Research Update:Comfrey leaf or Symphytum officinale.

  seminal trace...Comfrey Leaf Extract.Comfrey extract.Symphytum officinale.CAS No.:084696-05-9.Comfrey extract;Extract of comfrey;Extract of comfrey leaf;Comfrey,Symphytum officinale, ext...

 


   Phytochemical info of Comfrey leaf or Symphytum officinale.

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 Definition:Comfrey leaf or Symphytum officinale are majorly composed of
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   Research Update:Comfrey leaf or Symphytum officinale.

  Efficacy of a comfrey root (Symphyti offic. radix) extract ointment in the treatment of patients with painful osteoarthritis of the knee: results of a double-blind, randomised, bicenter, placebo-controlled trial.:Phytomedicine. 2007 Jan;14(1):2-10. Epub 2006 Dec 13.Grube B, Gr¨¹nwald J, Krug L, Staiger C.Merck Selbstmedikation GmbH, R?sslerstrasse 96, 64293 Darmstadt, Germany.

 This randomised, double-blind, bicenter, placebo-controlled clinical trial investigated the effect of a daily application of 6g Kytta-Salbe f (3 x 2 g) over a 3 week period with patients suffering from painful osteoarthritis of the knee. The two hundred and twenty patients examined consisted of 153 women and 67 men of an average age of 57.9 years. On average, the complaints relating to osteoarthritis of the knee had persisted for 6.5 years. Two hundred and twenty patients were included in the Full Analysis Set (FAS) and safety collective, 186 (84.5%) in the Valid Case Analysis Set (VCAS) collective. In the course of the trial, the visual analog scale (VAS) total score (primary target value) in the verum group dropped by 51.6 mm (54.7%) and in the placebo group by 10.1 mm (10.7%). The average difference between the groups of 41.5 mm (95% confidence interval=34.8 to 48.2 mm) or 44.0% is significant (p<0.001). The significance is confirmed through the evaluation of the diary, the VCAS evaluation and the separate assessment of the two centres. This also applies to the separate assessment of the VAS total score following pain at rest and on movement. The WOMAC (Western Ontario and McMaster Universities) total score (secondary target value) also improved similar to the VAS total score. At the end of the trial, a reduction by 60.4 mm (58.0%) was recorded for the verum group and a reduction of 14.7 mm (14.1%) for the placebo group. The average group difference of 45.7 mm (95% confidence interval=37.1 to 54.3 mm) or 43.9% is significant (p<0.001). The difference between the treatment groups increased systematically and significantly, in parallel with the duration of the treatment. Thus, the superiority of the treatment with Kytta-Salbe f over that with the placebo is proven, even by means of the multi-factorial multivariate analysis for repetitive measurements. In respect of the explorative secondary target values SF-36 (quality of life), angle measurement (mobility of the knee), CGI (clinical global impression) and global assessment of efficacy by the physician and the patient, a significant superiority (p<0.001 each) of the verum group over the placebo group was also proven. The results suggest that the comfrey root extract ointment is well suited for the treatment of osteoarthritis of the knee. Pain is reduced, mobility of the knee improved and quality of life increased.

  Analysis of gene expression changes in relation to toxicity and tumorigenesis in the livers of Big Blue transgenic rats fed comfrey (Symphytum officinale).:BMC Bioinformatics. 2006 Sep 26;7 Suppl 2:S16.Mei N, Guo L, Zhang L, Shi L, Sun YA, Fung C, Moland CL, Dial SL, Fuscoe JC, Chen T.Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, FDA, Jefferson, AR 72079, USA. nan.mei@fda.hhs.gov.

 ABSTRACT : BACKGROUND : Comfrey is consumed by humans as a vegetable and a tea, and has been used as an herbal medicine for more than 2000 years. Comfrey, however, is hepatotoxic in livestock and humans and carcinogenic in experimental animals. Our previous study suggested that comfrey induces liver tumors by a genotoxic mechanism and that the pyrrolizidine alkaloids in the plant are responsible for mutation induction and tumor initiation in rat liver. RESULTS : In this study, we identified comfrey-induced gene expression profile in the livers of rats. Groups of 6 male transgenic Big Blue rats were fed a basal diet and a diet containing 8% comfrey roots, a dose that resulted in liver tumors in a previous carcinogenicity bioassay. The animals were treated for 12 weeks and sacrificed one day after the final treatment. We used a rat microarray containing 26,857 genes to perform genome-wide gene expression studies. Dietary comfrey resulted in marked changes in liver gene expression, as well as in significant decreases in the body weight and increases in liver mutant frequency. When a two-fold cutoff value and a P-value less than 0.01 were selected, 2,726 genes were identified as differentially expressed in comfrey-fed rats compared to control animals. Among these genes, there were 1,617 genes associated by Ingenuity Pathway Analysis with particular functions, and the differentially expressed genes in comfrey-fed rat livers were involved in metabolism, injury of endothelial cells, and liver injury and abnormalities, including liver fibrosis and cancer development. CONCLUSION : The gene expression profile provides us a better understanding of underlying mechanisms for comfrey-induced hepatic toxicity. Integration of gene expression changes with known pathological changes can be used to formulate a mechanistic scheme for comfrey-induced liver toxicity and tumorigenesis.

  Rat toxicogenomic study reveals analytical consistency across microarray platforms.:Nat Biotechnol. 2006 Sep;24(9):1162-9.Guo L, Lobenhofer EK, Wang C, Shippy R, Harris SC, Zhang L, Mei N, Chen T, Herman D, Goodsaid FM, Hurban P, Phillips KL, Xu J, Deng X, Sun YA, Tong W, Dragan YP, Shi L.National Center for Toxicological Research, US Food and Drug Administration, Jefferson, Arkansas 72079, USA.

