Chemicals and Drugs Commons^™

Pharmacologic Profiling Of Novel Compounds Via Fluorometric Analyses Of Monoamine Transporter Responses, Ashkhan Hojati

Theses and Dissertations

In humans and other organisms, monoaminergic systems are crucial in neuronal function and behavior. The monoamine transporters (MATs), which can be found on the presynaptic plasma membrane of neurons in the central nervous system (CNS), are crucial in the regulation of neurotransmitter concentration in the synaptic cleft. As the duration and concentration of neurotransmitters in the cleft affect further downstream signaling responses, these proteins are important targets for both understanding neuronal physiology and compounds of interest. Multiple theories exist proponing the contribution of MATs to a variety of mental and neurological disorders, including depression. This theory establishes that depression is …

Inhibition Of Cancer Stem Cells By Glycosaminoglycan Mimetics, Connor P. O'Hara

Theses and Dissertations

Connor O’Hara July 29, 2019

Inhibition of Cancer Stem Cells by Glycosaminoglycan Mimetics

In the United States cancer is the second leading cause of death, with colorectal cancer (CRC) being the third deadliest cancer and expected to cause over 51,000 fatalities in 2019 alone.¹ The current standard of care for CRC depends largely on the staging, location, and presence of metastasis.² As the tumor grows and invades nearby lymph tissue and blood vessels, CRC has the opportunity to invade not only nearby tissue but also metastasize into the liver and lung (most commonly).³ The 5-year survival rate …

Myopia Outcome Study Of Atropine In Children (Mosaic): Design And Methodology, Saoirse Mccrann, Daniel Ian Flitcroft, John Butler, James Loughman

Articles

Purpose

The Myopia Outcome Study of Atropine in Children (MOSAIC) aims to explore the efficacy, safety, acceptability and mechanisms of action of 0.01% atropine for myopia control in a European population.

Methods

MOSAIC is an investigator-led, double-masked, placebo-controlled, randomised clinical trial investigating the efficacy, safety and mechanisms of action of 0.01% atropine eyedrops in myopic progression management. During phase 1 of the trial, 250 children aged 6-16 years with progressive myopia apply eye drops once nightly in both eyes from randomisation to month 24. No treatment is given during phase 2 from month 24 to 36 (washout period) for those …

The Potential Of Biobanked Liquid Based Cytology Samples For Cervical Cancer Screening Using Raman Spectroscopy., D. Traynor, S. Duraipandian, R. Bhatia, K. Cuschieri, C. M. Martin, J. J. O'Leary, Fiona Lyng

Articles

Patient samples are unique and often irreplaceable. This allows biobanks to be a valuable source of material. The aim of this study was to assess the ability of Raman spectroscopy to screen for histologically confirmed cases of Cervical Intraepithelial neoplasia (CIN) using biobanked liquid based cytology (LBC) samples. Two temperatures for long term storage were assessed; 80°C and -25°C. The utility of Raman spectroscopy for the detection of CIN was compared for fresh LBC samples and biobanked LBC samples. Two groups of samples were used for the study with one group associated with disease (CIN 3) and the other associated …

The Impact Of Medical Marijuana On The Opioid Crisis, Carl David Eastep

Physician Assistant Scholarly Project Posters

• The opioid crisis dictates the need for research into alternative treatments for acute and chronic pain.

• Comprehensive literature review was conducted to determine if medical marijuana might play a role in the treatment of acute and chronic pain.

• The addiction profiles of medical marijuana and prescription opiates were compared along with the adverse effects and quality of life.

• No use for medical marijuana for the treatment of acute pain.

• Likely some benefits from medical marijuana for chronic pain.

