DOCSLIB.ORG

Beta Adrenoceptor Response in Asthma Judith Kathleen1greenacre

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Beta Adrenoceptor Response in Asthma Judith Kathleen1greenacre BETA ADRENOCEPTOR RESPONSE IN ASTHMA A Thesis submitted by JUDITH KATHLEEN1GREENACRE for The degree of Doctor of Philosophy in the University of London Department of Clinical Pharmacology Royal Postgraduate Medical School Hammersmith Hospital London W12 OHS 1978 :i : ABSTRACT An inherent defect of beta adrenergic receptor function has been suggested as the underlying mechanism in bronchial asthma. Many investigators have presented data to support this hypothesis but few have considered the possibility that treatment with beta adrenergic stimulants might adversely affect beta adrenoceptor function. The experiments described in this thesis were designed to examine this possibility. Because human lung tissue is not readily available, the peripheral blood lymphocyte was studied. Beta adrenoceptor function was evaluated by measuring cyclic 3' 5' adenosine monophosphate (cyclic AMP) formation in -8 4 response to increasing concentrations of isoprenaline (10 to 10 moles. -1 litre ). Cells from asthmatics on beta adrenergic bronchodilators in large doses had a significantly reduced cyclic AMP response compared to lymphocytes from normals or from asthmatics on non-adrenergic medication (p< 0.001). Cells from normal subjects given salbutamol orally (12-16 mg/day) or by inhalation in excessive doses (3000pg/day) also showed depressed beta adrenergic responsiveness (p< 0.05 and p<0.01). Patients with phaeochromocytomata and high levels of circulating endogenous catecholamines had reduced lymphocyte cyclic AMP formation compared to normal subjects (p<0.01). A dose-related desensitization of beta adrenoceptor function was produced in vitro by incubating lymphocytes 8 -6 1 from normal subjects with isoprenaline (10 to 10 moles. litre ) for 24 hours (p< 0.05). Drug treatment with beta adrenergic stimulants depresses beta adrenoceptor function and there is little evidence that asthmatics have an inherent defect in this mechanism. ACKNOWLEDGEMENTS I would like to thank especially Dr. M.E. Conolly, my close associate and mentor in the work reported in this thesis. I am also grateful to Professor C.T. Dollery for invaluable advice on both the work and on its presentation. Mr. P. Scofield provided expert technical assistance and I must also thank the other members of the Department of Clinical Pharmacology at the Hammersmith Hospital. Aviva Petrie very kindly performed the statistical analysis. My thanks also go to Dr. F.H. Scadding, Professor C. Fletcher and Dr. N. Pride who allowed me to study some of their patients. I gratefully acknowledge Mrs. T. Turton, Mrs. J. Ellis and Mrs. J. Taylor who assisted in the preparation of the manuscript and typing. Finally, I would like to express my appreciation to the Medical Research Council whose generous support allowed me to do this work. Last, but not least, I would like to thank my husband for his patience. : iii : The list below is of published and "in press" work, some of which forms part of this thesis. beta-Adrenoceptor Function - Effect of Prolonged Exposure to beta- Adrenoceptor Agonists. Conolly, M.E. and Greenacre, J.K. (1975) No. 1241, 6th International Congress of Pharmacology Abstracts, Helsinki, Finland. The beta-Adrenoceptor of the Human Lymphocyte and Human Lung Parenchyma. Conolly, M.E. and Greenacre, J.K. (1977) Br. J. Pharmac., 21, 17-23. The Lymphocyte beta-Adrenoceptor in Normal Subjects and Patients with Bronchial Asthma: The Effect of Different Forms of. Treatment on Receptor Function. Conolly, M.E. and Greenacre, J.K. (1976) J. clin. Invest., 1307-1316. Desensitization of the beta-Adrenoceptor of Lymphocytes from Normal Subjects and Patients with PhaeoehromocytomakStudies