Formoterol counteracts the inhibitory effect of cigarette smoke on glucocorticoid-induced leucine zipper (GILZ) transactivation in human bronchial smooth muscle cells.

Cigarette smokers with asthma and chronic obstructive pulmonary disease (COPD) are less responsive to glucocorticoids (GCs). The anti-inflammatory action of GCs depends also on their ability to transactivate genes such as GC-induced leucine zipper (GILZ). We investigated the effects of aqueous cigarette smoke extract (CSE) on GILZ transactivation evoked by 17-beclomethasone monopropionate (BMP) or fluticasone propionate (FP) in the presence or absence of the long acting ß2-adrenoceptor agonist (LABA) bronchodilator formoterol or salmeterol in human primary cultures of human bronchial smooth muscle cells (HBSMC). We monitored GC receptor Ser211 phosphorylation by western blot analysis and GC receptor nuclear translocation by immunostaining followed high-content imaging analysis. BMP, as well as FP, induced GILZ expression in a concentration-dependent manner (EC50 of 0.87 and 0.16 nM respectively). Pre-incubation with CSE inhibited GC-evoked GILZ transactivation (>50%), GC receptor Ser211 phosphorylation and nuclear translocation. Both formoterol and salmeterol counteracted the effect of CSE on GC-induced GILZ expression but not on nuclear translocation or phosphorylation. The effect of formoterol was mimicked by the cAMP-elevating agent forskolin and blocked by ICI 118,551, a selective ß2-adrenoceptor antagonist. Pre-incubation with TNF-α also reduced GC-evoked GILZ transactivation but was not counteracted by formoterol undercovering a different responsiveness to LABAs of TNF-α in comparison to CSE. In sum, CSE inhibits GC-evoked transactivation of GILZ and such effect is counteracted by LABAs, through ß2-adrenoceptors and a cAMP-dependent mechanism. This study sheds light on a mechanism underlying complementary interactions between LABAs and inhaled GCs that could be relevant in smokers with asthma and COPD.

Influence of oral beclomethasone dipropionate on early non-infectious pulmonary outcomes after allogeneic hematopoietic cell transplantation: results from two randomized trials.

Early non-infectious pulmonary complications represent a significant cause of mortality after hematopoietic cell transplantation (HCT). We tested the hypothesis that oral beclomethasone dipropionate (BDP) is effective for preventing early non-infectious pulmonary complications after allogeneic HCT. We retrospectively reviewed the medical records of 120 patients, 60 in each treatment arm, to identify non-infectious and infectious pulmonary events and pulmonary function test results from all patients who participated in two randomized trials of oral BDP for treatment of acute gastrointestinal GVHD. 17-Beclomethasone monopropionate (17-BMP), the active metabolite of BDP, was evaluated in blood from the right atrium in four patients. Thirty-three of 42 (79%) placebo-treated patients experienced a decrease of the DL(CO) from pretransplant to day 80 after transplant, compared with 27 of 49 (55%) BDP-treated patients (P=0.02). In the first 200 days after randomization, there were no cases of non-infectious pulmonary complications in BDP-treated patients, vs four cases among placebo-treated patients (P=0.04). Levels of 17-BMP were detected in atrial blood at steady state. Delivery of a potent glucocorticoid such as 17-BMP to the pulmonary artery after oral dosing of BDP may be useful in modulating pulmonary inflammation and preventing the development of non-infectious pulmonary complications after allogeneic HCT.

Manipulation of corticosteroid release from a transiently supersaturated topical metered dose aerosol using a residual miscible co-solvent.

PURPOSE: The creation of supersaturation transiently after application overcomes the issue of drug instability. However, if the solvents used to drive supersaturation evaporate too quickly, drug recrystallisation or rapid film drying can occur which will inhibit drug release. As such the effects of a residual solvent, poly(ethylene glycol) 400 (PEG), on the release, mobility and supersaturation kinetics of a transiently supersaturated formulation were studied. MATERIALS AND METHODS: Metered dose aerosol (MDA) formulations consisting of hydrofluoroalkane 134a, ethanol, poly(vinyl pyrrolidone) K90, beclomethasone dipropionate (BDP), and 0%, 5% or 10% w/w PEG were prepared in canisters sealed with metered dose valves and tested for release and adhesion over time. RESULTS: The addition of 10% PEG to the MDA formulation resulted in a significant reduction (p < 0.05) in steady state drug release rate (230.4 +/- 17.3 microg/cm(2)/h for 0% PEG MDA, 83.6 +/- 4.9 microg/cm(2)/h for 10% PEG MDA). The presence of PEG caused a delay in dose depletion (2 h for 0% PEG MDA versus 4 h for 10% PEG), retarded supersaturation kinetics and increased film drying time. CONCLUSION: Whilst equivalent amounts of BDP were released, the residual solvent altered the drug release profile to achieve more constant delivery.

