EXP3174, the AII antagonist human metabolite of losartan, but not losartan nor the angiotensin-converting enzyme inhibitor captopril, prevents the development of lethal ischemic ventricular arrhythmias in a canine model of recent myocardial infarction.

OBJECTIVES: The antiarrhythmic efficacies of the competitive angiotensin II (AII) antagonist losartan, losartan's more potent noncompetitive AII antagonist human metabolite EXP3174 and the angiotensin-converting enzyme inhibitor captopril were assessed in a canine model of recent myocardial infarction. BACKGROUND: Multiple hemodynamic and electrophysiologic effects of AII may contribute to cardiac electrical instability. In the recent Losartan Heart Failure Study, Evaluation of Losartan in the Elderly (ELITE), a 722-patient trial primarily designed to assess effects on renal function, an unexpected survival benefit was observed with losartan compared with captopril, with the lower mortality using losartan primarily confined to a reduction in sudden cardiac death. METHODS: Intravenous losartan (1 mg/kg + 0.03 mg/kg/min), EXP3174 (0.1 mg/kg + 0.01 mg/kg/min), captopril (1 mg/kg + 0.5 mg/kg/h) or vehicle were infused in anesthetized dogs with recent (8.1 +/- 0.4 days) anterior myocardial infarction. Electrolytic injury of the left circumflex coronary artery to induce thrombotic occlusion and posterolateral ischemia was initiated 1 h after the start of treatment. RESULTS: Losartan, EXP3174 and captopril elevated plasma renin activities and comparably and significantly reduced mean arterial pressure. No significant electrocardiographic or cardiac electrophysiologic effects were noted with any treatment. Incidences of acute posterolateral ischemia-induced lethal arrhythmias were: vehicle, 7/9 (77%); losartan, 6/8 (75%); EXP3174, 2/8 (25%; p < 0.05 vs. vehicle control); captopril, 7/10 (70%). There were no among-group differences in time to onset of acute posterolateral ischemia or underlying anterior infarct size. CONCLUSIONS: EXP3174, but not losartan nor captopril, reduced the incidence of lethal ischemic ventricular arrhythmia in this preparation. The antiarrhythmic efficacy of EXP3174 may be due to an attenuation of deleterious effects of local cardiac AII formed during acute myocardial ischemia or, alternatively, a non-AII-related activity specific to EXP3174. These findings suggest that in humans, metabolic conversion of losartan to EXP3174 may afford antiarrhythmic protection.

The steady-state disposition of indinavir is not altered by the concomitant administration of clarithromycin.

STUDY OBJECTIVES: To evaluate the safety and potential pharmacokinetic interaction between indinavir and clarithromycin. STUDY METHODS: In a randomized, three-period, crossover fashion, 12 healthy adults received the following for 1 week: 800 mg oral indinavir sulfate every 8 hours with placebo, 500 mg oral clarithromycin every 12 hours with placebo, and indinavir sulfate with clarithromycin. Plasma indinavir, clarithromycin, and 14-hydroxyclarithromycin concentrations were determined after the last dose in each treatment period. RESULTS: Administration of indinavir sulfate with clarithromycin caused a statistically significant increase in four pharmacokinetic parameters: a 58% increase in plasma indinavir concentrations at 8 hours (P = .029), a 47% increase in values for clarithromycin area under the plasma concentration versus time curve from time zero to the last measured concentration [AUC(0-12h); P = .0002], and 49% and 48% decreases in 14-hydroxyclarithromycin AUC(0-12h) and maximum plasma concentration (Cmax) values, respectively (P = .0001 and P = .0001). These effects are not considered to be clinically significant in view of the insignificant effects on the values for indinavir area under the plasma concentration versus time curve from time zero to the last measured concentration [AUC(0-8h)] and Cmax, as well as the safety profile of clarithromycin. CONCLUSIONS: The combination of indinavir sulfate and clarithromycin is generally well tolerated and can be coadministered without dose adjustment.