in vivo. Greenacre, J.K. and Conolly, M.E. (in.press) Br. J. clin. Pharmac. Desensitization of the beta-Adrenoceptor of Lymphocytes froM Normal Subjects and Asthmatic Patients in vitro. Greenacre, J.K., Scofield, P. and Conolly, M.E. (in press) Br. J. clin. Pharmac. : 1 : TABLE OF CONTENTS Page CHAPTER I INTRODUCTION AND AIMS OF THE PRESENT STUDY 10 1.1 Introduction 11 1.2 Autonomic function in asthma 12 1.3 Cyclic adenosine 3' 5' monophosphate: the second messenger 15 1.4 The theory of partial beta adrenergic blockade in asthmatics 16 1.4.1 Szentivanyi's theory 16 1.4.2 Supporting evidence 18 1.5 Possible tolerance to beta adrenergic agents: the increase in asthma deaths 24 1.6 Evidence of tolerance to beta adrenergic stimulants in animals and man 26 1.7 in vitro production of tolerance to beta adrenoceptor agonists 30 1.8 Possible physiological and pathophysiological importance of tolerance 34 1.9 Purpose of the present study 36 CHAPTER II GENERAL MATERIALS AND METHODS 37 2.1 Introduction 38 2.2 Materials, drugs and chemicals 38 2.3 Preparation of chromatography materials 39 2.4 Preparation of binding protein 40 2.5 Cell separation and viability 41 2.6 Incubation 44 2.7 Cyclic AMP purification 45 2.8 Assay of cyclic AMP 45 2.9 Calculation of results 47 2.10 Statistical methods 50 CHAPTER III CHARACTERISTICS OF THE LYMPHOCYTE BETA ADRENOCEPTOR 51 3.1 Introduction 52 3.2 Methods 53 : 2 Page 3.3 Results 54 3.3.1 Lymphocytes: normal dose response curve to isoprenaline 54 3.3.2 Lymphocytes: response to salbutamol 57 3.3.3 Lymphocyte response to isoprenaline in the presence of beta adrenoceptor antagonists 57 3.3.4 Lung experiments: incubation with isoprenaline and salbutamol 62 3.3.5 Lung experiments: incubation with isoprenaline and propranolol or practolol 62 3.4 Discussion 67 3.4.1 Classification of the lymphocyte beta adrenoceptor 67 3.4.2 Variability of lymphocyte cyclic AMP response to isoprenaline 69 CHAPTER IV LYMPHOCYTE BETA ADRENOCEPTOR RESPONSE IN ASTHMATICS 72 4.1 Introduction 73 4.2 Subjects and methods 73 4.3 Results 77 4.3.1 Asthmatics on large doses of beta adrenergic bronchodilators 77 4.3.2 Asthmatics on non-adrenergic medication 77 4.3.3 Asthmatics studied serially, initially on large doses of beta adrenergic bronchodilators and subsequently on other anti-asthmatic drugs 84 4.4 Discussion 92 CHAPTER V NORMAL SUBJECTS "TREATED" WITH BETA ADRENERGIC STIMULANTS 95 5.1 Introduction 96 5.2 Subjects and methods 97 5.3 Results 100 5.3.1 Normal subjects on oral salbutamol 12-16 mg daily 100 5.3.2 Normal subjects taking excessive salbutamol by inhalation 100 5.3.3 Obstetric patients given prolonged infusions of isoxsuprine 100 5.3.4 Patients with phaeochromocytomata 109 5.4 Discussion 115 •3 : Ema CHAPTER VI PRODUCTION OF BETA ADRENOCEPTOR DESENSITIZATION IN VITRO 117 6.1 Introduction 118 6.2 Materials and methods for in vitro studies 119 6.3 Results 127 6.3.1 Cyclic AMP response of lymphocytes from normal subjects cultured with or without isoprenaline 127 6.3.2 Cyclic AMP response of lymphocytes from normal subjects and one asthmatic patient cultured with and without PGE 1 131 6.3.3 Cyclic AMP response of lymphocytes from asthmatic subjects cultured with and without isoprenaline or PGE 1 139 6.3.4 Assay of phosphodiesterase activity in lymphocytes cultured with isoprenaline or PGE1 139 6.4 Discussion 139 CHAPTER VII CONCLUSIONS 148 REFERENCES 153 APPENDIX 1 167 : 4 : TABLE OF TABLES Page Table I Normal subjects - lymphocyte response to isoprenaline in picomoles cyclic AMP above baseline unstimulated level 55 Normal subjects - lymphocyte response to Table II isoprenaline, percent increase in cyclic AMP 58 Table III pA2 values for propranolol and practolol observed in human lymphocytes 64 Table IV pA2 values for propranolol and practolol obtained in other laboratories 68 Table V