Antithrombotic efficacy of single subcutaneous administration of a recombinant nematode anticoagulant peptide (rNAP5) in a canine model of coronary artery thrombolysis.
We examined the adjunctive benefit of recombinant nematode anticoagulant peptide (rNAP5), a factor Xa inhibitor, in a canine model of recombinant (rt)-PA-induced thrombolysis. In anesthetized dogs, a stable occlusive thrombus was formed by electrolytic injury of the vessel wall, after which the animals were administered rt-PA (1.44 mg/kg, i.v.) and rNAP5 (0.1 mg/kg, s.c.: n=13), or rt-PA plus vehicle (1-2 ml, s.c.; n=13). Hemodynamic and coagulation parameters were monitored for 360 minutes. Single subcutaneous administration of rNAP5 resulted in a prolonged and sustained increase in the activated partial thromboplastin time (>100-fold), whereas prothrombin time was unchanged. The template bleeding time was not altered significantly throughout the protocol (maximum 1.4-fold). The incidence of reperfusion was similar in the two groups with a trend toward faster reperfusion in the rNAP5 group (34+/-4 minutes) compared to the vehicle group (63+/-15 minutes; p=0.07). After reperfusion, 80% of the vessels in the vehicle group reoccluded, whereas only 14% of vessels reoccluded in the rNAP5-treated group. Times to reocclusion were 65+/-21 minutes and 221+/-28 minutes, respectively (p<0.05). Single subcutaneous administration of rNAP5 sustained the coronary artery blood flow after reperfusion, such that at the end of protocol the flow was 47% of the preocclusion value as compared to the vehicle group in which the flow was 11% (p<0.05). Cyclic flow reductions were most prominent during rt-PA-induced reperfusion and were similar in both groups. The results indicate that a single subcutaneous administration of rNAP5 provides a sustained antithrombotic effect in maintaining the coronary artery patency during rt-PA-induced thrombolysis.
Rebello
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Department of Pharmacology, University of Michigan Medical School, Ann Arbor, USA. sam.rebello@aventis.com
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Lucchesi
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D000277:Adjuvants, Pharmaceutic; D000818:Animals; D000990:Antithrombin III / Q000627:therapeutic use; D001780:Blood Coagulation Tests; D001783:Blood Flow Velocity / Q000187:drug effects; D003328:Coronary Thrombosis / Q000150:complications / Q000188:drug therapy*; D004195:Disease Models, Animal; D004285:Dogs; D005343:Fibrinolytic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015801:Helminth Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use*; D009203:Myocardial Infarction / Q000209:etiology; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000627:therapeutic use; D015424:Reperfusion / Q000379:methods; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D014654:Vascular Patency / Q000187:drug effects
D000277:Adjuvants, Pharmaceutic; D005343:Fibrinolytic Agents; D015801:Helminth Proteins; D011994:Recombinant Proteins; C108605:anti-coagulant protein 5, Ancylostoma caninum; D000990:Antithrombin III; D010959:Tissue Plasminogen Activator