Antithrombotic efficacy of a recombinant nematode anticoagulant peptide (rNAP5) in canine models of thrombosis after single subcutaneous administration.
We describe the antithrombotic effects of recombinant nematode anticoagulant peptide (rNAP5), a selective and direct factor Xa inhibitor, after a single s.c. administration in canine models of arterial and venous thrombosis. The systemic anticoagulant effects of rNAP5 were evaluated initially in conscious dogs after s.c. dosing (0.03, 0.1 and 0.3 mg/kg) that resulted in a dose-dependent increase in the activated clotting time and the activated partial thromboplastin time. The antithrombotic effects of rNAP5 were evaluated in anesthetized dogs where saline or rNAP5 (0.03, 0.1 and 0.3 mg/kg s.c.) was administered 1 hr before the left circumflex coronary artery was subjected to electrolytic injury. In the saline group (n = 10), the left circumflex artery occluded in 79 +/- 9 min, and 5 of 10 animals progressed to sudden death due to ventricular fibrillation. rNAP5 significantly prolonged the time to occlusion in the 0.03 mg/kg (163 +/- 62 min) and 0.1 mg/kg (327 +/- 62) treatment groups (n = 6). In the 0.3 mg/kg group (n = 5), all of the injured vessels remained patent for 8 hr. There was a dose-dependent reduction in the thrombus mass in the rNAP5-treated animals as compared with controls, as well as a lower mortality rate. rNAP5, in the doses of 0.03 and 0.1 mg/kg, did not alter the bleeding time, whereas 0.3 mg/kg produced a 5-fold increase. In a separate study, we evaluated the efficacy of rNAP5 (0.1 mg/kg) in the prevention of carotid artery and jugular vein thrombosis. In response to endothelial injury, the carotid artery and jugular vein in the saline group (n = 6) occluded in 142 +/- 16 and 100 +/- 11 min, respectively, compared with rNAP5, which maintained vessel patency in the carotid artery (6/6) and jugular vein (5/6) and significantly decreased the thrombus weights. The results demonstrate that rNAP5 has antithrombotic efficacy in canine models of arterial and venous thrombosis after a single s.c. administration.
Rebello
S S
SS
Department of Pharmacology, University of Michigan Medical School, Ann Arbor 48109-0632, USA.
Blank
H S
HS
Rote
W E
WE
Vlasuk
G P
GP
Lucchesi
B R
BR
D000595:Amino Acid Sequence; D000722:Ancylostoma / Q000737:chemistry*; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000627:therapeutic use*; D015801:Helminth Proteins / Q000627:therapeutic use*; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use; D007279:Injections, Subcutaneous; D008969:Molecular Sequence Data; D011994:Recombinant Proteins / Q000627:therapeutic use; D013927:Thrombosis / Q000517:prevention & control*
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D015801:Helminth Proteins; D006495:Heparin, Low-Molecular-Weight; D011994:Recombinant Proteins; C108605:anti-coagulant protein 5, Ancylostoma caninum