A comparison of the potency of newly developed oximes (K074, K075) and currently available oximes (obidoxime, trimedoxime, HI-6) to counteract acute toxic effects of tabun and cyclosarin in mice

The potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, trimedoxime, and HI-6) to counteract tabun or cyclosarin-induced acute toxic effects was studied in mice. The therapeutic efficacy of trimedoxime and both newly developed oximes (K074, K075) was significantly higher than the potency of obidoxime and the oxime HI-6 in the case of acute tabun poisonings. On the other hand, the oxime HI-6 was significantly more efficacious than other studied oximes when mice were intoxicated with cyclosarin. The findings support the hypothesis that the therapeutic efficacy of oximes depends on the type of nerve agent. Due to their therapeutic efficacy, both newly developed K oximes can be considered to be promising oximes for the antidotal treatment of acute tabun poisonings, while the oxime HI-6 is still the most promising oxime for the treatment of acute cyclosarin poisonings due to its high potency to counteract cyclosarin-induced acute toxic effects.     

The evaluation of neuroprotective efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in cyclosarin-poisoned rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days following cyclosarin challenge. The results indicate that the oxime HI-6 combined with atropine seems to be the most effective antidote for a decrease in cyclosarin-induced neurotoxicity. Both newly developed oximes (K074, K075) as well as obidoxime are also able to counteract cyclosarin-induced acute neurotoxicity, but their neuroprotective potency is significantly lower compared with the oxime HI-6. Therefore, the oxime HI-6 is still the most suitable oxime for the antidotal treatment of acute poisonings with cyclosarin due to its neuroprotective as well as reactivating efficacy.     

A Comparison of the Therapeutic and Reactivating Efficacy of Newly Developed Oximes (K117, K127) and Currently Available Oximes (Obidoxime,Trimedoxime, HI-6) in Tabun-Poisoned Rats and Mice

The potency of newly developed bispyridinium compounds (K117, K127) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, oxime HI-6) by using in vivo methods. A study that determined the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K127 is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. The potency of another newly developed K117 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in the diaphragm, but it is significantly lower than the reactivating potency of trimedoxime and obidoxime in the blood and brain. The oxime, K127, was also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Its therapeutic efficacy is consistent with the therapeutic potency of obidoxime. On the other hand, the potency of the oxime, K117, to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and obidoxime. The therapeutic efficacy of K117 and K127 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in the diaphragm and brain. Contrary to obidoxime and trimedoxime, the oxime, HI-6, is not an effective oxime in the reactivation of tabun-inhibited acetycholinesterase and in reducing the lethal effects of tabun. The reactivating and therapeutic potency of both newly developed oximes does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.     

A comparison of the potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 micro g/kg i.m.; 80% LD(50)) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.     

A Comparison of the Potency of Newly Developed Oximes (K074, K075) and Currently Available Oximes (Obidoxime,HI-6) to Counteract Soman-Induced Neurotoxicity in Rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days after soman challenge. The results indicate that the oxime HI-6 combined with atropine seems to be an effective antidote for a decrease in soman-induced neurotoxicity, whereas the ability of both newly developed oximes (K074, K075) as well as obidoxime to counteract soman-induced acute neurotoxicity is negligible. Due to the absence of their neuroprotective potency, both newly developed oximes are not suitable oximes for antidotal treatment after exposure to soman. The oxime HI-6 is still the best acetylcholinesterase reactivator for the antidotal treatment of acute poisonings with soman.     

A comparison of the therapeutic and reactivating efficacy of newly developed oximes (K117, K127) and currently available oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice

The potency of newly developed bispyridinium compounds (K117, K127) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, trimedoxime, oxime HI-6) by using in vivo methods. A study that determined the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K127 is comparable with obidoxime and trimedoxime in blood but lower than the reactivating potency of trimedoxime and obidoxime in the diaphragm and brain. The potency of another newly developed K117 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in the diaphragm, but it is significantly lower than the reactivating potency of trimedoxime and obidoxime in the blood and brain. The oxime, K127, was also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Its therapeutic efficacy is consistent with the therapeutic potency of obidoxime. On the other hand, the potency of the oxime, K117, to reduce acute toxicity of tabun is significantly lower compared to trimedoxime and obidoxime. The therapeutic efficacy of K117 and K127 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in the diaphragm and brain. Contrary to obidoxime and trimedoxime, the oxime, HI-6, is not an effective oxime in the reactivation of tabun-inhibited acetycholinesterase and in reducing the lethal effects of tabun. The reactivating and therapeutic potency of both newly developed oximes does not prevail over the effectiveness of currently available obidoxime and trimedoxime and, therefore, they are not suitable for their replacement of commonly used oximes for the treatment of acute tabun poisoning.     

