Pharmacy and Pharmaceutical Sciences Commons^™

A Mechanical Study Of Cancer Drug-Receptor Interactions, Specifically In G-Quadruplex Dna And Topoisomerase I Enzymes, Kelly Ann Mulholland

Theses and Dissertations

Computational methods are becoming essential in drug discovery as they provide information that traditional drug development methods lack. Using these methods to understand drug-receptor interactions in detail, researchers are able to efficiently design promising drug candidates. In this study, extra precision Glide docking, molecular dynamics simulations and MMGBSA binding energy calculations provided information about the binding behavior of small molecules to two specific targets for current cancer therapeutics: G-quadruplex DNA and Topoisomerase I enzyme. The first study focuses on the compound Telomestatin, which induces apoptosis of various cancer cells with a relatively low effect on somatic cells due to its …

Implementing Prophylactic Amiodarone In Heart Surgery To Reduce Post -Operative Atrial Fibrillation, John M. Russell Msn, Apn, Fnp-Bc, Denise Wilson Phd, Apn, Fnp, Cde

Theses and Dissertations

Purpose: The purpose of this project is to evaluate a practice change of implementing peri-operative amiodarone infusion for cardiac surgical patients at a large northern Illinois hospital to reduce the incidence of post-operative atrial fibrillation. Evidence supports use of prophylactic amiodarone as a strategy to reduce its incidence. The sequelae of untreated post-op atrial fibrillation include increased risk of embolic stroke, extended hospitalization, and increased healthcare costs.

Data Sources: The Society of Thoracic Surgeons (STS) Adult Cardiac Surgical Database is a validated research tool used to collect comprehensive data on its member surgeons. A pre/post intervention case-controlled retrospective study design …

Chlor-Amidine, A Novel Pad Inhibitor, As An Effective Drug For The Treatment Of Ulcerative Colitis And Prevention Of Colorectal Cancer, Erin Witalison

Theses and Dissertations

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that affects the quality of life of millions of patients worldwide. This disease is associated with inflammation and ulceration of the colonic epithelium, leading to an increased risk for the development of UC-associated colorectal cancer (CRC). Current UC medications are designed to manage the symptoms and induce remission; however, several challenges are faced with current treatment options. 5-aminosalicyclic acid and corticosteroids have few side effects, but have limited efficacy and often the disease becomes refractory. Biologics are introduced after initial treatments fail, but serious side effects are often associated with these …

The Effect Of Depression And Antidepressants On Cost, Survival And Adherence To Hormone Therapy In Breast Cancer, Virginia Noxon

Theses and Dissertations

Introduction: Breast cancer patients with a depression diagnosis before or after cancer diagnosis have increased cost, shorter survival time and reduced adherence to hormone therapy. Treating depression in these patients should improve these outcomes; however, there is scarce literature on this topic. Currently, no study has determined the association of concurrent depression while adjusting for a history of depression or treating depression with antidepressants with cost, survival and adherence to hormone therapy. This study has two objectives: 1) to determine the association of concurrent depression with cost, survival and adherence to hormone therapy adjusting for a history of depression 2) …

Using Semiphysiologically-Based Pharmacokinetic (Semi-Pbpk) Modeling To Explore The Impact Of Differences Between The Intravenous (Iv) And Oral (Po) Route Of Administration On The Magnitude And Time Course Of Cyp3a-Mediated Metabolic Drug-Drug Interactions (Ddi) Using Midazolam (Mdz) As Prototypical Substrate And Fluconazole (Flz) And Erythromycin (Ery) As Prototypical Inhibitors, Mengyao Li

Theses and Dissertations

The purpose of the project was to investigate the impact of IV and PO routes difference for MDZ, a prototypical CYP3A substrate, and two CYP3A inhibitors (CYP3AI) -FLZ and ERY-, on the magnitude and time course of their inhibitory metabolic DDI.

