Medicine and Health Sciences Commons^™

Effect Of 2-Deoxyglucose On Colorectal Cancer Cell Lines, Alex Olinger, Pratik Muley, Hemachand Tummala

The Journal of Undergraduate Research

The third leading cause of cancer deaths in the U.S. is colon cancer. The major disadvantage of cancer chemotherapy is its non-selective toxicity to healthy cells at the therapeutic doses. A possible target selective for cancer cells is their dependence on glycolysis for cellular energy. 2-deoxyglucose (2-DG) is a glycolytic inhibitor that has been shown to be safe in both animals and humans. The molecular mechanisms for the anticancer effect of 2-DG cannot be explained solely by its glycolytic inhibition. In this manuscript we studied the effect of 2-DG on colon cancer cells and its possible molecular mechanism. Colon cancer …

New Oral Anticoagulants In The Treatment Of Pulmonary Embolism: Efficacy, Bleeding Risk, And Monitoring, Kelly M. Rudd, Elizabeth Phillips

Pharmacy Faculty/Staff Publications

Anticoagulation therapy is mandatory in patients with pulmonary embolism to prevent significant morbidity and mortality. The mainstay of therapy has been vitamin-K antagonist therapy bridged with parenteral anticoagulants. The recent approval of new oral anticoagulants (NOACs: apixaban, dabigatran, and rivaroxaban) has generated significant interest in their role in managing venous thromboembolism, especially pulmonary embolism due to their improved pharmacokinetic and pharmacodynamic profiles, predictable anticoagulant response, and lack of required efficacy monitoring. This paper addresses the available literature, on-going clinical trials, highlights critical points, and discusses potential advantages and disadvantages of the new oral anticoagulants in patients with pulmonary embolism.

The Design, Synthesis, And Biological Evaluation Of Aplysinopsin Analogs As Potential Neuromodulators, Kevin Lewellyn

Electronic Theses and Dissertations

Aplysinopsins are tryptophan-derived natural products that have been isolated from a variety of marine organisms and have been shown to possess a range of biological activities. Initial synthesis of a library of 50 aplysinopsin analogs revealed that of the 12 serotonin receptor subtypes and 34 other CNS receptors, aplysinopsin analogs shoa high affinity for the 5-HT2B and 5-HT2C receptor subtypes, with selectivity for 5-HT2B over 5-HT2C. Bromination at C-4 and C-5 of the indole ring resulted in greater binding affinities, with Ki's as low as 35 nM. In addition, biological evaluation of the MAO-A and MAO-B inhibitory activities of these …

Synthesis Of Natural Product-Based Sphingosine Derivatives, Zarana Daksh Chauhan

Electronic Theses and Dissertations

Marine sponges represent an excellent source of sphingolipids and their metabolites, especially sphingosine-1-phosphate (S1P). S1P plays an important role in cell differentiation, survival, proliferation and the immune response. The enzyme sphingosine kinase (SK) is critical for the phosphorylation of sphingosine to S1P and has been examined as a druggable target for the treatment of hyper-proliferative diseases, inflammation, cancer and other pathological conditions. Natural products that consist of an azetidine ring represents an interesting class of conformationally constrained scaffolds that may serve as effective lead compounds for SK inhibitor development. Hence, the goal of this thesis research was to synthesize natural-product …

Metabolic Stability And Pharmacokinetics In Lead Optimization Of Potential Anti-Psychostimulant Pharmacotherapies, Seshulatha Jamalapuram

Electronic Theses and Dissertations

Drug addiction is a chronic disorder characterized by obsessive and uncontrollable drug-seeking behaviors. It is a major public health problem globally as well as in the United States. Apart from causing severe medical complications it also leads to several socioeconomic problems like healthcare expenditures, lost earnings and increase in drug-related crime. The discovery and development of potential pharmacotherapies to treat cocaine dependence has been a high priority for more than two decades but still there is US-FDA approved medication. This illustrates the need for the development of effective medication to treat cocaine and methamphetamine abuse. Sigma receptors have recently been …

Dual Targeting Ligands Of Sigma Receptors And Dopamine Transporters As Potential Pharmacotherapy For Cocaine Abuse, Shivangi Awasthi

Electronic Theses and Dissertations

No abstract provided.

