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New Drugs for Asthma Allergy and Copd Progress in
Respiratory Research 1st Edition T. T. Hansel (Editor)
Digital Instant Download
Author(s): T. T. Hansel (Editor), Peter J. Barnes (Editor)
ISBN(s): 9783805568623, 0585441529
Edition: 1
File Details: PDF, 7.20 MB
Year: 2001
Language: english
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

New Drugs for Asthma, Allergy and COPD

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Progress in
Respiratory Research
Vol. 31

Series Editor Chris T. Bolliger, Cape Town

Basel W Freiburg W Paris W London W New York W

ABC New Delhi W Bangkok W Singapore W Tokyo W Sydney
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

New Drugs for Asthma,

Allergy and COPD

Volume Editors Trevor T. Hansel, London

Peter J. Barnes, London

195 colour figures and 72 tables, 2001

Basel W Freiburg W Paris W London W New York W

ABC New Delhi W Bangkok W Singapore W Tokyo W Sydney
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Trevor T. Hansel Peter J. Barnes

Clinical Studies Unit Department of Thoracic Medicine
National Heart and Lung Institute National Heart and Lung Institute
Imperial College Imperial College
London (UK) London (UK)

Library of Congress Cataloging-in-Publication Data

New drugs for asthma, allergy and COPD / volume editors, Trevor T. Hansel, Peter J. Barnes.
p. ; cm. – (Progress in respiratory research, ISSN 1422–2140 ; vol. 31)
Includes bibliographical references and indexes.
ISBN 3805568622 (alk paper : hard cover)
1. Respiratory agents. 2. Antiasthmatic agents. 3. Lungs – Diseases, Obstructive – Chemotherapy.
I. Hansel, T.T. (Trevor T.), 1956- II. Barnes, Peter J., 1946- III. Series.
[DNLM: 1. Asthma – drug therapy. 2. Anti-Asthmatic Agents – therapeutic use. 3. Hypersensitivity – drug therapy.
4. Lung Diseases, obstructive – drug therapy. WF 553 N5321 2001]
RM388.N49 2001
615).72–dc21 00-050644

Bibliographic Indices. This publication is listed in bibliographic All rights reserved. No part of this publication may be translated
services, including Current Contents® and Index Medicus. into other languages, reproduced or utilized in any form or by any
means, electronic or mechanical, including photocopying, recording,
Drug Dosage. The authors and the publisher have exerted every microcopying, or by any information storage and retrieval system,
effort to ensure that drug selection and dosage set forth in this text are without permission in writing from the publisher.
in accord with current recommendations and practice at the time of
publication. However, in view of ongoing research, changes in govern- © Copyright 2001 by S. Karger AG,
ment regulations, and the constant flow of information relating to drug P.O. Box, CH–4009 Basel (Switzerland)
therapy and drug reactions, the reader is urged to check the package www.karger.com
insert for each drug for any change in indications and dosage and for Printed in Switzerland on acid-free paper by
added warnings and precautions. This is particularly important when Reinhardt Druck, Basel
the recommended agent is a new and/or infrequently employed drug. ISBN 3–8055–6862–2, ISSN 1422–2140
 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Contents

VIII Foreword 64 Single-Isomer ß-Agonists

Handley, D.A. (Sepracor, Marlborough, Mass.); Morley, J.
IX Preface
(Haldane Research, Huntingdon); Nelson, H.S. (National Jewish
Medical and Research Center, Denver, Colo.)
General Aspects 68 Dual D2 Dopamine Receptor and ß2-Adrenoceptor
Agonists for the Modulation of Sensory Nerves in
2 The Need for New Therapy
COPD
Barnes, P.J.; Hansel, T.T. (NHLI, Imperial College, London)
Newbold, P.; Jackson, D.M.; Young, A.; Dougall, I.G.;
6 Current Therapy for Asthma Ince, F.; Rocchiccioli, K.M.S.; Holt, P.R. (AstraZeneca,
Barnes, P.J. (NHLI, Imperial College, London) Loughborough)

11 Current Therapy for COPD 72 Anticholinergics: Tiotropium

Pauwels, R. (Ghent University Hospital, Ghent) Disse, B.; Witek, T.J., Jr. (Boehringer Ingelheim, Ingelheim and
Ridgefield, Conn.)
15 Pharmacogenetics
Hall, I.P. (University Hospital, Nottingham); Hansel, T.T. 77 Potassium Channel Openers
(NHLI, Imperial College, London) Agents for the Treatment of Airway Hyperreactivity
20 Delivery of Biologics to the Lung Fozard, J.R.; Manley, P.W. (Novartis Pharma Ltd., Basel)
Cipolla, D.; Farr, S.; Gonda, I.; Otulana, B. 81 Urodilatin
(Aradigm Corporation, Hayward, Calif.) Forssmann, K.; Meyer, M.; Forssmann, W.G. (CardioPep
24 Immunopathology: Comparison of COPD and Pharma GmbH and IPF PharmaCeuticals GmbH, Hannover)

Asthma
Jeffery, P.K. (NHLI, Imperial College, London) Steroids
30 Monitoring Lung Function 86 Steroids: An Overview
Pride, N. (NHLI, Imperial College, London) Dahl, R.; Nielsen, L.P. (University of Aarhus, Aarhus)
35 Airway Hyperresponsiveness 91 Ciclesonide: An On-Site-Activated Steroid
Sterk, P.J. (Leiden University Medical Centre, Leiden) Dietzel, K.; Engelstätter, R.; Keller, A. (Byk Gulden
39 Airways Remodelling Pharmaceuticals, Konstanz)
Holgate, S.T.; Davies, D.E. (University of Southampton, 94 Soft Steroids
Southampton) Axelsson, B.; Brattsand, R. (AstraZeneca, Lund)
44 Exhaled Breath Analysis 98 Dissociated Steroids
Kharitonov, S.A.; Barnes, P.J. (NHLI, Imperial College, London) Brown, T.J.; Belvisi, M.G.; Foster, M.L. (Aventis
48 Clinical Studies on New Drugs Pharmaceuticals, Dagenham)
Hansel, T.T.; Barnes, P.J. (NHLI, Imperial College, London) 102 Oestradiol Metabolites
Effects on Airway Remodelling
Bronchodilators Stewart, A.G.; Vlahos, R.; Fernandes, D.J.; Hughes, R.A.
(University of Melbourne, Melbourne)
54 Bronchodilators: An Overview
Anderson, G.P. (University of Melbourne, Melbourne); Leukotriene Inhibitors
Rabe, K.F. (Leiden University Center, Leiden)
60 Long-Acting ß2-Agonists 108 Leukotriene Inhibitors: An Overview
Johnson, M.; Hagan, G.W.E. (GlaxoWellcome, Uxbridge) O’Byrne, P.M. (McMaster University, Hamilton);
Drazen, J.M. (Harvard Medical School, Boston, Mass.)