• Addictive profile

• Marijuana – marijuana withdrawal syndrome.
• Prescription Opiates – highly addictive

• Adverse …

Glycosaminoglycan Mimetics For The Treatment Of Cancer And Lung Inflammation, Shravan Morla

Theses and Dissertations

Glycosaminoglycans (GAGs) are linear polysaccharides whose disaccharide building blocks consist of an amino sugar and either uronic acid or galactose. They are expressed on virtually all mammalian cells, usually covalently attached to proteins, forming proteoglycans. GAGs are highly negatively charged due to an abundance of sulfate and carboxylic acid groups, and are structurally very diverse, with differences arising from chain length, the type of monomeric units, the linkages between each monomeric unit, the position of sulfate groups, and the degree of sulfation. GAGs are known to interact with a multitude of proteins, impacting diverse physiological and pathological processes. In addition, …

At Risk Alcohol Consumption With Smoking By National Background: Results From The Hispanic Community Health Study/Study Of Latinos, Frank C. Bandiera, Eliseo J. Pérez-Stable, Folefac Atem, Raul Caetano, Denise C. Vidot, Marc D. Gellman, Elena L. Navas-Nacher, Jianwen Cai, Gregory Talavera, Neil Schneiderman, Robert Kaplan

United States Food and Drug Administration: Publications

Introduction: Tobacco smoking and binge or excess drinking are unhealthy behaviors that frequently co-occur. Studies of Hispanics/Latinos have mostly been of Mexican Americans although there are substantial differences in smoking and drinking by heritage background. Associated with co-use by 5 subpopulations.

Methods: Cross-sectional data of 16,412 Hispanics/Latinos from Miami, the Bronx, Chicago and San Diego collected between 2008 and 2011 as part of the HCHS/SOL were analyzed. Smoking and alcohol consumption and demographic data were measured by self-report. Prevalence of smoking and alcohol consumption and co-use were reported. Logistic regression models examined the odds of co-use of smoking and binge …

Comparing Methods For Clinical Investigator Site Inspection Selection: A Comparison Of Site Selection Methods Of Investigators In Clinical Trials, Nicholas Hein, Elena Rantou, Paul Schuette

United States Food and Drug Administration: Publications

Background During the past two decades, the number and complexity of clinical trials have risen dramatically increasing the difficulty of choosing sites for inspection. FDA’s resources are limited and so sites should be chosen with care.

Purpose To determine if data mining techniques and/or unsupervised statistical monitoring can assist with the process of identifying potential clinical sites for inspection.

Methods Five summary-level clinical site datasets from four new drug applications (NDA) and one biologics license application (BLA), where the FDA had performed or had planned site inspections, were used. The num- ber of sites inspected and the results of the …

Impact Of Contemporary Low Dose Aspirin Use And Cardiovascular Disease, Pratik Sharma, Ramona Stone

Public Health Sciences Student Work

No abstract provided.

A Complete Approach To Predict Biodistribution Of Nanomaterials Within Animal Species From In-Vitro Data, Edward Price

Electronic Theses and Dissertations

Smart drug-design for antibody and nanomaterial-based therapies allows for optimization of drug efficacy and more efficient early-stage pre-clinical trials. The ideal drug must display maximum efficacy at target tissue sites, but to track and predict distribution to these sites, one must have a mechanistic understanding of the kinetics involved with the individual cells of the tissue itself. This process can be tracked through biological simulations coupled with in-vitro approaches, which result in a rapid and efficient in-depth understanding of drug transport within tissue vasculature and cellular environment. As a result, it becomes possible to predict drug biodistribution within live animal …

Mechanisms And Thermodynamics Of The Influence Of Solution-State Interactions Between Hpmc And Surfactants On Mixed Adsorption Onto Model Nanoparticles, Salin Gupta Patel

Theses and Dissertations--Pharmacy

Nanoparticulate drug delivery systems (NDDS) such as nanocrystals, nanosuspensions, solid-lipid nanoparticles often formulated for the bioavailability enhancement of poorly soluble drug candidates are stabilized by a mixture of excipients including surfactants and polymers. Most literature studies have focused on the interaction of excipients with the NDDS surfaces while ignoring the interaction of excipients in solution and the extent to which the solution-state interactions influence the affinity and capacity of adsorption. Mechanisms by which excipients stabilize NDDS and how this information can be utilized by formulators a priori to make a rational selection of excipients is not known.

