DOCSLIB.ORG

The Neurochemical Consequences of Aromatic L-Amino Acid Decarboxylase Deficiency

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
The Neurochemical Consequences of Aromatic L-Amino Acid Decarboxylase Deficiency The neurochemical consequences of aromatic L-amino acid decarboxylase deficiency Submitted By: George Francis Gray Allen Department of Molecular Neuroscience UCL Institute of Neurology Queen Square, London Submitted November 2010 Funded by the AADC Research Trust, UK Thesis submitted for the degree of Doctor of Philosophy, University College London (UCL) 1 I, George Allen confirm that the work presented in this thesis is my own. Where information has been derived from other sources, I confirm that this has been indicated in the thesis. Signed………………………………………………….Date…………………………… 2 Abstract Aromatic L-amino acid decarboxylase (AADC) catalyses the conversion of 5- hydroxytryptophan (5-HTP) and L-3,4-dihydroxyphenylalanine (L-dopa) to the neurotransmitters serotonin and dopamine respectively. The inherited disorder AADC deficiency leads to a severe deficit of serotonin and dopamine as well as an accumulation of 5-HTP and L-dopa. This thesis investigated the potential role of 5- HTP/L-dopa accumulation in the pathogenesis of AADC deficiency. Treatment of human neuroblastoma cells with L-dopa or dopamine was found to increase intracellular levels of the antioxidant reduced glutathione (GSH). However inhibiting AADC prevented the GSH increase induced by L-dopa. Furthermore dopamine but not L-dopa, increased GSH release from human astrocytoma cells, which do not express AADC activity. GSH release is the first stage of GSH trafficking from astrocytes to neurons. This data indicates dopamine may play a role in controlling brain GSH levels and consequently antioxidant status. The inability of L-dopa to influence GSH concentrations in the absence of AADC or with AADC inhibited indicates GSH trafficking/metabolism may be compromised in AADC deficiency. 5-HTP was demonstrated to potentially be mildly toxic to human neuroblastoma cells but not astrocytoma cells; however the concentrations required for this response are likely to be higher than pathophysiological levels in AADC deficiency. These results indicate the need for investigations addressing the effects of chronic 5-HTP exposure as only acute effects were investigated in the current study. This thesis also investigated the effect of altered availability of the AADC coenzyme pyridoxal 5‟-phosphate (PLP) on AADC activity, protein and expression. In two patients with inherited disorders of PLP metabolism reductions in plasma AADC activity were observed. Furthermore PLP- deficient human neuroblastoma cells were found to exhibit reduced levels of AADC activity and protein but not altered expression. These findings suggest maintaining adequate PLP availability may be important for optimal treatment of AADC deficiency. 3 Table of Contents THE NEUROCHEMICAL CONSEQUENCES OF AROMATIC L-AMINO ACID DECARBOXYLASE DEFICIENCY ............................................................................ 1 ABSTRACT ..................................................................................................................... 3 TABLE OF CONTENTS ................................................................................................ 4 TABLE OF FIGURES .................................................................................................. 13 LIST OF TABLES ........................................................................................................ 17 LIST OF ABBREVIATIONS ...................................................................................... 18 ACKNOWLEDGEMENTS .......................................................................................... 21 CHAPTER 1 .................................................................................................................. 23 1 INTRODUCTION ................................................................................................. 23 1.1 Monoamine Neurotransmitters ..................................................................... 24 1.1.1 Serotonin ................................................................................................... 24 1.1.2 Dopamine .................................................................................................. 25 1.2 Monoamine Metabolism ................................................................................ 25 1.2.1 Indoleamine Metabolism ........................................................................... 25 1.2.2 Catecholamine Metabolism ....................................................................... 26 1.3 Monoamine Neurotransmission .................................................................... 26 1.3.1 Vesicular Uptake ....................................................................................... 26 1.3.2 Release ...................................................................................................... 27 1.3.3 Receptors ................................................................................................... 29 1.3.4 Re-uptake .................................................................................................. 29 1.3.5 Degradation ............................................................................................... 31 4 1.4 Disorders of Aromatic Amino Acid Metabolism ......................................... 33 1.4.1 Hyperphenyalaninemia ............................................................................. 33 1.4.2 Monoamine Neurotransmitter Deficiency................................................. 