β2-Adrenergic receptor (β2-AR) agonists, as classic bronchodilators, serve as the cornerstone for asthma treatment. Herein, we designed and synthesized a series of derivatives based on the 5-hydroxy-4H-benzo[1,4]oxazin-3-one scaffold. Based on a comprehensive evaluation of four core indicators, including cAMP accumulation assays in HEK293 cells overexpressing human β2-AR or β1-AR, guinea pig tracheal strip assays, and in vitro cytotoxicity, compound C3 exhibited the best overall performance (β2-AR EC50 = 7 pM, β2/β1 selectivity > 97-fold; isolated tracheal relaxation Emax = 136.88, pD2 = 8.32; human bronchial epithelial cell BEAS-2B CC50 = 50.07 μM) and was selected as the candidate molecule. In a mouse asthma model, C3 administered at 200 μg/kg/day (458.5 nmol/kg/day) markedly suppressed inflammatory cell activity and improved lung function, showing anti-asthmatic efficacy comparable to that of salmeterol at 300 μg/kg/day (721.7 nmol/kg/day). In conclusion, C3 is a β2-AR agonist with potential application value, holding promise for the treatment of asthma.

The pulmonary microvasculature plays an essential role in maintaining alveolar integrity, but the direct effects of inhaled corticosteroids (ICS) on pulmonary endothelial cell function remain poorly understood. We investigated the effects of budesonide, formoterol, and their combination on endothelial network formation, apoptosis, migration, proliferation, and efferocytosis using human pulmonary microvascular endothelial cells (HPMEC-ST1.6R), A549 alveolar epithelial cells, and phagocytic cell models. Budesonide, alone or combined with formoterol, altered endothelial network formation on Matrigel by reducing total tubule length and the number of junctions while increasing tubule thickness, indicating reduced branching complexity. Budesonide also decreased epithelial secretion of the pro-angiogenic mediators VEGF, IL-8, and MCP-1. An independent set of experiments showed that fluticasone propionate similarly reduced VEGF, IL-8, MCP-1, TNF-α, and IL-6, supporting a class effect of corticosteroids on the epithelial secretome. Despite reducing angiogenic responses, budesonide protected endothelial cells from apoptosis, reduced caspase-3/7 activity, accelerated wound closure without affecting proliferation, preserved endothelial spheroid integrity, and enhanced efferocytosis. Formoterol alone had minimal effects and did not consistently enhance budesonide responses. Together, these in vitro findings suggest that, in the cell models studied, pulmonary endothelial responses to the ICS/LABA combinations tested are determined predominantly by the corticosteroid component, which suppresses pro-angiogenic mediator secretion while preserving endothelial survival and repair. As an exploratory cell-based study, these observations are hypothesis-generating and require confirmation in primary cells and in vivo models before clinical inferences can be drawn.

Dual long-acting bronchodilators are a standard treatment in chronic obstructive pulmonary disease (COPD), aimed at alleviating dyspnea, improving exercise tolerance, and preventing exacerbations. Metronome-paced tachypnea (MPT) offers a feasible alternative to exercise testing for the evaluation of dynamic hyperinflation (DH) in COPD. Because MPT can be performed during MRI, its combination with single-slice phase-resolved functional lung (PREFUL) MRI provides a promising approach to investigate changes in regional ventilation dynamics induced by DH. This approach was evaluated in a randomized, investigator-blinded, placebo-controlled, single-dose (SD) crossover trial with a two-week extension of once daily dual bronchodilator medication, in which patients with stable COPD underwent PREFUL MRI during resting tidal breathing (RTB) and during MPT. During RTB, no significant improvements in MRI-derived parameters were observed after SD treatment compared with placebo. During MPT, however, regional ventilation, flow-volume loop correlation, its defect percentage, and end-expiratory lung area improved significantly after SD treatment compared to the placebo scan (all p < 0.02). After multi-dose treatment, five out of six measured parameters improved during MPT, when compared to the baseline scan without bronchodilator treatment (all p < 0.03). In contrast to RTB, PREFUL MRI during MPT was able to detect changes in COPD patients already after SD treatment. The combination of MPT and PREFUL MRI represents a promising method to evaluate the effects of dual bronchodilators on regional ventilation dynamics and hyperinflation.

