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INTRODUCTION: Pulmonary function tests are vital for diagnosing lung diseases, assessing treatment responses, and monitoring respiratory health. Recent updates to interpretive standards by the European Respiratory and American Thoracic Societies (ERS/ATS) in 2022 introduced significant changes compared to the 2005 standards. They include incorporating lung volume measurements, non-specific and mixed disorders, introducing z-scores for functional abnormality assessment, reducing severity categories from five to three, and revising criteria for positive bronchodilator responses. METHODS: We conducted a retrospective, multi-center study across four centers using spirometric data spanning from 2002 to 2022. We categorized spirometry results using both the 2005 and 2022 ATS/ERS standards and calculated predicted values following the GLI 2012 equation (Caucasian subset). RESULTS: Among 79,039 subjects, we observed that 23% shifted from an obstructive diagnosis under the 2005 standard to a mixed pattern diagnosis under the 2022 standard, necessitating lung volume assessments. In the evaluation of bronchodilator responses among 59,203 tests, 12.3% of those initially classified as responders were reclassified as non-responders with the new standards. We found variations in severity categorization across age groups, with older patients tending to receive milder severity classifications and younger individuals receiving greater severity classifications under the 2022 standards. CONCLUSIONS: The 2022 document emphasizes early lung volume assessment, potentially leading to increased utilization of more complex tests. Furthermore, the bronchodilator response was predominant in extreme age groups and among individuals with milder spirometric impairments. This shift may impact treatment decisions, potentially initiating medication in milder cases and de-escalating treatment in more severe cases.
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BACKGROUND: Small airway dysfunction (SAD) is increasingly recognized as an important feature of pediatric asthma yet typically relies on spirometry-derived FEF25-75 to detect its presence. Multiple breath washout (MBW) and oscillometry potentially offer improved sensitivity for SAD detection, but their utility in comparison to FEF25-75, and correlations with clinical outcomes remains unclear for school-age asthma. We investigated SAD occurrence using these techniques, between-test correlation and links to clinical outcomes in 57 asthmatic children aged 8-18 years. METHODS: MBW and spirometry abnormality were defined as z-scores above/below ± 1.96, generating MBW reference equations from contemporaneous controls (n = 69). Abnormal oscillometry was defined as > 97.5th percentile, also from contemporaneous controls (n = 146). Individuals with abnormal FEF25-75, MBW, or oscillometry were considered to have SAD. RESULTS: Using these limits of normal, SAD was present on oscillometry in 63% (resistance at 5-20 Hz; R5-R20; >97.5th percentile), on MBW in 54% (Scond; z-scores> +1.96) and in spirometry FEF25-75 in 44% of participants (z-scores< -1.96). SAD, defined by oscillometry and/or MBW abnormality, occurred in 77%. Among those with abnormal R5-R20, Scond was abnormal in 71%. Correlations indicated both R5-R20 and Scond were linked to asthma medication burden, baseline FEV1 and reversibility. Additionally, Scond correlated with FENO and magnitude of bronchial hyper-responsiveness. SAD, detected by oscillometry and/or MBW, occurred in almost 80% of school-aged asthmatic children, surpassing FEF25-75 detection rates. CONCLUSIONS: Discordant oscillometry and MBW abnormality suggests they reflect different aspects of SAD, serving as complementary tools. Key asthma clinical features, like reversibility, had stronger correlation with MBW-derived Scond than oscillometry-derived R5-R20.
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RATIONALE: Spirometry reference equations that are derived from a large, nationally representative, general population are warranted in China and the impact of using pre- and post-BD spirometry reference values has yet to be assessed in Chinese populations. OBJECTIVES: To present both the pre-BD and post-BD spirometry reference values for Chinese adults using the China Pulmonary Health (CPH) study. METHODS: A reference population of 17969 healthy, non-smoking participants in the CPH study was used to calculate the pre- and post-BD reference values for the forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and FEV1/FVC. Both pre- and post-BD reference values were applied to the entire CPH population (50991 individuals) to illustrate the divergence between the use of references in determining the disease prevalence and severity grading. MEASUREMENTS AND MAIN RESULTS: The prevalence of airflow limitation was 5.36% using pre-BD reference and 8.02% using the post-BD reference. Individuals who had post-BD FEV1/FVC below post-BD but higher than pre-BD reference values were found to have significantly higher rates of self-reported respiratory symptoms, and significantly lower values in spirometry indicators than those above post-BD reference values. An additional 3.51% of participants were identified as grade II-IV COPD using the post-BD FEV1 predicted values. CONCLUSION: This study generated and applied pre- and post-bronchodilator spirometry reference values in a nationally representative Chinese adult population. Post-BD reference values may serve as an additional criterion in identifying individuals at risk for obstructive pulmonary diseases, its diagnostic and prognostic values should be further investigated.
