Inhaled Fluticasone Propionate Research Articles

Correlation Analysis of Serum 25-Hydroxyvitamin D Levels With Immune Function and Calcium-Phosphate Metabolism in Patients With Bronchial Asthma Treated With Combination Therapy

It was to investigate the clinical efficacy of the combination therapy of fluticasone propionate inhalation aerosol and vitamin D (VD) in pediatric bronchial asthma (BA) and analyze the correlation between serum 25-(OH)-D3 levels and immune function, as well as calcium-phosphorus metabolism. A total of 110 patients with BA were recruited. Regarding treatment plan, patients were randomly rolled into a single-drug treatment group (SDT, treated with fluticasone propionate inhalation aerosol alone) and a dual-drug treatment group (TDT, treated with the combination of fluticasone propionate inhalation aerosol and VD). The changes in serum 25-(OH)-D3 levels, immunoglobulins, T lymphocyte subsets, and inflammatory cytokine levels in children with BA under different treatment modalities were compared. Clinical symptom disappearance, asthma control, and quality of life (QoL) were assessed, and the total effective rate and adverse reactions (ARs) were compared. A control group consisting of 60 healthy children who underwent concurrent physical examinations was included. The differences in serum 25-(OH)-D3 levels, immunoglobulins, and T lymphocyte subset levels between children with BA and healthy controls were compared, and their correlations were analyzed. The TDT group showed a drastic reduction in the disappearance time of lung wheezing and dyspnea relative to the SDT group. Furthermore, the TDT group exhibited notable improvements in lung function parameters, including forced vital capacity (FVC), forced expiratory volume at one second (FEV1), FEV1/FVC, and peak expiratory flow (PEF). Blood gas analysis revealed a great decrease in PaCO2 and an increase in PaO2. The Childhood Asthma Control Test (C-ACT) scores for asthma control and Pediatric Asthma Quality of Life Questionnaire (PAQLQ) scores for QoL showed marked increases in the TDT group. Moreover, the TDT group demonstrated notable increases in serum 25-(OH)-D3 levels, immunoglobulins (IgA, IgG, and IgM), T lymphocyte subsets (CD4+ and CD8+), as well as blood calcium and phosphorus levels. Additionally, the TDT group exhibited a prominent increase in the anti-inflammatory cytokine interleukin (IL)-10 level and a drastic decrease in the pro-inflammatory cytokines IL-6 and tumor necrosis factor alpha (TNF-α) levels (all P<0.05). The total effective rates of treatment in the SDT group and TDT group were 83.64 % and 96.36 %, respectively, with AR rates of 16.36 % and 7.27 %. The TDT group exhibited a superior total effective rate and an inferior incidence of ARs to the SDT group (both P<0.05). Additionally, in contrast to the control group, the BA group showed notable decreases in serum 25-(OH)-D3 levels, immunoglobulins (IgA, IgG, and IgM), T lymphocyte subsets (CD4+, CD8+, and CD4+/CD8+), as well as blood calcium and phosphorus levels (all P<0.05). Prior to treatment, there was a positive correlation between serum 25-(OH)-D3 levels and immunoglobulins (IgA, IgG, and IgM), T lymphocyte subsets (CD4+ and CD8+), as well as blood calcium and phosphorus levels in children with BA (P<0.05). In patients with BA, combined treatment with inhaled fluticasone propionate aerosol and VD may have a regulatory effect on serum 25-hydroxyVD levels, immune function, and calcium-phosphate metabolism. The correlation between serum 25-(OH)-D3 levels and immune function, as well as calcium-phosphate metabolism, suggested that VD may play a crucial role in the immune regulation and calcium-phosphate metabolism of BA.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100μg FP/50μg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1µm, < 2µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.

