Cisplatin and Procaterol Combination in Gastric Cancer? Targeting Checkpoint Kinase 1 for Cancer Drug Discovery and Repurposing by an Integrated Computational and Experimental Approach.

Checkpoint kinase 1 (CHK1), a serine/threonine kinase, plays a crucial role in cell cycle arrest and is a promising therapeutic target for drug development against cancers. CHK1 coordinates cell cycle checkpoints in response to DNA damage, facilitating repair of single-strand breaks, and maintains the genome integrity in response to replication stress. In this study, we employed an integrated computational and experimental approach to drug discovery and repurposing, aiming to identify a potent CHK1 inhibitor among existing drugs. An e-pharmacophore model was developed based on the three-dimensional crystal structure of the CHK1 protein in complex with CCT245737. This model, characterized by seven key molecular features, guided the screening of a library of drugs through molecular docking. The top 10% of scored ligands were further examined, with procaterol emerging as the leading candidate. Procaterol demonstrated interaction patterns with the CHK1 active site similar to CHK1 inhibitor (CCT245737), as shown by molecular dynamics analysis. Subsequent in vitro assays, including cell proliferation, colony formation, and cell cycle analysis, were conducted on gastric adenocarcinoma cells treated with procaterol, both as a monotherapy and in combination with cisplatin. Procaterol, in synergy with cisplatin, significantly inhibited cell growth, suggesting a potentiated therapeutic effect. Thus, we propose the combined application of cisplatin and procaterol as a novel potential therapeutic strategy against human gastric cancer. The findings also highlight the relevance of CHK1 kinase as a drug target for enhancing the sensitivity of cytotoxic agents in cancer.

Corrigendum: Case report: deterioration of infantile hemangioma related to oral or nebulized administration of ß2-AR agonist: three cases reports.

[This corrects the article DOI: 10.3389/fonc.2022.1000099.].

Case report: Deterioration of infantile hemangioma related to oral or nebulized administration of ß2-AR agonist: Three cases reports.

Infantile hemangioma (IH) is a benign vascular tumor, characterized by a unique sequence of non-linear growth and spontaneous involution. Some hemangiomas require intensive treatment to avoid functional and aesthetic insufficiency. Although ß-adrenergic receptor (ß-AR) antagonists have been increasingly used as the first-line treatment since 2008, the IH rebound still exists with uncertain mechanism. Here, we report three cases of abrupt IH deteriorations that are mainly related to ß2-AR agonist administration. Potential IH proliferation induced by ß2-AR agonists, especially from oral or nebulized approaches, should be recognized more widely by healthcare providers. Additionally, it is necessary to carry out large sample studies to analyze the influence of ß2-AR agonist administration on the deterioration of IH.

CDK12 and PAK2 as novel therapeutic targets for human gastric cancer.

Background: Gastric cancer remains the second leading cause of cancer-related death, and the third in mortality due to lack of effective therapeutic targets for late stage cancer patients. This study aims to identify potential druggable target biomarkers as potential therapeutic options for patients with gastric cancer. Methods: Immunohistochemistry of human gastric tumor tissues was conducted to determine the expression level of cyclin-dependent kinase 12 (CDK12). Multiple in vitro and in vivo assays such as RNAi, mass spectrometry, computer docking models, kinase assays, cell xenograft NU/NU mouse models (CDXs) and patient-derived xenograft NOD/SCID mouse models (PDXs) were conducted to study the function and molecular interaction of CDK12 with p21 activated kinase 2 (PAK2), as well as to find CDK12 inhibitors as potential treatment options for human gastric cancer. Results: Here we identified that CDK12 is a driver gene in human gastric cancer growth. Mechanistically, CDK12 directly binds to and phosphorylates PAK2 at T134/T169 to activate MAPK signaling pathway. We further identified FDA approved clinical drug procaterol can serve as an effective CDK12 inhibitor, leading to dramatic restriction of cancer cell proliferation and tumor growth in human gastric cancer cells and PDXs. Conclusions: Our data highlight the potential of CDK12/PAK2 as therapeutic targets for patients with gastric cancer, and we propose procaterol treatment as a novel therapeutic strategy for human gastric cancer.

Persistent wheezing caused by carvedilol overdose in a non-asthmatic man.

