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Thromb Haemost ; 97(3): 400-7, 2007 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17334507

RESUMO

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMWH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p < 0.01). LMWH opening evident after balloon deflation slightly deteriorated over time compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMWH and control animals six hours post thrombus induction (p < 0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.


Assuntos
Anti-Inflamatórios/administração & dosagem , Hidroxiquinolinas/administração & dosagem , Selectina-P/efeitos dos fármacos , Trombose Venosa/prevenção & controle , Administração Oral , Animais , Anti-Inflamatórios/sangue , Anti-Inflamatórios/uso terapêutico , Anticoagulantes/administração & dosagem , Coagulação Sanguínea/efeitos dos fármacos , Testes de Coagulação Sanguínea , Cateterismo , Modelos Animais de Doenças , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Fibrinólise/efeitos dos fármacos , Heparina de Baixo Peso Molecular/administração & dosagem , Hidroxiquinolinas/sangue , Hidroxiquinolinas/uso terapêutico , Veia Ilíaca/cirurgia , Injeções Subcutâneas , Angiografia por Ressonância Magnética , Masculino , Papio anubis , Fatores de Tempo , Ultrassonografia Doppler em Cores , Grau de Desobstrução Vascular/efeitos dos fármacos , Trombose Venosa/sangue , Trombose Venosa/patologia , Trombose Venosa/fisiopatologia
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