¹Departments of Clinical Pharmacology, Division of Warner-Lambert Company, Ann Arbor, Mich., USA;Department of Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Freiburg, Germany .

Correspondence: James C. Strand, PhD, Departments of Clinical Pharmacology, Parke-Davis Pharmaceutical Research, 2800 Plymouth Road, Ann Arbor, MI 48105-2430.

^aCurrent affiliation: Kerckhoff-Klinik, Bad Neuheim, Germany.

^bCurrent affiliation: Medizinische Klinik, Innenstadt der Universität, München, Germany.

^cCurrent affiliation: Städtische Kliniken Fulda, Innere Medizin I-Kardiologie, Fulda, Germany.

^dCurrent affiliation: Städtische Kliniken, Medizin II, Kassel, Germany.

^eCurrent affiliation: Clinical Pharmacology Department, Parke-Davis Pharmaceutical Research, Ann Arbor, Mich.

^fCurrent affiliation: Drug Safety Surveillance Europe, Parke-Davis Pharmaceutical Research, Freiburg, Germany.

^*Supported by the Departments of Clinical Pharmacology, Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Mich., and Freiburg, Germany.

Received 6 September 1995; Accepted 23 December 1995.

Abstract

Objective: To assess the pharmacodynamic activity and safety of rising single and multiple doses of intravenous quinaprilat compared with placebo in patients with New York Heart Association (NYHA) class III and IV congestive heart failure who were receiving digitalis or diuretic therapy or both.

Methods: Patients were randomly assigned to three treatment groups to receive low (0.5 and 1.0 mg), medium (1.0 and 2.5 mg), or high (5.0 and 10.0 mg) single intravenous doses of quinaprilat or placebo on day 1. On the basis of responses observed on day 1, the three treatment groups received stable multiple intravenous doses of either quinaprilat or placebo every 6 hours on days 2 and 3. Hemodynamic measurements, hormonal assessments, and safety were evaluated before and at specified intervals during the study.

Results: Compared with placebo, single and multiple doses of quinaprilat increased cardiac index and reduced pulmonary capillary wedge pressure, mean arterial pressure, systemic vascular resistance, and right atrial pressure in a dose-related manner. No clinically important change in heart rate was observed. Hemodynamic changes after multiple-dose quinaprilat administration were similar to those observed after single doses and were generally sustained during the 6-hour dosing interval. Relative to placebo, quinaprilat reduced plasma angiotensin converting enzyme (ACE) activity, angiotensin II concentration, and aldosterone concentration and increased plasma renin activity; no prominent changes in plasma catecholamine and atrial natriuretic peptide concentrations were observed. There were no clinically important drug-related changes in the safety parameters.

Conclusions: Single and multiple intravenous doses of 0.5 to 10 mg quinaprilat are well-tolerated and produce favorable dose-dependent hemodynamic effects and hormonal changes consistent with those expected of an ACE inhibitor in patients with NYHA class III and IV congestive heart failure.