:: BPCO
E TERAPIA BRONCODILATATRICE INALATORIA (β2-AGONISTI)
::
 |
|
-
-
A benefit-risk assessment of inhaled long-acting beta2-agonists in the management of obstructive pulmonary disease.
Sovani MP, Whale CI, Tattersfield AE
- Division of Respiratory Medicine, City Hospital, Nottingham, UK
The two inhaled long-acting beta2-adrenoceptor agonists, salmeterol and formoterol, have been studied extensively since their introduction in the early 1990s. In this review we consider the evidence for their efficacy and safety in adults with asthma and chronic obstructive pulmonary disease (COPD), by reviewing long-term prospective studies in which these drugs have been compared with placebo or an alternative bronchodilator. We have also assessed safety, including data from postmarketing surveillance studies and case-control studies using large databases. In patients with asthma, salmeterol and formoterol increase lung function, reduce asthmatic symptoms and improve quality of life when compared with placebo. Both drugs protect against exercise-induced asthma, although some tolerance develops with regular use. Tolerance to the bronchodilator effects of formoterol has also been seen, although this is small and most of the beneficial effects are maintained long-term. Both drugs have been shown to reduce asthma exacerbations but only in studies in which most patients were taking an inhaled corticosteroid. Adding a long-acting beta2-agonist provided better control than increasing the dose of inhaled corticosteroid in several studies. Long-acting beta2-agonists also provide better asthma control than use of regular short-acting beta2-agonists and theophylline. Their relative efficacy compared with leukotriene antagonists is uncertain as yet. Formoterol appears to be at least as safe and effective as a short-acting beta2-agonist when used on an 'as required' basis. In patients with COPD, both salmeterol and formoterol offer improved lung function and reduced COPD symptoms compared with placebo, and quality of life has been improved in some studies. Some tolerance to the bronchodilating effect of salmeterol was seen in one study. Most studies have not found a significant reduction in exacerbations in COPD. Both drugs have provided greater benefit than ipratropium bromide or theophylline; there are limited data on tiotropium bromide. The long-acting beta2-agonists cause predictable adverse effects including headache, tremor, palpitations, muscle cramps and a fall in serum potassium concentration. Salmeterol can also cause paradoxical bronchospasm. There is some evidence that serious adverse events including dysrhythmias and life-threatening asthma episodes can occur; however, the incidence of such events is very low but may be increased in patients not taking an inhaled corticosteroid. Salmeterol 50 microg twice daily and formoterol 12 microg twice daily are effective and safe in treating patients with asthma and COPD. Higher doses cause more adverse effects, although serious adverse events are rare.
PMID: 15350154 [PubMed - in process]
-
-
The TORCH (towards a revolution in COPD health) survival study protocol.
Vestbo J; TORCH Study Group
- North West Lung Research Centre, Wythenshawe Hospital, Manchester, UK. jvestbo@man.ac.uk
Only long-term home oxygen therapy has been shown in randomised controlled trials to increase survival in chronic obstructive pulmonary disease (COPD). There have been no trials assessing the effect of inhaled corticosteroids and long-acting bronchodilators, alone or in combination, on mortality in patients with COPD, despite their known benefit in reducing symptoms and exacerbations. The "TOwards a Revolution in COPD Health" (TORCH) survival study is aiming to determine the impact of salmeterol/fluticasone propionate (SFC) combination and the individual components on the survival of COPD patients. TORCH is a multicentre, randomised, double-blind, parallel-group, placebo-controlled study. Approximately 6,200 patients with moderate-to-severe COPD were randomly assigned to b.i.d. treatment with either SFC (50/500 microg), fluticasone propionate (500 microg), salmeterol (50 microg) or placebo for 3 yrs. The primary end-point is all-cause mortality; secondary end-points are COPD morbidity relating to rate of exacerbations and health status, using the St George's Respiratory Questionnaire. Other end-points include other mortality and exacerbation end-points, requirement for long-term oxygen therapy, and clinic lung function. Safety end-points include adverse events, with additional information on bone fractures. The first patient was recruited in September 2000 and results should be available in 2006. This paper describes the "TOwards a Revolution in COPD Health" study and explains the rationale behind it.
PMID: 15332386 [PubMed - in process]
-
-
Effect of salmeterol on the ventilatory response to exercise in chronic obstructive pulmonary disease
O'Donnell DE, Voduc N, Fitzpatrick M, Webb KA
- Respiratory Investigation Unit, Dept of Medicine, Queen's University, Kingston, Canada. odonnell@post.queensu.ca
This study examined the effects of bronchodilator-induced reductions in lung hyperinflation on breathing pattern, ventilation and dyspnoea during exercise in chronic obstructive pulmonary disease (COPD). Quantitative tidal flow/volume loop analysis was used to evaluate abnormalities in dynamic ventilatory mechanics and their manipulation by a bronchodilator. In a randomised double-blind crossover study, 23 patients with COPD (mean +/- SEM forced expiratory volume in one second 42 +/- 3% of the predicted value) inhaled salmeterol 50 microg or placebo twice daily for 2 weeks each. After each treatment period, 2 h after dose, patients performed pulmonary function tests and symptom-limited cycle exercise at 75% of their maximal work-rate. After salmeterol versus placebo at rest, volume-corrected maximal expiratory flow rates increased by 175 +/- 52%, inspiratory capacity (IC) increased by 11 +/- 2% pred and functional residual capacity decreased by 11 +/- 3% pred. At a standardised time during exercise, salmeterol increased IC, tidal volume (VT), mean inspiratory and expiratory flows, ventilation, oxygen uptake (VO2) and carbon dioxide output. Salmeterol increased peak exercise endurance, VO2 and ventilation by 58 +/- 19, 8 +/- 3 and 12 +/- 3%, respectively. Improvements in peak VO2 correlated best with increases in peak VT; increases in peak VT and resting IC were interrelated. The reduction in dyspnoea ratings at a standardised time correlated with the increased VT. Mechanical factors play an important role in shaping the ventilatory response to exercise in chronic obstructive pulmonary disease. Bronchodilator-induced lung deflation reduced mechanical restriction, increased ventilatory capacity and decreased respiratory discomfort, thereby increasing exercise endurance.
PMID: 15293609 [PubMed - in process]
-
-
Effect of salmeterol on respiratory muscle activity during exercise in poorly reversible COPD
Man WD, Mustfa N, Nikoletou D, Kaul S, Hart N, Rafferty GF, Donaldson N, Polkey MI, Moxham J
- Respiratory Muscle Laboratory, Guy's, King's and St Thomas' School of Medicine, King's College Hospital, London, UK. william.man@kcl.ac.uk
BACKGROUND: Some patients with irreversible chronic obstructive pulmonary disease (COPD) experience subjective benefit from long acting bronchodilators without change in forced expiratory volume in 1 second (FEV(1)). Dynamic hyperinflation is an important determinant of exercise induced dyspnoea in COPD. We hypothesised that long acting bronchodilators improve symptoms by reducing dynamic hyperinflation and work of breathing, as measured by respiratory muscle pressure-time products. METHODS: Sixteen patients with "irreversible" COPD (<10% improvement in FEV(1) following a bronchodilator challenge; mean FEV(1) 31.1% predicted) were recruited into a randomised, double blind, placebo controlled, crossover study of salmeterol (50 micro g twice a day). Treatment periods were of 2 weeks duration with a 2 week washout period. Primary outcome measures were end exercise isotime transdiaphragmatic pressure-time product and dynamic hyperinflation as measured by inspiratory capacity. RESULTS: Salmeterol significantly reduced the transdiaphragmatic pressure-time product (294.5 v 348.6 cm H(2)O/s/min; p = 0.03), dynamic hyperinflation (0.22 v 0.33 litres; p = 0.002), and Borg scores during endurance treadmill walk (3.78 v 4.62; p = 0.02). There was no significant change in exercise endurance time. Improvements in isotime Borg score were significantly correlated to changes in tidal volume/oesophageal pressure swings, end expiratory lung volume, and inspiratory capacity, but not pressure-time products. CONCLUSIONS: Despite apparent "non-reversibility" in spirometric parameters, long acting bronchodilators can cause both symptomatic and physiological improvement during exercise in severe COPD.
