Antitargets and drug safety. (2015)

• Record Type: Book
• Further Information: Note: Edited by László Urbán, Vinod F. Patel, and Roy J. Vaz.
• Editors: Urban, Laszlo, 1951-; Patel, Vinod F; Vaz, Roy J
• Contents: List of Contributors XV Preface XXI A Personal Foreword XXIII Section 1 General Concept for Target-based Safety Assessment 1 1 Side Effects of Marketed Drugs: The Utility and Pitfalls of Pharmacovigilance 3 ; Steven Whitebread, Mateusz Maciejewski, Alexander Fekete, Eugen Lounkine, and László Urbán 1.1 Introduction 3 1.2 Postmarketing Pharmacovigilance 6 1.3 Polypharmacy and Pharmacological Promiscuity of Marketed Drugs 9 References 15 2 In Silico Prediction of Drug Side Effects 19 ; Michael J. Keiser 2.1 Large-Scale Prediction of Drug Activity 20 2.1.1 Networks of Known and New Target Activity 21 2.1.2 Resources for Multiscale Inquiry 25 2.2 Multiscale Models of Adverse Drug Reactions 30 2.2.1 Inferring Adverse Reactions 31 2.2.2 Forward Perturbation and Prediction of Mechanisms 33 References 36 3 Translational Value of Preclinical Safety Assessment: System Organ Class (SOC) Representation of Off-Targets 45 ; Mateusz Maciejewski, Eugen Lounkine, Andreas Hartmann, Steven Whitebread, and László Urbán 3.1 Introduction 45 3.2 Terminology: Medicinal Dictionary for Regulatory Activities (MedDRA) 46 3.2.1 Correct Use of MedDRA Terminology at Different Phases of Drug Discovery 48 3.2.2 Determination of Symptoms Associated with a Target 50 3.3 Data Interpretation: Modifying Factors 52 3.3.1 Access to Organs 52 3.3.2 Off-Target Promiscuity: Target Interactions (Synergies and Antagonism) 53 3.4 Conclusions 53 References 54 4 Pathological Conditions Associated with the Disturbance of the 5-HT System 57 ; Daniel Hoyer 4.1 Introduction 57 4.2 From “St. Anthony’s Fire” to Ergot Alkaloids, the Serotonin Syndrome, and Modern 5-HT Pharmacology 59 4.3 Appetite-Reducing Agents, Fenfluramine, and Other 5-HT Releasers 61 4.4 Gastrointestinal and Antiemetic Indications, the 5-HT3/5-HT4 Receptor Links 63 4.5 Antipsychotics and the 5-HT2/Dopamine D2 Link (and Many Other 5-HT Receptors) 65 4.6 Antimigraine Medications of Old and New and the 5-HT1B/1D Receptors 67 4.7 Antidepressants/Anxiolytics Acting at 5-HT and Other Transporters 69 4.8 Conclusions 71 References 72 Section 2 Hepatic Side Effects 81 5 Drug-Induced Liver Injury: Clinical and Diagnostic Aspects 83 ; John R. Senior 5.1 Introduction 83 5.1.1 Postmarketing Hepatotoxicity versus Hepatotoxicity in Development 84 5.1.2 Isoniazid – If It Were Newly Discovered, Would It Be Approved Today? 85 5.2 Special Problems of Postmarketing Hepatotoxicity 89 5.2.1 Voluntary Monitoring after Approval for Marketing 90 5.2.2 Prediction of Serious, Dysfunctional Liver Injury 90 5.2.3 Severity of Liver Injury Is Not Measured by Aminotransferase Elevations 91 5.2.4 Attempts to Standardize Terminology 91 5.2.5 What Is the “Normal” Range, or the “Upper Limit of Normal”? 92 5.2.6 Diagnostic Test Evaluation 93 5.2.7 Determination of the Likely Cause of Liver Abnormalities 94 5.2.8 Treatment and Management of DILI in Practice 95 5.3 Special Problems for New Drug Development 95 5.3.1 How Many? 95 5.3.2 How Much? 96 5.3.3 How Soon? 97 5.3.4 How Likely? 97 5.3.5 Compared with What? 97 5.3.6 ROC Curves 98 5.3.7 eDISH: Especially for Controlled Trials 99 5.3.8 Test Validation and Qualification 100 5.4 Closing Considerations 101 5.4.1 A Handful of “Do Nots” 101 5.4.2 Need to Standardize ALT Measurement and Interpretation of Normal Ranges 102 5.4.3 Research Opportunities 102 References 103 6 Mechanistic Safety Biomarkers for Drug-Induced Liver Injury 107 ; Daniel J. Antoine 6.1 Introduction 107 6.2 Drug-Induced Toxicity and the Liver 110 6.3 Current Status of Biomarkers for the Assessment of DILI 111 6.4 Novel Investigational Biomarkers for