title: Inhibition of carboxypeptidase U (TAFIa) activity improves rt-PA induced thrombolysis in a dog model of coronary artery thrombosis.
abstract: The objective of this study was to test the hypothesis if thrombolysis induced by recombinant tissue-type plasminogen activator, (rt-PA) could be facilitated by inhibiting carboxypeptidase U (CPU, active Thrombin Activatable Fibrinolysis Inhibitor, TAFIa) activity. The efficacy of rt-PA alone, or in combination with the carboxypeptidase inhibitor MERGETPA, was compared in a dog model of coronary artery thrombosis. Twenty dogs were randomised in two groups, one received rt-PA, 1 mg kg(-1), as intravenous infusion over 20 min starting 30 min after thrombus formation, and the other group received rt-PA, 1 mg kg(-1), as group one with the addition of MERGEPTA 5 mg kg(-1) starting 25 min prior to coronary artery occlusion and followed by infusion of 5 mg kg(-1) h(-1) until the end of experiment. Efficacy was assessed by determination of time to lysis, duration of patency and blood flow during patency. Both groups had similar baseline characteristics with respect to haemodynamic parameters, i.e., heart rate, blood pressure and coronary artery blood flow. Coadministration of rt-PA and MERGETPA resulted in significant decrease in time to lysis (15+/-1.5 min vs. 20+/-1.7 min, p=0.03), increased patency time (87+/-16 min vs. 46+/-12 min, p=0.047) and increased coronary blood flow during patency (1131 mL h(-1) vs. 405 mL h(-1), p=0.015), compared to rt-PA alone. These results indicate that an inhibitor of CPU activity may have a beneficial effect in patients undergoing thrombolytic therapy by attaining shorter time to reperfusion and improved coronary patency.
authors.affiliation: Department of Integrative Pharmacology, AstraZeneca R&D, S-431 83 Mölndal, Sweden. Jan-Arne.Bjorkman@astrazeneca.com
authors.forename: Jan-Arne E
authors.initials: JA
authors.lastname: Björkman
authors.forename: Tommy I
authors.initials: TI
authors.lastname: Abrahamsson
authors.forename: Viveca K
authors.initials: VK
authors.lastname: Nerme
authors.forename: Christer J
authors.initials: CJ
authors.lastname: Mattsson
mesh_terms: D015097:3-Mercaptopropionic Acid / Q000031:analogs & derivatives / Q000627:therapeutic use; D000818:Animals; D025901:Carboxypeptidase B2 / Q000037:antagonists & inhibitors*; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004359:Drug Therapy, Combination; D005260:Female; D005342:Fibrinolysis / Q000187:drug effects; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D001121:Lysine Carboxypeptidase / Q000037:antagonists & inhibitors; D008297:Male; D010960:Plasminogen Activators / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000627:therapeutic use; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D011994:Recombinant Proteins; C029729:2-mercaptomethyl-3-guanidinoethylthiopropionic acid; D015097:3-Mercaptopropionic Acid; D025901:Carboxypeptidase B2; D001121:Lysine Carboxypeptidase; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator