trimedoxime-bromide and asoxime-chloride

Beside the key inhibition of acetylcholinesterase (AChE), involvement of oxidative stress in organophosphate (OP)-induced toxicity has been supported by experimental and human studies. On the other hand, according to our best knowledge, possible antioxidant properties of oximes, the only causal antidotes to OP-inhibited AChE, have been examined only by a few studies. Thus, we have determined the effect of four conventional (obidoxime, trimedoxime, pralidoxime, asoxime) and two promising experimental oximes (K027, K203) on dichlorvos (DDVP)-induced oxidative changes in vivo. Wistar rats (5/group) were treated with oxime (5% LD

Topics: Animals; Aryldialkylphosphatase; Biomarkers; Brain; Cholinesterase Inhibitors; Dichlorvos; Male; Malondialdehyde; Obidoxime Chloride; Organophosphate Poisoning; Oxidative Stress; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Superoxide Dismutase; Trimedoxime

The potency of the oxime HI-6 and two combinations of oximes (HI-6 + trimedoxime, HI-6 + K203) to reduce sarin-induced acute neurotoxic signs and symptoms was evaluated in this study. Sarin-induced neurotoxicity and the neuroprotective effects of atropine alone or in combination with HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with sarin at a sublethal dose (108 μg/kg i.m.; 90% of LD(50) value) were monitored by a functional observatory battery (FOB) 24 h following sarin administration. The results indicate that both mixtures of oximes combined with atropine were able to survive sarin-poisoned rats 24 h following sarin administration while two non-treated sarin-poisoned rats and one sarin-poisoned rat treated with atropine alone or with atropine in combination with the oxime HI-6 died within 24 h following sarin poisoning. All types of antidotal treatment were able to decrease sarin-induced neurotoxic signs and symptoms but not completely. While atropine alone and atropine in combination with the oxime HI-6 were able to eliminate some sarin-induced neurotoxic signs and symptoms, the neuroprotective efficacy of both combinations of oximes with atropine was slightly higher. Thus, both tested combinations of oximes in combination with atropine bring a small benefit for the neuroprotective efficacy of antidotal treatment of acute sarin poisonings.

Topics: Animals; Antidotes; Atropine; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Drug Therapy, Combination; Male; Molecular Structure; Neuroprotective Agents; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Sarin; Trimedoxime

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.

Topics: Animals; Antidotes; Cholinesterase Reactivators; Mice; Mice, Inbred Strains; Organophosphorus Compounds; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

The potency of bispyridinium acetylcholinesterase reactivator KR-22934 in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with the oxime K203 and commonly used oximes. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed that the reactivating efficacy of KR-22934 was slightly higher than the reactivating efficacy of K203 and roughly corresponded to the reactivating efficacy of obidoxime and trimedoxime in blood and diaphragm. On the other hand, the oxime KR-22934 was not able to reactivate tabun-inhibited acetylcholinesterase in the brain. The therapeutic efficacy of all oximes studied approximately corresponded to their reactivating efficacy. Based on the results, one can conclude that the oxime KR-22934 is not suitable for the replacement of commonly used oximes for the antidotal treatment of tabun poisoning in spite of its potency to reactivate tabun-inhibited acetylcholinesterase in the peripheral compartment (blood, diaphragm).

Topics: Acetylcholinesterase; Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Mice; Obidoxime Chloride; Organophosphates; Oximes; Poisoning; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

Administration of acetylcholinesterase (AChE) reactivators (oximes) is usually used in order to counteract the poisoning effects of nerve agents. The possibility was suggested that oximes may show some therapeutic and/or adverse effects through their action in central nervous system. There are no sufficient data about interaction of oximes with monoaminergic neurotransmitter's systems in the brain. Oxime-type AChE reactivators pralidoxime, obidoxime, trimedoxime, methoxime and HI-6 were tested for their potential to affect the activity of monoamine oxidase of type A (MAO-A) and type B (MAO-B) in crude mitochondrial fraction of pig brains. The compounds were found to inhibit fully MAO-A with half maximal inhibitory concentration (IC(50)) of 0.375 mmol/l (pralidoxime), 1.53 mmol/l (HI-6), 2.31 mmol/l (methoxime), 2.42 mmol/l (obidoxime) and 4.98 mmol/l (trimedoxime). Activity of MAO-B was fully inhibited by HI-6 and pralidoxime only with IC(50) 4.81 mmol/l and 11.01 mmol/l, respectively. Methoxime, obidoxime and trimedoxime displayed non-monotonic concentration dependent effect on MAO-B activity. Because oximes concentrations effective for MAO inhibition could not be achieved in vivo at the cerebral level, we suppose that oximes investigated do not interfere with brain MAO at therapeutically relevant concentrations.