[Case of idiopathic bronchiolitis obliterans successfully treated by medication].

A 53-year-old woman visited a clinic for stridor and dyspnea, and was treated with steroid and heparin for bronchial asthma and pulmonary embolism. She was later admitted to our hospital for progressive dyspnea. Blood gas analysis showed severe hypoxemia with hypercapnia. Pulmonary funtion tests revealed severe obstractive pulmonary dysfunction. Chest computed tomography showed a mosaic perfusion pattern. Ventilation-perfusion scanning showed bilateral multiple matched defects, especially in the basal region. Since specimens of Video-assisted thoracoscopic surgical (VATS) lung biopsy showed lymphocytic infiltration in membranous bronchiole and occlusion of the membranous bronchiole lumen, bronchiolitis obliterans was diagnosed. We initiated treatment with steroids, macrolides and bronchodilators and her condition stabilized. Although these therapies did not cure the BO, they did retard its progression.

Esophageal candidiasis as a side effect of inhaled fluticasone propionate dry powder: recovery by switching over to hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP).

BACKGROUND: Esophageal candidiasis is one of the local side effects of inhaled corticosteroid treatment, and it is difficult to prevent this condition. Our previous report indicated that the prevalence of esophageal candidiasis among patients treated with inhaled fluticasone propionate dry powder (FP-dp) reached up to 37% in Japanese patients. Although a reduction in the daily dose of inhaled FP-dp can eliminate this infection, it may lead to asthma not being well-controlled in these patients. OBJECTIVE: The aim of this study was to estimate whether switching to an equal daily dose of inhaled hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP), the oropharyngeal deposition of which is very low, can eliminate the infection without deterioration of asthma. METHODS: A total of 10 stable asthmatic patients with esophageal candidiasis, induced by inhaled FP-dp treatment (400 or 800 microg/ day), were enrolled in this study. A second upper GI endoscopy was performed, more than 1 month but less than 3 months after switching to an equal dose of inhaled HFA-BDP with a tube spacer device, Duopacer. The patients' medications were not changed during the study. RESULTS: Esophageal candidiasis was eliminated in 9 of the 10 patients. The degree of candidiasis reduced in another patient. The forced expiratory volume in 1 sec (FEV1.0) did not worsen during the study. CONCLUSION: Switching from FP-dp to HFA-BDP with Duopacer is useful in preventing esophageal candidiasis.

Direct measurement of BDP and 17-BMP in bronchial and peripheral lung tissue after inhalation of HFA- vs CFC-driven aerosols.

Indirect assessments have shown a superior lung deposition of HFA-BDP (Ventolair/Qvar) compared to CFC-BDP (Aerobec). The aim of this study was to assess the concentrations of BDP and its metabolite 17-BMP in airways and peripheral tissue from resected lung specimens after inhalation of these BDP formulations. Immediately prior to surgery for lung cancer, 10 patients inhaled 1000 microg of either CFC-BDP (n = 5) or HFA-BDP (n = 5) Mouthwash was collected after inhalation, and serum before, during, and after surgery. There was no significant difference between CFC and HFA in the concentration of 17-BMP in bronchi (median, 4365 vs 4121 pg/g tissue). After CFC, concentrations of 17-BMP were lower in peripheral tissue (1424 vs 2089 pg/g; ANCOVA, p = 0.001) and in serum taken immediately after inhalation (688 vs 1219 pg/ml, p < 0.01). Furthermore, the CFC group showed a higher concentration of BDP in the mouthwash (17,660 vs 1320 ng/ml, p < 0.05), but the concentration of 17-BMP was lower (452 vs 1028 ng/ml, n.s.). These findings indicate a predominantly peripheral deposition of HFA-BDP, in line with previous data. They also provide evidence for a faster uptake and metabolism of HFA-BDP, probably because BDP is dissolved in HFA and has a smaller particle size distribution than the CFC suspensions.