Effects of Inhaled Fluticasone Propionate on Wound Healing After Surgical Phonotrauma Model in Rabbit Larynx

Effects of Inhaled Fluticasone Propionate on Wound Healing After Surgical Phonotrauma Model in Rabbit Larynx

Syndrome de Cushing sous fluticasone inhalée : interactions médicamenteuses à éviter

Cushing's syndrome is an iatrogenic event occurring during co-administration of inhaled corticosteroids and potent inhibitors of P450 cytochromes. We report the clinical case of a 29-year-old woman with a past history of asthma treated with inhaled fluticasone propionate (FP), chronic pulmonary aspergillosis and allergic bronchopulmonary aspergillosis (ABPA) treated with itraconazole (ITZ), and Mycobacterium xenopi infection treated with moxifloxacin (MXF), ethambutol (EMB) and clarithromycin (CLR). Four months after initiation of antibiotic and antifungal medication, the patient contracted Cushing's syndrome. Its etiology consisted in interaction between FP, ITZ and CLR, which led to pronouncedly increased corticosteroid concentrations in circulating plasma cells. Following on the one hand cessation of FP and ITZ and on the other hand hydrocortisone supplementation, evolution was favorable. Several cases of iatrogenic Cushing's syndrome induced by co-administration of FP and potent CYP3A4 inhibitors have been reported in the literature. If possible, FP should be avoided in patients being treated with CYP3A4 inhibitors. Due to its differing physicochemical properties, beclometasone may be considered as the safest therapeutic alternative.

Effects of inhaled corticosteroids on brain volumetry, depression and anxiety-like behaviors in a rat model of asthma

Brain functional deficits have been reported in asthma patients which can result in behavioral disorders like depression and anxiety. These deficits may be associated with factors like resistance to treatment, incorrect self-evaluation, and inadequate self-control. However, changes in the brain volume in allergic asthma and the effects of inhaled corticosteroids, the most common anti-inflammatory agents for asthma treatment, on these alterations remain largely unclear. Here, we evaluated depression and anxiety-like behavior as well as volume changes in different brain area, using magnetic resonance imaging in an animal model of allergic asthma with pretreatment of inhaled fluticasone propionate. Asthma-induced behavioral changes were partially, but not completely, prevented by pretreatment with inhaled fluticasone propionate. Volumetry findings showed that the allergen decreased volumes of the corpus callosum and subcortical white matter, as well as the septal region and hippocampus (especially CA1 and fimbria). However, volumes of neocortex, insular, and anterior cingulate cortex increased in asthmatic rats compared to controls. Namely, pretreatment with inhaled fluticasone propionate partially prevented asthma-induced brain volume changes, but not completely. These findings suggest that asthma is associated with structural alterations in the brain, which may contribute to the induction of psychological disorders. Thus, considering brain changes in the clinical assessments could have important implications for asthma treatment.

Corticosteroid treatment attenuates anxiety and mPFC-amygdala circuit dysfunction in allergic asthma

AimsAllergic asthma is associated with anxiety-related behaviors, leading to poor quality of life. Previous studies mainly described the neuropathophysiology of asthma-induced anxiety. However, the effects of corticosteroids, the most common anti-inflammatory agents for asthma treatment, on the neurophysiological foundations of allergic asthma-induced anxiety are unexplored. Main methodsHere, we evaluated lung and brain inflammation as well as anxiety in an animal model of allergic asthma pretreated with inhaled fluticasone propionate. Furthermore, to define the neurophysiological bases of these conditions, we studied the medial prefrontal cortex (mPFC)-amygdala circuit, which is previously shown to accompany asthma-induced anxiety. Key findingsOur data showed that allergen induces anxiety, mPFC and amygdala inflammation, as well as disruptions in the local and long-range oscillatory activities within the mPFC-amygdala circuit. Interestingly, we observed a roughly consistent trend of changes with inhaled fluticasone pretreatment. Namely, the asthma-induced behavioral, inflammatory, and neurophysiological changes were partly, but not totally, prevented by inhaled fluticasone pretreatment. SignificanceWe suggest that early treatment of asthmatic patients with inhaled corticosteroids improves mPFC-amygdala circuit function by attenuating neuroinflammation leading to reduced anxiety. These findings could lead clinical guidelines of asthma to consider the neuropsychiatric disorders of patients in treatment recommendations.

