Tiotropium bromide

Tiotropium bromide is a novel, inhaled, once-daily anticholinergic bronchodilator that has recently been approved in the United States for use in patients with COPD. Its unique feature is the persistence of bronchodilation for > 24 h due to prolonged M(3) muscarinic receptor blockade. Tiotropium provides significant improvement in spirometry and lung volumes. Clinically relevant outcomes such as the relief of dyspnea, improvement in the quality of life (health status), and reductions in the frequency and severity of acute exacerbations have been consistently obtained with tiotropium in clinical trials. In head-to-head trials, tiotropium administered once daily resulted in bronchodilation (peak, trough, and area under the curve) that was statistically superior to ipratropium administered four times daily and salmeterol administered twice daily. Clinical outcomes (dyspnea, quality of life, exacerbation frequency) were numerically but not always statistically better with tiotropium than salmeterol. Long-term studies of the combination of tiotropium with adrenergic agents, methylxanthines, or inhaled corticosteroids have not been reported in full. Several 1-year studies demonstrate that the only significant side effect of tiotropium was dryness of the mouth, which occurred in approximately 10 to 16% of patients; it is well tolerated by patients and safe.     

Adding a Second Bronchodilator in COPD: A Meta-Analysis on the Risk of Specific Cardiovascular Serious Adverse Events of Tiotropium/Olodaterol Fixed-Dose Combination

Abstract

Dual bronchodilation therapy represents the cornerstone for the treatment of COPD. A large retrospective study reports that adding a second long-acting bronchodilator in patients with COPD significantly increases the risk of heart failure. Nevertheless, retrospective studies are characterized by limitations including misdiagnosis and inaccuracy of recordkeeping. This study aimed to ascertain whether tiotropium/olodaterol (T/O) 5/5?μg fixed-dose combination (FDC) may modulate the risk of main cardiovascular outcomes in COPD patients enrolled in randomized controlled trials (RCTs). A meta-analysis (CRD42017070100) was performed by selecting RCTs reporting raw data from the ClinicalTrials.gov database concerning the impact of T/O 5/5?µg FDC vs. monocomponents on the occurrence of specific cardiovascular serious adverse events: arrhythmia, heart failure, myocardial infarction, and stroke. Data were reported as relative risk and 95% Confidence Interval, and the risk of publication bias assessed via Egger’s test. Eighty six full text articles were identified, and 10 RCTs published in 7 studies between 2015 and 2018 were included into the analysis. Data obtained from 12,690 COPD patients (44.47% T/O FDC, 55.53% monocomponents) were extracted. T/O 5/5?μg FDCs did not significantly modulate (p-value > 0.05) the risk of arrhythmia (1.02, 0.55 - 1.92), heart failure (0.88, 0.41 - 1.92), myocardial infarction (1.15, 0.70 - 1.87), and stroke (0.98, 0.44 - 2.16) vs. monocomponents. No significant publication bias affected the effect estimates of this meta-analysis. The results of this quantitative synthesis indicate that dual bronchodilation with T/O 5/5?μg FDC is characterized by an acceptable cardiovascular safety profile in COPD patients.     

噻托溴胺联合呼吸操训练治疗稳定期慢性阻塞性肺病患者的临床研究

目的探讨噻托溴胺联合呼吸操训练对慢性阻塞性肺疾病(chronic obstructive pulmonary disease,慢阻肺)稳定期患者的肺通气功能、生活质量以及运动耐力的影响。方法选择2014年10月至12月稳定期慢阻肺患者共73例,随机分为常规药物治疗组(A组,n=37)和呼吸操训练组(B组,n=36)。对A组患者常规吸入噻托溴胺,有氧疗指征者给予长期家庭氧疗。B组患者除应用噻托溴胺和(或)氧疗外,指导呼吸操训练,方法包括腹式呼吸、缩唇呼气及全身性呼吸体操。记录每例患者入组时及12周后的FEV1占预计值的百分比(FEV1%Pred)、圣乔治呼吸疾病问卷(SGRQ)评分及6 min步行距离(6MWD)。结果入组时两组患者的性别、平均年龄、肺功能分级、FEV1%Pred、SGRQ评分及6MWD均无显著差异(P0.05)。干预12周后两组患者FEV1%Pred、SGRQ评分及6MWD均较治疗前有显著变化。其中B组患者的SGRQ评分显著低于A组,B组患者的6MWD显著长于A组(P0.05)。结论在常规吸入长效抗胆碱能药物治疗外,配合呼吸操训练可更好的改善稳定期慢阻肺患者的生活质量及运动耐力。     

