Comprehensive Pharmacology

Description

Comprehensive Pharmacology, Seven Volume Set is organized into twelve sections that explore therapeutic areas, with a total of 320 comprehensive articles and 6,800 pages of important findings. Sections contain highly detailed coverage of information that has been overseen by an editorial board made up of well-respected, field leading experts. The content in this book offers readers an in-depth and easily accessible reference work on every aspect of pharmacological research surrounding the pharmacology of all therapeutic applications of drugs, their mechanism of action and their therapeutic values. These elements are essential as drugs are almost never tested and developed in the actual therapeutic system, but rather in test systems from which parameters must be determined to predict activity in systems of varying ambient physiology. As different technologies rapidly evolve, there is an ever-increasing level of knowledge about the pharmacology of known drugs, along with increasing capability to utilize pharmacological systems to predict new drug activity, all of which must be communicated to professionals in varying fields. Contains chapters that follow a consistent and templated approach, resulting in well-structured content that enhances user experience and appealOffers a comprehensive review on a wealth of information on pharmacology and how it utilizes concepts and techniques from a broad array of sciences, ranging from chemistry to physiology to medicineIncludes a wider use of color and multimedia content, with interactive features, links, computational modeling and animations to illustrate the effects of toxic substances in various contexts 9780128208762v1_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 1 FOREWORD PREFACE CONTENTS OF VOLUME 1 1.01 -Pharmacodynamics: Overview Reference 1.02 -The Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology: Achieving Con ... 1.02.1 An introduction to NC-IUPHAR 1.02.2 Membership, aims and objectives of NC-IUPHAR 1.02.3 Outputs from NC-IUPHAR 1.02.4 Reflections on nomenclature successes and “failures” 1.02.5 Future challenges Acknowledgments References 1.03 -Receptor Tyrosine Kinases 1.03.1 Introduction 1.03.2 Architecture of RTK extracellular domains 1.03.3 Overview of RTK kinase anatomy and function 1.03.4 ATP binding and the act of phosphorylation 1.03.5 Types of Inhibitors and how they work 1.03.6 Ligand traps 1.03.7 RTK subfamilies and their inhibitors 1.03.8 Challenges, alternative strategies, and outlook 1.03.9 Outlook References Relevant Websites 1.04 -Cytokine Receptors 1.04.1 Introduction 1.04.2 The class I cytokine receptor family 1.04.3 The class II receptor family References 1.05 -An Overview of Steady-State Enzyme Kinetics 1.05.1 Introduction 1.05.2 Nomenclature 1.05.3 Enzyme kinetics in the steady-state 1.05.4 Kinetic mechanism 1.05.5 Literature examples of kinetic mechanisms 1.05.6 Rate-limiting steps 1.05.7 Determination of the chemical mechanisms of enzyme catalysis using steady-state kinetics 1.05.8 Concluding remarks A Appendix References 1.06 -Ion Channels 1.06.1 Introduction 1.06.2 Ion channels: A diverse family of ion-transporting proteins 1.06.3 Ion channel structure 1.06.4 Functional properties of ion channels: Permeation and gating 1.06.5 Ion channel pharmacology 1.06.6 Characterization of ion channel-ligand interactions: From whole-tissue to single molecules 1.06.7 Emerging technologies and ion channel pharmacology 1.06.8 Conclusion References Relevant Websites 1.07 -Nuclear Receptors 1.07.1 Introduction 1.07.2 Drug discovery of nuclear receptors 1.07.3 Nuclear receptor domains 1.07.4 Homo and heterodimerization of nuclear receptors 1.07.5 Coregulatory recruitment to nuclear receptors 1.07.6 Modulation of nuclear receptor activity 1.07.7 Ligand binding to nuclear receptors 1.07.8 Antagonism of nuclear receptor activity 1.07.9 Diverging modulatory behavior of chemical analogs 1.07.10 Allosteric sites for nuclear receptor antagonism 1.07.11 Selectivity in nuclear receptor modulation 1.07.12 Concluding remarks References 1.08 -Neurotransmitter Transporters and Their Role in the Pharmacological Actions of Therapeutic and Abused Drugs 1.08.1 Introduction 1.08.2 Overview 1.08.3 Serotonin transporter 1.08.4 Dopamine transporter 1.08.5 Norepinephrine transporter 1.08.6 GABA transporters 1.08.7 Glycine transporters 1.08.8 Organic cation transporters 1.08.9 Concluding remarks Acknowledgments References Relevant Websites 1.09 -Pharmacological Receptor Theory 1.09.1 Introduction 1.09.2 Mass action building blocks 1.09.3 Pharmacodynamics: Historical perspective 1.09.4 Pharmacodynamics: Orthosteric interaction 1.09.5 Pharmacodynamics: Allosteric interaction 1.09.6 Molecular dynamics and probabilistic models of receptor function 1.09.7 Fitting pharmacodynamic models to determine drug parameters 1.09.8 Conclusions References 1.10 -Kinetics of Drug-Target Binding: A Guide for Drug Discovery 1.10.1 Introduction 1.10.2 Mechanics of target-ligand binding kinetics 1.10.3 In vivo efficacy and target binding kinetics 1.10.4 Other kinetic effects—Micro PK-PD relationships, fluctuating endogenous ligand concentration, and post-binding events 1.10.5 Impact of binding kinetics on in vitro assays of drug effect 1.10.6 Measuring receptor-ligand binding kinetics 1.10.7 Functional assays for measuring binding kinetics 1.10.8 Concluding remarks—When to measure binding kinetics in drug discovery References 1.11 -Orthosteric Receptor Antagonism 1.11.1 Introduction 1.11.2 What is “steric hindrance”? 1.11.3 Kinetics, competitive and non-competitive antagonism 1.11.4 Antagonists with efficacy 1.11.5 Verisimilitude to allosteric antagonism 1.11.6 Antagonist target coverage in vivo 1.11.7 Conclusions References 1.12 -Allosteric Modulation 1.12.1 Introduction 1.12.2 The geography of allosterism 1.12.3 Types of macroscopic functional response by allosteric modulators 1.12.4 Probe dependence: Can the functional attributes of a drug be defined independently of its chemical context? 1.12.5 Functional shifts: A bug or a feature? 1.12.6 Beyond allosterism 1.12.7 Summary: Allosterism and more effective drug discovery Acknowledgments References 1.13 -Analysis of the Function of Receptor Oligomers by Operational Models of Agonism 1.13.1 Introduction 1.13.2 Mathematical modeling of GPCR oligomerization 1.13.3 The operational model of agonism 1.13.4 Extending the operational model of agonism to account for receptor oligomerization 1.13.5 Inclusion of allosterism and constitutive activity in the mathematical modeling of receptor oligomerization 1.13.6 An operational model for receptor homodimers 1.13.7 An operational model for receptor heterodimers 1.13.8 Concluding remarks A Appendix References Relevant Websites 1.14 -Agonism and Biased Signaling 1.14.1 Introduction 1.14.2 Receptor protein dynamics forming different conformational states 1.14.3 Measuring the magnitude of agonist efficacy 1.14.4 The Black/Leff operational model of Agonism 1.14.5 Agonist biased signaling 1.14.6 Conclusions References 1.15 -The Pharmacology of WNT Signaling 1.15.1 The discovery of WNT signaling 1.15.2 WNT proteins 1.15.3 Receptors for WNT proteins 1.15.4 Signal transduction 1.15.5 Regulation of WNT signaling by internal mediators 1.15.6 WNT signaling in stem cells 1.15.7 WNT signaling in disease 1.15.8 Drugs targeting the WNT signaling pathway References 1.16 -Pharmacokinetics: Overview 1.17 -Oral Drug Delivery, Absorption and Bioavailability 1.17.1 Introduction 1.17.2 Physiology and function of the gastrointestinal tract and related organs 1.17.3 Pharmacokinetics and pharmacodynamics; processes to consider in oral dosage form research and development 1.17.4 Fundamental biopharmaceutical parameters for intestinal absorption and bioavailability: Solubility and dissolution, ... References 1.18 -PK Interpretation of Drug Distribution: General Concepts and Application to Special Populations 1.18.1 Introduction 1.18.2 General concept of drug distribution in pharmacokinetics (PK) 1.18.3 PK characteristics in pregnancy 1.18.4 Drug distribution into human milk 1.18.5 Neonates, infants and children References 1.19 -Drug Metabolism: Cytochrome P450 1.19.1 History 1.19.2 Significance 1.19.3 Regulation of P450s 1.19.4 Structures 1.19.5 Catalytic mechanism 1.19.6 Conformational changes and catalytic selectivity 1.19.7 Kinetics 1.19.8 Inhibition 1.19.9 P450 and reaction oxygen species (ROS) 1.19.10 P450 enzymes involved in drug metabolism 1.19.11 P450s as targets for drugs Acknowledgments References 1.20 -Drug Metabolism: Other Phase I Enzymes 1.20.1 Introduction 1.20.2 Flavin-containing monooxygenases 1.20.3 Aldehyde oxidase 1.20.4 Aldehyde dehydrogeneases 1.20.5 Alcohol dehydrogenases 1.20.6 Carboxylesterases 1.20.7 Conclusions and future perspectives References 1.21 -Drug Metabolism: Phase II Enzymes 1.21.1 Introduction 1.21.2 UDP-glucuronosyltransferases, UGTs 1.21.3 PAPS-sulfotransferases 1.21.4 Glutathione transferases, GSTs 1.21.5 N-acetyltransferases, NATs 