DOCSLIB.ORG

Severe Asthma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Severe Asthma Robert S. Hutcheson, Jr., M.D. Lectureship Severe Asthma Venkat K Kollipara, M.D Pulmonary and Critical care Physician 4/22/2021 • No conflict of interest Objectives Clinical scenario of asthma presentation Asthma phenotypes, endotypes and biomarkers Changes in new GINA guidelines 2019 and EPR-3 2020 update Management for severe asthma Case • Beth is a 25-yo-old schoolteacher with history of asthma, allergic rhinitis presented with chief complaint of worsening shortness of breath and cough. • She was diagnosed with asthma a kid and has been using inhalers since then. • She recently needed to use her albuterol about 3 x wk and is waking up nightly for cough. • She also states that she notes that at times she gets winded when climbing up the stairs to her classroom. Case • Currently she is taking Symbicort 160/4.5 bid, Singulair, OTC Allegra and Albuterol prn • Further pertinent history: o She had allergy shots while living in NC as a teenager for about 4-5 years, which she states did help o Lives in a house with mainly wood floors/linoleum. Central air and central heat. She has one indoor cat for the past 6 years. No other pets Exam • BP 125/77, Pulse 89, Temp 98.8 °F, Resp 15, BMI 31.2 kg/m2, SpO2 98% • ENT: no nasal polyps • Chest: clear to auscultation. No wheezes and no crackles • ACT 19, NIOX 45 What questions do you ask her next? Assess inhaler technique Types of inhaler devices • Metered dose inhalers, MDIs • Dry powder inhalers • Soft mist inhalers • Nebulizers • Spacers Mitigation Strategies • Allergen mitigation interventions are recommended only in individuals with asthma who are both exposed to and either sensitized to or develop symptoms on exposure to specific allergens • Multicomponent Allergen Mitigation Strategies • Dust mite–impermeable pillow and mattress covers • HEPA vacuums, carpet removal • Mold mitigation • Integrated pest management (rodents and/or cockroaches)- block infestation (eg, filling holes in walls, reducing standing water) and abatement (eg, traps, fumigation) Asthma • Asthma is a chronic inflammatory disorder of the airways characterized by bronchial hyperresponsiveness and variable airflow limitation • Affects > 300 million people worldwide • Majority of patients with asthma can achieve disease control with standard controller therapy • Approximately 5-10% have severe asthma that remains inadequately controlled despite adherence to standard treatment with a high-dose ICS plus LABA/LAMA Prevalence and burden of asthma The direct costs of uncontrolled asthma in adolescents and adults in the United States over the next 20 years is likely to be a staggering $1.5 trillion National Center for Environmental Health, CDC, 2017 Contributing Factors to Asthma Genetic Factors Environmental Factors Triggers Viral infections Exposure to allergens Occupational exposure Tobacco smoke Aspirin Indoor and outdoor pollutants Factors Influencing the Development of Atopy and Allergic Inflammation Mediated by Th2 Cells A.B. Kay, M.D, N Engl J Med 2001; 344:30-37 Asthma characteristics • Variable and recurrent symptoms • Reversible Airflow obstruction • Bronchial hyperresponsiveness • Airway inflammation Case cont.. Next clinic visit, patient stated she is using inhalers as prescribed and demonstrated good technique Still complaining of shortness of breath and episodic wheezing What further workup do you need? Terminology • Phenotype: The observable characteristics of a disease, such as morphology, development, biochemical or physiological properties, or behaviors. • Examples: allergic asthma, aspirin-exacerbated respiratory disease, severe eosinophilic asthma • Endotype: A subtype of disease, defined functionally and pathologically by a distinct molecular mechanism or by distinct treatment responses (Anderson, Lancet 2008) • Examples: emphysema due to alpha1-antitrypsin deficiency • Biomarker: A defined characteristic measured as an indicator of normal biologic processes, pathogenic processes or response to an intervention • Potential examples: FeNO, blood eosinophils – but these may not meet quality criteria for biomarkers Anderson, Lancet 2008; Reddel, ERJ Open Res 2019 © Global Initiative for Asthma, www.ginasthma.org Asthma endotypes • Heterogeneous disease with multiple phenotypes that are caused by a variety of pathophysiologic mechanisms, or endotypes • There are two specific endotypes, • Type 2 (T2) high • T2 low • These endotypes are defined based on their level of expression of cytokines such as IL-4, IL-5, and IL-13 that may be secreted by the classic T-helper cell type 2 (Th2)-type cells, such as the CD4 lymphocytes, or nonclassic immune cells, such as the innate lymphoid cells–type 2 (ILC-2) Mary Clare McGregor et al, Am J Respir Crit Care Med, Feb 15, 2019 Major biomarkers in Asthma • Blood eosinophils • Sputum eosinophils • FeNO • Periotin • Serum IgE Eosinophil as an Inflammatory Biomarker • Variable numbers of blood and airway eosinophils are present in patients with type 2 cytokine profiles • Likely relates to level of type 2 activation • Eosinophils in blood and airway are correlated with: • Frequency of asthma exacerbations • Degree of airflow limitation • Presence and severity of chronic rhinosinusitis/nasal polyposis Sputum Eosinophil Count • Sputum is induced with hypertonic saline (subject inhales aerosol of hypertonic saline for 15-minute periods and then is encouraged to cough up a sample of sputum) • Normal sputum eosinophils is 3% in adults Sputum Eosinophils • Sputum eosinophils appear to correlate well with disease severity, lung function, and BHR • Asthmatics treated with ICS show a decrease in sputum eosinophils NITRIC OXIDE • In asthma, there is some evidence that this enzyme is up-regulated, and elevated levels of NO have been detected in the exhaled air of asthmatic subjects • Potent vasodilator and bronchodilator • Utility of exhaled NO may be in monitoring asthma control, guiding therapy and providing an indication of corticosteroid sensitivity Source of exhaled nitric oxide • Current thinking is that exhaled NO is derived from the upper and lower respiratory tract (airway & alveolar) and diffuses by gaseous diffusion down a concentration gradient, thus conditioning exhaled air • Exhaled NO is produced by NO synthase in respiratory epithelium under direct control of IL-13 and possibly other factors • often, but no always correlated with sputum/blood eosinophil numbers • is a moderately reproducible marker of Th2 phenotype Periostin • Up-regulated by type 2 cytokines IL-4 and IL-13 • Serum periostin can predict the efficacy of anti-IL 13 antibodies (lebrikizumab) and anti-IgE antibodies (omalizumab) • Periostin-high asthma patients have several unique characteristics, including eosinophilia, high fraction of nitric oxide, aspirin intolerance, nasal disorders, and late onset Asthma Control Test (ACT) Case cont.. Component Value o Alternaria Alternata <0.10 kU/L o Cat Dander (E1) IgE 31.00 kU/L o Cladosporium Herbarum IGE <0.10 kU/L • Right now, using ICS/LABA and o American Cockroach (I206) IGE <0.10 kU/L PRN SABA o Common Ragweed IGE 1.04 kU/L • ACT 18, NIOX 45 o Dust Mite(D.Farinae) (D2) IGE <0.10 kU/L o Dust Mite(D.Pterno.) (D1) IGE <0.10 kU/L o Dog Dander (E5) 1.26 kU/L o Elm (T8) IGE 0.44 kU/L • What is your next step? o IgE 164 kU/L WBC 11,300, 3.6% eosinophils = 396 eosinophils Goals of asthma treatment • Few asthma symptoms • No sleep disturbance Symptom control • No exercise limitation • Maintain normal lung function • Prevent flare-ups (exacerbations) • Prevent asthma deaths Risk reduction • Avoid medication side-effects • The patient’s goals may be different from these • Symptoms and risk may be discordant – need to assess both The best predictor of future exacerbations was a history of previous exacerbation © Global Initiative for Asthma, www.ginasthma.org ATS/ERS Task Force Recommendations to diagnose Severe asthma • Consider and treat comorbidities • Exclude other diagnosis • Poor asthma control due to inadequate understanding of disease management by the patients must be excluded International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. European Respiratory Journal . 2014 43: 343-373. © 2019 Global Initiative for Asthma SMART (Single Maintenance And Reliever Therapy) • SMART is recommended in adolescents (aged 12-17 years) and adults (aged 18 years or older) with moderate persistent asthma as the preferred therapy for steps 3 and 4 (strong recommendation, high certainty of evidence). • SMART has been reported only with formoterol as the LABA, which is why the recommendation is specific to formoterol therapy. • Regular daily use in SMART is defined as 1 to 2 puffs once to twice daily. • As-needed use in SMART is defined as 1 to 2 puffs (4.5 μg of formoterol per puff) every 4 hours as needed for asthma symptoms, up to a maximum of 12 total puffs per day for individuals aged 12 years or older. 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program 2020 Asthma Guideline Update From the National Asthma Education and Prevention Program Case cont.. • You get all the labs results (+RAST, IgE- 164, blood eosinophils 396, FeNO 54, ACT 17) • Follow up clinic visit, patient is compliant with her inhalers, good tech, no triggers, well controlled allergies • Patient still symptomatic and recently admitted to hospital for asthma exacerbation • What treatment options do you have to better control her asthma? How to investigate uncontrolled asthma © 2019 Global Initiative for Asthma N Engl J Med 2012; 367:1198-1207
