801
Many drugs with possible effects against the vasospasm that occurs following a subarachnoid hemorrhage continue to be investigated with great enthusiasm. Among these drugs, the effect of Ginkgo biloba extract (EGb 761) on vasospasm has not been studied extensively. A model of vasospasm was constructed using 30 selected Sprague-Dawley rats. There were four groups in this study: Group I were the untreated control group; vasospasm was induced in Group II, but no treatment was administered; and Groups III and IV experienced vasospasm before being treated with 45 and 90 mg/kg per day EGb 761, respectively. In Group I, the luminal structures of the arteries were normal; the mean vessel lumen area, based on the number of microm(2) units counted in the lumen, was 4931 units. In Group II, signs of inflammation were observed, as well as marked luminal constriction and increase in the thickness of the vessel wall; the mean vessel lumen area was 235 units (p<0.001 vs Group I). In Group III, the endothelial lining was the same as in Group I; the mean luminal area was 4336 units. In Group IV, inflammation occurred as in Group II and the luminal radius was clearly narrowed; the mean luminal area was 131 units (p<0.001 vs Group I). When Ginkgo biloba extract was administered at a dose of 45 mg/kg per day in an experimental vasospasm model, it was effective against vasospasm. However, this effect disappeared at a dose of 90 mg/kg per day.

85.Cardioprotective effect of EGb 761 on myocardial ultrastructure of young and old rat heart and antioxidant status during acute hypoxia.:

Aging Clin Exp Res. 2009 Feb;21(1):14-21.PMID: 19225264
BACKGROUND AND AIMS: Acute hypoxia is a threatening clinical case of emergency and may result in ultrastructural damage, with complete loss of cellular and organ functions. However, little is known about the differences in hypoxia tolerance between young and old myocardia and the protective effects of radical scavenging agents in acute hypoxic stress situations.METHODS: We investigated the age-dependent differences of the myocardial ultrastructure and antioxidative status (superoxide-dismutase (SOD) activity and malondialdehyde (MDA) content) of young (6 months) and old (22-24 months) Wistar rats (Crl (Wi)Br) after acute respiratory hypoxia of 20 min at 5% v/v O2 in N2O mixture, and the protective effect of Ginkgo biloba extract (EGb 761).RESULTS: Ultrastructural-morphometric and biochemical age analysis only revealed a decrease in the sarcoplasma volume fraction, an increase in homogeneous intramitochondrial areas, significant higher SOD activity and lower MDA levels in the group of old rats. Pretreatment with EGb 761 led to a significant decrease in MDA content in both control groups. Acute hypoxic stress increased the volume fractions of sarcoplasmatic reticulum, t-tubules, vacuoles, and lipid droplets, and caused mitochondrial swelling, with a more significant increase in degenerated and homogeneous intramitochondrial areas in the old group. SOD activity decreased only in the old hypoxic group; MDA content fell in both. Pretreatment with EGb 761 reduced ultrastructural-morphometric hypoxic damage in both groups, significantly below the levels of control. Young rat myocardium showed significantly higher SOD activity after hypoxia than untreated or older specimens.CONCLUSIONS: Better hypoxia tolerance is demonstrated by the young myocardium, and an obvious hypoxia-protective effect of EGb 761 in both age groups.

86.Ginkgo biloba for intermittent claudication.:

Cochrane Database Syst Rev. 2009 Apr 15;(2):CD006888.PMID: 19370657
BACKGROUND: People with intermittent claudication suffer from pain in the muscles of the leg occurring during exercise which is relieved by a short period of rest. Symptomatic relief can be achieved by (supervised) exercise therapy and pharmacological treatments. Ginkgo biloba is a vasoactive agent and is used to treat intermittent claudication.OBJECTIVES: To assess the effect of Ginkgo biloba on walking distance in people with intermittent claudication.SEARCH STRATEGY: The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Trials Register (last searched 3 February 2009) and the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (last searched 2009, Issue 1). We searched MEDLINE/PUBMED (January 1966 to May 2008) and EMBASE (January 1985 to May 2008) and contacted manufacturers.SELECTION CRITERIA: Randomised controlled trials of Ginkgo biloba extract, irrespective of dosage, versus placebo in people with intermittent claudication.DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for selection, assessed study quality and extracted data. We extracted number of patients, mean walking distances or times and standard deviations. To standardise walking distance or time, caloric expenditures were used to express the difference between the different treadmill protocols, which were calculated from the speed and incline of the treadmill.MAIN RESULTS: Fourteen trials with a total of 739 participants were included. Eleven trials involving 477 participants compared Ginkgo biloba with placebo and assessed the absolute claudication distance. Following treatment with Ginkgo biloba at the end of the study the absolute claudication distance increased with an overall effect size of 3.57 kilocalories (confidence interval -0.10 to 7.23, P = 0.06), compared with placebo. This translates to an increase of just 64.5 (confidence interval -1.8 to 130.7) metres on a flat treadmill with an average speed of 3.2 km/h. Publication bias leading to missing data or "negative" trials is likely to have inflated the effect size.AUTHORS' CONCLUSIONS: Overall, there is no evidence that Ginkgo biloba has a clinically significant benefit for patients with peripheral arterial disease.

87.Improvement of contractile function in isolated cardiomyocytes from ischemia-reperfusion rats by ginkgolide B pretreatment.:

J Cardiovasc Pharmacol. 2009 Jul;54(1):3-9.PMID: 19487958
Ginkgo biloba extract is an important natural product for treatment of cerebral and cardiovascular diseases, whereas ginkgolide B (GB) is a main component of it. Its effects on ischemic heart and ventricular contractile function in Sprague-Dawley male rats are unclear yet. In the present study, we investigated the function of isolated hearts subjected to ischemia-reperfusion (IR) with or without GB pretreatment by using Millar transducer instruments. We also tested the left ventricular cardiomyocyte shortening amplitude after IR with different concentrations of GB pretreatment for 0.1, 1.0, 2.0, 5.0, and 10.0 microM. The infarct size was tested by triphenyltetrazolium chloride. The release of lactate dehydrogenase (LDH) in the coronary effluent was determined with LDH kit. The expressions of Bcl-2 and Bax were assessed by Western blotting. We found that GB improved the function of left ventricle from IR injury and decreased infarct size and the release of LDH. The cardiomyocyte shortening amplitude depended on different concentrations of GB, which increased significantly at 2.0 microM GB (P < 0.01). The expression of protein Bcl-2 was upregulated by GB and the ratio of Bax to Bcl-2 was decreased by GB. Our results showed that GB can partly prevent IR injury in rat heart.

88.Evaluation of cardioprotective activity of Ginkgo biloba and Ocimum sanctum in rodents.:

Altern Med Rev. 2009 Jun;14(2):161-71.PMID: 19594225
This study investigates the cardioprotective activity of a combined treatment of Ginkgo biloba phytosomes (GBP) and Ocimum sanctum extract (Os) in isoproterenol (ISO)-induced myocardial necrosis in rats. Significant myocardial necrosis, depletion of the endogenous antioxidants superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR), and glutathione (GSH), and increases in the serum marker enzymes aspartate aminotransferase (AST), lactate dehydrogenase (LDH), and creatine phosphokinase (CPK) were observed in ISO-treated rats compared with normal rats. Co-administration of GBP (100 mg per kg) with Os at two doses (50 and 75 mg per kg) for 30 days to rats treated with ISO (85 mg per kg, sc) on the 29th and 30th days demonstrated a significant decrease in ISO-induced serum marker enzyme elevations and a significant attenuation of the ISO-elevated myocardial lipid peroxidation marker malondialdehyde (MDA). A significant restoration of ISO-depleted activities and levels of AST, LDH, CPK, GSH, SOD, CAT, GPx, and GR in the hearts of the treatment groups was observed. The combination of Os 75 mg per kg and GBP 100 mg/kg elicited greater protection than the combination of Os 50 mg per kg and GBP 100 mg per kg. It may be concluded that GBP-Os oral treatment to ISO-challenged rats demonstrates significant cardiac protection, decreases lipid peroxidation, and restores antioxidant activities. However, the combined treatment failed to enhance cardioprotective activity of either herb when used alone.

89.Effects of Ginkgo biloba extract (EGB) on acute myocardial ischemia induced by isoproterenol in rats:

Zhongguo Zhong Yao Za Zhi. 2009 Apr;34(7):900-3.PMID: 19623992
OBJECTIVE: To investigate the therapeutic effects of Ginkgo biloba extract (EGb) in rats with acute myocardial injury induced by isoproterenol (ISO).METHOD: The rats, induced by Isoproterenol (4 mg x kg(-1) x d(-1), 10 d, sc), were divided into groups: sham, model, metoprolol (10 mg x kg(-1) x d(-1), 13 d, ig), EGb (100 mg x kg(-1) x d(-1), 13 d, ig).RESULT: The cardiac parameters of the Model group were compromised significantly in both systolic and diastolic function. Improvement in cardiac function by EGb was significant. In model groups, plasma activities of AST, LDH, CK, HBDH, CKMB and ventricular weight index (LV and RV/BW) were elevated significantly. With the treatment with EGb and metoprolol, the enzymes and ventricular weight index were significantly ameliorated.CONCLUSION: G. biloba extract was beneficial to cardiac performance by improving myocardium enzymes and cardiac function in isoproterenol induced myocardial injury in rats.

90.Does Ginkgo biloba reduce the risk of cardiovascular events?:

Circ Cardiovasc Qual Outcomes. 2010 Jan;3(1):41-7. Epub 2009 Nov 24.PMID: 20123670
BACKGROUND: Cardiovascular disease (CVD) was a preplanned secondary outcome of the Ginkgo Evaluation of Memory Study. The trial previously reported that Ginkgo biloba had no effect on the primary outcome, incident dementia.METHODS AND RESULTS: The double-blind trial randomly assigned 3069 participants over 75 years of age to 120 mg of G biloba EGb 761 twice daily or placebo. Mean follow-up was 6.1 years. The identification and classification of CVD was based on methods used in the Cardiovascular Health Study. Differences in time to event between G biloba and placebo were evaluated using Cox proportional hazards regression adjusted for age and sex. There were 355 deaths in the study, 87 due to coronary heart disease with no differences between G biloba and placebo. There were no differences in incident myocardial infarction (n=164), angina pectoris (n=207), or stroke (151) between G biloba and placebo. There were 24 hemorrhagic strokes, 16 on G biloba and 8 on placebo (not significant). There were only 35 peripheral vascular disease events, 12 (0.8%) on G biloba and 23 (1.5%) on placebo (P=0.04, exact test). Most of the peripheral vascular disease cases had either vascular surgery or amputation.CONCLUSIONS: There was no evidence that G biloba reduced total or CVD mortality or CVD events. There were more peripheral vascular disease events in the placebo arm. G biloba cannot be recommended for preventing CVD. Further clinical trials of peripheral vascular disease outcomes might be indicated.

91.Effect of Ginkgo biloba on blood pressure and incidence of hypertension in elderly men and women.:

Am J Hypertens. 2010 May;23(5):528-33. Epub 2010 Feb 18.PMID: 20168306
BACKGROUND: Accumulating evidence suggests that Ginkgo biloba is cardioprotective, in part, through its vasodilatory and antihypertensive properties. However, definitive data on its blood pressure (BP)-lowering effects in humans is lacking.METHODS: We determined the effects of G. biloba extract (240 mg/day) on BP and incident hypertension in 3,069 participants (mean age, 79 years; 46% female; 96% white) from the Ginkgo Evaluation of Memory (GEM) study. We also examined whether the treatment effects are modified by baseline hypertension status.RESULTS: At baseline, 54% of the study participants were hypertensive, 28% were prehypertensive, and 17% were normotensive. Over a median follow-up of 6.1 years, there were similar changes in BP and pulse pressure (PP) in the G. biloba and placebo groups. Although baseline hypertension status did not modify the antihypertensive effects of G. biloba, it did influence the changes in BP variables observed during follow-up, with decreases in hypertensives, increases in normotensives, and no changes in prehypertensives. Among participants who were not on antihypertensive medications at baseline, there was no difference between treatment groups in medication use over time, as the odds ratio (95% confidence interval (CI)) for being a never-user in the G. biloba group was 0.75 (0.48-1.16). The rate of incident hypertension also did not differ between participants assigned to G. biloba vs. placebo (hazard ratio (HR), 0.99, 95% CI, 0.84-1.15).CONCLUSIONS: Our data indicate that G. biloba does not reduce BP or the incidence of hypertension in elderly men and women.

W-Ginkgo Biloba:Chronic venous insufficiency,Blood circulation,Microcirculation,Research:

1.Increase in circulating endothelial cells in patients with primary chronic venous insufficiency: protective effect of Ginkor Fort in a randomized double-blind, placebo-controlled clinical trial.:

J Cardiovasc Pharmacol. 1999 Jan;33(1):7-11.PMID: 9890390
One possible mechanism that accounts for the alterations observed in varicose veins is the activation of endothelial cells by ischemia occurring in the leg veins during blood stasis and the cascade of reactions that follows. Because in vitro data suggest that endothelium alteration is a key event in the development of the pathology, it was important to confirm this hypothesis in patients. We used the number of circulating endothelial cells detached from the vascular wall as a criterion of the endothelium injury. We first compared the number of circulating endothelial cells (CECs) in patients with chronic venous insufficiency (CVI) with those of a control population. A twofold increase in the CEC count (1,001+/-127 CEC/ml of plasma compared with 514+/-82 CECs/ml) was observed in CVI patients, which indeed suggests an alteration of the endothelium in this disease. Second, the protective effect of a venotropic drug, Ginkgo biloba extract, troxerutine, and heptaminol (Ginkor Fort), was tested by a randomized double-blind, placebo-controlled clinical trial. In the active-treatment group, the mean values of the CEC count decreased by 14.5% after a 4-week treatment, whereas in the placebo group, the decrease was less (8.4%). The decrease from week 0 to the end of treatment was significantly higher in the active-treatment group than in the placebo group. These results confirm the important role of the endothelium alterations in the development of varicose veins and suggest a potential beneficial action of a venotropic drug on the venous wall.

2.Production technology and analysis of blood circulation improving tincture:

Medicina (Kaunas). 2003;39 Suppl 2:76-9.PMID: 14617864
This article deals with the production of the tincture of Ginkgo biloba leaves, Crataegus fruits and Leonurus herbs while selecting an extractant, the size of particles in a raw material and possible methods of extraction. The optimal composition of ethanol 70%, the particle size of Ginkgo biloba leaves and Crataegus fruits 2-3 mm of Leonurus herbs. The method of production--percolation, the flow speed 0.5 ml/min. The tincture was analyzed at determination of the sum of flavonoids in terms of quercetin, dry residue, relative density, ethanol concentration. The quality of the tincture was evaluated by high-pressure liquid chromatography and spectrophotometry. The stability of the tincture and its expiry date were fixed.

3.Comparative vasodilating actions among terpenoids and flavonoids contained in Ginkgo biloba extract.:

Clin Chim Acta. 2004 Jan;339(1-2):129-33.PMID: 14687903
BACKGROUND: Comparative vasodilating actions of the constituents of Ginkgo biloba extract (GBE), terpenoids (bilobalide, ginkgolides A, B and C) and flavonoids (quercetin and rutin), were examined using rat aorta ring strips.METHODS: Cumulative administrations of GBE and its constituents were followed with the pretreatment of 5 micromol/l NE.RESULTS: GBE at 0.03 to 3 mg/ml had a potent concentration-dependent relaxation; by 70 +/- 4.5% (n = 6, P < 0.001) at 3 mg/ml. Terpenoids and flavonoids at 0.1 to 100 micromol/l had potent concentration-dependent relaxation. At 100 micromol/l, bilobalide dilated by 17.6 +/- 3.9% (n = 7, P < 0.05), and ginkgolides A, B and C also caused it to the almost same extent. Quercetin (100 micromol/l) caused a potent vasorelaxation by 49.9 +/- 4.8% (n = 10, P < 0.001). Rutin at 100 micromol/l had weaker vasorelaxation; by 13.7 +/- 3.2% (n = 6, P < 0.01).CONCLUSIONS: All constituents of GBE have the concentration-dependent vasorelaxtant effect. The potency of GBE's action was not made simply by addition of those of the constituents. Each constituent itself would contribute to the GBE-induced vasodilation, although the constituents have the complicated interactions with each other.

4.The assessment of medical therapy effectiveness of patients with lower limb chronic venous insufficiency: the results of prospective study with Ginkor Fort:

Angiol Sosud Khir. 2005;11(3):47-52.PMID: 16439948
The results of prospective study on combined agent Ginkor Fort are presented. The study included 60 patients with variceal disease and clinical picture of chronic venous insufficiency (CVI), II-IV CEAP class. Besides the registration of common and well known subjective signs (lower limb pain, heaviness and discomfort feelings, night palsies and paresthesia, edema), the main outcome measures included the results of digital photo-plethysmography (PPG). Initial assessment demonstrated the decrease of both venous return time (To) and muscular-venous pump capacity (Vo) with the increase of CEAP class; the trend of To appeared to be statistically significant (p=0.0318). The treatment resulted in the regression of main clinical complaints according to the 6-score analog scale. PPG showed the rise of to from 19.5+/-4.9 s to 20.5+/-3.7 s, though this trend was statistically insignificant (p>0.05). Vo elevated significantly from 3.69+/-2.4% to 4.04+/-2.3% (p<0.05), demonstrating the grown functional capacities of leg pump. PPG with To and Vo analysis can be used in combination with ultrasonic examination for the quantitative assessment of venous outflow disturbances and accordingly, of the CVI severity. This method can serve as an indicator of conservative treatment effectiveness. Combined agent Ginkor Fort is feasible for adjunctive therapy in complex treatment of patients with lower limb CVI symptoms.

5.Influence of Ginkgo biloba on ocular blood flow.:

Acta Ophthalmol Scand. 2007 Jun;85(4):445-9. Epub 2007 Feb 27.PMID: 17324220
PURPOSE: To investigate the effect of Ginkgo biloba extract (EGb761) on ocular blood flow.METHODS: This randomized, double-masked, placebo-controlled, two-way crossover study included 15 healthy male volunteers. Measurements were taken with laser Doppler flowmetry, laser Doppler velocimetry, a retinal vessel analyser, laser interferometry and applanation tonometry, before and up to 3 hours after oral intake of 240 mg EGb761.RESULTS: At baseline, no significant differences in ocular and systemic haemodynamic parameters were observed between the two study days. Ginkgo biloba significantly decreased retinal venous diameters (p < 0.05 versus baseline), but there was no significant difference between the two groups. Blood pressure, retinal arterial and venous diameters, choroidal blood flow, fundus pulsation amplitude, intraocular pressure and retinal blood flow remained unchanged in both groups and did not differ between groups. Optic nerve head blood flow significantly increased in response to Ginkgo biloba (p < 0.002 versus baseline), but this effect was not significant compared with that of placebo.CONCLUSIONS: The results of this study indicate that a single administration of Ginkgo biloba does not influence ocular blood flow to a relevant degree. Whether the drug may influence ocular blood flow in patients with ocular vascular disease after longterm treatment remains to be investigated in a randomized, placebo-controlled clinical trial.

X-Ginkgo Biloba:Psychopharmacological effects,Cerebral tissue Research:General Pharmacology Property

1.The psychopharmacological effects of Ginkgo biloba extract in normal healthy volunteers.(Psycho):

Int J Clin Pharmacol Res. 1984;4(2):89-93.
Eight healthy female volunteers received Ginkgo biloba extract (G.B.E.) 120, 240, 600 mg and placebo according to a randomized, double-blind crossover design. One hour following treatment, subjects completed a battery of psychological tests including critical flicker fusion (CFF), choice reaction time (CRT), subjective ratings of drug effects (LARS) and a Sternberg memory scanning test. No statistically significant changes from placebo were observed on CFF, CRT or subjective ratings of drug effects. However, memory as assessed using the Sternberg technique was found to be significantly improved following treatment with G.B.E. 600 mg when compared to placebo and results suggested a localized effect of the drug on the serial comparison stage of the reaction process.

2.Effects of an extract of Ginkgo biloba on noradrenergic systems of rat cerebral cortex.(Psycho):

Pharmacol Res Commun. 1985 Nov;17(11):1063-72.PMID: 3003764
Oral treatment of rats with Ginkgo biloba extract (Gb) elicited a biphasic effect on normetanephrine (NMN) content of cerebral cortex; an initial decrease was evident after 45 minutes, followed by a marked increase that was evident after 14 days. Chronic treatment with Gb led to decreases in the density of 3H-dihydroalprenolol binding (after 27 days or 2 months) and in isoproterenol-stimulated adenylate cyclase activity (after 2 months) of the cerebral cortex. Taken together, these results indicate that the effects of Gb on the central beta-adrenergic system might be involved in its therapeutic actions.

3.Clinical psychopharmacology of Ginkgo biloba extract:(Psycho:)

Presse Med. 1986 Sep 25;15(31):1595-604.PMID: 2947109
From this general review of the pharmacological, psychopharmacological and clinical studies performed with Ginkgo biloba extract, the following conclusions can be drawn: the drug seems to be effective in patients with vascular disorders, in all types of dementia and even in patients suffering from cognitive disorders secondary to depression, because of its beneficial effects on mood. Of special concern are people who are just beginning to experience deterioration in their cognitive function. Ginkgo biloba extract might delay deterioration and enable these subject to maintain a normal life and escape institutionalization. In addition, Ginkgo biloba extract appears to be a safe drug, being well tolerated, even in doses many times higher than those usually recommended.

4.Effects of an extract of Ginkgo biloba on the 3',5'-cyclic AMP phosphodiesterase activity of the brain of normal and triethyltin-intoxicated rats.:(Psycho:)

J Neurochem. 1987 Jul;49(1):107-14.PMID: 3035090
For clarification of the beneficial effects of the extract of Ginkgo biloba (EGB) on triethyltin (TET) toxicity in rats, the phosphodiesterase (PDE) activities of the cerebral tissue were measured under in vitro and ex vivo conditions. Under in vitro conditions, low concentrations of EGB (0.25-4.0 mg/L) activated the enzyme, whereas after higher concentrations (5-250 mg/L), dose-dependent inhibition of the enzyme activity was observed. In the lower concentration range, the extract also partially restored the high-affinity PDE activity (measured with 0.25 microM cyclic AMP) of the particulate fraction of the brain inhibited by TET in vitro. In contrast, the inhibitory influence of TET on the low-affinity PDE activity (measured with 50 microM cyclic AMP) of the particulate fraction was enhanced by the extract. Although treatment with a single large dose of EGB lowered the particulate PDE activities of the brain of normal rats, no effects of the extract could be detected in animals after repeated daily administrations of EGB during a 4-day period. Curative treatment of the TET-intoxicated rats with EGB during a 7-day period accelerated the recovery of the edematous state of the white matter caused by the intoxication and also normalized the lowered PDE activity of the particulate fraction of the edematous brain tissue. Furthermore, when preventively administered, EGB counteracted both the edema formation and the fall in PDE activity observed with treatment by TET alone. These observations strongly suggest that some beneficial effects of EGB might be due to its modulating influences on cellular cyclic AMP levels via activation of membrane-bound PDE.

5.NCDEU update. Natural product formulations available in europe for psychotropic indications.:(Psycho)

Psychopharmacol Bull. 1995;31(4):745-51.PMID: 8851648
Until the middle of this century, development of medical treatment for human disease was intimately connected with the plant kingdom. Despite advances of the last three decades in utilizing chemical synthetic approaches to drug design and sophisticated structure-activity studies, there is still a great need for novel compounds with unique mechanisms of action in the field of medicine. While many thousands of structural analogs have been synthesized and tested, numerous gaps remain in the therapeutic armamentarium for psychiatric illnesses. Most new drugs marketed for psychotherapeutic indications in recent years have been only incremental improvements on existing medications. Major breakthroughs have resulted primarily from the study of natural products. Some of our most valuable drugs have been isolated from plant and animal sources, including aspirin, morphine, reserpine (the first antipsychotic), almost all of our antibiotics, digitalis, and such anti-cancer agents as vincristine, vinblastine, and taxol. Recent political and social events suggest that new emphasis will be placed on natural products research in the years to come. This article highlights therapeutic applications of Ginkgo biloba, Hypericum perforatum, Valerian officinalis, and Panex ginseng.

6.Peroxidation of synaptosomes alters the dopamine uptake complex but spares the exocytotic release of dopamine.:(Psycho:antioxidant)

Neurodegeneration. 1995 Jun;4(2):155-60.PMID: 7583679
Synaptosomes, prepared from the striata of mice, and incubated for 1 h in a Krebs-Ringer medium with the peroxidative combination of ascorbic acid (0.1 mM)/Fe2+ (1 microM), lose their ability to take up [3H] dopamine. This effect is associated with a decrease in binding of the dopamine uptake inhibitor [3H] GBR 12783. The free radical scavenger trolox C (0.1 mM) and the Ginkgo biloba extract EGb 761 (10 micrograms/ml) prevent both effects. Although submitted to these peroxidative conditions after loading with [3H] DA, superfused synaptosomes retain their ability to release [3H] DA when depolarized by high potassium concentrations (40 mM). This release is higher than that observed when synaptosomes are incubated without ascorbic acid/Fe2+, and does not seem to depend upon peroxidation, since it is also observed when incubation is performed in the presence of the free radical scavengers EGb 761 (10 micrograms/ml) and trolox C (0.1 mM).

7.Lipid peroxide, phospholipids, glutathione levels and superoxide dismutase activity in rat brain after ischaemia: effect of ginkgo biloba extract.:(Psycho:post-ischaemic injury)

Pharmacol Res. 1995 Nov;32(5):273-8.PMID: 8868056
The influence of ginkgo biloba extract on the lipid peroxide product (malondialdehyde, MDA), glutathione (GSH) and phospholipids levels as well as superoxide dismutase (SOD, 1.15.1.1) and lactate dehydrogenase (LDH, 1.1.1.27) activities in rat brain after occlusion of common carotid arteries was investigated. Two experimental models were studied: 60 min ischaemia without reperfusion and 60 min ischaemia followed by 60 min reperfusion. Compared to sham-operated animals, ischaemia followed by reperfusion increased cytosolic LDH activity and mitochondrial lipid peroxide content and decreased the superoxide dismutase activity and mitochondrial total phospholipids level. Preischaemic administration of ginkgo biloba extract (150 mg kg-1, p.o.) could normalize the SOD activity of the rat brain. The extract was also able to reduce the lipid peroxide and phospholipids contents of the mitochondrial rat brain. These effects could be explained on the basis of the antioxidant property of ginkgo biloba extract and suggests its beneficial role in the protection against post-ischaemic injury.

8.Central Nervous System Effects of Ginkgo Biloba, a Plant Extract.:(Psycho)

Am J Ther. 1996 Jan;3(1):63-73.PMID: 11856998
Extracts of Ginkgo biloba (EGb) are among the most prescribed drugs in France and Germany. EGb is claimed to be effective in peripheral arterial disorders and in "cerebral insufficiency." The mechanism of action is not yet well understood. Three of the ingredients of the extract have been isolated and found to be pharmacologically active, but which one alone or in combination is responsible for clinical effects is unknown. The recommended daily dose (3 x 40 mg extract) is based more on empirical data than on clinical dose-findings studies. However, despite these, according to double-blind, placebo-controlled clinical trials, EGb has therapeutic effects, at least, on the diagnostic entity of "cerebral insufficiency," which is used in Europe as synonymous with early dementia. To determine whether EGb has significant pharmacological effects on the human brain, a pharmacodynamic study was conducted using the Quantitative Pharmacoelectroencephalogram (QPEEG(R)) method. It was established that the pharmacological effects (based on a predetermined 7.5--13.0-Hz alpha frequency band in a computer-analyzed electroencephalogram = CEEG(R)) of EGb on the central nervous system (CNS) are significantly different than placebo, and the high and low doses could be discriminated from each other. The 120-mg, but particularly the 240-mg, single doses showed the most consistent CNS effects with an earlier onset (1 h) and longer duration (7 h). Furthermore, it was established that the electrophysiological effects of EGb in CNS are similar to those of well-known cognitive activators such as "nootropics" as well as tacrine, the only marketed "antidementia" drug currently available in the United States.

9.Herbal remedies in psychiatric practice.:(Psycho)

Arch Gen Psychiatry. 1998 Nov;55(11):1033-44.PMID: 9819073
Patients' use of alternative and complementary health services has created a need for physicians to become informed about the current literature regarding these treatments. Herbal remedies may be encountered in psychiatric practice when they are used to treat psychiatric symptoms; produce changes in mood, thinking, or behavior as a side effect; or interact with psychiatric medications. English-language articles and translated abstracts or articles (where available) found on MEDLINE and sources from the alternative/complementary health field were reviewed. Each herb was assessed for its safety, side effects, drug interactions, and efficacy in treating target symptoms or diagnoses. A synopsis of the information available for each herb is presented. In many cases the quantity and quality of data were insufficient to make definitive conclusions about efficacy or safety. However, there was good evidence for the efficacy of St John's wort for the treatment of depression and for ginkgo in the treatment of memory impairment caused by dementia. More research is required for most of the herbs reviewed, but the information published to date is still of clinical interest in diagnosing, counseling, and treating patients who may be taking botanical remedies.

10.Evidence that gingko biloba extract does not inhibit MAO A and B in living human brain.:(Psycho:)

Life Sci. 2000 Jan 21;66(9):PL141-6.PMID: 10698362
Extracts of Ginkgo biloba have been reported to reversibly inhibit both monoamine oxidase (MAO) A and B in rat brain in vitro leading to speculation that MAO inhibition may contribute to some of its central nervous system effects. Here we have used positron emission tomography (PET) to measure the effects of Ginkgo biloba on human brain MAO A and B in 10 subjects treated for 1 month with 120 mg/day of the Ginkgo biloba extract EGb 761, using [11C]clorgyline and [11C]L-deprenyl-D2 to measure MAO A and B respectively. A three-compartment model was used to calculate the plasma to brain transfer constant K1 which is related to blood flow, and lambdak3, a model term which is a function of the concentration of catalytically active MAO molecules. Ginkgo biloba administration did not produce significant changes in brain MAO A or MAO B suggesting that mechanisms other than MAO inhibition need to be considered as mediating some of its CNS effects.

11.Effects of bilobalide on amino acid release and electrophysiology of cortical slices.:(Psycho:neuroactive)

Amino Acids. 2002 Jun;22(4):369-79.PMID: 12107763
This study investigated the effects of bilobalide, a constituent of Ginkgo biloba, on potassium and veratridine-induced release of glutamate and aspartate from mouse cortical slices. We also studied its effects on spontaneous and N-methyl-D-aspartate (NMDA)-induced depolarizations elicited in magnesium-free artificial cerebrospinal fluid (aCSF) as well as its effect on NO-711 (a gamma-aminobutyric acid (GABA) uptake inhibitor)-induced depolarizations. Bilobalide, 100 microM significantly reduced both glutamate and aspartate release elicited by potassium or veratridine. Bilobalide (5-100 microM) also significantly reduced the frequency of NO-711 induced depolarizations, however, it had no effect on spontaneous or on NMDA-induced depolarizations at 5-200 microM. These results suggest that the neuroactive properties of bilobalide may be mediated by a reduction in excitatory amino acid neurotransmitter release.

12.Preparation of 7-substituted ginkgolide derivatives: potent platelet activating factor (PAF) receptor antagonists.:(Psycho:)

J Med Chem. 2003 Feb 13;46(4):601-8.PMID: 12570381
Ginkgolides are structurally unique constituents of Ginkgo biloba extracts and are known antagonists of the platelet-activating factor (PAF) receptor. Ginkgolide C is 25-fold less potent than ginkgolide B as a PAF receptor antagonist, due to the presence of the 7beta-OH. Recently, we found that 7alpha-fluoro ginkgolide B was equipotent to ginkgolide B underlining the critical importance of the 7-position of ginkgolides for PAF receptor activity. Herein we describe the synthesis of a series of ginkgolide B derivatives with modifications at the 7-position and the pharmacological evaluation of these derivatives as assayed by cloned PAF receptors. In two cases nucleophilic attack on a 7beta-O-triflate ginkgolide B did not lead to the expected products, but gave rise to two unprecedented ginkgolide derivatives, one with a novel rearranged skeleton. Furthermore, standard reduction of 7alpha-azido ginkgolide B did not give the expected primary amine, but instead yielded alkylated amines depending on the solvent employed. Pharmacological testing with cloned PAF receptors showed that ginkgolides with 7alpha-substitutents had increased affinity compared to 7beta-substituents, in particular 7alpha-chloro ginkgolide B, the most potent nonaromatic ginkgolide derivative described to date with a K(i) value of 110 nM.

13.Protective effects of ginkgo leaf extracts on neurons in spinal cord after ischemia-reperfusion injury in rabbits:(Psycho)

Zhong Xi Yi Jie He Xue Bao. 2006 Mar;4(2):181-4.PMID: 16529696
OBJECTIVE: To observe the protective effects of ginkgo leaf extracts on spinal cord after ischemia-reperfusion (IR) injury in rabbits and to find out its possible mechanism.METHODS: Twenty-seven New Zealand white rabbits were randomly divided into three groups, which were sham-operation group, untreated group and ginkgo leaf extracts-treated group. The locomotor scores of hindlimbs in rabbits after 24 and 48 h of reperfusion were evaluated, and the activity of superoxide dismutase (SOD) and the content of malondialdehyde (MDA) in ischemia spinal cord were examined. The apoptotic index (AI) of neurons in spinal cord was detected by terminal deoxyribonucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) method. The expressions of Bcl-2 and Bax proteins were examined by streptavidin-biotin peroxidase method.RESULTS: The locomotor scores of hindlimbs in rabbits after 24 and 48 h of reperfusion in the ginkgo leaf extracts-treated group were obviously elevated as compared with those in the untreated group (P<0.05). The activity of SOD was higher and the level of MDA was lower in ischemia spinal cord in the ginkgo leaf extracts-treated group than those in the untreated group (P<0.01). The decreased neuron AI and the expressions of up-regulated Bcl-2 protein and down-regulated Bax protein were also observed in the ginkgo leaf extracts-treated group.CONCLUSION: The protective effects of the ginkgo leaf extracts against spinal cord injury induced by IR may be related to scavenging oxygen free radicals, reducing lipid peroxidation injury and inhibiting apoptosis.

14.The Ginkgo biloba extract, EGb 761, fails to reduce brain infarct size in rats after transient, middle cerebral artery occlusion in conditions of unprevented, ischemia-induced fever.:(Psycho:)

Phytother Res. 2006 Jun;20(6):438-43.PMID: 16619358
There is much biochemical evidence, but very few studies in animal models of stroke in vivo, to suggest that Ginkgo biloba (EGb 761) may offer neuroprotection against regional, ischemic brain damage; additional investigations are needed to ensure future clinical trials. This study reports the effects of EGb 761 given acutely or chronically before ischemia. Rats were subjected to middle cerebral artery occlusion (MCAO) for 2 h and the brain infarct size was assessed 24 h later. Dipyrone (100 mg/kg, i.p.) was injected 30 min before ischemia, and 2.5 and 5.5 h after ischemia, to reduce ischemia-induced fever. EGb 761 (Tebonin) was given acutely (200 mg/kg, p.o., 60 min before ischemia) or chronically (100 mg/kg, p.o., once daily, for 14 days before ischemia). Acute or chronic treatment with EGb 761, either alone or in combination with dipyrone, did not reduce the infarct size compared with saline alone (p > 0.05). Dipyrone failed to prevent ischemia-induced fever during the intra-ischemic period (p > 0.05 vs saline; p < 0.001 vs sham). In the reperfusion phase, dipyrone reduced fever to normothermic levels in the group treated acutely with EGb 761 (p < 0.01 vs saline, p > 0.05 vs sham) but not after chronic EGb 761 (p < 0.01 vs sham), indicating possible pharmacokinetic interaction. In conclusion, within the context of unprevented, ischemia-induced fever, the present results demonstrate that EGb 761 has no significant effect on brain infarct size.

15.Effect of Ginkgo biloba (EGb 761) on treadmill walking time among adults with peripheral artery disease: a randomized clinical trial.:(Psycho:PAD)

J Cardiopulm Rehabil Prev. 2008 Jul-Aug;28(4):258-65.PMID: 18628657
PURPOSE: Medical therapies for treatment of peripheral artery disease (PAD) are limited. Ginkgo biloba has been reported to increase maximal and pain-free walking distance among patients with PAD; however, the evidence is inconsistent. The objective of this study was to compare the effects of 300 mg/d of Ginkgo biloba (EGb 761) versus placebo on treadmill walking time and related cardiovascular measures among patients with PAD.METHODS: A double-blind, placebo-controlled, parallel design trial with a 4-month duration was used. Participants were 62 adults, aged 70 +/- 8 years (mean +/- SD), with claudication symptoms of PAD. The primary study outcomes were maximal and pain-free walking time on a treadmill. Secondary outcomes included flow-mediated vasodilation, a measure of antioxidant status as assessed by determining antibody levels to epitopes of oxidized low-density lipoprotein, and questionnaires addressing walking impairment and quality of life.RESULTS: Maximal treadmill walking time increased by 20 +/- 80 and 91 +/- 242 seconds in the placebo and the EGb 761 groups, respectively (P = .12). Pain-free walking time increased by 15 +/- 31 and 21 +/- 43 seconds, respectively (P = .28). No significant differences were detected between groups for any of the secondary outcomes.CONCLUSIONS: In older adults with PAD, Ginkgo biloba produced a modest but insignificant increase in maximal treadmill walking time and flow-mediated vasodilation. These data do not support the use of Ginkgo biloba as an effective therapy for PAD, although a longer duration of use should be considered in any future trials.

16.Effects of Ginkgo biloba constituents related to protection against brain damage caused by hypoxia.:(Psycho:hypoxia-damage)

Pharmacol Res Commun. 1988 May;20(5):349-68.PMID: 3420139
The purpose of the present study was to approach the compound(s) responsible for the beneficial effects of an extract of Ginkgo biloba leaves (EGB) on animals subjected to hypoxia. In this first approach we compared the effects of the flavone and the non-flavone fraction of EGB with those of the whole extract on mice in lethal hypoxia (3.5% O2), on brain energy metabolism of artificially ventilated rats inspiring 7% O2, and on local cerebral blood flow (LCBF) of normoxic rats. The latter two experimental settings should also extend the knowledge about the underlying mechanisms of the antihypoxidotic actions. EGB as well as its non-flavone fraction considerably prolonged the survival time of mice under lethal hypoxia. EGB retarded the breakdown of brain energy metabolism in the hypoxic artificially ventilated rat. A corresponding effect was exerted by the non-flavone fraction while the flavone fraction even worsened the metabolic state. The non-flavone fraction increased LCBF in the majority of 35 examined brain regions; a similar effect could be seen after EGB-treatment, while the flavone fraction caused only minor alterations of LCBF. We conclude that the non-flavone fraction of EGB carries the antihypoxidotic activity. Metabolic effects are suggested to cause this activity. Further studies are necessary to elucidate the effective compound within this fraction.

17.Effect of Ginkgo biloba extract on arteriolar spasm in rabbits:(Psycho:spasm)

Presse Med. 1986 Sep 25;15(31):1520-3.PMID: 2947092
Injectable Ginkgo biloba extract, administered intravenously to rabbits, suppressed the vasospasm induced by the topic application of autologous serum on brain surface. This effect was dose-dependent as for as the normalization of the arterial diameter and duration of spasm were concerned. In animals previously treated with oral Ginkgo biloba extract, the almost complete disappearance of spasm was observed at intervals of time similar to those observed after intravenous injection.

18.Effects of bilobalide on gamma-aminobutyric acid levels and glutamic acid decarboxylase in mouse brain.:(Psycho:anticonvulsant)

Eur J Pharmacol. 1999 Feb 19;367(2-3):165-73.PMID: 10078989
We have previously demonstrated that bilobalide, a constituent of the Ginkgo biloba extract, possesses anticonvulsant activity, and suggested that the mechanism of its anticonvulsant action involves modulation of y-aminobutyric acid (GABA)-related neuronal transmission. This study examined the effects of bilobalide on the level of GABA and glutamate, the activity and the amount of glutamic acid decarboxylase (EC 4.1.1.15), and the function of GABA(A) receptors in the hippocampus, cerebral cortex and striatum of the mouse. GABA levels, glutamic acid decarboxylase activity, and the protein amount of 67 kDa glutamic acid decarboxylase in the hippocampus of mice treated with bilobalide (30 mg/kg, p.o., once a day for 4 days) were significantly higher than those in controls. However, there were no significant differences in glutamate levels or, the number and the dissociation constants of GABA(A) receptors in the hippocampus between control and bilobalide-treated mice. These results suggest that the anticonvulsant effect of bilobalide is due to elevation of GABA levels, possibly through potentiation of glutamic acid decarboxylase activity and enhancement of the protein amount of 67 kDa glutamic acid decarboxylase by bilobalide.

Xa-Ginkgo Biloba:Cerebral Ischemia Research:

1.Experimental model of cerebral ischemia preventive activity of Ginkgo biloba extract (author's transl):

Sem Hop. 1979 Dec 18-25;55(43-44):2047-50.
Unilateral embolization of the brain was performed in rats by intracarotid injection of 4 000 radioactive microspheres (50 mu). Local blood flow in hippocampus, striatum, hypothalamus and remainder of the brain were determined using the iodoantipyrine technique. Embolization resulted in a decreases in blood flow and modificationof the distribution of microflow. Furthermore, embolization produces changes in energy metabolism : particularly a fall in ATP and glucose levels and an increase in lactate level. Subsequently, severe vasogenic edema developed. There was a correlation between the number of microspheres injected and the amount of edema. Pretreatment using an extracted of Ginkgo biloba leaves partially suppressed the effect of embolization. An improvement of the flow in the ischemic areas associated with an improvement of the energy metabolism explain the decreases of the edema.

2.Effects of Ginkgo Biloba on changes induced by quantitative cerebral microembolization in rats.:

Arch Int Pharmacodyn Ther. 1980 Feb;243(2):236-44.PMID: 7377897
Unilateral embolization of the brain was performed in rats by the intracarotid injection of 4000 radioactive microspheres (50 micron). The local blood flow was determined using the iodoantipyrine technique in the hippocampus, hypothalamus, striatum and remainder of the brain. Embolization resulted in a decrease in the blood flow and a modification of the distribution of microflow. Besides, the embolization produced changes in energy metabolism, specially a fall in ATP and glucose levels and an increase in lactate level. Subsequently severe vasogenic cerebral edema developed. There was a correlation between the number of microspheres injected and the extent of edema. Pretreatment with an extract of Ginkgo Biloba leaves partially suppressed the effects of the embolization. An increase in the blood flow associated with normalization of cellular energy metabolism explained the decrease in brain edema.

3.Researches on the antiaggregative activity of Ginkgo biloba extract (author's transl):

Sem Hop. 1980 Feb 18-25;56(7-8):393-8.PMID: 6246639
Sodium lactate applied on the pia-mater of the rabbit induces the appearance of venous platelets thrombi. The same phenomenon occurs in the arteries after electric stimulation of the arterial wall. Gingo biloba extract, i.v. and per os, has been shown capable to partially antagonize these effects, particularly in the venous microcirculation. The ratio between the activity following the two modes of administration is about 1 to 5.

4.Cerebral ischemia after ligature of both carotid arteries in rats: effect of ginkgo biloba extracts (author's transl:

Sem Hop. 1982 Feb 18;58(7):403-6.
Simultaneous ligature of both carotid arteries in Long Evans rats results in death for all animals. 50% of the animals survive if the ligatures are separated by a four-day interval. Studies of variations in cerebral blood flow according to the time interval between the two ligatures show that alternative vascularization develops and that the balance between both hemibrains is restored. After giving L-dopa3H to animals with ligature of both carotids, increased synthesis of cerebral dopamine 3H and norepinephrine 3H can be demonstrated. When animals are given extracts of Ginkgo biloba leaves prior to carotid ligatures, survival rate is improved and dopamine synthesis increased, without marked changes in cerebral blood flow. This is related to increased brain cell activity in spite of hypoxia due to carotid ligature.

5.Double blind study of the hypoxia protective effect of a standardized Ginkgo biloba preparation after repeated administration in healthy subjects:

Arzneimittelforschung. 1985;35(8):1283-6.
A randomised, placebo-controlled, double-blind, crossover study was run in 8 healthy, male subjects (mean age 27.3 +/- 2.6 years, mean BW 75.3 +/- 9.7 kg) to demonstrate a possible hypoxia-protective effect of standardised Ginkgo flavone glycosides after subchronical administration. After a 14-days' treatment with Ginkgo bilobae extract (Tebonin) performance of subjects was studied--concerning assessments of oculomotor and complex choice reaction system as well as simple cardiorespiratory parameters under multiple exposure to hypoxic hypoxia (10.5% oxygen, 89.5% nitrogen)--using oculodynamic methodology (ODT). Hypoxia increased the corneoretinal resting-potential of the eye and stimulated respiration. Both parameters were significantly reduced by verum administration. Under cumulative exposure to hypoxic hypoxia fixation time of saccadic eye movements and complex choice reaction time were significantly improved by Ginkgo flavone glycosides vs placebo. These results could be explained as a hypoxia-protective phenomenon--supporting the therapy of cerebral insufficiency.

6.The Ginkgo biloba extract, EGb761, increases synaptosomal uptake of 5-hydroxytryptamine: in-vitro and ex-vivo studies.:

J Pharm Pharmacol. 1992 Nov;44(11):943-5.PMID: 1361545
The Ginkgo biloba extract (EGb 761) added to a synaptosomal fraction prepared from mice cerebral cortex modified [3H]5-hydroxytryptamine ([3H]5-HT) uptake in a biphasic manner. Between 4 and 16 micrograms mL-1 EGb 761 increased significantly the [3H]5-HT uptake (maximum + 23%). A similar increase was also obtained when synaptosomes were prepared from the cortex of mice treated orally with EGb 761, either acutely (100 mg kg-1, 14 h and 2 h before death) or semi-chronically (2 x 100 mg-1 kg daily for 4 consecutive days). The in-vitro increase in [3H]5-HT uptake induced by EGb 761 was not observed in the presence of 10(-6) M clomipramine, a 5-HT-uptake inhibitor. EGb 761 did not increase [3H]dopamine uptake by synaptosomes prepared from striatum of mice. We investigated different fractions of EGb 761 in order to determine the compounds inducing the increase in [3H]5-HT uptake. The BN 52063 extract (corresponding to the EGb 761 devoid of flavonoid substances) did not increase [3H]5-HT uptake. The Cp 202 extract (corresponding to the EGb 761 devoid of terpenic substances and containing mostly flavonoid substances) increased [3H]5-HT uptake. Among the flavonoids, quercetin has been tested and had no effect on the [3H]5-HT uptake. Since at the usual therapeutic doses of EGb 761, the effective concentrations of the components responsible for this increase are likely to be reached in the brain, one may suggest that this effect could contribute to the therapeutic effect of EGb 761.

7.A double blind placebo controlled trial of ginkgo biloba extract in acute cerebral ischaemia.:

J Assoc Physicians India. 1995 Nov;43(11):760-3.PMID: 8773035
A double blind placebo controlled trial was conducted in 55 patients of acute ischaemic stroke. Twenty one and twenty six patients were randomly allotted in group A and group B respectively. In group A, the patients received 40 mg Ginkgo biloba extract at 6 hourly intervals along with routine management. The placebo tablets were dispensed in the tablet form of same size, shape and colour and were given in the same way. After the patients were subjected to computerized tomographic (CT) scan to confirm acute ischaemic infarction, they were assessed on Mathew's scale and reassessed, at 2 weeks and 4 weeks of drug/placebo administration. Both groups showed significant improvement in Mathew's scale score after 2 weeks and 4 weeks. The difference in degree of change was negligible (p > 0.05) in either group. Estimation of relative changes of neurological deficit based on baseline values also showed negligible (p > 0.05) difference. A trial of Ginkgo biloba extract within 6 hours of stroke in a larger dose and in larger sample could be beneficial clinically in patients of cerebral ischaemic infarct, and needs further study. The usefulness of the plant extract has been demonstrated clinically and experimentally in more than 40 trials of chronic cerebral ischaemia, done elsewhere. This was not evident in our study as our study group was different (more than 48 hours after stroke). There appears to be no contraindication or adverse effect of this medication (Ginkgo biloba) in acute ischaemic stroke.

8.Extracts of Ginkgo biloba and ginsenosides exert cerebral vasorelaxation via a nitric oxide pathway.:

Clin Exp Pharmacol Physiol. 1997 Dec;24(12):958-9.PMID: 9406663
1. Extracts from the leaves of Ginkgo biloba (EGb) and ginsenosides (GS) have been reported to be effective at increasing vascular relaxation. In the present study, the actions of EGb and GS on the vascular functions of porcine basilar arteries were investigated in vitro using tissue bath techniques. 2. Both EGb and GS relaxed the basilar artery in a concentration-dependent and partly endothelium-dependent manner. However, EGb appeared to be more potent than GS. Relaxation induced by transmural nerve stimulation (TNS) was significantly enhanced by EGb (7.5, 15 and 30 micrograms/mL) and GS (20, 40 and 80 micrograms/mL) in both endothelium-intact and -denuded basilar arteries. Enhanced TNS-induced relaxations were abolished by 0.3 mmol/L N-L-arginine. 3. The present study demonstrates that nitric oxide plays a primary role in TNS-induced relaxation as well as in EGb- and GS-enhanced relaxation within the cerebral vasculature. In addition, our data support the potential of these compounds as therapeutic strategies in cerebral ischaemia and other related vascular dysfunctions.

9.Effects of EGb 761 on fatty acid reincorporation during reperfusion following ischemia in the brain of the awake gerbil.:

Mol Chem Neuropathol. 1998 May;34(1):79-101.PMID: 9778647
Transient cerebral ischemia (5 min) releases unesterified fatty acids from membrane phospholipids, increasing brain concentrations of fatty acids for up to 1 h following reperfusion. To understand the reported anti-ischemic effect of Ginkgo biloba extract (EGb 761), we monitored its effect on brain fatty acid reincorporation in a gerbil-stroke model. Both common carotid arteries in awake gerbils were occluded for 5 min, followed by 5 min of reperfusion. Animals were infused intravenously with labeled arachidonic (AA) or palmitic acid (Pam), and rates of incorporation of unlabeled fatty acid from the brian acyl-CoA pool were calculated by the model of Robinson et al. (1992), using quantitative autoradiography and biochemical analysis of brain acyl-CoA. Animals were treated for 14 d with 50 or 150 mg/kg/d EGb 761 or vehicle. Ischemia-reperfusion had no effect on the rate of unlabeled Pam incorporation into brain phospholipids from palmitoyl-CoA; this rate also was unaffected by EGb 761. In contrast, ischemia-reperfusion increased the rate of incorporation of unlabeled AA from brain arachidonoyl-CoA by a factor of 2.3-3.3 compared with the control rate; this factor was further augmented to 3.6-5.0 by pretreatment with EGb 761. There is selective reincorporation of AA compared with Pam into brain phospholipids following ischemia. EGb 761 further accelerates AA reincorporation, potentially reducing neurotoxic effects of prolonged exposure of brain to high concentrations of AA and its metabolites.

10.Effects of ginkgo biloba extract on impairment of learning induced by cerebral ischemia in mice.:

Am J Chin Med. 1998;26(2):127-32.PMID: 9799964
The effect of Ginkgo biloba extract (GbE) on cerebral ischemia induced by 10-min bilateral occlusion of the carotid arteries in mice was studied. Severe impairment of memory was apparent when the passive avoidance test was carried out 48 hr after bilaterally induced ischemia. When GbE at doses of 50 and 100 mg/kg was given p.o. 1 hr before the 10-min occlusion, there was a significant improvement in memory. The i.p. injection of ifenprodil (30 mg/kg) also showed improvement on learning tasks. The p.o. administration of flavonoid, a fraction isolated from GbE, showed high step-through latency on scopolamine-induced amnesia. All these findings indicate that GbE is beneficial for clinical use in amnesia accompanied with cerebral vascular disease.

11.The efficacy of treating cerebral ischemia due to changes in the major cerebral arteries by using the preparation Tanakan (EGB 761)]:

Lik Sprava. 1998 Aug;(6):125-7.PMID: 9844896
Cerebrovascular pathology is one of the chief causes of death. Effects were studied of the drug preparation "Tanakan" on the process of the rehabilitation of those patients (n = 150) operated on for abnormalities and deformity of brain major arteries. Two groups were identified: pathologies of the vertebral arteries (n = 50), carotid abnormalities (n = 51), control groups (n = 24 and 25 respectively). The drug was administered in a dose of 40 mg on a three-times daily schedule. Clinical approaches were used as were the dopplerographic, electroencephalographic, biochemical, micromorphological, neuropsychological methods of investigation. Determined in the study was a positive dynamics of clinical indices, which was more apparent for vertebrobasilar discirculations. EEG-investigation revealed differences in the course of changes in left- and right-hemispheric location of carotidogenous discirculations. Increase in blood serum antioxidant activity was recorded as was a positive transformation of vegetative indices and improvement of cognitive functions. Thus, the use of the above drug is indicated in the postoperative complex of rehabilitative measures in patients with cerebrovascular ischemia secondary to developmental anomalies and deformities of brain major arteries.

12.Ginkgo biloba extract (EGb 761) protects Na,K-ATPase activity during cerebral ischemia in mice.:

Neuroreport. 1999 Jan 18;10(1):47-51.PMID: 10094131
Neuroprotective drugs such as Ginkgo biloba extract (EGb 761) could prevent the ischemia-induced impairment of the Na,K-ATPase activity. In this study, Na,K-ATPase activity and expression, contents in fatty acids and malondialdehyde, an index of lipoperoxidation, were compared in the ipsilateral (ischemic) and the contralateral (unlesioned) cortices after 1 h of unilateral focal cortices cerebral ischemia in the mouse. EGb 761 (110 mg/kg) was administered daily to half of the animals for 10 days before ischemia. Ischemia significantly reduced Na,K-ATPase activity by about 40% and increased malondialdehyde content; EGb 761 pretreatment abolished these effects. The free radical scavenger properties of EGb 761 are a potential mechanism by which Na,K-ATPase injury and lipoperoxidation are prevented.

13.The protective effect of EGb 761 in isolated ischemic/reperfused rat hearts: a link between cardiac function and nitric oxide production.:

J Cardiovasc Pharmacol. 1999 Nov;34(5):711-7.PMID: 10547088
This study was conducted to evaluate the effect of Ginkgo biloba extract (EGb 761) on the nitric oxide (NO) production in relation to the recovery of postischemic cardiac function in isolated working rat hearts. Rats were orally treated with various doses (25, 50, 75, and 100 mg/kg/day) of EGb 761 for 10 days. Hearts were isolated in "working mode" and subjected to 30-min ischemia followed by 120 min of reperfusion. EGb 761 inhibited NO production measured by electron spin-resonance spectroscopy (ESR), and improved the recovery of postischemic cardiac function (coronary flow, aortic flow, left ventricular developed pressure and its first derivative) in the ischemic/reperfused myocardium. Thus in rats treated with 25, 50, 75, and 100 mg/kg/day of EGb 761 and in hearts subjected to 30-min ischemia followed by 120 min of reperfusion, aortic flow was increased from its postischemic drug-free control value of 8.0+/-0.4 to 8.6+/-0.4 ml/min (NS), 17.3+/-0.9 ml/min (p<0.05), 21.5+/-1.1 ml/min (p<0.05), and 23.6+/-1.2 ml/min, respectively. The same recovery in postischemic coronary flow, left ventricular developed pressure, and its first derivative also was observed. In the initial phase of reperfusion, NO production measured by ESR was reduced by 85% in the 75 mg/ kg/day of EGb 761-treated group in comparison with the drug-free ischemic/reperfused hearts. Inducible NO synthase (iNOS) messenger RNA (mRNA) measured by reverse transcription-polymerase chain reaction (RT-PCR) also was reduced by 41 and 58% in the groups treated with 75 and 100 mg/kg/day of EGb 761, respectively. Our findings show that EGb 761 directly acts as an NO scavenger and concomitantly inhibits the expression of iNOS mRNA. Thus, EGb 761 may act as a potent inhibitor of NO production under the condition of ischemia/reperfusion, improving the recovery of postischemic cardiac function.

14.Protective effect of ginkgo extract on rat brain with transient middle cerebral artery occlusion.:

Neurol Res. 2000 Jul;22(5):517-21.PMID: 10935227
It has been empirically known that Ginkgo extract is useful for reducing many symptoms associated with cerebral blood flow (CBF) insufficiency, but its mechanisms have been uncertain. In the present study, therefore, we gave Ginkgo extract to rats with per os digestion, and investigated its effect on CBF and ischemic brain damage with middle cerebral artery occlusion (MCAO). The treatment with Ginkgo extract (10 mg 100 g-1 rat) increased CBF in the normal condition, but the degree of increase in CBF was lesser during and after MCAO. TTC staining showed that infarct volume was reduced with Ginkgo treatment. TUNEL and HSP72 immunostaining confirmed the protective effect of Ginkgo treatment reducing numbers of TUNEL and HSP72 positive cells. Immunohistochemical analysis showed that caspase-3 expression was less abundant in Ginkgo treated rats. The present results suggest that Ginkgo extract contains a substance which increases normal CBF and reduces ischemic brain damage.

15.Preliminary EEG study of protective effects of Tebonin in transient global cerebral ischemia in rats.:

Rom J Physiol. 1998 Jan-Jun;35(1-2):161-8.PMID: 11000876
Free radicals and platelet activating factor (PAF) have been implicated as important mediators in neuronal injury after cerebral ischemia-reperfusion and, particularly, in postischemic hypoperfusion. The electroencephalography (EEG) is a real time reflection of changes in neuronal activity and metabolism. The objective of this study was to investigate the effects of preventive treatment with Ginkgo biloba extract (EGb 761--Tebonin) in cerebral global ischemia and reperfusion in rats using computerized EEG analysis. Ginkgo biloba extract, known to be, in vitro, a free radicals scavanger and a PAF--antagonist, was administrated in dose of 100 mg/kg over 24 hours, for 5 days before and 5 days after cerebral ischemia--reperfusion. The apparition of isoelectric EEG (flat-line) following 4-vessel occlusion was observed after a mean time of 25 sec. in Ginkgo biloba treated rats and after 18 sec. in control rats (p < 0.0015). Computerized spectral analysis of EEG has shown that the percentage of slow waves at 10 minutes after reperfusion was 117% higher in control group than in Ginkgo biloba group (p < 0.015) and the percentage of slow waves after 15 minutes of reperfusion was 100% higher in the control group than in the Ginkgo biloba group (p < 0.02). Five days after cerebral ischemia--reperfusion the percentage of slow waves was unsignificantly higher in the control group than in the Ginkgo biloba group (p > 0.05).

16.Neuroprotective effects of Ginkgo biloba extract in brain ischemia are mediated by inhibition of nitric oxide synthesis.:

Life Sci. 2000 Oct 20;67(22):2673-83.PMID: 11105983
We studied the effects of pre-treatment (15 days) with oral administration of Ginkgo biloba extract (Ph-Gb 37.5-150 mg/kg) on brain malonildialdehyde (MDA), brain edema, brain nitrite and nitrate and delayed neuronal death following transient cerebral ischemia in the Mongolian gerbil. Survival was not modified, however, pre-treatment with Ginkgo biloba significantly and in a dose-dependent way reduced post-ischemic brain MDA levels and post-ischemic brain edema. Delayed neuronal death in the CA1 of the hippocampus was attenuated by the highest dose of the extract. Increase of nitrite and nitrate was observed after cerebral ischemia in the hippocampus and it was dose-dependently reduced in animals pretreated with Ph-Gb, thus suggesting that neuroprotective effects of Ginkgo biloba may be due to an inhibitory action on nitric oxide formation.

17.The therapeutic effect of Ginkgo biloba extract in SHR rats and its possible mechanisms based on cerebral microvascular flow and vasomotion.:

Clin Hemorheol Microcirc. 2000;23(2-4):133-8.PMID: 11321432
This paper aimed to investigate the therapeutic effect of an extract of Ginkgo biloba leaves (EGb 761) on hypertension and its possible mechanisms in the view of cerebral microcirculation. Twenty normotensive rats and 24 SHR rats were used. Surgical preparation was made to produce a cranial window for observation of the capillary network on the cerebral cortex. The intravital videomicroscopy equipped with digital image processing system and laser Doppler flowmeter were used for this study. The arterial blood pressure, red cell velocity (V), microvacular diameter (D), number of open capillaries (OCN), circulating endothelial cells (CEC) in blood, relative blood flow (Flow) and frequency (Fc), amplitude (AMP) of vasomotion were measured. The obtained data were compared between EGb-treated rats that received per os 100 mg/kg/d for 9 days and placebo control rats. Untreated SHR rats showed very severe dysfunction in the microcirculation with high blood pressure (213 +/- 16.7 mmHg). The blood pressure decreased significantly to 153 +/- 20 mmHg in EGb-treated SHRs group, compared with those of untreated rats (p < 0.01). Both normotensive and hypertensive rats increased the blood flow velocity and LDF flow after EGb-treatment. The vasomotion property, the CEC and OCN changed greatly in EGb-treated SHR rats, but no significant difference was observed in normotensive rats. It was suggested that EGb 761 had therapeutic effect on SHR rats by increasing blood perfusion, regulating vasomotion function, opening efficiently capillaries and releasing the peripheral resistance. The injured vascular endothelium of SHR rats was also partly reversed by EGb-treatment. It was concluded that EGb 761 could be used to regulate hypertension and to protect the cerebral microcirculatory function.

18.Effects of Ginkgo biloba extract on somatosensory evoked potential, nitric oxide levels in serum and brain tissue in rats with cerebral vasospasm after subarachnoid hemorrhage.:

Clin Hemorheol Microcirc. 2000;23(2-4):139-44.PMID: 11321433
This study aimed to investigate the protective effects of Ginkgo biloba extract on cerebral vasospasm and neural damage following subarachnoid hemorrhage (SAH) in rats. It was found that the regional cerebral blood flow decreased immediately and persistently after SAH in SAH rats. The latency of somatosensory evoked potential delayed progressively. The nitric oxide levels in serum and brain tissue decreased and increased, respectively, after SAH. Ginkgo biloba extract effectively antagonized the changes of above parameters. It was concluded that somatosensory evoked potential is useful for the judgement of cerebral ischemic damage during cerebral vasospasm after SAH. Decrease in serum nitric oxide and increase in brain tissue nitric oxide are important factors leading to cerebral vasospasm and neural damage, respectively, after SAH. Ginkgo biloba extract relieves cerebral vasospasm and cerebral ischemic damage by reversing the pathological alteration of nitric oxide.

19.Relationship between endothelin-1 and ischemic brain damage after subarachnoid hemorrhage and protective effect of Ginkgo biloba extract:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 1998 Nov;18(11):677-9.PMID: 11477864
OBJECTIVE: To investigate the role of endothelin-1 (ET-1) in development of ischemic brain damage after subarachnoid hemorrhage (SAH), and the protective effect of Ginkgo biloba extract (GBE).METHODS: Wistar rat noncraniotomy models of SAH were divided into SAH group and GBE treated group, the diameter of basilar artery (BA) and dynamic changes of regional cerebral blood flow (rCBF) and ET-1 content of intracranial plasma within 24 hours after SAH of both groups were determined. And pathological examination of CA1 region of hippocampus was performed 3 days later.RESULTS: rCBF decreased and ET-1 content increased obviously and retained in 24 hours after SAH. Spasm of BA occurred half an hour after SAH and neurons of hippocampus CA1 region was damaged severely. GBE could antagonize the above-mentioned pathological changes effectively.CONCLUSION: Increase of ET-1 is an important factor leading to ischemic brain damage after SAH. GBE exerts its protective effect by antagonizing pathological increase of ET-1.

20.Protective effects of folium Ginkgo extract on experimental cerebral ischemia of mice:

Zhongguo Zhong Yao Za Zhi. 1998 Mar;23(3):169-71, inside backcover.PMID: 11596238
Folium Ginkgo extract(EGb761) has been proved able to significantly prolong the survival time of mice suffering from cerebral ischemia induced by occluding bilateral common carotids, and reduce the inhibition of cerebral GSH-Px and Na(+)-K(+)-ATPase activities during reperfusion processes of these mice. Pretreatment with EGb761 also helps alleviate the subcellular damages in hippocampus of cerebral ischemic mice.

21.Chronic daily administration of selegiline and EGb 761 increases brain's resistance to ischemia in mice.:

Brain Res. 2001 Nov 2;917(2):174-81.PMID: 11640903
Brief cerebral ischemia is reported to cause selective neuronal necrosis, apoptotic cell death, silent infarcts and, when recurrent, cognitive decline. Acute administration of selegiline and EGb 761 have been shown to have anti-apoptotic and neuroprotective effects in experimental ischemia. Their daily use is currently advised to slow down cognitive decline in patients with vascular dementia. Hence, unlike previous studies, we studied the neuroprotective action of chronic daily administration of these drugs in Swiss mice subjected to 30-min middle cerebral artery occlusion and 72 h of reperfusion since this model was reported to induce a slowly evolving infarct with profuse apoptotic cell death. Infarct area was evaluated by H&E staining on coronal brain sections and, apoptotic cells were identified by histological criteria, terminal transferase-mediated d-UTP nick-end labeling (TUNEL) and by immunohistochemical detection of caspase-cleaved actin fragments (fractin). Fifty-one mice received daily intraperitoneal injections of 10 mg/kg selegiline (n=18) or 50 mg/kg EGb 761 (n=17) or equal volume of saline (n=16) for 10-14 days before but not on the day of insult. The infarct volume, number of TUNEL- and fractin-positive cells were significantly reduced in treatment groups by 30, 42 and 51% (selegiline) and, 27, 27 and 29% (EGb 761), respectively. These data suggest that prophylactic use of selegiline and EGb 761 could increase the brain's resistance to mild ischemic injury.

22.Protective effect of extract of folium ginkgo on repeated cerebral ischemia-reperfusion injury:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000 May;20(5):356-8.PMID: 11789248
OBJECTIVE: To study the protective effect of extract of Folium Ginkgo (FGE) on repeated cerebral ischemia-reperfusion injury.METHODS: The model in waking mice induced by repeated cerebral ischemia-reperfusion were used in the experiment to observe the effect of FGE on behavior, oxygen free radical metabolism and prostaglandin E2 (PGE2) content by step-through experiment, diving stand and colorimetric method.RESULTS: FGE could obviously improve the learning ability and memory of model animals, and could lower obviously the content of malonyldialdehyde, nitric oxide and PGE2, restore the lowered activity of superoxide dismutase and catalase in cerebral tissue.CONCLUSION: FGE has highly protective effect against repeated ischemia-reperfusion injury, the mechanism might be related with its action on anti-lipid oxidatin, improve the activity of antioxidase and inhibit the producing of PGE2.

23.Gingko biloba extract (EGb 761) prevents increase of Bad-Bcl-XL interaction following cerebral ischemia.:

Am J Chin Med. 2009;37(5):867-76.PMID: 19885947
A standardized extract of Gingko biloba, EGb 761, has been shown to exert a neuroprotective effect against permanent and transient focal cerebral ischemia. This study investigated whether EGb 761 modulates Bcl-2 family proteins in ischemic brain injury. Male adult rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO), brain tissues were collected 24 hours after MCAO. EGb761 administration significantly decreased the number of TUNEL-positive cells in the cerebral cortex. Ischemic brain injury induced decrease of Bcl-2 and Bcl-X(L) levels. EGb 761 prevented not only the injury-induced decrease of Bcl-2 and Bcl-X(L) levels, but also the injury-induced increase of Bax. Moreover, in the presence of EGb 761, the interaction of Bad and Bcl-X(L) decreased compared to that of vehicle-treated animals. In addition, EGb 761 prevented the injury-induced increase of cleaved PARP. The finding suggests that EGb 761 prevents cell death against ischemic brain injury and EGb 761 neuroprotection is affected by preventing the injury-induced increase of Bad and Bcl-X(L) interaction.

24.Protective effects of a Ginkgo biloba extract (EGb 761) on ischemia-reperfusion injury:

Therapie. 2001 Sep-Oct;56(5):595-600.PMID: 11806299
EGb 761 is a standardized extract of dried leaves of Ginkgo biloba. EGb 761 is a neuroprotective and anti-ischaemic drug. Its broad spectrum of pharmacological activities allows it to be adequate to the numerous pathological requirements--haemodynamic, haemorrheological, metabolic--which occur in cerebral, retinal, cochleovestibular, cardiac or peripheral ischaemia. Moreover, EGb 761 has direct effects in retinal and myocardial ischaemia and reperfusion injuries. EGb 761 improves retinal microcirculation, reduces oedema of the retinal inner layer and protects chemoreceptors against free-radical injuries. On myocardial ischaemia-reperfusion models, EGb 761 improves myocardial functional recovery, and reduces the number of ventricular extrasytoles and the duration of ventricular tachycardia induced by reperfusion. EGb 761 protects the retina and the heart against ischaemia-reperfusion damage via its free radical-scavenging and anti-lipoperoxidative properties and its regulation of mitochondrial respiratory function.

25.Acute administration of Ginkgo biloba extract (EGb 761) affords neuroprotection against permanent and transient focal cerebral ischemia in Sprague-Dawley rats.:

J Neurosci Res. 2002 Jun 1;68(5):636-45.PMID: 12111854
We examined the neuroprotective action of a standardized extract of Ginkgo biloba leaves (EGb 761) in permanent and transient middle cerebral artery (MCA) occlusion models in Sprague-Dawley rats. Forty-four animals were given either EGb 761 (50-200 mg/kg) or vehicle intraperitoneally, 1 hr before permanent MCA occlusion, to evaluate the dose-response effects. An additional 58 animals received EGb 761 (200 mg/kg) or vehicle, 0.5- 4 hr after permanent MCA occlusion, for establishing the therapeutic window. Delayed treatment was also employed in 110 animals treated with either EGb 761 (100-200 mg/kg) or vehicle at 2-3 hr following transient focal cerebral ischemia induced by MCA occlusion for 2 hr. Neurobehavioral scores were determined 22-24 hr after permanent MCA occlusion and either 3 or 7 days after transient MCA occlusion, and brain infarction volumes were measured upon sacrifice. Local cortical blood flow (LCBF) was serially measured in a subset of animals receiving EGb 761 (100-200 mg/kg) or vehicle, 0.5 hr and 2 hr after permanent and transient MCA occlusion, respectively. Relative to vehicle-treated controls, rats pretreated with EGb761 (100 and 200 mg/kg) had significantly reduced infarct volumes, by 36% and 49%, respectively, and improved sensory behavior (P < 0.05). Delayed treatment with EGb 761 also significantly reduced brain infarction, by 20-29% and 31%, when given up to 2 and 3 hr following transient and permanent MCA occlusion, respectively, whereas improved neurobehavioral scores were noted up to 2 hr after the onset of MCA occlusion (P < 0.05). LCBF was significantly improved in the ipsilateral cortex following the EGb 761 treatment, whereas a higher dose showed a more sustained effect. In conclusion, EGb 761 protected against transient and permanent focal cerebral ischemia and was effective after a prolonged reperfusion period even when therapy is delayed up to 2 hr. This neuroprotection may be at least partially attributed to the beneficial effects of selectively improved LCBF in the area at risk of infarction.

26.Bilobalide, a component of the Ginkgo biloba extract (EGb 761), protects against neuronal death in global brain ischemia and in glutamate-induced excitotoxicity.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):663-9.PMID: 12396077
In this study, the effect of bilobalide, a purified terpene lactone component of the Ginkgo biloba extract (EGb 761), and EGb 761 against ischemic injury and against glutamate-induced excitotoxic neuronal death was compared. In the case of ischemic injury, neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in the hippocampal regions of gerbils was measured. A significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons at 7-days of reperfusion after 5 min of transient global forebrain ischemia. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected hippocampal CA1 neurons against ischemia-induced neuronal death and reductions in COX III mRNA. In rat cerebellar neuronal cultures, addition of bilobalide or EGb 761 protected in a dose-dependent manner against glutamate-induced excitotoxic neuronal death [effective concentration (EC50) = 5 microg/ml (12 microM) forbilobalide and 100 microg/ml for EGb 761]. These results suggest thatboth EGb 761 and bilobalide protect against ischemia-induced neuronal death in vivo and glutamate-induced neuronal death in vitro by synergistic mechanisms involving anti-excitotoxicity, inhibition of free radical generation, scavenging of reactive oxygen species, and regulation of mitochondrial gene expression.

27.Ginkgo biloba extract (EGb 761) protects Na,K-ATPase isoenzymes during cerebral ischemia.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):671-9.PMID: 12396078
Disturbances of Na,K-ATPase activity are implicated in the pathophysiology of cerebral ischemia. Previous experiments have shown that EGb 761 protects NaK-ATPase activity against one hour of cerebral ischemia. In the brain however, the 3 isoenzymes responsible for Na,K-ATPase activity may be differentially affected by various times of ischemia. In the present study, we investigated the effect of a longer period of ischemia, and the protection provided by a pre-treatment with EGb 761 on each of the 3 cerebral NaK-ATPase isoenzymes. In control and EGb 761 pre-treated mice exposed to a 6 hr unilateral occlusion of the middle cerebral artery, Na,K-ATPase activity was decreased by 60% and lipid peroxidation was increased by 40% in the ipsilateral (ischemic) cortex compared to the contralateral one. In parallel, membrane integrity was altered. The alteration of NaK-ATPase activity, as a whole, resulted from a decrease in the activity of the 3 isoenzymes. The two isoenzymes of high ouabain affinity however, had their affinities decreased while the sensitivity of the lowest affinity isoenzyme was increased. Pre-treatment with EGb 761 abolished the differences observed between ipsi- and contralateral cortex, with the exception of the change in ouabain affinity of the low affinity isoenzyme. Ischemia also induced changes in Na,K-ATPase isoenzyme ouabain affinities in the contralateral cortex that where not prevented by EGb 761.

28.Protective effects of Ginkgo biloba extract on rats during cerebral ischemia/reperfusion.:

Chin Med J (Engl). 2002 Sep;115(9):1316-20.PMID: 12411102
OBJECTIVE: To study the effect of Ginkgo biloba extract on rats during ischemia/reperfusion and its influence on intracellular calcium in hippocampal neurons.METHODS: Model of intraluminal occlusion of the middle cerebral artery (MCAO) was used to prepare the ischemia/reperfusion cortex tissue. Concentration of MDA was determined by measuring thiobarbituric acid-reactive substance. GSH-PX was quantified using the thiobarbituric acid (TBA) technique. SOD was assayed througha xanthine method. Endogenous amino acids were quantified by high performance liquid chromatographic (HPLC) analysis. Primary culturs of hippocampal neurons were prepared for a free intracellular calcium ([Ca(2+)]I) assay by Fura-2 based single cell microfluoremetric technique.RESULTS: Comparing control and treatment groups, the concentration of SOD and GSH-PX were higher, whereas that of MDA was much lower; the concentration of glutamate and aspartate decreased and that of GABA increased markedly at all time point (P < 0.01), Gly also decreased at some time points (P < 0.05). The differences were significant between the groups of 10 mg/kg, 15 mg/kg and the groups of 5 mg/kg. When 1 x 10(-5) mol/L glutamate was applied with 25 micro g/ml ginkgo biloba extract to cultured neurons, the increase in [Ca(2+)]I was lower than that caused by applying glutamate alone. Its peak value was much lower and increased phase was longer, its declining phase was shorter. After returning to baseline, the application of 1 x 10(-5) mol/L glutamate could induce the reaction to recover.CONCLUSIONS: Ginkgo biloba extract could protect damaged neurons by keeping the balance of inhibitory/excitatory aminoacids, enhancing the free radical scavengers system, and inhibiting the effect of glutamate on [Ca(2+)]I.

29.Effects of ginkgo biloba extract on somatosensory evoked potential and nitric oxide after subarachnoid hemorrhage:

Zhongguo Zhong Yao Za Zhi. 2001 May;26(5):329-32.PMID: 12528524
OBJECTIVE: To observe the changes of somatosensory evoked potential(SEP) and nitric oxide (NO) after subarachnoid hemorrhage(SAH), and the influence of Ginkgo biloba extract (EGb).METHOD: Rats in sham-operated group, SAH model group and EGb-treated group underwent measurement of dynamic changes of regional cerebral blood flow(rCBF), SEP and NO levels both in serum and in brain tissue within 24 h after operation.RESULT: In SAH group, rCBF decreased immediately after operation, with no tendency to recover within 24 h. The latency of SEP delayed progressively from 1 h to 24 h after SAH. NO levels in serum and in brain tissue decreased and increased respectively from 1 h to 24 h after SAH. EGb effectively antagonized the changes of above parameters.CONCLUSION: SEP is helpful in the judgement on brain ischemic damage after SAH. Decrease of NO in serum and increase of that in brain tissue may lead to cerebral vasospasm and ischemic brain damage respectively after SAH. EGb relieves SAH-induced brain ischemic damage by reversing the pathological alterations of NO.

30.Ginkgo biloba extract preserves pyruvate and enhances ascorbate in the cortex of gerbils during focal cerebral ischemia. A microdialysis-liquid chromatography study.:

J Chromatogr A. 2003 Jan 24;985(1-2):387-94.PMID: 12580507
The aim of this study was to evaluate dynamic changes in energy-related metabolites in the cortex of gerbils subjected to focal cerebral ischemia after pretreatment with Ginkgo biloba extract. Focal cerebral ischemia was induced by occlusion of the right common carotid artery and the right middle cerebral artery for 60 min in anesthetized gerbils. A microdialysis probe was inserted into the cortex to monitor extracellular lactate. pyruvate and ascorbate during ischemia and reperfusion. The present study demonstrated a dynamic decrease in pyruvate (25% of baseline) and increases in lactate (160% of baseline) and asorbate (300% of baseline) and a 5-fold increase in the lactate:pyruvate (L:P) ratio during cerebral ischemia in the control group. However. pyruvate levels were preserved and ascorbate levels were enhanced with a chronic pretreatment of Ginkgo biloba extract for 8 days (i.p., 100 mg kg(-1) day(-1)). Preservation of pyruvate and enhancement of ascorbate observed in this study may be associated with the neuroprotective effects of Ginkgo biloba extract.

31.The effects of Ginkgo biloba extracts on the memory and motor functions of rats with chronic cerebral insufficiency.:

Neuropsychobiology. 2003;47(1):47-51.PMID: 12606845
The main goal of the current study was to investigate the effects of two Ginkgo leaf extracts, EGb 761 and an extract of local Ginkgo leaf (LGb), on the memory and motor functions of rats with chronic cerebral insufficiency (produced by bilateral common carotid artery ligation). After the operation, spatial memory and motor functions were tested for over 80 days. Tests included (1) radial-arm maze test for testing spatial memory and locomotor activity and (2) muscle force and hind limbs for escape. The results indicate that both EGb 761 and LGb improved spatial memory from the second week after operation, but only EGb 761 delayed deterioration of motor functions from the fifth week after operation.

32.Effects of Ginkgo biloba extract on acute cerebral ischemia in rats analyzed by magnetic resonance spectroscopy.:

Acta Pharmacol Sin. 2003 May;24(5):467-71.PMID: 12740184
AIM: To study the effect of Ginkgo biloba extract (GbE) on acute cerebral ischemia in rats.METHODS: The rats were randomly divided into four groups: sham-operated group (group I as control), ischemic group (group II), the prophylactic (GbE premedication) group (group III) and GbE-treatment group (group IV). Magnetic resonance spectroscopy (MRS) was carried out to dynamically monitor the changes in biochemical metabolic variations 48 h after cerebral ischemia and effects of GbE (100 mg/kg, ip, qd).RESULTS: (1) Lactate (Lac) peak could be detectable at the infarction area 90 min after acute cerebral ischemia and increased with time. Lac peak in the prophylactic group was elevated slightly (P<0.01, n=6), whereas in the treatment group the elevation of Lac was more remarkable than that in the prophylactic group (P<0.05, n=6). (2) In the ischemic group, the level of N-acetyl aspartate (NAA) was decreased within 4 h after ischemia (P<0.05, n=6), and the decline persisted (P<0.01, n=6). In the treatment group and prophylactic group, NAA was decreased slightly after 24 h (P<0.05, n=6). (3)Twenty-four hours after ischemia, in both ischemic group and treatment group, choline (Cho) was elevated slightly (P<0.05, n=6) and creatine (Cr) was decreased slightly (P<0.05, n=6), but in the prophylactic group these changes occurred only after 48 h.CONCLUSION: GbE could prevent and treat acute cerebral ischemia. The effectiveness was more satisfactory when GbE was used preventively

33.The protective effect of EGb 761 in isolated isochemical/reperfused rat hearts:

Acta Pharm Hung. 2002;72(4):265-71.PMID: 12812048
This study was conducted to evaluate the effect of Ginkgo biloba extract (EGb 761) on the nitric oxide (NO) production in relation to the recovery of postischemic cardiac function in isolated working rat hearts. Rats were orally treated with various doses (25, 50, 75, and 100 mg/kg/day) of EGb 761 for 10 days. Hearts were isolated in "working mode" and subjected to 30 min ischemia followed by 120 min reperfusion. In the initial phase of reperfusion, NO production measured by electron spin resonance spectroscopy (ESR) was reduced by 85% in the 75 mg/kg/day of EGb 761 treated group in comparison with the drug-free ischemic/reperfused hearts. Inducible NO synthase (iNOS) messenger RNA (mRNA) measured by reverse transcription-polymerase chain reaction (RT-PCR) also was reduced by 41 and 58% in the groups treated with 75 and 100 mg/kg/day of EGb 761. Our findings show that EGb 761 directly acts as an NO scavenger and concomitantly inhibits the expression of iNOS mRNA. Thus, EGb 761 may act as a potent inhibitor of NO production under the condition of ischemia/reperfusion, improving the recovery of postischemic cardiac function.

34.Antioxidant nutrients and hypoxia/ischemia brain injury in rodents.:

Toxicology. 2003 Jul 15;189(1-2):55-61.PMID: 12821282
Cerebral ischemia and recirculation cause delayed neuronal death in rodents, such as Mongolian gerbils and stroke-prone spontaneously hypertensive rats (SHRSP), which were used as an experimental stroke model. It was documented that an enhanced nitric oxide production, the occurrence of apoptosis, and an attenuated redox regulatory system contribute to the development of delayed neuronal death. Many studies have suggested the beneficial antioxidant effects of antioxidant nutrients such as vitamin E, green tea extract, ginkgo biloba extract, resveratrol and niacin in cerebral ischemia and recirculation brain injury. These results are important in light of an attenuation of the deleterious consequences of oxidative stress in ischemia and recirculation injury.

35.Protective effect of ginkgo biloba extract on cerebral ischemia/reperfusion injury in rats:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2003 Jun;23(6):436-40.PMID: 12872397
OBJECTIVE: To study the effect of Ginkgo biloba extract (GbE) on dynamic equilibrium of free radicals and amino-acids in cortex of rats with cerebral ischemia/reperfusion (I/R) injury and its influence and characteristics to intracellular free calcium concentration ([Ca2+]i) in primary cultured hippocampal neuron of rats.METHODS: Amino-acids were quantified by high performance liquid chromatographic (HPLC) analysis. Concentration of MDA and GSH-Px were determined by thiobarbituric acid (TBA) technique. SOD was assayed through xanthine method, and microfluoremetric technique was used to assay the change of [Ca2+]i and its characteristics.RESULTS: Compared with the non-treated groups, at all time points (3 hrs after ischemia, 1 and 2 hrs after I/R separately), in the GbE treated groups, the levels of Glu, Asp and MDA were lower and SOD and GSH-Px were higher (P < 0.01 or P < 0.05), the GABA and Gly levels were lower in groups treated with middle (10 mg/kg) or high dosage (15 mg/kg) of GbE (P < 0.05). Compared with the group treated with small dosage GbE (5 mg/kg), Glu, Asp and MDA were lower and GABA, Gly, SOD and GSH-Px were higher in the groups treated with middle or high dosage of GbE (P < 0.05), while the difference in the latter two groups was insignificant. Level of [Ca2+]i in cultured neurons treated with 1 x 10(-5) mol/L glutamate combined 25 micrograms/ml GbE for 20s was lower with lower peak value and longer time for reaching the peak than that in neurons treated with 1 x 10(-5) mol/L glutamate alone. Besides, the time of decline phase was also shorter in the former, so the flatform stage was prolonged. The response was recovered by re-applying of glutamate after [Ca2+]i back to base line.CONCLUSION: GbE can protect damaged neurons through keeping the balance of inhibitory/excitatory amino-acids, enhancing free radicals scavengers system, and inhibiting the effect of glutamate to [Ca2+]i.

36.Effects of mexiletine, ginkgo biloba extract (EGb 761), and their combination on experimental head injury.:

Neurosurg Rev. 2003 Oct;26(4):288-91. Epub 2003 Jul 12.PMID: 12884054
Lipid peroxidation (LP) and brain edema are important factors that produce tissue damage in head injury. The purpose of this study was to investigate the effect of mexiletine, gingko biloba extract (EGb 761), and their combination on LP and edema after moderate head trauma. Forty rats were randomly and blindly divided into four groups of ten animals each: control group (bolus injection of physiological saline), mexiletine group (50 mg/kg per injection), EGb 761 group (30 mg/kg per injection), and mexiletine plus EGb 761 group (50 mg/kg and 30 mg/kg per injection, respectively). The injections were given intraperitoneally at 1 h, 9 h, and 17 h after trauma. Twenty-four hours after injury, the rats were killed, and malondialdehyde (MDA) levels and brain water content were determined. Rats treated with mexiletine, EGb 761, and mexiletine plus EGb 761 had significantly lower MDA levels than the control group (P<0.01). The lowest MDA levels were measured in the mexiletine plus EGb 761 group. However, there was no significant difference in brain water content between treated groups and the control group (P>0.05). These findings show the usefulness of mexiletine and its combination with EGb 761 as a cerebroprotective agent in this model of experimental head injury.

37.Effects of Ginko Biloba and caspase inhibitors on brain ischemia in the Mongolian Gerbil.:

J Neurosurg Sci. 2003 Sep;47(3):149-55.PMID: 14618128
AIM: Data reported in previous studies and our own previous experience have led us to explore the mechanism of and the degree of protection afforded by Ginko Biloba in a model of cerebral ischemia in the Mongolian Gerbil evaluating histological and neurological effects in this rodent.METHODS: Mongolian Gerbils were divided into experimental groups: Group A consisted of animals subjected only to experimental ischemia; 5 minutes occlusion of the carotid arteries. Group B consisted of animals subjected to experimental ischemia and to a dose of Ginko Biloba, given intraperitoneally immediately before the surgical procedure. Group C consisted of animals subjected to experimental ischemia and to a dose of Ginko Biloba, given intraperitoneally immediately after the surgical procedure. Group D consisted of animals subjected to experimental ischemia and to a dose of the caspase inhibitors z-VAD.FMK and z-DEVD.FMK injected intracerebroventricularly through the right hemisphere before the surgical procedure. Group E consisted of animals subjected to experimental ischemia and to a dose of caspase inhibitors injected after the surgical procedure. Group F consisted of Sham-operated animals. Histological controls were done by H and E and the TUNEL method in the frontal cortex and caudate-putamen.RESULTS: The percentage of normal cells was not statistically significant at analysis with H and E, whereas the TUNEL method showed good protection with Ginko Biloba and caspase inhibitors, when the latter is given in the reperfusion phase. These data were in agreement with data obtained at neurological examination.CONCLUSION: We could say that cellular morphology is in itself an untrustworthy tool for judging the effects of ischemia and protective drugs; the TUNEL method may add important information about the different components of cellular death; the reperfusion phase may be critical for apoptotic phenomena; Ginko Biloba might protect neurons of the frontal cortex from both necrotic and apoptotic death in this model of ischemia.

38.Effects of extract of Ginkgo biloba on spasms of the basilar artery and cerebral microcirculatory perfusion in rats with subarachnoid hemorrhage.:

Clin Hemorheol Microcirc. 2003;29(3-4):231-8.PMID: 14724346
This study was aimed at investigating the effects of extract of Ginkgo biloba (EGb) on cerebral vasospasm and microcirculatory perfusion after subarachnoid hemorrhage (SAH). An endovascular piercing method was used to induce Wistar rat SAH models, and animals were divided into sham-operated, vehicle controls, and EGb-treated groups. EGb was injected intraperitoneally 30 minutes before operation and was repeated every 6 hours, with a single dose of 15 mg/kg bw. Diameters of basilar arteries before and after operation were measured. Microcirculatory blood perfusion of parietal lobe cortex was detected using a laser Doppler flow-meter probe within 24 hours. Endothelin-1 levels in both plasma and brain tissue were detected at different time points. The results showed that SAH caused an immediate drop in microcirculatory blood flow in vehicle controls, which persisted for 24 hours. Endothelin-1 levels in both plasma and brain tissue increased after SAH. EGb partly reversed spasms of the basilar artery and antagonized a drop in microcirculatory blood flow. EGb also prevented an increase in endothelin-1 both in plasma and in brain tissue. In conclusion, EGb, by antagonizing the overproduction of endo- thelin-1, partly reverses cerebral vasospasm and improves microcirculation, and thus relieves secondary ischemic brain injury after experimental SAH.

39.Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury.:

Neurochem Int. 2004 Jul;45(1):157-70.PMID: 15082233
We evaluated whether combined treatment with selegiline, a selective MAO-B inhibitor, and EGb 761, a standard extract of Ginkgo biloba, has synergistic effects against ischemic reperfusion injury (IRI) in gerbils. Interestingly, we observed that pretreatment with EGb 761 significantly attenuated selegiline-induced hyperactivity. This finding paralleled striatal fos-related antigen immunoreactivity (FRA-IR) in mice. Four minutes of bilateral carotid artery occlusion caused substantial cell loss in the CA1 of the hippocampus 5 days post-ischemic insult. Pretreatment with EGb 761, with or without selegiline, significantly attenuated this neuronal loss. Combined treatment with EGb 761 plus selegiline was more efficacious in preventing this loss. Synaptosomal formations of protein carbonyl, lipid peroxidation (malondialdehyde (MDA) + 4-hydroxyalkenal (4-HDA)), and reactive oxygen species (ROS) in the hippocampus remained elevated 5 days post-ischemic insult. The antioxidant effects appeared to be most significant in the group treated with EGb 761 plus selegiline. This combined treatment produced more significant attenuation of IRI-induced alterations in intramitochondrial calcium accumulation, the mitochondrial transmembrane potential, and mitochondrial Mn-superoxide dismutase-like immunoreactivity (Mn-SOD-IR) than either treatment alone. Our results suggest that co-administration of EGb 761 and selegiline produces significant neuroprotective effects via suppression of oxidative stress and mitochondrial dysfunction without affecting neurological function.

40.Ginkgo biloba extract (EGb761) and FK506 preserve energy metabolites in the striatum during focal cerebral ischemia and reperfusion in gerbils monitored by microdialysis.:

J Biomed Sci. 2004 Sep-Oct;11(5):611-6.PMID: 15316136
Cell death after cerebral ischemia is mediated by the accumulation of excitatory amino acids, calcium influx into cells and the generation of free radicals. The aim of this study was to evaluate changes in energy-related metabolites in the striatum of gerbils subjected to focal cerebral ischemia after pretreatment with Ginkgo biloba extract (EGb761), a well-known antioxidant, and FK506, a calcium-dependent phosphatase calcineurin inhibitor. Ischemia was induced by occlusion of the right common carotid artery and the right middle cerebral artery for 60 min. A microdialysis probe was inserted into the right striatum to monitor extracellular glucose, lactate and pyruvate levels. This study showed decreases in glucose (10% of the baseline), pyruvate (20% of the baseline) and lactate (60% of the baseline), and a 5-fold increase in the lactate to pyruvate ratio during ischemia in the control group. Both EGb761 treatment and the combination (EGb761 and FK506) therapy significantly preserved glucose (50% of the baseline) and pyruvate (60% of the baseline) levels during ischemia. The marked increase in the lactate to pyruvate ratio was not observed in the combination group. These results suggest that preservation of cellular energy metabolism during cerebral ischemia and after restoration with reperfusion may contribute to the neuroprotective effects of EGb761 and FK506.

41.Effects of Gingko biloba extract on gap junction changes induced by reperfusion/reoxygenation after ischemia/hypoxia in rat brain.:

Am J Chin Med. 2005;33(6):923-34.PMID: 16355449
Gap junction communication between astrocytes plays an important role in the brain. The purpose of this study was to investigate the effects of Gingko biloba extract (GBE) on the changes of connexin 43 (Cx43) mRNA and protein expression levels of rat cortex and hippocampus induced by ischemia-reperfusion and astrocyte gap junction intercellular communication (GJIC) induced by hypoxia-reoxygenation. After 2 hours of middle cerebral artery occlusion (MCAO) followed by 24 hours of reperfusion, there was obvious neurological deficit in rats. Cx43 mRNA and protein expression levels of rat cortex and hippocampus in the ischemia hemisphere were decreased significantly. When GBE at doses of 50 and 100 mg/kg body weight was administrated by p.o. daily for 7 days, the neurological deficit was improved, and lower Cx43 mRNA and protein expression levels induced by ischemia-reperfusion were recovered to normal. The i.p. injection of nimodipine (0.7 mg/kg weight body) also showed improvement on neurological deficit and Cx43 expression levels. Astrocyte GJIC was measured by the fluorescence recovery after photobleaching (FRAP). Hypoxia-reoxygenation induced a significant decrease in GJIC. Pretreatment with GBE (100 mg/l) and nimodipine (1.6 mg/l) significantly prevented the hypoxia-reoxygenation inhibition of GJIC. These results suggest that GBE could exert its neuroprotective effects by improvement of Cx43 expression and GJIC induced by hypoxia/ischemia-reoxygenation/ reperfusion injury.

42.Effects of extract of Ginkgo biloba on intercellular adhesion molecule-1 and mRNA expression in rats with cerebral injury:

Zhong Yao Cai. 2005 Nov;28(11):1009-12.PMID: 16514890
OBJECTIVE: To investigate the effects of Extract of Ginkgo biloba on ICAM-1 and mRNA expression in rats with cerebral injury, and discuss its protective mechanism.METHODS: The acute closed brain injury model was set up in rats according Feeney's method. Seventy-two rats were randomly divided into four groups. The levels of ICAM-1 expression were observed using immunohistochemistry and computerized imaging technique and the expression of mRNA were studied using RT-PCR techniques.RESULTS: ICAM-1 positive cells located in the transitional zone between the necrotic core and normal cortex. ICAM-1 protein and mRNA expression began to show 6 hours after cerebral injury, peaked at 24 hours. As compared with the model group, ICAM-1 and mRNA expression was significantly reduced in the group EGb (P < 0.01).CONCLUSION: EGb can markedly reduce the injury of nerve cell in the transitional zone, alleviate rat cerebral injury, and decrease ICAM-1 and mRNA expression and neutrophils infiltration. The protection may be related with its inhibition on ICAM-1 and mRNA expression.