BACKGROUND: Cardiovascular dysfunction is the main manifestation of ß-blocker intoxication; however, respiratory manifestations have rarely been reported. CASE PRESENTATION: A 41-year-old man, who had ingested 300 mg carvedilol in a suicide attempt, was transferred to our emergency department. The patient had wheezing on arrival; however, he had no known history of bronchial asthma. In the absence of signs of heart failure, we gave the patient inhaled procaterol, a short-acting ß2 agonist. The wheezing disappeared approximately 60 h after carvedilol ingestion and did not recur thereafter. CONCLUSION: We report a case of wheezing caused by carvedilol intoxication. Although rare, clinicians should recognize that wheezing or bronchospasm can develop following ß-blocker intoxication, for which a short-acting ß2 agonist could be indicated.

Inhaled procaterol for the treatment of transient tachypnea of the newborn.

BACKGROUND: Transient tachypnea of the newborn (TTN) is a respiratory disorder that results from inadequate or delayed clearance of fetal lung fluid following delivery. At present, supportive care is generally practiced for the treatment of TTN. In this study, we focused on inhaled beta-agonists for the treatment of TTN, and the aim was to verify the efficacy and the safety of inhaled procaterol for the treatment of TTN. METHODS: Inhaled procaterol or normal saline solution was administered to infants. Respiratory rate and mixed venous carbon dioxide (PvCO2 ) were evaluated as the primary outcomes. The duration of hospitalization, duration of oxygen therapy, and changes in respiratory support were evaluated as secondary outcomes. RESULTS: Thirty-seven neonates diagnosed with TTN were randomly assigned to the procaterol group (n = 18) or the placebo group (n = 19). There were no differences in PvCO2 or respiratory rate between the two groups before and after intervention. Median duration of oxygen therapy (3 days; IQR, 3-6.5 days vs 2 days, IQR, 2-4.75 days; P = 0.13) and of hospitalization (15 days; IQR, 11.25-20 days vs 11 days, IQR, 8-15.5 days; P = 0.14) were not significantly different. CONCLUSIONS: Inhaled procaterol was not effective for the treatment of TTN.

Simultaneous voltammetry detection of dopamine and uric acid in human serum and urine with a poly(procaterol hydrochloride) modified glassy carbon electrode.

In the present study, procaterol hydrochloride (ProH) was successfully electropolymerized onto a glass carbon electrode (GCE) with simply cyclic voltammetry scans to construct a poly(procaterol hydrochloride) (p-ProH) membrane modified electrode. Compared with the bare GCE, much higher oxidation peak current responses and better peak potentials separation could be obtained for the simultaneous oxidation of dopamine (DA) and uric acid (UA), owning to the excellent electrocatalytic ability of the p-ProH membrane. And it's based on that a square wave voltammetry (SWV) method was developed to selective and simultaneous measurement of DA and UA. Under the optimum conditions, the linear dependence of oxidation peak current on analyte concentrations were found to be 1.0-100 µmol/L and 2-100 µmol/L, giving detection limits of 0.3 µmol/L and 0.5 µmol/L for DA and UA, separately. The as prepared modified electrode shows simplicity in construction with the merits of good reproducibility, high stability, passable selectivity and nice sensitivity. Finally, the proposed p-ProH membrane modified electrode was successfully devoted to the detection of DA and UA in biological fluids such as human serum and urine with acceptable results.

Evaluation of Inhaled Procaterol for Potential Assist Use in Patients with Stable Chronic Obstructive Pulmonary Disease.

OBJECTIVES: International guidelines recommend the use of long-acting bronchodilators for the treatment of chronic obstructive pulmonary disease (COPD), but the usefulness of short-acting bronchodilator assist use for stable COPD remains uncertain. The purpose of the present study was to objectively demonstrate the effects of assist use of procaterol, a short-acting ß2-agonist, on the respiratory mechanics of stable COPD patients treated with a long-acting bronchodilator using forced oscillation technique (FOT) and conventional spirometry. We also confirmed the length of time for which procaterol assist could significantly improve the pulmonary function. METHODS: We enrolled 28 outpatients with mild to severe COPD (Global Initiative for Obstructive Lung Disease stages I-III), who had used the same long-acting bronchodilator for longer than 3 months and who were in stable condition. All measures were performed using both FOT and spirometry sequentially from 15 min to 2 h after inhalation. RESULTS: Compared to baseline, inhaled procaterol assist use modestly but significantly improved spirometric and FOT measurements within 2 h after inhalation. These significant effects continued for at least 2 h. -Significant correlations were found between parameters -measured by spirometry and those measured by FOT. CONCLUSIONS: Procaterol assist use modestly but significantly improved pulmonary function determined by spirometry and respiratory mechanics in patients with stable COPD treated with long-acting bronchodilators. Thus, inhaled procaterol has the potential for assist use for COPD.

