Synergistic antithrombotic properties of G4120, a RGD-containing synthetic peptide, and argatroban, a synthetic thrombin inhibitor, in a hamster femoral vein platelet-rich thrombosis model.
The synergistic antithrombotic properties of G4120, a synthetic Arg-Gly-Asp (RGD) containing peptide which strongly inhibits platelet aggregation, and of Argatroban, a synthetic thrombin inhibitor, were examined in a reproducible quantitative hamster femoral vein platelet-rich mural thrombosis model. Bolus injections of G4120 and Argatroban inhibit thrombus formation in a dose-dependent way; 50% inhibition (ID50) is obtained with 11 micrograms/kg G4120 and with 2 mg/kg Argatroban. Combined bolus injections of 3 micrograms/kg G4120 with 0.5, 0.75 or 1 mg/kg Argatroban and of 1 mg/kg Argatroban with 1.5 or 3 micrograms/kg G4120 caused linear dose-dependent inhibition of thrombus formation, whereas 3 micrograms/kg G4120 or 1 mg/kg Argatroban alone had very little effect (less than 20% inhibition). ID50 was obtained with the combination of 3 micrograms/kg G4120 and 0.5 mg/kg Argatroban, corresponding to an equi-effective fractional combination of 0.62 with a 95% confidence interval of 0.50 to 0.74. Alternatively the ID50 was obtained with the combination of 1 mg/kg Argatroban and 1.3 micrograms/kg G4120, corresponding to an equi-effective fractional combination of 0.52 with a 95% confidence interval of 0.18 to 0.86. In both instances these results are indicative of a significant synergistic interaction. Bolus injection of 10 mg/kg aspirin, 100 U/kg heparin or the combination did not inhibit thrombus formation. The synergistic effect of the combination of platelet inhibiting RGD-peptides and synthetic thrombin inhibitors could be useful in the prevention of arterial occlusion with platelet-rich thrombus in patients with ischemic heart disease following thrombolytic therapy or angioplasty, although this combination is not expected to reverse platelet thrombus formation.
Imura
Y
Y
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Stassen
J M
JM
Vreys
I
I
Lesaffre
E
E
Gold
H K
HK
Collen
D
D
D000818:Animals; D000991:Antithrombins / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001241:Aspirin / Q000494:pharmacology; D001777:Blood Coagulation / Q000187:drug effects; D006224:Cricetinae; D004195:Disease Models, Animal; D004357:Drug Synergism; D005268:Femoral Vein; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000494:pharmacology; D007275:Injections, Intravenous; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010875:Pipecolic Acids / Q000494:pharmacology*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D010976:Platelet Count; D013449:Sulfonamides; D013454:Sulfoxides / Q000494:pharmacology*; D013927:Thrombosis / Q000097:blood / Q000188:drug therapy*
D000991:Antithrombins; D005343:Fibrinolytic Agents; D010456:Peptides, Cyclic; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D013449:Sulfonamides; D013454:Sulfoxides; C074915:G 4120; D006493:Heparin; D001120:Arginine; C031942:argatroban; D001241:Aspirin