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 beta-adrenergic blocking activities and type III phosphodiesterase inhibitory 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 end-diastolic left ventricular volume (20.16 ml) and exhibited a tendency to increase ejection fraction (0.04). 3. In dogs, M-2 dose-dependently increased cardiac contractility and reduced both preload and afterload. These effects appeared more potent in the failed heart than in the normal heart. At the same dose (30 micrograms/kg), the effects of M-2 seem to be more potent than those of milrinone. 4. We concluded that TZC-5665 is a useful medication for treating patients with chronic congestive heart failure (CHF) because of the positive inotropic and vasodilating effects due to its active metabolite in addition to its own beta-adrenergic blocking actions.
Araki
S
S
Department of Pharmacology, Hamamatsu University School of Medicine, Japan.
Uematsu
T
T
Nagashima
S
S
Matsuzaki
T
T
Gotanda
K
K
Ochiai
H
H
Hashimoto
H
H
Nakashima
M
M
D000328:Adult; D000818:Animals; D019540:Area Under Curve; D002317:Cardiovascular Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D004285:Dogs; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006207:Half-Life; D006321:Heart / Q000187:drug effects; D006333:Heart Failure / Q000188:drug therapy*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D020105:Milrinone; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D011724:Pyridazines / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011728:Pyridones / Q000627:therapeutic use; D013268:Stimulation, Chemical
D002317:Cardiovascular Agents; D011724:Pyridazines; D011728:Pyridones; C088090:TZC 5665; D020105:Milrinone