Principles of CNS Drug Development: From Test Tube to Patient / Edition 1

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Central Nervous System (CNS) disorders are responsible for a vast range of illnesses, including depression, schizophrenia, Parkinson's disease and Alzheimer's disease. Recent advances in areas such as genome sequencing and molecular biology have improved the potential for breakthrough treatments for these diseases, yet the drug development process for CNS disorders has remained stubbornly slow.

Principles of CNS Drug Development: From Test Tube to Patient outlines the core processes in drug discovery and development for CNS disorders, from evaluating drugs for desirable efficacy, safety and pharmacokinetic features in preclinical (using in vitro and in vivo models) and clinical experimentation to identifying future drug targets. Containing up-to-date experimental evidence and detailing the main impediments in the pipeline of CNS drug discovery and development, this is a key reference for those involved in all stages of CNS drug discovery.

Provides succinct background information on the major CNS diseases

Follows the development of a new drug from conception to clinical use and post-market surveillance using specific examples

Outlines the particular requirements and obstacles for CNS drugs

Highlights the primary reasons for drug failure at each stage

Addresses most likely future drug targets

Principles of CNS Drug Development: From Test Tube to Patient will be an invaluable resource for students, researchers and professionals in pharmacology, neuroscience and the pharmaceutical industry.

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Editorial Reviews

From the Publisher
"The data that have been presented in this book are accurate and informative." (Canadian Journal of Neurological Sciences, November 2010)
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Product Details

  • ISBN-13: 9780470519790
  • Publisher: Wiley
  • Publication date: 3/9/2010
  • Edition number: 1
  • Pages: 324
  • Product dimensions: 6.70 (w) x 9.60 (h) x 0.70 (d)

Meet the Author

John Kelly

John Kelly, who holds a graduate degree in European history, is the author and coauthor of ten books on science, medicine, and human behavior, including Three on the Edge, which Publishers Weekly called the work of "an expert storyteller." He lives in New York City.

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Table of Contents

Acknowledgements xi

Preface xiii

Abbreviations xvii

1 Introduction 1

1.1 The global burden of CNS disease 2

1.2 Assessment of the global burden of disease 3

1.3 The prevalence of CNS disorders 5

1.4 Disability due to CNS disorders 5

1.5 Economic Costs 8

1.6 Concluding comments 11

References 11

2 An overview of the major CNS disorders 13

2.1 Introduction 13

2.2 Overview of psychiatric disorders 17

2.3 Overview of neurological/neurodegenerative disorders 31

2.4 Concluding comments 37

References 38

3 Neurobiological substrates of CNS disorders 43

3.1 Introduction 43

3.2 Brief introduction to the principles of chemical neurotransmission 44

3.3 Stages of chemical neurotransmission 47

3.4 Approaches to investigating CNS alterations in CNS disorders 50

3.5 Evidence for a neurobiological rationale for CNS disorders 53

3.6 Concluding comments 61

References 62

4 Current pharmacological targets 65

4.1 Introduction 65

4.2 Pharmacological treatments for depression 67

4.3 Pharmacological treatments for schizophrenia 71

4.4 Pharmacological treatments for anxiety disorders 75

4.5 Pharmacological treatments for epilepsy 77

4.6 Pharmacological treatments for Parkinson's disease 80

4.7 Pharmacological treatments for Alzheimer's disease 82

4.8 Concluding comments 83

References 84

5 Premarketing efficacy evaluation 87

5.1 Introduction 87

5.2 Target identification 90

5.3 Lead optimisation 91

5.4 Target validation in animal models 97

5.5 The use of genetically modified animals in CNS drug development 100

5.6 A selection of animal models of psychiatric disease 101

5.7 A selection of animal models of neurodegenerative disease 108

5.8 Which models to choose 111

5.9 Clinical trials that evaluate drug efficacy 112

5.10 Specific drug profiles 120

References 121

6 Pharmacokinetic considerations: Absorption, distribution, metabolism and elimination 127

6.1 Introduction 127

6.2 What are the 'ideal' pharmacokinetic properties for a CNS drug? 129

6.3 Absorption 131

6.4 Distribution 141

6.5 Metabolism 150

6.6 Elimination 158

6.7 Measurement of drug concentrations 160

6.8 Factors that affect pharmacokinetics 161

6.9 Allometric scaling 163

6.10 Microdosing (Phase 0) Studies 163

6.11 Dose prediction and therapeutic drug monitoring 164

6.12 Stereoselectivity of metabolism of drugs 164

6.13 Specific drug profiles 165

6.14 Concluding comments 166

References 166

7 Safety concerns 173

7.1 Introduction 173

7.2 Postmarketing surveillance 174

7.3 Acute poisoning 175

7.4 Quantification of the relative risk of fatalities from CNS drugs 176

7.5 Adverse drug reactions (ADRs) 182

7.6 Specific types of toxicity encountered with psychotropic drugs 183

7.7 Safety concerns following long-term administration of CNS Drugs 185

7.8 Polypharmacy 199

7.9 Specific drug profiles 201

7.10 Concluding comments 203

References 204

Websites 210

8 Preclinical and clinical safety evaluation 211

8.1 Introduction 211

8.2 Preclinical exploratory toxicology and safety pharmacology evaluations 215

8.3 Primary and secondary pharmacology 216

8.4 Safety pharmacology 220

8.5 Toxicology studies required for regulatory purposes 224

8.6 Clinical Studies 238

8.7 Specific drug profiles 239

8.8 Concluding comments 240

References 241

Websites 244

9 CNS drug targets in development and future perspectives 245

9.1 Introduction 245

9.2 How much does it cost to develop a drug? 247

9.3 Clinical drug development times 248

9.4 Harmonisation between regulatory agencies 248

9.5 Development of biomarkers for clinical efficacy 249

9.6 Quality of life issues 255

9.7 Cost-effectiveness of novel treatments 257

9.8 Patient advocacy groups 258

9.9 Novel targets for CNS disorders 259

9.10 Targets in selected CNS disorders 261

9.11 Targeting of signalling pathways 270

9.12 Cardiovascular drugs in Alzheimer's disease 273

9.13 Modifying oxidative stress and inflammatory responses 274

9.14 Targeting of the amyloid-β protein in Alzheimer's disease 276

9.15 Concluding comments 278

References 279

Appendices 287

Index 295

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