Efficacy Assessment of an Uncharged ...
Type de document :
Article dans une revue scientifique: Article original
DOI :
PMID :
URL permanente :
Titre :
Efficacy Assessment of an Uncharged Reactivator of NOP-Inhibited Acetylcholinesterase Based on Tetrahydroacridine Pyridine-Aldoxime Hybrid in Mouse Compared to Pralidoxime.
Auteur(s) :
Calas, A. G. [Auteur]
Hanak, A. S. [Auteur]
Jaffré, N. [Auteur]
Nervo, A. [Auteur]
Dias, J. [Auteur]
Rousseau, C. [Auteur]
Courageux, C. [Auteur]
Brazzolotto, X. [Auteur]
Villa, P. [Auteur]
Obrecht, A. [Auteur]
Goossens, Jean-Francois [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365
Landry, C. [Auteur]
Hachani, J. [Auteur]
Gosselet, F. [Auteur]
Dehouck, M. P. [Auteur]
Yerri, J. [Auteur]
Kliachyna, M. [Auteur]
Baati, R. [Auteur]
Nachon, F. [Auteur]
Hanak, A. S. [Auteur]
Jaffré, N. [Auteur]
Nervo, A. [Auteur]
Dias, J. [Auteur]
Rousseau, C. [Auteur]
Courageux, C. [Auteur]
Brazzolotto, X. [Auteur]
Villa, P. [Auteur]
Obrecht, A. [Auteur]
Goossens, Jean-Francois [Auteur]
Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - ULR 7365
Landry, C. [Auteur]
Hachani, J. [Auteur]
Gosselet, F. [Auteur]
Dehouck, M. P. [Auteur]
Yerri, J. [Auteur]
Kliachyna, M. [Auteur]
Baati, R. [Auteur]
Nachon, F. [Auteur]
Titre de la revue :
Biomolecules
Nom court de la revue :
Biomolecules
Numéro :
10
Pagination :
858
Date de publication :
2020-06-13
ISSN :
2218-273X
Mot(s)-clé(s) :
organophosphorus nerve agents
oxime
cholinesterase
reactivation
ventilation
pharmacodynamics
blood-brain barrier crossing
oxime
cholinesterase
reactivation
ventilation
pharmacodynamics
blood-brain barrier crossing
Discipline(s) HAL :
Sciences du Vivant [q-bio]
Résumé en anglais : [en]
Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of ...
Lire la suite >Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.Lire moins >
Lire la suite >Background: Human exposure to organophosphorus compounds employed as pesticides or as chemical warfare agents induces deleterious effects due to cholinesterase inhibition. One therapeutic approach is the reactivation of inhibited acetylcholinesterase by oximes. While currently available oximes are unable to reach the central nervous system to reactivate cholinesterases or to display a wide spectrum of action against the variety of organophosphorus compounds, we aim to identify new reactivators without such drawbacks. (2) Methods: This study gathers an exhaustive work to assess in vitro and in vivo efficacy, and toxicity of a hybrid tetrahydroacridine pyridinaldoxime reactivator, KM297, compared to pralidoxime. (3) Results: Blood–brain barrier crossing assay carried out on a human in vitro model established that KM297 has an endothelial permeability coefficient twice that of pralidoxime. It also presents higher cytotoxicity, particularly on bone marrow-derived cells. Its strong cholinesterase inhibition potency seems to be correlated to its low protective efficacy in mice exposed to paraoxon. Ventilatory monitoring of KM297-treated mice by double-chamber plethysmography shows toxic effects at the selected therapeutic dose. This breathing assessment could help define the No Observed Adverse Effect Level (NOAEL) dose of new oximes which would have a maximum therapeutic effect without any toxic side effects.Lire moins >
Langue :
Anglais
Audience :
Internationale
Établissement(s) :
Université de Lille
CHU Lille
CHU Lille
Collections :
Date de dépôt :
2023-05-25T03:33:07Z
2023-10-18T08:50:02Z
2023-10-18T08:50:02Z