V
111 Cysteinyl Leukotriene Antagonists Allergen- and IgE-Directed Therapies
McMillan, R.M. (AstraZeneca, Macclesfield)
182 Allergen, IgE and Mast-Cell-Directed Responses:
115 5-Lipoxygenase Inhibitors
An Overview
Dahlén, S.-E. (Karolinska Institutet, Stockholm)
Larché, M.; Kay, A.B. (NHLI, Imperial College, London)
121 LTB4 Antagonism
186 Allergen Immunotherapy
Jennewein, H.M.; Anderskewitz, R.; Meade, C.J.; Pairet, M.;
Birke, F. (Boehringer Ingelheim, Ingelheim) Wilson, D.R.; Durham, S.R. (NHLI, Imperial College, London)
191 Peptide Immunotherapy
Mediator Inhibitors and Agonists Oldfield, W.L.G.; Kay, A.B.; Larché, M. (NHLI, Imperial
College, London)
128 H1-Antihistamines 195 Recombinant Allergens
De Vos, C.; Rihoux, J.P. (UCB Pharma SA, Brussels) Valenta, R.; Kraft, D. (University of Vienna, Vienna)
133 Histamine H3 Antagonists 201 Anti-IgE Antibody
McLeod, R.L.; Egan, R.W.; Cuss, F.M. (Schering-Plough, Boushey, H.A. (University of California, San Francisco, Calif.);
Kenilworth, N.J.); Bolser, D.C. (University of Gainesville, Fick, R. (Genentech, Inc., S. San Francisco, Calif.);
Gainesville, Fla.).; Hey, J.A. (Schering-Plough, Fahy, J.V. (University of California, San Francisco, Calif.)
Kenilworth, N.J.)
206 CD23
137 Kinin Receptor Antagonists Conrad, D.H. (Virginia Commonwealth University, Richmond,
Meini, S.; Maggi, C.A. (Menarini Ricerche SpA, Florence) Va.)
141 Endothelin Antagonists
Hay, D.W.P.; Compton, C.H. (SmithKline Beecham T Cell Immunomodulation
Pharmaceuticals, King of Prussia, Pa., and Harlow)
145 Tachykinin Antagonists 212 T Cell Immunomodulation: An Overview
Hay, D.W.P. (SmithKline Beecham Pharmaceuticals, Koulis, A.; Robinson, D.S. (NHLI, Imperial College, London)
King of Prussia, Pa.) 217 Costimulatory Molecules in T Cell Activation
151 Antioxidants Coyle, A.J.; Gutierrez-Ramos, J.-C. (Millennium
MacNee, W. (University of Edinburgh, Edinburgh) Pharmaceuticals Inc., Cambridge, Mass.)

156 Selective iNOS Inhibitors 222 GATA-3: A Th2-Selective Target

Manning, P.T.; Thompson, J.M. (Searle, St. Louis, Mo., and Ray, A.; Ray, P. (Yale University, New Haven, Conn.)
Skokie, Ill.); Currie, M.G. (Sepracor Inc., Marlborough, Mass.) 226 Mycobacterial Immunization
160 Mucus Regulation Agents to Limit Asthma
Rogers, D.F. (NHLI, Imperial College, London) Hopkin, J.M. (University of Wales, Swansea)

165 P2Y Receptor Agonists 229 CpG Oligodeoxynucleotides

Role in Mucosal Hydration and Mucociliary Clearance Kline, J.N.; Krieg, A.M. (University of Iowa, Iowa City, Iowa,
Pendergast, W.; Evans, R. (Inspire Pharmaceuticals, Inc., and Coley Pharmaceutical Group, Wellesley, Mass.)
Durham, N.C.) 233 CD8 T Cells: Potential Therapeutic Targets?
Out, T.A. (Academic Medical Center and
Protease Inhibitors CLB Sanquin Blood Supply Foundation, Amsterdam);
de Pater-Huijsen, F.L.; Jansen, H.M. (Academic Medical
170 Tryptase Inhibition Center, Amsterdam); Corrigan, C.J. (Guy’s, King’s and
St. Thomas’ School of Medicine, London)
Clark, J.M.; Van Dyke, R.E.; Kurth, M.C. (Axys
Pharmaceuticals, Inc., S. San Francisco, Calif.) 237 Macrocyclic Immunosuppressants
173 Neutrophil Elastase Inhibitors Keller, T.H.; Hersperger, R.; Della Cioppa, G. (Novartis,
Horsham and Basel)
Smith, R.A. (GlaxoWellcome, Stevenage); Stockley, R.A.
(Queen Elizabeth Hospital, Birmingham); Hodgson, S.T.
(GlaxoWellcome, Stevenage) Cytokine-Directed Therapy
177 Macrophage Metalloelastase Inhibitors
242 Cytokines: An Overview
Martin, R.L. (Roche Bioscience, Palo Alto, Calif.); Shapiro, S.D.
(Washington University, St. Louis, Mo.); Tong, S.E.; Chung, K.F. (NHLI, Imperial College, London)
Van Wart, H.E. (Roche Bioscience, Palo Alto, Calif.) 247 TNF Antagonism
McDonnell, N.D.; Abbott, N.M.; Mohler, K.M. (Immunex Corp.,
Seattle, Wash.); Hansel, T.T. (NHLI, Imperial College, London);
Kips, J.C. (Ghent University Hospital, Ghent)