An evaluation of therapeutic and reactivating effects of newly developed oximes (K156, K203) and commonly used oximes (obidoxime, trimedoxime, HI-6) in tabun-poisoned rats and mice

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.     

The development of new oximes and the evaluation of their reactivating, therapeutic and neuroprotective efficacy against tabun

Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. The antidotal treatment of tabun acute poisonings still represents a serious problem and the development of new, more effective AChE reactivators to achieve the satisfactorily effective antidotal treatment of acute poisonings with tabun still represents very important goal. Since 2003, we have prepared around 200 new AChE reactivators. Their potency to reactivate tabun-inhibited acetylcholinesterase has been subsequently evaluated using our in vitro screening test. Afterwards, promising compounds were selected and kinetic parameters and reactivation constants were determined. Then, the best reactivators were subjected to the in vivo studies (toxicity test, the evaluation of therapeutic, reactivating and neuroprotective efficacy) and their potency to counteract the acute toxicity of tabun is compared to the therapeutic, reactivating and neuroprotective efficacy of commonly used oximes - obidoxime and the oxime HI-6. According to the results obtained, the newly synthesized oxime K075 showed the highest potency to reduce tabun-induced acute lethal toxicity while the therapeutic potency of obidoxime and the oxime HI-6 was significantly lower. The therapeutic efficacy of oximes studied corresponds to their reactivating efficacy in vivo as well as in vitro. The potency of all newly synthesized oximes to reactivate tabun-inhibited AChE is comparable with obidoxime with the exception of K074 that is significantly more efficacious in the brain. In addition, all newly synthesized oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced acute neurotoxicity. While the neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly synthesized oximes, the ability of the oxime HI-6 combined with atropine to counteract tabun-induced acute neurotoxicity is significantly lower. Due to their therapeutic, reactivating and neuroprotective efficacy, all newly synthesized oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisonings.     

A comparison of the potency of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) to counteract soman-induced neurotoxicity in rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days after soman challenge. The results indicate that the oxime HI-6 combined with atropine seems to be an effective antidote for a decrease in soman-induced neurotoxicity, whereas the ability of both newly developed oximes (K074, K075) as well as obidoxime to counteract soman-induced acute neurotoxicity is negligible. Due to the absence of their neuroprotective potency, both newly developed oximes are not suitable oximes for antidotal treatment after exposure to soman. The oxime HI-6 is still the best acetylcholinesterase reactivator for the antidotal treatment of acute poisonings with soman.     

Evaluation of the Neuroprotective Efficacy of Newly Developed Oximes (K206, K269) and Currently Available Oximes (Obidoxime,HI‐6) in Cyclosarin‐Poisoned Rats

Abstract: The neuroprotective effects of newly developed oximes (K206, K269) and currently available oximes (obidoxime, HI‐6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin‐induced neurotoxicity was monitored using a functional observational battery at 24 hr following cyclosarin challenge. The results indicate that a newly developed oxime K206 is able to counteract cyclosarin‐induced neurotoxicity while the neuroprotective potency of another newly developed oxime (K269) is negligible. The neuroprotective efficacy of K206 is markedly higher than commonly used obidoxime; nevertheless, its potency to eliminate cyclosarin‐induced neurotoxicity is slightly lower compared to the oxime HI‐6. Thus, a newly developed oxime K206 seems to be a better oxime for the antidotal treatment of cyclosarin poisonings than obidoxime due to higher neuroprotective potency although the oxime HI‐6 is still the most suitable oxime for the antidotal treatment of acute poisonings with cyclosarin.     

A comparison of the efficacy of new asymmetric bispyridinium oximes (K027, K048) with currently available oximes against tabun by in vivo methods

The potency of newly developed asymmetric bispyridinium oximes (K027, K048) in reactivating tabun-inhibited acetylcholinesterase (AChE) and in eliminating tabun-induced acute toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determined the percent of reactivation of tabun-inhibited blood and tissue AChE in poisoned rats and showed that the reactivating efficacy of both newly developed oximes is comparable with obidoxime and trimedoxime, the most efficacious known reactivators of tabun-inhibited AChE. These were also found to be sufficiently efficacious in the elimination of acute lethal toxic effects in tabun-poisoned rats. The oxime HI-6, relatively efficacious against soman, did not seem to be an adequately effective oxime in reactivation of tabun-inhibited AChE and in counteracting acute lethal effects of tabun. In addition, our results confirm that the efficacy of oximes in reactivating tabun-inhibited AChE in blood, diaphragm, and brain correlates with the potency of oximes in protecting rats poisoned with supralethal doses of tabun.     

