Molecular basis of ß-arrestin coupling to formoterol-bound ß1-adrenoceptor.

The ß1-adrenoceptor (ß1AR) is a G-protein-coupled receptor (GPCR) that couples1 to the heterotrimeric G protein Gs. G-protein-mediated signalling is terminated by phosphorylation of the C terminus of the receptor by GPCR kinases (GRKs) and by coupling of ß-arrestin 1 (ßarr1, also known as arrestin 2), which displaces Gs and induces signalling through the MAP kinase pathway2. The ability of synthetic agonists to induce signalling preferentially through either G proteins or arrestins-known as biased agonism3-is important in drug development, because the therapeutic effect may arise from only one signalling cascade, whereas the other pathway may mediate undesirable side effects4. To understand the molecular basis for arrestin coupling, here we determined the cryo-electron microscopy structure of the ß1AR-ßarr1 complex in lipid nanodiscs bound to the biased agonist formoterol5, and the crystal structure of formoterol-bound ß1AR coupled to the G-protein-mimetic nanobody6 Nb80. ßarr1 couples to ß1AR in a manner distinct to that7 of Gs coupling to ß2AR-the finger loop of ßarr1 occupies a narrower cleft on the intracellular surface, and is closer to transmembrane helix H7 of the receptor when compared with the C-terminal α5 helix of Gs. The conformation of the finger loop in ßarr1 is different from that adopted by the finger loop of visual arrestin when it couples to rhodopsin8. ß1AR coupled to ßarr1 shows considerable differences in structure compared with ß1AR coupled to Nb80, including an inward movement of extracellular loop 3 and the cytoplasmic ends of H5 and H6. We observe weakened interactions between formoterol and two serine residues in H5 at the orthosteric binding site of ß1AR, and find that formoterol has a lower affinity for the ß1AR-ßarr1 complex than for the ß1AR-Gs complex. The structural differences between these complexes of ß1AR provide a foundation for the design of small molecules that could bias signalling in the ß-adrenoceptors.

Reduction of daily maintenance inhaled corticosteroids in patients with severe eosinophilic asthma treated with benralizumab (SHAMAL): a randomised, multicentre, open-label, phase 4 study.

BACKGROUND: Stepwise intensification of inhaled corticosteroids (ICS) is routine for severe eosinophilic asthma, despite some poor responses to high-dose ICS. Dose reductions are recommended in patients responding to biologics, but little supporting safety evidence exists. METHODS: SHAMAL was a phase 4, randomised, open-label, active-controlled study done at 22 study sites in four countries. Eligible participants were adults (aged ≥18 years) with severe eosinophilic asthma and a five-item Asthma Control Questionnaire score below 1·5 and who received at least three consecutive doses of benralizumab before screening. We randomly assigned patients (3:1) to taper their high-dose ICS to a medium-dose, low-dose, and as-needed dose (reduction group) or continue (reference group) their ICS-formoterol therapy for 32 weeks, followed by a 16-week maintenance period. The primary endpoint was the proportion of patients reducing their ICS-formoterol dose by week 32. The primary outcome was assessed in the reduction group, and safety analyses included all randomly assigned patients receiving study treatment. This study is registered at ClinicalTrials.gov, NCT04159519. FINDINGS: Between Nov 12, 2019, and Feb 16, 2023, we screened and enrolled in the run-in period 208 patients. We randomly assigned 168 (81%) to the reduction (n=125 [74%]) and reference arms (n=43 [26%]). Overall, 110 (92%) patients reduced their ICS-formoterol dose: 18 (15%) to medium-dose, 20 (17%) to low-dose, and 72 (61%) to as-needed only. In 113 (96%) patients, reductions were maintained to week 48; 114 (91%) of patients in the reduction group had zero exacerbations during tapering. Rates of adverse events were similar between groups. 91 (73%) patients had adverse events in the reduction group and 35 (83%) in the reference group. 17 patients had serious adverse events in the study: 12 (10%) in the reduction group and five (12%) in the reference group. No deaths occurred during the study. INTERPRETATION: These findings show that patients controlled on benralizumab can have meaningful reductions in ICS therapy while maintaining asthma control. FUNDING: AstraZeneca.

Albuterol-Budesonide Fixed-Dose Combination Rescue Inhaler for Asthma.

