Is it preferable to administer a bronchodilator once- or twice-daily when treating COPD?

Nocturnal and early morning symptoms are common and uncomfortable in many patients with COPD, and are likely to affect their long-term outcomes. However, it is still debated whether it is better to give long-acting bronchodilators once- or twice-daily to symptomatic COPD patients. The functional link between circadian rhythms of autonomic tone and airway calibre explains why the timing of administration of bronchodilators in chronic airway diseases can induce different effects when taken at different biological (circadian) times. However, the timing also depends on the pharmacological characteristics of the bronchodilator to be used. Because the profile of bronchodilation produced by once-daily vs. twice-daily long-acting bronchodilators differs throughout 24 h, selecting long-acting bronchodilators may be customized to specific patient preferences based on the need for further bronchodilation in the evening. This is especially helpful for people who experience respiratory symptoms at night or early morning. Compared to placebo, evening bronchodilator administration is consistently linked with persistent overnight improvements in dynamic respiratory mechanics and inspiratory neural drive. The current evidence indicates that nocturnal and early morning symptoms control is best handled by a LAMA taken in the evening. In contrast, it seems preferable to use a LABA for daytime symptoms. Therefore, it can be speculated that combining a LAMA with a LABA can improve bronchodilation and control symptoms better. Both LAMA and LABA must be rapid in their onset of action. Aclidinium/formoterol, a twice-daily combination, is the most studies of the available LAMA/LABA combinations in terms of impact on daytime and nocturnal symptoms.

Pharmacokinetic considerations surrounding triple therapy for uncontrolled asthma.

INTRODUCTION: Solid pharmacological rationale and clinical evidence support the use of a combination of an inhaled corticosteroid (ICS), a long-acting ß2-agonist, and a long-acting muscarinic antagonist in severe asthma, which clinically results in increased lung function, improved symptoms, and decreased exacerbation rates. AREAS COVERED: We examined the pharmacokinetic issues associated with triple therapy for uncontrolled asthma. We considered the pharmacokinetic characteristics of the three drug classes, the role of inhalers in influencing their pharmacokinetic behavior, and the impact of severe asthma on the pharmacokinetics of inhaled drugs. EXPERT OPINION: The pharmacokinetics of ICSs and bronchodilators are not affected to a great extent by severe asthma, according to a detailed review of the currently accessible literature. Compared to healthy people, patients with severe asthma show only minor variations in a few pharmacokinetic characteristics, which are unlikely to have therapeutic significance and do not require particular attention. However, the difficulty of obtaining pharmacokinetic profiles of the three drugs included in a triple therapy suggests that the clinical response should be followed over time, which can be considered a good surrogate indicator of whether the drugs have reached sufficient concentrations in the lung to exert a valid pharmacological action.

Biologic therapies for chronic obstructive pulmonary disease.

INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is a disorder characterized by a complicated chronic inflammatory response that is resistant to corticosteroid therapy. As a result, there is a critical need for effective anti-inflammatory medications to treat people with COPD. Using monoclonal antibodies (mAbs) to inhibit cytokines and chemokines or their receptors could be a potential approach to treating the inflammatory component of COPD. AREAS COVERED: The therapeutic potential that some of these mAbs might have in COPD is reviewed. EXPERT OPINION: No mAb directed against cytokines or chemokines has shown any therapeutic impact in COPD patients, apart from mAbs targeting the IL-5 pathway that appear to have statistically significant, albeit weak, effect in patients with eosinophilic COPD. This may reflect the complexity of COPD, in which no single cytokine or chemokine has a dominant role. Because the umbrella term COPD encompasses several endotypes with diverse underlying processes, mAbs targeting specific cytokines or chemokines should most likely be evaluated in limited and focused populations.

Pharmacotherapy of LAMA/LABA inhaled therapy combinations for chronic obstructive pulmonary disease: a clinical overview.

