Abstract
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.
Footnotes
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Send reprint requests to: Benedict R. Lucchesi, Ph.D., M.D., Department of Pharmacology, University of Michigan Medical School, 1301C Medical Science Research Building III, Ann Arbor, Michigan 48109-0632.
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↵1 This study was supported by a grant from the National Institutes of Health, Heart, Lung and Blood Institute, HL-19782-16 and by The Cardiovascular Research Fund, University of Michigan.
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↵2 H.S.B. was supported by a summer student research fellowship from the American Heart Association–Michigan Affiliate.
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↵3 From Corvas International Inc., 3030 Science Park Road, San Diego, California.
- Abbreviations:
- ACT
- activated clotting time
- aPTT
- activated partial thromboplastin time
- ATS
- antistasin
- BP
- blood pressure
- fXa
- factor Xa
- LCA
- left common carotid artery
- LCX
- left circumflex coronary artery
- LMWH
- low-molecular-weight heparin
- PRP
- platelet-rich plasma
- PPP
- platelet-poor plasma
- PT
- prothrombin time
- rNAP5
- recombinant nematode anticoagulant peptide
- TAP
- tick anticoagulant protein
- Received March 21, 1997.
- Accepted June 26, 1997.
- The American Society for Pharmacology and Experimental Therapeutics
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