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Introduction: The MERIT study in Malaysia is a real-world retrospective, observational, multicenter study that evaluated asthma control in patients with uncontrolled asthma who were switched from as-needed (pro re nata [PRN]) budesonide/formoterol or inhaled corticosteroid (ICS) whenever a short-acting beta-agonist (SABA) was taken, to proactive regular dosing of fluticasone propionate/salmeterol (FP/SAL PRD)., Methods: Data from the medical records of patients who were stepped up to FP/SAL PRD were extracted retrospectively at baseline and follow-up (between 3 and 6 months after stepping up to FP/SAL PRD). The primary endpoint was the percentage of patients with improvement in asthma control assessed via the Asthma Control Test (ACT). Secondary endpoints included safety and the percentage of patients with moderate and severe exacerbations. Additionally, patient-reported use of reliever medication, systemic corticosteroids, emergency department visits, or hospitalization was also analyzed., Results: One hundred twenty patients with uncontrolled asthma who were stepped up to FP/SAL PRD were enrolled in the study. Of these, 76 (63.3%) patients were on prior budesonide/formoterol PRN, and 44 (36.7%) were on prior ICS with SABA PRN treatment. After stepping up to FP/SAL PRD with a mean follow-up of 5.8 months, 110 (91.7%) patients achieved asthma control at the follow-up visit (p < 0.001). Similar improvements were observed regardless of prior PRN regimen. A statistically significant improvement was observed in the mean ACT score at the follow-up visit (p < 0.0001). The proportion of patients with moderate and severe exacerbations was also reduced after stepping up to FP/SAL PRD, with no adverse events reported. Over 80% of patients reported a decrease in the use of systemic corticosteroids, visits to the emergency department, or hospitalization., Conclusion: This study highlights the effectiveness of the FP/SAL PRD treatment approach in patients with uncontrolled asthma on a PRN treatment regimen., (© 2024. The Author(s).)

Background: Fibromyalgia (FM) is a syndrome of pervasive chronic pain accompanied by low mood, sleep disorders, and cognitive decline. The dysfunction of central pain processing systems along with neurotransmitter disturbances are possible contributing mechanisms. Genetic polymorphism of the 𝛽2 adrenergic receptors is reported in FM patients. It is reported that chronic β2 agonists administration is effective for neuropathic pain alleviation. No current information, however, exists on their potential to alleviate nociplastic pain, such as FM. Therefore, the purpose of the current study is to examine salmeterol's potential antiallodynic effects in experimentally produced FM and explore some of the possible contributing mechanisms., Methods: Thirty rats are allocated into three groups (n = 10): a normal group, a reserpine group that received reserpine (1 mg/kg; s.c.) for 3 days, and a reserpine + salmeterol group that received salmeterol (1 mg/kg; i.p.) for 21 consecutive days following last reserpine injection., Results: Reserpine administration resulted in behavioral and biochemical changes consistent with FM, including thermal and mechanical hyperalgesia, depressive behavior, and motor incoordination. This is coupled with disturbed spinal monoamine levels, depressed cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) signaling, disturbed mitochondrial function/dynamics, and compromised blood-nerve barrier integrity. Treatment with salmeterol conceivably reversed these effects., Conclusion: β2 receptor agonists such as salmeterol could be regarded as a promising strategy for the management of FM., (© 2024 Société Française de Pharmacologie et de Thérapeutique. Published by John Wiley & Sons Ltd.)

Objective: To compare the efficacy of inhaled salbutamol with salmeterol for the treatment of arterial hypoxaemia in anaesthetized horses., Study Design: Prospective, randomized, clinical study., Animals: A total of 108 client-owned horses (American Society of Anesthesiologists status I-V) anaesthetized for elective and emergency procedures., Methods: Horses were premedicated with acepromazine [intramuscularly 0.1 mg kg -1 or intravenously (IV) 0.05 mg kg -1 ] and xylazine (0.6 mg kg -1 IV). Midazolam (0.06 mg kg -1 IV) and ketamine (2.2 mg kg -1 IV) were combined to induce anaesthesia, and isoflurane in oxygen/air mixture (inspired oxygen fraction 0.7) was used for maintenance of anaesthesia. Mechanical ventilation was initiated without delay using the following ventilator settings: tidal volume 10 mL kg -1 , respiratory rate 8 breaths minute -1 , inspiratory-to-expiratory time ratio 1:2, no positive end-expiratory pressure. If arterial blood gas analysis revealed PaO 2 < 100 mmHg (13.3 kPa), the administration of either inhaled salbutamol (2 μg kg -1 ) or salmeterol (0.5 μg kg -1 ) was randomly assigned Blood gas analysis was repeated 15 and 30 minutes after treatment. The intervention was considered successful when PaO 2 after treatment ≥ 1.2 × PaO 2 before treatment (i.e. ≥20% increase). PaO 2 at 15 and 30 minutes was compared between groups using Mann-Whitney U test; p < 0.05 was considered significant., Results: Of the 108 horses, 60 were administered salbutamol, 65% and 60% responded successfully at 15 and 30 minutes, increasing their initial PaO 2 by 38% and 44%, respectively. The other 48 horses were administered salmeterol, 35% responded successfully at 15 and 30 minutes, increasing their initial PaO 2 by 3% and 4%, respectively. PaO 2 was significantly higher after salbutamol than after salmeterol at 15 and 30 minutes., Conclusions and Clinical Relevance: Using the described protocol, inhaled salbutamol was more effective than salmeterol in improving PaO 2 in anaesthetized horses with value < 100 mmHg (13.3 kPa)., (Copyright © 2024 Association of Veterinary Anaesthetists and American College of Veterinary Anesthesia and Analgesia. Published by Elsevier Ltd. All rights reserved.)

Introduction: The relationship between immediate symptom control, reliever medication use and exacerbation risk on treatment response and factors that modify it have not been assessed in an integrated manner. Here we apply simulation scenarios to evaluate the effect of individual baseline characteristics on treatment response in patients with moderate-severe asthma on regular maintenance dosing monotherapy with fluticasone propionate (FP) or combination therapy with fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)., Methods: Reduction in reliever medication use (puffs/24 h), change in symptom control scores (ACQ-5), and annualised exacerbation rate over 12 months were simulated in a cohort of patients with different baseline characteristics (e.g. time since diagnosis, asthma control questionnaire (ACQ-5) symptom score, smoking status, body mass index (BMI) and sex) using drug-disease models derived from large phase III/IV clinical studies., Results: Simulation scenarios show that being a smoker, having higher baseline ACQ-5 and BMI, and long asthma history is associated with increased reliever medication use (p < 0.01). This increase correlates with a higher exacerbation risk and higher ACQ-5 scores over the course of treatment, irrespective of the underlying maintenance therapy. Switching non-responders to ICS monotherapy to combination therapy after 3 months resulted in immediate reduction in reliever medication use (i.e. 1.3 vs. 1.0 puffs/24 h for FP/SAL and BUD/FOR, respectively). In addition, switching patients with ACQ-5 > 1.5 at baseline to FP/SAL resulted in 34% less exacerbations than those receiving regular dosing BUD/FOR (p < 0.01)., Conclusions: We have identified baseline characteristics of patients with moderate to severe asthma that are associated with greater reliever medication use, poor symptom control and higher exacerbation risk. Moreover, the effects of different inhaled corticosteroid (ICS)/long-acting beta agonist (LABA) combinations vary significantly when considering long-term treatment performance. These factors should be considered in clinical practice as a basis for personalised management of patients with moderate-severe asthma symptoms., (© 2024. The Author(s).)

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R 1 , R 2 , T 1 , T 2 ) of Advair Diskus (100 μg FP/50 μg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R 1 and R 2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUC inf ) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1 µm, < 2 µm) had a higher AUC inf . This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study., (© 2024. The Author(s), under exclusive licence to American Association of Pharmaceutical Scientists.)