Individual semi-PBPK models for MDZ, FLZ and ERY were developed and validated separately, using pharmacokinetic (PK) parameters from clinical/in-vitro studies and published physiological parameters. Subsequently, DDI sub-models between MDZ and CYP3AIs incorporated non-competitive and mechanism-based inhibition (MBI) for FLZ and ERY, respectively, on hepatic and gut wall (GW) CYP3A metabolism of MDZ, using available in-vitro/in-vivo information. Model-simulated MDZ …

The Effects Of Amixicile, A Pyruvate Ferredoxin Oxidoreductase Inhibitor, On Oral Treponemes, Lucas A. Reed

Theses and Dissertations

Periodontal disease (PD) is a polymicrobial infection characterized by inflammation of the gingiva, alveolar bone resorption, and tooth loss (edentulism). Treponema denticola along with Porphyromonas gingivalis and Tannerella forsythia are among the “Red Complex” and are main etiological agents in PD. Treponemes are a member of the Spirochaeta phylum and are obligate anaerobes, that express pyruvate ferredoxin oxidoreductase (PFOR). The enzyme catalyzes the oxidation of pyruvate to acetyl-CoA and reduced ferredoxin. Amixicile is a novel bacteriostatic derivative of nitazoxanide and an inhibitor of PFOR. In light of the fact that Treponemes express PFOR, this study was conducted to investigate the …

Multifunctional Nanocarriers For Cancer Therapy, Bei Cheng

Theses and Dissertations

Cancer is one of the leading causes of human mortality and mortality in all diseases. There has been a boost in developing nanocarrier-based therapies for treating cancer or other diseases during the past decade. One of the major advantages about nanocarrier (with the size range from 1-1000 nm) lies in its ability to specifically target tumor and maximize drug accumulation in tumor foci through the enhanced permeability and retention effect. Advancement in nanotechnology has opened a new paradigm in pharmaceutical field. But new challenges have to be overcome in order to fully exploit the technology and improve safety in clinical …

Selectivity Targeting Polo-Like Kinase 1 (Plk1) Using Novel Inhibitors Of The Polo-Box Domain, Merissa Lynnea Baxter

Theses and Dissertations

Polo-like Kinse 1 (PLK1) is a serine/threonine protein kinase that is expressed in dividing cells. It is a widely studied protein that plays an important role in regulating mitotic progression. PLK1 is over-expressed in several tumor types, and studies have shown that down-regulating PLK1 expression inhibits cancer cell proliferation, validating PLK1 as an oncotarget. Efforts to target this protein therapeutically has led to the development of several ATP-based inhibitors, although these are not exclusively specific. Because other PLK family members are tumor suppressors, it is important that PLK1 inhibitors selectively bind to PLK1 and not the other PLKs, particularly PLK3. …

Stimuli Responsive Nanoparticle For Cancer Targeted Therapy, Huacheng He

Theses and Dissertations

Nanoparticle is the particle with a size in the range from several nanometers to hundreds of nanometers. It has been extensively used for cancer diagnosis and therapy. However, it is still a great challenge to fabricate nanoparticles with spatiotemporally controllable delivery of anticancer drugs to tumors and with high therapeutic efficacy. This thesis mainly focuses on the development of stimuli responsive nanoparticles for cancer targeted therapy. These nanoparticles either response to internal stimuli such as pH and redox potential or external stimuli like temperature and light could effectively target tumors and control the release of anticancer drugs there to improve …

Characterization And Economic Burden Associated With Pediatric Opioid Exposures And Poisonings, Anisha M. Patel

Theses and Dissertations

Introduction

The main objectives of this study were: 1) to examine the prevalence and characteristics of opioid exposures, 2) to estimate the economic costs associated with opioid poisonings, and 3) to examine the characteristics associated with opioid poisoning-related health care resource use (HCRU) and costs in children.

Methods

Data from the National Poison Data System from January 1, 2010 to December 31, 2014 were utilized to examine the prevalence and characteristics of opioid exposures and poisonings in children <18 years. Economic costs were estimated using the 2012 Nationwide Emergency Department Sample, Kids’ Inpatient Database, Multiple Cause-of-Death file and other published sources, applying a societal perspective. Direct costs included costs associated with ED visits, hospitalizations and ambulance transports. Indirect cost included productivity costs due to caregivers’ absenteeism and premature mortality among children.

