Can the response to a single dose of beclomethasone dipropionate predict the outcome of long-term treatment in childhood exercise-induced bronchoconstriction?

BACKGROUND: Exercise-induced bronchoconstriction (EIB) is a frequent and highly specific symptom of childhood asthma. Inhaled corticosteroids (ICS) are the mainstay of controller therapy for EIB and asthma; however, a proportion of asthmatic children and adolescents is less responsive to ICS. We hypothesized that a single dose response to ICS could function as a predictor for individual long-term efficacy of ICS. OBJECTIVE: To assess the predictive value of the bronchoprotective effect of a single-dose beclomethasone dipropionate (BDP) against EIB for the bronchoprotective effect of 4 weeks of treatment, using an exercise challenge test (ECT). METHODS: Thirty-two steroid-naïve children and adolescents aged 6 to 18 years with EIB were included in this prospective cohort study. They performed an ECT at baseline, after a single-dose BDP (200µg) and after 4 weeks of BDP treatment (100 µg twice daily) to assess EIB severity. RESULTS: The response to a single-dose BDP on exercise-induced fall in FEV1 showed a significant correlation with the response on exercise-induced fall in FEV1 after 4 weeks of BDP treatment (r = .38, p = .004). A reduction in post-exercise fall in FEV1 of more than 8% after a single-dose BDP could predict BDP efficacy against EIB after 4 weeks of treatment with a positive predictive value of 100% (CI: 86.1-100%) and a negative predictive value of 29.4% (CI: 11.7%-53.7%). CONCLUSION: We found that the individual response to a single-dose BDP against EIB has a predictive value for the efficacy of long-term treatment with BDP. This could support clinicians in providing personalized management of EIB in childhood asthma.

Impact of body mass index on omalizumab response in adults with moderate-to-severe allergic asthma.

BACKGROUND: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI). OBJECTIVE: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category. METHODS: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m2 [normal or underweight], n = 397; 25 to <30 kg/m2 [overweight], n = 330; ≥ 30 kg/m2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance. RESULTS: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39]). CONCLUSION: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI. TRIAL REGISTRATION: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available.

Curcumin activates G protein-coupled receptor 97 (GPR97) in a manner different from glucocorticoid.

Curcumin is a yellow pigment in turmeric (Curcuma longa) with various physiological effects in the body. To elucidate the molecular mechanisms by which bioactive compounds exert their function, identification of their molecular targets is crucial. In this study, we show that curcumin activates G protein-coupled receptor 97 (GPR97). Curcumin dose-dependently activated serum-response element-, but not serum-response factor-response element-, nuclear factor of activated T-cell-response element-, or cAMP-response element-, mediated transcription in cells overexpressed with GPR97. The structure-activity relationship indicated that (i) the double-bonds of the central 7-carbon chain were essential for activation; (ii) a methoxy group on the aromatic ring was required for maximal activity; (iii) the addition of glucuronic acid moiety or a methoxy group to the aromatic ring, but not the methylation of the aromatic p-hydroxy group, eliminated the activity; (iv) the stability of curcumin would be related to receptor activation. Both mutant GPR97(T250A) lacking the cleavage at GPCR proteolysis site and mutant GPR97(ΔN) lacking the N-terminal extracellular region were activated by curcumin and its related compounds similar to wild-type GPR97. In contrast, the synthetic glucocorticoid beclomethasone dipropionate and l-Phe activated wild-type GPR97 and GPR97(T250A), but not GPR97(ΔN). Moreover, curcumin exerted an additive effect on the activation of wild-type GPR97 with beclomethasone dipropionate, but not with l-Phe. Taken together, these results indicate that curcumin activates GPR97 coupled to Gi/Go subunit, and suggest that curcumin and glucocorticoid activate GPR97 in a different manner.

Bronchodilating effects of a new beclometasone dipropionate plus formoterol fumarate formulation via pressurized metered-dose inhaler in asthmatic children: a double-blind, randomized, cross-over clinical study.

A new pediatric fixed combination of beclometasone dipropionate (BDP) 50 µg and formoterol fumarate (FF) 6 µg via pressurized metered-dose inhaler (pMDI) (CHF1535, Chiesi, Italy) was investigated. In a double-blind, randomized, placebo-controlled, cross-over study, a single CHF1535 administration using AeroChamber Plus™ spacer device (2 actuations, total dose BDP 100 µg/FF 12 µg) was compared to the same pMDI free combination in 56 asthmatic children aged ≥ 5 and < 12 years. Primary efficacy variable was forced expiratory volume during the first second (FEV1) area under the curve corrected by time over 12 h following morning dose (AUC0-12h). Further CHF1535 doses (50 µg/6 µg, 100 µg/12 µg, and 200 µg/24 µg) were also explored. Adverse events, electrocardiogram, and vital signs were monitored for safety. CHF1535 was non-inferior to free combination [adjusted mean difference (95% CI) 0.004 L (- 0.050, 0.041] with lower confidence limit greater than the limit set at 0.1 L. FEV1 AUC0-12h of each CHF1535 dose vs placebo were 0.037 L (p = 0.160), 0.119 L (p < 0.001), and 0.094 (p < 0.001) for 50/6, 100/12, and 200/24, respectively. No safety signals were found.Conclusion: CHF1535 was as effective as free combination BDP/FF, with a trend towards a dose-related response. All treatments were safe.Trial registration: ClinicalTrials.gov ID: NCT01584492 What is Known: •Inhaled pressurized metered-dose solutions (pMDI) are the preferred treatment for pediatric asthma. •Combination therapy of inhaled corticosteroids and long-acting ß2- agonists is a well-established approach to control airway inflammation and airway obstruction also in pediatric patients. What is New: •A novel pediatric pMDI fixed combination of beclomethasone dipropionate 50 µg and formoterol fumarate 6 µg (CHF 1535) was non-inferior to the free combination at the same dose in pulmonary function over the 12-h post-dose period in asthmatic children, with trend towards a dose-related response.

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: Synergy of triple combination therapy on human airway smooth muscle ex vivo.

BACKGROUND AND PURPOSE: Combining inhaled corticosteroids (ICSs), long-acting ß2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA glycopyrronium bromide in human airways. EXPERIMENTAL APPROACH: Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. KEY RESULTS: Beclomethasone/formoterol/glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of ß2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. CONCLUSION: Triple beclomethasone/formoterol/glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.

Pharmacokinetics, pharmacodynamics and safety of a novel extrafine BDP/FF/GB combination delivered via metered-dose inhaler in healthy Chinese subjects.

BACKGROUND: BDP/FF/GB pMDI is a novel triple fixed-dose combination of extra-fine inhalation aerosol beclomethasone dipropionate (BDP)/formoterol fumarate (FF)/glycopyrronium bromide (GB). Limited data on the pharmacokinetic (PK) and pharmacodynamic (PD) properties of BDP/FF/GB fixed-dose combination in healthy subjects was available. PURPOSES: This study aimed to evaluate the pharmacokinetics, pharmacodynamics and safety of BDP/FF/GB pMDI in healthy Chinese subjects. METHODS: This is an open-label, parallel-group, randomized, single and multiple dose study. In the single dose group, subjects received single supra-therapeutic inhaled dose of BDP/FF/GB pMDI (BDP/FF/GB 400/24/50 µg). In the multiple dose group, subjects received therapeutic inhaled dose of BDP/FF/GB pMDI (BDP/FF/GB 200/12/25 µg), twice daily, for 7 consecutive days. Plasma BDP, B17MP, formoterol and GB were determined by a validated ultra performance liquid chromatography method with tandem mass spectrometric detection (UPLC/MS-MS). Heart rate (HR), QTcF, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated as the surrogate indicators of pharmacodynamic effects. RESULTS: A total of 24 subjects were randomized and 22 (11 in each group) completed the study. The dose adjusted pharmacokinetic profiles of BDP, beclomethasone-17-monopropionate (B17MP, the most active metabolite of BDP), formoterol and GB were overall similar in therapeutic and supra- therapeutic dose group, showing dose proportional increase of the systemic exposure to BDP, B17MP, formoterol and GB. The pharmacodynamic variables were within the normal range and showed no significant difference between the two groups. All the treatment-emergent adverse events (TEAEs) were mild and no severe TEAE was reported. CONCLUSIONS: Dose adjusted PK profiles were similar between therapeutic and supra-therapeutic dose for all compounds, nearly dose proportional systemic exposure to B17MP, formoterol and GB after BDP/FF/GB pMDI administration in healthy Chinese subjects. BDP/FF/GB pMDI was safe and well tolerated in healthy Chinese subjects. The PK profiles were comparable to previously published data from Western European healthy Caucasian subjects.