 To validate and extend the findings of the MicroArray Quality Control (MAQC) project, a biologically relevant toxicogenomics data set was generated using 36 RNA samples from rats treated with three chemicals (aristolochic acid, riddelliine and comfrey) and each sample was hybridized to four microarray platforms. The MAQC project assessed concordance in intersite and cross-platform comparisons and the impact of gene selection methods on the reproducibility of profiling data in terms of differentially expressed genes using distinct reference RNA samples. The real-world toxicogenomic data set reported here showed high concordance in intersite and cross-platform comparisons. Further, gene lists generated by fold-change ranking were more reproducible than those obtained by t-test P value or Significance Analysis of Microarrays. Finally, gene lists generated by fold-change ranking with a nonstringent P-value cutoff showed increased consistency in Gene Ontology terms and pathways, and hence the biological impact of chemical exposure could be reliably deduced from all platforms analyzed.

  Drug-induced liver disease.:Curr Opin Gastroenterol. 2002 May;18(3):307-13.Lewis JH.Georgetown University Medical Center, Washington, District of Columbia 20007, USA. lewisjh@gunet.georgetown.edu

 Although the year 2001 did not see any prescription drugs withdrawn because of drug-induced liver disease, the US Food and Drug Administration requested that dietary supplements containing comfrey be taken off the market because of the danger of hepatic injury. The Food and Drug Administration remains very involved in the process by which drug-induced liver disease can be detected early in drug development and in the determination of how best to prevent hepatotoxicity after drug approval. A workshop on drug-induced liver disease cosponsored by the Food and Drug Administration, the Pharmaceutical Research and Manufacturers Association, and the American Association for the Study of Liver Diseases was held in Washington, DC, in February 2001, and the resulting white paper outlined several areas for research. A number of agents were newly described as causing various forms of liver injury, and several others had drug-induced liver disease confirmed by additional reports. Several investigators dealt with the difficulties inherent in establishing causality of drug-induced liver disease and the potential negative consequences of wrongly attributing hepatotoxicity to a particular agent. In one recent series, more than half the instances of alleged drug-induced liver disease were found to have other causes, often leading to a delay in the actual diagnosis and appropriate management. Case reports in particular were often misleading. Although several drug assessment scales have been developed, none appears to be foolproof.

  Topical symphytum herb concentrate cream against myalgia: a randomized controlled double-blind clinical study.:Adv Ther. 2005 Nov-Dec;22(6):681-92.Kucera M, Barna M, Hor¨¤cek O, K¨¤lal J, Kucera A, Hlad¨¬kova M.Department of Sports Medicine and Rehabilitation, 2nd Medical Faculty, Charles University in Prague, Czech Republic.

 The effectiveness and tolerability of the topical Symphytum product Traumaplant (Harras Pharma Curarina, M¨¹nchen, Germany) (10% active ingredient of a 2.5:1 aqueous-ethanolic pressed concentrate of freshly harvested, cultivated comfrey herb [Symphytum uplandicum Nyman], corresponding to 25 g of fresh herb per 100 g of cream) in the treatment of patients with myalgia (n=104) were tested against a 1% reference product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n=111). The primary efficacy parameter in this double-blind, reference- controlled, randomized, multicenter study of 215 patients with pain in the lower and upper back was pain in motion, assessed with the aid of a visual analogue scale. Secondary efficacy parameters included pain at rest, pain on palpation, and functional impairment. With high concentrations of the treatment product, amelioration of pain on active motion (P<5 x 10 -9 ), pain at rest (P<.001), and pain on palpation (P=5 x 10 -5 ) was significantly more pronounced than that attained with the reference product and was clinically highly relevant. A number needed to treat of 3.2 was calculated from the study results. Global efficacy was significantly better (P=1 x 10 -8 ) and onset of effects was faster (P=4 x 10 -7 ) with the high-concentration product. Tolerability of the highly concentrated study product was good to excellent in all patients. Study results confirm the known anti-inflammatory and analgesic effects of topical (Symphytum cream. As a new finding, applicability in certain forms of back pain can be concluded.


  Efficacy of a comfrey root extract ointment in comparison to a diclofenac gel in the treatment of ankle distortions: results of an observer-blind, randomized, multicenter study.:Predel HG, Giannetti B, Koll R, Bulitta M, Staiger C.Merck Selbstmedikation GmbH, Roesslerstr. 96, D-64293 Darmstadt, Germany.

 In the treatment of minor blunt injuries several topical drugs are known to have anti-inflammatory and analgesic properties. They represent, however, two fundamentally different major pharmacological therapy approaches: the "chemical-synthetical" and the "phytotherapeutical" approach. The main objective of this trial (CODEC_2004) was to compare the efficacy and tolerability of an ointment of Comfrey extract (Extr. Rad. Symphyti) with that of a Diclofenac gel in the treatment of acute unilateral ankle sprain (distortion). In a single-blind, controlled, randomized, parallel-group, multicenter and confirmatory clinical trial outpatients with acute unilateral ankle sprains (n=164, mean age 29.0 years, 47.6% female) received either a 6 cm long ointment layer of Kytta-Salbe f (Comfrey extract) (n=82) or of Diclofenac gel containing 1.16 g of diclofenac diethylamine salt (n=82) for 7 +/- 1 days, four times a day. Primary variable was the area-under-the-curve (AUC) of the pain reaction to pressure on the injured area measured by a calibrated caliper (tonometer). Secondary variables were the circumference of the joint (swelling; figure-of-eight method), the individual spontaneous pain sensation at rest and at movement according to a Visual Analogue Scale (VAS), the judgment of impaired movements of the injured joint by the method of "neutral-zero", consumption of rescue medication (paracetamol), as well as the global efficacy evaluation and the global assessment of tolerability (both by physician and patient, 4 ranks). In this study the primary variable was also to be validated prospectively. It was confirmatorily shown that Comfrey extract is non-inferior to diclofenac. The 95% confidence interval for the AUC (Comfrey extract minus Diclofenac gel) was 19.01-103.09h*N/cm2 and was completely above the margin of non-inferiority. Moreover, the results of the primary and secondary variables indicate that Comfrey extract may be superior to Diclofenac gel.

