Pharmacy and Pharmaceutical Sciences Commons^™

3-D Homology Modeling Of Organic Anion Transporters (Oats): Defining The Biochemical Basis For Oat-Substrate Interactions, Christopher Jay

Theses and Dissertations

A goal in the drug development process, as indicated by the FDA, is to evaluate a drug’s ADME profile, as potential drug interactions could exist, leading to adverse drug reactions or loss of efficacy. Transport proteins, specifically organic anion transporters (OATs) are involved in the absorption, distribution, and elimination of small, negatively charged compounds. Although there is an exhaustive list of structurally diverse organic anions which interact with OATs, interactions at a molecular level are still shrouded in mystery particularly due to the lack of a solved crystal structure. Therefore, in silico homology models (hOAT1, 2, 3) were generated using …

New Persistent And Chronic Opioid Use In Cancer Survivors After Curative Intent Radiation, Elena V. Fernández

Theses and Dissertations

Background: Emerging evidence suggests that as more patients are surviving cancer, new persistent opioid use (no prior exposure to opioids before cancer therapy but requiring opioid prescriptions after curative intent treatment; NPOU) is of greater concern. In patients receiving curative intent radiation (definitive radiation therapy and as treatment for cure; CIR), the extent to which patients develop NPOU or continue opioid use (COU) following CIR is not known. Neither are factors associated with NPOU or COU, opioid doses, or time to discontinuation (TTD) of opioids in 5CS known. Objectives: Describe longitudinal trends opioid use in cancer survivors who received CIR, …

Model-Based In-Vitro Pk/Pd Profiling Of Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) As Potential Sickle Cell Disease (Scd) Therapeutics, Xiaomeng Xu

Theses and Dissertations

Introduction: Allosteric effectors of hemoglobin (AEH) represent a class of synthetic aromatic aldehydes that transiently form covalent interactions (Schiff-base) with hemoglobin (Hb) to form Hb-AEH adduct, preventing the HbS polymerization and sickling of red blood cells (RBC). The overall objective of this research was to aid in the optimization of novel AEH by understanding their target-site disposition of AEH in relevant biological matrices, e.g., HbA solution, whole blood (WB) and human liver cytosol (HLC), a surrogate of aldehyde dehydrogenase (ALDH)-mediated oxidative metabolism.

Methods: A “universal” HPLC-UV/Vis assay method was developed for the quantitation of HbA-AEH adduct for chemically …

The Impact Of The Fda Warning On Post-Tonsillectomy Opioid Prescribing In Publicly And Privately Insured Children, Dianna J. Soelberg

Theses and Dissertations

Due to reports of significant adverse events, the U.S. FDA placed a Boxed Warning on the opioid codeine in February 2013 – contraindicating its use in pediatric patients undergoing tonsillectomy and/or adenoidectomy. Studies conducted in privately insured children showed a reduction in codeine prescribing and a slight increase in alterative opioid prescribing following the FDA warning, yet the extent to which the FDA warning impacted prescribing in publicly insured children is unknown. Using a quasi-experimental interrupted time series design, this study evaluated codeine and alternative opioid prescribing before and after the FDA warning in both publicly and privately insured children …

Development And Validation Of Predictive Risk And Multiple Criteria Decision Analysis Models To Evaluate Cardiovascular Outcomes Among Cancer Patients, Purva N. Parab

Theses and Dissertations

Objective: The objectives of our study were to characterize the study population with cancer and cardiovascular diseases (CVD) both as compared to those without and to build a predictive model using machine learning (ML) algorithms that can predict the risk of CVD in cancer patients. In addition, our objective was also to evaluate characteristics associated with cardiotoxic adverse events of breast cancer therapies and develop a multiple criteria decision analysis (MCDA) model to conduct benefit-risk assessment of breast cancer therapy regimens. Methods: We used Medical Expenditure Panel Survey (MEPS) and FDA Adverse Events Reporting System (FAERS) 2005-2015 files along with …

Development Of A Screening Assay For Type Iii Secretion System Inhibitors And High Throughput Screening Campaign Of Inhibitors Of Prp Of Staphylococcus Aureus, Heather A. Pendergrass

Theses and Dissertations

Antibiotics inhibit the growth or survival of bacteria by targeting their essential functions.¹ Due to weaknesses in traditional antibiotics and the increasing prevalence of antibiotic resistance genes, virulence factors are being targeted for therapeutic treatment of bacterial infection.² We have developed an assay to quantify and observe type III secretion system (T3SS) activity. The type III secretion system (T3SS) is a virulence factor present in some Gram-negative pathogens including enteropathogenic and enterohemorrhagic E. coli (EPEC and EHEC, respectively),³ and others.^4–9 The T3SS between EPEC and EHEC are highly conserved and share over 90% sequence identity with …