33 1.4.3 Treatment .................................................................................................. 34 1.4.4 Related Conditions .................................................................................... 35 1.5 AADC deficiency ............................................................................................ 38 1.5.1 Clinical Picture .......................................................................................... 38 1.5.2 Diagnosis ................................................................................................... 39 1.5.3 Inheritance ................................................................................................. 39 1.5.4 Treatment .................................................................................................. 40 1.6 Aromatic L-amino acid decarboxylase ......................................................... 42 1.6.1 Structure and Reaction Mechanism .......................................................... 42 1.6.2 Alternative Reactions ................................................................................ 44 1.6.3 Alternative Substrates ............................................................................... 44 1.6.4 AADC Splicing ......................................................................................... 45 1.6.5 AADC Localisation ................................................................................... 46 1.6.6 AADC Regulation ..................................................................................... 48 1.7 AADC Deficiency Pathogenesis ..................................................................... 50 1.7.1 Pathogenic Mechanism ............................................................................. 50 1.7.2 Precursor Accumulation ............................................................................ 51 1.7.3 Alternative metabolic pathways for 5-HTP .............................................. 52 1.7.4 Alternative Metabolic Pathways for L-dopa ............................................. 54 1.7.5 Oxidative Stress ........................................................................................ 56 5 1.7.6 Glutathione ................................................................................................ 58 1.7.7 Mitochondrial Respiratory Chain .............................................................. 59 1.8 Hypotheses ...................................................................................................... 62 1.9 Aims ................................................................................................................. 62 CHAPTER 2 .................................................................................................................. 66 2 MATERIAL AND METHODS ............................................................................ 66 2.1 Materials .......................................................................................................... 67 2.2 High performance liquid chromatography .................................................. 69 2.2.1 Catecholamine HPLC................................................................................ 69 2.2.2 Equipment ................................................................................................. 69 2.2.3 Measurement of Indoleamines by HPLC .................................................. 70 2.2.4 GSH HPLC ............................................................................................... 74 2.2.5 Measurement of PLP by HPLC ................................................................ 75 Tissue Culture ........................................................................................................... 76 2.2.6 SH-SY5Y neuroblastoma cell culture ....................................................... 76 2.2.7 1321N1 astrocytoma cell culture .............................................................. 81 2.2.8 Cell sample collection ..............................................................................
Load more

Recommended publications
  • Summary of Product Characteristics
    Package leaflet: Information for the patient Fluoxetine 20mg Capsules, hard fluoxetine Read all of this leaflet carefully before you start taking this medicine because it contains important information for you. • Keep this leaflet. You may need to read it again. • If you have further questions, ask your doctor or pharmacist. • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours. •If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. What is in this leaflet 1. What Fluoxetine is and what it is used for 2. What you need to know before you take Fluoxetine 3. How to take Fluoxetine 4. Possible side effects 5. How to store Fluoxetine 6. Contents of the pack and other information 1. What Fluoxetine is and what it is used for The name of your medicine is Fluoxetine 20mg Capsules, hard. It contains the active substance fluoxetine. Fluoxetine belongs to a group of medicines called selective serotonin reuptake inhibitor (SSRI) antidepressants. Fluoxetine can be given to treat the following conditions: Adults: • Major depressive episodes • The symptoms of a condition called obsessive-compulsive disorder (OCD). • The eating disorder bulimia nervosa. This medicine is used alongside psychotherapy for the reduction of binge-eating and purging. Children and adolescents aged 8 years and above: • Moderate to severe major depressive disorder, if the depression does not respond to psychological therapy after 4-6 sessions. Fluoxetine should be offered to a child or young person with moderate to severe major depressive disorder only in combination with psychological therapy.