Topics: Animals; Brain; Cholinesterase Reactivators; Monoamine Oxidase; Monoamine Oxidase Inhibitors; Obidoxime Chloride; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Swine; Trimedoxime

The influence of the combinations of oximes on the reactivating and therapeutic efficacy of antidotal treament of acute sarin poisoning was evaluated in this study. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate sarin-inhibited acetylcholinesterase and reduce acute toxicity of sarin was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo methods. Studies determining percentage of reactivation of sarin-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of the combination of oximes involving HI-6 and K203 is slightly higher than the reactivating efficacy of the most effective individual oxime in diaphragm and brain but the difference between them is not significant. The ability of combination of oximes involving HI-6 and trimedoxime to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating effects of the most effective individual oxime in blood as well as tissues. Moreover, both combinations of oximes were found to be as efficacious in the reduction of acute lethal toxic effects in sarin-poisoned mice as the most effective individual oxime. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the oxime HI-6 is markedly more effective than the oxime K203 and trimedoxime. Based on the obtained data, we conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the ability of the most effective individual oxime (HI-6) to reactivate sarin-inhibited rat acetylcholinesterase and to reduce acute toxicity of sarin in mice.

Topics: Acetylcholinesterase; Animals; Antidotes; Chemical Warfare Agents; Drug Therapy, Combination; Male; Mice; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Sarin; Trimedoxime

The ability of two combinations of oximes (HI-6+trimedoxime, HI-6+K203) to reduce soman-induced acute neurotoxic signs and symptoms was compared with the neuroprotective efficacy of the oxime HI-6 alone, using a functional observational battery. Soman-induced neurotoxicity and the neuroprotective effects of HI-6 alone and HI-6 combined with trimedoxime or K203 in rats poisoned with soman at a sublethal dose (90 μg/kg intramuscularly, i.m.; 80% of LD₅₀ value) were monitored by the functional observational battery at 24 hours following soman administration. The results indicate that both tested oxime mixtures combined with atropine were able to allow soman-poisoned rats to survive 24 hours following soman challenge, while 4 nontreated soman-poisoned rats and 1 soman-poisoned rat treated with oxime HI-6 alone combined with atropine died within 24 hours following soman poisoning. While the oxime HI-6 alone combined with atropine treatment was able to eliminate a few soman-induced neurotoxic signs and symptoms, both oxime mixtures showed higher neuroprotective efficacy in soman-poisoned rats. Especially, the combination of HI-6 with trimedoxime was able to eliminate most soman-induced neurotoxic signs and symptoms and markedly reduce acute neurotoxicity of soman in rats. Thus, both tested mixtures of oximes combined with atropine were able to increase the neuroprotective effectiveness of antidotal treatment of acute soman poisonings, compared to the individual oxime.

Topics: Animals; Behavior, Animal; Drug Therapy, Combination; Male; Molecular Structure; Motor Activity; Neuroprotective Agents; Neurotoxicity Syndromes; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Soman; Trimedoxime

The present experiment is based on biochemical assessment of nerve agent soman intoxication and atropine, respectively atropine and HI-6, trimedoxime or K203 treatment in rats.. Nerve agents are toxic substances irreversibly inhibiting enzyme acetylcholinesterase (AChE). Treatment is typically based on application of atropine and oxime reactivator. Atropine is able to protect overstimulation of muscarinic acetylcholine receptors. Application of oxime reactivator enable return of AChE activity and full suppression of intoxication.. In a total, fifteen biochemical markers were assayed in plasma or blood of intoxicated animals. 42 rats were divided into 7 groups each 6 individuals. The first group was exposed to atropine; the second group was exposed to one LD50 of soman and atropine. The groups 3-5 were exposed in a same way as the second group and were treated with oxime reactivators: HI-6 (group 3), trimedoxime (4) and K203 (5). The sixth group was control treated with saline solution only. The last (seventh) group was intoxicated with soman only.. The most striking shifts were found for blood acetylcholinesterase and plasma creatinine, glucose, inorganic phosphate as well as uric acid. Lactate dehydrogenase and aspartate aminotransferase assays were useless due to soman interference.. It was demonstrated that treatment was able to protect poisoned animals from metabolic disorder represented by hyperglycemia and nephropathy represented by hyperuricemia and elevated creatinine. Soman exposure and treatment with the oxime reactivators and/or atropine contains quite complex and still not well understood side mechanisms (Tab. 2, Fig. 1, Ref. 25).