Load more

Recommended publications
  • Japanese Guidelines for Adult Asthma 2020*
    Allergology International xxx (xxxx) xxx Contents lists available at ScienceDirect Allergology International journal homepage: http://www.elsevier.com/locate/alit Invited Review Article Japanese guidelines for adult asthma 2020* * Yoichi Nakamura a, , Jun Tamaoki b, Hiroyuki Nagase c, Masao Yamaguchi d, Takahiko Horiguchi e, Soichiro Hozawa f, Masakazu Ichinose g, Takashi Iwanaga h, Rieko Kondo e, Makoto Nagata i, Akihito Yokoyama j, Yuji Tohda h, The Japanese Society of Allergology a Medical Center for Allergic and Immune Diseases, Yokohama City Minato Red Cross Hospital, Yokohama, Japan b First Department of Medicine, Tokyo Women's Medical University, Tokyo, Japan c Division of Respiratory Medicine and Allergology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan d Third Department of Medicine, Teikyo University Chiba Medical Center, Chiba, Japan e Department of Respiratory Medicine, Fujita Health University Bantane Hospital, Nagoya, Japan f Hiroshima Allergy and Respiratory Clinic, Hiroshima, Japan g Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan h Department of Respiratory Medicine and Allergology, Kinki University Faculty of Medicine, Osaka, Japan i Department of Respiratory Medicine, Saitama Medical University Hospital, Saitama, Japan j Department of Hematology and Respiratory Medicine, Kochi University, Kochi, Japan article info abstract Article history: Bronchial asthma is characterized by chronic airway inflammation, which manifests clinically as variable Received 9 June 2020 airway narrowing (wheezes and dyspnea) and cough. Long-standing asthma may induce airway Available online xxx remodeling and become intractable. The prevalence of asthma has increased; however, the number of patients who die from it has decreased (1.3 per 100,000 patients in 2018).
    [Show full text]
  • Improved Homology Modeling of the Human & Rat EP4 Prostanoid Receptors
    Holt et al. BMC Molecular and Cell Biology (2019) 20:37 BMC Molecular and https://doi.org/10.1186/s12860-019-0212-5 Cell Biology RESEARCHARTICLE Open Access Improved homology modeling of the human & rat EP4 prostanoid receptors Melissa C. Holt, Chi S. Ho, M. Inés Morano, Stephen D. Barrett and Adam J. Stein* Abstract Background: The EP4 prostanoid receptor is one of four GPCRs that mediate the diverse actions of prostaglandin E2 (PGE2). Novel selective EP4 receptor agonists would assist to further elucidate receptor sub-type function and promote development of therapeutics for bone healing, heart failure, and other receptor associated conditions. The rat EP4 (rEP4) receptor has been used as a surrogate for the human EP4 (hEP4) receptor in multiple SAR studies. To better understand the validity of this traditional approach, homology models were generated by threading for both receptors using the RaptorX server. These models were fit to an implicit membrane using the PPM server and OPM database with refinement of intra and extracellular loops by Prime (Schrödinger). To understand the interaction between the receptors and known agonists, induced-fit docking experiments were performed using Glide and Prime (Schrödinger), with both endogenous agonists and receptor sub-type selective, small-molecule agonists. The docking scores and observed interactions were compared with radioligand displacement experiments and receptor (rat & human) activation assays monitoring cAMP. Results: Rank-ordering of in silico compound docking scores aligned well with in vitro activity assay EC50 and radioligand binding Ki. We observed variations between rat and human EP4 binding pockets that have implications in future small-molecule receptor-modulator design and SAR, specifically a S103G mutation within the rEP4 receptor.
