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Rapid nongenomic actions of inhaled corticosteroids on long-acting ?(2)-agonist transport in the airway.

ABSTRACT: Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting ?(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Corticosteroids caused a rapid, concentration-dependent inhibition of uptake of the cationic formoterol by airway smooth muscle cells, but not airway epithelial cells. Uptake of the non-charged lipophilic salmeterol was corticosteroid-insensitive in both cell types. In smooth muscle cells, inhaled corticosteroids inhibited formoterol uptake with a novel potency rank order: des-ciclesonide > budesonide > beclomethasone 17-monopropionate > beclomethasone dipropionate > ciclesonide > fluticasone. The inhibitory action was rapidly reversible, and was not enhanced by prolonged corticosteroid exposure or sensitive to a transcription inhibitor. Suppression of OCT3 expression using lentivirus-mediated production of shRNA reduced corticosteroid sensitivity of formoterol uptake by smooth muscle cells. Our data support a corticosteroid insensitive absorption and a corticosteroid-sensitive disposition mechanism for cationic long-acting ?(2)-agonist bronchodilators in the airway. Potency rank order and other 'classical' features of anti-inflammatory effects do not apply to inhaled corticosteroids' rapid drug transport actions.

SUBMITTER: Horvath G

PROVIDER: S-EPMC3220932 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature

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Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway.

Horvath Gabor G Mendes Eliana S ES Schmid Nathalie N Schmid Andreas A Conner Gregory E GE Fregien Nevis L NL Salathe Matthias M Wanner Adam A

Pulmonary pharmacology & therapeutics 20110908 6

Corticosteroids inhibit organic cation transporters (OCTs) that play an important role in drug absorption, tissue distribution and elimination. Corticosteroid sensitivity of bronchodilator trafficking in the airway tissue, however, is poorly understood. To assess the effects of inhaled corticosteroids on airway absorption and disposal mechanisms of long-acting β(2)-agonists, human airway epithelial and smooth muscle cell uptake of tritiated formoterol and salmeterol was measured in vitro. Cortic ...[more]

PMID: 21914487

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Project description:BACKGROUND:Both long-acting beta(2)-agonists and inhaled corticosteroids have been recommended in guidelines for the treatment of chronic obstructive pulmonary disease (COPD). Their co-administration in a combined inhaler is intended to facilitate adherence to medication regimens and to improve efficacy. Three preparations are currently available: fluticasone propionate/salmeterol (FPS). budesonide/formoterol (BDF) and mometasone furoate/formoterol (MF/F). OBJECTIVES:To assess the efficacy and safety of combined long-acting beta2-agonist and inhaled corticosteroid (LABA/ICS) preparations, as measured by clinical endpoints and pulmonary function testing, compared with inhaled corticosteroids (ICS) alone, in the treatment of adults with chronic obstructive pulmonary disease (COPD). SEARCH METHODS:We searched the Cochrane Airways Group Specialised Register of trials, which is compiled from systematic searches of multiple literature databases. The search was conducted in June 2013. In addition, we checked the reference lists of included studies and contacted the relevant manufacturers. SELECTION CRITERIA:Studies were included if they were randomised and double-blind. Compared studies combined LABA/ICS with the ICS component. DATA COLLECTION AND ANALYSIS:Two review authors independently assessed trial quality and extracted data. The primary outcomes were exacerbations, mortality and pneumonia. Health-related quality of life (as measured by validated scales), lung function and side effects were secondary outcomes. Dichotomous data were analysed as fixed-effect odds ratios with 95% confidence intervals (CIs), and continuous data as mean differences or rate ratios and 95% CIs. MAIN RESULTS:A total of 15 studies of good methodological quality met the inclusion criteria by randomly assigning 7814 participants with predominantly poorly reversible, severe COPD. Data were most plentiful for the FPS combination. Exacerbation rates were significantly reduced with combination therapies (rate ratio 0.87, 95% CI 0.80 to 0.94, 6 studies, N = 5601) compared with ICS alone. The mean exacerbation rate in the control (ICS) arms of the six included studies was 1.21 exacerbations per participant per year (range 0.88 to 1.60), and we would expect this to be reduced to a rate of 1.05 (95% CI 0.97 to 1.14) among those given combination therapy. Mortality was also lower with the combination (odds ratio (OR) 0.78, 95% CI 0.64 to 0.94, 12 studies, N = 7518) than with ICS alone, but this was heavily weighted by a three-year study of FPS. When this study was removed, no significant mortality difference was noted. The reduction in exacerbations did not translate into significantly reduced rates of hospitalisation due to COPD exacerbation (OR 0.93, 95% CI 0.80 to 1.07, 10 studies, N = 7060). Lung function data favoured combination treatment in the FPS, BDF and MF/F trials, but the improvement was small. Small improvements in health-related quality of life were measured on the St George's Respiratory Questionnaire (SGRQ) with FPS or BDF compared with ICS, but this was well below the minimum clinically important difference. Adverse event profiles were similar between the two treatments arms, and rates of pneumonia when it was diagnosed by chest x-ray (CXR) were lower than those reported in earlier trials. AUTHORS' CONCLUSIONS:Combination ICS and LABA offer some clinical benefits in COPD compared with ICS alone, especially for reduction in exacerbations. This review does not support the use of ICS alone when LABAs are available. Adverse events were not significantly different between treatments. Further long-term assessments using practical outcomes of current and new 24-hour LABAs will help determine their efficacy and safety. For robust comparisons as to their relative effects, long-term head-to-head comparisons are needed.

