Pharmacy and Pharmaceutical Sciences Commons^™

Hypusination Of Eif5a Regulates Cytoplasmic Tdp-43 Aggregation And Accumulation In A Stress-Induced Cellular Model, Shayna Smeltzer, Zainuddin Quadri, Abraian Miller, Frank Zamudio, Jordan Hunter, Nicholas J.F. Stewart, Sheba Saji, Daniel C. Lee, Dale Chaput, Maj-Linda B. Selenica

Sanders-Brown Center on Aging Faculty Publications

TAR DNA-binding protein 43 (TDP-43) is a nuclear RNA/DNA binding protein involved in mRNA metabolism. Aberrant mislocalization to the cytoplasm and formation of phosphorylated/aggregated TDP-43 inclusions remains the hallmark pathology in a spectrum of neurodegenerative diseases, including frontotemporal disorders and Alzheimer's disease. Eukaryotic Translation Initiation Factor 5A undergoes a unique post-translation modification of lysine to hypusine (K50), which determines eIF5A binding partners. We used a sodium arsenite-induced cellular stress model to investigate the role of hypusinated eIF5A (eIF5A^HypK50) in governing TDP-43 cytoplasmic mislocalization and accumulation in stress granule. Our proteomics and functional data provide evidence that eIF5A interacts …

Egfr Testing And Erlotinib Use In Non-Small Cell Lung Cancer Patients In Kentucky, Kara L. Larson, Bin Huang, Quan Chen, Thomas C. Tucker, Marissa Schuh, Susanne M. Arnold, Jill M. Kolesar

Markey Cancer Center Faculty Publications

This study determined the frequency and factors associated with EGFR testing rates and erlotinib treatment as well as associated survival outcomes in patients with non small cell lung cancer in Kentucky. Data from the Kentucky Cancer Registry (KCR) linked with health claims from Medicaid, Medicare and private insurance groups were evaluated. EGFR testing and erlotinib prescribing were identified using ICD-9 procedure codes and national drug codes in claims, respectively. Logistic regression analysis was performed to determine factors associated with EGFR testing and erlotinib prescribing. Cox-regression analysis was performed to determine factors associated with survival. EGFR mutation testing rates rose from …

Method And System For Terpene Production Platforms In Yeast, Joseph Chappell, Xun Zhuang, Shuiqin Wu

Pharmaceutical Sciences Faculty Patents

A method is provided for producing modified mutant yeast and the resulting yeast that can be used as a platform for terpene production. The method includes chemical mutagenesis to effect ergosterol dependent growth in yeast. Subsequently, these yeast are subjected to an erg9 knockout mutation to thereby produce ergosterol dependent growth/ erg9 knockout mutation yeast cell lines. The resulting yeast are well suited for use in the production of terpenes.

Expanding Pharmacotherapy Data Collection, Analysis, And Implementation In Eras® Programs—The Methodology Of An Exploratory Feasibility Study, Eric Johnson, Richard Parrish Ii, Gregg Nelson, Kevin Elias, Brian Kramer, Marian Gaviola

Pharmacy Practice and Science Faculty Publications

Surgical organizations dedicated to the improvement of patient outcomes have led to a worldwide paradigm shift in perioperative patient care. Since 2012, the Enhanced Recovery After Surgery (ERAS^®) Society has published guidelines pertaining to perioperative care in numerous disciplines including elective colorectal and gynecologic/oncology surgery patients. The ERAS^® and ERAS-USA^® Societies use standardized methodology for collecting and assessing various surgical parameters in real-time during the operative process. These multi-disciplinary groups have constructed a bundled framework of perioperative care that entails 22 specific components of clinical interventions, which are logged in a central database, allowing a system …

Nanoceria Distribution And Effects Are Mouse-Strain Dependent, Robert A. Yokel, Michael T. Tseng, D. Allan Butterfield, Matthew L. Hancock, Eric A. Grulke, Jason M. Unrine, Arnold J. Stromberg, Alan K. Dozier, Uschi M. Graham

