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Objective: To explore the clinical effect of various doses of Budesonide combined with Tiotropium bromide in the treatment of elderly patients with chronic obstructive pulmonary disease (COPD). Methods: Clinical data of elderly patients with COPD, admitted to Affiliated Hospital of Shaoxing University from April 2021 to February 2023, were retrospectively analyzed. Based on the dosage of Budesonide combined with Tiotropium bromide, patients were divided into Low-dose group (Budesonide = 1mg), Medium-dose group (Budesonide = 2mg), and High-dose group (Budesonide = 3mg). All groups were matched for age, gender, course of disease, and BMI. Patients treated with Tiotropium bromide alone were assigned to the Control group. The clinical effect, pulmonary function index level, symptom improvement, inflammatory factor index level and adverse reactions in all groups were analyzed and compared. Results: A total of 88 patients were included in this study with 22 patients in each group. The total efficacy of Medium-dose (90.91%) and High-dose group (90.91%) was significantly higher than that of Low-dose group (63.64%) and the Control group (59.09%) (P<0.05). After the treatment, levels of pulmonary function, symptom improvement and inflammatory factors in the High-dose and the Medium-dose groups were better than those in the Low-dose group and the Control group. Pulmonary function, symptom improvement and levels of inflammatory factors was significantly better in the Low-dose group compared to the Control group (P<0.05). Conclusions: Budesonide combined with tiotropium bromide is better than tiotropium bromide alone in the treatment of elderly patients with COPD. Compared with low (1mg) dosage, medium (2mg) and high (3mg) dosage of budesonide are more effective in improving lung function, alleviating symptoms, reducing inflammatory response,, and are not associated with increased rate of adverse reactions. [ABSTRACT FROM AUTHOR]

One of the most debilitating symptoms of chronic obstructive pulmonary disease (COPD) is breathlessness, which leads to avoidance of physical activities in daily living and hastens clinical deterioration. Treatment of patients with COPD with inhaled long-acting muscarinic antagonist (LAMA)/long-acting β2-agonist (LABA) combination therapy improves airflow limitation, reduces breathlessness compared with LAMA or LABA monotherapies, and improves health status and quality of life. A large clinical trial programme focusing on the effects of tiotropium/olodaterol combination therapy demonstrated that this LAMA/LABA combination improves lung function and reduces hyperinflation (assessed by serial inspiratory capacity measurements) compared with either tiotropium alone or placebo in patients with COPD. Tiotropium/olodaterol also increases exercise endurance capacity and improves patient perception of the intensity of breathlessness compared with placebo. In this narrative review, we focus on the relationship between improving symptoms during activity, the ability to remain active in daily life and how this may impact quality of life. We consider the benefits of therapy optimisation by means of dual bronchodilation with tiotropium/olodaterol, and present new data from meta-analyses/pooled analyses showing that tiotropium/olodaterol improves inspiratory capacity compared with placebo and tiotropium and improves exercise endurance time compared with placebo after 6 weeks of treatment. We also discuss the importance of taking a holistic approach to improving physical activity, including pulmonary rehabilitation and exercise programmes in parallel with bronchodilator therapy and psychological programmes to support behaviour change.

BackgroundExercise tolerance is an important endpoint in chronic obstructive pulmonary disease (COPD) clinical trials. Little is known about the comparative measurement properties of constant work rate cycle ergometry (CWRCE) and the endurance shuttle walking test (ESWT). The objective of this sub-analysis of the TORRACTO® study was to directly compare the endurance measurement properties of CWRCE and ESWT in patients with COPD in a multicentre, multinational setting. We predicted that both tests would be similarly reliable, but that the ESWT would be more responsive to bronchodilation than CWRCE.MethodsThis analysis included 151 patients who performed CWRCE and ESWT at baseline and week 6 after receiving once-daily placebo, tiotropium/olodaterol (T/O) 2.5/5 μg or T/O 5/5 μg. Reproducibility was assessed by comparing their respective performance at baseline and week 6 in the placebo group. Responsiveness to bronchodilation was assessed by comparing endurance time at week 6 with T/O with baseline values and placebo. The locus of symptom limitation and end-exercise Borg scales for breathing and leg discomfort for both tests were also analysed.ResultsThe intraclass correlation coefficients for CWRCE and ESWT were 0.56 [95% confidence interval (CI) 0.37-0.71] and 0.75 (95% CI 0.63-0.84). More patients were limited by breathing discomfort during the ESWT than during CWRCE, whereas more patients were limited by leg discomfort or breathing/leg discomfort during CWRCE than the ESWT (p

BACKGROUND:In many patients with mild, persistent asthma, the percentage of eosinophils in sputum is less than 2% (low eosinophil level). The appropriate treatment for these patients is unknown. METHODS:In this 42-week, double-blind, crossover trial, we assigned 295 patients who were at least 12 years of age and who had mild, persistent asthma to receive mometasone (an inhaled glucocorticoid), tiotropium (a long-acting muscarinic antagonist), or placebo. The patients were categorized according to the sputum eosinophil level (

Abstract Globally, a small proportion (5–12%) of asthma patients are estimated to have severe disease. However, severe asthma accounts for disproportionately high healthcare resource utilization. The Global Initiative for Asthma (GINA) management committee recommends treating patients with asthma with inhaled corticosteroids plus long-acting β2-agonists and, when needed, adding a long-acting muscarinic receptor antagonist or biologic agent. Five biologics, targeting different effectors in the type 2 inflammatory pathway, are approved for asthma treatment. However, biologics have not been compared against each other or add-on inhaled therapies in head-to-head clinical trials. As a result, their positioning versus that of current and anticipated small-molecule strategies is largely unknown. Furthermore, with the emergence of biomarkers for predicting response to biologics, a more personalized treatment approach—currently lacking with inhaled therapies—may be possible. To gain perspective, we reviewed recent advances in asthma pathophysiology, phenotypes, and biomarkers; the place of biologics in the management and personalized treatment of severe asthma; and the future of biologics and small-molecule drugs. We propose an algorithm for the stepwise treatment of severe asthma based on recommendations in the GINA strategy document that accounts for the broad range of phenotypes targeted by inhaled therapies and the specificity of biologics. In the future, both biologics and small molecules will continue to play key roles in the individualized treatment of severe asthma. However, as targeted therapies, their application will continue to be focused on patients with certain phenotypes who meet the specific criteria for use as identified in pivotal clinical trials.

BackgroundUse of inhaled corticosteroids (ICS) increases the risk of pneumonia in chronic obstructive pulmonary disease (COPD), but the magnitude of risk with different ICS remains unclear.MethodsA post hoc analysis of the 4-year UPLIFT® trial to assess whether pneumonia risk differed by type of ICS (fluticasone propionate [FP], other ICS, or no ICS) in permanent users (defined by use until end of study) or in users at baseline (sensitivity analysis).ResultsFor the permanent-users analysis, 825 patients receiving FP throughout the trial, 825 patients receiving other ICS and 825 patients not receiving ICS were matched on relevant baseline features 1:1:1. A significantly greater risk of pneumonia was observed for FP versus no ICS: the hazard ratio (HR) for risk of pneumonia was 1.33 (95% confidence interval [CI] 1.00, 1.75; p = 0.046) and the rate ratio (RR) was 1.58 (95% CI 1.05, 2.37; p = 0.028). A greater risk was also found for FP versus other ICS: HR 1.28 (95% CI 0.97, 1.68; p = 0.078) and RR 1.48 (95% CI 1.00, 2.19; p = 0.049). A higher proportion of patients on FP were hospitalized with pneumonia (7.9%) versus other ICS (6.7%) or no ICS (5.9%). Whilst other ICS use was associated with the highest number of fatal pneumonia events, the total number of fatal pneumonia incidents was low. A similar pattern was observed in the sensitivity analyses, which included 4002 patients on different treatments at baseline (FP, other ICS, and no ICS) and considered potential switches during the study.ConclusionThe results support existing evidence of an increased pneumonia risk with FP use compared with other ICS and no ICS use in patients with COPD. Healthcare professionals should evaluate the risk-benefit ratio of using ICS when making treatment decisions with their patients.Trial registrationPost hoc analysis of UPLIFT®. ClinicalTrials.gov number: NCT00144339 . Retrospectively registered September 2, 2005.

