Document Type

Dissertation - Open Access

Award Date

2024

Degree Name

Doctor of Philosophy (PhD)

Department / School

Chemistry and Biochemistry

First Advisor

Brian Logue

Abstract

When inhaled, toxic inhalation agents (TIAs) such as cyanide (CN), ammonia and sulfur compounds (e.g. methanethiol (MeSH)) can be fatal. Many TIAs cause cellular hypoxia, cytotoxic anoxia, apnea, respiratory failure, neurodegenerative disorder, circulatory collapse, seizures, and potential death by blocking mitochondrial cytochrome c oxidase. All TIA’s have the potential to be employed as chemical warfare agents, terrorist weapons, or dangerous occupational gases. Although many TIAs are potential threats, there are minimal FDA-approved treatments for these substances useful in a mass-casualty situation. Recently, cobinamide (Cbi) has come to light as a potential antidote for MeSH poisoning. However, methods for analyzing MeSH have severe drawbacks. We developed a simple dynamic headspace (DHS) gas chromatography mass spectroscopy (GC-MS) method for the analysis of MeSH protein adducts. Limit of detection (LOD) of 4.2 mg/kg, and a dynamic range of 5.6-67.2 mg/kg. This method produced a precision and intra and inter-assay accuracy good and MeSH adduct was detected in pigs exposed to MeSH. Novel anticholinergics have been suggested as treatments for cholinergic agents (e.g., nerve agents) N-5-(Tert-Butyl)isoxazol-3-yl)-2-(4-(5-(1-methyl-1H-pyrazol-4-yl)- 1H-benzo[d]imidazole-1-yl)phenyl) acetamide (Pz-1) is a promising therapeutic candidate for recovery of aging of AChE. Despite its promise, there is no LCMS-MS method for analyzing Pz-1 in biological matrix. Therefore, a liquid chromatography tandem mass spectrometry (LC-MS/MS) method was created to analyze Pz-1 in rat plasma. The validated technique yielded a LOD of 1 nM, a dynamic range of 3-100 nM, and good inter and intraof animal models is underway. This method can be used to further develop Pz-1 as a potential countermeasure for OP poisoning. Additionally, fluorometric and LC-MS/MS approaches were created to analyze ammonia in water. The technique yielded a fast microdiffusion technique with a quantification range from 40-800 μM. The method showed excellent selectivity for determining ammonia for the LC-MS/MS method. Several river water samples showed a large response to ammonia. The methods for ammonia analysis may be developed for use in future sensor development as well as detection of ammonia in biological fluids utilizing LC-MS/MS.

Publisher

South Dakota State University

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Chemistry Commons

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Rights Statement

In Copyright