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Silymarin: A Review of its Clinical Properties in the Management of Hepatic Disorders

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Summary

Abstract

The mechanisms of action of silymarin involve different biochemical events, such as the stimulation of the synthetic rate of ribosomal RNA (rRNA) species through stimulation of polymerase I and rRNA transcription, protecting the cell membrane from radical-induced damage and blockage of the uptake of toxins such as α-amanitin.

Studies in patients with liver disease have shown that silymarin increases Superoxide dismutase (SOD) activity of lymphocytes and erythrocytes, as well as the expression of SOD in lymphocytes. Silymarin has also been shown to increase patient serum levels of glutathione and glutathione peroxidase.

Silybin 20 to 48 mg/kg/day has shown promise as a clinical antidote to acute Amanita (deathcap mushroom) poisoning.

Primary efficacy data from 3 trials which examined the therapeutic potential of silymarin in patients with cirrhosis, and included patient survival as an endpoint, demonstrated that silymarin had no significant beneficial effect on patient mortality. However, upon subanalysis, silymarin 420 mg/day had a significantly beneficial effect on patient survival rate (compared with patients receiving placebo) in 1 randomised, double-blind trial in patients with alcoholic cirrhosis.

Silymarin 420 mg/day was also shown to improve indices of liver function [AST, ALT, γ-glutamyl transferase and bilirubin] in patients with liver disease of various aetiology, including those exposed to toxic levels of toluene or xylene; however, it was largely ineffective in patients with viral hepatitis.

Reports of adverse events while receiving silymarin therapy are rare. However, there have been accounts of nausea, epigastric discomfort, arthralgia, pruritus, headache and urticaria. Silymarin has also been reported to have possibly caused a mild laxative effect.

Conclusion: The antioxidant properties of silymarin (a mixture of at least 4 closely related flavonolignans, 60 to 70% of which is a mixture of 2 diastereomers of silybin) have been demonstrated in vitro and in animal and human studies. However, studies evaluating relevant health outcomes associated with these properties are lacking. Although silymarin has low oral absorption, oral dosages of 420 mg/day have shown some therapeutic potential, with good tolerability, in the treatment of alcoholic cirrhosis. Moreover, silybin 20 to 48 mg/kg/day has shown promise as an antidote for acute mushroom poisoning by Amanita phalloides; however, further studies paying attention to the amount of ingested mushroom and time elapsed before administration of treatment are needed to clarify its role in this indication. Studies in patients with the early onset of liver disease may demonstrate the liver regeneration properties that silymarin is promoted as possessing.

Pharmacodynamic Properties

Silymarin is a standardised extract from the seeds and fruits of the milk thistle Silybum marianum and contains, as its main constituents, the flavonolignans silybin, isosilybin, silydianin and silychristin. The major component of silymarin is silybin (which is a mixture of 2 diastereomers), which constitutes between 60 and 70% of the drug and is the major active component.

The mechanisms of action of silymarin involve different biochemical events, such as increasing the synthesis of ribosomal RNA (rRNA) species through stimulatio of polymerase I and rRNA transcription (thereby increasing the synthetic rate of structural and functional proteins), blockage of the uptake of toxins such as α-amanitin from Amanita phalloides (the deathcap mushroom), and protecting the cell membrane from osmotic stress and radical-induced damage.

Superoxide dismutase (SOD) and the glutathione system are the 2 main physiological defence mechanisms against free radicals, both of which are subject to depletion during a period of toxic substance overload.

Two studies showed that silymarin 420 mg/day significantly increased the SOD activity of lymphocytes and erythrocytes, as well as SOD expression in lymphocytes of patients with histologically proven micronodular cirrhosis.

In 2 further studies, silymarin 10 mg/L significantly increased SOD expression in lymphocytes from patients with liver cirrhosis. Silymarin 420 mg/day has also been shown to significantly increase serum levels of glutathione and glutathione peroxidase and SOD activity of erythrocytes and lymphocytes compared with placebo in patients with chronic alcoholic liver disease. Furthermore, silymarin 800 mg/day significantly reduced serum levels of malondialdehyde, the end-product of linoleic acid oxidation in cell membranes, in a double-blind, placebo-controlled trial involving 60 patients who had been taking psychotropic drugs for at least 5 years.

Among patients with liver cirrhosis and concomitant type 2 diabetes mellitus, silymarin significantly reduced glucagon-stimulated C-peptide levels compared with placebo.

Silymarin has also demonstrated regulatory action of cell membrane permeability which has been associated with an increase in membrane stability against oxidative stress [e.g. oxidative stress from α-amanitin, phalloidin, carbon tetrachloride, paracetamol (acetaminophen), ethanol (alcohol) and metals, among others]. Furthermore, silybin, silychristin and silydianin inhibit the formation of prostaglandins, which are associated with lipid peroxidation. Silymarin has also shown significant anti-inflammatory and antifibrotic activity in animal models as well as in vitro inhibition of carcinoma cell growth and DNA synthesis.

