Evaluation of PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid], a novel plasminogen activator inhibitor-1 inhibitor, in a canine model of coronary artery thrombosis
| Autor: | Mauricio Leal, Robert E. Swillo, Gregory S. Friedrichs, Amy L. Hreha, David L. Crandall, Thomas M. Antrilli, Gwen A. Morgan, James K. Hennan, Allena J. Ji, Hassan Mahmoud Elokdah |
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| Rok vydání: | 2005 |
| Předmět: |
Bleeding Time
Indoles Platelet Aggregation Endpoint Determination medicine.medical_treatment Blood Pressure Pharmacology Acetates chemistry.chemical_compound Dogs Fibrinolytic Agents Bleeding time Heart Rate Coronary Circulation Fibrinolysis Plasminogen Activator Inhibitor 1 medicine Animals Hemostasis medicine.diagnostic_test Indoleacetic Acids Ventricular Remodeling business.industry Coronary Thrombosis Area under the curve medicine.disease Thrombosis chemistry Coronary occlusion Anesthesia Plasminogen activator inhibitor-1 Molecular Medicine Partial Thromboplastin Time business Plasminogen activator Partial thromboplastin time |
| Zdroj: | The Journal of pharmacology and experimental therapeutics. 314(2) |
| ISSN: | 0022-3565 |
| Popis: | We tested a novel, orally active inhibitor of plasminogen activator inhibitor-1 (PAI-1) in a canine model of electrolytic injury. Dogs received by oral gavage either vehicle (control) or the PAI-1 inhibitor PAI-039 [{1-benzyl-5-[4-(trifluoromethoxy)phenyl]-1H-indol-3-yl}(oxo)acetic acid] (1, 3, and 10 mg/kg) and were subjected to electrolytic injury of the coronary artery. PAI-039 caused prolongation in time to coronary occlusion (control, 31.7 +/- 6.3 min; 3 mg/kg PAI-039, 66.0 +/- 6.4 min; 10 mg/kg, 56.7 +/- 7.4 min; n = 5-6; p0.05) and a reduced thrombus weight (control, 7.6 +/- 1.5 mg; 10 mg/kg PAI-039, 3.6 +/- 1.0 mg; p0.05). Although occlusive thrombosis was observed across all groups based upon the absence of measurable blood flow, a high incidence (60%) of spontaneous reperfusion occurred only in those groups receiving PAI-039. Spontaneous reperfusion in the 10 mg/kg PAI-039 group accounted for total blood flow (area under the curve of coronary blood flow) of 99.6 +/- 11.7 ml after initial thrombotic occlusion (p0.05 compared with control). Plasma PAI-1 activity was reduced in all drug-treated groups (percentage of reduction in activity p0.05; 10 mg/kg PAI-039), whereas ADP-, 9,11-dideoxy-11alpha,9alpha-epoxymethanoprostaglandin F(2alpha) (U46619)-, and collagen-induced platelet aggregation, as well as template bleeding and prothrombin time, remained unaffected by PAI-039. Ex vivo clot lysis analysis revealed normal clot formation but accelerated clot lysis in PAI-039-treated groups. The pharmacokinetic profile of PAI-039 indicated an oral bioavailability of 43 +/- 15.3% and a plasma half-life of 6.2 +/- 1.3 h. In conclusion, PAI-039 is an orally active prothrombolytic drug that inhibits PAI-1 and accelerates fibrinolysis while maintaining normal coagulation in a model of coronary occlusion. |
| Databáze: | OpenAIRE |
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