Part 1 book “General and molecular pharmacology” has contents: Essential lexicon of pharmacology, a short history of pharmacology, cellular basis of pharmacokinetics , drug absorption and administration routes, drug distribution and elimination, drug metabolism.
Trang 5General and Molecular PharMacoloGy
Principles of drug action
Edited By
Francesco cleMenti and Guido FuMaGalli
Co‐editors
christiano chiaMulera, eMilio cleMenti,
riccardo Fesce, dieGo Fornasari, and cecilia Gotti
Trang 6Il meccanismo d’azione dei farmaci”, 4th edition, by Francesco Clementi and Guido Fumagalli, © UTET SpA – Unione Tipografico-Editrice Torinese, Torino, Italy (2012).
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Library of Congress Cataloging-in-Publication Data
General and molecular pharmacology : principles of drug action / Francesco Clementi, Guido Fumagalli, editors ; Christiano Chiamulera,
Emilio Clementi, Riccardo Fesce, Diego Fornasari, Cecilia Gotti, co-editors.
1 online resource.
Includes bibliographical references and index.
Description based on print version record and CIP data provided by publisher; resource not viewed.
ISBN 978-1-118-76859-4 (pdf) – ISBN 978-1-118-76868-6 (epub) – ISBN 978-1-118-76857-0 (cloth : alk paper)
I Clementi, Francesco, editor II Fumagalli, Guido, editor
[DNLM: 1 Chemistry, Pharmaceutical 2 Molecular Biology 3 Pharmacological Phenomena QV 744]
Trang 7LIST OF CONTRIBUTORS xlvi
Francesco Clementi and Guido Fumagalli
The Social Impact of Pharmacology, 3
Birth and Historical Developments of Pharmacology, 8
From Magical and Natural Remedies of Ancient Medicine to Arabic Alchemy, 8From Monastic Medicine to Botanical Gardens, 9
From Anatomical Renaissance to the “Experienz”: Paracelsus’ Spagyric, 10From Iatrochemistry to the Age of Enlightenment, 11
From the Search of the Active Principle to the Discovery of Alkaloids
and Glucosides, 12
The Drug Synthesis Revolution: From Handmade to Industrial Production, 12Modern Pharmacology, 13
Ehrlich and Chemotherapy: The Concept of Receptor, 13
The Birth of Modern Pharmacology, 14
The Biotechnology Era and the Pharmacology in the Third Millennium, 15
The Impact of New Biotechnologies: Molecular Biology, Bioinformatics,
and Combinatorial Chemistry, 15
Biological Drugs and Pharmacology Perspectives, 16
CONTeNTS
Trang 8Personalized Therapies and New Sceneries in Pharmaceutical Industry, 17
Take‐Home Message, 18
Further Reading, 18
SeCTION 2 GeTTING THe DRUG TO ITS SITe OF aCTION 19
Riccardo Fesce and Guido Fumagalli
A Quick Journey with the Drug in the Body, 21
Absorption, 21
Distribution, 21
Drug Elimination, 22
Crossing Cell Membranes, 23
Passive Diffusion across Cell Membranes, 24
Drug Transport across Cell Membranes, 25
Endocytosis, 25
Drug Diffusion to organs and Tissues, 27
Properties of the Most Important Cell Barriers, 27
Take‐Home Message, 30
Further Reading, 30
Riccardo Fesce and Guido Fumagalli
General Rules About Drug Absorption Rate, 32
Partition Coefficient, 32
Drug Dispersion, 32
Extension of the Absorbing Surface, 32
Permeability of the Absorbing Surface, 32
Vascularization, 33
Enteral Routes of Administration, 33
oral Route, 33
Sublingual and Rectal Routes, 35
Systemic Parenteral Routes of Administration, 35
The Intravascular Route, 35
i.m Injection, 36
Subcutaneous and Intradermal Injections, 36
other Routes of Drug Administration, 36
Riccardo Fesce and Guido Fumagalli
Distribution, 46
Tissues and Avidity for Drugs, 46
The Apparent Distribution Volume, 48
Trang 9Drug Binding to Plasma Proteins, 50
Factors That Determine the Distribution Rate of Drugs to the Various
Compartments, 51
Elimination, 53
The Concept of Half‐Life, 53
The Concept of Clearance, 54
Renal Excretion of Drugs, 55
Glomerular Filtration, 56
Tubular Functions and Pharmacokinetics, 56
Active Transport of organic Anions and Cations, 56
Factors Determining Renal Clearance of Drugs, 57
Hepatic Excretion and Enterohepatic Cycle, 58
Perfusion, Binding to Plasma Proteins, Enzymatic Activity,
and Hepatic Clearance, 59
Take‐Home Message, 59
Further Reading, 60
Enzo Chiesara, Laura Marabini, and Sonia Radice
Metabolic Modification of Drug Activity, 61
Two Phases of Drug Metabolism, 62
Phase I Reactions, 62
Phase II Enzymatic Reactions, 66
Extrahepatic Biotransformations, 68
Biotransformation by the Intestinal Flora, 69
Pharmacometabolic Induction and Inhibition, 69
Induction of Drug Metabolism, 69
Inhibition of Drug Metabolism, 71
Take‐Home Message, 72
Further Reading, 72
Riccardo Fesce and Guido Fumagalli
Time Course of Drug Plasma Concentration Following a Single
Administration, 73
Drugs Distribute to organs and Tissues and then are Eliminated, 74
Description of Drug Plasma Concentration Time Course Following a Single
Administration, 74
Area under the Plasma Concentration Curve (AUC), 74
The Plasma Concentration Peak, 75
Drug Plasma Concentration Time Course During Repetitive Administrations, 75
During Repetitive Administrations, the Drug Plasma Concentration Time
Course Is Given by the Sum of the Time Courses of the Single Doses, 75
In a Chronic Therapy at Steady State, Each New Dose Replaces the Drug
Amount that has been Eliminated Since the Last Administration, 77
The Time to Reach the Steady State Depends on the Drug Half‐Life, 77
Plasma Concentration at Steady State, 78
The Single Dose to Administer is Computed as a Function of the Interval
between Successive Administrations, 78
Fluctuations of Drug Plasma Concentration at Steady State, 79
Absorption Kinetics Influence the Amplitude of oscillations in Plasma
Concentration at Steady State, 80
Loading (Attack) Doses to Rapidly Attain Steady‐State Concentration, 80
Multicompartmental Kinetics, 81
Drug Binding to Plasma Proteins and Tissue Equilibration with Plasma, 81
Trang 10The Particular Case of the Nephron, 82
Drugs Redistribution among Compartments, 83
Corrections of the Therapeutic Regimen, 83
Normally Available Pharmacokinetic Data Are Average Values, 84
Varying Dosage as a Function of Body Weight and Physical
Constitution, 84
Varying Dosage as a Function of Age, 84
Dosage Correction in the Presence of Hepatic Pathologies, 86
Dosage Correction in the Presence of Renal Pathologies, 86
Take‐Home Message, 87
Further Reading, 89
8 Drug–Receptor Interactions: Quantitative and Qualitative aspects 93
Gian Enrico Rovati and Valérie Capra
General Properties of Drug Receptors, 93
Drug Receptors Are Molecules Relevant for Cellular Functions, 93
Not All Drugs Interact with a Receptor, 94
Drug Activity Follows to Drug–Receptor Complex Formation, 94
Drug–Receptor Interaction Is Mostly Mediated by Weak Chemical Bonds, 94Reversible or Irreversible Drug–Receptor Interactions, 95
Characteristics of Drug–Receptor Interaction, 95
The Relationship between Drug Concentration and Drug–Receptor Complex
Is Similar to the Michaelis–Menten Equation, 97
The Binding Isotherm and Its Linear Transformations Allow to obtain
the Parameters of the Drug–Receptor Interaction, 97
Receptors Can Be Heterogeneous, 99
Drug Competition for a Same Receptor Binding Site, 99
Quantitative Aspects of Drug Effects: Dose–Response Curves, 99
Potency and Efficacy, 100
From Drug–Receptor Interaction to Drug Response, 101
Constitutively Active Receptors and Inverse Agonists, 107
Two‐State Receptor Model and Beyond: Multiple Receptor States
and “Biased” Signaling, 108
Take‐Home Message, 108
Further Reading, 108
Francesco Clementi and Guido Fumagalli
Classes of Receptors and Strategies of Signal Transduction, 109
Intracellular/Intranuclear Receptors, 110
Membrane Receptors, 110
Control of Receptor Localization in the Cell Membrane, 116
Intracellular Traffic of Cell Receptors, 117
How Receptors Reach the Cell Membrane and how Their Number
is Regulated, 117
Modulation of Receptor Responses, 117
Receptor Modulation By Drugs, 118
Trang 11Effects of Repeated Drug Exposure, 122
Drug Addiction as a Paradigm of Allostatic Adaptation, 123
Adaptation and Stages of Drug Addiction, 125
Research on Drug Addiction, 127
Therapy for Drug Dependence, 128
Take‐Home Message, 129
Further Reading, 129
11 Pharmacological Modulation of Posttranslational Modifications 130
Monica Di Luca, Flavia Valtorta, and Fabrizio Gardoni
Jacopo Meldolesi and Guido Fumagalli
The Cytosol: A Crossroad of Ca2+ Fluxes, 139
Free Ca2+ in the Cytosol and Total Cell Calcium, 139
The High‐Affinity Buffering of Cytosolic Proteins, 140
The Plasma Membrane: Channels, Pumps, and Transporters, 140
Surface Channels Permeable to Ca2+, 140
Surface Pumps and Transporters, 141
Ca2+ in Intracellular organelles, 142
The ER: A Rapidly Exchanging Ca2+ Pool, 142
Mitochondria as Local Buffers of [Ca2+]i, 143
ER and Mitochondria Allow Rapid Changes of [Ca2+]i within Cells, 144
[Ca2+]i Control in other Intracellular Structures, 145
Local Relevance of organelle Calcium Pools, 145
Trang 12Ca2+ in Cell Pathology, 145
Take‐Home Message, 146
Further Reading, 146
Lucia Vicentini and Maria Grazia Cattaneo
The MAPK Family and the Activation Mechanism, 147
The ERK Family, 147
Multiple Enzyme Isoforms, 151
Subcellular Localization and Interaction with Scaffold Proteins, 151
miRNAs, 151
Pharmacological Inhibition of MAPK, 151
Inhibition of the Ras/RAF/MEK/ERK Cascade, 151
Erzsébet Ligeti and Thomas Wieland
Structure and Function of SMGs, 154
Physiological Roles of Components of Major SMG Families, 155
Posttranslational Modification and Subcellular Localization
Bacterial Toxins Modifying Host RhoGTPases, 160
Bacterial Toxins Acting as GEFs or GAPs for Host GTPases, 162
Modulation of the Prenylation Process, 163
Dualism of Receptors in the Nucleus and In the Cytoplasm, 166
Heterogeneity of Receptor Assembly, 167
Transduction Cascades Depend on Crosstalk and Complementarity
Among Receptors, 168
A Comprehensive Scenario of Signal Transduction: From GSKβ3 to AKT
and mToR, 169
Trang 13Development of New Drugs and Therapies, 169
Take‐Home Message, 170
Further Reading, 171
Cecilia Gotti and Francesco Clementi
Tissue Distribution and Subcellular Localization of LGICs, 175
Molecular organization of LGICs, 176
Classification of LGICs, 176
Topology of LGICs, 179
The Binding Sites for Endogenous Ligands, 179
Structure and Localization of the Channel, 182
Functions of the Cytoplasmic Domain, 183
Modulation of LGIC Activity, 184
Desensitization, 185
Subunit Composition and Biophysical and Pharmacological Properties
of LGICs, 185
Crosstalk with other Receptor Systems, 186
Mechanisms of Action of Drugs That Modulate LGICs, 187
GPCR Mutations and Human Diseases, 192
Molecular organization and Function of G Protein, 192
The Adenylyl Cyclase System, 195
The Phospholipase C System, 196
Interaction of GPCRs with other Proteins, 198
GPCR‐Interacting Proteins: Control of Receptor Function, Intracellular
Trafficking, and Localization, 198
G‐Protein‐Independent Signaling, 199
Perspectives, 200
Take‐Home Message, 200
Further Reading, 200
Silvia Giordano, Carla Boccaccio, and Paolo M Comoglio
Molecular Structure of Growth Factor Receptors, 204
Growth Factor Receptors are Tyrosine Kinases with Modular Structure, 204
Modulatory Functions of the Transmembrane and Juxtamembrane Domains
of Growth Factor Receptors, 204
Trang 14Receptor Activation and Signal Transduction, 205
Receptor Dimerization and Activation, 205
Signal Transducers Binding to Phosphorylated Tyrosines, 207
RAS‐Dependent Transduction Pathway in Cell Proliferation and Neoplastic Transformation, 209
Activation of Enzymes Generating Lipid Second Messengers, 210