    [Show full text]
  • Monoamine Oxydases Et Athérosclérose : Signalisation Mitogène Et Études in Vivo
    UNIVERSITE TOULOUSE III - PAUL SABATIER Sciences THESE Pour obtenir le grade de DOCTEUR DE L’UNIVERSITE TOULOUSE III Discipline : Innovation Pharmacologique Présentée et soutenue par : Christelle Coatrieux le 08 octobre 2007 Monoamine oxydases et athérosclérose : signalisation mitogène et études in vivo Jury Monsieur Luc Rochette Rapporteur Professeur, Université de Bourgogne, Dijon Monsieur Ramaroson Andriantsitohaina Rapporteur Directeur de Recherche, INSERM, Angers Monsieur Philippe Valet Président Professeur, Université Paul Sabatier, Toulouse III Madame Nathalie Augé Examinateur Chargé de Recherche, INSERM Monsieur Angelo Parini Directeur de Thèse Professeur, Université Paul Sabatier, Toulouse III INSERM, U858, équipes 6/10, Institut Louis Bugnard, CHU Rangueil, Toulouse Résumé Les espèces réactives de l’oxygène (EROs) sont impliquées dans l’activation de nombreuses voies de signalisation cellulaires, conduisant à différentes réponses comme la prolifération. Les EROs, à cause du stress oxydant qu’elles génèrent, sont impliquées dans de nombreuses pathologies, notamment l’athérosclérose. Les monoamine oxydases (MAOs) sont deux flavoenzymes responsables de la dégradation des catécholamines et des amines biogènes comme la sérotonine ; elles sont une source importante d’EROs. Il a été montré qu’elles peuvent être impliquées dans la prolifération cellulaire ou l’apoptose du fait du stress oxydant qu’elles génèrent. Ce travail de thèse a montré que la MAO-A, en dégradant son substrat (sérotonine ou tyramine), active une voie de signalisation mitogène particulière : la voie métalloprotéase- 2/sphingolipides (MMP2/sphingolipides), et contribue à la prolifération de cellules musculaire lisses vasculaires induite par ces monoamines. De plus, une étude complémentaire a confirmé l’importance des EROs comme stimulus mitogène (utilisation de peroxyde d’hydrogène exogène), et a décrit plus spécifiquement les étapes en amont de l’activation de MMP2, ainsi que l’activation par la MMP2 de la sphingomyélinase neutre (première enzyme de la cascade des sphingolipides).
    [Show full text]
  • Remodeling Adipose Tissue Through in Silico Modulation of Fat Storage For
    Chénard et al. BMC Systems Biology (2017) 11:60 DOI 10.1186/s12918-017-0438-9 RESEARCHARTICLE Open Access Remodeling adipose tissue through in silico modulation of fat storage for the prevention of type 2 diabetes Thierry Chénard2, Frédéric Guénard3, Marie-Claude Vohl3,4, André Carpentier5, André Tchernof4,6 and Rafael J. Najmanovich1* Abstract Background: Type 2 diabetes is one of the leading non-infectious diseases worldwide and closely relates to excess adipose tissue accumulation as seen in obesity. Specifically, hypertrophic expansion of adipose tissues is related to increased cardiometabolic risk leading to type 2 diabetes. Studying mechanisms underlying adipocyte hypertrophy could lead to the identification of potential targets for the treatment of these conditions. Results: We present iTC1390adip, a highly curated metabolic network of the human adipocyte presenting various improvements over the previously published iAdipocytes1809. iTC1390adip contains 1390 genes, 4519 reactions and 3664 metabolites. We validated the network obtaining 92.6% accuracy by comparing experimental gene essentiality in various cell lines to our predictions of biomass production. Using flux balance analysis under various test conditions, we predict the effect of gene deletion on both lipid droplet and biomass production, resulting in the identification of 27 genes that could reduce adipocyte hypertrophy. We also used expression data from visceral and subcutaneous adipose tissues to compare the effect of single gene deletions between adipocytes from each