Inhaled corticosteroids in children with persistent asthma: effects of different drugs and delivery devices on growth.

BACKGROUND: Inhaled corticosteroids (ICS) are the most effective treatment for children with persistent asthma. Although treatment with ICS is generally considered to be safe in children, the potential adverse effects of these drugs on growth remains a matter of concern for parents and physicians. OBJECTIVES: To assess the impact of different inhaled corticosteroid drugs and delivery devices on the linear growth of children with persistent asthma. SEARCH METHODS: We searched the Cochrane Airways Trials Register, which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, Embase, CINAHL, AMED and PsycINFO. We handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases, or contacted the manufacturer, to search for potential relevant unpublished studies. The literature search was initially conducted in September 2014, and updated in November 2015, September 2018, and April 2019. SELECTION CRITERIA: We selected parallel-group randomized controlled trials of at least three months' duration. To be included, trials had to compare linear growth between different inhaled corticosteroid molecules at equivalent doses, delivered by the same type of device, or between different devices used to deliver the same inhaled corticosteroid molecule at the same dose, in children up to 18 years of age with persistent asthma. DATA COLLECTION AND ANALYSIS: At least two review authors independently selected studies and assessed risk of bias in included studies. The data were extracted by one author and checked by another. The primary outcome was linear growth velocity. We conducted meta-analyses using Review Manager 5.3 software. We used mean differences (MDs) and 95% confidence intervals (CIs ) as the metrics for treatment effects, and the random-effects model for meta-analyses. We did not perform planned subgroup analyses due to there being too few included trials. MAIN RESULTS: We included six randomized trials involving 1199 children aged from 4 to 12 years (per-protocol population: 1008), with mild-to-moderate persistent asthma. Two trials were from single hospitals, and the remaining four trials were multicentre studies. The duration of trials varied from six to 20 months.One trial with 23 participants compared fluticasone with beclomethasone, and showed that fluticasone given at an equivalent dose was associated with a significant greater linear growth velocity (MD 0.81 cm/year, 95% CI 0.46 to 1.16, low certainty evidence). Three trials compared fluticasone with budesonide. Fluticasone given at an equivalent dose had a less suppressive effect than budesonide on growth, as measured by change in height over a period from 20 weeks to 12 months (MD 0.97 cm, 95% CI 0.62 to 1.32; 2 trials, 359 participants; moderate certainty evidence). However, we observed no significant difference in linear growth velocity between fluticasone and budesonide at equivalent doses (MD 0.39 cm/year, 95% CI -0.94 to 1.73; 2 trials, 236 participants; very low certainty evidence).Two trials compared inhalation devices. One trial with 212 participants revealed a comparable linear growth velocity between beclomethasone administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) and beclomethasone administered via chlorofluorocarbon-metered dose inhaler (CFC-MDI) at an equivalent dose (MD -0.44 cm/year, 95% CI -1.00 to 0.12; low certainty evidence). Another trial with 229 participants showed a small but statistically significant greater increase in height over a period of six months in favour of budesonide via Easyhaler, compared to budesonide given at the same dose via Turbuhaler (MD 0.37 cm, 95% CI 0.12 to 0.62; low certainty evidence). AUTHORS' CONCLUSIONS: This review suggests that the drug molecule and delivery device may impact the effect size of ICS on growth in children with persistent asthma. Fluticasone at an equivalent dose seems to inhibit growth less than beclomethasone and budesonide. Easyhaler is likely to have less adverse effect on growth than Turbuhaler when used for delivery of budesonide. However, the evidence from this systematic review of head-to-head trials is not certain enough to inform the selection of inhaled corticosteroid or inhalation device for the treatment of children with persistent asthma. Further studies are needed, and pragmatic trials and real-life observational studies seem more attractive and feasible.

Glucocorticoids inhibit macrophage differentiation towards a pro-inflammatory phenotype upon wounding without affecting their migration.