The effect of low-dose inhaled fluticasone propionate on fractional exhaled nitric oxide in asthmatic pediatric patients with and without allergic rhinitis

The effect of low-dose inhaled fluticasone propionate on fractional exhaled nitric oxide in asthmatic pediatric patients with and without allergic rhinitis

Effect of Vitamin D3 Supplementation on Severe Asthma Exacerbations in Children With Asthma and Low Vitamin D Levels: The VDKA Randomized Clinical Trial

To investigate if supplementation with vitamin D3 would improve the time to a severe exacerbation in children at high risk with vitamin D insufficiency and taking low-dose inhaled corticosteroids (ICSs) for persistent asthma.The participants were recruited from 7 children’s hospitals across the United States. Participants, 6 to 16 years of age, had to have physician-diagnosed asthma for at least 1 year, being treated with low-dose ICSs, and have a serum 25-hydroxyvitamin D level less than 30 ng/mL. They also had to have at least 1 severe asthma exacerbation in the last year (defined as systemic steroids for at least 3 days or an emergency department visit or hospitalization requiring systemic corticosteroids). All participants had to show bronchodilator responsiveness or airway responsiveness to methacholine inhalation. The mean age of the participants was 9.8 years (40% girls). A total of 219 subjects passed screening and entered run-in. A total of 192 subjects were randomly assigned to active drug or placebo capsules.This was a randomized, double-blind, parallel, placebo-controlled clinical trial. Participants initially all received placebo capsules and were maintained on inhaled fluticasone propionate, 176 μg per day (6–11 years) or 220 μg per day (12–16 years) during run-in. They continued the ICSs and then were randomly assigned to daily vitamin D3 4000 IU or continuing placebo for 48 weeks. After 24 weeks, participants dose of fluticasone was reduced by 50%, if asthma was well controlled and spirometry was normal. Serum vitamin D levels and parameters of asthma control were measured every 16 weeks. The primary outcome was the time to a severe asthma exacerbation. Secondary outcomes included the time to a viral-induced severe exacerbation, the proportion of participants in whom the dose of ICS was reduced halfway through the trial, and the cumulative fluticasone dose during the trial.A total of 94% of randomly assigned subjects completed the trial. A total of 36 participants (37.5%) in the vitamin D3 group and 33 (34.4%) in the placebo group had ≥1 severe exacerbations. Compared with the placebo, vitamin D3 supplementation did not significantly improve the time to a severe exacerbation. The mean time to exacerbation was 240 days in the vitamin D3 group versus 253 days in the placebo group (mean group difference: −13.1 days; adjusted hazard ratio: 1.13; P = .63). Vitamin D3 supplementation, compared with the placebo, did not significantly improve the time to a viral-induced severe exacerbation, the proportion of participants whose dose of ICSs was reduced, or the cumulative fluticasone dose during the trial. Serious adverse events were similar in both groups (vitamin D3 group: n = 11; placebo group: n = 9).In children 6 to 16 years old with persistent asthma and low vitamin D levels, vitamin D3 supplementation, compared with a placebo, did not significantly improve the time to a severe asthma exacerbation or ICS dosing.As the authors note, in several observational studies, researchers have linked low serum vitamin D levels to severe asthma exacerbations, lower lung function, and reduced response to corticosteroids. Yet meta-analyses and reviews of vitamin D3 supplementation for severe asthma exacerbations have found insufficient evidence to recommend vitamin D3 supplementation in children. In this study, the authors, looking at a high-risk population for asthma exacerbations, add to that negative body of literature.

Beneficial Immunomodulatory Effects of Fluticasone Propionate in Chlamydia pneumoniae-Infected Mice.

The associations between inhaled corticosteroid (ICS) use and pulmonary infections remains controversial. Chlamydia pneumoniae (C. pneumoniae) accounts for asthma exacerbations; however, there are no data regarding ICS effects on C. pneumoniae infections. Thus, we investigated whether fluticasone propionate (FP) or budesonide (BUD) could affect C. pneumoniae infection in vitro and in vivo, focusing on the possible mechanisms that lead to potential anti-chlamydial outcomes. We performed direct qPCR to detect C. pneumoniae growth in infected, FP-treated, and BUD-treated A549 cells. Furthermore, FP or BUD was administered by inhalation to C. pneumoniae-infected mice. The recoverable C. pneumoniae was determined by indirect immunofluorescence. Expression levels of interferon (IFN)-γ and IFN-γ inducible chemokines were assessed by qPCR. We measured the protein concentrations of IFN-γ and of other cytokines that potentially participate in the anti-chlamydial response by ELISA. We found that FP treatment suppressed Chlamydia growth in A549 cells and in mice. Higher levels of IFN-γ gene expression were observed in FP-treated mice compared to the untreated and BUD-treated mice (p < 0.0001). IFN-γ and anti-chlamydial protein MIG/CXCL9 values were significantly higher after FP inhalation. Collectively, FP, but not BUD, suppressed C. pneumoniae growth in vitro and in vivo, which was likely due to the enhanced IFN-γ related responses.