Evaluation of Bioequivalence Between the New Procaterol Hydrochloride Hydrate Dry Powder Inhaler and the Approved Dry Powder Inhaler in Patients With Asthma in a Randomized, Double-Blind, Double-Dummy, Crossover Comparison Study: A Phase 3 Study.

Procaterol hydrochloride hydrate (procaterol) is a ß2 -adrenergic receptor agonist that induces a strong bronchodilatory effect. The procaterol dry powder inhaler (DPI) has been frequently used in patients with bronchial asthma or chronic obstructive pulmonary disease. We evaluated the bioequivalence and safety between the new procaterol DPI (new DPI) and the approved procaterol DPI (approved DPI). This study was a randomized, double-blind, double-dummy, crossover comparison to evaluate the pharmacodynamic equivalence of the new DPI and the approved DPI in patients with bronchial asthma. Primary efficacy variables were area under the concentration-time curve (AUC) forced expiratory volume in the first second (FEV1 )/h and maximum FEV1 during the 480-minute measurement period. Patients were divided into 2 groups, New-DPI-First (n = 8) and Approved-DPI-First (n = 8), according to the investigational medical product that was administered first. Patients inhaled 20 µg of procaterol in each period. FEV1 was measured by a spirometer at predose and at 15, 30, 60, 90, 120, 180, 240, 360, and 480 minutes after each investigational medical product administration. Equivalence was evaluated by confirming that the 2-sided 90%CIs for the difference between the new and the approved DPI in means of AUC (FEV1 )/h and maximum FEV1 were within the acceptance criteria of -0.15 to 0.15 L. The difference in means of AUC (FEV1 )/h and maximum FEV1 was 0.041 L and 0.033 L, respectively, and the 90%CI was 0.004 to 0.078 L and -0.008 to 0.074 L, respectively. These CIs were both within the acceptance criteria. The new DPI was assessed as being bioequivalent to the approved DPI.

ADRB2 gene polymorphism and emphysema heterogeneity can modulate bronchodilator response in patients with emphysema.

BACKGROUND: Genetic variation in the ß2-adrenergic receptor (ADRB2) gene has been thought to have an important role in the differential response to ß2-agonist therapy for asthma. However, previous studies have shown little evidence for an association between these ADRB2 variants and the bronchial dilator response (BDR) in chronic obstructive pulmonary disease (COPD) patients. This discrepancy could be explained by differences in the distribution and heterogeneity of pulmonary emphysema in COPD patients, since emphysema distribution and heterogeneity are thought to have a role in pulmonary function in COPD patients. We hypothesized that differences in emphysema distribution and heterogeneity may have masked significant alterations of the bronchodilator response among ADRB2 genotypes in COPD patients in previous studies. METHODS: The BDR (induced by 20 µg of procaterol) was measured in 211 patients who had a smoking history of more than 10 pack/years and had undergone chest high resolution computed tomography examination. A low attenuations area (<960 Hounsfield Units) was identified and the emphysema heterogeneity index (EHI%) was calculated with a range in value from -100% to 100%. ADRB2 Arg16Gly genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: The BDR was augmented in patients with homogenous emphysema compared with those with upper-dominant emphysema. In patients carrying the AA genotype of ADRB2, the BDR was significantly increased in patients with upper-dominant emphysema, but not in patients with lower-dominant emphysema. CONCLUSION: Combination analysis of ADRB2 Arg16Gly polymorphism and EHI% may predict the effectiveness of ß2-adrenergic receptor agonist treatment in patients with COPD and emphysema.

A Modified Method for Examining the Walking Pattern and Pace of COPD Patients in a 6-min Walk Test Before and After the Inhalation of Procaterol.

