In Vivo Models for Drug Discovery
, by Vela, José Miguel; Maldonado, Rafael; Hamon, Michel; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd
- ISBN: 9783527333288 | 3527333282
- Cover: Hardcover
- Copyright: 8/11/2014
This one-stop reference is the first to present the complete picture -- covering all relevant organisms, from single cells to mammals, as well as all major disease areas, including neurological disorders, cancer and infectious diseases.
Addressing the needs of the pharmaceutical industry, this unique handbook adopts a broad perspective on the use of animals in the early part of the drug development process, including regulatory rules and limitations, as well as numerous examples from real-life drug development projects.
After a general introduction to the topic, the expert contributors from research-driven pharmaceutical companies discuss the basic considerations of using animal models, including ethical issues. The main part of the book systematically surveys the most important disease areas for current drug development, from cardiovascular to endocrine disorders, and from infectious to neurological diseases. For each area, the availability of animal models for target validation, hit finding and lead profiling is reviewed, backed by numerous examples of both successes and failures among the use of animal models. The whole is rounded off with a discussion of perspectives and challenges.
Key knowledge for drug researchers in industry as well as academia.
Addressing the needs of the pharmaceutical industry, this unique handbook adopts a broad perspective on the use of animals in the early part of the drug development process, including regulatory rules and limitations, as well as numerous examples from real-life drug development projects.
After a general introduction to the topic, the expert contributors from research-driven pharmaceutical companies discuss the basic considerations of using animal models, including ethical issues. The main part of the book systematically surveys the most important disease areas for current drug development, from cardiovascular to endocrine disorders, and from infectious to neurological diseases. For each area, the availability of animal models for target validation, hit finding and lead profiling is reviewed, backed by numerous examples of both successes and failures among the use of animal models. The whole is rounded off with a discussion of perspectives and challenges.
Key knowledge for drug researchers in industry as well as academia.
Jose Miguel Vela obtained his PhD at the Autonomous University of Barcelona (UAB). He was working as a faculty member engaged in both teaching and research at the Department of Cell Biology, Physiology and Immunology of the UAB. In 2003 he joined ESTEVE R&D as Head of Target Validation, was then Director of Pharmacology, and currently is the Head of Drug Discovery and Preclinical Development. Starting as a neurobiologist he progressed as a neuropharmacologist. His current research is focused on the discovery and development of new analgetics. He has authored more than 100 scientific publications and 80 patent applications.
Rafael Maldonado is Professor of Pharmacology at the University Pompeu Fabra in Barcelona (Spain), where he founded the Laboratory of Neuropharmacology. His research is focused on the study of the neurochemical basis of drug dependence and related disorders, including affective, pain and eating disorders, with a particular focus on the development of novel behavioral models. He has published over 250 scientific articles in international journals and he has been Principal Investigator for 20 years of research grants funded by the main French, Spanish, European, and USA agencies. He is also member of the editorial board of several scientific journals, and has also collaborated with public authorities and private companies in the research policy and pharmaceuticals development on drug abuse and pain.
Michel Hamon is Professor of Neuropharmacology at the University Pierre and Marie Curie in Paris (France). He founded and led a Neuropsychopharmacology Unit of the French Institute for Health and Medical Research (INSERM) at the Faculty of Medicine Pitie-Salpetriere, with the focus on neurobiological mechanisms underlying key brain functions (nociception, sleep, neurovegetative regulations) and behavioral controls by using validated animal models. He has published more than 600 scientific articles. He edited 6 books, and was president of the French Society for Neuroscience and executive officer of the European College of Neuropsychopharmacology (ECNP).
Rafael Maldonado is Professor of Pharmacology at the University Pompeu Fabra in Barcelona (Spain), where he founded the Laboratory of Neuropharmacology. His research is focused on the study of the neurochemical basis of drug dependence and related disorders, including affective, pain and eating disorders, with a particular focus on the development of novel behavioral models. He has published over 250 scientific articles in international journals and he has been Principal Investigator for 20 years of research grants funded by the main French, Spanish, European, and USA agencies. He is also member of the editorial board of several scientific journals, and has also collaborated with public authorities and private companies in the research policy and pharmaceuticals development on drug abuse and pain.