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas Et Al
    US 20130253 056A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2013/0253056A1 Nemas et al. (43) Pub. Date: Sep. 26, 2013 (54) CONTINUOUS ADMINISTRATION OF (60) Provisional application No. 61/179,511, filed on May LEVODOPA AND/OR DOPA 19, 2009. DECARBOXYLASE INHIBITORS AND COMPOSITIONS FOR SAME Publication Classification (71) Applicant: NEURODERM, LTD., Ness-Ziona (IL) (51) Int. Cl. A63L/216 (2006.01) (72) Inventors: Mara Nemas, Gedera (IL); Oron (52) U.S. Cl. Yacoby-Zeevi, Moshav Bitsaron (IL) CPC .................................... A6 IK3I/216 (2013.01) USPC .......................................................... 514/538 (73) Assignee: Neuroderm, Ltd., Ness-Ziona (IL) (57) ABSTRACT (21) Appl. No.: 13/796,232 Disclosed herein are for example, liquid aqueous composi (22) Filed: Mar 12, 2013 tions that include for example an ester or salt of levodopa, or an ester or salt of carbidopa, and methods for treating neuro Related U.S. Application Data logical or movement diseases or disorders such as restless leg (63) Continuation-in-part of application No. 12/961,534, syndrome, Parkinson's disease, secondary parkinsonism, filed on Dec. 7, 2010, which is a continuation of appli Huntington's disease, Parkinson's like syndrome, PSP. MSA, cation No. 12/836,130, filed on Jul. 14, 2010, now Pat. ALS, Shy-Drager syndrome, dystonia, and conditions result No. 7,863.336, which is a continuation of application ing from brain injury including carbon monoxide or manga No. 12/781,357, filed on May 17, 2010, now Pat. No. nese intoxication, using Substantially continuous administra 8,193,243. tion of levodopa and/or carbidopa or ester and/or salt thereof.
    [Show full text]
  • Screening of a Composite Library of Clinically Used Drugs and Well
    HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Pharmacol Manuscript Author Res. Author Manuscript Author manuscript; available in PMC 2017 November 01. Published in final edited form as: Pharmacol Res. 2016 November ; 113(Pt A): 18–37. doi:10.1016/j.phrs.2016.08.016. Screening of a composite library of clinically used drugs and well-characterized pharmacological compounds for cystathionine β-synthase inhibition identifies benserazide as a drug potentially suitable for repurposing for the experimental therapy of colon cancer Nadiya Druzhynaa, Bartosz Szczesnya, Gabor Olaha, Katalin Módisa,b, Antonia Asimakopoulouc,d, Athanasia Pavlidoue, Petra Szoleczkya, Domokos Geröa, Kazunori Yanagia, Gabor Töröa, Isabel López-Garcíaa, Vassilios Myrianthopoulose, Emmanuel Mikrose, John R. Zatarainb, Celia Chaob, Andreas Papapetropoulosd,e, Mark R. Hellmichb,f, and Csaba Szaboa,f,* aDepartment of Anesthesiology, The University of Texas Medical Branch, Galveston, TX, USA bDepartment of Surgery, The University of Texas Medical Branch, Galveston, TX, USA cLaboratory of Molecular Pharmacology, Department of Pharmacy, University of Patras, Greece dCenter of Clinical, Experimental Surgery & Translational Research, Biomedical Research Foundation of the Academy of Athens, Greece eNational and Kapodistrian University of Athens, School of Pharmacy, Athens, Greece fCBS Therapeutics Inc., Galveston, TX, USA Abstract Cystathionine-β-synthase (CBS) has been recently identified as a drug target for several forms of cancer. Currently no
    [Show full text]
  • METABOLIC EVOLUTION in GALDIERIA SULPHURARIA By
