Harmonisation of ethics committees' practice in 10 European countries.

BACKGROUND: The Directive 2001/20/EC was an important first step towards consistency in the requirements and processes for clinical trials across Europe. However, by applying the same rules to all types of drug trials and transposing the Directive's principles into pre-existing national legislations, the Directive somewhat failed to meet its facilitation and harmonization targets. In the field of ethics, the Directive 2001/20/EC conditioned the way of understanding and transposing the "single opinion" process in each country. This led to a situation in which two models of research ethics committees organisation systems exist, being the model in which the "single opinion" is considered to be the decision made by a single ethics committee more effective and simpler in terms of administrative and logistic workload. METHOD: A survey was conducted in 10 European countries. Members of the European Clinical Research Infrastructures Network working party number 1, with expertise in the field of ethics, responded. RESULTS: There is a major heterogeneity in the composition of ethics committees among the surveyed countries based on the number of members, proportion of experts versus lay members and expertise of the scientific members. A harmonized education of the ethics committees' membership based in common curricula is recommended by the majority of countries. CONCLUSIONS: Despite the efforts for harmonization of the European Clinical Trial Directive, from an ethical point of view, there remains a plurality of ethics committees' systems in Europe. It is important to comprehend the individual national systems to understand the problems they are facing.

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 serum liver transaminase prohibiting an effective dosage in many patients. This 12-week randomised, double-blind, placebo-controlled study was undertaken to evaluate the ability of silymarin to antagonise or prevent the hepatotoxic 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: tacrine + silymarin and tacrine + placebo. The study was double-blind for silymarin and open for tacrine and was conducted in 22 French neurology and geriatric 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 assessed by MMSE and the Syndrome Kurtz test (SKT) were secondary evaluation criteria. Null hypotheses were evaluated with Fisher's exact test. FINDINGS: 222 patients were recruited and received silymarin and tacrine (110 patients) or placebo and tacrine (112 patients). 28 patients dropped out; 217 were included in the intent-to-treat analysis. No statistical difference was observed 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 notably gastrointestinal disorders were much less frequent in the silymarin group. 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 impact 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.

[Senna-containing laxatives: excretion in the breast milk?]. / Sennahaltiges Laxans: Ubertritt in Muttermilch?

The excretion of rhein, a cathartic with active metabolite from sennosides, was investigated in breast milk samples of 15 post-partum women for at least 24 h after the intake of a therapeutic dose (15 mg sennosides/day) of a standardized, fiber containing senna laxative (Agiolax). Rhein was analyzed by a HPLC-method with a lower limit of detection at 1 ng/ml rhein, taking into account a possible binding as monoglucuronide and monosulfate. Maximal concentrations up to 27 ng/ml and in 89% values below 10 ng/ml were measured. Related to the daily milk volume, 73% of the women excreted less than 2 ng rhein/day. Based on median values, 0.017% of the sennoside intake (calculated as rhein) was excreted in breast milk. The amount of rhein transmitted to the infant is therefore 0.3% of the rhein intake of the mother. This is far below the oral rhein dose necessary for inducing a laxative effect. Accordingly, none of the breast-fed infants (n = 8) showed any difference in stool consistency in comparison with the non breast-fed infants.

Relevance of rhein excretion into breast milk.

The excretion of rhein, a laxatively active metabolite of sennosides, was investigated in 100 breast milk samples of 20 post-partum women after intake of a standardized senna laxative (Agiolax), which also contains seeds of Plantago ovata as bulk substances. After daily doses of 5 g of the senna laxative containing 15 mg sennosides for 3 days, the rhein concentration in milk samples from every lactation during 24 h post-dose varied between 0 and 27 ng/ml with values below 10 ng/ml in 94%. Based on median values, 0.007% of the sennoside intake (calculated as rhein) was excreted in breast milk. None of the breast-fed infants had an abnormal stool consistency. Assuming a (theoretical) complete metabolism of sennosides to rhein in the mother, the amount of rhein delivered to the infant (ng/kg b.w.) is by the factor 10(-3) below the rhein intake of the mother.