Michel Hamon is Professor of Neuropharmacology at the University Pierre and Marie Curie in Paris (France). He founded and led a Neuropsychopharmacology Unit of the French Institute for Health and Medical Research (INSERM) at the Faculty of Medicine Pitie-Salpetriere, with the focus on neurobiological mechanisms underlying key brain functions (nociception, sleep, neurovegetative regulations) and behavioral controls by using validated animal models. He has published more than 600 scientific articles. He edited 6 books, and was president of the French Society for Neuroscience and executive officer of the European College of Neuropsychopharmacology (ECNP).
List of Contributors xix
Preface xxix
A Personal Foreword xxxi
Part I Transversal Issues Concerning Animal Models in Drug Discovery 1
1 The 3Ns of Preclinical Animal Models in Biomedical Research 3
José Miguel Vela, Rafael Maldonado, and Michel Hamon
1.1 First N: The Need for Use of Animal Models 3
1.2 Second N: The Need for Better Animal Models 5
1.2.1 Unbiased Design 8
1.2.2 Comprehensive Reporting 8
1.2.3 Selection of the Animal Model Based on Its Validity Attributes 9
1.2.4 Appropriate Time and Dosing 11
1.2.5 Use of Biomarkers 12
1.2.6 Use of Various Animal Models 13
1.2.7 Quantitative, Multiple, and Cross-Predictive Measurements 14
1.2.8 Pharmacokinetic–Pharmacodynamic Integration 15
1.2.9 Predefinition and Adherence to the Desired Product Profile 16
1.2.10 Comparison with Gold Standard References 18
1.2.11 Reverse Translation/Backtranslation (Bedside-to-Bench Approach) 18
1.3 Third N: The Need for 3Rs Guiding Principles 19
References 22
2 Alternative Models in Drug Discovery and Development Part I: In Silico and In Vitro Models 27
Luz Romero and José Miguel Vela
2.1 Introduction 27
2.2 In Silico Models 34
2.2.1 Quantitative Structure–Activity Relationship 34
2.2.2 Biokinetic Modeling 37
2.2.3 Disease- and Patient-Specific In Silico Models 42
2.3 In Vitro Models 43
2.3.1 Primary Cells, Cell Lines, Immortalized Cell Lines, and Stem Cells 44
2.3.2 Advanced In Vitro Models for the Prediction of Drug Toxicity 46
2.3.3 In Vitro Tumor Models 47
References 50
3 Alternative Models in Drug Discovery and Development Part II: In Vivo Nonmammalian and Exploratory/Experimental Human Models 59
Luz Romero and José Miguel Vela
3.1 Introduction 59
3.2 In Vivo Nonmammalian Models 59
3.2.1 Zebrafish 61
3.2.2 D. melanogaster 66
3.2.3 C. elegans 71
3.3 In Vivo Exploratory and Experimental Human Models 74
3.3.1 Phase 0 (Exploratory Human Models): Microdosing Studies 76
3.3.2 Phase IB/IIA (Proof-of-Concept) Studies: Experimental Human Models 81
References 84
4 Ethical Issues and Regulations and Guidelines Concerning Animal Research 91
David Sabaté
4.1 Introduction 91
4.2 Current Use of Animals in Biomedical and Pharmaceutical Research 92
4.3 Ethical Concerns and Positions on Animal Research 93
4.4 General Principles for the Ethical Use of Animals in Research 95
4.4.1 The 3Rs Principles (Replacement, Reduction, and Refinement) 95
4.4.2 The Principle of Justification 96
4.4.3 The Principle of Responsibility 97
4.5 Regulatory Framework for Use of Animals in Research 98