Development Of An R Script For Simple Lipidomic And Metabolomic Data Analysis, Suad Alshammari, Joshua M. Morriss, Daniel Contaifer, Dayanjan S. Wijesinghe, Monther Alsultan

Graduate Research Posters

Background: Metabolomic and lipidomic studies generate vast quantities of data that are often analysed in a closed software environment with little to no access to the underlying algorithms. As a result, data processed via different software pipelines yield different results thus leading to a widespread problem of low reproducibility within these fields. To address this problem, we are developing LipidAnalyst; an R based lipidomics software pipeline. As a part of this project, we are creating a simple statistical analysis and graphing module in R to generate accurate, reproducible, high-resolution figures.

Methods: R scripts were developed under version 3.5.3 with the …

Molecular Predictors Of Anakinra Treatment Success In Heart Failure Patients With Reduced Ejection Fraction, Joshua Morriss, Daniel Contaifer Jr, Leo F. Buckley, George Wohlford, Monther Alsultan, Suad Alshammari, Asanga D. Ranasinghe, Salvatore Carbone, Justin M. Canada, Cory Trankle, Elvin T. Price, Antonio Abbate, Benjamin W. Van Tassell, Dayanjan S. Wijesinghe

Graduate Research Posters

Background. Kineret (Anakinra) is an interleukin-1 antagonist that is under investigation for its novel clinical application treating patients that have heart failure with reduced (<50%) ejection fraction (HFrEF). A prior study from our group indicated that Anakinra may restore heart function by addressing dysregulations in HFrEF metabolic pathways. Herein, we attempt to elicit Anakinra’s effects on both metabolome and lipidome.

Methods. Lipids and metabolites that had previously been quantified by mass spectrometry (MS) from patients (n=49) who had ≥2 mg/L of high-sensitivity C-reactive protein (hs-CRP) were mTIC normalized and transformed. We conducted a stepwise Linear Discriminant Analysis (r- LDA) to test Anakinra (2 and 12 weeks) vs placebo for separation from combined baseline. Metabolic pathway analysis was performed with Fisher’s exact test algorithm for detection of over-represented and enriched analytes. Univariate analysis (one tailed t-test …

Local Lung Targeting Of Tumor Associated Macrophages Combined With Cytoreductive Therapy Decrease Tumor Burden In A Secondary Lung Cancer Model, Sulaiman Alhudaithi, Hanming Zhang, Rashed Almuqbil, Wei Du, Fatemah Sunbul, Paula Bos, Sandro Da Rocha

Graduate Research Posters

Backgrounds. The efficacy of a locally administered small molecule colony stimulating factor 1 receptor inhibitor (CSF-1Ri), PLX3397, alone or in combination with cytoreductive therapy (paclitaxel) in reducing the tumor burden of an in vivo model of secondary lung cancer was investigated in this work. Local administration of immunotherapy to the lungs may enhance lung biodistribution of such therapies and reduce potential unwanted off-target toxicity. In addition, combination of such therapy with low dose standard of care chemotherapy may offer improved anti-tumor effects.

Methods. Murine breast cancer cells (4T1, known to be highly metastasized to the lungs) were transduced to …

Providers’ Perception Of Alert Fatigue After Implementation Of User-Filtered Warnings, Hina Afaq, Sahaana Mukundan, Sadaf Zia, Alisa K. Escano Dr., Rebecca Lear Dr., Casey Washington Dr.

Pharmacotherapy and Outcomes Science Publications

Alert fatigue is a complex problem that many health institutions face when using an electronic health record (EHR). The addition of user-filtered warnings (UFW) is a physicians’ proposed intervention at Inova Health System (IHS), a large 5-hospital health system in Northern Virginia, that allows prescribers to filter out specific drug-drug interactions and pregnancy and lactation medication alerts for a 30-day period. This study aims to determine the impact of UFW on physicians’ perception of alert fatigue and to calculate the reduction of medication alerts. It was hypothesized that the reduction in alerts will significantly impact physicians’ perception of alert fatigue …

Glycosaminoglycans And Glycosaminoglycan Mimetics In Cancer And Inflammation, Shravan Morla

