BACKGROUND: Based on in vitro and in vivo rat experiments, the newly developed acetylcholinesterase (AChE) reactivator, K203, appears to be much more effective in the treatment of tabun poisonings than currently fielded oximes. METHODS: To determine if this reactivating efficacy would extend to humans, studies were conducted in vitro using human brain homogenate as the source of AChE. The efficacy of K203 was compared with commercially available oximes; pralidoxime, obidoxime and asoxime (HI-6). RESULTS: Reactivation studies showed that K203 was the most effective reactivator with a second order kinetic constant (kr) of 2142 min- 1. M- 1, which was 51 times higher than that obtained for obidoxime (kr = 42 min- 1. M- 1). Both pralidoxime and asoxime (HI-6) failed to significantly reactivate tabun-inhibited human AChE. DISCUSSION: According to these results and previous studies, using K203, it appears that oxime K203 is the most effective reactivator of tabun-inhibited cholinesterase in several species including humans and should be considered as a possible medical countermeasure to tabun exposure.

• Klíčová slova
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota metabolismus   MeSH
• cholinesterasové inhibitory metabolismus   MeSH
• krysa rodu Rattus MeSH
• lidé MeSH
• mozek enzymologie   MeSH
• organofosfáty metabolismus   MeSH
• oximy metabolismus   MeSH
• pyridinové sloučeniny metabolismus   MeSH
• reaktivátory cholinesterázy metabolismus   MeSH
• simulace molekulového dockingu MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• cholinesterasové inhibitory MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• tabun MeSH Prohlížeč

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.

• Klíčová slova
• acetylcholinesterase, functional observational battery, histopathology, neurotoxicity, oximes, rats, tabun,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• atropin terapeutické užití   MeSH
• chemické bojové látky otrava   MeSH
• lidé MeSH
• mozek účinky léků   enzymologie   MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• neurotoxické syndromy farmakoterapie   MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• reaktivátory cholinesterázy terapeutické užití   MeSH
• trimedoxim terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• atropin MeSH
• chemické bojové látky MeSH
• neuroprotektivní látky MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• tabun MeSH Prohlížeč
• trimedoxim MeSH

The potency of newly developed bispyridinium compounds (K117, K127) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oxime (obidoxime) using functional observational battery. The neuroprotective effects of atropine alone and atropine combined with one of three bispyridinium oximes (K117, K127, obidoxime) on rats poisoned with tabun at a sublethal dose (180 microg/kg i.m.; 80% of LD(50) value) were studied. Tabun-induced neurotoxicity was monitored using a functional observational battery and automatic measurement of motor activity at 24 h following tabun challenge. The results indicated that all tested oximes combined with atropine enabled tabun-poisoned rats to survive 24 h following tabun challenge while one tabun-poisoned rats died within 24 h after tabun poisoning when the rats were treated with atropine alone. Newly developed oxime K127 combined with atropine was the most effective in decreasing tabun-induced neurotoxicity in the case of sublethal poisonings among all oximes tested. Nevertheless, the differences of neuroprotective efficacy between K127 and obidoxime are not sufficient to replace obidoxime by K127 for the treatment of acute tabun poisonings.

• MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory otrava   MeSH
• krysa rodu Rattus MeSH
• neuroprotektivní látky farmakologie   MeSH
• organofosfáty MeSH
• otrava organofosfáty * MeSH
• oximy farmakologie   MeSH
• pohybová aktivita účinky léků   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• chemické bojové látky MeSH
• cholinesterasové inhibitory MeSH
• K117 compound MeSH Prohlížeč
• K127 compound MeSH Prohlížeč
• neuroprotektivní látky MeSH
• organofosfáty MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• tabun MeSH Prohlížeč

• Klíčová slova
• acetylcholinesterase, antidote, nerve agent, organophosphates, prophylaxis, therapy,
• Publikační typ
• časopisecké články MeSH

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).

• MeSH
• acetylcholinesterasa MeSH
• lidé MeSH
• organofosfáty antagonisté a inhibitory   MeSH
• organofosforové sloučeniny antagonisté a inhibitory   MeSH
• oximy chemická syntéza   MeSH
• pyridinové sloučeniny chemická syntéza   MeSH
• reaktivátory cholinesterázy chemická syntéza   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• 1-(4-hydroxyiminomethylpyridinium)-3-pyridiniumpropane MeSH Prohlížeč
• acetylcholinesterasa MeSH
• cyclohexyl methylphosphonofluoridate MeSH Prohlížeč
• organofosfáty MeSH
• organofosforové sloučeniny MeSH
• oximy MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy MeSH
• tabun MeSH Prohlížeč