-
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 15170026 [PubMed - indexed for MEDLINE]
-
-
Effects of formoterol and salmeterol on resting inspiratory capacity in COPD patients with poor FEV(1) reversibility
Bouros D, Kottakis J, Le Gros V, Overend T, Della Cioppa G, Siafakas N
- Department of Thoracic Medicine, University Hospital, Alexandroupolis, Greece. bouros@med.duth.gr
-
BACKGROUND: Recent studies suggest that inspiratory capacity (IC) measured at rest can be used to predict improvements in dyspnea and exercise tolerance in chronic obstructive pulmonary disease (COPD) patients. In this study we compared the effect of formoterol (Foradil, Aerolizer) and salmeterol (Serevent, Diskus) in terms of IC in patients with COPD. METHODS: This was a multicentre, randomized, placebo-controlled, single-dose, double-dummy, crossover study conducted in five secondary care centres in four European countries. A total of 47 patients with Stage II and III COPD, as defined by ATS criteria, with an increase in forced expiratory volume in 1s (FEV(1)) of minor or = 12% from the patient's predicted normal value after salbutamol inhalation were included. Patients inhaled single doses of formoterol (12 and 24 microg), salmeterol (50 and 100 microg) or matching placebo. IC was recorded before dosing and at 5, 10, 15 and 30 min and 1, 2, 3 and 4 h post-dose. RESULTS: Formoterol was significantly superior to salmeterol during the first hour post-dose as indicated by notable differences at all times during the first hour post-dose and by the ANCOVA analysis of the Area Under the IC Curve (AUC(0-1 h)). CONCLUSIONS: Both formoterol and salmeterol increase IC in patients with COPD, with formoterol 12 microg showing a significantly greater increase in IC over the first hour post-dose than salmeterol 50 microg, consistent with a more rapid onset of action.
Publication Types:
• Clinical Trial
• Multicenter Study
• Randomized Controlled Trial
PMID: 15140323 [PubMed - indexed for MEDLINE]
-
-
The role of long-acting bronchodilators in the management of stable COPD
Tashkin DP, Cooper CB
- Division of Pulmonary and Critical Care Medicine and the UCLA Pulmonary Function and Exercise Physiology Laboratory, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1690, USA. DTashkin@mednet.ucla.edu
-
Bronchodilators form the foundation of symptomatic treatment of COPD. Several long-acting bronchodilators are now available for use in COPD, but publications of large-scale studies of their efficacy have, for the most part, postdated the publication of major clinical guidelines. This article provides a critical review of large (> or =50 patients), double-blind, clinical trials of three long-acting bronchodilators in COPD (the once-daily anticholinergic tiotropium, and the twice-daily beta(2)-agonists formoterol and salmeterol) within the context of the objectives of treatment defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines. Fourteen published studies were identified, of which 12 studies were published since the release of the GOLD guidelines. All three long-acting bronchodilators were found to effectively improve lung function; however, they differed in their effects on outcomes other than bronchodilation, with salmeterol demonstrating inconsistent efficacy compared with placebo in preventing exacerbations and improving health status, and only tiotropium demonstrating consistent superiority to the short-acting bronchodilator ipratropium. Based on this review, a treatment algorithm for the introduction of long-acting bronchodilators to patients with COPD is proposed, which includes the use of long-acting bronchodilators early in the treatment algorithm.
Publication Types:
• Review
• Review, Tutorial
PMID: 14718448 [PubMed - indexed for MEDLINE]
-
-
The pharmacodynamic effects of single inhaled doses of formoterol, tiotropium and their combination in patients with COPD
Cazzola M, Marco FD, Santus P, Boveri B, Verga M, Matera MG, Centanni S
- Unit of Pneumology and Allergology, Department of Respiratory Medicine, A. Cardarelli Hospital, Via del Parco Margherita 24, Naples 80121, Italy. mcazzola@qubisoft.it
-
The aim of this double-blind, double-dummy, cross-over, randomized, pilot study was to compare the acute bronchodilator efficacy of a single dose of formoterol with that of tiotropium in patients with stable chronic obstructive pulmonary disease (COPD). Because the potential of tiotropium for additive effects is yet unknown, the acute effects of adding this anticholinergic agent to formoterol were also explored. A total of 20 outpatients with stable COPD were enrolled. Single doses of 12 microg formoterol, 18 microg tiotropium, and 12 microg formoterol+18 microg tiotropium were given. Serial measurements of FEV1 were performed over 24 h. Formoterol, either alone or in combination with tiotropium, elicited a significantly faster onset of action and showed a trend for a greater maximum bronchodilation than tiotropium alone. At 24 h, mean FEV1 continued to be significantly higher than pre-dosing value following tiotropium and formoterol+tiotropium. These findings indicate that formoterol and tiotropium have different profiles that make both agents attractive alternatives in the treatment of stable COPD. Since tiotropium ensures prolonged bronchodilation, whereas formoterol adds fast onset and a greater peak effect, the two drugs appear complementary.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 14643169 [PubMed - indexed for MEDLINE]
-
 |
|
-
Cardiovascular safety of salmeterol in COPD
Ferguson GT, Funck-Brentano C, Fischer T, Darken P, Reisner C
- Pulmonary Research Institute of SouthEast Michigan, Livonia, MI 48152, USA
-
BACKGROUND: Patients with COPD have an increased risk of cardiovascular disease. Despite the clinical benefits of long-acting beta-agonist agents in the treatment of COPD, patients may be at an increased risk of cardiovascular toxicity, including tachyarrhythmia due to beta-adrenergic stimulation. OBJECTIVE: To evaluate the cardiovascular safety of salmeterol in COPD patients by conducting a pooled analysis of cardiovascular safety data. DESIGN: Randomized, double-blind, parallel group, multiple-dose studies, which included salmeterol, 50 micro g bid, and placebo arms. STUDY SELECTION: Seven of a total of 17 studies met the predefined inclusion requirements and were pooled. A total of 1,443 patients received placebo, while 1,410 patients received salmeterol, 50 micro g bid. The median duration of treatment was 24 weeks (range, 12 to 52 weeks). RESULTS: Treatment with salmeterol, 50 micro g bid, showed no increased risk of cardiovascular adverse events (AEs) compared with placebo (relative risk, 1.03; 95% confidence interval, 0.8 to 1.3; p = 0.838). Both groups had a similar incidence of cardiovascular events (8%), including cardiovascular deaths. The incidence of cardiovascular AEs increased with age, concurrent cardiovascular conditions, and treatment with antiarrhythmic/bradycardic agents, although increases were comparable in both treatment groups. There were no episodes of sustained ventricular tachycardia, and no clinically significant differences were observed in 24-h heart rate, ventricular and supraventricular ectopic events, qualitative ECGs, QT intervals, or vital signs between the salmeterol, 50 micro g bid, group and the placebo group. Similar findings were observed when patients were stratified for age of > 65 years or the known presence of cardiovascular disease. CONCLUSIONS: Treatment with salmeterol, 50 micro g bid, does not increase the risk of cardiovascular AEs in this population of COPD patients compared with placebo.
Publication Types:
• Clinical Trial
• Randomized Controlled Trial
PMID: 12796155 [PubMed - indexed for MEDLINE]
-
-
Long-acting beta 2-adrenoceptor agonists or tiotropium bromide for patients with COPD: is combination therapy justified?
Tennant RC, Erin EM, Barnes PJ, Hansel TT
- Clinical Studies Unit, National Heart and Lung Institute, Imperial College, London, UK
-
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.
Publication Types:
• Review
• Review, Tutorial
PMID: 12810191 [PubMed - indexed for MEDLINE]
-
-
Conclusion. Lessons from the novel D2 dopamine receptor, beta2-adrenoceptor agonist, Viozan: chronic obstructive pulmonary disease and drug development implications.
Calverley P, Keating ET, Goldman M, Casty F.
- University Department of Medicine, University Hospital Aintree, Liverpool, UK. pmacal@liverpool.ac.uk
The development of novel drugs for the treatment of chronic obstructive pulmonary
disease (COPD) poses significant challenges. The mechanisms through which the chronic
symptoms of COPD arise are poorly understood, making identification of potential therapeutic
targets and in vivo evaluation of potential therapies extremely difficult.
Despite these challenges, a unique approach of combined D2 dopamine, beta2-adrenoceptor agonism
was identified as a valid potential target for the treatment of key COPD symptoms, the therapeutic
potential of which was investigated in a series of preclinical evaluations. Subsequent clinical
assessment has amassed a wealth of data from over 4000 patients, providing valuable insights into COPD,
clinical trial design and the value of patient self-assessment tools.
PMID: 12564613 [PubMed - indexed for MEDLINE]
-
-
-
Long-term use of Viozan (sibenadet HCl) in patients with chronic obstructive pulmonary disease: results of a 1-year study.
Hiller FC, Alderfer V, Goldman M.
- Division of Pulmonary and Critical Care Medicine, University of Arkansas for Medical Sciences and the Little Rock Veterans Administration Medical Center, AK 72205, USA.
Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor
agonist that has been investigated for efficacy in alleviating the symptoms of chronic obstructive
pulmonary disease (COPD). The slowly progressive nature of this disease means that patients will
require ongoing therapeutic management for many years, or even decades. With such long-term treatment,
the safety profile of new agents will be of paramount importance. As part of the large-scale assessment
of sibenadet, a 12-month safety study has been conducted. Following completion of a 2-week baseline period,
435 adults with stable, symptomatic, smoking-related COPD were randomized to receive either 500 microg
sibenadet or placebo delivered via pressurized metered dose inhaler (pMDI), three times daily for 52 weeks.
