Development of Anti-asthma Drugs

Transcription

1 Development of Anti-asthma Drugs Derek R. Buckle, BSc, PhD, ARCS, DIC, cchem, FRSC Manager, Anti-allergy Project Harry Smith, BSc, DSc Manager, Anti-asthma Project Beecham Pharmaceuticals Research Division Biosciences Research Centre Epsom, Surrey UNIVERStTATS BIBLIOpJEK \ Butterworths London Boston Durban Singapore Sydney Toronto Wellington

2 Contents Introduction D.R. Buckle and H. Smith 1 Part 1 Asthma the nature of the disease 1 Asthma the nature of the disease Maurice H. Lessof Definition what is asthma? 9 Natural history 13 Epidemiology 18 Pathological mechanisms 20 Part 2 Mediators 2 Histamine John C. Foreman 29 Introduction 29 Histamine release 31 Actions of histamine 47 Concluding remarks 49 3 Leukotrienes PriscillaJ. Piper 55 Introduction 55 Structure, formation and metabolism 56 Biological activities of the leukotrienes 60 Conclusions 68 4 Platelet-activating factor J.M. Lynch, G.S. Worthen and P.M. Henson 73 Introduction 73 Historical overview of platelet-activating factor Structure and metabolism of PAF PAF production in inflammation PAF-induced platelet stimulation Other inflammatory effects of PAF 79 Physiology 80

3 x Contents Effects on smooth muscle 80 Effects of vascular permeability 81 Pharmacological modulation 82 Conclusion 83 5 Eosinophils and neutrophils A. Barry Kay 89 Introduction 89 General properties of eosinophils and neutrophils 89 Allergy and the eosinophil 96 Allergy and the neutrophil 99 Inflammatory cells and the progression of asthma 99 Corticosteroids, eosinophils and neutrophils 102 Summary Acetylcholine Laurie J. Smith 107 Introduction 107 Acetylcholine as a neurotransmitter 107 The cholinergic nervous system in asthma 110 Summary 116 Part 3 Pharmacological approaches Section 1 Competitive antagonists Hi antihistamines Noemi Eiser 121 Introduction 121 Effects of Hx-receptor antagonists when given to asthmatics by various routes 124 Conclusions SRS-A antagonists J.R. Bantick, M.C. Holroyde, T.B. Lee and P. Sheard 133 Development of FPL Biological effects of FPL Characterization of leukotriene receptors 144 Other antagonists of SRS-A 146 Clinical evaluation of SRS-A antagonists Prospects Anti-cholinergic drugs Gary E. Pakes 159 The history of anti-cholinergic drugs in asthma 160 Mode and site of action 161 Atropine sulphate and methonitrate 162 Thiazinamium 167 Deptropine 167 Ipratropium bromide 168 Oxitropium bromide 175 Conclusions 177

4 Contents xi Section 2 Functional antagonists Drugs acting at adrenoceptors Ian F. Skidmore 185 Introduction 185 The development of ^-adrenoceptor stimulants 185 Receptor classification: the pharmacological basis for selectivity of action 190 The biochemical basis of pharmacological activity: receptorligand interaction and activation of adenylate cyclase 191 The biochemical basis of pharmacological activity: consequences of elevating cyclic AMP 194 Clinical activity of drugs acting at /^-receptors 196 a Antagonists in the treatment of asthma Theophylline Michael Cushley and Stephen T. Holgate 205 Introduction 205 Serum levels and clinical effects 207 The mechanism of action of theophylline at cellular level 210 Future developments Prostaglandins and related compounds Jehan Bagli 225 Introduction 225 Chemistry 226 Biology 243 Structure-activity relationships 244 Conclusions 257 Section 3 Inhibitors of mediator release Disodium cromoglycate and compounds with similar activities Derek R. Buckle 261 '. Introduction 261 Mechanism of action of disodium cromoglycate 262 Pharmacokinetics and clinical effectiveness of DSCG 267 Biological test systems for drugs of the DSCG type 268 Compounds with activities similar to DSCG in biological test systems 271 Structural rationalization of DSCG-like compounds 286 Conclusions and possible future developments Corticosteroids Stuart M. Harding 297 Introduction 297 Systemic steroids 298 Inhalational steroids and topical activity 299 Mechanisms of action 302 The future 309

5 xii Contents 15 Non-steroidal inhibitors of arachidonic acid metabolism T. Y. Shen anda.n. Tischler 315 Introduction 315 Phospholipase A 2 inhibitors 317 Inhibition of the cyclo-oxygenase pathway 318 Oxygen radicals 329 Inhibitors of the lipoxygenase pathway 331 Future developments 341 Section 4 Specific hyposensitization Specific hyposensitization David M. Moran and Alan W. Wheeler 349 Introduction 349 Immunological and mechanistic considerations 351 Clinical studies 356 Development in conventional hyposensitization treatments 366 Newer approaches to hyposensitization therapy 372 Summary 379 Index 391