1.21.6 Amino acid conjugation enzymes and drug-acyl-CoA pathways 1.21.7 Methyltransferases, MTs 1.21.8 Conclusions References 1.22 -Drug Transport—Uptake 1.22.1 Introduction 1.22.2 Basic principles of transport 1.22.3 Main drug uptake transporters 1.22.4 Summary and conclusions 1.22.5 Disclosure of interest References 1.23 -Drug Transporters: Efflux 1.23.1 Introduction 1.23.2 Important efflux transporters for pharmacokinetics 1.23.3 Absorption 1.23.4 Distribution 1.23.5 Hepatobiliary excretion 1.23.6 Renal excretion 1.23.7 Summary References 1.24 -Drug Excretion 1.24.1 Introduction 1.24.2 Kidney 1.24.3 Liver 1.24.4 Breast milk 1.24.5 Saliva, sweat, hair and respiration 1.24.6 Conclusion References Relevant Websites 1.25 -Mathematical Aspects of Clinical Pharmacokinetics 1.25.1 Introduction to quantitative aspects of pharmacokinetics 1.25.2 Bioavailability 1.25.3 Volume of distribution 1.25.4 Clearance 1.25.5 Half-life 1.25.6 Application of pharmacokinetics to routine drug therapy 1.25.7 Conclusions References 1.26 -Pharmacogenetics/Pharmacogenomics of Drug-Metabolizing Enzymes and Transporters 1.26.1 Introduction 1.26.2 PGx of phase I genes 1.26.3 PGx of non-P450 enzymes 1.26.4 PGx of drug transporters 1.26.5 PGx of other enzymes and antigens 1.26.6 Conclusion References 1.27 -Drug-Drug Interactions With a Pharmacokinetic Basis 1.27.1 Introduction 1.27.2 General pharmacokinetic principles 1.27.3 Metabolism 1.27.4 Alterations to AUC and unbound AUC (AUCu) based on the well-stirred model 1.27.5 Absorption 1.27.6 Transporters 1.27.7 Conclusion References Relevant Websites 1.28 -ADME of Biologicals and New Therapeutic Modalities 1.28.1 Introduction and basic overview to ADME properties of biologics 1.28.2 Novel therapeutic modalities 1.28.3 Approaches to characterizing the ADME properties of novel modalities 1.28.4 Conclusion References 1.29 -Role of Pharmacokinetics and Pharmacokinetic Modeling in Drug Development 1.29.1 Introduction 1.29.2 Absorption 1.29.3 Distribution 1.29.4 Metabolism 1.29.5 Excretion 1.29.6 Conclusions References 1.30 -Prediction of Drug Metabolism: Use of Structural Biology and In Silico Tools 1.30.1 Introduction 1.30.2 Ligand-based methods in CYP450 metabolism prediction 1.30.3 Structure-based methods in CYP450 metabolism prediction 1.30.4 Summary and outlook References 9780128208762v2_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 2 FOREWORD PREFACE CONTENTS OF VOLUME 2 2.01 Pharmacogenomics: Overview 2.02 -Ethical Perspectives on Pharmacogenomic Profiling 2.02.1 Pharmacogenomics in precision medicine 2.02.2 Ethical concerns of genomic data management 2.02.3 Ethical principles: Beneficence, non-maleficence, autonomy, and justice 2.02.4 Informed consent process in pharmacogenomics research 2.02.5 Considerations for population studies 2.02.6 Studies involving vulnerable groups 2.02.7 Clinical trial design for pharmacogenomic research 2.02.8 Barriers for pharmacogenomics implementation 2.02.9 Guidelines in pharmacogenomics 2.02.10 Legal and social issues 2.02.11 Conclusion Conflict of Interest References 2.03 -Pharmacogenomics in the Era of “Big Data” and Advanced Computational Approaches 2.03.1 Introduction References 2.04 -GPCR Patient Drug Interaction—Pharmacogenetics: Genome-Wide Association Studies (GWAS) 2.04.1 Introduction 2.04.2 Methodology of GWAS 2.04.3 Replication of GWAS findings and meta-analysis 2.04.4 Visualization of GWAS results 2.04.5 Genetic ancestry, admixture, and pharmacogenomics 2.04.6 Special considerations 2.04.7 Successes and limitations of GWAS 2.04.8 Innovations and challenges in pharmacogenomics GWAS 2.04.9 Clinical translatability References Relevant Websites 2.05 -Computational Methods and Approaches in Pharmacogenomic Research 2.05.1 Introduction 2.05.2 Overview of genetic profiling methods 2.05.3 The genetic structure of ADME genes 2.05.4 Star alleles and their functional interpretation 2.05.5 Star allele calling using computational methods 2.05.6 Tools for computational variant interpretations 2.05.7 Genetic structure of pharmacodynamics genes 2.05.8 Current overview of the implementation of pharmacogenomic testing 2.05.9 Conclusions Conflict of Interest References Relevant websites 2.06 -Computational Medicinal Chemistry to Target GPCRs 2.06.1 Receptor structure preparation 2.06.2 Incorporate dynamics: Molecular dynamics simulations 2.06.3 Identifying and filtering new ligands 2.06.4 Hit to lead and lead optimization 2.06.5 Current and future challenges References Relevant websites 2.07 -Simulating Time-Resolved Dynamics of Biomolecular Systems 2.07.1 Introduction 2.07.2 Study of biological features from a dynamics perspective 2.07.3 The theory behind MD 2.07.4 MD methods and their application 2.07.5 Current challenges of MD 2.07.6 Conclusions and perspectives Acknowledgments References 2.08 -Targeting GPCRs Via Multi-Platform Arrays and AI 2.08.1 Introduction 2.08.2 Machine learning 2.08.3 Machine learning key algorithms 2.08.4 Computer aided drug design: Ligand design and discovery 2.08.5 GPCR characterization and selection 2.08.6 Other areas of AI application to GPCRs 2.08.7 R&D companies 2.08.8 Concluding remarks 2.08.9 Funding References 2.09 -Pharmacology of Viral GPCRs: All-Round Chemokine Receptor Homologs 2.09.1 Introduction to viral GPCRs 2.09.2 Structural determinants of vGPCR pharmacology 2.09.3 Signal transduction by vGPCRs 2.09.4 vGPCR localization and trafficking 2.09.5 Role of post-translational modifications (PTMs) in vGPCR pharmacology 2.09.6 vGPCR interactome 2.09.7 Pharmacological modulation of vGPCRs 2.09.8 Conclusion and future perspectives Acknowledgment Authorship Contributions References 2.10 -Personalized Medicine Through GPCR Pharmacogenomics 2.10.1 Introduction 2.10.2 GPCR biology 2.10.3 GPCR pharmacogenomics 2.10.4 Outlook 2.10.5 Conclusions Acknowledgments References Relevant Websites 2.11 -Translating Pharmacogenomic Research to Therapeutic Potentials (Bench to Bedside) 2.11.1 Introduction 2.11.2 Historical evolution of pharmacogenomics 2.11.3 Biology of pharmacogenes 2.11.4 Research: The bench from single variants to genome-wide analysis 2.11.5 Clinical testing 2.11.6 Clinical implementation 2.11.7 Clinical cases References Relevant websites 2.12 -Applying Pharmacogenomics in Drug Therapy of Cardiovascular Disease 2.12.1 Current status of pharmacogenomic application in cardiovascular disease 2.12.2 Future application 2.12.3 Summary and conclusion References 2.13 -Applying Pharmacogenomics in Drug Therapy of Neurologic and Psychiatric Disorders 2.13.1 Introductions 2.13.2 Can pharmacogenomics work in neurological and psychiatric disorders? 2.13.3 Pharmacogenomics of drug treatment for epilepsy and Parkinson’s disease 2.13.4 HLA genes and adverse reactions to antiepileptics and clozapine 2.13.5 Application of pharmacogenomics in psychiatry and neurology 2.13.6 Conclusion References 2.14 -Personalized Pharmacotherapy: A Historical Perspective on the Pharmacogenomics of Depression⋆ 2.14.1 Pharmacogenomics: Getting from bench to bedside 2.14.2 Pharmacogenomics in major depression 2.14.3 Conclusions References 2.15 -Pharmacogenomics of Anti-Cancer Drugs 2.15.1 Introduction 2.15.2 Germ-line genetic risk factors for cancer drug safety 2.15.3 Pharmacogenomics of immunotherapy in oncology 2.15.4 Rare variants and polygenic risks scores 2.15.5 Genetic predictors of cancer drug efficacy and companion diagnostics 2.15.6 Emerging concepts in cancer pharmacogenomics 2.15.7 Conclusions References 2.16 Gene Therapy 2.16.1 Introduction 2.16.2 Viral-based gene therapy drugs 2.16.3 Nonviral-based gene therapy drugs 2.16.4 Cell-based gene therapy products References Relevant websites 2.17 -Drug Discovery: Overview References 2.18 -Drug Discovery in Induced Pluripotent Stem Cell Models 2.18.1 Introduction 2.18.2 iPSC-derived models of CNS disease 2.18.3 iPSC-derived models of the heart and cardiovascular system 2.18.4 Using biosensors to track cellular signaling events and disease progression 2.18.5 Drug screening in differentiated iPSC derivatives 2.18.6 Conclusion Acknowledgments References 2.19 -Pharmacological Target Engagement and Validation 2.19.1 Introduction 2.19.2 System-based discovery 2.19.3 Target-based discovery 2.19.4 Target validation 2.19.5 Target engagement 2.19.6 Choosing chemical targets 2.19.7 Target druggability 2.19.8 Achieving drug selectivity 2.19.9 The application of pharmacology to drug discovery: Know your molecule 2.19.10 Conclusions References 2.20 -The Role of Natural Products as Sources of Therapeutic Agents for Innovative Drug Discovery 2.20.1 Introduction 2.20.2 Innovative strategies for drug discovery with natural products 2.20.3 Conclusion References 2.21 -Drug Lead Optimization 2.21.1 Introduction 2.21.2 Compound screening 2.21.3 Lead optimization 2.21.4 Optimization of primary activity 2.21.5 Optimization of pharmacokinetic properties 2.21.6 Optimization for safety 2.21.7 Conclusions References 2.22 -Compound Screening 2.22.1 Introduction 2.22.2 The key components of a successful screen 2.22.3 Purpose for compound screening: What is your question? 