Silymarin.Milk Thistle and applications.

Contents

• Botanical Basic Data of Milk Thistle.
• Phytochemicals of milk thistle.
• History of Silymarin and foundation.
• Modern Application and function of Silymarin and silybin.
• Dosage and Administration.
• Milk Thistle:Pharmacology.
• The Awesome Power of the Milk Thistle.
• How Search engine think about Milk Thistle.
• Research Update of Silybum Marianum.Silymarin
• Photo Gallery of Silybum marianum.

Research Update of Silybum Marianum.Silymarin:

   Milk thistle for alcoholic and/or hepatitis B or C virus liver diseases.:A Rambaldi.

 Introduction:Date of Most Recent Substantive Amendment: 2005 01 14
 Background:Alcohol and hepatotoxic viruses cause the majority of liver diseases. Randomised clinical trials have assessed whether extracts of milk thistle, , have any effect in patients with alcoholic and/or hepatitis B or C virus liver diseases.
 Objectives:To assess the beneficial and harmful effects of milk thistle or milk thistle constituents versus placebo or no intervention in patients with alcoholic liver disease and/or viral liver diseases (hepatitis B and hepatitis C).
 Search strategy:and full text searches were combined (December 2003). Manufacturers and researchers in the field were contacted.
 Selection criteria:Only randomised clinical trials in patients with alcoholic and/or hepatitis B or C virus liver diseases (acute and chronic) were included. Interventions encompassed milk thistle at any dose or duration versus placebo or no intervention. The trials could be double blind, single blind, or unblinded. The trials could be unpublished or published and no language limitations were applied.
 Data collection and analysis:The primary outcome measure was mortality. Binary outcomes are reported as relative risks (RR) with 95% confidence interval (CI). Subgroup analyses were performed with regard to methodological quality.

 Main results:Thirteen randomised clinical trials assessed milk thistle in 915 patients with alcoholic and/or hepatitis B or C virus liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered adequately double – blinded. Milk thistle versus placebo or no intervention had no significant effect on mortality (RR 0.78, 95% CI 0.53 to 1.15), complications of liver disease (RR 0.95, 95% CI 0.83 to 1.09), or liver histology. Liver – related mortality was significantly reduced by milk thistle in all trials (RR 0.50, 95% CI 0.29 to 0.88), but not in high – quality trials (RR 0.57, 95% CI 0.28 to 1.19). Milk thistle was not associated with a significantly increased risk of adverse events (RR 0.83, 95% CI 0.46 to 1.50).

 Authors' conclusions:Our results question the beneficial effects of milk thistle for patients with alcoholic and/or hepatitis B or C virus liver diseases and highlight the lack of high – quality evidence to support this intervention. Adequately conducted and reported randomised clinical trials on milk thistle versus placebo are needed.

   Silybin and silymarin - new and emerging applications in medicine.:Curr Med Chem. 2007;14(3):315-88.Gazak R, Walterova D, Kren V.Laboratory of Biotransformation, Institute of Microbiology, Academy of Sciences of the Czech Republic, Videzska 1083, CZ-142 20 Prague, Czech Republic. kren@biomed.cas.cz.

  This review critically surveys the literature published mainly within this millennium on the new and emerging applications of silybin (pure, chemically defined substance) and silymarin (flavonoid complex from Silybum marianum - milk thistle seeds). These compounds used so far mostly as hepatoprotectants were shown to have other interesting activities, e.g. anticancer and canceroprotective and also hypocholesterolemic activity. These effects were demonstrated in a large variety of illnesses of different organs, e.g. prostate, lungs, CNS, kidneys, pancreas and also in the skin protection. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new functions based on the specific receptor interaction were discovered. These were studied on the molecular level and modulation of various cell-signaling pathways with silybin was disclosed - e.g. NF-kappaB, inhibition of EGFR-MAPK/ERK1/2 signaling, activity upon Rb and E2F proteins, IGF-receptor signaling. Proapoptotic activity of silybin in pre- and/or cancerogenic cells and anti-angiogenic activity of silybin are other important findings that bring silymarin preparations closer to respective application in the cancer treatment. Discovery of the inhibition and modulation of drug transporters, P-glycoproteins, estrogenic receptors, nuclear receptors by silybin and some of its new derivatives contribute further to the better understanding of silybin activity on the molecular level. Silymarin application in veterinary medicine is reviewed as well. Recent works using optically pure silybin diastereomers clearly indicate extreme importance of the use of optically active silybin namely in the receptor studies. Significance of silymarin and its components in the medicine is clearly indicated by an exponential growth of publications on this topic - over 800 papers in the last 5 years.

   Influence of silybin on biophysical properties of phospholipid bilayers.:Acta Pharmacol Sin. 2007 Feb;28(2):296-306.Wesolowska O, Lania-Pietrzak B, Kuzdzal M, Stanczak K,Mosiadz D, Dobryszycki P, Ozyhar A, Komorowska M, Hendrich AB, Michalak K.Department of Biophysics, Wroclaw Medical University, ul Chalubinskiego 10, 50-368 Wroclaw, Poland. olawes@biofiz.am.wroc.pl.[PMID: 17241534]

 AIM: Silybin (silibinin) is major biologically active flavonolignan extracted from milk thistle (Sylibum marianum). Its biological activities include hepato-protection, anticancer properties, and antioxidant- and membrane-stabilizing functions. Although membranes are postulated to be one of the cellular targets for silybin, little is known about its interaction with phospholipid bilayers. METHODS: In the present work, the interactions of silybin with phosphatidylcholine bilayers were studied in detail using fluorescence spectroscopy, microcalorimetry and electron spin resonance techniques. RESULTS: The results showed that silybin interacted with the surface of lipid bilayers. It affected the generalized polarization of the fluorescent probe Prodan, while not influencing the more deeply located Laurdan. Silybin lowered the main phospholipid phase transition temperature as judged by microcalorimetry, and caused the immobilization of spin probe Tempo-palmitate located on the surface of membranes. The mobility of spin probes 5- and 16-doxyl stearic acid was not affected by silybin. Silybin-induced quenching of 1,6-diphenyl-1,3,5-hexatriene fluorescence indicated that some flavonoid molecules partitioned into the hydrophobic region of membranes, which did not change significantly the biophysical properties of the deeper membrane regions. CONCLUSION: Such a behavior of silybin in membranes is in accordance with its postulated biological functions and neglectable side effects of therapies using silybin.

   Silibinin suppresses PMA-induced MMP-9 expression by blocking the AP-1 activation via MAPK signaling pathways in MCF-7 human breast carcinoma cells.:Biochem Biophys Res Commun. 2007 Mar 2;354(1):165-71. Epub 2007 Jan 2.Lee SO, Jeong YJ, Im HG, Kim CH, Chang YC, Lee IS.Department of Food Science and Technology and The Center for Traditional Microorganism Resources (TMR), Keimyung University, Daegu 704-701, Republic of Korea.[PMID: 17214970]

 Matrix metalloproteinase-9 (MMP-9) plays an important role in the invasion and metastasis of cancer cells. In this study, we examined the inhibitory effect of silibinin, a flavonoid antioxidant from milk thistle (Silybum marianum L.) on PMA-induced MMP-9 expression in MCF-7 human breast carcinoma cells. Silibinin significantly and selectively suppressed PMA-induced MMP-9 expression in MCF-7. Silibinin has been found to inhibit PMA-induced MMP-9 gene transcriptional activity by blocking the activation of AP-1 via MAPK signaling pathways. Moreover, the Matrigel invasion assay showed that silibinin reduces PMA-induced invasion of MCF-7 cells. These results suggest that silibinin represents a potential anti-metastatic agent suppressing PMA-induced cancer cell invasion through the specific inhibition of AP-1-dependent MMP-9 gene expression.

