title: Therapeutic and reactivating efficacy of oximes K027 and K203 against a direct acetylcholinesterase inhibitor.
abstract: As oxime-based structures are the only causal antidotes to organophosphate (OP)-inhibited acetylcholinesterase (AChE), the majority of studies on these have been directed towards their synthesis and testing. In this study, experimental bispyridinium oximes K027 and K203, which have shown promising results in the last decade of research, were examined in vivo for their therapeutic and reactivating ability in acute poisoning by the direct AChE-inhibitor dichlorvos (DDVP), used as a dimethyl OP structural model. Additionally, the efficacy of oximes K027 and K203 was compared with the efficacy of four oximes (pralidoxime, trimedoxime, obidoxime and HI-6), already used in efficacy experiments and human medicine. To evaluate therapeutic efficacy, groups of Wistar rats were treated with equitoxic doses of oximes (5% LD50, i.m.) and/or atropine (10mg/kg, i.m.) immediately after s.c. DDVP challenge (4-6 doses). Using the same antidotal protocol, AChE activity was measured in erythrocytes, diaphragm and brain 60min after s.c. DDVP exposure (75% LD50). The oxime K027 was the most efficacious in reducing the DDVP induced lethal effect in rats, while the oxime K203 was more efficacious than trimedoxime, pralidoxime and HI-6. Significant reactivation of DDVP inhibited AChE was achieved only with oxime K027 or its combination with atropine in erythocytes and the diaphragm. Moreover, the acute i.m. toxicity of oxime K027 in rats was lower than all other tested oximes. The results of this study support previous studies considering the oxime K027 as a promising experimental oxime structure for further testing against structurally-different OP compounds.
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Department of Toxicology "Akademik Danilo Soldatović", Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: evicaa@pharmacy.bg.ac.rs.
authors.forename: Evica
authors.initials: E
authors.lastname: Antonijevic
authors.affiliation: University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; University Hospital in Hradec Kralove, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: kamil.musilek@uhk.cz.
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.affiliation: University of Hradec Kralove, Faculty of Science, Department of Chemistry, Rokitanskeho 62, 500 03 Hradec Kralove, Czech Republic; University Hospital in Hradec Kralove, Biomedical Research Center, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: kamil.kuca@fnhk.cz.
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Department of Toxicology "Akademik Danilo Soldatović", Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: dakitox@pharmacy.bg.ac.rs.
authors.forename: Danijela
authors.initials: D
authors.lastname: Djukic-Cosic
authors.affiliation: National Poison Control Center, Military Medical Academy, Crnotravska 17, 11000 Belgrade, Serbia. Electronic address: zarkovuc@eunet.rs.
authors.forename: Slavica
authors.initials: S
authors.lastname: Vucinic
authors.affiliation: University of Belgrade, Faculty of Pharmacy, Department of Toxicology "Akademik Danilo Soldatović", Vojvode Stepe 450, 11221 Belgrade, Serbia. Electronic address: abiljana@pharmacy.bg.ac.rs.
authors.forename: Biljana
authors.initials: B
authors.lastname: Antonijevic
mesh_terms: D000818:Animals; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology*; D004006:Dichlorvos / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007928:Lethal Dose 50; D008297:Male; D010091:Oximes / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
chemical_list: C524716:1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene; C481758:1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D010091:Oximes; D011726:Pyridinium Compounds; D004006:Dichlorvos
keywords: Acethylcholinesterase; Dichlorvos; Efficacy; Oxime K027; Oxime K203; Rats