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The combination of aminophylline and salbutamol is frequently used in clinical practice in the treatment of obstructive lung diseases. While the side effects (including arrhythmias) of the individual bronchodilator drugs were well described previously, the side effects of combined treatment are almost unknown. We aimed to study the arrhythmogenic potential of combined aminophylline and salbutamol treatment in vitro. For this purpose, we used the established atomic force microscopy (AFM) model coupled with cardiac organoids derived from human pluripotent stem cells (hPSC-CMs). We focused on the chronotropic, inotropic, and arrhythmogenic effects of salbutamol alone and aminophylline and salbutamol combined treatment. We used a method based on heart rate/beat rate variability (HRV/BRV) analysis to detect arrhythmic events in the hPSC-CM based AFM recordings. Salbutamol and aminophylline had a synergistic chronotropic and inotropic effect compared to the effects of monotherapy. Our main finding was that salbutamol reduced the arrhythmogenic effect of aminophylline, most likely mediated by endothelial nitric oxide synthase activated by beta-2 adrenergic receptors. These findings were replicated and confirmed using hPSC-CM derived from two cell lines (CCTL4 and CCTL12). Data suggest that salbutamol as an add-on therapy may not only deliver a bronchodilator effect but also increase the cardiovascular safety of aminophylline, as salbutamol reduces its arrhythmogenic potential., (© 2024. The Author(s).)

Background: Bronchodilator response (BDR) is a measure of improvement in airway smooth muscle tone, inhibition of liquid accumulation and mucus section into the lumen in response to short-acting beta-2 agonists that varies among asthmatic patients. MicroRNAs (miRNAs) are well-known post-translational regulators. Identifying miRNAs associated with BDR could lead to a better understanding of the underlying complex pathophysiology., Objective: The purpose of this study is to identify circulating miRNAs associated with bronchodilator response in asthma and decipher possible mechanism of bronchodilator response variation., Methods: We used available small RNA sequencing on blood serum from 1,134 asthmatic children aged 6 to 14 years who participated in the Genetics of Asthma in Costa Rica Study (GACRS). We filtered the participants into the highest and lowest bronchodilator response (BDR) quartiles and used DeSeq2 to identify miRNAs with differential expression (DE) in high (N = 277) vs. low (N = 278) BDR group. Replication was carried out in the Leukotriene modifier Or Corticosteroids or Corticosteroid-Salmeterol trial (LOCCS), an adult asthma cohort. The putative target genes of DE miRNAs were identified, and pathway enrichment analysis was performed., Results: We identified 10 down-regulated miRNAs having odds ratios (OR) between 0.37 and 0.76 for a doubling of miRNA counts and one up-regulated miRNA (OR = 2.26) between high and low BDR group. These were assessed for replication in the LOCCS cohort, where two miRNAs (miR-200b-3p and miR-1246) were associated. Further, functional annotation of 11 DE miRNAs were performed as well as of two replicated miRs. Target genes of these miRs were enriched in regulation of cholesterol biosynthesis by SREBPs, ESR-mediated signaling, G1/S transition, RHO GTPase cycle, and signaling by TGFB family pathways., Conclusion: MiRNAs miR-1246 and miR-200b-3p are associated with both childhood and adult asthma BDR. Our findings add to the growing body of evidence that miRNAs play a significant role in the difference of asthma treatment response among patients as it points to genomic regulatory machinery underlying difference in bronchodilator response among patients., Trial Registration: LOCCS cohort [ClinicalTrials.gov number NCT00156819, Registration date 20050912], GACRS cohort [ClinicalTrials.gov number NCT00021840]., (© 2024. The Author(s).)

Previous studies based on animal models have raised concerns about salbutamol use in ozone air pollution with regard to ozone related lung injury. We conducted a double-blind, randomized, placebo-controlled crossover study including 18 subjects diagnosed with EIB by a eucapnic voluntary hyperpnea (EVH) test. Participants completed 30 min of standardized moderate to vigorous exercise in four conditions: ozone plus salbutamol; room air plus salbutamol; ozone plus placebo medication; and room air plus placebo medication. Spirometry, fraction of exhaled nitric oxide, and symptoms were measured before, immediately after, 30 min after and 1 h after exercise. Measurements between the four conditions were compared using percent change from pre to post exercise. There was a statistically significant difference between the salbutamol and placebo medication groups for spirometric variables including FEV1 (Estimate = 6.3, 95% CI: 4.23-8.37, p < 0.001). No differences were observed between ozone and room air exposures. There were no significant differences in FeNO response between experimental conditions. We found that salbutamol improved pulmonary function in individuals with EIB when exercising in ozone and did not increase eosinophilic airway inflammation as indicated by FeNO. This evidence suggests that it is safe for people with EIB to continue to use salbutamol as proscribed when ozone levels are elevated., (© 2024 The Author(s). Physiological Reports published by Wiley Periodicals LLC on behalf of The Physiological Society and the American Physiological Society.)

Obstructive sleep apnea (OSA) is highly prevalent in patients with asthma. Asthma, dose-dependently to its duration, promotes incident OSA, suggesting that asthma plays a role in OSA pathogenesis. We hypothesized that asthma-related inflammation alters breathing control mechanisms, specifically the carotid chemoreflex. Accordingly, we measured hypoxic ventilatory responses (HVR) in awake, unrestrained, ovalbumin (OVA)-sensitized Brown Norway rats and compared them with responses in sham-sensitized (SALINE) controls. To differentiate the role of allergic inflammation from bronchoconstriction, we repeated hypoxic ventilatory response (HVR) after administration of formoterol, a long-acting bronchodilator. Blood and bronchoalveolar lavage (BAL) fluid were collected for quantification of inflammatory cytokines. The rise in ventilatory equivalent for O 2 evoked by acute exposure to hypoxia was augmented following sensitization by OVA, whereas it remained stable after SALINE. This augmentation was driven by increased breathing frequency with no change in tidal volume. Tachypneic hyperventilation in normoxia was also observed with OVA. Neither the increased HVR nor excessive normoxic ventilation was affected by formoterol, suggesting that they were not secondary to lung mechanical constraints. Higher levels of inflammatory cytokines were observed in BAL fluid and serum of OVA versus SALINE. In OVA, serum interleukin-5 levels significantly correlated with change from baseline in ventilatory responses to severe hypoxia ([Formula: see text], 0.09). These observations are consistent with inflammation-induced enhancement of carotid chemoreflex function, i.e., increased controller gain, and they suggest a possible role for asthma-related allergic inflammation in the ventilatory instability known to promote upper airway collapse and sleep apnea in humans. NEW & NOTEWORTHY Asthma is a risk factor for obstructive sleep apnea (OSA); however, the mechanisms are incompletely understood. In a rat model of allergic inflammation associated with asthma, we found that ventilation in normoxia and ventilatory responses to hypoxia were markedly enhanced and related with systemic inflammation. These alterations indicating carotid chemoreflex sensitization, known to promote ventilatory instability during sleep in humans, may contribute to the increased OSA risk in asthma.

Inhaled beta-2 adrenoceptor agonists (iβ2A) are routinely used as bronchodilators in the treatment of asthma. However, their cardiac effects in athletes are scarcely examined. Thus, the aim of this study was to evaluate the effects of iβ2A on left ventricular (LV) systolic function (SF) by echocardiography in healthy, non-asthmatic female and male endurance athletes. A randomized, double-blinded, placebo-controlled, balanced, 4-way complete block cross-over study was conducted. Twenty-four healthy athletes (12f/12m: 22.9 ± 2.7/24.4 ± 4.6 years) randomly completed 4 study arms (placebo; salbutamol; formoterol; formoterol + salbutamol). After inhalation of the study medication, the participants performed a 10-min time trial (TT) on a bicycle ergometer. After each TT an echocardiography was performed to determine LVSF. Blood samples were collected pre, post, 3 h and 24 h post TT. In females, total serum concentrations for salbutamol and formoterol were higher. LV ejection fraction (LVEF) and LV global longitudinal strain (LVendoGLS) showed a treatment effect for the whole study group (p < 0.0001) and a sex effect on LVEF (p = 0.0085). In women, there was a significant treatment effect for all medication arms (at least p ≤ 0.01) both on LVEF and LVendoGLS. In men only formoterol and formoterol + salbutamol displayed a treatment effect on LVEF (p = 0.0427, p = 0.0330; respectively), whereas on LVendoGLS only formoterol + salbutamol was significant (p = 0.0473). The iβ2A significantly influenced LVSF after an acute bout of exercise in healthy endurance athletes. These effects were even more pronounced when combining both iβ2A that supports a dose-dependent effect on cardiac function. Moreover, female athletes had higher serum concentrations of β2 agonists and stronger effects on LVSF compared to male athletes. This is mainly explained by differences in body weight and related plasma volume and may indicate a potential risk when increasing dose above the tested concentrations. Trial registration: At the European Union Drug Regulating Authorities Clinical Trials (Eudra CT) with the number 201,500,559,819 (registered prospectively on 09/12/2015) and at the German register for clinical studies (DRKS number 00010574 registered retrospectively on 16/11/2021)., (© 2024. The Author(s).)

