Pharmacy and Pharmaceutical Sciences Commons^™

The Mechanism Of Pda-Peg/Copper Selectively Killing Cancer Cells And Its Application In Treating Triple-Negative Breast Cancer And Advanced Ovarian Cancer, Xiangxiang Hu

Theses and Dissertations

Cancer is one of the leading modality diseases. The number of cancer patients has increased in the last decades due to radiation, aging, stress condition, and other reasons. There are three traditional cancer therapies (radiation therapy, chemotherapy, and surgery). Even though these treatments improve the life span of cancer patients, many cancer patients still lost their lives due to the development of tolerance. Thus, it is urgent to develop new kinds of treatments to extend the life span of patients. In recent decades, nanomedicine, which utilizes nanotechnology to deliver chemotherapy agents into tumor sites and improve the anticancer effect and …

Pd-L1 Nano-Eraser: A Novel Intracellular Pd-L1 Degradation Approach And Its Application In Cancer And Alzheimer’S Disease Therapy, Mingming Wang

Theses and Dissertations

Nanoparticle-based targeted therapeutics have revolutionized the field of pharmaceutics by providing precise and efficient drug delivery systems. These therapeutics utilize nanoparticles as carriers to transport drugs selectively to the target site, reducing side effects and enhancing therapeutic efficacy. Although significant advancements have been made in nano-targeted therapies, there are many challenges that need to be addressed to fully realize their potential.

In this study, we proposed a novel approach to extend the potential application of anti-Programmed Death Ligand 1 (PD-L1) antibody (aPDL1) in cancer treatment and Alzheimer’s disease therapy by leveraging the Trim-Away pathway. aPDL1-based Trim-Away involves tagging target PD-L1 …

Catecholamine System Function Of The Medial Prefrontal Cortex Following Repetitive Mild Traumatic Brain Injury And The Use Of Benzoyl Chloride To Quantify And Identify Neurotransmitters, Leah Horvat

Theses and Dissertations

Traumatic brain injury (TBI) is a serious global health burden that causes a wide range of neurocognitive symptoms. These cognitive processes are regulated by catecholamine signaling within the prefrontal cortex (PFC) region of the brain. To quantify functional deficits in catecholamine signaling after TBI, norepinephrine (NE) and dopamine (DA) levels within the PFC were quantified from microdialysate samples using high-performance liquid chromatography coupled with electrochemical detection. A method for benzoyl chloride derivatization of neurotransmitters and analysis with liquid chromatography and tandem mass spectrometry instrumentation was also developed to detect and analyze these neurotransmitters. Overall, it was found that catecholamine signaling …

Artemisinin And Its Derivatives Reactions: Characterization Of The Reaction Products Using Lc/Tof Ms, Kogila Vijayan

Theses and Dissertations

Artemisinin (ART) is a sesquiterpene lactone and a popular malaria drug with potential anticancer properties. In this work, LC/TOF MS was used to investigate the reaction of ART with DNA bases and estradiol. ART-deoxyadenosine and ART-deoxycytidine interactions were studied in the presence of Fe (II) ions. ART-deoxyadenosine and ART-deoxycytidine reaction mixtures gave chromatographic signatures that remained unchanged at room temperature but grew after incubation at 37°C. The change in temperature from room temperature to 37°C was the main driver of adduct formation in these reactions. ART was found to react with Fe (II) ions as observed from several new chromatographic …

Computational Study Of Foldamer-Based Water Channels, Shadi Houshyar Azar

Theses and Dissertations

One of the most serious global challenges of this century is water scarcity, stemming primarily from the growing demand for freshwater and the depletion of freshwater resources. Water desalination has the potential to address this problem, but current technologies are expensive and inadequate. Here, we present novel, computationally designed channels with high water permeability and selectivity against ions, inspired by natural water channels, aquaporins. Aquaporin's unique property of transporting water while rejecting protons and other ions has led to numerous studies on incorporating such channels into different membranes for water purification applications. However, use of an aquaporin-incorporated membrane is limited …

Targeting Of Mediator Kinases For Cancer Therapy And Resistance Prevention, Zachary Thomas Mack

Theses and Dissertations

Estrogen receptor (ER)-positive breast cancers make up 70% of all breast cancer incidences in the US. Cell cycle progression of ER-positive breast cancer is highly dependent on cyclin-dependent kinases (CDK) 4 and 6, the G1/S checkpoint kinases. Inhibitors of CDK4/6 have become a major addition to the clinical arsenal against ER-positive breast cancers. CDK4/6 inhibitor palbociclib (IBRANCETM) has been approved for the treatment of ER-positive breast cancers. However, palbociclib treatment eventually fails due to the development of resistance. Laboratory studies revealed several diverse mechanisms of palbociclib resistance, making universal re-sensitization difficult to achieve. However, prevention of the adaptive process that …

