The Effect of Inhaled Tiotropium Bromide on Lung Mucociliary Clearance in Patients With COPD

doi:10.1378/chest.125.5.1726

Chest

Volume 125, Issue 5, May 2004, Pages 1726-1734

https://doi.org/10.1378/chest.125.5.1726 Get rights and content

Study objective

To assess the effects of tiotropium on lung mucociliary clearance in COPD.

Design

Randomized, double-blind, placebo-controlled, parallel-group study.

Setting

Outpatients of an urban-area university teaching hospital.

Patients

Thirty-four patients with COPD aged 40 to 75 years classified equally into two groups.

Intervention

Single (18 μg) daily dose of tiotropium inhalation capsules or of placebo for 21 days.

Methods

Six-hour tracheobronchial clearance of inhaled ^99mTc-labeled polystyrene particles using a 48-h retention measurement to determine the “nontracheobronchial” deposition fraction.

Results

Test radioaerosol penetration into the lungs increased significantly (p < 0.003) as did FEV₁ (p < 0.006) in the tiotropium-treated patients, but measured mucociliary clearance was not significantly changed despite the increased pathway length for clearance (mean ± SE area under the tracheobronchial retention curve changed from 442 ± 22 to 453 ± 20%/h). Smaller (nonsignificant) decreases of radioaerosol penetration and FEV₁ occurred in the placebo group together with a small (nonsignificant) decrease in the area under the retention curve.

Conclusion

Twenty-one days of inhaled tiotropium, 18 μg/d, as a dry powder does not retard mucus clearance from the lungs.

Section snippets

Study Design

This was a single-center, randomized, double-blind, placebo-controlled, and parallel-group study. Patients were asked to attend a screening visit to assess eligibility, at which time informed consent and blood samples were obtained, and a complete medical history and physical examination, which included BP and pulse rate, 12-lead ECG, and lung function, were assessed. Eligible patients entered a run-in period (2 to 7 days) during which patients measured their peak expiratory flow rate (PEFR)

Patient Demographics

A total of 38 patients were randomized into the study, of whom 34 completed the study. One patient from the tiotropium group failed to complete due to an adverse event, shortness of breath. The other three patients had incomplete data acquisition (unable to attend for 48-h postinhalation radioaerosol assessment), two from the placebo group. The two treatment groups had reasonably matched demographics and baseline characteristics (Table 1), with the exception of tobacco consumption, which was

Discussion

Bronchodilators are the mainstay of drug therapy for patients with COPD,²⁷ with an increasing reliance on the effectiveness and convenience of long-acting formulations. A recent study³⁸ has strongly argued that the potential benefit from a bronchodilator maintenance regime should be evaluated not just in terms of lung function but in terms of a more rounded assessment of health status. Relevant factors include symptoms of breathlessness and limitation of daily activities. We would argue that

