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 pACO₂. 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.