Hepatitis Central

The latest research & treatment news about Hepatitis C infection, diagnosis, symptoms and treatments.

 
Hepatology, October 1999, p. 1099-1104, Vol. 30, No. 4

HEPATOLOGY Clinical Challenge

Herbal Products for Liver Diseases:
A Therapeutic Challenge for the New Millennium

Detlef Schuppan1, Ji-Dong Jia1,2,Benno Brinkhaus1, and Eckhart G. Hahn1

From the 1Department of Medicine I, University of Erlangen-Nuernberg, and the 2Department of Gastroenterology and Hepatology, Klinikum B. Franklin, Free University of Berlin, Berlin, Germany.

INTRODUCTION

Use of herbal drugs in the treatment of liver diseases has a long tradition, especially in Eastern medicine. Standardization has been a problem, and randomized, placebo-controlled clinical trials to support efficacy are lacking. Some herbal extracts promoted for gastrointestinal or biliary disorders contain potent hepatotoxic alkaloids and are harmful. However, some of these extracts have yielded molecules, often related to flavonoids, with proven antioxidative, antifibrotic, antiviral, or anticarcinogenic properties, including glycyrrhizin, phyllanthin, silibinin, picroside, and baicalein, which derive from licorice root, Phyllanthus amarus, milk thistle, Picrorhiza kurroa, and sho-saiko-to, respectively, that can serve as primary compounds for the development of specific hepatotropic drugs.

BACKGROUND

Natural remedies represent a $1.8 billion market in the United States, and a single herbal preparation, silymarin, which is used almost exclusively for liver diseases, amounts to $180 million in Germany alone.1 Marketing of herbals tripled between 1992 and 1996,1 and nearly a third of outpatients attending liver clinics use these products.2 This is reflected in the internet home pages of hepatitis foundations. Herbal products have been classified as food supplements and thus are exempt from regulations on quality control and proof of efficacy that govern standard pharmaceuticals. This is contentious in view of the biological activity of many herbals and, more worrisome, their occasionally severe toxicity.

Use of herbal medicines can be traced back as far as 2100 B.C. in ancient China (Xia dynasty) and India (Vedic period). The first written reports date back to 600 B.C. with the Caraka Samhita of India and the early notes of the Eastern Zhou dynasty of China that became systematized around 400 B.C. The recipes, once formulated, were usually expanded rather than abandoned during subsequent centuries. Expansion was stimulated by a growing understanding of the natural evolution of frequently encountered diseases and by emerging hypotheses regarding their causes. Hepatitis was and continues to be prominent. Biliary stasis in patients with jaundice, often associated with ascites and encephalopathy, led to the discovery that the liver is responsible for bile production and excretion. However, contrary to the Aristotelian Western world, which preferred the analytical approach to medicine, even when based on unfounded assumptions, the Eastern hemisphere always considered disease a manifestation of a more general imbalance of the dichotomous energies that govern life as a whole and human life in particular. In China these energies are represented by the complementary Yin (representing earth and moon, moistness, darkness and passivity the female aspect) and Yang (representing sun, dryness, light, and activity the male aspect), the balance and timely sequence of which is necessary to maintain health. In the Ayurveda (sanskrit: ayur, life; veda, knowledge) of India, similar forces are agni (strength, health, and innovation) and ama (weakness, disease, and ntoxication).

With the revolution of the natural sciences and evidence-based medicine, the divide between Western and Eastern medicines appeared to widen. However, given the limitations of conventional treatment for chronic diseases and tumors, both patients and scientifically trained physicians are giving increased attention to the more holistic approach of Eastern medicine. Although this may represent in part a trend towards mysticism in our modern world, the effectiveness of Eastern medicine is amenable to Western analysis. One explanation is the placebo effect, part of which can be explained by modulation of neurotransmitters or the immune system in the brain, and another is the fact that some herbal drugs contain ingredients that specifically treat disease.

EFFICACY AND SAFETY OF HERBAL PRODUCTS

Any evaluation of herbal products faces major problems. The first is the use of mixed extracts (concoctions) and variations in methods of harvesting, preparing, and extracting the herb, which can result in dramatically different levels of certain alkaloids. The biologically active substances have been structurally defined and standardized for only a few of the herbs. Even then, it may not be known if this molecule is the sole active principle or if efficacy depends on the mixture of compounds.

The second problem is a lack of randomized, placebo-controlled clinical studies. Traditional Eastern medicine relies on empiricism and a holistic philosophy, and controlled studies are considered unnecessary. This is a view shared by many Western supporters of alternative medicine. Also, trials may not use end points, such as death from liver disease, histological fibrosis or inflammation, cancer, and transplantation.