A comparison of the reactivating and therapeutic efficacy of newly developed oximes (K347, K628) with commonly used oximes (obidoxime,HI-6) against tabun in rats and mice

The potency of newly developed reactivators of nerve agent–inhibited acetylcholinesterase (K347, K628) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with currently available oximes (obidoxime, the oxime HI-6), using in vivo methods. Studies that determined the percentage of reactivation of tabun-inhibited blood and tissue acetycholinesterase in poisoned rats showed that the reactivating efficacy of both newly developed oximes is comparable with the oxime HI-6, but it is significantly lower than the reactivating effects of obidoxime. The monopyridinium oxime, K347, was also found to be able to reduce lethal toxic effects in tabun-poisoned mice, while the therapeutic efficacy of another newly developed bispyridinium oxime, K628, was negligible. The therapeutic efficacy of K347 was higher than the potency of the oxime, HI-6, but it was lower than the therapeutic effects of obidoxime. Thus, the reactivating and therapeutic potency of both newly developed oximes (K347, K628) was not more effective then currently available oximes, and therefore, they are not suitable for the replacement of commonly used oximes (especially obidoxime) for the treatment of acute tabun poisoning.     

The evaluation of the neuroprotective effects of bispyridinium oximes in tabun-poisoned rats

Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to the group of highly toxic organophosphorus compounds that may be used as chemical warfare agents for military as well as terrorist purposes. Tabun differs from other highly toxic organophosphates by the fact that commonly used antidotes are not able adequately to prevent tabun-induced acute toxic effects. The neuroprotective effects of four bispyridinium oximes (K075, trimedoxime, HI-6, obidoxime) in combination with atropine on rats poisoned with tabun at a sublethal dose (150 microg/kg i.m.; 80% of LD50 value) were studied. Tabun-induced neurotoxicity was monitored using a functional observational battery and automatic measurement of motor activity at 24 h and 7 d following tabun challenge. The results indicated that all tested oximes combined with atropine enabled tabun-poisoned rats to survive 7 d following challenge. Trimedoxime combined with atropine was the most effective antidote in decreasing tabun-induced neurotoxicity in the case of sublethal poisonings among all oximes tested. Due to its neuroprotective effects, trimedoxime may be considered to be more suitable oxime for the antidotal treatment of acute tabun exposure than currently used oximes (obidoxime, HI-6) and the newly synthesized oxime K075.     

Evaluation of the Potency of Two Novel Bispyridinium Oximes (K456, K458) in Comparison with Oxime K203 and Trimedoxime to Counteract Tabun‐Induced Neurotoxicity in Rats

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.     

A comparison of the ability of newly-developed bispyridinium oxime K203 and currently available oximes (trimedoxime,obidoxime, HI-6) to counteract the acute neurotoxicity of soman in rats

The neuroprotective effects of newly-developed oxime K203 and currently available oximes (trimedoxime, obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24?h following soman challenge. The results indicate that the potency of a newly-developed oxime K203 to counteract soman-induced neurotoxicity is very low and roughly corresponds to the neuroprotective efficacy of currently available oximes. Among tested oximes, the oxime HI-6 seems to be the most efficacious to counteract acute neurotoxicity of soman, although the differences in neuroprotective efficacy of chosen oximes are not significant. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with soman and the oxime HI-6 should be still considered to be the best oxime for antidotal treatment of acute soman poisonings.     

The evaluation of the reactivating and therapeutic efficacy of three novel bispyridinium oximes (K454, K456, K458) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice

The potency of three newly developed bispyridinium compounds (K454, K456, K458) to reactivate tabun-inhibited acetylcholinesterase and reduce tabun-induced lethal toxic effects was compared with the oxime K203 and trimedoxime using in vivo methods. The study determining percentage of reactivation of tabun-inhibited diaphragm and brain acetylcholinesterase in poisoned rats showed that the reactivating efficacy of all newly developed oximes is comparable with K203 but lower than the reactivating potency of trimedoxime in diaphragm. In the brain, their potency to reactivate tabun-inhibited acetylcholinesterase is lower compared with trimedoxime and the oxime K203. All three newly developed oximes were also found to be relatively effective in reducing lethal toxic effects in tabun-poisoned mice. Their therapeutic efficacy is consistent with the therapeutic potency of the oxime K203. On the other hand, their potency to reduce acute toxicity of tabun is significantly lower compared with trimedoxime. In conclusion, the reactivating and therapeutic potency of all three 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.     

