tiotropium-bromide and olodaterol

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Dyspnea; Exercise; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide; Treatment Outcome

The natural course of chronic obstructive pulmonary disease usually includes exacerbations. chronic obstructive pulmonary disease patients suffer from 1-4 exacerbations per year on average. These are associated with worsening quality of life and increased mortality. Reducing and controlling the number of exacerbations is one of the main goals of chronic obstructive pulmonary disease treatment. Among current treatments, tiotropium is the active substance with the strongest evidence in the reduction of moderate/severe exacerbations, together with a good safety and tolerability profile. The addition of olodaterol to tiotropium offers well-tolerated and effective double bronchodilation for improving lung function, quality of life, and decreased dyspnoea compared to its single components. This also reduces the annual rate of moderate/severe exacerbations vs. tiotropium by 7%, although not reaching the pre-specified statistical significance level of P<.01.

Topics: Benzoxazines; Bronchodilator Agents; Drug Therapy, Combination; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

Inhaled bronchodilators are the key-stone of chronic obstructive pulmonary disease (COPD) management. Olodaterol 5 µg, a long-acting β2-adrenoceptor agonist (LABA) is one such bronchodilator indicated as a once-daily maintenance therapy. Areas covered: This article reviews the several trials that have assessed olodaterol as a COPD therapy. It covers safety and tolerability data and provides the reader with an expert opinion on its use as a treatment for COPD. Expert opinion: Olodaterol improves lung function for 24 h and reduces rescue medication use. It may also improve dyspnea, exercise tolerance, and health-related quality of life. It is well tolerated with an acceptable cardiovascular and respiratory adverse event profile. There is some evidence that olodaterol, as well as other LABAs, can reduce exacerbation frequency, but not FEV1 decline and death. LABAs alone are indicated in group A/B COPD subjects. Olodaterol and indacaterol are administered once-daily and may offer an adherence advantage over other LABAs with more frequent dosing schedules. Co-administration of an olodaterol/tiotropium fixed dose combination in a single inhaler device is recommended as step-up in group A/B COPD subjects not sufficiently treated by olodaterol alone or as initial therapy in those with severe exertional dyspnea.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Exercise Tolerance; Forced Expiratory Volume; Half-Life; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Several new fixed-dose combination bronchodilators have been launched in the world, and 3 different types are now available in Japan. Assessing their efficacy relative to each other has not been performed yet. In the present manuscript, characteristics of glycopyrronium/indacaterol, umeclidinium/vilanterol and tiotropium/olodaterol were reviewed. In particular, changes in trough and peak forced expiratory volume in 1 second (FEV1), St George's Respiratory Questionnaire (SGRQ) total scores, and transitional dyspnea index (TDI) focal scores were reviewed in these bronchodilators.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Delayed-Action Preparations; Drug Combinations; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Respiratory Function Tests; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is a progressive, debilitating disorder that results in frequent exacerbations and impacts quality of life. It represents a growing burden of health care cost, both from societal and economic perspectives. Short- and long-acting bronchodilators remain the mainstay of therapy in COPD patients. New fixed-dose combination inhalers with novel pharmacological combinations of long-acting β2-agonists and muscarinic antagonists and delivered once-daily through a variety of devices are currently being developed and licensed for the treatment of COPD. There is mounting research suggesting that combining a fixed dose of a β2-agonist and a muscarinic antagonist achieves better bronchodilation and clinical outcomes compared with either agent alone. These once-daily dosing inhalers are anticipated to impact favorably on patient preference and compliance. This review examines the fixed-dose combination of tiotropium bromide and olodaterol delivered by a Respimat(®) Soft Mist™ inhaler at doses of 2.5/5 μg and 5/5 μg in moderate-to-very-severe COPD, and its potential role in COPD compared with other long-acting β2-agonist with long-acting muscarinic antagonist combinations and delivery devices.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Drug Combinations; Dry Powder Inhalers; Exercise Tolerance; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Tiotropium Bromide; Treatment Outcome

A solid scientific rationale and an increasing body of clinical evidence for combining a β2-agonist with an antimuscarinic agent in COPD fully support the opinion that patients not controlled by a single bronchodilator should be given two bronchodilators with different mechanisms of action. Tiotropium is an established choice for the management of patients with stable COPD, and olodaterol is a new effective and safe once-daily long-acting β2-agonist. The parallel bronchodilating modes of action of olodaterol and tiotropium make them an attractive combination in COPD. The large ongoing TOviTO Phase III trial program is documenting the efficacy and safety of olodaterol/tiotropium fixed dose combination delivered via the Respimat Soft Mist Inhaler as maintenance therapy in patients with moderate to very severe COPD. However, we must still know whether this fixed-dose combination will affect exacerbations and hospitalizations, and ultimately death, and also the precise estimates of its relative cardiovascular safety.

Topics: Administration, Inhalation; Animals; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide

Topics: Administration, Inhalation; Animals; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Randomized Controlled Trials as Topic; Tiotropium Bromide

Chronic obstructive pulmonary disease (COPD), a respiratory disease characterized by a progressive decline in lung function, is considered to be a leading cause of morbidity and mortality. Long-acting inhaled bronchodilators, such as long-acting β2 agonists (LABAs) or long-acting muscarinic antagonists (LAMAs), are the cornerstone of maintenance therapy for patients with moderate-to-very-severe COPD. For patients not sufficiently controlled on a single long-acting bronchodilator, a combination of different bronchodilators has shown a significant increase in lung function. Tiotropium, a once-daily dosing LAMA, demonstrated sustained improvements in lung function as well as improved health-related quality of life, reduced exacerbations, and increased survival without altering the rate of decline in the mean forced expiratory volume in 1 second (FEV1) with fairly tolerable side effects. Olodaterol is a once-daily dosing LABA that has proven to be effective in improving lung function, reducing rescue medication use, and improving dyspnea and health-related quality of life, as well as improving exercise endurance with an acceptable safety profile. The combination of olodaterol and tiotropium provided additional improvements in lung function greater than monotherapy with each drug alone. Several well-designed randomized trials confirmed that the synergistic effect of both drugs in combination was able to improve lung function and health-related quality of life without a significant increase in adverse effects. The objective of this paper is to review available evidence on the clinical efficacy and safety of tiotropium, olodaterol, and their combination in patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cholinergic Antagonists; Cost-Benefit Analysis; Drug Administration Schedule; Drug Combinations; Drug Costs; Drug Synergism; Forced Expiratory Volume; Humans; Lung; Pulmonary Disease, Chronic Obstructive; Quality of Life; Recovery of Function; Tiotropium Bromide; Treatment Outcome

Olodaterol (Striverdi(®) Respimat(®)) is a novel, long-acting, β2-adrenergic receptor agonist developed by Boehringer Ingelheim for the treatment of chronic obstructive pulmonary disease (COPD). The drug is delivered via the Respimat(®) Soft Mist™ inhaler. Olodaterol received its first global approval for the once-daily maintenance treatment of COPD in Canada and Russia, and submissions for regulatory approval have also been made in the USA, the EU and elsewhere. Phase II trials have been conducted in patients with asthma. The company is also developing a fixed-dose combination of olodaterol with tiotropium bromide, a long-acting anti-muscarinic agent, for the treatment of COPD. This article summarizes the milestones in the development of olodaterol leading to this first approval for COPD.

Topics: Administration, Inhalation; Asthma; Benzoxazines; Bronchodilator Agents; Clinical Trials, Phase II as Topic; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

Long-acting bronchodilators (LABD), in general, reduce respiratory symptoms, improve exercise endurance time and pulmonary function in patients with chronic obstructive pulmonary disease (COPD). However, there might be heterogeneity in improvement for several outcomes on an individual level. Therefore, we aimed to profile the multidimensional response in patients receiving tiotropium/olodaterol (T/O) using self-organizing maps (SOM).. This is a secondary analysis of the TORRACTO study: a multicenter, multinational, randomized, double-blind, placebo-controlled, parallel-group trial to evaluate the effects of T/O (2.5/5 and 5/5 μg) compared with placebo after 6 and 12 weeks of treatment in patients with COPD. In the current study, we used endurance time, forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), inspiratory capacity (IC) at rest and IC at isotime (ICiso) to identify clusters by means of SOM in patients treated with T/O.. Six clusters with distinct response profiles were generated at week 12 in COPD patients receiving T/O (n = 268). Patients in cluster 1 improved significantly on all outcomes, whilst cluster 5 showed strong improvement in endurance time (357s); contrarily, FEV1, FVC, ICrest and ICiso decreased when compared to baseline.. Individual responses on endurance time and pulmonary function after 12 weeks of T/O are heterogeneous. This study identified clusters in COPD patients with markedly different multidimensional response on LABD.