    [Show full text]
  • Q4 2019/20 Initiation
    Duration Duration Duration between Research Integrate between between First Date Site Ethics d Date of Date Site Date Site Reasons Participan Confirme HRA Date Site Non- Date Site Committe Research Name of First Selected Selected Date Site Date Site Date Site for delay t d and Approval Confirmed Confirmat Ready To e Applicatio Trial Participant and Date and First Invited Selected Confirmed correspon Recruited First Date By Sponsor ion Status Start Reference n System Recruited Site Participan d to: ? Participan Number Number Confirme t t d Recruited Recruited VIVOTM non- invasive mapping 19/LO/03 Please Please 162140 257755 of Yes 03/07/2019 26 33 59 01/03/2019 05/05/2019 21/04/2019 15/05/2019 31/05/2019 31/05/2019 08 Select... Select... ventricula r arrhythmi a A Pilot Study to exPlOre the exisTence and impact of 19/LO/07 FRAILTY Please Please 162141 264744 Yes 20/08/2019 31 11 42 01/04/2019 09/07/2019 16/07/2019 24/07/2019 09/08/2019 09/08/2019 84 in Select... Select... patients over the age of 70 undergoin g cardiac interventi ons Duration Duration Duration between Research Integrate between between First Date Site Ethics d Date of Date Site Date Site Reasons Participan Confirme HRA Date Site Non- Date Site Committe Research Name of First Selected Selected Date Site Date Site Date Site for delay t d and Approval Confirmed Confirmat Ready To e Applicatio Trial Participant and Date and First Invited Selected Confirmed correspon Recruited First Date By Sponsor ion Status Start Reference n System Recruited Site Participan d to: ? Participan Number Number Confirme t t d Recruited Recruited "Pressure- controlled Intermitte nt Coronary Sinus 19/SC/00 Occlusion Please Please 162142 259683 Yes 23/09/2019 40 12 52 01/04/2019 02/08/2019 16/07/2019 14/08/2019 11/09/2019 16/09/2019 50 (PiCSO) in Select..
    [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]
  • Investigational Allergology and Clinical Immunology
    Journal of Investigational Allergology and Clinical Immunology ISSN 1018-9068 Volume 31, Supplement 1, 2021 Official Organ of Spanish Society of Allergology and Clinical Immunology www.jiaci.org GEMA5.0 SPANISH GUIDELINE ON THE MANAGEMENT OF ASTHMA Journal of Investigational Allergology and Clinical Immunology Volume 31, Suppl. 1, 2021 Official Organ of Spanish Society of Allergology and Clinical Immunology Editors in Chief A.G. Oehling, Servicio de Alergología, Clínica Rotger, C/ Santiago Rusiñol 3, E-07012 Palma de Mallorca, Spain (E-mail [email protected]) J.M. Olaguibel, Unidad de Asma Grave, Servicio de Alergología, Complejo Hospitalario de Navarra, C/Irunlarrea s/n, E-31008 Pamplona, Spain (Tel. +34 948 255-400, Fax +34 948 296-500, E-mail [email protected]) Associate Editors I. Dávila, Hospital Clínico Universitario, Paseo San Vicente s/n, E-37007 Salamanca, Spain P.M. Gamboa, Servicio de Alergología, Hospital de Cruces, Plaza de Cruces, s/n, E-48903 Baracaldo, Bizkaia, Spain R. Lockey, University of South Florida College of Medicine, Division of Allergy and Immunology, VA Medical Center, 13000 North 30th Street, Tampa, FL 33612, USA V. del Pozo, Senior Research, Immunology IIS-FJD, Avda. Reyes Católicos 2, E-28040 Madrid, Spain J. Sastre, Servicio de Alergia, Fundación Jiménez Díaz, Avda. Reyes Católicos 2, E-28040 Madrid, Spain J.M. Zubeldia, Servicio de Alergología, Hospital G.U. Gregorio Marañón, C/ Dr. Esquerdo 46, E-28007 Madrid, Spain Founding Editor A.K. Oehling †, Department of Allergology and Clinical Immunology, Clínica Universidad de Navarra, Apartado 4209, E-31008 Pamplona, Spain Editorial Assistant G. Betelu, Department of Allergology and Clinical Immunology, Clínica Universidad de Navarra, Apartado 4209, E-31008 Pamplona, Spain (Tel.
