长效支气管扩张剂噻托溴铵

慢性阻塞性肺病和哮喘都是以气流受限为特征的肺部疾病,支气管扩张剂是主要治疗药物类别之一。噻托溴铵为长效抗胆碱能药,能持续扩张支气管。本文就噻托溴铵的药理学性质、临床研究、不良反应及与其他药物联合治疗的研究进展作一概要介绍。     

噻托溴铵的药理作用和临床研究

自1980年引入异丙托溴铵以来,抗胆碱能药已成为慢性阻塞性肺疾病（COPD）的标准治疗药物。目前,各级COPD指南都推荐异丙托溴铵,但其作用持续时间只有4～6h,每日多次给药易导致患者依从性差。噻托溴铵是合成的非手性四价铵抗胆碱药,有两个特性：（1）对调节气道平滑肌收缩的M受体具有高度选择性;（2）作用时间长,每日只需给药1次。2002年,噻托溴铵已在除美国之外的部分国家使用。     

噻托溴铵治疗慢性阻塞性肺疾病的临床试验

噻托溴铵是新型的长效抗胆碱药，其扩张支气管的作用优于目前在临床作为治疗慢性阻塞性肺疾病（COPD）一线药物的异丙托溴铵，在2004年经美国FDA核准可作为COPD长期维持治疗用药。因此，我们首次采用国产噻托溴铵对稳定期COPD患者进行13周的随机、双盲、安慰剂平行对照临床试验，观察该药在国人COPD患者的疗效。     

一种治疗慢性阻塞性肺病的新药噻托溴铵

噻托溴铵是一类新型长效抗胆碱能类支气管扩张剂，用于治疗慢性阻塞性肺病(COPD)，每日仅需用药1次，经吸入给药。临床研究表明，与需每日数次吸入给药的临床一线抗胆碱能药异丙托溴铵、β2受体激动剂沙美特罗及安慰剂相比，噻托溴铵可明显改善肺功能、减少C0PD的急性发作，并极大地改善生活质量。该药耐受性良好，口干是其主要的副作用。     

雾化吸入复方异丙托溴铵溶液致尿潴留1例

复方异丙托溴铵溶液为异丙托溴铵和硫酸沙丁胺醇的复合制剂,主要通过激动支气管平滑肌的β2受体及拮抗交感神经的胆碱能受体,扩张支气管平滑肌,用于治疗气道阻塞性疾病的可逆性支气管痉挛, 并改善慢性阻塞性肺疾病患者的喘息症状.其中异丙托溴铵为短效抗胆碱药物,硫酸沙丁胺醇具有短效速效激动β2受体的作用,可用于缓解急性气管痉挛的发作.常见的药物不良反应为口干、恶心、呕吐、眩晕、头痛、心动过速及骨骼肌震颤等,较少出现眼痛、胃动力障碍和尿潴留.     

噻托溴铵治疗稳定期慢性阻塞性肺疾病的疗效评价

噻托溴铵是新一代治疗慢性阻塞性肺疾病(COPD)的吸入型长效抗胆碱药物,通过选择性作用于M1和M3受体,扩张支气管,疗效持续,每天只需使用一次.UPLIFT研究结果进一步证实,长期规律使用噻托溴铵能够改善中重度、极重度稳定期COPD患者肺功能情况,缓解症状、提高运动耐量及改善生活质量,延长急性发作的时间间隔、减少急性加重发作次数,降低COPD患者死亡率,具有良好的安全性.     

噻托溴铵治疗慢性阻塞性肺疾病随机双盲双模拟对照临床试验

目的 评价噻托溴铵治疗慢性阻塞性肺疾病（COPD）的疗效和安全性。方法 用双盲双模拟随机对照方法，观察了COPD病人吸人噻托溴铵（21例，18μg，qd）与异丙托溴铵（23例，40μg q6h）的支气管扩张作用及安全性。结果 用药后，噻托溴铵组病人第1秒用力呼气容积（FEV1）和用力肺活量（FVC）均显著增加（P〈0．001）；2，3h时，FEV1的增加较异丙托溴铵组有显著性差异（P〈0．05）；治疗2，4周时，噻托溴铵组病人FEV，谷值明显上升（P〈0.01），较异丙托溴铵组分别高0．14，0．05L。2组药物不良反应发生率无统计学差异。结论 噻托溴铵是治疗COPD病人有效和安全的支气管扩张药物，疗效和用法均优于异丙托溴铵。     

吸入噻托溴铵干粉与异丙托溴铵定量气雾剂治疗慢性阻塞性肺疾病的疗效观察

目的:观察吸入噻托溴铵干粉与异丙托溴铵定量气雾剂在治疗慢性阻塞性肺疾病方面的临床效果.方法:从我院2014年2月~2016年1月收治的慢性阻塞性肺疾病患者中随机选取70例,按照自愿原则将其分别纳入研究组与对照组,各35例.研究组给予噻托溴铵干粉剂吸入治疗,对照组应用异丙托溴铵定量气雾剂治疗.连续用药4周后,观察患者给药前及给药后的肺功能.结果:持续用药4周后,研究组FVC、FEV1、FEV1%、PaO2、PaCO2各项肺功能指标均要明显优于对照组,存在显著差异,均具有统计学意义(P<0.05).结论:噻托溴铵干粉剂吸入治疗慢性阻塞性肺疾病能够发挥更好的支气管扩张效果,且患者的耐受性好,其安全性基本等同于异丙托溴铵,具有较高的应用价值.     

