Pharmacy and Pharmaceutical Sciences Commons^™

Preclinical And Clinical Development Of The Lipophilic Camptothecin Analogue Ar-67, Eleftheria Tsakalozou

Theses and Dissertations--Pharmacy

AR-67 is a lipophilic third generation camptothecin analogue, currently under early stage clinical trials. It acts by targeting Topoisomerase 1 (Top1), a nuclear enzyme essential for DNA replication and transcription and is present in two forms, the pharmacologically active lipophilic lactone and the charged carboxylate. In oncology patients participating in a phase I clinical trial, AR-67 lactone was the predominant species in plasma. Similarly to other camptothecins, the identified dose-limiting toxicities for AR-67 were neutropenia, thrombocytopenia and fatigue. In addition, in vitro metabolism studies indicated AR-67 lactone as a substrate for CYP3A4/5 as well as the UGT1A7 and UGT1A8 enzymes …

The Pharmacokinetics Of Metal-Based Engineered Nanomaterials, Focusing On The Blood-Brain Barrier, Mo Dan

Theses and Dissertations--Pharmacy

Metal-based engineered nanomaterials (ENMs) have potential to revolutionize diagnosis, drug delivery and manufactured products, leading to greater human ENM exposure. It is crucial to understand ENM pharmacokinetics and their association with biological barriers such as the blood-brain barrier (BBB). Physicochemical parameters such as size and surface modification of ENMs play an important role in ENM fate, including their brain association. Multifunctional ENMs showed advantages across the highly regulated BBB. There are limited reports on ENM distribution among the blood in the brain vasculature, the BBB, and brain parenchyma.

In this study, ceria ENM was used to study the effect of …

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 …

Fine Tuning A Well-Oiled Machine: Influence Of Nk1.1 And Nkg2d On Nkt Cell Development And Function, Sunil K. Joshi, Mark L. Lang

Bioelectrics Publications

Natural killer T cells (NKT) represent a group of CD1d-restricted T-lineage cells that provide a functional interface between innate and adaptive immune responses in infectious disease, cancer, allergy and autoimmunity. There have been remarkable advances in understanding the molecular events that underpin NKT development in the thymus and in the complex array of functions in the periphery. Most functional studies have focused on activation of T cell antigen receptors expressed by NKT cells and their responses to CD1d presentation of glycolipid and related antigens. Receiving less attention has been several molecules that are hallmarks of Natural Killer (NK) cells, but …

Relationship Between Clandestine Methamphetamine Laboratory Seizures And Burns In Kentucky, David A. Wittmer

MPA/MPP/MPFM Capstone Projects

Methamphetamine is a highly addictive stimulant that is synthetically produced using equipment and chemicals available in the community. Its burden to society may be determined through a number of mechanisms, including the imposed strain on healthcare systems. The evolution of methamphetamine use and production methods has led to reports of increased methamphetamine related burn admissions among hospital burn units[1-3] . Current literature identifies an increase in injury severity, comorbid complications, and cost of care associated with methamphetamine related burn injuries[1-5]. The intent of this study is to identify burn injuries in Kentucky and assess whether a statistically significant association exists …

Nanoparticles Of Cobalt-Substituted Hydroxyapatite In Regeneration Of Mandibular Osteoporotic Bones, Nenad Ignjatović, Zorica Ajduković, Vojin Savić, Stevo Najman, Dragan Mihailović, Perica Vasilijević, Zoran Stojanović, Vuk Uskoković, Dragab Uskoković

Pharmacy Faculty Articles and Research

Indications exist that paramagnetic calcium phosphates may be able to promote regeneration of bone faster than their regular, diamagnetic counterparts. In this study, analyzed was the influence of paramagnetic cobalt-substituted hydroxyapatite nanoparticles on osteoporotic alveolar bone regeneration in rats. Simultaneously, biocompatibility of the material was tested in vitro, on osteoblastic MC3T3-E1 and epithelial Caco-2 cells in culture. The material was shown to be biocompatible and nontoxic when added to epithelial monolayers in vitro, while it caused a substantial decrease in the cell viability as well as deformation of the cytoskeleton and cell morphology when incubated with the osteoblastic …

The Antiinflammatory Action And Pharmacokinetics Of A Novel Glucosamine-Based Di-Peptide Aminosugar, Mohammad H. Gilzad-Kohan, Kamaljit Kaur, Fakhreddin Jamali

Pharmacy Faculty Articles and Research

Purpose. We have previously shown favorable in vitro gut permeability for three novel dipeptide esters of glucosamine (GlcN) likely facilitated by the peptide transporter 1 (PepT1). Herein, we report the development of a novel assay for the determination of bioavailability of the peptide ester of interest, the anti-inflammatory properties of a glycine-valine ester derivative of GlcN (GVG) as well as its pharmacokinetics under healthy and inflammatory conditions.