Objective The 6-min walk test (6MWT) is a simple test that is used to examine the exercise tolerance and outcomes in patients with chronic obstructive pulmonary disease (COPD). Although the 6MWT is useful for assessing exercise tolerance, it is difficult to evaluate time-dependent parameters such as the walking pattern. A modified 6MWT has been devised to assess the walking pattern by calculating the number of steps per second (NSPS). This study was performed to investigate walking pattern of COPD patients in the modified 6MWT before and after a single inhalation of the short-acting ß2-agonist procaterol. Methods Nine male COPD patients participated in this study. The 6MWT was performed before and after the inhalation of procaterol hydrochloride. A digital video recording of the 6MWT was made. After the 6MWT, the number of steps walked by the subject in each 5-s period was counted manually with a hand counter while viewing the walking test on the video monitor. Results After the inhalation of procaterol, the 6-min walking distance increased significantly in comparison to baseline (p<0.01). The mean NSPS was also significantly increased after the inhalation of procaterol in comparison to baseline (p<0.01). The walking pattern was displayed on a graph of time versus NSPS, and the walking pace was shown by a graph of time versus cumulative steps. Conclusion The analysis of the COPD patients' walking test performance and their walking pattern and pace in the 6MWT may help to evaluate the effects of drug treatment.

Electrochemical investigation and determination of procaterol hydrochloride on poly(glutamic acid)/carboxyl functionalized multiwalled carbon nanotubes/polyvinyl alcohol modified glassy carbon electrode.

Poly(glutamic acid) (P-GLU)/carboxyl functionalized multiwalled carbon nanotubes (MWCNTs-COOH)/polyvinyl alcohol (PVA) modified glassy carbon electrode (GCE) has been successfully prepared and the electrochemical behavior of procaterol hydrochloride (ProH) was studied. The results show that the as-prepared modified electrode exhibits a good electrocatalytic property towards the oxidation of ProH in 0.2M phosphate buffer solution (PBS) (pH 6.0) due to the enhanced oxidation peak current at ~+0.59V. Under optimal reaction conditions, the oxidation peak current of ProH is proportional to its concentration in the linear dynamic ranges of 0.060 - 8.0µM (R = 0.9974), with a detection limit of 8.0 × 10-9M. Finally, this method was efficiently used for the determination of ProH in tablets and human urine with recoveries of 88.5~98.7% and 89.2 ~ 108.0%, respectively.

A low [Ca2+]i-induced enhancement of cAMP-activated ciliary beating by PDE1A inhibition in mouse airway cilia.

This study demonstrated that PDE1 (phosphodiesterase 1) existing in the ciliary beat frequency (CBF)-regulating metabolon regulates CBF in procaterol-stimulated lung airway ciliary cells of mouse. Procaterol (an ß2-agonist) increased the ciliary bend angle (CBA) and CBF via cAMP accumulation in the ciliary cells of mice: interestingly, the time course of CBF increase was slower than that of CBA increase. However, IBMX (3-isobutyl-1-methylxanthine, an inhibitor of PDE) increased CBA and CBF in an identical time course. Lowering an intracellular Ca2+ concentration ([Ca2+]i) caused by switching to an EGTA-containing Ca2+-free solution from normal one elevated the procaterol-induced increasing rate of CBF. These observations suggest that Ca2+-dependent PDE1 controls cAMP-stimulated CBF increase. Either application of 8MmIBMX (8-methoxymethyl-IBMX, a selective PDE1 inhibitor), BAPTA-AM (an intracellular Ca2+ chelator), or calmidazolium (an inhibitior of calmodulin) alone increased CBA and CBF in the lung airway ciliary cells and increased cAMP contents in the isolated lung cells, and like IBMX, each application of the compound made the time courses of CBA and CBF increase stimulated by procaterol identical. The immunoelectron microscopic examinations revealed that PDE1A exists in the space between the nine doublet tubules ring and plasma membrane in the lung airway cilium, where the outer dynein arm (a molecular motor regulating CBF) functions. In conclusion, PDE1A is a key factor slowing the time course of the procaterol-induced increase in CBF via degradation of cAMP in the CBF-regulating metabolon of the mouse lung airway cilia.

Responsiveness to bronchodilator procaterol in COPD as assessed by forced oscillation technique.

The aim of this retrospective study was to assess responses to a bronchodilator by forced oscillation technique (FOT) and to relate the results of respiratory impedance (Zrs) to spirometric parameters in patients with chronic obstructive pulmonary disease (COPD). Zrs was measured as a function of frequency from 4 to 36Hz before and after inhalation of procaterol, a short-acting ß2-agonist (n=60). Respiratory resistance (Rrs) and reactance (Xrs) were significantly frequency-dependent, and inspiratory and expiratory phases were different both before and after procaterol inhalation. The Rrs at 4Hz and Xrs at 4-20Hz during a whole breath were significantly improved after procaterol inhalation. The response to procaterol inhalation varied among patients, and changes in Xrs at 4Hz significantly correlated with% change in forced expiratory volume in one second and changes in forced vital capacity. Taken together, Zrs, and specifically Xrs parameters, are sensitive to acute physiological responses to a bronchodilator in COPD.

