Pharmacology of Silymarin

F. Fraschini, G. Demartini, D. Esposti,

Disclosures

Clin Drug Invest. 2002;22(1) 

In This Article

4. Therapeutic Activity

The results of most clinical trials with the thistle (Silybum marianum) extract, silymarin, are difficult to interpret because of a variety of reasons: small sample size, variability in type and severity of the liver disorders, heterogeneous dosages, inconsistent use of a control group, poorly defined objectives. Furthermore, the intrinsic capacity of the liver to improve after exposure to hepatotoxins was not always taken into consideration.

4.1 Acute Viral Hepatitis

The results of double-blind clinical trials in patients with acute viral hepatitis indicate that therapy with silymarin reduces complications, reduces the duration of hospital stay and promotes recovery. In patients with acute hepatitis randomly allocated to receive silymarin 140mg or placebo three times daily for at least 3 weeks, the proportion of patients in whom AST normalised was much higher in the treated group (82%) than in controls (52%). The percentage of patients in whom bilirubin normalised was 40% in the active treatment group versus 11% in the control group.[71]

4.2 Hepatitis Induced by Toxins or Drugs

It has been shown that silymarin reduces the hepatic injury produced by poisoning with A phalloides, phenothiazines and butyrophenones in humans.[13] Generally, the mortality rate among patients poisoned with A phalloides and treated with various drugs, except silymarin, ranges from 22 to 40% in adults, and is higher in children.[71]

In a retrospective study performed in patients with intoxication caused by A phalloides, the severity of hepatic injury was found to be closely related to the time that had elapsed between ingestion and treatment with silibinin: the shorter the interval, the less severe the injury.[72] Silibinin was administered by intravenous infusion at a mean dosage of 33 mg/kg/day for on average 81.6 hours. All the 18 patients included in the study survived, except one who had taken a high dose to commit suicide. Other treatments were not related to reduction in liver injury.

Patients exposed long term to organic phosphates and treated with silymarin for 1 month did not exhibit any improvement in liver function as compared with controls, although serum levels of pseudocholinesterase were considerably increased. This may reflect blockage of toxin anti-cholinesterase activity by silymarin.[73]

The few studies on silymarin in toxic hepatitis in the literature have yielded positive results. An interesting clinical trial was performed in patients being treated with psychotropic agents (phenothiazines or butyrophenones). Patients were subdivided into two groups: in the first group treatment was discontinued, and in the other group treatment was continued at the same dose. The groups were further subdivided into two subgroups: one was given silymarin 800mg daily for 90 days, the other was given placebo. The results showed that silymarin is able to improve liver function, independently of the discontinuation of psychotropic therapy.[74] Similar results were obtained by other authors.[71]

4.3 Chronic Hepatitis and Cirrhosis

In a clinical trial performed in 170 patients with a positive biopsy for cirrhosis, followed up for 2 to 6 years and given oral silymarin 140mg three times daily (87 patients, of whom 46 had cirrhosis due to alcohol abuse) or placebo (83 patients, of whom 45 had cirrhosis due to alcohol abuse) the mean survival rate after 4 years was significantly (p = 0.036) higher in patients treated with silymarin (58 ± 9%) as compared with those treated with placebo (39 ± 9%), whereas no significant difference was found in biochemical markers. Analysis of subgroups revealed that treatment was more effective in patients with alcohol-related cirrhosis (p = 0.01) and in groups of patients with nonalcoholic cirrhosis, whereas it was ineffective in patients with class B or C portal hypertension.[15]

Another two interesting studies are reported in the review by Flora et al.[71] The first study was performed in 2637 patients with chronic liver disease, treated with high doses of silymarin (560 mg/day) for 8 weeks. Resolution of subjective symptoms was achieved in 63% of cases; AST diminished on average by 36%, ALT by 34% and GGT by 46%. Furthermore, the investigators reported a reduction in hepatomegaly upon palpation. The second study was performed under double-blind conditions in patients with persistent or aggressive chronic hepatitis, with or without cirrhosis, monitored for 3 to 12 months and treated with silymarin. Treatment did not produce any signs of improvement in liver function; however, histological examination revealed an improvement in portal inflammation, parenchymal alterations and necrosis.

4.4 Alcohol-Related Liver Disease

A randomised clinical trial was performed in patients with moderate alcohol-related liver disease (ALT and AST <200 U/ml) and persistent abnormalities of liver function after abstinence from alcohol for at least 1 month. Patients were treated with silymarin 420 mg/day or with placebo for 4 weeks. At the end of the study period, mean AST and ALT levels diminished by 30.1% and

40.8%, respectively, in patients treated with silymarin who had completed the study as compared with increases of 5.4% and 2.8%, respectively, in patients treated with placebo (p ≥0.001). There was no significant difference in bilirubin levels.[75]

Not all the clinical trials performed with silymarin in this indication have yielded positive results.[76] The results of a recent randomised double-blind study in 125 patients with histologically documented alcohol-related cirrhosis did not show any significant benefit on survival after 2 years of treatment with silymarin 450 mg/day by the oral route.[77]

4.5 Dosage and Administration

In the clinical trials described, the daily oral dose of silymarin used ranged from 280 to 800mg. This is equivalent to 400 to 1140mg of standardised extract containing 70% silymarin. The recommended dosage for active disease is 140mg of silymarin (200mg of extract) three times daily. If the preparation silipide (silymarin-phosphatidylcholine) is used, 100mg three times daily is the appropriate dosage.[71] At higher dosages (>1500 mg/day) silymarin may have a laxative effect due to an increase in secretion and bile flow.[13] Moderate allergic reactions have also been reported.[13,66]

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