title: A conjugate of pyridine-4-aldoxime and atropine as a potential antidote against organophosphorus compounds poisoning.
abstract: A conjugate of pyridine-4-aldoxime and atropine (ATR-4-OX) was synthesized and its antidotal efficiency was tested in vitro on tabun- or paraoxon-inhibited acetylcholinesterase (AChE) of human erythrocytes as well as in vivo using soman-, tabun- or paraoxon-poisoned mice. Its genotoxic profile was assessed on human lymphocytes in vitro and was found acceptable for further research. ATR-4-OX showed very weak antidotal activity, inadequate for soman or tabun poisoning. Conversely, it was effective against paraoxon poisoning both in vitro and in vivo. All animals treated with 5 % or 25 % LD(50) doses of the new oxime survived after administration of 10.0 or 16.0 LD(50) doses of paraoxon, respectively. Based on the persistence of toxicity symptoms in mice, the atropine moiety had questionable effects in attenuating such symptoms. It appears that ATR-4-OX has a therapeutic effect related to the reactivation of phosphylated AChE, but not to receptor antagonization.
authors.affiliation: University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Jasna
authors.initials: J
authors.lastname: Lovrić
authors.forename: Suzana
authors.initials: S
authors.lastname: Berend
authors.forename: Ana
authors.initials: A
authors.lastname: Lucić Vrdoljak
authors.forename: Božica
authors.initials: B
authors.lastname: Radić
authors.forename: Maja
authors.initials: M
authors.lastname: Katalinić
authors.forename: Zrinka
authors.initials: Z
authors.lastname: Kovarik
authors.forename: Davor
authors.initials: D
authors.lastname: Želježić
authors.forename: Nevenka
authors.initials: N
authors.lastname: Kopjar
authors.forename: Slavko
authors.initials: S
authors.lastname: Rast
authors.forename: Milan
authors.initials: M
authors.lastname: Mesić
mesh_terms: D000110:Acetylcholinesterase; D000328:Adult; D000818:Animals; D000931:Antidotes / Q000494:pharmacology*; D001286:Atropine Derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000506:poisoning*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D057075:Enzyme Assays; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D051379:Mice; D062025:Organophosphate Poisoning; D010755:Organophosphates; D010261:Paraoxon / Q000506:poisoning*; D011220:Pralidoxime Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D012999:Soman / Q000506:poisoning*
chemical_list: C561714:8-(4-(4-(-(hydroxyimino)methyl)-1-pyridiniumyl)butyl)-3-((3-hydroxy-2-phenylpropanoyl)oxy)-8-methyl-8-azoniabicyclo(3.2.1)octane; D000931:Antidotes; D001286:Atropine Derivatives; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010755:Organophosphates; D011220:Pralidoxime Compounds; D012999:Soman; D000110:Acetylcholinesterase; D010261:Paraoxon; C009374:tabun