Exploring the electrochemiluminescent behavior of procaterol hydrochloride in the presence of Ru(bpy)32+ and its analytical application in pharmaceutical preparation.

Based on the strong enhancement effect of procaterol hydrochloride on the electrochemiluminescence (ECL) of Ru(bpy)32+ (bpy = 2,2'-bipyridine) in an alkaline H3 PO4 -NaOH buffer solution on a bare Pt electrode, a simple, rapid and sensitive method was developed for the determination of procaterol hydrochloride. The optimum conditions for the enhanced ECL have been developed in detail in this work. Under optimum conditions, the logarithmic ECL enhancement vs. the logarithmic concentration of procaterol hydrochloride is linear over a wide concentration range of 2.0 × 10-7 to 2.0 × 10-4  M (r = 0.9976), with a limit of detection of 1.1 × 10-8  M (S/N = 3), and a relative standard deviation of 2.1% (n = 7, c = 5.0 × 10-6  M). The proposed method was applied to the determination of this drug in tablets with recoveries of 89.7%-98.5%. In addition, a possible mechanism for the enhanced ECL of Ru(bpy)32+ , which is caused by ProH, has also been proposed.

Involvement of Ca2+ Signaling in the Synergistic Effects between Muscarinic Receptor Antagonists and ß2-Adrenoceptor Agonists in Airway Smooth Muscle.

Long-acting muscarinic antagonists (LAMAs) and short-acting ß2-adrenoceptor agonists (SABAs) play important roles in remedy for COPD. To propel a translational research for development of bronchodilator therapy, synergistic effects between SABAs with LAMAs were examined focused on Ca2+ signaling using simultaneous records of isometric tension and F340/F380 in fura-2-loaded tracheal smooth muscle. Glycopyrronium (3 nM), a LAMA, modestly reduced methacholine (1 µM)-induced contraction. When procaterol, salbutamol and SABAs were applied in the presence of glycopyrronium, relaxant effects of these SABAs are markedly enhanced, and percent inhibition of tension was much greater than the sum of those for each agent and those expected from the BI theory. In contrast, percent inhibition of F340/F380 was not greater than those values. Bisindolylmaleimide, an inhibitor of protein kinase C (PKC), significantly increased the relaxant effect of LAMA without reducing F340/F380. Iberiotoxin, an inhibitor of large-conductance Ca2+-activated K⁺ (KCa) channels, significantly suppressed the effects of these combined agents with reducing F340/F380. In conclusion, combination of SABAs with LAMAs synergistically enhances inhibition of muscarinic contraction via decreasing both Ca2+ sensitization mediated by PKC and Ca2+ dynamics mediated by KCa channels. PKC and KCa channels may be molecular targets for cross talk between ß2-adrenoceptors and muscarinic receptors.

Pulmonary liposomal formulations encapsulated procaterol hydrochloride by a remote loading method achieve sustained release and extended pharmacological effects.

Drug inhalation provides localized drug therapy for respiratory diseases. However, the therapeutic efficacy of inhaled drugs is limited by rapid clearance from the lungs. Small hydrophilic compounds have short half-lives to systemic absorption. We developed a liposomal formulation as a sustained-release strategy for pulmonary delivery of procaterol hydrochloride (PRO), a short-acting pulmonary ß2-agonist for asthma treatment. After PRO-loaded liposomes were prepared using a pH gradient (remote loading) method, 100-nm liposomes improved residence times of PRO in the lungs. PRO encapsulation efficiency and release profiles were examined by screening several liposomal formulations of lipid, cholesterol, and inner phase. Although PRO loading was not achieved using the conventional hydration method, PRO encapsulation efficiency was >60% using the pH gradient method. PRO release from liposomes was sustained for several hours depending on liposomal composition. The liposomal formulation effects on the PRO behavior in rat lungs were evaluated following pulmonary administration in vivo. Sustained PRO release was achieved using simplified egg phosphatidylcholine (EPC)/cholesterol (8/1) liposome in vitro, and greater PRO remnants were observed in rat lungs following pulmonary administration. Extended pharmacological PRO effects were observed for 120min in a histamine-induced bronchoconstriction guinea pig model. We indicated the simplified EPC/cholesterol liposome potential as a controlled-release PRO carrier for pulmonary administration.