BACKGROUND: As asthma symptoms worsen, patients typically rely on short-acting ß2-agonist (SABA) rescue therapy, but SABAs do not address worsening inflammation, which leaves patients at risk for severe asthma exacerbations. The use of a fixed-dose combination of albuterol and budesonide, as compared with albuterol alone, as rescue medication might reduce the risk of severe asthma exacerbation. METHODS: We conducted a multinational, phase 3, double-blind, randomized, event-driven trial to evaluate the efficacy and safety of albuterol-budesonide, as compared with albuterol alone, as rescue medication in patients with uncontrolled moderate-to-severe asthma who were receiving inhaled glucocorticoid-containing maintenance therapies, which were continued throughout the trial. Adults and adolescents (≥12 years of age) were randomly assigned in a 1:1:1 ratio to one of three trial groups: a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide (with each dose consisting of two actuations of 90 µg and 80 µg, respectively [the higher-dose combination group]), a fixed-dose combination of 180 µg of albuterol and 80 µg of budesonide (with each dose consisting of two actuations of 90 µg and 40 µg, respectively [the lower-dose combination group]), or 180 µg of albuterol (with each dose consisting of two actuations of 90 µg [the albuterol-alone group]). Children 4 to 11 years of age were randomly assigned to only the lower-dose combination group or the albuterol-alone group. The primary efficacy end point was the first event of severe asthma exacerbation in a time-to-event analysis, which was performed in the intention-to-treat population. RESULTS: A total of 3132 patients underwent randomization, among whom 97% were 12 years of age or older. The risk of severe asthma exacerbation was significantly lower, by 26%, in the higher-dose combination group than in the albuterol-alone group (hazard ratio, 0.74; 95% confidence interval [CI], 0.62 to 0.89; P = 0.001). The hazard ratio in the lower-dose combination group, as compared with the albuterol-alone group, was 0.84 (95% CI, 0.71 to 1.00; P = 0.052). The incidence of adverse events was similar in the three trial groups. CONCLUSIONS: The risk of severe asthma exacerbation was significantly lower with as-needed use of a fixed-dose combination of 180 µg of albuterol and 160 µg of budesonide than with as-needed use of albuterol alone among patients with uncontrolled moderate-to-severe asthma who were receiving a wide range of inhaled glucocorticoid-containing maintenance therapies. (Funded by Avillion; MANDALA ClinicalTrials.gov number, NCT03769090.).

ß2-adrenoceptor agonist formoterol attenuates NLRP3 inflammasome activation and GSDMD-mediated pyroptosis in microglia through enhancing IκBα/NF-κB inhibition, SQSTM1/p62-dependent selective autophagy and ESCRT-III-mediated plasma membrane repair.

Microglia are immune cells that play important roles in the formation of the innate immune response within the central nervous system (CNS). The NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome is a multiple protein complex that is crucial for innate immunity, and excessive activation of the inflammasome for various reasons contributes to the pathogenesis of neurodegenerative diseases (NDs). ß2-adrenoceptor agonists have become the focus of attention in studies on NDs due to the high synthesis of ß2-adrenoceptors in the central nervous system (CNS). Promising results have been obtained from these studies targeting anti-inflammatory and neuroprotective effects. Formoterol is an effective, safe for long-term use, and FDA-approved ß2-adrenoceptor agonist with demonstrated anti-inflammatory features in the CNS. In this study, we researched the effects of formoterol on LPS/ATP-stimulated NLRP3 inflammasome activation, pyroptosis, NF-κB, autophagy, and ESCRT-III-mediated plasma membrane repair pathways in the N9 microglia cells. The results showed that formoterol, through the IκBα/NF-κB axis, significantly inhibited NLRP3 inflammasome activation, reduced the level of active caspase-1, secretion of IL-1ß and IL-18 proinflammatory cytokine levels, and the levels of pyroptosis. Additionally, we showed that formoterol activates autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair, which are significant pathways in the inhibition of NLRP3 inflammasome activation and pyroptosis. Our study suggests that formoterol efficaciously prevents the NLRP3 inflammasome activation and pyroptosis in microglial cells regulation through IκBα/NF-κB, autophagy, autophagosome formation, and ESCRT-III-mediated plasma membrane repair.

ß2-Adrenergic receptor agonists as a treatment for diabetic kidney disease.

