SBIR-STTR Award

The overall objective of this proposal is to demonstrated that imidazenil is a more potent and safer protective agent than diazepam against chemical warfare nerve agent (CWNA)-induced seizure/status epilepticus, neuropathology, and neurobehavioral deficits. Thus we will compare the dose-dependent efficacy of imidazenil or diazepam administered alone and in combination with levetiracetam in protecting rats against diisopropyl fluorophosphate (DFP)-induced toxicity using the following 2 aims. Aim I: To evaluate the dose-dependent efficacies of imidazenil or diazepam administered alone or in combination with levetiracetam in the absence or presence of atropine and/or pralidoxime chloride (2-PAM) against DFP-induced seizure/status epilepticus and neurobehavioral deficits. This will be achieved by telemetric monitoring of cortical electroencephalogram (EEG), core temperature and motor activity. Aim II: To evaluate the effects of imidazenil or diazepam administered alone or in combination with levetiracetam in the absence or presence of atropine and/or 2-PAM on DFP-induced neuropathology. Rat brains will be examined for neuronal degeneration using the deoxyribonucleic acid (DNA) fragmentation measurement and light microscopy histological analysis. These studies may provide new information regarding the potential role of imidazenil in the treatment or prevention of CWNA poisoning and the potential role of the combination of levetiracetam and imidazenil in minimizing CWNA-induced neuropathology

The overall objective of this Phase II proposal is to determine the advantages of imidazenil over diazepam or midazolam as a potential anticonvulsant agent for the prophylaxis and for the emergency treatment of organophosphate nerve agent exposure. Therefore, we will compare the dose-dependent efficacy and anticonvulsant tolerance liability of imidazenil or midazolam for protecting rats against diisopropyl fluorophosphates (DFP)-induced status epilepticus (SE) and on neuropathology using the following specific aims: Aim 1: Compare the dose-dependent efficacies of imidazenil, diazepam or midazolam administered alone or in combination with HI-6 and atropine against DFP-induced seizures or SE. Efficacy against DFP-induced SE will be evaluated by telemetric monitoring of cortical electroencephalogram (EEG), electromyogram (EMG), core body temperature and activity. Aim 2: Evaluate the dose-dependent protection elicited by imidazenil, diazepam or midazolam in combination with HI-6 and atropine on DFP-induced neuropathology. We will evaluate rat brains for neuronal degeneration using the deoxyribonucleic acid (DNA) fragmentation measurement and light microscopic histological examination. Aim 3: Compare the tolerance liability of imidazenil, diazepam or midazolam in the presence of HI-6 and atropine against DFP-induced seizures and neuropathology following a 14 day protracted treatment with increasing doses of these benzodiazepine recognition site agonists. After termination of protracted treatment, anticonvulsant efficacy will be evaluated with telemetric monitoring as described in aim 1 above. We hope that the results of these studies together with the widely published information regarding the favorable pharmacological profile of imidazenil (appendix 1), available preliminary data on the acute and chronic toxicity, and mutagenic effects of imidazenil (for details see appendix 2) will provide the rationale for future Phase III studies.

Keywords:
Imidazenil, Diazepam, Midazolam , Hi-6, Atropine, Status Epilepticus, Neuropathology, Organophosphate Nerve Agents.