Pharmacy and Pharmaceutical Sciences Commons^™

Aerosolized Surfactants: Formulation Development And Evaluation Of Aerosol Drug Delivery To The Lungs Of Infants, Susan Boc

Theses and Dissertations

The overall aim of this research project was to develop surfactant dry powder formulations and devices for efficient delivery of aerosol formulations to infants using the excipient enhanced growth (EEG) approach. Use of novel formulations and inline delivery devices would allow for more efficient treatment of infants suffering from neonatal respiratory distress syndrome and bronchiolitis.

A dry powder aerosol formulation has been developed using the commercial product, Survanta ® (beractant) and EEG technology to produce micrometer-sized hygroscopic particles. Spray drying and formulation parameters were initially determined with dipalmitoylphosphatidylcholine (DPPC, the dominant phospholipid in pulmonary surfactant), which produced primary particles 1 …

Development Of Small Molecule Neuroprotectants, Ashley Boice

Theses and Dissertations

Neurodegenerative diseases are a class of conditions that lead to progressive atrophy of different parts of the central nervous system (CNS). These diseases lead to devastating clinical outcomes to patients and give rise to an enormous socio-economical burden on society.¹ One commonality among some of the most well-known neurodegenerative disorders, e.g. Alzheimer’s disease (AD), Parkinson’s disease (PD), and multiple sclerosis (MS), is neuroinflammation.^2-4 Neuroinflammation stems from interactions of the innate immune system with toxins and insults to the central nervous system. In the case of irremovable or chronic insults and toxins, this leads to chronic damaging …

Prescription Drug Monitoring Programs And Opioid Poisoning: Evaluating The Impact Of Prescriber Use Mandates On Prescription Opioid Poisoning Emergency Department Visits, Sarah Almanie

Theses and Dissertations

Introduction: Prescription drug monitoring programs (PDMPs) are one strategy established to curb the prescription opioid abuse epidemic. Prescriber use mandates has emerged as a promising practice to increase PDMPs impact on prescription opioid abuse; however, evidence of its effectiveness has not yet been established. Kentucky was the first state to implement comprehensive prescriber use mandates in July 2012.

Objective: To assess the relationship between prescriber use mandates policy and emergency department (ED) visits related to prescription opioid poisoning among adults in Kentucky and

North Carolina. Secondary aim: to evaluate the economic impact of prescriber use mandates in Kentucky.

Methods: A …

Economic Burden Of Renal Cell Carcinoma (Rcc) And Treatment Patterns, Overall Survival And Healthcare Costs Among Older Metastatic Rcc Patients, Hrishikesh P. Kale

Theses and Dissertations

Background

Renal cell carcinoma (RCC) is the most common type of kidney cancer. Patients diagnosed with metastatic RCC (mRCC) have shorter overall survival compared to those diagnosed at earlier stages. Several targeted therapies, which cost from $7,000 - $16,000 per month have been approved since 2005 to treat mRCC. In addition, there is a growing interest in the use of cytoreductive nephrectomy (CN) with targeted therapies among mRCC patients. However, little is known regarding the economic burden of RCC and role of CN and prescribing patterns of targeted therapies among older mRCC patients.

Objectives

1) To assess the economic burden …

Association Between Warfarin Adherence Trajectories, Hospitalization Risk, And Healthcare Utilization Among Medicare Patients With Atrial Fibrillation: A Group-Based Trajectory Modelling Approach, Mai Alhazami

Theses and Dissertations

Introduction: Warfarin is the most commonly prescribed drug for stroke prevention among Atrial Fibrillation (AF) patients, especially in older adult populations, but medication nonadherence reduces its effectiveness in clinical practice. Group Based Trajectory Models (GBTM) have been used to identify distinct patterns of adherence behavior related to various medications and understand the patient characteristics associated with each trajectory. The objectives of the study were: 1) Describe trajectories of warfarin adherence among Medicare AF patients, 2) Assess impact of adherence trajectories on AF-related hospitalization, 3) Estimate the AF-related direct costs for each adherence trajectory group.