Topics: Bronchodilator Agents; Humans; Inspiratory Capacity; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Real-world evidence is needed to optimize pharmacotherapy for chronic obstructive pulmonary disease (COPD). The effectiveness of inhaled tiotropium/olodaterol according to baseline symptoms and previous COPD treatment and predictors of response were assessed.. Tiotropium/olodaterol improved symptoms and lung function in Japanese COPD patients. Our results support the possible use of tiotropium/olodaterol in treatment-naive patients and those with total CAT scores ≥ 10.. Clinicaltrials.gov Identifier for parent study: NCT02850978.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Product Surveillance, Postmarketing; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Overall, treatment with tiotropium/olodaterol significantly increased the time to, and reduced the risk of, CID versus tiotropium (median time to CID 226 versus 169 days; hazard ratio [HR] 0.76 [95% confidence interval 0.68, 0.85]; P < 0.0001). Significant reductions were also observed in patients with low exacerbation history (241 versus 170; HR 0.73 [0.64, 0.83]; P < 0.0001), GOLD 2 patients (241 versus 169; 0.72 [0.61, 0.84]; P < 0.0001) and maintenance-naïve patients (233 versus 171; 0.75 [0.62, 0.91]; P = 0.0030).. In patients with COPD, including patients with low exacerbation history, GOLD 2 patients and maintenance-naïve patients, tiotropium/olodaterol reduced the risk of CID versus tiotropium. These results demonstrate the advantages of treatment optimisation with tiotropium/olodaterol over tiotropium monotherapy.. ClinicalTrials.gov identifier: TONADO. COPD is a complicated disease that deteriorates over time. Worsening of COPD is associated with the lungs working less effectively, a fall in quality of life and a rise in sudden flare-ups of the disease. In this study, we looked at lung function, quality of life and flare-ups together using a measure called “clinically important deterioration” (CID). We looked at 2055 people with COPD to compare the effects of taking two bronchodilators (tiotropium and olodaterol) against taking one bronchodilator (tiotropium alone). Bronchodilators are a type of inhaled medication that relax the muscles in the lungs and widen airways, making it easier to breathe. They have also been shown to reduce sudden flare-ups of COPD. Across a wide range of people with COPD, we found that treatment with tiotropium/olodaterol reduced the risk of a CID compared with tiotropium alone. This includes in those patients at an early stage of disease, who may benefit from finding the best treatment option for them as early as possible.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) is one of the major causes of morbidity and mortality worldwide and in China. For patients with more severe symptoms, initial treatment with long acting β2-agonists and long-acting muscarinic antagonists combination therapy is recommended. Tiotropium + olodaterol fixed-dose combination (Tio + Olo FDC) is an aqueous solution of tiotropium bromide and olodaterol delivered by the RESPIMAT® Soft Mist™ inhaler for patients with moderate to very severe COPD.. This single site, open-label, phase Ib clinical study assessed the pharmacokinetic (PK) and safety profiles of once-daily Tio + Olo FDC (5 μg/5 μg) after single dose and at steady state in Chinese patients with moderate to severe COPD over 3 weeks. The PK and safety profiles of Japanese and Caucasian populations from 2 independent COPD studies were provided for comparison.. A total of 12 Chinese patients received Tio + Olo FDC. After multiple inhaled administration of Tio + Olo FDC, tiotropium and olodaterol were rapidly absorbed and reached peak plasma concentration at about 5 and 25 min, respectively. The accumulation ratios after multiple administrations were 1.3 and 1.6 for tiotropium and olodaterol in Chinese patients. Tio + Olo FDC was well-tolerated; all AEs were mild.. Tio + Olo FDC (5 μg/5 μg) was rapidly absorbed and had a good safety profile in Chinese patients with COPD.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; China; Drug Combinations; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Comparative effects on physical activity of mono and dual bronchodilators remain unclear in patients with treatment-naïve chronic obstructive pulmonary disease (COPD). We sought to compare the changes in physical activity before and after tiotropium and tiotropium/olodaterol treatment in treatment-naïve COPD patients.. A prospective, multicenter, randomized, open-labeled, and parallel interventional study was conducted. Eighty Japanese patients with treatment-naïve COPD were randomized to receive either tiotropium or tiotropium/olodaterol treatment for 12 weeks. Spirometry and dyspnea index were assessed, and COPD assessment test (CAT) and the 6-minute walk distance (6MWD) were conducted before and after treatment. Evaluation of physical activity was assessed by a triaxle accelerometer over a 2-week period before and after treatment.. This is the first study to report the impact of dual bronchodilator on physical activity in treatment-naïve COPD patients of Japanese with low BMI.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Combinations; Exercise; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Prospective Studies; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Smoking worsens underlying asthma inflammation and also induces resistance to inhaled corticosteroids (ICS). Small airways dysfunction measured by impulse oscillometry (IOS) is associated with worse control.. We investigated the effects on small airways of adding long-acting beta-agonist (LABA) alone or with long-acting muscarinic antagonist (LAMA) to ICS in asthmatic smokers.. Sixteen current smokers were enrolled: mean age 44 year, FEV1 84%, FEF25-75 47%, R5 158%, ACQ 1.69, 20 pack year . Patients were converted to a reference ICS as HFA-BDP during initial run-in at median dose of 800 µg/day. Open label olodaterol 5 µg od (OLO) or olodaterol 5 µg/tiotropium 5 µg od (OLO/TIO) was added to HFA-BDP for median duration of 3 weeks in a randomized cross over design, including run-in and washout periods on HFA-BDP. IOS and spirometry were measured after each treatment (BDP/OLO/TIO or BDP/OLO) and at baseline after run-in and washout (BDP).. After chronic dosing, IOS outcomes at trough except for R20 were all significantly improved with OLO/TIO compared to OLO. For the primary end-point of total airway resistance (as R5), the mean difference (95%CI) at trough was 0.06 (0.015-0.10) kPa/l/s, peripheral airways resistance (as R5-R20) 0.03 (0.003-0.06) kPa/l/s, peripheral lung reactance area (as AX) 0.38 (0.08-0.68) kPa/l and resonant frequency (as RF) 2.28 (0.45-4.12) Hz. FEF25-75 at trough was also better with OLO/TIO vs TIO: 0.93 (0.86 - 0.95) l/s while FEV1 was not different.. ICS/LABA/LAMA was superior to ICS/LABA on trough small airway outcomes in asthma patients who smoke.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Adult; Anti-Asthmatic Agents; Asthma; Benzoxazines; Cross-Over Studies; Drug Combinations; Female; Humans; Lung; Male; Muscarinic Antagonists; Nebulizers and Vaporizers; Recovery of Function; Scotland; Smokers; Smoking; Time Factors; Tiotropium Bromide; Treatment Outcome

Cardiovascular disease is a frequent comorbidity in patients with COPD. Many physicians, particularly pulmonologists, are reluctant to use β-adrenoceptor blocking agents (β-blockers) in patients with COPD, despite their proven effectiveness in preventing cardiovascular events.. The large (5,162 patients) phase III TONADO 1 and 2 studies assessed lung function and patient-reported outcomes in patients with moderate to very severe COPD receiving long-acting bronchodilator treatment across 1 year. This post hoc analysis characterized lung-function changes, patient-reported outcomes, and safety in the subgroup of patients receiving β-blockers in the studies.. In total, 557 of 5,162 patients (11%) received β-blockers at baseline. Postbronchodilator FEV. Lung function, overall respiratory status, and safety of tiotropium/olodaterol were not influenced by baseline β-blocker treatment in patients with moderate to very severe COPD. Results from this large patient cohort support the cautious and appropriate use of β-blockers in patients with COPD and cardiovascular comorbidity.. ClinicalTrials.gov; No.: NCT01431274 and No. NCT01431287; URL: www.clinicaltrials.gov.