The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a β2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The effect of bronchodilators is mainly assessed with forced expiratory volume in 1 s (FEV 1 ) in chronic obstructive pulmonary disease (COPD). Their impact on oxygenation and lung periphery is less known. Our objective was to compare the action of long-acting β 2 -agonists (LABA-olodaterol) and muscarinic antagonists (LAMA-tiotropium) on tissue oxygenation in COPD, considering their impact on proximal and peripheral ventilation as well as lung perfusion. FEV 1 , Helium slope (S He ) from a single-breath washout test (S He decreases reflecting a peripheral ventilation improvement), frequency dependence of resistance (R5-R19), area under reactance (AX), lung capillary blood volume (Vc) from double diffusion (DL NO /DL CO ), and transcutaneous oxygenation (TcO 2 ) were measured before and 2 h post-LABA ( day 1 ) and LAMA ( day 3 ) in 30 patients with COPD (FEV 1 54 ± 18% pred; GOLD A 31%/B 48%/E 21%) after 5-7 days of washout, respectively. We found that TcO 2 increased more ( P = 0.03) after LAMA (11 ± 12% from baseline, P < 001) compared with LABA (4 ± 11%, P = 0.06) despite a lower FEV 1 increase ( P = 0.03) and similar S He ( P = 0.98), AX ( P = 0.63), and R5-R19 decreases ( P = 0.37). TcO 2 and S He changes were negatively correlated ( r = -0.47, P = 0.01) after LABA, not after LAMA ( r = 0.10, P = 0.65). DL NO /DL CO decreased and Vc increased after LAMA ( P = 0.04; P = 0.01, respectively) but not after LABA ( P = 0.53; P = 0.24). In conclusion, LAMA significantly improved tissue oxygenation in patients with COPD, while only a trend was observed with LABA. The mechanisms involved may differ between both drugs: LABA increased peripheral ventilation, whereas LAMA increased lung capillary blood volume. Should oxygenation differences persist over time, LAMA could arguably become the first therapeutic choice in COPD. NEW & NOTEWORTHY Long-acting muscarinic antagonists (LAMAs) significantly improved tissue oxygenation in patients with COPD, while only a trend was observed with β 2 -agonists (LABAs). The mechanisms involved may differ between drugs: increased peripheral ventilation for LABA and likely lung capillary blood volume for LAMA. This could argue for LAMA as the first therapeutic choice in COPD.

Asthma is a disease characterized by chronic inflammation and hyper responsiveness of airways. We aimed to assess the relaxant potential of phosphodiesterase-4 (PDE4) inhibitors N-sulfonilhidrazonic derivatives on non-asthmatic and asthmatic guinea pig trachea. Firstly, guinea pigs were sensitized and challenged with ovalbumin, and then morphological, and contractile changes were evaluated resulting from asthma, followed by evaluation of relaxant effect of derivatives on guinea pig trachea and the cAMP levels measurement by ELISA. It has been evidenced hypertrophy of airway smooth muscle, inflammatory infiltrate, and vascular abnormalities. Moreover, only sensitized tracheal rings were responsive to OVA. Contractile response to histamine, but not to carbachol, was greater in sensitized animals, however the relaxant response to aminophylline and isoprenaline were the same in non-asthmatics and asthmatics. N-sulfonilhidrazonic derivatives presented equipotent relaxant action independent of epithelium, with exception of LASSBio-1850 that presented a low efficacy (< 50%) and LASSBio-1847 with a 4-fold higher potency on asthmatics. LASSBio-1847 relaxant curve was impaired in the presence of propranolol and potentiated by isoprenaline in both groups. Furthermore, relaxation was potentiated 54- and 4-fold by forskolin in non-asthmatics and asthmatics, respectively. Likewise, LASSBio-1847 potentiated relaxant curve of aminophylline 147- and 4-fold in both groups. The PKA inhibitor H-89 impaired the relaxant potency of the derivative. Finally, LASSBio-1847 increased tracheal intracellular cAMP levels similarly to rolipram, selective PDE4 inhibitor, in both animals. LASSBio-1847 showed to be promising to relax guinea pig trachea from non-sensitized and sensitized guinea pigs by activation of β 2 -adrenergic receptors/AC/cAMP pathway., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Ethnopharmacological Relevance: Zataria multiflora is employed as an antitussive, anti-spasmodic, analgesic and etc. Agent in traditional medicine. The modern medical studies are also confirmed effects of this plant for treatment of respiratory problems via anti-inflammatory, anti-oxidant and immunomodulatory properties., Aim of Study: We evaluated efficacy of Z. multiflora on tests of pulmonary function, respiratory symptoms, inhaled bronchodilator drugs use, and hematological factors in COPD patients., Methods: Patients (n = 45) were randomly grouped in the following three groups: placebo group (P), groups received Z. multiflora extract 3 and 6 mg/kg/day (Z3 and Z6). FEV 1 and MEF 25 - 75 , respiratory symptoms, inhaled bronchodilator drugs use and hematological factors were evaluated before and 1-2 months after treatment., Results: Z. multiflora led to significant enhancement of FEV 1 (p < 0.05 to p < 0.01). Respiratory symptoms were also considerably ameliorated following treatment with extracts for 1 and 2 months compared to baseline values (p < 0.05 to p < 0.001). In groups received extract, inhaled bronchodilator drugs use was remarkably declined at the end of study (both, p < 0.05). Reduction of total WBC was observed 1-2 months after treatment in treated groups with extract compared to baseline values (p < 0.05 to p < 0.001). Neutrophils were remarkably declined in Z3 and Z6 groups after 2-monthes compared to 1-month treatment (p < 0.05 to p < 0.01)., Conclusion: The evidence show therapeutic effect of this herb on COPD patients which could be result from properties that help to decrease inflammation., 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 © 2024 Elsevier B.V. All rights reserved.)

Background: Salbutamol and hyoscine butylbromide (HBB) are commonly used bronchodilators in horses with severe asthma (SA)., Objective: To compare the bronchodilation potency, duration, and adverse effects of salbutamol and HBB in SA., Animals: Six horses in exacerbation of SA., Methods: The effects of inhaled salbutamol (1000 μg) and HBB (150 mg, IV) were compared in a randomized, blinded, crossover experiment. Lung function, intestinal borborygmi and heart rate were assessed before and sequentially until 180 minutes after drug administration, and analyzed with 2-way repeated-measures ANOVA and Dunnett's multiple comparison tests., Results: Both treatments caused a similar improvement in lung function. Pulmonary resistance and reactance returned to baseline values within 30 minutes after HBB administration, whereas salbutamol improved reactance until 180 minutes (mean improvement at 180 minutes of 0.040 Kpa/L/s, 95% CI = 0.004 to 0.076; P = .02 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.028 to 0.045; P = .98 for HBB for the resistance at 3 Hz and of 0.040 Kpa/L/s, 95% CI = 0.007 to 0.074; P = .01 for salbutamol and of 0.009 Kpa/L/s, 95% CI = -0.024 to 0.042; P = .97 for HBB for the reactance at 7 Hz). From 5 to 30 minutes after HBB administration, the heart rate accelerated (mean increase of 3.3 beats per minute, 95% CI = -6.6 to 13.1; P = .92 for salbutamol, and of 13.0 beats per minute, 95% CI = 3.6 to 22.4; P = .002 for HBB at 30 minutes) and the gut sounds decreased (mean reduction of 1.3, 95% CI = -0.1 to 2.8; P = .09 for salbutamol and of 2.8 for the gastrointestinal auscultation score, 95% CI = 1.4 to 4.3; P < .0001 for HBB at 30 minutes)., Conclusions and Clinical Importance: Both drugs have a similar bronchodilator potency but with a longer duration for salbutamol. Gastrointestinal and cardiovascular effects were noted only with HBB, suggesting the preferential use of salbutamol to relieve bronchoconstriction in horses with asthma., (© 2024 The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals LLC on behalf of American College of Veterinary Internal Medicine.)

Aim: To determine and compare the work of breathing to overcome elastic resistance (Ael) in patients with bronchial asthma (BA) and chronic obstructive pulmonary disease (COPD) with similar changes in the elastic properties of the parenchyma in the same settings of ventilation disorders (grade 1)., Materials and Methods: Differences in the manifestations of similar changes in the elastic properties of the lungs in patients with BA and COPD were evaluated. To identify differences, a comparative study was conducted on Аel overcome in BA patients with positive bronchodilator (with salbutamol) and bronchoconstrictor (with methacholine) tests, with reduced and preserved bronchial conductance (groups 1 and 2, respectively), and in COPD patients with negative bronchodilator and bronchoconstrictor tests (group 3). All study patients showed a grade 1 lung ventilation disorder (a decrease in the one-second forced expiratory volume by 15-35%). The results were compared with each other and with the control group (group 4, healthy non-smokers). All study patients were comparable by age and sex. The respiration mechanics was studied using simultaneous registration of spirogram and transpulmonary pressure, and the parameters of bronchial conductance and ventilation were determined using body plethysmopressography using the Jager software and hardware system., Results and Conclusion: In COPD patients, Ael was significantly increased ( p >0.05), whereas in both BA groups, it was unchanged. Increased elastic work of breathing in patients with COPD may be associated with the involvement of certain types of contractile elements, which are preserved in patients with BA at the initial stages of the disease.