Results

There were a total of 83,418 pediatric opioid exposures and nearly half of them resulted in poisoning. The epidemiology of opioid …

Continuous Stationary Phase Gradients For Planar And Column Chromatography, Veeren Dewoolkar

Theses and Dissertations

Surfaces that exhibit a gradual change in their chemical and/or physical properties are termed as surface gradients. Based on the changes in properties they are classified either as physical or chemical gradients. Chemical gradients show variations in properties like polarity, charge, functionality concentration and have found potential applications in fields of biology, physics, biosensing, catalysis and separation science. In this dissertation, surface gradients have been prepared using controlled rate infusion (CRI).

CRI is a simple method in which a surface gradient is formed by carrying out the infusion of organoalkoxysilane in a time-dependent fashion using a set infusion rate. Depending …

High-Throughput Sequencing-Based Approaches For The Identification And Development Of Molecular Targets For Cancer Therapy, David Joel Oliver

Theses and Dissertations

Effective cancer treatment depends on the development of therapeutics that efficiently eliminate the disease without significant reduction to quality of life. Targeted therapeutics achieve these goals, but their long-term efficacy is limited by the ability of cancers to become resistant to these therapies over time. The identification of new therapeutic targets is crucial for the future of cancer treatment. In this work we present functional identification and characterization of novel targets for cancer therapy.

Loss-of-function screens are a well-founded approach for the functional identification of new therapeutic targets, and, in combination with high-throughput sequencing technology, can now be performed at …

Probing Allosteric, Partial Inhibition Of Thrombin Using Novel Anticoagulants, Stephen S. Verespy Iii

Theses and Dissertations

Thrombin is the key protease that regulates hemostasis; the delicate balance between procoagulation and anticoagulation of blood. In clotting disorders, like deep vein thrombosis or pulmonary embolism, procoagulation is up-regulated, but propagation of clotting can be inhibited with drugs targeting the proteases involved, like thrombin. Such drugs however, have serious side effects (e.g., excessive bleeding) and some require monitoring during the course of treatment. The reason for these side effects is the mechanism by which the drugs’ act. The two major mechanisms are direct orthosteric and indirect allosteric inhibition, which will completely abolish the protease’s activity. Herein we sought an …

Design And Structure-Activity Relationship Of Small Molecule C-Terminal Binding Protein (Ctbp) Inhibitors And Investigation Of The Scope Of Palladium Multi-Walled Carbon Nanotubes (Pd-Mwcnt) Catalyst In C–H Activation Reactions, Sudha Korwar

Theses and Dissertations

C-terminal binding proteins (CtBPs) are transcriptional co-repressors involved in developmental processes, and also implicated in a number of breast, ovarian, colon cancers, and resistance against cancer chemotherapy. CtBP is a validated novel potential anti-cancer target. In this project we sought to develop potent and selective small-molecule inhibitors of CtBP. Using a combination of classical medicinal chemistry and modern computational approaches, we designed a potent inhibitor HIPP (hydroxyimino-3-phenylpropanoic acid) that showed an IC₅₀ of 0.24 μM against recombinant CtBP. Further elucidation of the structure-activity relationship (SAR) of HIPP led to the design of more potent inhibitors 3-Cl HIPP (CtBP IC …

Sulfated Dehydropolymer Of Caffeic Acid For Repair Of Lung Damage And Emphysema, Tien M. Truong

Theses and Dissertations

The complex pathobiologic mechanisms of emphysema are not fully understood, leaving this deadly disease without effective pharmacotherapy for a cure. This project hypothesized that the sulfated dehydropolymer of caffeic acid (CDSO3) exhibits Fe²⁺ chelation-based hypoxia inducible factor-1a (HIF-1a) up-regulatory protective activities against in vitro emphysematous cell death and for in vivo reversal of emphysema induced with SU5416, a vascular endothelial growth factor blocker.

