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Abstract
Metal chelators are emerging as versatile tool with many medical applications. Their versatility allows them to be used in chelation therapy for treating diseases caused by toxic and heavy metal poisoning, chelating agents are capable of binding to toxic metal ions to form complex structures which are easily excreted from the body removing them from intracellular or extracellular spaces. In addition, metal chelators can also be applied as contrast agents in MRI scanning.
Metal Chelation in Medicine provides a clear and timely perspective on the role of chelating agents in the management of metal intoxications and storage diseases. Written by leaders in the field of chelators, this publication is at the cutting-edge of the subject. It covers a broad range of topics such as the use of metal chelators in non-invasive assessment of brain iron overload, and the treatment of systemic iron overload and neurodegenerative diseases. As such it is particularly valuable to clinicians treating metal poisonings and metal storage diseases. However, it is also a useful text for researchers, industry professionals and university students with a specific interest in medicinal chemistry, chelation, metal ions, imaging and non-invasive techniques.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Metal Chelation in Medicine | i | ||
| Preface | v | ||
| Contents | vii | ||
| Chapter 1 - Metal Toxicity – An Introduction | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 Essential Metals | 2 | ||
| 1.2.1 Sodium and Potassium | 2 | ||
| 1.2.2 Magnesium and Calcium | 2 | ||
| 1.2.3 Zinc | 3 | ||
| 1.2.4 Other Essential Metals | 3 | ||
| 1.3 Toxicity Due to Essential Metals | 4 | ||
| 1.3.1 Sodium and Potassium | 4 | ||
| 1.3.2 Calcium and Magnesium | 7 | ||
| 1.3.3 Zinc | 8 | ||
| 1.3.4 Other Essential Metals | 9 | ||
| 1.3.4.1 Cobalt Toxicity | 9 | ||
| 1.3.4.2 Manganese Toxicity | 9 | ||
| 1.3.4.3 Iron and Copper Toxicity | 10 | ||
| 1.3.4.4 Molybdeum Toxicity | 12 | ||
| 1.4 Non-Essential Metals | 12 | ||
| 1.5 Toxicity Due to Non-Essential Metals | 13 | ||
| 1.5.1 Lead | 13 | ||
| 1.5.2 Cadmium | 14 | ||
| 1.5.3 Mercury | 15 | ||
| 1.5.4 Aluminium | 15 | ||
| 1.6 Sources and Routes of Exposure with Particular Reference to Non-Essential Metals | 18 | ||
| 1.7 Conclusions | 19 | ||
| Abbreviations | 20 | ||
| References | 20 | ||
| Chapter 2 - Basic Principles of Metal Chelation and Chelator Design | 24 | ||
| 2.1 Introduction | 24 | ||
| 2.2 Ligand Chemistry | 26 | ||
| 2.3 Ligand Selectivity | 29 | ||
| 2.4 Comparison of Bidentate Ligands | 31 | ||
| 2.4.1 Catechols | 31 | ||
| 2.4.2 Hydroxamates | 33 | ||
| 2.4.3 Hydroxypyridinones | 33 | ||
| 2.4.4 Hydroxypyranones | 35 | ||
| 2.4.5 Aliphatic Diamines | 35 | ||
| 2.4.6 Heterocyclic Amines | 35 | ||
| 2.4.7 Hydroxyquinolines | 36 | ||
| 2.4.8 Aminocarboxylates (Including Oligodentate Ligands) | 36 | ||
| 2.4.9 Hydroxycarboxylates (Including Tri- and Hexadentate Ligands) | 37 | ||
| 2.5 Ligand Denticity – The Chelate Effect | 37 | ||
| 2.6 Complex Lability | 39 | ||
| 2.7 Redox Activity | 41 | ||
| 2.8 Biological Properties | 43 | ||
