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J Thromb Thrombolysis ; 10(2): 189-96, 2000 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-11005941

RESUMO

We sought to determine the efficacy of the combination of argatroban, a direct thrombin inhibitor, and G4120, a platelet glycoprotein (GP) IIb/IIIa blocker, to enhance thrombolysis with alteplase. Platelet-rich thrombus in the rabbit arterial thrombosis model is relatively resistant to alteplase despite the addition of aspirin and heparin. The adjunctive use of either direct thrombin inhibitors or GP IIb/IIIa inhibitors in thrombolysis has been investigated with encouraging, but limited, success. The usefulness of combining both agents as adjunctive therapy to thrombolysis has not been fully explored. Following platelet-rich thrombus formation in the rabbit, argatroban (3 mg/kg), G4120 (0.5 mg/kg), G4120 plus heparin (200 U/kg), or G4120 plus argatroban were intravenously infused over 60 minutes. Alteplase was given as intravenous boluses (0.45 mg/kg) at 15-minute intervals up to 4 doses or until reperfusion. Blood flow and bleeding time were monitored for 2 hours. The combination of G4120 plus argatroban resulted in a persistent patency in 5 of 7 animals compared with 0 of 6 for argatroban alone (p=0.02), 1 of 6 for G4120 alone (p=0.08), and 2 of 6 for G4120 plus heparin (p=0.2). Although during the infusion the bleeding times were longer in the groups that received G4120 (26+/-7.7 minutes vs. 14+/-10 minutes, p<0.05), by the end of the experiment there were no statistically significant differences. Similarly, during the infusion the activated partial thromboplastin times (aPTT) was higher in groups that received heparin or argatroban (99+/-51 seconds vs. 32+/-7.6 seconds, p<0.001), but by the end of the experiment the aPTTs had returned to close to baseline in all groups except the G4120 plus heparin group. These results suggest that lysis of platelet-rich thrombus with alteplase requires the addition of both potent platelet and thrombin inhibitors. Specifically designed agents, G4120 and argatroban, are effective without additional increased risk for bleeding.


Assuntos
Antitrombinas/administração & dosagem , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Reperfusão/métodos , Trombose/tratamento farmacológico , Ativador de Plasminogênio Tecidual/administração & dosagem , Animais , Antitrombinas/normas , Arginina/análogos & derivados , Tempo de Sangramento , Velocidade do Fluxo Sanguíneo , Plaquetas , Modelos Animais de Doenças , Combinação de Medicamentos , Avaliação de Medicamentos , Feminino , Artéria Femoral , Fibrinolíticos/administração & dosagem , Fibrinolíticos/normas , Heparina/administração & dosagem , Heparina/normas , Masculino , Tempo de Tromboplastina Parcial , Peptídeos/farmacologia , Peptídeos/normas , Peptídeos/uso terapêutico , Peptídeos Cíclicos/administração & dosagem , Peptídeos Cíclicos/normas , Ácidos Pipecólicos/administração & dosagem , Ácidos Pipecólicos/normas , Ativadores de Plasminogênio/administração & dosagem , Ativadores de Plasminogênio/normas , Coelhos , Sulfonamidas , Sulfóxidos/administração & dosagem , Sulfóxidos/normas , Trombose/sangue , Ativador de Plasminogênio Tecidual/normas
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