Details

In vivo Models for Drug Discovery


In vivo Models for Drug Discovery


Methods & Principles in Medicinal Chemistry, Band 62 1. Aufl.

von: José Miguel Vela, Rafael Maldonado, Michel Hamon, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

153,99 €

Verlag: Wiley-VCH
Format: EPUB
Veröffentl.: 31.07.2014
ISBN/EAN: 9783527679362
Sprache: englisch
Anzahl Seiten: 594

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Beschreibungen

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.<br> 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. <br> 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.<br> Key knowledge for drug researchers in industry as well as academia.
<p>List of Contributors xix</p> <p>Preface xxix</p> <p>A Personal Foreword xxxi</p> <p><b>Part I Transversal Issues Concerning Animal Models in Drug Discovery 1</b></p> <p><b>1 The 3Ns of Preclinical Animal Models in Biomedical Research 3<br /></b><i>José Miguel Vela, Rafael Maldonado, and Michel Hamon</i></p> <p>1.1 First N: The Need for Use of Animal Models 3</p> <p>1.2 Second N: The Need for Better Animal Models 5</p> <p>1.2.1 Unbiased Design 8</p> <p>1.2.2 Comprehensive Reporting 8</p> <p>1.2.3 Selection of the Animal Model Based on Its Validity Attributes 9</p> <p>1.2.4 Appropriate Time and Dosing 11</p> <p>1.2.5 Use of Biomarkers 12</p> <p>1.2.6 Use of Various Animal Models 13</p> <p>1.2.7 Quantitative, Multiple, and Cross-Predictive Measurements 14</p> <p>1.2.8 Pharmacokinetic–Pharmacodynamic Integration 15</p> <p>1.2.9 Predefinition and Adherence to the Desired Product Profile 16</p> <p>1.2.10 Comparison with Gold Standard References 18</p> <p>1.2.11 Reverse Translation/Backtranslation (Bedside-to-Bench Approach) 18</p> <p>1.3 Third N: The Need for 3Rs Guiding Principles 19</p> <p>References 22</p> <p><b>2 Alternative Models in Drug Discovery and Development Part I: In Silico and In Vitro Models 27<br /></b><i>Luz Romero and José Miguel Vela</i></p> <p>2.1 Introduction 27</p> <p>2.2 In Silico Models 34</p> <p>2.2.1 Quantitative Structure–Activity Relationship 34</p> <p>2.2.2 Biokinetic Modeling 37</p> <p>2.2.3 Disease- and Patient-Specific In Silico Models 42</p> <p>2.3 In Vitro Models 43</p> <p>2.3.1 Primary Cells, Cell Lines, Immortalized Cell Lines, and Stem Cells 44</p> <p>2.3.2 Advanced In Vitro Models for the Prediction of Drug Toxicity 46</p> <p>2.3.3 In Vitro Tumor Models 47</p> <p>References 50</p> <p><b>3 Alternative Models in Drug Discovery and Development Part II: In Vivo Nonmammalian and Exploratory/Experimental Human Models 59<br /></b><i>Luz Romero and Jos</i><i>é Miguel Vela</i></p> <p>3.1 Introduction 59</p> <p>3.2 In Vivo Nonmammalian Models 59</p> <p>3.2.1 Zebrafish 61</p> <p>3.2.2 D. melanogaster 66</p> <p>3.2.3 C. elegans 71</p> <p>3.3 In Vivo Exploratory and Experimental Human Models 74</p> <p>3.3.1 Phase 0 (Exploratory Human Models): Microdosing Studies 76</p> <p>3.3.2 Phase IB/IIA (Proof-of-Concept) Studies: Experimental Human Models 81</p> <p>References 84</p> <p><b>4 Ethical Issues and Regulations and Guidelines Concerning Animal Research 91<br /></b><i>David Sabat</i><i>é</i></p> <p>4.1 Introduction 91</p> <p>4.2 Current Use of Animals in Biomedical and Pharmaceutical Research 92</p> <p>4.3 Ethical Concerns and Positions on Animal Research 93</p> <p>4.4 General Principles