4.5.1 European Union 98
4.5.2 The United States 100
4.5.3 Canada 100
4.5.4 Japan 100
4.5.5 Australia 101
4.5.6 India 101
4.5.7 China 101
4.5.8 Brazil 102
4.5.9 Countries without a Specific Legal Framework 102
Acknowledgment 102
References 102
5 Regulatory Issues: Safety and Toxicology Assessment 107
Antonio Guzmán
5.1 Introduction 107
5.1.1 Animal Testing 107
5.1.2 Regulatory Context 109
5.1.3 Clinical Context 109
5.2 Animal Species in Toxicology Studies 110
5.2.1 Rodents 111
5.2.2 Nonrodents 112
5.2.3 Nonconventional Animal Models 114
5.3 Toxicology Studies 114
5.3.1 General Principles 114
5.3.2 General and Repeated Dose Toxicity Studies 116
5.3.3 Safety Pharmacology 118
5.3.4 Genotoxicity 119
5.3.5 Development and Reproductive Toxicity Studies 122
5.3.6 Carcinogenicity Studies 124
5.4 Translation to Clinics: Limitations and Difficulties 126
References 127
6 Generation and Use of Transgenic Mice in Drug Discovery 131
Guillaume Pavlovic, Véronique Brault, Tania Sorg, and Yann Hérault
6.1 Introduction 131
6.2 Improved Mouse Genetic Engineering 133
6.2.1 Recent Technical Developments 133
6.2.2 The Advent of New Mouse Mutant Resource: One Stop Shop 133
6.3 Functional Evaluation and Uses of Mouse Models 136
6.3.1 Standardization and Harmonization 136
6.3.2 Genetic Background and Environmental Influences 137
6.3.3 Challenges Ahead 137
6.3.4 Target Identification and Translation to Humans 138
6.3.5 Use of GEMMs in Pharmaceutical Industry and Risk Assessment 139
6.4 Translation to Clinics: Limitations and Difficulties 140
6.5 Perspectives 142
Acknowledgments 143
References 143
7 In Vivo Brain Imaging in Animal Models: A Focus on PET and MRI 149
Fabien Chauveau, Mathieu Verdurand, and Luc Zimmer
7.1 Introduction: Role of Animal in In Vivo Imaging 149
7.1.1 In Vivo Imaging as a Translational Approach for Basic Research 149
7.1.2 In Vivo Imaging in Animal Models in the Pharmaceutical Industry 150
7.1.3 In Vivo Imaging in Animal Models and the 3R Principles 150
7.2 The Choice of the Right Imaging Modality for Brain Imaging 151
7.3 Small Animal Magnetic Resonance Imaging 152
7.3.1 Principles 152
7.3.2 Magnetic Resonance Spectroscopy 152
7.3.3 Magnetic Resonance Imaging 153
7.4 Positron Emission Tomography 155
7.4.1 Basic Principles and Instrumentation 155
7.4.2 PET and Neuronal Metabolism 155
7.4.3 PET and Brain Receptors and Transporters 156
7.4.4 PET and Receptor Occupancy 158
7.4.5 PET and Neurotransmitter Release 159
7.5 Clinical Translation: Limitations and Difficulties 159
7.5.1 Anesthesia 160
7.5.2 Spatial Resolution and Sensitivity 160
7.5.3 The Mass Effect of Injected Tracers 161
7.5.4 Multimodal PET–MRI for Better Clinical Translation 162
References 163
Part II Animal Models in Specific Disease Areas of Drug Discovery 167
8 Substance Abuse and Dependence 169
Elena Martín-García, Patricia Robledo, Javier Guti_errez-Cuesta, and Rafael Maldonado
8.1 Introduction 169
8.2 Difficulties to Model Addiction in Animals 170
8.3 Tolerance, Sensitization, and Physical Withdrawal 172
8.3.1 Tolerance 172
8.3.2 Sensitization 173
8.3.3 Physical Manifestations of Withdrawal 174