Effect of inhaled fluticasone propionate on laryngotracheal stenosis after balloon dilation: a randomized controlled trial.

PurposeLaryngotracheal stenosis describes various airflow compromising conditions leading to laryngeal and tracheal narrowing, including subglottic and tracheal stenosis. Direct laryngobronchoscopy is the diagnostic gold standard for laryngotracheal stenosis. This study aimed to explore the effect of inhaled fluticasone propionate as adjuvant medical therapy in patients with laryngotracheal stenosis after balloon dilation. MethodsThis prospective randomized controlled trial was conducted from April 2019 to April 2020. Fourteen adults (≥ 18 years) with laryngotracheal stenosis consented to participate. All patients underwent endoscopic balloon dilation. Seven patients were treated with inhaled fluticasone propionate, and seven acted as controls. Detailed documentation of operative findings and pre- and post-balloon dilation spirometry measurements were recorded. Basic demographic data and operative details, including information about the percentage of laryngotracheal stenosis, distance of laryngotracheal stenosis from the vocal cords, the stenotic segment vertical length, and the largest endotracheal tube used before and after dilation were noted. ResultsSpirometry measurements were obtained on 34 occasions (17 before and 17 after balloon dilation). The two groups were similar in spirometry values after treatment. Both groups had significantly improved on most spirometry values after balloon dilation.ConclusionWe found that using inhaled steroids after balloon dilatation in patients with laryngotracheal stenosis had no benefit over non-user patients in spirometry parameters during the short postoperative follow-up. To confirm this outcome, we recommend a large-scale double-blind study with a longer follow-up period. Supplementary InformationThe online version contains supplementary material available at 10.1007/s00405-021-06622-x.

A mechanistic framework for a priori pharmacokinetic predictions of orally inhaled drugs.

The fate of orally inhaled drugs is determined by pulmonary pharmacokinetic processes such as particle deposition, pulmonary drug dissolution, and mucociliary clearance. Even though each single process has been systematically investigated, a quantitative understanding on the interaction of processes remains limited and therefore identifying optimal drug and formulation characteristics for orally inhaled drugs is still challenging. To investigate this complex interplay, the pulmonary processes can be integrated into mathematical models. However, existing modeling attempts considerably simplify these processes or are not systematically evaluated against (clinical) data. In this work, we developed a mathematical framework based on physiologically-structured population equations to integrate all relevant pulmonary processes mechanistically. A tailored numerical resolution strategy was chosen and the mechanistic model was evaluated systematically against data from different clinical studies. Without adapting the mechanistic model or estimating kinetic parameters based on individual study data, the developed model was able to predict simultaneously (i) lung retention profiles of inhaled insoluble particles, (ii) particle size-dependent pharmacokinetics of inhaled monodisperse particles, (iii) pharmacokinetic differences between inhaled fluticasone propionate and budesonide, as well as (iv) pharmacokinetic differences between healthy volunteers and asthmatic patients. Finally, to identify the most impactful optimization criteria for orally inhaled drugs, the developed mechanistic model was applied to investigate the impact of input parameters on both the pulmonary and systemic exposure. Interestingly, the solubility of the inhaled drug did not have any relevant impact on the local and systemic pharmacokinetics. Instead, the pulmonary dissolution rate, the particle size, the tissue affinity, and the systemic clearance were the most impactful potential optimization parameters. In the future, the developed prediction framework should be considered a powerful tool for identifying optimal drug and formulation characteristics.

