Silymarin
 

     



The herb milk thistle has been used for centuries as an herbal medicine for the treatment of liver disease. The common name, milk thistle, is derived from the "milky white" veins on the leaves. When broken open they yield a milky sap. (1-3)

Milk Thistle contains Silymarin, which is composed of the flavanolignans silybin, silydianin and silychristine. Silybin is the most biologically active component. The seeds also contain betaine, trimethylglycine and essential fatty acids that augment Silymarin's liver protecting and anti-inflammatory effects. (4-6)

MECHANISMS OF ACTION


Silymarin's hepatoprotective effects result from several synergistic mechanisms that include antioxidation, (7) inhibition of lipid peroxidation, (8) enhanced liver detoxification via inhibition of Phase I detoxification, enhanced glucuronidation (9, 10) and protection against glutathione depletion. (11)

Silymarin produces several anti-inflammatory effects that include the inhibition of leukotriene and prostaglandin synthesis, Kupffer cell inhibition, mast cell stabilization and inhibition of neutrophil migration. (12-16)

Silymarin increases hepatocyte protein synthesis and hepatic tissue regeneration. The increase in the production of new liver cells to replace the damaged old ones demonstrates that Silymarin exerts both a protective and restorative effect on the liver. (17)

In animal studies, silybin has inhibited the conversion of hepatic stellate cells into myofibroblasts and reversed liver cell fibrosis. (18) Other studies showed Silymarin has immunomodulatory effects on a diseased liver. (19, 20)

Silymarin is many times more potent in antioxidant activity than vitamin E. Silymarin not only prevents the depletion of glutathione (GSH) induced by alcohol and other liver toxins, but it has increased the basal GSH of the liver by 35 % over controls. This is extremely useful when exposure to toxic substances is high, due to glutathione's vital role in detoxification reactions.

PHARMOKINETICS AND ADMINISTRATION


Because Silymarin is not water-soluble and only moderately absorbable from the GI tract, it is best administered in capsules containing a standardized extract of 70-80 percent of Silymarin. Peak plasma levels occur in four to six hours after an oral administration dose. Silymarin is excreted primarily via the bile. However some clearance occurs via the kidneys. The clearance half-life of Silymarin is from 6 to 8 hours after administration. (21-22)

CLINICAL USAGES


Silymarin has a broad range of liver protecting and therapeutic uses.

Alcoholic Liver Disease:

Silymarin is especially effective in the treatment and prevention of alcohol induced liver damage. In clinical studies, Silymarin has normalized serum liver enzymes, normalized total bilirubin levels and improved liver histology in patients with alcoholic liver disease. (23)

Toxic Chemical and Drug-induced liver Damage:

Silymarin is especially effective in the treatment and prevention of toxic chemical induced liver damage. This has been confirmed by histological (biopsy), clinical and laboratory data. (24-27)

Cirrhosis of the Liver:

In patients with long term cirrhosis of the liver, administration of Silymarin resulted in a significant increase in survival compared to the placebo group.(28)

Hepatitis:

Silymarin is effective in treating both acute and chronic hepatitis. In acute viral hepatitis, Silymarin decreased treatment time and lowered serum bilirubin, AST, and ALT. In patients with chronic hepatitis, Silymarin significantly improved serum liver enzymes. (29)

Fatty infiltration of the liver:
Silymarin has effectively treated fatty infiltration of the liver (chemical and alcohol induced fatty liver) and inflammation of the bile duct.

Lowering High Cholesterol:

Animal research found that that Silymarin increases HDL cholesterol and lowered total cholesterol levels. (30-31)


Dosage Range:


Milk Thistle is usually administered as a standardized extract containing 70-80% of Silymarin. The typical dosage range for an adult is 100-300 mg. several times a day.

Toxicity:


Human and animal and human studies have shown that Silymarin is non-toxic. At high doses (greater than 1500 mg per day), a laxative effect may occur due to increased bile secretion and flow.