Topics: Adrenergic beta-Antagonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Of 3,041 patients included in this analysis, 1,333 (43.8%) had mild, 404 (13.3%) had moderate, and 5 (0.2%) had severe renal impairment; these were distributed equally between treatment groups. Almost one-quarter of all treated patients (23.4%) had a history of cardiac disorder, 45.6% had hypertension, and 13.3% had glucose metabolism disorders, including diabetes. AEs with olodaterol, tiotropium, and tiotropium/olodaterol occurred in 75.1%, 70.8%, and 72.0% of patients with no renal impairment, 75.7%, 74.0%, and 73.3% with mild renal impairment, and 84.3%, 79.5%, and 79.7% with moderate renal impairment, respectively. There was no notable effect of renal impairment on the proportion of patients with an AE, and no differences were observed between tiotropium/olodaterol versus the monocomponents. There was no difference in the incidence of major adverse cardiac events, renal and urinary tract AEs, or potential anticholinergic effects with increasing severity of renal impairment.. Over half the patients enrolled in the TONADO studies had renal impairment, and there was a high level of pre-existing cardiovascular comorbidity. The safety and tolerability of tiotropium/olodaterol is comparable to the monocomponents, irrespective of the level of renal impairment.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Kidney; Kidney Diseases; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

The DYNAGITO study was a Phase IIIb, randomized, double-blind, multicenter, active-controlled, parallel-group, 52-week study designed to determine the efficacy and safety of tiotropium and olodaterol combination therapy (TIO+OLO 5/5 μg) versus tiotropium monotherapy (TIO 5 μg) for reducing moderate-to-severe exacerbations of COPD. This is a prespecified analysis of the DYNAGITO data in Japanese patients.. Enrolled patients had a diagnosis of COPD with at least one moderate-to-severe exacerbation in the previous 12 months. Of the total 7,880 treated patients in the DYNAGITO study, 461 (TIO+OLO 5/5 μg: n=226, TIO 5 μg: n=235) were Japanese. The primary endpoint was the annualized rate of moderate-to-severe COPD exacerbations. The key secondary endpoint was the time to first moderate-to-severe COPD exacerbation, and other secondary endpoints included the annualized rate of exacerbations leading to hospitalization, time to first COPD exacerbation leading to hospitalization, and all-cause mortality. Safety data were analyzed descriptively.. Combination therapy with TIO+OLO resulted in a 29% lower rate of moderate-to-severe COPD exacerbations relative to TIO monotherapy (rate ratio 0.71; 99% CI: 0.46, 1.10;. In a prespecified subgroup analysis of Japanese patients in the DYNAGITO study, combination therapy with TIO+OLO was more effective than TIO in reducing exacerbations. Both treatments were well tolerated.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Cause of Death; Disease Progression; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Hospitalization; Humans; Male; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Time Factors; Tiotropium Bromide; Treatment Outcome

Long-term safety, particularly cardiovascular safety, is of special interest in maintenance treatment of chronic obstructive pulmonary disease (COPD) with long-acting β. This analysis comprised 3100 patients with moderate to very severe COPD, treated for ≤1 year, including 784 patients with cardiovascular co-morbidities. AEs were balanced across treatments in the total population as well as in patient subgroups with pre-existing cardiovascular co-morbidities. The incidence and nature of events were consistent with the disease under study and a 1-year trial duration. 494/3100 patients contributed to an adjudicated analysis of SAEs: 260 had respiratory-related, 53 had cardiovascular-related and 16 had cerebrovascular-related SAEs. Incidences of these SAEs were comparable between treatments. There was no evidence of any increased risk for the combination compared to the monotherapy groups.. These data provide confidence for clinicians that tiotropium/olodaterol 5/5 μg can be safely administered once-daily to patients with moderate to very severe COPD long-term, including those with significant cardiovascular co-morbidity.. ClinicalTrials.gov, Nos.: NCT01431274, NCT01431287.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cardiovascular Diseases; Comorbidity; Double-Blind Method; Drug Combinations; Female; Follow-Up Studies; Forced Expiratory Volume; Humans; Incidence; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Chronic obstructive pulmonary disease is associated with significant morbidity and mortality. Trials of maintenance chronic obstructive pulmonary disease treatments focus on improvement in lung function and reductions in exacerbations, while patients are much more concerned about symptoms and health status. Our aim was to investigate the effects of tiotropium + olodaterol on patient-reported health outcomes, breathlessness and night-time rescue medication use in patients with chronic obstructive pulmonary disease, compared to placebo, tiotropium or olodaterol monotherapy. Two pairs of replicate, phase III studies of 12 (OTEMTO 1 + 2) and 52 weeks' (TONADO 1 + 2) duration were evaluated, in which patients received either tiotropium + olodaterol 2.5/5 or 5/5 μg, tiotropium 2.5 or 5 μg, olodaterol 5 μg or placebo, all delivered once daily via Respimat inhaler. Patient-reported outcomes included breathlessness assessed by transition dyspnoea index focal score, health status assessed by St George's Respiratory Questionnaire total score and night-time rescue medication use at 12 or 24 weeks. Outcomes from the pooled study data are reported. Overall, 1621 and 5162 patients were treated in the OTEMTO and TONADO trials, respectively. Significantly larger improvements in St George's Respiratory Questionnaire and transition dyspnoea index focal scores were observed and a greater proportion of patients were responders to therapy (based on minimum clinically important differences in St George's Respiratory Questionnaire and transition dyspnoea index) with tiotropium + olodaterol compared to either monotherapy or to placebo. Tiotropium + olodaterol 5/5 µg significantly reduced night-time rescue medication usage.. COMBINED INHALER PROVES EFFECTIVE: Results from four in-depth studies show that a combined inhaler is very effective for treatment of moderate to severe chronic lung disease. Alleviating the symptoms of chronic obstructive pulmonary disease (COPD), particularly sleep disturbance, is crucial to enhancing patients' quality of life. Gary Ferguson at the Pulmonary Research Institute of Southeast Michigan, together with other scientists across the USA and Germany, analysed data from four large-scale studies to evaluate the efficacy of STIOLTO Respimat, a combination of two bronchodilators-tiotropium, and olodaterol, which tackle airway obstruction and breathlessness, improving long-term lung function. They found that the new drug combination triggered significant improvements in patients' quality of life and levels of breathlessness. Use of night-time rescue medication in patients on STIOLTO Respimat was considerably reduced. A greater number of patients responded positively to the combined inhaler than to monotherapy.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Therapy, Combination; Dyspnea; Female; Forced Expiratory Volume; Health Status; Humans; Male; Middle Aged; Patient Reported Outcome Measures; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Vital Capacity

The efficacy and safety of once-daily tiotropium+olodaterol (T+O) (2.5/5µg or 5/5µg) for treating chronic obstructive pulmonary disease (COPD) have been demonstrated in the large, multinational, randomized, Phase III studies TONADO. Patients were randomized to 52 weeks of double-blind treatment with once-daily T+O (2.5/5 or 5/5µg) or O (5µg) monotherapy via the Respimat. The incidence of adverse events (AEs) was comparable in the T+O 2.5/5µg (75.0%), T+O 5/5µg (85.4%), and O 5µg (80.5%) groups, with drug-related AEs being reported in 5.0%, 7.3%, and 4.9% of patients, respectively. Serious AEs were reported in 14 patients (11.5%). The change from baseline in forced expiratory volume in 1s (FEV. No safety concerns for long-term T+O treatment were identified in Japanese patients with COPD. A numerical improvement in lung function was observed with T+O treatment compared to O monotherapy.

Topics: Administration, Inhalation; Adult; Aged; Asian People; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Time Factors; Tiotropium Bromide; Treatment Outcome

