Medicine and Health Sciences Commons^™

Prescription For Critical Thinking: A Discussion Of Psychotropic Medication And Counseling, Barton W. Biggs

Educational Specialist, 2009-2019

This paper examines questions about the safety and efficacy of psychotropic medication, and looks at how these questions should impact the field of counseling. The paper first looks at increasing rates of use of psychotropic medication, and establishes that nearly every clinical mental health counselor will work with clients who are taking or considering taking such medication. The paper next examines the scientific literature and establishes that there is a legitimate basis for questions to be raised about the safety and efficacy of these medications. The paper goes on to establish that there is a foundation in ethical codes and …

Antiviral Peptide Nanocomplexes As Potential Therapeutics For The Treatment Of Infectious Diseases, Jinjin Zhang

Theses & Dissertations

Hepatitis C Virus (HCV) is recognized as a major burden in global public health, which can be further exacerbated by several cofactors such as human immunodeficiency virus (HIV). Currently, there is no vaccine for HCV. The emergence of potent and highly specific direct-acting antivirals (DAA) has marked a new era in HCV therapy, however, the remaining issues like affordability, genotype dependency, and potential resistance still necessitate the development of additional therapeutic approaches to be used instead or in combination with DAA.

Recently, the antiviral peptide C5A (in our studies designated as p1) and its cationic derivative p41 have been identified …

Biodegradable Hybrid Nanogels For Combination Chemotherapy, Swapnil Desale

Theses & Dissertations

Combination chemotherapy is commonly used to treat cancer, because such a therapy regimens usually involve sequential administration of multiple drugs and allow targeting different cell signaling pathway. The co-delivery of drug combination at a controlled ratio via the same vehicle is offering the advantages such as spatial-temporal synchronization of drug exposure, synergistic therapeutic effects and suppression of drug resistance. Undoubtedly, there are several molecular and pharmacological factors that determine the effectiveness of drug combinations. A rationally designed drug combination is required since certain drug ratios and the definitive exposure to the targets of interest can only be synergistic while others …

Using A Cost Benefit Analysis To Support The Development Of A Comprehensive Business Model For A Pre-Filled, Pre-Labeled, Pre-Diluted, Sterilely Packaged, Ready-To-Use, Syringe-Based Anesthesia Delivery System, Lance B. Kennedy

Doctoral Projects

The foundation of Certified Registered Nurse Anesthetists’ (CRNAs) entire profession is built on the ability to provide anesthetic services using a variety of medications in the safest, most efficient, cost-effective way possible. The purpose of this capstone is to address, via a comprehensive cost benefit analysis, whether pre-filled syringe drug trays are a more cost-effective way to address problems as compared to vial-filled drug trays and to implement the necessary transitions in order to improve outcomes. There are a number of identifiable problems related to anesthesia medication delivery via vial-filled medication, including increased cost of healthcare, decreased patient safety to …

Phenylephrine Versus Ephedrine: Safest Vasopressor For The Neonate During Caesarean Section, James S. Hale Jr.

Doctoral Projects

One of the most common side effects of spinal anesthesia is the development of hypotension. Data collected has determined that 80% of parturients that undergo spinal anesthesia for this mode of delivery experience hypotension (Chestnut et al., 2014).

Hypotension, if sustained and severe, can lead to fetal hypoxia, neonatal depression or injury, and decreased uteroplacental perfusion. Hypotension can also cause severe health issues for the parturient including apnea, altered level of consciousness, cardiac arrest, and pulmonary aspiration. This systematic review of the literature was conducted to determine whether the administration of phenylephrine or ephedrine was safer for the neonate to …

Overcoming Innate And Acquired Therapy Resistance By Targeting Dna Repair In Human Cancer Cells, Mateusz Rytelewski