Methods. A pre-column derivatization (with 9-fluorenylmethoxycarbonyl) HPLC assay was developed to study bioavailability of GVG, GlcN or cleaved GlcN in the rats that were cannulated in their right jugular vein for …

Kentucky Pharmacist Opinions Of The Potential Reclassification Of Pseudophedrine As A Legend Drug, Kathleen E. Monson

MPA/MPP/MPFM Capstone Projects

Methamphetamine is a drug of abuse, which is often produced in clandestine laboratories. Recent efforts to curb methamphetamine abuse are aimed at controlling access to precursors, including pseudoephedrine (PSE), used in illicit methamphetamine production. Currently, access to PSE is controlled in Kentucky by placement behind pharmacy counters, retail quantity limitations and electronic tracking. Recent legislation proposed in Kentucky to change PSE from non-prescription to a legend medication was unsuccessful and highly controversial. The objective of this project is to collect and analyze pharmacists’ opinions on the effectiveness of current precursor controls, proposed legislation to make PSE a legend drug and …

Pharmaceutical Policy Process: Lessons From The Newly Independent States, Irina Ghazaryan

Muskie School Capstones and Dissertations

Although the pharmaceutical sector in Armenia is currently mainly established, some challenges still cause a big concern. Such facts as a lack of important policies on pharmaceuticals, an outdated legislation and a lack of regulation suggest that the pharmaceutical policy process in Armenia is not effective enough and its insufficient effectiveness is one of the most important barriers for successful implementation of pharmaceutical reforms in the country. The goal of this capstone was to analyze pharmaceutical policy process in Armenia and other Newly Independent States and to develop recommendations for Armenia. Data and information were obtained from publication searches and …

Precision And Accuracy: Omnipod Pdm® (O-Pdm) Versus Freestyle Lite Meter® (Fsl Meter) Utilizing Freestyle Lite (Fsl)® Test Strips In Multiple Patient Situations, Christine M. Hayden

Honors Theses

Today, diabetes mellitus affects 8.3% of the people in the United States and is having detrimental effects on patient populations as well as health care. To this date, there are numerous monitors that all meet specific requirements and industry standards in order to aid patients in self-monitoring of blood glucose (SMBG). There is currently a large market for these monitors and efforts have been made to devise the monitors to be accurate and precise. Through this study, accuracy and precision were studied by evaluating the difference between the O-PDM and FSL meter monitoring systems. It was hypothesized that a difference …

Synthesis Of A New Scytovirin Protein Derivative, Sd1-Sd2-Sd2, To Decrease Hiv-1 Binding Affinity, Alexandra M. Wood

Honors Theses

Scytovirin is a novel anti-viral protein isolated from the cyanobacterium Scytonema varium. This protein has produced great scientific interest for its anti-human immunodeficiency virus (HIV) activity. Scytovirin disrupts the mechanism of HV infection by binding to HIV-1 proteins glycoprotein 120, glycoprotein 160, and glycoprotein 41. It does not bind to the CD4 receptor on human immune cells. The wild-type protein consists of a single 95 amino acid chain. When folded, Scytovirin's amino acid sequence is arranged into two distinct domains, each with a high degree of sequence conservation. This implicates the importance of both domains in anti-HIV activity. Primers were …

Potential Natural Product Phosphodiesterase Inhibitors, Michael John Cunningham

Electronic Theses and Dissertations

Three different studies set forth to investigate the role of phosphodiesterase (PDE) enzyme inhibitors in sexual dysfunction and mood regulation. First, naturalproducts were screened by computer modeling of PDE5A1. Second, compounds were isolated from a plant traditionally used as an aphrodisiac. Third, a new synthesis of psychoactive PDE4 inhibitor was attempted. An in silico screen was performed using chemical structures of isolated compounds thought to have some PDE inhibitory activity based on traditional use of the plants. A collection of compounds with structures similar to known natural product inhibitors was also included in the docking library. Glide docking software (Schrödinger) …

