Overcoming Steroid Insensitivity in Respiratory Disease 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..

Overcoming Steroid Insensitivity in Respiratory Disease 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.

Contents

1. Molecular Mechanisms of Glucocorticoid Receptor Action

• Glucocorticoid receptor
• Gene induction by GR
• GR transactivation and histone acetylation
• Post-translational modifications of GR
• Repression of NF-êB-induced inflammatory gene expression by GR–NF-êB
• GR–NF-êB cross-talk
• Role of HDAC2 in glucocorticoid function
• Overexpression of HDAC2 restores glucocorticoid sensitivity in alveolar macrophages
• Acetylation of hsp90 and regulation of GR function
• Other mechanisms of GR action

2. Side Effects of Topical and Oral Glucocorticoids

• Glucocorticoid-induced side effects

3. Glucocorticoid Receptor Subtypes and Steroid Sensitivity

• Overview of classic GR function
• GR subtypes arising from alternative splicing
• GR subtypes arising from alternative translation initiation

4. Dissociated Glucocorticoids

• Asthma and chronic obstructive pulmonary disease are chronic inflammatory diseases of the airways
• Regulation of inflammatory gene expression
• Effects on inflammation
• Mechanisms of glucocorticoid action
• Dissociated glucocorticoids
• GR cross-talk with other nuclear receptors and coactivators
• Overcoming steroid insensitivity
• Glucorticoid-sparing approaches to anti-inflammatory therapy

5. Generalized Glucocorticoid Insensitivity: Clinical Phenotype and Molecular Mechanisms

• Molecular mechanisms of glucocorticoid resistance

6. Corticosteroid Responsiveness in Asthma: Clinical Aspects

• Effects of corticosteroids in asthma
• Definition of corticosteroid insensitivity
• Oral CS responsiveness in asthma
• ICS responsiveness in asthma
• CS responsiveness in severe asthma
• Surrogates for CS responsiveness in asthma
• Pharmacokinetics of systemic CS in severe asthma
• CS responsiveness in cigarette smokers and chronic obstructive pulmonary disease
• Other diseases of CS insensitivity

7. Glucocorticoid-insensitive Asthma: Molecular Mechanisms

• GR abnormalities
• GR nuclear translocation
• Cross-talk with transcription factors
• NF-kB, GR, histones and chromatin remodelling
• Epigenetics and asthma

8. Cigarette Smoke, Oxidative Stress and Corticosteroid Responsiveness

• Oxidative stress
• Cigarette smoke/oxidative stress-induced NF-kB-mediated pro-inflammatory gene expression
• Histone acetylation and deacetylation
• Corticosteroids
• Histone deacetylases
• Reversing Glucocorticoids / Corticosteroid resistance

9. Regulation of Glucocorticoid Sensitivity by Macrophage Migration Inhibitory Factor

• MIF as a pro-inflammatory factor
• Relationship between MIF and glucocorticoids

10. Steroid-sparing Strategies: Long-acting Inhaled ß2 -Agonists

• Why and when is a steroid-sparing effect of LABA important in asthma?
• Effects of lower dose ICS/LABA versus a higher dose ICS on lung function, symptoms and use of reliever medication
• Effects of lower dose ICS/LABA versus higher dose ICS on exacerbations
• Protocols with tapering ICS doses with and without LABA while maintaining asthma control
• Reducing ICS doses using an adjustable ICS/LABA dosing regimen
• Reducing ICS doses using Symbicort® maintenance and reliever therapy
• Does enhanced anti-inflammatory efficacy explain steroid-sparing effects in ICS/LABA therapy?
• Possible Mechanisms of Steroid-sparing Effects by Addition of LABA to ICS

11. Steroid-sparing Strategies: Other Combinations

• Theophylline as steroid-sparing treatment in asthma and COPD
• Selective inhibitors of PDE4
• Modulators of the synthesis or action of key inflammatory mediators
• Anticholinergics
• Leukotriene synthesis inhibitors and leukotriene receptor antagonists
• Anti-lgE therapy
• Macrolides/ketolides
• TNFá inhibitors

12. Kinases as Anti-inflammatory Targets for Respiratory Disease

• Pharmacological targeting of kinases
• Targeting NF-êB activation
• Targeting the MAPKs
• Targeting PI3K
• Further potential kinase targets

13. Pharmacokinetic/Pharmacodynamic Factors and Steroid Sensitivity

• What factors are important for pulmonary efficacy and safety?
• Pharmacodynamic aspects
• Pharmacokinetic drug properties

14. Improved Lung Deposition: New Inhaler Devices

• Historical review of inhaled drug therapy
• Deposition of aerosols within the respiratory tract
• Assessing drug deposition in the lungs
• Aerosol generation devices for inhaled drug therapy

Index

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