噻托溴铵治疗慢性阻塞性肺疾病作用机制的研究进展

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

噻托溴铵对慢性阻塞性肺疾病患者肺功能的影响

目的 评价噻托溴铵治疗慢性阻塞性肺疾病(COPD)的疗效和安全性.方法 采用随机、双盲、平行对照方法,对轻、中度稳定期COPD患者吸入噻托溴铵(20例)与异丙托溴铵(20例)治疗4周,通过检测肺功能,观察其临床疗效.结果 用药后,噻托溴铵组患者第1秒用力呼气容积(FEV1)和用力肺活量(FVC)均显著增加(P<0.01);4周时,FEV1的增加较异丙托溴铵组差异有统计学意义(P<0.05);两组应急药物应用情况及药物不良反应发生率差异无统计学意义(P<0.05).结论 噻托溴铵是治疗COPD患者有效和安全的支气管扩张药物,疗效显著而且安全可靠.     

Anticholinergic agents in asthma and COPD

Anticholinergic agents have important uses as bronchodilators for the treatment of obstructive airway diseases, both asthma and, more particularly, chronic obstructive pulmonary disease (COPD). Those in approved clinical use are synthetic quaternary ammonium congeners of atropine, and include ipratropium bromide, oxitropium bromide, and tiotropium bromide, each of which is very poorly absorbed when given by inhalation. Ipratropium and oxitropium have relatively short durations of action (4-8 h). They have been widely used for many years, either alone or in combination with short-acting beta-adrenergic agents such as albuterol and fenoterol, for both maintenance treatment of stable disease and for acute exacerbations of airway obstruction. Tiotropium, which was introduced in the early 2000s, has a duration of action of at least 1-2 days making it suitable for once-daily maintenance treatment of COPD. All of the above agents have a wide therapeutic margin and are safe and well tolerated by patients.     

Anticholinergic drugs in the therapy of obstructive airway diseases

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

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

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

噻托溴铵治疗慢性阻塞性肺病的进展

噻托溴铵（tiotropium bromide）是一个新型的治疗慢性阻塞性肺病（COPD）的吸入型支气管扩张药物,通过与M3受体结合阻滞乙酰胆碱的作用从而缓解支气管平滑肌的痉挛,吸入一次疗效持续24h以上.临床试验结果表明该药对中重度COPD具有良好疗效,在改善呼吸困难、生活质量、减少住院次数方面优于沙美特罗,噻托溴铵qd对支气管的舒张作用明显好于溴化异丙托品qid和沙美特罗bid,且能改善通气功能和肺容积,耐受性和安全性较好.主要不良反应为口干.     

Tiotropium bromide

Tiotropium bromide is a new long-lasting anticholinergic drug which, like ipratropium bromide, is a quaternary ammonium derivative. It binds with high affinity to muscarinic receptors but dissociates very slowly from M(1)- and M(3)-muscarinic receptors. Pharmacology studies have demonstrated a prolonged protective effect against cholinergic agonists and cholinergic nerve stimulation in animal and human airways. In Phase II studies single inhaled doses of tiotropium bromide have a bronchodilator and bronchoprotective effect in asthmatic and chronic obstructive pulmonary disease (COPD) patients of over 24 h. In Phase III studies, once daily inhaled tiotropium is an effective bronchodilator in COPD patients, giving great improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. The drug is well-tolerated and the only side effect of note is dryness of the mouth which occurs in approximately 10% of patients. Since, anticholinergics are the bronchodilators of choice in COPD it is likely that tiotropium bromide will become the most widely used bronchodilator for COPD patients in the future.     