Purpose: To investigate the efficacy of indacaterol plus tiotropium bromide in chronic obstructive pulmonary disease (COPD) complicated by bronchiectasis and the impact on IL-8 and C reactive protein (CRP) levels. Methods: Sixty enrolled patients with COPD and bronchiectasis who received treatment in Yantai Qishan Hospital, Yuyan, China from June 2017 to December 2019 were randomly allocated to group A (n = 30) and group B (n = 30). Group A received inhalation of indacaterol plus tiotropium bromide. Group B received only tiotropium bromide inhalation therapy. Therapeutic effects and appropriate serum indicators were compared. Results: Maximal mid-expiratory flow (MMF), maximal voluntary ventilation (MVV), and forced expiratory volume in one second (FEV1.0) levels of the patients were significantly elevated, and group A showed a significantly higher values than group B (p < 0.05). The serum levels of IL-8, CRP, and serum calcitonin (PCT) in both groups were lower than before treatment, but the decrease in group A was significantly greater than that in group B (p < 0.05). The SaO2, PaO2, and PaO2/FiO2 levels in both groups increased, but the increase in group A was higher than that in group B (p < 0.05). Group A showed a significantly lower total incidence of complications than group B (p < 0.05). Conclusion: Indacaterol plus tiotropium bromide produced significant effects in the treatment of COPD with bronchiectasis, which ameliorate lung function and inflammation status in the body and therefore have the potential of being utilized in clinical practice. [ABSTRACT FROM AUTHOR]

Tiotropium bromide (TIO) is a long-acting bronchodilator used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma. Specifically, it is used to prevent patients from worsening breathing difficulties. In this study, a new TIO-imprinted electrochemical sensor was designed to detect TIO in serum and pharmaceutical samples. Methacryloyl-L-histidine-cobalt(II) [MAH-Co(II)] has been used as a metal-chelating monomer for synthesizing selective molecularly imprinted polymer (MIP). MIP film has been developed on glassy carbon electrodes using MAH-Co(II) as the functional monomer, 2-hydroxyethyl methacrylate (HEMA) as the basic monomer, and ethylene glycol dimethacrylate (EGDMA) as the cross-linker in the photopolymerization method. The surface characterization of the developed MAH-Co(II)@MIP/GCE electrochemical sensor was done using scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FTIR). Also, the electrochemical behavior of the sensor was provided by differential pulse voltammetry (DPV), cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS) techniques. Under optimized experimental conditions, the linearity range was in the range of 10–100 fM, and the limit of detection (LOD) and limit of quantitation (LOQ) values were calculated as 2.73 fM and 9.75 fM, respectively. The MAH-Co(II)@MIP/GCE sensor was used to precisely determine TIO in capsule and commercial serum samples. The results demonstrated that the MIP could specifically recognize TIO compared to structurally related drugs and could be reliably applied to the direct determination of drugs from real samples. [ABSTRACT FROM AUTHOR]

Background Neutrophilic asthma (NeuA) is usually resistant to corticosteroids. Tiotropium bromide (TIO) is a bronchodilator that is used as an add-on therapy to inhaled corticosteroid and long-acting β2 agonist in asthma treatment. However, the role of TIO in NeuA is not fully known. Thus, the aim of this study was to evaluate the effect of TIO on NeuA compared to that of corticosteroids. Methods C57BL/6 female mice were sensitized with ovalbumin and lipopolysaccharide to induce neutrophilic inflammation. Dexamethasone (DEX) was administered on days 14, 17, 20, and 23. TIO was inhaled on days 21, 21, and 23. On day 24, mice were sacrificed. Airway hyper-responsiveness, levels of cytokines in bronchoalveolar lavage (BAL) and lung homogenates, and lung tissue histopathology were compared between the two groups. Results Neutrophil counts, T helper 2 cells (TH2)/TH17 cytokines, and pro-inflammatory cytokine in BAL fluids were elevated in the NeuA group. TIO group showed lower total cells, neutrophil counts, and eosinophil counts in BAL fluids than the DEX group (p

BACKGROUND:The TORRACTO® study evaluated the effects of tiotropium/olodaterol versus placebo on endurance time during constant work-rate cycling and constant speed shuttle walking in patients with chronic obstructive pulmonary disease (COPD) after 12 weeks of treatment. METHODS:The effects of once-daily tiotropium/olodaterol (2.5/5 and 5/5 μg) on endurance time during constant work-rate cycle ergometry (CWRCE) after 6 and 12 weeks of treatment were compared with placebo in patients with COPD in a randomized, double-blind, placebo-controlled, parallel-group clinical trial. Endurance time during the endurance shuttle walk test (ESWT) after 6 and 12 weeks of treatment was also evaluated in a subset of patients. RESULTS:A total of 404 patients received treatment, with 165 participating in the ESWT substudy. A statistically significant improvement in endurance time during CWRCE was observed after 12 weeks (primary endpoint) with tiotropium/olodaterol 5/5 µg [14% ( p = 0.02)] but not with tiotropium/olodaterol 2.5/5 µg [9% ( p = 0.14)] versus placebo. In the ESWT substudy, a trend to improvement in endurance time during ESWT after 12 weeks (key secondary endpoint) was observed with tiotropium/olodaterol 5/5 µg [21% ( p = 0.055)] and tiotropium/olodaterol 2.5/5 µg [21% ( p = 0.056)] versus placebo. CONCLUSION:Tiotropium/olodaterol 5/5 µg improved endurance time during cycle ergometry versus placebo, with a strong tendency to also improve walking endurance time. [ ClinicalTrials.gov identifier: NCT01525615.].

Abstract Background The Global Initiative for Asthma has only recently added tiotropium bromide as adjunct controller therapy in severe asthma (Step 4 or 5) in adults (2015) and children (2019). Although not yet approved for pediatric use by Health Canada, it has been occasionally offered by asthma specialists as a therapeutic trial in children with troublesome asthma or treatment for adverse effects. The objective of this study was to describe the indications and real-life clinical experience in initiating tiotropium in children with asthma. Methods We designed a retrospective mixed-method case series study of children aged 1–17 years who initiated tiotropium in our tertiary-care centre between 2013 and 2020. Clinical information was extracted from electronic medical records and tiotropium dispensing, from drug claims. Parents/children and physicians independently completed a questionnaire about treatment goals, perceived efficacy, safety, satisfaction, and lessons learned. Results The 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4–17.8) years. Children were primarily on Step 4 (85%) or 5 (6%) prior to tiotropium initiation, yet most (84%) did not increase their treatment step after tiotropium initiation. The physicians’ treatment goals were to improve asthma control, alleviate adverse effects of current therapy, and/or improve lung function. The most improved symptoms were coughing/moist cough, difficulty breathing, whistling breath, and bronchial secretions/mucus. Although most parents and physicians reported a significant benefit with tiotropium bromide, physicians particularly remarked, as their “lesson learned’, on the improvement in chronic symptoms in asthmatic children, particularly those with prominent moist cough and in lung function, in those with seemingly none (or incompletely) reversible obstruction as well as the ability to decrease the ICS and/or LABA dose to lessen adverse effects. A few physicians raised caution on the risk of lower adherence with an additional inhaler. Conclusion In children with severe asthma on Step 4 or 5, tiotropium bromide was primarily used as substitute, rather than additional, adjunct therapy to improve asthma control, alleviate adverse effects, and/or to improve lung function. The latter two indications, combined with its perceived effectiveness in children with prominent moist cough, also suggest additional indications of tiotropium to be formally explored.