Clinical details of asthmatic patients on high doses of beta adrenergic bronchodilators 75 Table VI Clinical details of asthmatic patients on non-adrenergic medication 76 Table VII Asthmatic patients on large doses of beta adrenergic bronchodilators: lymphocyte cyclic AMP response to isoprenaline, percentage increase over baseline 79 Table VIII Asthmatic patients on large doses of beta adrenergic bronchodilators: lymphocyte response to isoprenaline, picomoles cyclic AMP over baseline 8o Table IX Asthmatic patients on non-adrenergic drugs: lymphocyte cyclic AMP response to isoprenaline, percentage increase over baseline 82 Table X Asthmatic patients on non-adrenergic drugs: lymphocyte response to isoprenaline in picomoles cyclic AMP over baseline 83 Table XI Asthmatics studied before and after changing from large doses of adrenergic bronchodilators to non-adrenergic drugs: percentage increase in lymphocyte cyclic AMP 88 Table XII Asthmatics studied before and after changing from large amounts of adrenergic bronchodilators to non-adrenergic drugs,absolute increase in lymphocyte cyclic AMP 89 Table XIII Clinical details of patients with phaeochromocytomata 99 :5 Page Table XIV Normal subjects taking oral salbutamol (12-16 mg/day): percentage increase in lymphocyte cyclic AMP in response to isoprenaline 102 Table XV Normal subjects taking oral salbutamol: absolute increase in lymphocyte cyclic AMP 103 Table XVI Normal subjects taking large amounts of inhaled salbutamol (30 inhalations/day): percentage increase in lymphocyte cyclic AMP in response to isoprenaline 105 Table XVII Normal subjects taking large amounts of inhaled salbutamol: absolute increase in lymphocyte cyclic AMP 106 Table XVIII Obstetric patients studied before and after infusions of isoxsuprine: percentage increase in lymphocyte cyclic AMP in response to isoprenaline 108 Table XIX Obstetric patients studied before and after isoxsuprine: absolute increase in lymphocyte cyclic AMP 110 Table XX Patients with phaeochromocytomata: percentage increase in lymphocyte cyclic
Load more

Recommended publications
  • 18 December 2020 – to Date)
    (18 December 2020 – to date) MEDICINES AND RELATED SUBSTANCES ACT 101 OF 1965 (Gazette No. 1171, Notice No. 1002 dated 7 July 1965. Commencement date: 1 April 1966 [Proc. No. 94, Gazette No. 1413] SCHEDULES Government Notice 935 in Government Gazette 31387 dated 5 September 2008. Commencement date: 5 September 2008. As amended by: Government Notice R1230 in Government Gazette 32838 dated 31 December 2009. Commencement date: 31 December 2009. Government Notice R227 in Government Gazette 35149 dated 15 March 2012. Commencement date: 15 March 2012. Government Notice R674 in Government Gazette 36827 dated 13 September 2013. Commencement date: 13 September 2013. Government Notice R690 in Government Gazette 36850 dated 20 September 2013. Commencement date: 20 September 2013. Government Notice R104 in Government Gazette 37318 dated 11 February 2014. Commencement date: 11 February 2014. Government Notice R352 in Government Gazette 37622 dated 8 May 2014. Commencement date: 8 May 2014. Government Notice R234 in Government Gazette 38586 dated 20 March 2015. Commencement date: 20 March 2015. Government Notice 254 in Government Gazette 39815 dated 15 March 2016. Commencement date: 15 March 2016. Government Notice 620 in Government Gazette 40041 dated 3 June 2016. Commencement date: 3 June 2016. Prepared by: Page 2 of 199 Government Notice 748 in Government Gazette 41009 dated 28 July 2017. Commencement date: 28 July 2017. Government Notice 1261 in Government Gazette 41256 dated 17 November 2017. Commencement date: 17 November 2017. Government Notice R1098 in Government Gazette 41971 dated 12 October 2018. Commencement date: 12 October 2018. Government Notice R1262 in Government Gazette 42052 dated 23 November 2018.
