ANTITHROMBOTIC ACTIVITY IN-VIVO OF SDZ-217-766, A LOW-MOLECULAR-WEIGHT THROMBIN INHIBITOR IN COMPARISON TO HEPARIN

Antithrombotic potency of SDZ 217-766, a potent inhibitor of thrombin and other trypsin-like serine proteases, was studied in comparison wit h heparin in rat models of thrombin induced lung plate let accumulatio n, of thrombosis in arterio-venous shunt, and of venous thrombosis ind uced by tissue factor. Thrombin-induced platelet accumulation in the l ung was inhibited dose-dependently by SDZ 217-766 following intravenou s (i.v.) administration of 0.03 mg/kg to 0.3 mg/kg as well as by intra duodenal (i.d.) administration of 3 mg/kg and 10 mg/kg. Comparable inh ibitory effects were observed with heparin at 30 IU/kg and 100 IU/kg. In the rat arterio-venous shunt, following i.v. administration of SDZ 217-766, thrombus formation was inhibited by 40% at 0.1 mg/kg, by 60% at 0.3 mg/kg and was abolished at 1.0 mg/kg whilst APTT was prolonged 1.1 fold over the control value at 0.1 mg/kg and 2.7 fold at 1.0 mg/kg . Similar inhibitory effects were observed following i.d. administrati on of 10 and 30 mg/kg with only marginal (1.2 to 1.8 fold) APTT elevat ion. In the same model, heparin administered either i.v., 30-300 IU/kg , or subcutaneously, 100 and 300 IU/kg, inhibited thrombus formation d ose dependently but in contrast to SDZ 217-766, the inhibitory effect was paralleled by 5- to >10 fold APTT elevation over baseline. In the venous thrombosis model, SDZ 217-766 infused at 10 mu g/kg/min and 20 mu g/kg/min, reduced thrombus formation by 35% and 70%, respectively. In comparison, thrombus formation was decreased by 22% when heparin wa s infused at 1 IU/kg/min, and abolished at 3 IU/kg/min. At the doses t ested, APTT was prolonged much less with SDZ 217-766 (1.6 to 2.7 fold over baseline) than with heparin (2.8 to >10 fold over baseline). The ability of SDZ 217-766, compared with heparin, to prevent thrombus for mation with a minimum degree of anticoagulation together with its pote ntial oral bioavailability make SDZ 217-766 an interesting candidate f or the use in thrombosis prevention. Far the use in thrombosis treatme nt: however, the restricted selectivity profile of SDZ 217-766 for thr ombin over other serine proteases may limit its therapeutic potential.