Objective: To explore the clinical effect of various doses of Budesonide combined with Tiotropium bromide in the treatment of elderly patients with chronic obstructive pulmonary disease (COPD)., Methods: Clinical data of elderly patients with COPD, admitted to Affiliated Hospital of Shaoxing University from April 2021 to February 2023, were retrospectively analyzed. Based on the dosage of Budesonide combined with Tiotropium bromide, patients were divided into Low-dose group (Budesonide = 1mg), Medium-dose group (Budesonide = 2mg), and High-dose group (Budesonide = 3mg). All groups were matched for age, gender, course of disease, and BMI. Patients treated with Tiotropium bromide alone were assigned to the Control group. The clinical effect, pulmonary function index level, symptom improvement, inflammatory factor index level and adverse reactions in all groups were analyzed and compared., Results: A total of 88 patients were included in this study with 22 patients in each group. The total efficacy of Medium-dose (90.91%) and High-dose group (90.91%) was significantly higher than that of Low-dose group (63.64%) and the Control group (59.09%) ( P <0.05). After the treatment, levels of pulmonary function, symptom improvement and inflammatory factors in the High-dose and the Medium-dose groups were better than those in the Low-dose group and the Control group. Pulmonary function, symptom improvement and levels of inflammatory factors was significantly better in the Low-dose group compared to the Control group ( P <0.05)., Conclusions: Budesonide combined with tiotropium bromide is better than tiotropium bromide alone in the treatment of elderly patients with COPD. Compared with low (1mg) dosage, medium (2mg) and high (3mg) dosage of budesonide are more effective in improving lung function, alleviating symptoms, reducing inflammatory response,, and are not associated with increased rate of adverse reactions., (Copyright: © Pakistan Journal of Medical Sciences.)

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.

Tiotropium bromide is the only long-acting muscarinic antagonist (LAMA) approved for treatment of patients aged ≥6 years old who have symptoms of uncontrolled asthma. Results from several clinical trials have found that once-daily inhaled tiotropium bromide is safe and efficacious in 6- to 17-year-olds with symptomatic asthma despite treatment with inhaled corticosteroids, with or without other medications. There are still few available studies investigating the impact of tiotropium bromide treatment in preschool children with suboptimal control. In this narrative review, we summarize the pharmacological effects of the LAMA tiotropium bromide, provide an overview about current asthma studies at different pediatric ages, and describe future research needs.

Globally, a small proportion (5–12%) of asthma patients are estimated to have severe disease. However, severe asthma accounts for disproportionately high healthcare resource utilization. The Global Initiative for Asthma (GINA) management committee recommends treating patients with asthma with inhaled corticosteroids plus long-acting β2-agonists and, when needed, adding a long-acting muscarinic receptor antagonist or biologic agent. Five biologics, targeting different effectors in the type 2 inflammatory pathway, are approved for asthma treatment. However, biologics have not been compared against each other or add-on inhaled therapies in head-to-head clinical trials. As a result, their positioning versus that of current and anticipated small-molecule strategies is largely unknown. Furthermore, with the emergence of biomarkers for predicting response to biologics, a more personalized treatment approach—currently lacking with inhaled therapies—may be possible. To gain perspective, we reviewed recent advances in asthma pathophysiology, phenotypes, and biomarkers; the place of biologics in the management and personalized treatment of severe asthma; and the future of biologics and small-molecule drugs. We propose an algorithm for the stepwise treatment of severe asthma based on recommendations in the GINA strategy document that accounts for the broad range of phenotypes targeted by inhaled therapies and the specificity of biologics. In the future, both biologics and small molecules will continue to play key roles in the individualized treatment of severe asthma. However, as targeted therapies, their application will continue to be focused on patients with certain phenotypes who meet the specific criteria for use as identified in pivotal clinical trials. [ABSTRACT FROM AUTHOR]

Purpose: To study the influence of non-invasive ventilator and tiotropium bromide on pulmonary function and sleep quality of patients with chronic obstructive pulmonary disease (COPD) combined with obstructive sleep apnea-hypopnea syndrome (OSAHS). Methods: One hundred and twenty patients with COPD-OSAHS were selected and randomly assigned to control group (CG) and treatment group (TG), with 60 subjects in each group. Non-invasive ventilator therapy was used in both groups, based on conventional therapy, while tiotropium bromide was added in TG. Treatment effectiveness in the two groups was evaluated and compared. Results: Total effectiveness was significantly higher in TG than in CG. Post-therapy arterial oxygen saturation (SaO2) and oxygen partial pressure (PaO2) were increased, while partial pressure of carbon dioxide (PaCO2) and lactic acid (Lac) were decreased in both groups (p < 0.05). Post-treatment values of indices of lung function, viz, forced expiratory volume (FEV1), forced vital capacity (FVC) and FEV1/FVC ratio were higher than the corresponding pre-treatment levels, and also values were significantly higher in TG than in CG (p < 0.05). Average sleep time, apnea and hypopnea index (AHI) and mechanical ventilation time of TG were less than those of CG. There were lower levels of Creactive protein (CRP), procalcitonin (PCT) and interleukin-17 (IL-17) in TG than in CG. During the treatment, no obvious adverse reaction was seen in both groups. Conclusion: Non-invasive ventilator, in combination with tiotropium bromide, is more effective in the treatment of COPD-OSAHS than the use of non-invasive ventilator alone. However, further clinical trials are required before its adoption in clinical practice. [ABSTRACT FROM AUTHOR]

Two replicate, double-blind, 6-week, incomplete-crossover studies (MORACTO 1 and 2) assessed the effects of tiotropium/olodaterol on inspiratory capacity and exercise endurance time in patients with moderate to severe chronic obstructive pulmonary disease.For each patient, four of five treatments were administered once daily for 6 weeks, with a 21-day washout between treatments: tiotropium/olodaterol 2.5/5 µg or 5/5 µg, tiotropium 5 µg, olodaterol 5 µg or placebo, all via the Respimat inhaler. Primary outcomes were inspiratory capacity prior to exercise and exercise endurance time during constant work-rate cycle ergometry to symptom limitation at 75% of peak incremental work rate after 6 weeks (2 h post-dose).295 and 291 patients were treated in MORACTO 1 and 2, respectively. Tiotropium/olodaterol 2.5/5 and 5/5 µg provided significant improvements in inspiratory capacity versus placebo and monotherapies (p

BackgroundDespite inhaled medications that decrease exacerbation risk, some COPD patients experience frequent exacerbations. We determined prospective risk factors for exacerbations among subjects in the COPDGene Study taking inhaled medications.Methods2113 COPD subjects were categorized into four medication use patterns: triple therapy with tiotropium (TIO) plus long-acting beta-agonist/inhaled-corticosteroid (ICS ± LABA), tiotropium alone, ICS ± LABA, and short-acting bronchodilators. Self-reported exacerbations were recorded in telephone and web-based longitudinal follow-up surveys. Associations with exacerbations were determined within each medication group using four separate logistic regression models. A head-to-head analysis compared exacerbation risk among subjects using tiotropium vs. ICS ± LABA.ResultsIn separate logistic regression models, the presence of gastroesophageal reflux, female gender, and higher scores on the St. George's Respiratory Questionnaire were significant predictors of exacerbator status within multiple medication groups (reflux: OR 1.62-2.75; female gender: OR 1.53 - OR 1.90; SGRQ: OR 1.02-1.03). Subjects taking either ICS ± LABA or tiotropium had similar baseline characteristics, allowing comparison between these two groups. In the head-to-head comparison, tiotropium users showed a trend towards lower rates of exacerbations (OR = 0.69 [95 % CI 0.45, 1.06], p = 0.09) compared with ICS ± LABA users, especially in subjects without comorbid asthma (OR = 0.56 [95% CI 0.31, 1.00], p = 0.05).ConclusionsEach common COPD medication usage group showed unique risk factor patterns associated with increased risk of exacerbations, which may help clinicians identify subjects at risk. Compared to similar subjects using ICS ± LABA, those taking tiotropium showed a trend towards reduced exacerbation risk, especially in subjects without asthma.Trial registrationClinicalTrials.gov NCT00608764, first received 1/28/2008.