Topics: Animals; Antidotes; Atropine; Biomarkers; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Soman; Trimedoxime

The ability of 2 combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate VX-inhibited acetylcholinesterase and reduce acute toxicity of VX was compared with the reactivating and therapeutic efficacy of antidotal treatment involving a single oxime (HI-6, trimedoxime, K203) in rats and mice. Our results showed that the reactivating efficacy of both combinations of oximes studied in rats is significantly higher than the reactivating efficacy of all individual oximes in diaphragm and roughly corresponds to the most effective individual oxime in blood and brain. Both combinations of oximes were found to be more effective in the reduction of acute lethal toxicity of VX in mice than the antidotal treatment involving the most efficacious individual oxime although the difference is not significant. Based on the obtained data, we can conclude that the antidotal treatment involving the chosen combinations of oximes brings benefit for the reactivation of VX-inhibited acetylcholinesterase in rats and for the antidotal treatment of VX-induced acute poisoning in mice.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Brain; Cholinesterase Inhibitors; Dose-Response Relationship, Drug; Drug Combinations; Lethal Dose 50; Male; Mice; Organothiophosphorus Compounds; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

Up to now, intensive attempts to synthesize a universal reactivator able to reactivate cholinesterases inhibited by all types of nerve agents/organophosphates were not successful. Therefore, another approach using a combination of two reactivators differently reactivating enzyme was used: in rats poisoned with tabun and treated with combination of atropine (fixed dose) and different doses of trimedoxime and HI-6, changes of acetylcholinesterase activities (blood, diaphragm and different parts of the brain) were studied. An increase of AChE activity was observed following trimedoxime treatment depending on its dose; HI-6 had very low effect. Combination of both oximes showed potentiation of their reactivation efficacy; this potentiation was expressed for peripheral AChE (blood, diaphragm) and some parts of the brain (pontomedullar area, frontal cortex); AChE in the basal ganglia was relatively resistant. These observations suggest that the action of combination of oximes in vivo is different from that observed in vitro.

Topics: Acetylcholinesterase; Animals; Central Nervous System; Cholinesterase Reactivators; Drug Therapy, Combination; Enzyme Activation; Female; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

The potency of newly developed bispyridinium compound K203 and its fluorinated analog KR-22836 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 the percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in rats showed that the reactivating efficacy of K203 is higher than the reactivating efficacy of its fluorinated analog KR-22836 as well as currently available oximes studied. The therapeutic efficacy of the oxime K203 and its fluorinated analog corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase. According to the results, the oxime K203 is more suitable than KR-22836 for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning due to its relatively high potency to counteract the acute toxicity of tabun.

Topics: Animals; Antidotes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Mice; Obidoxime Chloride; Organophosphates; Oximes; Pyridinium Compounds; Rats; Trimedoxime

Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino-methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 micromol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI-6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p < or = 0.005), whereas obidoxime (RR = 26%, p < or = 0.01), K-48 (RR = 29%, p < or = 0.005) and methoxime (RR = 26%, p < or = 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p < or = 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p < or = 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p < or = 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs.

