Antithrombotic effects of BCH 2763, a new direct thrombin inhibitor, in a canine model of venous thrombosis.
Deep venous thrombosis (DVT) is a common cardiovascular disease, resulting in significant mortality each year in the United States. Direct thrombin inhibitors represent a new class of drugs that could potentially be better than conventional antithrombotic therapy based on indirect inhibition of coagulation factors with heparin and warfarin. BCH 2763 is a potent, selective bifunctional thrombin inhibitor that blocks both the active catalytic site and the anion binding exosite. The objective of this study is to test the antithrombotic efficacy of BCH 2763 in a canine model of DVT induced through electrolytic injury to the femoral vein. BCH 2763 was administered at three dose levels: 0.125 mg/kg bolus followed by 10 microg/kg/min IV infusion (low-dose; n = 5), 0.25 mg/kg bolus followed by 20 microg/kg/min infusion (mid-dose; n = 5), and 0.75 mg/kg bolus followed by 60 microg/kg/min (high-dose; n = 5). The control group (n = 5) received a 5-ml intravenous bolus of saline followed by a 1 mL/kg/h infusion. The parameters evaluated were changes in activated partial thromboplastin time (aPTT), thrombin time (TT), prothrombin time (PT), time to formation of an occlusive thrombus in the femoral vein, and the amount of venous blood flow delivered over the course of the experiment. There were significant dose-dependent increases in aPTT, TT, and PT in the BCH 2763-treated animals compared with the control group. The time to formation of an occlusive thrombus in the control group averaged 69.6 +/- 9 minutes. Treatment with BCH 2763 prolonged the time to occlusion to 126.4 +/- 13 minutes in the low-dose group, 155.4 +/- 17 minutes in the mid-dose group, and 229 +/- 7 minutes in the high-dose group (80% remained patent for the duration of the study), which were all significantly greater than the controls. Femoral venous blood flow was significantly greater in the mid-dose (51 +/- 8%) and the high-dose (70 +/- 6%) groups compared with the control vessels (22 +/- 3%). In conclusion, the results of this study indicate that BCH 2763 is an effective intravenous antithrombotic agent in the canine electrolytic injury model of venous thrombosis.
McClanahan
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Cardiovascular Therapeutics and Biometrics Sections, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105, USA. Tom.McClanahan@wl.com
Ignasiak
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Juneau
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Finkle
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Winocour
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Gallagher
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D000818:Animals; D000838:Anions / Q000378:metabolism; D001665:Binding Sites / Q000187:drug effects; D001760:Bleeding Time; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D005260:Female; D005268:Femoral Vein; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D013917:Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013924:Thrombophlebitis / Q000188:drug therapy*
D000838:Anions; D005343:Fibrinolytic Agents; D009842:Oligopeptides; C111479:BCH 2763; D013917:Thrombin