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THERAPEUTIC STRATEGIES IN COPD

THERAPEUTIC STRATEGIES IN COPD

Edited by

Mario Cazzola, Bartolome Celli, Ronald Dahl and Stephen Rennard

CLINICAL PUBLISHING OXFORD

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Atlas Medical Publishing Ltd 2005

First published 2005 This edition published in the Taylor & Francis e-Library, 2005.

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ISBN 0-203-02470-2 Master e-book ISBN

ISBN 1 904392 42 3 (Print Edition)

The publisher makes no representation, express or implied, that the dosages in this book are correct. Readers must therefore always check the product information and clinical procedures with the most up-to-date published product information and data sheets provided by the manufacturers and the most recent codes of conduct and safety regulations. The authors and the publisher do not accept any liability for any errors in the text or for the misuse or misapplication of material in this

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Project manager: Gavin Smith

Cover image provided by Dr Adam T.Hill, University of Edinburgh, Scotland

Contents

Contributors vii

1. COPD: molecular and cellular mechanisms P.J.Barnes

1

2. Pathophysiology of airflow limitation in COPD S.Khirani , G.Polese , G.Morlini , A.Rossi 34

3. Beta-adrenoceptor agonists: basic pharmacology L.B.Fernandes , P.J.Henry , R.G.Goldie 62

4. Beta-adrenoceptor agonists: clinical use M.Cazzola , M.G.Matera 78

5. Anticholinergics: basic pharmacology M.G.Belvisi , H.J.Patel 98

6. The clinical use of anticholinergics B.R.Celli 116

7. Pharmacology of phosphodiesterase inhibitors V.Boswell-Smith , C.P.Page 133

8. Phosphodiesterase 4 inhibitors: a new class of agents for the treatment of chronic obstructive pulmonary disease K.F.Rabe

151

9. Combination therapy with bronchodilators S.I.Rennard 171

10. Corticosteroids: basic pharmacology G.Caramori , I.M.Adcock 188

11. Corticosteroids: clinical use P.M.A.Calverley 210

12. The pharmacology of combination therapy with long-acting -adrenoceptor agonists and glucocorticoids in COPD J.Ltvall , A.Lindn

229

13. The role of inhaled combination therapy with corticosteroids and long-acting 2-agonists in the management of COPD R.Dahl , M.Cazzola

246

14. Antioxidants and COPD W.MacNee 269

15. Antiprotease therapy T.D.Tetley 289

16. Mucoactive drugs L.Allegra 306

Abbreviations 346

Index 349

Contributors

IAN MICHAEL ADCOCK, PhD, Professor of Respiratory Cell and Molecular Biology, Airways Disease Section, National Heart & Lung Institute, Imperial College London, London, UK

LUIGI ALLEGRA, MD, Professor, Respiratory Diseases, University of Milan, Director, Cardiorespiratory Department, IRCCS, Policlinico Hospital, Milan, Italy

PETER J.BARNES, FMedSci, Professor of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK

MARIA G.BELVISI, BSc, PhD, Professor of Respiratory Pharmacology, Respiratory Pharmacology Group, Airway Disease Section, National Heart & Lung Institute, Imperial College School of Medicine, London, UK

VICTORIA BOSWELL-SMITH, BSc, Sackler Institute of Pulmonary Pharmacology, Guys, Kings and St Thomas School of Biomedical Sciences, Kings College London, London, UK

PETER M.A.CALVERLEY, MB ChB, FRCP, FRCPE, Professor of Medicine (Pulmonary & Rehabilitation), Clinical Sciences Centre, University Hospital Aintree, Liverpool, UK

GAETANO CARAMORI, MD, PhD, Centro di Ricerca su Asma e BPCO, Universit di Ferrara, Ferrara, Italy

MARIO CAZZOLA, MD, Consultant in Respiratory Medicine, Chief of Respiratory Medicine, Unit of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital, Naples, Italy

BARTOLOME R.CELLI, MD, Professor of Medicine, Tufts University, Chief, Pulmonary and Critical Care Medicine, Caritas St Elizabeths Medical Center, Boston, MA, USA

RONALD DAHL, MD, Dr.med.sci. Professor of Respiratory Medicine, Department of Respiratory Diseases, Aarhus University Hospital, Aarhus, Denmark

