Advances in Combination Therapy for Asthma and COPD

Preface xiii

1 Similarities and differences in the pathophysiology of asthma and COPD 1
J. Christian Virchow

1.1 Introduction 1

1.2 Pulmonary function abnormalities in asthma and COPD 3

1.3 Risk factors for asthma and COPD 5

1.4 Cellular inflammation in asthma and COPD 8

1.5 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

1.8 Beta-receptor blockers 10

1.9 Differential diagnosis of asthma and COPD 11

1.10 Overlap syndrome 12

1.11 Conclusion 12

References 13

2 Glucocorticoids: pharmacology and mechanisms 16
Peter J. Barnes

2.1 Introduction 16

2.2 Chemical structures 16

2.3 The molecular basis of inflammation 17

2.4 Cellular effects of glucocorticoids 19

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 2-adrenergic receptors 32

2.10 Conclusions 33

References 33

3 Inhaled corticosteroids: clinical effects in asthma and COPD 38
Paul M. O'Byrne and Desmond M. Murphy

3.1 Introduction 38

3.2 Anti-inflammatory activity of corticosteroids 38

3.3 Routes of administration 39

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 ICS 46

3.9 Conclusions 49

References 49

4 LABAs: pharmacology, mechanisms and interaction with anti-inflammatory treatments 53
Gary P. Anderson

4.1 Galenical forms of LABAs: formulations, isomers, enantiomers, diasteriomers and salts 55

4.2 Absolute and functional 2-adrenoceptor selectivity 56

4.3 Cellular organization of receptor clusters: functional structure of the 2-adrenoceptor and mode of signalling 58

4.4 Dimers and oligomers: homo- and heterodimerism/oligoism 60

4.5 Pharmacogenomics of the 2-adrenoceptor 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 agonism (pharmacological efficacy) 64

4.9 Beta-blockers not LABAs? 67

4.10 Non-receptor-mediated effects? 68

4.11 Biochemical basis of functional antagonism and its critical role in LABA action in disease and exacerbations 68

4.12 Molecular cooperativity between LABAs and steroids 69

4.13 Perspective 73

References 73

5 Long- and ultra-long-acting 2-agonists 81
Mario Cazzola and Maria Gabriella Matera

5.1 Introduction 81

5.2 Long-acting 2-agonists 82

5.3 Novel ultra-long-acting 2-agonists 86

5.4 Conclusion 95

References 95

6 The safety of long-acting beta-agonists and the development of combination therapies for asthma and COPD 102
Victor E. Ortega and Eugene R. Bleecker

6.1 Introduction 102

6.2 Asthma-related mortality and beta-agonist exposure 103

6.3 Long-acting beta-agonists and increased asthma-related mortality 105

6.4 Safety and efficacy of LABA therapy in asthma: retrospective analyses 107

6.5 Efficacy of LABA therapy as a component of combination therapy with ICS for the management of asthma 110

6.6 Scientific basis of the beneficial and adverse effects of beta-agonist therapy: in vitro data and the beta-agonist paradox 113

6.7 Conclusions regarding the safety of LABA therapy as a component of combination therapy with ICS for the management of asthma 114

6.8 Beta-agonist therapy and adverse events in COPD 115

6.9 Safety and efficacy of LABA therapy in the management of COPD: the clinical evidence 116

6.10 Role of LABA therapy as a component of combination therapy with ICS for the management of COPD 117

6.11 Conclusions regarding the safety of LABA therapy as a component of combination therapy for the management of COPD 120

6.12 Pharmacogenetics of LABAs and combination therapy 120

6.13 Safety and efficacy of LABA therapy and the development of combination therapies for the management of asthma and COPD 126

6.14 Summary and future directions 127

Acknowledgement 128

References 128

7 Inhaled combination therapy with glucocorticoids and long-acting 2-agonists in asthma and COPD, current and future perspectives 135
Jan Lötvall