Oral corticosteroids for post-infectious cough in adults: study protocol for a double-blind randomized placebo-controlled trial in Swiss family practices (OSPIC trial)

BackgroundCough is a common reason for patients to visit general practices. So-called post-infectious cough is defined as lasting 3 to 8 weeks after an upper respiratory tract infection. It can be disabling in daily activities, with substantial impact on physical and psychosocial health, leading to impaired quality of life and increased health care costs. Recommendations for the management of post-infectious cough in primary care are scarce and incoherent. A systematic review and meta-analysis of randomized clinical trials (RCT) assessing patient-relevant benefits and potential harms of available treatments identified six eligible RCTs assessing different treatment regimens (i.e. inhaled fluticasone propionate, inhaled budesonide, salbutamol plus ipratropium-bromide, montelukast, nociception-opioid-1-receptor agonist, codeine, gelatine). No RCT found clear patient-relevant benefits and most had an unclear or high risk of bias.Post-infectious cough is thought to be mediated by inflammatory processes that are also present in exacerbations of asthma or chronic obstructive pulmonary diseases for which there is strong evidence that oral corticosteroids provide patient-relevant benefit without relevant harm. We therefore plan to conduct the first RCT evaluating the effectiveness of oral corticosteroids for post-infectious cough.MethodsWe are conducting a triple-blinded randomized-controlled and multicentred superiority trial in primary health care practices in Switzerland. We will include 204 adult patients who consult their general practitioner (GP) for a cough lasting 3 to 8 weeks following an upper respiratory tract infection. Participants will be randomly allocated to either the 5-day treatment with oral corticosteroids or placebo. The primary outcome is cough-related quality of life assessed by the Leicester Cough Questionnaire score 14 days after randomization. Secondary outcomes include cough-related quality of life at several time points, overall cessation of cough and adverse events.DiscussionThis RCT will provide evidence on whether oral corticosteroids are beneficial and safe in patients with post-infectious cough. Results can have a substantial impact on the well-being and management of these patients in Switzerland and beyond. An evidence-based treatment for this condition may reduce re-consultations with GPs and spending for antitussive drugs, thus possibly having an impact on health care spending.Trial registrationClinicalTrials.gov NCT04232449. Prospectively registered on 18 January 2020.

Onset of action of inhaled glucocorticoids on bronchial and alveolar nitric oxide output

Fractional exhaled nitric oxide (FENO) is a marker of airway inflammation. Measuring FENO at multiple flow rates enables calculation of NO parameters: bronchial NO output (J awNO), bronchial wall (C awNO) and alveolar (C ANO) NO concentrations, and bronchial diffusion factor of NO (D awNO). FENO is known to rapidly reduce after the commencement of inhaled corticosteroid (ICS) treatment. However, little is known on the effect of ICS on the other NO parameters. We assessed (1) the onset of action of ICS treatment on the NO parameters and (2) whether the changes in bronchial NO output are due to changes in bronchial wall NO concentration or diffusion factor. FENO and other NO parameters were measured at baseline and after 1, 3 and 7 d of treatment with inhaled fluticasone propionate 250 μg b.i.d. in 23 allergic children with a history of asthma-like symptoms. There was a decrease in J awNO (from 680 (244/1791) (median (1st/3rd quartile)) to 357 (165/753) pl s−1, p < 0.001) and FENO50( from 13.8 (7.5/35) to 8.3 (5.36/17.0) ppb, p < 0.001) in 3 d from the first dose of ICS. Also, C awNO seemed to reduce after 3 d (from 171 (89/328) to 79 (54/157) ppb, p = 0.041), while D awNO remained unchanged. Furthermore, C ANO reduced during the 7 d treatment (from 3.0 (2.0/5.0) to 2.3 (1.9/2.6) ppb, p = 0.004). ICS treatment reduced FENO50 and J awNO rapidly and the decline was caused by decreased bronchial wall NO concentration while bronchial NO diffusion factor remained unchanged. These findings suggest that C awNO could be a more specific marker of airway inflammation and treatment response than J awNO or FENO50, which are both determined also by D awNO that seems to be resistant to the treatment with ICS.

Effects of inhaled fluticasone propionate on extrinsic tongue muscles in rats.