| 2.9 Lipophilicity and Molecular Weight | 43 | ||
| 2.10 Ligand Metabolism | 44 | ||
| 2.11 Ligand Binding to Serum Albumin | 45 | ||
| 2.12 Chelator Pharmacokinetics | 47 | ||
| 2.13 Toxicity of Chelators | 49 | ||
| 2.13.1 Inhibition of Metal-Dependent Enzymes | 49 | ||
| 2.13.2 Nephrotoxicity | 51 | ||
| 2.13.3 Neurotoxicity | 51 | ||
| 2.13.4 Immunotoxicity | 51 | ||
| 2.13.5 Genotoxicity | 52 | ||
| 2.14 Chelators and Nutrition | 52 | ||
| 2.15 Conclusions | 53 | ||
| Abbreviations | 53 | ||
| References | 53 | ||
| Chapter 3 - Chelation Therapy For Heavy Metals | 56 | ||
| 3.1 Introduction | 56 | ||
| 3.2 General Strategies Against Heavy Metal Intoxication | 58 | ||
| 3.2.1 Toxicology of Heavy Metals | 58 | ||
| 3.2.2 Treatment for Heavy Metal Intoxication | 59 | ||
| 3.2.2.1 Conventional Chelators | 61 | ||
| 3.2.2.2 New Chelators | 61 | ||
| 3.2.3 Drawbacks and Misuse of Chelators | 62 | ||
| 3.3 Arsenic | 63 | ||
| 3.3.1 Absorption and Metabolism of Arsenicals | 63 | ||
| 3.3.2 Toxicity of Arsenicals | 64 | ||
| 3.3.2.1 Mechanism of Arsenic Toxicity | 64 | ||
| 3.3.2.2 Clinical Toxicity of Arsenicals | 65 | ||
| 3.3.3 Diagnostic Measures and Interventional Levels | 66 | ||
| 3.3.4 Chelation Therapy for Arsenic Intoxication | 66 | ||
| 3.3.4.1 Chronic Arsenic Poisoning | 68 | ||
| 3.4 Mercury | 68 | ||
| 3.4.1 Absorption and Metabolism of Mercurials | 70 | ||
| 3.4.1.1 Hg0 | 70 | ||
| 3.4.1.2 Inorganic Mercury | 71 | ||
| 3.4.1.3 Organic Mercury | 72 | ||
| 3.4.2 Toxicology of Mercury | 73 | ||
| 3.4.2.1 Mechanism of Mercury Toxicity | 73 | ||
| 3.4.2.2 Clinical Toxicity of Mercury | 74 | ||
| 3.4.3 Diagnostics and Intervention Levels | 75 | ||
| 3.4.4 Chelation Treatment for Mercury Poisoning | 76 | ||
| 3.5 Lead | 78 | ||
| 3.5.1 Lead Absorption and Metabolism | 78 | ||
| 3.5.2 Toxicity of Lead | 80 | ||
| 3.5.2.1 Mechanism of Lead Toxicity | 80 | ||
| 3.5.3 Diagnostic Measures and Intervention Levels | 82 | ||
| 3.5.4 Treatment of Lead Poisoning | 82 | ||
| 3.6 Cadmium | 85 | ||
| 3.6.1 Absorption and Metabolism of Cadmium | 86 | ||
| 3.6.2 Toxicity of Cadmium | 87 | ||
| 3.6.2.1 Mechanism of Cadmium Toxicity | 88 | ||
| 3.6.2.2 Clinical Toxicity of Cd | 88 | ||
| 3.6.3 Diagnostic Markers and Intervention Level for Cd Intoxication | 90 | ||
| 3.6.4 Chelation Treatment for Cadmium Poisoning | 90 | ||
| 3.7 Noble Metals | 92 | ||
| 3.7.1 Silver Poisoning | 92 | ||
| 3.7.2 Gold Poisoning | 93 | ||
| 3.8 Other Metals | 94 | ||
| 3.8.1 Acute Iron Poisoning | 94 | ||
| 3.8.2 Acute Copper Poisoning | 95 | ||
| 3.8.3 Thallium Poisoning | 95 | ||
| 3.9 Conclusion | 96 | ||
| Abbreviations | 97 | ||
| References | 98 | ||
| Chapter 4 - Treatment of Systemic Iron Overload | 106 | ||
| 4.1 Consequences of Transfusional Iron Overload | 106 | ||
| 4.1.1 Iron Homeostasis in the Absence of Blood Transfusion | 106 | ||
| 4.1.2 Effects of Inherited Anaemias and Blood Transfusion on Iron Homeostasis | 107 | ||
| 4.2 Impact of Transfusion on Iron Distribution and its Consequences | 109 | ||
| 4.3 Desirable Features of Clinically Useful Iron Chelators | 113 | ||
| 4.3.1 High Iron Binding Constant and Selectivity for Iron | 113 | ||
