Safety and tolerability of NVA237, a once-daily long-acting muscarinic antagonist,in COPD patients

NVA237 is a novel once-daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This randomized, double-blind, placebo-controlled study evaluated the safety, tolerability and bronchodilator efficacy of two doses of NVA237 (100 and 200 μg), versus placebo, in patients with moderate-to-severe COPD (forced expiratory volume in 1 s [FEV₁] ≥ 30% and <80% predicted and FEV₁/forced vital capacity [FVC] < 0.7, 30 min after inhalation of 80 μg ipratropium bromide). After appropriate washout periods, patients were randomized to treatment with NVA237 100 μg (n = 92), NVA237 200 μg (n = 98) or placebo (n = 91) for 28 days. The primary objective was evaluation of safety, with efficacy measures included as secondary objectives. NVA237 was generally well tolerated and associated with a frequency and distribution of adverse events similar to placebo. Serious adverse events were uncommon and there was no evidence of adverse cardiovascular effects or unexpected events. Trough FEV₁ was significantly higher in those receiving NVA237 compared with placebo. For NVA237 100 μg the differences were 131 and 161 mL on Days 1 and 28, respectively (p < 0.05), and for NVA237 200 μg the differences were 146 and 151 mL on Days 1 and 28, respectively (p < 0.05). Peak FEV₁, FEV₁ at all timepoints up to 24 h after dosing, and FEV₁ area under the curve during 5 min–5 h post-dosing were also significantly higher in both NVA237 groups, compared with placebo. Patients receiving NVA237 required fewer daily puffs of rescue medication and had a higher percentage of days on which rescue medication was not required. Overall, the present study provides further evidence of the safety, tolerability and bronchodilator efficacy of once-daily treatment with NVA237 100 and 200 μg in patients with moderate-to-severe COPD.     

Bronchodilatory effects of NVA237, a once daily long-acting muscarinic antagonist, in COPD patients

NVA237 is a novel, once daily inhaled long-acting muscarinic antagonist administered via a dry powder inhaler. This study aimed to assess the 24-h bronchodilatory effect following 14 days of treatment with inhaled NVA237 in patients with mild, moderate or severe COPD. This was a randomized, double-blind, placebo-controlled, two-period, crossover, multicenter study. A total of 33 patients (≥ 40 years; smoking history of ≥ 10 pack-years) were randomized to receive NVA237 50 μg once daily followed by placebo or placebo followed by NVA237 50 μg for 14 days. Treatment periods were separated by a 7-14 day washout period. The primary variable was the mean forced expiratory volume in 1 s (FEV(1)) derived from the area under the curve (AUC) between 0 and 24 h post-dose on Day 14. The 24-h FEV(1) profiles showed a consistent bronchodilator effect for NVA237 versus placebo on Day 14. Least square (LS) mean difference in FEV(1) AUC(0-24 h) values between NVA237 and placebo was 163 mL (P < 0.001). There were significant increases in mean FEV(1) AUC(0-12 h) (LS mean difference 165 mL, P = 0.001) and FEV(1) AUC(12-24 h) (161 mL, P < 0.001) versus placebo. NVA237 significantly improved peak FEV(1) (by 208 mL, P < 0.001) and trough FEV(1) (by 154 mL, P = 0.003) versus placebo on Day 14. NVA237 was well tolerated; all adverse events were mild or moderate in intensity and not related to study drug. NVA237 50 μg once daily was well tolerated and showed significant and sustained 24-h bronchodilation in patients with COPD.     

Bronchodilator therapy for chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a heterogeneous group of diseases characterized by cough, sputum production, dyspnoea, airflow limitation and bronchial hyperreactivity. The airflow limitation declines progressively and is irreversible or partially reversible. Bronchodilator therapy is prescribed to relieve the symptoms, reverse airway obstruction and hopefully slow the rate of disease progression and decelerate the decline in pulmonary function. During acute exacerbation, inhalation of β2-agonists remain the therapy of choice. The usefulness of anticholinergic inhalation in acute attacks is investigated in order to determine if a higher dose and more frequent administration have same benefit as β2-agonists inhalation. Theophylline is usually given orally as a sustained release formulation for chronic maintenance therapy. Some patients may benefit from theophylline infusion during an acute phase when appropriately used; however, sympathomimetic agents fail to produce adequate bronchodilation. During interim periods of stability, inhalation of ipratropium bromide has increased in popularity as a regular long-term bronchodilator therapy. Although ipratropium and β2-agonists are equally efficacious when the dosage is adequate enough, a combination of both provides a rapid onset of action of the adrenergic agents and a prolonged action of the anticholinergic. Furthermore, this combination can be given in a reduced dose, thereby avoiding side-effects. Inhalation techniques can influence the efficacy of bronchodilator therapy. For severe dyspnoeic patients or patients with poor technique of co-ordination with metered-dose inhaler (MDI), attachment of a spacer to the MDI or using a nebulizer will overcome these difficulties. Bronchodilator therapy can not prevent the development of COPD or slow down the decline of pulmonary function, other interventions should be included in a comprehensive management programme.     

