Comparative evaluation of antidotal efficacy of 2-PAM and HNK-102 oximes during inhalation of sarin vapor in Swiss albino mice

Abstract

Efficacy of two oximes treatments evaluated during inhalation of sarin vapor (LCt₅₀, 755.9 mg/min/m³) in simulated real scenario in vivo. Majority of mice either became moribund or died within 1–2 min during exposure to multifold-lethal concentrations of sarin vapor. Protection indices were determined by exposing to sarin vapor in two sessions, 1 min exposure followed by treatments with or without HNK-102 (56.56 mg/kg, im) or 2-PAM (30 mg/kg, im) and atropine (10 mg/kg, ip), and again exposed for remaining 14 min. Protection offered by HNK-102 was found to be four folds higher compared to 2-PAM in the same toxic environment. Secondly, sub-lethal concentration of sarin vapor (0.8 × LCt₅₀ or 605 mg/min/m³), 24 h post investigations revealed that the oximes could not reactivate brain and serum acetylcholinesterase (AChE) activity. The treatments prevented increase in protein concentration (p < .05) and macrophages infiltration compared to sarin alone group in broncho-alveolar lavage fluid. Lung histopathology showed intense peribronchial infiltration and edema with desquamating epithelial lining and mild to moderate alveolar septal infiltration in sarin and atropine groups, respectively. Noticeable peeling-off observed in epithelial lining and sporadic mild infiltration of epithelial cells at bronchiolar region in 2-PAM and HNK-102 groups, respectively. The oximes failed to reactivate AChE activity; however, the mice survived up to 6.0 × LCt₅₀, proved involvement of non-AChE targets in sarin toxicity. Atropine alone treatment was found to be either ineffective or increased the toxicity. HNK-102, exhibited better survivability with lung protection, can be considered as a better replacement for 2-PAM to treat sarin inhalation induced poisoning.

Keywords:

• AChE
• HNK oximes
• nerve agent
• protection index
• sarin vapor inhalation

Acknowledgements

Authors profusely thank to Dr. D. K. Dubey, Director, Defense Research and Development Establishment, Jhansi Road, Gwalior 474002, India for his encouragement, keen interest in the study and providing necessary facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.