Oxime K203 seems to be the most promising oxime in case of reactivation of tabun-inhibited acetylcholinesterase (AChE). Although it was originally developed for treatment of tabun intoxications, it is able to reactivate cholinesterases inhibited by other nerve agents. This study is aimed at the evaluation of its potency in vitro against other nerve agents. For this purpose, sarin, tabun, cyclosarin, soman, VX, Russian VX and DFP were selected as members of the nerve agent family to check its universality. At high concentrations (10(-3) M), oxime K203 reached promising reactivation activity. At low concentrations, relevant for human use (10(-5) M), promising reactivation potency was obtained only with tabun. In conclusion, oxime K203 reactivates other nerve agents-inhibited cholinesterases, however its broad-spectrum reactivation is limited at high, for human not attainable, concentrations only.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• krysa rodu rattus MeSH
• lidé MeSH
• nervová bojová látka farmakologie   MeSH
• oximy farmakologie   MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterázy farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

For over 60 years, researchers across the world have sought to deal with poisoning by nerve agents, the most toxic and lethal chemical weapons. To date, there is no efficient causal antidote with sufficient effect. Every trialed compound fails to fulfil one or more criteria (e.g. reactivation potency, broad reactivation profile). In this recent contribution, we focused our attention to one of the promising compounds, namely the bis-pyridinium reactivator K203. The oxime K203 is very often cited as the best reactivator against tabun poisoning. Herein, we provide all the available literature data in comprehensive and critical review to address whether K203 could be considered as a new drug candidate against organophosphorus poisoning with the stress on tabun. We describe its development from the historical point of view and review all available in vitro as well as in vivo data to date. K203 is easily accessible by a relatively simple two-step synthesis. It is well accommodated in the enzyme active gorge of acetylcholinesterase providing suitable interactions for reactivation, as shown by molecular docking simulations. According to a literature survey, in vitro data for tabun-inhibited AChE are extraordinary. However, in vivo efficiency remains unconvincing. The K203 toxicity profile did not show any perturbations compared to clinically used standards; on the other hand versatility of K203 does not exceed currently available oximes. In summary, K203 does not seem to address current issues associated with the organophosphorus poisoning, especially the broad profile against all nerve agents. However, its reviewed efficacy entitles K203 to be considered as a backup or tentative replacement for obidoxime and trimedoxime, currently only available anti-tabun drugs.

• MeSH
• acetylcholinesterasa MeSH
• antidota farmakologie   terapeutické užití   MeSH
• nervová bojová látka otrava   MeSH
• obidoxim chlorid MeSH
• organofosfáty toxicita   MeSH
• otrava organofosfáty farmakoterapie   MeSH
• oximy terapeutické užití   MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• simulace molekulového dockingu MeSH
• trimedoxim MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

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.

• 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

The ability of a novel bispyridinium oxime K203 to reactivate VX agent-inhibited acetylcholinesterase was compared with the reactivating efficacy of four commonly used oximes (obidoxime, trimedoxime, methoxime, HI-6) using in vivo model. Our results showed that the reactivating efficacy of the oxime HI-6 is higher than the reactivating efficacy of the other oximes studied including the oxime K203 although the differrences between the oxime HI-6 and some other oximes are not significant, especially in the blood. Based on the obtained data, we can conclude that the antidotal treatment involving the oxime HI-6 brings the higher benefit for the antidotal treatment of acute poisonings with VX agent than other oximes.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• krysa rodu rattus MeSH
• molekulární struktura MeSH
• organothiofosforové sloučeniny antagonisté a inhibitory   farmakologie   toxicita   MeSH
• oximy chemie   farmakologie   MeSH
• potkani Wistar MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou 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

The neuroprotective effects of a novel oxime KR-22934, the oxime K203 and obidoxime in combination with atropine in rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 80% LD50) were studied. The tabun-induced neurotoxicity was monitored at 24 h following tabun challenge using a functional observational battery and an automatic measurement of motor activity. The results indicate that all tabun-poisoned rats treated with oximes in combination with atropine were able to survive within 24 h following tabun poisoning. One tabun-poisoned rat without antidotal treatment died within 24 h. The oximes KR-22934 and K203 combined with atropine showed a similar potency to decrease tabun-induced neurotoxicity at 24 h after tabun administration while the neuroprotective efficacy of obidoxime was slightly higher. However, no oxime was able to eliminate tabun-induced neurotoxicity completely. When atropine was administered alone, negligible neuroprotective efficacy was observed. Based on the results, a novel oxime KR-22934 did not bring any improvement of the neuroprotective efficacy of antidotal treatment of acute tabun poisonings.

• MeSH
• atropin aplikace a dávkování   terapeutické užití   MeSH
• chemické bojové látky * otrava   MeSH
• cholinesterasové inhibitory * otrava   MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• neurologické manifestace MeSH
• neurologické vyšetření statistika a číselné údaje   veterinární   MeSH
• neuroprotektivní látky aplikace a dávkování   terapeutické užití   MeSH
• obidoxim chlorid aplikace a dávkování   terapeutické užití   MeSH
• organofosfáty * MeSH
• oximy * aplikace a dávkování   terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny * aplikace a dávkování   terapeutické užití   MeSH
• statistika jako téma MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The ability of the oxime HI-6 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) using a functional observational battery. Tabun-induced neurotoxicity and the neuroprotective effects of HI-6 alone, and HI-6 combined with trimedoxime or K203, in rats poisoned with tabun at a sublethal dose (200 microg/kg i.m.; 80% of LD50 value), were monitored by the functional observational battery at 24 hours following tabun challenge. The results indicate that both oxime mixtures tested, combined with atropine are able to allow tabun-poisoned rats to survive for 24 hours following tabun challenge, while one non-treated tabun poisoned rat and one tabun-poisoned rat treated with the oxime HI-6 alone combined with atropine, died within 24 hours following tabun challenge. The oxime HI-6 alone, as well as both oxime mixtures combined with atropine, were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings, but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to reduce tabun-induced acute neurotoxcicity was almost the same, regardless of type of antidotal treatment. Thus, the tested combinations of oximes were not able to increase the neuroprotective effectiveness of the antidotal treatment of acute tabun poisonings compared to the individual oxime.

• MeSH
• antidota farmakokinetika   farmakologie   terapeutické užití   MeSH
• atropin terapeutické užití   MeSH
• chemické bojové látky škodlivé účinky   toxicita   MeSH
• experimenty na zvířatech statistika a číselné údaje   MeSH
• financování organizované MeSH
• fixní kombinace léků MeSH
• medicína založená na důkazech MeSH
• neuroprotektivní látky terapeutické užití   MeSH
• organofosfáty škodlivé účinky   toxicita   MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• statistika jako téma MeSH
• testy toxicity metody   využití   MeSH
• trimedoxim terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• tabulky MeSH

This study compares the abilities of the newly developed bispyridinium oxime K203 with currently available oximes (HI-6, obidoxime, and trimedoxime) in the reactivation of sarin-inhibited acetylcholinesterase and the reduction of the acute toxicity of sarin. The percentage of reactivation of sarin-inhibited rat blood and tissue acetylcholinesterase was determined in vivo and it was shown that the potency of bispyridinium oxime K203 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the relatively low reactivating efficacy of obidoxime and trimedoxime except in the diaphragm where K203 was not effective. On the other hand, the oxime HI-6 was found to be a very efficient reactivator of sarin-inhibited acetylcholinesterase in the peripheral as well as central compartment. The oxime HI-6 was able to reduce the acute toxicity of sarin by more than four times, but the other oximes studied, including K203, decreased the acute toxicity of sarin by less than three times. Based on these results, we can conclude that the reactivating and therapeutic efficacy of the oxime K203 is significantly lower compared to the oxime HI-6 and, therefore, it is not a suitable replacement for the oxime HI-6 in the antidotal treatment of acute sarin poisoning.

• MeSH
• acetylcholinesterasa MeSH
• experimenty na zvířatech MeSH
• financování organizované MeSH
• injekce intramuskulární MeSH
• klinické hodnocení nového léčiva MeSH
• myši MeSH
• obidoxim chlorid aplikace a dávkování   terapeutické užití   MeSH
• oximy aplikace a dávkování   diagnostické užití   terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   terapeutické užití   MeSH
• sarin aplikace a dávkování   diagnostické užití   škodlivé účinky   MeSH
• statistika jako téma MeSH
• trimedoxim aplikace a dávkování   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

The reactivating and therapeutic efficacy of two newly developed oximes (K305, K307) was compared with the oxime K203 and trimedoxime using in vivo methods The study determining percentage of reactivation of tabun-inhibited acetylcholinesterase in the peripheral as well as central nervous system (diaphragm, brain) in tabun-poisoned rats showed that the reactivating efficacy of both newly developed oximes is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While the ability of the oxime K305 to reduce acute toxicity of tabun in mice is approaching to the therapeutic efficacy of trimedoxime, the ability of another novel bispyridinium oxime K307 to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and the oxime K203. Thus, the reactivating and therapeutic efficacy of both examined newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

• MeSH
• acetylcholinesterasa účinky léků   MeSH
• antidota aplikace a dávkování   farmakologie   toxicita   MeSH
• atropin aplikace a dávkování   farmakologie   toxicita   MeSH
• bránice enzymologie   MeSH
• modely u zvířat MeSH
• mozek enzymologie   účinky léků   MeSH
• mutantní kmeny myší MeSH
• nervová bojová látka farmakologie   chemie   toxicita   MeSH
• organofosfáty farmakologie   toxicita   MeSH
• oximy * farmakologie   chemie   klasifikace   MeSH
• potkani Wistar MeSH
• reaktivátory cholinesterázy aplikace a dávkování   farmakologie   toxicita   MeSH
• trimedoxim farmakologie   chemie   klasifikace   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

The potency of two newly developed oximes (K361 and K378) to reactivate tabun-inhibited cholinesterase and to reduce acute toxicity of tabun was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm cholinesterase in poisoned rats showed that the reactivating efficacy of the oxime K378 is slightly lower than the reactivating potency of the oxime K203 and trimedoxime while the ability of the oxime K361 to reactivate tabun-inhibited cholinesterase is markedly lower compared with the oxime K203 and trimedoxime. In the brain, the potency of both newly developed oximes to reactivate tabun-inhibited cholinesterase was negligible. The therapeutic efficacy of both newly developed oximes roughly corresponds to their weak reactivating efficacy. Their potency to reduce acute toxicity of tabun was significantly lower compared with the oxime K203 as well as trimedoxime. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of the oxime K203 and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.

• MeSH
• cholinesterasové inhibitory otrava   MeSH
• hematoencefalická bariéra MeSH
• myši MeSH
• organofosfáty toxicita   MeSH
• oximy terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny terapeutické užití   MeSH
• reaktivátory cholinesterázy terapeutické užití   MeSH
• trimedoxim terapeutické užití   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

The ability of two newly developed bispyridinium oximes (K456, K458) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with oxime K203 and trimedoxime using the functional observational battery. The neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 85% of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by the functional observational battery and automatic measurement of motor activity at 2 hr after tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive till the end of experiment. Both newly developed oximes (K456, K458) combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings although they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease tabun-induced acute neurotoxicity was slightly higher than that of trimedoxime and oxime K203, but the difference in neuroprotective efficacy among all oximes studied is not large enough to make a decision about replacement of commonly used oximes (especially trimedoxime and obidoxime) in the treatment of acute tabun poisonings.

• MeSH
• atropin farmakologie   MeSH
• chemické bojové látky toxicita   MeSH
• krysa rodu rattus MeSH
• neuroprotektivní látky farmakologie   MeSH
• neurotoxické syndromy prevence a kontrola   MeSH
• organofosfáty toxicita   MeSH
• oximy farmakologie   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny farmakologie   MeSH
• trimedoxim 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