?Development of antidotes for toxic gases? The goal of this Program is to create a systematic process for developing antidotes against toxic gaseous chemicals by capitalizing on the proven track record of a team of physician-scientists backed by accomplished basic scientists. We will examine two acute pulmonary and cardiopulmonary toxidromes caused by the gaseous chemicals sharing common injury mechanisms: 1) alkylating agents, sulfur mustard (SM) and methyl isocyanate (MIC), that cause DNA crosslinking/damage, apoptosis, airway epithelial and endothelial injury, acute lung injury, and fibrosis, and 2) rapidly absorbed gases, methylmercaptan (CH3SH) and cyanide (HCN), that cause systemic mitochondrial failure. These toxic chemicals were chosen based on: 1) capacity to cause critical illness and death, 2) perceived threat(s), 3) recent and/or important past exposures, and 4) priorities of the NIH/CounterACT, BARDA, DoD, and international community. Therapies being advanced in Projects 1, 3, and 4 are intended as rescue countermeasures for mass casualty scenarios. Two of these (Projects 1 and 3) are intended to be for acute inhalation accidents or disasters. In Project 1, for MIC, three classes of therapies directed at receptor-mediated (TRP channel antagonist(s)), coagulation-related (plasminogen activator(s)), and biochemical (thiol compounds) events will be investigated in a new preclinical acute inhalation model. Therapies would be for immediate/delayed treatment, with intramuscular, airway, and enteral and/or intravenous delivery for TRP channel antagonists, plasminogen activators, and thiol compounds, respectively. In Project 2, the anti-fibrotic drugs pirfenidone and nintedanib will be evaluated via oral/airway delivery in a fibrotic chronic lung disease model in rats following sublethal SM exposure. In Project 3, the vitamin B12 analog cobinamide and sodium thiosulfate, both of which react directly with methyl mercaptan, will be tested as countermeasures against this acutely toxic gas in mice, rabbits, and pig models. In Project 4, a nanoparticle- associated cobinamide (Cbn) will be evaluated as acute rescue countermeasure for oral NaCN intoxication in rabbit and pig models. Because oral NaCN is absorbed as a gas (HCN) at the gastric mucosa, and since victims often will not be conscious, gastric lavage delivery will be used.
The Specific Aims are: 1) Determine potential of TRP channel antagonists, plasminogen activators, and thiols to decrease airway injury and lethality after MIC inhalation; 2) Define the efficacy of pirfenidone and other anti-fibrotic drugs against airway and parenchymal lung fibrosis after SM inhalation; 3) Establish efficacy of Cbn and thiosulfate for rescuing animals from lethal methylmercaptan exposures and 4) test the potential efficacy of nonabsorbable nano preparations of Cbn versus other Cbn preparations and routes in an oral NaCN poisoning and lethality model. Successful therapies from each project will be ready for advanced development and attain pre-IND status at or before the end of the cycle.

Public Health Relevance

- Composite Effective therapies for exposure to toxic gases are urgently needed, particularly for those agents on the priority list of NIH/CounterACT. This program will develop antidotes to treat exposure to toxic gases by capitalizing on the proven track record of a team of physician-scientists backed by accomplished basic scientists.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54ES027698-02
Application #
9357594
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Nadadur, Srikanth
Project Start
2016-09-30
Project End
2021-08-31
Budget Start
2017-09-01
Budget End
2018-08-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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Summerhill, Eleanor M; Hoyle, Gary W; Jordt, Sven-Eric et al. (2017) An Official American Thoracic Society Workshop Report: Chemical Inhalational Disasters. Biology of Lung Injury, Development of Novel Therapeutics, and Medical Preparedness. Ann Am Thorac Soc 14:1060-1072
McGraw, Matthew D; Rioux, Jaqueline S; Garlick, Rhonda B et al. (2017) From the Cover: ImpairedProliferation and Differentiation of the Conducting Airway Epithelium Associated With Bronchiolitis Obliterans After Sulfur Mustard Inhalation Injury in Rats. Toxicol Sci 157:399-409
McElroy, Cameron S; Min, Elysia; Huang, Jie et al. (2016) From the Cover: Catalytic Antioxidant Rescue of Inhaled Sulfur Mustard Toxicity. Toxicol Sci 154:341-353