43.Effects of Ginkgo biloba extract on lipid peroxidation and apoptosis after spinal cord ischemia/reperfusion in rabbits.:

Chin J Traumatol. 2006 Apr;9(2):77-81.PMID: 16533431
OBJECTIVE: To study the effects of Ginkgo biloba extract (GBE) on lipid peroxidation and apoptosis after spinal cord ischemia/reperfusion (I/R) in rabbits.METHODS: Spinal cord I/R injury model was established according to the description of Erten et al. A total of 27 New Zealand white rabbits were divided into three groups randomly: a sham group (9 rabbits treated with sham operation but without aortic occlusion), a model group (9 rabbits treated with aortic occlusion and volume-matched saline), and a GBE group (9 rabbits treated with aortic occlusion and Ginaton (100 mg/kg) injected 30 minutes before aortic clamping and at the onset of reperfusion). The neurological outcomes were evaluated at 24 and 48 hours after reperfusion, respectively. The spinal cord malondialdehyde (MDA) level, superoxide dismutase (SOD) were then detected. Neural cell apoptosis was determined by terminal deoxynucleotidyl t-ransferase (TdT)-mediated dUTP-fluorescence nick end labeling (TUNEL) method and the expression of bcl-2 and bax were examined histologically in the spinal cord with immunohistochemistry.RESULTS: I/R produced a significant decrease in neurological scoring. The motor scores of the GBE group were significantly higher than those of the model group at 24 and 48 hours after reperfusion (P<0.05). Compared with the model group, GBE ameliorated the down-regulation of SOD and produced a significant reduction of the MDA level (P<0.01). The positive cells for TUNEL in the model group were much more than those of the GBE group (P<0.01). The bcl-2 was up-regulated after I/R, especially in the GBE group (P<0.01). The up-regulation of bax was greatly diminished by GBE (P<0.01).CONCLUSIONS: GBE has protective effects against spinal cord I/R injury, and the mechanism may be that it can scavenge oxygen free radicals and inhibit the apoptosis of neural cells.

44.Impact of Ginkgo Biloba Extract EGb 761 on ischemia/reperfusion - induced oxidative stress products formation in rat forebrain.:

Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1343-53. Epub 2006 Apr 14.PMID: 16614948
Dysbalance in reactive oxygen/nitrogen species is involved in the pathogenesis of cerebral ischemia/reperfusion injury (IRI). Ginkgo biloba extract (Egb 761) pre-treatment was used to observe potential antioxidant/neuroprotective effect after global ischemia/reperfusion. Egb 761 significantly decreased the level of lipoperoxidation (LPO) in rat forebrain total membrane fraction (homogenate) induced by in vitro oxidative stress (Fe(2+)+H(2)O(2)). In animals subjected to four-vessel global ischemia for 15 min and 2-24 h reperfusion the EGb pretreatment slightly decreased LPO in forebrain homogenate. However, as detected in EGb treated group, the LPO-induced lysine conjugates are attenuated in comparison to non-treated IRI animals. EGb significantly improved parameters which indicate forebrain protein oxidative damage after IRI. The intensity of tryptophane fluorescence was increased by the 18.2% comparing to non-treated IRI group and bityrosine fluorescence was significantly decreased in ischemic (21%) and 24 h reperfused (15.9%) group in comparison non-treated IRI group. In addition, the level of total free SH- groups in pre-treated animals was significantly higher comparing to non-treated animals. Our results indicate that extract of EGb 761 has potent antioxidant activity and could play a role to attenuate the IRI-induced oxidative protein modification and lipoperoxidation in the neuroprotective process.

45.Extract EGb 761 pretreatment limits ubiquitin positive aggregates in rabbit spinal cord neurons after ischemia-reperfusion.:

Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1443-52. Epub 2006 May 3.PMID: 16670948
1. Ubiquitin immunohistochemistry was used for investigation of time dependent changes of ubiquitin in the nerve cells reacting to ischemic/reperfusion damage. In the rabbit spinal cord ischemia model a period of 30 min ischemia followed by 24 and 72 h of reperfusion caused neuronal degeneration selectively in the ventral horn motor neurons as well as interneurons of the intermediate zone. 2. Ubiquitin aggregates were accumulated in the neurons of lamina IX and the neurons of intermediate zone destined to die 72 h after 30 min of the spinal cord ischemia. 3. The activation of ubiquitin hydrolytic system is related to a defective homeostasis and could trigger different degenerative processes. Having in mind this, we used EGb 761 to rescue the motor neurons and interneurons against ischemia/reperfusion damage. Our results show that after 30 min of ischemia and 24 or 72 h of reperfusion with EGb 761 pre-treatment for 7 days the vulnerable neurons in the intermediate zone and lamina IX exhibit marked elevation of ubiquitin-positive granules in the cytoplasm, dendrites and nuclei. Abnormal protein aggregates have not been observed in these cells. 4. The rabbits were completely paraplegic after 30 min of ischemia and 24 or 72 h of reperfusion. However, after 7 days EGb 761 pre-treatment, 30 min of ischemia and 24 or 72 h of reperfusion the animals did not show paraplegia. 5. Evaluated ubiquitin-positive neurons of the L(5)-L(6) segments showed significant decrease in number and significant increase of density after 30 min of ischemia followed by 24 h and mainly 72 h of reperfusion. Ubiquitin immunohistochemistry confirmed the protective effect of EGb 761 against ischemia/reperfusion damage in the rabbit spinal cord.

46.Mapping of rat hippocampal neurons with NeuN after ischemia/reperfusion and Ginkgo biloba extract (EGb 761) pretreatment.:

Cell Mol Neurobiol. 2006 Oct-Nov;26(7-8):1193-204. Epub 2006 Jun 7.PMID: 16758319
1. The neuroprotective effect of Ginkgo biloba extract (EGb 761) against transient forebrain ischemia following 7 days of reperfusion was studied in male Wistar rats after four-vessel occlusion for 20 min. 2. NeuN, a neuronal specific nuclear protein was used for immunohistochemical detection of surviving pyramidal neurons in the hippocampus, as well as counterstaining with hematoxylin in the same sections for detection of neurons that underwent delayed neuronal death and for glial nuclei staining. GFAP immunohistochemistry was used for detection of astrocytes in the studied area of CA1 region. 3. In the group of rats pretreated 7 days with Ginkgo biloba extract (EGb 761), following 20 min of ischemia and 7 days of reperfusion without EGb 761, increased number of NeuN immunoreactive cells were counted in the most vulnerable CA1 pyramidal layer of hippocampus. On the other hand, the group of rats with 7 days of EGb 761 pretreatment following 20 min of ischemia and 7 days of reperfusion with EGb 761 showed decreased number of surviving NeuN immunoreactive CA1 pyramidal cells in comparison with the first above-mentioned experimental group. 4. Increased number of reactive astrocytes immunolabeled for GFAP (Glial fibrilary acidic protein) was observed in both experimental groups in the stratum oriens and stratum lacunosum and moleculare. 5. Twenty minutes of ischemia is lethal for most population of CA1 pyramidal cell layer. Our results showed that prophylactic oral administration of Ginkgo biloba extract (EGb 761) in the dose 40 mg/kg/day during the 7 days protects the most vulnerable CA1 pyramidal cells against 20 min of ischemia.

47.Sustained neuroprotection and facilitation of behavioral recovery by the Ginkgo biloba extract, EGb 761, after transient forebrain ischemia in rats.:

Behav Brain Res. 2006 Nov 1;174(1):70-7. Epub 2006 Aug 24.PMID: 16934342
The effects of the Ginkgo biloba extract, EGb 761, on ischemia-induced learning/memory impairments and hippocampal damage were evaluated in a non-food motivated, aversive radial maze task (AvRM). Rats were subjected to 15 min transient, global cerebral ischemia (TGCI). In the first experiment, rats were rendered ischemic, and 23 days later were tested for acquisition performance (post-operative training). In a second experiment, rats were trained for 10 days and then subjected to ischemia (pre-operative training); the retention of cognition performance was assessed on days 31, 35 and 39 after ischemia. Acquisition and retention performances were expressed by (a) latency to find a goal box, (b) number of reference memory errors, and (c) number of working memory errors. EGb 761 (50 or 150 mg/kg) was given orally, starting before ischemia and continuing for up to 3 days after ischemia. TGCI markedly disrupted both acquisition and retention performance (p < 0.001-0.05). EGb 761 (150 mg/kg) completely reversed acquisition impairment as measured by the parameters 'latency' and 'number of reference errors' when performance was examined across sessions (p < 0.01-0.05). The total number of reference errors was also completely abolished by EGb 761 (150 mg/kg). However, EGb 761 did not statistically reduce the effects of TGCI on the parameter 'working memory errors' (across session and total). At 50 mg/kg, EGb 761 did not affect ischemia-induced acquisition impairment at all. The retention deficit caused by ischemia was not statistically reduced by EGb 761 (150 mg/kg), whatever examined across session or as total. EGb 761 reduced the extent of hippocampal CA1 cell loss (p < 0.01-0.001), an effect sustained at least up to 40 days after ischemia. These findings show that EGb 761 is effective in reducing, at least partially, both the cognitive impairments and hippocampal damage after TGCI in rats, and suggest that its effect on behavioral recovery may be dissociated from the neuroprotective effect on the hippocampus. The present results also validate the AvRM as an alternative, reliable behavioral test to assess the effects of drugs on behavioral recovery after ischemic brain damage.

48.Effects of ginkgolides injection on experimental cerebral ischemia in mice and rats:

Zhongguo Zhong Yao Za Zhi. 2006 May;31(9):769-72.PMID: 17048690
OBJECTIVE: To investigate the effects of ginkgolides injection on experimental cerebral ischemia and its related mechanism of action.METHOD: The middle cerebral artery occlusion (MACO) model was induced by the FeCl3-occluding method to explore the protective effects of ginkgolides injection on the score of neurological deficits, the rate of cerebral infarction and the histomorphology of cerbral ischemia in rats. Thrombosis formation in vivo was induced by adrenaline-collagen in mice to explore the antithrombotic effect. Platelet aggregation was induced by ADP and hemorrheological parameters with hyper-viscosity by dextran T-500 were used to explore the effects of antiplatelet aggregation and decreasing viscosity of blood.RESULT: Ginkgolides injection could markedly decrease the infarct size and behavior deficits score, inhibit the thrombus formation in mice, decrease blood viscosity and ameliorate hemorrheological parameters in rat.CONCLUSION: Ginkgolides injection has the protective effects on focal cerebral ischemia, and its mechanism may be relative to its inhibition of platelet-dependent thrombosis and amelioration of hemarheological partments.

49.Ginkgo biloba leaf extract (EGb761) combined with neuroprotective agents reduces the infarct volumes of gerbil ischemic brain.:

Am J Chin Med. 2006;34(5):803-17.PMID: 17080546
Ginkgo biloba exerts many pharmacological actions. It possesses antioxidant properties, the ability of neurotransmitter/receptor modulation and antiplatelet activation factor. This research is designed to investigate the neuroprotective effects of long-term treatment with EGb761 (a standard form of the extract of Ginkgo biloba leaf) in combination with MgSO(4), FK506, or MK-801 on the infarct volume of male gerbils' brain induced by unilateral middle cerebral artery occlusion (MCAO). Thirty-five gerbils fed a standard diet were intragastrically given water or EGb761 (100 mg/kg/day) for one week. Five randomized groups were established: control (n = 7), EGb761 (n = 8), EGb761 + MgSO(4) (n = 7), EGb761 + FK506 (n = 7), and EGb761 + MK-801 (n = 6). The three drug-combination groups were injected with MgSO(4) (90 mg/kg), FK506 (0.5 mg/kg), or MK-801 (1 mg/kg), respectively 30 min before MCAO. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation for 24 hours. Postmortem infarct volumes were determined by quantitative image analysis of 2,3,5-triphenyltetrazolium chloride (TTC)-stained brain sections. Results showed that the total infarct volumes of the four treated groups either EGb761 alone or in combination with drugs were lower than the control group by 36.1% (EGb761 alone), 40.3% (EGb761 + MgSO(4)), 35.3% (EGb761 + FK506), and 56.4% (EGb761 + MK-801), respectively (p < 0.01). The main affected areas of the brain in the four treated groups were significantly focused between 4 and 6 mm from the frontal pole, when compared to the control group (p < 0.01). All animals in the five groups had infarctions in both cortex and subcortex. These results indicate that long-term pre-treatment of EGb761 administered either alone or in combination with drugs significantly effective neuroprotection on infarct volume in gerbil ischemic brains.

50.Neuroprotective effects of selenium and ginkgo biloba extract (EGb761) against ischemia and reperfusion injury in rat brain.:

Neurosciences (Riyadh). 2008 Jul;13(3):233-8.PMID: 21063330
OBJECTIVES: To determine the neuroprotective effects of Ginkgo biloba extract (EGb761) and Selenium (Se), and the combination of these agents on ischemia/reperfusion (I/R) injury in a rat model of transient global cerebral I/R.METHODS: This experimental study took place in the Animal Research Laboratory at Dokuz Eylul University, Izmir, Turkey in the year 2006. Fifty rats were subjected to cerebral I/R induced by right carotid artery occlusion technique for a duration of 45 minutes, and then were treated with EGb761 (50 mg/kg/day, ip) and Se (0.625 mg/kg, ip), alone or in combination for 14 days after surgery. Superoxide dismutase, and glutathione peroxidase activities were measured in the hippocampal tissues from 25 animals. Histopathological examinations were also carried out under light and electron microscopy from the rest of animals.RESULTS: The results suggest that EGb761 has a potent neuroprotective effect against cerebral I/R induced injury in rat brain that is comparable with that of Se. However, the combined use of EGb761 and Se does not further protect from neuronal injury when compared with the use of both agents alone.DISCUSSION: Our results suggest that administration of EGb761, Se and its combination with EGb761 have significant neuroprotective effects on I/R injury in rats via suppression of oxidative stress.

51.Extract of Ginkgo biloba promotes the expression of VEGF following subarachnoid hemorrhage in rats.:

Int J Neurosci. 2009;119(7):995-1005.PMID: 19466634
The study aimed to investigate the effect of extract of Ginkgo biloba (EGb) on the expression of vascular endothelial growth factor (VEGF) after subarachnoid hemorrhage (SAH). Wistar rats were divided into non-SAH, SAH, vehicle, EGb1 (low-dose), and EGb2 (high-dose) groups. VEGF mRNA and VEGF protein were measured from brain tissues. The expressions of VEGF mRNA in SAH and vehicle groups were enhanced 24 and 72 hr after the establishment of SAH. Increased VEGF positive cells were found in the brain tissues in SAH and vehicle groups. The expressions of VEGF mRNA and VEGF protein were further increased by the pretreatment of EGb. We concluded that EGb exerts protective effects on secondary cerebral ischemic injury after SAH via the promotion of the expression of VEGF.

52.Gingko biloba Extract (EGb 761) prevents ischemic brain injury by activation of the Akt signaling pathway.:

Am J Chin Med. 2009;37(3):547-55.PMID: 19606514
EGb 761 is a standardized extract of Gingko biloba that exerts protective effects against ischemic brain injury. This study investigated whether EGb 761 modulates the neuroprotective effects through Akt and its downstream targets, Bad and FKHR. Adult male rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO). Brains were collected 24 hours after MCAO and infarct volumes were analyzed. EGb 761 significantly reduced infarct volume. Potential activation was mearsured by phosphorylation of Akt at Ser(473), Bad at Ser(136), and FKHR at Ser(256) using Western blot analysis. EGb 761 prevented the injury-induced decrease of pAkt and its down stream targets, pBad and pFKHR. Furthermore, EGb 761 prevented the injury-induced increase of cleaved caspase-3 levels. In conclusion, this study suggests that EGb 761 prevents cell death due to brain injury and that EGb 761 protection is affected by preventing the injury-induce decrease of Akt phosphorylation.

Xb-Ginkgo Biloba:Psychopharmacological effects:Anti-Depressive,anxiolytic effects,Anti-Stress Research:

1.Dissociation between anxiolytic and hypomnestic effects for combined extracts of zingiber officinale and ginkgo biloba, as opposed to diazepam.:

Pharmacol Biochem Behav. 1998 Feb;59(2):527-35.PMID: 9477004
Previous work has shown that Zingicomb (ZC), a combination preparation of zingiber officinale and ginkgo biloba, exerts anxiolytic-like effects in the elevated plus-maze (EPM), possibly related to 5-HT antagonistic properties of its components. The first experiment of this study was performed to gauge the specificity of the anxiolytic action of ZC with respect to the mixture ratio of the single components in the combination preparation. Two different combinations of zingiber officinale and ginkgo biloba extracts (ratio of components: 1:1 or 1:2.5) were compared with the standard ratio adjusted for ZC (2.5:1). Each combination was administered intragastrically (I.G.) in five doses (0.01 to 10 mg/kg) before the rats were tested on the EPM. Zingicomb at 1 mg/kg elevated the time spent on the open arms, scanning of the open arms and excursions into the ends of the open arms, whereas the two other combinations (1:1 and 1:2.5) did not influence rats' behavior on the EPM in the entire dose range tested. With regard to the memory-disrupting effects of anxiolytics, particularly of diazepam (DZP), a second experiment was performed to compare the effects of ZC (0.5, 1, 10 mg/kg, I.G.) and DZP (1 or 5 mg/kg, I.P.) on the performance of rats in two different learning tasks. Rats were treated with DZP or ZC prior to the learning trial of a one-trial step-through inhibitory avoidance task. Retention testing 24 h later showed impaired retention for rats injected with DZP at 5 mg/kg but not for animals that had received ZC prior to training. In a further experiment, rats were treated once daily with DZP or ZC prior to the training trials in a water maze. Injections of DZP at 5 mg/kg impaired place and cue learning, whereas the treatment with ZC did not influence the navigation performance in the maze. The present results indicate that the anxiolytic-like effects of ZC are specific in that only the mixture ratio of zingiber officinale and ginkgo biloba adjusted for the phytopharmacon was active in the EPM. Furthermore, ZC did not interfere negatively with the performance on an inhibitory avoidance and a water maze task, as opposed to DZP. This finding is interesting with regard to other studies that have revealed a similar dissociation between anxiolytic and memory-disrupting effects for chemically defined 5-HT antagonists, especially for those acting at 5-HT3 receptors.

2.Anxiolytic activity of ginkgolic acid conjugates from Indian Ginkgo biloba.:

Psychopharmacology (Berl). 1998 Mar;136(2):148-52.PMID: 9551771
Ginkgolic acid conjugates (GAC) (6-alkylsalicylates, namely n-tridecyl-, n-pentadecyl-, n-heptadecyl-, n-pentadecenyl- and n-heptadecenylsalicylates) isolated from the leaves of Indian Ginkgo biloba Linn., (IGb) were tested for their putative role in anxiety in rats. Elevated plus maze, open-field behaviour, novelty-induced feeding latency and social interaction were the rodent behavioural models used in this study. GAC (0.3 and 0.6 mg/kg, each, p.o.) on single acute administration, showed dose-related changes in the behaviour. GAC (0.6 mg/kg) and DZ augmented open arm entries, the open arm/closed arm entries ratio and increased time spent in the open arm on the elevated plus maze. In the open field, GAC (0.6 mg/kg) and DZ significantly increased ambulation and reduced the immobility time. EGb 761 showed a similar profile. GAC (0.6 mg/kg) and DZ significantly attenuated the increased latency to feed in novel environment. By contrast, EGb 761 and Ginkocer further augmented feeding latency. None of the drugs tested showed any significant effect in the social interaction test. GAC showed consistent and significant anxiolytic activity in all the variables investigated. By contrast, EGb 761 and Ginkocer, which are devoid of GAC, did not evoke significant activity. However, increased rearing and decreased immobility time only in open field behaviour shown by EGb 761 may be due to some antianxiety activity of a lesser degree. Our observations suggest that GAC may be the active constituents of Ginkgo biloba responsible for the anxiolytic activity.

3.Can winter depression be prevented by Ginkgo biloba extract? A placebo-controlled trial.:

Acta Psychiatr Scand. 1999 Jul;100(1):62-6.PMID: 10442441
OBJECTIVE: The aim was to test the hypothesis that the Ginkgo biloba extract PN246, in tablet form (brand name Bio-Biloba), may prevent the symptoms of winter depression (WD) in patients with seasonal affective disorder (SAD).METHOD: A total of 27 SAD patients were randomized to receive double-blind placebo or Bio-Biloba for 10 weeks or until they developed symptoms of WD, starting in a symptom-free phase about 1 month before expected WD symptoms. An extended Montgomery-Asberg Depression Rating Scale was completed before and immediately after termination of medication. The patients also self-rated some key symptoms on a visual analogue scale every 2 weeks during the trial.RESULTS: There were no significant differences between the treatment groups in the number of patients who developed treatment-requiring WD, or in the development of single key symptoms during the trial.CONCLUSION: We did not find that Ginkgo biloba was able to prevent the development of the symptoms of winter depression.

4.Effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761) and its terpene trilactone constituents on barbital-induced narcosis in the mouse.:

Gen Pharmacol. 1999 Sep;33(3):249-56.PMID: 10480658
A mouse model of barbital-induced narcosis was used to examine the effects of single intraperitoneal injections of an extract of Ginkgo biloba (EGb 761), an extract devoid of terpene trilactones (CP 205), and three terpene trilactone constituents of the extract (ginkgolides A and B, bilobalide). Administration of sodium barbital (180 mg/kg, IP) to the mice caused narcosis, measured as a loss in righting reflex. Single injections of EGb 761 (25 and 50 mg/kg), given 60 min prior to sodium barbital, significantly shortened barbital-induced sleeping time, whereas these same doses of CP 205 were ineffective. Single injections of ginkgolide B (1 mg/kg) and bilobalide (2 and 5 mg/kg) significantly shortened sleeping time, whereas ginkgolide A was ineffective. The effects of ginkgolide B and bilobalide were reflected as increases in latency to onset of sleep and those of EGb 761, ginkgolide B, and bilobalide were correlated with decreases in the number of mice that slept. At the behavioral level, these potent in vivo effects of EGb 761, ginkgolide B, and bilobalide resemble those of certain antidepressants. At the molecular level, it is hypothesized that interactions with the picrotoxinin/TBPT site of GABA-regulated Cl- channels of the CNS may be involved. This information appears useful in explaining the clinically observed "vigilance-enhancing" and "antidepressant-like" actions of EGb 761.

5.In vivo regulation of cerebral monoamine oxidase activity in senescent controls and chronically stressed mice by long-term treatment with Ginkgo biloba extract (EGb 761).:

Mech Ageing Dev. 2000 Feb 15;113(3):157-68.PMID: 10714935
It is well recognized that Ginkgo biloba extract (EGb 761) exert beneficial effects against various age-related changes and is able to reduce the negative influence of stress. In view of the age-dependent increase in the activity of the B form of monoamine oxidase (MAO-B) and in view of the anti-stress action of EGb 761 hypothetically attributed to an inhibition of monoamine oxidase by this substance, we investigated the effects of long-term treatment with EGb 761 upon in vivo cerebral MAO-A and -B activities of stressed and unstressed 17- and 18-month-old mice. The stress was a 'chronic mild stress' regimen whose behavioral impact is known to be reduced by EGb 761. The results showed that: (1) EGb761 induced reductions in MAO activity in 18-month-old, but not in 17-month-old mice; the older animals having higher basal MAO activity; (2) in unstressed mice, EGb 761 appeared to reduce the age-induced increase in cerebral MAO activity; (3) MAO-A and -B activities of stressed and treated 18-month-old mice did not differ significantly from the levels observed in unstressed and untreated 17-month-old mice. These results may shed light on the anti-stress effects of Ginkgo biloba extract.

6.Evaluation of a ginkgo biloba extract (EGb 761) in functional tests for monoamine oxidase inhibition.:

Arzneimittelforschung. 2000 Mar;50(3):232-5.PMID: 10758773
A standardized extract of ginkgo biloba (EGb 761) was evaluated in functional tests for monoamine oxidase (MAO) inhibition in mice: l-dihydroxyphenylalanine (CAS 59-92-7,1-DOPA) potentiation, tryptamine (CAS 61-54-1) potentiation, 5-hydroxytryptophan (CAS 4350-07-6,5-HTP) potentiation and phenylethylamine (CAS 64-04-0) potentiation. The doses investigated (25, 50 and 100 mg/kg p.o once daily for 5 days) were those known to possess anti-stress properties in other animal models. In contrast to the reference substances investigated (nialamide (CAS 51-12-7), clorgyline (CAS 17780-75-5) and 1-deprenyl (CAS 14611-52-01), EGb 761 did not exhibit any activity indicative of MAO inhibition. It was concluded that MAO inhibition was not the mechanism primarily responsible for EGb 761's anti-stress activity.

7.Enhanced conditioned inhibitory avoidance by a combined extract of Zingiber officinale and Ginkgo biloba.:

Phytother Res. 2002 Jun;16(4):312-5.PMID: 12112284
Previous work has shown that intragastric administration of Zingicomb, a preparation consisting of Zingiber officinale and Ginkgo biloba extracts, has anxiolytic-like properties. The aim of the present study was to assess the effects of acute treatment with this preparation on inhibitory avoidance learning. The influence of pre-trial administered Zingicomb (ZC) on inhibitory avoidance conditioning was investigated in adult male Wistar rats, with a one-trial step-through avoidance task. The animals were treated intragastrically with either vehicle, 0.5, 1, 10 or 100 mg/kg ZC 60 min prior to the acquisition trial. When tested 24 h after training, rats which had received 10 mg/kg ZC exhibited significantly longer step-through latencies than vehicle treated animals. This result, thus, demonstrates the beneficial effects of Zingicomb on conditioned inhibitory avoidance. Unlike conventional anxiolytic drugs, such as the benzodiazepines, which tend to have amnesic properties, this phytopharmacon is a potent anxiolytic agent which, additionally, can facilitate performance on a learning task, indicating promising clinical applications.

8.Ginkgo biloba extract EGb 761 increases stress resistance and extends life span of Caenorhabditis elegans.:

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):725-31.PMID: 12396085
EGb 761, a standardized extract of Ginkgo biloba leaves, has been used in clinical trials for its beneficial effects on brain functions. In mammals, EGb 761 has been shown to enhance cognition, stress resistance, and longevity, but its molecular and cellular mechanisms are not known. In the present investigation, we used the model organism Caenorhabditis elegans to evaluate pharmacological effects of EGb 761 on aging. We tested the theory that EGb 761 augments the natural antioxidant system of C elegans, and thus increases stress resistance and longevity. We found that treatment of the wild-type worms with EGb 761 extended their median life span by 8%. Amongst several purified components of EGb 761, the flavonoid tamarixetin showed the most dramatic effect: it extended the median life span by 25%. Furthermore, EGb 761 increased the wild type's resistance to acute oxidative and thermal stress by 33% and 25%, respectively. Treatment of the prematurely aging mutant worms mev-1 with EGb 761 increased their resistance to acute oxidative and thermal stress by 33% and 11%, respectively. It appears that oxidative stress, a major determinant of life span, as well as other types of stress, can be successfully counteracted by the Ginlkgo biloba extract EGb 761.

9.Expression of the small heat-shock protein Hsp16-2 in Caenorhabditis elegans is suppressed by Ginkgo biloba extract EGb 761.:

FASEB J. 2003 Dec;17(15):2305-7. Epub 2003 Oct 2.PMID: 14525938
EGb 761, a standardized extract of Ginkgo biloba leaves, has been shown to have antioxidative properties. We have previously demonstrated that EGb 761 increases stress resistance and mean life span in the model organism Caenorhabditis elegans. In this study, the molecular mechanism of EGb 761 on alleviating effects of oxidative stress is further investigated using transgenic C. elegans expressing a jellyfish green fluorescent protein (GFP)-tagged inducible small heat-shock protein gene (hsp-16-2). The expression of hsp-16-2 induced by the pro-oxidant juglone and by heat shock was significantly suppressed by 86% and 33%, respectively, in the transgenic nematode fed with EGb 761. These effects of EGb 761 correlate with its ability to increase mean survival rate of the nematode in response to acute oxidative and thermal stresses, as well as to attenuate the basal levels of hydrogen peroxide in the organism. Thus, we interpret the suppression of hsp-16-2/GFP expression as an indication that EGb 761 decreases cellular stress resulting from exogenous treatments, therefore leading to a decreased transcriptional induction of the reporter transgene. These results support the hypothesis that EGb 761 augments the natural antistress system of C. elegans, thus increasing stress resistance and life span.

10.An anxiolytic-like effect of Ginkgo biloba extract and its constituent, ginkgolide-A, in mice.:

J Nat Prod. 2003 Oct;66(10):1333-7.
The anxiolytic-like effects of Ginkgo biloba extract (GBE) and its four terpenoid components (ginkgolide-A, ginkgolide-B, ginkgolide-C, and bilobalide) were assessed using the elevated plus-maze test in mice. Administration of GBE as a single oral dose (0.5 or 1 g/kg, po) caused a state of suppressed motor activity and, thus, shortened the time spent in the open-sided arms. However, when GBE (0.063-1 g/kg, po) was administered daily for 7 days and the plus-maze test was carried out 24 h after the final administration, the time spent in the open-sided arms was prolonged, with the peak anxiolytic-like effect at 0.125 g/kg. A combination of seven-day administration of GBE (0.125 g/kg) and a single dose of diazepam (1 mg/ kg, po, 10 min before testing) enhanced the anxiolytic-like effect. Flumazenil (0.3 mg/kg, ip, 10 min before testing) blocked the effect of diazepam, but not of GBE. Daily administration of ginkgolide-A (1 or 2 mg/kg, po) resulted in an anxiolytic-like effect by the third treatment, with the maximal effect observed after the fifth administration. Neither ginkgolide-B, ginkgolide-C, nor bilobalide produced any anxiolytic-like effects. At doses higher than 0.5 g/kg, GBE not only inhibited motor activity but also suppressed active avoidance behavior, reduced caffeine-induced stimulation, and enhanced pentobarbital-induced sleep, while ginkgolide-A (up to 20 mg/kg) did not exhibit these effects. Diazepam (1 mg/kg) is known to enhance pentobarbital-induced sleep. These results suggest that GBE produces a significant anxiolytic-like effect following repeated administration and that ginkgolide-A is most likely responsible for this effect. There are also indications that although GBE exerts a sedative effect at comparatively higher doses, ginkgolide-A has a relatively weak tendency to produce benzodiazepine-like side effects.

11.Effects of Ginkgo biloba on corticosterone stress responses after inescapable shock exposure in the rat.:

Pharmacol Biochem Behav. 2003 Dec;76(3-4):487-92.PMID: 14643848
Extracts from the leaves of the Ginkgo biloba tree (GBE) are found to be clinically effective in neuroprotection, cerebral and cardiovascular function and cognitive processing. Recent animal findings suggest that GBE also may improve stress adaptation and prevent learned helplessness, as evidenced by its reduction of behavioral acquisition deficits of active avoidance after inescapable shock exposure. In the present report, the effects of two doses of GBE were studied on corticosterone stress responses and acquisition of active avoidance after inescapable shock exposure. Forty-eight rats were divided into three groups: either receiving a daily dose of 50 mg/kg or 150 mg/kg of GBE (containing 24% flavonoid and 6% terpenoid) or vehicle for 2 weeks. After 2 weeks of administration, animals were trained for active-avoidance acquisition following inescapable shock exposure (stress induction) or nonshock exposure (nonstress). Administration of 150 mg/kg but not of 50 mg/kg of GBE significantly prevented a corticosterone stress response after inescapable shock exposure (P<.0001) without any beneficial behavioral effect on active avoidance. Repeated administration of GBE particularly improves biological adaptation to noxious stimuli without beneficial behavioral consequences. Present findings do not support previous claims about the benefits of G. biloba on improving behavioral stress adaptation and acquisition of active avoidance and on reducing behavioral deficits indicative of "learned helplessness."

12.Ginkgo biloba normalises stress-elevated alterations in brain catecholamines, serotonin and plasma corticosterone levels.:

Eur Neuropsychopharmacol. 2003 Oct;13(5):321-5.PMID: 12957329
Stress and depression and associated mental health problems have increased tremendously in modern times. The search for effective and safe alternatives from natural sources especially plant products should, therefore, continue. Forced immobilization is one of the best explored models of stress in rats and the role of corticosterone, serotonin and catecholamines, i.e. norepinephrine (NE), dopamine (DA) is well documented. Numerous studies have shown that Ginkgo biloba has antioxidant and neuroprotective properties and utility in cerebrovascular insufficiency and impaired cerebral performance. We investigated the effect of G. biloba on whole brain catecholamine, serotonin and plasma corticosterone levels following 1, 2 and 4 h restraint stress using HPLC and also plasma corticosterone using luminescence spectrophotometry. G. biloba extract (14 mg/kg p.o.) restored restraint stress-induced elevation in whole brain levels of catecholamines (NE, DA), 5-HT and plasma corticosterone to near normal levels. Further studies are warranted to explore the clinical potential of this encouraging lead in the management of stress and to elucidate the mechanisms involved.

13.Anti-stress effects of Ginkgo biloba and Panax ginseng: a comparative study.:

J Pharmacol Sci. 2003 Dec;93(4):458-64.PMID: 14737017
Stress is a global menace fortified by the advancement of industrialization. Failure of stress management is due to lack of proper evaluation of anti-stress products. We explored the anti-stress potential of the Ginkgo biloba (G. biloba, 30 mg/kg, p.o.) and compared it with that of Panax ginseng (P. ginseng, 100 mg/kg, p.o.) against acute stress (AS) and chronic stress (CS) models in rats. Immediately after AS and CS, the rats were sacrificed, and adrenal glands and stomach were dissected out for weight determination and scoring of the ulcer index (UI), respectively, as well as changes in biochemical parameters like plasma glucose (GL), triglycerides (TG), cholesterol (CL), creatine kinase (CK), and serum corticosterone (CORT) were also estimated. AS significantly increased UI, adrenal gland weight (AGW), GL, CK activity, and CORT, whereas G. biloba significantly reduced them. P. ginseng significantly reverted GL and CK activity. In CS, a significant increase was found in the UI, AGW, CK activity, and CORT with a decrease in the level of CL and TG. G. biloba did not produce any significant effect on CS-induced alterations. P. ginseng reduced the UI, AGW, plasma GL, TG, CK activity, and CORT level significantly. From the above study, G. biloba is more effective in AS, whereas for CS, P. ginseng will be a better option. Hence these extracts possess significant anti-stress properties and can be used for the treatment of stress-induced disorders.

14.The effect of ginkgo biloba on healthy elderly subjects:

Fortschr Med Orig. 2003;121(1):5-10.PMID: 15117063
BACKGROUND AND AIM: Over the past 25 years, numerous studies have confirmed the positive effect of the special ginkgo extract EGb 761 on the mental ability and emotional well-being of patients with cognitive disorders of vascular genesis, and Alzheimer-type dementia. The following study investigated the short-term effect of the special ginkgo extract EGb 761 on the subjective emotional well-being of healthy elderly subjects. STUDY POPULATION AND METHOD: The study was designed as a randomized double-blind, monocenter study with parallel groups. It included 66 healthy subjects of both sexes aged between 50 and 65 with no age-related cognitive impairments. For a period of 4 weeks, 34 subjects received a daily dose of 240 mg EGb 761, and 32 a placebo. Prior to starting medication and after 28 days of treatment, subjects completed the following scales and questionnaires to establish subjective emotional well-being: the Profile of Mood States (POMS), the Self Rating Depression Scale (SDS), three Visual Analog Scales to assess the quality of life (VAS-QoL), general health (VAS-GH) and mental health (VAS-MH), and a new instrument for assessing changes in general subjective well-being, the Subjective Intensity Score Mood (SIS Mood). Depending on the underlying distribution of the variables analyzed, parametric (t-tests) or nonparametric tests (U-tests) were performed to compare mean values and distributions both within and between the treatment groups.RESULTS: The final examination revealed a statistically significant difference between the two groups for the VAS mental health and quality of life, as also for SIS Mood at the telephone interview in week 2. A comparison of baseline with the final examination within the groups showed a statistically significant improvement in the EGb 761 group for the variables: depression, fatigue, anger and SDS. For none of the variables investigated was a worsening observed in the EGb 761 group.CONCLUSIONS: The results suggest a positive effect of EGb 761 on the subjective emotional well-being of healthy elderly persons.

15.Effects of extract of Ginkgo biloba with venlafaxine on brain injury in a rat model of depression.:

Chin Med J (Engl). 2005 Mar 5;118(5):391-7.PMID: 15780208
BACKGROUND: Recent studies have indicated that chronic stress may give rise to brain damage, which is related to the genesis of depression. The purpose of this study is to investigate the effects of extract of Ginkgo biloba (EGb) and venlafaxine on depression.METHODS: Rats were treated with chronic and comprehensive stress to create a depression model. Immunohistochemistry was used to detect the expression of brain-derived neurotrophic factor (BDNF) in the hippocampal CA3 neurons of rats treated with different drugs. Behavioral changes of these rats were also examined.RESULTS: The expression of BDNF in the hippocampal CA3 neurons of the depression model decreased with a reduction in exploring behavior and a significant increase in fecal production. The expression of neuron nitric-oxide synthase (nNOS) protein also increased in the rats compared to normal controls. The rats treated with EGb and venlafaxine showed an increase in expression of BDNF and exploring behavior compared to untreated rats, but a decrease in nNOS and fecal production.CONCLUSIONS: Rats sustain damage to the brain after being subjected to chronic and comprehensive stress. Our research has indicated that combined EGb with venlafaxine enhances the protection of neurons and decreases damage to the brain, while relieving the side effects of synthetic antidepressants.

16.Gingko biloba extract diminishes stress-induced memory deficits in rats:

Pharmacol Rep. 2005 Mar-Apr;57(2):176-87.PMID: 15886416
Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and undesired effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2 h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg/kg) impaired nonspatial memory as measured by an object recognition test. In control rats, EGB 761 improved spatial and nonspatial memory in Morris water maze and object recognition tests. Preventive doses of EGB 761 (100 mg/kg) normalized cognitive deficits, seen in rats chronically stressed or treated with corticosterone in object recognition test, and improved memory processes in these rats measured by Morris water maze test. There was no influence of our treatments on locomotor exploratory activity and anxiety measured in open field and elevated 'plus' maze tests, making a contribution of unspecific motor and emotional effects of the used drugs to their performance in the memory tests improbable.

17.Extract of Ginkgo biloba EGb 761 facilitates fear conditioning measured by fear-potentiated startle.:

Neurosci Lett. 2005 Jul 22-29;383(1-2):145-50. Epub 2005 Apr 21.PMID: 15936528
Extract of Ginkgo biloba EGb 761 has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, vigilance and cerebral vascular disorder. Recent results suggest that it can serve as a cognitive enhancer and anti-stress buffer. It raises a possibility that EGb 761 may be involved in the fear conditioning. In this study, we used fear-potentiated startle (FPS) to evaluate the possible effects of EGb 761 on the acquisition stage of fear conditioning. Our results showed that administration of EGb 761 30 min prior to the conditioning facilitated acquisition of conditioned fear in a dose dependent manner. No significant differences had been observed in either basal startle response or shock activity. These results indicated that the facilitation effect of EGb 761 was not the result of impaired basal startle response or enhanced pain perception. Subsequent control experiment results indicated that the facilitation effect of EGb 761 on the acquisition was not due to anxiogenic effect or non-specific effect. Our data present the first evidence that EGb 761 can enhance fear memory formation rather than serve as an anti-stress buffer.

18.Ginkgo biloba normalizes stress- and corticosterone-induced impairment of recall in rats.:

Pharmacol Res. 2006 Feb;53(2):123-8. Epub 2005 Oct 21.PMID: 16243535
Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and has been linked to the pathophysiology of mood and anxiety disorders. Antianxiety or sedative agents used in the management of stress have several disadvantages and side effects. Therefore, in this study, we investigated efficacy of a natural medicine, the extract of Ginkgo biloba (EGB 761), in prevention and treatment of the post-stress memory dysfunctions. The results showed that chronic restraint stress (2h for 21 days) or an 'equivalent' dose of exogenous corticosterone (5 mg kg(-1)) decreased re-entry latencies in the passive avoidance situation showing thus impairment of recall. Preventive doses of EGB 761 (100 mg kg(-1)), given 30 min before each restraint stress episode or corticosterone injection, abolished cognitive deficits seen in unprotected rats. There was no influence of stress, corticosterone, and EGB 761 on the acquisition of conditioned avoidance responses (CARs).

19.Antidepressant effect of extracts from Ginkgo biloba leaves in behavioral models.:

Biol Pharm Bull. 2006 Aug;29(8):1767-70.PMID: 16880641
Extracts of Ginkgo biloba (EGB) are a complex product prepared from green leaves of the Ginkgo biloba tree. In the present study, the antidepressant effect of EGB was examined using two behavioral models, the forced swimming test (FST) in rats and tail suspension test (TST) in mice. EGB significantly reduced immobility time in the FST at a dosage of 10 and 50 mg/kg body weight after repeated oral treatment for 14 d, although no change of motor dysfunction was observed with the same dosage in the open field test. These results indicate that EGB might possess an antidepressant activity. In addition, EGB markedly shortened immobility time in the TST after acute inter-peritoneal treatment at a dosage of 50 and 100 mg/kg body weight. The present study clearly demonstrated that EGB exerts an antidepressant effect in these two behavioral models.

20.The Ginkgo biloba extract EGb761 reduces stress sensitivity, ROS accumulation and expression of catalase and glutathione S-transferase 4 in Caenorhabditis elegans.:

Pharmacol Res. 2007 Feb;55(2):139-47. Epub 2006 Nov 26.PMID: 17207635
The standardised extract EGb761 from the leaves of Ginkgo biloba is a popular herbal dietary supplement and it is used as a phytopharmacon for the therapy of diverse cerebral insufficiencies. The beneficial impact of EGb761 is believed to be conferred by diverse biological actions under physiological conditions as well as in response to stress. In this study we examined effects of EGb761 in the model organism Caenorhabditis elegans. EGb761 reduced the body size but did not affect the reproduction of C. elegans. In fluorescence-based assays performed in microtiter plates we demonstrated the protective action of EGb761 by the increase of resistance to thermal stress and the attenuation of ROS accumulation under conditions of thermal stress in single living worms. Under normal conditions the lifespan of the worms was extended by the EGb761 supporting the beneficial effects found under stress conditions. In a reporter gene approach using individual living worms the expression of the stress-inducible glutathione S-transferase 4 was shown to be reduced by EGb761 under physiological conditions as well as under oxidative stress. EGb761 also led to a decrease in transcription of the stress-inducible catalase genes. These results suggest that the beneficial impact of EGb791 on resistance to thermal stress and lifespan in C. elegans is at least partially due to its ability to relieve oxidative stress.

21.Antidepressant and antistress activity of GC-MS characterized lipophilic extracts of Ginkgo biloba leaves.:

Phytother Res. 2007 Nov;21(11):1061-5.PMID: 17639553
Lipophilic extracts of Ginkgo biloba L. leaves were tested for their possible role on rodent models of depression and stress. Lipophilic extracts of Ginkgo leaves (LEG) at (50 and 100 mg/kg, p.o.) exhibited dose dependent, significant antidepressant activity in the behavioral despair test and learned helplessness rodent model of depression. The activities were comparable to that of imipramine (15 mg/kg) and EGb 761 (50 mg/kg). In the cold immobilization stress induced gastric ulcer model of stress, only the LEG showed a significant reduction in the ulcer index. GC-MS characterization of this bioactive extract was found to be rich in a group of 6-alkyl salicylates (6-AS), along with a fatty alcohol, fatty acids and cardanols. The n-heptadecenyl salicylate represented 60% of the 6-AS. Notable was the absence of dihydroxy alkylphenols which are linked to allergic reactions similar to the urushiols present in poison ivy. In commercial products of Ginkgo, these dihydroxy phenols as well as the favorable 6-AS are removed during enrichment of flavonol glycosides and terpenic lactones. The current findings suggest that intact carboxylic acid groups containing 6-AS are the bioactive components of the lipophilic extract of Ginkgo leaves with antidepressant and antistress activities

22.Effects of an extract of Ginkgo Biloba (EGB 761) on "learned helplessness" and other models of stress in rodents.:(Psycho:stress)

Pharmacol Biochem Behav. 1990 Aug;36(4):963-71.PMID: 2217527
The effects of repeated oral administration of an extract of Ginkgo Biloba (EGB 761) on various behavioral models of stress in rodents were investigated. The models in rats included "learned helplessness," shock-suppressed licking (Vogel conflict test) and forced swimming-induced immobility ("behavioral despair"). The models in mice included shock-suppressed exploration (four plates test), spontaneous exploration (staircase test) and food consumption in a novel situation (emotional hypophagia). Further tests in rats examined the effects of EGB 761 on memory (passive avoidance test) and responsiveness to shock to determine whether the preventive effects observed with EGB 761 in the learned helplessness procedure were due either to drug-induced impairment of memory or to reduced shock sensitivity. In all experiments EGB 761 was administered over 5 days at daily doses of 50 and 100 mg/kg PO. In some experiments (Vogel test, four plates test, staircase test, emotional hypophagia) the effects of acute administration were also investigated. The results showed that repeated administration of EGB 761 (50 and 100 mg/kg/day) before exposure to unavoidable shock (preventive treatment) clearly reduced the subsequent avoidance deficits in the learned helplessness procedure but was less effective when first administered after "helplessness" induction (curative treatment). EGB 761 did not affect performance in the passive avoidance task or alter the animals' response to electric shock, suggesting that the effects observed in the learned helplessness procedure were not due to impaired memory or reduced shock sensitivity. Anxiolytic-like activity was also seen in the emotional hypophagia test in mice where repeated administration of EGB 761 increased the amount of food consumed.

23.Isolation of bilobalide and ginkgolide A from Ginkgo biloba L. shorten the sleeping time induced in mice by anesthetics.:(Psycho:sleep)

Biol Pharm Bull. 1993 Feb;16(2):210-2.PMID: 8364459
The leaves of Ginkgo biloba L. and aqueous extract from them shortened the sleeping time induced in mice by anesthetics (hexobarbital, alpha-chloralose and urethane, i.p.). Two characteristic terpenoids in G. biloba, bilobalide and ginkgolide A, significantly shortened the sleeping time induced by anesthetics. A toxic substance, 4-O-methylpyridoxine (MPN), responsible for "gin-nan food poisoning" isolated from the seed of G. biloba, was not detected from the extract of the leaves of G. biloba. Therefore, the Ginkgo biloba extract has no toxicities for MPN.

24.Demonstration of the "anti-stress" activity of an extract of Ginkgo biloba (EGb 761) using a discrimination learning task.:(Psycho:anti-stress)

Gen Pharmacol. 1994 Sep;25(5):1009-16.PMID: 7835617
1. Young (4-month-old) and old (20-month-old) rats, maintained under water restriction, were trained to discriminate to obtain a small amount of drinking water as a reward. Each animal had to learn to press a lever corresponding to a light that was randomly distributed on the left or right. 2. Introduction of an auditory perturbation ("stress") during the discriminative phase of learning modified the capacity and rate of acquisition in both young and old animals, changes that were correlated with increases in plasma concentrations of epinephrine, norepinephrine and corticosterone. 3. Stress-induced detrimental changes in both discrimination learning and plasma hormones were suppressed by 20 days of oral treatment with an extract of Ginkgo biloba leaves (EGb 761; 50 or 100 mg/kg/day) in both young and old rats, effects that became statistically significant by the third day of learning (time of maximal acquisition rate). 4. EGb 761 treatment was less effective in increasing the percentage of efficient lever presses in old than in young rats, but more effective in decreasing the number of inefficient lever presses and reaction time in the older animals. 5. These results indicate that EGb 761 can facilitate behavioral adaptation despite adverse environmental influences, a property that supports its clinical use in treating cognitive impairment, especially in elderly patients.

25.Stress-induced 5-HT1A receptor desensitization: protective effects of Ginkgo biloba extract (EGb 761).:(Psycho:anti-stress)

Fundam Clin Pharmacol. 1995;9(2):169-74.PMID: 7628830
The effects of sub-chronic cold stress on the functioning of hippocampal 5-HT1A receptors in old isolated rats and the possible protective effects of Ginkgo biloba extract (EGb 761) were investigated. Cold exposure during five days, produced a significant reduction of the inhibitory effect of 8-hydroxy-2-(di-n-propylamino)tetraline (8-OH-DPAT) on forskolin-stimulated adenylyl cyclase activity. In contrast, neither the affinity nor the density of hippocampal [3H]8-OH-DPAT binding sites were affected indicating that the reduced sensitivity of 5-HT1A receptors induced by stress is probably due to a modification of their coupling mechanisms to adenylyl cyclase. The stress-induced desensitization of 5-HT1A receptors was prevented by the administration of EGb 761 (50 mg/kg per os/14 days). These results clearly indicate that 5-HT1A receptors are desensitized by stress and point out the reduced capacity of old rats to cope with the adverse effects of a chronic stressor. EGb 761 appears to restore the age-related decreased capacity to adapt to a chronic stressor.

26.Extracts of Ginkgo biloba leaves inhibit monoamine oxidase.:(Psycho:anti-stress/anxiolytic)

Life Sci. 1996;58(16):1315-21.PMID: 8614288
Extracts of Ginkgo biloba leaves produce reversible inhibition of rat brain monoamine (MAO). Both MAO-A and -B types were inhibited to a similar extent. The MAO inhibitory compound(s) were present in dried or fresh Ginkgo biloba leaves as well as in commercially available capsules of Ginkgo biloba and appear to be heat stable with relatively low molecular weight. MAO inhibition by Ginkgo biloba may be a mechanism underlying reported anti-stress and anxiolytic activities of this natural product.

27.Anxiolytic-like effect of combined extracts of Zingiber officinale and Ginkgo biloba in the elevated plus-maze.:(Psycho:anti-stress/anxiolytic)

Pharmacol Biochem Behav. 1996 Feb;53(2):271-5.PMID: 8808131
The effects of the known anxiolytic compound diazepam (DZ) on the behavior of rats in the elevated plus-maze were compared with those of zingicomb (ZC) (registered trademark of Mattern et Partner), a combination preparation of standardized extracts of Ginkgo biloba and Zingiber officinale. DZ was administered intraperitoneally (IP) in a reference dosage of 1 mg/kg 30 min before the rats were tested on the elevated plus-maze for 5 min. The treatment with DZ elevated the time spent on the open arms and excursions into the end of the open arms, increased scanning over the edge of an open arm, and decreased risk-assessment from an enclosed arm. ZC was administered intragastrically (IG) in four doses ranging between 0.5 and 100 mg/kg 60 min prior to plus-maze testing. The treatment with 0.5 mg/kg ZC elevated the time spent on the open arms and excursions into the end of the open arms; at the high dosage of 100 mg/kg, ZC led to fewer excursions to and less scanning of the open arms. Injection of 1 or 10 mg/kg ZC had no significant effect on the behavior in the maze. These data provide evidence that ZC has anxiolytic effects in the elevated plus-maze comparable to those of DZ, but that in high dosage the phytopharmacon may also have anxiogenic properties. The anxiolytic-like effects of ZC are discussed with regard to the known antiserotonergic action of ginger and Ginkgo biloba.

28.Effects of Ginkgo biloba extract (EGb 761) on learning and possible actions on aging.:(Psycho:anti-aging)

J Physiol Paris. 1997 Dec;91(6):291-300.PMID: 9457661
A study of the effect of Ginkgo biloba extract (EGb 761) has shown enhancing effects on training in adult and aged Swiss mice. An analysis of inbred mice has confirmed this sensitivity to EGb 761, but depending on the strains, with different effects at different ages. The most interesting results are related to improvements in performances observed with aged mice of the DBA/2J strain. The results obtained with inbred strains in the study of the mossy fibers of the hippocampus make it possible to suggest a link between the improvements in training and the histological structure of the hippocampus. This possibility, which can be confirmed by further studies, is presented here.

29.The effects of an extract of Ginkgo biloba, EGb 761, on cognitive behavior and longevity in the rat.:(Psycho:cognitive/longevity,anti-aging)

Physiol Behav. 1998 Feb 1;63(3):425-33.PMID: 9469738
Extracts of the leaves of the Ginkgo biloba tree are widely used throughout the world for their purportedly beneficial effects on brain function. In the present investigation, a standardized extract, EGb 761, was self-administered orally by male Fischer 344 rats that were then tested in an eight-arm radial maze. The tasks employed were a) continuous learning and b) delayed nonmatching to position. Chronic postsession administration of EGb 761 at a dose of 50 mg/kg had no effect on continuous learning but the same dose given presession resulted in a trend toward fewer sessions to reach criterion performance as well as fewer errors. In addition, it was observed that rats chronically treated with EGb 761 lived significantly longer than vehicle-treated subjects. In a delayed nonmatching to position task using a 30-min delay in 20-month-old rats. EGb 761 administered presession produced a dose-related decrease in total, retroactive, and proactive errors; a repeated-measures design was used, with subjects serving as their own controls. Following the dose-response determination, the group, now 26 months of age, was divided in two with half receiving EGb 761 at a dose of 200 mg/kg presession and the other half vehicle (sweetened condensed milk). A statistically significant positive effect of treatment with EGb-761 was observed. The present data are consistent with the beneficial effects on cognitive performance which have been widely reported in human subjects. In addition, the data suggest that the methods employed, i.e., continuous learning and delayed nonmatching to position tasks in aged rats, are capable of detecting drugs of possible value in the treatment of human cognitive impairment. Finally, the present results encourage a search for the pharmacologically active principles of EGb 761 and for their mechanisms of action.

30.Effect of chronic administration of Ginkgo biloba extract or Ginkgolide on the hypothalamic-pituitary-adrenal axis in the rat.:(Psycho:anti-stress)

Life Sci. 1998;62(25):2329-40.PMID: 9651122
The hypersecretion of glucocorticoids during exposure to various stressors may induce or worsen pathological states in predisposed subjects. Therefore it is of interest to evaluate drugs able to reduce glucocorticoid secretion. It has recently been shown that chronic administration of a Ginkgo biloba extract (EGb 761) inhibits stress-induced corticosterone hypersecretion through a reduction in the number of adrenal peripheral benzodiazepine receptors. The present study was designed to analyze the effect of EGb 761 and one of its components, Ginkgolide B on the biosynthesis and secretion of CRH and AVP, the hypothalamic neurohormones that regulate the pituitary-adrenal axis. Chronic administration of EGb 761 (50 or 100 mg/kg p.o. daily for 14 days) reduced basal corticosterone secretion and the subsequent increase in CRH and AVP gene expression. Under the same conditions, surgically-induced increase in CRH secretion was attenuated while the activation of CRH gene expression, ACTH and corticosterone secretion following insulin-induced hypoglycemia remained unchanged. Chronic i.p. injection of Ginkgolide B reduced basal corticosterone secretion without alteration in the subsequent CRH and AVP increase. However, the stimulation of CRH gene expression by insulin-induced hypoglycemia was attenuated by Ginkgolide B. These data confirm that the administration of EGb 761 and Ginkgolide B reduces corticosterone secretion. In addition, these substances act also at the hypothalamic level and are able to reduce CRH expression and secretion. However the latter effect appears to be complex and may depend upon both the nature of stress and substance (Ginkgolide B or other compounds of EGb 761).

31.Ginkgo biloba extract: cognitive enhancer or antistress buffer.:(Psycho:anti-stress)

Pharmacol Biochem Behav. 2002 Jul;72(4):913-22.PMID: 12062581
Constituents extracted from the leaves of the Ginkgo biloba tree possess beneficial properties that may buffer the aging nervous system from deterioration due to oxidative stress. In the present investigation, a standardized extract of G. biloba (EGb 761) or an equal volume of the vehicle was administered (100 mg/kg/day) to senescent (20-month) C57BL/6 male mice for up to 82 consecutive days. Animals were tested twice in the Morris water maze (MWM) after 28 and 70 days of treatment. No differences were observed in acquisition or retention of performance on the water maze. Elevated-plus maze (EPM) trials were conducted prior to and subsequent to the chronic treatment regimen. Marked baseline differences in plus-maze performance were present in the first experiment. A second experiment used a matched-pairs design to minimize preexisting differences. Results supported the hypothesis that EGb 761 may serve as an antistress buffer, attenuating the increase in anxiety typically observed in animals after cold water exposure. Tissue samples from the hippocampus and cortex were analyzed by Western blot for the transcription factor cyclic-AMP response element binding (CREB) protein. EGb 761 had no significant effect on immunoreactivity to CREB from either the hippocampus or the cerebral cortex.

32.The effects of Ginkgo biloba extract (LI 1370) supplementation on activities of daily living in free living older volunteers: a questionnaire survey.:(Psycho:anti-aging)

Hum Psychopharmacol. 2000 Jun;15(4):227-235.PMID: 12404317
This survey assessed the impact of four months supplementation with 120 mg/day of the standardized Ginkgo biloba special extract (LI 1370) on activities of daily living and various aspects of mood and sleep in a population of free living older volunteers using both observer- and self-rated scales. 5028 Participants (mean age 68.9 years) were recruited through a magazine editorial. One thousand received Ginkgo biloba extract (GBE) and the remainder were allocated to the Control group. The B-ADL (activities of daily living) Scale was completed at baseline and at the end of month 4 by an informant familiar with the participant, a Self-rating ADL scale and Line Analogue Ratings Scales of mood and sleep were completed by the participants at the end of months 1, 2, 3, and 4. There were significant differences between the GBE and Control groups on all scales at each time point. The GBE group felt better able to cope with their daily activities and showed positive changes in mood and sleep compared to the Control group. These results suggest that GBE supplementation has beneficial effects on areas of functioning that have implications for quality of life in an older population.

33.Anti-aging action of the total lactones of ginkgo on aging mice:(Psycho:antiaging)

Yao Xue Xue Bao. 2004 Mar;39(3):176-9.PMID: 15171650
AIM: To investigate the effects of total lactones of ginkgo on aging by using D-galactose induced aging mice and natural aging mice.METHODS: By using D-galactose induced aging mice, to detect the LF content in heart and liver, the Hyp content in liver, the MAO, GSH-Px activities and the NO content in cerebrum. The apoptosis of cerebral cell was determined by terminal deoxy-nucleotidyl transforase-mediated dUTP-digoxigenin nick end-labeling (Tunel) in natural aging mice.RESULTS: TLG was shown to increase the GSH-Px activities, reduce the NO content and decrease the MAO activity in cerebrum. Meanwhile, TLG was found to reduce the LF content in liver and heart and raise the Hyp content in liver. TLG was shown to inhibit apoptosis of cerebral cell and decrease the number of apoptotic cells in the brain.CONCLUSION: TLG possesses effect on antiaging via attenuating lipid peroxidation and NO and apoptosis of cerebral cells.

34.Long-term treatment with the antioxidant drug EGb 761 at senescence restored some neurobehavioral effects of chronic ultramild stress exposure seen in young mice.:(Psycho:antiaging)

Neurobiol Aging. 2004 Sep;25(8):1067-83.PMID: 15212832
In this study, we compared the effects of chronic ultramild stress (CUMS) exposure on decision-making behavior in a validated test, and on the stress responsive serotoninergic and dopaminergic systems in four age groups of B6D2F1 female mice (5-6, 11-12, 17-18 and 23-24 months old). The levels of serotonin (5-HT) and its metabolite 5-hydroxyindolacetic acid (5-HIAA) were measured in the brain stem, the cortex, the striatum and the hippocampus; the levels of dopamine (DA) and its metabolite dihydroxyphenylacetic acid (DOPAC) were measured in the brain stem and the striatum. The influence of a long-term treatment with the extract of Ginkgo biloba leaves EGb 761 (Tanakan) on age- and stress-related changes was also investigated in the two oldest age groups. In the absence of drug treatment, middle-age mice were the least efficient in making a decision, and senescent mice exhibited reduced levels of both 5-HT and DA and their metabolites in all the brain areas examined. CUMS facilitated evaluation and choice behavior in all age groups, but induced age-dependent reduction of hesitation, acceleration of information processing and reduction in serotoninergic neurotransmission. In senescent mice, EGb 761 reduced the impact of stress on evaluation and hesitation, and restored some stress-related neurobehavioral changes that were only seen in young mice, i.e. acceleration of information processing and reduction in brain 5-HIAA levels. Restoration of some plasticity of the serotoninergic systems might contribute to the stress alleviating influence of EGb 761 in old age.

35.Age-related effects of Ginkgo biloba extract on synaptic plasticity and excitability.:(Psycho:antiaging)

Neurobiol Aging. 2004 Aug;25(7):955-62.PMID: 15212849
EGb 761 is a standardized extract from the Ginkgo biloba leaf and is purported to improve age-related memory impairment. The acute and chronic effect of EGb 761 on synaptic transmission and plasticity in hippocampal slices from young adult (8-12 weeks) and aged (18-24 months) C57Bl/6 mice was tested because hippocampal plasticity is believed to be a key component of memory. Acutely applied EGb 761 significantly increased neuronal excitability in slices from aged mice by reducing the population spike threshold and increased the early phase of long-term potentiation, though there was no effect in slices from young adults. In chronically treated mice fed for 30 days with an EGb 761-supplemented diet, EGb 761 significantly increased the population spike threshold and long-term potentiation in slices from aged animals, but had no effect on slices from young adults. The rapid effects of EGb 761 on plasticity indicate a direct interaction with the glutamatergic system and raise interesting implications with respect to a mechanism explaining its effect on cognitive enhancement in human subjects experiencing dementia.

36.The effects of Ginkgo biloba extract (LI 1370) supplementation and discontinuation on activities of daily living and mood in free living older volunteers.:(Psycho:antiaging)

Phytother Res. 2004 Jul;18(7):531-7.PMID: 15305311
The aim of the study was to investigate the effects of continuing treatment with Ginkgo biloba extract (GBE) 120 mg/day on the activities of daily living (ADLs) and mood in healthy older volunteers who had immediately previously participated in a survey of the effects of a 4 month treatment with the drug. Following a prior postal survey investigating the effects of 4 months supplementation with GBE on ADLs and various aspects of mood and sleep, 1570 volunteers continued onto a 6 month follow-up postal survey. Subjects selected their own treatment option for the follow-up survey, which effectively created four groups: a continuation group who received GBE in the initial 4 month study and during the 6 month follow-up (GBE-GBE), a discontinuation group who received GBE in the initial study but not during the follow-up (GBE-NT), a new treatment group who did not receive GBE in the initial 4 month study but who did receive GBE during the 6 month follow-up (NT-GBE), and a no treatment group who received no treatment in either survey (NT-NT). At the end of the 6 month follow-up period each subject completed a line analogue rating scale (LARS) and a self-rating activities of daily living scale (SR-ADL). There were signi fi cant differences in the mean overall LARS and SR-ADL scores between the four treatment combination groups at the end of the follow-up period. A factor analysis of the LARS revealed two factors, 'mood' and 'alertness'. When scores from each of the treatment groups were examined over the whole 10 month period it was evident that the ratings of overall competence in the SR-ADL and both factors of the LARS were diminished on cessation of treatment with GBE, and improved when GBE treatment was initiated. The magnitude of the improvements on all scales was related to the overall duration of GBE supplementation.Signi fi cant differences between the groups of subjects treated with GBE for different periods of time (4-10 months) suggests that the extract has a demonstrable effect in improving mood and the self-assessed performance of the tasks of everyday living.

Xc-Ginkgo Biloba:Psychopharmacological effects:Mental performance,Cognitive,Cognitive-deficits,Behavioral Sensitization,Memory,Memory-deficit,Spatial memory,Dyslexia,Attention-deficit disorder

1.Study of the long-term action of a Ginkgo biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEG and psychometric measurements.(Psycho:mental performance):

Arzneimittelforschung. 1985;35(9):1459-65.
The action of a Ginkgo biloba extract (r?kan, Tanakan, G.B.E.) in promoting blood flow has been demonstrated in several animal and human pharmacological studies. The aim of this present study was to estimate the action of the substance on the central nervous system in order to be able to assess its potential use as a therapeutic agent in geriatric patients with cerebral insufficiency. Quantitative pharmaco-EEG is the method of choice for studying the vigilance-promoting effects of a drug. It is incomparable for confirming the findings of behavioural and psychometric studies. 60 volunteers of either sex participated in the double-blind trial. They were aged 57-77 years and showed mental deterioration corresponding to their age. They were randomly divided into three experimental groups: 20 subjects received 3 X 40 mg/day G.B.E., 20 received 5 mg nicergoline and 20 received a placebo of similar appearance. The subjects underwent an extensive series of examinations before and 4, 8 and 12 weeks after the start of medication. Analysis of the EEG results for the whole group revealed no significant advantage of G.B.E. over the two reference substances with regard to vigilance. However, a subclassification of the subjects showed that the vigilance of those persons with a more unfavourable initial situation measured in the resting EEG could be clearly improved by chronic G.B.E. medication. This increase in vigilance was reflected at the behavioural level by an improvement of reaction times in the G.B.E. group by comparison with the reference substances.

2.Effects of an extract of Ginkgo biloba on learning and memory in mice.:(Psycho:mental performance)

Pharmacol Biochem Behav. 1991 Jan;38(1):109-14.PMID: 2017439
The effects of an extract of Ginkgo biloba (EGb 761) on acquisition, performance, and retention of mice in an appetitive operant conditioning were investigated. The animals were trained for 30 consecutive days to acquire a two-lever response sequence followed by food reward. EGb 761 was administered daily at a dose level of 100 mg/kg PO. Drug treatment started four and eight weeks before the training and was maintained until a retention test 10 weeks after it. The results indicated that EGb 761 facilitated memory processes. EGb 761 quickened the acquisition and improved the performance of the two-response sequence: The number of correct responses was increased and correct responses were performed more frequently in the most effective manner. Besides, incorrect responses were reduced sooner and faster and to a lower level in EGb 761-treated mice. With regard to the retention EGb 761 improved the retrieval of the learned response.

3.Comparative effects of ginkgo biloba extracts on psychomotor performances and memory in healthy subjects:(Psycho:mental performance)

Therapie. 1991 Jan-Feb;46(1):33-6.PMID: 2020921
The effect on psychomotor and mnesic performances of acute oral dose (600 mg) of 2 Ginkgo biloba extracts were evaluated in twelve healthy female in a dummy placebo-controlled double blind study. Tests were performed comprising: objective measures of vigilance [critical flicker frequency (CFF), choice reaction time (CRT)], memory tasks (pictures and Sternberg scanning tests) and self-rating evaluation (visual analogue scales). Tests session took place before and 1 hour post-dosing. No statistically significant changes from placebo were observed on CFF, CRT or subjective rating of drug effects. No differences between treatment were evidenced on Sternberg scanning test and pictures recognition. Comparing to baseline, free recall score, while decreasing under placebo and Ginkgo, remained the same under Tanakan. As the differences between treatment are localized on one test, it appears important to examine the reproductility in healthy subjects. In order to verify the clinical relevance of these results, they need to be replicated in older healthy volunteers with age-associated memory impairment.

4.A double-blind, placebo controlled study of Ginkgo biloba extract ('tanakan') in elderly outpatients with mild to moderate memory impairment.:(Psycho:mental performance)

Curr Med Res Opin. 1991;12(6):350-5.PMID: 2044394
Thirty-one patients over the age of 50 years and showing a mild to moderate degree of memory impairment entered a 6-month double-blind, placebo controlled, parallel group design study to assess the effects of a standardized Ginkgo biloba extract (containing 24% flavonoid glycosides and 6% terpenes) on cognitive function. Patients were allocated at random to receive oral doses of 40 mg Ginkgo biloba extract or identical placebo 3-times daily. Assessments were made at baseline and after 12 and 24 weeks of treatment using a range of psychometric tests. Efficacy data were available for 27 patients (15 in the placebo group and 12 in the active treatment group). Statistical analysis of the data as compared to baseline suggests that Ginkgo biloba extract had a beneficial effect on cognitive function in this group of patients. Performance on the Digit Copying sub-test of the Kendrick battery was significantly improved at both 12 and 24 weeks, while the median speed of response on a computerized version of a classification task also showed a significant superiority over placebo at 24 weeks.

5.Improvement of memory in mice by extracts from leaves of Ginkgo biloba L:(Psycho:mental performance)

Zhongguo Zhong Yao Za Zhi. 1991 Nov;16(11):681-3, 704.PMID: 1804176
The study has shown that the extracts from leaves of Ginkgo biloba can significantly improve the NaNO2 and scopolamine induced impaired memory in mice. The potency of the ethanolic extract is greater than that of the aqueous extract. The ethanolic extract acts favorably on the memory function of normal animals. Both extracts help to prolong the survival time of mice receiving 200 mg/kg(ip)NaNO2.

6.Interaction between psychological and pharmacological treatment in cognitive impairment.:(Psycho:mental-cognitive)

Life Sci. 1994;55(25-26):2057-66.PMID: 7997065
In contrast to other kinds of psychotropic drugs, nootropics or cognition enhancing drugs may be indicated, not for the direct treatment of the pathology itself, but for improving or restoring the remaining brain functions. Brain functions are normally trained during various kinds of non-medical therapy, such as physiotherapy, speech therapy, occupational therapy, memory training etc... In research little attention has been paid to the combination of both kinds of therapeutic approaches, probably because of the important methodological difficulties. This combination however, offers various interesting perspectives: L. ISRAEL examined in two placebo-controlled studies the effects of either 160 mg/d of ginkgo biloba extractum (GBE) or piracetam 2.4 or 4.8 g/d, combined with a memory training program, in nondemented patients complaining of memory problems. The results of both studies suggest that nootropic drug treatment and memory training have each an effect on different cognitive functions and, hence, are complementary. Some functions, like attention/perception in the GBE study and learning in the piracetam study, seem to benefit from both treatments, suggesting a mutually potentiating effect of drug treatment and training. This potentiation is very clear in the treatment of dyslexic children: in a placebo-controlled study piracetam 3.3 g/d, in combination with normal school teaching and more specific logopedic therapy, allowed a normal progression during the full school year in reading accuracy and reading comprehension, while the placebo treated children getting a similar training progressed only with 50%. Recently promising results were obtained in the treatment of dysphasic patients with a combination of speech therapy and piracetam 4.8 g/d, especially when given during the first months after the stroke, or otherwise in combination with an intensive speech training. In both double-blind studies the piracetam treated group improved about 60% more than the group who only got speech therapy and placebo. All these data may be explained by the restorative or enhancing influence of nootropic drugs on neurotransmitter systems closely related to learning and memory functions. E.g. piracetam restores the availability and function of muscarinic and NMDA receptors in aging animals, most probably through a modulation of the psychico-chemical properties of the neuronal membrane such as the membrane fluidity.

7.Decreased cerebral 5-HT1A receptors during ageing: reversal by Ginkgo biloba extract (EGb 761).:(Psycho:mental-cognitive)

J Pharm Pharmacol. 1994 Apr;46(4):316-8.PMID: 8051617
Investigation of [3H]8-hydroxy-2(di-n-propylamino)tetralin binding to 5-HT1A receptors in cerebral cortex membranes of Wistar rats showed that the maximal number of binding sites (Bmax) was reduced significantly (22%) in aged (24-month-old) as compared with young (4-month-old) animals. Chronic treatment with Ginkgo biloba extract did not alter binding in young rats but increased binding density significantly (33%) in aged rats. These results confirm previously described age-related 5-hydroxytryptaminergic alterations. Together with data in the literature, they also suggest a restorative effect in aged rats, associated with decreased receptor density resulting from the protective action of Ginkgo biloba extract treatment on neuronal membrane.

8.Ginkgo biloba extract (EGb 761) independently improves changes in passive avoidance learning and brain membrane fluidity in the aging mouse:(Psycho:mental performance)

Pharmacopsychiatry. 1996 Jul;29(4):144-9.PMID: 8858713
Decreases in cell membrane fluidity may be a major mechanism of age-related functional decline. A prime cause for the decline of membrane fluidity may be the presence of free radicals. Gingko biloba extract EGb 761 protects neuronal cell membranes from free radical damage in vitro. Further, EGb 761 has repeatedly been shown to improve cognitive functions in man and in laboratory animals. To test if there is a link between these two actions we assessed the effects of EGb 761 on passive avoidance learning and on neuronal membrane fluidity in vivo in young (three-month-old), middle-aged (12-month-old) and aged (22 to 24-month-old) female NMRI mice. The animals were treated daily with 100 mg/kg EGb 761 for three weeks. There was a significant improvement in short-term memory, measured by the avoidance latency 60 seconds after the aversive stimulus (p < 0.0311), and of membrane fluidity (p < 0.01) in the aged animals, but no improvement in long-term memory as measured by the avoidance latency 24 hours after shock. However, no significant correlation between membrane fluidity and short-term memory performance was found. Taken together, these results indicate that EGb 761 independently improves changes in passive avoidance learning and brain membrane fluidity.

9.Clinical improvement of memory and other cognitive functions by Ginkgo biloba: review of relevant literature.:(Psycho:cognitive)

Adv Ther. 1998 Jan-Feb;15(1):54-65.PMID: 10178638
Ginkgo biloba is a plant extract used to alleviate symptoms associated with cognitive deficits, e.g., decreased memory performance, lack of concentration, decreased alertness, tinnitus, and dizziness. Pharmacologic studies have shown that the therapeutic effect of ginkgo is based on several active constituents with vasoactive and free radical-scavenging properties. The use of ginkgo extract in either dementias of the Alzheimer or multi-infarct type or in the case of cerebral insufficiency, a symptom complex related to age-dependent impairment of cerebral circulation, is based mainly on positive results from good-quality placebo-controlled studies that enrolled approximately 1,200 patients with criteria established by International Classification of Diseases (9th and 10th revisions, ICD-9 and ICD-10) or the 3rd revision of the Diagnostic and Statistical Manual (DSM-III-R) (uncomplicated dementia). Effect on cognitive symptoms was within the range of a 25% reduction. Memory, concentration, and alertness were the first symptoms to be relieved, with tinnitus and dizziness improving somewhat later. A minimum of 4 to 6 weeks were needed before a pronounced effect could be expected. The pharmacologic advantage of ginkgo seems to be a very tolerable side-effect profile, with a side-effect frequency at the placebo level.

10.Ginkgo biloba extract EGb761 reduces the development of amphetamine-induced behavioral sensitization: effects on hippocampal type II corticosteroid receptors.:(Psycho:mental performance-behavioral sensitization)

Brain Res. 1999 Feb 6;818(1):135-9.PMID: 9914446
Pretreatment of rats with the extract of Ginkgo biloba termed EGb761 reduced the behavioral sensitization induced by successive D-amphetamine administrations (0.5 mg/kg) as estimated by increasing values of locomotor activity. EGb761 pretreatment also prevented the reduced density of [3H]dexamethasone binding sites in the dentate gyrus and the CA1 hippocampal regions of D-amphetamine treated animals. These observations suggest that EGb761,by reducing glucocorticoid levels, could modulate the activity of the neuronal systems involved in the expression of the behavioral sensitization.

11.Ginkgo biloba and memory for a maze.:(Psycho:mental performance-memoral)

Psychol Rep. 1999 Apr;84(2):481-4.PMID: 10335061
A number of sources suggest that the natural herb ginkgo biloba enhances mental sharpness by increasing blood flow to the brain. A preliminary study was designed to examine whether memory for a maze would be enhanced in 5 mice who received a dietary supplement containing ginkgo biloba. The mice showed an improved memory for the maze as evidenced by a decrease in the number of errors in reaching the goal box when they received gingko biloba as a dietary supplement.

12.A review of nutrients and botanicals in the integrative management of cognitive dysfunction.:(Psycho:cognitive)

Altern Med Rev. 1999 Jun;4(3):144-61.PMID: 10383479
Dementias and other severe cognitive dysfunction states pose a daunting challenge to existing medical management strategies. An integrative, early intervention approach seems warranted. Whereas, allopathic treatment options are highly limited, nutritional and botanical therapies are available which have proven degrees of efficacy and generally favorable benefit-to-risk profiles. This review covers five such therapies: phosphatidylserine (PS), acetyl-l-carnitine (ALC), vinpocetine, Ginkgo biloba extract (GbE), and Bacopa monniera (Bacopa). PS is a phospholipid enriched in the brain, validated through double-blind trials for improving memory, learning, concentration, word recall, and mood in middle-aged and elderly subjects with dementia or age-related cognitive decline. PS has an excellent benefit-to-risk profile. ALC is an energizer and metabolic cofactor which also benefits various cognitive functions in the middle-aged and elderly, but with a slightly less favorable benefit-to-risk profile. Vinpocetine, found in the lesser periwinkle Vinca minor, is an excellent vasodilator and cerebral metabolic enhancer with proven benefits for vascular-based cognitive dysfunction. Two meta-analyses of GbE demonstrate the best preparations offer limited benefits for vascular insufficiencies and even more limited benefits for Alzheimer's, while "commodity" GbE products offer little benefit, if any at all. GbE (and probably also vinpocetine) is incompatible with blood-thinning drugs. Bacopa is an Ayurvedic botanical with apparent anti-anxiety, anti-fatigue, and memory-strengthening effects. These five substances offer interesting contributions to a personalized approach for restoring cognitive function, perhaps eventually in conjunction with the judicious application of growth factors.

13.Therapeutic value of Ginkgo biloba in reducing symptoms of decline in mental function.:(Psycho:mental performance)

J Pharm Pharmacol. 1999 May;51(5):535-41.PMID: 10411212
The Chinese tree Ginkgo biloba or "maiden hair tree" is extensively cultivated for the exploitation of the medicinal properties of its leaves. From these, a well-defined extract designated "EGb 761" has been developed, which was commercialized initially as Tanakan, Tebonin and Rokin; a similar product, Kaveri (LI 3170), also exists. The major therapeutic applications for these products are "cerebral insufficiency", other cerebral disorders, neurosensory problems and peripheral circulatory disturbances. Four primary concepts of action have been proposed to explain the pharmacotherapeutic benefits of EGb761; these are: vasoregulatory, cognition-enhancing, stress-alleviating, and gene-regulatory. These actions are believed to be realized through the principal active ingredients, flavonoids and the terpenoids ginkgolides and bilobalide acting simultaneously in concert, combination and synergy, so-called polyvalent action. It has been proposed that EGb761 may improve the memory of healthy volunteers, and in an assessment of [corrected] forty clinical studies, it was reported that Ginkgo was able to improve the twelve different symptoms comprising 'cerebral insufficiency', all of which are manifest in the elderly. These were supported in a second major study, using LI1370. However, in both instances, the evidence was largely based upon the results of self-assessment questionnaires. Latterly, in a large double blind study of men and women with the diagnosis of uncomplicated dementia who were administered Ginkgo for a year, a further positive outcome was claimed. In this study, patients were tested using ADAS-cog, GERRI and CGIC. It is suggested that whilst these different outcomes are compatible with (but do not affirm) a clinical benefit resulting from the use of Ginkgo, the application of a more objective system of assessment would be able to provide firm proof. It is proposed, therefore, that an objective, computer-based testing system for assessment of clinical improvement in volunteers and patients administered Ginkgo (such as CANTAB) would provide the convincing evidence currently being sought by patients, carers, physicians, legislators and the pharmaceutical industry.

14.The effects of acute doses of standardized Ginkgo biloba extract on memory and psychomotor performance in volunteers.:(Psycho:mental-performance/cognitive)

Phytother Res. 1999 Aug;13(5):408-15.PMID: 10441781
This study investigated the effects of acute doses of Ginkgo biloba extract (GBE) on memory and psychomotor performance in a randomized, double-blind and placebo controlled 5-way cross-over design. Thirty-one volunteers aged 30-59 years received GBE 150 mg (50 mg t. d.s), GBE 300 mg (100 mg t.d.s.), GBE 120 mg mane and GBE 240 mg mane and placebo for 2 days. Following baseline measures, the medication was administered at 0900 h for the single doses and at 0900, 1500 and 2100 h for the multiple doses. The psychometric test battery was administered pre-dose (0830 h) and then at frequent intervals until 11 h post dose. The results confirm that the effects of GBE extract on aspects of cognition in asymptomatic volunteers are more pronounced for memory, particularly working memory. They also show that these effects may be dose dependent though not in a linear dose related manner, and that GBE 120 mg produces the most evident effects of the doses examined. Additionally, the results suggest that the cognitive enhancing effects of GBE are more likely to be apparent in individuals aged 50-59 years.

15.Use of special Ginkgo biloba extract for cognitive disorders in the elderly:(Psycho:cognitive disorder)

Wien Med Wochenschr. 1999;149(8-10):231-4.PMID: 10483688
All dementias had been suggested to be the result of a vessel-disease, now it is known that the greatest part belongs to the dementias of Alzheimer's type but furtheron there exists no possibility for curing or stopping. Since Ginkgo biloba extract is available it is used in this diagnosis. Experimental and clinical studies have shown a widespread possibility to act in this disease and even a neuroprotective potential can be postulated.

16.Nutrients, age and cognitive function.:(Psycho:cognitive)

Curr Opin Clin Nutr Metab Care. 1998 Nov;1(6):579-85.PMID: 10565413
Many nutrients or indices of nutritional status are associated with cognitive functioning, although the size of the effects on cognitive performance may be small. Results from recent studies, however, seem consistently to indicate that supplementation with beta-carotene and alpha-tocopherol, substances that promote antioxidant vitamins A and E, respectively, can be beneficial to cognitive function in elderly people. Folate rather than vitamin B12 appears to be associated with cognitive functioning. Furthermore the daily intake of ginkgo biloba extract can enhance cognitive performance and has been proved to delay cognitive decline in dementia. A proper dietary composition with regard to the ratio of carbohydrates to proteins, as well as the inclusion of sufficient micronutrients, seems to be favourable in the maintenance of cognitive function in the elderly. Glucose can enhance cognitive function, but a rapid decline of glucose levels may impair cognitive function or may induce feelings of lack of energy. Low doses of caffeine may also enhance cognitive function, although most studies on caffeine and cognition, as with studies on glucose and cognition, have not been carried out in elderly individuals. The effects of nutritional supplements are modest but do not seem to be very different from those of medicinal or investigational cognition-enhancing or anti-dementia drugs.

17.Facilitative effects of EGb 761 on olfactory recognition in young and aged rats.:(Psycho:mental performance-memory)

Pharmacol Biochem Behav. 2000 Feb;65(2):321-6.PMID: 10672985
The aim of the present study was to evaluate the effects of chronic and acute treatment by the Gingko biloba extract, EGb 761 (IPSEN, France) on olfactory short-term memory in rats, using a spontaneous recognition procedure. The effects of a daily EGb 761 treatment (30 or 60 mg/kg) over a period of 30 days (Experiment 1) were evaluated in young male rats. Those of a single injection of EGb 761 were assessed either in young male rats at 60 or 120 mg/kg (Experiment 2) or in aged female rats at 60 mg/kg (Experiment 3). Results showed that, at the highest dose (60 mg/kg), chronic EGb 761 treatment enhanced the recognition performances, allowing recognition at delays at which control animals did not show any recognition. Acute treatment enhanced recognition at both doses tested. The results of the third experiment showed that EGb 761 had an overall enhancement effect on the performances of aged rats. In summary, our results provide evidence for a short-term memory enhancement effect of EGb 761 in both young and aged rats.

18.An examination of the efficacy of Ginkgo biloba extract EGb761 on the neuropsychologic functioning of cognitively intact older adults.:(Psycho:mental performance/neurocognitive)

J Altern Complement Med. 2000 Jun;6(3):219-29.PMID: 10890330
OBJECTIVES: Few investigations have examined the effectiveness of Ginkgo biloba extract for enhancing cognitive abilities in individuals with no history of significant neurocognitive dysfunction. The purpose of this research was to examine the relatively short-term (i.e., 6 weeks) efficacy of Ginkgo biloba extract EGb 761 on the cognitive functioning of cognitively intact persons over the age of 55 years via a diverse battery of neuropsychologic tests and measures.PARTICIPANTS: From the 48 cognitively intact participants between the ages of 55 and 86 years who initially enrolled in this study, 21 males and 19 females successfully completed the study's protocol and provided valid data sets.DESIGN: A 6-week, double-blind, fixed-dose, placebo-controlled, parallel-group experimental design was utilized. Participants were randomly assigned to either a Ginkgo biloba extract EGb 761 (180 mg/d) or placebo control group. To evaluate participants' cognitive and behavioral functioning, series of neuropsychological tests were administered to them prior to the initiation of the Ginkgo biloba extract/placebo therapy (i.e., pretreatment baseline) and again, just prior to the termination of the treatment regimen (i.e., after 6 weeks).RESULTS: Participants who received 180 mg of Ginkgo biloba extract EGb 761 daily for 6 weeks exhibited significantly more improvement on a task assessing speed of processing abilities (i.e., Stroop Color and Word Test color-naming task) by the end of treatment as compared to participants who received placebo. Trends favoring improved performances in the Ginkgo biloba group were also demonstrated in three of the four remaining tasks that involved a timed, speed of processing component, although they did not reach statistical significance. Furthermore, a significant relationship was found between the type of treatment (Ginkgo biloba extract or placebo) and participants' ratings of their overall abilities to remember. Specifically, more participants in the Ginkgo biloba extract group rated their overall abilities to remember by the end of treatment as "improved," as compared to the placebo group. In contrast, no significant differences were found between the Ginkgo biloba and placebo groups by treatment end on any of the four objective memory measures.CONCLUSIONS: Taken together, the findings from standardized neuropsychologic assessment and a subjective, self-report questionnaire suggested that relatively short-term (i.e., 6 weeks) utilization of Ginkgo biloba extract EGb 761 may prove efficacious in enhancing certain neurocognitive functions/processes of cognitively intact older adults.

19.Can the cognitive enhancing effects of ginkgo biloba be explained by its pharmacology?:(Psycho:mental performance/cognitive)

Med Hypotheses. 2000 Dec;55(6):491-3.PMID: 11090296
Pre-clinical and clinical studies have shown that the extract of the leaves of Ginkgo biloba has modest therapeutic potential as a cognitive enhancing drug. The pharmacology of Ginkgo biloba is complex due to its multiple active constituents. While Ginkgo biloba's cognitive enhancing effects have been attributed to its platelet-activating factor antagonistic effects and its free-radical scavenger activity, recent evidence suggests it may have direct effects on the cholinergic system which might explain both its acute and chronic cognitive enhancing effects. Ginkgo biloba's direct cholinergic actions include reduction of scopolamine-induced amnesia, modulation of pre-synaptic choline uptake and acetylcholine release, upregulation of post-synaptic muscarnic receptors and indirect effects on cholinergic function by modulation of the serotonergic system. The overall pharmacodynamic effect of Ginkgo biloba is likely due to a combination of platelet activating factor antagonistic effects, free radical scavenging activity and modulation of cholinergic function.

20.The memory enhancing effects of a Ginkgo biloba/Panax ginseng combination in healthy middle-aged volunteers.:(Psycho:mental performance/memory)

Psychopharmacology (Berl). 2000 Nov;152(4):353-61.PMID: 11140327
The effects of capsules containing 60 mg of a standardised extract of Ginkgo biloba (GK501) and 100 mg of a standardised extract of Panax ginseng (G115) on various aspects of cognitive function were assessed in healthy middle-aged volunteers. A double blind, placebo controlled, 14 week, parallel group, repeated assessment, multi-centre trial of two dosing regimens, 160 mg b.i.d. and 320 mg o.d. was conducted. Two hundred and fifty-six healthy middle-aged volunteers successfully completed the study. On various study days (weeks 0, 4, 8, 12 and 14) the volunteers performed a selection of tests of attention and memory from the Cognitive Drug Research computerised cognitive assessment system prior to morning dosing and again, at 1, 3 and 6 h later. The volunteers also completed questionnaires about mood states, quality of life and sleep quality. The Ginkgo/ginseng combination was found significantly to improve an Index of Memory Quality, supporting a previous finding with the compound. This effect represented an average improvement of 7.5% and reflected improvements to a number of different aspects of memory, including working and long-term memory. This enhancement to memory was seen throughout the 12-week dosing period and also after a 2-week washout. This represents the first substantial demonstration of improvements to the memory of healthy middle-aged volunteers produced by a phytopharmaceutical.

21.Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications.:(Psycho:mental performance)

Curr Drug Targets. 2000 Jul;1(1):25-58.PMID: 11475535
The effects of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e., individuals suffering from deteriorating cerebral mechanisms related to age-associated impairments of memory, attention and other cognitive functions. EGb 761 is currently used as symptomatic treatment for cerebral insufficiency that occurs during normal ageing or which may be due to degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer patients may also respond to treatment with EGb 761 since this extract has an "anti-stress" effect. Basic and clinical studies, conducted both in vitro and in vivo, support these beneficial neuroprotective effects of EGb 761. EGb 761 has several major actions; it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischaemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury. Identified chemical constituents of EGb 761 have been associated with certain actions. Both flavonoid and ginkgolide constituents are involved in the free radical-scavenging and antioxidant effects of EGb 761 which decrease tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase. With regard to its "anti-stress" effect, EGb 761 acts via its ginkgolide constituents to decrease the expression of the peripheral benzodiazepine receptor (PBR) of the adrenal cortex.

22.The effect of Ginkgo biloba on memory in healthy male volunteers.:(Psycho:memory)

Physiol Behav. 2001 Jul;73(4):659-65.PMID: 11495672
The purpose of this study was to investigate possible effects of Ginkgo biloba, a widely used herbal extract, on memory. This study incorporated a double-blind, placebo-controlled design, which used 30 healthy male subjects in each of two groups. The treatment group received two 60-mg tablets of BioGinkgo (27/7) [corrected] daily for 5 days, while the placebo group received a placebo. On the fifth day, after a 2-h waiting period, all subjects were given the Sternberg Memory Scanning Test [Q. J. Exp. Psychol. 27 (1975) 1.], a reaction time control test, the vocabulary and digit span subtests of the WAIS-R [Wechsler D. Manual for the Wechsler adult intelligence scale - revised. New York: Psychological Corporation, 1981.], a reading span test [J. Verbal Learn. Verbal Behav. 19 (1980) 450.] and a prose recall test [Discourse Proc. 13 (1990) 387.]. Blood pressure, heart rate and side effects were also monitored throughout the study. Nonsignificant results were found on all interactions involving treatment group on all tests except the Sternberg Memory Scanning Test. The extract appeared to be safe but largely ineffective in enhancing memory.

23.Differential, dose dependent changes in cognitive performance following acute administration of a Ginkgo biloba/Panax ginseng combination to healthy young volunteers.:(Psycho:cognitive)

Nutr Neurosci. 2001;4(5):399-412.PMID: 11842916
We have previously shown differential cognitive improvements following single doses of Ginkgo biloba and of Ginseng. There is also evidence that chronic administration of a combination of standardised extracts of Ginkgo biloba and Panax ginseng may improve aspects of cognitive performance both in pathological populations and the healthy middle aged. No investigation has thus far looked either at the cognitive effects of single doses of such a combination, nor the effects of the combination on healthy young volunteers. The present study investigated whether acute administration of a combination of standardised extracts of Ginkgo biloba (GK501, Pharmaton SA) and Ginseng (G115, Pharmaton SA) had any consistent effect on mood and aspects of cognitive performance ("quality of memory", "secondary memory", "working memory", "speed of memory", "quality of attention" and "speed of attention") that can be derived by factor analysis of the cognitive drug research computerised assessment battery. The study followed a placebo-controlled, double blind, balanced, crossover design. Twenty healthy young adult volunteers received 320, 640, and 960 mg of the combination, and a matching placebo, in an order dictated by random allocation to a Latin square, and with a seven-day wash-out period between treatments. Following a baseline cognitive assessment, further test sessions took place 1, 2.5,4 and 6 h after the day's treatment. The most striking result was a dose-dependent improvement in performance on the "quality of memory" factor for the highest dose. Further analysis revealed that this effect was differentially targeted at the secondary memory rather than the working memory component. There was also a dose dependent decrement in performance of the "speed of attention" factor for both the 320 and 640 mg doses. These results are discussed in the context of previous findings within this series of studies.

24.Modulation of cognition and mood following administration of single doses of Ginkgo biloba, ginseng, and a ginkgo/ginseng combination to healthy young adults.:(Psycho:cognitive)

Physiol Behav. 2002 Apr 15;75(5):739-51.PMID: 12020739
It has previously been demonstrated in separate studies that single doses of Ginkgo biloba, Panax ginseng, and a combination of the two extracts can improve different aspects of cognitive performance in healthy young volunteers. The present study directly compared the effects of single doses of G. biloba, ginseng, and a product combining the two on aspects of mood and cognitive performance in the same cohort of healthy, young adult volunteers. The study followed a randomised placebo-controlled, double-blind, balanced, cross-over design. Twenty participants received 360 mg of ginkgo, 400 mg of ginseng, 960 mg of a product combining the two extracts, and a matching placebo. Treatment order was dictated by random allocation to a Latin square, with a 7-day wash-out period between treatments. Cognitive testing comprised completion of the Cognitive Drug Research (CDR) computerised assessment battery and two serial subtraction mental arithmetic tasks. Mood was assessed with Bond-Lader visual analogue scales. Following a baseline cognitive assessment, further test sessions took place 1, 2.5, 4, and 6 h after the day's treatment was taken. The results largely supported previous findings. All three treatments were associated with improved secondary memory performance on the CDR battery, with the ginseng condition evincing some improvement in the speed of performing memory tasks and in the accuracy of attentional tasks. Following ginkgo and the ginkgo/ginseng combination performance of both the Serial Threes and Serial Sevens, subtraction tasks was also improved at the later testing sessions. No modulation of the speed of performing attention tasks was evident. Improvements in self-rated mood was also found following ginkgo and to a lesser extent the combination product.

25.Ginkgo for memory enhancement: a randomized controlled trial.:(Psycho:cognitive)

JAMA. 2002 Aug 21;288(7):835-40.PMID: 12186600
CONTEXT: Several over-the-counter treatments are marketed as having the ability to improve memory, attention, and related cognitive functions in as little as 4 weeks. These claims, however, are generally not supported by well-controlled clinical studies.OBJECTIVE: To evaluate whether ginkgo, an over-the-counter agent marketed as enhancing memory, improves memory in elderly adults as measured by objective neuropsychological tests and subjective ratings.DESIGN: Six-week randomized, double-blind, placebo-controlled, parallel-group trial.SETTING AND PARTICIPANTS: Community-dwelling volunteer men (n = 98) and women (n = 132) older than 60 years with Mini-Mental State Examination scores greater than 26 and in generally good health were recruited by a US academic center via newspaper advertisements and enrolled over a 26-month period from July 1996 to September 1998.INTERVENTION: Participants were randomly assigned to receive ginkgo, 40 mg 3 times per day (n = 115), or matching placebo (n = 115).MAIN OUTCOME MEASURES: Standardized neuropsychological tests of verbal and nonverbal learning and memory, attention and concentration, naming and expressive language, participant self-report on a memory questionnaire, and caregiver clinical global impression of change as completed by a companion.RESULTS: Two hundred three participants (88%) completed the protocol. Analysis of the modified intent-to-treat population (all 219 participants returning for evaluation) indicated that there were no significant differences between treatment groups on any outcome measure. Analysis of the fully evaluable population (the 203 who complied with treatment and returned for evaluation) also indicated no significant differences for any outcome measure.CONCLUSIONS: The results of this 6-week study indicate that ginkgo did not facilitate performance on standard neuropsychological tests of learning, memory, attention, and concentration or naming and verbal fluency in elderly adults without cognitive impairment. The ginkgo group also did not differ from the control group in terms of self-reported memory function or global rating by spouses, friends, and relatives. These data suggest that when taken following the manufacturer's instructions, ginkgo provides no measurable benefit in memory or related cognitive function to adults with healthy cognitive function.

26.Effect of Ginkgo biloba extract on beta-adrenergic receptors in different rat brain regions.:(Psycho:mental performance)

Phytother Res. 2002 Aug;16(5):488-90.PMID: 12203273
The effect of oral administration of Ginkgo biloba extract at a dose of 90 mg/kg for 7 consecutive days on rat brain beta-adrenergic receptors in the frontal cortex, hippocampus, striatum and hypothalamus was studied. Ginkgo biloba treatment induced a significant decrease in the density (B(max)) of beta-adrenoreceptors in the frontal cortex and hippocampus. It has been suggested that modulation of the beta-adrenergic system is implicated in the favourable effects of Ginkgo biloba extracts on learning and memory.