8.3.4 Affective Manifestations of Withdrawal 175
8.4 Reward and Reinforcement 177
8.4.1 Drug Discrimination 177
8.4.2 Conditioned Place Preference 178
8.4.3 Intracranial Self-Stimulation 180
8.4.4 Self-Administration 182
8.5 Translation to Clinics: Limitations and Difficulties 184
References 186
9 Mood and Anxiety Disorders 193
Guy Griebel and Sandra Beeské
9.1 Introduction 193
9.2 Animal Models of Anxiety Disorders 194
9.2.1 Preclinical Measures of Anxiety 194
9.2.2 Preclinical Anxiety Models and Endophenotypes 195
9.3 Animal Models of Mood Disorders 197
9.3.1 Major Depressive Disorder 197
9.3.1.1 Preclinical Measures of Depression 198
9.3.1.2 Endophenotype Models of Depression 199
9.3.2 Bipolar Disorder 199
9.4 Translation to Clinics: Limitations and Difficulties 200
Acknowledgment 201
References 202
10 Schizophrenia 207
Ronan Depoortère and Paul Moser
10.1 Introduction 207
10.2 Models Amenable to Use in Screening 209
10.2.1 Models Based on the Use of Pharmacological Agents 209
10.2.1.1 Dopaminergic Agonists 209
10.2.1.2 NMDA/Glutamate Receptor Antagonists 211
10.2.1.3 Other Pharmacological Agents Used to Induce Behavioural Changes 212
10.2.1.4 5-HT2A Receptor Agonists 212
10.2.1.5 Cannabinoid Receptor Agonists 212
10.2.1.6 Muscarinic Receptor Antagonists 213
10.2.1.7 Glycine B Receptor Antagonists 213
10.2.2 Models Not Based on the Use of Pharmacological Agents 213
10.2.2.1 Conditioned Avoidance Response 213
10.2.2.2 Potentiation of PPI of the Startle Reflex 214
10.2.3 Models More Time Consuming and/or Difficult to Implement 214
10.2.3.1 Models Aimed at Reproducing More Complex Symptoms of Schizophrenia 214
10.2.3.2 Models Aimed at Reproducing the Chronic Nature of Schizophrenia 216
10.2.3.3 Models Based on Genetic Manipulations 218
10.2.4 Models for Side Effects 218
10.2.4.1 Models for Motor Side Effects 219
10.2.4.2 Hyperprolactinemia 220
10.2.4.3 Sedation and Motor Incoordination 220
10.2.4.4 Models for Cognitive Side Effects 220
10.2.4.5 Metabolic Disorders Models 221
10.2.4.6 Models for Cardiovascular Effects 221
10.3 Translation to the Clinic: Limitations and Difficulties 221
10.3.1 Use of “Standard Subjects” 221
10.3.2 From Here to . . . ? 222
References 223
11 Migraine and Other Headaches 231
Inger Jansen-Olesen, Sarah Louise T. Christensen, and Jes Olesen
11.1 Introduction 231
11.2 Vascular Models 231
11.2.1 In Vitro 232
11.2.2 In Vivo 233
11.3 Neurogenic Inflammation 234
11.4 Nociceptive Activation of the Trigeminovascular System 234
11.4.1 Electrophysiological Recordings on Primary Dural Afferents in Trigeminal Ganglion 237
11.4.2 Electrophysiological Recordings in Trigeminal Nucleus Caudalis 239
11.4.3 Histological Markers after Nociceptive Stimulation of the Trigeminovascular System 239
11.5 Cortical Spreading Depression 240
11.6 Human Experimental Migraine Provoking Models 241
11.7 Animal Experimental Migraine Provoking Models 242
11.8 Transgenic Models 246
11.9 Behavioral Models 246
11.9.1 Allodynia or Hyperalgesia 247
11.9.2 Face Grooming 248
11.9.3 Photophobia 248
11.9.4 Various Behaviors 249
11.10 Translation to Clinics: Limitations and Difficulties 249
References 250