Related to these issues is concern about the safety of herbal remedies. Numerous reports of toxic effects contradict the popular view that herbals are natural and therefore harmless. A survey of the National Poison Information Service for the years 1991-1995 documented 785 cases of possible or confirmed adverse reactions to herbal drugs, among which hepatotoxicity was the most frequent.3 The real number is probably much higher because of underreporting. Although abnormal liver function tests mostly return to normal once the offending drug is withdrawn, cases of chronic disease and acute liver failure requiring transplantation have been reported.4 There are groups of plant alkaloids with well established hepatotoxicity (table 1).4-6 The pyrrolizidine alkaloids found in herbal teas or enemas containing Crotalaria, Senecio, Heliotropium, or Symphytum damage the hepatic central vein endothelia, causing veno-occlusive disease that may be lethal or require transplantation. Germander (Teucrium chamaedrys L.), broadly used in France as an antipyretic for treatment of abdominal discomfort and for weight reduction, contains hepatotoxic alkaloids identified as furano-diterpenoids that, after activation by the hepatic cytochrome P450 3A, deplete glutathione and precipitate hepatocyte necrosis, apoptosis, and cytoskeletal disorganization.7,8 Greater celandine (Chelidonium majus) has resulted in acute hepatitis; extracts of this herb are broadly used in Europe to treat gallstone disease and dyspepsia.9 Hepatotoxicity can result also from misidentification or mislabeling of a plant, contamination by chemicals such as heavy metals, and incorrect storage that leads to microbial or fungal growth and toxin production. Safety testing is needed. Before this can be implemented, however, preparations must be standardized and must replace in the market the uncontrolled and individualized concoctions currently being offered. Safety concerns notwithstanding, sufficient scientifically useful data have accumulated during the last few years to allow an overview of herbal compounds, some of which appear to be beneficial and may serve as a basis for future drug development.

To View This table

table 1.   Selection of Herbal Preparations With Proven Hepatotoxicity

STUDIES OF DEFINED FORMULATIONS OF HERBAL MEDICINES

Some herbal preparations exist as standardized extracts with major known ingredients or even pure compounds, for which pharmacodynamic and pharmacokinetic data are usually available. These resemble the medications of traditional Western medicine. In only a few cases, however, have studies documented their efficacy using accepted parameters of disease progression.

Glycyrrhizin. This group of related, sulfated saponins and lectins from the licorice root has been used for over 20 years to treat chronic viral hepatitis in Japan. It has a well-documented transaminase-lowering effect. The standardized aqueous extract (Stronger Neo-Minophagen C) has to be administered parenterally. A daily dose of 80 mg given for 2 weeks can normalize aspartate transaminase and alanine transaminase in over 60% of patients.10 The preparation has immunosuppressive and anti-inflammatory effects in cell culture, where glycyrrhizin inhibits CD4+-T cell- and tumor necrosis factor-mediated cytotoxicity.11 Furthermore, the extract modifies glycosylation and blocks sialylation of hepatitis B surface antigen (HBsAg), which leads to its retention in the trans-Golgi apparatus.12 In an uncontrolled trial of 17 hepatitis Be antigen-positive patients with chronic hepatitis B, a 4-week course of glycyrrhizin followed by 4 weeks of interferon-alfa produced loss of hepatitis B e antigen in 10 of 17 patients after 6 months.13 However, only 3 of the 10 patients underwent seroconversion to antibodies to e antigen, and virus titers were not reported. In a small randomized study of 28 patients with chronic hepatitis C who were nonresponders to interferon monotherapy, 13.3% became hepatitis C virus-RNA negative after interferon alone compared with 33.3% after a glycyrrhizin/interferon combination therapy over 3 months.14 However, this was not statistically significant. In a retrospective analysis of 84 patients with chronic hepatitis C virus infection who were treated with intravenous glycyrrhizin 2 to 7 times weekly for a median of 10.1 years, comparison with a matched group of 109 patients who remained untreated over 9.2  years revealed a 2.5-fold reduction of the relative risk of hepatocellular carcinoma.15 This could be due to an anti-inflammatory effect of the preparation rather than to its weak antiviral effect. Because of its aldosterone-like activities,16 use of the drug requires caution and monitoring for hypertension, hyperkalemia, and worsening ascites.

Phyllanthus amarus. This herb and related species are Indian plants that contain phyllantins, hypophyllantins, and polyphenoles with antiviral properties. An aqueous extract inhibited woodchuck hepatitis virus DNA polymerase and surface antigen expression17,18 and several protein kinases such as cAMP-dependent protein kinase, protein kinase C, and myosin light-chain kinase in rat liver.19 A nonrandomized clinical study showed a remarkable 59% (22 of 37 patients) clearance of HBsAg in chronic carriers who were treated for 30 days compared with only 4% (1 of 23 patients) given placebo.20 However, these results await confirmation. There was no effect of P. amarus on duck hepatitis B virus.21

Daphnoretin. This dicoumarin drug extracted from the Chinese herb Wilkstroemia indica was shown to suppress HBsAg in Hep3B cells, an effect mediated by activation of protein kinase C.22 The same investigators reported a powerful suppression of HBsAg by costunlite and dehydrocostus lactone, two alkaloids from Saussurea lappa Clarks root.23 However, no clinical studies with these compounds have been reported.