Methods: We identified elderly AF patients …

Mass Spectrometry-Based Proteomics Analysis Of Secreted Proteins, Emmanuel K. Cudjoe Jr

Theses and Dissertations

Secreted proteins play important roles in many cellular functions and molecular processes. Because secreted proteins potentially enter the blood stream, they can serve as valuable measures of health and disease useful for disease diagnosis and prognosis, therapeutic target identification, and patient stratification in personalized medicine. Consequently, significant interest exists in secreted protein analysis within complex biospecimens, particularly blood but significant bioanalytical challenges including the wide protein dynamic range >10 orders of magnitude remain. The cellular secretome therefore represents a viable alternative to direct biomarker discovery in biofluids. Finally, cellular systems are amenable to labeling for the production of intact stable …

Housing Status, Patient Characteristics, And Ed Utilization Associated With Medication Prescribing At Ed Discharge Among Homeless And Nonhomeless Adults In Urban Hospitals In The United States, Lauren Cox

Theses and Dissertations

This cross-sectional study used a weighted sample of ED visits contained in the 2010-2015 years of the National Hospital Ambulatory Care Survey-Emergency Department (NHAMCS-ED) dataset. The purpose of this study was to: 1) identify differences in predisposing, enabling, and need characteristics, and ED use and medication prescribing characteristics between homeless and nonhomeless ED users; 2) assess the association between housing status and medication prescribing at ED discharge, and identify variables contributing to the disparity in medication prescribing between homeless and nonhomeless ED users; and 3) assess the predisposing, enabling, need, and ED use characteristics that predict medication prescribing at ED …

Elucidation Of Substrate Binding Interactions For Human Organic Cation Transporters 1 (Slc22a1) And 2 (Slc22a2) Using In Silico Homology Modeling In Conjunction With In Vitro Site-Directed Mutagenesis And Kinetic Analysis, Raymond E. Lai

Theses and Dissertations

The organic cation transporters (OCTs) play a critical role in the absorption, distribution and elimination of many drugs, hormones, herbal medicines, and environmental toxins. Given the broad substrate specificity of OCTs, they fall victim to the high susceptibility for contributing to harmful drug-drug interactions. Further defining how human (h)OCTs mechanistically bind to its broad array of substrates will provide significant insight to the understanding and prediction of drug-drug interactions in polypharmacy patients and the advancement of future rational drug design for therapeutics targeting OCTs. The goal of the current study was to elucidate the critical amino acid residues for transporter-substrate …

Effects Of Hiv-1 Tat And Drugs Of Abuse On Antiretroviral Penetration Inside Different Cns Cell Types, Sulay H. Patel

Theses and Dissertations

Human immunodeficiency (HIV) infection can result in neurocognitive deficits in about one-half of infected individuals. Despite excellent systemic effectiveness, restricted antiretroviral penetration across the blood-brain barrier (BBB) is a major limitation in fighting HIV infection within the central nervous system (CNS). Drug abuse exacerbates cognitive impairment and pathologic CNS changes in HIV-infected individuals. This work investigates the effects of the HIV-1 protein, Tat, and drugs of abuse on factors affecting drug penetration into the brain.

Firstly, an in vitro model of the blood-brain barrier was built to study effects of HIV-1 Tat and methamphetamine (Meth) on integrity and function of …

Glycosaminoglycan Lyases In The Preparation Of Oligosaccharides, Alhumaidi B. Alabbas

Theses and Dissertations

Glycosaminoglycans are heterogeneous polysaccharides that mediate important biological functions. There has been considerable interest in deciphering the precise GAG sequences that are responsible for protein interactions. In fact, several GAG oligosaccharides have been discovered to date as targeting proteins with higher level of specificity. Yet, it has been difficult to develop GAG oligosaccharides as drugs. One of the key reasons for this state of art is that GAG synthesis is extremely challenging and is highly structure-specific. Thus, much of the biology and pharmacology of GAG remains unknown and unexploited to date.

An alternative approach is to prepare GAG oligosaccharides using …

Rational Design Of Allosteric Modulators Of Hemoglobin As Dual Acting Antisickling Agents, Piyusha P. Pagare

Theses and Dissertations

Intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) remains the principal cause of the pathophysiology associated with sickle cell disease (SCD). Naturally occurring and synthetic allosteric effectors of hemoglobin (AEH) have been investigated as potential therapeutic agents for the treatment of SCD. Several aromatic aldehydes, including vanillin, have been studied previously as AEHs for their antisickling activities. Specifically, these compounds form Schiff- base adduct with Hb to stabilize the oxygenated (R) state, increase Hb affinity for O2 and concomitantly prevent the hypoxia-induced primary pathophysiology of Hb S polymerization and RBC sickling, in turn, ameliorating several of the cascading secondary adverse …

Development And Validation Of A Semi-Physiological Pharmacokinetic (Pbpk) Model To Predict Systemic And Pulmonary Exposures After Intravenous, Oral Administration And Pulmonary Inhalation Of Selected Drugs, Budesonide, Tobramycin And Ciprofloxacin, In Humans, Bishoy Hanna

Theses and Dissertations

Using a semi-PBPK modeling/quantitative meta-analysis approach, this project investigated what factors affect pulmonary and systemic exposures of Budesonide (BUD), Tobramycin (TOB), and Ciprofloxacin (CIP) after inhalation:

Three structurally different pulmonary disposition models were developed for each drug, including pulmonary absorption (all three), excretion (TOB and CIP) and sequestration (TOB) in a peripheral and central lung compartment. Systemic disposition parameters were estimated using available human mean plasma (c_p(t)) and sputum (c_s(t)) concentration profiles after IV administration, and GI absorption parameters were estimated from these profiles after oral administration. Pulmonary disposition parameters were estimated from c_p(t) …

Detection And Quantification Of Glucuronidation Of Ursolic Acid (Ua) In Human Liver Microsomes (Hlms)., Kamola Tolliboeva, Philip M. Gerk

UROP Posters

No abstract provided.

The Anti-Sepsis Activity Of The Components Of Huanglian Jiedu Decoction With High Lipid A-Binding Affinity, Guirong Chen, Yubin Xu, Jing Jing, Brianna Mackie, Xinchuan Zheng, Xu Zhang, Jing Wang, Xuetao Li

Medicinal Chemistry Publications

Huanglian Jiedu Decoction (HJD), one of the classic recipes for relieving toxicity and fever, is a common method for treating sepsis in China. However, the effective components of HJD have not yet been identified. This experiment was carried out to elucidate the effective components of HJD against sepsis. Thus, seven fractions from HJD were tested using a biosensor to test their affinity for lipid A. The components obtained that had high lipid A-binding fractions were further separated, and their affinities to lipid A were assessed with the aid of a biosensor. The levels of LPS in the blood were measured, …

Chronic Health Conditions As A Risk Factor For Falls Among The Community-Dwelling Us Older Adults: A Zero-Inflated Regression Modeling Approach, Yoshita Paliwal, Patricia W. Slattum, Scott M. Ratliff

Pharmacotherapy and Outcomes Science Publications

Falls are an important health concern among older adults due to age-related changes in the body. Having a medical history of chronic health condition may pose even higher risk of falling. Only few studies have assessed a number of chronic health conditions as risk factor for falls over a large nationally representative sample of US older adults. In this study, Behavioral Risk Factor Surveillance System (BRFSS) 2014 participants aged 65 years and older (n = 159,336) were evaluated. It was found that 29.7% (n = 44,550) of the sample experienced at least one fall and 16.3% (n = 20,444) …

Impaired Myocardial Relaxation With Exercise Determines Peak Aerobic Exercise Capacity In Heart Failure With Preserved Ejection Fraction, Cory Trankle, Justin M. Canada, Leo Buckley, Salvatore Carbone, Dave Dixon, Ross Arena, Benjamin Van Tassell, Antonio Abbate

Pharmacotherapy and Outcomes Science Publications

Background

Heart failure with preserved ejection fraction (HFpEF) is a clinical syndrome characterized by impaired exercise capacity due to shortness of breath and/or fatigue. Assessment of diastolic dysfunction at rest and with exercise may provide insight into the pathophysiology of exercise intolerance in HFpEF.

