Evaluating the pharmacokinetics of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide delivered via pressurised metered-dose inhaler using a low global warming potential propellant.

INTRODUCTION: Use of propellants with high global warming potential (such as HFA-134a) for pressurised metered-dose inhalers (pMDIs) is being phased down. Switching to dry-powder inhalers may not be clinically feasible for all patients; an alternative is reformulation using propellants with low global warming potential. The combination of beclometasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FF/GB) is available for asthma or chronic obstructive pulmonary disease via pMDI using HFA-134a as propellant. This is being reformulated using the low global warming potential propellant HFA-152a. This manuscript reports three studies comparing BDP/FF/GB pharmacokinetics delivered via pMDI using HFA-152a vs HFA-134a. METHODS: The studies were four-way crossover, single-dose, randomised, double-blind, in healthy volunteers. In Studies 1 and 2, subjects inhaled four puffs of BDP/FF/GB (Study 1: 100/6/12.5 µg [medium-strength BDP]; Study 2: 200/6/12.5 µg [high-strength]), ingesting activated charcoal in two of the periods (once per propellant). In Study 3, subjects inhaled medium- and high-strength BDP/FF/GB using a spacer. All three studies compared HFA-152a vs HFA-134a in terms of lung availability and total systemic exposure of beclometasone-17-monopropionate (B17MP; active metabolite of BDP), BDP, formoterol and GB. Bioequivalence was concluded if the 90 % confidence intervals (CIs) of the ratios between formulations of the geometric mean maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between time zero and the last quantifiable timepoint (AUC0-t) for the analytes were between 80 and 125 %. RESULTS: In Studies 1 and 2, systemic exposure bioequivalence (i.e., comparisons without charcoal block) was demonstrated, except for GB Cmax in Study 2 (upper 90 % CI 125.11 %). For lung availability (i.e., comparisons with charcoal block), B17MP and formoterol demonstrated bioequivalence in both studies, as did BDP in Study 2; in Study 1, BDP upper CIs were 126.96 % for Cmax and 127.34 % for AUC0-t). In Study 1, GB AUC0-t lower CI was 74.54 %; in Study 2 upper limits were 135.64 % for Cmax and 129.12 % for AUC0-t. In Study 3, the bioequivalence criteria were met for BDP, B17MP and formoterol with both BDP/FF/GB strengths, and were met for GB AUC0-t, although not for Cmax. Both formulations were similarly well tolerated in all three studies. CONCLUSIONS: Overall, while formal bioequivalence cannot be concluded for all analytes, these data suggest therapeutic equivalence of the new formulation with the existing BDP/FF/GB pMDI formulation, therefore supporting reformulation using a propellant with low global warming potential.

Cardiovascular events and all-cause mortality in patients with chronic obstructive pulmonary disease using olodaterol and other long-acting beta2-agonists.

PURPOSE: We examined the effect of olodaterol on the risk of myocardial ischaemia, cardiac arrhythmia, and all-cause mortality compared with use of other long-acting beta2-agonists (LABAs). Channelling bias was also explored. METHODS: This Danish population-based cohort study used data linked from registries of hospital diagnoses, outpatient dispensings, and deaths. It included patients (aged ≥40 years) with a diagnosis of chronic obstructive pulmonary disease (COPD) who initiated olodaterol or another LABA. Using matching and propensity score (PS) stratification, we calculated adjusted incidence rate ratios (IRRs) using Poisson regression, followed by several additional analyses to evaluate and control channelling bias. RESULTS: The IRRs of cardiac arrhythmias or myocardial ischaemia among users of olodaterol (n = 14 239) compared to users of other LABAs (n = 51 167) ranged from 0.96 to 1.65 in various analyses, although some estimates had low precision. Initial analysis suggested an increased risk for death with olodaterol compared with other LABAs (IRR, 1.63; 95% CI, 1.44-1.84). Because olodaterol prescribing was associated with COPD severity, the mortality association was attenuated by using different methods of tighter confounding control: the IRRs were 1.26 (95% CI, 0.97-1.64) among LABA-naïve LABA/LAMA users without recent COPD hospitalisation; 1.27 (95% CI, 1.03-1.57) in a population with additional trimming from the tails of the PS distribution; and 1.32 (95% CI, 1.19-1.48) after applying overlap-weights analysis. CONCLUSIONS: Olodaterol users had a similar risk for cardiac arrhythmias or myocardial ischaemia as other LABA users. The observed excess all-cause mortality associated with olodaterol use could be due to uncontrolled channelling bias.

