Advancing Scientific Discovery, Drug Development and Diagnostics
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Interplay Between Gating and Block of Ligand-Gated Ion Channels
brain sciences Review Interplay between Gating and Block of Ligand-Gated Ion Channels Matthew B. Phillips 1,2, Aparna Nigam 1 and Jon W. Johnson 1,2,* 1 Department of Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA; [email protected] (M.B.P.); [email protected] (A.N.) 2 Center for Neuroscience, University of Pittsburgh, Pittsburgh, PA 15260, USA * Correspondence: [email protected]; Tel.: +1-(412)-624-4295 Received: 27 October 2020; Accepted: 26 November 2020; Published: 1 December 2020 Abstract: Drugs that inhibit ion channel function by binding in the channel and preventing current flow, known as channel blockers, can be used as powerful tools for analysis of channel properties. Channel blockers are used to probe both the sophisticated structure and basic biophysical properties of ion channels. Gating, the mechanism that controls the opening and closing of ion channels, can be profoundly influenced by channel blocking drugs. Channel block and gating are reciprocally connected; gating controls access of channel blockers to their binding sites, and channel-blocking drugs can have profound and diverse effects on the rates of gating transitions and on the stability of channel open and closed states. This review synthesizes knowledge of the inherent intertwining of block and gating of excitatory ligand-gated ion channels, with a focus on the utility of channel blockers as analytic probes of ionotropic glutamate receptor channel function. Keywords: ligand-gated ion channel; channel block; channel gating; nicotinic acetylcholine receptor; ionotropic glutamate receptor; AMPA receptor; kainate receptor; NMDA receptor 1. Introduction Neuronal information processing depends on the distribution and properties of the ion channels found in neuronal membranes. -
(12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen Et Al
USOO8603526B2 (12) United States Patent (10) Patent No.: US 8,603,526 B2 Tygesen et al. (45) Date of Patent: Dec. 10, 2013 (54) PHARMACEUTICAL COMPOSITIONS 2008. O152595 A1 6/2008 Emigh et al. RESISTANT TO ABUSE 2008. O166407 A1 7/2008 Shalaby et al. 2008/0299.199 A1 12/2008 Bar-Shalom et al. 2008/0311205 A1 12/2008 Habib et al. (75) Inventors: Peter Holm Tygesen, Smoerum (DK); 2009/0022790 A1 1/2009 Flath et al. Jan Martin Oevergaard, Frederikssund 2010/0203129 A1 8/2010 Andersen et al. (DK); Karsten Lindhardt, Haslev (DK); 2010/0204259 A1 8/2010 Tygesen et al. Louise Inoka Lyhne-versen, Gentofte 2010/0239667 A1 9/2010 Hemmingsen et al. (DK); Martin Rex Olsen, Holbaek 2010, O291205 A1 11/2010 Downie et al. (DK); Anne-Mette Haahr, Birkeroed 2011 O159100 A1 6/2011 Andersen et al. (DK); Jacob Aas Hoellund-Jensen, FOREIGN PATENT DOCUMENTS Frederikssund (DK); Pemille Kristine Hoeyrup Hemmingsen, Bagsvaerd DE 20 2006 014131 1, 2007 (DK) EP O435,726 8, 1991 EP O493513 7, 1992 EP O406315 11, 1992 (73) Assignee: Egalet Ltd., London (GB) EP 1213014 6, 2002 WO WO 89,09066 10, 1989 (*) Notice: Subject to any disclaimer, the term of this WO WO91,040 15 4f1991 patent is extended or adjusted under 35 WO WO95/22962 8, 1995 U.S.C. 154(b) by 489 days. WO WO99,51208 10, 1999 WO WOOOf 41704 T 2000 WO WO 03/024426 3, 2003 (21) Appl. No.: 12/701,429 WO WOO3,O24429 3, 2003 WO WOO3,O24430 3, 2003 (22) Filed: Feb. -
Abstracts Monday August 26
ABSTRACTS MONDAY AUGUST 26 KEYNOTES, SYMPOSIA, ORAL PRESENTATION SESSIONS, POSTER DISCUSSION SESSIONS, THEMATIC POSTER SESSIONS “On Air Table of contents Monday August 26, 9:00 AM – 10:00 AM ............................................................................................... 23 Keynote Lectures .................................................................................................................................. 23 Cities as unequal opportunities for good health ........................................................................................... 23 Challenges and Prospects of Environmental Epidemiology in Africa ............................................................ 24 Monday August 26 10:30 AM – 12:00 PM .............................................................................................. 25 S01: Mapping the Air Pollution Metabolome: Applications, Limitations, and the Path Forward ............... 25 Metabolic perturbations following exposures to traffic-related air pollution in a panel of commuters with and without asthma ...................................................................................................................................... 25 Traffic-Related Air Pollution Exposure and Altered Fatty Acid Oxidation Among Adolescents and Young Adults – the Interplay with Obesity .............................................................................................................. 26 The Maternal Serum Metabolome and Ambient Air Pollution Exposure during Pregnancy ....................... -
Improving the Understanding of Anti- Epileptic Drugs Using Quantitative Structure Activity Relationships
Improving the Understanding of Anti- Epileptic Drugs Using Quantitative Structure Activity Relationships Caroline Loewecke, Dr. Brad Reisfeld Department of Chemical and Biological Engineering. Colorado State University, Fort Collins, CO, USA Background Epilepsy • One of the more common neurological conditions • Recurrent, unprovoked seizures • Affects about 65 million people around the world (3 million in the U.S.) Issues with Current Treatments • Do not fully block seizure (epileptogenic) activity in all patients • Levels often prescribed in toxic range to properly control brain activity causing unwanted symptoms Gaps in Current Approaches • The research and development of new medicines is expensive and time consuming • There is a need for a better way to identify promising chemicals and narrow the testing pool Background (contd.) Quantitative Structure Activity Relationships (QSARs) • Using the physicochemical properties of chemicals with similar structures (training set) to make predictive models for similarly structured chemicals (test sets) • Narrows down chemicals to be researched for development • Predict environmental consequences based on known structural effects Similar structures from our chemical search Methods/Experimental Setup Noncompetitive NMDA Antagonists • Anticonvulsants • Decrease excitatory amino acid release • Treatment of epilepsy • Current research into preventative implications in Alzheimer’s and Parkinson’s disease Create group of chemicals with Download files containing 3D similar features/mechanisms chemical -
Third Party Controls
QUALITY CONTROL Q QThird Party Controls Complete QC solutions for results you can trust Contact us for more information on any of our products and services: [email protected] randoxqc.com +44 (0) 28 9442 2413 +44 (0) 28 9445 2912 Stay up-to-date with the latest news from Randox Quality Control by following us on: Facebook Google+ LinkedIn Twitter YouTube SlideShare For technical support contact: [email protected] QUALITY CONTROL Table of Contents Section Page No. 1. Introduction 2 - 3 2. Benefits 4 - 9 3. Quality 10 Internal Quality Controls 4. Antioxidants 11-14 5. Blood Gas 15-18 6. Cardiac 19-22 7. Clinical Chemistry 23-36 8. Coagulation and Haematology 37-40 9. Diabetes 41-44 10. Immunoassay 45-52 11. Immunology/Proteins 53-58 12. Lipids 59-62 13. Speciality and Research 63-72 14. Therapeutic Drugs 73-76 15. Toxicology 77-84 16. Urine 85-88 Tailor Made Controls 17. Customised Quality Control Sera 89 - 94 Acusera 24•7 18. Interlaboratory Data Management 95 - 98 RIQAS 19. External Quality Assessment 99 - 106 Index 20. Analyte Index 107 - 124 21. A-Z Index 125 - 128 1 Introduction Welcome Complete QC solutions for results you can trust Patient health is reliant on accurate and timely diagnosis, but this can With products and solutions available to suit all areas of laboratory only be facilitated through the use of high quality diagnostic testing medicine including routine chemistry, special chemistry, toxicology, solutions. serology, immunology, haemostasis and respiratory care; our customer base exceeds 100,000 laboratories in all four corners of the world. -
