DOCSLIB.ORG

Interaction Between Drugs and the Gut Microbiome

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Interaction Between Drugs and the Gut Microbiome Recent advances in basic science Interaction between drugs and the gut microbiome Rinse K Weersma ,1 Alexandra Zhernakova,2 Jingyuan Fu2,3 Gut: first published as 10.1136/gutjnl-2019-320204 on 14 May 2020. Downloaded from 1Department of ABStract Gastroenterology and The human gut microbiome is a complex ecosystem Key messages Hepatology, University of Groningen, University Medical that can mediate the interaction of the human host There is a complex bidirectional interaction Centre Groningen, Groningen, with their environment. The interaction between gut ► The Netherlands microbes and commonly used non-antibiotic drugs is between commonly used non- antibiotic drugs 2Department of Genetics, complex and bidirectional: gut microbiome composition and the gut microbiome. University of Groningen and can be influenced by drugs, but, vice versa, the gut ► Commonly used drugs such as proton pump University Medical Center inhibitors, metformin, selective serotonin Groningen, Groningen, The microbiome can also influence an individual’s response Netherlands to a drug by enzymatically transforming the drug’s reuptake inhibitors and laxatives influence gut 3Department of Pediatrics, structure and altering its bioavailability, bioactivity or microbiome composition and function. University Medical Center toxicity (pharmacomicrobiomics). The gut microbiome ► Proton pump inhibitor- induced changes in Groningen, Groningen, The the gut microbiome can lead to decreased Netherlands can also indirectly impact an individual’s response to immunotherapy in cancer treatment. In this review we colonisation resistance and the development of enteric infections, including Clostridium Difficile Correspondence to discuss the bidirectional interactions between microbes Dr Rinse K Weersma, and drugs, describe the changes in gut microbiota infections. Gastroenterology and induced by commonly used non-antibiotic drugs, and ► Gut microbiome composition is associated with Hepatology, University of their potential clinical consequences and summarise how antitumour response and the clinical efficacy of Groningen, University Medical treatment with immune checkpoint inhibition. Centre Groningen, Groningen the microbiome impacts drug effectiveness and its role Gut microbes can contribute to drug efficacy 9700 RB, The Netherlands; in immunotherapy. Understanding how the microbiome ► r. k. weersma@ umcg. nl metabolises drugs and reduces treatment efficacy will and safety by enzymatically transforming drug unlock the possibility of modulating the gut microbiome structure and altering drug bioavailability, Received 30 March 2020 to improve treatment. bioactivity or toxicity. Revised 21 April 2020 ► Insights into how the gut microbiome interacts Accepted 28 April 2020 with commonly used drugs enable interventions to modulate the gut microbiome and optimise treatment efficacy. INTRODUCTION In the past decade we have witnessed exciting discoveries linking the composition and function of http://gut.bmj.com/ the human gut microbiome to numerous common Finally, the gut microbiome can indirectly impact an diseases and phenotypes. Association studies have individual’s response to immunotherapy in cancer documented changes in the abundance of various treatment via its influence on the host’s general 13 gut bacteria in individuals with gastrointestinal immune status. These exciting new insights into phenotypes, including inflammatory bowel disease, the bidirectional interaction between non- antibiotic irritable bowel syndrome and colorectal cancer, and drugs and the gut microbiome are the focus of the with diseases of other systems and organs, including current review. on October 2, 2021 by guest. Protected copyright. cardiovascular and metabolic conditions, auto- immune conditions and psychiatric disorders.1–9 BackGROUND In addition to association analyses, intervention The development of gut microbiome research studies and animal studies have proven not only the Just a few decades ago our ability to analyse the association but also the causality of the gut micro- role of the gut microbiome in relation to human biome in relation to several diseases.10 Moreover, health was mainly defined by large technical chal- the influence of intrinsic and extrinsic factors on lenges. Historically, microbiome studies were gut microbiome composition is increasingly being performed using culturing methods in which one, understood. or a few, bacterial species were isolated and studied One very important recent finding is that many in relation to a disease. This research produced commonly used non- antibiotic drugs—such as numerous important findings, but our ability to proton pump inhibitors (PPIs) and metformin— analyse other components of the gut ecosystem