The goals of …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Targeting Lipoprotein Biogenesis: Considerations Towards Antimicrobials, Toufic El Arnaout, Tewfic Soulimane

Articles

Decades have passed without approval of a new antibiotic class. Several companies have recently halted related discovery efforts because of multiple obstacles. One promising route under research is to target the lipoprotein maturation pathway in light of major recent findings and the virulence roles of lipoproteins. To support the future design of selective drugs, considerations and priority-setting are established for the main lipoprotein processing enzymes (Lgt, LspA, and Lnt) based on microbiology, biochemistry, structural biology, chemical design, and pharmacology. Although not all bacterial species will be similarly impacted by drug candidates, several advantages make LspA a top target to pursue …

Hematologic Safety Of Chronic Brain-Penetrating Erythropoietin Dosing In App/Ps1 Mice, Jiahong Sun, Joshua Yang, Kathrine Whitman, Charlene Zhu, David H. Cribbs, Ruben J. Boado, William M. Pardridge, Rachita K. Sumbria

Pharmacy Faculty Articles and Research

Introduction: Low blood-brain barrier (BBB) penetration and hematopoietic side effects limit the therapeutic development of erythropoietin (EPO) for Alzheimer's disease (AD). A fusion protein of EPO and a chimeric monoclonal antibody targeting the mouse transferrin receptor (cTfRMAb) has been engineered. The latter drives EPO into the brain via receptor-mediated transcytosis across the BBB and increases its peripheral clearance to reduce hematopoietic side effects of EPO. Our previous work shows the protective effects of this BBB-penetrating EPO in AD mice but hematologic effects have not been studied. Herein, we investigate the hematologic safety and therapeutic effects of chronic cTfRMAb-EPO dosing, …

An Open-Label, Single-Dose Study To Evaluate The Safety, Tolerability, Pharmacokinetics, And Pharmacodynamics Of Cinacalcet In Pediatric Subjects Aged 28 Days To < 6 Years With Chronic Kidney Disease Receiving Dialysis., Winnie Y. Sohn, Anthony A. Portale, Isidro B. Salusky, Hao Zhang, Lucy L. Yan, Bella Ertik, Shahnaz Shahinfar, Edward Lee, Bastian Dehmel, Bradley A. Warady

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Calcimimetics, shown to control biochemical parameters of secondary hyperparathyroidism (SHPT), have well-established safety and pharmacokinetic profiles in adult end-stage renal disease subjects treated with dialysis; however, such studies are limited in pediatric subjects.

METHODS: In this study, the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of cinacalcet were evaluated in children with chronic kidney disease (CKD) and SHPT receiving dialysis. Twelve subjects received a single dose of cinacalcet (0.25 mg/kg) orally or by nasogastric or gastric tube. Subjects were randomized to one of two parathyroid hormone (PTH) and serum calcium sampling sequences: [(1) 2, 8, 48 h; or (2) …

Investigating The Effect Of Sodium Benzoate On Immune Cells And Microbial Populations In The Small Intestine Of Murine Species., Shelby Pedigo

Senior Honors Projects, 2010-2019

Dietary ingredients can influence the mucosal surface morphology and mucosal immunity of the gastrointestinal tract. Additional health concerns and behavioral changes have been attributed to the consumption of foods containing preservatives and additives. Sodium benzoate (SB) is a commonly used bacteriostatic in food and beverages. This study investigates the effects of SB on the gut bacteria and mucosal health in the gastrointestinal tract of laboratory mice. The extent of lymphocytic infiltration in intestinal villi and granular density of Paneth cells in the ileum were used as evaluators of mucosal immunity. Adult C57BL/6 mice were randomly assigned to two …

The Chemical Analysis And Biological Activities Of The Secondary Metabolites From Dalea Mollis And Dalea Albiflora, Nicholas Peter Hansen