Background: Asthma is a chronic respiratory disease that affects millions of children worldwide and can impair their quality of life and development. Inhaled glucocorticoids are the mainstay of asthma treatment, but some children require step-up therapy with additional drugs to achieve symptom control. Fluticasone propionate and salmeterol (FSC) has been shown to reduce asthma exacerbations and improve lung function in adults. However, the evidence for its efficacy and safety in children is limited., Objective: This study aims to provide a comprehensive basis for treatment selection by summarizing existing clinical randomized controlled trials (RCTs) on the efficacy of FSC compared to fluticasone propionate (FP) monotherapy in children with asthma who require step-up treatment., Methods: Five online databases and three clinical trial registration platforms were systematically searched. The effect size and corresponding 95% confidence interval (CI) were calculated based on the heterogeneity among the included studies., Results: Twelve RCTs were identified and a total of 9, 859 patients were involved. The results of the meta-analysis revealed that the use of FSC was associated with a greater reduction in the incidence of asthma exacerbations than FP alone when the dose of FP was the same or when the duration of treatment exceeded 12 weeks. In addition, FSC resulted in a greater proportion of time with asthma-free and without the use of albuterol compared to FP alone when the duration of treatment exceeded 12 weeks. No significant differences were observed between FSC and FP alone in the incidence of drug-related adverse events and other adverse events., Conclusion: Both FSC and FP alone are viable options for the initial selection of step-up treatment in asthmatic children. While, FSC treatment demonstrates a greater likelihood of reducing asthma exacerbations which is particularly important for reducing the personnel, social and economic burden in children requiring step-up asthma treatment., Competing Interests: Declaration of Competing Interest All the authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Cough variant asthma (CVA) is one of the most common respiratory diseases in children, which has a serious impact on the quality of life and daily activities of children. For severe CVA, immunomodulatory drugs are needed., Aim: To evaluate the efficacy of salmeterol combined with budesonide in the treatment of pediatric CVA., Methods: 130 children with CVA from January 2020 to December 2022 were prospectively selected and randomly divided into an observation group (salmeterol combined with budesonide) and a control group (budesonide combined with a placebo). Compare the clinical efficacy of two groups before and after intervention. The evaluation parameters include cough frequency score, nocturnal cough arousal, and lung function indicators. Serum inflammatory markers, immune function markers and airway anatomical indicators were also measured., Results: After the intervention, the total effective rate of the observation group was significantly higher than that of the control group, and the cough frequency score and the night cough wake rate of the observation group were lower than that of the control group, with a statistically significant difference. In addition, the changes of lung function indicators, serum markers and immune function markers in the observation group were better than those in the control group., Conclusion: The clinical efficacy of salmeterol combined with Budesonide in the treatment of CVA is better than that of Budesonide alone., Competing Interests: Conflict-of-interest statement: There are no conflicts of interest to report., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

Introduction: The assessment of future risk has become an important feature in the management of patients with asthma. However, the contribution of patient-specific characteristics and treatment choices to the risk of exacerbation is poorly understood. Here we evaluated the effect of interindividual baseline differences on the risk of exacerbation and treatment performance in patients receiving regular maintenance doses of inhaled corticosteroids (ICS) or ICS/long-acting beta-agonists (LABA) combination therapy., Methods: Exacerbations and changes to asthma symptoms 5-item Asthma Control Questionnaire (ACQ-5) were simulated over a 12-month period using a time-to-event and a longitudinal model developed from phase III/IV studies in patients with moderate-severe asthma (N = 16,282). Simulations were implemented to explore treatment performance across different scenarios, including randomised designs and real-world settings. Treatment options included regular dosing with ICS monotherapy [fluticasone propionate (FP)] and combination therapy [fluticasone propionate/salmeterol (FP/SAL) or budesonide/formoterol (BUD/FOR)]. Exacerbation rate was analysed using the log-rank test. The cumulative incidence of events was summarised stratified by treatment., Results: Being a woman, smoker, having higher baseline ACQ-5 and body mass index (BMI) and lower forced expiratory volume in the first second (FEV 1 ) are associated with increased exacerbation risk (p < 0.01). This risk is bigger in winter because of the seasonal variation effect. Across the different scenarios, the use of FP/SAL resulted in a 10% lower annual incidence of exacerbations relative to FP or regular dosing BUD/FOR, independently of baseline characteristics. Similar differences in the annual incidence of exacerbations were also observed between treatments in obese patients (BMI ≥ 25-35 kg/m 2 ) (p < 0.01) and in patients who do not achieve symptom control on FP monotherapy., Conclusions: Individual baseline characteristics and treatment choices affect future risk. Achieving comparable levels of symptom control whilst on treatment does not imply comparable risk reduction, as shown by the lower exacerbation rates in FP/SAL vs. BUD/FOR-treated patients. These factors should be considered as a basis for personalised clinical management of patients with moderate-severe asthma., (© 2023. The Author(s).)

Background: As-needed low-dose inhaled corticosteroid (ICS)-formoterol reliever is recommended in patients with asthma prescribed maintenance ICS-formoterol. Clinicians often ask whether ICS-formoterol reliever can be used with other maintenance ICS-long-acting β 2 -agonists., Objective: To evaluate the safety and effectiveness of as-needed formoterol in patients taking maintenance ICS-formoterol or ICS-salmeterol from the RELIEF study., Methods: RELIEF (SD-037-0699) was a 6-month, open-label study that randomized 18,124 patients with asthma to as-needed formoterol 4.5 μg or salbutamol 200 μg on top of maintenance therapy. This post hoc analysis included patients on maintenance ICS-formoterol or ICS-salmeterol (n = 5436). The primary safety outcome was a composite of serious adverse events (SAEs) and/or adverse events leading to discontinuation (DAEs); the primary effectiveness outcome was time-to-first exacerbation., Results: For both maintenance groups and both relievers, similar numbers of patients had ≥1 SAE and/or DAE. In patients taking maintenance ICS-salmeterol, but not ICS-formoterol, significantly more non-asthma-related and nonserious DAEs occurred with as-needed formoterol versus as-needed salbutamol (P = .0066 and P = .0034, respectively). In patients taking maintenance ICS-formoterol, there was a significantly lower risk in time-to-first exacerbation with as-needed formoterol versus as-needed salbutamol (hazard ratio [HR]: 0.82, 95% confidence interval [CI]: 0.70, 0.95; P = .007). In patients taking ICS-salmeterol maintenance, time-to-first exacerbation was not significantly different between treatment arms (HR: 0.95, 95% CI: 0.84, 1.06; P = .35)., Conclusions: As-needed formoterol significantly reduced exacerbation risk compared with as-needed salbutamol when added to maintenance ICS-formoterol, but not to maintenance ICS-salmeterol. More DAEs were seen with ICS-salmeterol maintenance therapy plus as-needed formoterol. Further research is needed to assess whether this is relevant to as-needed combination ICS-formoterol., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

The Precision Interventions for Severe and/or Exacerbation-Prone Asthma clinical trials network is actively assessing novel treatments for severe asthma during the coronavirus disease (COVID-19) pandemic and has needed to adapt to various clinical dilemmas posed by the COVID-19 pandemic. Pharmacologic interactions between established asthma therapies and novel drug interventions for COVID-19 infection, including antivirals, biologics, and vaccines, have emerged as a critical and unanticipated issue in the clinical care of asthma. In particular, impaired metabolism of some long-acting beta-2 agonists by the cytochrome P4503A4 enzyme in the setting of antiviral treatment using ritonavir-boosted nirmatrelvir (NVM/r, brand name Paxlovid) may increase risk for adverse cardiovascular events. Although available data have documented the potential for such interactions, these issues are largely unappreciated by clinicians who treat asthma, or those dispensing COVID-19 interventions in patients who happen to have asthma. Because these drug-drug interactions have not previously been relevant to patient care, clinicians have had no guidance on management strategies to reduce potentially serious interactions between treatments for asthma and COVID-19. The Precision Interventions for Severe and/or Exacerbation-Prone Asthma network considered the available literature and product information, and herein share our considerations and plans for treating asthma within the context of these novel COVID-19-related therapies., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

The rational preparation of molecularly imprinted polymers (MIPs) in order to have selective extraction of salmeterol xinafoate (SLX) from serum was studied. SLX is an acting β-adrenergic receptor agonist used in the treatment of asthma and has an athletic performance-enhancing effect. Molecular dynamics were used for the simulation of the SLX-imprinted pre-polymerization system, to determine the stability of the system. The computational simulation showed that SLX as a template, 4-hydroxyethyl methacrylate (HEMA) as a monomer, and trimethylolpropane trimethacrylate (TRIM) as a crosslinker in mol ratio of 1:6:20 had the strongest interaction in terms of the radial distribution functional. To validate the computational result, four polymers were synthesized using the precipitation polymerization method, and MIP with composition and ratio corresponding with the system with the strongest interaction as an MD simulation result showed the best performance, with a recovery of 96.59 ± 2.24% of SLX in spiked serum and 92.25 ± 1.12% when SLX was spiked with another analogue structure. Compared with the standard solid phase extraction sorbent C-18, which had a recovery of 79.11 ± 2.96%, the MIP showed better performance. The harmony between the simulation and experimental results illustrates that the molecular dynamic simulations had a significant role in the study and development of the MIPs for analysis of SLX in biological fluid.