Sibenadet therapy was generally well tolerated, with the only notable differences seen in the incidence of
tremor and taste of treatment (16.9% vs. 4.1% and 14.5% vs. 4.1% in the sibenadet and placebo groups
respectively). There were a total of 79 patients with serious adverse events (SAEs), 43 (14.8%) in the
sibenadet pMDI group and 36 (24.8%) in the placebo group. No clinically significant abnormal laboratory
values or overall differences between treatment groups were noted. Similarly, there were no clinically
significant differences between the two treatment groups for cardiac variables, or in vital signs.
The secondary variables showed no notable differences with respect to lung function, exacerbations or
health-related quality of life. Due to the effective beta2-agonist properties, patients in the sibenadet
group did, however, report reduced rescue medication usage at all timepoints. While the results of this
study show that, overall, sibenadet therapy was well tolerated, the lack of sustained benefit reported in
large-scale clinical efficacy studies means that sibenadet development will not be continued.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12564610 [PubMed - indexed for MEDLINE]
-
-
-
The role of the novel D2/beta2-agonist, Viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease: results of a large-scale clinical investigation.
Laursen LC, Lindqvist A, Hepburn T, Lloyd J, Perrett J, Sanders N, Rocchiccioli K.
- Department of Lung Medicine, KAS Gentofte, Hellerup, Denmark. lala@gentoftehosp.kbhamt.dk
Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist,
developed specifically to treat the key symptoms of chronic obstructive pulmonary disease (COPD),
breathlessness, cough and sputum. The dual sensory nerve modulation and bronchodilator effects of
sibenadet have been demonstrated in initial dose-ranging studies of patients with COPD and large-scale
clinical evaluation has now been completed. Sibenadet efficacy was determined by assessing symptomatic
changes, as defined by the novel assessment tool, the Breathlessness, Cough and Sputum Scale (BCSS).
The findings of two placebo-controlled studies are reported. These multicentre, double-blind,
placebo-controlled studies recruited over 2000 patients with stable COPD, randomized to receive sibenadet
(500 microg) or placebo, pressurized metered-dose inhaler (pMDI) (three times daily) for a period of 12 or 26 weeks.
Diary cards were completed daily by patients throughout the study to record BCSS scores, peak expiratory
flow (PEF), study drug and rescue bronchodilator usage, changes in concomitant medication and adverse events.
The primary endpoints were defined as change from baseline to the final 4 weeks of the treatment period in
mean BCSS total score, and forced expiratory volume in one second (FEV1) measured 1 hour after administration
of the final dose of study drug and expressed as a percentage of the predicted FEV1. In addition,
clinic assessments were made to determine changes in pulmonary function, health-related quality of life,
perception of treatment efficacy and adverse events. Despite initial improvements in mean daily BCSS total
scores in patients receiving sibenadet, the difference in the change from baseline to the final 4 weeks of
the treatment period between the two treatment groups was neither statistically significant, nor considered
to be of clinical importance. Although marked bronchodilator activity was seen early on with sibenadet
treatment, the duration of effect diminished as the studies progressed.
Sibenadet use was not associated with any safety concerns. These studies, utilizing the novel BCSS,
have clearly illustrated that, despite initial symptomatic improvement with sibenadet therapy, this clinical
benefit was not sustained over the course of the study.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12564608 [PubMed - indexed for MEDLINE]
-
-
-
Early clinical investigation of Viozan (sibenadet HCl), a novel D2 dopamine receptor, beta2-adrenoceptor agonist for the treatment of chronic obstructive pulmonary disease symptoms.
Ind PW, Laitinen L, Laursen L, Wenzel S, Wouters E, Deamer L, Nystrom P.
- National Heart and Lung Institute, London, UK. p.ind@ic.ac.uk
Viozan, (Sibenadet HCl, AR-C68397AA) is a dual D2 dopamine receptor, beta2-adrenoceptor agonist
that combines bronchodilator activity with the sensory afferent modulating effects associated
with D2-receptor agonism. Investigation in animal models of key chronic obstructive pulmonary
disease (COPD) symptoms has demonstrated that sibenadet effectively inhibits sensory nerve activity,
thereby reducing reflex cough, mucus production and tachypnoea. The results of the early clinical
evaluation of this novel agent are reported. An initial proof of concept study (Study 1) aimed to determine
the clinical potential of this novel agent by assessing the effects of three doses of sibenadet therapy
relative to placebo, with two commonly used bronchodilators, intended to provide a benchmark against
which sibenadet activity could be judged. In all, 701 patients were randomized to one of three sibenadet
dose groups (400, 600 or 1000 microg ex valve), salbutamol 200 microg, ipratropium bromide (IB) 40 microg
or placebo, all three times daily via pressurized metered dose inhaler (pMDI) for 4 weeks.
Once the results of Study 1 had been evaluated, a dose-ranging, study (Study 2) involving 872 patients
randomized to receive sibenadet (45, 270, or 495 microg ex actuator), or placebo all three times daily
via pMDI, for 6 weeks commenced. Both studies were preceded by a 2-week baseline phase and followed by
a 2-week follow up period.The primary efficacy variable identified changes in key COPD symptoms over
the treatment period (compared with baseline data) as determined by the novel Breathlessness,
Cough and Sputum Scale (BCSS). In addition, data on lung function, health-related quality of life and
adverse events were collected. Patients receiving sibenadet therapy three times daily exhibited
statistically significantly greater improvements in BCSS total score than those receiving placebo or
bronchodilator therapy alone. A clear dose-response was evident in Study 2. Symptom improvement in this
study was also accompanied by improved lung function and health-related quality of life.
Sibenadet therapy was well tolerated with an adverse events profile comparable to current bronchodilator
therapy. These data were viewed as extremely encouraging, warranting further, large-scale clinical
investigation.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12564607 [PubMed - indexed for MEDLINE]
-
-
-
Dual dopamine D2 receptor and beta2-adrenoceptor agonists for the treatment of chronic obstructive pulmonary disease: the pre-clinical rationale.
Dougall IG, Young A, Ince F, Jackson DM.
- Department of Discovery BioScience, AstraZeneca R&D Charnwood, Loughborough, Leicestershire, UK. Iain.Dougall@astrazeneca.com
This paper describes the rationale for the development of dual dopamine D2-receptor
and beta2-adrenoceptor agonists as potential treatments for the symptoms of chronic
obstructive pulmonary disease (COPD). The putative involvement of pulmonary sensory
afferent nerves in mediating the key COPD symptoms of breathlessness, cough and excess
sputum production is outlined and the hypothesis that activation of D2-receptors on such
nerves would modulate their activity is developed.
This premise was tested, in a range of animal models, using the first of a novel class of
dual dopamine D2-receptor and beta2-adrenoceptor agonists, sibenadet HCl (Viozan, AR-C68397AA).
In the course of these studies it was demonstrated that sibenadet, through activation of D2-receptors,
inhibited discharge of rapidly adapting receptors and was effective in reducing reflex-induced tachypnoea,
mucus production and cough in the dog. Sibenadet, through its activation of beta2-adrenoceptors, was also
shown to be an effective bronchodilator with a prolonged duration of action following topical administration
to the lungs. These studies also indicated that sibenadet had a wide therapeutic ratio with respect
to expected undesirable side-effects such as emesis and cardiovascular disturbances.
These results provided a compelling rationale for the initiation of a clinical development programme with
sibenadet for the treatment of COPD.
PMID: 12564606 [PubMed - indexed for MEDLINE]
-
 |
|
-
-
Effects of formoterol and ipratropium bromide in COPD: a 3-month placebo-controlled study.
Wadbo M, Lofdahl CG, Larsson K, Skoogh BE, Tornling G, Arwestrom E, Bengtsson T, Strom K; Swedish Society of Respiratory Medicine.
- Dept of Respiratory Medicine in Malmo General University Hospital, Malmo, Sweden.
The aim of this study was to compare the effects of formoterol,
ipratropium bromide and a placebo on walking distance, lung function,
symptoms and quality of life (QoL) in chronic obstructive pulmonary disease (COPD)
patients. A total of 183 patients (mean age 64 yrs, 86 female) with moderate-to-severe
nonreversible COPD participated in this randomised, double-blind, parallel-group study.
After a 2-week placebo run-in, patients were randomised to formoterol Turbuhaler 18 microg b.i.d. (delivered dose),
ipratropium bromide 80 microg t.i.d. via a pressurised metered dose inhaler, or placebo for 12 weeks.
Inhaled short-acting beta2-agonists were allowed as relief medication and inhaled glucocorticosteroids
were allowed at a constant dose. The primary variable was walking distance in the shuttle walking test
(SWT). Baseline mean SWT distance was 325 m, mean forced expiratory volume in one second (FEV1) was 40%
predicted. Clinically significant improvements in SWT (>30 m) were seen in 41, 38 and 30% of formoterol,
ipratropium and placebo patients, respectively (not significant).
Mean increases from run-in were 19, 17 and 5 m in the formoterol, ipratropium and placebo groups, respectively.
Both active treatments significantly improved FEV1, forced vital capacity, peak expiratory flow and daytime dyspnoea
score compared with placebo. Formoterol reduced relief medication use compared with placebo.