2.22.4 Assays and assay technologies 2.22.5 Conclusions and outlook References 2.23 -Target Validation—Prosecuting the Target 2.23.1 Introduction 2.23.2 Case studies 2.23.3 Emerging target validation and engagement technologies 2.23.4 Conclusions and perspectives Acknowledgments Disclaimer References Relevant Websites 2.24 -Models for Lead Optimization 2.24.1 Introduction 2.24.2 Determination of affinity 2.24.3 Determination of efficacy 2.24.4 Allosteric modulation 2.24.5 Determination of binding kinetic constants A Appendix References 2.25 -Structure-Based Virtual Screening: Theory, Challenges and Guidelines 2.25.1 Introduction 2.25.2 VS and docking algorithms 2.25.3 Limitations and circumvention approaches 2.25.4 Considerations and guidelines 2.25.5 Examples 2.25.6 Summary References 2.26 -Computational and Artificial Intelligence Techniques for Drug Discovery and Administration 2.26.1 Introduction 2.26.2 Mathematical techniques 2.26.3 Computational techniques 2.26.4 Artificial intelligence techniques 2.26.5 Conclusion and perspectives References 2.27 -Replicability and Reproducibility in Drug Discovery 2.27.1 Introduction 2.27.2 Principles of GSP 2.27.3 Pre-specification and pre-registration 2.27.4 Current ideas for replicating results 2.27.5 Current ideas for reproducible results 2.27.6 Concluding thoughts References 2.28 -Holistic Assessment of Compound Properties—In Vitro to In Vivo Pharmacology 2.28.1 Introduction 2.28.2 R&D productivity paradigm 2.28.3 Design-make-test cycle 2.28.4 Screening types in progress from hit to candidate 2.28.5 Assay cascades 2.28.6 Structure-based and phenotypic discovery 2.28.7 Screening libraries 2.28.8 Isolated protein binding assays 2.28.9 Receptor assays 2.28.10 Enzymatic assays 2.28.11 Binding confirmation and confounding factors 2.28.12 Cell-based screening 2.28.13 Off-target binding 2.28.14 Lipophilicity 2.28.15 Solubility measurement and interpretation 2.28.16 Permeability and transport 2.28.17 Plasma protein binding and fraction unbound 2.28.18 Cellular concentration and the free drug hypothesis 2.28.19 Clearance 2.28.20 Drug-drug interactions: Induction, inhibition, and transport 2.28.21 In vivo pharmacokinetic screens 2.28.22 Modeling approaches in ADMET optimization and in silico PK prediction 2.28.23 Optimization rules and guidance 2.28.24 Pharmacodynamic and toxicokinetic screens 2.28.25 Translation to human 2.28.26 Effective screening in drug discovery 2.28.27 Disclaimer References Further reading 2.29 -Translational Pharmacology and Clinical Trials 2.29.1 Attrition in the translational research pathway 2.29.2 Approaches to improve the predictive value of translational research 2.29.3 Translational biomarkers: From preclinical testing to clinical practice 2.29.4 Concluding remarks and future perspectives Acknowledgements References 2.30 -Biomarkers 2.30.1 Introduction 2.30.2 Biomarker’s concept 2.30.3 Types and role of biomarkers in the clinical practice 2.30.4 Samples and technologies used in the searching of biomarkers 2.30.5 Crucial role of biomarkers for drug discovery: From preclinical to clinical studies 2.30.6 Biomarkers discovery and validation for clinical use: Diagnostic and predictive accuracy 2.30.7 Established biomarkers in drug development and health care 2.30.8 Biomarkers in psychiatric and neurological disorders 2.30.9 Future directions for the establishment of clinically relevant biomarkers Acknowledgments References Relevant Websites 2.31 -Systems Pharmacology: Enabling Multidimensional Therapeutics 2.31.1 Introduction 2.31.2 Intersection of systems pharmacology with complex systems 2.31.3 Quantification of complex pharmacological systems 2.31.4 High dimensionality appreciation of biological networks 2.31.5 Systemic G protein-coupled receptor axes 2.31.6 Pathological modulation and remediation of physiological systems 2.31.7 Informatic platforms for systems pharmacology 2.31.8 Discussion References 2.32 -Magic bullets: Drug repositioning and drug combinations 2.32.1 Introduction 2.32.2 Drug repositioning: In silico approaches 2.32.3 Computational discovery of drug combinations 2.32.4 De novo drug discovery: Generative models 2.32.5 Computational drug discovery: COVID-19 2.32.6 Conclusion References 2.33 -Drug Combinations 2.33.1 Introduction 2.33.2 Combination drug therapy—Rationale and challenges 2.33.3 Drug combination methodology 2.33.4 Select clinically relevant examples of drug combination therapies 2.33.5 Perspectives References Relevant Websites 2.34 -Drug Repurposing 2.34.1 Introduction 2.34.2 Off-label use: A particular case of (unlicensed) drug repurposing 2.34.3 Drug rescue examples: Breathing life into abandoned drugs 2.34.4 Drug repurposing “on the fly” 2.34.5 Drug repurposing of approved drugs 2.34.6 From unorganized to organized pursue of drug repurposing opportunities 2.34.7 Commercial barriers to drug repurposing 2.34.8 Drug repurposing for rare and neglected conditions 2.34.9 Personalized drug repurposing 2.34.10 Conclusion Conflict of interest References 9780128208762v3_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 3 FOREWORD PREFACE CONTENTS OF VOLUME 3 3.01 -Central Nervous System Pharmacology: Overview References 3.02 -Dystonias 3.02.1 Introduction 3.02.2 Epidemiology 3.02.3 Clinical features of dystonia 3.02.4 Etiology of dystonia 3.02.5 Principles of management 3.02.6 Etiology-specific therapies 3.02.7 Symptomatic therapies 3.02.8 Medical treatment 3.02.9 Botulinum toxin 3.02.10 Surgical treatment 3.02.11 Unmet needs Acknowledgment References 3.03 -Essential Tremor 3.03.1 Introduction 3.03.2 Clinical presentation 3.03.3 Classification and diagnosis 3.03.4 Epidemiology 3.03.5 Pathophysiology 3.03.6 Pharmacotherapy 3.03.7 Neurosurgical procedures 3.03.8 Emerging therapies References 3.04 -Alzheimer’s Disease Pharmacology 3.04.1 Etiology, epidemiology, and risk factors of Alzheimer’s disease 3.04.2 Clinical pharmacology in Alzheimer’s disease 3.04.3 Drugs used to treat symptomatology 3.04.4 Medical foods 3.04.5 Pharmaceuticals targeting amyloid-β 3.04.6 Pharmaceuticals targeting tau protein 3.04.7 Pharmaceuticals targeting secretases 3.04.8 Regulation of neurotransmission 3.04.9 Regulation of neuroinflammation 3.04.10 Pharmaceuticals targeting oxidative stress 3.04.11 Gene and cell therapies for AD 3.04.12 Perspectives and alternative approaches Acknowledgments References 3.05 -Neuroprotection Following Stroke 3.05.1 Introduction 3.05.2 Definition of stroke 3.05.3 Epidemiology and risk factors 3.05.4 Pathogenesis and classification 3.05.5 Pathobiological mechanisms 3.05.6 Reperfusion strategies 3.05.7 Neuroprotection 3.05.8 Conclusions References 3.06 -The Epilepsies 3.06.1 Introduction 3.06.2 Epilepsy overview 3.06.3 Epilepsy treatment 3.06.4 ASMs with predominant Na channel mechanism of action 3.06.5 ASMs with predominant gamma-butyric acid (GABA) signaling mechanism of action 3.06.6 ASMs with predominant synaptic vesicle protein signaling mechanism of action 3.06.7 ASMs with predominant calcium channel signaling mechanism of action 3.06.8 ASMs with predominant glutamate signaling mechanism of action 3.06.9 Conclusions Reference 3.07 -Lennox-Gastaut Syndrome 3.07.1 Introduction 3.07.2 Definition 3.07.3 Epidemiology 3.07.4 Etiology 3.07.5 Network studies 3.07.6 Clinical characteristics 3.07.7 Electroencephalographic features 3.07.8 Differential diagnosis 3.07.9 Treatment 3.07.10 Prognosis 3.07.11 Conclusions 3.07.12 Questions 3.07.13 Answers 3.07.14 Conflicts of interest References 3.08 -Bell’s Palsy 3.08.1 Introduction 3.08.2 Epidemiology 3.08.3 Pathophysiology 3.08.4 Symptoms and signs 3.08.5 Diagnosis 3.08.6 Assessing severity 3.08.7 Treatment 3.08.8 Prognosis 3.08.9 Trials/Systematic reviews 3.08.10 Bell’s palsy guidelines References 3.09 -Trigeminal Neuralgia 3.09.1 Introduction 3.09.2 Epidemiology 3.09.3 Etiology 3.09.4 Pathophysiology 3.09.5 Diagnosis 3.09.6 Treatment strategies 3.09.7 Conclusion References 3.10 -Review of Select Sleep Medicine Pharmacology: Treatments of Insomnia and Circadian Rhythm Sleep-Wake Disorders 3.10.1 Introduction 3.10.2 Insomnia 3.10.3 Circadian rhythm sleep-wake disorders References 3.11 -Review of Select Sleep Medicine Pharmacology: Treatments of Hypersomnias and Parasomnia 3.11.1 Introduction 3.11.2 Hypersomnia 3.11.3 Parasomnias References 3.12 -Obsessive Compulsive Disorder: Neurobiology and Treatment 3.12.1 Introduction: Obsessive compulsive and related disorders 3.12.2 Obsessive-compulsive symptoms acquired due to neurological insult 3.12.3 Non-pathological obsessive compulsive-like experiences 3.12.4 Developmental stages and physiological states that favor obsessive compulsive experiences 3.12.5 Neurobiological models of OCD 3.12.6 OCD therapies rooted in neurobiological models of OCD 3.12.7 Therapies based on cognitive models of OCD 3.12.8 Pharmacological strategies for treating OCD 3.12.9 Pharmacological therapies in the context of appraisal, behavioral output, and feedback processing systems References 