| 4.3.2 Chelation of Iron Pools for Balance Without Inhibition of Key Metabolic Pools | 114 | ||
| 4.4 Monitoring Iron Overload and Its Treatment | 117 | ||
| 4.4.1 Monitoring Trajectory of Iron Overload and Distribution | 117 | ||
| 4.4.1.1 Serum Ferritin (SF) | 117 | ||
| 4.4.1.2 Liver Iron Concentration (LIC) Monitoring | 120 | ||
| 4.4.1.3 Methods for Measuring LIC | 121 | ||
| 4.4.1.4 Myocardial Iron Estimation (T2* or Other Measures) | 122 | ||
| 4.4.1.5 Monitoring of Other Organ Functions and Iron-Mediated Damage | 122 | ||
| 4.4.1.6 Urinary 24 h Iron Estimation | 123 | ||
| 4.4.1.7 Plasma Non-Transferrin Iron (NTBI) and Labile Plasma Iron (LPI) | 123 | ||
| 4.5 Properties and Clinical Beneficial Effects of Available Iron Chelators | 124 | ||
| 4.5.1 Desferrioxamine (Desferal) DFO | 124 | ||
| 4.5.1.1 Physicochemical Properties and Iron Binding | 124 | ||
| 4.5.1.2 Pharmacokinetics of Free Ligand and Iron Complexes | 125 | ||
| 4.5.1.3 Effects on Iron Balance and Ferritin | 125 | ||
| 4.5.1.4 Long-Term Effects on Survival | 126 | ||
| 4.5.1.5 Effects on the Heart | 126 | ||
| 4.5.1.6 Other Long-Term Effects on Morbidity | 127 | ||
| 4.5.2 Deferiprone (DFP) | 127 | ||
| 4.5.2.1 Physicochemical Properties and Iron Binding | 127 | ||
| 4.5.2.2 Pharmacokinetics | 128 | ||
| 4.5.2.3 Effects on Iron Balance | 129 | ||
| 4.5.2.4 Effects on the Heart | 129 | ||
| 4.5.3 Deferasirox (Exjade®) DFX | 130 | ||
| 4.5.3.1 Pharmacokinetics and Metabolism | 130 | ||
| 4.5.3.2 Iron Excretion and Iron Balance | 131 | ||
| 4.5.3.3 Effects on the Heart | 132 | ||
| 4.6 Unwanted Effects of Iron Chelators | 132 | ||
| 4.6.1 Role of Iron Deprivation in Chelator Toxicity | 132 | ||
| 4.6.2 Desferrioxamine Tolerability and Unwanted Effects | 133 | ||
| 4.6.3 Deferiprone Tolerability and Unwanted Effects | 134 | ||
| 4.6.4 Deferasirox Tolerability and Unwanted Effects | 134 | ||
| 4.7 Practical Use of Chelators: A Personal Approach | 135 | ||
| 4.7.1 Patients with Acceptable Levels of Body Iron but Continuing Transfusion | 135 | ||
| 4.7.2 Patients with Unacceptably High Levels of Body Iron | 136 | ||
| 4.7.3 Patients with Unacceptably High Levels of Myocardial Iron | 136 | ||
| 4.7.4 Patients in Heart Failure | 137 | ||
| 4.7.5 Patients with Rapidly Falling Serum Ferritin or Low Values <1000 µ L−1 | 138 | ||
| 4.7.6 Patients not Responding to Monotherapy Regimes: Combined Chelators | 139 | ||
| 4.7.7 Combinations of DFP with DFO | 139 | ||
| 4.7.8 Combinations of DFO Plus DFX | 140 | ||
| 4.7.9 Combination of DFP Plus DFX | 140 | ||
| 4.8 Conclusions | 140 | ||
| Abbreviations | 141 | ||
| References | 141 | ||
| Chapter 5 - Treatment of Neurodegenerative Diseases by Chelators | 153 | ||
| 5.1 Introduction | 153 | ||
| 5.2 The Aging Brain | 154 | ||
| 5.2.1 Brain Iron Homeostasis and Aging | 154 | ||
| 5.2.2 Brain Copper Homeostasis and Aging | 156 | ||
| 5.2.3 Brain Zinc Homeostasis and Aging | 156 | ||
| 5.3 Inflammation and Aging | 157 | ||
| 5.4 Neurodegenerative Diseases | 157 | ||
| 5.5 Blood Brain Barrier | 158 | ||
| 5.6 Metal Ions and Neurodegenerative Diseases | 159 | ||
| 5.6.1 Parkinson’s Disease (PD) | 160 | ||
| 5.6.2 Alzheimer’s Disease (AD) | 163 | ||