Neither active treatment improved QoL. Formoterol and ipratropium improved airway function and symptoms,
without significant improvements in the shuttle walking test.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12449166 [PubMed - indexed for MEDLINE]
-
-
| Pharmacotherapy 2002 Sep;22(9):1129-39 |
|
-
Formoterol therapy for chronic obstructive pulmonary
disease: a review of the literature.
Friedman M, Della Cioppa G, Kottakis J.
- Tulane University School of Medicine, New Orleans, Louisiana, USA.
Numerous clinical trials have investigated the use of formoterol,
a long-acting beta2-agonist, for the treatment of chronic obstructive
pulmonary disease (COPD). Formoterol provides bronchodilation as rapidly
as albuterol, yet its efficacy and duration of action are similar to those
of salmeterol. It demonstrates better spirometric efficacy than either ipratropium
or theophylline alone, and its efficacy improves when administered in combination
with ipratropium. Formoterol improves patients' quality of life and has a good safety
profile. It is better tolerated than theophylline and has a similar tolerability to
albuterol, salmeterol, and ipratropium. In short, formoterol is a bronchodilator with
rapid onset of action and prolonged duration of action with a favorable efficacy,
safety, and tolerability profile when used in patients with COPD.
It provides a valid therapeutic option in the pharmacologic treatment of this disease.
-
-
-
Formoterol as dry powder oral
inhalation compared with salbutamol metered-dose inhaler
in acute exacerbations of chronic obstructive pulmonary
disease.
Cazzola M, D'Amato M, Califano C, Di
Perna F, Calderaro E, Matera MG, D'Amato G.
- Department of Respiratory Medicine, A. Cardarelli
Hospital, Naples, Italy. mcazzola@qubisoft.it
BACKGROUND: Acute exacerbations of chronic obstructive
pulmonary disease (COPD) are managed with increased
doses or frequency of the patient's existing bronchodilator
therapy. The use of formoterol in the treatment of
mild acute exacerbations of COPD has been suggested;
however, a comparison of cumulative doses of formoterol
with salbutamol, the gold standard bronchodilator
agent for this pathologic condition, is still lacking.
OBJECTIVE: The aim of the study was to compare the
inhaled beta2-agonists salbutamol (rapid onset, short
duration of action) and formoterol (rapid onset, long
duration of action), both used as needed in patients
attending outpatient clinics because of mild acute
exacerbations of COPD (Anthonisen exacerbation type
I or II). METHODS: A dose-response curve to formoterol
via Turbuhaler or salbutamol via pressurized metered-dose
inhaler (pMDI) was constructed. On 2 consecutive days,
the patients received, in randomized order, both of
the following active dose regimens: A = 12 + 12 +
24 microg formoterol via Turbuhaler (48-microg cumulative
metered dose); B = 200 + 200 + 400 microg salbutamol
via pMDI (800-microg cumulative metered dose). Dose
increments were given at 30-minute intervals, with
measurements made 25 minutes after each dose. The
maximum forced expiratory volume in 1 second (FEV1)
value during the dose-response curve to formoterol
or salbutamol was chosen as the primary outcome variable
to compare the 2 treatments. Oxygen saturation by
pulse oximetry (SpO2) and pulse rate were also measured
at each assessment period. Every adverse event, either
reported spontaneously by the patients or observed
by the investigators, was recorded. RESULTS: Sixteen
patients (2 women, 14 men) aged 51 to 77 years (most
older than 65 years) participated in the study. Both
formoterol and salbutamol induced a large, significant,
dose-dependent increase in FEV1, inspiratory capacity
(IC), and forced vital ca- pacity (FVC). There was
no significant difference between FEV1, IC, and FVC
values after 48 microg formoterol and 800 microg salbutamol.
There was no significant difference in FEV1 after
24 microg formoterol and 800 microg salbutamol; however,
the difference in FEV1 after 24 and 48 microg formoterol
was significant. Neither heart rate (mean differences
from baseline after 48 microg formoterol, 1.9 beats/min
[95% CI, -3.4, 7.2] and 800 microg salbutamol, 3.7
beats/min [95% CI, -1.1, 8.5]) nor SpO2 (mean percentage
differences from baseline after 48 microg formoterol,
-0.37% [95% CI, -1.22, 0.47] and 800 microg salbutamol,
-0.75% [95% CI, -1.73, 0.23]) changed significantly.
However, SpO2 decreased below 90% in 2 patients after
the highest dose of formoterol and in 1 patient after
the highest dose of salbutamol. CONCLUSIONS: In this
small, selected group of patients with mild acute
exacerbations of COPD, formoterol via Turbuhaler induced
a fast bronchodilation that was dose dependent and
not significantly different from that caused by salbutamol.
Furthermore, formoterol appeared to be as well tolerated
as salbutamol.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 12017404 [PubMed - indexed for MEDLINE]
-
-
-
Long-acting beta2-agonists
for chronic obstructive pulmonary disease patients
with poorly reversible airflow limitation.
Appleton S, Poole P, Smith B, Veale A, Bara A.
- Department of Medicine, The Queen Elizabeth Hospital,
Woodville Rd., Woodville, Adelaide, Australia. sappleto@medicine.adelaide.edu.au
BACKGROUND: Chronic obstructive pulmonary disease
(COPD) is characterised by partially reversible airflow
limitation. Many patients have little reversibility
to short acting bronchodilators, but long acting bronchodilators
are frequently advocated. OBJECTIVES: To determine
the effectiveness of long acting beta-2 adrenoceptor
agonists in COPD patients with low reversibility to
short-acting bronchodilators. SEARCH STRATEGY: The
Cochrane Airways Group register was searched. Bibliographies
of identified randomised controlled trials (RCTs)
were also searched. Authors of identified RCTs were
contacted for other published and unpublished studies
and unpublished studies were obtained from pharmaceutical
companies. SELECTION CRITERIA: All RCTs over four
weeks in duration comparing treatment with long-acting
beta-2 adrenoceptor agonists (salmeterol or formoterol)
with placebo in patients with stable poorly-reversible
COPD. DATA COLLECTION AND ANALYSIS: Data extraction
and study quality assessment was performed independently
by two reviewers. Where further or missing data were
required, authors of studies were contacted. MAIN
RESULTS: Eight RCTs met the inclusion criteria review.
Six were parallel group studies of 12-16 weeks in
duration and two were cross-over studies with four
week treatment arms. All eight assessed the efficacy
of salmeterol in COPD compared to placebo. Few of
the results could be combined in meta-analyses because
of differences in methods of reporting data. Isolated
trials reported an improvement in one or other outcome
in favour of salmeterol, but the only possible meta-analysis
of FEV1 showed no overall benefit (Standardised mean
difference 0.14 (95% Confidence Interval -0.16, 0.44,
n=4). There was no consistent effect on Health Related
Quality of LIfe or symptoms scores. Overall, breathlessness
was not reduced, but in one study more subjects in
the salmeterol group had low Borg dyspnoea scores
compared to placebo (Peto Odds Ratio = 0.60, 95% CI:
0.40; 0.88). There was no effect on COPD exacerbations
over the short period of the studies. REVIEWER'S CONCLUSIONS:
In the few studies that could be included in this
review, treatment of patients with COPD with long
acting beta-2 agonists produces only small increases
in FEV1. The improvement in airways function does
not seem to be associated with a consistent effect
on other outcomes such as health related quality of
life or reductions in breathlessness.
Publication Types:
- Meta-Analysis
- Review
- Review, Academic
PMID: 12137617 [PubMed - indexed for MEDLINE]
-
-
-
Acute effects of higher than customary
doses of salmeterol and salbutamol in patients with
acute exacerbation of COPD.
Cazzola M, Califano C, Di Perna F, D'Amato M, Terzano
C, Matera MG, D'Amato G, Marsico SA.
- A Cardarelli Hospital, Department of Respiratory
Medicine, Naples, Italy. mcazzola@qubisoft.it
Worsening of underlying bronchospasm may be associated
with acute exacerbations of chronic obstructive pulmonary
disease (COPD). As airway obstruction becomes more
severe, the therapeutic option is to add salbutamol,
but not salmeterol, as needed to cause rapid relief
of bronchospasm. Unfortunately the most effective
dosage of beta2-agonists may increase above that recommended
during acute exacerbations. In this study, we compared
the acute effects of higher than customary doses of
salmeterol and salbutamol in 20 patients with acute
exacerbation of COPD. A dose-response curve to salmeterol
pMDI, 25 microg/puff or salbutamol pMDI, 100 microg/puff,
was constructed using 1, 1, and 2 puff' i.e., a total
cumulative dose of 100 microg salmeterol or 400 microg
salbutamol on 2 consecutive days. After baseline measurements,
dose increments were given at 30-min intervals with
measurements being made 25 min after each dose. Hear
rate (HR) and pulse-oximetry (SpO2) measurements were
then taken. Both salmeterol and salbutamol induced
a larg and significant (P < 0.05) dose-dependent
increase in FEV1 [mean differences from baseline (L)
= after 100 microg salmeterol 0.174 (95% CI: 0.112
to 0.237); after 400 microg salbutamol: 0.165 (95%
CI: 0.080 to 0.249)], in IC [mean differences from
baseline (L) = after 100 microg salmeterol: 0.332
(95% CI: 0.165 to 0.499); after 400 microg salbutamol:
0.281 (95% CI: 0.107 to 0.456)] (Fig. 2), and in FVC
mean differences from baseline (L) = after 100 microg
salmeterol: 0.224 (95% CI: 0.117 to 0.331); after
400 microg salbutamol: 0.242 (95% CI: 0.090 to 0.395)].
