How Inhaled Corticosteroids Changed Asthma Therapy
Robert P. Schleimer in Inhaled Steroids in Asthma, 2001
In the late 1960s and early 1970s, inhaled corticosteroids became available for clinical evaluation. The experience in these trials eventually led to their use in the treatment of asthma. This represented a major advance and has subsequently revolutionized, in my mind, the treatment of asthma. Prior to the availability of inhaled corticosteroids, asthma therapy primarily involved oral and inhaled bronchodilators. Treatment was, in large part, directed toward rescue therapy. The regular administration of asthma medications, although common, was not the usual practice, and side effects with oral bronchodilators were common.
Osteonecrosis and osteochondritis
Ashley W. Blom, David Warwick, Michael R. Whitehouse in Apley and Solomon’s System of Orthopaedics and Trauma, 2017
Osteonecrosis appears as a distinctive feature in a number of non-traumatic disorders: joint infection, Perthes' disease, caisson disease, Gaucher's disease, systemic lupus erythematosus (SLE), high-dosage corticosteroid administration and alcohol abuse. Various mechanisms leading to capillary thrombosis have been demonstrated in patients with non-traumatic osteonecrosis. Computed tomography (CT) involves considerable radiation exposure and it is not very useful for diagnosing osteonecrosis. Where risk factors for osteonecrosis are recognized, preventive steps can be taken especially in the management of corticosteroid medication and alcohol abuse. 'Spontaneous' osteonecrosis of the knee is similar to osteochondritis dissecans of the medial femoral condyle, but it is distinguished by three important features: it appears in elderly people who are osteoporotic and the lesion invariably appears on the highest part of the medial femoral condyle. Similar 'bone marrow oedema changes' are sometimes seen in areas around typical lesions of osteonecrosis.
Combination Therapies Using Inhaled Corticosteroids
Robert P. Schleimer in Inhaled Steroids in Asthma, 2001
The reappraisal of bronchial asthma as being a chronic inflammatory disease of the airways (1) resulted in the late 1980s and early 1990s in a number of asthma treatment guidelines. Before the introduction of long-acting inhaled bronchodilators and leukotriene receptor antagonists, the treatment guidelines recommended a stepwise increase (from step 2 to step 4) in the daily doses of inhaled corticosteroids. With increasing knowledge about the efficacy and safety profiles of inhaled corticosteroids, it became apparent that their benefit /risk ratio peaked somewhere around daily doses of 1000 mg. Up to this dose level a dose-dependent increase in efficacy can be demonstrated, but increasing the daily dose to 2000 mg per day and higher increases the risk of systemic side effects and does not result in additional benefits for the majority of patients with asthma (2). The first guidelines to mention a treatment alternative for step 3-a moderate dose of an inhaled corticosteroid plus a long-acting inhaled b2-agonist-was the Swedish guidelines published in 1992 (3). This treatment alternative is also recommended in the most widely distributed document, the Global Initiative for Asthma (GINA) guidelines (4).
Therapeutic targets for new therapy for corticosteroid refractory asthma
Published in Expert Opinion on Therapeutic Targets, 2009
Background: Corticosteroids are the most potent anti-inflammatory agents for the treatment of mild to moderate asthma. However, a small percentage of the asthma population (< 10%) do not respond well, or at all, to corticosteroid therapy, and this severe corticosteroid-refractory asthma contributes to more than 50% of health care expenditure for all asthma because these is no appropriate pharmacological therapy. Methods: If the molecular mechanism of corticosteroid insensitivity is uncovered, it may in turn provide insights into the key mechanism of corticosteroid action and rational implementation of treatment regimens that restore corticosteroid sensitivity or replace corticosteroid therapy. This review focuses on why severe asthma patients are corticosteroid-insensitive, and discusses present and future therapeutic and preventative strategies for corticosteroid-refractory asthma. Conclusions: Corticosteroid-refractory asthma is a heterogeneous disease and can be controlled by add-on treatment of corticosteroid-sparing agents or effective new drugs based on individual abnormalities. The elucidation of the cause of the relative lack of corticosteroid response in this subgroup of asthmatic individuals may have important implications for other diseases.
Oxidative stress and steroid resistance in asthma and COPD: pharmacological manipulation of HDAC-2 as a therapeutic strategy
Published in Expert Opinion on Therapeutic Targets, 2007
John A Marwick, Kazuhiro Ito, Ian M Adcock, Paul A Kirkham
Insensitivity to corticosteroid treatment in inflammatory conditions, such as asthma and chronic obstructive pulmonary disease, present considerable management problems and cost burdens to health services. Oxidative stress is a major component of chronic inflammation and can have a significant suppressive effect on corticosteroid efficacy. Recent advances in the understanding of both the mechanisms of corticosteroid action and corticosteroid insensitivity have provided hope for a therapeutic strategy of restoring corticosteroid sensitivity. Histone deacetylase 2 (HDAC-2) plays a pivotal role in corticosteroid action and is reduced in many cases of steroid insensitivity. Moreover, it has shown that oxidative stress can be responsible for this reduction in HDAC-2 activity. Two structurally different compounds; methyl-xanthine theophylline and polyphenol curcumin restore HDAC activity, thereby restoring corticosteroid function. Low, subbronchodilator doses of theophylline can also act as corticosteroid-sparing drugs in asthmatics. Although these compounds appear to restore corticosteroid function and may initially provide therapeutic potential, they lack specificity and the mechanism of their action is unknown. Once their mechanisms of action are established, it is likely that derivatives of these compounds may be used as a therapeutic strategy to restore corticosteroid insensitivity in the future.
Quercetin restores corticosteroid sensitivity in cells from patients with chronic obstructive pulmonary disease
Published in Experimental Lung Research, 2017
Akihisa Mitani, Aishah Azam, Chaitanya Vuppusetty, Kazuhiro Ito, Nicolas Mercado, Peter J. Barnes
ABSTRACT Corticosteroid resistance is a major barrier to the effective treatment of chronic obstructive pulmonary disease (COPD). Oxidative stress from cigarette smoke and chronic inflammation is likely to induce this corticosteroid insensitivity. Quercetin is a polyphenol that has been reported to be an active oxygen scavenger as well as a functional adenosine monophosphate-activated protein kinase (AMPK) activator. The aim of this study was to investigate the effect of quercetin on corticosteroid responsiveness in COPD cells. Corticosteroid sensitivity was examined in human monocytic U937 cells exposed to cigarette smoke extract (CSE) and peripheral blood mononuclear cells (PBMC) collected from patients with COPD. Corticosteroid sensitivity was determined as the dexamethasone concentration causing 40% inhibition of tumor necrosis factor alpha-induced CXCL8 production (Dex-IC40) in the presence or absence of quercetin. In U937 cells, treatment with quercetin activated AMPK and induced expression of nuclear factor erythroid 2-related factor 2, and consequently reversed CSE-induced corticosteroid insensitivity. PBMC from patients with COPD showed corticosteroid insensitivity compared with those from healthy volunteers, and treatment with quercetin restored corticosteroid sensitivity. In conclusion, quercetin restores corticosteroid sensitivity, and has the potential to be a novel treatment in combination with corticosteroids in COPD.
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