We have previously shown that the long-acting ß2-adrenergic receptor (ß2-AR) agonist formoterol induced recovery from acute kidney injury in mice. To determine whether formoterol protected against diabetic nephropathy, the most common cause of end-stage kidney disease (ESKD), we used a high-fat diet (HFD), a murine type 2 diabetes model, and streptozotocin, a murine type 1 diabetes model. Following formoterol treatment, there was a marked recovery from and reversal of diabetic nephropathy in HFD mice compared with those treated with vehicle alone at the ultrastructural, histological, and functional levels. Similar results were seen after formoterol treatment in mice receiving streptozotocin. To investigate effects in humans, we performed a competing risk regression analysis with death as a competing risk to examine the association between Veterans with chronic kidney disease (CKD) and chronic obstructive pulmonary disease (COPD), who use ß2-AR agonists, and Veterans with CKD but no COPD, and progression to ESKD in a large national cohort of Veterans with stage 4 CKD between 2011 and 2013. Veterans were followed until 2016 or death. ESKD was defined as the initiation of dialysis and/or receipt of kidney transplant. We found that COPD was associated with a 25.6% reduction in progression from stage 4 CKD to ESKD compared with no COPD after adjusting for age, diabetes, sex, race-ethnicity, comorbidities, and medication use. Sensitivity analysis showed a 33.2% reduction in ESKD in Veterans with COPD taking long-acting formoterol and a 20.8% reduction in ESKD in Veterans taking other ß2-AR agonists compared with those with no COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a treatment for diabetic nephropathy and perhaps other forms of CKD.NEW & NOTEWORTHY Diabetic nephropathy is the most common cause of ESKD. Formoterol, a long-acting ß2-adrenergic receptor (ß2-AR) agonist, reversed diabetic nephropathy in murine models of type 1 and 2 diabetes. In humans, there was an association with protection from progression of CKD in patients with COPD, by means of ß2-AR agonist intake, compared with those without COPD. These data indicate that ß2-AR agonists, especially formoterol, could be a new treatment for diabetic nephropathy and other forms of CKD.

The carbon footprint of as-needed budesonide/formoterol in mild asthma: a post hoc analysis.

INTRODUCTION: The use of pressurised metered-dose inhalers (pMDIs) and asthma exacerbations necessitating healthcare reviews contribute substantially to the global carbon footprint of healthcare. It is possible that a reduction in carbon footprint could be achieved by switching patients with mild asthma from salbutamol pMDI reliever-based therapy to inhaled corticosteroid-formoterol dry powder inhaler (DPI) reliever therapy, as recommended by the Global Initiative for Asthma. METHODS: This post hoc analysis included all 668 adult participants in the Novel START trial, who were randomised 1:1:1 to treatment with as-needed budesonide/formoterol DPI, as-needed salbutamol pMDI or maintenance budesonide DPI plus as-needed salbutamol pMDI. The primary outcome was carbon footprint of asthma management, expressed as kilograms of carbon dioxide equivalent emissions (kgCO2e) per person-year. Secondary outcomes explored the effect of baseline symptom control and adherence (maintenance budesonide DPI arm only) on carbon footprint. RESULTS: As-needed budesonide/formoterol DPI was associated with 95.8% and 93.6% lower carbon footprint compared with as-needed salbutamol pMDI (least-squares mean 1.1 versus 26.2 kgCO2e; difference -25.0, 95% CI -29.7 to -20.4; p<0.001) and maintenance budesonide DPI plus as-needed salbutamol pMDI (least-squares mean 1.1 versus 17.3 kgCO2e; difference -16.2, 95% CI -20.9 to -11.6; p<0.001), respectively. There was no statistically significant evidence that treatment differences in carbon footprint depended on baseline symptom control or adherence in the maintenance budesonide DPI arm. CONCLUSIONS: The as-needed budesonide/formoterol DPI treatment option was associated with a markedly lower carbon footprint than as-needed salbutamol pMDI and maintenance budesonide DPI plus as-needed salbutamol pMDI.

Effects of inhaled beclometasone dipropionate/formoterol fumarate/glycopyrronium vs. beclometasone dipropionate/formoterol fumarate and placebo on lung hyperinflation and exercise endurance in chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: The single-inhaler triple combination of beclometasone dipropionate, formoterol fumarate, and glycopyrronium (BDP/FF/G) is available for maintenance therapy of chronic obstructive pulmonary disease (COPD). Cardinal features of COPD are lung hyperinflation and reduced exercise capacity. TRIFORCE aimed to evaluate the effect of BDP/FF/G on lung hyperinflation and exercise capacity in patients with COPD. METHODS: This double-blind, randomised, active- and placebo-controlled, crossover study recruited adults with COPD aged ≥ 40 years, who were hyperinflated and symptomatic, and were receiving mono- or dual inhaled maintenance COPD therapy. In the three treatment periods, patients were randomised to receive BDP/FF/G, BDP/FF, or placebo, each for 3 weeks, with a 7-10-day washout between treatment periods. Assessments included slow inspiratory spirometry (for resting inspiratory capacity [IC]) and constant work-rate cycle ergometry (for dynamic IC and exercise endurance time). The primary objective was to compare BDP/FF/G and BDP/FF vs. placebo for resting IC at Week 3. Key secondary objectives were to compare BDP/FF/G and BDP/FF vs. placebo for dynamic IC and exercise endurance time during constant work rate cycle ergometry at Week 3. RESULTS: Of 106 patients randomised, 95 completed the study. Resting IC adjusted mean differences vs. placebo were 315 and 223 mL for BDP/FF/G and BDP/FF, respectively (p < 0.001 for both). Adjusted mean differences vs. placebo for the key secondary endpoints were: 245 mL for dynamic IC (p < 0.001) and 69.2 s for exercise endurance time (nominal p < 0.001) with BDP/FF/G, and 96 mL (p = 0.053) and 70.1 s (nominal p < 0.001) with BDP/FF. Differences between BDP/FF/G and BDP/FF for resting and dynamic IC were 92 and 149 mL (p < 0.01 for both). All three treatments were generally well tolerated, with 27.3%, 25.3% and 19.0% of patients reporting adverse events with BDP/FF/G, BDP/FF and placebo, respectively, all mild or moderate. CONCLUSIONS: In patients with COPD, BDP/FF/G provided significant and clinically relevant improvements vs. placebo and BDP/FF in static and dynamic hyperinflation, with an improvement vs. placebo in exercise endurance. TRIAL REGISTRATION: ClinicalTrials.gov (NCT05097014), registered 27th October 2021.

