ANTITHROMBOTIC EFFECTS OF CX-397, A RECOMBINANT HIRUDIN ANALOG, IN A CANINE MODEL OF CORONARY-ARTERY THROMBOSIS

CX-397, a recombinant hirudin analog, is a potent and specific inhibit or of human alpha-thrombin. We conducted a comparative study of CX-397 and heparin in a canine model of left circumflex (LCX) coronary arter y thrombosis to evaluate the anti-thrombotic efficacy of CX-397. Admin istration of drugs (i.v.; bolus + infusion) was commenced 10 min prior to the initiation of LCX coronary artery electrolytic injury (100 mu A for 300 min). All saline-treated control animals (7/7) developed thr ombotic occlusion during the experimental period, leaving a residual t hrombus mass of 15.4 +/- 3.8 mg. Treatment with CX-397 at three increm ental dose levels reduced the incidence of occlusion (4/7, 2/5 and 0/7 ) and decreased thrombus weight (12.6 +/- 2.5 mg, 6.3 +/- 3.0 mg and 2 .1 +/- 1.3 mg, respectively) in a dose-dependent manner. At the interm ediate dose (15,000 ATU/kg + 15,000 ATU/kg/h) or higher, CX-397 showed significant anti-thrombotic effects (p <0.05 and p <0.01) and suppres sed increases in thrombin-antithrombin III complex (TAT) levels (p <0. 01 and p <0.001). In the heparin (80 U/kg + 60 U/kg/h)-treated group, the incidence of occlusion (5/7) and thrombus weight (14.1 +/- 6.2 mg) did not differ significantly from the control group. Plasma TAT level s in the heparin group decreased compared with the control group (p <0 .01), but was less potent than the intermediate dose CX-397 (p <0.01). The anti-coagulation (activated partial thromboplastin time and activ ated clotting lime) and template bleeding time prolongation effects of heparin were more potent than those of the intermediate dose CX-397 w hich showed significant anti-thrombotic effects. In conclusion, CX-397 dose-dependently suppressed thrombus formation by inhibition of throm bin activity in a canine coronary artery injury model. The anti-thromb otic efficacy of CX-397 was more potent than that of heparin at equiva lent anti-coagulation dosage.