DOCSLIB.ORG

Molecular Effects of Olecular Effects of Idebenone Idebenone

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Molecular Effects of Olecular Effects of Idebenone Idebenone MMMolecularMolecular Effects of Idebenone Inauguraldissertation zur Erlangung der Würde eines Doktors der Philosophie vorgelegt der Philosophisch-Naturwissenschaftlichen Fakultät der Universität Basel von Roman Hans Haefeli aus Wetzikon, ZH Winterthur, 2012 Molecular Effects of Idebenone 1 Table of Content Genehmigt von der Philosophisch-Naturwissenschaftlichen Fakultät auf Antrag von Prof. Dr. Markus Rüegg PD Dr. Thomas Meier PD Dr. Dirk Fischer Basel, den 20. September 2011 Prof. Dr. Martin Spiess Dekan 2 Molecular Effects of Idebenone Table of Contents Table of Contents Table of Contents .................................................................................................................................................................................................. 3 1 Abstract ................................................................................................................................................................................................... 7 2 Introduction .......................................................................................................................................................................................... 9 2.1 Mitochondria-Related Diseases ............................................................................................................................................... 9 2.1.1 Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-Like Syndrome (MELAS) ................. 10 2.1.2 Leber’s Hereditary Optic Neuropathy (LHON) .......................................................................................................... 10 2.1.3 Duchenne Muscular Dystrophy ............................................................................................................................................ 11 2.2 Mitochondria and Energy-Generating Systems .............................................................................................................. 13 2.2.1 Glycolysis Produces ATP Independent of Mitochondria ......................................................................................... 14 2.2.2 Electron Transport Chain and Oxidative Phosphorylation ......................................................................................15 2.2.3 Other Relevant Electron Transport Systems ................................................................................................................. 18 2.2.4 Janus-faced Mitochondria: The Rise of Reactive Oxygen Species during Respiration ............................... 20 2.3 The Importance of the Redox Environment .................................................................................................................... 23 2.3.1 Oxidative Stress ........................................................................................................................................................................... 23 2.3.2 Redox Environment and ROS Signaling............................................................................................................................ 25 2.4 Idebenone ........................................................................................................................................................................................ 26 2.4.1 Quinones ........................................................................................................................................................................................ 26 2.4.2 Idebenone: An Overview.........................................................................................................................................................27 2.4.3 Idebenone: Preclinical Data of the Brain .......................................................................................................................... 28 2.4.4 Idebenone: Interaction with the Electron Transport Chain .................................................................................... 28 2.4.5 Idebenone: Preclinical Evidence for an Antioxidant Effect ..................................................................................... 29 2.4.6 Idebenone: Additional Findings ........................................................................................................................................... 29 2.4.7 Idebenone: Clinical Data ......................................................................................................................................................... 30 2.5 Perspectives .................................................................................................................................................................................... 30 3 Results ................................................................................................................................................................................................... 31 3.1 Confirmation of Duchenne Muscular Dystrophy Model Systems ........................................................................ 31 3.2 Influence of Idebenone on Mitochondrial Activity ...................................................................................................... 37 3.3 Idebenone Rescues ATP Levels under Conditions of Dysfunctional Complex I ........................................... 39 3.4 Investigating the Mode of Quinone-Dependent ATP Rescue ................................................................................. 43 3.5 Can Idebenone Ameliorate ATP Levels Via AMPK? ................................................................................................. 45 3.6 Quinone-Dependent ATP Rescue Is Dependent on NQO1 and Complex III ................................................ 46 3.7 The Influence of Cell Medium on ATP Rescue Experiments .................................................................................51 3.8 Idebenone Reduced ATP Levels in Cells Deficient of NQO1 ................................................................................. 52 3.9 Interactions of Idebenone with Additional Oxidoreductases .................................................................................. 54 3.10 Potential Benefits from ATP Rescue in Disorders with Deficient Complex I ................................................. 59 3.11 Toxicological Analyses of Idebenone and Related Quinones .................................................................................. 