Aspirin has been postulated to exert a dose dependent, selective inhibition of thromboxane synthesis. We propose to compare the effects of acute and chronic administration of a wide range of aspirin doses on prostanoid generation and platelet function. In particular, we shall focus on the recovery of prostacyclin biosynthesis following aspirin as our preliminary data indicates prolonged suppression after chronic dosing. Aspirin is rapidly converted to salicylate in vivo and salicylate prevents inhibition of platelet thrombosane synthesis by aspirin in vitro. Thus, we also propose to assess the effects of sodium salicylate on endogenous prostanoid generation and the effects of salicylate consumption on aspirin inhibition of prostanoid generation in man. Novel synthesis of a deuterated derivative of aspirin will permit us to relate the pharmacokinetics of a range of aspirin doses to their pharmacodynamic effects and to characterize the potential interactions of aspirin and dipyridamole, two antiplatelet agents often used in combination in clinical practice. In vitro sulfinpyrazone inhibits platelet cyclooxygenase and platelet aggragation. The influence of sulfinpyrazone upon biosynthesis in man is unknown and in vitro studies suggest that metabolites, rather than the parent compound may mediate its antiplatelet effects in vivo. We propose to relate the pharmacokinetics of sulfinpyrazone and its metabolites during acute and chronic dosing to platelet function, and prostanoid production in man. Selective inhibition of thromboxane synthesis would be theoretically attractive, in that depression of prostacyclin synthesis would not occur as with cyclooxygenase inhibitors such as aspirin. We shall test the functional importance of such selectivity by a controlled comparison of the effects of such an inhibitor, dazoxiben, with high and low dose aspirin on indices of venous graft obstruction in patients with peripheral vascular disease. Such a study will also clarify whether diversion of endoperoxide metabolism towards increased biosynthesis of other prostanoids occurs during therapy with a thrombozane synthase inhibitor. Substantial resource has been devoted to clinical trials of antiplatelet drug with inconclusive results. By clarifying their clinical pharmacology, the proposed studies will permit more rational evaluation of these agents in the future.
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