Abstract
The antithrombotic activity of recombinant, human activated protein C (rh-APC, LY203638) was examined in a model of canine coronary artery thrombosis. Three doses of rh-APC (0.5, 1.0, and 2.0 mg/kg/h) were administered intravenously for 2 h. Whole blood clotting times (thrombin time, activated partial thromboplastin time), ex vivo platelet aggregation, and template bleeding times were determined. Activated partial thromboplastin time significantly increased 2- and 3.7-fold during the 2-h infusion of rh-APC (1.0 and 2.0 mg/kg/h, respectively); thrombin time did not change. Intravenous infusions of rh-APC (1.0 and 2.0 mg/kg/h) produced significant prolongations to occlusion, 186 ± 21 and 190 ± 22 min, respectively, compared with the vehicle and the 0.5 mg/kg/h group (86 ± 12 and 93 ± 17 min, respectively). Vessel patency was better at the end of the experiment in the intermediate- and high-dose groups (3 of 6 and 3 of 5 vessels, 1.0 and 2.0 mg/kg/h, respectively) compared with the vehicle and 0.5 mg/kg/h groups (0/5 and 0/6, respectively). Only the 1.0 mg/kg/h group was found to have significantly elevated template bleeding times, with peak increases seen 60 min into the drug infusion. All groups had returned to baseline values by the end of the study. There was no observed inhibition of platelet aggregation. These data demonstrate that recombinant, human activated protein C is an effective anticoagulant and antithrombotic agent in the dog.
Footnotes
-
Send reprint requests to: Charles V. Jackson, Ph.D., Cardiovascular Research Division, Lilly Research Laboratories, Lilly Corporate Center—MC304, Indianapolis, IN 46285-0524. E-mail:jacksoncv{at}lilly.com
- Abbreviations:
- rh-APC
- recombinant human activated protein C, LY203638
- LCCA
- left circumflex coronary artery
- TBT
- template bleeding time
- APTT
- activated partial thromboplastin time
- PAF
- 1-O-hexadecyl-2-O-acetyl-sn-glycero-3-phosphorylcholine
- AA
- arachidonic acid
- PRP
- platelet-rich plasma
- Received April 17, 2000.
- Accepted July 19, 2000.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|