Inhibitors of blood coagulation factors Xa and IIa synergize to reduce thrombus weight and thrombin generation in vivo and in vitro

Journal of Thrombosis and Haemostasis : JTH
W R GouldR J Leadley

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 prot...Continue Reading

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Citations

May 1, 2010·Catheterization and Cardiovascular Interventions : Official Journal of the Society for Cardiac Angiography & Interventions·Robert S Schwartz
Dec 17, 2009·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Edward C GiardinoBruce E Maryanoff
Jun 21, 2012·The Journal of the Acoustical Society of America·Wu-Jung LeeTimothy K Stanton
Aug 7, 2009·Blood Coagulation & Fibrinolysis : an International Journal in Haemostasis and Thrombosis·Sadia Meddahi, Meyer Michel Samama
Nov 16, 2016·Future Medicinal Chemistry·Ana R NevesMadalena Pinto
Mar 20, 2019·Marine Drugs·Francisca CarvalhalMarta Correia-da-Silva

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