Using in vitro chromogenic competitive inhibition assays, CDSO3 was shown to chelate Fe²⁺ (IC₅₀ of 23 µM), but not Fe³⁺ ions. The trypan blue exclusion and lactate

dehydrogenase assays were then employed to …

Quantitative Analysis Of 5-Chloro-2-Methoxy-N-[2-(4-Sulfamoylphenyl)Ethyl]Benzamide (Glyburide Analogue, Ga) In Mouse Plasma And Whole Blood Using A Micro-Extraction And Liquid Chromatography-Tandem Mass Spectrometry, Ankit Zalavadia

Theses and Dissertations

Pharmacokinetic evaluation of 5-chloro-2-methoxy-N-[2-(4- sulfamoylphenyl)ethyl]benzamide in mouse plasma demanded for a suitable bioanalytical method. No reported bioanalytical method exists to-date that can quantify concentration of this compound in any biological matrix. The purpose of this study was 1) to develop and validate a new bioanalytical method using a micro-extraction and LC-MS/MS to quantify the target analyte in mouse plasma and 2) to partially validate the method in whole blood. A bioanalytical method was developed and validated in both matrices for a linear concentration range of 2-1000 ng/ml. For both matrices, the reverse predicted concentration of calibration standards (-8.95% to 12.16% …

Resource Utilization And Costs Associated With Off-Label Use Of Atypical Antipsychotics In An Adult Population, Della Varghese

Theses and Dissertations

Introduction: Atypical Antipsychotics (AAPs) are approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia and bipolar disorder. AAPs are commonly used off-label to treat depression, post-traumatic stress disorder and neuropsychiatric symptoms in dementia due to lack of alternative treatment options and treatment resistance. Concerns for off-label use arise since AAPs increase the risk of cardiovascular events and death. The objectives were 1) describe patterns of RU and costs among off-label AAPs users in a nationally representative population 2) identify prevalence of off-label use in the Medicare population 3) compare RU and costs between off-label AAPs …

Curcumin/Melatonin Hybrids As Neuroprotective Agents For Alzheimer's Disease, John Saathoff

Theses and Dissertations

Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the leading cause of dementia, affecting ~5.2 million Americans. Current FDA approved medications provide mainly symptomatic relief and there are no agents available to delay or cure this disease. Multiple factors such as amyloid-β aggregates, dyshomeostasis of biometals, oxidative stress, and neuroinflammation have been implicated in the development of AD. Even though significant advances have been made in understanding the mechanisms leading to AD, the exact etiology still remains elusive. Given AD’s multifactorial nature, a multifunctional strategy of small molecule design would help to identify novel chemical templates. Recently our lab …

Exploring The Concept Of Human Oct3 Inhibitors As A Novel Class Of Antidepressants, Kavita A. Iyer

Theses and Dissertations

The Dukat laboratory developed 2-amino-6-chloro-3,4-dihydroquinazoline (A6CDQ) as a 5-HT₃ receptor ligand. A6CDQ and one of its positional isomers, the 7-chloro analog A7CDQ, produced antidepressant-like effects in the mouse tail suspension test (TST). We investigated and systematically ruled out a solely 5-HT₃ receptor or hSERT mediated mechanism of antidepressant-like effect for both A6CDQ and A7CDQ.

The role of organic cation transporter 3 (OCT3) as an alternative mechanism in the regulation of neurotransmitters including serotonin (5-HT) and the therapeutic potential of targeting hOCT3 to achieve antidepressant effects has been established. By virtue of possessing protonatable nitrogen atoms, 2-aminodihyroquinazolines could potentially …

The Slc22 Transporter Family: Novel Insights To Roles In Drug Efficacy, Drug-Drug Interactions And Mood Disorders, Xiaolei Pan

Theses and Dissertations

Numerous studies have demonstrated the impact of organic cation (OCTs; SLC22 family) and anion transporters (OATs; SLC22 family) on the efficacy and safety of clinically important therapeutics. To be specific, OCTs and OATs have been identified as determinants for uptake into and secretion from enterocytes, hepatocytes and renal proximal tubular cells, and are frequent sites of drug-drug interaction (DDI). In addition, OCTs expressed in brain are components of the low-affinity, high capacity clearance pathway (uptake-2) for biogenic monoamine neurotransmitters. As a result, OCTs may represent novel targets for mood disorders.