Silymarin. A standardized extract from the milk thistle Silybum marianum contains as its main constituents the flavonoids silybinin, silydianin, and silychristin.24 Milk thistle extracts were used as early as the 4th century B.C., became a favored medicine for hepatobiliary diseases in the 16th century, and experienced a revival in central Europe in the late 1960s (table 2). The flavonoid silibinin, which constitutes 60% to 70% of silymarin, has been identified as the major active ingredient.25,26 Its pharmacological profile is well defined, and studies in cell culture and animal models clearly show its hepatoprotective action with little or no toxicity.26,27,33-41 Silymarin enhances the activity of hepatocyte RNA-polymerase I,26 complexes toxic free iron,33 protects the cell membrane from radical-induced damage,34 and blocks the uptake of toxins such as Amanita phalloides toxin.32,35 A potent scavenger, it prevents lipid peroxidation and normalizes the lipid profile of hepatocyte membranes.36 Silymarin provided liver protection in rat models of liver damage induced by carbon tetrachloride and paracetamol.37,38 Four of 12 dogs fed lyophilized Amanita toxin and given supportive care died from hepatic failure and coma within 35 to 54 hours, whereas all 11 dogs receiving high-dose silymarin survived.39 In a retrospective analysis of 205 patients with Amanita intoxication, of whom 30 received treatment, the death rate of those given intravenous silymarin was reduced significantly (12.8% vs. 22.4%).40

To View This table

table 2.   History of the Milk Thistle as a Liver Remedy

In recent in vitro studies, silymarin down-regulated the proinflammatory leukotriene B4 in Kupffer cells.41 In randomized clinical trials for acute viral hepatitis A or B, oral silymarin either exerted no benefit29 or accelerated clinical recovery, causing a significantly more rapid normalization of bilirubin and aspartate transaminase than did the control.30 Similarly, in alcohol-related hepatitis treated with silymarin, transaminase levels dropped more rapidly than in the untreated disease.42 A 4-month course of silymarin in patients with moderately active alcohol-related liver disease led to a 41% reduction of alanine transaminase, compared with no change in controls.43 In a randomized trial, 170 biopsy-proven cirrhotic patients, 92 with alcohol-related and 78 with nonalcohol-related liver disease, were treated with silymarin or placebo for a mean of 41 months.44 Although serum biochemistry values did not differ between the 2 groups, the number of surviving cirrhotic patients with alcohol-related liver disease was significantly higher in the silymarin group, especially in those with Child-Pugh class A cirrhosis. Most of the latter patients continued to drink, which may have influenced the results. Also, the dropout rate was high, although dropouts were counted as therapy failures. A subsequent randomized, placebo-controlled study of 200 patients with alcohol-related cirrhosis, 75 of whom dropped out, could not confirm a survival benefit.45

These data point up the difficulty of studying a heterogeneous group of patients and of using death as the endpoint for a condition that progresses over many years. An intermediate endpoint is progression of fibrosis to cirrhosis, which is the primary determinant of morbidity and mortality in patients with chronic liver diseases. In vitro, silymarin blocks proliferation of hepatic stellate cells, the main source of excess collagen in fibrosis. This is accompanied by down-regulation of the profibrogenic transforming growth factor beta .46 In liver injury induced by complete occlusion of the biliary system in the rat, oral silymarin reduced collagen accumulation in a dose-dependent fashion.47 It was similarly antifibrotic when administered from weeks 4 to 6, i.e., starting at a time when liver collagen is already increased 4-fold, a situation encountered in most patients with chronic liver disease. The antifibrotic effect was accompanied by reduced numbers of activated stellate cells48 and a greater than 50% reduction of both procollagen I and tissue inhibitor of metalloproteinase messenger RNA, both being major effectors of fibrogenesis.49 These data have spawned randomized, placebo-controlled studies of silymarin in patients with chronic viral hepatitis that include follow-up biopsies and a panel of serum markers of liver fibrosis.50

Picroliv. Picroliv is an alcoholic extract from the root of Picrorhiza kurroa that contains the iridoid glycosides kutkoside and picroside. In the rat these glycosides act as antioxidants51 and ameliorate the hepatotoxic effects of carbon tetrachloride,52 thioacetamide, galactosamine,53 and paracetamol.54 Despite their wide oral usage in India, no reliable data for human liver disease exist.

