Characterisation of CYP3A gene subfamily expression in human gastrointestinal tissues.

The human CYP3A subfamily is of interest due to its multiplicity, activity toward known carcinogens, and extrahepatic expression. In situ hybridisation analysis of formalin fixed, routinely processed biopsy specimens was used to localise CYP3A mRNA in human gastrointestinal tissues from several individuals. CYP3A mRNA is abundant in human liver and in mucosal epithelial cells of all segments of the human small intestine. RNA blot analyses showed that the mRNA species observed in most livers and in human small intestine represent CYP3A3/3A4 transcripts. This was confirmed at the protein level by immunoblot comparison of small intestine microsomes to in vitro expressed CYP3A4 and CYP3A5 proteins. In liver and small intestine, CYP3A mRNA is not uniformly distributed, with grain density highest in cells within the respective non-proliferative compartments. CYP3A mRNA was also observed in human oesophagus and colon. RNA blot analysis of multiple colons showed heterogeneity in the CYP3A mRNAs present. Two CYP3A mRNAs (CYP3A3/3A4 and CYP3A5) were detected in colon samples from several individuals. In addition to those localisation studies, the capacity of expressed CYP3A4 and CYP3A5 to activate the dietary heterocyclic amine MeIQ in the presence of alpha-naphthoflavone was shown. These results show that there is considerable heterogeneity in the expression of the CYP3A subfamily in human gastrointestinal tissues

A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee

Many clinical trials have evaluated the benefit of long-term use of antiplatelet drugs in reducing the risk of clinical thrombotic events. Aspirin and ticlopidine have been shown to be effective, but both have potentially serious adverse effects. Clopidogrel, a new thienopyridine derivative similar to ticlopidine, is an inhibitor of platelet aggregation induced by adenosine diphosphate. METHODS: CAPRIE was a randomised, blinded, international trial designed to assess the relative efficacy of clopidogrel (75 mg once daily) and aspirin (325 mg once daily) in reducing the risk of a composite outcome cluster of ischaemic stroke, myocardial infarction, or vascular death; their relative safety was also assessed. The population studied comprised subgroups of patients with atherosclerotic vascular disease manifested as either recent ischaemic stroke, recent myocardial infarction, or symptomatic peripheral arterial disease. Patients were followed for 1 to 3 years. FINDINGS: 19,185 patients, with more than 6300 in each of the clinical subgroups, were recruited over 3 years, with a mean follow-up of 1.91 years. There were 1960 first events included in the outcome cluster on which an intention-to-treat analysis showed that patients treated with clopidogrel had an annual 5.32% risk of ischaemic stroke, myocardial infarction, or vascular death compared with 5.83% with aspirin. These rates reflect a statistically significant (p = 0.043) relative-risk reduction of 8.7% in favour of clopidogrel (95% Cl 0.3-16.5). Corresponding on-treatment analysis yielded a relative-risk reduction of 9.4%. There were no major differences in terms of safety. Reported adverse experiences in the clopidogrel and aspirin groups judged to be severe included rash (0.26% vs 0.10%), diarrhoea (0.23% vs 0.11%), upper gastrointestinal discomfort (0.97% vs 1.22%), intracranial haemorrhage (0.33% vs 0.47%), and gastrointestinal haemorrhage (0.52% vs 0.72%), respectively. There were ten (0.10%) patients in the clopidogrel group with significant reductions in neutrophils (< 1.2 x 10(9)/L) and 16 (0.17%) in the aspirin group. INTERPRETATION: Long-term administration of clopidogrel to patients with atherosclerotic vascular disease is more effective than aspirin in reducing the combined risk of ischaemic stroke, myocardial infarction, or vascular death. The overall safety profile of clopidogrel is at least as good as that of medium-dose aspirin