VI Contents
251 GM-CSF Antagonists Inhibition of Cell Signalling
Williams, W.V. (SmithKline Beecham, Philadelphia, Pa.)
316 Eosinophil G-Protein-Coupled Receptor Signalling:
256 Interleukin-4 Antagonism
An Overview
Borish, L. (University of Virginia, Charlottesville, Va.);
Agosti, J.M. (Immunex Corporation, Seattle, Wash.) Lindsay, M.A.; De Souza, P.M.; Lynch, O.T.; Giembycz, M.A.
(NHLI, Imperial College, London)
260 Interleukin-13 Antagonism
321 Phosphodiesterase 4 Inhibitors
Donaldson, D.D. (Wyeth-Ayerst, Andover, Mass.); Elias, J.A.
(Yale University, New Haven, Conn.); Wills-Karp, M. (Johns Torphy, T.J.; Compton, C.H.; Marks, M.J. (SmithKline
Hopkins University, Baltimore, Md.) Beecham, King of Prussia, Pa., Harlow, and Collegeville, Pa.);
Sturton, G. (Bayer plc, Slough)
265 Interleukin-5 Antagonism
Leckie, M.J. (NHLI, Imperial College, London); Walker, C.
Therapies Acting on Transcription
(Novartis Research Centre, Horsham)
269 Interleukin-10 328 Therapies Acting on Transcription: An Overview
Narula, S.; Cuss, F. (Schering-Plough Research Institute, Caramori, G.; Adcock, I.M. (NHLI, Imperial College, London)
Kenilworth, N.J.)
332 Chromatin Modification
274 Interleukin-12, Interleukin-18 and Interferon-Á Urnov, F.D.; Wolffe, A.P. (Sangamo Biosciences, Richmond,
Bryan, S. (NHLI, Imperial College, London); Kobayashi, M. Calif.)
(Wyeth-Ayerst, Andover, Mass.); Sur, S. (University of Texas,
337 Activator Protein-1 and Nuclear Factor-Kappa B
Galveston, Tex.)
Bennett, B.L.; Manning, A.M. (Signal Pharmaceuticals, Inc.,
San Diego, Calif.)
Chemokine Receptor Inhibition
342 Inhibition of p38 MAP Kinase
280 Chemokines: An Overview Underwood, D.C.; Griswold, D.E. (SmithKline Beecham
Sabroe, I.; Williams, T.J. (Imperial College, South Kensington) Pharmaceuticals, King of Prussia, Pa.)

284 Chemokine Receptors on Th1 and Th2 Cells 346 STAT6

Sinigaglia, F. (Roche Milano Ricerche, Milan); Fabbri, L.M. Role in IL-4-Mediated Signaling
(University of Modena, Modena); D’Ambrosio, D. (Roche Schaefer, G.; Venkataraman, C.; Schindler, U. (Tularik, Inc.,
Milano Ricerche, Milan) S. San Francisco, Calif.)

288 CCR-3 Antagonists 350 Retinoids

Bryan, S.A. (NHLI, Imperial College, London); Ponath, P.D. Belloni, P.N. (Roche Bioscience, Palo Alto, Calif.)
(LeukoSite, Inc., Cambridge, Mass.); Wilhelm, R.S. (Roche
Bioscience, Palo Alto, Calif.)
Genetic Therapy
293 Interleukin-8 Receptor (CXCR2) Antagonists
Sarau, H.M.; Widdowson, K.L.; Palovich, M.R.; White, J.R.; 358 Asthma and COPD Genetics and Genomics:
Underwood, D.C.; Griswold, D.E. (SmithKline Beecham An Overview
Pharmaceuticals, King of Prussia, Pa.) Morrison, J.F.J. (AstraZeneca, Macclesfield)
361 Respirable Antisense Oligonucleotides
Adhesion Molecule Inhibitors Nyce, J.W. (EpiGenesis Pharmaceuticals, Inc., Princeton, N.J.)

298 Adhesion Molecule Antagonism: An Overview 365 Antisense Therapy

Bochner, B.S. (Johns Hopkins University, Baltimore, Md.) Bennett, C.F. (Isis Pharmaceuticals, Inc., Carlsbad, Calif.)

302 Small-Molecule VLA-4 Antagonists 370 Ribozyme Therapy

Adams, S.P.; Lobb, R.R. (Biogen Inc., Cambridge, Mass.) Sandberg, J.A.; Lee, P.A.; Usman, N. (Ribozyme
Pharmaceuticals, Inc., Boulder, Colo.)
306 Selectin Antagonists
Therapeutics for Airway Inflammation 374 Gene Therapy
Kolb, M.; Gauldie, J. (McMaster University, Hamilton)
Berens, K.L.; Vanderslice, P.; Dupré, B.; Dixon, R.A.F.
(Texas Biotechnology Corporation, Houston, Tex.)
310 ICAM-1 and VCAM-1 Antagonists 379 Author Index
Richards, I.M.; Slatter, V.K. (Pharmacia Corporation, 381 Subject Index
Kalamazoo, Mich.)
388 Abbreviations

Contents VII
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Foreword

For this first volume written in the new millennium I cise chapters addressing every possible drug from estab-
decided to go for a book on new drugs for asthma and lished, commercially available substances to compounds
COPD which would be of interest to many doctors in- in their early testing phase.
volved in the treatment of these diseases. When looking The final product exceeds my wildest expectations.
for someone to edit this 31st volume of the series ‘Pro- Trevor and Peter managed to rally a fantastic group of
gress in Respiratory Research’ I was fortunate enough to authors, whose names reflect a ‘who’s who’ in the field.
get Trevor T. Hansel and Peter J. Barnes interested. Dur- The chapters rarely exceed 4 printed pages, limiting the
ing our initial meeting in Madrid in September 1999, I information to the essentials. The book is lavishly illus-
told them that I would be interested in ‘real’ progress in trated with 72 tables and 195 colour figures, which have
drug research and not in a book which would be outdated been edited by Trevor to obtain uniformity; that means
by the time it is printed. After some moments of hesita- an eosinophil looks the same in every figure of the book!
tion they said that this would mean involvement of a lot of This book will serve as a key reference of current and
researchers from pharmaceutical companies together with future developments in the treatment of asthma, allergy,
clinicians, and what about conflicts of interest!? When I and COPD; it will appeal to the practising physician as
replied that this mix represented the real world, and was well as to the pulmonologist with a special pharmacologi-
exactly what I wanted, they promised to think about it cal interest. Get it and enjoy it!
and get back to me. After a short period they announced Chris T. Bolliger
their concept of putting together a book with 80 ultra con- Series Editor

VIII
 OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Preface

Asthma and COPD have now become amongst the

commonest diseases in the world, and both are increasing.
There have been major advances in our understanding of
asthma and significant improvement in asthma manage-
ment, particularly with the early and more widespread use
of inhaled corticosteroids. Yet, despite effective therapy
for asthma, there is a pressing need for new and more spe-
cific therapies that control the disease or even cure the
underlying disease process. Progress in understanding
and treating COPD has been much slower, mainly be-
cause the disease has been relatively neglected. None of
the treatments available today prevent the relentless pro-
gression of COPD and there is an urgent need to develop
novel approaches.
The aim of this book is to offer a state-of-the-art
description of the exciting progress in research and devel-
opment that is being made with new therapies for asthma, T.T.H. P.J.B.
allergy and COPD. We are very aware that many large
tomes that contain review chapters by leading scientific
and clinical authorities are already available on allergic
and respiratory diseases. On this basis, our major inten- to provide concise and highly condensed information. In
tion was to link the biotechnology and pharmaceutical this way we have tried to have specialists from the indus-
industry with academic and clinical opinion. In order to try writing on their own fields of interest. This is a rapidly
develop better therapies, we rely on this partnership, since advancing field, and this format of segmented brief chap-
the modern-day reality is that novel drug discovery and ters has allowed us to put information on the internet, and
production generally occur from within the industry. should permit provision of regular updates.
We have been amazed by the enthusiastic response The book has 14 sections that range from an intro-
from our colleagues in the pharmaceutical industry in duction covering general aspects of drug development
providing as much information as they can about early for asthma and COPD to a review of currently available
developments with their novel potential therapies. By small-molecular-weight synthetic medicinal chemical
way of introduction to these contributions, we have over- classes: bronchodilators, corticosteroids, anti-leukotrienes,
views written by leading academic clinical scientists. and mediator and protease inhibitors. We then proceed
With over 200 authors, and a total of 80 chapters, we hope from allergen and IgE-directed therapies to T cell immu-

IX
nomodulation and cytokine-directed therapy, to chemo- Karger Medical Publishers, Basel, a superbly professional
kine receptor and adhesion molecule inhibition, to thera- group of people to interact with.
py directed against cell signalling and transcription, be- We hope that you will find this book interesting and
fore looking at future prospects for genetic therapy. helpful, and that it will give as much enjoyment to you,
A considerable team has been involved in producing the reader, as we have had in its design and editing. Final-
this volume, and we are very grateful for the vision of ly, and most importantly of all, we hope that this book will
Chris Bolliger, Editor of Progress in Respiratory Research, help in the process of finding better therapy for patients
who always wanted us to go for something ‘completely dif- with allergic and respiratory diseases.
ferent’! In addition, we have found the entire staff at Trevor T. Hansel
Peter J. Barnes

X Preface
OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

General Aspects
 Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy and COPD.
Prog Respir Res. Basel, Karger, 2001, vol 31, pp 2–5

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

The Need for New Therapy

Peter J. Barnes Trevor T. Hansel
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK

Summary children and in patients with severe asthma who require

The perspectives for new therapies in asthma and COPD are high doses. Many patients are reluctant to take inhaled cor-
quite different. In asthma we already have relatively cheap and safe ticosteroids because of the fear of adverse effects of ste-
therapies that are effective in controlling the disease, so that the need
roids; the general public has ‘corticophobia’ as a result of
for new treatments is somewhat limited. However, important ad-
vances can still be made to improve long-term therapy for patients stories in the press about side effects of oral corticosteroids
with more severe persistent asthma, as well as acute therapy for and anabolic steroids. Local side effects of inhaled cortico-
emergency exacerbations of asthma, while in the future there is the steroid, particularly dysphonia, may be a problem in some
prospect of allergen immunotherapy causing disease modification patients, such as lecturers and singers. The dose of inhaled
and even cure. In COPD, however, both bronchodilator and anti-
corticosteroids that most patients require for asthma con-
inflammatory therapy is less effective, and there are currently no
therapies that reduce the progression of the disease. Driven by the trol is relatively low so that systemic side effects are unlike-
urgent need for new therapies, a shift in resources from discovery of ly. However, a recent community study suggests that there
drugs for asthma to COPD is taking place. was a linear relationship between the cumulative dose of
inhaled steroid used and the risk of fracture [4].
Inhaled ß2-agonists, while highly effective as bron-
Asthma chodilators, also have side effects in some patients, partic-
New Asthma Treatments. Asthma therapy has been ularly the elderly. Tremor and palpitations can be dis-
revolutionized over the last decade by the earlier and tressing in some patients, but can usually be avoided by
more widespread use of inhaled corticosteroids. Short- reducing the dose or frequency and adding an anticholin-
acting ß2-agonists are very effective in relief of symptoms ergic inhaler. Tolerance to the bronchodilator effects of
and the introduction of long-acting inhaled ß2-agonists ß2-agonists is a potential problem, but although there is a
has greatly improved asthma control. Fixed-combination small reduction in the protective effect of ß2-agonists
inhalers of corticosteroid with long-acting bronchodila- against challenges, such as allergen and exercise, this is of
tors have recently been introduced and provide highly relatively small degree and is not progressive [5].
effective control of asthma for the majority of patients. Theophylline is a useful treatment for patients with
This treatment is simple and very convenient for patients, severer asthma, but at the doses that are needed for bron-
so it is likely to dominate asthma therapy in the foreseen chodilatation, side effects are relatively common. How-
future. However, there are some areas of asthma therapy ever, lower doses of theophylline are also effective in asth-
where improvements may be possible through the devel- ma control and avoid many of the problems with side
opment of improved existing treatments or introduction effects. The side effects of existing anti-asthma therapies
of novel therapies [1] (fig. 1). are due to their non-pulmonary effects, since corticoste-
Problems with Existing Treatments. Although current roids, ß2-agonists and theophylline have effects on many
asthma therapy is effective and well tolerated, there are different cell types. This suggests that it may be necessary
some limitations [2]. Inhaled corticosteroids are very effec- to develop more specific therapies, targeted at specific
tive in controlling asthma in most patients [3]. However, abnormalities in allergic inflammation, in order to reduce
there are still concerns about side effects, particularly in the risk of adverse effects [6].

