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The ability of newly developed oximes (K347, K628) to reduce tabun-induced acute neurotoxic signs and symptoms was compared with currently available oximes (obidoxime, HI-6) using a functional observational battery. The neuroprotective effects of the oximes studied (K347, K628, obidoxime, HI-6) combined with atropine on rats poisoned with tabun at a sublethal dose (220 μg/kg i.m.; 80 % of LD50 value) were evaluated. Tabun-induced neurotoxicity was monitored by a functional observational battery and automatic measurement of motor activity at 24 hours following tabun challenge. The results indicate that all tested oximes combined with atropine enable tabun-poisoned rats to survive 24 hours following tabun challenge. Both newly developed oximes (K347, K628) combined with atropine are able to decrease tabun-induced neurotoxicity in the case of sublethal poisonings but they do not eliminate all tabun-induced acute neurotoxic signs and symptoms. Their ability to decrease the tabun-induced acute neurotoxicity is higher than that of the oxime HI-6 and it is slightly slower than the neuroprotective efficacy of obidoxime. As the neuroprotective potency of both newly developed oximes (K347, K628) is not as high as the potency of obidoxime, they are not a suitable replacement for obidoxime for the treatment of acute tabun poisonings.

The neuroprotective effects of newly developed oximes (K156, K203) 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 24 hours after cyclosarin challenge. The results indicate that a newly developed oxime K156 is able to counteract slightly cyclosarin-induced neurotoxicity while another newly developed oxime K203 is completely ineffective in reducing cyclosarin-induced neurotoxic signs and symptoms. The neuroprotective efficacy of K156 is comparable with commonly used obidoxime and oxime HI-6. Thus, none of the newly developed oximes achieves better neuroprotective efficacy than both commonly used oximes. They are therefore not suitable replacements for antidotal treatment of acute poisonings with cyclosarin.

In the past, scientists focused on the development of antidotes (mainly anticholinergics in combination with reactivators of inhibited acetylcholinesterase – oximes) to increase the number of surviving nerve agent-intoxicated individuals. Recently, they are interested in antidotes able not only to protect nerve agent-poisoned men from lethal toxic effects but also to improve their life quality by improvement of their central cognitive functions. In our study, the water maze was used to measure spatial working learning and memory in the case of tabun-induced cognitive impairment in albino Wistar rats. Antidotal treatment consisted of atropine alone or a combination of atropine with an oxime (obidoxime, trimedoxime or oxime HI-6). Our results suggest that atropine alone is not sufficient as a treatment for saving cognitive functions impaired by tabun. On the other hand, the addition of oxime to atropine contributes to improvement of cognitive performance in tabun-poisoned rats regardless of type of oxime.

1. The efficacy of the oxime HLö-7 and currently used oximes (pralidoxime, obidoxime, HI-6) to reactivate acetylcholinesterase inhibited by various nerve agents (sarin, tabun, cyclosarin, VX) was tested by in vitro methods. 2. Both H oximes (HLö-7, HI-6) were found to be more efficacious reactivators of sarin and VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase is very low and does not reach the reactivating efficacy of obidoxime. In the case of cyclosarin, the oxime HI-6 was only found to be able to sufficiently reactivate cyclosarin-inhibited acetylcholinesterase in vitro. 3. Thus, the oxime HLö-7 does not seem to be more efficacious reactivator of nerve agent-inhibited acetylcholinesterase than HI-6 according to in vitro evaluation of their reactivation potency and, therefore, it is not more suitable to be introduced for antidotal treatment of nerve agent-exposed people than HI-6.