Cytoplasmic Tyrosine Kinases, 211
Tyrosine Phosphatases Modulating Tyrosine Kinase Activity, 212
STATs, 212
Pharmacological Approaches to the Control of Growth Factor Receptor
Activity, 213
mAbs and Small Kinase Inhibitors, 213
Growth Factor Receptors as Targets for Anticancer Drugs, 215
Tyrosine Kinase Receptors, 218
The IL‐1/IL‐18 Receptor Family, 218
The TNFR Family (Jelly Roll Motif Cytokines), 219
Chemokine Receptors, 219
Cytokines in Their Biological Settings, 220
Hematopoietic Cytokines, 220
Cytokines in Innate Immunity, 220
Cytokines of Adaptive Immunity, 222
Anti‐inflammatory Cytokines, 223
Pharmacology of Cytokines and Their Receptors, 223
Take‐Home Message, 224
Further Reading, 224
Giorgio Berton and Carlo Laudanna
Adhesion Receptors, 225
Classification, 225
Functions, 226
Signal Transduction By Adhesion Receptors, 229
FAK and Src‐Family Kinases in Integrin Signal Transduction, 229
Signal Transduction by Cadherins, 232
Signal Transduction by CD44, 232
Adhesion Receptors as Drug Targets, 233
Take‐Home Message, 234
Further Reading, 234
21 Soluble Cytokine Receptors and Monoclonal antibodies
Alberto Mantovani and Annunciata Vecchi
Soluble Receptors, 235
The Paradigm of Viral Receptors for Cytokines, 236
“Decoy” Receptors: Molecular Traps for Agonists, 236
Soluble Receptors: Mechanisms of Generation and Action, 237
Soluble Receptors: Antagonist Effects, 237
Trang 15Soluble Receptors: Agonist Effects, 238
Soluble Receptors as Pharmacological Agents, 238
Roberta Benfante and Diego Fornasari
Introduction to the Mechanisms of Transcriptional Regulation, 243
General Transcription Factors, 243
The Promoter: A Multifunctional Region with Positive and Negative
Regulatory Elements, 244
Additional Factors Required to Stabilize PIC Structure, 246
Mediator, 246
Control of Specificity and Inducibility of Gene Expression, 246
Coregulatory Complexes and Covalent Modification of Histones, 248
Toward a Unified Theory of Transcriptional Regulation, 250
Transcriptional Regulation By Extracellular Stimuli, 251
Three Classes of Inducible Transcription Factors, 251
From the Pharmacology of Transcription to Pharmacoepigenomics, 252
Genetic Basis of Variability in Drug Response, 256
Genes and Pharmacogenetics, 256
Allelic Variants of Genes Involved in Drug Response, 257
Copy Number Variation, 257
Genetic Polymorphisms and Drug Metabolism, 258
Genetic Polymorphisms in Genes Encoding Phase I Enzymes, 258
Polymorphisms of CYP2D6, 258
Allelic Variants in the CYP2C Subfamily, 260
Role of Phase I Enzymes in Prodrug Activation, 260
Thiopurine Methyltransferase, 262
UGT1A1 and Irinotecan: A Case Already under Evaluation by the
Regulatory Agencies, 263
Genetic Polymorphisms in Genes Encoding Transporters Involved in Drug
Absorption, Distribution, and Excretion, 263
ABCB1 and Multidrug Resistance, 263
The oAT1B1 Transporter and Statin‐Induced Myopathy, 264
Genetic Polymorphisms in Genes Encoding Molecular Targets of Drug Action, 264
β1 Receptor Polymorphism and the Response to β‐Blockers in Heart
Failure, 264
β2 Receptor Polymorphism and the Response to Antiasthma
Therapy, 265
Methods of Pharmacogenetic Studies, 265
The Future of Pharmacogenetic, 266
Take‐Home Message, 266
Further Reading, 267
Trang 1624 Intracellular Receptors 268
Adriana Maggi and Elisabetta Vegeto
Structural Features of Intracellular Receptors, 268
Intracellular Receptor Classification, 268
Molecular organization and Functional Domains, 272
Intracellular Receptors as Ligand‐Regulated Transcription Factors, 274
Temporal oscillations of DNA Binding of Intracellular Receptors, 277
Physiological Activities and Pharmacological Control of Intracellular
Receptors, 278
Specificity of Action of Homologous Receptors, 278
Tissue Specificity of Nuclear Receptor Activity, 278
Receptor Agonists and Antagonists, 278
CAR and SXR Receptors, 283
Take‐Home Message, 283
Further Reading, 283
25 RNa Molecule as a Drug: From RNa Interference to aptamers 284
Valerio Fulci and Giuseppe Macino
Mechanisms of Action of RNA Drugs, 284
Cellular Pharmacokinetics and Toxicology, 289
Systemic Pharmacokinetics and Toxicology, 290
Present Use and Future Perspectives, 290
Take‐Home Message, 292
Further Reading, 292
Luciano Conti and Elena Cattaneo
Principles of Regenerative Medicine, 296
Definition, Classification, and Features of Stem Cells, 296
Trang 17Pluripotent Stem Cells, 298
Multipotent (or Adult) Stem Cells, 299
Stem Cell‐Based Drugs, 299
Cell Therapy and Regenerative Medicine, 299
Regenerative Medicine Approaches to Epithelial
Lesions, 300
Regenerative Medicine to Treat Cardiac Dysfunctions, 301
Stem Cell‐Based Therapies for Skeletal Muscle Diseases, 301
Stem Cell‐Based Therapies for Brain Diseases, 302
Gene Therapy, 303
Protocols for Gene Therapy, 303
Gene Therapy for Monogenic Inherited Diseases, 304
Maurizio Taglialatela and Enzo Wanke
Ion Channels and Transporters, 311
Characterization and Function of Ion Channels, 312
Channel Classification According to Permeating Ions and Gating
Mechanisms, 312
Permeation and Concentration Gradients, 312
Transmembrane Voltage Triggers Conformational Changes, 315
Current–Voltage Relationships and The Rectification Process, 315
Structural organization of Ion Channels, 316
The Voltage Sensor of VGICs, 316
Inactivation, 319
Ion Selectivity, 319
Drugs and Ion Channels, 319
Drugs Interacting Directly with Ion Channels, 319
Modulation of Ion Channel Activity by Drugs Acting on Receptors
Functionally Coupled to Ion Channels, 321
Structural organization of Potassium Channels, 332
Nonselective Channels, Anionic Channel, and others, 339
Cationic Channels Modulated by Cyclic Nucleotides, 339
Take‐Home Message, 343
References, 343
Further Reading, 344
