Novel pyridinium oximes enhance 24-h survivability against a lethal dose of nerve agent surrogate in adult female rats

Abstract

Our laboratory has developed novel substituted phenoxyalkyl pyridinium oximes (US Patent 9,227,937) designed to more efficiently penetrate the central nervous system to enhance survivability and attenuate seizure-like signs and neuropathology. Previous studies with male Sprague-Dawley rats indicated that survivability was enhanced against the nerve agent (sarin) surrogate, 4-nitrophenyl isopropyl methylphosphonate (NIMP). In this study, female adult Sprague-Dawley rats, tested specifically in diestrus, were challenged subcutaneously with lethal concentrations of NIMP (0.6 mg/kg). After development of seizure-like behavior and other signs of cholinergic toxicity, human equivalent dosages of atropine (0.65 mg/kg) and one of four oximes (2-PAM, or novel oxime 15, 20, or 55; 0.146 mmol/kg) or Multisol vehicle was administered alone or in binary oxime combinations intramuscularly. Animals were closely monitored for signs of cholinergic toxicity and 24 h survivability. Percentages of animals surviving the 24 h NIMP challenge dose were 35 % for 2-PAM and 55 %, 70 %, and 25 % for novel oximes 15, 20, and 55, respectively. Improvements in survival were also observed over 2-PAM alone with binary combinations of 2-PAM and either oxime 15 or oxime 20. Additionally, administration of novel oximes decreased the duration of seizure-like behavior as compared to 2-PAM suggesting that these oximes better penetrate the blood-brain barrier to mitigate central nervous system hypercholinergic activity. Efficacies were similar between females and previously reported males. These data indicate that the novel pyridinium oximes enhance survivability against lethal OP toxicity as compared to 2-PAM in adult female rats.