溴化异丙托品对哮喘和COPD的支气管扩张作用

目的　比较溴化异丙托品气雾剂 (IPB)与沙丁胺醇 (SA)气雾剂对哮喘和慢性阻塞性肺疾病 (COPD)患者的支气管扩张作用。方法　对 15例急性发作期哮喘患者和 16例急性加重期慢性阻塞性肺疾病 (COPD)患者于试验前及试验后分别测定第一秒用力呼气容积 (FEV1 )。结果　哮喘患者使用 SA前后 FEV1 分别为 1.86± 0 .40和 2 .14± 0 .42 L(P<0 .0 0 1) ,使用 IPB前后 FEV1分别为 1.85± 0 .36和 2 .0 0± 0 .37L (P<0 .0 0 1) ,使用 SA后 FEV1 的改变较 IPB更显著 (P<0 .0 1)。COPD患者使用 SA前后 FEV1分别为 1.0 5± 0 .45和 1.19± 0 .5 0 L(P<0 .0 0 1) ,使用 IPB前后 FEV1 分别为 1.0 6± 0 .42和 1.2 4± 0 .5 0 L(P<0 .0 0 1) ,但两组的改善无明显差异。结论　 SA和 IPB对哮喘和 COPD均有较好的支扩作用 ,IPB对哮喘患者的支扩作用不及 SA,而对于 COPD患者两者的支扩作用无明显差异。     

Influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in COPD

We examined the influence of higher than conventional doses of oxitropium bromide on formoterol-induced bronchodilation in patients with partially reversible stable COPD. Twenty outpatients inhaled one or two puffs of formoterol (12 microg puff(-1)), or placebo. Two hours after inhalation, a dose-response curve to inhaled oxitropium bromide (100 microg puff(-1)) or placebo was constructed using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 microg oxitropium bromide. Doses were given at 20-min intervals and measurements made 15 min after each dose. On six separate days, all patients received one of the following: (1) formoterol 12 microg + oxitropium bromide 600 microg, (2) formoterol 12 microg + placebo, (3) formoterol 24 microg + oxitropium bromide 600 microg, (4) formoterol 24 microg + placebo, (5) placebo + oxitropium bromide 600 microg, or (6) placebo + placebo. Both formoterol 12 microg and 24 microg induced a good bronchodilation (formoterol 12 microg, 0.19-0.20 l; formoterol 24 microg 0.22-0.24 l). The dose-response curve of oxitropium, but not placebo, showed an evident increase in FEV1, with a further significant increase of respectively 0.087 l and 0.082 l after the formoterol 12 microg and formoterol 24 microg pre-treatment. This study shows that improved pulmonary function in patients with stable COPD may be achieved by adding oxitropium 400-600 microg to formoterol. There is not much difference in bronchodilation between combining oxitropium with formoterol 12 microg or 24 microg. In any case, formoterol 24 microg alone seems sufficient to achieve the same bronchodilation induced by oxitropium 600 microg alone in most patients.     

慢性阻塞性肺疾病与支气管哮喘患者支气管舒张反应曲线的比较

目的 建立慢性阻塞性肺疾病(COPD)和支气管哮喘(以下简称哮喘)支气管舒张反应曲线,探讨COPD和哮喘大、小气道扩张的特点.方法 动态观测2004年5月至2005年8月中山大学附属第五医院收治的COPD和哮喘患者吸入福莫特罗前后肺通气功能的变化.结果 COPD患者吸入福莫特罗后,第1秒用力呼气量(FEV1)和用力肺活量(FVC)的支气管舒张反应曲线在15 min内升高,120 min后开始下降,1秒率(FEV1/FVC)支气管舒张反应曲线呈波浪样变化,呼出50%肺活量时最大呼气流量(FEF50)与最大呼气中段流量(FEF75/25)的支气管舒张反应曲线在30 min内升高后即开始下降;FEV1,FVC,FEF50随时间点变化的拟合二次曲线模型方程差异有显著性意义(P＜0.05).哮喘患者FEV1,FVC,FEV1/FVC,FEF50,FEF75和FEF75/25的支气管舒张反应曲线在15～30 min内升高明显,120 min后开始下降;FEV1,FEV1/FVC,FEF75/25随时间点变化的拟合二次曲线模型方程差异有显著性意义(P＜0.05).结论 COPD与哮喘患者大、小气道舒张具有不同的特点,支气管舒张反应曲线可以用来鉴别两者.     

