Medicine and Health Sciences Commons^™

Fluoroethoxy-1,4-Diphenethylpiperidine And Piperazine Derivatives: Potent And Selective Inhibitors Of [3H]Dopamine Uptake At The Vesicular Monoamine Transporter-2, Emily R. Hankosky, Shyam R. Joolakanti, Justin R. Nickell, Venumadhav Janganati, Linda P. Dwoskin, Peter A. Crooks

Pharmaceutical Sciences Faculty Publications

A small library of fluoroethoxy-1,4-diphenethyl piperidine and fluoroethoxy-1,4-diphenethyl piperazine derivatives were designed, synthesized and evaluated for their ability to inhibit [³H]dopamine (DA) uptake at the vesicular monoamine transporter-2 (VMAT2) and dopamine transporter (DAT), [³H]serotonin (5-HT) uptake at the serotonin transporter (SERT), and [³H]dofetilide binding at the human-ether-a-go-go-related gene (hERG) channel. The majority of the compounds exhibited potent inhibition of [³H]DA uptake at VMAT2, with Ki values in the nanomolar range (K_i = 0.014–0.073 μM). Compound 15d exhibited the highest affinity (K_i = 0.014 μM) at VMAT2, and had 160-, 5-, …

Buspirone Maintenance Does Not Alter The Reinforcing, Subjective, And Cardiovascular Effects Of Intranasal Methamphetamine, Anna R. Reynolds, Justin Charles Strickland, William W. Stoops, Joshua A. Lile, Craig R. Rush

Pharmaceutical Sciences Faculty Publications

Background—Medications development efforts for methamphetamine-use disorder have targeted central monoamines because these systems are directly involved in the effects of methamphetamine. Buspirone is a dopamine autoreceptor and D3 receptor antagonist and partial agonist at serotonin 1A receptors, making it a logical candidate medication for methamphetamine-use disorder. Buspirone effects on abuse-related behaviors of methamphetamine have been mixed in clinical and preclinical studies. Experimental research using maintenance dosing, which models therapeutic use, is limited. This study evaluated the influence of buspirone maintenance on the reinforcing effects of methamphetamine using a self-administration procedure, which has predictive validity for clinical efficacy. The impact …

Medicaid Managed Care And The Health Care Utilization Of Foster Children, Makayla Palmer, James Marton, Aaron Yelowitz, Jeffery Talbert

Economics Faculty Publications

A recent trend in state Medicaid programs is the transition of vulnerable populations into Medicaid managed care (MMC) who were initially carved out of such coverage, such as foster children or those with disabilities. The purpose of this article is to evaluate the impact of the transition of foster children from fee-for-service Medicaid coverage to MMC coverage on outpatient health care utilization. There is very little empirical evidence on the impact of managed care on the health care utilization of foster children because of the recent timing of these transitions as well as challenges associated with finding data sets large …

Diverse Amide Analogs Of Sulindac For Cancer Treatment And Prevention, Bini Mathew, Judith V. Hobrath, Michele C. Connelly, R. Kiplin Guy, Robert C. Reynolds

Pharmaceutical Sciences Faculty Publications

Sulindac is a non-steroidal anti-inflammatory drug (NSAID) that has shown significant anticancer activity. Sulindac sulfide amide (1) possessing greatly reduced COX-related inhibition relative to sulindac displayed in vivoantitumor activity that was comparable to sulindac in a human colon tumorxenograft model. Inspired by these observations, a panel of diverse sulindac amide derivatives have been synthesized and their activity probed against three cancer cell lines (prostate, colon and breast). A neutral analog, compound 79 was identified with comparable potency relative to lead 1 and activity against a panel of lymphoblastic leukemia cell lines. Several new series also show good …

Influence Of Β-Lactam Infusion Strategy On Acute Kidney Injury, Sarah E. Cotner, Wilbur Cliff Rutter, Donna R. Burgess, Katie L. Wallace, Craig A. Martin, David S. Burgess