The impact of regular bisoprolol on the response to salbutamol in asthma: A double-blind randomized placebo-controlled crossover trial.

BACKGROUND AND OBJECTIVE: Non-selective beta-blockers impair the bronchodilator response to beta2 -agonists. Cardio-selective beta1 -blockers are less likely to cause this effect, yet they remain relatively contraindicated in asthma. We investigated whether the response to salbutamol is impaired during cardio-selective beta1 -blocker treatment in people with asthma. METHODS: A random-order, double-blind, placebo-controlled, non-inferiority, crossover study was conducted comparing up to 5 mg bisoprolol daily for 2 weeks with matching placebo, with an open-label extension of up to 10 mg bisoprolol daily. After each treatment period, mannitol was inhaled to induce bronchoconstriction with a 15% fall in forced expiratory volume in 1 s (FEV1 ). Immediately after mannitol challenge, salbutamol (100, 100 and 200 µg) was administered via spacer at 5-min intervals with repeated FEV1 measures. The FEV1 recovery with salbutamol was measured as an area under recovery curve (AUC). Based on earlier research, a clinically relevant non-inferiority limit of a 30% reduction in the AUC was set. RESULTS: A total of 19 adults with mild asthma and positive inhaled mannitol challenge completed the study. Adjusting for the FEV1 fall induced by mannitol and treatment sequence, the mean AUC response to salbutamol after bisoprolol was 5% lower than after placebo, with a one-sided 95% confidence interval (CI) of 26% lower. Thirteen participants completed the open-label extension up to 10 mg bisoprolol daily with mean AUC 11% higher after bisoprolol with a 95% CI of 5% lower. CONCLUSION: The bronchodilator response to rescue salbutamol after mannitol-induced bronchoconstriction is non-inferior during regular treatment with the cardio-selective beta1 -blocker, bisoprolol, compared to placebo. CLINICAL TRIAL REGISTRATION: ACTRN12618000306213 at https://www.anzctr.org.au.

Functions of beta2-adrenergic receptor in human periodontal ligament cells.

Adrenergic receptors (ARs) are receptors of noradrenalin and adrenalin, of which there are nine different subtypes. In particular, ß2 adrenergic receptor (ß2-AR) is known to be related to the restoration and maintenance of homeostasis in bone and cardiac tissues; however, the functional role of signaling through ß2-AR in periodontal ligament (PDL) tissue has not been fully examined. In this report, we investigated that ß2-AR expression in PDL tissues and their features in PDL cells. ß2-AR expressed in rat PDL tissues and human PDL cells (HPDLCs) derived from two different patients (HPDLCs-2G and -3S). Rat PDL tissue with occlusal loading showed high ß2-AR expression, while its expression was downregulated in that without loading. In HPDLCs, ß2-AR expression was increased exposed to stretch loading. The gene expression of PDL-related molecules was investigated in PDL clone cells (2-23 cells) overexpressing ß2-AR. Their gene expression and intracellular cyclic adenosine monophosphate (cAMP) levels were also investigated in HPDLCs treated with a specific ß2-AR agonist, fenoterol (FEN). Overexpression of ß2-AR significantly promoted the gene expression of PDL-related molecules in 2 to 23 cells. FEN led to an upregulation in the expression of PDL-related molecules and increased intracellular cAMP levels in HPDLCs. In both HPDLCs, inhibition of cAMP signaling by using protein kinase A inhibitor suppressed the FEN-induced gene expression of α-smooth muscle actin. Our findings suggest that the occlusal force is important for ß2-AR expression in PDL tissue and ß2-AR is involved in fibroblastic differentiation and collagen synthesis of PDL cells. The signaling through ß2-AR might be important for restoration and homeostasis of PDL tissue.

