Medicine and Health Sciences Commons^™

Molecular Mechanisms Of Thromboxane A2 Receptor-Mediated Invasion In Lung Cancer Cells, Xiuling Li

Theses and Dissertations--Pharmacy

Thromboxane A2 receptor (TP) has been shown to play important roles in multiple aspects of cancer development including regulation of tumor growth, survival and metastasis. Molecular mechanisms of TP mediated cancer cell invasion remain to be identified. TP agonist, I-BOP, significantly elevated several matrix metalloproteinases (MMPs) including MMP-1, MMP-3, MMP-9 and MMP-10 in A549 human lung adenocarcinoma cells overexpressing TPα (A549-TPα) or TPβ (A549-TPβ). Signaling pathways of I-BOP-induced MMP-1 expression were examined in further detail as a model system for MMPs induction. Signaling molecules involved in I-BOP-induced MMP-1 expression were identified by using specific inhibitors including small interfering (si)-RNAs of …

Polymorph Formation Of Tolfenamic Acid: An Investigation Of Pre-Nucleation Association, Alessandra Mattei

Theses and Dissertations--Pharmacy

The majority of pharmaceutical products are formulated as solids in the crystalline state. With the potential to exist in different crystalline modifications or polymorphs, each solid form bears its own physical and chemical properties, influencing directly bioavailability and manufacturability of the final dosage form. In view of the importance of crystalline form selection in the drug development process, it is imperative for pharmaceutical scientists to work arduously on various aspects of polymorphism, ranging from fundamental understanding of the phenomenon at the molecular level to practical utilization of a specific crystalline form. One common feature of organic crystals is the existence …

Clinical Evaluation Of Novel Methods For Extending Microneedle Pore Lifetime, Nicole K. Brogden

Theses and Dissertations--Pharmacy

Microneedles are a minimally invasive method for delivering drugs through the impermeable skin layers, and have been used to deliver a variety of compounds including macromolecules, vaccines, and naltrexone. Microneedles can be applied to the skin once, creating micropores that allow for drug delivery into the underlying circulation from a drug formulation. The utility of this technique, however, is blunted by rapid micropore closure. This research project sought to: 1) characterize micropore lifetime and re-sealing kinetics, and 2) prolong micropore lifetime via inhibition of the skin’s barrier restoration processes. Impedance spectroscopy was used as a surrogate technique in animals and …

Influence Of Oncotype Dx® On Chemotherapy Prescribing In Early Stage Breast Cancer Patients: A Claims-Based Evaluation Of Utilization In The Real World, Kenneth Neil Kennedy

Theses and Dissertations--Pharmacy

The decision for adjuvant therapy in women with early stage breast cancer (ESBC) has historically been guided by the presence or absence of specific biological markers (hormone and HER2 receptors), age, and extent of nodal involvement. Oncotype DX® is a validated assay that quantifies protein expression that can predict the risk of cancer recurrence. This study evaluates if the use of Oncotype DX® impacts chemotherapy prescribing in ESBC. This retrospective, cohort study identified patients with ESBC from a large commercially insured population from January 2007 through June 2009. Patients were identified as having ESBC by utilizing procedure and diagnosis codes …

Role Of Alternative Macrophage Activation In Mediating Fibrosis In Pseudomonas Aeruginosa Pneumonia, Susan Elizabeth Birket

Theses and Dissertations--Pharmacy

Patients with cystic fibrosis who are infected with the pathogen Pseudomonas aeruginosa have shown favorable responses to the drug azithromycin (AZM). This drug works in an anti-inflammatory capacity, improving clinical outcomes and improving quality of life in this population. The drug has also been shown to affect macrophage polarization by shifting these cells away from an inflammatory phenotype toward an alternatively activated anti-inflammatory phenotype. The full impact of this phenotypic change is not well understood in the context of the response to P. aeruginosa infection, or the overall immune response in cystic fibrosis.