Pharmacokinetic Profile

Following oral administration of silymarin 560mg to 6 healthy volunteers, maximum plasma concentrations of total silybin (both diastereomers of free and conjugated silybin) of 0.34 mg/L were reached within 1.32 hours, and the area under the plasma concentration-time curve was 1.14 mg/L · h. Between 75 and 90% of the administered dose of silybin is metabolised to glucuronide and sulphate conjugates. The plasma elimination half-life of total silybin is approximately 6 hours, and between 1 and 5% of an oral dose of silymarin is excreted unchanged in the urine. Between 20 and 40% of the administered dose of silybin is recovered, in conjugated form, in the bile. Plasma levels of silybin in patients with compensated liver cirrhosis were found to be within the normal range compared with those obtained in healthy volunteers.

Therapeutic Efficacy

Cirrhosis of the Liver: The effect of silymarin on the survival of patients with liver cirrhosis has been examined in 3 randomised, double-blind studies, none of which demonstrated a significantly beneficial effect on patient mortality. However, subanalysis in 1 of the studies demonstrated that long term treatment with silymarin 420 mg/day significantly increased the 4-year patient survival rate compared with placebo in a randomised, double-blind trial involving 170 patients with alcoholic (n = 91) or nonalcoholic (n = 79) cirrhosis of the liver. Furthermore, among patients with alcoholic cirrhosis, 22% (10 of 46) of the silymarin group died compared with 42% (19 of 45) of the control group (p = 0.01).

In a randomised, double-blind trial investigating the ability of silymarin to normalise parameters of liver function in patients with liver disease, treatment was significantly better with silymarin than with placebo. 36 patients were randomised to receive silymarin 420 mg/day in 3 divided doses or placebo for 6 months. During the course of silymarin treatment, mean patient serum levels of bilirubin normalised and AST, ALT and γ-glutamyl transferase (GGT) decreased significantly compared with baseline values.

Similarly, in a randomised double-blind trial involving 97 consecutive patients with liver disease induced by alcohol, silymarin 420 mg/day significantly improved serum levels of AST and ALT compared with placebo.

In a 6-month trial involving 27 patients with compensated active cirrhosis, silymarin 420 mg/day had no significant effect on patient serum levels of ALT, AST or bilirubin.

Patients With Cirrhosis and Type 2 Diabetes Mellitus: Compared with placebo, silymarin 600 mg/day for 12 months reduced lipid peroxidation of liver cell membranes and decreased the endogenous production of insulin and the need for exogenous insulin in a randomised, nonblind study involving 60 patients with type 2 diabetes mellitus and alcoholic liver cirrhosis.

Amanita Mushroom Poisoning: Among 175 patients with acute Amanita poisoning who were treated with silymarin (as silybin), only 8.6% died (data were published as case reports). However, 131 of the patients were also receiving benzylpenicillin (penicillin G) treatment. Of the remaining 44 patients who received silymarin alone, only 1 patient died and that was because of a suicidal intake of mushroom. Most patients received intravenous silybin 20 to 48 mg/kg/day. However, 5 patients were given oral silymarin as well as intravenous silybin; 1 patient received only oral silymarin 1.4 to 4.2 g/day.

Viral Hepatitis: Silymarin was largely ineffective in the treatment of viral hepatitis. In 59 patients with uncomplicated acute viral hepatitis A or B, silymarin 420 mg/day significantly lowered serum levels of bilirubin and AST compared with placebo over a treatment period of between 21 and 28 days. There were no significant between-group effects on serum levels of GGT, ALT, alkaline phosphatase and cholinesterase or on prothrombin time.

Furthermore, there were no between-group differences in liver function parameters in 3 trials involving 187 patients with acute or chronic viral hepatitis who were given silymarin 420 mg/day or placebo for between 5 weeks and 1 year.

Other Studies: Silymarin significantly improved serum indices of liver function in 49 patients who had been exposed to toxic levels of toluene or xylene. However, it had no significant effect on tacrine-induced elevated serum levels of ALT or AST in a 12-week, randomised, double-blind, placebo-controlled trial among 222 patients with Alzheimer’s disease.

Tolerability

In 2 trials involving 295 patients with liver cirrhosis, 9 patients (4 of whom withdrew from treatment) who received silymarin 420 or 450 mg/day complained of adverse events compared with 6 receiving placebo. Adverse events included nausea, epigastric discomfort, arthralgia, pruritus, headache and urticaria. However, assessment of tolerability was often not included in the trial designs.

Silymarin 420 mg/day for 30 days was reported to have caused a mild laxative effect in 4 of 24 patients who were being treated for exposure to organophosphates.

Dosage and Administration

The German Commission E indications for silymarin are for treatment of acute mushroom poisoning, adjunctive treatment of hepatic cirrhosis with or without a history of ethanol abuse or concurrent chronic hepatitis C infection, adjunctive treatment of acute viral hepatitis due to hepatitis A or B infection, and as a nutritional supplementation to promote healthy liver function.