2
 Fig. 1. Needs for new therapy
for asthma.

Severe and Emergency Asthma. Most asthmatic patients drugs, and patients may find it difficult to use inhalers.
can be controlled on inhaled corticosteroid with or without Oral therapy for asthma may have advantages as it would
a long-acting inhaled ß2-agonist and in patients with sever- be easier to take and this may improve compliance [11].
er disease with the addition of theophylline and an anticho- Anti-leukotrienes, which are much less effective in the
linergic bronchodilator. However, about 5% of patients control of asthma than inhaled corticosteroids, have
have severe asthma and require high doses of inhaled corti- proved popular with patients as they are available as a
costeroids and in approximately 1% of patients by mainte- once- or twice-daily tablet. Another important advantage
nance doses of oral corticosteroids [7]. These patients have of oral therapy that inhibits allergic inflammation is that
the potential for improvement since they usually respond it will control concomitant allergic diseases such as rhini-
to even higher doses of oral corticosteroid. These steroid- tis and atopic dermatitis that commonly coincide with
dependent patients are relatively steroid-resistant, while asthma [6].
occasionally patients have complete resistance to the ef- Disease Modification. Although inhaled corticosteroids
fects of corticosteroids [8, 9]. These patients, while com- are very effective at controlling asthma, symptoms recur
prising only F5% of all asthmatic patients, account for when inhaled corticosteroids are withdrawn and there is an
over 50% of medical costs [10], and it should be stressed increase in markers of inflammation [12, 13]. This indi-
that admissions to hospital following severe exacerbations cates that corticosteroids suppress inflammation in asth-
of asthma generally result in a 4-day hospital stay. Some matic airways, but do not change the underlying unknown
new form of treatment is needed for these patients with driving mechanism, so that when steroids are discontin-
severe asthma that is independent of the molecular mecha- ued, the inflammation and asthma symptoms recur. The
nisms of action of corticosteroids and several possible concept of disease-modifying drugs is well established in
approaches are discussed in this volume. rheumatology. It implies that a treatment will alter the dis-
Inhaled versus Oral Therapy. The most effective cur- ease process and maintain disease control even when dis-
rently available therapies for asthma, corticosteroids and continued. So far this has not been established for any
ß2-agonists, are given by inhalation to reduce or avoid existing asthma therapy, but it is possible that new treat-
side effects due to the systemic actions of these non-spe- ments aimed at upstream immunological pathways may
cific therapies. However, it is difficult to develop inhaled have the potential for disease modification.

The Need for New Therapy 3

 A Cure for Asthma? No currently available treatment with COPD have been treated with anti-asthma therapies,
for asthma is curative, but potentially a cure is possible but these drugs may be inappropriate in a disease with a
through strategies that prevent or reverse the immunolog- different pathophysiology, involving different cells, me-
ical abnormalities in atopy. There are several approaches diators and inflammatory effects [21]. Thirdly, since in
to reduce the preponderance of Th2 cells in atopy by most patients COPD is the result of long-term heavy ciga-
switching the balance in favour of Th1 cells. This can be rette smoking it has been felt to be the ‘fault’ of the
achieved in animals by exposure to bacterial products patient. Fourthly, there has been little interest in the
such as BCG, Mycobacterium vaccae or unmethylated molecular and cell biology of COPD to identify new thera-
cytosine-guanosine dinucleotide-containing oligonucleo- peutic targets and there are no satisfactory animal models
tides (CpG ODN) [14–16]. This suggests that vaccination for early drug testing [22]. Lastly, there are uncertainties
with allergens, immunomodulators and adjuvants may be about how to test new drugs for COPD, which may
a future strategy for the prevention or cure of asthma [17]. require long-term studies in large numbers of patients and
However, the long-term consequences of altering the im- a lack of surrogate markers to monitor the short-term effi-
mune response are not yet certain and clinical studies may cacy of new treatments. However, some progress is under
be difficult. Initial studies with BCG vaccination in young way and there are several classes of drug that are now in
children are equivocal and more studies are needed [18]. preclinical and clinical development [23, 24].
Problems with Existing Therapies. COPD is poorly
COPD reversible with current therapies. Bronchodilators are the
Compared to asthma, COPD has been surprisingly only treatments which provide symptomatic benefit, but
neglected in terms of mechanistic research, drug develop- the effects of bronchodilators are less than seen in asthma,
ment, and therapeutic advances. Yet this is a common and high doses are required to achieve a maximal effect.
disease with an increasing prevalence that is potentially Long-acting inhaled ß2-agonists have been an important
treatable with novel therapies. advance, and the new once-daily inhaled anticholinergic
Size of the Problem. It is estimated that approximately drug, tiotropium bromide, is likely to be an important
14 million people in the USA are currently affected by advance [25–27]. But bronchodilators do not change the
COPD. In the US Third National Health and Nutrition natural history of COPD and do not reduce the acceler-
Examination Survey (NHANESIII) study airflow obstruc- ated decline in lung function that is typical of the disease
tion was found in approximately 14% of white male smok- [28]. Indeed, apart from quitting smoking, no currently
ers compared to approximately 3% in non-smokers, with available therapies alter the progression of COPD.
slightly lower figures in white women and blacks [19]. Because COPD involves a chronic inflammation of the
COPD is now the fourth leading cause of death in the USA airways and lung parenchyma, it was assumed that in-
and the only common cause of death that is increasing. This haled corticosteroid would be effective in reducing dis-
is pobably a gross underestimate, as COPD is likely to be ease progression. However, several large long-term stud-
contributory to other common causes of death. There has ies have now demonstrated that even high doses of
been an increase in COPD prevalence and mortality, even inhaled corticosteroids are ineffective [29–31]. This is
in industrialized countries, and COPD now represents a probably because corticosteroids are ineffective in sup-
major world-wide health problem. The World Health Or- pressing the inflammation of COPD, in contrast to their
ganization global impact of disease analysis predicts that marked efficacy in asthma [32, 33]. This means that new
COPD will rise from its current ranking of 12th most prev- classes of anti-inflammatory drugs must be sought.
alent disease world-wide to 5th position, and from the 6th New Therapies for COPD. In order to develop novel
commonest cause of death to 3rd by 2020 [20]. Reasons for therapies for COPD, there is a need to understand the dis-
the dramatic increase in COPD include reduced mortality ease better at a cellular and molecular level [34]. Our cur-
from other causes, such as cardiovascular diseases, in rent understanding of COPD suggests several possible tar-
industrialized countries and infectious diseases in develop- gets, including mediator inhibitors, anti-proteases, and
ing countries, with a marked increase in cigarette smoking novel classes of anti-inflammatory drugs. An example of a
and environmental pollution in developing countries. new class of drug that appears to be promising in COPD
The Neglect of COPD. There are several reasons why are phosphodiesterse-4 inhibitors, which target different
COPD has been relatively neglected in terms of new drug aspects of the inflammatory process to corticosteroids
development. Firstly, COPD has been perceived as ‘un- [35]. It is likely that several new classes of drug will be
treatable’ fixed airflow obstruction. Secondly, patients developed for the treatment of COPD and many of these

4 Barnes/Hansel
are discussed in this volume. There is also a need to find now well treated with existing therapies, but there is a need
drugs that prevent exacerbations which account for a large to find better treatment for patients with severe disease
proportion of health care spending in COPD. Exacerba- and emergency exacerbations, who represent a small pro-
tions are poorly understood but it is clear that many are portion of patients but disproportionate medical costs.
not due to bacterial infections, as previously assumed. There is also a need to find an oral therapy that is as safe
and effective as inhaled corticosteroids, and to find treat-
Conclusions ments that are disease-modifying or curative. By contrast,
Asthma and COPD are amongst the commonest COPD is poorly treated with currently available drugs and
chronic diseases world-wide and there is evidence that there is a need to find new classes of drug that slow the
both diseases are increasing. This represents an enormous progression of the disease and reduce exacerbations. More
and growing therapeutic market and there is therefore an research into the underlying cellular and molecular mecha-
opportunity for development of new drugs. Asthma is nisms in COPD is needed in order to identify new targets.

