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Pregled bibliografske jedinice broj: 207739

In vitro and in vivo evaluation of pyridinium oximes : mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity


Čalić, Maja; Lucić Vrdoljak, Ana; Radić, Božica; Jelić, Dubravko; Jun, Daniel; Kuča, Kamil; Kovarik, Zrinka
In vitro and in vivo evaluation of pyridinium oximes : mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity // Toxicology, 219 (2006), 1/3; 85-96 doi:10.1016/j.tox.2005.11.003 (međunarodna recenzija, članak, znanstveni)


Naslov
In vitro and in vivo evaluation of pyridinium oximes : mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity
(In vitro and in vivo evaluation of pyridinium oxime : mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity)

Autori
Čalić, Maja ; Lucić Vrdoljak, Ana ; Radić, Božica ; Jelić, Dubravko ; Jun, Daniel ; Kuča, Kamil ; Kovarik, Zrinka

Izvornik
Toxicology (0300-483X) 219 (2006), 1/3; 85-96

Vrsta, podvrsta i kategorija rada
Radovi u časopisima, članak, znanstveni

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], TMB-4 [1, 3-bis(4-hydroxyiminomethylpyridinium) propane dibromide] and HI-6 [(1-(2-hydroxyiminomethylpyridinium)-3-(4-carbamoylpyridinium)-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 TMB-4, K027 and K048, with the overall reactivation rate constants of 306, 376 and 673 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 with both soman and tabun. 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 TMB-4 for tabun poisoning, and HI-6 for soman poisoning. Moreover, all tested oximes showed no cytotoxic effect on several cell lines in concentrations up to 0.8 mM. The potency of the oximes K048 and K027 to protect mice from 5-fold LD50 of tabun and their low toxicity make these compounds leading in the therapy of tabun poisoning. The combination of HI-6 and atropine is the therapy of choice for soman poisoning.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Farmacija



POVEZANOST RADA


Projekt / tema
0022014
0022015

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb,
Pliva-Istraživački institut

Časopis indeksira:


  • Current Contents Connect (CCC)
  • Web of Science Core Collection (WoSCC)
    • Science Citation Index Expanded (SCI-EXP)
    • SCI-EXP, SSCI i/ili A&HCI
  • Scopus
  • MEDLINE


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