Medicine and Health Sciences Commons^™

Early-Onset Colorectal Cancer In Mice, Qi Zhang

Theses and Dissertations

Early-onset colorectal cancer (EOCRC) is the second most common cancer and the third leading cause of cancer mortality in people under 50 years old in the United States. Our hypothesis is that a high-fat diet (HFD), Allura Red AC, and/or psychological stress causes distal and rectal colon inflammation, which are associated with dysbiosis. Furthermore, chronic exposure to one or more of these elements increases the risk of EOCRC. A/J inbred mice were utilized in this study. The results are consistent with our hypothesis.

Overall findings are the following: (1) An HFD increased inflammatory scores and polyps’ burden in the distal …

Investigation Of The Sequence-Structure-Activity Relationship In Ponericin L1 From Neoponera Goeldii & Synergistic Interactions Of Ionic Liquids And Antimicrobials To Improve Efficacy, Alexandria S. Senetra

Theses and Dissertations

Non-traditional antimicrobials have been an area of great interest due to the increasing prevalence of antimicrobial resistance (AMR) in bacteria. Antimicrobial peptides (AMPs) & ionic liquids (ILs) are two examples that have been investigated as a potential solution. Most AMPs are naturally derived & exhibit high selectivity against bacterial targets over host cells. The venom-derived peptide, ponericin L1 from Neoponera goeldii, was used to investigate the role of cationic residues & net charge on peptide activity. Using both in vitro & microbiological methods, L1 peptide & derivatives exhibited an alpha-helical conformation with enhanced binding to lipid vesicles containing anionic lipids …

Searching For New Medications For The Treatment Of Alcohol Use Disorder, Harley M. Buechler

Theses and Dissertations

Alcohol use disorder (AUD) affects more than 15 million people in the United States. Current pharmacotherapeutic treatments for AUD are only modestly effective, necessitating the identification of new targets for medications development. In this study, the effects of the D4 receptor antagonist, L-745,870, and the CB1 negative allosteric modulator, PSNCBAM-1, were both tested for effects in ethanol conditioned place preference (CPP) and oral ethanol self-administration. Food-restricted adult male mice were trained in operant chambers to nose poke for delivery of rewards, trained on ascending concentrations of alcohol with descending concentrations of Ensure and water, until the mixture self-administered was 8% …

Searching For New Analgesics Without Addiction Risks, Mohammad Atiqur Rahman

Theses and Dissertations

Opioids are widely used to treat acute and chronic pain. But opioid addiction to these compounds can cause social and life-threatening health problems, including the risk of overdose. In this thesis, I evaluated IBNtxA (3-iodobenzoyl naltrexamine), a novel mu opioid receptor (MOR) agonist structurally related to the classical MOR antagonist naltrexone, in drug discrimination studies in order to better understand its subjective effects and more thoroughly its abuse liability. IBNtxA represents an intriguing lead compound for preclinical drug development specifically targeting MOR splice variants, potentially creating effective analgesics with reduced side effects. These results indicate that IBNtxA produces potent antinociception …

Function Of Gpr68 In Normal Hematopoiesis And Malignant Hematopoietic Diseases, Xiaofei He

Theses and Dissertations

G protein-coupled receptor 68 (GPR68), as a proton-sensing receptor, is involved in numerous physiological processes. However, its specific functions in normal hematopoiesis and malignant hematopoietic diseases were unknown. Using a genetic loss of function approach (i.e. whole-body Gpr68^-/- mouse model), B lymphocytes were reduced under stressed conditions, such as aging and hematopoietic regeneration. However, hematopoietic stem cells (HSC) from Gpr68^-/- mice exhibited comparable function as HSC from wild type mice either under steady-state or upon stress. To determine whether the unaltered HSC function of Gpr68^-/- mice was due to compensatory effects of Gpr68 in nonhematopoietic cells, a …

Synthesizing Modified Polymeric Nanoparticles For Biofilm Inhibition, Antibiotic Encapsulation, And Specific Targeting Against Pseudomonas Aeruginosa, Logan Schnorbus

Theses and Dissertations

Widespread usage of antibiotics is a growing concern due to antibiotic resistance development in bacteria. This is due to common use of antibiotics in agricultural, livestock, and clinical usage. Antibiotic resistance is developing at a rate in which it is outpacing new drugs on the market. New strategies in drug development are necessary to combat the increasing resistance. We designed several motifs of sugar-modified nanoparticles to inhibit the biofilm formation of Pseudomonas aeruginosa.