Patterns of use of long-acting bronchodilators in patients with COPD: A nationwide follow-up study of new users in New Zealand.

BACKGROUND AND OBJECTIVE: While several studies have found that prescribing practices do not conform to chronic obstructive pulmonary disease (COPD) treatment guidelines, none have examined longitudinal patterns of use of long-acting beta2 -agonist (LABA) and long-acting muscarinic antagonist (LAMA) therapy across an entire country. We undertook a nationwide follow-up study to describe treatment patterns in new users of long-acting bronchodilators. METHODS: National health and pharmaceutical dispensing data were used to identify patients aged ≥45 years who initiated LABA and/or LAMA therapy for COPD between 1 February 2006 and 31 December 2013. Dispensings of LABAs, LAMAs and inhaled corticosteroids (ICSs) were aggregated into episodes of use of therapeutic regimens. Kaplan-Meier curves, sunburst plots and sequence index plots were generated to summarize, respectively, the duration of the first regimen, the sequences in which unique regimens were used and the patterns of use and non-use during follow-up. RESULTS: The study cohort included 83 435 patients with 290 400 person-years of follow-up. The most commonly initiated regimen was a LABA with an ICS. ICS use was inconsistent with international guidelines: over- and under-treatment occurred in patients with infrequent and frequent exacerbations, respectively, and ICS monotherapy was common. The median duration of the first regimen was 46 days. Many patients used multiple regimens over time and periods of non-use were common. CONCLUSION: In this nationwide study, patterns of use of LABAs, LAMAs and ICSs were complex and often did not comply with treatment guidelines. Further work is required to address the discrepancy between guidelines and prescribing practices.

Evaluation of short-acting Beta-2-agonist prescriptions and associated clinical outcomes: Findings from the SABA use IN Asthma (SABINA) study in Asia.

Background: The extent of short-acting Beta-2-agonist (ß2-agonist) (SABA) use across Asian countries is not well documented. As part of the SABA use IN Asthma (SABINA) III study, we assessed SABA prescriptions and clinical outcomes in patients with asthma from Asia. Methods: This cross-sectional study recruited patients (aged ≥12 years) with asthma from 8 Asian countries. Data on disease characteristics and asthma treatments were collected using electronic case report forms. Patients were classified by practice type (primary or specialist care) and investigator-defined asthma severity (per Global Initiative for Asthma [GINA] 2017 recommendations). The association of SABA prescriptions with clinical outcomes was analyzed using multivariable regression models. Results: Overall, 3066 patients were analyzed, with a mean (standard deviation) age of 51.8 (16.7) years; of these patients, 2116 (69%) were female, 2517 (82.1%) had moderate-to-severe asthma and 2498 (81.5%) and 559 (18.2%) were treated in specialist and primary care, respectively. In total, 1423 (46.4%) patients had partly controlled/uncontrolled asthma, with 1149 (37.5%) patients experiencing ≥1 severe asthma exacerbation in the previous year. Overall, 800 (26.7%) patients were prescribed ≥3 SABA canisters in the previous year, which is regarded as overprescription and was associated with a significantly decreased odds of at least partly controlled asthma and increased incidence rates of severe exacerbations (P < 0.01 for both associations). Conclusion: The findings from this cohort of predominantly specialist-treated patients with asthma indicate SABA overprescription in at least 1 in every 4 patients, and this overprescription is associated with poor clinical outcomes. These data highlight the need for adherence to recently updated asthma treatment recommendations in Asia.

ß2-Adrenoceptor Agonists in Asthma or Chronic Obstructive Pulmonary Disease and Risk of Parkinson's Disease: Nested Case-Control Study.