Tiotropium + olodaterol has demonstrated improvements beyond lung function benefits in a large Phase III clinical program as a once-daily maintenance treatment for COPD and may be a potential option for the initiation of maintenance treatment in COPD. Despite guideline recommendations that combined long-acting β2-agonists and inhaled corticosteroids should only be used in individuals at high risk of exacerbation, there is substantial use in individuals at lower risk. This raises the question of the comparative effectiveness of this combination as maintenance treatment in this group compared to other combination regimens.. The study aimed to assess the effect on lung function of once-daily tiotropium + olodaterol versus twice-daily salmeterol + fluticasone propionate in all participants with Global initiative for chronic Obstructive Lung Disease 2 or 3 (moderate to severe) COPD.. This was a randomized, double-blind, double-dummy, four-treatment, complete crossover study in which participants received once-daily tiotropium + olodaterol (5/5 µg and 2.5/5 µg) via Respimat(®) and twice-daily salmeterol + fluticasone propionate (50/500 µg and 50/250 µg) via Accuhaler(®) for 6 weeks. The primary end point was change in forced expiratory volume in 1 second (FEV1) area under the curve from 0 hour to 12 hours (AUC0-12) relative to the baseline after 6 weeks.. Tiotropium + olodaterol 5/5 µg and 2.5/5 µg demonstrated statistically significant improvements in FEV1 AUC0-12 compared to salmeterol + fluticasone propionate (improvements from baseline were 317 mL and 295 mL with tiotropium + olodaterol 5/5 µg and 2.5/5 µg, and 188 mL and 192 mL with salmeterol + fluticasone propionate 50/500 µg and 50/250 µg, respectively). Tiotropium + olodaterol was superior to salmeterol + fluticasone propionate in lung function secondary end points, including FEV1 area under the curve from 0 hour to 24 hours (AUC0-24).. Once-daily tiotropium + olodaterol in participants with moderate-to-severe COPD provided superior lung function improvements to twice-daily salmeterol + fluticasone propionate. Dual bronchodilation can be considered to optimize lung function in individuals requiring maintenance treatment for COPD.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Combinations; Drug Monitoring; Female; Fluticasone; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Salmeterol Xinafoate; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease is generally progressive and associated with reduced physical activity. Both pharmacological therapy and exercise training can improve exercise capacity; however, these are often not sufficient to change the amount of daily physical activity a patient undertakes. Behaviour-change self-management programmes are designed to address this, including setting motivational goals and providing social support. We present and discuss the necessary methodological considerations when integrating behaviour-change interventions into a multicentre study.. PHYSACTO is a 12-week phase IIIb study assessing the effects on exercise capacity and physical activity of once-daily tiotropium+olodaterol 5/5 µg with exercise training, tiotropium+olodaterol 5/5 µg without exercise training, tiotropium 5 µg or placebo, with all pharmacological interventions administered via the Respimat inhaler. Patients in all intervention arms receive a behaviour-change self-management programme to provide an optimal environment for translating improvements in exercise capacity into increases in daily physical activity. To maximise the likelihood of success, special attention is given in the programme to: (1) the Site Case Manager, with careful monitoring of programme delivery; (2) the patient, incorporating patient-evaluation/programme-evaluation measures to guide the Site Case Manager in the self-management intervention; and (3) quality assurance, to help identify and correct any problems or shortcomings in programme delivery and ensure the effectiveness of any corrective steps. This paper documents the comprehensive methods used to optimise and standardise the behaviour-change self-management programme used in the study to facilitate dialogue on the inclusion of this type of programme in multicentre studies.. The study has been approved by the relevant Institutional Review Boards, Independent Ethics Committee and Competent Authority according to national and international regulations. The results of this study will be disseminated through relevant, peer-reviewed journals and international conference presentations.. NCT02085161.

Topics: Adult; Aged; Australia; Benzoxazines; Bronchodilator Agents; Canada; Combined Modality Therapy; Double-Blind Method; Europe; Exercise Test; Exercise Therapy; Female; Humans; Male; Middle Aged; New Zealand; Pulmonary Disease, Chronic Obstructive; Quality of Life; Research Design; Self Care; Tiotropium Bromide; Treatment Outcome; United States; Walking

Efficacy and safety of tiotropium+olodaterol fixed-dose combination (FDC) compared with the mono-components was evaluated in patients with moderate to very severe chronic obstructive pulmonary disease (COPD) in two replicate, randomised, double-blind, parallel-group, multicentre, phase III trials. Patients received tiotropium+olodaterol FDC 2.5/5 μg or 5/5 μg, tiotropium 2.5 μg or 5 μg, or olodaterol 5 μg delivered once-daily via Respimat inhaler over 52 weeks. Primary end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response, trough FEV1 response and St George's Respiratory Questionnaire (SGRQ) total score at 24 weeks. In total, 5162 patients (2624 in Study 1237.5 and 2538 in Study 1237.6) received treatment. Both FDCs significantly improved FEV1 AUC0-3 and trough FEV1 response versus the mono-components in both studies. Statistically significant improvements in SGRQ total score versus the mono-components were only seen for tiotropium+olodaterol FDC 5/5 μg. Incidence of adverse events was comparable between the FDCs and the mono-components. These studies demonstrated significant improvements in lung function and health-related quality of life with once-daily tiotropium+olodaterol FDC versus mono-components over 1 year in patients with moderate to very severe COPD.

Topics: Administration, Inhalation; Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Humans; Internationality; Male; Maximum Tolerated Dose; Metered Dose Inhalers; Middle Aged; Pulmonary Disease, Chronic Obstructive; Risk Assessment; Severity of Illness Index; Spirometry; Tiotropium Bromide; Treatment Outcome

This study investigated the effects on 24-h lung function and lung volume of a once-daily fixed-dose combination (FDC) of the long-acting muscarinic antagonist tiotropium and the long-acting β2-agonist olodaterol in patients with chronic obstructive pulmonary disease.. This was a randomised, double-blind, placebo-controlled, Phase III trial with an incomplete crossover design. Patients received four of the following six treatment options for 6 weeks each: placebo, olodaterol 5 μg, tiotropium 2.5 μg, tiotropium 5 μg, tiotropium + olodaterol FDC 2.5/5 μg and tiotropium + olodaterol FDC 5/5 μg, all delivered via the Respimat(®) inhaler. The primary end point was forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 24 h (AUC0-24) response after 6 weeks of treatment; key secondary end points were FEV1 AUC from 0 to 12 h and AUC from 12 to 24 h, and further end points included lung-volume parameters measured using body plethysmography (subset of patients), measures of peak and trough FEV1, and incidence of adverse events.. A significant improvement in FEV1 AUC0-24 response was observed with tiotropium + olodaterol 5/5 μg and 2.5/5 μg versus placebo and monotherapies after 6 weeks of treatment; mean response with tiotropium + olodaterol 5/5 μg versus placebo was 0.280 L (p < 0.0001). Differences to monotherapies with tiotropium + olodaterol 5/5 μg were 0.115 L versus olodaterol 5 μg, 0.127 L versus tiotropium 2.5 μg and 0.110 L versus tiotropium 5 μg (p < 0.0001 for all comparisons). Secondary end points supported these data. No safety concerns were identified.. Overall, this study demonstrated improvements in lung function over 24 h with an FDC of tiotropium + olodaterol over tiotropium or olodaterol alone, with no observed difference in tolerability. ClinicalTrials.gov number: NCT01559116.

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Drug Combinations; Humans; Male; Middle Aged; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Respiratory Function Tests; Time Factors; Tiotropium Bromide; Treatment Outcome

The once-daily long-acting muscarinic antagonist (LAMA) tiotropium and once-daily long-acting β2-agonist (LABA) olodaterol have been studied as a once-daily fixed-dose combination (FDC) in patients with chronic obstructive pulmonary disease (COPD). Two large, 52-week, double-blind, parallel-group studies in patients with moderate-very severe COPD demonstrated that tiotropium + olodaterol significantly improved lung function and symptoms versus the monocomponents. This post hoc analysis determined effects on lung function by prior LAMA or LABA maintenance treatment and initial disease severity.. 5162 patients were randomized and treated with olodaterol 5 µg, tiotropium 2.5 µg, tiotropium 5 µg, tiotropium + olodaterol 2.5/5 µg, or tiotropium + olodaterol 5/5 µg (all once daily via Respimat(®) inhaler). Primary efficacy (lung-function) end points were forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) and trough FEV1 responses (i.e., change from baseline). Pooled data are presented for the following subgroups: prior maintenance treatment with LAMA or LABA, Global initiative for chronic Obstructive Lung Disease (GOLD) 2 (predicted FEV1 50% to <80%) and 3 (30% to <50%)/4 (<30%), sex, age, and prior use of inhaled corticosteroids.. Tiotropium + olodaterol FDC improved lung function over the monocomponents in patients with GOLD 2 and 3-4 disease, irrespective of prior LAMA or LABA maintenance therapy; most comparisons between FDCs and their respective monocomponents were statistically significant (P < 0.05). FEV1 AUC0-3 and trough FEV1 responses for the individual treatments were generally greater in patients with less severe COPD at baseline.. Tiotropium + olodaterol 5/5 µg significantly improved FEV1 AUC0-3 and trough FEV1 in all GOLD severity groups compared to olodaterol 5 µg and tiotropium 5 µg alone, irrespective of whether patients had received prior LAMA or LABA maintenance treatment. Improvements from baseline in lung function were generally greater in patients with less severe disease.. Boehringer Ingelheim.. ClinicalTrials.gov numbers, NCT01431274 and NCT01431287.