Electronic Thesis and Dissertation Repository

Genomic instability and a high mutation rate lead to heterogeneity in human tumors. Mathematical modelling predicts that these characteristics promote acquired resistance to cytotoxic and targeted therapies, by increasing the likelihood that resistant subpopulations exist at the start of treatment (and promoting the accumulation of de novo resistance mutations during treatment). As a result, genome plasticity promotes increased fitness on the population level, but individual tumor cells must nonetheless maintain a level of DNA integrity that allows for continued survival, particularly in the context of DNA-damaging therapy (which DNA repair counteracts). Thus, DNA repair proteins are a source of innate …

Synthesis Of Medicinally Relevant Thiazolyl Aryl Ketones Under Mild Conditions, Danielle M. Gardner

Health, Human Performance and Recreation Undergraduate Honors Theses

Purpose: The growing amount of clinical resistance observed in current antifungal drugs and in anti-HIV pharmaceuticals is a concern in the medical community. The purpose of this study is to develop a mild synthetic process for biomedically relevant thiazolyl aryl ketones that can be used to develop antifungal and anti-HIV drugs. We hypothesized that the proposed synthetic technique would be more efficient, produce fewer unwanted byproducts, and be more tolerant of functional groups than existing methods.

Methods: Prior to each of the ketone reactions, the necessary salt was synthesized by mixing thiazole and 9-bromofluorene neat in a reaction tube heated …

Development And Evaluation Of Amphotericin B Loaded Iron Oxide Nanoparticles For Targeted Drug Delivery To Systemic Fungal Infections, Pavan Balabathula

Theses and Dissertations (ETD)

A targeted nanotheronostic drug delivery system to diagnose and treat life threatening invasive fungal infections (IFIs) such as cryptococcal meningitis was designed, developed, characterized, and evaluated. To address the development processes, first, iron oxide nanoparticles (IONP) (34-40 nm) coated with bovine serum albumin (BSA), loaded and targeted with amphotericin B (AMB) (AMB-IONP) was formulated by applying a layer by layer approach. Several designs (A, B, C, D, & E) of AMB-IONP were developed and their physicochemical properties such as drug loading with HPLC method, particle size, poly dispersity index (PDI), and ζ-potential using dynamic light scattering (DLS) technique, morphology with …

Development Of Oral Vaccines Against Lyme Disease, Rita Raquel Dos Anjos De Carvalho E Melo

Theses and Dissertations (ETD)

Lyme Disease, caused by the spirochete Borrelia burgdorferi, is the most common vector-borne disease in the United States and Europe. If left untreated, it can lead to permanent damage to the nervous and musculoskeletal systems. In some cases, patients that receive the recommended antibiotic therapy develop a debilitating health condition associated with substantial health care costs. Despite current preventive measures, the incidence and the geographic distribution of Lyme Disease continues to increase. Recent estimates from CDC suggest that the true number of cases of Lyme Disease in the US is approximately 300,000 per year. Yet, there is currently no vaccine …

Optimization Of Lead Spectinamide Compounds As Novel Anti-Tuberculosis Agents With A Pharmacometric Approach, Ashit Rasendu Trivedi

Theses and Dissertations (ETD)

In an effort to combat the global Tuberculosis pandemic, Dr.Richard E. Lee and his group at St.Jude Children’s Research Hospital designed a novel series of anti-tuberculosis agents, spectinamides – semi-synthetic analogs of spectinomycin. Spectinamides are a potent inhibitor of mycobacterial ribosomes and overcome efflux mediated drug resistance in M. tb. Spectinamides have shown an excellent in vitro activity, which makes them well suited for further lead optimization and preclinical development. We hypothesized that through pharmacokinetic (PK) and pharmacodynamics (PD) model-based dosing optimization studies, we could strategically guide the selection and refinement of more potent and effective anti-TB spectinamides. Biopharmaceutical in …

The Chemopreventive Effect Of Polymethoxyflavones: Targeting The Colorectal Cancer Stem Cells, Fei Xu