To understand how the AZM-polarized macrophage affects …

Role Of Cyclooxygenase-2 In Abdominal Aortic Aneurysms In Mice, Kamalika Mukherjee

Theses and Dissertations--Pharmacy

Abdominal aortic aneurysm (AAA) is a chronic inflammatory disease with no available pharmacological treatment. AAA formation reduces the structural integrity of the vessel and increases the susceptibility to rupture. The inflammatory response within human aneurysmal tissue is characterized by increased expression of cyclooxygenase-2 (COX-2). Similarly, in a mouse model of the disease induced by chronic Angiotensin II (AngII) infusion, we have shown that COX-2 expression in the abdominal aortic smooth muscle layer increases early in the development of the disease. Furthermore, genetic or pharmacological inactivation of COX-2 prior to disease initiation reduces AAA incidence.

The current study utilized nonhyperlipidemic mice …

The Identification And Reduction Of Energy Streams Within The Pharmaceutical Sector Using Software Algorithms, Raymond Corbett

Theses

Pharmaceutical companies are under increasing financial pressure to optimise production costs, due to a growing number of products coming off patent, research and development costs increasing exponentially and the difficulty of bringing genuinely innovative products to market. Generic drug manufacturers are not exempt from these pressures; costs must be driven down by all drug manufacturers due to the increasingly competitive healthcare market.

The operating costs of a modern Pharmaceutical Plant run to several Million Euros per annum. Complex process’s involving the consumption of large amounts of energy, and hence costs, are a necessity. Any increase in the efficiency of a …

Predictors Of Carbapenem Resistant Gram-Negative Bacteria In A Consortium Of Academic Medical Center Hospitals, Mera Ababneh

Theses and Dissertations

Background: Gram-negative resistance is a growing problem worldwide. It is generally believed that rates of resistant bacteria within a hospital are a function of antibiotic use, resistant organisms brought into the hospital, infection control efforts, and underlying severity of patient illness. The relative contribution of each to a particular resistance phenotype is unclear. P. aeruginosa is responsible for many hospital acquired infections and it may become resistant to carbapenems. In addition, newer threats to the future utility of the carbapenems are carbapenemase-producing K. pneumoniae Purpose: To determine if there is an association between the volume and composition of antibiotic use, …

The Use Of Peppermint Oil To Reduce The Nausea Of The Palliative Care And Hospice Patient, Mary Seale

Nursing Theses and Capstone Projects

A descriptive study was initiated to investigate the use of peppermint oil to reduce the nausea of the palliative care and hospice patient. Two local palliative care and hospice programs were used as sites for the study. Patients eighteen and older complaining of nausea were invited to participate in the study. The study was conducted for one and a half months. A total of eight patients consented to participate in the study with a mean age of seventy one years. The Bieri Scale, a visual-numeric analog, was used as the measurement instrument for the patients to evaluate their nausea. Results …

Nanocrystals Of Chemotherapeutic Agents For Cancer Theranostics: Development And In Vitro And In Vivo Evaluation, Christin P. Hollis

Theses and Dissertations--Pharmacy

The majority of pharmacologically active chemotherapeutics are poorly water soluble. Solubilization enhancement by the utilization of organic solvents often leads to adverse side effects. Nanoparticle-based cancer therapy, which is passively targeted to the tumor tissue via the enhanced permeation and retention effect, has been vastly developed in recent years. Nanocrystals, which exist as crystalline and carry nearly 100% drug loading, has been explored for delivering antineoplastic agents. Additionally, the hybrid nanocrystal concept offers a novel and simple way to integrate imaging agents into the drug crystals, enabling the achievement of theranostics. The overall objective of this dissertation is to formulate …

Localization And Functional Characterization Of Oatp4c1 Transporter In In Vitro Cell Systems And Human/Rat Tissues, Kuei-Ling Kuo

Theses and Dissertations--Pharmacy

The organic anion transporting polypeptide 4c1 (Oatp4c1) was previously identified as a novel uptake transporter predominantly expressed at the basolateral membrane in the rat kidney proximal tubules. Its functional role was suggested to be a vectorial transport partner of an apically-expressed efflux transporter for the efficient translocation of physiological substrates into urine, some of which were suggested to be uremic toxins. In vitro studies in polarized cell lines showed that upon transfection rat Oatp4c1 localizes at the apical membrane. The objectives of this project were to further validate the subcellular localization of Oatp4c1/OATP4C1 in rat and human tissues as well …