Third Party Controls
THIRD PARTY CONTROLS ACUSERA ACUSERA TRUE THIRD PARTY CONTROLS OFFERING COMPLETE TEST MENU CONSOLIDATION 01 BENEFITS 03 ISO REQUIREMENTS 04 CONSOLIDATION 05 COMMITMENT TO QUALITY 06 ANTIOXIDANTS 09 BLOOD GAS 12 CARDIAC 17 CLINICAL CHEMISTRY 29 COAGULATION AND HAEMATOLOGY 33 DIABETES AND WHOLE BLOOD 37 IMMUNOASSAY 45 IMMUNOLOGY/PROTEINS 52 INFECTIOUS DIESASE (SEROLOGY) 57 LIPIDS 65 SPECIALITY AND RESEARCH 68 THERAPEUTIC DRUGS 74 TOXICOLOGY 74 URINE 74 ACCESSORIES 79 CUSTOMISED QUALITY CONTROL SERA 84 INTERLABORATORY DATA MANAGEMENT 88 EXTERNAL QUALITY ASSESSMENT 96 CALIBRATION VERIFICATION SETS 102 ANALYTE INDEX 119 RANDOX - A GLOBAL DIAGNOSTIC SOLUTIONS PROVIDER 120 CONTACT US 1 BENEFITS For more than 35 years Randox has been shaping the future of clinical diagnostics with our pioneering high quality, cost effective laboratory solutions. With approximately 70% of clinical decisions based on laboratory test results, it is essential that the results provided are accurate and reliable in order to prevent potential misdiagnosis or inappropriate treatment. Quality Control is our passion; we believe in producing high quality material that can help streamline procedures, whilst saving time and money for laboratories of all sizes and budgets. With an extensive product offering comprising third party quality controls & calibrators, interlaboratory data management, external quality assessment, calibration verification and molecular IQC and EQA for infectious disease testing, you can count on Randox to deliver trustworthy results time and time again. Just ask one of our 60,000 users worldwide. Commutability All Acusera controls are designed to react to the test system in the same manner as the patient sample, helping to meet ISO 15189:2012 requirements whilst reducing inconvenient and costly shifts in QC results when reagent batch is changed. -
Medications in Patients with Dementia and Behavioral Disturbance
Journal of Alzheimer’s Disease Reports 5 (2021) 535–540 535 DOI 10.3233/ADR-210023 IOS Press Research Report Medications in Patients with Dementia and Behavioral Disturbance Wenjun Zhonga,∗, Xinyue Liua, Tiffini Vossb, Sauzanne Khaliliehb, Rezaul Karim Khandkera, Edward Bortnichaka and Kai-Li Liawa aCenter for Observational and Real-World Evidence (CORE), Merck & Co., Inc., Kenilworth, NJ, USA bGlobal Clinical Development, Merck & Co., Inc., Kenilworth, NJ, USA Accepted 19 May 2021 Pre-press 8 June 2021 Abstract. Background: Behavioral disturbance (BD) is common in dementia patients, with no FDA approved medications for this condition. Little data exists on the real-world medication use in this population. Objective: To describe real-world medications use in this population. Methods: A cross-sectional study was conducted using the MarketScan database for outpatient medications and the Cerner database for inpatient medications. The study period was Oct 2015–Jun 2018. Patients with dementia and BD were identified through ICD-10-CM. We examined outpatient medications prescribed during 6-month before or after BD event date, and inpatient medications during inpatient visits, especially on central nervous systems (CNS) drugs including antidementia drugs, antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Results: A total of 56,544 outpatients and 34,245 patient hospitalizations were assessed separately. Among outpatients, patients filled more medications after a BD event. The use of the five CNS drug classes generally increased after a BD event, and the largest increase was seen in antipsychotics (23% to 33%). Among inpatients, the median number of medications used in each hospitalization was 14. The use of antipsychotics was particularly high (64%), followed by anxiolytics (51%). -
