Role of indacaterol,a once-daily bronchodilator,in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is characterized by progressive airflow obstruction that can lead to lung destruction and dyspnea. Although there has been a slight reduction in mortality in recent decades, COPD is still a serious health problem that has enormous costs and utilizes significant medical resources. There have been a number of pharmacologic interventions that have been developed for the treatment of COPD. Current guidelines recommend the use of long-acting bronchodilators for the treatment of moderate and severe stage COPD, since they have been shown to improve lung function, respiratory symptoms, and quality of life. Indacaterol is a once-daily beta2-agonist (β2-agonist) delivered by a single-dose dry powder inhaler used for the treatment of COPD. It is currently approved at a dose of 75 μg in the United States and a dose of 150 μg with a maximal dose of 300 μg in Europe and other countries. Several studies show that indacaterol was statistically superior to both long-acting β2-agonist, formoterol and salmeterol, as well as, noninferior to tiotropium. Indacaterol is generally well tolerated and has a good safety profile. Other studies show that there is an additive bronchodilator response with the addition of indacaterol to tiotropium, which would provide a once-daily treatment option for patient with moderate to severe COPD. This review discusses the pharmacokinetic, comparative efficacy and safety data for indacaterol.KEYWORDS : Indacaterol, chronic obstructive pulmonary disease (COPD), long-acting beta2-agonist (β2-agonist), tiotropium, salmeterol, formoterol, bronchodilator     

国产噻托溴铵粉雾剂治疗慢性阻塞性肺疾病的多中心临床研究

目的 评价国产噻托溴铵粉雾剂治疗COPD的临床疗效和安全性.方法 采用多中心、随机、双盲、安慰剂平行对照的研究方法,对205例筛选合格的I、Ⅱ级COPD稳定期患者,采用随机数字表法给予国产噻托溴铵粉雾剂18μg,每日1次,或用安慰剂治疗12周.在筛选期、用药后6和12周分别测定肺功能.结果 103例入选噻托溴铵组,用药后12周临床症状的控制率为25.2%(26/103),有效率为65.1%(67/103);102例入选对照组,用药后12周临床控制率为5.1%(5/99),有效率为30.3%(30/99).噻托溴铵组用药后12周FEV1增加值和增加率[(0.2±0.3)L和(19.2±29.1)%]明显高于对照组[(0.0±0.2)L和(0.8±18.2)%],FVC增加值和增加率(0.2 L和11.6%)明显高于对照组(0.0 L和2.2%).噻托溴铵组不良反应主要为口干和咽喉不适等,发生率(7.8%,8/103)略低于对照组(12.8%,13/102),差异无统计学意义(X2=1.381,P>0.05).结论 国产噻托溴铵粉雾剂可显著改善COPD患者的临床症状和肺功能,临床应用有效、安全.     

茚达特罗与噻托溴铵对强迫振荡技术测定慢阻肺患者呼吸力学参数的影响对比

目的评估并比较茚达特罗和噻托溴铵单药治疗对慢性阻塞性疾病(简称"慢阻肺")患者气流限制和呼吸阻抗的影响。方法选取2014年3月至2015年1月于我院诊断为慢阻肺患者78例(平均年龄为72.4岁,平均FEV1预计值为61.6%),随机分为两组,每组各39例,分别接受茚达特罗或噻托溴铵治疗。在药物治疗开始及治疗8周后,对患者进行肺功能测试、慢阻肺评估测试(CAT)和多频强迫振荡技术测试。在全呼吸、吸气和呼气阶段测定5 Hz和20 Hz振动频率时的粘性阻力(R_5和R-20),5 Hz时电抗(X——5)和共振频率(Fres)及低频电抗面积(ALX)。结果茚达特罗与噻托溴铵均可改善慢阻肺患者的气流受限情况,平均FEV1值分别提高170 m L和90 m L。患者接受茚达特罗药物治疗后CAT得分由11.2±4.3降为7.5±2.3,治疗前后具有显著性差异(P0.001)。与噻托溴铵相比,茚达特罗可明显改善患者的FEV1值,FEV1百分比预计值及CAT得分(P分别为0.042,0.008和0.027)。对于呼吸阻抗,两种药物在全呼吸、吸气和呼气阶段都可改变患者的R_5、X_5、Fres及ALX值。茚达特罗组R_5、R_5-R_20、X_5、Fres及ALX值的变化与FEV1变化显著相关。结论茚达特罗可显著改善慢阻肺患者的气流受限情况和症状。对于呼吸阻抗,茚达特罗和噻托溴铵两种支气管扩张药物改善强迫振荡技术参数的程度相似,均可用于慢阻肺患者的临床治疗。     