INTRODUCTION: Long-acting muscarinic receptor antagonist (LAMA)/ß2-agonist (LABA) combinations represent a significant improvement in the treatment of chronic obstructive pulmonary disease (COPD) due to their remarkable ability to improve lung function, dyspnea, quality of life, and exercise capacity compared to mono-components. AREAS COVERED: This article aims to report the latest information on the clinical impact of dual bronchodilation in COPD. EXPERT OPINION: The available data supports the use of inhaled LAMA/LABA FDCs in treating COPD patients, particularly those with severe or very severe disease. These combinations provide short - and long-term benefits to COPD patients without increasing the dose of the single components, which reduces the risk of adverse events while ensuring an improvement in clinical efficacy. Unfortunately, head-to-head studies comparing all exiting LABA/LAMA combinations are relatively few. Since each available LAMA/LABA combination has a unique efficacy/safety profile that must be considered for personalized COPD therapy, further randomized controlled trials and real-world studies lasting at least one year are needed to assess what differences, if any, there are in terms of clinical outcomes when dual LAMA/LABA inhalers are compared to LAMA or LABA single inhalers, and to compare different LAMA/LABA FDCs.

Clinically important deterioration: a composite tool for managing patients with COPD.

Clinically important deterioration (CID) is a composite tool developed to measure COPD's progression. It is a promising concept that can improve treatment choices for COPD patients because it provides a more holistic assessment of their status in everyday clinical practice. The post hoc analysis of several trials that were important for improving COPD treatment provides increasing evidence of the importance of assessing CID. These retrospective evaluations suggest that dual bronchodilation should be preferred over a single bronchodilator if treatment aims to reduce a possible clinical deterioration of COPD. Should dual bronchodilation prove ineffective, evidence shows that triple therapy, including an inhaled corticosteroid, is effective in preventing CID, especially in the presence of high blood eosinophil counts. CID initially included changes in FEV1 ≥100 mL from baseline, an increase in total SGRQ score ≥4 units, or a moderate/severe exacerbation. These thresholds were chosen arbitrarily because they were considered clinically relevant. Therefore, this multidimensional tool is being improved by including outcomes and thresholds that consider the peculiarities of the COPD population and the duration of the assessment. However, at present, studies that have assessed the impact of CID on COPD are almost all retrospective. Therefore, prospective studies need to be conducted that allow the complete validation of this instrument and better define the most effective components in assessing the risk of deterioration of COPD.

Sex differences in adult asthma and COPD therapy: a systematic review.

BACKGROUND: Although asthma is more prevalent in women and the prevalence of COPD is increasing in women, the current international recommendations for the management and prevention of asthma and COPD provide no sex-related indication for the treatment of these diseases. Therefore, we systematically reviewed the evidence across literature on the sex-related effectiveness of asthma and COPD therapy. METHODS: This systematic review has been registered in PROSPERO and performed according to PRISMA-P. The PICO framework was applied for the literature search strategy: "patient problem" included adult patients suffering from asthma or COPD, "Intervention" regarded the pharmacological treatments for asthma or COPD, "Comparison" was vs. baseline, active controls, or placebo, "Outcome" was any difference sex-related in the effectiveness of interventions. RESULTS: In asthma 44% of the evidence reported that men responded better than women to the therapy, whereas this percentage was 28% in COPD. ICS was generally less effective in women than in men to treat asthma, and consistent evidence suggests that in asthmatic patients ICS/LABA/LAMA combination may be equally effective in both men and women. Due to the inconsistent available evidence, it is not possible to identify specific treatments whose effectiveness is related to sex difference in COPD patients. CONCLUSIONS: There is a strong need of investigating the sex-related impact of asthma and COPD treatments. Pre-specified analyses in men and women should be planned in future trial protocols, a necessary condition that should be requested also by the regulatory agencies to overcome the anachronistic "one-size-fits-all" approach to therapeutics associated with suboptimal outcomes for patients.

Dual bronchodilation for the treatment of COPD: From bench to bedside.

Because there is a solid pharmacological rationale based on positive interactions between long-acting muscarinic receptor antagonists (LAMAs) and long-acting ß-agonists (LABAs) for their ability to relax human airway smooth muscle in vitro alongside several randomised controlled trials (RCTs) and real-world observational studies that support the use of LAMA/LABA fixed-dose combinations (FDCs) for the treatment of patients with chronic obstructive pulmonary disease (COPD), in this narrative review we discuss the preclinical and clinical proofs supporting the use of LAMA + LABA therapy in COPD and why this therapeutic approach optimises bronchodilation. Robust evidence indicates that all LAMA/LABA FDCs are consistently more effective than LAMA or LABA administered alone in improving lung function, dyspnoea, quality of life and exercise capacity in patients with COPD. However, the ability of dual bronchodilation with FDCs of LAMA/LABA to prevent or reduce the risk of COPD exacerbations remains unclear due to conflicting data from large RCTs, despite several mechanisms explaining why such combinations should be of value in decreasing the frequency of COPD exacerbations. Both LABAs and LAMAs mechanistically can affect the cardiovascular system, but from clinical studies to date, LAMA/LABA FDCs have an acceptable cardiovascular safety profile, at least in the COPD population enrolled in RCTs. Indirect evidence suggests that some FDCs may even exert a protective role against serious cardiovascular adverse events compared to monotherapies. Consequently, several LAMA/LABA FDCs have been developed and approved for clinical use as treatments for patients with COPD. However, to date, there are unfortunately very few head-to-head studies comparing the safety and efficacy of different LAMA/LABA FDCs, making it difficult to choose the most appropriate combination, although the use of meta-analyses has provided some information in this regard. Endurance time Exercise time until exhaustion measured by a standard endurance test. Inspiratory capacity The maximum volume of air that can be inspired after reaching the end of a normal, quiet expiration. It is the sum of the tidal volume and the inspiratory reserve volume. St George's Respiratory Questionnaire (SGRQ) A tool to measure health status in patients with respiratory disease. It has three domains: symptoms, activity and impacts. A total score is also calculated. A minimal important difference (range) of ∼4 (2.4-5.6) units in the SGRQ total score is supported by published studies. Surface under the cumulative ranking curve analysis (SUCRA) A numerical representation of the overall rating that displays a single value for each treatment. SUCRA levels vary from 0% to 100%. The higher the SUCRA value and the closer it is to 100%, the more likely therapy is in the top rank or one of the top rankings; the lower the SUCRA value and the closer it is to 0%, the more likely therapy is in the bottom rank or one of the bottom ranks. Transition dyspnoea index (TDI) Widely used in clinical studies of COPD to measure shortness of breath, indicating change in response to an intervention. The total score ranges from -9 to 9; the negative value indicates deterioration, whereas a positive value indicates improvement. There is sufficient evidence to suggest that the minimal important difference for the TDI score is 1 unit. Trough FEV1 The mean volume of air that can be forced out in 1 second approximately 12 (with a twice-daily agent) or 24 (with a once-daily agent) hours after the last administration of bronchodilator.

Potential Drawbacks of ICS/LABA/LAMA Triple Fixed-Dose Combination Therapy in the Treatment of Asthma: A Quantitative Synthesis of Safety Profile.

Introduction: Inhaled corticosteroid/long-acting ß2-adrenoceptor agonist/long-acting muscarinic antagonist (ICS/LABA/LAMA) fixed-dose combination (FDC) is currently recommended as controller option at asthma Step 4 and as preferred treatment at asthma Step 5, but no research investigated the potential drawbacks of this therapeutic option in a large asthmatic population. Thus, the aim of this study was to quantify the potential drawbacks of triple FDC therapy in asthma. Methods: A pairwise meta-analysis was performed according to PRISMA-P guidelines to assess the risk of overall serious adverse events (SAEs), cardiovascular SAEs, and pneumonia reported as SAE in asthmatic patients treated with ICS/LABA/LAMA FDC vs ICS/LABA FDC. A pooled analysis was performed to calculate the frequency of SAEs. Results: Data from 7204 asthmatic patients were extracted from the CAPTAIN, IRIDIUM, TRIMARAN, and TRIGGER studies. Triple FDC vs ICS/LABA FDC did not increase the risk of total SAEs (RR 0.99 95% CI 0.83-1.18) and cardiac SAEs (RR 0.74 95% CI 0.39-1.40), whereas the sensitivity analysis performed to resolve heterogeneity resulted in increased risk of vascular SAEs (RR 3.23 95% CI 1.05-9.90, P<0.05). The level of ICS dose did not modulate the risk of pneumonia, in any case pneumonia was the most frequent SAE (0.57%). These results were not affected by significant risk of bias. Conclusion: Triple FDC is a safe pharmacological therapy in severe asthmatic patients; it is characterized by a favourable safety profile and few potential drawbacks, namely, the increased risk of vascular SAEs, that certainly are worthy of future investigations.

A single inhaler triple therapy fluticasone furoate/umeclidinium/vilanterol for the treatment of COPD.

INTRODUCTION: Single inhaler triple therapy (SITT) with an inhaled corticosteroid, a long-acting ß2-agonist, and a long-acting muscarinic antagonist is an effective and attractive therapeutic option codified in the recommendations of guidelines and treatment strategies for the management of COPD. AREAS COVERED: The preclinical and clinical development in COPD of fluticasone furoate (FF)/umeclidinium (UMEC)/vilanterol (VI) SITT and its use in the real world. EXPERT OPINION: Findings from phase III/IV trials and the use of FF/UMEC/VI in the real-world setting support the view that it may be a useful, safe, and cost-effective option for the maintenance treatment of COPD, especially when dealing with patients who are not adequately controlled with dual ICS/LABA or LAMA/LABA therapy. Only direct head-to-head comparisons will be able to establish whether FF/UMEC/VI may be preferable to the other SITTs approved for COPD due to its pharmacokinetic and pharmacodynamic characteristics and especially the fact that it is the only one that can be taken once-daily. In addition, there is a need for further studies, especially in the real world, to optimize the positioning of FF/UMEC/VI in the treatment of COPD, also considering the availability of FF/VI and UMEC/VI and the need for better differentiation between the three treatments.

Beyond Dual Bronchodilation - Triple Therapy, When and Why.

Although pharmacological treatment of COPD is codified in different guidelines and strategy documents, there is abundant evidence of discrepancy between what they suggest and what health professionals prescribe, especially in low-risk groups where there is widespread overprescription of triple therapy. It is therefore necessary to clarify when the use of triple therapy is indicated in COPD patients and when it is preferable to maintain treatment with dual bronchodilation. In this article, we discuss our views based on our experience and what is reported in the literature and try to give answers to these two questions. The evidence generated by pivotal RCTs supports the use of triple therapy in patients who present for the first time and have severe airway obstruction, are symptomatic, have had frequent moderate or severe exacerbations in the previous year, and have peripheral eosinophilia. However, it is difficult to determine whether step-up is useful in all other cases because the available data are quite conflicting. It is likely that the inconsistency in the information generated by the various available studies may explain the prescribing behaviour of many physicians who do not adhere to recommendations of guidelines and strategies. However, it is necessary to establish whether and when the addition of an ICS to the LAMA/LABA combination is effective, to determine whether triple therapy can induce an additional clinical benefit over dual bronchodilation, irrespective of a preventive effect on COPD exacerbations, to establish its value, and to examine whether cost differences can support the use of triple therapy over combined LAMA/LABA therapy in real life.

Clinical characteristics, treatment patterns and adherence in patients with asthma on multiple inhaler triple therapy: a review of findings.

INTRODUCTION: The value of treating asthma with the triple regimen of inhaled corticosteroid (ICS), long-acting ß2-agonist (LABA), and long-acting muscarinic antagonist (LAMA) delivered using multiple inhalers (MITT), or a single inhaler (SITT) is supported by a growing body of evidence, although research is still limited regarding the use of MITT. AREAS COVERED: Clinical characteristics, treatment patterns, disease burden, and persistence/adherence associated with MITT use in asthma. The MEDLINE database was searched to identify references from inception until October 2022. EXPERT OPINION: The use of MITT is not very frequent in asthma patients, although it improves lung function and reduces the incidence of severe exacerbations. This may be due to existing concerns about using different devices on adherence and persistence to treatment, with a negative influence on outcomes, and to the fear that the patient will discontinue ICS/LABA but not LAMA. Nevertheless, although the current trend favors the SITT approach, some physicians may be induced to prescribe MITT over SITT because it allows the titration of individual components of triple therapy to be increased or decreased. Therefore, there is an evident need for pragmatic real-life studies to document when to prefer SITT and when MITT should be used.

Impact of long-acting muscarinic antagonists on small airways in asthma and COPD: A systematic review.

Small airway disease is recognized as a cardinal pathological process of chronic obstructive pulmonary disease (COPD), and recently small airways have been recognized as a major site of airflow obstruction also in asthmatic patients. The transversal involvement of small airways in COPD and asthma has warranted research efforts to identify therapeutic strategies able to unlock the small airway compartment. The mainstay of COPD treatment is represented by long-acting ß2-adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs). In asthma, the efficacy of LAMAs administered add-on to inhaled corticosteroids (ICSs) or ICS/LABA combinations has been investigated only in recent years. The aim of this systematic review was to examine the current literature concerning the impact of LAMAs on small airways and their lung deposition in both COPD and asthma. LAMAs administered either alone or in combination induced an effective bronchorelaxant effect of small airways, however the effectiveness of respiratory medications not only relies on the selected drug, but also on the employed inhalation device and patient's adherence. Tiotropium delivered via Respimat® SMI achieved a superior drug deposition in the peripheral lung compared to HandiHaler® dry powder inhaler and metered-dose inhalers (MDIs). The use of co-suspension™ delivery technology for MDIs and the introduction of the eFlow® nebulizer to deliver glycopyrronium improved aerosol drug delivery to the peripheral lung, by achieving uniform distribution of drug particles. This systematic review provides a synthesis of current literature concerning the impact of LAMAs on small airways and an insight on LAMAs distribution within the lung.

Evaluating triple ICS/LABA/LAMA therapies for COPD patients: a network meta-analysis of ETHOS, KRONOS, IMPACT, and TRILOGY studies.

OBJECTIVES: In some studies comparing triple with dual combination therapies in COPD there might be a possible effect of inhaler bias resulting from different inhaler devices being used in comparator arms. The aim of this study was a quantitative synthesis by considering the studies that directly compared triple ICS/LABA/LAMA vs. either dual LABA/LAMA or ICS/LABA therapies administered at fixed-dose combination (FDC) via the same inhaler device. METHODS: A network meta-analysis was performed to assess the efficacy/safety impact of triple ICS/LABA/LAMA FDC compared with dual LABA/LAMA and ICS/LBA FDCs administered via the same inhaler device in COPD patients. The treatment ranking was reported via the surface under the cumulative ranking curve analysis (SUCRA). RESULTS: Data obtained from 21,909 COPD patients were extracted from the ETHOS, KRONOS, IMPACT, and TRILOGY studies, the only that fulfilled the strict inclusion criteria of this research. The weighted efficacy/safety profile resulting from SUCRA provided the following ranking in patients with low eosinophil count: ICS/LABA/LAMA>LABA/LAMA≫ICS/LABA; whereas in patients with high eosinophil count the ranking was as follows: ICS/LABA/LAMA>LABA/LAMA>ICS/LABA FDC. CONCLUSION: Triple ICS/LABA/LAMA FDC and dual LABA/LAMA or ICS/LABA FDCs are characterized by specific efficacy/safety profiles in agreement with the level of blood eosinophil count at baseline.

Efficacy and safety of triple combination therapy for treating chronic obstructive pulmonary disease: an expert review.

Introduction: The current recommendations of chronic obstructive pulmonary disease (COPD) suggest to escalate from inhaled corticosteroid/long-acting ß2-adrenoceptor agonist (ICS/LABA) treatment to triple therapy in patients experiencing persistent breathlessness, exercise limitation, or exacerbation. The addition of an ICS to LABA/long-acting muscarinic antagonist (LAMA) combination is recommended for frequently exacerbating patients with high levels of blood eosinophils. Nowadays, three triple therapies have been approved as fixed-dose combinations (FDCs) for the treatment of COPD: beclomethasone dipropionate/formoterol fumarate/glycopyrronium bromide (BDP/FOR/GLY), fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), and budesonide/glycopyrronium bromide/formoterol fumarate (BUD/GLY/FOR).Areas covered: This narrative review evaluates the efficacy and safety profile of triple FDC therapy for the treatment of COPD, by evaluating the data originating from pivotal randomized-controlled trials (RCTs).Expert opinion: The currently approved triple FDCs exert a protective effect against the risk of COPD exacerbation compared to ICS/LABA and LABA/LAMA, with some concerns regarding the risk of pneumonia for some specific FDCs. Since the assessed RCTs were characterized by important confounders, the obtained results should be interpreted with caution. Indeed, FDCs provide advantages in terms of improved adherence to treatment and lower errors in COPD management; however, direct head-to-head comparisons are needed to establish real differences between the currently approved triple FDCs.

The role of triple therapy in the management of COPD.

INTRODUCTION: Triple therapy in COPD is becoming increasingly important with the cumulative documentation of its ability to reduce the risk of AECOPD. However, it must be established which patients benefit most from it compared to other treatments. AREAS COVERED: We critically review the literature to determine, if possible, the real role of triple therapy in the treatment of COPD. We have identified studies from several databases and selected the information thought to be more significant. EXPERT OPINION: It is still unclear whether and when addition of an ICS to the LAMA/LABA combination provides real additional clinical value, regardless of a preventive effect on exacerbations. There are many doubts about the value of the blood eosinophil count as a valid biomarker to predict AECOPD risk and the clinical response to ICS, also because no association was found in observational studies. In any case, before starting a therapy involving ICS, the risk factors for the development of pneumonia must always be evaluated. Adding a LAMA to an ICS/LABA combination seems to be less problematic. However, each LABA/LAMA combination has a specific efficacy/safety profile that needs to be considered for personalized therapy in COPD even in the context of triple therapy.

New perspectives on the role of muscarinic antagonists in asthma therapy.

INTRODUCTION: There is increasing evidence that tiotropium, a long-acting muscarinic agent (LAMA), is useful in the presence of severe-uncontrolled asthma despite the optimization of therapy with inhaled corticosteroids (ICSs) and long-acting ß2 agonists (LABAs) as recommended by the current guidelines. Furthermore, in recent years there have been several  preclinical and clinical studies on the pharmacological and therapeutic impact of other LAMAs in asthma. AREAS COVERED: We have conducted an extensive search on muscarinic antagonists in asthma therapy throughout several sources and discuss what has emerged in the last 3 years (January 2017-March 2020). EXPERT OPINION: New evidence indicates that the effectiveness of adding a LAMA, at least tiotropium, is independent of the degree of the type 2 inflammation and age of patient. Therefore, tiotropium can be administered without the need for patient phenotyping. Umeclidinium and glycopyrronium also appear effective in asthma. Initial treatment with LAMA+ICS for those with mild asthma may be an equally effective therapeutic option as LABA+ICS but this hypothesis should be confirmed by statistically powered trials.

Emerging muscarinic receptor antagonists for the treatment of asthma.

INTRODUCTION: The increased acetylcholine signaling in asthma pathophysiology offers the rationale for the use of LAMAs in the treatment of asthmatic patients. Tiotropium is still the only LAMA approved for use in asthma but there is a real interest in developing novel LAMAs for the treatment of asthma, or at least to extend this indication to other LAMAs already on the market. AREAS COVERED: We examined and discussed trials and research that have studied or are evaluating the role of LAMAs already on the market in asthma and possible novel muscarinic acetylcholine receptor antagonists. EXPERT OPINION: Glycopyrronium and umeclidinium will soon be included in the GINA strategy with the same current indications of tiotropium. It is likely that the choice of the LAMA will be influenced not so much by its pharmacological profile as by the type of triple therapy chosen. It is extremely difficult to identify a new LAMA that is more effective than tiotropium, but is it plausible that new technologies that will allow delivering the drug in a more targeted way and with a lower risk of adverse effects may represent the real progress in the use of LAMAs in asthma in the coming years.

Evaluation of fluticasone propionate/salmeterol for the treatment of COPD: a systematic review.

Introduction: Recently, the generic formulation of FP/SAL FDC has been approved in COPD. Although FP/SAL FDC has been the first long-acting FDC approved in COPD, no systematic review assessed the effect of this combination for the treatment of COPD by considering specifically Phase IV studies. The aim of this review was to systematically assess the effect of FP/SAL FDC in COPD patients enrolled in Phase IV studies.Areas covered: The question of this systematic review was to examine the evidence regarding the impact of FP/SAL FDC for the treatment of COPD by searching for Phase IV studies in the ClinicalTrials.gov database.Expert opinion: Generic drugs represent an effective cost-saving step for health-care budgets in the treatment of COPD and should be used in agreement with current recommendations and prescription accuracy. FP/SAL FDC is recommended for the initiation therapy just in a small percentage of symptomatic patients that are at high risk of exacerbation with blood eosinophil counts ≥300 cells per µl. At follow-up, FP/SAL FDC can be escalated to triple ICS/LABA/LAMA combination or switched to LABA/LAMA combination by considering symptoms, exacerbations, lack of response to ICS, inappropriate original indication, and ICS-related adverse events such as pneumonia.

Beclomethasone dipropionate, formoterol fumarate and glycopyrronium bromide: Synergy of triple combination therapy on human airway smooth muscle ex vivo.

BACKGROUND AND PURPOSE: Combining inhaled corticosteroids (ICSs), long-acting ß2 -adrenoceptor agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) is recommended to treat severe forms of asthma and chronic obstructive pulmonary disease (COPD). Clinical benefits have been demonstrated for ICS/LABA/LAMA combinations. This study characterized the interaction between the ICS beclomethasone dipropionate, the LABA formoterol fumarate and the LAMA glycopyrronium bromide in human airways. EXPERIMENTAL APPROACH: Human passively sensitized airways and bronchi from COPD donors were stimulated with histamine or carbachol. Tissues were incubated overnight with beclomethasone and then treated with formoterol and glycopyrronium, alone or in triple combination. The interaction was assessed by using Bliss Independence and Unified Theory theorems. KEY RESULTS: Beclomethasone/formoterol/glycopyrronium combination synergistically relaxed medium bronchi and small airways. Beclomethasone/formoterol/glycopyrronium combination at 100:6:12.5 combination ratio was a balanced drug mixture leading to very strong synergistic effect on relaxation of medium bronchi (Combination Index: from 0.042 to 0.96) and middle to very strong synergy in small airways (Combination Index: from 0.018 to 0.310). The synergy was related with the activation of intracellular glucocorticoid receptors and Gsα subunit G-protein of ß2 -adrenoceptors, leading to the modulation of cyclic AMP-dependent PKA pathway. CONCLUSION: Triple beclomethasone/formoterol/glycopyrronium combination induces synergistic bronchorelaxant effect in medium and small human airways, at least in ex vivo experiments. Further research is needed to confirm these findings in clinical studies in patients with asthma or COPD.