In Vivo Models for Drug Discovery

by Vela, José Miguel; Maldonado, Rafael; Hamon, Michel; Mannhold, Raimund; Kubinyi, Hugo; Folkers, Gerd

• ISBN13: 9783527333288
• ISBN10: 3527333282
• Edition: 1st
• Format: Hardcover
• Copyright: 2014-08-11
• Publisher: Wiley-VCH

Summary

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.

Author Biography

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).

Table of Contents

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