老年人稳定期慢阻肺应用噻托溴铵的临床观察

目的探讨老年人COPD稳定期应用噻托溴铵治疗的疗效。方法选取58例慢性阻塞性肺疾病稳定期的患者,并随机分成两组即噻托溴铵组(30例)和异丙托溴铵组(28例),噻托溴铵组给予噻托溴铵治疗,异丙托溴铵组给予异丙托溴铵治疗,两组疗程均为60天,通过观察两组患者临床症状及肺功能改善情况等指标,分析对比两组疗效差别。结果噻托溴铵组的临床症状、肺功能改善情况明显优于异丙托溴铵组相关指标,P<0.05。结论噻托溴铵用于稳定期COPD的治疗效果优于异丙托溴铵。     

噻托溴铵治疗COPD稳定期的疗效观察

目的探讨噻托溴铵治疗COPD稳定期的临床疗效。方法选取我院COPD稳定期的患者64例,分为观察组与对照组,各32例,观察组使用噻托溴铵治疗,对照组使用常规治疗,观察比较两组患者的治疗效果、不良反应发生率,并比较治疗前后急性加重次数,治疗前和治疗后2周末、4周末、8周末、16周末、24周末的FEV1和FEV1/FVC的值。结果观察组治疗总有效率为90.6%(29/32),不良反应发生率为6.3%(2/32),对照组治疗总有效率为68.8%(22/32),不良反应发生率为3.1%(1/32),两组治疗总有效率比较有明显差异(P<0.05),具有统计学意义。结论噻托溴铵在治疗COPD稳定期的临床疗效显著,明显优于常规治疗。     

Role of tiotropium in the treatment of COPD

Tiotropium is a potent, long-acting, selective anticholinergic bronchodilator. Treatment with tiotropium produces sustained improvements in lung function, particularly FEV₁ (peak, trough, average, and area under the curve) compared with either placebo or ipratropium in patients with moderate to severe COPD. Preliminary evidence suggests that treatment with tiotropium may slow the rate of decline in FEV₁, but this finding awaits confirmation. Tiotropium reduces lung hyperinflation, with associated improvements in exercise capacity. Tiotropium, compared with either placebo or ipratropium, improves a variety of patient-centered outcomes, including subjective dyspnea ratings and HRQL scores. Tiotropium reduces the frequency of COPD exacerbations and of hospitalizations due to exacerbations, but has not been shown to reduce all-cause mortality. Compared with the long-acting bronchodilators, tiotropium provides incrementally better bronchodilation, but it is not clearly superior in terms of patient-centered outcomes. Tiotropium has a good safety profile; however patients with severe cardiac disease, bladder outlet obstruction, or narrow angle glaucoma were excluded from all studies. Medico economic analyses suggest that treatment with tiotropium may also be cost-effective, primarily by reducing costs associated with hospitalizations.     

The role of anticholinergic bronchodilators in adult asthma and chronic obstructive pulmonary disease

Our renewed interest in anticholinergic bronchodilator therapy has been sparked by the development of safe yet effective quaternary anticholinergic compounds including ipratropium bromide, oxitropium and atropine methonitrate. These agents offer gradual and sustained bronchodilatation to patients with asthma and to patients with COPD. However, their role in the maintenance treatment of these two diseases differs significantly. In asthma, the anticholinergic drugs have useful additive properties when used with adrenergic drugs or theophylline. They may be a particularly useful component of combination regimens in patients with disease of more than mild severity and in older patients. The combination of inhaled adrenergic and anticholinergic drugs is also useful in the acute setting for acute exacerbations of asthma. In chronic obstructive lung disease, the anticholinergic compounds offer greater bronchodilatation than adrenergic drugs for the majority of patients. Thus, the inhaled anticholinergic drugs may be considered as useful initial choices in the chronic maintenance therapy of COPD.     

