Investigation of the pharmacodynamics and pharmacokinetics of 2-(2,4-Dimethoxyphenyl)-Imidazo-[4,5-b]-pyridine hydrochloride (AR-L 57 CL) in man

Summary

AR-L 57 CL is an imidazole derivative which has been shown in animal studies to have a pronounced positive inotropic effect. This effect and the pharmacokinetics of AR-L 57 CL have been investigated by non-invasive methods in 8 healthy volunteers. After a single intravenous dose of 200 mg, administered as part of Phase 1 of the clinical studies, AR-L 57 CL plasma concentrations were measured by fluorimetry at intervals for up to one hour. Its inotropic action on the heart was demonstrated by changes in the systolic time intervals: QS₂ = duration of electro-mechanical systole; PEP = pre-ejection period; LVET = left ventricular ejection time. The decrease in plasma concentration could be expressed in terms of an open two-compartment pharmacokinetic model. The shorter elimination phase had a t_1/2 of 4 min and the longer a t_1/2 of 30 min. Immediately after injection, QS₂ and PEP (corrected for heart rate) as well as PEP/LVET (independent of heart rate) decreased considerably. They had returned to normal by 22 min after injection. The plasma concentrations of AR-L 57 CL of 2 – 5 µg-equivalents/ml showed a highly significant correlation with the decrease in systolic time intervals. Both systolic and diastolic blood pressure rose briefly after injection. The AV conduction time fell initially and the heart-rate increased briefly. Thus AR-L 57 CL was shown to be a short acting drug with a high degree of positive inotropic action. It did not cause bradycardia or increase atrioventricular transmission time and appeared to be easily controllable.