The antithrombotic effects of CI-1031 (ZK-807834) and enoxaparin in a canine electrolytic injury model of arterial and venous thrombosis
Introduction
The activated serine protease Factor Xa plays an important role in the blood coagulation cascade because of its central location at the point where the extrinsic and intrinsic pathways converge. Factor Xa inhibitors prevent the generation of thrombin, thereby disrupting the thrombin feedback loop which amplifies thrombin production Gardell and Sanderson, 1998, Al-Obeidi and Ostrem, 1999. By reducing thrombin generation, inhibitors of Factor Xa may also attenuate platelet activity and clot stabilization. Several preclinical studies have demonstrated an enhanced efficacy-to-bleeding ratio with Factor Xa inhibitors compared to other antithrombotic strategies Lynch et al., 1994, Nicolini et al., 1996, Lefkovits et al., 1996, Sato et al., 1998a, Vlasuk et al., 1991. Therefore, the development of new antithrombotic agents that target Factor Xa may provide greater efficacy and reduced bleeding risk than current therapeutic approaches to thrombosis.
Low molecular weight heparins mediate inhibition of Factor Xa by enhancing antithrombin III activity and have been shown to provide more reliable anticoagulation with fewer side effects than standard unfractionated heparin (Zed, 1999). Enoxaparin is a low molecular weight heparin that is currently approved for the prevention and treatment of deep vein thrombosis and, more recently, to prevent ischemic events in patients with unstable angina (Brener, 2000). A number of limitations with low molecular weight heparins, including the inability to inactivate fibrin-bound thrombin and the risk of heparin-induced thrombocytopenia and osteoporosis, leave significant room for the development of safe, effective anticoagulants (Weitz, 1997).
Direct inhibitors of Factor Xa, in contrast to low molecular weight heparin, bind directly to the active site of Factor Xa and have been proven to be effective anticoagulants in experimental models of thrombosis (Weitz and Hirsh, 1998). CI-1031 (N-[2-[5-amidino-2-hydroxyphenoxy]-6-[3-(1-methyl-1H-imidazolin-2-yl)-phenoxy]-3,5-difluoropyrid), a potent and selective Factor Xa inhibitor with a Ki of 0.11 nM Phillips et al., 1998, Subramanyam et al., 1998, has previously been shown to attenuate thrombus progression in a rabbit model of thrombosis (Abendschein et al., 2000). The objective of this study was to evaluate CI-1031 and establish a dose–response relationship for antithrombotic efficacy versus bleeding risk. The study also compares the efficacy of CI-1031 with enoxaparin in an established canine model of arterial and venous thrombosis.
Section snippets
Surgical procedure
This study was conducted in compliance with the Animal Welfare Act Regulations and with the Guide for the Care and Use of Laboratory Animals (National Research Council, 1996). Mongrel dogs of either sex weighing 11–19 kg were anesthetized with 30 mg/kg intravenous sodium pentobarbital and intubated and ventilated with room air (Harvard dog ventilator, South Natick, MA). Arterial blood gasses were measured periodically to verify that pO2 exceeded 100 mm Hg and that pCO2 and pH were within normal
Time to occlusion and thrombus weights
The time to thrombotic occlusion in the control group was 69±5 min in the femoral artery compared to 127±19, 192±33 and 219±15 min in the 1.25, 2.5 and 5 μg/kg/min CI-1031 groups, respectively (Fig. 1). In the femoral veins, control occlusion times averaged 56±11 min compared to 153±22, 137±30 and 214±26 min in the respective CI-1031 treatment groups. In the arteries, the times to occlusion were significantly greater than control values in the 2.5 and 5 μg/kg/min groups. In the veins, the 1.25
Discussion
Inhibition of Factor Xa attenuates thrombin production while maintaining a level of thrombin activity necessary for primary hemostasis, thereby providing a potential advantage over other antithrombotics in regard to safety Verstraete and Zoldhelyi, 1995, Nicolini et al., 1996. A number of experimental studies have generated support for Factor Xa inhibitors as a potential improvement in antithrombotic therapy. Vlasuk et al. (1991) demonstrated that the selective peptide Factor Xa inhibitors
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