ANTITHROMBOTIC ACTIVITY OF ARGATROBAN IN EXPERIMENTAL THROMBOSIS IN THE RABBIT

Argatroban was evaluated in three models of thrombosis in the rabbit: the Wessler model (thromboplastin plus stasis of the left jugular vein ), an arteriovenous shunt model, and a model of arterial thrombosis in duced by endothelial and intimal damage of the left femoral artery. Ca lcium heparin was used as a comparator. Both substances inhibited thro mbus formation in the Wessler model with ID50 values of 0.32 and 0.16 mg/kg intravenous bolus for argatroban and heparin respectively, with similar changes in thrombin time (4 to 5 times control) and activated partial thromboplastin time (APTT) (1.6 to 2.1 times control) for both substances at antithrombotic doses. The ID50 values of both substance s were 2.4 mu g/kg/min (argatroban) and 0.5 mu g/kg/min (heparin). Whe n they were administered by continuous infusion, no significant effect s on the APTT were noted. In the arteriovenous shunt, the ID50 values for argatroban and heparin (respectively) were 0.16 and 0.07 mg/kg int ravenous bolus, and 4.5 and 2.8 mu g/kg/ min intravenous infusion. Ves sel clamping followed immediately by electrical stimulation (5 mA dire ct current, 5 minutes) of the left femoral artery leads to the formati on of an occlusive thrombus approximately 30 minutes after clamping. A rgatroban infused for 60 minutes before the vascular lesion and throug hout the 90 minute observation period led to a dose-dependent delay in arterial occlusion with significant effects seen at 5 mu g/kg/min wit h five of eight animals showing normal femoral blood flow at 90 minute s postlesion at 20 mu g/kg/min; no significant increases (Dunnett's te st) in APTT were noted with argatroban. Heparin was without effect eve n at 40 mu g/kg/min, despite an eightfold increase in APTT at 20 mu g/ kg/min and values of more than 300 seconds at 40 mu g/kg/min. Thus, in models of arterial but not venous thrombosis, argatroban is a more po tent antithrombotic agent than heparin on a weight basis, with antithr ombotic effects at a much lower degree of systemic anticoagulation.