Project description:BACKGROUND:We previously showed that the long-acting beta agonist (LABA) salmeterol as inhalation powder or metered-dose inhaler improves lung-function parameters assessed by impulse oscillometry (IOS) in 2- to 5-year-old children with reversible-airway disease within 15 minutes. OBJECTIVE:We studied 12- to 45-year-olds with mild persistent asthma in order to compare the onset and extent of peripheral airway effects following the first dose and after 4 weeks dosing with two inhaled corticosteroid (ICS)/LABA combinations: fluticasone propionate/salmeterol 115/21 and budesonide/formoterol 160/4.5. METHODS:Thirty subjects with mild persistent asthma using only an as-needed short-acting beta-agonist (albuterol) who had at least a 40% change in integrated low-frequency reactance postalbuterol were selected and randomized to receive either fluticasone propionate/salmeterol or budesonide/formoterol (15 subjects each). We collected three to six IOS replicates at baseline, at 5, 20, 40, 60, 120, and 240 minutes postdose at randomization, and after 4 weeks of twice-daily dosing. Blinded investigators calculated IOS frequency-dependent resistance and reactance (R5-R20 and AX), indicative of small-airway dysfunction, and also estimated the peripheral airway resistance (Rp ) and peripheral airway compliance (Cp ), using a respiratory-impedance model. RESULTS:At randomization visits, onset of action was detected as early as 5 minutes (t-test, P < 0.05) after fluticasone propionate/salmeterol by Cp , and within 5 minutes after budesonide/formoterol by R5-R20, AX, Rp , and Cp . However, after 4 weeks of dosing, only Rp was significantly different (from 60 to 120 minutes) after fluticasone propionate/salmeterol, while R5-R20, AX, Rp , and Cp were not significantly different within 240 minutes after budesonide/formoterol. CONCLUSION:These two ICS/LABA combinations initially improved the peripheral airway function of 12- to 45-year-old asthmatics significantly in about 5 minutes or less, as measured by R5-R20, AX, Rp , and/or Cp . After regular dosing for 4 weeks, pre- to postdose differences in these parameters had diminished significantly due to improved predose status of peripheral airways. Single dosing with ICS/LABA combinations in mild persistent asthma improves small-airway function, and the effect is maintained over a 12-hour interval by regular use for 4 weeks.

Dataset Information

Rapid nongenomic actions of inhaled corticosteroids on long-acting ?(2)-agonist transport in the airway.

Publications

Rapid nongenomic actions of inhaled corticosteroids on long-acting β(2)-agonist transport in the airway.

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