  Cosmeceuticals containing herbs: fact, fiction, and future.:Dermatol Surg. 2005 Jul;31(7 Pt 2):873-80; discussion 880. Review.Thornfeldt C.Oregon Health Sciences University, Portland, Oregon, USA. drcarl@epionce.com

 BACKGROUND: Modern medicine is rooted in ethnobotanical traditions using indigenous flora to treat symptoms of human diseases or to improve specific aspects of the body condition. Herbal medicine is now used by over half of the American population. Yet the American medical community generally lacks knowledge of the function, metabolism, interaction, adverse reactions, and preparation of herbal products. OBJECTIVE: Because over 60 botanicals are marketed in cosmeceutical formulations, dermatologists need to obtain working knowledge of the major botanicals. The preparation, traditional uses, mechanisms of action, human clinical data, adverse reactions, and interactions all impact herbal efficacy and are discussed below. METHOD: English-language medical journal and symposium searches. RESULTS: The most important botanicals pertaining to dermatologic uses, such as cosmeceuticals, include teas, soy, pomegranate, date, grape seed, Pycnogenol, horse chestnut, German chamomile, curcumin, comfrey, allantoin, and aloe. All are documented to treat dermatologic conditions. Only green and black tea, soy, pomegranate, and date have published clinical trials for the treatment of parameters of extrinsic aging. CONCLUSIONS: Preparation of botanical-based cosmeceuticals is complex. Very few of these products are supported by evidence-based science.

  Investigation of pyrrolizidine alkaloids and their N-oxides in commercial comfrey-containing products and botanical materials by liquid chromatography electrospray ionization mass spectrometry.:J AOAC Int. 2005 Mar-Apr;88(2):406-12.Altamirano JC, Gratz SR, Wolnik KA.U.S. Food and Drug Administration, Forensic Chemistry Center, Cincinnati, OH 45237-3097, USA.

 Pyrrolizidine alkaloids (PAs) and their N-oxides are found in several plant families throughout the world. PAs are potentially toxic to the liver and/or lungs in humans and may cause acute liver failure, cirrhosis, pneumonitis, or pulmonary hypertension. PAs are also carcinogenic to animals, and they have been linked to the development of hepatocellular and skin squamous cell carcinomas as well as liver angiosarcomas. According to experimental studies, the quantity of PAs in some herbal teas and dietary supplements is sufficient to be carcinogenic in exposed individuals. A method for the extraction and identification of PAs and their N-oxides in botanical materials and commercial comfrey-containing products has been developed using liquid chromatography electrospray ionization mass spectrometry. Following optimization of the extraction procedure and the chromatographic conditions, the method was applied to the analysis of 10 herbal remedies. All of the products that were labeled to contain comfrey were found to contain measurable quantities of PAs.

  Mutagenicity of comfrey (Symphytum Officinale) in rat liver.:Br J Cancer. 2005 Mar 14;92(5):873-5.Mei N, Guo L, Fu PP, Heflich RH, Chen T.Division of Genetic and Reproductive Toxicology, National Center for Toxicological Research, US Food and Drug Administration, HFT-130, 3900 NCTR Road, Jefferson, AR 72079, USA.

 Comfrey is a rat liver toxin and carcinogen that has been used as a vegetable and herbal remedy by humans. In order to evaluate the mechanisms underlying its carcinogenicity, we examined the mutagenicity of comfrey in the transgenic Big Blue rat model. Our results indicate that comfrey is mutagenic in rat liver and the types of mutations induced by comfrey suggest that its tumorigenicity results from the genotoxicity of pyrrolizidine alkaloids in the plant.

  Physical and chemical characterization of allantoin-beta-cyclodextrin inclusion complex:Rev Med Chir Soc Med Nat Iasi. 2004 Jan-Mar;108(1):173-6. Romanian.Gafi?anu C, Popescu C, Singurel G, Macocinschi D.Universitatea de Medicin? ?i Farmacie Gr.T. Popa Ia?i, Facultatea de Farmacie, Disciplina de Tehnologie farmaceutic? ?i Biofarmacie.

 Solubility and bioavailability of poorly water-soluble drugs have been improved by the preparation as cyclodextrin inclusion complexes. The aim of this study is to obtain and characterize the inclusion compound allantoin-beta-cyclodextrin. Allantoin is a vegetable drug, poorly water-soluble (1:300), isolated from roots of Symphytum off. The solid inclusion complex was prepared by mixing with a adequate quantity of water and drying at 50 degrees C to the constant weight. It was used a different proportions between allantoin and beta-cyclodextrin (1:4, 3:7). The inclusion complex was characterized with RMN and IR spectrum and compared with results obtained from beta-cyclodextrin and allantoin alone. The experimental results were demonstrated the inclusion of allantoin in the lipophilic cavity of beta-cyclodextrin without physico-chemical changes.


  Efficacy and safety of topically applied Symphytum herb extract cream in the treatment of ankle distortion: results of a randomized controlled clinical double blind study.:Wien Med Wochenschr. 2004 Nov;154(21-22):498-507.Kucera M, Barna M, Hor¨¢cek O, Kov¨¢rikov¨¢ J, Kucera A.Department for Sports Medicine and Rehabilitation, 2nd Medical Faculty of the Charles University Prague, Prague. miroslav.kucera@lfmotol.cuni.cz

 In a controlled, double blind, randomized multicentre study, the efficacy and safety of the topical comfrey product Traumaplant (10% active ingredient of a 2.5:1 aqueous ethanolic pressed juice of freshly harvested, cultivated comfrey herb (Symphytum x uplandicum NYMAN), corresponding to 25 g of fresh herb per 100 g of cream; n = 104) was tested against a 1% product (corresponding to 2.5 g of fresh comfrey herb in 100 g of cream; n = 99) in 203 patients with acute ankle distortion. With the high concentration, decrease of the scores for pain on active motion, pain at rest and functional impairment was highly significant and clinically relevant on days T3-4 as well as T7 (p < 0.001). Amelioration of swellings as compared to reference was also significant on day 3-4 (p < 0.01). Efficacy was judged good to excellent in 85.6% of cases with verum and in 65.7% of cases with reference on day 3-4. Overall tolerability was excellent.

  Efficacy and tolerance of a comfrey root extract (Extr. Rad. Symphyti) in the treatment of ankle distorsions: results of a multicenter, randomized, placebo-controlled, double-blind study.:Phytomedicine. 2004 Sep;11(6):470-7.Koll R, Buhr M, Dieter R, Pabst H, Predel HG, Petrowicz O, Giannetti B, Klingenburg S, Staiger C.Merck Selbstmedikation GmbH, Roesslerstr. 96, D-64293 Darmstadt, Germany.