Effect of formoterol, tiotropium, and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease: a pilot study

The aim of our study was to evaluate the pharmacodynamic effects of 1-day treatment with formoterol, tiotropium and their combination in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Twenty-one (19 males, mean age 72+/-8 years, mean FEV1 38+/-14% of predicted values) patients with mild to moderate AECOPD were enrolled. Patients received formoterol (12 microg deliver via Modulite b.i.d.), tiotropium (18 microg dry powder capsules delivered via HandiHaler once daily), and their combination, in randomized sequence. Serial measurements of FEV1, FVC, IC, SpO2 and HR were performed over 24h. Formoterol, tiotropium, and their combination significantly improved the area under curves (AUCs) for FEV1, FVC and IC over 12 and 24h. The mean FEV1, FVC and IC AUC(0-12h) and AUC(0-24h) after formoterol and tiotropium combination were significantly higher than formoterol and tiotropium alone, whereas the differences between the two single drugs were not statistically significant. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action, and combination elicited a greater maximum bronchodilation than both single drugs in terms of FEV1 and FVC. After 24h the bronchodilating effect of the three treatments disappeared, with the exception of the combination on FEV1. The results of this study have documented that, although the time course of the effects of evaluated drugs differs significantly from that in stable COPD, with a shorter bronchodilation both for tiotropium and formoterol, these two long-acting bronchodilators appear to also be complementary in mild to moderate AECOPD.     

噻托溴铵治疗慢性阻塞性肺疾病独特的作用

噻托溴铵对慢性阻塞性肺疾病（ chronic obstructive pulmonary disease, COPD）维持治疗有重要作用,不少临床报道都肯定这点。该药被认同为治疗C（）PD的一线药物。新近Donald等报道。噻托溴铵对5593例中、重度COPD患者为期4年治疗肺功能潜在长期疗效研究（即UPL1FT研究）,     

Comparison of tiotropium plus formoterol to tiotropium alone in stable chronic obstructive pulmonary disease: a meta-analysis

Background and objective: It is not clear whether combination therapy with tiotropium plus formoterol has greater efficacy, without increasing the burden of adverse events, compared with tiotropium alone. This meta‐analysis was performed to evaluate the differences in efficacy and adverse events associated with combination therapy compared with tiotropium alone, in patients with stable COPD. Methods: MEDLINE, EMBASE, CINAHL and the Cochrane trials database were searched for this analysis. Randomized controlled trials of 2 or more weeks of treatment with tiotropium plus formoterol or arformoterol, compared with tiotropium alone, were reviewed. Studies were pooled to yield odds ratio (OR) or weighted mean differences (WMD), with 95% confidence interval (CI). Results: Eight trials, involving 1868 randomized patients, met the inclusion criteria. Treatment with tiotropium plus formoterol significantly improved the average FEV₁ (WMD 105 mL, 95% CI: 69–142), average FVC (WMD 135 mL, 95% CI: 96–174) and trough FEV₁ (WMD 53 mL, 95% CI: 30–76), compared with tiotropium alone, although the difference was not statistically significant for trough FVC. The mean change in transitional dyspnoea index (TDI) was markedly greater with tiotropium plus formoterol (WMD 1.50, 95% CI: 1.01–1.99) than with tiotropium alone, and there was a similar difference in the proportion of patients with a clinically significant change in TDI (OR 2.34, 95% CI: 1.58–3.46). There tended to be fewer adverse events and COPD exacerbations with tiotropium plus formoterol, compared with tiotropium alone, but the differences were not statistically significant. Conclusions: Tiotropium plus formoterol significantly improved lung function and symptom scores compared with tiotropium alone. There was a trend towards a reduction in adverse events, although the difference was not statistically significant. Long‐term trials are necessary to evaluate the effects of tiotropium plus formoterol and to clarify the role of combination therapy, compared with tiotropium alone.     

