Citation

Nahum V, Nili U, Bloch-Shilderman E, Smolkin B, Ashkenazi N. Int. J. Pharm. 2021; ePub(ePub): ePub.

Copyright

(Copyright © 2021, Elsevier Publishing)

DOI

10.1016/j.ijpharm.2021.120689

PMID

unavailable

Abstract

Dermal exposure to low volatility organophosphorus chemical warfare agents (OP CWA) poses a great risk to the exposed person. Due to their lipophilic nature, these compounds rapidly absorb into the skin, leading to the formation of a "dermal reservoir" from which they slowly enter the blood stream causing prolonged intoxication. Traditionally, strategies to counter the toxicity of such substances consist of chemical decontamination/physical removal of the residual agent from the skin surface (preferably as soon as possible following the exposure) and administration of antidotes in the case of intoxication signs. Hence, these strategies are unable to counter a substantial amount of the agent, which accumulates in the dermal reservoir. More than a decade ago, the concept of a "catch-up therapy" intended to neutralize the dermal reservoir was suggested. Herein, we describe examples of potential "catch-up therapy" lotions - vehicles designed to deliver small nucleophilic molecules into the skin and potentially decompose the remaining CWA before it reaches the blood stream. Eleven nucleophilic compounds, based on approved drugs, were initially screened. They were then tested in various binary solutions, for their detoxification efficacy and degradation ability towards lipophilic OPCWA's model such as dibutylphosphofluoridate and o-nitro-phenyl diphenyl phosphate, as well as the nerve agent VX, by means of kinetic (31)P NMR and UV-Vis spectroscopy. Of these, the Potassium and diethyl ammonium salts of acetohydroxamic acid (AHAK and AHA DEA) in (DMSO/H(2)O 1:4) were found to be the most active nucleophiles, hydrolyzing VX in practical time scales (t(1/2) =5.28 and 6.78 min, respectively). The vehicle solution DMSO/H(2)O 1:4 promoted the penetration of substantial amounts of AHA K and AHA DEA through excised pig skin in in-vitro studies, suggesting that such formulations may serve as useful CWA nucleophilic scavengers for both on and within -skin detoxification. These findings may pave the way to a more efficacious treatment against low volatility OP CWA percutaneous poisoning.

Language: en

Keywords

“Catch-up therapy”; Dermal depot; Dermal lotion; Hydroxamic acids; Nucleophilic scavengers; Percutaneous poisoning; VX