 Comfrey (Symphytum officinale L.) is a medicinal plant with anti-inflammatory, analgesic and tissue regenerating properties. In a double-blind, multicenter, randomized, placebo-controlled, group comparison study on patients suffering from unilateral acute ankle sprains (n = 142, mean age 31.8 years, 78.9% male), the percutaneous efficacy of an ointment of comfrey extract (Kytta-Salbe f, four treatments per day for 8 days) was confirmed decisively. Compared to placebo, the active treatment was clearly superior regarding the reduction of pain (tonometric measurement, p<0.0001, as the primary efficacy variable) and ankle edema (figure-of-eight method, p = 0.0001). Statistically significant differences between active treatment and placebo could also be shown for ankle mobility (neutral zero method), and global efficacy. Under active treatment, no adverse drug reactions were reported. The good local and global tolerance of the trial medication could also be confirmed. The study results are consistent with the known pre-clinical and clinical data concerning comfrey.

  A rapid cleanup method for the isolation and concentration of pyrrolizidine alkaloids in comfrey root.:J AOAC Int. 2004 Sep-Oct;87(5):1049-57.Gray DE, Porter A, O'Neill T, Harris RK, Rottinghaus GE.Midwest Research Institute, 425 Volker Blvd, Kansas City, MO 64110-2299, USA. dgray@mriresearch.org

 Preparations from comfrey (Symphytum officinale and S. x uplandicum) root and leaf contain varying levels of the hepatotoxic pyrrolizidine alkaloids (PAs). Reference compounds for comfrey are not commercially available, and there is currently no rapid extraction or analytical method capable of determining low levels in raw materials or as adulterants in commercially available extracts. A solid-phase extraction (SPE) method was developed using an Ergosil cleanup column that specifically binds the PAs. With this method, powdered comfrey root was extracted by sonication and shaking with basic chloroform. The extract was applied to the cleanup column under vacuum, washed with 2 mL acetone-chloroform (8 + 2, v/v) followed by 2 mL petroleum ether to remove excess chloroform. The column was dried under vacuum, and the PAs were eluted with 2 successive 1 mL aliquots methanol. Percent recoveries of the PAs following Ergosil SPE had an overall average of 96.8%, with RSD of 3.8% over a range of 1.0 to 25.0 g extracted in 100 mL. Average precision of the method (n = 3 over 4 extraction concentrations) gave an overall RSD of 6.0% for the 5 alkaloids, with a range of 0.8% (5 g in 100 mL) to 11.2% (25 g in 100 mL). Recovery optimization testing showed that 1.0 g comfrey root extracted in 100 mL yielded the greatest recovery (% dry weight) of the PAs, with an extraction efficiency and accuracy of 94.2%, and RSD of 1.7% (n = 9). The unique properties of the Ergosil cleanup column provide rapid sample cleanup, volume reduction, and concentration of PAs from comfrey extracts, and allow the eluant to be analyzed directly by traditional chromatographic methods.

  Analysis of herbal teas made from the leaves of comfrey (Symphytum officinale): reduction of N-oxides results in order of magnitude increases in the measurable concentration of pyrrolizidine alkaloids.:Public Health Nutr. 2004 Oct;7(7):919-24. Oberlies NH, Kim NC, Brine DR, Collins BJ, Handy RW, Sparacino CM, Wani MC, Wall ME.Natural Products Laboratory, RTI International, Research Triangle Park, NC 27709, USA. oberlies@rti.org

 OBJECTIVES: To determine the relative quantities of two hepatotoxic pyrrolizidine alkaloids, symphytine and echimidine, in teas prepared from comfrey leaves (Symphytum officinale), and to determine the potential contribution of the N-oxide forms of these alkaloids to levels of the parent alkaloids. DESIGN: Comfrey leaves were purchased from three commercial sources and used to prepare tea in a manner consistent with the methods used by consumers. An extraction scheme was devised for extraction of the alkaloids, and a gas chromatographic method was developed to quantify the two major alkaloids, symphytine and echimidine. Recognising that the N-oxide derivatives of these alkaloids have also been identified in comfrey preparations, chemical reduction was applied to determine the total quantities of the alkaloids as free bases and as N-oxide derivatives. RESULTS: The concentration of symphytine and echimidine varied considerably between teas prepared from leaves purchased from the different vendors of plant material. Moreover, a much higher concentration of symphytine was found in the tea when steps were included to reduce N-oxides prior to analysis. The treatment of pure symphytine with hot water did not generate the N-oxide derivative de novo. CONCLUSIONS: Since the pyrrolizidine alkaloids are known to be hepatotoxic, consumption of herbal teas made from comfrey leaves may be ill-advised. The concentration of pyrrolizidine alkaloids in such teas may be underestimated substantially unless the concentration of N-oxides is taken into consideration.

  Evaporative light scattering detection of pyrrolizidine alkaloids.:Phytochem Anal. 2004 Jan-Feb;15(1):36-9.Schaneberg BT, Molyneux RJ, Khan IA.National Center for Natural Products Research, Research Institute of Pharmaceutical Sciences, School of Pharmacy, The University of Mississippi, University, MS 38677, USA.

 A reverse-phase high-performance liquid chromatography method utilizing evaporative light scattering detection (ELSD) has been developed for the simultaneous detection of hepatotoxic pyrrolizidine alkaloids with and without chromophores, namely, riddelliine, riddelliine N-oxide, senecionine, senecionine N-oxide, seneciphylline, retrorsine, integerrimine, lasiocarpine and heliotrine. Pyrrolizidine alkaloids were detected in five plant extracts (Senecio spartioides, S. douglasii var. longilobus, S. jacobaea, S. intergerrimus var. exaltatus and Symphytum officinale). The detection of heliotrine (which does not contain a chromophore) was much improved by ELSD compared with photodiode array detection.