噻托溴铵治疗慢性阻塞性肺疾病研究进展

噻托溴铵是一种新型的胆碱能M3受体阻断剂,长期每天吸入1次(18 μg)可有效地改善稳定期慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)患者的肺功能,减少呼气末气体陷闭,减少动态肺过度充气,缓解呼吸困难,从而可以进一步改善其生存和生活质量,减少急性发作的次数,推迟急性发作出现的时间,减少患者的住院天数.噻托溴铵为稳定期COPD患者的治疗提供了新的手段.     

Chronic obstructive pulmonary disease in China: the potential role of indacaterol

Chronic obstructive pulmonary disease (COPD) is becoming a leading cause of morbidity and mortality in China, with tobacco smoking, biomass fuel use and genetic susceptibility being the major risk factors. COPD poses a high economic burden with the total expenditure per patient costing 40% and nearly one-third of an average family income in urban and rural areas of China, respectively. Despite the use of the Global Initiative for Chronic Obstructive Lung Disease strategy document being recommended for the diagnosis and management of COPD, the majority of patients with COPD go undiagnosed or are not managed appropriately by physicians. Long-acting β₂-agonists (LABAs) have long been used for symptomatic management of COPD, with salmeterol and formoterol being the commonly used twice-daily treatments. Indacaterol is the first once-daily LABA, approved at a dose of 150 µg once daily in China. Several phase III studies have shown that indacaterol 150 µg improves lung function, breathlessness, health status, exacerbations, rescue medication use and symptoms, as compared with placebo and other bronchodilators, in patients with COPD, with a rapid onset of action following first dose and a good safety and tolerability profile. In this review we elaborate on the efficacy and safety results from several such studies.KEY WORDS : China, chronic obstructive pulmonary disease (COPD), indacaterolChronic obstructive pulmonary disease (COPD) is a disease characterized by persistent airflow limitation that is usually progressive and not fully reversible (1). The burden of the disease is high as it leads to disability and impairs quality of life (2), in addition to having a high impact on health care costs (3). Dyspnea, chest discomfort, chronic cough, and sputum production are the characteristic symptoms of COPD (1). It is usually seen that COPD patients initially seek a physician’s advice after encountering breathing problems, even though cough is the first symptom that appears in these patients and often goes unrecognized. By the time the patient consults the physician, the condition is already aggravated (4). In addition, COPD is quite often under-diagnosed by physicians because of lack of diagnostic skills, delay in diagnostic testing (5,6), and underestimation of the symptom severity (7). Patients can also be reluctant to seek medical treatment, which further contributes toward the under-diagnosis. All these factors together make COPD a leading cause of morbidity and mortality world-wide (8). Without adequate diagnosis, continued exposure to the risk factors for COPD, including tobacco smoke, air pollution, smoke from biofuels, and occupational dusts and chemicals, contributes to the worsening of the disease (1). Additionally, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy document for the pharmacological management of COPD recommends an individualized step-up, or treatment intensification approach, when the management of symptoms is not satisfactory; this requires continuous close monitoring of patients, and access to a wide range of medications (1).     

