title: Thrombostatin inhibits cyclic flow variations in stenosed canine coronary arteries.
abstract: Thrombostatins are a group of compounds based upon a breakdown product of bradykinin, RPPGF. They inhibit alpha-thrombin-induced platelet activation by binding to protease activated receptor 1 and, at a lower affinity, by interacting with thrombin's active site. After a single intravenous infusion of MAP4-RPPGF (11.58 mg/kg), its t1/2alpha was 4.5 min with a clearance of 2.0 ml/min. MAP4-RPPGF administration had a sustained antiplatelet effect, preventing gamma-thrombin-induced (12.5 nM) platelet activation for 4 h. Its antiplatelet effect summated with that of aspirin and/or clopidogrel. MAP4-RPPGF was compared with aspirin and clopidogrel in the Folts model of coronary artery thrombosis. Dogs were randomized to 3 treatment groups: aspirin 1.14 mg/kg i.v., clopidogrel 0.5 mg/kg i.v., or MAP4-RPPGF 0.77 mg/kg i.v. Cyclic flow variations (CFV) were recorded in 5 untreated dogs hourly for 3 successive hours and for 1 h before (all groups >11 CFV/h), and for 2 h after drug infusion in each of the 3 treatment groups. After 1 h drug treatment, all groups of animals had <6 CFV/h; after 2 h treatment, all had <1 CFV/h. All agents significantly reduced CFV from control at each hour, but none was significantly better than any other. Thrombostatin was as effective as aspirin or clopidogrel in inhibiting coronary artery thrombosis in this canine model.
authors.affiliation: Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0640, USA.
authors.forename: A A
authors.initials: AA
authors.lastname: Hasa
authors.forename: A H
authors.initials: AH
authors.lastname: Schmaier
authors.forename: M
authors.initials: M
authors.lastname: Warnock
authors.forename: D
authors.initials: D
authors.lastname: Normolle
authors.forename: E
authors.initials: E
authors.lastname: Driscoll
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
authors.forename: S W
authors.initials: SW
authors.lastname: Werns
mesh_terms: D000818:Animals; D001241:Aspirin / Q000008:administration & dosage / Q000494:pharmacology; D001780:Blood Coagulation Tests; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000493:pharmacokinetics* / Q000494:pharmacology; D000077144:Clopidogrel; D023921:Coronary Stenosis; D003328:Coronary Thrombosis / Q000188:drug therapy / Q000517:prevention & control*; D004195:Disease Models, Animal; D004285:Dogs; D004341:Drug Evaluation; D008657:Metabolic Clearance Rate; D010446:Peptide Fragments / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology; D010979:Platelet Function Tests; D012039:Regional Blood Flow / Q000187:drug effects*; D013810:Therapeutic Equivalency; D013988:Ticlopidine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
chemical_list: C472709:MAP4-RPPGF; D010446:Peptide Fragments; C079000:bradykinin (1-5); D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin; D001920:Bradykinin