Topics: Adrenergic beta-Agonists; Aged; Benzoxazines; Bronchodilator Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Severity of Illness Index; Tiotropium Bromide

Tiotropium + olodaterol improves lung function and symptoms compared to monotherapies in chronic obstructive pulmonary disease (COPD). The OTEMTO 1 and 2 studies investigated the effects of tiotropium + olodaterol on lung function and health-related quality of life compared to placebo in patients with moderate to severe COPD.. In these two replicate, double-blind, parallel-group, placebo-controlled trials, patients were randomised to receive tiotropium + olodaterol 5/5 μg, 2.5/5 μg, tiotropium 5 μg or placebo for 12 weeks, via the Respimat(®) inhaler. Primary end points were St George's Respiratory Questionnaire (SGRQ) total score, forced expiratory volume in 1 s (FEV1) area under the curve from 0 to 3 h (AUC0-3) response and trough FEV1 response.. In OTEMTO 1 and 2, tiotropium + olodaterol 5/5 μg improved SGRQ total score by 4.89 (95% confidence interval [CI] -6.90, -2.88) and 4.56 (95% CI -6.50, -2.63) units versus placebo (both p < 0.0001), and 2.49 (95% CI -4.47, -0.51; p < 0.05) and 1.72 (95% CI -3.63, 0.19) units versus tiotropium 5 μg. Tiotropium + olodaterol 2.5/5 μg significantly improved SGRQ score compared to placebo. Both doses significantly improved FEV1 AUC0-3 response compared to placebo and tiotropium 5 μg. Tiotropium + olodaterol 5/5 and 2.5/5 μg also significantly improved trough FEV1 response compared to placebo (both studies) and separated from tiotropium 5 μg in OTEMTO 2. Adverse-event incidence was similar between treatment groups.. Tiotropium + olodaterol improved lung function and quality of life compared to placebo and tiotropium 5 μg.. ClinicalTrials.gov: NCT01964352 and NCT02006732.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Tiotropium Bromide

Combining long-acting muscarinic antagonists (LAMAs) and long-acting β2-agonists (LABAs) is beneficial in chronic obstructive pulmonary disease (COPD), as the two classes of bronchodilator have complementary modes of action. The optimal dose for the fixed-dose combination of the LAMA tiotropium and the LABA olodaterol needed to be determined. In this phase II trial, the dose response of tiotropium on top of olodaterol was investigated in a free-dose combination, while other phase II studies have explored different doses of olodaterol on top of tiotropium, with both drugs delivered using the Respimat(®) inhaler.. This was a double-blind incomplete crossover trial in which 233 patients with moderate or severe COPD were randomized to receive four out of eight free-dose combinations of olodaterol (5 or 10 µg) and tiotropium (1.25, 2.5, or 5 µg) or placebo for 4 weeks each. Primary end point was trough forced expiratory volume in 1 s (FEV1) change from baseline (response) after 4 weeks.. Addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 5 µg increased mean trough FEV1 response by 0.054, 0.065, and 0.084 L, respectively; addition of tiotropium 1.25, 2.5, and 5 µg to olodaterol 10 µg increased mean trough FEV1 response by 0.051, 0.083, and 0.080 L, respectively. All treatments were well tolerated and incidence of adverse events was similar with all treatments.. Overall, a dose response for tiotropium on top of both doses of olodaterol was observed, with increasing improvements in trough FEV1 compared to olodaterol alone as the tiotropium dose was increased.. Boehringer Ingelheim.. ClinicalTrials.gov number, NCT01040403.

Topics: Aged; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Male; Middle Aged; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Combining bronchodilators with different mechanisms of action may improve efficacy and reduce risk of side effects compared to increasing the dose of a single agent in chronic obstructive pulmonary disease (COPD). We investigated this by combining two long-acting bronchodilators: once-daily muscarinic antagonist tiotropium and once-daily β2-agonist olodaterol.. Two replicate, double-blind, randomized, 12-week studies (ANHELTO 1 [NCT01694771] and ANHELTO 2 [NCT01696058]) evaluated the efficacy and safety of olodaterol 5 μg once daily (via Respimat(®)) combined with tiotropium 18 μg once daily (via HandiHaler(®)) versus tiotropium 18 μg once daily (via HandiHaler(®)) combined with placebo (via Respimat(®)) in patients with moderate to severe COPD. Primary efficacy end points were area under the curve from 0-3 hours of forced expiratory volume in 1 second (FEV1 AUC0-3) and trough FEV1 after 12 weeks (for the individual trials). A key secondary end point was health status by St George's Respiratory Questionnaire (SGRQ) total score (combined data set).. Olodaterol + tiotropium resulted in significant improvements over tiotropium + placebo in FEV1 AUC0-3 (treatment differences: 0.117 L [P<0.001], ANHELTO 1; 0.106 L [P<0.001], ANHELTO 2) and trough FEV1 (treatment differences: 0.062 L [P<0.001], ANHELTO 1; 0.040 L [P=0.0029], ANHELTO 2); these were supported by secondary end points. These effects translated to improvements in SGRQ total scores (treatment difference -1.85; P<0.0001). The tolerability profile of olodaterol + tiotropium was similar to tiotropium monotherapy.. These studies demonstrated that olodaterol (Respimat(®)) and tiotropium (HandiHaler(®)) provided bronchodilatory effects above tiotropium alone in patients with COPD. In general, both treatments were well tolerated.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Equipment Design; Female; Forced Expiratory Volume; Humans; Lung; Male; Middle Aged; Muscarinic Antagonists; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Spirometry; Surveys and Questionnaires; Time Factors; Tiotropium Bromide; Treatment Outcome; United States

ATS and GOLD guidelines recommend treating low-exacerbation risk COPD patients with dual (LAMA/LABA) agents and reserving triple therapy (TT; LAMA/LABA and inhaled corticosteroids [ICS]) for severe cases with higher-exacerbation risk. However, TT often is prescribed across the COPD spectrum. This study compared COPD exacerbations, pneumonia diagnosis, healthcare resource utilization, and costs for patients initiating tiotropium bromide/olodaterol (TIO/OLO) and a TT, fluticasone furoate/umeclidinium/vilanterol (FF/UMEC/VI), stratified by exacerbation history.. COPD patients who initiated TIO/OLO or FF/UMEC/VI between 06/01/2015-11/30/2019 (index date=first pharmacy fill-date with ≥30 consecutive treatment days) were identified from the Optum Research Database. Patients were ≥40 years old and continuously enrolled for 12 months during the baseline period and ≥30 days during follow-up. Patients were stratified into GOLD A/B (0-1 baseline non-hospitalized exacerbation), No exacerbation (subset of GOLD A/B), and GOLD C/D (≥2 non-hospitalized and/or ≥1 hospitalized baseline exacerbation). Baseline characteristics were balanced with propensity score matching (1:1). Adjusted risks of exacerbation, pneumonia diagnosis, and COPD and/or pneumonia-related utilization and costs were evaluated.. Adjusted exacerbation risk was similar in GOLD A/B and No exacerbation subgroups, and lower in GOLD C/D for FF/UMEC/VI versus TIO/OLO initiators (hazard ratio: 0.87; 95% CI: 0.78, 0.98, p=0.020). Adjusted pneumonia risk was similar between cohorts across the GOLD subgroups. Adjusted COPD and/or pneumonia-related population annualized pharmacy costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators across subgroups, p<0.001. Adjusted COPD and/or pneumonia-related population annualized total healthcare costs were significantly higher for FF/UMEC/VI versus TIO/OLO initiators in the GOLD A/B and No exacerbation, subgroups, p<0.001 (cost ratio [95% CI]: 1.25 [1.13, 1.38] and 1.21 [1.09, 1.36], respectively), but similar in the GOLD C/D subgroup.. These real-world results support ATS and GOLD recommendations for treating low-exacerbation risk COPD patients with dual bronchodilators and TT for more severe, higher-exacerbation risk COPD patients.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Fluticasone; Humans; Patient Acceptance of Health Care; Pneumonia; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Tiotropium Bromide

This retrospective cohort study used primary care data from the Clinical Practice Research Datalink Aurum database linked with secondary care administrative data from Hospital Episode Statistics. Patients with a COPD diagnosis at age ≥35 years were included (indexed) following initiation of single-inhaler UMEC/VI or TIO/OLO between July 1, 2015, and September 30, 2019. Outcomes included the number of rescue medication prescriptions at 12-months (primary), and at 6-, 18- and 24-months (secondary), adherence at 6-, 12-, 18- and 24-months post-index, defined as proportion of days covered ≥80% (secondary), and time-to-initiation of triple therapy (exploratory). Inverse probability of treatment weighting (IPTW) was used to balance potential confounding baseline characteristics. Superiority of UMEC/VI versus TIO/OLO for the primary outcome of rescue medication prescriptions was assessed using an intention-to-treat analysis with a p-value < 0.05.. In total, 8603 patients were eligible (UMEC/VI: n = 6536; TIO/OLO: n = 2067). Following IPTW, covariates were well balanced across groups. Patients initiating UMEC/VI had statistically significantly fewer (mean [standard deviation]; p-value) rescue medication prescriptions versus TIO/OLO in both the unweighted (4.84 [4.78] vs 5.68 [5.00]; p < 0.001) and weighted comparison (4.91 [4.81] vs 5.48 [5.02]; p = 0.0032) at 12 months; consistent results were seen at all timepoints. Adherence was numerically higher for TIO/OLO versus UMEC/VI at all timepoints. Time-to-triple therapy was similar between treatment groups.. UMEC/VI was superior to TIO/OLO in reducing rescue medication prescriptions at 12 months after treatment initiation in a primary care cohort in England, potentially suggesting improvements in symptom control with UMEC/VI compared with TIO/OLO.