Medicinal Chemistry Publications

Glycosaminoglycans (GAGs) are a class of biomolecules expressed virtually on all mammalian cells and usually covalently attached to proteins, forming proteoglycans. They are present not only on the cell surface, but also in the intracellular milieu and extracellular matrix. GAGs interact with multiple ligands, both soluble and insoluble, and modulate an important role in various physiological and pathological processes including cancer, bacterial and viral infections, inflammation, Alzheimer’s disease, and many more. Considering their involvement in multiple diseases, their use in the development of drugs has been of significant interest in both academia and industry. Many GAG-based drugs are being developed …

Metabolic Modulation Predicts Heart Failure Tests Performance, Daniel Contaifer Jr., Leo F. Buckley, George Wohlford, Naren G. Kumar, Joshua M. Morriss, Asanga D. Ranasinghe, Salvatore Carbone, Justin M. Canada, Cory Trankle, Antonio Abbate, Benjamin W. Van Tassell, Dayanjan S. Wijesinghe

Pharmacotherapy and Outcomes Science Publications

The metabolic changes that accompany changes in Cardiopulmonary testing (CPET) and heart failure biomarkers (HFbio) are not well known. We undertook metabolomic and lipidomic phenotyping of a cohort of heart failure (HF) patients and utilized Multiple Regression Analysis (MRA) to identify associations to CPET and HFBio test performance (peak oxygen consumption (Peak VO₂), oxygen uptake efficiency slope (OUES), exercise duration, and minute ventilation-carbon dioxide production slope (VE/VCO₂ slope), as well as the established HF biomarkers of inflammation C-reactive protein (CRP), beta-galactoside-binding protein (galectin-3), and N-terminal prohormone of brain natriuretic peptide (NT-proBNP)). A cohort of 49 patients with …

A Preliminary Investigation Towards The Risk Stratification Of Allogeneic Stem Cell Recipients With Respect To The Potential For Development Of Gvhd Via Their Pre-Transplant Plasma Lipid And Metabolic Signature, Daniel Contaifer Jr., Catherine H. Roberts, Naren Gajenthra Kumar, Ramesh Natarajan, Bernard J. Fisher, Kevin Leslie, Jason Reed, Amir A. Toor, Dayanjan S. Wijesinghe

Pharmacotherapy and Outcomes Science Publications

The clinical outcome of allogeneic hematopoietic stem cell transplantation (SCT) may be influenced by the metabolic status of the recipient following conditioning, which in turn may enable risk stratification with respect to the development of transplant-associated complications such as graft vs. host disease (GVHD). To better understand the impact of the metabolic profile of transplant recipients on post-transplant alloreactivity, we investigated the metabolic signature of 14 patients undergoing myeloablative conditioning followed by either human leukocyte antigen (HLA)-matched related or unrelated donor SCT, or autologous SCT. Blood samples were taken following conditioning and prior to transplant on day 0 and the …

Pharmaceutical Industry's Effect On Socioeconomic Development In Sub-Saharan Africa In Relation To Family Planning Accessibility, Tessa Demarest

AUCTUS: The Journal of Undergraduate Research and Creative Scholarship

There is a large unmet need for family planning services in sub-Saharan Africa (Goodkind et al, 2018). Pharmaceutical companies contribute to the accessibility of medications in developing countries (Cottingham & Berer, 2011). If the pharmaceutical industry strongly affects access to contraceptives in sub-Saharan Africa, then it is possible that adjustments made to the industry would increase access to contraceptives. I explored how contraceptives change the economic and social development of subSaharan Africa to determine if contraception benefits Africans enough for their shortage to be a serious injustice. This is followed by how the pharmaceutical industry affects access to and types …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Development Of Bivalent Ligands Targeting The Putative Mu Opioid Receptor And Chemokine Receptor Cxcr4 Heterodimer, Bethany A. Reinecke

Theses and Dissertations

Human immunodeficiency virus (HIV) and opioid abuse have been described as synergistic epidemics. Pharmacologically, it has been found that opioids have the capacity to enhance HIV infection and replication. Research has shown that activation of the mu-opioid receptor (MOR) elevates the expression of the HIV-1 entry co-receptor CXCR4 on T-lymphocytes in the peripheral nervous system, thus allowing for enhanced viral entry and invasion. Although the exact mechanism for opioid modulation of CXCR4 expression and subsequent exacerbation of HIV is unknown, several hypotheses exist. One hypothesis is that MOR and CXCR4 are functionally interacting through the formation of a heterodimer. This …

Design, Synthesis And Pharmacological Characterization Of Potential Mu Opioid Receptor Selective Ligands, Abhishek S. Kulkarni

Theses and Dissertations

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement …

Diuretic, Natriuretic, And Vasodepressor Activity Of A Lipid Fraction Enhanced In Medium Of Cultured Mouse Medullary Interstitial Cells By A Selective Faah Inhibitor, Zdravka P. Daneva

