Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits.
Inhibition of factor Xa (FXa) may interrupt thrombus progression. This study compared the antithrombotic activity of a novel FXa inhibitor, ZK-807834 [MW, 527 D; Ki (human FXa), 0.11 nM], with recombinant tick anticoagulant peptide [rTAP; MW, 6,685 D; Ki, (human FXa) = 0.28 nM], and DX-9065a [MW 445 D, Ki (human FXa), 40 nM] in rabbits with arterial thrombosis induced by electrical vascular injury. ZK-807834 also was compared with low molecular weight heparin (LMWH; MW, 5,500 D) during venous thrombosis induced by placing a copper wire and threads in the vena cava. Inhibitors were administered as an i.v. bolus and 2-h infusion. Total dosages of ZK-807834, > or =0.7 micromol/kg (n = 18); rTAP, > or =1 micromol/kg (n = 18); or DX-9065a, > or =11 micromol/kg (n = 18) decreased the incidence of arterial thrombotic occlusion compared with control animals (p < 0.05). However, five of six animals given the lowest effective dosage of rTAP and four of six animals given DX-9065a bled from a surgical incision >5 min, but only two of six animals given ZK-807834 bled >5 min. Venous clot weights were reduced compared with controls for dosages of ZK-807834 > or =0.007 micromol/kg (n = 36) or LMWH > or =0.2 micromol/kg (n = 18). Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were unchanged from baseline at the minimally effective dose of ZK-807834, whereas aPTT was increased twofold at the effective dose of LMWH. Thus ZK-807834 may be useful to attenuate thrombosis at lower dosages and with less perturbation of systemic hemostasis compared with available agents.
Abendschein
D R
DR
Cardiovascular Division, Washington University School of Medicine, St. Louis, Missouri 63110, USA. dabendsc@imgate.wustl.edu
Baum
P K
PK
Martin
D J
DJ
Vergona
R
R
Post
J
J
Rumennik
G
G
Sullivan
M E
ME
Eisenberg
P R
PR
Light
D R
DR
D000578:Amidines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000990:Antithrombin III / Q000493:pharmacokinetics / Q000627:therapeutic use*; D060829:Arthropod Proteins; D003328:Coronary Thrombosis / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005260:Female; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D009281:Naphthalenes / Q000627:therapeutic use; D010455:Peptides / Q000627:therapeutic use; D011422:Propionates / Q000627:therapeutic use; D011725:Pyridines / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011817:Rabbits; D013045:Species Specificity; D020246:Venous Thrombosis / Q000378:metabolism / Q000517:prevention & control*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000578:Amidines; D000925:Anticoagulants; D060829:Arthropod Proteins; D036341:Intercellular Signaling Peptides and Proteins; D009281:Naphthalenes; D010455:Peptides; D011422:Propionates; D011725:Pyridines; C063967:tick anticoagulant peptide; C114592:Fidexaban; D000990:Antithrombin III