61 3.12 Idebenone Influences Akt-1 Status ...................................................................................................................................... 62 3.13 Idebenone Protects Cells from Oxidative Stress-Induced Cell Death ................................................................. 65 3.14 Alteration in Gene Expression as a Mode of Action of Idebenone?..................................................................... 70 3.15 Metabolic Effects of Idebenone in Vivo ............................................................................................................................. 74 3.16 Characterization of Idebenone Analogs ............................................................................................................................. 79 4 Discussion ............................................................................................................................................................................................ 86 4.1 Choice of Suitable Model Systems....................................................................................................................................... 86 4.2 Influence of Idebenone on Mitochondrial Parameters in Healthy Mitochondria ........................................... 88 4.3 Idebenone Is an Inhibitor of Complex I ............................................................................................................................ 88 4.4 Idebenone Restores ATP Levels under Conditions of Impaired Complex I .................................................... 91 4.5 ATP Restoration in Presence of Dysfunctional Complex I Is Carried Out by Cytosolic-Mitochondrial Electron Shuttling .......................................................................................................................................................................................... 92 4.6 Idebenone Is Reduced by Other Oxidoreductases than NQO1 as Well ............................................................ 98 4.7 Idebenone Inhibits Complex I in Vivo and Thereby Changes Metabolism....................................................... 98 4.8 Idebenone Is a Mild Pro-Oxidant ....................................................................................................................................... 101 4.9 Idebenone Analogs Exhibit a High Disparity in Biological Function ................................................................. 102 4.10 Idebenone Protects From Oxidative Stress-Induced Cell Death .......................................................................... 103 4.11 Implications of this Thesis on Mitochondrial Diseases: DMD, MELAS, and LHON ................................. 105 4.11.1 Duchenne Muscular Dystrophy ......................................................................................................................................... 105 4.11.2 Mitochondrial Encephalomyopathy, Lactic Acidosis, and Stroke-like Syndrome ..................................... 106 4.11.3 Leber’s Hereditary Optic
Load more

Recommended publications
  • Synthesis and Evaluation of Chromone Derivatives As Inhibitors of Monoamine Oxidase
    Synthesis and evaluation of chromone derivatives as inhibitors of monoamine oxidase AN Mpitimpiti 21253005 Dissertation submitted in fulfilment of the requirements for the degree Magister Scientiae in Pharmaceutical Chemistry at the Potchefstroom Campus of the North-West University Supervisor: Dr ACU Lourens Co-supervisors: Dr A Petzer Prof JP Petzer November 2014 The financial assistance of the National Research Foundation (NRF) and the Medical Research Council (MRC) towards this research is hereby acknowledged. Opinions expressed and conclusions arrived at are those of the author and are not necessarily to be attributed to the NRF or MRC. Acknowledgements • All glory be to God. • I am deeply indebted to the following for their immense support and contribution: o My supervisor - Dr A.C.U Lourens (your guidance is truly boundless). o My co-supervisors, Prof J.P Petzer and Dr A. Petzer. o Dr J.Jordaan. • My mother, Magret Chigeza (for your unconditional love and support). • My family and friends. • All those who knowingly and unknowingly supported me through out this journey. Psalm 115 verse 1: ‘Not to us, O Lord, not to us, but to Your Name be the glory, because of Your love and faithfulness’ i Table of Contents Abstract ...........................................................................................................................iv Opsomming ....................................................................................................................vii List of abbreviations .......................................................................................................xi
    [Show full text]
  • Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A And
    www.nature.com/scientificreports OPEN Bioenergetic Impairment in Congenital Muscular Dystrophy Type 1A and Leigh Syndrome Received: 20 September 2016 Accepted: 23 February 2017 Muscle Cells Published: 03 April 2017 Cibely C. Fontes-Oliveira1, Maarten Steinz1, Peter Schneiderat2, Hindrik Mulder3 & Madeleine Durbeej1 Skeletal muscle has high energy requirement and alterations in metabolism are associated with pathological conditions causing muscle wasting and impaired regeneration. Congenital muscular dystrophy type 1A (MDC1A) is a severe muscle disorder caused by mutations in the LAMA2 gene. Leigh syndrome (LS) is a neurometabolic disease caused by mutations in genes related to mitochondrial function. Skeletal muscle is severely affected in both diseases and a common feature is muscle weakness that leads to hypotonia and respiratory problems. Here, we have investigated the bioenergetic profile in myogenic cells from MDC1A and LS patients. We found dysregulated expression of genes related to energy production, apoptosis and proteasome in myoblasts and myotubes. Moreover, impaired mitochondrial function and a compensatory upregulation of glycolysis were observed when monitored in real-time. Also, alterations in cell cycle populations in myoblasts and enhanced caspase-3 activity in myotubes were observed. Thus, we have for the first time demonstrated an impairment of the bioenergetic status in human MDC1A and LS muscle cells, which could contribute to cell cycle disturbance and increased apoptosis. Our findings suggest that skeletal muscle metabolism might be a promising pharmacological target in order to improve muscle function, energy efficiency and tissue maintenance of MDC1A and LS patients. Skeletal muscle is the largest organ in the human body and is used to respond to a broad range of functional demands in each animal species.
