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Methods for assessing cytochrome c oxidase inhibitors and potential antidotes

Frawley, Kristin (2019) Methods for assessing cytochrome c oxidase inhibitors and potential antidotes. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The Countermeasures Against Chemical Terrorism (CounterACT) Program, sponsored by the U.S. Department of Homeland Security, seeks to promote and support research aimed at finding new (therapeutics) pharmaceuticals that are antidotal toward toxicants considered likely to pose significant terrorist threat. More specifically, this means countermeasures to toxicants that can be easily prepared from readily available precursors in quantities suitable for inflicting mass casualties on civilian and/or military targets. The challenge to Public Health issued by the CounterACT program is to identify and develop antidotes to any such toxicants deemed to be of particular concern, including the mitochondrial poisons sulfide, cyanide and azide. Ideally, in addition to efficacy, the antidotes should be stable enough for stockpiling and safe enough for self-administration. Herein, various biological systems mimicking some relevant aspects of acute poisonings in humans have been tested for their usefulness as experimental “models” suitable for examining toxic mechanisms and assessing the efficacies of putative antidotes. Larvae of the greater wax moth (Galleria mellonella) are shown to be a convenient and inexpensive invertebrate model for investigating the action of some mitochondrial poisons and their antidotes. The acute toxicities of sulfide, cyanide and azide have been studied together with the ameliorating effects of sodium nitrite and a cobalt-based scavenging agent. The results obtained with the larvae are compared to findings employing a cultured mammalian cell line (bovine pulmonary artery endothelial cells) and rodents (Swiss-Webster mice). The Galleria mellonella larvae are argued to be an extremely useful intact organism for (i) pre-screening putative antidotes for efficacy and (ii) circumventing any confounding effects that can arise in some studies of intracellular processes due to the presence of blood in intact vertebrates.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Frawley, Kristinkrf34@pitt.edu
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairPeterson, Jimjimmyp@pitt.edu
Committee CoChairBarchowsky, Aaronaab20@pitt.edu
Committee MemberPearce, Lindalip10@pitt.edu
Committee MemberHaight, Joeljhaight@pitt.edu
Date: 26 September 2019
Date Type: Publication
Defense Date: 6 August 2019
Approval Date: 26 September 2019
Submission Date: 23 July 2019
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 209
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Environmental and Occupational Health
Degree: DrPH - Doctor of Public Health
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: G. mellonella, wax worms, sulfide, cyanide, azide, bovine pulmonary artery endothelial cells, BPAEC,
Date Deposited: 26 Sep 2019 16:38
Last Modified: 26 Sep 2019 16:38
URI: http://d-scholarship.pitt.edu/id/eprint/37168

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