for the Ethical Use of Animals in Research 95</p> <p>4.4.1 The 3Rs Principles (Replacement, Reduction, and Refinement) 95</p> <p>4.4.2 The Principle of Justification 96</p> <p>4.4.3 The Principle of Responsibility 97</p> <p>4.5 Regulatory Framework for Use of Animals in Research 98</p> <p>4.5.1 European Union 98</p> <p>4.5.2 The United States 100</p> <p>4.5.3 Canada 100</p> <p>4.5.4 Japan 100</p> <p>4.5.5 Australia 101</p> <p>4.5.6 India 101</p> <p>4.5.7 China 101</p> <p>4.5.8 Brazil 102</p> <p>4.5.9 Countries without a Specific Legal Framework 102</p> <p>Acknowledgment 102</p> <p>References 102</p> <p><b>5 Regulatory Issues: Safety and Toxicology Assessment 107<br /></b><i>Antonio Guzm</i><i>án</i></p> <p>5.1 Introduction 107</p> <p>5.1.1 Animal Testing 107</p> <p>5.1.2 Regulatory Context 109</p> <p>5.1.3 Clinical Context 109</p> <p>5.2 Animal Species in Toxicology Studies 110</p> <p>5.2.1 Rodents 111</p> <p>5.2.2 Nonrodents 112</p> <p>5.2.3 Nonconventional Animal Models 114</p> <p>5.3 Toxicology Studies 114</p> <p>5.3.1 General Principles 114</p> <p>5.3.2 General and Repeated Dose Toxicity Studies 116</p> <p>5.3.3 Safety Pharmacology 118</p> <p>5.3.4 Genotoxicity 119</p> <p>5.3.5 Development and Reproductive Toxicity Studies 122</p> <p>5.3.6 Carcinogenicity Studies 124</p> <p>5.4 Translation to Clinics: Limitations and Difficulties 126</p> <p>References 127</p> <p><b>6 Generation and Use of Transgenic Mice in Drug Discovery 131<br /></b><i>Guillaume Pavlovic, Véronique Brault, Tania Sorg, and Yann H</i><i>érault</i></p> <p>6.1 Introduction 131</p> <p>6.2 Improved Mouse Genetic Engineering 133</p> <p>6.2.1 Recent Technical Developments 133</p> <p>6.2.2 The Advent of New Mouse Mutant Resource: One Stop Shop 133</p> <p>6.3 Functional Evaluation and Uses of Mouse Models 136</p> <p>6.3.1 Standardization and Harmonization 136</p> <p>6.3.2 Genetic Background and Environmental Influences 137</p> <p>6.3.3 Challenges Ahead 137</p> <p>6.3.4 Target Identification and Translation to Humans 138</p> <p>6.3.5 Use of GEMMs in Pharmaceutical Industry and Risk Assessment 139</p> <p>6.4 Translation to Clinics: Limitations and Difficulties 140</p> <p>6.5 Perspectives 142</p> <p>Acknowledgments 143</p> <p>References 143</p> <p><b>7 In Vivo Brain Imaging in Animal Models: A Focus on PET and MRI 149<br /></b><i>Fabien Chauveau, Mathieu Verdurand, and Luc Zimmer</i></p> <p>7.1 Introduction: Role of Animal in In Vivo Imaging 149</p> <p>7.1.1 In Vivo Imaging as a Translational Approach for Basic Research 149</p> <p>7.1.2 In Vivo Imaging in Animal Models in the Pharmaceutical Industry 150</p> <p>7.1.3 In Vivo Imaging in Animal Models and the 3R Principles 150</p> <p>7.2 The Choice of the Right Imaging Modality for Brain Imaging 151</p> <p>7.3 Small Animal Magnetic Resonance Imaging 152</p> <p>7.3.1 Principles 152</p> <p>7.3.2 Magnetic Resonance Spectroscopy 152</p> <p>7.3.3 Magnetic Resonance Imaging 153</p> <p>7.4 Positron Emission Tomography 155</p> <p>7.4.1 Basic Principles and Instrumentation 155</p> <p>7.4.2 PET and Neuronal Metabolism 155</p> <p>7.4.3 PET and Brain Receptors and Transporters 156</p> <p>7.4.4 PET and Receptor Occupancy 158</p> <p>7.4.5 PET and Neurotransmitter Release 159</p> <p>7.5 Clinical Translation: Limitations and Difficulties 159</p> <p>7.5.1 Anesthesia 160</p> <p>7.5.2 Spatial Resolution