AND COPD ADVANCES IN COMBINATION THERAPY FOR ASTHMA. Jan Lotvall. Editor. Krefting Research Centre, University of Gothenburg,

Transcription

1 ADVANCES IN COMBINATION THERAPY FOR ASTHMA AND COPD Editor Jan Lotvall Krefting Research Centre, University of Gothenburg, Sweden A Wiley Sons, Ltd., Publication

2 Contents Contributors xi Preface 1 Similarities and differences in the pathophysiology of asthma and COPD J. Christian Virchow 1.1 Introduction 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 Patterns of epithelial injury in asthma and COPD Airway hyperresponsiveness 10 Beta-receptor blockers 1 Differential diagnosis of asthma and COPD 1.10 Overlap syndrome Conclusion 12 2 Glucocorticoids: pharmacology and mechanisms 16 Peter Barnes 2.1 Introduction 2.2 Chemical structures 2.3 The molecular basis of inflammation Cellular effects of glucocorticoids 2.5 Glucocorticoid receptors Glucocorticoid activation of gene transcription Suppression of inflammatory genes Steroid resistance Interaction with receptors Conclusions 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 Routes of administration 39

3 vi CONTENTS 3.4 Absorption and fate of corticosteroids Currently available inhaled corticosteroids Efficacy in asthma Efficacy in COPD Side effects of Conclusions LABAs: mechanisms and interaction with anti-inflammatory treatments 53 Gary P. Anderson 4.1 Galenical forms of LABAs: formulations, isomers, and salts Absolute and functional selectivity Cellular organization of receptor clusters: functional structure of the and mode of signalling and oligomers: homo- and heterodimerism/oligoism of the and adenylate cyclase polymorphism in relation to LABAs Understanding the 'reassertion' paradox, 'exosites' and relative speed of onset: the membrane diffusion microkinetic model of LABA action Regulation and desensitization Full versus partial (pharmacological efficacy) Beta-blockers not LABAs? 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 Long-acting Novel ultra-long-acting Conclusion 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 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

4 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 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 Effects of adding LABA to inhaled glucocorticoids in asthma Steroid treatment in COPD Effects of LABAs in COPD 7.6 Combination inhalers versus two separate inhalers for inhaled Regular treatment alone versus additional combinations as reliever therapy 7.8 Currently available combination inhalers 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 Current asthma and COPD therapies The need for new therapies 8.4 Improving current therapies Targeting and their receptors in asthma and COPD 8.6 Targeting and proinflammatory cytokines in asthma COPD 169

5 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 Intracellular signalling pathways 8.12 Inhibition of transcription factors in asthma and COPD 8.13 Antioxidants in asthma and COPD and anti-allergy treatments in asthma and COPD 8.15 Conclusions 185 Acknowledgements Novel biologicals alone and in combination in asthma and allergy 203 M. Nyenhuis and William W. Busse 9.1 Introduction Targets of therapy Tumor necrosis Immunoglobulin E vaccines Future directions Conclusion Anti-infective treatments in asthma and COPD 232 Jonathan D.R. and Sebastian L Johnston 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 Anti-infectives in COPD exacerbations 250 Use of antibiotics in stable COPD Role of vaccination Conclusion Long-acting muscarinic antagonists in asthma and COPD 268 M. Diane Lougheed, Josuel Ora and Denis E. Introduction 268 Innervation of the airways 268

6 CONTENTS 11.3 Cholinergic mechanisms in asthma and COPD 270 Role of long-acting anticholinergic bronchodilators in obstructive lung disease Summary Phosphodiesterase inhibitors in obstructive lung disease 296 Jan and Bo Lundback 12.1 Introduction Phosphodiesterase enzymes Different pharmacological agents blocking PDE4 298 Biological effects of PDE4 inhibition, preclinical information Clinical effects of PDE4 inhibition in COPD Effects of PDE4 inhibitors on systemic processes in COPD Side effects of inhibitors 304 PDE4 inhibitors in COPD management plans 305 Future prospects with PDE4 inhibitors in obstructive airways disease Summary 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 Conclusions therapy' in the management of COPD: inhaled steroid, long-acting anticholinergic and long-acting 333 Ronald 14.1 Introduction Long-acting inhaled anticholinergic (LAMA) and (LABA) bronchodilators Treatment strategies for COPD Inhaled corticosteroids and COPD 334 Combination treatment with ICS, LAMA and LABA: 'triple therapy' Extracted data from TORCH and UPLIFT studies Conclusions