Surgical therapy for chronic obstructive pulmonary disease

Many patients with severe chronic obstructive pulmonary disease (COPD) experience incapacitating breathlessness and exercise limitation. Multiple surgical techniques have been utilized to achieve resection of giant, localized bullae with documented short-term benefit in pulmonary function and dyspnea in highly selected patients. The poorest long-term outcome has been noted in those with greater degrees of emphysema in the remaining lung, greater underlying chronic bronchitis, and a bulla occupying less than one third of the hemithorax, particularly if compressed normal lung is not evident. Lung volume reduction surgery (LVRS) in the absence of giant bullae has become more widely accepted in selected patients. Bilateral LVRS procedures appear to result in greater short-term improvement than unilateral LVRS, whereas physiological benefits appear similar with video-assisted thoracoscopy (VATS) or median sternotomy (MS) techniques. Improvement in dyspnea and health status after LVRS has been documented and appears to be better preserved over longer-term follow-up than physiological improvement. Clear direction has been provided in identifying optimal candidates for bilateral LVRS; patients with a postbronchodilator forced expiratory volume in 1 second (FEV (1)) < or = 20% predicted and a diffusing capacity for carbon monoxide (DL (CO)) < or = 20% predicted or homogeneous emphysema exhibit a much higher mortality with LVRS than with medical management. Patients with upper-lobe predominant emphysema and a low postrehabilitation exercise tolerance exhibited a decreased risk of mortality after LVRS. Patients with non-upper lobe predominant emphysema on high-resolution computed tomography (HRCT) and a high postrehabilitation exercise capacity exhibit an increased risk of death after LVRS. Patients with upper lobe predominant emphysema and a high postrehabilitation exercise capacity or patients with non-upper lobe predominant emphysema and a low postrehabilitation exercise capacity do not have a survival advantage or disadvantage, whereas those with upper lobe predominant emphysema treated surgically are more likely to improve their exercise capacity after surgery. Lung transplantation is an option for a more limited number of patients. Consistent short-term spirometric improvement after both single- and double-lung transplant has been documented. Long-term results of lung transplantation are limited by significant complications that impair survival; an approximately 80% 1-year, 50% 5-year, and 35% 10-year survival has been reported. Bronchiolitis obliterans is the most important long-term complication of lung transplantation resulting in decreased pulmonary function. In general, a COPD patient can be considered an appropriate candidate for transplantation when the FEV (1) is below 25% predicted and/or the paCO (2) is > or = 55 mm Hg.     

慢性阻塞性肺疾病的气道毒蕈碱M受体变化与抗胆碱治疗的研究

慢性阻塞性肺疾病(COPD)支气管阻塞的重要病理生理机制包括由迷走神经控制的黏液高分泌以及由胆碱能机制诱发的支气管平滑肌张力的增加，因此，抗胆碱治疗已成为其第一选择。     

Tiotropium, a novel muscarinic M3 receptor antagonist, improved symptoms of chronic obstructive pulmonary disease complicated by chronic heart failure.

A 77-year-old man was referred to hospital because of dyspnea on exertion. Although the patient had been fully medicated for chronic heart failure (CHF) caused by hypertensive heart disease, the echo-estimated left ventricular end-diastolic pressure (LVEDP) and brain natriuretic peptide (BNP) level had continued to be high for at least 2 years. Pulmonary functional examination revealed concomitant chronic obstructive pulmonary disease (COPD). Because beta-agonists were expected to exacerbate the CHF, inhalation of tiotropium, a non-beta-adrenergic bronchodilator and novel M3 muscarinic receptor antagonist, was used to treat the COPD. Not only did the pulmonary function improved but the treatment also safely ameliorated CHF signs including LVEDP and plasma BNP.     

