Abstract
War and terrorism demonstrate the need for an improved antidote against nerve agents that cause brain damage following inhibition of acetylcholinesterase (AChE). Our laboratories invented substituted phenoxyalkyl pyridinium oxime AChE reactivators (US patent 9,227,937) that demonstrate the ability to cross the blood–brain barrier in in vivo rat tests with a sarin surrogate by reducing time to cessation of seizure‐like behaviors, glial fibrillary acidic protein levels, and neuropathology, compared to the FDA-approved oxime, 2‐pyridine aldoxime methyl chloride (2‐PAM). This study investigated the safety profile of novel oximes through evaluation of their cytotoxicity and genotoxicity. Cytotoxicity was evaluated in mouse areolar fibroblasts using a lactate dehydrogenase (LDH) assay and an MTS assay. All novel oximes showed no toxicity in the LDH assay from 1.25 nM to 5 mM, whereas 2-PAM did; novel oximes were significantly different from 2-PAM (P < .00001). The MTS assay demonstrated that novel oximes at 2 µM to 500 µM significantly reduced the metabolic activity of fibroblasts compared to 2-PAM (P = .00001). A modified Ames assay using 5 bacterial strains with and without S9 assessed the genotoxicity of the lead compound, Oxime 20, at concentrations from 100 µM to 10 mM. No concentration, whether with S9 or without, showed any genotoxicity. The LDH and Ames results indicated no cytotoxicity or genotoxicity was caused by the novel oximes.
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