D raise from the bleeding time inside the vehicle group had been calculated by linear regression evaluation; the dose was estimatedFigureConcentration-response curve for ADP-induced platelet aggregation in prasugrel- (A) and ticagrelor-treated rats (B). Prasugrel and ticagrelor had been orally administered to rats 4 h ahead of blood collection. Ex vivo platelet aggregation in PRP was induced by 5, 20, 50 and 200 mmol -1 ADP. Benefits are presented as the imply SEM (n = 5). **P 0.01, considerably diverse from car group (Dunnett’s test). British Journal of Pharmacology (2013) 169 82?9BJPA Sugidachi et al.without the need of logarithmic transformation on the bleeding time. These values (ED200) have been 3.0 mg g-1 for prasugrel and 13 mg g-1 for ticagrelor.Platelet transfusion studyBoth prasugrel (10 mg g-1) and ticagrelor (30 mg g-1) significantly prolonged the bleeding time compared with vehicle-treated manage groups (P 0.BuyAzido-PEG2-C2-amine 001 and P 0.01, respec-tively) (Figure five). Platelet transfusion at three h soon after prasugrel or ticagrelor dosing resulted in equivalent substantial increases (1.61- and 1.56-fold, respectively) in blood platelet numbers in prasugrel- and ticagrelor-treated rats (information not shown). In contrast, red blood cell numbers were not changed by platelet transfusion in either group (information not shown). In the prasugrel-treated group, platelet transfusion resulted in substantial shortening of bleeding time (P 0.05, Figure five). Within the ticagrelor-treated group, by contrast, platelet transfusion didn’t adjust bleeding time (P 0.05, Figure five). As a result, though the prolongation of bleeding time induced by high-dose of prasugrel might be considerably reversed by platelet transfusion, this was not the case for ticagrelor.Discussion and conclusionsThienopyridines which includes prasugrel are antiplatelet prodrugs and their action is mediated by their active metabolites generated in vivo (Savi et al.1-(Difluoromethyl)-4-iodo-1H-pyrazole Price , 2000; Sugidachi et al.PMID:25959043 , 2000). In contrast, ticagrelor itself has antiplatelet activity (Springthorpe et al., 2007) and Sill et al. (2010) have reported not too long ago that ticagrelor also has an in vivo active metabolite AR-C124910XX, with potency related to that of ticagrelor (van Giezen and Humphries, 2005; Teng and Butler, 2010). To our knowledge, nevertheless, there isn’t any detailed report describing the antiplatelet activity of ticagrelor’s active metabolite. The present study is definitely the initial report showing antiplatelet activity of AR-C124910XX, which was two.4- to two.9 instances a lot more potent than its parent, ticagrelor, in rat PRP. Additionally, our preliminary experiment showed similarly potent activity of AR-C124910XX in human PRP (data not shown). The pharmacokinetic profile of AR-C124910XX in rats is not recognized, but, in humans, the AUC0�� of AR-C124910XX is about half to one-fifth of ticagrelor’s AUC0�� (Teng and Butler, 2010; Husted et al., 2012). Taken together, for that reason, these final results suggest that clinically, bothFigureEx vivo effects of prasugrel or ticagrelor on collagen-induced platelet aggregation in rats. Prasugrel and ticagrelor have been orally administered to rats 4 h just before blood collection. Ex vivo platelet aggregation in PRP was induced by 5 mg L-1 collagen. Outcomes are presented because the mean + SEM (n = 5). **P 0.01, considerably different from car group (Dunnett’s test).FigureEffects of prasugrel or ticagrelor on AV shunt thrombosis (A) and bleeding time (B) in rats. Prasugrel and ticagrelor were orally administered to rats four h just before circulation of blood by way of the AV shunt or bleed.