P. aeruginosa is an opportunistic pathogenic bacterium that is responsible for common life-threatening infection in hospitals. This gram-negative opportunistic pathogenic bacterium infects hosts with compromised immune systems …

An In Silico Study Of Small Molecule Anti-Cancer Agents Targeting Dna G-Quadruplexes, Holli-Joi Sullivan

Theses and Dissertations

Free ligand binding molecular dynamic simulations are a powerful tool used to probe the ligand binding process, mechanism and pathway and the insight gained can help expedite the early stages of drug discovery. Using these methods, we model the binding of two small molecule anti-cancer agents BRACO19 and CX-5461 to a variety of DNA G-quadruplexes (G4s) and a DNA Duplex. The first study focuses on the binding of BRACO19 to three different topological folds (parallel, anti-parallel and hybrid) of the human telomeric G4s. Our detailed analysis identified the most stable binding modes were end stacking and groove binding for the …

Expansion Of Medication Therapy Management Services To Rural Sites For Patients With An Employer-Sponsored Health Plan, Taylor Thooft Pharmd

Theses and Dissertations

Previous literature supports that pharmaceutical care provider in the ambulatory care setting can improve clinical, economic, and humanistic outcomes for recipients, and when utilized in employer-provided health plans can lead to reduced spending on healthcare costs by employers. A large health system in central Minnesota offers an Employee Medication Therapy Management (MTM) benefit that offers further financial incentives to meet with an MTM Pharmacist for a comprehensive review of one’s medications. Currently, this program is underutilized due to both lack of awareness of the program and geographic for employees in the wester region of the health system. This project sought …

Prediction Of Drug-Drug Interaction Potential Using Machine Learning Approaches, Joseph Scavetta

Theses and Dissertations

Drug discovery is a long, expensive, and complex, yet crucial process for the benefit of society. Selecting potential drug candidates requires an understanding of how well a compound will perform at its task, and more importantly, how safe the compound will act in patients. A key safety insight is understanding a molecule's potential for drug-drug interactions. The metabolism of many drugs is mediated by members of the cytochrome P450 superfamily, notably, the CYP3A4 enzyme. Inhibition of these enzymes can alter the bioavailability of other drugs, potentially increasing their levels to toxic amounts. Four models were developed to predict CYP3A4 inhibition: …

Treatment With Protease Inhibitor And Development Of Diabetes Among Medicare Beneficiaries With Human Immune Virus/Acquired Immune Deficiency Syndrome (Hiv/Aids), Eric Ejike Chinaeke

Theses and Dissertations

Background: The possibility of an association between the use of protease inhibitors (PI) by HIV/AIDS patients and the occurrence of T2DM mellitus (T2DM) is largely debated. Medicare recipients are disproportionally affected by T2DM. Unfortunately, evidence is unavailable from that particular segment of the population. Clinical management of HIV/AIDS is progressively expanding to include chronic/metabolic complications, which may pose a significant economic burden to both the patients and the Medicare system, which are disproportionally impacted. Objectives: The aims of this project were to (1) examine the association between the use of PIs and the odds of developing T2DM among Medicare beneficiaries …

Gm-1111 Preserves Phagocytic Function Of Macrophages Exposed To Prolonged Hyperoxia Via Interruption Of Hmgb1-Mediated Signaling, Leanne Daley

Theses and Dissertations

Supraphysiological levels of oxygen (i.e. hyperoxia) are used to treat patients with respiratory distress. Prolonged exposure to hyperoxia can impair alveolar macrophage functions and increase susceptibility to ventilator-associated pneumonia (VAP). Hyperoxia-induced alveolar macrophage dysfunction is, in part, mediated by high airway levels of the pro-inflammatory mediator, high mobility group box-1 (HMGB1). An early generation glycosaminoglycan (GAG), 2-O, 3-O desulfated heparin (ODSH), attenuates hyperoxia-compromised innate immunity by preventing the binding of HMGB1 with receptors that activate pro-inflammatory pathways. In this study, we investigated whether the next generation GAG, GM-1111, can attenuate hyperoxia-compromised macrophage function. GM-1111 (100μM) prevented hyperoxia-induced (95% O2 for …

