Antithrombotic effects and bleeding time prolongation with synthetic platelet GPIIb/IIIa inhibitors in animal models of platelet-mediated thrombosis.
Cyclic Arg-Gly-Asp (RGD) containing synthetic peptides such as L-cysteine, N-(mercaptoacetyl)-D-tyrosyl-L-arginylglycyl-L-alpha-aspartyl- cyclic (1-->5)-sulfide, 5-oxide (G4120) and acetyl-L-cysteinyl-L-asparaginyl-L-propyl-L-arginyl-glycyl-L-alpha- aspartyl-[0-methyltyrosyl]-L-arginyl-L-cysteinamide, cyclic 1-->9-sulfide (TP9201) bind with high affinity to the platelet GPIIb/IIIa receptor. The relationship between antithrombotic effect, ex vivo platelet aggregation and bleeding time prolongation with both agents was studied in hamsters with a standardized femoral vein endothelial cell injury predisposing to platelet-rich mural thrombosis, and in dogs with a carotid arterial eversion graft inserted in the femoral artery. Intravenous administration of G4120 in hamsters inhibited in vivo thrombus formation with a 50% inhibitory bolus dose (ID50) of approximately 20 micrograms/kg, ex vivo ADP-induced platelet aggregation with ID50 of 10 micrograms/kg, and bolus injection of 1 mg/kg prolonged the bleeding time from 38 +/- 9 to 1,100 +/- 330 s. Administration of TP9201 in hamsters inhibited in vivo thrombus formation with ID50 of 30 micrograms/kg, ex vivo platelet aggregation with an ID50 of 50 micrograms/kg and bolus injection of 1 mg/kg did not prolong the template bleeding time. In the dog eversion graft model, infusion of 100 micrograms/kg of G4120 over 60 min did not fully inhibit platelet-mediated thrombotic occlusion but was associated with inhibition of ADP-induced ex vivo platelet aggregation and with prolongation of the template bleeding time from 1.3 +/- 0.4 to 12 +/- 2 min.(ABSTRACT TRUNCATED AT 250 WORDS)
Collen
D
D
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
Lu
H R
HR
Stassen
J M
JM
Vreys
I
I
Yasuda
T
T
Bunting
S
S
Gold
H K
HK
D000595:Amino Acid Sequence; D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000502:physiology*; D001807:Blood Vessel Prosthesis; D002339:Carotid Arteries; D006224:Cricetinae; D004285:Dogs; D005260:Female; D005263:Femoral Artery / Q000601:surgery; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D006083:Graft Occlusion, Vascular; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D017202:Myocardial Ischemia / Q000188:drug therapy; D009842:Oligopeptides / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D012039:Regional Blood Flow; D013045:Species Specificity; D013454:Sulfoxides / Q000494:pharmacology*; D013927:Thrombosis / Q000209:etiology / Q000517:prevention & control*
D005343:Fibrinolytic Agents; D009842:Oligopeptides; D010456:Peptides, Cyclic; D010980:Platelet Membrane Glycoproteins; D013454:Sulfoxides; C074915:G 4120; C047981:arginyl-glycyl-aspartic acid; C085362:TP 9201