    [Show full text]
  • Study Protocol
    EspeRare_RIM_001 Rimeporide in DMD patients Page 1 of 85 Clinical Study Protocol Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending oral doses of Rimeporide in patients with Duchenne Muscular Dystrophy Acronym: Rim4DMD Sponsor: EspeRare Foundation 14 Chemin des Aulx 1228 Plan-les-Ouates Switzerland Study Sponsor’s number: ESPERARE_RIM_001 EudraCT number: 2015-002530-50 Version: 2.1 Date: February 19th, 2016 Amendment number: 2 This document is a confidential communication of EspeRare. Acceptance of this document constitutes the agreement by the recipient that no unpublished information contained within will be published or disclosed without prior written approval, except as required to permit review by responsible Ethics Committees and Health Authorities or to obtain informed consent from potential patients. EudraCT Number 2015-002530-50 CONFIDENTIAL [Rim4DMD] – Final Version 2.1_ February 19th, 2016 EspeRare_RIM_001 Rimeporide in DMD patients Page 2 of 85 Investigator Agreement Protocol Number: EspeRare_RIM_001 EudraCT Number: 2015-002530-50 Protocol version and date: 2.1._ February 19th 2016 Sponsor: EspeRare Foundation Study drug: Rimeporide. Study title: A phase Ib, open label study to evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of multiple ascending oral doses of rimeporide in patients with Duchenne Muscular Dystrophy. Acronym: Rim4DMD. Investigator endorsement: I, the undersigned, am responsible for the conduct of this study at this site and agree to conduct the study according to the protocol and any approved protocol amendments, study specific procedures, all applicable laws and regulatory authority requirements including but not limited to European directives, ICH Good Clinical Practice (GCP), the Ethical principles that have their origins in the Declaration of Helsinki and applicable privacy laws.
    [Show full text]
  • Recent Research Developments in Parkinson's Disease
    Page 12 to 30 Current Opinions in Neurological Science ISSN: 2575-5447 Review Article Volume 5 Issue 1 • 2020 Recent Research Developments in Parkinson’s Disease Alain L. Fymat Institute Professor, International Institute of Medicine & Science, California, U.S.A Received : February 09, 2020 Published : February 24, 2020 *Corresponding Author: Alain L. Fymat, Professor, International Institute of Medicine & Science, California, U.S.A Copyright © All rights are reserved by Alain L. Fymat. Abstract Important research developments have recently occurred in the understanding of Parkinson’s mechanisms and the symptomatic therapy of the disease. This article reviews such developments and their place in the disease’s therapeutic armamentarium. It also assesses their potential contribution(s) to our search for the root cause(s) of the disease. Improved symptomatic therapy has taken place for both motor and non-motor systems with the progressive development of several therapeutic drugs. This article also explores new research vistas including the role of gene therapy in the search for Parkinson’s disease-modifying therapy and neuroprotective treatments such as neural transplantation, stem cell transplantation, and transcranial magnetic stimulation. In this context, our two interacting brains (brain-in-the-skull, brain-in-the-gut) should underpin Braak’s hypothesis as to the origin of Parkinson’s. In the search for disease-modifying therapies, the article reviews the two therapeutic strategies currently followed, the correlation between a reduced occurrence or prevalence (or both) of PD and the consumption of compounds such as caffeine or nicotine. The three different principles of therapeutic action epidemiological findings and large clinical prospective trials reporting a are addressed: active and passive immunotherapy, modulation of alpha-synuclein aggregation, and enhancement of autophagy of alpha-synuclein.