Part A: Antimalarial Agents Modified At The C-16 Position Of Artemisinin; Part B: Lead Optimization Of Falcipain-2 And Falcipain-3 Inhibitors, Yunshan Wu

Electronic Theses and Dissertations

Part A: Antimalarial Agents modified at the C-16 position of Artemisinin. Malaria is a widespread tropical and subtropical parasitic disease which is caused by malarial parasites and transmitted by the infected anopheles mosquitoe. The natural product artemisinin and its derivatives are currently considered the most effective drugs against drug resistant plasmodium falciparum. However, its undesired physicochemical proprieties have limited its usage. In order to improve its effectiveness, scientists around the world have developed novel methodology to synthesize artemisinin derivatives on different positions of the artemisinin skeleton. Previous work in our group has shown that many analogues modified at the C-16 …

Multifunctional Hydroxyapatite And Poly(D,L-Lactide-Co-Glycolide) Nanoparticles For The Local Delivery Of Cholecalciferol, Nenad Ignjatović, Vuk Uskoković, Zorica Ajduković, Dragan Uskoković

Pharmacy Faculty Articles and Research

Cholecalciferol, vitamin D3, plays an important role in bone metabolism by regulating extracellular levels of calcium. Presented here is a study on the effects of the local delivery of cholecalciferol (D3) using nanoparticulate carriers composed of hydroxyapatite (HAp) and poly(D,L-lactide-co-glycolide) (PLGA). Multifunctional nanoparticulate HAp-based powders were prepared for the purpose of: (a) either fast or sustained, local delivery of cholecalciferol, and (b) the secondary, osteoconductive and defect-filling effect of the carrier itself. Two types of HAp-based powders with particles of narrowly dispersed sizes in the nano range were prepared and tested in this study: HAp nanoparticles as direct cholecalciferol delivery …

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 …

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 …

Phase Composition Control Of Calcium Phosphate Nanoparticles For Tunable Drug Delivery Kinetics And Treatment Of Osteomyelitis. Part 1: Preparation And Drug Release, Vuk Uskoković, Tejal A. Dasai

Pharmacy Faculty Articles and Research

Developed in this study is a multifunctional material for simultaneous osseoinduction and drug delivery, potentially applicable in the treatment of osteomyelitis. It is composed of agglomerates of nanoparticles of calcium phosphate (CAP) with different monophasic contents. The drug loading capacity and the release kinetics were investigated on two model drug compounds with different chemical structures, sizes and adsorption propensities: bovine serum albumin and fluorescein. Loading of CAP powders with small molecule drugs was achieved by physisorption and desiccation-induced agglomeration of nanoparticulate subunits into microscopic blocks. The material dissolution rate and the drug release rate depended on the nature of the …

High-Activity Mutants Of Human Butyrylcholinesterase For Cocaine Abuse Treatment, Liu Xue

Theses and Dissertations--Pharmacy

Cocaine is a widely abused drug without an FDA-approved medication. It has been recognized as an ideal anti-cocaine medication to accelerate cocaine metabolism producing biologically inactive metabolites via a route similar to the primary cocaine-metabolizing pathway, i.e. butyrylcholinesterase (BChE)-catalyzed hydrolysis. However, the native BChE has a low catalytic activity against cocaine. We recently designed and discovered a set of BChE mutants with a high catalytic activity specifically for cocaine. An ideal, therapeutically valuable mutant of human BChE should have not only a significantly improved catalytic activity against cocaine, but also certain selectivity for cocaine over neurotransmitter acetylcholine (ACh) such …

Computational Modeling, Design, And Characterization Of Cocaine-Metabolizing Enzymes For Anti-Cocaine Medication, Lei Fang

Theses and Dissertations--Pharmacy

Cocaine is a widely abused and addictive drug, resulting in serious medical and social problems in modern society. Currently, there is no FDA-approved medication specific for cocaine abuse treatment. The disastrous medical and social consequences of cocaine abuse have made the development of an anti-cocaine medication a high priority. However, despite decades of efforts, traditional pharmacodynamic approach has failed to yield a truly useful small-molecule drug due to the difficulties inherent in blocking a blocker like cocaine without affecting the normal functions of the transporters or receptors. An alternative approach, i.e. pharmacokinetic approach, is to interfere with the delivery of …

High Dose Simvastatin As A Potential Anticancer Therapy In Leukemia Patients, Tamer Ahmed

Theses and Dissertations--Pharmacy

Simvastatin is a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor that is used for the treatment of hyperlipidemia. Simvastatin has recently been studied for its potential use in cancer therapy. In-vitro studies have shown that simvastatin displays anticancer activity, but at concentrations unlikely to be achieved in patients being receiving typical antihyperlipidemic treatment doses. Thus, several clinical trials were conducted to study the tolerability of high dose statins in cancer patients. The maximum tolerated dose of simvastatin was determined to be 15 mg/kg/day, 25-fold higher than a typical dose. However, it is not known if simvastatin plasma concentrations can reach those …

Towards Elucidation Of A Viral Dna Packaging Motor, Chad T. Schwartz

Theses and Dissertations--Pharmacy

Previously, gp16, the ATPase protein of phi29 DNA packaging motor, was an enigma due to its tendency to form multiple oligomeric states. Recently we employed new methodologies to decipher both its stoichiometry and also the mechanism in which the protein functions to hydrolyze ATP and provide the driving force for DNA packaging. The oligomeric states were determined by biochemical and biophysical approaches. Contrary to many reported intriguing models of viral DNA packaging, it was found that phi29 DNA packaging motor permits the translocation of DNA unidirectionally and driven cooperatively by three rings of defined shape. The mechanism for the generation …