Pharmacy Practice and Science Faculty Publications

Limited literature is available assessing nephrotoxicity with prolonged β-lactam infusions. This study compared the incidence of acute kidney injury (AKI) associated with a prolonged β-lactam infusion or an intermittent infusion. This was a retrospective, matched-cohort study at an academic medical center from July 2006 to September 2015. Adult patients who received piperacillin-tazobactam (TZP), cefepime (FEP), or meropenem (MEM) for at least 48 h were evaluated. Patients were excluded for preexisting renal dysfunction or pregnancy. The primary outcome was difference in incidence of AKI evaluated using the RIFLE (risk, injury, failure, loss, and end-stage) criteria. Patients in the intermittent group …

Design And Validation Of Patient-Centered Communication Tools (Pact) To Measure Students' Communication Skills, Gloria R. Grice, Nicole M. Gattas, Theresa Prosser, Mychal Voorhees, Clark D. Kebodeaux, Amy Tiemeier, Tricia M. Berry, Alexandria Garavaglia Wilson, Janelle Mann, Paul Juang

Pharmacy Practice and Science Faculty Publications

Objective. To develop a comprehensive instrument specific to student pharmacist-patient communication skills, and to determine face, content, construct, concurrent, and predictive validity and reliability of the instrument.

Methods. A multi-step approach was used to create and validate an instrument, including the use of external experts for face and content validity, students for construct validity, comparisons to other rubrics for concurrent validity, comparisons to other coursework for predictive validity, and extensive reliability and inter-rater reliability testing with trained faculty assessors.

Results. Patient-centered Communication Tools (PaCT) achieved face and content validity and performed well with multiple correlation tests with significant findings for …

Statin Use And Venous Thromboembolism In Cancer: A Large, Active Comparator, Propensity Score Matched Cohort Study, Sherif M. El-Refai, Esther P. Black, Val R. Adams, Jeffery C. Talbert, Joshua D. Brown

Pharmaceutical Sciences Faculty Publications

Background—Statins have been shown to have a protective effect for venous thromboembolism (VTE) in the general population. This study sought to assess the association between statins and the risk for cancer-associated deep vein thrombosis (DVT) and pulmonary embolism (PE).

Methods—Patients with newly diagnosed cancer were followed for up to one year in a healthcare claims database (2010–2013). Three treatment groups included statin users, non-statin cholesterol lowering medication users, and an untreated group with pre-existing indications for statin therapy (hyperlipidemia, diabetes, or heart disease). Propensity score matched groups were compared using competing risks survival models for DVT and PE …

Heroin Use Onset Among Nonmedical Prescription Opioid Users In The Club Scene, Hilary L. Surratt, Steven P. Kurtz, Mance Buttram, Maria A. Levi-Minzi, Maria E. Pagano, Theodore J. Cicero

Center for Health Services Research Faculty Publications

Background—Nonmedical prescription opioid use (NMPOU) is well documented among participants in the club scene, yet prior studies have not examined transition to heroin use. We prospectively examined heroin initiation among a sample of young adults with drug involvement associated with participation in the club scene, to understand factors that influence transition from NMPOU to heroin and to identify opportunities for intervention.

Methods—Data were drawn from a randomized trial that enrolled 750 Miami-based club and prescription drug users through respondent driven sampling, and tested the efficacy of assessment interventions in reducing risk. Participants reported current substance use at baseline, …

Design, Synthesis, And Biological Activity Of 5'-Phenyl-1,2,5,6-Tetrahydro-3,3'-Bipyridine Analogues As Potential Antagonists Of Nicotinic Acetylcholine Receptors, Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D Showalter, Chang-Guo Zhan

Pharmaceutical Sciences Faculty Publications

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (K_i = 123 nM) …

Loss Of Fructose-1,6-Bisphosphatase Induces Glycolysis And Promotes Apoptosis Resistance Of Cancer Stem-Like Cells: An Important Role In Hexavalent Chromium-Induced Carcinogenesis, Jin Dai, Yanli Ji, Wei Wang, Donghern Kim, Leonard Yenwong Fai, Lei Wang, Jia Luo, Zhuo Zhang

Toxicology and Cancer Biology Faculty Publications

Hexavalent chromium (Cr(VI)) compounds are confirmed human carcinogens for lung cancer. Our previous studies has demonstrated that chronic exposure of human bronchial epithelial BEAS-2B cells to low dose of Cr(VI) causes malignant cell transformation. The acquisition of cancer stem cell-like properties is involved in the initiation of cancers. The present study has observed that a small population of cancer stem-like cells (BEAS-2B-Cr-CSC) exists in the Cr(VI)-transformed cells (BEAS-2B-Cr). Those BEAS-2B-Cr-CSC exhibit extremely reduced capability of generating reactive oxygen species (ROS) and apoptosis resistance. BEAS-2B-Cr-CSC are metabolic inactive as evidenced by reductions in oxygen consumption, glucose uptake, ATP production, and lactate …