Background: There is no uniform standard for a strongly positive bronchodilation test (BDT) result. In addition, the role of bronchodilator response in differentiating between asthma, chronic obstructive pulmonary disease (COPD), and asthma-COPD overlap (ACO) in patients with a positive BDT result is unclear. We explored a simplified standard of a strongly positive BDT result and whether bronchodilator response combined with fractional exhaled nitric oxide (FeNO) can differentiate between asthma, COPD, and ACO in patients with a positive BDT result., Methods: Three standards of a strongly positive BDT result, which were, respectively, defined as post-bronchodilator forced expiratory volume in 1-s responses (ΔFEV 1 ) increasing by at least 400 mL + 15% (standard I), 400 mL (standard II), or 15% (standard III), were analyzed in asthma, COPD, and ACO patients with a positive BDT result. Receiver operating characteristic curves were used to determine the optimal values of ΔFEV 1 and FeNO. Finally, the accuracy of prediction was verified by a validation study., Results: The rates of a strongly positive BDT result and the characteristics between standards I and II were consistent; however, those for standard III was different. ΔFEV 1  ≥ 345 mL could predict ACO diagnosis in COPD patients with a positive BDT result (area under the curve [AUC]: 0.881; 95% confidence interval [CI] 0.83-0.94), with a sensitivity and specificity of 90.0% and 91.2%, respectively, in the validation study. When ΔFEV 1 was < 315 mL combined with FeNO < 28.5 parts per billion, patients with a positive BDT result were more likely to have pure COPD (AUC: 0.774; 95% CI 0.72-0.83)., Conclusion: The simplified standard II can replace standard I. ΔFEV 1 and FeNO are helpful in differentiating between asthma, COPD, and ACO in patients with a positive BDT result., (© 2024. The Author(s).)

Background: A positive bronchodilator response has been defined as a 12% increase in the forced expiratory volume in one second (FEV 1 ) or forced vital capacity (FVC) from their respective pre-bronchodilator values, combined with at least a 0.2 L absolute change. Recent recommendations suggested the use of the percent change in FEV 1 and FVC relative to their predicted normal values without having applied them in patients with airflow obstruction. The aim of the current study was to compare the two approaches over a wide range of pre-bronchodilator FEV 1 and FVC values., Methods: A retrospective review of consecutive patients undergoing spirometry and bronchodilator testing was completed. The change in FEV 1 and FVC with a bronchodilator was expressed relative to the pre-bronchodilator and predicted normal FEV 1 and FVC., Results: In 1,040 patients with a non-paradoxical change in FEV 1 , 19.0% had a ≥ 12% change in FEV 1 using their pre-bronchodilator value compared to 5.7% using their predicted normal value. For FVC, the respective values were 12.7% vs. 5.8%. The difference was retained in patients with a ≥ 0.2 L change in FEV 1 or FVC. In unobstructed patients, the upper threshold (two standard deviations above the mean) of the bronchodilator response was 14% for FEV 1 and 10% for FVC using predicted normal values., Conclusions: Expressing the percent change in FEV 1 and FVC relative to predicted normal values reduces the over-estimation of the bronchodilator response, especially in patients with a very low pre-bronchodilator FEV1, including in those with a ≥ 0.2 L change in FEV 1 . Irrespective of pre-bronchodilator values, a ≥ 14% change in FEV 1 and ≥ 10% change in FVC relative to the predicted normal values could be considered a positive bronchodilator response., (© 2024. The Author(s).)

Purpose: The primary objective of this study was to optimize formulation variables and investigate the in vitro characteristics of fluticasone propionate (FP)-loaded mixed polymeric micelles, which were composed of depolymerized chitosan-stearic acid copolymer (DC-SA) in combination with either tocopheryl polyethylene glycol succinate or dipalmitoylphosphatidylcholine for pulmonary drug delivery., Methods: A D-optimal design was employed for the optimization procedure, considering lipid/ polymer ratio, polymer concentration, drug/ polymer ratio, and lipid type as independent variables. Dependent variables included particle size, polydispersion index, zeta potential, drug encapsulation efficiency, and loading efficiency of the polymeric micelles. Additionally, the nebulization efficacy and cell viability of the optimal FP-loaded DC-SA micellar formulations were evaluated., Results: The mixed polymeric micelles were successfully prepared with properties falling within the desired ranges, resulting in four optimized formulations. The release of FP from the optimal systems exhibited a sustained release profile over 72 hours, with 70% of the drug still retained within the core of the micelles. The nebulization efficiency of these optimal formulations reached up to 63%, and the fine particle fraction (FPF) ranged from 41% to 48%. Cellular viability assays demonstrated that FP-loaded DC-SA polymeric micelles exhibited lower cytotoxicity than the free drug but were slightly more cytotoxic than empty mixed micelles., Conclusion: In conclusion, this study suggests that DC-SA/ lipid mixed micelles have the potential to serve as effective carriers for nebulizing poorly soluble FP., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Asthma has been recognised as a respiratory disorder for millennia and the focus of targeted drug development for the last 120 years. Asthma is one of the most common chronic non-communicable diseases worldwide. Chronic obstructive pulmonary disease (COPD), a leading cause of morbidity and mortality worldwide, is caused by exposure to tobacco smoke and other noxious particles and exerts a substantial economic and social burden. This chapter reviews the development of the treatments of asthma and COPD particularly focussing on the β-agonists, from the isolation of adrenaline, through the development of generations of short- and long-acting β-agonists. It reviews asthma death epidemics, considers the intrinsic efficacy of clinical compounds, and charts the improvement in selectivity and duration of action that has led to our current medications. Important β2-agonist compounds no longer used are considered, including some with additional properties, and how the different pharmacological properties of current β2-agonists underpin their different places in treatment guidelines. Finally, it concludes with a look forward to future developments that could improve the β-agonists still further, including extending their availability to areas of the world with less readily accessible healthcare., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Objective: To evaluate the bronchodilatory mechanism of Astragalus sarcocolla (ASE) extract on tracheal smooth muscles of rabbits., Study Design: In-vitro experimental study. Place and Duration of the Study: The animal house of CMH Lahore Medical College, Lahore, and Institute of Dentistry, NUMS, from October 2022 to May 2023., Methodology: Six rabbits were randomly divided into four groups. After euthanising the rabbit, the trachea was carefully dissected out and stabilised in Kreb's Henseleit solution for 30 minutes and then, stimulated by acetylcholine (Ach) 1µm, under mimicked physiological conditions. Group I served as the control group with tracheal smooth muscles stabilised with 1g tension. In Group II (positive control), tracheal smooth muscles were stimulated by potassium chloride (KCl) (80 mM and 25 mM, respectively) to get maximum tracheal smooth muscle contractions. Later, the tissue was exposed to theophylline with three molar concentrations 0.2, 0.4, 0.6, and 0.8 mM, and cumulative dose response curves were formed. In Group III (ASE group), tracheal smooth muscles were stimulated by KCl (80 mM and 25 mM) and was exposed to increasing concentration of ASE. In group IV, tissue was stimulated by KCl (25 mM) and glibenclamide (3 µM), later exposed to increasing concentration of ASE to confirm the bronchodilatory mechanism. The change in isometric contraction of the tissue was recorded using the force displacement transducer connected to a PowerLab data acquisition system. Concentration response curves were drawn, and median effective concentrations (EC50 values) and percentage inhibition were calculated. Non-linear regression was applied for the analysis of the concentration-response curves., Results: ASE inhibited the KCl-induced low potassium (25 mM) contractions (EC50 = 0.38 mg/ml, 95% CI: 0.04 - 0.38, n = 6). It only partially inhibited the high potassium-induced contractions in tracheal smooth muscles. Pretreatment with glibenclamide showed a rightward shift of the dose-response curve. Theophylline and ASE significantly reduced the low K+ induced smooth muscle contractions in comparison to the control group (p <0.001, each)., Conclusion: Astragalus sarcocolla extract produced bronchodilator effects through the activation of ATP sensitive potassium channels in isolated rabbit trachea., Key Words: Astragalus sarcocolla, Bronchodilators, ATP-sensitive potassium channels, Effective concentration 50, Concentration response curves.

