Thiberville_2025_Int.J.Pharm_674_125505

Nerve agents, such as VX and sarin, represent a significant threat to global security due to their devastating neurotoxic effects and potential for misuse. The therapeutic inefficacy of current countermeasures underscores the urgent need for more effective alternatives. In this context, recent advances have identified JDS364.HCl, an uncharged hybrid antidote, as a promising candidate. However, its instability in aqueous solution remains a significant challenge. To address this, cyclodextrin-based formulations were developed using two EMA-approved cyclodextrins: HP-beta-CD and SBE-beta-CD. These formulations significantly improved JDS364.HCl stability for over two months at room temperature. Interaction studies revealed a 1:1 stoichiometry for both cyclodextrin complexes, with JDS364.HCl: SBE-beta-CD exhibiting a 100-fold higher affinity constant, attributed to additional electrostatic interactions with SBE-beta-CD sidechains. While SBE-beta-CD provided superior plasma stability compared to HP-beta-CD, the high binding affinity of JDS364.HCl: SBE-beta-CD complexes hindered the molecule's release and reduced its ability to cross the BBB, as observed in a human BBB model. Nonetheless, the results for both cyclodextrins are encouraging, as they enhance JDS364.HCl's stability in plasma while allowing its passage across the BBB. Notably, JDS364.HCl demonstrated superior BBB permeability compared to marketed antidotes such as 2-PAM. These findings highlight the potential of cyclodextrins to improve the efficacy of JDS364.HCl as a nerve agent antidote.