Chemicals and Drugs Commons^™

Investigating The Efficacy And Anti-Resistance Activity Of Fexinidazole In Conjunction With Eflornithine Against Trypanosoma Brucei For Treatment Of Human African Trypanosomiasis, Mercy Toma

Selected Honors Theses

Human African Trypanosomiasis (HAT) is one of 17 neglected tropical disease prioritized by the World Health Organization (WHO). Neglected tropical diseases are diseases which affect poor or developing countries and which do not get as much as attention as the ‘big three’: malaria, tuberculosis and HIV/AIDS. HAT specifically affects coutries in Sub-Saharan Africa and is caused by a parasitic protozoa, Trypanosoma brucei. There are two stages of HAT: the early haemolymphatic and late meningo-encephalitic stages. There are also two subtypes of the disease caused by either T. b. gambiense or T.b rhodesiense forms of the parasite. There are four drugs …

Micro- And Nanoparticulates For Dna Vaccine Delivery, Eric Farris, Deborah M. Brown, Amanda Ramer-Tait, Angela K. Pannier

Department of Agricultural and Biological Systems Engineering: Faculty Publications

DNA vaccination has emerged as a promising alternative to traditional protein-based vaccines for the induction of protective immune responses. DNA vaccines offer several advantages over traditional vaccines, including increased stability, rapid and inexpensive production, and flexibility to produce vaccines for a wide variety of infectious diseases. However, the immunogenicity of DNA vaccines delivered as naked plasmid DNA is often weak due to degradation of the DNA by nucleases and inefficient delivery to immune cells. Therefore, biomaterial-based delivery systems based on micro- and nanoparticles that encapsulate plasmid DNA represent the most promising strategy for DNA vaccine delivery. Microparticulate delivery systems allow …

Add-On Laba In A Separate Inhaler As Asthma Step-Up Therapy Versus Increased Dose Of Ics Or Ics/Laba Combination Inhaler., David B Price, Gene Colice, Elliot Israel, Nicolas Roche, Dirkje S Postma, Theresa W Guilbert, Willem M C Van Aalderen, Jonathan Grigg, Elizabeth V Hillyer, Victoria Thomas, Richard J Martin

Medicine Faculty Publications

Asthma management guidelines recommend adding a long-acting β2-agonist (LABA) or increasing the dose of inhaled corticosteroid (ICS) as step-up therapy for patients with uncontrolled asthma on ICS monotherapy. However, it is uncertain which option works best, which ICS particle size is most effective, and whether LABA should be administered by separate or combination inhalers. This historical, matched cohort study compared asthma-related outcomes for patients (aged 12-80 years) prescribed step-up therapy as a ≥50% extrafine ICS dose increase or add-on LABA, via either a separate inhaler or a fine-particle ICS/LABA fixed-dose combination (FDC) inhaler. Risk-domain asthma control was the primary end-point …

Needle Exchange Programs And Hiv/Aids: A Comparison Of The Use Of Harm Reduction Methods In Switzerland And The United States Of America, Margaret House

Independent Study Project (ISP) Collection

This paper explores the connections between needle exchange programs and rates of HIV/AIDS in Switzerland and the United States of America. While these two countries are very similar in their general political philosophies, they have some key cultural and historical differences which has shaped their responses to HIV/AIDS and injection drug use. Switzerland’s unique experience with a very open injection drug use scene in the 1980s guided this country to a more pragmatic, harm reduction-based response. By contrast, United States responded to the AIDS epidemic that struck violently in the 1980s with a mix of fear and denial. Though both …

An Analysis Of Women’S Access To Acute Opioid Detoxification Services In Maine: Identifying The Barriers To Treatment, Karen E. Conley

Muskie School Capstones and Dissertations

The lack of treatment facilities and services for opioid use disorder in Maine, combined with an increased prevalence of addiction, creates a potential for health inequity between men and women that may be intensified by barriers in access to care. This capstone study utilized detoxification screening inquiry forms and data obtained from the Milestone Foundation’s acute opioid detoxification program to assess and categorize barriers to access by gender. A barriers model was developed based on existing literature and was to identify potential associations among and between the known barriers to accessing treatment. Barriers were described as internally or externally based, …

Analysis Of Mammalian Carboxypeptidase O Expression Patterns, Christian Bardan

Honors Theses

Carboxypeptidase 0 (CPO) is a protease that cuts acidic amino acids from the carboxy termini of substrate proteins. This study aims to describe the expression patterns of CPO in small mammals. We have sampled tissue from four different species: thirteen-lined ground squirrel, eastern chipmunk, eastern mole, and northern short-tailed shrew. Samples were analyzed via Western blot using two CPO antibodies. Immunoreactive bands likely to be CPO, with molecular weights approximately 42 kDa, were seen predominantly in kidney, liver, and intestinal tissue samples. This suggests CPO could play a specific physiological function in these organs.

