ADVANCES IN COMBINATION THERAPY FOR ASTHMA AND COPD Editor Jan Lotvall Krefting Research Centre, University of Gothenburg, Sweden A Wiley Sons, Ltd., Publication
Contents Contributors xi Preface 1 Similarities and differences in the pathophysiology of asthma and COPD J. Christian Virchow 1.1 Introduction 1 1.2 Pulmonary function abnormalities in asthma and COPD 3 Risk factors for asthma and COPD 5 Cellular inflammation in asthma and COPD 8 Distribution and consequences of inflammation in asthma and COPD 9 1.6 Patterns of epithelial injury in asthma and COPD 10 1.7 Airway hyperresponsiveness 10 Beta-receptor blockers 1 Differential diagnosis of asthma and COPD 1.10 Overlap syndrome 12 1.11 Conclusion 12 2 Glucocorticoids: pharmacology and mechanisms 16 Peter Barnes 2.1 Introduction 2.2 Chemical structures 2.3 The molecular basis of inflammation 17 2.4 Cellular effects of glucocorticoids 2.5 Glucocorticoid receptors 20 2.6 Glucocorticoid activation of gene transcription 22 2.7 Suppression of inflammatory genes 23 2.8 Steroid resistance 29 2.9 Interaction with receptors 32 2.10 Conclusions 33 33 3 Inhaled corticosteroids: clinical effects in asthma and COPD 38 Paul O'Byrne and Desmond Murphy 3.1 Introduction 3.2 Anti-inflammatory activity of corticosteroids 38 3.3 Routes of administration 39
vi CONTENTS 3.4 Absorption and fate of corticosteroids 41 3.5 Currently available inhaled corticosteroids 41 3.6 Efficacy in asthma 43 3.7 Efficacy in COPD 44 3.8 Side effects of 46 3.9 Conclusions 49 49 4 LABAs: mechanisms and interaction with anti-inflammatory treatments 53 Gary P. Anderson 4.1 Galenical forms of LABAs: formulations, isomers, and salts 55 4.2 Absolute and functional selectivity 56 4.3 Cellular organization of receptor clusters: functional structure of the and mode of signalling 58 4.4 and oligomers: homo- and heterodimerism/oligoism 60 4.5 of the and adenylate cyclase polymorphism in relation to LABAs 61 4.6 Understanding the 'reassertion' paradox, 'exosites' and relative speed of onset: the membrane diffusion microkinetic model of LABA action 61 4.7 Regulation and desensitization 63 4.8 Full versus partial (pharmacological efficacy) 64 4.9 Beta-blockers not LABAs? 67 4.10 Non-receptor-mediated effects? 68 Biochemical basis of functional antagonism and its critical role in LABA action in disease and exacerbations 68 Molecular cooperativity between LABAs and steroids 69 Perspective 73 5 Long- and ultra-long-acting 81 Mario Cazzola and Maria Matera 5.1 Introduction 81 5.2 Long-acting 82 5.3 Novel ultra-long-acting 86 5.4 Conclusion 95 95 6 The safety of long-acting beta-agonists and the development of combination therapies for asthma and COPD Victor E. Ortega and Eugene Bleecker 6.1 Introduction 102 6.2 Asthma-related mortality and beta-agonist exposure 6.3 Long-acting beta-agonists and increased asthma-related mortality 6.4 Safety and efficacy of LABA therapy in asthma: retrospective analyses
CONTENTS vii 6.5 Efficacy of LABA therapy as a component of combination therapy with 1CS for the management of asthma 6.6 Scientific basis of the beneficial and adverse effects of beta-agonist therapy: in vitro data and the beta-agonist paradox 6.7 Conclusions regarding the safety of LABA therapy as a component of combination therapy with for the management of asthma 6.8 Beta-agonist therapy and adverse events in COPD 6.9 Safety and efficacy of LABA therapy in the management of COPD: the clinical evidence 116 Role of LABA therapy as a component of combination therapy with for the management of COPD 7 Conclusions regarding the safety of LABA therapy as a component of combination therapy for the management of COPD 6.12 Pharmacogenetics of LABAs and combination therapy 120 Safety and efficacy of LABA therapy and the development of combination therapies for the management of asthma