Development of Anti-Asthma Drugs (eBook)

Front Cover 1
Development of Anti-Asthma Drugs 4
Copyright Page 5
Table of Contents 10
Preface 6
Contributors 8
Introduction 14
Part 1: Asthma––the nature of the disease 20
Chapter 1. Asthma—the nature of the disease 22
Definition—what is asthma? 22
Natural history 26
Epidemiology 31
Pathological mechanisms 33
Part 2: Mediators 40
Chapter 2. Histamine 42
Introduction 42
Histamine release 44
Actions of histamine 60
Concluding remarks 61
Chapter 3. Leukotrienes 68
Introduction 68
Structure, formation and metabolism 69
Biological activities of the leukotrienes 73
Conclusions 81
Chapter 4. Platelet-activating factor 86
Introduction 86
Historical overview of platelet-activating factor 86
Structure and metabolism of PAF 88
PAF production in inflammation 91
PAF-induced platelet stimulation 91
Other inflammatory effects of PAF 92
Physiology 93
Effects on smooth muscle 93
Effects of vascular permeability 94
Pharmacological modulation 95
Conclusion 96
Chapter 5. Eosinophils and neutrophils 102
Introduction 102
General properties of eosinophils and neutrophils 102
Allergy and the eosinophil 109
Allergy and the neutrophil 112
Inflammatory cells and the progression of asthma 112
Corticosteroids, eosinophils and neutrophils 115
Summary 116
Chapter 6. Acetylcholine 120
Introduction 120
Acetylcholine as a neurotransmitter 120
The cholinergic nervous system in asthma 123
Summary 129
Part 3: Pharmacological approaches 132
Section 1: Competitive antagonists 134
Chapter 7. Hi antihistamines Noemi Eiser 134
Introduction 134
Effects of H!-receptor antagonists when given to asthmatics by various routes 137
Conclusions 141
Chapter 8. SRS-A antagonists 146
Development of FPL 55712 146
Biological effects of FPL 55712 151
Characterization of leukotriene receptors 157
Other antagonists of SRS-A 159
Clinical evaluation of SRS-A antagonists 166
Prospects 167
Chapter 9. Anti-cholinergic drugs 172
The history of anti-cholinergic drugs in asthma 173
Mode and site of action 174
Atropine sulphate and methonitrate 175
Thiazinamium 180
Deptropine 180
Ipratropium bromide 181
Oxitropium bromide 188
Conclusions 190
Section 2: Functional antagonists 198
Chapter 10. Drugs acting at adrenoceptors 198
Introduction 198
The development of ß2-adrenoceptor stimulants 198
Receptor classification: the pharmacological basis for selectivity of action 203
The biochemical basis of pharmacological activity: receptor–ligand interaction and activation of adenylate cyclase 204
The biochemical basis of pharmacological activity: consequences of elevating cyclic AMP 207
Clinical activity of drugs acting at ß2 receptors 209
a-Antagonists in the treatment of asthma 212
Chapter 11. Theophylline 218
Introduction 218
Serum levels and clinical effects 220
The mechanism of action of theophylline at cellular level 223
Future developments 230
Chapter 12. Prostaglandins and related compounds 238
Introduction 238
Chemistry 239
Biology 256
Structure–activity relationships 257
Conclusions 270
Section 3: Inhibitors of mediator release 274
Chapter 13. Disodium cromoglycate and compounds with similar 274
Introduction 274
Mechanism of action of disodium cromoglycate 275
Pharmacokinetics and clinical effectiveness of DSCG 280
Biological test systems for drugs of the DSCG type 281
Compounds with activities similar to DSCG in biological test systems 284
Structural rationalization of DSCG-like compounds 299
Conclusions and possible future developments 300
Chapter 14. Corticosteroids 310
Introduction 310
Systemic steroids 311
Inhalational steroids and topical activity 312
Mechanisms of action 315
The future 322
Chapter 15. Non-steroidal inhibitors of arachidonic acid metabolism 328
Introduction 328
Inhibition of phospholipase A 330
Inhibition of the cyclo-oxygenase pathway 331
Oxygen radicals 342
Inhibitors of the lipoxygenase pathway 344
Future developments 354
Section 4: Specific hyposensitization 362
Chapter 16. Specific hyposensitization 362
Introduction 362
Immunological and mechanistic considerations 364
Clinical studies 369
Development in conventional hyposensitization treatments 379
Newer approaches to hyposensitization therapy 385
Summary 392
Index 404