27.A comparative study in rodents of standardized extracts of Bacopa monniera and Ginkgo biloba: anticholinesterase and cognitive enhancing activities:(Psycho:cognitive)

Pharmacol Biochem Behav. 2002 Nov;73(4):893-900.PMID: 12213536
Bacopa monniera and Ginkgo biloba are well-known cognitive enhancers in Indian and Chinese traditional medicine systems. Standardized extracts of B. monniera and G. biloba were used to evaluate the antidementic and anticholinesterase activities in adult male Swiss mice. Antidementic activity was tested against scopolamine (3 mg/kg ip)-induced deficits in passive avoidance test. Three different extracts of B. monniera (30 mg/kg) and extract of G. biloba (15, 30 and 60 mg/kg) were administered postoperatively, daily for 7 days and 60 min after the last dose, i.e., on Day 7, first trial was conducted. In passive avoidance test, increased transfer latency time (TLT) and no transfer response (NTR) were taken as criteria for learning. TLT and NTR were significantly increased and decreased in second trial, 24 h after the first trial in control group and scopolamine-dementia group, respectively. The B. monniera- and G. biloba-treated groups produced significant increase in TLT and NTR on second trial (40-80%) after scopolamine treatment, thus, attenuating its antidementic effect. Both the extracts showed a dose (10-1000 microg)-dependent inhibitory effect on acetylcholinesterase (AChE) activity (in vitro), performed spectrophotometrically. IC(50) of G. biloba was 268.33 microg, whereas none of the extracts of B. monniera showed more than 50% inhibition. At a dose concentration of 30 and 60 mg/kg, extracts of G. biloba showed a cognitive enhancing property and, at the same time, a significant decrease in AChE-specific activity in both per se and scopolamine-dementia groups. These extracts possess a significant anticholinesterase and antidementic properties, which may be useful in the treatment of dementia.

28.Cognitive effects of a Ginkgo biloba/vinpocetine compound in normal adults: systematic assessment of perception, attention and memory.:(Psycho:mental performance/cognitive)

Hum Psychopharmacol. 2001 Jul;16(5):409-416.PMID: 12404561
A computerized test battery was used in a double-blind design to assess the cognitive effects of a nutrient compound containing Ginkgo biloba in 24 normal adults. Ten tasks (perceptual, attention and short-term memory) were presented in a standardized manner designed to maximize performance, with substantial pre-test practice employed to minimize response variability. Subjects were given either placebo or Ginkgo biloba extract capsules to consume for 14 days, after which they performed all tasks twice. They then received the other condition, and after 14 days completed the final test session. Response time and error rate stabilized after pre-test practice. A 'working memory capacity' paradigm demonstrated a reliable 50 ms response time decrease between the placebo and Ginkgo biloba testing, suggesting that Ginkgo biloba speeds short-term working memory processing in normal adults.

29.A double-blind, placebo-controlled, randomized trial of Ginkgo biloba extract EGb 761 in a sample of cognitively intact older adults: neuropsychological findings.:(Psycho:mental performance/cognitive)

Hum Psychopharmacol. 2002 Aug;17(6):267-77.PMID: 12404671
There appears to be an absence of large-scaled clinical trials that have examined the efficacy of Ginkgo biloba extract on the neuropsychological functioning of cognitively intact older adults. The importance of such clinical research appears paramount in light of the plethora of products containing Ginkgo biloba that are currently being widely marketed to predominantly cognitively intact adults with claims of enhanced cognitive performances. The purpose of this research was to conduct the first known, large-scaled clinical trial of the efficacy of Ginkgo biloba extract (EGb 761) on the neuropsychological functioning of cognitively intact older adults. Two hundred and sixty-two community-dwelling volunteers (both male and female) 60 years of age and older, who reported no history of dementia or significant neurocognitive impairments and obtained Mini-Mental State Examination total scores of at least 26, were examined via a 6-week, randomized, double-blind, fixed-dose, placebo-controlled, parallel-group, clinical trial. Participants were randomly assigned to receive either Ginkgo biloba extract EGb 761(n = 131; 180 mg/day) or placebo (n = 131) for 6 weeks. Efficacy measures consisted of participants' raw change in performance scores from pretreatment baseline to those obtained just prior to termination of treatment on the following standardized neuropsychological measures: Selective Reminding Test (SRT), Wechsler Adult Intelligence Scale-III Block Design (WAIS-III BD) and Digit Symbol-Coding (WAIS-III DS) subtests, and the Wechsler Memory Scale-III Faces I (WMS-III FI) and Faces II (WMS-III FII) subtests. A subjective Follow-up Self-report Questionnaire was also administered to participants just prior to termination of the treatment phase. Analyses of covariance indicated that cognitively intact participants who received 180 mg of EGb 761 daily for 6 weeks exhibited significantly more improvement on SRT tasks involving delayed (30 min) free recall (p < 0.04) and recognition (p < 0.01) of noncontextual, auditory-verbal material, compared with the placebo controls. The EGb 761 group also demonstrated significantly greater improvement on the WMS-III FII subtest assessing delayed (30 min) recognition (p < 0.025) of visual material (i.e. human faces), compared with the placebo group. However, based on the significant difference (p < 0.03) found between the two groups' pretreatment baseline scores on the WMS-III FII, this result should be interpreted with caution. An examination of the participants' subjective ratings of their overall abilities to remember by treatment end on the Follow-up Self-report Questionnaire also revealed that significantly more (p = 0.05) older adults in the EGb 761 group rated their overall abilities to remember by treatment end as 'improved' compared with the placebo controls. Overall, the results from both objective, standardized, neuropsychological tests and a subjective, follow-up self-report questionnaire provided complementary evidence of the potential efficacy of Ginkgo biloba EGb 761 in enhancing certain neuropsychological/memory processes of cognitively intact older adults, 60 years of age and over.

30.Acute, dose-dependent cognitive effects of Ginkgo biloba, Panax ginseng and their combination in healthy young volunteers: differential interactions with cognitive demand.:(Psycho:cognitive)

Hum Psychopharmacol. 2002 Jan;17(1):35-44.PMID: 12404705
The present paper describes three studies examining the acute effects of single doses of Ginkgo biloba (GK501), Ginseng (G115) and their combination (Ginkoba M/E, Pharmaton SA) on the performance of healthy young adults (mean age 21 years) during serial arithmetic tasks with differing cognitive load. In each double-blind, placebo-controlled study three different treatment doses and a placebo were administered, according to a balanced crossover design, with a 7-day washout period between each dose. Participants' scores on two computerised serial subtraction tasks (Serial Threes and Serial Sevens) were assessed pre-dosing and at 1, 2.5, 4 and 6 h thereafter. A number of significant time, dose and task-specific effects were associated with each treatment. There was a dose-dependent improvement in speed of responding during Serial Threes following Ginkgo biloba. Different doses of Ginseng improved accuracy and slowed responses during Serial Sevens. The most striking result, however, was a highly significant and sustained increase in the number of Serial Sevens responses following 320 mg of the Ginkgo-Ginseng combination at all post-treatment testing times. This was accompanied by improved accuracy during Serial Sevens and Serial Threes following the 640 mg and the 960 mg dose, respectively. The paper concludes with speculation into the possible mechanisms underlying these effects.

31.Ginkgo biloba: a smart drug? A systematic review of controlled trials of the cognitive effects of ginkgo biloba extracts in healthy people.:(Psycho:cognitive)

Psychopharmacol Bull. 2002 Summer;36(3):108-23.PMID: 12473969
Extracts of Ginkgo biloba are widely used to alleviate or delay the progress of age-related cognitive impairment. Its use as a "smart" drug by healthy individuals has also been commercially promoted. The aim of this study was to systematically review and critically evaluate the trial data to test whether Ginkgo biloba enhances cognitive function in healthy subjects. Literatures searches of 6 computerised databases were made for placebo-controlled, double-blind trials of the effect of standardized Ginkgo biloba extracts on cognitive function in healthy subjects. Trials published in any language were included and data were extracted independently by the authors following a standardized protocol. Nine trials were identified, and these were mainly short term. The longest had a treatment period of 30 days. Trials were mostly of good intrinsic methodological quality, but certain aspects of methodology were inadequately reported by all trials. Taken together, these studies indicate no marked or consistent positive effects of Ginkgo biloba on any particular objective measure of cognitive function. A positive subjective effect was reported only in the longest trial. It is concluded that a positive effect of Ginkgo biloba on cognitive function is not proven by data from rigorous clinical trials. The use of Ginkgo biloba as a "smart" drug cannot be recommended on the basis of the evidence available to date, and there is a particular need for further long-term trials with healthy subjects.

32.Cognitive performance, SPECT, and blood viscosity in elderly non-demented people using Ginkgo biloba.:(Psycho:cognitive-deficits)

Pharmacopsychiatry. 2003 Jul;36(4):127-33.PMID: 12905098
The aging process is associated with several cognitive alterations. This study looks at the effects of taking dried extract of Ginkgo biloba, which has been used in several countries in an attempt to minimize these effects. The subjects were 48 men aged 60 - 70 matched between control and experimental groups for educational level. Evaluation was based on a number of neuropsychological tests in an attempt to cover the largest possible number of functions including Single Photon Emission Computer Tomography (SPECT) and measures of blood viscosity. The study was run on a double-blind basis with placebo and Ginkgo biloba groups evaluated over a period of 8 months. After treatment, the experimental group showed a reduction in blood viscosity, improved cerebral perfusion in specific areas and improved global cognitive functioning. The control group showed the opposite - higher blood viscosity, a reduction in cerebral perfusion (in specific areas), and cognitive deterioration in different functions. Although the mechanisms by which Ginkgo biloba may contribute to overall enhancement of the parameters evaluated have not been specified, this plant extract certainly appears to be effective in the treatment of cognitive deficits in older people. Further research into its use is called for on the basis of the results obtained here.

33.Cognitive and other behavioral effects of EGb 761 in animal models.:(Psycho:cognitive)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S24-31.PMID: 13130385
Extensive pre-clinical and clinical studies conducted over more than three decades have established that EGb 761 (definition see editorial) represents a polyvalent therapeutic principle that is useful in the therapy of mildly to moderately severe dementia and other cognitive disorders. Besides cognition, other emotional and affective aspects of brain function also seem to benefit from EGb 761 treatment. Extensive behavioural studies in experimental animals are generally in line with clinical data since cognition improvement, stress protection, and antidepressive effects have been identified with this extract in proper animal models. While individual effects in all areas have been reported for adult animals and acute dosing, more pronounced effects are usually seen in aged animals and after subchronic treatment. Specifically, for the cognition improving properties pronounced beneficial effects are mainly present in those situations where cognition was impaired by aging or other noxious stimuli. Since all these conditions are associated with mitochondrial dysfunction, the stabilizing or even protecting effect of EGb 761 on mitochondrial function seems to be a major mechanism associated with many of EGb 761's behavioural effects. Bilobalide is most important in this respect. Moreover, bilobalide and the ginkgolides have recently been shown to affect chloride conductance by interfering with the function of membrane proteins related to receptor-gated chloride channels. These mechanisms are probably associated with behavioural effects requiring acute changes of neuronal activity, but might indirectly also improve mitochondrial function.

34.Magnitude of effect and special approach to Ginkgo biloba extract EGb 761 in cognitive disorders.:(Psycho:cognitive)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S44-9.PMID: 13130388
In the early 70's, improvements in methodical procedures of extraction and standardization of ginkgo preparation allowed the production of a highly concentrated and stable extract (EGb 761) (definition see editorial) by the company Dr. Willmar Schwabe, which could be systematically tested in scientific programs. Consequently, numerous studies have been undertaken and provided replicable outcomes to demonstrate its efficacy in human population. EGb 761 is currently registered as an ethical drug in more than 50 countries around the world, and is prescribed for a range of neurological and vascular disorders including dementia, arterial occlusive disease, retinal deficit, and tinnitus. The following chapter will focus on the relevant data that support EGb 761 efficacy in the treatment of cognitive disorders in general, and dementia in particular. Besides the published data, the author will provide original results unveiling different factors that could interfere with EGb 761 efficacy and may be the source of the variations observed among studies in the EGb 761 literature. In the author's opinion, such factors should be taken into consideration when implementing the design of future research and optimizing individual EGb 761 response in the clinical practice. Within the framework of this new approach, the author will not only answer the question as to whether EGb 761 works over placebo in cognitive disorders, but also attempt to estimate how well it works in particular conditions.

35.Effects of Ginkgo biloba on mental functioning in healthy volunteers.:(Psycho:cognitive/mental performance)

Arch Med Res. 2003 Sep-Oct;34(5):373-81.PMID: 14602503
BACKGROUND: There has been a lack of investigations examining the effects of Ginkgo biloba extract EGb 761 on mental functions and quality of life in healthy subjects with no cognitive impairment. Thus, the objective of the present study was to evaluate the relatively short-term (i.e., 4 weeks) effects of EGb 761 on mental functioning and quality of life in healthy volunteers.METHODS: The trial was conducted as a 4-week, randomized, double-blind, placebo-controlled, parallel-group, monocentric study. Sixty six healthy volunteers aged between 50 and 65 years without age-associated cognitive impairment were randomized, 32 into the placebo and 34 into the EGb 761-treatment group (240 mg, t.i.d.). Safety and compliance were monitored after 1, 2, 3 and 4 weeks. Primary outcome measures in this study are the subjects' judgment of their own mental health (MH), their general health (GH) and their quality of life (QoL) operationalized on the basis of three different visual analog scales (VAS). Secondary outcome measures are 15 tests and experimental procedures based on a neurobiologically based classification or taxonomy of functions.RESULTS: Intergroup differences in self-estimated mental health as well as self-estimated quality of life were significant in favor of EGb 761. No intergroup differences were found in self-estimated general health. Secondary outcomes supporting the notion of superiority of the active drug were found for both motor performance and emotional evaluation. This study did not reveal evidence of unknown drug-induced side effects or intolerance. No serious adverse events were observed during the study.CONCLUSIONS: Both questions treated in this study, efficacy and safety, are important from a medical perspective because many persons take the agent studied in an effort to enhance their mental functioning and general well-being. The findings of this study support the adequacy of intake of EGb 761 to improve the functions indicated previously.

36.The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers.:(Psycho:mental performance/memory)

Psychopharmacology (Berl). 2004 Apr;172(4):430-4. Epub 2003 Nov 25.PMID: 14647971
RATIONALE: The use of herbal remedies, such as Ginkgo biloba and Ginseng, for improving cognitive performance has become increasingly popular during recent years. Several previous studies have indicated that administration of Ginkgo biloba and Ginseng may improve aspects of learning and memory in healthy volunteers. These results, however, are generally not supported by well-controlled clinical studies. Also, positive results have often been reported from studies investigating effects related to short-term, chronic administration of the extract. Nonetheless, both Ginkgo biloba and Ginseng are marketed as having the capacity to enhance cognitive functions, such as memory and learning, in the long term.OBJECTIVE: This study aimed at investigating whether the use of Ginkgo biloba and Ginseng for a long period of time has positive effects on performance on learning and memory.METHODS: Community-dwelling volunteers ( n=3500) from The Betula prospective cohort study: memory, health, and aging were included in the study.RESULTS: It was found that the use of neither Ginkgo biloba ( n=40) nor Ginseng ( n=86) was associated with enhanced memory performance in any of the eight memory tests examined, relative to control groups either using or not using nutritional supplements.CONCLUSIONS: These findings indicate that use of Ginkgo biloba or Ginseng does not provide any quantifiable beneficial effects on memory performance in the long-term in healthy adult volunteers.

37.Behavioral effects of Ginkgo biloba L., Panax ginseng C.A. Mey. and Gincosan.:(Psycho:cognitive)

Am J Chin Med. 2003;31(6):841-55.PMID: 14992537
The behavioral effects of a standardized extract from Panax ginseng roots (G115), of a standardized extract from Ginkgo biloba leaves (GK501) and of their combination (PHL-00701) (Gincosan) were examined in experiments on rats with undisturbed memory and on rats with experimentally-impaired memory (by alcohol or by muscarinic- and dopamine-receptor antagonists), using methods for active avoidance (shuttle-box) and passive avoidance (step-down and step-through). On multiple administration G115, GK501 and PHL-00701 exerted favorable effects on learning and memory. These effects varied with the dose and administration schedules, with the rat strain and with the behavioral method. Based on earlier results, we discuss the role of changes in brain biogenic amines induced by the extracts in their mechanism of action. The present results allow for ranking G115, GK501 and their combination PHL-00701 (Gincosan) among cognition-enhancing (nootropic) drugs.

38.Effects of Ginkgo biloba on alertness and chemosensory function in healthy adults.:(Psycho:cognitive)

Hum Psychopharmacol. 2004 Mar;19(2):81-90.PMID: 14994317
Ginkgo biloba is reported to enhance cognitive function in patients with selected neural disorders. Its effects in healthy, young adults are less well characterized. This work explored whether Ginkgo biloba could ameliorate decrements in alertness post-prandially and/or enhance chemosensory function. Both are functions that could be influenced by enhanced cerebral blood flow and neuronal metabolism, reported properties of the compound. A double-blind placebo-controlled study was conducted with 19 males and 20 females with a mean age of 23.6 +/- 5.4 years and mean weight of 70.0 +/- 1.9 kg. Participants were supplemented for 13 weeks with either Ginkgo biloba (mean dose 184.5 mg/d (range 130-234 mg/d)) or placebo and administered various alertness, performance, affective state and chemosensory tests at weeks 1, 5, 9 and 13. Participants did experience the post-prandial affective state decrement (i.e. post-lunch dip), but not the performance decrement. Performance on the chemosensory tests improved over the 13-week study. However, Ginkgo biloba was ineffective at alleviating the symptoms of the post-lunch dip or at enhancing taste and smell function.

39.Effects of a combined extract of Ginkgo biloba and Bacopa monniera on cognitive function in healthy humans.:(Psycho:cognitive)

Hum Psychopharmacol. 2004 Mar;19(2):91-6.PMID: 14994318
Extracts of Ginkgo biloba and Bacopa monniera have been shown to produce positive effects on cognitive function in healthy subjects. While the exact mechanisms are not known, it has been suggested that antioxidant properties and cholinergic modulation may play a role. In the current study the sub-chronic (2 weeks) and chronic (4 weeks) effects of an extract containing Ginkgo biloba (120 mg) and Bacopa monniera (300 mg) (Blackmores Ginkgo Brahmi) on cognitive function were examined. The study was a randomized, double-blind, placebo-controlled, independent group design in which 85 healthy subjects were allocated to one of two treatment conditions (placebo or combined Ginkgo biloba and Bacopa monniera extract). Testing was conducted at baseline and 2 and 4 weeks post treatment. The results showed that the combined extract relative to placebo did not demonstrate any significant effects on tests investigating a range of cognitive processes including attention, short-term and working memory, verbal learning, memory consolidation, executive processes, planning and problem solving, information processing speed, motor responsiveness and decision making. These findings suggest that at least within the current treatment duration and doses, an extract containing Ginkgo biloba and Bacopa monniera had no cognitive enhancing effects in healthy subjects.

40.Magnitude of effect and special approach to Ginkgo biloba extract EGb 761 in cognitive disorders.:(Psycho:cognitive disorder)

41.Ginkgo biloba promotes short-term retention of spatial memory in rats.:(Psycho:mental performance)

Pharmacol Biochem Behav. 2004 Mar;77(3):533-9.PMID: 15006464
This study examines possible interactions between exposure to Ginkgo biloba extract and enriched environments on the acquisition and retention of spatial learning following massed and spaced trials. After 4 weeks of exposure to either ginkgo or vehicle, 8-week-old rats were tested using a Morris Water Maze in either massed or spaced trials. While ginkgo did not have an effect on maze acquisition or long-term retention, it did promote short-term retention of spatial memory. Following reversal training, ginkgo promoted short-term retention for two groups but impaired retention for a third. These results suggest that ginkgo has powerful effects on short-term retention that vary with training conditions.

42.Cognitive and physiological effects of an "energy drink": an evaluation of the whole drink and of glucose, caffeine and herbal flavouring fractions.:(Psycho:cognitive/mental performance)

Psychopharmacology (Berl). 2004 Nov;176(3-4):320-30. Epub 2004 Jul 31.PMID: 15549275
RATIONALE: Both glucose and caffeine can improve aspects of cognitive performance and, in the case of caffeine, mood. There are few studies investigating the effects of the two substances in combination.OBJECTIVES: We assessed the mood, cognitive and physiological effects of a soft drink containing caffeine and glucose as well as flavouring levels of herbal extracts. The effects of different drink fractions were also evaluated.METHODS: Using a randomised, double-blind, balanced, five-way crossover design, 20 participants who were overnight fasted and caffeine-deprived received 250 ml drinks containing 37.5 g glucose; 75 mg caffeine; ginseng and ginkgo biloba at flavouring levels; a whole drink (containing all these substances) or a placebo (vehicle). Participants were assessed in each drink condition, separated by a 7-day wash-out period. Cognitive, psychomotor and mood assessment took place immediately prior to the drink then 30 min thereafter. The primary outcome measures included five aspects of cognitive performance from the Cognitive Drug Research assessment battery. Mood, heart rate and blood glucose levels were also monitored.RESULTS: Compared with placebo, the whole drink resulted in significantly improved performance on "secondary memory" and "speed of attention" factors. There were no other cognitive or mood effects.CONCLUSIONS: This pattern of results would not be predicted from the effects of glucose and caffeine in isolation, either as seen here or from the literature addressing the effects of the substances in isolation. These data suggest that there is some degree of synergy between the cognition-modulating effects of glucose and caffeine which merits further investigation.

43.Prolyl endopeptidase inhibitors from the leaves of Ginkgo biloba.:(Psycho:memory/mental performance)

Planta Med. 2004 Dec;70(12):1228-30.PMID: 15643562
Prolyl endopeptidase (PEP, EC 3.4.21.26) hydrolyzes proline-containing neuropeptides, such as vasopressin, substance P, and thyrotropin-releasing hormone (TRH), and is suggested to participate in learning and memory processes. Ginkgo biloba leaves, upon examination for anti-amnestic constituents as new types of PEP inhibitors, showed significant PEP inhibition. PEP activity-guided fractionation and column chromatography of the MeOH extracts of G. biloba leaves resulted in the isolation of 6-(8'Z-pentadecenyl)salicylic acid (1) and 6-(10'Z-heptadecenyl)salicylic acid (2). The kinetic study indicated that compounds 1 and 2 are non-competitive inhibitors of prolyl endopeptidase with Ki values of 0.87 and 0.80 microM, respectively.

44.Differential cognitive effects of Ginkgo biloba after acute and chronic treatment in healthy young volunteers.:(Psycho:mental performance/cognitive)

Psychopharmacology (Berl). 2005 May;179(2):437-46. Epub 2005 Mar 1.PMID: 15739076
RATIONALE: Acute doses of Ginkgo biloba have been shown to improve attention and memory in young, healthy participants, but there has been a lack of investigation into possible effects on executive function. In addition, only one study has investigated the effects of chronic treatment in young volunteers.OBJECTIVES: This study was conducted to compare the effects of ginkgo after acute and chronic treatment on tests of attention, memory and executive function in healthy university students.METHODS: Using a placebo-controlled double-blind design, in experiment 1, 52 students were randomly allocated to receive a single dose of ginkgo (120 mg, n=26) or placebo (n=26), and were tested 4 h later. In experiment 2, 40 students were randomly allocated to receive ginkgo (120 mg/day; n=20) or placebo (n=20) for a 6-week period and were tested at baseline and after 6 weeks of treatment. In both experiments, participants underwent tests of sustained attention, episodic and working memory, mental flexibility and planning, and completed mood rating scales.RESULTS: The acute dose of ginkgo significantly improved performance on the sustained-attention task and pattern-recognition memory task; however, there were no effects on working memory, planning, mental flexibility or mood. After 6 weeks of treatment, there were no significant effects of ginkgo on mood or any of the cognitive tests.CONCLUSIONS: In line with the literature, after acute administration ginkgo improved performance in tests of attention and memory. However, there were no effects after 6 weeks, suggesting that tolerance develops to the effects in young, healthy participants.

45.Protective effects of Ginkgo biloba leaf extract on aluminum-induced brain dysfunction in rats.:(Psycho:mental performance)

Life Sci. 2005 May 27;77(2):140-8. Epub 2005 Feb 25.PMID: 15862599
This study examined the protective effects of Ginkgo biloba extract (GbE) on the learning and memory function in aluminum-treated rats and potential mechanisms. Wistar rats were given daily aluminum chloride 500 mg/kg, i.g, for one month, followed by continuous exposure via the drinking water containing 1600 ppm aluminum chloride for up to 5 months. The ability of spatial learning and memory was tested by Morris water maze. Aluminum administration significantly increased escape latency and searching distance, indicative of brain dysfunction. GbE treatment (50-200 mg/kg, i.g) significantly protected against aluminum-induced brain dysfunction, as evidenced by decreased escape latency and searching distance compared with the Al alone group. To examine the mechanisms of the protection, the expressions of amyloid precursor protein (APP) and caspase-3 in brain regions were examined by immunohistochemistry. GbE treatment reduced the contents of APP and caspase-3 in hippocampus of aluminum-treated rats in a dose-dependent manner. At the highest dose of GbE (200 mg/kg), the immunostain for APP and caspase-3 was returned to normal levels. In summary, this study demonstrates that GbE is effective in improving the ability of spatial learning and memory of aluminum-intoxicated rats. This protection appears to be due to a decreased expression of APP and caspase-3 in rat brain, resulting in a decrease in the production of insoluble fragments of Abeta-amyloid.

46.No alteration in the PFA-100 in vitro bleeding time induced by the Ginkgo biloba special extract, EGb 761, in elderly patients with mild cognitive impairment.:(Psycho:cognitive)

Blood Coagul Fibrinolysis. 2005 Jul;16(5):349-53.PMID: 15970719
EGb 761 is widely used in the management of mild cognitive impairment in the elderly population. Elucidation of the effects of EGb 761 on primary haemostasis via PFA-100 could represent an important step for better understanding of the haemostatic safety of EGb 761. The purpose of this prospective study is to assess the effects of Ginkgo biloba special extract, EGb 761, on PFA-100 in vitro bleeding time in elderly patients with mild cognitive impairment. A total of 40 elderly patients aged 65-79 years who were referred for geriatric assessment and who were diagnosed as having mild cognitive impairment were included. Patients were started on 80 mg EGb-761 three times daily. The complete set of PFA-100 in vitro bleeding time and coagulation parameters including prothrombin time, activated partial thromboplastin time and International Normalized Ratio were assessed before and on the seventh day of treatment with EGb 761. There was no statistically significant prolongation in PFA-100 in vitro bleeding time or coagulation parameters in patients receiving EGb 761 after 7 days. The data about the safety of EGb 761 from the point of primary haemostasis in our elderly patient population with mild cognitive impairment casts hope for the future management of this 'difficult-to-treat' population with the promising Ginkgo extracts.

47.Extract of Ginkgo biloba leaves reverses yohimbine-induced spatial working memory deficit in rats.:(Psycho:memory-deficit)

Behav Pharmacol. 2005 Dec;16(8):651-6.PMID: 16286817
Extract of Ginkgo biloba is used to alleviate age-related decline in cognitive function, which may be associated with the loss of catecholamines in the prefrontal cortex. The purpose of this study was to verify whether alpha-2 adrenergic activity is involved in the facilitative effects of extract of Ginkgo biloba on prefrontal cognitive function. Male Wistar rats were trained to reach criterion in the delayed alternation task (0, 25, and 50-s delay intervals). A pilot study found that 3 or 4 mg/kg of yohimbine (intraperitoneal) reduced the choice accuracy of the delayed alternation task in a dose and delay-dependent manner, without influencing motor ability or perseverative behaviour. Acute oral pre-treatment with doses of 50, 100, or 200 mg/kg (but not 25 mg/kg) of extract of Ginkgo biloba prevented the reduction in choice accuracy induced by 4 mg/kg yohimbine. These data suggest that the prefrontal cognition-enhancing effects of extract of Ginkgo biloba are related to its actions on alpha-2-adrenoceptors.

48.Ginkgo biloba: no robust effect on cognitive abilities or mood in healthy young or older adults.:(Psycho:cognitive)

Hum Psychopharmacol. 2006 Jan;21(1):27-37.PMID: 16329161
Ginkgo biloba extracts are commonly used to prevent or treat memory problems but evidence on the efficacy of ginkgo is equivocal. In any case, the psychological locus of ginkgo's effects is unknown. A 12-week, double-blind, placebo-controlled study assessed effects of ginkgo (120 mg per day) on a wide range of cognitive abilities, executive function, attention and mood in 93 healthy older adults (55-79 years) and in 104 young adults (18-43 years). For the older adult sample, longer-term memory assessed by associational learning tasks showed improvement with ginkgo (d = 0.52, p = 0.04). There was no statistically significant difference on any other measure. For the young adult group no measure showed statistically significant effects of ginkgo enhancement. There were no side effects unequivocally attributable to treatment with ginkgo and those reported by participants in the ginkgo groups were mild and similar to those reported elsewhere.

49.The in vivo synaptic plasticity mechanism of EGb 761-induced enhancement of spatial learning and memory in aged rats.:(Psycho:mental performance)

Br J Pharmacol. 2006 May;148(2):147-53.PMID: 16547523
It has not been uniform to date that the Ginkgo biloba extracts enhance cognitive function in aged animals, and the mechanisms of action remain difficult to elucidate. In this study, the Morris water maze task and electrophysiological methods were used to study the effects of repeated daily administration of EGb 761, a standardized extract from G. biloba leaves, on hippocampal-dependent spatial learning and memory and synaptic plasticity of aged rats. The adult subjects perform the Morris water maze task better than aged rats, as a cellular mechanism, the hippocampal long-term potentiation (LTP) elicited from adult animals is robust (139.29+/-2.7%). In addition, the spatial learning and memory of aged rats that had been fed on an EGb 761-supplemented diet (60 mg kg(-1)) for 30 days were significantly better than those of control aged rats. The magnitude of LTP (116.63+/-3.6%) recorded in vivo from the hippocampus CA1 area of aged rats was significantly enhanced by EGb 761 (60 mg kg(-1)). In conclusion, the spatial learning and memory of aged rats is worse than that of young subjects, and EGb 761, acting as a 'cognitive enhancer', has benefit on synaptic plasticity and cognition in aged rats. The present data further confirmed that enhancement of synaptic plasticity of the hippocampus might ameliorate the deficit in spatial learning and memory in aged rats.

50.Protective effect of Ginkgo biloba leaf extract on learning and memory deficit induced by aluminum in model rats.:(Psycho:mental performance-memory deficit)

Chin J Integr Med. 2006 Mar;12(1):37-41.PMID: 16571282
OBJECTIVE: To examine the protective effect of Ginkgo biloba leaf extract (GbE) on learning and memory deficit induced by aluminum chloride (AlCl(3)), and explore its mechanisms.METHODS: The rat models with learning and memory deficit were induced by administering via gastrogavage and drinking of AlCl(3) solution. And the model rats were treated with GbE at the dose of 50, 100, 200 mg/kg every day for 2 months accompanied with drinking of AlCl(3) solution, respectively. Their abilities of spatial learning and memory were tested by Morris water maze, and the acetylcholinesterase (AChE) activity in serum was assayed with chemical method, the AChE expression in hippocampus was observed by immunohistochemistry assay, and then quantitative analysis was done by BI 2000 image analysis system.RESULTS: Learning and memory deficit of rats could be induced by AlCl(3) solution (P < 0.01), and AChE expressions in rats hippocampus were increased (P < 0.01); GbE ameliorated learning and memory deficit and reduced AChE expression in rats hippocampus in a dose-dependent manner, while GbE significantly increased serum AChE activity at the dose of 200 mg/kg each day (P < 0.05).CONCLUSION: GbE can ameliorate learning and memory deficit induced by AlCl(3), which may be due to its inhibition of the AChE expression in hippocampus.

51.Use of herbal medicine and other dietary supplements in community-dwelling older people: Baseline data from the ginkgo evaluation of memory study.:(Psycho:mental pformance)

J Am Geriatr Soc. 2006 Nov;54(11):1725-35.PMID: 17087700
OBJECTIVES: To analyze baseline data from the Ginkgo Evaluation of Memory (GEM) study, in which information was collected on the use of all dietary supplements.DESIGN: Cross-sectional regression analysis.SETTING: GEM study sites in California, Maryland, North Carolina, and Pennsylvania.PARTICIPANTS: The GEM study enrolled 3,072 ambulatory individuals aged 75 and older between September 2000 and June 2002.MEASUREMENTS: Self-reported use of dietary supplements and use identified through bottles brought to the clinic.RESULTS: Respectively, 59.4%, 66.6%, and 27.4% of the GEM study cohort used a multivitamin, at least one individual vitamin or mineral supplement, and some type of nonvitamin/nonmineral dietary supplement (NVNMDS). In logistic regression models, multivitamin use was associated with female sex, a higher income, a higher modified Mini-Mental State Examination score, difficulty with mobility, and asthma history; use of any other vitamin or mineral was associated with female sex, white race, nonsmoking, more years of schooling, difficulty walking, a history of osteoporosis, and reading health and senior magazines; and NVNMDS use was associated with residing in California, having difficulties with muscle strength, and reading health and senior magazines.CONCLUSION: There were substantial differences between individuals who used vitamins and minerals and those who used NVNMDS. These data require that trial investigators pay close attention to participant use of off-protocol dietary supplements. In addition, these findings may help identify elderly individuals likely to combine NVNMDS and prescription drugs.

52.Ginkgo biloba extract improves spatial memory in rats mainly but not exclusively via a histaminergic mechanism.:(Psycho:memory deficit)

Brain Res. 2007 Jan 19;1129(1):161-5. Epub 2006 Dec 6.PMID: 17157275
In order to clarify the mechanism of Ginkgo biloba extract (GBE) on learning and memory, we studied the effect of GBE on spatial memory deficits induced by diphenhydramine, pyrilamine and scopolamine using the eight-arm radial maze performance of rats, in comparison with donepezil. Total error (TE), reference memory error (RME) and working memory error (WME) were used as indices of spatial memory deficits. Both GBE and donepezil caused a potent antagonistic effect on the increase in TE, RME and WME induced by diphenhydramine. GBE and donepezil also antagonized scopolamine-induced spatial memory deficits. Although the antagonistic effect of GBE on pyrilamine-induced spatial memory deficits was weak, a significant difference was observed with TE and WME. However, donepezil caused no antagonistic effect on pyrilamine-induced memory deficits. From these findings, we concluded that the effects of GBE are mainly contributable to cholinergic activity and perhaps partly due to a histaminergic mechanism.

53.Ginkgo biloba for the improvement of cognitive performance in multiple sclerosis: a randomized, placebo-controlled trial.:(Psycho:mental performance)

Mult Scler. 2007 Apr;13(3):376-85. Epub 2007 Jan 29.PMID: 17439907
OBJECTIVES: To determine if Ginkgo biloba (GB) improves the cognitive performance of subjects with multiple sclerosis (MS).METHODS: Randomized, double-blind, placebo-controlled trial of GB, 120 mg twice a day or placebo for 12 weeks. The primary outcomes were: the long delay free recall from the California Verbal Learning Test-II; the Paced Auditory Serial Addition Test; the Controlled Oral Word Association Test; the Symbol Digit Modalities Test; Useful Field of View Test; and the color-word interference condition from the Stroop Color and Word Test.RESULTS: On completion, the GB group (n=20) was 4.5 seconds (95% confidence interval (CI) (7.6, 0.9), P=0.015) faster than the placebo group (n=18) on the color-word interference condition of the Stroop test. Subjects who were more impaired at baseline experienced more improvement with GB (treatment*baseline interaction, F=8.10, P=0.008). We found no differences on the other neuropsychological tests. Subjects on GB reported fewer cognitive difficulties in the Retrospective Memory Scale of the Perceived Deficits Questionnaire than subjects on placebo (1.5 points, 95% CI (2.6, 0.3), P=0.016). No serious drug related side-effects occurred and GB did not alter platelet function assays.CONCLUSION: Overall, GB did not show a statistically significant improvement in cognitive function. A treatment effect trend, limited to the Stroop test, suggests that GB may have an effect on cognitive domains assessed by this test, such as susceptibility to interference and mental flexibility.

54.Acute cognitive effects of standardised Ginkgo biloba extract complexed with phosphatidylserine.:(Psycho:mental performance)

Hum Psychopharmacol. 2007 Jun;22(4):199-210.PMID: 17457961
Recent data suggest that the complexation of standardised Ginkgo biloba extract (GBE) with soy-derived phospholipids enhances the bioavailability of GBE's active components. The current study therefore aimed to assess the comparative cognitive and mood effects of a low dose of GBE and products complexing the same extract with either phosphatidylserine or phosphatidylcholine. The study utilised a placebo-controlled, multi-dose, double-blind, balanced-crossover design. Twenty-eight healthy young participants received 120 mg GBE, 120 mg GBE complexed with phosphatidylserine (Virtiva), 120 mg GBE complexed with phosphatidylcholine and a matching placebo, on separate days 7 days apart. Cognitive performance was assessed using the Cognitive Drug Research (CDR) computerised test battery and Serial Subtraction tasks immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were the four aspects of cognitive performance, which have previously been derived by factor analysis of CDR subtests. Levels of terpenoids (bilobalide, ginkgolide A and ginkgolide B) were concomitantly assessed in plasma samples taken pre-dose and at 3 and 6.5 h post-dose.In keeping with previous research utilising the same methodology, 120 mg of GBE was not associated with markedly improved performance on the primary outcomes. However, administration of GBE complexed with phosphatidylserine resulted both in improved secondary memory performance and significantly increased speed of memory task performance across all of the post-dose testing sessions. Enhancement following GBE complexed with phosphatidylcholine was restricted to a modest improvement in secondary memory performance which was restricted to one post-dose time point. All three treatments were associated with improved calmness. There were no significant differences in post-dose levels of terpenoids between the Ginkgo containing treatments, although this latter finding may be attributable to methodological factors. Complexation with phosphatidylserine appears to potentiate the cognitive effects associated with a low dose of GBE. Further research is required to identify whether this effect is due to the complexation of the extracts, their mere combination, or the separate psychopharmacological actions of the two extracts.

55.Ginkgo biloba is not a smart drug: an updated systematic review of randomised clinical trials testing the nootropic effects of G. biloba extracts in healthy people.:(Psycho:mental performance/negative)

Hum Psychopharmacol. 2007 Jul;22(5):265-78.PMID: 17480002
Here, we update our earlier systematic review of 2001, which critically evaluated the data from clinical trials to determine whether Ginkgo biloba enhances cognitive function in healthy subjects. Literatures searches of six computerised databases, updated to January 2007, were made for randomised, placebo-controlled, double-blind clinical trials of the effects of standardised Ginkgo biloba (G. biloba) extracts on cognitive function in healthy subjects under the age of 60 years. Trials published in any language were included, and data were extracted independently by the two authors following a standardised protocol. We include 15 randomised clinical trials of which 7 are single-dose studies and 8 are longer term studies with treatment periods ranging from 2 days to 13 weeks. Three single dose studies and 4 longer term studies are newly included. Several of the studies have methodological flaws. A number of the acute studies used multiple outcomes and report positive effects on one or more of these at particular time points with particular doses but these findings are either not replicated, or are directly contradicted by other studies. The evidence from longer term studies is largely negative. Of those studies which measured subjective effects, only one of five acute studies and one of six longer term studies reported any significant positive results. Overall, and in line with our previous conclusions, we have found no convincing evidence from randomised clinical trials for a robust positive effect of G. biloba ingestion upon any aspect of cognitive function in healthy young people, after either acute or longer term administration.

56.Preventive action of Ginkgo biloba in stress- and corticosterone-induced impairment of spatial memory in rats.:(Psycho:mental performance/spatial memory)

Phytomedicine. 2009 Jan;16(1):40-6. Epub 2007 May 4.PMID: 17482446
In this study, we tested preventive effects of a natural medicine the extract of Ginkgo biloba (EGB 761) on post-stress cognitive dysfunction. Exposure to chronic restraint stress in rats and psychosocial stress in humans has been shown to alter cognitive functions such as learning and memory and have been linked to the pathophysiology of mood and anxiety disorders. Our findings indicate that chronic restraint stress impaired egocentric spatial memory as observed in the eight-arm radial maze but it did not alter the allocentric spatial memory in the Morris water maze. In control rats EGB 761 (100mg/kg, orally) improved spatial memory in these two tests. Also, EGB 761 normalized cognitive deficits seen in rats chronically stressed or treated with an 'equivalent' dose of exogenous corticosterone (5mg/kg, subcutaneously). We conclude that, in rats, repeated administration of EGB 761 prevents stress- and corticosterone-induced impairments of spatial memory.

57.Ginkgo biloba in dyslexia: a pilot study.:(Psycho:mental performance/dyslexia)

Phytomedicine. 2007 Jun;14(6):367-70. Epub 2007 May 22.PMID: 17517502
OBJECTIVES: The purpose of this study was to collect preliminary information on the possible efficacy and tolerability of EGb 761 standardized plant extract of Ginkgo biloba as a treatment of dyslexia in school-aged children.METHODS: Fifteen children (5-16 year old) with dyslexia participated in an open-label trial of EGb 761 given as a single morning dose of 80 mg. Standardized tests for dyslexia were administered at baseline and at the end of the study.RESULTS: All 15 children completed the trial. The score of the standardized tests for dyslexia decreased. On the list of words the score decreased from mean 4.33 (SD=2.37) at baseline to 2.66 (SD=1.58) at the end of the study (p<0.01), on the list of non-words from mean 3.39 (SD=1.5) at baseline to 2.26 (SD=0.92) at the end of the study (p<0.02) and on the reading piece from mean 3.52 (SD=2.11) to 2.13 (SD=1.25); at the end of the study (p<0.05). At the end of the study 9 children did not perform below the -2 SD on the list of words and 7 on reading text and so they no longer fulfilled the DSM-IV-TR criteria for dyslexia. A brief period of headache was reported by the parents of two children.CONCLUSION: These data suggest that EGb 761 standardized plant extract of Ginkgo biloba has acceptable acute tolerability at single doses up to 80 mg/day and is possibly efficacious in decreasing dyslexia difficulties. The need for a double-blind trial is discussed by the authors.

58.Modulation of cognitive performance following single doses of 120 mg Ginkgo biloba extract administered to healthy young volunteers.:(Psycho:mental performance/cognitve)

Hum Psychopharmacol. 2007 Dec;22(8):559-66.PMID: 17902186
Previous research from our laboratory demonstrated that administration of single doses (120, 240, 360 mg) of standardised Ginkgo biloba extract (GBE) had linear, dose-dependent, positive effects on the speed of performing attention tasks in comparison to placebo. However, whilst the lowest dose, which is typical of a recommended daily dose, had no effect on the speed of attention task performance it did engender mild improvements in secondary memory performance. The current study presents a reanalysis of data from three methodologically identical studies that each included a treatment of 120 mg GBE and matched placebo. All three studies were of a multiple dose, placebo-controlled, double-blind, balanced-crossover design, employing four or five treatment arms in total. Across the studies 78 healthy young participants received 120 mg GBE and placebo in randomly counterbalanced order, separated by a wash-out period of at least 7 days. On each study day participants' performance on the Cognitive Drug Research (CDR) computerised cognitive assessment battery was measured immediately prior to dosing and at 1, 2.5, 4 and 6 hr following treatment, with scores collapsed into the six measures (speed of attention, accuracy of attention, secondary memory, working memory, speed of memory, quality of memory) which have previously been derived by factor analysis of the data from CDR subtests. The results showed that 120 mg of Ginkgo engendered a significant improvement on the 'quality of memory' factor that was most evident at 1 and 4 hr post-dose, but had a negative effect on performance on the 'speed of attention' factor that was most evident at 1 and 6 hr post-dose. The current study confirmed the previous observation of modestly improved memory performance following 120 mg of GBE, but suggests that acute administration of this typical daily dose may have a detrimental effect on the speed of attention task performance which is opposite to that seen previously following higher doses.

59.Chronic administration of a Ginkgo biloba leaf extract facilitates acquisition but not performance of a working memory task.:(Psycho:mental performance/memory)

Psychopharmacology (Berl). 2009 Jan;202(1-3):173-85. Epub 2008 Jul 2.PMID: 18594796
RATIONALE: Ginkgo biloba leaf extracts have been shown to improve learning and memory when administered chronically prior to the learning phase. However, the influence of Ginkgo on learning without prior chronic treatment and on memory per se (i.e., post-training administration) is less clear. Thus, experiment 1 investigated the influence of Ginkgo on acquisition, and experiment 2 examined the acute and chronic effects of Ginkgo on memory in rats using a food-reinforced two-component double Y-maze task.MATERIALS AND METHODS: In experiment 1, 17 rats were treated daily with a standardized G. biloba extract (13.75 mg/kg, i.p.) or vehicle 30 min prior to daily maze training for 14 days. In experiment 2, 12 rats received 24 training trials daily, then received Ginkgo (0, 0.25, 2.5, 13.75, or 25 mg/kg, i.p.) 30 min prior to each test session. Subsequently, the same rats received daily injections of either Ginkgo (13.75 mg/kg, i.p.) or its vehicle. Memory was tested after 10 and 20 days of drug treatment, once under the influence of the drug and once in a drug-free state.RESULTS: In experiment 1, Ginkgo-treated rats reached the training criteria significantly faster and made fewer errors. In experiment 2, post-training Ginkgo administration did not enhance memory.DISCUSSION: Taken together, results demonstrate that repeated daily pre-session Ginkgo injection subtly facilitates acquisition of a spatial working memory task, but neither acute nor chronic post-training exposure enhances spatial working memory. We conclude that ongoing Ginkgo administration does not offer any continued beneficial effects in an already-learned working memory task.

60.Ginkgo biloba extract (EGb761) influences monoaminergic neurotransmission via inhibition of NE uptake, but not MAO activity after chronic treatment.:(Psycho:mental performance/cognition)

Pharmacol Res. 2009 Jul;60(1):68-73. Epub 2009 Mar 21.PMID: 19427589
In order to explain cognition-enhancing effects of standardized Ginkgo biloba extract (EGb761), an increase of central monoaminergic neurotransmission has been suggested, but the underlying mechanisms have not yet been elucidated. Here, we confirm that the norepinephrine (NET), the serotonin (SERT), the dopamine (DAT) uptake transporters and MAO activity are inhibited by EGb761 in vitro, although rather high concentrations are required for inhibition of MAO-A and MAO-B activity. However, after 14 days of daily oral treatment with 100mg/kg EGb761 only NE uptake is significantly decreased in NMRI mice, while 5-HT uptake and MAO activity are not affected. As synaptic dopamine clearance in the frontal cortex is mediated by NET, not DAT, these findings may give an explanation for the enhancement of dopaminergic neurotransmission by EGb761 seen in animal models, presumably linked to its positive effects on cognition and attention.

61.Ginkgo biloba treating patients with attention-deficit disorder.:(Psycho:mental performance/attention-deficit disorder)

Phytother Res. 2010 Jan;24(1):26-7.PMID: 19441138
Various medications such as clonidine facilitate calming, enhance frustration tolerance and reduce aggression in attention-deficit disorder (ADD) patients. The use of Ginkgo biloba was studied as an herbal alternative. Six psychiatric outpatients diagnosed with ADD were rated at baseline and while taking Ginkgo biloba to determine its efficacy as a treatment for ADD. Comparisons of Wender Utah ratings within subject were used to measure behavioral changes in the subjects. During Ginkgo biloba treatment, the patients' mean scores improved significantly overall and in hyperactivity, inattention, and immaturity factors. This preliminary study indicates that Ginkgo biloba might be a beneficial and useful treatment of ADD, with minimal side effects.

62.Ginkgo biloba: specificity of neuropsychological improvement--a selective review in search of differential effects.:(Psycho:mental performance/cognitive)

Hum Psychopharmacol. 2009 Jul;24(5):345-70.PMID: 19551805
Extracts of Ginkgo biloba are widely used for the treatment of cognitive impairment. Whereas reviews have focused on the question whether ginkgo is effective to enhance cognition in general, little is known about specificity of improvement. This might be crucial for future trials, thus enabling hypotheses about sensitive outcome measures. Therefore, this article summarizes such information, i.e. neuropsychological effects of chronic administration of ginkgo in healthy and cognitively impaired subjects of any age. Objective psychometric test results were considered if they reflected distinct cognitive functions from randomized controlled group-studies (RCT). We reviewed 29 RCTs yielding 209 placebo-drug comparisons of psychometric scores in four different cognitive domains comprising 14 sub-functions. Whereas little specific information can be obtained from trials for treatment of dementia, a pattern of pharmacological actions on cognitive processes emerges here from studies for mild cognitive impairment (MCI), depression, multiple sclerosis and healthy young and elderly subjects. There is consistent evidence that chronic administration improves selective attention, some executive processes and long-term memory for verbal and non-verbal material. Further trials should be more comprehensive as there are few data available on some cognitive functions and psychometric flaws in the selection of tests and the interpretation of their results favouring predominantly beta-errors. Thus, though this pattern is encouraging it also asks for a cautious interpretation to date.

63.Ginkgo biloba for preventing cognitive decline in older adults: a randomized trial.:(Psycho:mental performance/cognitive deficit)

JAMA. 2009 Dec 23;302(24):2663-70.PMID: 20040554
CONTEXT: The herbal product Ginkgo biloba is taken frequently with the intention of improving cognitive health in aging. However, evidence from adequately powered clinical trials is lacking regarding its effect on long-term cognitive functioning.OBJECTIVE: To determine whether G. biloba slows the rates of global or domain-specific cognitive decline in older adults.DESIGN, SETTING, AND PARTICIPANTS: The Ginkgo Evaluation of Memory (GEM) study, a randomized, double-blind, placebo-controlled clinical trial of 3069 community-dwelling participants aged 72 to 96 years, conducted in 6 academic medical centers in the United States between 2000 and 2008, with a median follow-up of 6.1 years.INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or identical-appearing placebo (n = 1524).MAIN OUTCOME MEASURES: Rates of change over time in the Modified Mini-Mental State Examination (3MSE), in the cognitive subscale of the Alzheimer Disease Assessment Scale (ADAS-Cog), and in neuropsychological domains of memory, attention, visual-spatial construction, language, and executive functions, based on sums of z scores of individual tests.RESULTS: Annual rates of decline in z scores did not differ between G. biloba and placebo groups in any domains, including memory (0.043; 95% confidence interval [CI], 0.034-0.051 vs 0.041; 95% CI, 0.032-0.050), attention (0.043; 95% CI, 0.037-0.050 vs 0.048; 95% CI, 0.041-0.054), visuospatial abilities (0.107; 95% CI, 0.097-0.117 vs 0.118; 95% CI, 0.108-0.128), language (0.045; 95% CI, 0.037-0.054 vs 0.041; 95% CI, 0.033-0.048), and executive functions (0.092; 95% CI, 0.086-0.099 vs 0.089; 95% CI, 0.082-0.096). For the 3MSE and ADAS-Cog, rates of change varied by baseline cognitive status (mild cognitive impairment), but there were no differences in rates of change between treatment groups (for 3MSE, P = .71; for ADAS-Cog, P = .97). There was no significant effect modification of treatment on rate of decline by age, sex, race, education, APOE*E4 allele, or baseline mild cognitive impairment (P > .05).CONCLUSION: Compared with placebo, the use of G. biloba, 120 mg twice daily, did not result in less cognitive decline in older adults with normal cognition or with mild cognitive impairment.

64.Study of the long-term action of a Ginkgo biloba extract on vigilance and mental performance as determined by means of quantitative pharmaco-EEG and psychometric measurements.(Psycho:mental performance):

65.Effects of Ginkgo biloba extract on functional brain activity.. An assessment of clinical and experimental studies:(Psycho:mental performance)

Presse Med. 1986 Sep 25;15(31):1588-91.PMID: 2947107
Electroencephalography is the only convenient method for functional exploration of the brain. The recent introduction of signal analysis techniques has given it a quantitative dimension and has resulted in pharmacological studies of electoencephalograms. In four studies of this kind the effects of Ginkgo biloba extract were investigated on three pathological animal models, in young healthy volunteers and in elderly people with dementia disorders. In man, the EEG tracings could be analyzed in relation to different psychometric tests. The results obtained confirm those of clinical trials, and notably the activity of Ginkgo biloba extract on alertness.

66.Activity of Ginkgo biloba extract on short-term memory:(Psycho:mental performance-memory)

Presse Med. 1986 Sep 25;15(31):1592-4.PMID: 2947108
Eight healthy female volunteers were included in a double-blind, cross-over trial comparing Ginkgo biloba extract in acute and ascending doses (120, 240, 600 mg) with a placebo. One hour after treatment they were subjected to a battery of tests, including: critical flicker fusion, choice reaction time, subjective rating scale and Sternberg memory scanning test. No statistically significant differences with the placebo were observed in the first three tests. In contrast, short term memory, as assessed by the Sternberg technique, was very significantly improved following 600 mg of Ginkgo biloba extract, as compared with the placebo. These results differentiate Ginkgo biloba extract from sedative and stimulant drugs and suggest a specific effect on memory processes.

67.Memory effects of standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK 501) and their combination Gincosan (PHL-00701).:(Psycho:mental performance)

Planta Med. 1993 Apr;59(2):106-14.PMID: 8488188
In experiments on young (aged 3 months) and old (aged 26 months) rats, using some conditioned-reflex methods with punishment or positive reinforcement for active and passive avoidance (shuttle-box, step-down, step-through, and water maze), we studied the effects of the standardized extracts of Panax ginseng (G115), Ginkgo biloba (GK501) and their combination Gincosan (PHL-00701). The extracts were administered orally for 7 days before training at three increasing doses: 17, 50, and 150 mg/kg for G115; 10, 30, and 90 mg/kg for GK501; and 27, 80, and 240 mg/kg for PHL-00701. The two extracts and their combination improved the retention of learned behavior. This effect varied considerably with the extracts, with the dose and with the behavioral method used. The results suggest that the Panax ginseng G115 and the Ginkgo biloba GK501 extracts possess properties similar in every respect to those of nootropic drugs. The favorable effects on learning and memory of the combination of G115 plus GK501 and the other pharmacological activities inherent in the extracts characterize this combination, offered as Gincosan as a particularly promising drug in geriatric practice.

68.Effect of two doses of ginkgo biloba extract (EGb 761) on the dual-coding test in elderly subjects.:(Psycho:mental performance/aging)

Clin Ther. 1993 May-Jun;15(3):549-58.PMID: 8364946
The subjects of this double-blind study were 18 elderly men and women (mean age, 69.3 years) with slight age-related memory impairment. In a crossover-study design, each subject received placebo or an extract of Ginkgo biloba (EGb 761) (320 mg or 600 mg) 1 hour before performing a dual-coding test that measures the speed of information processing; the test consists of several coding series of drawings and words presented at decreasing times of 1920, 960, 480, 240, and 120 ms. The dual-coding phenomenon (a break point between coding verbal material and images) was demonstrated in all the tests. After placebo, the break point was observed at 960 ms and dual coding beginning at 1920 ms. After each dose of the ginkgo extract, the break point (at 480 ms) and dual coding (at 960 ms) were significantly shifted toward a shorter presentation time, indicating an improvement in the speed of information processing.

69.Cognitive psychophysiology in nootropic drug research: effects of Ginkgo biloba on event-related potentials (P300) in age-associated memory impairment.:(Psycho:mental performance-cognitive)

Pharmacopsychiatry. 1995 Jul;28(4):134-42.PMID: 7491367
Extracts from the leaves of Ginkgo biloba have been suggested to be useful in the treatment of various symptoms of impaired brain functions in advanced age. To elucidate specific mechanisms of the possible clinical benefit, the effects of Ginkgo biloba extract Ginkobene on cognitive information-processing were investigated by means of long-latency auditory event-related potentials. In a double-blind placebo-controlled study, 48 patients (29 women and 19 men) aged between 51 and 79 years with the diagnosis of age-associated memory impairment had 57 days' treatment with a daily dosage of 3 x 40 mg Ginkobene or placebo. To evaluate acute, chronic, and superimposed drug effects, psychophysiological investigations were carried out on day 1 and day 57 before and 3 hours after drug administration. ERP investigations were carried out by means of a two-tone auditory oddball paradigm. In addition to 17 EEG leads, vertical and horizontal EOGs were recorded. After minimizing ocular artifacts and visual artifact rejection, latencies and topographic distributions of N1 and P2 components (non-targets) and N2 and P300 components (targets) were calculated by an automatic procedure. When compared to the placebo group, in the Ginkobene group no consistent and unequivocal changes on N1, P2, N2, and P300 amplitudes or on N1, P2, and N2 latencies were observed. P300 latency was shortened by 31 ms, 38 ms, and 32 ms in the Ginkgo biloba group after acute, chronic, and superimposed drug administration. It may therefore be hypothesized that the decrease of P300 latency in the Ginkgo biloba group may reflect shorter stimulus-evaluation time.

70.Possibilities and limits of therapy of cognition disorders in the elderly:(Psycho:mental performance-cognition disorders)

Z Gerontol Geriatr. 1995 Nov-Dec;28(6):457-62.PMID: 8581765
Pharmacological treatment of patients suffering from sporadic late-onset dementia of Alzheimer type (DAT) is controversely discussed, omitting the fact that this age-related most frequently occurring DAT form is based on a heterogenous pathogenesis, but forms a rather uniform clinical phenotype. Furthermore, sporadic late-onset DAT is influenced in two different ways, 1) by the aging process, and 2) by the disease process itself. In this context, changes in brain glucose/energy metabolism, maintenance of calcium homeostasis, and membrane stability are discussed. It is concluded that some nootropic drugs such as dihydroergotoxine, Ginkgo biloba, nicergoline, nimodipine, piracetam, and pyritinol-HCI, registered in FRG, exert a positive effect on the clinical phenotype in approximately 30% of treated cases being in an incipient state of the disease. This effect has not been proven for advanced states. There is clear evidence that Ginkgo biloba acts on membrane lability, nimodipine on the maintenance of calcium homeostasis, and both piracetam and pyritinol-HCI on glucose/energy metabolism. These diverse effects on different underlying pathogenetic abnormalities can be assumed to be the reason why only subgroups of patients respond to the treatment with nootropic drugs.

71.The cognitive, subjective, and physical effects of a ginkgo biloba/panax ginseng combination in healthy volunteers with neurasthenic complaints.:(Psycho:cognitive)

Psychopharmacol Bull. 1997;33(4):677-83.PMID: 9493479
We evaluated the effects of a Ginkgo biloba/ginseng combination on cognitive function in this 90-day, double-blind, placebo-controlled, parallel-group study. Sixty-four healthy volunteers (aged 40 to 65 years), selected on the basis of fulfilling the ICD-10 F48.0 criteria for neurasthenia, were assigned randomly to four equal dosing groups, receiving 80, 160, or 320 mg of the combination b.i.d. or placebo. Assessments were performed on the day before dosing, and again at Days 1, 30, and 90 at 1 hour after the morning dose and 1 hour after the afternoon dose. The assessments included the Cognitive Drug Research (CDR) computerized assessment system, the Vienna Determination Unit, cycle ergometry, and various questionnaires. The treatments were well tolerated by all volunteers. On Day 90 at 1 hour post morning dosing, dose-related improvements were seen on the CDR tests, the 320 mg dose being significantly superior to placebo. These effects, however, were reversed 1 hour after the afternoon dose, possibly suggesting that a longer inter-dosing interval would be preferable. The 80-mg dose produced a significant benefit on the ergometry assessment of heart rate at maximum load. There were also several supporting changes from other assessments, including an advantage of 320 mg over placebo on the global score from the Symptom Checklist-90-revised (SCL-90-R) at Day 90.

72.Integrated medicine and the prevention and reversal of memory loss.:(Psycho:mental performance-memory)

Altern Ther Health Med. 1998 Nov;4(6):38-43.PMID: 9810066
This article, based on scientific research and clinical observations, suggests that memory loss is not an inevitable consequence of aging and that Alzheimer's disease can be prevented and reversed using an integrated medical approach. Three new associations with memory loss other than age, heredity, and genetics are described. They include a high-fat diet, chronic unbalanced stress with its attendant risk in the adrenal hormone cortisol, and the presence of cardiovascular disease. A 4-pillar integrative medical program on brain longevity is presented. The program includes a diet consisting of 15% fat and supplementation with brain-specific nutrients such as vitamin B complex, vitamin E, ubiquinone, ginkgo biloba, and phosphatidylserine. In addition, stress-relieving meditation, mind-body and cognitive exercise, antiaging drugs like L-deprenyl citrate, as well as hormones such as dehydroepiandrosterone and pregnenolone complete the program. Patient benefits such as greater wisdom and spiritual happiness are also explored.

Xd-Ginkgo Biloba:Psychopharmacological effects:Cerebral

1.Effect of an extract of Ginkgo biloba on triethyltin-induced cerebral edema.(Psycho:cerebral):

Acta Neuropathol. 1986;69(1-2):54-65.PMID: 3962598
The effect of an extract of Ginkgo biloba was studied on cerebral edema in rats intoxicated with triethyltin chloride (TET). Brains of TET-treated rats showed elevated water and sodium levels and a significant increase in the sodium/potassium ratio. Animals treated with TET plus the extract did not show water and electrolyte changes. The course of intoxication and treatment was studied light- and electron-microscopically. A severe edema with extensive vacuolization was seen in the cerebral and cerebellar white matter. Morphometric measurements revealed a significant decrease in these manifestations of the cytotoxic edema when the animals were treated with an extract of Ginkgo biloba. Thus, we conclude that this extract has a protective effect on the development of a cytotoxic edema in the white matter of the brain.

2.Neuromediator changes during cerebral aging. The effect of Ginkgo biloba extract:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1488-90.PMID: 2878426
Ginkgo biloba extract exerts a specific effect on the noradrenergic system and on beta-receptors. No variation was found in alpha 2-receptors and serotonin uptake. These findings provide the first evidence of central effects of a drug acting on cerebral ageing, connected specifically to reactivation of the noradrenergic system in the cerebral cortex.

3.Neuromediator binding to receptors in the rat brain. The effect of chronic administration of Ginkgo biloba extract:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1491-3.PMID: 2878427
The present data confirm the results of others that post-synaptic receptor changes may contribute to the decline in brain cholinergic function in ageing and dementia. We have also shown that chronic oral treatment with an extract of Gingko biloba increases the apparent muscarinic receptor population in the hippocampus of the aged Fisher 344 rat. The possible effect on (3H) kainic acid binding to the kainate-excitatory amino acid site is also interesting because of the proposed association of neurodegenerative disease and excessive excitatory amino neurotransmission.

4.Cerebral glucose consumption. The effect of Ginkgo biloba extract:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1494-7.PMID: 2947087
Deoxyglucose is transported under the same conditions as glucose from blood to cerebral tissue. Deoxyglucose-6-phosphate, which cannot be neither metabolized nor eliminated, accumulates in cells. This accumulation is correlated with glucose consumption. In this study, two parameters, transfer rate of deoxyglucose and glucose consumption were measured by means of quantitative autoradiography in two experimental models: normobaric hypoxia and carotid clamping in rats. Normobaric hypoxia induced a decrease in both transfer rate and glucose consumption. Ligature of the carotid artery induced a diminution of glucose consumption greater than that of transfer rate. After administration of Ginkgo biloba extract, glucose consumption was partly reestablished in both experimental models, but the transfer rate of deoxyglucose was increased only in normobaric hypoxia.

5.Protective effects of Ginkgo biloba extract on the early rupture of the hemato-encephalic barrier in the rat:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1502-5.PMID: 2947088
During the hours immediately following an hypertensive burst or a cerebral ischemia induced by the intracarotid administration of microspheres, damage to the blood brain barrier can be observed with molecules of low molecular weight, such as angiotensin, whereas albumin or large proteins will not yet have been able to cross over and there is virtually no edema. Gingko biloba extract causes the brain uptake index of angiotensin hypertensive animals. This effect is proportional to the dose of extract used (500-100 mg/kg). A similar effect can be observed in animals showing embolism in one hemisphere. The process can therefore doubtlessly be explained by the stabilizing effect of Ginkgo biloba on membranes.

6.Mechanism of action of Ginkgo biloba extract in experimental cerebral edema:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1506-10.PMID: 2947089
Oedema is one of the major complication of cerebral ischaemia being at the same time a consequence and an aggravating factor. Its first phase is intracellular and cytotoxic, with breakdown of ionic pumps through loss of energy, resulting in a whole sequence of ionic perturbations characterized by loss of intracellular K+ and accumulation of water and Na+, Cl-, and Ca2+ ions in the cells of the ischaemic zone. The second phase, termed vasogenic, applies to the accumulation of lactates, inorganic phosphates and free polyunsaturated fatty acids and in particular, arachidonic acid. This last compound is responsible for the production of membrane "aggressors", amongst which free radicals play an important r?le. Ginkgo biloba extract limits the formation of cerebral oedema and suppresses its neurological consequences, whether the oedema is of cytotoxic (triethyltin) or vasogenic (unilateral traumatic oedema) origin. Several membrane mechanisms could be implicated in the protective action manifested by Ginkgo biloba extract against cerebral oedema.

7.Effects of Ginkgo biloba extract on a cerebral ischemia model in gerbils:(Psycho:cerebral-ischemia)

Presse Med. 1986 Sep 25;15(31):1511-5.PMID: 2947090
Certain anatomical characteristics peculiar to the gerbil make it the animal model best adapted to experimental pathology studies of acute ischaemia. In this animal species, devoid of any substitute vertebro-basilar vascular tissue, unilateral ligature of the carotid artery produces a cerebral ischaemia with neurological signs (well quantifiable), metabolic perturbations (especially mitochondrial) and cerebral oedema development closely resembling the symptoms revealed by physiopathology in human clinical studies. Using this model and under the experimental conditions described, clear-cut, highly significant results were obtained with Ginkgo biloba, whether by oral or intravenous administration. These results were normalization of mitochondrial respiration, diminution of cerebral oedema, correction of the accompanying ionic perturbations, and practically total functional restoration revealed by a normal neurological index in the gerbils treated with Ginkgo biloba extract.

8.Treatment of cerebral aging disorders with Ginkgo biloba extract. A longitudinal multicenter double-blind drug vs. placebo study:(Psycho:cerebral)

Presse Med. 1986 Sep 25;15(31):1583-7.PMID: 2947106
The effectiveness of Ginkgo biloba extract in the treatment of cerebral disorders due to ageing was evaluated in a multicentric, double-blind, drug versus placebo trial involving 166 patients. In this study carried out under strict methodological conditions a specially devised geriatric clinical evaluation scale was used. The results confirmed that Ginkgo biloba extract is effective against cerebral disorders due to ageing. The difference between control and treatment groups became significant at 3 months and increased during the following months. These results were concordant with the overall clinical assessment made by the specialist in charge.

9.Influence of an extract of Ginkgo biloba on cerebral blood flow and metabolism.:(Psycho:cerebral)

Life Sci. 1986 Dec 15;39(24):2327-34.PMID: 3796196
The purpose of the present investigation was to examine the effects of an extract of Ginkgo biloba (EGB) on blood glucose levels, on local cerebral blood flow as well as on cerebral glucose concentration and consumption. The local cerebral blood flow (LCBF) was measured in conscious rats by means of the 14C-iodoantipyrine technique and local cerebral glucose utilization (LCGU) by 14C-2-deoxy-glucose autoradiography. EGB increased the LCBF in 39 analyzed, anatomically defined brain structures by 50 to 100 per cent. No influence of EGB on LCGU was demonstrable. However, EGB enhanced the blood glucose level dose-dependently. Substrates and metabolites of energy metabolism were measured in the cortex of the isolated rat brain perfused at constant rate and with 7 mmol/l glucose added to the perfusion medium. In these experiments EGB decreased the cortical glucose concentration without other substrate levels being changed. These results suggest that glucose uptake may be inhibited by EGB. It is argued that the effects of EGB on brain glucose concentration and blood flow may contribute to its protection of brain tissue against ischemic or hypoxic damage.

10.Therapy of cerebral ischemia:(Psycho:cerebral)

Z Kardiol. 1987;76 Suppl 4:87-98.PMID: 3327270
The primary cause of ischaemic neuronal damage is the reduction in the regional cerebral blood flow below the threshold critical for preservation of nervous structures. The development of infarction, however, is not determined only by the severity of ischaemia but also by the duration of a blood flow disturbance below a critical level. During the ischaemic period, and also after reperfusion, secondary mechanisms are triggered (cytotoxic and vasogenic oedema, tissue lactacidosis, entry of Ca++, synthesis of prostaglandins and leukotrienes, production of free radicals and liberation of neurotransmitters), which contribute to the ischaemic cell damage. These pathophysiological mechanisms in the development of ischaemic cell damage suggest three approaches for therapeutic intervention: a. Improvement of cell tolerance against ischaemia b. Increased cerebral blood flow c. Inhibition of secondary damage. a. An improvement of the tolerance of brain cells to ischaemia can be experimentally achieved by hypothermia and barbiturate loading; due to severe side effects, these therapeutical regimens are not clinically applicable. b. An increase in cerebral blood flow, which must be induced within a short period of time, can be obtained by various drugs with different modes of action. While vasodilators are not clinically efficient, haemodilution with low molecular dextran has been shown to be a promising therapeutic concept. Other strategies to improve rheological properties of blood (venesection, other haemodiluting infusions, hydroxyethyl starch drugs acting directly on blood rheology, such as extract of ginkgo biloba) can also be applied. Anticoagulation can be performed only in a few special cases with ischaemic infarction. The increase in perfusion pressure is helpful in hypotonic patients to improve blood supply in the ischaemic region. Cerebral perfusion can also be augmented by drugs which activate function and metabolism. c. Secondary damage to cells surviving the primary ischaemic insult can be inhibited by suppression or diminution of perifocal brain oedema; under ischaemic conditions, osmotherapy is superior to corticosteroids for this purpose. Pathological biochemical mechanisms initiated during or shortly after the ischaemic episode and causing additional cell damage can be influenced by pharmacological interaction (Ca++ entry blockers, inhibitors of prostaglandin synthesis, scavengers of free radicals, e.g. flavones, opiate antagonists). However, the routine application of these drugs in clinical practice still necessitates more controlled trials. Excessive lactacidosis can be controlled by regulation of plasma glucose levels.

11.Drug therapy of disorders of cerebral performance. Randomized comparative study of dihydroergotoxine and Ginkgo biloba extract:(Psycho:cerebral-disorder)

Fortschr Med. 1990 Jun 30;108(19):384-8.PMID: 2199358
In a randomized trial lasting six weeks and involving 80 elderly patients with cerebrovascular disorders, the effectiveness and tolerance of dihydroergotoxine was compared with an extract of Ginkgo biloba. On the basis of psychometric tests and assessment scales, it was shown that treatment with either substance improved the condition of the patients. While, for the most part, intergroup comparison revealed no major statistically significant differences, such changes, affecting various parameters, were found during follow-up--more frequently within the dihydroergotoxine group than within the group treated with Ginkgo biloba extract.

12.Cerebral insufficiency--treatment with Ginkgo-biloba extract. Time of onset of effect in a double-blind study with 60 inpatients:(Psycho:cerebral-insufficiency)

Fortschr Med. 1990 Oct 10;108(29):557-60.PMID: 2242846
Sixty inpatients with cerebral insufficiency and the leading symptom depressive mood, were treated in a double-blind study for 6 weeks with a daily dose of 160 mg Ginkgo biloba extract or placebo. After 2, 4 and 6 weeks, changes in 12 typical symptoms in comparison with the last examination, were evaluated. In the group receiving placebo, small, but progressive improvements were observed. In the Ginkgo-biloba group, the overall number of improvements was significantly larger. After 2 weeks the differences were marked for only a few of the symptoms; after 4 and 6 weeks in contrast, in 11 of the 12 symptoms. The largest number of improvements in the Ginkgo-biloba group was observed between the 2nd and 4th weeks of treatment. In this period, about two-thirds of the patients on Ginkgo-biloba, and about one-fifth of the patients on placebo showed improvements.

13.Therapeutic follow-up using automatic perimetry in chronic cerebroretinal ischemia in elderly patients. Prospective double-blind study with graduated dose ginkgo biloba treatment (EGb 761)].:(Psycho:cerebroretinal ischemia)

Klin Monbl Augenheilkd. 1991 Dec;199(6):432-8.PMID: 1791685
The chronic cerebral retinal insufficiency syndrome in elderly patients is an organ specific expression of a generalized vascular cerebral deficiency. The progress of the disease is characterized by complex symptoms, variation in course, spontaneous remissions and, until recently inadequate diagnostic measurement methods. The new method of automated perimetry with the octopus 2000 P offers a patient-friendly procedure for indirect non-invasive diagnosis of circulatory state in limited cerebral retinal perfusion. In the present study measurements were made with this method on 24 patients (4 men and 20 women with an age of 74.9 +/- 6.9 years). The effect of the extract of Ginkgo biloba (EGb 761) on the reversibility of visual field disturbances was tested using a randomized and double blind study-design in two phases and with two dose levels. The main parameter investigated in this study was the change in the luminous density difference threshold after therapy with EGb 761. In group B (EGb 761 dose 160 mg/day) a significant increase in retinal sensitivity was seen within 4 weeks (p less than 0.05). In the lower dose (80 mg EGb 761/day) group (A), this change in retinal sensitivity was first seen after increasing the dose to 160 mg/day (p less than 0.01). The relative sensitivity of damaged retinal areas was more strongly influenced than "healthy" areas. The assessment by both doctors and patients of the general condition of the patients showed a significant improvement after the course of therapy. The results presented here show that damage to the visual field by chronic lack of bloodflow are significantly reversible

14.Alpha 2-adrenoceptor changes during cerebral ageing. The effect of Ginkgo biloba extract.:(Psycho:cerebral ageing)

J Pharm Pharmacol. 1992 Jan;44(1):24-7.PMID: 1350623
[3H]Rauwolscine binding to alpha 2-adrenoceptors in cerebral cortex and hippocampus membranes of young (4 months) and aged (24 months) Wistar rats has been investigated. In aged rats, Bmax values of [3H]rauwolscine binding were significantly reduced (25-32%) in the cerebral cortex and hippocampus, as compared with the number of alpha 2-adrenoceptors found in young rats. Chronic treatment with Ginkgo biloba extract did not alter [3H]rauwolscine binding in the hippocampus of young rats, but significantly increased (28%) the [3H]rauwolscine binding density in aged rats. These data confirm the previously described age-related noradrenergic alteration and suggest that noradrenergic activity in aged rats is more susceptible to Ginkgo biloba extract treatment.

15.Ginkgo biloba for cerebral insufficiency.:(Psycho:cerebral-insufficiency)

Br J Clin Pharmacol. 1992 Oct;34(4):352-8.PMID: 1457269
1. By means of a critical review we tried to establish whether there is evidence from controlled trials in humans on the efficacy of Ginkgo biloba extracts in cerebral insufficiency. 2. The methodological quality of 40 trials on Ginkgo and cerebral insufficiency was assessed using a list of predefined criteria of good methodology, and the outcome of the trials was interpreted in relation to their quality. A comparison of the quality was made with trials of co-dergocrine, which is registered for the same indication. 3. There were eight well performed trials out of a total of 40. Shortcomings were limited numbers of patients included, and incomplete description of randomization procedures, patient characteristics, effect measurement and data presentation. In no trial was double-blindness checked. Virtually all trials reported positive results, in most trials the dosage was 120 mg Ginkgo extract a day, given for at least 4-6 weeks. For the best trials, there were no marked differences in the quality of the evidence of the efficacy of Ginkgo in cerebral insufficiency compared with co-dergocrine. The results of the review may be complicated by a combination of publication bias and other biases, because there were no negative results reported in many trials of low methodological quality. 4. Positive results have been reported for Ginkgo biloba extracts in the treatment of cerebral insufficiency. The clinical evidence is similar to that of a registered product which is prescribed for the same indication. However, further studies should be conducted for a more detailed assessment of the efficacy.

16.The comprehensiveness of Medline and Embase computer searches. Searches for controlled trials of homoeopathy, ascorbic acid for common cold and ginkgo biloba for cerebral insufficiency and intermittent claudication.(Psycho:cerebral-insufficiency):

Pharm Weekbl Sci. 1992 Oct 16;14(5):316-20.PMID: 1437515
OBJECTIVE: To assess the comprehensiveness of Medline and Embase computer searches for controlled trials.DESIGN: Comparison of articles found after an exhaustive search of the literature with the yield of a Medline or Embase search. This was performed for controlled clinical trials on the efficacy of three interventions: homoeopathy, ascorbic acid for common cold, and ginkgo biloba for intermittent claudication and cerebral insufficiency. The number of controlled trials found by exhaustive search of the literature was 107, 61 and 45, respectively.RESULTS: For homoeopathy, ascorbic acid and ginkgo the proportion of all trials found by Medline was 17%, 36% and 31% respectively and for Embase 13%, 25% and 58% respectively. After checking of the references in the Medline articles 44%, 79% and 76% of all trials were identified. After checking of the references in the Embase articles 42%, 72% and 93% of all trials were identified. About 20% of the articles was not correctly indexed. Of the best trials 68%, 91% and 83% could be found with Medline and 55%, 82% and 92% of the best trials were identified through Embase.CONCLUSIONS: For the topics mentioned, Medline and Embase searches are sufficient to get an impression of the evidence from controlled trials, but only if references in the articles are followed for further evidence. If one wants to get a more complete picture, additional search strategies make sense. Of course, this picture may be different for other topics.

17.Flow cytometric estimation of the effect of Ginkgo biloba extract on the content of hydrogen peroxide in dissociated mammalian brain neurons.:(Psycho:cerebral-neurons-antioxidant)

Jpn J Pharmacol. 1992 Dec;60(4):385-8.PMID: 1287275
The effect of Ginkgo biloba extract (GBE) on the content of hydrogen peroxide was estimated in cerebellar neurons dissociated from rats, by means of a flow-cytometer and 2',7'-dichlorofluorescein (DCF) diacetate, a fluorescent dye for intracellular hydrogen peroxide. The GBE started to reduce the DCF fluorescence of the neuron at 0.1 microgram/ml to 0.3 microgram/ml. Further increases in the GBE concentration (up to 3 micrograms/ml) produced a dose-dependent decrease in the DCF fluorescence, suggesting that GBE reduces the content of hydrogen peroxide or suppresses the reactive oxygen species (ROS) formation of cerebellar neurons. The present technique may be useful for preliminary evaluations of agents affecting the ROS formation in mammalian brain neurons.

18.Prevention by Ginkgo biloba extract (EGb 761) and trolox C of the decrease in synaptosomal dopamine or serotonin uptake following incubation.:(Psycho:cerebral-neurons-antioxidant)

Biochem Pharmacol. 1992 Dec 15;44(12):2395-401.PMID: 1472105
Prolonged incubation of synaptosomes in Krebs-Ringer oxygenated medium in the presence of ascorbic acid (10(-4) M) led, after 20 min, to a decrease in [3H]dopamine (DA) (synaptosomes prepared from the striatum) and [3H]serotonin (5HT) (synaptosomes prepared from the cortex) uptake. The decrease was progressive and uptake was virtually abolished after a 60 min incubation period. A concentration-dependent (from 5 x 10(-6) M) role of ascorbic acid in the decrease of [3H]DA or [3H]5HT uptake was demonstrated. This decrease was potentiated by Fe2+ ions and prevented by the ferrous chelating agent desferrioxamine. Thus, the progressive decrease in synaptosomal uptake of either [3H]DA or [3H]5HT could depend on the generation of free radicals by the association of ascorbic acid with Fe2+ ions. The decrease in synaptosomal uptake was prevented, in a concentration-dependent manner, by the Ginkgo biloba extract EGb 761 (4-16 micrograms/mL) and the vitamin E analog trolox C (10(-4) M). The terpenic fraction of EGb 761, Bn 52063 (up to 0.5 microgram/mL), did not prevent the reduction of [3H]amine uptake. In contrast, the flavonoidic fraction, Cp 202, was effective (from 1 microgram/mL) and its efficacy was shared by the flavonoid quercetin (from 0.1 microgram/mL). The prolongation of the ability of synaptosomes to take up [3H]amine elicited by EGb 761, in particular its flavonoidic fraction, as well as by trolox C could be due to their free radical scavenger properties.

19.Ca(2+)-induced increase in oxidative metabolism of dissociated mammalian brain neurons: effect of extract of ginkgo biloba leaves.:(Psycho:cerebral-neurons-antioxidant)

20.Decreased electroconvulsive shock-induced diacylglycerols and free fatty acid accumulation in the rat brain by Ginkgo biloba extract (EGb 761): selective effect in hippocampus as compared with cerebral cortex.:(Psycho:cerebral)

J Neurochem. 1993 Oct;61(4):1438-44.PMID: 8376997
The effect of Ginkgo biloba extract (EGb 761) treatment (100 mg/kg/day, per os, for 14 days) on electroconvulsive shock (ECS)-induced accumulation of free fatty acids (FFA) and diacylglycerols (DAG) was analyzed in rat cerebral cortex and hippocampus. EGb 761 reduced the FFA pool size by 33% and increased the DAG pool by 36% in the hippocampus. These endogenous lipids were unaffected in cerebral cortex. During the tonic seizure (10 s after ECS) the fast accumulation of FFA, mainly 20:4, was similar in sham- and EGb 761-treated rats, in both the cerebral cortex and hippocampus. However, further accumulation of free 18:0 and 20:4, observed in the hippocampus of sham-treated rats during clonic seizures (30 s to 2 min after ECS), did not occur in EGb 761-treated animals. The rise in DAG content triggered in the cortex and hippocampus by ECS was delayed by EGb 761 treatment from 10 s to 1 min, when values similar to those in sham animals were attained. Moreover, in the hippocampus the size of the total DAG pool was decreased by 19% during the tonic seizure. At later times, DAG content showed a faster decrease in EGb 761-treated rats. By 2 min levels of all DAG acyl groups decreased to values significantly lower than in sham animals in both cortex and hippocampus. This study shows that EGb 761 treatment affects, with high selectivity, lipid metabolism and lipid-derived second messenger release and removal in the hippocampus, while affecting to a lesser extent the cerebral cortex.

21.Evidence for a therapeutic effect of Ginkgo biloba special extract. Meta-analysis of 11 clinical studies in patients with cerebrovascular insufficiency in old age:(Psycho:cerebrovascular insufficiency)

Arzneimittelforschung. 1994 Sep;44(9):1005-13.PMID: 7986236
Eleven controlled clinical trials were evaluated in a meta-analysis in order to proof the effectiveness of the ginkgo biloba special extract LI 1370 (Kaveri forte). All included studies were placebo controlled randomized double blind studies, using in most of the cases a daily dosage of 150 mg extract. The requirements for the quality of the studies were the basic criteria for the performance of clinical drug tests analysed from the biometrical scope. The analysis of the individual studies revealed that three studies had to be excluded from the meta-analysis according to methodological or objective reasons. In two further studies the evaluation of the physician or the patients was missing, therefore the studies could not be used for the analysis of the "global effectiveness". All other studies were comparable with regard to diagnoses, inclusion and exclusion criteria as well as methodology. Therefore a statistical meta-analysis could be performed for them, analysing the parameters "single symptoms", total score of clinical symptoms and "global effectiveness". For all analyzed single symptoms significant differences could be concluded, indicating the superiority of ginkgo biloba in comparison to placebo. The analysis of the total score of clinical symptoms from all relevant studies indicated that 7 studies confirmed the effectiveness (Ginkgo biloba being better compared to placebo) while only one study was inconclusive (the medications were not different). This relation confirms the therapeutical effectiveness of ginkgo biloba regarding the clinical symptom complex. Finally the parameter "global effectiveness" was evaluated

22.Platelet-activating factor is an important mediator in hypoxic ischemic brain injury in the newborn rat. Flunarizine and Ginkgo biloba extract reduce PAF concentration in the brain.:(Psycho:hypoxic-ischemic brain injury)

Biol Neonate. 1998 Dec;74(6):439-44.PMID: 9784635
Hypoxic-ischemic encephalopathy is still a very important cause of neonatal mortality and morbidity. Recently, platelet-activating factor (PAF) has been accused of being responsible for the neuronal damage in hypoxic-ischemic brain. We investigated tissue PAF concentrations in hypoxic-ischemic brain injury in immature rats. Endogenous PAF concentration in brain tissue showed a marked increase in hypoxic-ischemic pups (85.6 +/- 15.5 pg/mg protein) when compared to that of control (9.05 +/- 3.1 pg/mg protein). In addition, we examined the effects of flunarizine, a selective calcium channel blocker, and Ginkgo biloba extract (EGb 761) on endogenous PAF concentration in hypoxic-ischemic brain injury. Endogenous PAF concentrations in both flunarizine-pretreated (16.6 +/- 4.8 pg/mg protein) and EGb 761-pretreated (33.5 +/- 8.9 pg/mg protein) pups were significantly lower than the untreated group. These results indicate that PAF is an important mediator in immature rat model of cerebral hypoxic-ischemic injury. The suppressor effect of flunarizine and EGb 761 on PAF production may open new insight into the treatment of hypoxic-ischemic brain injury.

23.Actions of Ginkgo Biloba related to potential utility for the treatment of conditions involving cerebral hypoxia.:(Psycho:cerebral)

Life Sci. 2000 Aug 11;67(12):1389-96.PMID: 10983836
Neuronal hypoxia results from a variety of cerebrovascular accidents or 'normal' age-associated anatomic changes. The consequences vary from mild deficits in neurologic function to massive neuropathology. Present pharmacotherapeutic therapy is not ideal. Two apparently disparate approaches to the search for better treatment or prevention-one involving reassessment of herbal remedies as 'alternative' medicine and the other one involving the desirability of increased structural diversity in HTS (high-throughput screening) libraries and as combinatorial chemistry templates-have converged in a rekindling of interest and a reevaluation of the pharmacologic properties of substances such as extract from the leaves of Ginkgo biloba Linne (form. Salisburia adiantifolia Sm.). There are reports of positive results from a small number of controlled clinical trials (albeit with small numbers of patients) sufficient to suggest that 'Ginkgo' might have therapeutic benefit in some situations or subset of patients. The pharmacologic mechanism by which Ginkgo might be able to provide the observed effect is not clear. However, it is believed that the flavonoid and terpenoid components of Ginkgo extract might produce beneficial therapeutic effects through mechanisms acting separately or in concert, such as the antagonism of PAF (platelet activating factor), antioxidant and metabolic actions, and effects on neurotransmitters. These mechanisms are reviewed in this article.

24.The dose-dependent cognitive effects of acute administration of Ginkgo biloba to healthy young volunteers.:(Psycho:cerebral)

Psychopharmacology (Berl). 2000 Sep;151(4):416-23.PMID: 11026748
RATIONALE: Chronic administration of extracts from the leaves of the tree Ginkgo biloba is known to improve aspects of cognitive performance. However, little is known about the effects of acute doses of Ginkgo on coherent cognitive domains. Recent factor analysis of test measures from subtasks of the Cognitive Drug Research (CDR) computerised assessment battery has revealed that four primary cognitive 'factors' corresponding to speed of attention, accuracy of attention, speed of memory and quality of memory can be useful to describe cognitive function changes.OBJECTIVE: The present study aimed at assessing whether acute administration of Ginkgo biloba had any consistent effect on the four CDR factors.METHODS: The study utilised a placebo-controlled, multi-dose, double-blind, balanced, crossover design. Twenty participants received 120 mg, 240 mg and 360 mg of a standardised extract of Ginkgo (GK501, Pharmaton, SA) or a matching placebo. Cognitive performance was assessed using the CDR computerised test battery immediately prior to dosing and at 1, 2.5, 4 and 6 h thereafter. The primary outcome measures were the four aspects of cognitive performance, which have previously been derived by factor analysis of CDR subtests.RESULTS: Compared with the placebo, administration of Ginkgo produced a number of significant changes on the performance measures. The most striking of these was a dose-dependent improvement of the 'speed of attention' factor following both 240 mg and 360 mg of the extract, which was evident at 2.5 h and was still present at 6 h. Additionally, there were a number of time- and dose-specific changes (both positive and negative) in performance of the other factors.CONCLUSIONS: We conclude that acute administration of Ginkgo biloba is capable of producing a sustained improvement in attention in healthy young volunteers.

25.Efficacy of antioxidant therapies in transient focal ischemia in mice.:(Psycho:ischemia)

Stroke. 2001 Apr;32(4):1000-4.PMID: 11283403
BACKGROUND AND PURPOSE: Ginkgo biloba extract (EGb) and alpha-lipoic acid (LA) are commercially available "antioxidant supplements" with a variety of actions that may be beneficial during acute stroke. These actions include inhibiting platelet and leukocyte activation and adhesion, reducing free radical generation, and increasing cerebral blood flow. Both EGb and LA have been shown to be neuroprotective in cell culture and global central nervous system ischemia models. In this study we investigated the neuroprotective efficacy of EGb and LA in a clinically relevant, transient focal central nervous system ischemic model.METHODS: In the EGb study, 60 adult C57blk mice were randomized to treatment with EGb given orally (via gavage) for 7 days: low dose, 50 EGb mg/kg daily; high dose, 100 mg/kg daily; matched placebo. On day 7, reversible middle cerebral artery occlusion was produced by advancing a silicone-coated 8-0 filament into the internal carotid artery for 45 minutes followed by reperfusion. At 24 hours, the animals were evaluated on a 28-point clinical scale, and infarct volume was determined with the use of triphenyltetrazolium chloride. In the LA study, 24 C57blk mice were treated with 100 mg/kg SC of LA or placebo 1.5 hours before transient MCAO, as in the EGb study.RESULTS: In the EGb study, values for infarct volume at 24 hours were as follows (mean+/-SD): low dose (n=18), 13+/-5 mm(3); high dose (n=22), 22+/-12 mm(3); placebo (n=20), 20+/-10 mm(3) (P:=0.03 overall; P=0.02, low dose versus placebo). Infarct percentage of hemisphere values were as follows: low dose, 14+/-5%; high dose, 21+/-11%; placebo, 20+/-9% (P=0.03 overall; P=0.02, low dose versus placebo). Ten percent of the high-dose group showed significant intracerebral hemorrhage (ICH) within the infarct, while no ICH was seen in the other groups. Neurological function scores were as follows: low dose, 11.8+/-1.5; high dose, 11.4+/-1.7; placebo, 11.3+/-1.8 (P=NS). In the LA study, infarct volume was as follows: 100 mg/kg LA (n=12), 16.8+/-8.3 mm(3); placebo (n=12), 27.2+/-14.6 mm(3) (P<0.05). LA also produced a significant improvement in neurological function at 24 hours: LA, 9.5+/-1.2; placebo, 11.2+/-1.8 (P=0.02). There was no evidence of ICH in any of the animals.CONCLUSIONS: Both oral EGb and LA therapies produced significant reductions in stroke infarct volume. However, for EGb this beneficial effect appears to be dose related, with higher doses potentially increasing the risk of ICH.

Xe-Ginkgo Biloba:Psychopharmacological effects:Neuroprotective,Brain-injury,Neuropathy,Neurotoxicity,

1.Ginkgo biloba extract and folic acid in the therapy of changes caused by autonomic neuropathy:(Psycho:neuropathy)

Acta Med Austriaca. 1989;16(2):35-7.PMID: 2665410
10 patients suffering from neuropathies caused by various diseases and with an autonomic disregulation of skin were treated intravenously with a new combination of 87.5 mg Ginkgo-biloba-extract standardized to 21.0 mg Flavonglycosids and 3 mg folic acid during 14 days. The autonomic nerve-function was measured immediately before onset and after the end of therapy with the hyperthermal laser-Doppler-Flowmetry. Additionally pain, superficial and deep sensibility were described. After the end of treatment the autonomic nerve-function was improved in a significant manner (p less than 0.01). An improvement of the described parameters for pain and for perception could be observed too. Therefore this new combination seems to be suited for treatment of polyneuropathies.

2.Ginkgo biloba extract facilitates recovery from penetrating brain injury in adult male rats.:(Psycho:brain-injury)

Exp Neurol. 1989 Jul;105(1):62-71.PMID: 2744128
Adult, male Sprague-Dawley rats received 100 mg/kg Ginkgo biloba extract (GBE) intraperitoneally for 30 days. GBE reduced overall activity and decreased sensitivity to light in the open field maze. The rats were also less responsive to noxious stimuli after 13 days of treatment with GBE. After the last injection, all subjects were trained on a delayed-spatial alternation task. Subsequent to acquisition of the spatial task, the rats received either sham operations and saline or bilateral frontal cortex lesions treated with either saline or GBE. Thirty additional days of treatment began on the day of injury, and open field behavior, analgesia, and metabolic activity measurements were again measured. The rats with lesions treated with saline were more active than their GBE-treated counterparts and sham controls but there were no differences in response to illumination or noxious stimuli. Retention of the delayed-spatial alternation indicated that rats with lesions treated with GBE were less impaired than brain-injured subjects receiving saline treatment. Histological examination showed that GBE reduced the extent of brain swelling in response to the injury.

3.Prevention by a Ginkgo biloba extract (GBE 761) of the dopaminergic neurotoxicity of MPTP.:(Psycho:neurotoxicity)

J Pharm Pharmacol. 1990 Nov;42(11):785-9.PMID: 1982302
In mice implanted subcutaneously with osmotic minipumps releasing the neurotoxic agent N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 days (105 micrograms h-1/mouse) (approximately 100 mg kg-1 day-1) a significant reduction (approximately 25%) in the striatal dopaminergic nerve endings was observed. This neurotoxic effect was prevented by the semi-chronic ingestion of a Ginkgo biloba extract for 17 days (GBE 761, approximately 100 mg kg-1 day-1). The high concentrations (approximately 1 g L-1) at which GBE 761 in-vitro either prevented the uptake of [3H]dopamine by synaptosomes prepared from striatum, or prevented the specific binding of the pure dopamine uptake inhibitor [3H]GBR 12783 to membranes prepared from striatum suggests that the prevention of the MPTP neurotoxicity does not depend on an inhibition of the MPTP uptake by dopamine neurons. This is also suggested by the lack of prevention of the in-vitro striatal binding of [3H]GBR 12783 administered i.v. at a tracer dose, in mice pretreated for 8 days with GBE 761 (100 mg kg-1 p.o.) and receiving a supplementary gastric administration of GBE 761 (100 mg kg-1) 1 h before testing. Similar treatment with GBE 761 did not modify the toxicity for dopamine neurons of 6-hydroxydopamine (20 micrograms) directly injected into the striatum of rats.

4.The neuroprotective properties of the Ginkgo biloba leaf: a review of the possible relationship to platelet-activating factor (PAF).:(Psycho:neuroprotective)

J Ethnopharmacol. 1996 Mar;50(3):131-9.PMID: 8691847
Ginkgo biloba (Ginkgoaceae) is an ancient Chinese tree which has been cultivated and held sacred for its health-promoting properties. There is substantial experimental evidence to support the view that Ginkgo biloba extracts have neuroprotective properties under conditions such as hypoxia/ischemia, seizure activity and peripheral nerve damage. Research on the biochemical effects of Ginkgo biloba extracts is still at a very early stage. One of the components of Ginkgo biloba, ginkgolide B, is a potent platelet-activating factor (PAF) antagonist. Although the terpene fraction of Ginkgo biloba, which contains the ginkgolides, may contribute to the neuroprotective properties of the Ginkgo biloba leaf, it is also likely that the flavonoid fraction, containing free radical scavengers, is important in this respect. Taken together, the evidence suggests that Ginkgo biloba extracts are worthy of further investigation as potential neuroprotectant agents.

5.Ginkgo biloba extract protects brain neurons against oxidative stress induced by hydrogen peroxide.:(Psycho:neuron protect)

Brain Res. 1996 Mar 18;712(2):349-52.PMID: 8814913
Effect of Ginkgo biloba extract was examined on dissociated rat cerebellar neurons suffering from oxidative stress induced by hydrogen peroxide using a flow cytometer and ethidium bromide. Hydrogen peroxide at a concentration of 3 mM increased the number of neurons stained with ethidium (presumably dead neurons) in a time-dependent manner. Pretreatment of neurons with G. biloba extract (10 micrograms/ml) greatly delayed a time-dependent increase in number of dead neurons during exposure to hydrogen peroxide. It was true, but less effective, in the case of treatment with G. biloba extract immediately or 60 min after start of oxidative stress. Results implicate G. biloba extract as a potential agent in protecting the neurons suffering from oxidative stress induced by hydrogen peroxide.