Introduction: Although ß2-adrenoceptor (ß2AR) agonists have been associated with a lower risk of Parkinson's disease (PD), the findings are inconclusive and may reflect confounding by indication. We studied the association between inhaled ß2AR agonists and risk of PD in persons with asthma or chronic obstructive pulmonary disease (COPD). Methods: The nested case-control study was conducted within a register-based Finnish Parkinson's disease study (FINPARK) and included 1406 clinically verified PD cases diagnosed during 1999-2015, who also had asthma/COPD >3 years before PD. PD cases were matched with up to seven controls by age, sex, duration of asthma/COPD, pulmonary diagnosis, and region (N = 8630). Cumulative and average annual exposure to short- and long-acting ß2AR agonists before a 3-year lag period was assessed with quartiles of defined daily doses (DDDs). Adjusted odds ratios (aORs) were calculated with 95% confidence intervals (CIs) using conditional logistic regression. Results: Cumulative exposure to either short- or long-acting ß2AR agonists was not associated with a risk of PD. With average annual exposure, a decreased risk was observed only for the highest quartile of long-acting ß2AR agonists (aOR 0.75; 95% CI 0.58-0.97). In the stratified analysis the lowest risk estimates were observed among those with both asthma and COPD diagnoses. The suggestion of an inverse association was seen for the highest quartile of long-acting ß2AR agonists in asthma. Discussion: Higher levels of exposure to ß2AR agonists were not consistently associated with a reduced risk of PD. The inverse association in the highest category of average annual exposure to long-acting ß2AR agonists may be explained by unmeasured confounding, such as disease severity or smoking.

Comparison of Dry-Powder Inhaler and Pressurized Metered-Dose Inhaler Formulations of Extrafine Beclomethasone Dipropionate/Formoterol Fumarate/Glycopyrronium in Patients with COPD: The TRI-D Randomized Controlled Trial.

BACKGROUND: Three 52-week studies in COPD have assessed the efficacy and safety of single-inhaler extrafine formulation triple therapy combining beclomethasone dipropionate (BDP), formoterol fumarate (FF) and glycopyrronium (G) delivered via pressurized metered-dose inhaler (pMDI). BDP/FF/G is now being developed for delivery via multi-dose dry-powder inhaler (DPI; NEXThaler). This study aimed to demonstrate non-inferiority of BDP/FF/G DPI vs pMDI for lung function. METHODS: Multicenter, randomized, double-blind, double-dummy, active-controlled, three-way cross-over study in patients with COPD and post-bronchodilator forced expiratory volume in 1 second (FEV1) 30-80% predicted. Patients received BDP/FF/G 100/6/10µg via DPI and pMDI, and BDP/FF 100/6µg via pMDI, all two inhalations twice daily for four weeks, with treatments separated by two-week washout. The two co-primary objectives were to demonstrate non-inferiority between the two BDP/FF/G formulations for FEV1 area under the curve between 0 and 12 hours post-dose (AUC0-12h) normalized by time and trough FEV1 at 24 hours, both on Day 28. EudraCT 2017-004405-41. RESULTS: Of 449 patients screened, 366 were randomized, with 342 (93.4%) completing all three treatment periods. The primary objectives were met, with changes from baseline in FEV1 AUC0-12h and trough FEV1 on Day 28 similar for the two BDP/FF/G formulations, and the confidence intervals for the difference lying entirely within the pre-specified non-inferiority criterion (-50mL): -20 (-35, -6) mL and 3 (-15, 20) mL for AUC0-12h and trough FEV1, respectively. BDP/FF/G pMDI and DPI were statistically superior to BDP/FF for these endpoints (p<0.001). A similar proportion of patients experienced adverse events with each treatment (15.5%, 18.7% and 15.4% with BDP/FF/G DPI and pMDI, and BDP/FF, respectively); the majority were mild or moderate, with few related to treatment. CONCLUSION: Extrafine BDP/FF/G DPI and pMDI demonstrated similar efficacy and safety in patients with COPD, supporting the DPI formulation as a valid alternative.

Many continuous variables should be analyzed using the relative scale: a case study of ß2-agonists for preventing exercise-induced bronchoconstriction.