Silymarin can be administered either as capsules or tablets containing silymarin extract (usually 70 or 140mg) or as an infusion of milk thistle fruits. The German Commission E recommends a daily dosage of 12 to 15g of crude herb or 200 to 400mg of silymarin calculated as silybin.

Adult patients with hepatic cirrhosis, regardless of prior history of ethanol abuse or concurrent hepatitis C infection, may receive silymarin 420 mg/day before meals. Patients should also abstain from any alcohol consumption.

Silybin dihemisuccinate, a derivative of silybin, is used as a clinical antidote for acute Amanita mushroom poisoning. The initial dosage should consist of silybin dihemisuccinate 5 mg/kg by intravenous infusion over the course of 1 hour followed by 20 mg/kg/day by continuous infusion for 6 days.

Because of insufficient data, silymarin should be used during pregnancy only when the benefits to the mother outweigh the risks to the fetus. Furthermore, it is unknown if silymarin is excreted in breast milk and a decision should be made whether to discontinue breast feeding when taking silymarin.

Silymarin should not be administered to children under 12 years of age unless the benefits outweigh the risks.

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References

  1. Schuppan D, Jia J-D, Brinkhaus B, et al. Herbal products for liver diseases: a therapeutic challenge for the new millennium. Hepatology 1999; 30(4): 1099–104

    Article  CAS  PubMed  Google Scholar 

  2. Morazzoni P, Bombardelli E. Silybum. marianum (Carduus marianus). Fitoterapia 1995; LXVI(1): 3–42

    Google Scholar 

  3. Simánek V, Kren V, Ulrichová J. Silymarin: what is in the name? An appeal for a change of editorial policy. Hepatology 2000; 32(2): 442–4

    Article  PubMed  Google Scholar 

  4. Leng-Peschlow E. Alcohol-related liver diseases — use of Legalon for therapy. Pharmedicum 1994; 2(3): 22–7

    Google Scholar 

  5. Madaus AG. Legalon 140. Available from: URL http://www.madaus.de/englisch/html/health/products/plegal140.htm [Accessed 2001 Mar 20]

  6. German Commission E. The complete German Commission E monographs: therapeutic guide to herbal medicines. Austin, Texas: The American Botanical Council, 1999

    Google Scholar 

  7. Luper S. A review of plants used in the treatment of liver disease: part 1. Altern Med Rev 1998; 3: 410–21

    CAS  PubMed  Google Scholar 

  8. Valenzuela A, Garrido A. Biochemical bases of the pharmacological action of the flavonoid silymarin and of its structural isomer silibinin. Biol Res 1994; 27: 105–12

    CAS  PubMed  Google Scholar 

  9. Flora K, Hahn M, Rosen H, et al. Milk thistle (Silybum. marianum) for the therapy of liver disease. Am J Gastroenterol 1998; 93: 139–43

    Article  CAS  PubMed  Google Scholar 

  10. Miadonna A, Tedeschi A, Leggieri E, et al. Effects of silybin on histamine release from human basophil leucocytes. Br J Clin Pharmacol 1987; 24: 747–52

    Article  CAS  PubMed  Google Scholar 

  11. Ahmad N, Gali H, Javed S, et al. Skin cancer chemopreventive effects of a flavonoid antioxidant silymarin are mediated via impairment of receptor tyrosine kinase signaling and perturbation in cell cycle progression. Biochem Biophys Res Commun 1998; 247: 294–301

    Article  CAS  PubMed  Google Scholar 

  12. Meroni PL, Barcellini W, Borghi MO, et al. Silybin inhibition of human T-lymphocyte activation. Int J Tissue React 1988; 10(3): 177–81

    CAS  PubMed  Google Scholar 

  13. Shear NH, Malkiewicz IM, Klein D, et al. Acetaminophen-in-duced toxicity to human epidermoid cell line A431 and hepatoblastoma cell line Hep G2, in vitro, is diminished by silymarin. Skin Pharmacol 1995; 8: 279–91

    Article  CAS  PubMed  Google Scholar 

  14. Bhatia N, Zhao J, Wolf DM, et al. Inhibition of human carcinoma cell growth and DNA synthesis by silibinin, an active constituent of milk thistle: comparison with silymarin. Cancer Lett 1999; 147: 77–84

    Article  CAS  PubMed  Google Scholar 

  15. Kim DH, Jin Y-H, Park J-B, et al. Silymarin and its components are inhibitors of β-glucuronidase. Biol Pharm Bull 1994; 17: 443–5

    Article  CAS  PubMed  Google Scholar 

  16. Dehmlow C, Erhard J, de-Groot H. Inhibition of Kupffer cell functions as an explanation for the hepatoprotective properties of silibinin. Hepatology 1996; 23: 749–54

    Article  CAS  PubMed  Google Scholar 

  17. Dehmlow C, Murawski N, deGroot H. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life sci 1996; 58: 1591–600

    Article  CAS  PubMed  Google Scholar 

  18. Miguez M-P, Anundi I, Sainz-Pardo LA, et al. Hepatoprotective mechanism of silymarin: no evidence for involvement of cytochrome P450 2E1. Chem Biol Interact 1994; 91: 51–63