A randomised, placebo-controlled, dose-finding study of AZD9668, an oral inhibitor of neutrophil elastase, in patients with chronic obstructive pulmonary disease treated with tiotropium

AZD9668 is a fully reversible, selective, oral inhibitor of neutrophil elastase, a protease implicated in chronic obstructive pulmonary disease (COPD). Efficacy, safety and tolerability of AZD9668 (5, 20 and 60 mg bid) were compared with placebo in a randomised, double-blind, placebo-controlled, 12-week, Phase IIb trial (NCT00949975: approved by an Investigational Review Board), in patients with symptomatic COPD receiving maintenance tiotropium. The primary endpoint was pre-bronchodilator forced expiratory volume in 1 second (FEV?). Secondary endpoints included forced vital capacity and inspiratory capacity, peak expiratory flow, Breathlessness, Cough and Sputum Scale score, exercise capacity, quality of life (QoL), exacerbation assessments, safety and pharmacokinetics. Exploratory endpoints included inflammatory and tissue degradation biomarkers. A total of 838 patients were randomised to AZD9668 5 mg bid (212 patients), 20 mg bid (206 patients), 60 mg bid (202 patients) or placebo (218 patients). AZD9668 showed no effect on lung function, respiratory signs and symptoms, QoL or biomarkers. At end of treatment, the change in mean pre-bronchodilator FEV? for AZD9668 60 mg bid compared with placebo was 0.00L (95% confidence interval: -0.05, 0.04; p = 0.873). Overall, AZD9668 was well tolerated; the numbers of patients with adverse events (AEs), serious AEs and AEs leading to discontinuation were similar in each of the four study groups. AZD9668 60 mg bid showed no clinical benefit and no effect on biomarkers of inflammation or tissue degradation when added to tiotropium in patients with COPD. These results raise important questions for future investigation of anti-inflammatory and disease-modifying agents in patients with COPD.     

A long-term evaluation of once-daily inhaled tiotropium in chronic obstructive pulmonary disease.

Currently available inhaled bronchodilators used as therapy for chronic obstructive pulmonary disease (COPD) necessitate multiple daily dosing. The present study evaluates the long-term safety and efficacy of tiotropium, a new once-daily anticholinergic in COPD. Patients with stable COPD (age 65.2+/-8.7 yrs (mean+/-SD), n=921) were enrolled in two identical randomized double-blind placebo-controlled 1-yr studies. Patients inhaled tiotropium 18 microg or placebo (mean screening forced expiratory volume in one second (FEV1) 1.01 versus 0.99 L, 39.1 and 38.1% of the predicted value) once daily as a dry powder. The primary spirometric outcome was trough FEV1 (i.e. FEV1 prior to dosing). Changes in dyspnoea were measured using the Transition Dyspnea Index, and health status with the disease-specific St. George's Respiratory Questionnaire and the generic Short Form 36. Medication use and adverse events were recorded. Tiotropium provided significantly superior bronchodilation relative to placebo for trough FEV1 response (approximately 12% over baseline) (p<0.01) and mean response during the 3 h following dosing (approximately 22% over baseline) (p<0.001) over the 12-month period. Tiotropium recipients showed less dyspnoea (p<0.001), superior health status scores, and fewer COPD exacerbations and hospitalizations (p<0.05). Adverse events were comparable with placebo, except for dry mouth incidence (tiotropium 16.0% versus placebo 2.7%, p<0.05). Tiotropium is an effective, once-daily bronchodilator that reduces dyspnoea and chronic obstructive pulmonary disease exacerbation frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic obstructive pulmonary disease therapy.     

吸入噻托溴铵对慢性阻塞性肺疾病患者运动耐量的影响

慢性阻塞性肺疾病(chronic obstructive pulmonary disease,COPD)患者呼气气流受限导致气体陷闭和肺过度充气,从而导致COPD患者特征性的临床症状.每天一次噻托溴铵18μg,通过长效的抗胆碱能作用维持24 h气道通畅,已显示出能持续减轻COPD患者呼吸困难症状,提高运动耐量和健康相关性生活质量.     