All Master's Theses

Multidrug resistance has increased since the introduction of drugs used to prevent growth and kill microorganisms in a host. This has caused a worldwide search to discover new drugs effective against microorganisms. Mechanisms of drug resistance include, but are not limited to, the production of biofilms and efflux pumps. Efflux pumps prevent antimicrobial drugs from reaching their biological target, so the coordinated use of efflux pump inhibitors and antimicrobial drugs has been identified as a potential treatment for multidrug-resistant microorganisms. The secondary metabolites of Dalea mollis and Dalea albiflora were tested against multidrug-resistant (MDR) and engineered strains of the fungi …

Breaking The Paradigm: Dr Insight Empowers Signature-Free, Enhanced Drug Repurposing, Jinyan Chan, Xuan Wang, Jacob A. Turner, Nicole E. Baldwin, Jinghua Gu

Faculty Publications

Motivation: Transcriptome-based computational drug repurposing has attracted considerable interest by bringing about faster and more cost-effective drug discovery. Nevertheless, key limitations of the current drug connectivity-mapping paradigm have been long overlooked, including the lack of effective means to determine optimal query gene signatures. Results: The novel approach Dr Insight implements a frame-breaking statistical model for the ‘hand-shake’ between disease and drug data. The genome-wide screening of concordantly expressed genes (CEGs) eliminates the need for subjective selection of query signatures, added to eliciting better proxy for potential disease-specific drug targets. Extensive comparisons on simulated and real cancer datasets have validated the …

Leucine Supplementation In Cuprizone-Induced Oligodendrocyte Toxicity, Michael Ley

Williams Honors College, Honors Research Projects

Cuprizone is a copper chelator that induces demyelination in the central nervous system when fed to mice. This compound is thought to target Complex IV and disrupt mitochondrial metabolism leading to loss of myelin-producing oligodendrocytes. In this proposal, we further examine the chemical and toxicological properties of cuprizone. Immunofluorescence imaging and microarray data on MO3.13 cells treated with cuprizone revealed the possibility of alterations in lysosomal function, as well as mitochondrial disruption via mTOR and Electron Transport Chain (ETC) related pathways. Cell viability assays conducted suggest that addition of Branched-Chain Amino Acids, most commonly used from literature, leucine, can increase …

Multidimensional Mass Spectrometry Of Chemonic™ Ccg-6 Nonionic Surfactant With Separation By Polarity And Shape, Charles Johnson

Williams Honors College, Honors Research Projects

Chemonic™ CCG-6 surfactant is a water-soluble poly(ethylene glycol) (PEG) conjugated alkyl glyceride emollient. This surfactant exists as a complex mixture of a glycerol cores conjugated with poly(ethylene glycol) branches (PEGylation) that were partially esterified with caprylic (C8) and capric (C10) acids. These may be esterified on one, two, or all three arms of the glyceride. The architecture of the structures in this mixture was studied using multidimensional mass spectrometry (MS). Mass spectrometry was interfaced with ultra-performance liquid chromatography (UPLC) and ion mobility (IM) separation. The mixture was separated by reversed-phase LC, oligomers of the star-branched polymer were separated according to …

Developmental Expression Of Monocarboxylate Transporter 1 And 4 In Rat Liver, Michael Ng, Justin Louie, Jieyun Cao, Melanie A. Felmlee

School of Pharmacy Faculty Articles

PURPOSE: Monocarboxylate transporters (MCT) are proton-coupled integral membrane proteins that control the influx and efflux of endogenous monocarboxylates such as lactate, acetate and pyruvate. They also transport and mediate the clearance of drugs such as valproate and gamma-hydroxybutyrate. CD147 functions as ancillary protein that chaperones MCT1 and MCT4 to the cell membrane. There is limited data on the maturation of MCT and CD147 expression in tissues related to drug distribution and clearance. The objective of the present study was to quantify hepatic MCT1, MCT4, and CD147 mRNA, whole cell and membrane protein expression from birth to sexual maturity.

