Glucocorticoids

One potential explanation for apparently refractory symptoms and airway dysfunction, particularly in clinical practice, is poor treatment adherence. Krishnan and colleagues evaluated this using a range of measures, including an electronic medication monitor, in 60 adults who had been discharged after an episode of acute severe asthma. Poor adherence (< 50% doses taken) was present in one half of the population studied when an assessment was made at 1 week. When present, it was associated with significantly worse symptom control. Perhaps the most important message of this study was that poor adherence was best detected using the electronic medication monitor; self-reported adherence, canister weight, and pill count all had a low sensitivity for detecting poor adherence.

A novel approach to management of patients with severe asthma and persistent eosinophilic airway inflammation is the use of the long-acting corticosteroid triamcinalone. ten Brink and colleagues showed that 2 weeks after an intramuscular injection of 120 mg of triamcinalone, all patients with refractory symptoms and eosinophilic airway inflammation, despite high-dose inhaled and sometimes oral corticosteroid, had an improvement in symptoms, improved FEV₁, and a reduction in the sputum eosinophil count. The study participants were apparently compliant with inhaled and oral treatment before entry into the study, suggesting that intramuscular triamcinolone might have additional properties. However, this management approach might be particularly useful in high-risk patients with poor treatment adherence and persistent eosinophilic airway inflammation.

The use of high-dose inhaled corticosteroids brings into focus the potential adverse effects of therapy and the importance of careful study of systemic toxicity. A good example of the latter is the thorough assessment of adrenal function and bone metabolism after escalating doses of fluticasone and mometasone described by Fardon and colleagues. This study showed approximately equivalent effects of fluticasone and mometasone on a microgram basis on overnight urinary cortisol–creatinine ratio and other markers. These findings are not consistent with the view that mometasone has negligible systemic bioavailability.

Chaudhuri and coworkers asked, "Does cigarette smoking influence the response to oral glucocorticoids in patients with asthma?". To answer this question, they did a randomized, placebo-controlled crossover study of prednisolone (40 mg daily) or placebo for 2 weeks in 14 smokers with asthma, 10 exsmokers with asthma, and 26 never-smokers with asthma. Compared with the smokers with asthma, the never-smokers with asthma showed greater increases in FEV₁ (237 versus 47 ml) and peak expiratory flow (36.8 versus 6.5 liters per minute) and a greater decrease in asthma control score (-0.72 versus -0.05). The exsmokers with asthma showed improvements in morning and nighttime peak expiratory flow (29.1 and 52.4 liter per minute), but not in FEV₁ or asthma control score. The authors conclude that active smoking impairs the efficacy of short-term glucocorticoid therapy in patients with asthma. An editorial commentary by Bel accompanies this article.

The actions of glucocorticoids are determined in part by the type 2 isoform of 11ß-hydroxysteroid dehydrogenase. In a line of human bronchial epithelial cells (BEAS-2B), Suzuki and coworkers determined whether inhibition of this enzyme potentiates the inhibitory action of dexamethasone on release of interleukin-8 and whether the enzyme is upregulated during prolonged treatment with dexamethasone. Carbenoxolone, an inhibitor of 11ß-hydroxysteroid dehydrogenase, increased the potency of dexamethasone almost 10-fold. Incubation of the epithelial cells with increasing concentrations of dexamethasone for up to 72 hours led to considerable increases in messenger RNA and protein levels of the enzyme. Prolonged treatment with dexamethasone increased the activity of the enzyme in a dose- and time-dependent fashion. The authors conclude that bronchial epithelial cells autoregulate the bioactive levels of glucocorticoids by inducing expression of 11ß-hydroxysteroid dehydrogenase type 2 and that this enzyme may locally regulate the action of inhaled glucocorticoids.

To determine whether inhaled glucocorticoid alters the vascular component of airway remodeling, Chetta and coworkers did a randomized, double-blind, parallel-group study of low-dose (100 µg twice daily) and high-dose (500 µg twice daily) fluticasone propionate in 30 patients with mild-to-moderate asthma. At baseline, bronchial biopsies revealed an increase in the number of vessels and vascular area in patients with asthma as compared with eight healthy subjects. In patients with asthma, the number of vessels correlated with vascular area (r = 0.58) and with the number of mast cells (r = 0.67). Both low- and high-dose fluticasone propionate decreased symptoms, bronchial responsiveness to methacholine, and inflammatory cells. Only the high dose of fluticasone propionate caused a decrease in the number of vessels, the vascular area, and thickness of the basement membrane. The authors conclude that a high dose of fluticasone propionate (500 µg twice daily) over 6 weeks alters airway remodeling consequent to a decrease in submucosal vascularity and thickness of the basement membrane.