Chemical Space Exploration Around Thieno[3,2-D]Pyrimidin-4(3h)-One Scaffold Led To A Novel Class Of Highly Active Clostridium Difficile Inhibitors, Xuwei Shao

Theses and Dissertations

Clostridium difficile infection (CDI) is the leading cause of healthcare-associated infection in the United States. Therefore, development of novel treatments for CDI is a high priority. Toward this goal, we began in vitro screening of a structurally diverse in-house library of 67 compounds against two pathogenic C. difficile strains (ATCC BAA 1870 and ATCC 43255), which yielded a hit compound, 2-methyl-8-nitroquinazolin-4(3H)-one (2) with moderate potency (MIC = 312/156 µM). Optimization of 2 gave lead compound 6a (2-methyl-7-nitrothieno[3,2-d]pyrimidin-4(3H)-one) with improved potency (MIC = 19/38 µM), selectivity over normal gut microflora, CC50s >606 µM against mammalian cell lines, and acceptable stability in …

Development Of Abuse Deterrent Formulations Using Hot Melt Extrusion, Pavan Kumar Nukala

Theses and Dissertations

In recent years prescription drug diversion, misuse, abuse represent a growing problem for the United States. Oral ingestion, snorting, injection are most commonly employed routes of abuse. To circumvent this problem hot melt extrusion (HME) was employed to prepare abuse deterrent formulation (ADF). Abuse Deterrent Immediate Release Egg-Shaped Tablet Using 3D Printing Technology: Quality by Design to Optimize Drug Release and Extraction. In current work, we developed egg-shaped tablet (egglet) using fused deposition modeling (FDM) 3D printing. Drug-loaded polymeric filaments (1.5 mm) were prepared using HME followed by printing into egglets of different sizes and infill densities. Based on printability, …

Development, Evaluation And Application Of Insulin Solution And Film Dosage Forms For Sublingual Administration, Anuja Paprikar

Theses and Dissertations

The major barrier for sublingual absorption of large molecules like insulin is low permeability owing to the hydrophilic nature of insulin. One approach to overcome this barrier is to sublingually co-administer insulin with permeation enhancers (HPβCD and poloxamer 188). In vitro performance of permeation enhancers was screened across cellulose acetate membrane to select the concentrations of both enhancers, which were further evaluated across four models (MatTek tissue model, MDCK cell line, rat and porcine esophagus). The insulin solution with combination of HPβCD (5%) and poloxamer 188 (0.5%) indicates higher permeation as compared to that of only insulin across all the …

Nvestigation Of Dissolution And Dispersion Behavior Of Ritonavir From Amorphous Solid Dispersion, Nitprapa Siriwannakij

Theses and Dissertations

The aim of this study was to develop ritonavir amorphous solid dispersion (ASD) formulation, investigate its aqueous dissolution and dispersion behavior, and predict potential pharmacokinetic parameters by in-silico modeling. The binary/ternary ASDs of ritonavir with PVPVA or HPMCAS-MG in the absence or presence of surfactants were prepared by using the hot-melt extrusion method. The amount of ritonavir was fixed at 20 %w/w, while amount of polymer and surfactant in the formulation was varied. The film-casting technique was used to confirm the miscibility of drug and polymer in the absence and presence of surfactant in different formulations. PXRD and DSC analyze …

Oil/Water Nanoemulsion Biodistribution In Mice Upon Intravenous Administration, Jiayi Chen

Theses and Dissertations

The present study aimed to explore the biodistribution of O/W nanoemulsions (NE) upon intravenous administration. Three NEs were prepared with distinctive droplet sizes: SE (29 ± 1 nm), ME (214 ± 2 nm) and LE (883 ± 16 nm) without overlapping of the size distribution. Kolliphor® HS15 was used as the only surfactant for these three NEs, so that their droplets had similar surface structure. The NEs droplet size was stable under room temperature for minimum 3 days in phosphate buffer saline (PBS) and in mice plasma in vitro for 4-hour at 37°C. A lipophilic fluorescent dye, 1, 1’-dioctadecyl-3, 3, …

Agal Antigen And Rutinose Glycosides As Model Compounds For The Design Of Classical And Conformational Glycomimetics, Dhwani Ashish Mehta

