Overcoming Steroid Insensitivity in Respiratory Disease

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ISBN: 9780470058084 | 0470058080
Cover: Hardcover
Copyright: 4/28/2008

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Written by well-known experts in field, this is the first book dedicated to dealing with the single most challenging management issue in long-term steroid therapy.Overcoming Steroid Insensitivity in Respiratory Disease reviews important new advances in therapeutics and provides the clinician with the most up to date information on one of the most significant therapeutic challenges to effective management of these diseases. This unique book is an invaluable resource for all postgraduate students and specialist physicians in pulmonology allergy and asthma. It is also of interest for workers in biomedical and pharmaceutical research.

List of contributors	p. ix
Preface	p. xi
Molecular Mechanisms of Glucocorticoid Receptor Action	p. 1
Introduction	p. 1
Glucocorticoid receptor	p. 2
Gene induction by GR	p. 2
GR transactivation and histone acetylation	p. 3
Post-translational modifications of GR	p. 5
Repression of NF-[kappa]B-induced inflammatory gene expression by GR-NF-[kappa]B	p. 6
GR-NF-[kappa]B cross-talk	p. 7
Role of HDAC2 in glucocorticoid function	p. 8
Overexpression of HDAC2 restores glucocorticoid sensitivity in alveolar macrophages	p. 9
Acetylation of hsp90 and regulation of GR function	p. 10
Other mechanisms of GR action	p. 10
Conclusions	p. 12
Side Effects of Topical and Oral Glucocorticoids	p. 19
Introduction	p. 19
Glucocorticoid-induced side effects	p. 21
Summary	p. 33
Glucocorticoid Receptor Subtypes and Steroid Sensitivity	p. 39
Introduction	p. 39
Overview of classic GR function	p. 40
GR subtypes arising from alternative splicing	p. 43
GR subtypes arising from alternative translation initiation	p. 47
Conclusions	p. 49
Dissociated Glucocorticoids	p. 55
Introduction	p. 55
Asthma and chronic obstructive pulmonary disease are chronic inflammatory diseases of the airways	p. 55
Regulation of inflammatory gene expression	p. 56
Effects on inflammation	p. 57
Mechanisms of glucocorticoid action	p. 58
Dissociated glucocorticoids	p. 60
GR cross-talk with other nuclear receptors and coactivators	p. 62
Overcoming steroid insensitivity	p. 64
Glucorticoid-sparing approaches to anti-inflammatory therapy	p. 65
Conclusion	p. 66
Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms	p. 73
Introduction	p. 73
Molecular mechanisms of glucocorticoid resistance	p. 75
Conclusions	p. 85
Corticosteroid Responsiveness in Asthma: Clinical Aspects	p. 89
Introduction	p. 89
Effects of corticosteroids in asthma	p. 89
Definition of corticosteroid insensitivity	p. 90
Oral CS responsiveness in asthma	p. 91
ICS responsiveness in asthma	p. 94
CS responsiveness in severe asthma	p. 97
Surrogates for CS responsiveness in asthma	p. 99
Pharmacokinetics of systemic CS in severe asthma	p. 100
CS responsiveness in cigarette smokers and chronic obstructive pulmonary disease	p. 101
Other diseases of CS insensitivity	p. 102
Conclusions	p. 102
Glucocorticoid-insensitive Asthma: Molecular Mechanisms	p. 109
Introduction	p. 109
GR abnormalities	p. 110
GR nuclear translocation	p. 112
Cross-talk with transcription factors	p. 115
NF-[kappa]B, GR, histones and chromatin remodelling	p. 116
Epigenetics and asthma	p. 119
Conclusions	p. 120
Cigarette Smoke, Oxidative Stress and Corticosteroid Responsiveness	p. 125
Oxidative stress	p. 125
Cigarette smoke/oxidative stress-induced NF-[kappa]B-mediated pro-inflammatory gene expression	p. 127
Histone acetylation and deacetylation	p. 129
Corticosteroids	p. 129
Histone deacetylases	p. 133
Reversing Glucocorticoids / Corticosteroid resistance	p. 138
Conclusion	p. 141
Regulation of Glucocorticoid Sensitivity by Macrophage Migration Inhibitory Factor	p. 145
Introduction	p. 145
MIF as a pro-inflammatory factor	p. 145
Relationship between MIF and glucocorticoids	p. 151
Conclusions	p. 155
Steroid-sparing Strategies: Long-acting Inhaled [beta subscript 2]-Agonists	p. 163
Introduction	p. 163
Why and when is a steroid-sparing effect of LABA important in asthma?	p. 163
Effects of lower dose ICS/LABA versus a higher dose ICS on lung function, symptoms and use of reliever medication	p. 164
Effects of lower dose ICS/LABA versus higher dose ICS on exacerbations	p. 165
Protocols with tapering ICS doses with and without LABA while maintaining asthma control	p. 166
Reducing ICS doses using an adjustable ICS/LABA dosing regimen	p. 167
Reducing ICS doses using Symbicort maintenance and reliever therapy	p. 168
Does enhanced anti-inflammatory efficacy explain steroid-sparing effects in ICS/LABA therapy?	p. 170
Possible Mechanisms of Steroid-sparing Effects by Addition of LABA to ICS	p. 175
Steroid-sparing Strategies: Other Combinations	p. 187
Introduction	p. 187
Theophylline as steroid-sparing treatment in asthma and COPD	p. 187
Selective inhibitors of PDE4	p. 190
Modulators of the synthesis or action of key inflammatory mediators	p. 193
Anticholinergics	p. 193
Leukotriene synthesis inhibitors and leukotriene receptor antagonists	p. 195
Anti-IgE therapy	p. 198
Macrolides/ketolides	p. 199
TNF[alpha] inhibitors	p. 200
Conclusions	p. 202
Kinases as Anti-inflammatory Targets for Respiratory Disease	p. 207
Introduction	p. 207
Pharmacological targeting of kinases	p. 208
Targeting NF-[kappa]B activation	p. 210
Targeting the MAPKs	p. 217
Targeting PI3K	p. 225
Further potential kinase targets	p. 229
Conclusions	p. 232
Pharmacokinetic/Pharmacodynamic Factors and Steroid Sensitivity	p. 243
Introduction	p. 243
What factors are important for pulmonary efficacy and safety?	p. 243
Pharmacodynamic aspects	p. 246
Pharmacokinetic drug properties	p. 247
Conclusion	p. 257
Improved Lung Deposition: New Inhaler Devices	p. 263
Introduction	p. 263
Historical review of inhaled drug therapy	p. 263
Deposition of aerosols within the respiratory tract	p. 265
Assessing drug deposition in the lungs	p. 268
Aerosol generation devices for inhaled drug therapy	p. 271
Index	p. 283
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Overcoming Steroid Insensitivity in Respiratory Disease

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