Doctoral Dissertations

Among all the cancers, the death rate of colorectal cancer is one of the highest. Evidence from both murine xenograft model and human trials have shown cancer stem cells (CSCs) are responsible for the initiation, metastasis and recurrence of multiple cancers therefore targeting colorectal CSCs would be a promising chemo-preventive/ therapeutic strategy. Polymethoxyflavones including nobiletin (NBT) and 5-demethylatednobiletin (5DN) are exclusively found in citrus peels and have been shown to have anti-cancer effects. Our previous studies in the biotransformation and tissue distribution of NBT and 5DN have shown that in order to fuller evaluate the biological impact of those two …

Design And Synthesis Of Novel Chloroquine-Based Antimalarials, Kevin Vincent Murphy

Dissertations and Theses

Malaria is an infectious, often fatal disease that afflicts nearly 200 million people every year. The disease, characterized by recurring and extreme flu-like symptoms, is caused by the protozoan parasite Plasmodium falciparum. Victims usually contract the disease through a mosquito vector. Chloroquine is a chemotherapeutic that was introduced in the 1940s. For many years the drug was the foremost treatment of malaria, being effective and producing few side effects. Unfortunately, tolerance to chloroquine developed when the parasite evolved a resistance mechanism. Newer drugs have been developed and implemented, but these medicines also show a decreasing effect with continued administration. …

Challenges In The Pharmacokinetics Of Therapeutic Proteins, Wararat Limothai

Theses and Dissertations (ETD)

Due to the complex structure and complicated disposition pattern of therapeutic macromolecules, their pharmacokinetic interpretation has many challenges. Two of these challenges were investigated in this dissertation: 1) the error of classical bioavailability assessment observed during subcutaneous (SC) administration of therapeutic macromolecules that undergo target-mediated drug disposition (TMDD) and 2) the ontogeny of the neonatal Fc receptor (FcRn) expression along with its effect on the pharmacokinetics of monoclonal antibodies (mAbs) during development.

TMDD often well describes the pharmacokinetics of therapeutic proteins that have high specificity and affinity of binding to their target receptors. The target receptors can be saturated by …

Discovery Of Novel Tubulin Polymerization Inhibitors And Survivin Inhibitors As Potential Anticancer Agents, Min Xiao

Theses and Dissertations (ETD)

Melanoma is the most dangerous form of skin cancer and accounts for the majority of skin cancer death. Although considerable advances have been made in melanoma treatment in recent years, there are many problems associated with current therapies. Drug resistance to targeted therapies is almost inevitable after short term treatment. Immunotherapies generally have low response rate and the effects vary among patients. Therefore, the need to develop new and more effective treatment for melanoma is high.

The work presented here focuses on discovery of novel anticancer agents for melanoma by targeting two important cancer targets: tubulin and survivin. Microtubules play …

Polymeric Nanocarriers For Treatment Of Melanoma And Genetically Modified Mesenchymal Stem Cells To Improve Outcome Of Islet Transplantation, Vaibhav Mundra

Theses & Dissertations

Melanoma is a lethal malignancy with limited treatment options for advanced metastatic stages. New targeted therapeutic options with discovery of BRAF and MEK inhibitors have shown significant survival benefit. Despite the recent progress, inefficient tumor accumulation and dose limiting systemic toxicity remains pressing challenges for treating metastatic melanoma and there is a need for drug delivery approach to improve therapeutic index of chemotherapeutics. Nanoparticle based drug delivery represents promising approach to enhance efficacy and reduce the dose limiting systemic toxicity. Nanoparticles can be formulated either by physical encapsulation of drugs or by covalent conjugation of drugs to the polymeric backbone. …

Development Of Hypoxia Trapping Enhanced Bb2r-Targeted Radiopharmaceutics For Prostate Cancer, Zhengyuan Zhou

Theses & Dissertations

The Gastrin-Releasing Peptide Receptor (BB2r) has been investigated as a diagnostic and therapeutic target for prostate and other cancers due to the high expression level on neoplastic relative to normal tissues. A variety of BB2r-targeted agents have been developed utilizing the bombesin(BBN) peptide, which has shown nanomolar binding affinity to human BB2r. However, as with most of the low-molecular weight, receptor-targeted drugs, a major challenge to clinical translation of BB2r-targeted agents is the low retention at the tumor site due to intrinsically high diffusion and efflux rates. Our laboratory seeks to address this deficiency by developing synthetic approaches to selectively …

