title: An easy method for the determination of active concentrations of cholinesterase reactivators in blood samples: Application to the efficacy assessment of non quaternary reactivators compared to HI-6 and pralidoxime in VX-poisoned mice.
abstract: Organophosphorus nerve agents, like VX, are highly toxic due to their strong inhibition potency against acetylcholinesterase (AChE). AChE inhibited by VX can be reactivated using powerful nucleophilic molecules, most commonly oximes, which are one major component of the emergency treatment in case of nerve agent intoxication. We present here a comparative in vivo study on Swiss mice of four reactivators: HI-6, pralidoxime and two uncharged derivatives of 3-hydroxy-2-pyridinaldoxime that should more easily cross the blood-brain barrier and display a significant central nervous system activity. The reactivability kinetic profile of the oximes is established following intraperitoneal injection in healthy mice, using an original and fast enzymatic method based on the reactivation potential of oxime-containing plasma samples. HI-6 displays the highest reactivation potential whatever the conditions, followed by pralidoxime and the two non quaternary reactivators at the dose of 50 mg/kg bw. But these three last reactivators display equivalent reactivation potential at the same dose of 100 μmol/kg bw. Maximal reactivation potential closely correlates to surviving test results of VX intoxicated mice.
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France; COGNition and ACtion Group, UMR 8257, CNRS-MD-UPV, Centre universitaire des Saints-Pères, Paris, France. Electronic address: guilhem.calas@irba.fr.
authors.forename: André-Guilhem
authors.initials: AG
authors.lastname: Calas
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France.
authors.forename: José
authors.initials: J
authors.lastname: Dias
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France; COGNition and ACtion Group, UMR 8257, CNRS-MD-UPV, Centre universitaire des Saints-Pères, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Rousseau
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Arboléas
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France.
authors.forename: Mélanie
authors.initials: M
authors.lastname: Touvrey-Loiodice
authors.affiliation: Normandie Université, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Mercey
authors.affiliation: Normandie Université, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Ludovic
authors.initials: L
authors.lastname: Jean
authors.affiliation: Normandie Université, COBRA, UMR 6014 & FR 3038, Université de Rouen, INSA Rouen, CNRS, 1 rue Tesnière, 76821 Mont-Saint-Aignan Cedex, France.
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Renard
authors.affiliation: Institut de Recherche Biomédicale des Armées, Brétigny-sur-Orge Cédex, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Nachon
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001774:Blood Chemical Analysis / Q000379:methods*; D001812:Blood-Brain Barrier / Q000187:drug effects* / Q000378:metabolism; D002619:Chemical Warfare Agents / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000097:blood*; D004912:Erythrocytes / Q000166:cytology / Q000201:enzymology; D006207:Half-Life; D006801:Humans; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D009946:Organothiophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000378:metabolism / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000378:metabolism / Q000494:pharmacology*; D020011:Protective Agents / Q000378:metabolism / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D000110:Acetylcholinesterase; D002619:Chemical Warfare Agents; D002801:Cholinesterase Reactivators; D009946:Organothiophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D020011:Protective Agents; D011726:Pyridinium Compounds; C009680:VX-agent; C022870:asoxime chloride; C028797:pralidoxime
keywords: Blood clearance; Cholinesterase; Organophosphorus-nerve agents; Oxime; Reactivation