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 …

Pharmacovigilance Of Biosimilars, Lipika Chablani

Pharmacy Faculty/Staff Publications

In lieu of an abstract, here is the article's first paragraph:

Biotech industry forms the backbone of the current pharmaceutical products. Seven out of top ten anticipated drugs of the industry in 2014 will be biologics [1]. Considering the fast pace growth of the biotechnological products, there is a parallel demand of biosimilars. As defined by FDA, “A biosimilar is a biological product that is highly similar to a U.S.-licensed reference biological product notwithstanding minor differences in clinically inactive components, and for which there are no clinically meaningful differences between the biological product and the reference product in terms of …

Variceal Bleeding From Cirrhosis: A Clinical Review Of Causes And Pharmacotherapy Options, Hillary Aphaisuwan, Ibrahim Lala, Laura Tsu

Pharmacy Faculty Articles and Research

This home-study CPE activity has been developed to educate pharmacists on the prevention and treatment of hemorrhagic esophageal varices resulting from cirrhosis.

Disparity Implications Of The Medicare Medication Therapy Management Eligibility Criteria: A Literature Review, Kiraat D. Munshi, Ya-Chen Tina Shih, Lawrence M. Brown, Samuel Dagogo-Jack, Jim Y. Wan, Junling Wang

Pharmacy Faculty Articles and Research

The emphasis on eliminating racial and ethnic disparities in healthcare has received national attention, with various policy initiatives addressing this problem and proposing solutions. However, in the current economic era requiring tight monetary constraints, emphasis is increasingly being placed on economic efficiency, which often conflicts with the equality doctrine upon which many policies have been framed. The authors’ review aims to highlight the disparity implications of one such policy provision – the predominantly utilization-based eligibility criteria for medication therapy management services under Medicare Part D – by identifying studies that have documented racial and ethnic disparities in health status and …

Assessment Of The Feasibility Of Co-Administration Of Phenolic Dietary Compounds With Phenylephrine To Increase Its Bioavailability, Zhenxian Zhang

Theses and Dissertations

R-(-)-Phenylephrine (PE) is the most commonly used nonprescription oral nasal decongestant in the United States. It is a selective α1-adrenergic receptor agonist and has many years of safe usage. However, the efficacy of PE is controversial, due to its extensive pre-systemic metabolism, which leads to low and variable oral bioavailability (38 ± 9%, mean ± SD). Sulfation plays a very important role in pre-systemic metabolism of PE. The sulfation of PE occurs at its phenolic group, which is the preferred structural feature of many sulfotransferase (SULT) substrates. Compounds with phenolic groups have similar structures to PE, which may share the …

In-Vitro Pk/Pd Profiling And Modeling Of The Anti-Sickling Agents, 5-Hydroxymethyl Furfural (5-Hmf) And Novel Synthetic Allosteric Effectors Of Hemoglobin (Aeh) In Human Whole Blood, Apurvasena Parikh

Theses and Dissertations

Introduction. 5-HMF and novel INN-compounds are left-shifting AEH, shown to have anti-sickling action by forming transiently covalent Schiff-base adducts with hemoglobin (Hb), thereby increasing the Hb O2-affinity. They are hypothesized to be substrates for aldehyde dehydrogenase (ALDH) in the liver and red blood cells (RBC). Methods. Biopharmaceutical assessments were made for AEH, using calculated physicochemical properties. Their in-vitro hepatic metabolism (mediated by ALDH) was characterized using hepatic cytosol, and in-vitro-in-vivo extrapolations (IVIVE) were made. Inter-species differences in hepatic cytosolic ALDH activity were investigated using acetaldehyde as a model substrate in different mammalian species. Time- and concentration-dependent in-vitro disposition of 5-HMF …

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 …

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 …

Avoidance Disruptive Effect Of Clozapine And Olanzapine Is Potentiated By Increasing The Test Trials: Further Test Of The Motivational Salience Hypothesis, Min Feng, Nan Sui, Ming Li

Department of Psychology: Faculty Publications

Antipsychotic drugs suppress animals’ ability to avoid an aversive stimulus in the conditioned avoidance response model (CAR). This behavioral effect is thought to reflect antipsychotic activity and is suggested to be mediated by a drug’s action in attenuating the motivational salience of a conditioned stimulus (CS). In the present study, we tested whether atypical antipsychotic drugs clozapine and olanzapine act through this behavioral mechanism by manipulating the number of avoidance test trials. We reasoned that more CS trials in the present of clozapine or olanzapine would afford the drug more opportunities to decrease the motivational salience of the CS, thus …