Topics: Animals; Cholinesterase Inhibitors; Cholinesterase Reactivators; Isoflurophate; Male; Obidoxime Chloride; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

The influence of the combination of oximes on the reactivating and therapeutic efficacy of antidotal treatment of acute soman poisoning was evaluated. The ability of two combinations of oximes (HI-6 + trimedoxime and HI-6 + K203) to reactivate soman-inhibited acetylcholinesterase and reduce acute toxicity of soman was compared with the reactivating and therapeutic efficacy of antidotal treatment involving single oxime (HI-6, trimedoxime, K203) using in vivo model. Studies determining percent of reactivation of soman-inhibited blood and diaphragm acetylcholinesterase in poisoned rats showed that the reactivating efficacy of both combinations of oximes is slightly greater than the reactivating efficacy of the most effective individual oxime, but the difference among them is not significant. Both combinations of oximes were found to be as effective in the reduction of acute lethal toxic effects in soman-poisoned mice as the antidotal treatment involving the most efficacious individual oxime. Thus, the efficacy of oximes is comparative in rats vs mice. A comparison of reactivating and therapeutic efficacy of individual oximes showed that the newly developed oxime K203 is approximately as effective as commonly used trimedoxime; nevertheless, their reactivating and therapeutic efficacy is markedly lower compared to the oxime HI-6. Based on the obtained data, one can conclude that the antidotal treatment involving chosen combinations of oximes does not significantly influence the potency of the most effective individual oxime (HI-6) to reactivate soman-inhibited rat acetylcholinesterase and to reduce acute toxicity of soman.

Topics: Animals; Antidotes; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Drug Combinations; Male; Mice; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Soman; Trimedoxime

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.

Topics: Acetylcholinesterase; Animals; Antidotes; Brain; Cholinesterase Inhibitors; Diaphragm; Male; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

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.

Topics: Acetylcholinesterase; Animals; Antidotes; Atropine; Cholinesterase Inhibitors; Cholinesterase Reactivators; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Injections, Intramuscular; Lethal Dose 50; Male; Mice; Molecular Structure; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Oximes; Pyridinium Compounds; Rats; Rats, Wistar; Seizures; Species Specificity; Toxicity Tests, Acute; Trimedoxime

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.

Topics: Animals; Antidotes; Atropine; Butanes; Cholinesterase Inhibitors; Cholinesterase Reactivators; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Therapy, Combination; Lethal Dose 50; Male; Mice; Muscarinic Antagonists; Obidoxime Chloride; Organophosphate Poisoning; Organophosphates; Organophosphorus Compounds; Oximes; Poisoning; Pyridinium Compounds; Trimedoxime

In vitro comparison of reactivation efficacy of five currently used oximes - pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6 (at two concentrations: 10-5 and 10-3 M) - against acetylcholinesterase (AChE; E.C. 3.1.1.7) inhibited by six different nerve agents (VX, Russian VX, sarin, cyclosarin, tabun, soman) and organophosphorus insecticide chlorpyrifos was the aim of this study. As a source of AChE in the experiments, rat brain homogenate was used. According to the results obtained, no AChE reactivator was able to reach sufficient potency for AChE inhibited by all nerve agents used. Moreover, oxime HI-6 (the most effective one) was not able to reactivate tabun- and soman-inhibited AChE. Due to this fact, it could be designated as a partially broad-spectrum reactivator.

Topics: Animals; Brain; Chemical Warfare Agents; Chlorpyrifos; Cholinesterase Inhibitors; Cholinesterase Reactivators; Dose-Response Relationship, Drug; Obidoxime Chloride; Organophosphates; Organophosphorus Compounds; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Wistar; Sarin; Soman; Tissue Extracts; Trimedoxime

In the oximolysis reaction para-aldoximes K027 and TMB-4 react faster with ATCh than ortho-aldoximes HI-6 and K033. The reaction rate constants at 25 degrees C were 22 M(-1) min(-1) for HI-6 and K033, 230 M(-1) min(-1) for TMB-4 and 306 M(-1) min(-1) for K027. Semi-empirical calculations showed that differences in rates do not origin from different electron density on the oxygen of the oxime group, but can be explained by the steric hindrance of the oxime group within the molecule. Thermodynamic parameters, DeltaG#, DeltaH# and DeltaS#, were also determined for oximolysis reaction.