Glucocorticoid drugs are widely used to treat immune-related diseases, but their use is limited by side effects and by resistance, which especially occurs in macrophage-dominated diseases. In order to improve glucocorticoid therapies, more research is required into the mechanisms of glucocorticoid action. In the present study, we have used a zebrafish model for inflammation to study glucocorticoid effects on the innate immune response. In zebrafish larvae, the migration of neutrophils towards a site of injury is inhibited upon glucocorticoid treatment, whereas migration of macrophages is glucocorticoid resistant. We show that wounding-induced increases in the expression of genes that encode neutrophil-specific chemoattractants (Il8 and Cxcl18b) are attenuated by the synthetic glucocorticoid beclomethasone, but that beclomethasone does not attenuate the induction of the genes encoding Ccl2 and Cxcl11aa, which are required for macrophage recruitment. RNA sequencing on FACS-sorted macrophages shows that the vast majority of the wounding-induced transcriptional changes in these cells are inhibited by beclomethasone, whereas only a small subset is glucocorticoid-insensitive. As a result, beclomethasone decreases the number of macrophages that differentiate towards a pro-inflammatory (M1) phenotype, which we demonstrated using a tnfa:eGFP-F reporter line and analysis of macrophage morphology. We conclude that differentiation and migration of macrophages are regulated independently, and that glucocorticoids leave the chemotactic migration of macrophages unaffected, but exert their anti-inflammatory effect on these cells by inhibiting their differentiation to an M1 phenotype. The resistance of macrophage-dominated diseases to glucocorticoid therapy can therefore not be attributed to an intrinsic insensitivity of macrophages to glucocorticoids.

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.

Single inhaler triple therapy with extrafine beclomethasone, formoterol, and glycopyrronium for the treatment of chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) management focuses on the alleviation of symptoms and prevention of exacerbations. Inhaled long acting bronchodilators and inhaled corticosteroids (ICS) are the main classes of treatment for COPD. Triple therapy with a long acting beta2-agonist (LABA), long acting muscarinic antagonist (LAMA), and ICS is commonly prescribed for symptomatic COPD patients experiencing regular exacerbations. Triple therapy is usually administered using separate inhalers; there is little clinical trial evidence of an effect on exacerbation prevention with this approach. Areas covered: This evaluation reviews the single inhaler extrafine combination containing beclometasone diproprionate (BDP), formoterol fumarate (FF), and glycopyrronium bromide (GB) which has been developed as a simplified triple regime. BDP/FF/GB significantly reduced exacerbation rates in three clinical trials (1-year duration) compared against LAMA monotherapy (20% exacerbation reduction), ICS/LABA combination (23% exacerbation reduction), and LAMA/LABA combination (15% exacerbation reduction). Expert opinion: The practical benefits of single inhaler triple therapy in the real world have not been studied. However, the robust clinical trial evidence that BDP/FF/GB reduces exacerbations compared to double combination treatments and LAMA monotherapy cements triple therapy positioning as an escalation step in COPD management pathways.

Effect of delayed pMDI actuation on the lung deposition of a fixed-dose combination aerosol drug.

Lack of coordination between the beginning of the inhalation and device triggering is one of the most frequent errors reported in connection with the use of pMDI devices. Earlier results suggested a significant loss in lung deposition as a consequence of late actuation. However, most of our knowledge on the effect of poor synchronization is based on earlier works on CFC devices emitting large particles with high initial velocities. The aim of this study was to apply numerical techniques to analyse the effect of late device actuation on the lung dose of a HFA pMDI drug emitting high fraction of extrafine particles used in current asthma and COPD therapy. A computational fluid and particle dynamics model was combined with stochastic whole lung model to quantify the amount of drug depositing in the extrathoracic airways and in the lungs. High speed camera measurements were also performed to characterize the emitted spray plume. Our results have shown that for the studied pMDI drug late actuation leads to reasonable loss in terms of lung dose, unless it happens in the second half of the inhalation period. Device actuation at the middle of the inhalation caused less than 25% lung dose reduction relative to the value characterizing perfect coordination, if the inhalation time was between 2 and 5 s and inhalation flow rate between 30 and 150 L/min. This dose loss is lower than the previously known values of CFC devices and further support the practice of triggering the device shortly after the beginning of the inhalation instead of forcing a perfect synchronization and risking mishandling and poor drug deposition.

[Treatment of allergic and vasomotor rhinitis: the role of beclomethasone dipropionate and hyaluronic acid (with high molecular weight).] / Trattamento delle riniti allergiche e vasomotorie: il ruolo del beclometasone dipropionato e dell'acido ialuronico (ad alto peso molecolare).

