title: The antithrombotic efficacy of lotrafiban (SB 214857) in canine models of acute coronary thrombosis.
abstract: In patients with acute coronary syndromes, inhibition of platelet aggregation with parenteral alpha(IIb)/beta(III) antagonists has proven effective at preventing nonfatal myocardial infarction and repeat percutaneous coronary interventions. Paradoxically, the efficacy observed for acute indications and parenteral agents has not extended to oral agents and chronic prevention of secondary thrombotic events, despite robust antithrombotic properties in preclinical thrombosis models. This report documents the preclinical data of Lotrafiban, an oral alpha(IIb)/beta(III) antagonist that recently failed in a phase III clinical trial (BRAVO) for the prevention of secondary thrombosis. Lotrafiban was characterized in a dog circumflex artery electrical injury model, and a cyclic flow reduction model ("Folts"). The data demonstrate that both oral (1.0-50.0 mg/kg) and intravenous (0.1-0.8ug/kg/min) administration of lotrafiban produced dose-related inhibition (45%-95%) of ex vivo platelet aggregation. In the electrical injury model, the dose-related inhibition correlated with a significant reduction in the frequency of coronary occlusion, size of the developing thrombus, and the extent of left ventricular ischemic damage. Effects on blood flow and bleeding time were also dose related. The combination of low dose lotrafiban (0.1ug/kg/min) and aspirin (5.0 mg/kg) generated additive antithrombotic effects, approximating the antithrombotic efficacy of a 2-4 fold higher dose of lotrafiban while only modestly prolonging the bleeding time. For purposes of comparison, the ADP receptor antagonist clopidogrel was also assessed in the electrical injury model. Clopidogrel (5.0-10.0 mg/kg, iv.) significantly reduced the resulting left ventricular infarct areas, but lacked the overall efficacy of lotrafiban. In the "Folts" model, lotrafiban inhibited cyclic blood flow reductions (CFR's) by 100% in animals insensitive to the antithrombotic effects of aspirin. Overall, the preclinical data demonstrated that alpha(IIb)/beta(III) antagonism with lotrafiban was a well tolerated and effective strategy for attenuating acute arterial thrombosis. The lack of a correlation between these preclinical data and the outcome of the clinical trial BRAVO are unexplained. However, the combined evidence suggests that these acute canine thrombosis studies may not completely capture the pathology reflected in chronic human atherothrombotic disease.
authors.affiliation: Department of Cardiovascular Pharmacology, GlaxoSmithKline, 709 Swedeland Road, PO Box 1539, Mail code UW 2510, King of Prussia, PA 19406, USA. John_R_Toomey@sbphrd.com
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: James
authors.initials: J
authors.lastname: Samanen
authors.forename: Richard E
authors.initials: RE
authors.lastname: Valocik
authors.forename: Paul F
authors.initials: PF
authors.lastname: Koster
authors.forename: Frank C
authors.initials: FC
authors.lastname: Barone
authors.forename: Robert N
authors.initials: RN
authors.lastname: Willette
mesh_terms: D000208:Acute Disease; D000818:Animals; D001569:Benzodiazepines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D003328:Coronary Thrombosis / Q000188:drug therapy* / Q000503:physiopathology; D004195:Disease Models, Animal; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005343:Fibrinolytic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects / Q000502:physiology
chemical_list: D005343:Fibrinolytic Agents; D010880:Piperidines; D001569:Benzodiazepines; C412702:lotrafiban