Theses and Dissertations

αGal or Galili epitope (αGal(1→3)βGal(1→4)GlcNAc) is a natural trisaccharide associated with cell-surface glycoproteins of certain mammalian and non-mammalian cells. The saccharide is not expressed by humans and anti-αGal antibodies account for ~1% of the total circulating antibodies in sera as a result of our constant exposition to the antigen from food and intestinal flora. Our interest in αGal relies on its involvement in a variety of pathologies including red meat allergy, hyperacute xenotransplant rejection, and parasitic and bacterial infections. In particular, we have an interest in developing structurally simple glycomimetics for engaging in high-affinity binding αGal-recognizing receptors such as the …

Chemical Synthesis And Evaluation Of Azotochelin Analogs As Anticancer Agents And Their Ability To Reverse Anticancer Drug Resistance, Nishant Karadkhelkar

Theses and Dissertations

Cancer has been plaguing the humanity for several decades. In the meanwhile, multi-drug resistance (MDR) is causing abatement of effective therapeutic drugs, necessitating discovery of new class of anticancer agents. Natural products have been proved to be a promising source of structurally new anticancer agents. A specific class of bacterial secondary metabolites, named siderophores have been explored as potential anticancer agents. Enterobactin is one of the most studied siderophores as a potential anticancer agent. Azotochelin is a structurally similar but structurally simpler siderophore compared to enterobactin. Our research project focused on the evaluation of the structure activity relationship assessment of …

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 …

Strategies And Devices For Improving Respiratory Drug Delivery To Infants And Children With Cystic Fibrosis, Karl Bass

Theses and Dissertations

Cystic Fibrosis (CF) is a degenerative disease, which causes thickening of the airway surface liquid and reduced mucociliary clearance, which provides an ideal habitat for bacterial infections. Early treatment of CF in children can prevent chronic infection, improve quality of life, and increase life expectancy. The most predominant bacteria found in CF-diseased lungs is Pseudomonas aeruginosa (Pa), which can be treated with inhaled tobramycin. Excipient enhanced growth (EEG) powder formulations are well suited for administering tobramycin to children, as the EEG approach provides minimal upper airway loss and targeted drug delivery. This method uses an initially small aerosol for high …

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 …

Anticholinergic Burden And Risk Of Cognitive Impairment In Older Adults, Syeda Hashimi

Theses and Dissertations

Studies reveal that 10-27% of older adults chronically use anticholinergic medications. Increased cumulative anticholinergic burden scores are associated with increased risks of dementia. The mechanisms by which anticholinergic drugs negatively impact cognition remain elusive. However, researchers speculate that the drug’s impairment of cholinergic neurons promotes neuroinflammation.

We hypothesize that drugs with anticholinergic properties will induce inflammation in the brain. MCP1 and IL 6 are chemokines that contribute to neuroinflammation. We investigated the influence of diphenhydramine (Benadryl) on the production of MCP1 and IL-6 in Normal Human Astrocytes and Paroxetine on the production of MCP1 in Normal Human Astrocytes and Normal …

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 …

Ndrg1 And Myelin-Related Disease: Alcoholism And Chemotherapy-Induced Neuropathy, Guy Harris

Theses and Dissertations

Alcohol use disorder (AUD) is a prevalent neuropsychiatric disease with profound health, social, and economic consequences. With an estimated 50% heritability, identifying genes that engender risk and contribute to the underlying neurobiological mechanisms represents an important first step in developing effective treatments. Gene expression studies are an important source of candidate genes for studying AUD, providing windows into the molecular machinery engaged by the brain in response to ethanol. Our laboratory has implicated N-myc down-regulated gene 1 (Ndrg1) as a potential candidate gene that modulates ethanol-induced changes in myelin-related gene expression and acute sensitivity to ethanol. Analysis of …

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 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 …

Epigenetic Regulation Of Drug Metabolizing Enzymes In Normal Aging, Mohamad M. Kronfol

Theses and Dissertations

Geriatric populations are at a higher risk for adverse drug reactions (ADRs). This may be partly due to changes in drug metabolism in old age, but the underlying mechanisms are poorly understood. Prior research in humans and mice has shown age-associated changes to the expression of several genes involved in drug metabolism. Furthermore, studies of human blood showed that epigenetic regulation of genes encoding drug metabolizing enzymes change with age. However, it is unknown if genes in the liver are similarly affected. Therefore, we hypothesize that genes encoding drug metabolizing enzymes may show differential epigenetic regulation in the liver with …