Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis

• Published in: British journal of pharmacology Vol. 133; no. 7; pp. 1190 - 1198
• Main Authors: Rebello, Sam S, Bentley, Ross G, Morgan, Suzanne R, Kasiewski, Charles J, Chu, Valeria, Perrone, Mark H, Leadley, Robert J
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01-08-2001; Nature Publishing
• Subjects: Animals; Anticoagulants - therapeutic use; Biological and medical sciences; Blood Coagulation - drug effects; Blood. Blood coagulation. Reticuloendothelial system; Coronary Circulation - drug effects; Coronary thrombolysis; Coronary Thrombosis - drug therapy; Coronary Thrombosis - physiopathology; Cyclic N-Oxides - therapeutic use; Disease Models, Animal; Dogs; Dose-Response Relationship, Drug; factor Xa inhibitor; Factor Xa Inhibitors; Female; Fibrinolytic Agents - therapeutic use; FXV673; Heparin - therapeutic use; Male; Medical sciences; Partial Thromboplastin Time; Peptides - therapeutic use; Pharmacology. Drug treatments; Platelet Aggregation - drug effects; Platelet Glycoprotein GPIIb-IIIa Complex - antagonists & inhibitors; Prothrombin - antagonists & inhibitors; Prothrombin Time; Pyridines - therapeutic use; Recombinant Proteins - therapeutic use; reperfusion; Thrombolytic Therapy; Time Factors; Tissue Plasminogen Activator - therapeutic use; Treatment Outcome; Vascular Patency - drug effects; Cardiovascular disease; Coagulation Factor Xa; Anticoagulant; t-Plasminogen activator; Arterial disease; Vascular disease; Prevention; Reperfusion; Dog; Fissipedia; Carnivora; Glycoprotein IIbIIIa; Serine endopeptidases; Enzyme; Treatment efficiency; Coronary artery; Coronary heart disease; Fibrinolysis; Thrombosis; Biological activity; Antiplatelet agent; Peptidases; Vertebrata; Chemotherapy; Mammalia; Animal; Hydrolases; Heparin; Comparative study
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/sj.bjp.0704182

We compared the antithrombotic efficacy of a potent factor Xa inhibitor, FXV673, to heparin and RPR109891, a GPIIb/IIIa antagonist, when used as adjunctive therapy in a canine model of rt‐PA‐induced coronary thrombolysis.
Thrombus formation was induced by electrolytic injury to stenosed coronary artery. After thrombotic occlusion, a 135 min infusion of saline (n=8), FXV673 (10, 30 or 100 μg kg−1+1, 3, or 10 μg kg−1 min−1, respectively; n=8 per dose), heparin (60 u kg−1+0.7 u kg−1 min−1, n=8), or RPR109891 (30 μg kg−1+0.45 μg kg−1 min−1, n=8), was initiated. Aspirin (5 mg kg−1, i.v.) was administered to all animals. Fifteen minutes after the start of drug infusion, rt‐PA was administered (100 μg kg−1+20 μg kg−1 min−1 for 60 min).
The incidence of reperfusion in the high dose FXV673 (8/8, 100%) was significantly greater than that in the heparin group (4/8, 50%), with a trend to faster reperfusion (23±5 min for FXV673 versus 41±11 min for heparin). Only 2/8 (25%) of the vessels reoccluded in the high dose FXV673 group, compared to 4/4 (100%) and 5/5 (100%) vessels in the heparin and RPR109891 groups, respectively (P<0.05).
Throughout the protocol, blood flow was higher in the FXV673 treated group compared to other groups. FXV673 enhanced vessel patency in a dose‐dependent manner.
Compared to vehicle and heparin groups, the thrombus mass was decreased by 60% in the high dose FXV673. FXV673, heparin and RPR109891 increased the bleeding time by 2.7, 1.7 and 4 fold, and APTT by 2.8, 2.7 and 1.2 fold, respectively.
In conclusion, FXV673 is more effective than heparin and at least as effective as RPR109891 when used as an adjunct during rt‐PA‐induced coronary thrombolysis.
British Journal of Pharmacology (2001) 133, 1190–1198; doi:10.1038/sj.bjp.0704182