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Citation |
Nick HJ, Johnson CA, Stewart AR, Christeson SE, Bloomquist LA, Appel AS, Donkor AB, Veress LA, Logue BA, Bratcher PE, White CW. J. Pharmacol. Exp. Ther. 2023; ePub(ePub): ePub. |
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Copyright |
(Copyright © 2023, American Society for Pharmacology and Experimental Therapeutics) |
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DOI |
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PMID |
37541763 |
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Abstract |
Inhalation of high levels of sulfur mustard (SM), a potent vesicating and alkylating agent used in chemical warfare, results in acutely lethal pulmonary damage. Sodium 2-mercaptoethane sulfonate (mesna) is an organosulfur compound that is currently FDA-approved for decreasing the toxicity of mustard-derived chemotherapeutic alkylating agents like ifosfamide and cyclophosphamide. The nucleophilic thiol of mesna is a suitable reactant for the neutralization of the electrophilic group of toxic mustard intermediates. In a rat model of SM inhalation, treatment with mesna (3 doses: 300 mg/kg intraperitoneally 20 min, 4 h, and 8 h post-exposure) afforded 74% survival at 48 h, compared to 0% survival at less than 17 h in the untreated and vehicle-treated control groups. Protection from cardiopulmonary failure by mesna was demonstrated by improved peripheral oxygen saturation and increased heart rate through 48 h. Additionally, mesna normalized arterial pH and pACO(2) Airway fibrin cast formation was decreased by more than 66% in the mesna-treated group at 9 h after exposure compared to the vehicle group. Finally, analysis of mixtures of a mustard agent and mesna by a DTNB assay and HPLC-MS/MS demonstrate a direct reaction between the compounds. This study provides evidence that mesna is an efficacious, inexpensive, FDA-approved candidate antidote for SM exposure. Significance Statement Despite the use of SM as a chemical weapon for over 100 years, an ideal drug candidate for treatment after real-world exposure situations has not yet been identified. Utilizing a uniformly lethal animal model, the results of the present study demonstrate that mesna is a promising candidate for repurposing as an antidote, decreasing airways obstruction and improving pulmonary gas exchange, tissue oxygen delivery and survival following high level SM inhalation exposure, and warrants further consideration. Language: en |
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Keywords |
drug discovery; respiratory toxicants |