    [Show full text]
  • Ehealth DSI [Ehdsi V2.2.2-OR] Ehealth DSI – Master Value Set
    MTC eHealth DSI [eHDSI v2.2.2-OR] eHealth DSI – Master Value Set Catalogue Responsible : eHDSI Solution Provider PublishDate : Wed Nov 08 16:16:10 CET 2017 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 1 of 490 MTC Table of Contents epSOSActiveIngredient 4 epSOSAdministrativeGender 148 epSOSAdverseEventType 149 epSOSAllergenNoDrugs 150 epSOSBloodGroup 155 epSOSBloodPressure 156 epSOSCodeNoMedication 157 epSOSCodeProb 158 epSOSConfidentiality 159 epSOSCountry 160 epSOSDisplayLabel 167 epSOSDocumentCode 170 epSOSDoseForm 171 epSOSHealthcareProfessionalRoles 184 epSOSIllnessesandDisorders 186 epSOSLanguage 448 epSOSMedicalDevices 458 epSOSNullFavor 461 epSOSPackage 462 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 2 of 490 MTC epSOSPersonalRelationship 464 epSOSPregnancyInformation 466 epSOSProcedures 467 epSOSReactionAllergy 470 epSOSResolutionOutcome 472 epSOSRoleClass 473 epSOSRouteofAdministration 474 epSOSSections 477 epSOSSeverity 478 epSOSSocialHistory 479 epSOSStatusCode 480 epSOSSubstitutionCode 481 epSOSTelecomAddress 482 epSOSTimingEvent 483 epSOSUnits 484 epSOSUnknownInformation 487 epSOSVaccine 488 © eHealth DSI eHDSI Solution Provider v2.2.2-OR Wed Nov 08 16:16:10 CET 2017 Page 3 of 490 MTC epSOSActiveIngredient epSOSActiveIngredient Value Set ID 1.3.6.1.4.1.12559.11.10.1.3.1.42.24 TRANSLATIONS Code System ID Code System Version Concept Code Description (FSN) 2.16.840.1.113883.6.73 2017-01 A ALIMENTARY TRACT AND METABOLISM 2.16.840.1.113883.6.73 2017-01
    [Show full text]
  • Hexoprenaline: Β-Adrenoreceptor Selectivity in Isolated Tissues from the Guinea-Pig
    Clinical and Experimental Pharmacology and Physiology (1975) 2, 541-547. Hexoprenaline: p-adrenoreceptor selectivity in isolated tissues from the guinea-pig Stella R. O’Donnell and Janet C. Wanstall Department of Physiology, University of Queenstand, Brisbane, Australia (Received 12 March 1975; revision received 22 April 1975) SUMMARY 1. A catecholamine P-adrenoreceptor agonist, hexoprenaline, was examined in vitro on five guinea-pig tissues and its potency relative to isoprenaline (as 100) obtained. 2. Hexoprenaline clearly delineated between those tissues classified as containing P,-adrenoreceptors (trachea, hind limb blood vessels and uterus; relative potencies 219, 110 and 76 respectively) and those classified as containing P,-adrenoreceptors (atria and ileum; relative potencies 3.3 and 1.0 respectively). 3. Hexoprenaline differed from some previously studied noncatecholamine P-adrenoreceptor agonists in being only two-fold less potent, relative to isoprena- line, as a vasodilator in perfused hind limb than as a tracheal relaxant. Key words : j3-adrenoreceptors, blood vessels, bronchodilators, guinea-pig, hexo- prenaline, selectivity, trachea. INTRODUCTION In a previous study using in vitro preparations from the guinea-pig, O’Donnell & Wanstall (1974a) examined potential sympathomimetic bronchodilator compounds for their potency as tracheal relaxants (p,-adrenoreceptors), atrial stimulants (P,-adrenoreceptors) and vasodilators in the perfused hind limb (p2-adrenoreceptors). Some resorcinolamines showed selectivity for trachea compared with not only atria but also blood vessels. There is some evidence in dogs in vivo that other noncatecholamines, namely carbuterol (Wardell et al., 1974), and salbutamol and terbutaline (Wasserman & Levy, 1974), display similar select- ivity. If selectivity between respiratory and vascular smooth muscle represents selectivity at the p-adrenoreceptor level, it poses the question whether the P1/p2subclassification (Lands et al., 1967a; Lands, Luduena & Buzzo, 1967b) is too rigid.