    [Show full text]
  • Idebenone Protects Against Acute Murine Colitis Via Antioxidant and Anti-Inflammatory Mechanisms
    International Journal of Molecular Sciences Article Idebenone Protects against Acute Murine Colitis via Antioxidant and Anti-Inflammatory Mechanisms Sonia Shastri 1,*, Tanvi Shinde 1,2 , Sukhwinder Singh Sohal 1, Nuri Gueven 3 and Rajaraman Eri 1,* 1 Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston, Tasmania 7250, Australia; [email protected] (T.S.); [email protected] (S.S.S.) 2 Centre for Food Safety and Innovation, Tasmanian Institute of Agriculture, University of Tasmania, Launceston, Tasmania 7250, Australia 3 Pharmacy, School of Medicine, College of Health and Medicine, University of Tasmania, Hobart, Tasmania 7005, Australia; [email protected] * Correspondence: [email protected] (S.S.); [email protected] (R.E.); Tel.: +61-4-4992-4236 (S.S.); +61-3-6226-5017 (R.E.) Received: 3 December 2019; Accepted: 9 January 2020; Published: 12 January 2020 Abstract: Oxidative stress is a key player of the inflammatory cascade responsible for the initiation of ulcerative colitis (UC). Although the short chain quinone idebenone is considered a potent antioxidant and a mitochondrial electron donor, emerging evidence suggests that idebenone also displays anti-inflammatory activity. This study evaluated the impact of idebenone in the widely used dextran sodium sulphate (DSS)-induced mouse model of acute colitis. Acute colitis was induced in C57BL/6J mice via continuous exposure to 2.5% DSS over 7 days. Idebenone was co-administered orally at a dose of 200 mg/kg body weight. Idebenone significantly prevented body weight loss and improved the disease activity index (DAI), colon length, and histopathological score.
    [Show full text]
  • Table of Contents
    PI name: Carsten G. Bönnemann, MD Date: 01-Dec-2017 NIH Protocol number: 15-N-0018 NIH Version: 16 Santhera Protocol number: SNT-I-015 Santhera Version: 10 Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In Children and Adolescents with Assessment of Safety and Tolerability of Omigapil (CALLISTO) Clinical Research Protocol Abbreviated Title: CALLISTO NIH Protocol Number: 15-N-0018 Santhera Protocol Number: SNT-I-015 Date of This Submission/Version (see header) IND Number: 113,370 Eudract Number: 2012-002700-40 Compound: Omigapil Hydrogen Maleate CRADA 2012-0097 (expiration 2020) Confidential Property of Santhera Pharmaceuticals (Switzerland) Ltd. 1 PI name: Carsten G. Bönnemann, MD Date: 01-Dec-2017 NIH Protocol number: 15-N-0018 NIH Version: 16 Santhera Protocol number: SNT-I-015 Santhera Version: 10 Synopsis Study Title Congenital Muscular Dystrophy Ascending Multiple Dose Cohort Study anaLyzing Pharmacokinetics at three dose Levels In Children and Adolescents with Assessment of Safety and Tolerability of Omigapil Study Number SNT-I-015 Study Phase 1 Study Acronym CALLISTO Planned Study Duration 84 weeks (16 weeks recruitment, 68 weeks study conduct). The above duration is assuming cohorts are dosed in staggered parallel. Patient participation will be up to 28 weeks (up to 4 weeks screening, 4 weeks run-in, 12 weeks treatment and a follow-up visit 8 weeks post last dose taken) Investigational Product Omigapil oral solution (0.1 and 0.25 mg/ml in Humco® Cherry Syrup)
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • TREAT-NMD Newsletter No.34
    TREATTREAT --NMDNMD NeuromuscularNeuromuscular NetworkNetwork 30th May 2008 Newsletter No. 34 Welcome to the latest newsletter. This edition features Newsletter contents a report from the EuroBioBank Annual Meeting and a call for Eastern European applicants for 6 TREAT-NMD Fellowships to attend the WMS Teaching Course. About this newsletter ……………………………. 1 The TREAT-NMD web site is currently migrating to a Working with us…………………………………… 1 new format and the web pages will be updated on an TREAT-NMD news and reports……………….. 2 ongoing basis over the coming days. Please bear with us Other news………………………………………….. 5 during this transitional period. Thank you. Resources...………….....………………………….. 6 Please forward any items that you would like to be Meetings and workshops…….……………....... 7 included in future editions to [email protected] . Partner section …………..…….……………....... 7 Best wishes, The TREAT-NMD coordination team ***IMPORTANT MESSAGE TO ALL OUR READERS*** We’d like to remind readers that receiving this newsletter does not automatically make you a member of TREAT-NMD. If you have not completed our membership application form, you are not a member! If you are interested in developing closer links with us, we encourage you to read our Members’ Charter and complete the membership application form. These documents can be found on our web site at the address below. Become a Member of TREAT-NMD If you are interested in becoming a member of the TREAT-NMD Network please visit our web site to download our membership charter. An application form is also available for download. The web link to our Members’ sec- tion is: http://www.treat-nmd.eu/research/get-involved/ .