Topics: Acetylthiocholine; Oximes; Pyridinium Compounds; Thermodynamics; Trimedoxime

The efficacy of H oximes (HI-6, HLö-7), the oxime BI-6, and currently used oximes (pralidoxime, obidoxime, trimedoxime) to reactivate acetylcholinesterase inhibited by two nerve agents (tabun, VX agent) was tested in vitro. Both H oximes (HI-6, HLö-7) and the oxime BI-6 were found to be more efficacious reactivators of VX-inhibited acetylcholinesterase than pralidoxime and obidoxime. On the other hand, their potency to reactivate tabun-inhibited acetylcholinesterase was low and did not reach the reactivating efficacy of trimedoxime and obidoxime. Thus, none of these compounds can be considered to be a broad-spectrum reactivator of nerve agent-inhibited acetylcholinesterase in spite of high potency to reactivate acetylcholinesterase inhibited by some nerve agents. More than one oxime may be necessary for the antidotal treatment of nerve agent-exposed individuals.

Topics: Acetylcholinesterase; Animals; Antidotes; Brain; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Male; Obidoxime Chloride; Organophosphates; Organothiophosphorus Compounds; Oximes; Pralidoxime Compounds; Pyridines; Pyridinium Compounds; Rats; Rats, Wistar; Trimedoxime

This paper discusses the toxicity and antidotal effects of 32 compounds. Screening studies have shown that these compounds combined with atropine are effective antidotes against the organophosphate nerve agents Tabun and/or Soman, having a therapeutic factor equal or greater than 2.0 when tested in mice or rats. We analysed the results of these studies, and recommend that these compounds should be studied in more detail simultaneously with conventional antidotes (PAM-2, HI-6, Toxogonin, TMB-4) in order to assess whether they could broaden the choice of compounds now available for the treatment of organophosphate poisoning.

Topics: Animals; Antidotes; Chemical Warfare Agents; Cholinesterase Inhibitors; Cholinesterase Reactivators; Mice; Obidoxime Chloride; Organophosphates; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Soman; Trimedoxime

It has recently been shown that oximes can amplify the ability of cholinesterases to scavenge organophosphorus (OP) agents. Since both OP agents and oximes can disrupt performance, behavioral evaluation of bioscavenger therapies using oximes can be hindered. Therefore, we investigated the ability of three oximes, administered alone, to disrupt performance. The effects of trimedoxime bromide (TMB-4) (3.16-56.2 mg/kg), pralidoxime chloride (2-PAM) (10.0-237.1 mg/kg), and, 1-([[4-amincarbonyl)pyridino]-methoxy]-methyl)-2, 4-bis[(hydroxyimino)methyl] pyridinium dichloride monohydrate (HI-6) (10.0-237.1 mg/kg) were evaluated in rats using a variable-interval 56 (VI 56) s schedule of food reinforcement. Under control conditions, the VI 56 s schedule produced a constant rate of responding (i.e., lever-pressing). All three oximes produced dose-dependent decreases in responding, and the largest doses of TMB-4 and 2-PAM produced complete or nearly complete suppression of responding in all rats. Only the largest dose of HI-6 suppressed responding. Analysis of the dose-effect functions demonstrated that TMB-4 was substantially more potent than 2-PAM, which was slightly more potent than HI-6, for producing response suppression. These results establish doses of each oxime that will not contribute to disruption of responding, and thus, facilitate future evaluation of bioscavenger therapies against OP toxicity.

Topics: Animals; Behavior, Animal; Cholinesterase Inhibitors; Conditioning, Operant; Dose-Response Relationship, Drug; Male; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rats; Rats, Sprague-Dawley; Reinforcement Schedule; Trimedoxime

The reaction of human erythrocyte acetylcholinesterase (AChE) with a set of structurally related phosphoramidates was studied in order to investigate the properties of phosphorylated enzyme and the effects of 4 oximes PAM-2, TMB-4, HI-6 and BDB-106 on the reactivation of inhibited AChE. Second-order rate constant of the phosphorylation reaction of the compounds towards the active site of AChE range between 5.0 x 10(2) and 4.9 x 10(6) M-1min-1 and their inhibitory power (I50) was from 7.3 x 10(-5) to 5.7 x 10(-9) M for 20 min incubation at 37 degrees C. The oximes used were weak reactivators of inhibited AChE except for (C4H9O)(NH2)P(O)DCP (DCP, -O-2,5-dichlorphenyl group) and (C6H13O)(NH2)P(O)SCH3 where we have obtained good reactivation. Imidazole oxime BDB-106 proved to be a potent reactivator of tabun-inhibited AChE.