Pharmaceutical Sciences Faculty Publications

Prior studies showed nanoparticle clearance was different in C57BL/6 versus BALB/c mice, strains prone to Th1 and Th2 immune responses, respectively. Objective: Assess nanoceria (cerium oxide, CeO₂ nanoparticle) uptake time course and organ distribution, cellular and oxidative stress, and bioprocessing as a function of mouse strain. Methods: C57BL/6 and BALB/c female mice were i.p. injected with 10 mg/kg nanoceria or vehicle and terminated 0.5 to 24 h later. Organs were collected for cerium analysis; light and electron microscopy with elemental mapping; and protein carbonyl, IL-1β, and caspase-1 determination. Results: Peripheral organ cerium significantly increased, generally more …

Application Of Enzymes In Regioselective And Stereoselective Organic Reactions, Ruipu Mu, Zhaoshuai Wang, Max C. Wamsley, Colbee N. Duke, Payton H. Lii, Sarah E. Epley, London C. Todd, Patty J. Roberts

Pharmaceutical Sciences Faculty Publications

Nowadays, biocatalysts have received much more attention in chemistry regarding their potential to enable high efficiency, high yield, and eco-friendly processes for a myriad of applications. Nature’s vast repository of catalysts has inspired synthetic chemists. Furthermore, the revolutionary technologies in bioengineering have provided the fast discovery and evolution of enzymes that empower chemical synthesis. This article attempts to deliver a comprehensive overview of the last two decades of investigation into enzymatic reactions and highlights the effective performance progress of bio-enzymes exploited in organic synthesis. Based on the types of enzymatic reactions and enzyme commission (E.C.) numbers, the enzymes discussed in …

Evaluation Of Biased And Balanced Salvinorin A Analogs In Preclinical Models Of Pain, Kelly F. Paton, Andrew Biggerstaff, Sophia Kaska, Rachel S. Crowley, Anne C. La Flamme, Thomas E. Prisinzano, Bronwyn M. Kivell

Pharmaceutical Sciences Faculty Publications

In the search for safer, non-addictive analgesics, kappa opioid receptor (KOPr) agonists are a potential target, as unlike mu-opioid analgesics, they do not have abuse potential. Salvinorin A (SalA) is a potent and selective KOPr agonist, however, clinical utility is limited by the short duration of action and aversive side effects. Biasing KOPr signaling toward G-protein activation has been highlighted as a key cellular mechanism to reduce the side effects of KOPr agonists. The present study investigated KOPr signaling bias and the acute antinociceptive effects and side effects of two novel analogs of SalA, 16-Bromo SalA and 16-Ethynyl SalA. 16-Bromo …

Plasma And Serum Proteins Bound To Nanoceria: Insights Into Pathways By Which Nanoceria May Exert Its Beneficial And Deleterious Effects In Vivo, D. Allan Butterfield, Binghui Wang, Peng Wu, Sarita S. Hardas, Jason M. Unrine, Eric A. Grulke, Jian Cai, Jon B. Klein, William M. Pierce, Robert A. Yokel, Rukhsana Sultana

Chemistry Faculty Publications

Nanoceria (CeO2, cerium oxide nanoparticles) is proposed as a therapeutic for multiple disorders. In blood, nanoceria becomes protein-coated, changing its surface properties to yield a different presentation to cells. There is little information on the interaction of nanoceria with blood proteins. The current study is the first to report the proteomics identification of plasma and serum proteins adsorbed to nanoceria. The results identify a number of plasma and serum proteins interacting with nanoceria, proteins whose normal activities regulate numerous cell functions: antioxidant/detoxification, energy regulation, lipoproteins, signaling, complement, immune function, coagulation, iron homeostasis, proteolysis, inflammation, protein folding, protease inhibition, adhesion, protein/RNA …

Population Data-Driven Formulation Of A Covid-19 Therapeutic, Heather R. Campbell, Regan P. Cecil, Robert A. Lodder

Pharmaceutical Sciences Faculty Publications

This study is designed to utilize computer modeling of the US population through the ongoing CDC NHANES trial to reduce the need for preclinical formulation and toxicology studies of an Ebola antiviral (BSN389) being repurposed for COVID-19, and to thereby speed the candidate therapeutic to the clinic. BSN389 has poor solubility in water and that limits its bioavailability. BCD greatly increases the solubility of BSN389 and results in high bioavailability of BSN389 in animal studies. The goal of this study is to determine the current daily exposure of the population to beta cyclodextrin (BCD), and then keep the amount of …