   Anticancer potential of silymarin: from bench to bed side.:Anticancer Res. 2006 Nov-Dec;26(6B):4457-98.Agarwal R, Agarwal C, Ichikawa H, Singh RP, Aggarwal BB. Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.[PMID:17201169]

 Silymarin consists of a family of flavonoids (silybin, isosilybin, silychristin, silydianin and taxifoline) commonly found in the dried fruit of the milk thistle plant Silybum marianum. Although silymarin's role as an antioxidant and hepatoprotective agent is well known, its role as an anticancer agent has begun to emerge. Extensive research within the last decade has shown that silymarin can suppress the proliferation of a variety of tumor cells (e.g., prostate, breast, ovary, colon, lung, bladder); this is accomplished through cell cycle arrest at the G1/S-phase, induction of cyclin-dependent kinase inhibitors (such as p15, p21 and p27), down-regulation of anti-apoptotic gene products (e.g., Bcl-2 and Bcl-xL), inhibition of cell-survival kinases (AKT, PKC and MAPK) and inhibition of inflammatory transcription factors (e.g., NF-kappaB). Silymarin can also down-regulate gene products involved in the proliferation of tumor cells (cyclin D1, EGFR, COX-2, TGF-beta, IGF-IR), invasion (MMP-9), angiogenesis (VEGF) and metastasis (adhesion molecules). The antiinflammatory effects of silymarin are mediated through suppression of NF-kappaB-regulated gene products, including COX-2, LOX, inducible iNOS, TNF and IL-1. Numerous studies have indicated that silymarin is a chemopreventive agent in vivo against a variety of carcinogens/tumor promoters, including UV light, 7,12-dimethylbenz(a)anthracene (DMBA), phorbol 12-myristate 13-acetate (PMA) and others. Silymarin has also been shown to sensitize tumors to chemotherapeutic agents through down-regulation of the MDR protein and other mechanisms. It binds to both estrogen and androgen receptors, and down-regulates PSA. In addition to its chemopreventive effects, silymarin exhibits antitumor activity against human tumors (e.g., prostate and ovary) in rodents. Various clinical trials have indicated that silymarin is bioavailable and pharmacologically safe. Studies are now in progress to demonstrate the clinical efficacy of silymarin against various cancers.
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   Structure elucidation and antioxidant activity of (-)-isosilandrin isolated from Silybum marianum L.:Chem Biodivers. 2004 Nov;1(11):1668-77.Samu Z, Nyiredy S, Baitz-Gacs E, Varga Z, Kurtan T, Dinya Z, Antus S. Research Institute for Medicinal Plants, P.O. Box 11, H-2011 Budakalasz.[PMID: 17191807]

 A regioisomer of the known flavanolignan (-)-silandrin (3a), named (-)-isosilandrin (8a), was isolated from the fruits of a white-flowered variant of Silybum marianum L. populated in Hungary. Its structure was established both by spectroscopic methods and total synthesis, and its absolute configuration was determined by means of circular dichroism. This compound showed stronger inhibitory activity on the superoxide anion (O2*-) release by human polymorphonuclear leukocytes (PMNL) than (+)-silybin (1a,b).

   Silibinin protects against isoproterenol-induced rat cardiac myocyte injury through mitochondrial pathway after up-regulation of SIRT1.:J Pharmacol Sci. 2006 Dec;102(4):387-95.Zhou B, Wu LJ, Li LH,Chinan Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, China.[PMID: 17170512]

 Terminally differentiated adult injured cardiac myocytes have been used for various animal models of heart failure. It has recently been shown that isoproterenol induces injury in rat neonatal cardiac myocytes via a beta-adrenergic pathway, suggesting that it might be one of the factors involved in myocardial cell injury in heart failure in vivo. In the study, silibinin, a plant flavanoid from milk thistle was first evaluated for its protective effect against beta-adrenergic agonist isoproterenol-induced injury in cultured rat neonatal cardiac myocytes. The viability, activation of lactate dehydrogenase (LDH), and content of maleic dialdehyde (MDA) were chosen for measuring the degree of cardiac myocytes injury. As a result, silibinin protected isoproterenol-treated rat cardiac myocytes from death and significantly decreased LDH release and MDA production. Silibinin increased superoxide dismutase activity, decreased [Ca(2+)](i), and increased mitochondrial membrane potential (DeltaPsi). Furthermore, the release of pro-apoptotic cytochrome c from mitochondria was reduced by silibinin. Silibinin increased the expression of anti-apoptotic Bcl-2 family protein Bcl-2, and up-regulation of SIRT1 inhibited the translocation of Bax from cytoplasm to mitochondria, which caused mitochondrial dysfunction and cell injury. These results demonstrate that silibinin protects against isoproterenol-induced cardiac myocytes injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members.

   Protective effects of silymarin, a milk thistle (Silybium marianum) derivative on ethanol-induced oxidative stress in liver.: Indian J Biochem Biophys. 2006 Oct;43(5):306-11.Das SK, Vasudevan DM.Department of Biochemistry, Amrita Institute of Medical Sciences, Cochin 682 026, Kerala, India. subirkumardas@aims.amrita.edu.[PMID: 17133738]

 The production of reactive oxygen species (ROS) is considered to be a major factor in oxidative cell injury. The antioxidant activity or the inhibition of the generation of free radicals is important in providing protection against such hepatic damage. Silymarin, derived from the milk thistle plant, Silybium marianum, has been used in traditional medicine as a remedy for diseases of the liver and biliary tract. In the present study, the effect of hepatoprotective drug silymarin on body weight and biochemical parameters, particularly, antioxidant status of ethanol-exposed rats was studied and its efficacy was compared with the potent antioxidant, ascorbic acid as well as capacity of hepatic regeneration during abstention. Ethanol, at a dose of 1.6 g/kg body wt/day for 4 wks affected body weight in 16-18 week-old male albino rats (Wistar strain weighing 200-220 g). Thiobarbituric acid reactive substance (TBARS) level, superoxide dismutase (SOD), and glutathione-s-transferase (GST) activities were significantly increased, whereas GSH content, and catalase, glutathione reductase (GR) and GPx (glutathione peroxidase) activities significantly reduced, on ethanol exposure. These changes were reversed by silybin and ascorbic acid treatment. It was also observed that abstinence from ethanol might help in hepatic regeneration. Silybin showed a significant hepatoprotective activity, but activity was less than that of ascorbic acid. Furthermore, preventive measures were more effective than curative treatment.

