Effective use of BCH-2763, a new potent injectable direct thrombin inhibitor, in combination with tissue plasminogen activator (tPA) in a rat arterial thrombolysis model.
Current therapeutic use of heparin as an adjunct to thrombolytic therapy for myocardial infarction is suboptimal with respect to efficacy and bleeding risk. In a rat carotid arterial thrombolysis model (FeCl3-induced injury) we evaluated the combined effect of tPA (2.0 mg/kg/30 min) with our potent injectable direct thrombin inhibitor, BCH-2763 (Ki 0.11 nM; MW 1.5 kDa), which, unlike heparin, inhibits bound and free thrombin; comparisons were with standard heparin (SH), other direct thrombin inhibitors, r-hirudin (MW 6.5 kDa) and hirulog (MW 2.3 kDa), or tPA alone. Time to lysis (TL), patency time (PT), aPTT (fold increase) and bleeding time (BT) were determined. ED100 (100% of rats reperfused) for BCH-2763, hirulog or r-hirudin was 1, 3 or 2 mg/kg/60 min, respectively; 67% of rats reperfused with SH at the highest dose tested (220 U/kg/60 min) and 43% with tPA alone. At these doses, TL (min) was shorter (p < 0.01) with BCH-2763 (0.5 +/- 0.1), hirulog (3.3 +/- 2.3) or r-hirudin (2.3 +/- 1.0) than SH (66.3 +/- 30.8) or tPA alone (93.4 +/- 21.4). The aPTT fold increase after 15 min infusion was markedly greater (p < 0.001) for SH (32.0 +/- 0.8) than BCH-2763 (3.7 +/- 0.5), hirulog (5.2 +/- 0.3) or r-hirudin (4.5 +/- 0.8) in combination with tPA or tPA alone (1.1 +/- 0.1). In addition, the BT (min) for BCH-2763 (3.0 +/- 0.4) was similar to tPA alone (1.6 +/- 0.3), but prolonged (p < 0.05) for hirulog (7.5 +/- 2.7), r-hirudin (6.6 +/- 0.8) or SH (7.3 +/- 1.8). Comparisons at same aPTT fold increase revealed that in combination with tPA, BCH-2763 required a lower anticoagulant level to shorten the TL and prolong the PT than hirulog, r-hirudin or SH. Thus, in this rat arterial thrombolysis model direct thrombin inhibitors are more effective than SH as antithrombotic adjuncts to tPA. BCH-2763 is effective at a lower gravimetric dose and more modest aPTT fold increase than hirulog or r-hirudin with less alteration in haemostasis, which may confer an improved safety index.
Deschênes
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BioChem Therapeutic Inc., Laval, Quebec, Canada.
Finkle
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CD
Winocour
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PD
D000595:Amino Acid Sequence; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D002339:Carotid Arteries; D004195:Disease Models, Animal; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D006493:Heparin / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives; D007267:Injections; D008297:Male; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000009:adverse effects / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*
D000925:Anticoagulants; D005343:Fibrinolytic Agents; D006629:Hirudins; D009842:Oligopeptides; D010446:Peptide Fragments; D011994:Recombinant Proteins; C111479:BCH 2763; D006493:Heparin; D013917:Thrombin; D010959:Tissue Plasminogen Activator; C074619:bivalirudin