Summary: 1. The influence of the time of administration of antidotal treatment consisting of anticholinergic drug (atropine) and oxime (pralidoxime, obidoxime, HI-6 or trimedoxime) on its effectiveness to eliminate tabun-induced lethal effects was studied in mice. 2. The therapeutic efficacy of antidotal treatment of tabun-induced acute poisoning depends on the time of its administration when obidoxime or the oxime HI-6 was used as an acetylcholinesterase reactivator. 3. Pralidoxime is practically ineffective to eliminate acute toxic effects of tabun regardless of the time of its administration. 4. Our results show that trimedoxime seems to be the most effective to eliminate lethal effects of tabun. In addition, its efficacy does not decrease when it is administered 5 min after tabun poisoning. 5. The findings support the hypothesis that trimedoxime appears to be the most suitable oxime to counteract acute toxicity of tabun because of its ability to eliminate lethal effects of tabun when it is injected 5 min after tabun challenge on the contrary to other oximes tested.

1. The influence of some acetylcholinesterase reactivators (HI-6, obidoxime, pralidoxime) on the efficacy of antidotal treatment to eliminate soman-induced disturbance of respiration and circulation and to protect experimental animals poisoned with supralethal dose of soman (1.5 × LD50) was investigated in a rat model with on-line monitoring of respiratory and circulatory parameters. 2. Obidoxime or pralidoxime in combination with atropine were insufficient to enable soman-poisoned rats to survive for 2 hours when given 1 minute after the administration of soman. 3. On the other hand, the ability of the oxime HI-6 in combination with atropine to prevent soman-induced alteration of respiration and circulation was significantly higher. Some rats treated with HI-6 in combination with atropine were fully protected against the lethal toxic effects of soman within 2 hours following soman administration. 4. Our findings confirm that the oxime HI-6 seems to be a much more suitable and efficacious acetylcholinesterase reactivator for the antidotal treatment of severe acute soman-induced poisoning than currently used obidoxime or pralidoxime.

1. The neuroprotective effects of antidotes (atropine, obidoxime/atropine mixture, HI-6/atropine mixture) on rats poisoned with soman at a sublethal dose (48 μg/kg i.m.; 60% of LD50 value) were studied. The neurotoxicity was monitored using a functional observational battery (FOB) and an automatic measurement of motor activity. The neurotoxicity of soman was monitored at 24h and 7d following soman poisoning. 2. The results indicate that atropine alone and the oxime HI-6 in combination with atropine seem to be effective antidotal treatment for the elimination of soman-induced neurotoxicity in the case of sublethal poisonings. 3. On the other hand, the combination of obidoxime with atropine appears to be practically ineffective in diminishing neurotoxic soman-induced symptoms. 4. Dealing with neuroprotective effects of antidotes, the oxime HI-6 in combination with atropine seems to be more suitable antidotal mixture than obidoxime in combination with atropine even in the case of sublethal poisoning with nerve agents.

The toxicity of cyclohexyl methylphosphonofluoridate (GF-agent; cyclosarin) and therapeutic efficacy of four oximes (trimedoxime, methoxime, obidoxime and HI-6) in combination with atropine or benactyzine (BNZ) was studied in mice. The oxime therapy combined with anticholinergic drug was administered intramusculary (i.m.) 1 or 2 min after i.m. GF-agent challenge. All the drugs were applied in dose of 20% of LD50. Obidoxime and trimedoxime that were combined with atropine were less effective than methoxime and HI-6 in combination with BNZ when applied 2 minutes after GF-agent poisoning. When the drugs were administered 1 min after GF-agent challenge already, in case of methoxime, the faster application of therapy resulted in significantly higher protective ratio, while for obidoxime the therapeutic effectivity did not depend significantly on the seasonableness of therapeutic intervention. The present findings show that all four combinations of oxime with anticholinergic drug decrease the GF-agent toxicity more than twofold regardless of the time of treatment administration.

1. The therapeutic efficacy of various oximes (pralidoxime, obidoxime, methoxime, HI-6, HLö-7, BI-6) against supralethal nerve agent poisoning (soman, sarin, cyclosin) in mice was tested. 2. New oxime BI-6, synthesized in our laboratory, is significantly more efficacious than conventional oximes but a little less efficacious than other H-oximes (HI- 6, HLö-7). 3. H-oximes (HI-6, HLö-7) seem to be the most efficacious reactivators of nerve agent-inhibited acetylcholinesterase for antidotal treatment of supralethal nerve agent poisoning in mice.