   A phase I and pharmacokinetic study of silybin-phytosome in prostate cancer patients.:Invest New Drugs. 2007 Apr;25(2):139-46. Epub 2006 Nov 1.Flaig TW, Gustafson DL, Su LJ, Zirrolli JA, Crighton F, Harrison GS, Pierson AS, Agarwal R, Glode LM.Department of Medicine, Division of Medical Oncology, University of Colorado at Denver and Health Sciences Center, Denver, Colorado, USA.[PMID: 17077998]

 Silibinin is a polyphenolic flavonoid isolated from milk thistle with anti-neoplastic activity in several in vitro and in vivo models of cancer, including prostate cancer. Silybin-phytosome is a commercially available formulation containing silibinin. This trial was designed to assess the toxicity of high-dose silybin-phytosome and recommend a phase II dose. Silybin-phytosome was administered orally to prostate cancer patients, giving 2.5-20 g daily, in three divided doses. Each course was 4 weeks in duration. Thirteen patients received a total of 91 courses of silybin-phytosome. Baseline patient characteristics included: median age of 70 years, median baseline prostate specific antigen (PSA) of 4.3 ng/ml, and a median ECOG performance status of 0. The most prominent adverse event was hyperbilirubinemia, with grade 1-2 bilirubin elevations in 9 of the 13 patients. The only grade 3 toxicity observed was elevation of alanine aminotransferase (ALT) in one patient; no grade 4 toxicity was noted. No objective PSA responses were observed. We conclude that 13 g of oral silybin-phytosome daily, in 3 divided doses, appears to be well tolerated in patients with advanced prostate cancer and is the recommended phase II dose. Asymptomatic liver toxicity is the most commonly seen adverse event.

   Alternative therapy use in liver transplant recipients.:Prog Transplant. 2006 Sep;16(3):226-31.Tickerhoof L, Wagener MM, Cacciarelli TV, Singh N.VA Pittsburgh Healthcare System, Pittsburgh, PA, USA.[PMID: 17007157]

 BACKGROUND: The extent of use of alternative therapies and the psychosocial variables predictive of their use have not been well defined in liver transplant recipients. OBJECTIVE: To determine types of alternative therapies used by liver transplant recipients and to assess psychosocial, behavioral, and quality of life variables associated with the use of alternative therapies in these patients. METHODS: Assessment of types of alternative therapies used, demographic characteristics, satisfaction with social support, coping styles, sense of personal control (mastery), quality of life, and health beliefs in 32 liver transplant recipients. RESULTS: Overall, 34.4% of the liver transplant recipients used a form of alternative therapy. Herbal products were used by 45% of the alternative therapy users and included milk thistle (silymarin), eclipta, and green beet leaf-all considered "hepatic tonics". Alternative therapy users tended to have greater problem-focused coping skills than nonusers (P = .08). Nineteen percent of the patients incurred annual out-of-pocket expense of at least dollars 100 for alternative therapies. Patients incurring out-of-pocket expenses reported better overall health (P = .02), were more likely to be employed (P = .025), and had higher mastery scores (P = .01). CONCLUSIONS: Use of alternative therapies is common after liver transplantation. Herbal products used by liver transplant recipients are disease specific; that is, they claim to promote liver health.
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   Silibinin protects rat cardiac myocyte from isoproterenol-induced DNA damage independent on regulation of cell cycle.:Biol Pharm Bull. 2006 Sep;29(9):1900-5.Zhou B, Wu LJ,.China Research Institute of Medical and Pharmaceutical Sciences, Shenyang Pharmaceutical University, Shenyang, China.[PMID: 16946506]

 Silibinin, derived from the milk thistle plant, Silybum marianum, has been traditionally used as an antihepatotoxic agent for the treatment of liver disease. Our preliminary study demonstrated that silibinin has protected rat cardiac myocytes against beta-adrenergic agonist isoproterenol-induced injury through resuming mitochondrial function and regulating the expression of SIRT1 and Bcl-2 family members. In this study, we investigate whether silibinin has anti-apoptotic effect on isoproterenol-treated rat cardiac myocytes. DNA damage, detected by the TUNEL and DNA fragmentation assay, was diminished after treatment of silibinin. Results of nitrite and Western blot assays showed that the amount of NO and the expression of iNOS were decreased after treatment with silibinin, while the expression of procaspase-3 and digestion of caspase-3 substrates, the inhibitor of caspase-activated DNase (ICAD) and poly-(ADP-ribose) polymerase (PARP), were increased simultaneously. The DNA damage was reversed by down-regulation of p53 phosphorylation after treatment with silibinin. Result of flowcytometric analysis showed that the cell cycle was not affected, and the expression of cell cycle regulatory protein p21 also had no change. Consequently, silibinin protected cardiac myocytes against isoproterenol-induced DNA damage through caspase pathway and the expression of p53, but independent on regulation of cell cycle.

   Analysis and comparison of active constituents in commercial standardized silymarin extracts by liquid chromatography-electrospray ionization mass spectrometry.:J Chromatogr B Analyt Technol Biomed Life Sci. 2007 Jan 1;845(1):95-103. Epub 2006 Aug 30.Lee JI, Narayan M, Barrett JS.Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Abramson Research Center 916H, Philadelphia, PA 19104-4399, USA.[PMID: 16942922]

 A sensitive method for the simultaneous quantitation of six active constituents in commercial silymarin standardized extracts was developed based on liquid chromatography (LC) in combination with mass spectrometry (MS). The six main active constituents, namely, silydianin, silychristin, diastereoisomers of silybin (silybin A and B), and diastereoisomers of isosilybin (isosilybin A and B) were completely separated and quantified by LC/MS. Silymarin obtained from Sigma-Aldrich Co. was evaluated and used as standard reference material for the six individual constituents in comparing the relative content of silymarin and the relative ratio of each constituent in commercial standardized silymarin extracts, respectively. Significant variation was found between different commercial silymarin sources. As a result, this method has proven useful in evaluating and quantifying the six active constituents in commercial milk thistle extracts. The calibration curves were over the range from 0.25 to 100 microg/mL for silychristin and silydianin, and from 0.10 to 100 microg/mL for silybin A, silybin B, isosilybin A and isosilybin B, respectively (r(2)> or =0.9958). For all six active constituents, the overall intra-day precision values, based on the relative standard deviation replicate for four QC levels, ranged from 1.18% to 12.4% and accuracy ranged from 89.4% to 112%. This methodology could easily be incorporated into standardized testing to assess content uniformity including lot-to-lot variation as part of routine process controls as well as a means to describe cross-product variation among the exiting marketed formulations.

   Effect of silibinin on the growth and progression of primary lung tumors in mice.:J Natl Cancer Inst. 2006 Jun 21;98(12):846-55.Singh RP, Deep G, Chittezhath M, Kaur M, Dwyer-Nield LD, Malkinson AM, Agarwal R.4200 E. 9th Ave., Box C238, Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado Cancer Center, Denver, CO 80262, USA.[PMID: 16788158]

 BACKGROUND: Silibinin, a flavanone from milk thistle, inhibits the growth of tumors in several rodent models. We examined the effects of dietary silibinin on the growth, progression, and angiogenesis of urethane-induced lung tumors in mice. METHODS: A/J mice (15 per group) were injected with urethane (1 mg/g body weight) or saline alone and fed normal diets for 2 weeks, after which they were fed diets containing different doses of silibinin (0%-1% [wt/wt] silibinin) for 18 or 27 weeks. Immunohistochemistry and Western blot analysis were used to examine angiogenesis and enzymatic markers of inflammation, proliferation, and apoptosis. All statistical tests were two-sided. RESULTS: Urethane-injected mice exposed to silibinin had statistically significantly lower lung tumor multiplicities than urethane-injected mice fed the control diet lacking silibinin (i.e., control mice). Mice that received urethane and 1% (wt/wt) dietary silibinin for 18 weeks had 93% fewer large (i.e., 1.5-2.5-mm-diameter) lung tumors than control mice (mean number of tumors/mouse: 27 in the urethane group versus 2 in the urethane + 1% silibinin group, difference = 25 tumors/mouse, 95% confidence interval [CI] = 13 to 37 tumors/mouse, P = .005). Lung tumors of silibinin-fed mice had 41%-74% fewer cells positive for the cell proliferation markers proliferating cell nuclear antigen and cyclin D1 than lung tumors of control mice. Tumor microvessel density was reduced by up to 89% with silibinin treatment (e.g., 56 microvessels/400x field in tumors from control mice versus 6 microvessels/400x field in tumors from urethane + 1% silibinin-treated mice [difference = 50 microvessels/400x field, 95% CI = 46 to 54 microvessels/400x field; P<.001]). Silibinin decreased lung tumor expression of vascular endothelial growth factor (VEGF) and of inducible nitric oxide synthase and cyclooxygenase-2, two enzymes that promote lung tumor growth and progression by inducing VEGF expression. CONCLUSIONS: Silibinin inhibits lung tumor angiogenesis in an animal model and merits investigation as a chemopreventive agent for suppressing lung cancer progression.