Topics: Administration, Inhalation; Adult; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Drug Prescriptions; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Quinuclidines; Retrospective Studies; Tiotropium Bromide; Treatment Outcome

Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China.. A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis.. TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by $2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses.. Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.

Topics: China; Cost-Effectiveness Analysis; Humans; Pulmonary Disease, Chronic Obstructive; Quality of Life; Tiotropium Bromide

Long-acting beta-agonists (LABA) and long-acting muscarinic antagonists (LAMA) combination therapy improved lung function and health-related quality-of-life and reduced exacerbation rates and dyspnea in symptomatic chronic obstructive pulmonary disease (COPD) patients. We compared the real-world effects of three fixed-dose LABA/LAMA combinations for COPD in Taiwan.. This multicenter, retrospective study evaluated 1-year outcomes after LABA/LAMA combination therapy in patients with symptomatic COPD. Exacerbations and symptoms of COPD, lung functions, and therapy escalation were compared among patients using tiotropium/olodaterol, umeclidinium/vilanterol and indacaterol/glycopyrronium. Propensity score matching (PSM) was applied to balance the baseline characteristics.. Data of 1,617 patients were collected. After PSM, time to first moderate-to-severe COPD exacerbation was comparable among three groups, while the annualized rates of the exacerbation (episodes/patient/year) in patients receiving tiotropium/olodaterol (0.19) or umeclidinium/vilanterol (0.17) were significantly lower than those receiving indacaterol/glycopyrronium (0.38). COPD-related symptoms were stable over the treatment period, and there was no significant difference in the changes of symptom scores including CAT and mMRC among three groups at the end of the study period.. This study presented valuable real-world outcome in terms of exacerbation and treatment response of COPD patients treated with fixed-dose LABA/LAMA regimens in Taiwan. The annualized rates of moderate-to-severe exacerbation in patients receiving tiotropium/olodaterol or umeclidinium/vilanterol were significantly lower than those receiving indacaterol/glycopyrronium, though the time to first moderate-to-severe exacerbation was similar among different fixed-dose LABA/LAMA combinations.

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Benzyl Alcohols; Bronchodilator Agents; Chlorobenzenes; Drug Combinations; Glycopyrrolate; Humans; Indans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Quinuclidines; Retrospective Studies; Taiwan; Tiotropium Bromide; Treatment Outcome

Health‑related quality of life in patients with chronic obstructive pulmonary disease (COPD) can be measured by the Clinical COPD Questionnaire (CCQ). In this study, the CCQ was used to assess the therapeutic success of a fixed‑dose tiotropium / olodaterol combination treatment in Polish COPD patients.. We aimed to evaluate the changes in the CCQ score in Polish patients with COPD after 6 weeks of treatment with tiotropium / olodaterol and to assess the predictors of response to this treatment.. Data of the Polish subgroup of the NIS‑CCQ observational study (NCT03663569) were extracted. COPD patients who had received a new tiotropium / olodaterol prescription were included. The primary end point was therapeutic success predefined as a 0.4‑point reduction in the CCQ score after 6 weeks of tiotropium / olodaterol treatment. Post‑hoc logistic regression analysis was performed to identify the predictors of response to the treatment.. After 6 weeks of treatment, 72.4% of patients achieved therapeutic success. The therapy was successful in 83.4% of treatment‑naïve patients, as compared with 62.6% and 73.3% of those previously treated with long‑acting muscarinic antagonists or long‑acting β2 agonists in monotherapy and in combination with inhaled corticosteroids, respectively. Therapeutic success was achieved by at least 50% of patients regardless of the COPD severity and exacerbation history but it was more frequent in patients with more severe disease. The airflow limitation severity grades 2 to 4, modified Medical Research Council Dyspnea Scale classes 2 to 4, exacerbations within the last year before the study, and treatment‑naïve status predicted a better response to tiotropium / olodaterol.. Tiotropium / olodaterol treatment improved clinical control in Polish COPD patients. Therapeutic success was the most pronounced in individuals with more severe COPD and in the treatment‑naïve group but occurred also in those with moderate disease and in previously treated participants.

Topics: Benzoxazines; Bronchodilator Agents; Humans; Poland; Pulmonary Disease, Chronic Obstructive; Quality of Life; Surveys and Questionnaires; Tiotropium Bromide; Treatment Outcome

The aim: Show the efficacy of the Tiotropium / olodaterol combination in real clinical practice.. Materials and methods: 100 patients with the diagnosis of COPD were included onto the study during the period of 2019-2020, an average age was 64.09±1.94 years, 66 were men (66 %) and 34 were women (34 %). There were 68 % of smokers with the average smoking experience of 24.44±4.84 pack-years. Average COPD duration was 9.35±2.42 years. There were 3 visits in the study - visit 1 (baseline), visit 2 (4-6 weeks) visit 3 (1 year). Source documentation was assessed at visit 1 and visit 3 for amount of exacerbations, antibiotic, glucocorticosteroid, methylxanthines use; mMRC and CAT were assessed at all visits.. Results: Combined therapy with tiotropium/olodaterol improves clinical course of COPD, which is characterized by the significant decreased of the amount of exacerbations (2.63±0.29 to 1.63±0.21) and hospital admissions (1.2±0.2 tо 0.37±0.11). Improvement of symptoms and amount of exacerbation leads to much less use of antibiotics and glucocorticosteroids. A part of patients that used antibiotics decreased from 86±6.9 % to 67±9.3 %, amount of antibiotic courses from 1.37±0.17 tо 0.88±0.15, duration of treatment with antibiotics from 10.85±1.53 to 6.12±1.17 days. Part of the patients that used glucocorticosteroids decreased from 50±9.9 % tо 30±9.1 %, duration of treatment with antibiotics reduced from 3.97±1.06 tо 1.86±0.91 days. There also was a tendency towards a lesser used of methylxanthines. Combined therapy with tiotropium/olodaterol significantly decreased symptoms of COPD according to the mMRC (2.3±0.14 to 1.87±0.15) and САТ (23.28±1.71 to 15.77±1.58).. Conclusions: Tiotropium/olodaterol combination showed its efficacy in real clinical practice. There was significant reduction in amount of exacerbation and antibiotic, gluco¬corticosteroid use during the study, which was also accompanied by the reduction is symptoms.

Topics: Administration, Inhalation; Aged; Bronchodilator Agents; Drug Combinations; Female; Humans; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

The total population consisted of 61,985 patients (tiotropium/olodaterol n = 2684; LABA/ICS n = 59,301); after reweighting, the total was 42,953 patients (tiotropium/olodaterol n = 2600; LABA/ICS n = 40,353; mean age 65 years; female 54.5%). Patients treated with tiotropium/olodaterol versus LABA/ICS experienced a reduction in the risk of COPD exacerbations (adjusted hazard ratio 0.76 [95% confidence interval 0.68, 0.85]), pneumonia (0.74 [0.57, 0.97]), escalation to triple therapy (0.22 [0.19, 0.26]), and any one of these events (0.45 [0.41, 0.49]); the combined risk was similar irrespective of baseline eosinophils and exacerbation history.. In patients with COPD, tiotropium/olodaterol was associated with a lower risk of COPD exacerbations, pneumonia, and escalation to triple therapy versus LABA/ICS, both individually and in combination; the combined risk was reduced irrespective of baseline eosinophils or exacerbation history.. ClinicalTrials.gov identifier, NCT04138758 (registered 23 October 2019).