TJ-9. TJ-9, commonly prescribed in China as xiao-chai-hu-tang and in Japan as sho-saiko-to, is an aqueous extract from the roots of scutellaria, glycyrrhiza, bupleurum, and ginseng; the pinella tuber; the jujube fruit; and the thew ginger rhizome. Two major alkaloids from scutellaria, baicalin and baicalein, are strong inhibitors of lipid peroxidation.55 The extract prevented hepatocellular membrane damage and restored mitochondrial function in endotoxin-treated rats, increasing hepatic levels of superoxide dismutase and glutathione.56,57 Other in vitro effects that are related to the observed antitumour activity of sho-saiko-to include up-regulation of the inducible nitric oxide synthase in hepatocytes cultured in the presence of interferon gamma 58 and inhibition of proliferation and induction of apoptosis in hepatoma cells.59,60 The extract modulated the in vitro cytokine production in peripheral blood mononuclear cells, stimulated release of tumor necrosis factor-alpha and granulocyte-colony-stimulating factor in patients with hepatocellular carcinoma and down-regulated synthesis of interleukin-4 and -5 in favor of interleukin-10 in patients with chronic hepatitis C.61,62 Other in vitro effects include stimulation of inducible nitric oxide synthase and down-regulation of interleukin-4 and -5 in favor of interleukin-10 in patients with chronic hepatitis C.61,62 In the rat model of dimethylnitrosamine-induced liver injury, the extract sho-saiko-to protected liver synthetic function63 and restored hepatic retinoid levels.64 Sho-saiko-to reduced hepatic collagen content in the rat models of fibrosis due to choline-deficiency,65 dimethylnitrosamine, and pig serum.66 The latter work identified baicalin and baicalein, which are structurally similar to silibinin,67 as major active compounds, leading to the hypothesis that these agents may have an antifibrotic activity separable from their effect as inhibitors of lipid peroxidation. Whereas information on the antiviral efficacy of sho-saiko-to is at best rudimentary,68 a prospective randomized 5-year study of 260 patients with cirrhosis showed a near-significant (P <  .053) survival benefit for the treated patients; this reached significance in those patients without HBs-Ag.69

FORMULAS CONTAINING MIXTURES OF HERBS WITH PARTIALLY KNOWN OR LARGELY UNKNOWN INGREDIENTS

The literature is replete with experimental studies using herbs of largely unknown composition. The following are those preparations for which human studies or mechanistic data exist.

Compound 861. Known as cpd 861, this is an aqueous extract of 10 defined herbs based on traditional Chinese medicine. The aim of traditional Chinese medicine is resolution of blood stasis and liver stagnation, two conditions that form the basis of liver pathology and patient discomfort.70 The chief herbs used in cpd 861 are Salvia miltiorrhiza, Astragalus membranaceous, and Spatholobus suberectus.71 Rats with experimental liver fibrosis showed a 50% reduction of the 5-fold increased hepatic collagen level when cpd 861 was administered daily by gavage.72 This was accompanied by a comparable down-regulation of hepatic messenger RNA for transforming growth factor beta 1 and for procollagens I, III, and IV, as well as by increased hepatic collagenase activity. Because procollagen messenger RNAs, major effectors of liver fibrogenesis, were also down-regulated in cultures of hepatic stellate cells, a direct antifibrotic effect was proposed.73 From 1993 to 1995, 60 patients with chronic hepatitis B were treated in an open trial with cpd 861.71 After 2 years, subjective improvement was reported by 50 patients (83%), and this was accompanied by a reduction in spleen size in 41% and a decrease in liver enzyme levels and serum fibrosis markers such as PIIINP and laminin. In a nonrandomized controlled trial, 22 patients with chronic hepatitis B were treated with cpd 861 for 6 months and compared with 12 matched patients receiving a control herbal medicine.74 Follow-up liver biopsy results showed a statistically significant improvement in both histological inflammation and fibrosis in the cpd 861 group but no change in the control subjects.

LIV.52. An extract of several plants prepared for ayurvedic medicine has been marketed in the West as LIV.52. Standardization, chemical characterization, functional, and pharmacological studies are not well documented. The extract was reported to improve serum biochemistry values in rats with toxic liver damage,75 and uncontrolled observations in patients with liver disease seemingly gave similar results.76 Furthermore, it lowered circulating levels of acetaldehyde in healthy adults consuming alcohol.77 Therefore, Fleig et al.78 performed a randomized, placebo-controlled, 2-year clinical trial in 188 patients with alcohol-related cirrhosis. LIV.52 did not affect the survival rate of Child class A and B patients but increased mortality among the 59 Child class C patients (81% in the treated group, compared with 40% in the placebo group). Twenty-two of 23 deaths in the LIV.52 group were related to bleeding or liver disease compared with only 3 of 11 deaths in the placebo group. This result led to immediate withdrawal of the drug. It highlights the danger of ill-defined herbal preparations and the necessity for in-depth preclinical testing.

FUTURE DIRECTIONS

There is no doubt that certain herbal products contain chemically defined components that can protect the liver from oxidative injury, promote virus elimination, block fibrogenesis, or inhibit tumor growth. Although additive effects may be lost, the active molecules must be isolated and tested in suitable culture and animal experiments and finally in randomized, placebo-controlled studies to enable rational clinical use of the agents. Biologically active molecules derived from herbal extracts can serve as suitable primary compounds for effective and targeted hepatotropic drugs.

Abbreviation

Abbreviation: HBsAg, hepatitis B surface antigen.

FOOTNOTES

Received February 25, 1999; accepted August 4, 1999.

Supported in part by grant IZKF B18 from the Federal Ministry of Research and by the Balsen and Schoeller Foundations for Research into Natural Medicine.

Address reprint requests to: Detlef Schuppan, M.D., Ph.D., Department of Medicine I, Division of Gastroenterology, Hepatology and Infectiology, University of Erlangen-Nuernberg, Krankenhausstr. 12, 91054 Erlangen, Germany. E-mail: detlef.schuppan@med1.med.uni-erlangen.de; fax: (49) 9131.85.36003.