Chronic obstructive pulmonary disease (COPD) is currently one of the most socially significant diseases that leads to a significant decrease in the daily activity and productivity of patients, as well as their rapid invalidization. In this regard, its treatment remains the most important problem of medicine. Currently, the main goals of treatment of patients with COPD are: relief of symptoms, improvement of exercise tolerance, improvement of General health, prevention and effective treatment of complications, prevention and effective treatment of exacerbations, prevention of disease progression, and reduction of mortality. The article presents a clinical case from the practice of a patient with COPD who received olodaterol + Tiotropium bromide. In view of the patient’s low adherence to therapy, further progression of the disease was observed, which led to a significant violation of airway patency during spirometry, and a decrease in exercise tolerance. The patient was assigned a new representative of combined drugs with 24-hour action - Vilanterol + Umeclidinium 22/55 mcg, with a new method of drug delivery. After 6 months of therapy with Vilanterol + Umeclidinium, the patient’s exercise tolerance increased, lung function improved, and quality of life improved.

Purpose: To investigate the effect of application of tiotropium bromide and N-acetylcysteine in combination with respiratory training on the treatment of patients with chronic obstructive pulmonary disease (COPD), and the effect of the combined treatment on pulmonary function, tolerance of physical activity, and quality of life. Methods: One hundred COPD patients admitted to The First People's Hospital of Guiyang (February 2019 - March 2021) were randomly and equally assigned to groups X and Y. Patients in Y were given tiotropium bromide in combination with N-acetylcysteine, while group X was treated with respiratory training, in addition to the treatment regimen in Y. Treatment efficacy, incidence of adverse reactions, pulmonary function indices, activity tolerance, quality of life (QLI) score, activities of daily living (ADL) score, and incidence of COPD at 2 weeks, 1 month and 2 months after treatment were determined, and compared between the two groups. Results: Relative to group Y, group X had significantly higher treatment efficacy, QLI score and ADL score (p < 0.05). Furthermore, group X also had better pulmonary function indices and activity tolerance, lower incidence of adverse reactions, and lower COPD incidence at 2 weeks, 1 month and 2 months after treatment (p < 0.05). Conclusion: Tiotropium bromide and N-acetylcysteine in combination with respiratory training enhanced therapeutic effect, pulmonary function, activity tolerance and quality of life of COPD patients. [ABSTRACT FROM AUTHOR]

BackgroundTiotropium is an anticholinergic bronchodilator for symptom relief and reducing exacerbations with an established safety profile in patients with chronic obstructive pulmonary disease (COPD). Using data from the 4-year Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) study, we re-evaluated the safety of tiotropium HandiHaler® in patients who experienced recent myocardial infarction (MI), heart failure or unstable rhythm disorder during the study.MethodsA post-hoc analysis of all-cause mortality and serious cardiac adverse events (cardiac SAEs), including cardiac deaths and death unknown, was conducted in patients who had experienced cardiac arrhythmia, MI or cardiac failure during UPLIFT® and who completed the study. Descriptive analyses were performed.ResultsMost patients experiencing cardiac events, for which they would have been excluded at baseline, remained in the trial. Kaplan-Meier analyses revealed a trend to later occurrence of cardiac SAEs with tiotropium HandiHaler® versus placebo. Patients who experienced a cardiac event and continued in UPLIFT® were not found to be at subsequently increased risk of all-cause mortality or cardiac SAEs with tiotropium treatment. Evaluation of deaths by major adverse cardiac events composite endpoints also showed that patients treated with tiotropium were not at increased risk of mortality or cardiac SAEs compared with placebo.ConclusionsRisk of cardiac events, mortality or SAEs was not increased by tiotropium in patients experiencing cardiac events for which they would have been excluded at study baseline. The findings support the cardiac safety of tiotropium HandiHaler® in patients with COPD.

Elucidating the detailed process of ligand binding to a receptor is pharmaceutically important for identifying druggable binding sites. With the ability to provide atomistic detail, computational methods are well poised to study these processes. Here, accelerated molecular dynamics (aMD) is proposed to simulate processes of ligand binding to a G-protein-coupled receptor (GPCR), in this case the M3 muscarinic receptor, which is a target for treating many human diseases, including cancer, diabetes and obesity. Long-timescale aMD simulations were performed to observe the binding of three chemically diverse ligand molecules: antagonist tiotropium (TTP), partial agonist arecoline (ARc) and full agonist acetylcholine (ACh). In comparison with earlier microsecond-timescale conventional MD simulations, aMD greatly accelerated the binding of ACh to the receptor orthosteric ligand-binding site and the binding of TTP to an extracellular vestibule. Further aMD simulations also captured binding of ARc to the receptor orthosteric site. Additionally, all three ligands were observed to bind in the extracellular vestibule during their binding pathways, suggesting that it is a metastable binding site. This study demonstrates the applicability of aMD to protein-ligand binding, especially the drug recognition of GPCRs.

Background: The Global Initiative for Asthma has only recently added tiotropium bromide as adjunct controller therapy in severe asthma (Step 4 or 5) in adults (2015) and children (2019). Although not yet approved for pediatric use by Health Canada, it has been occasionally offered by asthma specialists as a therapeutic trial in children with troublesome asthma or treatment for adverse effects. The objective of this study was to describe the indications and real-life clinical experience in initiating tiotropium in children with asthma. Methods: We designed a retrospective mixed-method case series study of children aged 1–17 years who initiated tiotropium in our tertiary-care centre between 2013 and 2020. Clinical information was extracted from electronic medical records and tiotropium dispensing, from drug claims. Parents/children and physicians independently completed a questionnaire about treatment goals, perceived efficacy, safety, satisfaction, and lessons learned. Results: The 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4–17.8) years. Children were primarily on Step 4 (85%) or 5 (6%) prior to tiotropium initiation, yet most (84%) did not increase their treatment step after tiotropium initiation. The physicians' treatment goals were to improve asthma control, alleviate adverse effects of current therapy, and/or improve lung function. The most improved symptoms were coughing/moist cough, difficulty breathing, whistling breath, and bronchial secretions/mucus. Although most parents and physicians reported a significant benefit with tiotropium bromide, physicians particularly remarked, as their "lesson learned', on the improvement in chronic symptoms in asthmatic children, particularly those with prominent moist cough and in lung function, in those with seemingly none (or incompletely) reversible obstruction as well as the ability to decrease the ICS and/or LABA dose to lessen adverse effects. A few physicians raised caution on the risk of lower adherence with an additional inhaler. Conclusion: In children with severe asthma on Step 4 or 5, tiotropium bromide was primarily used as substitute, rather than additional, adjunct therapy to improve asthma control, alleviate adverse effects, and/or to improve lung function. The latter two indications, combined with its perceived effectiveness in children with prominent moist cough, also suggest additional indications of tiotropium to be formally explored. [ABSTRACT FROM AUTHOR]

This paper observes the effect of pulmonary rehabilitation combined with tiotropium bromide on BODE index in clinical stable patients with chronic obstructive pulmonary (COPD) disease. For this purpose, a retrospective cohort was designed. In this work, 200 patients with COPD at stable stage were enrolled as research subjects. They were divided into the control group (n=100) given conventional treatment (bronchodilator, antioxidant, expectorant antitussive) and the research group (n=100) given pulmonary rehabilitation combined with tiotropium bromide treatment. The BODE indexes of two groups were compared and observed at 4 and 8 months of follow-up. After four months the research group showed significant improvement in dyspnea, 6MWD, FEVl% pred, BMI and BODE index, p<0.05. At eight months of treatment, the improvement was sustained for all outcomes at the research group, at p<0.05. Pulmonary rehabilitation combined with tiotropium bromide therapy for clinical stable patients with COPD can produce significant improvement in patients' BODE index. [ABSTRACT FROM AUTHOR]