   Pilot study of oral silibinin, a putative chemopreventive agent, in colorectal cancer patients: silibinin levels in plasma, colorectum, and liver and their pharmacodynamic consequences.:Clin Cancer Res. 2006 May 1;12(9):2944-50.Hoh C, Boocock D, Marczylo T, Singh R, Berry DP, Dennison AR, Hemingway D, Miller A, West K, Euden S, Garcea G, Farmer PB, Steward WP, Gescher AJ. Cancer Biomarkers and Prevention Group, Department of Cancer Studies, University of Leicester, United Kingdom.[PMID: 16675592]

 Silibinin, a flavonolignan from milk thistle, has intestinal cancer chemopreventive efficacy in rodents. It is a strong antioxidant and modulates the insulin-like growth factor (IGF) system by increasing circulating levels of IGF-binding protein 3 (IGFBP-3) and decreasing levels of IGF-I. Here, the hypothesis was tested that administration of oral silibinin generates agent levels in human blood and colorectal and hepatic tissues consistent with pharmacologic activity. Patients with confirmed colorectal adenocarcinoma received silibinin formulated with phosphatidylcholine (silipide) at dosages of 360, 720, or 1,440 mg silibinin daily for 7 days. Blood and biopsy samples of normal and malignant colorectum or liver were obtained before dosing, and blood and colorectal or hepatic tissues were collected at resection surgery after the final silipide dose. Levels of silibinin were quantified by high-pressure liquid chromatography-UV, and plasma metabolites were identified by liquid chromatography-mass spectrometry. Blood levels of IGFBP-3, IGF-I, and the oxidative DNA damage pyrimidopurinone adduct of deoxyguanosine (M1dG) were determined. Repeated administration of silipide was safe and achieved levels of silibinin of 0.3 to 4 micromol/L in the plasma, 0.3 to 2.5 nmol/g tissue in the liver, and 20 to 141 nmol/g tissue in colorectal tissue. Silibinin monoglucuronide, silibinin diglucuronide, silibinin monosulfate, and silibinin glucuronide sulfate were identified in the plasma. Intervention with silipide did not affect circulating levels of IGFBP-3, IGF-I, or M1dG. The high silibinin levels achieved in the human colorectal mucosa after consumption of safe silibinin doses support its further exploration as a potential human colorectal cancer chemopreventive agent.

   The absorption characteristics of silybin in small intestine of rat.:Yao Xue Xue Bao. 2006 Feb;41(2):138-41.Luan LB, Zhao N.Department of Pharmaceutics, China Pharmaceutical University, Nanjing 210009, China. luanlibiao@126.com.[PMID: 16671544]

 AIM: To investigate the intestinal absorption of silybin (SLB) in male rats. METHODS: Single-pass intestinal perfusion (SPIP) technique was performed in each isolated region of the small intestine at a flow rate of 0.1 mL x min(-1). The samples of perfusate and portal plasma were collected at the designated periods of time after rat intestinal perfusion and analyzed for drug by HPLC. RESULTS: The absorption rate constant (k(a)) and the effective permeability (P(eff)) of SLB at 190 microg x mL(-1) were determined for each segment. These data indicated the absorption rate were duodenum > jejunum > ileum > colon. SPIP was also performed in duodenum with three concentrations of SLB (80, 190 and 300 microg x mL(-1)). The concentration dependent changes of k(a) and P(eff) were evident in the duodenum perfusion of silybin. At silybin perfusate concentrations of 80 microg x mL(-1), k(a) and P(eff) were different from the values at either of the two higher concentrations (190 and 300 microg x mL(-1), P < 0.05). However there was no difference between 190 microg x mL(-1) and 300 microg x mL(-1) groups. The drug mass appearing in the plasma further indicated the absorption were duodenum > jejunum > ileum > colon. CONCLUSION: SLB can be absorbed in whole intestinal sections. When the concentration raises to a certain level, the uptake of SLB will not increase.
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   Separation and characterization of silybin, isosilybin, silydianin and silychristin in milk thistle extract by liquid chromatography-electrospray tandem mass spectrometry.:J Chromatogr A. 2006 May 26;1116(1-2):57-68. Epub 2006 Apr 24.Lee JI, Hsu BH, Wu D, Barrett JS.Division of Clinical Pharmacology & Therapeutics, The Children's Hospital of Philadelphia, Abramson Research Center 916H, Philadelphia, PA 19104-4399, USA.[PMID: 16631762]

 A selective and sensitive liquid chromatography/tandem mass spectrometry (LC/MS/MS) method has been developed for the characterization of silymarin in commercially available milk thistle extract. In this study, six main active constituents, including silydianin, silychristin, diastereomers of silybin (silybin A and B) and diastereomers of isosilybin (isosilybin A and B) in silymarin, were completely separated on a YMC ODS-AQ HPLC column using a gradient mobile phase system comprised of ammonium acetate and methanol/water/formic acid. Identification and characterization of the major constituents were based not only on the product ion scan, which provided unique fragmentation information of a selected molecular ion, but also on the specific fragmentation of multiple reaction monitoring (MRM) data, which confirmed the retention times of LC chromatographic peaks. The method was applied in the analysis of human plasma samples in the presence of silymarin and appeared to be suitable for the pharmacokinetic studies in which the discrimination of silymarin constituents is essential.

   Silymarin as a new hepatoprotective agent in experimental cholestasis: new possibilities for an ancient medication.:Curr Med Chem. 2006;13(9):1055-74.Crocenzi FA, Roma MG. Instituto de Fisiologia Experimental (IFISE), Facultad de Ciencias Bioquimicas y Farmaceuticas (CONICET--U.N.R.), S2002LRL, Rosario, Argentina.[PMID:16611084]

 Silymarin is a purified extract from milk thistle (Silybum marianun (L.) Gaertn), composed of a mixture of four isomeric flavonolignans: silibinin (its main, active component), isosilibinin, silydianin and silychristin. This extract has been empirically used as a remedy for almost 2000 years, and remains being used as a medicine for many types of acute and chronic liver diseases. Despite its routinely clinical use as hepatoprotectant, the mechanisms underlying its beneficial effects remain largely unknown. This review addresses in detail a number of recent studies showing a novel feature of silymarin as a hepatoprotective drug, namely: its anticholestatic properties in experimental models of hepatocellular cholestasis with clinical correlate. For this purpose, this review will cover the following aspects: 1. The chemistry of silymarin, including chemical composition and properties. 2. The current clinical applications of silymarin as a hepatoprotective agent, including the mechanisms by which silymarin is thought to exert its hepatoprotective properties, when known. 3. The physiological events involved in bile formation, and the mechanisms of hepatocellular cholestasis, focusing on cellular targets and mechanisms of action of drugs used to reproduce experimentally cholestatic diseases of clinical interest, in particular estrogens and monohydroxylated bile salts, where anticholestatic properties of silymarin have been tested so far. 4. The recent findings describing the impact of silymarin on normal bile secretion and its novel, anticholestatic properties in experimental models of cholestasis, with particular emphasis on the cellular/molecular mechanisms involved, including modulation of bile salt synthesis, biotransformation/depuration of cholestatic compounds, changes in transporter expression/activity, and evocation of signaling pathways.