and Sensitivity 160</p> <p>7.5.3 The Mass Effect of Injected Tracers 161</p> <p>7.5.4 Multimodal PET–MRI for Better Clinical Translation 162</p> <p>References 163</p> <p><b>Part II Animal Models in Specific Disease Areas of Drug Discovery 167</b></p> <p><b>8 Substance Abuse and Dependence 169<br /></b><i>Elena Martín-García, Patricia Robledo, Javier Guti_errez-Cuesta, and Rafael Maldonado</i></p> <p>8.1 Introduction 169</p> <p>8.2 Difficulties to Model Addiction in Animals 170</p> <p>8.3 Tolerance, Sensitization, and Physical Withdrawal 172</p> <p>8.3.1 Tolerance 172</p> <p>8.3.2 Sensitization 173</p> <p>8.3.3 Physical Manifestations of Withdrawal 174</p> <p>8.3.4 Affective Manifestations of Withdrawal 175</p> <p>8.4 Reward and Reinforcement 177</p> <p>8.4.1 Drug Discrimination 177</p> <p>8.4.2 Conditioned Place Preference 178</p> <p>8.4.3 Intracranial Self-Stimulation 180</p> <p>8.4.4 Self-Administration 182</p> <p>8.5 Translation to Clinics: Limitations and Difficulties 184</p> <p>References 186</p> <p><b>9 Mood and Anxiety Disorders 193<br /></b><i>Guy Griebel and Sandra Beesk</i><i>é</i></p> <p>9.1 Introduction 193</p> <p>9.2 Animal Models of Anxiety Disorders 194</p> <p>9.2.1 Preclinical Measures of Anxiety 194</p> <p>9.2.2 Preclinical Anxiety Models and Endophenotypes 195</p> <p>9.3 Animal Models of Mood Disorders 197</p> <p>9.3.1 Major Depressive Disorder 197</p> <p>9.3.1.1 Preclinical Measures of Depression 198</p> <p>9.3.1.2 Endophenotype Models of Depression 199</p> <p>9.3.2 Bipolar Disorder 199</p> <p>9.4 Translation to Clinics: Limitations and Difficulties 200</p> <p>Acknowledgment 201</p> <p>References 202</p> <p><b>10 Schizophrenia 207<br /></b><i>Ronan Depoort</i><i>ère and Paul Moser</i></p> <p>10.1 Introduction 207</p> <p>10.2 Models Amenable to Use in Screening 209</p> <p>10.2.1 Models Based on the Use of Pharmacological Agents 209</p> <p>10.2.1.1 Dopaminergic Agonists 209</p> <p>10.2.1.2 NMDA/Glutamate Receptor Antagonists 211</p> <p>10.2.1.3 Other Pharmacological Agents Used to Induce Behavioural Changes 212</p> <p>10.2.1.4 5-HT2A Receptor Agonists 212</p> <p>10.2.1.5 Cannabinoid Receptor Agonists 212</p> <p>10.2.1.6 Muscarinic Receptor Antagonists 213</p> <p>10.2.1.7 Glycine B Receptor Antagonists 213</p> <p>10.2.2 Models Not Based on the Use of Pharmacological Agents 213</p> <p>10.2.2.1 Conditioned Avoidance Response 213</p> <p>10.2.2.2 Potentiation of PPI of the Startle Reflex 214</p> <p>10.2.3 Models More Time Consuming and/or Difficult to Implement 214</p> <p>10.2.3.1 Models Aimed at Reproducing More Complex Symptoms of Schizophrenia 214</p> <p>10.2.3.2 Models Aimed at Reproducing the Chronic Nature of Schizophrenia 216</p> <p>10.2.3.3 Models Based on Genetic Manipulations 218</p> <p>10.2.4 Models for Side Effects 218</p> <p>10.2.4.1 Models for Motor Side Effects 219</p> <p>10.2.4.2 Hyperprolactinemia 220</p> <p>10.2.4.3 Sedation and Motor Incoordination 220</p> <p>10.2.4.4 Models for Cognitive Side Effects 220</p> <p>10.2.4.5 Metabolic Disorders Models 221</p> <p>10.2.4.6 Models for Cardiovascular Effects 221</p> <p>10.3 Translation to the Clinic: Limitations and Difficulties 221</p> <p>10.3.1 Use of “Standard Subjects” 221</p> <p>10.3.2 From Here to . . . ? 