Pharmacy and Pharmaceutical Sciences Commons^™

Formulation Optimization For Pore Lifetime Enhancement And Sustained Drug Delivery Across Microneedle Treated Skin, Priyanka Ghosh

Theses and Dissertations--Pharmacy

Microneedle (MN) enhanced drug delivery is a safe, effective and efficient enhancement method for delivery of drug molecules across the skin. The “poke (press) and patch” approach employs solid stainless steel MN to permeablize the skin prior to application of a regular drug patch over the treated area. It has been previously shown that MN can be used to deliver naltrexone (NTX) at a rate that provides plasma concentrations in the lower end of the therapeutic range in humans. The drug delivery potential of this technique is, however, limited by the re-sealing of the micropores in a 48-72h timeframe. The …

Microglia Activation In A Rodent Model Of An Alcohol Use Disorder: The Importance Of Phenotype, Initiation, And Duration Of Activation, Simon A. Marshall

Theses and Dissertations--Pharmacy

Chronic ethanol exposure results in neuroadaptations that drive the progression of an alcohol use disorder (AUD). One such driving force is alcohol-induced neurodegeneration. Neuroinflammation has been proposed as a mechanism underlying this damage. Although neuroinflammation is a physiological response to damage, overactivation of its pathways can lead to neurodegeneration. A hallmark indicator of neuroinflammation is microglial activation, but microglial activation is a heterogeneous continuum of phenotypes that can promote or inhibit neuroinflammation. Furthermore acute microglial activation is necessary to restore homeostasis, but prolonged activation can exacerbate damage. The diversity of microglia makes both the level and timecourse of activation vital …

Polymer Micelles For Tunable Drug Release And Enhanced Antitumor Efficacy, Andrei G. Ponta

Theses and Dissertations--Pharmacy

Cancer remains a leading cause of death in the United States. The most common treatment options include chemotherapy, but poor solubility, adverse side effects and differential drug sensitivity hamper clinical applications. Current chemotherapy generally aims to deliver drugs at the limit of toxicity, assuming that higher dosage increases efficacy, with little attention paid to potential benefits of tunable release. Growing evidence suggests that releasing drugs at a constant rate will be as effective as a single bolus dose. To test this hypothesis, it is critical to develop drug delivery systems that fine-tune drug release and elucidate the impact of tunable …

Methylphenidate And Atomoxetine Treatment During Adolescence In The Spontaneously Hypertensive Rat: Mechanisms Underlying High Cocaine Abuse Liability In Attention Deficit/Hyperactivity Disorder, Sucharita S. Somkuwar

Theses and Dissertations--Pharmacy

Effects of pharmacotherapies for Attention Deficit/Hyperactivity Disorder (ADHD) on cocaine abuse liability in ADHD are not understood. Spontaneously Hypertensive Rats (SHR), an ADHD model, exhibited greater cocaine self-administration than control Wistar-Kyoto and Wistar rats. Methylphenidate, but not atomoxetine during adolescence enhanced cocaine self-administration in adult SHRs compared to controls. The mesocortical dopaminergic system, including medial prefrontal (mPFC) and orbitofrontal (OFC) cortices, is important for ADHD and cocaine addiction. Dopamine and norepinephrine transporter (DAT and NET) are molecular targets for methylphenidate, atomoxetine and cocaine action.

In the current studies, SHR, Wistar-Kyoto and Wistar were administered methylphenidate (1.5 mg/kg/day, p.o.), atomoxetine (0.3 …

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 …

Chronic Opioid Use In Fibromyalgia Syndrome: Characteristics And Outcomes, Jacob T. Painter

Theses and Dissertations--Pharmacy

Fibromyalgia syndrome (FMS) is a chronic pain condition with significant societal and personal burdens of illness. Chronic opioid therapy in the treatment of chronic nonmalignant pain has increased drastically over the past decade. This is a worrisome trend in general, but specifically, given the pathophysiologic characteristics seen in fibromyalgia syndrome patients, the use of this class of medication deserves special scrutiny. Although the theoretical case against this therapy choice is strong, little empirical evidence exists. In order to supplement this literature, retrospective analysis methods are utilized to examine the association of state-, provider-, and patient level characteristics with the prevalence …

Discovery Of Gz-793a, A Novel Vmat2 Inhibitor And Potential Pharmacotherapy For Methamphetamine Abuse, David B. Horton