Inflammatory rhinitis is a very common disorder. It includes allergic rhinitis (AR) and non-allergic rhinitis (NAR). Nasal inflammation is shared by both disorders. So, anti-inflammatory treatment is indicated for both. Beclomethasone dipropionate (BDP) is a corticosteroid that is long time available both as intranasal spray and aerosol solution. BDP is a corticosteroid with proved efficacy in the treatment of rhinitis, both as spray and aerosol. Safety issue has been satisfactory explored, thus BDP is usually safe and well tolerated. Hyaluronic acid (HA) with high molecular weight has anti-inflammatory activity associated with wetting-lubricating effect. BDP may be usefully employed in acute forms, HA may be also used in chronic ones.

The beclomethasone anti-inflammatory effect occurs in cell/mediator-dependent manner and is additively enhanced by formoterol: NFkB, p38, PKA analysis.

AIMS: Beclomethasone/formoterol (BDP/FOR) has been reported to be more effective than its separate components in airway disease control and in airway inflammation improvement. However, BDP/FOR effects on cytokine-induced inflammation in structural cells have not been described and whether these effects occur in a cell- and mediator-dependent manner has not been fully elucidated. We sought to evaluate BDP and/or FOR effects on endothelial ICAM-1, E-selectin, IL-8 and on bronchial epithelial ICAM-1 and IL-8. Specific intracellular signaling pathways were also investigated. MATERIALS AND METHODS: Surface adhesion molecule expression and IL-8 release induced by TNF-alpha were measured by ELISA. Intracellular signaling pathways were investigated by a) EMSA and Western blot analysis to evaluate NF-κB DNA-binding and MAPK-p38 phosphorylation; b) PDTC/SB203580 as NF-κB/p38 inhibitors; c) forskolin/H-89 as PKA activator/inhibitor. KEY FINDINGS: BDP/FOR additively reduced endothelial E-selectin and IL-8 as well as bronchial epithelial ICAM-1 and IL-8. BDP/FOR and SB203580 showed the highest inhibitory effect on epithelial IL-8, whereas endothelial ICAM-1 was never affected by BDP/FOR and PDTC. TNF-alpha-induced NF-κB DNA-binding and MAPK-p38 phosphorylation were not influenced by BDP/FOR. Forskolin mimicked FOR effects; H-89 partially reversed the BDP/FOR inhibition in a mediator-dependent manner. SIGNIFICANCE: The BDP/FOR inhibition degree was related to the inflammatory mediator- and cell-type considered. FOR additively enhanced BDP effects by partially involving both dependent- and independent-PKA mechanisms. Our results might contribute to highlight the strong relationship between specific molecular pathways and different sensitivity to the corticosteroid/ß2-agonist effects and to clarify the molecular mechanisms underlying the BDP/FOR anti-inflammatory activity in vivo.

Opportunity and challenges of nasal powders: Drug formulation and delivery.

In the field of nasal drug delivery, among the preparations defined by the European Pharmacopoeia, nasal powders facilitate the formulation of poorly water-soluble active compounds. They often display a simple composition in excipients (if any), allow for the administration of larger drug doses and enhance drug diffusion and absorption across the mucosa, improving bioavailability compared to nasal liquids. Despite the positive features, however, nasal products in this form still struggle to enter the market: the few available on the market are Onzetra Xsail® (sumatriptan) for migraine relief and, for the treatment of rhinitis, Rhinocort® Turbuhaler® (budesonide), Teijin Rhinocort® (beclomethasone dipropionate) and Erizas® (dexamethasone cipecilate). Hence, this review tries to understand why nasal powder formulations are still less common than liquid ones by analyzing whether this depends on the lack of (i) real evidence of superior therapeutic benefit of powders, (ii) therapeutic and/or commercial interest, (iii) efficient manufacturing methods or (iv) availability of suitable and affordable delivery devices. To this purpose, the reader's attention will be guided through nasal powder formulation strategies and manufacturing techniques, eventually giving up-to-date evidences of therapeutic efficacy in vivo. Advancements in the technology of insufflation devices will also be provided as nasal drug products are typical drug-device combinations.

Effectiveness of inhaled corticosteroids in real life on clinical outcomes, sputum cells and systemic inflammation in asthmatics: a retrospective cohort study in a secondary care centre.

