Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
31629733
DOI
10.1016/j.taap.2019.114776
PII: S0041-008X(19)30384-9
Knihovny.cz E-resources
- Keywords
- Cholinergic receptor, Cytotoxicity, Maximal tolerated dose, NMDA receptor, Reactivator,
- MeSH
- CHO Cells MeSH
- Cricetulus MeSH
- Cricetinae MeSH
- Chickens MeSH
- Humans MeSH
- Maximum Tolerated Dose * MeSH
- Mice, Inbred BALB C MeSH
- Mice MeSH
- Cell Line, Tumor MeSH
- Organophosphorus Compounds toxicity MeSH
- Oximes administration & dosage toxicity MeSH
- Pralidoxime Compounds administration & dosage toxicity MeSH
- Pyridinium Compounds administration & dosage toxicity MeSH
- Cholinesterase Reactivators administration & dosage toxicity MeSH
- Cell Survival drug effects physiology MeSH
- Animals MeSH
- Check Tag
- Cricetinae MeSH
- Humans MeSH
- Male MeSH
- Mice MeSH
- Female MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- asoxime chloride MeSH Browser
- Organophosphorus Compounds MeSH
- Oximes MeSH
- pralidoxime MeSH Browser
- Pralidoxime Compounds MeSH
- Pyridinium Compounds MeSH
- Cholinesterase Reactivators MeSH
The major function of compounds with an oxime moiety attached to a quarternary nitrogen pyridinium ring is to reactivate acetylcholinesterase inhibited by organophosphorus agent (OP). However, other oxime mechanisms (e.g. modulation of cholinergic or glutamatergic receptor) may be involved in the recovery. The main disadvantage of positively charged reactivators is their low ability to penetrate into the brain although crossing the blood brain barrier could be supported via increasing the dose of administered oxime. Thus, this study presents maximal tolerated doses (MTD) for marketed oximes (TMB-4, MMB-4, LüH-6, HI-6, 2-PAM) and the most promising K-oximes (K027, K048, K203) which can be used in OP therapy in the future. No signs of sarin intoxication were observed in mice treated with 100% MTD of HI-6 in contrast to those treated with atropine and only 5% LD50 of HI-6. 100% MTD of HI-6 resulted in levels of 500 μM and 12 μM in plasma and brain, respectively. This concentration is by a far margin safe with respect to direct effects on neuronal cell viability and, on the other hand, does not have any effects on central NMDA receptors or central nACh receptors. However, a weak antimuscarinic activity in case of LüH-6 and a weak peripheral antinicotinic action in case of TMB-4 and 2-PAM could be observed at their respective 100% MTD dose. These high doses, represented by MTD, are, however, irrelevant to clinical practice since they led to mild to moderate toxic side effects. Therefore, we conclude that clinically used doses of marketed oxime reactivators have no significant direct pharmacological effect on the tested receptors.
References provided by Crossref.org
Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
