Adverse Drug Reactions (Handbook of Experimental Pharmacology 196)

This book provides the current state of knowledge of basic mechanisms of adverse drug reactions (ADRs). The main focus is on idiosyncratic drug reactions because they are the most difficult to deal with. It starts with a general description of the major targets for ADRs followed by a description of what are presently believed to be mediators and biochemical pathways involved in idiosyncratic drug reactions. There is also a description of several examples of ADRs that serve to illustrate specific aspects of ADR mechanisms. Eventually the book shows that ultimately better methods are needed to predict which drug candidates are likely to cause ADRs and which patients are at increased risk. But at present research seems to be far from this goal. Pt. 1. Target organ toxicity. Drug-induced liver injury / Michael Holt, Cynthia Ju. Drug herpersensitivity reactions involving skin / Oliver Hausmann, Benno Schnyder, Werner J. Pichler. Adverse drug reactions affecting blood cells / Richard H. Aster. Molecular mechanisms of adverse drug reactions in cardiac tissue / Reza Tabrizchi. Mechanisms of drug-induced nephrotoxicity / Thomas D. Nolin, Jonathan Himmelfarb. Receptor- and reactive intermediate-mediated mechanisms of teratogenesis / Peter G. Wells, Crystal J.J. Lee, Gordon P. McCallum, Julia Perstin, Patricia A. Harper. Pt. II. Mediators/Biochemical pathways. Role of reactive metabolites in drug-induced hepatotoxicity / A.M. Srivastava, J. L. Maggs, D. J. Antoine, D. P. Williams, D. A. Smith, B. K. Park. Role of cytokines in the mechanism of adverse drug reactions / Mary Jane Masson, Lindsay A. Collins, Lance R. Poh. Keap1-Nrf2 cellular defense pathway: mechanisms of regulation and role in protection against drug-induced toxicity / Ian M. Copple, Christopher E. Goldring, Neil R. Kitteringham, B. Kevin Park. Signal transduction pathways involved in drug-induced liver injury / Derick Han, Mie Shinohara, Maria D. Ybanez, Behnam Saberi, Neil Kaplowitz. Mictrochondrial involvement in drug-induced liver injury / Dominique Pessayre, Abdellah Mansouri, Alain Berson, Bernard Fromenty. Pt. III. Examples/Models. Mechanisms of acetaminophen-induced liver necrosis / Jack A. Hinson, Dean W. Roberts, Laura P. James. Drug-induced liver injury in humans: the case of Ximelagtran / M. Keisu, T.B. Andersson. Troglitazone / Tsuyoshi Yokoi. Neviropine hypersensitivity / M. Popovic, J.M. Shenton, J. Chen, A. Baban, T. Tharmanathan, B. Mannargudi, D. Abdulla, J.P. Uetrecht. Mechanisms of adverse drug reactions to biologics / Janet B. Clarke. Pt. IV. Risk factors/Screening drug candidates. Pharmacogenetics of idiosyncratic adverse drug reactions / Munir Pirmohamed. Danger hypothesis applied to idiosyncratic drug reactions / Jinze Li, Jack P. Uetrecht. Approaches for minimizing metabolic activation of new drug candidates in drug discovery / Sanjeev Kumar, Kaushik Mitra, Kelem Kassahun, Thomas A. Baillie. Front Matter....Pages 1-9 Front Matter....Pages 1-1 Drug-Induced Liver Injury....Pages 3-27 Drug Hypersensitivity Reactions Involving Skin....Pages 29-55 Adverse Drug Reactions Affecting Blood Cells....Pages 57-76 Molecular Mechanisms of Adverse Drug Reactions in Cardiac Tissue....Pages 77-109 Mechanisms of Drug-Induced Nephrotoxicity....Pages 111-130 Receptor- and Reactive Intermediate-Mediated Mechanisms of Teratogenesis....Pages 131-162 Front Matter....Pages 164-164 Role of Reactive Metabolites in Drug-Induced Hepatotoxicity....Pages 165-194 The Role of Cytokines in the Mechanism of Adverse Drug Reactions....Pages 195-231 The Keap1-Nrf2 Cellular Defense Pathway: Mechanisms of Regulation and Role in Protection Against Drug-Induced Toxicity....Pages 233-266 Signal Transduction Pathways Involved in Drug-Induced Liver Injury....Pages 267-310 Mitochondrial Involvement in Drug-Induced Liver Injury....Pages 311-365 Front Matter....Pages 368-368 Mechanisms of Acetaminophen-Induced Liver Necrosis....Pages 369-405 Drug-Induced Liver Injury in Humans: The Case of Ximelagatran....Pages 407-418 Troglitazone....Pages 419-435 Nevirapine Hypersensitivity....Pages 437-451 Mechanisms of Adverse Drug Reactions to Biologics....Pages 453-474 Front Matter....Pages 476-476 Pharmacogenetics of Idiosyncratic Adverse Drug Reactions....Pages 477-491 The Danger Hypothesis Applied to Idiosyncratic Drug Reactions....Pages 493-509 Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery....Pages 511-544 Back Matter....Pages 1-12 3642006620 1 Preface 5 Contents 7 Contributors 9 Part I Target Organ Toxicity 11 1 Drug-Induced Liver Injury 12 2 Drug Hypersensitivity Reactions Involving Skin 37 3 Adverse Drug Reactions Affecting Blood Cells 64 4 Molecular Mechanisms of Adverse Drug Reactions in Cardiac Tissue 84 5 Mechanisms of Drug-Induced Nephrotoxicity 117 6 Receptor- and Reactive Intermediate-Mediated Mechanisms of Teratogenesis 137 Part II Mediators/Biochemical Pathways 169 7 Role of Reactive Metabolites in Drug-Induced Hepatotoxicity 170 8 The Role of Cytokines in the Mechanism of Adverse Drug Reactions 200 9 The Keap1-Nrf2 Cellular Defense Pathway: Mechanisms of Regulation and Role in Protection Against Drug-Induced Toxicity 237 10 Signal Transduction Pathways Involved in Drug-Induced Liver Injury 271 11 Mitochondrial Involvement in Drug-Induced Liver Injury 315 Part III Examples/Models 370 12 Mechanisms of Acetaminophen-Induced Liver Necrosis 371 13 Drug-Induced Liver Injury in Humans: The Case of Ximelagatran 408 14 Troglitazone 420 15 Nevirapine Hypersensitivity 437 16 Mechanisms of Adverse Drug Reactions to Biologics 452 Part IV Risk Factors/Screening Drug Candidates 474 17 Pharmacogenetics of Idiosyncratic Adverse Drug Reactions 475 18 The Danger Hypothesis Applied to Idiosyncratic Drug Reactions 490 19 Approaches for Minimizing Metabolic Activation of New Drug Candidates in Drug Discovery 507 Index 541