REFERENCES

1. Breevort P. The U.S. botanical market-an overview. Herbalgramm 1996;36:49-57
2. Flora KD, Rosen HR, Brenner KG. The use of neuropathic remedies for chronic liver disease. Am J Gastroenterol 1996;91:2654-265
3. Shaw D, Leon C, Kolev S, Murray V. Traditional remedies and food supplements. A 5-year toxicological study (1991-1995). Drug Saf 1997;17:342-35.
4. Yoshida EM, McLean CA, Chen ES, Blanc PD, Somberg KA, Ferrell LD, Lake JR. Chinese herbal medicine, fulminant hepatitis, and liver transplantation. Am J Gastroenterol 1996;91:1436-1438.
5. Larrey D, Pageaux GP. Hepatotoxicity of herbal remedies and mushrooms. Sem Liver Dis 1995;15:183-18.
6. Kaplowitz N. Hepatotoxicity of herbal remedies: insight into the intricacies of plant-animal warfare and cell death. Gastroenterology 1997;113:1408-1412.
7. Lekhehal M, Pessayre D, Lereau JM, Moulis C, Fouraste F, Fau D. Hepatotoxicity of the herbal medicine germander. Metabolic activation of its furano diterpenoids by cytochrome P450 3A depletes cytoskeleton-associated protein thiols and forms plasma membrane blebs in hepatocytes. HEPATOLOGY 1996;24:212-21.
8. Fau D, Lekehal M, Farrell G, Moreau A, Moulis C, Feldmann G, Haouzi D, et al. Diterpenoids from germander, a herbal medicine, induce apoptosis in isolated rat hepatocytes. Gastroenterology 1997;113:1408-1412.
9. Benninger J, Schneider HT, Schuppan D, Kirchner T, Hahn EG. Acute hepatitis induced by greater celandine (Chelidonium majus). Gastroenterology (in press).
10. Yamamura Y, Kotaki H, Tanaka N, Aikawa T, Sawada Y, Iga T. The pharmacokinetics of glycyrrhizin and its restorative effect on hepatic function in patients with chronic hepatitis and in chronically carbon-tetrachloride-intoxicated rats. Biopharm Drug Dispos 1997;18:717-72.
11. Yoshikawa M, Matsui Y, Kawamoto H, Umemoto N, Oku K, Koizumi M, Yamao J, et al. Effects of glycyrrhizin on immune-mediated cytotoxicity. J Gastroenterol Hepatol 1997;12:243-247.
12. Takahara T, Watanabe A, Shiraki K. Effects of glycyrhizin on hepatitis B surface antigen: a biochemical and morphological study. J Hepatol 1994;21:601-609.
13. Hayashi J, Kajiyama W, Noguchi A, Nahashima K, Hirata M, Hayashi S, Kashiwagi S. Glycyrrhizin withdrawal followed by human lymphoblastoid interferon in the treatment of chronic hepatitis B. Gastroenterol Jpn 1991;26:742-7.
14. Abe Y, Ueda T, Kato T, Kohli Y. Effectiveness of interferon, glycyrrhizin combination therapy in patients with chronic hepatitis C. Nippon Rinsho 1994;52:1817-18.
15. Arase Y, Ikeda K, Murashima N, Chayama K, Tsubota A, Koida I, Suzuki Y, et al. The long-term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer 1997;79:1494-150.
16. Kageyama Y, Suzuki H, Saruta T. Renin-dependency of glycyrrhizin-induced pseudohyperaldosteronism. Endocrinol Jpn 1991;38:103-10
17. Venkateswaran PS, Millman I, Blumberg BS. Effects of an extract of Phyllanthus niuri on hepatitis B and woodchuck hepatitis viruses: in vitro and in vivo studies. Proc Natl Acad Sci U S A 1987;84:274-278
18. Ott M, Thyagarajan SP, Gupta S. Phyllanthus amarus suppresses hepatitis B virus by interrupting interactions between HBV enhancer I and cellular transcription factors. Eur J Clin Invest 1997;27:908-915
19. Polya GM, Wang BH, Foo LY. Inhibition of signal regulated protein kinases by plant-derived hydrolyzable tannins. Phytochemistry 1995;38:307-314
20. Thyagajaran SP, Subramanian S, Thirunalasundari T, Venkateswaran PS, Blumberg BS. Effect of Phyllanthus amarus on chronic carriers of hepatitis B virus. Lancet 1988;2:764-76
21. Munshi A, Mehrota R, Panda SK. Evaluation of Phyllanthus amarus and phyllanthus mederaspatensis as agents for postexposure prophylaxis in neonatal duck hepatitis B virus infection. J Med Virol 1993;40:53-58.
22. Chen HC, Chou CK, Kuo YH, Yeh SF. Identification of a protein kinase C (PKC) activator, daphnoretin, that suppresses hepatitis B virus gene expression in human hepatoma cells. Biochem Pharmacol 1996;52:1025-1032
23. Chen HC, Chou CK, Lee SD, Wang JC, Yeh SF. Active compounds from Saussurea lappa Clarks that suppress hepatitis B surface antigen gene expression in human hepatoma cells. Antiviral Res 1995;27:99-109
24. Flora K, Hahn M, Rosen H, Brenner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol 1996;93:139-143
25. Wagner H, Diesel P, Seitz M. The chemistry and analysis of silymarin from Silybum marianum Gaertn. Arzneimittelforsch 1974;24:466-47
26. Sonnenbichler J, Zetl I. Biochemical effects of the flavolignane silibinin on RNA, protein and DNA synthesis in rat liver. Progr Clin Biol Res 1986;213:319-33
