Reversal of lipophilic weak bases using pH gradient acidic centre liposomes: demonstration of effect in dabigatran-induced anticoagulation.

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Show simple item record Cave, Grant en Wu, Zimei en Hunter, Nicole en Damitz, Rob en Chauhan, Anuj en Harvey, Martyn en 2018-10-11T03:06:25Z en 2016-06 en
dc.identifier.issn 1556-3650 en
dc.identifier.uri en
dc.description.abstract Liposomes have recently emerged as rational vehicles for drug detoxification. Modification of the core pH may further enhance the ability of liposomes to sequester lipophilic toxins that are weak bases. Dabigatran, a reversible inhibitor of thrombin, has been widely promoted as a novel oral anticoagulant. As a lipophilic weak-base, it provides a rational target for reversal with acidic-centred liposomal preparations. The present study tests the hypothesis that acidic centre liposomes will reverse dabigatran induced anticoagulation.Following enteric dabigatran dosing in vitro assessment of thrombin clotting times (TCT) was undertaken in rabbit plasma spiked with incremental liposome concentrations. Tail vein bleeding was assessed following intravenous liposome injection in rats after enteric dabigatran administration.Liposomes achieved reversal of TCT to baseline at low levels of thrombin inhibition, and partial reversal of TCT at higher levels. Liposomes completely reversed the effects of dabigatran on rat tail vein bleeding time (134.0 (6.7) s liposomes vs. 410 (37.8) s control; p < 0.01).Dabigatran-induced coagulopathy was reversed in vitro and in vivo by acidic-centred liposomes. pH-modified liposomes are a promising investigational entity in the antidotal treatment of pharmacologic weak bases that are lipid soluble at physiologic pH. en
dc.format.medium Print-Electronic en
dc.language eng en
dc.relation.ispartofseries Clinical toxicology (Philadelphia, Pa.) en
dc.rights Items in ResearchSpace are protected by copyright, with all rights reserved, unless otherwise indicated. Previously published items are made available in accordance with the copyright policy of the publisher. en
dc.rights.uri en
dc.subject Animals en
dc.subject Rabbits en
dc.subject Rats en
dc.subject Rats, Sprague-Dawley en
dc.subject Disease Models, Animal en
dc.subject Hemorrhage en
dc.subject Thrombin en
dc.subject Antithrombins en
dc.subject Anticoagulants en
dc.subject Liposomes en
dc.subject Administration, Oral en
dc.subject Blood Coagulation en
dc.subject Dose-Response Relationship, Drug en
dc.subject Hydrogen-Ion Concentration en
dc.subject Time Factors en
dc.subject Female en
dc.subject Dabigatran en
dc.title Reversal of lipophilic weak bases using pH gradient acidic centre liposomes: demonstration of effect in dabigatran-induced anticoagulation. en
dc.type Journal Article en
dc.identifier.doi 10.3109/15563650.2016.1155125 en
pubs.issue 5 en
pubs.begin-page 428 en
pubs.volume 54 en
dc.rights.holder Copyright: The author en
dc.identifier.pmid 27019991 en
pubs.end-page 433 en
pubs.publication-status Published en
dc.rights.accessrights en
pubs.subtype Journal Article en
pubs.elements-id 525638 en Medical and Health Sciences en Pharmacy en
dc.identifier.eissn 1556-9519 en
pubs.record-created-at-source-date 2016-04-25 en
pubs.dimensions-id 27019991 en

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