Pharmacological and toxicological in vitro and in vivo effect of higher doses of oxime reactivators
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
31629733
DOI
10.1016/j.taap.2019.114776
PII: S0041-008X(19)30384-9
Knihovny.cz E-zdroje
- Klíčová slova
- Cholinergic receptor, Cytotoxicity, Maximal tolerated dose, NMDA receptor, Reactivator,
- MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- křečci praví MeSH
- kur domácí MeSH
- lidé MeSH
- maximální tolerovaná dávka * MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- organofosforové sloučeniny toxicita MeSH
- oximy aplikace a dávkování toxicita MeSH
- pralidoximové sloučeniny aplikace a dávkování toxicita MeSH
- pyridinové sloučeniny aplikace a dávkování toxicita MeSH
- reaktivátory cholinesterázy aplikace a dávkování toxicita MeSH
- viabilita buněk účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- lidé MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- asoxime chloride MeSH Prohlížeč
- organofosforové sloučeniny MeSH
- oximy MeSH
- pralidoxime MeSH Prohlížeč
- pralidoximové sloučeniny MeSH
- pyridinové sloučeniny MeSH
- reaktivátory cholinesterázy 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.
Citace poskytuje Crossref.org
Development of versatile and potent monoquaternary reactivators of acetylcholinesterase