Targeted Magnetite Tissue Delivery For Antiretroviral Pharmacokinetics, Tianyuzi Li

Theses & Dissertations

Pharmacokinetics and pharmacodynamics studies are required for bench to bedside translation of any new drug, formulation or device. Multifunctional magnetite nanocarriers enable magnetic resonance imaging tracking of nanomaterial encased antiretroviral drugs serving to improve the effectiveness of formulation developments. Targeting ligands used to deliver nanoparticles to HIV harboring cells can be tested using multifunctional magnetite nanocarriers. To this end, two types of magnetite nanocarriers were developed. These included small magnetite antiretroviral therapy particles. The second were ALN-PEG coated magnetite particles for testing macrophages targeting ligands. Overall, these works should serve to speed the development of long acting nanoformulated ART to …

Role Of Macrophages In Muscle Transfection With Pdna/Pluronic Formulation, Vivek Mahajan

Theses & Dissertations

Non-ionic amphiphilic block copolymers of poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO), Pluronics, arranged in a tri-block structure PEO-PPO-PEO, have raised a considerable interest in skeletal muscle Gene Therapy. Previous studies have demonstrated that co-administration of Pluronics with naked plasmid DNA (pDNA) by direct i.m. injection enhanced transgene expression not only in muscle but also in distal lymphoid organs (spleen and lymph nodes) and this response was strain-dependent; not observed in athymic (BALB/c nu/nu) mouse; suggesting a role of immune cells in gene transfer to skeletal muscles. Therefore, we first evaluated the role of inflammation and inflammatory cells, on muscle …

Computational Modeling Of Rna-Small Molecule And Rna-Protein Interactions, Lu Chen

Dissertations & Theses (Open Access)

The past decade has witnessed an era of RNA biology; despite the considerable discoveries nowadays, challenges still remain when one aims to screen RNA-interacting small molecule or RNA-interacting protein. These challenges imply an immediate need for cost-efficient while predictive computational tools capable of generating insightful hypotheses to discover novel RNA-interacting small molecule or RNA-interacting protein. Thus, we implemented novel computational models in this dissertation to predict RNA-ligand interactions (Chapter 1) and RNA-protein interactions (Chapter 2).

Targeting RNA has not garnered comparable interest as protein, and is restricted by lack of computational tools for structure-based drug design. To test the potential …

Regulation Of Receptor Tyrosine Kinases By Ubiquilin1., Zimple Kurlawala

Electronic Theses and Dissertations

Receptor Tyrosine Kinases (RTK’s) like EGFR, Insulin Receptor, IGF1R and others mediate growth, proliferation and balance between apoptosis and survival. Dysregulation of RTK activity has been identified in a wide range of cancers and contributes to initiation, progression and metastasis of tumors. Ubiquilins (UBQLN) are fairly novel proteins and are studied mostly in the field of neurodegenerative disorders. Our laboratory recently discovered a link between UBQLN1 function and tumorigenesis. UBQLN1 is lost in about 50% of non-small cell lung cancer (NSCLC) cases. We have identified an interaction between UBQLN1 and IGF1R. Furthermore, UBQLN1 regulates activity of IGF1R and EGFR. Following …

Metabolomics Of Transformed Mda-Mb-231 Cell Lines Expressing Different Levels Of Human Arylamine N-Acetyltransferase 1 (Nat1)., Samantha Marie Carlisle

Electronic Theses and Dissertations

Human arylamine N-acetyltransferase 1 (NAT1) is a phase II xenobiotic metabolizing enzyme that is found in almost all tissues of the body. Expression of NAT1 is commonly elevated in several cancers including breast cancer. However, the exact mechanism by which NAT1 expression affects cancer risk and progression remains unclear. Three MDA-MB-231 breast adenocarcinoma cell lines that stably express wild-type, increased, and decreased levels of human NAT1 have been constructed and characterized for NAT1 mRNA, NAT1 acetylation activity, cell doubling rates, and endogenous acetyl-CoA levels. Differences in polar metabolic profile between these three cell lines were investigated using a comprehensive GC×GC−TOF …