β2-agonist toxicity is a rare complication of asthma treatment, but there is little information about its interplay in pregnancy with maternal and fetal physiology. This case describes a woman in her early 30s at 37 weeks gestation with supratherapeutic use of inhaled salbutamol and salmeterol in the setting of worsening shortness of breath in the third trimester of pregnancy. She presented to the emergency department with chest discomfort and shortness of breath with a raised maternal lactate and troponin. Fetal cardiotocography was abnormal, so birth was expedited by emergency caesarean section due to concerns for fetal distress secondary to β2-agonist toxicity. This case highlights the risks of inhaled β2-agonist toxicity in pregnancy, which can be associated with troponin rise and fetal distress, even in the absence of a severe asthma exacerbation. It also highlights the importance of antenatal asthma education to ensure care is appropriately escalated when needed.

Background/Objectives: Asthma's preventable burden is heavily driven by severe exacerbations (SE). Replacing standalone short-acting β2-agonists (SABAs), which risk reducing patient tolerance, with inhaled corticosteroid/long-acting β2-agonist combinations optimizes care through maintenance, reliever, and maintenance-and-reliever therapy (MART). This systematic review and meta-analysis evaluated the efficacy, effectiveness, and safety of Budesonide/Formoterol (B/F). Methods: PubMed, Cochrane, and Embase were searched for randomized controlled trials (RCTs) and non-randomized controlled trials (non-RCTs) through May 15, 2026. Bias was assessed via the Cochrane Risk of Bias tool version 2 (RoB 2) and the Risk ff Bias in Non-randomized Studies of Interventions (ROBINS-I) version 2.0. Primary outcomes (time to first SE, annual SE rate) were pooled using a random-effects meta-analysis, yielding hazard ratios (HRs) and rate ratios (RRs). Results: We included 19 studies (15 RCTs, 4 non-RCTs) comprising 104,600 patients (primarily aged ≥12 years with mild-to-severe asthma). Most RCTs had a low risk of bias, whereas the non-RCTs had a high risk of bias. B/F MART significantly delayed the first SE and reduced annual rates versus Budesonide + SABA (HR = 0.57; RR = 0.55), B/F + SABA (HR = 0.62; RR = 0.58), and Fluticasone/Salmeterol + SABA (HR = 0.75; RR = 0.72). As-needed B/F reduced first SE hazard and annual rates versus SABA alone (HR = 0.43; RR = 0.42). Compared with Budesonide + SABA, it delayed the first SE (HR = 0.85) but showed non-significant rate reductions (RR = 0.90). Adverse events were balanced between groups over 12-52 weeks. Conclusions: B/F MART demonstrates high efficacy in mitigating the risk of the first SE. However, limited trial data leave the evidence for maintenance or reliever regimens controversial. Across all regimens, B/F is well-tolerated within 6 to 12 months.

The use of inhaled corticosteroids (ICs) could influence the respiratory microbiota. In animals with asthma it is, however, difficult to separate the immunomodulatory effects of ICs from their indirect effects via improvement of ventilation. Our objective was to determine if ICs alter the pulmonary microbiota independently from their effects on lung function, using a blinded, controlled trial in an experimental model of asthma exacerbation in horses. We treated horses with severe asthma with either bronchodilators alone, or in combination with ICs. Twelve horses in exacerbation received long-acting β2-agonist (LABA, salmeterol) or ICs/LABA (fluticasone/salmeterol) by inhalation, for 2 weeks. Lung function and bronchoalveolar lavages (BAL) were performed before and after treatment. 16S rRNA gene quantification and sequencing were performed on BAL fluid, using digital droplet PCR and the Illumina MiSeq platform. Data were processed using the software package mothur v. 1.44.2. In the LABA group, pulmonary bacterial load and the relative abundance of Actinobacteria and Verrucomicrobia phyla decreased with treatment (p < 0.05 for both), and β-diversity differed from baseline (p = 0.007). The relative abundance of families and genera belonging to the Bacteroidetes phylum increased with ICs/LABA (p < 0.05). Lung function significantly improved with both treatments, suggesting that treatment-related differences in pulmonary microbiota could be attributed in part to medication, not solely to change in ventilation. However, it is not clear if these changes are positive or detrimental to the lung environment. Furthermore, lung function following treatment was not perfectly identical between groups.