References
1 Barnes PJ: New treatments for asthma. Eur J creased airway reactivity in an animal model. J 28 Anthonisen NR, Connett JE, Kiley JP, Altose
Int Med 2000;11:9–20. Allergy Clin Immunol 1998;102:867–874. MD, Bailey WC, Buist AS, et al: Effects of
2 Barnes PJ: Current therapies for asthma: 15 Wang CC, Rook GA: Inhibition of an estab- smoking intervention and the use of an inhaled
Promise and limitations. Chest 1997;111:17S– lished allergic response to ovalbumin in BALB/ anticholinergic bronchodilator on the rate of
22S. c mice by killed Mycobacterium vaccae. Immu- decline of FEV1. JAMA 1994;272:1497–1505.
3 Barnes PJ, Pedersen S, Busse WW: Efficacy nology 1998;93:307–313. 29 Vestbo J, Sorensen T, Lange P, Brix A, Torre P,
and safety of inhaled corticosteroids: An up- 16 Sur S, Wild JS, Choudhury BK, Sur N, Alam R, Viskum K: Long-term effect of inhaled bude-
date. Am J Respir Crit Care Med 1998;157:S1– Klinman DM: Long term prevention of allergic sonide in mild and moderate chronic obstruc-
S53. lung inflammation in a mouse model of asthma tive pulmonary disease: A randomised con-
4 Wong CA, Walsh LJ, Smith CJ, Wisniewski by CpG oligodeoxynucleotides. J Immunol trolled trial. Lancet 1999;353:1819–1823.
AF, Lewis SA, Hubbard R, et al: Inhaled corti- 1999;162:6284–6293. 30 Pauwels RA, Lofdahl CG, Laitinen LA,
costeroid use and bone-mineral density in pa- 17 Holt PG: A potential vaccine strategy for asth- Schouten JP, Postma DS, Pride NB, et al:
tients with asthma. Lancet 2000;355:1399– ma and allied atopic diseases during infancy. Long-term treatment with inhaled budesonide
1403. Lancet 1994;344:456–458. in persons with mild chronic obstructive pul-
5 Pauwels RA, Lofdahl C-G, Postma DS, Tat- 18 Hopkin JM: Atopy, asthma and mycobacteria. monary disease who continue smoking. N Engl
tersfield AE, O’Byrne PM, Barnes PJ, et al: Thorax 2000;55:443–445. J Med 1999;340:1948–1953.
Effect of inhaled formoterol and budenoside on 19 Center for Disease Control: Vital and health 31 Burge PS, Calverley PMA, Jones PW, Spencer
exacerbations of asthma. N Engl J Med 1997; statistics: Current estimates from the National S, Anderson JA, Maslen T: Randomised, dou-
337:1412–1418. Health Interview Survey, 1995. DHHS Publ ble-blind, placebo-controlled study of flutica-
6 Barnes PJ: Therapeutic strategies for allergic No 96-1527, 1998. sone propionate in patients with moderate to
diseases. Nature 1999;402:B31–B38. 20 Lopez AD, Murray CC: The global burden of severe chronic obstructive pulmonary disease;
7 Barnes PJ, Woolcock AJ: Difficult asthma. Eur disease, 1990–2020. Nat Med 1998;4:1241– the ISOLDE trial. Br Med J, in press.
Respir J 1998;12:1209–1218. 1243. 32 Keatings VM, Jatakanon A, Worsdell YM,
8 Barnes PJ, Greening AP, Crompton GK: Glu- 21 Barnes PJ: Mechanisms in COPD: Differences Barnes PJ: Effects of inhaled and oral glucocor-
cocorticoid resistance in asthma. Am J Respir from asthma. Chest 2000;117:10S–14S. ticoids on inflammatory indices in asthma and
Crit Care Med 1995;152:125S–140S. 22 Barnes PJ: Novel approaches and targets for COPD. Am J Respir Crit Care Med 1997;155:
9 Szefler SJ, Leung DY: Glucocorticoid-resistant treatment of chronic obstructive pulmonary 542–548.
asthma: Pathogenesis and clinical implications disease. Am J Respir Crit Care Med 1999;160: 33 Culpitt SV, Nightingale JA, Barnes PJ: Effect
for management. Eur Respir J 1997;10:1640– S72–S79. of high dose inhaled steroid on cells, cytokines
1647. 23 Barnes PJ: New therapies for chronic obstruc- and proteases in induced sputum in chronic
10 Barnes PJ, Jonsson B, Klim J: The costs of asth- tive pulmonary disease. Thorax 1998;53:137– obstructive pulmonary disease. Am J Respir
ma. Eur Respir J 1996;9:636–642. 147. Crit Care Med 1999;160:1635–1639.
11 Kelloway JS, Wyatt RA, Adlis SA: Comparison 24 Barnes PJ: Chronic obstructive pulmonary dis- 34 Barnes PJ: Recent advances in chronic obstruc-
of patients’ compliance with prescribed oral ease: New opportunities for drug development. tive pulmonary disease. N Engl J Med, in press.
and inhaled asthma medications. Arch Intern Trends Pharmacol Sci 1998;19:415–423. 35 Torphy TJ, Barnette MS, Underwood DC,
Med 1994;154:1349–1352. 25 Disse B, Speck GA, Rominger KL, Witek TJ, Griswold DE, Christensen SB, Murdock RD, et
12 Vathenen AS, Knox AJ, Wisniewski A, Tatters- Hammer R: Tiotropium (Spiriva): Mechanisti- al: Ariflo (SB 207499), a second generation
field AE: Time course of change in bronchial cal considerations and clinical profile in ob- phosphodiesterase 4 inhibitor for the treatment
reactivity with an inhaled corticosteroid in structive lung disease. Life Sci 1999;64:457– of asthma and COPD: From concept to clinic.
asthma. Am Rev Respir Dis 1991;143:1317– 464. Pulm Pharmacol Ther 1999;12:131–136.
1321. 26 Barnes PJ: The pharmacological properties of
13 Jatakanon A, Lim S, Barnes PJ: Changes in tiotropium. Chest 2000;117:63S–66S. Peter J. Barnes
sputum eosinophils predict loss of asthma con- 27 Littner MR, Ilowite JS, Tashkin DP, Friedman Department of Thoracic Medicine
trol. Am J Respir Crit Care Med 2000;161:64– M, Serby CW, Menjoge SS, et al: Long-acting National Heart and Lung Institute
72. bronchodilation with once-daily dosing of tio- Imperial College, Dovehouse Street
14 Herz U, Gerhold K, Gruber C, Braun A, Wahn tropium (Spiriva) in stable chronic obstructive London SW3 6LY (UK)
U, Renz H, et al: BCG infection suppresses pulmonary disease. Am J Respir Crit Care Med Tel. +44 171 351 3050, Fax +44 171 351 5675
allergic sensitization and development of in- 2000;161:1136–1142. E-Mail [email protected]

