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Book Details
Abstract
Despite ongoing efforts to prohibit the production, storage and use of chemical warfare agents recent world events highlight the enduring threat to the population from these agents. Research efforts in various countries have resulted in novel insights into chemical warfare toxicology that has enabled the development of new approaches for the diagnosis and treatment of chemical warfare poisoning. This book provides an up-to-date treatise on the diagnosis and verification of exposure, and the pre- and post-exposure treatment of poisoning. Focussing on the most important representative nerve and blistering agents, whilst also covering other potential chemical warfare agents, this book will give the reader a comprehensive overview of the many different aspects of chemical warfare agent toxicology. The text will appeal to toxicologists, biochemists and weapons specialists working in industry and academia, and anyone with an interest in chemical warfare toxicology or exposure.
Table of Contents
| Section Title | Page | Action | Price |
|---|---|---|---|
| Cover | Cover | ||
| Chemical Warfare Toxicology Volume 2: Management of Poisoning | i | ||
| Preface | vii | ||
| References to Material in The National Archives | ix | ||
| Contents | xi | ||
| Chapter 1 - Treatment of Nerve Agent Poisoning | 1 | ||
| 1.1 Introduction | 1 | ||
| 1.2 OP Compounds | 2 | ||
| 1.2.1 General Remarks That Are Relevant for Therapy | 2 | ||
| 1.2.2 Toxicology of OP Compounds | 3 | ||
| 1.2.2.1 Toxicokinetic Aspects Relevant for Therapy | 3 | ||
| 1.2.2.2 Toxicodynamics of Nerve Agents | 4 | ||
| 1.2.2.2.1\rReactions of Nerve Agents with AChE.OP compounds, i.e. nerve agents and pesticides, inhibit serine esterases such as AChE (E.C. ... | 4 | ||
| 1.2.2.2.2\rBinding of Nerve Agents to Other Targets.As highly reactive compounds, nerve agents are able to interact with a variety of prote... | 5 | ||
| 1.3 Protective Measures and Decontamination | 6 | ||
| 1.4 Clinical Picture of Nerve Agent Poisoning | 8 | ||
| 1.4.1 Acute Nerve Agent Poisoning | 8 | ||
| 1.4.1.1 Central Nervous System | 8 | ||
| 1.4.1.2 Autonomic Nervous System | 8 | ||
| 1.4.1.2.1\rSympathetic Nervous System.Nicotinic ACh receptors are located at paravertebral sympathetic ganglions. In response to the pregan... | 8 | ||
| 1.4.1.2.2\rParasympathetic Nervous System.ACh is the primary neurotransmitter of the parasympathetic nervous system and neurotransmission o... | 9 | ||
| 1.4.1.3 Somatic Nervous System | 9 | ||
| 1.4.1.4 Conclusion | 9 | ||
| 1.4.2 Intermediate Syndrome | 10 | ||
| 1.4.3 Organophosphate Induced Delayed Neuropathy | 10 | ||
| 1.5 Pretreatment | 10 | ||
| 1.6 Differences Between Nerve Agent and OP Compound Pesticide Poisoning | 11 | ||
| 1.7 Therapeutic Regimen of Nerve Agent Poisoning | 12 | ||
| 1.7.1 General Considerations | 12 | ||
| 1.7.2 Atropine | 12 | ||
| 1.7.2.1 Self and Buddy Aid | 13 | ||
| 1.7.2.2 Treatment by Medical Specialists | 14 | ||
| 1.7.3 Oximes | 16 | ||
| 1.7.3.1 General Background | 16 | ||
| 1.7.3.2 Effectiveness of Oximes in Nerve Agent Poisoning | 17 | ||
| 1.7.3.3 Interaction with Persisting Poison Load | 20 | ||
| 1.7.3.4 Oxime Dosing Strategies | 21 | ||
| 1.7.3.5 Monitoring of Oxime Therapy | 22 | ||
| 1.7.3.6 Obidoxime | 22 | ||
| 1.7.3.7 Pralidoxime | 24 | ||
| 1.7.3.8 HI-6 | 25 | ||
| 1.7.3.9 Benzodiazepines | 26 | ||
| 1.7.3.10 Magnesium | 27 | ||
| 1.7.3.11 Alkalinization by Sodium Bicarbonate | 29 | ||
| 1.7.3.12 Supportive Treatment | 30 | ||
| 1.8 Summary and Outlook | 30 | ||