27. Platt D, Schnorr B. Biochemical and electronoptic study on the possible effect of silymarin on ethanol-induced liver damage in rats. Arzneimittelforsch 1971;21:1206-1208
28. Schriewer D, Kastrup W, Wiemann W, Rauen HM. The antihepatotoxic effect of silymarin on lipid metabolism in the rat disturbed by phalloidine intoxication. Arzneimittelforsch 1975;25:188-194
29. Bode JC, Schmidt U, Durr HK. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial. Med Klin 1977;72:513-518
30. Magliulo E, Gagliardi B, Fiori GP. Zur Wirkung von Silymarin bei der Behandlung der akuten Virushepatitis. Med Klin 1978;73:1060-1065
31. Benda L, Dittrich H, Ferenci P, Frank H, Wewalka F. The influence of therapy with silymarin on the survival rate of patients with liver cirrhosis. Wie Klin Wochenschr 1980;92:678-683
32. Hruby K, Csomos G, Fuhrmann M, Thaler H. Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 1983;2:138-19
33. Pietrangelo A, Borella F, Casalgrandi G, Montosi G, Cecarelli D, Gallesi D, Giovanni F, et al. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology 1995;109:1941-194
34. Mira L, Silva M, Manso CF. Scavenging of reactive oxygen species by silibinin hemisuccinate. Biochem Pharmacol 1994;48:753-759
35. Desplace A, Choppin J, Vogel G, Trost W. The effects of silymarin on experimental phalloidine poisoning. Arzneim Forsch 1975;25:89-96
36. Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 1990;10:275-27
37. Mourelle M, Muriel P, Favari L, Franco T. Prevention of CCl4-induced liver cirrhosis by silymarin. Fundam Clin Pharmacol 1989;3:183-191
38. Muriel P, Garciapina T, Perez-Alvarez V, Mourelle M. Silymarin protects against paracetamol-induced lipid peroxidation and liver damage. J Appl Toxicol 1992;12:439-442
39. Vogel G, Tuchweber B, Trost W, Mengs U. Protection by silybinin against Amanita phalloides intoxication in beagles. Toxicol Appl Pharmacol 1984;73:355-36
40. Floersheim GL, Weber O, Tschumi P, Ulbrich M. Poisoning by the deathcup fungus (Amanita phalloides): prognostic factors and therapeutic measures. Schweiz Med Wochenschr 1982;112:1164-1177
41. Dehmlow C, Erhard J, de Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. HEPATOLOGY 1996;23:749-754
42. Fintelmann V, Albert A. Nachweis der therapeutischen Wirsamkeit von Legalon bei toxischen Leberkrankheiten im Doppelblindversuch. Therapiewoche 1980;30:5589-5594
43. Salmi HA, Sarna S. Effect of silymarin on chemical, functional and morphological alterations of the liver: a double blind study. Scand J Gastroenterol 1982;17:517-522
44. Ferenci P, Dragosics B, Dittrich H, Frank H, Benda L, Lochs H, Meryn S, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113
45. Pares A, Planes R, Torres M, Caballeria J, Viver JM, Acero D, Panes J, et al. Effects of silymarin in alcoholic patients with cirrhosis of the liver. Results of a controlled, double-blind, randomized and multicenter trial. J Hepatol 1998;28:615-621
46. Fuchs EC, Weyhenmeyer R, Meiner OH. Effects of silybinin and a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Arzneimittelforschung 1997;47:1383-1387
47. Boigk G, Stroedter L, Herbst H, Waldschmidt J, Riecken EO, Schuppan D. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. HEPATOLOGY 1987;26:643-64
48. Boigk G, Herbst H, Jia JD, Riecken EO, Schuppan D. Effect of antifibrotic agent silymarin on liver cell regeneration in a rat model of secondary biliary fibrosis: a morphometric analysis. J Phytother Res 1998;12(Suppl):S42-S44
49. Jia JD, Boigk G, Bauer M, Ruehl M, Strefeld T, Riecken EO, Schuppan D. Silymarin downregulates TIMP-1 and collagen I mRNA in rats with secondary biliary cirrhosis [Abstr]. HEPATOLOGY 1998;28(Suppl):546
50. Schuppan D, Stoelzel U, Oesterling C, Somasundaram R. Serum assays for liver fibrosis. J Hepatol 1995;22(Suppl 2):82S-88S
51. Chander R, Kapoor NK, Dhawan BN. Picroliv, picroside I and kutkoside from Picrorhiza kurroa are scavengers of superoxide anions. Biochem Phamacol 1992;44:180-18
52. Dwivedi Y, Rastogi R, Chander R, Sharma SK, Kapoor NK, Garg NK, Dhawan BN. Hepatoprotective activity of picroliv against carbon tetrachloride-induced liver damage in rats. Indian J Med Res 1990;92:195-200
53. Dwivedi Y, Rastogi R, Garg NK, Dhawan BN. Perfusion with picroliv reverses biochemical changes induced in livers of rats intoxicated with galactosamine or thioacetamide. Planta Med 1993;59:418-420
54. Ansari RA, Tripathi SC, Patnaik GK, Dhawan BN. Antihepatotoxic effects of picroliv, an active traction from rhizomes of Picrorhiza kurroa. J Ethnopharmacol 1991;34:61-6
55. Miyahara M, Tatsumi Y. Suppression of lipid peroxidation by sho-saiko-to and its components in rat liver subcellular membranes. Yakugaku Zasshi 1990;110:407-413