Trang 18Structure, Distribution, and Function, 350
Regulation of the Gastric Proton Pump, 350
Pharmacology of the Gastric Proton Pump, 351
Plasma Membrane Ca2+‐ATPase, 351
Sarcoplasmic/Endoplasmic Reticulum Ca2+‐ATPase, 352
Structure, Distribution, and Regulatory Mechanisms of SERCA, 352
Physiological Properties and Pharmacological Modulation, 353
Na+/Ca2+ Exchanger, 353
Structure and Distribution, 353
Biophysical Properties and Physiological Role, 354
NCX in Pathologies and Pharmacological Modulation, 354
Na+/H+ Exchanger, 355
Structure, Distribution, and Functional Properties, 355
Functional Significance and Pharmacological Modulation, 356
Neurotransmitter Transporters and Synaptic Function, 359
Regulation of Transporter Activity and Traffic, 360
Neurotransmitter Transporter Families, 361
Na+/K+‐Dependent Transporters for Excitatory Amino Acids, 361
Na+/Cl−‐Dependent Plasma Membrane Transporters, 364
Molecular Mechanism of Transport, 366
GABA Transporters, 367
The Serotonin Transporter, 369
The Dopamine Transporter, 371
The Noradrenaline and Adrenaline Transporters, 371
H+‐Dependent Vesicular Transporters, 372
The Vesicular Monoamine Transporters, 373
The Vesicular Acethylcholine Transporter, 374
The Vesicular Transporters for Excitatory Amino Acids, GABA,
and Glycine, 374
Take‐Home Message, 374
Further Reading, 374
Trang 19SeCTION 8 CONTROL OF PROTeOLYSIS 377
Fabio Di Lisa and Edon Melloni
General Characteristics of Proteases, 379
Classification, 379
Characteristics and Regulation of Intracellular Proteolysis, 381
Function and Pharmacological Modulation of the Main Intracellular
Proteolytic Systems, 382
Lysosomal Proteases, 382
Types and Families of Lysosomal Enzymes, 383
Compartmentalized Proteases with Specific Functions, 385
other Serine Proteases for Protein Quality Control, 388
Caspases: Initiators and Executors of Apoptosis, 389
Calpain, 391
Exogenous Intracellular Proteases, 392
HIV and Inhibitors of Viral Proteases, 392
Take‐Home Message, 393
Further Reading, 393
Francesco Blasi
The Extracellular Matrix Proteolytic Degradation Systems, 395
Plasminogen System and its Activators, 396
PAs as Fibrinolytic Agents, 396
Localized Activation of uPA by Interaction with a Specific Receptor, 397
Function and Pharmacological Modulation of the PA System, 398
Pharmacological Inhibition of the PA System in Neoplastic Processes, 399
Matrix Metalloproteases, 399
Modular Structure of MMPs, 399
MMP Activation at the Plasma Membrane, 399
Function and Pharmacological Modulation of MMP, 400
Take‐Home Message, 400
Further Reading, 401
SeCTION 9 CONTROL OF CeLL CYCLe aND CeLLULaR
PROLIFeRaTION 403
Marco Corazzari and Mauro Piacentini
Cell Cycle, 405
Timely Regulated Expression of Cyclins and Cell Cycle Progression, 405
Trang 20Role of Retinoblastoma Binding Protein during G1–S Transition, 406
Cdk Inhibitors and Cell Cycle “Checkpoints”, 407
Morphological Features of Necrosis, 412
Role of Mitochondria in the Necrotic Process, 413
Drugs and Apoptosis, 413
Proapoptotic Drugs, 413
Drugs That Inhibit Apoptosis, 413
Take‐Home Message, 414
Further Reading, 414
Giovanni Luca Beretta, Laura Gatti, and Paola Perego
Conventional Antitumor Drugs, 417
Alkylating Agents, 417
Platinum Compounds, 418
Antimetabolites, 418
Drugs Acting on Microtubules, 420
DNA Topoisomerase Inhibitors, 421
Target‐Specific Antitumor Drugs, 423
Inhibitors of Survival Factors, 423
Proteasome Inhibitors, 425
Epigenetic Factors as Drug Targets, 426
Telomers and Telomerase, 426
Monoclonal Antibodies in Clinical Use, 427
34 Mitochondria, Oxidative Stress, and Cell Damage:
Clara De Palma, Orazio Cantoni, and Fabio Di Lisa
Reactive oxygen Species (RoS), 433
Mitochondrial Formation of RoS, 434
Physiological Role of RoS, 434
Pathophysiological Role of RoS in Mitochondrial Ca2+ Homeostasis, 435
The Mitochondrial PTP, 436
Drugs and Mitochondria, 437
Antioxidants Directed to Mitochondria, 437
Drugs Acting on Mitochondrial Channels to Prevent Mitochondrial
Dysfunction, 437
Drugs Promoting Mitochondrial Dysfunction for Possible Antineoplastic
Treatments, 437
Trang 21Drugs Acting on the Mitochondrial Metabolism, 437
Take‐Home Message, 438
Further Reading, 438
Lorenzo Arnaboldi, Alberto Corsini, and Nicola Ferri
Cholesterol Biosynthesis, 439
Statins: Inhibitors of the HMG‐CoA Reductase, 441
Farnesyl Pyrophosphate Synthase Inhibitors (Nitrogen‐Containing
Bisphosphonates), 441
Squalene Synthase Inhibitors, 442
Biosynthesis of Fatty Acids, 443
Fatty Acid Synthase and Its Inhibitors, 443
Fatty Acid Desaturases and Their Inhibitors, 444
Triglyceride Biosynthesis, 444
Inhibitors of Diacylglycerol Acyltransferase, 445
Transcriptional Control of Genes Involved in Lipid Metabolism, 446
Liver X Receptors and Liver X Receptor Synthetic Ligands, 446
Peroxisome Proliferator‐Activated Receptors and Their
Pharmacological Modulation, 447
Lipid Transfer Proteins, 448
ACAT and Its Inhibitors, 448
CETP and Its Inhibitors, 449
The MTP and Its Inhibitors, 450
Take‐Home Message, 451
Further Reading, 451
36 Glucose Transport and Pharmacological Control of Glucose Metabolism 452
Paolo Moghetti and Giacomo Zoppini
Mechanisms of Glycemic Control, 452
Modulation of GLUT4 Transporter Function by Insulin and Physical
Activity, 456
Insulin Receptors and Signal Transduction Pathway, 456
Pharmacology of Glycemic Control, 457
Pharmacological Stimulation of β‐Cell Activity, 458
Modulation of Insulin Signaling, 459
Modulation of Intestinal Glucose Absorption, 460
Insulin Resistance and New Therapeutic Perspectives, 461
Take‐Home Message, 461
Further Reading, 461
37 Pharmacological Regulation of Synaptic Function 465
Michela Matteoli, Elisabetta Menna, Costanza Capuano, and Claudia Verderio
The Synapse, 465
