Chelation Therapy in the Treatment of Metal Intoxication Page left intentionally blank Chelation Therapy in the Treatment of Metal Intoxication Jan Aaseth Department of Public Health Hedmark University College, Elverum Department of Internal Medicine Innlandet Hospital, Kongsvinger Hedmark, Norway Guido Crisponi Department of Chemical and Geological Sciences University of Cagliari Cagliari, Italy Ole Andersen Department of Science and Environment Roskilde University Roskilde, Denmark AMSTERDAM • BOSTON • HEIDELBERG • LONDON NEW YORK • OXFORD • PARIS • SAN DIEGO SAN FRANCISCO • SINGAPORE • SYDNEY • TOKYO Academic Press is an Imprint of Elsevier Academic Press is an imprint of Elsevier 125 London Wall, London EC2Y 5AS, UK 525 B Street, Suite 1800, San Diego, CA 92101-4495, USA 50 Hampshire Street, 5th Floor, Cambridge, MA 02139, USA The Boulevard, Langford Lane, Kidlington, Oxford OX5 1GB, UK Copyright © 2016 Elsevier Inc. All rights reserved. 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British Library Cataloguing-in-Publication Data A catalogue record for this book is available from the British Library Library of Congress Cataloging-in-Publication Data A catalog record for this book is available from the Library of Congress ISBN: 978-0-12-803072-1 For information on all Academic Press publications visit our website at https://www.elsevier.com/ Typeset by Thomson Digital Contents Contributors xi Preface xiii List of Abbreviations xv 1. General Chemistry of Metal Toxicity and Basis for Metal Complexation Jan Aaseth, Lars Gerhardsson, Marit Aralt Skaug, Jan Alexander 1.1 General Chemistry of Metals 1 1.2 Essential and Nonessential Elements 3 1.3 Effects of Toxic Exposure of an Essential or Nonessential Metal 7 1.3.1 Basic Concepts in Chemical Toxicity Testing 7 1.3.2 Exposure Patterns and Mechanisms of Metal Toxicity 10 1.3.3 Gastrointestinal Effects of Metal Exposure 11 1.3.4 Respiratory Effects of Metal Exposure 11 1.3.5 Hepatic and Renal Effects 12 1.3.6 Effects on the Nervous System 13 1.3.7 Hematological Effects 14 1.3.8 Cardiovascular Effects 15 1.3.9 Metal Allergies 15 1.3.10 Carcinogenic Effects 15 1.4 Basis for Metal Complex Formation with Endogenous and Exogenous Ligands 16 1.5 Endogenous Complexing and Detoxification Compounds 20 1.5.1 Albumin 20 1.5.2 Transferrin and Ferritin 21 1.5.3 Glutathione 24 1.5.4 Metallothionein 26 1.5.5 Selenoproteins 28 1.6 Conclusions 28 References 29 2. Chelating Agents as Therapeutic Compounds—Basic Principles Guido Crisponi, Valeria Marina Nurchi 2.1 Chemical and Biological Principles for in Vivo Chelation 35 2.1.1 Stability 36 2.1.2 Selectivity 38 v vi Contents 2.1.3 Kinetic Aspects of Chelation 39 2.1.4 Absorption and Bioavailability of Chelating Agents 41 2.2 Chelating Agents: Chemistry, Kinetics, and Toxicology 41 2.2.1 BAL, DMPS, DMSA 42 2.2.2 D-penicillamine 46 2.2.3 Triethylenetetramine 49 2.2.4 Deferoxamine, Deferiprone, and Deferasirox 50 2.2.5 EDTA and DTPA 53 2.2.6 Prussian Blue 56 References 57 3. Diagnosis and Evaluation of Metal Poisonings and Chelation Therapy Petr Dusek, Jan Aaseth 3.1 Introduction 63 3.2 History of Symptoms and Exposure 63 3.3 Clinical Findings 66 3.4 Genetic Disorders with Systemic Metal Accumulation 71 3.5 Toxicological Analyses 73 3.6 Biochemical Measurements 75 3.7 Physiological, Radiological, and Ultrasonographic Investigations 76 References 78 4. Chelation Treatment During Acute and Chronic Metal Overexposures—Experimental and Clinical Studies Ole Andersen 4.1 Introduction 86 4.2 Aluminum 88 4.2.1 Selected Representative Animal Studies 93 4.2.2 Selected Representative Clinical Studies 95 4.2.3 Conclusions 97 4.3 Antimony 97 4.3.1 Animal Experiments 98 4.3.2 Clinical Cases 99 4.3.3 Conclusion 101 4.4 Arsenic 101 4.4.1 Selected Animal Experiments 102 4.4.2 Clinical Studies 107 4.4.3 Discussion and Conclusion 112 4.5 Beryllium 113 4.5.1 Experimental Chelation Studies 114 4.5.2 Clinical Experience 116 4.5.3 Conclusion 116 Contents vii 4.6 Bismuth 116 4.6.1 Animal Chelation