METHODS: Liver …

Hiv Viral Rebound Due To A Possible Drug-Drug Interaction Between Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide And Calcium-Containing Products: Report Of 2 Cases, S. Lena Kang-Birken, Dena El-Sayed, John Prichard

School of Pharmacy Faculty Articles

Elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) is a potent fixed-dose, once-daily regimen for HIV-1 treatment and has rare emergence of drug resistance. We report a potential drug-drug interaction in 2 female patients both receiving treatment for HIV and cerebral toxoplasmosis: one case between E/C/F/TAF with calcium carbonate and a second case involving leucovorin as calcium salt. Both cases resulted in rise in HIV RNA levels and emergence of M184 V mutation and resistance to elvitegravir and raltegravir. To the best of our knowledge, these 2 cases are the first reports of rapid emergence of mutation from coadministration of E/C/F/TAF and calcium.

Responsible, Safe, And Effective Use Of Biologics In The Management Of Low Back Pain: American Society Of Interventional Pain Physicians (Asipp) Guidelines, Annu Navani, Laxmaiah Manchikanti, Sheri L. Albers, Richard E. Latchaw, Jaya Sanapati, Alan David Kaye, Sairam Atluri, Sheldon Jordan, Ashim Gupta, David Cedeno, Alejandro Vallejo, Bert Fellows, Nebojsa Nick Knezevic, Miguel Pappolla, Sudhir Diwan, Andrea M. Trescot, Amol Soin, Adam M. Kaye, Steve M. Aydin, Aaron K. Calodney, Kenneth D. Candido, Sanjay Bakshi, Ramsin M. Benyamin, Ricardo Vallejo, Art Watanabe, Douglas Beall, Todd P. Stitik, Patrick M. Foye, Erik M. Helander, Joshua A. Hirsch

School of Pharmacy Faculty Articles

BACKGROUND: Regenerative medicine is a medical subspecialty that seeks to recruit and enhance the body's own inherent healing armamentarium in the treatment of patient pathology. This therapy's intention is to assist in the repair, and to potentially replace or restore damaged tissue through the use of autologous or allogenic biologics. This field is rising like a Phoenix from the ashes of underperforming conventional therapy midst the hopes and high expectations of patients and medical personnel alike. But, because this is a relatively new area of medicine that has yet to substantiate its outcomes, care must be taken in its public …

Mechanisms Underlying Neuroprotection By The Nsaid Mefenamic Acid In An Experimental Model Of Stroke, Parto S. Khansari, Robert F. Halliwell

School of Pharmacy Faculty Articles

Stroke is a devastating neurological event with limited treatment opportunities. Recent advances in understanding the underlying pathogenesis of cerebral ischemia support the involvement of multiple biochemical pathways in the development of the ischemic damage. Fenamates are classical non-steroidal anti-inflammatory drugs but they are also highly subunit-selective modulators of GABAA receptors, activators of IKS potassium channels and antagonists of non-selective cation channels and the NLRP3 inflammosome. In the present study we investigated the effect of mefenamic acid (MFA) in a rodent model of ischemic stroke and then addressed the underlying pharmacological mechanisms in vitro for its actions in vivo. The efficacy …

Design, Synthesis And Pharmacological Characterization Of Potential Mu Opioid Receptor Selective Ligands, Abhishek S. Kulkarni

Theses and Dissertations

Selective Mu Opioid Receptor (MOR) antagonists possess immense potential in the treatment of opioid abuse/addiction. Utilizing the “message-address” concept, our laboratory reported a novel, reversible, non-peptide MOR selective antagonist 17-cyclopropylmethyl-3,14β-dihydroxy-4,5α-epoxy-6β-[(4՛-pyridyl)carboxamido]morphinan (NAP). Molecular modeling studies revealed that the selectivity of NAP for the MOR is because of a π-π stacking interaction of its pyridine ring with the Trp318residue in theMOR. Pharmacological characterization showed that NAP is a P-glycoprotein substrate, thereby limiting its use in the treatment of opioid abuse/addiction. Thus, to modify NAP, we replaced the pyridine ring with its isosteric counterpart thiophene. Isosteric replacement …