Clinical Policy: Critical Issues in the Sedation of Pediatric Patients in The
PEDIATRICS/CLINICAL POLICY Clinical Policy: Critical Issues in the Sedation of Pediatric Patients in the Emergency Department From the EMSC Panel (Writing Committee) on Critical Issues in the Sedation of Pediatric Patients in the Emergency Department: Sharon E. Mace, MD, Chair, American College of Emergency Physicians (ACEP) Lance A. Brown, MD, MPH (ACEP) Lisa Francis, BSN, RN (Society of Pediatric Nurses) Steven A. Godwin, MD (ACEP) Sigrid A. Hahn, MD (ACEP) Patricia Kunz Howard, PhD, RN, CEN (Emergency Nurses Association) Robert M. Kennedy, MD (American Academy of Pediatrics) David P. Mooney, MD (American Pediatric Surgical Association) Alfred D. Sacchetti, MD (ACEP) Robert L. Wears, MD, MS, Methodologist (ACEP) Randall M. Clark, MD (American Society of Anesthesiologists) Other members of the EMSC Panel included: Approved by the ACEP Board of Directors, October 5, 2007 Ramon W. Johnson, MD (ACEP Board Liaison) Supported by the Emergency Nurses Association, Rhonda R. Whitson, RHIA (Clinical Policies Manager, October 5, 2007 ACEP) Endorsed by the Society of Pediatric Nurses, November Tuei Doong (Vice President, The Nakamoto Group, Inc) 3, 2007 Jenni Nakamoto-Yingling (President, The Nakamoto Endorsed by the American Pediatric Surgical Group, Inc) Association, December 20, 2007 Karen Belli (Public Policy and Partnerships Specialist, Organizational representation does not imply EMSC) endorsement of this document by that organization. Tasmeen Singh, MPH, NREMT-P (Executive Director, National Resource Center, EMSC) This clinical policy was developed by a multidisciplinary Tina Turgel (Nurse Consultant, EMSC) panel and funded by Project #HHSH240200515109P of the Emergency Medical Services for Children Program, Maternal and Child Health Bureau, Health Resources and Services Administration, US Department of Health and Human Services. -
Slow Mg Unblock and Inherent Voltage Dependence of NMDA Receptors By
Slow Mg2+ unblock and inherent voltage dependence of NMDA receptors by Richard J. Clarke Bachelor of Science, Allegheny College, 2000 Submitted to the Graduate Faculty of Arts and Sciences in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Pittsburgh 2006 UNIVERSITY OF PITTSBURGH School of Arts and Sciences This dissertation was presented by Richard J. Clarke It was defended on July 17, 2006 and approved by Elias Aizenman, Ph.D. Germán Barrionuevo, M.D. Peter Drain, Ph.D. Stephen Traynelis, Ph.D. Nathan Urban, Ph.D. Dissertation Advisor: Jon Johnson, Ph.D. ii Copyright © by Richard J. Clarke 2006 iii Slow Mg2+ unblock and inherent voltage dependence of NMDA receptors Richard J. Clarke, PhD University of Pittsburgh, 2006 N-methyl-D-aspartate (NMDA) receptors are a subtype of ligand-gated ionotropic glutamate receptors that are involved in most fast, excitatory neuronal transmission in the mammalian central nervous system (CNS). NMDA receptor activity is crucial for normal brain function, and NMDA receptor dysregulation has been linked to a number of diseases of the CNS. There are several NMDA receptor subtypes. Each subtype has a unique temporal and spatial expression pattern, suggesting that different subtypes play different physiological roles in the CNS. Here, we have investigated how changes in membrane voltage impact the activity of various NMDA receptor subtypes in the absence and presence of the highly physiologically relevant channel blocker magnesium (Mg2+). Mg2+ strongly blocks all NMDA receptor subtypes at, and near, typical resting membrane potentials. Only upon depolarization is Mg2+ block relieved. We found that, upon depolarization, NMDA receptors containing NR2C or NR2D subunits unblock Mg2+ very rapidly (τ < 1 ms), while Mg2+ unblock from NMDA receptors containing the NR2A or NR2B subunit displays a prominent slow component (τ of several ms). -