Delirium Reduction Strategies For The Critically Ill, June Chaves, Sam Canonico, Will Cheney, Tammy Corey, Gil Fraser, Alex Kowalewski, Jen Low, Cardiac Intensive Care Unit, Haley Pelletier, Cathy Palleschi, Stephen Tyzik, Suneela Nayak, Ruth Hanselman

MaineHealth Maine Medical Center

Delirium, an acute and fluctuating disturbance of consciousness and cognition, is a common manifestation of acute brain dysfunction in critically ill patients. Patients with delirium have longer hospital stays and a lower 6-month survival rate than do patients without delirium. Preliminary research suggests that delirium may be associated with cognitive impairment that persists months to years after discharge.

In a large acute care hospital, the cardiac intensive care staff became interested in mitigating their unit’s high delirium rate of ventilated patients. At baseline, many members of the healthcare team did not believe that delirium could be prevented and the predominant …

Strategies To Improve Control Of Blood A1c In Diabetics, Jennifer Aronson, Leanne Bellino, Elizabeth Eisenhardt, Diane Bryant, Haley Pelletier, Internal Medicine Team, Adult Outpatient Clinic

MaineHealth Maine Medical Center

A1c monitoring is an important aspect of controlling the health of a diabetic patient. An adult internal medicine clinic noted that the percentage of their diabetic patients who had an A1c higher than 9 or no reading within the past year exceeded the national average. As a result, operational excellence methods were implemented with the overall goal to reduce their percentage to 18% or less.

A root cause analysis identified several deficiencies to includelack of essential equipment, variations in

staff education and the absence of daily reminders.

Post KPI implementations, an overall decrease in the percentage of patients with poorly …

Communication Of Medication Side Effects In An Acute Care Hospital, Deb Bachand, Rachel Caiola, R6 Neurology Med-Surg Unit, Haley Pelletier, Brendan Lilley, Suneela Nayak, Ruth Hanselman, Stephen Tyzik

MaineHealth Maine Medical Center

COMMUNICATION OF MEDICATION SIDE EFFECTS IN AN ACUTE CARE HOSPITAL

Effective patient education of prescribed medication side effects improves patient safety and reduces overall risk. On an acute care hospital unit, nursing staff felt previous attempts at this education had been ineffective as demonstrated by their HCAHPs scores for communication about medications.

A root cause analysis demonstrated some flaws and several countermeasures were instituted. The goal of this KPI project was to attain a higher than national average for the specific HCAHPs score.

Post KPI inception, the unit’s HCAHPs data showed steady improvement. Within one month, the goal of an …

Selective Inhibitors Of Human Mpges-1 From Structure-Based Computational Screening, Ziyuan Zhou, Yaxia Yuan, Shuo Zhou, Kai Ding, Fang Zheng, Chang-Guo Zhan

Molecular Modeling and Biopharmaceutical Center Faculty Publications

Human mPGES-1 is recognized as a promising target for next generation of anti-inflammatory drugs. Although various mPGES-1 inhibitors have been reported in literature, few have entered clinical trials and none has been proven clinically useful so far. It is highly desired for developing the next generation of therapeutics for inflammation-related diseases to design and discover novel inhibitors of mPGES-1 with new scaffolds. Here, we report the identification of a series of new, potent and selective inhibitors of human mPGES-1 with diverse scaffolds through combined computational and experimental studies. The computationally modeled binding structures of these new inhibitors with mPGES-1 provide …

Polymer Nanoassemblies With Hydrophobic Pendant Groups In The Core Induce False Positive Sirna Transfection In Luciferase Reporter Assays, Steven Rheiner, Derek Alexander Reichel, Piotr G. Rychahou, Tadahide Izumi, Hsin-Sheng Yang, Younsoo Bae

