A randomized, placebo-controlled, crossover study of E5510 and aspirin in healthy volunteers

Platelet inhibition significantly reduces the risk of cardiovascular mortal ity and morbidity. However, current antiplatelet therapies have limitations , and more efficacious agents are needed. E5510 is a novel compound that ha s multiple platelet inhibitory effects in in vitro studies. We compared the in vivo, pharmacodynamic effects of maximal antiplatelet doses of E5510 (2 0 mg) with 300 mg aspirin in a placebo-controlled, triple crossover trial i n nine healthy volunteers. Collagen-induced platelet aggregation and serum thromboxane B-2 (TxB(2)) were similarly inhibited by both compounds in the first 12 h but showed recovery at 24 h in the E5510 group only (p < 0.05). Thrombin and Udr6619-induced platelet aggregation, as well as basal and pro staglandin E-2 (PGE(2))-stimulated platelet cyclic adenosine monophosphate (cAMP) levels were unchanged after ingestion of either agent. E5510 and asp irin reduced systemic thromboxane formation without affecting prostacyclin biosynthesis. Neither E5510 nor aspirin inhibited the excretion of 8-epi PG F(2 alpha) and 5,6-DHET, two indices of cyclooxygenase-independent arachido nate metabolism. In conclusion, (a) E5510 in vivo most likely induces a rev ersible inhibition of cyclooxygenase, without affecting thromboxane synthet ase, phosphodiesterase, thrombin, or thromboxane receptor-mediated signalin g; (b) single doses of aspirin or E5510 affect thromboxane/prostacyclin pro files favorably, supporting their use in acute coronary syndromes. This stu dy outlines a comprehensive and minimally invasive approach for the assessm ent of the in vivo mechanism of action of novel antiplatelet agents.