Up to 22% of the population in the world suffer from bronchial asthma according to the data from different regions and sources. This is about 358 million people. At the same time, accurate figures for the prevalence of this disease cannot be obtained. Despite the many ongoing studies of this disease, developed treatment options, asthma hasn’t become a fully controlled disease. The problem of control and treatment of the disease as well as patient compliance is of great concern to modern clinicians. Every year GINA releases new documents and makes changes in the treatment and diagnosis of this chronic bronchopulmonary disease. Children’s asthma has become not only the most common chronic disease, but also the most common cause of children hospitalization.This article provides an overview of the international randomized clinical trials results and expert opinions regarding the treatment of uncontrolled bronchial asthma in children and adolescents. The results of 2017–2020 meta-analyzes regarding the use of tiotropium in children and adolescents are described. The use of basic therapy schemes is disclosed, including the use of tiotropium bromide in accordance with the recommendations of the Russian Respiratory Society and GINA.The authors also presented a clinical case of difficultly controlled bronchial asthma in a child of 12 years old. The use of tiotropium bromide in this patient is described in detail and the effectiveness of this drug is demonstrated.

Plain Language Summary Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone’s breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230.

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Objective: To explore and study the effects of tiotropium bromide adjuvant treatment of respiratory distress syndrome on serum nitric oxide (NO) and vascular endothelial growth factor (VEGF) levels. Methods: From September 2016 to September 2020, 84 cases of patients with respiratory distress syndrome were selected for emergency treatment in this hospital. All the cases were divided into tiotropium bromide group and control group with 42 cases each groups accorded to the random number table method. The control group were treated with nasal congestion continuous positive airway pressure, and the tiotropium bromide group were treated with tiotropium bromide on the basis of the control group. Both groups were treated and observed for 2 weeks, and serum NO and VEGF expression changes were detected. Results: After treatment, the total effective rates of the tiotropium bromide group were 97.6 %, which were higher than 85.7 % of the control group (P<0.05). The oxygenation index of the two groups after treatment were higher than that before treatment (P<0.05), and the tiotropium bromide group were higher than the control group (P<0.05). The FEV1 and FVC values of the two groups after treatment were higher than those before treatment (P<0.05), and the tiotropium bromide group were higher than the control group (P<0.05). The serum NO value of the two groups after treatment were higher than before treatment (P<0.05), and the serum VEGF value were lower than before treatment (P<0.05), the difference compared between the tiotropium bromide group and the control group were also statistically significant (P<0.05). Conclusion: Tiotropium bromide adjuvant treatment of respiratory distress syndrome can inhibit the expression of serum VEGF and promote the release of NO, improve the patient's lung function and oxygenation status, thereby enhance the therapeutic effect. [ABSTRACT FROM AUTHOR]

Background Efficacy and safety of tiotropium bromide, a muscarinic receptor antagonist, in treatment of asthma have been reported. However, its effect on airway remodeling in chronic asthma of the elderly has not been clearly verified. The objective of this study was to investigate the effect of tiotropium and expression of muscarinic receptors as its related mechanism in an aged mouse model of chronic asthma with airway remodeling. Methods BALB/c female mice age 6 weeks, 9 and 15 months were sensitized and challenged with ovalbumin (OVA) for three months. Tiotropium bromide was administered during the challenge period. Airway hyperresponsiveness (AHR) and pulmonary inflammation were measured. Parameters of airway remodeling, and expression levels of M2 and M3 receptors were examined. Results Total cell with eosinophils, increased in the OVA groups by age, was decreased significantly after treatment with tiotropium bromide, particularly in the age group of 15 months. AHR and levels of interleukin (IL)-4, IL-5, and IL-13 were decreased, after tiotropium administration. In old aged group of 9- and 15-months-treated groups, hydroxyproline contents and levels of α-smooth muscle actin were attenuated. Tiotropium enhanced the expression of M2 but decreased expression of M3 in all aged groups of OVA. Conclusion Tiotropium bromide had anti-inflammatory and anti-remodeling effects in an aged mouse model of chronic asthma. Its effects seemed to be partly mediated by modulating expression M3 and M2 muscarinic receptors. Tiotropium may be a beneficial treatment option for the elderly with airway remodeling of chronic asthma.

Today, chronic obstructive pulmonary disease is the fourth global cause of deaths worldwide. A number of studies showed that 11 to 16 million people might suffer from the chronic obstructive pulmonary disease in Russia. The prevalence and high mortality of this disease lead to a significant socio-economic burden. A pharmacoeconomic comparison of two alternative drug technologies in the studied groups grants the reasonable opportunity to transfer patients to the domestic analogues, confirming that efficiency unit costs for using Tiotropium-native and Ipraterol-native are lower than the same costs for using the foreign drugs Spiriva and Berodual.

BackgroundTiotropium has activity as an asthma controller. However, predictors of a positive response to tiotropium have not been described.ObjectiveWe sought to describe individual and differential responses of asthmatic patients to salmeterol and tiotropium when added to an inhaled corticosteroid, as well as predictors of a positive clinical response.MethodsData from the double-blind, 3-way, crossover National Heart, Lung, and Blood Institute's Asthma Clinical Research Network's Tiotropium Bromide as an Alternative to Increased Inhaled Glucocorticoid in Patients Inadequately Controlled on a Lower Dose of Inhaled Corticosteroid (ClinicalTrials.gov number, NCT00565266) trial were analyzed for individual and differential treatment responses to salmeterol and tiotropium and predictors of a positive response to the end points FEV1, morning peak expiratory flow (PEF), and asthma control days (ACDs).ResultsAlthough approximately equal numbers of patients showed a differential response to salmeterol and tiotropium in terms of morning PEF (n = 90 and 78, respectively) and ACDs (n = 49 and 53, respectively), more showed a differential response to tiotropium for FEV1 (n = 104) than salmeterol (n = 62). An acute response to a short-acting bronchodilator, especially albuterol, predicted a positive clinical response to tiotropium for FEV1 (odds ratio, 4.08; 95% CI, 2.00-8.31; P < .001) and morning PEF (odds ratio, 2.12; 95% CI, 1.12-4.01; P = 0.021), as did a decreased FEV1/forced vital capacity ratio (FEV1 response increased 0.39% of baseline for every 1% decrease in FEV1/forced vital capacity ratio). Higher cholinergic tone was also a predictor, whereas ethnicity, sex, atopy, IgE level, sputum eosinophil count, fraction of exhaled nitric oxide, asthma duration, and body mass index were not.ConclusionAlthough these results require confirmation, predictors of a positive clinical response to tiotropium include a positive response to albuterol and airway obstruction, factors that could help identify appropriate patients for this therapy.

This article discusses issues of clinical diagnosis and course of bronchial asthma in children. We discuss assessment of asthma severity and, accordingly, the extent of the step-by-step therapy according to updated recommendations (GINA 2018). Particular attention is paid to the possibility of improving the control of asthma with the help of the M-cholinolytic drug of long-acting tiotropium bromide, presented as a special inhalation form of tiotropium Respimat and registered in the Russian Federation for treatment of asthma in children of moderate and severe course from 6 years of age. Application tiotropium Respimat in children with insufficient control of asthma allows to improve lung function and asthma control.