    METABOLIC EVOLUTION IN GALDIERIA SULPHURARIA By CHAD M. TERNES Bachelor of Science in Botany Oklahoma State University Stillwater, Oklahoma 2009 Submitted to the Faculty of the Graduate College of the Oklahoma State University in partial fulfillment of the requirements for the Degree of DOCTOR OF PHILOSOPHY May, 2015 METABOLIC EVOLUTION IN GALDIERIA SUPHURARIA Dissertation Approved: Dr. Gerald Schoenknecht Dissertation Adviser Dr. David Meinke Dr. Andrew Doust Dr. Patricia Canaan ii Name: CHAD M. TERNES Date of Degree: MAY, 2015 Title of Study: METABOLIC EVOLUTION IN GALDIERIA SULPHURARIA Major Field: PLANT SCIENCE Abstract: The thermoacidophilic, unicellular, red alga Galdieria sulphuraria possesses characteristics, including salt and heavy metal tolerance, unsurpassed by any other alga. Like most plastid bearing eukaryotes, G. sulphuraria can grow photoautotrophically. Additionally, it can also grow solely as a heterotroph, which results in the cessation of photosynthetic pigment biosynthesis. The ability to grow heterotrophically is likely correlated with G. sulphuraria ’s broad capacity for carbon metabolism, which rivals that of fungi. Annotation of the metabolic pathways encoded by the genome of G. sulphuraria revealed several pathways that are uncharacteristic for plants and algae, even red algae. Phylogenetic analyses of the enzymes underlying the metabolic pathways suggest multiple instances of horizontal gene transfer, in addition to endosymbiotic gene transfer and conservation through ancestry. Although some metabolic pathways as a whole appear to be retained through ancestry, genes encoding individual enzymes within a pathway were substituted by genes that were acquired horizontally from other domains of life. Thus, metabolic pathways in G. sulphuraria appear to be composed of a ‘metabolic patchwork’, underscored by a mosaic of genes resulting from multiple evolutionary processes.
    [Show full text]
  • Gait Analysis in Advanced Parkinson's Disease – Effect of Levodopa And
    ORIGINAL ARTICLE Gait Analysis in Advanced Parkinson’s Disease – Effect of Levodopa and Tolcapone Din-E Shan, Shwn-Jen Lee, Ling-Yi Chao, and Shyh-Ing Yeh ABSTRACT: Objective: To determine the therapeutic effect of levodopa/benserazide and tolcapone on gait in patients with advanced Parkinson’s disease. Methods: Instrumental gait analysis was performed in 38 out of 40 patients with wearing-off phenomenon during a randomized, double-blind, placebo- controlled trial of tolcapone. R e s u l t s : Gait analysis disclosed a significant improvement by levodopa/benserazide in walking speed, stride length and the range of motion of hip, knee and ankle joints. At the end of the study, both the UPDRS motor scores during off-period and the percentage of off time improved significantly using tolcapone. However, gait analysis could not confirm this improvement. With respect to levodopa/benserazide effect, the reduction in rigidity correlated with improved angular excursion of the ankle, whereas the decreased bradykinesia correlated with improved stride length and angular excursion of the hip and knee joints. Conclusion: The results of our gait analysis confirmed that in parkinsonian patients with fluctuating motor symptoms levodopa/benserazide, but not tolcapone, produced a substantial improvement. RÉSUMÉ: Analyse de la démarche chez les patients en phase avancée de la maladie de Parkinson – Effet de la lévodopa et du tolcapone. Objectif: Le but de cette étude était de déterminer l’effet thérapeutique de la lévodopa/bensérazide et du tolcapone sur la démarche, chez les patients en phase avancée de la maladie de Parkinson. Méthodes: Une analyse instrumentale de la démarche a été réalisée chez 38 de 40 patients ayant un phénomène de détérioration de fin de dose pendant un essai randomisé, en double insu, contrôlé par placebo, du tolcapone.