    [Show full text]
  • Quick Screening of Priority Beta-Agonists in Urine Using Automated Turboflow™ - LC/Exactive Mass Spectrometry Thorsten Bernsmann, Peter Fuerst, Michal Godula
    Quick screening of priority beta-agonists in urine using automated TurboFlow™ - LC/Exactive mass spectrometry Thorsten Bernsmann, Peter Fuerst, Michal Godula To cite this version: Thorsten Bernsmann, Peter Fuerst, Michal Godula. Quick screening of priority beta-agonists in urine using automated TurboFlow™ - LC/Exactive mass spectrometry. Food Additives and Contaminants, 2011, 28 (10), pp.1352-1363. 10.1080/19440049.2011.619504. hal-00743048 HAL Id: hal-00743048 https://hal.archives-ouvertes.fr/hal-00743048 Submitted on 18 Oct 2012 HAL is a multi-disciplinary open access L’archive ouverte pluridisciplinaire HAL, est archive for the deposit and dissemination of sci- destinée au dépôt et à la diffusion de documents entific research documents, whether they are pub- scientifiques de niveau recherche, publiés ou non, lished or not. The documents may come from émanant des établissements d’enseignement et de teaching and research institutions in France or recherche français ou étrangers, des laboratoires abroad, or from public or private research centers. publics ou privés. Food Additives and Contaminants This paper describes a method for the determination of priority β -agonists in urine based on a fully automated sample preparation procedure using the online TurboFlow™ chromatography clean -up step and determination on the Orbitrap™ mass analyzer technology. The principle of the method after enzymatic hydrolysis over night on a small column packed with a special stationary phase (TurboFlow™) while flushing away sample matrix and interfering compounds. Thereafter the analytes are transferred onto an analytical column and detected by id chromatography/high resolution mass spectrometry in full scan mode at a resolution of R=50,000 FWHM (full width at half maximum) and in HCD (Higher Energy Collisional Dissociation) scan mode at a resolving power of 10,000 FWHM.
