Tiotropium bromide: a novel once-daily anticholinergic bronchodilator for the treatment of COPD

Tiotropium bromide (Spiriva, BA679BR, Boehringer Ingelheim) is a novel inhaled, long-acting anticholinergic bronchodilator that is employed as a once-daily maintenance treatment for patients with chronic obstructive pulmonary disease (COPD). Like ipratropium bromide, tiotropium bromide is a quaternary ammonium derivative that binds to muscarinic receptors. However, although tiotropium binds with high affinity to muscarinic receptors of M1-, M2- and M3-subtypes, it dissociates very slowly from M1- and M3-receptors but more rapidly from M2-receptors, thereby giving it a unique kinetic selectivity. To date, the short-acting anticholinergic agents ipratropium and oxitropium bromide have been extensively employed as bronchodilator therapy for patients with COPD. Indeed, the Global Initiative for Chronic Obstructive Lung Disease (GOLD) strategy emphasises the role of bronchodilators in symptomatic management of all stages of COPD. It is encouraging that tiotropium given once daily from a dry powder inhaler at 18 g has been shown to cause greater improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. Furthermore, clinical studies over a 1-year period have demonstrated that tiotropium has impressive and maintained effects on lung function, symptoms and health-related quality of life, and may also reduce exacerbations. In a recent large scale comparative study over 6 months, tiotropium has been shown to cause superior bronchodilation and symptomatic improvement when compared to twice daily salmeterol in COPD. The only significant reported adverse event is dry mouth, which is found in approximately 10%-15% of subjects, but this is reversible and rarely causes discontinuation of therapy. Based on these promising features, it is likely that tiotropium used alone or in combination with other bronchodilators will emerge as first-line maintenance treatment for patients with airway obstruction due to COPD.     

Anticholinergic drugs in the therapy of obstructive airway diseases

The anticholinergic effects from botanical preparations of the deadly nightshade family have been used for hundreds of years for the treatment of obstructive airway diseases. Nowadays, derivatives of the plant alkaloids with quaternary ammonium structure, ipratropium bromide and tiotropium bromide, are used, which retain the bronchodilator properties of the parent compounds but are much safer since they are poorly absorbed across biologic membranes. They are the bronchodilators of choice in the management of chronic obstructive pulmonary disease (COPD). However, ipratropium is considered a second-line agent in the treatment of asthma as the bronchodilatory effects seen with ipratropium are less than those seen with beta-adrenergic drugs. Tiotropium is only approved for use in COPD. Though, a recent study provides some evidence that this agent may be an alternative to long-acting beta agonists as an add-on therapy to inhaled glucocorticoids for asthma.     

Combination inhaled bronchodilator therapy in the management of chronic obstructive pulmonary disease

The Global Obstructive Lung Disease (GOLD) guidelines suggest the potential use of combination bronchodilator therapy in patients with stage II or higher chronic obstructive pulmonary disease (COPD). Guidelines from the American Thoracic Society also mention that certain combinations of bronchodilators may prevent exacerbations. Combinations of several agents may benefit patients with COPD not only by improving lung function, but also by decreasing exacerbation rates and improving overall symptoms. A MEDLINE search was conducted to gather published data and clinical trial reports regarding the clinical effect of combining bronchodilators in the treatment of COPD. Agents such as oxitropium, which is not available in the United States, were not included in the analysis. Although the data are somewhat limited, trials suggest many potential benefits for combination bronchodilator therapy in patients with COPD. Information on combining long-acting anticholinergic drugs with long-acting beta2-agonists is scarce, but the combination of two long-acting agents may provide additional benefits by improving patient compliance with prescribed regimens. More studies evaluating outcomes in patients with COPD may help solidify the potential benefits of combination inhaled bronchodilator therapy.     

噻托溴铵治疗慢性阻塞性肺疾病作用机制的研究进展

慢性阻塞性肺疾病(COPD)是呼吸系统疾病中常见的疾病,可引起呼吸衰竭、肺源性心脏病、心力衰竭等严重疾病。噻托溴铵作为长效的抗胆碱制剂,现为临床治疗慢性阻塞性肺炎的常用药物,其可通过扩张支气管、抑制炎症因子和抑制气道重塑的作用机制,进而有效缓解支气管痉挛、呼吸困难和降低炎症反应。主要对噻托溴铵治疗慢性阻塞性肺疾病的作用机制进行综述。     

Pharmacology and therapeutics of bronchodilators

Bronchodilators are central in the treatment of of airways disorders. They are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) and are critical in the symptomatic management of asthma, although controversies around the use of these drugs remain. Bronchodilators work through their direct relaxation effect on airway smooth muscle cells. at present, three major classes of bronchodilators, β(2)-adrenoceptor (AR) agonists, muscarinic receptor antagonists, and xanthines are available and can be used individually or in combination. The use of the inhaled route is currently preferred to minimize systemic effects. Fast- and short-acting agents are best used for rescue of symptoms, whereas long-acting agents are best used for maintenance therapy. It has proven difficult to discover novel classes of bronchodilator drugs, although potential new targets are emerging. Consequently, the logical approach has been to improve the existing bronchodilators, although several novel broncholytic classes are under development. An important step in simplifying asthma and COPD management and improving adherence with prescribed therapy is to reduce the dose frequency to the minimum necessary to maintain disease control. Therefore, the incorporation of once-daily dose administration is an important strategy to improve adherence. Several once-daily β(2)-AR agonists or ultra-long-acting β(2)-AR-agonists (LABAs), such as indacaterol, olodaterol, and vilanterol, are already in the market or under development for the treatment of COPD and asthma, but current recommendations suggest the use of LABAs only in combination with an inhaled corticosteroid. In addition, some new potentially long-acting antimuscarinic agents, such as glycopyrronium bromide (NVA-237), aclidinium bromide, and umeclidinium bromide (GSK573719), are under development, as well as combinations of several classes of long-acting bronchodilator drugs, in an attempt to simplify treatment regimens as much as possible. This review will describe the pharmacology and therapeutics of old, new, and emerging classes of bronchodilator.     

抗胆碱药物在哮喘治疗中的地位

作为支气管扩张药,抗胆碱药物在治疗阻塞性气道疾病(包括哮喘和慢性阻塞性肺疾病)方面有重要地位。本文就短效和长效抗胆碱药物治疗哮喘的有效性和不良反应进行综述。异丙托溴铵和速效β受体激动药合用可有效控制不同年龄哮喘的急性发作。噻托溴铵是长效支气管扩张药,它与M1、M2、M3受体竞争结合,与异丙托溴铵相比噻托溴铵从M1、M3胆碱能受体复合物上解离的速度要比从M2胆碱能受体复合物上解离的速度慢。噻托溴铵能减少Th2细胞因子和气道炎症,降低气道重塑和气道高反应性。噻托溴铵与吸入激素联合用药能有效控制未完全缓解的哮喘患者的症状并改善其肺功能。吸入抗胆碱药物不易吸收入血,因而全身不良反应小。     

Airway nitrergic pathways: is there therapeutic potential in asthma and COPD?

Airway diseases such as asthma and chronic obstructive pulmonary disease (COPD) are characterised by airway hyperresponsiveness, epithelial damage, oxidative stress and airway inflammation. Inflammatory cells, including macrophages, neutrophils, eosinophils and lymphocytes, are crucial in the pathogenesis of asthma and COPD. The prevalence of asthma and COPD is increasing, especially in Western countries. Symptomatic treatment is based on reduction of airway obstruction by inhalation of beta(2)-receptor agonists and attenuation of the underlying inflammatory reactions by inhalation of corticosteroids. Because these agents only suppress symptoms, there is a need for medicines that remove the cause of these airway diseases.     

Is combination therapy with inhaled anticholinergics and beta2-adrenoceptor agonists justified for chronic obstructive pulmonary disease?

Chronic obstructive pulmonary disease (COPD) is a debilitating condition characterised by progressive, irreversible airflow limitation. The economic and social burden of the disease is enormous. The treatment of COPD is guided by the stage of the disease and is aimed primarily at control of symptoms. Bronchodilators are the cornerstone of pharmacological management of COPD. Short-acting bronchodilators (beta(2)-adrenoceptor agonists and anticholinergics) have been available for many years and have been extensively studied as individual agents and in combination. When administered in combination, short-acting bronchodilators provide superior bronchodilation compared with individual agents given alone. However, the improvement in bronchodilation does not translate into an improvement in quality-of-life (QOL) indices. More recently, long-acting beta(2)-adrenoceptor agonists (LABAs) and anticholinergics have been introduced, and current guidelines recommend regular use of these agents in COPD of Global initiative for chronic Obstructive Lung Disease (GOLD) stage II or more. Combining short-acting anticholinergics with LABAs for daily use has been evaluated, but this combination does not confer any advantage in terms of subjective improvement or prevention of exacerbations. Combining the long-acting anticholinergic tiotropium bromide with formoterol given once or twice daily improves airway obstruction and hyperinflation. However, the effects of combinations of long-acting bronchodilators on patients' symptom scores, QOL and exacerbations remain to be studied. Ultra-LABAs, which are in development, may enable use of a combination of long-acting bronchodilators in a single inhaler for once-daily use, thus simplifying the regimen. This article discusses the results of various clinical trials comparing the efficacy of bronchodilators given alone or in combination to patients with COPD, with emphasis on the effects of these agents on bronchodilation, symptomatic and objective improvements in QOL and prevention of exacerbations.     

Tiotropium for chronic obstructive pulmonary disease

In 2001, we concluded that patients with symptoms of stable chronic obstructive pulmonary disease (COPD) inadequately controlled by an 'as-required' inhaled short-acting beta 2 agonist can be helped by regular use of an inhaled antimuscarinic bronchodilator or a long-acting beta 2 agonist. Since then, a new antimuscarinic drug [symbol: see text] tiotropium bromide (Spiriva--Pfizer/Boehringer Ingelheim) has been licensed as a once-daily bronchodilator for maintenance treatment of COPD in people aged 18 years or over. Here, we review the evidence for efficacy of tiotropium and discuss its role in the maintenance treatment of COPD.     

Long-term effect of the beta2-receptor agonist procaterol on daily life performance and exercise capacity in patients with stable chronic obstructive pulmonary disease. Clinical study with special reference to health-related quality of life and activities of daily living

The present study was undertaken to evaluate the long-term effect of procaterol hydrochloride (CAS 62929-91-3, Meptin), a third generation beta2-receptor agonist on lung function, exercise capacity, health-related quality of life (HRQOL) and activities of daily living (ALDs) in patients with stable chronic obstructive pulmonary disease (COPD). Twenty patients were randomly assigned to the procaterol group or to the control group, who received oxitropium bromide (CAS 30286-75-0), an anticholinergic agent. Procaterol was inhaled three times a day at a dose of 20 pg, while oxitropium was inhaled three times a day at a dose of 200 microg. The subjects were evaluated based on spirometry, exercise capacity, the Borg Scale, HRQOL, and ADLs before and after 12, 24 and 52 weeks of therapy. The values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), total lung capacity (TLC), functional residual capacity (FRC), residual volume (RV), maximal inspiratory pressure (PImax), and maximal expiratory pressure (PEmax) were significantly improved at 12, 24 and 52 weeks compared with baseline values in the procaterol group (p < 0.05, p < 0.01), while these values did not differ from baseline values at any point in the oxitropium group (p > 0.05). Additionally, 6-min walking distances and Borg Scale values showed significant improvement at 12, 24 and 52 weeks compared with baseline values in the procaterol group (p < 0.05, p < 0.01), but did not significantly differ from baseline values in the oxitropium group at any point (p > 0.05). Likewise, the scores for dyspnea, fatigue, emotional function, mastery, total scores and ADLs were significantly higher at 12, 24 and 52 weeks compared with the baseline values in the procaterol group (p < 0.05, p < 0.01), but did not differ at any point in the oxitropium group (p > 0.05). These results suggest the effectiveness of long-term regular bronchodilator therapy with the beta2-receptor agonist procaterol in patients with stable COPD.     

Once-daily glycopyrronium via the Breezhaler® device for the treatment of COPD: pharmacological and clinical profile

In the management of chronic obstructive pulmonary disease (COPD), there is an unmet medical need for effective bronchodilator treatments that not only have a fast onset of action, but also a long duration of action and are delivered using a simple, easy-to-use device. Long-acting muscarinic antagonists such as glycopyrronium and tiotropium, along with long-acting beta-2 agonists such as indacaterol, formoterol and salmeterol are the pillars of pharmacological therapy for the long-term management of patients with COPD. Glycopyrronium, the quaternary ammonium ion of glycopyrronium bromide, acts as a competitive antagonist by selectively binding to the muscarinic receptors in the bronchial smooth musculature, thus inhibiting acetylcholine-mediated bronchoconstriction. Glycopyrronium is an inhaled once-daily long-acting muscarinic antagonist recently approved for the maintenance treatment of patients with COPD. Glycopyrronium is administered by a single-dose, dry-powder inhaler, the Breezhaler® device, designed specifically to have a low internal resistance, be easy to use and confirm efficient drug delivery in patients with a wide range of COPD severities, irrespective of the age. Glycopyrronium has been shown to provide rapid and sustained improvements in lung function, dyspnea, health status, exercise endurance and exacerbation risk and an acceptable safety and tolerability profile.     

Use of ipratropium bromide in obstructive lung disease

The chemistry, pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage of ipratropium bromide are reviewed. Ipratropium bromide, a synthetic quaternary isopropyl derivative of atropine, interrupts vagally mediated bronchoconstriction by inhibiting the cyclic guanosine 3',5'-monophosphate system at parasympathetic nerve endings. Ipratropium bromide is poorly absorbed after oral and inhaled administration but diffuses rapidly into tissue after i.v. or i.m. administration. The elimination half-life is 3.2-3.8 hours. After inhalation, the drug is eliminated in the urine and feces. The bronchodilatory effect of ipratropium bromide in stable chronic obstructive pulmonary disease appears to be comparable, and may be superior, to that of the beta-sympathomimetic agents. In acute exacerbations, ipratropium bromide is useful but may not be the preferred agent because of a delayed onset of action (within 15 minutes; mean dose-dependent duration of effect, three to five hours). Combination therapy with other bronchodilating drugs has proved useful. Ipratropium bromide may be a useful adjunctive agent in the treatment of asthma. Since the onset of action is delayed, ipratropium bromide should not be used as single-drug therapy in an acute asthmatic exacerbation. Reported adverse effects, including cough, nausea, palpitations, dry mouth, nervousness, gastrointestinal distress, and dizziness, have been mild. The usual dosage is two inhalations (36 micrograms) four times daily, and the maximum number of doses per day should not exceed 12. Although ipratropium bromide is currently indicated only for maintenance therapy in stable chronic bronchitis and emphysema, it may be useful as adjunctive therapy in asthma and in the management of acute exacerbations of chronic bronchitis and asthma. Additional experience in a variety of chronic obstructive pulmonary disorders will help to clarify the role of ipratropium bromide in the treatment of obstructive pulmonary disease.     

中药治疗慢性阻塞性肺疾病的作用机制研究进展

慢性阻塞性肺疾病（COPD）是一种气流不完全受限的常见慢性呼吸系统疾病,发病率高、致死率高,已成为全球范围内威胁人类健康的主要慢性病之一,目前尚无有效的治疗药物,近年来COPD的防治已成为广大医药工作者的研究热点,尤其是中药对于COPD作用机制的研究较多。中药能够控制气道和肺部炎症、改善气道重塑、降低气道反应、调控氧化–抗氧化过程,并对蛋白酶–抗蛋白酶失衡、免疫失衡及肺功能、血液流变学、血清标记物的病理改变起到一定的调整作用。归纳总结中药治疗COPD作用机制的研究,为中药COPD作用机制的研究及COPD的治疗提供新的思路和途径。     

Long-acting beta2 agonists in the management of stable chronic obstructive pulmonary disease

Long-acting beta2 agonist bronchodilators (e.g. formoterol, salmeterol) are a new interesting therapeutic option for patients with chronic obstructive pulmonary disease (COPD). In the short term, both salmeterol and formoterol appear to be more effective than short-acting beta2 agonists, and in patients with stable COPD they are more effective than anticholinergic agents and theophylline. Regular treatment of patients with COPD with long-acting beta2 agonists can induce an improvement in the respiratory function and certain aspects of quality of life. Moreover, salmeterol seems to be better than ipratropium and theophylline in improving lung function at the recommended doses after a long term treatment. Use of combination therapy of a long-acting inhaled beta2 agonist and an anticholinergic agent or theophylline in patients with COPD has not been sufficiently studied. Combination of usual doses of ipratropium or oxitropium with usual doses of salmeterol or formoterol does not appear to improve pulmonary function, but this lack of improvement with the combination should not, in itself, prevent implementation of further therapeutic steps in patients responsive to an anticholinergic agent and/or salmeterol or formoterol administered singly. Neither formoterol nor salmeterol elicit significant cardiovascular effects in healthy individuals and patients with reversible airway obstruction. However, adverse cardiac events might occur in patients with COPD with pre-existing cardiac arrhythmias and hypoxaemia if they use long-acting 12 agonists, although the recommended single dose of salmeterol 50 microg or formoterol 12 microg ensures a relatively higher safety margin than formoterol 24 microg. The bronchodilatory effect of long-acting beta2 agonists seems to be fairly stable after regular treatment with these bronchodilators. Moreover, pre-treatment with a conventional dose of formoterol or salmeterol does not preclude the possibility of inducing further bronchodilation with salbutamol in patients with partially reversible COPD. All these findings support the use of long-acting beta2 agonist bronchodilators as first-line bronchodilator therapy for the long term treatment of airflow obstruction in patients with COPD. However, since physicians must always choose a drug that is highly efficacious, well tolerated and inexpensive, the cost-effectiveness analysis in relation to other bronchodilators will determine the proper place of long-acting beta2 agonists in the long term therapy of stable COPD.     

The future of combining inhaled drugs for COPD

Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality globally, and its prevalence is projected to continue to increase owing to trends in smoking. Treatment of COPD has evolved from the initial adaptations of drugs and treatment strategies successfully used in asthma into more specific pharmacological strategies following global guidelines. Bronchodilating anticholinergic and beta-2-stimulating agents and anti-inflammatory corticosteroid drugs delivered by inhalators are the mainstay of COPD treatment. Despite significant progress, current pharmacotherapies neither fully alleviate the airway obstruction in COPD, nor reverse the progressive nature of the disease. This review discusses inhalation therapies which have recently become clinically available or are being developed, with focus on combination therapies. There is accumulating evidence that the combination of two or all three drug classes, triple therapy, is superior to single drug therapy. Several fixed combinations of both currently available and novel molecules will be launched for clinical use within the next few years. Also, improved understanding of subgroups within the clinical spectrum of COPD, is likely to offer new potentials to improve COPD care.     

Tiotropium: an inhaled,long-acting anticholinergic drug for chronic obstructive pulmonary disease

Inhaled anticholinergic drugs are considered one of the principal bronchodilator treatments for chronic obstructive pulmonary disease (COPD). Ipratropium bromide is an anticholinergic drug frequently administered for the treatment of COPD. Unfortunately, ipratropium has a short duration of action, requiring administration every 6 hours; this regimen affects adherence to drug therapy. Tiotropium bromide is structurally similar to ipratropium and is under development in the United States. The duration of action of tiotropium is approximately 24 hours, allowing for once-daily dosing. Other than xerostomia being more common with tiotropium than with ipratropium, the safety profiles of these drugs were similar in studied populations. On the basis of its improvements in trough spirometric measurements and improved pharmacokinetic profile compared with that of ipratropium, tiotropium is likely to become the first-line anticholinergic agent in the treatment of patients with COPD.     

Once-daily glycopyrronium bromide (Seebri Breezhaler®) for the treatment of chronic obstructive pulmonary disease (COPD)

Introduction: Long-acting bronchodilators are the mainstay of pharmacological therapy for patients with chronic obstructive pulmonary disease (COPD). The choice of optimal bronchodilator therapy for COPD is increasingly difficult for clinicians as new treatments are marketed.Areas covered: Inhaled glycopyrronium bromide (Seebri Breezhaler®) is a well-tolerated long-acting anti-muscarinic agent (LAMA) with a fast onset of action. In patients with moderate to severe COPD, glycopyrronium bromide has clinically important effects on level of FEV₁, use of relief medication, day-time dyspnea scores, and probably also on health status. Furthermore, glycopyrronium bromide also has beneficial effects on dynamic hyperinflation and, probably by that, exercise tolerance. Glycopyrronium bromide has been shown to reduce the rate of exacerbations in patients with moderate to severe COPD, although as a secondary outcome only. Expert opinion: Once-daily inhaled glycopyrronium bromide has positive impact on important COPD outcomes, comparable to the effects of other marketed LAMAs. Once-daily administration may improve adherence, and glycopyrronium bromide has the potential for a role in the future management of COPD similar to that of other long-acting anti-muscarinic agents, including tiotropium. Studies of glycopyrronium bromide with exacerbation rate as the primary outcome of interest is needed.     

Indacaterol: a review of its use as maintenance therapy in patients with chronic obstructive pulmonary disease

Indacaterol inhalation powder (Onbrez? Breezhaler?) is a long-acting, selective β(2)-adrenoceptor agonist that is indicated for the maintenance bronchodilator treatment of airflow obstruction in adults with chronic obstructive pulmonary disease (COPD). This article reviews the clinical efficacy and tolerability of indacaterol 150 and 300?μg once daily in adults with moderate to severe COPD, as well as reviewing indacaterol's pharmacological properties and results of a cost-utility analysis. Indacaterol has a fast onset of action after the first dose and is effective over 24 hours, allowing for once-daily administration. In short-term trials (≤21 days) in patients with COPD, once-daily indacaterol 150 or 300?μg significantly improved lung function, exercise endurance and lung hyperinflation relative to placebo. In large, longer-term clinical studies (12 weeks to 1 year) in patients with moderate to severe COPD, once-daily indacaterol 150 or 300?μg improved lung function (primary endpoint) significantly more than placebo, and improvements were significantly greater than twice-daily formoterol 12?μg or salmeterol 50?μg, and noninferior to once-daily tiotropium bromide 18?μg (all agents were administered via inhalation). Overall, indacaterol improved dyspnoea, use of rescue medication and general health status significantly more than placebo, salmeterol or tiotropium bromide, and the degree of improvement in these endpoints was similar to or greater than that achieved with formoterol. Improvements were sustained over the long term (1 year), with no evidence of tolerance. Combination therapy with indacaterol plus tiotropium bromide improved lung function, dyspnoea, rescue medication use and general health status significantly more than tiotropium bromide alone in patients with moderate to severe COPD. Indacaterol is generally well tolerated when used alone or in combination with tiotropium bromide in patients with COPD and has not been associated with any safety issues. The most common adverse event in clinical trials was COPD worsening, which occurred more commonly with placebo than indacaterol. Indacaterol was not associated with an increased risk of cardiovascular adverse events. In a cost-utility analysis from a German healthcare payer perspective, once-daily indacaterol 150?μg was dominant (i.e. more effective with lower total costs) to once-daily tiotropium bromide 18?μg and twice-daily salmeterol 50?μg in the treatment of patients with COPD. In conclusion, indacaterol provides a valuable option for the maintenance treatment of adults with COPD.     

Targeting the issues in chronic obstructive lung disease

Chronic obstructive pulmonary disease (COPD) is a disease of unclear aetiology and variable pathology among patients. Little is known about the cellular mechanisms which cause this condition and, although the incidence of COPD has been rising worldwide for some time, research efforts have only very recently increased. Medication thus far has focused on symptom treatment rather than targeting identifiable disease mechanisms. Such treatment has consisted primarily of bronchodilators, both beta-agonists and anticholinergic in action. Treatment with steroids has been disappointing, except in the case of acute exacerbation, and this has shifted the research focus to characterising the inflammatory process in COPD as distinct from that in asthma. New targets for pharmacotherapy are coming to light as information is gained about specific inflammatory mediators active in COPD and the role of oxidative stress in this disease. In addition, new approaches include describing the role of exogenous antiproteases in restoring the balance between protease-antiprotease mechanisms that may be defective in this disease. Ultimately, exploration of the molecular genetics of COPD will provide new targets for future pharmacological agents.     

Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?

Bronchodilators are the mainstay of therapy for patients with established chronic obstructive pulmonary disease (COPD) but, at present, the majority of patients use short-acting agents. There is increasing evidence that long-acting agents, such as the beta(2)-adrenoceptor agonists salmeterol and formeterol, and the new anticholinergic tiotropium bromide provide a better therapeutic option. In the treatment of COPD, long-acting beta(2)-adrenoceptor agonists (LABAs) given twice daily cause the same degree of bronchodilation as tiotropium bromide given once daily. Combined use of an inhaled LABA with tiotropium bromide should provide important therapeutic benefits, as these drugs have distinct and complementary pharmacological actions in the airways. Although clinical trials of this combination have not been performed, clinical experience with Combivent, a combination of a short-acting beta(2)-adrenoceptor agonist (salbutamol) and a short-acting anticholinergic (ipratropium bromide), in COPD is encouraging because the bronchodilation produced is of a magnitude greater than that of either component alone. However, because LABAs are given twice daily but tiotropium bromide is required only once daily, the challenge is to develop a combined inhaler that can be employed on a daily basis.