Obstructive sleep apnea (OSA) is more common in patients with asthma, and inhaled corticosteroids may contribute to OSA pathogenesis in these patients. This study tested the effects of orally inhaled fluticasone propionate (FP) on extrinsic tongue muscles. Unanesthetized rats were treated with FP or placebo for 28 days. On day 29, tongue retrusive and protrusive functions were tested via hypoglossal nerve stimulation under a state of anesthesia, followed by genioglossus (GG), styloglossus (SG) and hyoglossus (HG) muscle extraction, after euthanasia, for histology [myosin heavy chain (MHC) fibers and laminin content reflecting extracellular matrix (ECM)]. On protrusive testing, FP increased percent maximum tetanic force at 40 Hz (P = 0.03 vs. placebo) and endurance index (P = 0.029 vs. placebo). On retrusive testing, FP increased maximum twitch (P = 0.026 vs. placebo) and tetanic forces (P = 0.02 vs. placebo) with no effect on endurance index. On histology, FP increased GG cross-sectional area of MHC type IIa (P = 0.036 vs. placebo) and tended to increase type IIb (P = 0.057 vs. placebo) fibers and HG MHC IIx fibers (P = 0.065). The FP group had significantly increased laminin-stained areas, of greatest magnitude in the HG muscle. FP affects tongue protrusive and retrusive functions differently, concurrent with a shift in MHC fibers and increased ECM accumulation. These differential alterations may destabilize the tongue's "muscle hydrostat" during sleep and promote collapse.NEW & NOTEWORTHY The effects of inhaled corticosteroid on upper airway may contribute to OSA pathogenesis in asthma. In this study, we tested the effects of orally inhaled fluticasone propionate on tongue protrusive and retrusive functions and on tongue extrinsic muscle fiber composition and molecular properties. We found that fluticasone treatment: 1) increased protrusive endurance and retrusive maximum twitch and tetanic force; and 2) on histology, increased cross-sectional area of myosin heavy chain (MHC) type IIa fibers and tended to increase cross-sectional area of MHC type IIb fibers in the protrusive muscle and of MHC IIx fibers in the retrusors. It also increased laminin-stained areas, across extrinsic tongue muscles, of greatest magnitude in the retrusors; and 3) reduced protein degradation and activated pathways associated with increased protein synthesis in the protrusor. These differential effects on the protrusors and retrusors may destabilize the tongue's "muscle hydrostat" properties during sleep and promote collapse.

The Efficacy and Safety of Fluticasone/Salmeterol Compared to Fluticasone in Children Younger Than Four Years of Age

The combination of inhaled corticosteroid (ICS) and long-acting β-2 agonist (LABA) is widely used as maintenance therapy for children with asthma. However, use in young children has not been well studied. This study investigates the efficacy and safety of combination therapy with fluticasone propionate 50 µg and salmeterol xinafoate 25 µg in children up to 4 years of age.Study participants were children aged 6 months to 4 years with asthma diagnosed according to the Japanese Pediatric Guideline for the Treatment and Management of Asthma 2012 and in whom ICS and LABA was considered necessary by their physician.This 27-week double-blind, randomized controlled trial was conducted from May 2014 to October 2016 in 70 Japanese pediatric centers. The study consisted of 4 time intervals: (1) a 2-week run-in period, during which all children received inhaled fluticasone propionate twice daily; (2) an 8-week randomized treatment period, during which fluticasone only or fluticasone and salmeterol was administered twice daily; (3) a 16-week open-label period, during which all children received fluticasone and salmeterol twice daily; and (4) a 1-week follow-up period, during which children received care that the investigator felt was appropriate. Children <2 years received 1 inhalation per dose, whereas children 2 years or older received 1 to 2 inhalations per dose, according to the investigator’s judgment. The number of inhalations remained consistent during the run-in and treatment phases but could be adjusted during the open-label phase, if appropriate. As needed, salbutamol 100 µg was allowed as a rescue inhaler. Study endpoints and compliance were assessed via twice-daily recordings in a patient diary by the parent or legal guardian.A total of 300 patients were randomized 1:1 to the double-blind period, of whom 148 completed treatment with ICS and LABA, and 142 completed treatment with ICS only. The study was completed by 268 patients. In both treatment groups, boys predominated, and the majority (≥90%) of patients had moderate or severe persistent asthma. Both groups showed reduction in total asthma symptom scores; however, the primary end point of mean change in total asthma symptom scores from baseline to the last 7 days of the treatment period was not significantly different between the 2 groups (−3.97 for ICS and LABA versus −3.01 for ICS only, P = .21). Secondary outcome analysis showed fewer exacerbations in the ICS and LABA group (3% vs 5% in the ICS group) and statistically greater mean change from baseline in Japanese Pediatric Asthma Control scores in the ICS and LABA group (0.4 points vs −0.3 points for ICS only, P = .04). Little change from baseline in daily rescue medication use or percentage of rescue-free days was seen, with no statistically significant differences between the groups. Incidence of adverse effects was virtually identical between the ICS and LABA (74%) and ICS only (73%) groups and was not associated with age or number of inhalations. No new safety concerns were identified during the open-label period. Decreased plasma cortisol was reported in 6 children during the open-label and follow-up periods, although most values normalized on recheck. No serious adverse effects were considered by the investigators to be drug related.Combination therapy with ICS and LABA showed similar safety profiles to ICS alone in children with asthma up to 4 years of age. Although combination therapy improved total asthma symptom scores, it did not show superior efficacy to ICS alone.Asthma management in young children is challenging because of inability to perform pulmonary function tests and the intermittent nature of symptoms, with many children being clinically well in between exacerbations. Importantly, this study provides new evidence regarding the safety of ICS and LABA use in young children. Regarding efficacy, statistically significant differences were seen for some secondary outcomes, which may suggest better symptom control with ICS and LABA, although it is unclear if these differences warrant the use of ICA and LABA over ICS only in this age group. Further studies are needed to make this determination and support the findings in this study.