3.13 -Attention Deficit Hyperactivity Disorder 3.13.1 Introduction 3.13.2 ADHD treatment 3.13.3 Conclusions and final remarks References Relevant Websites 3.14 -The Role(s) of Psychopharmacology in the Treatment of PTSD 3.14.1 Introduction 3.14.2 Historical approaches to psychopharmacological treatment 3.14.3 Studies targeting trauma-reactivity 3.14.4 Trauma-focused therapies—The 1st line treatment for PTSD 3.14.5 Conclusions References Relevant websites 3.15 -Antidepressant Drugs 3.15.1 Introduction 3.15.2 History 3.15.3 Classes of antidepressants 3.15.4 Efficacy 3.15.5 Pharmacokinetics 3.15.6 Adverse effects 3.15.7 Mechanism of action Acknowledgment References 3.16 -Bipolar Disorder 3.16.1 Introduction 3.16.2 Lithium 3.16.3 Anticonvulsants 3.16.4 Antipsychotics 3.16.5 Antidepressants 3.16.6 Unmet therapeutic needs in bipolar disorder 3.16.7 Financial Disclosures References 3.17 -Eating Disorders (Anorexia Nervosa and Bulimia Nervosa, Binge Eating Disorder) 3.17.1 Introduction 3.17.2 Anorexia nervosa 3.17.3 Bulimia nervosa 3.17.4 Binge eating disorder 3.17.5 Conclusion References 3.18 -Autism Spectrum Disorder 3.18.1 Introduction 3.18.2 Aggression/violence/irritability 3.18.3 Anxiety and RRBs 3.18.4 Depression 3.18.5 Hallucinations and delusions 3.18.6 Hyperactivity/impulsivity/ADHD 3.18.7 Sleep dysfunction/disorders 3.18.8 Search for new pharmacologic anti-ASD agents 3.18.9 Conclusions References 3.19 -Medications Used for the Treatment of Restless Legs Syndrome 3.19.1 Introduction 3.19.2 Medications used in the treatment of RLS 3.19.3 Iron therapy 3.19.4 Dopamine agonists 3.19.5 Alpha-2 delta ligands 3.19.6 Opioids 3.19.7 Benzodiazepines and non-benzodiazepine benzodiazepine receptor agonists 3.19.8 Other medications 3.19.9 Medication treatment of RLS in special populations 3.19.10 Conclusions References Relevant Websites 3.20 -Pharmacology of Alcohol Use 3.20.1 Introduction 3.20.2 Alcohol structure and pharmacokinetics 3.20.3 Molecular targets of alcohol 3.20.4 Neural circuitry in the phases of addiction 3.20.5 Alcohol and dopamine in reward systems 3.20.6 Alcohol and allostasis 3.20.7 Alcohol and negative affect 3.20.8 Alcohol and neural development 3.20.9 Current and emerging treatment for alcohol use disorders (AUDs) 3.20.10 Concluding remarks References Relevant websites 3.21 -Pharmacological Diversity in Opioid Analgesics: Lessons From Clinically Useful Drugs 3.21.1 Introduction 3.21.2 Historical overview of clinically used opioids 3.21.3 Molecular receptor pharmacology 3.21.4 G protein biased MOR ligands 3.21.5 Conclusions Acknowledgments and Funding References 3.22 -Sedatives and Hypnotics Abuse 3.22.1 Definition of addiction, substance use disorder, drug dependence 3.22.2 Clinical use of benzodiazepines and Z-drugs 3.22.3 Behavioral and psychosocial correlates of BZD use 3.22.4 Prevention 3.22.5 Diagnosis 3.22.6 Therapy 3.22.7 Conclusions References 3.23 -Sensory Pharmacology: Overview 3.24 -Pain—Acute Versus Chronic Pain & Anesthesia 3.24.1 Introduction 3.24.2 Nociceptive pain processing 3.24.3 Acute and chronic pain 3.24.4 Post-surgical pain: Transition from acute to chronic pain 3.24.5 Chronic post-surgical pain (CPSP) 3.24.6 Prevention of CPSP 3.24.7 Treatment of CPSP References 3.25 -Animal Models to Evaluate Expression, Mechanisms, and Treatment of Pain 3.25.1 Introduction 3.25.2 The components of animal pain models 3.25.3 Experimental design and interpretation of results for animal pain models 3.25.4 Conclusions and future directions References 3.26 -Atypical Analgesics 3.26.1 Introduction 3.26.2 Antidepressants 3.26.3 Antiepileptics 3.26.4 Antipsychotics 3.26.5 Cannabinoids 3.26.6 Others References 3.27 -Migraine 3.27.1 Brief introduction to migraine 3.27.2 Paracetamol 3.27.3 Ibuprofen 3.27.4 Naproxen 3.27.5 Preventive treatments References 3.28 -Headache 3.28.1 Introduction 3.28.2 Pathophysiology of headache 3.28.3 Current therapeutic targets in headache 3.28.4 Novel targets for treating headache 3.28.5 Conclusions and future directions Acknowledgment References 3.29 -Glaucoma 3.29.1 Introduction 3.29.2 Prostaglandins 3.29.3 Beta-adrenergic antagonists 3.29.4 Carbonic anhydrase inhibitors 3.29.5 Alpha-adrenergic agonists 3.29.6 Rho kinase inhibitors 3.29.7 Parasympathomimetics 3.29.8 Hyperosmotic agents 3.29.9 Fixed-combinations medications 3.29.10 Issues with the current glaucoma medications 3.29.11 Future glaucoma medical therapy 3.29.12 Non-topical ocular drug delivery 3.29.13 Conclusion References 3.30 -Gene Therapy, Diet and Drug Approaches to Treating Inherited Retinal Disease 3.30.1 Introduction 3.30.2 Disease description 3.30.3 Therapeutic approaches 3.30.4 Clinical trials 3.30.5 Future directions 3.30.6 Conclusion References Relevant Websites 3.31 -Cystoid Macular Edema 3.31.1 Introduction 3.31.2 Routes of ocular drug delivery 3.31.3 Clinical characteristics of cystoid macular edema 3.31.4 Mechanisms of cystoid macular edema 3.31.5 Clinical diagnosis 3.31.6 Pharmaceutical options for CME 3.31.7 Management of common causes of cystoid macular edema 3.31.8 Future perspectives 3.31.9 Regulatory considerations 3.31.10 Conclusion References Relevant Websites 3.32 -Hearing Loss: Environmental, Sensorineural, Drug Induced (Cisplatinin, Antibiotics) 3.32.1 Introduction 3.32.2 Sensorineural hearing loss 3.32.3 Environmental causes of SNHL 3.32.4 Cisplatin ototoxicity 3.32.5 Aminoglycoside ototoxicity Acknowledgments References Relevant website 3.33 -Tinnitus 3.33.1 Introduction 3.33.2 Tinnitus pathophysiology 3.33.3 Pharmacological studies 3.33.4 Challenges in the identification of pharmacological compounds for tinnitus treatment 3.33.5 Conclusion Competing interests References 3.34 -Balance Disorders Including Ménière’s Disease 3.34.1 Introduction 3.34.2 Acute vestibular syndrome 3.34.3 Episodic vestibular disorders 3.34.4 Persistent balance disorders References 9780128208762v4_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 4 FOREWORD PREFACE CONTENTS OF VOLUME 4 4.01 -Endocrinology: Hormones are the Puppeteers of Physiology References 4.02 -GPCR’s and Endocrinology 4.02.1 Introduction to G-protein-coupled receptor biology 4.02.2 The melanocortin receptor family 4.02.3 GHSR1a in food intake regulation 4.02.4 The role of thyroid-stimulating hormone receptor (TSHR) in thyroid function 4.02.5 GPCRs involved in bone and calcium 4.02.6 GLP-1R and GIPR in the treatment of diabetes 4.02.7 SSTRs in growth and pituitary 4.02.8 GPCRs involved in reproduction References 4.03 -The Microbiome as an Endocrine Organ 4.03.1 Introduction to the gut microbiome 4.03.2 The gut microbiome as an endocrine organ 4.03.3 The recently proposed thyroid-gut axis 4.03.4 The gut microbiota, the diabetes and the metabolic syndrome 4.03.5 Probiotics intervention as possible translational options 4.03.6 Conclusions and future research perspectives References 4.04 -Pharmacological Induction of Puberty 4.04.1 Introduction 4.04.2 Goals and timing of pubertal induction in DP 4.04.3 Induction of puberty in males 4.04.4 Induction of puberty in females 4.04.5 Mini-puberty hormone replacement 4.04.6 Conclusions References 4.05 -Male Sexual and Reproductive Health 4.05.1 Introduction 4.05.2 Physiology 4.05.3 Etiology of male infertility 4.05.4 Management 4.05.5 Erectile dysfunction 4.05.6 Androgens and hypogonadism 4.05.7 Conclusions References 4.06 -Pharmacology of Endometriosis 4.06.1 Introduction 4.06.2 Pathogenesis 4.06.3 Available treatment options 4.06.4 Pain and quality of life 4.06.5 Infertility 4.06.6 Mechanism of action 4.06.7 Discussion 4.06.8 Formulas 4.06.9 Disclosures References 4.07 -Kisspeptin: From Bench to Bedside 4.07.1 Introduction 4.07.2 Kisspeptin in normal physiology 4.07.3 Implications in humans 4.07.4 Development of kisspeptin analogues for clinical use 4.07.5 Conclusion References 4.08 -Pharmacology of the Thyroid 4.08.1 Physiology of the thyroid gland 4.08.2 Thyroid hormone replacements 4.08.3 Treating with thyroid hormones 4.08.4 Thyroid replacement in special situations 4.08.5 Antithyroid drugs 4.08.6 The role of iodine 4.08.7 Graves orbitopathy 4.08.8 Drug influences on the thyroid 4.08.9 Summary and conclusion References 4.09 -Endocrinology of Bone and Growth Disorders 4.09.1 Introduction 4.09.2 Osteoporosis 4.09.3 Miscellaneous bone disorders 4.09.4 Disorders of mineralization 4.09.5 Growth disorders References Relevant Websites 4.10 -Type 2 Diabetes Mellitus 4.10.1 Introduction 4.10.2 Lifestyle 4.10.3 Pharmacotherapy of T2DM 4.10.4 Metformin 4.10.5 Sulfonylureas 4.10.6 Dipeptidyl peptidase-4 (DPP-4) inhibitors 4.10.7 Thiazolidinediones (TZDs) 4.10.8 Sodium glucose co-transporter-2 inhibitors (SGLT-2 inhibitors) 4.10.9 Glucagon-like peptide agonists (GLP-1 agonists) 4.10.10 Meglitinides 4.10.11 Special circumstances 4.10.12 Appendix 1 4.10.13 Appendix 2 References 4.11 -Targeting Islet GPCRs to Improve Insulin Secretion 4.11.1 Historical context 4.11.2 G protein-coupled receptors (GPCRs) 4.11.3 Role of GPCRs in regulating insulin secretion 4.11.4 Conclusions References 4.12 -A