title: Reversal of lipophilic weak bases using pH gradient acidic centre liposomes: demonstration of effect in dabigatran-induced anticoagulation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
  
  
  RESULTS
  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).
  
  
  CONCLUSIONS
  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.
authors.affiliation: a Emergency and Intensive Care Department , Tamworth Base Hospital , Tamworth , NSW , Australia ;
authors.forename: Grant
authors.initials: G
authors.lastname: Cave
authors.affiliation: b Department of Pharmacy, School of Medicine , Senior Lecturer, University of Auckland , Auckland , New Zealand ;
authors.forename: Zimei
authors.initials: Z
authors.lastname: Wu
authors.affiliation: c Medical Student, University of Melbourne , Melbourne , Australia ;
authors.forename: Nicole
authors.initials: N
authors.lastname: Hunter
authors.affiliation: d Department of Chemical Engineering , Universtiy of Florida , Miami , FL , USA ;
authors.forename: Rob
authors.initials: R
authors.lastname: Damitz
authors.affiliation: d Department of Chemical Engineering , Universtiy of Florida , Miami , FL , USA ;
authors.forename: Anuj
authors.initials: A
authors.lastname: Chauhan
authors.affiliation: e Waikato Hospital Emergency Department , Hamilton , New Zealand.
authors.forename: Martyn
authors.initials: M
authors.lastname: Harvey
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000925:Anticoagulants / Q000633:toxicity*; D000991:Antithrombins / Q000633:toxicity*; D001777:Blood Coagulation / Q000187:drug effects; D000069604:Dabigatran / Q000633:toxicity*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D006470:Hemorrhage / Q000139:chemically induced / Q000628:therapy; D006863:Hydrogen-Ion Concentration; D008081:Liposomes / Q000737:chemistry*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013997:Time Factors
chemical_list: D000925:Anticoagulants; D000991:Antithrombins; D008081:Liposomes; D013917:Thrombin; D000069604:Dabigatran
keywords: Complications of poisoning; heart; organ/tissue specific