Certain AChE reactivators, asoxime, obidoxime, K027, K048, and K075, when taken in overdoses and sometimes even when introduced within therapeutic ranges, may injure the different organs. As a continuation of previously published data, in this study, Wistar rats have sacrificed 24 hrs and 7 days after single im application of 0.1LD50, 0.5LD50 and 1.0LD50 of each reactivator, and examinated tissue samples were obtained for pathohistological and semiquantitative analysis. A severity of tissue alteration, expressed as different tissue damage scores were evaluated. Morphological structure of examinated tissues treated with of 0.1LD50 of all reactivators was comparable with the control group of rats. Moderate injuries were seen in visceral tissues treated with 0.5LD50 of asoxime, obidoxime and K027. Acute damages were enlarged after treatment with 0.5LD50 and 1.0LD50 of all reactivators during the next 7 days. The most prominent changes were seen in rats treated with 1.0LD50 of K048 and K075 (P < 0.001 vs. control and asoxime-treated group). All reactivators given by a single, high, unitary dose regimen, have an adverse effect not only on the main visceral tissue, but on the whole rat as well, but the exact mechanism of cellular injury remains to be confirmed in further investigation.

• MeSH
• Biopsy MeSH
• Chemical Warfare Agents adverse effects   chemistry   toxicity   MeSH
• Histocytochemistry MeSH
• Rats MeSH
• Lethal Dose 50 MeSH
• Molecular Structure MeSH
• Organ Specificity MeSH
• Oximes administration & dosage   adverse effects   chemistry   toxicity   MeSH
• Lung drug effects   metabolism   pathology   MeSH
• Viscera drug effects   pathology   MeSH
• Dose-Response Relationship, Drug MeSH
• Stomach drug effects   pathology   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chemical Warfare Agents MeSH
• Oximes MeSH

Therapeutic application of newly developed oximes is limited due to their adverse effects on different tissues. Within this article, it has been investigated which morphological changes could be observed in Wistar rats after the treatment with increasing doses of selected acetyl cholinesterase reactivators - asoxime, obidoxime, K027, K048, and K075. Subsequently, heart, diaphragm and musculus popliteus were obtained for pathohistological and semiquantitative analysis 24 hrs and 7 days after im administration of a single dose of 0.1 LD50, 0.5 LD50, and 1.0 LD50 of each oxime. Different muscle damage score was based on an estimation scale from 0 (no damage) to 5 (strong damage). In rats treated with 0.1 LD50 of each oxime, muscle fibres did not show any change. The intensive degeneration was found in all muscles after treatment with 0.5 LD50 of asoxime and obidoxime, respectively. Acute toxic muscle injury was developed within 7 days following treatment with 0.5 LD50 and 1.0 LD50 of each oxime, with the highest values in K048 and K075 group (P < 0.001 vs. control and asoxime), respectively. The early muscle alterations observed in our study seem to contribute to the pathogenesis of the oxime-induced toxic muscle injury, which probably manifests as necrosis and/or inflammation.

• MeSH
• Diaphragm drug effects   injuries   MeSH
• Muscle, Skeletal drug effects   injuries   MeSH
• Rats MeSH
• Myositis chemically induced   MeSH
• Necrosis MeSH
• Oximes toxicity   MeSH
• Rats, Wistar MeSH
• Pyridinium Compounds toxicity   MeSH
• Heart drug effects   MeSH
• Muscles drug effects   pathology   MeSH
• Toxicity Tests, Acute MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) propane dibromide MeSH Browser
• 1-(4-hydroxyiminomethylpyridinium)-4-(4-carbamoylpyridinium)butane MeSH Browser
• K075 compound MeSH Browser
• Oximes MeSH
• Pyridinium Compounds MeSH

The acetylcholinesterase (AChE) reactivators (e.g., obidoxime, asoxime) became an essential part of organophosphorus (OP) poisoning treatment, together with atropine and diazepam. They are referred to as a causal treatment of OP poisoning, because they are able to split the OP moiety from AChE active site and thus renew its function. In this approach, fifteen novel AChE reactivators were determined. Their molecular design originated from former K-oxime compounds K048 and K074 with remaining oxime part of the molecule and modified part with heteroarenium moiety. The novel compounds were prepared, evaluated in vitro on human AChE (HssAChE) inhibited by tabun, paraoxon, methylparaoxon or DFP and compared to commercial HssAChE reactivators (pralidoxime, methoxime, trimedoxime, obidoxime, asoxime) or previously prepared compounds (K048, K074, K075, K203). Some of presented oxime reactivators showed promising ability to reactivate HssAChE comparable or higher than the used standards. The molecular modelling study was performed with one compound that presented the ability to reactivate GA-inhibited HssAChE. The SAR features concerning the heteroarenium part of the reactivator's molecule are described.

