A comparison of the reactivating and therapeutic efficacy of two novel bispyridinium oximes (K727, K733) with the oxime HI-6 and obidoxime in sarin-poisoned rats and mice
Language English Country England, Great Britain Media print-electronic
Document type Comparative Study, Journal Article, Research Support, Non-U.S. Gov't
- Keywords
- Acetylcholinesterase, K727, K733, oximes, sarin,
- MeSH
- Acetylcholinesterase blood chemistry metabolism MeSH
- Muscarinic Antagonists therapeutic use MeSH
- Antidotes therapeutic use MeSH
- Atropine therapeutic use MeSH
- Diaphragm drug effects enzymology MeSH
- Cholinesterase Inhibitors administration & dosage chemistry toxicity MeSH
- Drug Therapy, Combination MeSH
- Brain drug effects enzymology MeSH
- Mice MeSH
- Neurons drug effects enzymology MeSH
- Neurotoxicity Syndromes blood drug therapy etiology metabolism MeSH
- Obidoxime Chloride therapeutic use MeSH
- Animals, Outbred Strains MeSH
- Oximes therapeutic use MeSH
- Rats, Wistar MeSH
- Nerve Tissue Proteins agonists antagonists & inhibitors metabolism MeSH
- Pyridinium Compounds therapeutic use MeSH
- Cholinesterase Reactivators therapeutic use MeSH
- Sarin administration & dosage antagonists & inhibitors toxicity MeSH
- Dose-Response Relationship, Drug MeSH
- Animals MeSH
- Check Tag
- Male MeSH
- Mice MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Comparative Study MeSH
- Names of Substances
- 4-(ethylcarboxyl)-2'-(hydroxyiminomethyl)-1,1'-(phenylene-1,3-diyl)-bispyridinium MeSH Browser
- Acetylcholinesterase MeSH
- Muscarinic Antagonists MeSH
- Antidotes MeSH
- asoxime chloride MeSH Browser
- Atropine MeSH
- Cholinesterase Inhibitors MeSH
- naphthylene-2,7-diyl-bis(2-hydroxyiminomethylpyridinium) MeSH Browser
- Obidoxime Chloride MeSH
- Oximes MeSH
- Nerve Tissue Proteins MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
- Sarin MeSH
The ability of two novel bispyridinium oximes K727 and K733 and currently available oximes (HI-6, obidoxime) to reactivate sarin-inhibited acetylcholinesterase and to reduce acute toxicity of sarin was evaluated. To investigate the reactivating efficacy of the oximes, the rats were administered intramuscularly with atropine and oximes in equitoxic doses corresponding to 5% of their LD50 values at 1 min after the intramuscular administration of sarin at a dose of 24 µg/kg (LD50). The activity of acetylcholinesterase was measured at 60 min after sarin poisoning. The LD50 value of sarin in non-treated and treated mice was assessed using probit-logarithmical analysis of death occurring within 24 h after intramuscular administration of sarin at five different doses. In vivo determined percentage of reactivation of sarin-inhibited rat blood, diaphragm and brain acetylcholinesterase showed that the potency of both novel oximes K727 and K733 to reactivate sarin-inhibited acetylcholinesterase roughly corresponds to the reactivating efficacy of obidoxime. On the other hand, the oxime HI-6 was found to be the most efficient reactivator of sarin-inhibited acetylcholinesterase. While the oxime HI-6 was able to reduce the acute toxicity of sarin >3 times, both novel oximes and obidoxime decreased the acute toxicity of sarin <2 times. Based on the results, we can conclude that the reactivating and therapeutic efficacy of both novel oximes K727 and K733 is significantly lower compared to the oxime HI-6 and, therefore, they are not suitable for the replacement of the oxime HI-6 for the antidotal treatment of acute sarin poisoning.
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