Substance Use Disorders And The Behavioral Effects Of Novel And Existing Compounds, Sarah Uribe

Theses and Dissertations

These investigations aimed to study the effects of experimental compounds for use in treating and preventing substance use disorders, particularly opioid use disorder (OUD) and alcohol use disorder (AUD). Identifying and testing potential medications for these two diseases is critical since current FDA-approved medications are only modestly effective, and addiction continues to spread. We previously demonstrated that co-administration of morphine and MP-III-024 produced synergistic effects in hot plate and von Frey assays. This study evaluated whether MP-III-024 also produced synergistic effects in behavioral tests sensitive to the side effects of morphine. Our findings suggest that co-administration of morphine and MP-III-024 …

Formulation Of Encapsulated Nanoparticles Of Leek Extract As Antimicrobial And Anticancer Agent, Rawan Hassan Mohamed Elghanam

Theses and Dissertations

Leek extract (LEK) has broad therapeutic activity. However, plant extract use has many drawbacks, which could be resolved using nanocarriers. The purpose of this research work was to prepare chitosan nanoparticles (CS NPs) encapsulating LEK and investigate their antioxidant, antimicrobial, and anticancer activity. Gas chromatography-mass spectroscopy was used to determine the LEK components. The CS-LEK NPs were produced by tripolyphosphate (TPP) crosslinking with chitosan (CS) the ionic gelation methodology. The particle size was 331 nm, zeta potential (ZP) was 28.9 mv, polydispersity index (PDI) was 0.4, encapsulation efficiency (EE) was 65.6%, and loading capacity (LC) was 28.8 % of the …

Design And Synthesis Of Substituted N,3,3-Triphenylpropanamide And 1-Benzhydryl-N-Phenylazetidine-3-Carboxamide Analogs And Their Biological Evaluation, Michael Dorogan

Theses and Dissertations

As D₁R agonism has significant implications in the treatment of cognitive deficits, we sought to develop novel D₁R PAMs, through the derigidification of BMS D₁R PAM hit compound. While we were able to synthesize derigidified analogs of the BMS hit compound, derigidification did not produce active D₁R ligands.

Role Of Histone Deacetylase (Hdac) In Epithelial To Mesenchymal Transition (Emt) In A Human Cholangiocyte Model Of Ischemic Cholangiopathy, Priyanshi Pragnesh Parikh

Theses and Dissertations

Organ transplants are a vital intervention for many diseases that result in end stage organ failure. Currently, the donation pool is not meeting the demands of the transplant list. Expanding this pool to include donation after cardiac death (DCD) is highly sought-after. However, the use of DCD livers can lead to increased odds of graft failure and ischemic cholangiopathy. The loss of epithelialization and fibrosis that occurs during ischemic cholangiopathy is characteristic of these cells undergoing epithelial-to-mesenchymal transition (EMT). The biological changes the cell experiences enhance migratory capacity, invasiveness, and increased resistance to apoptosis. Our earlier studies have shown differential …

The Impact Of Hiv-1 Tat And Morphine On Spatial Distribution Of Drugs In The Brain., Austin M. Jones

Theses and Dissertations

Despite combination antiretroviral therapy effectively suppressing HIV within the periphery, the central nervous system (CNS) remains affected by the virus. Approximately half of people living with HIV will experience HIV-associated neurocognitive disorders (HAND) or neuroHIV. Concurrent opioid use exacerbates neuroHIV by promoting neuroinflammation, viral replication, and potentially altering the antiretroviral concentrations within the brain.

Using a transgenic mouse that expresses the HIV-1 Tat protein, we examined the effects of Tat and morphine on antiretroviral accumulation and distribution and the effects of Tat on morphine accumulation within the brain using infrared matrix-assisted laser desorption electrospray ionization with mass spectrometry imaging (IR-MALDESI-MSI). …

Assessing Drug Development Proporties Of Antithrombotic And Anti - Cancer Agents, Elsamani I. Abdelfadiel