   The use of flavolignans of "Silybum marianum (L.) Gaertn." to create a new fat product--fortified butter.:Vopr Pitan. 2005;74(6):42-5.Spiridonov AM, Popov AD, Kurkin VA, Berezin II, Zinina ML.[PMID: 16605010]

 The results of study on substantiating the possibilities of the use of flavolignans of Silybum marianum (L.) Gaertn. with a purpose to create a new fat product--butter fortified by an "Liguid extract Silybum marianum (L.) Gaertn." are being discussed. Slowdown of peroxidation process is revealed in fortified butter in comparison with ordinary butter. With the help of spectrometry method higher content of flavolignans was deteeted in fortified butter (converting to silibin--the main component of "Liguid Exstract Silybum marianum (L) Gaertn"), what allows to speak about increase of its potential therapeutic effect.

   Enhancement of mammary carcinogenesis in two rodent models by silymarin dietary supplements.:Carcinogenesis. 2006 Sep;27(9):1739-47. Epub 2006 Apr 5.Malewicz B, Wang Z, Jiang C, Guo J, Cleary MP, Grande JP, Lu J.The Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.[PMID: 16597642]

 Silymarin is a mixture of polyphenolic flavonoids isolated from milk thistle (Silybum marianum) with anticancer activities reported for several organ sites. The present study tested the efficacy of dietary silymarin against mammary carcinogenesis in two rodent models. In the Sprague-Dawley rat model, female rats were fed a purified diet supplemented with none, 0.03, 0.1, 0.3 or 1% (w/w) of silymarin from 21 days of age (DOA) and carcinogenesis was initiated by a single i.p. injection of 1-methyl-1-nitrosourea (MNU) at 51 DOA. Mammary tumor (MT) development was followed till 110 days after carcinogen injection. In the MMTV-neu/HER2 transgenic mouse mammary carcinogenesis model, homozygous transgenic females were fed a purified diet supplemented with none or 0.3% silymarin, either from 28 or 120 DOA and MT development was followed to approximately 300 DOA. The results showed that dietary silymarin increased the plasma concentration of free and total silibinin, a major component of silymarin, in a dose-dependent manner in the rat, but did not decrease either MT incidence or number. Instead silymarin modestly increased the number of MNU-induced MTs in rats. Similarly, silymarin increased MT incidence and multiplicity and non-MTs in the neu-transgenic mice. In cell culture, treatment of human MCF-7 breast cancer cells with serum-achievable concentrations of silymarin in the rodent models stimulated their growth, in part through an estrogen-like activity. Because silymarin is being used in the treatment of liver cirrhosis and a variety of other human ailments, and is sold as a dietary supplement, our findings add a cautionary note to its application in breast cancer prevention.

   Treatment of alcoholic liver disease.:Dig Dis. 2005;23(3-4):275-84.Bergheim I, McClain CJ, Arteel GE.Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY 40292, USA.[PMID: 16508292]

 Alcoholic liver disease (ALD) remains a major cause of morbidity and mortality worldwide. For example, the Veterans Administration Cooperative Studies reported that patients with cirrhosis and superimposed alcoholic hepatitis had a 4-year mortality of >60% (worse than many common cancers such as breast and prostate). The cornerstone for therapy for ALD is lifestyle modification, including drinking cessation and treatment of decompensation, if appropriate. Nutrition intervention has been shown to play a positive role on both an in-patient and out-patient basis. Corticosteroids are effective in selected patients with alcoholic hepatitis, and treatment with pentoxifylline appears to be a promising anti-inflammatory therapy. Recent studies have indicated anti-TNFalpha therapy, at least for alcoholic hepatitis. Some complementary and alternative medicinal agents, such as milk thistle and S-adenosylmethionine, may be effective in alcoholic cirrhosis. Treatment of the complications of ALD can improve the quality of life and, in some cases, decrease short-term mortality.
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   An in vitro study of the protective effect of the flavonoid silydianin against reactive oxygen species.:Phytother Res. 2006 Feb;20(2):115-9.Zielinska-Przyjemska M, Wiktorowicz K. Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Grunwaldzka 6, 60-780 Poznan, Poland. mzielin@am.poznan.pl.[PMID: 16444663]

 The inhibitory effect of silydianin, an active constituent of Silybium marianum, on the in vitro production and release of oxidative products has been examined. Polymorphonuclear neutrophils (PMNs) play a primary role in the initiation and propagation of inflammatory responses. Their apoptosis is a major mechanism associated with the resolution of inflammatory reactions. Neutrophils were assessed for caspase-3 activity, the rst step in the execution phase of apoptosis. When cells were cultured with 100 microM silydianin for 24 h, caspase-3 was activated. Induction of apoptosis by silydianin was accompanied by a decrease in luminol-enhanced chemiluminescence as well as superoxide radical (O2*-) release in freshly isolated cells and lipid peroxidation in mouse spleen microsomes. No significant effect of silydianin on PMN hydrogen peroxide production evaluated by a flow cytometric dichlorofluorescin oxidation assay was found. Such results indicate a possible antiinflammatory activity for silydianin, which regulates caspase-3 activation, affects cell membranes and acts as a free radical scavenger.

   Efficacy of deguelin and silibinin on benzo(a)pyrene-induced lung tumorigenesis in A/J mice.:Neoplasia. 2005 Dec;7(12):1053-7.Yan Y, Wang Y, Tan Q, Lubet RA, You M. Department of Surgery, Washington University School of Medicine, Campus Box 8109, 660 South Euclid Avenue, St. Louis, MO 63110, USA.[PMID: 16354587]

 We evaluated deguelin and silibinin in A/J mice treated with the tobacco-specific carcinogen benzo(a)pyrene (BP) for their ability to inhibit pulmonary adenoma formation and growth. Animals were treated with either deguelin (5.0 or 10.0 mg/kg body weight, by gavage) or silibinin at doses of 0.05% and 0.1% in the diet, approximately 10 days before a single intraperitoneal dose of BP. We found that oral administration of deguelin reduced tumor multiplicity by 56% and tumor load by 78%, whereas silibinin treatment at doses of 0.05% and 0.1% in the diet did not show any significant efficacy on either tumor multiplicity or tumor load. The result indicates that deguelin significantly inhibits pulmonary adenoma formation and growth in A/J mice. Finding new and effective agents that can prevent lung cancer is urgently needed because cancer of the lungs remains the principal cause of cancer deaths in the United States and because effective chemoprevention of this cancer type remains elusive. Thus, deguelin appears to be a promising new preventive agent for lung cancer and may be considered for further studies in other animal models and in clinical trials.