Structural Characterization And Bioactivity Of Cranberry Oligosaccharides, Kimberly M. Auker

Electronic Theses and Dissertations

Complex carbohydrates from plant sources, such as the fruits of cranberry (Vaccinium macrocarpon Aiton), promote human health in a variety of ways. However, complete studies of carbohydrate function often hinge on a detailed understanding and thorough elucidation of the chemical structure. Several methods have been used in the structure elucidation of cranberry oligosaccharides, such as derivatization folloby analysis using gas chromatography-mass spectrometry (GC-MS). In this manner, the identity and quantity of glycosyl units within two cranberry oligosaccharides were investigated through hydrolysis of the oligomers and subsequent synthesis of trimethylsilyl and alditol acetate derivatives. Further analysis using partially methylated alditol acetate …

Molecular Modeling And Sar Studies Of Cdk5/P25 Selective Inhibitors, Arindam Chatterjee

Electronic Theses and Dissertations

Alzheimer's disease (AD) is one of the most dreaded forms of progressive neurodegenerative diseases. The two main hallmarks of AD are the formation of amyloid senile plaques and neurofibrillary tangles. Cyclin dependent kinase 5 (CDK5) is a proline directed serine/threonine kinase, which expressed primarily in the central nervous system. In the biochemical process the CDK5-natural activator, p35 is cleaved by calpain to a shorter protein p25, which in turn hyperphosphorylates Tau, forms neurofibrillary tangles and causes AD. CDK5 deregulation is also indicated in other neurodegenerative diseases, such as Huntington's chorea, stroke, Parkinson's disease, amyotrophic lateral sclerosis, major depression and substance …

Scaffold Perception, Compharmacophore Model Development, And Quantitative Structure-Affinity Relationships Of Sigma Site Ligands, David Enos Watson

Electronic Theses and Dissertations

Sigma receptors are endogenous proteins with potential utility in treating psychological disorders, ischemia, the psychological and convulsive effects of drugs of abuse, and as an imaging agent for cancerous tissues, among others. Drug design efforts targeting these receptors have been hindered by a lack of structural information of the receptors themselves. Traditional ligand-based approaches have succeeded in generating many compounds with high affinity, and quite a few with selectivity for σ-1 receptors. There are few selective ligands for use as pharmacological probes for the σ-2 receptor. Much effort has gone into exploring the structure activity relationships of ligands targeting these …

Medicare Part D Roulette: Potential Implications Of Random Assignment And Plan Restrictions, Rajul A. Patel, Mark P. Walberg, Joseph A. Woelfel, Michelle M. Amaral, Paresh Varu

School of Pharmacy Faculty Articles

Background: Dual-eligible (Medicare/Medicaid) beneficiaries are randomly assigned to a benchmark plan, which provides prescription drug coverage under the Part D benefit without consideration of their prescription drug profile. To date, the potential for beneficiary assignment to a plan with poor formulary coverage has been minimally studied and the resultant financial impact to beneficiaries unknown.

Objective: We sought to determine cost variability and drug use restrictions under each available 2010 California benchmark plan.

Methods: Dual-eligible beneficiaries were provided Part D plan assistance during the 2010 annual election period. The Medicare Web site was used to determine benchmark plan costs and prescription …

Identification Of Distant Drug Off-Targets By Direct Superposition Of Binding Pocket Surfaces., Marcel Schumann, Roger S Armen

College of Pharmacy Faculty Papers

Correctly predicting off-targets for a given molecular structure, which would have the ability to bind a large range of ligands, is both particularly difficult and important if they share no significant sequence or fold similarity with the respective molecular target ("distant off-targets"). A novel approach for identification of off-targets by direct superposition of protein binding pocket surfaces is presented and applied to a set of well-studied and highly relevant drug targets, including representative kinases and nuclear hormone receptors. The entire Protein Data Bank is searched for similar binding pockets and convincing distant off-target candidates were identified that share no significant …