Theses and Dissertations

The current GAG anticoagulants such as heparin, heparin derivatives, and vitamin K antagonists, such as warfarin continue to be the backbone of anticoagulant therapy. These drugs act through an indirect mechanism to convey inhibition of several coagulation enzymes. However, xv their use leads to several serious adverse effects, such as excessive bleeding risk and unpredictability of patient response. Regardless of their clinical achievement, every individual agent is accompanied by several side effects, particularly major/minor bleeding, thrombocytopenia, drug-food or drug-drug interactions, or absence of antidote. Of all these side effects, bleeding, and a lack of an effective antidote to reverse excessive …

Unraveling The Anti-Inflammatory Mechanisms And Efficacy Of Cannabidiol On The Progression Of A Murine Model Of Multiple Sclerosis From The Innate To The Adaptive Immune System To Clinical Symptoms, Christa Marie Frodella

Theses and Dissertations

Cannabidiol (CBD), a non-psychotropic phytocannabinoid with structural similarity to Δ 9 -tetrahydrocannabinol (THC), is currently being investigated as a therapeutic for its immunosuppressive effects. One disease for which CBD is extensively researched is multiple sclerosis (MS), a demyelinating, autoimmune disorder, and its murine model counterpart, experimental autoimmune encephalomyelitis (EAE). The focus of this dissertation aimed to analyze the transcriptomic brain pathways in EAE and its comparison to MS in addition to CBD’s immunosuppressive mechanisms in the innate and adaptive immune systems. Evidence presented here showed that transcriptomic signaling pathways in the EAE brain of mice with clinical symptoms were similar …

Changes In The Regulation Of The Unfolded Protein Response During Aging In Peromyscus, Elham Soltanmohammadi

Theses and Dissertations

Endoplasmic reticulum (ER) stress has been linked to various metabolic pathologies, neurodegeneration, and aging. Although various mechanistic aspects of the resulting unfolded protein response (UPR) have been elucidated, its regulation in genetically diverse populations remains elusive. In the present study we evaluated the expression of chaperones BiP/GRP78, GRP94 and calnexin (CANX) in the lungs, liver, and brain of 7 months old and 2–3 years old outbred deer mice P. maniculatus and P. leucopus. Chaperones’ _expression was highly variable between species, tissues and ages suggesting that levels of expression of individual chaperones do not change consistently during aging. Despite this variation, …

Genomic Analysis Workflows To Identify Mutational Signatures And Structural Variations In Ovcar8 Cells And Rad51d-Deficient Mouse Embryonic Fibroblasts, Manli Yang

Theses and Dissertations

Specific genomic profiles associated with exposure to DNA damaging agents have been identified in cancer related genes, revealing that mutational patterns can be carcinogen- specific. However, there have been limited efforts to demonstrate similar clear relationships for endogenous mutational processes. One endogenous source of mutations is contamination of the deoxynucleotide pool with damaged bases that, if incorporated into DNA, cause mutations.

The Catalog of Somatic Mutations In Cancer (COSMIC) represents an international effort to characterize mutations in cancer. A mutational signature is the pattern of mutations generated by a mutational process. Each mutational process contains two parts: DNA damage and …

Development Of Peptidomimetic Inhibitors Targeting The Polo Box Domain Of Plk1 As Potential Cancer Therapeutics, Jessy Mariam Stafford

Theses and Dissertations

PLK1 overexpression has shown to be associated with tumor progression and an unfavorable prognosis in a wide variety of cancer types. Interfering with PLK1 genetically and chemically induces apoptotic cell death in cancer cells thus confirming PLK1 as a validated anticancer target. From a drug discovery perspective, PLK1 offers two functionally distinct, essential, and interconnected target sites in one molecule. These are the ATP binding kinase domain (KD) and the unique Polo Box Domain (PBD), where the interplay between these results in dynamic structural regulation of catalytic activity and sub cellular localization. Since the KD is conserved among kinases and …

Peromyscus Maniculatus Bairdii And Peromyscus Maniculatus Sonoriensis Polymorphisms, Matthew Dixon Lucius

Theses and Dissertations

Sequencing technology has advanced greatly over the past couple of decades. This has led to many studies developing hypotheses based on genomic data. This requires many genomic studies to have up-to-date information on the species’ or subject’s genome being investigated. If a study does not have accurate or up-to-date background information, then they cannot fully develop their theories that are being established. In this study, I utilize outbred Peromyscus maniculatus, deer mice that are genetically diverse, to record the polymorphisms that are found throughout the Peromyscus maniculatus genome. I first explore the differences between the polymorphisms found in Peromyscus …

Medication Therapy Management Implementation In Conjunction With A Rural Health Clinic In Minnesota: A Cqi Impact On Diabetes Metrics, Abigail Sirek Pharmd

