RT Journal Article
SR Electronic
T1 Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 405
OP 412
DO 10.1124/jpet.116.234575
VO 358
IS 3
A1 Xueping Zhou
A1 Weizhen Wu
A1 Lin Chu
A1 David E. Gutstein
A1 Dietmar Seiffert
A1 Xinkang Wang
YR 2016
UL http://jpet.aspetjournals.org/content/358/3/405.abstract
AB 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.