A dose-ranging study of tiotropium delivered via Respimat? Soft MistTM Inhaler or HandiHaler? in COPD patients

This was a multicenter, randomized, double-blind within device, parallel-group, dose-ranging study. COPD patients (n = 202; 86% male; mean age: 61 years) were randomized to receive tiotropium 1.25 μg, 2.5 μg, 5 μg, 10 μg, or 20 μg Respimat^® SMI (a novel, propellant-free device); tiotropium 18 μg HandiHaler^®; placebo Respimat^®; or placebo HandiHaler^® for 3 weeks. The primary endpoint was trough FEV₁ on Day 21. Other assessments included FVC, PEFR, rescue medication use, safety, and pharmacokinetics. In general, all active treatments improved the primary and secondary endpoints on Day 21 (steady state) compared with placebo. Tiotropium 5 μg Respimat^®, 20 μg Respimat^®, and tiotropium 18 μg HandiHaler^® were statistically significantly higher than placebo for the primary endpoint (mean change in trough FEV₁ was 150 mL (both Respimat^® doses) versus 20 mL (placebo Respimat^®); p < 0.05; and 230 mL (HandiHaler^®) versus −90 mL (placebo HandiHaler^®); p ≤ 0.001). The urinary excretion (up to 2 hours post-dose) of tiotropium 5–10 μg Respimat^® was comparable with tiotropium 18 μg HandiHaler^®; the overall incidence of adverse events was comparable across treatment groups. Tiotropium 5 and 10 μg Respimat^® improve lung function in COPD patients and appear to be comparable with tiotropium 18 μg HandiHaler^®.     

Pharmacodynamic steady state of tiotropium in patients with chronic obstructive pulmonary disease.

Tiotropium (Spiriva) is a new once-daily inhaled anticholinergic that has its effect through prolonged muscarinic (M)3 receptor antagonism. It has a clinically documented, long duration of action with once-daily dosing in chronic obstructive pulmonary disease (COPD). A single-centre, double-blind, ipratropium-controlled study was conducted in order to characterize the onset of pharmacodynamic steady state of tiotropium in patients with COPD. Thirty-one patients (25 male, six female) with a mean age of 62 yrs and a mean forced expiratory volume in one second (FEV1) of 1.13 L (38% of predicted) were randomly assigned to receive either tiotropium 18 microg once-daily from a dry-powder inhaler (HandiHaler, 20 patients), or ipratropium 40 microg four-times daily from a pressurized metered-dose inhaler (11 patients) for a period of 1 week. FEV1 and forced vital capacity (FVC) were measured 1 h prior to, and just before inhalation (mean value of the two measurements on test-day 1 was the baseline value, while on all other test days it was the trough value), and 0.5, 1, 2, 3, 4, 5, and 6 h after inhalation of the morning dose of the study drug (one capsule and two puffs) on days 1, 2, 3, and 8. Trough FEV1 following 8 days of tiotropium was 0.19 L (18%) above baseline. Approximately 90% of this increase was achieved within 24 h of the first dose (0.17 L, 16%). Trough FVC increased 0.67 L (27%) on test-day 8. Approximately 70% of the improvement was observed after two tiotropium doses (0.47 L, 19%). Achievement of FVC steady state was delayed compared to FEV1. Ipratropium performed typically with an onset of action within 30 min, a peak response between 1-2 h postdosing and a duration of action of approximately 4 h. It was concluded that forced expiratory volume in one second steady state with tiotropium is reached within 48 h, while continued improvements in forced vital capacity can be expected over or beyond the first week of therapy. The continued increases in forced vital capacity beyond 48 h suggests that maintenance bronchodilator therapy is required to achieve maximal changes in hyperinflation.