    [Show full text]
  • The Clinical Trial Landscape in Amyotrophic Lateral Sclerosis—Past, Present, and Future
    Received: 16 September 2019 | Revised: 8 December 2019 | Accepted: 27 January 2020 DOI: 10.1002/med.21661 REVIEW ARTICLE The clinical trial landscape in amyotrophic lateral sclerosis—Past, present, and future Heike J. Wobst1 | Korrie L. Mack2,3 | Dean G. Brown4 | Nicholas J. Brandon1 | James Shorter2 1Neuroscience, BioPharmaceuticals R&D, AstraZeneca, Boston, Massachusetts Abstract 2 Department of Biochemistry and Biophysics, Amyotrophic lateral sclerosis (ALS) is a fatal neurodegen- Perelman School of Medicine, University of erative disease marked by progressive loss of muscle func- Pennsylvania, Philadelphia, Pennsylvania ‐ 3Merck & Co, Inc, Kenilworth, New Jersey tion. It is the most common adult onset form of motor 4Hit Discovery, Discovery Sciences, neuron disease, affecting about 16 000 people in the United BioPharmaceuticals R&D, AstraZeneca, Boston, States alone. The average survival is about 3 years. Only two Massachusetts interventional drugs, the antiglutamatergic small‐molecule Correspondence riluzole and the more recent antioxidant edaravone, have Heike J. Wobst, Jnana Therapeutics, Northern been approved for the treatment of ALS to date. Therapeutic Avenue, Boston, MA 02210. Email: [email protected] strategies under investigation in clinical trials cover a range of different modalities and targets, and more than 70 dif- James Shorter, Department of Biochemistry and Biophysics, Perelman School of Medicine, ferent drugs have been tested in the clinic to date. Here, we University of Pennsylvania, Philadelphia, PA summarize and classify interventional therapeutic strategies 19104. Email: [email protected] based on their molecular targets and phenotypic effects. We also discuss possible reasons for the failure of clinical trials in Present address Heike J. Wobst, Dean G.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2016/0354335 A1 COHEN Et Al
    US 20160354335A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2016/0354335 A1 COHEN et al. (43) Pub. Date: Dec. 8, 2016 (54) COMBINATION OF BACLOFEN, Publication Classification ACAMPROSATE AND MEDIUM CHAN TRGLYCERDES FOR THE TREATMENT (51) Int. Cl. OF NEUROLOGICAL DISORDERS A6II 3L/23 (2006.01) A6II 3/85 (2006.01) (71) Applicant: PHARNEXT, Issy Les Moulineaux A636/85 (2006.01) (FR) A 6LX 3L/97 (2006.01) (52) U.S. Cl. (72) Inventors: DANIEL COHEN, SAINT CLOUD CPC ............. A6 IK3I/23 (2013.01); A61K 31/197 (FR), ILYA CHUMAKOV, (2013.01); A61K 31/185 (2013.01); A61 K VAUX-LE-PENIL (FR), SERGUEI 36/185 (2013.01) NABIROCHKIN, CHATENAY-MALABRY (FR): (57) ABSTRACT RODOLPHE HAJJ, SAINT The present invention relates to combinations and methods GERMAIN EN LAYE (FR) for the treatment of neurological disorders related Amyloid (21) Appl. No.: 15/117,774 beta toxicity and/or neuronal death and/or glucose impaired neuronal metabolism. More specifically, the present inven (22) PCT Fed: Feb. 10, 2015 tion relates to novel combinatorial therapies of Alzheimer's disease, Alzheimer's disease related disorders, frontotempo (86) PCT No.: PCT/EP2015/052694 ral dementia, Parkinson's disease, Lewy body dementia, Huntington's disease, peripheral neuropathies, alcoholism S 371 (c)(1), or alcohol withdrawal, neurological manifestations of drug (2) Date: Aug. 10, 2016 abuse or drug abuse withdrawal, amyotrophic lateral scle rosis, multiple Sclerosis, spinal cord injury, epilepsy, trau Related U.S. Application Data matic brain injury or brain ischemic events based on (60) Provisional application No. 61/938,340, filed on Feb.
