Richard Eugene Frye Editors Michael Berk The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine Richard Eugene Frye • Michael Berk Editors The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine Editors Michael Berk Richard Eugene Frye IMPACT SRC Barrow Neurological Institute Deakin University & Barwon Health Phoenix Children’s Hospital Geelong University of Arizona Victoria College of Medicine – Phoenix Australia Phoenix, AZ USA ISBN 978-981-10-5310-8 ISBN 978-981-10-5311-5 (eBook) https://doi.org/10.1007/978-981-10-5311-5 Library of Congress Control Number: 2018941104 © Springer Nature Singapore Pte Ltd. 2019 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Adis imprint is published by the registered company Springer Nature Singapore Pte Ltd. The registered company address is: 152 Beach Road, #21-01/04 Gateway East, Singapore 189721, Singapore This book is dedicated to my wife Cara and children Mairin and Quinn, for their daily support and endless joy and to my family, friends, and colleagues who encouraged me to continue forward even when the path ahead was opaque and uncertain. Richard Eugene Frye, MD, PhD Editor Preface I work in the field of autism where effective treatments are few and treatment targets are still ill defined. One principle when looking for a potential effective treatment, especially for children, is to assure safety of the treatment because the young body is vulnerable and because the treatment, if effective, could be required lifelong. My journey into treating children with autism led me to an interest in metabolic disor- ders that affect the nervous system. I met Dr. S. Jill James and Dr. Stephen Kahler at a scientific think-tank on autism. They introduced me to redox regulation abnor- malities associated with autism as well as treatments to improve these abnormali- ties. We were very excited when Dr. Antonio Hardan published his double-blind clinical trial on the use of N-Acetylcysteine (NAC) in autism that supported our premise that targeting redox metabolism could improve important symptoms asso- ciated with autism. Dr. Hardan’s article showed that NAC could reduce a common symptom associated with autism called irritability. This is extremely important since the primary treatments for irritability are antipsychotic medications, which can have significant adverse effects to general health both in the short and long term. As I began to learn more about NAC, I found the wide variety of diseases it could treat, leading to our collaboration with Dr. Michael Berk and the systematic review published in Neuroscience and Biobehavioral Reviews on the use of NAC in neurol- ogy and psychiatry. One of the amazing things that we noticed when reviewing the clinical literature was the safety of NAC, allowing it to be applied to many disor- ders. This led to a more expanded work that is this book. This book is divided into three parts. First, we have the honor to have Dr. Leonore A Herzenberg, one of the pioneers of redox physiology and NAC, to write a history of the use and development of NAC from her perspective. Second is a series of chapters on the role of NAC in important physiological processes, including redox metabolism, neurotransmitter systems, mitochondrial function, apoptosis, and inflammation, from a basic science point of view. Lastly the book has a series of clinically oriented chapters that comprehensively review the literature on important disorders in which NAC has been found to be effective, including toxicity and neu- rological, psychiatric, renal, pulmonary, cardiovascular, and gastrointestinal disor- ders. The clinical evidence that NAC alters biological processes in the clinical setting is also reviewed. Another chapter led by Dr. Leonore A Herzenberg is also presented to suggest that the effectiveness of NAC may signal a new medical phe- nomenon that may be an important part of many diseases, glutathione deficiency. vii viii Preface Lastly we review the studies on the pharmacology and adverse effects of NAC. Overall we hope this book will give the reader a broad introduction into this interesting medical treatment. Phoenix, AZ, USA Richard Eugene Frye Contents Part I Introduction 1 History of N-Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 Leonore A. Herzenberg Part II The Basic Science of N-Acetylcysteine (NAC) 2 Neurotransmitter Systems: Glutamate . . . . . . . . . . . . . . . . . . . . . . . . . . 19 M. Foster Olive, Gregory Powell, Erin McClure, and Cassandra D. Gipson 3 Neurotransmitter Systems: Dopamine . . . . . . . . . . . . . . . . . . . . . . . . . . 29 Nihit Kumar 4 Oxidative Stress in Psychiatric Disorders . . . . . . . . . . . . . . . . . . . . . . . . 53 Lawrence Fung and Antonio Hardan 5 Mitochondrial Metabolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 73 Shannon Rose and Sirish C. Bennuri 6 Apoptosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 Sirish C. Bennuri, Shannon Rose, and Richard Eugene Frye 7 Inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 Rabindra Tirouvanziam Part III The Clinical Use of N-Acetylcysteine (NAC) 8 Clinical Trials on N-Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 Richard Eugene Frye 9 N-Acetylcysteine in the Poisoned Patient . . . . . . . . . . . . . . . . . . . . . . . . 