LYNETTE B.FERNANDES, BSc, PhD, Lecturer in Pharmacology, Western Australian Institute for Medical Research, Pharmacology Unit, School of Medicine & Pharmacology, The University of Western Australia, Australia

ROY G.GOLDIE, BSc, PhD, Executive Dean, Faculty of Health Sciences, Western Australian Institute for Medical Research, Pharmacology Unit, School of Medicine & Pharmacology, The University of Western Australia, Australia

PETER J.HENRY, BSc, PhD, Senior Lecturer in Pharmacology, Western Australian Institute for Medical Research, Pharmacology Unit, School of Medicine & Pharmacology, The University of Western Australia, Australia

SONIA KHIRANI, PhD, Doctor in Biomedical Engineering, Ospedale Riuniti di Bergamo, Bergamo, Italy

ANDERS LINDN, MD, PhD, Associate Professor, Certified Specialist in Respiratory Medicine and Allergology, Lung Pharmacology Group, Department of Respiratory Medicine and Allergology, Gteborg, Sweden

JAN LTVALL, MD, PhD, Professor of Allergy, Head of Department, Department of Respiratory Medicine and Allergology, Gteborg University, Gteborg, Sweden

WILLIAM MACNEE, MBChB, MD(Hons), FRCP (Glas), FRCP (Edin), Professor of Respiratory and Environmental Medicine, ELEGI Colt Laboratory, MRC Centre for Inflammation Research, University of Edinburgh Medical School, Edinburgh, UK

MARIA GABRIELLA MATERA, MD, PhD, Researcher in Pharmacology and Consultant in Clinical Pharmacology, Unit of Pharmacology, Department of Experimental Medicine, School of Medicine, Second University, Naples, Italy

GIACOMO MORLINI, RRT, Respiratory Therapist, Ospedale Riuniti di Bergamo, Bergamo, Italy

CLIVE PETER PAGE, BSc, PhD, Professor of Pharmacology, Sackler Institute of Pulmonary Pharmacology, Guys, Kings and St Thomas School of Biomedical Sciences, Kings College London, London, UK

HEMA J.PATEL, BSc, PhD, Respiratory Pharmacology Group, Airway Disease Section, Imperial College School of Medicine at the National Heart & Lung Institute, London, UK

GUIDO POLESE, MD, Pulmonary Division, Ospedale Riuniti di Bergamo, Bergamo, Italy

KLAUS F.RABE, MD, PhD, Leiden University Medical Centre, Leiden, The Netherlands

STEPHEN I.RENNARD, MD, Larson Professor of Medicine, University of Nebraska Medical Center, Omaha, Nebraska, USA

ANDREA Rossi, MD, Director, Pulmonary Division, Ospedale Riuniti di Bergamo, Bergamo, Italy

TERESA D.TETLEY, BSc, PhD, Reader in Lung Cell Biology, National Heart & Lung Institute, Imperial College, London, UK

1 COPD: molecular and cellular mechanisms

P.J.Barnes

INTRODUCTION

COPD is a major and increasing global health problem, which is currently the 4th commonest cause of death and predicted to become the the 5th commonest cause of disability in the world by 2020. While there have been major advances in the understanding and management of asthma, COPD has been relatively neglected and there are no current therapies that reduce the inevitable progression of this disease. However, because of the enormous burden of disease and escalating health care costs, there is now renewed interest in the underlying cellular and molecular mechanisms [1] and a search for new therapies [2], resulting in a re-evaluation of this disease [3].

COPD is characterised by slowly progressive development of airflow limitation that is poorly reversible, in sharp contrast to asthma where there is variable airflow obstruction that is usually reversible spontaneously or with treatment. The definition of COPD adopted by the Global Initiative on Obstructive Lung Disease (GOLD) for the first time encompasses the idea that COPD is a chronic inflammatory disease and much of the recent research has focused on the nature of this inflammatory response [4].

COPD includes chronic obstructive bronchiolitis with fibrosis and obstruction of small airways, and emphysema with enlargement of airspaces and destruction of lung parenchyma, loss of lung elasticity and closure of small airways. Chronic bronchitis, by contrast, is defined by a productive cough of more than 3 months duration for more than 2 successive years; this reflects mucus h