The inhibitory effects of several therapeutic agents, designed drugs and …

Identifying Problems During Transitions Of Care And Reasons For Emergency Department Utilization In Community-Dwelling Older Adults, Antoinette B. Coe

Theses and Dissertations

A mixed methods approach was used for this study. The setting was a low-income, subsidized housing apartment building for community-dwelling older and younger disabled adults identified as a health care hot spot due to high rates of ambulance use. The study purpose was to identify reasons for ED use and problems during transition from ED to home, predictors of zip code 23220 (health care hot spot) in emergent and non-emergent ED visits, and predictors of total ED costs in community-dwelling older adults living in a health care hot spot. Semi-structured interviews with residents who used the ED, an existing database …

Development And Validation Of A Discrete Event Simulation Model To Evaluate The Long Term Use Of Electronic Cigarettes In Us Population, Kunal Saxena

Theses and Dissertations

Introduction: Cigarette smoking is associated with lung cancer, cardiovascular disease, and chronic respiratory conditions. It is responsible for high mortality and morbidity risk in the US population. Smokers find sudden quitting difficult and it is reported that a large number of unassisted quitting attempts are eventually unsuccessful. Electronic cigarette or e-cig is a novel battery-driven, nicotine delivery product, currently being used as a smoking cessation tool by current and former smokers. Since its resemblance to a conventional cigarette, and its non-combustible nature, e-cig use has risen exponentially in the last few years. To address such public health issues, the US …

Cost Effectiveness Of Warfarin In Anticoagulant Clinic After Introduction Of Dabigatran For Stroke Prevention In Atrial Fibrillation Patients In The United States, Mai Alhazami

Theses and Dissertations

OBJECTIVES: To assess cost effectiveness of anticoagulant clinics after FDA approval of New Oral Anticoagulants (NOACs) for preventing ischemic stroke in Atrial Fibrillation (AF) patients in the United States. METHODS: A decision tree was built to compare cost and effectiveness of 150mg dabigatran twice a day to adjusted dose of warfarin within anticoagulation clinic. The analysis was for one year using a societal perspective. The population in this analysis was a cohort of AF patients, ≥ 65 years old, with a CHADS₂ score>2, and no contraindication to anticoagulation. RESULTS: The base case analysis showed that changing from warfarin …

Elaboration And Design Of Α7 Nachr Negative Allosteric Modulators, Osama I. Alwassil

Theses and Dissertations

α7 Neuronal nicotinic acetylcholine receptors are one of two major classes of receptors responsible for cholinergic neurotransmission in the central nervous system. The existence of α7 neuronal nAChRs in different regions of the nervous system suggests their involvement in certain essential physiological functions as well as in disorders such as Alzheimer’s disease (AD), drug dependence, and depression. This project was aimed toward the discovery and development of small–molecule arylguanidines that modulate α7 nAChR function with improved subtype-selectivity through an allosteric approach. Identifying the required structural features of these small molecules allowed optimization of their negative allosteric modulator (NAM) actions at …

Economic Impact Of Waste In Prescribing, Dispensing, And Medication Consumption In The United States, Sarah Almanie

Theses and Dissertations

Abstract

ECONOMIC IMPACT OF WASTE IN PRESCRIBING, DISPENSING, AND MEDICATION CONSUMPTION IN THE UNITED STATES

By Sarah A. Almanie, M.S.

A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University.

Virginia Commonwealth University, 2015.