Vesicular Monoamine Transporter-2 Ligands And Their Use In The Treatment Of Psychostimulant Abuse, Linda P. Dwoskin, Peter Anthony Crooks, Guangrong Zheng, Justin Robert Nickell, Zheng Cao, Na-Ra Lee

Pharmaceutical Sciences Faculty Patents

The present invention relates to methods of treatment of a disease or pathology of the central nervous system, an eating disorder, or substance use disorder, drug dependence/abuse and withdrawal therefrom comprising administering at least one N-phenylalkyl amphetamine derivative and pharmaceutical compositions comprising at least one N-phenylalkyl amphetamine derivative to an individual in need thereof.

Lipid Bilayer-Integrated Spp1 Connector Protein Nanopore And Spp1 Connector Protein Variants For Use As Lipid Bilayer-Integrated Nanopore, Peixuan Guo, Shaoying Wang

Pharmaceutical Sciences Faculty Patents

A conductive channel-containing membrane includes a membrane layer, and a SPPl connector polypeptide variant that is incorporated into the membrane layer to form an aperture through which conductance can occur when an electrical potential is applied across the membrane. A method of sensing a molecule, such as a polypeptide or nucleic acid molecule, makes use of the conductive channel- containing membrane. A method of DNA sequence makes use of the conductive channel-containing membrane.

Ccne1 Amplification As A Predictive Biomarker Of Chemotherapy Resistance In Epithelial Ovarian Cancer, Justin W. Gorski, Frederick R. Ueland, Jill M. Kolesar

Obstetrics and Gynecology Faculty Publications

Ovarian cancer is the most-deadly gynecologic malignancy, with greater than 14,000 women expected to succumb to the disease this year in the United States alone. In the front-line setting, patients are treated with a platinum and taxane doublet. Although 40-60% of patients achieve complete clinical response to first-line chemotherapy, 25% are inherently platinum-resistant or refractory with a median overall survival of about one year. More than 80% of women afflicted with ovarian cancer will recur. Many attempts have been made to understand the mechanism of platinum and taxane based chemotherapy resistance. However, despite decades of research, few predictive markers of …

First-In-Human Studies Of Mw01-6-189wh, A Brain-Penetrant, Antineuroinflammatory Small-Molecule Drug Candidate: Phase 1 Safety, Tolerability, Pharmacokinetic, And Pharmacodynamic Studies In Healthy Adult Volunteers, Linda J. Van Eldik, Lumy Sawaki, Karen Bowen, Daniel T. Laskowitz, Robert J. Noveck, Byron Hauser, Lynn Jordan, Tracy G. Spears, Huali Wu, Kevin Watt, Shruti Raja, Saktimayee M. Roy, D. Martin Watterson, Jeffrey T. Guptill

Sanders-Brown Center on Aging Faculty Publications

MW01-6-189WH (MW189) is a novel central nervous system-penetrant small-molecule drug candidate that selectively attenuates stressor-induced proinflammatory cytokine overproduction and is efficacious in intracerebral hemorrhage and traumatic brain injury animal models. We report first-in-human, randomized, double-blind, placebo-controlled phase 1 studies to evaluate the safety, tolerability, and pharmacokinetics (PK) of single and multiple ascending intravenous doses of MW189 in healthy adult volunteers. MW189 was safe and well tolerated in single and multiple doses up to 0.25 mg/kg, with no clinically significant concerns. The most common drug-related treatment-emergent adverse event was infusion-site reactions, likely related to drug solution acidity. No clinically concerning changes …

Method And System For Diterpene Production Platforms In Yeast, Joseph Chappell, Xun Zhuang, Shuiqin Wu

Pharmaceutical Sciences Faculty Patents

A method is provided for modifying yeast to express mutant avian farnesyl disphospate synthase and the resulting modified yeast. The yeast advantageously includes additional mutants including but not limited to having ergosterol dependent growth and being erg-. The modified yeast are beneficial for the production of various terpenes including diterpenes.