The Need for New Therapy 5

 Hansel TT, Barnes PJ (eds): New Drugs for Asthma, Allergy and COPD.
Prog Respir Res. Basel, Karger, 2001, vol 31, pp 6– 10

OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO

Current Therapy for Asthma

Peter J. Barnes
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK

Summary E minimize (ideally abolish) symptoms

Currently available therapy for asthma is highly effective and is E restore normal or best possible lung function
able to control the majority of patients so that they can lead a normal E prevent severe attacks
life. National and international guidelines for the treatment of asth-
E prevent the slow decline in lung function
ma are generally based on use of inhaled ß2-agonists together with
inhaled corticosteroids. Advances in therapy have been due to the E prevent death
introduction of more effective and safer treatments and to changes in These aims should be achieved by using the minimum
the way that these treatments are administered to patients. This of treatment with the lowest incidence of side effects, but
represented an important change in strategy from the treatment of it is important to remember that severe asthma is associ-
symptoms as they arose largely with bronchodilator therapy to con-
ated with a high morbidity and mortality, so that side
trol and prevent symptoms with anti-inflammatory treatments.
effects of drugs may be acceptable in patients with severer
disease. The aims of asthma therapy should be more than
The earlier and more widespread use of inhaled corti- alleviation of symptoms, since effective therapies are now
costeroids has revolutionized asthma therapy over the last available to control all but the most severe asthma. An
10 years, with improvement in asthma control, a reduc- important aim of therapy is to control symptoms so that
tion in asthma morbidity and almost certainly a decrease normal life is possible. This includes the normal participa-
in mortality [1]. In most countries, guidelines for asthma tion in sporting activities and the ability to work normal-
therapy have now been introduced and these form the ly. Now that home monitoring of PEF is recommended
framework of modern management, with a stepwise esca- for some patients with more difficult asthma, an addition-
lation in therapy [2, 3]. Asthma therapies are now classi- al aim of therapy is to keep the PEF at the best possible
fied as relievers that provide rapid relief of symptoms level. This is particularly important in patients who may
(short-acting ß2-agonists, anticholinergics) that are used as have a poor perception of the severity of their asthma and
needed and controllers which provide long-term control who tolerate severe impairment of lung function. Asthma
of symptoms that are used as a regular treatment (cortico-
steroids, theophylline, long-acting inhaled ß2-agonists,
cromones, anti-leukotrienes and immunomodulators) (ta-
ble 1). Table 1. Asthma therapy

Reliever Controllers
General Issues
Aims of Therapy. Therapy should be aimed at control- Short-acting ß2-agonists Inhaled corticosteroids
ling symptoms so that normal life is possible. If currently Anticholinergics Long-acting inhaled ß2-agonists
available treatment is used correctly, it is likely that the Theophylline
Cromones
vast majority of adults with asthma can lead normal lives
Anti-leukotrienes
and participate in normal leisure activities. Therapy of Immunomodulators
asthma should aim to:

6
exacerbations should be regarded as a failure in therapy, and unstable asthma, which has higher risk of death [4].
and an important aim of therapy is to prevent such Evidence that regular use of short-acting inhaled ß2-ago-
attacks, if necessary by changing treatment. Since poorly nists resulted in poorer control of asthma [5] has now been
controlled asthma may lead to a progressive decline in refuted by studies showing that there is no difference
lung function, it is also hoped that more effective control between ‘as required’ and ‘four times a day’ salbutamol in
of airway inflammation may prevent the progressive either mild or severer asthma [6, 7]. However, short-act-
increase in airway obstruction which occurs in patients ing inhaled ß2-agonists are best given as required as this is
with severe asthma, and that it will also prevent death a useful measure of how well asthma is controlled. Regu-
from asthma. lar use of short-acting inhaled ß2-agonists four times a day
Diagnosis. An objective diagnosis of asthma should be have now been superseded by the use of long-acting
made, based on a documented bronchodilator response inhaled ß2-agonists twice daily, which give more effective
(112% increase in FEV1), a 15% improvement with corti- symptom control [8]. There have also been concerns
costeroid therapy or variability in PEF over time of about the development of tolerance to the bronchodilator
120%. Bronchial provocation tests (methacholine or his- effects of ß2-agonists. However, although a reduction in
tamine challenge and exercise challenge) have little place the protective effect of short-acting ß2-agonists has been
in routine diagnosis, but may be useful in patients who demonstrated, this is not progressive and most of the pro-
present with cough or exercise-induced symptoms. tective effect is preserved [9].
Environmental Control. Avoidance of factors that Long-Acting ß2-Agonists. Inhaled salmeterol and for-
worsen asthma control is an important part of manage- moterol give bronchodilatation and bronchoprotection
ment. Patients should quit smoking, which may interfere lasting over 12 h and are therefore suitable for twice daily
with the anti-inflammatory effects of corticosteroids. Par- dosing [8]. Like short-acting ß2-agonists, they have no
ents of asthmatic children should also stop smoking. Most effect on chronic inflammation and therefore should not
asthmatic patients are atopic and environmental allergen be used without corticosteroids. Inhaled long-acting ß2-
exposure should be avoided as much as possible. There agonists give better asthma control than increasing the
are several strategies to avoid exposure to house dust mite dose of inhaled corticosteroids in moderate and severe
and furry pets (especially cats), although complete avoid- asthma and also reduce mild and severe exacerbations
ance of house dust mites is very difficult in temperate cli- [10–12]. Salmeterol and formoterol have a similar dura-
mates. Occupational exposure to allergens and sensitizers tion of action, but there are pharmacological differences.
should be avoided where relevant. Formoterol is a nearly full agonist whereas salmeterol is a
partial agonist and this may account for the small degree
Pharmacological Therapy of bronchodilator tolerance seen with formoterol. Formo-
Short-Acting ß2-Agonists. Beta-agonists are by far the terol has a more rapid onset of action than salmeterol and
most effective bronchodilators and are well tolerated therefore may be useful as relief medication. Oral ß2-ago-
when given by inhalation. Beta-agonists work as function- nists are not normally recommended, but a long-acting
al antagonists on airway smooth muscle and therefore pre- oral ß2-agonist bambuterol is as effective as salmeterol in
vent and reverse bronchoconstriction irrespective of the controlling symptoms, although side effects may be more
mechanism. They also inhibit mast cell mediator release common [13].
and are effective in preventing exercise- and allergen- Anticholinergics. Inhaled anticholinergic drugs (ipra-
induced asthma. However, they do not suppress chronic tropium bromide, oxitropium bromide) are less effective
airway inflammation and do not reduce airway hyperre- bronchodilators than ß2-agonists in asthma. They are
sponsiveness and are therefore not adequate alone to treat used as additional bronchodilators in patients already
persistent asthma. Side effects are not usually a problem treated with ß2-agonists. As they are additive to ß2-ago-
when ß2-agonists are administered by inhalation, but nists, they may be used to reduce the dose in patients who
become more frequent with oral and intravenous admin- have side effects from ß2-agonists.
istrations. The commonest adverse effects are muscle Theophylline. Theophylline has been used in asthma
tremor and palpitations, which are more common in treatment for over 50 years but has become less popular as
elderly patients. There were concerns that inhaled ß2-ago- ß2-agonists are more effective bronchodilators and the
nists may be associated with increased asthma mortality, high doses needed for bronchodilatation are frequently
but it now seems that the association between a high dose associated with side effects, such as nausea and headaches
of ß2-agonist and mortality is more a reflection of severe [14]. However, more recent studies have demonstrated

