CARDIAC AND HEMODYNAMIC-EFFECTS OF TZC-5665, A NOVEL PYRIDAZINONE DERIVATIVE, AND ITS METABOLITE IN HUMANS AND DOGS

1. TZC-5665 is a novel pyridazinone derivative with vasodilatory and b eta-adrenergic blocking activities and type III phosphodiesterase inhi bitory action. 2. In healthy volunteers, TZC-5665 was rapidly absorbed and immediately metabolized. Its main metabolite, M-2, remained at a higher concentration in plasma. Orally administered TZC-5665 reduced e nd-diastolic left ventricular volume (20.16 ml) and exhibited a tenden cy to increase ejection fraction (0.04). 3. In dogs, M-2 dose-dependen tly increased cardiac contractility and reduced both preload and after load. These effects appeared more potent in the failed heart than in t he normal heart. At the same dose (30 mu g/kg), the effects of M-2 see m to be more potent than those of milrinone. 4. We concluded that TZC- 5665 is a useful medication for treating patients with chronic congest ive heart failure (CHF) because of the positive inotropic and vasodila ting effects due to its active metabolite in addition to its own beta- adrenergic blocking actions. (C) 1997 Elsevier Science Inc.