Using Medical Claims Database To Develop A Population Disease Progression Model For Leuprorelin-Treated Subjects With Hormone-Sensitive Prostate Cancer, Yixuan Zou, Fei Tang, Jeffery C. Talbert, Chee M. Ng

Pharmacy Practice and Science Faculty Publications

Androgen deprivation therapy (ADT) is a widely used treatment for patients with hormone-sensitive prostate cancer (PCa). However, duration of treatment response varies, and most patients eventually experience disease progression despite treatment. Leuprorelin is a luteinizing hormone-releasing hormone (LHRH) agonist, a commonly used form of ADT. Prostate-specific antigen (PSA) is a biomarker for monitoring disease progression and predicting treatment response and survival in PCa. However, time-dependent profile of tumor regression and growth in patients with hormone-sensitive PCa on ADT has never been fully characterized. In this analysis, nationwide medical claims database provided by Humana from 2007 to 2011 was used to …

Rna Nanoparticles For Brain Tumor Treatment, Peixuan Guo, Carlo M. Croce, Tae Jin Lee, Farzin Haque, Hui Li

Pharmaceutical Sciences Faculty Patents

The presently-disclosed subject matter relates to an artificial RNA nanostructure molecule and method to treat brain tumor in a subject. More particularly, the presently disclosed subject matter relates to a RNA nanostructure containing a multiple branched RNA nanoparticle, a brain tumor targeting module, and an effective amount of a therapeutic agent. Further, the presently disclosed subject matter relates to a method of using the RNA nanostructure composition to treat brain tumor in a subject having or at risk of having brain tumor.

Serum Amyloid A Is Not Incorporated Into Hdl During Hdl Biogenesis, Ailing Ji, Xuebing Wang, Victoria P. Noffsinger, Drew Jennings, Maria C. De Beer, Frederick C. De Beer, Lisa R. Tannock, Nancy R. Webb

Saha Cardiovascular Research Center Faculty Publications

Liver-derived serum amyloid A (SAA) is present in plasma where it is mainly associated with HDL and from which it is cleared more rapidly than are the other major HDL-associated apolipoproteins. Although evidence suggests that lipid-free and HDL-associated forms of SAA have different activities, the pathways by which SAA associates and disassociates with HDL are poorly understood. In this study, we investigated SAA lipidation by hepatocytes and how this lipidation relates to the formation of nascent HDL particles. We also examined hepatocyte-mediated clearance of lipid-free and HDL-associated SAA. We prepared hepatocytes from mice injected with lipopolysaccharide or an SAA-expressing adenoviral …

Identification Of Ebsulfur Analogues With Broad-Spectrum Antifungal Activity, Sylvie Garneau-Tsodikova, Huy X. Ngo, Sanjib K. Shrestha

Pharmaceutical Sciences Faculty Patents

The invention relates to novel ebsulfur analogues and novel pharmaceutical compositions comprising ebsulfur analogues. The invention also relates to novel methods of treating infections caused by fungal species comprising administration of ebselen, ebsulfur, and ebsulfur analogues.

Vancomycin Dosing Practices Among Critical Care Pharmacists: A Survey Of Society Of Critical Care Medicine Pharmacists, Alexander H. Flannery, Drayton A. Hammond, Douglas R. Oyler, Chenghui Li, Adrian Wong, Andrew P. Smith, Qiu Min Yeo, Whitney Chaney, Caitlin E. Pfaff, Angela M. Plewa-Rusiecki, Paul Juang

Pharmacy Practice and Science Faculty Publications

Introduction: Critically ill patients and their pharmacokinetics present complexities often not considered by consensus guidelines from the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Prior surveys have suggested discordance between certain guideline recommendations and reported infectious disease pharmacist practice. Vancomycin dosing practices, including institutional considerations, have not previously been well described in the critically ill patient population.

Objectives: To evaluate critical care pharmacists' self-reported vancomycin practices in comparison to the 2009 guideline recommendations and other best practices identified by the study investigators.

Methods: An online survey developed by the …

Utilization Of A Community Pharmacy-Based Service For The Treatment Of Uncomplicated Urinary Tract Infections In Scotland, Robert Borchardt

Theses and Dissertations--Public Health (M.P.H. & Dr.P.H.)