    [Show full text]
  • Leaflet Bremax.Cdr
    Leaflet Bremax Syrup & Tabs. Size: 220 x 140mm Date: 10-07-2015, 27-06-2015 Ammara Commerial Printers (Pvt.) Ltd. Subacute Toxicity The maximum safe dose of tulobuterol was estimated to be 50 mg/kg in the rat. Chronic Toxicity In rats, the maximum safe dose of tulobuterol, orally, was 18 mg/kg/day for six months and 9 mg/kg/day for twelve months. In dogs, the non-toxic dose level was 50 mg/kg/day. CARCINOGENESIS, MUTAGENESIS AND IMPAIRMENT OF FERTILITY Carcinogenicity Potential tumorigenic effects of tulobuterol were evaluated in mice and rats by prolonged dietary administration in doses of 1, 3 and 9 mg/kg/day for two years. The Syrup highest dose used in these studies was greater than 100 times the recommended human dose (0.08 mg/kg/day). DESCRIPTION Mice Tulobuterol is a synthetic beta 2-agonist with potent and prolonged bronchodilator No abnormal clinical signs were detected and longevity was not affected. Food activity of the sympathomimetic amine class related structurally and consumption was not altered, but treated males gained less weight. Minor changes pharmacologically to epinephrine, isoproterenol, salbutamol (albuterol), in differential leukocytes were reported. metaproterenol, terbutaline, clorprenaline, carbuterol and procaterol. The incidence of uterine smooth muscle tumors (leiomyoma, leiomyosarcoma) in / Tulobuterol is an odorless and bitter tasting white crystalline powder. It is soluble in mice receiving the highest dose of tulobuterol (9 mg/kg/day) was not statistically methanol, water, acetic acid, ethanol, chloroform, and 1,2-dichloroethane, only significant. The tendency for these treated females to develop lymphoreticular slightly soluble in acetone, isopropanol and dioxane and practically insoluble in tumors was not greater than the background incidence in this strain of mice benzene, ether, cyclohexane and isopropylether.
    [Show full text]
  • BMJ Open Is Committed to Open Peer Review. As Part of This Commitment We Make the Peer Review History of Every Article We Publish Publicly Available
    BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email [email protected] http://bmjopen.bmj.com/ on September 26, 2021 by guest. Protected copyright. BMJ Open BMJ Open: first published as 10.1136/bmjopen-2018-027935 on 5 May 2019. Downloaded from Treatment of stable chronic obstructive pulmonary disease: a protocol for a systematic review and evidence map Journal: BMJ Open ManuscriptFor ID peerbmjopen-2018-027935 review only Article Type: Protocol Date Submitted by the 15-Nov-2018 Author: Complete List of Authors: Dobler, Claudia; Mayo Clinic, Evidence-Based Practice Center, Robert D.
    [Show full text]
  • Anatomical Classification Guidelines V2021 EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2021
    EPHMRA ANATOMICAL CLASSIFICATION GUIDELINES 2021 Anatomical Classification Guidelines V2021 "The Anatomical Classification of Pharmaceutical Products has been developed and maintained by the European Pharmaceutical Marketing Research Association (EphMRA) and is therefore the intellectual property of this Association. EphMRA's Classification Committee prepares the guidelines for this classification system and takes care for new entries, changes and improvements in consultation with the product's manufacturer. The contents of the Anatomical Classification of Pharmaceutical Products remain the copyright to EphMRA. Permission for use need not be sought and no fee is required. We would appreciate, however, the acknowledgement of EphMRA Copyright in publications etc. Users of this classification system should keep in mind that Pharmaceutical markets can be segmented according to numerous criteria." © EphMRA 2021 Anatomical Classification Guidelines V2021 CONTENTS PAGE INTRODUCTION A ALIMENTARY TRACT AND METABOLISM 1 B BLOOD AND BLOOD FORMING ORGANS 28 C CARDIOVASCULAR SYSTEM 36 D DERMATOLOGICALS 51 G GENITO-URINARY SYSTEM AND SEX HORMONES 58 H SYSTEMIC HORMONAL PREPARATIONS (EXCLUDING SEX HORMONES) 68 J GENERAL ANTI-INFECTIVES SYSTEMIC 72 K HOSPITAL SOLUTIONS 88 L ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS 96 M MUSCULO-SKELETAL SYSTEM 106 N NERVOUS SYSTEM 111 P PARASITOLOGY 122 R RESPIRATORY SYSTEM 124 S SENSORY ORGANS 136 T DIAGNOSTIC AGENTS 143 V VARIOUS 145 Anatomical Classification Guidelines V2021 INTRODUCTION The Anatomical Classification was initiated in 1971 by EphMRA. It has been developed jointly by Intellus/PBIRG and EphMRA. It is a subjective method of grouping certain pharmaceutical products and does not represent any particular market, as would be the case with any other classification system.