6.Preventive effect of Ginkgo biloba extract on apoptosis in rat cerebellar neuronal cells induced by hydroxyl radicals.:(Psycho:neroprotective)

Neurosci Lett. 1996 Aug 23;214(2-3):115-8.PMID: 8878097
The ability of oxidative stress to induce apoptosis, and the effect of Ginkgo biloba extract (EGb761) on this induction were studied in primary cultured rat cerebellar neuronal cells. Cells were exposed to hydroxyl radicals by treating them with 20-50 microM hydrogen peroxide (H2O2) and 100 microM ferrous sulfate. Hydroxyl radical treatment fragmented the DNA in a manner typical of apoptosis cells, producing a ladder pattern of 200 base pair increments on 1% agarose gel electrophoresis. Pretreatment of cells with 100 micrograms/ml EGb reduced hydroxyl radical induced cells apoptosis (determined by flow cytometry) and DNA fragmentation. The results indicate that hydroxyl radicals induce apoptosis in rat cerebellar neuronal cells and this induction can be prevented by EGb.

7.In vivo regulation of peripheral-type benzodiazepine receptor and glucocorticoid synthesis by Ginkgo biloba extract EGb 761 and isolated ginkgolides.(Psycho:neuroprotective/antistress):

Endocrinology. 1996 Dec;137(12):5707-18.PMID: 8940403
Glucocorticoid excess has broad pathogenic potential including neurotoxicity, neuroendangerment, and immunosuppression. Glucocorticoid synthesis is regulated by ACTH, which acts by accelerating the transport of the precursor cholesterol to the mitochondria where steroidogenesis begins. Ginkgo biloba is one of the most ancient trees, and extracts from its leaves have been used in traditional medicine. A standardized extract of Ginkgo biloba leaves, termed EGb 761 (EGb), has been shown to have neuroprotective and antistress effects. In vivo treatment of rats with EGb, and its bioactive components ginkgolide A and B, specifically reduces the ligand binding capacity, protein, and messenger RNA expression of the adrenocortical mitochondrial peripheral-type benzodiazepine receptor (PBR), a key element in the regulation of cholesterol transport, resulting in decreased corticosteroid synthesis. As expected, the ginkgolide-induced decrease in glucocorticoid levels resulted in increased ACTH release, which in turn induced the expression of the steroidogenic acute regulatory protein. Because ginkgolides reduced the adrenal PBR expression and corticosterone synthesis despite the presence of high levels of steroidogenic acute regulatory protein, these data demonstrate that PBR is indispensable for normal adrenal function. In addition, these results suggest that manipulation of PBR expression could control circulating glucocorticoid levels, and that the antistress and neuroprotective effects of EGb are caused by to its effect on glucocorticoid biosynthesis.

8.Neuron degeneration induced by verapamil and attenuated by EGb761.:(Psycho:neuroprotective)

J Basic Clin Physiol Pharmacol. 1997;8(4):301-14.PMID: 9651802
Calcium channel blockers are used as neuroprotective agents, as glutamate antagonists. However, it has been found that calcium channel blockers may compromise neuronal survival after long-term exposure. To explore the mechanisms of the toxicity of calcium channel blockers on neurons, we studied the morphological characteristics and biochemical changes of cultured cortical neurons treated with verapamil, a calcium channel blocker. We now report that cerebral cortical cultures exposed to verapamil for 48 h undergo neuronal degeneration in both concentration-dependent and time-dependent fashion, possibly partially through the activation of apoptosis. On the other hand, it was found that Ginkgo biloba extract (EGb761) attenuated verapamil-induced neuronal injury, suggesting the possibility of using verapamil combined with EGb761 clinically. Furthermore, both B-50 immunoactivity (BIA) and the concentration of intracellular calcium in single neurons ([Ca2+]i) decreased after a 48-h exposure to verapamil, suggesting that the mechanisms of verapamil-induced degeneration may be associated with the disruption of intracellular calcium homeostasis and the inhibition of normal axonal elongation.

9.Antagonistic effects of extract from leaves of ginkgo biloba on glutamate neurotoxicity.:(Psycho:neurotoxicity)

Zhongguo Yao Li Xue Bao. 1997 Jul;18(4):344-7.PMID: 10072919
AIM: To determine whether the extract of leaves of Ginkgo biloba L (EGb) and several active constituents of EGb have protective effects against glutamate (Glu)-induced neuronal damage.METHODS: Microscopy and image analysis of nucleus areas in the arcuate nuclei (AN) of mice were made. The neuronal viability in primary cultures from mouse cerebral cortex was assessed using MTT [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromide] staining and the intracellular free calcium concentration ([Ca2+]i) of single neuron was measured using Fura-2.RESULTS: EGb (2.5 mg.L-1) and its constituent ginkgolide B (Gin B, 2 mg.L-1) protected the neuronal viability against Glu-induced injury, and prevented the Glu-induced elevation in [Ca2+]i. EGb (3-10 mg.kg-1) attenuated the decrease of nucleus areas in arcuate nuclei induced by Glu (1 g.kg-1, s.c.).CONCLUSION: EGb and Gin B prevent neurons from Glu neurotoxicity through reduction of the rise in [Ca2+]i.

10.Inhibition of serum deprivation- and staurosporine-induced neuronal apoptosis by Ginkgo biloba extract and some of its constituents.:(Psycho:neuroprotective)

Eur J Pharmacol. 1999 Feb 19;367(2-3):423-30.PMID: 10079019
Previous studies have already demonstrated that some constituents of an extract of Ginkgo biloba (EGb), such as ginkgolide B and bilobalide, protect cultured neurons from hypoxia- and glutamate-induced damage. This prompted us to investigate whether they were also able to inhibit neuronal apoptosis. We induced apoptosis in cultured chick embryonic neurons as well as in mixed cultures of neurons and astrocytes from neonatal rat hippocampus by serum deprivation and staurosporine. The increase in the percentage of apoptotic chick neurons from 12% in controls to 30% after 24 h of serum deprivation was reduced to control level by EGb (10 mg/l), ginkgolide B (10 microM), ginkgolide J (100 microM) and bilobalide (1 microM). After treatment with staurosporine (200 nM) for 24 h we observed 74% apoptotic chick neurons. This percentage of apoptotic neurons was reduced to 24%, 62% and 31% in the presence of EGb (100 mg/l), ginkgolide J (100 microM) and ginkgolide B (10 microM), respectively. Bilobalide (10 microM) decreased apoptotic damage induced by staurosporine treatment for 12 h nearly to the control level. In mixed neuronal/glial cultures, the extract of EGb (100 mg/l) and bilobalide (100 microM) rescued rat neurons from apoptosis caused by serum deprivation, whereas, bilobalide (100 microM) and ginkgolide B (100 microM) reduced staurosporine-induced apoptotic damage. Ginkgolide A revealed no anti-apoptotic effect in either serum-deprived or staurosporine-treated neurons. Our results suggest that EGb and some of its constituents possess anti-apoptotic capacity and that bilobalide is the most potent constituent.

11.The results of using different forms of a Ginkgo biloba extract (EGb 761) in the combined treatment of patients with circulatory encephalopathy:(Psycho:neuroprotective)

Lik Sprava. 1998 Dec;(8):123-8.PMID: 10204370
Studies made in 208 patients with discirculatory encephalopathy using clinical and neuropsychological tests, apparatus (REG, ECG, EEG, Doppler sonography) and laboratory (coagulogramme) methods showed the prescription of drug preparations from ginkgo extract to be a worth-while exercise likely to benefit the patient during different stages of his/her affection. Positive time-related course was recordable of change in elastic and tonic characteristics of vessels, of bioelectric brain activity, emotional and behavioral, cognitive and mnestic features. The above-mentioned drugs will, we believe, help in developing new options for the outpatient, hospital, and rehabilitative stage of managing a patient. Potentiation of the positive action of ginkgo preparations showed up when being combined with a complex of components of the tricarboxylic acid cycle.

12.Involvement of monoamine oxidase inhibition in neuroprotective and neurorestorative effects of Ginkgo biloba extract against MPTP-induced nigrostriatal dopaminergic toxicity in C57 mice.:(Psycho:neuroprotective)

Life Sci. 1999;65(2):157-64.PMID: 10416821
The present study investigated the neuroprotective and neurorestorative effects of Ginkgo biloba extract (EGb 761) and its two components ginkgolides A (BN52020) and B (BN52021) in mice. 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (30 mg/kg/d i.p. for six days) significantly reduced striatal dopamine (DA) levels in C57 mice measured by high performance liquid chromatography with electrochemical detection (HPLC-EC). When C57 mice were pretreated with EGb 761 (20, 50, 100 mg/kg/d i.p.) for 7 days and then treated with the same extract 30 min before MPTP injection for 6 days, the neurotoxic effect of MPTP was antagonized in a dose-dependent fashion. Similar treatment with ginkgolides A and B (5, 10, 50 mg/kg/d i.p.) showed no protective effect. When C57 mice were treated with EGb 761 (50 mg/kg/d i.p.) after MPTP-lesion, the recovery of striatal dopamine (DA) levels was accelerated. However, similar treatment with ginkgolides A or B (10 mg/kg/d i.p.) did not show any effect. EGb 761, but not ginkgolides A and B, nonselectively inhibited mouse brain MAO activity in vitro (IC50 = 36.45 +/- 1.56 microg/ml) tested by an improved fluorimetric assay. The results demonstrate that EGb 761 administered before or after MPTP treatment effectively protects against MPTP-induced nigrostriatal dopaminergic neurotoxicity and that the inhibitory effect of EGb 761 on brain MAO may be involved in its neuroprotective effect.

13.Bilobalide, a constituent of Ginkgo biloba, inhibits NMDA-induced phospholipase A2 activation and phospholipid breakdown in rat hippocampus.:(Psycho:neuroprotective)

Naunyn Schmiedebergs Arch Pharmacol. 1999 Dec;360(6):609-15.PMID: 10619176
In rat hippocampal slices superfused with magnesium-free buffer, glutamate (1 mM) caused the release of large amounts of choline due to phospholipid breakdown. This phenomenon was mimicked by N-methyl-D-aspartate (NMDA) in a calcium-sensitive manner and was blocked by NMDA receptor antagonists such as MK-801 and 7-chlorokynurenate. The NMDA-induced release of choline was not caused by activation of phospholipase D but was mediated by phospholipase A2 (PLA2) activation as the release of choline was accompanied by the formation of lyso-phosphatidylcholine (lyso-PC) and glycerophospho-choline (GPCh) and was blocked by 5-[2-(2-carboxyethyl)-4-dodecanoyl-3,5-dimethylpyrrol-1-yl]pentano ic acid, a PLA2 inhibitor. Bilobalide, a constituent of Ginkgo biloba, inhibited the NMDA-induced efflux of choline with an IC50 value of 2.3 microM and also prevented the formation of lyso-PC and GPCh. NMDA also caused a release of choline in vivo when infused into the hippocampus of freely moving rats by retrograde dialysis. Again, the effect was completely inhibited by bilobalide which was administered systemically (20 mg/kg i.p.). Interestingly, convulsions which were observed in the NMDA-treated rats were almost totally suppressed by bilobalide. We conclude that release of choline is a sensitive marker for NMDA-induced phospholipase A2 activation and phospholipid breakdown. Bilobalide inhibited the glutamatergic excitotoxic membrane breakdown both in vitro and in vivo, an effect which may be beneficial in the treatment of brain hypoxia and/or neuronal hyperactivity.

14.Damaged neuronal energy metabolism and behavior are improved by Ginkgo biloba extract (EGb 761).:(Psycho:neuroprotective)

J Neural Transm. 1999;106(11-12):1171-88.PMID: 10651112
The standardized extract EGb 761 from the dried green leaves of Ginkgo biloba is a complex mixture of ingredients with an uniquely broad spectrum of pharmacological activities on the central nervous system e.g. in memory enhancing properties and in the regulation of cerebral glucose/energy metabolism. To test these effects on both behavioral and metabolic brain parameters, the animal model of intracerebroventricular (i.c.v.) streptozotocin (STZ) treatment was used. To quantify the experimental data more precisely, animals that were good performers were separated from poor performers by means of the holeboard test before i.c.v. administration of STZ. Good performers only were considered for the study. After a 1-week training period on the holeboard improvement was seen in all animals in learning, memory and cognition, and the improvement was maintained over the investigation period of 12 weeks in the control group. In this group, the energy pool in the cerebral parietotemporal cortex was found to be large and the energy turnover high. After triplicate i.c.v. STZ injection, working memory (WM), reference memory (RM), and passive avoidance (PA) behavior fell off and continued to deteriorate throughout the investigation period. Otherwise there were no significant differences in locomotor activity, excluding the possibility that activity per se might have contributed to the behavioral abnormalities. These were accompanied by a permanent deficit in cerebral energy metabolism. The ongoing deterioration in behavior and the maintained deficit in cerebral energy metabolism occurring after a triplicate i.c.v. STZ injection were significantly slowed down by EGb761. The deficits in learning, memory and cognition were partially compensated, and the disturbances in cerebral energy metabolism returned to almost completely normal values. These findings underscore the beneficial effect of EGb761 that had been reported in dementia disorders.

15.Identification of kaempferol as a monoamine oxidase inhibitor and potential Neuroprotectant in extracts of Ginkgo biloba leaves.:(Psycho:neuroprotective)

J Pharm Pharmacol. 2000 Apr;52(4):451-9.PMID: 10813558
The effects of Ginkgo biloba leaf extract on rat brain or livermonoamine oxidase (MAO)-A and -B activity, biogenic amine concentration in nervous tissue, N-methyl-D-aspartate (NMDA)- and N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4)-induced neurotoxicity and antioxidant activity was investigated to determine the effects of the extract on monoamine catabolism and neuroprotection. Ginkgo biloba leaf extract was shown to produce in-vitro inhibition of rat brain MAO-A and -B. The Ginkgo biloba extract was chromatographed on a reverse-phase HPLC system and two of the components isolated were shown to be MAO inhibitors (MAOIs). These MAOIs were identified by high-resolution mass spectrometry as kaempferol and isorhamnetin. Pure kaempferol and a number of related flavonoids were examined as MAOIs in-vitro. Kaempferol, apigenin and chrysin proved to be potent MAOIs, but produced more pronounced inhibition of MAO-A than MAO-B. IC50 (50% inhibition concentration) values for the ability of these three flavones to inhibit MAO-A were 7 x 10(-7), 1 x 10(-6) and 2 x 10(-6) M, respectively. Ginkgo biloba leaf extract and kaempferol were found to have no effect ex-vivo on rat or mouse brain MAO or on concentrations of dopamine, noradrenaline, 5-hydroxytryptamine and 5-hydroxyindoleacetic acid. Kaempferol was shown to protect against NMDA-induced neuronal toxicity in-vitro in rat cortical cultures, but did not prevent DSP-4-induced noradrenergic neurotoxicity in an in-vivo model. Both Ginkgo biloba extract and kaempferol were demonstrated to be antioxidants in a lipid-peroxidation assay. This data indicates that the MAO-inhibiting activity of Ginkgo biloba extract is primarily due to the presence of kaempferol. Ginkgo biloba extract has properties indicative of potential neuroprotective ability.

16.Neuroprotective effects of NV-31, a bilobalide-derived compound: evidence for an antioxidative (Psycho:neuroprotective)

Brain Res. 2001 Feb 2;890(2):338-42.PMID: 11164801
In previous studies we have already shown that the extract of Ginkgo biloba, and some of its constituents, such as ginkgolide B and bilobalide, protected cultured neurons against apoptotic and excitotoxic damage and reduced the infarct volume after focal cerebral ischemia in mice and rats. In this work, we determined the neuroprotective and antioxidative effects of 4-hydroxy-4-tert-butyl-2,3,5,6-tetrahydrothiopyran-1-oxide (NV-31), a stable compound which was synthesized to mimic the pharmacological activity profile of bilobalide. In pure neuronal cultures from chick embryo telencephalon, damage was induced by serum deprivation (24 h) and exposure to staurosporine (200 nM, 24 h) which caused an increase in the percentage of apoptotic neurons from 14 (controls) to 30 and 55%, respectively. NV-31 (1-100 nM) protected dose-dependently chick neurons against both serum deprivation- and staurosporine-induced apoptosis. Similarly, NV-31 (100 nM) reduced staurosporine (300 nM, 24 h)-induced neuronal damage in mixed cultures of neurons and astrocytes from neonatal rat hippocampus. The cellular ROS content increased 6-fold 4 h after serum deprivation as well as 4 h after the exposure to staurosporine and this increase was reduced by 50% in the presence of 10 and 100 nM NV-31, respectively. In mice, a treatment with 10 and 20 mg/kg NV-31 60 min before and immediately after focal cerebral ischemia, respectively, significantly reduced the infarct area compared with vehicle-treated animals. In the present study, we show that NV-31 promotes neuronal survival and we suggest that its antioxidative property contributes to the mechanism of neuroprotection.

17.Prevention of neuronal cell damage induced by oxidative stress in-vitro: effect of different Ginkgo biloba extracts.:(Psycho:neuroprotective)

J Pharm Pharmacol. 2001 Mar;53(3):387-92.PMID: 11291754
The effect of two different Ginkgo biloba extracts (GB1 and GB4) was studied in-vitro on cultured neurons exposed to oxidative stress caused by H2O2(50 micromol L(-1)) and FeSO4(100 micromol L(-1)). Only about 50% of the neurons were still viable at the end of the experiment (8 h) in control conditions, while the two extracts dose dependently increased the number of viable cells, in the concentration range 10-200 microg mL(-1). The two Ginkgo biloba extracts differed in their effect on hydroxyl-radical-scavenging capacity: GB1 and GB4 had an IC50 (50% inhibiting concentration) value of 78 microg mL(-1) and 186 microg mL(-1), respectively. However, both extracts inhibited apoptosis in cortical neurons after oxidative stress in-vitro. These observations make one suppose that different preparations of Ginkgo biloba have quantitatively different actions and outline the importance of the contribution of apoptosis prevention toward their neuroprotective action.

18.The in vivo neuromodulatory effects of the herbal medicine ginkgo biloba.:(Psycho:neuroprotective)

Proc Natl Acad Sci U S A. 2001 Jun 5;98(12):6577-80. Epub 2001 May 29.PMID: 11381109
Extracts of Ginkgo biloba leaves are consumed as dietary supplements to counteract chronic, age-related neurological disorders. We have applied high-density oligonucleotide microarrays to define the transcriptional effects in the cortex and hippocampus of mice whose diets were supplemented with the herbal extract. Gene expression analysis focused on the mRNAs that showed a more than 3-fold change in their expression. In the cortex, mRNAs for neuronal tyrosine/threonine phosphatase 1, and microtubule-associated tau were significantly enhanced. Hyperphosphorylated tau is the major constituent of the neurofibrillary tangles in the brains of Alzheimer's disease patients. The expression of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-2, calcium and chloride channels, prolactin, and growth hormone (GH), all of which are associated with brain function, were also up-regulated. In the hippocampus, only transthyretin mRNA was upregulated. Transthyretin plays a role in hormone transport in the brain and possibly a neuroprotective role by amyloid-beta sequestration. This study reveals that diets supplemented with Ginkgo biloba extract have notable neuromodulatory effects in vivo and illustrates the utility of genome-wide expression monitoring to investigate the biological actions of complex extracts.

19.Role of nitric oxide in blood-brain barrier permeability, brain edema and cell damage following hyperthermic brain injury. An experimental study using EGB-761 and Gingkolide B pretreatment in the rat.:(Psycho:neuroprotective)

Acta Neurochir Suppl. 2000;76:81-6.PMID: 11450097
The role of oxidative stress in hyperthermia induced upregulation of constitutive and inducible isoforms of nitric oxide synthase (NOS) in the central nervous system (CNS) was investigated using immunohistochemistry in a rat model. Exposure of rats to heat stress at 38 degrees C for 4 h resulted in marked upregulation of constitutive NOS (cNOS) and a mild but significant expression of inducible NOS (iNOS) in several brain regions exhibiting leakage of the blood-brain barrier (BBB), brain edema formation and cell injury. Pretreatment with the potent antioxidative compound EGB-761 or its constituent, Ginkgolide B significantly attenuated upregulation of cNOS and iNOS in the brain and also reduced the BBB permeability disturbances, brain edema and cell injury. These neuroprotective effects were most marked in the EGB-761 pretreated rats. Our observations strongly suggest that (i) EGB-761 and Ginkgolide B pretreatment offer significant neuroprotection in hyperthermic brain injury, (ii) upregulation of cNOS and iNOS are injurious to the cell and, (iii) oxidative stress plays an important role in NOS expression and cell injury.

20.Extracts of Ginkgo biloba and Panax ginseng protect brain proteins from free radical induced oxidative damage in vitro.:(Psycho:neuroprotective)

Acta Neurochir Suppl. 2000;76:87-90.PMID: 11450098
Oxidative damage to normal human brain tissue was induced following exposure to hydroxyl (OH.) or superoxide (O2-.) free radical species generated by CO60 irradiation in vitro. Both enzymic and cytoskeletal proteins showed substantial (dose dependent) oxidative damage following exposure to OH. or O2-., as quantified by SDS-polyacrylamide gel electrophoretic analysis. Extracts of Ginkgo biloba or Panax ginseng showed a remarkable capacity to protect brain tissue proteins from oxidative damage in vitro, even at extreme (2000 kRads) dosage levels of OH. or O2-.. We suggest, therefore, that the beneficial effect of these plant extracts in preventing brain tissue damage in vivo (e.g. following ischemia-reperfusion) may result from their action in protecting brain proteins from oxidative damage, in addition to their previously reported capacity to reduce free radical induced lipid peroxidation.

21.Neuropsychological changes after 30-day Ginkgo biloba administration in healthy participants.:(Psycho:neuroprotective)

Int J Neuropsychopharmacol. 2001 Jun;4(2):131-4.PMID: 11466162
Ginkgo biloba extract (EGb) from the world's oldest living tree has been reputed to ameliorate cognitive decline in the elderly and slow cognitive deterioration in patients with dementia of the Alzheimer's type. EGb remains as one of the most popular plant extracts to alleviate symptoms associated with a range of cognitive disorders such as Alzheimer's disease, vascular dementia and age-related amnesic conditions. EGb is known to contain a range of chemically active components that have antagonistic effects on platelet-activating factor, free-radical scavenging activity and direct effects on the cholinergic neurotransmitter system. Recently there has been much speculation, that EGb may act as a 'smart drug' or nootropic agent in the healthy young to improve intelligence. We conducted a 30-d randomized, double-blind, placebo-controlled clinical trial in which 61 participants were administered a battery of validated neuropsychological tests before and after treatment. Statistical analysis indicated significant improvements in speed of information processing working memory and executive processing attributable to the EGb.

22.Neuroprotective effects of bilobalide, a component of the Ginkgo biloba extract (EGb 761), in gerbil global brain ischemia.:(Psycho:Neuroprotective)

Brain Res. 2001 Dec 20;922(2):282-92.PMID: 11743961
The neuroprotective effect of Ginkgo biloba extract (EGb 761) against ischemic injury has been demonstrated in animal models. In this study, we compared the protective effect of bilobalide, a purified terpene lactone from EGb 761, and EGb 761 against ischemic injury. We measured neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in vulnerable hippocampal regions of gerbils. At 7 days of reperfusion after 5 min of transient global forebrain ischemia, a significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected CA1 neurons from death and from ischemia-induced reductions in COX III mRNA. In addition, both bilobalide and EGb 761 protected against ischemia-induced reductions in COX III mRNA in CA1 neurons prior to their death, at 1 day of reperfusion. These results suggest that oral administration of bilobalide and EGb 761 protect against ischemia-induced neuron death and reductions in mitochondrial gene expression.

23.The CNS effects of Ginkgo biloba extracts and ginkgolide B.:(Psycho:neuroprotective)

Prog Neurobiol. 2002 Jun;67(3):235-57.PMID: 12169298
Ginkgo biloba extracts such as EGb-761 have been suggested to have a multitude of beneficial effects on CNS function, from enhancing cognitive function in dementia to facilitating recovery from acute forms of neural damage such as hypoxia/ischemia. Ginkgolide B, one of the major components of EGb-761, is a potent platelet-activating factor (PAF) receptor antagonist, which is also regarded as having neuroprotective effects in the CNS. The aim of this review is to summarise and to critically evaluate the current evidence on the CNS effects of EGb-761 and ginkgolide B, with particular emphasis on the data relating to their neuroprotective effects.

24.Natural extracts as possible protective agents of brain aging.:(Psycho:neuroprotective/anti-aging)

Neurobiol Aging. 2002 Sep-Oct;23(5):891-97.PMID: 12392793
A growing number of studies suggest that natural extracts and phytochemicals have a positive impact on brain aging. We examined the potential of the Ginkgo biloba extract EGb 761 and red wine-derived constituents on cell death produced by beta-amyloid (Abeta) peptides and oxidative stress, with respect to their possible deleterious role in age-related neurological disorders. We found that EGb 761, possibly through the antioxidant properties of its flavonoids, was able to protect hippocampal cells against toxic effects induced by Abeta peptides. Moreover, we showed that an exposure of rat hippocampal cells to the nitric oxide (NO) donor sodium nitroprusside (SNP) resulted in a decrease in cell survival and increase in reactive oxygen species (ROS) accumulation. However, EGb 761 and red wine-derived polyphenols protected against these events, due to their antioxidant activities, and their ability to block SNP-stimulated activity of protein kinase C (PKC). Taken together, these results support the hypothesis that dietary intake of natural substances may be beneficial in normal aging of the brain.

25.The Ginkgo biloba extract EGb 761 increases viability of hnt human neurons in culture and affectsthe expression of genes implicated in the stress response.:(Psycho:neuroprotective)

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):641-6.PMID: 12396074
There are numerous studies describing the neuroprotective effects of Ginkgo biloba extract EGb 761 on patients with disturbances of vigilance, memory and cognitive functions associated with aging and senility. Describing the pattern of gene expression in EGb 761-treated human hNT neurons may elucidate the molecular pathways leading to the neuroprotection. We used cDNA macroarrays including genes implicated in the antioxidant and stress responses to define the transcriptional effects of EGb 761 (250 microg/ml, 24 hr) on human hNT neurons. Seven genes were identified whose expression was strongly modified by the EGb 761 treatment. Three groups are distinguished: genes encoding transcription factors (increase of NF-kappaB p65 subunit and zinc finger protein 91 mRNAs, and decrease of c-myc transcripts), genes involved in antioxidant defenses (increase of the CuZn SOD mRNAs, and decrease of glutathione reductase and glutathione S-transferase pi mRNAs) and genes involved in stress responses (up-regulation of HSP70 transcripts). Consistent with the modulation of mRNAs by EGb 761, the enzymatic activities of glutathione reductase and glutathione S-transferase were decreased. Surprisingly, CuZn SOD activity was decreased despite increased abundance of the mRNAs; furthermore MnSOD activity was unmodified, and thus the effect of EGb 761 was specific to CuZn SOD. These results support the idea that modulation of target genes and transcription factors may be involved in the neuroprotective action of EGb 761.

26.Effects of chronic administration of bilobalide on amino acid levels in mouse brain.:(Psycho:neuroprotective)

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):681-4.PMID: 12396079
We have previously demonstrated that 4-day-treatment of mice with bilobalide, a sesquiterpene of Ginkgo biloba L., increases GABA levels in mouse brain, but, effects of chronic treatment with it are not clear. To study effects of chronic treatment of mice with bilobalide on amino acid levels in the brain, we determined the levels of aspartate, glutamate, serine, glutamine, glycine, taurine and GABA in the hippocampus, striatum and cortex. Bilobalide (3 mg/kg/day) was administered orally to 4-week-old mice for 40 days. Bilobalide treatment resulted in a significant increase in the levels of glutamate, aspartate, gamma-aminobutyric acid (GABA), and glycine in the hippocampus of mice compared with the control. An increased level of glycine after bilobalide treatment was also detected in the striatum. In the cortex, bilobalide increased the GABA level, whereas it decreased the level of aspartate. These changes in the levels of various amino acids may be involved in the broad spectrum of pharmacological activities of the extract of Ginkgo biloba on the central nervous system.

27.EGb 761 is a neuroprotective agent against beta-amyloid toxicity.:(Psycho:neuroprotective)

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):693-7.PMID: 12396081
Beta-amyloid (Abeta) deposition likely plays a causal role in the lesions that occur in Alzheimer's disease (AD). The Ginkgo biloba extract EGb 761 is widely prescribed in the treatment of cognitive deficits that are associated with normal and pathological brain aging such as AD. We have investigated here the potential effectiveness of EGb 761 against cell death produced by Abeta fragments on primary cultures of hippocampal cells, these cells being severely damaged in AD. A co-treatment with EGb 761 protected cells against toxicity induced by Abeta fragments in a concentration dependent manner. The effect of EGb 761 was even significant if added up to 8 hr to cells and was shared by its flavonoid fraction CP 205, whereas the terpenes bilobalide and ginkgolide B were ineffective. EGb 761 also displayed protective effects against toxicity produced by either H2O2 or nitric oxide, two neurotoxic agents that possibly mediate Abeta toxicity. Moreover, EGb 761, and to a lesser extent CP 205, completely blocked Abeta-induced events, such as reactive oxygen species accumulation and apoptosis. Taken together, these results and those obtained by other groups highlight the neuroprotective abilities of EGb 761 against dysfunction and death of neurons caused by Abeta deposits.

28.Anti-apoptotic properties of Ginkgo biloba extract EGb 761 in differentiated PC12 cells.:(Psycho:neuroprotective)

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):699-707.PMID: 12396082
Standard Ginkgo biloba leaf extract (EGb 761) has been known to have neuroprotective effects ranging from molecular and cellular, to animal and human studies, however, the cellular and molecular mechanisms remain unclear. Using PC 12 cells, a well-established model for studying neuroprotection, we have determined the mechanism of action of EGb 761 on cell survival following apoptosis induced by serum-deprivation or treatment with staurosporine (STS). Our results show that EGb 761 treatments of PC12 cells are able to prevent serum deprivation- and STS-induced mitochondrial damage, attenuate release of cytochrome c and DNA fragmentation. EGb 761, but not vitamin E. inhibited STS-induced activation of the caspase-3 enzyme. Two of the EGb 761 components, bilobalide B and ginkgolide C show more significant inhibition than the EGb 761 extract. Furthermore, DNA microarray assay results indicate that transcription of multiple apoptosis-related genes is either up- or down-regulated in cells treated with EGb 761. These results suggest that inhibition of apoptotic machinery may, at least in part, mediate multiple neuroprotective effects of EGb 761, and that EGb 761 and vitamin E act on different molecular paths to provide neuroprotection.

29.Bilobalide and neuroprotection.:(Psycho:neuroprotective)

Pharmacol Res. 2002 Dec;46(6):565-8.PMID: 12457632
In vivo studies have indicated that systemically administered bilobalide, a sesquiterpene trilactone constituent of Ginkgo biloba leaf extracts, can reduce cerebral edema produced by triethyltin, decrease cortical infarct volume in certain stroke models, and reduce cerebral ischemia. In vitro and ex vivo studies indicate that bilobalide has multiple mechanisms of action that may be associated with neuroprotection, including its preservation of mitochondrial ATP synthesis, its inhibition of apoptotic damage induced by staurosporine or by serum-free medium, its suppression of hypoxia-induced membrane deterioration in the brain, and its actions of increasing the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome c oxidase and the ND1 subunit of NADH dehydrogenase. As multiple modes of action may apply to bilobalide, it could be useful in developing therapy for disorders involving cerebral ischemia and neurodegeneration.

30.The effect of Ginkgo biloba extract (EGb 761) on gliotic reactions in the hippocampal formation after unilateral entorhinal cortex lesions.:(Psycho:neuroprotective)

Restor Neurol Neurosci. 2000;16(2):87-96.PMID: 12671211
PURPOSE: Ginkgo biloba extract (EGb 761) has been shown to facilitate behavioral and neuro-morphological recovery from brain injury, but less is known about its effects on glia. Since gliosis may be an important component of the recovery process, we tested the hypothesis that EGb 761 alters the time course and development of microglial activation and astrocytosis after brain injury.METHODS: Rats were treated with either saline or EGb 761 and killed at 2 hrs, 1, 3, 7, and 14 days following unilateral entorhinal cortex (EC) lesions. Microglia and their precursors were visualized with a silver impregnation method, and astrocytes with GFAP.RESULTS: Blood-borne monocytes/macrophages were seen as early as 2 hrs after injury in all animals. The side contralateral to the injury showed minimal microglial activation and there were no significant effects of drug treatment. On the side ipsilateral to the lesion EGb 761 enhanced microglial activation at 3, 7, and 14 days in the molecular layer and the hilus of the dentate gyrus; the areas of most profound deaf-ferentation after EC injury. Regions of the corpus callosum also showed enhanced microglial activation over the same time course. Reactive astrocytes were stained with GFAP and were found to be more numerous than activated microglia, particularly in the ipsilateral corpus callo-sum. EGb 761 treatment enhanced astrocytosis at 3 days in the molecular layer, the hilus, and the corpus callosum on the ipsilateral side.CONCLUSIONS: Taken together our results show that EGb 761 enhances, accelerates and prolongs the activation of microglia and astrocytosis at the site of injury.

31.Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus.:(Psycho:neuroprotective)

Brain Res Dev Brain Res. 2003 Sep 10;144(2):169-80.PMID: 12935914
Hippocampal neuron survival/growth and gene expression have been examined after prenatal (in utero) exposure of rats to EGb 761, a leaf extract of Ginkgo biloba. Oral administration of EGb 761 (100 or 300 mg/kg/day) to pregnant dams for 5 days increased the number of hippocampal neurons (maintained in culture) of their fetuses, indicating a neurotrophic effect of the extract. Using large-scale oligonucleotide microarrays containing over 8000 combined rat genes and expressed sequence tag clusters, it was shown that treatment of pregnant dams with EGb 761 (25, 50 or 100 mg/kg/day for 5 days) altered the expression of 187 genes in the hippocampi of male fetuses and 160 genes in those of female fetuses. Using gene-cluster analysis, these genes were grouped into 18 distinct clusters for males and 17 distinct clusters for females. Among these clusters, 35 genes shared a common expression pattern in male and female hippocampal development. Of these genes, the changes observed in insulin growth factor II, insulin growth factor binding protein 2, testosterone repressed prostate message-2, glutathione-dependent dehydroascorbate reductase, lipoprotein lipase, guanylate cyclase and DNA binding protein Brn-2 were confirmed by real-time quantitative polymerase chain reaction. These findings, which have provided the first genetic profile of the effects of EGb 761 on the developing rat hippocampus, increase our understanding of the molecular and genetic programs that are activated by the extract. These effects of EGb 761 may underlie its neuroprotective properties.

32.Effects of bilobalide on cerebral amino acid neurotransmission.:(Psycho:neuroprotective)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S84-8.PMID: 13130394
Bilobalide is one of many active constituents found in EGb 761 (definition see editorial), which is extracted from Ginkgo biloba leaves. Whilst there is good, sound evidence that bilobalide exhibits neuroprotective actions in a variety of model systems, there is currently no consensus on its mechanism of action. This present communication summarises the results we have obtained with this compound on excitatory amino acid neurotransmission in the central nervous system using both neurochemical and electrophysiological techniques. Bilobalide was shown to reduce glutamate and aspartate release elicited by both high potassium-containing artificial cerebrospinal fluid (aCSF) or veratridine from mouse cortical slices. In addition, bilobalide had a very potent effect (IC (50) 2.7 microM) on glutamate release elicited by hypoxia/hypoglycaemia-induced release from rat cortical slices. Electrophysiologically, bilobalide also decreased the frequency of gamma-aminobutyric acid (GABA) uptake inhibitor-induced depolarisations in mouse cortical slices, an effect probably mediated by a decrease in glutamate release. No definitive conclusions can be reached concerning the mechanism of action of bilobalide, but an ability to decrease excitotoxic amino acid release, particularly glutamate, would suggest that this is a probable mechanism to account for its neuroprotective properties.

33.Neuroprotective effects of bilobalide, a component of Ginkgo biloba extract (EGb 761) in global brain ischemia and in excitotoxicity-induced neuronal death.:(Psycho:neuroprotective)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S89-94.PMID: 13130395
In this study, we compared the protective effect of bilobalide, a purified terpene lactone component of ginkgo biloba extract EGb 761, (definition see editorial) and EGb 761 against ischemic injury and against glutamate-induced excitotoxic neuronal death. In ischemic injury, we measured neuronal loss and the levels of mitochondrial DNA (mtDNA)-encoded cytochrome oxidase (COX) subunit III mRNA in vulnerable hippocampal regions of gerbils. At 7 days of reperfusion after 5 min of transient global ischemia, a significant increase in neuronal death and a significant decrease in COX III mRNA were observed in the hippocampal CA1 neurons. Oral administration of EGb 761 at 25, 50 and 100 mg/kg/day and bilobalide at 3 and 6 mg/kg/day for 7 days before ischemia progressively protected CA1 neurons from death and from ischemia-induced reductions in COX III mRNA. In rat cerebellar neuronal cultures, addition of bilobalide or EGb 761 protected in a dose-dependent manner against glutamate-induced excitotoxic neuronal death (effective concentration [EC (50)] = 5 microg/ml (12 microM) for bilobalide and 100 microg/ml for EGb 761. These results suggest that both EGb 761 and bilobalide are protective against ischemia-induced neuronal death in vivo and glutamate-induced neuronal death in vitro by synergistic mechanisms involving anti-excitotoxicity, inhibition of free radical generation, scavenging of reactive oxygen species, and regulation of mitochondrial gene expression.

34.Effect of one week treatment with Ginkgo biloba extract (EGb761) on ischemia-induced infarct volume in gerbils.:(Psycho:neuroprotective)

Am J Chin Med. 2003;31(4):533-42.PMID: 14587876
The present study was designed to evaluate the neuroprotective effects of Ginkgo biloba leaf extract (EGb761) in male gerbils subjected to focal cerebral ischemia produced by permanent occlusion of the right middle cerebral artery. In this study, gerbils were fed standard chow with or without EGb761 (100 mg/kg/day, i.g.) prior to cerebral ischemia for 1 week. Gerbils were anesthetized and craniectomized to expose the right middle cerebral artery (MCA). The right MCA was constricted with an 8-0 suture to produce a permanent ligation. Infarct volume was assessed by TTC (2,3,5-triphenyl-tetrazolium chloride) staining 24 hours after initiation of cerebral ischemia. Results showed that the EGb761 group had significant reduction of infarct volume 4 and 6 mm from the frontal pole by 40% and 30%, respectively when compared to the control group (p < 0.05). Mean locomotor activity of gerbils was reduced 24 hours after the occlusion of the MCA in both groups. However, there was no difference in locomotor activity between groups either 30 minutes before or 24 hours after the occlusion (p > 0.05).

35.Effects of mexiletine, ginkgo biloba extract (EGb 761), and their combination on experimental head injury.:(Psycho:neuroprotective/head injury)

36.Prenatal exposure of rats to Ginkgo biloba extract (EGb 761) increases neuronal survival/growth and alters gene expression in the developing fetal hippocampus.:(Psycho:neuroprotective)

37.Effect of Ginkgo biloba (EGb 761) on staurosporine-induced neuronal death and caspase activity in cortical cultured neurons.:(Psycho:neuroprotective)

Brain Res. 2004 Mar 26;1002(1-2):76-85.PMID: 14988036
Previous studies suggest the protective potentiality of Ginkgo biloba (EGb 761) against apoptotic cell death induced by hydroxyl radicals, staurosporine, serum deprivation and beta-amyloid (betaA) peptide. We have extended these observations to cultured cortical neurons and studied the effect of EGb 761 on neuronal survival (evaluated as MTT reduction), the presence of condensed nuclei (monitored as Hoechst staining), the time-course of caspase-1, caspase-3 and caspase-9 activation (measured by cleavage of specific fluorescent substrates) and superoxide anion production (evaluated by hydroethidine staining) after the exposure to staurosporine. Results show that 200 microg/ml of EGb 761 increased cell survival and reduced the number of condensed nuclei after the exposure to 200 nM staurosporine. Vitamin E and the spin trapper alpha-phenyl-N-tert-butylnitrone (PBN) also significantly increased cell survival. In contrast, the broad-spectrum caspase inhibitors ZVAD and ZBIOT showed no protection. Similarly, selective inhibitors of caspase-1 (YVAD-CHO), caspase-2 (VDVAD-CHO), caspase-3 (DEVD-CHO) and caspase-8 (IETD-CHO) did not protect against cell damage induced by staurosporine. The protective effect of EGb 761 was not enhanced when coincubated with vitamin E or DEVD-CHO. Caspase-3 activity was maximally induced 5-8 h after staurosporine exposure. Both EGb 761 and vitamin E showed a tendency to decrease caspase-3 activity. In contrast, activation of caspase-1 and caspase-9 was not observed at any of the times studied after STS exposure. Exposure to staurosporine resulted in increased superoxide production that was maximal at 5 h. EGb 761 significantly inhibited superoxide production at short times after staurosporine exposure. Vitamin E and PBN also significantly reduced superoxide production. Results suggest that EGb 761 neuroprotective effect might be mediated by its well-known antioxidant activity, which might also influence caspase-3 activation. Inhibition of capase-3 induced by EGb 761 and vitamin E does not seem to contribute to their observed protective action.

38.The effect of Ginkgo extract EGb761 in cisplatin-induced peripheral neuropathy in mice.:(Psycho:neuroprotective/peripheral neuropathy)

Toxicol Appl Pharmacol. 2004 Apr 1;196(1):169-75.PMID: 15050418
Neuroprotective effect of Ginkgo biloba extract EGb761 in cisplatin (cis-diamminedi-chloroplatinum, or CDDP)-induced peripheral neuropathy was investigated. Swiss albino mice were treated with CDDP, 2 mg/kg ip twice a week for nine times. One group of the animals also received EGb761 in the drinking water at an estimated dosage of 100 mg/kg per day. Two other groups received vehicle (control) or EGb761 only. Development of neuropathy was evaluated with changes in sensory nerve conduction velocity (NCV). Following the treatments, dorsal root ganglia (DRGs) were microscopically examined and some were cultured for 3 days. EGb761 proved effective in preventing the reduction in NCV (P < 0.0001) caused by CDDP. CDDP caused a decrease in the number of migrating cells (P < 0.01) and in the length of outgrowing axons (P < 0.01) while EGb761 treatment prevented the latter. CDDP led to smaller nuclear and somatic sizes in neurons (P < 0.01), while with EGb761 co-administration, both were close to control values. Animals having EGb761 only had similar results with controls. In conclusion, EGb761 was found to be effective in preventing some functional and morphological deteriorations in CDDP-induced peripheral neuropathy.

39.Ginkgo biloba and neurodegenerative disorders.:(Psycho:neuroprotective/neurodegenerative disorders)

Front Biosci. 2004 Sep 1;9:3091-104.PMID: 15353340
The Gingko biloba extract EGb 761 has been the subject of many studies which confirm its usefulness for the prevention and treatment of neurodegenerative pathologies. These studies have focused on: a) the probable mechanisms of action that are involved in these disorders (including non-specific mechanisms implicated in diverse neurodegenerative disorders, particularly oxidative stress, or specific mechanisms such as those associated with beta-amyloid in Alzheimer's disease) and the processes of neuronal death; b) available animal models, and c) healthy individuals or those suffering from mild cognitive impairment or Alzheimer's disease. This data must be completed, particularly with regard to new knowledge about the pathogenesis of these disorders. Ambitious interventional studies are underway and may provide new evidence regarding the effect of EGb 761 in preventing Alzheimer's disease in humans. Positive findings would be particularly interesting since this drug is very safe to use.

40.Neuroprotective effect of Ginkgo biloba L. extract in a rat model of Parkinson's disease.:(Psycho:neuroprotective)

Phytother Res. 2004 Aug;18(8):663-6.PMID: 15472919
The neuroprotective effects of a standardized extract of Ginkgo biloba L. (EGb 761) were investigated on 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in the nigrostriatal dopaminergic system of the rat brain. Rats were given a week of pretreatment with daily administrations of EGb 761. Unilateral striatal injection of 6-OHDA was followed by treatment with EGb 761 for a week. Serial measurement of contralateral forepaw adjusting steps revealed a progressive deficit in motor activity. At 8 weeks after 6-OHDA lesion the number of contralateral forepaw adjusting steps was significantly higher in rats that were treated with high doses of EGb 761 (100 mg/kg daily) than in those treated with low doses (50 mg/kg) or with the vehicle. Dopamine neuron loss in the substantia nigra and a depletion in striatal dopamine corresponded with behavioural deficit. These data suggest that the neuroprotective effects of EGb 761 reduce the behavioural deficit in 6-OHDA lesions in rat and also indicates a possible role for the extract in the treatment of Parkinson's disease.

41.The homeopathic preparation Vertigoheel versus Ginkgo biloba in the treatment of vertigo in an elderly population: a double-blinded, randomized, controlled clinical trial.:(Psycho:neuroprotective/vertigo)

J Altern Complement Med. 2005 Feb;11(1):155-60.PMID: 15750375
OBJECTIVE: Alternative medical practices are common in the treatment of vertigo. This study compared the effects of Ginkgo biloba treatment with the homeopathic remedy Vertigoheel (Biologische Heilmittel Heel GmbH, Baden-Baden, Germany).DESIGN: Randomized, double-blinded, parallel group study.SUBJECTS: One hundred and seventy (170) patients, ages 60-80 years, with atherosclerosis-related vertigo.INTERVENTIONS: Patients were randomly allocated to receive treatment with either Vertigoheel (n = 87) or G. biloba (n = 83).OUTCOME MEASURES: The results were analyzed for the non-inferiority of Vertigoheel to G. biloba on the combined endpoint of changes from baseline to week 6 in dizziness score (assessed by questionnaire), frequency, duration, and intensity of vertigo episodes (recorded in patient diaries).RESULTS: Both treatments improved vertigo status. From a baseline mean value of 26.1 +/- 5.2 (on a 50-point scale) in the Vertigoheel group, the dizziness questionnaire score improved by -10.6 +/- 10.0, and by -10.7 +/- 9.0 from 25.8 - 4.7 in the G. biloba group. Statistical analysis of this endpoint showed that Vertigoheel was not inferior to G. biloba. The 95% confidence interval for the difference between treatment did not reach the inferiority threshold of 0.36 at any of the time points tested. The results were supported by the results of a line walking test, Unterberger's stepping test, and patient and physician global assessments of therapeutic effect. Both treatments were well tolerated.CONCLUSIONS: Vertigoheel is an appealing alternative to established G. biloba therapy for atherosclerosis-related vertigo.

42.Extract of Ginkgo biloba leaves attenuates kainate-induced increase in intracellular Ca2+ concentration of rat cerebellar granule neurons.:(Psycho:neuroprotective)

Biol Pharm Bull. 2005 May;28(5):934-6.PMID: 15863911
In order to reveal one of possible mechanisms for neuronal protective action of extract of Ginkgo biloba leaves (EGBL), the effect of EGBL on kainate- and KCl-induced increases in intracellular Ca(2+) concentration ([Ca(2+)]i) of rat cerebellar neurons was examined using a confocal laser microscope with appropriate fluorescent probes. EGBL at 3 microg/ml started to attenuate kainate-induced increase of [Ca(2+)]i and further increase in EGBL concentration (up to 30 microg/ml) concentration-dependently and significantly inhibited the kainate response. The complete inhibition by EGBL was observed in some neurons when the concentration was 10-30 microg/ml. The kainate-induced increase in [Ca(2+)]i was mainly due to Ca(2+) influx through voltage-dependent Ca(2+) channel opened by membrane depolarization via activation of kainate receptor-channel. However, the increase in [Ca(2+)]i by KCl was not significantly affected by EGBL at concentrations where the kainate response was greatly inhibited. EGBL consisting of flavone glycosides and terpene lactones is known to be an antioxidant. Furthermore, in this study, it is shown that EGBL exerts an inhibitory action on kainate receptor (a subtype of glutamate receptor). Since some of neurodegenerative diseases are due to cell death induced by glutamate excitotoxicity and oxidative stress, EGBL may be very suitable for preventing and/or treating such diseases.

43.Stabilization of mitochondrial membrane potential and improvement of neuronal energy metabolism by Ginkgo biloba extract EGb 761.:(Psycho:neuroprotective)

Ann N Y Acad Sci. 2005 Nov;1056:474-85.PMID: 16387710
Ginkgo biloba extract EGb 761 has been used for many years to treat age-related cognitive disorders including Alzheimer's disease. EGb 761 given shortly after initiating mitochondrial damage by sodium nitroprusside (nitric oxide donor) improved the mitochondrial membrane potential of PC12 cells significantly and dose dependently. Under these conditions, EGb 761 also reversed the decrease in ATP production. In addition, similar protection against oxidative damage was found in dissociated brain cells and isolated brain mitochondria after in vitro or in vivo treatment with EGb 761. Moreover, PC12 cells bearing an Alzheimer's disease-related mutation in the amyloid precursor protein, which leads to enhanced beta amyloid production, showed greater benefit from treatment with EGb 761 than did control cells. Taken together, our findings clearly show stabilization and protection of mitochondrial function as a specific and very sensitive property of EGb 761 at therapeutically relevant doses.

44.Protective effects of extract of Ginkgo biloba (EGb 761) on nerve cells after spinal cord injury in rats.:(Psycho:neuroprotective)

Spinal Cord. 2006 Nov;44(11):662-7. Epub 2006 Jan 17.PMID: 16415923
STUDY DESIGN: An experimental animal model was used to assess spinal cord injury following lateral hemitransection at thoracic spinal cord level.OBJECTIVE: To determine whether extract of Ginkgo biloba (EGb) could have a neuroprotective effect in spinal cord injury (SCI) in rats.SETTING: Department of Biological Sciences and Biotechnology, Tsinghua University, China.METHODS: A total of 72 adult rats were divided randomly into three groups: the EGb group, normal saline (NS) group, and sham operation group (sham group). After thoracic spinal cord hemitransection was performed at the level of the 9th thoracic vertebra (T9), rats in the EGb group were given 100 mg/kg EGb 761 daily, while rats in the NS group received NS. The rats in the sham group only underwent laminectomy without spinal cord hemitransection. At various time points after surgery, thoracic spinal cords were sampled and sliced for histochemistry, immunohistochemistry of inducible nitric oxide synthase (iNOS), and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) of apoptotic cells.RESULTS: Myelin staining showed that the area of cavities was small and the demyelinated zones were limited at and around the injury site of the spinal cord in the EGb group, while the area of cavities was large and the demyelinated zones were serious in the NS group. Nissl staining showed that the ratio of bilateral ventral horn neurons (transection side/uninjured side) in the EGb group was higher than that in the NS group (P<0.05). The apoptotic index and the percentage of iNOS-positive cells were lower in the EGb group than in the NS group. Furthermore, the percentage of iNOS-positive cells positively correlated with the apoptotic index (r( 2)=0.729, P<0.01) after SCI.CONCLUSION: This study demonstrated that EGb 761 could inhibit iNOS expression and have neuroprotective effect by preventing nerve cells from apoptosis after SCI in rats.

45.Molecular evidence of the neuroprotective effect of Ginkgo biloba (EGb761) using bax/bcl-2 ratio after brain ischemia in senescence-accelerated mice, strain prone-8.:(Psycho:neuroprotective)

Brain Res. 2006 May 23;1090(1):23-8. Epub 2006 May 4.PMID: 16677616
In the present studies, we investigated the molecular mechanism of one of the active ingredients of Ginkgo biloba, EGb761, to affect the levels of several apoptotic markers in six brain regions following global ischemia in senescence-accelerated mice. A 4-day treatment with EGb761 significantly decreased bax/bcl-2 ratios in all brain regions in both young and aged mice. Our findings indicate that the bax/bcl-2 ratio provides a suitable index of apoptosis and modulation of these markers may explain the neuroprotective action of EGb761.

46.The effect of Ginkgo biloba on functional measures in multiple sclerosis: a pilot randomized controlled trial.:(Psycho:neuroprotective/Multiple sclerosis)

Explore (NY). 2006 Jan;2(1):19-24.PMID: 16781604
BACKGROUND: Multiple sclerosis (MS) is a chronic demyelinating neurological disease afflicting young and middle-aged adults, resulting in problems with coordination, strength, cognition, affect, and sensation.OBJECTIVE: The objective of this study was to determine whether a ginkgo extract (EGb 761) improved functional performance in individuals with MS.DESIGN: This study used a double-blind, placebo-controlled, parallel group design. The end point was change between baseline (ie, preintervention) and follow-up evaluation following a regimen of four tablets per day at 60 mg per tablet for four weeks.SETTING: The study was conducted in academic and clinical-based settings.PATIENTS/PARTICIPANTS: Twenty-two individuals with MS were randomly assigned to either the treatment or control condition. Groups did not differ with respect to age, IQ, and education.INTERVENTION: Half of the subjects received 240 mg per day of ginkgo special extract (EGb 761), and the other half received placebo.MAIN OUTCOME MEASURE: The main outcome measures assessed depression (Center for Epidemiologic Studies of Depression Scale [CES-D]), anxiety (State-Trait Anxiety Inventory [STAI]), fatigue (Modified Fatigue Impact Scale [MFIS]); symptom severity (Symptom Inventory [SI]) and functional performance (Functional Assessment of Multiple Sclerosis [FAMS]).RESULTS: The ginkgo group had significantly more individuals showing improvement on four or more measures with improvements associated with significantly larger effect sizes on measures of fatigue, symptom severity, and functionality. The ginkgo group also exhibited less fatigue at follow-up compared with the placebo group.CONCLUSIONS: This exploratory pilot study showed that no adverse events or side effects were reported and that ginkgo exerted modest beneficial effects on select functional measures (eg, fatigue) among some individuals with MS.

47.Brain protective effects of ginkgo biloba leaf extract (ginaton) in patients undergoing hypothermic cardiopulmonary bypass:(Psycho:neuroprotective)

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2006 Sep;26(9):795-8.PMID: 17058828
OBJECTIVE: To investigate the brain protective effects of Ginkgo biloba leaf extract (Ginaton) in patients who underwent hypothermic cardiopulmonary bypass (CPB).METHODS: Sixty patients with rheumatic heart disease of ASA grade II-III, who were scheduled for mitral valve replacement with intravenous anaesthesia, were randomly assigned to two groups, the Ginaton group (30 patients) treated with Ginaton 1 mg/kg by intravenous dripping before open heart for CPB, and the control group (30 patients) with normal saline instead. Blood was synchronously collected from arteriae radialis and vena jugularis interna at 5 time points, namely, before CPB (T1), nasopharyngeal temperature (lowered to 30-31 degrees C) stabilized stage (T2), nasopharyngeal temperature restoration (36 degrees C) stage (T3), 30 min after CPB (T4) and 3 after CPB (Ts) for determining blood gas, lactate acid concentration, activity of superoxide dismutase (SOD) and malonaldehyde (MDA) content. And the oxygen content in artery (CaO2) and jugular vein (CjvO2), the difference of oxygen contents in arterial and jugular vein (Ca-jvO2), the cerebral oxygen extraction ratio (ERO2) as well as the arteriojugular lactate difference (ADVL) were calculated.RESULTS: After the beginning of CPB, as compared with those in the control group, in the Ginaton group, the reduction of Ca-jvO2 and ERO2 was significantly higher (P < 0.05 or P < 0.01) and the increase of lactate acid, ADVL and MDA were significantly lower, and with a remarkably higher SOD activity (P < 0.01).CONCLUSION: Ginaton could improve cerebral oxygen supply, promote SOD activity to inhibit production of free radicals in patients undergoing CPB, and thus shows an evident protective effect in the brain

48.Protection by EGb 761 against beta-amyloid-induced neurotoxicity: involvement of NF-kappaB, SIRT1, and MAPKs pathways and inhibition of amyloid fibril formation.:(Psycho:neuroprotective)

Free Radic Biol Med. 2006 Dec 15;41(12):1781-94. Epub 2006 Aug 25.PMID: 17157181
Abeta peptide-induced toxicity is mediated through oxidative stress and is associated with an activation of intracellular signaling such as the redox-sensitive transcription factor NF-kappaB and MAPK pathways. We demonstrate on neuroblastoma cell line N2a that EGb 761 could prevent the activation of NF-kappaB, ERK1/2, and JNK pathways induced by Abeta. Furthermore, our results show that EGb 761 can also activate SIRT1. This activation could explain the reduction of NF-kB activity by promoting the deacetylation of Lys310 of subunit p65. On the other hand, aggregation of Abeta to insoluble fibrils is a crucial step in Abeta-induced neurotoxicity. Using fluorescence spectroscopy with thioflavin T and electron microscopy, we demonstrate that EGb 761 and its flavonoid fraction (CP 205) could prevent the Abeta fibril (fAbeta) formation in vitro. Finally we show that Abeta is less toxic to N2a neuroblastoma cells when the peptide is previously incubated with the flavonoid fraction or EGb 761 during the fibril formation period. On the other hand, the ginkgolide compound BN 52021 was not able to prevent fAbeta formation. Interestingly it could also protect cells against Abeta toxicity. Our study demonstrates that the protection of neuronal cells by EGb 761 against Abeta could involve different mechanisms as the regulation of several key intracellular pathways and the inhibition of fAbeta formation and implicate more than its free radical scavenging property.

49.Ginkgo biloba extract EGb 761 attenuates hippocampal neuronal loss and cognitive dysfunction resulting from chronic restraint stress in ovariectomized rats.:(Psycho:neuroprotective)

Neuroscience. 2007 Oct 26;149(2):256-62. Epub 2007 Aug 9.PMID: 17869007
We have recently found that a combination of ovariectomy (OVX) and chronic restraint stress causes cognitive dysfunction and reduces hippocampal CA3 neurons in female rats and that estrogen replacement suppresses the OVX/stress-induced behavioral and morphological changes. In this study, we examined the effect of Ginkgo biloba extract (EGb 761), a popular herbal supplement, on the cognitive dysfunction and neuromorphological change in OVX/stress-subjected rats. Female Fisher 344 rats were randomly divided into three groups: vehicle-treated OVX, EGb 761 (50 mg/kg) -treated OVX and vehicle-treated sham-operated control groups. Two months after ovariectomy, all animals received restraint stress for 21 days (6 h/day), and were then subjected to a novel object recognition test followed by morphological examination by Nissl staining. EGb 761 was orally administered once daily until the behavioral analysis was done. Treatment with EGb 761 improved memory impairment and neuronal loss of hippocampus in the OVX/stress-subjected group in the same ways as 17beta-estradiol. On the other hand, EGb 761 did not affect the loss of bone mineral density and increase in body weight after OVX, although 17beta-estradiol attenuated them. These results have important implications for neuroprotective and cognition enhancing effects of EGb 761 in postmenopausal women and suggest that the effects are mediated by a different mechanism from estrogen.

50.Ginkgo biloba extract neuroprotective action is dependent on heme oxygenase 1 in ischemic reperfusion brain injury.:(Psycho:neuoprotective)

Stroke. 2008 Dec;39(12):3389-96. Epub 2008 Oct 9.PMID: 18845796
BACKGROUND AND PURPOSE: Ginkgo biloba extracts are now prescribed in several countries for their reported health benefits, particularly for medicinal properties in the brain. The standardized Ginkgo extract, EGb761, has been reported to protect neurons against oxidative stress, but the underlying mechanisms are not fully understood.METHODS: To characterize the oral consumption of EGb761 in transient ischemia, we performed the middle cerebral artery occlusion (MCAO) filament model in wild-type and heme oxygenase 1 (HO-1) knockouts. Mice were pretreated for 7 days before the transient occlusion or posttreated acutely during reperfusion; then neurobehavioral scores and infarct volumes were assessed. Furthermore, primary cortical neuronal cultures were used to investigate the contribution of the antioxidant enzyme HO-1 in the EGb761-associated cytoprotection.RESULTS: Mice that were pretreated with EGb761 had 50.9+/-5.6% less neurological dysfunction and 48.2+/-5.3% smaller infarct volumes than vehicle-treated mice; this effect was abolished in HO-1 knockouts. In addition to the prophylactic properties of EGb761, acute posttreatment 5 minutes and 4.5 hours after reperfusion also led to significant reduction in infarct size (P<0.01). After our previous demonstration that EGb761 significantly induced HO-1 levels in a dose- and time-dependent manner in neuronal cultures, here we revealed that this de novo HO-1 induction was required for neuroprotection against free radical damage and excitotoxicity as it was significantly attenuated by the enzyme inhibitor.CONCLUSIONS: These results demonstrate that EGb761 could be used as a preventive or therapeutic agent in cerebral ischemia and suggest that HO-1 contributes, at least in part, to EGb761 neuroprotection.

51.The effects of Ginkgo biloba extract EGb 761 on mechanical and cold allodynia in a rat model of neuropathic pain.:(Psycho:neuroprotive/neuropathic pain)

Anesth Analg. 2009 Jun;108(6):1958-63.PMID: 19448231
BACKGROUND: Neuropathic pain is chronic pain that is caused by an injury to the peripheral or central nervous system. The symptoms of neuropathic pain are continuing pain, hyperalgesia, and allodynia. Ginkgo biloba extract is an oriental herbal medicine that has various pharmacological actions. We examined the effect of Ginkgo biloba extract, EGb 761, on the mechanical and cold allodynia in a rat model of neuropathic pain.METHODS: Male Sprague-Dawley rats were prepared by tightly ligating the left L5 and L6 spinal nerves. All the rats developed mechanical and cold allodynia 7 days after surgery. Fifty neuropathic rats were assigned into five groups for the intraperitoneal administration of drugs. The study was double-blind and the order of the treatments was randomized. Normal saline and EGb 761 (50, 100, 150, and 200 mg/kg) were administered, respectively, to the individual groups. We examined mechanical and cold allodynia at preadministration and at 15, 30, 60, 90, 120, 150, and 180 min after intraperitoneal drug administration. Mechanical allodynia was quantified by measuring the paw withdrawal threshold to stimuli with von Frey filaments of 1.0, 1.4, 2.0, 4.0, 6.0, 8.0, 10.0, 12.0, 15.0, and 26.0 g. Cold allodynia was quantified by measuring the frequency of foot lift with applying 100% acetone. We measured the locomotor function of the neuropathic rats by using the rotarod test to reveal if EGb 761 has side effects, such as sedation or reduced motor coordination.RESULTS: The control group showed no differences for mechanical and cold allodynia. For the EGb 761 groups, the paw withdrawal thresholds to mechanical stimuli and withdrawal frequencies to cold stimuli were significantly reduced versus the preadministration values and versus the control group. The duration of antiallodynic effects increased in a dose-dependent fashion, and these were maintained for 120 min at the highest dose (P < 0.05). Only at the highest dose (200 mg/kg) did EGb 761 reduce the rotarod performance time.CONCLUSION: We conclude that Ginkgo biloba extract, EGb 761, attenuates mechanical and cold allodynia in a rat model of neuropathic pain, and it may be useful for the management of neuropathic pain.

52.Protective effects of Ginkgo biloba extract (EGb761) and its constituents quercetin and ginkgolide B against beta-amyloid peptide-induced toxicity in SH-SY5Y cells.:(Psycho:neuroprotive)

Chem Biol Interact. 2009 Sep 14;181(1):115-23. Epub 2009 May 21.PMID: 19464278
Ginkgo biloba extract EGb761 has been shown to protect against beta-amyloid peptide (Abeta)-induced neurotoxicity but the specific mechanisms remain unclear. In the present study, effects of EGb761 and two of its constituents, quercetin and ginkgolide B, on the cytotoxic action of Abeta (1-42) were tested with human neuroblastoma SH-SY5Y cells. We found that EGb761 was able to block Abeta (1-42)-induced cell apoptosis, reactive oxygen species (ROS) accumulation, mitochondrial dysfunction and activation of c-jun N-terminal kinase (JNK), extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt signaling pathways. Both quercetin and ginkgolide B may be involved in the inhibitory effects of EGb761 on JNK, ERK1/2 and Akt signaling pathways. Ginkgolide B also helped to improve mitochondrial functions but quercetin failed to show this effect. Additional experiments suggest that, protective effects of EGb761 against Abeta toxicity may be associated with its antioxidant and platelet activating factor (PAF) antagonist activities. Quercetin but not ginkgolide B is one of the constituents responsible for the antioxidant action of EGb761. Both quercetin and ginkgolide B may be involved in the PAF antagonist activity of EGb761. Overall, actions of individual EGb761 components provide further insights into direct mechanisms underlying the neuroprotective effects of EGb761.

53.Efficacy of Ginkgolide B in the prophylaxis of migraine with aura.:(Psycho:neuroprotective/migraine)

Neurol Sci. 2009 May;30 Suppl 1:S121-4.PMID: 19415441
In a multicentric, open, preliminary trial, we evaluated the use of ginkgolide B, a herbal constituent extract from Ginkgo biloba tree leaves, in the prophylactic treatment of migraine with aura (MA). Fifty women suffering from migraine with typical aura, or migraine aura without headache, diagnosed according to International Headache Society criteria, entered a six-month study. They underwent a two month run-in period free of prophylactic drugs, followed by a four month treatment period (subdivided into two bimesters, TI and TII) with a combination of 60 mg ginkgo biloba terpenes phytosome, 11 mg coenzyme Q 10, and 8.7 mg vitamin B2 (Migrasoll), administered twice daily. A detailed diary reporting neurological symptoms, duration, and frequency of MA was compiled by patients throughout the trial. The number of MA significantly decreased during treatment (from 3.7 +/- 2.2 in the run-in period, to 2.0 +/- 1.9 during TI and to 1.2 +/- 1.6 during TII; Anova for repeated measures: P < 0.0001). There was also a statistically significant decrease in the average MA duration, which was 40.4 +/- 19.4 min during run-in, 28.2 +/- 19.9 during TI, and 17.6 +/- 20.6 during TII. Total disappearance of MA was observed in 11.1% patients during TI and in 42.2% of patients during T2. No serious adverse event was provoked by Migrasoll administration. Ginkgolide B is effective in reducing MA frequency and duration. The effect is clearly evident in the first bimester of treatment and is further enhanced during the second.

54.Neuroprotective effect of extract of Ginkgo biloba against excitotoxicty compared with ginkgolide B in neuron cell of rat:(Psycho:neuroprotective)

Zhongguo Zhong Yao Za Zhi. 2010 Jan;35(1):114-7.PMID: 20349729
OBJECTIVE: To observe the effect of the extract of Ginkgo biloba (EGb761) and the components isolated from the extract named ginkgolide B (GB) against damage of glutamate in pretreatment modes so that determine their application value and approach.METHOD: Based on glutamate-induced excitotoxicity to primary cultures from neonatal Sprague-Dawley (SD) rat hippocampal neuron, our experiment utilized trypan blue, TUNEL and LDH to study the effect of EGb761 and GB on neuron in different doses pretreatment modes, as well as to compare with the NMDA receptor uncompetitive antagonist-MK-801.RESULT: EGb761 and GB can recrease cell viability, reduce apoptosis rate and decrease LDH leakage in different degree and depended on dose in certain range. The maximal protection was achieved at a concentration of 100 mg x L(-1), 100 micromol x L(-1), but inferior to MK-801 (10 micromol x L(-1)). The protective effect of GB is superior to EGb761.CONCLUSION: Treatment with EGb761 and GB could protect the neurons against glutamate-induced injury. The maximal protection of GB was achieved by pretreatment is superior to EGb761, so its precautionanary intervention to high-risk population could have more value.

55.Effects of Ginkgo biloba extracts on NMDA-activated currents in acutely isolated hippocampal neurons of the rat.:(Psycho:neuroprotective)

Phytother Res. 2011 Jan;25(1):137-41. doi: 10.1002/ptr.3235.PMID: 20632296
Ginkgo biloba extracts (GBE) have long been used as a traditional herbal medicine for treating central nervous system diseases and peripheral vascular diseases, but the underlying mechanisms have yet to be elucidated. Furthermore, traditional GBE is in the form of microsomes and only dissolves in organic solvents; its clinical applications have been greatly limited. Therefore, in the present study, nanometer GBE (nGBE) was prepared utilizing supercritical anti-solvent (SAS) upon CO(2) -supercritical fluid extraction (CO(2) -SPF). Using whole-cell patch clamp techniques, the effects of different preparations of GBE on N-methyl-D-aspartate (NMDA)-activated currents (I(NMDA) ) from acutely isolated rat hippocampal neurons were investigated and the difference in protective potency between nGBE and mGBE evaluated. The results showed that the inward current activated by NMDA could be depressed by mGBE and nGBE. The inhibitory rates were 40% ± 17% and 64% ± 15%, and the half-inhibition concentrations (IC(50) ) were 0.0210 ± 0.0055 and 0.0262 ± 0.0038 mg/mL, respectively. In comparison, the modulatory effect of nGBE (dissolved in extracellular solution) on NMDA-activated current was significantly greater than that of mGBE (dissolved in DMSO) (p < 0.05). This indicated that the modulatory effects of GBE on NMDA-activated current may contribute to the neuroprotective effects of GBE and the modulatory effect of nGBE on NMDA-activated current was greater than that of mGBE.

56.Effect of the herbal extract combination Panax quinquefolium and Ginkgo biloba on attention-deficit hyperactivity disorder: a pilot study.:

J Psychiatry Neurosci. 2001 May;26(3):221-8.PMID: 11394191
OBJECTIVE: A combination herbal product containing American ginseng extract, Panax quinquefolium, (200 mg) and Ginkgo biloba extract (50 mg) (AD-FX; CV Technologies, Edmonton, Alta.) was tested for its ability to improve the symptoms of attention-deficit hyperactivity disorder (ADHD).DESIGN: Open study.PATIENTS: 36 children ranging in age from 3 to 17 years who fit the diagnostic criteria for ADHD.INTERVENTIONS: AD-FX capsules were taken twice a day on an empty stomach for 4 weeks. Patients were instructed not to change any other medications during the study.OUTCOME MEASURES: At the beginning of the study, after 2 weeks, and then at the end of the 4-week trial, parents completed the Conners' Parent Rating Scale--revised, long version, a questionnaire that assesses a broad range of problem behaviours (and was used as an indication of ADHD symptom severity).RESULTS: After 2 weeks of treatment, the proportion of the subjects exhibiting improvement (i.e., decrease in T-score of at least 5 points) ranged from 31% for the anxious-shy attribute to 67% for the psychosomatic attribute. After 4 weeks of treatment, the proportion of subjects exhibiting improvement ranged from 44% for the social problems attribute to 74% for the Conners' ADHD index and the DSM-IV hyperactive-impulsive attribute. Five (14%) of 36 subjects reported adverse events, only 2 of which were considered related to the study medication.CONCLUSIONS: These preliminary results suggest AD-FX treatment may improve symptoms of ADHD and should encourage further research on the use of ginseng and Ginkgo biloba extracts to treat ADHD symptoms.

57.Effects of Ginkgolide on the development of NOS and AChE positive neurons in the embryonic basal forebrain.:

Cell Biol Int. 2006 Jun;30(6):500-4. Epub 2006 May 23.PMID: 16716609
Extract of Ginkgo biloba (EGb) has been therapeutically used for several decades to increase peripheral and cerebral blood flow so as to prevent cardiovascular and neurovascular diseases. However, the role of EGb in neuroprotective effects has received much attention recently. In this study, we investigated the effect of EGb on the development of NOS and AChE positive neurons in the rat embryonic basal forebrain. The results showed that treated with EGb, the OD of MTT staining analysis, and the numbers, the cell sizes and circumferences of NOS and AChE positive neurons were greatly promoted. These data suggest that EGb had similar effects of the neurotrophins such as NGF and BDNF in promoting the development of NOS and AChE positive neurons in the rat embryonic basal forebrain.

Xf-Ginkgo Biloba:Psychopharmacological effects:Dementia,Alzheimer's disease (AD),Parkinson disease (PD).

1.A natural and broad spectrum nootropic substance for treatment of SDAT--the Ginkgo biloba extract.:(Psycho:AD-)

Prog Clin Biol Res. 1989;317:1247-60.PMID: 2602410
The efficacy of the Ginkgo biloba extract was not only found clinically or in standardised ratings but also documented by objective data, obtained by a computerized EEG method, the DYNAMIC BRAIN MAPPING and BRAIN FUNCTION MONITORING SYSTEM (Dr. T. Itil, New York). A one year open trial comprise 25 parkinson patients with additional signs of SDAT. Data from 3 selected cases were given: The short time efficacy of the substance after the infusion and the long-term result after the oral medication. The maps showed less slower and more faster waves. Without any side effects the Ginkgo biloba extract seems to be a substance with a broad spectrum of influence. Our therapeutic findings in parkinsonian patients with SDAT and the data taken from healthy elderly volunteers revealed that the computerized EEG method may have another big advantage: It seems that the so-called anteriorisation of the Theta waves can be taken as a preclinical sign of an incipient change in brain metabolism. As a consequence--it might be that these changes are reversible by an adequate nootropic treatment. Further studies and treatment experiences must confirm these preliminary findings.

2.Natural substances in psychiatry (Ginkgo biloba in dementia).:(Psycho:dementia)

Psychopharmacol Bull. 1995;31(1):147-58.PMID: 7675979
Natural substances and/or their synthetically developed active ingredients are frequently used in medicine. In psychiatry, two of the most well known natural compounds are reserpine and Ginkgo biloba extract (EGb). EGb is among the most popular over-the-counter medicines in Europe and is also available in the United States, primarily in health food stores. Already the European medical community has recognized EGb as an effective compound in the treatment of cerebral insufficiency. In a pilot bioequivalency study, the effects of three different commercially available EGb products were examined. Findings indicated significant quantitative central nervous system (CNS) effects in, at least, one of the three. Furthermore, the CNS effects of Ginkgold were similar to other psychoactive compounds classified as cognitive activators. Recent studies in which EGb 761 demonstrated therapeutic effects in the treatment of dementia have earned EGb the approval of the German BGA (Bundesgesundheit Amt) for use in the treatment of dementia.

3.Interaction of neuroprotective substances with human brain superoxide dismutase. An in vitro study.:(Psycho:dementia)

J Neural Transm Suppl. 1995;45:271-9.PMID: 8748635
Human brain total superoxide dismutase activity (SOD) was assayed in the presence of increasing concentrations of neuroprotectives. Superoxide-dependent nitrobluetetrazolium (NBT) reduction served as control for direct radical interaction of these substances. High concentrations of the dopamimetic substances L-DOPA slightly and the monoamine oxidase B inhibitor selegiline more effectively inhibit SOD activity. The MAO-B inhibitor RO 16-6491 (N-(2-aminoethyl)-4-chlorobenzamide hydrochloride) has no effect on SOD enzyme activity. Reduced glutathione stimulates SOD activity. Moreover it exhibits slight activity in scavenging radicals in vitro. Oxidized glutathione and vitamin E are unable to do so. Ascorbic acid mimics the activity of reduced glutathione, but directly interacts with NBT reduction. Thioctic acid shows no effect on SOD activity but stimulates superoxide-dependent NBT reduction. The Ginkgo biloba extract EGb 761 is highly active in inhibiting superoxide-dependent NBT reduction as well as SOD activity.

4.Therapy approaches in cerebral cognitive deficits--neuropsychiatric aspects:(Psycho:dementia)

Wien Med Wochenschr. 1996;146(21-22):546-8.PMID: 9092214
According to the latest research the therapy of dementia includes following strategies: Above all there is a necessity for thoroughly diagnostic tests to exclude diseases which secondary induce reduced brain function. The early onset of non pharmacological treatments e.g. "brain-jogging" is essential. Pharmacological therapy with nootropics (e.g. Codergocrin, Nicergolin, Ginkgo biloba, Piracetam, Pyritinol, Naftidrofuryl) is recommended as early as possible, because they have no relevant side effects. Calcium antagonists may also be administered because of their neuroprotective properties. One pharmacological approach to enhance cholinergic functions involves inhibiting ACH-degradation by inhibiting acetylcholinesterase. Although this relatively new therapy has benefits, in some patients it has not been effective and has a potential to cause serious adverse (hepatic) events; only mild to medium severe dementias of Alzheimer's disease should be treated with this therapeutic principle. In the case of personality disorders there are psychotherapy and the administration of psychoactive drugs necessary.

5.Proof of efficacy of the ginkgo biloba special extract EGb 761 in outpatients suffering from mild to moderate primary degenerative dementia of the Alzheimer type or multi-infarct dementia.:(Psycho:AD-dementia)

Pharmacopsychiatry. 1996 Mar;29(2):47-56.PMID: 8741021
The efficacy of the ginkgo biloba special extract EGb 761 in outpatients with presenile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) according to DSM-III-R was investigated in a prospective, randomized, double-blind, placebo-controlled, multi-center study. After a 4-week run-in period, 216 patients were included in the randomized 24-week treatment period. These received either a daily oral dose of 240 mg EGb 761 or placebo. In accordance with the recommended multi-dimensional evaluation approach, three primary variables were chosen: the Clinical Global Impressions (CGI Item 2) for psychopathological assessment, the Syndrom-Kurztest (SKT) for the assessment of the patient's attention and memory, and the Nürnberger Alters-Beobachtungsskala (NAB) for behavioral assessment of activities of daily life. Clinical efficacy was assessed by means of a responder analysis, with therapy response being defined as response in at least two of the three primary variables. The data from the 156 patients who completed the study in accordance with the study protocol were taken into account in the confirmatory analysis of valid cases. The frequency of therapy responders in the two treatment groups differed significantly in favor of EGb 761, with p < 0.005 in Fisher's Exact Test. The intent-to-treat analysis of 205 patients led to similar efficacy results. Thus, the clinical efficacy of the ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type and multi-infarct dementia was confirmed. The investigational drug was found to be well tolerated.

6.Effectiveness of brief infusions with Ginkgo biloba Special Extract EGb 761 in dementia of the vascular and Alzheimer type:(Psycho:dementia)

Z Gerontol Geriatr. 1996 Jul-Aug;29(4):302-9.PMID: 8974721
In a placebo-controlled, randomized, double-blind clinical trial, 40 patients with a mean age of 68 (+/- 12.5) years suffering from moderate dementia (Alzheimer, vascular, or mixed type) according to DSM-III-R criteria were included. Severity of the disease had to correspond to stages 4 or 5 of Reisberg's Global Deterioration Scale. Infusions of either EGb 761 or placebo were administered 4 days per week for 4 weeks. Primary outcome measure was the activities of daily living as assessed by the Nürnberger-Alters-Beobachtungsskala (NAB). The Clinical Global Impressions of change (CGI, item 2) and the actual intelligence as assessed by the Kurztest für Allgemeine Intelligenz (KAI) were further target variables. No relevant group differences could be detected at baseline. After therapy, patients of the active substance group scored significantly better (p < 0.05) on each outcome measure than those who received placebo. Using a sequential testing procedure, a global significance level of p < 0.05 could be assured. Superiority of EGb 761 therapy was also found with respect to a self-rating scale for instrumental activities of daily living (Nürnberger-Alters-Alltagsaktivit?tenskala), the improvement of the most prominent symptom of illness, and the decrease of depression. Thus clinical efficacy of EGb 761 could be shown on three planes of assessment: the behavioral, the psychopathologic and the psychometric plane. It could be confirmed that, in patients with moderate dementia, short-term intravenous infusion therapy with EGb 761 results in an improvement of psychopathology and cognitive performance, which is reflected in an increased ability to cope with the demands of daily living.

7.A placebo-controlled, double-blind, randomized trial of an extract of Ginkgo biloba for dementia. North American EGb Study Group.:(Psycho:dementia)

JAMA. 1997 Oct 22-29;278(16):1327-32.PMID: 9343463
CONTEXT: EGb 761 is a particular extract of Ginkgo biloba used in Europe to alleviate symptoms associated with numerous cognitive disorders. Its use in dementias is based on positive results from only a few controlled clinical trials, most of which did not include standard assessments of cognition and behavior.OBJECTIVE: To assess the efficacy and safety of EGb in Alzheimer disease and multi-infarct dementia.DESIGN: A 52-week, randomized double-blind, placebo-controlled, parallel-group, multicenter study.PATIENTS: Mildly to severely demented outpatients with Alzheimer disease or multi-infarct dementia, without other significant medical conditions.INTERVENTION: Patients assigned randomly to treatment with EGb (120 mg/d) or placebo. Safety, compliance, and drug dispensation were monitored every 3 months with complete outcome evaluation at 12, 26, and 52 weeks.PRIMARY OUTCOME MEASURES: Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI), and Clinical Global Impression of Change (CGIC).RESULTS: From 309 patients included in an intent-to-treat analysis, 202 provided evaluable data for the 52-week end point analysis. In the intent-to-treat analysis, the EGbgroup had an ADAS-Cog score 1.4 points better than the placebo group (P=.04) and a GERRI score 0.14 points better than the placebo group (P=.004). The same patterns were observed with the evaluable data set in which 27% of patients treated with EGb achieved at least a 4-point improvement on the ADAS-Cog, compared with 14% taking placebo (P=.005); on the GERRI, 37% were considered improved with EGb, compared with 23% taking placebo (P=.003). No difference was seen in the CGIC. Regarding the safety profile of EGb, no significant differences compared with placebo were observed in the number of patients reporting adverse events or in the incidence and severity of these events.CONCLUSIONS: EGb was safe and appears capable of stabilizing and, in a substantial number of cases, improving the cognitive performance and the social functioning of demented patients for 6 months to 1 year. Although modest, the changes induced by EGb were objectively measured by the ADAS-Cog and were of sufficient magnitude to be recognized by the caregivers in the GERRI

8.Clinical efficacy of Ginkgo biloba special extract EGb 761 in dementia of the Alzheimer type.:(Psycho:dementia)

J Psychiatr Res. 1997 Nov-Dec;31(6):645-55.PMID: 9447569
Among the psychiatric illnesses associated with old age primary degenerative dementia of the Alzheimer type (DAT) has gained increasing importance in recent years. Even though a curative treatment of the disease is currently impossible, various drugs can be used to slow down its progression. In the present study the influence of oral treatment with 240 mg/day of Ginkgo bilabo special extract EGb 761 (Tebonin forte, manufactured by Dr Willmar Schwabe, Karlsruhe) on the clinical course of DAT was investigated in a double-blind, randomized, placebo-controlled parallel-group design in 20 outpatients. The duration of treatment was 3 months. The primary outcome variable was the sum score in the SKT-test for the determination of attention and memory. Other psychometric tests (trailmaking test, ADAS, CGI) and electrophysiological investigations (EEG topography) were evaluated descriptively. Although the active-treatment group, with a mean sum score of 19.67 points in the, S.K.T., had a poorer baseline level than the placebo group (18.11 points), it experienced an improvement to 16.78 points under treatment with EGb 761 whereas the placebo group deteriorated to 18.89 points. The differences between the baseline and final values formed the basis for a statistical group comparison, which gave a result favourable to EGb 761, at a significance level of p < .013. In addition to this psychometric confirmation of efficacy, certain descriptive trends were found at the psychopathological (Clinical Global Impression) and dynamic functional (EEG findings) levels, which can be interpreted as evidence of effectiveness of Ginkgo biloba special extract EGb 761 in mild to moderate dementia and of local effects in the central nervous system. Inter-group differences in the ADAS cognitive and non-cognitive subscales did not reach statistical significance, probably because of the small sample size.

9.The pharmacologic treatment of Alzheimer's disease: a guide for the general psychiatrist.:(Psycho:AD)

Can J Psychiatry. 1998 Sep;43(7):689-97.PMID: 9773218
OBJECTIVE: To review the drug treatment of Alzheimer's disease (AD) and to provide guidelines for the physician on how to integrate these treatments into the overall management of this disorder.METHOD: A qualitative review of randomized, double-blind, placebo-controlled trials of medications used to treat cognitive deficits, disease progression, agitation, psychosis, or depression in AD. A computerized search of Medline was used to identify relevant literature published during the period 1968-1998. Key words used in the search were 'randomized controlled trials,' with 'dementia' and with 'Alzheimer's disease'.RESULTS: Agents that are currently available in Canada to treat the cognitive deficits of AD include donepezil, ginkgo biloba, selegiline, and ergoloid mesylates. Donepezil and ginkgo biloba are associated with a statistically significant but clinically modest improvement in cognitive function in a substantial minority of patients with mild to moderate AD. Selegiline may have a mild beneficial effect on cognitive function in some patients with AD, but the data are inconclusive. Ergoloid mesylates have questionable efficacy in AD and can only be recommended as a last line of treatment. The results of a single trial suggest that vitamin E or selegiline (both have antioxidant properties) may slow the progression of AD. Antipsychotic medications can result in clinically significant improvement in agitation and psychosis. Carbamazepine also appears to be an effective treatment for agitation in AD, and there is preliminary evidence that the selective serotonin reuptake inhibitor citalopram reduces irritability in this disorder. There is no evidence that other nonneuroleptic medications are more efficacious than placebo in treating agitation in AD. Limited data indicate that depression in dementia responds to antidepressant medication.CONCLUSION: These data indicate that selected medications can be used to treat cognitive deficits, disease progression, agitation, psychosis, and depression in AD. However, there is considerable heterogeneity in patients' responses to these medications. Pharmacotherapy needs to be considered as a component of a package of care that also includes psychosocial and environmental interventions and support of the caregiver.

10.Combination therapy for early Alzheimer's disease: what are we waiting for?(Psycho:AD):

J Am Geriatr Soc. 1998 Oct;46(10):1322-4.PMID: 9777922
The practical pharmacological approaches currently available to palliate the cognitive and functional losses in early Alzheimer's disease (AD) include cholinesterase inhibitors (ChEI), antioxidants (e.g., vitamin E), anti-inflammatory agents, estrogen, seligiline, vasoactive agents, and ginkgo biloba. Reviewing available data on these therapies and using models from medical illnesses such as cancer and hypertension, we highlight the urgent need for evaluating combination therapies in early AD

11.The pharmacological effects of ginkgo biloba, a plant extract, on the brain of dementia patients in comparison with tacrine.:(Psycho:dementia)

Psychopharmacol Bull. 1998;34(3):391-7.PMID: 9803773
In 1994, a standardized dry extract of Ginkgo biloba leaves (SeGb), has been approved by German health authorities for the treatment of primary degenerative dementia and vascular dementia. More than 24 different brands of Ginkgo biloba extract are sold in the United States. Tacrine, also known as tetrahydroaminoacrine (THA), and donepezil are currently the only drugs approved in the United States for the treatment of Alzheimer's disease. Previous studies demonstrated that SeGb and tacrine induce significant pharmacological effects on the brains of young, healthy human males, as determined by bioelectrical activity measurements obtained using the quantitative pharmaco-electroencephalogram (QPEEG) method. The type of central nervous system (CNS) effects we have seen on computer-analyzed EEGs (CEEGs) after administration of tacrine or EGb suggests both are "cognitive activators" which are, as a class of products, characterized by a (prepost) relative increase of 7.5 to 13 Hz ("alpha") and decrease of 1.3 to 7.5 Hz ("delta" and "theta") activity. To determine whether EGb or tacrine had noticeable pharmacological effects on elderly subjects diagnosed with possible or probable Alzheimer's, the present open, uncontrolled trial was conducted. Data from 18 subjects (11 males, 7 females) at an average age of 67.4 years with light to moderate dementia (Mini Mental mean score = 23.7, ranges: 15-29 [Geriatric Depression Scale mean scores = 3.7; range: 3.2-5.4]) were analyzed for this presentation. Each subject was randomly administered a single oral "Test-Dose" of either 40 mg of tacrine or 240 mg of EGb2 in two separate sessions within 3- to 7-day intervals. Before drug administration and at 1- and 3-hour intervals after drug administration, CEEGs were recorded for a minimum of 10 minutes. The CEEGs were analyzed using Period Analysis programs we developed for QPEEG. The results indicated that both EGb and, to a lesser degree, tacrine induced pharmacological effects, as established by QPEEG measurements, in the CNS similar to those previously established in healthy, young subjects. The type of CNS effects produced by EGb (as established by HZI's CEEG psychotropic drug database) in elderly dementia patients were similar to those induced by tacrine responders as well as those seen after the administration of other "cognitive activators" (pramiracetam, vinpocetine, BMY-21502, suloctidil, and lisuride) and anti-dementia drugs approved in the United States or Europe (tacrine, donepezil, nimodipine, piracetam, and oxiracetam) from our database. The results also showed that 240 mg of EGb has typical cognitive activator CEEG profiles (responders) in more subjects (8 of 18) than 40 mg tacrine (3 of 18 subjects). Because of the small sample size, we could not test the hypothesis that subjects who showed cognitive activator-type pharmacological response to the first Test-Dose of EGb or tacrine also exhibit more therapeutic effects (compared to nonresponders) when drugs are administered chronically.

12.The efficacy of Ginkgo biloba on cognitive function in Alzheimer disease.:(Psycho:AD-cognitive)

Arch Neurol. 1998 Nov;55(11):1409-15.PMID: 9823823
OBJECTIVE: To determine the effect of treatment with Ginkgo biloba extract on objective measures of cognitive function in patients with Alzheimer disease (AD) based on formal review of the current literature.METHODS: An attempt was made to identify all English and non-English-language articles in which G. biloba extract was given to subjects with dementia or cognitive impairment. Inclusion criteria for the meta-analysis were (1) sufficiently characterized patients such that it was clearly stated there was a diagnosis of AD by either Diagnostic and Statistical Manual of Mental Disorders, Revised Third Edition, or National Institute of Neurological Disorders and Stroke-Alzheimer's Disease and Related Disorders Association criteria, or there was enough clinical detail to determine this by our review; (2) clearly stated study exclusion criteria, ie, those studies that did not have stated exclusions for depression, other neurologic disease, and central nervous system-active medications were excluded; (3) use of standardized ginkgo extract in any stated dose; (4) randomized, placebo-controlled and double-blind study design; (5) at least 1 outcome measure was an objective assessment of cognitive function; and (6) sufficient statistical information to allow for meta-analysis.RESULTS: Of more than 50 articles identified, the overwhelming majority did not meet inclusion criteria, primarily because of lack of clear diagnoses of dementia and AD. Only 4 studies met all inclusion criteria. In total there were 212 subjects in each of the placebo and ginkgo treatment groups. Overall there was a significant effect size of 0.40 (P<.0001). This modest effect size translated into a 3% difference in the Alzheimer Disease Assessment Scale-cognitive subtest.CONCLUSIONS: Based on a quantitative analysis of the literature there is a small but significant effect of 3- to 6-month treatment with 120 to 240 mg of G. biloba extract on objective measures of cognitive function in AD. The drug has not had significant adverse effects in formal clinical trials but there are 2 case reports of bleeding complications. In AD, there are limited and inconsistent data that preclude determining if there are effects on noncognitive behavioral and functional measures as well as on clinician's global rating scales. Further research in the area will need to determine if there are functional improvements and to determine the best dosage. Additional research will be needed to define which ingredients in the ginkgo extract are producing its effect in individuals with AD.

13.Current status of antioxidant therapy for Alzheimer's Disease.:(Psycho:AD-antioxidant)

J Am Geriatr Soc. 1998 Dec;46(12):1566-72.PMID: 9848820
Accumulating evidence from preclinical and clinical studies supports the hypothesis that oxidative stress may be associated with the onset and progression of Alzheimer's Disease (AD). Antioxidant therapies are being promoted in the lay press to enhance mental functions and delay cognitive losses with aging. An increasing number of physicians are also recommending antioxidant therapies, such as high dose vitamin E, for subjects with AD and other neurodegenerative disorders. High dose vitamin E, ginkgo biloba, and selegiline are three putative antioxidants that have been tested in randomized multicenter trial conditions in the US. This paper summarizes the oxidative stress hypothesis of AD and reviews the strengths and limitations of published antioxidant studies in AD in relation to the role of such therapies in practice.

14.Medicinal plants and Alzheimer's disease: Integrating ethnobotanical and contemporary scientific evidence.:(Psycho:AD)

J Altern Complement Med. 1998 Winter;4(4):419-28.PMID: 9884179
The use of complementary medicines such as plant extracts in dementia therapy, varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive or memory enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Ginkgo biloba in which the ginkgolides have antioxidant, neuroprotective, and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo biloba extracts in Alzheimer's disease in placebo-controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Ginkgo biloba are minimal. Old European reference books (eg, medical herbals) document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activities in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (Opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically based hypothesis of cholinergic derangement in Alzheimer's disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesic and dementia-inducing properties.

15.What's new in Alzheimer's disease treatment? Reasons for optimism about future pharmacologic options.:(Psycho:AD)

Postgrad Med. 1999 Jan;105(1):109-18.PMID: 9924498
There is reason for optimism about future treatment options for Alzheimer's disease, despite uncertainties about which subgroups of patients will respond to treatment, the magnitude of therapeutic effects, the duration of benefit, and the long-term outcomes from disease-modifying agents. Because Alzheimer's disease is a heterogeneous disorder, the range of treatment responses likely will remain variable. The decision to initiate treatment must be individualized to the therapeutic goals of the patient and his or her caregiver. Advances in the understanding of the pathogenesis of Alzheimer's disease have led to new treatment strategies. Augmentation of cholinergic function through the use of acetylcholinesterase inhibitors with favorable side-effect profiles (e.g., donepezil, possibly metrifonate) can create the potential for improved memory and cognition. Antiinflammatory drugs, estrogen, alpha-tocopherol, selegiline, and ginkgo biloba are the subject of ongoing clinical trials to determine their effectiveness in Alzheimer's disease. Future treatment strategies will likely include a combination of acetylcholinesterase inhibitors and disease-modifying agents. A greater understanding of the pathogenesis of Alzheimer's disease may lead to the development of new neuroprotective agents. The long-term human and social costs, as well as potential benefits, of prolonging the natural course of the disease can only become evident with study of these agents in years to come.

16.Future scenarios for the prevention and delay of Alzheimer disease onset in high-risk groups. An ethical perspective.:(Psycho:AD)

Am J Prev Med. 1999 Feb;16(2):105-10.PMID: 10343886
CONTEXT: Alzheimer disease (AD) presents a major scientific and social challenge in our aging society. Strategies to prevent or delay onset of symptoms, as well as to prevent the decline into the advanced stage, are urgently needed. While these strategies do not yet exist in a proven and clinically applicable form, the science is progressing rapidly.OBJECTIVES: The pre-eminent goal is to identify asymptomatic persons at high risk for AD and to then apply pharmacologic and lifestyle interventions that delay onset of disease. In this scenario, genetic susceptibility testing may eventually prove accurate enough to be of use in identifying at-risk individuals decades before probable onset, allowing maximal preventive efforts. Second, an important goal is to delay or prevent the onset of moderate and advanced AD through applying compounds that slow the progression of disease, thereby allowing patients to die of unrelated ailments of old age before they lose their capacities to recognize loved ones and to communicate by speech.CONCLUSIONS: This article provides a discussion of these strategies with attention to a variety of ethical issues that should be of concern to physicians and caregivers. An assessment of the scientific evidence for preventing or delaying AD should be coupled with values analysis.