New Understanding of Metformin 4.12.1 Introduction 4.12.2 Pharmacokinetics of metformin 4.12.3 Metabolic effects of metformin in humans 4.12.4 Biguanides bind Cu2+ ions 4.12.5 Molecular mechanisms of action of metformin in the liver 4.12.6 Effects of metformin on skeletal muscle 4.12.7 Effects of metformin on the gut 4.12.8 Summary and conclusions Acknowledgments References 4.13 -Pharmacology of Gut Hormone Mimetics for Obesity and Diabetes 4.13.1 Introduction 4.13.2 Stomach 4.13.3 Duodenum and jejunum 4.13.4 Ileum and colon 4.13.5 Concluding remarks References 4.14 -Targeting Enteroendocrine Cells to Treat Metabolic Disease 4.14.1 Introduction 4.14.2 Concluding remarks References 4.15 -Cardiovascular, Hematopoietic, Urinary and Respiratory Pharmacology: Overview References 4.16 -Positive Inotropic Drugs for Treating Heart Failure 4.16.1 Introduction 4.16.2 Targets that failed 4.16.3 Future considerations References Relevant Websites 4.17 -Coronary Heart Disease and Myocardial Ischemia 4.17.1 Introduction 4.17.2 NO and related compounds 4.17.3 Other antianginal drugs 4.17.4 Miscellaneous cardioactive drugs 4.17.5 Primary and secondary prevention of ischemic heart disease 4.17.6 Experimental approaches in the therapy of cardiovascular diseases 4.17.7 Concluding remarks References 4.18 -Myocarditis and Pericarditis 4.18.1 Myocarditis 4.18.2 Treatment of myocarditis and inflammatory cardiomyopathy 4.18.3 Pericarditis 4.18.4 Other pericardial syndromes 4.18.5 Summary 4.18.6 Funding References 4.19 -Arrhythmias 4.19.1 Introduction 4.19.2 Cardiac electrophysiology and arrhythmogenesis 4.19.3 Non-pharmacological treatment of cardiac arrhythmias 4.19.4 Pharmacological management of cardiac arrhythmias 4.19.5 Major properties of commonly used AADs 4.19.6 Future perspectives on cardiac arrhythmia management 4.19.7 Concluding remarks 4.19.8 Acknowledgment References 4.20 -Arterial Hypertension 4.20.1 Introduction 4.20.2 Hemodynamics in hypertension 4.20.3 The renin angiotensin aldosterone system and angiotensin-derived peptides in hypertension 4.20.4 Sex hormones and hypertension 4.20.5 Oxidative stress and hypertension 4.20.6 Inflammation and the immune system in hypertension 4.20.7 The kidney, salt and hypertension 4.20.8 The autonomic nervous system and blood pressure control 4.20.9 Diagnosis and management of hypertension in the clinic 4.20.10 Conclusions Acknowledgments References 4.21 -Orthostatic Hypotension Therapeutics 4.21.1 Introduction 4.21.2 Relevant animal models in experimental studies 4.21.3 Pharmacological therapies 4.21.4 Conclusion References 4.22 -β-Adrenoceptor Antagonists 4.22.1 Uses and indications 4.22.2 General properties of β-blockers 4.22.3 Inverse agonists 4.22.4 Biased signaling 4.22.5 Acute versus chronic effects of β-blockers 4.22.6 Summary/conclusions References 4.23 -Ca2+-Channel Inhibitors 4.23.1 Introduction 4.23.2 Basic pharmacology of Ca2+-channel inhibitors 4.23.3 Clinical pharmacology 4.23.4 Outlook 4.23.5 Appendix: Supplementary material References Relevant Websites 4.24 -Renin-Angiotensin-Aldosterone System 4.24.1 Introduction 4.24.2 Physiology and pathophysiology of the RAAS 4.24.3 Components of the RAAS 4.24.4 Angiotensin peptides acting upon angiotensin receptors 4.24.5 RAS inhibitors and antagonists 4.24.6 Concluding statements Acknowledgments References 4.25 -Anemia 4.25.1 Introduction and scope of this chapter 4.25.2 Anemias due to decreased production of red cells 4.25.3 Anemias due to increased destruction of red cells Acknowledgments References 4.26 -Established Drugs and Emerging Targets in Aplastic Anemia 4.26.1 Introduction 4.26.2 Cyclosporine 4.26.3 Growth factors 4.26.4 Anti-thymocyte globulin (ATG) or anti-lymphocyte globulin (ALG) 4.26.5 Androgens 4.26.6 Conclusions References 4.27 -Anticoagulants and Antiplatelet Drugs 4.27.1 Introduction 4.27.2 Thrombosis and anticoagulants 4.27.3 Antiplatelet drug 4.27.4 Future considerations References 4.28 -Diuretic Agents 4.28.1 Introduction 4.28.2 Mechanism of action of diuretics 4.28.3 Drugs References Relevant Websites 4.29 -Vasopressin Type 2 Receptor Agonists and Antagonists 4.29.1 Introduction 4.29.2 Ligands for vasopressin receptors 4.29.3 V2R agonists 4.29.4 V2R antagonists 4.29.5 V2R pharmacological chaperones: Agonists, biased agonists, and antagonists 4.29.6 Conclusions References 4.30 -Medical Management of Renal and Ureteral Stones 4.30.1 Introduction 4.30.2 Management of acute renal colic 4.30.3 Medical expulsive therapy 4.30.4 Chemolitholysis 4.30.5 Pharmacological prevention of recurrent stone formation References Relevant Websites 4.31 -Medications and Drug Targets for the Treatment of Diseases of the Urinary Bladder and Urethra 4.31.1 Introduction 4.31.2 Anatomy and physiology 4.31.3 Diseases 4.31.4 Pathology and pathophysiology 4.31.5 Disease models 4.31.6 Established drug targets and treatments 4.31.7 Potential drug targets 4.31.8 Perspective References Relevant Websites 4.32 -Pharmacology of the Prostate in Non-Infectious Diseases 4.32.1 Introduction 4.32.2 Voiding symptoms and BPH 4.32.3 Animal models for BPH and LUTS 4.32.4 Prostate smooth muscle contraction 4.32.5 Relaxation of prostate smooth muscle 4.32.6 Prostate growth 4.32.7 Available medications 4.32.8 Emerging targets and compounds References 4.33 -Cough and Common Cold 4.33.1 Introduction 4.33.2 Mechanisms of symptoms of URTI 4.33.3 Analgesics 4.33.4 Nasal decongestants 4.33.5 Antitussives 4.33.6 Antihistamines 4.33.7 Anticholinergics 4.33.8 Expectorants 4.33.9 Mucolytics 4.33.10 Menthol 4.33.11 Sore throat lozenges, mouth washes and sprays 4.33.12 Multi-ingredient common cold and cough medicines References 4.34 -Pharmacological Management of Asthma and COPD 4.34.1 Introduction 4.34.2 Strengths and limitations of research in asthma, COPD 4.34.3 Current OLD drugs and their targets 4.34.4 The future of OLD drugs 4.34.5 Conclusion Acknowledgments References 4.35 -Pulmonary Fibrosis 4.35.1 Introduction 4.35.2 Nintedanib (NIN) 4.35.3 In pursuit of new treatments for PF References 4.36 -Pulmonary Hypertension 4.36.1 Anatomy and physiology 4.36.2 Definition and classification 4.36.3 Pathological mechanisms 4.36.4 Animal models in PH 4.36.5 Current treatments for PH 4.36.6 Novel therapeutic targets and drugs in PH 4.36.7 Future considerations References 9780128208762v5_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 5 FOREWORD PREFACE CONTENTS OF VOLUME 5 5.01 -Gastrointestinal System – Overview 5.02 -The Physiology and Pharmacology of Diabetic Gastropathy Management 5.02.1 Introduction 5.02.2 Normal physiology of gastric motility 5.02.3 Pathophysiological and cellular changes in DGP 5.02.4 Initial evaluation 5.02.5 Initial management 5.02.6 Pharmacotherapy 5.02.7 Non-pharmacological treatments 5.02.8 Conclusion References 5.03 -Nausea and Vomiting 5.03.1 Introduction 5.03.2 Pathophysiology 5.03.3 Diagnosis 5.03.4 Management 5.03.5 Antiemetic agents 5.03.6 Prokinetic agents 5.03.7 Neuromodulators 5.03.8 Pediatric considerations 5.03.9 Cyproheptadine 5.03.10 Unmet therapeutic needs References 5.04 -Pharmacological Treatments for Constipation and Opioid-Induced Constipation 5.04.1 Introduction 5.04.2 Algorithm for management of chronic constipation 5.04.3 Drug classes for chronic constipation 5.04.4 Modulating ion exchangers/transporters for functional constipation 5.04.5 Prokinetics 5.04.6 Network meta-analyses 5.04.7 Conclusions of pharmacological treatment of chronic constipation 5.04.8 Pharmacological treatment of opiate-induced constipation 5.04.9 Gastrointestinal effects of μ-opioid agonists 5.04.10 Drugs approved for OIC 5.04.11 Clinical guidance in care of patients with OIC-related to non-cancer pain 5.04.12 Conclusion Acknowledgments References 5.05 -Antimicrobial Treatments of Infectious Diarrhea 5.05.1 Introduction 5.05.2 Antimicrobial therapy 5.05.3 Antibiotic-associated diarrhea and Clostridium difficile infection 5.05.4 Post-infectious diarrhea 5.05.5 Probiotics in the treatment of diarrhea 5.05.6 Prevention of infectious diarrhea References 5.06 -Pharmacology of Secretory Diarrhea 5.06.1 Introduction 5.06.2 Pharmacological targeting of transporters in diarrhea 5.06.3 Mechanisms of secretory diarrhea 5.06.4 Macromolecular protein complexes of CFTR for pharmacological targeting in secretory diarrhea 5.06.5 Discussion 5.06.6 Concluding remarks Acknowledgments Conflicts of interest References 5.07 -Small Intestinal Bacterial Overgrowth 5.07.1 Introduction 5.07.2 Definitions of small intestinal bacterial overgrowth 5.07.3 Clinical manifestations of SIBO 5.07.4 Relationship between bacteria and the small intestine 5.07.5 SIBO in various diseases 5.07.6 SIBO in irritable bowel syndrome (IBS) 5.07.7 How does small intestinal bacterial overgrowth cause symptoms? 