Pharmaceutical Sciences Faculty Publications

Poly(ethylene glycol)-conjugated polyethylenimine (PEG-PEI) is a widely studied cationic polymer used to develop non-viral vectors for siRNA therapy of genetic disorders including cancer. Cell lines stably expressing luciferase reporter protein typically evaluate the transfection efficacy of siRNA/PEG-PEI complexes, however recent findings revealed that PEG-PEI can reduce luciferase expression independent of siRNA. This study elucidates a cause of the false positive effect in luciferase assays by using polymer nanoassemblies (PNAs) made from PEG, PEI, poly-(L-lysine) (PLL), palmitate (PAL), and deoxycholate (DOC): PEG-PEI (2P), PEG-PEI-PAL (3P), PEG-PLL (2P′), PEG-PLL-PAL (3P′), and PEG-PEI-DOC (2PD). In vitro transfection and western blot assays of luciferase …

Effectiveness Of Switching Smoking-Cessation Medications Following Relapse, Bryan W. Heckman, K. Michael Cummings, Karin A. Kasza, Ron Borland, Jessica L. Burris, Geoffrey T. Fong, Ann Mcneill, Matthew J. Carpenter

Psychology Faculty Publications

Introduction—Nicotine dependence is a chronic disorder often characterized by multiple failed quit attempts (QAs). Yet, little is known about the sequence of methods used across multiple QAs or how this may impact future ability to abstain from smoking. This prospective cohort study examines the effectiveness of switching smoking-cessation medications (SCMs) across multiple QAs.

Methods—Adult smokers (aged ≥ 18 years) participating in International Tobacco Control surveys in the United Kingdom, U.S., Canada, and Australia (N=795) who: (1) completed two consecutive surveys between 2006 and 2011; (2) initiated a QA at least 1 month before each survey; and (3) provided …

Blocking An N-Terminal Acetylation-Dependent Protein Interaction Inhibits An E3 Ligase, Daniel C. Scott, Jared T. Hammill, Jaeki Min, David Y. Rhee, Michele Connelly, Vladislav O. Sviderskiy, Deepak Bhasin, Yizhe Chen, Su-Sien Ong, Sergio C. Chai, Asli N. Goktug, Guochang Huang, Julie K. Monda, Jonathan Low, Ho Shin Kim, Joao A. Paulo, Joe R. Cannon, Anang A. Shelat, Taosheng Chen, Ian R. Kelsall, Arno F. Alpi, Vishwajeeth Pagala, Xusheng Wang, Junmin Peng, Bhuvanesh Singh, J. Wade Harper, Brenda A. Schulman, R. Kiplin Guy

Pharmaceutical Sciences Faculty Publications

N-terminal acetylation is an abundant modification influencing protein functions. Because ∼80% of mammalian cytosolic proteins are N-terminally acetylated, this modification is potentially an untapped target for chemical control of their functions. Structural studies have revealed that, like lysine acetylation, N-terminal acetylation converts a positively charged amine into a hydrophobic handle that mediates protein interactions; hence, this modification may be a druggable target. We report the development of chemical probes targeting the N-terminal acetylation–dependent interaction between an E2 conjugating enzyme (UBE2M or UBC12) and DCN1 (DCUN1D1), a subunit of a multiprotein E3 ligase for the ubiquitin-like protein NEDD8. The inhibitors are …

A Direct In Vivo Comparison Of The Melanocortin Monovalent Agonist Ac-His-Dphe-Arg-Trp-Nh2 Versus The Bivalent Agonist Ac-His-Dphe-Arg-Trp-Pedg20-His-Dphe-Arg-Trp-Nh2: A Bivalent Advantage, Cody J Lensing, Danielle N Adank, Stacey L Wilber, Katie T Freeman, Sathya M Schnell, Robert Charles Speth, Adam T Zarth, Carrie Haskell-Luevano

Faculty Articles

Bivalent ligands targeting putative melanocortin receptor dimers have been developed and characterized in vitro, however studies of their functional in vivo effects have been limited. The current report compares the effects of homobivalent ligand CJL-1-87, Ac-His-DPhe-Arg-Trp-PEDG20-His-DPhe-Arg-Trp-NH₂, to monovalent ligand CJL-1-14, Ac-His-DPhe-Arg-Trp-NH₂ on energy homeostasis in mice after central intracerebroventricular (ICV) administration into the lateral ventricle of the brain. Bivalent ligand CJL-1-87 had noteworthy advantages as an anti-obesity probe over CJL-1-14 in a fasting-refeeding in vivo paradigm. Treatment with CJL-1-87 significantly decreased food intake compared to CJL-1-14 or saline (50% less intake 2 to 8 hours after …