  Simultaneous analysis of hepatotoxic pyrrolizidine alkaloids and N-oxides in comfrey root by LC-ion trap mass spectrometry.:Analyst. 2004 Feb;129(2):150-6. Epub 2004 Jan 8.Wuilloud JC, Gratze SR, Gamble BM, Wolnik KA.US Food and Drug Administration, Forensic Chemistry Center, Cincinnati, Ohio 45237-3097, USA.

 The purpose of the current study was to develop a LC-MS(n) method for the analysis of pyrrolizidine alkaloids (PAs) in comfrey. Published data presents an extensive list of PAs and their N-oxides present in comfrey. However, standards are not commercially available for any of the PAs typically present in comfrey. Those PAs that are not stereoisomers were readily resolved on a C(18) column using a water-acetonitrile gradient as the mobile phase. The use of a selective technique, LC-MS/MS, allowed us to identify groups of PAs and their N-oxides, as well as identify the number of PAs present in each group, including those that were not completely resolved chromatographically.

  Therapeutic characteristance and tolerance of topical comfrey preparations. Results of an observational study of patients.:Fortschr Med Orig. 2002;120(1):1-9. German.Koll R, Klingenburg S.Merck Selbstmedikation GmbH, Darmstadt.

 AIM: To analyze the anti-inflammatory and analgetic properties of the topical comfrey, preparations Kytta-Salbe f, Kytta-Plasma f and Kytta-Balsam f applied to bruises, sprains and distortions and painful conditions of the muscles and joints. METHOD: A prospective open multicentric observational study complying with paragraph 67(6) of the AMG and involving 162 general practitioners. During the two-week period of observation, the patients received an average of one to three applications of the comfrey preparation per day. All 492 questionnaires were evaluated. Efficacy and tolerability were assessed by both physician and patient. RESULTS: Pain at rest and on movement, as also tenderness, improved in the overall observation group by an average of 45-47%. The duration of morning joint stiffness decreased from 20 minutes initially to 3 minutes. During the course of treatment with comfrey, more than two-thirds of the patients were able to reduce or even discontinue their intake of non-steroidal anti-inflammatory drugs and other specific concomitant medication. In most of the cases, both effectiveness and tolerability were assessed to be excellent or good. CONCLUSION: The results of the study confirm the effectiveness and tolerability of the topical comfrey preparation investigated in the treatment of bruises, sprains and distortions as well as painful conditions affecting muscles and joints.

  Review of abnormal laboratory test results and toxic effects due to use of herbal medicines.:Am J Clin Pathol. 2003 Jul;120(1):127-37. Review.Dasgupta A.Dept of Pathology and Laboratory Medicine, University of Texas-Houston Medical School, 6431 Fannin, MSB 2.292, Houston, TX 77030, USA.

 Herbal medicines are used widely in the United States, and according to a recent survey, the majority of people who use herbal medicines do not inform their physicians about their use. Herbal medicines can cause abnormal test results and confusion in proper diagnosis. Herbal medicines can alter test results by direct interference with certain immunoassays. Drugherb interactions can result in unexpected concentrations of therapeutic drugs. For example, low concentrations of several drugs (e.g., cyclosporine, theophylline, digoxin) can be observed in patients who initiated self-medication with St John's wort. Herbal medicines can alter physiology, and these changes can be reflected in abnormal test results. For example, kavakava can cause drug-induced hepatitis, leading to unexpected high concentrations of liver enzymes. Use of toxic herbal products such as ma huang (an ephedra-containing herbal product), Chan Su, and comfrey may cause death. Other toxic effects of herbal medicines include cardiovascular toxic effects, hematologic toxic effects, neurotoxic effects, nephrotoxic effects, carcinogenic effects, and allergic reactions.

  Novel biologically active polymer of 3-(3,4-dihydroxyphenyl)glyceric acid from two types of the comphrey Symphytum asperum and S. caucasicvum (Boraginoceae).:Bioorg Khim. 2002 Jul-Aug;28(4):362-6. Russian.Barbakadze VV, Kemertelidze EP, Targamadze IL, Shashkov AS, Usov AI.Kutateladze Institute of Pharmacochemistry, Academy of Sciences of Georgia, ul. P. Saradzhishvili 36, Tbilisi, 380059 Georgia.

 Two high-molecular water-soluble preparations with high anticomplement and antioxidant activity were isolated from the roots of Symphytum asperum and S. caucasicum. Their main chemical constituent was found to be poly[oxy-1-carboxy-2-(3,4-dihydroxyphenyl)ethylene] according to IR and NMR spectroscopy. The English version of the paper: Russian Journal of Bioorganic Chemistry, 2002, vol. 28, no. 4; see also http://www.maik.ru.

  Simultaneous determination of N-oxides and free bases of pyrrolizidine alkaloids by cation-exchange solid-phase extraction and ion-pair high-performance liquid chromatography.:J Chromatogr A. 2002 Mar 8;949(1-2):249-62.Mroczek T, Glowniak K, Wlaszczyk A.Department of Pharmacognosy, Medical University, Lublin, Poland.

 Cation-exchange solid-phase extraction using LiChrolut SCX (Merck, Darmstadt) cartridges filled with polymeric strong cation-exchanger enabled efficient isolation of both N-oxides and free bases of pyrrolizidine alkaloids (PAs). The recoveries were about 80% for retrorsine-N-oxide, 90% for retrorsine and 100% for senkirkine and were assessed both by TLC-densitometry and ion-pair high-performance liquid chromatography (HPIPC) on Hypersil BDS C8 stationary phase and hexane-l-sulfonic acid as ion-pairing agent. The applied HPIPC gradient procedure was suitable for separation of PAs with various types of structures (N-oxides, free bases, otonecine-PAs). The method limits of detection and quantitation, respectively, ranged from 0.06 ng/microl (senecionine) and 0.2 ng/microl (senkirkine) to 0.1 and 0.35 ng/microl for retrorsine-N-oxide. For each component calibrated by linear regression method, correlation coefficients were higher than 0.9995 (six-point calibration from 4 to 100 microg/ml). The elaborated procedure was used in searching for PAs in plant derived samples from Symphytum sp. (comfrey), Petasites hybridus and Petasites albus (butterbur), Tussilago farfara (coltsfoot), Emilia coccinea (tassel flower) and Doronicum columnae (leopard's bane). For the last three samples macrocyclic PAs (senecionine, senecionine-N-oxide. senkirkine) have been detected for the first time. Details of precision of the analyses are also included.