Theses and Dissertations

The purpose of this continuous quality improvement project was to implement a pharmacist-led Medication Therapy Management (MTM) clinic in rural, central Minnesota and assess the impact on patients’ healthcare over a six-month period. Patients were identified through the clinic’s diabetes registry, which included patients 18 through 75 years old with a diagnosis of diabetes not meeting all five D5 goals, as recommended by the Minnesota Community Measurements, independently referred by the provider, or be identified by their insurance company as a patient that would benefit from an MTM visit. The D5 focuses on blood pressure and blood sugar control, appropriate …

Discovery And Mechanistic Study Of Novel Pbd-Targeted Inhibitors Of Plk1 For Prostate Cancer Treatment, Danda Pani Chapagai

Theses and Dissertations

Polo-like kinase 1 (PLK1) is a central player in regulating entry into and progression through mitosis. Inhibition of sub-cellular localization and kinase activity of PLK1 through the Polo-box domain (PBD) is emerging as a viable alternative to ATP binding site directed drugs for which the development of resistant mutants and inhibition of closely related members of the PLK family (tumor suppressor roles) are primary concerns. I describe related novel non-peptidic PBD binding inhibitors, termed abbapolins, identified through successful application of the REPLACE strategy and demonstrate their potent antiproliferative activity in prostate tumors and other cell lines. Furthermore, the abbapolins show …

Mediator Kinase Inhibitors For Breast Cancer Therapy, Xiaokai Ding

Theses and Dissertations

Breast cancers (BrCa) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel …

Selective Small Molecule Targeting Of Mcl-1 In Multiple Myeloma, Omar S. Al Odat

Theses and Dissertations

Multiple Myeloma (MM) is a deadly blood malignancy, characterized by the uncontrolled proliferation of aberrantly differentiated plasma cells. MM is challenging to diagnose and treat, accounting for approximately 12% of hematologic malignancies. The overexpression of anti-apoptotic group of Bcl-2 family proteins, particularly Myeloid cell leukemia 1 (Mcl-1), play a critical role in the pathogenesis of MM. The overexpression of Mcl-1 is associated with drug resistance and overall poor prognosis. Thus, inhibition of the Mcl-1 protein is an attractive therapeutic strategy against myeloma cells. Over the last decade, the development of selective Mcl-1 inhibitors has seen remarkable advancement. In this project, …

Repurposing Of Small Molecule Inhibitor Ym-155 Inhibits High-Risk Neuroblastoma Growth By Directly Inhibiting Survivin Protein, Danielle Crystal Rouse

Theses and Dissertations

High-risk neuroblastoma (NB) is an aggressive pediatric tumor which develops from the extracranial sympathetic nervous system and accounts for almost 15% of all childhood cancer-related deaths. Current therapies include high-dose chemotherapy and radiation which have long-term toxic side-effects. Despite these intensive therapies, the overall survival rate of NB is less than 50%. Therefore, developing novel therapeutic approaches by directly targeting the molecular mechanisms that drives NB progression is very important. In the present study, we analyzed genomic datasets of 1235 NB patients and discovered that overexpression of survivin coding gene BIRC5 strongly correlates with poor overall and event-free survival of …

Budget Impact Analysis Of Upadacitinib For The Management Of Moderate-To-Severe Atopic Dermatitis In Patients Treated With Systemic Therapies In The United States, Haya O. Alobaid

Theses and Dissertations

Objective: This study evaluated the budget impact of introducing upadacitinib for patients with uncontrolled moderate-to-severe atopic dermatitis (AD) from a United States (U.S.) private payer perspective.

Methods: The model estimated costs before and after the adoption of upadacitinib for a hypothetical one million covered lives over 3 years. The model included immunosuppressant agents and dupilumab. Market uptake was assumed to be 2% per year. Treatments incur a cost for drug acquisition, and the costs associated with drug administration, laboratory testing, and clinic visits. The model calculated the impact on the budget in 2022 U.S. dollars. Various assumptions on market …

The Economic Value Of Pharmacist-Physician Collaborative Care Models In Hypertension Management, Jessica S. Jay

Theses and Dissertations

Background: Hypertension is highly prevalent in the United States, affecting nearly half of all adults (43%). Studies have shown that pharmacy-physician collaborative care models (PPCCM) for hypertension management significantly improve blood pressure (BP) control rates and provide consistent control of BP. Time in target range (TTR) for systolic BP is a novel measure of BP control consistency that is independently associated with decreased cardiovascular (CV) risk. There is no evidence observed improvement in TTR for systolic BP with PPCCM is cost effective.