The Effects Of Omega-3 Fatty Acids On Intracellular Inositol Levels In Saccharomyces Cerevisiae, Jee Yeon (Joanne) Lee

Honors Theses

Bipolar disorder is a severe and chronic debilitating mental disorder characterized by extreme mood swings between mania and depression. The current medications for bipolar disorder, lithium and valproate, have been associated with numerous negative side effects. Although the therapeutic mechanism by which lithium and valproate (VPA) exert their effect is unknown, a leading hypothesis implicates inositol depletion as a mechanism of action. On the other hand, omega-3-fatty acids have been shown to relieve symptoms of bipolar disorder. In this study, we compare the effects of VPA to the effects of decosahexaenoic acid (DHA) on Saccharomyces cerevisiae growth and intracellular inositol …

Impact Of Individual Acute Phase Serum Amyloid A Isoforms On Hdl Metabolism In Mice, Myung-Hee Kim, Maria C. De Beer, Joanne M. Wroblewski, Richard J. Charnigo, Ailing Ji, Nancy R. Webb, Frederick C. De Beer, Deneys R. Van Der Westhuyzen

Internal Medicine Faculty Publications

The acute phase (AP) reactant serum amyloid A (SAA), an HDL apolipoprotein, exhibits pro-inflammatory activities, but its physiological function(s) are poorly understood. Functional differences between SAA1.1 and SAA2.1, the two major SAA isoforms, are unclear. Mice deficient in either isoform were used to investigate plasma isoform effects on HDL structure, composition, and apolipoprotein catabolism. Lack of either isoform did not affect the size of HDL, normally enlarged in the AP, and did not significantly change HDL composition. Plasma clearance rates of HDL apolipoproteins were determined using native HDL particles. The fractional clearance rates (FCRs) of apoA-I, apoA-II, and SAA were …

Identification Of Potential Drug Targets In Cancer Signaling Pathways Using Stochastic Logical Models, Peican Zhu, Hamidreza Montazeri Aliabadi, Hasan Uludag, Jie Han

Pharmacy Faculty Articles and Research

The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no …

Toward Earlier Inclusion Of Pregnant And Postpartum Women In Tuberculosis Drug Trials: Consensus Statements From An International Expert Panel., Amita Gupta, Jyoti S. Mathad, Susan M. Abdel-Rahman, Jessica D. Albano, Radu Botgros, Vikki Brown, Renee S. Browning, Liza Dawson, Kelly E. Dooley, Devasena Gnanashanmugam, Beatriz Grinsztejn, Sonia Hernandez-Diaz, Patrick Jean-Philippe, Peter Kim, Anne D. Lyerly, Mark Mirochnick, Lynne M. Mofenson, Grace Montepiedra, Jeanna Piper, Leyla Sahin, Radojka Savic, Betsy Smith, Hans Spiegel, Soumya Swaminathan, D Heather Watts, Amina White

Manuscripts, Articles, Book Chapters and Other Papers

Tuberculosis is a major cause of morbidity and mortality in women of childbearing age (15-44 years). Despite increased tuberculosis risk during pregnancy, optimal clinical treatment remains unclear: safety, tolerability, and pharmacokinetic data for many tuberculosis drugs are lacking, and trials of promising new tuberculosis drugs exclude pregnant women. To advance inclusion of pregnant and postpartum women in tuberculosis drug trials, the US National Institutes of Health convened an international expert panel. Discussions generated consensus statements (>75% agreement among panelists) identifying high-priority research areas during pregnancy, including: (1) preventing progression of latent tuberculosis infection, especially in women coinfected with human …

Design, Synthesis, And Evaluation Of Chitosan Conjugated Ggrgdsk Peptides As A Cancer Cell-Targeting Molecular Transporter, Naglaa Salem El-Sayed, Amir Nasrolahi Shirazi, Magda Goda El-Meligy, Ahmed Kamel El-Ziaty, Zenat A. Nagieb, Keykavous Parang, Rakesh Tiwari