Eletrocardiographic Monitoring in COPD Patients Receiving Tiotropium

Tiotropium is a once‐daily, inhaled anticholinergic for the treatment of chronic obstructive pulmonary disease that acts as a prolonged antagonist of the M3‐receptor. To ascertain whether electrophysiologic effects can be detected following tiotropium treatment in patients with chronic obstructive pulmonary disease, serial electrocardiograms were incorporated into multiple placebo‐controlled clinical trials including long‐term (6 and 12‐month) trials with tiotropium 18 mcg daily (n = 2,128) and a 4‐week dose‐ranging study with tiotropium up to 36 mcg daily (n = 169). In addition, 24‐hour electrocardiographic (Holter) monitoring was performed as part of a 6‐week, placebo‐controlled trial with tiotropium 18 mcg daily (n = 121). Electrocardiograms were performed before and up to 6 times during treatment in the 12‐month trials, and before and at the end of treatment in the 6‐month trials. For both the 12 and 6‐month trials, electrocardiograms were recorded as adverse events if significant changes occurred, and were retrospectively sent for centralized analysis. During the 6‐week trial, Holter monitoring was performed prior to the first dose and following 6 weeks of treatment. In all of these trials, no significant differences were observed in any of the electrocardiogram or Holter outcome parameters compared to placebo. Specifically, there was no clinically relevant difference in heart rate, atrio‐ventricular conduction or the occurrence of ventricular or supraventricular arrhythmias. In conclusion, tiotropium was not associated with any signs of cardiac safety concerns as defined by electrocardiographic evaluations in placebo‐controlled clinical trials.     

噻托溴铵联合双水平气道正压通气对稳定期慢性阻塞性肺疾病患者疗效及外周血SOD、LPO的影响

目的观察噻托溴铵联合双水平气道正压通气(Bi PAP)对稳定期慢性阻塞性肺疾病(慢阻肺)患者疗效及外周血超氧化物歧化酶(SOD)、脂质过氧化物(LPO)的影响。方法选取240例稳定期慢阻肺患者随机分为噻托溴铵组,Bi PAP组和联合组各80例,另选同期健康体检者80例为对照组,噻托溴铵组在常规治疗基础上加用噻托溴铵治疗,而Bi PAP组则加用Bi PAP通气治疗,联合组加用噻托溴铵联合Bi PAP治疗,分析三组治疗前及治疗后14d,3个月外周血SOD,LPO水平,以及治疗后1年内复发人数及不良反应发生情况;将噻托溴铵组按慢阻肺中重度,极重度分为A1,B1亚组,Bi PAP组同理分为A2,B2亚组,联合组为A3,B3亚组,A1-A3亚组均有55例,B1-B3亚组均有25例,分析A1-3,B1-3亚组治疗前与治疗后14d,3个月慢阻肺疾病评估测试问卷评分(CAT)及症状评分。结果 3组治疗前SOD均远低于而LPO则远高于对照组(P0.05);治疗后较治疗前均有显著改善,但治疗后联合组改善幅度均显著大于噻托溴铵组和Bi PAP组(P0.05)。治疗后A1-3亚组无论是CAT还是症状评分均较治疗前有明显改善,且治疗后3个月又明显优于14d时,但改善幅度上,另两亚组明显不如A3亚组;而B1亚组治疗后14d相对于治疗前上述评分均未见显著变化,但治疗后3个月相较于治疗前及治疗后14d则有明显改善;而B2,B3亚组则治疗后分值较治疗前均有明显降低,但B3亚组变化幅度均远大于另外两亚组(P均0.05)。治疗后联合组复发率远低于噻托溴铵及BiPAP组(7.5%vs 35%vs 38.8%);而联合组与另两组在不良反应发生率上未见显著差异(P0.05)。结论噻托溴铵联合Bi PAP治疗稳定期慢阻肺疗效确切,且能够有效改善外周血SOD,LPO,值得临床推广。     