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Secretory hyperresponsiveness and pulmonary mucus hypersecretion
2014, Chest
Citation Excerpt :
The diagnosis may overlap with diseases such as asthma, and the airway plugging sometimes seen in allergic bronchopulmonary aspergillosis, although PB is characteristically refractory to asthma therapy.80,81 Diseases such as congenital heart disease with single ventricle physiology, lymphatic anomalies, influenza infections, and sickle cell acute chest syndrome have all been associated with PB.80–85 PB is currently classified based on underlying disease.
The term bronchial hyperresponsiveness is generally used to describe a heightened airway smooth muscle bronchoconstrictor response measured by bronchoprovocation testing. However, the airway also responds to inflammation or bronchoprovocation with increased mucus secretion. We use the term “secretory hyperresponsiveness” to mean increased mucus secretion either intrinsically or in response to bronchoprovocation. This is not the same as retained phlegm or sputum. Unlike smooth muscle contraction, which is rapidly reversible using a bronchodilator, mucus hypersecretion produces airflow limitation that reverses more slowly and depends upon secretion clearance from the airway. Certain groups of patients appear to have greater mucus secretory response, including those with middle lobe syndrome, cough-dominant (“cough-variant”) asthma, and severe asthma. Secretory hyperresponsiveness also is a component of forms of lung cancer associated with bronchorrhea. An extreme form of secretory hyperresponsiveness may lead to plastic bronchitis, a disease characterized by rigid branching mucus casts that obstruct the airway. Secretory hyperresponsiveness and mucus hypersecretion appear to be related to activation of the extracellular-regulated kinase 1/2, signaling through the epidermal growth factor receptor, or secretory phospholipases A2. Recognizing secretory hyperresponsiveness as a distinct clinical entity may lead to more effective and targeted therapy for these diseases.
Airway Mucus and the Mucociliary System
2014, Middleton's Allergy: Principles and Practice: Eighth Edition
Effects of formoterol and tiotropium bromide on mucus clearance in patients with COPD
2011, Respiratory Medicine
Citation Excerpt :
Bronchodilating drugs may influence mucus clearance,8,9 but the nature of the effects depend on the type of drug and the length of time for which it is administered. While tertiary ammonium compounds such as atropine may slow mucociliary clearance,9,10 quaternary ammonium compounds such as ipratropium bromide11 and tiotropium bromide12 have been reported not do so. Beta-agonists including fenoterol,13 salbutamol,14 and formoterol15 have been reported to enhance mucus clearance in patients, or to increase ciliary beat frequency in animal models.16
Lung mucociliary clearance is impaired in patients with chronic obstructive pulmonary disease (COPD). Treatment guidelines recommend that patients with COPD receive maintenance therapy with long-acting beta-agonists and anticholinergic agents.
Twenty-four patients with mild to moderate COPD received formoterol (12 μg, twice daily from Turbuhaler^® dry powder inhaler (DPI)) or tiotropium (18 μg, once daily from Handihaler^® DPI) for 14 days. They also received single doses of formoterol, tiotropium, salbutamol (200 μg) and placebo. A radioaerosol technique was used to assess the effects on mucus clearance of 14 days treatment with formoterol or tiotropium, as well as single doses of these drugs.
The 4 h whole lung retention of radioaerosol was significantly higher after 14 days treatment with tiotropium (P = 0.016), but not after 14 days treatment with formoterol. However, patients bronchodilated after 14 days treatment with both drugs, so that the deposited radioaerosol may have had an increased distance to travel in order to be cleared by mucociliary action. A single dose of formoterol enhanced radioaerosol clearance significantly compared to other single dose treatments (P < 0.05).
Formoterol (12 μg) enhances mucus clearance in patients with mild to moderate COPD when given as a single dose, and may do so when given for 14 days. Studies of longer duration would be needed in order to assess the effects of the study drugs on mucus clearance when they are used for long-term maintenance therapy.
Alternative mechanisms for tiotropium
2009, Pulmonary Pharmacology and Therapeutics
Tiotropium is commonly used in the treatment of chronic obstructive pulmonary disease. Although largely considered to be a long-acting bronchodilator, its demonstrated efficacy in reducing the frequency of exacerbations and preliminary evidence from early studies indicating that it might slow the rate of decline in lung function suggested mechanisms of action in addition to simple bronchodilation. This hypothesis was examined in the recently published UPLIFT study and, although spirometric and other clinical benefits of tiotropium treatment extended to four years, the rate of decline in lung function did not appear to be reduced by the addition of tiotropium in this study. This article summarizes data from a variety of investigations that provide insights into possible mechanisms to account for the effects of tiotropium. The report summarizes the discussion on basic and clinical research in this field.
Anticholinergic Bronchodilators
2009, Asthma and COPD
This chapter considers the pharmacology, biochemistry, and potential anti-inflammatory actions of anticholinergic bronchodilators, including possible anti-inflammatory actions, as well as clinical trial evidence for the safety and efficacy of these therapies. Important outcome measures for LAMAs involve considerations of effects on symptoms, lung function, dynamic hyperinflation and exercise responses, quality of life, health economics, exacerbations, survival, and the natural history of chronic obstructive pulmonary disease (COPD). Anticholinergics are muscarinic receptor antagonists, inhibiting cholinergic reflex bronchoconstriction, and reducing vagal cholinergic tone, which is the main reversible component in COPD. Normal airways have a small degree of vagal cholinergic tone, but because the airways are patent this has no perceptible effect and does not reduce airflow. Anticholinergics may reduce mucus hypersecretion. Anticholinergics have no apparent effect on pulmonary vessels, and therefore do not cause a fall in Pao₂, as may sometimes be seen with β₂-agonists and theophylline. The existence of several subtypes of muscarinic receptor in human airways has suggested that more selective muscarinic antagonists may have advantages over nonselective agents, such as ipratropium bromide and oxitropium bromide. Interestingly, anticholinergic may benefit asthmatics with COPD-like inflammation in asthma, viral hyperreactivity, and emergency asthma.
The impact of long-acting muscarinic antagonists on mucus hypersecretion and cough in chronic obstructive pulmonary disease: a systematic review
2022, European Respiratory Review

View all citing articles on Scopus

: This study was supported through a grant from Boehringer Ingelheim (UK) Ltd.

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Chest

Clinical InvestigationsCOPDThe Effect of Inhaled Tiotropium Bromide on Lung Mucociliary Clearance in Patients With COPD

Study objective

Design

Setting

Patients

Intervention

Methods

Results

Conclusion

Section snippets

Study Design

Patient Demographics

Discussion

Chest

Life Sci

Life Sci

Chest

Chest

Lancet

Br J Dis Chest

Chest

Respir Med

Respir Med

Chest

Chest

Management of chronic obstructive pulmonary disease

N Engl J Med

The role of anticholinergic bronchodilators in adult asthma and COPD

Lung

Anticholinergic, antimuscarinic bronchodilators

Am Rev Respir Dis

Optimal assessment and management of chronic obstructive pulmonary disease (COPD)

Eur Respir J

Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease

Eur Respir J

Long-acting bronchodilation with one-daily dosing of tiotropium (Spiriva) in stable chronic obstructive pulmonary disease

Am J Respir Crit Care Med

Improved health outcomes in patients with COPD during 1 yr's treatment with tiotropium

Eur Respir J

Clinical Investigations
COPD
The Effect of Inhaled Tiotropium Bromide on Lung Mucociliary Clearance in Patients With COPD