Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents

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Project Summary The overall goal of this proposal is to identify novel ‘water-soluble’ neurosteroid anticonvulsants that will control benzodiazepine-resistant seizures and brain injury caused by acute organophosphate (OP) intoxication. Exposure to nerve agents or OP compounds can result in persistent seizures, status epilepticus (SE), and permanent brain injury. Benzodiazepine anticonvulsants are the primary therapy for OP-induced SE but they do not sufficiently protect the brain from SE at later time after exposure. Neurosteroids are robust anticonvulsants against SE induced by a variety of OP agents and hence they can overcome key limitations of benzodiazepines. The objective of this project is to investigate the efficacy and pilot safety of new water-soluble synthetic analogs of brexanolone (FDA-approved) as adjunct anticonvulsants to midazolam therapy for OP intoxication. Test drugs are administered as adjunctive treatment either with midazolam or after midazolam has failed to control SE. The goal is to rapidly stop seizures, reducing the further brain damage. This novel therapy is based on the molecular mechanisms of neurosteroids and cellular changes involved in refractory SE caused by OP agents. The proposed adjunct therapy is based on central hypothesis that synthetic neurosteroids that enhance phasic and extrasynaptic tonic inhibition more effectively control nerve agent-induced SE and neuronal damage than benzodiazepines alone and thereby completely mitigate morbidity. The neurosteroid brexanolone is highly effective for controlling OP-induced SE and neuronal damage in rat models, but has certain limitations for its launch as medical countermeasure. Valaxanolone and lysaxanolone are two lead hydrophilic analogs of the neurosteroid with improved biopharmaceutical and pharmacological (extrasynaptic-preferring) properties. Test drugs can be formulated as dry powder for injection for extended stability and they have promising efficacy as medical countermeasures for OP-induced SE. The key emphasis is to generate requisite data on the efficacy and safety profile of lead candidates and identify at least one lead drug for further development. The proposed goals will be implemented by addressing three specific aims: (Aim 1) To determine the adjunct efficacy of hydrophilic neurosteroid analogs against DFP-induced SE and brain damage; (Aim 2) To determine the adjunct efficacy of hydrophilic neurosteroid analogs against Soman-induced SE and brain damage; and (Aim 3) To determine the preclinical pharmacokinetics and pilot safety of lead drugs. The project will be implemented as per the progressive “go/no-go” milestones plan focusing on three primary outcome measures: (i) anticonvulsant efficacy; (ii) neuroprotectant efficacy; and (iii) prevention of neurodegeneration and behavior dysfunction. The outcome from this project will identify a novel adjunct anticonvulsant to midazolam for OP intoxication and that the “dry-power for injection” system would provide a lengthy shelf-life for stockpiling at the military and civilian centers. Thus, such neurosteroidmidazolam combination will be highly efficient investment for the biodefense program.