# Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents

> **NIH NIH U01** · TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR · 2020 · $454,500

## Abstract

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 woul...

## Key facts

- **NIH application ID:** 10013749
- **Project number:** 1U01NS117278-01
- **Recipient organization:** TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
- **Principal Investigator:** Doodipala Samba Reddy
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $454,500
- **Award type:** 1
- **Project period:** 2020-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013749

## Citation

> US National Institutes of Health, RePORTER application 10013749, Novel Water-Soluble Adjunct Anticonvulsants for Nerve Agents (1U01NS117278-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10013749. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*