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
The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.
- Keywords
- acetylcholinesterase, functional observational battery, histopathology, neurotoxicity, oximes, rats, tabun,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Atropine therapeutic use MeSH
- Chemical Warfare Agents poisoning MeSH
- Humans MeSH
- Brain drug effects enzymology MeSH
- Neuroprotective Agents therapeutic use MeSH
- Neurotoxicity Syndromes drug therapy MeSH
- Organophosphates toxicity MeSH
- Organophosphate Poisoning drug therapy MeSH
- Oximes therapeutic use MeSH
- Rats, Wistar MeSH
- Pyridinium Compounds therapeutic use MeSH
- Cholinesterase Reactivators therapeutic use MeSH
- Trimedoxime therapeutic use MeSH
- Animals MeSH
- Check Tag
- Humans MeSH
- Male MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Comparative Study MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Atropine MeSH
- Chemical Warfare Agents MeSH
- Neuroprotective Agents MeSH
- Organophosphates MeSH
- Oximes MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
- tabun MeSH Browser
- Trimedoxime MeSH
- Keywords
- acetylcholinesterase, antidote, nerve agent, organophosphates, prophylaxis, therapy,
- Publication type
- Journal Article MeSH