Aims

To measure echocardio-Doppler-derived parameters of diastolic function as they relate to various indices of aerobic exercise capacity in HFpEF.

Methods

We selected 16 subjects with clinically stable HFpEF, no evidence of volume overload, but impaired functional capacity by cardiopulmonary exercise testing [peak oxygen consumption (VO₂)]. We measured the transmitral E and A flow …

The Impact Of Objective Quality Ratings On Patient Selection Of Community Pharmacies: A Discrete Choice Experiment And Latent Class Analysis, Julie A. Patterson

Theses and Dissertations

Background: Pharmacy-related performance measures have gained significant attention in the transition to value-based healthcare. Pharmacy-level quality measures, including those developed by the Pharmacy Quality Alliance, are not yet publicly accessible. However, the publication of report cards for individual pharmacies has been discussed as a way to help direct patients towards high-quality pharmacies. This study aimed to measure the relative strength of patient preferences for community pharmacy attributes, including pharmacy quality. Additionally, this study aimed to identify and describe community pharmacy market segments based on patient preferences for pharmacy attributes.

Methods: This study elicited patient preferences for community pharmacy attributes …

Structure-Activity Relationship Studies Of Bupropion And Related 3-Substituted Methcathinone Analogues At Monoamine Transporters, Abdelrahman R. Shalabi

Theses and Dissertations

The khat plant, catha edulis, has been abused for some time in the Middle East and the African horn for its short-term stimulant effects. However, it was not until 1975 when cathinone, β-ketoamphetamine, was identified as the major stimulant component of khat. Structural analogues of cathinone, synthetic cathinones, are new psychoactive substances available on the clandestine market of numerous countries including the USA. Abuse of these new illicit stimulants is a worldwide growing health concern which necessitates the investigation of the pharmacological properties of these new drugs of abuse. The abuse liabilities of these compounds seem to be related …

Evaluation Of The Regional Drug Deposition Of Nasal Delivery Devices Using In Vitro Realistic Nasal Models, Mandana Azimi

Theses and Dissertations

The overall objectives of this research project were i) to develop and evaluate methods of characterizing nasal spray products using realistic nasal airway models as more clinically relevant in vitro tools and ii) to develop and evaluate a novel high-efficiency antibiotic nanoparticle dry powder formulation and delivery device. Two physically realistic nasal airway models were used to assess the effects of patient-use experimental conditions, nasal airway geometry and formulation / device properties on the delivery efficiency of nasal spray products. There was a large variability in drug delivery to the middle passages ranging from 17 – 57 % and 47 …

Study Of Molecular Interactions Of Glycosaminoglycans And Glycosaminoglycan Mimetics With Their Protein Targets, Daniel K. Afosah

Theses and Dissertations

Glycosaminoglycans (GAGs) are complex linear chain carbohydrate molecules found on virtually all animal cell surfaces. Owing to their negatively charged nature, GAGs interact with a number of different proteins. Thus, although they have great potential as therapeutic agents, their apparent promiscuous interactions increase their side effect risk. GAG mimetics, including GAG oligosaccharides and non-saccharide GAG mimetics (NSGMs) are viable approaches to address this. This work discusses sulfated benzofuran thrombin inhibitors with submaximal protease inhibition, sulfated diflavonoid inhibitors of plasmin and GAG oligosaccharides with selectivity for human neutrophil elastase (HNE).