A Consensus Definitive Classification Of Scavenger Receptors And Their Roles In Health And Disease, Mercy R Prabhudas, Cynthia L Baldwin, Paul L Bollyky, Dawn M E Bowdish, Kurt Drickamer, Maria Febbraio, Joachim Herz, Lester Kobzik, Monty Krieger, John Loike, Benita Mcvicker, Terry K Means, Soren K Moestrup, Steven R Post, Tatsuya Sawamura, Samuel Silverstein, Robert Charles Speth, Janice C Telfer, Geoffrey M Thiele, Xiang-Yang Wang, Samuel D Wright, Joseph El Khoury

Faculty Articles

Scavenger receptors constitute a large family of proteins that are structurally diverse and participate in a wide range of biological functions. These receptors are expressed predominantly by myeloid cells and recognize a diverse variety of ligands including endogenous and modified host-derived molecules and microbial pathogens. There are currently eight classes of scavenger receptors, many of which have multiple names, leading to inconsistencies and confusion in the literature. To address this problem, a workshop was organized by the United States National Institute of Allergy and Infectious Diseases, National Institutes of Health, to help develop a clear definition of scavenger receptors and …

Application Of Fluoroquinolone Resistance Score In Management Of Complicated Urinary Tract Infections, Ansal Shah, Julie Ann Justo, P Brandon Bookstaver, Joseph Kohn, Helmut Albrecht, Majdi N. Al-Hasan

Faculty Publications

The fluoroquinolone resistance score (FQRS) predicts the probability of fluoroquinolone resistance with good discrimination. The score has been derived from patients with bloodstream infections caused by Gram-negative bacteria and is based on fluoroquinolone use within the past 6 months, among other clinical and health care exposure criteria. This study aims to examine the utility of the FQRS in patients with complicated urinary tract infections (cUTI) and determine whether extension of prior fluoroquinolone use to 12 months improves model discrimination. Adults with cUTI at Palmetto Health in central South Carolina, USA, from 1 April 2015 through 31 July 2015 were prospectively …

Outcomes After Diagnosis Of Mild Cognitive Impairment In A Large Autopsy Series, Erin L. Abner, Richard J. Kryscio, Frederick A. Schmitt, David W. Fardo, Daniela C. Moga, Eseosa T. Ighodaro, Gregory A. Jicha, Lei Yu, Hiroko H. Dodge, Chengjie Xiong, Randall L. Woltjer, Julie A. Schneider, Nigel J. Cairns, David A. Bennett, Peter T. Nelson

Epidemiology and Environmental Health Faculty Publications

OBJECTIVE: To determine clinical and neuropathological outcomes following a clinical diagnosis of mild cognitive impairment (MCI).

METHODS: Data were drawn from a large autopsy series (N = 1,337) of individuals followed longitudinally from normal or MCI status to death, derived from 4 Alzheimer Disease (AD) Centers in the United States.

RESULTS: Mean follow‐up was 7.9 years. Of the 874 individuals ever diagnosed with MCI, final clinical diagnoses were varied: 39.2% died with an MCI diagnosis, 46.8% with a dementia diagnosis, and 13.9% with a diagnosis of intact cognition. The latter group had pathological features resembling those with a final clinical …

Buprenorphine Physician Supply: Relationship With State-Level Prescription Opioid Mortality, Hannah K. Knudsen, Jennifer R. Havens, Michelle R. Lofwall, Jamie L. Studts, Sharon L. Walsh

Behavioral Science Faculty Publications

Background: Buprenorphine is an effective treatment for opioid use disorder but the supply of buprenorphine physicians is currently inadequate to address the nation’s prescription opioid crisis. Perception of need due to rising opioid overdose rates is one possible reason for physicians to adopt buprenorphine. This study examined associations between rates of growth in buprenorphine physicians and prescription opioid overdose mortality rates in US states.

