title: Oximes: Reactivators of phosphorylated acetylcholinesterase and antidotes in therapy against tabun poisoning.
abstract: One of the therapeutic approaches to organophosphate poisoning is to reactivate AChE with site-directed nucleophiles such as oximes. However, pyridinium oximes 2-PAM, HI-6, TMB-4 and obidoxime, found as the most effective reactivators, have limiting reactivating potency in tabun poisoning. We tested oximes varying in the type of ring (pyridinium and/or imidazolium), the length and type of the linker between rings, and in the position of the oxime group on the ring to find more effective oximes to reactivate tabun-inhibited human erythrocyte AChE. Three of our tested pyridinium oximes K027, K048, K074, along with TMB-4, were the most promising for AChE reactivation. Promising oximes were further tested in vivo on tabun poisoned mice not only as antidotes in combination with atropine but also as pretreatment drug. Herein, we showed that a promising treatment in tabun poisoning by selected oximes and atropine could be improved if oximes are also used in pretreatment. Since the reactivating efficacy of the oximes in vitro corresponded to their therapeutic efficacy in vivo, it seems that pharmacological effect of these oximes is indeed primarily related to the reactivation of tabun-phosphorylated AChE.
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska c. 2, Zagreb, Croatia. zrinka.kovarik@imi.hr
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Maja
authors.initials: M
authors.lastname: Calić
authors.forename: Goran
authors.initials: G
authors.lastname: Sinko
authors.forename: Anita
authors.initials: A
authors.lastname: Bosak
authors.forename: Suzana
authors.initials: S
authors.lastname: Berend
authors.forename: Ana Lucić
authors.initials: AL
authors.lastname: Vrdoljak
authors.forename: Bozica
authors.initials: B
authors.lastname: Radić
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D000931:Antidotes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D004793:Enzyme Reactivators / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062025:Organophosphate Poisoning; D010755:Organophosphates; D010091:Oximes / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D010766:Phosphorylation; D011041:Poisoning / Q000188:drug therapy
chemical_list: D000931:Antidotes; D002800:Cholinesterase Inhibitors; D004793:Enzyme Reactivators; D010755:Organophosphates; D010091:Oximes; D000110:Acetylcholinesterase; C009374:tabun