    [Show full text]
  • United States Patent (19) 11 Patent Number: 6,110,9749 9 Aberg Et Al
    USOO6110974A United States Patent (19) 11 Patent Number: 6,110,9749 9 Aberg et al. (45) Date of Patent: Aug. 29, 2000 54 METHODS OF ACCELERATING MUSCLE 52 U.S. Cl. .............................................................. 514/653 GROWTH AND IMPROVING FEED 58 Field of Search ............................................... 514/653 EFFICIENCY IN ANIMALS BY USING OPTICALLY PURE EUTOMERS OF 56) References Cited ADRENERGIC BETA-2 RECEPTOR AGONISTS, AND FOOD SUPPLEMENTS U.S. PATENT DOCUMENTS CONTAINING THE SAME 5,552,442 9/1996 Maltin ..................................... 514/620 5,708,036 1/1998 Pesterfield ............................... 514/653 75 Inventors: A. K. Gunnar Aberg, Sarasota, Fla.; Paul J. Fawcett, Dunedin, New Primary Examiner Kimberly Jordan Zealand Attorney, Agent, or Firm Nields, Lemack & Dingman 73 Assignee: Bridge Pharma, Inc., Sarasota, Fla. 57 ABSTRACT Method for improvingp 9. health, Survival and muscle growth9. 21 Appl. No.: 09/069,512 rate of animals, while reducing carcass fat and improving feed efficiency by administering an optically pure eutomer 22 Filed: Apr. 29, 1998 of an adrenergic beta-2 agonist. The invention is also Related U.S. Application Data directedagSh to food composiuOnSiti compriSIngising linethe adrenergicad 60 Provisional application No. 60/045,120, Apr. 30, 1997. (51) Int. Cl. .............................................. A61K 31/135 6 Claims, No Drawings 6,110,974 1 2 METHODS OF ACCELERATING MUSCLE the drugs and decreasing total drug residues in the body of GROWTH AND IMPROVING FEED the animal. The method has proved particularly useful in EFFICIENCY IN ANIMALS BY USING animals that have demonstrated a propensity for health OPTICALLY PURE EUTOMERS OF disorders, in which the health status and the Survival rate is ADRENERGIC BETA-2 RECEPTOR improved by eutomers of beta-2 agonists, and in animals that AGONISTS, AND FOOD SUPPLEMENTS have a muscular growth rate that needs to be improved and CONTAINING THE SAME in cases where improved feed efficiency is Sought.
    [Show full text]
  • EU Transition Strategy for Mdis
    EUROPEAN COMMUNITY STRATEGY FOR THE PHASEOUT OF CFCs IN METERED DOSE INHALERS A Communication from the European Commission to the Council and the European Parliament CONTENTS Chapter 1 Introduction Page 3 Chapter 2 Executive Summary Page 4 Chapter 3 CFCs and MDIs Page 6 Chapter 4 Patient Needs Page 9 Chapter 5 Developing Alternatives to CFC-containing MDIs Page 13 Chapter 6 Approval of new products and post-authorisation surveillance Page 18 Chapter 7 Phasing out CFCs Page 25 Chapter 8 Awareness raising Page 34 Chapter 9 Exports of MDIs from the EC Page 38 Chapter 10 CFC production Issues Page 40 Chapter 11 The Essential Use Process -Overview and Timetable Page 43 CHAPTER 1 INTRODUCTION 1.1 Decision IX/19 of the Parties to the Montreal Protocol requires Parties requesting essential use nominations for chlorofluorocarbons CFCs for metered-dose inhalers (MDIs) to present to the Ozone Secretariat an initial national or regional transition strategy if possible by 31 January 1998, and in any case by 31 January 1999. The European Community is a Party to the Montreal Protocol, and this document is its transition strategy prepared in accordance with decision IX/19 of the Parties. The European Community believes that a transition strategy is necessary to set out how the transition out of CFCs in MDIs is to be managed such that the CFCs can be phased out as quickly as possible without putting in jeopardy supplies of necessary medicines to patients in need. 1.2 The European Community, on behalf of the Member States, submits a joint request every year to the Parties for the continued use of CFCs to manufacture MDIs.
