Direct factor XA inhibitors

Rationale for direct factor Xa inhibitors in acute coronary syndromes... 

In contrast to unfractionated heparin, the factor Xa inhibitor tick anticoagulant peptide (TAP) effectively inhibited coronary arterial thrombosis in a canine electrolytic injury model (57). TAP was also effective in inhibition of the procoagulant properties of whole blood clots in vitro however, it was stated that TAP might be not optimal due to its slow binding kinetics (54). Meanwhile, several low molecular weight direct factor Xa inhibitors are in clinical development (Table I), some of them specifically for the treatment and secondary prevention of ACS. DX-9065a, ZK-807834 and otamixaban have been intensively characterized in vitro and in vivo and are in clinical investigations for the treatment of acute arterial thrombosis. 

The first evidence for the ex vivo antithrombotic effects of a direct factor Xa inhibitor in humans was provided in the Badimon chamber (71). Healthy volunteers received escalating... 

A further direct factor Xa inhibitor, otamixaban, is currently being investigated in the SEPIA-PCI trial in patients undergoing nonurgent PCI in comparison to heparin (78). 

Gerotziafas GT Elalamy I, Chakroun T et al. The oral, direct factor Xa inhibitor—BAY 59-7939—inhibits thrombin generation in vitro after tissue factor pathway activation. J Thromb Haemost 2005 3(suppl l) P2295. 

Harder S, Graff J, von Hentig N, et al. Effects of BAY 59-7939, an innovative, oral, direct Factor Xa inhibitor, on thrombin generation in healthy volunteers. Pathophysiol Haemost Thromb 2003 33(suppl 2) PO078. 

Paccaly A, Ozoux ML, Chu V et al. Pharmacodynamic markers in the eariy clinical assessment of otamixaban, a direct factor Xa inhibitor. Thromb Haemost 2005 94 1 156-1 163. 

Just M, Lorenz M, Skrzipczyk HJ, et al. Otamixaban, a direct factor Xa inhibitor, more potently inhibits experimental coronary thrombosis than bivalirudin, a direct thrombin inhibitor. J Thromb Haemost 2005 3(suppl I ) P01 15. 

Shimbo D, Osende J, Chen J, et al. Antithrombotic effects of DX-9065a, a direct factor Xa inhibitor a comparative study in humans versus low molecular weight heparin. Thromb Haemost 2002 88 733-738. 

Hinder M, Frick A, Rosenburg R, et al. Anticoagulant and antiplatelet effects are maintained following coadministration of otamixaban, a direct factor Xa inhibitor, and acetylsalicylic acid. Thromb Haemost 2006 95 224-228. 

Becker RC, Alexander JH, Dyke C, et al. Effect of the novel direct factor Xa inhibitor DX-9065a on thrombin generation and inhibition among patients with stable atherosclerotic coronary artery disease. Thromb Res 2006 I 17 439-446,... 

In summary, rivaroxaban 1 is an oral direct factor Xa inhibitor and is the first approved factor Xa inhibitor on the European and Canadian market. This class of inhibitors is expected to expand, with new members currently in late-stage clinical development. Rivaroxaban is indicated for the prevention of venous thromboembolic events in patients who have undergone elective total hip or total knee replacement surgery. Rivarobaxan was underwent extensive clinical program that included three Phase III trials of rivaroxaban involving a total of nearly 12,000 patients. The results from these three studies demonstrated the superior efficacy of the factor Xa inhibitor, both in head-to-head comparisons with enoxaparin and when comparing extended-duration (5 weeks) rivaroxaban with short-duration (2 weeks) enoxaparin. In all three... 

Indications Prevention of venous thromboembolism. Category Direct factor Xa inhibitor Half-life 3.5 hours... 

Wong PC, Crain EJ, Watson CA, Xin B. Favorable therapeutic index of the direct factor Xa inhibitors, apixaban and rivaroxaban, compared with the thrombin inhibitor dabigatran in rabbits. J Thromb Haemost 2009 7(8) 1313—1320. 

Kubitza D, Becka M, Mueck W, Halabi A, Maatouk H, Klause N, Lufft V, Wand DD, Philipp T, Bruck H. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct Factor Xa inhibitor. Br J Clin Pharmacol 2010 70(5) 703-12. 

Walenga JM, Prechel M, Jeske WP, Hoppensteadt D, Maddineni J, Iqbal O, Messmore HL, Bakhos M. Rivaroxa-ban—an oral, direct factor Xa inhibitor — has potential for the management of patients with heparin-induced thrombocytopenia. BrJ Haematol 2008 143(1) 92-9. 

DIRECT FACTOR XA INHIBITORS [SEDA>33, 635 SEDA 34, 546 SEDA 35, 620] Rivaroxaban [SEDA-34, 546 SEDA-35, 620]... 

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