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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 (ETA) 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 ETA receptor. This form of pharmacodynamic modelling may be useful in the development of ERAs in cardiovascular disease. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the accumulated information from genetic association studies investigating the impact of variants of the cytochrome P450 (CYP) 2C19 genotype on the clinical efficacy of clopidogrel., Design: Systematic review and meta-analysis with a structured search algorithm and prespecified eligibility criteria for retrieval of relevant studies; dominant genetic model assumptions and quantitative methods for calculating summary effect estimates from study level odds ratios; systematic assessment of bias within and between studies; and grading of the cumulative evidence by consensus criteria., Data Sources: Medline, Embase, the Cochrane Library, online databases, contents pages and bibliographies of general medical, cardiovascular, pharmacological, and genetic journals. Eligibility criteria for selecting studies Original full length reports assessing the cumulative incidence of major adverse cardiovascular events or stent thrombosis over a follow-up period of at least a month in association with carrier status for the loss of function or gain of function CYP2C19 allele in adult patients with coronary artery disease and a clinical presentation of acute coronary syndrome or stable angina pectoris who were taking clopidogrel., Results: 15 studies met the inclusion criteria. The random effects summary odds ratio for stent thrombosis in carriers of at least one CYP2C19 loss of function allele versus non-carriers combining nine studies was 1.77 (95% confidence interval 1.31 to 2.40; P < 0.001). This nominally significant odds ratio was subject to considerable bias across the studies (small study effect bias and replication diversity). The adjustment for these quality modifiers tended to abolish the association. The corresponding random effects summary odds ratio of major adverse cardiovascular events for 12 studies combined was 1.11 (0.89 to 1.39; P = 0.36). The random effects summary odds ratio of stent thrombosis in carriers versus non-carriers of at least one CYP2C19*17 gain of function allele for three studies combined was 0.99 (0.60 to 1.62; P = 0.96), and the corresponding odds ratio of major adverse cardiovascular events in five studies was 0.93 (0.75 to 1.14; P = 0.48). The overall quality of epidemiological evidence was graded as low, which excludes reliable clinical assessments., Conclusions: Accumulated information from genetic association studies does not indicate a substantial or consistent influence of CYP2C19 gene polymorphisms on the clinical efficacy of clopidogrel. The current evidence does not support the use of individualised antiplatelet regimens guided by CYP2C19 genotype.