OBJECTIVES: The impact of inhaled corticosteroids (ICS) on eosinophilic inflammation in asthma is well established, but their effect in a real-life setting has not been extensively studied. Our purpose was to investigate the effect of ICS on airway and systemic inflammation as well as on clinical outcomes in patients with asthma from clinical practice. DESIGN, SETTING AND PARTICIPANTS: We conducted a retrospective analysis on asthmatics from a secondary care centre in whom ICS were initiated/increased (n=101), stopped/decreased (n=60) or remained stable (n=63, used as a control group) between two visits with available sputum and blood cell counts. RESULTS: The median time between both visits ranged from 1 to 2 years. Initiating or increasing ICS (median variation (IQR): 800 (400-1200) µg beclomethasone equivalent dose per day) reduced sputum eosinophils and fractional exhaled nitric oxide (P<0.0001) and to a lesser extent blood eosinophils (P<0.0001), while withdrawing or decreasing ICS (median variation (IQR): 900 (500-1200) µg beclomethasone equivalentdose per day) resulted in increased sputum eosinophils (P=0.008). No change was found in patients with a stable dose. The effectiveness of ICS in improving asthma control, quality of life, forced expiratory volume in 1 s (FEV1), bronchial hyper-responsiveness and exacerbation rate was only observed in the eosinophilic phenotype (sputum eosinophils ≥3%, n=79). In non-eosinophilic asthmatics, stepping-down ICS resulted in an improvement in asthma control and quality of life, without any significant change in FEV1 (n=38). CONCLUSIONS: Our results confirm the effectiveness of ICS on eosinophilic inflammation in real life and demonstrate that their clinical benefit seems to be restricted to eosinophilic asthmatics. Our data also support a try for stepping-down ICS in non-eosinophilic asthmatics.

Budesonide, fluticasone propionate, and azithromycin do not modulate the membrane vesicle release by THP-1 macrophages and respiratory pathogens during macrophage infection.

Patients with more severe chronic obstructive pulmonary disease frequently experience exacerbations and it is estimated that up to 50% of these exacerbations are associated with bacterial infections. The mainstay treatment for these infection-related exacerbations constitutes the administration of glucocorticoids, alone or in combination with antibiotics. A recent line of evidence demonstrates that many hormones including the steroid beclomethasone can also directly affect bacterial growth, virulence, and antibiotic resistance. The effect of these regimens on the release of potentially virulent and toxic membrane vesicles (MVs) is at present unclear. In this study, we determined the effect of several pharmacological agents on MVs release by and bacterial growth of common respiratory pathogens. We found that neither the release of MVs nor the bacterial growth was affected by the glucocorticoids budesonide and fluticasone. The macrolide antibiotic azithromycin only inhibited the growth of Moraxella catarrhalis but no effects were observed on bacterial MV release at a concentration that is achieved locally in the epithelial lining on administration. The macrophage pro-inflammatory response to MVs was significantly reduced after treatment with budesonide and fluticasone but not by azithromycin treatment. Our findings suggest that these glucocorticoids may have a positive effect on infection-related inflammation although the bacterial growth and MV release remained unaffected.

Effects of Carbocysteine and Beclomethasone on Histone Acetylation/Deacetylation Processes in Cigarette Smoke Exposed Bronchial Epithelial Cells.

Histone deacetylase expression/activity may control inflammation, cell senescence, and responses to corticosteroids. Cigarette smoke exposure, increasing oxidative stress, may negatively affect deacetylase expression/activity. The effects of cigarette smoke extracts (CSE), carbocysteine, and beclomethasone dipropionate on chromatin remodeling processes in human bronchial epithelial cells are largely unknown. The present study was aimed to assess the effects of cigarette smoke, carbocysteine, and beclomethasone dipropionate on histone deacetylase 3 (HDAC3) expression/activity, N-CoR (nuclear receptor corepressor) expression, histone acetyltransferases (HAT) (p300/CBP) expression, p-CREB and IL-1 m-RNA expression, neutrophil chemotaxis. Increased p-CREB expression was observed in the bronchial epithelium of smokers. CSE increased p-CREB expression and decreased HDAC3 expression and activity and N-CoR m-RNA and protein expression. At the same time, CSE increased the expression of the HAT, p300/CBP. All these events increased acetylation processes within the cells and were associated to increased IL-1 m-RNA expression and neutrophil chemotaxis. The incubation of CSE exposed cells with carbocysteine and beclomethasone counteracted the effects of cigarette smoke on HDAC3 and N-CoR but not on p300/CBP. The increased deacetylation processes due to carbocysteine and beclomethasone dipropionate incubation is associated to reduced p-CREB, IL-1 m-RNA expression, neutrophil chemotaxis. These findings suggest a new role of combination therapy with carbocysteine and beclomethasone dipropionate in restoring deacetylation processes compromised by cigarette smoke exposure. J. Cell. Physiol. 232: 2851-2859, 2017. © 2016 Wiley Periodicals, Inc.