联合吸入糖皮质激素和长效β-受体激动剂治疗慢性阻塞性肺疾病的研究进展

COPD是一个严重的健康问题.WHO预测到2020年COPD将成为全球第5大疾病负担和第3大死亡原因[1].目前COPD被认为是一种多因素构成的疾病,包括肺脏内外结构和功能的改变[2],炎症在疾病发病进展过程中起着核心作用[3-4].     

Adjunct therapy in chronic obstructive pulmonary disease

There have been several studies of acceptable design in which neither subjective nor objective benefit of physiotherapy has been demonstrated. It is possible that the subjective benefit reported in unmatched groups reflects the patients' desire to satisfy a hard-working physiotherapist. Pursed lips breathing affords immediate benefit, but the question of long-term benefit has not been examined.Despite the well documented immediate effects of intermittent positive pressure breathing (IPPB), studies in which its long-term effects have been examined have failed to demonstrate either subjective or objective benefit to patients with chronic obstructive pulmonary disease in interval. IPPB, used as a more effective method of administering bronchodilator aerosols, has been shown repeatedly not to alter significantly the response obtained with voluntary inhalation of the aerosols. Similarly there has been no demonstration that inhalation of water or saline solution, droplets or aerosol (as opposed to humidification) has any measurable effect in the chronic phase of this disease other than immediate transitory increases in airway resistance.Exercise training appears to result in definite subjective improvement in exercise tolerance and in objective indirect improvement. No consistent direct effect on any measurable pulmonary function parameters has been observed. Since most of the studies on the effects of exercise to date suffer from the lack of a control group, or at least a control period, it is not certain which of the documented alterations after exercise training are specific responses to the training; however, current evidence suggests that training is a useful adjunct to therapy. The question of altered survival has not yet been examined in a controlled fashion.The usefulness of oxygen supplementation as an aid to an exercise program and to ameliorate long-term complications such as cor pulmonale and secondary polycythemia is well documented. Decreased mortality is implied, but we found no specific studies on the effects of oxygen therapy alone upon mortality.     

慢性阻塞性肺疾病稳定期的治疗进展

慢性阻塞性肺疾病是临床上常见的疾病之一,其发病率和病死率逐年升高,是一种不可逆转且进行性加重的呼吸系统疾病.本文综述慢性阻塞性肺疾病治疗的新进展.     

Bronchodilator therapy in chronic obstructive pulmonary disease

This paper reviews new developments in bronchodilator therapy for chronic obstructive pulmonary disease (COPD). Most patients with COPD respond to bronchodilators, but we have no reliable way to predict which patients will respond. When responsiveness is assessed, changes in lung volume as well as improvements in FEV1 should be considered. The combination of a beta-agonist and an anticholinergic agent produces greater improvement than either agent alone. Anticholinergic agents have few adverse side effects in patients with COPD, but concern remains about the possible cardiac side effects of beta-agonists. No clear answer exists about whether new, long-acting beta-agonists, such as salmeterol, should supplant anticholinergic agents as "first-line" therapy in COPD.     

Update on pharmacologic therapy for chronic obstructive pulmonary disease

As described throughout this article, significant improvements continue to occur in the pharmacologic management of COPD. These improvements range from improved medication targeting to better understanding of mechanisms of action, to better delivery of medications, to lower side effects. New areas of pharmacologic intervention, if not ready for use today, hold great promise for the not-too-distant future. In addition to the many agents described here, multiple mediator antagonists and anti-inflammatory agents are also under investigation for use in COPD. Interestingly, repair of alveolar tissue may be possible. Indeed, preliminary animal studies suggest that retinoic acid may be able to induce regeneration of lung alveoli. Overall, more effort is needed to broaden awareness and provide for the appropriate diagnosis of COPD, better explain pharmacologic therapies for COPD, simplify and disseminate guidelines, and highlight key differences between asthma and COPD, including their treatment strategies. As interest in COPD continues to grow, future updates on COPD management will continue to add new pharmacologic options for this devastating and preventable disease.     

