The Therapeutic Use of N-Acetylcysteine (NAC) in Medicine

392 Pages·2019·6.19 MB·English

by  Richard Eugene Frye

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
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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
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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
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