Pharmacology, pharmacokinetics and tissue disposition of zwitterionic hydroxyiminoacetamido alkylamines as reactivating antidotes for organophosphate exposure (CROSBI ID 251342)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Sit, Rakesh K. ; Kovarik, Zrinka ; Maček Hrvat, Nikolina ; Žunec, Suzana ; Green, Carol ; Fokin, Valery V. ; Sharpless, K. Barry ; Radić, Zoran ; Taylor, Palmer
engleski
Pharmacology, pharmacokinetics and tissue disposition of zwitterionic hydroxyiminoacetamido alkylamines as reactivating antidotes for organophosphate exposure
In the development of antidotal therapy for treatment of organophosphate exposure from pesticides used in agriculture and nerve agents insidiously used in terrorism, the methylpyridinium aldoximes have received primary attention since their early development by I.B. Wilson in the 1950's. Yet these agents, by virtue of their quaternary structure, are limited in crossing the blood-brain barrier, and require administration parenterally to achieve full distribution in the body. Oximes lacking cationic charges or presenting a tertiary amine have been considered as alternatives. Herein, we examine the pharmacokinetic properties in the mouse of a lead ionizable, zwitterionic hydroxyiminoacetamido alkylamine to develop a framework for studying these agents in vivo and generate sufficient data for their consideration as appropriate antidotes for humans. Consequently, in vitro and in vivo efficacies of immediate structural congeners were explored to feasible backups for animal studies. We have compared oral and parenteral dosing, and developed an intramuscular loading and oral maintenance dosing scheme in mice. Steady-state plasma and brain levels of the antidote are achieved with sequential administration out to 10 hours, with brain exceeding plasma levels shortly after administration. Moreover, the zwitterionic oxime shows substantial protection after gastric lavage, whereas the classic methylpyridinium aldoxime, 2-PAM, is without evident protection. While further studies in other animal species are necessary, ionizing zwitterionic aldoximes present viable alternatives to existing antidotes for prophylaxis and treatment of large numbers of individuals in terrorist-led events with nerve agent organophosphates, such as sarin, and in organophosphate pesticide exposure.
acetylcholinesterase ; organophosphates ; oxime reactivators ; blood-brain barrier
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Podaci o izdanju
367 (2)
2018.
363-372
objavljeno
0022-3565
1521-0103
10.1124/jpet.118.249383
Povezanost rada
Kemija