Effects of the ACAT inhibitor CL 277,082 on cholesterol metabolism in humans.

A common pharmacologic approach to lowering elevated serum cholesterol levels has been to interfere with intestinal sterol absorption. Inhibitors of acyl coenzyme A: cholesterol acyltransferase (ACAT) should produce this effect. In this study, we examined the effects of CL 277,082, N-(2,4-difluorophenyl)-N-(4-neopentylbenzyl)-N-(n-heptyl)urea, an ACAT inhibitor, on cholesterol metabolism in humans. Eight healthy male volunteers were given a placebo for 14 days, followed by 750 mg/day CL 277,082 for 20 days in a single-blind, crossover design. Subjects were studied in a hospital research unit and were fed strictly controlled diets. Cholesterol absorption was measured by the dual isotope method during the final week of both the placebo and the drug phases. Sterol balance was also assessed during these two periods by measuring cholesterol intake, and fecal neutral and acidic sterol excretion rates. Plasma lipids and lipoproteins were measured at the end of each period. The drug was well tolerated and produced no detectable clinical or laboratory side effects. Cholesterol absorption, sterol excretion rates, and plasma lipoprotein levels were all unaffected by treatment. We conclude that CL 277,082 may not interfere with ACAT activity or cholesterol absorption in humans at the doses given under the conditions tested in this study.

Prostaglandin E2 analogue elicits renal and hormonal compensatory mechanisms in human hypertension.

Endogenous prostaglandin E2 appears to play an important role in cardiovascular homeostasis. When administered exogenously, it is a potent vasodilator, but the requirement for intravenous administration and its short duration of action have limited studies to its acute effects. A novel prostaglandin E2 analogue, CL 115347, can be administered transdermally on a long-term basis. The cardiovascular responses to the chronic administration of CL 115347 were studied in a double-blind, placebo-controlled trial in 26 subjects with essential hypertension (16 given drug, 10 placebo) maintained on a 100-mEq sodium diet. Administration of CL 115347 produced a fall in diastolic blood pressure of 7.8 +/- 1.3 mm Hg, compared with a 2.3 +/- 1.7 mm Hg fall in controls (p = 0.02), with no change in heart rate. The direct vascular effect of the drug was confirmed by attenuation of the vasoconstrictor response to angiotensin II infusion (13.4 +/- 3.1 vs 21 +/- 2 mm Hg at 3.0 ng/kg/min; p less than 0.05). However, the chronic blood pressure effect of CL 115347 was modest. Subjects receiving active drug showed significant compensatory increases in plasma renin, aldosterone, and norepinephrine levels accompanied by sodium retention and kaliuresis. In summary, chronic administration of this prostaglandin E2 analogue resulted in a modest decrease in blood pressure and antagonism of angiotensin II-mediated vasoconstriction. However, its effects were largely offset by compensatory increases in vasoconstrictor hormones and sodium retention.

Blood and tissue levels of [14C]isosorbide dinitrate after oral and intravenous administration to rat.

Rat blood and various tissues were analyzed for levels of isosorbide dinitrate (ISDN), an antianginal drug, after the administration of 14C-labeled compound. Unaltered [14C]ISDN was found in all tissues analyzed and in the circulating blood for up to 4 hours after p.o. or i.v. administration. These results clearly show that ISDN is not completely degraded in a single pass through the liver after either route of administration. ISDN concentration (nanograms of ISDN per gram wet weight of tissue) in vascular tissue were significantly greater than other tissues or the blood.