Metaproteomic Investigation Of The Vaginal Microbiome In Pregnancy, Zaneera Hassan

Theses and Dissertations

The development of early diagnostics and prevention strategies for preterm birth is an important global health challenge with the potential to impact over 15 million children annually, by improving health outcomes and reducing economic burden. Advances in microbial sequencing technology have opened the door to 16S rRNA gene survey, whole metagenomics, and whole transcriptomics, providing molecular evidence that the composition of the vaginal microbiome affects pregnancy outcomes in women, particularly those of African descent. A current gap in our molecular level understanding of the vaginal microbiome as it relates to healthy pregnancies is the metaproteome which comprises proteins from both …

Characterization Of The Microbial Phosphonate-Activating Pntc Enzymes, Kyle Rice

Theses and Dissertations (Comprehensive)

New strategies are urgently needed to combat infectious diseases in an era of rising antibiotic resistance. Furthermore, an emerging appreciation for the human microbiome’s role in maintaining health motivates discovery of species-specific antibiotics that minimally disrupt our native bacterial communities. Small molecule modifications to bacterial cell surfaces represent a potentially rich source of new targets for next generation antibiotics, as these molecules mediate virulence and evasion of the host immune response. Phosphocholine (PCho) is a rare cell surface modification that contributes to virulence, and modifications with phosphonates like 2-aminoethylphosphonate (AEP) are even more unusual and therefore provide opportunities for species- …

Crystal Structure Of Vapbc-1 From Nontypeable Haemophilus Influenzae And The Effect Of Pin Domain Mutations On Survival During Infection, Ashley L. Molinaro, Maithri M. Kashipathy, Scott Lovell, Kevin P. Battaile, Nathan P. Coussens, Min Shen, Dayle A. Daines

Biological Sciences Faculty Publications

Toxin-antitoxin (TA) gene pairs have been identified in nearly all bacterial genomes sequenced to date and are thought to facilitate persistence and antibiotic tolerance. TA loci are classified into various types based upon the characteristics of their antitoxins, with those in type II expressing proteic antitoxins. Many toxins from type II modules are ribonucleases that maintain a PilT N-terminal (PIN) domain containing conserved amino acids considered essential for activity. The vapBC (virulence-associated protein) TA system is the largest subfamily in this class and has been linked to pathogenesis of nontypeable Haemophilus influenzae (NTHi). In this …

Diuretic And Natriuretic Activity Of Faah Inhibition In The Renal Medulla: A Proposed Role Of Palmitoylethanolamide And Its Regulation By Renal Medullary Interstitial Cells, Sara Dempsey

Theses and Dissertations

Hypertension is a critical public health issue worldwide, and in the United States, it is the leading cause of heart disease, stroke, and kidney failure, contributing to more than 1,100 deaths per day. It is proposed that the renal medulla combats increased blood pressure by releasing a neutral lipid from the lipid droplets of medullary interstitial cells, termed medullipin, which induces diuresis- natriuresis and vasodepression. The renal medulla is enriched with fatty acid lipid ethanolamides including the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA), and oleoylethanolamide (OEA), along with their primary hydrolyzing enzyme fatty acid amide hydrolase (FAAH). Our lab is investigating …

Discovery Of Selective Probes Targeting Rna Polymerase I, Xiao Tan

Theses and Dissertations--Chemistry

RNR Polymerase I (RNA Pol I) is a “factory” that orchestrate the transcription of ribosomal rRNA for constructing ribosomes as a primary workshop for protein translation to sustain cell growth. Misregulation of RNA Pol I can cause uncontrolled cell proliferation, which leads to the development of cancer. Yeast (Saccharomyces cerevisiae) is a valuable model system to study RNA Pol I. Recently, the X-ray crystal structure of the yeast homologue of RNA Pol I was elucidated, offering the structural basis to selectively target this transcriptional machinery. The approach to selective RNA Pol I targeting was to disrupt the interaction …