12 Nociceptive, Visceral, and Cancer Pain 261
Christophe Mallet, Denis Ardid, and David Balayssac
12.1 Introduction 261
12.2 Acute Pain Tests 261
12.2.1 Introduction 261
12.2.2 Electrical Stimulus 263
12.2.3 Thermal Stimulus 264
12.2.4 Mechanical Stimulus 264
12.2.5 Chemical Stimulus 265
12.3 Visceral Pain Models 265
12.3.1 Introduction 265
12.3.2 Pain Achievement Test 266
12.3.3 Animal Models 267
12.3.4 Pathophysiology and Pharmacology 269
12.4 Cancer Pain Models 270
12.4.1 Introduction 270
12.4.2 Pain Assessment in Animal Models of Cancer Pain 270
12.4.3 Animal Models 271
12.4.4 Pathophysiology and Pharmacology 272
12.4.5 Conclusions 272
12.5 Translation to Clinics: Difficulties and Limitations 273
12.5.1 Acute Pain Tests 273
12.5.2 Visceral Pain Models 274
12.5.3 Cancer Pain Models 274
12.5.4 Conclusions 275
References 275
13 Inflammatory, Musculoskeletal/Joint (OA and RA), and Postoperative Pain 283
Laurent Diop and Yassine Darbaky
13.1 Introduction: Evaluation of Pain in Animal Models 283
13.2 Inflammatory Pain 287
13.2.1 Formalin Test 287
13.2.2 Carrageenan-Induced Hyperalgesia 287
13.2.3 Complete Freund’s Adjuvant-Induced Hyperalgesia 288
13.2.4 Capsaicin-Induced Hyperalgesia 288
13.3 Musculoskeletal/Joint Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Pain 289
13.3.1 Osteoarthritis Pain Models 289
13.3.2 Rheumatoid Arthritis Pain Models 293
13.4 Postoperative Pain 297
13.4.1 Incisional Pain 298
13.4.2 Laparotomy 299
13.4.3 Ovariohysterectomy 299
13.4.4 Other Models of Postoperative Pain 299
13.5 Translation to Clinics: Limitations and Difficulties 300
References 302
14 Neuropathic Pain 305
Said M’Dahoma, Sylvie Bourgoin, and Michel Hamon
14.1 Introduction 305
14.2 Main Types of Neuropathic Pain in Humans 306
14.2.1 Neuropathic Pain Caused by Peripheral Nerve Lesions 306
14.2.1.1 Diabetes-Induced Neuropathic Pain 306
14.2.1.2 Human Immunodeficiency Virus-Related Pain 306
14.2.1.3 Postherpetic Neuralgia 307
14.2.1.4 Neuropathic Pain Caused by Anticancer Drugs 307
14.2.2 Neuropathic Pain Caused by Central Lesions 307
14.2.2.1 Spinal Cord Injury 307
14.2.2.2 The Various Types of Pain in SCI Patients 308
14.3 Modelization of Chronic Pain in Rodents 309
14.3.1 Models of Peripheral Nerve Injury 309
14.3.1.1 Nerve Section 309
14.3.1.2 Nerve Ligation, Compression, and Other Lesion Procedures 310
14.3.1.3 Drug- and Virus-Induced Neuropathic Pain 314
14.3.2 Models of Spinal Cord Injury 318
14.3.2.1 Spinal Cord Contusion 318
14.3.2.2 Clip Compression Injury 319
14.3.2.3 Spinal Cord Transection 319
14.3.2.4 Spinal Cord Ischemia 319
14.3.3 Neuropathic-Like Pain Evoked by Chemicals Administered at the Spinal Level 320
14.3.3.1 Intrathecal Administration of ATP 320
14.3.3.2 Intrathecal Administration of BDNF 320
14.3.3.3 Excitotoxic Injury to the Spinal Cord 321
14.4 Translation to Clinics: Limitations and Difficulties 321
References 324
15 Obesity and Metabolic Syndrome 333
Sunil K. Panchal, Maharshi Bhaswant, and Lindsay Brown
15.1 Introduction 333
15.2 Why Metabolic Syndrome? 333
15.3 Classical Animal Models of Obesity and Metabolic Syndrome 335
15.3.1 Genetic Models of Obesity and Diabetes 336