Theses and Dissertations

The relationship between the endocannabinoid system in the renal medulla and the long-term regulation of blood pressure is not well understood. To investigate the possible role of the endocannabinoid system in renomedullary interstitial cells, mouse medullary interstitial cells (MMICs) were obtained, cultured and characterized for their responses to treatment with a selective inhibitor of fatty acid amide hydrolase (FAAH), PF-3845. Treatment of MMICs with PF-3845 increased cytoplasmic lipid granules detected by Sudan Black B staining and multilamellar bodies identified by transmission electron microscopy. HPLC analyses of lipid extracts of MMIC culture medium revealed a 205nm-absorbing peak that showed responsiveness to …

National And Local Antibiotic Prescribing Trends And Prescribing Appropriateness In Older Adults, Fawaz M. Alotaibi

Theses and Dissertations

Background: Antibiotic overuse/misuse has been documented in several reports to increase the risk of Clostridioides difficile (C.diff) infection and antibiotic resistance. The older adult population is more prone to use antibiotic medications than any other age group due to decreased immune function, use of urinary catheters, ventilation during hospitalization and other factors. Antibiotic resistance and C.diff are major public health problems. However, studies examining the trends of antibiotic use and the association between the antibiotic use and negative health outcomes among older adults in the outpatient and emergency department settings are limited.

Objectives: The main objectives of this …

Understanding Medication Self-Management Capacity Among Older Adults Living In Low-Income Housing Communities, Amal M. Badawoud

Theses and Dissertations

Understanding Medication Self-Management Capacity among Older Adults Living in Low-Income Housing Communities

ABSTRACT

Background: Medication self-management capacity (MMC) is an individual’s cognitive and functional ability to self-administer a medication regimen as prescribed. Poor MMC is an issue in older adults often resulting in negative health outcomes and loss of independence. Therefore, understanding low-income older adults’ capacity to manage their medications may help identify individuals who are at risk for developing medication mismanagement and guide future intervention strategies based on an individual need to promote safe medication use and healthy aging in place in the community.

Objectives: 1) To determine the …

Structure-Activity Relationship Studies Of Synthetic Cathinones And Related Agents, Rachel A. Davies

Theses and Dissertations

Synthetic cathinones and related agents represent an international drug abuse problem, and at the same time an important class of clinically useful compounds. Structure-activity relationship studies are needed to elucidate molecular features underlying the pharmacology of these agents. Illicit methcathinone (i.e., MCAT), the prototype of the synthetic cathinone class, exists as a racemic mixture. Though the differences in potency and target selectivity between the positional and optical isomers of synthetic cathinones and related agents have been demonstrated to have important implications for abuse and therapeutic potential, the two MCAT isomers have never been directly compared at their molecular targets: the …

A Hybrid Molecule Of Melatonin And Curcumin For Therpeutic Use In Pulmonary Fibrosis, Varsha V. Nair

Theses and Dissertations

Pulmonary fibrosis (PF) is a serious lung disease, as its life expectancy is only 3-5 years upon occurrence and more than 50 % of the cases are idiopathic, i.e., unknown cause. Two drugs, pirfenidone (PIR) and nintedanib, have recently been approved; however, their efficacies are moderate without evidence of prolonged survival. While this is primarily due to our insufficient knowledge about key PF pathogenesis, inductions of oxidative stress and transforming growth factor-b1 (TGF-b1) have been suggested in PF lungs. Hence, anti-oxidative melatonin (MEL) and curcumin (CUR) have been studied yet their efficacies remain moderate without clear understanding about the mechanisms …

Molecular Pharmacology Of Non-Phyto-Cannabinoid Approaches For Treatment Of Neuropathic Pain, Nadejda A. Blajkevich

Theses and Dissertations

Approximately twenty million people in United States have some form of peripheral neuropathy. It has been shown that the CB₂ cannabinoid receptor is upregulated when there is peripheral nerve injury and activating the CB₂ receptor produces anti-inflammatory effects that translate to a reduction in signs of “neuropathic pain” in animal models. Elevating endogenous cannabinoids by inhibiting degradative enzymes has also been used to reduce neuropathic pain signs in laboratory animal models of pain. We hypothesize that the molecular pharmacology of these two approaches can be leveraged to optimize CB₁/CB₂ activation to improve non-phyto-cannabinoid treatments for …

Polygenic Scores For Metabolic Traits And Related Drug Prescriptions In The Michigan Genomics Initiative, Samuel K. Handelman, Xiaomeng Du, Yanhua H. Chen, Elizabeth K. Speliotes

Biology and Medicine Through Mathematics Conference

No abstract provided.