5.07.8 Diagnosis of small intestinal bacterial overgrowth 5.07.9 Culturing bacteria from the small intestine 5.07.10 Hydrogen breath test (HBT) 5.07.11 Hydrogen breath test procedure 5.07.12 Limitations of hydrogen breath tests 5.07.13 Pathogenesis of symptoms in patients with SIBO 5.07.14 Treatment of SIBO References 5.08 -Abdominal Pain 5.08.1 Introduction 5.08.2 Prevalence of abdominal pain disorders 5.08.3 Treatment of abdominal pain disorders 5.08.4 Understanding the pathways of visceral pain 5.08.5 Sensitization and chronic visceral pain 5.08.6 Sex differences in visceral pain disorders 5.08.7 Summary References 5.09 -Mechano-Regulation of Gene Expression in the Gut: Implications in Pathophysiology and Therapeutic Approaches in Obstr ... 5.09.1 Introduction: Mechanical stress in the gastrointestinal tract 5.09.2 Mechano-transcription in the gastrointestinal tract 5.09.3 Pathophysiological significance of mechano-transcription in gastrointestinal disorders 5.09.4 Mechano-transcription process as potential therapeutic targets for obstructive bowel disorders 5.09.5 Mechano-transcription process as potential therapeutic targets for inflammatory bowel disease 5.09.6 Mechano-transcription process as potential therapeutic targets for functional bowel disorders 5.09.7 Conclusions Acknowledgments References 5.10 -Intestinal Transport of Lipopolysaccharides 5.10.1 Introduction 5.10.2 Transcellular transport of LPS 5.10.3 Paracellular permeability & transport of LPS 5.10.4 Interventions that decrease paracellular permeability 5.10.5 Conclusions References 5.11 -Regulation of Gut Barrier Function by RNA-Binding Proteins and Noncoding RNAs 5.11.1 Introduction 5.11.2 RBPs in gut barrier function 5.11.3 miRNAs in gut barrier function 5.11.4 LncRNAs in gut barrier function 5.11.5 CircRNAs in gut epithelium homeostasis 5.11.6 Conclusions and future perspectives Acknowledgments References 5.12 -Pharmacology of NASH 5.12.1 Introduction 5.12.2 Metabolic targets (Table 3) 5.12.3 Cell injury targets 5.12.4 Inflammation targets 5.12.5 Fibrosis targets 5.12.6 Other targets 5.12.7 Conclusions References 5.13 -Drug-Induced Liver Injury 5.13.1 Introduction 5.13.2 Epidemiology of DILI 5.13.3 Hepatic drug metabolism and risk factors of DILI 5.13.4 Clinical presentation and diagnosis of DILI 5.13.5 Mechanisms of DILI 5.13.6 Common DILI-associated drugs 5.13.7 Herbal induced liver injury (HILI) 5.13.8 Resources of DILI 5.13.9 Future Prospects Acknowledgments References 5.14 -Microbial Therapeutics in Liver Disease 5.14.1 Rationale for microbial therapeutics in liver disease 5.14.2 Microbiota changes in pre-cirrhotic liver disease 5.14.3 Microbiota changes after the development of cirrhosis 5.14.4 The sections below discuss therapies targeting the intestinal microbiota with a focus on fecal microbiota transplant ... 5.14.5 Toxicity potential of FMT and other live biotherapeutic products 5.14.6 Drug-drug interactions 5.14.7 FMT trials in chronic liver disease: Potentials and pitfalls 5.14.8 Conclusion References 5.15 -Pharmacological Management of Acute and Chronic Pancreatitis 5.15.1 Introduction 5.15.2 Management of acute pancreatitis 5.15.3 Management of chronic pancreatitis 5.15.4 Conclusion References 5.16 -Immunopharmacology/Musculoskeletal System Pharmacology: Overview 5.17 -Eosinophils, Mast Cells and Basophils 5.17.1 Introduction 5.17.2 Eosinophils 5.17.3 Mast cells 5.17.4 Basophils 5.17.5 Concluding remarks Funding Information References 5.18 -Effects of Selected Non-biological and Biological Disease-Modifying Anti-rheumatic Drugs, and mRNA Vaccines on Mononu ... 5.18.1 Introduction 5.18.2 The mononuclear phagocyte system (dendritic cells, monocytes and macrophages) 5.18.3 The mechanism of action of selected non-biological DMARDs on the mononuclear phagocyte system 5.18.4 The mechanism of action of biological DMARDs on the mononuclear phagocyte system 5.18.5 The role of the mononuclear phagocyte system (predominantly antigen-presenting cells) associated with mRNA vaccines 5.18.6 Conclusion Funding References 5.19 -Natural Autoantibodies in Health and Disease 5.19.1 Introduction 5.19.2 The discovery of natural autoantibodies 5.19.3 Evolutionary aspects 5.19.4 Production 5.19.5 The variable region of natural autoantibodies 5.19.6 Polyreactivity 5.19.7 The biological role of natural autoantibodies 5.19.8 NAbs in disease 5.19.9 Applications in biomedicine 5.19.10 Concluding remarks References 5.20 -Immunosuppression in Liver Transplantation 5.20.1 Introduction 5.20.2 Acute cellular rejection 5.20.3 Immunosuppressive agents 5.20.4 Use of immunosuppressive agents in liver transplantation in the United States 5.20.5 Calcineurin inhibitors-cyclosporine and tacrolimus 5.20.6 Corticosteroids 5.20.7 Mammalian target of rapamycin inhibitors-sirolimus and everolimus 5.20.8 Purine synthesis inhibitors 5.20.9 Mycophenolate mofetil 5.20.10 Anti-lymphocytic antibody therapy 5.20.11 Monoclonal anti-T-cell receptor antibodies 5.20.12 Polyclonal anti-bodies 5.20.13 Alemtuzumab/campath-1H 5.20.14 Interleukin-2 receptor antibodies 5.20.15 Immunosuppressants in development 5.20.16 FK 778 5.20.17 JAK3 inhibitors 5.20.18 FTY 720 5.20.19 Belatacept-costimulatory signal blockade 5.20.20 Summary References 5.21 -Immunomodulatory and Anti-Inflammatory Properties of Glucocorticoids 5.21.1 Introduction 5.21.2 Physiological GC regulation, production, and mechanisms of action 5.21.3 Anti-inflammatory and immunosuppressive effects of GCs 5.21.4 Therapeutic indications for GCs 5.21.5 Adverse effects 5.21.6 Resistance and dependence on glucocorticoid therapy 5.21.7 Conclusions References 5.22 -Biologics Targeting Immune Modulation in Inflammatory Disorders 5.22.1 Introduction 5.22.2 Rheumatoid arthritis 5.22.3 Psoriasis and psoriatic arthritis 5.22.4 Axial spondyloarthritis and ankylosing spondylitis 5.22.5 Inflammatory bowel diseases 5.22.6 Systemic lupus erythematosus 5.22.7 ANCA-associated vasculitis 5.22.8 Future perspectives of molecular targeting therapy in rheumatic diseases Competing interests References 5.23 -Rheumatoid Arthritis, Osteoarthritis, and Gout 5.23.1 Rheumatoid arthritis 5.23.2 Osteoarthritis 5.23.3 Gout References 5.24 -Systemic Lupus Erythematosus 5.24.1 Introduction 5.24.2 Epidemiology 5.24.3 Etiology and pathogenesis 5.24.4 Genetic factors 5.24.5 Hormonal factors 5.24.6 Environmental factors 5.24.7 Chemical/physical factors 5.24.8 Immunopathology 5.24.9 Apoptosis 5.24.10 Clinical features 5.24.11 General manifestations 5.24.12 Activity and damage assessment in patients with SLE 5.24.13 Section on conventional therapy in SLE 5.24.14 Section on biologic treatment in SLE 5.24.15 B cell depletion 5.24.16 Blocking B cell activating factors 5.24.17 More recent developments 5.24.18 Other approaches 5.24.19 Conclusions References Relevant Websites 5.25 -Myasthenia Gravis 5.25.1 Introduction 5.25.2 Clinical features 5.25.3 Disease subgroups 5.25.4 Pathophysiology 5.25.5 Genetics 5.25.6 Etiology 5.25.7 Diagnostic procedures 5.25.8 Symptomatic drug treatment 5.25.9 Immunosuppressive drug treatment 5.25.10 Thymectomy 5.25.11 Therapy for severe exacerbations 5.25.12 Supportive therapy 5.25.13 Pregnancy and giving birth 5.25.14 Juvenile disease 5.25.15 Drugs with caution 5.25.16 Comorbidity 5.25.17 Future perspectives 5.25.18 Conclusions References 5.26 -Immune Dysfunction and Drug Targets in Autoinflammatory Syndromes 5.26.1 Introduction 5.26.2 The role of innate immunity in host defense 5.26.3 The main pathophysiological pathways involved in autoinflammation 5.26.4 Pharmacological treatment for autoinflammatory diseases 5.26.5 Biologic agents 5.26.6 Conclusion References 5.27 -The Gut Microbiota and Immunopathophysiology 5.27.1 Introduction 5.27.2 Microbiota composition in healthy state: Host-microbiota homeostasis 5.27.3 Microbiota composition in disease state: Immunopathologies 5.27.4 The perspective of therapeutic strategies of gut microbiota modulation 5.27.5 Conclusion References 5.28 -The Pharmacology of Antihistamines 5.28.1 The effects of histamine in allergic disease 5.28.2 The discovery and development of antihistamines 5.28.3 The histamine H1-receptor and H1-antihistamines 5.28.4 Preclinical pharmacology 5.28.5 Clinical effectiveness of H1-antihistamines 5.28.6 H4-Antihistamines in allergic diseases 5.28.7 Conclusion Disclosure of Potential Conflict of Interest References 5.29 -Chronic Urticaria 5.29.1 Introduction 5.29.2 Definition 5.29.3 Classification 5.29.4 Epidemiology 5.29.5 Pathogenesis 5.29.6 Clinical picture 5.29.7 Diagnostics 5.29.8 Comorbidities 5.29.9 Therapy References 5.30 -Novel Immunomodulatory Therapies for Respiratory Pathologies 5.30.1 Introduction 5.30.2 Inflammation in the lungs: The good, the bad and the ugly 5.30.3 Asthma 5.30.4 Chronic obstructive pulmonary disease 5.30.5 Cystic fibrosis 5.30.6 Pneumonia 5.30.7 Summary and perspectives References Relevant Websites 5.31 -Anaphylaxis 5.31.1 Introduction 5.31.2 Not all hypersensitivity reactions are allergic 5.31.3 Definitions of anaphylaxis 5.31.4 Epidemiology 5.31.5 Clinical presentation 5.31.6 Pathophysiology 5.31.7 Acute treatment 5.31.8 Long-term management and prevention References 9780128208762v6_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 6 FOREWORD PREFACE CONTENTS OF VOLUME 6 6.01 -Cancer: Overview 6.01.1 