15.3.2 Artificially Induced Metabolic Syndrome in Animals 337
15.3.2.1 Monosodium Glutamate-Induced Obesity 338
15.3.2.2 Intrauterine Growth-Restricted Rats 338
15.4 Human Experimental Models 344
15.5 Translation to Clinics: Difficulties and Limitations 344
References 344
16 Cognitive Disorders: Impairment, Aging, and Dementia 349
Nick P. van Goethem, Roy Lardenoije, Konstantinos Kompotis, Bart P.F. Rutten, Jos Prickaerts, and Harry W.M. Steinbusch
16.1 Introduction 349
16.2 Pharmacological Models 349
16.2.1 Inhibition of Energy/Glucose Metabolism 350
16.2.2 Cholinergic Interventions 350
16.2.3 Glutamatergic Antagonists 352
16.2.4 Serotonergic Intervention 353
16.3 Aging and Transgenic Models 353
16.3.1 Normal Aging 354
16.3.2 Alzheimer’s Disease 355
16.3.3 Parkinson’s Disease 358
16.3.4 Huntington’s Disease 358
16.3.5 Frontotemporal Dementia 359
16.3.6 Down Syndrome 360
16.4 Translation to Clinics: Limitations and Difficulties 360
References 362
17 Stroke and Traumatic Brain Injury 367
Dominique Lerouet, Valérie C. Besson, and Michel Plotkine
17.1 Introduction 367
17.2 Stroke Models 368
17.2.1 Global Stroke Models 368
17.2.2 Focal Stroke Models 369
17.2.2.1 Extravascular Models 369
17.2.2.2 Photothrombosis Model 370
17.2.2.3 Intraluminal Occlusion Model 370
17.2.2.4 Thromboembolic Models 370
17.3 Traumatic Brain Injury Models 371
17.3.1 TBI Models with Craniotomy 372
17.3.1.1 Weight-Drop Model 372
17.3.1.2 Lateral Fluid Percussion Model 372
17.3.1.3 Controlled Cortical Impact Model 372
17.3.2 TBI Models without Craniotomy 372
17.3.2.1 Weight-Drop Model 373
17.3.2.2 Impact/Acceleration Model 373
17.3.2.3 Acceleration/Deceleration Model 373
17.3.3 Blast Injury Models 373
17.3.4 Repetitive TBI Models 374
17.4 Outcome Assessment 375
17.5 Translation to Clinics: Limitations and Difficulties 377
17.5.1 The Actual Target: From the Neuron to the Neurogliovascular Unit 377
17.5.2 From Bench to Bedside to Bench: Recommendations for Improving the Translational Research 378
References 379
18 Movement Disorders: Parkinson’s Disease 387
Houman Homayoun and Christopher G. Goetz
18.1 Introduction 387
18.1.1 Parkinson’s Disease 387
18.2 Drug- and Toxin-Based Models of PD 389
18.2.1 Reserpine 389
18.2.2 Haloperidol 390
18.2.3 6-OHDA 390
18.2.4 MPTP 393
18.2.5 Rotenone 396
18.2.6 Paraquat and Other Environmental Toxins 398
18.3 Genetic and Functional Models of PD 398
18.3.1 Rodent Genetic Models 399
18.3.1.1 Adult-Onset Rodent Gene-Based Models 401
18.3.2 Rodent Function-Based Models 403
18.3.3 Nonrodent Genetic Models of PD 404
18.4 Translation to Clinics: Limitations and Difficulties 405
References 409
19 Epilepsy: Animal Models to Reproduce Human Etiopathology 415
Isabelle Guillemain, Christophe Heinrich, and Antoine Depaulis
19.1 Introduction 415
19.2 What Animal Species to Use to Model Epilepsy? 416
19.3 Which Type of Models Provide the Most Reliable Information on the Pathophysiology of Epilepsies? 417
19.4 Modeling Four Prototypic Forms of Epilepsy 418
19.4.1 Idiopathic Generalized Epilepsies with Convulsive Seizures 418
19.4.2 Idiopathic Generalized Epilepsies with Absence Seizures 419
