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No-observed-adverse-effect-level (NOAEL) assessment as an optimized dose of cholinesterase reactivators for the treatment of exposure to warfare nerve agents in mice.
Trancart, Marilène; Hanak, Anne-Sophie; Dambrune, Chloé; Madi, Méliati; Voros, Camille; Baati, Rachid; Calas, André-Guilhem.
  • Trancart M; French Armed Forces Biomedical Research Institute, CBRN Defense Division, Toxicology and Chemical Risks Department, Brétigny-sur-Orge, France.
  • Hanak AS; French Armed Forces Biomedical Research Institute, CBRN Defense Division, Toxicology and Chemical Risks Department, Brétigny-sur-Orge, France.
  • Dambrune C; French Armed Forces Biomedical Research Institute, CBRN Defense Division, Toxicology and Chemical Risks Department, Brétigny-sur-Orge, France; Ecole de Chimie Polymère et Matériaux ECPM, Université de Strasbourg, ICPEES UMR CNRS 7515, 25, Rue Becquerel, F-67087, Strasbourg, France.
  • Madi M; French Armed Forces Biomedical Research Institute, CBRN Defense Division, Toxicology and Chemical Risks Department, Brétigny-sur-Orge, France.
  • Voros C; Ecole de Chimie Polymère et Matériaux ECPM, Université de Strasbourg, ICPEES UMR CNRS 7515, 25, Rue Becquerel, F-67087, Strasbourg, France.
  • Baati R; Ecole de Chimie Polymère et Matériaux ECPM, Université de Strasbourg, ICPEES UMR CNRS 7515, 25, Rue Becquerel, F-67087, Strasbourg, France.
  • Calas AG; French Armed Forces Biomedical Research Institute, CBRN Defense Division, Toxicology and Chemical Risks Department, Brétigny-sur-Orge, France. Electronic address: guilhem.calas@def.gouv.fr.
Chem Biol Interact ; 392: 110929, 2024 Apr 01.
Article en En | MEDLINE | ID: mdl-38417730
ABSTRACT
Despite the international convention on the prohibition of chemical weapons ratified in 1997, the threat of conflicts and terrorist attacks involving such weapons still exists. Among these, organophosphorus-nerve agents (OPs) inhibit cholinesterases (ChE) causing cholinergic syndrome. The reactivation of these enzymes is therefore essential to protect the poisoned people. However, these reactivating molecules, mainly named oximes, have major drawbacks with limited efficacy against some OPs and a non-negligible ChE inhibitor potential if administered at an inadequate dose, an effect that they are precisely supposed to mitigate. As a result, this project focused on assessing therapeutic efficacy, in mice, up to the NOAEL dose, the maximum dose of oxime that does not induce any observable toxic effect. NOAEL doses of HI-6 DMS, a reference oxime, and JDS364. HCl, a candidate reactivator, were assessed using dual-chamber plethysmography, with respiratory ventilation impairment as a toxicity criterion. Time-course modeling parameters and pharmacodynamic profiles, reflecting the interaction between the oxime and circulating ChE, were evaluated for treatments at their NOAEL and higher doses. Finally, the therapeutic potential against OPs poisoning was determined through the assessment of protective indices. For JDS364. HCl, the NOAEL dose corresponds to the smallest dose inducing the most significant therapeutic effect without causing any abnormality in ChE activity. In contrast, for HI-6 DMS, its therapeutic benefit was observed at doses higher than its NOAEL, leading to alterations in respiratory function. These alterations could not be directly correlated with ChE inhibition and had no adverse effects on survival. They are potentially attributed to the stimulation of non-enzymatic cholinergic targets by HI-6 DMS. Thus, the NOAEL appears to be an optimal dose for evaluating the efficacy of oximes, particularly when it can be linked to respiratory alterations effectively resulting from ChE inhibition.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sustancias para la Guerra Química / Reactivadores de la Colinesterasa / Agentes Nerviosos Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Sustancias para la Guerra Química / Reactivadores de la Colinesterasa / Agentes Nerviosos Límite: Animals / Humans Idioma: En Año: 2024 Tipo del documento: Article