Background: Fixed dose dual bronchodilators such as long-acting muscarinic antagonists (LAMAs) plus long-acting β2-agonists (LABAs) are a new and important inhaled preparation for COPD treatment in China. Among these, umeclidinium/vilanterol (UMEC/VIL) is increasingly being used in China, especially among the elderly., Purpose: This study aimed to assess the cost-effectiveness of maintenance treatment with UMEC/VIL compared with salmeterol/fluticasone (FSC) as one of the main therapeutic drugs for moderate to very severe COPD in China., Methods: A Markov model was developed to estimate the costs and outcomes from a societal perspective in a 10-year time horizon. Patients with moderate-to-very severe COPD were treated with UMEC/VIL (62.5/25µg) or FSC (50/500ug). Data concerning clinical efficacy, costs, utilities, transition probability, exacerbation rate, and mortality were obtained from the published literature and official government datasets. The costs were presented in US dollars based on 2021 prices. The indicators of total costs, life years (LYs), quality-adjusted life-years (QALYs), and mortality were used as the model output. Costs and outcomes were discounted at a 5% annual rate. Incremental cost-effectiveness ratios were calculated considering the threshold recommended by WHO. One-way and probabilistic sensitivity analyses were conducted to assess the stability of results., Results: Compared with FSC, treatment with UMEC/VIL could save $1947.18, with a gain of 0.12 life-years and 0.05 QALYs. Further, 28.0% patients treated with UMEC/VIL and 29.2% patients treated with FSC were predicted to die after 10 years. Incremental cost effectiveness analysis showed that UMEC/VIL was dominant to FSC. Sensitivity analyses confirmed that the results were robust., Conclusion: UMEC/VIL is a cost-effective treatment option compared with FSC among patients with moderate-to-very severe COPD., Competing Interests: The authors report no conflicts of interest related to this study., (© 2022 Lan et al.)

In this research, the simultaneous absorption of Salmeterol (SAL) and Fluticasone (FLU) in Seroflo spray was investigated using a spectrophotometric device via employing continuous wavelet transform (CWT) and radial basis function neural network (RBF-NN) methods. Root mean square error (RMSE) related to the RBF model was obtained 3.17 × 10 -13 and 1.41 × 10 -13 for SAL and FLU, respectively. Limit of detection (LOD) and limit of quantification (LOQ) corresponding to the CWT method were 0.004, 0.280 μg/mL, and 0.431, 0.479 μg/mL for SAL and FLU, respectively. Root mean square error (RMSE) of SAL and FLU was obtained 3.17 × 10 -13 and 1.41 × 10 -13 , respectively in RBF-NN method. In the end, the results obtained from all methods were compared with the high-performance liquid chromatography (HPLC) as a reference method. According to the one-way analysis of variance with a 95% confidence level, there is no significant difference between the proposed techniques and HPLC. Therefore, chemometrics methods are sufficiently accurate, as the reference method for the analysis of drugs. The suggested methods are simple, fast, and cheap. Also, there is no need for pre-preparation steps. These methods can be used for quality control laboratories in the pharmaceutical industry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Introduction: Dual bronchodilators are recommended as maintenance treatment for patients with symptomatic COPD in the UK; further evidence is needed to evaluate cost-effectiveness versus monotherapy. Cost-effectiveness of umeclidinium/vilanterol versus umeclidinium and salmeterol from a UK healthcare perspective in patients without exacerbations in the previous year was assessed using post hoc EMAX trial data., Methods: The validated GALAXY model was populated with baseline characteristics and treatment effects from the non-exacerbating subgroup of the symptomatic EMAX population (COPD assessment test score ≥10) and 2020 UK healthcare and drug costs. Outputs included estimated exacerbation rates, costs, life-years (LYs), and quality-adjusted LYs (QALYs); incremental cost-effectiveness ratio (ICER) was calculated as incremental cost/QALY gained. The base case (probabilistic model) used a 10-year time horizon, assumed no treatment discontinuation, and discounted future costs and QALYs by 3.5% annually. Sensitivity and scenario analyses assessed robustness of model results., Results: Umeclidinium/vilanterol treatment was dominant versus umeclidinium and salmeterol, providing an additional 0.090 LYs (95% range: 0.035, 0.158) and 0.055 QALYs (-0.059, 0.168) with total cost savings of £690 (£231, £1306) versus umeclidinium, and 0.174 LYs (0.076, 0.286) and 0.204 QALYs (0.079, 0.326) with savings of £1336 (£1006, £2032) versus salmeterol. In scenario and sensitivity analyses, umeclidinium/vilanterol was dominant versus umeclidinium except over a 5-year time horizon (more QALYs at higher total cost; ICER=£4/QALY gained) and at the lowest estimate of the St George's Respiratory Questionnaire treatment effect (fewer QALYs at lower total cost; ICER=£12,284/QALY gained); umeclidinium/vilanterol was consistently dominant versus salmeterol. At willingness-to-pay threshold of £20,000/QALY, probability that umeclidinium/vilanterol was cost-effective in this non-exacerbating subgroup was 95% versus umeclidinium and 100% versus salmeterol., Conclusion: Based on model predictions from a UK perspective, symptomatic patients with COPD and no exacerbations in the prior year receiving umeclidinium/vilanterol are expected to have better outcomes at lower costs versus umeclidinium and salmeterol., Competing Interests: SS, AM, IB, CC, DAL, and ASI are GSK employees and hold shares and stocks in GSK. PWJ was a GSK employee at the time of the study and he is now a contingent worker on assignment at GSK, and holds shares and stocks in GSK. DS, NAR, and RK are ICON employees and hold shares and stocks in ICON. CFV has received grants from AstraZeneca, Boehringer Ingelheim, GSK, Grifols, and Novartis, and has received lecturing and personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Aerogen and Nuvaira. LT is a contingent worker on assignment at GSK. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abelló, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis, and Teva. EK has served on advisory boards, speaker panels or received travel reimbursement for Amphastar, AstraZeneca, Boehringer Ingelheim, Chiesi, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance, and has received consulting fees from Cipla and GSK. FM has received research grants for participating in multicenter trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols, and Novartis. FM also reports financial participation in Oxynov, a company which is developing an oxygen delivery system. The authors report no other conflicts of interest in this work., (© 2021 Shukla et al.)

