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• W2125810010 abstract "We determined the dose response of the ADP antagonist clopidogrel (0.3-50 mg/kg p.o.) in rat models of thrombosis and provoked bleeding and correlated these activities to ex vivo platelet activation. Carotid artery thrombosis was induced by FeCl₂. Bleeding time was measured by mesenteric vessel puncture and renal cortex or cuticle incision. Platelet biomarkers included standard ADP-induced aggregation, P2Y₁₂ receptor occupancy, and phosphorylation of vasodilator-stimulated phosphoprotein. Clopidogrel decreased thrombus weight up to 78%, caused maximal prolongation of cuticle and mesenteric bleeding, but had little effect on renal bleeds. Due to the steep mesenteric dose response, further comparisons concentrated on cuticle bleeding. The half-maximal inhibitory dose (ED₅₀) for thrombus reduction was 2.4 ± 0.4 mg/kg, with 10 mg/kg providing optimal blood flow preservation and thrombus reduction. The ED₅₀ for bleeding was 10.5 ± 3.4 mg/kg. Increased bleeding was intermediate (3-fold) at 10 mg/kg and maximal (6-fold) at 30 mg/kg. All biomarkers were affected, but with differing sensitivity. ED₅₀s for peak platelet aggregation to 10 μM ADP (11.9 ± 0.4 mg/kg) and the vasodilator-stimulated phosphoprotein index (16.4 ± 1.3 mg/kg) approximated the higher ED₅₀ for bleeding. ED₅₀s for ligand binding (3.0 ± 0.3 mg/kg) and late aggregation (5.1 ± 0.4 mg/kg) better matched the lower ED₅₀ for antithrombotic activity. Aspirin exerted lesser effects on bleeding (42-70% increase in all models) and thrombosis (24% inhibition). In summary, antithrombotic doses of clopidogrel have limited effects on bleeding and standard measures of platelet aggregation. Other biomarkers may be more sensitive for tracking antithrombotic efficacy." @default.
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• W2125810010 date "2007-04-09" @default.
• W2125810010 modified "2023-10-12" @default.
• W2125810010 title "Biomarker Optimization to Track the Antithrombotic and Hemostatic Effects of Clopidogrel in Rats" @default.
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• W2125810010 doi "https://doi.org/10.1124/jpet.106.119156" @default.
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