Anticoagulants are very important for the treatment of thrombotic diseases. The …

E-Cigarettes And Smoking Cessation: Economic Impact On Current Smokers With Chronic Obstructive Pulmonary Disease, Anal A. Shah

Theses and Dissertations

Introduction:

Awareness and usage of Electronic cigarettes (e-cigs) among smokers have increased rapidly over the past few years, majorly in quitting smoking. The main objectives for this study were: 1) To estimate the prevalence and study sociodemographic predictors for e-cigs use among individuals with Chronic Obstructive Pulmonary Disease (COPD) 2) To examine the predictors and estimate the total healthcare costs among current smokers with COPD 3) To estimate the economic impact of adopting e-cigs as a smoking cessation tool among current smokers with COPD.

Methods:

The National Health Interview Survey data from the year 2014 was utilized to estimate the …

A Biorelevant In Vitro Model To Characterize In Vivo Release Of Bone Morphogenetic Protein-2 (Rhbmp-2), Deblina Biswas

Theses and Dissertations

Biorelevant in vitro release/dissolution tests are designed to predict the in vivo behavior of a drug and are crucial in understanding its in vivo performance. Currently, there is no standardized compendial in vitro release testing methods or regulatory guidance’s for release/dissolution testing of implants due to their complex physiological locations.Furthermore, existing compendial methods do not capture the local release profile of ‘novel’ parenterals in physiological low fluid volume surrounding areas.

Long acting and in situ forming implants with orthobiologic proteins and peptides have increased over the past few decades due to a better understanding of genetic engineering. One of these …

Investigation Of Polymeric Composites For Controlled Drug Release, Hsi-Wei Yeh

Theses and Dissertations

The Electrospray (ES) technique is a promising particle generation method for drug delivery due to its capabilities of producing monodisperse PLGA composite particles with unique configurations and high drug encapsulation efficiency. In the dissertation work, the coaxial dual capillary ES was used to generate drug-loaded core-shell PLGA particles to study the effects of particle filling materials, drug loading locations and particle shell thicknesses on the resultant in vitro release behaviors of the hydrophilic and/ or hydrophobic model drugs. Through release profile characterization of drug-loaded PLGA particles (particle size: 400 nm and 1 μm), it was confirmed that the co-encapsulation of …

Investigation Of Anticoagulation Properties Of Sulfated Glycosaminoglycan Mimetics, Elsamani I. Abdelfadiel

Theses and Dissertations

Abstract

INVESTEGATION OF ANTICOAGULATION PROPERTIES OF SULFATED

GLYCOSAMINOGLYCAN MIMETICS

By Elsamani Ismail Abdelfadiel, MS

A thesis submitted in partial fulfillment of the requirements for the degree of Master of

Science at Virginia Commonwealth University

Virginia Commonwealth University, 2017.

Supervisor: Umesh R Desai

Professor, Department of Medicinal Chemistry

The existence of thrombosis in numerous pathophysiological situations formed a vast necessity for anticoagulation therapy. Thrombin and factor Xa are the only two factors of the entire coagulation cascade that have been major targets for regulation of clotting via the direct and indirect mechanism of inhibition. Our recent discovery of sulfated non-saccharide glycosaminoglycan …

Understanding Over-The-Counter Medication Use And Decision-Making Among Community-Dwelling Us Older Adults: A Mixed-Methods Approach, Yoshita Paliwal

Theses and Dissertations

Introduction

Older adults are regular consumers of over-the-counter (OTC) medications. OTC medications are generally considered safe, and convenient to use without requiring a prescription. However, the safety of an OTC medication and the final health outcome depends in part upon consumers’ perceptions, beliefs, and their decision-making about OTC medication use. The main objectives of this study were: 1) to examine the prevalence and characteristics of OTC medication use among community-dwelling US older adults (65 years and older), 2) to explore older adults’ knowledge, attitudes, beliefs and experiences about OTC medications, and 3) to elicit the OTC medication decision-making process in …