19.4.3 Focal Epilepsies Associated with Cortical Dysplasia 420
19.4.4 Modeling Focal Epilepsies Associated with Hippocampal Sclerosis 422
19.5 Translation to Clinics: Limitations and Difficulties 423
References 425
20 Lung Diseases 431
Laurent Boyer, Armand Mekontso-Dessap, Jorge Boczkowski, and Serge Adnot
20.1 Introduction 431
20.2 Animal Models of Lung Emphysema or Chronic Obstructive Pulmonary Disease 432
20.2.1 Cigarette Smoke-Induced COPD 432
20.2.2 COPD Induced by Tracheal Elastase Instillation 433
20.2.3 Genetically Modified Models of COPD 434
20.2.4 Conclusions 434
20.3 Animal Models of Pulmonary Hypertension 434
20.3.1 Relevance of Experimental Animal Models of PH to Human PH 435
20.3.2 The Monocrotaline Model of Pulmonary Hypertension 436
20.3.3 Fawn-Hooded Rats 437
20.3.4 Hypoxic PH 437
20.3.5 SU5416 Treatment Combined with Hypoxia in Mice 438
20.3.6 PH Related to COPD or Smoke Exposure 439
20.4 Animal Models of Fibrotic Lung Diseases 439
20.4.1 Bleomycin-Induced Pulmonary Fibrosis 439
20.4.2 Other Models 440
20.5 Animal Models of Acute Respiratory Distress Syndrome 440
20.6 Translation to Clinics: Limitations and Difficulties 445
References 446
21 Heart Failure 449
Jin Bo Su and Alain Berdeaux
21.1 Introduction 449
21.2 Hypertension-Related Heart Failure 450
21.3 Pressure and Volume Overload-Induced Heart Failure 452
21.3.1 Pressure Overload-Induced Heart Failure 452
21.3.2 Volume Overload-Induced Heart Failure 454
21.3.3 Double Pressure and Volume Overload-Induced Heart Failure 454
21.4 Toxic Molecule-Induced Heart Failure 455
21.4.1 Adriamycin-Induced Heart Failure in Rats 455
21.4.2 Monocrotaline-Induced Right Ventricular Heart Failure 455
21.5 Heart Failure Models Related to Myocardial Ischemia and/or Myocardial Infarction 456
21.5.1 Myocardial Ischemia and/or Myocardial Infarction 456
21.5.2 Coronary Microembolization-Induced Heart Failure 457
21.6 Pacing-Induced Heart Failure 458
21.7 Gene Mutation-Induced Cardiomyopathies 460
21.7.1 Cardiomyopathic Hamsters 460
21.7.2 Golden Retriever Muscular Dystrophy Dogs 460
21.7.3 Genetic Modification-Induced Cardiomyopathies in Mice 461
21.8 Translation to Clinics: Limitations and Difficulties 462
References 462
22 Endocrine Disorders 473
Thomas Cuny, Anne Barlier, and Alain Enjalbert
22.1 Introduction 473
22.2 Animal Models in Autoimmune Endocrine Diseases 474
22.2.1 Animal Models of Autoimmune Thyroiditis 474
22.2.2 Animal Models for Addison’s Disease 476
22.2.3 Animal Models for Other Endocrine Autoimmune Diseases 476
22.3 Animal Models in Endocrine Tumors 477
22.3.1 Multiple Endocrine Neoplasia Syndromes 477
22.3.2 Adrenal Tumorigenesis 478
22.3.3 Thyroid Tumorigenesis 481
22.3.4 Pituitary Tumorigenesis 482
22.4 Animal Models in Endocrine Physiology: Organogenesis, Reproduction, and Metabolism 485
22.4.1 Pituitary Development Disorders: Lessons from Animal Models 485
22.4.2 Animal Models and Reproductive Function 487
22.4.3 Animal Models Used in Calcium Homeostasis Studies 489
22.5 Translation to Clinics: Limitations and Difficulties 490
References 491
23 Gastrointestinal Disorders: A Patho-biotechnology Approach to Probiotic Therapy 497