DILI 113 6.4.1 Glutamate Dehydrogenase (GLDH) 114 6.4.2 Acylcarnitines 115 6.4.3 High-Mobility Group Box-1 (HMGB1) 116 6.4.4 Keratin 18 (K18) 116 6.4.5 MicroRNA-122 (miR-122) 117 6.5 Conclusions and Future Perspectives 118 References 120 7 In Vitro Models for the Prediction of Drug-Induced Liver Injury in Lead Discovery 125 ; Frederic Moulin and Oliver Flint 7.1 Introduction 125 7.2 Simple Systems for the Detection and Investigation of Hepatic Toxicants 130 7.2.1 Primary Hepatocytes 130 7.2.2 Liver-Derived Cell Lines 135 7.2.3 Differentiated Pluripotent Stem Cells 137 7.3 Models to Mitigate Hepatocyte Dedifferentiation 140 7.3.1 Liver Slices 140 7.3.2 Selective Engineering of Metabolism 141 7.4 Understanding Immune-Mediated Hepatotoxicity 144 7.4.1 Use of Inflammatory Cofactors 145 7.4.2 Innate Immune System and Inflammasome 147 7.5 Conclusions 148 References 149 8 Transporters in the Liver 159 ; Bruno Stieger and Gerd A. Kullak-Ublick 8.1 Introduction 159 8.2 Role of Organic Anion Transporters for Drug Uptake 159 8.3 Drug Interaction with the Bile Salt Export Pump 160 8.4 Susceptibility Factors for Drug–BSEP Interactions 161 8.5 Role of BSEP in Drug Development 162 References 163 9 Mechanistic Modeling of Drug-Induced Liver Injury (DILI) 173 ; Kyunghee Yang, Jeffrey L. Woodhead, Lisl K. Shoda, Yuching Yang, Paul B. Watkins, Kim L.R. Brouwer, Brett A. Howell, and Scott Q. Siler 9.1 Introduction 173 9.2 Mechanistic Modules in DILIsym?D version 3A 175 9.2.1 Oxidative Stress-Mediated Toxicity 175 9.2.2 Innate Immune Responses 178 9.2.3 Mitochondrial Toxicity 179 9.2.4 Bile Acid-Mediated Toxicity 181 9.3 Examples of Bile Acid-Mediated Toxicity Module 184 9.3.1 Troglitazone and Pioglitazone 184 9.3.2 Bosentan and Telmisartan 187 9.4 Conclusions and Future Directions 190 References 191 Section 3 Cardiovascular Side Effects 199 10 Functional Cardiac Safety Evaluation of Novel Therapeutics 201 ; Jean-Pierre Valentin, Brian Guth, Robert L. Hamlin, Pierre Lainée, Dusty Sarazan, and Matt Skinner 10.1 Introduction: What Is the Issue? 201 10.2 Cardiac Function: Definitions and General Principles 203 10.2.1 Definition and Importance of Inotropy and Difference from Ventricular Function 203 10.2.2 Definition and Importance of Lusitropy 207 10.2.3 Components and Importance of the Systemic Arterial Pressure 211 10.3 Methods Available to Assess Cardiac Function 213 10.4 What Do We Know About the Translation of the Nonclinical Findings to Humans? 217 10.5 Risk Assessment 219 10.5.1 Hazard Identification 219 10.5.2 Risk Assessment 221 10.5.3 Risk Management 224 10.5.4 Risk Mitigation 225 10.6 Summary, Recommendations, and Conclusions 227 References 228 11 Safety Aspects of the Cav1.2 Channel 235 ; Berengere Dumotier and Martin Traebert 11.1 Introduction 235 11.2 Structure of Cav1.2 Channels 235 11.2.1 α-Subunit of Cav1.2 Channel 236 11.2.2 β-Subunit of Cav1.2 Channel 236 11.3 Function of Cav1.2 Channels in Cardiac Tissue 237 11.3.1 Role in Conduction and Contractility 239 11.3.2 Modulation of Cav1.2 Channels 240 11.3.3 Cav1.2 and Cardiac Diseases 244 11.4 Pharmacology of Cav1.2 Channels: Translation to the Clinic 245 11.4.1 Cav1.2 Antagonists: Impact on
• Publisher Details: Place of publication not identified : Wiley-VCH
• Publication Date: 2015
• Extent: 1 online resource (528 pages)
• Subjects: 615.19; Drug development; Drugs -- Design; Drugs -- Side effects; Drug interactions
• Languages: English
• ISBNs: 9783527673667
• Access Rights: Legal Deposit; Only available on premises controlled by the deposit library and to one user at any one time; The Legal Deposit Libraries (Non-Print Works) Regulations (UK).
• Access Usage: Restricted: Printing from this resource is governed by The Legal Deposit Libraries (Non-Print Works) Regulations (UK) and UK copyright law currently in force.