    Article  CAS  PubMed  Google Scholar 

  19. Manna SK, Mukhopadhyay A, Van NT, et al. Silymarin suppresses TNF-induced activation of NF-kB, c-Jun N-terminal kinase, and apoptosis. J Immunol 1999; 163: 6800–9

    CAS  PubMed  Google Scholar 

  20. Fuchs EC, Weyhenmeyer R, Weiner OH. Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Arzneimittelforschung 1997; 47: 1383–7

    CAS  PubMed  Google Scholar 

  21. Machicao F, Sonnenbichler J. Mechanism of the stimulation of RNA synthesis in rat liver nuclei by silybin. Hoppe Seylers Z Physiol Chem 1977; 358: 141–7

    Article  CAS  PubMed  Google Scholar 

  22. Bindoli A, Cavallini L, Siliprandi N. Inhibitory action of silymarin of lipid peroxide formation in rat liver mitochondria and microsomes. Biochem Pharmacol 1977; 26: 2405–9

    Article  CAS  PubMed  Google Scholar 

  23. Koch HP, Bachner J, Löffler E. Silymarin: potent inhibitor of cyclic AMP phosphodiesterase. Methods Find Exp Clin Pharmacol 1985; 7(8): 409–13

    CAS  PubMed  Google Scholar 

  24. Valenzuela A, Aspillaga M, Vial S, et al. Selectivity of silymarin on the increase of the glutathione content in different tissues of the rat. Planta Med 1989 Oct; 55: 420–2

    Article  CAS  PubMed  Google Scholar 

  25. Tuchweber B, Sieck R, Trost W. Prevention by silybin of phalloidin-induced acute hepatoxicity. Toxicol Appl Pharmacol 1979 Nov; 51: 265–75

    Article  CAS  PubMed  Google Scholar 

  26. Trost W, Halbach G. Anti-phalloidine and anti-α-amanitine action of silybin in comparison with compounds similarto structural parts of silybin. Experientia 1978 Aug 15; 34: 1051–2

    Article  CAS  PubMed  Google Scholar 

  27. Pietrangelo A, Borella F, Casalgrandi G, et al. Antioxidant activity of silybin in vivo during long-term iron overload in rats. Gastroenterology 1995 Dec; 109: 1941–9

    Article  CAS  PubMed  Google Scholar 

  28. Mourelle M, Favari L, Amezcua JL. Protection against thallium hepatotoxicity by silymarin. J Appl Toxicol 1988 Oct; 8(5): 351–4

    Article  CAS  PubMed  Google Scholar 

  29. Muriel P, Mourelle M. Prevention by silymarin of membrane alterations in acute CCl4 liver damage. J Appl Toxicol 1990 Aug; 10: 275–9

    Article  CAS  PubMed  Google Scholar 

  30. Valenzuela A, Lagos C, Schmidt K, et al. Silymarin protection against hepatic lipid peroxidation induced by acute ethanol intoxication in the rat. Biochem Pharmacol 1985 Jun 15; 34: 2209–12

    Article  CAS  PubMed  Google Scholar 

  31. Crocenzi FA, Pellegrino JM, Sánchez Pozzi EJ, et al. Effect of silymarin on biliary bile salt secretion in the rat. Biochem Pharmacol 2000 Apr 15; 59: 1015–22

    Article  CAS  PubMed  Google Scholar 

  32. Haková H, Mišúrová E. The effect of silymarin and gamma radiation on nucleic acids in rat organs. J Pharm Pharmacol 1993 Oct; 45: 910–2

    Article  Google Scholar 

  33. Campos R, Garrido A, Guerra R, et al. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989 Oct; 55:417–9

    Article  CAS  PubMed  Google Scholar 

  34. Valenzuela A, Guerra R, Garrido A. Silybin dihemisuccinate protects rat erythrocytes against phenylhydrazine-induced lipid peroxidation and hemolysis. Planta Med 1987 Oct; 53: 402–5

    Article  CAS  PubMed  Google Scholar 

  35. Valenzuela A, Barria T, Guerra R, et al. Inhibitory effect of the flavonoid silymarin on the erythrocyte hemolysis induced by phenylhydrazine. Biochem Biophys Res Commun 1985 Jan 31; 126:712–8

    Article  CAS  PubMed  Google Scholar 

  36. Bokemeyer C, Fels LM, Dunn T, et al. Silibinin protects against cisplatin-induced nephrotoxicity without compromising cisplatin or ifosfamide anti-tumour activity. Br J Cancer 1996 Dec; 74: 2036–41

    Article  CAS  PubMed  Google Scholar 

  37. Gaedeke J, Fels LM, Bokemeyer C, et al. Cisplatin nephrotoxicity and protection by silibinin. Nephrol Dial Transplant 1996 Jan; 11:55–62