BACKGROUND: The relative scale adjusts for baseline variability and therefore may lead to findings that can be generalized more widely. It is routinely used for the analysis of binary outcomes but only rarely for continuous outcomes. Our objective was to compare relative vs absolute scale pooled outcomes using data from a recently published Cochrane systematic review that reported only absolute effects of inhaled ß2-agonists on exercise-induced decline in forced-expiratory volumes in 1 s (FEV1). METHODS: From the Cochrane review, we selected placebo-controlled cross-over studies that reported individual participant data (IPD). Reversal in FEV1 decline after exercise was modeled as a mean uniform percentage point (pp) change (absolute effect) or average percent change (relative effect) using either intercept-only or slope-only, respectively, linear mixed-effect models. We also calculated the pooled relative effect estimates using standard random-effects, inverse-variance-weighting meta-analysis using study-level mean effects. RESULTS: Fourteen studies with 187 participants were identified for the IPD analysis. On the absolute scale, ß2-agonists decreased the exercise-induced FEV1 decline by 28 pp., and on the relative scale, they decreased the FEV1 decline by 90%. The fit of the statistical model was significantly better with the relative 90% estimate compared with the absolute 28 pp. estimate. Furthermore, the median residuals (5.8 vs. 10.8 pp) were substantially smaller in the relative effect model than in the absolute effect model. Using standard study-level meta-analysis of the same 14 studies, ß2-agonists reduced exercise-induced FEV1 decline on the relative scale by a similar amount: 83% or 90%, depending on the method of calculating the relative effect. CONCLUSIONS: Compared with the absolute scale, the relative scale captures more effectively the variation in the effects of ß2-agonists on exercise-induced FEV1-declines. The absolute scale has been used in the analysis of FEV1 changes and may have led to sub-optimal statistical analysis in some cases. The choice between the absolute and relative scale should be determined based on biological reasoning and empirical testing to identify the scale that leads to lower heterogeneity.

Beta-2 Adrenergic Receptor Agonists Enhance AChR Clustering in C2C12 Myotubes: Implications for Therapy of Myasthenic Disorders.

BACKGROUND: Congenital myasthenic syndromes (CMS) are a group of inherited neuromuscular transmission disorders causing fatiguable muscle weakness. ADRB2 agonists have been observed to provide therapeutic benefit where destabilisation of NMJ structures is part of the underlying pathology, such as in DOK7, COLQ and MuSK CMS as well as in slow channel syndrome. However, very little is known about the molecular mechanisms underlying the effects of ADRB2 agonists in CMS. OBJECTIVE: In vitro investigation into whether an ADRB2 agonist affects the AChR clustering pathway and has the potential to increase the number and stability of AChR clusters. METHODS: Cultured C2C12 mouse myotubes overexpressing the common DOK7 frameshift mutation c.1124_1127dupTGCC were incubated with salbutamol sulphate and the effect on AChR cluster numbers were investigated. Moreover, agrin-induced AChR clusters in C2C12 WT cells were left to disperse after agrin-wash-off, and the effects of incubation with salbutamol sulphate on AChR cluster numbers were explored. RESULTS: Salbutamol sulphate induced a significant increase in the number of AChR clusters formed on C2C12 cells overexpressing c.1124_1127dupTGCC. Furthermore, significantly more clusters remained in C2C12 WT myotubes incubated with salbutamol sulphate following agrin wash-off. CONCLUSIONS: The results suggest that ADRB2 agonists directly affect proteins located at the neuromuscular junction and exert a stabilising effect on AChR clusters.

Efficacy of inhalation therapy with montelukast sodium, budesonide and formoterol in combination in the treatment of bronchial asthma in adult patients and its effects on cytokines / 中国基层医药