17.Medicinal plants and Alzheimer's disease: from ethnobotany to phytotherapy.:(Psycho:AD)

J Pharm Pharmacol. 1999 May;51(5):527-34.PMID: 10411211
The use of complementary medicines, such as plant extracts, in dementia therapy varies according to the different cultural traditions. In orthodox Western medicine, contrasting with that in China and the Far East for example, pharmacological properties of traditional cognitive- or memory-enhancing plants have not been widely investigated in the context of current models of Alzheimer's disease. An exception is Gingko biloba in which the gingkolides have antioxidant, neuroprotective and cholinergic activities relevant to Alzheimer's disease mechanisms. The therapeutic efficacy of Ginkgo extracts in Alzheimer's disease in placebo controlled clinical trials is reportedly similar to currently prescribed drugs such as tacrine or donepezil and, importantly, undesirable side effects of Gingko are minimal. Old European reference books, such as those on medicinal herbs, document a variety of other plants such as Salvia officinalis (sage) and Melissa officinalis (balm) with memory-improving properties, and cholinergic activities have recently been identified in extracts of these plants. Precedents for modern discovery of clinically relevant pharmacological activity in plants with long-established medicinal use include, for example, the interaction of alkaloid opioids in Papaver somniferum (opium poppy) with endogenous opiate receptors in the brain. With recent major advances in understanding the neurobiology of Alzheimer's disease, and as yet limited efficacy of so-called rationally designed therapies, it may be timely to re-explore historical archives for new directions in drug development. This article considers not only the value of an integrative traditional and modern scientific approach to developing new treatments for dementia, but also in the understanding of disease mechanisms. Long before the current biologically-based hypothesis of cholinergic derangement in Alzheimer' s disease emerged, plants now known to contain cholinergic antagonists were recorded for their amnesia- and dementia-inducing properties.

18.Diagnosis and management of Alzheimer disease.:(Psycho:AD)

J Am Board Fam Pract. 1999 Sep-Oct;12(5):375-85.PMID: 10534086
BACKGROUND: Alzheimer disease afflicts millions of older Americans, with an estimated cost to society approaching $100 million annually. Family physicians will care for an increasing number of patients with Alzheimer disease as well as their caregivers and families.METHODS: A comprehensive and systematic review of the literature published between 1985 and 1998 about diagnosing and treating Alzheimer disease was conducted, using "dementia," "Alzheimer's disease," and "treatment" as search strategy key words. Data and information that reported significant conclusions were critically reviewed. Potentially important new data about new agents that might be of benefit when caring for patients with Alzheimer disease are discussed.RESULTS AND CONCLUSIONS: The primary goals when treating Alzheimer disease patients are enhancing autonomy and functional abilities and maintaining quality of life for patients and caregivers. In addition to diagnostic and pharmacologic treatment, primary care physicians will be called upon to provide nonpharmacologic support to assist with behavioral, social, and living environment problems faced by these patients and their families. The most common pharmacologic treatment is cholinesterase inhibition. Two cholinesterase inhibitors, tacrine and donepezil, are effective in treating cognitive and global function. Newer cholinesterase inhibitors should soon be available that might offer safety advantages as well as efficacy in treating behavioral and psychiatric symptoms related to Alzheimer disease. Other agents, including vitamin E, nonsteroidal anti-inflammatory drugs, estrogen, and Ginkgo biloba, are under investigation. Nonpharmacologic measures are important components in the management of Alzheimer disease. Support groups can help to diminish behavioral problems, maintain the patient's independence, and provide relief for caregivers and families.

19.Oxidative stress and Alzheimer disease.:(Psycho:AD)

Am J Clin Nutr. 2000 Feb;71(2):621S-629S.PMID: 10681270
Research in the field of molecular biology has helped to provide a better understanding of both the cascade of biochemical events that occurs with Alzheimer disease (AD) and the heterogeneous nature of the disease. One hypothesis that accounts for both the heterogeneous nature of AD and the fact that aging is the most obvious risk factor is that free radicals are involved. The probability of this involvement is supported by the fact that neurons are extremely sensitive to attacks by destructive free radicals. Furthermore, lesions are present in the brains of AD patients that are typically associated with attacks by free radicals (eg, damage to DNA, protein oxidation, lipid peroxidation, and advanced glycosylation end products), and metals (eg, iron, copper, zinc, and aluminum) are present that have catalytic activity that produce free radicals. beta-Amyloid is aggregated and produces more free radicals in the presence of free radicals; beta-amyloid toxicity is eliminated by free radical scavengers. Apolipoprotein E is subject to attacks by free radicals, and apolipoprotein E peroxidation has been correlated with AD. In contrast, apolipoprotein E can act as a free radical scavenger and this behavior is isoform dependent. AD has been linked to mitochondrial anomalies affecting cytochrome-c oxidase, and these anomalies may contribute to the abnormal production of free radicals. Finally, many free radical scavengers (eg, vitamin E, selegeline, and Ginkgo biloba extract EGb 761) have produced promising results in relation to AD, as has desferrioxamine-an iron-chelating agent-and antiinflammatory drugs and estrogens, which also have an antioxidant effect.

20.Treatment options for Alzheimer's disease.:(Psycho:AD)

J Am Osteopath Assoc. 1999 Sep;99(9 Suppl):S6-8.
An understanding of the basic pathophysiology and molecular mechanisms of Alzheimer's disease is essential to effective treatment of the disease. Despite multiple hypotheses related to the development and progression of Alzheimer's disease, no unifying theory is currently available. Inflammation, oxidation stress, estrogen hormone status, pathways for production of beta-amyloid42, apolipoprotein E state, cholinergic neuron depletion, and head injury are all possible contributors and therefore provide points of intervention or potential intervention in the development and progression of Alzheimer's disease. Thus, this article reviews current therapeutic modalities, including estrogen replacement therapy, Ginkgo biloba, and the two cholinesterase inhibitors approved in the United States, tacrine and donepezil.

21.Practice guidelines for the diagnosis and treatment of Alzheimer's disease in a managed care setting: Part II--Pharmacologic therapy. Alzheimer's Disease (AD) Managed Care Advisory Council.:(Psycho:AD)

Manag Care Interface. 2000 Jan;13(1):51-6.PMID: 10747691
The progressive loss of social and physical functioning associated with Alzheimer's disease (AD) results in extensive social and economic costs to society. The early diagnosis and treatment of AD may reduce cognitive and behavioral symptoms of this disease and may slow disease progression, thereby alleviating some of these social and economic costs. The Alzheimer's Disease Managed Care Advisory Council, a panel of experts from managed care, academic medicine, and the Los Angeles chapter of the Alzheimer's Association was convened to synthesize current evidence-based recommendations for AD diagnostic and treatment guidelines and to integrate these guidelines for use in MCOs. This paper presents conclusions from this panel and provides an algorithm for the treatment of AD specifically for managed care settings. When combined with other necessary efforts to educate providers, these guidelines should improve the cost-effectiveness and quality of care for individuals with dementia in managed care.

22.Clinical issues in current drug therapy for dementia.:(Psycho:dementia)

Alzheimer Dis Assoc Disord. 2000;14 Suppl 1:S103-8.PMID: 10850737
Dementia resulting from Alzheimer disease is one of the most prevalent medical problems. Elaborate expert guidelines for the diagnosis and treatment of Alzheimer disease do not always take sufficient account of the resources available in general practice. The focus on pure Alzheimer disease can be inappropriate for the large proportion of mixed dementia cases in old age. Because of such guidelines, treatment with modern and effective drugs is often delayed until conservative dementia criteria are satisfied. Criteria for the discontinuation of antidementia drugs are highly questionable. Antidementia drug sales in Germany demonstrate that the majority of prescribers hold on to conservative attitudes and prefer Ginkgo biloba and memantine to acetylcholinesterase inhibitors. Disappointment after exaggerated expectations and financial restrictions in the health care sector may aggravate current underprescribing of antidementia drugs. Even though contemporary symptomatic treatments for Alzheimer disease are unsatisfactory, modern medicine has been very successful in the early diagnosis and treatment of other potential causes of dementia. Future strategies will include models for the early identification of individuals carrying a high risk of developing cognitive impairment during their lifetime.

23.A 26-week analysis of a double-blind, placebo-controlled trial of the ginkgo biloba extract EGb 761 in dementia.:(Psycho:dementia)

Dement Geriatr Cogn Disord. 2000 Jul-Aug;11(4):230-7.PMID: 10867450
This intent-to-treat (ITT) analysis was performed to provide a realistic image of the efficacy that could be expected after 26 weeks treatment with a 120-mg dose (40 mg t.i.d.) of EGb 761 (EGb). The data were collected during a 52-week, double-blind, placebo-controlled, fixed dose, parallel-group, multicenter study. Patients were mildly to severely impaired and diagnosed with uncomplicated Alzheimer's disease or multi-infarct dementia according to ICD-10 and DSM-III-R criteria. The primary outcome measures included the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Geriatric Evaluation by Relative's Rating Instrument (GERRI) and Clinical Global Impression of Change. From 309 patients included in the ITT analysis, 244 patients (76% for placebo and 73% for EGb) actually reached the 26th week visit. In comparison to the baseline values, the placebo group showed a statistically significant worsening in all domains of assessment, while the group receiving EGb was considered slightly improved on the cognitive assessment and the daily living and social behavior. Mean treatment differences favored EGb with 1.3 and 0.12 points, respectively, on the ADAS-Cog (p = 0.04) and the GERRI (p = 0.007). In the group receiving EGb, 26% of the patients achieved at least a 4-point improvement on the ADAS-Cog, compared to 17% with placebo (p = 0.04). On the GERRI, 30% of the EGb group improved and 17% worsened, while the placebo group showed an opposite trend with 37% of patients worsening for 25% improved (p = 0.006). Regarding safety, no differences between EGb and placebo were observed.

24.Reactive oxygen species-induced apoptosis in PC12 cells and protective effect of bilobalide.:(Psycho:AD-dementia-neuroprotective)

J Pharmacol Exp Ther. 2000 Jun;293(3):982-8.PMID: 10869401
Although clinical studies have demonstrated that EGb 761, a standard extract of Ginkgo biloba, was effective in mild-to-moderate dementia of the Alzheimer's disease patients, the mechanism underlying its neuroprotective effect remains unclear. In this study, effects of bilobalide, the main constituent of the nonflavone fraction of EGb 761, on reactive oxygen species (ROS)-induced apoptosis in PC12 cells was studied. Exposure of cells to xanthine (100 microM)/xanthine oxidase (150 mU/ml) (ROS producer) resulted in a characteristic DNA fragmentation and an increase in the apoptosis rate. When p53, c-Myc, Bcl-2, Bcl-x(L), and Bax were measured by flow cytometry and the activities of caspase-1- and caspase-3-like protease determined with Ac-YVAD-AMC or Ac-DEVD-AMC as substrates, the profile of ROS-induced changes in these apoptosis regulatory and effector proteins suggests that elevation of c-Myc, p53, and Bax and activation of caspase-3 play an important role in the apoptosis. When cells were treated with ROS and bilobalide (25-100 microM) simultaneously, a dose-dependent reduction in the apoptotic rate was found. The percentage of cells with positive staining for c-Myc and p53 decreased from 27.8 and 50.1% to 16.7 and 23.2%, respectively, when bilobalide (25 microM) was present. Bilobalide also reduced ROS-induced elevation of Bax and activation of caspase-3 effectively. Our results provide the first direct evidence that bilobalide can protect neurons against oxidative stress. Bilobalide may block the apoptosis in the early stage and then attenuate the elevation of c-Myc, p53, and Bax and activation of caspase-3 in cells.

25.The Ginkgo biloba extract (EGb 761) protects hippocampal neurons against cell death induced by beta-amyloid.:(Psycho:AD)

Eur J Neurosci. 2000 Jun;12(6):1882-90.PMID: 10886329
Substantial evidence suggests that the accumulation of beta-amyloid (Abeta)-derived peptides, and to a lesser extent free radicals, may contribute to the aetiology and/or progression of Alzheimer's disease (AD). Ginkgo biloba extract (EGb 761) is a well-defined plant extract containing two major groups of constituents, i.e. flavonoids and terpenoids. It is viewed as a polyvalent agent with a possible therapeutic use in the treatment of neurodegenerative diseases of multifactorial origin, e.g. AD. We have investigated here the potential effectiveness of EGb 761 against toxicity induced by (Abeta)-derived peptides (Abeta25-35, Abeta1-40 and Abeta1-42) on hippocampal primary cultured cells, this area being severely affected in AD. A co-treatment with EGb 761 concentration-dependently (10-100 microg/mL) protected hippocampal neurons against toxicity induced by Abeta fragments, with a maximal and complete protection at the highest concentration tested. Similar, albeit less potent protective effects were seen with the flavonoid fraction of the extract (CP 205), while the terpenes were ineffective. Most interestingly, EGb 761 (100 microg/mL) was even able to protect (up to 8 h) hippocampal cells from a pre-exposure to Abeta25-35 and Abeta1-40. EGb 761 was also able to both protect and rescue hippocampal cells from toxicity induced by H2O2 (50-150 microM), a major peroxide possibly involved in mediating Abeta toxicity. Moreover, EGb 761 (10-100 microg/mL), and to a lesser extent CP 205 (10-50 microg/mL), completely blocked Abeta-induced events, e.g. reactive oxygen species accumulation and apoptosis. These results suggest that the neuroprotective effects of EGb 761 are partly associated with its antioxidant properties and highlight its possible effectiveness in neurodegenerative diseases, e.g. AD via the inhibition of Abeta-induced toxicity and cell death.

26.Effect of Ginkgo biloba extract (EGb 761) on rats in an experimental model of acute encephalopathy after total body irradiation:(Psycho:AD)

27.The efficacy of ginkgo for elderly people with dementia and age-associated memory impairment: new results of a randomized clinical trial.:(Psycho:dementia)

J Am Geriatr Soc. 2000 Oct;48(10):1183-94.PMID: 11037003
OBJECTIVES: To evaluate the efficacy, the dose-dependence, and the durability of the effect of the ginkgo biloba special extract EGb 761 (ginkgo) in older people with dementia or age-associated memory impairment.DESIGN: A 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial.SETTING: Homes for the elderly in the southern part of the Netherlands.PARTICIPANTS: Older persons with dementia (either Alzheimer's dementia or vascular dementia; mild to moderate degree) or age-associated memory impairment (AAMI). 214 Participants were recruited from 39 homes for the elderly.INTERVENTION: The participants were allocated randomly to treatment with EGb 761 (2 tablets per day, total dosage either 240 (high dose) or 160 (usual dose) mg/day) or placebo (0 mg/d). The total intervention period was 24 weeks. After 12 weeks of treatment, the initial ginkgo users were randomized once again to either continued ginkgo treatment or placebo treatment. Initial placebo use was prolonged after 12 weeks.MEASUREMENTS: Outcomes were assessed after 12 and 24 weeks of intervention. Outcome measures included neuropsychological testing (trail-making speed (NAI-ZVT-G), digit memory span (NAI-ZN-G), and verbal learning (NAI-WL)), clinical assessment (presence and severity of geriatric symptoms (SCAG), depressive mood (GDS), self-perceived health and memory status (report marks)), and behavioral assessment (self-reported level of instrumental daily life activities).RESULTS: An intention-to-treat analysis showed no effect on each of the outcome measures for participants who were assigned to ginkgo (n = 79) compared with placebo (n = 44) for the entire 24-week period. After 12 weeks of treatment, the combined high dose and usual dose ginkgo groups (n = 166) performed slightly better with regard to self-reported activities of daily life but slightly worse with regard to self-perceived health status compared with the placebo group (n = 48). No beneficial effects of a higher dose or a prolonged duration of ginkgo treatment were found. We could not detect any subgroup that benefited from ginkgo. Ginkgo use was also not associated with the occurrence of (serious) adverse events.CONCLUSIONS: The results of our trial suggest that ginkgo is not effective as a treatment for older people with mild to moderate dementia or age-associated memory impairment. Our results contrast sharply with those of previous ginkgo trials.

28.Oxidative injury in diseases of the central nervous system: focus on Alzheimer's disease.:(Psycho:AD)

Am J Med. 2000 Nov;109(7):577-85.PMID: 11063960
Alzheimer's disease is one of the most challenging brain disorders and has profound medical and social consequences. It affects approximately 15 million persons worldwide, and many more family members and care givers are touched by the disease. The initiating molecular event(s) is not known, and its pathophysiology is highly complex. However, free radical injury appears to be a fundamental process contributing to the neuronal death seen in the disorder, and this hypothesis is supported by many (although not all) studies using surrogate markers of oxidative damage. In vitro and animal studies suggest that various compounds with antioxidant ability can attenuate the oxidative stress induced by beta-amyloid. Recently, clinical trials have demonstrated potential benefits from treatment with the antioxidants, vitamin E, selegiline, extract of Gingko biloba, and idebenone. Further studies are warranted to confirm these findings and explore the optimum timing and antioxidant combination of such treatments in this therapeutically frustrating disease.

29.Cholinesterase inhibitors and Gingko extracts--are they comparable in the treatment of dementia? Comparison of published placebo-controlled efficacy studies of at least six months' duration.:(Psycho:dementia)

Phytomedicine. 2000 Jan;6(6):393-401.PMID: 10755847
The efficacy of four cholinesterase inhibitors (tacrine, donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 in Alzheimer's disease were compared. The differences in the effects of the active substance and placebo on cognition were measured on the ADAS-Cog scale, taking into account the different degrees of dementia in the various studies and the dropout rate due to adverse drug reactions. Efficacy, expressed as the delay in symptom progression or the difference in response rate between active substance and placebo, showed no major differences between the four cholinesterase inhibitors and the Ginkgo special extract. Only tacrine exhibited a high dropout rate due to adverse drug reactions. In view of this, the subject of new prescriptions should be critically reviewed. Second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) and Ginkgo special extract EGb 761 should be considered equally effective in the treatment of mild to moderate Alzheimer's dementia.

30.The Ginkgo biloba extract EGb 761 rescues the PC12 neuronal cells from beta-amyloid-induced cell death by inhibiting the formation of beta-amyloid-derived diffusible neurotoxic ligands.:(Psycho:AD)

Brain Res. 2001 Jan 19;889(1-2):181-90.PMID: 11166702
beta Amyloid (Abeta) treatment induced free radical production and increased glucose uptake, apoptosis and cell death in PC12 nerve cells. Addition of the standardized extract of Ginkgo biloba leaves, EGb 761 together with the Abeta protein prevented, in a dose-dependent manner, the Abeta-induced free radical production, increased glucose uptake, apoptosis and cell death. However, pretreatment of the cells with EGb 761 did not rescue the cells from the Abeta-induced toxicity although it prevented the Abeta-induced reactive oxygen species generation. Moreover, the terpene and flavonoid-free EGb 761 extract, HE 208, although inhibited the Abeta-induced increased glucose uptake, it failed to protect the cells from apoptosis and cytotoxicity induced by Abeta. In conclusion, these results indicate that the terpenoid and flavonoid constituents of EGb 761, acting probably in combination with components present in HE 208, are responsible for rescuing the neuronal cells from Abeta-induced apoptosis and cell death; their mechanism of action being distinct of their antioxidant properties. Because pre- and post-treatment with EGb 761 did not protect the cells from Abeta-induced neurotoxicity, we examined whether EGb 761 interacts directly with Abeta. Indeed, in vitro reconstitution studies demonstrated that EGb 761 inhibits, in a dose-dependent manner, the formation of beta-amyloid-derived diffusible neurotoxic soluble ligands (ADDLs), suggested to be involved in the pathogenesis of Alzheimer's disease.

31.Protective effect and mechanism of Ginkgo biloba leaf extracts for Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.:(Psycho:Neuroprotective/PD)

Acta Pharmacol Sin. 2001 Dec;22(12):1089-93.PMID: 11749805
AIM: To observe the effects of extracts of Ginkgo biloba leaves (EGb) on the Parkinson disease (PD) models induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its ion 1-methyl-4-phenylpyridinium (MPP+).METHODS: MPTP was microinjected into substantia nigra of rats to induce a behavior change of rotation. EGb (ip, 50 or 100 mg.kg(1 . d-1) was pretreated consecutively for 19 d before MPTP administered and 1 d after MPTP administered. The contents of malondialdehyde (MDA), superoxide dismutase (SOD), and dopamine (DA) in substantia nigra of model rats were determined. Apoptosis of PC12 cells was induced by MPP+, and the protective effect of EGb (25, 50, and 100 mg/L) was also observed. The cells of apoptosis were observed under a microscope and counted under a fluoroscope after stained with AO/EB.RESULTS: EGb (100 mg . kg-1 . d-1) decreased the duration and frequency of the rotation of rats (P < 0.05, n = 10 ) while EGb (50 or 100 mg/L)inhibited the decreases of DA and SOD and the increase of MDA induced by MPTP, (P < 0.05 or P < 0.01, n = 10). MPP+ (10 micromol/L) induced the apoptosis of PC12 cells, and EGb (50 or 100 mg/L) prevented cells from apoptosis at 6 h, 12 h, and 24 h (P < 0.05 or P < 0.01, n = 3).CONCLUSION: EGb possesses protective effect on the PD models in vivo and in vitro. The anti-oxidation and anti-apoptosis may be one of the mechanisms underlying the neuroprotective effect of EGb.

32.A comparison of cholinesterase inhibitors and ginkgo extract in treatment of Alzheimer dementia:(Psycho:dementia)

Fortschr Med Orig. 2001 Nov 29;119(3-4):135-8.PMID: 11789125
AIM: To compare the effectiveness of second-generation cholinesterase inhibitors (donepezil, rivastigmine, metrifonate) with that of the special ginkgo extract EGb 761R in Alzheimer's disease.METHOD: Analysis of the effect on cognition with the aid of the ADAS-cog.scale, placebo-adjusted, within six months; statistical evaluation of the effect using the confidence interval for the potential mean improvement.RESULTS: All medications are statistically significantly superior to placebo. The mean improvement is larger for the cholinesterase inhibitors than for the ginkgo extract. In the statistically unfavorable case, the effect of the cholinesterase inhibitors is still appreciable, but not for the ginkgo extract.CONCLUSION: Until the results of direct comparative studies are available, the present results indicate a superior effect of cholinesterase inhibitors over the ginkgo extract in the treatment of mild to moderate Alzheimer's disease.

33.Influence of the severity of cognitive impairment on the effect of the Gnkgo biloba extract EGb 761 in Alzheimer's disease.:(Psycho:AD)

Neuropsychobiology. 2002;45(1):19-26.PMID: 11803237
OBJECTIVE: To explore the treatment effect of EGb 761((R)) (EGb) in Alzheimer's disease depending on baseline severity.METHODS: We applied stratification to the intent-to-treat data set collected during a 52-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter study with 120 mg of EGb, using cutoff points of 23 and 14 for the Mini-Mental State Examination (MMSE) score. Outcome measures used were the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog) and the Geriatric Evaluation by Relative's Rating Instrument (GERRI).RESULTS: In the severity stratum 1 (MMSE >23), the placebo group did not show significant changes, while the EGb group improved significantly by 1.7 points on the ADAS-Cog and by 0.09 points on the GERRI. In the severity stratum 2 (MMSE <24), the placebo group worsened by 4.1 points on the ADAS-Cog and 0.18 points on the GERRI, whereas the EGb group showed 60% less decline on the ADAS-Cog (treatment difference of 2.5 points) and no change on the GERRI (treatment difference of 0.25 points). The most severely impaired subgroup (MMSE <15) showed slightly more pronounced worsening for both treatment groups. However, in comparison to placebo, EGb induced virtually the same magnitude of effect as was observed in the entire stratum 2.CONCLUSIONS: The results of this retrospective analysis indicated that a treatment effect favorable to EGb could be observed with respect to cognitive performance (p = 0.02) and social functioning (p = 0.001) regardless of the stage of dementia, whether mild or moderately severe. However, the relative changes from baseline measured at endpoint depended heavily on the severity at baseline. Improvement was observed in the group of patients with very mild to mild cognitive impairment, while in more severe dementia, the mean EGb effect should be considered more in terms of stabilization or slowing down of worsening, as compared to the greater deterioration observed with placebo.

34.Symptomatic therapy of Alzheimer dementia:(Psycho:dementia)

Wien Med Wochenschr. 2002;152(3-4):77-80.PMID: 11925776
No causal treatment or highly effective preventive strategies are available for Alzheimer's disease to date. Symptomatic measures are still essential to improve cognitive and behavioural deficits. Acetylcholinesterase inhibitors, the NMDA-antagonist memantine and the phytopharmaco ginkgo biloba are currently the substances most extensively studied and most widely used to improve cognition and activities of daily living. Behavioural disturbances oftentimes respond to antidementia drugs, but may demand specific treatment with neuroleptics, antidepressants, stabilizers and other substances.

35.Dementing disorders. What benefits do the new anti-dementia drugs have?:(Psycho:dementia)

MMW Fortschr Med. 2002 May 6;Suppl 2:24-6, 28-9.
A critical analysis of the latest studies and meta-analyses dealing with antidementia agents, show that the efficacy of donepezil, galantamine, ginkgo biloba EGb 761, memantine, rivastigmine and tacrine in Alzheimer's disease is adequately confirmed. With the exception of tacrine, none of these substances are commonly associated with severe side effects. In the case of vascular dementia, the efficacy of ginkgo biloba EGb 761 and memantine has been demonstrated. Studies on the effectiveness of the cholinesterase inhibitors for this indication have been initiated. Antidementia agents can delay progression of the disease by about 6 to 12 months. Further studies are needed to confirm evidence of a prophylactic effect and a synergistic action of combinations.

36.Starting Alzheimer therapy in early stages whenever possible. Activities of daily living remain intact longer:(Psycho:AD)

MMW Fortschr Med. 2002 May 16;144(20):36-9.PMID: 12119881
In recent years, the efficacy of symptomatic antidementive drugs in the treatment of Alzheimer's disease (AD) has been well documented. A prerequisite for maximally effect antidementive treatment is early diagnosis and a subsequent specific diagnostic clarification. A further essential is early initiation of treatment to delay progression of the disease and thus early loss of daily skills and independence ending in the need for intensive nursing care. Currently, cholinesterase inhibitors, the efficacy of which has been confirmed in placebo-controlled multicenter studies, are recommended for the treatment of mild to moderate AD. Further substances with proven efficacy are memantine, ginkgo biloba extract EGb761 and certain classical nootropics. To treat behavioral and other psychological disturbances, symptom-related substances such as selective serotonin reuptake inhibitors and atypical neuroleptics should be employed. In addition to their positive effect on cognitive disturbances, cholinesterase inhibitors also have an appreciable impact on concomitant psychopathological symptoms.

37.Antioxidant strategies for Alzheimer's disease.:(Psycho:AD)

Proc Nutr Soc. 2002 May;61(2):191-202.PMID: 12133201
Oxidative damage is present within the brains of patients with Alzheimer's disease (AD), and is observed within every class of biomolecule, including nucleic acids, proteins, lipids and carbohydrates. Oxidative injury may develop secondary to excessive oxidative stress resulting from beta-amyloid-induced free radicals, mitochondrial abnormalities, inadequate energy supply, inflammation or altered antioxidant defences. Treatment with antioxidants is a promising approach for slowing disease progression to the extent that oxidative damage may be responsible for the cognitive and functional decline observed in AD. Although not a uniformly consistent observation, a number of epidemiological studies have found a link between antioxidant intake and a reduced incidence of dementia, AD and cognitive decline in elderly populations. In AD clinical trials molecules with antioxidant properties such as vitamin E and Ginkgo biloba extract have shown modest benefit. A clinical trial with vitamin E is currently ongoing to determine if it can delay progression to AD in individuals with mild cognitive impairment. Combinations of antioxidants might be of even greater potential benefit for AD, especially if the agents worked in different cellular compartments or had complementary activity (e.g. vitamins E, C and ubiquinone). Naturally-occurring compounds with antioxidant capacity are available and widely marketed (e.g. vitamin C, ubiquinone, lipoic acid, beta-carotene, creatine, melatonin, curcumin) and synthetic compounds are under development by industry. Nevertheless, the clinical value of these agents for AD prevention and treatment is ambiguous, and will remain so until properly designed human trials have been performed.

38.Pharmacologic treatments of dementia.:(Psycho:dementia)

Med Clin North Am. 2002 May;86(3):657-74.PMID: 12171061
The management of dementia patients encompasses pharmacologic, behavioral, and psychosocial intervention strategies. Before pharmacologic intervention is instituted, it is important that sources of excess disability and comorbidity be eliminated or reduced. Identification of comorbid medical and psychiatric conditions, such as depression and delirium, should be identified and appropriately treated. Providing caregivers with education, support, and practical advice is a critical component of the management of the demented patient. The current standard of care for pharmacologic management of the cognitive and functional disabilities of AD consists of the combination of a cholinesterase inhibitor and high-dose vitamin E. This standard is based on the results of large-scale, double-blind, placebo-controlled trials. Cholinesterase inhibitors are the only FDA-approved pharmacologic treatments for AD. Cholinesterase inhibitors have been shown to be effective in the treatment of the cognitive, behavioral, and functional deficits of AD. Large-scale placebo-controlled trials of tacrine, donepezil, rivastigmine, and galantamine have demonstrated moderate benefits in patients with mild to moderate AD. Donepezil, rivastigmine, and galantamine are the first-line choices in the treatment of AD because of their lack of hepatotoxicity, ease of administration, few significant drug-drug interactions, and mild to moderate side effects. There are few contraindications to the use of cholinesterase inhibitors. Known hypersensitivity to a specific drug or its derivatives is the only true contraindication. Cautious administration of cholinesterase inhibitors is advised in patients who have a previous history of allergy or adverse reactions to prior cholinesterase inhibitors, severe liver disease, preexisting bradycardia, peptic ulcer disease, current alcoholism, asthma, or chronic obstructive pulmonary disease. Nausea, vomiting, diarrhea, and anorexia are the most common side effects of cholinesterase inhibitors. These gastrointestinal side effects can be minimized by gradual dose increases, administration with food, adequate hydration, and judicious use of an antiemetic. Vitamin E has been demonstrated to slow the progression of AD in several small and one large placebo-controlled trials. Because of its low cost and safety, it is recommended in addition to a cholinesterase inhibitor for the treatment of AD. There are no FDA-approved treatments for DLB and VaD. One small placebo-controlled trial demonstrated that rivastigmine may be effective in the treatment of DLB. More large-scale placebo-controlled trials are needed to confirm the results of this study. Treatment of VaD focuses on the control, identification, and management of cerebrovascular disease and vascular risk factors. Although there are no peer-reviewed reports on the efficacy of cholinesterase inhibitors for VaD or mixed AD/VaD, early reports suggest that these agents may also be effective for mixed AD/VaD. The indications for the use of cholinesterase inhibitor drugs are eventually likely to broaden to include DLB, mixed AD/VaD, and AD in its more advanced stages.

39.Inhibition of amyloid-beta aggregation and caspase-3 activation by the Ginkgo biloba extract EGb761.:(Psycho:AD/dementia)

Proc Natl Acad Sci U S A. 2002 Sep 17;99(19):12197-202. Epub 2002 Sep 4.PMID: 12213959
Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, has been used in clinical trials for its beneficial effects on brain functions, particularly in connection with age-related dementias and Alzheimer's disease (AD). Substantial experimental evidence indicates that EGb761 protects against neuronal damage from a variety of insults, but its cellular and molecular mechanisms remain unknown. Using a neuroblastoma cell line stably expressing an AD-associated double mutation, we report that EGb761 inhibits formation of amyloid-beta (Abeta) fibrils, which are the diagnostic, and possibly causative, feature of AD. The decreased Abeta fibrillogenesis in the presence of EGb761 was observed both in the conditioned medium of this Abeta-secreting cell line and in solution in vitro. In the cells, EGb761 significantly attenuated mitochondrion-initiated apoptosis and decreased the activity of caspase 3, a key enzyme in the apoptosis cell-signaling cascade. These results suggest that (i) neuronal damage in AD might be due to two factors: a direct Abeta toxicity and the apoptosis initiated by the mitochondria; and (ii) multiple cellular and molecular neuroprotective mechanisms, including attenuation of apoptosis and direct inhibition of Abeta aggregation, underlie the neuroprotective effects of EGb761.

40.Ginkgo biloba neuroprotection: Therapeutic implications in Alzheimer's disease.:(Psycho:AD/neuroprotective)

J Alzheimers Dis. 2001 Aug;3(4):401-407.PMID: 12214044
An extract of Ginkgo biloba leaves, EGb761, is becoming one of the most popular dietary supplements in the United States to enhance memory. In Europe it is a commonly prescribed drug for treatment of age-related deterioration, including degenerative dementias of the Alzheimer type (AD). Substantial experimental evidence indicates that EGb761 has neuroprotective potency under conditions such as ischemia, seizures and peripheral nerve damage. However, the mechanisms of such neuroprotective effects remain unknown, partially because of the complex chemical composition of EGb761 and the resulting so-called "polyvalent" action. This review focuses on cellular and molecular approaches towards understanding the polyvalent action of EGb761 neuroprotective effect. Two potential mechanisms of action, reducing oxidative damage and stimulating cell survival machinery, are discussed. Better understanding of the neuroprotective mechanisms of EGb761 will provide impetus for possible combination therapies and for the design of rational, "mechanism-based" strategies that target age-related neurodegeneration and Alzheimer's disease.

41.Value of Ginkgo biloba in treatment of Alzheimer dementia:(Psycho:AD/dementia)

Wien Med Wochenschr. 2002;152(15-16):418-22.PMID: 12244890
During the last decade, there has been an explosive growth of research concerning the extract of Ginkgo biloba termed Egb 761. In experimental studies, animal studies and clinical studies Ginkgo biloba has shown a similar pharmacological potency and clinical efficacy like synthetic defined drugs in the therapy of reduced cerebral performance. Ginkgo biloba special extract Egb 761 is a standardized and highly purified extract of Ginkgo leaves. Among the active constituents are the ginkgo-flavone glycosides and the terpene-lactones (ginkgolides, bilobalide). The multifactorial principle of action of Ginkgo biloba is characterized by rheological and blood-flow-promoting properties, protective effects against ischaemia and hypoxia, effects on nerve cell energy metabolism, antioedematous and myelin-protective effects, radical-scavenger activity, effects on various cerebral transmitter and receptor systems. These action principles constitute the rationale for clinical trials in vascular dementia and primary degenerative dementia of the Alzheimer type, and in mixed forms of both. The cerebral bioavailability of Ginkgo biloba extract has been demonstrated by electroencephalography. In clinical trials of different working-groups, effects of Ginkgo biloba on the cognitive performance, global function, and activities of the daily living have been found. Metaanalysis in the indication--demential disorders--comparing Ginkgo biloba versus acetylcholinesterase inhibitors have shown a similar clinical efficacy of both therapy regimens with an additional drug safety benefit for Ginkgo. Due to the clinical efficacy the WHO accepted Ginkgo biloba as an antidementiv drug and add it in January 2000 into the recent ATC-Classification Index. In future antidementive therapy drugs with an different mode of action should be given in combination. Furthermore clinical trials with fixed combinations of acetylcholinesterase inhibitors with Ginkgo biloba extracts in moderate or severe dementia would be necessary.

42.Pharmaco-economic evaluation of Ginkgo special extract EGb 761 for dementias in Austria:(Psycho:dementia)

Wien Med Wochenschr. 2002;152(15-16):427-31.PMID: 12244892
The aim of the study was to carry out an economic evaluation of the therapeutic effects achievable with ginkgo special extract Egb 761 in dementia in Austria. The care-cost savings that could be achieved with ginkgo special extract Egb 761 therapy were estimated on the basis of the extent to which it delayed growing dependency and an increasing need for care--this being ascertained from the active treatment/placebo differences on GERRI after 6 months of treatment with Egb 761 and evaluated using the rates of the Austrian Federal Care Allowance Law--and compared with the cost of this therapy. The duration of illness, the start and duration of treatment, and the Egb 761 dose were varied in a series of scenarios in a sensitivity analysis. In all the scenarios the care-cost savings exceed the costs of the ginkgo special extract Egb 761 therapy. The cost/savings ratio is most favourable when the treatment is started early and when it is used in patients with dementia of the Alzheimer type. For every month by which the transition from the stage requiring a small to moderate amount of care to the stage requiring considerable or very considerable care can be delayed, one can save 812 [symbol: see text]. Prescribing ginkgo special extract Egb 761 for dementia makes sense from the national economic viewpoint because the product can yield care-cost savings that exceed the cost of the treatment itself.

43.Ginkgo biloba extract: from molecular mechanisms to the treatment of Alzhelmer's disease.:(Psycho:AD)

Cell Mol Biol (Noisy-le-grand). 2002 Sep;48(6):613-23.PMID: 12396071
Ginkgo biloba is registered for the treatment of several diseases and disorders in Europe. In the United States, it is marketed as a dietary supplement; the French and the German agencies consider it to be effective for the treatment of several diseases, and the immense amount of clinical studies concerning Ginkgo biloba makes it worth revising the existing literature about this notable plant. A brief history of the common use of this drug will be followed by a short botanic characterization. The biochemical composition of the original drug, the leaf itself, will be described in detail together with a brief discussion of commercial extracts and the problem of studying Ginkgo biloba clinically to verify the safety and efficacy of its extracts in the treatment of disorders like Alzheimer's diseases. Aspects of molecular mechanisms modifying the efficacy of this drug will be outlined. Several agents like antioxidants, anti-inflammatory drugs, cholinergic agents, estrogens, or neurotrophic factors are in use for the treatment of this neurodegenerative disease, but none can prove fully convincing benefit. In this field, Ginkgo biloba appears as a useful and sensible supplementary medication to treat Alzheimer's disease, as it seems to be a synthesis of all the different profiles of action of the various, commonly used drugs but with less side effects.

44.Ginkgo biloba for cognitive impairment and dementia.(Psycho:dementia):

Cochrane Database Syst Rev. 2002;(4):CD003120.PMID: 12519586
BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed in Germany and France for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals.OBJECTIVES: The aim of the review is to assess the efficacy and safety of Ginkgo biloba for the treatment of patients with dementia or cognitive decline.SEARCH STRATEGY: Trials were identified on 26 June 2002 through a search of the CDCIG Specialized Register which contains records from all main medical databases (MEDLINE, EMBASE, CINAHL, PsycINFO, SIGLE,LILACS), from ongoing trials databases such as Clinicaltrials.gov and Current Controlled Trials and many other sources. The search terms used were ginkgo*, tanakan, EGB-761, EGB761 and "EGB 761".SELECTION CRITERIA: All relevant, unconfounded, randomized, double-blind controlled studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity.DATA COLLECTION AND ANALYSIS: Data for the meta-analyses are based on reported summary statistics for each study. For the intention-to-treat analyses we sought data for each outcome measure on every patient randomized, irrespective of compliance. For the analyses of completers we sought data on every patient who completed the study on treatment. For continuous or ordinal variables, such as psychometric test scores, clinical global impression scales, and quality of life scales, there are two possible approaches. If ordinal scale data appear to be approximately normally distributed, or if the analyses reported by the investigators suggest that parametric methods and a normal approximation are appropriate, then the outcome measures will be treated as continuous variables. The second approach, which may not exclude the first, is to concatenate the data into two categories which best represent the contrasting states of interest, and to treat the outcome measure as binary. For binary outcomes, the endpoint itself is of interest and the Peto method of the typical odds ratio is used.MAIN RESULTS: Overall, there are no significant differences between Ginkgo and placebo in the proportion of participants experiencing adverse events. Most studies report the analyses of data from participants who completed the treatment, there are few attempts at ITT analyses. Therefore we report completers analyses only. The CGI scale, measuring clinical global improvement as assessed by the physician, was dichotomized between participants who showed improvement and those who were unchanged or worse. There are benefits associated with Ginkgo (dose less than 200mg/day) compared with placebo at less than 12 weeks (54/63 showed improvement compared with 20/63, OR 15.32, 95% CI 5.90 to 39.80, P=<.0001), and Ginkgo (dose greater than 200mg/day) at 24 weeks (57/79 compared with 42/77, OR 2.16, 95% CI 1.11 to 4.20, P=.02). Cognition shows benefit for Ginkgo (dose less than 200mg/day) compared with placebo at 12 weeks (SMD -0.57, 95% CI -1.09, -0.05, P=0.03, random effects model), Ginkgo (greater than 200 mg/day) at 12 weeks (SMD -0.56, 95% CI -1.12 to -0.0, P=0.05), at 12 weeks (Ginkgo any dose) (SMD -0.71, 95% CI -1.23 to -0.19 P=0.008, random effects model) at 24 weeks (Ginkgo any dose) (SMD -0.17, 95% CI -0.32 to -0.02 P=0.03) and at 52 weeks (Ginkgo less than 200 mg/day) (SMD -0.41, 95% CI -0.71 to -0.11, P=<.01). Activities of Daily Living (ADL) shows benefit for Ginkgo (dose less than 200mg/day) compared with placebo at 12 weeks (SMD -1.10, 95% CI -1.79, -0.41, P=0mg/day) compared with placebo at 12 weeks (SMD -1.10, 95% CI -1.79, -0.41, P=<.01), Ginkgo (dose less than 200 mg/day ) at 24 weeks (SMD -0.25, 95% CI -0.49 to -0.00, P=.05), and at 52 weeks (Ginkgo less than 200 mg/day) (SMD -0.41, 95% CI -0.71 to -0.11, P=<.01). Measures of mood and emotional function show benefit for Ginkgo (dose less than 200 mg/day) compared with placebo at less than 12 weeks (SMD -0.51, 95% CI -0.99 to -0.03, P=.04) and Ginkgo (dose less than 200mg/day) at 12 weeks (SMD -1.94, 95% CIs -2.73, -1.15 P=<.0001). There are no significant differences between Ginkgo and placebo in the proportion of participants experiencing adverse events. There are no data available on Quality of Life, measures of depression or dependency.REVIEWER'S CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. Overall there is promising evidence of improvement in cognition and function associated with Ginkgo. However, the three more modern trials show inconsistent results. Our view is that there is need for a large trial using modern methodology and permitting an intention-to-treat analysis to provide robust estimates of the size and mechanism of any treatment effects.

45.Association of Alzheimer's disease onset with ginkgo biloba and other symptomatic cognitive treatments in a population of women aged 75 years and older from the EPIDOS study.:(Psycho:AD)

J Gerontol A Biol Sci Med Sci. 2003 Apr;58(4):372-7.PMID: 12663701
BACKGROUND: Peripheral C4A treatment (cerebral and peripheral vasotherapeutics) and especially Ginkgo biloba extracts are prescribed for a number of symptoms, particularly memory impairment, in elderly patients. It is postulated that because of its pharmacological actions, this treatment could prevent the decline of cognitive function, but no studies have been published to date to test its efficacy in prevention of Alzheimer's disease. The potential association between use of C4A treatments, in particular EGb 761 (standardized Ginkgo biloba extracts), and dementia of the Alzheimer type was investigated.METHODS: A case-control study was nested in a cohort of 1462 community-dwelling elderly women aged over 75 years. Sixty-nine women with Alzheimer-type dementia were compared with 345 paired women whose cognitive function remained normal. This study involved women whose cognitive function was evaluated at baseline by use of Pfeiffer's test and whose medication history was taken. The onset of cognitive impairment was investigated over a 7-year follow-up period. In order to study the factors associated with the onset of dementia, the data concerning women with a score of > or = 8 on Pfeiffer's test at inclusion, indicating normal cognitive function, were analyzed.RESULTS: A multivariate analysis including potential confounding factors showed that fewer women who developed Alzheimer's dementia had been prescribed C4A treatment (including EGb 761) for at least 2 years (odds ratio = 0.31, 95% confidence interval = 0.12-0.82, p =.018). Figures for EGb 761 alone were similar but did not reach statistical significance (odds ratio = 0.38, 95% confidence interval = 0.08-1.76, p =.22).CONCLUSION: These results suggest that C4A treatment may reduce the risk of developing Alzheimer's dementia in elderly women. The potential preventive effect of C4A treatments, including EGb 761, requires further examination. To establish a causal relationship, these findings have to be confirmed with prospective studies.

46.Ginkgo for elderly people with dementia and age-associated memory impairment: a randomized clinical trial.:(Psycho:dementia)

J Clin Epidemiol. 2003 Apr;56(4):367-76.PMID: 12767414
Preparations based on special extracts of the Ginkgo biloba tree are popular in various European countries. Previous studies have suggested the clinical efficacy of Ginkgo in patients with dementia, cerebral insufficiency, or related cognitive decline. However, most of these studies did not fulfill the current methodologic requirements. We assessed the efficacy of the G. biloba special extract EGb 761 in patients with dementia and age-associated memory impairment in relation to dose and duration of treatment. Our study was a 24-week, randomized, double-blind, placebo-controlled, parallel-group, multicenter trial. Study participants were elderly patients with dementia (Alzheimer disease or vascular dementia) or age-associated memory impairment (AAMI). A total of 214 participants, recruited from 39 homes for the elderly in the Netherlands, were randomly allocated to Ginkgo (either 240 mg/d or 160 mg/d) or placebo (0 mg/d). After 12 weeks, the subjects in the two Ginkgo groups were randomized to continued Ginkgo treatment or placebo treatment. Primary outcome measures in this study were the Syndrome Kurz Test (SKT; psychometric functioning), the Clinical Global Impression of change (CGI-2; psychopathology, assessed by nursing staff), and the Nuremberg Gerontopsychological Rating Scale for Activities of Daily Living (NAI-NAA; behavioral functioning). One hundred twenty-three patients received Ginkgo (n=79, 240 and 160 mg/d combined) or placebo (n=44) during the 24-week intervention period. We found no statistically significant differences in mean change of scores between Ginkgo and placebo. The differences were SKT: +0.4 (90% confidence interval [CI] -0.9-1.7); CGI-2: +0.1 (90% CI -0.3-0.4), and NAI-NAA: -0.4 (90% CI -1.9-1.2). A positive difference is in favor of Ginkgo. Neither the dementia subgroup (n=36) nor the AAMI subgroup (n=87) experienced a significant effect of Ginkgo treatment. There was no dose-effect relationship and no effect of prolonged Ginkgo treatment. The trial results do not support the view that Ginkgo is beneficial for patients with dementia or age-associated memory impairment.

47.Ginkgo extract or cholinesterase inhibitors in patients with dementia: what clinical trials and guidelines fail to consider.:(Psycho:dementia)

Phytomedicine. 2003;10 Suppl 4:74-9.PMID: 12807348
Dementia of Alzheimer's type (DAT), together with vascular dementia, is the most important indication for Ginkgo biloba extract (EGb). The therapeutic efficacy of this extract is founded on neuroprotective, metabolic and rheological effects. In addition to these mechanisms--which also form the basis of the activity of the older synthetic nootropics--the hypothesis that DAT is due to a "cholinergic deficit" at central synapses has led, over the last decade, to the development of a new group of drugs for this indication, the cholinesterase (ChE) inhibitors. Thus nowadays, EGb is competing, on the synthetic side, with the ChE inhibitors tacrine, donepezil, rivastigmine and galantamine. No direct comparative trials have been undertaken, but long-term studies lasting 24-56 weeks to demonstrate efficacy have been carried out with both groups of substances in accordance with current EU guidelines. To date, only one psychometric scale has gained general acceptance as the primary criterion of efficacy, namely the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), whose scores range from 0 to 70 (the lower the better). The initial scores of patients in the trials were between 20 and 30; the improvements after 6 months treatment (less those seen with placebo) were about 2 points under Ginkgo extract and 2 to 4 points with the ChE inhibitors. However, the relatively small differences are called into question by the occurrence of drug-specific side effects with the ChE inhibitors. Unlike the treatment with EGb, up to 90% of the patients given the ChE inhibitors developed nausea and vomiting, so there is a suspicion that methodological reasons in the sense of an "unblinding" of the treatment groups caused the apparent superiority in the intensity of the effect. In addition, the benefits of treatment were rapidly reversed after ending administration of ChE inhibitors, which did not occur to the same extent with EGb. Adverse drug reactions are more than 10 times more common with the ChE inhibitors and the treatment costs about five times higher than with EGb. Given the limited therapeutic options for DAT, treatment with EGb still appears to be the method of choice compared to the ChE inhibitors.

48.Perspectives in the treatment of vascular dementia.:(Psycho:dementia)

Drugs Today (Barc). 2000 Sep;36(9):641-53.PMID: 12847569
The diagnosis and treatment of vascular dementia (VaD) are particularly challenging because of its multiple causal lesions and the variety of its clinical presentations. Even poststroke dementia cases may be due to preexisting Alzheimer's disease. Diagnostic criteria for clinical trials have been implemented quite recently. Of the vasodilator agents, only the ergoloid mesylates have shown mild benefit. The calcium channel blocker nimodipine appears to be useful in subcortical VaD. Of the nootropic agents, memantine appears to be promising. Pentoxifylline produced significant improvement in multi-infarct VaD. Aspirin, triflusal and Ginkgo biloba extract were associated with some stabilization of dementia progression, perhaps due to their antiplatelet effects. Acetyl-cholinesterase inhibitors appear to be useful in improving memory and activities of daily living in VaD. Results of a large trial of donepezil in VaD should be available soon. Hyperbaric oxygen has been reported to be effective in Binswanger's disease. From the public health perspective, stroke prevention, particularly in atrial fibrillation, and the early and adequate treatment of arterial hypertension clearly decrease the incidence of VaD.

49.Experimental study on inhibition of neuronal toxical effect of levodopa by ginkgo biloba extract on Parkinson disease in rats.:(Psycho:neuroprotective/PD)

J Huazhong Univ Sci Technolog Med Sci. 2003;23(2):151-3.PMID: 12973934
In order to observe neuronal toxical effect of Levodopa and investigate if using Levodopa together with Ginkgo Bilobar Extract (EGb) would be an workable method to treat Parkinson disease, rat models of Parkinson disease (PD) were made by injecting 6-OHDA stereotaxically to right side of the mesencephic ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Rotational behavioral observation, TUNEL, immunocytochemistry, Nissl's body staining were performed to measure the difference between group treated by Levodopa (50 mg/kg every day for 3 days, 5 days, 7 days, L-dopa group) and group treated by Levodopa combined with EGb (100 mg/kg every day, E-D group). The results showed that in the L-dopa group, the numbers of apoptosis of substantial nigra, rings of rotational behavior were more than those in the E-D group (P < 0.05). The numbers of Nissl's cells in L-dopa group were fewer than in E-D group (P < 0.05). The results suggested that Levodopa had neur toxic effect and EGb may decrease the toxicity of levodopa. The combined use of EGb with Levodopa may be a workable method to treat PD and may be better than using Levodopa alone.

50.Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease.:(Psycho:AD)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S8-14.PMID: 13130383
The standardized Ginkgo biloba extract EGb 761(definition see editorial) has been shown to produce neuroprotective effects in different in vivo and in vitro models. Since EGb 761 is a complex mixture containing flavonoid glycosides, terpene lactones (non-flavone fraction) and various other constituents, the question arises as to which of these compounds mediates the protective activity of EGb 761. Previous studies have demonstrated that the non-flavone fraction was responsible for the antihypoxic activity of EGb 761. Thus, we examined the neuroprotective and anti-apoptotic ability of the main constituents of the non-flavone fraction, the ginkgolides A, B, C, J and bilobalide. In focal cerebral ischemia models, the administration of bilobalide (5-20 mg/kg, s. c.) 60 min before ischemia dose-dependently reduced the infarct area in mouse brain and the infarct volume in rat brain 2 days after the onset of the injury. 30 minutes of pretreatment with ginkgolide A (50 mg/kg, s. c.) and ginkgolide B (100 mg/kg, s. c.) reduced the infarct area in the mouse model of focal ischemia. In primary cultures of hippocampal neurons and astrocytes from neonatal rats, ginkgolide B (1 microM) and bilobalide (10 microM) protected the neurons against damage caused by glutamate (1 mM, 1 h) as evaluated by trypan blue staining. In addition, bilobalide (0.1 microM) was able to increase the viability of cultured neurons from chick embryo telencepalon when exposed to cyanide (1 mM, 1h). Furthermore, we attempted to find out whether ginkgolides A, B, and J and bilobalide were also able to inhibit neuronal apoptosis (determined by nuclear staining with Hoechst 33 258 and TUNEL-staining). Ginkgolide B (10 microM), ginkgolide J (100 microM) and bilobalide (1 microM) reduced the apoptotic damage induced by serum deprivation (24h) or treatment with staurosporine (200 nM, 24h) in cultured chick embryonic neurons. Bilobalide (100 microM) rescued cultured rat hippocampal neurons from apoptosis caused by serum deprivation (24h), whereas ginkgolide B (100 microM) and bilobalide (100 microM) reduced apoptotic damage induced by staurosporine (300 nM, 24h). Ginkgolide A failed to affect apoptotic damage neither in serum-deprived nor in staurosporine-treated neurons. The results suggest that some of the constituents of the non-flavone fraction of EGb 761 possess neuroprotective and anti-apoptotic capacity, and that bilobalide is the most potent one. In contrast, ginkgolic acids (100-500 microM) induced neuronal death, which showed features of apoptosis as well as of necrosis, but these constituents were removed from EGb 761 below an amount of 0.0005 %. Taking together, there is experimental evidence for a neuroprotective effect of EGb 761 that agrees with clinical studies showing the efficacy of an oral treatment in patients with mild and moderate dementia.

51.The impact of drugs against dementia on cognition in aging and mild cognitive impairment.:(Psycho:dementia)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S38-43.PMID: 13130387
OBJECTIVE: To define the actual knowledge of the impact of drugs for the treatment of dementia on the improvement of cognition in aging and mild cognitive impairment.METHOD: We conducted a Medline search for studies with the parameters drug and cognition. Only drugs that had demonstrated cognition improvements in dementia according to actual methodological standards were included. Drugs had to be approved in at least one American or European nation.RESULTS: Donepezil, galantamine, Ginkgo biloba EGb 761 (definition see editorial), memantine and rivastigmine fulfilled these criteria. There were no systematic investigations on the effects of these drugs on cognition in healthy adults or patients with mild cognitive impairment (MCI). Regarding Ginkgo biloba, two studies on MCI patients could be identified. In healthy adults, we could only include one study investigating donepezil and seven investigating Ginkgo biloba EGb 761. According to the findings, donepezil significantly increased the percentage of REM sleep and REM density, whereas REM latency was reduced. This was interpreted as a sign of improved cognition. Ginkgo biloba EGb 761 improved cognition in healthy controls according to Delayed Free Recall and Delayed Recognition of the WAIS-III and the Color Naming of the Stroop Test as well as in MCI in Digit Copying, Dual Coding Task and speed of response on a computerized version of a classification task. The highest effects were observed after 6 weeks of treatment with 180 mg/d.CONCLUSIONS: Due to the lack of standard procedures for investigating cognition improvement in healthy aging, results have to be interpreted cautiously. In healthy adults as well as in individuals categorized as having MCI, Ginkgo biloba EGb 761 improved cognition in some but not all neuropsychological tests. The single positive result with donepezil raises hope that other drugs may also contribute to cognitive improvement, even in healthy adults. However, the data do not allow any conclusions regarding an improvement following a specific "neuropsychological cluster." Studies on prevention have not been completed so far.

52.Response patterns of EGb 761 in Alzheimer's disease: influence of neuropsychological profiles.:(Psycho:AD)

Pharmacopsychiatry. 2003 Jun;36 Suppl 1:S50-5.PMID: 13130389
We conducted an exploratory analysis of the influence of baseline neuropsychological (NP) profiles on the effect of EGb 761 (definition see editorial) in Alzheimer's disease (AD). Using this perspective, we stratified the intent-to-treat data set collected during a 52-week, randomized, double-blind, placebo-controlled study with 120 mg EGb 761 based on cut-off points applied to naming and constructional praxis items of the Alzheimer's Disease Assessment Scale-Cognitive subscale (ADAS-Cog). Mean changes over baseline and percentage of responders in each NP group and overall efficacy were analyzed, using the ADAS-Cog subscale as outcome measurements for assessing cognitive performance and the Geriatric Evaluation using the Relative's Rating Instrument (GERRI) to measure social functioning. Three subgroups were identified: (1) right AD (RAD) subgroup, including 83 patients with primarily visual-constructional impairment; (2) left AD (LAD) with 25 patients showing predominant verbal deficits; (3) general AD (GAD) including 60 patients impaired in both cognitive domains. At the endpoint, the EGb 761 group of RAD showed an improvement of 1.7 points according to ADAS-Cog and 0.15 points according to GERRI, while the placebo group worsened by 1.3 and 0.02 points, respectively. The LAD patients worsened regardless of treatment; however, to a lesser degree in those receiving EGb 761 as assessed by the increase of 4.7 ADAS-Cog points and 0.13 GERRI points compared to 6.8 points and 0.20 points, respectively, for placebo. In GAD, the EGb 761 group showed minimal changes, whereas the placebo group slightly worsened on both assessments, resulting in favorable treatment differences of 1.6 ADAS-Cog points and 0.23 GERRI points. Retrospective analysis of overall efficacy indicated that a quantitative treatment effect favorable to EGb 761 could be observed in cognitive performance (p = 0.04) and social functioning (p = 0.02), even taking NP differences and baseline severity into account. However, qualitative EGb 761 effects could greatly depend on NP profiles--improvement could be expected with RAD patients, while EGb 761 effect should be considered more in terms of stabilization for GAD and delayed worsening for LAD population.

53.Elevation of oxidative free radicals in Alzheimer's disease models can be attenuated by Ginkgo biloba extract EGb 761.:(Psycho:AD)

J Alzheimers Dis. 2003 Aug;5(4):287-300.PMID: 14624024
The role of amyloid beta-peptide (Abeta) in the free-radical oxidative-stress model of neurotoxicity in Alzheimer's disease (AD) has received much attention recently. In this study, we have employed both in vitro and in vivo models displaying endogenous Abeta production to study the effects of Abeta on intracellular free radical levels. We employed a neuroblastoma cell line stably expressing an AD-associated double mutation, which exhibits both increased secretion and intracellular accumulation of Abeta when stimulated, as well as transgenic Caenorhabditis elegans constitutively expressing human Abeta. A rise in levels of hydrogen peroxide (H2O2) was observed in both in vitro and in vivo AD-associated transgenic models expressing the Abeta peptide compared with the wild type controls. Treatment of the cells or C. elegans with Ginkgo biloba extract EGb 761 significantly attenuated the basal as well as the induced levels of H2O2-related reactive oxygen species (ROS). Among individual EGb 761 components tested, kaempferol and quercetin provided maximum attenuation in both models. Furthermore, an age-dependent increase in H2O2-related ROS was observed in wild type C. elegans, which is accelerated in the AD-associated C. elegans mutant. These results support the hypothesis of the involvement of Abeta and ROS in association with AD.

54.Prevention of age-related spatial memory deficits in a transgenic mouse model of Alzheimer's disease by chronic Ginkgo biloba treatment.:(Psycho:AD)

Exp Neurol. 2003 Nov;184(1):510-20.PMID: 14637120
Alzheimer's disease (AD) is characterized by cognitive decline and deposition of beta-amyloid (Abeta) plaques in cortex and hippocampus. A transgenic mouse AD model (Tg2576) that overexpresses a mutant form of human Abeta precursor protein exhibits age-related cognitive deficits, Abeta plaque deposition, and oxidative damage in the brain. We tested the ability of Ginkgo biloba, a flavonoid-rich antioxidant, to antagonize the age-related behavioral impairment and neuropathology exhibited by Tg2576 mice. At 8 months of age, 16 female Tg2576 and 15 female wild-type (wt) littermate mice were given ad lib access to tap water or Ginkgo biloba (70 mg/kg/day in water). After 6 months of treatment, all mice received Morris water maze training (4 trials/day for 10 days) to assess hippocampal dependent spatial learning. All mice received a 60-s probe test of spatial memory retention 24 h after the 40th trial. Untreated Tg2576 mice exhibited a spatial learning impairment, relative to wt mice, while Ginkgo biloba-treated Tg2576 mice exhibited spatial memory retention comparable to wt during the probe test. Spatial learning was not different between Ginkgo biloba-treated and untreated wt mice. There were no group differences in learning to swim to a visible platform. Soluble Abeta and hippocampal Abeta plaque burden did not differ between the Tg2576 groups. Brain levels of protein carbonyls were paradoxically elevated in Ginkgo biloba-treated mice. These data indicate that chronic Ginkgo biloba treatment can block an age-dependent decline in spatial cognition without altering Abeta levels and without suppressing protein oxidation in a transgenic mouse model of AD.

55.Ginkgo biloba extract EGb 761 in dementia: intent-to-treat analyses of a 24-week, multi-center, double-blind, placebo-controlled, randomized trial.:(Psycho:dementia)

Pharmacopsychiatry. 2003 Nov;36(6):297-303.PMID: 14663654
In 1996, Kanowski et al. reported about the beneficial effects of ginkgo biloba special extract EGb 761 (240 mg/day) in outpatients with pre-senile and senile primary degenerative dementia of the Alzheimer type (DAT) and multi-infarct dementia (MID) of mild to moderate severity. The comparison of the results of this double-blind, placebo-controlled, randomized, multi-center study with other dementia studies is hampered by the fact that only the responder analysis of the per-protocol (PP) population, which was pre-specified in the protocol as confirmatory analysis, has been published in detail so far. Moreover, cognitive functioning was measured using the Syndrom-Kurztest (SKT), whereas results of other studies are based on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-cog). Therefore, the conventional intention-to-treat (ITT) analysis of this study is provided with an estimation of ADAS-cog scores based on measured SKT scores. After 24 weeks of treatment, the ITT analysis of the SKT and estimated ADAS-cog scores revealed a mean decrease in the total score by -2.1 (95 % CI: -2.7; -1.5) points and -2.7 (95 % CI: -3.5; -1.9) points, respectively, for the EGb 761 group, which indicates an improvement in cognitive function. On the contrary, the placebo group exhibited only a minimal change of -1.0 (95 % CI: -1.6; -0.3) and -1.3 (95 % CI: -2.0; -0.4) points, respectively. The changes from baseline differed significantly between treatment groups by 1.1 (SKT) and 1.4 (estimated ADAS-cog) points, respectively (P = 0.01). The Clinical Global Impression of Change (CGI, Item 2) favored the EGb 761 group with a mean difference of 0.4 points (P = 0.007). Changes in the rating related to activities of daily living (Nürnberger-Alters-Beobachtungs-Skala, NAB) showed a favorable trend for EGb 761R. A subgroup analysis regarding patients with DAT yielded comparable results. Using a decrease of at least 4 points on the estimated ADAS-cog scores as cutoff criterion for treatment response, 35 % of EGb 761-treated patients were considered responders versus only 19 % for the placebo group (P = 0.01). The results of this ITT analysis substantiate the outcomes previously obtained with a responder analysis of the per-protocol population and confirm that EGb 761 improves cognitive function in a clinically relevant manner in patients suffering from dementia. The therapeutic effect is in line with the outcome of another EGb 761 study conducted in the U.S.

56.Pathomechanisms and hypothesis-guided therapeutic strategies for late-onset Alzheimer's disease:(Psycho:AD)

Fortschr Neurol Psychiatr. 2003 Jul;71 Suppl 1:S16-26.PMID: 12947539
Even though the clinical effectiveness of the presently used pharmaceutical therapy of sporadic Alzheimer Disease seems to be proven sufficient, their effective mechanisms are much less known or are disregarded in the evaluation of the clinical effects. However, it seems to be inevitable to know both clinical effect and effective mechanisms of pharmaceutics in order to be able to judge their adversity and benefit. In reference to the pharmaceutics implemented on sporadic AD in Germany, total different effective mechanisms are shown. In consideration of the shown pathomechanisms which have been recognized for sporadic AD, therapeutic rationales on application of Ginkgo biloba extract (EGb 761) and Memantine are evident. The application of acetylcholinesterase inhibitors, often looked on as agent of choice, is to be considered critically because of the danger of the occurrence of myopathological dysfunction, resp. the Gulf War Syndrome. Sophisticated and hastily advertised therapy strategies with statins or vaccination against beta A4 should not be used because of a lack of sufficient evidence based on the pathophysiological pattern of damage as known in sporadic AD. Future development must take in account that with sporadic AD aging influences cannot or can hardly be influenced. Therapeutic goals should consist to improve the cellular energy status and the membrane functioning.

57.Pharmacological studies supporting the therapeutic use of Ginkgo biloba extract for Alzheimer's disease.:(Psycho:AD)

58.Response patterns of EGb 761 in Alzheimer's disease: influence of neuropsychological profiles:(Psycho:AD)

59.Protection of plasmid DNA by a Ginkgo biloba extract from the effects of stannous chloride and the action on the labeling of blood elements with technetium-99m.:(Psycho:AD)

Braz J Med Biol Res. 2004 Feb;37(2):267-71. Epub 2004 Jan 30.PMID: 14762583
Ginkgo biloba extract (EGb) is a phytotherapeutic agent used for the treatment of ischemic and neurological disorders. Because the action of this important extract is not fully known, assays using different biological systems need to be performed. Red blood cells (RBC) are labeled with technetium-99m (Tc-99m) and used in nuclear medicine. The labeling depends on a reducing agent, usually stannous chloride (SnCl2). We assessed the effect of different concentrations of EGb on the labeling of blood constituents with Tc-99m, as sodium pertechnetate (3.7 MBq), and on the mobility of a plasmid DNA treated with SnCl2 (1.2 microg/ml) at room temperature. Blood was incubated with EGb before the addition of SnCl2 and Tc-99m. Plasma (P) and RBC were separated and precipitated with trichloroacetic acid, and soluble (SF-P and SF-RBC) and insoluble (IF-P and IF-RBC) fractions were isolated. The plasmid was incubated with Egb, SnCl2 or EGb plus SnCl2 and agarose gel electrophoresis was performed. The gel was stained with ethidium bromide and the DNA bands were visualized by fluorescence in an ultraviolet transilluminator system. EGb decreased the labeling of RBC, IF-P and IF-RBC. The supercoiled form of the plasmid was modified by treatment with SnCl2 and protected by 40 mg/ml EGb. The effect of EGb on the tested systems may be due to its chelating action with the stannous ions and/or pertechnetate or to the capability to generate reactive oxygen species that could oxidize the stannous ion.

60.Causes and consequences of disturbances of cerebral glucose metabolism in sporadic Alzheimer disease: therapeutic implications.:(Psycho:AD)

Adv Exp Med Biol. 2004;541:135-52.PMID: 14977212
Alzheimer disease is not a single disorder. Etiologically, two different types or even diseases exist: inheritance in 5% to 10% of all Alzheimer cases versus 90% to 95% AD cases whith sporadic origin (SAD). Different susceptibility genes along with adult lifestyle risk-factors- in the case of SAD the risk factor aging- may be assumed to cause the latter disorder. There is evidence that a disturbance in the insulin signal transduction pathway may be a central and early pathophysiologic event in SAD. Both, hypercortisolemia and increased adrenergic activity, in both old age and SAD may render the function of the neuronal insulin receptor vulnerable resulting in a diminished production of ATP. The reduced availability of ATP may damage the function of the endoplasmic reticulum/Golgi apparatus/trans Golgi network generating misfolded and malfolded proteins retained in the cell. In SAD, amyloid precursor protein is found to accumulate intracellularly thus not representing the cause but a driving force in the pathogenesis of SAD. Additionally, both disturbed insulin signaling and reduced ATP forward the hyperphosphorylation of tau protein. Thus, abnormalities in oxidative brain metabolism lead to the formation of two main morphologic hallmarks of SAD: senile plaques and neurofibrillary tangles. Therefore, the therapeutic goal in SAD should be the improvement of the neuronal energy state. Findings from both basic and clinical studies showed that Ginkgo biloba extract (EGb 761) may be appropiate to approach that goal.

61.Ginkgo biloba compared with cholinesterase inhibitors in the treatment of dementia: a review based on meta-analyses by the cochrane collaboration.:(Psycho:dementia)

Dement Geriatr Cogn Disord. 2004;18(2):217-26. Epub 2004 Jun 28.PMID: 15237280
Data were derived from the Cochrane Collaboration meta-analyses of the efficacies of ginkgo, donepezil, rivastigmine and galantamine on changes in cognitive function in patients with dementia and, where necessary, were transformed to standardized mean differences. The proportion of patients discontinuing trials was used as a proxy measure of tolerability. Outcomes were assessed after 6 months of treatment. Trial data for cholinesterase inhibitors were more consistent than those for ginkgo, particularly regarding patient populations and outcome measures. Significant benefits on cognition vs. placebo were seen with donepezil, 5 and 10 mg, rivastigmine, 6-12 mg, and galantamine, 16 and 24 mg. Significant benefit vs. placebo with ginkgo was seen only when all doses were pooled. Similar proportions of patients discontinued treatment with ginkgo and placebo. Cholinesterase inhibitors were also well tolerated, although a significantly greater proportion of patients receiving active treatment discontinued vs. placebo with some doses. An evidence-based medicine approach, taking into account the quality of clinical trials, is essential when assessing the safety and efficacy of medications.

62.Ginkgolide B inhibits the neurotoxicity of prions or amyloid-beta1-42.:(Psycho:AD)

J Neuroinflammation. 2004 May 11;1(1):4.PMID: 15285798
BACKGROUND: Neuronal loss in Alzheimer's or prion diseases is preceded by the accumulation of fibrillar aggregates of toxic proteins (amyloid-beta1-42 or the prion protein). Since some epidemiological studies have demonstrated that the EGb 761 extract, from the leaves of the Ginkgo biloba tree, has a beneficial effect on Alzheimer's disease, the effect of some of the major components of the EGb 761 extract on neuronal responses to amyloid-beta1-42, or to a synthetic miniprion (sPrP106), were investigated.METHODS: Components of the EGb 761 extract were tested in 2 models of neurodegeneration. SH-SY5Y neuroblastoma cells were pre-treated with ginkgolides A or B, quercetin or myricetin, and incubated with amyloid-beta1-42, sPrP106, or other neurotoxins. After 24 hours neuronal survival and the production of prostaglandin E2 that is closely associated with neuronal death was measured. In primary cortical neurons apoptosis (caspase-3) in response to amyloid-beta1-42 or sPrP106 was measured, and in co-cultures the effects of the ginkgolides on the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia was tested.RESULTS: Neurons treated with ginkgolides A or B were resistant to amyloid-beta1-42 or sPrP106. Ginkgolide-treated cells were also resistant to platelet activating factor or arachidonic acid, but remained susceptible to hydrogen peroxide or staurosporine. The ginkgolides reduced the production of prostaglandin E2 in response to amyloid-beta1-42 or sPrP106. In primary cortical neurons, the ginkgolides reduced caspase-3 responses to amyloid-beta1-42 or sPrP106, and in co-culture studies the ginkgolides reduced the killing of amyloid-beta1-42 or sPrP106 damaged neurons by microglia.CONCLUSION: Nanomolar concentrations of the ginkgolides protect neurons against the otherwise toxic effects of amyloid-beta1-42 or sPrP106. The ginkgolides also prevented the neurotoxicity of platelet activating factor and reduced the production of prostaglandin E2 in response to platelet activating factor, amyloid-beta1-42 or sPrP106. These results are compatible with prior reports that ginkgolides inhibit platelet-activating factor, and that platelet-activating factor antagonists block the toxicity of amyloid-beta1-42 or sPrP106. The results presented here suggest that platelet-activating factor antagonists such as the ginkgolides may be relevant treatments for prion or Alzheimer's diseases.

63.Ginkgo biloba extract (Egb 761) inhibits beta-amyloid production by lowering free cholesterol levels.:(Psycho:cognitive/AD)

J Nutr Biochem. 2004 Dec;15(12):749-56.PMID: 15607648
Ginkgo biloba extract (EGb 761) can improve cognitive function in patients with Alzheimer's disease, but the molecular mechanisms underlying this effect remain undefined. Because free cholesterol may be involved in the production of beta-amyloid precursor protein and amyloid beta-peptide, key events in the development of Alzheimer's disease, we examined EGb 761 in relation to cholesterol and amyloidogenesis. In aging rats, EGb 761 treatment lowered circulating free cholesterol and inhibited the production of brain beta-amyloid precursor protein and amyloid beta-peptide. Exposure of PC12 cells to EGb 761 decreased the processing of beta-amyloid precursor protein and abolished cholesterol-induced overproduction of this protein. Exposure of human NT2 cells to EGb 761 decreased free cholesterol influx and increased free cholesterol efflux. Our findings indicate that free circulating and intracellular cholesterol levels affect the processing of beta-amyloid precursor protein and amyloidogenesis. Our findings also provide the first demonstration that EGb 761 can influence these mechanisms.

64.Delay in progression of dependency and need of care of dementia patients treated with Ginkgo special extract EGb 761:(Psycho:dementia)

Wien Med Wochenschr. 2004 Nov;154(21-22):511-4.PMID: 15638069
In studies on the efficacy of antidementia drugs, a delay in symptom progression was often postulated based on a comparison of the change upon treatment and an assumed "natural" progression. Such comparisons were usually based on the cognitive subscore of the Alzheimer's Disease Assessment Scale (ADAS-cog), using either the drug-placebo differences after randomized treatment or the changes upon active drug treatment in open-label extension studies. Considering quality of life, competence, cost of care, and economics of therapeutic measures, a delay in the progression of dependency and need of care appears to be more relevant than a delay in cognitive abilities not directly related to activities of daily living. Therefore, for dementia patients treated with the Ginkgo special extract EGb 761, the delay in loss of capacities needed to cope with the demands of daily living was estimated, based on the Geriatric Evaluation of Relative's Rating Instrument (GERRI). The drug-placebo differences documented after 26 and 52 weeks of treatment corresponded to a delay in progression by 10 and 21 months, respectively. Regarding the subgroup with dementia of the Alzheimer type, the estimated delay was 16 and 25 months, respectively. It could thus be shown that by treatment with EGb 761 the progression of dependency and need of care can be slowed down, which may have an impact on costs for care, e.g. by delaying nursing home placement.

65.Effect of Ginkgo biloba extract on neuronal apoptosis in rabbit with kaolin-induced syringomyelia:(Psycho:dementia)

Di Yi Jun Yi Da Xue Xue Bao. 2005 Jan;25(1):83-6.PMID: 15684006
OBJECTIVE: To evaluate the effect of Ginkgo biloba extract (GBE) on neuronal apoptosis in rabbits with kaolin-induced syringomyelia.METHODS: Twenty-four of 30 Chinese white rabbits were subjected to injection of 25% kaolin mixed with equal volume (0.6 ml) of cerebrospinal fluid drawn from the cisterna magna under ketamine anesthesia. Twelve of these 24 rabbits then received intravenous injection of 5 ml of GBE (5 ml/days for 14 days, GBE treatment group) while the other 12 were treated with the same amount of saline administered in similar manner (saline group). The 6 rabbits without kaolin treatment received a sham operation to serve as the control group. At different time points after the operation, the rabbits were killed and the spinal cord samples examined by immunohistochemistry.RESULTS: Histologically, ischemia and edema in the cervical cord of rabbits in GBE treatment group were less severe than those in saline group. TUNEL-positive and bax-positive neurons were less numerous in GBE treatment group than in saline group, and the former group showed more Bcl-2-positive neurons. The number of apoptotic neurons reached the peak level on day 7 after kaolin injection.CONCLUSION: GBE can ameliorate kaolin-induced hydrocephalus in the upper cervical cord and inhibit kaolin-induced neuron apoptosis.

66.Ginkgo biloba affords dose-dependent protection against 6-hydroxydopamine-induced parkinsonism in rats: neurobehavioural, neurochemical and immunohistochemical evidences.:(Psycho:anti-parkinsonian)

J Neurochem. 2005 Apr;93(1):94-104.PMID: 15773909
Ginkgo biloba extract (EGb), a potent antioxidant and monoamine oxidase B (MAO-B) inhibitor, was evaluated for its anti-parkinsonian effects in a 6-hydroxydopamine (6-OHDA) rat model of the disease. Rats were treated with 50, 100, and 150 mg/kg EGb for 3 weeks. On day 21, 2 microL 6-OHDA (10 microg in 0.1% ascorbic acid saline) was injected into the right striatum, while the sham-operated group received 2 microL of vehicle. Three weeks after 6-OHDA injection, rats were tested for rotational behaviour, locomotor activity, and muscular coordination. After 6 weeks, they were killed to estimate the generation of thiobarbituric acid reactive substances (TBARS) and reduced glutathione (GSH) content, to measure activities of glutathione-S-transferase (GST), glutathione reductase (GR), glutathione peroxidase (GPx), catalase, and superoxide dismutase (SOD), and to quantify catecholamines, dopamine (DA) D2 receptor binding, and tyrosine hydroxylase-immunoreactive (TH-IR) fibre density. The increase in drug-induced rotations and deficits in locomotor activity and muscular coordination due to 6-OHDA injections were significantly and dose-dependently restored by EGb. The lesion was followed by an increased generation of TBARS and significant depletion of GSH content in substantia nigra, which was gradually restored with EGb treatment. EGb also dose-dependently restored the activities of glutathione-dependent enzymes, catalase, and SOD in striatum, which had reduced significantly by lesioning. A significant decrease in the level of DA and its metabolites and an increase in the number of dopaminergic D2 receptors in striatum were observed after 6-OHDA injection, both of which were significantly recovered following EGb treatment. Finally, all of these results were exhibited by an increase in the density of TH-IR fibers in the ipsilateral substantia nigra of the lesioned group following treatment with EGb; the lesioning had induced almost a complete loss of TH-IR fibers. Considering our behavioural studies, biochemical analysis, and immunohistochemical observation, we conclude that EGb can be used as a therapeutic approach to check the neuronal loss following parkinsonism.

67.Ginkgolide B, a constituent of Ginkgo biloba, facilitates glutamate exocytosis from rat hippocampal nerve terminals.:(Psycho:AD)

Eur J Pharmacol. 2005 May 9;514(2-3):141-9.PMID: 15910800
Although previous studies have demonstrated that Ginkgo biloba extract has modest effects in the improvement of memory and cognitive function of the Alzheimer's disease patients, the mechanism(s) underlying its beneficial effects remain(s) unclear. In this study, the effect of ginkgolide B, one of the major constituents of Ginkgo biloba extract, on the release of endogenous glutamate from rat hippocampal nerve terminals (synaptosomes) was studied. Ginkgolide B facilitated the Ca2+-dependent release of glutamate evoked by 4-aminopyridine in a concentration-dependent manner. The facilitatory action of ginkgolide B was not due to it increasing synaptosomal excitability because ginkgolide B did not alter the 4-aminopyridine-evoked depolarization of the synaptosomal plasma membrane potential. Rather, examination of the effect of ginkgolide B on cytosolic free Ca2+ concentration revealed that the facilitation of glutamate release could be attributed to an enhancement of presynaptic voltage-dependent Ca2+ influx. Consistent with this, the ginkgolide B-mediated facilitation of glutamate release was significantly prevented in synaptosomes pretreated with a wide spectrum blocker of N-, P-, and Q-type Ca2+ channels, omega-conotoxin MVIIC. Moreover, the facilitation produced by ginkgolide B was completely abolished by the protein kinase A inhibitor, but not by the protein kinase C inhibitor. These results suggest that ginkgolide B effects a increase in protein kinase A activation, which subsequently enhances the Ca2+ entry through voltage-dependent N- and P/Q-type Ca2+ channels to cause a increase in evoked glutamate release from rat hippocampal nerve terminals. In addition, glutamate release elicited by Ca2+ ionophore (ionomycin) was also facilitated by ginkgolide B, which suggests that ginkgolide B may have a direct effect on the secretory apparatus downstream of Ca2+ entry. These actions of ginkgolide B may provide some information regarding the beneficial effects of Ginkgo biloba in the central nervous system.

68.Preliminary assessment of ginkgo biloba (Ginkofar) in patients with dementia:(Psycho:dementia)

Psychiatr Pol. 2005 May-Jun;39(3):559-66.PMID: 16149765
AIM: This preliminary open-label study was undertaken to assess the efficacy and tolerability of ginkgo biloba (Ginkofar) (manufactured by Biofarm Poznań) during a 6-month period in Alzheimer type dementia, vascular and mix dementia.METHOD: Patients were required to have at entry a diagnosis of dementia Alzheimer type or vascular according to ICD-10 criteria. The presence of both types of dementia was classified as mix dementia. 30 patients were included into the study. Overall 27 patients entered treatment and completed a 6 months period.RESULTS: Results of clinical scales (IADL, Clock Test) during period of treatment (baseline, 3 months and 6 months) were stable. MMSE results demonstrated slight benefit.CONCLUSION: The results show that ginkgo biloba was well tolerated. The patients treated with Ginkofar remaining in the study demonstrate no clinically evident loss of cognitive function.

69.The situation of patients with dementia may be rectified by Ginkgo biloba. Results of a health services research study concerning the ability of patients with dementia, quality of life of the nursing family members and total treatment costs:(Psycho:dementia)

MMW Fortschr Med. 2005 Oct 6;147 Suppl 3:127-33.PMID: 16261949
BACKGROUND AND ISSSUES: Ginkgo biloba-extracts are often used in therapy of patients with dementia. In this study, benefit and structure of Ginkgo biloba-extract EGb 761 in treatment of patients with dementia was examined.PATIENTS AND METHODS: For the assessment of quality of life of care-taking relatives and patients as well as treatment costs were documented. The study was conducted as a non-randomised, two-armed cohort study with an open design for 683 slightly or moderately demented patients, aged between 65 and 80 years. Society's perspective was taken. Barthel-Index and MMST were also documented. Because of significant differences at inclusion of both cohorts, a matched-pairs-analysis and multiple regression analysis conducted.RESULTS: According to PLC a significant improvement in quality-of-life of care-taking relatives (p < 0.001) and patients (positive mood p = 0.018, negative mood p < 0.001) was only observed in the Ginkgo-cohort. Also Barthel-Index indicated an improvement in the Ginkgo-cohort (p < or = 0,001). MMST-scores increased significantly only in the Ginkgo-cohort (p < 0.001). Average total cost per patient amounted to 3.614,75 euro in the standard-cohort, whereas these costs per patient in the Ginkgo-cohort amounted to 3.031,78 euro (p = 0.067). Results were confirmed by matched-pairs-analysis.RESULTS: Ginkgo treatment has a valid place in caretaking structure of health services. Gingko attributes to a higher quality of life for both care-takers and patients, the progression of disease is slowed down and treatment costs are lower.

70.Pharmacological strategies for the prevention of Alzheimer's disease.:(Psycho:AD)

Expert Opin Pharmacother. 2006 Jan;7(1):1-10.PMID: 16370917
This review examines key pharmacological strategies that have been clinically studied for the primary or secondary prevention of Alzheimer's disease. Much information (neuropsychological, genetic and imaging) is already available to characterise an individual's risk for developing Alzheimer's disease. However, regulatory pathways for obtaining a prevention indication are less well charted, and such trials tend to involve 3- to 7-year studies of 1000 - 5000 individuals, depending on baseline status. Treatments developed for prevention will also need to have superior safety. For these reasons, > 100 proprietary pharmacological products are currently being developed for an Alzheimer's disease treatment, but only a few are being studied for prevention. Randomised trial data are available for antihypertensive agents (calcium channel blockers, angiotensin-converting enzyme inhibitors), pravastatin, simvastatin, conjugated oestrogen, raloxifene, rofecoxib, CX516 (AMPA agonist) and cholinesterase inhibitors regarding efficacy for Alzheimer's disease prevention. At least four large prevention trials of conjugated oestrogen, selenium and vitamin E, Ginkgo biloba and statins are currently underway. Strategies using other agents have not yet been evaluated in Alzheimer's disease prevention clinical trials. These include anti-amyloid antibodies, active immunisation, selective secretase inhibitors and modulators, microtubule stabilisers (e.g., paclitaxel), R-flurbiprofen, xaliproden, ONO-2506, FK962 (somatostatin releaser), SGS 742 (GABA(B) antagonist), TCH 346 (apoptosis inhibitor), Alzhemedtrade mark, phophodiesterase inhibitors, rosiglitazone, leuprolide, interferons, metal-protein attenuating compounds (e.g., PBT2), CX717, rasagaline, huperzine A, antioxidants and memantine. Studies combining lifestyle modification and drug therapy have not been conducted. Full validation of surrogate markers for disease progression (such as amyloid imaging) should further facilitate drug development. Reducing the complexity of prevention trials and gaining regulatory consensus of design is a high priority for the field.

71.A randomized, double-blind, placebo-controlled trial of two doses of Ginkgo biloba extract in dementia of the Alzheimer's type.:(Psycho:dementia/AD)

Curr Alzheimer Res. 2005 Dec;2(5):541-51.PMID: 16375657
CONTEXT: Previous studies of Ginkgo biloba extract (GbE) in patients with various forms of cognitive impairment or dementia have shown promising results.OBJECTIVE: To determine the clinical efficacy of GbE in mild to moderate dementia of the Alzheimer type.DESIGN: Randomized, placebo-controlled, double-blind, parallel-group, multicenter trial.SETTING: Outpatient clinics of universities and private research centers specialized in dementia.PATIENTS: 513 outpatients with uncomplicated dementia of the Alzheimer's type scoring 10 to 24 on the Mini-Mental State Examination and less than 4 on the modified Hachinski Ischemic Score, free of other serious illnesses and not requiring continuous treatment with any psychoactive drug.INTERVENTION: 26-week treatment with GbE at daily doses of 120 mg or 240 mg or placebo.MAIN OUTCOMES: Cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog), Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC).RESULTS: There were no significant between-group differences for the whole sample. There was little cognitive and functional decline of the placebo-treated patients, however. For a subgroup of patients with neuropsychiatric symptoms there was a greater decline of placebo-treated patients and significantly better cognitive performance and global assessment scores for the patients on GbE.CONCLUSION: The trial did not show efficacy of GbE, however, the lack of decline of the placebo patients may have compromised the sensitivity of the trial to detect a treatment effect. Thus, the study remains inconclusive with respect to the efficacy of GbE.

72.A review of antioxidants and Alzheimer's disease.:(Psycho:AD)

Ann Clin Psychiatry. 2005 Oct-Dec;17(4):269-86.PMID: 16402761
BACKGROUND: In this article, we review a diverse body of research and draw conclusions about the usefulness, or lack there-of, of specific antioxidants in the prevention of Alzheimer's disease (AD).METHODS: The National Library of Medicine's database was searched for the years 1996-2004 using the search terms "Alzheimer's, anti-oxidants, antioxidants."RESULTS: Over 300 articles were identified and 187 articles were selected for inclusion based on relevance to the topic. Agents that show promise in helping prevent AD include: 1) aged garlic extract, 2) curcumin, 3) melatonin, 4) resveratrol, 5) Ginkgo biloba extract, 6) green tea, 7) vitamin C and 8) vitamin E.CONCLUSIONS: While the clinical value of antioxidants for the prevention of AD is often ambiguous, some can be recommended based upon: 1) epidemiological evidence, 2) known benefits for prevention of other maladies, and 3) benign nature of the substance. Long-term, prospective studies are recommended.

73.Alzheimer's disease, the nematode Caenorhabditis elegans, and ginkgo biloba leaf extract.:(Psycho:AD)

Life Sci. 2006 Mar 27;78(18):2066-72. Epub 2006 Feb 28.PMID: 16507312
Alzheimer's disease (AD) is affecting larger and larger proportions of our population as lifespan increases. Thus, the means to prevent or reduce the rate of this disorder is a high priority for medical research. A standardized extract of Ginkgo biloba leaves EGb 761 is a popular dietary supplement taken by the general public to enhance mental focus and by the elderly to delay onset of age-related loss of cognitive function. EGb 761 has been used for treatment of certain cerebral dysfunctions and dementias associated with aging and AD. Substantial evidence indicates that EGb 761 has neuroprotective effects. But, mechanisms of action of the components of the extract are, unfortunately, poorly understood. Research in my laboratory focuses on understanding mechanisms of action of the components of the herbal extract EGb 761 in protection against Alzheimer's disease. We have demonstrated that EGb 761 inhibited amyloid beta aggregation in vitro and attenuates reactive oxidative species (ROS) in a model organism - the round worm Caenorhabditis elegans. Furthermore, EGb 761 eased its toxicity in the transgenic C. elegans. We also found that only a certain size of the amyloid beta aggregates is toxic to the worms. These findings suggest that EGb 761 has a clear therapeutic potential for prevention and/or treatment of AD. A better understanding of the mechanisms of neuroprotection by EGb 761 will be important for designing therapeutic strategies, for basic understanding of the underlying neurodegenerative processes, and for a better understanding of the effectiveness and complexity of this herbal medicine.

74.Extract of Ginkgo biloba EGb761 facilitates extinction of conditioned fear measured by fear-potentiated startle.:(Psycho:AD)

Neuropsychopharmacology. 2007 Feb;32(2):332-42. Epub 2006 Mar 22.PMID: 16554745
A standard extract of Ginkgo biloba (EGb761) has been used in the treatment of various common geriatric complaints including vertigo, short-term memory loss, hearing loss, lack of attention, or vigilance. We demonstrated that acute systemic administration of EGb761 facilitated the acquisition of conditioned fear. Many studies suggest the neural mechanism underlies extinction is similar to the acquisition. This raises a possibility that EGb761 may modulate and accelerate the fear extinction process. We tested this possibility by using fear-potentiated startle (FPS) on laboratory rats. Acute systemic injection of EGb761 (10, 20, or 50 mg/kg) 30 min before extinction training facilitated extinction in a dose-dependent manner. Intra-amygdaloid infusion of EGb761 (28 ng/side, bilaterally) 10 min before extinction training also facilitated extinction. Control experiments showed that facilitation effect of EGb761 was not the result of impaired expression of conditioned fear or accelerated forgetting. Rats previously injected with EGb761 showed significant FPS after retraining. Extinction of conditioned fear appeared to result from acute drug effects rather than from toxic action. Systemic administration of EGb761 immediately after extinction training did not facilitate extinction, suggested the EGb761 facilitation effect is contributed to the acquisition phase of extinction learning. Western blot results showed that extinction induced amygdaloid extracellular signal-regulated kinase (ERK1/2) phosphorylation was significantly elevated by EGb761 treatment. Intra-amygdala injection of ERK1/2 inhibitor PD98059 completely blocked the EGb761 effect. Therefore, acute EGb761 administration modulated extinction of conditioned fear by activating ERK1/2.

75.The Ginkgo Evaluation of Memory (GEM) study: design and baseline data of a randomized trial of Ginkgo biloba extract in prevention of dementia.:(Psycho:dementia)

Contemp Clin Trials. 2006 Jun;27(3):238-53. Epub 2006 Apr 19.PMID: 16627007
The epidemic of late life dementia, prominence of use of alternative medications and supplements, and initiation of efforts to determine how to prevent dementia have led to efforts to conduct studies aimed at prevention of dementia. The GEM (Ginkgo Evaluation of Memory) study was initially designed as a 5-year, randomized double-blind, placebo-controlled trial of Ginkgo biloba, administered in a dose of 120 mg twice per day as EGb761, in the prevention of dementia (and especially Alzheimer's disease) in normal elderly or those with mild cognitive impairment. The study anticipates 8.5 years of participant follow-up. Initial power calculations based on estimates of incidence rates of dementia in the target population (age 75+) led to a 3000-person study, which was successfully recruited at four clinical sites around the United States from September 2000 to June 2002. Primary outcome is incidence of all-cause dementia; secondary outcomes include rate of cognitive and functional decline, the incidence of cardiovascular and cerebrovascular events, and mortality. Following screening to exclude participants with incident dementia at baseline, an extensive neuropsychological assessment was performed and participants were randomly assigned to treatment groups. All participants are required to have a proxy who agreed to provide an independent assessment of the functional and cognitive abilities of the participant. Assessments are repeated every 6 months. Significant decline at any visit, defined by specific changes in cognitive screening scores, leads to a repeat detailed neuropsychological battery, neurological and medical evaluation and MRI scan of the brain. The final diagnosis of dementia is achieved by a consensus panel of experts. Side effects and adverse events are tracked by computer at the central data coordinating center and unblinded data are reviewed by an independent safety monitoring board. Studies such as these are necessary for this and a variety of other potential protective agents to evaluate their effectiveness in preventing or slowing the emergence of dementia in the elderly population.

76.Ginkgo biloba and donepezil: a comparison in the treatment of Alzheimer's dementia in a randomized placebo-controlled double-blind study.:(Psycho:dementia/AD)

Eur J Neurol. 2006 Sep;13(9):981-5.PMID: 16930364
The Ginkgo biloba special extract EGb 761 seems to produce neuroprotective effects in neurodegenerative diseases of multifactorial origin. There is still debate about the efficacy of Ginkgo biloba special extract EGb 761 compared with second-generation cholinesterase inhibitors in the treatment of mild to moderate Alzheimer's dementia. Our aim is to assess the efficacy of the Ginkgo biloba special extract E.S. in patients with dementia of the Alzheimer type in slowing down the disease's degenerative progression and the patients' cognitive impairment compared with donepezil and placebo. The trial was designed as a 24-week randomized, placebo-controlled, double-blind study. Patients aged 50-80 years, suffering from mild to moderate dementia, were allocated into one of the three treatments: Ginkgo biloba (160 mg daily dose), donepezil (5 mg daily dose), or placebo group. The degree of severity of dementia was assessed by the Syndrom Kurz test and the Mini-Mental State Examination. Clinical Global Impression score was recorded to assess the change in the patients' conditions and the therapeutic efficacy of tested medications. Our results confirm the clinical efficacy of Ginkgo biloba E.S. (Flavogin) in the dementia of the Alzheimer type, comparable with donepezil clinical efficacy. There are few published trials that have directly compared a cholinesterase inhibitor with Ginkgo for dementia. This study directly compares a cholinesterase inhibitor with Ginkgo biloba for dementia of the Alzheimer type and could be a valid contribution in this debate. Our study suggests that there is no evidence of relevant differences in the efficacy of EGb 761 and donepezil in the treatment of mild to moderate Alzheimer's dementia, so the use of both substances can be justified. In addition, this study contributes to establish the efficacy and tolerability of the Ginkgo biloba special extract E.S. in the dementia of the Alzheimer type with special respect to moderately severe stages.

77.Recruitment of the elderly into a pharmacologic prevention trial: the Ginkgo Evaluation of Memory Study experience.:(Psycho:dementia)

Contemp Clin Trials. 2006 Dec;27(6):541-53. Epub 2006 Jul 4.PMID: 16949348
The difficulty involved in recruiting healthy older adults into clinical trials, especially those involving pharmacologic agents, is an important issue in research. The Ginkgo Evaluation of Memory (GEM) Study, a double-blind, placebo-controlled randomized clinical trial evaluating Ginkgo biloba to prevent dementia, successfully recruited 3072 participants age 75 years and older at four U.S. sites from September 2000 through June 2002. Using targeted mailing lists, an estimated 243,400 study brochures were mailed out to potential participants. Subsequent attempts were made to reach 14,603 households by telephone, from which 12,186 (83.4%) successful contacts were made. Overall, telephone or in-person evaluations identified 2149 (17.6%) ineligible persons for cognitive (20.6%), medical (49.4%), or other (30.0%) reasons. A total of 6944 (57.0%) refused participation resulting in 3072 enrolled into the study, a recruitment rate of 25.2% based on telephone contacts made or 1.3% of all mailed brochures. Recruitment rates were stable over the 21-month enrollment period but were higher for the two urban centers than the two rural ones. Recruitment was dependent most on mailing lists available, density of older adults in the catchment areas, and Institutional Review Board restrictions. Men and persons under age 85 were more likely to enroll. Primary reason for refusals involved lack of interest (48.4%) or self-perceived poor health (16.2%). Over 9% were unwilling to give up current Ginkgo supplementation or would not accept assignment to placebo. An additional 7% did not want another medication and almost 4% had care-giving responsibilities which prevented involvement. Mass mailings were the most successful approach for recruitment at all four sites and the method through which the vast majority of interviewees had learned about the study. Information on the experience of the GEM Study recruitment may be helpful to other clinical trials attempting to randomize older adults into prevention trials.