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Aged; Benzoxazines; Bronchodilator Agents; Drug Therapy, Combination; Female; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Chronic obstructive pulmonary disease (COPD) guidelines advocate treatment with combinations of long-acting bronchodilators for patients with COPD who have persistent symptoms or continue to have exacerbations while using a single bronchodilator. This study assessed the cost-utility of the fixed dose combination of the bronchodilators tiotropium and olodaterol versus two comparators, tiotropium monotherapy and long-acting β2 agonist/inhaled corticosteroid (LABA/ICS) combinations, in three European countries: Finland, Sweden and the Netherlands.. A previously published COPD patient-level discrete event simulation model was updated with most recent evidence to estimate lifetime quality-adjusted life years (QALYs) and costs for COPD patients receiving either tiotropium/olodaterol, tiotropium monotherapy or LABA/ICS. Treatment efficacy covered impact on trough forced expiratory volume in 1 s (FEV. Treatment with tiotropium/olodaterol gained QALYs ranging from 0.09 (Finland and Sweden) to 0.11 (the Netherlands) versus tiotropium and 0.23 (Finland and Sweden) to 0.28 (the Netherlands) versus LABA/ICS. The Finnish payer's incremental cost-effectiveness ratio (ICER) of tiotropium/olodaterol was €11 000/QALY versus tiotropium and dominant versus LABA/ICS. The Swedish ICERs were €6200/QALY and dominant, respectively (societal perspective). The Dutch ICERs were €14 400 and €9200, respectively (societal perspective). The probability that tiotropium/olodaterol was cost-effective compared with tiotropium at the country-specific (unofficial) threshold values for the maximum willingness to pay for a QALY was 84% for Finland, 98% for Sweden and 99% for the Netherlands. Compared with LABA/ICS, this probability was 100% for all three countries.. Based on the simulations, tiotropium/olodaterol is a cost-effective treatment option versus tiotropium or LABA/ICS in all three countries. In both Finland and Sweden, tiotropium/olodaterol is more effective and cost saving (ie, dominant) in comparison with LABA/ICS.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Cost-Benefit Analysis; Finland; Humans; Netherlands; Pulmonary Disease, Chronic Obstructive; Sweden; Tiotropium Bromide; Treatment Outcome

Patients with chronic obstructive pulmonary disease (COPD) and cardiovascular comorbidities may have an increased risk of medication-related cardiac arrhythmias. We therefore performed an analysis of Holter electrocardiogram (ECG) data from two large, long-term, controlled clinical COPD trials to investigate whether tiotropium/olodaterol increased the risk of cardiac arrhythmia and mean heart rate.. After 12 weeks of treatment, there was no difference in the number of patients who had an increase or decrease from baseline in 24-hour supraventricular premature beats or ventricular premature beats between tiotropium/olodaterol 5/5 µg combination therapy and its monocomponents. Compared with baseline, a small but statistically significant increase in adjusted mean heart rate was observed for tiotropium 5 µg (+1.6 beats per minute [bpm]; P=0.0010), but no difference was observed for olodaterol 5 µg (+0.3 bpm; P=0.2778) or tiotropium/olodaterol 5/5 µg (-0.1 bpm; P=0.4607). MACE and fatal MACE were limited to 1 to 3 patients across treatment groups.. Compared with the compounds given as monotherapy, treatment with tiotropium/olodaterol fixed-dose combination therapy is not associated with medically relevant or statistically significant effects on arrhythmia as assessed by Holter ECG. Based on these findings, there is no evidence to assume a clinically relevant impact on cardiac function from dual tiotropium/olodaterol treatment.. TONADO 1 (ClinicalTrials.gov: NCT01431274); TONADO 2 (ClinicalTrials.gov: NCT01431287).

Topics: Administration, Inhalation; Arrhythmias, Cardiac; Benzoxazines; Bronchodilator Agents; Double-Blind Method; Electrocardiography, Ambulatory; Forced Expiratory Volume; Heart Rate; Humans; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Topics: Adrenergic beta-2 Receptor Agonists; Benzoxazines; Bronchodilator Agents; Drug Combinations; Humans; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Pulmonary Medicine; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Aged; Aged, 80 and over; Benzoxazines; Delayed-Action Preparations; Drug Combinations; Dry Powder Inhalers; Forced Expiratory Volume; Glycopyrrolate; Humans; Indans; Male; Muscarinic Antagonists; Pulmonary Disease, Chronic Obstructive; Quinolones; Tiotropium Bromide; Vital Capacity

Topics: Animals; Benzoxazines; Bronchi; Bronchoconstriction; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Female; Horses; Male; Tiotropium Bromide

Topics: Anti-Inflammatory Agents; Benzoxazines; Double-Blind Method; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide

The superiority of tiotropium/olodaterol is demonstrated in improvement of lung function, dyspnea, lung hyperinflation, and quality of life compared with either monotherapy in patients with chronic obstructive pulmonary disease (COPD). Japanese Respiratory Society Guidelines for COPD management include improvement of exercise tolerance and daily physical activity as the treatment goals; however, there is limited evidence in Japanese patients with COPD.. A total of 180 Japanese patients with COPD, aged ≥40 years will be enrolled into the double-blind, multicenter, active-controlled, crossover study (NCT02629965) and will be randomized to receive either tiotropium/olodaterol FDC or tiotropium for 6 weeks each [two puffs via RESPIMAT. The VESUTO. ClinicalTrials.gov: NCT02629965 (registered on December 1, 2015).. The VESUTO study was funded by Nippon Boehringer Ingelheim Co., Ltd., Tokyo, Japan.

Topics: Administration, Inhalation; Adult; Aged; Aged, 80 and over; Benzoxazines; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Female; Humans; Japan; Male; Middle Aged; Pulmonary Disease, Chronic Obstructive; Quality of Life; Respiratory Function Tests; Tiotropium Bromide

One of the major goals of asthma therapy is to maintain asthma control and prevent acute exacerbations. Long-acting bronchodilators are regularly used for the treatment of asthma patients and in clinical studies the anti-cholinergic tiotropium has recently been shown to reduce exacerbations in patients with asthma. So far it is unclear how tiotropium exerts this effect. For this purpose, we designed an allergen-driven rechallenge model of allergic airway inflammation in mice, to assess the effectiveness of tiotropium and the long-acting β-2 adrenoceptor agonist olodaterol on allergen-induced exacerbations of airway disease. Female C57BL/6J mice were sensitized intranasally (i.n.) with 1 μg of house dust mite (HDM) extract followed by a challenge regime (5 consecutive days 10 μg HDM extract i.n.) after one week. Mice were exposed to a secondary challenge five weeks after sensitization and were treated i.n. with different concentrations of tiotropium or olodaterol (1, 10 and 100 μg/kg) or a combination thereof (10 μg/kg each) prior to and during the secondary challenge period. Three days after the last challenge, bronchoalveolar lavage (BAL) fluid and lung tissue were collected for flow cytometry and histologic analysis, respectively. Secondary challenge with HDM extract strongly induced allergic airway disease reflected by inflammatory cell infiltration and goblet cell metaplasia. Treatment with tiotropium, but not with olodaterol reduced tissue inflammation and goblet cell metaplasia in a dose-dependent manner. The combination of tiotropium and olodaterol was more effective in significantly reducing tissue inflammation compared to tiotropium treatment alone, and also led to a decrease in BAL cell counts. These data suggest that in a model of relapsing allergic airway disease tiotropium directly prevents exacerbations by reducing inflammation and mucus production in the airways. In addition, the combination of tiotropium and olodaterol exerts synergistic effects.

