title: Pretreatment with pyridinium oximes improves antidotal therapy against tabun poisoning.
abstract: Oximes K033 [1,4-bis(2-hydroxyiminomethylpyridinium) butane dibromide] and K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide] were tested as pretreatment drugs in tabun-poisoned mice followed by treatment with atropine plus K033, K048, K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], TMB-4 [1,3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-2-oxapropane dichloride)]. Oxime doses of 25% or 5% of its LD(50) were used for pretreatment 15 min before tabun-poisoning and for treatment 1 min after tabun administration to mice. The best therapeutic effect was obtained when oxime K048 (25% of its LD(50)) was used in both pretreatment and treatment with atropine. This regiment insured survival of all tested animals after the application of 10 LD(50) of tabun. In addition, since butyrylcholinesterase (BChE; EC 3.1.1.8) is considered an endogenous bioscavenger of anticholinesterase compounds and its interactions with oximes could be masked by AChE interactions, we evaluated kinetic parameters for interactions of tested oximes with native and tabun-inhibited human plasma BChE and compared them with results obtained previously for human erythrocyte acetylcholinesterase (AChE; EC 3.1.1.7). Progressive inhibition of BChE by tabun was slightly faster than that of AChE. The reactivation of tabun-inhibited BChE by oximes was very slow, and BChE binding affinity for oximes was lower than AChE's. Therefore, BChE could scavenge tabun prior to AChE inhibition, but fast oxime-assisted reactivation of tabun-inhibited AChE or protection of AChE by oxime against inhibition with tabun would not be obstructed by interaction between BChE and oximes.
authors.affiliation: Institute for Medical Research and Occupational Health, Ksaverska c 2, Zagreb, Croatia.
authors.forename: Ana
authors.initials: A
authors.lastname: Lucić Vrdoljak
authors.forename: Maja
authors.initials: M
authors.lastname: Calić
authors.forename: Bozica
authors.initials: B
authors.lastname: Radić
authors.forename: Suzana
authors.initials: S
authors.lastname: Berend
authors.forename: Daniel
authors.initials: D
authors.lastname: Jun
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
mesh_terms: D000110:Acetylcholinesterase / Q000187:drug effects; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001285:Atropine / Q000494:pharmacology; D002091:Butyrylcholinesterase / Q000187:drug effects; D002619:Chemical Warfare Agents / Q000506:poisoning*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004336:Drug Antagonism; D004359:Drug Therapy, Combination; D004912:Erythrocytes / Q000201:enzymology; D006801:Humans; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D062025:Organophosphate Poisoning; D010755:Organophosphates; D010091:Oximes / Q000494:pharmacology*; D011041:Poisoning / Q000517:prevention & control*; D011726:Pyridinium Compounds / Q000494:pharmacology*
chemical_list: C489959:1,4-bis(2-hydroxyiminomethylpyridinium)butane; C488676:1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane; D000931:Antidotes; D002619:Chemical Warfare Agents; D002800:Cholinesterase Inhibitors; D010755:Organophosphates; D010091:Oximes; D011726:Pyridinium Compounds; D001285:Atropine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; C009374:tabun