Mesna Improves Outcomes of Sulfur Mustard Inhalation Toxicity in an Acute Rat Model.

Autor:	Nick HJ; 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.) nickh@njhealth.org., Johnson CA; 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.)., Stewart AR; 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.)., Christeson SE; 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.)., Bloomquist LA; 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.)., Appel AS; 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.)., Donkor AB; 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.)., Veress LA; 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.)., Logue BA; 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.)., Bratcher PE; 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.)., White CW; 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.).
Jazyk:	angličtina
Zdroj:	The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2024 Jan 17; Vol. 388 (2), pp. 576-585. Date of Electronic Publication: 2024 Jan 17.
DOI:	10.1124/jpet.123.001683
Abstrakt:	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 2 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. (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)
Databáze:	MEDLINE
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