Synthesis Of Novel Azetidines, Amber Thaxton

University of New Orleans Theses and Dissertations

Azetidine is a four-membered nitrogen-containing heterocyclic ring that has recently received a great deal of attention as a molecular scaffold for the design and preparation of biologically active compounds. Structure-activity studies employing functionalized azetidines have led to the development of variety of drug molecules and clinical candidates encompassing a broad spectrum of biological activities.

Herein, the synthesis a novel series of 3-aryl-3-arylmethoxyazetidines is described. Selected 3-aryl-3-arylmethoxyazetidines were evaluated for their binding affinity to multiple monoaminergic transporters for the potential treatment of methamphetamine addiction. It was discovered that this scaffold exhibits high binding affinity (nM) for both the serotonin and dopamine …

Tobramycin Disposition In The Lung Following Airway Administration, Min Li

Theses and Dissertations

Tobramycin disposition following airway administration was evaluated by meta-analysis of human data in the literature and, experimentally, using a realistic ex vivo model, the isolated perfused rat lung preparation (IPRL). Pulmonary bioavailability of inhaled tobramycin in published studies was re-evaluated separately for CF and healthy adults, with the drug’s intrinsic pharmacokinetic (PK) parameters obtained from intravenous (IV) studies in the literature. While large variations in tobramycin’s clearance precluded accurate assessment of its bioavailability, the results were indicative of substantial pulmonary absorption, in spite of its hydrophilic and poly cationic properties. To explore its disposition kinetics and mechanisms following airway administration, …

Evaluation Of Vdr-Coactivator Inhibitors Using Biochemical And Cell-Based Assays, Athena Marie Baranowski

Theses and Dissertations

ABSTRACT

EVALUATION OF VDR–COACTIVATOR INHIBITORS USING BIOCHEMICAL AND CELL–BASED ASSAYS

by

Athena Baranowski

The University of Wisconsin–Milwaukee, 2013

Under the Supervision of Dr. Alexander Arnold

The vitamin D receptor (VDR) is a ligand–dependent transcription factor, which belongs to the nuclear receptor superfamily. VDR–mediated gene regulation is governed by coregulators (coactivators and corepressors). VDR coregulator binding inhibitors (CBIs), which were discovered using high throughput screening (HTS), were evaluated using cell–based assays and biochemical assays to determine their ability to inhibit the interaction between VDR and steroid receptor coactivator–2 (SRC–2). Determining their ability to inhibit the VDR–SRC–2 interaction can lead to the …

Erg11-Mediated Azole Resistance In Candida Albicans, Stephanie Ann Flowers

Theses and Dissertations (ETD)

Although many medically important Candida species are commensal to the gut or colonizers of the skin, these organisms have the propensity to cause disease in the event of a waning immune system. Clinical manifestations of infections with Candida species can range from superficial mucosal infections to deep organ involvement usually resulting from haematogenous spread of infection. Despite significant progress made in the management of patients with fungal infections, the emergence of antifungal resistant clinical isolates creates significant problem in regards to antifungal prophylaxis and empirical treatment strategies. Antifungal resistance is associated with high mortality rates and hefty medical costs. The …

Attenuation Of Parenteral Nutritionassociated Liver Disease By Omega-3 Long-Chain Polyunsaturated Fatty Acids, Emma Monique Tillman

Theses and Dissertations (ETD)

No abstract provided.

Alcohol And Medication Use In Community-Dwelling Older Adults: Understanding The Effect Of Alcohol And Central Nervous System-Acting Medications On The Risk For Falls, Maitreyee Mohanty

Theses and Dissertations

Introduction: Aging, comorbid conditions, and use of medications render older adults more susceptible to alcohol-disease or alcohol-drug interactions that may lead to harmful outcomes. In this dissertation project the risk profile of alcohol and medications use among older adults was investigated. Considering the rise in CNS-acting medication use and the adverse effect profile linked to CNS-acting medications, it was also of interest to find if older adults were at risk of falling due to interactions between alcohol and CNS-acting medication. Objectives: The objectives were as follows: 1) to determine the prevalence, pattern and factors associated with at-risk drinking, 2) to …

Cyclin E Induction And Oncolytic Replication Of E1b-Deleted Adenoviruses., Pei-Hsin Cheng

