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Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870

Identifikátory výsledku

  • Kód výsledku v IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F62690094%3A18470%2F22%3A50019292" target="_blank" >RIV/62690094:18470/22:50019292 - isvavai.cz</a>

  • Nalezeny alternativní kódy

    RIV/60162694:G44__/23:00558178 RIV/00179906:_____/22:10447229

  • Výsledek na webu

    <a href="https://www.sciencedirect.com/science/article/pii/S0278691522004343?via%3Dihub" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0278691522004343?via%3Dihub</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1016/j.fct.2022.113236" target="_blank" >10.1016/j.fct.2022.113236</a>

Alternativní jazyky

  • Jazyk výsledku

    angličtina

  • Název v původním jazyce

    Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870

  • Popis výsledku v původním jazyce

    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 (pK(a)) to obtain more versatile oxime reactivators.

  • Název v anglickém jazyce

    Toxicity, pharmacokinetics, and effectiveness of the ortho-chlorinated bispyridinium oxime, K870

  • Popis výsledku anglicky

    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 (pK(a)) to obtain more versatile oxime reactivators.

Klasifikace

  • Druh

    J<sub>imp</sub> - Článek v periodiku v databázi Web of Science

  • CEP obor

  • OECD FORD obor

    30108 - Toxicology

Návaznosti výsledku

  • Projekt

    <a href="/cs/project/GA21-03000S" target="_blank" >GA21-03000S: Modifikované nukleofily pro reaktivaci cholinesteras inhibovaných organofosforovými sloučeninami</a><br>

  • Návaznosti

    P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Ostatní

  • Rok uplatnění

    2022

  • Kód důvěrnosti údajů

    S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Údaje specifické pro druh výsledku

  • Název periodika

    Food and chemical toxicology

  • ISSN

    0278-6915

  • e-ISSN

    1873-6351

  • Svazek periodika

    167

  • Číslo periodika v rámci svazku

    September

  • Stát vydavatele periodika

    GB - Spojené království Velké Británie a Severního Irska

  • Počet stran výsledku

    10

  • Strana od-do

    "Article Number: 113236"

  • Kód UT WoS článku

    000828006900001

  • EID výsledku v databázi Scopus

    2-s2.0-85133438055