In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor

Abstract

Summary. BAY 59-7939 is an oral, direct Factor Xa (FXa) inhibitor in development for the prevention and treatment of arterial and venous thrombosis. BAY 59-7939 competitively inhibits human FXa (K i 0.4 nM) with > 10 000-fold greater selectivity than for other serine proteases; it also inhibited prothrombinase activity (IC 50 2.1 nM). BAY 59-7939 inhibited endogenous FXa more potently in human and rabbit plasma (IC 50 21 nM) than rat plasma (IC 50 290 nM). It demonstrated anticoagulant effects in human plasma, doubling prothrombin time (PT) and activated partial thromboplastin time at 0.23 and 0.69 lM, respectively. In vivo, BAY 59-7939 reduced venous thrombosis (fibrin-rich, platelet-poor thrombi) dose dependently (ED 50 0.1 mg kg )1 i.v.) in a rat venous stasis model. BAY 59-7939 reduced arterial (fibrinand platelet-rich) thrombus formation in an arteriovenous (AV) shunt in rats (ED 50 5.0 mg kg )1 p.o.) and rabbits (ED 50 0.6 mg kg )1 p.o.). Slight inhibition of FXa (32% at ED 50 ) reduced thrombus formation in the venous model; to affect arterial thrombosis in the rat and rabbit, stronger inhibition of FXa (74%, 92% at ED 50 ) was required. Calculated plasma levels in rabbits at the ED 50 were 14-fold lower than in the rat AV shunt model, correlating with the 14-fold lower IC 50 of FXa inhibition in rabbit compared with rat plasma; this may suggest a correlation between FXa inhibition and antithrombotic activity. Bleeding times in rats and rabbits were not significantly affected at antithrombotic doses (3 mg kg )1 p.o., AV shunt). Based on these results, BAY 59-7939 was selected for clinical development.

Rivaroxaban Does Not Increase Hemorrhage after Thrombolysis in Experimental Ischemic Stroke

“…20 Therefore, three additional animals per group and time point received 30 mg/kg rivaroxaban or 10 ml/kg control solution without anticoagulant. After 1,8,16, and 24 hours in mice as well as 1, 4, and 8 hours in rats, 1 mL of whole blood was drawn from animals into a citrate tube. Platelet-poor plasma was obtained by immediate centrifugation at 2500 g for 15 minutes and stored at À 801C.…”

Comparison of antithrombin‐dependent and direct inhibitors of factor Xa or thrombin on the kinetics and qualitative characteristics of blood clots

“…The antithrombin‐dependent anticoagulants may selectively inhibit activated factor Xa (FXa), like fondaparinux or both FXa and thrombin, like low‐molecular‐weight heparins (LMWH) or unfractionated heparin (UFH). Rivaroxaban selectively and competitively inhibits free FXa and prothrombinase/clot‐associated FXa through reversible interactions, thereby inhibiting thrombin generation and decreasing fibrin clot formation 7, 8, 9. Fondaparinux, a methoxy form of the natural pentasaccharide sequence, is also a selective antithrombin (AT)‐dependent FXa inhibitor.…”

TEG ir naujieji peroraliniai antikoaguliantai

“…Rivaroksabanas yra geriamasis selektyvus tiesioginis aktyvuoto X (Xa) faktoriaus inhibitorius [5,14]. Rivaroksabanas gali slopinti laisvą, prisijungusį prie trombocitų ir protrombinazės komplekse esantį Xa faktorių, kai tuo tarpu netiesioginiai Xa faktoriaus inhibitoriai (pvz., fondaparinuksas) slopina tik protrombinazės komplekse esantį Xa faktorių [5,15,16].…”

“…Šis vaistas taip pat gali būti skiriamas venų tromboembolijos profilaktikai suaugusiems asmenims, kuriems atliekamos sąnario pakeitimo operacijos bei insulto ir sisteminės embolijos profilaktikai, esant prieširdžių virpėjimui [5,14]. Planuojant atlikti invazinę procedūrą, rivaroksabano vartojimą rekomenduojama nutraukti likus mažiausiai 12 val.…”