Chlorine gas is a toxic gas as a weapon of choice in chemical warfare, most recently in Syria, killing numerous persons and injuring thousands of others. Current treatment of survivors after acute chlorine exposure consists of supportive therapy aimed at improving pulmonary sequelae, including bronchoconstriction, hypoxemia and pulmonary edema. Unfortunately, no medical countermeasure (MCM) exists to improve survival after high dose chlorine exposure. Therefore, any therapy that would greatly improve survival after high dose exposure would be a major advancement. High dose chlorine inhalation can be quickly fatal, mortality occurring within 4 hours of exposure. The mechanisms of injury causing mortality after chlorine exposure are poorly understood and rarely studied. In our rat model of high dose chlorine exposure, preliminary studies (generated via an R21 mechanism) show severe multi-systemic effects that surpass the respiratory tract, including cardiovascular dysfunction, neuromuscular dysfunction, and evidence of significant neurotoxicity (abnormal epileptiform discharges on EEG, histopathological hippocampus toxicity). We also found decreased cholinesterase enzyme activity after exposure, with associated signs of muscarinic hyperstimulation akin to pesticide toxicity (bronchial secretions, rhinorrhea, bronchoconstriction, dyspnea, bradycardia, tremors, and convulsions). Thus, high dose chlorine exposure appears to cause a pattern of multi-systemic injury similar to pesticide toxicity, such as that seen after organochlorine exposures. Therapeutics used as rescue in pesticide toxicity include anticholinergics, such as atropine and scopolamine, and anticonvulsants such as midazolam, all of which are already FDA-approved in humans for other indications. Preliminary studies from our lab have shown that treatment of rats with atropine (IM), scopolamine (IM, IN) and/or midazolam (IM) greatly improve survival and other morbidity measures after high dose chlorine exposure. Herein, we propose to clearly define the acute and late neurotoxicity effects of high dose chlorine exposure. In addition, we propose to conduct extensive early development studies in a rat model of high dose chlorine inhalation, to test the efficacy of MCM candidates atropine (IM), scopolamine (IM, IN) and/or midazolam (IM), alone and in combination, to improve survival and decrease serious morbidity after high dose chlorine inhalation. The ultimate goal of these studies is to advance candidate drug(s) for FDA approval via the Animal Rule for this indication, through securing BARDA support. We have a proven track record for advancing candidate MCM to BARDA for chemical exposure indications (current BARDA-funded contract: ?Alteplase for rescue against sulfur mustard inhalation? ? PI:Veress). Provisional patents for all proposed MCM within this proposal have been filed by the PI (Veress) and the University of Colorado. Pfizer/ Meridian Medical Technologies, Inc., and Defender Pharmaceuticals, Inc., are engaged for sponsorship of these studies and the proposed development pathway. This proposal will develop practical drugs for field rescue after high dose chlorine inhalation.
Current treatment plan for chlorine gas inhalation injury is supportive therapy measures, and to date, no rescue therapy exists to prevent death from chlorine exposure. New evidence suggests potential toxicity of chlorine to the nervous system, similar to certain nerve agent poisons, contributing to death after high dose exposure. In this project, we will study two anticholinergic drugs, atropine and scopolamine, as well as a benzodiazepine drug, midazolam, alone and in combination, as rescue therapies against high dose chlorine, with efficacy gauged as their abilities to improve survival and decrease morbidity in the acute setting.