Benefits of budesonide/glycopyrronium/formoterol fumarate dihydrate on lung function and exacerbations of COPD: a post-hoc analysis of the KRONOS study by blood eosinophil level and exacerbation history.

BACKGROUND: Japanese guidelines recommend triple inhaled corticosteroid (ICS)/long-acting muscarinic antagonist (LAMA)/long-acting ß2-agonist (LABA) therapy in patients with chronic obstructive pulmonary disease (COPD) and no concurrent asthma diagnosis who experience frequent exacerbations and have blood eosinophil (EOS) count ≥ 300 cells/mm3, and in patients with COPD and asthma with continuing/worsening symptoms despite receiving dual ICS/LABA therapy. These post-hoc analyses of the KRONOS study in patients with COPD and without an asthma diagnosis, examine the effects of fixed-dose triple therapy with budesonide/glycopyrronium/formoterol fumarate dihydrate (BGF) versus dual therapies on lung function and exacerbations based on blood EOS count - focusing on blood EOS count 100 to < 300 cells/mm3 - as a function of exacerbation history and COPD severity. METHODS: In KRONOS, patients were randomized to receive treatments that included BGF 320/14.4/10 µg, glycopyrronium/formoterol fumarate dihydrate (GFF) 14.4/10 µg, or budesonide/formoterol fumarate dihydrate (BFF) 320/10 µg via metered dose inhaler (two inhalations twice-daily for 24 weeks). These post-hoc analyses assessed changes from baseline in morning pre-dose trough forced expiratory volume in 1 s (FEV1) over 12-24 weeks and moderate or severe COPD exacerbations rates over 24 weeks. The KRONOS study was not prospectively powered for these subgroup analyses. RESULTS: Among patients with blood EOS count 100 to < 300 cells/mm3, least squares mean treatment differences for lung function improvement favored BGF over BFF in patients without an exacerbation history in the past year and in patients with moderate and severe COPD, with observed differences ranging from 62 ml to 73 ml across populations. In this same blood EOS population, moderate or severe exacerbation rates were reduced for BGF relative to GFF by 56% in patients without an exacerbation history in the past year, by 47% in patients with moderate COPD, and by 50% in patients with severe COPD. CONCLUSIONS: These post-hoc analyses of patients with moderate-to-very severe COPD from the KRONOS study seem to indicate clinicians may want to consider a step-up to triple therapy in patients with persistent/worsening symptoms with blood EOS count > 100 cells/mm3, even if disease severity is moderate and there is no recent history of exacerbations. TRIAL REGISTRATION: ClinicalTrials.gov registry number NCT02497001 (registration date, 13 July 2015).

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.

Improvement of asthma control in adult patients using extrafine inhaled beclomethasone/formoterol fixed combination as maintenance therapy as well as maintenance and reliever therapy - CONTROL study.