Introduction: In November 2013, Scotland piloted a program in Grampian for the treatment of Urinary Tract Infections (UTIs) in community pharmacies, increasing health access for patients and reducing general practitioner workload. This program became known as ‘Pharmacy First’ and was later implemented nationwide in November 2017. This paper seeks to understand utilization of the Pharmacy First program across Scotland by patients and potential barriers to access.

Methods: Using data from the Prescribing Information System collected by the National Health Service of Scotland from July 2013 to April 2019, orders for uncomplicated UTIs were gathered by examining all nitrofurantoin and trimethoprim …

Dalbavancin In The Community Emergency Department, Wesley Johnson

Theses and Dissertations--Public Health (M.P.H. & Dr.P.H.)

Introduction

Dalbavancin is an antibiotic within the class of medications known as lipoglycopeptides. This medication is given to patients presenting to the hospital with acute skin and skin-structure infections (ABSSSI). This is a unique medication because it is given as a one-time dose in the outpatient setting and it could prevent patients from requiring admission to the hospital.

Methods

The emergency department (ED) at Good Samaritan community hospital performed a trial period with dalbavancin and data was collected from November 2018 to March 2020. Retrospective chart review was performed to obtain patient data and outcomes. Patients would be contacted by …

Measuring The Effects Of Lobinaline-N-Bioxide (419) On Alcohol Consumption, Nicotine Locomotor Sensitization, And Conditioned Place Preference In Mice And Rats, Cocanut M. Suhail

Theses and Dissertations--Medical Sciences

Objective: Novel drug 419 was examined to see the effect it has in vivo mice and rats on alcohol consumption, nicotine locomotor sensitization, and conditioned place preference (CPP) models regarding behavioral tests on dopamine transporter activity.

Methods: Mice and rats were used to see how they react to the drug 419 and control vehicle, in each of the models. The animals were assessed to pre- and post- drug administration of novel drug 419. We examined each model to see the association between how drug 419 will help with treating drug abuse.

Results: We found that in alcohol consumption model the …

Meaningful Measurement Matters: Defining Potentially Inappropriate Medication Use To Target Cognitive Outcomes, Ashley I. Martinez

Theses and Dissertations--Pharmacy

Preventable and unintended consequences of medication use occur in more than 25% of ambulatory and hospitalized patients, and nearly half of long-term care patients. Unfortunately, many medications used to treat common health conditions in older adults (such as anxiety, behavioral disturbances, incontinence, insomnia, depression, and pain) have also been linked to cognitive impairment and decline. Recently, substantial efforts to investigate medications and medication classes that may be associated with cognitive impairment and decline in older adults have been undertaken. Unfortunately, studies have used a wide variety of different tools to define “potentially inappropriate medication” (PIM) use, and no published literature …

Relationship Between Initial Prescription Opioid Exposure Length And Future Opioid Use Disorder Diagnosis In Opioid Naive Adolescents, Eric Lindahl

Theses and Dissertations--Pharmacy

Objectives: The long-term risks associated with the use of short-term prescription opioids in opioid naïve adolescents in not well characterized. The purpose of this study was to explore the potential association between the days’ supply of the initial prescription opioid exposure and the rates of diagnosed OUD in the subsequent 3-year period. Methods: We conducted a retrospective cohort study using a nationwide database of commercially-insured adolescents aged 12-17 at the time of the index opioid fill. A multivariable Cox Proportional Hazard regression model was developed to analyze the association of interest while accounting for known risk factors for the development …

The Impact Of Bone Marrow Transplantion On Patients With Psychiatric Diagnoses: Medication Adherence Assessment, Brittany Galop

Theses and Dissertations--Pharmacy

Objectives: We investigated whether there is a measurable difference in medication utilization for psychiatric conditions before and after bone marrow transplantation (BMT). Previous studies have identified a potential association between psychiatric conditions and immune function. We hypothesized that medication utilization for psychiatric diagnoses would be impacted by BMT.