change microbiome composition and function.11 12 was limited. The development of the technique to © Author(s) (or their These changes can influence health outcomes (in sequence the bacterial 16S ribosomal RNA gene employer(s)) 2020. Re- use permitted under CC BY. the case of PPIs) or reduce drug efficacy (in the case allowed overall taxonomic assessment of the gut Published by BMJ. of metformin). At the same time, more data has microbiome, and this has dramatically increased become available showing that the gut microbiome our knowledge of the broad variations in micro- To cite: Weersma RK, can directly influence an individual’s response to bial composition. More recently, whole genome Zhernakova A, Fu J. Gut Epub ahead of print: [please a specific drug by enzymatically transforming the shotgun sequencing, or metagenomic sequencing include Day Month Year]. drug’s structure and altering its bioavailability, (MGS), has become a powerful methodology for doi:10.1136/ bioactivity or toxicity—a phenomenon now studying the microbiome. MGS allows identifica- gutjnl-2019-320204 referred to as pharmacomicrobiomics (figure 1). tion of not only bacteria, but also viruses, protozoa Weersma RK, et al. Gut 2020;0:1–10. doi:10.1136/gutjnl-2019-320204 1 Recent advances in basic science Gut: first published as 10.1136/gutjnl-2019-320204 on 14 May 2020. Downloaded from Figure 1 Schematic overview of different interactions between the gut microbiome and commonly used non- antibiotic drugs. SCFA, short- chain http://gut.bmj.com/ fatty acids. and fungi, and it enables focussed analysis of bacterial genes and Human cohort- based analysis has further shown that the predicted biological pathways. However, as with all sequencing- dynamic nature of the gut ecosystem reflects a complex inter- based methods, MGS results are very dependent on the method action of the host with lifestyle, dietary, ecological and other used to isolate DNA from stool samples, and this is the major factors. Hundreds of intrinsic and environmental factors influ- on October 2, 2021 by guest. Protected copyright. source of the technical variability in the results of microbiome ence the gut microbiome in healthy individuals, including diet, studies.14 Other omics approaches, such as metatranscriptomics, medication, smoking, lifestyle, host genetics and diseases.15 17 metametabolomics and metaproteomics, are also increasingly Among all environmental factors, commonly used drugs play a being used to get a comprehensive picture of the gut ecosystem. particularly important role in the gut ecosystem. Finally, culturomics analysis, which allows deep characterisation of individual associated species and strains, is again becoming an important method to understand the role of specific taxa in Association of gut microbiome composition with commonly relation to diseases. used drugs in human cohorts Several human cohort studies have reported associations between Intrinsic and extrinsic factors influencing the gut microbiome use of specific drugs and altered microbial composition and func- With the aid of next-generating sequencing, gut microbiome tional profiles (summarised in table 1). One of the first studies analysis has been applied to several human cohorts. One to see this was conducted in the Dutch LifeLines-DEEP cohort, important finding is the large interindividual variability of the and this study reported microbial associations to 19 out of 42 17 gut ecosystem: only a minority of gut microbes are shared across commonly used drugs. In addition to antibiotics, many human- the majority of individuals. For example, in a European data targeted non- antibiotic drugs were associated with changes in set of 3000 samples, only 17 bacteria were identified as a core microbial composition. The top microbiome- associated drugs microbiome present in >95% of all samples.15 The majority of included PPIs, lipid- lowering statins, laxatives, metformin, beta- bacteria are rare. Of the 639 species identified in a population blockers and ACE inhibitors, and selective serotonin reuptake study of 1135 Dutch individuals, 469 (73%) were present in inhibitor antidepressants, and similar associations were also fewer than 10 individuals.16 This high interindividual variability observed in a Belgium Flemish cohort15 and in the TwinsUK potentially leads to variations in the metabolic functions carried cohort18 (table 1). It is also worth noting that these drug- microbe out by the gut microbiome. associations were mostly assessed for individual drugs. However, 2 Weersma RK, et al. Gut 2020;0:1–10. doi:10.1136/gutjnl-2019-320204 Weersma RK, Weersma RK, et al Table 1 Effect of common drugs on the microbiome in population studies . Gut NL% UK% Effect on Effect on beta- div/prop. 2020; Name (analogue UK) n=1124 n=2737 alpha div
Load more

Recommended publications
  • Pharmacomicrobiomics: a Novel Route Towards Personalized Medicine?