    Article  CAS  PubMed  Google Scholar 

  38. Alarcon de la Lastra C, Martin MJ, Marhuenda E. Gastric antiulcer activity of silymarin, a lipoxygenase inhibitor, in rats. J Pharm Pharmacol 1992 Nov; 44: 929–31

    Article  Google Scholar 

  39. Alarcön de la Lastra AC, Martin MJ, Motilva V, et al. Gastroprotection induced by silymarin, the hepatoprotective principle of Silybum. marianum. in ischemia-reperfusion mucosal injury: role of neutrophils. Planta Med 1995 Apr; 61: 116–9

    Article  Google Scholar 

  40. Krecman V, Skottová N, Walterová D, et al. Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta Med 1998 Mar; 64: 138–42

    Article  CAS  PubMed  Google Scholar 

  41. Mereish KA, Bunner DL, Ragland DR, et al. Protection against microcystin-LR-induced hepatotoxicity by silymarin: biochemistry, histopathology, and lethality. Pharm Res 1991 Feb; 8(2): 273–7

    Article  CAS  PubMed  Google Scholar 

  42. Utrilla MR Natural products with hepatoprotective action. Methods Find Exp Clin Pharmacol 1996; 18 Suppl. B: 11–2

    Google Scholar 

  43. Ramellini G, Meldolesi J. Liver protection by silymarin: in vitro effect on dissociated rat hepatocytes. Arzneimittelforschung 1976; 26: 69–73

    CAS  PubMed  Google Scholar 

  44. Ramellini G, Meldolesi J. Stabilization of isolated rat liver plasma membranes by treatment in vitro with silymarin. Arzneimittelforschung 1974 May; 24: 806–8

    CAS  PubMed  Google Scholar 

  45. Schriewer H, Weinhold F. The influence of silybin from Silybum. marianum. (L.) Gaertn. on in vitro phosphatidyl choline biosynthesis in rat livers. Arzneimittelforschung 1979; 29:791–2

    CAS  PubMed  Google Scholar 

  46. Montanini I, Castigli E, Arienti UG, et al. The effect of silybin on liver phospholipid synthesis in the rat in vivo. Farmaco sci1977 Feb; 32(2): 141–6

    CAS  PubMed  Google Scholar 

  47. Castigli E, Montanini I, Roberti R, et al. The activity of silybin on phospholipid metabolism of normal and fatty liver in vivo. Pharmacol Res Commun 1977 Jan; 9(1): 59–69

    Article  CAS  PubMed  Google Scholar 

  48. Fehér J, Lang I, Nákém K, et al. Effect of silibinin on the activity and expression of Superoxide dismutase in lymphocytes from patients with chronic alcoholic liver disease. Free Radic Res Commun 1987; 3: 373–7

    Article  PubMed  Google Scholar 

  49. Fehér J, Láng I, Nekám K, et al. In vivo effect of free radical scavenger hepatoprotective agents on Superoxide dismutase (SOD) activity in patients. Tokai J Exp Clin Med 1990 May; 15: 129–34

    PubMed  Google Scholar 

  50. Fehér J, Cornides A, Pál J, et al. Livercell protection in toxic liver lesion. Acta Physiol Hung 1989; 73(2-3): 285–91

    PubMed  Google Scholar 

  51. Múzes G, Deák G, Láng I, et al. Effect of the bioflavonoid silymarin on the in vitro activity and expression of Superoxide dismutase (SOD) enzyme. Acta Physiol Hung 1991; 78(1): 3–9

    PubMed  Google Scholar 

  52. Pascual C, González R, Armesto J, et al. Effect of silymarin and silybinin on oxygen radicals. Drug Dev Res 1993; 29(1): 73–7

    Article  CAS  Google Scholar 

  53. Fehér J, Láng I, Deák G, et al. Free radicals in tissue damage in liver diseases and therapeutic approach. Tokai J Exp Clin Med 1986; 11 Suppl.: 121–34

    PubMed  Google Scholar 

  54. Féher J, Lengyel G, Blázovics A. Oxidative stress in the liver and biliary tract diseases. Scand J Gastroenterol 1998; 33 Suppl. 228: 38–46

    Google Scholar 

  55. Palasciano G, Portincasa P, Palmieri V, et al. The effect of silymarin on plasma levels of malon-dialdehyde in patients receiving long-term treatment with psychotropic drugs. Curr Ther Res 1994 May; 55(5): 537–45

    Article  Google Scholar 

  56. Pall HS, Williams AC, Blake DR, et al. Evidence of enhanced lipid peroxidation in the cerebrospinal fluid of patients taking phenothiazines. Lancet 1987 Sep 12; II 596–9

    Article  Google Scholar 

  57. Conti M, Malandrino S, Magistretti MJ. Protective activity of silipide on liver damage in rodents. Jpn J Pharmacol 1992 Dec; 60: 315–21

    Article  CAS  PubMed  Google Scholar 

  58. Fiebrich F, Koch H. Silymarin, an inhibitor of prostaglandin synthetase. Experientia 1979 Dec 15; 35: 1550–2

    Article  CAS  PubMed  Google Scholar 

  59. Velussi M, Cernigoi AM, DeMonte A, et al. Long-term (12 months) treatment with an anti-oxidant drug (silymarin) is effective on hyperinsulinemia, exogenous insulin need and malondialdehyde levels in cirrhotic diabetic patients. J Hepatol 1997 Apr; 26: 871–9