Theses and Dissertations--Pharmacy

Methamphetamine abuse is a serious public health concern affecting millions of people worldwide, and there are currently no viable pharmacotherapies to treat methamphetamine abuse. Methamphetamine increases extracellular dopamine (DA) concentrations through an interaction with the DA transporter (DAT) and the vesicular monoamine transporter-2 (VMAT2), leading to reward and abuse. While numerous studies have focused on DAT as a target for the discovery of pharmacotherapies to treat psychostimulant abuse, these efforts have been met with limited success. Taking into account the fact that methamphetamine interacts with VMAT2 to increase DA extracellular concentrations; the focus of the current work was to develop …

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 …

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 …

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 …

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 …

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 …

Mechanism And Kinetics Of Covalent Amide-Linked Adduct Formation In Solution And Solid Peptide Formulations, Michael Paul Dehart

Theses and Dissertations--Pharmacy

Peptides and proteins are prone to chemical and physical degradation in solutions and solids. One of the most common chemical degradation pathways involves deamidation of asparagine residues through a reactive succinimide intermediate resulting in the formation of aspartyl and isoaspartyl degradation products.

In this work, kinetic studies in aqueous solutions demonstrated that the succinimide intermediate is susceptible to attack by nucleophiles other than water. This may lead to a variety of alternative degradants. In solutions containing high concentrations of ammonia, the succinimide generated in the deamidation of the model peptides Phe-Asn-Gly and Phe-isoAsn-Gly underwent back-reaction with ammonia leading to peptide …

Target Validation Of Uk-101 And Functional Studies Of Β1i, Marie V. Wehenkel

Theses and Dissertations--Pharmacy

β1i is a major catalytic subunit of the immunoproteasome, an alternative form of the constitutive proteasome, and its upregulation has been demonstrated in a variety of disease states including cancer. Our lab has developed a small molecule inhibitor of β1i, dubbed UK-101. While UK-101 causes apoptosis in cancer cell lines, it was not clear whether this apoptotic effect was directly mediated by its irreversible inhibition of β1i. Since off-target effects are major roadblocks for the development of new and effective pharmaceuticals, target validation studies in this system would assist in the further progression of β1i inhibitors towards preclinical trials. Our …

Studies Of Solubilization Of Poorly Water-Soluble Drugs During In Vitro Lipolysis Of A Model Lipid-Based Drug Delivery System And In Mixed Micelles, Lin Song

Theses and Dissertations--Pharmacy

Lipid-based drug delivery systems (LBDDSs) are becoming an increasingly popular approach to improve the oral absorption of poorly-water soluble drugs. Several possible mechanisms have been proposed to explain the means by which LBDDSs act in vivo to enhance absorption. The goal of the current dissertation is to provide a better understanding of one proposed mechanism; the capability of lipoidal components in LBDDS formulations to create and maintain a drug in a supersaturated state under simulated GI conditions. Moreover, molecular details of equilibrium solubilization of a drug in a series of model lipid assemblies were examined. The results of these studies …

Preclinical Evaluation Of Lobeline For The Treatment Of Adhd: Comparison With Psychostimulant Therapies, Yolanda D. Williams

Theses and Dissertations--Pharmacy

This dissertation work investigated the effect of acute and repeated in vivo administration of lobeline on dopamine transporter (DAT) and vesicular monoamine transporter (VMAT2) function. The effects of lobeline were then compared to the effects of acute and repeated in vivo administration of methylphenidate and amphetamine to determine if lobeline produced similar effects compared to these Attention Deficit Hyperactivity Disorder (ADHD) medications. These medications are considered the first line of pharmacotherapy for ADHD, although there is a growing concern associated with their potential for abuse and other side effects. This merits the need for novel ADHD treatments that have a …

Xenobiotic Transporters In Lactating Mammary Epithelial Cells: Predictions For Drug Accumulation In Breast Milk, Philip Earle Empey

Theses and Dissertations--Pharmacy

Recent literature has established that breast cancer resistance protein (ABCG2) is upregulated during lactation and is responsible for the greater than predicted accumulation of many drugs in breast milk. The objectives of this project were (1) to investigate the role of this transporter in the reported apically-directed nitrofurantoin flux in the CIT3 cell culture model of lactation, (2) to develop a mathematical model for drug transfer into breast milk to relate initial flux rates, steady-state concentrations, efflux ratios, and in vivo milk to serum ratios (M/S) and (3) to identify xenobiotic transporters that are highly expressed, and therefore potentially important …