SILYMARIN REFERENCES

  1. Bisset N. Herbal Drugs and Pharmaceuticals. London: CRC Press; 1994:121-123.
  2. Gruenwald J, Brendler T, Jaenicke C. PDR for Herbal Medicines. Montvale, NJ: Medical Economics Company, Inc.; 1998:1138-1141.
  3. Luper S. A review of plants used in the treatment of liver disease: part 1. Altern Med Rev 1998;4:410-421.
  4. Wagner H. Antihepatotoxic flavonoids. In: Cody V, Middleton E, and Harbourne JB eds. Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological, and Structure-Activity Relationships. New York, NY: Alan R. Liss, Inc.; 1986:545-558.
  5. Adzet T. Polyphenolic compounds with biological and pharmacological activity. Herbs Spices Medicinal Plants 1986;1:167-184.
  6. Hikino H, Kiso Y, Wagner H, Feibig M. Antihepatotoxic actions of flavonolignans from Silybum marianum fruits. Planta Medica 1984;50:248-250.
  7. Wagner H. Plant constituents with antihepatotoxic activity. In: Beal JL, Reinhard E eds. Natural Products as Medicinal Agents. Stuttgart: Hippokrates-Verlag; 1981.
  8. Bosisio E, Benelli C, Pirola O, et al. Effect of the flavano lignans of Silybum marianum L. on lipid peroxidation in rat liver microsomes and freshly isolated hepatocytes. Pharmacol Res 1992;25:147-154.
  9. Baer-Dubowska W, Szaefer H, Drajka-Kuzniak V. Inhibition of murine hepatic cytochrome P450 activities by natural and synthetic phenolic compounds. Xenobiotica 1998;28:735-743.
  10. Halim AB, el-Ahmady O, Hassab-Allah S, et al. Biochemical effect of antioxidants on lipids and liver function in experimentally-induced liver damage. Ann Clin Biochem 1997;34:656-663.
  11. Campos R, Garido A, Guerra R, et al. Silybin dihemisuccinate protects against glutathione depletion and lipid peroxidation induced by acetaminophen on rat liver. Planta Med 1989;55:417-419.
  12. Fiebrich F, Koch H. Silymarin, an inhibitor of lipoxygenase. Experentia 1979;35:150-152.
  13. 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.
  14. Fantozzi R, Brunelleschi S, Rubino A, et al. FMLP-activated neutrophils evoke histamine release from mast cells. Agents Actions 1986;18:155-158.
  15. Dehmlow C, Murawski N, de Groot H, et al. Scavenging of reactive oxygen species and inhibition of arachidonic acid metabolism by silibinin in human cells. Life Sci 1996;58:1591-1600.
  16. De La Puerta R, Martinez E, Bravo L. Effect of Silymarin on different acute inflammation models and on leukocyte migration. J Pharm Pharmacol 1996;48:968-970.
  17. Sonnenbichler J, Zetl I. Biochemical effects of the flavanolignane silibinin on RNA, protein and DNA synthesis in rat livers. In: Cody V, Middleton E, Harbourne JB, eds. Plant Flavonoids in Biology and Medicine: Biochemical, Pharmacological, and Structure-Activity Relationships. New York, NY; 1986:319-331.
  18. Fuchs EC, Weyhenmeyer R, Weiner OH, et al. Effects of silibinin and of a synthetic analogue on isolated rat hepatic stellate cells and myofibroblasts. Arzneimittelforschung 1997;26:643-649.
  19. Deak G, Muzes G, Lang I. Immunomodulator effect of Silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 1990:131:1291-1292, 1295-1296.
  20. Lang I, Nekam K, Gonzalez-Cabello R. Hepatoprotective and immunological effects of antioxidant drugs. Tokai J Exp Clin Med 1990;15:123-127.
  21. Schandalik R, Gatti G, Perucca E, et al. Pharmacokinetics of silybin in bile following administration of silipide and Silymarin in cholecystectomy patients. Arzneimittelforschung 1992;42:964-968.
  22. Tyler V. Herbalgram 1994;30:24-30.
  23. Feher I, Deak G, Muzes G. Liver protective action of Silymarin therapy in chronic alcoholic liver diseases. Orv Hetil 1989;130:2723-2727. [Article in Hungarian]
  24. Salmi, H.A., and Sarna, S., "Effect of Silymarin on chemical, functional, and morphological alteration of the liver. A double-blind controlled study" Scand.J.Gastroenterol., 1982, 17, pp 417-21
  25. Scheiber, V., and Wohlzogen, F.X., "Analysis of a certain type of 2 x 3 tables, exemplified by biopsy findings in a controlled clinical trial", Int.J.Clin.Pharmacol., 1978, 16, pp 533-5
  26. Boari, C., Montanari, M., Galleti, G.P., et al., "Occupational toxic liver diseases. Therapeutic effects of Silymarin", Min.Med., 1985, 72, pp 2,679-88.
  27. Wagner, H., "Plant constituents with antihepatotoxic activity", in Beal, J.L. and Reinhard, E. (eds) Natural Products as Medicinal Agents, Hippokrates-Verlang, Stuttgart, 1981
  28. Ferenci P, Dragosics B, Dittrich H, et al. Randomized controlled trial of Silymarin treatment in patients with cirrhosis of the liver. J Hepatol 1989;9:105-113.
  29. 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. Med Klin 1978;73:1060-1065. [Article in German]
  30. Kreeman V, Skottova N, Walterova D, et al. Silymarin inhibits the development of diet-induced hypercholesterolemia in rats. Planta Med 1998;64:138-142.
  31. Skottova N, Krecman V. as a potential hypocholesterolaemic drug. Physiol Res 1998;47(1):1-7


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