   Silibinin efficacy against human hepatocellular carcinoma.:Clin Cancer Res. 2005 Dec 1;11(23):8441-8.Varghese L, Agarwal C, Tyagi A, Singh RP, Agarwal R.Department of Pharmaceutical Sciences, School of Pharmacy and University of Colorado Cancer Center, University of Colorado Health Sciences Center, Denver, Colorado 80262, USA.[PMID: 16322307]

 PURPOSE: Hepatocellular carcinoma (HCC) is one of the most common recurrent malignancies, for which, currently, there is no effective therapy. Considering the antihepatotoxic activity of silibinin, a widely used drug and supplement for various liver disorders, together with its strong preventive and anticancer efficacy against various epithelial cancers, we investigated the efficacy of silibin against human HCC cells. EXPERIMENTAL DESIGN: Silibinin effects were examined on growth, cytotoxicity, apoptosis, and cell cycle progression in two different HCC cell lines, HepG2 (hepatitis B virus negative; p53 intact) and Hep3B (hepatitis B virus positive; p53 mutated). At molecular level, cell cycle effects of silibinin were assessed by immunoblotting and in-bead kinase assays. RESULTS: Silibinin strongly inhibited growth of both HepG2 and Hep3B cells with a relatively stronger cytotoxicity in Hep3B cells, which was associated with apoptosis induction. Silibinin also caused G1 arrest in HepG2 and both G1 and G2-M arrests in Hep3B cells. Mechanistic studies revealed that silibinin induces Kip1/p27 but decreases cyclin D1, cyclin D3, cyclin E, cyclin-dependent kinase (CDK)-2, and CDK4 levels in both cell lines. In Hep3B cells, silibinin also reduced the protein levels of G2-M regulators. Furthermore, silibinin strongly inhibited CDK2, CDK4, and CDC2 kinase activity in these HCC cells. CONCLUSION: Together, these results for the first time identify the biological efficacy of silibinin against HCC cells, suggesting the importance of conducting further investigations in preclinical HCC models, especially on in vivo efficacy, to support the clinical usefulness of silibinin against hepatocellular carcinoma in addition to its known clinical efficacy as an antihepatotoxic agent.

   Solubility of silybin in aqueous poly(ethylene glycol) solution.:Int J Pharm. 2006 Feb 3;308(1-2):100-6.Bai TC, Yan GB, Hu J, Zhang HL, Huang CG. Department of Chemistry and Chemical Engineering, Suzhou University, Dushu-Lake Higher Education Town, Suzhou 215123, China. tcbai@suda.edu.cn.[PMID: 16321487]

 Silybin is a main component in silymarin, which is an antihepatotoxic polyphenolic substance isolated from the milk thistle plant, Silybum marianum. A major problem in the development of an oral solid dosage form of this drug is the extremely poor aqueous solubility. In present work, the solubility of silybin in aqueous poly(ethylene glycol) 6,000 (PEG 6,000) solution at the temperature range from 293.15 to 313.15K was measured by a solid liquid equilibrium method. The aim of this study is to investigate the possible effect of poly(ethylene glycol) concentration and temperature on the solubility of the drug, and to reveal the solubilization capacity of the polymer for the drug. Experimental results reveal that the solubility of silybin increases with the increase both in PEG's concentration and temperature. With the increase in PEG's concentration, the transfer enthalpy and entropy for silybin from water to aqueous PEG solution increases first in a positive region, and then decreases to a negative region. The transfer enthalpy is lower than the entropy term. A modified Universal Quasi Chemical (UNIQUAC) model was used to correlate solubility data.

   Milk thistle for alcoholic and/or hepatitis B or C liver diseases--a systematic cochrane hepato-biliary group review with meta-analyses of randomized clinical trials.:Am J Gastroenterol. 2005 Nov;100(11):2583-91.Rambaldi A, Jacobs BP, Iaquinto G, Gluud C.Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen University Hospital, Denmark.[PMID: 16279916]

 OBJECTIVES: Our objectives were to assess the beneficial and harmful effects of milk thistle (MT) or MT constituents versus placebo or no intervention in patients with alcoholic liver disease and/or hepatitis B and/or C liver diseases. METHODS: Randomized clinical trials studying patients with alcoholic and/or hepatitis B or C liver diseases were included (December 2003). The randomized clinical trials were evaluated by components of methodological quality. RESULTS: Thirteen randomized clinical trials assessed MT in 915 patients with alcoholic and/or hepatitis B or C liver diseases. The methodological quality was low: only 23% of the trials reported adequate allocation concealment and only 46% were considered double blind. MT versus placebo or no intervention for a median duration of 6 months had no significant effects on all-cause mortality (relative risk (RR) 0.78, 95% confidence interval (CI) 0.53-1.15), complications of liver disease, or liver histology. Liver-related mortality was significantly reduced by MT in all trials (RR 0.50, 95% CI 0.29-0.88), but not in high-quality trials (RR 0.57, 95% CI 0.28-1.19). MT was not associated with a significantly increased risk of adverse events. CONCLUSIONS: Based on high-quality trials, MT does not seem to significantly influence the course of patients with alcoholic and/or hepatitis B or C liver diseases. MT could potentially affect liver injury. Adequately conducted randomized clinical trials on MT versus placebo may be needed.
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   Effect of milk thistle (Silybum marianum) on the pharmacokinetics of irinotecan.:Clin Cancer Res. 2005 Nov 1;11(21):7800-6.van Erp NP, Baker SD, Zhao M, Rudek MA, Guchelaar HJ, Nortier JW, Sparreboom A, Gelderblom H.Department of Clinical Pharmacy and Toxicology, Leiden University Medical Center, the Netherlands.[PMID: 16278402]

 PURPOSE: Milk thistle (Silybum marianum) is one of the most commonly used herbal therapies, and its principal constituent silybin significantly inhibits cytochrome P450 isoform 3A4 (CYP3A4) and UDP glucuronosyltransferase isoform 1A1 (UGT1A1) in vitro. Here, we investigated whether milk thistle affects the pharmacokinetics of irinotecan, a substrate for CYP3A4 and UGT1A1, in humans. EXPERIMENTAL DESIGN: Six cancer patients were treated with irinotecan (dose, 125 mg/m(2)) given as a 90-minute infusion once every week. Four days before the second dose, patients received 200 mg milk thistle, thrice a day, for 14 consecutive days. Pharmacokinetic studies of irinotecan and its metabolites 7-ethyl-10-hydroxycamptothecin (SN-38), 7-ethyl-10-[3,4,5-trihydroxy-pyran-2-carboxylic acid]-camptothecin (SN-38-glucuronide), and 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin were done during the first three irinotecan administrations. RESULTS: Short-term (4 days) or more prolonged intake of milk thistle (12 days) had no significant effect on irinotecan clearance (mean, 31.2 versus 25.4 versus 25.6 L/h; P = 0.16). The area under the curve ratio of SN-38 and irinotecan was slightly decreased by milk thistle (2.58% versus 2.23% versus 2.17%; P = 0.047), whereas the relative extent of glucuronidation of SN-38 was similar (10.8 versus 13.5 versus 13.1; P = 0.64). Likewise, the area under the curve ratio of 7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]-carbonyloxycamptothecin and irinotecan was unaffected by milk thistle (0.332 versus 0.285 versus 0.337; P = 0.53). The maximum plasma concentrations of silybin ranged between 0.0249 and 0.257 micromol/L. CONCLUSIONS: Silybin concentrations after intake of milk thistle are too low to significantly affect the function of CYP3A4 and UGT1A1 in vivo, indicating that milk thistle is unlikely to alter the disposition of anticancer drugs metabolized by these enzymes.