Mechanism Of Action Of A Novel Antifungal Compound, Amber Ward

Honors Theses

Opportunistic fungal infections have become problematic in recent years. There has been an emergence of new fungal pathogens, development of antifungal resistance, and increasing prevalence. In addition, toxicity, resistance, and lack of efficacy as a single agent limit the effectiveness of current antifungal drugs. Therefore, new drugs targeting new pathways are greatly needed. An analog derived from the marine natural product phloeodictine, analog PHL5-34A, was identified as having strong in vitro antifungal activity. In this study, its mechanism of action (MOA) was investigated in the model yeast, Saccharomyces cerevisiae. This study made use of a collection of 166 yeast mutants …

Discovery, Isolation, And Identification Of Antimalarials From Fungal Endophytes, Andrekeus Lee

Electronic Theses and Dissertations

We examined fungal endophytes for their ability to inhibit bacterial, fungal and protozoal pathogens. Once antimalarial activity was discovered and confirmed, we sought to isolate and identify the active constituent(s) of our extracts. Bioassay-guided fractionation techniques were used to isolate our active compound, the structure of which was elucidated using 1H- and 13C-NMR. 2D-NMR and LC-MS analyses helped confirm that our endophytes were indeed producing artemisinin. Growth versus production studies were conducted to optimize our growth and extraction conditions while several other variables, like temperature and culture medium, were evaluated in an effort to improve our yields. Artemisinin production under …

Antileishmania Compounds From An Unidentified Endophytic Fungus And Biotransformation Of 5,7,2`,4`,5`-Pentahydroxyflavonol, Ahmed Idris

Electronic Theses and Dissertations

Leishmaniasis is a parasitic disease remaining a major public health problem. It causes illness and death especially in developing countries. Comchemotherapeutic agents currently used are often inadequate, requiring long courses of parenteral administration, having toxic side effects or becoming less effective due to the emergence of resistant strains. Thus, there is an urgent need for new, effective, and inexpensive drugs. In the fight against leishmaniasis, natural products are important sources of novel therapeutic agents. The goal of our research is to study secondary metabolites from endophytic fungi as a source of effective antileishmanial agents. Many crude extracts from endophytic fungi …

The Effects Of A Multi-Component Wellness Program On Employee Biometrics, Jennifer Erin Patrick

Electronic Theses and Dissertations

Corporate wellness initiatives are gaining momentum as a critical indicator of business performance. Metabolic Syndrome is commonly used within corporations to assess the health of their employees and estimate potential healthcare costs. Using five risk factors (blood pressure, high density lipoprotein (HDL-C), triglycerides (TG), fasting blood glucose, and waist circumference) individuals with three or more risk factors are classified as having Metabolic Syndrome. Voluntary pre and post health screenings were conducted at a rural manufacturing plant. A multi-component wellness program was conducted over six months to determine if the program would have significant beneficial effects on employee biometrics and Metabolic …

Antimalarials From Plant Pathogenic Fungi, Mallika Kumarihamy

Electronic Theses and Dissertations

The purpose of this study was to discover antimalarial compounds from necrotropic plant pathogenic fungi. Various phytotoxins released by necrotropic plant pathogenic fungi may inhibit the plant-like metabolic pathways in the apicoplast, a chloroplast-like organelle, essential for the survival of apicomplexan parasites, such as Plasmodium which cause malaria in humans. This dissertation describes the isolation, characterization, and biological evaluation of secondary metabolites of eight fungal strains. In addition to the antiplasmodial assay, all the extracts were subjected to phytotoxic, antimicrobial, and cytotoxic bioassays. Isolation of metabolites was performed by chromatographic methods and identification was carried out by spectroscopic and spectrometric …

Isolation, Structure Elucidation And Biological Evaluation Of Natural Products From Plants And Fungi, Xiaoning Wang