Cost-effectiveness of combination therapy for chronic obstructive pulmonary disease

BACKGROUND:

There is evidence that combination therapy (CT) in the form of long-acting beta₂-agonists (LABAs) and inhaled corticosteroids can improve lung function for patients with chronic obstructive pulmonary disease (COPD).

OBJECTIVE:

To determine the cost-effectiveness of using CT in none, all or a selected group of COPD patients.

METHODS:

A Markov model was designed to compare four treatment strategies: no use of CT regardless of COPD severity (patients receive LABA only); use of CT in patients with stage 3 disease only (forced expiratory volume in 1 s [FEV₁] less than 35% of predicted); use of CT in patients with stages 2 and 3 disease only (FEV₁ less than 50% of predicted); and use of CT in all patients regardless of severity of COPD. Estimates of mortality, exacerbation and disease progression rates, quality-adjusted life years (QALYs) and costs were derived from the literature. Three-year and lifetime time horizons were used. The analysis was conducted from a health systems perspective.

RESULTS:

CT was associated with a cost of $39,000 per QALY if given to patients with stage 3 disease, $47,500 per QALY if given to patients with stages 2 and 3 disease, and $450,333 per QALY if given to all COPD patients. Results were robust to various assumptions tested in a Monte Carlo simulation.

CONCLUSION:

Providing CT for COPD patients in stage 2 or 3 disease is cost-effective. The message to family physicians and specialists is that as FEV₁ worsens and reaches 50% of predicted values, CT is recommended.     

Update in surgical therapy for chronic obstructive pulmonary disease

Bullectomy for giant bullae, lung volume reduction surgery, and lung transplantation are three surgical therapies that may benefit highly selected patients with advanced chronic obstructive pulmonary disease. In this article, each procedure is reviewed, with an emphasis on guidelines for patient selection and clinical outcomes for the practicing pulmonologist. Recent results from the National Emphysema Treatment Trial, updated International Society for Heart and Lung Transplantation Registry data, and revised guidelines for patient selection for lung transplantation are discussed.     

Rebound hyperresponsiveness to muscarinic stimulation after chronic therapy with an inhaled muscarinic antagonist

In 9 young subjects with mild asthma, we investigated the possibility that chronic daily administration of an inhaled muscarinic antagonist (ipratropium bromide) might increase the response of muscarinic receptors in airway smooth muscle to agonist stimulation caused by receptor upregulation. Subjects inhaled 60 micrograms of ipratropium 4 times daily for 3 wk. Methacholine bronchoprovocation (with or without acute pretreatment with ipratropium) was performed before (control period) and during 3 wk of daily ipratropium therapy (medication period). At the end of the medication period, subjects returned at 12, 24, 48, and 72 h after the last dose of ipratropium (withdrawal period) to determine the provocative concentration of methacholine producing a 20% decrease in FEV1 (PC20). During the medication period, there was no significant diminution of the acute bronchodilator response to ipratropium or of the protective effect of ipratropium against methacholine-induced bronchospasm when compared with the control period. During the withdrawal period, mean in PC20 was significantly less (increased airway responsiveness) at 24 h than during the control period (p less than 0.01) and returned to the control period value within 48 to 72 h. We conclude that daily administration of ipratropium to mildly asthmatic subjects for 3 wk does not produce tolerance to either the bronchodilator effect of ipratropium or to its inhibition of methacholine-induced bronchospasm but does induce transient supersensitivity of airway cholinergic receptors to muscarinic stimulation.     

重新认识祛痰治疗在慢性阻塞性肺疾病中的作用

气道黏液高分泌是以COPD为代表的慢性气道炎症性疾病的重要病理生理特征之一,临床上主要表现为反复的咳嗽、咳痰.长期以来对气道黏液高分泌的认识存在一个误区,认为由气道黏液高分泌导致的咳嗽、咳痰仅是一种临床症状,与COPD患者肺功能恶化和急性加重等的关系不大,因此对气道黏液高分泌和基于气道黏液高分泌的祛痰治疗缺乏相对整体、客观的认识.随着对气道黏液高分泌研究的不断深入,目前已知其远远超过单纯临床症状的范畴,除对症治疗外,祛痰在COPD治疗中还发挥了更重要的作用.因此,深入探索气道黏液高分泌在COPD致病机制中的重要作用,开发新型祛痰类药物,以及开展祛痰类药物的临床研究等已成为目前的研究热点.