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Research ArticleCardiovascular

Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits

Xueping Zhou, Weizhen Wu, Lin Chu, David E. Gutstein, Dietmar Seiffert and Xinkang Wang
Journal of Pharmacology and Experimental Therapeutics September 2016, 358 (3) 405-412; DOI: https://doi.org/10.1124/jpet.116.234575
Xueping Zhou
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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Weizhen Wu
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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Lin Chu
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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David E. Gutstein
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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Dietmar Seiffert
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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Xinkang Wang
Cardiometabolic Disease Biology (X.Z., W.W., D.E.G., D.S., X.W.) and Discovery Pharmaceutical Sciences (L.C.), Merck Research Laboratories, Kenilworth, New Jersey
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Abstract

Cerebral microembolic signal (MES) is an independent predictor of stroke risk and prognosis. The objective of this study is to assess the effects of apixaban, as a representative of the novel oral anticoagulant class, on a rabbit model of cerebral MES. A clinical transcranial Doppler ultrasound instrument was used to assess MESs in the middle cerebral artery in a 30% FeCl3-induced carotid arterial thrombosis model in male New Zealand White rabbits. Ascending doses of apixaban were evaluated as monotherapy and in combination with aspirin on both arterial thrombosis and MES. Pharmacokinetic and pharmacodynamic responses were also evaluated. The effective dose for 50% inhibition (ED50) of thrombus formation for monotherapy was 0.04 mg/kg per hour apixaban, i.v. (0.03 μM plasma exposure) for the integrated blood flow, 0.13 mg/kg per hour apixaban (0.10 μM plasma exposure) for thrombus weight, and 0.03 mg/kg per hour apixaban (0.02 μM plasma exposure) for MES. Dual treatment with aspirin (5 mg/kg, PO) and apixaban (0.015 mg/kg per hour, i.v.) resulted in a significant reduction in cerebral MES (P < 0.05) compared with monotherapy with either agent. Pharmacokinetic analysis of apixaban and pharmacodynamic assays using activated partial thromboplastin time (aPTT) and prothrombin time (PT) for apixaban- and arachidonic acid-induced platelet aggregation for aspirin were used to confirm the exposure-response relationships. In summary, our study demonstrates that apixaban in a concentration-dependent manner inhibits both arterial thrombosis and MES, suggesting a potential association between factor Xa (FXa) blockade and the reduction in MES in patients at risk of ischemic stroke.

Footnotes

    • Received April 22, 2016.
    • Accepted June 29, 2016.
  • dx.doi.org/10.1124/jpet.116.234575.

  • ↵Embedded ImageThis article has supplemental material available at jpet.aspetjournals.org.

  • Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics
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Journal of Pharmacology and Experimental Therapeutics: 358 (3)
Journal of Pharmacology and Experimental Therapeutics
Vol. 358, Issue 3
1 Sep 2016
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Research ArticleCardiovascular

Apixaban Inhibits Cerebral Microembolic Signals

Xueping Zhou, Weizhen Wu, Lin Chu, David E. Gutstein, Dietmar Seiffert and Xinkang Wang
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 405-412; DOI: https://doi.org/10.1124/jpet.116.234575

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Research ArticleCardiovascular

Apixaban Inhibits Cerebral Microembolic Signals

Xueping Zhou, Weizhen Wu, Lin Chu, David E. Gutstein, Dietmar Seiffert and Xinkang Wang
Journal of Pharmacology and Experimental Therapeutics September 1, 2016, 358 (3) 405-412; DOI: https://doi.org/10.1124/jpet.116.234575
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