    Article  CAS  PubMed  Google Scholar 

  60. Boigk G, Stroedter L, Herbst H, et al. Silymarin retards collagen accumulation in early and advanced biliary fibrosis secondary to complete bile duct obliteration in rats. Hepatology 1997 Sep; 26: 643–9

    Article  CAS  PubMed  Google Scholar 

  61. Fantozzi R, Brunelleschi S, Rubino A, et al. FMLP-activated neutrophils evoke histamine release from mast cells. Agents Actions 1986 Apr; 18: 155–8

    Article  CAS  PubMed  Google Scholar 

  62. de laPuerta R, Martinez E, Bravo L, et al. Effect of silymarin on different acute inflammation models and on leukocyte migration. J Pharm Pharmacol 1996 Sep; 48: 968–70

    Article  Google Scholar 

  63. Schulz HU, Schürer M, Krumbiegel G, et al. Investigation of dissolution and bioequivalence of silymarin products [in German]. Arzneimittelforschung 1995 Jan; 45: 61–4

    CAS  PubMed  Google Scholar 

  64. Lorenz D, Lücker PW, Mennicke WH, et al. Pharmacokinetic studies with silymarin in human serum and bile. Methods Find Exp Clin Pharmacol 1984 Oct; 6: 655–61

    CAS  PubMed  Google Scholar 

  65. Barzaghi N, Crema F, Gatti G, et al. Pharmacokinetic studies on IdB 1016, a silybin-phosphatidylcholine complex, in healthy human subjects. Eur J Drug Metab Pharmacokinet 1990 Oct-Dec; 15: 333–8

    Article  CAS  PubMed  Google Scholar 

  66. Weyhenmeyer R, Mascher H, Birkmayer J. Study on dose-linearity of the pharmacokinetics of silibinin diastereomers using a new stereospecific assay. Int J Clin Pharmacol Ther Toxicol 1992 Apr; 30: 134–8

    CAS  PubMed  Google Scholar 

  67. Rickling B, Hans B, Kramarczyk R, et al. Two high-performance liquid Chromatographic assays for the determination of free and total silibinin diastereomers in plasma using column switching with electrochemical detection and reversed-phase chromatography with ultraviolet detection. J Chromatogr B Biomed Appl 1995 Aug 18; 670: 267–77

    Article  CAS  PubMed  Google Scholar 

  68. Flory PJ, Krug G, Lorenz D, et al. Studies on elimination of silymarin in cholecystectomized patients. I. Biliary and renal elimination after a single oral dose [in German]. Planta Med 1980 Mar; 38: 227–37

    Article  CAS  PubMed  Google Scholar 

  69. Orlando R, Fragasso A, Lampertico M, et al. Silybin kinetics in patients with liver cirrhosis: a comparative study of silybin-phosphatidilcholine complex and silymarin. Med sci Res 1990; 18(21): 861–3

    Google Scholar 

  70. Angulo P, Patel T, Jorgensen RA, et al. Silymarin in the treatment of patients with primary biliary cirrhosis with a suboptimal response to ursodeoxycholic acid. Hepatology 2000 Nov; 32(5): 897–900

    Article  CAS  PubMed  Google Scholar 

  71. Magliulo E, Gagliardi B, Fiori GP. Results of a double blind study on the effect of silymarin in the treatment of acute viral hepatitis, carried out at two medical centres [in German]. Med Klin 1978 Jul 14; 73: 1060–5

    CAS  PubMed  Google Scholar 

  72. Kiesewetter E, Leodolter I, Thaler H. Results of two double-blind studies on the effect of silymarine in chronic hepatitis [in German]. Leber Magen Darm 1977 Oct; 7: 318–23

    CAS  PubMed  Google Scholar 

  73. Bode JC, Schmidt U, Dürr HK. Silymarin for the treatment of acute viral hepatitis? Report of a controlled trial [in German]. Med Klin 1977 Mar 25; 72: 513–8

    CAS  PubMed  Google Scholar 

  74. Tănăsescu C, Petrea S, Băldescu R, et al. Use of the Romanian product Silimarina in the treatment of chronic liver diseases. Med Interne 1988 Oct-Dec; 26(4): 311–22

    PubMed  Google Scholar 

  75. Szilárd S, Szentgyörgyi D, Demeter I. Protective effect of Legalon in workers exposed to organic solvents. Acta Med Hung 1988; 45: 249–56

    PubMed  Google Scholar 

  76. Allain H, Schück S, Lebreton S, et al. Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer’s disease. Dement Geriatr Cogn Disord 1999; 10(3): 181–5

    Article  CAS  PubMed  Google Scholar 

  77. Lirussi F, Nassuato G, Orlando R, et al. Treatment of active cirrhosis with ursodeoxycholic acid and a free radical scavenger: a two year prospective study. Med sci Res 1995 Jan; 23: 31–3