Objective: This study aimed to compare the cost-effectiveness of PPCCM with usual care for the management of hypertension …

Trajectories Of Medication Non-Adherence With Time-Varying Predictors And Association With Health Outcomes: A Comparison Of Classical Statistical Methods With Machine Learning Algorithms, Vasco Pontinha

Theses and Dissertations

Background: Medication adherence is a major obstacle to improving health care outcomes in long-term therapies for chronic diseases. According to the World Health Organization, interventions for improving medication adherence can have a higher impact on the health of the population than any other advance in medical treatments. Approximately 125,000 individuals die every year in the U.S. because of non-adherence to medication, representing societal costs of $100-289 billion. Previous research has successfully used group-based trajectories methods to identify similar longitudinal medication adherence trajectories. However, medication adherence is not an isolated behavior and is influenced by many factors that current interventions fail …

Examining Ayahuasca Constituents At 5-Ht2a Receptors In Search Of Antidepressant Action, Jeremy D. Rolquin

Theses and Dissertations

Recently, it has been reported that ligands of the 5-HT_2A receptor can have drastic and fast-acting efficacy towards a number of different mental health disorders, such as depression and anxiety. A mixture of Amazonian plants calledayahuasca contains multiple compounds which have been shown to interact with the serotonergic system, and the 5-HT_2Areceptor in particular.

The structurally similar compounds (DMT, harmine, harmaline, and tetrahydroharmine) found in ayahuasca were examined for differences in their physiochemical properties that might contribute to their binding affinity for the 5-HT_2Areceptor. 3D Molecular modeling and docking studies of these compounds were …

Structure-Based Drug Discovery And Development Of Protein Structure Prediction Tools Using An Empirical Force Field, Noah B. Herrington

Theses and Dissertations

Traditional drug discovery has rapidly accelerated thanks to development of computational molecular modeling. The crucial component that these computational studies hinge upon is having a well-defined, and energetically favorable structure. Structures of proteins and ligands that meet these criteria are important for accurately simulating models used to study drug binding. To demonstrate the role of accurate structure simulation in the study of these events, this thesis presents, first, a story examining the problem of accurate structure modeling of ionizable residues within protein structures, specifically aspartic acid, glutamic acid, and histidine. I present our method, which uses the HINT force field …

Protein Structure And Interaction: The Role Of Aromatic Residues In Protein Structure And Interactions Between Pyridoxine 5'-Phosphate Oxidase/Dopa Decarboxylase, Mohammed H. Al Mughram

Theses and Dissertations

Naturally developed proteins are capable of carrying out a wide variety of molecular functions due to their highly precise three-dimensional structures, which are determined by their genetically encoded sequences of amino acids. A thorough knowledge of protein structures and interactions at the atomic level will enable researchers to get a deep foundational understanding of the molecular interactions and enzymatic processes required for cells, resulting in more effective therapeutic interventions. This dissertation intends to use structural knowledge from solved protein structures for two distinct objectives.

In the first project, we conducted a bioinformatics structural analysis of experimental protein structures using our …

Development And Optimization Of A Low Volume Air-Jet Dry Powder Inhaler (Dpi) Platform For The Delivery Of High Dose Aerosolized Powder To Infants, Connor Howe

Theses and Dissertations

The goal of this research project was to develop an infant air-jet dry powder inhaler (DPI) platform for high-efficiency nose-to-lung (N2L) aerosol administration to infants through optimization of individual system components followed by expansion of the system to higher doses and different formulations using a new approach. Primary challenges associated with aerosol delivery to infants using the N2L route include the extremely narrow extrathoracic airways, short inspiratory times (~0.2 sec), low safe airway pressure (H₂O), and very low volumes of air (~10 mL) available to form the aerosol. The infant air-jet DPI system was comprised of three main …

Pharmacists' Role In Opioid Use Disorder And Overdose Prevention And Treatment And Their Attitudes And Perceptions Towards Distributing Naloxone Under A Standing Order, Stephen C. Ijioma

Theses and Dissertations

Background: Opioids are a class of drugs that bind to opioid receptors (mu, delta, and kappa), located in the central and peripheral nervous systems, to exert responses such as analgesia, respiratory depression, euphoria, and miosis. The opioid epidemic is characterized in large part by an increase in opioid overdose deaths. Community pharmacists are one of the most accessible healthcare professionals who frequently interact with patients and can implement OUD and opioid overdose prevention strategies. Treatment for opioid overdose and OUD include naloxone for overdose deaths as well as medication-assisted treatment for OUD.

Objective: The specific aims of this thesis include …