Assessing the safety of warfare nerve agents antidotes using dual-chamber plethysmography

Despite international treaties, the use of chemical weapons remains a concern nowadays. Organophosphorus-nerve agents (OPs) act by inhibiting cholinesterases (ChE), preventing the degradation of some neurotransmitters. Their excessive accumulation can impair neuronal transmission, leading to cholinergic syndrome, which can cause symptoms such as respiratory failure and, in severe cases, death.

Oximes are molecules that can reverse the effect of OPs. While they can be used as treatment, their high affinity for ChE can lead to toxicity at high doses, and the optimal therapeutic dose for many oximes has yet to be determined.

Since an altered respiratory profile is one of the consequences of an overdose of oximes, Trancart et al. used emka double chamber plethysmography to measure ventilatory parameters in mice and determine the no-observed-adverse-effect-level (NOAEL) for several oximes. The NOAEL dose is defined as the highest dose at which no harmful effects are observed, using ventilatory alterations as the toxicity criterion. One of the aims of this study was to see if the NOAEL dose corresponded to the optimal therapeutic dose for different oximes.

Figure 1 - Blog_Assessing the safety of chemical warfare antidotes using double chamber plethysmography
Figure 1. Illustration of the mains ventilatory parameters measured by dual-chamber plethysmography. Marilène Trancart, Anne-Sophie Hanak, Chloé Dambrune, Méliati Madi, Camille Voros, Rachid Baati, André-Guilhem Calas, 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, Chemico-Biological Interactions, Volume 392, 2024.

To determine the NOAEL dose, the researchers performed a visual analysis of the ventilatory signal in real time using the IOX2 software. They monitored deviations from baseline ventilatory parameters after administering a calculated oxime dosage. They then iteratively adjusted the dosage administered to the next animal until three consecutive animals injected with the same dosage showed no signs of ventilatory impairment. The data collected with the plethysmography chambers was further analyzed afterward, confirming that no significant deviations from normal ventilatory function were observed for the selected doses, validating the reliability of the visual analysis used.

The results showed that for one of the oximes (JDS364. HCl), the NOAEL dose was the same as the optimal therapeutic dose. However, for the oxime HI-6 DMS, the optimal therapeutic dose was higher than the NOAEL dose. This divergence can most likely be explained by the fact that HI-6, unlike JDS364.HCl, did not affect respiration through an inhibition of ChE.

Overall, the researchers concluded that the combination of plethysmography and NOAEL dose testing was relevant for the screening of potential ChE reactivators, especially for oximes that have a toxicity effect on respiration through inhibition of ChE.  


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