and COPD 6.14 Summary and future directions 127 Acknowledgement 128 128 7 Inhaled combination therapy with glucocorticoids and long-acting in asthma and COPD, current and future perspectives Jan Lotvall 7.1 Pharmacological management guidelines of asthma and COPD 7.2 Steroid treatment in asthma 136 7.3 Effects of adding LABA to inhaled glucocorticoids in asthma 137 7.4 Steroid treatment in COPD 140 7.5 Effects of LABAs in COPD 7.6 Combination inhalers versus two separate inhalers for inhaled 141 7.7 Regular treatment alone versus additional combinations as reliever therapy 7.8 Currently available combination inhalers 145 7.9 Upcoming and alternative combinations of inhaled GCS and LABAs Future of combined inhalation therapy in respiratory disease 8 Novel anti-inflammatory treatments for asthma and COPD Paul A. Caetano K. Fan Chung and M. Adcock 8.1 Introduction 154 8.2 Current asthma and COPD therapies 158 8.3 The need for new therapies 8.4 Improving current therapies 162 8.5 Targeting and their receptors in asthma and COPD 8.6 Targeting and proinflammatory cytokines in asthma COPD 169
CONTENTS 8.7 Targeting adhesion molecules in asthma and COPD 8.8 Growth factor blockers in asthma and COPD 8.9 Mucous cells, submucosal glands and mucus production in asthma COPD 173 Infections in asthma and COPD 1 74 8.11 Intracellular signalling pathways 8.12 Inhibition of transcription factors in asthma and COPD 8.13 Antioxidants in asthma and COPD 181 8.14 and anti-allergy treatments in asthma and COPD 8.15 Conclusions 185 Acknowledgements 186 9 Novel biologicals alone and in combination in asthma and allergy 203 M. Nyenhuis and William W. Busse 9.1 Introduction 203 9.2 Targets of therapy 204 9.3 204 9.4 207 9.5 211 9.6 Tumor necrosis 212 9.7 Immunoglobulin E 215 9.8 vaccines 220 9.9 Future directions 222 9.10 Conclusion 224 225 10 Anti-infective treatments in asthma and COPD 232 Jonathan D.R. and Sebastian L Johnston 10.1 232 10.2 Current guidelines 234 Acute exacerbations of asthma 236 Increased susceptibility to infection in asthmatics 236 Role of atypical bacteria in asthma 237 Role of viruses in asthma exacerbations 244 10.7 Anti-infectives in COPD exacerbations 250 Use of antibiotics in stable COPD 256 10.9 Role of vaccination 257 10.10 Conclusion 259 260 Long-acting muscarinic antagonists in asthma and COPD 268 M. Diane Lougheed, Josuel Ora and Denis E. Introduction 268 Innervation of the airways 268
CONTENTS 11.3 Cholinergic mechanisms in asthma and COPD 270 Role of long-acting anticholinergic bronchodilators in obstructive lung disease 271 11.5 Summary 287 288 Phosphodiesterase inhibitors in obstructive lung disease 296 Jan and Bo Lundback 12.1 Introduction 296 12.2 Phosphodiesterase enzymes 297 12.3 Different pharmacological agents blocking PDE4 298 Biological effects of PDE4 inhibition, preclinical information 300 12.5 Clinical effects of PDE4 inhibition in COPD 302 12.6 Effects of PDE4 inhibitors on systemic processes in COPD 304 12.7 Side effects of inhibitors 304 PDE4 inhibitors in COPD management plans 305 Future prospects with PDE4 inhibitors in obstructive airways disease 305 12.10 Summary 306 306 Biological therapies in development for COPD /. Morjaria and R. Polosa 13.1 Introduction Inflammatory cells involved in the pathogenesis of COPD 13.3 Cytokines and in COPD 315 Development of biological agents in COPD 320 13.5 Conclusions 323 323 therapy' in the management of COPD: inhaled steroid, long-acting anticholinergic and long-acting 333 Ronald 14.1 Introduction 333 14.2 Long-acting inhaled anticholinergic (LAMA) and (LABA) bronchodilators 333 14.3 Treatment strategies for COPD 334 14.4 Inhaled corticosteroids and COPD 334 Combination treatment with ICS, LAMA and LABA: 'triple therapy' 335 14.6 Extracted data from TORCH and UPLIFT studies 337 14.7 Conclusions 340 341 343