Electronic Theses and Dissertations

Natural products have provided considerable value for drug discovery over the past half-century. Nearly four fifth of drugs were natural products or inspired by natural compounds. Bioactive secondary metabolites isolated from natural source, either fungal or terrestrial, are relatively safer for human health and the environment and can serve as drug or as drug leads for the development of synthetic or semi-synthetic analogs. Natural products have also been successfully used in agriculture as plant growth regulators, signal transductions, fungicides, herbicides and tranquilizers. In our continued efforts to identify bioactive compounds, seventy-seven plant and fungal extracts were evaluated using a direct-bioautography …

Functional Studies Of Novel Bioactives From Complex Host-Microbiomes As Drug Leads For Cancer, Infectious Disease, Depression And Pain, John Jason Bowling

Electronic Theses and Dissertations

The drug discovery process has become increasingly complex in comparison to early efforts particularly those involving diseases or conditions that affect large numbers of the human population. It is difficult to point directly to one factor leading evolution of the process but the definition of a mechanism of pharmacological action for a drug lead has noticeably become a higher priority. This evolution has helped diminish the stigma of natural products and compound supply issues. The issue of compound supply has also been addressed to some extent with the emergence of recombinant technologies and new synthetic methodology. With approximately 60 years …

Discovery Of Novel Glycogen Synthase Kinase-3beta Inhibitors: Molecular Modeling, Virtual Screening, And Biological Evaluation, Gang Fu

Electronic Theses and Dissertations

Glycogen synthase kinase-3 (GSK-3) is a multifunctional serine/threonine protein kinase which is engaged in a variety of signaling pathways, regulating a wide range of cellular processes. Due to its distinct regulation mechanism and unique substrate specificity in the molecular pathogenesis of human diseases, GSK-3 is one of the most attractive therapeutic targets for the unmet treatment of pathologies, including type-II diabetes, cancers, inflammation, and neurodegenerative disease. Recent advances in drug discovery targeting GSK-3 involved extensive computational modeling techniques. Both ligand/structure-based approaches have been well explored to design ATP-competitive inhibitors. Molecular modeling plus dynamics simulations can provide insight into the protein-substrate …

Design And Synthesis Of Hiv-1 Integrase Inhibitors, Sarah Chajkowski Scarry

Electronic Theses and Dissertations

In recent years, HIV-1 integrase (IN) has emerged as an attractive target for the treatment of human immunodeficiency virus type 1 (HIV-1), the causative pathogen of acquired immuno-deficiency syndrome (AIDS). Several classes of IN inhibitors are known but many of these compounds are toxic, do not show antiviral activity or display decreased potency. Therefore, new classes of potent IN inhibitors are desperately needed. The b-diketo (b-DK) class of compounds has emerged as one of the most successful classes of IN inhibitors. Although several b-DK inhibitors with potent antiviral activity are known, compounds containing b-DK motifs have limitations in drug development. …

Preformulation Characterization And Formulation Development Of Δ9-Tetrahydrocannabinol Prodrugs For Potential Treatment Of Glacuoma, Tushar Hingorani

Electronic Theses and Dissertations

Relationship between smoking marihuana and a drop in intraocular pressure (IOP) was first reported in 1971. Research efforts since then have identified a number of constituents that could be linked to this observation. Delta-9-Tetrahydrocannabinol (THC) was one of the ingredients identified. However, four decades and numerous research efforts since the first observation, it has still not been concluded whether THC is effective in the treatment of glaucoma or not. Current therapy for IOP control in glaucoma, though effective, cannot prevent vision loss completely. Thus, identification of agents that can lower IOP as well as protect the retinal ganglion cells from …

Phytochemical Studies On The Medicinal Plant Sutherlandia Frutescens, Xiang Fu

Electronic Theses and Dissertations

Sutherlandia frutescens (L.) R. Br (Fabaceae) is a multipurpose medicinal plant with diverse biological activities, and has been widely used for the treatment of cancer, AIDS, diabetes, and infectious diseases in southern Africa. The primary goal of this study was to investigate the chemical constituents of S. frutescens and develop an analytical method to analyze this plant and the dietary supplements derived from this plant. The dissertation is composed of six chapters. Chapter 1 introduces the general background of S. frutescens, including traditional uses and chemical and biological studies on the plant. Chapter 2 describes the phytochemical studies that have …

