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i
DEVELOPMENT OF IVERMECTIN AS A PLATFORM FOR THE TREATMENT
AND/OR PREVENTION OF ALCOHOL USE DISORDERS
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the Requirements for the Degree
DOCTOR OF PHILOSOPHY
(MOLECULAR PHARMACOLOGY & TOXICOLOGY)
July 2014
Copyright 2014 Megan M. Yardley
Object Description
| Title | Development of ivermectin as a platform for the treatment and/or prevention of alcohol use disorders |
| Author | Yardley, Megan M. |
| Author email | yardley@usc.edu;mmyardley@gmail.com |
| Degree | Doctor of Philosophy |
| Document type | Dissertation |
| Degree program | Molecular Pharmacology and Toxicology |
| School | School of Pharmacy |
| Date defended/completed | 2014-05-19 |
| Date submitted | 2014-07-18 |
| Date approved | 2014-07-18 |
| Restricted until | 2016-01-18 |
| Date published | 2016-01-18 |
| Advisor (committee chair) |
Cadenas, Enrique Davies, Daryl L. |
| Advisor (committee member) |
Richmond, Frances J. Neely, Michael J. |
| Abstract | Alcohol use disorders (AUDs) affect over 18 million people in the United States alone, cost over $235 billion, and yet only 8% of this population receives treatment and even less use a medication approved by the U.S. Food and Drug Administration (FDA) as part of that treatment. Despite considerable efforts focusing on new drug development to reduce ethanol abuse, high rates of harmful drinking persist. This is, in part, due to the fact that current therapeutic strategies are largely inadequate to treat these disorders. Thus, developing novel therapeutics for the treatment of AUDs is of paramount importance. The working hypothesis of our laboratory is that ivermectin (IVM) can be repurposed as a therapeutic agent for the treatment of AUDs. As IVM is currently FDA‐approved and used by millions of humans each year for other indications, the repurposing of IVM for the treatment of AUDs represents a fast and economically feasible approach for drug development. Initial support suggesting that IVM can be developed as a novel drug candidate for the treatment of AUDs comes from previous work demonstrating that IVM is able to antagonize the effect of ethanol in vitro on P2X4 receptors (PRX4Rs). Studies included in this dissertation test the hypothesis that IVM can be repurposed as a therapeutic agent for the treatment of AUDs using multiple preclinical mouse models of ethanol intake and behavior. Chapter 2 describes initial efficacy studies using 3 distinct models of ethanol intake and explores the pharmacokinetics (PK) of IVM. Chapter 3 characterizes the intrinsic properties of IVM using a battery of behavioral paradigms to test for effects such as depression, anxiety, locomotion, memory, and rewarding properties. Chapter 4 evaluates the sustainability and safety of multi‐day IVM administration. Finally, Chapter 5 focuses on the use of IVM as a platform for developing novel therapeutics for AUDs by testing two related avermectins, selamectin (SEL) and abamectin (ABM). Findings from my work support the hypothesis that IVM is able to reduce ethanol intake using multiple murine models of ethanol intake without causing overt toxicity. Overall, the studies presented within this dissertation set the stage for first-in-human testing of IVM for this new indication. |
| Keyword | medications development; alcoholism therapy; drug repositioning |
| Language | English |
| Format (imt) | application/pdf |
| Part of collection | University of Southern California dissertations and theses |
| Publisher (of the original version) | University of Southern California |
| Place of publication (of the original version) | Los Angeles, California |
| Publisher (of the digital version) | University of Southern California. Libraries |
| Provenance | Electronically uploaded by the author |
| Type | texts |
| Legacy record ID | usctheses-m |
| Contributing entity | University of Southern California |
| Rights | Yardley, Megan M. |
| Physical access | The author retains rights to his/her dissertation, thesis or other graduate work according to U.S. copyright law. Electronic access is being provided by the USC Libraries in agreement with the author, as the original true and official version of the work, but does not grant the reader permission to use the work if the desired use is covered by copyright. It is the author, as rights holder, who must provide use permission if such use is covered by copyright. The original signature page accompanying the original submission of the work to the USC Libraries is retained by the USC Libraries and a copy of it may be obtained by authorized requesters contacting the repository e-mail address given. |
| Repository name | University of Southern California Digital Library |
| Repository address | USC Digital Library, University of Southern California, University Park Campus MC 7002, 106 University Village, Los Angeles, California 90089-7002, USA |
| Repository email | cisadmin@lib.usc.edu |
| Filename | etd-YardleyMeg-2720.pdf |
| Archival file | uscthesesreloadpub_Volume14/etd-YardleyMeg-2720.pdf |
Description
| Title | Page 1 |
| Repository email | cisadmin@lib.usc.edu |
| Full text | i DEVELOPMENT OF IVERMECTIN AS A PLATFORM FOR THE TREATMENT AND/OR PREVENTION OF ALCOHOL USE DISORDERS A Dissertation Presented to the FACULTY OF THE USC GRADUATE SCHOOL UNIVERSITY OF SOUTHERN CALIFORNIA In Partial Fulfillment of the Requirements for the Degree DOCTOR OF PHILOSOPHY (MOLECULAR PHARMACOLOGY & TOXICOLOGY) July 2014 Copyright 2014 Megan M. Yardley |