    [Show full text]
  • 2016 Medicines in Development for Rare Diseases a LIST of ORPHAN DRUGS in the PIPELINE
    2016 Medicines in Development for Rare Diseases A LIST OF ORPHAN DRUGS IN THE PIPELINE Autoimmune Diseases Product Name Sponsor Official FDA Designation* Development Status Actemra® Genentech treatment of systemic sclerosis Phase III tocilizumab South San Francisco, CA www.gene.com Adempas® Bayer HealthCare Pharmaceuticals treatment of systemic sclerosis Phase II riociguat Whippany, NJ www.pharma.bayer.com ARA 290 Araim Pharmaceuticals treatment of neuropathic pain in patients Phase II Tarrytown, NY with sarcoidosis www.ariampharma.com ARG201 arGentis Pharmaceuticals treatment of diffuse systemic sclerosis Phase II (type 1 native bovine skin Collierville, TN www.argentisrx.com collagen) BYM338 Novartis Pharmaceuticals treatment of inclusion body myositis Phase III (bimagrumab) East Hanover, NJ www.novartis.com CCX168 ChemoCentryx treatment of anti-neutrophil cytoplasmic Phase II (5a receptor antagonist) Mountain View, CA auto-antibodies associated vasculitides www.chemocentryx.com (granulomatosis with polyangitis or Wegener's granulomatosis), microscopic polyangitis, and Churg-Strauss syndrome * This designation is issued by the FDA's Office of Orphan Products Development while the drug is still in development. The designation makes the sponsor of the drug eligible for entitlements under the Orphan Drug Act of 1983. The entitlements include seven years of marketing exclusivity following FDA approval of the drug for the designated use. Medicines in Development: Rare Diseases | 2016 1 Autoimmune Diseases Product Name Sponsor Official FDA
    [Show full text]
  • Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Frontiers - Publisher Connector REVIEW published: 18 October 2016 doi: 10.3389/fphar.2016.00340 Inhibitors of MAO-A and MAO-B in Psychiatry and Neurology John P. M. Finberg 1* and Jose M. Rabey 2 1 Rappaport Faculty of Medicine, Technion, Israel Institute of Technology, Haifa, Israel, 2 Assaf Harofe Medical Center, Affiliated to Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel Inhibitors of MAO-A and MAO-B are in clinical use for the treatment of psychiatric and neurological disorders respectively. Elucidation of the molecular structure of the active sites of the enzymes has enabled a precise determination of the way in which substrates and inhibitor molecules are metabolized, or inhibit metabolism of substrates, respectively. Despite the knowledge of the strong antidepressant efficacy of irreversible MAO inhibitors, their clinical use has been limited by their side effect of potentiation of the cardiovascular effects of dietary amines (“cheese effect”). A number of reversible MAO-A inhibitors which are devoid of cheese effect have been described in the literature, but only one, moclobemide, is currently in clinical use. The irreversible inhibitors of MAO-B, selegiline and rasagiline, are used clinically in treatment of Parkinson’s disease, and a recently introduced reversible MAO-B inhibitor, safinamide, has also been found efficacious. Modification of the pharmacokinetic characteristics of selegiline by transdermal administration has led to the development of a new drug form for treatment of depression. The clinical potential of MAO inhibitors together with detailed knowledge Edited by: of the enzyme’s binding site structure should lead to future developments with these Rona R.
    [Show full text]