Clopidogrel and drug metabolism: absence of effect on hepatic enzymes in healthy volunteers.

The influence of clopidogrel 75 mg, given once daily for 10 days on hepatic P-450 mixed function oxidases, was examined by assessing its effect on the disposition of antipyrine, on urinary 6-betahydroxycortisol (6beta-OHC) and on the plasma activity of gamma-glutamyl transpeptidase. This double-blind, randomized, placebo-controlled study was conducted in two parallel groups of 10 healthy young volunteers. Subjects were required to fast for 12 hours before and for 4 hours after dosing. Antipyrine 10 mg/kg was administered in the morning, two days before treatment (day -2) and 24 hours after the last dose of clopidogrel or placebo. Plasma levels of antipyrine, and urinary excretion of antipyrine, 3-hydroxymethyl-antipyrine and nor-antipyrine were measured over 36 hours post-drug for pharmacokinetic determinations. Bleeding time and platelet aggregation induced by 5 microM of ADP were measured before treatment (baseline) and at regular intervals after dosing during treatment. Clopidogrel treatment had a marked effect on platelet aggregation and bleeding time. No significant change in the disposition of antipyrine was observed after the ingestion of clopidogrel over 10 days: mean AUC ratio (+/-SEM) for plasma antipyrine was 1.021+/-0.023 for the clopidogrel group versus 1.001+/-0.019 for the placebo group; mean day 10/day -2 t 1/2 ratios were 1.019+/-0.018 and 1.027+/-0.023, respectively. Urinary excretions of antipyrine and metabolites were unchanged by clopidogrel compared to placebo. The changes in plasma cortisol concentrations, 6beta-OHC excretion and serum gamma-glutamyl transpeptidase activities observed at the end of treatment were fully comparable between the two treatment groups. Thus, the different tests showed no evidence of hepatic enzyme induction by clopidogrel in a pharmacologically effective dose regimen.

Results of EMATAP: a double-blind placebo-controlled multicentre trial of ticlopidine in patients with peripheral arterial disease.

EMATAP, a randomized stratified, placebo-controlled double-blind multicentre trial was performed in Argentina in order to confirm the effect of ticlopidine in the prevention of thrombotic events in patients with intermittent claudication. Twenty-one clinical centres enrolled 615 patients, 304 (88 diabetic and 216 non diabetic) were assigned to the ticlopidine group and 311 (95 diabetic and 216 non diabetic) to the placebo group. Treatments were given for 24 weeks. The baseline characteristics were identical in both groups. The compliance was good and only 34 patients (17 in each group) did not reach the last visit. Their status however was checked and known at that time and according to the protocol, there was no patient lost to follow-up. Twenty-five patients experienced a first event during the follow-up period and the results show a very dramatic reduction of events in the ticlopidine group (5 vs 20), the difference being highly significant (p = 0.002) in intention-to-treat analysis. If we consider the subgrouping of outcome events: sudden deaths, myocardial infarctions and strokes on the one hand, vascular surgery on the other hand, a significant reduction is found in the ticlopidine group. Taking into account the total deaths plus non-fatal events (9 vs 21), the results were also significant (p = 0.027). These above results therefore demonstrate a consistent reduction in all outcome events. As regard side effects there were fewer gastro-intestinal disturbances and skin reactions than seen in North American trials.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the efficacy of propranolol and amiodarone in suppressing ventricular arrhythmias following myocardial infarction.

The purpose of this prospective randomized trial was to compare the efficacy of propranolol and amiodarone in suppressing ventricular arrhythmias during the first 6 months following myocardial infarction (MI). 97 patients were treated with either amiodarone (n = 48) or propranolol (n = 49) starting on the 9th day following MI. Holter monitoring was carried out on four occasions: on D7, D21, D90 and D180. There was no statistical difference in the incidence of 'major' arrhythmias (an average of at least 10 ventricular premature complexes (VPCs) h-1, multiform or paired VPCs or runs) between the two groups on D7. A significant difference in favour of amiodarone became apparent at D180 (P = 0.04). Patients were also classified according to whether treatment failed or was successful. 'Success' was recorded when arrhythmias remained minor or became minor (less than 10 uniform VPCs h-1) and 'failure' when arrhythmias remained major or became major, or when patients were withdrawn because of side-effects, or lost to follow-up. The difference remained in favour of amiodarone (P = 0.03 at D21; P = 0.05 at D90; P = 0.06 at D180). Evaluation of the percentage reduction in the number of VPCs at D21, D90 or D180 compared with D7 showed superiority of amiodarone at D90 (P less than 0.01) and D180 (P less than 0.04). In this study, the overall effect of amiodarone on ventricular arrhythmias following MI was shown to be superior to that of propranolol.

[Comparative efficacy of amiodarone and propranolol on ventricular arrhythmia in the post-infarction period]. / Efficacité comparée de l'amiodarone et du propranolol sur les arythmies ventriculaires dans les suites d'infarctus du myocarde.

Beta-blockers are known to be effective against post-infarction ventricular arrhythmias and amiodarone has recently been shown to have this property. The purpose of this prospective randomized study was to compare the effects of beta-blockers and amiodarone during the first 6 months following infarction. Nine days after the onset of myocardial infarction, 97 patients were put on either amiodarone (48) or propranolol (49). Holter monitoring was performed on four occasions: on the 7th post-infarction day (baseline), then on the 21st, 90th and 180th days (under treatment). On D7 the two groups were similar in age, sex, risk factors, medical history, characteristics of the infarction and type of arrhythmia. For result analysis purposes the patients were divided into two categories depending on whether their arrhythmia was "moderate" (less than 10 monomorphous and isolated ventricular extrasystoles per hour) or "severe" (at least 10 ventricular extrasystoles per hour, or polymorphous or repetitive ventricular extrasystoles). Concerning the frequency of "severe" arrhythmia, there was no statistical difference between the two treatment groups on D7 (p = 0.53), but differences in favour of amiodarone became increasingly important during the study (p = 0.08 on D21; p = 0.07 on D90; p = 0.04 on D180).(ABSTRACT TRUNCATED AT 250 WORDS)