Thiberville_2026_Res.Sq__

JDS364.HCl, an oxime-based reactivator developed for the treatment of organophosphorus nerve agent intoxication, has recently emerged as a promising uncharged broad-spectrum hybrid antidote. Building on previously reported in vitro stability data of JDS364.HCl formulated with cyclodextrins, the present study provides an ex vivo characterization and in vivo evaluation of the toxicity, biodistribution, metabolism, and therapeutic efficacy of the formulated reactivator in a murine model. Toxicological assessment identified injection route- and formulation-dependent NOAEL values, highlighting the influence of both the route of administration and cyclodextrin complexation on systemic toxicity. A dose-dependent inhibition of acetylcholinesterase activity was observed in specific tissues, particularly the brain and respiratory organs, providing mechanistic insights into the physiological alterations associated with higher doses of JDS364.HCl reactivator. Pharmacokinetic and biodistribution analyses revealed that formulated JDS364.HCl was rapidly distributed systemically, crossed the blood-brain barrier, and was predominantly eliminated via renal clearance. Metabolic profiling further demonstrated extensive and rapid metabolization, primarily through glucuronidation and dehydration pathways. Finally, the in vivo efficacy study indicated that, although formulation with HP--CD improved the stability of JDS364.HCl in solution, it did not significantly increase the protective efficacy index against VX intoxication compared with the unformulated antidote.