%0 Journal Article
%T The reversible P2Y12 antagonist ACT©\246475 causes significantly less blood loss than ticagrelor at equivalent antithrombotic efficacy in rat
%A Beat Steiner
%A Edgar Weber
%A Eva Caroff
%A Francis Hubler
%A Franck Haag
%A Keith Morrison
%A Markus A. Riederer
%A Markus Kramberg
%A Markus Rey
%A Martine Baumann
%A Martine Clozel
%A Patrick Hess
%A Roland Ernst
%J Archive of "Pharmacology Research & Perspectives".
%D 2017
%R 10.1002/prp2.338
%X The P2Y12 receptor is a validated target for prevention of major adverse cardiovascular events in patients with acute coronary syndrome. The aim of this study was to compare two direct©\acting, reversible P2Y12 antagonists, ACT©\246475 and ticagrelor, in a rat thrombosis model by simultaneous quantification of their antithrombotic efficacy and surgery©\induced blood loss. Blood flow velocity was assessed in the carotid artery after FeCl3©\induced thrombus formation using a Doppler flow probe. At the same time, blood loss after surgical wounding of the spleen was quantified. Continuous infusions of ACT©\246475 and ticagrelor prevented the injury©\induced reduction of blood flow in a dose©\dependent manner. High doses of both antagonists normalized blood flow and completely abolished thrombus formation as confirmed by histology. Intermediate doses restored baseline blood flow to ¡Ý65%. However, ACT©\246475 caused significantly less increase of blood loss than ticagrelor; the difference in blood loss was 2.6©\fold (P < 0.01) at high doses and 2.7©\fold (P < 0.05) at intermediate doses. Potential reasons for this unexpected difference were explored by measuring the effects of ACT©\246475 and ticagrelor on vascular tone. At concentrations needed to achieve maximal antithrombotic efficacy, ticagrelor compared with ACT©\246475 significantly increased carotid blood flow velocity in vivo (P = 0.003), induced vasorelaxation of precontracted rat femoral arteries, and inhibited contraction of femoral artery induced by electrical field stimulation or by phenylephrine. Overall, ACT©\246475 showed a significantly wider therapeutic window than ticagrelor. The absence of vasodilatory effects due to high selectivity of ACT©\246475 for P2Y12 provides potential arguments for the observed safety advantage of ACT©\246475 over ticagrelor
%K ACT©\246475
%K P2Y12
%K thrombosis
%K ticagrelor
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5625150/