INTRODUCTION: Extrafine formulation of beclomethasone/formoterol fixed combination (BDP/F pMDI HFA) is approved for both fixed maintenance and maintenance and reliever therapy (MART) of asthma, and recent data has proven that BDP/F pMDI HFA maintenance and reliever therapy is an effective alternative to other regimens. OBJECTIVE: This study aimed to assess the level of asthma control in a real-life setting in adult patients using extrafine BDP/F pMDI HFA fixed combination in a pressurized metered-dose inhaler (pMDI) as fixed maintenance dosing as well as maintenance and maintenance and reliever therapy. Additionally, we examined patients' satisfaction with the inhaler device and compliance with therapy as essential factors determining asthma control. METHODS: This multicenter prospective non-interventional observational study lasted 4 months with 3 patient visits. We used the Asthma Control Questionnaire 7 (ACQ-7) to evaluate the degree of asthma control and Morisky Medication Adherence Scale (MMAS-4) to assess compliance. A self-developed questionnaire was used to assess satisfaction with the inhaler device. RESULTS: 2179 patients using BDP/F pMDI HFA fixed combination as maintenance and reliever therapy or BDP/F pMDI HFA as maintenance therapy and SABA (short-acting beta2-agonist) as a reliever for at least 2 months were included. During the prospective follow-up, we observed an upward trend in the FEV1% (forced expiratory volume in 1 s) predicted values, improvement in the control of symptoms as indicated by a decline in the mean ACQ-7 score was noted (1.62 at Visit 1 vs. 1.21 at Visit 2 vs. 0.94 at Visit 3, p < 0.001) and increase in patients' compliance (the number of patients that reported forgetting at times to take their medication was reduced from 49.7 % to 27.1 %, p < 0.001). At the same time, we noted a reduction in the number of as-needed doses used for symptom relief (p < 0.001). Most patients were satisfied with the pMDI, considered it easy and convenient to use, and preferred it to a dry powder inhaler (p < 0.001). CONCLUSIONS: The use of extrafine BDP/F pMDI HFA as maintenance as well as reliever therapy seems to be associated with increased asthma control and better compliance to therapy.

Cost-effectiveness of budesonide-formoterol vs inhaled epinephrine in US adults with mild asthma.

BACKGROUND: The management of mild asthma has lacked an over-the-counter (OTC) option aside from inhaled epinephrine, which is available in the United States. However, inhaled epinephrine use without an inhaled corticosteroid may increase the risk of asthma death. OBJECTIVE: To compare the cost-effectiveness of OTC as-needed budesonide-formoterol as a plausible alternative to inhaled epinephrine. METHODS: We developed a probabilistic Markov model to compare OTC as-needed budesonide-formoterol inhaler use vs inhaled epinephrine use in adults with mild asthma from a US societal perspective over a lifetime horizon, with a 3% annual discount rate (2022 US dollars). Inputs were derived from the SYmbicort Given as-needed in Mild Asthma (SYGMA) trials, published literature, and commercial costs. Outcomes were quality-adjusted life-years (QALY), costs, incremental net monetary benefit (INMB), severe asthma exacerbations, well-controlled asthma days, and asthma-related deaths. Microsimulation was used to evaluate underinsured Americans living with mild asthma (n = 5,250,000). RESULTS: Inhaled epinephrine was dominated (with lower QALYs gains at a higher cost) by both as-needed budesonide-formoterol (INMB, $15,541 at a willingness-to-pay of $100,000 per QALY) and the no-OTC inhaler option (INMB, $1023). Adults using as-needed budesonide-formoterol had 145 more well-controlled asthma days, 2.79 fewer severe exacerbations, and an absolute risk reduction of 0.23% for asthma-related death compared with inhaled epinephrine over a patient lifetime. As-needed budesonide-formoterol remained dominant in all sensitivity and scenario analyses, with a 100% probability of being cost-effective compared with inhaled epinephrine in probabilistic sensitivity analysis. CONCLUSION: If made available, OTC as-needed budesonide-formoterol for treating mild asthma in underinsured adults without HCP management improves asthma outcomes, prevents fatalities, and is cost-saving.

In symptomatic patients on as-needed inhaled corticosteroids-formoterol, VAS asthma is associated with small airways resistance.

OBJECTIVES: Impulse oscillometry (IOS) can demonstrate small airways disease even when spirometry values are normal. However, it is unknown if the absence of symptoms excludes increased small airways resistance in asthma patients. We aimed to correlate symptoms (assessed through visual analogue scales) with measures of small airways resistance in patients with asthma and to determine whether less symptomatic patients have increased small airways resistance. METHODS: We conducted a single center, prospective cohort study. We included controlled asthma patients on as-needed inhaled corticosteroids-formoterol. Patients were evaluated on their symptom VASs, Spirometry and IOS (with R5-R20% measuring small airways resistance) which were measured both in periods when they were less symptomatic and symptomatic. Symptoms were assessed using MASK-air®, an mHealth app that includes a daily monitoring questionnaire with validated VASs. We correlated MASK-air VASs with small airways resistance. RESULTS: We assessed 29 patients. There was a significant correlation between VAS asthma and R5-R20% in symptomatic periods (r = 0.43; 95% CI = 0.13;0.68, p = 0.019), but not in less symptomatic periods (0.04; 95% CI-0.40;0.46; p = 0.825). In less symptomatic periods, patients presenting with low VAS asthma (VAS < 30) displayed a lower median R5-R20% than the remainder (0.26 versus 0.35), as well as a lower R5% (0.13 versus 0.15) (p < 0.001). In 68.9% of less symptomatic patients, R5-R20 values remained higher than normal values. CONCLUSION: In symptomatic patients on as-needed inhaled corticosteroids-formoterol, VAS asthma was associated with small airways resistance. However, even if these patients are less symptomatic, small airways resistance may be higher than normal. Since SAD significantly affects asthma control, patients should be carefully followed-up, even in less symptomatic periods.

