# Anticholinergic and antiepileptic Therapies for Chlorine Toxicity

> **NIH NIH U01** · UNIVERSITY OF COLORADO DENVER · 2020 · $441,024

## Abstract

Chlorine gas is a toxic gas as a weapon of choice in chemical warfare, most recently in Syria, killing numerous
persons and injuring thousands of others. Current treatment of survivors after acute chlorine exposure consists
of supportive therapy aimed at improving pulmonary sequelae, including bronchoconstriction, hypoxemia and
pulmonary edema. Unfortunately, no medical countermeasure (MCM) exists to improve survival after high dose
chlorine exposure. Therefore, any therapy that would greatly improve survival after high dose exposure
would be a major advancement. High dose chlorine inhalation can be quickly fatal, mortality occurring within 4
hours of exposure. The mechanisms of injury causing mortality after chlorine exposure are poorly understood
and rarely studied. In our rat model of high dose chlorine exposure, preliminary studies (generated via an R21
mechanism) show severe multi-systemic effects that surpass the respiratory tract, including cardiovascular
dysfunction, neuromuscular dysfunction, and evidence of significant neurotoxicity (abnormal epileptiform
discharges on EEG, histopathological hippocampus toxicity). We also found decreased cholinesterase enzyme
activity after exposure, with associated signs of muscarinic hyperstimulation akin to pesticide toxicity (bronchial
secretions, rhinorrhea, bronchoconstriction, dyspnea, bradycardia, tremors, and convulsions). Thus, high dose
chlorine exposure appears to cause a pattern of multi-systemic injury similar to pesticide toxicity, such
as that seen after organochlorine exposures. Therapeutics used as rescue in pesticide toxicity include
anticholinergics, such as atropine and scopolamine, and anticonvulsants such as midazolam, all of which are
already FDA-approved in humans for other indications. Preliminary studies from our lab have shown that
treatment of rats with atropine (IM), scopolamine (IM, IN) and/or midazolam (IM) greatly improve survival and other
morbidity measures after high dose chlorine exposure. Herein, we propose to clearly define the acute and late
neurotoxicity effects of high dose chlorine exposure. In addition, we propose to conduct extensive early
development studies in a rat model of high dose chlorine inhalation, to test the efficacy of MCM
candidates atropine (IM), scopolamine (IM, IN) and/or midazolam (IM), alone and in combination, to
improve survival and decrease serious morbidity after high dose chlorine inhalation. The ultimate goal of
these studies is to advance candidate drug(s) for FDA approval via the Animal Rule for this indication, through
securing BARDA support. We have a proven track record for advancing candidate MCM to BARDA for chemical
exposure indications (current BARDA-funded contract: “Alteplase for rescue against sulfur mustard inhalation” –
PI:Veress). Provisional patents for all proposed MCM within this proposal have been filed by the PI (Veress) and
the University of Colorado. Pfizer/ Meridian Medical Technologies, Inc., and Defender Pharma...

## Key facts

- **NIH application ID:** 9989663
- **Project number:** 5U01NS102101-03
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Livia Agnes Veress
- **Activity code:** U01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $441,024
- **Award type:** 5
- **Project period:** 2018-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989663

## Citation

> US National Institutes of Health, RePORTER application 9989663, Anticholinergic and antiepileptic Therapies for Chlorine Toxicity (5U01NS102101-03). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/9989663. Licensed CC0.

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