• Keywords
• acetylcholinesterase, in vitro, molecular docking, organophosphate, oxime, reactivation,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Spectrometry, Mass, Electrospray Ionization MeSH
• Inhibitory Concentration 50 MeSH
• Humans MeSH
• Carbon-13 Magnetic Resonance Spectroscopy MeSH
• Organophosphorus Compounds toxicity   MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Cholinesterase Reactivators chemical synthesis   chemistry   pharmacology   MeSH
• Recombinant Proteins metabolism   MeSH
• Molecular Docking Simulation * MeSH
• In Vitro Techniques MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphorus Compounds MeSH
• Cholinesterase Reactivators MeSH
• Recombinant Proteins 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.

• Keywords
• Antidotes, Chemical warfare agents, Oxime, Poisoning, Reactivator, Treatment,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Antidotes metabolism   MeSH
• Cholinesterase Inhibitors metabolism   MeSH
• Rats MeSH
• Humans MeSH
• Brain enzymology   MeSH
• Organophosphates metabolism   MeSH
• Oximes metabolism   MeSH
• Pyridinium Compounds metabolism   MeSH
• Cholinesterase Reactivators metabolism   MeSH
• Molecular Docking Simulation MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-carbamoylpyridinium)-4-(4-hydroxyiminomethylpyridinium)but-2-ene MeSH Browser
• Acetylcholinesterase MeSH
• Antidotes MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

• Keywords
• acetylcholinesterase, antidote, nerve agent, organophosphates, prophylaxis, therapy,
• Publication type
• Journal Article MeSH

Preparation of 1-(4-hydroxy-iminomethylpyridinium)-3-pyridiniumpropane dibromide is described. This compound represents a new acetylcholinesterase (AChE) reactivator, which has no substituents on the second pyridinium ring as found in other commonly used AChE reactivators. The reactivation ability of this reactivator was tested on tabun- and cyclosarin-inhibited AChE. According to the results obtained, the new compound (without substitution and with decreased molecule size) showed increased reactivation potency in case of cyclosarin inhibited AChE. A potent oxime for treatment of tabun and cyclosarin-caused intoxications was thus obtained via slight modification of the reactivator structure (compared to trimedoxime and K027).

• MeSH
• Acetylcholinesterase MeSH
• Humans MeSH
• Organophosphates antagonists & inhibitors   MeSH
• Organophosphorus Compounds antagonists & inhibitors   MeSH
• Oximes chemical synthesis   MeSH
• Pyridinium Compounds chemical synthesis   MeSH
• Cholinesterase Reactivators chemical synthesis   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1-(4-hydroxyiminomethylpyridinium)-3-pyridiniumpropane MeSH Browser
• Acetylcholinesterase MeSH
• cyclohexyl methylphosphonofluoridate MeSH Browser
• Organophosphates MeSH
• Organophosphorus Compounds MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser

In this work, two oximes for the treatment of tabun-inhibited acetylcholinesterase (AChE; EC 3.1.1.7), K074 (1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide) and K075 ((E)-1,4-bis(4-hydroxyiminomethylpyridinium)but-2-en dibromide), were tested in vitro as reactivators of AChE. Comparison was made with currently used AChE reactivators (pralidoxime, HI-6, methoxime and obidoxime). Human brain homogenate was taken as an appropriate source of the cholinesterases. As resulted, oxime K074 appears to be the most potent reactivator of tabun-inhibited AChE, with reactivation potency comparable to that of obidoxime. A second AChE reactivator, K075, does not attain as great a reactivation potency as K074, although its maximal reactivation (17%) was achieved at relevant concentrations for humans.

• MeSH
• Acetylcholinesterase metabolism   MeSH
• Enzyme Activation drug effects   MeSH
• Butanes chemistry   pharmacology   MeSH
• Cholinesterase Inhibitors toxicity   MeSH
• Humans MeSH
• Caudate Nucleus drug effects   enzymology   MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Organophosphates toxicity   MeSH
• Oximes chemistry   pharmacology   MeSH
• Pralidoxime Compounds chemistry   pharmacology   MeSH
• Pyridinium Compounds chemistry   pharmacology   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• In Vitro Techniques MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• 1,4-bis(4-hydroxyiminomethylpyridinium)butane dibromide MeSH Browser
• Acetylcholinesterase MeSH
• asoxime chloride MeSH Browser
• Butanes MeSH
• Cholinesterase Inhibitors MeSH
• K075 compound MeSH Browser
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Browser
• Obidoxime Chloride MeSH
• Organophosphates MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser