Long-acting Anticholinergics Research Articles

Accuracy of diagnostic registers and management of chronic obstructive pulmonary disease: the Devon primary care audit.

BackgroundGuidelines on COPD diagnosis and management encourage primary care physicians to detect the disease at an early stage and to treat patients according to their condition and needs. Problems in guideline implementation include difficulties in diagnosis, using spirometry and the disputed role of reversibility testing. These lead to inaccurate diagnostic registers and inadequacy of administered treatments. This study represents an audit of COPD diagnosis and management in primary care practices in Devon.MethodsSix hundred and thirty two patients on COPD registers in primary care practices were seen by a visiting Respiratory Specialist Nurse. Diagnoses were made according to the NICE guidelines. Reversibility testing was carried out either routinely or based on clinical indication in two sub-samples. Dyspnoea was assessed. Data were entered into a novel IT-based software which computed guideline-based treatment recommendations. Current and recommended treatments were compared.ResultsFive hundred and eighty patients had spirometry. Diagnoses of COPD were confirmed in 422 patients (73%). Thirty nine patients were identified as asthma only, 94 had normal spirometry, 23 were restrictive and 2 had a cardiac disorder. Reversibility testing changed diagnosis of 11% of patients with airflow obstruction, and severity grading in 18%. Three quarters of patients with COPD had been offered practical help with smoking cessation. Short and long-acting anticholinergics and long acting beta-2 agonists had been under-prescribed; in 15–18% of patients they were indicated but not received. Inhaled steroids had been over-prescribed (recommended in 17%; taken by 60%), whereas only 4% of patients with a chronic productive cough were receiving mucolytics. Pulmonary rehabilitation was not available in some areas and was under-used in other areas.ConclusionDiagnostic registers of COPD in primary care contain mistakes leading to inaccurate prevalence estimates and inappropriate treatment decisions. Use of pre-bronchodilator readings for diagnosis overestimates the prevalence and severity in a significant minority, thus post bronchodilator readings should be used. Management of stable COPD does often not correspond to guidelines. The IT system used in this study has the potential to improve diagnosis and management of COPD in primary care.

Radiological quiz

Few studies have assessed the safety and efficacy of potential asthma medications in children younger than 5 years. We descriptively assessed the safety and efficacy of tiotropium, a long-acting anticholinergic drug, in children aged 1–5 years with persistent asthmatic symptoms.This exploratory 12-week, randomised, double-blind, placebo-controlled, parallel-group, phase 2/3, regulatory multicentre trial was done at 32 hospitals, clinics, and clinical research units in 11 countries in Asia, Europe, and North America. Children aged 1–5 years with at least a 6-month history of persistent asthmatic symptoms and a need for inhaled corticosteroids were eligible. Patients were randomly allocated using an interactive voice or web-based response system to receive once-daily tiotropium 2·5 μg, tiotropium 5 μg, or placebo as an add-on to inhaled corticosteroids with or without additional controller medication. Patients and investigators were masked to study group assignment. Tiotropium was given via the Respimat inhaler once daily as two puffs of 1·25 μg in the 2·5 μg group, two puffs of 2·5 μg in the 5 μg group, or two puffs of placebo. The primary outcomes were safety, which was assessed by comparing adverse events between the tiotropium and placebo groups, and efficacy, which was measured as the change in weekly mean combined daytime asthma symptom score from baseline to week 12. Statistical analyses of treatment effects were exploratory; although endpoints were defined, they were used for descriptive analyses only. The safety and primary analyses were done in all patients who received at least one dose of their assigned treatment. This study is registered with ClinicalTrials.gov (NCT01634113), and is completed.Between July 26, 2012, and Dec 4, 2014, 102 children were randomly assigned to the three treatment groups (36 to receive tiotropium 2·5 μg, 32 to receive tiotropium 5 μg, and 34 to receive placebo). 101 children completed the study and were included in the analyses. The changes in adjusted weekly mean combined daytime asthma symptom scores between baseline and week 12 were not significantly different between any of the groups. The adjusted mean difference between the tiotropium 2·5 μg group and placebo group was −0·080 (95% CI −0·312 to 0·152) and the difference between tiotropium 5 μg and placebo group was −0·048 (−0·292 to 0·195). Adverse events were less frequent with tiotropium treatment than with placebo (20 [56%] of 36 children with tiotropium 2·5 μg, 18 [58%] of 31 with tiotropium 5 μg, and 25 [74%] of 34 with placebo), although no formal statistical comparison between groups was performed. A greater proportion of children reported asthma exacerbations as adverse events in the placebo group (ten [29%] of 34) than in the tiotropium groups (five [14%] of 36 in the 2·5 μg group and two [6%] of 31 in the 5 μg group). Serious adverse events were reported in three patients (all of whom received placebo); no adverse events led to discontinuation of treatment or death.To our knowledge, our small study is the first to assess the safety and efficacy of tiotropium in children aged 1–5 years with persistent asthmatic symptoms. Tolerability of tiotropium was similar to that of placebo, which is consistent with previous findings in older populations. Although mean daytime asthma symptom scores were not significantly different between groups, tiotropium showed the potential to reduce asthma exacerbation risk compared with placebo. The findings of the study are limited by the small sample size and descriptive statistical analyses. Additional well powered trials are needed to further assess the safety and efficacy of tiotropium in young children.Boehringer Ingelheim.

Management of Stable Chronic Obstructive Pulmonary Disease: A Systematic Review for a Clinical Practice Guideline

Chronic obstructive pulmonary disease (COPD) is a common and disabling condition in adults. Information about therapeutic effectiveness and adverse effects of common treatment options and how clinical and spirometric characteristics affect outcomes is not well known but is important for clinicians caring for patients with stable COPD. To evaluate the effectiveness of COPD management strategies. English-language publications in MEDLINE and the Cochrane Library through March 2007. Randomized, controlled trials (RCTs) and previous systematic reviews of inhaled therapies, pulmonary rehabilitation, disease management, and supplemental oxygen in adults with COPD. Participant, study, and intervention characteristics; exacerbations; deaths; respiratory health status; exercise capacity; hospitalizations; and adverse effects. Eight meta-analyses and 42 RCTs examined inhaled therapies: short-acting anticholinergics (n = 7), long-acting anticholinergics (n = 10), long-acting beta2-agonists (n = 22), corticosteroids (n = 14), dual D2 dopamine receptor-beta2-agonist (n = 3), or short-acting beta2-agonist plus ipratropium (n = 3). Evidence for nonpharmacologic therapies included 3 reviews of 39 RCTs plus 6 additional RCTs of pulmonary rehabilitation, 2 reviews of 13 RCTs plus 2 additional RCTs of disease management, and 8 RCTs of oxygen. Overall, long-acting inhaled therapies, used alone or in combination, reduced exacerbations more than placebo by 13% to 25% and had similar effectiveness to each other. Average improvements in health status scores were less than what is considered to be clinically noticeable. Inhaled monotherapy did not reduce mortality rates. Inhaled corticosteroids plus long-acting beta2-agonists reduced deaths in relative terms compared with placebo (relative risk, 0.82 [95% CI, 0.69 to 0.98]) and inhaled corticosteroids alone (relative risk, 0.79 [CI, 0.67 to 0.94]) but not compared with long-acting beta2-agonists alone (relative risk, 0.82 [CI, 0.52 to 1.28]). Absolute reductions were 1% or less and were not statistically significant. Pulmonary rehabilitation improved health status and dyspnea but not walking distance. Neither disease management nor ambulatory oxygen improved measured outcomes. Supplemental oxygen reduced mortality rates among symptomatic patients with resting hypoxia (relative risk, 0.61 [CI, 0.46 to 0.82]). Insufficient evidence supports using spirometry to guide therapy. Articles were limited to those in the English language. Treatment adherence, adverse effects, and effectiveness may differ among clinical settings. Short-acting inhalers for "rescue therapy" were not evaluated. Long-acting inhaled therapies, supplemental oxygen, and pulmonary rehabilitation are beneficial in adults who have bothersome respiratory symptoms, especially dyspnea, and FEV1 less than 60% predicted.

Optimizing Maintenance Therapy for Chronic Obstructive Pulmonary Disease: Strategies for Improving Patient-Centered Outcomes

Background: Chronic obstructive pulmonary disease (COPD) is associated with substantial morbidity and mortality. Published practice guidelines and treatment algorithms for COPD are designed to increase awareness of the problem and improve patient care; however, <40% of subjects diagnosed with COPD are receiving appropriate maintenance therapy. Objective: This paper reviews the use of maintenance therapy in COPD and examines the optimal timing for initiating such therapy based on the available literature. Methods: Relevant publications were identified through a search of MEDLINE (1995-May 2007) using the terms COPD, guidelines, treatment, maintenance therapy, bronchodilator, ipratropium, tiotropium, β-agonist, salmeterol, and inhaled corticosteroid. English-language publications discussing pharmacologic maintenance therapy for COPD, including practice statements/guidelines, randomized controlled clinical trials, systematic reviews, and meta-analyses, with a focus on agents currently approved for use in the United States, were selected for inclusion. Results: Although guidelines and algorithms agree on the importance of regularly scheduled maintenance therapy to reduce symptoms of COPD, minimize activity limitations, and improve health status, the timing of the initiation of such therapy is debatable. In most instances, maintenance medications, which include long-acting β 2-agonists, long-acting anticholinergics, and combination products, are prescribed late in the disease process and mainly for patients with severe disease. However, there is increasing evidence that the use of maintenance therapy early in the disease process may be associated with improvements in such outcomes as lung function, symptoms, exercise tolerance, exacerbations of COPD, and quality of life. Conclusion: The high burden associated with COPD highlights the need to initiate maintenance therapy before a substantial decline in lung function has occurred.

Inflammation in Chronic Obstructive Pulmonary Disease: Implications for New Treatment Strategies

Chronic obstructive pulmonary disease (COPD) is a treatable and preventable disease but current predictions are that it will continue to rise as an important cause of mortality and morbidity worldwide. COPD is a complex inflammatory disease with both airway and parenchymal lung injury. Currently there is growing recognition that the inflammatory response extends beyond the lung, with evidence of systemic inflammation, which may account for the multi-organ effects associated with COPD. Early diagnosis and timely therapeutic intervention are likely to make a significant contribution to tackling this disease. Smoking cessation remains the single most effective means of preventing lung function decline and reducing mortality. At present, no currently available drugs have been shown to slow the progression of the disease. Pharmacological treatment has focused largely on symptomatic relief and short-acting bronchodilators have been the mainstay therapy. Long-acting beta-2 agonists and anti-cholinergics have provided additional benefit and anti-inflammatory agents such as inhaled corticosteroids and theophylline seem to offer benefit in selected patients. Combinations of the different classes of treatment, particularly in the same inhaler device, seem to confer particular advantage with improvements in symptoms, exercise capacity, health status and reductions in exacerbations. More research is needed to unravel the important cellular and molecular processes involved in the pathophysiology of COPD and ultimately to develop new and more effective forms of therapy.

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.

The Combination of Tiotropium and Budesonide in the Treatment of Chronic Obstructive Pulmonary Disease

Because additive effects of inhaled corticosteroids and long-acting anticholinergics are unclear, we undertook this study to compare the efficacy of tiotropium alone and tiotropium plus budesonide in patients with chronic obstructive pulmonary disease. The study subjects were randomized to receive either tiotropium 18 µg once daily with or without budesonide 200 µg twice daily for 6 weeks. The efficacy variables were changes in trough forced expiratory volume in one second (FEV1), St. George's Respiratory Questionnaire (SGRQ), 6-minute walk distance (6MWD), and use of rescue medication. One hundred patients were randomized and 81 completed the study. The mean age was 64.0 yr, and the mean FEV1 was 39.7% predicted. Compared with tiotropium alone (N=40), the tiotropium/budesonide combination (N=41) was related to an improvement in the SGRQ total score (tiotropium -2.8 units and tiotropium/budesonide -5.6 units, p=0.003). 6MWD was improved by 13.5 m in the tiotropium group and by 22.5 m in the tiotropium/budesonide group (p=0.031). Changes in trough FEV1 and the use of rescue medication were similar between two groups. In conclusion, compared with tiotropium alone, the tiotropium/budesonide combination was related to an improved health-related quality of life. These data support that low-dose budesonide may enhance the efficacy of tiotropium.

Management of Acute Exacerbations of Chronic Obstructive Pulmonary Disease in the Elderly

Chronic obstructive pulmonary disease (COPD) is a debilitating disease with rising worldwide prevalence. Exacerbations of COPD cause significant morbidity and become more common with advancing age. Healthcare providers caring for elderly patients should therefore be familiar with effective treatments for exacerbations of COPD. An extensive body of literature has identified several effective drug therapies for exacerbations. These drugs include inhaled bronchodilators, systemic corticosteroids and antibacterials. The two main classes of inhaled bronchodilators are beta-adrenoceptor agonists and anticholinergics. These drugs optimise lung function during exacerbations, with neither class demonstrating clear superiority over the other. Systemic corticosteroids are effective when used either for inpatient or outpatient treatment of exacerbations. They hasten recovery from exacerbations and reduce relapse rates. Antibacterials decrease morbidity from exacerbations and may decrease mortality in the more severe exacerbations. Other effective therapies for the treatment of acute exacerbations of COPD include oxygen and non-invasive ventilation. Oxygen can be safely administered in acute exacerbations associated with hypoxaemia, with titration of oxygen delivery to a goal oxygen saturation of 90%. Non-invasive ventilation reduces the morbidity and mortality associated with acute exacerbations complicated by hypercapnic respiratory failure. Strategies to prevent COPD exacerbations include smoking cessation, long-acting inhaled beta-adrenoceptor agonists, inhaled long-acting anticholinergics, inhaled corticosteroids and vaccination. Mucolytic agents, pulmonary rehabilitation, and case management programmes may also reduce exacerbation risk, but the current evidence supporting these interventions is weaker.

Prevention of Exacerbations: How Are We Doing and Can We Do Better?

Prevention of exacerbations of chronic obstructive pulmonary disease (COPD) can involve removing the cause or reducing the patient's vulnerability to the cause. This article addresses the following issues: What is the problem during an exacerbation, what are the causes of an exacerbation, what can prevent exacerbations, and who are we? The difference between a patient with COPD during an exacerbation and after recovery is small. It is unlikely that patients with early COPD experience less exposure to exacerbation causes than those with severe disease; it is just that the consequences are more severe for those with severe disease. Interventions that produce small absolute benefits can therefore have a disproportionately large effect on exacerbation reduction. Recognized causes include season, cold weather, pollution events, bacterial infection, viral infection, and treatment withdrawal. Countries with warmer climates have much larger mortality in cold weather than those with colder climates. Reducing exacerbations in more temperate climates may be altered as much by changes in clothing and bedroom heating as by changes in treatment. Taking more exercise in cold weather may be the underlying reason for the reduction of exacerbations after pulmonary rehabilitation. Influenza vaccination reduces influenza severity and reduces transmission from health care workers to patients. There are a number of pharmacologic interventions shown to reduce (the effect of) exacerbations, including inhaled corticosteroids, long-acting beta-agonists, long-acting anticholinergics, mucolytics, and perhaps antibiotics that reduce Haemophilus carriage. The effect of the bronchodilators is additive to inhaled corticosteroids; how far the other interventions are complementary is unclear. So far, we have had a very medical response to COPD exacerbations. Altering social and behavioral aspects is likely to be complementary.

ADDITION OF FORMOTEROL TO TIOTROPIUM PRODUCES BETTER FEV1 AND FVC RESPONSES WHEN MEASURED OVER 24 HOURS FOLLOWING SINGLE-DOSE ADMINISTRATION IN SUBJECTS WITH MODERATE-TO-SEVERE COPD

PURPOSE: Tiotropium, a new long-acting anticholinergic drug is recommended as first-line bronchodilator in the management of COPD. The aim of this study was to investigate whether addition of Formoterol, a long-acting b2-agonist produces a superior bronchodilator response when compared to Tiotropium alone in subjects with moderate-to-severe stable COPD.

Bronchodilator treatment of stable COPD: long-acting anticholinergics

Since airflow obstruction in chronic obstructive pulmonary disease (COPD) is to some extent reversible, bronchodilators play an important role in the maintenance treatment of COPD the more they reduce hyperinflation and, as a result, improve dyspnoea and exercise capacity. Since parasympathetic activity is the dominant reversible component of airflow obstruction in COPD, inhaled short-acting anticholinergic agents (SAAC), in particular ipratropium, became an efficient and safe first-line treatment, especially when combined with a short-acting b2-adrenergic receptor agonist. Even better results were obtained when combining the SAAC ipratropium to a long-acting b2-adrenergic receptor agonist (LABA), once they became available. Recently, tiotropium bromide, the first of a new class of selective and long-acting anticholinergic agents was introduced for once-daily maintenance treatment of COPD patients. Several large long-term randomised clinical trials comparing tiotropium to placebo as well as to the SAAC ipratropium and the LABA salmeterol, have confirmed the long-acting and superior bronchodilator effect of tiotropium without any evidence of drug tolerance developing. These studies also have clearly demonstrated that tiotropium positively affects several other important health outcomes, such as dyspnoea sensation, exercise capacity, utilisation of rescue bronchodilators, health-related quality of life, COPD exacerbations and hospitalisations because of exacerbations. The improvement in these real-life outcomes appears related to the reduction in both static and dynamic hyperinflation. In all these studies, tiotropium was well tolerated and safe; the only relevant side-effect encountered being dry mouth, usually mild and often transitory. Finally, it has been shown that the combination of tiotropium with a LABA affords superior bronchodilatation than both agents alone, indicating that both classes of long- acting bronchodilators should be regarded as complements rather than opponents. In conclusion, a sufficiently large and convincing database now exists to propose the once-daily long-acting anticholinergic tiotropium as first-line maintenance treatment for all chronic obstructive pulmonary disease patients in global initiative for chronic obstructive lung disease (GOLD)-class II and above, with a step-up to its combination with a long-acting b2-adrenergic receptor agonist in case of suboptimal clinical effect.

Role of Bronchodilators in Chronic Obstructive Pulmonary Disease

The prevalence of chronic obstructive pulmonary disease (COPD) continues to be on the rise. Bronchodilators are first line agents for the symptomatic management of this disease and have proven to be effective in both stable disease status and exacerbations. The stepwise escalation of therapy for COPD according to severity has been outlined in international guidelines. Different classes of bronchodilators exist. The most experience is available for short-acting beta-agonists and anticholinergics. These agents are mainly recommended for the treatment of mild COPD and for symptomatic patients on an as needed basis. Long-acting beta-agonists and anticholinergics have been developed more recently. They are more convenient to use for patients with advanced disease who require maintenance therapy with bronchodilators, and have been shown in this group of patients to provide superior efficacy compared with short-acting agents. Tiotropium, a long-acting anticholinergic, appears to be particularly powerful and may eventually replace ipratropium as the primary agent for COPD treatment. In contrast, the usage of theophylline, which used to be part of the mainstay of treatment for COPD, has declined, mainly secondary to a narrow therapeutic margin and side effects, but it is inexpensive and still has its role. New agents like phosphodiesterase-4-inhibitors are interesting substances that may become important adjuncts in COPD management, but there is limited experience so far. None of the bronchodilators have been shown to change outcome in COPD, but this issue is under active investigation.

The Airway Pathophysiology of COPD: Implications for Treatment

The pathophysiology of chronic obstructive pulmonary disease (COPD) is complex and can be attributed to multiple components: mucociliary dysfunction, airway inflammation and structural changes, all contributing to the development of airflow limitation, as well as an important systemic component. Current pharmacotherapies vary in their ability to address the underlying multi-component nature of COPD. Long-acting anticholinergics and long-acting β2-agonists (LABAs) can both provide effective and convenient bronchodilation in moderate COPD (Stage II–GOLD) and are recommended as regular therapy in global treatment guidelines. However, there is evidence to suggest that LABAs can mediate additional benefits independent of their bronchodilatory effects and may help address the multi-component nature of COPD. Effects on mucociliary dysfunction and reduced bacterial-induced damage have been experimentally proven with LABAs, and anti-inflammatory activity and structural effects have also been suggested. The use of inhaled corticosteroids (ICSs) is now recommended for the treatment of COPD patients with frequent exacerbations. In addition, ICSs provide a range of anti-inflammatory effects in COPD and thus have effects that are complementary to those of LABAs. Recent data indicate that LABA/ICS combinations produce wide-ranging clinical benefits that are greater than with either agent alone. Other new strategies include selective phosphodiesterase 4 (PDE4) inhibitors, which in addition to anti-inflammatory activity, have been shown to provide bronchodilation in COPD. In summary, the potential to address the multicomponent nature of COPD with strategies such as LABA/ICS combination therapy, and the development of new treatments directed at novel targets means that the future for sufferers of COPD can be more optimistic.

Bronchodilator Efficacy of Combined Salmeterol and Tiotropium in Patients With Chronic Obstructive Pulmonary Disease

Bronchodilators are still the most effective drugs for controlling the symptoms of chronic obstructive pulmonary disease (COPD). Tiotropium bromide, a long-acting anticholinergic drug, has recently been added to the therapeutic arsenal for the disease. To date, there have been no studies combining 2 long-acting bronchodilators. The aim of the present trial was to determine whether the combination of salmeterol and tiotropium improved lung function in COPD patients more than either of them alone. Twenty-two patients (20 men) diagnosed with COPD, with a mean age of 64 years, were enrolled in this cross-over trial. Active smokers were excluded. Mean (SD) forced expiratory volume in 1 second (FEV1) was 43% (14%) of predicted. All patients were experienced in the use of inhalers. The following 3 therapeutic combinations were randomly assigned to be administered for a 1-week period: a) fluticasone (500 microg/12 h), salmeterol (50 microg/12 h) and placebo; b) fluticasone, tiotropium (18 microg/24 h), and placebo; and c) fluticasone, salmeterol, and tiotropium. At the end of each period, forced spirometry was performed before inhalation of the therapeutic combination (between 8:30 am and 9:30 am) and 2 hours after inhalation. Throughout the week, morning peak flow rates measured immediately before inhalation were recorded, and there was a 48-hour wash-out period between each therapeutic combination. All the patients completed the protocol. There were no significant differences in preinhalation or postinhalation FEV1 with salmeterol compared to tiotropium (preinhalation FEV1, 1.17 [0.55] L compared to 1.19 [0.49] L; postinhalation FEV1, 1.32 [0.65] L compared to 1.29 [0.61] L). In all cases postinhalation FEV1 was significantly higher than preinhalation FEV1. The combination of fluticasone, salmeterol, and tiotropium proved superior to the other 2 combinations with respect to both preinhalation FEV1 and postinhalation FEV1 (preinhalation FEV1, 1.32 [0.56] L, [P<.03 in both comparisons]; postinhalation FEV1, 1.49 [0.68] L [P<.001 in both comparisons]). Peak flow rate was also significantly higher with the combination of the 2 bronchodilators (345 L/min compared to 291 L/min and 311 mL, respectively [P <.04 in both cases]). There were no notable side effects. In terms of improvement in lung function, the combination of salmeterol and tiotropium together with fluticasone is more effective in patients with moderate-to-severe COPD than either of the 2 bronchodilators administered alone.

COPD, a multicomponent disease: implications for management

Chronic obstructive pulmonary disease (COPD) is a multicomponent disease. These components affect both the lungs and organs outside the lungs (the so-called systemic effects of COPD) and can be of either a structural (including airway remodelling, emphysema, skeletal muscle wasting) or functional nature (inflammation, apoptosis, senescence). Further, these components are interdependent in a closely linked 'vicious cycle'. Accordingly, optimal therapies should therefore aim to address more than one of these components to break such a cycle. This needs to be considered not only in the development of future treatments but also in the current clinical management of patients with COPD. In this paper, evidence that supports the concept that COPD is a multicomponent disease is presented. The effects of currently available therapeutic options, including long-acting anticholinergics and long-acting beta2-agonist/inhaled corticosteroid combination therapies, upon each of these components is reviewed. In addition, potential new avenues for drug development and improved patient care are highlighted. By developing a better understanding of how different therapies impact upon the 'vicious cycle' of COPD, treatment regimens can be optimised to provide the greatest benefits to patients.

The Role of Tiotropium Bromide, a Long-Acting Anticholinergic Bronchodilator, in the Management of COPD

Bronchodilator therapy forms the mainstay of treatment for symptomatic patients with COPD. Long-acting bronchodilators, which maintain sustained airway patency over a 24-hour period, represent an advance in therapy. Tiotropium bromide is a new long-acting inhaled anticholinergic agent with superior pharmacodynamic properties compared with the short-acting anticholinergic, ipratropium bromide. Tiotropium bromide has been consistently shown to have a greater impact than ipratropium bromide on clinically important outcome measures such as health status. The mechanisms of clinical benefit with tiotropium bromide are multifactorial, but improved airway function, which enhances lung emptying and allows sustained deflation of over-inflated lungs, appears to explain improvements in dyspnea and exercise endurance in COPD. Inhaled tiotropium bromide therapy has also been associated with reduction in acute exacerbations of COPD as well as reduced hospitalizations. The safety profile of tiotropium bromide is impressive: dry mouth is the most common adverse event and rarely necessitates termination of the drug. No tachyphylaxis to tiotropium bromide has been demonstrated in clinical trials lasting up to 1 year. There is preliminary information that the combination of long-acting anticholinergics and long-acting beta2-adrenoceptor agonists provides additive physiological and clinical benefits. According to recent international guidelines, long-acting bronchodilators should be considered early in the management of symptomatic patients with COPD in order to achieve effective symptom alleviation and reduction in activity limitation. Tiotropium bromide, because of its once-daily administration and its established efficacy and tolerability profile, has emerged as an attractive therapeutic option for this condition.

Overcoming Gaps in the Management of Asthma in Older Patients

Asthma is under-recognised and undertreated in older populations. This is not surprising, given that one-third of older people experience significant breathlessness. The differential diagnosis commonly includes asthma, chronic obstructive pulmonary disease (COPD), heart failure, malignancy, aspiration and infections. Because symptoms and signs of several cardiorespiratory diseases are nonspecific in older people and diseases commonly co-exist, investigations are important. A simple strategy for the investigation of breathlessness in older people should include a full blood count, chest radiograph, ECG, peak flow diary and/or spirometry with reversibility as a minimum. If there are major abnormalities on the ECG, an echocardiogram should also be performed. Diurnal variability in peak flow readings >or=20% or >or=15% reversibility in forced expiratory volume in 1 second, spontaneously or with treatment, support a diagnosis of asthma. Distinguishing asthma from COPD is important to allow appropriate management of disease based on aetiology, accurate prediction of treatment response, correct prognosis and appropriate management of the chest condition and co-morbidities. The two conditions are usually readily differentiated by clinical features, particularly age at onset, variability of symptoms and nocturnal symptoms in asthma, supported by the results of reversibility testing. Full lung function tests may not necessarily help in differentiating the two entities, although gas transfer factor is characteristically reduced in COPD and usually normal or high in asthma. Methacholine challenge tests previously mainly used in research are now also used widely and safely to confirm asthma in clinical settings. Interest in exhaled nitric oxide as a biomarker of airways inflammation is increasing as a noninvasive tool in the diagnosis and monitoring of asthma. Regular inhaled corticosteroids (ICS) are the mainstay of treatment of asthma. Even in mild disease in older adults, regular preventive treatment should be considered, given the poor perception of bronchoconstriction by older asthmatic patients. If symptoms persist despite ICS, addition of long-acting beta(2)-adrenoceptor agonists (LABA) should be considered. Addition of LABA to ICS improves asthma control and allows reduction in ICS dose. However, older people have been grossly under-represented in trials of LABA, many trials having excluded those >or=65 years of age. On meta-analysis, beta(2)-adrenoceptor agonists (both short acting and long acting) are associated with increased cardiovascular mortality and morbidity in asthma and COPD. While the evidence for excess cardiovascular mortality is stronger for short-acting beta(2)-adrenoceptor agonists, it would be prudent to exercise particular care in using beta(2)-adrenoceptor agonists (long acting and short acting) in those at risk of adverse cardiovascular outcomes, including older people. Regular review of cardiovascular status (and monitoring of serum potassium concentration) in patients taking beta(2)-adrenoceptor agonists is crucial. The response to LABA should be carefully monitored and alternative 'add-on' therapy such as leukotriene receptor antagonists (LRA) should be considered. LRA have fewer adverse effects and in individual cases may be more effective and appropriate than LABA. Long-term trials evaluating beta(2)-adrenoceptor agonists and other bronchodilator strategies are needed particularly in the elderly and in patients with cardiovascular co-morbidities. There is no evidence that addition of anticholinergics improves control of asthma further, although the role of long-acting anticholinergics in the prevention of disease progression is currently being researched. Older patients need to be taught good inhaler technique to improve delivery of medications to lungs, minimise adverse effects and reduce the need for oral corticosteroids. Nurse-led education programmes that include a written asthma self-management plan have the potential to improve outcomes.

Les bronchodilatateurs dans la BPCO : dernières recommandations, données récentes et perspectives

DEMONSTRATED EFFICACY: Inhaled bronchodilators improve the quality of life of COPD patients by reducing dyspnea and exacerbation frequency. There is no data supporting the superiority of one of the families of inhaled bronchodilators (i.e. beta 2 agonists and anticholinergic agents) over the other. Thus, the choice has to be based on the individual symptomatic response. These agents can be combined. OTHER POSSIBILITIES: Long-acting beta 2 agonists are already available and long-acting anticholinergics should be marketed soon. Theophylline has a lower efficacy/tolerance ratio than inhaled bronchodilators but can provide additional benefits when associated with the latter in some patients. Phosphodiesterase inhibitors with both bronchodilating and anti-inflammatory effect are being developed. THE BENEFITS OF CORTICOSTEROIDS: Finally, in symptomatic patients with FEV1<50% predicted and repeated exacerbations despite bronchodilators, inhaled corticosteroids can be added.

Anticholinergic drugs in therapy of chronic obstructive lung disease (COPD)

Chronic obstructive pulmonary disease (COPD) is a severe respiratory disorder responsible for a significant morbidity and mortality in western societies. In the vast majority of patients, COPD is caused by tobacco smoke. Contributing factors leading to airway obstruction and lung hyperinflation in COPD differ from those observed in asthma, with a major role of hypersecretion and peripheral airway obstruction due to increased cholinergic airway smooth muscle tone. Therefore, anticholinergics are considered the firstline therapy to improve airway obstruction in COPD. In addition to effects on lung function, anticholinergics may also improve exercise tolerance, quality of life and sleep quality in these patients. When compared with other classes of bronchodilators, anticholinergics show an equal potency of bronchodilation, with a favorable safety profile. Due to their unique mechanism of action, anticholinergics can also be combined with different types of bronchodilators. Novel, long-acting anticholinergics may hold a future potential for further improvement of therapy in COPD, particularly in terms of user friendliness and compliance.

The Pharmacological Properties of Tiotropium

Tiotropium is a long-acting anticholinergic drug. Studies with cloned human muscarinic receptors show that tiotropium binds equally well to M(1), M(2), and M(3) receptors. However, it dissociates very slowly from M(1) and M(3) receptors compared with ipratropium, and more rapidly from M(2) receptors. Binding studies with [(3)H]tiotropium in human lung show that it is approximately 10-fold more potent than ipratropium. In vitro, tiotropium has a potent inhibitory effect against cholinergic nerve-induced contraction of airways. It dissociates extremely slowly, compared with the dissociation of atropine and ipratropium. Clinical studies with single doses of inhaled tiotropium confirm that it is a potent and long-lasting bronchodilator. Furthermore, it protects against cholinergic bronchoconstriction for > 24 h. Pharmacokinetic studies show that little of the inhaled drug is absorbed, thus predicting a high margin of safety.