The ability of oxime mixtures to increase the reactivating and therapeutic efficacy of antidotal treatment of cyclosarin poisoning in rats and mice

The reactivating and therapeutic efficacy of two combinations ofoximes (HI-6 + trimedoxime and HI-6 + K203) was compared with the effectiveness of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly higher than the reactivating efficacy of the most effective individual oxime in blood, diaphragm as well as in brain. Moreover, both combinations of oximes were found to be slightly more efficacious in the reduction of acute lethal toxic effects in cyclosarin-poisoned mice than the antidotal treatment involving single oxime. Based on the obtained data, we can conclude that the antidotal treatment involving chosen combinations of oximes brings a beneficial effect for its ability to counteract the acute poisoning with cyclosarin.     

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 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.     

Effect of atropine and the oxime HI-6 on low-level sarin-induced alteration of performance of rats in a T-maze

1. To study the influence of antidotes on low-level sarin-induced alteration of cognitive functions, male albino Wistar rats were exposed to three various low concentrations of sarin for 60 minutes in the inhalation chamber. One minute following sarin exposure, the rats were i.m. treated with the oxime HI-6 in combination with atropine. Control rats were treated with antidotes as experimental rats but exposed to the pure air instead of sarin. Cognitive functions of the rats were tested using a T-maze where spatial memory and spatial orientation were evaluated. The performance of sarin-exposed and treated rats in the T-maze was tested several times within six weeks (single exposure) or five weeks (repeated exposure) following inhalation exposure to evaluate cognitive impairments. 2. In the case of single exposure to sarin, no statistically significant differencies between the performances of the control and the experimental groups in the alteration of spatial memory and spatial orientation were observed. The repeated exposure of treated rats to clinically asymptomatic dose of sarin (LEVEL 2) did not change the effect of low-level sarin exposure on spatial memory of the experimental rats compared to the single exposure to the same dose of sarin. 3. The decrease in the T-maze performance of the control rats was caused by the impairments of rat's mobility due to the features of a solution of antidotes.