    Protein Cell 2018, 9(5):432–445 https://doi.org/10.1007/s13238-018-0547-2 Protein & Cell REVIEW Pharmacomicrobiomics: a novel route towards personalized medicine? Marwah Doestzada1,2, Arnau Vich Vila1,3, Alexandra Zhernakova1, Debby P. Y. Koonen2, Rinse K. Weersma3, Daan J. Touw4, Folkert Kuipers2,5, Cisca Wijmenga1,6, Jingyuan Fu1,2& 1 Departments of Genetics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands 2 Departments of Paediatrics, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands 3 Departments of Gastroenterology & Hepatology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands 4 Departments of Clinical Pharmacy & Pharmacology, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, The Netherlands Cell 5 Departments of Laboratory Medicine, University Medical Center Groningen, PO Box 30001, 9700 RB Groningen, & The Netherlands 6 K.G. Jebsen Coeliac Disease Research Centre, Department of Immunology, University of Oslo, P.O. Box 1072, Blindern, 0316 Oslo, Norway & Correspondence: [email protected] (J. Fu) Received March 5, 2018 Accepted April 16, 2018 Protein ABSTRACT INTRODUCTION Inter-individual heterogeneity in drug response is a Individual responses to a specific drug vary greatly in terms serious problem that affects the patient’s wellbeing and of both efficacy and toxicity. It has been reported that poses enormous clinical and financial burdens on a response rates to common drugs for the treatment of a wide societal level. Pharmacogenomics has been at the variety of diseases fall typically in the range of 50%–75%, forefront of research into the impact of individual indicating that up to half of patients are seeing no benefit genetic background on drug response variability or drug (Spear et al., 2001).
    [Show full text]
  • Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development
    Clinical Pharmacology 1: Phase 1 Studies and Early Drug Development Gerlie Gieser, Ph.D. Office of Clinical Pharmacology, Div. IV Objectives • Outline the Phase 1 studies conducted to characterize the Clinical Pharmacology of a drug; describe important design elements of and the information gained from these studies. • List the Clinical Pharmacology characteristics of an Ideal Drug • Describe how the Clinical Pharmacology information from Phase 1 can help design Phase 2/3 trials • Discuss the timing of Clinical Pharmacology studies during drug development, and provide examples of how the information generated could impact the overall clinical development plan and product labeling. Phase 1 of Drug Development CLINICAL DEVELOPMENT RESEARCH PRE POST AND CLINICAL APPROVAL 1 DISCOVERY DEVELOPMENT 2 3 PHASE e e e s s s a a a h h h P P P Clinical Pharmacology Studies Initial IND (first in human) NDA/BLA SUBMISSION Phase 1 – studies designed mainly to investigate the safety/tolerability (if possible, identify MTD), pharmacokinetics and pharmacodynamics of an investigational drug in humans Clinical Pharmacology • Study of the Pharmacokinetics (PK) and Pharmacodynamics (PD) of the drug in humans – PK: what the body does to the drug (Absorption, Distribution, Metabolism, Excretion) – PD: what the drug does to the body • PK and PD profiles of the drug are influenced by physicochemical properties of the drug, product/formulation, administration route, patient’s intrinsic and extrinsic factors (e.g., organ dysfunction, diseases, concomitant medications,
    [Show full text]
  • Pharmacogenetic Testing: a Tool for Personalized Drug Therapy Optimization
    pharmaceutics Review Pharmacogenetic Testing: A Tool for Personalized Drug Therapy Optimization Kristina A. Malsagova 1,* , Tatyana V. Butkova 1 , Arthur T. Kopylov 1 , Alexander A. Izotov 1, Natalia V. Potoldykova 2, Dmitry V. Enikeev 2, Vagarshak Grigoryan 2, Alexander Tarasov 3, Alexander A. Stepanov 1 and Anna L. Kaysheva 1 1 Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 109028 Moscow, Russia; [email protected] (T.V.B.); [email protected] (A.T.K.); [email protected] (A.A.I.); [email protected] (A.A.S.); [email protected] (A.L.K.) 2 Institute of Urology and Reproductive Health, Sechenov University, 119992 Moscow, Russia; [email protected] (N.V.P.); [email protected] (D.V.E.); [email protected] (V.G.) 3 Institute of Linguistics and Intercultural Communication, Sechenov University, 119992 Moscow, Russia; [email protected] * Correspondence: [email protected]; Tel.: +7-499-764-9878 Received: 2 November 2020; Accepted: 17 December 2020; Published: 19 December 2020 Abstract: Pharmacogenomics is a study of how the genome background is associated with drug resistance and how therapy strategy can be modified for a certain person to achieve benefit. The pharmacogenomics (PGx) testing becomes of great opportunity for physicians to make the proper decision regarding each non-trivial patient that does not respond to therapy. Although pharmacogenomics has become of growing interest to the healthcare market during the past five to ten years the exact mechanisms linking the genetic polymorphisms and observable responses to drug therapy are not always clear. Therefore, the success of PGx testing depends on the physician’s ability to understand the obtained results in a standardized way for each particular patient.