Alzheimer's disease (AD) is a multifactorial neurodegenerative disorder for which the current treatments remain largely symptomatic. Pleiotropic prodrug strategies offer a promising approach to address this complexity, combining complementary pharmacological mechanisms within a single molecular entity. In this study, we report the design, synthesis, and biological evaluation of novel carbamate-based pleiotropic prodrugs that combine butyrylcholinesterase (BuChE) inhibition and β2-adrenergic receptor (β2-AR) agonism. Seven salmeterol-derived carbamates were synthesized and evaluated for their cholinesterase inhibitory activity, β2-AR activity, and neuroprotective potential. Several derivatives exhibited potent and selective inhibition of human BuChE in the nanomolar range, revealing a clear structure-activity relationship driven by carbamate substitution and amine protection. Kinetics and LC-MS analyses demonstrated a pseudo-irreversible covalent inhibition mechanism associated with rapid enzyme reactivation, thereby enabling controlled salmeterol release. While carbamates behaved as inactive prodrugs at the β2-AR level, selected compounds displayed significant neuroprotective effects in a cellular model of amyloid-β-induced toxicity. Collectively, these findings validate salmeterol-derivated carbamates as innovative pleiotropic prodrugs and support the potential of combining BuChE inhibition and β2-AR agonism as a disease-modifying strategy for Alzheimer's disease.

Salmeterol is a medication used in the management and treatment of asthma and COPD. It is in the beta-2 adrenergic agonist class medications. This activity reviews the indications, mechanism of action, and contraindications for salmeterol as a valuable agent in treating asthma and COPD. This activity will highlight the mechanism of action, adverse event profile, and dosing pertinent for members of the interprofessional team in the treatment of patients with asthma and related conditions.

Pulmonary fibrosis (PF) can lead to respiratory distress, persistent dry cough, and a decline in quality of life, and may be life-threatening in severe cases. The aim is to mine and analyze drug-related PF signals, summarize potential risk medications, and provide references for clinical medication safety. This research accessed data from the US Food and Drug Administration Adverse Event Reporting System covering reports from January 2004 to September 2024. Proportional disproportionality methods were utilized to explore the relationship between drugs and PF, and to assess demographic information, drug-related PF risks, and the timing of PF onset. The Food and Drug Administration Adverse Event Reporting System database contained reports of 830 drugs associated with PF. Through disproportionality analysis and subsequent filtering, 33 drugs were identified as having significant risks. Fifteen antitumor and immunomodulatory drugs (45.45%) were noted, including bleomycin (reporting odds ratio [ROR] = 41.68), interferon gamma-1B (ROR = 12.11), and anagrelide (ROR = 6.63). Four cardiovascular system drugs (12.12%) included amiodarone (ROR = 41.92), dronedarone (ROR = 10.25), and simvastatin (ROR = 6.94). Four respiratory system drugs (12.12%) included indacaterol (ROR = 6.87), salmeterol/fluticasone (ROR = 4.30), and olodaterol (ROR = 3.76). Four antipathogenic microbial drugs (12.12%) included nitrofurantoin (ROR = 22.92), sulfasalazine (ROR = 5.69), and hydroxychloroquine (ROR = 3.51). Six other drugs (18.18%) included iodine-131 (ROR = 19.72), calcium carbonate (ROR = 8.59), and tamsulosin (ROR = 7.48). Amiodarone (Bayesian confidence propagation neural network [BCPNN] = 5.26), bleomycin (BCPNN = 4.95), and nitrofurantoin (BCPNN = 4.40) were the 3 drugs characterized by the greatest associated PF risk. The time to PF onset from antitumor and immunomodulatory drugs was significantly shorter than that from other drug types (P = .0082). The study identified 33 drugs showing disproportionality signals suggestive of potential associations with PF, most notably among antitumor and immunomodulatory agents, which exhibited a significantly shorter time to PF onset compared with other drug classes. The 3 drugs associated with the greatest PF risk were amiodarone, bleomycin, and nitrofurantoin. These findings highlight potential pharmacovigilance signals that warrant clinical vigilance and further validation through prospective studies.