Identification of treatments for chemical threat agent seizures

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Summary: The overall objective of this project is to identify new, more effective medical countermeasures for the acute seizures produced by organophosphate (OP) anticholinesterase inhibitor and GABAA receptor antagonist chemical threat agents. By preventing or stopping the acute seizures, these countermeasures will improve the survival and long-term outcome of individuals exposed to seizure-inducing doses of these agents. We have selected two OP agents diisopropylfluorophosphate (DFP) and soman (0-pinacolyl methylphosphonofluoridate; GD) and one GABAA receptor antagonist tetramethylenedisulfotetramine (TETS) to represent the two broad classes of chemical threat agents. Soman, a representative of the OP neurotoxin chemical warfare agents ("nerve agents"), is classified as a Schedule 1 substance under the Chemical Weapons Convention of 1993. DFP, while less potent than the nerve agents in the Chemical Weapons Convention toxic chemicals list, has nearly identical effects. As a volatile agent that could rapidly spread inside closed areas, it could cause many injuries and deaths and is therefore a credible threat agent. TETS, a representative of the GABAA receptor antagonist convulsants is a highly lethal toxin that has been used as a rodenticide but is now banned in most countries of the world. Nevertheless, lethal poisoning with TETS occur regularly. On a mg basis, TETS is equal in lethality to the OP chemical warfare agents. Recently, we have had the opportunity to characterize the convulsant activity of TETS in mice and rats when administered by the i.p., i.v., oral and intracerebroventricular routes. As a result of this work, we have developed the first animal model in which to evaluate potential treatments for TETS when administered before and after exposure. In this project, DFP and soman are administered to rats and TETS is administered to mice to induce seizures. The animals are treated before or at various intervals following exposure with various potential therapeutic agents (or combinations) to assess the ability of the test agent to prevent or terminate behavioral or electrographic seizure activity. Testing in the OP models occurs in a step-wise fashion, first against DFP seizures because DFP has reduced safety concerns and can be used in a regular laboratory environment, and then with soman, which requires extreme safety precautions available at the US Army Medical Research Institute of Chemical Defense. All test agents are compared with diazepam, the current standard of care for the emergency treatment of chemical exposure seizures. Diazepam may be effective if administered early in the course of seizures but seizures may recur and the drug may be inactive if administered later in the course of seizures. In addition, diazepam can depress blood pressure and respiration. A further concern is that diazepam is erratically absorbed when administered by the i.m. route (as with the injector systems stockpiled for use in mass casualty situations). We are seeking agents (or combinations) that improve upon diazepam with respect to any of these liabilities. We have identified a series of potential therapies (Tier 1) that are either currently approved for sale in the U.S. or for which human data is available and can therefore be rapidly deployed. In addition, novel potential therapies that are new molecular entities (Tier 2) will be developed in Core B and Project 3. Therapies that exhibit superior activity to diazepam will be studied in Project 2 for their ability to mitigate seizure-induced brain damage. Finally, in order to advance the most promising therapies, we will complete various additional studies, including formulation development and safety, toxicology and ADME studies in conjunction with Cores A and B, to assist in making go/no-go decisions regarding further development.