Modeling Pharmaceutical Inhibition Of Glucose-Stimulated Renin-Angiotensin System In Kidneys, Ashlee N. Ford Versypt, Minu R. Pilvankar, Hui Ling Yong

Biology and Medicine Through Mathematics Conference

No abstract provided.

Untargeted Lipidomic Analysis To Broadly Characterize The Effects Of Pathogenic And Non-Pathogenic Staphylococci On Mammalian Lipids, Naren Gajenthra Kumar, Daniel Contaifer Jr., Paul Rs Baker, Kim Ekroos, Kimberly K. Jefferson, Dayanjan S. Wijesinghe

Pharmacotherapy and Outcomes Science Publications

Modification of the host lipidome via secreted enzymes is an integral, but often overlooked aspect of bacterial pathogenesis. In the current era of prevalent antibiotic resistance, knowledge regarding critical host pathogen lipid interactions has the potential for use in developing novel antibacterial agents. While most studies to date on this matter have focused on specific lipids, or select lipid classes, this provides an incomplete picture. Modern methods of untargeted lipidomics have the capacity to overcome these gaps in knowledge and provide a comprehensive understanding of the role of lipid metabolism in the pathogenesis of infections. In an attempt to determine …

Kinetics And Inhibition Studies Of The L205r Mutant Of Camp-Dependent Protein Kinase Involved In Cushing’S Syndrome, Nicole M. Luzi, Charles E. Lyons, Darrell L. Peterson, Keith C. Ellis

Medicinal Chemistry Publications

Overproduction of cortisol by the hypothalamus–pituitary–adrenal hormone system results in the clinical disorder known as Cushing's syndrome. Genomics studies have identified a key mutation (L205R) in the α‐isoform of the catalytic subunit of cAMP‐dependent protein kinase (PKACα) in adrenal adenomas of patients with adrenocorticotropic hormone‐independent Cushing's syndrome. Here, we conducted kinetics and inhibition studies on the L205R‐PKACα mutant. We have found that the L205R mutation affects the kinetics of both Kemptide and ATP as substrates, decreasing the catalytic efficiency (k_cat/K_M) for each substrate by 12‐fold and 4.5‐fold, respectively. We have also determined the IC …

Identifying Medication Management Smartphone App Features Suitable For Young Adults With Developmental Disabilities: Delphi Consensus Study, Teresa M. Salgado, Alexa Fedrigon, Donna Riccio Omichinski, Michelle A. Meade, Karen B. Farris

Pharmacotherapy and Outcomes Science Publications

Background: Smartphone apps can be a tool to facilitate independent medication management among persons with developmental disabilities. At present, multiple medication management apps exist in the market, but only 1 has been specifically designed for persons with developmental disabilities. Before initiating further app development targeting this population, input from stakeholders including persons with developmental disabilities, caregivers, and professionals regarding the most preferred features should be obtained.

Objective: The aim of this study was to identify medication management app features that are suitable to promote independence in the medication management process by young adults with developmental disabilities using a Delphi consensus …

Variability In Antifungal Utilization Among Neonatal, Pediatric, And Adult Inpatients In Academic Medical Centers Throughout The United States Of America, Jeremy S. Stultz, Rose Kohinke, Amy L. Pakyz

Pharmacotherapy and Outcomes Science Publications

Background
Identification of factors associated with antifungal utilization in neonatal, pediatric, and adult patient groups is needed to guide antifungal stewardship initiatives in academic medical centers.

Methods
For this hospital-level analysis, we analyzed antifungal use in hospitals across the United States of America, excluding centers only providing care for hematology/oncology patients. Analysis of variance was used to compare antifungal use between patient groups. Three multivariable linear regression models were used to determine independent factors associated with antifungal use in the neonatal, pediatric, and adult patient groups.

Results
For the neonatal, pediatric, and adult patient groups, 54, 44, and 60 hospitals …

Galantamine's Deconstruction In The Quest Of A Pam Pharmacophore, Malaika Argade

Theses and Dissertations

Alzheimer’s disease is a progressive neurodegenerative disorder generally affecting people above the age of 65 years. Even though the pathophysiological hallmarks of AD were established more than a hundred years ago, there is yet to be a drug that can stop its characteristic neuronal damage. Of the five currently FDA-approved drugs, galantamine has a unique mechanism of action. Apart from being an AChE inhibitor, galantamine can effectively potentiate (positive allosteric modulator) the effect of agonists at nAChRs at concentrations lower than those required for its action as an AChE inhibitor. Perhaps the clinical benefits observed with galantamine are associated mainly …