Synaptic organization Complexity and Synaptopathies, 466
The Presynaptic Compartment: Neurotransmitter Release, 468
Chemical Messengers: Neurotransmitters and Neuropeptides, 468
Secretory Granules and SVs, 469
Neurotransmitter Fate, 471
Trang 22The Postsynaptic Compartment: Signal Reception, 472
Synapse Formation, Maintenance, and Plasticity, 472
The Pharmacology of Neurosecretion, 474
Drugs Interfering with Secretory Vesicle Transport, 474
Drugs Interfering with Neurotransmitter Loading into Vesicles, 475
Drugs and Toxins Interfering with Late Steps of Neuroexocytosis, 475
Take‐Home Message, 476
Further Reading, 476
Pier Franco Spano, Maurizio Memo, M Cristina Missale, Marina Pizzi,
and Sandra Sigala
The Catecholaminergic System in the Autonomic Nervous System, 477
Anatomical organization of the Sympathetic System, 478
Cardiovascular Effects of the Sympathetic System, 479
other Noncardiovascular Effects of Catecholamines, 479
The Catecholaminergic Systems in the CNS, 480
Distribution and Functions of the Adrenergic and Noradrenergic
Systems, 480
Distribution of the Dopaminergic System, 481
Functions of the Dopaminergic Systems in the CNS, 482
Synthesis of Catecholamines, 483
Vesicular Storage and Release of Catecholamines, 484
Catabolism and Reuptake of Catecholamines, 485
Catecholamine Reuptake, 486
Catecholamine Receptors, 487
Adrenergic Receptors, 487
DA Receptors, 489
Principles of Drug Action on Catecholaminergic Receptors, 490
Drugs Acting on α‐Adrenergic Receptors, 490
Drugs Acting on β‐Adrenergic Receptors, 491
Drugs Acting on DA Receptors, 493
Take‐Home Message, 495
Further Reading, 495
Giancarlo Pepeu
Distribution and Function of the Cholinergic Systems, 496
Cholinergic Transmission in the Peripheral Nervous System, 496
The Cholinergic Transmission in the Central Nervous System, 497
Role of Brain Cholinergic System in Learning, Memory,
and Movement, 498
ACh Synthesis and Metabolism, 498
ACh Precursors, 499
ACh Hydrolysis by ChEs, 499
ACh Intracellular Storage and Release, 500
ACh Release, 501
Cholinergic Receptors, 501
Nicotinic Receptors, 501
Muscarinic Receptors, 503
Drugs Acting on Cholinergic Receptors, 504
Drugs Active on Nicotinic Receptors, 504
Trang 23Drugs Active on Muscarinic Receptors, 504
Take‐Home Message, 507
Further Reading, 508
Maurizio Popoli, Laura Musazzi, and Giorgio Racagni
Functions and Distribution of the Serotonergic System in the Body, 509
5‐HT in the Nervous System, 509
5‐HT and the Cardiovascular System, 511
5‐HT in Gastrointestinal and Genitourinary Systems, 513
5‐HT in Metabolism and Endocrine System, 513
Synthesis and Metabolism of Serotonin, 513
Vesicular Storage, Release, and Extracellular Clearance of Serotonin, 514
The 5‐HT Reuptake System, 515
Classification of Serotonin Receptors, 515
Drugs Acting on Serotonin Receptors, 516
Pharmacology of the 5‐HT1 Receptors, 516
Pharmacology of the 5‐HT2 Receptors, 516
Pharmacology of the 5‐HT3 Receptor, 517
Pharmacology of the 5‐HT4 Receptors, 518
Emanuela Masini and Laura Lucarini
Distribution and Function of the Histaminergic System, 521
Histaminergic Neurons in the CNS, 521
Functions of the Histaminergic System, 522
Histamine in the CNS, 522
Histamine in the Cardiovascular System, 523
Histaminergic System in the Stomach, 523
Histamine Effects on Smooth Muscles, 524
Histamine and the Immune Response, 524
Synthesis and Metabolism of Histamine, 524
Histamine Metabolism, 525
Storage and Release of Histamine, 525
Pharmacological Modulation of Histamine Metabolism and Release, 526
Histamine Receptors and Their Pharmacological Modulation, 526
Drugs Active on Histamine Receptors, 526
Take‐Home Message, 528
Further Reading, 528
Mariangela Serra, Enrico Sanna, and Giovanni Biggio
GABA Distribution, Synthesis, and Metabolism, 529
GABA Release and Reuptake, 530
GABA Receptor Classification, 531
GABAA Receptors, 531
Drug Binding Sites on GABAA Receptors, 531
Subunit Composition of Native Receptors, 533
Trang 24Extrasynaptic GABAA Receptors: Phasic and Tonic
Inhibition, 533
Pharmacology of GABAA Receptors, 534
GABAB Receptors, 537
Pharmacology of GABAB Receptors, 539
Schematic overview of the Main Pharmacological Interventions on Gabaergic Synapses, 539
Glutamate Synthesis and Metabolism, 541
Glutamate Transporters, Vesicular Accumulation, and Signal
Glutamate Neurotransmission in Physiology and Pathology, 547
Glutamate and Excitotoxicity, 547
Glutamate and Depression, 549
Drugs and Excitatory Neurotransmission, 549
Glutamate‐Mediated Neurotransmission in Brief, 551
Take‐Home Message, 551
Further Reading, 551
Stefania Ceruti, Flaminio Cattabeni, and Maria Pia Abbracchio
Purines as Intercellular Transmitters, 554
Source, Metabolism, and Release of Purines, 555
Generation of Active Metabolites by ATP Hydrolysis, 555
Receptors for Purines, 557
P1 Adenosine Receptors, 557
P2 Receptors for ATP, 557
P2X Ion Channel Receptors, 557
P2Y GPCRs, 559
Biological Roles of Purines, 560
Effects on the Cardiovascular System, 560
Effects on the CNS and Peripheral Nervous System, 561
Effects on the Respiratory System, 562
Effects on other Systems, 563
Adenosine Effects Independent of Receptor Activation, 563
Purines and Antitumor Therapy, 564
Trang 25Storage and Secretion of Neuropeptides, 567
Patrizia Romualdi and Sanzio Candeletti
Endogenous opioid Peptides, 572
opioid System Distribution, 574
opioid Receptors, 575
Signal Transduction, 575
opioid Receptor Distribution and Effects, 576
Modulation of Nociceptive Transmission, 576
Respiratory Depression, 579
Cardiovascular Effects, 579
Effects on the GI Tract and other Smooth Muscles, 579
Effects on Food Intake and Body Temperature, 580
Effects on the Immune System, 580
Tolerance and Physical Dependence to opiates, 580
