Comparison of the antithrombotic effects and bleeding risk of fractionated aurin tricarboxylic acid and the GPIIb/IIIa antagonist GR144053 in a hamster model of stenosis.
The present study compared the antithrombotic properties of fractionated aurin tricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (GP) Ib, and GR144053, a GPIIb/IIIa antagonist, in a hamster model of stenosis. Endothelial cell injury in the hamster carotid artery was achieved by a 2F modified catheter. Arterial blood flow in the control groups was interrupted 5.4+/-0.9 minutes after the injury. When ATA (0.01, 0.03, 0.1, 0.3, and 1.0 mg/kg per hour) or GR144053 (0.1, 0.3, and 1.0 mg/kg per hour) were continuously infused intravenously, the time elapse before the vessel completely occluded was prolonged in a dose-dependent manner. However, all arteries in the ATA-treated groups ultimately occluded during the observation period even if the aggregation of platelets ex vivo and induced by botrocetin was completely inhibited. When either ATA (0.1 mg/kg per hour) or GR144053 (0.3 mg/kg per hour) were infused via an implanted osmotic pump together with tissue-type plasminogen activator (tPA), late patency of the reperfused artery was improved compared to that of arteries treated with TPA alone. However, the cyclic reflow pattern after reperfusion on days 0 and 1 was not reduced by the ATA treatment. The bleeding time was significantly prolonged when either ATA or GT144053 was coadministered with tPA. The treatment with ATA showed an especially marked prolongation of the bleeding time. In conclusion, both inhibition of platelet activation by ATA or GR144053 prevent arterial thrombosis and enhance the thrombolytic effect of tPA, but GR144053 was more protective in its antithrombotic effect and more effective during thrombolytic therapy than ATA.
Ito
T
T
Department of Pharmacology, Gifu University School of Medicine, Japan.
Matsuno
H
H
Kozawa
O
O
Niwa
M
M
Sakai
N
N
Uematsu
T
T
D000818:Animals; D001312:Aurintricarboxylic Acid / Q000008:administration & dosage* / Q000009:adverse effects; D016893:Carotid Stenosis / Q000188:drug therapy* / Q000473:pathology; D002404:Catheterization; D006224:Cricetinae; D004730:Endothelium, Vascular / Q000473:pathology; D006470:Hemorrhage / Q000139:chemically induced; D007262:Infusions, Intravenous; D008297:Male; D008647:Mesocricetus; D010879:Piperazines / Q000008:administration & dosage* / Q000009:adverse effects; D010880:Piperidines / Q000008:administration & dosage* / Q000009:adverse effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors
C090662:GR 144053; D010879:Piperazines; D010880:Piperidines; D010975:Platelet Aggregation Inhibitors; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D001312:Aurintricarboxylic Acid