| 5.6.3 Intracerebral Haemorrhage | 166 | ||
| 5.6.4 Multiple Sclerosis | 168 | ||
| 5.6.5 Friederich’s Ataxia | 168 | ||
| 5.7 Neurodegeneration with Brain Iron Accumulation (NBIA) Diseases | 169 | ||
| 5.7.1 Mutation in Genes Associated with Iron Metabolism | 169 | ||
| 5.7.1.1 Aceruloplasminaemia | 169 | ||
| 5.7.1.2 Neuroferritinopathy | 172 | ||
| 5.7.1.3 Pantothenate Kinase-Associated Neurodegeneration | 172 | ||
| 5.7.1.4 Huntington’s Disease | 174 | ||
| 5.7.1.5 Wilson’s Disease | 175 | ||
| 5.8 Macular Degeneration | 176 | ||
| 5.9 Conclusion and Perspectives | 177 | ||
| Abbreviations | 177 | ||
| References | 177 | ||
| Chapter 6 - Chelation of Actinides | 183 | ||
| 6.1 The Medical and Public Health Relevance of Actinide Chelation | 183 | ||
| 6.1.1 Actinide Metabolism and Clinical Course | 184 | ||
| 6.1.2 Current Treatment Recommendations for Actinide Contamination | 186 | ||
| 6.1.3 Limitations of Current Therapies | 187 | ||
| 6.2 Designing Chemical Structures for Actinide Chelation | 187 | ||
| 6.2.1 Coordination Chemistry Criteria | 188 | ||
| 6.2.2 Synthetic Approaches to New Actinide-Selective Agents | 188 | ||
| 6.2.2.1 Polyamino-Carboxylic Acid Derivatives | 189 | ||
| 6.2.2.2 Siderophore Mimics | 190 | ||
| 6.2.2.3 Poly-Phosphonic Acid Chelators and Macrocyclic Structures | 192 | ||
| 6.3 Evaluating Actinide Chelation Efficacy | 193 | ||
| 6.3.1 In vitro Evaluation Techniques | 193 | ||
| 6.3.1.1 Solution Thermodynamics | 193 | ||
| 6.3.1.2 High-Throughput Screening Methods | 194 | ||
| 6.3.1.3 In vitro and Ex vivo Binding | 195 | ||
| 6.3.2 In vivo Efficacy Determination | 196 | ||
| 6.3.2.1 Animal Model Selection | 196 | ||
| 6.3.2.2 In vivo Decorporation Studies | 197 | ||
| 6.4 Development of Viable Actinide Chelation Treatments | 199 | ||
| 6.4.1 Formulation Development | 199 | ||
| 6.4.1.1 Structural Modifications of DTPA | 200 | ||
| 6.4.1.2 Pharmaceutical Approaches | 201 | ||
| 6.4.2 Safety Determination and Regulatory Approval | 202 | ||
| 6.4.2.1 The Animal Rule | 203 | ||
| 6.4.2.2 Current Status of Existing Actinide Chelation Products | 205 | ||
| Abbreviations | 206 | ||
| References | 207 | ||
| Chapter 7 - Evaluation of Iron Overload by Non-Invasive Measurement Techniques | 213 | ||
| 7.1 Introduction | 213 | ||
| 7.2 Principles of Iron Measurement Techniques | 215 | ||
| 7.2.1 Reference Standards for Iron Quantification Methods | 215 | ||
| 7.2.1.1 Liver Biopsy | 215 | ||
| 7.2.1.2 Quantitative Heart Biopsy and Autopsy | 216 | ||
| 7.2.1.3 Bone Marrow Iron | 216 | ||
| 7.2.1.4 Post-Mortem Brain Iron | 216 | ||
| 7.2.2 Biochemical Properties of Iron Storage Molecules | 217 | ||
| 7.2.3 Magnetic Properties of Iron Storage Molecules | 218 | ||
| 7.2.3.1 Specific Magnetic Volume Susceptibility (Electron Magnetism) | 220 | ||
| 7.2.3.2 Iron Concentration and Wet-to-Dry Weight Ratio | 223 | ||
| 7.2.3.3 Other Magnetic Properties | 224 | ||
| 7.3 Iron Measurements: Technique, Analysis, and Calibration | 224 | ||
| 7.3.1 Spin-Echo Relaxometry (R2/T2) | 226 | ||
| 7.3.2 Spin-Lattice Relaxometry (T1/R1) | 229 | ||
| 7.3.3 Gradient-Echo Relaxometry (T2*/R2*) | 229 | ||
| 7.3.3.1 Hepatic R2* | 230 | ||