A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats

The neuroprotective effects of newly developed oximes (K027, K048) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (170 microg kg(-1) i.m.; 80% of LD(50) value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 h and 7 days following tabun challenge. The results indicate that the oxime HI-6 in combination with atropine was not able to protect the rats from the lethal effects of tabun. Two non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine combined with HI-6 died within 2 h. On the other hand, all other tested oximes combined with atropine allowed all the tabun-poisoned rats to survive 7 days following tabun challenge. Both newly developed oximes combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The neuroprotective efficacy of obidoxime in combination with atropine approached the potency of newly developed oximes but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity was significantly lower, especially at 24 h after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisoning.     

The evaluation of the reactivating and therapeutic efficacy of two novel oximes (K361 and K378) in comparison with the oxime K203 and trimedoxime in tabun-poisoned rats and mice

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.     

A Comparison of the Reactivating and Therapeutic Efficacy of Two Newly Developed Oximes (K727 and K733) with Oxime K203 and Trimedoxime in Tabun‐Poisoned Rats and Mice

The reactivating and therapeutic efficacy of three original bispyridinium oximes (K727, K733 and K203) and one currently available oxime (trimedoxime) was evaluated in tabun‐poisoned rats and mice. The oxime‐induced reactivation of tabun‐inhibited acetylcholinesterase was measured in diaphragm and brain of tabun‐poisoned rats. The results showed that the reactivating efficacy of two recently developed oximes (K727 and K733) does not achieve the level of the reactivation of tabun‐inhibited acetylcholinesterase induced by oxime K203 and trimedoxime. While all oximes studied were able to increase the activity of tabun‐inhibited acetylcholinesterase in diaphragm, oxime K733 was not able to reactivate tabun‐inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied roughly corresponds to their reactivating efficacy. While both recently developed oximes were able to reduce acute toxicity of tabun less than 1.5‐fold, another original oxime K203 and commonly used trimedoxime reduced the acute toxicity of tabun almost two times. In conclusion, the reactivating and therapeutic potency of both newly developed oximes does not prevail the effectiveness of oxime K203 and trimedoxime, and therefore, they are not suitable for their replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.     

Comparison of reactivating and therapeutic efficacy of two salts of the oxime HI-6 against tabun, soman and cyclosarin in rats

The reactivating and therapeutic efficacy of two salts of the oxime HI-6 (dichloride and dimethanesulphonate) against chosen nerve agents (tabun, soman and cyclosarin) was compared in rats. The potency of both salts of HI-6 to decrease the acute toxicity of tabun, soman and cyclosarin was similar in nerve agent-poisoned rats. While the potency of HI-6 dichloride and HI-6 dimethanesulphonate to counteract acute toxic effects of tabun is rather low, both salts of HI-6 were able to decrease the acute toxicity of soman two times and acute toxicity of cyclosarin more than three times. The therapeutic efficacy of both salts of the oxime HI-6 corresponds to their reactivating potency. While the reactivating efficacy of HI-6 dichloride as well as HI-6 dimethanesulphonate against tabun was negligible, their potency to reactivate soman-inhibited acetylcholinesterase and cyclosarin-inhibited acetylcholinesterase in peripheral (blood) and central (brain) compartment was relatively high. HI-6 dichloride showed a somewhat higher potency to reactivate tabun-inhibited acetylcholinesterase in brain, and soman-inhibited acetylcholinesterase in blood and brain than HI-6 dimethanesulphonate but the differences were not significant. Thus, the replacement of dichloride anion by dimethanesulphonate anion in the oxime HI-6 does not influence the therapeutic and reactivating efficacy of the oxime HI-6 against nerve agents. In addition, the higher solubility and stability of HI-6 dimethanesulphonate in comparison with HI-6 dichloride makes it possible to increase the dose and thus, the effectiveness of the oxime HI-6 in the antidotal treatment of acute nerve agent poisonings.