Concluding remarks References 6.02 -Estrogen Receptor Positive Breast Cancer: 8p11-p12 Amplicon and Therapeutic Response 6.02.1 Introduction 6.02.2 The curious case of FGFR1 6.02.3 Characterizing the 8p11-p12 amplicon 6.02.4 Clinical trials directed at 8p11-p12 genes 6.02.5 Discussion References 6.03 -HER2-Positive (HER2+) Breast Cancer 6.03.1 Introduction 6.03.2 Clinical presentation and prevalence 6.03.3 Obstacles to diagnosis and treatment 6.03.4 Preclinical models of testing 6.03.5 Proposed mechanisms of pathology 6.03.6 Selected drug targets: Preclinical evidence and clinical trial results 6.03.7 Conclusions and future perspectives Acknowledgments References 6.04 -Triple Negative Breast Cancer 6.04.1 Introduction 6.04.2 Triple negative breast cancer clinical presentation and prevalence 6.04.3 Molecular classification of TNBC 6.04.4 Current treatments for TNBC 6.04.5 Experimental therapeutics 6.04.6 Conclusion Acknowledgments References 6.05 -Ovarian Cancer: Towards Personalizing Ovarian Cancer Treatments Using Patient-Derived Organoids 6.05.1 Introduction 6.05.2 Ovarian cancer biology 6.05.3 Understanding ovarian cancer heterogeneity 6.05.4 Treatment and management of ovarian cancer 6.05.5 Emerging ovarian cancer treatments 6.05.6 Tumor organoids biobanks for precision medicine 6.05.7 Personalizing treatments using cancer organoids 6.05.8 Future perspectives 6.05.9 Acknowledgments 6.05.10 Declaration of interest References 6.06 -Lung Cancer 6.06.1 Lung cancer biology, risk and incidence 6.06.2 NSCLC histology 6.06.3 SCLC histology 6.06.4 Lung cancer staging 6.06.5 NSCLC genetics 6.06.6 SCLC genetics 6.06.7 Stage specific treatment 6.06.8 Therapy for metastatic NSCLC 6.06.9 SCLC treatment 6.06.10 Conclusions Acknowledgment References 6.07 -Esophageal Cancers: Leveraging Alterations in Mitochondrial Biology to Improve Patient Outcomes 6.07.1 Introduction 6.07.2 Alterations in mitochondrial biology are associated with esophageal carcinogenesis 6.07.3 Mitochondrial biology in relation to esophageal cancer therapy 6.07.4 Opportunities and challenges in leveraging esophageal cancer-associated alterations in mitochondrial biology to impr ... 6.07.5 Acknowledgment References 6.08 -Liver Cancer (Current Therapies) 6.08.1 Introduction 6.08.2 Treatment options and outcomes for HCC 6.08.3 Risk factors for HCC and HCC development 6.08.4 Molecular pathways involved in HCC development 6.08.5 Biomarkers for HCC diagnosis 6.08.6 Glycan biomarkers for cancer 6.08.7 Future directions and conclusions References 6.09 -Understanding the Role of Plasticity in Glioblastoma 6.09.1 Introduction 6.09.2 Conclusion and future direction References 6.10 -Intraocular and Orbital Cancers 6.10.1 Introduction 6.10.2 Retinoblastoma 6.10.3 Uveal melanoma 6.10.4 Intraocular medulloepithelioma 6.10.5 Primary intraocular lymphoma 6.10.6 Ocular adnexal lymphoma 6.10.7 Orbital rhabdomyosarcoma 6.10.8 Lacrimal gland cancer 6.10.9 Ocular surface squamous neoplasm 6.10.10 Conjunctival melanoma 6.10.11 Conclusions Acknowledgements References Relevant Websites 6.11 -Malignant Melanoma: From Molecular Characterization to Targeted Therapies 6.11.1 Introduction 6.11.2 Clinical presentation and prevalence 6.11.3 Obstacles to diagnosis and treatment and application of ancillary testing 6.11.4 Preclinical models of testing 6.11.5 Mechanisms and pathways of pathology 6.11.6 Melanoma treatments and drug targets: Preclinical evidence and clinical trials 6.11.7 Conclusions and future perspectives Acknowledgments References 6.12 -Bladder Cancer 6.12.1 Introduction 6.12.2 Epidemiology 6.12.3 Diagnosis 6.12.4 Molecular pathobiology 6.12.5 Tumor microenvironment (TME) 6.12.6 Metastatic bladder cancer (mBCa) 6.12.7 Metabolic programing of bladder cancer 6.12.8 Treatment of bladder cancer 6.12.9 Conclusion Acknowledgment References 6.13 -Multiple Myeloma 6.13.1 Introduction 6.13.2 Epidemiology 6.13.3 Etiology and pathogenesis 6.13.4 Clinical manifestation 6.13.5 Diagnosis and differentiation diagnosis 6.13.6 Evaluation 6.13.7 Treatment 6.13.8 Supportive care treatment (NCCN®, 2020) 6.13.9 Novel agents for MM treatment 6.13.10 Challenges and future perspective References 6.14 -Cell Signaling and Translational Developmental Therapeutics 6.14.1 Introduction: Early Days 6.14.2 Further development of signal transduction 6.14.3 MAP kinase pathways 6.14.4 Autophagy 6.14.5 Using our understanding of autophagy and cell signaling to therapeutically kill tumor cells 6.14.6 Conceptual developmental therapeutics strategies 6.14.7 Conclusions References 6.15 -Prospects for Targeted Kinase Inhibition in Cancer: Neurofibromatosis Type 1-Related Neoplasia 6.15.1 Introduction 6.15.2 Kinases as drug targets in cancer 6.15.3 Neurofibromatosis type 1-associated neoplasia 6.15.4 Kinase inhibitor therapy for NF1 patients 6.15.5 Summary and future directions Acknowledgments References 6.16 -E2F Transcription Factors in Cancer, More than the Cell Cycle 6.16.1 Historical prelude 6.16.2 Brief overview 6.16.3 Structure and domains 6.16.4 Homologs and transcription factor complexes in other species 6.16.5 The DREAM complex 6.16.6 Regulation of E2Fs/RB/CDK 6.16.7 E2F targets identified through ChIP-chip and ChIP-seq 6.16.8 Canonical E2F functions: Cell cycle and proliferation 6.16.9 Specific activities of the activator E2Fs 6.16.10 E2Fs in cancer 6.16.11 Enabling mechanisms: Genome instability, inducing inflammation and coopting immune cells 6.16.12 Pharmacological targets, both tried and to be tested 6.16.13 Conclusions References 6.17 -The Oncogenic Protein, Breakpoint Cluster (BCR)-Abelson Kinase (ABL) and Chronic Myelocytic Leukemia (CML): Insight I ... 6.17.1 Chronic myeloid leukemia and BCR-ABL oncogene 6.17.2 Mechanisms that produce resistance to the inhibition of the BCR-ABL protein in CML patients 6.17.3 Treatment options for CML 6.17.4 Conclusion and perspective References 6.18 -Notch in Human Cancers—A Complex Tale 6.18.1 Canonical and non-canonical Notch signaling 6.18.2 Notch in hematological malignancies 6.18.3 Notch in solid tumors 6.18.4 Therapeutic targeting of Notch in cancer 6.18.5 Summary References 6.19 -NF-κB and Cancer Therapy Drugs 6.19.1 Introduction 6.19.2 NF-κB and carcinogenesis 6.19.3 Pharmacological strategies of inhibiting NF-κB signaling 6.19.4 Conclusion and perspectives Acknowledgements References 6.20 -Ras and Ras Signaling as a Therapeutic Target in Cancer 6.20.1 Introduction 6.20.2 Overview of Ras 6.20.3 Therapeutics 6.20.4 Conclusions Acknowledgements References 6.21 -Role of Hexosamine Biosynthetic Pathway on Cancer Stem Cells: Connecting Nutrient Sensing to Cancer Cell Plasticity 6.21.1 Introduction 6.21.2 Cancer cell metabolism and hexosamine biosynthetic pathway 6.21.3 Cancer stem cells 6.21.4 HBP and O-GlcNAcylation regulates stem cells 6.21.5 O-GlcNAcylation and cancer stem cells maintenance and function 6.21.6 O-GlcNAcylation regulation of oncogenic EMT plasticity 6.21.7 Current status and challenges of HBP/O-GlcNAc inhibitors 6.21.8 Future perspectives Acknowledgments References 6.22 -Connexins/Gap Junction Based Agents in Cancer 6.22.1 Introduction 6.22.2 Connexins and gap junctions in carcinogenesis and cancer: Tumor suppressor and tumor promoter evidences 6.22.3 Gap junctions, connexins and cancer stem cells (CSCs) 6.22.4 Gap junctions, connexins and cancer chemoprevention 6.22.5 Gap junction/connexin based therapies in cancer: What is available so far 6.22.6 The bystander effect 6.22.7 Conclusions and future perspectives References 6.23 -Hypoxia 6.23.1 Introduction 6.23.2 Signaling in hypoxia 6.23.3 Biological effects of hypoxia 6.23.4 Therapeutic and clinical strategies 6.23.5 Conclusions References 6.24 -Targeting (de)acetylation: A Diversity of Mechanism and Disease 6.24.1 Chromatin organization 6.24.2 Cellular processes regulated by acetylation and deacetylation 6.24.3 HATs and HDACs in therapeutics 6.24.4 Summary 6.24.5 Funding References Relevant Websites 6.25 -Mitochondria and Tumor Metabolic Flexibility: Mechanisms and Therapeutic Perspectives 6.25.1 Mitochondria in cancer: A historical perspective 6.25.2 Mitochondrial bioenergetics and biosynthesis in non-proliferating cells 6.25.3 Mitochondria, bioenergetics, and the Warburg phenotype in cancer 6.25.4 Mitochondria and tumor metabolic flexibility 6.25.5 The “heterogenous” back and forth between oxidative phosphorylation and glycolysis in cancer 6.25.6 VDAC, a metabolic gateway in the outer mitochondrial membrane 6.25.7 Cancer stem cells, tumor heterogeneity and metabolic flexibility 6.25.8 Mitochondrial targets for chemotherapy 6.25.9 VDAC: The special case of a mitochondrial switch 6.25.10 Concluding remarks Acknowledgments References 6.26 -Epithelial to Mesenchymal Transition 6.26.1 Introduction 6.26.2 The TGFβ signaling pathway 6.26.3 TGFβ in physiology and pathology 6.26.4 TGFβ in cancer 6.26.5 EMT targeted therapies Acknowledgments References 6.27 -Cellular Indoctrination: How the Tumor Microenvironment Reeducates Macrophages Towards Nefarious Ends 6.27.1 Introduction 6.27.2 