Objective:To investigate the efficacy of combination treatment with montelukast sodium, budesonide and formoterol in the treatment of bronchial asthma in adults and its effects on cytokines.Methods:A total of 100 adult patients with bronchial asthma who received treatment in The First People's Hospital of Yongkang from January 2019 to December 2020 were included in this study. They were randomly assigned to receive either budesonide inhalation alone (control group, n = 50) or combination inhalation of montelukast sodium, budesonide and formoterol (observation group, n = 50) for 12 weeks. Efficacy was compared between the two groups. Lung function [forced expiratory volume in one second (FEV 1), peak expiratory flow (PEF) and FEV 1/forced vital capacity (FVC) ratio], cytokines [interleukin (IL)-2, IL-4, IL-6], Asthma Quality of Life Questionnaire (AQLQ) score, and Asthma Control Test (ACT) score measured before and 12 weeks after treatment were compared between the two groups. Results:Total response rate in the observation group was significantly higher than that in the control group [92.00% (46/50) vs. 72.00% (36/50), χ2 = 6.77, P < 0.05). After 12 weeks of treatment, FEV 1, PEF and FEV1/FVC in the observation group were (2.17 ± 0.23) L, (246.56 ± 17.86) L/s, and (83.86 ± 3.98)%, respectively, which were significantly higher than (1.86 ± 0.17) L, (203.12 ± 20.10) L/s, (74.82 ± 5.67)% in the control group ( t = 7.66, 11.42, 9.22, P < 0.05). Serum IL-2 level in the observation group was significantly higher than that in the control group [(10.85 ± 0.86) ng/L vs. (8.94 ± 1.03) ng/L, t = 10.06, t < 0.05]. Serum IL-4 and IL-6 in the observation group were (24.98 ± 3.08) ng/L and (98.46 ± 9.76) μg/L, respectively, which were significantly lower than (36.75 ± 4.34) ng/L and (125.84 ± 13.19) μg/L in the control group ( t =15.63, 11.79, both P < 0.05). AQLQ score and ACT score in the observation group were (121.03 ± 8.69) points and (22.08 ± 1.35) points, respectively, which were significantly higher than (110.93 ± 7.86) points and (19.74 ± 1.76) points in the control group ( t = 6.095, 7.460, both P < 0.05). Conclusion:Inhalation therapy with montelukast sodium, budesonide and formoterol produces obvious therapeutic effects on bronchial asthma in adult patients and the combined therapy can reduce inflammatory reactions.

Overuse of short-acting beta-agonist bronchodilators in COPD during periods of clinical stability.

BACKGROUND: Overuse of short-acting beta-agonists (SABA) is described in asthma, but little is known about overuse of SABA in chronic obstructive pulmonary disease (COPD). METHODS: Prospective 3-month cohort study of patients with moderate-to-severe COPD who were provided a portable electronic inhaler sensor to monitor daily SABA use. Subjects wore a pedometer for 3 seven-day periods and were asked to complete a daily diary of symptoms and inhaler use. Overuse was defined as >8 actuations of their SABA per day while clinically stable. RESULTS: Among 32 participants, 15 overused their SABA inhaler at least once (mean 8.6 ± 5.0 puffs/day), and 6 overused their inhaler more than 50% of monitored days. Compared to those with no overuse, overusers had greater dyspnea (modified Medical Research Council Dyspnea Scale: 2.7 vs. 1.9, p = 0.02), were more likely to use home oxygen (67% vs. 29%, p = 0.04), and were more likely to be on maximal inhaled therapy (long-acting beta-agonist, long-acting antimuscarinic agent, and an inhaled steroid: 40% vs. 6%, p = 0.03), and most had completed pulmonary rehabilitation (67% vs. 0%, p < 0.001). However, 27% of overusers of SABA were not on guideline-concordant COPD therapy. CONCLUSIONS: Overuse of SABA was common and associated with increased disease severity and symptoms, even though overusers were on more COPD-related inhalers and more had completed pulmonary rehabilitation. More research is needed to understand factors associated with inhaler overuse and how to improve correct inhaler use.

Novel albuterol multidose dry powder inhaler in patients with exercise-induced bronchoconstriction: A single-dose, double-blind, randomized, 2-way crossover study.