Major Director: David A. Holdford, R.Ph., M.S., Ph.D., FAPhA

Professor

Department of Pharmacotherapy and Outcomes Science

OBJECTIVES: This research examines waste associated with the medication use process which consists of unfilled prescriptions, abandoned prescriptions, or unused prescription medications. The aim of this study is to quantify the direct medical costs of medication waste in delivery of …

Molecular Mechanisms Underlying Environmental Enrichment-Induced Neuroprotection In Vulnerability To Nicotine Addiction, Adrian Michael Gomez

Theses and Dissertations

Tobacco use is the number one preventable cause of death in the world. Nicotine is the principal, addictive component in tobacco responsible for its reinforcing properties that drive the behavioral manifestations of nicotine addiction. Environment is becoming increasingly implicated in nicotine susceptibility. However, the molecular mechanisms that underlie susceptibility to nicotine addiction remain unknown. An ideal animal model that addresses environmental factors uses rats raised in an enriched condition (EC), a standard condition (SC), and an impoverished condition (IC); which differ in novelty, social cohorts, handling, and physical activity. EC rats exhibit a neuroprotective-like phenotype in the behavioral resistance to …

Investigation Of Phenylephrine Sulfation And Inhibition Using A Novel Hilic Assay Method, Heta N. Shah

Theses and Dissertations

Phenylephrine (PE) is the most commonly used over-the-counter nasal decongestant. The problem associated with phenylephrine is that it undergoes extensive first pass metabolism in the intestinal gut wall leading to its poor and variable oral bioavailability.

This research project aims at developing strategies in order to increase the oral bioavailability of PE by co-administration of GRAS compounds. A HILIC assay method was developed to detect the parent drug, phenylephrine (PE) and its sulfate metabolite (PES).The enzyme kinetic studies were done with phenolic dietary or GRAS compounds using LS180 human intestinal cell model, recombinant SULT enzymes and human intestinal cytosol (HIC). …

Enhancement Of The Placental Transmission Of Lopinavir Using A Transporter Targeted Prodrug Strategy, Meng Wang

Theses and Dissertations

Lopinavir (LPV) is a potent protease inhibitor specific for HIV-1. However, LPV has poor placental penetration due to substrate activity for efflux transporter by P-glycoprotein (P-gp). Since fatty acid transporters are highly expressed in the placenta during pregnancy, we designed fatty acid ester prodrug of lopinavir as substrates of fatty acid transporter in order to improve their uptake into placenta. Seven dicarboxylic acid esters of lopinavir have been made in our lab. The structures were characterized by ¹H-NMR, ¹³C-NMR, LC-MS/MS, HRMS, IR and melting points. After making the prodrugs, an LC-MS/MS method with high specificity and sensitivity, as …

Generation And Delivery Of Charged Aerosols To Infant Airways, Landon T. Holbrook

Theses and Dissertations

The administration of pharmaceutical aerosols to infants on mechanical ventilation needs to be improved by increasing the efficiency of delivery devices and creating better ways of evaluating potential therapies. Aerosolized medicines such as surfactants have been administered to ventilated infants with mixed results, but studies have shown improvement in respiratory function with a much lower dose than with liquid instillation through an endotracheal tube (ETT). An aerosolized medicine must be transported through the ventilation tubing and deposit in the lungs to have the desired therapeutic response.

This work has taken a systematic approach to (i) develop new devices for the …

Psychoactive Synthetic Cathinones (Or 'Bath Salts'): Investigation Of Mechanisms Of Action, Farhana Sakloth

Theses and Dissertations

Synthetic cathinones represent threatening and high abuse-potential designer drugs. These are analogs of cathinone (the b-keto analog of amphetamine (AMPH)) a naturally occurring stimulant found in the plant Catha Edulis. Methcathinone (MCAT) was the first synthetic analog of cathinone to be identified in 1987 by Glennon and co-workers and it exerted its action primarily through the dopamine transporter (DAT). Most central stimulants exert their action via monomaine transporters by causing either the release (e.g. cathinone analogs such as MCAT) or by preventing the reuptake (e.g. cocaine) of the neurotransmitter dopamine (DA) thus increasing the extracellular synaptosomal concentration of this …