    [Show full text]
  • Stembook 2018.Pdf
    The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances FORMER DOCUMENT NUMBER: WHO/PHARM S/NOM 15 WHO/EMP/RHT/TSN/2018.1 © World Health Organization 2018 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: “This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition”. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. The use of stems in the selection of International Nonproprietary Names (INN) for pharmaceutical substances. Geneva: World Health Organization; 2018 (WHO/EMP/RHT/TSN/2018.1). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data.
    [Show full text]
  • Study Protocol and Statistical Analysis Plan
    ABCD TITLE PAGE Protocol for observational studies based on existing data Document Number: c02330001-03 BI Study Number: 1222.54 BI Investigational Olodaterol Product(s): Title: Cohort study of cardiovascular events in patients with chronic obstructive pulmonary disease initiating olodaterol or other long- acting beta2-agonists Protocol version 3.0 identifier: Date of last version of 14 Oct 2014 protocol: PASS: Yes EU PASS register Study not registered number: Active substance: Olodaterol Medicinal product: Striverdi, Respimat Product reference: BI 1744 Procedure number: Not applicable Marketing authorisation holder(s): Joint PASS: No Date: 28 October 2016 Page 1 of 69 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved. This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission Boehringer Ingelheim Page 2 of 69 Protocol for observational studies based on existing data BI Study Number 1222.54 c02330001-03 Proprietary confidential information © 2016 Boehringer Ingelheim International GmbH or one or more of its affiliated companies Additional Information Research question and Examine the risk of selected cardiac arrhythmias in patients objectives: with chronic obstructive pulmonary disease (COPD) exposed to olodaterol compared with the risk in patients exposed to other long-acting beta2-agonists (LABAs) Examine the risk of acute myocardial infarction (AMI) and other serious
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 8.426,475 B2 Weidner Et Al
    USOO8426475B2 (12) United States Patent (10) Patent No.: US 8.426,475 B2 Weidner et al. (45) Date of Patent: Apr. 23, 2013 (54) TREATMENT OF CONNECTIVE TISSUE W W 28:8: A: 2.38 DISEASES OF THE SKN WO WO 2006/027579 A2 3, 2006 (75) Inventors: Morten Sloth Weidner, Virum (DK); OTHER PUBLICATIONS Hans Christian Wulf, Epsergaerde (DK) Pullen, Jr., R.; “Managing Subacute cutaneous lupus erythematosus' (73) Assignee: Astion Development A/S, Copenhagen Dermatology Nursing, Dec. 2001, pp. 1-3. O (DK) Freitas et al. "Chronic cutaneous Lupus erythematosus: Sudy of 290 patients'. An bras Dermatol, Rio de Janeiro, 2003, vol. 78(6), pp. 703-771.* (*) Notice: Subject to any disclaimer, the term of this Patent Abstract of Japan, 07258067 A, Oct. 9, 1995. patent is extended or adjusted under 35 Patent Abstracts of Japan, 07304647 A, Nov. 21, 1995. U.S.C. 154(b) by 1273 days. Patent Abstracts of Japan, 09 110674 A. Apr. 28, 1997. Patent Abstracts of Japan, 630 10716 A, Jan. 19, 1988. (21) Appl. No.: 11/402,255 Dawn Baramki BSN et al., “Modulation of T-cell function by (R)- and (S)-isomers of albuterol: Anti-inflammatory influences of (R)- (22) Filed: Apr. 12, 2006 isomers are negated in the presence of the (S)-isomers'. J. Allergy Clin. Immunol. 2002, 109(3):449-454. (65) Prior Publication Data Peter J. Barnes, “Effect of beta-agonists on inflammatory cells'. J. Allergy Clin. Immunol. 1999, 104(2 Pt 2):510-517. US 2006/0235048A1 Oct. 19, 2006 Richard Kalish et al., “Sensitization of mice to topically applied drugs: albuterol, chlorpheniramine, clonidine and nadolol.
    [Show full text]