    [Show full text]
  • PDCO Minutes of the 20-23 February 2018 Meeting
    23 February 2018 EMA/PDCO/113780/2018 Inspections, Human Medicines Pharmacovigilance and Committees Division Paediatric Committee (PDCO) Minutes of the meeting on 20-23 February 2018 Chair: Dirk Mentzer – Vice-Chair: Koenraad Norga 20 February 2018, 14:00- 17:00, room 3A 21 February 2018, 08:30- 19:00, room 3A 22 February 2018, 08:30- 19:00, room 3A 23 February 2018, 08:30- 13:00, room 3A Disclaimers Some of the information contained in this set of minutes is considered commercially confidential or sensitive and therefore not disclosed. With regard to intended therapeutic indications or procedure scopes listed against products, it must be noted that these may not reflect the full wording proposed by applicants and may also vary during the course of the review. Additional details on some of these procedures will be published in the PDCO Committee meeting reports (after the PDCO Opinion is adopted), and on the Opinions and decisions on paediatric investigation plans webpage (after the EMA Decision is issued). Of note, this set of minutes is a working document primarily designed for PDCO members and the work the Committee undertakes. Further information with relevant explanatory notes can be found at the end of this document. Note on access to documents Some documents mentioned in the minutes cannot be released at present following a request for access to documents within the framework of Regulation (EC) No 1049/2001 as they are subject to on-going procedures for which a final decision has not yet been adopted. They will become public when adopted or considered public according to the principles stated in the Agency policy on access to documents (EMA/127362/2006).
    [Show full text]
  • Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition
    Article Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition Graphical Abstract Authors Lei Wang, Dandan Yao, R.N.V. Krishna Deepak, ..., Weimin Gong, Zhiyi Wei, Cheng Zhang Correspondence [email protected] (Z.W.), [email protected] (C.Z.) In Brief Wang et al. reported crystal structures of antagonist-bound human CRTH2 as a new asthma drug target. Chemically diverse antagonists occupy a similar semi-occluded pocket with distinct binding modes. Structural analysis suggests a potential ligand entry port and an opposite charge attraction-facilitated binding process for the endogenous CRTH2 ligand prostaglandin D2. Highlights d Crystal structures of antagonist-bound human CRTH2 are solved d A well-structured N terminus covers ligand binding pocket d Conserved and divergent binding features of CRTH2 antagonists are revealed d A multiple-step binding process of prostaglandin D2 is proposed Wang et al., 2018, Molecular Cell 72, 48–59 October 4, 2018 ª 2018 Elsevier Inc. https://doi.org/10.1016/j.molcel.2018.08.009 Molecular Cell Article Structures of the Human PGD2 Receptor CRTH2 Reveal Novel Mechanisms for Ligand Recognition Lei Wang,1,7 Dandan Yao,2,3,7 R.N.V. Krishna Deepak,4 Heng Liu,1 Qingpin Xiao,1,5 Hao Fan,4 Weimin Gong,2,6 Zhiyi Wei,5,* and Cheng Zhang1,8,* 1Department of Pharmacology and Chemical Biology, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA 2Key Laboratory of RNA Biology, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China 3University
    [Show full text]
  • (CRTH2) Antagonists in Asthma: a Systematic Review and Meta-Analysis Protocol AUTHORS Liu, Wei; Min, Jie; Jiang, Hongli; Mao, Bing