222</p> <p>References 223</p> <p><b>11 Migraine and Other Headaches 231<br /></b><i>Inger Jansen-Olesen, Sarah Louise T. Christensen, and Jes Olesen</i></p> <p>11.1 Introduction 231</p> <p>11.2 Vascular Models 231</p> <p>11.2.1 In Vitro 232</p> <p>11.2.2 In Vivo 233</p> <p>11.3 Neurogenic Inflammation 234</p> <p>11.4 Nociceptive Activation of the Trigeminovascular System 234</p> <p>11.4.1 Electrophysiological Recordings on Primary Dural Afferents in Trigeminal Ganglion 237</p> <p>11.4.2 Electrophysiological Recordings in Trigeminal Nucleus Caudalis 239</p> <p>11.4.3 Histological Markers after Nociceptive Stimulation of the Trigeminovascular System 239</p> <p>11.5 Cortical Spreading Depression 240</p> <p>11.6 Human Experimental Migraine Provoking Models 241</p> <p>11.7 Animal Experimental Migraine Provoking Models 242</p> <p>11.8 Transgenic Models 246</p> <p>11.9 Behavioral Models 246</p> <p>11.9.1 Allodynia or Hyperalgesia 247</p> <p>11.9.2 Face Grooming 248</p> <p>11.9.3 Photophobia 248</p> <p>11.9.4 Various Behaviors 249</p> <p>11.10 Translation to Clinics: Limitations and Difficulties 249</p> <p>References 250</p> <p><b>12 Nociceptive, Visceral, and Cancer Pain 261<br /></b><i>Christophe Mallet, Denis Ardid, and David Balayssac</i></p> <p>12.1 Introduction 261</p> <p>12.2 Acute Pain Tests 261</p> <p>12.2.1 Introduction 261</p> <p>12.2.2 Electrical Stimulus 263</p> <p>12.2.3 Thermal Stimulus 264</p> <p>12.2.4 Mechanical Stimulus 264</p> <p>12.2.5 Chemical Stimulus 265</p> <p>12.3 Visceral Pain Models 265</p> <p>12.3.1 Introduction 265</p> <p>12.3.2 Pain Achievement Test 266</p> <p>12.3.3 Animal Models 267</p> <p>12.3.4 Pathophysiology and Pharmacology 269</p> <p>12.4 Cancer Pain Models 270</p> <p>12.4.1 Introduction 270</p> <p>12.4.2 Pain Assessment in Animal Models of Cancer Pain 270</p> <p>12.4.3 Animal Models 271</p> <p>12.4.4 Pathophysiology and Pharmacology 272</p> <p>12.4.5 Conclusions 272</p> <p>12.5 Translation to Clinics: Difficulties and Limitations 273</p> <p>12.5.1 Acute Pain Tests 273</p> <p>12.5.2 Visceral Pain Models 274</p> <p>12.5.3 Cancer Pain Models 274</p> <p>12.5.4 Conclusions 275</p> <p>References 275</p> <p><b>13 Inflammatory, Musculoskeletal/Joint (OA and RA), and Postoperative Pain 283<br /></b><i>Laurent Diop and Yassine Darbaky</i></p> <p>13.1 Introduction: Evaluation of Pain in Animal Models 283</p> <p>13.2 Inflammatory Pain 287</p> <p>13.2.1 Formalin Test 287</p> <p>13.2.2 Carrageenan-Induced Hyperalgesia 287</p> <p>13.2.3 Complete Freund’s Adjuvant-Induced Hyperalgesia 288</p> <p>13.2.4 Capsaicin-Induced Hyperalgesia 288</p> <p>13.3 Musculoskeletal/Joint Osteoarthritis (OA) and Rheumatoid Arthritis (RA) Pain 289</p> <p>13.3.1 Osteoarthritis Pain Models 289</p> <p>13.3.2 Rheumatoid Arthritis Pain Models 293</p> <p>13.4 Postoperative Pain 297</p> <p>13.4.1 Incisional Pain 298</p> <p>13.4.2 Laparotomy 299</p> <p>13.4.3 Ovariohysterectomy 299</p> <p>13.4.4 Other Models of Postoperative Pain 299</p> <p>13.5 Translation to Clinics: Limitations and Difficulties 300</p> <p>References 302</p> <p><b>14 Neuropathic Pain 305<br /></b><i>Said M’Dahoma, Sylvie Bourgoin, and Michel Hamon</i></p> <p>14.1 Introduction 305</p> <p>14.2 Main Types of Neuropathic Pain in Humans 306</p> <p>14.2.1 Neuropathic Pain Caused by Peripheral Nerve Lesions 306</p> <p>14.2.1.1 Diabetes-Induced Neuropathic Pain 306</p> <p>14.2.1.2 Human Immunodeficiency Virus-Related Pain 306</p> <p>14.2.1.3 