Antithrombotic assessment of the effects of combination therapy with the anticoagulants efegatran and heparin and the glycoprotein IIb-IIIa platelet receptor antagonist 7E3 in a canine model of coronary artery thrombosis.
BACKGROUND
There is a paucity of data regarding the antithrombotic pharmacology of the drug-drug interactions between the newer anticoagulant and antiplatelet agents. In this investigation, we have studied the antithrombotic effects of combinations of minimum effective doses of the glycoprotein IIb-IIIa receptor antagonist 7E3 [murine F(ab')2] with both heparin and the novel tripeptide arginal antithrombin efegatran (LY294468) in a canine model of coronary artery thrombosis.


RESULTS
Thrombogenesis was initiated by electrolytic injury of the intimal surface of the left circumflex coronary artery. The groups studied were efegatran (0.25 mg . kg-1. h-1), heparin (80 U/kg, single injection, plus 30 U . kg-1. h-1), 7E3 (0.4 mg/kg, single injection), 7E3+efegatran, and 7E3+heparin. The combination of 7E3+efegatran was found to maintain better vessel patency (P < .05) at the end of the experiment (4 of 5 vessels) than all other groups (0 of 5, 0 of 4, 1 of 6, 2 of 7, and 1 of 6 for the vehicle-, heparin-, 7E3-, efegatran-, and 7E3+heparin-treated groups, respectively). Bleeding times were increased (P < .05) in both the 7E3+heparin group (fourfold) and the 7E3+efegatran group (threefold). 7E3 alone and both combination treatments produced significant reductions in ADP, arachidonic acid, and thrombin-induced platelet aggregation, whereas efegatran and heparin abolished only thrombin-induced aggregation.


CONCLUSIONS
The present investigation demonstrates that combination therapy with minimum effective doses of 7E3+efegatran provided enhanced antithrombotic efficacy compared with 7E3+heparin in this model of thrombosis.
Shetler
T J
TJ
Cardiovascular Research Division, Lilly Research Laboratories, Eli Lilly and Co. Indianapolis, Ind., USA.
Crowe
V G
VG
Bailey
B D
BD
Jackson
C V
CV
D000077284:Abciximab; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001760:Bleeding Time; D001794:Blood Pressure / Q000187:drug effects; D003328:Coronary Thrombosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D006339:Heart Rate / Q000187:drug effects; D006493:Heparin / Q000627:therapeutic use*; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D008297:Male; D009842:Oligopeptides / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D007140:Immunoglobulin Fab Fragments; D009842:Oligopeptides; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D006493:Heparin; C064289:efegatran; D000077284:Abciximab