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Interactions Between Milk Thistle and Antiretrovirals?

Question
Are there any known interactions between milk thistle and drugs used in HAART?
Gabriel G. Szego, MD

Response from Stephen C. Piscitelli, PharmD, 04/11/00
Milk thistle (Silybum marianum) is an herbal remedy widely used in HIV-infected patients for the treatment or prevention of liver disease caused by hepatitis and hepatotoxic drugs. The active constituent of milk thistle, silymarin, consists of a mixture of 3 biologically active flavonoids that are found in the fruit, seeds, and leaves of the plant.[1]
Clinical trials of silymarin have generally had small sample sizes,
heterogeneous populations, and various dosages, and many are not well controlled for factors such as stopping alcohol use. Despite these limitations, silymarin does appear to be more effective than placebo for viral hepatitis, as well as hepatitis caused by toxins and alcohol.[1,2]
It has been postulated to prevent liver damage caused by a variety of drugs, including phenytoin, halothane, and phenothiazines.[3] The drug is generally well tolerated with minimal adverse effects, primarily loose stools at high dosages and mild allergic reactions.[1,3]
There are very limited data in terms of the drug interaction potential for milk thistle. Animal studies have suggested some effect on the cytochrome P450 system, responsible for metabolism of protease inhibitors and NNRTIs.[4-6] However, a clinical study examining the effect of 28 days of therapy with silymarin showed no effect on the metabolism of aminopyrine
and phenylbutazone.[6] It should be noted that the dose of silymarin used in this trial was lower than that commonly used in clinical studies and for treatment of liver disease. Thus, a cross-over study evaluating the effect of standard doses of milk thistle on concentrations of protease inhibitors is certainly warranted.

As with all herbal remedies and alternative medications, great caution should be used by the patient since these products are unregulated and their content, side effects, and drug interaction potential has generally not been evaluated. Clearly, some alternative medicines can cause harm to the HIV-infected patient when combined with antiretrovirals.[7] It is unrealistic to ask patients not to use these products, since many will
continue to do so without informing their provider. Therefore,
physicians should include alternative medicines in the patient's drug history and note the dates at which the patients initiated and discontinued these products. These dates can then be compared with the onset or resolution of adverse effects and any change in the immunologic response, or virologic response to therapy.

The field of drug-herb interactions is likely to receive great
attention in the near future. Studies are currently ongoing to assess a variety of products. Many herbal products are indeed pharmacologically active.
Clinicians need to ask about herbal remedies and include these
products in the evaluation of adverse effects and response to therapy.


References
Pepping J. Milk thistle: Silybum marianum. Am J Health Syst Pharm. 1999; 56:1195-1197.
Flora K, Hahn M, Rosen H, Benner K. Milk thistle (Silybum marianum) for the therapy of liver disease. Am J Gastroenterol. 1998; 93:139-143.
Jellin JM, Batz F, Hitchens K. Milk Thistle. Natural Medicines
Comprehensive Database. Therapeutic Research Facility, Stockton, CA, 1999.
Zima T, Kamenikova L, Janebova M, Buchar E, Crkovska J, Tesar V. The effect of silibinin on experimental cyclosporine nephrotoxicity. Ren Fail.
1998; 20:471-479.
Racz K, Feher J, Csomos G, Varga I, Kiss R, Glaz E. An antioxidant drug, silibinin, modulates steroid secretion in human pathological adrenocortical cells. J Endocrinol. 1990; 124:341-345.
Leber HW, Knauff S. Influence of silymarin on drug metabolizing
enzymes in rat and man. Arzneimittelforschung. 1976; 26:1603-1605. Piscitelli SC, Burstein AH, Chaitt D, Alfaro RM, Falloon J. Indinavir concentrations and St. John's wort. Lancet. 2000; 355:547-548.