Objective: To investigate the effect of modified Maxingshigan decoction combined with tiotropium bromide on pulmonary function, blood gas index and inflammatory factors in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Methods: 97 patients with AECOPD in our hospital from February 2018 to November 2019 were selected, they were divided into control group (n=48, tiotropium bromide treatment) and study group (n=49, modified Maxingshigan decoction and tiotropium bromide treatment) by random number table method. The therapeutic effect, TCM syndrome score, lung function, blood gas index, inflammatory factors and adverse reactions were compared between the two groups. Results: 14 d after treatment, the total clinical effective rate of the study group was higher than that of the control group (P<0.05). There was no difference in the incidence of adverse reactions between the two groups (P>0.05). The scores of TCM syndromes in the two groups 14 d after treatment decreased, and the study group was lower than the control group(P<0.05). The forced expiratory volume at 1 second (FEV1), forced vital capacity (FVC) and FEV1/ FVC at 14 d after treatment in the two groups were higher than those before treatment, and the study group was higher than control group (P<0.05). 14 d after treatment, the arterial oxygen partial pressure (PO2) of the two groups increased, and the study group was higher than that of the control group (P<0.05), and the partial pressure of carbon dioxide (PCO2) of the study group was lower than that of the control group (P<0.05). The levels of interleukin-8 (IL-8), c-reactive protein (CRP) in the two groups decreased at 14 d after treatment, and the level in the study group was lower than that in the control group (P<0.05). Conclusion: Modified Maxingshigan decoction combined with tiotropium bromide is effective in the treatment of AECOPD, which can effectively improve the clinical symptoms, lung function, blood gas index and inflammatory factors, and is safe and reliable [ABSTRACT FROM AUTHOR]

Tiotropium Bromide is a long-acting bronchodilator that is used in the treatment of chronic obstructive pulmonary disease (COPD) and asthma bronchodilator or bronchiolitis, which are substances that expand the bronchi and reduce resistance in the respiratory tract and increase airflow to the lungs. For Tiotropium Bromide found in inhaler capsules to treat COPD, determining the relevant impurities G and H, which are not UV active, is crucial. For this purpose, a new and sensitive liquid chromatography triple-quadrupole mass spectrometry (LC-MS/MS) detection with electrospray ionization by using multiple reaction monitoring in the positive mode method was developed and validated. The identity of the compounds was supported by using LC-Q/TOF. All chromatographic studies were performed with a Zorbax Eclipse XDB-C8 (150 mm x 4.6 mm, 5.0 µm) column with a total injection time of 13 min at a flow rate of 0.4 ml/min as a gradient. The limit of detection (LOD) and limit of quantitation (LOQ) in the current study range were determined as 1.0 ppb and 2.5 ppb, respectively. The results of the validation parameters following the ICH Q2(R1) guideline were determined within the acceptance criteria., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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BackgroundData have highlighted the potential bias introduced by withdrawal of inhaled corticosteroids at randomization in chronic obstructive pulmonary disease trials examining inhaled corticosteroids. Analyses were conducted to determine whether this was true of inhaled anticholinergic withdrawal in tiotropium trials.MethodsA pooled analysis of randomized, double-blind, placebo-controlled, parallel-group tiotropium trials of at least six months' duration was performed. Trials had similar inclusion and exclusion criteria. Exacerbation definition was standardized. Patients were divided into two groups, ie, D (anticholinergics discontinued at randomization, previously prescribed) and ND (anticholinergics not discontinued, not previously prescribed).ResultsDemographics were balanced between the D (n = 5846) and ND (n = 6317) groups, except for higher cumulative smoking (56 pack-years versus 48 pack-years), lower forced expiratory volume in one second (FEV(1))/forced vital capacity (43% versus 48%), and lower baseline FEV(1) (35.8% predicted versus 42.4% predicted) in the D group. In both groups, tiotropium reduced the risk for an exacerbation (hazard ratio [HR] = 0.83, P < 0.0001 [D] versus 0.79, P < 0.0001 [ND]) and a hospitalized exacerbation (HR = 0.85, P = 0.0467 versus 0.79, P = 0.0094). Tiotropium reduced the number of exacerbations per patient-year (rate ratio [RR] = 0.82, P < 0.0001 [D] versus RR = 0.80, P < 0.0001 [ND]) and associated hospitalizations per patient-year (RR = 0.88, P = 0.015 [D] versus RR = 0.74, P < 0.0001 [ND]).ConclusionTiotropium reduced exacerbations in patients who did and did not have anticholinergics discontinued upon randomization in clinical trials.

BackgroundBecause treadmill exercise testing is more representative of daily activity than cycle testing, we developed treadmill protocols to be used in various clinical settings as part of a two-year, multicenter, chronic obstructive pulmonary disease (COPD) trial evaluating the effect of tiotropium on exercise.MethodsWe enrolled 519 COPD patients aged 64.6 ± 8.3 years with a postbronchodilator forced expiratory volume in one second (FEV(1)) of 1.25 ± 0.42 L, 44.3% ± 11.9% predicted. The patients performed symptom-limited treadmill tests where work rate (Ẇ) was increased linearly using speed and grade adjustments every minute. On two subsequent visits, they performed constant Ẇ tests to exhaustion at 90% of maximum Ẇ from the incremental test.ResultsMean incremental test duration was 522 ± 172 seconds (range 20-890), maximum work rate 66 ± 34 watts. For the first and second constant Ẇ tests, both at 61 ± 33 watts, mean endurance times were 317 ± 61 seconds and 341 ± 184 seconds, respectively. The mean of two tests had an intraclass correlation coefficient of 0.85 (P < 0.001). During the second constant Ẇ test, 88.2% of subjects stopped exercise because of breathing discomfort; 87.1% for Global Initiative for Chronic Obstructive Lung Disease (GOLD) Stage II, 88.5% for GOLD Stage III, and 90.2% for GOLD Stage IV.ConclusionThe symptom-limited incremental and constant work treadmill protocol was well tolerated and appeared to be representative of the physiologic limitations of COPD.

Li-Chuan Tan,1 Wen-Jie Yang,2 Wei-Ping Fu,1 Ping Su,2 Jing-Kui Shu,1 Lu-Ming Dai1 1Department of Respiratory and Critical Care Medicine, First Affiliated Hospital of Kunming Medical University, Kunming 650032, People’s Republic of China; 2Department of Respiratory, Baoshan People’s Hospital, Baoshan 678000, People’s Republic of China Background: Heterogeneity of COPD results in different therapeutic effects for different patients receiving the same treatment. COPD patients need to be individually treated according to their own characteristics. The purpose of this study was to explore the differences in different CT phenotypic COPD by molecular metabolites through the use of metabolomics. Methods: According to the characteristics of CT imaging, 42 COPD patients were grouped into phenotype E (n=20) or phenotype M (n=24). Each COPD patient received tiotropium bromide powder for inhalation for a therapeutic period of 3 months. All subjects were assigned into phenotype E in pre-therapy (EB, n=20), phenotype E in post-therapy (EA, n=20), phenotype M in pre-therapy (MB, n=22), phenotype M in post-therapy (MA, n=22), or normal control (N, n=24). The method of metabolomics based on 1H nuclear magnetic resonance (1H-NMR) was used to compare the changes in serum metabolites between COPD patients and normal controls and between different phenotypes of COPD patients in pre- and post-therapy. Results: Patients with COPD phenotype E responded better to tiotropium bromide than patients with COPD phenotype M in terms of pulmonary function and COPD assessment test scores. There were differences in metabolites in COPD patients vs normal control people. Differences were also observed between different COPD phenotypic patients receiving the treatment in comparison with those who did not receive treatment. The changes of metabolites involved lactate, phenylalanine, fructose, glycine, asparagine, citric acid, pyruvic acid, proline, acetone, ornithine, lipid, pyridoxine, maltose, betaine, lipoprotein, and so on. These identified metabolites covered the metabolic pathways of amino acids, carbohydrates, lipids, genetic materials, and vitamin. Conclusion: The efficacy of tiotropium bromide on COPD phenotype E is better than that of phenotype M. Metabolites detected by 1H-NMR metabolomics have potentialities of differentiation of COPD and healthy people, discrimination of different COPD phenotypes, and giving insight into the individualized treatment of COPD. Keywords: COPD, metabolomics, tiotropium bromide, CT phenotyping, individualized treatment