Current Therapy for Asthma 7

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- Sub-point: Additional details and explanations
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Formula: [Mathematical expression or equation]
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Note: Case studies and real-world applications
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Example 35: Learning outcomes and objectives
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 36: Critical analysis and evaluation
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 37: Diagram/Chart/Graph]
Example 37: Case studies and real-world applications
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Research findings and conclusions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Critical analysis and evaluation
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Summary 5: Theoretical framework and methodology
Note: Current trends and future directions
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 41: Diagram/Chart/Graph]
Remember: Key terms and definitions
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 42: Statistical analysis and interpretation
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Fundamental concepts and principles
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 44: Current trends and future directions
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Best practices and recommendations
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 46: Literature review and discussion
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Theoretical framework and methodology
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 48: Diagram/Chart/Graph]
Practice Problem 48: Statistical analysis and interpretation
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Study tips and learning strategies
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 50: Diagram/Chart/Graph]
Abstract 6: Study tips and learning strategies
Remember: Ethical considerations and implications
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Ethical considerations and implications
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 52: Diagram/Chart/Graph]
Remember: Problem-solving strategies and techniques
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
[Figure 53: Diagram/Chart/Graph]
Definition: Current trends and future directions
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Important: Fundamental concepts and principles
• Statistical analysis and interpretation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Ethical considerations and implications
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Case studies and real-world applications
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 57: Theoretical framework and methodology
• Practical applications and examples
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Key terms and definitions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 59: Diagram/Chart/Graph]
Note: Experimental procedures and results
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Quiz 7: Historical development and evolution
Key Concept: Experimental procedures and results
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Key Concept: Study tips and learning strategies
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Theoretical framework and methodology
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Practical applications and examples
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Theoretical framework and methodology
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 65: Diagram/Chart/Graph]
Remember: Research findings and conclusions
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Definition: Theoretical framework and methodology
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Key Concept: Key terms and definitions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Note: Theoretical framework and methodology
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Assessment criteria and rubrics
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Part 8: Best practices and recommendations
Key Concept: Study tips and learning strategies
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Experimental procedures and results
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Critical analysis and evaluation
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Learning outcomes and objectives
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Comparative analysis and synthesis
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Comparative analysis and synthesis
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Remember: Assessment criteria and rubrics
• Key terms and definitions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
[Figure 77: Diagram/Chart/Graph]
Example 77: Interdisciplinary approaches
• Ethical considerations and implications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 78: Historical development and evolution
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Example 79: Interdisciplinary approaches
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Quiz 9: Comparative analysis and synthesis
Definition: Theoretical framework and methodology
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 81: Diagram/Chart/Graph]
Definition: Experimental procedures and results
• Experimental procedures and results
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Important: Literature review and discussion
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Study tips and learning strategies
• Interdisciplinary approaches
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Learning outcomes and objectives
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Remember: Assessment criteria and rubrics
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 86: Diagram/Chart/Graph]
Remember: Historical development and evolution
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 87: Theoretical framework and methodology
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Statistical analysis and interpretation
• Historical development and evolution
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Practice Problem 89: Assessment criteria and rubrics
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Review 10: Literature review and discussion
Important: Fundamental concepts and principles
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Definition: Study tips and learning strategies
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Remember: Best practices and recommendations
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Important: Learning outcomes and objectives
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 94: Historical development and evolution
• Study tips and learning strategies
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Key Concept: Learning outcomes and objectives
• Comparative analysis and synthesis
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Formula: [Mathematical expression or equation]
Definition: Key terms and definitions
• Research findings and conclusions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Note: Ethical considerations and implications
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Key Concept: Fundamental concepts and principles
• Assessment criteria and rubrics
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 99: Key terms and definitions
• Literature review and discussion
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Appendix 11: Study tips and learning strategies
Example 100: Best practices and recommendations
• Learning outcomes and objectives
- Sub-point: Additional details and explanations
- Example: Practical application scenario
Important: Research findings and conclusions
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
[Figure 102: Diagram/Chart/Graph]
Important: Experimental procedures and results
• Case studies and real-world applications
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Best practices and recommendations
• Critical analysis and evaluation
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 104: Practical applications and examples
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
[Figure 105: Diagram/Chart/Graph]
Example 105: Practical applications and examples
• Fundamental concepts and principles
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Note: Statistical analysis and interpretation
• Current trends and future directions
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Definition: Interdisciplinary approaches
• Best practices and recommendations
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Example 108: Literature review and discussion
• Problem-solving strategies and techniques
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
Formula: [Mathematical expression or equation]
Example 109: Study tips and learning strategies
• Theoretical framework and methodology
- Sub-point: Additional details and explanations
- Example: Practical application scenario
- Note: Important consideration
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