Ethnopharmacological Relevance: Rosa webbiana (Family: Rosaceae) is used by South Asian herbalists to treat gastrointestinal and respiratory disorders., Aim of the Study: This research aimed at multiple targets to verify R. webbiana for treating diarrhea and asthma. In vitro, in vivo, and in silico experiments were planned to demonstrate the antispasmodic and bronchodilator potential of R. webbiana., Materials and Methods: The bioactive compounds of R. webbiana were identified and quantified through LC ESI-MS/MS and HPLC. These compounds were predicted for muti-mechanisms of bronchodilator and antispasmodic potential in network pharmacology and molecular docking. In vitro methods (isolated rabbit trachea, bladder, and jejunum tissues) confirmed these multi-mechanisms for antispasmodic and bronchodilator effects. Antiperistalsis, antidiarrheal, and antisecretory experiments were conducted in in-vivo experiments., Results: The phytochemical analysis indicates the presence of rutin (742.91 μg/g), kaempferol (726.32 μg/g), and quercitrin (688.20 μg/g) in Rw. EtOH. These bioactive compounds in network pharmacology interfere with the pathogenic genes of diarrhea and asthma, which are the members of calcium-mediated signaling pathways and showed the stronger binding affinity towards voltage-gated L-type calcium channels, myosin light chain-kinase, Calcium calmodulin-dependent-kinase, Phosphodiesterase-4, and phosphoinositide phospholipase-C in molecular docking. Rw. EtOH elicited a spasmolytic response in isolated jejunum, trachea, and urine preparations by relaxing K + (80 mM) and CCh (1 μM) spastic contractions. Additionally, it suppressed calcium concentration-response curves to the right, like verapamil. Like dicyclomine, it caused a rightward parallel shift of the CCh curves, followed by a non-parallel shift at higher concentrations with suppression of the maximal response. Like papaverine, it also caused isoprenaline-induced inhibitory CRCs to shift to the left. Verapamil did not potentiate isoprenaline-induced inhibitory CRCs, although it was more efficacious against K + (80 mM) than CCh (1 μM)-induced contractions. R. webbiana EtOH extract exhibited complete antiperistalsis (21.55%), antidiarrheal (80.33%), and antisecretory (82.59±0.60) activities in vivo experiments at the dose of 300 mg/kg., Conclusion: Thus, Rw. EtOH modulated multiple pathways, produced calcium antagonistic, anticholinergic, and phosphodiesterase inhibitory actions, and had antidiarrheal and bronchodilator effects., 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 © 2023 Elsevier B.V. All rights reserved.)

Background: The impact of the new 2021 European Respiratory Society (ERS)/American Thoracic Society (ATS) pulmonary function test interpretation guidelines on the interpretation of bronchodilator responsiveness (BDR) in subjects with airway obstruction is still required. Therefore, the objective of this study was to explore the agreement between the 2005 and 2021 ERS/ATS criteria regarding the interpretation of the BDR. Moreover, we explore the factors that influenced the discordance of positive bronchodilator responsiveness (BDR+) between these two criteria., Methods: The agreement regarding the interpretation of BDR + between the two criteria was assessed using kappa (κ). The percentage of agreement in the interpretation of BDR + between the two criteria was calculated. The factors that influenced the discordance of BDR + between these two criteria were also analyzed., Results: A total of 500 subjects with a mean age of 60.5 ± 15.6 years, 62.2% male were included. The study observed a good level of agreement in the interpretation of BDR + between the two criteria with kappa values = 0.782. The percentages of agreement on the interpretation of BDR + between the two criteria were high, with values = 90.6%. Male sex was the only factor that influenced the discordance of BDR + between these two criteria., Conclusion: A good level of agreement was observed in the interpretation of BDR + between the 2005 and 2021 criteria. Therefore, the 2005 and 2021 ERS/ATS criteria for BDR can be used interchangeably. However, the discordance of BDR + between these two criteria could be affected by sex., 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 © 2023 Elsevier Ltd. All rights reserved.)

Asthma is a respiratory disease caused by the interaction of genetic and environmental factors. The adenylyl cyclase type 9 (ADCY9) enzyme produces the cyclic-adenosinemonophosphate (cAMP), important mediator involved in bronchodilation and immunomodulatory response. The aim of this study was to investigate if rs2601796 and rs2532019 variants in the ADCY9 gene are associated with asthma and lung function. The study comprised 1,052 subjects. Logistic regressions were done using PLINK 1.9 adjusted by sex, age, BMI, smoke and principal components. Bronchodilator responsiveness was assessed using the percentage of difference in FEV1 before and after the bronchodilator use. The in silico analysis for gene expression was performed in the GTEx Portal. The variant rs2601796 (AA/AG genotype) was positively associated with asthma severity (OR: 1.60 IC95%: 1.08-2.39) and with obstruction in individuals with severe asthma (OR: 3.10, IC95%: 1.11-8.62). Individuals with severe asthma and the AA/AG genotype of rs2601796 had less responsiveness to bronchodilators and also a lower expression of ADCY9 in lung and whole blood. The variant rs2532019 (TT/GT genotype) also downregulated the ADCY9 gene expression, but no significant association with the studied phenotypes was found. Thus, the variant in ADCY9 was associated with worse asthma outcomes, including a lower response to bronchodilators, likely due to the impact on its gene expression rate. This variant may be useful in the future to assist in personalized management of patients with asthma., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Álvaro A. Cruz: Reports grants from: i. CNPq (Brazil) - National Research Council; ii. FAPESB - State agency for research in Bahia; iii. GSK, during the conduct of the study (Investigator initiated grant). Reports personal fees from: i. SANOFI (Advisor, lecturer and conduction of clinical trial); ii. AstraZeneca (Advisor, lecturer and conduction of clinical trial); iii. GSK (Advisor); iv. Boehringer-Ingelheim (Advisor, lecturer and developer of educational materials); v. Novartis (Lecturer and developer of educational materials); vi. Mantecorp (Advisor, lecturer and developer of educational materials); vii. EUROFARMA (Lecturer and developer of educational materials); viii. Mylan (Advisor, lecturer and developer of educational materials). The other authors declare that have no relevant conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Introduction: Mechanisms underlying lung dysfunction after preterm birth are poorly understood. Studying phenotypes of prematurity-associated lung disease may aid understanding of underlying mechanisms. Preterm-born children with and without lung dysfunction and term controls were assessed using oscillometry before and after exercise, and after postexercise bronchodilation., Methods: Preterm-born children, born at gestation of 34 weeks or less, were classified into those with prematurity-associated obstructive lung disease (POLD; FEV 1  < LLN, FEV 1 /FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm; FEV 1  < LLN, FEV 1 /FVC ≥ LLN) and compared to preterm (FEV 1  ≥ LLN) and term controls (%predicted FEV 1  > 90%). All children underwent cardiopulmonary exercise, and oscillometry assessment at baseline, postexercise, and after postexercise bronchodilator administration., Results: From 241 participants aged 7-12 years, complete data were available from 179: 15 children with POLD and 11 with pPRISm were compared with 93 preterm and 60 term controls. POLD group, when compared to both control groups, had impaired impedance, greater resistance, more negative (greater magnitude) reactance at low frequencies, and also had decreased compliance. pPRISm group demonstrated impaired reactance and compliance compared to term controls. No differences were noted between the preterm and term controls. Exercise had little impact on oscillometry values, but children with POLD had greatest improvements after postexercise bronchodilator administration, with decreased resistance and decreased magnitude of reactance, particularly at low frequencies., Conclusion: Preterm-born children with obstructive airway disease had the greatest oscillometry impairments and the largest improvements after postexercise bronchodilator compared to control groups. Oscillometry can potentially be used to identify preterm-born children with lung disease to institute treatment., (© 2023 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Introduction: The standard therapy for bronchial asthma consists of combinations of acute (short-acting ß 2 -sympathomimetics) and, depending on the severity of disease, additional long-term treatment (including inhaled glucocorticoids, long-acting ß 2 -sympathomimetics, anticholinergics, anti-IL-4R antibodies). The antidepressant amitriptyline has been identified as a relevant down-regulator of immunological T H 2-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 (ß 2 -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 T H 2-allergic phenotype and on acute airway hyperresponsiveness with bronchoconstriction, especially when inhaled., (© 2023. The Author(s).)