Spirometric changes in children with asthma exposed to environmental tobacco smoke and treated with inhaled corticosteroids

Background/Aim. Corticosteroids are the most frequently prescribed anti-inflammatory treatment in asthma. A purpose of this study was to compare the spirometric parameters as a response to inhaled fluticasone propionate (FP) treatment in children with asthma, exposed and nonexposed to environmental tobacco smoke (ETS). Methods. The study included 527 children aged between 1 and 16 years with persistent asthma divided into the groups of ETS exposed (ETSE, n = 337) and ETS free (ETSF, n = 190) children. Spirometry was performed before (1st set of results) and after 6 months of FP treatment (2nd set of results). Good lung function (GLF) was defined as forced expiratory volume in one second (FEV1) ? 85%, and ?poor lung function? (PLF) as FEV1 &lt; 85%. Results. Among the ETSE children, 208 had one smoking parent, 129 had two, 228 had smoking mothers and 238 smoking fathers. The ETSE children received a higher FP dose (p &lt; 0.0001) which was increased with the increase of the number of smokers in the family. The ETSE children had significantly lower lung function both in the 1st and 2nd sets of tests compared to the ETSF children (p &lt; 0.05). After the FP treatment, both groups improved all spirometric parameters (p &lt; 0.001). In the 2nd set of the spirometric tests, the children of smoking mothers had lower spirometry values compared to the children of smoking fathers (p &lt; 0.05). The proportion of the children improving from the PLF to GLF after 6 months of FP was much higher among the ETSF than the ETSE children (p &lt; 0.05). Conclusions. The ETSE children had lower spirometric values before FP. After 6-months of the FP treatment children in both groups improved the spirometric values, but the improvement was higher in the ETSF children.

Swept-source optical coherence tomography analysis in asthmatic children under inhaled corticosteroid therapy

Purpose: To evaluate retinal nerve fiber layer thickness (RNFLT), ganglion cell layer thickness (GCLT), subfoveal choroidal thickness (SFCT), and central retinal thickness (CRT) in asthmatic children who were under inhaled corticosteroid treatment by using Swept-Source Optical Coherence Tomography (SS-OCT).Material and methods: Fifty-three children were prospectively analyzed in the study. Group 1 included 31 asthmatic children and group 2 included 22 healthy children. Asthmatic children received a dose 250 μg daily of inhaled fluticasone propionate (Flexotide, GlaxoSmithKline, Middlesex, UK). Allergy parameters including, exposure to smoke, eosinophil count, percentage of eosinophils, immunoglobuline (Ig) E levels, number of asthma attacks, number of sensitivity to allergens and follow-up time were recorded. The RNFLT, GCLT, SFCT, and CRT were analyzed with SS-OCT and the data were compared between the groups.Results: There were 13 girls (41.9%) and 18 boys (58.1%) in group 1 and 13 girls (59.1%) and 9 boys (40.9%) in group 2 (p = 0.22). The mean age was 9.3 ± 2.2 years in group 1 and 9.9 ± 1.5 years in group 2 (p = 0.08). The mean CRT (239.26 ± 34.56 µm versus 226.82 ± 26.23 µm, p = 0.22) and mean SFCT (273.97 ± 40.95 µm versus 280.41 ± 32.78 µm, p = 0.54) did not significantly differ between the groups. The superior, inferior, and average RNFLT were significantly lower in group 1 than group 2 (p < 0.05). There were significant correlations between total corticosteroid dose and RNFLT (p < 0.05) and between IgE levels and GCLT (p < 0.05).Conclusions: The SS-OCT revealed that asthmatic children under inhaled corticosteroid treatment have lower RNFLT than healthy subjects.