| 7.3.3.2 Cardiac R2* (T2*) | 230 | ||
| 7.3.3.3 Chemical Shift Relaxometry (CSR) | 232 | ||
| 7.3.4 Biomagnetic Susceptometry | 233 | ||
| 7.3.4.1 Biomagnetic Liver Susceptometry (Electronic Susceptometry) | 233 | ||
| 7.3.4.2 MR-Biosusceptometry and MR-QSM (Nuclear Susceptometry) | 234 | ||
| 7.3.5 Other MRI Iron Measurement Techniques | 235 | ||
| 7.3.6 Quantitative X-ray Iron Measurement Techniques | 237 | ||
| 7.4 Applications of In vivo Iron Assessment | 237 | ||
| 7.4.1 Liver | 238 | ||
| 7.4.2 Spleen | 239 | ||
| 7.4.3 Heart | 240 | ||
| 7.4.4 Pancreas | 240 | ||
| 7.4.5 Pituitary | 241 | ||
| 7.4.6 Brain | 242 | ||
| 7.4.7 Iron in Other Organs, Glands, and Tissue | 244 | ||
| 7.4.7.1 Kidney | 244 | ||
| 7.4.7.2 Adrenal Glands | 245 | ||
| 7.4.7.3 Thyroid | 245 | ||
| 7.4.7.4 Testes and Ovaries | 245 | ||
| 7.4.7.5 Bone Marrow | 246 | ||
| 7.5 Conclusion and Prospects | 247 | ||
| Abbreviations | 248 | ||
| Acknowledgement | 248 | ||
| References | 248 | ||
| Chapter 8 - Chelators for Diagnostic Molecular Imaging with Radioisotopes of Copper, Gallium and Zirconium | 260 | ||
| 8.1 Introduction | 260 | ||
| 8.1.1 Positron Emission Tomography and Molecular Imaging with Peptides and Proteins | 261 | ||
| 8.1.2 Reactive Functional Groups for Attachment to Biomolecules | 262 | ||
| 8.1.3 Requirements for Chelators that Complex Positron-Emitting Metal Radioisotopes | 263 | ||
| 8.2 Macrocyclic Chelators for Copper-64: Lessons in Kinetic Stability | 265 | ||
| 8.2.1 Cu Complexes of Macrocycles: Radiolabelling and In vivo Stability | 266 | ||
| 8.2.1.1 Cyclen, Cyclam, Teta and Dota – Not All Macrocycles are Equal to the Task! | 266 | ||
| 8.2.1.2 Alternatives to Teta and Dota – Towards Greater In vivo Stability | 269 | ||
| 8.2.1.3 Nota and Sarcophagine Derivatives – The State of the Art in Bifunctional Chelators for 64Cu | 271 | ||
| 8.2.2 Kinetic Stability is Critical to In vivo Stability – You Can’t Have One Without the Other | 275 | ||
| 8.2.3 Targeting Based on Chelate Reactivity: Bioreduction and Dissociation | 281 | ||
| 8.2.4 Outlook for Clinical Applications of Copper-64 | 282 | ||
| 8.3 Acyclic and Macrocyclic Chelators for Gallium-68: A Short Half-Life Necessitates Efficient Radiolabelling | 283 | ||
| 8.3.1 Gallium-68 in the Clinic: Its Current Utility and Future Potential | 283 | ||
| 8.3.2 Macrocycles for Gallium-68 | 286 | ||
| 8.3.3 Halfway Between Macrocycles and Open-Chain Chelators: Data Derivatives | 289 | ||
| 8.3.4 Acyclic Chelators for Gallium-68 Provide Rapid Radiolabelling at Room Temperature | 290 | ||
| 8.3.5 Siderophores for Coordination of Gallium-68 | 294 | ||
| 8.3.6 Chelator Design and Clinical Impact | 295 | ||
| 8.4 Development of Chelators for Zirconium-89: Work in Progress | 295 | ||
| 8.4.1 Hexadentate Chelators for Zirconium-89: Sufficient, But Suboptimal | 296 | ||
| 8.4.2 Octadentate Chelators for 89Zr4+: Will Saturation of the Coordination Sphere Provide Enhanced Stability In vivo | 299 | ||
| 8.4.3 Metastable Lipophilic Zirconium Chelates | 302 | ||
| 8.5 Conclusions | 303 | ||
| Abbreviations | 304 | ||
| Acknowledgements | 305 | ||
| References | 305 | ||
| Subject Index | 313 |