Abstract
A Phase I study of E-1020, a new positive inotropic agent, was performed on normal healthy volunteers to define its pharmacological characteristics, safety, and tolerance. The study evaluated both single (0.5, 1.0, 2.5, 5.0, 10.0, and 20.0 mg, n=4 for each) and repeated (5 and 10 mg t. i. d. for 7 days, n=6 for each) oral administration of E-1020. In all studies, subjects were evaluated by physical examination, blood pressure measurement, heart rate measurement, plasma concentration of E-1020, clinical laboratory tests, ECG and echocardiography during the administration of the drug and for varying periods thereafter.
1) Conjunctival hyperemia, flushing, and headache secondary to vasodilatory action, and palpitations due to positive inotropic and/or chronotropic action were observed in some cases. However, all symptoms were short-lived and of a mild nature, resulting in no clinically serious problems.
2) Both single and repeated dosing resulted in dose-related increases in plasma E-1020 Cmax and AUC with a t1/2 of 2 hr and urinary recovery of 40-50%.
3) The heart rate increased at higher doses, but blood pressure remained unchanged. An increase in fractional shortening, and cardiac output as assessed by M-mode echocar-diography indicated positive inotropic action.
We conclude that E-1020 is a potent positive inotrope with vasodilator properties and that it is well tolerated. There were no clinically significant adverse effects. The drug can be effective as an oral agent in patients with heart failure.