Inhibition Of Oxidative And Conjugative Metabolism Of Buprenorphine Using Generally Recognized As Safe (Gras) Compounds Or Components Of Dietary Supplements, Neha V. Maharao

Theses and Dissertations

This dissertation aimed at developing an inhibitor strategy to improve the oral bioavailability (F_oral) and systemic exposure (AUC_∞) of buprenorphine (BUP) as well as reduce the variability associated with them. Twenty-seven generally recognized as safe (GRAS) compounds or dietary substances were evaluated for their potential to inhibit the oxidative and conjugative metabolism of BUP, using pooled human intestinal and liver microsomes. In both the organs, oxidation appeared to be the major metabolic pathway with a 6 fold (intestine) and 4 fold (liver) higher intrinsic clearance than glucuronidation. Buprenorphine was predicted to show low and variable F …

Design, Synthesis, And Biological Screening Of Selective Mu Opioid Receptor Ligands As Potential Treatments For Opioid Addiction, Samuel Obeng

Theses and Dissertations

Today, more Americans die each year because of drug overdoses than are killed in motor vehicle accidents. In fact, in 2015, more than 33,000 individuals died due to an overdose of heroin or prescription opioids. Sadly, 40-60 % of patients on current opioid addiction treatment medications relapse. Studies have shown that the addiction/abuse liability of opioids are abolished in mu opioid receptor (MOR) knock-out mice; this indicates that the addiction and abuse liability of opioids are mainly mediated through MOR. Utilizing the “message-address concept”, the our laboratory reported a novel non-peptide, reversible MOR selective ligand 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6α (isoquinoline-3-carboxamido)morphinan (NAQ). Molecular modeling …

Lung Disposition Model-Based Analyses Of Clinical Pharmacokinetic Profiles For Inhaled Drugs, Anuja Raut

Theses and Dissertations

There has been a desire to accurately interpret the inhaled pharmacokinetic (PK) profiles of drugs in humans to aid successful inhaled drug and product developments. However, challenges are layered, as 1) the drug dose delivered to the lung (DTL) from inhalers is a portion of the formulated dose but rarely determined; 2) lung delivery and regional deposition differ, depending on drug, formulation and inhaler; 3) drugs are not only absorbed from the lung but may also be from the gastrointestinal (GI) tract; and 4) in addition to absorption into the systemic circulation, multiple non-absorptive processes also eliminate drugs from the …

Chemical Probes For Protein Α-N-Terminal Methylation, Brianna D. Mackie

Theses and Dissertations

While protein α-N-terminal methylation has been known for nearly four decades since it was first uncovered on bacteria ribosomal proteins L33, the function of this modification is still not entirely understood. Recent discoveries have demonstrated α-N-terminal methylation is essential to stabilize the interactions between regulator of chromosome condensation 1 (RCC1) and chromatin during mitosis, to localize and enhance the interaction of centromere proteins (CENPs) with chromatin, and to facilitate the recruitment of DNA damage-binding protein 2 (DDB2) to DNA damage foci. Identification of N-terminal methyltransferase 1 (NTMT1) unveiled the eukaryotic methylation writer for protein α-N-termini. In addition, NTMT2 that shares …

The Association Between Sleep Problems, Sleep Medication Use, And Falls In Community-Dwelling Older Adults: Results From The Health And Retirement Study 2010, Yaena Min, Pramit A. Nadpara, Patricia W. Slattum

Pharmacotherapy and Outcomes Science Publications

Background. Very few studies have assessed the impact of poor sleep and sleep medication use on the risk of falls among community-dwelling older adults. The objective of this study was to evaluate the association between sleep problems, sleep medication use, and falls in community-dwelling older adults. Methods. The study population comprised a nationally representative sample of noninstitutionalized older adults participating in the 2010 Health and Retirement Study. Proportion of adults reporting sleep problems, sleep medication use, and fall was calculated. Multiple logistic regression models were constructed to examine the impact of sleep problems and sleep medication use on …