Bispyridinium oximes as antidotal treatment of cyclosarin poisoning-in vitro and in vivo testing.
The mechanism of intoxication with organophosphorus compounds, including highly toxic nerve agents and less toxic pesticides, is based on the formation of irreversibly inhibited acetylcholinesterase, which causes cumulation of neuromediator acetylcholine in synaptic clefts and subsequent overstimulation of cholinergic receptors, that is followed by a generalized cholinergic crisis. Nerve agent poisoning is conventionally treated using a combination of a cholinolytic (atropine mostly) to counteract the accumulation of acetylcholine and acetylcholinesterase reactivators (pralidoxime or obidoxime) to reactivate inhibited acetylcholinesterase. In this study of cyclosarin poisoning treatment, oximes of different chemical structures (obidoxime, HI-6, BI-6, and HS-6) were tested in vitro on rat brain acetylcholinesterase (enzyme source: rat brain homogenate), and afterwards, they were tested in vivo in equimolar doses, in mice and rats. The HI-6 oxime appeared to be the most effective oxime in vitro and in vivo.
Bartosova
Lucie
L
Department of Toxicology, Faculty of Military Health Sciences, Trebesska 1575, 500-01 Hradec Kralove, Czech Republic.
Kuca
Kamil
K
Jun
Daniel
D
Kunesova
Gabriela
G
D000818:Animals; D000931:Antidotes / Q000494:pharmacology / Q000627:therapeutic use; D001285:Atropine / Q000627:therapeutic use; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002800:Cholinesterase Inhibitors / Q000633:toxicity*; D002801:Cholinesterase Reactivators / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000633:toxicity; D005260:Female; D066298:In Vitro Techniques; D007700:Kinetics; D007928:Lethal Dose 50; D051379:Mice; D018727:Muscarinic Antagonists / Q000627:therapeutic use; D009768:Obidoxime Chloride / Q000494:pharmacology / Q000627:therapeutic use; D009943:Organophosphorus Compounds / Q000633:toxicity*; D010091:Oximes / Q000494:pharmacology* / Q000627:therapeutic use; D011726:Pyridinium Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000931:Antidotes; C118647:BI 6; D002800:Cholinesterase Inhibitors; D002801:Cholinesterase Reactivators; D004791:Enzyme Inhibitors; D018727:Muscarinic Antagonists; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; D009768:Obidoxime Chloride; D001285:Atropine; C022870:asoxime chloride; C053914:cyclohexyl methylphosphonofluoridate