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.

Keywords: Aspirin; bradykinin; prostacyclin; thromboxane.

Figures

Figure 1

Study Protocol. Subjects in Group 1 were randomized to receive immediate‐release aspirin 81 mg, 162.5 mg, or identical‐appearing placebo daily for 5 days. Subjects in Group 2 were randomized to receive an extended‐release formulation (NHP‐554C) 81 mg, 162.5, mg or matching placebo. Subjects collected their urine for 24‐h for measurement of the stable metabolites of thromboxane A2 and prostacyclin. On the fifth day of study medication, subjects underwent a bradykinin infusion study (inset). Each treatment period was separated by 2 weeks.

Figure 2

Effect of 5‐day treatment with two doses of immediate‐release aspirin (ASA) or NHP‐554C on 24 h urinary excretion of (top) the stable metabolite of thromboxane, 11‐dehydro‐thromboxane B2, and (bottom) the stable metabolite of prostacyclin, 2,3‐dinor‐6‐keto‐PGF 1α. In the first six subjects randomized to each treatment group, we also measured basal serum thromboxane B2 (middle). Data are presented as means ±standard error of the mean. *P < 0.05 versus ASA group, †P < 0.05 versus placebo, ‡P < 0.05 versus 81 mg/d NHP‐554C.

Figure 3

Effect of 5‐day treatment with two doses of short‐acting aspirin (ASA) or NHP‐554C on urine 2,3‐dinor‐6‐keto‐PGF 1α and 11‐dehydro‐thromboxane B2 before and after 1 h intravenous administration of bradykinin. Data are presented as means ±standard error of the mean. *P < 0.05 versus time 0, †P < 0.05 versus placebo, ‡P < 0.05 versus 81 mg/d.