Studies of hypervascularity of the bronchial wall in the airway remodeling of asthma have been confined to biopsy specimens. To investigate subepithelial vessels in a less invasive manner, Tanaka and coworkers used a novel, high-magnification bronchovideoscope in 24 patients with stable asthma, 13 patients with COPD, and 12 healthy control subjects. In patients with asthma, the redness of the bronchial mucosa seen on conventional bronchoscopy was found to be caused by a fine vascular network. The density of subepithelial vessels, in terms of both area and length, was greater in patients with asthma than in patients with COPD or the healthy subjects. The increase in subepithelial vessels was equivalent in 8 steroid-naive and 16 patients with asthma receiving inhaled glucocorticoids. The authors conclude that patients with asthma have increased subepithelial microvessels in the tracheal mucosa and these vessels are present even in newly diagnosed patients.

In 28 patients with mild asthma, O'Sullivan and coworkers determined whether adding montelukast (10 mg at night) would have an additional effect over inhaled fluticasone propionate (100 µg twice a day) on airway inflammation. Patients received inhaled fluticasone propionate plus montelukast for 8 weeks, and were then crossed over to the alternate treatment for another 8 weeks. After 8 weeks there were no differences in percent-predicted FEV₁ or the dose of histamine producing a 20% decrease in FEV₁. Both treatment arms achieved equivalent decreases in T cells, CD45RO+, mast cells, activated eosinophils in bronchial biopsies, and percentage area stained for interferon- or interleukin-4. The authors conclude that the addition of a leukotriene receptor antagonist, montelukast, did not significantly after the airway inflammatory response in patients with mild asthma as compared with treatment with inhaled fluticasone propionate alone.

To determine whether the addition of a leukotriene receptor antagonist is beneficial in patients being treated with an optimal dose of inhaled glucocorticoid alone or inhaled glucocorticoid combined with a long-acting ß₂-agonist, Currie and coworkers did a double-blind controlled trial in 22 patients with mild-to-moderate asthma. Compared with a 2-week run-in consisting of a combination of fluticasone propionate (250 µg) and salmeterol (50 µg), delivered as 1 puff twice daily, the addition of montelukast (10 mg daily) achieved a reduction in inflammatory mediators, although lung function was not affected. Compared with the fluticasone–salmeterol run-in, the addition of montelukast decreased blood eosinophils, decreased exhaled nitric oxide, decreased the recovery time after adenosine monophosphate challenge, and increased the threshold of adenosine monophosphate. The authors conclude that the addition of montelukast to an inhaled glucocorticoid (alone or in combination with a long-acting ß₂-agonist) produced a decrease in surrogate markers of inflammation without having a beneficial effect on lung function.

In 15 children aged 8 to 14 years, Agertoft and Pedersen compared the lung deposition of budesonide inhaled from a Turbuhaler and fluticasone propionate inhaled from a Diskus. A secondary goal was to investigate whether the study design of pharmacokinetic studies could be simplified. When the two agents were administered on separate days, the mean lung deposition was 30.8% for the Turbuhaler and 8.0% for the Diskus. When the two agents were administered on the same day, the mean lung deposition was 29.5% for the Turbuhaler and 7.6% for the Diskus. The authors conclude that lung deposition is four times higher after inhalation of fluticasone propionate via a Turbuhaler than via a Diskus, and that it is possible to undertake pharmacokinetic studies by administering the two agents on the same day.

Citations 1-12 of 12 total displayed.

Corticosteroid Use after Hospital Discharge among High-risk Adults with Asthma

Jerry A. Krishnan, Kristin A. Riekert, Jonathan V. McCoy, Dana Y. Stewart, Spencer Schmidt, Arjun Chanmugam, Peter Hill, and Cynthia S. Rand
Am. J. Respir. Crit. Care Med. 170: 1281 -1285. First published online as doi:10.1164/rccm.200403-409OC [Abstract] [Full text]  

Adrenal Suppression with Dry Powder Formulations of Fluticasone Propionate and Mometasone Furoate