Background: Albuterol is the first-line asthma medication used in diverse populations. Although DNA methylation (DNAm) is an epigenetic mechanism involved in asthma and bronchodilator drug response (BDR), no study has assessed whether albuterol could induce changes in the airway epithelial methylome. We aimed to characterize albuterol-induced DNAm changes in airway epithelial cells, and assess potential functional consequences and the influence of genetic variation and asthma-related clinical variables., Results: We followed a discovery and validation study design to characterize albuterol-induced DNAm changes in paired airway epithelial cultures stimulated in vitro with albuterol. In the discovery phase, an epigenome-wide association study using paired nasal epithelial cultures from Puerto Rican children (n = 97) identified 22 CpGs genome-wide associated with repeated-use albuterol treatment (p < 9 × 10 -8 ). Albuterol predominantly induced a hypomethylation effect on CpGs captured by the EPIC array across the genome (probability of hypomethylation: 76%, p value = 3.3 × 10 -5 ). DNAm changes on the CpGs cg23032799 (CREB3L1), cg00483640 (MYLK4-LINC01600), and cg05673431 (KSR1) were validated in nasal epithelia from 10 independent donors (false discovery rate [FDR] < 0.05). The effect on the CpG cg23032799 (CREB3L1) was cross-tissue validated in bronchial epithelial cells at nominal level (p = 0.030). DNAm changes in these three CpGs were shown to be influenced by three independent genetic variants (FDR < 0.05). In silico analyses showed these polymorphisms regulated gene expression of nearby genes in lungs and/or fibroblasts including KSR1 and LINC01600 (6.30 × 10 -14  ≤ p ≤ 6.60 × 10 -5 ). Additionally, hypomethylation at the CpGs cg10290200 (FLNC) and cg05673431 (KSR1) was associated with increased gene expression of the genes where they are located (FDR < 0.05). Furthermore, while the epigenetic effect of albuterol was independent of the asthma status, severity, and use of medication, BDR was nominally associated with the effect on the CpG cg23032799 (CREB3L1) (p = 0.004). Gene-set enrichment analyses revealed that epigenomic modifications of albuterol could participate in asthma-relevant processes (e.g., IL-2, TNF-α, and NF-κB signaling pathways). Finally, nine differentially methylated regions were associated with albuterol treatment, including CREB3L1, MYLK4, and KSR1 (adjusted p value < 0.05)., Conclusions: This study revealed evidence of epigenetic modifications induced by albuterol in the mucociliary airway epithelium. The epigenomic response induced by albuterol might have potential clinical implications by affecting biological pathways relevant to asthma., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Introduction: Bronchial thermoplasty is an effective intervention to improve respiratory symptoms and to reduce the rate of exacerbations in uncontrolled severe asthma. A reduction in airway smooth muscle is arguably the most widely discussed mechanisms accounting for these clinical benefits. Yet, this smooth muscle reduction should also translate into an impaired response to bronchodilator drugs. This study was designed to address this question., Methods: Eight patients with clinical indication for thermoplasty were studied. They were uncontrolled severe asthmatics despite optimal environmental control, treatment of comorbidities, and the use of high-dose inhaled corticosteroids and long-acting β 2 -agonists. Lung function measured by spirometry and respiratory mechanics measured by oscillometry were examined pre- and post-bronchodilator (salbutamol, 400 μg), both before and at least 1 year after thermoplasty., Results: Consistent with previous studies, thermoplasty yielded no benefits in terms of baseline lung function and respiratory mechanics, despite improving symptoms based on two asthma questionnaires (ACQ-5 and ACT-5). The response to salbutamol was also not affected by thermoplasty based on spirometric readouts, including forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), and FEV 1 /FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (X rs5 ) and reactance area (Ax), showing an attenuated response to salbutamol after thermoplasty., Conclusions: Thermoplasty attenuates the response to a bronchodilator. We argue that this result is a physiological proof of therapeutic efficacy, consistent with the well-described effect of thermoplasty in reducing the amount of airway smooth muscle., Competing Interests: Declaration of competing interest YB's laboratory received funds from Boston Scientific Inc (25800$) to conduct this project. AC is funded partially by GlaxoSmithKline, and has received consulting fees and honoraria for lectures from AstraZeneca, Sanofi, GlaxoSmithKline, Regeneron and Valeo pharma. CH, SB, MB, KG, JC and ML declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

β 2- adrenoceptors agonists and phosphodiesterase (PDE) inhibitors are effective bronchodilators, due to their ability to increase intracellular cyclic AMP (cAMP) levels and induce airway smooth muscle (ASM) relaxation. We have shown that increment of intracellular cAMP induced by β 2 -adrenoceptors agonist fenoterol is followed by efflux of cAMP, which is converted by ecto-PDE and ecto-5'-nucleotidases (ecto-5'NT) to adenosine, leading to ASM contraction. Here we evaluate whether other classical bronchodilators used to treat asthma and chronic obstructive pulmonary disease (COPD) could induce cAMP efflux and, as consequence, influence the ASM contractility. Our results showed that β 2 -adrenoceptor agonists formoterol and PDE inhibitors IBMX, aminophylline and roflumilast induced cAMP efflux and a concentration-dependent relaxation of rat trachea precontracted with carbachol. Pretreatment of tracheas with MK-571 (MRP transporter inhibitor), AMP-CP (ecto-5'NT inhibitor) or CGS-15943 (nonselective adenosine receptor antagonist) potentiated the relaxation induced by β 2 -adrenoceptor agonists but did not change the relaxation induced by PDE inhibitors. These data showed that all bronchodilators tested were able to induce cAMP efflux. However, only β 2 -adrenoceptor-induced relaxation of tracheal smooth muscle was affected by cAMP efflux and extracellular cAMP-adenosine pathway., 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 © 2023 Elsevier B.V. All rights reserved.)

Aiming at the inhaled treatment of pulmonary diseases, the optimization process of the previously reported MAPI compound 92a is herein described. The project was focused on overcoming the chemical stability issue and achieving a balanced bronchodilator/anti-inflammatory profile in rats in order to be confident in a clinical effect without having to overdose at one of the biological targets. The chemical strategy was based on fine-tuning of the substitution pattern in the muscarinic and PDE4 structural portions of the dual pharmacology compounds, also making use of the analysis of a proprietary crystal structure in the PDE4 catalytic site. Compound 10f was identified as a chemically stable, potent, and in vivo balanced MAPI lead compound, as assessed in bronchoconstriction and inflammation assays in rats after intratracheal administration. After the in-depth investigation of the pharmacological and solid-state profile, 10f proved to be safe and suitable for development.

Patient symptom relief is often heavily influenced by the residence time of the inhibitor-target complex. For the human muscarinic receptor 3 (hMR3), tiotropium is a long-acting bronchodilator used in conditions such as asthma or chronic obstructive pulmonary disease (COPD). The mechanistic insights into this inhibitor remain unclear; specifically, the elucidation of the main factors determining the unbinding rates could help develop the next generation of antimuscarinic agents. Using our novel unbinding algorithm, we were able to investigate ligand dissociation from hMR3. The unbinding paths of tiotropium and two of its analogues, N -methylscopolamin and homatropine methylbromide, show a consistent qualitative mechanism and allow us to identify the structural bottleneck of the process. Furthermore, our machine learning-based analysis identified key roles of the ECL2/TM5 junction involved in the transition state. Additionally, our results point to relevant changes at the intracellular end of the TM6 helix leading to the ICL3 kinase domain, highlighting the closest residue L482. This residue is located right between two main protein binding sites involved in signal transduction for hMR3's activation and regulation. We also highlight key pharmacophores of tiotropium that play determining roles in the unbinding kinetics and could aid toward drug design and lead optimization.

Asthma is a heterogeneous chronic airway disease with an unmet need for improved therapeutics in uncontrolled severe disease. The calcium-sensing receptor (CaSR) is a G protein-coupled receptor upregulated in asthma. The CaSR agonist, spermine, is also increased in asthmatic airways and contributes to bronchoconstriction. CaSR negative allosteric modulators (NAMs) oppose chronic airway inflammation, remodeling, and hyperresponsiveness in murine and guinea pig asthma models, but whether CaSR NAMs are effective acute bronchodilators compared with standard of care has not yet been established. Furthermore, the ability of different classes of NAMs to inhibit spermine-induced CaSR signaling or methacholine (MCh)-induced airway contraction has not been quantified. Here, we show CaSR NAMs differentially inhibit spermine-induced intracellular calcium mobilization and inositol monophosphate accumulation in HEK293 cells stably expressing the CaSR. NAMs reverse MCh-mediated airway contraction in mouse precision-cut lung slices with similar maximal relaxation compared with the standard treatment, salbutamol. Of note, the bronchodilator effects of CaSR NAMs are maintained under conditions of β 2 -adrenergic receptor desensitization when salbutamol efficacy is abolished. Furthermore, overnight treatment with some, but not all, CaSR NAMs prevents MCh-mediated bronchoconstriction. These findings further support the CaSR as a putative drug target and NAMs as alternative or adjunct bronchodilators in asthma.

The journey of using anticholinergics in the treatment of asthma started with anticholinergic-containing plants such as Datura stramonium and Atropa belladonna, followed by ipratropium bromide and continued with tiotropium, glycopyrronium, and umeclidinium. Although antimuscarinics were used in the maintenance treatment of asthma over a century ago, after a long time (since 2014), it has been recommended to be used as an add-on long-acting antimuscarinic agent (LAMA) therapy in the maintenance treatment of asthma. The airway tone controlled by the vagus nerve is increased in asthma. Allergens, toxins, or viruses cause airway inflammation and inflammation-related epithelial damage, increased sensory nerve stimulation, ganglionic and postganglionic acetylcholine (ACh) release by inflammatory mediators, intensification of ACh signaling at M1 and M3 muscarinic ACh receptors (mAChRs), and dysfunction of M2 mAChR. Optimal anticholinergic drug for asthma should effectively block M3 and M1 receptors, but have minimal effect on M2 receptors. Tiotropium, umeclidinium, and glycopyrronium are anticholinergic agents with this feature. Tiotropium has been used in a separate inhaler as an add-on treatment to inhaled corticosteroid (ICS)/long-acting β2-agonist (LABA), and glycopyrronium and umeclidinium have been used in a single inhaler as a combination of ICS/LABA/LAMA in asthma in recent years. Guidelines recommend this regimen as an optimization step for patients with severe asthma before initiating any biologic or systemic corticosteroid therapy. In this review, the history of antimuscarinic agents, their effectiveness and safety in line with randomized controlled trials, and real-life studies in asthma treatment will be discussed according to the current data.

The new high selective mAChRs M3 inhibitors with IC 50 in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC 50 values of 1.62 ⋅ 10 -7  M and 3.09 ⋅ 10 -9  M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors., (© 2023 Wiley-VCH GmbH.)

Novel gamma-aminobutyric acid receptor (GABA A R) ligands structurally related to imidazobenzodiazepine MIDD0301 were synthesized using spiro-amino acid N-carboxyanhydrides (NCAs). These compounds demonstrated increased resistance to phase 2 metabolism and avoided the formation of a 6H isomer. Compound design was guided by molecular docking using the available crystal structure of the α 1 β 3 γ 2 GABA A R and correlated with in vitro binding data. The carboxylic acid containing GABA A R ligands have high aqueous solubility, low permeability, and low cell toxicity. The inability of GABA A R ligands to cross the blood-brain barrier was confirmed in vivo by the absence of sensorimotor inhibition. Pharmacological activities at lung GABA A Rs were demonstrated by ex vivo relaxation of guinea pig airway smooth muscle and reduction of methacholine-induced airway hyperresponsiveness (AHR) in conscious mice. We identified bronchodilator 5c with an affinity of 9 nM for GABA A Rs that was metabolically stable in the presence of human and mouse microsomes.

Nitric oxide (NO) is an important product of eosinophilic metabolism, and its increase is associated with bronchial remodeling and airway hyperresponsiveness. Fractional exhaled NO (FENO) in the expired air of patients with suspected or diagnosed asthma has been used as a marker for eosinophilic inflammation. This cohort study included asthmatic patients classified under steps 3, 4, or 5 of the global strategy for asthma management and prevention. In the morning of the same day, all patients underwent blood collection for eosinophil counts, followed by FENO measurement and spirometry. We considered 2 groups based on the bronchodilation (BD) response on spirometry (>10% of FVC or FEV1): positive (BD+) and negative (BD-). Differences between the 2 groups were analyzed for demographic features, FENO values, and predictive correlations between FENO and BD. Both groups of patients showed an increase in the eosinophil count (BD+, P = .03; BD-, P = .04) and FENO values (P = .015 for both) with an increase in the asthma severity from step 3 to step 5 of the global strategy for asthma management and prevention. The correlations of FENO and eosinophils as well as FENO values and BD + were 0.127 (95% confidence interval,-0.269 to -0.486) and 0.696 (95% confidence interval, 0.246-0.899; P = .007), respectively. Measuring FENO levels may be useful for identifying patients with BD+., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

To compare lung function in wheezing and non-wheezing infants with pneumonia through tidal breathing analysis and explore the correlation between tidal breathing lung function and clinical characteristics. This retrospective observational study included infants with pneumonia hospitalized in the Affiliated Hospital of Guizhou Medical University between January 2018 and December 2018. Medical records were used to obtain the demographic characteristics, clinical characteristics, tidal breathing lung function results before and after a bronchodilator test, and positive remission rates after the bronchodilator test for each patient. Eighty-six wheezing infants (64 males, aged 6.5 [4.8, 9] months) and 27 non-wheezing infants (18 males, aged 7 [5, 12] months) were included. Non-wheezing infants were more likely to have normal airway function compared to wheezing infants (44.4% vs 23.3%, P = .033). Peak tidal expiration flow/tidal expiratory flow (TEF)25 in wheezing infants was significantly higher than that in non-wheezing infants (162.4 [141.2, 200.7] vs 143.3 [131, 178.8], P = .037). The positive remission rate of tidal inspiratory flow (TIF50)/TEF50 (53.5% vs 29.6%, P = .03) and TEF50 (58.1% vs 33.3%, P = .024) were significantly higher in the wheezing infants compared to non-wheezing infants (P = .03 and P = .024, respectively). Furthermore, respiratory rate, tidal volume, peak expiration flow, TEF25, TEF50, and TEF75 were significantly correlated to the age, height, weight, and platelet counts of infants in both the wheezing and non-wheezing infants (all P < .05). Wheezing infants with pneumonia were more likely to have worse tidal breathing lung function compared to non-wheezing infants with pneumonia. The tidal breathing lung function parameter (respiratory rate, tidal volume, peak expiration flow, TEF25, TEF50, and TEF75) were correlated to the age, height, weight, and platelet counts of both wheezing and non-wheezing infants., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Ethnopharmacological Relevance: Berberis lycium Royle, a member of the Berberidaceae family, is a high-value medicinal plant with a documented history of usage in traditional medicine and has demonstrated significant therapeutic results among local populations throughout the globe. It is used traditionally in many parts of Pakistan to treat diarrhea, abdominal spasms, coughs, and chest problems., Aim of the Study: To investigate the antispasmodic, bronchodilator, and antidiarrheal effects of B. lycium and its possible underlying mechanisms through in silico, in vitro, and in vivo studies., Materials and Methods: LC ESI-MS/MS analysis was used to identify bioactive components within the hydromethanolic extract of B. lycium. In silico studies, including network pharmacology and molecular docking, were utilized to investigate the antispasmodic and bronchodilator properties of the extract's bioactive components. In vitro pharmacological studies were conducted using isolated rabbit jejunum, trachea, urinary bladder, and rat ileum preparations. In vivo antidiarrheal activities were conducted in mice, including castor oil-induced diarrhea, intestinal transit, and castor oil-induced enteropooling., Results: The LC ESI-MS/MS analysis of the hydromethanolic extract of B. lycium identified 38 bioactive compounds. Network pharmacology study demonstrated that the mechanism of BLR for the treatment of diarrhea might involve IL1B, TLR4, PIK3R1, TNF, PTPRC, IL2, PIK3CD, and ABCB1, whereas, for respiratory ailments, it may involve PIK3CG, TRPV1, STAT3, ICAM1, ACE, PTGER2, PTGS2, TNF, MMP9, NOS2, IL2, CCR5, HRH1, and VDR. Molecular docking research revealed that chlorogenic acid, epigallocatechin, isorhamnetin, quinic acid, gallic acid, camptothecin, formononetin-7-O-glucoside, velutin, caffeic acid, and (S)-luteanine exhibited a higher docking score than dicyclomine with validated proteins of smooth muscle contractions such as CACB2&#95;HUMAN, ACM3&#95;HUMAN, MYLK&#95;HUMAN, and PLCG1&#95;HUMAN. In vitro investigations demonstrated that Blr.Cr, Blr.EtOAc, and Blr.Aq relaxed spontaneously contracting jejunum preparations; carbachol (1 μM)-induced and K + (80 mM)-induced jejunum, trachea, and urinary bladder contractions in a concentration-dependent manner, similar to dicyclomine. Moreover, Blr.Cr, Blr.EtOAc, and Blr.Aq exhibited a rightward shift in Ca +2 and carbachol cumulative response curves, similar to dicyclomine, demonstrating the coexistence of antimuscarinic and Ca +2 antagonistic mechanisms due to the presence of alkaloids and flavonoids. In vivo antidiarrheal activities showed that the hydromethanolic extract was significantly effective against castor oil-induced diarrhea and castor oil-induced enteropooling, similar to loperamide, and charcoal meal intestinal transit, similar to atropine, in mice at doses of 50, 100, and 200 mg/kg body weight, which supports its traditional use in diarrhea., Conclusion: The dual blocking mechanism of muscarinic receptors and Ca +2 channels behind the smooth muscle relaxing activity reveals the therapeutic relevance of B. lycium in diarrhea, abdominal spasms, coughs, and chest problems., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Objective: Some of the most common causes of chronic cough include cough variant asthma (CVA), bronchial asthma (BA), and asthma-COPD overlap (ACO). Although there is some overlap in the etiology of these diseases, it is clinically important to attempt an early differential diagnosis due to treatment strategies and prognoses. Methods: Spirometry and impulse oscillometry (IOS) before and after bronchodilator inhalation were analyzed for clinically diagnosed CVA (cCVA, n  = 203), BA (cBA, n  = 222), and ACO (cACO, n  = 61). Results: A significant difference in ΔFEV 1 was observed between cBA and cCVA (ΔFEV 1 improvement of 122.5 mL/5.4% and 65.7 mL/2.2%, respectively), but no difference was observed in ΔPEF, ΔV50, or ΔV25. Except for R20 (resistance at 20 Hz), significant differences between the three groups were observed in IOS. In IOS, cCVA and cBA showed comparable peripheral airway response to bronchodilator which was thought to be commensurate with changes in V50 and V25. cACO improved ΔFEV 1 improvement of 81.0 mL/6.2% and was distinguished by a downward respiratory system reactance (Xrs) waveform with a limited bronchodilator response. FEV 1 /FVC, %FEV 1 , and %V25 had relatively strong correlations with the three IOS parameters, X5 (reactance at 5 Hz), resonant frequency (Fres), and low-frequency reactance area (ALX), in the correlation between IOS and spirometers. Conclusion: Changes in IOS parameters were more sensitive in this study than changes in FEV 1 or the flow-volume curve. Considering the benefits and relevance of the two different tests, simultaneous IOS and spirometry testing were useful in the diagnosis of asthmatic cough.

Rationale : COPD diagnosis requires relevant symptoms and an FEV1/FVC ratio of <0.7 post-bronchodilator on spirometry. Patients are frequently labeled as COPD based on clinical presentation and admitted to the hospital with this diagnosis even though spirometry is either not available or has never been performed. The aim of this study was to evaluate the accuracy of COPD diagnosis based on post-bronchodilator spirometry, following hospital admission for COPD exacerbation. Methods : This is a retrospective study with a cross-sectional analysis of a subgroup of patients. Demographic and clinical data and pre-admission spirometry were collected from electronic records of patients hospitalized with a primary diagnosis of COPD. Patients without available spirometry were contacted for a pulmonary consultation and spirometry. Three groups were compared: patients with a confirmed COPD diagnosis (FEV1/FVC < 0.7), without COPD (FEV1/FVC > 0.7), and those who have never performed spirometry. Results : A total of 1138 patients with a recorded diagnosis of COPD were identified of which 233 patients were included in the analysis. Only 44.6% of patients had confirmed COPD according to GOLD criteria. In total, 32.6% of the patients had never undergone spirometry but were treated as COPD, and 22.7% had performed spirometry without evidence of COPD. Recurrent admission due to COPD was a strong predictor of a confirmed COPD diagnosis. Conclusions : Among the patients admitted to the hospital with a COPD diagnosis, a high proportion were not confirmed by the current GOLD report or had never performed spirometry. Stricter implementation of the diagnostic criteria of COPD in admitted patients is necessary to improve diagnosis and the treatment outcomes in these patients.

Chronic obstructive pulmonary disease (COPD) is a common respiratory disease with high disability and mortality. Clinical studies have shown that the Traditional Chinese Medicine Bufei Granule (BFG) has conspicuous effects on relieving cough and improving lung function in patients with COPD and has a reliable effect on the treatment of COPD, whereas the therapeutic mechanism is vague. In the present study, the latent bronchodilators and mechanism of BFG in the treatment of COPD were discussed through the method of network pharmacology. Then, the molecular docking and molecular dynamics simulation were performed to calculate the binding efficacy of corresponding compounds in BFG to muscarinic receptor. Finally, the effects of BFG on bronchial smooth muscle were validated by in vitro experiments. The network pharmacology results manifested the anti-COPD effect of BFG was mainly realized via restraining airway smooth muscle contraction, activating cAMP pathways and relieving oxidative stress. The results of molecular docking and molecular dynamics simulation showed alpinetin could bind to cholinergic receptor muscarinic 3. The in vitro experiment verified both BFG and alpinetin could inhibit the levels of CHRM3 and acetylcholine and could be potential bronchodilators for treating COPD. This study provides an integrating network pharmacology method for understanding the therapeutic mechanisms of traditional Chinese medicine, as well as a new strategy for developing natural medicines for treating COPD., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Bronchodilators and anti-inflammatory agents are the mainstream treatments in chronic obstructive and pulmonary disease (COPD) and asthma. The combination of β 2 adrenergic receptor (β 2 AR) agonists and muscarinic antagonists shows superior bronchoprotective effects compared to these agents individually. Navafenterol (AZD8871) is a single-molecule, dual pharmacology agent combining muscarinic antagonist and β 2 AR agonist functions, currently in development as a COPD therapeutic. In precision-cut human lung slices (hPCLS), we investigated the bronchoprotective effect of navafenterol against two non-muscarinic contractile agonists, histamine and thromboxane A 2 (TxA 2 ) analog (U46619). Navafenterol pre-treatment significantly attenuated histamine-induced bronchoconstriction and β 2 AR antagonist propranolol reversed this inhibitory effect. TxA 2 analog-induced bronchoconstriction was attenuated by navafenterol pre-treatment, albeit to a lesser magnitude than that of histamine-induced bronchoconstriction. Propranolol completely reversed the inhibitory effect of navafenterol on TxA 2 analog-induced bronchoconstriction. In the presence of histamine or TxA 2 analog, navafenterol exhibits bronchoprotective effect in human airways and it is primarily mediated by β 2 AR agonism of navafenterol.

Bronchial asthma is one of the much known long-term respiratory conditions. Incidence is increasing, in developing countries like Bangladesh. Cross-sectional type of observational study was carried out over one year (July 2017 to June 2018) in the department of Pharmacology with collaboration of the department of Respiratory Medicine and Medicine, Mymensingh Medical College and Hospital, Mymensingh, Bangladesh. A total of 160 patients were selected non-randomly for the study. Inhalation route (52.35%) was the most preferred one over oral route (47.65%). In total 245 drugs, 131 FDC drugs (Salmeterol + Fluticasone) were prescribed with inhalation therapy which is 53.46%, another 9 FDC drugs that is (Ipratropium bromide + Salbutamol) were prescribed with inhalation therapy which is 3.67%, 101 drugs (Salbutamol) were prescribed with inhalation therapy that is 41.23%, 4 drugs (Beclomethasone) were prescribed with inhalation therapy that is 1.64%. Majority of patient were taking inhalation form of anti-asthmatic drugs.

Background: Children with asthma are at risk for low lung function extending into adulthood, but understanding of clinical predictors is incomplete., Objective: We sought to determine phenotypic factors associated with FEV 1 throughout childhood in the Severe Asthma Research Program 3 pediatric cohort., Methods: Lung function was measured at baseline and annually. Multivariate linear mixed-effects models were constructed to assess the effect of baseline and time-varying predictors of prebronchodilator FEV 1 at each assessment for up to 6 years. All models were adjusted for age, predicted FEV 1 by Global Lung Function Initiative reference equations, race, sex, and height. Secondary outcomes included postbronchodilator FEV 1 and prebronchodilator FEV 1 /forced vital capacity., Results: A total of 862 spirometry assessments were performed for 188 participants. Factors associated with FEV 1 include baseline Feno (B, -49 mL/log 2 PPB; 95% CI, -92 to -6), response to a characterizing dose of triamcinolone acetonide (B, -8.4 mL/1% change FEV 1 posttriamcinolone; 95% CI, -12.3 to -4.5), and maximal bronchodilator reversibility (B, -27 mL/1% change postbronchodilator FEV 1 ; 95% CI, -37 to -16). Annually assessed time-varying factors of age, obesity, and exacerbation frequency predicted FEV 1 over time. Notably, there was a significant age and sex interaction. Among girls, there was no exacerbation effect. For boys, however, moderate (1-2) exacerbation frequency in the previous 12 months was associated with -20 mL (95% CI, -39 to -2) FEV 1 at each successive year. High exacerbation frequency (≥3) 12 to 24 months before assessment was associated with -34 mL (95% CI, -61 to -7) FEV 1 at each successive year., Conclusions: In children with severe and nonsevere asthma, several clinically relevant factors predict FEV 1 over time. Boys with recurrent exacerbations are at high risk of lower FEV 1 through childhood., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: The bronchodilator response (BDR) depends on many factors, including genetic ones. Numerous single nucleotide polymorphisms (SNPs) influencing BDR have been identified. However, despite several studies in this field, genetic variations are not currently being utilized to support the use of bronchodilators., Areas Covered: In this narrative review, the possible impact of genetic variants on BDR is discussed., Expert Opinion: Pharmacogenetic studies of β 2 -agonists have mainly focused on ADRB2 gene. Three SNPs, A46G, C79G, and C491T, have functional significance. However, other uncommon variants may contribute to individual variability in salbutamol response. SNPs haplotypes in ADRB2 may have a role. Many variants in gene coding for muscarinic ACh receptor (mAChR) have been reported, particularly in the M 2 and, to a lesser degree, M 3 mAChRs, but no consistent evidence for a pharmacological relevance of these SNPs has been reported. Moreover, there is a link between SNPs and ethnic and/or age profiles regarding BDR. Nevertheless, replication of pharmacogenetic results is limited and often, BDR is dissociated from what is expected based on SNP identification. Pharmacogenetic studies on bronchodilators must continue. However, they must integrate data derived from a multi-omics approach with epigenetic factors that may modify BDR.

Background: In children, obesity typically reduces functional residual capacity (FRC), which reduces airway caliber and increases airway resistance. Whether these obesity-related changes in respiratory function can alter bronchodilator responsiveness is unknown., Objective: To investigate bronchodilator responsiveness in nonasthmatic children with and without obesity., Methods: Seventy nonasthmatic children, 8-12 years old, without (n = 19) and with (n = 51) obesity, completed spirometry, impulse oscillometry, and airway resistance measurements through plethysmography pre/post 360 µg of inhaled albuterol. FRC was assessed pre albuterol. A two-way analysis of variance determined the effects of obesity (group) and inhaled albuterol (pre-post) on outcome measures., Results: FRC (%total lung capacity) was 16% lower in children with obesity compared with those without obesity. There was no significant group by pre-post albuterol interaction on any outcome variables. Albuterol inhalation reduced total, central and peripheral airway resistance and increased airway reactance (i.e., less negative) to a similar degree in children with and without obesity. In children with obesity, airway resistance was increased whether measured by impulse oscillometry or plethysmography. However, once airway resistance was adjusted for lung volumes (i.e., specific airway resistance or sR aw ), there were no differences between children with and without obesity. In addition, significant but moderate associations were detected between chest mass and FRC (r = -0.566; p < 0.001), FRC and total airway resistance (i.e., R aw ; r = -0.445; p < 0.001)., Conclusions: In nonasthmatic early pubescent children, obesity increases total, central, and peripheral respiratory system resistance. However, the added respiratory system resistance and low lung volume breathing with obesity are not sufficient to reduce bronchodilator responsiveness., (© 2022 Wiley Periodicals LLC.)

Ethnopharmacological Relevance: Since pre-Columbian era, the resin of Araucaria araucana tree has been used traditionally for the treatment of ulcers and wounds. Araucaria species have also been used to treat inflammation, respiratory problems, viral infections, ulcers, and rheumatoid, cardiovascular, and neurological disorders., Aims and Objective: Due to its popular use, the authors aimed to scrutinize the potential of this plant as an antispasmodic and an antiemetic agent. Furthermore broncho- and vasodilatory effects of this plant was explored to rationalize its folkloric uses., Materials and Methods: Araucaria araucana crude extract (Aa.Cr) was evaluated in isolated preparations of rabbit jejunum, trachea, aorta, and atria to investigate the antispasmodic, bronchodilator, and vasodilator effects. The potential mechanistic approaches were compared with the standard drug 'verapamil'. The antiemetic activity was determined and compared with the standard drug 'domperidone' via chick emesis model., Results: Aa.Cr dose-dependently relaxed both spontaneous and K + -induced contractions in the isolated jejunum preparations of rabbits. In concentration-response curves of calcium (Ca ++ ), Aa.Cr also triggered the rightward shift like verapamil. Applying carbachol and phenylephrine (1 μM) and K+ (80 mM) to the isolated tracheal and aortic tissue preparation, respectively, resulted in broncho- and vasodilatory activities, respectively which may be due to the inhibition of Ca++ channels. Aa.Cr inhibited atrial force and spontaneous contractions in the rabbit's right atria. Aa.Cr exhibited significant antiemetic activity (P < 0.001 vs. saline) in dose-dependent (50-150 mg/kg) manner like domperidone. In silico molecular docking was performed to investigate the biological targets of purified components of Aa.Cr which revealed that cadinol dominantly targets β2 receptors to cause bronchodilation, however, eudesmin binds non-specifically to all the selected targets, while secoisolariciresinol mediated high hydrogen bonding with muscarinic receptors (M1 and M3) and Ca ++ channels, thus shows the suggested mechanistic pathways of targeted activities., Conclusions: The results of this study indicates that Aa.Cr may exhibit antispasmodic activity, bronchodilation, and vasodilation by inhibiting voltage-dependent Ca ++ channels and release of subcellular calcium. This explains its folkloric use in hypertension, bronchospasms, gastrointestinal spasms, and emesis., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Published guidelines on spirometry interpretation suggest an elevated FVC and FEV1 > 100% of predicted with an obstructive ratio may represent a physiological variant. Further evidence is needed on whether this finding indicates symptomatic airways obstruction and what additional evaluation should be done., Methods: Participants were prospectively enrolled to undergo additional testing for a technically adequate spirometry study with an FEV1 > 90% of predicted, and FEV1/FVC below the lower limit of normal, based on 95th percentile confidence intervals. Further testing consisted of full pulmonary function testing, impulse oscillometry (IOS), post-bronchodilator testing, fractional exhaled nitric oxide (FeNO), and methacholine challenge testing (MCT)., Results: A total of 49 patients meeting entry criteria enrolled and completed testing. Thirty-three were considered symptomatic based on clinical indications for initial testing and 16 were considered asymptomatic. Baseline pulmonary function test values were not different between groups while IOS R5 values (% predicted) were higher in the symptomatic group (126.5 ± 0.37 vs 107.1 ± 0.31). Bronchodilator responsiveness on PFT or IOS was infrequent in both groups. There was a 29% positivity rate for MCT in the symptomatic group compared to one borderline study in asymptomatic participants. FeNO was similar for symptomatic, 26.17 ± 31.3 ppb, compared to asymptomatic, 22.8 ± 13.5 ppb (p = 0.93). The dysanapsis ratio was higher in the symptomatic (0.15 ± 0.03) compared to the asymptomatic (0.13 ± 0.02) (p < 0.05)., Conclusion: Normal FEV1 > 90% of predicted and obstructive indices may not represent a normal physiological variant in all patients. In symptomatic patients, a positive MCT and elevated baseline IOS values were more common than in asymptomatic patients with similar PFT characteristics. These findings suggest that clinicians should still evaluate for airway hyperresponsiveness in patients with exertional dyspnea with airway obstruction and FEV1 > 90% of predicted and consider alternative diagnoses to include a normal physiologic variant if non-reactive., (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2021. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective. Viral lower respiratory tract infections (LRTI) are the leading cause for acute admission to the intensive care unit in infants and young children. Nebulized bronchodilators are often used when treating the most severe cases. The aim of this study was to investigate the bronchodilator effect on respiratory mechanics during intensive care with electrical impedance tomography (EIT) and to assess the feasibility of EIT in this context. Approach. We continuously monitored the children with chest EIT for up to 72 h in an observational study design. The treatment decisions were done by clinical assessment, as the clinicians were blinded to the EIT information during data collection. In a retrospective analysis, clinical parameters and regional expiratory time constants determined by EIT were used to assess the effects of bronchodilator administration, especially regarding airway resistance. Main results. We included six children from 11 to 27 months of age requiring intensive care due to viral LRTI and receiving bronchodilator agents. Altogether 131 bronchodilator administrations were identified during EIT monitoring. After validation of the exact timing of events and EIT data quality, 77 administrations were included in the final analysis. Fifty-five bronchodilator events occurred during invasive ventilation and 22 during high-flow nasal cannulae treatment. Only 17% of the bronchodilator administrations resulted in a relevant decrease in calculated expiratory time constants. Significance. Continuous monitoring with EIT might help to optimize the treatment of LRTI in pediatric intensive care units. In particular, EIT-based regional expiratory time constants would allow objective assessment of the effects of bronchodilators and other respiratory therapies., (© 2022 Institute of Physics and Engineering in Medicine.)

Introduction: The goal of the present study is to assess the relationship between functional respiratory parameters measured by the forced oscillation technique (FOT) in COPD patients and (1) dyspnea; (2) inspiratory capacity (IC), along with the variations occurring subsequent to bronchodilation., Methods: This cross-sectional study analyzed 40 stable COPD patients. Dyspnea was assessed by means of the San Diego Shortness of Breath Questionnaire. Forced oscillations were measured before and after bronchodilation by means of routine pulmonary function tests (PFTs)., Results: The reactance parameters measured by the FOT correlated with dyspnea (AX5: r=0.46; P=0.003) similarly to IC (r=-0.46; P=0.003). Changes in AX5 following bronchodilation led to a predicted 12% and 200mL improvement in IC, AX5 (area under the ROC curve=0.85, P<0.001)., Conclusions: Forced oscillation technique (FOT) appears to be an interesting complement to routine PFTs in COPD assessment. Reactance parameters are correlated with dyspnea and their response to bronchodilators is a predictor of significantly improved inspiratory capacity (IC). All in all, FOT may be considered as a functional test with regard to pulmonary hyperinflation, a critical determinant of dyspnea., (Copyright © 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.)