  Antifungal activity of aqueous extracts from the leaf of cowparsnip and comfrey.:Izv Akad Nauk Ser Biol. 2001 Jul-Aug;(4):435-41. Russian.Karavaev VA, Solntsev MK, Iurina TP, Iurina EV, Poliakova IB, Kuznetsov AM.Department of Physics, Moscow State University, Moscow, 119899 Russia.

 We found that extracts from the leaves of medicinal comfrey and cowparsnip strongly inhibit the germination of Erysiphe graminis conidia and uredospores of Puccinia graminis. Spraying wheat seedlings with these extracts, in contrast to the irrigation of soil, markedly diminished infection in plants with powdery mildew. Antifungal activity in vitro and protective activity (when plants were sprayed) correlated with the level of phenolic compounds in these extracts. Experiments with healthy plants have demonstrated that the photosynthetic apparatus of wheat plants is stimulated by extracts. Spraying seedlings with the extracts resulted in an increased rate of O2 evolution calculated per unit of chlorophyll, an increase in the ratio (FM-FT)/FT in the experiments that recorded slow fluorescence induction, an increase in the relative light intensity of band A, and a decrease of relative intensity of band C in experiments with thermoluminescence of wheat leaves. These results provide evidence that the protective activity of comfrey and cowparsnip extracts is associated with their action on the pathogenic fungus and with the activation of natural defense reactions of the host plant.

  Isolation of symlandine from the roots of common comfrey (Symphytum officinale) using countercurrent chromatography.:J Nat Prod. 2001 Feb;64(2):251-3.Kim NC, Oberlies NH, Brine DR, Handy RW, Wani MC, Wall ME.Chemistry and Life Sciences, Research Triangle Institute, 3040 Cornwallis Road, Research Triangle Park, North Carolina 27709, USA.

 Three pyrrolizidine alkaloids, symlandine, symphytine, and echimidine (1-3), were isolated from the roots of Symphytum officinale using a one-step countercurrent chromatography procedure. The structures of 1-3 were confirmed by several spectroscopic techniques including 2D NMR methods. This is the first description of the separation of symlandine (1) from its stereoisomer, symphytine (2).

  The efficacy and safety of comfrey.:Public Health Nutr. 2000 Dec;3(4A):501-8. Review.Stickel F, Seitz HK.Department of Medicine I, Division of Gastroenterology and Hepatology, University of Erlangen-Nuernberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. felix.stickel@med1.med.uni-erlangen.de

 Herbal medication has gathered increasing recognition in recent years with regard to both treatment options and health hazards. Pyrrolizidine alkaloids have been associated with substantial toxicity after their ingestion as tea and in the setting of contaminated cereals have led to endemic outbreaks in Jamaica, India and Afghanistan. In Western Europe, comfrey has been applied for inflammatory disorders such as arthritis, thrombophlebitis and gout and as a treatment for diarrhoea. Only recently was the use of comfrey leaves recognized as a substantial health hazard with hepatic toxicity in humans and carcinogenic potential in rodents. These effects are most likely due to various hepatotoxic pyrrolizidine alkaloids such as lasiocarpine and symphytine, and their related N-oxides. The mechanisms by which toxicity and mutagenicity are conveyed are still not fully understood, but seem to be mediated through a toxic mechanism related to the biotransformation of alkaloids by hepatic microsomal enzymes. This produces highly reactive pyrroles which act as powerful alkylating agents. The main liver injury caused by comfrey (Symphytum officinale) is veno-occlusive disease, a non-thrombotic obliteration of small hepatic veins leading to cirrhosis and eventually liver failure. Patients may present with either acute or chronic clinical signs with portal hypertension, hepatomegaly and abdominal pain as the main features. Therapeutic approaches include avoiding intake and, if hepatic failure is imminent, liver transplantation. In view of the known serious hazards and the ban on distributing comfrey in Germany and Canada, it is difficult to understand why comfrey is still freely available in the United States.

  Analysis, separation, and bioassay of pyrrolizidine alkaloids from comfrey (Symphytum officinale).:Nat Toxins. 1996;4(4):163-7.Couet CE, Crews C, Hanley AB.CSL Food Science Laboratory, Norwich Research Park, Colney, Norfolk, United Kingdom.

 Pyrrolizidine alkaloids have been linked to liver and lung cancers and a range of other deleterious effects. As with many natural toxicants, major problems arise in determining the effects of the different members of the class and the importance of various forms of ingestion. In this study we have investigated the levels of pyrrolizidine alkaloids in comfrey (Symphytum officinale), determined the levels in different parts of the plant and in herbal remedies, separated the alkaloids into two main groups--the principal parent alkaloids and the corresponding N-oxides--and, finally, carried out a simple bioassay based upon the mutagenic capability of the separated compounds in a human cell line. We conclude that the part of the plant ingested is important in terms of alkaloid challenge and that the effect of two of the major groups of alkaloids individually is different from that of alkaloids in the whole plant extract.

  Determination of pyrrolizidine alkaloids in commercial comfrey products (Symphytum sp.).:J Pharm Sci. 1994 May;83(5):649-53.Betz JM, Eppley RM, Taylor WC, Andrzejewski D.Center for Food Safety and Applied Nutrition, Food and Drug Administration, Washington, DC 20204.

 The presence of hepatotoxic pyrrolizidine alkaloids in comfrey (Symphytum sp.) and the widespread use of decoctions of this plant as a beverage (herbal tea) are of increasing concern. A method for the extraction and solid-phase concentration and capillary gas chromatographic determination of these alkaloids and their N-oxides in botanical materials has been developed and was applied to eleven comfrey-containing products purchased from retail health-food outlets in the Washington, DC, area during May-June 1989. Nine of the 11 products were found to contain measurable quantities of one or more of the alkaloids, in ranges from 0.1 to 400.0 ppm. Products containing comfrey leaf in combination with one or more other ingredients were found to contain the lowest alkaloid levels. Highest levels were found in bulk comfrey root, followed by bulk comfrey leaf. The species of the bulk material was verified by thin-layer chromatography and other means.