78.Amyloid-beta-induced pathological behaviors are suppressed by Ginkgo biloba extract EGb 761 and ginkgolides in transgenic Caenorhabditis elegans.:(Psycho:AD/Amyloid-beta (Abeta) toxicity)

J Neurosci. 2006 Dec 13;26(50):13102-13.PMID: 17167099
Amyloid-beta (Abeta) toxicity has been postulated to initiate synaptic loss and subsequent neuronal degeneration seen in Alzheimer's disease (AD). We previously demonstrated that the standardized Ginkgo biloba extract EGb 761, commonly used to enhance memory and by AD patients for dementia, inhibits Abeta-induced apoptosis in neuroblastoma cells. In this study, we use EGb 761 and its single constituents to associate Abeta species with Abeta-induced pathological behaviors in a model organism, Caenorhabditis elegans. We report that EGb 761 and one of its components, ginkgolide A, alleviates Abeta-induced pathological behaviors, including paralysis, and reduces chemotaxis behavior and 5-HT hypersensitivity in a transgenic C. elegans. We also show that EGb 761 inhibits Abeta oligomerization and Abeta deposits in the worms. Moreover, reducing oxidative stress is not the mechanism by which EGb 761 and ginkgolide A suppress Abeta-induced paralysis because the antioxidant L-ascorbic acid reduced intracellular levels of hydrogen peroxide to the same extent as EGb 761, but was not nearly as effective in suppressing paralysis in the transgenic C. elegans. These findings suggest that (1) EGb 761 suppresses Abeta-related pathological behaviors, (2) the protection against Abeta toxicity by EGb 761 is mediated primarily by modulating Abeta oligomeric species, and (3) ginkgolide A has therapeutic potential for prevention and treatment of AD.

79.Ginkgo biloba special extract in dementia with neuropsychiatric features. A randomised, placebo-controlled, double-blind clinical trial.:(Psycho:dementia)

Arzneimittelforschung. 2007;57(1):4-11.PMID: 17341003
BACKGROUND: In previous trials of the Ginkgo biloba special extract EGb 761 improvements in cognitive functioning and behavioural symptoms were found in patients with aging-associated cognitive impairment or dementia. This trial was undertaken to assess the efficacy of EGb 761 in mild to moderate dementia with neuropsychiatric features.METHODS: Double-blind trial including 400 patients aged 50 years or above with Alzheimer's disease (AD) or vascular dementia (VaD), randomized to receive EGb 761 or placebo for 22 weeks. Patients scored below 36 on the Test for the Early Detection of Dementia with Discrimination from Depression (TE4D), between 9 and 23 on the SKT test battery and at least 5 on the Neuropsychiatric Inventory (NPI).RESULTS: There was a mean -3.2-point improvement in the SKT upon EGb 761 treatment and an average deterioration by +1.3 points on placebo (p < 0.001, two-sided, ANOVA). EGb 761 was significantly superior to placebo on all secondary outcome measures, including the NPI and an activities-of-daily-living scale. Treatment results were essentially similar for AD and VaD subgroups. The drug was well tolerated; adverse events were no more frequent under drug than under placebo treatment.CONCLUSION: The data add further evidence on the safety and efficacy of EGb 761 in the treatment of cognitive and non-cognitive symptoms of dementia.

80.Ginkgo biloba for cognitive impairment and dementia.:(Psycho:dementia/mental performance)

Cochrane Database Syst Rev. 2007 Apr 18;(2):CD003120.PMID: 17443523
BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals.OBJECTIVES: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline.SEARCH STRATEGY: Trials were identified on 10 October 2006 through a search of the Cochrane Dementia and Cognitive Improvement Group's Specialized Register which contains records from all main medical databases (MEDLINE, EMBASE, CINAHL, PsycINFO, SIGLE, LILACS), from ongoing trials databases such as Clinicaltrials.gov and Current Controlled Trials and many other sources. The search terms used were ginkgo*, tanakan, EGB-761, EGB761, "EGB 761" and gingko*.SELECTION CRITERIA: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity.DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.MAIN RESULTS: Clinical global improvement as assessed by the physician, was dichotomized between participants who showed improvement or were unchanged and those who were worse. There are benefits associated with Ginkgo (dose greater than 200 mg/day) at 24 weeks (207/276 compared with 178/273, OR 1.66, 95% CI 1.12 to 2.46, P=.001) (2 studies), but not for the lower dose. Cognition shows benefit for Ginkgo (any dose) at 12 weeks (SMD -0.65, 95% CI -1.22 to -0.09 P=0.02, 5 studies) but not at 24 weeks. Five studies assessed activities of daily living (ADLs), using different scales. Some scales are more comprehensive than just ADLs. The results show benefit for Ginkgo (dose less than 200 mg/day) compared with placebo at 12 weeks (MD -5.0, 95% CI -7.88, -2.12, p=0.0007, one study), and at 24 weeks (SMD -0.16, 95% CI -0.31 to -0.01, p=0.03, 3 studies) but there are no differences at the higher dose. No study assessed mood and function separately, but one study used the ADAS-Noncog, which assesses function over several domains, but not cognitive function. There was no difference between Ginkgo and placebo. There are no significant differences between Ginkgo and placebo in the proportion of participants experiencing adverse events. There are no data available on Quality of Life, measures of depression or dependency.AUTHORS' CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and we cannot exclude publication bias. The evidence that Ginkgo has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unconvincing

81.Protective effects of Ginkgo biloba extract on paraquat-induced apoptosis of PC12 cells.:(Psycho:Parkinson's disease)

Toxicol In Vitro. 2007 Sep;21(6):1003-9. Epub 2007 Feb 21.PMID: 17509817
Previous studies have suggested that Ginkgo biloba extract (EGb761) has a protective potentiality against apoptosis of neurons or neuron-like cells induced by MPTP. In this study, the effects of EGb761 on PC12 cells injured by paraquat (PQ), a neurotoxin, were tested. The results showed that after incubation of PC12 cells with EGb761 prior to PQ exposure, the PQ-induced decrease of cell viability was significantly reversed, the collapse of mitochondrial membrane potential (MMP) was attenuated and the percentage of apoptotic cells was reduced. Moreover, EGb761 pretreatment evidently increased the numbers of tyrosine hydroxylase (TH) positive and bcl-2 positive cells and degraded the number of caspase-3 positive cells in PQ-injured PC12 cells, in comparison to the treatment with PQ alone. This study indicates that EGb761 has a neuroprotective effect on paraquat-induced apoptosis of PC12 cells. The mechanism underlying the protective effects of EGb761 in PQ-injured PC12 cells might be related to the increase of bcl-2 activation, maintenance of MMP stability and decrease of caspase-3 activation through mitochondria-dependent pathway. The results from this study provide an experimental basis for the potential use of EGb761 in treatment of Parkinson's disease.

82.Ginkgo biloba extract (EGb 761) in Alzheimer's disease: is there any evidence?:(Psycho:AD)

Curr Alzheimer Res. 2007 Jul;4(3):253-62.PMID: 17627482
For centuries, extracts from the leaves of the Ginkgo biloba tree have been used as Chinese herbal medicine to treat a variety of health disorders. The standardized Ginkgo biloba extract EGb 761 was marketed in France and Germany 30 years ago for various vascular and cerebral deficits and is now classified as a food supplement in the United States. EGb 761 is currently the focus of phase-III clinical trials, GEM and GuidAge studies, to evaluate its efficacy on the prevention of Alzheimer's disease (AD) in subjects over 70 years old. This review summarizes recent advancements in our understanding of the potential role of EGb 761 in the prevention of AD. Besides its well-known free radical scavenging properties, the ability of EGb 761 to protect neurons probably also involves other intracellular pathways. We will point out potential targets of EGb 761 in the amyloid cascade such as its antiamyloidogenic properties or the regulation of gene expression. Moreover we will discuss the complexity of the cellular and molecular mechanisms of EGb 761 and the significance of the synergic effect of different constituents of EGb 761.

83.Chinese herbs and herbal extracts for neuroprotection of dopaminergic neurons and potential therapeutic treatment of Parkinson's disease.:(Psycho:Parkinson's disease (PD))

CNS Neurol Disord Drug Targets. 2007 Aug;6(4):273-81.PMID: 17691984
Parkinson's disease (PD) is a common and debilitating degenerative disease resulting from massive degenerative loss of dopamine neurons, particularly in the substantia nigra. The most classic therapy for PD is levodopa administration, but the efficacy of levodopa treatment declines as the disease progresses. The neuroprotective strategies to rescue nigral dopamine neurons from progressive death are currently being explored, and among them, the Chinese herbs and herbal extracts have shown potential clinical benefit in attenuating the progression of PD in human beings. Growing studies have indicated that a range of Chinese herbs or herbal extracts such as green tea polyphenols or catechins, panax ginseng and ginsenoside, ginkgo biloba and EGb 761, polygonum, triptolide from tripterygium wilfordii hook, polysaccharides from the flowers of nerium indicum, oil from ganoderma lucidum spores, huperzine and stepholidine are able to attenuate degeneration of dopamine neurons and sympotoms caused by the neurotoxins 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) in vitro and in vivo conditions. In addition, accumulating data have suggested that Chinese herbs or herbal extracts may promote neuronal survival and neurite growth, and facilitate functional recovery of brain injures by invoking distinct mechanisms that are related to their neuroprotective roles as the antioxidants, dopamine transporter inhibitor, monoamine oxidase inhibitor, free radical scavengers, chelators of harmful metal ions, modulating cell survival genes and signaling, anti-apoptosis activity, and even improving brain blood circulation. New pharmaceutical strategies against PD will hopefully be discovered by understanding the various active entities and valuable combinations that contribute to the biological effects of Chinese herbs and herbal extracts.

84.Evaluation of the effect of Ginkgo biloba extract (EGb 761) on the myenteric plexus of the small intestine of Wistar rats.:(Psycho:Parkinson's disease (PD))

J Gastroenterol. 2007 Aug;42(8):624-30. Epub 2007 Aug 24.PMID: 17701125
BACKGROUND: The aging process causes a reduction in the myenteric neuronal population, related to oxidative stress, resulting in malfunctioning of the digestive tract. The purpose of this study was to evaluate the action of Ginkgo biloba extract (EGb 761), an important antioxidant drug, on the myenteric plexus of the jejunum and ileum of rats after treatment for 120 days.METHODS: Fragments of the jejunum and ileum were collected from three groups of rats: a 90-day-old group (group Y), a 210-day-old group (group A), and a 210-day-old group treated daily with the extract EGb 761 (50 mg/kg body weight) (group TA). The analysis was carried out by using the myosin-V immunohistochemical technique. Neuronal densities were estimated, and a study of the neuronal profile area of 500 neurons from each group was carried out.RESULTS: In the jejunum, there was a significant neuronal population reduction of 17% only in group A compared with group Y. In the ileum, there was a significant neuronal reduction of 36% in group A compared with group Y, and a significant reduction in group TA of 20%. The difference in the reduction between groups A and TA in the ileum was also significant. In the jejunum, only group A showed a significant increase in neuronal profile area, but in the ileum, there was a significant increase in both groups A and TA.CONCLUSIONS: A daily dose of 50 mg/kg body weight of Ginkgo biloba extract has a significant neuroprotector effect on the myenteric plexus of the ileum during the aging process in rats.

85.Effects of Ginkgo biloba extract EGb 761 on neuropsychiatric symptoms of dementia: findings from a randomised controlled trial.:(Psycho:dementia)

Wien Med Wochenschr. 2007;157(13-14):295-300.PMID: 17704975
In a randomised, double-blind, 22-week trial 400 patients with dementia associated with neuropsychiatric features were treated with Ginkgo biloba extract EGb 761 (240 mg/day) or placebo. Patients with probable Alzheimer's disease, possible Alzheimer's disease with cerebrovascular disease or vascular dementia were eligible if they scored 9 to 23 on the SKT cognitive test battery and at least 5 on the Neuropsychiatric Inventory (NPI). EGb 761 was significantly superior to placebo with respect to the primary (SKT test battery) and all secondary outcome variables. The mean composite score (frequency x severity) and the mean caregiver distress score of the NPI dropped from 21.3 to 14.7 and 13.5 to 8.7, respectively, in the EGb 761-treated patients, but increased from 21.6 to 24.1 and 13.4 to 13.9, respectively, under placebo (p < 0.001). The largest drug-placebo differences in favour of EGb 761 were found for apathy/indifference, anxiety, irritability/lability, depression/dysphoria and sleep/nighttime behaviour.

86.Ginkgo and Alzheimer's disease: little or no different from placebo.:(Psycho:AD)

Prescrire Int. 2007 Oct;16(91):205-7.PMID: 17926840
(1) Drug treatments for Alzheimer's disease have no more than modest and transient efficacy but can cause significant adverse effects. Other treatments are therefore being explored, including plant extracts. (2) Is Ginkgo biloba (maidenhair tree) any more effective than placebo in Alzheimer's disease? To answer this question, we carried out a review of available evidence based on Prescrire's standard methodology. (3) Ginkgo biloba has been widely used for many years by people with symptoms attributed to "cerebrovascular insufficiency", despite the lack of evidence of a causal role. (4) About thirty placebo-controlled trials in patients with various types of dementia have been published, with highly inconsistent results. If these studies showed any effect on cognition, it was weak and did not last more than 6 months. (5) Cases of haemorrhage were reported, and this means that caution is needed, especially in patients at increased risk of haemorrhage, such as those on ongoing anticoagulant or antiplatelet treatment. (6) In practice, Ginkgo biloba extract appears to be little or no different from placebo in the treatment of Alzheimer's disease. Its short-term use is acceptable under some conditions, but the potential risk of bleeding must be kept in mind.

87.Restoration of impaired phosphorylation of cyclic AMP response element-binding protein (CREB) by EGb 761 and its constituents in Abeta-expressing neuroblastoma cells.:(Psycho:AD)

Eur J Neurosci. 2007 Nov;26(10):2931-9.PMID: 18001288
Cyclic AMP response element-binding protein (CREB) plays important roles in neuronal plasticity and amyloid beta-peptide (Abeta)-induced cognitive impairment in Alzheimer's disease (AD). Here we demonstrated that Ginkgo biloba extract, EGb 761, displayed the neuron protective effect by activating the CREB signaling pathway. Wild-type neuroblastoma cells cultured in a conditioned medium containing cell-secreted Alphabeta exhibited reduced levels of phosphorylated CREB (pCREB). Addition of EGb 761 (100 microg/mL) or an anti-oligomer-specific antibody (A-11) to the conditioned medium could restore pCREB level. In a neuroblastoma cell line expressing Alphabeta, treatment with EGb 761 increased levels of pCREB and brain-derived neurotrophic factor. Furthermore, CREB phosphorylation induced by EGb 761 was blocked by inhibitors of several upstream signaling pathways of CREB, including protein kinase C, ERK, ribosomal S6 kinase(RSK)90 and nitric oxide pathway. Moreover, these inhibitors differentially blocked the effects of individual components of EGb 761, ginkgolide C, quercetin and bilobalide, which suggest diverse effects of the EGb 761 individual components. Actions of individual EGb 761 components provide further insights into direct mechanisms underlying the effect of EGb 761 on enhancing the cognitive performance of patients with AD.

88.Ginkgolides protect against amyloid-beta1-42-mediated synapse damage in vitro.:(Psycho:AD/early stages of AD)

Mol Neurodegener. 2008 Jan 7;3:1.PMID: 18179689
BACKGROUND: The early stages of Alzheimer's disease (AD) are closely associated with the production of the Abeta1-42 peptide, loss of synapses and gradual cognitive decline. Since some epidemiological studies showed that EGb 761, an extract from the leaves of the Ginkgo biloba tree, had a beneficial effect on mild forms of AD, the effects of some of the major components of the EGb 761 extract (ginkgolides A and B, myricetin and quercetin) on synapse damage in response to Abeta1-42 were examined.RESULTS: The addition of Abeta1-42 to cortical or hippocampal neurons reduced the amounts of cell associated synaptophysin, a pre-synaptic membrane protein that is essential for neurotransmission, indicating synapse damage. The effects of Abeta1-42 on synapses were apparent at concentrations approximately 100 fold less than that required to kill neurons; the synaptophysin content of neuronal cultures was reduced by 50% by 50 nM Abeta1-42. Pre-treatment of cortical or hippocampal neuronal cultures with ginkgolides A or B, but not with myrecitin or quercetin, protected against Abeta1-42-induced loss of synaptophysin. This protective effect was achieved with nanomolar concentrations of ginkgolides. Previous studies indicated that the ginkgolides are platelet-activating factor (PAF) receptor antagonists and here we show that Abeta1-42-induced loss of synaptophysin from neuronal cultures was also reduced by pre-treatment with other PAF antagonists (Hexa-PAF and CV6209). PAF, but not lyso-PAF, mimicked the effects Abeta1-42 and caused a dose-dependent reduction in the synaptophysin content of neurons. This effect of PAF was greatly reduced by pre-treatment with ginkgolide B. In contrast, ginkgolide B did not affect the loss of synaptophysin in neurons incubated with prostaglandin E2.CONCLUSION: Pre-treatment with ginkgolides A or B protects neurons against Abeta1-42-induced synapse damage. These ginkgolides also reduced the effects of PAF, but not those of prostaglandin E2, on the synaptophysin content of neuronal cultures, results consistent with prior reports that ginkgolides act as PAF receptor antagonists. Such observations suggest that the ginkgolides are active components of Ginkgo biloba preparations and may protect against the synapse damage and the cognitive loss seen during the early stages of AD.

89.Ginkgo biloba extract and its flavonol and terpenelactone fractions do not affect beta-secretase mRNA and enzyme activity levels in cultured neurons and in mice.:(Psycho:AD/negative)

Planta Med. 2008 Jan;74(1):6-13. Epub 2008 Jan 10.PMID: 18186016
Numerous clinical trials have reported beneficial effects of the Ginkgo biloba extract EGb761 in the prevention and therapy of cognitive disorders including Alzheimer's disease (AD). Although neuroprotective properties of EGb761 have been consistently reported, the molecular mechanisms of EGb761 and the specific role of its major constituents, the flavonols and terpenlactones, are largely unknown. One major hallmark of AD is the deposition of amyloid-beta (A beta) as amyloid plaques in the brain. A beta is a cleavage product of amyloid precursor protein (APP). Certain proteases, called beta-secretases (BACE), are crucial in the formation of A beta. The purpose of the present study was to investigate the efficacy of EGb761 and its flavonol and terpenelactone fraction to modulate BACE-1 enzyme activity and mRNA levels in vitro and in vivo. Neither EGb761 nor its fractions affected BACE-1 activity in vitro. Furthermore, also in Neuro-2a cells and wild-type as well as transgenic (Tg2576) laboratory mice, no significant effect of EGb761 on BACE-1 enzyme activity and mRNA levels were observed. Current findings suggest that BACE-1 may not be a major molecular target of EGb761 and its flavonol and terpenelactone fraction.

90.Ginkgo biloba for mild to moderate dementia in a community setting: a pragmatic, randomised, parallel-group, double-blind, placebo-controlled trial.:(Psycho:dementia)

Int J Geriatr Psychiatry. 2008 Dec;23(12):1222-30.PMID: 18537221
OBJECTIVES: Doubt over the cost-effectiveness of the cholinesterase inhibitors in dementia has renewed interest in alternative treatments such as Ginkgo biloba. We aimed to determine the effectiveness and the safety profile of Ginkgo biloba for treating early stage dementia in a community setting.METHODS: We conducted a community-based, pragmatic, randomised, double-blind, parallel-group trial where participants were given a standardised extract of Ginkgo biloba (120 mg daily) or a placebo control for 6 months. Our primary outcomes were cognitive functioning (ADAS-Cog) and participant and carer-rated quality of life (QOL-AD).RESULTS: We recruited 176 participants, mainly through general practices. In the ANCOVA model with baseline score as a co-variate (n = 176), Ginkgo did not have a significant effect on outcome at six months on either the ADAS-Cog score (p = 0.392), the participant-rated QOL-AD score (p = 0.787) nor the carer-rated QOL-AD score (p = 0.222).CONCLUSION: We found no evidence that a standard dose of high purity Ginkgo biloba confers benefit in mild-moderate dementia over 6 months.

91.GuidAge study: a 5-year double blind, randomised trial of EGb 761 for the prevention of Alzheimer's disease in elderly subjects with memory complaints. i. rationale, design and baseline data.:(Psycho:AD)

Curr Alzheimer Res. 2008 Aug;5(4):406-15.PMID: 18690838
Primary and secondary prevention strategies for Alzheimer's disease (AD) are urgently needed. We have initiated a five-year prospective prevention study involving patients spontaneously reporting memory complaints. The primary objective is to determine the effect of treatment with EGb 76 on the rate of conversion from memory complaints to AD using survival analysis. Ambulatory patients aged at least 70 years who spontaneously reported a memory complaint during a GP or memory centre consultation were eligible for inclusion. Patients with major objective memory impairment or clinically relevant symptoms of anxiety and depression were excluded. Subjects were randomised to receive either EGb 761 120mg bid or matching placebo. Participants undergo an annual visit at a memory centre, where a series of neuropsychological tests are administered to assess cognitive function (Grober and Buschke, Trail-Making and controlled oral word association tests) and cognitive status (MMS and CDR). Functional status is evaluated with the Instrumental Activities of Daily Living questionnaire. The primary outcome is the transition to a diagnosis of AD (DSM-IV and NINCDS-ADRDA criteria), determined at the annual memory centre visit. A total of 4066 patients were screened for participation, of whom 2854 fulfilled the eligibility criteria and were entered into the study. Their mean age was 76.8+/-4.4 years and 66.7% were female. The mean MMSE score was 27.8+/-1.7 and 55.5% presented a CDR score of 0.5. This study will enable us to evaluate the efficacy of EGb761 in the prevention of AD, and to assess the usefulness of various baseline characteristics as predictors of conversion to AD in this population.

92.Effects of ginkgo biloba extract EGb761 on expression of RAGE and LRP-1 in cerebral microvascular endothelial cells under chronic hypoxia and hypoglycemia.:(Psycho:AD)

Acta Neuropathol. 2008 Nov;116(5):529-35. Epub 2008 Oct 1.PMID: 18830615
Alzheimer's disease (AD), characterized by accumulation of amyloid-beta protein (Abeta) in brain parenchyma, is closely associated with brain ischemia. Decreased clearance of Abeta from brain is the main cause of Abeta accumulation in sporadic AD. However, the mechanisms underlying ischemia-mediated AD pathogenesis remain unclear. The receptor for advanced end glycation products (RAGE) and low-density lipoprotein receptor-related protein-1 (LRP-1) expressed at blood brain barrier (BBB) are actively involved in Abeta clearance. RAGE is thought to be a primary transporter of Abeta across BBB into the brain from the systemic circulation, while LRP-1 mediates the transport of Abeta out of the brain. Ginkgo biloba extract EGb761, a traditional Chinese medicine, has been widely used in the treatment of AD. To investigate the effects of EGb761 on the expression of RAGE and LRP-1 in endothelial cells in response to ischemic injury, we cultured bEnd.3 cells, an immortalized mouse cerebral microvessel endothelial cell line, under a chronic hypoxic and hypoglycemic condition (CHH) to mimic ischemic injury of BBB, and then treated with EGb 761. We found that EGb 761 markedly ameliorated the damage (evaluated by MTT assay) from CHH. Moreover, we demonstrated that CHH led to a significant increase in the expression of RAGE both at the mRNA and protein levels at all times (24, 36, and 48 h), conversely; CHH induced a dramatic decrease in LRP-1 mRNA and protein expression at both 36 and 48 h. The results indicated that CHH has differential effects on the expression of RAGE and LRP-1. Furthermore, EGb761 significantly reversed CHH-induced upregulation of RAGE expression and downregulation of LRP-1 expression. Our findings suggest that EGb761 favor clearance of Abeta via regulating the expression of RAGE and LRP-1 during brain ischemia. This may provide a new insight into a possible molecular mechanism underlying brain ischemia-mediated AD pathogenesis, and potential therapeutic application of EGb 761 in treatment of AD.

93.Effect of a short- and long-term treatment with Ginkgo biloba extract on amyloid precursor protein levels in a transgenic mouse model relevant to Alzheimer's disease.(Psycho:neuoprotective/AD)

Arch Biochem Biophys. 2009 Jan 15;481(2):177-82. Epub 2008 Oct 30.PMID: 18996078
Several clinical trials have reported beneficial effects of the Ginkgo biloba extract EGb761 in the prevention and therapy of cognitive disorders including Alzheimer's disease (AD). The aim of the present long-term feeding trial was to study the impact of dietary EGb761 on Amyloid precursor protein (APP) metabolism in mice transgenic for human APP (Tg2576). Tg2576 mice were fed diets with and without EGb761 (300 mg/kg diet) for 1 and 16 months, respectively. Long-term treatment (16 months) with EGb761 significantly lowered human APP protein levels by approximately 50% as compared to controls in the cortex but not in the hippocampus. However, APP levels were not affected by EGb761 in young mice. Current data indicate that APP seems to be an important molecular target of EGb761 in relation to the duration of the Ginkgo biloba treatment and/or the age of the animals. Potential neuroprotective properties of EGb761 may be, at least partly, related to its APP lowering activity.

94.Ginkgo biloba for prevention of dementia: a randomized controlled trial.:(Psycho:dementia)

JAMA. 2008 Nov 19;300(19):2253-62.PMID: 19017911
CONTEXT: Ginkgo biloba is widely used for its potential effects on memory and cognition. To date, adequately powered clinical trials testing the effect of G. biloba on dementia incidence are lacking.OBJECTIVE: To determine effectiveness of G. biloba vs placebo in reducing the incidence of all-cause dementia and Alzheimer disease (AD) in elderly individuals with normal cognition and those with mild cognitive impairment (MCI).DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled clinical trial conducted in 5 academic medical centers in the United States between 2000 and 2008 with a median follow-up of 6.1 years. Three thousand sixty-nine community volunteers aged 75 years or older with normal cognition (n = 2587) or MCI (n = 482) at study entry were assessed every 6 months for incident dementia.INTERVENTION: Twice-daily dose of 120-mg extract of G. biloba (n = 1545) or placebo (n = 1524).MAIN OUTCOME MEASURES: Incident dementia and AD determined by expert panel consensus.RESULTS: Five hundred twenty-three individuals developed dementia (246 receiving placebo and 277 receiving G. biloba) with 92% of the dementia cases classified as possible or probable AD, or AD with evidence of vascular disease of the brain. Rates of dropout and loss to follow-up were low (6.3%), and the adverse effect profiles were similar for both groups. The overall dementia rate was 3.3 per 100 person-years in participants assigned to G. biloba and 2.9 per 100 person-years in the placebo group. The hazard ratio (HR) for G. biloba compared with placebo for all-cause dementia was 1.12 (95% confidence interval [CI], 0.94-1.33; P = .21) and for AD, 1.16 (95% CI, 0.97-1.39; P = .11). G. biloba also had no effect on the rate of progression to dementia in participants with MCI (HR, 1.13; 95% CI, 0.85-1.50; P = .39).CONCLUSIONS: In this study, G. biloba at 120 mg twice a day was not effective in reducing either the overall incidence rate of dementia or AD incidence in elderly individuals with normal cognition or those with MCI. Trial Registration clinicaltrials.gov Identifier: NCT00010803.

95.Effect of EGb761 supplementation on the content of copper in mouse brain in an animal model of Parkinson's disease.:(Psycho:PD/Parkinson's disease)

Nutrition. 2009 Apr;25(4):482-5. Epub 2008 Dec 16.PMID: 19091511
OBJECTIVE: EGb761 is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves with neuroprotective effects in an animal model of Parkinson's disease induced by 1-methyl-4-phenylpyridinium (MPP(+)). Because copper has been implicated in Parkinson's disease, we investigated whether the protective effect of EGb761 in MPP(+) neurotoxicity is related to the regulation of copper in the brain.METHODS: C-57BL/6 mice were pretreated with EGb761 (10 mg/kg) daily for 17 d followed by administration of MPP(+) (0.72 mg/kg); the mice were sacrificed 24 h later. The copper content of the striatum, midbrain, hippocampus, frontal cortex, and cerebellum was analyzed by graphite furnace atomic absorption spectrophotometry. Copper content is expressed as mug of copper per gram of wet tissue.RESULTS: Copper content was reduced in the corpus striatum (45%; P < 0.05), and increased in the midbrain (65%; P < 0.05) and hippocampus (116%; P < 0.001) after MPP(+) administration. EGb761 pretreatment of the MPP(+) group prevented changes in the copper content of the striatum, midbrain, and hippocampus. No significant changes were found in the copper content of the cerebellum and frontal cortex in all treatment groups.CONCLUSION: We showed that the protective effect of EGb761 against MPP(+) neurotoxicity may be due in part to the regulation of copper homeostasis in the brain.

96.Ginkgo biloba for cognitive impairment and dementia.:(Psycho:PD/Parkinson's disease)

Cochrane Database Syst Rev. 2009 Jan 21;(1):CD003120.PMID: 19160216
BACKGROUND: Extracts of the leaves of the maidenhair tree, Ginkgo biloba, have long been used in China as a traditional medicine for various disorders of health. A standardized extract is widely prescribed for the treatment of a range of conditions including memory and concentration problems, confusion, depression, anxiety, dizziness, tinnitus and headache. The mechanisms of action are thought to reflect the action of several components of the extract and include increasing blood supply by dilating blood vessels, reducing blood viscosity, modification of neurotransmitter systems, and reducing the density of oxygen free radicals.OBJECTIVES: To assess the efficacy and safety of Ginkgo biloba for dementia or cognitive decline.SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 20 September 2007 using the terms: ginkgo*, tanakan, EGB-761, EGB761, "EGB 761" and gingko*. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many trials databases and grey literature sources.SELECTION CRITERIA: Randomized, double-blind studies, in which extracts of Ginkgo biloba at any strength and over any period were compared with placebo for their effects on people with acquired cognitive impairment, including dementia, of any degree of severity.DATA COLLECTION AND ANALYSIS: Data were extracted from the published reports of the included studies, pooled where appropriate and the treatment effects or the risks and benefits estimated.MAIN RESULTS: 36 trials were included but most were small and of duration less than three months. Nine trials were of six months duration (2016 patients). These longer trials were the more recent trials and generally were of adequate size, and conducted to a reasonable standard. Most trials tested the same standardised preparation of Ginkgo biloba, EGb 761, at different doses, which are classified as high or low. The results from the more recent trials showed inconsistent results for cognition, activities of daily living, mood, depression and carer burden. Of the four most recent trials to report results three found no difference between Ginkgo biloba and placebo, and one found very large treatment effects in favour of Ginkgo biloba.There are no significant differences between Ginkgo biloba and placebo in the proportion of participants experiencing adverse events.A subgroup analysis including only patients diagnosed with Alzheimer's disease (925 patients from nine trials) also showed no consistent pattern of any benefit associated with Ginkgo biloba.AUTHORS' CONCLUSIONS: Ginkgo biloba appears to be safe in use with no excess side effects compared with placebo. Many of the early trials used unsatisfactory methods, were small, and publication bias cannot be excluded. The evidence that Ginkgo biloba has predictable and clinically significant benefit for people with dementia or cognitive impairment is inconsistent and unreliable.

97.Efficacy and tolerability of Ginkgo biloba extract EGb 761 by type of dementia: analyses of a randomised controlled trial.:(Psycho:dementia)

J Neurol Sci. 2009 Aug 15;283(1-2):224-9. Epub 2009 Mar 14.PMID: 19286192
Secondary analyses of a randomised controlled trial were performed to find out whether treatment effects of Ginkgo biloba extract EGb 761 differed by type of dementia. Three hundred ninety-five patients aged 50 years or above, with dementia with neuropsychiatric features were treated with EGb 761 (240 mg/day) or placebo for 22 weeks. Patients scored between 9 and 23 on the Short Syndrome Test (SKT), a cross-culturally validated cognitive test battery. Their total score on the Neuropsychiatric Inventory (NPI) was at least 5. Efficacy was assessed by the SKT test battery (primary outcome measure), the Verbal Fluency Test, the Clock-Drawing Test, the NPI, the Hamilton Rating Scale for Depression (HAMD), and the Gottfries-Bråne-Steen Scale (GBS). Applying standard research diagnostic criteria 214 patients were diagnosed with Alzheimer's disease (probable AD or possible AD with cerebrovascular disease) and 181 with probable vascular dementia (VaD). Under EGb 761 treatment the SKT total score improved by -3.0+/-2.3 and -3.4+/-2.3 points in patients with AD and VaD, respectively, whereas the patients on placebo deteriorated by +1.2+/-2.5 and +1.5+/-2.2 points, respectively (p<0.01 for both drug-placebo differences). Significant drug-placebo differences were found for all secondary outcome variables with no major differences between AD and VaD subgroups. The rate of adverse events tended to be higher for the placebo group.

98.Ginkgo biloba extract EGb 761(R), donepezil or both combined in the treatment of Alzheimer's disease with neuropsychiatric features: a randomised, double-blind, exploratory trial.:(Psycho:AD)

Aging Ment Health. 2009 Mar;13(2):183-90.PMID: 19347685
OBJECTIVE: This randomised, double-blind exploratory trial was undertaken to compare treatment effects and tolerability of EGb 761(R), donepezil and combined treatment in patients with AD and neuropsychiatric features.METHOD: We enrolled 96 outpatients, aged 50 years or above, who met the NINCDS/ADRDA criteria for probable AD, scored below 36 on the TE4D, a screening test for dementia, below 6 on the Clock-Drawing Test (CDT) and between 9 and 23 on the SKT, a cross-culturally validated cognitive test battery. They scored at least five on the 12-item Neuropsychiatric Inventory (NPI). EGb 761(R) (240 mg per day), donepezil (initially 5 mg, after 4 weeks 10 mg per day) or EGb 761(R) and donepezil combined (same doses) were administered for 22 weeks.RESULTS: Changes from baseline to week 22 and response rates were similar for all three treatment groups with respect to all outcome measures (SKT, NPI, total score and activities-of-daily-living sub-score of the Gottfries-Bråne-Steen Scale, Hamilton Rating Scale for Depression, CDT and Verbal Fluency Test). An apparent tendency in favour of combination treatment warrants further scrutiny. Compared to donepezil mono-therapy, the adverse event rate was lower under EGb 761(R) treatment and even under the combination treatment.CONCLUSION: These exploratory findings helped to develop three hypotheses that will have to be proven in further studies: (1) there is no significant difference in the efficiency between EGb 761(R) and donepezil, (2) a combination therapy will be superior to a mono-therapy with one of both substances and (3) there will be less side effects under a combination therapy than under mono-therapy with donepezil.

99.Drug development for Alzheimer's disease: where are we now and where are we headed?:(Psycho:AD)

Am J Geriatr Pharmacother. 2009 Jun;7(3):167-85.PMID: 19616185
OBJECTIVE: The aim of this article was to provide a survey of the clinical development of pharmacotherapy for Alzheimer's disease (AD).METHODS: A search of PubMed to identify pertinent English-language literature was conducted using the terms Alzheimer's disease AND clinical trials (2003-2008), dementia AND prevention AND clinical trials (2003-2008), and the chemical names of all compounds mentioned in articles on new drugs for AD published since 2005. www.ClinicalTrials.gov was searched for relevant trials. Abstracts of the 2008 International Conference on Alzheimer's Disease (ICAD) were reviewed for relevance, as were pharmaceutical company and AD advocacy Web sites. Articles selected for review were primary reports of data from preclinical studies and clinical trials.RESULTS: A large number of drugs with differing targets and mechanisms of action are under development for the treatment of AD. Phase III trials of Ginkgo biloba, NSAIDs, phenserine, statins, tarenflurbil, tramiprosate, and xaliproden have been completed, none of them demonstrating adequate efficacy. Encouraging results from completed Phase II trials of dimebon, huperzine A, intravenous immunoglobulin, and methylthioninium chloride were reported at ICAD 2008. Nineteen compounds are currently in Phase II trials, and 3 compounds (AN1792, lecozotan SR, and SGS742) failed at this stage of development.CONCLUSIONS: Despite disappointing results from recently completed Phase III trials of several novel compounds, the extent and breadth of activity at all phases of clinical development suggest that new pharmacotherapeutic options for the treatment of AD will become available within the next decade.

100.Ginkgo biloba extract EGb 761 in the treatment of dementia: evidence of efficacy and tolerability:(Psycho:dementia)

Fortschr Neurol Psychiatr. 2009 Sep;77(9):494-506. Epub 2009 Jul 20.PMID: 19621278
The Ginkgo biloba extract EGb 761 interferes with pathomechanisms relevant to dementia, such as Abeta aggregation, mitochondrial dysfunction, insulin resistance, and hypoperfusion. The efficacy of EGb 761 in the treatment of dementia (Alzheimer's disease and vascular dementia) has been studied in 10 randomised, controlled, double-blind clinical trials. In three of the four large trials conducted in accordance with recent recommendations EGb 761 was significantly superior to placebo with respect to cognitive performance and one or more further (global, functional or behavioural) outcomes demonstrating the clinical relevance of the findings. The findings from the six smaller trials are in line with those of the large trials. One trial was inconclusive, but of questionable external validity due to uncommonly rigorous patient selection. Subgroup analyses of this study together with the findings from the most recent clinical trial suggest that EGb 761 may be most beneficial to patients with neuropsychiatric symptoms, who actually constitute the majority of dementia patients. Delay in symptom progression, rates of clinically significant treatment response and numbers needed to treat (NNT) found for EGb 761 are in the same range as those reported for cholinesterase inhibitors. In an exploratory trial comparing EGb 761 and donepezil, no statistically significant or clinically relevant differences were seen. Hence, EGb 761 has its place in the treatment of dementia.

101.A systematic review of single Chinese herbs for Alzheimer's disease treatment.:(Psycho:AD)

Evid Based Complement Alternat Med. 2009 Sep 8.PMID: 19737808
The objectives here are to provide a systematic review of the current evidence concerning the use of Chinese herbs in the treatment of Alzheimer's disease (AD) and to understand their mechanisms of action with respect to the pathophysiology of the disease. AD, characterized microscopically by deposition of amyloid plaques and formation of neurofibrillary tangles in the brain, has become the most common cause of senile dementia. The limitations of western medications have led us to explore herbal medicine. In particular, many Chinese herbs have demonstrated some interesting therapeutic properties. The following databases were searched from their inception: MEDLINE (PUBMED), ALT HEALTH WATCH (EBSCO), CINAH and Cochrane Central. Only single Chinese herbs are included. Two reviewers independently extracted the data and performed quality assessment. The quality assessment of a clinical trial is based on the Jadad criteria. Seven Chinese herbs and six randomized controlled clinical trials were identified under the predefined criteria. Ginkgo biloba, Huperzine A (Lycopodium serratum) and Ginseng have been assessed for their clinical efficacy with limited favorable evidence. No serious adverse events were reported. Chinese herbs show promise in the treatment of AD in terms of their cognitive benefits and more importantly, their mechanisms of action that deal with the fundamental pathophysiology of the disease. However, the current evidence in support of their use is inconclusive or inadequate. Future research should place emphasis on herbs that can treat the root of the disease.

102.Ginkgo biloba extract in Alzheimer's disease: From action mechanisms to medical practice.:(Psycho:AD)

Int J Mol Sci. 2010 Jan 8;11(1):107-23.PMID: 20162004
Standardized extract from the leaves of the Ginkgo biloba tree, labeled EGb761, is one of the most popular herbal supplements. Numerous preclinical studies have shown the neuroprotective effects of EGb761 and support the notion that it may be effective in the treatment and prevention of neurodegenerative disorders such as Alzheimer's disease (AD). Despite the preclinical promise, the clinical efficacy of this drug remains elusive. In this review, possible mechanisms underlying neuroprotective actions of EGb761 are described in detail, together with a brief discussion of the problem of studying this herb clinically to verify its efficacy in the treatment and prevention of AD. Moreover, various parameters e.g., the dosage and the permeability of the blood brain barrier (BBB), impacting the outcome of the clinical effectiveness of the extract are also discussed. Overall, the findings summarized in this review suggest that, a better understanding of the neuroprotective mechanisms of EGb761 may contribute to better understanding of the effectiveness and complexity of this herb and may also be helpful for design of therapeutic strategies in future clinical practice. Therefore, in future clinical studies, different factors that could interfere with the effect of EGb761 should be considered.

103.Treatment of Alzheimer's disease with a cholinesterase inhibitor combined with antioxidants.:(Psycho:AD)

Neurodegener Dis. 2010;7(1-3):193-202. Epub 2010 Mar 12.PMID: 20224285
A formula (formula F) was prepared to counteract oxidative stress (OS) in the brain. The formula contained the most common antioxidants and was intended to: (a) protect proteins, lipids, DNA and proteoglycans from oxidation (carnosine, coenzyme Q(10), vitamin E, vitamin C, beta-carotene, selenium, L-cysteine and ginkgo biloba); (b) reduce homocysteine (HCy) blood levels (vitamins B(6), B(9) and B(12)), and (c) sustain the pentose phosphate cycle in circulating cells (vitamins B(1), B(2) and B(3)). Formula F contained low doses of each antioxidant component and was administered in a two-phase ampoule. A cohort of 52 patients (21 males and 31 females) affected with moderate probable AD (according to NINCDS-ARDA and NINCS-AIREN criteria) already being treated with donepezil (5 mg/day for at least two months) was randomly divided into two groups, and followed for 6 months. A double-blind design was used in which 26 cases were treated once a day with formula F plus donepezil, and the other 26 with placebo plus donepezil. The level of OS was measured on the basis of a d-ROMs test (which measures plasma hydroperoxides), plasma HCy and glutathione, and percentage of sickle erythrocytes. The two patient groups were comparable for all variables (age, sex, concomitant diseases, ApoE epsilon4, MMSE II score, OS, antioxidant reserve and sickle erythrocytes). Forty-eight subjects completed the trial. Significant decreases in OS and HCy were only observed when there was an increase in glutathione (in erythrocytes) and a decrease in sickle erythrocytes in patients treated with formula F. The MMSE II score remained almost the same in the group treated with donepezil and placebo, whereas some significant improvements were found in the group treated with donepezil plus formula F.

104.Effects of Ginkgo biloba in dementia: systematic review and meta-analysis.:(Psycho:dementia)

BMC Geriatr. 2010 Mar 17;10:14.PMID: 20236541
BACKGROUND: The benefit of Ginkgo biloba has been discussed controversially. The aim of this review was to assess the effects of Ginkgo biloba in Alzheimer's disease as well as vascular and mixed dementia covering a variety of outcome domains.METHODS: We searched MEDLINE, EMBASE, the Cochrane databases, CINAHL and PsycINFO for controlled trials of ginkgo for Alzheimer's, vascular or mixed dementia. Studies had to be of a minimum of 12 weeks duration with at least ten participants per group. Clinical characteristics and outcomes were extracted. Meta-analysis results were expressed as risk ratios or standardized mean differences (SMD) in scores.RESULTS: Nine trials using the standardized extract EGb761(R) met our inclusion criteria. Trials were of 12 to 52 weeks duration and included 2372 patients in total. In the meta-analysis, the SMDs in change scores for cognition were in favor of ginkgo compared to placebo (-0.58, 95% confidence interval [CI] -1.14; -0.01, p = 0.04), but did not show a statistically significant difference from placebo for activities in daily living (ADLs) (SMD = -0.32, 95% CI -0.66; 0.03, p = 0.08). Heterogeneity among studies was high. For the Alzheimer subgroup, the SMDs for ADLs and cognition outcomes were larger than for the whole group of dementias with statistical superiority for ginkgo also for ADL outcomes (SMD = -0.44, 95% CI -0.77; -0.12, p = 0.008). Drop-out rates and side effects did not differ between ginkgo and placebo. No consistent results were available for quality of life and neuropsychiatric symptoms, possibly due to the heterogeneity of the study populations.CONCLUSIONS: Ginkgo biloba appears more effective than placebo. Effect sizes were moderate, while clinical relevance is, similar to other dementia drugs, difficult to determine.

105.Efficacy and safety of a once-daily formulation of Ginkgo biloba extract EGb 761 in dementia with neuropsychiatric features: a randomized controlled trial.:(Psycho:dementia)

Int J Geriatr Psychiatry. 2010 Dec 7.PMID: 21140383
OBJECTIVE: To test the efficacy and safety of a once-daily formulation of EGb 761 in the treatment of patients with dementia with neuropsychiatric features.METHODS: Multi-centre trial of 410 outpatients with mild to moderate dementia (Alzheimer's disease, vascular dementia or mixed form) scoring between 9 and 23 on the SKT cognitive test battery, at least five on the Neuropsychiatric Inventory (NPI) and three or higher in at least one item of the NPI. Patients were randomly allocated to double-blind treatment with 240 mg of EGb 761 or placebo once daily for 24 weeks. Primary outcomes were the changes from baseline in the SKT total score and the NPI total score. The Alzheimer's Disease Cooperative Study Clinical Global Impression of Change (ADCS-CGIC), Activities of Daily Living International Scale (ADL-IS), NPI distress score, DEMQOL-Proxy quality-of-life scale and Verbal Fluency Test were secondary outcomes.RESULTS: At endpoint, patients treated with EGb 761 (n = 202) improved by -1.4 (95% confidence interval -1.8; -1.0) points on the SKT and by -3.2 (-4.0; -2.3) on the NPI total score, whereas those receiving placebo (n = 202) deteriorated by +0.3 (-0.1; 0.7) on the SKT and did not change on the NPI total score (-0.9; 0.9). Both drug-placebo comparisons were significant at p < 0.001. EGb 761 was significantly superior to placebo with respect to all secondary outcome measures. Adverse event rates were similar for both treatment groups.CONCLUSIONS: EGb 761, 240 mg once-daily, was found significantly superior to placebo in the treatment of patients with dementia with neuropsychiatric symptoms.

Xg-Ginkgo Biloba:Psychopharmacological effects:Psychiatric Disorders,Schizophrenia,Spilepsy,Stroke

1.Therapeutic effect of shuxuening combining neuroleptics for the treatment of chronic schizophrenia--a double blind study:(Psycho:schizophrenia)

Zhongguo Zhong Xi Yi Jie He Za Zhi. 1997 Mar;17(3):139-42.PMID: 9863076
OBJECTIVE: To assess the therapeutic effect of Shuxuening (SXN), the extractum of Ginkgo biloba761 (EGb761) in treating chronic schizophrenia.METHODS: A double-blind, placebo-controlled multi-center research on the treatment of chronic schizophrenics with SXN was used. Five hundred and forty-five patients were randomly divided into either SXN group or the control group. Patients in the former group received SXN 120 mg three times daily. Patients in both groups received their maintenance neuroleptics throughout the 16-week research treatment.RESULTS: The patients' rating scores of brief psychiatric rating scale (BPRS) and Scale for the Assessment of Negative Symptoms reduced much greater in SXN group than those in the control group from the sixth week of treatment (P < 0.01). The effect of SXN for BPRS factors of retardation and thought disturbance was better than that of the control. SXN presented a better therapeutic effect for chronic schizophrenics than the control when rated with traditional global rating method as well, in which 44.98% marked improvement was obtained in SXN group compared to 20.98% in the control group.CONCLUSION: SXN combining neuroleptics, was an effective medicine for chronic schizophrenics. Moreover, it appeared few side-effects within the recommended dose range.

2.Dietary supplements and natural products as psychotherapeutic agents.:(Psycho:psychiatric disorders)

Psychosom Med. 1999 Sep-Oct;61(5):712-28.PMID: 10511018
Alternative therapies are widely used by consumers. A number of herbs and dietary supplements have demonstrable effects on mood, memory, and insomnia. There is a significant amount of evidence supporting the use of Hypericum perforatum (St. John's wort) for depression and Ginkgo biloba for dementia. Results of randomized, controlled trials also support the use of kava for anxiety and valerian for insomnia. Although evidence for the use of vitamins and amino acids as sole agents for psychiatric symptoms is not strong, there is intriguing preliminary evidence for the use of folate, tryptophan, and phenylalanine as adjuncts to enhance the effectiveness of conventional antidepressants. S-adenosylmethionine seems to have antidepressant effects, and omega-3 polyunsaturated fatty acids, particularly docosahexaenoic acid, may have mood-stabilizing effects. More research should be conducted on these and other natural products for the prevention and treatment of various psychiatric disorders.

3.A review of herbal medicines for psychiatric disorders.:(Psycho:psychiatric disorders)

Psychiatr Serv. 2000 Sep;51(9):1130-4.PMID: 10970915
OBJECTIVE: This review examines herbs commonly used for psychiatric symptoms-St. John's wort, kava, ginkgo biloba, and valerian.METHODS: MEDLINE was searched for articles related to the use of herbs in psychiatry published after 1990. A secondary search examined sources cited in articles obtained from the MEDLINE search.RESULTS: Of nine controlled and standardized trials of St. John's wort, five showed the herb's superiority to placebo, and four found no differences in effectiveness when compared with antidepressant drugs. The pharmacologically active components are not known. Several double-blind, placebo-controlled trials have demonstrated the anxiolytic efficacy of kava, but these studies had ill-defined patient populations, small sample sizes, and short treatment duration. All but one of 40 controlled trials of ginkgo extracts in the treatment of dementia found clinically significant improvement in memory loss, concentration, fatigue, anxiety, and depressed mood. Most studies of gingko had poorly defined patient populations and small sample sizes and used nonstandard measures. A recent well-designed multicenter study showed significantly less decline in cognitive function among patients with dementia receiving gingko. Valerian has been shown to decrease sleep latency and nocturnal awakenings and improve subjective sleep quality, but placebo effects were marked in some studies, and in some cases the beneficial effects were not seen until two to four weeks of therapy.CONCLUSIONS: Although evidence of the efficacy of herbal preparations in treating psychiatric conditions is growing, translating the results of efficacy studies into effective treatments for patients is hampered by the chemical complexity of the products, the lack of standardization of commonly available preparations, and the paucity of well-controlled studies.

4.The effect of extract of ginkgo biloba added to haloperidol on superoxide dismutase in inpatients with chronic schizophrenia.:(Psycho:schizophrenia)

J Clin Psychopharmacol. 2001 Feb;21(1):85-8.PMID: 11199954
The purpose of the study was to evaluate the effect of the classic antipsychotic haloperidol plus extract of ginkgo biloba (EGb) on treatment-resistant chronic schizophrenia and on blood superoxide dismutase (SOD) levels. Eighty-two patients with chronic refractory schizophrenia were studied. Forty-three patients were treated with haloperidol plus extract of ginkgo biloba (group 1), and 39 received haloperidol plus placebo (group 2). SOD levels of these patients were measured before and after treatment and were compared with SOD levels of 30 healthy volunteers. Therapeutic efficiency was equated with a change in clinical rating scores assessed by standardized measurement tools that included the Scale for the Assessment of Positive Symptoms and the Scale for the Assessment of Negative Symptoms (SANS) over this period. Patients in group 1 improved significantly as demonstrated by scores from these two assessment instruments; those in group 2 improved significantly only as shown by scores on SANS. SOD levels before treatment in all patients were significantly higher than those in healthy controls; after treatment, the SOD level decreased significantly in group 1 but not in group 2. These results suggest that EGb may enhance the efficiency of the classic antipsychotic haloperidol in patients with schizophrenia, especially on their positive symptoms, and that EGb may work through an antioxidant effect that is involved in the therapeutic mechanism in patients with chronic refractory schizophrenia.

5.The effects of classic antipsychotic haloperidol plus the extract of ginkgo biloba on superoxide dismutase in patients with chronic refractory schizophrenia.:(Psycho:schizophrenia)

Chin Med J (Engl). 1999 Dec;112(12):1093-6.PMID: 11721446
OBJECTIVES: To explore the association between schizophrenic symptoms and superoxide dismutase (SOD), and to investigate the effect of classic antipsychotic haloperidol plus the extract of Ginkgo biloba (EGb) on SOD.METHODS: In 54 patients with chronic refractory schizophrenia, 27 were treated with haloperidol plus EGb (group 1), and the rest received haloperidol plus placebo (group 2). Superoxide dismutase (SOD) levels of these patients were measured before and after treatment and compared with the levels of 25 healthy volunteers. Therapeutic efficacy was equated with a change in clinical rating scores assessed by standardized measurement tools including the Scale for Assessment of Positive Symptoms (SAPS) and the Scale for Assessment of Negative Symptoms (SANS).RESULTS: Patients in group 1 improved significantly as demonstrated by scores from both SAPS and SANS, while those in group 2 only by scores from SANS. Assessed by SAPS, the response of patients receiving haloperidol plus EGb was more significant than those receiving haloperidol only. SOD levels before treatment in all patients were significantly higher than those in normal controls. After treatment, SOD levels decreased significantly in group 1 but not in group 2. In addition, before treatment, SOD levels in all patients correlated significantly with SAPS score. The levels of SOD measured before treatment were also correlated with the improvement of patients as measured by SAPS and SANS after 12 weeks.CONCLUSIONS: EGb may enhance the efficacy of classic antipsychotic haloperidol on schizophrenia, especially on positive symptoms. It may work through an antioxidant efficacy that is involved in the therapeutic mechanism.

6.A double-blind, placebo-controlled trial of extract of Ginkgo biloba added to haloperidol in treatment-resistant patients with schizophrenia.:(Psycho:schizophrenia)

J Clin Psychiatry. 2001 Nov;62(11):878-83.PMID: 11775047
BACKGROUND: Many studies have indicated that excess free radical formation may be involved in the pathogenesis of patients with schizophrenia. Some investigators suggested that the use of free radical scavengers might provide improvement in schizophrenia. The aim of this study was to determine the effectiveness and to evaluate the side effects of extract of Ginkgo biloba (EGb) plus haloperidol in chronic, treatment-resistant inpatients with schizophrenia.METHOD: One hundred nine patients meeting DSM-III-R criteria for schizophrenia completed a double-blind, placebo-controlled, parallel-group study of EGb plus haloperidol. Fifty-six of the patients were randomly assigned to receive a fixed dose of 360 mg/day of EGb plus a stable dose of haloperidol, 0.25 mg/kg/day, and 53 were assigned to receive placebo plus the same dose of haloperidol for 12 weeks. Patients were assessed using the Brief Psychiatric Rating Scale (BPRS), the Scale for the Assessment of Negative Symptoms (SANS), and the Scale for the Assessment of Positive Symptoms (SAPS) at baseline, week 6, and week 12 and the Treatment Emergent Symptom Scale (TESS) for side effects at week 12.RESULTS: There was a significant reduction in both groups in BPRS total score after 12 weeks of treatment (p < .05). However, a significant reduction in total SAPS and SANS scores was noted in the EGb group (p < .05), but not in the placebo group. There was a lower SAPS total score in the EGb group than in the placebo group at the end of 12 weeks of treatment (p < .05). Of those treated with EGb plus haloperidol, 57.1% were rated as responders as compared with only 37.7% of those receiving placebo plus haloperidol when assessed by the SAPS (chi2 = 4. 111, p = .043). After 12 weeks of treatment, TESS subscore 1 (behavioral toxicity) and subscore 3 (symptoms of nerve system) were significantly decreased in the EGb group compared with the placebo group (p < .05).CONCLUSION: EGb treatment may enhance the effectiveness of antipsychotic drugs and reduce their extrapyramidal side effects.

7.Effects of ginkgo biloba extract on an experimental model of epilepsy:(Psycho:schizophrenia/epilepsy)

Med Pregl. 2004 Nov-Dec;57(11-12):541-4.PMID: 16106999
INTRODUCTION: The active ingredients of ginkgo biloba extracts were determined by biochemical analyses in the last ten years and they are widely used in classical medicine. The active substances of ginkgo biloba extract, mostly affect muscarinic receptors and adrenergic receptors to a lesser degree. Recently, potential effects of ginkgo biloba on NMDA receptors and on epileptogenic seizures have been considered. The main goal of this research was to investigate effects of ginkgo biloba extracts on the experimantal model of epilepsy.MATERIAL AND METHODS: The research was carried out on chinchilla rabbits. GINGIUM solution was used with 40 mg in 1 ml of dry extract of ginkgo biloba leaves. The epileptogenic area was formed by stimulating hippocampus. Bioelectrical activity was registered 60 minutes before the epileptogenic area was formed as well as 90 minutes later. Ginkgo biloba extract was given via i.m, in a single daily dose of 1 ml/kg/BW.RESULTS: A statistically significantly higher frequency of paroxysmal seizures was established after usage of ginkgo biloba.CONCLUSION: According to the results obtained in this research, we can conclude that ginkgo biloba extracts have a proconvulsive activity.

8.The effect of extract of ginkgo biloba addition to olanzapine on therapeutic effect and antioxidant enzyme levels in patients with schizophrenia.:(Psycho:schizophrenia)

Psychiatry Clin Neurosci. 2005 Dec;59(6):652-6.PMID: 16401239
It has been suggested that the extract of gingko biloba (EGb) may enhance the efficiency of the classic antipsychotic haloperidol in patients with chronic schizophrenia, especially on positive symptoms, and reduce serum superoxide dismutase (SOD) levels. Therefore, we decided to evaluate the therapeutic effect of EGb and to examine the effect of it on the levels of antioxidant enzymes in schizophrenic patients on olanzapine treatment. We hypothesized that EGb would have the beneficial effects on schizophrenic symptoms and might cause reductions in antioxidant enzymes. The subjects were randomly assigned to the two groups: olanzapine plus EGb (group I) (n=15) and olanzapine alone (group II) (n=14). The patients were evaluated at baseline and at week 8 with respect to the Positive and Negative Syndrome Scale (PANSS), serum SOD, catalase (CAT), and glutathion peroxidase (GPX) levels. At baseline, no statistically significant difference regarding the mean total PANSS scores between treatment groups was found. At the evaluation of week 8, a significant difference in mean Scale for the Assessment of Postive Symptoms (SAPS) scores but not in Scale for the Assessment of Negative Symptoms scores between groups was found. Total patients had statistically significant higher serum SOD, CAT and GPX levels compared to control groups at baseline. At 8 weeks, there were significant differences in the mean decrease in SOD and CAT levels but not in GPX levels between treatment groups. The changes in SOD and CAT levels were correlated with the change in SAPS in group I, but not in the group II. The present study supported the findings of the previous study demonstrating that EGb might enhance the efficiency of antipsychotic in patients with schizophrenia, particularly on positive symptoms of the disorder.

9.A comparison study of cerebral protection using Ginkgo biloba extract and Losartan on stroked rats.:(Psycho:Stroke)

Neurosci Lett. 2006 May 1;398(1-2):28-33. Epub 2006 Jan 27.PMID: 16443325
It has been well documented that oxidative stress is involved in stroke. Currently, many neuroprotective strategies have been targeted at molecules that are able to act as an oxidant to intervene with free-radical mediated apoptosis in the ischemic penumbra. In particular, natural products which contain antioxidant properties have undoubtedly efficacious for stroke treatment. In the current study, therapeutic effects of Ginkgo biloba extract (EGb) against cerebral protection in Wistar rats underwent middle cerebral artery occlusion (MCAO) was evaluated. A comparison study was conducted by using Losartan, an antihypertensive drug. Gene expression levels of pro-apoptotic genes (AT2 receptor, Fas, Bax and Bcl-xS) have shown to have significant reduction by EGb- and Losartan-treated groups as compared to vehicle group. Significant reduction of immunoreactivity of protein production of these genes, together with least nuclear green fluorescence observed in TUNEL, EGb, as an antioxidant drug, is concluded to have potent and promising therapeutic effect for stroke treatment.

10.Ginkgo biloba use in nursing home elderly with epilepsy or seizure disorder.:(Psycho:schizophrenia/epilepsy)

Epilepsia. 2006 Feb;47(2):323-9.PMID: 16499756
PURPOSE: Ginkgo biloba, among the most widely used herbs, possesses the capacity both to induce and to inhibit seizures. The purpose of this study was to describe the prevalence of ginkgo and other common herb prescribing in a sample of nursing home (NH) elderly diagnosed with epilepsy/seizure (Epi/Sz) disorder and to determine demographic, clinical, and functional factors associated with ginkgo use.METHODS: This was a 1-year prevalence study of 68,403 NH residents living in 557 nursing facilities throughout the United States.RESULTS: Overall, herb use in the NHs was very low (0.41%). Ginkgo was prescribed 162 times, more than any other herb. St. John's wort was prescribed 40 times; garlic, 29 times; and all others, <20 times, for a total of 307 herb orders. Among all residents with an herb order, ginkgo was prescribed for 61.9% of residents with an Epi/Sz diagnosis and 58.0% (p = 0.820) of residents without an Epi/Sz diagnosis. Dementia, educational level, and the interaction of age group with cognitive impairment were all significantly associated with herb use among Epi/Sz residents. Cognitive impairment and the interaction of Epi/Sz disorder with dementia were associated specifically with ginkgo use.CONCLUSIONS: Ginkgo is the most frequently prescribed herb in this population in which >50% of all herb orders were written for ginkgo. The concern with ginkgo use among elderly with Epi/Sz is the lack of standardization that characterizes ginkgo products. In the absence of standardization, the likelihood is increased that ginkgo products may be adulterated with the Ginkgo biloba plant parts most commonly associated with seizure provocation.

11.The use of Ginkgo biloba extract in acute ischemic stroke.:(Psycho:stroke)

Explore (NY). 2006 May;2(3):262-3.PMID: 16781654
BACKGROUND: Ginkgo biloba extract is widely used in the treatment of acute ischemic stroke in China. The Cochrane Re-view authors aimed to assess the evidence from randomized controlled trials and quasirandomized controlled trials on the use of Ginkgo biloba extract in acute ischemic stroke.OBJECTIVES: The primary objective is to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischemic stroke. Secondary objectives are to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life.SEARCH STRATEGY: The authors searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials Register of the Cochrane Complementary Medicine Field (last searched October 2004), and the Chinese Stroke Trials Register (last searched June 2004). In addition,the authors searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3,2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED(1985 to May 2002), and the China Biological Medicine Database (CBM-disk,1979 to August 2004). The authors searched relevant clinical trials and re-search registers and contacted pharmaceutical companies and researchers in an ef-fort to identify further published and unpublished studies.SELECTION CRITERIA: Randomized controlled trials or quasirandomized controlled clinical trials comparing Ginkgo biloba extract with placebo or open control(no placebo) in patients with acute ischemic stroke.DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion, assessed trial quality, and extracted data.MAIN RESULTS: Fourteen trials were identified, of which 10 trials (792 patients)were included. Four trials are awaiting assessment. In the 10 included trials, follow-up was performed at 14 to 35 days after stroke. In all studies, neurological outcome was assessed, but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analyzing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR)2.66; 95% confidence interval (CI): 1.79-3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed)0.81; 95% CI: -8.9-10.52). No deaths or major adverse events were reported during the follow-up period.CONCLUSIONS: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomized controlled trials are needed to test its efficacy.

12.The effects of Ginkgo biloba extract added to haloperidol on peripheral T cell subsets in drug-free schizophrenia: a double-blind, placebo-controlled trial.:(Psycho:schizophrenia)

Psychopharmacology (Berl). 2006 Sep;188(1):12-7. Epub 2006 Aug 12.PMID: 16906395
OBJECTIVE: To investigate the effects of Ginkgo biloba extract (EGb) administration on T lymphocyte subsets and superoxide dismutase (SOD) levels in schizophrenia.METHODS: One hundred and nine schizophrenic inpatients were randomly assigned to 12 weeks of treatment with 360 mg/day of EGb plus a stable dose of 0.25 mg kg(-1) day(-1) of haloperidol and placebo plus the same dose of haloperidol using a double-blind design. Clinical efficacy was determined using the Brief Psychiatric Rating Scale (BPRS), Scale for Assessment of Positive Symptoms, and Scale for Assessment of Negative Symptoms. T lymphocytes (CD3+), T helper cells (CD4+), T suppressor cells (CD8+), and IL-2-secreting cells were measured using the alkaline phosphatase/antialkaline phosphatase technique; and SOD levels were measured by radioimmunometric assay at baseline and at posttreatment, as compared to 30 sex- and age-matched normal subjects.RESULTS: Patients demonstrated significantly lower CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, and significantly higher blood SOD levels than did healthy controls at baseline. There was a significantly negative relationship between SOD and CD4+ cells in the schizophrenic group at baseline. After a 12-week treatment, CD3+, CD4+, and IL-2-secreting cells, together with CD4/CD8 ratio, showed a significant increase, but a significant decrease in SOD levels in the EGb group. There was only a significant increase in CD4+ cells but no change in SOD levels in the placebo group. There was a significant correlation between the change in CD4+ cells at posttreatment vs pretreatment and a reduction of BPRS total score in the whole patient group.CONCLUSIONS: EGb may improve the decreased peripheral immune functions in schizophrenia. The beneficial effects of EGb on the immune systems and the improvement of schizophrenic symptoms may be medicated through its antioxidant activity.

13.Meta-analysis of traditional Chinese patent medicine for ischemic stroke.:(Psycho:stroke)

Stroke. 2007 Jun;38(6):1973-9. Epub 2007 Apr 26.PMID: 17463317
BACKGROUND AND PURPOSE: A large number of traditional Chinese patent medicine (TCPM) are widely used for ischemic stroke in China. The aim of this study was to systematically review the existing clinical evidence on TCPM for ischemic stroke.METHODS: We identified all TCPM that were listed in the Chinese National Essential Drug list of 2004 and those commonly used TCPM in current clinical practice for ischemic stroke. Fifty-nine TCPM were identified for further evaluation. We applied Cochrane systematic review methods. We searched for reports of randomized controlled trials and controlled clinical trials on any of the 59 TCPM for ischemic stroke comparing one TCPM with control. Primary outcomes included death or dependency at the end of follow-up (at least 3 months) and adverse events. Effects on neurological impairments were a secondary outcome.RESULTS: One-hundred ninety-one trials (19,338 patients) on 22 TCPM were available and included, of which 120 were definite or possible randomized controlled trials and 71 were controlled clinical trials. The methodological quality of included trials was generally "poor." Few trials reported methods of randomization. Three trials were randomized, double blind, and placebo-controlled. Primary outcomes: one trial on Puerarin and one trial on Shenmai injection assessed death or dependency at the end of long-term follow-up (at least 3 months) and found no statistically significant difference between 2 groups. The reported adverse events including allergic reaction, headache, nausea, diarrhea, bellyache, blood pressure change, and subcutaneous ecchymosis. Most of the adverse events were not severe. Secondary outcomes: analysis of the secondary outcome, "marked improvement in neurological deficit," showed apparent benefits of about the same magnitude for all the TCPM studied. Of the 22 TCPM, 8 drugs (Milk vetch, Mailuoning, Ginkgo biloba, Ligustrazine, Danshen agents, Xuesetong, Puerarin, and Acanthopanax) had relatively more studies and patient numbers.CONCLUSIONS: There was insufficient good quality evidence on the effects of TCPM in ischemic stroke on the primary outcome (death or dependency). We considered the apparent benefit on neurological impairment was as likely to be attributable to bias from poor methodology as to a real treatment effect. However, because the agents assessed appeared potentially beneficial and nontoxic, further randomized controlled trials are justified. Eight drugs could be further research priorities.

14.Heme oxygenase 1, beneficial role in permanent ischemic stroke and in Gingko biloba (EGb 761) neuroprotection.:(Psycho:stroke)

Neuroscience. 2011 Feb 17PMID: 21334424
Ginkgo biloba extract, EGb 761, a popular and standardized natural extract, contains 24% ginkgo-flavonol glycosides and 6% terpene lactones. EGb 761 is used worldwide to treat many ailments, and while a number of studies have shown its neuroprotective properties, the mechanisms of action have not been elucidated fully. We hypothesize that EGb 761 and some of its bioactive components [Bilobalide (BB), Ginkgolide A (GA), Ginkgolide B (GB), and Terpene Free Material (TFM)] could provide neuroprotection in ischemic conditions through heme oxygenase 1 (HO1). Mice were subjected to permanent distal middle cerebral artery occlusion (pMCAO) and survived for 7 days. HO1(-/-) mice showed significantly higher (p<0.05) infarct volume and Neurologic Deficit Scores (NDS) as compared to their wildtype (WT) counterparts. In another cohort, WT mice subjected to pMCAO and treated at 4 h of pMCAO with 100mg/kg EGb 761, 6mg/kg BB, GA, GB, or 10mg/kg TFM showed significantly lower (p<0.05) infarct volumes (BB; 29.0±3.9%, GA; 31.3±4.0%, GB; 32.0±3.8%, TFM; 32.5±3.5%, and EGb 761; 27.4±4.5%) than those in the vehicle-treated mice (46.0±3.7%). Similarly, NDS were lower in BB: 7.1±1.8, GA; 7.4±2.1, GB; 7.9±1.8, TFM; 7.7±1.7, and EGb 761; 6.8±2.0 groups as compared with the vehicle-treated group (13.8±1.5). Interestingly, the protective effect of EGb 761 was essentially lost when HO1 knockout mice were treated with EGb 761. In another cohort, HO1, VEGF and eNOS protein levels in the brain cortices appeared to be higher in EGb 761 and BB but not in GA, GB and TFM treated groups. Together, these results suggest that HO1 plays, at least in part, an important role in the neuroprotective mechanism of EGb 761 and in delayed ischemia. Targeting this pathway could lead to neuroprotective agents against ischemic stroke.

15.A placebo-controlled study of extract of ginkgo biloba added to clozapine in patients with treatment-resistant schizophrenia.:(Psycho:schizophrenia)

Int Clin Psychopharmacol. 2008 Jul;23(4):223-7.PMID: 18545061
The focus of this study was the systematic evaluation of the clinical effects of the extract of ginkgo biloba (EGb) as an adjunct to the atypical antipsychotic clozapine in the treatment of refractory schizophrenia. In a placebo-controlled study, 42 patients with chronic, treatment-resistant schizophrenia, who were maintained on optimal doses of clozapine, were administered either 120 mg/day of EGb (N=20) or placebo (N=22) for 12 weeks. Clinical evaluations with the Brief Psychiatric Rating Scale, the Scale for the Assessment of Positive Symptoms, and the Scale for the Assessment of Negative Symptoms were completed biweekly. The use of EGb as an adjunct to clozapine was effective in decreasing negative symptoms, but not positive and overall psychopathology symptoms. EGb produced a mean 7.9+/-7.0 point reduction in the total Scale for the Assessment of Negative Symptoms score compared with a mean 1.8+/-3.5 point reduction in the placebo group (P=0.034). These preliminary data suggested that EGb was found useful for enhancing the effect of clozapine on negative symptoms in patients with treatment-resistant schizophrenia.

16.Effect of extracts of Ginkgo biloba leaf on learning-memory ability and NMDA receptor 1 expression in the hippocampus in rats with kindling-induced epilepsy:(Psycho:schizophrenia/epilepsy)

Zhongguo Dang Dai Er Ke Za Zhi. 2008 Jun;10(3):367-70.PMID: 18554470
OBJECTIVE: To study the effect of extracts of Ginkgo biloba leaf (EGb), a catalyzer of central nervous system, on learning-memory ability and possible mechanism in rats with kindling-induced epilepsy.METHODS: Forty postnatal day 21 (P21) and 40 postnatal day 35 (P35) Sprague-Dawley (SD) rats were randomly respectively assigned to five groups: normal sodium (NS) control, kindling epilepsy model, high, middle and low dosage of EGb-treated kindling epilepsy. The kindling epilepsy model was established by an intraperitoneal injection of pentetrazole (PTZ). The learning-memory ability and NMDA receptor 1 (NMDAR1) expression in the hippocampus were measured by Y-maze test and immunohistochemistry assay respectively.RESULTS: The stimulation times for reaching to academic standard in the Y-maze test in the two ages PTZ kindling groups was significantly more than that in the corresponding NS control groups (P<0.01). After EGb treatment the achievement of the Y-maze test in the three treatment groups was significantly improved in a dose-dependent manner, the higher the dosage, the better the achievement (P<0.01). Immunohistochemistry assay showed that the expression of NMDAR1 in the two ages PTZ kindling groups was significantly higher than that in the corresponding NS control groups (P<0.01). Compared with the corresponding untreated kindling model groups, the expression of NMDAR1 in the two ages EGb treatment groups was significantly reduced in a dose-dependent manner (P<0.01).CONCLUSIONS: EGb can improve learning-memory ability in epileptic rats at different developmental phases in a dose-dependent manner, possibly through a reduction of NMDAR1 expression in the hippocampus.

17.Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia.:(Psycho:schizophrenia)

Int J Neuropsychopharmacol. 2010 Mar;13(2):257-71. Epub 2009 Sep 24.PMID: 19775502
This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were: criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo. They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms, and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post-trial scores and its pooled standard deviation were used to compute standardized mean difference (SMD). Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=-0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored.

18.Extract of ginkgo biloba treatment for tardive dyskinesia in schizophrenia: a randomized, double-blind, placebo-controlled trial.:(Psycho:schizophrenia)

J Clin Psychiatry. 2010 Sep 21.PMID: 20868638
OBJECTIVE: Free radicals may be involved in the pathogenesis of tardive dyskinesia (TD). Extract of Ginkgo biloba (EGb) is a potent antioxidant possessing free radical-scavenging activities. The aim of the study was to evaluate the efficacy of EGb-761, a standardized extract given in capsule form, in treating TD in schizophrenia patients.METHOD: Inpatients with DSM-IV-diagnosed schizophrenia and TD (n = 157) in a mainland China Veterans Affairs psychiatric hospital were randomly assigned to 12 weeks of treatment with either EGb-761, 240 mg/d (n = 78) or a placebo (n = 79) in a double-blind manner. Primary outcome measures were (1) change from baseline in the Abnormal Involuntary Movement Scale (AIMS) score and (2) proportion of patients with a ≥ 30% reduction in their AIMS total score at week 12. Secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS) and cognitive performance as measured by the Continuous Performance Test-37 Version and the 3-card Stroop task. Patients were recruited for the study between December 2006 and May 2007.RESULTS: Of the 157 patients who were randomly assigned, 152 (96.8%) completed the study. EGb-761 treatment significantly decreased the AIMS total score in patients with TD compared to those who were given a placebo (2.13 ± 1.75 vs -0.10 ± 1.69; P < .0001), with 40 (51.3%) and 4 (5.1%) patients achieving response in the EGb-761 and placebo treatment groups, respectively. There were no between-group differences in the PANSS total score or cognitive measures from baseline to week 12.CONCLUSIONS: EGb-761 appears to be an effective treatment for reducing the symptoms of TD in schizophrenia patients, and improvement may be mediated through the well-known antioxidant activity of this extract.TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT00672373.

19.Ginkgo biloba for acute ischaemic stroke.:(Psycho:stroke)

Cochrane Database Syst Rev. 2005 Oct 19;(4):CD003691.PMID: 16235335
BACKGROUND: Ginkgo biloba extract is widely used in the treatment of acute ischaemic stroke in China. We aimed to assess the evidence from randomised controlled trials and quasi-randomised controlled trials on the use of Ginkgo biloba extract in acute ischaemic stroke.OBJECTIVES: The primary objective was to determine whether Ginkgo biloba extract improves functional outcome without causing undue harm in patients with acute ischaemic stroke. Secondary objectives were to assess the effect of Ginkgo biloba extract on neurological impairment and quality of life.SEARCH STRATEGY: We searched the Cochrane Stroke Group Trials Register (last searched October 2004), the Trials Register of the Cochrane Complementary Medicine Field (last searched October 2004) and the Chinese Stroke Trials Register (last searched June 2004). In addition, we searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2004), MEDLINE (1966 to August 2004), EMBASE (1980 to June 2004), AMED (1985 to May 2002) and the China Biological Medicine Database (CBM-disc, 1979 to August 2004). We searched relevant clinical trials and research registers and contacted pharmaceutical companies and researchers in an effort to identify further published and unpublished studies.SELECTION CRITERIA: Randomised controlled trials or quasi-randomised controlled clinical trials comparing Ginkgo biloba extract with placebo or open control (no placebo) in patients with acute ischaemic stroke.DATA COLLECTION AND ANALYSIS: Two reviewers independently selected trials for inclusion, assessed trial quality and extracted the data.MAIN RESULTS: Fourteen trials were identified, of which 10 trials (792 patients) were included. Four trials are awaiting assessment. In the 10 included trials follow up was performed at 14 to 35 days after stroke. In all studies neurological outcome was assessed but none of them reported on disability (activities of daily living function) or quality of life. Only three trials reported adverse events. In nine trials, all of them assessed to be of inferior quality, significant improvement in neurological deficit at the end of the treatment was used as the outcome measure. When analysing these trials together, Ginkgo biloba extract was associated with a significant increase in the number of improved patients (Peto odds ratio (OR) 2.66; 95% confidence interval (CI) 1.79 to 3.94). One placebo-controlled trial, assessed to be of good quality, reported neurological outcome as a continuous variable. It failed to show an improvement of neurological deficit at the end of treatment (weighted mean difference (fixed) 0.81; 95% CI -8.9 to 10.52). No deaths or major adverse events were reported during the follow-up period.AUTHORS' CONCLUSIONS: There was no convincing evidence from trials of sufficient methodological quality to support the routine use of Ginkgo biloba extract to promote recovery after stroke. High-quality and large-scale randomised controlled trials are needed to test its efficacy.

Xh-Ginkgo Biloba:Emotional-subject Problems:dependence,anxiety,autism,etc.

1.Ginkgo biloba special extract EGb 761 in generalized anxiety disorder and adjustment disorder with anxious mood: a randomized, double-blind, placebo-controlled trial.:(Psycho:emotional/anxiety disorder)

J Psychiatr Res. 2007 Sep;41(6):472-80. Epub 2006 Jun 30.PMID: 16808927
Ginkgo biloba special extract EGb 761, an anti-dementia drug, enhances cognitive functioning and stabilizes mood in cognitively impaired elderly subjects. Moreover, EGb 761 had been found to alleviate symptoms of anxiety in people with mental decline, therefore it was now tested for clinical efficacy in younger patients suffering from anxiety. One hundred and seven patients with generalized anxiety disorder (GAD, n=82) or adjustment disorder with anxious mood (ADWAM, n=25) according to the diagnostic and statistical manual of mental disorders, third edition - revised (DSM-III-R) were randomized to daily doses of 480 mg EGb 761, 240 mg EGb 761 or placebo for 4 weeks. Intention-to-treat (ITT) analyses were performed on the primary outcome measure, the Hamilton rating scale for anxiety (HAMA), and the secondary variables, the clinical global impression of change (CGI-C), the Erlangen anxiety tension and aggression scale (EAAS), the list of complaints (B-L'), and the patient's global rating of change. The HAMA total scores decreased by -14.3 (+/-8.1), -12.1 (+/-9.0) and -7.8 (+/-9.2) in the high-dose EGb 761, the low-dose EGb 761 and the placebo group, respectively. Changes were significantly different from placebo for both treatment groups with p=0.0003 (high-dose group) and p=0.01 (low-dose). Regression analyses revealed a dose-response trend (p=0.003). EGb 761 was significantly superior to placebo on all secondary outcome measures. It was safe and well tolerated and may thus be of particular value in elderly patients with anxiety related to cognitive decline.

2.First preliminary results of an observation of Ginkgo Biloba treating patients with autistic disorder.:(Psycho:emotional/autism)

Phytother Res. 2009 Nov;23(11):1645-6.PMID: 19274699
Deficits in reciprocal social interaction, verbal and nonverbal communication, and imaginative activity are the main characteristics of autism. From the psychopharmacological point of view, clonidine, metylphenidate and neuroleptics may improve some of these aspects, but with a remarkable risk of adverse side effects. In our observational study, three patients received 2 x 100 mg Ginkgo Biloba EGb 761 for 4 weeks and showed some improvement on the Aberrant Behavior and Symptom Checklist. These results suggest, that Ginkgo Biloba might be effective at least as an add-on therapy.

3.Treatment of the disorders of aging with Ginkgo biloba extract. From pharmacology to clinical medicine:(Psycho:aging-disorder)

Presse Med. 1986 Sep 25;15(31):1540-5.PMID: 3024145
Ginkgo biloba extract is prescribed in psychic and behavioural disorders of the elderly, in peripheral vascular deficiency and in functional disorders of ischaemic origin in the E.N.T. and eye areas. Numerous controlled clinical trials justify these prescriptions and are in agreement with the pharmacological data currently available. Experimentally, Ginkgo biloba extract has proved active on the circulatory and rheological functions, on neuronal metabolism threatened by ischaemia or hypoxia, on neurotransmission and on membrane lesions caused by free oxygenated radicals. Concerning Alzheimer's disease and dementia, no firm conclusion can be drawn for the time being due to the lack of animal model. However, experimental data suggest that the product may act on a number of major elements of these diseases. From what is already known about Ginkgo biloba extract, it appears that it fulfills the conditions laid down by the W.H.O. concerning the development of drugs effective against cerebral ageing.

Xi-Ginkgo Biloba:Subject dependence Research:

1.A pilot trial of piracetam and ginkgo biloba for the treatment of cocaine dependence.:

Addict Behav. 2003 Apr;28(3):437-48.PMID: 12628617
BACKGROUND: Chronic cocaine use is associated with cognitive deficits that may reduce the effectiveness of psychosocial treatment and promote relapse in newly abstinent cocaine-dependent patients. Nootropic agents, such as piracetam and ginkgo biloba, may improve cognitive function and reduce the incidence of relapse in these patients.METHODS: This was a 10-week, double-blind, placebo-controlled pilot trial involving 44 cocaine-dependent subjects. Subjects received either piracetam (4.8 g/day), ginkgo biloba (120 mg/day), or placebo. Subjects were required to attain abstinence from cocaine during a 2-week baseline phase demonstrated by providing at least one benzoylecgonine (BE)-negative urine toxicology screen. Outcome measures included treatment retention, urine toxicology screens, Clinical Global Impression (CGI) scores, and results from the Addiction Severity Index (ASI).RESULTS: Ginkgo biloba was not superior to placebo in any outcome measure. Piracetam was associated with more cocaine use and lower CGI scores compared to placebo.CONCLUSIONS: Neither piracetam nor ginkgo biloba appears to be a promising medication for the treatment of cocaine dependence.

Xj-Ginkgo Biloba:Subject Sleep Research:

1.The effect of Li 1370, extract of Ginkgo biloba, on REM sleep in humans.:

Pharmacopsychiatry. 2001 Jul;34(4):155-7.PMID: 11518478
Ginkgo biloba extracts (GBE) have been shown to be as effective as anti-cholinesterase inhibitors in improving the cognitive test scores of patients with dementia. Although it has been assumed that GBE works via its antioxidant and vascular effects, some evidence has emerged that GBE may have some pro-cholinergic activity. We wished to test the hypothesis that a standardised preparation of GBE, Li 1370, increases cholinergic activity by measuring its effect on the sleep polysomnogram. In particular, latency to Rapid Eye Movement (REM) sleep is sensitive to cholinergic activity. For this purpose we recruited 10 healthy volunteers of both sexes and recorded sleep polysomnograms in a randomised cross-over study, comparing sleep polysomnograms taken the night after a single evening dose of Li 1370 (240 mg) with sleep polysomnograms taken after an evening dose of placebo. No significant differences in sleep parameters (including REM sleep measures) were detected; however sleep efficiency measures and subjective sleep quality reports showed that Li 1370 was well tolerated.

Y-Ginkgo Biloba:Subject Constituents/Standardization Research:

1.Cytokinins in the Leaves of Ginkgo biloba: I. The Complex in Mature Leaves.:

Plant Physiol. 1983 Oct;73(2):223-7.
Cytokinin conjugates of zeatin, ribosylzeatin, and their respective dihydro derivatives tentatively have been identified as the major cytokinins present in mature Ginkgo biloba L. leaves. Ribosylzeatin was present in higher levels than zeatin and dihydrozeatin. No evidence could be found that 6-(2,3,4-trihydroxy-3-methylbutylamino)purine occurs as a metabolite in the mature leaves. From the available evidence, it is concluded that cytokinin conjugates are probably the major metabolites formed in the leaves of this deciduous gymnosperm.

2.HPLC Separation and Quantitative Determination of Biflavones in Leaves from Ginkgo biloba.:

Planta Med. 1983 Dec;49(12):204-7.
An HPLC method for separation and quantitative determination of biflavones in crude leaf extracts from GINKGO BILOBA L. is described. A system using a Lichrosorb(R)-Diol column and the ternary elution system: hexane-chloroform-tetrahydrofuran, was suitable for separation of sciadopitysin, ginkgetin, isoginkgetin and bilobetin. The biflavones were detected at 330 nm; their calibration curves were established and their response factors were calculated using acacetin as internal standard. This method was used for the quantitative determination of the biflavones in crude leaf extracts; the seasonal variations of the biflavone content were studied and showed a higher amount in autumn leaves.

3.Water-soluble polysaccharides from Ginkgo biloba leaves.:

Phytochemistry. 1991;30(9):3017-20.PMID: 1367794
The water-soluble polysaccharides from dried Ginkgo biloba leaves were isolated after exhaustive extraction with organic solvents. The polysaccharide mixture could be separated into a neutral (GF1) and two acidic (GF2 and GF3) polysaccharide fractions by ion exchange chromatography. According to the Mr distribution GF1 and GF3 seemed to be homogenous, whereas GF2 could be further fractionated into two subfractions (GF2a and GF2b) by gel permeation chromatography. GF1 (Mr 23,000) showed the structural features of a branched arabinan. The main chain was composed of 1,5-linked arabinose residues and three in 12 arabinose molecules were branched via C-2 or C-3. GF2a (Mr 500,000) consisted mainly of 1,2,4-branched mannose (29%), 1,4-linked glucuronic (32%) and galacturonic (8%) acid as well as terminal rhamnose (25%). After removal of ca 70% of the terminal rhamnose the remaining polysaccharide showed a decrease in 1,2,4-branched mannose and an increase in 1,2-linked mannose indicating that at least half of the rhamnose residues were linked to mannose via C-4. GF3 (Mr 40,000) consisted of 1,4-linked galacturonic (30%) and glucuronic (16) acid, 1,3,6-branched galactose (15%), 1,2-linked (5%) and 1,2,4-branched (3.5%) rhamnose as well as 1,5-linked arabinose (11%). Rhamnose (5%) and arabinose (10%) were present as terminal groups. Mild acid hydrolysis selectively cleaved arabinose and the remaining polysaccharide showed an increased amount of 1,6-linked and terminal galactose and a decreased quantity of 1,3,6-branched galactose. These results indicated that the terminal as well as the 1,5-linked arabinose were mainly connected to galactose via C-3. The GF3 polysaccharide appeared to be a rhamnogalacturonan with arabinogalactan side chains.

4.Protective effect of Ginkgo biloba extract (EGB 761) on free radical-induced changes in the electroretinogram of isolated rat retina.:

Drugs Exp Clin Res. 1991;17(12):571-4.PMID: 1841050
The retina is a tissue particularly rich in polyunsaturated fatty acids and thus highly sensitive to lipid peroxidation initiated by oxygenated free radicals. By recording the electroretinogram (ERG) b wave amplitude on isolated rat retina, the authors have investigated the anti-oxidant properties of Ginkgo biloba extract (EGB 761). Two groups of rats were used: one group was treated with EGB 761 at a dose of 100 mg/kg/day per os for 10 days; the other one of untreated animals served as a control. At the end of the treatment (10 days), rats were sacrificed, one retina isolated and perfused in order to record ERG. Lipid peroxidation was induced by adding a mixture of (FeSO4 + Na ascorbate) to the perfusion solution. In the untreated rats a 50% decrease in ERG was observed after only 55 min. Such a delay in the decrease and subsequent maintenance of ERG b wave amplitude confirm that the anti-oxidant properties of EGB 761 can protect the retina against lipoperoxidation.

5.Seasonal Variations of the Flavonoid Content from Ginkgo biloba Leaves.:

Planta Med. 1991 Oct;57(5):430-3.PMID: 17226181
An HPLC method for the separation and the quantitative determination of flavonol glycosides, acylflavonol glycosides, and biflavones in crude leaf extracts from GINKGO BILOBA is described. The results, expressed in percentage of rutine, kaempferol P-coumaroyl glucorhamnoside, and bilobetin showed a higher amount of acylflavonol glycosides in buds, of flavonol glycosides in spring leaves, and of biflavones in autumn leaves.

6.Concentration of Ginkgolides and Bilobalide in Ginkgo biloba Leaves in Relation to the Time of Year.:

Planta Med. 1992 Oct;58(5):413-6.PMID: 17226498
The concentrations of ginkgolides A, B, and C, and bilobalide were determined in the leaves of 3 different Dutch GINKGO BILOBA trees from late spring until late autumn 1990. The concentration versus harvest time plots were roughly the same for all the compounds in each of the 3 trees. Concentration was lowest in spring and then gradually increased until a maximum in late summer or early autumn was reached. Thereafter the concentration declined until leaf fall. The difference in ginkgolide and bilobalide content between the 3 trees was very high. For ginkgolide B, the pharmacologically most potent compound, the maximum concentration was less than 3, 68 and 204 ppm respectively. Possible reasons for these differences and consequences for phytotherapy are discussed briefly.

7.EEG profile of three different extractions of Ginkgo biloba.:

Neuropsychobiology. 1993;27(1):40-5.PMID: 8515823
Two experiment were conducted to assess the electroencephalographic effects of (1) three different dosages of a total extract of Ginkgo biloba (EGb 761, Tebonin) and (2) three different extractions of G. biloba (Tebonin and two fractions from it). The medicament was tested against placebo using a double-blind cross-over design in 12 normal healthy males for each experiment. Medication was administered for 3 days preceding the recording sessions. 25 parameters were computed from the EEG spectra. Medication-related effects were obtained for most of the power measures, whereas dominant frequencies of the respective frequency band remained largely unchanged. The differences between the EEG effects of the two studies are critically discussed.

8.Ontogenic Aspects of Ginkgolide Production in Ginkgo biloba.:

Planta Med. 1993 Jun;59(3):232-9.PMID: 17235964
The ontogenic aspects of ginkgolide production were studied by using GINKGO BILOBA seedlings, greenhouse plants, young trees, mature trees cuttings, and plant tissue cultures. Ginkgolide yield appeared to be increased with the age of the plants when the plants were grown under the same environmental conditions. Ginkgolide content in the leaves was increased when seedlings, young plants, and young trees were treated with fluridone, a carotenoid biosynthesis inhibitor. Ginkgolides appeared to be independently biosynthesized in leaves and roots of the GINKGO and stored in root bark and stem as more hydroxylated forms such as ginkgolide B or ginkgolide C.

9.Determination of flavonol glycosides in the leaf of Ginkgo biloba L. by TLC scanning:

Zhongguo Zhong Yao Za Zhi. 1996 Feb;21(2):106-8, 128.PMID: 8758765
A TLC scanning method for the determination of flavonol glycosides in the leaf of Ginkgo biloba has been established. The method includes hydrolysis of the flavonoids and subsequent quantitative TLC scanning assay of the aglycones obtained. Determinations were carried out with a Shimadzu CS-930 scanner, with lambda(S) = 370 nm and lambda(R) = 650 nm. The recoveries were 96.0%-99.6% with RSD of 1.03%-2.08%.

10.Chemical constituents of the leaves of Ginkgo biloba:

Zhongguo Zhong Yao Za Zhi. 1997 Feb;22(2):106-7, 128.PMID: 10743204
Four compounds were isolated from ethyl acetate extract of the leaves of Ginkgo biloba. Compounds II, III, IV were identified as ginkgolides A, B and C respectively, Compound I, which was obtained from the leaves of G. biloba for the first time, was identified as 3,3'-dimethoxy-4,4'-dihydroxy-stilbene by spectroscopic methods.

11.Phenolic acids from Ginkgo biloba L. Part I. Qualitative analysis of free and liberated by hydrolysis phenolic acids.:

Acta Pol Pharm. 1997 May-Jun;54(3):225-8.PMID: 9511449
The presence of phenolic acids in the leaves, roots and seed testas of Ginkgo biloba L. (Ginkgoaceae) was analyzed. Seven free and liberated by hydrolysis phenolic acids were identified by chromatographic (TLC) and spectral (UV) methods as protocatechuic, p-hydroxybenzoic, vanillic, caffeic, p-coumaric, ferulic and chlorogenic acids.

12.Phenolic acids from Ginkgo biloba L. Part II. Quantitative analysis of free and liberated by hydrolysis phenolic acids.:

Acta Pol Pharm. 1997 May-Jun;54(3):229-32.PMID: 9511450
HPLC was applied to the quantitative assay of seven free phenolic acids from the leaves, roots and seed testas of Ginkgo biloba L. (Ginkgoaceae). The concentration of the free phenolic acids amounted to: 19.693 micrograms/g of fresh leaves, 345.321 micrograms/g of roots and 2.708 micrograms/g of testas: protocatechuic acid is a dominant one. The concentration of the phenolic acids liberated by acid-mediated and alkaline hydrolysis was determined as well.

13.HPLC determination of six flavonoid constituents in Ginkgo biloba leaves:

Yao Xue Xue Bao. 1997 Aug;32(8):625-8.PMID: 11596315
Six flavonoid constituents (quercetin, isorhamnetin, kaempferol, bilobetin, ginkgetin and sciadopitysin) were isolated from Ginkgo biloba leaves and determined by reversed phase HPLC using salvianolic acid B as internal standard. The column employed was Zorbax ODS (150 mm x 4 mm ID, 5 microns). The mobile phase consisted of solvent A (methanol) and solvent B [tetrahydrofuran--water--formic acid (34:65:1)] for gradient elution. The flow rate was 1 ml.min-1 and detection was effected at 350 nm. This method is accurate, rapid and reproducible. Analytical data for various samples were given.

14.Chemistry and biology of alkylphenols from Ginkgo biloba L.:

Pharmazie. 1997 Oct;52(10):735-8.PMID: 9362086
Ginkgolic acid and related alkylphenols constitute major components of the lipid fraction of the fruit pods of Ginkgo biloba L. In addition, this class of substances is present in Ginkgo leaves which are widely used to prepare extracts for the treatment of peripheral or cerebral circulatory disorders, as well as vascular and Alzheimer type dementia. The present paper reviews the literature on chemical and biological aspects of alkylphenols from Ginkgo with special reference to their allergic and other undesired properties. As these compounds are present in crude leaf extracts, their completest possible removal has therefore to be guaranteed for therapeutically used extracts by the production process. Technically this does not imply any problem and most preparations available on the market fulfil the requirements of the Monograph of the Commission E of the former Federal German Health Authority (Bundesgesundheitsamt, BGA) requesting a maximal concentration of 5 ppm ginkgolic acids.

15.The bioavailability of ginkgolides in Ginkgo biloba extracts.:

Planta Med. 1997 Dec;63(6):563-5.PMID: 9434615
A new Ginkgo biloba leaf extract, BioGinkgo 27/7, was prepared using a method that enriches ginkgolide B. The bioavailability of ginkgolides in these extracts was assessed in rabbits in comparison with a commercially available standardized 24/6 extract. It was found that, after a single dose, a higher concentration of ginkgolides was maintained for a longer period of time with these extracts than was found with commercial extract prepared by existing methods.

16.Solid-phase extraction and gas chromatography-mass spectrometry determination of kaempferol and quercetin in human urine after consumption of Ginkgo biloba tablets.:

J Chromatogr B Biomed Sci Appl. 1999 Feb 19;723(1-2):203-10.PMID: 10080647
A method was developed for the quantification of the flavonoids quercetin and kaempferol in human urine using a solid-phase extraction procedure followed by gas chromatography-mass spectrometry. Deuterated internal standards of the analytes were spiked into the samples prior to extraction. The limit of detection of the method was ca. 10 pg on column and precision of the method for quantification in a sample of urine was +/-9.40% for kaempferol and +/-7.34% for quercetin (n = 6). The levels of quercetin and kaempferol found in urine samples were only a small fraction of the amount ingested. The treatment of urine samples with beta-glucuronidase markedly increased the levels of flavonoids detected, supporting the view that kaempferol and quercetin are eliminated in the urine as glucuronides.

17.Production of ginkgolides and bilobalide by Ginkgo biloba plants and tissue cultures.:

Planta Med. 1999 Oct;65(7):620-6.PMID: 10575377
The accumulation of the terpenes ginkgolides and bilobalide in Ginkgo biloba was reported in plants as well as in plant cell cultures. Several hundred plants cultivated under controlled conditions in the field have been analyzed for their terpene production over many years. Cross-pollination experiments were performed with mature trees and the terpene content of the progeny was analyzed. The age of the tree is the main factor influencing the terpene content of the leaves as the level always decreases dramatically between young and old trees. 80 cell culture strains have been established and ginkgolides analyzed by GC/MS. These cell cultures reveal very low amounts of terpenes (1 microgram g-1 D.W. or less). On the contrary, isolated in vitro root cultures accumulate terpenes at the same concentration as the young plant leaves (4 mg g-1 D.W.). Attempts to obtain rapid growing roots or even hairy-roots did not succeed but the possibility to transform Ginkgo cell strains has been demonstrated.

