title: Potency of new structurally different oximes to reactivate cyclosarin-inhibited human brain acetylcholinesterases.
abstract: Antidotes currently used for organophosphorus pesticide and nerve agent intoxications consist of anticholinergics (atropine mainly) and acetylcholinesterase (AChE, EC 3.1.1.7) reactivators called oximes. Owing to the wide-spread of these toxic compounds worldwide, development of antidotes in the case of first aid is needed. To select the most promising AChE reactivators is a very time consuming process, which is necessary before approval of these compounds to be used as human antidotes. Because of ethical reasons, many developing experiments have been conducted on laboratory animals. However, these results often could not be transferred directly to human. Here, we have tested five newly developed AChE reactivators--K027, K033, K048, K074 and K075, which showed promising reactivation activity on rodents, as reactivators of inhibited human brain cholinesterases. For this purpose, cyclosarin was used as member of the nerve agent family. Oxime HI-6 and pralidoxime were used as AChE reactivator standards. Two AChE reactivators, K027 and K033, achieved comparable reactivation potency as HI-6. Moreover, oxime K033 reached its maximal reactivation potency at the lowest concentration which could be attained in humans.
authors.affiliation: Department of Toxicology, Faculty of Military Health Sciences, University of Defence, Hradec Kralove, Czech Republic. kucakam@pmfhk.cz
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Jiri
authors.initials: J
authors.lastname: Cabal
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Jiri
authors.initials: J
authors.lastname: Bajgar
authors.forename: Martina
authors.initials: M
authors.lastname: Hrabinova
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D002801:Cholinesterase Reactivators / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D009943:Organophosphorus Compounds / Q000494:pharmacology*; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D011220:Pralidoxime Compounds / Q000494:pharmacology; D011726:Pyridinium Compounds / Q000494:pharmacology
chemical_list: D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D009943:Organophosphorus Compounds; D010091:Oximes; D011220:Pralidoxime Compounds; D011726:Pyridinium Compounds; D000110:Acetylcholinesterase; C022870:asoxime chloride; C028797:pralidoxime; C053914:cyclohexyl methylphosphonofluoridate