Methods: This study was a retrospective, quasi-experimental cohort design. De-identified data was compiled from the Truven database for patients ranging from January 2009 through December 2016. Two measurements of medication utilization, proportion of days covered (PDC) and medication possession ratio (MPR) were calculated for each included Medispan-defined class of medications before analyzing …

Population Pharmacokinetic Modeling And Genetic Association Analysis In Infants With Neonatal Abstinence Syndrome Receiving Morphine Or Clonidine, Fei Tang

Theses and Dissertations--Pharmacy

Neonatal abstinence syndrome, or NAS, is a postnatal opioid withdrawal syndrome occurring in 55% to 94% of neonates as a result of in utero exposure to opioids. It has emerged as a significant public health issue, as its incidence more than quadrupled in the past decade. There is significant variability in disease severity and treatment outcomes in neonates with NAS due to patient-specific factors and treatment- or site-specific factors. To understand what contributes to variability in length of hospital stay and other outcomes in neonates with NAS, we assessed population pharmacokinetics (PK) of clonidine and morphine, and we investigated potential …

Extensively Drug-Resistant Pseudomonas Aeruginosa In Vitro Susceptibility And Mechanisms Of Resistance, Chanah Gallagher

Theses and Dissertations--Pharmacy

Pseudomonas aeruginosa causes severe healthcare-associated infections. Forty-eight extensively drug-resistant (XDR)-P. aeruginosa isolates were selected from 287 isolates collected for evaluation based on clinical susceptibility data. In vitro activity of commonly utilized antimicrobials (i.e. antipseudomonal beta-lactams, aminoglycosides, fluoroquinolones, and polymyxins) plus ceftolozane-tazobactam, ceftazidime-avibactam, and aztreonam-avibactam against XDR-P. aeruginosa were determined. The mechanism of resistance profile was determined through phenotypic expression analysis. Overall, polymyxin B and colistin were 100% susceptible. Apart from the polymyxins, ceftolozane-tazobactam had the highest susceptibility (94%) followed by ceftazidime-avibactam (90%) and amikacin (83%). Ceftolozane-tazobactam activity was not significantly different from ceftazidime-avibactam (p=0.6831). Only 40% of isolates …

Combination Of Investigational Cell-Based Therapy And Deep Brain Stimulation To Alter The Progression Of Parkinson’S Disease, Nader El Seblani

Theses and Dissertations--Pharmacy

Parkinson’s disease (PD) is the second most common neurodegenerative disorder and the motor symptoms are caused by progressive loss of midbrain dopamine neurons. There is no current treatment that can slow or reverse PD. Our current “DBS-Plus” clinical trial (NCT02369003) features the implantation in vivo of autologous Schwann cells (SCs) derived from a patient’s sural nerve into the substantia nigra pars compacta (SNpc) in combination with Deep Brain Stimulation (DBS) therapy for treating patients with advanced PD.

The central hypothesis of our research is that transdifferentiated SCs within conditioned nerve tissue will deliver pro-regenerative factors to enhance the survival of …

Correlating The Physicochemical Properties Of Magnesium Stearate With Tablet Dissolution And Lubrication, Julie L. Calahan

Theses and Dissertations--Pharmacy

Magnesium stearate (MgSt) is the most commonly used pharmaceutical excipient and is present in over half the tablet formulations on the market. In spite of its popularity as an effective lubricant, it has been repeatedly recognized that there is significant variability between MgSt samples, which can cause inconsistent lubrication between batches of MgSt. The hypothesis of this research is that the batch-to-batch variability in tablet lubrication and dissolution observed in tablet formulations containing different MgSt samples can be correlated with differences in MgSt physicochemical properties (fatty acid salt composition, crystal hydrate form, particle size and surface area). Developing correlations between …

Novel Small Molecule Antifungals For Invasive Fungal Infections, Emily Dennis

Theses and Dissertations--Pharmacy

Human fungal pathogens cause a range of diseases from benign skin conditions (i.e., ringworm) to thrush, mucosal membrane infections, and life-threatening systemic infections including bloodstream infections (i.e., aspergillosis and candidiasis) and Cryptococcal meningitis. These systemic infections occur most often in immunocompromised individuals and have high mortality rates. Current antifungal agents used in the clinic belong to three main classes: the polyenes (e.g., amphotericin B (AmB)), the echinocandins (e.g., caspofungin (CFG)), and the azoles (e.g., fluconazole (FLC)). In addition, the antimetabolite pyrimidine analogue flucytosine is used in combination with AmB. The …