There was no significant difference between the FEV1
values (P=0.418), the ICvalues (P=0.585), and the
FVCvalue (P=0.610) after 100 microg salmeterol and
400 microg salbutamol. HR [mean differences from baseline
(beats/min) = after 100 microg salmeterol: 3.15 (95%
CI: -0.65 to 6.96); after 400 microg salbutamol: 2.30
(95% CI: -0.91 to 5.51)] and SpO2 [mean differences
from baseline (%) = after 100 microg salmeterol: -0.20
(95% CI: -1.00 to 0.60); after 400 microg salbutamol:
-0.11 (95% CI: -1.00 to 0.79)] did not change significantly
from baseline (P > 0.05). These data indicate that
salmeterol is effective and safe in the treatment
of acute exacerbation of COPD and support its use
in this clinical condition.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12412978 [PubMed - indexed for MEDLINE]
-
-
-
The effect of inhaled beta2-agonists
on clinical outcomes in chronic obstructive pulmonary
disease.
Mahler DA.
- Section of Pulmonary and Critical Care Medicine,
Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756,
USA.
The major clinical outcomes measured in evaluating
the responses to pharmacotherapy in patients with
chronic obstructive pulmonary disease (COPD) include
the severity of dyspnea, exercise capacity, exacerbations,
and health status. Various studies have demonstrated
that testing for acute bronchodilator reversibility
in the pulmonary function laboratory does not predict
the clinical responses to a trial of bronchodilator
therapy in patients with COPD. Separate studies have
shown that inhaled albuterol, both a single dose (300
microg) and 2 weeks of therapy (200 microg/4x/day),
reduces dyspnea. There is more published information
available about the effects of long-acting (>/=12
hours' duration of action) inhaled beta(2)-agonists
because of greater interest in considering clinical
outcomes at the time of drug testing. In one randomized
clinical trial, formoterol reduced symptoms (as recorded
in a home diary) and improved health status. Nine
clinical studies have examined the effects of salmeterol
on clinical outcomes. Salmeterol reduced the perception
of breathlessness (in 6 of 9 studies) and improved
health status (in 3 of 4 studies). These results collectively
demonstrate that long-acting inhaled beta(2)-agonists
not only relax bronchial smooth muscle but also provide
important clinical benefits in symptomatic patients
with COPD.
Publication Types:
PMID: 12464939 [PubMed - indexed for MEDLINE]
-
-
Anti-cholinergic
bronchodilators versus beta2-sympathomimetic agents
for acute exacerbations of chronic obstructive pulmonary
disease (Cochrane Review)
McCrory DC, Brown CD.
Center for Clinical Health Policy Research, Duke University
Medical Center, 2200 W. Main St., Suite 230, Durham,
NC, USA, 27705. douglas.mccrory@duke.edu
BACKGROUND: Inhaled brocnhodilators form the mainstay
of treatment for acute exacerbations of COPD. Two
types of agent are used routinely, either singly or
in combination: anticholinergic agents and beta2-sympathomimetic
agonists. OBJECTIVES: To assess the effect of anti-cholinergic
agents on lung function and dyspnea in patients with
acute exacerbations of COPD, compared with placebo
or short-acting beta-2 agonists. SEARCH STRATEGY:
A comprehensive search of the literature was carried
out on MEDLINE, EMBASE, CINAHL and the Cochrane COPD
Trials Register, using the terms: bronchodilator*
OR ipratropium OR oxitropium. References listed in
each included trial were searched for additional trial
reports. SELECTION CRITERIA: Studies were included
if the participants were adult patients with a known
diagnosis of COPD and had symptoms consistent with
criteria for acute exacerbation of COPD. All randomized
controlled trials that compared inhaled ipratropium
bromide or oxitropium bromide to appropriate controls
were considered. Appropriate control treatments included
placebo, other bronchodilating agents, or combination
therapies. Studies of acute asthma or ventilated patients
were excluded. DATA COLLECTION AND ANALYSIS: All trials
that appeared to be relevant were assessed by two
reviewers who independently selected trials for inclusion.
Differences were resolved by consensus. MAIN RESULTS:
Four trials compared the short-term effects of ipratropium
bromide vs. a beta2-agonist. Short-term changes in
FEV1 (up to 90 minutes) showed no significant difference
between beta2-agonist and ipratropium bromide treated
patients. The differences were similar among the studies
and when combined: Weighted Mean Difference (WMD)
0.0 liters (95% Confidence Interval (95% CI) -0.19,
0.19). There was no significant additional increase
in change in FEV1 on adding ipratropium to beta2-agonist:
WMD 0.02 liter (95% CI -0.08, 0.12). Long-term effects
(24 hours) of the ipratropium bromide and beta2-agonist
treatment combination were similar: WMD 0.05 liters
(95%CI -0.14, 0.05). Neither of two studies found
significant changes in PaO2, either short- or long-term,
with ipratropium vs. beta-agonist, although one showed
an increase in PaO2 in subjects receiving ipratropium
bromide at 60 minutes. Adverse drug reactions included
dry mouth and tremor. REVIEWER'S CONCLUSIONS: There
was no evidence that the degree of bronchodilation
achieved with ipratropium bromide was greater than
that using a short-acting beta2-agonist. The combination
of a beta2-agonist and ipratropium did not appear
to increase the effect on FEV1 more than either used
alone.
-
| Am
J Manag Care 2002 Oct;8(10):902-11 |
|
-
Delivery of ipratropium and albuterol
combination therapy for chronic obstructive pulmonary
disease: effectiveness of a two-in-one inhaler versus
separate inhalers.
Chrischilles E, Gilden D, Kubisiak J, Rubenstein
L, Shah H.
University of Iowa, Iowa City, USA. echrischilles@uiowa.edu
OBJECTIVE: To determine whether a combined formulation
consisting of ipratropium and an inhaled beta2 agonist
(2-in-1 therapy) leads to lower respiratory-related
healthcare use and charges and improved compliance
compared with treatment with separate ipratropium
and beta2-agonist inhalers (separate inhaler therapy).
STUDY DESIGN: Retrospective inception cohort study.
PATIENTS AND METHODS: Healthcare use, charges, and
treatment compliance were examined for adults age
38 years or older who initiated ipratropium therapy
on or after July 1997, based on health claims data
for United Healthcare enrollees from 5 health plans
from July 1997 through December 1998. A total of 428
patients received 2-in-1 therapy, and 658 patients
received separate inhaler therapy. To adjust for disease
severity and other confounders, the following were
determined for the preinitiation period: age; sex;
use of oral steroids, antibiotics, or albuterol; respiratory-related
healthcare use; and respiratory diagnoses. Compliance
was defined as not interrupting or discontinuing therapy
during the follow-up period. RESULTS: After adjusting
for baseline covariates, 2-in-1 therapy users had
a significantly lower risk of emergency department
use or hospitalization (relative risk = 0.58, 95%
confidence interval [CI] = 0.36, 0.94), lower mean
monthly healthcare charges (P= .015), shorter hospital
stays (2.05 vs 4.61 days, P = .040), and greater likelihood
of compliance (odds ratio = 1.77, 95% CI = 1.46, 2.14).
CONCLUSION: A single inhaler containing both ipratropium
and albuterol can increase compliance and decrease
respiratory morbidity and charges over and above the
effects achieved with separate inhalers for these
2 agents.
PMID: 12395958 [PubMed - indexed for MEDLINE]
-
| Respir
Med 2002 Aug;96(8):559-66 |
|
-
Effects of formoterol (Oxis Turbuhaler)
and ipratropium on exercise capacity in patients with
COPD.
Liesker JJ, Van De Velde V, Meysman M, Vincken
W, Wollmer P, Hansson L, Kerstjens HA, Qvint U, Pauwels
RA.
Department of Pulmonary Diseases, University Hospital
Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
Although long-acting inhaled beta 2-agonists improve
various outcome measures in COPD, no double-blind
study has yet shown a significant effect of these
drugs on exercise capacity. In a randomized, double-blind,
placebo-controlled, crossover study, patients received
formoterol (4, 5, 9, or 18 micrograms b.i.d. via Turbuhaler),
ipratropium bromide (80 micrograms t.i.d. via pMDI
with spacer), or placebo for 1 week. Main endpoint
was time to exhaustion (TTE) in an incremental cycle
ergometer test. Secondary endpoints were Borg dyspnoea
score during exercise, lung function, and adverse
events. Thirty-four patients with COPD were included,
mean age 64.8 years, FEV1 55.6% predicted, reversibility
6.1% predicted. All doses of formoterol, and ipratropium
significantly improved TTE, FEV1, FEF25-75%, FRC,
IVC, RV and sGAW compared with placebo. A negative
dose-response relationship was observed with formoterol.
Ipratropium increased time to exhaustion more compared
with formoterol, 18 micrograms, but not with formoterol,
4.5 and 9 micrograms. No changes in Borg score were
found. There was no difference in the adverse event
profile between treatments. In conclusion, 1 week
of treatment with formoterol and ipratropium significantly
improved exercise capacity and lung function compared
with placebo. However, a negative dose-response relation
for formoterol was unexpected and needs further investigation.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12195835 [PubMed - indexed for MEDLINE]
-
| Chest
2002 Jul;122(1):47-55 |
|
-
A 6-month, placebo-controlled study
comparing lung function and health status changes
in COPD patients treated with tiotropium or salmeterol.
Donohue JF, van Noord JA, Bateman ED, Langley SJ,
Lee A, Witek TJ Jr, Kesten S, Towse L.
Division of Pulmonary Medicine, University of North
Carolina, Chapel Hill, NC 27599-7020, USA. jdonohue@med.unc.edu
BACKGROUND: Tiotropium, a once-daily anticholinergic,
and salmeterol represent two inhaled, long-acting
bronchodilators from different pharmacologic classes.
A trial was designed to examine the efficacy and safety
of both compounds with multiple outcome measures,
including lung function, dyspnea, and health-related
quality of life (HRQoL) in patients with COPD. METHODS:
A 6-month, randomized, placebo-controlled, double-blind,
double-dummy, parallel-group study of tiotropium,
18 microg once daily via dry-powder inhaler, compared
with salmeterol, 50 microg bid via metered-dose inhaler,
was conducted in patients with COPD. Efficacy was
assessed by 12-h monitoring of spirometry, transition
dyspnea index (TDI), and the St. George's Respiratory
Questionnaire (SGRQ). RESULTS: A total of 623 patients
participated (tiotropium, n= 209; salmeterol, n =
213; and placebo, n = 201). The groups were similar
in age (mean, 65 years), gender (75% men), and baseline
FEV(1) (mean, 1.08 +/- 0.37 L; percent predicted,
40 +/- 12% [+/- SD]). Compared with placebo treatment,
the mean predose morning FEV(1) following 6 months
of therapy increased significantly more for the tiotropium
group (0.14 L) than the salmeterol group (0.09 L;
p < 0.01). The average FEV(1) (0 to 12 h) for tiotropium
was statistically superior to salmeterol (difference,
0.08 L; p < 0.001). Tiotropium improved TDI focal
score by 1.02 U compared with placebo (p = 0.01),
whereas there was no significant change in TDI focal
score with salmeterol (0.24 U). Tiotropium was superior
to salmeterol in improving TDI focal score (p <
0.05). At 6 months, the mean improvement in SGRQ total
score vs baseline was tiotropium, - 5.14 U (p <
0.05 vs placebo); salmeterol, - 3.54 U (p = 0.4 vs
placebo); and placebo, - 2.43 U. A statistically higher
proportion of patients receiving tiotropium achieved
at least a 4-U change in SGRQ score compared to patients
receiving placebo. Both active drugs reduced the need
for rescue albuterol (p < 0.0001). CONCLUSIONS:
Tiotropium once daily produces superior bronchodilation,
improvements in dyspnea, and proportion of patients
achieving meaningful changes in HRQoL compared to
twice-daily salmeterol in patients with COPD.
Publication Types:
- Clinical Trial
- Randomized Controlled Trial
PMID: 12114338 [PubMed - indexed for MEDLINE]
-
| Eur
Respir J 2002 May;19(5):936-43 |
|
-
Formoterol in patients with chronic
obstructive pulmonary disease: a randomized, controlled,
3-month trial.
Aalbers R, Ayres J, Backer V, Decramer M, Lier
PA, Magyar P, Malolepszy J, Ruffin R, Sybrecht GW.
Martini Hospital, Groningen, The Netherlands.
The aim of this study was to investigate formoterol,
an inhaled long-acting beta2-agonist, in patients
with chronic obstructive pulmonary disease (COPD).
Six-hundred and ninety-two COPD patients, mean baseline
forced expiratory volume in one second (FEV1) 54%,
FEV1/forced vital capacity 75% of predicted, reversibility
6.4% pred, were treated with formoterol (4.5, 9 or
18 microg b.i.d.) or placebo via Turbuhaler for 12
weeks. Symptoms were recorded daily. Spirometry and
the incremental shuttle walking test (SWT) were performed
at clinic visits. Compared with placebo, 18 microg
b.i.d. formoterol reduced the mean total symptom score
by 13% and increased the percentage of nights without
awakenings by 15%. Formoterol (9 and 18 microg b.i.d.)
significantly reduced symptom scores for breathlessness
(-7% and -9%, respectively) and chest tightness (-11%
and -8%, respectively), reduced the need for rescue
medication (-25% and -18%, respectively), and increased
symptom-free days (71% and 86%, respectively). FEV1
improved significantly after all three doses of formoterol
(versus placebo). No differences were found between
groups in SWT walking distance. No unexpected adverse
events were seen. In conclusion, 9 and 18 microg b.i.d.
formoterol reduced symptoms and increased the number
of symptom-free days in a dose-dependent manner in
chronic obstructive pulmonary disease patients. Formoterol
improved lung function at a dose of 4.5 microg b.i.d.
and higher.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 12030736 [PubMed - indexed for MEDLINE]
 |
|
-
-
Use of a long-acting inhaled beta2-adrenergic
agonist, salmeterol xinafoate, in patients with chronic
obstructive pulmonary disease.
Rennard SI, Anderson W, ZuWallack R, Broughton
J, Bailey W, Friedman M, Wisniewski M, Rickard K.
- University of Nebraska Medical Center, Omaha, Nebraska,
USA. srennard@mail.unmc.edu
Chronic obstructive pulmonary disease (COPD) is
a condition in which continuous bronchodilation
may have clinical advantages. This study evaluated
salmeterol, a beta-agonist bronchodilator with a
duration of action substantially longer than that
of short-acting beta-agonists, compared with ipratropium,
an anticholinergic bronchodilator, and placebo in
patients with COPD. Four hundred and five patients
with COPD received either salmeterol 42 microg twice
daily, ipratropium bromide 36 microg four times
daily, or placebo for 12 wk in this randomized,
double-blind, parallel-group study. Patients were
stratified on the basis of bronchodilator response
to albuterol (> 12% and > 200-ml improvement)
and were randomized within each stratum. Bronchodilator
response was measured over 12 h four times during
the treatment period. Salmeterol provided similar
maximal bronchodilatation to ipratropium but had
a longer duration of action and a more constant
bronchodilatory effect with no evidence of bronchodilator
tolerance. Both active treatments were well tolerated.
Salmeterol was an effective bronchodilator with
a consistent effect over this 12-wk study in patients
with COPD, including those "unresponsive"
to albuterol. The long duration of action of salmeterol
offers the advantage of twice daily dosing compared
with the required four times a day dosing with ipratropium.
Publication Types:
Clinical Trial
Multicenter Study
Randomized Controlled Trial
PMID: 11316640 [PubMed - indexed for MEDLINE]
-
| Drugs Aging 2001;18(6):441-72 |
Related
Articles
|
-
Inhaled salmeterol: a review of
its efficacy in chronic obstructive pulmonary disease.
Jarvis B, Markham A.
- Adis International Limited, Mairangi Bay, Auckland,
New Zealand. demail@adis.co.nz
Inhaled salmeterol is a long-acting, selective
beta2-adrenoceptor agonist bronchodilator. The drug
has been compared with placebo, ipratropium bromide
and oral theophylline in patients with chronic obstructive
pulmonary disease (COPD) in randomised, clinical
trials. Inhaled salmeterol 50 microg twice daily
produced significant improvement in forced expiratory
volume in 1 second (FEV1), equivalent to that obtained
with inhaled ipratropium bromide 40 microg 4 times
daily and greater than that obtained with placebo
or oral theophylline in randomised trials. Use of
as-needed salbutamol (albuterol) was significantly
reduced during treatment with inhaled salmeterol
or ipratropium bromide compared with placebo or
oral theophylline. The time to first COPD exacerbation
was significantly longer during 12 weeks of treatment
with inhaled salmeterol 50 microg twice daily than
ipratropium bromide 40 microg 4 times daily. Compared
with baseline and placebo, patients treated for
16 weeks with salmeterol 50 microg (but not 100
microg) twice daily reported significant improvement
in total St George's Respiratory Questionnaire (SGRQ)
scores. Similarly, more patients treated with inhaled
salmeterol 50 microg twice daily or ipratropium
bromide 40 microg 4 times daily experienced an increase
of > or = 10 points in Chronic Respiratory Disease
Questionnaire (CRQ) scores, the minimum clinically
significant increment. Compared with placebo, inhaled
salmeterol 50 microg twice daily alone, or concurrent
with ipratropium bromide 40 microg 4 times daily
improved lung function and reduced symptoms in patients
with stable COPD in a 12-week, randomised, double-blind
study. Clinically meaningful improvement in CRQ
scores was documented in significantly more patients
treated with the combination of the 2 drugs than
either salmeterol monotherapy or placebo. Inhaled
salmeterol 50 microg twice daily plus oral theophylline
had additive effects on lung function, increased
the proportion of symptom-free days and decreased
requirements for as-needed salbutamol compared with
either agent alone according to a pooled analysis
of 2 multicentre, randomised, double-blind studies.
Conclusion: When used at the optimal dosage, 50
microg twice daily, salmeterol provides symptomatic
relief and improves lung function and health-related
quality of life in patients with COPD. Available
evidence suggests that the drug is as effective
as ipratropium bromide and more effective than oral
theophylline in patients with COPD. Moreover salmeterol
has additive effects when used in combination with
inhaled ipratropium bromide or oral theophylline.
These qualities make the drug suitable for first-line
use in patients with COPD who require regular bronchodilator
therapy to manage symptoms.
Publication Types:
Review
Review, Tutorial
PMID: 11419918 [PubMed - indexed for MEDLINE]
-
-
Inhaled short-acting
beta2-agonists versus ipratropium for acute exacerbations
of chronic obstructive pulmonary disease.
McCrory DC, Brown CD.
- Pulmonary and Critical Care Medicine, Duke University
Medical Center, Box 3221, 350 Bell Building, Durham,
North Carolina, 27710, USA.
BACKGROUND: Inhaled short acting beta2 adrenergic
agonists and ipratropium bromide are both used in
the treatment of acute exacerbations of chronic obstructive
pulmonary disease. OBJECTIVES: In patients with acute
exacerbations of COPD to: 1. To assess the efficacy
of short-acting beta-2 agonists against placebo; 2.
Compare the efficacy of short-acting beta-2 agonists
and ipratropium. SEARCH STRATEGY: A comprehensive
search of the literature was carried out of EMBASE,
MEDLINE, CINAHL and the Cochrane COPD trials register
was carried out using the terms: bronchodilator* OR
albuterol OR metaproterenol OR terbutaline OR isoetharine
OR pirbuterol OR salbutamol OR beta-2 agonist. SELECTION
CRITERIA: All trials that appeared to be relevant
were assessed by two reviewers who independently selected
trials for inclusion. Differences were resolved by
consensus. DATA COLLECTION AND ANALYSIS: All trials
that appeared to be relevant were assessed by two
reviewers who independently selected trials for inclusion.
Differences were resolved by consensus. References
listed in each included trial were searched for additional
trial reports. Trials were combined using Review Manager
using a fixed effects model. The size of the treatment
effects were tested for heterogeneity. MAIN RESULTS:
We identified no placebo-controlled comparisons of
beta-2 agonists. Three studies permitted comparison
of ipratropium to an inhaled beta-2 agonist. These
studies included a total of 103 patients. The beta2-agonists
used were: fenoterol and metaproterenol. One study
was a parallel group trial of regular therapy for
seven days. The other two were cross over studies
of single dose treatments, with efficacy measured
90 min post dose. There was no washout period between
treatments. Both treatments produced an improvement
in forced expiratory volume (FEV1) after 90 min in
the range 150-250 ml. The was no difference between
treatments, mean difference in FEV1 10 ml; 95% CI
-220, 230 ml. In one small crossover study (n=10)
there was a significant improvement in arterial PaO2
after 30 minutes with ipratropium (+5.8 mm Hg +/-
3.0 (SEM)) compared to metaproterenol (-6.2 +/- 1.2
mm Hg), but this was not significant at 90 min. There
were no data concerning respiratory symptoms. The
crossover studies showed no evidence of an additive
effect of the two treatments, although they were not
designed specifically to test this. REVIEWER'S CONCLUSIONS:
There are few controlled trial data concerning the
use of inhaled beta2-agonist agents in acute exacerbations
of COPD and none that have compared these agents directly
with placebo. None of the studies used the more modern
beta2-agonists used most widely in this setting (salbutamol
and terbutaline). Beta2-agonists and ipratropium both
produce small improvements in FEV1, but beta2-agonists
may worsen PaO2 for a period. We could not draw conclusions
concerning possible additive effects.
Publication Types:
PMID: 11406052 [PubMed - indexed for MEDLINE]
-
-
-
Inhaled formoterol
dry powder versus ipratropium bromide in chronic obstructive
pulmonary disease.
Dahl R, Greefhorst LA, Nowak D, Nonikov V, Byrne
AM, Thomson MH, Till D, Della Cioppa G; Formoterol
in Chronic Obstructive Pulmonary Disease I Study Group.
University Hospital Aarhus, Department of Respiratory
Diseases, Aarhus, Denmark. rda@aaa.dk
We compared the effectiveness of inhaled formoterol
with that of ipratropium in the treatment of chronic
obstructive pulmonary disease (COPD). After a 2-wk
run-in period, 780 patients with COPD were randomized
to receive for 12 wk formoterol dry powder 12 or 24
microg twice daily, ipratropium bromide 40 microg
four times daily, or placebo in a multicenter, double-blind,
parallel-group study. The primary efficacy variable
was the area under the curve for forced expiratory
volume in 1 s (FEV(1)) measured over 12 h after 12
wk of treatment. Secondary variables included diary
symptoms and quality of life. Both doses of formoterol
and ipratropium significantly increased the area under
the curve for FEV(1) in comparison with placebo (all
p < 0.001). Both doses of formoterol were also
significantly superior to ipratropium (all p <
0.025). Compared with placebo, both doses of formoterol
significantly improved symptoms (all p < or = 0.007)
and quality of life (p < 0.01 for total scores)
whereas ipratropium did not show significant effects
(all p > or = 0.3). All study treatments exhibited
a similar safety profile. We conclude that formoterol
is more effective than ipratropium bromide in the
treatment of COPD, as the efficacy of ipratropium
on airflow obstruction does not translate into a clinical
benefit that patients can perceive.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 11549532 [PubMed - indexed for MEDLINE]
-
-
Use of a long-acting inhaled beta2-adrenergic
agonist, salmeterol xinafoate, in patients with chronic
obstructive pulmonary disease.
Rennard SI, Anderson W, ZuWallack R, Broughton
J, Bailey W, Friedman M, Wisniewski M, Rickard K.
University of Nebraska Medical Center, Omaha, Nebraska,
USA. srennard@mail.unmc.edu
Chronic obstructive pulmonary disease (COPD) is a
condition in which continuous bronchodilation may
have clinical advantages. This study evaluated salmeterol,
a beta-agonist bronchodilator with a duration of action
substantially longer than that of short-acting beta-agonists,
compared with ipratropium, an anticholinergic bronchodilator,
and placebo in patients with COPD. Four hundred and
five patients with COPD received either salmeterol
42 microg twice daily, ipratropium bromide 36 microg
four times daily, or placebo for 12 wk in this randomized,
double-blind, parallel-group study. Patients were
stratified on the basis of bronchodilator response
to albuterol (> 12% and > 200-ml improvement)
and were randomized within each stratum. Bronchodilator
response was measured over 12 h four times during
the treatment period. Salmeterol provided similar
maximal bronchodilatation to ipratropium but had a
longer duration of action and a more constant bronchodilatory
effect with no evidence of bronchodilator tolerance.
Both active treatments were well tolerated. Salmeterol
was an effective bronchodilator with a consistent
effect over this 12-wk study in patients with COPD,
including those "unresponsive" to albuterol. The long
duration of action of salmeterol offers the advantage
of twice daily dosing compared with the required four
times a day dosing with ipratropium.
Publication Types:
- Clinical Trial
- Multicenter Study
- Randomized Controlled Trial
PMID: 11316640 [PubMed - indexed for MEDLINE]
-
-
The impact of combined inhaled bronchodilator
therapy in the treatment of COPD.
Benayoun S, Ernst P, Suissa S.
Department of Epidemiology and Biostatistics, McGill
University, Montreal, Quebec, Canada.
BACKGROUND: Treatment guidelines recommend concomitant
use of ipratropium bromide and inhaled beta2-agonists
as severity of COPD progresses. While the use of these
two agents in a single inhaler may enhance patient
compliance and result in cost savings, it may, by
itself, increase medication use. We assessed whether
the introduction of a combined inhaled bronchodilator
in the treatment of COPD modifies the use and costs
related to prescribed medications. METHOD: A cohort
of subjects > or =45 years old initiating treatment
with either a combined inhaled bronchodilator (641
subjects) or ipratropium bromide and inhaled beta2
-agonist (411 subjects) between July 1, 1996, and
June 30, 1997, was identified using the Saskatchewan
Health databases. The primary outcomes were prescribed
medication usage and the subsequent related costs
during a 1-year follow-up period. Poisson regression
analysis was used to estimate rate ratios (RRs) adjusted
for drug use and hospitalization during the year prior
to cohort entry. RESULTS: The adjusted RR of inhaled
bronchodilator use was elevated for combined inhaled
bronchodilator therapy (adjusted RR, 1.16; 95% confidence
interval [CI], 1.07 to 1.26). However, the overall
costs associated with these inhaled bronchodilators
were reduced with combined inhaled bronchodilator
therapy (adjusted mean ratio, 0.83; 95% CI, 0.76 to
0.92). The rate of use of other respiratory drugs
and antibiotics was similar (adjusted RR, 1.03; 95%
CI, 93 to 1.16). Applying the rate ratio for cost
savings to all new, combined inhaled bronchodilator
users led to estimated annual savings in Canadian
dollars of 103,468 dollars (95% CI, 48,694 dollars
to 146,082 dollars) in this province. CONCLUSION:
The introduction of a simpler bronchodilator dosing
regimen did not significantly alter the treatment
of COPD and resulted in appreciable cost savings.