Comparison of extrafine beclomethasone dipropionate/formoterol fumarate dry powder inhaler and pressurized metered-dose inhaler in Chinese patients with asthma: the FORTUNE study.

OBJECTIVE: When selecting inhaled therapies, it is important to consider both the active molecules and the device. Extrafine formulation beclomethasone dipropionate plus formoterol fumarate (BDP/FF) has been available for some years delivered via pressurized metered-dose inhaler (pMDI). More recently, a breath-activated, multi-dose dry-powder inhaler (DPI), the NEXThaler, has been approved. The current study aimed to demonstrate the non-inferiority of BDP/FF delivered via the DPI vs. via the pMDI, in Chinese adults with asthma. METHODS: After a four-week run-in period, when all patients received BDP/FF pMDI 100/6 µg, two inhalations twice daily (BID), patients were randomized equally to BDP/FF pMDI or DPI, both 100/6 µg, two inhalations BID for 12 weeks. The primary objective was to demonstrate non-inferiority of BDP/FF DPI vs. BDP/FF pMDI in terms of average pre-dose morning peak expiratory flow (PEF) over the entire treatment period. RESULTS: Of 252 and 242 patients in the DPI and pMDI groups, respectively, 88.5% and 88.8% completed the study. The primary objective was met, with no statistically significant difference between the treatments in average pre-dose morning PEF, and with the lower limit of the 95% CI above the -15 L/min non-inferiority margin (adjusted mean difference: 5.25 L/min [95% CI: -0.56, 11.06]). Adverse events were reported by 48.4% and 49.6% patients in the DPI and pMDI groups, respectively, most mild or moderate. CONCLUSIONS: The NEXThaler DPI is a similarly effective device to the pMDI for the administration of BDP/FF in adults, so extending the options available for the management of asthma.

Inhaled beta2 -agonist, formoterol, enhances intense exercise performance, and sprint ability in elite cyclists.

PURPOSE: Many athletes use long-acting beta2 -agonist formoterol in treatment of asthma. However, studies in non-athlete cohorts demonstrate that inhaled formoterol can enhance sprint performance calling into question whether its use in competitive sports should be restricted. We investigated whether formoterol at upper recommended inhaled doses (54 µg) would enhance sprint ability and intense exercise performance in elite cyclists. METHODS: Twenty-one male cyclists (V̇O2max : 70.4 ± 4.3 mL × min-1 × kg-1 , mean ± SD) completed two 6-s all-out sprints followed by 4-min all-out cycling after inhaling either 54 µg formoterol or placebo. We also assessed cyclists' leg muscle mass by dual-energy X-ray absorptiometry and muscle fiber type distribution of vastus lateralis biopsies. RESULTS: Peak and mean power output during the 6-s sprint was 32 W (95% CI, 19-44 W, p < 0.001) and 36 W (95% CI, 24-48 W, p < 0.001) higher with formoterol than placebo, corresponding to an enhancing effect of around 3%. Power output during 4-min all-out cycling was 9 W (95% CI, 2-16 W, p = 0.01) greater with formoterol than placebo, corresponding to an enhancing effect of 2.3%. Performance changes in response to formoterol were unrelated to cyclists' VO2max and leg lean mass, whereas muscle fiber Type I distribution correlated with change in sprinting peak power in response to formoterol (r2 = 0.314, p = 0.012). CONCLUSION: Our findings demonstrate that an inhaled one-off dose of 54 µg formoterol has a performance-enhancing potential on sprint ability and short intense performance in elite male cyclists, which is irrespective of training status but partly related to muscle fiber type distribution for sprint ability.

Comparison of Budesonide/formoterol versus Fluticasone furoate/vilanterol as maintenance and reliever therapy for asthma control: a real-world observational study.