BACKGROUND: A novel, inhalation-driven, multidose dry powder inhaler (MDPI) was developed that eliminates the need to coordinate device actuation with inhalation as is required with conventional metered-dose inhalers. OBJECTIVE: To evaluate albuterol MDPI efficacy and safety in patients with exercise-induced bronchoconstriction (EIB). METHODS: This single-dose, double-blind, 2-way crossover study randomized adolescents and adults with EIB (≥20% fall from pre-exercise challenge FEV(1)) to treatment sequences of albuterol MDPI (180 µg [2 inhalations of 90 µg each])/placebo MDPI (n = 19) or the reverse sequence (n = 19). FEV(1) was measured 30 and 5 min predose, 30 min postdose (ie, 5 min before treadmill exercise challenge; baseline) and 5, 10, 15, 30, and 60 min after exercise challenge. The primary efficacy endpoint was maximum percentage fall from baseline in FEV(1) up to 60 min post-exercise challenge. RESULTS: Mean maximum percentage fall in FEV(1) within 60 min post-exercise challenge was 6.2 ± 1.4% for albuterol MDPI versus 22.4 ± 1.4% for placebo MDPI (between-treatment difference: -16.2%; 95% CI: -20.2% to -12.1%; P < 0.0001). A significantly higher percentage of albuterol MDPI-treated patients were protected against EIB (<10% maximum FEV(1) fall post-exercise challenge) versus placebo MDPI (84.2% vs 15.8%; P < 0.0001). Protection with albuterol MDPI was evident within 5 min and maintained through 30 min; recovery was complete for both groups at 60 min. Treatment with a single dose of albuterol MDPI was generally well tolerated. CONCLUSIONS: Albuterol MDPI provides clinically significant protection from EIB in adolescents and adults with EIB; no new safety issues were observed with short-term albuterol MDPI use. ClinicalTrials.gov identifier NCT01791972.

Beta-2 agonists for the treatment of bronchiolitis. / Beta-2 agonistas para el tratamiento de bronquiolitis.

INTRODUCCIÓN: La bronquiolitis es la inflamación aguda de las vías aéreas de pequeño calibre, teniendo como causa principal las infecciones virales. Es altamente frecuente en menores de dos años, sobretodo en menores de 12 meses. Existe gran controversia sobre el manejo de esta patología, siendo especialmente cuestionable el uso de beta-2 agonistas de corta acción tanto en el ámbito ambulatorio como hospitalario. MÉTODOS: Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES: Identificamos siete revisiones sistemáticas que en conjunto incluyen 47 estudios primarios, de los cuales 44 corresponden a ensayos aleatorizados. Concluimos que el uso de beta-2 agonistas podría no tener ningún beneficio en el manejo de la bronquiolitis, en términos de necesidad de hospitalización y/o duración de la misma. Por otra parte, podría aumentar efectos adversos como arritmias, sin embargo, la certeza de esta evidencia es baja.

Beta-2 agonistas para el tratamiento de bronquiolitis / Beta-2 agonists for the treatment of bronchiolitis

INTRODUCCIÓN La bronquiolitis es la inflamación aguda de las vías aéreas de pequeño calibre, teniendo como causa principal las infecciones virales. Es altamente frecuente en menores de dos años, sobretodo en menores de 12 meses. Existe gran controversia sobre el manejo de esta patología, siendo especialmente cuestionable el uso de beta-2 agonistas de corta acción tanto en el ámbito ambulatorio como hospitalario. MÉTODOS Para responder esta pregunta utilizamos Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud a nivel mundial, la cual es mantenida mediante búsquedas en múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, reanalizamos los datos de los estudios primarios, realizamos un metanálisis, y preparamos una tabla de resumen de los resultados utilizando el método GRADE. RESULTADOS Y CONCLUSIONES Identificamos siete revisiones sistemáticas que en conjunto incluyen 47 estudios primarios, de los cuales 44 corresponden a ensayos aleatorizados. Concluimos que el uso de beta-2 agonistas podría no tener ningún beneficio en el manejo de la bronquiolitis, en términos de necesidad de hospitalización y/o duración de la misma. Por otra parte, podría aumentar efectos adversos como arritmias, sin embargo, la certeza de esta evidencia es baja

A pilot study assessing the effect of bronchodilator on dynamic hyperinflation in LAM.

INTRODUCTION: Positive responses to bronchodilators (BDs) on spirometry can be found in up to 30% of patients with lymphangioleiomyomatosis (LAM). However, no previous studies have investigated the impact of BDs on exercise outcomes, including dynamic hyperinflation (DH). METHODS: A randomised, double-blind, placebo-controlled, crossover trial was conducted on 38 patients with LAM, comparing inhaled placebo versus salbutamol. Pulmonary function tests and a cycle endurance test at 75% of the maximal work capacity, with evaluation of DH by serial measurement of inspiratory capacity (IC), which was the primary endpoint, were performed after each intervention. RESULTS: Although salbutamol produced a slight improvement in airway obstruction, compared with placebo, there was no significant variation in resting IC or air trapping. A total of 18% of the patients met the criteria for a positive response to BD. During submaximal exercise, BD did not reduce DH or dyspnoea nor did it improve exercise tolerance in the entire population. In addition, BD produced only slight improvement in FEV1 and air trapping in patients who had DH during incremental cardiopulmonary exercise testing, without the beneficial effects on exercise outcomes. CONCLUSIONS: Although salbutamol produced a slight improvement in airway obstruction, it did not lead to a reduction in DH or increase in exercise tolerance in patients with LAM. CLINICAL TRIAL REGISTRATION: Brazilian Registry of Clinical Trials (ReBEC); www.ensaiosclinicos.gov.br; registration number: RBR-49sk2j.

Avaliação da eficácia e segurança da associação de budesonida e formoterol em dose fixa e cápsula única no tratamento de asma não controlada: ensaio clínico randomizado, duplo-cego, multicêntrico e controlado / Evaluation of the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination in uncontrolled asthma: a randomized, double-blind, multicenter, controlled clinical trial

OBJETIVO: Avaliar a eficácia e a segurança da associação de budesonida e formoterol em dose fixa e cápsula única, em comparação ao uso de budesonida isolada em pacientes com asma não controlada. MÉTODOS: Ensaio clínico randomizado, duplo-cego, multicêntrico, de fase III, com grupos paralelos, comparando a eficácia de curto prazo e a segurança da formulação em pó de budesonida (400 µg) e formoterol (12 µg) com a formulação em pó de budesonida (400 µg) em 181 participantes com asma não totalmente controlada. A idade dos participantes variou de 18-77 anos. Após um período de run-in de 4 semanas, durante o qual todos os participantes receberam budesonida duas vezes por dia, houve a randomização para um dos tratamentos do estudo. O tratamento foi administrado duas vezes ao dia por 12 semanas. Os principais desfechos foram VEF1, CVF e PFE matinal. Os dados foram analisados por intenção de tratar. RESULTADOS: O grupo tratado com a associação, quando comparado ao grupo budesonida isolado, teve uma melhora significativa no VEF1 (0,12 L vs. 0,02 L; p = 0.0129) e no PFE matinal (30,2 L/min vs. 6,3 L/min; p = 0,0004). Esses efeitos foram acompanhados por boa tolerabilidade e segurança, como demonstrado pela baixa frequência de eventos adversos menores. CONCLUSÕES: A associação em cápsula única de budesonida e formoterol mostrou ser eficaz e segura. Os resultados demonstram que essa formulação é uma opção terapêutica válida para a obtenção e manutenção do controle da asma.

OBJECTIVE: To evaluate the efficacy and safety of a fixed-dose, single-capsule budesonide-formoterol combination, in comparison with budesonide alone, in patients with uncontrolled asthma. METHODS: This was a randomized, double-blind, multicenter, phase III, parallel clinical trial, comparing the short-term efficacy and safety of the combination of budesonide (400 µg) and formoterol (12 µg), with those of budesonide alone (400 µg), both delivered via a dry powder inhaler, in 181 patients with uncontrolled asthma. The age of the patients ranged from 18 to 77 years. After a run-in period of 4 weeks, during which all of the patients received budesonide twice a day, they were randomized into one of the treatment groups. for 12 weeks. The treatment consisted of the administration of the medications twice a day for 12 weeks. The primary outcome measures were FEV1, FVC, and morning PEF. We performed an intention-to-treat analysis of the data. RESULTS: In comparison with the budesonide-only group patients, those treated with the budesonide-formoterol combination showed a significant improvement in FEV1 (0.12 L vs. 0.02 L; p = 0.0129) and morning PEF (30.2 L/min vs. 6.3 L/min; p = 0.0004). These effects were accompanied by good tolerability and safety, as demonstrated by the low frequency of adverse events, only minor adverse events having occurred. CONCLUSIONS: The single-capsule combination of budesonide and formoterol appears to be efficacious and safe. Our results indicate that this formulation is a valid therapeutic option for obtaining and maintaining asthma control. (ClinicalTrials.gov Identifier: NCT01676987 [http://www.clinicaltrials.gov/]).