The increa­sing prevalence of asthma (A) and diabetes mellitus type 2 (DM2T) necessitates administration of the adequate antia­sthmatic long-term basic therapy with consideration of comorbid states. The purpose consisted in revealing the therapeutic potential of Tiotropium bromide (TB) and L-arginine (Tivortine) in patients having uncontrolled moderately severe asthma in combination with DM2T (A+DM2T). Forty seven A+DM2T patients underwent an in-depth study before and after their treatment. They were divided into 2 groups: treatment (group 1, n=28) and comparison (group 2, n=19). Both groups received the standard 2-component therapy: budesonide/formoterol fumarate dihydrate – 160/4.5µg by 2 breaths twice a day and metformin at a dose of 500 mg twice a day. The complex of their basic therapy for group 1 additionally included TB (18 µg a day) and arginine hydrochloride preparation (Tivortine® aspartate, Yuriya-Farm) orally by 15 ml twice a day during 3 months (90 days). The patients were followed up 3 months and one year later. Their general condition demonstrated positive dynamics in both groups, the number of exacerbations in group 1 reducing by a factor of 4. The complex use of L-arginine and TB preparations against a background of the basic therapy in A+DM2T patients produced a better control over the disease, a more rapid elimination of obstruction manifestations, achievement and prolongation of the clinical spirographic remission, an improvement of the quality of life, correction of disturbances in haemocoagulation, fibrinolysis and the functional state of endothelium.

The aim of the study was to investigate the effectiveness of tiotropium bromide in patients with severe persistent asthma under conditions of real clinical practice. The study group included 20 outpatients who, despite the maximum volumes of basic therapy, maintained an uncontrolled course of the disease. In addition to previous therapy, patients were given tiotropium bromide 5 mg per day. The study lasted five months. During this period, clinical symptoms, the presence of exacerbations of asthma, spirometry parameters, the level of disease control according to the questionnaire Asthma Control Questionnaire™ (ACQ-5) and the quality of life of patients were monthly evaluated. It has been found that the inclusion of tiotropium bromide in the treatment regimen causes a significant improvement in asthma control, the ACQ-5 index decreased by 48 %. There was also a significant dynamics of postbronchodilation FEV1 and quality of life indicators. None of the patients had a worsening of the disease during the observation period. However, in order to achieve a therapeutic effect, systematic tiotropium bromide therapy was required for at least three months. The results obtained confirmed the positive effect of tiotropium bromide on the control of asthma and the quality of life.

The course of COPD is punctuated by acute exacerbations that are associated with an increase in the morbidity and mortality related to this chronic disease and may contribute to its rate of progression. Therefore, preventing and treating exacerbations are major goals of COPD management. The role of tiotropium in the prevention of exacerbations has been investigated in several placebo-controlled randomized clinical trials varying in duration from 3 months to 4 years in patients with moderate to very severe COPD. In all of these trials, tiotropium has uniformly reduced the proportion of patients experiencing at least one exacerbation and delayed the time to the first exacerbation compared with placebo. In the longer trials (> or =6 months' duration) tiotropium has also reduced the exposure-adjusted incidence rate of exacerbations. In trials of at least 1 year in duration, tiotropium either significantly reduced the risk of hospitalization for an exacerbation and/or the proportion of patients with an exacerbation-related hospitalization. In a meta-analysis that included 15 trials of tiotropium vs either placebo (n = 13) and/or a long-acting beta-agonist (LABA; n = 4), tiotropium significantly reduced the odds of experiencing an exacerbation compared to placebo as well as a LABA. The potential additive benefits of tiotropium to those of a LABA and/or inhaled corticosteroid in reducing exacerbations require further investigation. The mechanism whereby tiotropium reduces exacerbations is not due to an anti-inflammatory effect but more likely relates to its property of causing a sustained increase in airway patency and reduction in hyperinflation, thereby counteracting the tendency for respiratory insults to worsen airflow obstruction and hyperinflation. For the management of acute exacerbations, an increase in short-acting inhaled bronchodilators is recommended as needed, while the potential role of long-acting bronchodilators, such as tiotropium, in conjunction with short-acting agents, is unclear and warrants further study.

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Introduction: Airway obstruction is usually assessed by measuring forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC) and peak expiratory flow (PEF). This post hoc study investigated comparative responses of lung function measurements in adults and adolescents (full analysis set, N = 3873) following treatment with tiotropium Respimat®. Methods: Lung function outcomes were analysed from five phase III trials in adults (≥ 18 years) with symptomatic severe, moderate and mild asthma (PrimoTinA-asthma®, MezzoTinA-asthma® and GraziaTinA-asthma®, respectively), and one phase III trial in adolescents (12–17 years) with symptomatic moderate asthma (RubaTinA-asthma®). Changes from baseline versus placebo in FEV1, FVC, PEF and FEV1/FVC ratio with tiotropium 5 µg or 2.5 µg added to at least stable inhaled corticosteroids at week 24 (week 12 in GraziaTinA-asthma) were analysed. Results: All lung function measures improved in all studies with tiotropium 5 µg (mean change from baseline versus placebo), including peak FEV1 (110–185 mL), peak FVC (57–95 mL) and morning PEF (15.8–25.6 L/min). Changes in adolescents were smaller than those in adults, and were statistically significant primarily for FEV1 and PEF, but not for FVC. Conclusion: Consistent improvements were seen across all lung function measures with the addition of tiotropium to other asthma treatments in adults across all severities, whereas the improvements with tiotropium in adolescents primarily impacted measures of flow rather than lung volume. This may reflect less pronounced airway remodelling and air trapping in adolescents with asthma versus adults. Plain Language Summary: Asthma is characterised by problems with the way that the lungs work, particularly narrowing of the airways. Doctors can measure the effect of asthma on someone's breathing in different ways. We looked to see whether these different methods work for different people with asthma, and whether treatment affects all measurements in a similar way. Lung function was measured after treatment with a drug that opens the airways (tiotropium), and comparisons were made between adults and adolescents with asthma. We also looked at people with severe asthma and those whose asthma was less severe. Tiotropium improved all the measures of lung function in both age groups and across severities. One measure improved more in adults than in adolescents. This may be because adolescents had better lung function at the start and thus less room for improvement, or because the adolescents had not had asthma for as long, and so may have had less long-term damage to their airways than adults. Trial Registration Numbers: NCT00772538, NCT00776984, NCT01172808, NCT01172821, NCT01316380, NCT01257230. [ABSTRACT FROM AUTHOR]

Objective: To analyze the legal demands of tiotropium bromide to treat chronic obstructive pulmonary disease. Methods: We included secondary data from the pharmaceutical care management systems made available by the Paraná State Drug Center. Results: Public interest civil action and ordinary procedures, among others, were the most common used by the patients to obtain the medicine. Two Health Centers in Paraná (Londrina and Umuarama) concentrated more than 50% of the actions. The most common specialty of physicians who prescribed (33.8%) was pulmonology. There is a small financial impact of tiotropium bromide on general costs with medicines of the Paraná State Drug Center. However, a significant individual financial impact was observed because one unit of the medicine represents 38% of the Brazilian minimum wage. Conclusion: Our study highlights the need of incorporating this medicine in the class of long-acting anticholinergic bronchodilator in the Brazilian public health system. [ABSTRACT FROM AUTHOR]