Molecular Mechanisms of Cellular Adaptation to Chronic Exposure
to opiates, 580
Molecular Mechanisms of Withdrawal, 582
Regulation of Gene Transcription by opioids, 582
Addiction to opioids, 583
Take‐Home Message, 584
Further Reading, 584
Daniela Parolaro and Tiziana Rubino
Biological Functions of Endocannabinoid System, 588
EC‐Mediated Synaptic Plasticity, 589
other Biological Functions, 589
Drugs Affecting the ECS, 593
Trang 26Biochemistry of No, 599
No and Activation of Guanylate Cyclase, 599
No and Inhibition of Cytochrome c oxidase, 600
Nitrosylation of Thiols, 601
No and MicroRNAs, 602
Systemic and organ Effects of No, 602
Effects in the Cardiovascular System, 602
No and the Respiratory System, 603
No and Metabolic Diseases, 603
No in Central and Peripheral Nervous Systems, 603
No and Skeletal Muscle, 604
No and the Immune System, 605
Carlo Patrono and Paola Patrignani
Arachidonic Acid Release from Membrane Lipids, 609
Enzymatic Metabolism of Arachidonic Acid, 610
PGH‐Synthase Pathway, 610
Cyclic Endoperoxide Metabolism, 613
The Lipoxygenase Pathway, 615
LTA4 Metabolism, 616
Transcellular Metabolism of PGH2 and LTA4, 617
Nonenzymatic Metabolism of Arachidonic Acid, 617
50 Pharmacological Modulation of the Immune System 625
Carlo Riccardi and Graziella Migliorati
The Immune Response, 625
The Concept of Autoimmunity, 626
Immunosuppressive Drugs, 626
Anticancer Chemotherapeutic Agents, 626
Immunosuppressive Drugs with Higher Specificity, 629
Thalidomide, 630
Calcineurin Inhibitors, 630
Antibodies as Selective Immunosuppresants, 635
other Biological Drugs with Immunomodulatory
Activity, 636
Issues Associated with the Use of Antibodies as Pharmacological
Agents, 637
Trang 27Antibacterial Drugs and Their Mechanisms of Action, 641
Inhibitors of Peptidoglycan Synthesis, 643
Inhibitors of Peptidoglycan Polymerization, 645
Transcription Inhibitors, 646
Translation Inhibitors, 646
Inhibitors of DNA Synthesis and Replication, 649
Inhibitors of Cytoplasmic Membrane Functions, 649
Mechanisms of Resistance to Antibacterial Drugs, 650
Antifungal Drugs, 651
Drugs Acting on the Cell Wall, 651
Drugs Acting on the Cytoplasmic Membrane, 652
Inhibitors of DNA and Protein Synthesis, 653
Inhibitors of Enzymatic Metabolic Pathways, 653
Mitotic Inhibitors, 653
Mechanisms of Resistance to Antifungal Drugs, 653
Antiviral Drugs, 654
Mechanisms of Action of Antiviral Drugs, 654
Inhibitors of Viral DNA Replication, 654
Drugs Active against Influenza Virus, 656
Drugs Mainly Active on Hepatitis C Viruses (HCV), 657
New HCV drugs, 658
other Drugs Active on HCV, 658
Drugs Active against Hepatitis B virus (HBV), 658
Drugs Active against Immunodeficiency virus (HIV), 659
Reverse Transcriptase Inhibitors, 659
HIV Protease Inhibitors, 660
Inhibitors of Virus Entry into the Host Cells, 660
Trang 28Toxicological Evaluation of New and Existing Chemicals, 669
General Requirements for Hazard Identification and Risk Assessment, 669
Acute Toxicity, Subchronic Toxicity, and Chronic Toxicity, 669
Irritation and Phototoxicity, 670
Sensitization and Photosensitization, 670
Alternatives to Animal Experiments, 672
General Approach for Hazard Identification and Risk Assessment, 673
Evaluation of Mixtures, 674
Evaluation of Uncertainties, 674
Toxicological Issues Related to Specific Chemical Classes, 674
Classification and Labelling (C&L) of Chemicals, 675
The Threshold of Toxicological Concern Concept, 675
The Precautionary Principle, 676
Achille P Caputi, Giuseppina Fava, and Angela De Sarro
Pharmacokinetic Drug Interactions, 678
Interactions during Drug oral Absorption, 679
Interactions during Drug Distribution, 681
Interactions during Drug Biotransformation, 681
Interaction during Drug Excretion, 683
Pharmacodynamic Drug Interactions, 684
Chemical Antagonism, 684
Antidotes, 684
Pharmaceutical Interactions and Incompatibility, 685
Interactions Between Herbal Remedies and Drugs, 685
Interactions Between Dietary Supplements and Drugs, 685
Take‐Home Message, 686
Further Reading, 686
54 Preclinical Research and Development of New Drugs 689
Ennio Ongini
Technological Innovation and Scientific Knowledge in Current Pharmaceutical Research, 689
The Research Strategies, 691
Patent as a Driving Force for Innovation, 692
The Research Stages, 692
Start‐Up of a New Project and Identification of the Lead Compound, 692
Pharmaceutical Chemistry: From the Mainstream Approach to the Molecular Modeling, 692
Trang 29Drug Selection: in Vitro Assays and Experimental Models, 693
Biological Drugs, 694
Impact of Genomics Studies on Drug Research, 694
Pharmacokinetic Studies, 694
The Developmental Stages, 696
The Role of National and Supranational Legislation, 696
Scaling Up from Laboratory to Industrial Drug Preparation, 697
Choice of the Pharmaceutical Form, 697
55 Role of Drug Metabolism and Pharmacokinetics in Drug Development 700
Simone Braggio and Mario Pellegatti
DMPK in Drug Discovery, 700
Evolution of DMPK in Drug Discovery, 701
DMPK in the Regulatory Phase of Drug Development, 702
Clinical Development of a New Drug, 708
Principles and Rules of Clinical Investigation, 708
The Path of Clinical Development of a New Drug, 709
observational Studies and Randomized Clinical Trials, 710
The Key Role of the Primary Hypothesis, 711
The Choice of the Primary End Point, 711
Sample Size Calculation, 712
A Look At the Future, 712
Take‐Home Message, 713
Further Reading, 713
INDeX 714
Trang 30SUPPLeMeNTaRY CONTeNTS (FOR ONLINe)
(The supplementary materials are correlated with the textbook and the relevance of each supplement to the content of the chapters
is indicated by the symbol ☞ in the proper chapters)
e 1.1 alternative or Nonconventional Therapies
Is the Lack of Clear Data Related to a Lack of Research Funds?