Postherpetic Neuralgia 307</p> <p>14.2.1.4 Neuropathic Pain Caused by Anticancer Drugs 307</p> <p>14.2.2 Neuropathic Pain Caused by Central Lesions 307</p> <p>14.2.2.1 Spinal Cord Injury 307</p> <p>14.2.2.2 The Various Types of Pain in SCI Patients 308</p> <p>14.3 Modelization of Chronic Pain in Rodents 309</p> <p>14.3.1 Models of Peripheral Nerve Injury 309</p> <p>14.3.1.1 Nerve Section 309</p> <p>14.3.1.2 Nerve Ligation, Compression, and Other Lesion Procedures 310</p> <p>14.3.1.3 Drug- and Virus-Induced Neuropathic Pain 314</p> <p>14.3.2 Models of Spinal Cord Injury 318</p> <p>14.3.2.1 Spinal Cord Contusion 318</p> <p>14.3.2.2 Clip Compression Injury 319</p> <p>14.3.2.3 Spinal Cord Transection 319</p> <p>14.3.2.4 Spinal Cord Ischemia 319</p> <p>14.3.3 Neuropathic-Like Pain Evoked by Chemicals Administered at the Spinal Level 320</p> <p>14.3.3.1 Intrathecal Administration of ATP 320</p> <p>14.3.3.2 Intrathecal Administration of BDNF 320</p> <p>14.3.3.3 Excitotoxic Injury to the Spinal Cord 321</p> <p>14.4 Translation to Clinics: Limitations and Difficulties 321</p> <p>References 324</p> <p><b>15 Obesity and Metabolic Syndrome 333<br /></b><i>Sunil K. Panchal, Maharshi Bhaswant, and Lindsay Brown</i></p> <p>15.1 Introduction 333</p> <p>15.2 Why Metabolic Syndrome? 333</p> <p>15.3 Classical Animal Models of Obesity and Metabolic Syndrome 335</p> <p>15.3.1 Genetic Models of Obesity and Diabetes 336</p> <p>15.3.2 Artificially Induced Metabolic Syndrome in Animals 337</p> <p>15.3.2.1 Monosodium Glutamate-Induced Obesity 338</p> <p>15.3.2.2 Intrauterine Growth-Restricted Rats 338</p> <p>15.4 Human Experimental Models 344</p> <p>15.5 Translation to Clinics: Difficulties and Limitations 344</p> <p>References 344</p> <p><b>16 Cognitive Disorders: Impairment, Aging, and Dementia 349<br /></b><i>Nick P. van Goethem, Roy Lardenoije, Konstantinos Kompotis, Bart P.F. Rutten, Jos Prickaerts, and Harry W.M. Steinbusch</i></p> <p>16.1 Introduction 349</p> <p>16.2 Pharmacological Models 349</p> <p>16.2.1 Inhibition of Energy/Glucose Metabolism 350</p> <p>16.2.2 Cholinergic Interventions 350</p> <p>16.2.3 Glutamatergic Antagonists 352</p> <p>16.2.4 Serotonergic Intervention 353</p> <p>16.3 Aging and Transgenic Models 353</p> <p>16.3.1 Normal Aging 354</p> <p>16.3.2 Alzheimer’s Disease 355</p> <p>16.3.3 Parkinson’s Disease 358</p> <p>16.3.4 Huntington’s Disease 358</p> <p>16.3.5 Frontotemporal Dementia 359</p> <p>16.3.6 Down Syndrome 360</p> <p>16.4 Translation to Clinics: Limitations and Difficulties 360</p> <p>References 362</p> <p><b>17 Stroke and Traumatic Brain Injury 367<br /></b><i>Dominique Lerouet, Val</i><i>érie C. Besson, and Michel Plotkine</i></p> <p>17.1 Introduction 367</p> <p>17.2 Stroke Models 368</p> <p>17.2.1 Global Stroke Models 368</p> <p>17.2.2 Focal Stroke Models 369</p> <p>17.2.2.1 Extravascular Models 369</p> <p>17.2.2.2 Photothrombosis Model 370</p> <p>17.2.2.3 Intraluminal Occlusion Model 370</p> <p>17.2.2.4 Thromboembolic Models 370</p> <p>17.3 Traumatic Brain Injury Models 371</p> <p>17.3.1 TBI Models with Craniotomy 372</p> <p>17.3.1.1 Weight-Drop Model 372</p> <p>17.3.1.2 Lateral Fluid Percussion Model 372</p> <p>17.3.1.3 Controlled Cortical Impact Model 372</p> <p>17.3.2 TBI Models without Craniotomy 372</p> <p>17.3.2.1 Weight-Drop Model 373</p> <p>17.3.2.2 Impact/Acceleration