    [Show full text]
  • Rational Design of Resveratrol O-Methyltransferase for the Production of Pinostilbene
    International Journal of Molecular Sciences Article Rational Design of Resveratrol O-methyltransferase for the Production of Pinostilbene Daniela P. Herrera 1 , Andrea M. Chánique 1,2 , Ascensión Martínez-Márquez 3, Roque Bru-Martínez 3 , Robert Kourist 2 , Loreto P. Parra 4,* and Andreas Schüller 4,5,* 1 Department of Chemical and Bioprocesses Engineering, School of Engineering, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago 7820244, Chile; [email protected] (D.P.H.); [email protected] (A.M.C.) 2 Institute of Molecular Biotechnology, Graz University of Technology, Petersgasse 14, 8010 Graz, Austria; [email protected] 3 Department of Agrochemistry and Biochemistry, Faculty of Science and Multidisciplinary Institute for Environmental Studies “Ramon Margalef”, University of Alicante, 03690 Alicante, Spain; [email protected] (A.M.-M.); [email protected] (R.B.-M.) 4 Institute for Biological and Medical Engineering, Schools of Engineering, Medicine and Biological Sciences, Pontificia Universidad Católica de Chile, Vicuña Mackenna 4860, Santiago 7820244, Chile 5 Department of Molecular Genetics and Microbiology, School of Biological Sciences, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O’Higgins 340, Santiago 8320000, Chile * Correspondence: [email protected] (L.P.P.); [email protected] (A.S.) Abstract: Pinostilbene is a monomethyl ether analog of the well-known nutraceutical resveratrol. Both compounds have health-promoting properties, but the latter undergoes rapid metabolization and has low bioavailability. O-methylation improves the stability and bioavailability of resveratrol. In plants, these reactions are performed by O-methyltransferases (OMTs). Few efficient OMTs that Citation: Herrera, D.P.; Chánique, monomethylate resveratrol to yield pinostilbene have been described so far.
    [Show full text]
  • Table 2. Significant
    Table 2. Significant (Q < 0.05 and |d | > 0.5) transcripts from the meta-analysis Gene Chr Mb Gene Name Affy ProbeSet cDNA_IDs d HAP/LAP d HAP/LAP d d IS Average d Ztest P values Q-value Symbol ID (study #5) 1 2 STS B2m 2 122 beta-2 microglobulin 1452428_a_at AI848245 1.75334941 4 3.2 4 3.2316485 1.07398E-09 5.69E-08 Man2b1 8 84.4 mannosidase 2, alpha B1 1416340_a_at H4049B01 3.75722111 3.87309653 2.1 1.6 2.84852656 5.32443E-07 1.58E-05 1110032A03Rik 9 50.9 RIKEN cDNA 1110032A03 gene 1417211_a_at H4035E05 4 1.66015788 4 1.7 2.82772795 2.94266E-05 0.000527 NA 9 48.5 --- 1456111_at 3.43701477 1.85785922 4 2 2.8237185 9.97969E-08 3.48E-06 Scn4b 9 45.3 Sodium channel, type IV, beta 1434008_at AI844796 3.79536664 1.63774235 3.3 2.3 2.75319499 1.48057E-08 6.21E-07 polypeptide Gadd45gip1 8 84.1 RIKEN cDNA 2310040G17 gene 1417619_at 4 3.38875643 1.4 2 2.69163229 8.84279E-06 0.0001904 BC056474 15 12.1 Mus musculus cDNA clone 1424117_at H3030A06 3.95752801 2.42838452 1.9 2.2 2.62132809 1.3344E-08 5.66E-07 MGC:67360 IMAGE:6823629, complete cds NA 4 153 guanine nucleotide binding protein, 1454696_at -3.46081884 -4 -1.3 -1.6 -2.6026947 8.58458E-05 0.0012617 beta 1 Gnb1 4 153 guanine nucleotide binding protein, 1417432_a_at H3094D02 -3.13334396 -4 -1.6 -1.7 -2.5946297 1.04542E-05 0.0002202 beta 1 Gadd45gip1 8 84.1 RAD23a homolog (S.