Possible Reasons for the Success of Nonconventional Medicine
Ethical Problems Posed by Homeopathy
How to Study the Placebo Effect
Biological Properties of Placebo and Nocebo
Use of Placebo in Clinical Trials
Ethical Problems Posed by the Use of Placebo
The Placebo in Medical Practice
References
Trang 31e 2.1 The Drugs of the ancients
End of an Era and Birth of Pharmacovigilance
Molecules Never Die: The Return of the “Damned Drug” and Its New
Therapeutic options
Further Reading
e 3 Pharmacokinetics
Riccardo Fesce and Guido Fumagalli
A Rapid Journey with the Drug in the organism
The Drug Must Be Absorbed to Reach Its Target organ
The Drug Reaches Its Target organ but It Is also Distributed to the
Various Tissues in the Body
The Drug Is Eliminated
Passage across Cellular Membranes
Passive Diffusion across Cell Membranes
Drug Transport across Cell Membranes
Diffusion of Drugs to organs and Tissues
Properties of the Most Important Cell Barriers
Suggested Reading
Drug Absorption and Administration Routes
General Rules about Drug Absorption Speed
oral Route: Drug Absorption along the Gastrointestinal Tract
Buccal (Sublingual) and Rectal Routes
Systemic Parenteral Routes
Tissues Display Different Avidities for the Drug
Apparent Distribution Volume
Drug Binding to Plasma Proteins
The Factors that Determine the Distribution Rate of Drugs to the Various
Compartments
Drug Elimination from the organism
Trang 32The Concept of Half-Life
The Concept of Clearance
Renal Excretion of Drugs
Hepatic Excretion and Enterohepatic Cycle
The Relation Between Metabolism and Excretion
Suggested Reading
Control of Drug Plasma Concentration
The Time Course of Drug Plasma Concentration Following a Single Administration
Time Course of Drug Plasma Concentration during Repetitive
Administration
Multicompartmental Kinetics
Equilibrium Concentrations Can Be Different Among Tissues
The Rate of Equilibration of a Tissue with Plasma Depends on Local
Plasma Flow and the Tissue Apparent Distribution Volume, Vd
The Velocity of Equilibration of Tissues with Plasma Depends on Drug Binding to Plasma Proteins
The Particular Case of the Nephron
Drugs Can Redistribute among Compartments
The Distribution of Drugs Administered by Inhalation
Corrections of the Therapeutic Regimen
Normally Available Pharmacokinetic Data Are Average Values
Varying Dosage as a Function of Body Weight and Physical
Constitution
Varying Dosage as a Function of Age
Dosage Correction in the Presence of Hepatic Pathologies
Dosage Correction in the Presence of Renal Pathologies
Suggested Reading
e 6.1 Factors that Modify Drug Metabolism
Enzo Chiesara, Laura Marabini, and Sonia Radice
Physiological Factors
Differences Based on Species
Differences Within Species
Differences Related to Age or Gender
Pathological Factors
External Factors
Diet
Environment
e 6.2 Induction of Drug Metabolism
Enzo Chiesara, Laura Marabini, and Sonia Radice
Morphological and Biochemical Aspects of the Induction of Drug
Trang 33e 7.1 Therapeutic Drug Monitoring
Dario Cattaneo
optimization of Drug Therapy Guided by Pharmacokinetics
The Importance of AUC (Area Under the Plasma Concentration Curve)
Use of TDM through Single Sampling Strategies
Further Reading
e 7.2 The Distribution of Drugs administered by Inhalation
Riccardo Fesce and Guido Fumagalli
e 8.1 Methods for Receptor Investigations
Gian Enrico Rovati and Valérie Capra
Concentration-Response (in Vitro) or Dose-Response (in Vivo) Curves
e 8.2 Receptor Binding assays
Gian Enrico Rovati and Valérie Capra
e 9.1 Birth and evolution of the Receptor Theory
Francesco Clementi, Guido Fumagalli, and Vittorio A Sironi
References
e 9.2 Regulation of Receptor Response
Francesco Clementi and Guido Fumagalli
Desensitization
Homologous and Heterologous Desensitization
Desensitization of Ligand-Gated Ion Channels
Desensitization of G Protein-Coupled Receptors
Desensitization of Tyrosine Kinase Receptors
Desensitization of Receptors with Intrinsic Guanylcyclase Activity
Desensitization of Intracellular Receptors
Receptor Down-Regulation
Early Downregulation
Late Downregulation
Receptor Endocytosis and Signal Transduction
Desensitization Can occur via Modulation of G Protein Activity
Differences in Downregulation of Receptors Coupled to Phospholipase
C Activation
Downregulation of Tyrosine Kinase Receptors
Sensitization or Receptor Upregulation
Drugs May Induce Expression of New Receptors
References
Trang 34e 9.3 Intracellular Trafficking of Receptors
Francesco Clementi and Guido Fumagalli
Intracellular Traffic of Receptors
Receptor Localization to Specific Plasma Membrane Domains
Function of Lipid Rafts and Submembrane Matrix
Receptor Removal from the Membrane
Endocytosis or Lateral Diffusion?
