Department of Pediatrics, National Jewish Health, Denver, Colorado (H.J.N., S.E.C., P.E.B.); Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado (H.J.N., C.A.J., A.R.S., S.E.C., L.A.B., L.A.V., P.E.B., C.W.W.); and Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota (A.S.A., A.B.D., B.A.L.)
Department of Pediatrics, National Jewish Health, Denver, Colorado (H.J.N., S.E.C., P.E.B.); Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado (H.J.N., C.A.J., A.R.S., S.E.C., L.A.B., L.A.V., P.E.B., C.W.W.); and Department of Chemistry and Biochemistry, South Dakota State University, Brookings, South Dakota (A.S.A., A.B.D., B.A.L.).
J Pharmacol Exp Ther. 2024 Jan 17;388(2):576-585. doi: 10.1124/jpet.123.001683.
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 Food and Drug Administration (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 (three doses: 300 mg/kg intraperitoneally 20 minutes, 4 hours, and 8 hours postexposure) afforded 74% survival at 48 hours, compared with 0% survival at less than 17 hours 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 hours. Additionally, mesna normalized arterial pH and pACO Airway fibrin cast formation was decreased by more than 66% in the mesna-treated group at 9 hour after exposure compared with the vehicle group. Finally, analysis of mixtures of a mustard agent and mesna by a 5,5'-dithiobis(2-nitrobenzoic acid) assay and high performance liquid chromatography tandem mass spectrometry 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 sulfur mustard (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 sodium 2-mercaptoethane sulfonate is a promising candidate for repurposing as an antidote, decreasing airway obstruction and improving pulmonary gas exchange, tissue oxygen delivery, and survival following high level SM inhalation exposure, and warrants further consideration.
吸入高浓度的芥子气（SM），一种在化学战中使用的强效糜烂性和烷化剂，会导致急性致命性肺损伤。巯基乙磺酸单钠盐（mesna）是一种有机硫化合物，目前已获得美国食品和药物管理局（FDA）批准，用于降低芥子气衍生的化疗烷化剂（如异环磷酰胺和环磷酰胺）的毒性。Mesna 的亲核硫醇是中和有毒芥子气中间体的亲电基团的合适反应物。在 SM 吸入的大鼠模型中，mesna（三种剂量：腹腔内 300mg/kg，暴露后 20 分钟、4 小时和 8 小时）治疗组在 48 小时时提供了 74%的存活率，而未治疗和载体治疗对照组的存活率不到 17 小时。Mesna 通过改善外周血氧饱和度和增加心率至 48 小时，证明了对心肺衰竭的保护作用。此外，Mesna 使动脉 pH 和 pACO2 正常化。与载体组相比，暴露后 9 小时时，Mesna 治疗组气道纤维蛋白塞形成减少了 66%以上。最后，通过 5,5'-二硫代双（2-硝基苯甲酸）测定法和高效液相色谱串联质谱分析芥子气和 Mesna 的混合物表明，这两种化合物之间存在直接反应。这项研究提供了证据表明，Mesna 是一种有效、廉价、已获得 FDA 批准的 SM 暴露治疗候选药物。
尽管芥子气（SM）作为一种化学武器已经使用了 100 多年，但在实际暴露情况下，仍未确定理想的治疗药物候选物。利用统一的致死性动物模型，本研究的结果表明，巯基乙磺酸单钠盐是一种有前途的重新利用候选药物，可减少气道阻塞，改善肺气体交换，组织氧输送，并提高吸入高浓度 SM 后的存活率，值得进一步考虑。