Model 373</p> <p>17.3.2.3 Acceleration/Deceleration Model 373</p> <p>17.3.3 Blast Injury Models 373</p> <p>17.3.4 Repetitive TBI Models 374</p> <p>17.4 Outcome Assessment 375</p> <p>17.5 Translation to Clinics: Limitations and Difficulties 377</p> <p>17.5.1 The Actual Target: From the Neuron to the Neurogliovascular Unit 377</p> <p>17.5.2 From Bench to Bedside to Bench: Recommendations for Improving the Translational Research 378</p> <p>References 379</p> <p><b>18 Movement Disorders: Parkinson’s Disease 387<br /></b><i>Houman Homayoun and Christopher G. Goetz</i></p> <p>18.1 Introduction 387</p> <p>18.1.1 Parkinson’s Disease 387</p> <p>18.2 Drug- and Toxin-Based Models of PD 389</p> <p>18.2.1 Reserpine 389</p> <p>18.2.2 Haloperidol 390</p> <p>18.2.3 6-OHDA 390</p> <p>18.2.4 MPTP 393</p> <p>18.2.5 Rotenone 396</p> <p>18.2.6 Paraquat and Other Environmental Toxins 398</p> <p>18.3 Genetic and Functional Models of PD 398</p> <p>18.3.1 Rodent Genetic Models 399</p> <p>18.3.1.1 Adult-Onset Rodent Gene-Based Models 401</p> <p>18.3.2 Rodent Function-Based Models 403</p> <p>18.3.3 Nonrodent Genetic Models of PD 404</p> <p>18.4 Translation to Clinics: Limitations and Difficulties 405</p> <p>References 409</p> <p><b>19 Epilepsy: Animal Models to Reproduce Human Etiopathology 415<br /></b><i>Isabelle Guillemain, Christophe Heinrich, and Antoine Depaulis</i></p> <p>19.1 Introduction 415</p> <p>19.2 What Animal Species to Use to Model Epilepsy? 416</p> <p>19.3 Which Type of Models Provide the Most Reliable Information on the Pathophysiology of Epilepsies? 417</p> <p>19.4 Modeling Four Prototypic Forms of Epilepsy 418</p> <p>19.4.1 Idiopathic Generalized Epilepsies with Convulsive Seizures 418</p> <p>19.4.2 Idiopathic Generalized Epilepsies with Absence Seizures 419</p> <p>19.4.3 Focal Epilepsies Associated with Cortical Dysplasia 420</p> <p>19.4.4 Modeling Focal Epilepsies Associated with Hippocampal Sclerosis 422</p> <p>19.5 Translation to Clinics: Limitations and Difficulties 423</p> <p>References 425</p> <p><b>20 Lung Diseases 431<br /></b><i>Laurent Boyer, Armand Mekontso-Dessap, Jorge Boczkowski, and Serge Adnot</i></p> <p>20.1 Introduction 431</p> <p>20.2 Animal Models of Lung Emphysema or Chronic Obstructive Pulmonary Disease 432</p> <p>20.2.1 Cigarette Smoke-Induced COPD 432</p> <p>20.2.2 COPD Induced by Tracheal Elastase Instillation 433</p> <p>20.2.3 Genetically Modified Models of COPD 434</p> <p>20.2.4 Conclusions 434</p> <p>20.3 Animal Models of Pulmonary Hypertension 434</p> <p>20.3.1 Relevance of Experimental Animal Models of PH to Human PH 435</p> <p>20.3.2 The Monocrotaline Model of Pulmonary Hypertension 436</p> <p>20.3.3 Fawn-Hooded Rats 437</p> <p>20.3.4 Hypoxic PH 437</p> <p>20.3.5 SU5416 Treatment Combined with Hypoxia in Mice 438</p> <p>20.3.6 PH Related to COPD or Smoke Exposure 439</p> <p>20.4 Animal Models of Fibrotic Lung Diseases 439</p> <p>20.4.1 Bleomycin-Induced Pulmonary Fibrosis 439</p> <p>20.4.2 Other Models 440</p> <p>20.5 Animal Models of Acute Respiratory Distress Syndrome 440</p> <p>20.6 Translation to Clinics: Limitations and Difficulties 445</p> <p>References 446</p> <p><b>21 Heart Failure 449<br /></b><i>Jin Bo Su and Alain Berdeaux</i></p> <p>21.1 Introduction 449</p> <p>21.2 Hypertension-Related Heart Failure 450</p> <p>21.3 Pressure and Volume Overload-Induced