Electronic Theses and Dissertations

Virus-mediated oncolysis has been considered as a new and promising cancer therapeutic approach. Although adenoviruses (Ads) with deletion of E1b55K preferentially replicate in cancer cells and have been used in numerous cancer treatments, the selective replication mechanism of this kind of virus still remains controversial. The lack of a well-established studies focusing on possible mechanisms enabling tumor selectivity of oncolytic Ads has hindered the further development of virotherapies and limits their clinical applications. Therefore, uncovering the molecular basis behind the tumor-killing phenomena will fill critical gaps in our understanding of the oncolytic adenovirology. Previously our laboratory has demonstrated that Ad …

Patients' Perceptions Of Provider Communication, Provider Knowledge And Provider Competence And Associations With Potentially Inappropriate Medication Use Among Medicare Part D Beneficiaries, Engels Nnamdi Obi

Open Access Dissertations

The objectives for this study were to determine prevalence and incidence of potentially inappropriate medication (PIM) use among community-dwelling Medicare Part D beneficiaries, and to assess associations between patients' perceptions of provider communication, provider knowledge, and provider competence with PIM use. A retrospective observational analysis was conducted using data from the Medicare Current Beneficiary Survey. Individuals were included in the prevalence sample if they were aged 65 years or older in 2008, continuously enrolled in Medicare Part D from October 2007 through December 2008, and living in the community from October 2007 through December 2008. Individuals were included in the …

Patient Perceptions Of Physicians And Medication Adherence Among Medicare Part D Beneficiaries, Lori Marquinne Ward

Open Access Dissertations

Ward, Lori Marquinne. Ph.D., Purdue University, December, 2013. Patient Perceptions of Physicians and Medication Adherence Among Medicare Part D Beneficiaries. Major Professor: Joseph Thomas III.

An observational database analysis using Medicare Current Beneficiary Survey data was conducted to examine patient perceptions of physicians and associations with adherence to antihypertensive medication among Medicare beneficiaries enrolled in Medicare Part D. The study sample included beneficiaries if they were 65 years or older, dwelling in the community, had a diagnosis of hypertension in 2007, were enrolled in Medicare Part D all 12 months in 2008, and had Medicare Part D claims for antihypertensive …

Health Care Resource Utilization And Expenditures In Persons With Autosomal Dominant Polycystic Kidney Disease, Neeraj Neelakantan Iyer

Open Access Dissertations

The objectives of this study were to determine prevalence of autosomal dominant polycystic kidney disease (ADPKD), to determine all-cause health care resource utilization and all-cause health care expenditures, to determine incremental health care resource utilization, and to determine incremental health care expenditures associated with ADPKD. An observational database analysis of a privately insured population was conducted using information from a large administrative claims database. Individuals 18 years of age or older and enrolled in a tracked health plan anytime during the period from April 1, 2011 through March 31, 2012, were eligible for inclusion in the sample for determination of …

Assessment Of The Drug-Drug Interaction Potential Of Anionic Components In The Diet And Herbal Medicines On Organic Anion Transporters (Slc22 Family), Li Wang

Theses and Dissertations

Numerous natural products are widely used as first-line/alternative therapeutics and dietary supplements in both western and eastern society. However, the safety and efficacy profiles for herbal products are still limited. Organic anion transporters (OATs; SLC22 family) are expressed in many barrier organs and mediate in vivo body disposition of a broad array of endogenous substances and clinically important drugs. As some dietary flavonoids and phenolic acids were previously demonstrated to interact with OATs, it is necessary to explore the potential interaction of such components found in natural products in order to avoid potential OAT-mediated drug-drug interactions (DDIs). The inhibitory effects …

Role Of Inos In Septic Pulmonary Microvascular Endothelial Cell Activation, Zahra Asad

Electronic Thesis and Dissertation Repository

Abstract

Background. Neutrophils and nitric oxide (NO) derived from inducible NO synthase (iNOS) contributes importantly to the pathophysiology of acute lung injury (ALI) and pulmonary microvascular endothelial cell (PMVEC) injury. However, the mechanism of neutrophil and neutrophil iNOS dependent PMVEC injury has not been addressed. In our studies, we assessed PMVEC activation under septic conditions, and defined the role of PMVEC vs. bone-marrow polymorphonuclear leukocytes (PMN) iNOS in this septic PMVEC activation.