Methods: The total buprenorphine physician supply and number of physicians approved to treat 100 patients (per 100,000 population) were measured from June 2013 to January 2016. States were divided into two groups: those with rates of …

Another Look At Pyrroloiminoquinone Alkaloids-Perspectives On Their Therapeutic Potential From Known Structures And Semisynthetic Analogues., Sheng Lin, Erin P. Mccauley, Nicholas Lorig-Roach, Karen Tenney, Cassandra N. Naphen, Ai-Mei Yang, Tyler A. Johnson, Thalia Hernadez, Ramandeep Rattan, Frederick A. Valeriote, Phillip Crews

Natural Sciences and Mathematics | Faculty Scholarship

This study began with the goal of identifying constituents from Zyzzya fuliginosa extracts that showed selectivity in our primary cytotoxicity screen against the PANC-1 tumor cell line. During the course of this project, which focused on six Z. fuliginosa samples collected from various regions of the Indo-Pacific, known compounds were obtained consisting of nine makaluvamine and three damirone analogues. Four new acetylated derivatives were also prepared. High-accuracy electrospray ionization mass spectrometry (HAESI-MS) m/z ions produced through MS² runs were obtained and interpreted to provide a rapid way for dereplicating isomers containing a pyrrolo[4,3,2-de]quinoline core. In vitro human pancreas/duct epithelioid …

Mccrearamycins A-D, Geldanamycin-Derived Cyclopentenone Macrolactams From An Eastern Kentucky Abandoned Coal Mine Microbe, Xiachang Wang, Yinan Zhang, Larissa V. Ponomareva, Qingchao Qiu, Ryan M. Woodcock, Sherif I. Elshahawi, Xiabin Chen, Ziyuan Zhou, Bruce E. Hatcher, James C. Hower, Chang-Guo Zhan, Sean Parkin, Madan K. Kharel, S. Randal Voss, Khaled A. Shaaban, Jon S. Thorson

Center for Pharmaceutical Research and Innovation Faculty Publications

Four cyclopentenone‐containing ansamycin polyketides (mccrearamycins A–D), and six new geldanamycins (Gdms B–G, including new linear and mycothiol conjugates), were characterized as metabolites of Streptomyces sp. AD‐23‐14 isolated from the Rock Creek underground coal mine acid drainage site. Biomimetic chemical conversion studies using both simple synthetic models and Gdm D confirmed that the mccrearamycin cyclopentenone derives from benzilic acid rearrangement of 19‐hydroxy Gdm, and thereby provides a new synthetic derivatization strategy and implicates a potential unique biocatalyst in mccrearamycin cyclopentenone formation. In addition to standard Hsp90α binding and cell line cytotoxicity assays, this study also highlights the first assessment of Hsp90α …

Adverse Events And Treatment Discontinuations Of Antimuscarinics For The Treatment Of Overactive Bladder In Older Adults: A Systematic Review And Meta-Analysis, Scott Martin Vouri, Clark D. Kebodeaux, Paul M. Stranges, Besu F. Teshome

Pharmacy Practice and Science Faculty Publications

Introduction

Antimuscarinics should be used with caution in older adults with overactive bladder (OAB) due to anticholinergic adverse events (AEs). Systematic reviews and meta-analyses (SRMAs) have analyzed safety-related outcomes but have not specified risk in the elderly, the population at highest risk for AEs. The aim of this review is to explore and evaluate AEs and treatment discontinuations in adults 65 or older taking antimuscarinics for OAB.

Methods

Keywords were searched in MEDLINE, EMBASE, SCOPUS, and Cochrane Central Register for Controlled Trials. Randomized controlled trials (RCTs) along with sub-analyses and pooled analyses that compared antimuscarinics to placebo or another antimuscarinic …

Efficacy And Tolerability Of Adjunctive Brivaracetam In Patients With Prior Antiepileptic Drug Exposure: A Post-Hoc Study., Ali A. Asadi-Pooya, Michael R. Sperling, Steve Chung, Pavel Klein, Anyzeila Diaz, Sami Elmoufti, Jimmy Schiemann, John Whitesides

