title: Comparative effects of immediate-release and extended-release aspirin on basal and bradykinin-stimulated excretion of thromboxane and prostacyclin metabolites.
abstract: A goal of aspirin therapy is to inhibit thromboxane production and platelet aggregation without inhibiting endothelial production of the vasodilator and anti-thrombotic prostacyclin. This study tested the hypothesis that extended-release aspirin (NHP-554C) would have increased selectivity for inhibition of basal and simulated thromboxane formation compared to immediate-release aspirin (ASA). Thirty-six healthy subjects were randomized to NHP-554C or ASA groups. Within each group, subjects were randomized to 5-day treatment with 81 mg/d, 162.5 mg/d and placebo in a crossover design in which treatment periods were separated by 2-week washout. On the fifth day of treatment, 81 mg/d and 162.5 mg/d ASA reduced basal urinary excretion of the stable thromboxane metabolite 11-dehydro-thromboxane B2 62.3% and 66.2% and basal excretion of the stable prostacyclin metabolite 2,3-dinor-6-keto-PGF1α 22.8% and 26.5%, respectively, compared to placebo. NHP-554C 81 mg/d and 162.5 mg/d reduced 11-dehydro-thromboxane B2 53% (P = 0.03 vs. ASA 81 mg/d) and 67.9% and 2,3-dinor-6-keto-PGF1α 13.4% and 18.5%, respectively. NHP-554C 81 mg/d did not significantly reduce basal excretion of the prostacyclin metabolite. Both doses of ASA and NHP significantly reduced excretion of both thromboxane and prostacyclin metabolites following intravenous bradykinin. During NHP-554C 162.5 mg/d, but not during ASA, bradykinin significantly increased urinary 2,3-dinor-6-keto-PGF1α. Nevertheless, 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-PGF1α responses to bradykinin were statistically similar during ASA and NHP-554C. In conclusion, at doses of 81 and 162.5 mg/d immediate- and extended-release aspirin selectively decrease basal thromboxane production. Both forms of aspirin decrease bradykinin-stimulated thromboxane and prostacyclin production, but some stimulated prostacyclin production remains during treatment with NHP-554C.
authors.affiliation: Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Jorge L
authors.initials: JL
authors.lastname: Gamboa
authors.affiliation: Division of Endocrinology Department of Medicine Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Jessica K
authors.initials: JK
authors.lastname: Devin
authors.affiliation: Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Claudia E
authors.initials: CE
authors.lastname: Ramirez
authors.affiliation: Department of Biostatistics Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Chang
authors.initials: C
authors.lastname: Yu
authors.affiliation: Department of Biostatistics Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Hui
authors.initials: H
authors.lastname: Nian
authors.affiliation: Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Rhonda H
authors.initials: RH
authors.lastname: Lee
authors.affiliation: Division of Clinical Pharmacology Department of Medicine Vanderbilt University Medical Center Nashville Tennessee.
authors.forename: Nancy J
authors.initials: NJ
authors.lastname: Brown
keywords: Aspirin; bradykinin; prostacyclin; thromboxane