| References | 31 | ||
| Chapter 2 - Nerve Agents: Catalytic Scavengers as an Alternative Approach for Medical Countermeasures | 43 | ||
| 2.1 Introduction | 43 | ||
| 2.2 The Scavenger Concept | 44 | ||
| 2.3 Endogenous Bioscavengers | 46 | ||
| 2.4 Stoichiometric Scavengers | 46 | ||
| 2.5 Pseudo-Catalytic Scavengers | 48 | ||
| 2.6 Catalytic Scavengers | 49 | ||
| 2.7 Requirements for Operational Catalytic Scavengers | 49 | ||
| 2.8 Potential Enzymes | 52 | ||
| 2.8.1 Phosphotriesterases | 52 | ||
| 2.8.1.1 Bacterial PTEs | 52 | ||
| 2.8.1.2 Human Paraoxonase | 54 | ||
| 2.8.1.3 Other Mammalian PTEs | 55 | ||
| 2.8.2 Engineered ChEs and CaEs | 56 | ||
| 2.8.3 Oxidases | 59 | ||
| 2.8.3.1 Glutathione S-Transferases | 59 | ||
| 2.8.3.2 Laccases | 59 | ||
| 2.9 Catalytic Antibodies | 60 | ||
| 2.10 Artificial Enzymes | 60 | ||
| 2.11 Future Directions | 60 | ||
| References | 62 | ||
| Chapter 3 - Nicotinic Receptors as Targets for Nerve Agent Therapy | 82 | ||
| 3.1 Introduction | 82 | ||
| 3.2 Current Therapy for Nerve Agent Poisoning | 83 | ||
| 3.3 Potential Benefits of Nicotinic Antagonists in Nerve Agent Poisoning | 84 | ||
| 3.4 Nicotinic ACh Receptors | 85 | ||
| 3.5 The Muscle nAChR | 86 | ||
| 3.6 Blockers of Neuromuscular Transmission | 89 | ||
| 3.7 Effects of AChE Inhibitors at the NMJ | 92 | ||
| 3.8 Anti-Nicotinic Effects of Oximes | 93 | ||
| 3.9 Optimisation of the Anti-Nicotinic Properties of Bispyridinium Compounds | 94 | ||
| 3.10 Protection Against Delayed Respiratory Failure | 97 | ||
| 3.11 Neuronal Nicotinic Receptors | 98 | ||
| 3.12 Drugs Acting at Neuronal Nicotinic Receptors | 101 | ||
| 3.13 Neuronal Nicotinic Effects in Nerve Agent Poisoning | 102 | ||
| 3.13.1 Mecamylamine | 102 | ||
| 3.13.2 Benthiactzine | 103 | ||
| 3.14 Summary | 103 | ||
| References | 104 | ||
| Chapter 4 - Mustard: Pathophysiology and Therapeutic Approaches | 120 | ||
| 4.1 Introduction | 120 | ||
| 4.2 Chemistry | 121 | ||
| 4.3 Toxicokinetics | 121 | ||
| 4.4 Clinical Picture | 124 | ||
| 4.4.1 Skin | 124 | ||
| 4.4.2 Lungs | 125 | ||
| 4.4.3 Eyes | 125 | ||
| 4.5 Therapeutic Interventions for SM Injury in Correlation with the Molecular Pathology | 126 | ||
| 4.5.1 Search for Novel Therapies, the Animal Efficacy Rule, Regulatory Requirements and Their Effect on Research Strategies | 128 | ||
| 4.5.2 Alkylation | 129 | ||
| 4.5.3 Direct SM Scavengers | 131 | ||
| 4.5.4 Inflammation | 131 | ||
| 4.5.5 Anti-Inflammatory Therapy | 132 | ||
| 4.5.6 Repair of SM Induced DNA Lesions with a Focus on PARP | 133 | ||
| 4.5.7 PARP Inhibitors | 134 | ||
| 4.5.8 SM and Cell Death | 135 | ||
| 4.5.9 Limitation of Extrinsic Apoptosis | 137 | ||
| 4.5.10 Reactive Species Formation After SM Exposure | 137 | ||
| 4.5.11 Anti-Oxidative Interventions | 138 | ||
| 4.5.12 Other Therapeutic Approaches | 140 | ||
| 4.5.12.1 Macrolide Antibiotics | 140 | ||
| 4.5.12.2 Silibinin | 142 | ||
| 4.5.12.3 Phytopharmaceuticals | 143 | ||
| 4.5.12.4 Cell Therapies | 144 | ||
| 4.6 Summary and Outlook | 145 | ||
| References | 146 | ||
| Chapter 5 - Clinical and Laboratory Diagnosis of Chemical Warfare Agent Exposure | 157 | ||
| 5.1 Introduction | 157 | ||
| 5.2 Structure and Mechanism | 158 | ||
| 5.3 Clinical Diagnosis | 159 | ||
| 5.3.1 Clinical Signs of Nerve Agent Poisoning | 160 | ||
| 5.3.2 Clinical Signs After Exposure to Volatile Nerve Agents | 161 | ||
| 5.3.3 Clinical Signs After Exposure to Low Volatility Nerve Agents | 162 | ||
| 5.3.4 Alternative Indicators of Nerve Agent Exposure | 164 | ||
| 5.4 Laboratory Diagnosis | 164 | ||