Methods and Results. We isolated PMVEC from iNOS+/+ and iNOS-/- mice lungs magnetically by microbeads attached to anti-PECAM antibodies, sorted by flow cytometry (FACS) by DiI-acetylated low density …

Development Of Hif-1Α/Hif-1Β Heterodimerization Inhibitors Using A Novel Bioluminescence Reporter Assay System For In Vitro High Throughput Screening And In Vivo Imaging, Yun-Chen Chiang

Dissertations & Theses (Open Access)

Tumor growth often outpaces its vascularization, leading to development of a hypoxic tumor microenvironment. In response, an intracellular hypoxia survival pathway is initiated by heterodimerization of hypoxia-inducible factor (HIF)-1α and HIF-1β, which subsequently upregulates the expression of several hypoxia-inducible genes, promotes cell survival and stimulates angiogenesis in the oxygen-deprived environment. Hypoxic tumor regions are often associated with resistance to various classes of radio- or chemotherapeutic agents. Therefore, development of HIF-1α/β heterodimerization inhibitors may provide a novel approach to anti-cancer therapy. To this end, a novel approach for imaging HIF-1α/β heterodimerization in vitro and in vivo was developed in this study …

Polysaccharide-Based Nanocarriers For Improved Drug Delivery, Nan Zhang

Dissertations - ALL

The field of drug delivery has provided a solution to the limited efficacy and high toxicity of many drugs. Nano-sized drug carriers are popular because their size allows for selective accumulation in the diseased area. Polysaccharides are non-toxic and biodegradable natural polymers that can serve as the basis for these nano-sized carriers. Polysialic acid (PSA) is such a polysaccharide with strong hydrophilicity that may reduce uptake by the reticuloendothelial system and prolong drug circulation. In this study, we developed PSA-based nanocarriers, specifically micelles and nanoparticles, for improved drug delivery with improved efficacy and minimized toxicity. PSA-based micelle systems were developed …

An Evidence Based Recommendation For The Use Of 5% Human Albumin Vs. Normal Saline With Hypotension Secondary To Hypovolemia In Adult Post Operative Patients, Katherine Anne Marshall

Master of Science in Nursing Evidence-Based Practice Projects

Problem: 5% human albumin is used very frequently in the hospital setting with hypotensive post-surgical patients. There are associated risks with the use of human albumin and it has been shown that normal saline is at least as effective in treating extreme hypotension in this patient population.

Significance: Associated risks that are present with the use of human albumin may be equal to those of the risks of whole blood transfusions. In addition weight gain and fluid retention are complications associated with the use of human albumin versus the use of normal saline. Furthermore, human albumin costs $40.59 more than …

Design, Development, And Characterization Of Novel Antimicrobial Peptides For Pharmaceutical Applications, Yazan H. Akkam

Graduate Theses and Dissertations

Candida species are the fourth leading cause of nosocomial infection. The increased incidence of drug-resistant Candida species has emphasized the need for new antifungal drugs. Histatin 5 is a naturally occurring human salivary antifungal peptide and the first line of defense against infections of the oral cavity. This research has focused on understanding the activity of histatin 5, and subsequently designing novel peptides that may serve as models for the further development of therapeutics to treat fungal infection.

This objective has been achieved in three steps: studying the structural requirement of histatin 5 involved in antifungal activity, the identification of …

A Novel Biorelevant In Vitro System To Predict The In Vivo Performance Of Oral Transmucosal Products, Poonam Delvadia

Theses and Dissertations

In vitro dissolution, release and permeation testing is a common practice during drug product research and development. These in vitro tests, if predictive, are referred to as biorelevant tests and can play diverse roles to facilitate and expedite product development in a cost effective manner. Oral transmucosal products (OTPs) are currently tested using compendial and modified in vitro tests which may or may not be good predictors of in vivo performance due to a lack of biorelevance. A critical need for a broadly applicable and biorelevant in vitro system for OTPs has been expressed in the literature and the goal …

Synthesis, Testing And Crystallographic Studies Of Allosteric Modifiers Of Hemoglobin, Tanvi Deshpande

Theses and Dissertations

The major physiological function of hemoglobin (Hb) is to bind, transport and deliver oxygen to tissues; made efficient by endogenous effectors, such as protons and 2,3-diphosphoglycerate. Synthetic allosteric effectors of Hb (AEHs) are also known to modulate Hb oxygen affinity, showing potential for the treatment of sickle cell disease (SCD) and ischemic-related diseases. In this project, AEHs which increase Hb affinity for oxygen, including derivatives of the anti-sickling compounds, 5HMF and benzaldehydes, as well as an AEH that decreases Hb affinity for oxygen, RSR-13, were synthesized for their effects on Hb oxygen binding property and their capability to release NO …