An Example of Receptor Plasticity in Non-Nervous Tissues:
β-Adrenergic Receptors in the Heart
Pathologies Associated with Defects in Receptor Trafficking
operant Conditioning and Reinforcement
e 10.2 a Modern Definition of Memory
e 12.1 Cytosolic Proteins that Bind Ca 2+ with High affinity
Jacopo Meldolesi and Guido Fumagalli
e 12.4 Ca 2+ -Binding Proteins of the eR Lumen
Jacopo Meldolesi and Guido Fumagalli
References
e 12.5 eR Channels: IP 3 and Ryanodine Receptors
Jacopo Meldolesi and Guido Fumagalli
References
Trang 35e 12.6 Local Ca 2+ Spikes Can evolve Into Oscillations and Waves
Jacopo Meldolesi and Guido Fumagalli
References
e 12.7 Mitochondria: Semiautonomous Organelles that Need the eR to Operate
Jacopo Meldolesi and Guido Fumagalli
References
e 12.8 The Nucleus is also Operative in Ca 2+ Homeostasis
Jacopo Meldolesi and Guido Fumagalli
References
e 13.1 Phosphatases with Dual Specificity as Regulators of MaPK activity
Lucia Vicentini and Maria Grazia Cattaneo
Further Reading
e 13.2 Role of MaPKs in Memory and Learning
Lucia Vicentini and Maria Grazia Cattaneo
Mutations in Genes Encoding ERK Cascade Components and Central
Nervous System Diseases
Further Reading
e 13.3 eRK activation by G Protein–Coupled Receptors
Lucia Vicentini and Maria Grazia Cattaneo
Models and Approaches Used to Study pLGIC Structure and Function
Structure of Pentameric Ligand–Gated Ion Channels
Agonist Binding and Channel opening
Role of Loop C in Channel opening
Channel opening
The Channel Gate
pLGIC Mutations Causing Channelopathies
References
e 16.2 How to Identify the amino acids that Make Up the Inner Wall
of Ligand-Gated Ion Channels
Cecilia Gotti
Reference
Trang 36e 17.1 Orphan Receptors
Lucia Vallar, Maria Pia Abbracchio, and Lucia Vicentini
GPCR “Deorphanization,” Implications for the Drug Discovery ProcessDeorphanization of Receptors other than GPCRs: Example of Receptor Channels
Some Unsolved Issues and Future Directions
Further Reading
e 17.2 Structure and Conformation Modifications of GPCRs
Lucia Vallar, Maria Pia Abbracchio, and Lucia Vicentini
Further Reading
e 17.3 Drugs active on Phosphodiesterases
Lucia Vallar, Maria Pia Abbracchio, and Lucia Vicentini
e 20.1 adhesion and Platelet activation
Giorgio Berton and Carlo Laudanna
Further Reading
e 20.2 adhesion and Leukocyte Recruitment
Giorgio Berton and Carlo Laudanna
Covalent Modifications of Histones and Chromatin Function
Transcription Factors and the Recruitment of Histone Modifying Enzymes
Epigenetic Alterations and Human Pathologies
Epigenomic Drugs
Inhibitors of DNA Methylation
Inhibitors of DNA Demethylation
Inhibitors of Histone Deacetylase
Epigenomic Drugs and Brain
Epigenomics and Adverse Drug Reactions
Trang 37e 24.1 Ligands of Intracellular Receptors
Adriana Maggi and Elisabetta Vegeto
Chemical Structure of Ligands and their Interactions with the Intracellular
Receptors
Intracellular Receptor Genomic Interactions
Pharmacological Properties
e 26.1 History and Development of iPS Cell Research
Luciano Conti and Elena Cattaneo
Further Reading
e 26.2 Use of Blood Stem Cells in Hematology
Luciano Conti and Elena Cattaneo
Allogeneic Applications
Autologous Applications
Further Reading
e 26.3 Viral Vectors for Gene Therapy in Somatic Cells
Luciano Conti and Elena Cattaneo
e 26.4 Gene Therapy for Cystic Fibrosis and Tumors
Luciano Conti and Elena Cattaneo
Cystic Fibrosis
Tumors
Further Reading
e 27.1 How to Observe Ion Channel Currents in Real Time
Maurizio Taglialatela and Enzo Wanke
e 27.2 How to Study Interactions between Drugs and Ion Channels
Maurizio Taglialatela and Enzo Wanke
Heterologous Expression Systems
Functional Assays of Ion Channel Activity
Electrophysiology-Based Assays
Binding Studies
Flux Assays
optical Technologies
Membrane Potential Indicators
Ion-Selective optical Probes
Fluorescence Resonance Energy Transfer
e 27.3 Natural Peptide Toxins
Maurizio Taglialatela and Enzo Wanke
e 27.4 Physiopathology and Pharmacology of Muscular Contraction
Maurizio Taglialatela and Enzo Wanke
Striatal Muscle Contraction
Smooth Muscle Contraction
Role of Ryanodine Receptors in Muscular Contraction
Trang 38E 27.5 Physiopathology of VGCCs: Genetic Studies in Animal Models And Humans
Maurizio Taglialatela and Enzo Wanke
Knockout mice models of Cav1 Genes
Knockout mice models of Cav2 Genes
Knockout mice models of Cav3 Genes
perspectives
E 27.6 Drug-Induced Long QT Syndrome
Maurizio Taglialatela and Enzo Wanke
reference
E 27.7 TRP Channels
Maurizio Taglialatela and Enzo Wanke
Further reading
E 27.8 Nonvoltage-Dependent Na + Channels and their Roles as Mechanosensitive
and Acid-Sensitive Transducers
Maurizio Taglialatela and Enzo Wanke
E 27.10 Water Channels: Aquaporins
Maurizio Taglialatela and Enzo Wanke
E 27.11 Voltage-Independent Ca 2+ Channels Activated by Store Depletion
Maurizio Taglialatela and Enzo Wanke
references
E 27.12 Pharmacological Modulation of gap Junction Channels and Electrical
Synapses
Maurizio Taglialatela, Enzo Wanke, and Francesco Clementi
Structure and Function of Gap Junctions
physio-pharmacological Control of Gap Junctions
electrical Synapses
references
E 28.1 Systems for Drug Extrusion
Lucio Annunziato, Giuseppe Pignataro, and Gianfranco Di Renzo
E 28.2 Cardiac Glycosides
Lucio Annunziato, Giuseppe Pignataro, and Gianfranco Di Renzo
pharmacokinetics
mechanism of action
Trang 39Diuretics Acting on the Ascending Henle’s Loop
Diuretics of the Distal Convoluted Tubule
Diuretics Acting on Collecting Ducts
e 28.4 The Na + /Ca 2+ exchanger as a New Molecular Target for the Development of
Drugs to Treat Cerebral Ischemia
Lucio Annunziato, Giuseppe Pignataro, and Gianfranco Di Renzo
e 29.1 Therapeutic Properties of GaBa Transporter Inhibitors
e 30.1 Protease Classification and Nomenclature
Fabio Di Lisa and Edon Melloni
Physiopathological and Therapeutic Relevance
oxidative Stress and Aging
e 30.4 Ubiquitin and Proteasome
Fabio Di Lisa and Edon Melloni
Trang 40e 31.1 Plasminogen activators and Cardiovascular Diseases
Genes Involved in the Metastatic Phenotype
Evidences of uPA Involvement in Tumor Invasiveness
uPA Activity and uPA/uPAR Interaction as Targets for Antimetastatic Therapy
e 31.3 uPaR, Cancer and Stem Cells
Francesco Blasi
References
e 32.1 p53: Regulator of Mitotic Cycle Progression and apoptosis Inducer
Marco Corazzari and Mauro Piacentini
e 32.2 Mitotic Catastrophe
Marco Corazzari and Mauro Piacentini
e 32.3 Intrinsic apoptotic Pathway Induced by endoplasmic Reticulum
Marco Corazzari and Mauro Piacentini
e 33.1 Mechanisms of Drug Resistance in Cancer Chemotherapy
Giovanni Luca Beretta, Laura Gatti, and Paola Perego
Mechanisms of Resistance to Conventional Antitumor Agents
Alkylating Agents
Platinum Compounds
Antimetabolites
Antimitotic Agents
DNA Topoisomerase Inhibitors
Mechanisms of Resistance to Target-Specific Drugs
Additional Clinically Relevant Drugs
Further Reading
e 34.1 Structure, Organization, and Dynamics of Mitochondria
Clara De Palma
e 35.1 Pharmacology of the Mevalonate Pathway
Lorenzo Arnaboldi, Alberto Corsini, and Nicola Ferri
Mechanism of Action of Statins
Pleiotropic Effects of Statins