Improved Oncolytic Virotherapy By Increasing Virus Spread Within Tumors., Stephen Wechman

Electronic Theses and Dissertations

Oncolytic adenoviruses (Ads) have great therapeutic potential for lung cancer. Cancer selective E1b-deleted Ads are safe, however their efficacy remains limited clinically. To improve E1b-deleted Ads, Adhz60 was selected for greater anti-cancer efficacy by a process called bioselection, producing AdUV. AdUV preferentially lysed A549 and H1299 lung cancer cells more effectively than both the cancer selective Adhz60 and non-selective Ad5. AdUV induced greater LC3-II expression, relative to LC3-I, indicating that AdUV (30.9-fold) induced autophagy more effectively than Ad5 (12.2-fold) and Adhz60 (7.8-fold) in A549 cells. Mice treated with AdUV had significantly smaller tumors (p-value < 0.001) and prolonged survival (p-value = 0.0005) than mice treated with the negative control AdGFP. These results suggest that AdUV efficiently lyses lung cancer cells in vitro and in vivo.

Identifying Hepatocellular Carcinoma (Hcc) Cells With Cancer Stem Cell-Like Properties., Harshulkumar M. Pandit

Electronic Theses and Dissertations

Hepatocellular Carcinoma (HCC) is a challenging condition to treat in the clinic due to its distinct tumor phenotype, aggressive growth, and chemotherapy resistance. Cancer Stem Cells (CSCs) are a poorly differentiated subpopulation of cells within the tumor microenvironment, and role of CSCs in tumor initiation and chemotherapy resistance is not well understood in HCC. In this study, we have successfully identified HCC cells with CSC-like properties that showed resistance to Doxorubicin. Using the established serum free culture techniques, we have enriched CSC-like cells among hepatocellular cancer cells. These enriched cells exhibit all CSC-like properties i.e. self-renewal capability, anchorage independent growth …

Chronic Ethanol Exposure Sensitizes The Lung In A Mouse Model Of Endotoxemia-Induced Acute Lung Injury : Potential Role Of Plasminogen Activator Inhibitor-1., Lauren G. Poole

Electronic Theses and Dissertations

The goal of this project is to characterize a new mouse model of alcohol-enhanced acute lung injury (ALI) and to determine the role of plasminogen activator inhibitor-1 (PAI-1) in this model. Male mice (WT and PAI-1-/-) were exposed to ethanol-containing Lieber-DeCarli diet or pair-fed control diet for 6 weeks; some animals were administered intraperitoneal lipopolysaccharide (LPS) prior to sacrifice. Chronic alcohol feeding enhanced induction of the chemokines MIP-2 and KC (murine IL-8 homologues) after LPS injection in wild type animals. This enhanced chemokine expression did not correlate with enhanced pulmonary neutrophil infiltration, however animals exposed to chronic ethanol showed sustained …

Suramin Protects From Cisplatin-Induced Acute Kidney Injury., Tess Dupre

Electronic Theses and Dissertations

In rodent models, suramin improves recovery following acute kidney injury (AKI). We hypothesized that suramin would be useful in protection against cisplatin-induced AKI. This hypothesis was tested by pre-treating C57BL/6j mice with suramin prior to cisplatin. Our data indicates that suramin protects the kidney from injury by decreasing cisplatininduced decreases in kidney function. Renal histology indicated that suramin significantly protected from cisplatin-induced AKI. Data indicate that suramin pretreatment attenuated mRNA expression of pro-inflammatory cytokines and chemokines following cisplatin treatment, while also decreasing markers of cell stress and cell death. We utilized the same experimental design with 10-month old FVB mice …

The Regulation And Mechanisms Of Egfr-Mediated Apoptosis In Mda-Mb-468 Cells., Nicole Marion Jackson

