title: Orally effective CVS-1123 prevents coronary artery thrombosis in the conscious dog.
abstract: BACKGROUND
  We examined the oral efficacy of a direct thrombin inhibitor, CVS-1123 [(CH3CH2CH2)(2)-CH-CO-Asp (OCH3)-Pro-Arg-CHO; MW, 575]. The object was to determine whether thrombin inhibition could reduce the incidence of occlusive coronary artery thrombosis in response to arterial wall injury.
  
  
  RESULTS
  Arterial wall injury was induced in conscious dogs by a 150-muA anodal current applied to the intimal surface of the circumflex coronary artery 30 minutes after oral CVS-1123 (20 mg/kg every 8 hours for three doses; n = 11) or placebo containing diluent (n = 10). Dogs were monitored for 8 hours and at 24 hours. The coronary artery remained patent for 24 hours in 8 of 11 CVS-1123-treated dogs. All dogs (n = 10) in the placebo group developed a sustained, occlusive arterial thrombus. Two hours after the initial oral dose, the plasma CVS-1123 concentration was 13 +/- 1 microgram/mL, reaching a maximum of 15 +/- 1 micrograms/mL after the second dose and 4.4 +/- 0.5 micrograms/mL at 24 hours. Ex vivo platelet aggregation to gamma-thrombin was inhibited and activated partial thromboplastin time was increased after treatment with CVS-1123 (P < .05).
  
  
  CONCLUSIONS
  The direct thrombin inhibitor CVS-1123 is effective after oral administration in reducing the incidence of primary thrombus formation in an experimental model of arterial wall injury. Thrombin-specific inhibitors, such as CVS-1123, may be alternative antithrombotic agents in clinical settings in which heparin-associated thrombosis is a complicating factor or when long-term anticoagulation is required.
authors.affiliation: Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
authors.forename: G R
authors.initials: GR
authors.lastname: Cousins
authors.forename: G S
authors.initials: GS
authors.lastname: Friedrichs
authors.forename: Y
authors.initials: Y
authors.lastname: Sudo
authors.forename: S S
authors.initials: SS
authors.lastname: Rebello
authors.forename: W E
authors.initials: WE
authors.lastname: Rote
authors.forename: G P
authors.initials: GP
authors.lastname: Vlasuk
authors.forename: T G
authors.initials: TG
authors.lastname: Nolan
authors.forename: C
authors.initials: C
authors.lastname: Mendoza
authors.forename: B R
authors.initials: BR
authors.lastname: Lucchesi
mesh_terms: D000284:Administration, Oral; D000577:Amides / Q000378:metabolism; D000818:Animals; D000991:Antithrombins / Q000008:administration & dosage* / Q000494:pharmacology; D001158:Arteries; D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003328:Coronary Thrombosis / Q000517:prevention & control*; D004285:Dogs; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D009842:Oligopeptides / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics; D009994:Osmolar Concentration; D010314:Partial Thromboplastin Time; D010974:Platelet Aggregation / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors
chemical_list: D000577:Amides; D000991:Antithrombins; C101948:CVS 1123; D009842:Oligopeptides; D013917:Thrombin