PMID: 11157588 [PubMed - indexed for MEDLINE]
 |
|
-
-
Long-acting beta2-agonists for chronic
obstructive pulmonary disease.
Appleton S, Smith B, Veale A, Bara A.
- Dept. of Medicine, The Queen Elizabeth Hospital,
Woodville Rd., Woodville, Adelaide, AUSTRALIA, 5011.
sappleto@medicine.adelaide.edu.au
BACKGROUND: Chronic obstructive pulmonary disease
(COPD) is characterised by airflow limitation which
is only partially reversible. Long acting beta2-agonists,
effective in the management of asthma,are also recommended
for COPD management so it is important to establish
whether these drugs are effective in reducing COPD
symptoms in view of the potential side effect and
cost burden. OBJECTIVES: To determine the effectiveness
of long acting beta2-adrenoceptor agonists in improving
lung function and quality of life and reducing dyspnoea
in patients with COPD. SEARCH STRATEGY: A search
was carried out using the Cochrane Airways Group
register. Bibliographies of identified RCTs were
searched for additional relevant RCTs. Authors of
identified RCTs were contacted for other published
and unpublished studies. In addition, unpublished
studies were also obtained from the pharmaceutical
companies that manufacture long acting beta2- adrenoceptor
agonists. SELECTION CRITERIA: All randomised controlled
trials over four weeks in duration comparing treatment
with long-acting beta2-adrenoceptor agonists (salmeterol
and formoterol) with placebo in patients with stable
non-reversible COPD. Outcome measures included forced
expiratory volume in one second (FEV1), peak expiratory
flow rate (PEFR), symptom scores, six minute walk
distance, quality of life scores, Borg scores for
dyspnoea and rescue bronchodilator use. DATA COLLECTION
AND ANALYSIS: Data extraction and study quality
assessment was performed independently by two reviewers.
Where further or missing data were required, authors
of studies were contacted. MAIN RESULTS: Thirty
three abstracts were identified as potentially relevant.
Of these, four randomised controlled trials (RCTs)
were included in this review. Two were parallel
group studies of 16 week duration and two were cross-over
studies with four week treatment arms. All four
RCTs assessed the efficacy of salmeterol in COPD.
In a 16 week study of salmeterol 50 mcg and 100
mcg twice daily treatment, a significant increase
in FEV1 was seen in both treatment groups. The weighted
mean difference (WMD) for the increase in FEV1 for
the 50 mcg group was 0.10 litre (95% CI: 0.05;0.
15) and in the 100 mcg group the WMD was 0.12 litre
(95% CI: 0.06; 0. 17 ). In the two cross-over studies
of four weeks treatment, salmeterol 50 mcg twice
daily treatment did not show significant increases
in FEV1 (WMD = 0.04 litre, 95% CI: -0.06; 0.15).
Similarly, morning and night time PEFR was not significantly
improved with salmeterol treatment. In a 16 week
study, disease-specific quality of life, measured
using the St. George's Respiratory Questionnaire
(SGRQ), showed a significant improvement after 50
mcg twice daily, but not after 100 mcg twice daily.
This improvement exceeded the threshold for a clinically
significant change with this questionnaire. General
health status, as measured by the Medical Outcomes
Short Form 36, did not improve in any of the eight
components with either salmeterol dose. No significant
difference was demonstrated in the mean change from
baseline in the six minute walk distance (WMD =
1.9 metres, 95% CI: -15.4;19.3). Breathlessness
was reduced in one study in patients receiving salmeterol
50 mcg twice daily group. Significantly more patients
in this group had Borg scores for breathlessness
less than three (a score of three indicating moderate
dyspnoea) compared to the placebo treated group
(Peto Odds Ratio = 0.60, 95% CI: 0.40; 0.88). Neither
dose of salmeterol influenced the incidence of COPD
exacerbations, (50 mcg: Peto Odds Ratio = 0.74,
95% CI: 0.47, 1.15) and (100 mcg: Peto Odds Ratio
= 0.98, 95% CI: 0.64, 1.52). REVIEWER'S CONCLUSIONS:
Treatment of patients with COPD with long acting
beta2-agonists produces only small increases in
FEV1. In one study, a dose of salmeterol 50 mcg
twice daily produced a reduction in breathlessness
and a clinically significant improvement in quality
of life. (ABSTRACT TRUNCATED)
Publication Types:
Review
Review, Academic
PMID: 10796594 [PubMed - indexed for MEDLINE]
-
Update in:
Short-acting beta
2 agonists for stable chronic obstructive pulmonary
disease.
Sestini P, Ram FS.
Institute of Respiratory Diseases, University of Siena,
Viale Bracci 3, 53100, Siena, Italy. sestini@unisi.it
BACKGROUND: Chronic Obstructive Pulmonary Disease
(COPD) is a chronic condition characterised by progressive
airflow limitation that is at most partially reversible.
Despite the lack of reversibility patients often report
symptomatic improvement with short-acting beta 2 bronchodilator
medications. They are used on either an "as required"
or a "regular plus as required basis" and they may
be used in conjunction with other bronchodilator medicines
such as ipratropium and methylxanthines. These medicines
are used in the management of both stable and acute
exacerbations of COPD. This review examined the effect
of short-acting beta 2 bronchodilators given by inhalation
in stable COPD. OBJECTIVES: To determine the clinical
effect and assess the adverse effects of inhaled short-acting
beta 2 agonist bronchodilators compared with placebo
in stable COPD. SEARCH STRATEGY: Only randomised controlled
trials (RCTs) were considered. RCTs were identified
using the Cochrane Airways Group database (CENTRAL).
In addition, the reference lists of review articles
and RCTs retrieved in full were searched for other
potentially relevant citations. SELECTION CRITERIA:
Only trials with adult patients with stable COPD,
as defined by internationally accepted guidelines
(ATS, ERS or BTS) were included in this review. All
trials had a minimum duration of 7 days of regular
treatment with short-acting beta 2 bronchodilators
given by inhalation and compared with placebo. Data
from trials where beta 2 agonists were used alone
or in combination with other medicines (e.g. ipratropium
bromide) were used only if there was a direct comparison
between beta 2 bronchodilator alone and placebo. DATA
COLLECTION AND ANALYSIS: Outcomes were analysed as
continuous or dichotomous outcomes, using standard
statistical techniques. For continuous outcomes, the
weighted mean difference (WMD) and 95% confidence
intervals were calculated and for dichotomous outcomes,
the odds ratio was calculated with 95% confidence
intervals by Peto's methods. Funnel plots were used
to test for publication bias. MAIN RESULTS: Thirteen
studies were included in this review. Most had small
sample sizes and some of the sutides used very short-acting
outdated compounds. All the studies used a cross-over
design and were of high quality. Spirometry done at
the end of study period was measured after administration
of treatment (post-bronchodilator) which showed both
FEV1 (0.150 L/min, 95%CI: 0. 02-0.28) and FVC (0.310
L, 95%CI: 0.00-0.62) to improve significanly but slightly
when compared to placebo. A few studies measured FRC,
airway resistance or conductance at the end of the
study period. In all cases these measurements were
done several hours after treatment, and no significant
differences (p>0.05 in all cases) were found between
the bronchodilator and placebo groups. Walking test
Large increases in 6MW distance was observed in two
studies, however one study did not show any positive
improvements. There was a large increase in the 12MW
distance as shown by one study. Due to the small number
of studies reporting this outcome no significant differences
were found in the walking distance between the bronchodilator
and placebo groups. Peak Flow Rate Both morning (36.
04 L/min; 95%CI: 0.80-71.27) and evening (36.68 L/min;
95%CI: 2. 47-70.89) PEFR were significantly higher
during active treatment than during placebo. Symptoms
Breatlessness was measured on various scales therefore
data that were presented in a suitable form were combined
using standardized means for inclusion in the analysis.
A significant improvement (-0.33; 95%CI: -0.58 to
-0.07 with p=0.01) in the breathlessness score was
observed during treatment with beta-2 agonist when
compared to placebo. Cough was reported to improve
significantly (data not usable) during treatment with
beta2 agonist in one study but not in two others.
A non-significant decrease in sputum production was
reported by Wilson 1980, however four other studies
reported no
Publication Types:
PMID: 10796652 [PubMed - indexed for MEDLINE]
|