147 Angela L. Chiew and Geoffrey K. Isbister 10 The Use of N-Acetylcysteine as a Chelator for Metal Toxicity . . . . . . . .169 Daniel A. Rossignol ix x Contents 11 Application of N-Acetylcysteine in Neurological Disorders . . . . . . . . . 181 Reza Bavrsad Shahripour, Ana Hossein Zadeh Maleki, and Andrei V. Alexandrov 12 Application of N-Acetylcysteine in Psychiatric Disorders . . . . . . . . . . . 203 John Slattery and Richard Eugene Frye 13 Clinical Treatment of Addictive Disorders with  N-Acetylcysteine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219 Gregory Powell, Erin A. McClure, M. Foster Olive, and Cassandra D. Gipson 14 The Clinical Use of N-Acetylcysteine for the Treatment and Protection Against Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . 235 Richard Eugene Frye 15 Application of N-Acetylcysteine in Pulmonary Disorders. . . . . . . . . . . 255 Carol Conrad 16 The Clinical Use of N-Acetylcysteine in Cardiology . . . . . . . . . . . . . . . 277 John P. Marenco and Richard Eugene Frye 17 The Clinical Use of N-Acetylcysteine in Gastrointestinal Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 289 Richard Eugene Frye 18 The Clinical Use of N-Acetylcysteine in Other Medical Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 Richard Eugene Frye 19 The Physiological Effects of N-Acetylcysteine in Clinical Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 331 Richard Eugene Frye 20 Cysteine/Glutathione Deficiency: A Significant and Treatable Corollary of Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 Pietro Ghezzi, Kevin V. Lemley, James P. Andrus, Stephen C. De Rosa, Arne Holmgren, Dean Jones, Farook Jahoor, Richard Kopke, Ian Cotgreave, Teodoro Bottiglieri, Neil Kaplowitz, Hajime Nakamura, Frank Staal, Stephen W. Ela, Kondala R. Atkuri, Rabindra Tirouvanziam, Kartoosh Heydari, Bita Sahaf, Andrew Zolopa, Richard Eugene Frye, John J. Mantovani, Leonard A. Herzenberg, and Leonore A. Herzenberg 21 Pharmacology, Formulations, and Adverse Effects . . . . . . . . . . . . . . . . 387 Richard Eugene Frye, James P. Andrus, Kevin V. Lemley, Stephen C. De Rosa, Pietro Ghezzi, Arne Holmgren, Dean Jones, Farook Jahoor, Richard Kopke, Ian Cotgreave, Teodoro Bottiglieri, Neil Kaplowitz, Hajime Nakamura, Frank Staal, Stephen W. Ela, Kondala R. Atkuri, Rabindra Tirouvanziam, Kartoosh Heydari, Bita Sahaf, Andrew Zolopa, John J. Mantovani, Leonard A. Herzenberg, and Leonore A. Herzenberg About the Editors Michael Berk is an NHMRC Senior Principal Research Fellow and is the Alfred Deakin Chair of Psychiatry at Deakin University and Barwon Health, where he heads the IMPACT Strategic Research Centre. He is also an Honorary Professorial Research Fellow in the Department of Psychiatry, the Florey Institute for Neuroscience and Mental Health and Orygen Youth Health at Melbourne University, as well as in the School of Public Health and Preventive Medicine at Monash University. His major interests are in the discovery and implementation of novel therapies, and risk factors and prevention of psychiatric disorders. Richard Eugene Frye is the Chief of Neurodevelopmental Disorders at the Barrow Neurological Institute at Phoenix Children’s Hospital and Professor of Child Health at the University of Arizona College of Medicine—Phoenix. He is also the Director of the Autism, Down Syndrome and Fragile X Programs at the Barrow Neurological Institute at Phoenix Children’s Hospital and the Director of the Laboratory for the Biological Basis of Neurodevelopmental Disorders at University of Arizona College of Medicine—Phoenix. Dr. Frye received his MD and PhD degrees from Georgetown University Medical Center in Washington DC. He completed a Residency in Pediatrics at the University of Miami/Jackson Memorial Hospital, Residency in Child Neurology and Fellowship in Behavioral Neurology and Learning Disabilities at Harvard University/Children’s Hospital Boston, and Fellowship in Psychology at Boston University. He holds board certifications in General Pediatrics and in Neurology with Special Competence in Child Neurology. Dr. Frye is a leader in autism research. He has authored over 200 peer-reviewed publications and book chapters, and serves on several editorial boards. Over the past several years Dr. Frye has completed several clinical studies on children with autism spectrum disorder (ASD), including studies focusing on defining the clinical, behavioral, cognitive, and genetic characteristics of children with ASD with meta- bolic disorders, particularly those affected by folate, cobalamin, or mitochondrial metabolism abnormalities. Dr. Frye has completed several clinical trials demon- strating the efficacy of safe and novel treatments that address underlying physiolog- ical abnormalities in children with ASD, including open-label trials on xi