7.1 Pharmacological management guidelines of asthma and COPD 135

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 140

7.6 Combination inhalers versus two separate inhalers for inhaled GCS and LABAs 141

7.7 Regular treatment alone versus additional formoterol-containing combinations as reliever therapy 143

7.8 Currently available combination inhalers 145

7.9 Upcoming and alternative combinations of inhaled GCS and LABAs 146

7.10 Future of combined inhalation therapy in respiratory disease 148

References 149

8 Novel anti-inflammatory treatments for asthma and COPD 154
Paul A. Kirkham, Gaetano Caramori, K. Fan Chung and Ian M. Adcock

8.1 Introduction 154

8.2 Current asthma and COPD therapies 158

8.3 The need for new therapies 160

8.4 Improving current therapies 162

8.5 Targeting chemokines and their receptors in asthma and COPD 166

8.6 Targeting T-cell-derived and proinflammatory cytokines in asthma and COPD 169

8.7 Targeting adhesion molecules in asthma and COPD 172

8.8 Growth factor blockers in asthma and COPD 173

8.9 Mucous cells, submucosal glands and mucus production in asthma and COPD 173

8.10 Infections in asthma and COPD 174

8.11 Intracellular signalling pathways 175

8.12 Inhibition of transcription factors in asthma and COPD 178

8.13 Antioxidants in asthma and COPD 181

8.14 Immunomodulation and anti-allergy treatments in asthma and COPD 182

8.15 Conclusions 185

Acknowledgements 186

References 186

9 Novel biologicals alone and in combination in asthma and allergy 203
Sharmilee M. Nyenhuis and William W. Busse

9.1 Introduction 203

9.2 Targets of therapy 204

9.3 Interleukin-4 204

9.4 Interleukin-5 207

9.5 Interleukin-13 211

9.6 Tumor necrosis factor-212

9.7 Immunoglobulin E 215

9.8 DNA vaccines 220

9.9 Future directions 222

9.10 Conclusion 224

References 225

10 Anti-infective treatments in asthma and COPD 232
Jonathan D.R. Macintyre and Sebastian L. Johnston

10.1 Introduction 232

10.2 Current guidelines 234

10.3 Acute exacerbations of asthma 236

10.4 Increased susceptibility to infection in asthmatics 236

10.5 Role of atypical bacteria in asthma 237

10.6 Role of viruses in asthma exacerbations 244

10.7 Anti-infectives in COPD exacerbations 250

10.8 Use of antibiotics in stable COPD 256

10.9 Role of vaccination 257

10.10 Conclusion 259

References 260

11 Long-acting muscarinic antagonists in asthma and COPD 268
M. Diane Lougheed, Josuel Ora and Denis E. O'Donnell

11.1 Introduction 268

11.2 Innervation of the airways 268

11.3 Cholinergic mechanisms in asthma and COPD 270

11.4 Role of long-acting anticholinergic bronchodilators in obstructive lung disease 271

11.5 Summary 287

References 288

12 Phosphodiesterase inhibitors in obstructive lung disease 296
Jan Lötvall and Bo Lundbä ck

12.1 Introduction 296

12.2 Phosphodiesterase enzymes 297

12.3 Different pharmacological agents blocking PDE4 298

12.4 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 PDE4 inhibitors 304

12.8 PDE4 inhibitors in COPD management plans 305

12.9 Future prospects with PDE4 inhibitors in obstructive airways disease 305

12.10 Summary 306

References 306

13 Biological therapies in development for COPD 311
J. Morjaria and R. Polosa

13.1 Introduction 311

13.2 Inflammatory cells involved in the pathogenesis of COPD 312

13.3 Cytokines and chemokines in COPD 315

13.4 Development of biological agents in COPD 320

13.5 Conclusions 323

References 323

14 'Triple therapy' in the management of COPD: inhaled steroid, long-acting anticholinergic and long-acting 2-agonist 333
Ronald Dahl

14.1 Introduction 333

14.2 Long-acting inhaled anticholinergic (LAMA) and 2-agonist (LABA) bronchodilators 333

14.3 Treatment strategies for COPD 334

14.4 Inhaled corticosteroids and COPD 334

14.5 Combination treatment with ICS, LAMA and LABA: 'triple therapy' 335

14.6 Extracted data from TORCH and UPLIFT studies 337

14.7 Conclusions 340

References 341

Index 343