Heart Failure 452</p> <p>21.3.1 Pressure Overload-Induced Heart Failure 452</p> <p>21.3.2 Volume Overload-Induced Heart Failure 454</p> <p>21.3.3 Double Pressure and Volume Overload-Induced Heart Failure 454</p> <p>21.4 Toxic Molecule-Induced Heart Failure 455</p> <p>21.4.1 Adriamycin-Induced Heart Failure in Rats 455</p> <p>21.4.2 Monocrotaline-Induced Right Ventricular Heart Failure 455</p> <p>21.5 Heart Failure Models Related to Myocardial Ischemia and/or Myocardial Infarction 456</p> <p>21.5.1 Myocardial Ischemia and/or Myocardial Infarction 456</p> <p>21.5.2 Coronary Microembolization-Induced Heart Failure 457</p> <p>21.6 Pacing-Induced Heart Failure 458</p> <p>21.7 Gene Mutation-Induced Cardiomyopathies 460</p> <p>21.7.1 Cardiomyopathic Hamsters 460</p> <p>21.7.2 Golden Retriever Muscular Dystrophy Dogs 460</p> <p>21.7.3 Genetic Modification-Induced Cardiomyopathies in Mice 461</p> <p>21.8 Translation to Clinics: Limitations and Difficulties 462</p> <p>References 462</p> <p><b>22 Endocrine Disorders 473<br /></b><i>Thomas Cuny, Anne Barlier, and Alain Enjalbert</i></p> <p>22.1 Introduction 473</p> <p>22.2 Animal Models in Autoimmune Endocrine Diseases 474</p> <p>22.2.1 Animal Models of Autoimmune Thyroiditis 474</p> <p>22.2.2 Animal Models for Addison’s Disease 476</p> <p>22.2.3 Animal Models for Other Endocrine Autoimmune Diseases 476</p> <p>22.3 Animal Models in Endocrine Tumors 477</p> <p>22.3.1 Multiple Endocrine Neoplasia Syndromes 477</p> <p>22.3.2 Adrenal Tumorigenesis 478</p> <p>22.3.3 Thyroid Tumorigenesis 481</p> <p>22.3.4 Pituitary Tumorigenesis 482</p> <p>22.4 Animal Models in Endocrine Physiology: Organogenesis, Reproduction, and Metabolism 485</p> <p>22.4.1 Pituitary Development Disorders: Lessons from Animal Models 485</p> <p>22.4.2 Animal Models and Reproductive Function 487</p> <p>22.4.3 Animal Models Used in Calcium Homeostasis Studies 489</p> <p>22.5 Translation to Clinics: Limitations and Difficulties 490</p> <p>References 491</p> <p><b>23 Gastrointestinal Disorders: A Patho-biotechnology Approach to Probiotic Therapy 497<br /></b><i>Roy D. Sleator</i></p> <p>23.1 Introduction 497</p> <p>23.2 Delivery: Improving Probiotic Resistance to Process-Induced Stresses and Storage Conditions 498</p> <p>23.3 Survival: Improving Probiotic–Host Colonization 500</p> <p>23.4 Efficacy: “Designer Probiotics” 500</p> <p>23.5 Translation to Clinics: Limitations and Difficulties 501</p> <p>Acknowledgment 502</p> <p>References 502</p> <p><b>24 Renal Disorders 505<br /></b><i>Dominique Guerrot, Christos Chatziantoniou, and Jean-Claude Dussaule</i></p> <p>24.1 Introduction 505</p> <p>24.2 Animal Models 506</p> <p>24.2.1 The RenTg Model of CKD 507</p> <p>24.2.1.1 Benefits of the RenTg Model 509</p> <p>24.2.2 Unilateral Ureteral Obstruction 510</p> <p>24.2.2.1 Technical Aspects 510</p> <p>24.2.2.2 Pathology and Pathophysiology 511</p> <p>24.2.2.3 Clinical Relevance and Limits 511</p> <p>24.2.3 Renal Ischemia–Reperfusion 511</p> <p>24.2.3.1 Technical Aspects 512</p> <p>24.2.3.2 Pathology and Pathophysiology 512</p> <p>24.2.3.3 Clinical Relevance and Limits 513</p> <p>24.2.4 Experimental Alloimmune Glomerulonephritis 513</p> <p>24.2.4.1 Technical Aspects 513</p> <p>24.2.4.2 Pathology and Pathophysiology 514</p> <p>24.2.4.3 Clinical Relevance and Limits 514</p> <p>24.2.5 Angiotensin II-Mediated