Comparative efficacy of daily inhaled fluticasone propionate and episodic inhaled combined salmeterol/fluticasone propionate in children with recurrent wheezing

Comparative efficacy of daily inhaled fluticasone propionate and episodic inhaled combined salmeterol/fluticasone propionate in children with recurrent wheezing

Study of voice disorders in patients with bronchial asthma and chronic obstructive pulmonary disease

BackgroundChronic obstructive pulmonary disease (COPD) and bronchial asthma are known to cause adverse effects on voice, which might affect the quality of life of an individual.AimThe study was designed to study the voice disorders in patients with COPD and bronchial asthma and its relation to disease severity and medication.Patients and methodsTotally, 60 patients were recruited: 30 stable bronchial asthma patients and 30 stable COPD patients. All participants underwent spirometry and study of voice parameters using auditory perceptual assessment, videolaryngostroboscopy system, voice recording, and acoustic analysis.ResultsImpaired voice quality and various grades of dysphonia were detected in the COPD group in 30% by means of auditory perceptual assessment; structural changes in the vocal folds (diffuse congestion, unhealthy mucosa, and edema) were detected in 36.6%. In the bronchial asthma group, impaired voice quality and various grades of dysphonia were detected in 16.7% and structural changes were detected in 20% of them, whereas acoustic analysis showed a highly significant increase in jitter and shimmer and decreased harmonic-to-noise ratio in 100% of patients of both groups. These changes were greater in metered dose inhaler users than in dry-powder inhaler users. In the bronchial asthma group, fluticasone propionate users had a significantly decreased harmonic-to-noise ratio compared with beclomethasone dipropionate and budesonide users, as well as the least pitch and highest shimmer and jitter. A significant statistical correlation was found between ipratropium inhalation usage and increased shimmer in the COPD group. There was a highly significant correlation between spirometric severity and both grade of dysphonia and character of voice in bronchial asthma patients.ConclusionAll COPD and bronchial asthma patients had dysphonia, either due to organic causes or due to functional causes. Voice changes were directly correlated with degree of severity and fluticasone propionate inhalation use in bronchial asthma patients, and with ipratropium bromide inhalation in the COPD group.

Randomized, Double-Blind, Crossover, Clinical-End-Point Pilot Study to Examine the Use of Exhaled Nitric Oxide as a Bioassay for Dose Separation of Inhaled Fluticasone Propionate.

This was a randomized, double-blind, crossover, clinical-end-point pilot study examining the hypothesis that inhaled fluticasone propionate decreases exhaled nitric oxide (eNO) concentrations within a week of beginning treatment and shows evidence of dose separation across the marketed dose range. Subjects had a ≥6-month history of asthma and screening eNO ≥60 parts per billion. At the start of each treatment period, eNO was ≥55 parts per billion, and forced expiratory volume in 1 second was ≥50% predicted. Subjects attended a clinic visit daily on consecutive mornings during each of 3 1-week treatment periods to measure eNO and receive once-daily doses of 100/50, 250/50, or 500/50 fluticasone propionate/salmeterol combination product (Advair® Diskus). Daily eNO value recorded was the highest of 3 measurements; 1 inhalation of treatment was then administered. Procedures were repeated for 3 treatment cycles, separated by 14-day minimum washouts. A total of 105 subjects were screened; 22 were randomized; and 17 completed all treatments. Mean percentage eNO decrease (standard deviation) from day 1 baseline for each treatment period was 36.6 (±18.7), 45.3 (±16.5), and 54.6 (±12.5) with Advair® 100/50, 250/50, and 500/50, respectively. Mean percentage decrease in eNO across each treatment (dose) was modeled using a mixed-model ANOVA. Although the overall treatment was significant (P = .0015), because of the relatively small sample size and within-subject variability, only the 100/50 vs 500/50 (P = .0003) and 250/50 vs 500/50 (P = .047) treatments were significantly different.