    BMJ Open: first published as 10.1136/bmjopen-2017-020882 on 20 April 2018. Downloaded from PEER REVIEW HISTORY BMJ Open publishes all reviews undertaken for accepted manuscripts. Reviewers are asked to complete a checklist review form (http://bmjopen.bmj.com/site/about/resources/checklist.pdf) and are provided with free text boxes to elaborate on their assessment. These free text comments are reproduced below. ARTICLE DETAILS TITLE (PROVISIONAL) Chemoattractant Receptor-Homologous Molecule Expressed on Th2 Cells (CRTH2) antagonists in asthma: a systematic review and meta-analysis protocol AUTHORS liu, wei; Min, Jie; Jiang, Hongli; Mao, Bing VERSION 1 – REVIEW REVIEWER Hugo Farne Imperial College London United Kingdom REVIEW RETURNED 05-Jan-2018 GENERAL COMMENTS This is an interesting proposal as the findings have indeed been contradictory. My major comment is about the language - this paper would benefit significantly from proof-reading by a native English speaker (e.g. first para page 8). http://bmjopen.bmj.com/ Other comments: Strengths & Limitations (p5): - As there are no head-to-head trials of CRTH2 antagonists, subgroup analyses cannot directly assess the efficacy of CRTH2 antagonists relative to each other - By having no cut-off in terms of minimum duration of treatment (e.g. 12 weeks or 16 weeks), the study may include trials on September 28, 2021 by guest. Protected copyright. that were underpowered, which in turn may dilute any effect – I would note this. Introduction (p7) - CRTH2 is also expressed on Type 2 Innate Lymphoid Cells (ILC2s) - CRTH2 is not expressed on mast cells (except intracellularly, with unknown function) so production of cytokines from mast cells is not a consequence of PGD2 binding to CRTH2 on mast cells - The rationale for the CRTH2 receptor as a drug target in asthma is not explained fully.
    [Show full text]
  • Fevipiprant (QAW039), a Slowly Dissociating Crth2 Antagonist with the Potential for Improved Clinical Efficacy S
    Supplemental material to this article can be found at: http://molpharm.aspetjournals.org/content/suppl/2016/02/25/mol.115.101832.DC1 1521-0111/89/5/593–605$25.00 http://dx.doi.org/10.1124/mol.115.101832 MOLECULAR PHARMACOLOGY Mol Pharmacol 89:593–605, May 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Fevipiprant (QAW039), a Slowly Dissociating CRTh2 Antagonist with the Potential for Improved Clinical Efficacy s David A. Sykes, Michelle E. Bradley, Darren M. Riddy, Elizabeth Willard, John Reilly, Asadh Miah, Carsten Bauer, Simon J. Watson, David A. Sandham, Gerald Dubois, and Steven J. Charlton Novartis Institutes for Biomedical Research, Horsham, West Sussex, UK (D.A.S., M.E.B., D.M.R., E.W., J.R., A.M., S.W., D.A.S., G.D., S.J.C.); Novartis Institutes for Biomedical Research, Cambridge, Massachusetts (D.A.Sa., J.R.); Novartis Institutes for Biomedical Research, Basel, Switzerland (C.B.); School of Life Sciences, Queen’s Medical Centre, University of Nottingham, Downloaded from Nottingham, UK (D.A.Sy., S.J.C.) Received September 22, 2015; accepted February 22, 2016 ABSTRACT Here we describe the pharmacologic properties of a series of reversed by increasing concentrations of PGD2 after an initial molpharm.aspetjournals.org clinically relevant chemoattractant receptor-homologous mole- 15-minute incubation period. This behavior is consistent with cules expressed on T-helper type 2 (CRTh2) receptor antago- its relatively slow dissociation from the human CRTh2 receptor. nists, including fevipiprant (NVP-QAW039 or QAW039), which is In contrast for the other ligands tested this time-dependent currently in development for the treatment of allergic diseases.