18.Liquid chromatography/electrospray mass spectrometry of bioactive terpenoids in Ginkgo biloba L.:

J Mass Spectrom. 1999 Dec;34(12):1361-7.PMID: 10587633
Standardized extracts of Ginkgo biloba leaves are mainly used in the treatment of peripheral and celebral circulation disorders, and also as a remedy against asthma, coughs, bladder inflammation, blenorrhagia and alcohol abuse. The leaf extracts contain biflavones, flavonol glycosides and terpene lactones. This paper reports a method based on liquid chromatography coupled with electrospray mass spectrometry for the analysis of terpenoids in G. biloba extracts. This method allows the rapid isocratic separation of underivatized ginkgolides (GA, GB, GC and GJ) and bilobalide at very low levels (10 pg on the column) and their quantitative detection by external standardization with relative standard deviations of 3 and 5% for intra- and inter-day analyses, respectively.

19.Biosynthesis of 4'-O-methylpyridoxine (Ginkgotoxin) from primary precursors.:

J Nat Prod. 2000 Feb;63(2):185-9.PMID: 10691705
Cell suspension cultures of Ginkgo biloba and Albizia tanganyicensis were investigated for the presence of 4'-O-methylpyridoxine (ginkgotoxin, 2), the 4'-O-methyl derivative of vitamin B(6) (pyridoxine, 1). The cultures produced the toxin even in the absence of vitamin B(6) (a common additive to plant cell culture media). This indicates that the pyridoxine ring system of ginkgotoxin is synthesized de novo by the cultured cells. A feeding experiment with D-[U-(13)C(6)]glucose revealed that the mode of incorporation of label into the pyridoxine moiety of 2 matched that observed for 1 in Escherichia coli. Thus, the data obtained in this investigation provide independent proof supporting the current hypothesis on vitamin B(6) biosynthesis. The 4'-O-methyl group of ginkgotoxin (2) was labeled from L-[methyl-(13)C(1)]methionine. This indicates that ginkgotoxin is likely to be derived by 4'-O-methylation of pyridoxine (1). The G. biloba cell suspension culture may be a suitable system to get further insight into vitamin B(6) and/or ginkgotoxin biosynthesis.

20.Changes in N-linked oligosaccharides during seed development of Ginkgo biloba.:

Biosci Biotechnol Biochem. 2000 Mar;64(3):562-8.PMID: 10803954
Structural changes in N-linked oligosaccharides of glycoproteins during seed development of Ginkgo biloba have been explored to discover possible endogenous substrate(s) for the Ginko endo-beta-N-acetylglucosaminidase (endo-GB; Kimura, Y., et al. (1998) Biosci. Biotechnol. Biochem., 62, 253-261), which should be involved in the production of high-mannose type free N-glycans. The structural analysis of the pyridylaminated oligosaccharides with a 2D sugar chain map, by ESI-MS/MS spectroscopy, showed that all N-glycans expressed on glycoproteins through the developmental stage of the Ginkgo seeds have the xylose-containing type (GlcNAc2 approximately 0Man3Xyl1Fuc1 approximately 0GlcNAc2) but no high-mannose type structure. Man3Xyl1Fuc1GlcNAc2, a typical plant complex type structure especially found in vacuolar glycoproteins, was a dominant structure through the seed development, while the amount of expression of GlcNAc2Man3Xyl1Fuc1GlcNAc2 and GlcNAc1Man3Xyl1Fuc1GlcNAc2 decreased as the seeds developed. The dominantly occurrence of xylose-containing type structures and the absence of the high-mannose type structures on Ginkgo glycoproteins were also shown by lectin-blotting and immunoblotting of SDS-soluble glycoproteins extracted from the developing seeds at various developmental stages. Concerning the endogenous substrates for plant endo-beta-N-acetylglucosaminidase, these results suggested that the endogenous substrates might be the dolicol-oligosaccharide intermediates or some glycopeptides with the high-mannose type N-glycan(s) derived from misfolded glycoproteins in the quality control system for newly synthesized glycoproteins.

21.Analysis of Ginkgo biloba for the presence of ginkgotoxin and ginkgotoxin 5'-glucoside.:

J AOAC Int. 2000 Nov-Dec;83(6):1313-20.PMID: 11128132
Hot water extracts of Ginkgo biloba seeds were analyzed for the presence of ginkgotoxin (4'-O-methylpyridoxine) by reversed-phase liquid chromatography (LC) using methanol-0.05M KH2PO4 (1 + 9, v/v) adjusted to pH 3 as mobile phase. Detection was by fluorescence (excitation 280 nm, emission 370 nm). A straight line calibration curve was obtained for the 10-100 ng injected. After addition of beta-glucosidase (37 degrees C/h), an earlier eluting peak disappeared and the ginkgotoxin peak increased. The identity of the ginkgotoxin was confirmed by LC/MS and LC/MS/MS. LC/MS/MS also confirmed the 5'-glucoside by comparison with the 3-glucoside. This is the first identification of a glucoside of ginkgotoxin in Ginkgo biloba. An unknown compound of MW 267 also observed in the Ginkgo biloba seed extract was shown not to be 3,5'-diacetylginkgotoxin by its different LC retention time. Extraction of ground Ginkgo biloba seeds with boiling water in a Soxhlet for 2 x 2 h yielded a total of 179 microg/g of free ginkgotoxin. The concentration in powder from Ginkgo biloba capsules was several times lower than this (17-64 microg/g) in 3 samples but higher in another (457 microg/g). Canned ginkgo seeds (white nuts) contained no detectable free ginkgotoxin but the glucoside was present. Different extraction times were studied: 0.5 h gave only 52 microg/g free ginkgotoxin in the ginkgo seeds. However, boiling an extract for 4 h showed about 15% loss of ginkgotoxin and its glucoside.

22.Alkylresorcinols in fruit pulp and leaves of Ginkgo biloba L.:

Z Naturforsch C. 2000 Nov-Dec;55(11-12):881-5.PMID: 11204190
These studies were undertaken to characterise resorcinolic lipids (5-n-alk(en)ylresorcinols) composition and to determine their seasonal fluctuations in fruit pulp and leaves of Ginkgo biloba L. Resorcinolic lipid concentrations were consistently higher in fruit pulp than in leaves. In pulp, several mono- and di-unsaturated homologs of alkylresorcinols were the predominant group of analysed lipids. Contrary to the fruit pulp, only 5-n-pentadecylresorcinol was demonstrated in leaves. Initially, the alkylresorcinol's content both in pulp and leaves increased until June-July and decreased following seeds ripening. This trend continued until senescence of leaves in late September and October.

23.Analysis of terpenelactones in Ginkgo biloba by high performance liquid chromatography and evaporative light scattering detection.:

Chem Pharm Bull. 2001 Sep;49(9):1170-3.PMID: 11558605
A reversed phase HPLC method permitting the determination of 5 terpenelactones in Ginkgo biloba, without the need of any sample preparation is presented in this paper. The compounds were successfully separated within 25 min by using a C-12 column, an evaporative light scattering (ELS) detector and a mobile phase comprising of ammonium acetate buffer, methanol and isobutanol. All terpenelactones were detectable at concentrations as low as 20.3 microg/ml. The analysis of G. biloba market products showed remarkable variations in the lactone content, and more than 2 fold differences in the suggested daily doses of the total lactones, from 8.84 mg to 18.28 mg, respectively.

24.A flavonoid compound in Ginkgo biloba L. leaves:

Zhongguo Zhong Yao Za Zhi. 1998 Apr;23(4):233-4, 256.PMID: 11596251
One compound was isolated for the first time from ethyl acetate extract of Ginkgo biloba leaves and identified as kaempferol-3-O-rhamnoside by spectroscopic methods

25.Seasonal and sexual variety of Ginkgo flavonol glycosides in the leaves of Ginkgo biloba L:

Zhongguo Zhong Yao Za Zhi. 1998 May;23(5):267-9, 319.PMID: 11601311
HPLC methods have been developed for the determination of Ginkgo flavonol glycosides in the Ginkgo biloba leaves obtained from May to November in the fallen leaves and in the leaves obtained from female and male trees. The method includes hydrolysis of the leaves and subsequent quantitative chromatographic assay of the aglycones, followed by calculation of Ginkgo flavonol glycosides content. The result shows that the leaves obtained in May have the highest content of 0.96%, and then the content decreases from May to August, and from August to November remains almost the same, that is 0.5% also. Fallen leaves have the lowest content of 0.44%. The content range is 0.96% to 0.44%. Male trees have higher content of glycosides than female trees.

26.Preparative isolation and dual column high-performance liquid chromatography of ginkgolic acids from Ginkgo biloba.:

J Chromatogr A. 2001 Sep 28;930(1-2):109-17.PMID: 11681568
A chromatographic procedure for the preparative isolation of six different 6-alkylsalicylic acids (syn. ginkgolic acids) with as alkyl substituents C13:0, C15:0, C15:1, C17:1, C17:2 and, tentatively C17:3 from Ginkgo biloba leaves was developed. The procedure consisted of a combination of normal-phase, reversed-phase and argentation chromatography. The compounds were characterised by means of UV, 1H-NMR and 13C-NMR spectroscopy, and mass spectrometry after silylation. A 15 cm C18 RP-HPLC column connected in series with a 20 cm silver(I) loaded cation exchanger HPLC column in combination with the solvent methanol-water (93:7) acidified with 0.1% formic acid was capable of separating the ginkgolic acids C13:0, C15:1, C17:2, C15:0 and C17:1 within 21 min on an analytical scale. The separation is based on a combination of reversed-phase mechanisms and double bond complexation. Detection took place by UV at 311 nm. The separation is a good starting point for the development of a quantitative procedure for the five major ginkgolic acids in Ginkgo leaves and standardised extracts.

27.Coumaroyl flavonol glycosides from the leaves of Ginkgo biloba.:

Phytochemistry. 2001 Dec;58(8):1251-6.PMID: 11738417
Two coumaroyl flavonol glycosides, isorhamnetin 3-O-alpha-L-[6"'-p-coumaroyl-(beta-D)-glucopyranosyl-(1,2)-rhamnopyranoside], and kaempferol 3-O-alpha-L-[6"'-p-coumaroyl-(beta-D)-glucopyranosyl-(1,2)-rhamnopyranoside]-7-O-beta-D-glucopyranoside, were isolated from the n-BuOH extract of Ginkgo biloba leaves. These two, together with six other flavonol glycosides, kaempferol 3-O-alpha-L-[6"'-p-coumaroyl-(beta-D)-glucopyranosyl-(1,2)-rhamnopyranoside], quercetin 3-O-alpha-L-[6"'-p-coumaroyl-(beta-D)-glucopyranosyl-(1,2)-rhamnopyranoside], quercetin 3-O-alpha-L-[6"'-p-coumaroyl-(beta-D)-glucopyranosyl-(1,2)-rhamnopyranoside]-7-O-beta-D-glucopyranoside, quercetin 3-O-beta-D-glucopyranosyl-(1-2)-alpha-L-rhamnopyranoside, quercetin 3-O-beta-rutinoside, and quercetin 3-O-beta-D-glucopyranoside, showed profound antioxidant activities in DPPH and cytochrome-c reduction assays using the HL-60 cell culture system.

28.Extraction of pharmaceutical components from Ginkgo biloba leaves using supercritical carbon dioxide.:

J Agric Food Chem. 2002 Feb 13;50(4):846-9.PMID: 11829655
Ginkgo biloba extract (GBE) has many remarkable pharmacological and clinical effects, and it is the most frequently used product as a phytomedicine in many countries. The combination of primary extraction with 70% ethanol followed by extraction using supercritical carbon dioxide provides an efficient and economical means for obtaining flavonoids and terpenoids from Ginkgo biloba leaves. The supercritical fluid extraction (SFE) is affected by pressure, temperature, and the concentration of modifier in the extractant. At the most favorable experimental conditions of 300 MPa, 60 degrees C, and carbon dioxide containing 5% ethanol as modifier, the yield of GBE powder is 2.1% (based on the air-dry weight of Ginkgo biloba leaves) compared to a yield of only 1.8% by conventional solvent extraction. The contents of flavonoids and terpenoids in SFE products are 35.9% and 7.3%, respectively, which are significantly higher than the general standards of 24% and 6%, respectively.

29.Reversed-phase argentation high-performance liquid chromatography in phytochemical analysis of ginkgolic acids in leaves from Ginkgo biloba L.:

J Chromatogr A. 2002 Jan 18;943(2):303-9.PMID: 11833651
A reversed-phase argentation high-performance liquid chromatographic method has been achieved for the determination of ginkgolic acids. Liquid chromatography coupled with electrospray ionization (ESI) mass spectrometry in the negative ion mode is applied to identify ginkgolic acids from ginkgo leaves. The leaves are extracted with ethanol and then cleaned-up by extraction of analytes with hexane after addition of an acidified saturated solution of sodium sulfate and siliceous earth to the matrix solution. Ginkgolic acids are determined within 30 min on a C18 column with methanol-5% aqueous acetic acid (90:10) containing 0.03 mol l(-1) silver nitrate as eluent and with ultraviolet detection at 310 nm. Addition of silver ions as complexation agent into the mobile phase decreases retention time of ginkgolic acids with an unsaturated side chain. Four ginkgolic acids are successfully separated from each other and from other interfering components by the high selectivity of reversed-phase argentation HPLC, which is confirmed by the spectra identification. The average recovery of the method is around 97%. Good reproducibility is obtained with relative standard deviations varying from 2 to 5%.

30.Three ginkgolide hydrates from Ginkgo biloba L.: ginkgolide A monohydrate, ginkgolide C sesquihydrate and ginkgolide J dihydrate, all determined at 120 K.:

Acta Crystallogr C. 2002 Mar;58(Pt 3):o195-8. Epub 2002 Feb 28.PMID: 11870327
A low-temperature structure of ginkgolide A monohydrate, (1R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-4,7b-dihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione monohydrate, C(20)H(24)O(9) x H(2)O, obtained from Mo K alpha data, is a factor of three more precise than the previous room-temperature determination. A refinement of the ginkgolide A monohydrate structure with Cu K alpha data has allowed the assignment of the absolute configuration of the series of compounds. Ginkgolide C sesquihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11S,11aR)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b,11-tetrahydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione sesquihydrate, C(20)H(24)O(11) x 1.5H(2)O, has two independent diterpene molecules, both of which exhibit intramolecular hydrogen bonding between OH groups. Ginkgolide J dihydrate, (1S,2R,3S,3aS,4R,6aR,7aR,7bR,8S,10aS,11aS)-3-(1,1-dimethylethyl)-hexahydro-2,4,7b-trihydroxy-8-methyl-9H-1,7a-epoxymethano-1H,6aH-cyclopenta[c]furo[2,3-b]furo[3',2':3,4]cyclopenta[1,2-d]furan-5,9,12(4H)-trione dihydrate, C(20)H(24)O(10) x 2H(2)O, has the same basic skeleton as the other ginkgolides, with its three OH groups having the same configurations as those in ginkgolide C. The conformations of the six five-membered rings are quite similar across ginkgolides A-C and J, except for the A and F rings of ginkgolide A.

31.Liquid chromatography-atmospheric pressure chemical ionisation/mass spectrometry: a rapid and selective method for the quantitative determination of ginkgolides and bilobalide in ginkgo leaf extracts and phytopharmaceuticals.:

Phytochem Anal. 2002 Jan-Feb;13(1):31-8.PMID: 11899603
In order to evaluate the composition of active constituents in phytopharmaceutical preparations, valid analytical methods are required. For the determination of the active terpene constituents of Ginkgo biloba (the ginkgolides and bilobalide), a liquid chromatography-mass spectrometry (LC-MS) method has been developed using atmospheric pressure chemical ionisation (APCI) in the negative ion mode. This detection mode was found to be much more sensitive and selective compared to UV; indeed the ginkgo terpene trilactones lack strong UV chromophores and flavonoids interfere with their UV detection. LC-APCI/MS detection allowed a considerable reduction in analysis time when compared to LC-UV, because LC resolution was only needed between the pair of isomers ginkgolide B and ginkgolide J. All compounds were selectively detected by single ion monitoring of their specific deprotonated molecules [M-H]-. The samples were directly injected without pre-purification, and a fast gradient was applied, reducing the total time of analysis to 14 min. With this method, the ginkgo terpene trilactones were detected on-line in the picogram range. Several commercial ginkgo preparations on the Swiss market were analysed, and the ginkgolide and bilobalide contents were evaluated using the method described.

32.Plant biotechnology: an avant-garde research for an ancestral tree, the Ginkgo biloba:

Ann Pharm Fr. 2002 Jan;60(1):22-7.PMID: 11976546
A biotechnology program on Ginkgo biloba was implemented in early 80's, in order to improve the biosynthesis in the whole plant and in cell cultures of therapeutically active substances, mainly terpenes like ginkgolides. This program led to very interesting results in various directions In addition, by the mean of in vitro culture, metabolic studies have given some pertinent fundamental results adding to the basic understanding of Ginkgo biloba: ginkgolides and bilobalide are biosynthesized in the roots of the plant and then translocated to the leaves. Two separate and independent metabolic pathways have been underlined for the formation of isopentenylpyrophosphate (IPP), the fundamental unit involved both in the biosynthesis of the sitosterol and the ginkgolides. The possibilities offered by plant biotechnology allowed the implementation of new tools for propagation and improvement of the Ginkgo biloba and have enriched the knowledge of the biosynthesis of active principles.

33.Efficient extraction of ginkgolides and bilobalide from Ginkgo biloba leaves.:

J Nat Prod. 2002 Oct;65(10):1501-4.PMID: 12398553
An efficient and rapid protocol has been developed for extracting ginkgolides and bilobalide (terpene trilactones) from Ginkgo biloba leaves. The procedure takes advantage of the extraordinary stability of the terpene trilactone structure to a variety of chemical treatments, especially oxidation, despite the presence of multiple oxygen functions. The protocol involves boiling the aqueous extract of leaves with dilute hydrogen peroxide, extraction with ethyl acetate, washing with basic solutions, and charcoal filtration to yield an off-white powder, terpene trilactone content 60-70%. It is likely that the hydrogen peroxide treatment degrades the undesired leaf constituents that lead to intense emulsification during extractions. Further reversed-phase chromatography of the extracts with polymeric resins removes the undesirable ginkgolic acids to amounts less than 10 ppm. The extracts are suited for pure terpene trilactone preparation, enrichment of terpene trilactone content in nutraceuticals, and preparations of low-flavonoid/high-terpene trilactone controls in medicinal studies. The four ginkgolides (ginkgolides A, B, C, J) and bilobalide isolated from the extract were identical in all respects with authentic specimens.

34.Rapid analysis of terpene lactones in extract of Ginkgo biloba L. by high performance liquid chromatography.:

Se Pu. 2000 Sep;18(5):394-7.PMID: 12541697
A new rapid analytical method was developed for the quantification of terpene lactones (bilobalide(BB) and ginkgolide A, B, C, J) in extract of Ginkgo biloba L. (EGb) using a liquid-liquid solvent extraction procedure followed by high performance liquid chromatography. EGb was dissolved in 30% ethanol and extracted with ether. After evaporation, the residue was then determined by HPLC on a C18 column with methanol-water-orthophosphoric acid (25:75:0.1, V/V) as eluent and refractive index (RI) detection. Results showed that the excellent sample clean-up procedure is more simple and specific, and saves more time (less than 20 min) than any other methods that have been reported, and also leads to high recoveries (> 99.0%) and low RSDs (< 2.0%). The reproducible method is regarded to be very useful for evaluating the quality of extract of Ginkgo biloba L.

35.Component analysis on polysaccharides in exocarp of Ginkgo biloba:

Zhong Yao Cai. 1997 Sep;20(9):461-3.PMID: 12572425
This paper reports the content and component analysis on polysaccharides in exocarp of Ginkgo biloba. The results show that the content of total saccharides is 89.7%; content of polysaccharides is 84.6%; content of reductic saccharides is 5.1%; the polysaccharides are composed of glucose, fructose, galactose and rhamnose.

36.Quantitative analysis of bilobalide and ginkgolides from Ginkgo biloba leaves and Ginkgo products using (1)H-NMR.:

Chem Pharm Bull. 2003 Feb;51(2):158-61.PMID: 12576648
1H-NMR spectrometry was applied to the quantitative analysis of the bilobalide, ginkgolides A, B, and C in Ginkgo biloba leaves and six kinds of commercial Ginkgo products without any chromatographic purification. The experiment was performed by the analysis of each singlet H-12, which were well separated in the range of delta 6.0-7.0 in the (1)H-NMR spectrum. However, the H-12 protons of bilobalide and ginkgolides may have overlapped with H-6 or H-8 protons of the Ginkgo flavonoids. Therefore, the optimum (1)H-NMR solvent for the analysis of the compound was selected through the evaluation of solvent effects on the resolution of these signals from the compounds. Acetone-d(6)-benzene-d(6) (50 : 50) was found to be the best one among the solvents evaluated. The quantity of the compounds was calculated by the relative ratio of the intensity of each compound to the known amount of internal standard (25 microgram), phloroglucinol. This method allows rapid and simple quantitation of underivatized bilobalide and ginkgolides in 5 min without any pre-purification steps.

37.A simple HPLC-UV method for the assay of ginkgolic acids in Ginkgo biloba extracts.:

Fitoterapia. 2003 Apr;74(3):247-56.PMID: 12727489
Extracts from the leaves of Ginkgo biloba are among the most widely used phytotherapeutics. Some alkylphenols (ginkgolic acids, cardanols and cardols) have been described as potentially hazardous constituents in Ginkgo extracts. Accordingly, a requirement for a maximum concentration of ginkgolic acids has been proposed in the UE and US pharmacopoeias Ginkgo monographs establishing a limit value of 5 ppm. A novel HPLC-UV method, developed by the use of HPLC-APCI-MS HPLC-DAD techniques and allowing the identification of ginkgolic acids and related phenols, is described. The new analytical method, not requiring enrichment procedures, can be used for the quantification of ginkgolic acids in Ginkgo extracts.

38.Variation in Ginkgo biloba L. leaf characters across a climatic gradient in China.:

Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7141-6. Epub 2003 May 30.PMID: 12777617
Fossil leaves assigned to the genus Ginkgo are increasingly being used to reconstruct Mesozoic and Tertiary environments based on their stomatal and carbon isotopic characteristics. We sought to provide a more secure basis for understanding variations seen in the plant fossil record by determining the natural variability of these properties of sun and shade leaf morphotypes of Ginkgo biloba trees under the present atmospheric CO2 concentration and a range of contemporary climates in three Chinese locations (Lanzhou, Beijing, and Nanjing). Climate had no major effects on leaf stomatal index (proportion of leaf surface cells that are stomata) but did result in more variable stomatal densities. The effects of climate and leaf morphotype on stomatal index were rather conserved (<1%) and much less than the response of trees to recent CO2 increases. Leaf carbon isotope discrimination (delta) was highest for trees in Nanjing, which experience a warm, moist climate, whereas trees in the most arid site (Lanzhou) had the lowest delta values. Interestingly, the variation in delta shown by leaf populations of trees from China and the United Kingdom was very similar to that of fossil Ginkgo cuticles dating to the Mesozoic and Tertiary, which suggests to us that the physiology of leaf carbon uptake and regulation of water loss in Ginkgo has remained highly conserved despite the potential for evolutionary change over millions of years.

39.Determination of ginkgolic acids in Ginkgo biloba extract and its preparations by high performance liquid chromatography:

Yao Xue Xue Bao. 2003 Nov;38(11):846-9.PMID: 14991999
AIM: To establish a high performance liquid chromatographic method for determination of ginkgolic acids in Ginkgo biloba extract and its preparations.METHODS: Ginkgo biloba extract and its preparations were extracted with petroleum ether in Soxhlet apparatus, and then concentrated under vacuum. The ginkgolic acids were determined directly by HPLC, and identified by LC/DAD/ESI/MS. The chromatographic column was Inertsil ODS-2; the mobile phase was methanol-3% aqueous acetic acid(92:8); the flow rate was 1.0 mL.min-1; the column temperature was 40 degrees C; the detection wavelength was 310 nm.RESULTS: There were six kinds of ginkgolic acid (C13:0, C15:1, C17:2, C15:0, C17:1 and an unknown compound C17:3 tentatively) in the Ginkgo biloba extract. The relative percentage content of ginkgolic acids C13:0, C15:1 and C17:1 was above 94%. The content of ginkgolic acids in Ginkgo biloba extract containing high content ginkgolic acids was 1.12%, and RSD was 2.4% (n = 5). The content of ginkgolic acids in one kind of EGb preparations (tablet) was 49.2 micrograms.g-1, and RSD was 4.3% (n = 5). The average recovery was 98.2%, RSD was 2.6% (n = 5).CONCLUSION: The method is accurate, fast, simple, and can be used for determination of ginkgolic acids in Ginkgo biloba extract and its preparations.

40.Chemistry and biology of terpene trilactones from Ginkgo biloba.:

Angew Chem Int Ed Engl. 2004 Mar 19;43(13):1640-58.PMID: 15038029
Ginkgo biloba, the ginkgo tree, is the oldest living tree, with a long history of use in traditional Chinese medicine. In recent years, the leaf extracts have been widely sold as phytomedicine in Europe and as a dietary supplement worldwide. Effects of Ginkgo biloba extracts have been postulated to include improvement of memory, increased blood circulation, as well as beneficial effects to sufferers of Alzheimer's disease. The most unique components of the extracts are the terpene trilactones, that is, ginkgolides and bilobalide. These structurally complex molecules have been attractive targets for total synthesis. Terpene trilactones are believed to be partly responsible for the neuromodulatory properties of Ginkgo biloba extracts, and several biological effects of the terpene trilactones have been discovered in recent years, making them attractive pharmacological tools that could provide insight into the effects of Ginkgo biloba extracts.

41.A method for extraction and quantification of Ginkgo terpene trilactones.:

Anal Chem. 2004 Aug 1;76(15):4332-6.PMID: 15283569
A method was developed for the extraction and quantification of pharmacologically active terpene trilactones (ginkgolides, bilobalide) from the tissues of Ginkgo biloba L. and pharmaceutical ginkgo products by RP-HPLC, based on the theory of terpene trilactones ionization. Four ginkgolides (GA, GB, GC, GJ) and bilobalide (BB) from both the ginkgo leaves and commercially available ginkgo extracts were quantitatively extracted by using this method. The recovery rate of the method was 97.5-100% with RSD of 1.2-2.8%. The detection limit was 0.05-0.1 microg, and the linear range was 0.1-12 microg. This detection limit represents a marked improvement over previously reported methods, suggesting the new method is a viable technique for routine analysis of ginkgo terpene trilactones in natural and commercial samples. The method reported by van Beek et al. in 1991 (van Beek, T. A.; Scheeren, H. A.; Rantio T.; Melger, W. C.; Lelyveld, G. P. J. Chromatogr. 1991, 543, 375-387.) was used as a reference method to monitor the accuracy of extraction and analysis in this study. SSI-MS technique was used to identify isolated target components. Carbohydrase treatment and solubility of terpene trilactones in various solvents were also discussed.

42.Studies on purification of polyprenol from Ginkgo biloba L. leaves:

Zhong Yao Cai. 2004 May;27(5):337-9.PMID: 15376386
OBJECTIVE: To research the methods of purifying polyprenol from leaves of Ginkgo biloba L..METHODS: The purity of polyprenol was determined by HPLC to select the optimal purifying conditions.RESULTS: The optimal conditions were degreased by 160 times of petroleum ether-ethyl acetate (9:1) firstly, then through a silica gel column (100-140 mesh) and eluted with petroleum etherethyl acetate (19:1).CONCLUSION: The methods are feasible to purify polyprenol from leaves of Ginkgo biloba L. and could increase the purity of polyprenol obviously.

43.Progress in research on constituents and pharmacological activities of sarcotestas of Ginkgo biloba:

Zhongguo Zhong Yao Za Zhi. 2004 Feb;29(2):111-5.PMID: 15719673
The latest progress in research on constituents and pharmacological activities of sarcotestas of Ginkgo biloba has been studied. The main constituents in sarcotestas of G. biloba include flavones, ginkgolides, alkylphenols, polysaccharides and amino acids, etc. They show the following activities, such as bacteriostatic, bactericidal and pesticidal activities, antitumor and mutagenic, carcinogenic effects, antianaphylaxis and allergenic activity, effects on immunologic function, scavenging free radical, antisenile action, etc. The problems at present and the reseach direction for the future on sarcotestas of G. biloba have been put forward.

44.Biflavone glucosides from Ginkgo biloba yellow leaves.:

Chem Pharm Bull. 2005 Sep;53(9):1200-1.PMID: 16141598
Phytochemical investigation of Ginkgo biloba (Ginkgoaceae) has resulted in the isolation of two new biflavone glucosides, ginkgetin 7''-O-beta-D-glucopyranoside (1) and isoginkgetin 7-O-beta-D-glucopyranoside (2). The structures were determined on the basis of chemical and spectroscopic evidences.

45.Determination of terpene trilactones in Ginkgo biloba solid oral dosage forms using HPLC with evaporative light scattering detection.:

J Pharm Biomed Anal. 2006 Apr 11;41(1):135-40. Epub 2006 Jan 9.PMID: 16406712
A reversed phase high performance liquid chromatographic method with evaporative light scattering detection (RP-HPLC-ELSD) was developed for the quantitative determination of the terpene trilactones, ginkgolide A, B, C and J and the sesquiterpene, bilobalide in Ginkgo biloba solid oral dosage forms. Separation was achieved using a minibore Phenomenex Luna (5 microm) C18 column with dimensions 250 mm x 2.00 mm maintained at a temperature of 45 degrees C. A simple gradient method using a mobile phase of methanol:water and a flow rate of 350 microl/min facilitated baseline separation of the selected marker compounds within 14 min. The ELSD parameters affecting the detector response were optimized prior to the validation. The limits of detection and quantification were 31.25 and 62.50 ng, respectively. The percentage relative errors of the recovery ranged between -3.16 and +1.88 and both intra-day and inter-day percentage standard deviations were all better than 6%. This method was used to assay commercially available Ginkgo biloba products and proved to be suitable for the routine analysis of such products for quality control purposes.

46.Study on the comparison of polysaccharides in Ginkgo biloba leaves:

Zhong Yao Cai. 2006 Nov;29(11):1139-41.PMID: 17228652
OBJECTIVE: To determine the suitable tree's age, tree's sex and gathering seasons for Ginkgo biloba leaves.METHODS: The twelve different polysaccharides were obtained by extracting and precipitating from Ginkgo biloba leaves and to see if there were differences among them. The concentration of Ginkgo biloba leaf polysaccharides with the highest gain ratio will be determined by HPLC.RESULT: The average gain ratio of Ginkgo biloba leaf polysaccharides was 4.29%, among them the gain ratio of 10-years old female Ginkgo biloba leaf collected in the last ten days of September was the highests, its polysaccharides concentration was 61.5% with RSD = 2.5% (n = 6). CONCLUSIOn: The gain ratios were different in different Ginkgo biloba leaves and the changing rules provide scientific basis for the GAP of medicinal plants.

47.The human pyridoxal kinase, a plausible target for ginkgotoxin from Ginkgo biloba.:

FEBS J. 2007 Feb;274(4):1036-45. Epub 2007 Jan 19.PMID: 17250738
Ginkgotoxin (4'-O-methylpyridoxine) occurring in the seeds and leaves of Ginkgo biloba, is an antivitamin structurally related to vitamin B(6). Ingestion of ginkgotoxin triggers epileptic convulsions and other neuronal symptoms. Here we report on studies on the impact of B(6) antivitamins including ginkgotoxin on recombinant homogeneous human pyridoxal kinase (EC 2.7.1.35). It is shown that ginkgotoxin serves as an alternate substrate for this enzyme with a lower K(m) value than pyridoxal, pyridoxamine or pyridoxine. Thus, the presence of ginkgotoxin leads to temporarily reduced pyridoxal phosphate formation in vitro and possibly also in vivo. Our observations are discussed in light of Ginkgo medications used as nootropics.

48.2,3-Dihydrobiflavone from Ginkgo biloba.:

Planta Med. 1999 Jun;65(5):482-4.PMID: 17260276
From the yellow leaves of Ginkgo biloba 2,3-dihydrosciadopitysin (5,5'',7''-trihydroxy-7,4',4'''-trimethoxy-3',8''-flavanone/flavone) was isolated as a mixture of two diastereomers. Its structure was elucidated employing 2D NMR techniques.

49.Purification and identification of genistein in Ginkgo biloba leaf extract:

Se Pu. 2007 Jul;25(4):509-13.PMID: 17970108
The Ginkgo biloba leaf extract was hydrolyzed under acidic conditions and neutralized with 5% aqueous NaOH. The hydrolysate was extracted with a mixture of ethyl acetate and tetrahydrofuran (7:3, v/v), and was concentrated by the vacuum evaporation of organic solvent. Genistein was isolated from the hydrolysate using silica gel column chromatography with a gradient elution of dichloromethane and acetic ether and further recrystallized in dichloromethane. The whole process was monitored using high performance liquid chromatograph, equipped with photodiode array detector and electrospray ionization mass spectrometer/mass spectrometer (HPLC-PDA-ESI-MS/MS). The HPLC chromatogram with UV at 260 nm showed that the purity of genistein was higher than 98%. The structure of genistein was identified using UV absorption curves, nuclear magnetic resonance (1H NMR, 13C NMR) spectra, ESI-MS in negative mode and tandem MS spectra. The fragmentation mechanism for genistein was also discussed in detail: collision induced dissociation (CID) of the [M-H]- ion (m/z 269) showed that the quasi-molecular ions [M-H]- were prone to process rearrangement in the skeleton and lose neutrals, such as C3O2, CO2, CO. The Retro-Diels-Alder fragmentation was another characteristic decomposition of the ions.

50.A new polysaccharide from leaf of Ginkgo biloba L.:

Fitoterapia. 2009 Jan;80(1):43-7. Epub 2008 Oct 15.PMID: 18977417
A water-soluble polysaccharide, GPB, was obtained from leaf of Ginkgo biloba L by hot water extraction followed by precipitation with ethanol and fractionation with gel chromatography. The results of HPLC with TSK-GEL column and gel filtration chromatography with Sepharose CL-6B analysis indicated GPB was uniform in polarity and its molecular weight (MW) was about 10 kDa. The structure of GPB was analysed using chemical methods, IR spectroscopy, and NMR spectroscopy. GPB has a high branched structure with polygalactose as core part of backbone. The repeating unit of polygalactose consists of 1,6-linked Galactose (Gal) and 1,3,6-linked Gal.

51.Biological standardization of Ginkgo extracts:

Planta Med. 1993 Apr;59(2):155-60.PMID: 8488195
The determination of the inhibition of PAF (platelet-activating factor)-induced platelet aggregation has been proposed as a biological standardization method for commercially available Ginkgo biloba extracts by measuring the characteristic pharmacological effect of ginkgolides in vitro. The determination is specific for ginkgolides A, B, C, and J and is not influenced by other constituents present in Ginkgo biloba extracts. IC50 values of ginkgolide B can be used to standardize various Ginkgo extracts produced by special extraction methods with respect to equi-effective ginkgolide B contents. In order to compare values obtained by a chemical-analytical procedure with those obtained by the biological assay, the equi-effective total ginkgolide content of each Ginkgo extract had to be calculated. Accordingly, the concentrations of the individual ginkgolides in the various Ginkgo extracts were determined chromatographically by assaying ginkgolides as trime-thylsilyl derivatives. Their individual contributions towards the measured in vitro effects were derived from their respective IC50 values. The calculated equi-effective total ginkgolide contents of the Ginkgo extracts were in good agreement with those obtained by gas chromatography. The results demonstrate that, in addition to a chemical standardization, the biological standardization of Ginkgo extract preparations is also feasible.

52.Assay of terpenes in the leaves of Ginkgo biloba extract and its preparations by in situ fluorometric TLC:

Zhongguo Zhong Yao Za Zhi. 1997 Mar;22(3):159-62, 191.PMID: 10743185
A new TLC method for the assay of terpene lactones in Ginkgo biloba extract and its preparations has been established by means of optimized development condition and post-chromatographic thermal fluorescence derivatization. Satisfactory results can be obtained through polynomial regression calibration. The data obtained by this method have been proved ten times higher in sensitivity than those obtained by HPLC-refracto-detector.

53.Ginkgo biloba extract (EGb 761). State of knowledge in the dawn of the year 2000:

Ann Pharm Fr. 1999 Jul;57 Suppl 1:1S8-88.PMID: 10481350
EGb 761 is a standardized extract of dried leaves of Ginkgo biloba containing 24% ginkgo-flavonol glycosides, 6% terpene lactones such as ginkgolides A, B, C, J and bilobalide. Its broad spectrum of pharmacological activities allows it to be in adequacy to the numerous pathological requirements--hemodynamic, hemorheological, metabolic--which occur in cerebral, retinal, cochleovestibular, cardiac or peripheral ischemia. Moreover, EGb 761 has direct effects against necrosis and apoptosis of neurons and improves neural plasticity as evidenced in vestibular compensation. At the molecular and the cellular levels, some evidence obtained with animal models indicates that EGb 761 can interact as a free radical-scavenger and a inhibitor of lipid peroxidation with all, or nearly all reactive oxygen species; maintains ATP content by a protection of mitochondrial respiration and preservation of oxidative phosphorylations; exerts arterial and venous vasoregulator effects involving the release of endothelial factors and the catecholaminergic system. Moreover, EGb 761 regulates ionic balance in damaged cells and exerts a specific and potent Platelet-activating factor antagonist activity. Numerous well-controlled clinical studies, realized in Europe and in USA, have revealed that EGb 761 is an effective therapy for a wide variety of disturbances of cerebral function, ranging from cerebral impairment of ischemic vascular origins (i.e. multi infarct dementia), early cognitive decline to mild-to-moderate cases of the more severe types of senile dementias (including Alzheimer's disease) or mixed origins (i.e. psychoorganic origin). Improvement of signs and symptoms have been demonstrated for cognitive functions, particularly for memory loss, attention, alertness, vigilance, arousal and mental fluidity. Some clinical studies have showed that EGb 761 treatment may improve the capacity of geriatric patients to cope with the stressful demands of daily life. The explanation is a dual stress-alleviating action of EGb 761: its facilitates behavioral adaptation to stress and may decrease the excess of cortisol release to stress. Moreover, EGb 761 shows a specific neuroprotective effects to hippocampic cells. Regarding the visual system, experimental studies have shown that EGb 761 can inhibit or reduce the functional retinal impairments resulting from ischemia-reperfusion, photo-degeneration, diabetic or proliferative retinopathy. Clinical studies have revealed that EGb 761 may be useful in treating visual activity impairments and damages to the visual field associated with chronic cerebrovascular insufficiency, senile macular degeneration and diabete mellitus. Regarding the vestibular and auditory systems, experimental and clinical studies have shown the efficacy of EGb 761 in treating hypoacusis, tinnitus, vertigo, dizziness and other symptoms of vestibulocochlear disorders. At least, adequatly controlled studies in patients with peripheral arterial occlusive disease have provided good evidence for therapeutic efficacy in intermittent claudication. The future of EGb 761 is undoubtedly in the promise in slowing the progression of Alzheimer's disease. Indeed, two recent american clinical studies have shown the efficacy and safety of EGb 761 in patients with mild to severe Alzheimer's disease and multi-infarct dementia. In clinical terms, progression of symptoms was delayed by approximately 6 months. Actually new clinical studies are undertaken in USA and Europe. At the dawn of the third millenium (the Sixth for Ginkgo biloba) we propose a state of art about it.

54.High-performance liquid chromatography-electrospray ionization-mass spectrometry study of ginkgolic acid in the leaves and fruits of the ginkgo tree (Ginkgo biloba).:

J Chromatogr Sci. 2000 Apr;38(4):169-73.PMID: 10766484
A method is developed for qualitative analysis of ginkgolic acids in the leaves and fruits of Ginkgo biloba by high-performance liquid chromatography (HPLC)-electrospray ionization-mass spectrometry technique. Negative ionization mode is successful in obtaining a very abundant deprotonated molecule [M - H]-. The mass detection sensitivity is higher than ultraviolet detection but relies heavily on the concentration of acetic acid in the HPLC eluent, which consists of acetonitrile-water-acetic acid. The method is also very specific for the analysis of ginkgolic acid with no interferences from the sample matrix.

55.Determination of trace amounts of ginkgolic acids in Ginkgo biloba L. leaf extracts and phytopharmaceuticals by liquid chromatography-electrospray mass spectrometry.:

J Chromatogr B Biomed Sci Appl. 2000 Jul 21;744(2):249-55.PMID: 10993512
Ginkgolic acids (GAs) are toxic phenolic compounds present in the fruits and leaves of Ginkgo biloba L. (Ginkgoacae). Their maximum level in phytopharmaceuticals containing ginkgo extracts has been recently restricted to 5 microg/g by the Commission E of the former Federal German Health Authority. In order to detect ginkgolic acids at these low levels, a sensitive and selective analytical method, based on liquid chromatography-electrospray mass spectrometry (LC-ES-MS) has been developed. The three main phenolic acids (1-3) of the chloroform fruit extract were isolated and used as standards for quantification. In the LC-ES-MS negative ion mode, calibration curves with good linearities (r=0.9973, n=6) were obtained in the range of 0.5-10 microg/g for compounds 1, 2 and between 0.1 and 7.5 microg/g (r=0.9949, n=6) for ginkgolic acid 3. The detection limits at a SIN ratio of 3 were 0.1 (3) and 0.25 microg/g (1, 2). Recoveries were around 101% at 5 microg/g for the substances detected in the leaf extracts. Good precision was achieved with relative standard deviations of less than 4% (n=6). The optimised method was applied to verify whether the amount of gingkolic acids was below 5 microg/g in a standardised leaf extract which is a constituent of a phytopreparation.

56.High performance liquid chromatographic determination of quercetin in the extract of Ginkgo biloba L. leaves:

Zhongguo Zhong Yao Za Zhi. 1997 Oct;22(10):616-7, 640.PMID: 11038931
This paper reports the HPLC determination of one of the flavones quercetin in the extract of Ginkgo biloba leaves. Quercetin was separated completely on an YWG-C18 column(0.46 cm x 15 cm), using a mixture of methanol, water and phosphoric acid(50:49.8:0.2) as mobile phase, with UV detection at 360 nm. The results have shown the recoveries to be between 95.3%-103.2% and RSD 1.86%.

57.Pharmaceutical quality of different Ginkgo biloba brands.:

J Pharm Pharmacol. 2002 May;54(5):661-9.PMID: 12005361
Ginkgo biloba-containing brands are one of the top sellers within the growing market for herbal remedies in many European countries as well as in the USA. In the consumers' interest, these brands should feature a certain quality and should be transparent in quality claims. In this investigation, a variety of products on the USA market was studied with respect to pharmaceutical quality, such as quantity of constituents and in-vitro dissolution. In terms of the content of active substances, flavone glycosides ranged from 24% to 36% and terpene lactones from 4% to 11%. With ginkgolic acids, there was a very large range, from < 500 ppm to about 90000 ppm. Comparing the dissolution rates of terpene lactones and flavone glycosides within the single products, most were approximately the same. Thus, terpene lactones and flavone glycosides were released from these products and dissolved at the same rate in most cases. Furthermore, most of the products investigated released more than the required 75% of the content of both components within 30 min. However, several products showed clear and relevant differences in dissolution rates to the rest (e.g. < 75% within 30 min or even less than 25% after 60 min in one case, indicating much poorer pharmaceutical quality). Beside the comparability respectively standardisation of the extracts used, the in-vitro dissolution of the relevant constituents should be similar to other drugs to guarantee comparable in-vivo performance of herbal products. An important step in standardising pharmaceutical quality is the pharmacopoeial monograph for Ginkgo biloba extract in Germany, standardising the content of pharmacologically relevant substances (flavone glycosides 22-27% and terpenlactones 5-7%, 2.8-3.4% ginkgolides A, B, C and 2.6-3.2% bilobalide thereof). Many of the investigated products, which refer to the German Commission E (of the Federal Institute for Drugs and Medicinal Devices) monograph, are not in accordance with this specification. Thus, they can not be considered to be pharmaceutically equivalent.

58.Extraction of ginkgolides from Ginkgo biloba:

Zhongguo Zhong Yao Za Zhi. 2010 May;35(9):1127-9.PMID: 20707065
OBJECTIVE: To establish the technology for extraction of ginkgolides from Ginkgo Biloba with alcohol-water.METHOD: The parameters such as alcohol concentration, pH of extracting solution, ratio of dosage liquor, temperature and time, the extraction of ginkgolides from G. biloba was investigated, and its parameters were optimized.RESULT: The optimized parameters were alcohol concentration 30%, extracting temperature 50 degrees C, extracting time 2 h, pH 5 solid-liquid ratio 1:15.CONCLUSION: This method has the merits of low cost and simple operation.

Z-Ginkgo Biloba:Components metabolism and Bioavailability Research:

1.Pharmacokinetic properties of Bilobalide and Ginkgolides A and B in healthy subjects after intravenous and oral administration of Ginkgo biloba extract (EGb 761)].:

Therapie. 1995 Mar-Apr;50(2):137-44.PMID: 7631288
The pharmacokinetics of Ginkgolide A, Ginkgolide B and Bilobalide, which are compounds extracted from the dried leaves of the Ginkgo biloba tree, were investigated in 12 young healthy volunteers (six men and six women; mean +/- SD age = 25 +/- 5 years) after single-dose administration of Ginkgo biloba extract. Subjects were given, on three occasions, Ginkgo biloba extract as a solution either orally (in fasting conditions and after a standard meal) or intravenously; corresponding to single doses of Ginkgolide A, Ginkgolide B and Bilobalide ranging from 0.90 mg to 3.36 mg. After each dosing, blood and urine samples were collected for up to 36 h and 48 h, for measurements of Ginkgolide A, Ginkgolide B and Bilobalide. Plasma and urine concentrations of these compounds were quantitatively measured by gas chromatography/mass spectrometry using negative chemical ionization, by applying a very sensitive method which allowed plasma concentrations as low as 0.2 ng/ml of each compound to be measured. When given orally, while fasting, the extents of bioavailability are high, as shown by bioavailability coefficients (FAUC) mean (+/- SD) values equal to 0.80 (+/- 0.09), 0.88 (+/- 0.21) and 0.79 (+/- 0.30) for Ginkgolide A, Ginkgolide B and Bilobalide respectively. Food intake does not change AUC quantitatively but increases Tmax. For the three compounds of interest, after oral dosing while fasting, differences can be noted for the elimination half-lives (T1/2Z), which exhibit mean values equal to 4.50, 10.57 and 3.21 h, as well as mean residence times (MRT), equal to 5.86, 11.25 and 4.89 h, for Ginkgolide A, Ginkgolide B and Bilobalide respectively

2.Comparative pharmacokinetics and bioavailability of flavonoid glycosides of Ginkgo biloba after a single oral administration of three formulations to healthy volunteers.:

Mater Med Pol. 1995 Oct-Dec;27(4):141-6.PMID: 9000837
Eighteen healthy volunteers received three different formulations of Ginkgo biloba: capsules (A) and drops (B) (delivered by Agon Pharma), and tablets (C) (Tebonin-Dr. W. Schwabe) in equal an quantity, orally as a single dose, at an interval of at least five days. The pharmacokinetic parameters of the most important flavonoid glycosides: quercetin, kaempferol and isorhamnetin were established. The bioavailability was estimated using capsules as a standard formulation. Only the time to reach the peak concentration (tmax) of quercetin, kaempforol and isorhamnetin administered in the form of capsules, was significantly prolonged as compared with drops and tablets. Area under the curve (AUC) was the largest for formulation B for all the evaluated flavonoid glycosides, however the differences were not statistically significant. It is concluded that the three formulations of Ginkgo biloba extract are bioequivalent.

3.Identification of flavonoid metabolites after oral administration to rats of a Ginkgo biloba extract.:

J Chromatogr B Biomed Appl. 1995 Nov 3;673(1):75-80.PMID: 8925077
An extract of Ginkgo biloba leaves (EGb) was administered by gastric probe to Wistar female rats, and urine and faeces samples were collected for 5 days and whole blood samples were withdrawn every 30 min for 6 h. After purification with SPE C18 cartridges, the samples were analysed by reversed-phase LC-diode array detection (LC-DAD) for residual flavonoid glycosides, aglycones and metabolites. No glycosides or aglycones were detected in urine, faeces or blood and extensive degradation of EGb flavonoids within 24 h was detected. Among the seven different phenylalkyl acids detected by LC-DAD, 3,4-dihydroxyphenylacetic acid (I), hippuric acid (II), 3-hydroxyphenylacetic acid (III), homovanillic acid (IV) and benzoic acid (VII) were directly confirmed by on-line mass spectrometry using an electrospray interface (ES-MS). Peaks V and VI needed to be collected and separately examined and they were found to be 3-(4-hydrophenyl)propionic acid and 3-(3-hydrophenyl)propionic acid, respectively. As further evidence, the identity of metabolites I, II, III, IV, V and VII was confirmed by co-chromatography with authentic standards.

4.Identification of Gingko biloba flavonol metabolites after oral administration to humans.:

J Chromatogr B Biomed Sci Appl. 1997 May 23;693(1):249-55.PMID: 9200545
An extract of Ginkgo biloba leaves (EGb) was given to healthy volunteers. Urine samples were collected for 3 days, and blood samples were withdrawn every 30 min for 5 h. The samples were purified through SPE C18 cartridges and analyzed by reversed-phase LC-diode array detection for the presence of EGb metabolites. Only urine samples contained detectable amounts of substituted benzoic acids, i.e., 4-hydroxybenzoic acid conjugate, 4-hydroxyhippuric acid, 3-methoxy-4-hydroxyhippuric acid, 3,4-dihydroxybenzoic acid, 4-hydroxybenzoic acid, hippuric acid and 3-methoxy-4-hydroxybenzoic acid (vanillic acid). In contrast to rats no phenylacetic acid or phenylpropionic acid derivatives were found in urine, thus indicating that in humans a more extensive metabolism takes place. As for rats the metabolites found in human urines accounted for less than 30% of the flavonoids given. The same procedure was applied to blood samples, and no metabolites could be detected.

5.Bioavailability of ginkgolides and bilobalide from extracts of ginkgo biloba using GC/MS.:

Planta Med. 1999 Mar;65(2):192-3.PMID: 10193211
The bioavailability of ginkgolides A, B and bilobalide was studied in rats after single oral administration of 30, 55 and 100 mg/kg Ginkgo extract EGb 761. The plasma levels of the terpene lactones were measured by a specific GC/MS method. The pharmacokinetics of the mentioned substances were found to be dose-linear. For the lowest dose maximum concentrations were 68, 40 and 159 ng/ml and half-lives 1.7, 2.0 and 2.2 h for ginkgolide A, B and bilobalide, respectively. Clearance values ranged from 24.2 to 37.6 ml/min/kg.

6.Studies on the callus cultures of Ginkgo biloba and its metabolites-ginkgolides.:

Chin J Biotechnol. 1999;15(1):51-8.PMID: 10668135
The production of ginkgolides in callus culture of Ginkgo biloba was reported. The affection of some physical factors and chemical substances on the induction and growth of calli was also investigated. A biologically quantitative method (platelet aggregation induced by PAF) and HPLC were successfully used for the determination of Ginkgolides A and B in all kinds of callus cultures. The result showed that the content of Ginkgolides B in the callus cultures varies from 0.005% to 0.01%, which is one of the best results for the callus culture of G.biloba in the world.

7.Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry of terpene lactones in plasma of volunteers dosed with Ginkgo biloba L. extracts.:

Rapid Commun Mass Spectrom. 2001;15(12):929-34.PMID: 11400198
Liquid chromatography/atmospheric pressure chemical ionization mass spectrometry (LC/APCI-ITMS) was applied to evaluate the levels of ginkgolides A and B and bilobalide in plasma of volunteers after administration of Ginkgo biloba extracts in free (Ginkgoselect) or phospholipid complex (Ginkgoselect Phytosome) forms, providing 9.6 mg of total terpene lactones. The maximum plasma concentrations, C(max), of total ginkgolides A, B and bilobalide were 85.0 and 181.8 microg/mL for Ginkgoselect and Ginkgoselect Phytosome, respectively. The C(max) values were reached at 120 min for the free form and at 180--240 min for the phospholipid complex form. In both cases, the mean elimination half-life of each terpene lactone was in the range 120--180 min. Due to its sensitivity (about 1 ng/mL) and specificity, LC/APCI-ITMS proved to be a very powerful tool for pharmacokinetic studies of these phytochemicals.

8.Pharmacokinetics and bioavailability of a Ginkgo biloba extract.:

J Ocul Pharmacol Ther. 2002 Apr;18(2):197-202.PMID: 12002672
The aim of the present study was to assess the bioavailability of the main active ingredient in Ginkgo biloba extract, ginkgolid B. The study also focused on the pharmacokinetics of two different dosage regimens for orally administered Gingko biloba extract, 80 mg once daily and 40 mg twice daily for 7 days. Twelve healthy volunteers took part in the study. They were randomly assigned to one of the two treatment groups: 40 mg twice daily or 80 mg once daily, with an interval of 21 days between cycles. Statistical analysis was used to assess the main pharmacokinetic parameters. The results show that a dosage of 40 mg twice daily (every 12 hrs) is accompanied by a significantly longer half-life (t1/2) and mean residence time (MRT) than a single 80 mg dose, even though the latter causes a higher concentration peak (Cmax). The maximum concentration time (Tmax) is 2.3 hrs after administration in both treatments.

9.Biologically active secondary metabolites from Ginkgo biloba.:

J Agric Food Chem. 2002 May 22;50(11):3150-5.PMID: 12009978
Three new compounds, (7E)-2beta,3alpha-dihydroxy-megastigm-7-en-9-one (1), 3-[5,7-dihydroxy-2-(4-methoxyphenyl)-4-oxo-4H-chromen-8-yl]-4-methoxybenzoic acid (2), and 4'-O-methyl myricetin 3-O-(6-O-alpha-L-rhamnopyranosyl)-beta-D-glucopyranoside (3), were isolated from Ginkgo biloba, together with 27 known compounds. The structures of the new compounds were determined primarily from 1D- and 2D-NMR analysis. The 4-O-methylbenzoic acid structural feature at C-8 in 2 is encountered for the first time. The antioxidant activities of 29 compounds isolated from Ginkgo biloba were evaluated on intracellular reactive oxygen species in HL-60 cells. It was found that quercetin, kampferol, and tamarixetin had antioxidant activity that was approximately 3-fold greater than that of their respective glycosides and also approximately 3-fold greater than that of a standard ascorbic acid with an IC(50) at maximum effectiveness.

10.Metabolism of quercetin and kaempferol by rat hepatocytes and the identification of flavonoid glycosides in human plasma.:

Xenobiotica. 2002 Apr;32(4):279-87.PMID: 12028662
1. The metabolism of the flavonoids quercetin and kaempferol by rat hepatocytes was investigated using liquid chromatography coupled with electrospray mass spectrometry (LC-ESI MS). Quercetin and kaempferol were extensively metabolized (98.8 +/- 0.1% and 81.0 +/- 5.1% respectively, n = 4), with four glucuronides of quercetin and two of kaempferol being detected after incubation. 2. The glucuronides of quercetin and kaempferol formed upon incubation with rat hepatocytes were identified as the same ones formed after incubation with the UDP-glucuronosyltransferase isoform UGT1A9. 3. In addition, plasma samples from human volunteers taken after consumption of capsules of Ginkgo biloba, a plant rich in flavonoid glycosides, were analysed by LC-MS for the presence of flavonoid glucuronides and flavonoid glycosides. Reported is evidence for the presence of flavonoid glycosides in samples of plasma. 4. The results suggest that UGT1A9 is a key UDP-glucuronosyltransferase isoform for the metabolism of flavonoids, and that absorption of intact flavonoid glycosides is possible.

11.Effects of a Ginkgo biloba extract on forearm haemodynamics in healthy volunteers.:

Clin Physiol Funct Imaging. 2002 Nov;22(6):375-8.PMID: 12464140
The aim was to validate possible vasodilating effects of a Ginkgo biloba extract with a secondary aim of finding a pharmacodynamic signal relating to the active component of these extracts. We studied the effect of G. biloba extract on forearm haemodynamics in 16 healthy subjects (nine females, seven males) with a median age of 32 years (range: 21-47). The study was conducted as a randomized, double-blinded cross-over design using oral treatment with G. biloba extract (Gibidyl Forte(R) t.i.d. or placebo for 6 weeks. Forearm blood flow and venous capacity were measured by strain-gauge plethysmography. Blood pressure was measured by standard sphygmomanometry, and forearm vascular resistance (FVR) was derived. Measurements were made at baseline and after 3, 6, 9 and 12 weeks of treatment. Forearm blood flow was significantly higher during active treatment after 3 and 6 weeks as compared with placebo treatment for 3 and 6 weeks (P<0.05). Mean arterial blood pressure was unchanged, making the calculated FVR significantly lower during active treatment (P<0.02). It is concluded that oral treatment with a G. biloba extract (Gibidyl Forte(R)) is able to dilate forearm blood vessels causing increments in regional blood flow without changing blood pressure levels in healthy subjects. The increments in blood flow may be used as a biological signal for pharmacokinetic studies.

12.Influence of pharmaceutical quality on the bioavailability of active components from Ginkgo biloba preparations.:

J Pharm Pharmacol. 2002 Nov;54(11):1507-14.PMID: 12495553
To be effective, herbal medicinal products are expected to meet comparable standards concerning the assessment of efficacy, safety and biopharmaceutical quality as chemically defined synthetic drugs as food supplements. However, these requirements are often not fulfilled, particularly regarding the characterization of biopharmaceutical properties such as in-vitro dissolution and in-vivo bioavailability. With respect to the relevance of biopharmaceutical quality of herbal medicinal products, two different Ginkgo biloba brands (test product: Ginkgo biloba capsules; reference product: Ginkgold) were analysed for dissolution rates and bioavailability of the most relevant active ingredients. Dissolution rates at pH 1 and 4.5 were determined according to the USP 23. The relative bioavailability of ginkgolide A, ginkgolide B and bilobalide was investigated after single oral administration of 120 mg Ginkgo biloba extract as tablets or capsules. Bioavailability data (area under the curve and peak concentration in plasma) were clearly different and did not show bioequivalence of test and reference products. The slow in-vitro dissolution of the test product resulted in a large decrease in bioavailability. These results indicate for the first time that the pharmaceutical properties of a herbal medicinal product have a significant impact on the rate and extent of drug absorption, and very likely on efficacy in humans.

13.Enteric disposition and recycling of flavonoids and ginkgo flavonoids.:

J Altern Complement Med. 2003 Oct;9(5):631-40.PMID: 14629841
OBJECTIVE: The objective of this study was to determine the intestinal and microbial disposition of flavonoids and how these disposition processes affect their enteric recycling.DESIGN: Studies were performed using a perfused rat intestinal model or using enrichment cultures and a pure isolate of Enterococcus avium (LY1).RESULTS: In the rat intestine, aglycones, such as quercetin and apigenin, were as permeable (P*(eff) > or = 2) as compounds such as propranolol (100% absorption). However, a significant portion of the absorbed aglycones was conjugated and the metabolites were excreted into the lumen. Flavonoid glycosides, such as isoquercitrin and apigenin-7-O-glucoside, also had high apparent P*(eff) values (> or = 2) in the upper small intestine because of rapid hydrolysis. However, isoquercitrin was absorbed much slower (P*(eff) < or = 0.7, p < 0.05) when hydrolysis was absent or inhibited by 20 mmol gluconolactone. Absorption of other intact glycosides was similar to intact isoquercitrin and was much slower than the corresponding aglycones (P*(eff) < or = 0.7, p < 0.05). Intestinal bacteria, such as LY1, hydrolyzed the flavonoid glycosides used in the study. Excreted glycosidases were involved in the hydrolysis of glycosides because glycosides were poorly taken up by LY1. In conclusion, glycosidase-catalyzed hydrolysis is a critical first step in the intestinal and microbial disposition of flavonoid glycosides. Aglycones were not only rapidly absorbed, but also rapidly metabolized into phase II conjugates, which were then excreted back into the lumen. Therefore, intestinal and microbial glycosidases and intestinal phase II enzymes make a significant contribution to the disposition of flavonoids via the proposed enteric and enterohepatic recycling scheme.

14.Ginkgo flavones in in vitro metabolism and its clinical application:

Yao Xue Xue Bao. 2003 Dec;38(12):938-41.PMID: 15040090
AIM: To develop a method for assaying Ginkgo flavones in rat hepatical microsome.METHODS: Quercetin, isorhamnetin and keampferol were added to microsome incubate and incubated for a given time then extracted with ether-acetone. After evaporated, the residue was reconstituted with 100 microL of phosphate buffer solution (pH 2.0)-tetrahydrofuran-methanol-isopropanol (60:15:10:20). An aliquot of 20 microL was injected into the HPLC system. According to the result of estimate by means of HPLC, the results of metabolism of Ginkgo flavones in different conditions was compared.RESULTS: The assay was linear over the rang of 0.2-8 mg.L-1 for Ginkgo flavones. The limit of quantification was 0.1 mg.L-1 (n = 3). The recoveries of three components of Ginkgo flavones were 99.9%-113.8% for quercetin (RSD < 0.8%), 100.8%-117.3% for isorhamnetin (RSD < 1.9%) and 100.7%-116.5% for keampferol (RSD < 1.03%, n = 5).CONCLUSION: The method is simple, fast and accurate. It can be used for investigation of the metabolism of Ginkgo flavones.

15.In vivo biodistribution of ginkgolide B, a constituent of Ginkgo biloba, visualized by MicroPET.:

Planta Med. 2005 Jul;71(7):622-7.PMID: 16041647
The in vivo dynamic behavior of ginkgolide B (GB), a terpene lactone constituent of the Ginkgo biloba extracts, in the living animal was visualized by positron emission tomographic (PET) imaging using a GB analogue labeled with the positron emitter (18)F. The in vivo imaging studies, combined with ex vivo dissection experiments, reveal that GB exists in 2 forms in the body: the original GB with its lactone rings closed and a second form with one of the rings open. The original GB in plasma is taken up rapidly by various organs including the liver, the intestine and possibly the stomach. Consequently, in plasma, the proportion of the ionized form of GB increases dramatically with time. Thereafter the ratio between the 2 forms appears to shift slowly towards equilibrium. The results suggest that more attention needs to be focused on in vivo dynamics between the 2 forms of GB.

Ginkgo Biloba:Subject Myth Lengend Research:

1.Ginkgo--myth and reality:

Praxis (Bern 1994). 1995 Jan 3;84(1):1-6.PMID: 7839037
Ginkgo biloba is one of the oldest, still existing plants. Extracts from its leaves were already used in ancient China whereas in the Western World, they have been utilized only since the Sixties when it became technically possible and feasible to isolate the essential substances of Ginkgo biloba. Pharmacologically, there are two groups of substances which are of some significance: the flavonoids, effective as oxygen-free radical scavengers, and the terpenes (i.e. the ginkgolides) with their highly specific action as platelet activating factor (PAF) inhibitors. Clinically important indications for Ginkgo biloba extracts are cerebral insufficiency and atherosclerotic disease of peripheral arteries of intermediate severity. In several placebo-controlled clinical studies, symptoms of cerebral insufficiency have been effectively and significantly influenced. Most of these investigations have examined the efficacy of Ginkgo biloba extracts such as EGb 761 and LI 1370.

Za-Ginkgo Biloba:Subject Interaction cautions,negative effects,safety Research:

1.Interactions of Ginkgo biloba extract (EGb 761), diazepam and ethyl beta-carboline-3-carboxylate on social behavior of the rat.:

Pharmacol Biochem Behav. 1997 Feb;56(2):333-9.PMID: 9050093
The social interaction test was used to examine the effects of an extract of Ginkgo biloba (EGb 761) and its possible interactions with diazepam and ethyl beta-carboline-3-carboxylate (beta-CCE). Pairs of naive (unfamiliar) male Wistar AF rats subjected to the same treatment were placed in a novel test arena that was brightly illuminated, and the duration (in s) of social contact was observed over a 10 min period. Single injections of EGb 761 (8-16 mg/kg, i.p.), given 30 min prior to testing, or repeated oral administration of the extract (48 or 96 mg/kg/day) for 8 days, significantly decreased social contact under conditions that did not influence locomotor activity. Injection of diazepam (1 mg/kg, i.p.), 30 min before testing, significantly increased social contact. Injection of diazepam to animals that had received repeated oral treatment with EGb 761 (96 mg/kg/ day) increased social interaction to an extent greater than observed with diazepam alone. Injection of beta-CCE (2-16 mg/kg, i.p.), 15 min before testing, significantly decreased social contact. When the animals were treated with EGb 761 (48 or 96 mg/kg/day, p.o. for 8 days) and beta-CCE (4 mg/kg), both of which decreased social interaction when administered alone, the resulting level of social contact was similar to that of control animals. Interactions with certain sites of central GABAA/ benzodiazepine/Cl- channel receptor complexes could be involved in mediating these effects of EGb 761, diazepam and beta-CCE.

2.The discriminative stimulus properties of EGb 761, an extract of Ginkgo biloba.:

Pharmacol Biochem Behav. 1999 Mar;62(3):543-7.PMID: 10080249
Stimulus control was established in a group of nine rats using a dose of EGb 761 of 10 mg/kg, administered i.p., 15 min before training. A two-lever operant task using a fixed-ratio 10 schedule of sweetened milk reinforcement was used. Based upon a criterion for the presence of stimulus control of five consecutive sessions during which 83% or more of all responses were on the appropriate lever, a mean of 24 sessions was required to reach criterion performance. Subsequently, it was observed that EGb 761-induced stimulus control is significantly antagonized by the selective 5-HT1A antagonist WAY-100635, but is unaffected by the 5-HT2 antagonist pirenperone. Furthermore, EGb 761 generalized to the selective 5-HT1A agonist, 8-hydroxy-dipropylaminotetralin [8-OH-DPAT], and this generalization was blocked by WAY-100635. The present results indicate that EGb 761 is able to induce stimulus control when administered via the intraperitoneal route, and that its stimulus effects are mediated in part by activity at the 5-HT1A receptor.

3.Herbal remedies: adverse effects and drug interactions.:

Am Fam Physician. 1999 Mar 1;59(5):1239-45.PMID: 10088878
A growing number of Americans are using herbal products for preventive and therapeutic purposes. The manufacturers of these products are not required to submit proof of safety and efficacy to the U.S. Food and Drug Administration before marketing. For this reason, the adverse effects and drug interactions associated with herbal remedies are largely unknown. Ginkgo biloba extract, advertised as improving cognitive functioning, has been reported to cause spontaneous bleeding, and it may interact with anticoagulants and antiplatelet agents. St. John's wort, promoted as a treatment for depression, may have monoamine oxidase-inhibiting effects or may cause increased levels of serotonin, dopamine and norepinephrine. Although St. John's wort probably does not interact with foods that contain tyramine, it should not be used with prescription antidepressants. Ephedrine-containing herbal products have been associated with adverse cardiovascular events, seizures and even death. Ginseng, widely used for its purported physical and mental effects, is generally well tolerated, but it has been implicated as a cause of decreased response to warfarin. Physicians must be alert for adverse effects and drug interactions associated with herbal remedies, and they should ask all patients about the use of these products.

4.Dietary supplement-drug interactions.:

J Am Med Womens Assoc. 1999 Fall;54(4):191-2,195.PMID: 10531760
Recent surveys show that 18% of adults in the United States use prescription drugs concurrently with herbal or vitamin products, placing an estimated 15 million patients at risk of potential drug-supplement interactions. Despite this widespread concurrent use of conventional and alternative medicines, documented drug-herb interactions are sparse. This review focuses on possible interactions between drugs and herbal medicines used for phytoestrogen-hormone and antiplatelet-oral anticoagulant therapy. Interactions with phytoestrogens are purely speculative, based on competitive estrogen-receptor binding or antiestrogenic effects. In contrast, several case reports document bleeding complications with Ginkgo biloba, with or without concomitant drug therapy. Case reports are also suggestive of interaction between warfarin and dong quai or Panax ginseng. Recommendations for counseling patients at highest risk of adverse interactions are given.

5.Herbal-drug therapy interactions: a focus on dementia.:

Curr Opin Clin Nutr Metab Care. 2001 Jan;4(1):29-34.PMID: 11122556
Older people with dementia are often prescribed numerous medications. Use of herbal therapies in addition to these conventional drug therapies may lead to interactions that result in an adverse drug event. We have conducted a systematic review to identify all studies that examined interactions between herbal and conventional drug therapies (i.e. prescription or over-the-counter). Using a MEDLINE search of English-language studies published between 1980 and 2000, we limited our search to those herbal therapies most likely to be used for the treatment of dementia (memory loss and decreased concentration) and related symptoms. We identified 28 articles that describe interactions between these herbal (i.e. St. John's wort, ginkgo biloba, kava, valerian, and ginseng) and conventional drug therapies. Of these articles, 11 examined St. John's wort, four examined ginkgo biloba, five examined kava, one examined valerian, and seven examined ginseng. We identified a series of potential interactions between herbal and conventional drug therapy that place older people at risk for an adverse drug event. Health care professionals need to be aware of these potential interactions.

6.Herb-drug interactions.:

Lancet. 2000 Jan 8;355(9198):134-8.PMID: 10675182
Concurrent use of herbs may mimic, magnify, or oppose the effect of drugs. Plausible cases of herb-drug interactions include: bleeding when warfarin is combined with ginkgo (Ginkgo biloba), garlic (Allium sativum), dong quai (Angelica sinensis), or danshen (Salvia miltiorrhiza); mild serotonin syndrome in patients who mix St John's wort (Hypericum perforatum) with serotonin-reuptake inhibitors; decreased bioavailability of digoxin, theophylline, cyclosporin, and phenprocoumon when these drugs are combined with St John's wort; induction of mania in depressed patients who mix antidepressants and Panax ginseng; exacerbation of extrapyramidal effects with neuroleptic drugs and betel nut (Areca catechu); increased risk of hypertension when tricyclic antidepressants are combined with yohimbine (Pausinystalia yohimbe); potentiation of oral and topical corticosteroids by liquorice (Glycyrrhiza glabra); decreased blood concentrations of prednisolone when taken with the Chinese herbal product xaio chai hu tang (sho-salko-to); and decreased concentrations of phenytoin when combined with the Ayurvedic syrup shankhapushpi. Anthranoid-containing plants (including senna [Cassia senna] and cascara [Rhamnus purshiana]) and soluble fibres (including guar gum and psyllium) can decrease the absorption of drugs. Many reports of herb-drug interactions are sketchy and lack laboratory analysis of suspect preparations. Health-care practitioners should caution patients against mixing herbs and pharmaceutical drugs.

7.Ginkgo biloba extract: mechanisms and clinical indications.:

Arch Phys Med Rehabil. 2000 May;81(5):668-78.PMID: 10807109
OBJECTIVE: Ginkgo biloba may have a role in treating impairments in memory, cognitive speed, activities of daily living (ADL), edema, inflammation, and free-radical toxicity associated with traumatic brain injury (TBI), Alzheimer's dementia, stroke, vasoocclusive disorders, and aging. The purpose of this review is to provide a synthesis of the mechanisms of action, clinical indications, and safety of Ginkgo biloba extract.DATA SOURCES: Empirical studies, reviews, chapters, and conference proceedings were identified in the following databases: Medline, the Research Council for Complementary Medicine based on the British Library database, and Psychlnfo. Ginkgo biloba, EGb 761, Tanakan, Tebonin, Rokan, and LI 1370 were the principal index terms.STUDY SELECTION AND DATA EXTRACTION: Controlled clinical studies with both positive and negative findings are included, in addition to animals studies illustrating mechanisms of activity.DATA SYNTHESIS: Ginkgo has shown activity centrally and peripherally, affecting electrochemical, physiologic, neurologic, and vascular systems in animals and humans with few adverse side effects or drug interactions. Ginkgo shows promise in patients with dementia, normal aging, and cerebrovascular-related disorders. Clinical indications include memory, information processing, and ADL.CONCLUSIONS: Ginkgo shows promise in treating some of the neurologic sequelae associated with Alzheimer's disease, TBI, stroke, normal aging, edema, tinnitus, and macular degeneration. Mechanisms of action may include antioxidant, neurotransmitter/receptor modulatory, and antiplatelet activating factor properties. While safe, caution is advised when recommending ginkgo to patients taking anticoagulants. Future studies should examine dose effects, component activity, mechanisms, and clinical applications.

8.Interactions of warfarin with garlic, ginger, ginkgo, or ginseng: nature of the evidence.:

Ann Pharmacother. 2000 Dec;34(12):1478-82.PMID: 11144706
OBJECTIVE: To review and characterize the evidence describing potential interactions between warfarin and garlic, ginger, ginkgo, or ginseng.DATA SOURCES: Searches of MEDLINE (1966-1999), other bibliographic databases, several abstracting services, and tertiary references were conducted.STUDY SELECTION AND DATA EXTRACTION: Articles were examined by each author, and additional citations were obtained from the references of these articles. Preference was given to Englishlanguage articles of human studies.DATA SYNTHESIS: Evidence is lacking for an interaction of warfarin wth galic or ginger. One case report associates ginseng use with decreased warfarin-maintained anticoagulation effect. Another case report links concomitant use of ginkgo and warfarin with the development of intracerebral hemorrhage. Hemorrhage and tendencies were noted in four cases with ginkgo use and in three cases with garlic; in none of these cases were patients receiving warfarin.CONCLUSIONS: The true risks of these interactions and effects are difficult to characterize due to the limited number and nature of existing reports.

9.Efficacy and safety of a Ginkgo biloba extract.:

Public Health Nutr. 2000 Dec;3(4A):495-9.PMID: 11276297
This review of the literature documents the efficacy of a standard extract of Ginkgo biloba (EGb) in managing signs and symptoms associated with memory disorders and dementia. Analysis of the discrepant findings reveals that study outcomes may vary with the type of population studied, the outcome measurements selected, and the dosing tested. Overall, the efficacy of EGb was more frequently reported in trials enrolling dementia patients than healthy volunteers. In contrast to narrow memory tests, broad cognitive assessments were more likely to detect the treatment effect. Although a dose--response relationship is not yet established, 240 mg day(-1) EGb seems to show a higher rate of treatment response than does 120 mg day(-1). Regarding safety, in all trials reviewed the adverse event profile of EGb was not different from that of the placebo.

10.Evidence for toxic effects of alkylphenols from Ginkgo biloba in the hen's egg test (HET).:

Phytomedicine. 2001 Mar;8(2):133-8.PMID: 11315756
Extracts from the leaves of the Gingko tree (Ginkgo biloba L.) are therapeutically used for the treatment of peripheral and cerebral vascular disorders as well as multi-infarct or Alzheimer-type dementia. As constituents with potential contact allergenic and toxic properties in crude Ginkgo extracts a group of alkylphenols (e.g., ginkgolic acids, ginkgol, bilobol) has been described. Thus, for reasons of drug safety a maximal concentration (< or = 5 ppm) of ginkgolic acids is requested by the Monograph of the Commission E of the former German Federal Health Agency (Bundesgesundheitsamt, BGA). During production of the standardized Ginkgo extract EGb 761, alkylphenols are largely eliminated as water insoluble compounds (decanter sludge) from the primary acetone extract. To further assess the adverse properties of alkylphenols, different fractions derived from the decanter sludge were evaluated for their embryotoxic effects in the hen's egg test (HET). A fraction enriched for ginkgolic acids (16%) and biflavones (6.7%) was found to induce death of 50% of the chick embryos (LD50) at a dose of 1.8 mg/egg (approximately/= 33 ppm). A similar strong lethal effect (LD50: 3.5 mg/egg; 64 ppm) was oberserved for a fraction which contained 58% ginkgolic acids but less than 0.02% biflavones. In contrast, an extreme low toxic potential (LD50: 250 mg/egg or 4540 ppm) was established for a fraction containing 16% biflavones and 1% ginkgolic acids. Thus, the present investigations confirm the high toxic potential of ginkgolic acids, although it can not be excluded that biflavones or some other constituents in the different fractions may amplify the adverse effect of these substances. Since no contribution of alkylphenols to the therapeutic efficacy of Ginkgo extracts has been confirmed and their elimination during the manufacturing process does not cause technical problems, these results further support the requirement for the completest possible removal of these compounds under toxicological considerations.

11.Efficacy, safety, and use of ginkgo biloba in clinical and preclinical applications.:

Altern Ther Health Med. 2001 Sep-Oct;7(5):70-86, 88-90.PMID: 11565403
Ginkgo biloba is a dioecious tree with a history of use in traditional Chinese medicine. Although the seeds are most commonly employed in traditional Chinese medicine, in recent years standardized extracts of the leaves have been widely sold as a phytomedicine in Europe and as a dietary supplement in the United States. The primary active constituents of the leaves include flavonoid glycosides and unique diterpenes known as ginkgolides; the latter are potent inhibitors of platelet activating factor. Clinical studies have shown that ginkgo extracts exhibit therapeutic activity in a variety of disorders including Alzheimer's disease, failing memory, age-related dementias, poor cerebral and ocular blood flow, congestive symptoms of premenstrual syndrome, and the prevention of altitude sickness. Due in part to its potent antioxidant properties and ability to enhance peripheral and cerebral circulation, ginkgo's primary application lies in the treatment of cerebrovascular dysfunctions and peripheral vascular disorders.

12.Evaluation of the allergenic potential of Ginkgo biloba extracts.:

Wien Klin Wochenschr. 2001 Aug 16;113(15-16):580-7.PMID: 11571835
Ginkgo biloba extracts are used for the treatment of central and peripheral malperfusion, cerebral insufficiency and dementia. Between 1996 and 1998, several patients in Austria who had received parenteral Ginkgo extracts were reported to have developed allergy-like symptoms. The aim of the present study was to determine whether Ginkgo biloba extracts contain type I allergens. The protein content of Ginkgo biloba extracts was determined by BCA protein determination and SDS-PAGE. We used sera from 95 polysensitized plant-allergic patients (the sera contained IgE antibodies against most plant allergens), and rabbit antisera raised against defined recombinant plant allergens. The presence of allergens in Ginkgo extracts was determined by dot-blotting and Wester blot. Neither rabbit antisera nor IgE antibodies of patients reacted to the Ginkgo extracts. In addition, it was shown that prick testing of the skin could be conveniently used to study Gingko extracts for allergenic activity. In conclusion, no evidence for the presence of type I allergens in Ginkgo extracts was found. We recommend serological and/or skin testing to exclude sensitisation to components of Ginkgo biloba extracts.

13.N-linked oligosaccharides of glycoproteins from Ginkgo biloba pollen, an allergenic pollen.:

Biosci Biotechnol Biochem. 2001 Sep;65(9):2001-6.PMID: 11676012
The pollen of Ginkgo biloba is one of the allergens that cause pollen allergy symptoms. The plant complex type N-glycans bearing beta1-2 xylose and/or alpha1-3 fucose residue(s) linked to glycoallergens have been considered to be critical epitopes in various immune reactions. In this report, the structures of N-glycans of total glycoproteins prepared from Ginkgo biloba pollens were analyzed to confirm whether such plant complex type N-glycans occur in the pollen glycoproteins. The glycoproteins were extracted by SDS-Tris buffer. N-Glycans liberated from the pollen glycoprotein mixture by hydrazinolysis were labeled with 2-aminopyridine and the resulting pyridylaminated (PA-)N-glycans were purified by a combination of size-fractionation HPLC and reversed-phase HPLC. The structures of the PA-sugar chains were analyzed by a combination of two-dimensional sugar chain mapping, IS-MS, and MS/MS. The plant complex type structures (GlcNAc2Man3Xyl1Fuc1GlcNAc2 (31%), GlcNAc2Man3Xyl1GlcNAc2 (5%), Man3Xyl1Fuc1GlcNAc2 (13%), GlcNAc1Man3Xyl1Fuc1GlcNAc2 (8%), and GlcNAc1Man3Xyl1GlcNAc2 (17%)) have been found among the N-glycans of the glycoproteins of Ginkgo biloba pollen, which might be candidates for the epitopes involved in Ginkgo pollen allergy. The remaining 26% of the total pollen N-glycans have the typical high-mannose type structures: Man8GlcNAc2 (11%) and Man6GlcNAc2 (15%).

14.Ginkgolic acids induce neuronal death and activate protein phosphatase type-2C.:

Eur J Pharmacol. 2001 Oct 26;430(1):1-7.PMID: 11698056
The standardized extract from Ginkgo biloba (EGb 761) is used for the treatment of dementia. Because of allergenic and genotoxic effects, ginkgolic acids are restricted in EGb 761 to 5 ppm. The question arises whether ginkgolic acids also have neurotoxic effects. In the present study, ginkgolic acids caused death of cultured chick embryonic neurons in a concentration-dependent manner, in the presence and in the absence of serum. Ginkgolic acids-induced death showed features of apoptosis as we observed chromatin condensation, shrinkage of the nucleus and reduction of the damage by the protein synthesis inhibitor cycloheximide, demonstrating an active type of cell death. However, DNA fragmentation detected by the terminal-transferase-mediated ddUTP-digoxigenin nick-end labeling (TUNEL) assay and caspase-3 activation, which are also considered as hallmarks of apoptosis, were not seen after treatment with 150 microM ginkgolic acids in serum-free medium, a dose which increased the percentage of neurons with chromatin condensation and shrunken nuclei to 88% compared with 25% in serum-deprived, vehicle-treated controls. This suggests that ginkgolic acid-induced death showed signs of apoptosis as well as of necrosis. Ginkgolic acids specifically increased the activity of protein phosphatase type-2C, whereas other protein phosphatases such as protein phosphatases 1A, 2A and 2B, tyrosine phosphatase, and unspecific acid- and alkaline phosphatases were inhibited or remained unchanged, suggesting protein phosphatase 2C to play a role in the neurotoxic effect mediated by ginkgolic acids.

15.The risk-benefit profile of commonly used herbal therapies: Ginkgo, St. John's Wort, Ginseng, Echinacea, Saw Palmetto, and Kava.:

Ann Intern Med. 2002 Jan 1;136(1):42-53.PMID: 11777363
Because use of herbal remedies is increasing, a risk-benefit profile of commonly used herbs is needed. This article provides a clinically oriented overview of the efficacy and safety of ginkgo, St. John's wort, ginseng, echinacea, saw palmetto, and kava. Wherever possible, assessments are based on systematic reviews of randomized clinical trials. Encouraging data support the efficacy of some of these popular herbal medicinal products, and the potential for doing good seems greater than that for doing harm. The published evidence suggests that ginkgo is of questionable use for memory loss and tinnitus but has some effect on dementia and intermittent claudication. St. John's wort is efficacious for mild to moderate depression, but serious concerns exist about its interactions with several conventional drugs. Well-conducted clinical trials do not support the efficacy of ginseng to treat any condition. Echinacea may be helpful in the treatment or prevention of upper respiratory tract infections, but trial data are not fully convincing. Saw palmetto has been shown in short-term trials to be efficacious in reducing the symptoms of benign prostatic hyperplasia. Kava is an efficacious short-term treatment for anxiety. None of these herbal medicines is free of adverse effects. Because the evidence is incomplete, risk-benefit assessments are not completely reliable, and much knowledge is still lacking.

16.Ginkgo seed poisoning.:

Pediatrics. 2002 Feb;109(2):325-7.PMID: 11826216
A 2-year-old girl presented with vomiting and diarrhea 7 hours after eating a large quantity of ginkgo seeds. She exhibited an afebrile convulsion 9 hours after ingestion. The serum concentration of 4-metoxypyridoxine was as high as 360 ng/mL. Although reported cases of ginkgo seed poisoning usually involve children who exhibit repetitive seizures that can be fatal, prompt administration of pyridoxal phosphate (2 mg/kg) may have prevented additional seizures. This is the first English-language case report measuring 4-metoxypyridoxine concentration during ginkgo seed poisoning. Awareness of the potential danger of overconsumption of this traditional food and its prompt treatment with pyridoxal phosphate may hasten recovery.

17.Safety of dietary supplements: chronotropic and inotropic effects on isolated rat atria.:

Biol Pharm Bull. 2002 Feb;25(2):197-200.PMID: 11853165
We investigated the effects of dietary supplements on atria isolated from male Wistar rats. The examined supplements, which are increasingly used in Japan, those were Ginkgo biloba extract (GBE), catechins, isoflavones, sodium iron chlorophyllin and sodium copper chlorophyllin. GBE at 100-1000 microg/ml significantly increased the beat rate and the contractile force. Catechins at 1-100 microg/ml significantly potentiated the contractile force but did not effect the beat rates. However, isoflavones, sodium iron and sodium copper chlorophyllins did not change the contractile force or the beat rates. To identify the active ingredient of GBE, ginkgolide B, quercetin and amentoflavone on the atria were tested. Ginkgolide B weakened the contractile force. Quercetin potentiated the contractile force at only 30 microg/ml. Amentoflavone significantly increased the beat rate. From these findings, amentoflavone and quercetin were considered to be the principal ingredients of GBE producing the positive chronotropic and inotropic actions, respectively. In the case of catechins, (-)-epigallocatechin gallate (EGCg), one of the principal ingredients, produced inotropic actions. These findings suggest that there are some dietary supplements which affect cardiac function, such GBE and catechins.

18.Update on natural product--drug interactions.:

Am J Health Syst Pharm. 2002 Feb 15;59(4):339-47.PMID: 11885397
The interactions of natural products with drugs are discussed. Interactions between natural products and drugs are based on the same pharmacokinetic and pharmacodynamic principles as drug-drug interactions. Clinically important interactions appear to involve effects on drug metabolism via cytochrome P-450 isoenzymes, impairment of hepatic or renal function, and other possible mechanisms. Natural products that have been reported to interact with drugs in humans include coenzyme Q10, dong quai, ephedra, Ginkgo biloba, ginseng, glucosamine sulfate, ipriflavone, melatonin, and St. John's wort. In many cases, more research is needed to confirm these interactions and to determine whether other natural products may also interact with drugs. To effectively counsel patients about interactions involving natural products, pharmacists should be familiar with the most commonly used products and have access to information on more obscure products. In view of the less than stringent provisions of the Dietary Supplement Health and Education Act, pharmacists should consult reliable, independent sources of information on natural products rather than rely on literature provided by manufacturers. Pharmacists should recommend only those products that are manufactured to high quality-control standards. Natural products can interact with drugs and with other natural products by the same mechanisms as drugs.

19.Gas chromatography-mass spectrometry analysis of 4-O-methylpyridoxine (MPN) in the serum of patients with ginkgo seed poisoning.:

J Anal Toxicol. 2002 Apr;26(3):138-43.PMID: 11991529
The 4-O-methylpyridoxine (MPN) present in the seeds of the Ginkgo biloba (maidenhair tree) has anti-vitamin B6 actions, and ginkgo seed poisoning can induce convulsions. We developed a specific quantitative method using gas chromatography-mass spectrometry for the analysis of MPN in human serum. The trifluoroacyl (TFA) derivative of MPN was obtained by treating MPN with trifluoroacetic anhydride at 50 degrees C for 5 min and remained stable for 6 h. The calibration curve of standard MPN obtained in the selective ion mode using the base ion (m/z 343) was linear between 100 pg and 10 ng, and the detection limit was 50 pg. The full mass spectrum of 100 pg of the TFA derivative of MPN was obtained easily. MPN was extracted from the serum with the use of a C18 solid-phase extraction cartridge. The recovery rate of MPN added to the serum at a concentration of 0.1 microg/mL was 90.0%.

20.Bleeding complications precipitated by unrecognized Gingko biloba use after liver transplantation.:

Transpl Int. 2002 Jul;15(7):377-9. Epub 2002 Jun 19.PMID: 12122516
Because of its neurocognitive enhancing effects, Gingko biloba has emerged as amongst the most commonly used herbal products. We report a liver transplant recipient with potentially life-threatening toxicity resulting from Gingko biloba use. Seven days after a second liver transplantation for recurrent hepatitisB virus infection, subphrenic hematoma was documented in a 59-year-old Korean patient. Failure to control bleeding with CT-guided drainage necessitated exploratory laparotomy for the evacuation of a large subphrenic hematoma. Three weeks later, an episode of vitreous hemorrhage was documented. Unbeknownst to his care providers, the patient had been consuming Gingko biloba throughout the postoperative period. No further bleeding episodes occurred after the cessation of Gingko biloba use. Unrecognized use of herbal products may be associated with serious side effects and adverse clinical sequelae in transplant recipients. Given their increasing popularity, the use of herbal products should be routinely sought as part of the history in transplant recipients.

21.Effects of herbal components on cDNA-expressed cytochrome P450 enzyme catalytic activity.:

Life Sci. 2002 Aug 16;71(13):1579-89.PMID: 12127912
We evaluated the effects of 25 purified components of commonly used herbal products on the catalytic activity of cDNA-expressed cytochrome P450 isoforms in in vitro experiments. Increasing concentrations of the compounds were incubated with a panel of recombinant human CYP isoforms (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4) and their effects on the conversion of specific surrogate substrates measured fluorometrically in a 96-well plate format. For each test substance, the IC50 (the concentration required to inhibit metabolism of surrogate substrates by 50%) was estimated and compared with IC50's for the positive control inhibitory drugs furafylline, sulfaphenazole, tranylcypromine, quinidine, and ketoconazole. Constituents of Ginkgo biloba (ginkgolic acids I and II), kava (desmethoxyyangonin, dihydromethysticin, and methysticin), garlic (allicin), evening primrose oil (cis-linoleic acid), and St. John's wort (hyperforin and quercetin) significantly inhibited one or more of the cDNA human P450 isoforms at concentrations of less than 10 uM. Some of the test compounds (components of Ginkgo biloba, kava, and St. John's wort) were more potent inhibitors of the isoforms 1A2, 2C19, and 2C19 than the positive controls used in each assay (furafylline, sulfaphenazole, and tranylcypromine, respectively), which are known to produce clinically significant drug interactions. The enzyme most sensitive to the inhibitory of effects of these compounds was CYP2C19, while the isoform least effected was CYP2D6. These data suggest that herbal products containing evening primrose oil, Ginkgo biloba, kava, and St. John's Wort could potentially inhibit the metabolism of co-administered medications whose primary route of elimination is via cytochrome P450.

22.Cytochrome P450 phenotypic ratios for predicting herb-drug interactions in humans.:

Clin Pharmacol Ther. 2002 Sep;72(3):276-87.PMID: 12235448
OBJECTIVES: Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Single-time point phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1, or CYP3A4 activity.METHODS: Twelve healthy volunteers (6 females) were randomly assigned to receive either St John's wort, garlic oil, P ginseng, or G biloba for 28 days. For each subject, a 30-day washout period was interposed between each supplementation phase. Probe-drug cocktails of midazolam, caffeine, chlorzoxazone, and debrisoquin (INN, debrisoquine) were administered before supplementation (baseline) and at the end of supplementation. Presupplementation and postsupplementation phenotypic trait measurements were determined for CYP3A4, CYP1A2, CYP2E1, and CYP2D6 with the use of 1-hydroxymidazolam/midazolam serum ratios (1-hour sample), paraxanthine/caffeine serum ratios (6-hour sample), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour sample), and debrisoquin urinary recovery ratios (8-hour collection), respectively.RESULTS: Comparisons of presupplementation and postsupplementation ratios indicated that St John's wort significantly induced the activity of CYP2E1 and CYP3A4 (P <.0001). Among female subjects, St John's wort produced significantly greater increases in CYP3A4 phenotypic ratios that appeared to be unrelated to body mass index. This finding is suggestive of a sexual dimorphism in CYP3A4 inducibility. Garlic oil reduced CYP2E1 activity by 39% (P =.030), whereas no significant effect on CYP activity was observed for P ginseng and G biloba.CONCLUSIONS: Single-time point phenotypic metabolic ratios may provide a practical means of predicting CYP-mediated herb-drug interactions in humans.

23.Feeding of Ginkgo biloba extract (GBE) enhances gene expression of hepatic cytochrome P-450 and attenuates the hypotensive effect of nicardipine in rats.:

Life Sci. 2002 Apr 26;70(23):2783-92.PMID: 12269382
Ginkgo biloba extract (GBE) has been used clinically for improving peripheral vascular diseases in France and Germany and is ingested widely as a herbal medicine in some countries. However, accurate information about its safety as an herbal medicine has not been sufficiently established. To address this issue, we examined the effect of GBE on hepatic drug metabolizing enzymes and their influence on hypotensive drug in rats. Male rats were fed either a control diet or diet containing GBE (0.5% w/w) for 4 weeks. The feeding of a GBE diet did not change the serum transaminase activity, but increased the liver weight and the phospholipid concentration in the liver. In addition, the GBE diet markedly increased the content of cytochrome P-450 (CYP), and the activity of glutathione S-transferase in the liver. Furthermore, the GBE diet markedly induced levels of CYP2B1/2, CYP3A1 and CYP3A2 mRNA in the liver. The levels of CYP1A1, CYP1A2, CYP2E1, CYP2C11 and CYP4A1 were unchanged. The feeding of GBE for 4 weeks significantly reduced the hypotensive effect of nicardipine that was reported to be metabolized by CYP3A2 in rats. These findings suggest that GBE reduces the therapeutic potency of the Ca2+ channel blocker, nicardipine, via enhancement of cytochrome P-450 expression.

24.Spontaneous hyphema caused by Ginkgo biloba extract:

J Fr Ophtalmol. 2002 Sep;25(7):731-2.PMID: 12399731
We report the first case of a patient in whom Ginkgo biloba extract proved to be the unique cause of spontaneous hyphema. Extensive ophthalmological and biological investigations were undertaken in order to assess the role of Ginkgo biloba: platelet numbering, hemostasis factors, Willebrand antigen, ristocetin cofactor, platelet glycoprotein immunophenotyping, glycoprotein expression after activation by thrombin, inflammatory markers, B-scan ultrasonography, and fluorescent iridography. No putative causes of hyphema were recorded other than Gingko biloba intake. The bleeding originated from the 12-o'clock position of the iris margin. Anamnesis identified Ginkgo biloba extract ingestion from 2 weeks before the appearance of the patient's visual trouble. Ginkgo biloba intake was stopped and the hemorrhage resolved with no recurrence during the 18 months of follow-up. Ginkgo biloba is known for platelet inhibition and is extensively used in the elderly because of its beneficial effects as a vascular protector. The clinical progression of the present case strongly suggests that Ginkgo biloba may cause hemorrhage and hyphema, even in the absence of any other predisposing factor.

25.Ginkgo biloba extract markedly induces pentoxyresorufin O-dealkylase activity in rats.:

Jpn J Pharmacol. 2002 Dec;90(4):345-51.PMID: 12501011
We examined the effect of Ginkgo biloba extract (GBE) on hepatic drug-metabolizing enzymes, particularly cytochrome P450 (CYP), in rats. Rats were fed a GBE-containing diet or received GBE by intragastric gavage. The concentration of CYP and activity of various CYP enzymes in the liver were increased in a dose- and time-dependent manner. Significant increases in the concentration and activities of CYP enzymes were detected on day 1 of feeding of a 0.5% GBE diet and after administration of 10 mg GBE/kg body weight for 5 days by intragastric gavage. Among the CYP enzymes, the activity of pentoxyresorufin O-dealkylase (PROD), a CYP2B enzyme, was especially markedly increased. The induction of CYP2B enzyme by GBE was confirmed by Western blot analysis. Addition of GBE to a CYP assay system in vitro caused concentration-dependent inhibition of various CYP enzyme activities. The inhibition was more marked for the microsomal enzymes from GBE-treated rats than for those from control rats and more marked against PROD activity among the CYP enzymes tested. When the inhibition of various CYP enzymes activities by GBE in vitro was compared, no marked difference was observed between rat and human hepatic microsomal enzymes. These results indicate that excess intake of GBE induces CYP enzymes, particularly PROD, and may modify the efficacy of drugs taken simultaneously.

