Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870
Language English Country England, Great Britain Media print-electronic
Document type Journal Article
PubMed
35738326
DOI
10.1016/j.fct.2022.113236
PII: S0278-6915(22)00434-3
Knihovny.cz E-resources
- Keywords
- Acetylcholinesterase, Asoxime, Organophosphate, Oxime K870, Pralidoxime, Reactivation,
- MeSH
- Acetylcholinesterase metabolism MeSH
- Antidotes MeSH
- Cholinesterase Inhibitors metabolism toxicity MeSH
- Rats MeSH
- Mice MeSH
- Organophosphates MeSH
- Oximes * MeSH
- Pyridinium Compounds toxicity MeSH
- Cholinesterase Reactivators * therapeutic use MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Acetylcholinesterase MeSH
- Antidotes MeSH
- Cholinesterase Inhibitors MeSH
- Organophosphates MeSH
- Oximes * MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators * MeSH
Oxime reactivators are causal antidotes for organophosphate intoxication. Herein, the toxicity, pharmacokinetics, and reactivation effectiveness of o-chlorinated bispyridinium oxime K870 are reported. Oxime K870 was found to have a safe profile at a dose of 30 mg/kg in rats. It exhibited rapid absorption and renal clearance similar to those of other charged oximes after intramuscular administration. Its isoxazole-pyridinium degradation product was identified in vivo. Although it showed some improvement in brain targeting, it was nevertheless rapidly effluxed from the central nervous system. Its reactivation effectiveness was evaluated in rats and mice intoxicated with sarin, tabun, VX, and paraoxon and compared with pralidoxime and asoxime. K870 was found to be less effective in reversing tabun poisoning compared to its parent unchlorinated oxime K203. However, K870 efficiently reactivated blood acetylcholinesterase for all tested organophosphates in rats. In addition, K870 significantly protected against intoxication by all tested organophosphates in mice. For these reasons, oxime K870 seems to have a broader reactivation spectrum against multiple organophosphates. It seems important to properly modulate the oximate forming properties (pKa) to obtain more versatile oxime reactivators.
References provided by Crossref.org
Strategies for enhanced bioavailability of oxime reactivators in the central nervous system
