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• W2074548352 abstract "Many compounds currently in development for treatment of thrombotic disorders demonstrate high specificity for single targets of blood coagulation such as factor Xa (FXa) or thrombin.The aim of this study is to determine if inhibition of both FXa and thrombin by simultaneous administration of PD0313052 and argatroban, respectively, synergistically increases the effect of either drug alone in vivo and in vitro.Analyses of thrombin generation from combined inhibition in human plasma using statistical methods of Bliss independence identified a synergistic reduction in thrombin production 30% lower than predicted by simple additivity. The greatest synergy occurred at concentrations of each compound below their individual IC50 values. In a rabbit arterio-venous shunt model (RAV) of thrombosis, co-administration of PD0313052 and argatroban reduced thrombus weight (TW) to a much greater degree than expected by additivity alone producing a synergistic decrease of 45% over the level predicted by additivity. Analyses of thrombin generation in plasma samples from the RAV also demonstrated 38% synergy ex vivo. Furthermore, at plasma concentrations with the greatest synergistic effect, no increase in bleeding or appreciable change in prothrombin time, activated partial thromboplastin time, or activated clotting time was observed, but thrombus weight reduction was greater than twofold higher than that expected from simple additivity.These results demonstrate a significant synergistic antithrombotic effect of combining low doses of PD0313052 and argatroban and support the hypothesis that simultaneous targeting of multiple coagulation enzymes may offer an improved therapeutic index in the prevention and treatment of thrombosis." @default.
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• W2074548352 date "2006-04-01" @default.
• W2074548352 modified "2023-10-14" @default.
• W2074548352 title "Inhibitors of blood coagulation factors Xa and IIa synergize to reduce thrombus weight and thrombin generation in vivo and in vitro" @default.
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• W2074548352 doi "https://doi.org/10.1111/j.1538-7836.2006.01830.x" @default.
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