Neville F Ford | PubMed Health

PubMed2005

Vasodilator effects of the endothelin ET receptor selective antagonist BMS-193884 in healthy men.

AIMS: A number of endothelin receptor antagonists (ERAs) are currently in clinical development as potential therapies in states characterized by vasoconstriction, such as systemic hypertension. We investigated the haemodynamic effects of locally and systemically active doses of BMS-193884, an endothelin A (ET(A)) receptor selective ERA, and its influence on vasoconstriction to endothelin-1 (ET-1) in healthy men. METHODS: In three separate randomized, placebo-controlled studies, the forearm blood flow (FBF) response to intra-arterial (i.a.) infusion of ET-1 (5 pmol min(-1)) was assessed during i.a. co-infusion of BMS-193884 (5 and 50 nmol min(-1)), and at 12 and at 24 h after oral administration of BMS-193884 (50, 100 and 200 mg at 12 h; and 200 mg at 24 h). Data were examined by repeated-measures analysis of variance (anova) with treatment and subject as factors. RESULTS: ET-1 caused significant forearm vasoconstriction, attenuated after oral dosing with BMS-193884 (200 mg) at 12 (P < 0.01) and 24 h (P < 0.0001). BMS-193884 (50 nmol min(-1), i.a.) caused local vasodilatation (25 +/- 11%) when infused alone (P = 0.02) and abolished forearm vasoconstriction to ET-1 (P < 0.0001 vs. ET-1 alone). Orally, BMS-193884 (200 mg) caused a reduction in total systemic vascular resistance at 12 (-14 +/- 9%, P = 0.03) and 24 h (-12 +/- 7%, P < 0.0001). There was no rise in plasma ET-1 levels. CONCLUSION: BMS-193884 causes local and systemic vasodilatation and attenuation of local vasoconstriction to ET-1. The absence of a rise in plasma endothelin levels suggests BMS-193884 is selective for the ET(A) receptor. This form of pharmacodynamic modelling may be useful in the development of ERAs in cardiovascular disease.

Administration, Oral↗

PubMed2004

Additive benefits of pravastatin and aspirin to decrease risks of cardiovascular disease: randomized and observational comparisons of secondary prevention trials and their meta-analyses.

BACKGROUND: In randomized trials of secondary prevention, pravastatin sodium and aspirin reduce risks of cardiovascular disease. Pravastatin has a predominantly delayed antiatherogenic effect, and aspirin has an immediate antiplatelet effect, raising the possibility of additive clinical benefits. METHODS: In 5 randomized trials of secondary prevention with pravastatin (40 mg/d), comprising 73 900 patient-years of observation, aspirin use was also prescribed in varying frequencies, and data were available on a large number of confounding variables. We tested whether pravastatin and aspirin have additive benefits in the 2 large trials (Long-term Intervention With Pravastatin in Ischaemic Disease trial and the Cholesterol and Recurrent Events trial) that were designed to test clinical benefits. We also performed meta-analyses of these 2 trials and 3 smaller angiographic trials that collected clinical end points. In all analyses, multivariate models were used to adjust for a large number of cardiovascular disease risk factors. RESULTS: Individual trials and all meta-analyses demonstrated similar additive benefits of pravastatin and aspirin on cardiovascular disease. In meta-analysis, the relative risk reductions for fatal or nonfatal myocardial infarction were 31% for pravastatin plus aspirin vs aspirin alone and 26% for pravastatin plus aspirin vs pravastatin alone. For ischemic stroke, the corresponding relative risk reductions were 29% and 31%. For the composite end point of coronary heart disease death, nonfatal myocardial infarction, coronary artery bypass graft, percutaneous transluminal coronary angioplasty, or ischemic stroke, the relative risk reductions were 24% and 13%. All relative risk reductions were statistically significant. CONCLUSION: More widespread and appropriate combined use of statins and aspirin in secondary prevention of cardiovascular disease will avoid large numbers of premature deaths.

Aged↗