Knemometry is more sensitive to systemic effects of inhaled corticosteroids in children with asthma than 24-hour urine cortisol excretion.

BACKGROUND: Pharmacodynamic assessment of the systemic effect of inhaled corticosteroids (ICSs) is often done by measuring 24-hour urine free cortisol (UFC) excretion. Knemometry assessing short-term lower-leg growth rate (LLGR) is a more rarely used alternative. OBJECTIVE: The primary aim of this study was to compare the sensitivity of LLGR and 24-hour UFC excretion for evaluating systemic exposure to ICSs in prepubertal children with asthma. The secondary aim was to evaluate factors influencing the precision of LLGR calculated by the traditional 1 leg nonparametric method versus a new 2 leg parametric method. METHODS: The study evaluated 60 children with mild asthma aged 5 to 12 years participating in a randomized controlled trial of ICSs with longitudinal concomitant assessments of LLGR and 24-hour UFC excretion. The sensitivity of the safety assessments was analyzed by comparing LLGR and 24-hour UFC in the placebo run-in period with values in the ICS treatment period by using paired t tests. Factors with a potential influence on LLGR were analyzed by means of ANOVA and the Levene test of homogeneity. RESULTS: The mean LLGR was significantly reduced during the ICS versus placebo run-in periods: 0.18 mm/wk (SD, 0.55 mm/wk) versus 0.45 mm/wk (SD, 0.39 mm/wk), with a mean difference of 0.27 mm/wk (95% CI, 0.05-0.48 mm/wk; P = .02). In contrast, there was no difference in 24-hour UFC excretion: 6.91 nmol/mmol (SD, 4.67 nmol/mmol) versus 7.58 nmol/mmol (SD, 6.17 nmol/mmol), with a mean difference of 0.67 nmol/mmol (95% CI, -1.13 to 2.48 nmol/mmol; P = .46). We observed no significant difference in parametric determined LLGR caused by the child's age or sex, investigator, or season of measurement, whereas some differences were observed for the nonparametric LLGR. CONCLUSION: These findings suggest that knemometry is a more sensitive pharmacodynamic measure of systemic effects of ICSs than 24-hour UFC excretion and that a parametric determination of LLGR increases the sensitivity of the method. These findings should be considered by legislative authorities in the future.

Effect of tranilast in comparison with beclomethasone in chronic murine model of asthma.

AIM OF THE STUDY: The current investigation was taken to scrutinize the action of tranilast on the airway remodeling in chronic asthma in mice. MATERIALS AND METHODS: Intraperitoneal injection of ovalbumin was applied to mice for sensitization and subsequent inhalation of 1% ovalbumin three times week for 10 weeks for challenge. Beclomethasone or tranilast were given daily for the 10 week challenge period. At the end of the study, lung weight index, total collagen content, bronchoalveolar lavage level of total and differential cell counts, interleukin-13, in addition to lung tissue nitrate/nitrite and transforming growth beta-1 were measured. Also, histological analysis was done. RESULTS: Asthmatic mice demonstrated apparent fibrotic changes. Significant airway fibrosis was demonstrated by hyperplasia of goblet cells and thickening of airway epithelium, increased content of lung collagen, lung and bronchoalveolar lavage of transforming growth factor beta-1 and interleukin-13 mutually accompanied by reduction in nitrate/nitrite generation. CONCLUSIONS: Beclomethasone influence on airway remodeling was mediated mainly via suppression of eosinophilic recruitment into the airways and reduction of interleukin-13 cytokine levels. Whereas, tranilast effects on airway remodeling was found to be mainly mediated via its inhibitory effect on transforming growth beta-1. Both beclomethasone and tranilast influence airway remodeling by different degrees and mechanisms.