Cardiovascular effects of a new inotropic drug in dog and normal man

Abstract

Cardiovascular effects of 1-butyl-3(1-(6,7-dimethoxyquinazolin-4-yl) piperidin 4 yl urea) (BDPU) were studied in 16 anesthetized dogs and in 7 healthy male volunteers. In animal experiments intravenous doses of 100, 250, and 500 mug/kg/min produced dose-related, significant increases in cardiac output and peak left ventricular dp/dt. No changes in heart rate and blood pressure occurred at 100 mug/kg/min, whereas higher doses caused falls in both systolic and diastolic blood pressures, accompanied by significant rises in heart rate. Inotropic effects could also be demonstrated in man. Changes of the systolic time intervals were dose-related and began at 64 mug/kg/min. At 250 mug/kg/min, the highest dose administered, the pre-ejection period decreased by 14.8 +/- 4.42 msec and its ratio with left ventricular ejection time by 0.049 +/- 0.017 against their respective control values (p less than 0.01). In contrast to animal experiments, no hypotension or tachycardia was observed in any subject. Pharmacokinetic studies showed a plasma elimination half-life of 76 +/- 3 min (mean +/- SE). There were no subjective side effects and standard laboratory tests were not altered, but there was a slight but significant rise in the urinary enzymes, lactic dehydrogenase (LDH) and glutamic oxaloacetic transaminase (GOT), which persisted up to 7 days.

Some aspects of the cardiovascular pharmacology of UK 14,275 in patients with coronary artery disease.

“…This haemodynamic study confirms previous experimental work in both conscous and anaesthetized animals (Danilewicz et al, 1976;Follath et al, 1976). We have demonstrated at 24% increase in cardiac output and a 43% improvement in LV dp/dtmax.…”

The inotropic effects of UK 14,275, a phosphodiesterase inhibitor, in man.

“…In the dose range that was investigated there was no chronotropic effect and the duration of action of the drug was 10 min with no evidence of any cumulative effect. These findings support those of Follath et al (1976).…”

“…Since diastolic pressure and heart rate were not affected by UK 14,275 in this study the shortening of PEP may be taken as a reliable indication of an increase in LV contractility in response to the drug. Follath et al (1976) showed a reduction in the inotropic potency of UK 14,275 after ,J-adrenergic :eceptor blockade in dogs. In our investigation UK 14,275 produced no shortening of PEP following ,6-adrenoceptor blockade which is of interest since the inotropic effect is thought to result from inhibition of cardiac phosphodiesterase (Alabaster et al, 1977).…”

“…UK 14,275 is a new compound chemically unrelated (Figure 1) to the cardiac glycosides or the catecholamines. The compound has been shown to have inotropic activity in intact instrumented dogs and non-invasively in man (Follath, Kersting, Lewis, Walden, Woolhouse & Dollery, 1976). It has been shown to inhibit cardiac phosphodiesterase activity in vitro with a potency 20 times that of theophylline and this activity is thought to be the basis of the inotropic effect (Alabaster, Blackburn, Joice, Massingham & Scholfield, 1977).…”

Cardiovascular effects of a new inotropic agent, U. K. 14275, in patients with coronary heart disease.

“…Follath, Kersting, Lewis, Walden, Woolhouse & Dollery (1976) have shown in human volunteers that the intravenous infusion of U.K. 14275 resulted in an increase in myocardial contractility without significant alteration in heart rate or blood pressure.…”