title: Induction of sustained patency after clot-selective coronary thrombolysis with Hybrid-B, a genetically engineered plasminogen activator with a prolonged biological half-life.
abstract: BACKGROUND
  Despite the utility of tissue-type plasminogen activator (t-PA) in eliciting coronary thrombolysis clinically, early reocclusion remains a problem, occurring despite anticoagulation in 5-30% of patients with initially successful recanalization. This study evaluated the utility of Hybrid-B, a molecular variant of t-PA with a prolonged half-life in the circulation, in eliciting coronary thrombolysis and maintaining patency in the presence of a continuing thrombogenic stimulus.
  
  
  RESULTS
  In intact, anesthetized dogs, either 18 mg Hybrid-B over 30 minutes (n = 15) or 50 mg t-PA (Activase) over 60 minutes (n = 8) was administered starting 60 minutes after left anterior descending coronary artery occlusion was induced with a thrombogenic copper coil. Time to lysis averaged 54 +/- 26 (means +/- SD) minutes and 64 +/- 34 minutes with Hybrid-B and t-PA, respectively (p = NS). When Hybrid-B was administered as a bolus (20 mg over 1 minute) to induce a high initial concentration in blood, time to lysis was shortened markedly and averaged 15 +/- 5 minutes. Dogs given Hybrid-B by either infusion or bolus exhibited prolonged time to reocclusion (337 +/- 192 minutes compared with 192 +/- 125 minutes in dogs given t-PA, p less than 0.03), reflecting maintenance of a subthrombolytic but persistently active concentration of activator in blood. Despite the persistence of Hybrid-B in blood, concentrations of fibrinogen and alpha 2-antiplasmin were not depleted markedly and remained at 77 +/- 25 and 56 +/- 24%, respectively, of control values.
  
  
  CONCLUSIONS
  Thus, Hybrid-B, a novel variant of t-PA with unique pharmacokinetic properties, elicits prompt, sustained, and clot-selective coronary thrombolysis.
authors.affiliation: Cardiovascular Division, Washington University School of Medicine, St. Louis, Mo 63110.
authors.forename: C J
authors.initials: CJ
authors.lastname: Weinheimer
authors.forename: H L
authors.initials: HL
authors.lastname: James
authors.forename: N K
authors.initials: NK
authors.lastname: Kalyan
authors.forename: J
authors.initials: J
authors.lastname: Wilhelm
authors.forename: S G
authors.initials: SG
authors.lastname: Lee
authors.forename: P P
authors.initials: PP
authors.lastname: Hung
authors.forename: B E
authors.initials: BE
authors.lastname: Sobel
authors.forename: S R
authors.initials: SR
authors.lastname: Bergmann
mesh_terms: D000818:Animals; D003328:Coronary Thrombosis / Q000188:drug therapy*; D004285:Dogs; D006207:Half-Life; D010960:Plasminogen Activators / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000493:pharmacokinetics / Q000627:therapeutic use; D012008:Recurrence; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000493:pharmacokinetics / Q000627:therapeutic use; D014654:Vascular Patency
chemical_list: C068262:Hybrid-B; D011994:Recombinant Proteins; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator