Long-acting B-2 agonists (LABA) or long-acting muscarinic antagonists (LAMA): which one may be the first option in group A COPD patients?

INTRODUCTION: Long-acting muscarinic antagonists (LAMA) or beta-2 agonists (LABA) have been recommended for symptom control in group A COPD patients as a first-line bronchodilator treatment in GOLD guidelines. However, there is no mention of priority/superiority between the two treatment options. We aimed to compare the effectiveness of these treatments in this group. METHODS: The study cohort was formed of all subjects from six pulmonology clinics with an initial diagnosis of COPD who were new users of a LAMA or LABA from January 2020 to December 2021. Seventy-six group A COPD patients, in whom LABA or LAMA therapy had been started in the last 1 month as a first-line treatment, were included in our study. Participants were evaluated with spirometry, COPD Assessment Test (CAT), mMRC scale, and St. George Respiratory Questionnaire (SGRQ) for three times (baseline, 6-12th months). RESULTS: There were 76 group A COPD patients with LAMA (67.1%) and LABA (32.9%). The number of patients who improved in CAT score at the end of the first year was significantly higher in patients using LAMA than those using LABA (p = 0.022); the improvement at minimum clinically important difference (MCID) in CAT score of LAMA group at 1st year was also significant (p = 0.044). SGRQ total and impact scores were found to be statistically lower at 1st year compared to baseline in patients using LAMA (p = 0.010 and 0.006, respectively). Significant improvement was detected in CAT and SGRQ scores at the 6th month visit in the LAMA group having emphysema (p = 0.032 and 0.002, respectively). CONCLUSION: According to significant improvements in CAT and SGRQ score, LAMA may be preferred over LABA as a bronchodilator agent in group A COPD patients, especially in emphysema-dominant phenotype.

Single inhaler combination inhaled corticosteroid-formoterol as both maintenance and reliever (SMART) compared with a step up of treatment with fixed-dose inhaled corticosteroid-long-acting ß2-agonist maintenance with a short-acting ß2-agonist as reliever in adolescents and adults with poorly controlled asthma in Colombia: a cost-utility analysis.

OBJECTIVE: The aim of the present study was to determine the cost-utility of single inhaler combination inhaled corticosteroid and a long-acting ß2-agonist (ICS/LABAs) as both maintenance and reliever (SMART) compared with a step-up maintenance treatment with a fixed medium to high dose of ICS combined with LABA and a short-acting ß2-agonist (SABA) as reliever (ICS-LABA maintenance plus SABA) among patients aged 12 years or more with poorly controlled asthma in Colombia. METHODS: A Markov-type model was developed to estimate the costs and health outcomes of a simulated cohort of patients aged 12 years or more with uncontrolled asthma treated for 12 months. The main effectiveness data were obtained from a recent meta-analysis. The main outcome was the variable ''quality-adjusted life-years'' (QALYs). RESULTS: The base-case analysis showed that the budesonide/formoterol (BUD/FORM) SMART strategy was associated with lower overall treatment costs (US $3,062.37 vs. $4,462.02 average cost per patient over 12 months) and the greatest gain in QALYs (0.8511 vs. 0.8258 QALYs on average per patient over 12 months) compared with ICS-LABA maintenance plus SABA at step 4, thus leading to dominance. CONCLUSIONS: In patients aged 12 years or more with uncontrolled asthma at GINA step 3 or 4, the BUD/FORM SMART strategy at either step 3 or 4 is cost-effective compared with the ICS-LABA maintenance plus SABA at step 4 strategy, because it shows a greater gain in QALYs at lower total treatment costs.

Sample Preparation Techniques for Growth-Promoting Agents in Various Mammalian Specimen Preceding MS-Analytics.

The misuse of growth-promoting drugs such as beta-2 agonists and steroids is a known problem in farming and sports competitions. Prior to the analysis of biological samples via liquid chromatography (LC)-mass spectrometry (MS) or gas chromatography (GC)-MS, sufficient sample preparation is required to reliably identify or determine the residues of drugs. In practice, broad screening methods are often used to save time and analyze as many compounds as possible. This review was conceptualized to analyze the literature from 2018 until October 2023 for sample preparation procedures applied to animal specimens before LC- or GC-MS analysis. The animals were either used in farming or sports. In the present review, solid phase extraction (SPE) was observed as the dominant sample clean-up technique for beta-2 agonists and steroids, followed by protein precipitation. For the extraction of beta-2 agonists, mixed-mode cation exchanger-based SPE phases were preferably applied, while for the steroids, various types of SPE materials were reported. Furthermore, dispersive SPE-based QuEChERs were utilized. Combinatory use of SPE and liquid-liquid extraction (LLE) was observed to cover further drug classes in addition to beta-2 agonists in broader screening methods.

Heterogeneity of Treatment Response to Asthma.

The definition of asthma has evolved over the years with significant heterogeneity of the disease increasingly recognized. Complex gene and environment interactions result in different pheno-endotypes of asthma that respond differently to the same treatment. Multiple studies have revealed pharmacogenomic and endophenotypic factors that predict treatment response to standard therapies for asthma. Recent advances in biologic medications have enabled a more tailored approach to the care of patients with moderate to severe asthma, taking into consideration clinical traits and measurable biomarkers. This chapter will review heterogeneity in treatment response to different medication classes for asthma: inhaled and systemic corticosteroids, beta-2 agonists, leukotriene modifiers, muscarinic antagonists, macrolides, and biologics.

Transcriptome analysis in patients with asthma after inhaled combination therapy with long-acting ß2-agonists and corticosteroids.

Introduction: Asthma is one of the major public health problems that imposes a great burden on societal, financial, and healthcare around the world. Asthma poorly affects the health-related quality of life and daily activities of patients. Treatment of asthma, including inhaled corticosteroids (ICS) and long-acting beta-agonists (LABAs), mainly aims to improve the lung function and reduce symptoms and exacerbations. Current treatment regimens are symptom-based strategies, and the status of airway inflammation after treatment is yet unknown. We conducted this study to understand the comprehensive inflammation or airway remodeling status of patients after ICS-LABA treatment through RNA transcriptome analysis. Materials and methods: Eight newly diagnosed asthmatic patients and two healthy subjects were recruited in this study. Asthmatic patients underwent blood tests, lung function test, and RNA transcriptome analysis before and after ICS-LABA treatment. Results: In comparison with healthy subjects, pretreatment asthmatic patients had higher expression of protein tyrosine kinase and related signaling pathways. After ICS-LABA treatment, the expression of nuclear receptor transcription coactivator, N-acetyltransferase, protein tyrosine kinase, nuclear receptor, and RNA polymerase II-activating transcription factor were downregulated. However, the post-treatment asthmatic patients still had higher expression of cysteine-type endopeptidase, endodeoxyribonuclease, apolipoprotein, and unfolded protein was still upregulated than healthy subjects. Conclusions: The combination of ICS/LABAs decreased airway inflammatory and remodeling pathways. However, allergen stimulation-related pathways were still upregulated in patients after ICS/LABA treatment. The combination of medication and allergen removal is a complete strategy for asthma.

Can GPCRs Be Targeted to Control Inflammation in Asthma?

Historically, the drugs used to manage obstructive lung diseases (OLDs), asthma, and chronic obstructive pulmonary disease (COPD) either (1) directly regulate airway contraction by blocking or relaxing airway smooth muscle (ASM) contraction or (2) indirectly regulate ASM contraction by inhibiting the principal cause of ASM contraction/bronchoconstriction and airway inflammation. To date, these tasks have been respectively assigned to two diverse drug types: agonists/antagonists of G protein-coupled receptors (GPCRs) and inhaled or systemic steroids. These two types of drugs "stay in their lane" with respect to their actions and consequently require the addition of the other drug to effectively manage both inflammation and bronchoconstriction in OLDs. Indeed, it has been speculated that safety issues historically associated with beta-agonist use (beta-agonists activate the beta-2-adrenoceptor (ß2AR) on airway smooth muscle (ASM) to provide bronchoprotection/bronchorelaxation) are a function of pro-inflammatory actions of ß2AR agonism. Recently, however, previously unappreciated roles of various GPCRs on ASM contractility and on airway inflammation have been elucidated, raising the possibility that novel GPCR ligands targeting these GPCRs can be developed as anti-inflammatory therapeutics. Moreover, we now know that many GPCRs can be "tuned" and not just turned "off" or "on" to specifically activate the beneficial therapeutic signaling a receptor can transduce while avoiding detrimental signaling. Thus, the fledging field of biased agonism pharmacology has the potential to turn the ß2AR into an anti-inflammatory facilitator in asthma, possibly reducing or eliminating the need for steroids.

Weight status and nonadherence to asthma maintenance therapy among children enrolled in a public drug insurance plan.

Objective: The pediatric obese-asthma phenotype is associated with poor control, perhaps because of medication nonadherence. This study aimed to assess whether weight status is associated with nonadherence in children prescribed new asthma maintenance therapies.Methods: A historical cohort was constructed from a clinical database linking individual patient and prescription data to Quebec's prescription claims registry. Children aged 2-18 years with specialist-diagnosed asthma who were newly prescribed one of the following maintenance controllers: leukotriene receptor antagonists (LTRA); low-dose inhaled corticosteroids (ICS); medium/high-dose ICS; or combination therapy (ICS with long-acting beta-2 agonists and/or LTRA), at the Asthma Center of the Montreal Children's Hospital from 2000-2007 were included. Primary nonadherence was defined as not claiming any prescriptions, whereas secondary nonadherence was measured with the proportion of prescribed days covered (PPDC ≤ 50%) among primary adherers over a 6-month follow-up period. A modified Poisson regression model served to estimate the effect of excess weight (BMI > 85th percentile) on primary and secondary nonadherence.Results: Approximately one third of patients were primary nonadherers and 60% took less than 50% of prescribed therapy. Excess weight was associated with a trend toward increased risk of primary nonadherence in children newly prescribed low-dose ICS (RR 1.53, 95%CI 0.94-2.49), and of secondary nonadherence in children initiating medium/high-dose ICS (RR 1.24; 95%CI 0.98-1.59).Conclusions: Excess weight status is a possible determinant of primary nonadherence in children initiating low-dose ICS and secondary nonadherence to higher-dose ICS regimens. This hypothesis-generating study suggests that nonadherence may be a potential contributor to higher morbidity in children with obese-asthma.

The pharmacokinetics, safety, and tolerability of single, high-strength doses of fluticasone propionate and fluticasone propionate/salmeterol delivered via a novel multidose dry powder inhaler in adolescents and adults with persistent asthma.

OBJECTIVE: Characterize fluticasone propionate (Fp) and combination fluticasone propionate and salmeterol (FS) pharmacokinetic and safety profiles, delivered via a novel, inhalation-driven, multidose dry powder inhaler (MDPI). METHODS: This multicenter, open-label, four-period crossover, single-dose study randomized patients aged ≥12 years with persistent asthma to Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, Fp dry powder inhaler (DPI) 500 mcg (250 mcg × 2 inhalations), or FS DPI 500/50 mcg. Blood samples for determination of Fp and salmeterol pharmacokinetic parameters including Cmax, AUC0-t, AUC0-inf, tmax, and t½ were collected predose through 36 h postdose (14 time points). Safety assessments comprised adverse events, vital signs, and physical examinations. The institutional review board approved the study protocol. RESULTS: The pharmacokinetic analysis set and safety population each included 40 patients. Fp systemic exposure (Cmax, AUC0-t, and AUC0-inf) was highest for Fp DPI 500 mcg and similar for Fp MDPI 200 mcg, FS MDPI 200/12.5 mcg, and FS DPI 500/50 mcg. Fp geometric mean t½ values were similar across treatments. Salmeterol Cmax was 20% lower and AUC0-t and AUC0-inf were approximately 50% lower with FS MDPI versus FS DPI. Median tmax and geometric mean t½ were similar between FS MDPI and FS DPI. Adverse events were similar across treatments with no relevant changes in vital signs, physical examinations, or hematology test results. CONCLUSIONS: Fp MDPI and FS MDPI produced similar or lower systemic exposure to Fp and salmeterol, despite lower doses, versus conventional DPI devices, suggesting improved efficiency due to formulation and device differences.

Randomized, double-blind trial evaluating the efficacy and safety of fluticasone propionate and fluticasone propionate/salmeterol delivered via multidose dry powder inhalers in patients with persistent asthma aged 12 years and older.

OBJECTIVE: To assess the efficacy and safety of fluticasone propionate (Fp) and Fp/salmeterol (FS) administered via a novel multidose dry powder inhaler (MDPI) that is easy to use correctly in asthma patients. METHODS: This phase-3, multicenter, double-blind, parallel-group study evaluated asthmatic patients (≥12 years of age) previously treated with either low- or mid-dose inhaled corticosteroids (ICSs) or ICS/long-acting beta agonists. After a 14- to 21-day run-in, patients were randomized to Fp MDPI 50 mcg, Fp MDPI 100 mcg, FS MDPI 50/12.5 mcg, FS MDPI 100/12.5 mcg, or placebo twice daily for 12 weeks. Change from baseline in forced expiratory volume in 1 second (FEV1; primary endpoint) was evaluated at week 12, and serial spirometry was collected at day 1 and week 12 (subset of patients). Safety was assessed by adverse events (AEs). RESULTS: The full analysis and serial spirometry subset included 640 and 312 patients, respectively. At week 12, FS MDPI significantly improved FEV1 from baseline at each dose vs corresponding Fp MDPI doses (p < 0.05). Change from baseline in FEV1 for active treatment groups was significantly greater vs placebo (p < 0.05). After 12 weeks, serial spirometry was significantly greater at all time points in the FS MDPI groups vs corresponding Fp MDPI groups (p < 0.05). Improvements in serial spirometry on day 1 were maintained through week 12. AEs were similar across groups. CONCLUSIONS: Pulmonary function was significantly improved with Fp MDPI and FS MDPI vs placebo and FS MDPI vs Fp MDPI. Active treatments had a safety profile comparable to placebo.

Fluticasone furoate/vilanterol once daily improves night-time awakenings in asthma patients with night symptoms: Post hoc analyses of three randomized controlled trials.

OBJECTIVE: Symptoms, including night-time awakenings, affect the quality of life of people with asthma. Fluticasone furoate/vilanterol (FF/VI) reduces exacerbations, improves lung function, and rescue-free and symptom-free 24-hour periods in patients with asthma. These post hoc analyses compared daytime and night-time symptoms in patients with asthma who received FF/VI, versus FF, fluticasone propionate (FP) or placebo. METHODS: Daytime and night-time symptoms were collected via electronic daily diary cards in three Phase III randomized studies of once-daily FF/VI in patients with uncontrolled asthma on inhaled corticosteroids (ICSs) ± long-acting beta2 agonists (n = 609/1039/586). Endpoints included change from baseline in symptom-free days and nights (analyzed by Analysis of Covariance, covariates: baseline, region, sex, age, and treatment), time for patients to achieve seven consecutive symptom-free nights (analyzed by Cox proportional hazards' model, covariates as above), and proportion of patients experiencing 100% symptom-free nights per week (analyzed by logistic regression, covariates: percentage of symptom-free nights, sex, age, and treatment). RESULTS: Improvements in symptom-free days and nights were generally observed for all treatments. More patients who received FF/VI experienced 100% symptom-free nights in the last week of the treatment period than patients who received ICS alone or placebo. FF/VI also reduced time to achieve seven consecutive symptom-free nights. Patients with at least one night of symptoms at baseline experienced an additional 2.7 and 2.0 symptom-free nights per week with FF/VI 100/25 µg, versus 1.9 and 1.7 with FF alone; similar findings were seen with FF/VI 200/25 µg. CONCLUSIONS: Benefits in terms of symptom-free days and nights were observed for patients receiving FF/VI versus comparators in these post hoc analyses.

LABA/LAMA Fixed Dose Combination in Chronic Obstructive Pulmonary Disease: The Impact on Health-Related Quality of Life.

BACKGROUND: While fixed dose combinations (FDCs) of long-acting beta 2-agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) are increasingly tested on their efficacy in improving lung function, their effectiveness on Patient Reported Outcomes (PROs) such as Health Related Quality of Life (HRQoL) and Health Status (HS) deserve more attention. OBJECTIVES: To review current available evidence about the treatment effect of fixed LABA/LAMA FDCs on HRQoL. METHODS: A systematic literature search for randomized controlled trials (RCTs) about the impact of LABA/LAMA FDCs versus placebo, LABA or LAMA or LABA/ICS on HRQoL in Chronic obstructive pulmonary disease (COPD) patients has been performed. RESULTS: Twenty-eight RCTs (n = 32, 165 COPD patients) investigating the impact of fixed LABA/LAMA combinations on HRQoL were included. Using the St George' s Respiratory Questionnaire, 27 out of 28 trials assessed HRQoL. LABA/LAMA FDCs significantly improved HRQoL versus placebo in 9 out of 11 trials, while change when compared to other LABA or LAMA monocomponents was significantly better in 11 out 24. In 5 out of 6 RCTs having LABA/ICS as comparators, LABA/LAMA FDC had a similar effect and only 1 showed significant improvement in HRQL compared to LABA/ICS FDC. CONCLUSION: LABA/LAMA FDCs may be helpful in improving HRQoL, but because of the heterogeneity of performed trials, strong conclusions cannot be drawn. Moreover, due to the different molecule properties, treatment schedule, and device characteristics of each FDC, a generalized judgment seems inappropriate. Pragmatic trials powered to detect real-life differences in HRQoL and head-to-head comparison are needed to guide clinical practice in terms of PROs.

Formoterol and fluticasone propionate combination improves histone deacetylation and anti-inflammatory activities in bronchial epithelial cells exposed to cigarette smoke.

BACKGROUND: The addition of long-acting beta2-agonists (LABAs) to corticosteroids improves asthma control. Cigarette smoke exposure, increasing oxidative stress, may negatively affect corticosteroid responses. The anti-inflammatory effects of formoterol (FO) and fluticasone propionate (FP) in human bronchial epithelial cells exposed to cigarette smoke extracts (CSE) are unknown. AIMS: This study explored whether FP, alone and in combination with FO, in human bronchial epithelial cellline (16-HBE) and primary bronchial epithelial cells (NHBE), counteracted some CSE-mediated effects and in particular some of the molecular mechanisms of corticosteroid resistance. METHODS: 16-HBE and NHBE were stimulated with CSE, FP and FO alone or combined. HDAC3 and HDAC2 activity, nuclear translocation of GR and NF-κB, pERK1/2/tERK1/2 ratio, IL-8, TNF-α, IL-1ß mRNA expression, and mitochondrial ROS were evaluated. Actin reorganization in neutrophils was assessed by fluorescence microscopy using the phalloidin method. RESULTS: In 16-HBE, CSE decreased expression/activity of HDAC3, activity of HDAC2, nuclear translocation of GR and increased nuclear NF-κB expression, pERK 1/2/tERK1/2 ratio, and mRNA expression of inflammatory cytokines. In NHBE, CSE increased mRNA expression of inflammatory cytokines and supernatants from CSE exposed NHBE increased actin reorganization in neutrophils. FP combined with FO reverted all these phenomena in CSE stimulated 16-HBE cells as well as in NHBE cells. CONCLUSIONS: The present study provides compelling evidences that FP combined with FO may contribute to revert some processes related to steroid resistance induced by oxidative stress due to cigarette smoke exposure increasing the anti-inflammatory effects of FP.

Risk of congenital anomalies after exposure to asthma medication in the first trimester of pregnancy - a cohort linkage study.

OBJECTIVE: To examine the effect of maternal exposure to asthma medications on the risk of congenital anomalies. DESIGN: Meta-analysis of aggregated data from three cohort studies. SETTING: Linkage between healthcare databases and EUROCAT congenital anomaly registries. POPULATION: 519 242 pregnancies in Norway (2004-2010), Wales (2000-2010) and Funen, Denmark (2000-2010). METHODS: Exposure defined as having at least one prescription for asthma medications issued (Wales) or dispensed (Norway, Denmark) from 91 days before to 91 days after the pregnancy start date. Odds ratios (ORs) were estimated separately for each register and combined in meta-analyses. MAIN OUTCOME MEASURES: ORs for all congenital anomalies and specific congenital anomalies. RESULTS: Overall exposure prevalence was 3.76%. For exposure to asthma medication in general, the adjusted OR (adjOR) for a major congenital anomaly was 1.21 (99% CI 1.09-1.34) after adjustment for maternal age and socioeconomic position. The OR of anal atresia was significantly increased in pregnancies exposed to inhaled corticosteroids (3.40; 99% CI 1.15-10.04). For severe congenital heart defects, an increased OR (1.97; 1.12-3.49) was associated with exposure to combination treatment with inhaled corticosteroids and long-acting beta-2-agonists. Associations with renal dysplasia were driven by exposure to short-acting beta-2-agonists (2.37; 1.20-4.67). CONCLUSION: The increased risk of congenital anomalies for women taking asthma medication is small with little confounding by maternal age or socioeconomic status. The study confirmed the association of inhaled corticosteroids with anal atresia found in earlier research and found potential new associations with combination treatment. The potential new associations should be interpreted with caution due to the large number of comparisons undertaken. TWEETABLE ABSTRACT: This cohort study found a small increased risk of congenital anomalies for women taking asthma medication.

A methodological comparison of two European primary care databases and replication in a US claims database: inhaled long-acting beta-2-agonists and the risk of acute myocardial infarction.

PURPOSE: Results from observational studies on inhaled long-acting beta-2-agonists (LABA) and acute myocardial infarction (AMI) risk are conflicting, presumably due to variation in methodology. We aimed to evaluate the impact of applying a common study protocol on consistency of results in three databases. METHODS: In the primary analysis, we included patients from two GP databases (Dutch-Mondriaan, UK-CPRD GOLD) with a diagnosis of asthma and/or COPD and at least one inhaled LABA or a "non-LABA inhaled bronchodilator medication" (short-acting beta-2-agonist or short-/long-acting muscarinic antagonist) prescription between 2002 and 2009. A claims database (USA-Clinformatics) was used for replication. LABA use was divided into current, recent (first 91 days following the end of a treatment episode), and past use (after more than 91 days following the end of a treatment episode). Adjusted hazard ratios (AMI-aHR) and 95 % confidence intervals (95 % CI) were estimated using time-dependent multivariable Cox regression models stratified by recorded diagnoses (asthma, COPD, or both asthma and COPD). RESULTS: For asthma or COPD patients, no statistically significant AMI-aHRs (age- and sex-adjusted) were found in the primary analysis. For patients with both diagnoses, a decreased AMI-aHR was found for current vs. recent LABA use in the CPRD GOLD (0.78; 95 % CI 0.68-0.90) and in Mondriaan (0.55; 95 % CI 0.28-1.08), too. The replication study yielded similar results. Adjusting for concomitant medication use and comorbidities, in addition to age and sex, had little impact on the results. CONCLUSIONS: By using a common protocol, we observed similar results in the primary analysis performed in two GP databases and in the replication study in a claims database. Regarding differences between databases, a common protocol facilitates interpreting results due to minimized methodological variations. However, results of multinational comparative observational studies might be affected by bias not fully addressed by a common protocol.

Effects of acute and 2-week administration of oral salbutamol on exercise performance and muscle strength in athletes.

Our objective was to investigate effects of acute and 2-week administration of oral salbutamol on repeated sprint ability, exercise performance, and muscle strength in elite endurance athletes. Twenty male elite athletes [VO2max: 69.4 ± 1.8 (Mean ± SE) mL/min/kg], aged 25.9 ± 1.4 years, were included in a randomized, double-blinded and placebo-controlled parallel study. At baseline, after acute administration, and again after 2-week administration of the study drugs (8 mg salbutamol or placebo), subjects' maximal voluntary contraction (MVC) of m. quadriceps and isometric endurance of m. deltoideus were measured, followed by three repeated Wingate tests. Exercise performance at 110% of VO2max was determined on a bike ergometer. Acute administration of salbutamol increased peak power during first Wingate test by 4.1 ± 1.7% (P < 0.05). Two-week administration of salbutamol increased (P < 0.05) peak power during first and second Wingate test by 6.4 ± 2.0 and 4.2 ± 1.0%. Neither acute nor 2-week administration of salbutamol had any effect on MVC, exercise performance at 110% of VO2max or on isometric endurance. No differences were observed in the placebo group. In conclusion, salbutamol benefits athletes' sprint ability. Thus, the present study supports the restriction of oral salbutamol in competitive sports.

Effects of beclomethason/formoterol and budesonide/formoterol fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma--an exploratory study.

RATIONALE: Asthma is a chronic inflammatory airway disease of the whole bronchial tree. In this exploratory study we investigated the effects of beclomethasone/formoterol (becl/form) and budesonide/formoterol (bud/form) fixed combinations on lung function and airway inflammation in patients with mild to moderate asthma. METHODS: 22 adult patients with asthma (mean FEV1 91.6% pred.) were recruited to this prospective phase IV, double-blind, double-dummy, two-way cross-over, single-centre, randomised study. After a 7 days run-in period with bud 200 µg bid patients were randomised to receive 4 weeks of becl/form (100/6 µg) bid in a pressurised metered dose inhaler or bud/form (160/4.5 µg) bid administered via dry powder inhaler. We measured spirometry, bodyplethysmography, impulse oscillometry, nitric oxide (NO) and its alveolar fraction (CAlv), and assessed sputum cellularity. RESULTS: CAlv significantly decreased after 4 weeks of treatment in each treatment period. The adjusted geometric mean (log transformed data, end of treatment vs. baseline) was 0.942 ppb (95% CI: 0.778-1.141 ppb) for becl/form and 0.903 ppb (95% CI: 0.741-1.099 ppb) for bud/form. Impulse oscillometry revealed a significant decrease in mean Delta R5-R20 of -0.033 kPa * L(-1) * sec(-1) for becl/form (95% CI: -0.064 to -0.002) and of -0.048 033 kPa * L(-1) * sec(-1) for bud/form (95% CI: -0.079 to -0.017). Other parameters of lung function and NO showed numerically small and in most cases statistically non-significant changes. CONCLUSIONS: In patients with mild to moderate asthma pre-treated with inhaled corticosteroids, the use of ICS/LABA formulations led to improvements of CAlv and Delta R5-R20 indicating that these parameters might be helpful to further assess the effects of inhaled ICS/LABA combinations on lung function and airway inflammation.

Increased stroke risk among adult asthmatic patients.

BACKGROUND: We conducted a nationwide population-based cohort study to investigate the effects of asthma on the risk of stroke development in an Asian population. MATERIALS AND METHODS: Newly diagnosed asthmatic patients aged ≥ 18 years were identified, and asthma-free controls were randomly selected from the general population and frequency matched according to age, sex and index year using records obtained from the National Health Insurance Research Database between 2000 and 2010. Both cohorts were followed up until the end of 2011 to measure the incidence of stroke. The risk of stroke was analysed using Cox proportional hazard regression models, including factors such as sex, age and comorbidities. RESULTS: We followed the asthmatic patients for 104 697 person-years and followed the nonasthmatic people for 426 729 person-years. The incidence density rate of stroke increased in all of the groups of asthmatic patients compared with that of the controls when stratified according to sex, age and comorbidities. The hazard ratio (HR) of stroke was 1·37-fold greater for the asthmatic cohort, compared with that for the nonasthmatic cohort, after adjusting for sex, age and comorbidities. The adjusted HR of developing stroke substantially increased with older age and the increased frequency of asthmatic exacerbation and hospitalization. The patients receiving beta-2 agonists as a treatment exhibited a significantly greater risk of stroke compared with the patients receiving only inhaled corticosteroids, after adjusting for covariates. CONCLUSION: Asthma may be an independent risk factor for stroke, and its severity exhibits a dose response of stroke development.

Tiotropium sustains the anti-inflammatory action of olodaterol via the cyclic AMP pathway.

Mesenchymal cells (fibroblasts) of the airway wall respond to cholinergic stimulation by releasing pro-inflammatory and chemotactic cytokines and may thus contribute to chronic inflammation of the lung. Here, we studied the anti-inflammatory potential of olodaterol, a long acting ß2-adrenergic receptor agonist, and tiotropium, a long-acting muscarinic receptor antagonist, and whether they interact at the level of the cyclic AMP dependent signaling pathway. Pulmonary fibroblasts of asthmatic (n = 9) and non-asthmatic (n = 8) subjects were stimulated with the muscarinic receptor agonist carbachol and interleukin-1ß (IL-1 beta) in presence or absence of tiotropium or olodaterol alone, or their combination. We also measured cAMP levels and phosphorylation of the cAMP response element binding protein (CREB). As single components, carbachol, olodaterol and tiotropium did not affect IL-6 and IL-8 release. Carbachol concentration-dependently enhanced the production of IL-1ß-induced IL-6 and IL-8, which was blocked by the simultaneous addition of tiotropium. The combination of olodaterol plus tiotropium further reduced IL-6 and IL-8 release. Olodaterol induced cAMP and the phosphorylation of CREB, an effect counteracted by carbachol, but rescued by tiotropium. We conclude that olodaterol plus tiotropium cooperate to decrease the inflammatory response in pulmonary fibroblasts in vitro.

From Bronchodilation to Lactic Acidosis: A Case Report on Salbutamol's Adverse Effect.

Asthma is one of the most prevalent chronic respiratory diseases, characterized by bronchial hyper-responsiveness and intermittent airflow obstruction. Short-acting ß2 agonists (SABA) remain the cornerstone of acute asthma management due to its properties in smooth muscle relaxation and bronchodilatation. Rarely, these drugs might be associated with adverse effects, including the development of metabolic and hydro-electrolytic imbalances. We report a case of lactic acidosis secondary to ß2 agonists in a young female patient admitted with severe acute asthma. After initial management and significant improvement of the respiratory distress with nebulized and subcutaneous salbutamol, the patient developed high anion gap metabolic acidosis due to hyperlactacidemia and hypokalemia. Alternative causes of lactic acidosis were discarded, such as severe hypoxemia, systemic hypoperfusion, sepsis, and organ dysfunction, and SABA-related lactic acidosis was suspected. This treatment was halted, and tachypnea, metabolic acidosis, and lactate levels rapidly resolved. The remainder of the hospital stay was uneventful, and the patient was discharged after a period of five days. Although rare, the development of unexplained lactic acidosis in a SABA-treated patient should alert the treating physician to this ß2 agonist side-effect.

Left ventricular systolic function after inhalation of beta-2 agonists in healthy athletes.

Inhaled beta-2 adrenoceptor agonists (iß2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iß2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iß2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iß2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of ß2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021).