Topics: Allergens; Animals; Asthma; Benzoxazines; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Flow Cytometry; Goblet Cells; Inflammation; Mice; Mice, Inbred C57BL; Pyroglyphidae; Tiotropium Bromide

Topics: Adrenergic beta-2 Receptor Agonists; Animals; Benzoxazines; Bronchi; Bronchodilator Agents; Dose-Response Relationship, Drug; Drug Synergism; Female; Horses; Male; Muscarinic Antagonists; Muscle Contraction; Muscle, Smooth; Tiotropium Bromide

Topics: Benzoxazines; Bronchodilator Agents; Forced Expiratory Volume; Humans; Pulmonary Disease, Chronic Obstructive; Scopolamine Derivatives; Tiotropium Bromide; Treatment Outcome

Topics: Albuterol, Ipratropium Drug Combination; Benzoxazines; Drug Approval; Drug Combinations; Germany; Humans; Long-Term Care; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide; Treatment Outcome

Topics: Benzoxazines; Delayed-Action Preparations; Drug Combinations; Humans; Nebulizers and Vaporizers; Pulmonary Disease, Chronic Obstructive; Tiotropium Bromide

Mesenchymal cells (fibroblasts) of the airway wall respond to cholinergic stimulation by releasing pro-inflammatory and chemotactic cytokines and may thus contribute to chronic inflammation of the lung. Here, we studied the anti-inflammatory potential of olodaterol, a long acting β2-adrenergic receptor agonist, and tiotropium, a long-acting muscarinic receptor antagonist, and whether they interact at the level of the cyclic AMP dependent signaling pathway. Pulmonary fibroblasts of asthmatic (n = 9) and non-asthmatic (n = 8) subjects were stimulated with the muscarinic receptor agonist carbachol and interleukin-1β (IL-1 beta) in presence or absence of tiotropium or olodaterol alone, or their combination. We also measured cAMP levels and phosphorylation of the cAMP response element binding protein (CREB). As single components, carbachol, olodaterol and tiotropium did not affect IL-6 and IL-8 release. Carbachol concentration-dependently enhanced the production of IL-1β-induced IL-6 and IL-8, which was blocked by the simultaneous addition of tiotropium. The combination of olodaterol plus tiotropium further reduced IL-6 and IL-8 release. Olodaterol induced cAMP and the phosphorylation of CREB, an effect counteracted by carbachol, but rescued by tiotropium. We conclude that olodaterol plus tiotropium cooperate to decrease the inflammatory response in pulmonary fibroblasts in vitro.

Topics: Adrenergic beta-2 Receptor Agonists; Adult; Aged; Anti-Inflammatory Agents; Asthma; Benzoxazines; Bronchodilator Agents; Carbachol; Cyclic AMP; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Fibroblasts; Humans; In Vitro Techniques; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Middle Aged; Muscarinic Antagonists; Phosphorylation; Scopolamine Derivatives; Signal Transduction; Tiotropium Bromide

The novel once-daily β₂-agonist bronchodilator drug olodaterol has recently been shown to be effective in patients with allergic asthma for >24 hours. An increased cholinergic tone common to these patients may decrease the effectiveness of β₂-agonists. This could provide a rationale for combination therapy with olodaterol and the long-acting anticholinergic tiotropium to aim for a once-daily treatment regimen. In guinea pigs, we evaluated the protective effects of olodaterol, alone and in combination with tiotropium, on airway responsiveness to histamine, which is partially mediated by a cholinergic reflex mechanism. In addition, using a guinea pig model of acute allergic asthma, we examined the cooperative effects of these bronchodilators on allergen-induced early (EAR) and late (LAR) asthmatic reactions, airway hyper-responsiveness (AHR) to histamine, and airway inflammation. It was demonstrated that the protective effect of olodaterol against histamine-induced bronchoconstriction was synergistically enhanced and prolonged in the presence of tiotropium. In addition, tiotropium synergistically augmented both the reversal of and the protection against the allergen-induced AHR after the EAR by olodaterol. Olodaterol and tiotropium were highly effective in inhibiting the magnitude of the allergen-induced EAR and LAR, and both reactions were fully inhibited by the combination of these drugs. It is remarkable that these effects were not associated with an effect on inflammatory cell infiltration in the airways. In conclusion, the results indicate that combination therapy with olodaterol and tiotropium may be highly effective in the treatment of allergen-induced asthmatic reactions and AHR.

Topics: Administration, Inhalation; Adrenergic beta-2 Receptor Agonists; Animals; Animals, Outbred Strains; Anti-Allergic Agents; Benzoxazines; Bronchi; Bronchoconstriction; Bronchodilator Agents; Cholinergic Antagonists; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Synergism; Drug Therapy, Combination; Guinea Pigs; Histamine; Male; Protective Agents; Respiratory Hypersensitivity; Respiratory Mucosa; Scopolamine Derivatives; Tiotropium Bromide

T-lymphocytes, including Th17-cells and T-cells expressing acetylcholine (ACh), are key components of systemic inflammation in chronic obstructive pulmonary disease (COPD). We investigated whether ACh promotes Th17 cells in COPD. ACh, IL-17A, IL-22, RORγt, FOXP3 expression and AChIL-17A, AChIL-22, AChRORγt coexpression was evaluated in peripheral blood mononuclear cells (PBMC) from COPD patients (n=16), healthy smokers (HS) (n=12) and healthy control subjects (HC) (n=13) (cultured for 48 h with PMA) by flow cytometry. Furthermore, we studied the effect of Tiotropium (Spiriva®) (100 nM) and Olodaterol (1nM) alone or in combination, and of hemicholinium-3 (50 μM) on AChIL-17A, AChIL-22, AChRORγt, and FOXP3 expression in CD3+PBT-cells of PBMC from COPD patients (n=6) cultured for 48 h with PMA. CD3+PBT-cells expressing ACh, IL-17A, IL-22 and RORγt together with CD3+PBT-cells co-expressing AChIL-17A, AChIL-22 and AChRORγt were significantly increased in COPD patients compared to HC and HS subjects with higher levels in HS than in HC without a significant difference. CD3+FOXP3+PBT-cells were increased in HS than in HC and COPD. Tiotropium and Olodaterol reduced the percentage of CD3+PBT-cells co-expressing AChIL-17A, AChIL-22, and AChRORγt while increased the CD3+FOXP3+PBT-cells in PBMC from COPD patients, cultured in vitro for 48 h, with an additive effect when used in combination. Hemicholnium-3 reduced the percentage of ACh+IL-17A+, ACh+IL-22+, and ACh+RORγt+ while it did not affect FOXP3+ expression in CD3+PBT-cells from cultured PBMC from COPD patients. We concluded that ACh might promote the increased levels of Th17-cells in systemic inflammation of COPD. Long-acting β2-agonists and anticholinergic drugs might contribute to control this event.

Topics: Acetylcholine; Aged; Aged, 80 and over; Benzoxazines; Cholinergic Antagonists; Female; Forkhead Transcription Factors; Humans; Interleukin-17; Interleukin-22; Interleukins; Intracellular Space; Leukocytes, Mononuclear; Male; Middle Aged; Nuclear Receptor Subfamily 1, Group F, Member 3; Pulmonary Disease, Chronic Obstructive; Risk Factors; Scopolamine Derivatives; Th17 Cells; Tiotropium Bromide

We quantified TGF-β1 and acetylcholine (ACh) concentrations in induced sputum supernatants (ISSs) from 18 healthy controls (HC), 22 healthy smokers (HS) and 21 COPDs. ISSs from HC, HS and COPD as well as rhTGF-β1 were also tested in neutrophil adhesion and in mAChR2, mAChR3 and ChAT expression experiments in human bronchial epithelial cells (16-HBE). Finally, we evaluated the effects of Olodaterol (a novel inhaled β(2)-adrenoceptor agonist) and Tiotropium Spiriva®, alone or in combination, on neutrophil adhesion and mAChRs and ChAT expression in stimulated 16-HBE. The results showed that 1) TGF-β1 and ACh concentrations are increased in ISSs from COPD in comparison to HC and HS, and TGF-β1 in HS is higher than in HC; 2) ISSs from COPD and HS caused increased neutrophil adhesion to 16-HBE when compared to ISSs from HC. The effect of ISSs from COPD was significantly reduced by TGF-β1 depletion or by the pretreatment with Olodaterol or Tiotropium alone or in combination, while the effect of ISSs from HS was significantly reduced by the pretreatment with Olodaterol alone; 3) mAChR2, mAChR3 and ChAT expression was increased in 16-HBE stimulated with ISSs from COPD and TGF-β1 depletion significantly reduced this effect on mAChR3 and ChAT expression; 4) rhTGF-β1 increased mAChR2, mAChR3 and ChAT expression in 16-HBE; 5) Olodaterol did not affect the expression of mAChRs and ChAT in 16-HBE. Our findings support the use of β₂ long-acting and anticholinergic drugs to control the bronchoconstriction and TGF-β1-mediated neutrophilic inflammation in COPD.

Topics: Acetylcholine; Adrenergic beta-2 Receptor Agonists; Aged; Analysis of Variance; Benzoxazines; Bronchoconstriction; Bronchodilator Agents; Case-Control Studies; Cell Adhesion; Cell Line, Transformed; Choline O-Acetyltransferase; Cholinergic Antagonists; Drug Therapy, Combination; Epithelial Cells; Female; Flow Cytometry; Humans; Male; Middle Aged; Neutrophils; Pulmonary Disease, Chronic Obstructive; Receptor, Muscarinic M2; Receptor, Muscarinic M3; Scopolamine Derivatives; Smoking; Sputum; Tiotropium Bromide; Transforming Growth Factor beta1