Introduction: Smoking may reduce the efficacy of inhaled corticosteroids (ICS) in patients with chronic obstructive pulmonary disease (COPD), but its impact on bronchodilator efficacy is unclear. This analysis of the EMAX trial explored efficacy and safety of dual- versus mono-bronchodilator therapy in current or former smokers with COPD., Methods: The 24-week EMAX trial evaluated lung function, symptoms, health status, exacerbations, clinically important deterioration, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving ICS. Current and former smoker subgroups were defined by smoking status at screening., Results: The analysis included 1203 (50%) current smokers and 1221 (50%) former smokers. Both subgroups demonstrated greater improvements from baseline in trough FEV 1 at week 24 (primary endpoint) with umeclidinium/vilanterol versus umeclidinium (least squares [LS] mean difference, mL [95% CI]; current: 84 [50, 117]; former: 49 [18, 80]) and salmeterol (current: 165 [132, 198]; former: 117 [86, 148]) and larger reductions in rescue medication inhalations/day over 24 weeks versus umeclidinium (LS mean difference [95% CI]; current: - 0.42 [- 0.63, - 0.20]; former: - 0.25 - 0.44, - 0.05]) and salmeterol (current: - 0.28 [- 0.49, - 0.06]; former: - 0.29 [- 0.49, - 0.09]). Umeclidinium/vilanterol increased the odds (odds ratio [95% CI]) of clinically significant improvement at week 24 in Transition Dyspnea Index versus umeclidinium (current: 1.54 [1.16, 2.06]; former: 1.32 [0.99, 1.75]) and salmeterol (current: 1.37 (1.03, 1.82]; former: 1.60 [1.20, 2.13]) and Evaluating Respiratory Symptoms-COPD versus umeclidinium (current: 1.54 [1.13, 2.09]; former: 1.50 [1.11, 2.04]) and salmeterol (current: 1.53 [1.13, 2.08]; former: 1.53 [1.12, 2.08]). All treatments were well tolerated in both subgroups., Conclusions: In current and former smokers, umeclidinium/vilanterol provided greater improvements in lung function and symptoms versus umeclidinium and salmeterol, supporting consideration of dual-bronchodilator therapy in symptomatic patients with COPD regardless of their smoking status., (© 2021. The Author(s).)

Salmeterol and fluticasone are included in the Prohibited List annually issued by the World Anti-Doping Agency. While for other permitted beta-2 agonists a threshold has been established, above which any finding constitutes an Adverse Analytical Finding, this is not the case with salmeterol. The salmeterol metabolite, α-hydroxysalmeterol, has been described as a potentially more suitable biomarker for the misuse of inhaled salmeterol. In this study, a new and rapid UHPLC-QTOF-MS method was developed and validated for the simultaneous quantification of salmeterol, α-hydroxysalmeterol and fluticasone in human urine and plasma, which can be used for doping control. The analytes of interest were extracted by means of solid phase extraction and were separated on a Zorbax Eclipse Plus C 18 column. Detection was performed in a quadrupole time-of-flight mass spectrometer equipped with an electrospray ionization source, in positive mode for the detection of salmeterol and its metabolite and in negative mode for the detection of fluticasone. Method was validated over a linear range from 0.10 to 2.00 ng/ml for salmeterol and fluticasone, and from 1.00 to 20.0 ng/ml for α-hydroxysalmeterol, in urine, whereas in plasma, the linear range was from 0.025 to 0.500 ng/ml for salmeterol and fluticasone, respectively., (© 2021 John Wiley & Sons, Ltd.)

Introduction: Limited prospective evidence is available to guide selection of first-line maintenance therapy in patients with COPD. This pre-specified analysis of the EMAX trial explored the efficacy and safety of dual- versus mono-bronchodilator therapy in maintenance-naïve and maintenance-treated patients., Methods: The 24-week EMAX trial evaluated lung function, symptoms (including rescue medication use), exacerbations, and safety with umeclidinium/vilanterol, umeclidinium, and salmeterol in symptomatic patients at low exacerbation risk who were not receiving inhaled corticosteroids. Maintenance-naïve and maintenance-treated subgroups were defined by maintenance bronchodilator use 30 days before screening., Results: The analysis included 749 (31%) maintenance-naïve and 1676 (69%) maintenance-treated patients. For both subgroups, improvements from baseline in trough FEV 1 at Week 24 (primary endpoint) were greater with umeclidinium/vilanterol versus umeclidinium (mean difference [95% CI]; maintenance-naïve: 44 mL [1, 87]; maintenance-treated: 77 mL [50, 104]), and salmeterol (maintenance-naïve: 128 mL [85, 171]; maintenance-treated: 145 mL [118, 172]), and in rescue medication inhalations/day over 24 weeks versus umeclidinium (maintenance-naïve: -0.44 [-0.73, -0.16]; maintenance-treated: -0.28 [-0.45, -0.12]) and salmeterol (maintenance-naïve: -0.37 [-0.66, -0.09]; maintenance-treated: -0.25 [-0.41, -0.08]). In maintenance-naïve patients, umeclidinium/vilanterol numerically improved scores at Week 24 for Transition Dyspnea Index versus umeclidinium (0.37 [-0.21, 0.96]) and versus salmeterol (0.47 [-0.10, 1.05]) and Evaluating Respiratory Symptoms-COPD versus umeclidinium (-0.26 [-1.04, 0.53]) and versus salmeterol (-0.58 [-1.36, 0.20]), with similar improvements seen in maintenance-treated patients. All treatments were well tolerated across both subgroups., Conclusion: Similar to maintenance-treated patients, maintenance-naïve patients receiving umeclidinium/vilanterol showed greater improvements in lung function and symptoms compared with patients receiving umeclidinium or salmeterol. These findings provide support for the consideration of dual bronchodilator treatment in symptomatic maintenance-naïve patients with COPD., Competing Interests: IHB, DAL, CC, and PWJ are employees of GSK and hold stocks and shares in GSK. IHB’s current affiliation is Medical Emerging Markets, GSK, Brentford, Middlesex, UK. IPN was an employee of GSK at the time of the study, holds stocks and shares in GSK, and was a contingent worker on assignment at AstraZeneca. IPN’s current affiliation is RAMAX Ltd, Bramhall, Cheshire, UK. LT is a contingent worker on assignment at GSK. FM has received research grants for participating in multicenter trials for AstraZeneca, Boehringer Ingelheim, GSK, Sanofi, and Novartis, and has received unrestricted research grants and personal fees from Boehringer Ingelheim, Grifols, and Novartis. LB has received honoraria for giving a lecture or attending an advisory board for Airsonett, ALK-Abello, AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Meda, Novartis and Teva. EMK has served on advisory boards, speaker panels or received travel reimbursement from for Amphastar, AstraZeneca, Boehringer Ingelheim, Connect Biopharma, GSK, Mylan, Novartis, Pearl, Sunovion, Teva, and Theravance and has received consulting fees from Cipla and GSK. CFV has received grants from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK, Grifols, Novartis, and the German Federal Ministry of Education and Research (BMBF) Competence Network Asthma and COPD (ASCONET), and has received personal fees from AstraZeneca, Boehringer Ingelheim, Berlin Chemie/Menarini, Chiesi, CSL Behring, GSK, Grifols, MedUpdate, Novartis, Nuvaira, and Teva. The authors report no other conflicts of interest in this work., (© 2021 Bjermer et al.)

Purpose: The purpose of this review is to discuss the development of Wixela™ Inhub™, a generic equivalent of Advair Diskus ® , a fixed-dose combination of fluticasone propionate/salmeterol powder for oral inhalation for patients with asthma whose symptoms are not controlled with inhaled corticosteroids alone and for those with chronic obstructive pulmonary disease (COPD) who are at a high risk for exacerbations. We provide an overview of the Inhub device and the bioequivalence studies that have been conducted to date. Briefly, the in vitro performance, improvements in forced expiratory volume in 1 s, and the fluticasone propionate/salmeterol dose strengths for Wixela Inhub and Advair Diskus were comparable., Conclusion: The bioequivalence demonstrated by the totality of clinical and in vitro data supports the use of Wixela Inhub and provides a treatment option for patients with asthma or COPD.

