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Role of asymmetric bispyridinium oxime K048 in counteracting tabun poisoning in rats


Berend, Suzana; Lucić Vrdoljak, Ana; Radić, Božica
Role of asymmetric bispyridinium oxime K048 in counteracting tabun poisoning in rats // 13th Medical Chemical Defence Conference, Current Status of Therapeutic Approaches to Nerve Agent Poisoning
Munchen, Njemačka, 2011. (poster, međunarodna recenzija, sažetak, znanstveni)


Naslov
Role of asymmetric bispyridinium oxime K048 in counteracting tabun poisoning in rats

Autori
Berend, Suzana ; Lucić Vrdoljak, Ana ; Radić, Božica

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

Izvornik
13th Medical Chemical Defence Conference, Current Status of Therapeutic Approaches to Nerve Agent Poisoning / - , 2011

Skup
13th Medical Chemical Defence Conference

Mjesto i datum
Munchen, Njemačka, 13-14.04.2011

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
Bispyridinium oxime; tabun; rat

Sažetak
Oxime reactivation is currently the most important treatment modality for organophosporous (OP) compounds poisoning. They exhibit their potency by enabling recovery of an active acetylcholinesterase (AChE) in contrast to sympatomatic treatment of excessive cholinergic stimulation largely in the periphery with atropine. Till now only four pyridinium oximes (2-PAM, TMB-4, HI-6 and obidoxime) have found clinical application but their reactivation potency is still limited, especially in the case of nerve agent tabun poisoning. Our recent in vitro and in vivo studies on mice draw attention to oxime 1-(4- hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)-butane dibromide (K048) as a very potent reactivator of tabun-inhibited AChE. Therefore a new study was conducted: in rats poisoned with tabun and treated with atropine alone or a combination of oxime K048 (25 % LD50) and atropine, temporal changes of ChE/AChE activities in plasma, brain and diaphragm were studied. During the first hour of exposure, tabun markedly inhibited plasma ChE activity (~90 %). However, at that time point therapy with K048 and atropine administered 1 min after tabun significantly increased enzyme activities. Moreover, observed reactivation potency was about 50 %. After 6 and 24 h, plasma activities in poisoned rats increased (max. 42%) but the positive effect of therapy (oxime + atropine) was still present. Notable AChE inhibition was observed in brain (~60%) and diaphragm (~50%) tissues at 1 h after tabun challenge and such inhibition was maintained till 24 h after poisoning. Brain and diaphragm AChE activities did not differ significantly between poisoned and oxime plus atropine treated rats. Administration of atropine alone as therapy did not affect the enzyme activity which is in accordance with the fact that atropine relieves the symptoms of OP poisoning but it does not treat the poisoning itself. Judging by the followed time course of changes for cholinesterase activity, it seems that the therapeutic effect of oxime K048 is indeed related to the reactivation of tabun-inhibited enzyme. Although the efficiency of oximes can be improved if given with atropine, our results confirmed the hypothesis that oxime reactivation is necessary for a recovery of the original condition of an active enzyme molecule.

Izvorni jezik
Engleski

Znanstvena područja
Temeljne medicinske znanosti



POVEZANOST RADA


Projekt / tema
022-0222148-2139 - Terapijski učinak novosintetiziranih spojeva pri otrovanju organofosfatima (Ana Lucić Vrdoljak, )

Ustanove
Institut za medicinska istraživanja i medicinu rada, Zagreb