  Hepatocyte membrane injury and bleb formation following low dose comfrey toxicity in rats.:Int J Exp Pathol. 1993 Apr;74(2):211-7.Yeong ML, Wakefield SJ, Ford HC.Department of Pathology, Wellington School of Medicine, New Zealand.

 Comfrey, a popular herbal remedy, contains hepatotoxic pyrrolizidine alkaloids and has been implicated in recent human toxicity. Although alkaloids from other plant sources have been extensively researched, studies on the hepatotoxic effects of comfrey alkaloids are scant. The effects of high dose comfrey toxicity have been studied and the present investigation was undertaken to identify changes associated with relatively low dose toxicity. Eight young adult rats were dosed weekly for six weeks with 50 mg/kg of comfrey derived alkaloids. The animals were dissected one week after the last dose and the livers examined by light and electron microscopy. Changes at the light microscopic level showed vascular congestion, mild zone 3 necrosis and loss of definition of hepatocyte cellular membranes. Extensive ultrastructural abnormalities were identified in the form of endothelial sloughing and the loss of hepatocyte microvilli. A striking finding was florid bleb formation on the sinusoidal borders of hepatocytes. Many blebs were shed into the space of Disse and extruded to fill, and sometimes occlude, sinusoidal lumina. Platelets were frequently found in areas of bleb formation. There was evidence of late damage in collagenization of Disse's space. Hepatocyte bleb formation is known to occur under a variety of pathological conditions but there is little to no information in the literature on the effects, if any, of bleb formation on fibrogenesis and the microcirculation and its role in the pathogenesis of liver disease. The pyrrolizidine alkaloids of comfrey may serve as an experimental tool to study the process of bleb formation and the intimate relationship between hepatocyte and sinusoidal injury in the liver.

  The effects of comfrey derived pyrrolizidine alkaloids on rat liver.:Pathology. 1991 Jan;23(1):35-8.Yeong ML, Clark SP, Waring JM, Wilson RD, Wakefield SJ.Department of Pathology, Wellington School of Medicine, University of Otago.

 Three groups of young adult rats were fed pyrrolizidine alkaloids derived from Russian comfrey to study the effects of the herb on the liver. Group I animals received a single dose of 200 mg/kg body wt, Group II 100 mg/kg three times a week for 3 weeks and Group III 50 mg/kg three times a week for 3 weeks. All rats showed light and electron-microscopic evidence of liver damage, the severity of which was dose dependent. There was swelling of hepatocytes and hemorrhagic necrosis of perivenular cells. There was a concomitant loss of sinusoidal lining cells with disruption of sinusoidal wall and the sinusoids were filled with cellular debris, hepatocyte organelles and red blood cells. Extravasation of red blood cells was evident. Terminal hepatic venules were narrowed by intimal proliferation, and in Group II and III, reiculin fibres radiated from these vessels. These appearances have been described in veno-occlusive disease due to pyrrolizidine alkaloids from other plant sources such as Senecio and Crotalaria. The safety of comfrey, a widely used herb, in relation to human consumption requires further investigation.

  The Budd-Chiari syndrome and hepatic veno-occlusive disease. Recognition and treatment.:Arch Surg. 1990 Apr;125(4):525-7.McDermott WV, Ridker PM.Department of Surgery, New England Deaconess Hospital, Boston, Mass 02215.

 In a review of 29 patients who were surgically treated by combined hepatic and portal decompression for intractable ascites, 18 were identified as falling into the category of the Budd-Chiari syndrome, with varying causes. Of this group, 2 patients were distinguished by the classical hepatic venous endophlebitis described by Chiari and later by Bras et al. Recently, this disease entity has been recognized as being due to the toxic effects of pyrrolizidine alkaloids contained in the Senecio and Crotolaria plants. In the first of these two cases the patient had emigrated from Jamaica and was exposed to "bush trees," but no chemical measurements were done. The second patient had consumed a large amount of comfrey teas, which were shown to contain high levels of pyrrolizidine alkaloids. These two cases add further weight to the existing evidence of the toxic effect of these alkaloids, and also demonstrate the effectiveness of hepatic and portal decompression.

  Natural plant toxicants in milk: a review.:J Anim Sci. 1990 Mar;68(3):892-904. Review.Panter KE, James LF.U.S. Department of Agriculture, Logan, UT 84321.

 Elimination of plant toxicants via milk by lactating animals is considered a minor route of excretion; however, it may be important when the health of the neonate or food safety in humans is considered. Among plant toxicants excreted in milk is tremetol or tremetone, the toxin in white snakeroot (Eupatorium rugosum) and rayless goldenrod (Haplopappus heterophyllus). These plants have been responsible for intoxication of cows and their suckling calves and for many human poisonings. Other plant toxins excreted through the milk that pose a toxicity hazard include pyrrolizidine alkaloids in Senecio, Crotalaria, Heliotropium, Echium, Amsinckia, Symphytum (comfrey), Cynoglossum (hounds tongue) and Festuca (tall fescue); piperidine alkaloids in Conium, tobacco and others; quinolizidine alkaloids in Lupinus; sesquiterpene lactones of bitterweed and rubber weed; and glucosinolates in Amoracia (horseradish), Brassica (cabbage, broccoli, etc.), Limnanthes (meadowfoam), Nasturtium (watercress), Raphanus (radish) and Thlaspi (stinkweed). Many plants such as Astragalus, Oonopsis, Stanleya, Xylorrhiza, Aster, Atriplex, Sideranthus and Machaeranthera accumulate selenium and may cause intoxication when grazed. Selenium is found in the milk at concentrations relative to the amounts ingested by the lactating animal. Excretion of selenium via the milk is important in the deficiency state, but when in excess it may cause toxicity to offspring.

  Hepatic veno-occlusive disease associated with comfrey ingestion.:J Gastroenterol Hepatol. 1990 Mar-Apr;5(2):211-4.Yeong ML, Swinburn B, Kennedy M, Nicholson G.Department of Pathology, Auckland Hospital, New Zealand.

