Contemporary Aspects of Biomedical Research (eBook)

Cover 1
CONTEMPORARY ASPECTS OF BIOMEDICAL RESEARCH: DRUG DISCOVERY 4
Copyright Page 5
Contents 6
Contributors 10
Preface 12
Chapter 1 Defining the Role of Pharmacology in the Emerging World of Translational Research 14
Abstract 14
I. Introduction 15
II. Historical Perspective of Pharmacology 17
III. Initiatives to Improve Drug Discovery Productivity 20
IV. Pharmacology as an Enabling Science in Translational Research 29
V. Conclusion 34
Acknowledgments 35
References 35
Chapter 2 Anti-Inflammatory Agents as Cancer Therapeutics 44
Abstract 44
I. Introduction 45
II. Blocking Chemokines and or Chemokine Receptors as Approaches to Cancer Therapy 50
III. Evidence that NSAIDs Protect Against Cancer 51
IV. Inhibition of Prostanoid Receptors for Cancer Prevention 54
V. LOX Cascades 56
VI. Nitric Oxide-Releasing NSAIDs (NO-NSAIDS and NONO-NSAIDs) A. Nitric Oxide Signaling 61
VII. Hydrogen Sulfide-Releasing NSAIDs 74
VIII. Natural Products for Cancer Prevention 80
IX. Conclusion 83
Acknowledgments 84
References 84
Chapter 3 The Development and Pharmacology of Proteasome Inhibitors for the Management and Treatment of Cancer 104
Abstract 104
I. Introduction 105
II. Molecular and Biological Roles of the Proteasome Complex in Cellular Homeostasis and Disease 106
III. Historical Perspective of Proteasome Inhibitors in Development: Chemistry and Primary Mechanisms of Action A. Dipeptidyl Boronic Acids: Bortezomib and CEP-18770 112
IV. Preclinical In vitro and In Vivo Pharmacology of Proteasome Inhibitors in Hematological and Non-hematological Cancers 116
V. Clinical Studies with Proteasome Inhibitors 126
VI. Clinical Studies with "Next-Generation” Proteasome Inhibitors 135
VII. Conclusion 138
References 139
Chapter 4 Subtype-Selective GABAA Receptor Modulation Yields a Novel Pharmacological Profile: The Design and Development of TPA023 150
Abstract 150
I. Introduction 151
II. Identification of TPA023 159
III. Preclinical Features of TPA023 162
IV. Preclinical Metabolism and Pharmacokinetics of TPA023 172
V. Human Studies 175
VI. Additional Anxioselective and Other GABAA Receptor Modulators 186
VII. Conclusion 190
Acknowledgments 191
References 191
Chapter 5 New Approaches for the Treatment of Sleep Disorders 200
Abstract 200
I. Introduction 201
II. Narcolepsy 202
III. Obstructive Sleep Apnea 210
IV. Insomnia 218
V. Restless Leg Syndrome 228
VI. Conclusion 236
Acknowledgments 236
References 237
Chapter 6 Current and Emerging Strategies for Treating Dyslipidemia and Macrovascular Disease 250
Abstract 250
I. Introduction 251
II. Mechanisms of Action 254
III. Conclusion 260
References 261
Chapter 7 Discovery of Drugs to Treat Cocaine Dependence: Behavioral and Neurochemical Effects of Atypical Dopamine Transport Inhibitors 266
Abstract 266
I. Introduction 267
II. Behavioral Studies 271
III. Pharmacokinetic Studies 284
IV. Studies of In Vivo Binding of BZT Analogs at the DAT and Relationship with Behavioral and Neurochemical Effects 284
V. Influence of Off-Target Actions of BZT Analogs 287
VI. Studies of DAT Structure as Related to Its Function 292
VII. Conclusion 295
Acknowledgements 295
References 296
Chapter 8 Novel Strategies and Targets for the Management of Hypertension 304
Abstract 304
I. Introduction 305
II. Physiological Regulation of Blood Pressure 322
III. Experimental Models of Hypertension 331
IV. Novel Targets/Agents for Therapeutic Management of Hypertension 337
V. Conclusion 347
References 348
Chapter 9 New Approaches to the Pharmacological Management of Major Depressive Disorder 360
Abstract 360
I. Introduction 361
II. Mood Disorders 362
III. Antidepressants 362
IV. New Targets in Discovery and Development 365
V. Glutamate Modulation 376
VI. Conclusion 382
Acknowledgments 382
References 383
Chapter 10 Preclinical Behavioral Models for Predicting Antipsychotic Activity 394
Abstract 394
I. Introduction 395
II. Procedures for Evaluating Positive Symptoms 398
III. Procedures for Evaluating Negative Symptoms 403
IV. Procedures for Evaluating Cognitive Deficits 405
V. Procedures for Evaluating EPS 413
VI. Conclusion 419
Acknowledgments 422
References 422
Chapter 11 New Developments in the Therapy of Pulmonary Fibrosis 432
Abstract 432
I. Introduction 433
II. Fibrosis and Fibrogenesis 433
III. Fibrotic Diseases 435
IV. Search for Antifibrotic Drugs A. Endothelin Antagonists 441
V. Pirfenidone 453
VI. Gene Therapy 458
VII. Conclusion 459
Acknowledgments 461
References 461
Index 478
Contents of Previous Volumes 496