   Silybin and silymarin--new effects and applications.:Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2005 Jun;149(1):29-41.Kren V, Walterova D.Institute of Microbiology, Academy of Sciences of the Czech Republic, Prague.[PMID: 16170386]

 This article aims to review critically literature published mainly within this millennium on the new and emerging applications of silymarin, the polyphenolic fraction from the seeds of Silybum marianum and its main component silybin. Silymarin and silybin used so far mostly as hepatoprotectants were shown to have other interesting activities as e.g., anticancer and canceroprotective. These activities were demonstrated in a large variety of illnesses of different organs as e.g., prostate, lungs, CNS, kidneys, pancreas and others. Besides the cytoprotective activity of silybin mediated by its antioxidative and radical-scavenging properties also new activities based on the specific receptor interaction were discovered--e.g., inhibition and modulation of drug transporters, P-glycoproteins, estrogenic receptors, nuclear receptors and some others. New derivatives of silybin open new ways to its therapeutic applications. Pharmacology dealing with optically pure silybin diastereomers may suggest new mechanisms of its action.

   Mechanisms and preclinical efficacy of silibinin in preventing skin cancer.:Eur J Cancer. 2005 Sep;41(13):1969-79.Singh RP, Agarwal R.Department of Pharmaceutical Sciences, School of Pharmacy, University of Colorado at Denver and Health Sciences Center, 4200 East Ninth Avenue, Box C238, Denver, CO 80262, USA.[PMID: 16084079]

 Eukaryotic cellular machineries including the genome face continuous challenge from environmental deleterious agents, as well as from the by products of their own metabolism. Our skin is the most important barrier. It protects us from xenobiotic and genotoxic agents including ultraviolet (UV) solar radiation and potential carcinogens, which are notorious for causing skin cancer. There is a rise in non-melanoma skin cancer (NMSC), which is diagnosed in more than a million people every year in the United States alone, and is also prevalent in the other Western countries. In addition to sunscreens, chemoprevention of skin cancer by natural non-toxic compounds is suggested as an effective strategy to prevent the incidence of skin cancer. Our extensive animal studies on silibinin, a non-toxic bioactive component in milk thistle, suggest that it has a strong potential to prevent skin cancer incidence, promotion and progression in response to chemical carcinogens and tumour promoters as well as UV radiation. Our data suggest that silibinin has multiple targets in the cell, and can be protective against the harmful effects of cytotoxic agents such as reactive oxygen species and inflammation. Further, silibinin modulates mitogenic and survival signalling, p53, Cip1/p21 and other cell cycle regulatory molecules to prevent UVB-induced skin carcinogenesis. Our ongoing studies also suggest the positive effect of silibinin on the repair of UVB-induced DNA damage in mouse skin. Overall, the protective efficacy of silibinin against skin cancer is supported by sound mechanistic rationale in animal and cell culture studies, and suggests its potential use for humans.

   review of Silybum marianum (milk thistle) as a treatment for alcoholic liver disease.:J Clin Gastroenterol. 2005 Jul;39(6):520-8.Ball KR, Kowdley KV.University of Washington, Seattle, WA, USA.[PMID: 15942440]

 Silybum marianum (milk thistle) and its derivatives have been used for centuries for the treatment of liver disease. This review focuses exclusively on published literature pertaining to the potential use of Silybum marianum or its derivatives for the treatment of alcoholic liver disease. Clinical studies have varied greatly in quality, with the majority limited by inadequate sample size, lack of uniformity in the population treated, lack of standardization of preparations studied, variability in dosing regimens, inconsistent outcome measures, and lack of information on concurrent use of alcohol during the treatment period. While Silybum marianum and its derivatives appear to be safe and the available evidence on the mechanisms of action appears promising, there are currently insufficient data from well-conducted clinical trials to recommend their use in patients with alcoholic liver disease.

   Simultaneous determination of abietane-type diterpenes, flavonolignans and phenolic compounds in compound preparations of Silybum marianum and Salvia miltiorrhiza by HPLC-DAD-ESI MS.:J Pharm Biomed Anal. 2005 Jul 1;38(3):564-70. Epub 2005 Feb 26.Zhao Y, Chen B, Yao S.Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research, Ministry of Education, Hunan Normal University, Changsha 410081, China.[PMID: 15925261]

 A gradient HPLC-DAD-ESI MS method has been developed for simultaneous determination of multiple bioactive compounds such as abietane-type diterpenes, flavonolignans and phenolic compounds in compound preparations of Silybum marianum and Salvia miltiorrhiza. The separation was completed on an ODS column using 0.5% (v/v) formic acid aqueous solution and methanol as gradient mobiles. Fourteen components can be identified by ESI MS working on ESI(-) and ESI(+) switching mode, respectively. Ten components can be quantified by using external standard method with UV detecting at 254 and 280 nm, respectively. The correlation coefficients of all the calibration curves were found to be higher than 0.992. The recoveries of the standards were about 96-101%. Besides quantification of the components, the chromatograms acquired by this method can be used as the bioactive components fingerprints for the quality control of compound preparations of S. marianum and S. miltiorrhiza.
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   New prospects of using milk thistle (Silybum marianum) preparations.:Eksp Klin Farmakol. 2004 Jul-Aug;67(4):77-80.Samigullina LI, Lazareva DN.[PMID: 15500055]

 Well-known and newfound properties of milk thistle (Silybum marianum) preparations are considered (including hepatoprotector, immunostimulant, antiproliferative, antisclerotic, etc.) and the ways of their realization are analyzed. Good prospects of further development of the drugs based on this medicinal plant are emphasized and the possibilities of wider clinical use are discussed.

   The clinical utility of milk thistle (Silybum marianum) in cirrhosis of the liver.:J Herb Pharmacother. 2002;2(2):11-7.Boerth J, Strong KM.University of Connecticut College of Pharmacy, USA.[PMID: 15277093]

 Milk thistle (Silybum marianum) is a flowering herb utilized for its potentially protective effects on the liver. Although the mechanism of action is not fully understood, one explanation may be that it concentrates in the hepatocytes and competes with toxins for hepatocyte binding and penetration. Preliminary clinical evaluations of milk thistle for cirrhosis of the liver indicate potential benefits in healthier patients with alcoholic cirrhosis. However, major flaws in many of the studies make it difficult to draw solid conclusions. Milk thistle appears to be relatively safe, even with long-term use.

   Extraction of nutraceuticals from milk thistle: part II. Extraction with organic solvents.:Appl Biochem Biotechnol. 2003 Spring;105 -108:891-903.Wallace SN, Carrier DJ, Clausen E. Department of Biological and Agricultural Engineering, University of Arkansas, 203 Engineering Hall, Fayetteville, AR 72701, USA.[PMID: 12721426]

 Seeds from milk thistle (Silybum marianum Gaert L.) contain flavanolignan and dihydroflavanol compounds that have interesting and important therapeutic activities. The recovery of these silymarin compounds generally involves a two-step defatting and extraction process using organic solvents. This study examined the batch, single-stage extraction of whole and defatted seeds using ethanol, methanol, acetonitrile, and acetone as the solvents. In extracting defatted milk thistle seeds with organic solvents, extraction with ethanol resulted in the highest silymarin yield, although some potential degradation was observed. The maximum yields of taxifolin, silychristin, silydianin, silybinin A, and silybinin B in ethanol were 0.6, 4.0, 0.4, 4.0, and 7.0 mg/g of defatted seed, respectively. However, if silybinin A were the diastereoisomer of choice, methanol would be the preferred extraction solvent because it yielded the highest silybinin A to silybinin B ratio. Interestingly, lipid removal is an important extraction step, because defatted material yields twice the silymarin concentration.

