RESUMO
1. The antithrombotic effect of the glycoprotein IIb/IIIa receptor antagonist, CRL42796, was examined in canine models of carotid and coronary artery thrombosis. 2. In the carotid artery thrombosis model, occlusion occurred in all control vessels (time to thrombosis 47.6+/-8.9 min). After treatment with low dose CRL42796 (15 microg kg(-1) loading dose +0.31 microg kg(-1) min(-1) i.v.), two of five vessels occluded. Time to thrombosis increased significantly to 155.2+/-23.1 min. When the drug infusion was increased (0.69 microg kg(-1) min(-1)), each of five vessels remained patent. 3. Ex vivo platelet aggregation in response to arachidonic acid (AA) and ADP was examined in platelet rich plasma (PRP) prepared from citrate or heparin anticoagulated blood. CRL42796 reduced platelet reactivity at low and high doses in PRP from citrate anticoagulated blood. However, in PRP from heparin anticoagulated blood, only the higher infusion dose produced a significant reduction in ex vivo platelet responses. 4. A combination of oral aspirin (4.6 mg kg(-1) -41, -17 h) and the low infusion dose of CRL42796 did not produce an additional benefit beyond that provided by CRL42796 alone. 5. Coronary artery thrombosis was inhibited in four of five vessels treated with the lower infusion dose of CRL42796 and in five of five vessels treated with the higher infusion. Time to thrombosis increased with both doses (Control, 90.8+/-10.4 min; low dose, 165.8+/-14.2 min; high dose, >180.0+/-0 min). 6. The results indicate that CRL42796 is an effective in vivo antithrombotic agent against experimentally-induced carotid and coronary artery thrombosis.
Assuntos
Trombose das Artérias Carótidas/prevenção & controle , Trombose Coronária/prevenção & controle , Dipeptídeos/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Complexo Glicoproteico GPIIb-IIIa de Plaquetas/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Aspirina/farmacologia , Tempo de Sangramento , Constrição Patológica , Dipeptídeos/administração & dosagem , Dipeptídeos/uso terapêutico , Cães , Relação Dose-Resposta a Droga , Infusões Intra-Arteriais , Inibidores da Agregação Plaquetária/administração & dosagem , Inibidores da Agregação Plaquetária/uso terapêutico , Sulfonamidas/administração & dosagem , Sulfonamidas/uso terapêuticoRESUMO
The antithrombotic effect of the glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist (2S)-2-[(2-naphthyl-sulfonyl)amino]-3-[[2-([4-(4-piperidinyl)-2-[2-(4-piperidinyl)ethyl] butanoyl]amino)acetyl]amino] propanoic acid dihydrochloride (CRL42796), administered alone, or in combination with aspirin, and/or enoxaparin, was examined in a canine left circumflex (LCX) coronary artery rethrombosis model. The electrolytic induction of arterial thrombosis was followed by intracoronary recombinant tissue plasminogen activator administration to achieve thrombolysis, and the adjunctive therapy was initiated 15 min earlier and maintained for 4 h. Thirty-five purpose-bred beagle dogs were randomized to receive one of the following treatments: group 0 (n = 6, placebo); group 1 (n = 6, CRL42796 15 microg/kg i.v. loading dose followed by 0.31 microg/kg/min i.v. infusion), group 2 (n = 6, aspirin 7 mg/kg, administered orally, at -47, -23, -17 h before entry into the experimental protocol); group 3 (n = 6, aspirin + CRL42796); group 4 (n = 6, aspirin + enoxaparin 0.6 microg/kg i.v. loading dose followed by 6.0 microg/kg/min i.v. infusion); and group 5 (n = 5, aspirin + CRL42796 + enoxaparin). The incidence of LCX reocclusion was as follows: group 0, 6/6; group 1, 3/6; group 2, 5/6; group 3, 2/6; group 4, 2/6; and group 5, 0/5. Aspirin pretreatment increased the tongue-bleeding time, whereas the addition of CRL42796 or enoxaparin did not prolong bleeding time to a further degree. However, the combination of the three drugs did increase bleeding time significantly, from 173.9 +/- 19.8 to 620.0 +/- 98.7 s. In conclusion, low-dose CRL42796 together with aspirin and enoxaparin prevented coronary artery rethrombosis, although bleeding time was prolonged. The latter may be of concern in the clinical use of combination therapy.