Origins of macrophages 6.27.3 Trophic macrophages: From organogenesis to disease 6.27.4 Macrophage polarization 6.27.5 Phagocytosis 6.27.6 Regulation: Checkpoint receptors in macrophages 6.27.7 Chronic deleterious inflammation and cancer 6.27.8 The role of tumor-associated macrophages in cancer progression 6.27.9 Immunosuppressive role of TAMs 6.27.10 Sexual dimorphism in macrophage-mediated immunity 6.27.11 Contribution of race to TAM dynamics 6.27.12 Therapeutic targeting of TAMs 6.27.13 Resistance to chemotherapy 6.27.14 Combining TAM-targeted immunotherapy with conventional cancer treatments 6.27.15 Emerging TAM-mediated immunotherapies: To live or die by the CAR 6.27.16 Demographic factors in response to immunotherapy 6.27.17 Conclusions 6.27.18 Acknowledgments References 6.28 -Chemotherapy-Induced Peripheral Neuropathy 6.28.1 Introduction 6.28.2 The clinical study of CIPN 6.28.3 The preclinical study of CIPN 6.28.4 Summary References 6.29 -Bioactive Dietary Compounds and Epigenetics in Women’s Reproductive Cancers 6.29.1 Introduction 6.29.2 Epigenetic regulations in women’s reproductive cancers 6.29.3 Bioactive dietary compounds with epigenetic regulatory properties 6.29.4 Dietary chemoprevention and therapy in gynecologic cancers 6.29.5 Conclusion Acknowledgments Author Contributions References 9780128208762v7_WEB Front Cover COMPREHENSIVE PHARMACOLOGY COMPREHENSIVE PHARMACOLOGY Copyright EDITOR IN CHIEF ASSOCIATE EDITOR IN CHIEF EDITORIAL BOARD Editor In Chief Associate Editor In Chief Section Editors CONTRIBUTORS TO VOLUME 7 FOREWORD PREFACE CONTENTS OF VOLUME 7 7.01 -Anti-infectives: Overview References 7.02 -Beta lactam 7.02.1 Introduction 7.02.2 Structure 7.02.3 Mechanism of action 7.02.4 Resistance mechanisms 7.02.5 Pharmacological properties 7.02.6 Classification of β-lactam antibiotics 7.02.7 Penicillins 7.02.8 Temocillin 7.02.9 Cephalosporins 7.02.10 β-Lactam-β-lactamase inhibitors 7.02.11 Monobactams 7.02.12 Carbapenems References 7.03 -Glycopeptide and Lipoglycopeptide Antibiotics 7.03.1 Introduction 7.03.2 Vancomycin 7.03.3 Teicoplanin 7.03.4 Telavancin 7.03.5 Dalbavancin 7.03.6 Oritavancin References 7.04 -Fosfomycin 7.04.1 Introduction 7.04.2 Mechanism of action 7.04.3 Spectrum of activity 7.04.4 Mechanism of resistance 7.04.5 Pharmacological properties 7.04.6 Clinical applications 7.04.7 Dosages 7.04.8 Adverse effects 7.04.9 Transparency declaration References 7.05 -Daptomycin 7.05.1 Introduction/history 7.05.2 Mechanism of action 7.05.3 Spectrum of activity and licensed usages 7.05.4 Antimicrobial susceptibility testing 7.05.5 Daptomycin resistance 7.05.6 Pharmacodynamics and pharmacokinetics 7.05.7 Pregnancy and breastfeeding 7.05.8 Adverse effects of daptomycin therapy 7.05.9 Other uses of daptomycin 7.05.10 Conclusion References Relevant websites 7.06 -Colistin 7.06.1 Introduction 7.06.2 Revival of colistin 7.06.3 Discovery and history of colistin 7.06.4 Structure of colistin 7.06.5 Formulations available 7.06.6 Mechanism of action 7.06.7 Antimicrobial spectrum of colistin 7.06.8 Pharmacokinetics and pharmacodynamics (PK-PD) of colistin 7.06.9 Minimum inhibitory concentration testing of colistin 7.06.10 Resistance to colistin 7.06.11 Clinical uses and modes of administration 7.06.12 Toxicity and adverse effects 7.06.13 Conclusion References 7.07 -Tetracyclines 7.07.1 Introduction 7.07.2 Spectrum of activity 7.07.3 Mechanism of action 7.07.4 Tetracycline resistance 7.07.5 Glycylcycline 7.07.6 Omadacycline 7.07.7 Fluorocycline 7.07.8 Future directions References 7.08 -Aminoglycoside Antibiotics 7.08.1 Introduction 7.08.2 Pharmacokinetics and pharmacodynamics 7.08.3 Mechanism of antimicrobial action 7.08.4 Resistance and its mechanisms 7.08.5 Spectrum of activity and clinical uses 7.08.6 Adverse effects References 7.09 -Macrolide Antibiotics 7.09.1 Introduction 7.09.2 Spectrum of activity and epidemiology 7.09.3 Mechanism of action 7.09.4 Mechanism of resistance 7.09.5 Pharmacological properties 7.09.6 Adverse effects 7.09.7 Clinical application 7.09.8 Ketolides References 7.10 -Lincosamide Antibiotics 7.10.1 Introduction 7.10.2 Spectrum of activity 7.10.3 Mechanism of action 7.10.4 Mechanism of resistance 7.10.5 Pharmacological properties 7.10.6 Adverse effects 7.10.7 Toxin suppressive effects of clindamycin 7.10.8 Clinical application of clindamycin References 7.11 -Oxazolidinone: Linezolid 7.11.1 Introduction 7.11.2 Spectrum of activity 7.11.3 Mechanism of action 7.11.4 Linezolid resistance 7.11.5 Pharmacological properties 7.11.6 Adverse effects 7.11.7 Drug interactions 7.11.8 Clinical trials and indications References 7.12 -Tedizolid 7.12.1 Description 7.12.2 Spectrum of antimicrobial activity 7.12.3 Mechanism of action 7.12.4 Clinical uses 7.12.5 Dosing and administration 7.12.6 Pharmacokinetics and pharmacodynamics 7.12.7 Adverse drug reactions References 7.13 -Fidaxomicin 7.13.1 Introduction 7.13.2 Indication, dosage and administration 7.13.3 Structure and mechanism of action 7.13.4 Spectrum of activity and resistance 7.13.5 Other in vitro data 7.13.6 Pharmacokinetics—Absorption and distribution 7.13.7 Pharmacokinetics—Metabolism and elimination 7.13.8 Clinical studies and therapeutic efficacy 7.13.9 Alternative dosing regimens 7.13.10 Safety and tolerability 7.13.11 Environmental contamination 7.13.12 Pharmacoeconomics and cost effectiveness data 7.13.13 Formulary placement and treatment guidelines 7.13.14 Conclusion References 7.14 -Quinolones 7.14.1 Description/Introduction 7.14.2 Mechanism of action 7.14.3 Antimicrobial activity 7.14.4 Pharmacokinetics and pharmacodynamics 7.14.5 Mode of administration and dosage 7.14.6 Interactions 7.14.7 Side effects and toxicity 7.14.8 Clinical uses 7.14.9 Summary References 7.15 -Non-Quinolone Inhibitors of the Bacterial DNA Gyrase 7.15.1 Introduction and background 7.15.2 The ATPase functioning inhibitors or Gyr-B/Par-E subunit inhibitors 7.15.3 Future directions References 7.16 -Trimethoprim and Its Derivatives 7.16.1 Basic drug information 7.16.2 Clinical usage 7.16.3 Side effects of trimethoprim therapy 7.16.4 Interactions with other drugs 7.16.5 Main mechanism of resistance 7.16.6 Structural modifications of TMP molecules 7.16.7 Functional modifications of the TMP molecule due to activity 7.16.8 Atypical applications of TMP 7.16.9 Conclusions and perspectives References 7.17 -Nitrofurantoin 7.17.1 Introduction 7.17.2 Description 7.17.3 Pharmacodynamics and pharmacokinetics 7.17.4 Mechanism of action 7.17.5 Adverse events to consider 7.17.6 Conclusions References 7.18 -Fusidic Acid 7.18.1 Introduction 7.18.2 Chemical structure 7.18.3 Mechanism of action 7.18.4 Antimicrobial activity 7.18.5 Resistance mechanisms 7.18.6 Formulation 7.18.7 Pharmacokinetics 7.18.8 Side effects 7.18.9 Clinical applications 7.18.10 Conclusion References Relevant websites 7.19 -Metronidazole 7.19.1 Introduction 7.19.2 Spectrum of activity 7.19.3 Mechanism of action 7.19.4 Mechanism of resistance 7.19.5 Pharmacological profile 7.19.6 Therapeutic uses 7.19.7 Adverse effects References 7.20 -Amphotericin-B 7.20.1 Introduction 7.20.2 Chemistry 7.20.3 Molecular pharmacology 7.20.4 Main indications 7.20.5 Mechanism of action and spectrum of activity 7.20.6 Resistance 7.20.7 Pharmacokinetics 7.20.8 Pharmacodynamics 7.20.9 Clinical efficacy 7.20.10 Safety 7.20.11 Availability, storage, and stability 7.20.12 Dosing 7.20.13 Special populations 7.20.14 Routes of administration 7.20.15 Drug interactions 7.20.16 Monitoring parameters (Ambisome package insert, 2020; Groll et al., 2019; Amphotericin B package insert, 2010; Abel ... 7.20.17 Summary References 7.21 -Azoles 7.21.1 Introduction 7.21.2 Spectrum of activity 7.21.3 Overview of clinical use and guideline recommendations 7.21.4 Mechanism of action 7.21.5 Mechanisms of resistance 7.21.6 Pharmacological and pharmacokinetic properties 7.21.7 Adverse effects, cautions and contraindications 7.21.8 Drug interactions 7.21.9 Therapeutic drug monitoring 7.21.10 Conclusion References 7.22 -Echinocandins 7.22.1 History 7.22.2 Introduction 7.22.3 Mechanism of action 7.22.4 Mechanism of resistance 7.22.5 Rezafungin: The future echinocandin? 7.22.6 Pharmacological properties 7.22.7 Echinocandins dosages 7.22.8 Adverse effects 7.22.9 Drug-drug interactions 7.22.10 Clinical application 7.22.11 Conclusion References 7.23 -Triterpenoids 7.23.1 Introduction 7.23.2 Molecular pharmacology 7.23.3 Spectrum of antifungal activity 7.23.4 Resistance 7.23.5 Pharmacokinetics 7.23.6 Pharmacodynamics 7.23.7 Toxicity 7.23.8 Drug interactions 7.23.9 Clinical data 7.23.10 Trials in progress References 7.24 -5-Flucytosine 7.24.1 Introduction 7.24.2 Evolution of antifungal drugs 7.24.3 Flucytosine (5-FC) References 7.25 -Antivirals Against Influenza 7.25.1 Introduction 7.25.2 Influenza antiviral therapy 7.25.3 Avian influenza 7.25.4 Combination therapy for the treatment of influenza 7.25.5 Current guidelines References Index A B C D E F G H I J K L M N O P Q R S T U V W X Y Z Author Index A B C D E F G H I J K L M N O P Q R S T V W X Y Z