Broad screening and identification of ß-agonists in feed and animal body fluid and tissues using ultra-high performance liquid chromatography-quadrupole-orbitrap high resolution mass spectrometry combined with spectra library search.

Broad screening and identification of ß-agonists in feed, serum, urine, muscle and liver samples was achieved in a quick and highly sensitive manner using ultra high performance liquid chromatography-quadrupole-orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS) combined with a spectra library search. Solid-phase extraction technology was employed for sample purification and enrichment. After extraction and purification, the samples were analyzed using a Q-Orbitrap high-resolution mass spectrometer under full-scan and data-dependent MS/MS mode. The acquired mass spectra were compared with an in-house library (compound library and MS/MS mass spectral library) built with TraceFinder Software which contained the M/Z of the precursor ion, chemical formula, retention time, character fragment ions and the entire MS/MS spectra of 32 ß-agonist standards. Screening was achieved by comparing 5 key mass spectral results and positive matches were marked. Using the developed method, the identification results from 10 spiked samples and 238 actual samples indicated that only 2% of acquired mass spectra produced false identities. The method validation results showed that the limit of detection ranged from 0.021-3.854 µg kg(-1)and 0.015-1.198 ng mL(-1) for solid and liquid samples, respectively.

Efficacy of procaterol and montelukast on children with moderate persistent asthma / 中国基层医药

Objective To investigate the efficacy of procaterol and montelukast on lung function in children with moderate persistent asthma.Methods 86 children with moderate persistent asthma from January 2014 to December 2014 in our hospital were studied,and according to the random number table method,they were divided into the control group and the observation group,43 cases in each group.The observation group was treated with procaterol combined with montelukast,the control group was treated with procaterol.The cough relief and disappearance time,the improvement of pulmonary function after treatment,the clinical effect and the control of asthma after one month of the two groups were compared.Results After treatment,children cough relief and disappeared time of the observation group was significantly shorter than the control group (t =4.418 5,3.784 4,P =0.000 0,0.000 3).After treatment, the pulmonary function was found to improve the situation of the observation group being good than the control group, PEF,FVC,FEV1 ,FEV1 /FVC predicted values were significantly higher than the control group (all P <0.05).The total effective rate of the observation group (93.00%)was significantly higher than 74.40% of the control group (u =2.223 2,P =0.026 2).After one month of treatment,the basic control rate of the observation group(88.37%) was significantly higher than 67.40% of the control group(u =2.386 6,P =0.017 0).The incidence rate of adverse reactions of the observation group (6.98%)was significantly lower than 51.16% of the control group(P <0.05). Conclusion Procaterol combined with montelukast in the treatment of children with moderate persistent bronchial asthma can improve clinical efficacy,safety,and improve symptom control rate,it is worthy of promotion.

Effect of Indacaterol on Cough and Phlegm in Chronic Obstructive Pulmonary Disease Patients: A Meta-Analysis of Five Randomized Controlled Trials.

We investigated the effects of indacaterol on cough and phlegm in patients with stable chronic obstructive pulmonary disease (COPD). We performed a meta-analysis with five randomized controlled trials (RCTs) of indacaterol in stable COPD patients. The symptom severity was defined using the St. George's Respiratory Questionnaire (SGRQ). We analyzed patients treated with 150 µg (n = 945) and 300 µg (n = 832) out of 3,325 patients who completed the SGRQ from five RCTs. After a 12-week treatment of 150 µg indacaterol, cough improvement was reported in 36.5% (316/866) of patients treated with indacaterol vs. 32.2% (259/804) patients treated with placebo (Relative Ratio [RR], 1.13; 95% confidence interval [CI], 0.99-1.29). Phlegm improvement was reported in 31.0% (247/798) of patients treated with indacaterol vs. 30.6% (225/736) of patients treated with placebo (RR, 1.01; 95% CI, 0.87-1.18). Dyspnea improvement was reported in 39.5% (324/820) of patients treated with indacaterol vs. 31.5% (237/753) patients treated with placebo (RR, 1.33; 95% CI, 1.03-1.71; P = 0.001, I(2) = 55.1%). Only dyspnea improvement was significant compared to placebo even at the 300 µg indacaterol dose. Compared to placebo, a 12-week treatment of the long-acting beta-agonist, indacaterol might not have a significant effect on cough or phlegm in stable COPD.