 A 23 year old man presented with hepatic veno-occlusive disease and severe portal hypertension and subsequently died from liver failure. Light microscopy and hepatic angiography showed occlusion of sublobular veins and small venous radicles of the liver, associated with widespread haemorrhagic necrosis of hepatocytes. The patient had been on a predominantly vegetarian diet and, prior to his illness, took comfrey leaves which are known to contain hepatotoxic pyrrolizidine alkaloids. Comfrey is widely used as a herbal remedy, but so far has only been implicated in two other documented cases of human hepatic veno-occlusive disease. A possible causal association of comfrey and this patient's veno-occlusive disease is suggested by the temporal relationship of the ingestion of comfrey to his presentation, the histological changes in the liver and the exclusion of other known causes of the disease.


  Comfrey: assessing the low-dose health risk.:Med J Aust. 1988 Dec 5-19;149(11-12):678-82. Review. Abbott PJ.Toxicology Unit, Department of Community Services and Health, Canberra, ACT.

 The regular use of comfrey as part of the diet or for medicinal purposes may be a potential health risk as a result of the presence of naturally-occurring pyrrolizidine alkaloids. The majority of these alkaloids are hepatotoxic in both animals and humans, and some have been shown to induce tumours in experimental animals. In this article, the toxic properties of pyrrolizidine alkaloids are reviewed briefly, with particular reference to their presence in comfrey. The acute and long-term health risks at the normally-low levels of comfrey consumption are evaluated and discussed. On the basis of the data that are available currently, the small but significant long-term risk that is associated with the consumption of comfrey justifies the need to limit its intake. This is being achieved by controls under various state Poisons Acts, but also requires further education on the potential dangers of naturally-occurring chemicals of plant origin.

  Hepatic venocclusive disease associated with the consumption of pyrrolizidine-containing dietary supplements.:Gastroenterology. 1985 Apr;88(4):1050-4.Ridker PM, Ohkuma S, McDermott WV, Trey C, Huxtable RJ.

 Venocclusive disease, a form of Budd-Chiari syndrome, was diagnosed in a 49-yr-old woman. The patient had portal hypertension associated with obliteration of the smaller hepatic venules. A liver biopsy specimen showed centrilobular necrosis and congestion. Analysis of food supplements the woman regularly consumed showed the presence of pyrrolizidine alkaloids. The major source was a powder purporting to contain ground comfrey root (Symphytum sp). We calculated that during the 6 mo before the woman was hospitalized, she had consumed a minimum of 85 mg of pyrrolizidine alkaloids (15 micrograms/kg body wt X day). The clinical and analytic findings were consistent with chronic pyrrolizidine intoxication, indicating that low-level, chronic exposure to such alkaloids can cause venocclusive disease.

  An evaluation of acetone extracts from six plants in the Ames mutagenicity test.:Toxicol Lett. 1983 Jan;15(1):25-31.White RD, Krumperman PH, Cheeke PR, Buhler DR.

 Acetone extracts from six plants were evaluated for mutagenic activity with the Salmonella/mammalian-microsome mutagenicity test (Ames) utilizing tester strains TA98 and TA100 and in the presence and absence of induced rat liver microsomes. Extracts from alfalfa (Medicago sativa), lettuce (Lactuca sativa) and thread-leaf groundsel (Senecio longilobus) produced only negative responses. Comfrey (Symphytum officinale) and tansy ragwort (Senecio jacobaea) extracts produced toxic responses that were abolished in the presence of the microsomal bioactivation system. Bracken (Pteridium aquilinum) and tansy ragwort extracts produced positive responses following bioactivation with the liver microsomal system. The results suggest that the Ames mutagenicity test may be of some value in initial evaluations for potential toxic effects of plants consumed by animals and man.

  Consumption of poisonous plants (Senecio jacobaea, Symphytum officinale, Pteridium aquilinum, Hypericum perforatum) by rats: chronic toxicity, mineral metabolism, and hepatic drug-metabolizing enzymes.:Toxicol Lett. 1982 Feb;10(2-3):183-8.Garrett BJ, Cheeke PR, Miranda CL, Goeger DE, Buhler DR.

 Effect of dietary tancy ragwort (Senecio jacobaea), comfrey (Symphytum officinale), bracken (Pteridium aquilinum) and alfalfa (Medicago sativa) on hepatic drug-metabolizing enzymes in rats were measured. Tansy ragwort and bracken increased (P less than 0.05) the activity of glutathione transferase and epoxide hydrolase. Comfrey and alfalfa increased (P less than 0.05) the activity of aminopyrine N-demethylase. Feeding bracken or St. John's wort (Hypericum perforatum) in conjunction with tansy ragwort did not influence chronic toxicity of tansy ragwort as assessed by rat survival time. Dietary tansy ragwort resulted in increased (P less than 0.05) hepatic copper levels; the other plants did not affect copper levels. The results do not suggest any major interaction in the toxicity of tansy ragwort with bracken or St. John's wort.

  Structure and toxicity of the alkaloids of Russian comfrey (symphytum x uplandicum Nyman), a medicinal herb and item of human diet.:Experientia. 1980 Apr 15;36(4):377-9.Culvenor CC, Clarke M, Edgar JA, Frahn JL, Jago MV, Peterson JE, Smith LW.

 Eight pyrrolizidine alkaloids of hepatotoxic type have been indentified in leaves of Symphytum X uplandicum. The combined alkaloids exhibit chronic hepatotoxicity in rats.


  Carcinogenic activity of Symphytum officinale.:J Natl Cancer Inst. 1978 Sep;61(3):865-9.Hirono I, Mori H, Haga M.

 The carcinogenicity of Symphytum officinale L., Russian comfrey, used as a green vegetable or tonic, was studied in inbred ACI rats. Three groups of 19--28 rats each were fed comfrey leaves for 480--600 days; four additional groups of 15--24 rats were fed comfrey roots for varying lengths of time. A control group was given a normal diet. Hepatocellular adenomas were induced in all experimental groups that received the diets containing comfrey roots and leaves. Hemangioendothelial sarcoma of the liver was infrequently induced.


  Scientific References:

  1.Research Update:Comfrey leaf or Symphytum officinale