噻托溴铵对肺外血管内皮细胞功能的影响

目的探讨噻托溴铵肺外血管内皮细胞功能的调节作用,并分析患者肺功能改善状况。方法选择本院收治的98例稳定期慢阻肺患者,应用噻托溴铵治疗。评估患者治疗前、后最大肺活量(FVC)、一秒钟用力呼气量(FEV1)和FEV1/FVC,并检测血清中内皮素-1(ET-1)、一氧化氮(NO)和血管内皮生长因子(VEGF)的水平。结果治疗后FEV1/FVC、FEV1和FEV1/FVC(%)均高于治疗前(P0.05)。治疗后ET-1低于治疗前,差异有统计学意义(P0.05)。治疗后NO和VEGF均高于治疗前(P0.05)。治疗后MMP-9和IL-8低于治疗前,差异有统计学意义(P0.05)。结论噻托溴铵可明显提高内皮细胞功能,有利于患者肺功能的改善。     

国产噻托溴铵粉雾剂与沙美特罗替卡松治疗COPD的肺功能观察

目的分析国产噻托溴铵粉雾剂与沙美特罗替卡松治疗COPD的肺功能变化。方法选取48例门诊Ⅱ级中度COPD患者,男28例,女20例,其中单一吸入国产噻托溴铵粉雾剂(天晴速乐,18μg)14例,单一吸入沙美特罗替卡松(舒利迭,50/250μg)34例。用药前、用药后第4周、第8周记录肺功能。结果所有入选患者在用药4周及8周后肺功能均较前改善,噻托溴铵组的第4周FEV1增加值为133.5±11.8 ml,第8周为68.8±22.0 ml,第4周FVC增加值为151.1±55.8 ml,第8周为55.9±19.6 ml;沙美特罗替卡松组第4周FEV1增加值100.6±24.0 ml,第8周为60.1±17.6 ml,第4周FVC增加值为137.5±41.3 ml,第8周为55±22.4 ml。两组FEV1、FVC增加值无统计学差异。结论国产噻托溴铵粉雾剂与沙美特罗替卡松均可在短期内改善COPD患者肺功能,两组各自的FEV1、FVC增加值差异无统计学意义,噻托溴铵组患者依从性逊于沙美特罗替卡松组。     

Effect of tiotropium on health-related quality of life as a primary efficacy endpoint in COPD

Clinical manifestations of chronic obstructive pulmonary disease (COPD), including airflow limitation, dyspnea, and activity limitation, ultimately lead to impaired health-related quality of life (HRQoL). This 9-month, randomized, double-blind, multicenter study compared the effect of once-daily tiotropium 18 μg and placebo on HRQoL, spirometric parameters, and exacerbations in 554 patients with moderate-to-severe COPD. HRQoL was assessed using the St. George’s Respiratory Questionnaire (SGRQ) and the new 8-item Visual Simplified Respiratory Questionnaire (VSRQ), which is currently being validated. The primary efficacy endpoint was the proportion of patients achieving a reduction of at least 4 units in the SGRQ total score at study end (Month 9). Mean ± SD baseline SGRQ total score was 47.4 ± 18.1. Significantly more tiotropium-treated patients achieved a reduction of at least 4 units in the SGRQ score vs placebo at study end (59.1% vs 48.2%, respectively; p = 0.029). Tiotropium significantly improved spirometric parameters (forced expiratory volume in 1 second [FEV₁]: 0.11 ± 0.02 L vs 0.01 ± 0.02 L; between-group difference: 0.10 ± 0.03 L, p = 0.0001) and reduced exacerbations vs placebo. Maintenance treatment with tiotropium provided significant and clinically relevant improvements in HRQoL, as measured by the SGRQ.     

Orbital emphysema in COPD with bronchopleural fistula

Orbital emphysema is usually a benign, self-limited condition. Intraorbital extension of the entrapped air in the absence of an orbital fracture is extremely rare. Although benign, a careful periodic monitoring of intraocular pressure, optic nerve examinations, and prompt management are warranted in order to prevent tension pneumoobitus secondary to increasing intraorbital pressure by the orbital air.     