26.Effect of Coenzyme Q10 and Ginkgo biloba on warfarin dosage in patients on long-term warfarin treatment. A randomized, double-blind, placebo-controlled cross-over trial:

Ugeskr Laeger. 2003 Apr 28;165(18):1868-71.PMID: 12772396
INTRODUCTION: A few case-stories claim that the anti-oxidant Coenzyme Q10 and possibly also Ginkgo biloba interact with warfarin treatment. A decreased response to warfarin in the Coenzyme Q10 cases and an increased response in the Ginkgo biloba case have been described.MATERIAL AND METHODS: Twenty-four outpatients on stable, long-term warfarin treatment were included in a randomised, double blind, placebo-controlled crossover trial. Coenzyme Q10 100 mg daily, Ginkgo-Biloba 100 mg daily and placebo were given in random order over treatment periods of four weeks, each followed by a two week wash out period. The international normalized ratio (INR) INR was kept between 2.0 and 4.0 by appropriate adjustment of the warfarin dosage.RESULTS: Fourteen women and ten men, median ages 64.5 years (33-79) were included. Three patients withdrew from the study for personal reasons. The INR was stable during all treatment periods. The geometric mean dosage of warfarin did not change during the treatment periods: Ginkgo biloba 36.7 mg/week (95% confidence interval: 29.2-46.0); CoQ10 36.5 mg/week (29.1-45.8); placebo 36.0 mg/week (28.6-45.1).CONCLUSION: The study indicated that Coenzyme Q10 and Ginkgo biloba do not influence the clinical effect of warfarin.

27.Interaction of Ginkgo biloba extract (GBE) with hypotensive agent, nicardipine, in rats.:

In Vivo. 2003 Sep-Oct;17(5):409-12.PMID: 14598602
The effect of Ginkgo biloba extract (GBE, 0.5%) orally administered for 2 weeks on the antihypertensive action of oral nicardipine was examined in Wistar rats. GBE significantly increased hepatic P-450 content and reduced the hypotensive effect of nicardipine. GBE administration resulted in a significant decrease in maximal nicardipine plasma concentration (Cmax) and the 23-hour area under the curve (AUC0-23). Thus, it is suggested that GBE attenuated the therapeutic potency of nicardipine, probably secondary to increased hepatic drug metabolism.

28.No alteration in platelet function or coagulation induced by EGb761 in a controlled study.:

Clin Lab Haematol. 2003 Aug;25(4):251-3.PMID: 12890165
Some cases of spontaneous bleeding have been reported in patients treated with Ginkgo biloba. A prospective, double-blind, randomized, placebo-controlled study was carried out in 32 young male healthy volunteers to evaluate the effect of three doses of Ginkgo biloba extract (120, 240 and 480 mg/day for 14 days) on hemostasis, coagulation and fibrinolysis. This study did not reveal any alteration of platelet function or coagulation. This suggests that the reported clinical bleeding events in patients receiving Ginkgo biloba extract are not related to pharmacological properties of EGb761.

29.Studies on interactions between functional foods or dietary supplements and medicines. I. Effects of Ginkgo biloba leaf extract on the pharmacokinetics of diltiazem in rats.:

Biol Pharm Bull. 2003 Sep;26(9):1315-20.PMID: 12951478
The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan, on the pharmacokinetics of diltiazem (DTZ), a typical probe of cytochrome P450 (CYP) 3A, were examined in rats. The simultaneous addition of GBE to small intestine and liver microsomes inhibited the formation of N-demethyl DTZ (MA), an active metabolite of DTZ produced by CYP3A, in a concentration-dependent manner, with an IC(50) of about 50 and 182 microg/ml, respectively. This inhibition appeared to be caused, at least in part, by a mechanism-based inhibition. Both the rate of formation of MA and total amount of CYP in intestinal or hepatic microsomes after a single oral pretreatment with GBE (20 mg/kg) decreased transiently. The pretreatment significantly decreased the terminal elimination rate constant and increased the mean residence time, after intravenous administration of DTZ (3 mg/kg). Furthermore, it significantly increased the area under the concentration-time curve and absolute bioavailability after oral administration of DTZ (30 mg/kg). These results indicated that the concomitant use of GBE in rats increased the bioavailability of DTZ by inhibiting both intestinal and hepatic metabolism, at least in part, via a mechanism-based inhibition for CYP3A.

30.Experimental study on inhibition of neuronal toxical effect of levodopa by ginkgo biloba extract on Parkinson disease in rats.:

31.Glucuronidation and in vitro interaction of Ginkgo flavonoids with other drugs:

Zhejiang Da Xue Xue Bao Yi Xue Ban. 2004 Jan;33(1):15-20.PMID: 14966933
OBJECTIVE: To obtain the information on the glucuronidation of Ginkgo flavonoid and the interaction profile of Ginkgo flavones with other drugs in vitro.METHODS: Ginkgo flavonoids (quercetin, isorhamnetin and keampferol) and other drugs were co-incubated with rat hepatic microsome at 25 degree; the residual concentrations of flavonoids were determined by HPLC. The enzymatic parameters of quercetin, isorhamnetin and keampferol metabolism were assessed. The interactions between flavonoids and these drugs on glucuronidation were observed.RESULT: The K(m) values were ( 24+/-0.05), (148+/-0.09) and (110+/-0.03) micromol/L and the V(max) values were (60+/-0.21), (48+/-0.02) and (34+/-0.02) micromol x g(-1) x min(-1) for quercetin, isorhamnetin and kaempferol, respectively. The IC(50) of nifedipine propafenone ipriflavone and diphenytriazol on flavonoids metabolism were 54 - 70, 69 - 122, 85 - 98 and 210 - 362 micromol, respectively. The inhibition constants (Ki) of diphenytriazol propafenone and ipriflavone on quercetin, isorhamnetin and keampferol metabolism were (57.6, 50.5, 33.1) (33.6, 59.5, 45.2) and(13.7,24.0,15.7) microg/ml respectively. The ratio [I]/[Ki] of the plasma concentration and inhibition constant for propafenone was 0.002 - 0.003.CONCLUSION: The metabolic level of quercetin is the strongest among three Ginkgo flavonoids. Nifedipine propafenone and ipriflavone inhibit the metabolism of quercetin, isorhamnetin and keampferol at different levels. Because of the interaction between Ginkgo flavonoids with nifedipine, caution must be taken when two drugs are used together clinically.

32.Quantification of allergenic urushiols in extracts of Ginkgo biloba leaves, in simple one-step extracts and refined manufactured material (EGb 761).:

Phytochem Anal. 2004 Jan-Feb;15(1):1-8.PMID: 14979519
Extracts of leaves of Ginkgo biloba (family Ginkgoaceae), widely used in the treatment of peripheral and cerebral circulatory disorders as well as for dementia of different aetiology, contain long chain alkylphenols (with allergenic, cytotoxic, mutagenic and tumour-promoting properties) together with the extremely potent allergens, the urushiols. Such hazardous compounds can be present only in very low concentrations in phytopharmaceutical preparations and hence, for the purposes of drug safety, techniques must be available for the identification and quantification of these allergens at extremely low levels in refined manufactured materials. GC-MS analysis of samples collected at various stages during the production process of a standardised extract of G. biloba (EGb 761) demonstrated that all alkylphenols present in the primary acetone extracts were removed in parallel with the same efficiency irrespective of their aromatic substitution pattern. Furthermore, in the final product the content of urushiols was generally below the detection limit of 0.03 ppm. Therefore, it is concluded that demonstrating the absence of the predominant, and easily quantifiable, ginkgolic acids provides a reliable means for the control of pharmaceutical quality of the final product.

33.Pretreatment with Ginkgo biloba extract weakens the hypnosis action of phenobarbital and its plasma concentration in rats.:

J Pharm Pharmacol. 2004 Mar;56(3):401-5.PMID: 15025867
In a previous study, we found that orally administered Ginkgo biloba extract (GBE) induced hepatic cytochrome P450 (CYP) in rats, especially the CYP2B type. This fact suggested that GBE influenced the availability and safety of drugs that were metabolized via CYP2B type enzymes. To confirm this possibility, in this study we examined the effect of feeding a 0.1, 0.5 and 1.0% GBE diet for 2 weeks on the pharmacokinetics and pharmacological action of phenobarbital, which is known to be metabolized by CYP2B in Wistar rats. The feeding of GBE markedly shortened the sleeping time in rats. Furthermore, the maximal phenobarbital plasma concentration (Cmax) and the 24-h area under the curve (AUC0-24) were decreased in rats fed GBE. These findings indicate that GBE reduces the therapeutic potency of phenobarbital via enhancement of cytochrome P450 expression, and raises the possibility that GBE and drug interactions may occur clinically.

34.The effects of Ginkgo biloba extracts on the pharmacokinetics and pharmacodynamics of donepezil.:

J Clin Pharmacol. 2004 May;44(5):538-42.PMID: 15102875
The effects of ginkgo supplementation on the steady-state plasma concentration of donepezil and the activity of cholinesterase in red blood cells and cognitive function were examined. Fourteen inpatients with Alzheimer's disease received donepezil 5 mg/day, supplemented with extracts of Ginkgo biloba 90 mg/day for 30 days. Blood samples were collected before and during ginkgo supplementation and 30 days after its discontinuation, together with an assessment of cognitive function. Plasma drug concentration was measured using high-performance liquid chromatography (HPLC), and cholinesterase in red blood cells was measured using Ellman methods. Cognitive function was evaluated using the Mini-Mental Scale Examination (MMSE). Plasma concentration of donepezil during ginkgo supplementation (mean +/- SD [95% confidence interval]; 24.4 +/- 12.6 ng/mL [17.1-31.7 ng/mL]) was not significantly different from that before ginkgo supplementation (22.7 +/- 10.3 ng/mL [16.8-28.7 ng/mL]) or that 4 weeks after its discontinuation (25.0 +/- 12.9 ng/mL [17.6-32.4 ng/mL]). There was no significant difference between cholinesterase in red blood cells before ginkgo supplementation (1.75 +/- 0.21 U [1.63-1.87 U]), during ginkgo supplementation (1.91 +/- 0.27 U [1.76-2.07 U]), and 4 weeks after its discontinuation (1.83 +/- 0.29 U [1.66-2.00 U]). Ginkgo supplementation did not alter MMSE scores throughout the study. The present study shows that ginkgo supplementation does not have major impact on the pharmacokinetics and pharmacodynamics of donepezil.

35.The inhibitory effects of herbal components on CYP2C9 and CYP3A4 catalytic activities in human liver microsomes.:

Am J Ther. 2004 May-Jun;11(3):206-12.PMID: 15133536
Herbal medicines are widely consumed by patients in different clinical settings in the United States and all over the world. In this study, 7 herbal components ginsenosides Rb1, Rb2, Rc, and Rd (from ginseng quercetin) ginkgolides A and B (from ginkgo biloba) were investigated for their inhibitory effects on hepatic CYP2C9 and CYP3A4 catalytic activities in human liver microsomes. Tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation were used as index reactions of CYP2C9 or CYP3A4 catalytic activities, respectively. The metabolites of both reactions were measured by high-performance liquid chromatography and used as indicators of whether enzymes were inhibited or unaffected by these agents. Herbal components were studied at various concentrations (0.1, 1, 10, 100, 200 micromol/L). The herbal compounds investigated were capable of inhibiting CYP2C9 and CYP3A4 catalytic activities, but the potencies differed. Quercetin showed marked inhibitory effects on both tolbutamide 4-methylhydroxylation and testosterone 6beta-hydroxylation with IC(50) values of 35 and 38 micromol/L, respectively. Ginsenoside Rd also had significant inhibitory potency on both CYP2C9- and CYP3A4-mediated index reactions with IC(50) values of 105 and 62 micromol/L, respectively. Ginsenosides Rb1, Rb2, and Rc had limited inhibitory activities on both enzyme reaction systems, whereas the effects of ginkgolides A and B appeared negligible. It is concluded that the components of ginseng and ginkgo biloba screened are capable of inhibiting CYP2C9- and CYP3A4-mediated metabolic reactions. Our findings suggest that quercetin and ginsenoside Rd have the potential to interact with conventional medicines that are metabolized by CYP2C9 and CYP3A4 in vivo.

36.Inhibition of human P450 enzymes by multiple constituents of the Ginkgo biloba extract.:

Biochem Biophys Res Commun. 2004 Jun 11;318(4):1072-8.PMID: 15147983
The Ginkgo biloba extract EGb761 was tested for its ability to inhibit the major human cytochrome P450 enzymes (CYPs). The full extract was found to strongly inhibit CYP2C9 (Ki = 14+/- 4 microg/mL), and to a lesser extent, CYP1A2 (Ki = 106 +/- 24 microg/mL), CYP2E1 (Ki = 127 +/- 42 microg/mL), and CYP3A4 (Ki = 155 +/- 43 microg/mL). The terpenoidic and flavonoidic fractions of the extract were tested separately against the same P450s to identify the source of inhibition by EGb761. The terpenoidic fraction inhibited only CYP2C9 (Ki = 15 +/-6 microg/mL) whereas the flavonoidic fraction of EGb761 showed high inhibition of CYP2C9, CYP1A2, CYP2E1, and CYP3A4 (Ki's between 4.9 and 55 microg/mL). The flavonoidic fraction was further fractionated using extraction and chromatography. Inhibition studies indicated that the majority of these fractions inhibited P450s at a significant level (IC50 < 40 microg/mL).

37.Influence of a 7-day treatment with Ginkgo biloba special extract EGb 761 on bleeding time and coagulation: a randomized, placebo-controlled, double-blind study in healthy volunteers.:

Blood Coagul Fibrinolysis. 2004 Jun;15(4):303-9.PMID: 15166915
During recent years, several case reports have been published in which the authors have voiced their suspicion of a causal relationship between hemorrhagic complications and the intake of Ginkgo biloba preparations. Therefore, a trial was conducted to investigate the influence of Ginkgo biloba special extract EGb 761 on hemostasiological parameters. Fifty healthy, male volunteers underwent 7 days of crossover treatment with 2 x 120 mg/day EGb 761 and placebo in randomized sequence. Between the two treatment phases, a washout-period of at least 3 weeks was inserted. The study's main outcome measures were bleeding time, coagulation parameters, platelet activity in response to various agonists and platelet morphology. The equivalence of the two treatments was analyzed by computing the 90% Fieller confidence intervals for the ratio between the means of the pre-post treatment differences for EGb 761 and placebo, respectively. Treatment safety was investigated by clinical laboratory and vital signs assessment and by adverse events monitoring. Among the 29 coagulation and bleeding parameters assessed, none showed any evidence of an inhibition of blood coagulation and platelet aggregation through EGb 761. Furthermore, the study did not reveal any evidence to substantiate a causal relationship between the administration of EGb 761 and hemorrhagic complications. As regards treatment tolerability, there were no interpretable differences between EGb 761 and placebo except for a slight increase of gastrointestinal complaints during administration of the herbal extract.

38.Herbal remedies in the United States: potential adverse interactions with anticancer agents.:

J Clin Oncol. 2004 Jun 15;22(12):2489-503.PMID: 15197212
PURPOSE: Interest in the use of herbal products has grown dramatically in the Western world. Recent estimates suggest an overall prevalence for herbal preparation use of 13% to 63% among cancer patients. With the narrow therapeutic range associated with most anticancer drugs, there is an increasing need for understanding possible adverse drug interactions in medical oncology.METHODS: In this article, a literature overview is provided of known or suspected interactions of the 15 best-selling herbs in the United States with conventional allopathic therapies for cancer.RESULTS: Herbs with the potential to significantly modulate the activity of drug-metabolizing enzymes (notably cytochrome p450 isozymes) and/or the drug transporter P-glycoprotein include garlic (Allium sativum), ginkgo (Ginkgo biloba), echinacea (Echinacea purpurea), ginseng (Panax ginseng), St John' s wort (Hypericum perforatum), and kava (Piper methysticum). All of these products participate in potential pharmacokinetic interactions with anticancer drugs.CONCLUSION: It is suggested that health care professionals and consumers should be aware of the potential for adverse interactions with these herbs, question their patients on their use of them, especially among patients whose disease is not responding to treatments as expected, and urge patients to avoid herbs that could confound their cancer care.

39.Ginkgo biloba extract modifies hypoglycemic action of tolbutamide via hepatic cytochrome P450 mediated mechanism in aged rats.:

Life Sci. 2004 Jul 16;75(9):1113-22.PMID: 15207658
We examined hepatic cytochrome P450 (CYP)-mediated interactions between Ginkgo biloba extract (GBE) and tolbutamide, an oral anti-diabetic agent, in aged and young rats. Tolbutamide was orally given to rats with or without GBE treatment, and time-dependent changes in blood glucose were monitored. The basal activity of six CYP subtypes in liver was lower in the aged rats than in the young rats, while the inductions of these enzymes by 5 day pretreatment of 0.1% GBE diet were more in the aged rats. Further, the pretreatment of GBE significantly attenuated the hypoglycemic action of tolbutamide in the aged rats, corresponding well to the enhanced activity of (S)-warfarin 7-hydroxylase, which is responsible for CYP2C9 subtype, a major isoform metabolizing tolbutamide. In contrast, the simultaneous administration of GBE with tolbutamide potentiated the hypoglycemic action of this drug. The in vitro experiments revealed that GBE competitively inhibited the metabolism of tolbutamide by (S)-warfarin 7-hydroxylase in the rat liver microsomes. In the young rats, the 5 day pretreatment with GBE significantly attenuated the hypoglycemic action of tolbutamide, but a simultaneous treatment had little influence on the tolbutamide effect. In conclusion, the present study has shown that the simultaneous and continuous intake of GBE significantly affects the hypoglycemic action of tolbutamide, possibly via a hepatic CYP enzyme-mediated mechanism, particularly in the aged rats. Therefore, it is anticipated that the intake of GBE as a dietary supplement with therapeutic drugs should be cautious, particularly in elderly people.

40.Inhibition of human cytochromes P450 by components of Ginkgo biloba.:

J Pharm Pharmacol. 2004 Aug;56(8):1039-44.PMID: 15285849
The extraction, isolation and characterization of 29 natural products contained in Ginkgo biloba have been described, which we have now tested for their in-vitro capacity to inhibit the five major human cytochrome P450 (CYP) isoforms in human liver microsomes. Weak or negligible inhibitory activity was found for the terpene trilactones (ginkgolides A, B, C and J, and bilobalide), and the flavonol glycosides. However 50% inhibitory activity (IC50) was found at concentrations less than 10 microg L(-1) for the flavonol aglycones (kaempferol, quercetin, apigenin, myricetin, tamarixetin) with CYP1A2 and CYP3A. Quercetin, the biflavone amentoflavone, sesamin, as well as (Z,Z)-4,4'-(1,4-pentadiene-1,5-diyl)diphenol and 3-nonadec-8-enyl-benzene-1,2-diol, were also inhibitors of CYP2C9. The IC50 of amentoflavone for CYP2C9 was 0.019 microg mL(-1) (0.035 microM). Thus, the principal components of Ginkgo biloba preparations in clinical use (terpene trilactones and flavonol glycosides) do not significantly inhibit these human CYPs in-vitro. However, flavonol aglycones, the biflavonol amentoflavone and several other non-glycosidic constituents are significant in-vitro inhibitors of CYP. The clinical importance of these potential inhibitors will depend on their amounts in ginkgo preparations sold to the public, and the extent to which their bioavailability allows them to reach the CYP enzymes in-situ.

41.Studies on interactions between functional foods or dietary supplements and medicines. IV. Effects of ginkgo biloba leaf extract on the pharmacokinetics and pharmacodynamics of nifedipine in healthy volunteers.:

Biol Pharm Bull. 2004 Dec;27(12):2006-9.PMID: 15577221
The effects of Ginkgo biloba leaf extract (GBE), a widely used herbal dietary supplement in Japan, on the pharmacokinetics and pharmacodynamics of nifedipine (NFP), a calcium-channel blocker, were studied using 8 healthy volunteers. Simultaneous oral ingestion of GBE (240 mg) did not significantly affect any of the mean pharmacokinetic parameters of either NFP or dehydronifedipine, a major metabolite of NFP, after oral administration of NFP (10 mg). However, the maximal plasma NFP concentrations in 2 subjects were approximately doubled by GBE, and they had severer and longer-lasting headaches with GBE than without GBE, with dizziness or hot flushes in combination with GBE. The mean heart rate after oral administration of NFP with GBE tended to be faster than that without GBE at every time point. Accordingly, it was concluded that GBE and NFP should not be simultaneously ingested as much as possible, and careful monitoring is needed when administering NFP concomitantly with GBE to humans.

42.Studies on interactions between functional foods or dietary supplements and medicines. III. Effects of ginkgo biloba leaf extract on the pharmacokinetics of nifedipine in rats.:

Biol Pharm Bull. 2004 Dec;27(12):2042-5.PMID: 15577230
The effects of Ginkgo biloba leaf extract (GBE), one of the most widely used herbal dietary supplements in Japan and the United States, on the pharmacokinetics of nifedipine (NFP), a typical probe of P450 (CYP) 3A, but not a substrate of the multidrug transporter P-glycoprotein (P-gp), were studied using rats. Simultaneous oral treatment with GBE (20 mg/kg) did not affect the pharmacokinetics after intravenous administration of NFP (2.5 mg/kg). However, the maximal plasma NFP concentration, the area under the concentration-time curve and absolute bioavailability after oral administration of NFP (5 mg/kg) were significantly increased by simultaneous oral treatment with GBE, approximately 1.6-fold, 1.6-fold and 2.1-fold, respectively. These results suggest that the concomitant oral use of GBE appeared to reduce the first-pass metabolism of orally administered NFP, by inhibiting CYP3A, possibly but not P-gp, in rats.

43.Inhibition of platelet activating factor (PAF)-induced aggregation of human thrombocytes by ginkgolides: considerations on possible bleeding complications after oral intake of Ginkgo biloba extracts.:

Phytomedicine. 2005 Jan;12(1-2):10-6.PMID: 15693702
The special Ginkgo biloba leaf extract EGb 761 is marketed for more then two decades. During this time its therapeutic efficacy and favorable safety profile have been proven in numerous clinical trails as well as by postmarketing surveillance in accordance with German drug regulations. During recent years, however, several cases of hemorrhage have been reported to occur in coincidence with the use of Ginkgo products. Although a clear causality between Ginkgo intake and bleeding could not be established, these observations have generally been explained by the platelet-activating factor (PAF)-antagonistic action of ginkgolides, which represent characteristic constituents of Ginkgo extracts. PAF was originally characterized by inducing aggregation and secretion of serotonin and histamine from rabbit platelets. We now confirmed that induction of aggregation of human platelets by PAF requires at least 200 times higher concentration when compared to rabbit cells. Under the chosen experimental conditions, PAF-mediated aggregation of human platelets was half-maximally inhibited by ginkgolide B, A, C and J at concentrations of 2.5, 15.8, 29.8 and 43.5 microg/ml, respectively. These concentrations are generally more than 100 times higher as the peak plasma values measured after oral intake of EGb 761 at recommended doses between 120 and 240 mg. As PAF is a 'weak' platelet activator, which does not appear to be of importance for primary hemostasis, our results rise serious doubts that the PAF antagonistic effect of ginkgolides could be responsible for hemorrhage in patients taking EGb 761.

44.Interactions between herbal and conventional medicines.:

Expert Opin Drug Saf. 2005 Mar;4(2):355-78.PMID: 15794726
Herb-drug interactions are subject to much interest at present, but for various reasons reports may be unreliable or unsubstantiated. Herbal medicines are variable in composition and quality, which may affect their interaction profile as well as the reliability of reports concerning them. In this review, clinical and experimental reports have been collated, evaluated and summarised, and the theoretical and clinical evidence presented. There is an explanation of the particular issues involved with herbal medicines as compared with conventional drugs, and reasons why comparisons may or may not be valid, which is intended for those without specialist experience in herbal products. It has become apparent that only a few herbal drugs have so far been cited in interaction reports, for example St John's Wort, Ginkgo biloba, Dan Shen, liquorice, Ma huang and garlic, and that the main drugs involved are those which are already susceptible to interactions with many other conventional drugs, such as warfarin, protease inhibitors and anti-cancer drugs. An attempt has been made to put the matter into perspective and recommendations have been given for health professionals to advise or develop strategies to safeguard patients, without resorting to speculation or scaremongering.

45.Effect of ginkgo and ginger on the pharmacokinetics and pharmacodynamics of warfarin in healthy subjects.:

Br J Clin Pharmacol. 2005 Apr;59(4):425-32.PMID: 15801937
AIM: The aim of this study was to investigate the effect of two common herbal medicines, ginkgo and ginger, on the pharmacokinetics and pharmacodynamics of warfarin and the independent effect of these herbs on clotting status.METHODS: This was an open label, three-way crossover randomized study in 12 healthy male subjects, who received a single 25 mg dose of warfarin alone or after 7 days pretreatment with recommended doses of ginkgo or ginger from herbal medicine products of known quality. Dosing with ginkgo or ginger was continued for 7 days after administration of the warfarin dose. Platelet aggregation, international normalized ratio (INR) of prothrombin time, warfarin enantiomer protein binding, warfarin enantiomer concentrations in plasma and S-7-hydroxywarfarin concentration in urine were measured. Statistical comparisons were made using anova and the 90% confidence intervals (CIs) of the ratio of log transformed parameters are reported.RESULTS: INR and platelet aggregation were not affected by administration of ginkgo or ginger alone. The mean (95% CI) apparent clearances of S-warfarin after warfarin alone, with ginkgo or ginger were 189 (167-210) ml h(-1), 200 (173-227) ml h(-1) and 201 (171-231) ml h(-1), respectively. The respective apparent clearances of R-warfarin were 127 (106-149) ml h(-1), 126 (111-141) ml h(-1) and 131 (106-156) ml h(-1). The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.98-1.21) and for R-warfarin was 1.00 (0.93-1.08) when coadministered with ginkgo. The mean ratio (90% CI) of AUC(0-168) of INR was 0.93 (0.81-1.05) when coadministered with ginkgo. The mean ratio (90% CI) of apparent clearance for S-warfarin was 1.05 (0.97-1.13) and for R-warfarin was 1.02 (0.95-1.10) when coadministered with ginger. The mean ratio (90% CI) of AUC(0-168) of INR was 1.01 (0.93-1.15) when coadministered with ginger. The mean ratio (90% CI) for S-7-hydroxywarfarin urinary excretion rate was 1.07 (0.85-1.32) for ginkgo treatment, and 1.00 (0.81-1.23) for ginger coadministration suggesting these herbs did not affect CYP2C9 activity. Ginkgo and ginger did not affect the apparent volumes of distribution or protein binding of either S-warfarin or R-warfarin.CONCLUSIONS: Ginkgo and ginger at recommended doses do not significantly affect clotting status, the pharmacokinetics or pharmacodynamics of warfarin in healthy subjects.

46.Possible contraindications and adverse reactions associated with the use of ocular nutritional supplements.:

Ophthalmic Physiol Opt. 2005 May;25(3):179-94.PMID: 15854063
The role of oxidation in the development of age-related eye disease has prompted interest in the use of nutritional supplementation for prevention of onset and progression. Our aim is to highlight possible contraindications and adverse reactions of isolated or high dose ocular nutritional supplements. Web of Science and PubMed database searches were carried out, followed by a manual search of the bibliographies of retrieved articles. Vitamin A should be avoided in women who may become pregnant, in those with liver disease, and in people who drink heavily. Relationships have been found between vitamin A and reduced bone mineral density, and beta-carotene and increased risk of lung cancer in smoking males. Vitamin E and Ginkgo biloba have anticoagulant and anti-platelet effects respectively, and high doses are contraindicated in those being treated for vascular disorders. Those patients with contraindications or who are considered at risk of adverse reactions should be advised to seek specialist dietary advice via their medical practitioner.

47.Influence of the Ginkgo extract EGb 761 on rat liver cytochrome P450 and steroid metabolism and excretion in rats and man.:

J Pharm Pharmacol. 2005 May;57(5):641-50.PMID: 15901353
Extracts from leaves of Ginkgo biloba L. are among the most used herbal medicinal products worldwide. Based on in-vitro tests and studies in rats, concern has been expressed that intake of Ginkgo extracts may affect hepatic metabolism of xenobiotics and cause drug interactions, although no evidence for modulation of cytochrome P450 (CYP450) enzyme activity was obtained in human trials. Because of these contradictory findings, we investigated the effects of the standardised extract EGb 761 on hepatic CYP450 in rats. EGb 761 (100 mg kg-1 daily, p.o., for 4 days) strongly increased liver CYP450 content and altered the ex-vivo biotransformation of androstendione, as well as metabolism of endogenous steroids. However, in human subjects no effect on the urinary steroid profile was observed after intake of EGb 761 for 28 days (240 mg daily). These results indicate that the effects of EGb 761 on drug metabolising enzymes are specific for rats and may not be extrapolated to man.

48.Clinical assessment of effects of botanical supplementation on cytochrome P450 phenotypes in the elderly: St John's wort, garlic oil, Panax ginseng and Ginkgo biloba.:

Drugs Aging. 2005;22(6):525-39.PMID: 15974642
OBJECTIVES: Elderly patients are more likely to ingest prescription medications concurrently with botanical supplements, and may therefore be vulnerable to herb-drug interactions. Phytochemical-mediated modulation of cytochrome P450 (CYP) activity may underlie many herb-drug interactions. Some evidence suggests that CYP activity may decrease in the elderly. If so, herb-mediated changes in CYP activity may take on greater clinical relevance in this population. In this study, single timepoint, phenotypic metabolic ratios were used to determine whether long-term supplementation of St John's wort, garlic oil, Panax ginseng, and Ginkgo biloba affected CYP1A2, CYP2D6, CYP2E1 or CYP3A4 activity in elderly subjects.METHODS: Twelve healthy volunteers between the ages of 60 and 76 years (mean age 67 years) were randomly assigned to receive each botanical supplement for 28 days followed by a 30-day washout period. Probe drug cocktails of midazolam, caffeine, chlorzoxazone and debrisoquine were administered before and at the end of supplementation. Pre- and post-supplementation phenotypic ratios were determined for CYP3A4, CYP1A2, CYP2E1 and CYP2D6 using 1-hydroxymidazolam/midazolam serum ratios (1-hour), paraxanthine/caffeine serum ratios (6-hour), 6-hydroxychlorzoxazone/chlorzoxazone serum ratios (2-hour) and debrisoquine urinary recovery ratios (8-hour), respectively. The content of purported 'active' phytochemicals was determined for each supplement.RESULTS: Comparisons of pre- and post-St John's wort phenotypic ratios revealed significant induction of CYP3A4 (approximately 140%) and CYP2E1 activity (approximately 28%). Garlic oil inhibited CYP2E1 activity by approximately 22%. P. ginseng inhibition of CYP2D6 was statistically significant, but the magnitude of the effect (approximately 7%) did not appear to be clinically relevant. None of the supplements tested in this study appeared to affect CYP1A2 activity.CONCLUSIONS: Elderly subjects, like their younger counterparts, are susceptible to herb-mediated changes in CYP activity, especially those involving St John's wort. Pharmacokinetic herb-drug interactions stemming from alterations in CYP activity may adversely affect drug efficacy and/or toxicity. When compared with earlier studies that employed young subjects, the data suggest that some age-related changes in CYP responsivity to botanical supplementation may exist. Concomitant ingestion of botanical supplements with prescription medications, therefore, should be strongly discouraged in the elderly.

49.Fibrinolytic effects of Ginkgo biloba extract.:

Exp Clin Cardiol. 2005 Summer;10(2):85-7.PMID: 19641664
A multitude of factors are involved in regulating the blood coagulation homeostatic processes in the body, which may ultimately lead to thromboemboli and thrombosis. The resolution of blood clots after healing is as important as clot formation at the site of a vascular lesion. This is accomplished by fibrinolytic drugs such as streptokinase (SK) and urokinase.It must be noted that administration of SK may be accompanied by the lysis of blood clots in unwanted sites, and complications such as general lytic conditions, severe hemorrhaging, reduced serum fibrinogen and allergies can occur. Anti-SK antibodies neutralize the effects of SK. Studies on natural compounds and medicinal herbs with fewer side effects have been ongoing. In the present study, the fibrinolytic effect of Ginkgo biloba, an herb grown in Iran, was investigated.A polyphenolic method was used to obtain Ginkgo extract from its leaves. The fibrinolytic effects of SK (positive control) were compared with those of Ginkgo extract using a fluorometry method.In producing a labelled clot, fibrinogen was labelled with the fluorescent agent fluorescein isothiocyanate and precipitated in the presence of Ca(2+). SK (100 U/mL to 1000 U/mL) and Ginkgo extract were added to labelled fibrin in a plasma environment at dilutions of 1, 1:10, 1:100 and 1:1000 (volume/volume). The fluorescence of the solution was measured between 15 min and 60 min later.A linear relationship was observed between the fluorescence measured and SK concentrations ranging from 300 U/mL to 700 U/mL. Ginkgo extract displayed a remarkable effect in resolving the clot. As Ginkgo extract remained in the environment, fluorescence increased notably, showing a time-dependent relationship.Overall, the results indicate that the effects of Ginkgo extract on the fibrinolytic system are similar to those of SK; hence, this herbal extract can be used as a complement to or a substitute for SK. Additionally, it is proposed that the effects of the active ingredients of Ginkgo extract should be studied in animals. Further studies are warranted for evaluating the possible side effects and toxicity of Ginkgo extract in human subjects.

50.Analysis of the inhibitory potential of Ginkgo biloba, Echinacea purpurea, and Serenoa repens on the metabolic activity of cytochrome P450 3A4, 2D6, and 2C9.:

J Altern Complement Med. 2005 Jun;11(3):433-9.PMID: 15992226
OBJECTIVE: To study the potential of three top-selling herbal products, Ginkgo biloba, Echinacea purpurea, and Serenoa repens to inhibit the in vitro enzymatic activity of three of the most important drug metabolizing enzymes, cytochrome P450 (CYP) 3A4, 2D6, and 2C9.METHODS: High throughput CYP inhibition screening was used to test the inhibitory capacity of extracts of commercially available herbal medications on the metabolism of CYP enzyme substrates.RESULTS: S. repens showed potent inhibition of the metabolic activity of all three CYPs tested. The effects of G. biloba and E. purpurea varied. E. purpurea demonstrated mild inhibition of CYP3A4 activity with 7- benzyloxy-4-trifluoromethylcoumarin (BFC) as the model substrate, but mild inducing effects in the presence of the model substrate resorufin benzyl ether (BzRes). Little effect on CYP2D6 and moderate inhibition of CYP2C9 was seen with both E. purpurea and G. biloba. G. biloba also showed mild-to-moderate inhibition of CYP3A4 depending on the model substrate.CONCLUSIONS: The inhibitory capacity of herbal products varies depending on the concentrations of the model substrate and the herbal extract, as well as the identity of the model substrate, as demonstrated by the varied effects of CYP3A4 enzymatic activity with different model substrates. The potential for strong adverse interactions exists for Serenoa repens, which was a potent inhibitor of all three CYPs examined. Physicians are encouraged to advise patients of the risks of combining herbal products with prescription medications.

51.Spontaneous bleeding associated with ginkgo biloba: a case report and systematic review of the literature: a case report and systematic review of the literature.:

J Gen Intern Med. 2005 Jul;20(7):657-61.PMID: 16050865
BACKGROUND: Ginkgo biloba (ginkgo) is a herbal remedy used by over 2% of the adult population in the United States. Several review articles have suggested that ginkgo may increase the risk of bleeding.OBJECTIVE: To report a case of bleeding associated with using ginkgo, to systematically review the literature for similar case reports, and to evaluate whether using ginkgo is causally related to bleeding.DATA SOURCES: We searched MEDLINE, EMBASE, IBIDS, and the Cochrane Collaboration Database from 1966 to October 2004 with no language restrictions.REVIEW METHODS: Published case reports of bleeding events in persons using ginkgo were selected. Two reviewers independently abstracted a standard set of information to assess whether ginkgo caused the bleeding event.RESULTS: Fifteen published case reports described a temporal association between using ginkgo and a bleeding event. Most cases involved serious medical conditions, including 8 episodes of intracranial bleeding. However, 13 of the case reports identified other risk factors for bleeding. Only 6 reports clearly described that ginkgo was stopped and that bleeding did not recur. Bleeding times, measured in 3 reports, were elevated when patients were taking ginkgo.CONCLUSION: A structured assessment of published case reports suggests a possible causal association between using ginkgo and bleeding events. Given the widespread use of this herb and the serious nature of the reported events, further studies are needed. Patients using ginkgo, particularly those with known bleeding risks, should be counseled about a possible increase in bleeding risk.

52.Effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats:

Zhongguo Zhong Yao Za Zhi. 2005 Jul;30(13):1009-13.PMID: 16161431
OBJECTIVE: To observe the effects of ginkgolides on gene expression of hepatic cytochrome P-450 in rats.METHOD: Sprague-Dawley rats were administered ginkgolides (100 mg x kg(-1) body weight) through oral gavage once daily for four consecutive days. The level of gene expression in liver tissues was analyzed by competitive reverse transcription-polymerase chain reaction (competitive RT-PCR).RESULT: A single and prospective band of CYP1A1, CYP1A2, CYP2B1/B2, CYP2C11, CYP2E1, CYP4A1 and cyclophilin was observed after polymerase chain reaction (PCR) when the reactive system of reverse transcription (RT) had no target RNA, which confirmed the competitor had a specific capacity to bind to the CYP or cyclophilin primer. CYP1A1 mRNA was not dectectable in the livers of untreated control rats and ginkgolides-treated rats. The levels of CYP2C11 and CYP2E1 were not changed by ginkgolides treatment. In contrast, the levels of gene expression for CYP1A2 and CYP2B1/B2 were decreased, however, the levels of gene expression for CYP3A1 and CYP4A1 in ginkgolides group were distinctly increased compared with the control.CONCLUSION: A specific effect of ginkgolides on cytochrome P-450 gene expression was observed in this investigation. Ginkgolides had various effects on different cytochrome P-450 isoforms.

53.Identification of adverse drug reactions by evaluation of a prescription database, demonstrated for "risk of bleeding".:

Methods Inf Med. 2005;44(5):697-703.PMID: 16400379
OBJECTIVE: Information about adverse drug reactions plays an important role when assessing the benefit/risk profile of a drug. Identifying rare adverse drug reactions, however, is a difficult task. This paper illustrates the advantages of using a prescription database for this purpose.METHODS: The mediplus database used in our analysis covered data from 320,644 outpatients observed between July 1999 and June 2002. The example of bleeding complications during intake of antidementia drugs is used to illustrate this approach. The comparison of cohorts and subgroups is nearly always a problem in surveys. For our analyses we considered a set of patients who had taken a selected medication for a certain period of time and compared the frequency of adverse events with those occurring when the same patients did not take this medication. Hence, the comparison with versus without a certain medication is based on the same set of patients as in a cross-over study.RESULTS: Our evaluations indicate that the rate of bleeding complications is low when taking any of the widely used antidementia drugs, glutamate modulators, cholinesterase inhibitors, calcium antagonists or the phytomedicine Ginkgo biloba.CONCLUSION: Basing the comparison of the rates of complications during periods with and without intake of a certain drug on the same set of patients may be a useful tool for assessing adverse drug reactions from data reported in prescription databases.

54.Fatal seizures due to potential herb-drug interactions with Ginkgo biloba.:

J Anal Toxicol. 2005 Oct;29(7):755-8.PMID: 16419414
Alternative therapy including herbal drugs and complementary medicine is becoming increasingly popular. However, the rise in the incidence of herb-drug interactions is causing concern, especially in the absence of warning labels addressing potential adverse effects. We present the case of a 55-year-old male who suffered a fatal breakthrough seizure, with no evidence of non-compliance with his anticonvulsant medications. The autopsy report revealed subtherapeutic serum levels for both anticonvulsants Depakote and Dilantin. Concomitant with his prescribed medications, the decedent was also self-medicating with a cornucopia of herbal supplements and nutraceuticals, prominent among which was Ginkgo biloba. Ginkgo, an herbal extract from the leaves of the Ginkgo biloba tree, has been used medicinally for centuries and has been touted as a cure for a variety of medical conditions. The induction of Cytochrome P450 enzymes by components of herbal drugs has been known to affect the metabolism of various drugs. Dilantin is primarily metabolized by CYP2C9, and secondarily metabolized by CYP2C19. Valproate metabolism is also modulated in part by CYP2C9 and CYP2C19. A recent study revealed significant inductive effect of ginkgo on CYP2C19 activity. CYP2C19 induction by ginkgo could be a plausible explanation for the subtherapeutic levels of Dilantin and Depakote. Additionally, ginkgo nuts contain a potent neurotoxin, which is known to induce seizure activity. Evidence of other herbal drugs diminishing the efficacy of anticonvulsant medication does exist; however, there has been only one other documented instance of ginkgo potentiating seizure activity in the presence of anticonvulsant therapy. Highlighting the potential adverse effects and drug interactions of ginkgo on the packaging of the drug may help prevent inadvertent use in vulnerable individuals.

55.Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.:

Am J Ther. 2006 Jan-Feb;13(1):24-31.PMID: 16428919
Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki=14.8 microg/mL, and the inhibition was increased by acid hydrolysis (apparent Ki=9.1 microg/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.

56.Ginkgo biloba does not alter clearance of flurbiprofen, a cytochrome P450-2C9 substrate.:

J Clin Pharmacol. 2006 Feb;46(2):214-21.PMID: 16432273
The effect of Ginkgo biloba on the activity of CYP2C9, the isoform responsible for S-warfarin clearance, was assessed in 11 healthy volunteers who received single 100-mg doses of flurbiprofen, a probe substrate for CYP2C9. Subjects also received either a standardized G biloba leaf preparation (Ginkgold, 3 doses of 120 mg) or matching placebo in a randomized, double-blind, 2-way crossover study. Mean kinetic variables for flurbiprofen with either placebo or G biloba were elimination half-life, 3.9 versus 3.5 hours; total AUC, 57 versus 55 microg/mL h; and oral clearance, 32.9 versus 31.6 mL/min. None of these differences was significant. Based on highperformance liquid chromatography analysis, each 60-mg Ginkgold tablet contained 6.6 mug of amentoflavone and 61.2 microg of quercetin, both previously identified as CYP2C9 inhibitors. These amounts were apparently too low to inhibit CYP2C9 function in vivo. The results confirm previous controlled clinical studies showing no effect of ginkgo on the kinetics or dynamics of warfarin.

57.Studies on the reproductive, cytological and biochemical toxicity of Ginkgo Biloba in Swiss albino mice.:

J Ethnopharmacol. 2006 Sep 19;107(2):222-8. Epub 2006 Mar 27.PMID: 16624513
Ginkgo biloba (an herbal product), used as a folkloric medicine in the treatment of dementia, was evaluated for its effects on reproductive, cytological and biochemical toxicity in male Swiss albino mice. The mice were treated with different doses (25, 50 and 100mg/kg/day) of the aqueous suspension of Ginkgo biloba for 90 days by oral gavage. The following parameters were evaluated: (1) reproductive organ weight; (2) motility and content of sperms; (3) spermatozoa morphology; (4) cytology of the testes chromosomes; (5) study on reproduction; (6) biochemical study on proteins, nucleic acids, malondialdehyde (MDA) and nonprotein sulfhydryl (NP-SH). The treatment caused significant changes in the weight of caudae epididymis, prostate, chromosomal aberrations, rate of pregnancy and pre-implantation loss. However, the percent motility, sperm count and morphology of spermatozoa were not affected. Our study on biochemical parameters showed depletion of nucleic acids, NP-SH and increase of MDA, which elucidated the role of free radical species in the induced changes in testis chromosomes and the reproductive function. The exact mechanism is not known, however, the activation of GABA, glycine and glutamate under the influence of Ginkgo biloba and its constituents might have generated free radicals and depleted cellular glutathione by calcium influx and membrane depolarization. The observed toxicity is attributed to the toxic constituents (ginkgolic acids, biflavones, cardanols, cardols, bilobalides and quercetin) of Ginkgo biloba. Our results warrant careful use of Ginkgo biloba as a remedy for impotence and/or erectile dysfunction.

58.The effect of the ingestion of Ginkgo biloba extract (EGb 761) on the pharmacokinetics of metformin in non-diabetic and type 2 diabetic subjects--a double blind placebo-controlled, crossover study.:

Clin Nutr. 2006 Aug;25(4):606-16. Epub 2006 May 15.PMID: 16698134
BACKGROUND & AIMS: Ginkgo biloba extract (EGb 761) has been shown to ameliorate some defects associated with the insulin resistance syndrome and so patients with Type 2 diabetes mellitus (T2DM) may be inclined to co-ingest the herb with their medications, such as metformin. This study was designed to determine if the co-ingestion of EGb 761 and metformin would alter the pharmacokinetic properties of metformin in T2DM patients and persons without diabetes, who may ingest it for other purposes.METHOD: Normal glucose tolerance (NGT) subjects (n=10; age, 39.2+/-14.0 years; fasting plasma glucose (FPG), 90+/-7 mg/dl; body mass index (BMI), 24.1+/-3.7 kg/m(2)) and 10 T2DM patients (n=10; age, 51.7+/-8.9 years; FPG, 150+/-7 mg/dl; BMI, 33.7+/-5.7 kg/m(2)) completed a randomized, double-blind, placebo-controlled crossover study. They ingested either EGb 761 (12 0mg/day as a single dose) or a vegetable-based placebo during each arm for 3 months. At the end of each arm, the NGT subject ingested a single 500 mg dose of metformin (non-diabetics) and the T2DM subject took his/her prescribed metformin dose (250-850 mg) with 120 mg EGb 761. Blood and urine samples were collected over an 8-h period, and in the case of T2DM subjects, additionally over the first 2h of the subsequent 3 days.RESULTS: Ingestion of EGb 761 produced no significant changes in diagnostic laboratory tests in either group, except reducing glycosylated hemoglobin A(1c) levels (from 7.7+/-1.2 to 7.2+/-0.9%, P<0.05) in T2DM the subjects. The pharmacokinetic parameters of metformin were all significantly different (P<0.05) between the NGT (500 mg) and 8 out of 10 of the T2DM subjects who were prescribed 500 mg of metformin during the placebo cycles. During the EGb 761 cycles, only the elimination half-life in the T2DM subjects was significantly increased (0.117+/-0.085 to 0.141+/-0.100, P<0.05).CONCLUSION: The co-ingestion of 120 mg of EGb 761 and 500 mg of metformin did not significantly affect the pharmacokinetic properties of metformin. Further studies are required to verify this observation for smaller and larger dose of metformin with other doses of EGb 761, since T2DM patients on medication constitute a very heterogeneous group.

59.Does Ginkgo biloba special extract EGb 761 provide additional effects on coagulation and bleeding when added to acetylsalicylic acid 500 mg daily?:

Drugs R D. 2006;7(3):163-72.PMID: 16752942
OBJECTIVE: The aim of this study was to determine whether Ginkgo biloba special extract EGb 761 amplifies the known effects of acetylsalicylic acid (ASA) on platelet aggregation, bleeding time or other coagulation parameters in healthy subjects. METHODS: In a double-blind, double-dummy procedure, 50 healthy male subjects (20-44 years) were randomly allocated in equal numbers to one of two possible treatment sequences, i.e. ASA followed by ASA + EGb 761 or ASA + EGb 761 followed by ASA. Each treatment lasted 7 days; the washout period between treatments was 3 weeks. Study medication was taken twice daily (ASA group: ASA 500 mg tablet + placebo-coated tablet in the morning and placebo tablet + placebo-coated tablet in the evening; ASA + EGb 761 group: ASA 500 mg tablet + EGb 761 120 mg-coated tablet in the morning and placebo tablet + EGb 761 120 mg-coated tablet in the evening), resulting in a daily dose of ASA 500 mg in the ASA group and 500 mg ASA + 240 mg EGb 761 in the ASA + EGb 761 group. Bleeding time, coagulation parameters and platelet activity in response to various agonists were determined. In addition, adverse events, laboratory variables and vital signs were measured. The primary variable bleeding time was assessed in confirmatory analysis, all other variables were evaluated descriptively. The coagulation variables were analysed by ANOVA under the crossover model.RESULTS: ASA given alone clearly prolonged bleeding time. ASA and the combination of ASA + EGb 761 exerted quite similar effects on all coagulation parameters measured, including bleeding time (ASA alone: 4.1 min before therapy, 6.2 min after therapy; ASA + EGb 761: 4.2 min before therapy, 6.3 min after therapy; ratio of means: 1.01, 90% CI 0.86, 1.19) and agonist-induced platelet aggregation (collagen-induced platelet aggregation - ASA: 84.5% before therapy, 81.0% after therapy; ASA + EGb 761: 86.6% before therapy, 81.0% after therapy; ratio of means: 1.00, 90% CI 0.95, 1.05; adenosine diphosphate-induced platelet aggregation - ASA: 72.6% before therapy, 47.2% after therapy; ASA + EGb 761: 71.7% before therapy, 44.8% after therapy; ratio of means: 0.95, 90% CI 0.85, 1.06). Both treatments were well tolerated, and both the number and nature of adverse events in the two groups were similar.CONCLUSIONS: Our findings suggest that co-administration of ASA and EGb 761 does not constitute a safety risk, including in an elderly patient population undergoing treatment with EGb 761.

60.Marked decrease of cyclosporin bioavailability caused by coadministration of ginkgo and onion in rats.:

Food Chem Toxicol. 2006 Sep;44(9):1572-8. Epub 2006 Apr 26.PMID: 16762474
Quercetin was reported to modulate CYP isoenzymes and P-glycoprotein (Pgp), a drug efflux transporter. Our previous study reported that quercetin significantly decreased the bioavailability of cyclosporin, a substrate for CYP3A4 and Pgp, in rats and pigs. Ginkgo and onion contain quercetin and its glycosides as St. John's Wort. The coadministration of cyclosporin with ginkgo or onion may be subject to clinically relevant interactions as St. John's Wort. Therefore, this study aimed to investigate the influences of ginkgo and onion on the absorption and disposition of cyclosporin in rats. Cyclosporin was administered orally and intravenously to rats with and without an oral dose of ginkgo or onion in crossover designs. Blood samples were collected via cardiopuncture and blood cyclosporin concentration was assayed by a specific monoclonal fluorescence polarization immunoassay. Everted gut sac was used to investigate the effects of ginkgo and onion on the function of intestinal Pgp. Oral coadministration of ginkgo and onion significantly decreased the Cmax of cyclosporin by 62% and 60%, and reduced the AUC0-t by 51% and 68%, respectively, whereas no influence was observed when cyclosporin was given intravenously. This indicates that the interactions between cyclosporin and ginkgo or onion occurred mainly at the absorption site. In conclusion, ginkgo and onion markedly decreased the oral bioavailability of cyclosporin. We suggest that concurrent intake of quercetin-rich herbs or foods with cyclosporin are better avoided in order to ensure the efficacy of cyclosporin.

61.Acute generalised exanthematous pustulosis induced by the herbal remedy Ginkgo biloba.:

Med J Aust. 2006 Jun 5;184(11):583-4.PMID: 16768668
Acute generalised exanthematous pustulosis (AGEP) is a clinical reaction pattern that is induced, in over 90% of cases, by systemic drugs (most frequently antibacterial drugs). This is the first reported case of AGEP caused by the herbal remedy Ginkgo biloba.

62.Induction of propranolol metabolism by Ginkgo biloba extract EGb 761 in rats.:

Curr Drug Metab. 2006 Aug;7(6):577-87.PMID: 16918313
Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. When used in the elderly, Ginkgo has a high potential for interactions with cardiovascular drugs. This study aimed to investigate the effects of the standard Ginkgo biloba extract (EGB 761) treatment on the pharmacokinetics of propranolol and its metabolism to form N-desisopropylpropranolol (NDP) in rats. We also examined the activity and expression of cytochrome P450 (CYP) 1A and other CYPs in rats treated with EGb 761 at 10 and 100 mg/kg/day for 10 days. A single oral dose of propranolol (10 mg/kg) was administered on day 11 and the concentrations of both propranolol and NDP were determined using validated liquid chromatography-mass spectrometry (LC-MS) methods. The levels of mRNA and protein of various CYPs were determined by RT-PCR and Western blotting analysis, respectively. Pretreatment of EGb 761 at 100 mg/kg, but not 10 mg/kg, for 10 days significantly reduced the area under the plasma concentration-time curve (AUC) and maximum plasma concentration (Cmax) of propranolol, whereas those values of NDP were significantly increased. CYP1A1, 1A2, 2B1/2, and 3A1 activities and gene expression in the rat liver were significantly increased in a dose-dependent manner by pretreatment with EGb 761. The ex-vivo formation of NDP in liver microsomes from rats pretreated with EGb 761 was markedly enhanced. The formation of NDP from propranolol in liver microsomes was significantly inhibited by alpha-naphthoflavone (ANF, a selective CYP1A2 inhibitor), but not by quinidine (a CYP2D inhibitor). These results indicated that EGb 761 pretreatment decreased the plasma concentrations of propranolol by accelerated conversion of parental drug to NDP due to induction of CYP1A2. EGb 761 pretreatment also significantly induced CYP2B1/2 and CYP3A1, suggesting potential interactions with substrate drugs for these two enzymes. Further study is needed to explore the potential for gingko-drug interactions and the clinical impact.

63.Effects of individual ginsenosides, ginkgolides and flavonoids on CYP2C19 and CYP2D6 activity in human liver microsomes.:

Clin Exp Pharmacol Physiol. 2006 Sep;33(9):813-5.PMID: 16922812
1. The effects of four individual ginsenosides (Rb1, Rb2, Rc and Rd), two ginkgolides (A and B) and one flavonoid (quercetin) on CYP2C19-dependent S-mephenytoin 4 cent-hydroxylation and CYP2D6-mediated bufuralol 1 cent-hydroxylation were evaluated in human liver microsomes. 2. Increasing concentrations of each test compound were added to microsomal incubation mixtures containing a well-characterized marker substrate (S-mephenytoin for CYP2C19 or bufuralol for CYP2D6) to determine their IC(50) values (compound concentration yielding 50% inhibition of a marker enzyme activity), which were estimated by graphical inspection. 3. For CYP2C19, the IC(50) values were 46, 46 and 62 micromol/L for ginsenoside Rd, quercetin and ginsenoside Rb2, respectively, whereas only ginsenoside Rd had an IC(50) value of 57 micromol/L for CYP2D6. 4. The data suggest that the tested compounds are not likely to inhibit the metabolism of the concurrent use of a given drug whose primary route of elimination is through CYP2C19 or CYP2D6.

64.Pharmacodynamic interaction studies of Ginkgo biloba with cilostazol and clopidogrel in healthy human subjects.:

Br J Clin Pharmacol. 2007 Mar;63(3):333-8. Epub 2006 Sep 29.PMID: 17010102
AIMS: Ginkgo biloba is available as an over-the-counter drug and reported to cause haemorrhage when coadministered with other antiplatelet agents. We set out to study the interactions of G. biloba with cilostazol and clopidogrel.METHODS: A randomized, open-label, crossover study of 10 healthy male volunteers. The dosage schedules were 120 mg G. biloba, 240 mg G. biloba, 100 mg cilostazol, 200 mg cilostazol, 75 mg clopidogrel, 150 mg clopidogrel, 120 mg G. biloba+ 100 mg cilostazol and 120 mg G. biloba+ 75 mg clopidogrel. Platelet aggregation, platelet count, bleeding time and clotting time were measured 0 and 6 h after drug administration. Platelet aggregation was performed using a dual channel aggregometer, by the turbimetric technique using adenosine diphosphate 5 micromol and 10 micromol, and collagen 1 microg ml(-1).RESULTS: Platelet inhibition with the combination of G. biloba and clopidogrel or cilostazol was not statistically significant compared with individual doses of drugs, with all the three aggregants. There was significant (P < 0.05) potentiation of prolongation of bleeding time with the combination of cilostazol and G. biloba compared with individual doses of both the drugs. There was no significant change in clotting time and platelet count.CONCLUSIONS: Coadministration of G. biloba either with cilostazol or clopidogrel did not enhance antiplatelet activity compared with individual agents. Ginkgo biloba potentiated the bleeding time prolongation effect of cilostazol. There was no significant correlation between prolongation of bleeding time and inhibition of platelet aggregation.

65.Potential drug-herb interaction with antiplatelet/anticoagulant drugs:

Complement Ther Clin Pract. 2006 Nov;12(4):236-41. Epub 2006 Jul 25.PMID: 17030294
This is a cross-sectional survey evaluating the use of herbal medicines in medical wards patients that may interfere with the effect of antiplatelet or anticoagulant therapy. Among the 250 patients participated, 42.4% (n=106) were taking herbs with 76 patients (71.7%) using herbs for the past 12 months. Overall, almost 31% (n=23, N=76) of patients were taking one or more of the specified herbal medicines [ginseng (Panax ginseng), garlic (Allium sativum), ginkgo (Gingko biloba) thought to interact with antiplatelet or anticoagulant therapy. The study showed that 21% (n=16, N=76) of patients co-ingested specified herbs with antiplatelet or anticoagulant therapy, of which half of them were at risk of potential drug-herb interactions. A large proportion of respondents involved in potential drug-herb interaction were elderly people (62.5%, n=5). However, more than 90% of herbal users did not disclose the use of herbal medicine to their health professionals. It is thus prudent for all care givers to be aware of the possibility of drug-herb interaction and inquire about herbal use from patients.

66.Effects of Ginkgo biloba extract on pharmacokinetics and pharmacodynamics of tolbutamide and midazolam in healthy volunteers.:

J Clin Pharmacol. 2006 Nov;46(11):1290-8.PMID: 17050793
This study was undertaken to clarify the influence of repeated oral administration of Ginkgo biloba extract (GBE) on CYP2C9 and CYP3A4. CYP2C9 probe (tolbutamide, 125 mg) and CYP3A4 probe (midazolam, 8 mg) were orally administered to 10 male healthy volunteers before and after GBE intake (360 mg/d) for 28 days, and they received 75 g glucose after the dosing of tolbutamide. Plasma drug concentrations and blood glucose levels were measured. The area under concentration versus time curve (AUC0-infinity) for tolbutamide after GBE intake was slightly but significantly (16%) lower than that before GBE intake. Concomitantly, GBE tended to attenuate AUC0-2 of blood glucose-lowering effect of tolbutamide. AUC0-infinity for midazolam was significantly (25%) increased by GBE intake and oral clearance was significantly (26%) decreased. Thus, it is suggested that the combination of GBE and drugs should be cautious in terms of the potential interactions, especially in elderly patients or patients treated with drugs exerting relatively narrow therapeutic windows.

67.Safety and efficacy of ginkgo (Ginkgo biloba) during pregnancy and lactation.:

Can J Clin Pharmacol. 2006 Fall;13(3):e277-84. Epub 2006 Nov 3.PMID: 17085776
BACKGROUND: There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbal medicines used in pregnancy and lactation. This is one article in a series that systematically reviews the evidence for commonly used herbs during pregnancy and lactation.OBJECTIVES: To systematically review the literature for evidence on the use, safety, and pharmacology of ginkgo focusing on issues pertaining to pregnancy and lactation.METHODS: We searched 7 electronic databases and compiled data according to the grade of evidence found.RESULTS: There is some very weak scientific evidence from animal and in vitro studies that ginkgo leaf has antiplatelet activity, which may be of concern during labour as ginkgo use could prolong bleeding time. Low-level evidence based on expert opinion shows that ginkgo leaf may be an emmenagogue and have hormonal properties. The safety of ginkgo leaf during lactation is unknown. Patients and clinicians should be aware of past reports of ginkgo products being adulterated with colchicine.CONCLUSIONS: Ginkgo should be used with caution during pregnancy, particularly around labour where its anti-platelet properties could prolong bleeding time. During lactation the safety of ginkgo leaf is unknown and should be avoided until high quality human studies are conducted to prove its safety.

68.Safety and efficacy of a ginkgo biloba-containing dietary supplement on cognitive function, quality of life, and platelet function in healthy, cognitively intact older adults.:

J Am Diet Assoc. 2007 Mar;107(3):422-32.PMID: 17324660
OBJECTIVE: To determine if a ginkgo biloba-containing supplement improves cognitive function and quality of life, alters primary hemostasis, and is safe in healthy, cognitively intact older adults.DESIGN: Four-month, randomized, double-blind, placebo-controlled parallel design.SUBJECTS/SETTING: Ninety men and women (age range 65 to 84 years) were recruited to a university clinic. Eligibility included those without dementia or depression, not taking psychoactive medications or medications or supplements that alter hemostasis.INTERVENTION: Ninety subjects were randomly assigned to placebo or a ginkgo biloba-based supplement containing 160 mg ginkgo biloba, 68 mg gotu kola, and 180 mg decosahexaenoic acid per day for 4 months.MAIN OUTCOME MEASURES: Assessments included: six standardized cognitive function tests, the SF-36 Quality of Life questionnaire, the Platelet Function Analyzer-100 (Dade Behring, Eschbom, Germany), and the monitoring of adverse events.STATISTICAL ANALYSES: Baseline characteristics and study hypotheses were tested using analysis of covariance. Tests were two-tailed with a 0.05 significance level.RESULTS: Seventy-eight subjects (87%) completed both baseline and 4-month testing (n=36 in placebo group, n=42 in ginkgo biloba group). At baseline, the participants' cognitive function was above average. One of six cognitive tests indicated significant protocol differences at 4 months (P=0.03), favoring the placebo. There were no significant differences in quality of life, platelet function, or adverse events.CONCLUSIONS: These finding do not support the use of a ginkgo biloba-containing supplement for improving cognitive function or quality of life in cognitively intact, older, healthy adults. However, high baseline scores may have contributed to the null findings. The ginkgo biloba product seems safe and did not alter platelet function, though additional studies are needed to evaluate the interaction of varying doses of ginkgo biloba and ginkgo biloba-containing supplements with medications and supplements that alter hemostasis.

69.Bilobalide in Ginkgo biloba extract is a major substance inducing hepatic CYPs.:

J Pharm Pharmacol. 2007 Jun;59(6):871-7.PMID: 17637180
In a search for substances related to the marked induction of hepatic cytochrome P450 (CYP) by ginkgo biloba extract (GBE), mice were given either GBE (1000 mg kg(-1)) or fractions of GBE for 5 days. The content and activity of CYPs were induced markedly by a bilobalide-rich fraction, but not by flavonoid-rich fractions. The level of induction by the bilobalide-rich fraction was almost the same as that induced by the unfractionated GBE, suggesting that bilobalide is largely responsible for the CYPs induction. To confirm these findings, mice were given various doses of bilobalide (10.5, 21 and 42 mg kg(-1)), or GBE (1000 mg kg(-1), containing bilobalide at 42 mg kg(-1)). Treatment with bilobalide induced CYPs markedly and in a dose-dependent manner, and the level of induction was quite similar between bilobalide (42 mg kg(-1)) and GBE. Treatment with GBE and with bilobalide greatly induced pentoxyresorufin O-dealkylase activity. These findings indicate that bilobalide is the major substance in GBE that induces hepatic CYPs.

70.Herb-drug interactions: Effect of Ginkgo biloba extract on the pharmacokinetics of theophylline in rats.:

Food Chem Toxicol. 2007 Dec;45(12):2441-5. Epub 2007 Jun 21.PMID: 17681658
Herbal medicines have received great attention as alternative medicines in recent years and are also referred to as a dietary supplement or health food. Ginkgo biloba extract (GBE) is one of the most popular herbal medicines. However, little is known about the metabolic interactions between GBE and clinically used drugs. This study attempted to investigate the effect of GBE on the pharmacokinetics of theophylline, a cytochrome P450 (CYP) 1A2 substrate and an important therapeutic agent with narrow therapeutic window used for the treatment of asthma. Commercial GBE (10 or 100 mg/kg, p.o.) or water (control group) was given to rats (6 rats for each group) for 5 consecutive days and on the sixth day theophylline (10 mg/kg) was administered either orally or intravenously. The results showed that pretreatment of rats with GBE resulted in an increase in the total clearance of theophylline of about 30% (GBE 10 mg/kg, P<0.05) and 70% (GBE 100 mg/kg, P<0.01) compared with the control group after intravenous administration of theophylline (10 mg/kg). After oral administration of theophylline (10 mg/kg), the AUC(0-24h) of theophylline was reduced by 40% following pretreatment with GBE (100 mg/kg, P<0.01). These results demonstrate that GBE pretreatment increased CYP1A2 metabolic activity and the clearance of theophylline in rats.

71.Induction of cytochrome P450 3A by the Ginkgo biloba extract and bilobalides in human and rat primary hepatocytes.:

Drug Metab Lett. 2008 Jan;2(1):60-6.PMID: 19356072
Ginkgo biloba is one of the most popular herbal medicines in the world, due to its purported pharmacological effects, including memory-enhancing, cognition-improving, and antiplatelet effects. The study aimed to investigate the activity and expression of cytochrome P450 (CYP) 3A in human and rat primary hepatocytes treated with standardized G. biloba extract (100, 500, and 2500 ng/ml) for 72 hr, and to measure the protein expression of CYP3A in human and rat primary hepatocytes treated with bilobalide (2, 10, and 50 ng/ml) and ginkgolides B (2, 10, and 50 ng/ml). The activity of CYP3A was measured by the quantification of dehydronifedipine formation using a validated tandem liquid chromatography mass spectrometry (LC/MS/MS) method. The levels of mRNA and protein of CYP3A were determined by reverse transcription-polymerase chain reaction (RT-PCR) and Western-blotting analysis, respectively. The G. biloba extract at 100-2,500 ng/ml significantly induced the activity, protein and mRNA expression of CYP3A in a dose-dependent manner in human and rat primary hepatocytes. Bilobalide at 2-50 ng/ml significantly increased CYP3A protein expression in a dose-dependent manner in human and rat primary hepatocytes. However, ginkgolide B did not affect CYP3A protein expression in vitro. The results indicate that G. biloba extract pretreatment significantly induced the expression of CYP3A protein and mRNA and increased CYP3A activity, and there was no significant species difference between human and rat. G. biloba may cause potential interactions with substrate drugs of CYP3A. Bilobalide might play a key role in the enzyme-inducing effects of G. biloba extract. Further study is needed to identify the substances in GBE that induce CYPs in vivo, and elucidate the molecular mechanism of CYP3A induction by GBE and bilobalides.

72.Effect of Ginkgo biloba extract on lopinavir, midazolam and fexofenadine pharmacokinetics in healthy subjects.:

Curr Med Res Opin. 2008 Feb;24(2):591-9.PMID: 18205997
OBJECTIVE: Animal and in vitro data suggest that Ginkgo biloba extract (GBE) may modulate CYP3A4 activity. As such, GBE may alter the exposure of HIV protease inhibitors metabolized by CYP3A4. It is also possible that GBE could alter protease inhibitor pharmacokinetics (PK) secondary to modulation of P-glycoprotein (P-gp). The primary objective of the study was to evaluate the effect of GBE on the exposure of lopinavir in healthy volunteers administered lopinavir/ritonavir. Secondary objectives were to compare ritonavir exposure pre- and post-GBE, and assess the effect of GBE on single doses of probe drugs midazolam and fexofenadine.METHODS: This open-label study evaluated the effect of 2 weeks of standardized GBE administration on the steady-state exposure of lopinavir and ritonavir in 14 healthy volunteers administered lopinavir/ritonavir to steady-state. In addition, single oral doses of probe drugs midazolam and fexofenadine were administered prior to and after 4 weeks of GBE (following washout of lopinavir/ritonavir) to assess the influence of GBE on CYP3A and P-gp activity, respectively.RESULTS: Lopinavir, ritonavir and fexofenadine exposures were not significantly affected by GBE administration. However, GBE decreased midazolam AUC(0-infinity) and C(max) by 34% (p = 0.03) and 31% (p = 0.03), respectively, relative to baseline. In general, lopinavir/ritonavir and GBE were well tolerated. Abnormal laboratory results included mild elevations in hepatic enzymes, cholesterol and triglycerides, and mild-to-moderate increases in total bilirubin.CONCLUSIONS: Our results suggest that GBE induces CYP3A metabolism, as assessed by a decrease in midazolam concentrations. However, there was no change in the exposure of lopinavir, likely due to ritonavir's potent inhibition of CYP3A4. Thus, GBE appears unlikely to reduce the exposure of ritonavir-boosted protease inhibitors, while concentrations of unboosted protease inhibitors may be affected. Limitations to our study include the single sequence design and the evaluation of a ritonavir-boosted protease inhibitor exclusively.

73.Multifaceted therapeutic benefits of Ginkgo biloba L.: chemistry, efficacy, safety, and uses.:

J Food Sci. 2008 Jan;73(1):R14-9.PMID: 18211362
The new age of nutraceuticals is now embracing the centuries old herbal extract of Ginkgo biloba (Mantissa Plantarum Altera, 1771, Ginkgoceae). The standardized preparation of the Ginkgo leaf extract (EGb 761) contained 2 main bioactive constituents, flavonoid glycosides (24%) and terpene lactones (6%), along with less than 5 ppm of the allergenic component, ginkgolic acid. The Ginkgo leaf extract has been reported to have neuroprotective, anticancer, cardioprotective, stress alleviating, and memory enhancing effects and possible effects on tinnitus, geriatric complaints, and psychiatric disorders. The therapeutic mechanisms of action of the Ginkgo leaf extract are suggested to be through its antioxidant, antiplatelet, antihypoxic, antiedemic, hemorrheologic, and microcirculatory actions, where the flavonoid and the terpenoid constituents may act in a complementary manner. Toxicity studies show that the Ginkgo leaf extract is relatively safe for consumption, although a few side effects have been reported, that is, intracerebral hemorrhage, gastrointestinal disturbances, headaches, dizziness, and allergic skin reactions. The use of Ginkgo leaf extract may be promising for treatment of certain conditions, although its long-term use still needs to be evaluated.

74.Potential interaction of Ginkgo biloba leaf with antiplatelet or anticoagulant drugs: what is the evidence?:

Mol Nutr Food Res. 2008 Jul;52(7):764-71.PMID: 18214851
Some writers hold the view that the combination of Ginkgo biloba with anticoagulant or antiplatelet drugs represents a serious health risk. Such concerns are largely based on the assumption that Ginkgo has clinically relevant antiplatelet activity, as well as accounts of bleeding episodes associated with Ginkgo consumption. To investigate whether these bleeding episodes have a pharmacodynamic, idiosyncratic or coincidental basis, a review of controlled clinical studies and case reports was undertaken. Results from controlled studies consistently indicate that Ginkgo does not significantly impact haemostasis nor adversely affect the safety of coadministered aspirin or warfarin. Most of these studies were undertaken using EGb 761, a well-defined extract of Ginkgo biloba. In contrast, EGb 761 has not generally been implicated in the case reports. In general, the quality of these case reports is low. Nevertheless, the possibility of an idiosyncratic bleeding event due to Ginkgo use cannot be excluded on the basis of the available information. However, there is scant information from case reports or controlled trials to support the suggestion that Ginkgo potentiates the effects of anticoagulant or antiplatelet drugs. Such high-level safety concerns for this herb are deemed to be unsupported by the currently available evidence.

75.Induction of cytochrome P450s by terpene trilactones and flavonoids of the Ginkgo biloba extract EGb 761 in rats.:

Xenobiotica. 2008 May;38(5):465-81.PMID: 18421621
1. Ginkgo biloba is one of the most popular herbal medicines worldwide due to its memory-enhancing and cognition-improving effects. The current study was designed to investigate the effects of five major constituents (bilobalide, ginkgolide A, B, quercetin, and kaempferol) in the standardized G. biloba extract EGb 761 on various cytochrome P450s (CYPs) in rats. 2. The activity of CYP450 was measured by the quantification of six metabolites from multiple cytochrome P450 probe substrates using a validated liquid chromatography coupled with tandem mass spectrometry detection (LC-MS/MS) method. The levels of messenger RNA (mRNA) and protein of various CYPs were determined by reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blotting analysis, respectively. 3. Bilobalide significantly induced the activity, protein, and mRNA expression of CYP3A1 and 1A2, and increased CYP2E1 activity and CYP2B1/2 protein expression in a dose-dependent manner. 4. Ginkgolide A, B, quercetin, and kaempferol did not affect CYP3A1, but induced CYP1A2 in a dose-dependent manner. EGb 761 and the five individual constituents had no effects on rat CYP2D2, 2C11 and 2C7. 5. The results indicate that bilobalide, and to a lesser extent ginkgolide A, B, quercetin, and kaempferol, play a key role in the effects of EGb 761 on CYP induction. Further study is needed to elucidate the mechanism of CYP3A induction by EGb 761 and bilobalide.

76.Ginkgo biloba extract 761 reduces doxorubicin-induced apoptotic damage in rat hearts and neonatal cardiomyocytes.:

Cardiovasc Res. 2008 Nov 1;80(2):227-35. Epub 2008 Jul 16.PMID: 18632596
AIMS: The objective of this study was to investigate whether a cytoprotective herb-derived agent, Ginkgo biloba extract (EGb) 761, could have a beneficial effect on doxorubicin-induced cardiac toxicity in vitro and in vivo.METHODS AND RESULTS: Primary cultured neonatal rat cardiomyocytes were treated with the vehicle, doxorubicin (1 microM), EGb761 (25 microg/mL), or EGb761 plus doxorubicin. After 24 h, doxorubicin upregulated p53 mRNA expression, disturbed Bcl-2 family protein balance, disrupted mitochondrial membrane potential, precipitated mitochondrion-dependent apoptotic signalling, induced apoptotic cell death, and reduced viability of cardiomyocytes, whereas EGb761 pretreatment suppressed all the actions of doxorubicin. Similarly, rats treated with doxorubicin [3 mg/kg intraperitoneally (i.p.) three doses every other day] displayed retarded growth of body and heart as well as elevated apoptotic indexes in heart tissue at both 7 and 28 days after exposure, whereas EGb761 pretreatment (5 mg/kg i.p. 1 day before each dose of doxorubicin) effectively neutralized the aforementioned gross and cellular adverse effects of doxorubicin.CONCLUSION: Doxorubicin impairs viability of cardiomyocytes at least partially by activating the p53-mediated, mitochondrion-dependent apoptotic signalling. EGb761 can effectively and extensively counteract this action of doxorubicin, and may potentially protect the heart from the severe toxicity of doxorubicin.

77.Trade herbal products and induction of CYP2C19 and CYP2E1 in cultured human hepatocytes.:

Basic Clin Pharmacol Toxicol. 2009 Jul;105(1):58-63. Epub 2009 Apr 3.PMID: 19371257
The aim of this study was to evaluate in vitro the dose-dependent induction potential of six commonly used trade herbal products on CYP2C19 and CYP2E1 metabolic activities in cultured human hepatocytes. S-mephenytoin and chlorzoxazone were used as specific CYP substrates, respectively, and rifampicin was used as a positive induction control for both enzymes. The hepatocytes were exposed to herbal extracts in increasing and biological relevant concentrations for 72 hrs and CYP substrate metabolites were quantified by validated HPLC methodologies. The major findings were that St John's wort was the most potent CYP-modulating herb, showing a dose-dependent induction/inhibition of both CYP2C19 and CYP2E1, with induction at low dosages and inhibition at higher. Ginkgo biloba showed an induction/inhibition profile towards CYP2C19 which was similar but weaker than that observed for St John's wort. If cooperative mechanisms are involved is still an open question. Common sage induced CYP2C19 in a log-linear dose-dependent manner with increasing concentrations. Common valerian was a weak inducer of CYP2C19, while horse chestnut and cone flower were characterized as non-inducers of CYP2C19. Only St John's wort showed an inductive effect towards CYP2E1. In addition to St John's wort, Gingko biloba and common sage should be considered as possible candidates for clinically relevant drug-herb interactions with selected CYP2C19 substrates.

78.Effects of Ginkgo biloba extract ingestion on the pharmacokinetics of talinolol in healthy Chinese volunteers.:

Ann Pharmacother. 2009 May;43(5):944-9. Epub 2009 Apr 28.PMID: 19401473
BACKGROUND: Ginkgo biloba extract (GBE), the best selling herbal medicine in the world, has been reported to inhibit P-glycoprotein in vitro. However, the effects of GBE on P-glycoprotein activity in humans have not been clarified.OBJECTIVE: To investigate the effects of single and repeated GBE ingestion on the oral pharmacokinetics of talinolol, a substrate drug for P-glycoprotein in humans.METHODS: Ten unrelated healthy male volunteers were selected to participate in a 3-stage sequential study. Plasma concentrations of talinolol from 0 to 24 hours were measured by high-performance liquid chromatography after talinolol 100 mg was administrated alone, with a single oral dose of GBE (120 mg), and after 14 days of repeated GBE ingestion (360 mg/day).RESULTS: A single oral dose of GBE did not affect the pharmacokinetics of talinolol. Repeated ingestion of GBE increased the talinolol maximum plasma concentration (C(max)) by 36% (90% CI 10 to 68; p = 0.025), the area under the concentration-time curve (AUC)(0-24) by 26% (90% CI 11 to 43; p = 0.008) and AUC(0-infinity) by 22% (90% CI 8 to 37; p = 0.014), respectively, without significant changes in elimination half-life and the time to C(max).CONCLUSIONS: Our results suggest that long-term use of GBE significantly influenced talinolol disposition in humans, likely by affecting the activity of P-glycoprotein and/or other drug transporters.

79.Inhibition of human CYP2B6-catalyzed bupropion hydroxylation by Ginkgo biloba extract: effect of terpene trilactones and flavonols.:

Drug Metab Dispos. 2009 Sep;37(9):1931-7. Epub 2009 Jun 1.PMID: 19487249
Cytochrome P450 2B6 (CYP2B6) is expressed predominantly in human liver. It catalyzes the oxidative biotransformation of various drugs, including bupropion, which is an antidepressant and a tobacco use cessation agent. Serious adverse effects of high dosages of bupropion have been reported, including the onset of seizure. As Ginkgo biloba extract may be consumed with bupropion or another CYP2B6 drug substrate, potential exists for an herb-drug interaction. Therefore, we investigated the effect of G. biloba extract and some of its chemical constituents (terpene trilactones and flavonols) on the in vitro catalytic activity of CYP2B6 as assessed by the bupropion hydroxylation assay with recombinant enzyme and hepatic microsomes. The amount of hydroxybupropion was quantified by a novel and validated ultraperformance liquid chromatography/mass spectrometry method. Enzyme kinetic analysis indicated that G. biloba extract competitively inhibited hepatic microsomal CYP2B6-catalyzed bupropion hydroxylation (apparent K(i) was 162 +/- 14 microg/ml). Bilobalide and ginkgolides A, B, C, and J were not responsible for the inhibition of CYP2B6 catalytic activity by the extract. Whereas the 3-O-glucoside and 3-O-rutinoside of quercetin, kaempferol, and isorhamnetin had no effect, the corresponding aglycones (10 and 50 microg/ml) decreased hepatic microsomal bupropion hydroxylation. The inhibition of CYP2B6 by kaempferol was competitive (apparent K(i) was 10 +/- 1 microg/ml). In summary, G. biloba extract and its flavonol aglycones are naturally occurring inhibitors of in vitro CYP2B6 catalytic activity and bupropion hydroxylation. Future studies are needed to investigate whether G. biloba extract interacts in vivo with bupropion or other clinically important CYP2B6 drug substrates.

80.Safety and effectiveness of a traditional ginkgo fresh plant extract - results from a clinical trial.:

Forsch Komplementmed. 2009 Jun;16(3):156-61. Epub 2009 May 14.PMID: 19657199
BACKGROUND: In Chinese medicine, Ginkgo biloba is used for a variety of indications. In the current study, the safety and efficacy of a traditional fresh plant extract was investigated in patients with mild cognitive impairment.PATIENTS AND METHODS: 59 elderly patients were treated for 6 weeks with a twice daily tablet containing 90 mg of fresh plant Ginkgo biloba extract. The patients suffered from age-related mild cognitive impairment of the non-Alzheimer type assessed by the DemTect score and the presence of symptoms, such as forgetfulness, memory problems, and difficulties in concentration. At the end of the treatment period, safety was primarily assessed by the occurrence of adverse events and efficacy by the DemTect score, the SF-12 quality of life questionnaire, and the change in cognitive symptoms, as well as the judgment of the investigators and patients.RESULTS: At the final visit, the SF-12 mental score had increased significantly from 48.3 +/- 10.1 to 51.3 +/- 7.9, whereas the SF-12 body score (44.5 +/- 9.2 to 45.3 +/- 8.1) and the DemTect score (15.9 +/- 2.0 to 16.0 +/- 2.3) had not changed significantly. About half of all patients experienced an improvement in their memory and their ability to concentrate, as well as a decrease in symptoms of forgetfulness. The majority of investigators and patients judged the treatment to be effective. The tablets were very well tolerated and, as a treatment for their cognitive impairment, highly accepted (90% would take them again).CONCLUSION: This newly developed, holistic fresh leaf extract of Ginkgo biloba is a safe, effective, and, at least, adjuvant treatment option for patients with mild cognitive impairments.

81.Effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers.:

Br J Clin Pharmacol. 2009 Aug;68(2):201-6.PMID: 19694739
AIMS: To assess the effects of Ginkgo biloba extract on the pharmacokinetics of bupropion in healthy volunteers.METHODS: Fourteen healthy male volunteers (age range 19-25 years) received orally administered bupropion (150 mg) alone and during treatment with G. biloba 240 mg day(-1) (two 60-mg capsules taken twice daily) for 14 days. Serial blood samples were obtained over 72 h after each bupropion dose, and used to derive pharmacokinetic parameters of bupropion and its CYP2B6-catalysed metabolite, hydroxybupropion.RESULTS: Ginkgo biloba extract administration resulted in no significant effects on the AUC(0-infinity) of bupropion and hydroxybupropion. Bupropion mean AUC(0-infinity) value was 1.4 microg.h ml(-1)[95% confidence interval (CI) 1.2, 1.6] prior to G. biloba treatment and 1.2 microg.h ml(-1) (95% CI 1.1, 1.4) after 14 days of treatment. Hydroxybupropion mean AUC(0-infinity) value was 8.2 microg.h ml(-1) (95% CI 6.5, 10.4) before G. biloba administration and 8.7 microg.h ml(-1) (95% CI 7.1, 10.6) after treatment. The C(max) of hydroxybupropion increased from 221.8 ng ml(-1) (95% CI 176.6, 278.6) to 272.7 ng ml(-1) (95% CI 215.0, 345.8) (P = 0.038) and the t(1/2) of hydroxybupropion fell from 25.0 h (95% CI 22.7, 27.5) to 21.9 h (95% CI 19.9, 24.1) (P = 0.000).CONCLUSIONS: Ginkgo biloba extract administration for 14 days does not significantly alter the basic pharmacokinetic parameters of bupropion in healthy volunteers. Although G. biloba extract treatment appears to reduce significantly the t(1/2) and increase the C(max) of hydroxybupropion, no bupropion dose adjustments appear warranted when the drug is administered orally with G. biloba extract, due to the lack of significant change observed in AUC for either bupropion or hydroxybupropion.

82.Effects of Ginkgo biloba extracts on diazepam metabolism: a pharmacokinetic study in healthy Chinese male subjects.:

Eur J Clin Pharmacol. 2010 May;66(5):503-9. Epub 2010 Feb 26.PMID: 20186406
AIM: It has been reported that Ginkgo biloba extract (GBE) is an inducer or inhibitor of microsomal cytochrome P450 (CYP) 2C19, and diazepam is a substrate of CYP2C19. Thus, it could be expected that GBE may alter the metabolism of diazepam.METHODS: The pharmacokinetic parameters of diazepam and one of its metabolites, N-demethyldiazepam, were compared after oral administration of diazepam (10 mg) in the absence or presence of oral GBE (120 mg bid, for 28 days) in 12 healthy volunteers. The pharmacokinetic analysis was performed using a noncompartmental method.RESULTS: The 90% confidence intervals (CIs) of the ratios of mean pharmacokinetic parameters of diazepam presence and absence of GBE were well within the 80-125% bioequivalence range, indicating no pharmacokinetic interaction. The ratio of AUC(0-408) with GBE to AUC(0-408) without GBE was 95.2 (90%CI: 91.6-98.8) and 101.8 (90%CI: 99.4-104.1) for diazepam and N-desmethyldiazepam, respectively. The two drugs were well tolerated, and no drug-related serious adverse events were reported.CONCLUSION: The above data suggest that GBE, when taken in normally recommended doses over a 4-week time period, may not affect the pharmacokinetics of diazepam via CYP2C19 and the excretion of N-desmethyldiazepam in healthy volunteers. No drug-drug interaction was observed between GBE and diazepam.

83.An update on drug interactions with the herbal medicine Ginkgo biloba.:

Curr Drug Metab. 2010 Feb;11(2):171-81.PMID: 20359286
Medicinal plants are gaining in popularity due to the various advantages they offer, such as fewer side-effects, better patient compliance, relatively low cost and high accessibility as well as their high acceptability due to a long history of use. There is a widespread belief among the general public that herbal preparations are "good for humans" as they are "all natural". However, the increasing use of herbal medicinal products in the community where people are also receiving prescription medicines suggests that adverse herb-drug interactions may be have significant public health consequences. There is little understanding or appreciation of the fact that these "all natural" preparations are actually a combination of potentially biologically active compounds already existing in marketed products in unknown quantities. Among the most popular herbal products used worldwide is Ginkgo biloba, used for the treatment of cerebral insufficiency, peripheral vascular diseases, and frequently taken for the enhancement of memory function. Although the safety of Ginkgo biloba is promising, accumulated data show evidence of significant interactions with medications, which can place individual patients at great risk. In this review, we examined the literature from 2000 to 2008 and focused on the importance of the risk of drug interactions and potential side effects when Ginkgo biloba is involved. The aim of this systematic review is to assess the clinical evidence on interactions between Ginkgo biloba and drugs.

84.Effects of Ginkgo biloba extract on the embryo-fetal development in Wistar rats.:

Birth Defects Res B Dev Reprod Toxicol. 2010 Apr;89(2):133-8.PMID: 20437472
BACKGROUND: Ginkgo biloba extract (GBE) is an herbal medicine used for treating neurodegenerative diseases, cerebrovascular insufficiency, peripheral arterial occlusive disease, and also vestibular disturbance. Some components of GBE have presented estrogenic effects and, in a previous study, high dosages of GBE caused intra-uterine growth retardation in fetuses of Wistar rats treated during the fetogenesis period.METHODS: Pregnant Wistar rats were treated, through gavage, with different dosages of aqueous GBE (3.5, 7.0, and 14.0 mg/Kg/day), during the tubal transit and implantation period. Rats were killed on the 15th day of pregnancy and the following parameters were evaluated: clinical symptoms of maternal toxicity; maternal body weight; feed and water intake; maternal liver, kidney, and ovary weights; number of corpora lutea; implants per group ratio; pre- and post-implantation loss per group ratio; live fetuses mean; dead fetuses percentage; fetus and placenta weight per offspring ratio; and fetal external malformation.RESULTS: No significant alteration was found for both the maternal and embryonic parameters evaluated.CONCLUSIONS: The GBE treatment in pregnant Wistar rats, during the tubal transit and implantation period, caused no toxic effect on the maternal organism and did not induce embryonic death, growth retardation, and/or fetal malformations.

85.Herbs and the brain: friend or foe? The effects of ginkgo and garlic on warfarin use.:(Psycho:warfarin interaction)

J Neurosci Nurs. 2000 Aug;32(4):229-32.PMID: 10994537
In the quest for longevity and as an alternative to Western medicine, there has been a resurgence in traditional remedies. However, several concerns have been raised about the increased use of herbal remedies, including potential interactions with "Western" medicines, the lack of quality control, the assessment of herbal clinical trials, and the adulteration of herbal remedies by traditional prescribers. Taking an herbal history is not usually a part of medical/nursing practice, and patients usually do not readily volunteer such information. In the cerebrovascular and cardiac settings, it is particularly important to gain such a history and to educate patients and family members about the potential interactions of herbal remedies with anticoagulants. Two herbal supplements in particular, ginkgo biloba and garlic, have demonstrated effects on warfarin.

86.Potential interactions between herbal medicines and conventional drug therapies used by older adults attending a memory clinic.:(Psycho:interaction)

Drugs Aging. 2002;19(11):879-86.PMID: 12428996
OBJECTIVE: Herbal medicines and conventional drug therapies are often taken in combination. The objective of our study was to identify the range of natural health products and conventional drug therapies used by older adults (aged 65 years and over) attending a memory clinic, and to specifically evaluate the frequency of potential interactions between herbal medicines and conventional drug therapies.DESIGN: We interviewed consecutive patients attending the Memory Disorders Clinic at the Baycrest Centre for Geriatric Care, a University of Toronto teaching hospital, between 4 July and 15 August 2000. Patients were asked to bring to their appointment all natural health products (i.e. herbal medicines, vitamins and minerals) and conventional drug therapies (i.e. prescription and over-the-counter) they were currently using. We collected information on current and previously used natural health products and current conventional drug therapies. Patients were classified as having the potential for an interaction if they were using a current herbal medicine in combination with a conventional drug therapy and the interaction had been reported previously in the medical literature.PARTICIPANTS: We interviewed 195 consecutive patients attending the Memory Disorders Clinic at the Baycrest Centre for Geriatric Care, Toronto, Ontario, Canada.RESULTS: Of the 195 patients in our sample, 33 (17%) were 'current users', 19 (10%) were 'past users', and 143 (73%) were 'never users' of herbal medicines. Among the 52 patients who were 'current or past users', the most frequently used herbal medicines were ginkgo (Ginkgo biloba) [39 users], garlic (n = 10), glucosamine sulphate (n = 9) and echinacea (n = 8). Among the 33 patients who were current users, the most commonly used herbal medicines were Ginkgo biloba (n = 22), glucosamine sulphate (n = 8) and garlic (n = 6). Among the 33 current users, we identified 11 potential herb-drug interactions in nine patients. The 11 herb-drug interactions we identified were between ginkgo and aspirin (acetylsalicylic acid) [n = 8], ginkgo and trazodone (n = 1), ginseng and amlodipine (n = 1) and valerian and lorazepam (n = 1).CONCLUSIONS: Herbal medicines are widely used. Almost one-third of current users of herbal medicines were at risk of a herb-drug interaction. The most common potential herb-drug interaction was between ginkgo and aspirin. This finding has important potential implications because both of these products are regularly used by older people. Physicians and other healthcare providers should be aware of potential herb-drug interactions and should monitor and inform their patients accordingly.

87.Possible subdural hematoma associated with Ginkgo biloba.:

J Herb Pharmacother. 2002;2(2):57-63.PMID: 15277097
A 78-year-old Caucasian man developed headache, confusion and progressive right-sided weakness following a fall resulting in ecchymosis over the left eye orbit five days prior to admission. A subdural hematoma was diagnosed upon CAT scan. Upon evacuation, a very large left frontoparietal subdural hematoma with the appearance of mixed elements of hemorrhage and older fluid was noted. The finding was chronic subdural hematoma described as "crankcase oil." The patient's only prior medications were lisinopril 20 mg daily and ginkgo biloba 50 mg three times a day. Ginkgo biloba is advocated to augment cerebral blood flow to enhance memory and improve dementia. One of Ginkgo biloba's components is ginkgolide B, a potent inhibitor of platelet activating factor essential for induction of arachidonate-independent platelet aggregation. We believe Ginkgo biloba either caused or predisposed this patient to subdural hematoma and is of concern given ginkgo's widespread use with minimal or no monitoring.

88.Amikacin ototoxicity enhanced by Ginkgo biloba extract (EGb 761).:

Hear Res. 2002 Jul;169(1-2):121-9.PMID: 12121745
An animal study was realized to investigate the possible beneficial effect of EGb 761 as an antioxidant agent on amikacin ototoxicity by measuring distortion product otoacoustic emissions (DPOAEs). Twenty-eight adult rats were grouped equally as follows. GROUP AMIKACIN: rats received amikacin 600 mg/kg/day intramuscularly between postnatal days (PND) 30 and PND44. Group amikacin/EGb 761: rats received amikacin 600 mg/kg/day intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. Group EGb 761: rats received equivolume saline intramuscularly between PND30 and PND44 and EGb 761 100 mg/kg/day orally between PND30 and PND50. NO TREATMENT GROUP: rats received nothing. Group amikacin was found to be affected only on the last measurement day of study (PND57). The frequencies greater than 2002 Hz were significantly reduced compared with the amplitudes of PND30 (P<0.05). Group amikacin/EGb 761 was most and earliest affected by amikacin-induced ototoxicity. DPOAE amplitudes were found in this group to be decreased at 2-6 kHz starting on PND50. The results of Group EGb 761 and No treatment group were not significantly changed. For the DPOAE input/output amplitude thresholds, Group amikacin (P<0.05) and Group amikacin/EGb 761 (P<0.01) had significantly elevated thresholds on PND57, except at 5 kHz for Group amikacin (P=0,06). According to the results of the study, EGb 761 may be regarded as a facilitating drug for the development of amikacin ototoxicity. The results of the present study may warn against concomitant use of aminoglycosides, specifically amikacin, with EGb 761.

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23.Experimental study on effect of antagonizing platelet-activating factor and histamine of synthetic ginkgolide F in guinea-pigs:

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2000 May;20(5):365-7.PMID: 11789251
OBJECTIVE: To investigate the antagonizing effect of synthetic Ginkgolide F (SGF) on platelet-activating factor (PAF) and histamine (HA) in guinea-pigs.METHODS: The contraction rate of isolated lung tissue of guinea-pig and the change of pulmonary function of sensitized guinea-pig after SGF treatment were examined.RESULTS: (1) The contraction rate of guinea-pigs' isolated trachea and lung strip induced by HA reduced from (50.97 +/- 16.00)% and (54.24 +/- 12.17)% to (21.69 +/- 3.85)% and (22.97 +/- 17.78)% after SGF treatment (P < 0.05). (2) PAF induced relative contraction of isolated guinea-pig lung strip was reduced from (89.49 +/- 16.00)% to (46.21 +/- 14.23)% in presence of SGF (P < 0.05). (3) The pulmonary function of sensitized animal had a tendency of being improved by SGF.CONCLUSION: SGF can antagonize the contraction of isolated lung tissue induced by HA or PAF in vitro, and has a tendency to improve the pulmonary function of sensitized guinea-pig, therefore, it may be a promising drug in treatment of bronchial asthma.

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What is Ginkgo Biloba? What is Ginkgo Biloba Extract or GBE?

This article written and edited via herbalist of MDidea Extracts Professional. They run a range of online descriptions about this herb,including general information related and summarized updating discoveries from findings of professional scientisits this field related.Describe style aimed to form a useful detecting literature space where the intertwined threshold and related questions raise out and visualize themselves.

♣ last edit date:08th,Oct.2010.

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Name:Ginkgo Biloba Extract
Serie No:S-011.
Specifications:flavone glycosides24%,terpene lactones6%HPLC.
INCI Name:GINKGO BILOBA EXTRACT
EINECS/ELINCS No.:289-896-4
CAS:090045-36-6
Chem/IUPAC Name:Ginkgo Biloba Extract is a plant material obtained from the leaves of the maidenhair tree,Ginkgo biloba,Ginkgoaceae

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Ginkgo extract.Ginkgo Biloba extract.CAS.NO.090045-36-6.Ginkgo Biloba Leaf extract.24/6,Flavone 24% Lactone 6%HPLC.Extract of maidenhair tree Ginkgo extract Ginkgo biloba ext

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