The value of bronchodilator response in FEV1 and FeNO for differentiating between chronic respiratory diseases: an observational study.

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 (ΔFEV1) 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 ΔFEV1 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. ΔFEV1 ≥ 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 ΔFEV1 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. ΔFEV1 and FeNO are helpful in differentiating between asthma, COPD, and ACO in patients with a positive BDT result.

Zataria multiflora affects pulmonary function tests, respiratory symptoms, bronchodilator drugs use and hematological parameters in chronic obstructive pulmonary disease patients: A randomized doubled-blind clinical trial.

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). FEV1 and MEF25-75, 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 FEV1 (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.

A comparative study of bronchodilator response: utilizing pre-bronchodilator versus predicted normal values.

BACKGROUND: A positive bronchodilator response has been defined as a 12% increase in the forced expiratory volume in one second (FEV1) 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 FEV1 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 FEV1 and FVC values. METHODS: A retrospective review of consecutive patients undergoing spirometry and bronchodilator testing was completed. The change in FEV1 and FVC with a bronchodilator was expressed relative to the pre-bronchodilator and predicted normal FEV1 and FVC. RESULTS: In 1,040 patients with a non-paradoxical change in FEV1, 19.0% had a ≥ 12% change in FEV1 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 FEV1 or FVC. In unobstructed patients, the upper threshold (two standard deviations above the mean) of the bronchodilator response was 14% for FEV1 and 10% for FVC using predicted normal values. CONCLUSIONS: Expressing the percent change in FEV1 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 FEV1. Irrespective of pre-bronchodilator values, a ≥ 14% change in FEV1 and ≥ 10% change in FVC relative to the predicted normal values could be considered a positive bronchodilator response.

The Bronchodilator Potential of Astragalus sarcocolla: An in vitro Experiment.

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.

Amitriptyline inhibits bronchoconstriction and directly promotes dilatation of the airways.

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.

Impact of the new European respiratory (ERS)/American Thoracic Society (ATS) pulmonary function test interpretation guidelines 2021 on the interpretation of bronchodilator responsiveness in subjects with airway obstruction.

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.

Epigenomic response to albuterol treatment in asthma-relevant airway epithelial cells.

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.

Peripheral airway dysfunction in prematurity-associated obstructive lung disease identified by oscillometry.

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; FEV1 < LLN, FEV1 /FVC < LLN), prematurity-associated preserved ratio of impaired spirometry (pPRISm; FEV1 < LLN, FEV1 /FVC ≥ LLN) and compared to preterm (FEV1 ≥ LLN) and term controls (%predicted FEV1 > 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.

Optimization of M3 Antagonist-PDE4 Inhibitor (MAPI) Dual Pharmacology Molecules for the Treatment of COPD.

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.

The rs2601796 variant in ADCY9 gene is associated with severe asthma and less bronchodilator response.

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.

Design, Synthesis, and Biological Evaluation of Novel Spiro Imidazobenzodiazepines to Identify Improved Inhaled Bronchodilators.

Novel gamma-aminobutyric acid receptor (GABAAR) 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 α1ß3γ2 GABAAR and correlated with in vitro binding data. The carboxylic acid containing GABAAR ligands have high aqueous solubility, low permeability, and low cell toxicity. The inability of GABAAR ligands to cross the blood-brain barrier was confirmed in vivo by the absence of sensorimotor inhibition. Pharmacological activities at lung GABAARs 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 GABAARs that was metabolically stable in the presence of human and mouse microsomes.

Impact of the cAMP efflux and extracellular cAMP-adenosine pathway on airway smooth muscle relaxation induced by formoterol and phosphodiesterase inhibitors.

ß2-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 ß2-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 ß2-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 ß2-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 ß2-adrenoceptor-induced relaxation of tracheal smooth muscle was affected by cAMP efflux and extracellular cAMP-adenosine pathway.

Use of fractional exhaled nitric oxide as a potential predictor of bronchodilator response.

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+.

Investigating the Unbinding of Muscarinic Antagonists from the Muscarinic 3 Receptor.

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.

The Role of Long-Acting Antimuscarinic Agents in the Treatment of 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 ß2-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.

Bronchial thermoplasty attenuates bronchodilator responsiveness.

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 ß2-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 (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio. However, a significant interaction was observed between thermoplasty and salbutamol for two oscillometric readouts, namely reactance at 5 Hz (Xrs5) 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.

The impact of genomic variants on patient response to inhaled bronchodilators: a comprehensive update.

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 ß2-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 M2 and, to a lesser degree, M3 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.

Ethnopharmacological basis and pharmacodynamics prospectives for folkloric claims of Rosa webbiana wall. Ex. Royle in diarrhea and asthma via In vitro, In vivo and In silico techniques.

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.

Computer-aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones.

The new high selective mAChRs M3 inhibitors with IC50 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 IC50 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.