Cardiac and hemodynamic effects of TZC-5665, a novel pyridazinone derivative, and its metabolite in humans and dogs.

Abstract

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.

• Authors: S Araki, T Uematsu, S Nagashima, T Matsuzaki, K Gotanda, H Ochiai, H Hashimoto, M Nakashima
• Journal: General pharmacology (Gen Pharmacol) Vol. 28 Issue 4 Pg. 545-53 (Apr 1997) ISSN: 0306-3623 [Print] England
• PMID: 9147023 (Publication Type: Clinical Trial, Comparative Study, Journal Article)

Chemical References

• Cardiovascular Agents
• Pyridazines
• Pyridones
• TZC 5665
• Milrinone

Topics

• Adult
• Animals
• Area Under Curve
• Cardiovascular Agents (pharmacokinetics, therapeutic use)
• Dogs
• Electrocardiography (drug effects)
• Female
• Half-Life
• Heart (drug effects)
• Heart Failure (drug therapy)
• Hemodynamics (drug effects)
• Humans
• Male
• Middle Aged
• Milrinone
• Myocardial Contraction (drug effects)
• Myocardium (pathology)
• Pyridazines (pharmacokinetics, therapeutic use)
• Pyridones (therapeutic use)
• Stimulation, Chemical