BACKGROUND: Previous studies have reported reduced acute exacerbation rates and improved symptom control in asthma patients treated using inhaled corticosteroids plus formoterol maintenance and reliever therapy (MART). Fluticasone furoate (FF) and vilanterol (VIL) also provide rapid bronchodilation and sustained anti-inflammatory effects, however no studies have investigated FF/VIL as MART for asthma control. METHODS: From October 1, 2021 to September 30, 2023, this retrospective study included asthma patients classified as step 3 or 4 according to the Global Initiative for Asthma guidelines, who were then divided into two groups. One group received BUD/FOR as MART, while the other received FF/VIL as MART. Pulmonary function tests, exacerbation rates, Asthma Control Test (ACT), fractional exhaled nitric oxide (FeNO) levels, and blood eosinophil counts were measured before and after 12 months of treatment. RESULTS: A total of 161 patients were included, of whom 36 received BUD/FOR twice daily as MART, and 125 received FF/VIL once daily as MART. After 12 months of treatment, the FF/VIL group showed a significant increase in ACT scores by 1.57 (p < 0.001), while the BUD/FOR group had an increase of 0.88 (p = 0.11). In terms of FeNO levels, the BUD/FOR group experienced a decline of -0.2 ppb (p = 0.98), whereas the FF/VIL group had a mild increase of + 0.8 ppb (p = 0.7). Notably, there was a significant difference in the change of FeNO between the two groups (∆ FeNO: -0.2 ppb in BUD/FOR; + 0.8 ppb in FF/VIL, p < 0.001). There were no significant alterations observed in FEV1, blood eosinophil count, or acute exacerbation decline in either group. CONCLUSIONS: In the current study, patients treated with FF/VIL as MART showed improvements in ACT scores, while those treated with BUD/FOR as MART exhibited a reduction in FeNO levels. However, the difference between the two treatment groups did not reach clinical significance. Thus, FF/VIL as MART showed similar effectiveness to BUD/FOR as MART.

Acute Asthma Exacerbations: Management Strategies.

Asthma exacerbations, defined as a deterioration in baseline symptoms or lung function, cause significant morbidity and mortality. Asthma action plans help patients triage and manage symptoms at home. In patients 12 years and older, home management includes an inhaled corticosteroid/formoterol combination for those who are not using an inhaled corticosteroid/long-acting beta2 agonist inhaler for maintenance, or a short-acting beta2 agonist for those using an inhaled corticosteroid/long-acting beta2 agonist inhaler that does not include formoterol. In children four to 11 years of age, an inhaled corticosteroid/formoterol inhaler, up to eight puffs daily, can be used to reduce the risk of exacerbations and need for oral corticosteroids. In the office setting, it is important to assess exacerbation severity and begin a short-acting beta2 agonist and oxygen to maintain oxygen saturations, with repeated doses of the short-acting beta2 agonist every 20 minutes for one hour and oral corticosteroids. Patients with severe exacerbations should be transferred to an acute care facility and treated with oxygen, frequent administration of a short-acting beta2 agonist, and corticosteroids. The addition of a short-acting muscarinic antagonist and magnesium sulfate infusion has been associated with fewer hospitalizations. Patients needing admission to the hospital require continued monitoring and systemic therapy similar to treatments used in the emergency department. Improvement in symptoms and forced expiratory volume in one second or peak expiratory flow to 60% to 80% of predicted values helps determine appropriateness for discharge. The addition of inhaled corticosteroids, consideration of stepping up asthma maintenance therapy, close follow-up, and education on asthma action plans are important next steps to prevent future exacerbations.

Update on Asthma Management Guidelines.

The Global Initiative for Asthma (GINA) was established in 1993 and publishes a yearly global strategy to improve asthma awareness, prevention and management of asthma worldwide, based on a review of the most updated evidence. The current 2024 GINA update advises that all adults and adolescents with asthma receive inhaled corticosteroid (ICS)- containing medication and should not be treated with short acting beta agonist (SABA) alone. The 2024 GINA strategy divides treatment into two 'Tracks": Track 1 (preferred Track), the reliever is as-needed combination low dose ICS-formoterol; Track 2 uses SABA as the reliever along with a separate ICS inhaler. The updates also stress the importance that individuals with asthma should have a written asthma action plan, and asthma management should be tailored to the individual to help reduce the occurrence of serious exacerbations, fatalities, and hospitalizations.

Rhinovirus C15 Attenuates Relaxation and cAMP Production in Human Airways and Smooth Muscle.