Pharmacy Faculty Articles and Research

Targeting cancer cells using integrin receptor is one of the promising targeting strategies in drug delivery. In this study, we conjugated an integrin-binding ligand (GGRGDSK) peptide to chitosan oligosaccharide (COS) using (sulfo-SMCC) bifunctional linker affording COS-SMCC-GGRGDSK. The conjugated polymer was characterized by FT-IR, ¹H NMR, ¹³C NMR, and SEM. COS-SMCC-GGRGDSK did not show cytotoxicity up to a concentration of 1 mg/mL in the human leukemia cell line (CCRF-CEM). The conjugate was evaluated for its ability to enhance the cellular uptake of cell-impermeable cargoes (e.g., FAM and F′-G(pY)EEI phosphopeptide) in CCRF-CEM, and human ovarian carcinoma (SK-OV-3) cancer …

Acid-Base Equilibria In Organic-Solvent/Water Mixtures And Their Relevance To Gas/Particle Partitioning In The Atmosphere And In Tobacco Smoke, Julia Lynn Degagne

Dissertations and Theses

Acid-base equilibria in organic particulate matter (PM) are poorly understood, but have important implications for air quality and public health. First, acid-base reactions in organic particulate matter affect the gas/particle partitioning of organic compounds in the atmosphere, and these processes are not currently represented in atmospheric and climate change models. Second, the acid-base balance of tobacco smoke affects the amount of nicotine absorbed by the smoker, and a greater understanding of this balance would help to relate cigarette smoke composition to the addictive properties of cigarettes. This work presents data related to both air quality and tobacco smoke modeling.

The …

“Zipped Synthesis” By Cross-Metathesis Provides A Cystathionine Β‑Synthase Inhibitor That Attenuates Cellular H2S Levels And Reduces Neuronal Infarction In A Rat Ischemic Stroke Model, Christopher D. Mccune, Su Jing Chan, Matthew L. Beio, Weijun Shen, Woo Jin Chung, Laura M. Szczesniak, Chou Chai, Shu Qing Koh, Peter T.-H. Wong, David B. Berkowitz

David Berkowitz Publications

The gaseous neuromodulator H₂S is associated with neuronal cell death pursuant to cerebral ischemia. As cystathionine β-synthase (CBS) is the primary mediator of H2S biogenesis in the brain, it has emerged as a potential target for the treatment of stroke. Herein, a “zipped” approach by alkene cross-metathesis into CBS inhibitor candidate synthesis is demonstrated. The inhibitors are modeled after the pseudo-C₂-symmetric CBS product (L,L)-cystathionine. The “zipped” concept means only half of the inhibitor needs be constructed; the two halves are then fused by olefin cross-metathesis. Inhibitor design is also mechanism-based, exploiting the favorable kinetics associated with …

Theoretical Investigation Of Interaction Between The Set Of Ligands And Α7 Nicotinic Acetylcholine Receptor, O. E. Glukhova, Tatiana Prytkova, D. S. Shmygin

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

Nicotinic acetylcholine receptors (nAChRs) are neuron receptor proteins that provide a transmission of nerve impulse through the synapses. They are composed of a pentametric assembly of five homologous subunits (5 α7 subunits for α7nAChR, for example), oriented around the central pore. These receptors might be found in the chemical synapses of central and peripheral nervous system, and also in the neuromuscular synapses. Transmembrane domain of the one of such receptors constitutes ion channel. The conductive properties of ion channel strongly depend on the receptor conformation changes in the response of binding with some molecule, f.e. acetylcholine. Investigation of interaction between …

Is Androgen Excess Masked In Alopecia Areata Patients: A Retrospective Data Analysis Of 1,587 Patients, G. Cheyana Ranasinghe, Melissa Piliang, Wilma Bergfeld

GW Research Days 2016 - 2020

Studies on the pathophysiology and comorbidities associated with alopecia areata (AA) are limited. The purpose of this study was to determine the prevalence of androgen excess in AA and its subtypes, in relation to demographics and comorbidities. Medical records of 1,587 Patchy AA, AT, AU, and ophiasis patients seen in the Department of Dermatology at the Cleveland Clinic Foundation in Ohio between 2005 and 2015 were reviewed. Out of this cohort, 226 patients met the inclusion criteria. There is evidence that patients with AA had significantly greater prevalence of polycystic ovary syndrome (PCOS) than the general population (p<0.001). Androgen excess was identified in 42.5% (n=96) of the 226 patients with AA or any subtype (p<0.001). The androgen excess group was significantly more likely to present with irregular menses, hirsutism, adult acne, PCOS, and/or ovarian cysts (p<0.001). This study was limited by being retrospective. Our study demonstrated that AA is associated with androgen excess.

