Naslov
Evaluation of a novel centrally active oxime as antidote in OP exposed mice
(Evaluation of a novel centraylly active oxime as antidote in OP exposed mice)

Autori
Žunec, Suzana ; Radić, Zoran ; Sit, Rakesh K. ; Taylor, Palmer ; Kovarik, Zrinka

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Book of Abstracts / Katalinić, Maja ; Kovarik, Zrinka - Zagreb : Hrvatsko društvo za biokemiju i molekularnu biologiju (HDBMB), 2016, 111-111

Skup
Congress of the Croatian Society of Biochemistry and Molecular Biology on the Occasion of the 40th Anniversary, HDBMB2016

Mjesto i datum
Split, Hrvatska, 01.07.2016. - 04.07.2016

Vrsta sudjelovanja
Poster

Vrsta recenzije
Domaća recenzija

Ključne riječi
RS2-138B ; 2-PAM ; sarin ; cyclosarin ; VX ; paraoxon ; tabun

Sažetak
Organophosphates (OPs) are potent covalent inhibitors of cholinesterases and are among the most formidable man-made poisons. OP nerve agents continue to be a threat as a terrorist weapon to civilian populations. Their high toxicity, extreme potency, ease of manufacture and dispersal, and the rapid onset of lethal toxic effects make them ideal weapons for producing a high number of casualties. In the third world OP pesticide poisoning is a significant human health hazard either from chronic low level exposures in agriculture or high dose life threatening poisonings due to suicide attempts or accidental ingestion. Acute OP poisoning is treated by administration of atropine as an anticonvulsant, with an oxime, typically pralidoxime (2-PAM), HI-6 or related bis-quaternary ammonium structures. The limitations of the current therapy are significant: the drugs have very narrow safety margins ; none of the currently used oximes act sufficiently rapidly to prevent the migration of the nerve agent to the CNS ; the oximes are rapidly excreted from the organism ; and charged oxime-based reactivators cannot penetrate the blood-brain barrier to reactivate acetylcholinesterase (AChE), essential enzyme for neurotransmition. Out of large library of novel uncharged oximes, N-substituted 2- hydroxyiminoacetamido alkylamines were selected as lead reactivators of human AChE covalently conjugated with OP nerve agents. Oxime RS2-138B showed substantially improved in vitro reactivation kinetics compared with standard oxime 2-PAM. Therefore, it was further evaluated for toxicity and efficacy in mouse animal model. Both therapeutic and a combination of therapeutic and prophylactic efficacies of RS2-138B in treatment of OPs (sarin, cyclosarin, VX, paraoxon and tabun) exposed mice yielded high protective indices upon i.m. oxime administration. It was also found to be less toxic than standard reference oxime 2-PAM. Taken together, desirable in vitro reactivation properties of RS2-138B coupled with its in vivo therapeutic efficiency reveal its potential as centrally and peripherally active antidote for counteracting the OP toxicity. This work was supported by the CounterACT Program, National Institutes of Health Office of the Director (NIH OD)(Grant No. R21 NS084904-01) and by the Croatian Science Foundation (Project No. 4307).

Izvorni jezik
Engleski

Znanstvena područja
Kemija

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