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Pediatric asthma is a common condition, and its exacerbations can be associated with significant morbidity and mortality. The role of nebulised magnesium as adjunct therapy for children with asthma exacerbations is still unclear. To compare clinical and functional outcomes for children with asthma exacerbation taking either nebulised magnesium sulfate added to standard medical therapy (SMT) versus SMT alone. PubMed, Embase, and Cochrane Library were systematically searched for randomised clinical trials (RCT) comparing the use of SMT with vs. without nebulised magnesium. The outcomes were respiratory rate, heart rate, % predicted peak expiratory flow rate (PEFR), % predicted forced expiratory volume (FEV1), peripheral O2 saturation, asthma severity scores, and need for intravenous (IV) bronchodilator use. Twelve RCTs and 2484 children were included. Mean age was 5.6 (range 2-17) years old, mean baseline % predicted FEV1 was 69.6%, and 28.66% patients were male. Children treated with magnesium had a significantly higher % predicted PEFR (mean difference [MD] 5.33%; 95% confidence interval [CI] 4.75 to 5.90%; p < 0.01). Respiratory rate was significantly lower in the magnesium group (MD -0.70 respirations per minute; 95% CI -1.24 to -0.15; p < 0.01). Need for IV bronchodilators, % predicted FEV1, heart rate, asthma severity scores, and O2 saturation were not significantly different between groups. CONCLUSION: In children with asthma exacerbation, treatment with nebulised magnesium and SMT was associated with a statistically significant, but small improvement in predicted PEFR and respiratory rate, as compared with SMT alone. WHAT IS KNOWN: ⢠Magnesium sulfate has bronchodilating properties and aids in the treatment of asthma exacerbation when administered intravenously. ⢠There is no significant evidence of benefit of nebulised magnesium as an adjunct therapy to the standard medical treatment for children with asthma exacerbations. WHAT IS NEW: ⢠Our study suggests nebulised magnesium sulfate may have a statistically significant, but small benefit in respiratory rate and peak expiratory flow rate. The addition of nebulised magnesium does not seem to increase adverse events.
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Asma , Sulfato de Magnesio , Nebulizadores y Vaporizadores , Humanos , Asma/tratamiento farmacológico , Niño , Sulfato de Magnesio/administración & dosificación , Adolescente , Broncodilatadores/administración & dosificación , Administración por Inhalación , Preescolar , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Femenino , Antiasmáticos/administración & dosificación , MasculinoRESUMEN
PURPOSE: This study aimed to examine reports of cardiovascular adverse events (CV AEs) observed in the real-world during treatment with aclidinium, tiotropium, glycopyrronium, and umeclidinium alone or in combination with a LABA and, in the context of triple therapy, with the addition of an ICS, and submitted to the food and drug administration adverse event reporting system (FAERS). METHODS: A retrospective disproportionality analysis was conducted utilizing CV AE reports submitted to the FAERS from January 2020 to 30 September 2023. Disproportionality was measured by calculating the reporting odds ratio. RESULTS: Compared with ipratropium, tiotropium was associated with fewer reports of CV AEs. Compared with tiotropium, other LAMAs were more likely to be associated with reports of CV AEs. Combinations of glycopyrronium with indacaterol or formoterol and umeclidinium with vilanterol significantly reduced reports of CV AEs compared with the respective LAMA. The addition of an ICS to these combinations further reduced the risk of CV AE reports. CONCLUSION: Our study suggests that inhaled LAMAs are not free from cardiac AE risks. This risk may be more evident when the newer LAMAs are used, but it is generally significantly reduced when COPD patients are treated with dual bronchodilators or triple therapy. However, these results do not prove that LAMAs cause CV AEs, as FAERS data alone are not indicative of a drug's safety profile. Given the frequency with which COPD and cardiovascular disease co-exist, a large study in the general population could shed light on this very important issue.