A natural, accurate, extremely rapid, and precise spectrofluorometric method has been developed and validated for determination of salmeterol (SAL) xinafoate in its medicinal commercial form and spiked human plasma. The native SAL fluorescence has been measured at 415 nm (after 340 nm as excitation) in distilled water. Different factors affecting the native fluorescence consistency of SAL were surveyed and optimized. The suggested procedure was capable of SAL determination over concentrations ranging 200-2000 ng.mL -1 with excellent correlation coefficient of 0.9995. The limits of detection and quantification were estimated as 44.44 ng mL -1 and 134.66 ng mL -1 , respectively. The method has good accuracy and precision. The green spectrofluorometric method was used for determination of SAL in its commercial preparations and the results were in accordance with other reported methods regarding accuracy and precision. Moreover, the proposed procedure was enforced for stability indicating assay of SAL and for SAL determination in spiked human plasma. Nearly no cost, high sensitivity, and wide application make the proposed method ideally suited for analysis of SAL in quality control laboratories., (© 2021 John Wiley & Sons, Ltd.)

Background: Ovarian chronic inflammation has been known to incidence in the laying hen mainly via increasing laying frequency and microbial infection, especially during late stage of production period. This study was aimed to evaluate beta-2 adrenergic agonist (Beta-2 Adrenergic Agonist, BAA) Salmeterol and beta blocker (Beta Blocker, BB) Propranolol on the gene expression of the ovarian pro- and anti-inflammatory mediators, inflammatory responses of immune system, ovarian functions and, hormones in the laying hens on the late stage of production period. Forty-eight White Leghorn hens aged 92 weeks were used for 4 weeks to be supplemented by Salmeterol and Propranolol. Ovulation rate and follicular growth were determined based on laying frequency and ovarian visual evaluation, respectively; the mRNA expressions of follicular beta-2 adrenergic receptor (Beta-2 Adrenergic Receptor, β2ADR), cyclooxygenases (Cyclooxygenases, COX) 1 and 2, and cytokines were measured by real-time PCR. The plasma concentration of ovarian hormones, cellular, and humoral immune responses were measured via ELISA, heterophil to lymphocyte ratio (Heterophil to Lymphocyte ratio, H:L), and sheep red blood cell (Sheep Red Blood Cell, SRBC) test, respectively., Results: As compared to control, both of BAA Salmeterol and BB Propranolol resulted in a significant decrease in the mRNA expression of β2ADR, cyclooxygenases, and pro- and anti-inflammatory cytokines (P < 0.01). A significant elevation was observed in the ovulation rate (P < 0.05), plasma estradiol content on both treated groups (P < 0.05), and the content of progesterone and was just significantly (P < 0.05) increased in Salmeterol group. H:L was reduced in BAA group (P < 0.05), and immunoglobulin (Ig) M was elevated in both treated hens, when compared to control. The results indicated that Salmeterol significantly increases body weight (P < 0.05)., Conclusion: The stimulation and inhibition of beta-2 adrenergic signaling could reduce ovarian inflammatory condition in addition to enhancing laying efficiency in the aged laying hens.

Chronic obstructive pulmonary disease (COPD) has remained a leading cause of death worldwide and is expected to increase its burden on the healthcare system in the coming future. Numerous clinical trials have been conducted over the years and as a result, many drugs became a part of the treatment protocols of COPD. Currently, there are also several drugs under development. This review will help future researchers to grasp salient features of previous studies and use them in their future trials in order to reduce the morbidity and mortality of COPD. Randomized control trials provide strong evidence for any hypothesis in a research study. This review focuses on major COPD trials in the last two decades including TORCH, UPLIFT, POET, WISDOM, and TIOSPIR. It showcases the main clinical question, primary outcome, and result of these five trials., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2021, ElSaygh et al.)

Background: Stepping down treatment for well-controlled mild asthma is challenging to clinicians. The step-down strategy using regularly-intermittent low-dose inhaled corticosteroid has been applied at the University Medical Center (UMC) of Ho Chi Minh City, called as "UMC" approach., Objective: This study aimed to evaluate the efficiency of UMC step-down strategy in well- controlled mild asthma., Methods: A real-world retrospective descriptive study was conducted at UMC from 2009 to 2018. All asthmatic patients (age ≥ 12) who received step-down therapy using this UMC approach were evaluated., Results: Among 2,072 asthma patients to be treated with UMC step-down strategy, only 112 subjects were eligible. The median age was 38.5 years and female was 62.5%. Most patients at their initial presentation were indicated step 4 treatment (87.5%). The controller medications before initiation of UMC treatment included fluticasone propionate 125 μg once-daily, salmeterol/fluticasone propionate 25/125 μg once-daily, and formoterol/budesonide 4.5/160 μg once-daily. After being treated with the UMC approach, the rates of well-controlled asthma ranged from 67.6% to 91.1%. During 1 year with UMC treatment, pulmonary function remained stable and only 7 subjects (6.3%) developed exacerbation., Conclusion: The UMC step-down treatment for well-controlled mild asthma was relatively efficient in maintaining asthma control, stabilization of pulmonary function, and reducing risk of severe exacerbation., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2021. Asia Pacific Association of Allergy, Asthma and Clinical Immunology.)

Objective: This real-world observational study compared medication adherence and persistence among patients with asthma receiving the once-daily inhaled corticosteroid/long-acting β 2 -agonist (ICS/LABA) fluticasone furoate/vilanterol (FF/VI) versus the twice-daily ICS/LABAs budesonide/formoterol (B/F) and fluticasone propionate/salmeterol (FP/SAL)., Methods: This retrospective cohort study conducted using IQVIA TM Health Plan Claims Data included patients with asthma ≥18 years of age initiating ICS/LABA therapy with FF/VI, B/F, or FP/SAL between January 1, 2014 and June 30, 2016 (index date). Patients had ≥12 months and ≥3 months of continuous eligibility pre- and post-index date, respectively. Patients receiving FF/VI were separately matched 1:1 with patients receiving B/F or FP/SAL using propensity score matching (PSM) and multivariable regression to balance baseline covariates between cohorts. The primary endpoint was medication adherence, measured by proportion of days covered (PDC). Secondary endpoints included proportion of patients achieving PDC ≥ 0.5 and PDC ≥ 0.8 and persistence with index medication, measured by time to discontinuation (>45-day gap in therapy)., Results: After PSM, 3,764 and 3,339 patients receiving FF/VI were matched with patients receiving B/F or FP/SAL, respectively. Mean PDC was significantly higher for FF/VI versus B/F (0.453 vs 0.345; adjusted p  < 0.001) and FP/SAL (0.446 vs 0.341; adjusted p  < 0.001). The proportion of patients achieving PDC ≥ 0.5 or PDC ≥ 0.8, and treatment persistence were significantly higher for FF/VI versus B/F and FP/SAL (all p  < 0.001)., Conclusions: In this real-world study, patients initiating FF/VI had better adherence and lower risk of discontinuing treatment versus B/F or FP/SAL, suggesting that once-daily ICS/LABA treatment might improve adherence and persistence compared with twice-daily alternatives.

Background: Wixela ® Inhub ® is a dry powder inhaler approved as a generic equivalent to Advair ® Diskus ® (fluticasone propionate [FP]/salmeterol fixed-dose combination) for patients with asthma or chronic obstructive pulmonary disease (COPD). This study aimed at confirming the local (lung) therapeutic equivalence of both the FP and salmeterol components of Wixela Inhub (test [T]) to Advair Diskus (reference [R]) after inhalation. Methods: This randomized, double-blind, double-dummy, placebo-controlled, parallel-group study in patients ≥18 years with mild-to-moderate persistent asthma compared the local therapeutic equivalence (using forced expiratory volume in 1 second [FEV 1 ]) of FP/salmeterol (100/50 μg) after inhaled delivery via T and R. Results: Randomized patients ( N  = 1127) received T ( n  = 512), R ( n  = 512), or placebo ( n  = 103). T and R significantly increased day 1 FEV 1 area under the effect curve over 12 hours of the change from baseline (AUC [0-12] ) and day 29 trough FEV 1 over placebo, indicating that these endpoints were sufficiently sensitive for evaluation of bioequivalence. On day 1, T and R each increased FEV 1 AUC (0-12) over placebo (3.134 L•h [T], 2.677 L•h [R]; each p  < 0.0001). Following twice-daily dosing for 28 days, T and R also each increased trough FEV 1 (measured on day 29) over placebo (235 mL [T], 215 mL [R]; each p  < 0.0001). Least-squares mean T/R ratios (90% confidence intervals) for day 1 FEV 1 AUC (0-12) and day 29 trough FEV 1 were 1.120 (1.016-1.237) and 1.069 (0.938-1.220), respectively, indicating that T and R were bioequivalent for both co-primary endpoints. FP/salmeterol was well tolerated when administered via either T or R. Conclusions: These results demonstrate that the therapeutic effects of Wixela Inhub are bioequivalent to Advair Diskus in the lung. Wixela Inhub represents a therapeutically equivalent new FP/salmeterol treatment option for use in the treatment of asthma and COPD.

Objective: To evaluate the efficacy and safety of fluticasone propionate/formoterol (FP/FORM) versus fluticasone propionate/salmeterol (FP/SAL) in treating pediatric asthma during a 12-week treatment cycle., Methods: Randomized controlled trials of FP/FORM compared with FP/SAL in treating pediatric asthma were searched systematically using Medline, Embase, and the Cochrane Controlled Trials Register., Results: Two articles including 546 patients were evaluated. The FP/SAL group showed obvious improvements in pre-dose forced expiratory volume in 1 s (FEV 1 ) from day 0 to 84, asthma symptom scores, and sleep disturbance scores compared with the FP/FORM group; however, the FP/FORM group had improved peak expiratory flow rate (PEFR). In terms of 2-hour post-dose FEV 1 from day 0 to 84, 2-hour forced expiratory flow at 25%, 50%, and 75%, and 2-hour forced vital capacity, we observed no significant differences between the two groups. For safety, including patients with at least one adverse event, bronchitis, cough, or pharyngitis, both groups had similar incidences, differing only in incidence of nasopharyngitis., Conclusion: Compared with FP/FORM, FP/SAL showed a clear improvement in pre-dose FEV 1 , asthma symptom scores, and sleep disturbance scores. However, FP/FORM resulted in improved PEFR with a lower incidence of nasopharyngitis.

Background: Wixela ® Inhub ® was developed to deliver inhaled fluticasone propionate/salmeterol (FP/S) combination as a substitutable generic equivalent to Advair ® Diskus ® . These studies aimed to confirm the pharmacokinetic bioequivalence (BE) of FP/S after single doses of Wixela Inhub (test [T]) and Advair Diskus (reference [R]). Methods: Three open-label, randomized, two-way crossover, single-dose studies in healthy subjects ( N  = 66 each) compared the systemic exposure of FP and salmeterol after inhalation from three dose strengths of FP/S (100/50, 250/50, or 500/50 μg) delivered from T and R. Primary BE endpoints were the area under the plasma concentration-time curve from time = 0 to the last measurable concentration (AUC (0-t) ) and the maximum observed plasma concentration (C max ) for both FP and S. The BE acceptance criteria specified that the 90% confidence intervals (CIs) of the geometric mean T/R ratios for AUC (0-t) and C max can be contained within 0.80-1.25 for both FP and salmeterol. Results: Wixela Inhub met the acceptance criteria for BE for FP and salmeterol at each dose strength. Estimated AUC (0-t) and C max geometric mean ratios (T/R [90% CI]) for FP were, respectively, 1.04 (1.00-1.08) and 0.92 (0.87-0.96) for 100/50 μg FP/S, 1.07 (1.02-1.13) and 1.01 (0.95-1.07) for 250/50 μg, and 0.97 (0.92, 1.00) and 0.90 (0.86-0.93) for 500/50 μg. Estimated AUC (0-t) and C max ratios for salmeterol were, respectively, 1.08 (1.04-1.11) and 1.00 (0.94-1.04) for 100/50 μg FP/S, 1.03 (0.99-1.07) and 0.93 (0.87-1.00) for 250/50 μg, and 1.00 (0.96-1.04) and 0.86 (0.81-0.91) for 500/50 μg. FP/S at all doses via both T and R was comparably well tolerated. Conclusions: Wixela Inhub was bioequivalent to Advair Diskus at all three dose strengths for both FP and S, providing direct evidence of equivalent systemic safety and indirect evidence for equivalent pulmonary deposition.

A series of β 2 -adrenoceptor agonists with an 8-(2-amino-1-hydroxyethyl)-6-hydroxy-1,4-benzoxazine-3(4H)-one moiety is presented. The stimulatory effects of the compounds on human β 2 -adrenoceptor and β 1 -adrenoceptor were characterized by a cell-based assay. Their smooth muscle relaxant activities were tested on isolated guinea pig trachea. Most of the compounds were found to be potent and selective agonists of the β 2 -adrenoceptor. One of the compounds, (R)-18c, possessed a strong β 2 -adrenoceptor agonistic effect with an EC 50 value of 24 pM. It produced a full and potent airway smooth muscle relaxant effect same as olodaterol. Its onset of action was 3.5 min and its duration of action was more than 12 h in an in vitro guinea pig trachea model of bronchodilation. These results suggest that (R)-18c is a potential candidate for long-acting β 2 -AR agonists., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Asthma is widely treated using inhaled corticosteroid/long-acting beta agonist (LABA) combinations, for example, fluticasone propionate/salmeterol (FPS) dry powder inhaler, marketed as Advair ® Diskus ® . Some regulators require generics to demonstrate local (lung) therapeutic equivalence (LTE) for each component of the FPS reference, ideally with a dose-response within the approved FPS dose range. We sought to develop a methacholine challenge (MeCh) LTE methodology for assessing the LABA (salmeterol) component of FPS. Methods: Forty-six patients with asthma received single doses of albuterol (active control; 90 or 180 μg), FPS (100/50 or 200/100 μg), and placebo on 5 separate study days. Spirometry and MeCh were performed 1, 6, and 10 hours after study drug inhalation. Primary endpoint was provocative concentration of methacholine producing a 20% fall in forced expiratory volume in 1 second (PC 20 ). Study entry required screening PC 20 ≤8 mg/mL, with a greater than fourfold increase (and PC 20 ≤128 mg/mL) after 180 μg albuterol. Results: Both albuterol (90 and 180 μg) and FPS (100/50 and 200/100 μg) significantly increased PC 20 compared with placebo (sustained 6 and 10 hours postdose with FPS but not albuterol). The dose-response slopes (95% confidence interval) estimated 1 hour after treatment were 0.374 (-0.068 to 0.815) and 0.310 (-0.135 to 0.754) between low and high doses of albuterol and FPS, respectively, both nonsignificant. Slopes were shallower than those available in the literature for albuterol and formoterol, but similar to those for salmeterol. Conclusions: These data confirm that the bronchoprotective effect of FPS lasts longer than that of albuterol. The shallow dose-response slope we observed for albuterol is contrary to previous reports, probably due to the measurement of PC 20 beginning at 1 hour postdose. The results suggest that use of MeCh to assess LTE for salmeterol formulations may be more difficult to accomplish than it is for albuterol and formoterol products.

β-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). β-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the β-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of β 2 -adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their β-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter β-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and β-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of β-arrestin-biased β 2 -adrenoceptor agonists, whereas salmeterol was found to be G s -biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

Background: Loss of bronchoprotection (LOBP) with a regularly used long-acting β 2 -adrenergic receptor agonist (LABA) is well documented. LOBP has been attributed to β 2 -adrenergic receptor (B2AR) downregulation, a process requiring farnesylation, which is inhibited by alendronate., Objective: We sought to determine whether alendronate can reduce LABA-associated LOBP in inhaled corticosteroid (ICS)-treated patients., Methods: We conducted a randomized, double-blind, placebo-controlled, parallel-design, proof-of-concept trial. Seventy-eight participants with persistent asthma receiving 250 μg of fluticasone twice daily for 2 weeks were randomized to receive alendronate or placebo while initiating salmeterol for 8 weeks. Salmeterol-protected methacholine challenges (SPMChs) and PBMC B2AR numbers (radioligand binding assay) and signaling (cyclic AMP ELISA) were assessed before randomization and after 8 weeks of ICS plus LABA treatment. LOBP was defined as a more than 1 doubling dose reduction in SPMCh PC 20 value., Results: The mean doubling dose reduction in SPMCh PC 20 value was 0.50 and 0.27 with alendronate and placebo, respectively (P = .62). Thirty-eight percent of participants receiving alendronate and 33% receiving placebo had LOBP (P = .81). The after/before ICS plus LABA treatment ratio of B2AR number was 1.0 for alendronate (P = .86) and 0.8 for placebo (P = .15; P = .31 for difference between treatments). The B2AR signaling ratio was 0.89 for alendronate (P = .43) and 1.02 for placebo (P = .84; P = .44 for difference). Changes in lung function and B2AR number and signaling were similar between those who did and did not experience LOBP., Conclusion: This study did not find evidence that alendronate reduces LABA-associated LOBP, which relates to the occurrence of LOBP in only one third of participants. LOBP appears to be less common than presumed in concomitant ICS plus LABA-treated asthmatic patients. B2AR downregulation measured in PBMCs does not appear to reflect LOBP., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Purpose: Ipratropium and salmeterol were found to stimulate oligodendrocyte differentiation in a high-throughput drug screening assay; thus, they may play a role in the risk reduction of multiple sclerosis (MS). So far, they have not been examined in any clinical data. This study aims at investigating the association between ipratropium and salmeterol and reduced diagnosis of MS with the use of real-world clinical data., Methods: We conducted a 1:10 matched case-control study that compared the exposure of ipratropium and salmeterol between patients with MS and control patients over the past 2 years, using the MS Flowsheet Registry of OSF HealthCare Saint Francis Medical Center. Cases were matched to control patients, based on service year/quarter, age, sex, race, and payer type. The relationship was examined with a Poisson regression model and a generalized structural equation model., Findings: The sample in our analysis included 217 patients with MS and 2164 matched control patients. The mean (SD) age for both patients with MS and control patients was 41 (11.8) years with a range of 18 to 75 years. The MS group had consistently less prescriptions of ipratropium and salmeterol than the control group in the past 1, 2, and 3 years before the index date. Our multivariable analysis found that the control group had 3.2 more prescriptions (95% CI, 1.4-7.1; P = 0.006) of either ipratropium or salmeterol in the past 2 years than the MS group, even if controlling for other confounders. In the generalized structural equation model, we found that use of ipratropium and salmeterol was significantly associated with reduced diagnosis of MS (P = 0.036), whereas smokers and people with family history of MS were more likely to have a diagnosis of MS (P < 0.001)., Implications: The observed association between ipratropium and salmeterol use and reduced diagnosis of MS indicates that they might potentially serve as agents in the treatment of MS., (Copyright © 2019. Published by Elsevier Inc.)

A simple selective luminescent dependent approach was established for quantitation of two selective β 2 agonists namely; Fenoterol hydrobromide (FEN) and Salmeterol xinafoate (SAL). This approach utilizes the capability of the cited drugs to undergo a complexation reaction with Europium ion (Eu 3+ ) in the presence of 1,10-phenanthroline as a co-ligand. The resultant complex leads to a hypersensitive transition and enhancement of the Eu 3+ emission peak at 615nm (279nm excitation). Under the optimized conditions, the rectilinear concentration plots of both drugs were (70-1500ngmL -1 ) and (100-2000ngmL -1 ) with limit of quantitation 51.3 and 84.4ngmL -1 for FEN and SAL, respectively. The luminescence properties of the complex and its optimum formation conditions were carefully investigated according to the regulations of ICH and the method was successfully applied in plasma. The good accuracy and selectivity of the suggested method allowed extending the proposed protocol into stability study of the cited drugs., (Copyright © 2019. Published by Elsevier B.V.)

A series of novel β 2 -adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent β 2 -adrenoceptor agonistic effects and high β 2 /β 1 -selectivity with EC 50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates., (Copyright © 2018. Published by Elsevier Ltd.)

Background: The design of inhaler devices may potentially influence adherence/persistence and outcomes in asthma. Objective: The primary objective was to assess asthma control and any change in the quality of life in patients using an intuitive dry powder inhaler containing fluticasone propionate/salmeterol (AirFluSal ® Forspiro ® ) for the treatment of asthma in everyday practice. Methods: ASSURE was a multicenter, noninterventional, open-label, prospective study in patients with asthma, aged ≥12 years and treated with the Forspiro device in Denmark, Sweden and Norway. Patients' opinions of their asthma control were assessed by the Asthma Control Test (ACT) questionnaire and asthma-related quality of life by the Mini Asthma Quality of Life Questionnaire (miniAQLQ) at baseline and at two follow-up visits (approximately 4-8-week intervals). Results: Of 321 patients enrolled in the study, 299 received at least one dose of fluticasone propionate/salmeterol via the Forspiro device and 204 had evaluable data at the baseline visit and at least one later visit. Patients showed improvements in asthma control and quality of life during the study. The mean sum score of ACT increased from 18.0 (SD 4.5) at visit 1 to 19.9 (4.2) at visit 2 and 20.5 (4.3) at visit 3. Overall, 38.2% of patients improved by the minimal clinically important difference (MCID) of ≥3 points (45.6% among those with a baseline score below 23 [ie, not already well controlled]). The mean score on the miniAQLQ increased from 5.16 (SD 1.24) at visit 1 to 5.58 (SD 1.20) at visit 2 and 5.82 (SD 1.04) at visit 3. Overall, 42.6% of patients improved by the MCID of ≥0.5. Conclusion: This real-life study suggests that treatment with fluticasone propionate/salmeterol via the Forspiro device can improve asthma symptom control and quality of life., Competing Interests: Andreas Søderman is an employee of Sandoz AS. Spencer Jones is an employee of Sandoz International GmbH and holds stock in Novartis. Leif Bjermer reports honoraria from ALK, Airsonette, AstraZeneca, Boehringer, Chiesi, GlaxoSmithKline, Novartis, Teva, outside the submitted work. Olav Kåre Refvem reports personal fees from Boehringer-Ingelheim, outside the submitted work, and is the owner of Lungepraksis AS. The authors report no other conflicts of interest in this work.

Background: Fluticasone propionate 50 μg/salmeterol xinafoate 25 μg (FP/SAL) is widely used in adults and children with asthma, but there is sparse information on its use in very young children., Methods: This was a randomized, double-blind, multicentre, controlled trial conducted in children aged 8 months to 4 years. During a 2-week run-in period, they all received FP twice daily. At randomization, they commenced FP/SAL or FP twice daily for 8 weeks. All were then given FP/SAL only, in a 16-week open-label study continuation. Medications were inhaled through an AeroChamber Plus with attached face mask. The primary end-point was mean change in total asthma symptom scores from baseline to the last 7 days of the double-blind period. Analyses were undertaken in all children randomized to treatment and who received at least one dose of study medication., Results: Three hundred children were randomized 1:1 to receive FP/SAL or FP. Mean change from baseline in total asthma symptom scores was -3.97 for FP/SAL and -3.01 with FP. The between-group difference was not statistically significant (P = 0.21; 95% confidence interval: -2.47, 0.54). No new safety signals were seen with FP/SAL., Conclusion: This is the first randomized, double-blind study of this size to evaluate FP/SAL in very young children with asthma. FP/SAL did not show superior efficacy to FP; no clear add-on effect of SAL was demonstrated. No clinically significant differences in safety were noted with FP/SAL usage., (© 2018 The Authors. Pediatric Allergy and Immunology Published by John Wiley & Sons Ltd.)

