Naslov
In vitro and in vivo evaluation of pyridinium oximes: Mode of interaction with acetylcholinesterase and effect on tabun and soman poisoned mice

Autori
Kovarik, Zrinka ; Čalić, Maja ; Lucić Vrdoljak, Ana ; Radić, Božica

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

Izvornik
XII International Symposium on Cholinergic Mechanisms, Scientific Program and Abstracts, Conference Handbook, Alicante, Spain / Gonzales-Ros, Jose Manuel - Alicante : Institute of Molecular and Cellular Biology, University Miguel Hernandez, 2005

Skup
XII International Symposium on Cholinergic Mechanisms

Mjesto i datum
Alicante, Španjolska, 01.10.2005. - 05.10.2005

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
acetylcholinesterase; antidote; nerve agent; inhibition; reactivation; oxime; antidotal treatment

Sažetak
The increased concern about terrorist use of nerve agents prompted us to search for new, more effective oximes against tabun and soman poisoning. We investigated the interactions of five bispyridinium oximes: K027 [1-(4-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium) propane dibromide], K048 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], K033 [1, 4-bis(2-hydroxyiminomethylpyridinium) butane dibromide], TMB4 [1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and HI-6 [(1-(2’ -hydroxyiminomethyl-1'-pyridinium)-3-(4''-carbamoyl-1''-pyridinium)-2-oxapropane dichloride)] with human erythrocyte acetylcholinesterase (AChE ; E.C. 3.1.1.7) and their effects on tabun and soman poisoned mice. All the oximes reversibly inhibited AChE, and the enzyme-oxime dissociation constants were between 17 and 180  M. Tabun-inhibited AChE was completely reactivated by TMB4, K027 and K048, with the overall reactivation rate constants of 311, 381 and 659 min-1M-1, respectively. The reactivation of tabun-inhibited AChE by K033 reached 50 % after 24 hours, while HI-6 failed to reactivate any AChE at all. Soman-inhibited AChE was resistant to reactivation by 1 mM oximes. All studied oximes protected AChE from phosphorylation by both soman and tabun. Our results obtained from in vivo experiments showed that the studied oximes were relatively toxic to mice ; K033 was the most toxic (LD50=33.4 mg/kg), while K027 was the least toxic (LD50=672.8 mg/kg). The best antidotal efficacy was obtained with K048, K027 and TMB4 for tabun poisoning, and HI-6 for soman poisoning. Therefore, the potency of the oximes to protect mice from 5-fold LD50 of tabun makes these compounds important in the therapy of tabun poisoning. Whatever its shortcomings, the combination of HI-6 and atropine has been the therapy of choice for soman poisoning.

Izvorni jezik
Engleski

Znanstvena područja
Kemija

POVEZANOST RADA