Objective: A resolution passed by the government of the Brazilian state of São Paulo established a protocol for requesting free COPD medications, including tiotropium bromide, creating regional authorization centers to evaluate and approve such requests, given the high cost of those medications. Our objective was to analyze the requests received by an authorization center that serves cities in the greater metropolitan area of (the city of) São Paulo between 2011 and 2016. Methods: Data regarding the authorization, return, or rejection of the requests were compiled and analyzed in order to explain those outcomes. Subsequently, the clinical and functional data related to the patients were evaluated. Results: A total of 7,762 requests for dispensing COPD medication were analyzed. Requests related to male patients predominated. Among the corresponding patients, the mean age was 66 years, 12% were smokers, 88% had frequent exacerbations, and 84% had severe/very severe dyspnea. The mean FEV1 was 37.2% of the predicted value. The total number of requests decreased by 24.5% from 2012 to 2013 and was lowest in 2015. Most (65%) of the requests were accepted. The main reasons for the rejection/return of a request were a post-bronchodilator FEV1/FVC ratio > 0.7, a post-bronchodilator FEV1 > 50% of the predicted value, and failure to provide information regarding previous use of a long-acting ß2 agonist. During the study period, the total number of requests returned/rejected decreased slightly, and there was improvement in the quality of the data included on the forms. Conclusions: Here, we have identified the characteristics of the requests for COPD medications and of the corresponding patients per region served by the authorization center analyzed, thus contributing to the improvement of local public health care measures. [ABSTRACT FROM AUTHOR]

BackgroundImprovements in ventilatory mechanics with tiotropium increases exercise tolerance during pulmonary rehabilitation. We wondered whether tiotropium also increased physical activities outside of pulmonary rehabilitation.MethodsCOPD patients participating in 8 weeks of pulmonary rehabilitation were studied in a randomized, double-blind, placebo-controlled trial of tiotropium 18 microg daily (tiotropium = 47, placebo = 44). Study drug was administered for 5 weeks prior to, 8 weeks during, and 12 weeks following pulmonary rehabilitation. Patients completed a questionnaire documenting participation in pre-defined activities outside ofpulmonary rehabilitation during the 2 weeks prior to each visit. Patients who submitted an activity questionnaire at week 4 and on at least one subsequent visit were included in the analysis. For each patient, the number of sessions was multiplied with the duration of each activity and then summed to give overall activity duration.ResultsPatients (n = 46) had mean age of 67 years, mean baseline FEVJ of 0.84 L (33% predicted). Mean (SE) increase in duration of activities (minutes during 2 weeks prior to each visit) from week 4 (prior to PR) to week 13 (end of PR) was 145 (84) minutes with tiotropium and 66 (96) minutes with placebo. The increase from week 4 to week 25 (end of follow-up) was 262 (96) and 60 (93) minutes for the respective groups. Increases in activity duration from week 4 to weeks 17, 21, and 25 were statistically significant with tiotropium. No statistical differences over time were observed within the placebo-treated group and differences between groups were not significant.ConclusionsTiotropium appears to amplify the effectiveness of pulmonary rehabilitation as seen by increases in patient self-reported participation in physical activities.

Dimitrios Toumpanakis,1,2 Konstantinos Loverdos,1,2 Vassiliki Tzouda,1,2 Vyronia Vassilakopoulou,1,2 Eleni Litsiou,1,2 Christina Magkou,3 Vassiliki Karavana,1,2 Michael Pieper,4 Theodoros Vassilakopoulos1,2 1First Critical Care Department, Pulmonary Unit, National and Kapodistrian University of Athens Medical School, Evangelismos General Hospital, 2George P. Livanos and Marianthi Simou Laboratories, Thorax Foundation, 3Department of Pathology, Evangelismos General Hospital, Athens, Greece; 4Boehringer Ingelheim Pharma GmbH & Co. KG Div. Research Germany, Biberach, Germany Introduction: Resistive breathing (RB), a hallmark of obstructive airway diseases, is characterized by strenuous contractions of the inspiratory muscles that impose increased mechanical stress on the lung. RB is shown to induce pulmonary inflammation in previous healthy animals. Tiotropium bromide, an anticholinergic bronchodilator, is also shown to exert anti-inflammatory effects. The effect of tiotropium on RB-induced pulmonary inflammation is unknown.Methods: Adult rats were anesthetized, tracheostomized and breathed spontaneously through a two-way non-rebreathing valve. Resistances were connected to the inspiratory and/or expiratory port, to produce inspiratory resistive breathing (IRB) of 40% or 50% Pi/Pi,max (40% and 50% IRB), expiratory resistive breathing (ERB) of 60% Pe/Pe,max (60% ERB) or combined resistive breathing (CRB) of both 40% Pi/Pi,max and 60% Pe/Pe,max (40%/60% CRB). Tiotropium aerosol was inhaled prior to RB. After 6 h of RB, mechanical parameters of the respiratory system were measured and bronchoalveolar lavage (BAL) was performed. IL-1β and IL-6 protein levels were measured in lung tissue. Lung injury was estimated histologically.Results: In all, 40% and 50% IRB increased macrophage and neutrophil counts in BAL and raised IL-1β and IL-6 lung levels, tissue elasticity, BAL total protein levels and lung injury score. Tiotropium attenuated BAL neutrophil number, IL-1β, IL-6 levels and lung injury score increase at both 40% and 50% IRB. The increase in macrophage count and protein in BAL was only reversed at 40% IRB, while tissue elasticity was not affected. In all, 60% ERB raised BAL neutrophil count and total protein and reduced macrophage count. IL-1β and IL-6 levels and lung injury score were increased. Tiotropium attenuated these alterations, except for the decrease in macrophage count and the increase in total protein level. In all, 40%/60% CRB increased macrophage and neutrophil count in BAL, IL-1β and IL-6 levels, tissue elasticity, total protein in BAL and histological injury score. Tiotropium attenuated the aforementioned alterations.Conclusion: Tiotropium inhalation attenuates RB-induced pulmonary inflammation. Keywords: resistive breathing, inflammation, tiotropium bromide

Background and Objectives: Severe asthma seen in substantial proportion of patients has been a poorly controlled disease, with recurring symptoms and exacerbations despite the use of inhaled glucocorticoids (ICS), long-acting beta-agonists (LABAs-2), leukotriene receptor antagonist (LTRA), and theophyllines. A potential alternative approach is addition of a second bronchodilator with an alternative mode of action, the anticholinergic tiotropium bromide. Hence, the present study was undertaken to evaluate clinical effectiveness of tiotropium bromide 18 mcg as add-on therapy in severe asthma patients. Methodology: A single-blinded randomized study was carried in patients with severe asthma. The patients were randomized into two groups. The study group received an addition of 18 mcg of tiotropium while both groups were continued on LABA and high dose ICS combination, theophyllines, and LTRA. Improvement in lung function (forced expiratory volume in 1 s [FEV1], forced vital capacity [FVC], and peak expiratory flow rate [PEFR]), clinical symptoms, and quality of life were assessed by mini asthma quality of life questionnaire (mini-AQLQ) at 4, 8, and 12 weeks. Results: Seventy patients were included in the study, of which 63 completed the study period. Baseline characteristics were well matched between the groups. At the end of 12 weeks, the tiotropium group showed a mean improvement in FEV1 and FVC of 450 ml and 560 ml, respectively, as compared to the control group (P < 0.0001). PEFR showed mean difference of 16.8 L/min in the study group at the end of 12 weeks as compared to the control group and it was statistically significant (P < 0.0001). Quality of life as assessed by mini-AQLQ was statistically significant in study group as compared to control group (3.42 vs. 3.07; P < 0.0001). In study group, about 21 patients (65.62%) had no exacerbations compared to eight patients (25.8%) in the control group (P = 0.045). Conclusions: The addition of once-daily tiotropium to severe asthma treatment regimen including high-dose ICS plus LABA, theophyllines, and LTRA significantly improves lung functions and quality of life over 12 weeks of therapy.