Tom C. Fardon, Daniel K. C. Lee, Kay Haggart, Lesley C. McFarlane, and Brian J. Lipworth
Am. J. Respir. Crit. Care Med. 170: 960 -966. First published online as doi:10.1164/rccm.200404-500OC [Abstract] [Full text]  

"Refractory" Eosinophilic Airway Inflammation in Severe Asthma: Effect of Parenteral Corticosteroids

Anneke ten Brinke, Aeilko H. Zwinderman, Peter J. Sterk, Klaus F. Rabe, and Elisabeth H. Bel
Am. J. Respir. Crit. Care Med. 170: 601 -605. First published online as doi:10.1164/rccm.200404-440OC [Abstract] [Full text]  

Asthma Exacerbations after Glucocorticoid Withdrawal Reflects T Cell Recruitment to the Airway

Mario Castro, Sharon R. Bloch, Michelle V. Jenkerson, Steve DeMartino, Daniel L. Hamilos, Rebecca B. Cochran, Xueping E. Liang Zhang, Haochuan Wang, Joseph P. Bradley, Kenneth B. Schechtman, and Michael J. Holtzman
Am. J. Respir. Crit. Care Med. 169: 842 -849. First published online as doi:10.1164/rccm.200208-960OC [Abstract] [Full text]  

Increased Airway Vascularity in Newly Diagnosed Asthma Using a High-magnification Bronchovideoscope

Hiroshi Tanaka, Gen Yamada, Toyohiro Saikai, Midori Hashimoto, Shintaro Tanaka, Kazuhiko Suzuki, Masaru Fujii, Hiroki Takahashi, and Shosaku Abe
Am. J. Respir. Crit. Care Med. 168: 1495 -1499. First published online as doi:10.1164/rccm.200306-727OC [Abstract] [Full text]  

Smoking: A Neglected Cause of Glucocorticoid Resistance in Asthma

Elisabeth H. Bel
Am. J. Respir. Crit. Care Med. 168: 1265-1266. [Full text]  

Cigarette Smoking Impairs the Therapeutic Response to Oral Corticosteroids in Chronic Asthma

Rekha Chaudhuri, Eric Livingston, Alex D. McMahon, Lorna Thomson, William Borland, and Neil C. Thomson
Am. J. Respir. Crit. Care Med. 168: 1308 -1311. First published online as doi:10.1164/rccm.200304-503OC [Abstract] [Full text]  

Lung Deposition and Systemic Availability of Fluticasone Diskus and Budesonide Turbuhaler in Children

Lone Agertoft and Søren Pedersen
Am. J. Respir. Crit. Care Med. 168: 779 -782. First published online as doi:10.1164/rccm.200302-200OC [Abstract] [Full text]  

Effects of Montelukast on Surrogate Inflammatory Markers in Corticosteroid-treated Patients with Asthma

Graeme P. Currie, Daniel K. C. Lee, Kay Haggart, Caroline E. Bates, and Brian J. Lipworth
Am. J. Respir. Crit. Care Med. 167: 1232 -1238. First published online as doi:10.1164/rccm.200209-1116OC [Abstract] [Full text]  

Dexamethasone Upregulates 11ß-Hydroxysteroid Dehydrogenase Type 2 in BEAS-2B Cells

Satoshi Suzuki, Kaori Koyama, Andrew Darnel, Hironori Ishibashi, Seiichi Kobayashi, Hiroshi Kubo, Takashi Suzuki, Hironobu Sasano, and Zygmund S. Krozowski
Am. J. Respir. Crit. Care Med. 167: 1244 -1249. First published online as doi:10.1164/rccm.200210-1139OC [Abstract] [Full text]  

Effect of the Addition of Montelukast to Inhaled Fluticasone Propionate on Airway Inflammation

Siobhán O'Sullivan, Martijn Akveld, Conor M. Burke, and Leonard W. Poulter
Am. J. Respir. Crit. Care Med. 167: 745 -750. First published online as doi:10.1164/rccm.200208-783OC [Abstract] [Full text]  

Vascular Component of Airway Remodeling in Asthma Is Reduced by High Dose of Fluticasone

Alfredo Chetta, Andrea Zanini, Antonio Foresi, Mario Del Donno, Antonio Castagnaro, Raffaele D'Ippolito, Simonetta Baraldo, Renato Testi, Marina Saetta, and Dario Olivieri
Am. J. Respir. Crit. Care Med. 167: 751 -757. First published online as doi:10.1164/rccm.200207-710OC [Abstract] [Full text]