Roy D. Sleator
23.1 Introduction 497
23.2 Delivery: Improving Probiotic Resistance to Process-Induced Stresses and Storage Conditions 498
23.3 Survival: Improving Probiotic–Host Colonization 500
23.4 Efficacy: “Designer Probiotics” 500
23.5 Translation to Clinics: Limitations and Difficulties 501
Acknowledgment 502
References 502
24 Renal Disorders 505
Dominique Guerrot, Christos Chatziantoniou, and Jean-Claude Dussaule
24.1 Introduction 505
24.2 Animal Models 506
24.2.1 The RenTg Model of CKD 507
24.2.1.1 Benefits of the RenTg Model 509
24.2.2 Unilateral Ureteral Obstruction 510
24.2.2.1 Technical Aspects 510
24.2.2.2 Pathology and Pathophysiology 511
24.2.2.3 Clinical Relevance and Limits 511
24.2.3 Renal Ischemia–Reperfusion 511
24.2.3.1 Technical Aspects 512
24.2.3.2 Pathology and Pathophysiology 512
24.2.3.3 Clinical Relevance and Limits 513
24.2.4 Experimental Alloimmune Glomerulonephritis 513
24.2.4.1 Technical Aspects 513
24.2.4.2 Pathology and Pathophysiology 514
24.2.4.3 Clinical Relevance and Limits 514
24.2.5 Angiotensin II-Mediated Hypertensive Nephropathy 514
24.2.5.1 Technical Aspects 515
24.2.5.2 Pathology and Pathophysiology 515
24.2.5.3 Clinical Relevance and Limits 516
24.2.6 L-NAME-Mediated Hypertensive Nephropathy 516
24.2.6.1 Technical Aspects 516
24.2.6.2 Pathology and Pathophysiology 516
24.2.6.3 Clinical Relevance and Limits 517
24.3 Translation to Clinics: Limitations and Difficulties 518
References 518
25 Genitourinary Disorders: Lower Urinary Tract and Sexual Functions 523
Pierre Clément, Delphine Behr-Roussel, and FranScois Giuliano
25.1 Introduction 523
25.2 Lower Urinary Tract Function 523
25.2.1 Physiology of Micturition 524
25.2.2 Investigation of Lower Urinary Tract Function 524
25.2.2.1 Cystometry Evaluation 524
25.2.2.2 Evaluation of Urethral Function 525
25.2.2.3 Bladder Afferent Recording 526
25.2.3 Pathophysiological Models 527
25.2.3.1 Bladder Outlet Obstruction 527
25.2.3.2 Overactive Bladder 527
25.2.3.3 Neurogenic Detrusor Overactivity 528
25.2.3.4 Painful Bladder Syndrome/Interstitial Cystitis 528
25.3 Sexual Functions 529
25.3.1 Physiology of Female and Male Sexual Response 529
25.3.2 Models for Sexual Behavior 530
25.3.2.1 Sexual Preference Paradigms 530
25.3.2.2 Copulatory Tests 531
25.3.3 Investigation of the Peripheral Female Sexual Response 532
25.3.4 Investigation of Erection 532
25.3.4.1 Penile Reflex 532
25.3.4.2 Erection in Conscious Animals 533
25.3.4.3 Intracavernosal Pressure Measurement 533
25.3.4.4 Pharmacologically Induced Erection 534
25.3.4.5 Neurally Evoked Erection 534
25.3.5 Investigation of Ejaculation 534
25.3.5.1 Physiological Markers of Emission and Expulsion Phases 534
25.3.5.2 Pharmacologically Induced Ejaculation 535
25.3.5.3 Lumbar Spinothalamic Neurons Electrical Stimulation 535
25.3.5.4 Expulsion Spinal Reflex 535
25.3.6 Pathophysiological Models 536
25.3.6.1 Female Sexual Dysfunctions 536
25.3.6.2 Erectile Dysfunction 536
25.3.6.3 Ejaculatory Disorders 538
25.4 Translation to Clinics: Difficulties and Limitations 538
References 540
Index 543
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