Electronic Theses and Dissertations

Background: The Epidermal Growth Factor Receptor (EGFR) is a 170- kilodalton transmembrane protein that belongs to the ErbB family of receptor tyrosine kinases. Upon ligand-mediated activation, the EGFR responsible for cell growth, proliferation, and tissue homeostasis in epithelial cells; however, the EGFR is overexpressed in many human malignancies including MDA-MB-468 cells, a metastatic breast epithelial cell line. Previous studies have indicated that within the MDA-MB-468 cell line, receptors at the cell surface promote cell growth when activated with Epidermal Growth Factor (EGF) ligand. Activated receptors that are internalized to the endosomes however induce apoptosis. This contrasting response at different cellular …

Searching For Novel Ligands For The Cannabinoid And Related Receptors., Pritesh Prakash Kumar

Electronic Theses and Dissertations

The first purpose of the present dissertation was to apply a high throughput assay to systematically screen a library of food and drug administration (FDA)-approved drugs as potential ligands for the cannabinoid receptor 2 (CB2). A cell-based, homogenous time resolved fluorescence (HTRF) method for measuring changes in intracellular cAMP levels was validated and found to be suitable for testing ligands that may act on CB2. Among the 640 FDA-approved drugs screened, raloxifene, a drug used to treat/prevent post-menopausal osteoporosis, was identified for the first time to be a novel CB2 inverse agonist. The dissertation reporting these results demonstrated that by …

Promoting Differentiation And Survival Of Human C-Kit+ Cardiac Progenitor Cells Ex Vivo., Tareq Al-Maqtari

Electronic Theses and Dissertations

c-kit+ cardiac progenitor cells (CPCs) have recently gained much attention due to the therapeutic effects they exert on cardiac function following their administration into the infarcted heart as evidenced by animal studies and by a recent clinical trial (SCIPIO). However, injecting these cells in the heart is associated with poor differentiation into specialized cardiac cell types and with rapid death of the engrafted cells. With the ultimate goal of advancing cardiac stem cell therapy, we sought to facilitate the differentiation of human CPCs into cardiac cell types (e.g. cardiomyocytes, smooth muscle cells, endothelial cells and cardiac fibroblasts) by overexpressing selected …

Biodegradable Nano-Hybrid Polymer Composite Networks For Regulating Cellular Behavior, Charles Henley Sprague

Masters Theses

Photo-crosslinkable polymeric biomaterials have emerged in the field of biomedical research to promote tissue regeneration. For example, scaffolds that can be crosslinked and hardened in situ have been known to make suitable implant alternatives. Since injectable and photo-crosslinkable biomaterials offer the advantage of being minimally invasive, they have emerged to compete with autografts, a current highly invasive method to repair diseased tissue. A series of novel photo-crosslinkable, injectable, and biodegradable nano-hybrid polymers consisting of poly(ε-caprolactone fumarate) (PCLF) and polyhedral oligomeric silsesquioxane (POSS) has been synthesized in our laboratory via polycondensation. To engineer the material properties of the nano-hybrid networks, varied …

Overcoming Acquired Resistance To Braf Inhibitors By Novel Synergistic Drug Combination And Discovery Of Novel Smac Mimetics As Selective Survivin Inhibitors, Jin Wang

Theses and Dissertations (ETD)

The first part (Chapter 1 and 2) of this dissertation presents a novel combination study of melanoma therapy. Acquired clinical resistance to vemurafenib, a selective BRAFV600E inhibitor, arises frequently after short term chemotherapy. Since the inhibitions of targets in the RAFMEK-ERK pathway result in G0/G1 cell cycle arrest, vemurafenib-resistant cancer cells are expected to escape this cell cycle arrest and progress to subsequent G2/M phase. We hypothesized that a combined therapy using vemurafenib with a G2/M phase blocking agent will trap resistant cells and overcome vemurafenib resistance. To test this hypothesis, we first determined the combination index (CI) values of …