    [Show full text]
  • Measuring Ligand Efficacy at the Mu- Opioid Receptor Using A
    RESEARCH ARTICLE Measuring ligand efficacy at the mu- opioid receptor using a conformational biosensor Kathryn E Livingston1,2, Jacob P Mahoney1,2, Aashish Manglik3, Roger K Sunahara4, John R Traynor1,2* 1Department of Pharmacology, University of Michigan Medical School, Ann Arbor, United States; 2Edward F Domino Research Center, University of Michigan, Ann Arbor, United States; 3Department of Pharmaceutical Chemistry, School of Pharmacy, University of California San Francisco, San Francisco, United States; 4Department of Pharmacology, University of California San Diego School of Medicine, La Jolla, United States Abstract The intrinsic efficacy of orthosteric ligands acting at G-protein-coupled receptors (GPCRs) reflects their ability to stabilize active receptor states (R*) and is a major determinant of their physiological effects. Here, we present a direct way to quantify the efficacy of ligands by measuring the binding of a R*-specific biosensor to purified receptor employing interferometry. As an example, we use the mu-opioid receptor (m-OR), a prototypic class A GPCR, and its active state sensor, nanobody-39 (Nb39). We demonstrate that ligands vary in their ability to recruit Nb39 to m- OR and describe methadone, loperamide, and PZM21 as ligands that support unique R* conformation(s) of m-OR. We further show that positive allosteric modulators of m-OR promote formation of R* in addition to enhancing promotion by orthosteric agonists. Finally, we demonstrate that the technique can be utilized with heterotrimeric G protein. The method is cell- free, signal transduction-independent and is generally applicable to GPCRs. DOI: https://doi.org/10.7554/eLife.32499.001 *For correspondence: [email protected] Competing interests: The authors declare that no Introduction competing interests exist.
    [Show full text]
  • Antimalarial Drug Efficacy and Drug Resistance: 2000–2010 WHO Library Cataloguing-In-Publication Data
    GLOBAL REPORT ON ANTIMALARIAL DRUG EFFICACY AND DRUG RESISTANCE: 2000–2010 WHO Library Cataloguing-in-Publication Data Global report on antimalarial drug efficacy and drug resistance: 2000-2010. 1.Malaria - prevention and control. 2.Malaria - drug therapy. 3.Antimalarials - therapeutic use. 4.Epidemiologic surveillance - methods. 5.Drug resistance. 6.Drug monitoring. 7.Treatment outcome. 8.Thailand. 8.Cambodia. I.World Health Organization. ISBN 978 92 4 150047 0 (NLM classification: QV 256) © World Health Organization 2010 All rights reserved. Publications of the World Health Organization can be obtained from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; e-mail: [email protected]). Requests for permission to reproduce or translate WHO publications – whether for sale or for noncommercial distribution – should be addressed to WHO Press, at the above address (fax: +41 22 791 4806; e-mail: [email protected]). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters.
    [Show full text]
  • Technical Expert Group on Drug Efficacy and Response 1–2 June 2017 Room M 605, Headquarters, World Health Organization, Geneva, Switzerland
    Global Malaria Programme Technical Expert Group on Drug Efficacy and Response 1–2 June 2017 Room M 605, Headquarters, World Health Organization, Geneva, Switzerland Minutes of the Technical Expert Group on Drug Efficacy and Response This document was prepared as a pre-read for the meeting of the Malaria Policy Advisory Committee and is not an official document of the World Health Organization. WHO/HTM/GMP/MPAC/201712 Page 2 of 35 Minutes of the Technical Expert Group on Drug Efficacy and Response Contents Acknowledgments ................................................................................................................................... 4 Abbreviations .......................................................................................................................................... 4 Summary and recommendations............................................................................................................ 5 1 Welcome and introduction of guest speakers ................................................................................ 9 2 Declarations of interest................................................................................................................... 9 3 Minutes and action points of TEG 2015 .......................................................................................... 9 4 Session 1. Molecular markers: genotyping and monitoring drug resistance ................................. 9 4.1 Molecular markers of piperaquine resistance .......................................................................
