Abstract Novichoks are the latest known and most toxic class of organophosphorus chemical warfare agents (OP CWAs) to have been developed. Among the documented Novichoks, A-232 is the most toxic and most potent inhibitor of AChE, as well as the most resistant to reactivation by oximes, and thus likely the most challenging to treat. Here we characterize the intoxication following dermal exposure to the Novichok A-232 in swine, and describe a novel countermeasure against it. Our results demonstrate that percutaneous poisoning by a lethal dose of A-232 (2 mg/kg) is characterized by slow appearance and exacerbation of intoxication signs. We further show that conventional antidotal treatment against such poisoning, administered upon appearance of intoxication signs, provides only temporary relief after which intoxication signs reoccur, and that further repeated such treatment is not sufficient to enable survival. The above likely stem from formation of a dermal depot of A-232 from which the agent slowly penetrates into the bloodstream, coupled with its resistance to reactivation by oximes. Accordingly, we developed the AHAK lotion (potassium acetohydroxamate in DMSO/H 2 O, derived from the FDA approved medication acetohydroxamic acid (AHA)), intended to act as a ‘catch-up therapy’ enabling both skin surface and intradermal decomposition of persistent low-volatility OP CWAs. We demonstrate that combining conventional antidotal treatment with dermal application of AHAK following percutaneous poisoning by a lethal dose of A-232, leads to survival of all animals. Additionally, using a low dose (0.33–0.41 mg/kg) of A-232, we show that AHAK is expected to exert a beneficial effect also following late application. Hence, the results of the current study, coupled with our previous results regarding the contribution of AHAK to countering percutaneous intoxication by VX and the safety of prolonged whole-body application of AHAK, delineate the aptness of AHAK to serve as a generic medical countermeasure against percutaneous intoxication by persistent low-volatility OP CWAs, of both the V and Novichok families.
Nili et al. (Mon,) studied this question.