长、短效抗胆碱能药物对轻中度稳定期COPD患者的疗效比较

目的:比较异丙托溴铵气雾剂、噻托溴铵干粉剂治疗轻、中度稳定期慢性阻塞性肺疾病(COPD)患者的疗效。方法:采用随机、单盲、平行对照试验设计,将42例稳定期COPD患者,随机分为噻托溴铵组(每次18μg,qd,吸入)和异丙托溴铵组(每次40μg,qid,吸入),2组疗程均为12周。结果:治疗6周末,2组间肺功能比较差异无统计学意义(P>0.05);治疗12周末,噻托溴铵组第1秒用力肺活量(FEV1)、吸气峰流速(PEF)明显改善,与异丙托溴铵组比较,差异有统计学意义(P<0.05);噻托溴铵组症状评分、机体状况评分及精神状态评分均较异丙托溴铵组显著下降(P<0.05)。结论:噻托溴铵较异丙托溴铵更能改善轻、中度稳定期COPD患者的肺功能,并提高患者的生活质量。     

UPLIFT Study: the effects of long-term therapy with inhaled tiotropium in chronic obstructive pulmonary disease

Background: In chronic obstructive pulmonary disease (COPD), inhaled tiotropium bromide, a long-acting anticholinergic, has been shown to exert a sustained bronchodilator effect and to be superior to ipratropium bromide, a short-acting formulation of the same pharmacological class. Objective: To discuss the effects of long-term therapy with tiotropium in COPD. Methods/results: Analysis of efficacy and safety data on tiotropium from a 4-year randomized placebo controlled study performed in moderate to very severe COPD patients. Tiotropium was found to reduce significantly COPD-related morbidity, to improve health-related quality of life (HRQoL) irrespective of disease severity and to slow significantly lung function decline in patients not using inhaled corticosteroids or other long-acting bronchodilators. The safety profile – and in particular cardiovascular safety – of tiotropium was good. Conclusions: Tiotropium bromide, alone or in combination with other inhaled therapies, can maintain an adequate control of COPD on a long-term basis.     

Tiotropium bromide

Tiotropium bromide is an anticholinergic bronchodilator that antagonises muscarinic M(1), M(2) and M(3) receptors. It dissociates more slowly from M(1) receptors and, importantly, from M(3) receptors (which are located in bronchial smooth muscle) than from M(2) receptors and subsequently has a long duration of action permitting once-daily administration. In patients with chronic obstructive pulmonary disease (COPD), tiotropium 18microg once daily significantly improved lung function compared with placebo and ipratropium 40microg four times daily in 1-year trials or salmeterol 50microg twice daily in a 6-month study. The incidence of COPD exacerbations decreased and use of rescue medication was lower with tiotropium compared with placebo or ipratropium. There was no evidence of tachyphylaxis during 1-year treatment with tiotropium. Compared with placebo, salmeterol and ipratropium, tiotropium produced significant improvements in patients' perception of dyspnoea and health-related quality of life. Tiotropium is generally well tolerated; dry mouth is the most common drug-related adverse event, occurring in about 10 to 16% of patients in clinical trials.     

Tiotropium bromide

Tiotropium bromide is a new long-lasting anticholinergic drug which, like ipratropium bromide, is a quaternary ammonium derivative. It binds with high affinity to muscarinic receptors but dissociates very slowly from M₁- and M₃-muscarinic receptors. Pharmacology studies have demonstrated a prolonged protective effect against cholinergic agonists and cholinergic nerve stimulation in animal and human airways. In Phase II studies single inhaled doses of tiotropium bromide have a bronchodilator and bronchoprotective effect in asthmatic and chronic obstructive pulmonary disease (COPD) patients of over 24 h. In Phase III studies, once daily inhaled tiotropium is an effective bronchodilator in COPD patients, giving great improvement in lung function and reduction in symptoms than ipratropium bromide given four times daily. The drug is well-tolerated and the only side effect of note is dryness of the mouth which occurs in approximately 10% of patients. Since, anticholinergics are the bronchodilators of choice in COPD it is likely that tiotropium bromide will become the most widely used bronchodilator for COPD patients in the future.     

Muscarinic antagonists in early stage clinical development for the treatment of asthma

Introduction: Parasympathetic neurons utilize the neurotransmitter acetylcholine to modulate and constrict airway smooth muscles at the muscarinic acetylcholine receptor. Inhaled agents that antagonize the muscarinic (M) acetylcholine receptor, particularly airway M3 receptors, have increasing data supporting use in persistent asthma.

Areas covered: Use of inhaled long-acting muscarinic antagonists (LAMA) in asthma is explored. The LAMA tiotropium is approved for maintenance in symptomatic asthma patients despite the use of inhaled corticosteroids (ICS), leukotriene receptor antagonists (LTRA) and/or long-acting beta₂ agonists (LABA). LAMA agents currently approved for chronic obstructive pulmonary disease (COPD) include tiotropium, glycopyrrolate/glycopyrronium, umeclidinium and aclidinium. These agents are reviewed for their pharmacological differences and clinical trials in asthma.

Expert opinion: Current guidelines place inhaled LAMAs as adjunctive maintenance therapy in symptomatic asthma not controlled by an ICS and/or a LTRA. LAMA agents will play an increasing role in moderate to severe symptomatic asthma patients. Additional LAMA agents are likely to seek a maintenance indication perhaps as a combined inhaler with an ICS or with an ICS and a LABA. These fixed-dose combination inhalers are being tested in COPD and asthma patients. Once-a-day dosing of inhaled LAMA agents in severe asthma patients will likely become the future standard.