56. Sakaguchi S, Tsutsumi E, Yokota K. Preventive effects of a traditional Chinese medicine (sho-saiko-to) against oxygen toxicity and membrane damage during endotoxemia. Biol Pharm Bull 1993;16:782-786
57. Sakaguchi S, Tsutsumi E, Yokota K. Defensive effects of a traditional Chinese medicine (sho-saiko-to) against metabolic disorders during endotoxemia. Biol Pharm Bull 1994;17:232-23
58. Hattori Y, Kasai K, Sekiguchi Y, Hattori S, Banba N, Shimoda S. The herbal medicine sho-saiko-to induces nitric oxide synthase in rat hepatocytes. Life Sci 1995;56:143-148
59. Yano H, Mizoguchi A, Fukuda K, Haramaki M, Ogasawara S, Momosaki S, Kojira M. The herbal medicine sho-saiko-to inhibits proliferation of cancer cells by inducing apoptosis and arrest at the G0/G1 phase. Cancer Res 1994;54:448-454
60. Matsuzaki Y, Kurokawa N, Terai S, Matsumara Y, Kobayashi N, Okita K. Cell death induced by baicalein in human hepatocellular carcinoma cells. Jpn J Cancer Res 1996;87:170-177
61. Yamashiki M, Nishimura A, Nomoto M, Suzuki H, Kosaka Y. Herbal medicine sho-saiko-to induces tumour necrosis factor-alpha and granulocyte colony-stimulating factor in vitro in peripheral blood mononuclear cells of patients with hepatocellular carcinoma. J Gastroenterol Hepatol 1996;11:137-14
62. Yamashiki M, Nishimura A, Sakaguchi S, Kosaka Y. Effects of the Japanese herbal medicine sho-saiko-to (TJ-9) on in vitro interleukin-10 production by peripheral blood mononuclear cells of patients with chronic hepatitis C. HEPATOLOGY 1997;25:1390-1397
63. Ohta Y, Nishida K, Sasaki E, Kongo M, Hayashi T, Nagata M, Ishiguro I. Comparative study of oral and parenteral administration of sho-saiko-to (xiao-chaihu-tang) extract on D-galactosamine-induced liver injury in rats. Am J Chinese Med 1997;25:333-342
64. Miyamura M, Ono M, Kyotani S, Nishioka Y. Effects of sho-saiko-to extract on fibrosis and regeneration of the liver in rats. J Pharm Pharmacol 1998;50:97-105
65. Sakaida I, Matsumura Y, Akiyama S, Hayashi K, Ishige A, Okita K. Herbal medicine sho-saiko-to (TJ-9) prevents liver fibrosis and enzyme-altered lesions in rat liver cirrhosis induced by a choline-deficient L-amino acid-defined diet. J Hepatol 1998;28:298-306
66. Shimizu I, Ma YR, Mizobuchi Y, Liu F, Nakai Y, Yasuda M, Shiba M, et al. Effects of sho-saiko-to, a Japanese herbal medicine, on hepatic fibrosis in rats. HEPATOLOGY 1999;29:149-160
67. Geerts A, Rogiers V. Sho-saiko-to: the right blend of traditional oriental medicine and liver cell biology. HEPATOLOGY 1999;29:282-28.
68. Tajiri H, Kozaiwa K, Ozaki Y, Miki K, Shimizu K, Okada S. Effect of sho-saiko-to (xiao-chai-hu-tang) on HBeAg clearance in fourteen children with chronic hepatitis B virus infection and with sustained liver disease. Am J Chinese Med 1991;19:121-129
69. Oka H, Yamamoto S, Kuroki T, Harihara S, Marumo T, Kim SR, Monna T, et al. Prospective study of chemoprevention of hepatocellular carcinoma with sho-saiko-to (TJ-9). Cancer 1995;76:743-749
70. Han DW. Hepatic Pathophysiology. Taiwan: Shanxi University Press, 1992.
71. Wang HJ, Wang BE. Long-term follow-up result of compound Dan Shen granule (861 Chong Fu Ji) in treating hepatofibrosis. Chin J Integr Trad West Med 1995;5:4-5
72. Jia JD, Wang BE, Dong Z, Cui L, Zhu JX, Che JT. The effect of herbal compound 861 on mRNA levels for type I, III and IV collagens and TGF in immune complex rat liver fibrosis. Chin J Hepatol 1996;4:214-216
73. Jia JD, Wang BE, Ma XM. The effect of herbal Cpd 861 on type IV collagen mRNA levels in cultured rat lipocytes. Chin J Hepatol 1996;4:142-14
74. Wang TL, Wang BE, Zhang HH, Liu X, Duan ZP, Zhang J, Ma H, Li XM, Li NZ. Pathological study of the therapeutic effect on HBV-related liver fibrosis with herbal compound 861. Chin J Gastroenterol Hepatol 1998;7:148-15
75. Pandey S, Gujrati VR, Shanker K, Singh N, Dhawan KN. Hepato- protective effect of LIV.52 against CCl4-induced lipid peroxidation in liver of rats. In J Exp Biol 1994;32:694-697.
76. Sama SK, Krishnamurthy L, Ramachandran K, Lal K. Efficacy of an indigenous compound preparation (LIV.52) in acute viral hepatitis--a double blind study. Indian J Med Res 1976;64:738-742
77. Chauhan BL, Kulkarni RD. Effect of LIV.52, a herbal preparation, on absorption and metabolism of ethanol in humans. Eur J Clin Pharmacol 1991;40:189-19
78. Fleig WW, Morgan MY, Hölzer MA, a European multicenter study group. The ayurvedic drug LIV.52 in patients with alcoholic cirrhosis. Results of a prospective, randomized, double-blind, placebo-controlled clinical trial [Abstr]. J Hepatol 1997;26 (Suppl 1):127