    Google Scholar 

  78. Schuppan D, Strösser W, Burkard G, et al. Legalon lessens fibrosing activity in patients with chronic liver diseases: effect of Legalon 140 on collagen metabolism in patients with chronic liver diseases — appraisal by PIIINP determinations. Z Allg Med 1998; 74: 577–84

    Google Scholar 

  79. Mori F, Verucchi G, Attard L, et al. Treatment of chronic viral hepatitis: beneficial effect of ursodeoxycholic acid plus silymarin [abstract]. Ital J Gastroenterol 1995 Dec; 27 Suppl. 1: 178–9

    Google Scholar 

  80. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989 Jul; 9: 105–13

    Article  CAS  PubMed  Google Scholar 

  81. Parés A, Planas R, Torres M, 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 Apr; 28: 615–21

    Article  PubMed  Google Scholar 

  82. Bunout D, Hirsch S, Petermann M, et al. Effects of silymarin on alcoholic liver disease. Acontrolled trial [in Spanish]. Rev Med Chil 1992 Dec; 120: 1370–5

    CAS  PubMed  Google Scholar 

  83. Fehér J, Deák G, Muzes G, et al. Hepatoprotective action of silymarin therapy in chronic alcoholic liver disease [in Hungarian]. Orv Hetil 1989 Dec 17; 130: 2723–7

    PubMed  Google Scholar 

  84. Salmi HA, Sarna S. Effect of silymarin on chemical, functional, and morphological alterations of the liver: a double-blind controlled study. Scand J Gastroenterol 1982 Jun; 17: 517–21

    Article  CAS  PubMed  Google Scholar 

  85. Hraby K, Csomos G, Fuhrmann M, et al. Chemotherapy of Amanita phalloides poisoning with intravenous silibinin. Hum Toxicol 1983 Apr; 2: 183–95

    Article  Google Scholar 

  86. Hofer JF, Egermann G, Mach K, et al. Treatment of Amanita phalloides poisoning with silybin in combination with penicillin and cortisone [in German]. Wien Klin Wochenschr 1983 Apr 1; 95: 240–3

    CAS  PubMed  Google Scholar 

  87. Zilker TR, Felgenhauer NJ, Michael H, et al. Grading of severity and therapy of 154 cases of Amanita poisoning. Germany: Madaus AG, 1993. (Data on file)

    Google Scholar 

  88. Carducci R, Armellino MF, Volpe C, et al. Silibinin and acute poisoning with Amanita phalloides [in Italian]. Minerva Anestesiol 1996 May; 62: 187–93

    CAS  PubMed  Google Scholar 

  89. Vogel G, Tuchweber B, Trost W, et al. Protection by silibinin against Amanita phalloides intoxication in beagles. Toxicol Appl Pharmacol 1984 May; 73: 355–62

    Article  CAS  PubMed  Google Scholar 

  90. Boari C, Baldi E, Rizzoli O, et al. Silymarin in the protection against exogenous noxae. Drugs Exptl Clin Res 1981; VII(2): 115–20

    Google Scholar 

  91. Adverse Drag Reactions Advisory Committee. An adverse reaction to the herbal medication milk thistle (Silybum marianum). Med J Aust 1999 Mar; 170: 218–9

    Google Scholar 

  92. Clinical Pharmacology 2000. Milk thistle, Silybum. marianum.. Available from: URL http://cp.gsm.com/apps/default.asp?entry=&quickjump=11&rNum=299 [Accessed 2001 Feb 14]

  93. Fleming T, editor. PDR for herbal medicines. Montvale: Medical Economics Company, 2000

    Google Scholar 

  94. Zilker TR. Deathcap fungus poisoning — experts draft: up-to-date therapeutic recommendations. Notfall Medizin 1993; 19: 297–9

    Google Scholar 

  95. Pockros PJ. Cirrhosis. In: Rakel RE, editor. Conn’s current therapy. Philadelphia: Saunders, 2000: 465–71

    Google Scholar 

  96. Epstein FH. Cytokines in alcoholic and nonalcoholic steatohepatitis. N Engl J Med 2000; 343(20): 1467–76

    Article  Google Scholar 

  97. Kershenobich D, Vargas F, Garcia-Tsao G, et al. Colchicine treatment of cirrhosis of the liver. N Engl J Med 1988; 318(26): 1709–13

    Article  CAS  PubMed  Google Scholar 

  98. Orrego H, Blake JE, Blendis LM, et al. Long-term treatment of alcoholic liver disease with propylthiouracil. N Engl J Med 1987 Dec; 317(23): 1421–7

    Article  CAS  PubMed  Google Scholar 

  99. Keiding S, Badsberg JH, Becker U, et al. The prognosis of patients with alcoholic liver disease. An international randomized, placebo-controlled trial on the effect of malotilate on survival. J Hepatol 1994; 20: 454–60

