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Titolo:
Intravenous and oral antithrombotic efficacy of the novel platelet GPIIb/IIIa antagonist roxifiban (DMP754) and its free acid form, XV459
Autore:
Mousa, SA; Kapil, R; Mu, DX;
Indirizzi:
Dupont Merck Pharmaceut Co, Expt Stn, Wilmington, DE 19880 USA Dupont Merck Pharmaceut Co Wilmington DE USA 19880 lmington, DE 19880 USA
Titolo Testata:
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
fascicolo: 10, volume: 19, anno: 1999,
pagine: 2535 - 2541
SICI:
1079-5642(199910)19:10<2535:IAOAEO>2.0.ZU;2-Z
Fonte:
ISI
Lingua:
ENG
Soggetto:
GLYCOPROTEIN IIB/IIIA RECEPTOR; MYOCARDIAL-INFARCTION; MONOCLONAL-ANTIBODY; CLINICAL-TRIALS; INTEGRIN; ANTIPLATELET; INHIBITORS; IIIA; SPECIFICITY; MECHANISMS;
Keywords:
platelet GPIIb/IIIa; integrin; thrombosis; antiplatelet; anticoagulant; roxifiban;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
35
Recensione:
Indirizzi per estratti:
Indirizzo: Mousa, SA Dupont Merck Pharmaceut Co, Expt Stn, E400 3470,141 & Henry ClayRd, Wilmington, DE 19880 USA Dupont Merck Pharmaceut Co E400 3470,141 & Henry Clay Rd Wilmington DE USA 19880
Citazione:
S.A. Mousa et al., "Intravenous and oral antithrombotic efficacy of the novel platelet GPIIb/IIIa antagonist roxifiban (DMP754) and its free acid form, XV459", ART THROM V, 19(10), 1999, pp. 2535-2541

Abstract

Currently used antiplatelet drugs, including aspirin, ticlopidine, and others, are effective against certain but not all of the many endogenous platelet activators. Because of their limited efficacy, a significant number of serious thromboembolic complications still occur, highlighting the need fora more effective therapy. DMP754 (roxifiban), a prodrug of XV459, is a recently discovered, potent antiplatelet agent with high affinity and specificity for platelet GPIIb/IIIa receptors that blocks platelet aggregate formation regardless of the agonist (IC50=0.030 to 0.05 mu mol/L) or anticoagulant used for blood collection. DMP754 rapidly converts to its active free-acid form, XV459, which has a comparable high affinity for both resting and activated platelets (K-d=1 to 2 nmol/L) and a relatively slow rate of dissociation from resting platelets. The present study was undertaken to determineintravenous and oral antithrombotic efficacies of DMP754 and XV459 and to compare them with those of other antiplatelet and anticoagulant agents in canine models of arterial thrombosis. In these models, thrombosis was induced either electrolytically (200-mu A anodal current) in the carotid artery or mechanically by external clamping of the femoral artery along with stenosis, which resulted in either total occlusive thrombus formation or cyclic flow reduction, respectively. DMP754 and XV459 were given either intravenously (0.1 mg/kg bolus) or orally (0.1 to 0.4 mg/kg). Additionally, the antithrombotic efficacies of DMP754, aspirin, heparin, and ticlopidine in the canine carotid artery electrolytic injury model were compared. DMP754 demonstrated oral bioavailability of 20.8% in dogs after administration at different doses and prevented cyclic flow reduction (ED90-100= <0.1 mg/kg IV or PO). Additionally, both DMP754 and XV459 (0.1 mg/kg IV or 0.3 to 0.4 mg/kg PO)demonstrated maximal antithrombotic efficacy in preventing electrically induced carotid and coronary artery thrombosis and significant antithromboticefficacy (P<0.001) at relatively low doses in different settings of arterial thrombosis in the canine model. DMP754 resulted in a significant reduction in thrombus mass and sustained arterial blood flow with 100% prevention of occlusive and nonocclusive thrombosis. In contrast, administration of aspirin (10 mg/kg PO for 2 days), heparin (10 IU/kg IV bolus followed by 90 IU/kg TV infusion over 3 hours), or ticlopidine (300 mg/kg PO for 3 days) before initiation of arterial thrombosis did not reduce the incidence of electrolytic injury-induced occlusive arterial thrombosis. These studies demonstrated a distinct antithrombotic efficacy of DMP754 as compared with existing strategies and suggest potential intravenous and oral antithrombotic uses of DMP754 in the prevention and treatment of thromboembolic disorders.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 05/12/20 alle ore 08:11:01