A randomized, placebo-controlled, crossover study of E5510 and aspirin in healthy volunteers.
Platelet inhibition significantly reduces the risk of cardiovascular mortality and morbidity. However, current antiplatelet therapies have limitations, and more efficacious agents are needed. E5510 is a novel compound that has multiple platelet inhibitory effects in in vitro studies. We compared the in vivo, pharmacodynamic effects of maximal antiplatelet doses of E5510 (20 mg) with 300 mg aspirin in a placebo-controlled, triple crossover trial in nine healthy volunteers. Collagen-induced platelet aggregation and serum thromboxane B2 (TxB2) 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 U46619-induced platelet aggregation, as well as basal and prostaglandin E2 (PGE2)-stimulated platelet cyclic adenosine monophosphate (cAMP) levels were unchanged after ingestion of either agent. E5510 and aspirin reduced systemic thromboxane formation without affecting prostacyclin biosynthesis. Neither E5510 nor aspirin inhibited the excretion of 8-epi PGF2alpha and 5,6-DHET, two indices of cyclooxygenase-independent arachidonate metabolism. In conclusion, (a) E55 10 in vivo most likely induces a reversible inhibition of cyclooxygenase, without affecting thromboxane synthetase, phosphodiesterase, thrombin, or thromboxane receptor-mediated signaling; (b) single doses of aspirin or E5510 affect thromboxane/prostacyclin profiles favorably, supporting their use in acute coronary syndromes. This study outlines a comprehensive and minimally invasive approach for the assessment of the in vivo mechanism of action of novel antiplatelet agents.
Reilly
M P
MP
Division of Cardiology, University of Pennsylvania, School of Medicine, Philadelphia, USA.
Moran
N
N
Meagher
E
E
Delanty
N
N
Cucchiara
A E
AE
Lawson
J A
JA
Catella-Lawson
F
F
D000328:Adult; D001241:Aspirin / Q000493:pharmacokinetics / Q000494:pharmacology*; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D018592:Cross-Over Studies; D000242:Cyclic AMP / Q000378:metabolism; D004311:Double-Blind Method; D015777:Eicosanoids / Q000652:urine; D005229:Fatty Acids, Monounsaturated / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D013931:Thromboxanes / Q000097:blood
D015777:Eicosanoids; D005229:Fatty Acids, Monounsaturated; D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D000242:Cyclic AMP; D001241:Aspirin; C054678:Satigrel