Department of Neurology Faculty Papers

Brivaracetam (BRV), a selective, high-affinity ligand for synaptic vesicle protein 2A, is a new antiepileptic drug (AED) for adjunctive treatment of focal (partial-onset) seizures in adults with epilepsy. This post-hoc analysis was conducted to explore the efficacy of adjunctive BRV in patients with prior levetiracetam (LEV) exposure and whether changes in efficacy were related to the similar mechanism of action of these two drugs. Data were pooled from three Phase III studies (NCT00490035; NCT00464269; NCT01261325) of adults with focal seizures taking 1-2 AEDs who received placebo or BRV 50-200mg/day without titration over a 12-week treatment period. Patients taking concomitant LEV …

Inhibition Of Cdk8 Mediator Kinase Suppresses Estrogen Dependent Transcription And The Growth Of Estrogen Receptor Positive Breast Cancer, Martina S. Mcdermott, Alexander A. Chumanevich, Chang-Uk Lim, Jiaxin Liang, Mengqian Chen, Serena Altilia, David Oliver, James M. Rae, Michael Shtutman, Hippokratis Kiaris, Balázs Győrffy, Igor Roninson, Eugenia Broude

Faculty Publications

Hormone therapy targeting estrogen receptor (ER) is the principal treatment for ER-positive breast cancers. However, many cancers develop resistance to hormone therapy while retaining ER expression. Identifying new druggable mediators of ER function can help to increase the efficacy of ER-targeting drugs. Cyclin-dependent kinase 8 (CDK8) is a Mediator complex-associated transcriptional regulator with oncogenic activities. Expression of CDK8, its paralog CDK19 and their binding partner Cyclin C are negative prognostic markers in breast cancer. Meta-analysis of transcriptome databases revealed an inverse correlation between CDK8 and ERα expression, suggesting that CDK8 could be functionally associated with ER. We have found that …

Mechanisms Of Modulation Of Brain Microvascular Endothelial Cells Function By Thrombin., Eugen Brailoiu, Megan M. Shipsky, Guang Yan, Mary E. Abood, G. Cristina Brailoiu

College of Pharmacy Faculty Papers

Brain microvascular endothelial cells are a critical component of the blood-brain barrier. They form a tight monolayer which is essential for maintaining the brain homeostasis. Blood-derived proteases such as thrombin may enter the brain during pathological conditions like trauma, stroke, and inflammation and further disrupts the permeability of the blood-brain barrier, via incompletely characterized mechanisms. We examined the underlying mechanisms evoked by thrombin in rat brain microvascular endothelial cells (RBMVEC). Our results indicate that thrombin, acting on protease-activated receptor 1 (PAR1) increases cytosolic Ca

A Quantitative Lc-Ms/Ms Method For Simultaneous Determination Of Cocaine And Its Metabolites In Whole Blood, Xiabin Chen, Xirong Zheng, Kai Ding, Ziyuan Zhou, Chang-Guo Zhan, Fang Zheng

Molecular Modeling and Biopharmaceutical Center Faculty Publications

As new metabolic pathways of cocaine were recently identified, a high performance liquid chromatography tandem mass spectrometry (LC–MS/MS) method was developed to simultaneously determine cocaine and nine cocaine-related metabolites in whole blood samples. One-step solid phase extraction was used to extract all of the ten compounds and corresponding internal standards from blood samples. All compounds and internal standards extracted were separated on an Atlantis T3 (100 Å, 3 μm, 2.1 mm × 150 mm I.D) column and detected in positive ion and high sensitivity mode with multiple reaction monitoring. This method was validated for its sensitivity, linearity, specificity, accuracy, precision, …

Nephrotoxicity During Vancomycin Therapy In Combination With Piperacillin-Tazobactam Or Cefepime, Wilbur Cliff Rutter, Jessica N. Cox, Craig A. Martin, Donna R. Burgess, David S. Burgess

Pharmacy Practice and Science Faculty Publications

Recent reports have demonstrated that vancomycin (VAN) may lead to an increase in the incidence of acute kidney injury (AKI) when it is combined with antipseudomonal beta-lactams. This study compared the incidence of AKI associated with VAN plus piperacillin-tazobactam (TZP) or cefepime (FEP). This was a retrospective, matched cohort study that was conducted at an academic medical center between September 2010 and September 2014 and that included adult patients without severe chronic or structural kidney disease, dialysis, pregnancy, cystic fibrosis, or a hospital transfer receiving TZP-VAN or FEP-VAN for at least 48 h. The primary outcome was the difference in …