Abstract 479: Pyrazole Analgesics Interfere With Aspirin-Induced Platelet Inhibition - A Novel and Clinically Significant Drug Interaction
Background : Aspirin may not sufficiently inhibit platelet function when administered together with ibuprofen and naproxen. We investigated whether pyrazole analgesics, which are weak inhibitors of platelet cyclooxygenase, may also interfere with the antiplatelet effect of aspirin.
Methods: Platelet rich plasma was obtained from healthy donors. Aliquots were pretreated with selected pyrazole derivatives at therapeutically relevant concentrations prior to the addition of aspirin. Thereafter, arachidonic acid-induced aggregation (turbidimetry), thromboxane B2 (TX) formation (immunoassay) and P-selectin expression (flow cytometry) were determined.
Results: Aspirin (30 μmol/L) completely suppressed arachidonic acid-induced platelet aggregation. However, aggregation was inhibited only by 63, 14 and 17% when aspirin was added in the presence of 1, 3 and 10 μmol/L methylaminoantipyrine (MAA), the active metabolite of dipyrone (n=4–6, p<0.05). Aspirin (30 μmol/L) also inhibited TX formation from 1309 ± 243 (control) to 114 ± 11 ng/L. Addition of MAA (1, 3 and 10 μmol/L) prior to aspirin resulted in significantly increased TX concentrations (223 ± 17, 324 ± 31 and 542 ± 96 ng/L, respectively, n=4–6, each p<0.05 vs. aspirin alone). Moreover, MAA largely prevented the aspirin-induced inhibition of platelet P-selectin expression. MAA (1, 3 and 10 μmol/L) by itself did not inhibit platelet aggregation and only moderately reduced TX formation (100 ± 7, 77 ± 6 and 48 ± 9% of control, respectively, n=4–6). We also studied additional, structurally related pyrazoles (bromphenazone, methylphenazone, ethylphenazone, propyphenazone) and obtained comparable results.
Conclusion: This study is the first to demonstrate that platelet inhibition by aspirin is antagonized by several pyrazole-related compounds, which are widely used for analgesic and antipyretic therapy. These drugs should be used with great caution in patients with cardio- and cerebrovascular disease who need antiplatelet treatment with aspirin.