Perioperative Aspirin Recommendations In Children With Fenestrated Fontan Undergoing Adenotonsillectomy, Mariam Ashraf, Pamela A. Mudd, Jamie Mcelrath Schwartz, Karen Thompson

GW Research Days 2016 - 2020

Objective: Pediatric patients who have undergone the Fontan procedure are often on a long term aspirin regimen which can complicate perioperative management. In high risk procedures such as adenotonsillectomy, hemorrhage can be a significant complication and aspirin use may increase the risk. There is a need for evidence-based protocol on how to manage aspirin intake in the perioperative period for Fontan patients. We report the case of a patient with Fontan palliation who underwent adenotonsillectomy and presented with postoperative hemorrhage.

Methods: PubMed was searched for guidelines, case reports, and reviews on pediatric Fontan patients, adenotonsillectomy, and perioperative aspirin …

Pharmaceutical Contaminants As Stressors On Rocky Intertidal And Estuarine Organisms: A Case Study Of Fluoxetine, Joseph Richard Peters

Dissertations and Theses

Contaminants such as pharmaceuticals are of increasing concern due to their ubiquitous use and persistence in surface waters worldwide. Limited attention has been paid to the effects of pharmaceuticals on marine life, despite widespread detection of these contaminants in the marine environment. Of the existing studies, the majority assess the negative effects of pharmaceuticals over an exposure period of 30 days or less and focus on cellular and subcellular biomarkers. Longer studies are required to determine if chronic contaminant exposure poses risks to marine life at environmentally relevant concentrations. Also scarce in the literature is examination of whole organism effects …

Pharmacokinetics And Bioequivalence Of A Liquid Formulation Of Hydroxyurea In Children With Sickle Cell Anemia., Jeremie H. Estepp, Chiara Melloni, Courtney D. Thornburg, Paweł Wiczling, Zora Rogers, Jennifer A. Rothman, Nancy S. Green, Robert Liem, Amanda M. Brandow, Shelley E. Crary, Thomas H. Howard, Maurine H. Morris, Andrew Lewandowski, Uttam Garg, William J. Jusko, Kathleen A. Neville, Best Pharmaceuticals For Children Act-Pediatric Trials Network Administrative Core Committee

Manuscripts, Articles, Book Chapters and Other Papers

Hydroxyurea (HU) is a crucial therapy for children with sickle cell anemia, but its off-label use is a barrier to widespread acceptance. We found HU exposure is not significantly altered by liquid vs capsule formulation, and weight-based dosing schemes provide consistent exposure. HU is recommended for all children starting as young as 9 months of age with sickle cell anemia (SCA; HbSS and HbSβspan(0) thalassemia); however; a paucity of pediatric data exists regarding the pharmacokinetics (PK) or the exposure-response relationship of HU. This trial aimed to characterize the PK of HU in children and to evaluate and compare the bioavailability …

Retigabine Holds Kv7 Channels Open And Stabilizes The Resting Potential, Aaron Corbin-Leftwich, Sayeed M. Mossadeq, Junghoon Ha, Iwona Ruchala, Audrey Han Ngoc Le, Carlos A. Villalba-Galea

School of Pharmacy Faculty Articles

The anticonvulsant Retigabine is a KV7 channel agonist used to treat hyperexcitability disorders in humans. Retigabine shifts the voltage dependence for activation of the heteromeric KV7.2/KV7.3 channel to more negative potentials, thus facilitating activation. Although the molecular mechanism underlying Retigabine's action remains unknown, previous studies have identified the pore region of KV7 channels as the drug's target. This suggested that the Retigabine-induced shift in voltage dependence likely derives from the stabilization of the pore domain in an open (conducting) conformation. Testing this idea, we show that the heteromeric KV7.2/KV7.3 channel has at least two open states, which we named O1 …

Role Of Flippases In Protein Glycosylation In The Endoplasmic Reticulum, Jeffrey S. Rush

Molecular and Cellular Biochemistry Faculty Publications

Glycosylation is essential to the synthesis, folding, and function of glycoproteins in eukaryotes. Proteins are co- and posttranslationally modified by a variety of glycans in the endoplasmic reticulum (ER); modifications include C- and O-mannosylation, N-glycosylation, and the addition of glycosylphosphatidylinositol membrane anchors. Protein glycosylation in the ER of eukaryotes involves enzymatic steps on both the cytosolic and lumenal surfaces of the ER membrane. The glycans are first assembled as precursor glycolipids, on the cytosolic surface of the ER, which are tethered to the membrane by attachment to a long-chain polyisoprenyl phosphate (dolichol) containing a reduced α-isoprene. The lipid-anchored building blocks …