title: Apixaban Inhibits Cerebral Microembolic Signals Derived from Carotid Arterial Thrombosis in Rabbits.
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.
authors.affiliation: 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.
authors.forename: Xueping
authors.initials: X
authors.lastname: Zhou
authors.affiliation: 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.
authors.forename: Weizhen
authors.initials: W
authors.lastname: Wu
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Chu
authors.affiliation: 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.
authors.forename: David E
authors.initials: DE
authors.lastname: Gutstein
authors.affiliation: 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.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Seiffert
authors.affiliation: 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 xinkang.wang@merck.com wangxk2000@yahoo.com.
authors.forename: Xinkang
authors.initials: X
authors.lastname: Wang
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects* / Q000473:pathology*; D002341:Carotid Artery Thrombosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D011720:Pyrazoles / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011728:Pyridones / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D011817:Rabbits; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: D000925:Anticoagulants; D011720:Pyrazoles; D011728:Pyridones; C522181:apixaban