Aminotransferase levels and silymarin in de novo tacrine-treated patients with Alzheimer's disease

Background: Silymarin is a well-known hepatoprotective agent. Tacrine, the first drug marketed for Alzheimer's disease (AD), induces an elevation of s erum liver transaminase prohibiting an effective dosage in many patients. T his 12-week randomised, double-blind, placebo-controlled study was undertak en to evaluate the ability of silymarin to antagonise or prevent the hepato toxic effects of tacrine and to analyse its action on tacrine efficacy and tolerability. Methods: Outpatients suffering from mild-to-moderate dementia of the Alzheimer type were randomly assigned to two treatment groups: tacr ine + silymarin and tacrine + placebo. The study was double-blind for silym arin and open for tacrine and was conducted in 22 French neurology and geri atric centres. Silymarin (420 mg/day) was given first (1 week) and tacrine was added at 40 mg/day for 6 weeks, then increased to 80 mg/day (6 weeks). Serum ALAT was the main evaluation criterion (> upper limit of normal, ULN) . Serum ASAT as well as adverse side effects and cognitive performance asse ssed by MMSE and the Syndrome Kurtz test (SKT) were secondary evaluation cr iteria. Null hypotheses were evaluated with Fisher's exact test. Findings: 222 patients were recruited and received silymarin and tacrine (110 patient s) or placebo and tacrine (112 patients). 28 patients dropped out; 217 were included in the intent-to-treat analysis. No statistical difference was ob served between the two groups for serum ALAT (p = 0.39). Fewer patients had ALAT levels >5 ULN in the silymarin group (-33.3%). Side effects and notab ly gastrointestinal disorders were much less frequent in the silymarin grou p. Cognitive performance remained unchanged in both groups. Interpretation: Silymarin does not prevent tacrine-induced ALAT elevation but does reduce the rate of gastrointestinal and cholinergic side effects without any impac t on cognitive status. As a consequence, silymarin (420 mg/day) could be co -administered with tacrine to improve tolerability in the initial phases of AD treatment.