Antithrombotic activity in vivo of SDZ 217-766, a low-molecular weight thrombin inhibitor in comparison to heparin.

Abstract

Antithrombotic potency of SDZ 217-766, a potent inhibitor of thrombin and other trypsin-like serine proteases, was studied in comparison with heparin in rat models of thrombin induced lung platelet accumulation, of thrombosis in arterio-venous shunt, and of venous thrombosis induced by tissue factor. Thrombin-induced platelet accumulation in the lung was inhibited dose-dependently by SDZ 217-766 following intravenous (i.v.) administration of 0.03 mg/kg to 0.3 mg/kg as well as by intraduodenal (i.d.) administration of 3 mg/kg and 10 mg/kg. Comparable inhibitory 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. administration of 10 and 30 mg/kg with only marginal (1.2 to 1.8 fold) APTT elevation. In the same model, heparin administered either i.v., 30-300 IU/kg, or subcutaneously, 100 and 300 IU/kg, inhibited thrombus formation dose 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 micrograms/kg/min and 20 micrograms/kg/min, reduced thrombus formation by 35% and 70%, respectively. In comparison, thrombus formation was decreased by 22% when heparin was infused at 1 IU/kg/min, and abolished at 3 IU/kg/min.(ABSTRACT TRUNCATED AT 250 WORDS)

• Authors: C Tapparelli, R Metternich, P Gfeller, B Gafner, M Powling
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 73 Issue 4 Pg. 641-7 (Apr 1995) ISSN: 0340-6245 [Print] Germany
• PMID: 7495072 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Dipeptides
• Fibrinolytic Agents
• Guanidines
• SDZ 217766
• Heparin
• Thrombin

Topics

• Animals
• Dipeptides (therapeutic use)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Fibrinolytic Agents (therapeutic use)
• Guanidines (therapeutic use)
• Heparin (therapeutic use)
• Male
• Platelet Activation (drug effects)
• Rats
• Rats, Wistar
• Thrombin (antagonists & inhibitors)
• Thrombosis (blood, drug therapy)