    [Show full text]
  • Data on the Oral Crth2 Antagonist QAW039 (Fevipiprant) in Patients with Uncontrolled Allergic Asthma
    Data in Brief 9 (2016) 199–205 Contents lists available at ScienceDirect Data in Brief journal homepage: www.elsevier.com/locate/dib Data Article Data on the oral CRTh2 antagonist QAW039 (fevipiprant) in patients with uncontrolled allergic asthma Veit J. Erpenbeck a,n, Todor A. Popov b, David Miller c, Steven F. Weinstein d, Sheldon Spector e, Baldur Magnusson a, Wande Osuntokun f, Paul Goldsmith f, Markus Weiss a, Jutta Beier g a Novartis Pharma AG, Basel, Switzerland b Clinic of Allergy & Asthma, Medical University Sofia, Sofia, Bulgaria c NEMRA, North Dartmouth, MA, United States d Allergy & Immunology, Allergy and Asthma Specialists Medical Group and Research Center, CA, United States e Allergy & Asthma, California Allergy and Asthma Medical Group Inc, CA, United States f Novartis Pharmaceuticals, Horsham, United Kingdom g INSAF, Respiratory Research Institute GmbH, Wiesbaden, Germany article info abstract Article history: This article contains data on clinical endpoints (Peak Flow Expiratory Received 21 June 2016 Rate, fractional exhaled nitric oxide and total IgE serum levels) and Received in revised form plasma pharmacokinetic parameters concerning the use of the oral 10 August 2016 CRTh2 antagonist QAW039 (fevipiprant) in mild to moderate asthma Accepted 19 August 2016 patients. Information on experimental design and methods on how Available online 29 August 2016 this data was obtained is also described. Further interpretation and discussion of this data can be found in the article “The oral CRTh2 antagonist QAW039 (fevipiprant): a phase II study in uncontrolled allergic asthma” (Erpenbeck et al., in press) [1]. & 2016 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
    [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]
  • Risk Assessment of Reactive Metabolites in Drug Discovery: a Focus on Acyl Glucuronides and Acyl-Coa Thioesters
    Risk Assessment of Reactive Metabolites in Drug Discovery: A Focus on Acyl Glucuronides and Acyl-CoA Thioesters The Delaware Valley Drug Metabolism Discussion Group 2017 Rozman Symposium HUMAN BIOTRANSFORMATION: THROUGH THE MIST Langhorne, PA, June 13, 2017 Mark Grillo, PhD Drug Metabolism & Pharmacokinetics MyoKardia South San Francisco, CA [email protected] CommercializationDrug Process Discovery Overview & Development Therapeutic Area/Disease Lead Selection & Product Strategy Market Readiness & Launch / Post-Launch Opportunity Assessment Pre-clinical Testing Development Regulatory Approval Lifecycle Management Hit-to- Lead Post- Discovery Screen Pre-clinical Phase 1 Phase 2 Phase 3 Filing Launch Lead Optimization Launch Preclinical Pharmacokinetics & Drug Metabolism Assays Target Selection & Validation Lead compound Selection Discovery Screen Hit-to-Lead Lead Optimization Optimize Pharmacokinetics Characterize Preclinical Candidate Liver microsomal stability Intrinsic clearance Membrane permeability Excretion balance Efflux/transport assays Definitive metabolite ID Plasma stability Higher species PK Rat PK Human PK prediction Protein binding Assess DDI Potential Blood to plasma ratio Competitive CYP IC50 Early DDI Assessment Time-dependent CYP inhibition Enzyme induction PXR activation Hepatocyte induction CYP inhibition CYP reaction phenotyping Detection and Assessment of Chemically-Reactive Metabolites 2 Circumstantial Evidence Links Reactive Metabolites to Adverse Drug Reactions • Toxicity is a frequent cause of drug withdrawal
    [Show full text]