    [Show full text]
  • Targeting the Tryptophan Hydroxylase 2 Gene for Functional Analysis in Mice and Serotonergic Differentiation of Embryonic Stem Cells
    TARGETING THE TRYPTOPHAN HYDROXYLASE 2 GENE FOR FUNCTIONAL ANALYSIS IN MICE AND SEROTONERGIC DIFFERENTIATION OF EMBRYONIC STEM CELLS Inaugural-Dissertation to obtain the academic degree Doctor rerum naturalium (Dr. rer. nat.) submitted to the Department of Biology, Chemistry and Pharmacy of Freie Universität Berlin by Dana Kikic, M.Sc. in Molecular biology and Physiology from Nis June, 2009 The doctorate studies were performed in the research group of Prof. Michael Bader Molecular Biology of Peptide Hormones at Max-Delbrück-Center for Molecular Medicine in Berlin, Buch Mai 2005 - September 2008. 1st Reviewer: Prof. Michael Bader 2nd Reviewer: Prof. Udo Heinemann date of defence: 13. August 2009 ACKNOWLEDGMENTS Herewith, I would like to acknowledge the persons who made this thesis possible and without whom my initiation in the world of basic science research would not have the spin it has now, neither would my scientific illiteracy get the chance to eradicate. I am expressing my very personal gratitude and recognition to: Prof. Michael Bader, for an inexhaustible guidance in all the matters arising during the course of scientific work, for an instinct in defining and following the intellectual challenge and for letting me following my own, for necessary financial support, for defining the borders of reasonable and unreasonable, for an invaluable time and patience, and an amazing efficiency in supporting, motivating, reading, correcting and shaping my scientific language during the last four years. Prof. Harald Saumweber and Prof. Udo Heinemann, for taking over the academic supervision of the thesis, and for breathing in it a life outside the laboratory walls and their personal signature.
    [Show full text]
  • 210913Orig1s000 CLINICAL PHARMACOLOGY REVIEW(S)
    CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 210913Orig1s000 CLINICAL PHARMACOLOGY REVIEW(S) Office of Clinical Pharmacology Review NDA Number 212489 Link to EDR \\cdsesub1\evsprod\nda212489 Submission Date 04/26/2019 Submission Type 505(b)(1) NME NDA (Standard Review) Brand Name ONGENTYS Generic Name opicapone Dosage Form/Strength and Capsules: 25 mg and 50 mg Dosing Regimen 50 mg administered orally once daily at bedtime Route of Administration Oral Proposed Indication Adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s Disease experiencing “OFF” episodes Applicant Neurocrine Biosciences, Inc. (NBI) Associated IND IND (b) (4) OCP Review Team Mariam Ahmed, Ph.D. Atul Bhattaram, Ph.D. Sreedharan Sabarinath, Ph.D. OCP Final Signatory Mehul Mehta, Ph.D. 1 Reference ID: 4585182 Table of Contents 1. EXECUTIVE SUMMARY .............................................................................................................................................................. 4 1.1 Recommendations ..................................................................................................................................................... 4 1.2 Post-Marketing Requirements and Commitments ......................................................................................... 6 2. SUMMARY OF CLINICAL PHARMACOLOGY ASSESSMENT ............................................................................................. 6 2.1 Pharmacology and Clinical Pharmacokinetics ..................................................................................................
    [Show full text]
  • Azilect, INN-Rasagiline
    SCIENTIFIC DISCUSSION 1. Introduction AZILECT is indicated for the treatment of idiopathic Parkinson’s disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations. Rasagiline is administered orally, at a dose of 1 mg once daily with or without levodopa. Parkinson’s disease is a common neurodegenerative disorder typified by loss of dopaminergic neurones from the basal ganglia, and by a characteristic clinical syndrome with cardinal physical signs of resting tremor, bradikinesia and rigidity. The main treatment aims at alleviating symptoms through a balance of anti-cholinergic and dopaminergic drugs. Parkinson’s disease (PD) treatment is complex due to the progressive nature of the disease, and the array of motor and non-motor features combined with early and late side effects associated with therapeutic interventions. Rasagiline is a chemical inhibitor of the enzyme monoamine oxidase (MAO) type B which has a major role in the inactivation of biogenic and diet-derived amines in the central nervous system. MAO has two isozymes (types A and B) and type B is responsible for metabolising dopamine in the central nervous system; as dopamine deficiency is the main contributing factor to the clinical manifestations of Parkinson’s disease, inhibition of MAO-B should tend to restore dopamine levels towards normal values and this improve the condition. Rasagiline was developed for the symptomatic treatment of Parkinson’s disease both as monotherapy in early disease and as adjunct therapy to levodopa + aminoacids decarboxylase inhibitor (LD + ADI) in patients with motor fluctuations. 2. Quality Introduction Drug Substance • Composition AZILECT contains rasagiline mesylate as the active substance.
    [Show full text]