Copyright © 1999 by the American Association for the Study of Liver Diseases.

0270-9139/99/3004-0037$3.00/0

Site Topics

  • Frequently Asked Questions

    Some of our most commonly asked questions and our answers to them.

  • What Is Hepatitis C?

    Learn about the Hepatitis C Virus (HCV).

  • Hepatitis C Transmission

    Information about the transmission of Hepatitis C.

  • Hepatitis C Symptoms

    You'll find links to a comprehensive symptoms list, as well as various studies and discussions about Hepatitis C symptoms.

  • Hepatitis C Conventional Treatment

    Learn about the conventional medical treatments used to fight Hepatitis C.

  • Hepatitis C Medicines

    Numerous links to studies, info sheets, FAQs, and analysis of Ribavirin/Rebetron medicines.

  • Hepatitis C Alternative Therapies

    Alternative methods of treatment due to side effects and dissatisfication with current medical treatments.

  • Hepatitis C Natural Remedies

    A number of herbal products useful in the management of liver disease.

  • Hepatitis C Survivor Stories

    Stories from those having direct experience with hepatitis c.

  • Hepatitis Central News Signup

    Receive the latest news on hepatitis treatments, clinical trials, social issues and important breakthroughs.

  • Hepatitis C Genotypes

    Learn about Hepatitis C Genotypes and their variants.

  • Hepatitis C Doctors

    A state-by-state and worldwide reference listing physicians who treat HCV, including an email link to submit your physician for inclusion.

  • Hepatitis C Links

    Convenient links to other sites external to Hepatitis-Central.

  • Hepatitis C Forum External link

    A Bulletin Board for discussions on hepatitis, treatments, etc.

  • Hepatitis C Activism External link

    An easy way to get involved in urging our government to do more for Hepatitis C awareness and treatment research.

  • Hepatitis B

    Numerous links to various Hepatitis B related information, including transmission, symptoms and treatment.

  • Biopsy Information

    A comprehensive resource of information relating to the liver biopsy.

  • Cirrhosis

    Many discussions and analyses of cirrhosis, including causes, complications, pathology, symptoms, and much more.

  • Glossary

    Commonly used medical terms and definitions.

  • Lab Tests

    What they are and what they mean. Helps you interpret & understand all the various hepatitis lab tests likely to be encountered.

  • Liver Cancer

    Liver Cancer/Hepatocellular Carcinoma studies, info sheets, FAQs, and analysis.

  • Liver Disease and Drugs

    An exhaustive list of links to studies, info sheets, FAQs, and analysis of the various drugs used to treat liver disease.

  • Top 5 Liver Supplements

    Provides information regarding the best known liver supporting supplements.

  • Top 5 Milk Thistles

    Provides information regarding the best known milk thistle supplements.

  • Viral Load

    Provides detailed information on how to analyze and interpret viral load numbers as well as a link to a convenient Viral Load Chart.

  • What is...?

    Learn more about various Hepatitis C related topics, including HCV, Ascites, Biopsies, and much more.

  • Hepatitis C Books

    Recommended reading for those interested in hepatitis information.

Advertisement(s)

Advertisement