Engineering Spores To Display G Protein-Coupled Receptors For Directed Evolution, Alyssa Misoo Kim

Theses

All human cells are surrounded by a plasma membrane made from a phospholipid bilayer, which is responsible for maintaining a biologically active species, while stopping entry of deleterious substances from the outside. G protein-coupled receptors (GPCRs) are the membrane proteins, which transmit signals across the cell membrane. GPCRs are involved in almost every physiological process, and irregular control leads to pathological conditions. Therefore, they are major drug targets. Crystal structure determination is required to understand the molecular details of activation/deactivation. However, GPCRs are difficult to crystallize because of stability issues. An efficient protein engineering system needs to be developed. The …

Effect Of Tablet Compression On The Dissolution Of Aspirin Tablets Using A Novel Off-Center Paddle Impeller (Opi) Dissolution Testing System, Chuan Sun

Theses

In the pharmaceutical industry, dissolution testing is routinely carried out to determine the dissolution rate of oral solid dosage forms. Among several testing devices, the USP Dissolution Apparatus 2 is the device most commonly used. However, despite its widespread use, this apparatus has been shown to produce test failures and to be very sensitive to a number of small geometry changes.

The objective of this study was to determine whether a novel dissolution system termed “OPI” for “off-center paddle impeller” was sensitive enough to determine differences in tablet dissolution profiles caused by different compression pressure during the tablet manufacturing process. …

Hollow Fiber Membrane-Based Air Gap Membrane Distillation, Xuan Wang

Theses

Membrane Distillation (MD) is a thermally-driven separation process. In this research, desalination of 1 % NaCl solution is achieved by one type of MD namely, Air Gap Membrane Distillation (AGMD). The characteristics of AGMD are evaluated by using a hollow-fiber-set-based compact device. Hot brine solution and cold water are passed through two different fiber sets separately: porous hydrophobic polyvinylidene fluoride hollow fibers of the E type (PVDF E) and solid polypropylene (PP) hollow fibers. Vapor from the hot brine crosses the membrane pores of the PVDF fibers and the air gap, and finally condenses over the surface of solid hollow …

Dissolution Of Different Commercial Aspirin Tablets Using A Novel Off-Center Paddle Impeller (Opi) Dissolution Testing System, Yang Qu

Theses

Dissolution testing is routinely conducted in the pharmaceutical industry to provide in vitro drug release information for quality control purposes. The most common dissolution testing system for solid dosage forms is the United States Pharmacopeia (USP) Dissolution Testing Apparatus 2. In this work, a modified Apparatus 2, termed "OPI" System for "off-center paddle impeller," in which the impeller is placed 8 mm off center in the vessel is tested to determine its sensitivity to differentiate between the dissolution profiles of differently formulated and manufactured tablets. Dissolution tests are conducted with both the OPI System and the Standard System using three …

Qsar Modeling Of Chemical Penetration Enhancers Using Novel Replacement Algorithms, Hui Qiu

Theses

The applications of transdermal delivery are limited because of the resistance of the skin to drug diffusion. Only potent drugs, with molecular weight less than 500 Da, are suitable to cross the skin barrier. Chemical Penetration Enhancers (CPEs) are used to promote the absorption of solutes across the dermal layers. In this investigation, a Quantitative Structure-Activity Relationship (QSAR) model is applied to relate chemical penetration enhancer structures with the flux enhancement ratio through a statistical approach.

A database, consisting of 61 non-polar CPEs, is selected for the study. Each compound is represented by 777 QSAR descriptors, which encode the physical …

Hydrodynamic Effects Of A Cannula In A Usp Dissolution Testing Apparatus 2, Qianqian Liu

Theses

Dissolution testing is routinely used in the pharmaceutical industry to provide in vitro drug release information for drug development and quality control purposes. The USP Testing Apparatus 2 is the most common dissolution testing system for solid dosage forms. Usually, sampling cannulas are used to take samples manually from the dissolution medium. However, the inserted cannula can alter the normal fluid flow within the vessel and produce different dissolution testing results.

The hydrodynamic effects introduced by a permanently inserted cannula in a USP Dissolution Testing Apparatus 2 were evaluated by two approaches. Firstly, the dissolution tests were conducted with two …

Changes In Student Attitudes Towards The Elderly Following A Hypertension Education And Screening Event, David William Martin

Undergraduate Honors Thesis Collection

Objective: To assess student comfort levels and perceptions toward geriatric care after participation in a hypertension screening and education event, and to assess knowledge retention in the elderly participants.