Effects Of Off-Label Prescribing On Patient Decision Making, Douglas Paul

Electronic Theses and Dissertations

Objectives: Despite the comuse of off-label prescribing in the US, no research has been conducted to understand the impact of off-label prescribing on patient decision making. This study sought to measure the impact on trust in physicians, intentions of involvement in the decision making, beliefs about the drug, and initial compliance intentions in elderly and nonelderly populations. Methods. This study was designed to assess the effects of off-label prescribing using a 2 × 2 × 2 design. Using an online panel, 830 consumers were surveyed, 409 elderly and 421 nonelderly, using 8 different scenarios based on disease criticality, off-label use …

An Evaluation Of Medicaid Programs Using Medication Use-Related Quality Measures, Vennela Thumula

Electronic Theses and Dissertations

Objective: To assess quality of care provided to Medicaid beneficiaries using medication use-related quality indicators. Methods: This study is a retrospective analysis of 2006 & 2007 Medicaid administrative claims data from 45 states and DC. Eleven medication use-related measures (adherence/persistence and standard of care) from the AHRQ initial core set were included. A composite measure of medication use-related quality was also created. Patient case-mix adjusted measure scores were computed using hierarchical logistic regression models. States were ranked on both case-mix adjusted and unadjusted scores and categorized into top (?20%), medium (60%) and bottom (?20%) performers. Agreement in rankings and groups …

Enantioselective Demethylation: The Key To The Nornicotine Enantiomeric Composition In Tobacco Leaf, Bin Cai

Theses and Dissertations--Plant and Soil Sciences

Nicotine and nornicotine are the two main alkaloids that accumulate in Nicotiana tabacum L. (tobacco), and nornicotine is the N-demethylation metabolite of nicotine. Nicotine is synthesized in the root, and probably primarily in the root tip. Both nicotine and nornicotine exist as two isomers that differ from each other by the orientation of H atom at the C-2' position on the pyrrolidine ring. (S)-nicotine is the dominant form in tobacco leaf and the enantiomer fraction of nicotine (EF_nic), the fraction of (R)-enantiomer over the total nicotine, is approximately 0.002. Despite considerable efforts to elucidate nicotine and nornicotine …

Influence Of Prescription Drug Monitoring Programs On Acetaminophen-Related Liver Toxicity, Aaron Barcelo

MPA/MPP/MPFM Capstone Projects

No executive summary.

Factors Influencing Pharmacists’ Decision To Report Adverse Events Related To Dietary Supplements, Ali M. Alhammad

Theses and Dissertations

Background: The increasing consumption of dietary supplements (DS) has drawn the attention of regulatory agencies, researchers and healthcare professionals. The US Food and Drug Administration (FDA) does not require premarketing assessment of DS considering them safe unless proven otherwise. However, the reporting rate of DS adverse events (DS-AE) is low. Objective: To describe pharmacists’ attitudes and knowledge of DS and DS information resources, and to determine the importance of selected attributes in pharmacists’ decisions to report a DS-AE. Methods: A convenience sample of practicing pharmacists in Virginia was surveyed using a web-based self-administered questionnaire. A conjoint analysis exercise was developed …

Designing Direct And Indirect Factor Xa Inhibitors, Rami Al-Horani

Theses and Dissertations

Anticoagulants are the basis for treatment and prevention of thrombotic diseases. The currently available medicines are associated with a wide range of adverse reactions that mandates developing new anticoagulants. Several lines of evidence support the superiority of factor Xa (FXa) as a promising target to develop novel anticoagulants. This work focuses on the design of direct and indirect FXa inhibitors using an interdisciplinary approach. As indirect FXa inhibitors, a focused library of tetrasulfated N–arylacyl tetrahydroisoquinoline (THIQ) nonsaccharide allosteric antithrombin activators was designed, synthesized, and biochemically evaluated to establish their structure–activity relationship (SAR). An N–arylacyl THIQ analog having carboxylate at position–3, …