Rhinoviruses (RVs) evoke as many as 85% of acute asthma exacerbations in children and 50% in adults and can induce airway hyperresponsiveness and decrease efficacy of current therapeutics to provide symptom relief. Using human precision-cut lung slices (hPCLSs), primary human air-liquid interface-differentiated airway epithelial cells (HAECs), and human airway smooth muscle (HASM) as preclinical experimental models, we demonstrated that RV-C15 attenuates agonist-induced bronchodilation. Specifically, airway relaxation to formoterol and cholera toxin, but not forskolin (Fsk), was attenuated following hPCLS exposure to RV-C15. In isolated HASM cells, exposure to conditioned media from RV-exposed HAECs decreased cellular relaxation in response to isoproterenol and prostaglandin E2, but not Fsk. Additionally, cAMP generation elicited by formoterol and isoproterenol, but not Fsk, was attenuated following HASM exposure to RV-C15-conditioned HAEC media. HASM exposure to RV-C15-conditioned HAEC media modulated expression of components of relaxation pathways, specifically GNAI1 and GRK2. Strikingly, similar to exposure to intact RV-C15, hPCLS exposed to UV-inactivated RV-C15 showed markedly attenuated airway relaxation in response to formoterol, suggesting that the mechanism(s) of RV-C15-mediated loss of bronchodilation is independent of virus replication pathways. Further studies are warranted to identify soluble factor(s) regulating the epithelial-driven smooth muscle loss of ß2-adrenergic receptor function.

Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism.

Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathological comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with ß2 receptor agonists (e.g. formoterol) improves metabolic and skeletal muscle function. We aimed first to examine if restricting physical activity following injury affects metabolic and skeletal muscle function, and second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24 h evaluations of physical activity and whole-body metabolism were conducted following VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity and untargeted metabolomics. Restricting activity chronically after VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate following VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force-producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. KEY POINTS: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modelling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The ß2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury.

Triple Inhaled Therapy at Two Glucocorticoid Doses in Moderate-to-Very-Severe COPD.

BACKGROUND: Triple fixed-dose regimens of an inhaled glucocorticoid, a long-acting muscarinic antagonist (LAMA), and a long-acting ß2-agonist (LABA) for chronic obstructive pulmonary disease (COPD) have been studied at single dose levels of inhaled glucocorticoid, but studies at two dose levels are lacking. METHODS: In a 52-week, phase 3, randomized trial to evaluate the efficacy and safety of triple therapy at two dose levels of inhaled glucocorticoid in patients with moderate-to-very-severe COPD and at least one exacerbation in the past year, we assigned patients in a 1:1:1:1 ratio to receive twice-daily inhaled doses of triple therapy (inhaled glucocorticoid [320 µg or 160 µg of budesonide], a LAMA [18 µg of glycopyrrolate], and a LABA [9.6 µg of formoterol]) or one of two dual therapies (18 µg of glycopyrrolate plus 9.6 µg of formoterol or 320 µg of budesonide plus 9.6 µg of formoterol). The primary end point was the annual rate (the estimated mean number per patient per year) of moderate or severe COPD exacerbations, as analyzed in the modified intention-to-treat population with the use of on-treatment data only. RESULTS: The modified intention-to-treat population comprised 8509 patients. The annual rates of moderate or severe exacerbations were 1.08 in the 320-µg-budesonide triple-therapy group (2137 patients), 1.07 in the 160-µg-budesonide triple-therapy group (2121 patients), 1.42 in the glycopyrrolate-formoterol group (2120 patients), and 1.24 in the budesonide-formoterol group (2131 patients). The rate was significantly lower with 320-µg-budesonide triple therapy than with glycopyrrolate-formoterol (24% lower: rate ratio, 0.76; 95% confidence interval [CI], 0.69 to 0.83; P<0.001) or budesonide-formoterol (13% lower: rate ratio, 0.87; 95% CI, 0.79 to 0.95; P = 0.003). Similarly, the rate was significantly lower with 160-µg-budesonide triple therapy than with glycopyrrolate-formoterol (25% lower: rate ratio, 0.75; 95% CI, 0.69 to 0.83; P<0.001) or budesonide-formoterol (14% lower: rate ratio, 0.86; 95% CI, 0.79 to 0.95; P = 0.002). The incidence of any adverse event was similar across the treatment groups (range, 61.7 to 64.5%); the incidence of confirmed pneumonia ranged from 3.5 to 4.5% in the groups that included inhaled glucocorticoid use and was 2.3% in the glycopyrrolate-formoterol group. CONCLUSIONS: Triple therapy with twice-daily budesonide (at either the 160-µg or 320-µg dose), glycopyrrolate, and formoterol resulted in a lower rate of moderate or severe COPD exacerbations than glycopyrrolate-formoterol or budesonide-formoterol. (Funded by AstraZeneca, ETHOS ClinicalTrials.gov number, NCT02465567.).