Topics: Acetylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Erythrocytes; Humans; Kinetics; Organophosphorus Compounds; Oximes; Pyridinium Compounds; Trimedoxime

The intravenous pharmacokinetics of the oximes HI-6 (pyridinium-1-(((4-carbamoil-pyridinio)metoxy)methyl)2 -(hydroxyiminomethyl)dichloride monohydrate), (132.54 mu mol/kg) and trimedoxime (1,1'-(1,3'-propanedyl)bis((4-hydroxyimino) methyl)-pyridinium dibromide), (55.98 mu mol/kg) in mice was investigated. The concentrations of oximes in plasma determined by high pressure liquid chromatography (HPLC) corresponded to a two-compartment pharmacokinetic open model. The oximes were rapidly eliminated from mice plasma, with half-times of 57.93 min. for HI-6 and 108.08 min. for trimedoxime. Although the oximes passed from circulation into the tissues at approximately the same rate, their transport back to the central compartment was two-times slower in the case of trimedoxime: t(1/2k21) was 77.9 min. for trimedoxime and 41.7 min. for HI-6. The total body clearance (CI(tot)) of HI-6 was about 25% higher than that of trimedoxime. The central compartment volume of HI-6 distribution (V(1)) was greater, whereas the volume of distribution of the peripheral compartment (V(2)) was lower for about 35% with respect to the corresponding parameters of trimedoxime. The calculated pharmacokinetic parameters for the oxime HI-6 and trimedoxime show that trimedoxime is eliminated more slowly in mice, and penetrates better into the peripheral compartment where it remains longer.

Topics: Animals; Cholinesterase Reactivators; Chromatography, High Pressure Liquid; Half-Life; Injections, Intravenous; Mice; Oximes; Pyridinium Compounds; Trimedoxime

The role of the functional substituents on the pyridinium ring of bisquaternary pyridinium compounds, mostly oximes, in exerting reversible and irreversible inhibition of binding of [3H]-N-methyl-4-piperidyl benzilate [( 3H]-4NMPB) to rat brain stem muscarinic receptors was studied. The drugs tested, i.e. HGG-42, HGG-12, HGG-52, HI-6, obidoxim, SAD-128 and TMB-4, could reversibly inhibit binding of [3H]-4NMPB, with the highest potency (KI = 1.7 - 6 microM) exhibited by analogs possessing hydrophobic substituents at position 3 or 4 of the pyridinium ring. Bisquaternary drugs possessing an oxime moiety at position 2, but not at position 4 of the pyridinium ring, could also induce about 30% reduction of maximal binding capacity (Bmax) (loss of muscarinic receptors) in addition to their reversible effect. Thus the structural correlates of the reversible and the irreversible effects of these drugs are different.

Topics: Animals; Benzilates; Binding, Competitive; Brain Stem; Cell-Free System; Obidoxime Chloride; Oximes; Parasympatholytics; Piperidines; Pyridinium Compounds; Rats; Receptors, Muscarinic; Structure-Activity Relationship; Trimedoxime

Topics: Acetylcholinesterase; Animals; Brain; Carbamates; Cattle; Erythrocytes; Humans; Oximes; Pralidoxime Compounds; Pyridinium Compounds; Rabbits; Trimedoxime

HI-6 and TMB-4 were the most effective and safe of 7 cholinesterase reactivators tested as agents for the prophylaxis of proserine poisoning of male mice. The reactivator HI-6 strongly potentiated the prophylactic efficacy of a mixture of atropine and arpenal administered in the doses sufficient for the blockade of both the m- and h-cholinoreactive systems of mice. As demonstrated by experiments in vitro, HI-6 and TMB-4 did not reacivate proserine-inhibited cholinesterase. The natural anticholinesterase activity of HI-6 was negligible. Based on the correlation of the data obtained to the reported data indicating that HI-6 has a low ganglioblocking activity it is inferred that the direct effect on the receptor is of no importance for the potentiating effect. It is assumed that HI-6 modulates the cholinoreactive systems, which leads to a dramatic increase of the efficacy of cholinolytics.

Topics: Animals; Antidotes; Atropine; Butanones; Cholinesterase Reactivators; Diphenylacetic Acids; Drug Synergism; Male; Mice; Neostigmine; Obidoxime Chloride; Oximes; Parasympatholytics; Pralidoxime Compounds; Pyridinium Compounds; Trimedoxime