| 5.4.1 Cholinesterases as Diagnostic Markers | 165 | ||
| 5.4.2 Onsite Determination of Cholinesterase Activity | 166 | ||
| 5.4.3 Therapeutic Monitoring: The Cholinesterase Status | 168 | ||
| 5.5 Summary and Outlook | 171 | ||
| References | 172 | ||
| Chapter 6 - Verification of Exposure to Chemical Warfare Agents | 179 | ||
| 6.1 Introduction | 179 | ||
| 6.2 Biomarkers of Exposure | 180 | ||
| 6.2.1 Analytical Methods and Instrumentation | 182 | ||
| 6.3 Sulphur Mustard | 184 | ||
| 6.3.1 Application to Human Samples | 185 | ||
| 6.3.1.1 Intact Agent and Metabolites | 185 | ||
| 6.3.1.2 Protein and DNA Adducts | 191 | ||
| 6.3.1.3 Recent Human Exposures to Sulphur Mustard | 193 | ||
| 6.4 Nerve Agents | 194 | ||
| 6.4.1 Application to Human Samples | 200 | ||
| 6.4.1.1 Samples from Japanese Casualties of Sarin Exposure | 201 | ||
| 6.4.1.2 Sample from a Japanese Casualty of VX Exposure | 203 | ||
| 6.4.1.3 Samples from an Accidental VX Exposure | 204 | ||
| 6.5 Other Agents | 205 | ||
| 6.5.1 Analogues of Sulphur Mustard | 205 | ||
| 6.5.2 Nitrogen Mustards | 205 | ||
| 6.5.3 Lewisite | 206 | ||
| 6.5.4 Quinuclidinyl Benzilate | 207 | ||
| 6.5.5 Phosgene and Hydrogen Cyanide | 207 | ||
| 6.6 Further Developments | 208 | ||
| References | 208 | ||
| Chapter 7 - The Impact of New Technologies on the Elucidation of Chemical Warfare Agent Toxicology | 219 | ||
| 7.1 Introduction | 219 | ||
| 7.2 Transcriptomics | 220 | ||
| 7.2.1 The Use of Microarrays to Study CWA Toxicology | 221 | ||
| 7.2.1.1 Nerve Agents | 223 | ||
| 7.2.1.2 Vesicants | 226 | ||
| 7.2.1.3 Toxic Industrial Chemicals | 229 | ||
| 7.2.1.4 Toxins | 230 | ||
| 7.2.2 Alternative RNA Based Approaches | 231 | ||
| 7.2.2.1 RNA Sequencing Transcriptomics | 231 | ||
| 7.2.2.2 RNA Interference | 232 | ||
| 7.2.3 Transcriptomics Conclusion | 233 | ||
| 7.3 Proteomics | 234 | ||
| 7.3.1 The Principle Strategy of Proteomics | 234 | ||
| 7.3.2 Two-Dimensional Gel Electrophoresis | 235 | ||
| 7.3.3 Mass Spectrometry | 236 | ||
| 7.3.3.1 Matrix Assisted Laser Desorption/Ionisation Mass Spectrometry | 236 | ||
| 7.3.3.2 Electrospray Ionisation Mass Spectrometry | 238 | ||
| 7.3.4 Special Analytical Feature for Relative or Absolute Protein/Peptide Quantification | 238 | ||
| 7.3.4.1 Stable Isotope Labelling by Amino Acids in Cell Culture | 239 | ||
| 7.3.4.2 Isobaric Tagging for Relative and Absolute Quantification | 239 | ||
| 7.3.5 Proteomic Research of CWAs | 241 | ||
| 7.3.5.1 Organophosphorus Agents | 241 | ||
| 7.3.5.2 HD and Alkylating Agents | 242 | ||
| 7.3.5.3 Protein Adducts as Biomarkers | 243 | ||
| 7.3.6 Proteomics Conclusion | 244 | ||
| 7.4 In silico Approaches | 245 | ||
| 7.5 Overall Conclusion | 247 | ||
| References | 248 | ||
| Chapter 8 - Chemical Defence Against Fentanyls | 259 | ||
| 8.1 Introduction | 259 | ||
| 8.2 Brief History | 260 | ||
| 8.3 Medicinal Uses | 263 | ||
| 8.4 Military Interest | 265 | ||
| 8.5 Illegal Trade | 267 | ||
| 8.6 Moscow Theatre Siege | 269 | ||
| 8.7 Resurgence of Military Interest | 273 | ||
| 8.8 Biological Effects | 273 | ||
| 8.8.1 Inhalation Toxicity | 273 | ||
| 8.8.2 Dermal Toxicity | 275 | ||
| 8.8.3 Opioid Antagonists | 276 | ||
| 8.8.4 Opioid Receptors | 279 | ||
| 8.9 Chemistry | 280 | ||
| 8.9.1 Properties | 280 | ||
| 8.9.2 Pyrolysis | 281 | ||
| 8.9.3 Hydrolysis | 283 | ||
| 8.9.4 Decontamination | 285 | ||
| 8.9.5 Detection | 289 | ||
| 8.10 Identification | 290 | ||
| 8.10.1 Environmental Samples | 290 | ||
| 8.10.2 Biomedical Samples | 290 | ||
| 8.11 Conclusions | 293 | ||
| References | 294 | ||
| Subject Index | 314 |