β 2 -adrenoceptors are a subtype of G-protein coupled receptors whose activation leads to increased protein synthesis and decreased degradation in mammalian skeletal muscle, causing hypertrophy. In this study, we compared the effects of the classical β 2 -agonist noradrenaline (NA) with two representatives of a new generation of agonists (formoterol, FOR and salmeterol, SALM) on growth and metabolism of primary cultured muscle cells of gilthead sea bream. Activation of signaling pathways, cell development and expression of relevant genes were analyzed in day 4 myocytes. The three agonists increased either cAMP levels or PKA phosphorylation, plus TOR phosphorylation, and the proportion of proliferating cell nuclear antigen (PCNA)-positive cells, in parallel with pcna mRNA levels. Thus, demonstrating that these cells are β 2 -agonists-responsive, and supporting enhanced cell proliferation. The expression of the myogenic factor myf5 was significantly down-regulated, suggesting that the cells were already destined to the muscular linage; while insulin-like growth factors (igf-1 and igf-2) transcript levels were up-regulated, proposing an additional anabolic effect through their local production. Furthermore, SALM treatment up-regulated expression of the lipases (hsl and lipa) and the β-oxidation marker cpt1a, and all three agonists increased mitochondrial dehydrogenase hadh mRNA levels. These data correspond with a situation of enhanced lipolytic and β-oxidation capacity, a fact supported by the higher glycerol released into the media induced by the agonists. Overall, these results suggest a hyperplastic growth condition and a favorable protein/fat ratio profile upon these treatments; consequently, β 2 -agonists (especially SALM) may be considered good candidates to optimize the growth in this aquaculture species., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: There is a scarcity of studies that assessed the association between adherence to combination therapy and asthma control in pediatric patients. The authors investigated the association between adherence to fluticasone propionate/salmeterol xinafoate combination-metered aerosol and the level of asthma control in children., Methods: This was a prospective observational study of 84 patients aged 5-16 years with moderate persistent asthma, who remained uncontrolled despite the use of 1000μg/day of inhaled nonextrafine-hydrofluoric alkane-beclomethasone dipropionate in the three months prior to study enrollment. Participants were prescribed two daily doses of FP (125μg)/salmeterol xinafoate (25μg) combination by metered aerosol/spacer for six months. Adherence rates were assessed using the device's dose counter after the 2nd, 4th, and 6th months of follow up. Asthma control was assessed using a simplified Global Initiative for Asthma 2014 Report classification., Results: Mean adherence rates after the second, fourth, and sixth months were 87.8%, 74.9%, and 62.1% respectively, for controlled asthma, and 71.7%, 56.0%, and 47.6% respectively, for uncontrolled asthma (all p-values≤0.03). The proportion of children achieving asthma control increased to 42.9%, 67.9% and 89.3% after the 2nd, 4th and 6th months of follow-up, respectively (p≤0.001)., Conclusion: Adherence rates between 87.8% in the 2nd month and 62.1% in the 6th month were strong determinants of asthma control., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Microglial activation contributes to chronic inflammation and neuronal loss in progressive neurodegenerative disorders such as Parkinson's disease (PD). Thus, treatments suppressing microglial activation may have therapeutic benefits to prevent neuronal loss in neurodegenerative diseases. Our previous findings show that Salmeterol, a long-acting β2-adrenergic receptor (β2-AR) agonist, is neuroprotective in two distinct animal models of PD, including where lipopolysaccharide (LPS) from E. coli was used to initiate chronic neurodegeneration. Salmeterol was found to be a potent inhibitor of dopaminergic neurodegeneration by regulating the production of pro-inflammatory mediators from activated microglial cells. In the present study, we investigated the molecular basis of the anti-inflammatory effects of Salmeterol on LPS-activated murine microglial BV2 cells. BV2 cells were pretreated with Salmeterol and followed by stimulation with LPS. Salmeterol inhibited LPS-induced release of the pro-inflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and nitric oxide from BV2 cells. Additionally, Salmeterol suppressed nuclear translocation of nuclear factor kappa-B (NF-κB) p65 by inhibiting the IκB-α degradation and TAK1 (transforming growth factor-beta-activated kinase1) phosphorylation. We have also found that Salmeterol increases the expression of β-arrestin2 and enhances the interaction between β-arrestin2 and TAB1 (TAK1-binding protein), reduced TAK1/TAB1 mediated activation of NFκB and expression of pro-inflammatory genes. Furthermore, silencing of β-arrestin2 abrogates the anti-inflammatory effects of Salmeterol in LPS-stimulated BV2 cells. Our findings suggest that the anti-inflammatory properties of Salmeterol is β-arrestin2 dependent and also offers novel therapeutics targeting inflammatory pathways to prevent microglial cell activation and neuronal loss in neuroinflammatory diseases like PD., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Objective: Combination long-acting β 2 -agonist/long-acting muscarinic antagonist (LABA/LAMA) has demonstrated superior clinical outcomes over LABA/inhaled corticosteroid (ICS) in chronic obstructive pulmonary disease (COPD) patients; however, data from blinded randomized controlled trials on direct switching from LABA/ICS to LABA/LAMA are lacking. FLASH (Assessment of switching salmeterol/Fluticasone to indacateroL/glycopyrronium in A Symptomatic COPD patient coHort) investigated if direct switch, without a washout period, from salmeterol/fluticasone (SFC) to indacaterol/glycopyrronium (IND/GLY) in COPD patients improves lung function and is well tolerated., Methods: In this 12-week, multicentre, double-blind study, patients with moderate-to-severe COPD and up to one exacerbation in previous year, receiving SFC for ≥3 months, were randomized to continue SFC 50/500 μg twice daily (bd) or switch to IND/GLY 110/50 μg once daily (od). Primary endpoint was pre-dose trough forced expiratory volume in 1 s (FEV 1 ) at Week 12., Results: In total, 502 patients were randomized (1:1) to IND/GLY or SFC. Patients switched to IND/GLY demonstrated superior lung function (pre-dose trough FEV 1 ) versus SFC at Week 12 (treatment difference (Δ) = 45 mL; P = 0.028). IND/GLY provided significant improvements in pre-dose trough forced vital capacity (FVC; Δ = 102 mL; P = 0.002) and numerical improvements in transition dyspnoea index (TDI; Δ = 0.46; P = 0.063). Rescue medication use and COPD assessment test (CAT) scores were comparable between groups. Both treatments had similar safety profiles., Conclusion: FLASH demonstrated that a direct switch to IND/GLY from SFC improved pre-dose FEV 1 and FVC in COPD patients with up to one exacerbation in the previous year. No new safety signals were identified., (© 2018 Asian Pacific Society of Respirology.)

Background: Easyhaler ® dry powder inhaler (DPI) containing salmeterol and fluticasone propionate was developed for the treatment of asthma and chronic obstructive pulmonary disease. Three different Salmeterol/fluticasone Easyhaler test products (Orion Pharma, Finland) were compared against the reference product Seretide ® Diskus ® DPI (GlaxoSmithKline, United Kingdom) to study whether any of the test products are bioequivalent with the reference., Methods: Open and randomized pharmacokinetic four-period crossover study on 65 healthy volunteers was performed in a single center to compare the lung deposition and total systemic exposure of salmeterol and fluticasone propionate after administration of single doses (two inhalations of 50/500 μg/inhalation strength) in fasting conditions. Blood samples were drawn before dosing and at frequent time points between 2 minutes and 34 hours after dosing for determination of drug concentrations. The primary variables for total systemic exposure and lung deposition of fluticasone propionate were maximum concentration of the concentration-time curve (C max ) and area under the concentration-time curve from time zero to the last sample with quantifiable concentration (AUC t ). For salmeterol, the primary variables for total systemic exposure were C max and AUC t and for lung deposition C max and AUC up to 30 minutes after study treatment administration (AUC 30min )., Results: One of the Easyhaler test products met all the criteria for bioequivalence with the reference. The 96.7% confidence intervals (CIs) for the test/reference ratios of fluticasone propionate C max and AUC t were 0.9901-1.1336 and 0.9448-1.0542, respectively. Ninety percent CIs for salmeterol C max , AUC 30min , and AUC t ratios were 1.0567-1.2012, 1.0989-1.2255, and 1.0769-1.1829, respectively. Median salmeterol time to maximum concentration (t max ) was 4.0 minutes. Median fluticasone propionate t max was from 1.5 to 2.0 hours. Terminal elimination half-life was 11 hours for salmeterol and 9-10 hours for fluticasone propionate., Conclusions: Salmeterol/fluticasone Easyhaler was shown to be bioequivalent with the reference product.