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 thera py for myocardial infarction is suboptimal with respect to efficacy an d bleeding risk. In a rat carotid arterial thrombolysis model (FeCl3-i nduced injury) we evaluated the combined effect of tPA (2.0 mg/kg/30 m in) 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 th rombin inhibitors, r-hirudin (MW 6.5 kDa) and hirulog (MW 2.3 kDa), or tPA alone. Time to lysis (TL), patency time (PT), aPPT (fold increase ) and bleeding time (BT) were determined, ED100 (100% of rats reperfus ed) for BCH-2763. hirulog or r-hirudin was 1, 3 or 2 mg/kg/60 min, res pectively; 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 g reater (p < 0.001) for SH (32.0 +/- 0.8) than BCH-1763 (3.7 +/- 0.5), hirulog (5.2 +/- 0.3) or r-hirudin (4.5 +/- 0.8) in combination with t Pa 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 com bination with tPA, BCH-2763 required a lower anticoagulant level to sh orten the TL and prolong the PT than hirulog, r-hirudin or SH, Thus. i n 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 increa se than hirulog or r-hirudin with less alteration in haemostasis, whic h may confer an improved safety index.