Latin Name: Silybum marianum (L) Gaertner
Pharmacopoeial name; Cardui mariae fructus
Other names; blessed milk thistle, St. Mary thistle
About Milk Thistle
Milk thistle (Silybum marianum) was used in classical Greece to treat liver and gallbladder diseases and to protect the liver against toxins. It recently has been investigated for use as a cytoprotectant, and a supportive treatment for liver damage. Its active ingredient is silymarin, found primarily in the seeds. Silymarin undergoes enterohepatic recirculation, which results in higher concentrations in liver cells than in serum (1) It is made up of components called flavonolignans, the most common being silybin (2).
A number of studies have suggested that silymarin is an anti-inflammatory. It regulates inflammatory mediators such as tumor necrosis factor (TNF),TNF-alpha, nitrous oxide, interleukin-6, and interleukin-1 receptor antagonist (3-5). Silymarin also increases lymphocyte proliferation, interferon gamma, interleukin-4, and interleukin-10 cytokines, in a dose-dependent manner (6,7).
Taken together, these effects suggest a possible role in preventing or treating infectious disease. Several mechanisms of cytoprotection have been identified. In some studies, milk thistle promoted neuronal differentiation and survival (8). In others, silymarin inhibited leukotriene formation by Kupffer cells and increased expression of growth factor beta-1 and c-myc. (9,10) In animal studies, it has shown protective effects against damage to the pancreas from cyclosporin; damage to the kidney from paracetamol, cisplatin, and vincristine; and damage to the liver, partly by reducing lipid peroxidation (11-14). In another preclinical study, silymarin slowed the progression of alcohol-induced liver fibrosis. (15).
Milk thistle is an example of a product that is required to be in the standardised, concentrated form in order to fully convey the desired, in this case, hepatoprotectant effects. Milk Thistle preparations are usually standardised to a concentration of 70 to 80% of three flavonolignans (silibinin, silychrisin and silydianin), collectively known as silymarin. According to research conducted by the original manufacturer and primary researcher of milk thistle extract, this level of concentration of silymarin is required to survive degradation by gastric fluids and in order to enter the bloodstream via the intestinal wall. Silymarin is poorly absorbed (20-50%) from the gastrointestinal tract; thus, the concentrated extract is recommended.
Uses of Milk Thistle
Liver Disease
There have been over 120 clinical studies carried out on proprietary, milk thistle preparations , which suggest or confirm the efficacy of milk thistle extract various hepatic disorders, including hepatitis A, alcoholic cirrhosis and exposure to hazardous chemicals. In most countries Milk thistle is most commonly used to treat viral infections and cirrhosis of the liver.
Clinical trials have produced conflicting results. In a study of patients with cirrhosis, 170 patients (46 with alcoholism) were randomized to a proprietary product standardized to contain 70 to 80 percent silymarin, or placebo (16). In the 146 patients who completed 24 to 41 months of therapy, there was a lower mortality rate among the patients treated with silymarin. The greatest benefit occurred in those whose cirrhosis was caused by alcoholism and in those who had less severe cirrhosis on entry.
In a 6 month double blind study of 36 patients with chronic alcoholic liver disease, the group given the same product showed normalization of their bilirubin, aspartate transaminase and alanine transaminase serum levels, and also showed improvement in histology. These effects did not occur in the placebo group (17).
In another study, 106 patients with mild acute and subacute liver disease characterized by elevated serum transaminase levels were randomized to receive silymarin or placebo. Of the 97 patients who completed the four-week study, there was a statistically significant greater decrease in transaminase levels in the silymarin group (18).
In addition, results of a smaller study of 20 patients with chronic active hepatitis randomized to placebo or silybin showed that the milk thistle group had significantly lower trans- aminase, bilirubin, and gamma-glutamyltranspeptidase levels than the placebo group (19). This study used a complex of silybin with phosphatidylcholine, which appears to increase bioavailability.
Other studies have not duplicated these positive effects. In a study of 200 patients with alcoholic cirrhosis, there were no differences in time to death or progression to liver failure in the 125 patients who completed 24 months of therapy (20). Similarly, in a study of 72 patients with alcoholic liver disease, there were no differences in mortality or laboratory values between the placebo and silymarin groups (21). Finally, a three-month study of 116 patients with histologically proven alcoholic hepatitis randomized to placebo or silymarin showed non-significant differences in serum transaminase activity or histologic fibrosis scores (22).
Two meta-analyses of milk thistle for liver disease detail the major limitations of prior studies and conclude that data are insufficient to support its use at this time (23,24).
The two main limitations are the heterogeneity of the study populations, caused by lack of precise inclusion and exclusion criteria and the noncomparability of doses received. Most studies did not report or use objective criteria to determine the severity and aetiology of cirrhosis and did not control for confounding factors such as infection with hepatitis B or C and ongoing alcohol intake. In addition, the trials vary considerably in duration, ranging from one week to 41 months, without agreement on the minimum duration needed to see effect. The effect of silymarin is thought to be dose-dependent, and it is not known whether the bioavailability of different formulations is equivalent.
Because the studies used different products, it is not known whether participants in the different studies received equivalent doses. These limitations make comparisons of studies difficult to interpret. Efforts are under way to isolate, and extensively characterize the biologic activities of the flavonolignans that constitute silymarin (25). Most clinical trials have used daily dosages of 420 to 480 mg silymarin, divided into two or three doses daily.
Safety
The Agency for healthcare research and Quality reviewed the effects of milk thistle on liver disease and cirrhosis, noting that serious adverse reactions are virtually unheard of (23). The most common reported complaints were gastro- intestinal disturbances, but the overall incidence was no different from placebo. Allergic reactions, ranging from pruritus and rash to eczema and anaphylaxis, are rare. Drug interactions do not appear to be problematic. Silybin inhibits the activities of CYP2D6, CYP2e1, and CYP3A4, but at physiologic concentrations far higher than those given clinically (24) In a study of 10 healthy volunteers, administration of 175 mg of milk thistle three times daily for three weeks had no significant effect on concomitantly administered indinavir (25).
Keywords: milk thistle; liver disease
There is no EMEA monograph for milk thistle
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