    [Show full text]
  • Understanding Key Determinants of Drug Activity
    CASE STUDY Dr. Kevin Lustig, President and CEO, The Assay Depot, Inc. Greater San Diego Area Understanding Key Determinants of Drug Activity SUMMARY This article highlights the increasing role that drug metabolism and transport proteins have in the drug approval process. CASE STUDY: The Assay Depot, Inc. The dynamics of drug metabolizing enzymes and transporters is critical to the development of personalized medicine strategies. Abstract / Summary The dynamics of drug metabolizing enzymes and transporters is critical to the develop- ment of personalized medicine strategies. A multitude of factors regulate enzymes and transporters, which in turn affect the pharmacokinetic properties of drugs and medi- ate drug interactions. Evaluation of drug interaction profiles is a critical step in drug development and necessitates detailed in vitro and in vivo studies along with predictive modeling. PharmaPendium® via its Metabolizing Enzymes and Transporters Module provides unprecedented depth of data on drug metabolizing enzymes and transporters and offers a unique platform for modeling advanced drug interactions. This Module will prove to be a valuable resource capable of improving workflows and accelerating devel- opment by enabling intelligent, in silico drug design. By providing scientists with all of the available knowledge about drug metabolism, we can significantly reduce the need for costly and time-consuming lab work and animal models. Requiring these only to answer the true unknowns where no one else has gone before. Introduction Every successful drug discovery and development effort needs to factor in drug efficacy Dr. Kevin Lustig, Author and safety, both of which are intimately linked to drug metabolism. Hence knowledge President & CEO, The Assay Depot Inc.
    [Show full text]
  • Pharmacokinetics and Pharmacology of Drugs Used in Children
    Drug and Fluid Th erapy SECTION II Pharmacokinetics and Pharmacology of Drugs Used CHAPTER 6 in Children Charles J. Coté, Jerrold Lerman, Robert M. Ward, Ralph A. Lugo, and Nishan Goudsouzian Drug Distribution Propofol Protein Binding Ketamine Body Composition Etomidate Metabolism and Excretion Muscle Relaxants Hepatic Blood Flow Succinylcholine Renal Excretion Intermediate-Acting Nondepolarizing Relaxants Pharmacokinetic Principles and Calculations Atracurium First-Order Kinetics Cisatracurium Half-Life Vecuronium First-Order Single-Compartment Kinetics Rocuronium First-Order Multiple-Compartment Kinetics Clinical Implications When Using Short- and Zero-Order Kinetics Intermediate-Acting Relaxants Apparent Volume of Distribution Long-Acting Nondepolarizing Relaxants Repetitive Dosing and Drug Accumulation Pancuronium Steady State Antagonism of Muscle Relaxants Loading Dose General Principles Central Nervous System Effects Suggamadex The Drug Approval Process, the Package Insert, and Relaxants in Special Situations Drug Labeling Opioids Inhalation Anesthetic Agents Morphine Physicochemical Properties Meperidine Pharmacokinetics of Inhaled Anesthetics Hydromorphone Pharmacodynamics of Inhaled Anesthetics Oxycodone Clinical Effects Methadone Nitrous Oxide Fentanyl Environmental Impact Alfentanil Oxygen Sufentanil Intravenous Anesthetic Agents Remifentanil Barbiturates Butorphanol and Nalbuphine 89 A Practice of Anesthesia for Infants and Children Codeine Antiemetics Tramadol Metoclopramide Nonsteroidal Anti-infl ammatory Agents 5-Hydroxytryptamine
    [Show full text]
  • Comparison of Pharmacokinetics and Efficacy of Oral and Injectable Medicine Outline
    Comparison of pharmacokinetics and efficacy of oral and injectable medicine Outline • Background • Results – Antibiotics – Non steroidal anti-inflammatory drugs (NSAIDs) – Vitamins • Conclusions and recommendations Outline • Background • Results – Antibiotics – Non steroidal anti-inflammatory drugs (NSAIDs) – Vitamins • Conclusions and recommendations Injections given with sterile and reused South America (lower mortality) equipment worldwide Central Europe South America (higher mortality) West Africa Injections given with non-sterile equipment East and Southern Africa Injections given with sterile equipment South East Asia Regions China and Pacific Eastern Europe and Central Asia South Asia Middle East Crescent - 2.0 4.0 6.0 8.0 10.0 12.0 Number of injections per person and per year Injections: A dangerous engine of disease • Hepatitis B – Highly infectious virus – Highest number of infections (21 million annually) – 32% of HBV infections • Hepatitis C – More than 2 million infections each year – More than 40% of HCV infections • HIV – More than 260 000 infections – Approximately 5% of HIV infections Reported common conditions leading to injection prescription • Infections • Asthma – Fever • Other – Upper Respiratory – Malaise Infection/ Ear Infection – Fatigue – Pneumonia – Old Age – Tonsillitis – Pelvic Inflammatory Disease – Skin Infections – Diarrhea – Urinary tract infection Simonsen et al. WHO 1999 Reported injectable medicines commonly used • Antibiotics • Anti-inflammatory agents / Analgesics • Vitamins Simonsen et al. WHO 1999