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Enfermedades Cardiovasculares , Enfermedad Pulmonar Obstructiva Crónica , Estados Unidos/epidemiología , Humanos , Bromuro de Tiotropio/efectos adversos , Glicopirrolato/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Enfermedad Pulmonar Obstructiva Crónica/inducido químicamente , Estudios Retrospectivos , United States Food and Drug Administration , Agonistas de Receptores Adrenérgicos beta 2 , Combinación de Medicamentos , Antagonistas Muscarínicos/uso terapéutico , Broncodilatadores , Enfermedades Cardiovasculares/inducido químicamente , Enfermedades Cardiovasculares/epidemiología , Receptores Muscarínicos/uso terapéutico , Administración por InhalaciónRESUMEN
BACKGROUND: In tobacco-exposed persons with preserved spirometry (active smoking or secondhand smoke [SHS] exposure), air trapping can identify a subset with worse symptoms and exercise capacity. The physiologic nature of air trapping in the absence of spirometric airflow obstruction remains unclear. The aim of this study was to examine the underlying pathophysiology of air trapping in the context of preserved spirometry and to determine the utility of bronchodilators in SHS tobacco-exposed persons with preserved spirometry and air trapping. METHODS: We performed a double-blinded placebo-controlled crossover randomized clinical trial in nonsmoking individuals at risk for COPD due to exposure to occupational SHS who had preserved spirometry and air trapping defined as either a residual volume-to-total lung capacity ratio (RV/TLC) > 0.35 or presence of expiratory flow limitation (EFL, overlap of tidal breathing on maximum expiratory flow-volume loop) on spirometry at rest or during cardiopulmonary exercise testing (CPET). Those with asthma or obesity were excluded. Participants underwent CPET at baseline and after 4-week trials of twice daily inhalation of 180 mcg of albuterol or placebo separated by a 2-week washout period. The primary outcome was peak oxygen consumption (VO2) on CPET. Data was analyzed by both intention-to-treat and per-protocol based on adherence to treatment prescribed. RESULTS: Overall, 42 participants completed the entire study (66 ± 8 years old, 91% female; forced expiratory volume in 1 s [FEV1] = 103 ± 16% predicted; FEV1 to forced vital capacity [FVC] ratio = 0.75 ± 0.05; RV/TLC = 0.39 ± 0.07; 85.7% with EFL). Adherence was high with 87% and 93% of prescribed doses taken in the treatment and placebo arms of the study, respectively (P = 0.349 for comparison between the two arms). There was no significant improvement in the primary or secondary outcomes by intention-to-treat or per-protocol analysis. In per-protocol subgroup analysis of those with RV/TLC > 0.35 and ≥ 90% adherence (n = 27), albuterol caused an improvement in peak VO2 (parameter estimate [95% confidence interval] = 0.108 [0.014, 0.202]; P = 0.037), tidal volume, minute ventilation, dynamic hyperinflation, and oxygen-pulse (all P < 0.05), but no change in symptoms or physical activity. CONCLUSIONS: Albuterol may improve exercise capacity in the subgroup of SHS tobacco-exposed persons with preserved spirometry and substantial air trapping. These findings suggest that air trapping in pre-COPD may be related to small airway disease that is not considered significant by spirometric indices of airflow obstruction.
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Albuterol , Enfermedad Pulmonar Obstructiva Crónica , Anciano , Femenino , Humanos , Masculino , Persona de Mediana Edad , Albuterol/farmacología , Ejercicio Físico , Volumen Espiratorio Forzado , Pulmón , Enfermedad Pulmonar Obstructiva Crónica/epidemiología , Espirometría/métodos , Capacidad Vital/fisiologíaRESUMEN
BACKGROUND: Children with asthma may have a reduced ventilatory capacity, which could lead to symptoms and early termination of a cardiopulmonary exercise test (CPET). The purpose of this study was to examine the effects of short-acting beta agonist (albuterol) administration on estimated ventilatory capacity in children with asthma. METHODS: Fifteen children (eleven boys, 10.6 ± 0.9 years) completed spirometry at baseline, after 180 µg of albuterol, and after the CPET in this cross-sectional study. Ventilatory capacity was calculated from forced vital capacity (FVC) and isovolume forced expiratory time from 25 to 75% of FVC (isoFET25-75) as follows: FVC/2 × [60/(2 × isoFET25-75)]. Differences in outcome variables between baseline, after albuterol administration, and after the CPET were detected with repeated measures mixed models with Bonferroni post hoc corrections. RESULTS: Estimated ventilatory capacity was higher after albuterol (68.7 ± 21.2 L/min) and after the CPET (75.8 ± 25.6 L/min) when compared with baseline (60.9 ± 22.0 L/min; P = 0.003). Because forced vital capacity did not change, the increased ventilatory capacity was primarily due to a decrease in isoFET25-75 (i.e., an increase in mid-flows or isoFEF25-75). CONCLUSION: Albuterol administration could be considered prior to CPET for children with asthma with relatively well-preserved FEV1 values to increase ventilatory capacity pre-exercise and potentially avoid symptom-limited early termination of testing.
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INTRODUCTION: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß2-sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß2-sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological TH2-phenotype in asthma, acting-at least partially-through inhibition of acid sphingomyelinase (ASM), an enzyme involved in sphingolipid metabolism. Here, we investigated the non-immunological role of amitriptyline on acute bronchoconstriction, a main feature of airway hyperresponsiveness in asthmatic disease. METHODS: After stimulation of precision cut lung slices (PCLS) from mice (wildtype and ASM-knockout), rats, guinea pigs and human lungs with mediators of bronchoconstriction (endogenous and exogenous acetylcholine, methacholine, serotonin, endothelin, histamine, thromboxane-receptor agonist U46619 and leukotriene LTD4, airway area was monitored in the absence of or with rising concentrations of amitriptyline. Airway dilatation was also investigated in rat PCLS by prior contraction induced by methacholine. As bronchodilators for maximal relaxation, we used IBMX (PDE inhibitor) and salbutamol (ß2-adrenergic agonist) and compared these effects with the impact of amitriptyline treatment. Isolated perfused lungs (IPL) of wildtype mice were treated with amitriptyline, administered via the vascular system (perfusate) or intratracheally as an inhalation. To this end, amitriptyline was nebulized via pariboy in-vivo and mice were ventilated with the flexiVent setup immediately after inhalation of amitriptyline with monitoring of lung function. RESULTS: Our results show amitriptyline to be a potential inhibitor of bronchoconstriction, induced by exogenous or endogenous (EFS) acetylcholine, serotonin and histamine, in PCLS from various species. The effects of endothelin, thromboxane and leukotrienes could not be blocked. In acute bronchoconstriction, amitriptyline seems to act ASM-independent, because ASM-deficiency (Smdp1-/-) did not change the effect of acetylcholine on airway contraction. Systemic as well as inhaled amitriptyline ameliorated the resistance of IPL after acetylcholine provocation. With the flexiVent setup, we demonstrated that the acetylcholine-induced rise in central and tissue resistance was much more marked in untreated animals than in amitriptyline-treated ones. Additionally, we provide clear evidence that amitriptyline dilatates pre-contracted airways as effectively as a combination of typical bronchodilators such as IBMX and salbutamol. CONCLUSION: Amitriptyline is a drug of high potential, which inhibits acute bronchoconstriction and induces bronchodilatation in pre-contracted airways. It could be one of the first therapeutic agents in asthmatic disease to have powerful effects on the TH2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled.
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Asma , Broncoconstricción , Ratones , Ratas , Humanos , Animales , Cobayas , Cloruro de Metacolina/farmacología , Amitriptilina/farmacología , Amitriptilina/uso terapéutico , Histamina/farmacología , Broncodilatadores/farmacología , Broncodilatadores/uso terapéutico , Serotonina/farmacología , Serotonina/uso terapéutico , Acetilcolina/farmacología , Simpatomiméticos/farmacología , Simpatomiméticos/uso terapéutico , 1-Metil-3-Isobutilxantina/farmacología , 1-Metil-3-Isobutilxantina/uso terapéutico , Dilatación , Pulmón , Asma/tratamiento farmacológico , Albuterol , Endotelinas/farmacología , Endotelinas/uso terapéutico , Tromboxanos/farmacología , Tromboxanos/uso terapéuticoRESUMEN
Data from the phase III ENHANCE clinical trials provide compelling evidence that ensifentrine, an inhaled 'bifunctional' dual phosphodiesterase 3/4 inhibitor, can provide additional benefit to existing treatments in patients with chronic obstructive pulmonary disease and represents a 'first-in-class' drug having bifunctional bronchodilator and anti-inflammatory activity in a single molecule. Ensifentrine, generally well tolerated, can provide additional bronchodilation when added to muscarinic receptor antagonists or ß2-agonists and reduce the exacerbation risk. This information allows us to consider better the possible inclusion of ensifentrine in the future treatment of chronic obstructive pulmonary disease. However, there is less information on whether it provides additional benefit when added to inhaled corticosteroid or 'triple therapy' and, therefore, when this drug is best utilized in clinical practice.
Chronic obstructive pulmonary disease (COPD) is the name for a group of lung conditions that cause breathing difficulties/airflow limitations. The airflow limitation is not completely reversible and is associated with a state of chronic inflammation of lung tissue. Treatment of the disease is still heavily dependent on the use of medications called bronchodilators and corticosteroids. However, corticosteroids have little-to-no impact on the underlying inflammation in most COPD patients. Therefore, innovative anti-inflammatory approaches are required. In this context, single molecules that are capable of simultaneously inducing bronchodilation, relaxing the muscles in the lungs and widening the airways (bronchi), and anti-inflammatory activity are a highly intriguing possibility for treating COPD. One approach is to develop drugs that can simultaneously inhibit enzymes called phosphodiesterase (PDE)3 and PDE4. Enzymes are proteins that help speed up metabolism, or the chemical reactions in our bodies. PDE4 inhibitors are intracellular enzymes (work inside the cell) expressed in most inflammatory cells, even in neutrophils (a type of white blood cells), which are involved in the pathogenesis of COPD, where an infection turns into a disease. However, its inhibition does not produce severe bronchodilator effects, which is instead obtained by inhibiting PDE3, the PDE isoenzyme (a different form of the same enzyme) that is predominantly expressed in airway smooth muscle cells. A treatment called ensifentrine is a dual PDE3/4 inhibitor (inhibits both PDE3 and PDE4). Two recent phase III studies (ENHANCE-1 and ENHANCE-2) have shown that it induces significant bronchodilation and reduces the risk of COPD worsening, exerting an anti-inflammatory effect. Data from the ENHANCE studies also showed the benefit of adding ensifentrine to treatment with bronchodilators. Certainly, the drug represents a useful therapeutic option, but further clinical studies are needed to be able to correctly position ensifentrine in the context of regular COPD treatment.
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Enfermedad Pulmonar Obstructiva Crónica , Humanos , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Isoquinolinas/farmacología , Isoquinolinas/uso terapéutico , Pirimidinonas/uso terapéutico , Broncodilatadores/uso terapéutico , Administración por InhalaciónRESUMEN
BACKGROUND: Deep inspiration (DI) has been shown to induce bronchodilation and bronchoprotection in bronchochallenged healthy subjects, but not in asthmatics. Strain-induced relaxation of airway smooth muscle (ASM) is considered one of the factors responsible for these effects. Other factors include the release or redistribution of pulmonary surfactant, alteration in mucus plugs, and changes in airway heterogeneity. MAIN BODY: The present review is focused on the DI effect on ASM function, based on recent findings from ex vivo sheep lung experiments showing a large change in airway diameter during a DI. The amount of stretch on the airways, when applied to isolated airway rings in vitro, caused a substantial decrease in ASM contractility that takes many minutes to recover. When challenged with a bronchoconstrictor, the increase in pulmonary resistance in the ex vivo ovine lungs is mostly due to the increase in airway resistance. CONCLUSIONS: Although non-ASM related factors cannot be excluded, the large strain on the airways associated with a DI substantially reduces ASM contractility and thus can account for most of the bronchodilatory and bronchoprotective effects of DI.
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Asma , Bronquios , Humanos , Animales , Ovinos , Pulmón , Inhalación/fisiología , Músculo LisoRESUMEN
OBJECTIVE: Aim: To analyze the effectiveness of rehabilitation treatment in the conditions of halo aerosol therapy and when using different groups of fixed-dose aerosol inhalers in patients with asthma, chronic obstructive pulmonary diseases and asthma-chronic obstructive pulmonary diseases overlap. PATIENTS AND METHODS: Materials and Methods: A total 112 patients with asthma, chronic obstructive pulmonary diseases and asthma-chronic obstructive pulmonary diseases overlap. All patients carefully collected allergic history, anamnesis of life, and disease. The study includes assessment of resting anthropometric data, physical activity habits, blood pressure, structure and quality of nutrition, family and economic data. RESULTS: Result: After a course of rehabilitation treatment, lung ventilation improved in all groups of patients compared to controls. The dynamics of FER indicators after the rehabilitation treatment had some differences for each group of patients in relation to the control groups. If in all A groups (control) the increase in FER indicators was insignificant, then in all B groups of patients it was significant, and differed from 14,6% up to 36%. CONCLUSION: Conclusions: Thus, a differentiated approach to the use of fixed-dose aerosol inhalers increases the effectiveness of rehabilitation treatment under conditions of halo aerosol therapy in patients with various genesis of bronchi-obstructive syndrome.
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AVANT was a Phase 3, 24-week, randomized, parallel-group, double-blind, double-dummy, placebo-controlled study to assess the efficacy and safety of aclidinium/formoterol 400 µg/12 µg combination vs monotherapies and aclidinium vs placebo (1:1:1:1) in Asian patients (â¼70% of whom were Chinese) with moderate-to-severe stable chronic obstructive pulmonary disease. Endpoints were analyzed hierarchically to incorporate type I error control. At Week 24, aclidinium/formoterol demonstrated improvements from baseline in 1-h morning post-dose forced expiratory volume in 1 s (FEV1) vs aclidinium (least squares [LS] mean 92 mL; 95% confidence interval [CI] 60, 124 mL; p < 0.001), and in trough FEV1 vs formoterol (LS mean 85 mL; 95% CI 53, 117 mL; p < 0.001). Furthermore, aclidinium provided improvements in trough FEV1 vs placebo (LS mean 134 mL; 95% CI 103, 166 mL; p < 0.001). There was an improvement in transition dyspnea index focal score at Week 24 for aclidinium/formoterol vs placebo (LS mean 0.8; 95% CI 0.2, 1.3; p = 0.005) but not for aclidinium vs placebo (LS mean 0.4; 95% CI -0.1, 1.0; p = 0.132). Improvements in St George's Respiratory Questionnaire total scores occurred for aclidinium/formoterol vs placebo (LS mean -4.0; 95% CI -6.7, -1.4; p = 0.003) and aclidinium vs placebo (LS mean -2.9; 95% CI -5.5, -0.3; p = 0.031). Aclidinium/formoterol and aclidinium were well tolerated and safety findings were consistent with known profiles; rates of treatment-emergent adverse events (AEs) (aclidinium/formoterol: 54.8%; aclidinium: 47.4%; placebo: 53.9%), serious AEs (7.2, 7.9, and 7.8%, respectively), and AEs leading to discontinuation of study medication (2.3, 1.5, and 2.2%, respectively) were similar between groups.
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Broncodilatadores , Enfermedad Pulmonar Obstructiva Crónica , Humanos , Administración por Inhalación , Agonistas de Receptores Adrenérgicos beta 2/efectos adversos , Agonistas de Receptores Adrenérgicos beta 2/uso terapéutico , Broncodilatadores/efectos adversos , Broncodilatadores/uso terapéutico , Método Doble Ciego , Pueblos del Este de Asia , Volumen Espiratorio Forzado , Fumarato de Formoterol/efectos adversos , Fumarato de Formoterol/uso terapéutico , Antagonistas Muscarínicos/efectos adversos , Antagonistas Muscarínicos/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Resultado del Tratamiento , Tropanos/efectos adversos , Tropanos/uso terapéuticoRESUMEN
The ongoing Coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has imposed a huge threat to public health across the world. While vaccinations are essential for reducing virus transmission and attenuating disease severity, the nature of high mutation rate of SARS-CoV-2 renders vaccines less effective, urging quick development of effective therapies for COVID-19 disease. However, developing novel drugs remains extremely challenging due to the lengthy process and high cost. Alternatively, repurposing of existing drugs on the market represents a rapid and safe strategy for combating COVID-19 pandemic. Bronchodilators are first line drugs for inflammatory lung diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Compared to other anti-inflammatory drugs repurposed for COVID-19, bronchodilators are unique in that they have both anti-inflammatory and bronchodilating properties. Whether the dual properties of bronchodilators empower them greater potential to be repurposed for COVID-19 is worth exploring. In fact, clinical and preclinical studies have recently emerged to investigate the benefits of bronchodilators such assalbutamol, formoterol and theophylline in treating COVID-19, and many of them have shown encouraging efficacy on attenuating disease severity of pneumonia and other associated symptoms. To comprehensively understand the latest progress on COVID-19 intervention with bronchodilators, this review will summarize recent findings in this area and highlight the promising clinical benefits and possible adverse effects of bronchodilators as therapeutic options for COVID-19 with a focus on ß2 receptor agonists, anticholinergic drugs and theophylline.
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Rhinoviruses (RVs) evoke as many as 85% of acute asthma exacerbations in children and 50% in adults and can induce airway hyperresponsiveness and decrease efficacy of current therapeutics to provide symptom relief. Using human precision-cut lung slices (hPCLSs), primary human air-liquid interface-differentiated airway epithelial cells (HAECs), and human airway smooth muscle (HASM) as preclinical experimental models, we demonstrated that RV-C15 attenuates agonist-induced bronchodilation. Specifically, airway relaxation to formoterol and cholera toxin, but not forskolin (Fsk), was attenuated following hPCLS exposure to RV-C15. In isolated HASM cells, exposure to conditioned media from RV-exposed HAECs decreased cellular relaxation in response to isoproterenol and prostaglandin E2, but not Fsk. Additionally, cAMP generation elicited by formoterol and isoproterenol, but not Fsk, was attenuated following HASM exposure to RV-C15-conditioned HAEC media. HASM exposure to RV-C15-conditioned HAEC media modulated expression of components of relaxation pathways, specifically GNAI1 and GRK2. Strikingly, similar to exposure to intact RV-C15, hPCLS exposed to UV-inactivated RV-C15 showed markedly attenuated airway relaxation in response to formoterol, suggesting that the mechanism(s) of RV-C15-mediated loss of bronchodilation is independent of virus replication pathways. Further studies are warranted to identify soluble factor(s) regulating the epithelial-driven smooth muscle loss of ß2-adrenergic receptor function.
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Infecciones por Enterovirus , Rhinovirus , Adulto , Niño , Humanos , Rhinovirus/fisiología , Isoproterenol/farmacología , Músculo Liso/metabolismo , Pulmón/metabolismo , Fumarato de Formoterol/farmacología , Fumarato de Formoterol/metabolismo , Colforsina/farmacología , Relajación MuscularRESUMEN
Hemoglobin (Hb) present in the lung epithelium is of unknown significance. However Hb being an nitric oxide (NO) scavenger can bind to NO and reduce its deleterious effects. Hence we postulated an NO scavenging role for this lung Hb. Doing transwell co-culture with bronchial epithelial cells, A549/16-HBE (apical) and human airway smooth muscle cells (HASMCs as basal), we found that Hb can protect the smooth muscle soluble guanylyl cyclase (sGC) from excess NO. Inducing the apical A549/16-HBE cells with cytokines to trigger iNOS expression and NO generation caused a time dependent increase in SNO-sGC and this was accompanied with a concomitant drop in sGC-α1ß1 heterodimerization. Silencing Hbαß in the apical cells further increased the SNO on sGC with a faster drop in the sGC heterodimer and these effects were additive along with further silencing of thioredoxin 1 (Trx1). Since heme of Hb is critical for NO scavenging we determined the Hb heme in a mouse model of allergic asthma (OVA) and found that Hb in the inflammed OVA lungs was low in heme or heme-free relative to those of naïve lungs. Further we established a direct correlation between the status of the sGC heterodimer and the Hb heme from lung samples of human asthma, iPAH, COPD and cystic fibrosis. These findings present a new mechanism of protection of lung sGC by the epithelial Hb, and suggests that this protection maybe lost in asthma or COPD where lung Hb is unable to scavenge the NO due to it being heme-deprived.
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Asma , Enfermedad Pulmonar Obstructiva Crónica , Ratones , Animales , Humanos , Guanilil Ciclasa Soluble/genética , Guanilil Ciclasa Soluble/metabolismo , Guanilato Ciclasa/genética , Óxido Nítrico/metabolismo , Pulmón/metabolismo , Asma/genética , Músculo Liso/metabolismo , Hemoglobinas , Hemo/metabolismo , Epitelio/metabolismoRESUMEN
Extracellular adenosine 5'-triphosphate (ATP) acts as an autocrine and paracrine agent, the actions of which on affected cells are mediated by P2 receptors (P2R), which include trans cell-membrane cationic channels (P2XRs), and G protein coupled receptors (P2YRs). The mammalian P2X receptors form homotrimeric or heterotrimeric cationic channels, each of which contains three ATP-binding sites. There are seven homotrimeric P2X receptors (P2X1-7) and three heteromeric (P2X2/P2X3, P2X4/P2X6, P2X1/P2X5). In the lungs and airways, ATP activates P2X3 and P2X2/3 receptors (P2X3R, P2X2/3R, respectively) localized on vagal sensory nerve terminals resulting in bronchoconstriction, and cough, and probably also localized release of pro-inflammatory neuropeptides via the axon reflex. Currently, several P2X3R and P2X2/3R antagonists are being developed as drug-candidates for the treatment of chronic cough. This report presents the receptor affinity data of a novel water-soluble small molecule, DT-0111, that acts as a selective P2X3R antagonist.
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Tos , Receptores Purinérgicos P2X3 , Animales , Antagonistas del Receptor Purinérgico P2X/farmacología , Adenosina Trifosfato/metabolismo , Pulmón/metabolismo , Receptores Purinérgicos P2X2 , Mamíferos/metabolismoRESUMEN
The increase in asthma associated with the obesity epidemic cannot simply be due to airway hyperresponsiveness from chronic lung compression because chronic lung compression is a feature of obesity in general. We therefore sought to investigate what other factors might be at play in the impaired lung function seen in obese individuals with asthma. We measured respiratory system impedance in four groups-Lean Control, Lean Allergic Asthma, Obese Control, and Obese Allergic Asthma-before and after administration of albuterol. Impedance measurements were fit with an anatomically based computational model of lung mechanics that represents the airway tree as a branching structure with a uniform degree of asymmetry and a fixed radius scaling ratio, γ, between branches of sequential order. The two model parameters that define the airway tree, γ and tracheal radius, varied only modestly between the four study groups, indicating relatively minor differences in airway caliber. In contrast, respiratory system elastance was 57, 34, 143, and 271 cmH2O/L, respectively, for the four groups, suggesting that obesity induced significant lung de-recruitment that was exacerbated by allergic asthma. In addition, when the radii of the individual branches of the airway tree were varied randomly, we found that roughly half the terminal airways had to be closed to have the model fit the data well. We conclude that de-recruitment of small airways is a particular feature of Obese Allergic Asthma, and this can be inferred from respiratory system impedance fit with an anatomically based computational model.NEW & NOTEWORTHY Using a novel anatomically based computational model to interpret oscillometry measurements of impedance, we show that respiratory system elastance is increased in obesity and is increased dramatically in individuals with obese allergic asthma. A significant component of this increased elastance in obese allergic asthma appears to be due to closure of small airways rather than alveolar atelectasis, and this closure is partially mitigated by albuterol. These findings potentially point to nonpharmacological therapies in obese allergic asthma aimed at recruiting closed airways.
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Asma , Humanos , Pulmón , Obesidad/complicaciones , Pruebas de Función Respiratoria , Albuterol/uso terapéuticoRESUMEN
OBJECTIVE: There are few studies in clinically healthy subjects describing and quantifying exercise-induced bronchodilation (EIBd). This study aimed to describe and compare the magnitude and time course changes in post-exercise forced expired volume at the first second (FEV1) in healthy adolescents, younger adults, and older adults. METHODS: Adolescent (n = 73, aged 10-17 years), younger adult (n = 35, aged 18-25 years), and older adult (n = 25, aged 35-66 years) subjects with normal spirometry z-scores completed a maximal cardiopulmonary exercise test using the standardized exponential exercise test protocol on a cycle ergometer performed at stable temperature and humidity. Spirometry was performed pre-exercise and at 1-, 3-, 5-, and 10-minutes post-exercise to determine the percentage change in FEV1 compared to baseline. EIBd was defined as a ≥ 5% increase in post-exercise FEV1. RESULTS: Increases in FEV1 at one-minute post-exercise were observed in the adolescents (1.3%) and young adults (6.0%) with FEV1 returning to baseline after ten minutes. Compared to the adolescents, the older adults showed significantly greater and sustained increases in FEV1 at 1-, 3-, 5-, and 10-minutes post-exercise (6.4, 4.6, 4.7, and 3.8%, p < 0.05). At 1-minute post exercise a significantly greater proportion of younger adults (54%, p < 0.01) and older adults (64%, p < 0.01) demonstrated EIBd compared to the adolescent group (15%). CONCLUSION: Healthy older adults had a higher prevalence, greater magnitude and more prolonged EIBd compared to healthy adolescent and young adult subjects.
Asunto(s)
Asma Inducida por Ejercicio , Asma , Adulto Joven , Humanos , Adolescente , Anciano , Adulto , Pruebas de Función Respiratoria , Espirometría/métodos , Ejercicio Físico , Prueba de Esfuerzo , Volumen Espiratorio ForzadoRESUMEN
Background: Many patients with cough variant asthma (CVA) are underdiagnosed and undertreated due to the atypical symptoms, low diagnostic sensitivity of bronchodilator response (BDR), and limited application of bronchial challenge test. Objective: To investigate whether airway reversibility in BDR can predict CVA diagnosis in patients with chronic cough and negative BDR. Methods: This open-label, prospective cohort study included patients with chronic cough, nearly normal chest CT scan, and negative BDR results. Inhaled corticosteroids and long-acting ß2 agonists were given for 4 weeks. The confirmed diagnosis of CVA was defined as improved symptoms and an increase of forced expiratory volume in 1 s (FEV1) by >12% and >200 mL after 4 weeks of treatment. Results: Of 155 patients recruited, 140 completed the study. Patients in the CVA positive diagnosis group had greater absolute (Δ) and percent (Δ%) improvements in FEV1 and forced expiratory flows (FEFs), and higher fractional exhaled nitric oxide (FENO) than in the CVA negative diagnosis group. The area under the receiver operating characteristic curves (AUCs) of ΔFEV1%, FEF25-75%pred (percentage of predicted forced expiratory flow at 25% to 75%) and FENO for CVA positive diagnosis was 0.825, 0.714, and 0.637, with cutoff values of 5.90%, 61.99% and 41.50 ppb, respectively. A joint model of ΔFEV1% combined with FEF25-75%pred or FENO increased the AUC to 0.848 and 0.847, respectively. Conclusion: ΔFEV1% in BDR can predict a CVA diagnosis and response to anti-asthma treatment in patients with chronic cough and negative BDR. Clinical trial registration: [http://www.chictr.org.cn/index.aspx], identifier [ChiCTR2000029065].
RESUMEN
Beta-adrenoceptor (ß-AR) agonists inhibit cholinergic contractions of airway smooth muscle (ASM), but the underlying mechanisms are unclear. ASM cells express M3 and M2 muscarinic receptors, but the bronchoconstrictor effects of acetylcholine are believed to result from activation of M3Rs, while the role of the M2Rs is confined to offsetting ß-AR-dependent relaxations. However, a profound M2R-mediated hypersensitization of M3R-dependent contractions of ASM was recently reported, indicating an important role for M2Rs in cholinergic contractions of ASM. Here, we investigated if M2R-dependent contractions of murine bronchial rings were inhibited by activation of ß-ARs. M2R-dependent contractions were apparent at low frequency (2Hz) electric field stimulation (EFS) and short (10s) stimulus intervals. The ß1-AR agonist, denopamine inhibited EFS-evoked contractions of ASM induced by reduction in stimulus interval from 100 to 10 s and was more effective at inhibiting contractions evoked by EFS at 2 than 20 Hz. Denopamine also abolished carbachol-evoked contractions that were resistant to the M3R antagonist 4-DAMP, similar to the effects of the M2R antagonists, methoctramine and AFDX-116. The inhibitory effects of denopamine on EFS-evoked contractions of ASM were smaller in preparations taken from M2R -/- mice, compared to wild-type (WT) controls. In contrast, inhibitory effects of the ß3-AR agonist, BRL37344, on EFS-evoked contractions of detrusor strips taken from M2R -/- mice were greater than WT controls. These data suggest that M2R-dependent contractions of ASM were inhibited by activation of ß1-ARs and that genetic ablation of M2Rs decreased the efficacy of ß-AR agonists on cholinergic contractions.