The goal of this project is to demonstrate that lead CounterAct compounds atenolol (AT) and levetiracetam (LV) given after organophosphate (OP) pesticide and nerve agent induced status epilepticus (SE) are a safe and effective treatment to reduce OP SE mortality and morbidity, including behavioral abnormalities, cognitive impairment, acquired epilepsy (AE) and mossy fiber sprouting. SE is a major medical emergency seen with exposure to OPs from chemical threats from terrorist attacks or from exposure by accident or natural disasters. Advances have been made to treat the seizures associated with SE and the cholinergic crisis from OP exposure, but at present there are no therapies available to prevent mortality and the long term morbidities associated with OP SE. Our research has made a major advance in understanding how OP SE causes mortality. Our PR indicate that cardiac irritability in the first 7 days after OP SE is the major cause of mortality and this can be reduced by treatment with AT and LV. We made a breakthrough in our preliminary results (PR) indicating that AT plus LV may reduce mortality by greater than 70% and also significantly reduce morbidity by greater than 50%, including behavioral abnormalities, cognitive impairments and the development of AE. This PR also suggests that AT and LV can reduce cardiac irritability and cardiac and neuronal damage after OP SE. This study will use the OP pesticide paraoxon (POX), the OP nerve agent surrogate diisopropyl- fluorophosphate (DFP) and the nerve agent sarin to induce SE in rats. Our laboratory is ideally suited to conduct these studies and has developed the necessary skills to carry out the following specific aims:
Aim 1 : Determine whether AT and LV can reduce mortality following POX induced SE and conduct pharmacokinetic and pharmacodynamic analyses for CounterACT lead compounds AT and LV when administered intra- muscularly and orally.
Aim 2 : Determine whether AT and LV can reduce mortality following DFP and sarin induced SE and evaluate the acute and chronic effects of intramuscular injections on injection site musculature.
Aim 3 : Evaluate whether AT and LV can reduce cardiac irritability and cardiac pathological changes following POX, DFP and sarin SE.
Aim 4 : Determine whether AT plus LV can reduce the development of depression-like symptoms and provide neuroprotection following POX, DFP and sarin SE.
Aim 5. Evaluate whether AT plus LV can reduce the development of cognitive impairment, the development of AE and mossy fiber sprouting following POX, DFP and sarin SE. The PR demonstrate the feasibility of these studies and underscore the potential significance of conducting this research. AT and LV have been used for many years clinically to treat hypertension and seizures, respectively, and thus their use in humans has been well established. If these preliminary findings are documented in this study, we will conduct a pre-IND meeting with the FDA for ultimately getting an IND for the use of AT and LV by intramuscular administration as an effective treatment for reducing mortality and morbidity from OP SE.
Organophosphate (OP) Status Epilepticus (SE) is a major complication of OP pesticide and nerve agent toxicity and is associated with mortalities exceeding 20-30% and with chronic morbidities. Our PR indicate that we have identified lead CounterAct compounds that are effective in reducing mortality and the debilitating chronic morbidities associated with survival of OP SE. The ultimate goal of this research project is to generate the necessary research to be able to conduct a pre IND meeting with the FDA by the end of the grant and ultimately develop a successful IND application for the use of these lead compounds as CounterAct agents to treat OP SE.