Studies 117 4.6.2 Clinical Chelation Studies 118 4.6.3 Conclusion 120 4.7 Cadmium 120 4.7.1 Animal Chelation Experiments 121 4.7.2 Clinical Chelation Studies 124 4.7.3 Conclusion 124 4.8 Chromium 124 4.8.1 Animal Experimental Studies 125 4.8.2 Clinical Cases 127 4.8.3 Conclusion 129 4.9 Cobalt 129 4.9.1 Chelation, Animal Experiments 130 4.9.2 Chelation, Clinical Studies 132 4.9.3 Conclusions 132 4.10 Copper 133 4.10.1 Animal Chelation Studies 135 4.10.2 Human Clinical Chelation Studies 135 4.10.3 Conclusions 137 4.11 Gallium 137 4.11.1 Experimental Animal Chelation Studies 138 4.11.2 Clinical Chelation 139 4.11.3 Conclusions 139 4.12 Gold 139 4.12.1 Animal Experimental Studies 140 4.12.2 Clinical Studies 142 4.12.3 Conclusions 143 4.13 Iron 144 4.13.1 Selected Animal Studies 145 4.13.2 Clinical Chelation Cases 146 4.13.3 Clinical Reviews 149 4.13.4 Conclusions 150 4.14 Lead 151 4.14.1 Animal Chelation Studies 153 4.14.2 Clinical Studies 157 4.14.3 Summary and Conclusions 165 4.15 Manganese 166 4.15.1 Animal Experimental Chelation Studies 167 4.15.2 Clinical Chelation Studies 168 4.15.3 Conclusion 168 4.16 Mercury 169 4.16.1 Experimental Animal Studies 171 4.16.2 Clinical Studies 174 4.16.3 Conclusions 184 4.17 Nickel 185 4.17.1 Experimental Chelation Studies 186 viii Contents 4.17.2 Clinical Studies 189 4.17.3 Conclusions 191 4.18 Platinum 192 4.18.1 Experimental Animal Studies 194 4.18.2 Clinical Studies 195 4.18.3 Conclusions 195 4.19 Silver 196 4.20 Thallium 197 4.20.1 Animal Studies 200 4.20.2 Clinical Cases 201 4.20.3 Conclusions 203 4.21 Tin 203 4.21.1 Animal Experimental and Clinical Studies 205 4.21.2 Conclusions 205 4.22 Zinc 205 4.22.1 Experimental and Clinical Chelation Studies 207 4.22.2 Conclusions 208 4.23 Summary, Conclusions, and Perspectives 208 References 210 5. Decorporation of Radionuclides Ole Andersen 5.1 Introduction 253 5.2 Americium 255 5.3 Cesium 258 5.4 60Cobalt 260 5.5 Plutonium 261 5.6 Polonium 265 5.7 Radium 269 5.8 Strontium 270 5.9 Technetium 271 5.10 Thorium 271 5.11 Uranium 273 5.12 Development of New Chelators and Off-Label Use of Chelating Agents 277 5.13 Conclusions and Perspectives 278 References 279 6. Chelating Therapy in Metal Storage Diseases Petr Dusek, Jan Aaseth 6.1 Introduction 286 6.2 Wilson’s Disease 286 6.2.1 Penicillamine in Wilson’s Disease 287 6.2.2 Trientine Treatment—The Treatment of Choice Today? 287 Contents ix 6.2.3 Ammonium Tetrathiomolybdate—An Alternative Agent? 288 6.2.4 Zinc—An Agent for Maintenance Therapy 289 6.2.5 Dimercaptosuccinic Acid (DMSA)—Useful in Wilson’s Disease? 289 6.2.6 Liver Transplantation 290 6.2.7 Conlusive Guidelines for Therapeutic Monitoring of Wilson’s Disease 290 6.3 Other Neurodegenerative Diseases 291 6.3.1 Friedreich’s Ataxia 291 6.3.2 Aceruloplasminemia 292 6.3.3 Pantothenate Kinase Associated Neurodegeneration 295 6.3.4 Other Neurodegenerations with Brain Iron Accumulation 296 6.3.5 Parkinson’s Disease 298 6.3.6 Demyelinating Disorders and Neuroinflammation 299 6.4 Transfusional and Hereditary Siderosis—Including Thalassemias 300 6.4.1 Deferoxamine (Desferrioxamine) in Transfusional Siderosis 301 6.4.2 Deferiprone Therapy 302 6.4.3 Deferasirox 302 6.4.4 Bone Marrow Transplantation in Thalassemia 303 6.4.5 Hemochromatosis—and Therapeutic Elimination by the Endogenous “Heme Chelate” 304 6.5 Concluding Remarks 304 References 305 7. Guidance for Clinical Treatment of Metal Poisonings—Use and Misuse of Chelating Agents Lars Gerhardsson, Jan Aaseth 7.1 Introduction 314 7.2 Reducing the Absorbed Dose 314 7.2.1 Removal From Exposure 314 7.2.2 Removal of Toxic Element From the Gastrointestinal Tract 315 7.2.3 Use of Gastric Lavage, Activated Charcoal, or Unabsorbed Resins 315 7.3 General Supportive Therapy 316 7.3.1 Maintenance of Respiration and Circulation 316 7.3.2 Maintenance of Water and Electrolyte Balance 316 7.3.3 Control of Cerebral Functions 317 7.4 Elimination of Absorbed Poison 317 7.4.1 Diuresis 317 7.4.2 Biliary Excretion 317 7.4.3 Dialysis 318 7.4.4 Exchange