    [Show full text]
  • Antibiotic Resistance Threats in the United States, 2019
    ANTIBIOTIC RESISTANCE THREATS IN THE UNITED STATES 2019 Revised Dec. 2019 This report is dedicated to the 48,700 families who lose a loved one each year to antibiotic resistance or Clostridioides difficile, and the countless healthcare providers, public health experts, innovators, and others who are fighting back with everything they have. Antibiotic Resistance Threats in the United States, 2019 (2019 AR Threats Report) is a publication of the Antibiotic Resistance Coordination and Strategy Unit within the Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention. Suggested citation: CDC. Antibiotic Resistance Threats in the United States, 2019. Atlanta, GA: U.S. Department of Health and Human Services, CDC; 2019. Available online: The full 2019 AR Threats Report, including methods and appendices, is available online at www.cdc.gov/DrugResistance/Biggest-Threats.html. DOI: http://dx.doi.org/10.15620/cdc:82532. ii U.S. Centers for Disease Control and Prevention Contents FOREWORD .............................................................................................................................................V EXECUTIVE SUMMARY ........................................................................................................................ VII SECTION 1: THE THREAT OF ANTIBIOTIC RESISTANCE ....................................................................1 Introduction .................................................................................................................................................................3
    [Show full text]
  • Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling
    Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) January 2013 Clinical Pharmacology Clinical/Medical 10300.fnl.doc Guidance for Industry Clinical Pharmacogenomics: Premarket Evaluation in Early-Phase Clinical Studies and Recommendations for Labeling Additional copies are available from: Office of Communications Division of Drug Information, WO51, Room 2201 10903 New Hampshire Ave. Silver Spring, MD 20993-0002 Phone: 301-796-3400; Fax 301-847-8714 http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm or Office of Communication, Outreach, and Development (HFM-40) Center for Biologics Evaluation and Research Food and Drug Administration 1401 Rockville Pike, Rockville, MD 20852-1448 http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm (Tel) 800-835-4709 or 301-827-1800 or Office of Communication, Education, and Radiation Programs Division of Small Manufacturers, International and Consumer Assistance Center for Devices and Radiological Health Food and Drug Administration 10903 New Hampshire Ave. WO66, Room 4613 Silver Spring, MD 20993-0002 http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm Email: [email protected] Fax: 301-827-8149 (Tel) Manufacturers Assistance: 800-638-2041 or 301-796-7100 (Tel) International Staff: 301-796-5708 U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research (CDER) Center for Biologics Evaluation and Research (CBER) Center for Devices and Radiological Health (CDRH) January 2013 Clinical Pharmacology Clinical/Medical TABLE OF CONTENTS I.
    [Show full text]
  • 1.11 Antidepressants and the Gut Microbiota
    UCC Library and UCC researchers have made this item openly available. Please let us know how this has helped you. Thanks! Title Effects of psychotropic drugs on the microbiota-gut-liver-brain axis Author(s) Cussotto, Sofia Publication date 2019 Original citation Cussotto, S. 2019. Effects of psychotropic drugs on the microbiota-gut- liver-brain axis. PhD Thesis, University College Cork. Type of publication Doctoral thesis Rights © 2019, Sofia Cussotto. http://creativecommons.org/licenses/by-nc-nd/3.0/ Item downloaded http://hdl.handle.net/10468/9468 from Downloaded on 2021-09-23T15:30:09Z Ollscoil na hÉireann, Corcaigh National University of Ireland, Cork Department of Anatomy and Neuroscience Head of Dept. John F. Cryan Effects of Psychotropic Drugs on the Microbiota-Gut-Liver-Brain Axis Thesis presented by Sofia Cussotto, MPharm Under the supervision of Prof. John F. Cryan Prof. Timothy G. Dinan For the degree of Doctor of Philosophy June 2019 Table of Contents Declaration ......................................................................................................... IV Author Contributions .......................................................................................... IV Acknowledgments ............................................................................................... V Publications and presentations ........................................................................... VI Abstract ............................................................................................................ VIII
    [Show full text]