A phase I study of E-1020. Intravenous injection.

A phase I study of E-1020, a newly synthesized selective phosphodiesterase inhibitor that possesses both positive inotropic and vasodilatory properties, was carried out in healthy Japanese male volunteers.E-1020 was administered by intravenous infusion to evaluate its safety, and to establish its pharmacokinetic and pharmacodynamic profiles, at doses of 1. 25 μg/kg to 50 μg/kg with 5-min infusion (Step 1 to Step 7) and at doses of 61. 25 μg/kg to 163. 75 μg/kg with a combination of 15-min loading dose and following 165-min maintenance dose (Step 8 to Step 10).E-1020 was generally well tolerated by all subjects at each dose level, except for episodes of mild hyperemia in the eyes, a warm feeling in the face and/or the earlobes, and palpitation. These symptoms disappeared within a few hours after dosing, and seemed to be attributable to the pharmacological effects of the drug. Significant increments of heart rate were observed at the dose of 50 μg/kg (Step 7) and 61. 25 μg/kg to 163. 75 μg/kg (Step 8 to Step 10). However, no clinically significant changes in blood pressure, electrocardiograms, or clinical laboratory test values were noted.A significant increase in the mean values of the fractional shortening as assessed by echocardiography was observed after administration of the higher doses of E-1020.The plasma pharmacokinetics of E-1020 could be best described by an open linear two-compartment kinetic model. The half life in the β-phase was about 1 hr in all steps. The urinary excretion was about 80% of the dose, and mostly unchanged form.We conclude that the drug posesses a good tolerance and no clinically significant adverse effect as demonstrated in the present dose range of E-1020. Thus it is suitable for further clinical studies.