Methods: This multiphase, survey based study evaluated pharmacy and physician assistant students' comfort levels and perceptions of the elderly. The study also used questionnaires to assess knowledge retention in the elderly at immediate, one-month, and three-month intervals.

Results: Student comfort levels significantly increased and perceptions remained unchanged after participation in the education and screening event. Elderly participant knowledge retention remained at around a 90% correct response rate.

Conclusion: Increasing student interactions …

Development And Evaluation Of The Assessment Of Opioid Taking Behaviors And Adherence Scale (Aotba) In Patients With Sickle Cell Disease, Abdulkhaliq Jassem Alsalman

Theses and Dissertations

The rapid growth in opioid therapy for non-cancer pain has occurred without an adequate appreciation of the consequences of this growth. Few studies provide patient-centered evidence that can be used to inform the current proposed standards for efficacious (safe and effective) opioid prescribing in non-cancer pain. Furthermore, different terms may be used interchangeably in the literature to refer to opioid-taking behaviors, resulting in imprecise or vague interpretation of existing evidence. We therefore sought to explore patterns of opioid-taking behavior and their biopsychosocial-spiritual determinants in African-American adults with sickle cell disease (SCD). Many questions surround opioid use for non-cancer pain, but …

Reverse-Phase Ion-Pairing Ultra Performance Liquid Chromatography-Mass Spectrometry In Characterization And Fingerprinting Of Diverse Sulfated Glycosaminoglycan Mimetics, Pooja Ponnusamy

Theses and Dissertations

Heparin is a highly sulfated glycosaminoglycan with potent anticoagulant, antimetastatic, and anti-inflammatory effects. Polymeric and polyanionic nature of heparin makes dosing and side effects a nightmare for healthcare professionals. Our laboratory has proposed appropriately designed, small, highly sulfated aromatic molecules as potential mimetics of heparin. These easier-to-synthesize small molecules have been shown to possess interesting pharmacological and improved toxicological profiles. However, the detection and characterization of these highly sulfated molecules is challenging. A robust RP-IP UPLC-MS method was developed to successfully retain, resolve and quantify sulfated non-saccharide GAG mimetics without the requirement of pre- or post- column derivatization. Comparative analysis …

The Development And Applications Of The Hint Scoring Function: Exploring Colchicine-Site Anticancer Agents And Tautomerism, Chenxiao Da

Theses and Dissertations

The overall aim of this work was to apply HINT, an empirical scoring function based on the understanding of hydrophobicity, to analyze and predict the binding affinities and biological activities of colchicine-site anticancer agents. The second, concurrent aim was to improve the scoring function by incorporating tautomerism within the modeling process. Our belief is that proper evaluation of tautomeric forms for small molecules will improve performance of virtual screening. The novel pyrrole-based compounds targeting the colchicine site were docked into the receptor using HINT as a rescoring function. Two distinct binding modes dictated by the size and shape of a …

A Series Of Pharmaceutical Technology Concepts Applied To Pediatric Formulations, Hao Lou

Theses and Dissertations (ETD)

Pediatric formulations have received great attention from regulatory agencies in the United States and Europe. Since solid dosage forms such as tablets and capsules will not be able to improve pediatric patients’ compliance, customized pediatric formulations are needed. In response, formulators in the pharmaceutical industry have made significant effort into developing various pediatric formulations. However, developing satisfactory pediatric formulations is a process that is guided by case by case basis. The objective of this current study was to apply the scientific pharmaceutical technology concepts into developing modern pediatric formulations. We have shown that the drug delivery design will be affected …

The Study Of The Effect Of Two Flavone Isomers Derived From Gnaphalium Elegans And Achyrocline Bogotensis In Breast Cancer., Jessica J. Walker

Undergraduate Honors Theses

Flavonoids are ubiquitous to all terrestrial plants and many are known to have anti-tumor activities. In this research project we studied the differential cytotoxic effects of two flavone isomers on human breast cancer cells (BT-474, SKBR-3, and MCF-7) and normal breast cells as a control (MCF-10A). The basis of the relationships between chemical structures, type and position of substituent groups and the effects these compounds exert specifically on cancer cells are not completely elucidated. These flavones are derived from plants native of Colombia, South America. These plants of the family Asteraceae, genera Gnaphalium and Achyrocline are reputed to have anti-cancer …