    Article  CAS  PubMed  Google Scholar 

  100. Vendemiale G, Altomare E, Trizio T, et al. Effects of oral S-ad-enosyl-L-methionine on hepatic glutathione in patients with liver disease. Scand J Gastroenterol 1989; 24: 407–15

    Article  CAS  PubMed  Google Scholar 

  101. Mato JM, Camara J, Fernandez de Paz J, et al. S-adeno-sylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter trial. Hepatology 1999; 30(6): 1081–9

    Article  CAS  Google Scholar 

  102. Baker AL, Jaspan JB, Haines NW, et al. Arandomized clinical trial of insulin and glucagon infusion for treatment of alcoholic hepatitis: progress report in 50 patients. Gastroenterology 1981; 80: 1410–4

    CAS  PubMed  Google Scholar 

  103. Colman JC, Morgan NY, Scheuer PJ, et al. Treatment of alcohol-related liver disease with (+)-cyanidanol-3: a randomised double-blind trial. Gut 1980; 21: 965–9

    Article  CAS  PubMed  Google Scholar 

  104. O’Brien BL, Khuu L. A fata Sunday brunch: Amanita mushroom poisoning in a Gulf coast family. Am J Gastroenterol 1996; 91(3): 581–3

    PubMed  Google Scholar 

  105. Parish RC, Doering PL. Treatment of Amanita mushroom poisoning: a review. Vet Hum Toxicol 1986 Aug; 28: 318–22

    CAS  PubMed  Google Scholar 

  106. Floersheim GL. Treatment of human amatoxin mushroom poisoning: myths and advances in therapy. Med Toxicol 1987; 2: 1–9

    CAS  PubMed  Google Scholar 

  107. Floersheim GL, Weber O, Tschumi P, et al. Die klinische Knollenblätterpilzvergiftung (Amanita phalloides): prognostische Faktoren und therapeutische Massnahmen. Schweiz Med Wochenschr 1982; 112(34): 1164–77

    CAS  PubMed  Google Scholar 

  108. Beckurts KT, Hölscher AH, Heidecke CD, et al. The place of liver transplantation in the treatment of acute liver failure caused by Amanita phalloides poisoning [in German]. Dtsch Med Wochenschr 1997; 122(12): 351–5

    Article  CAS  PubMed  Google Scholar 

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Correspondence to Keri Wellington.

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R. Agarwal, AMC Cancer Research Center & Foundation, Denver, Colorado, USA; H. Allain, Laboratoire de Pharmacologie Expérimentale et Clinique, Université de Rennes I, Rennes, France; J. Barnes, School of Pharmacy, University of London, London, England; J. Chick, Royal Edinburgh & Associated Hospital Outpatients Department, Edinburgh, Scotland; L. Favari, Pharmacology and Toxicology Department, Centro de Investigación y de Estudios Avanzades del I.P.N., Mexico; P. Ferenci, 1st Department of Gastroenterology and Hepatology, University of Vienna, Vienna, Austria; P.C. Hayes, Department of Clinical and Surgical Sciences, Edinburgh University, Edinburgh, Scotland; Y. Mizushima, First Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan; B. Nalpas, Unite D’Hepatologie-Inserm U 370, Hôpital Necker, Paris, France; A. Parés, Alcohol and Liver Units, Hospital Clínici Provincial, Barcelona, Spain; J.D. Phillipson, School of Pharmacy, University of London, London, England; M.G. Roma, Instituto de Fisiología Experimental, CONICET-Universidad Nacional de Rosario, Rosario, Argentina; D. Schuppan, Department of Medicine I, University of Erlangen-Neurnberg, Erlangen, Germany; C. Soto, Pharmacology and Toxicology Department, Centro de Investigación y de Estudios Avanzades del I.P.N., Mexico; F. Stickel, Department of Medicine 1, University of Erlangen-Neurnberg, Erlangen, Germany; H. Tilg, Department of Medicine, University Hospital Innsbruck, Innsbruck, Austria; M. Velussi, Centro Antidiabetico, Ospedale Monfalcone, Gorizia, Italy.

Data Selection

Sources: Medical literature published in any language since 1966 on Silymarin, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘Silymarin’ and ‘Silybin’ and ‘Silibin’ and ‘Silibinin’. EMBASE search terms were ‘Silymarin’ and ‘Silybin’ and ‘Silibin’ and ‘Silibinin’. AdisBase search terms were ‘Silymarin’ and ‘Silybin’ and ‘Silibin’ and ‘Silibinin’. Searches were last updated 18 Jul 2001.

Selection: Studies in patients with liver disease or Amanita mushroom poisoning who received silymarin or silybin. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: liver disease, cirrhosis, Amanita mushroom poisoning, hepatitis, viral hepatitis, type 2 diabetes mellitus, pharmacodynamics, pharmacokinetics, therapeutic use.

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Wellington, K., Jarvis, B. Silymarin: A Review of its Clinical Properties in the Management of Hepatic Disorders. BioDrugs 15, 465–489 (2001). https://doi.org/10.2165/00063030-200115070-00005

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