   Extraction of nutraceuticals from milk thistle: I. Hot water extraction.:Appl Biochem Biotechnol. 2003 Spring;105 -108:881-9.Barreto JF, Wallace SN, Carrier DJ, Clausen EC. Department of Chemical Engineering, University of Arkansas, 3202 Bell Engineering Center, Fayetteville, AR 72701, USA.[PMID: 12721425]

 Milk thistle contains compounds that display hepatoxic protection properties. We examined the batch extraction of silymarin compounds from milk thistle seed meal in 50, 70, 85, and 100 degrees C water as a function of time. After 210 min of extraction at 100 degrees C, the yield of taxifolin was 1.2 mg/g of seed, a 6.2-fold increase over the results obtained in a Soxhlet extraction with ethanol on pretreated (defatted) seeds. Similarly, the yield of silychristin was 5.0 mg/g of seed, a 3.8-fold increase. The yields of silybinin A and silybinin B were 1.8 and 3.3 mg/g of seed, respectively, or roughly 30% of the Soxhlet yield. The ratios of the extracted compounds, and particularly the ratios at long extraction times, showed that the more polar compounds (taxifolin and silychristin) were preferentially extracted at 85 degrees C, while the less polar silybinin was favored at 100 degrees C.

   Silymarin protects dopaminergic neurons against lipopolysaccharide-induced neurotoxicity by inhibiting microglia activation.:Eur J Neurosci. 2002 Dec;16(11):2103-12.Wang MJ, Lin WW, Chen HL, Chang YH, Ou HC, Kuo JS, Hong JS, Jeng KC.Department of Education and Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan.[PMID: 12473078]

 An inflammatory response in the central nervous system mediated by activation of microglia is a key event in the early stages of the development of neurodegenerative diseases. Silymarin is a polyphenolic flavanoid derived from milk thistle that has anti-inflammatory, cytoprotective and anticarcinogenic effects. In this study, we first investigated the neuroprotective effect of silymarin against lipopolysaccharide (LPS)-induced neurotoxicity in mesencephalic mixed neuron-glia cultures. The results showed that silymarin significantly inhibited the LPS-induced activation of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and nitric oxide (NO), and reduced the damage to dopaminergic neurons. Therefore, the inhibitory mechanisms of silymarin on microglia activation were studied further. The production of inducible nitric oxide synthase (iNOS) was studied in LPS-stimulated BV-2 cells as a model of microglia activation. Silymarin significantly reduced the LPS-induced nitrite, iNOS mRNA and protein levels in a dose-dependent manner. Moreover, LPS could induce the activation of p38 mitogen-activated protein kinase (MAPK) and c-jun N-terminal kinase but not extracellular signal-regulated kinase. The LPS-induced production of NO was inhibited by the selective p38 MAPK inhibitor SB203580. These results indicated that the p38 MAPK signalling pathway was involved in the LPS-induced NO production. However, the activation of p38 MAPK was not inhibited by silymarin. Nevertheless, silymarin could effectively reduce LPS-induced superoxide generation and nuclear factor kappaB (NF-kappaB) activation. It suggests that the inhibitory effect of silymarin on microglia activation is mediated through the inhibition of NF-kappaB activation.
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   Immunostimulatory effect of Silybum Marianum (milk thistle) extract.:Med Sci Monit. 2002 Nov;8(11):BR439-43.Wilasrusmee C, Kittur S, Shah G, Siddiqui J, Bruch D, Wilasrusmee S, Kittur DS.Department of Surgery SUNY Upstate Medical University, Syracuse, New York 13210, USA. kitturd@upstate.edu.[PMID: 12444368]

 BACKGROUND: Herbal products are increasingly used for their effects on the immune system. Milk Thistle, a commonly used herbal product is known to inhibit growth of certain tumors, although the mechanism of this effect remains unknown. Previously we have shown that Milk Thistle extracts stimulate neurons in culture. Since other drugs that affect the neuronal; system also affect the immune system, we investigated the effects of Milk Thistle on the immune system. MATERIAL/METHODS: Standardized Milk Thistle extract was studied in murine lymphocyte proliferation tests using Concanavalin A (ConA) as mitogen for non-specific stimulation and mixed lymphocyte culture (MLC) as allospecific stimulation. Th1 and Th2 cytokine levels in MLC were assayed by two antibody capture ELISA technique. All tests were performed in triplicate and repeated twice. RESULTS: We found that Milk Thistle is immunostimulatory in vitro. It increased lymphocyte proliferation in both mitogen and MLC assays. These effects of Milk Thistle were associated with an increase in interferon gamma, interleukin (IL)-4 and IL-10 cytokines in the MLC (table). This immunostimulatory effect increased in response to increasing doses of Milk Thistle. CONCLUSIONS: Our study has uncovered a novel effect of milk thistle on the immune system. This immunostimulatory effect may be of benefit in increasing the immunity to infectious diseases.

   Neurotrophic and neuroprotective effects of milk thistle (Silybum marianum) on neurons in culture.:J Mol Neurosci. 2002 Jun;18(3):265-9.Kittur S, Wilasrusmee S, Pedersen WA, Mattson MP, Straube-West K, Wilasrusmee C, Lubelt B, Kittur DS.Department of Neurology, SUNY Upstate Medical University, Syracuse, NY 13210, USA. kitturs@upstate.edu.[PMID: 12059045]

 Herbal products are being increasingly used as dietary supplements and therapeutic agents. However, much more research must be performed in order to determine the biological basis for their putative clinical effects. We tested the effects of milk thistle (Silybum marianum) extract on the differentiation and survival of cultured neural cells. Milk thistle enhanced nerve growth factor (NGF)-induced neurite outgrowth in PC-12 neural cells and prolonged their survival in culture. Milk thistle extract also protected cultured rat hippocampal neurons against oxidative stress-induced cell death. Our data demonstrate that milk thistle extract can promote neuronal differentiation and survival, suggesting potential benefits of chemicals in this plant on the nervous system.

   Milk thistle, a herbal supplement, decreases the activity of CYP3A4 and uridine diphosphoglucuronosyl transferase in human hepatocyte cultures..:Drug Metab Dispos. 2000 Nov;28(11):1270-3.Venkataramanan R, Ramachandran V, Komoroski BJ, Zhang S, Schiff PL, Strom SC.Department of Pharmaceutical Sciences School of Pharmacy, Pennsylvania, USA. rv+@pitt.edu.[PMID: 11038151]

 Milk thistle extract is one of the most commonly used nontraditional therapies, particularly in Germany. Milk thistle is known to contain a number of flavonolignans. We evaluated the effect of silymarin, on the activity of various hepatic drug-metabolizing enzymes in human hepatocyte cultures. Treatment with silymarin (0.1 and 0.25 mM) significantly reduced the activity of CYP3A4 enzyme (by 50 and 100%, respectively) as determined by the formation of 6-beta-hydroxy testosterone and the activity of uridine diphosphoglucuronosyl transferase (UGT1A6/9) (by 65 and 100%, respectively) as measured by the formation of 4-methylumbelliferone glucuronide. Silymarin (0.5 mM) also significantly decreased mitochondrial respiration as determined by MTT reduction in human hepatocytes. These observations point to the potential of silymarin to impair hepatic metabolism of certain coadministered drugs in humans. Indiscriminate use of herbal products may lead to altered pharmacokinetics of certain drugs and may result in increased toxicity of certain drugs.
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♣ last edit date:Jan 16th 2013 at 14:30