Role of mucolytics in the management of COPD

There is, to date, no medical therapy that modifies the decline in lung function that occurs in COPD. As the disease becomes more severe, exacerbations of COPD become increasingly common, affecting patient quality of life and increasing health care costs. Mucolytic agents, through their actions on inflammatory and oxidative pathways, have potential benefits in COPD. This paper reviews the randomized controlled trial (RCT) evidence for the effectiveness of at least 2 months of daily therapy with oral mucolytics in COPD. Based on evidence from 26 RCTs, mucolytics reduce exacerbations by up to 0.8 exacerbations per year, with a greater effect in patients with more severe COPD. This effect appears to be of a similar magnitude to the reduction in exacerbations seen with tiotropium and inhaled corticosteroids (ICS), but RCTs that compared the agents would be required to confirm this. Mucolytics do not affect the rate of lung function decline, but they do not have any significant adverse effects. Mucolytic treatment should be considered in: patients with more severe COPD who have frequent or prolonged exacerbations; those who are repeatedly admitted to hospital; or in those patients with frequent exacerbations who are unable to take tiotropium or ICS.     

Tiotropium bromide inhibits relapsing allergic asthma in BALB/c mice

Recurrent relapses of allergic lung inflammation in asthmatics may lead to airway remodeling and lung damage. We tested the efficacy of tiotropium bromide, a selective long-acting, muscarinic receptor antagonist as an adjunct therapy in relapses of allergic asthma in mice. We compared the effectiveness of local intranasal administration of tiotropium and dexamethasone in acute and relapsing allergic asthma in BALB/c mice. Although tiotropium at low doses is a potent bronchodilator, we tested higher doses to determine effectiveness on inflammation and mucus hypersecretion. A 5-day course of twice daily intranasal tiotropium or dexamethasone (1 mg/kg (b.w.)) suppressed airway eosinophils by over 87% during disease initiation and 88% at relapse compared to vehicle alone. Both drugs were comparable in their capacity to suppress airway and parenchymal inflammation and mucus hypersecretion, though tiotropium was better than dexamethasone at reducing mucus secretion during disease relapse. Despite treatment with either drug, serum antigen-specific IgE or IgG1 antibody titres remained unchanged. Our study indicates that tiotropium at higher doses than required for bronchodilation, effectively suppresses inflammation and mucus hypersecretion in the lungs and airways of mice during the initiation and relapse of asthma. Tiotropium is currently not approved for use in asthma. Clinical studies have to demonstrate the efficacy of tiotropium in this respiratory disease.     

Tidal Expiratory Flow Limitation at Rest as a Functional Marker of Pulmonary Emphysema in Moderate-to-Severe COPD

Background: Tidal expiratory flow limitation (EFL) is a step of paramount importance in the functional decline in COPD. Among mechanisms contributing to EFL, loss of airway-parenchymal interdependence could mostly be involved. Aim: To assess if EFL is a functional marker more frequently linked to prevalent pulmonary emphysema rather than to prevalent chronic bronchiolitis in COPD patients with moderate-to-severe airflow obstruction. Methods: Forty consecutive stable COPD patients with FEV₁ between 59 and 30% of predicted were functionally evaluated by measuring spirometry, maximal flow-volume curve and lung diffusion capacity (DL_CO) and coefficient of diffusion (K_CO). EFL was assessed by the negative expiratory pressure (NEP) method both in sitting and supine position. Chronic dyspnea was also scored by modified Medical Research Council (mMRC) scale. Results: In sitting position 13 patients (33%) were flow limited (FL) and 27 were non-flow limited (NFL). Only FEV₁/FVC, FEV₁ and MEF_25–75% were different between FL and NFL patients (p < 0.01). In supine position, however, among NFL patients in sitting position those who developed EFL, had significantly lower values of DL_CO and K_CO (p < 0.05) and higher mMRC score (p < 0.01), but similar values of FEV₁ as compared to those who did not have EFL. Conclusions: In COPD EFL in sitting position is highly dependent by the severity of airflow obstruction. In contrast, the occurrence of EFL in supine position is associated with worse DL_CO and K_CO and greater chronic dyspnea, reflecting a prevalent emphysematous phenotype in moderate-to-severe COPD patients.