Hypertensive Nephropathy 514</p> <p>24.2.5.1 Technical Aspects 515</p> <p>24.2.5.2 Pathology and Pathophysiology 515</p> <p>24.2.5.3 Clinical Relevance and Limits 516</p> <p>24.2.6 L-NAME-Mediated Hypertensive Nephropathy 516</p> <p>24.2.6.1 Technical Aspects 516</p> <p>24.2.6.2 Pathology and Pathophysiology 516</p> <p>24.2.6.3 Clinical Relevance and Limits 517</p> <p>24.3 Translation to Clinics: Limitations and Difficulties 518</p> <p>References 518</p> <p><b>25 Genitourinary Disorders: Lower Urinary Tract and Sexual Functions 523<br /></b><i>Pierre Cl</i><i>ément, Delphine Behr-Roussel, and FranScois Giuliano</i></p> <p>25.1 Introduction 523</p> <p>25.2 Lower Urinary Tract Function 523</p> <p>25.2.1 Physiology of Micturition 524</p> <p>25.2.2 Investigation of Lower Urinary Tract Function 524</p> <p>25.2.2.1 Cystometry Evaluation 524</p> <p>25.2.2.2 Evaluation of Urethral Function 525</p> <p>25.2.2.3 Bladder Afferent Recording 526</p> <p>25.2.3 Pathophysiological Models 527</p> <p>25.2.3.1 Bladder Outlet Obstruction 527</p> <p>25.2.3.2 Overactive Bladder 527</p> <p>25.2.3.3 Neurogenic Detrusor Overactivity 528</p> <p>25.2.3.4 Painful Bladder Syndrome/Interstitial Cystitis 528</p> <p>25.3 Sexual Functions 529</p> <p>25.3.1 Physiology of Female and Male Sexual Response 529</p> <p>25.3.2 Models for Sexual Behavior 530</p> <p>25.3.2.1 Sexual Preference Paradigms 530</p> <p>25.3.2.2 Copulatory Tests 531</p> <p>25.3.3 Investigation of the Peripheral Female Sexual Response 532</p> <p>25.3.4 Investigation of Erection 532</p> <p>25.3.4.1 Penile Reflex 532</p> <p>25.3.4.2 Erection in Conscious Animals 533</p> <p>25.3.4.3 Intracavernosal Pressure Measurement 533</p> <p>25.3.4.4 Pharmacologically Induced Erection 534</p> <p>25.3.4.5 Neurally Evoked Erection 534</p> <p>25.3.5 Investigation of Ejaculation 534</p> <p>25.3.5.1 Physiological Markers of Emission and Expulsion Phases 534</p> <p>25.3.5.2 Pharmacologically Induced Ejaculation 535</p> <p>25.3.5.3 Lumbar Spinothalamic Neurons Electrical Stimulation 535</p> <p>25.3.5.4 Expulsion Spinal Reflex 535</p> <p>25.3.6 Pathophysiological Models 536</p> <p>25.3.6.1 Female Sexual Dysfunctions 536</p> <p>25.3.6.2 Erectile Dysfunction 536</p> <p>25.3.6.3 Ejaculatory Disorders 538</p> <p>25.4 Translation to Clinics: Difficulties and Limitations 538</p> <p>References 540</p> <p>Index 543</p>
<p>“I also found it to be a great resource for teaching.”  <i> (</i><i>ChemMedChem</i>, 1 January 2015)</p>
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.<br> <br> 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.<br> <br> 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).<br>
This one-stop reference presents the complete picture - covering all relevant organisms and physiological functions, from single cells to mammals, as well as all major disease areas.<br> <br> This 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.<br> <br> After a general introduction to the topic, the expert contributors 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, gastro-intestinal, urogenital disorders, cancer, migraine and chronic pain, and from infectious to neuropsychiatric 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.<br> <br> Key knowledge for drug researchers in industry as well as academia.<br>

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