COPD: maximization of bronchodilation

The most recent guidelines define COPD in a multidimensional way, nevertheless the diagnosis is still linked to the limitation of airflow, usually measured by the reduction in the FEV₁/FVC ratio below 70%. However, the severity of obstruction is not directly correlated to symptoms or to invalidity determined by COPD. Thus, besides respiratory function, COPD should be evaluated based on symptoms, frequency and severity of exacerbations, patient’s functional status and health related quality of life (HRQoL). Therapy is mainly aimed at increasing exercise tolerance and reducing dyspnea, with improvement of daily activities and HRQoL. This can be accomplished by a drug-induced reduction of pulmonary hyperinflation and exacerbations frequency and severity. All guidelines recommend bronchodilators as baseline therapy for all stages of COPD, and long-acting inhaled bronchodilators, both beta-2 agonist (LABA) and antimuscarinic (LAMA) drugs, are the most effective in regular treatment in the clinically stable phase. The effectiveness of bronchodilators should be evaluated in terms of functional (relief of bronchial obstruction and pulmonary hyperinflation), symptomatic (exercise tolerance and HRQoL), and clinical improvement (reduction in number or severity of exacerbations), while the absence of a spirometric response is not a reason for interrupting treatment, if there is subjective improvement in symptoms. Because LABA and LAMA act via different mechanisms of action, when administered in combination they can exert additional effects, thus optimizing (i.e. maximizing) sustained bronchodilation in COPD patients with severe airflow limitation, who cannot benefit (or can get only partial benefit) by therapy with a single bronchodilator. Recently, a fixed combination of ultra LABA/LAMA (indacaterol/glycopyrronium) has shown that it is possible to get a stable and persistent bronchodilation, which can help in avoiding undesirable fluctuations of bronchial calibre.     

Reproducibility of forced inspiratory and expiratory volumes after bronchodilation in patients with COPD or asthma

The aim of the present study was to assess the reproducibility of changes in forced inspiratory volumes after bronchodilator inhalation. Thirteen patients with chronic obstructive pulmonary disease (COPD) (FEV1, 32-75%pred) and 10 patients with asthma (FEV1, 43-75%pred) inhaled either 200 microg fenoterol or 200 microg oxitropium bromide or placebo, each of them on three occasions, on nine different days in a randomised, cross-over, double-blind fashion. Forced expiratory (FEV1) and inspiratory (FIV1) volumes were measured before and 30 min after inhalation. In patients with COPD, the increase in FEV1 (coefficient of variation) was 221 ml (43%) after fenoterol and 235 ml (33%) after oxitropium; changes in FIV1 were 301 ml (45%) and 360 ml (29%). In patients with asthma, FEV1 improved by 618 ml (26%) and 482 ml (25%), FIV1 by 553 ml (41%) and 475 ml (23%). In less severe COPD or asthma, the reduction in dyspnoea was associated with the improvements in both FIV1 and FEV1, but in severe COPD with the improvement in FIV1 only. The data demonstrate that, at least in terms of relative changes, the reproducibility of bronchodilator responses in terms of FIV1 is similar to that of FEV1 and they underline the assertion of FIV1 being a sensible parameter particularly in severe COPD.     

Additive benefits of tiotropium in COPD patients treated with long-acting beta agonists and corticosteroids

OBJECTIVE AND BACKGROUND: The addition of an alternative class of long-acting bronchodilator is recommended for COPD patients who do not respond satisfactorily to monotherapy. The aim of this study was to investigate the additive benefit of tiotropium in severe COPD and to establish whether the improvement in lung function in these patients can be predicted from their acute bronchodilator response to ipratropium or salbutamol. METHODOLOGY: Forty-six patients with severe COPD treated with inhaled long-acting beta(2) agonists and corticosteroids (LABA/CS) were enrolled. Their prebronchodilator FEV(1) was less than 50% of the predicted value. Tiotropium (18 microg, once daily) was added via a dry-powder inhaler device. After a month of treatment, tiotropium was stopped but their previous medication was continued. Patients were reassessed a month later. Acute bronchodilator response to ipratropium and salbutamol was assessed prior to tiotropium treatment. Pulmonary function and health status were evaluated. RESULTS: Adding tiotropium significantly improved FVC, FEV(1) and inspiratory capacity (IC). The increase in FVC was significantly associated with an increase in IC (r = 0.36, P = 0.019) and a decrease in residual volume (r =-0.56, P < 0.001). Total scores of St. George Respiratory Questionnaire scores were significantly improved after adding tiotropium treatment (P < 0.001). After tiotropium withdrawal, FVC, FEV(1) and IC decreased markedly. Bronchodilator response to ipratropium did not predict the tiotropium-mediated improvement in FEV(1) or FVC. CONCLUSIONS: Adding tiotropium to inhaled LABA/CS can yield clinical benefits in lung function and improved quality of life in COPD patients, as both drugs act through separate yet complementary pathways to maintain airway calibre.     

Bronchodilating effect of combined therapy with ipratropium bromide and ondansetron in patients with COPD

The objectives of this study were to determine the effect of single and repeat dosing with oral ondansetron, a 5-HT3-specific receptor blocker, on the degree and duration of bronchodilation induced by inhaled ipratropium bromide in patients with COPD. Five clinics and university medical centers in four countries participated in the study; 47 patients with COPD were randomized to treatment; 44 completed all treatments. Patients had a baseline (pre-bronchodilator) FEV1>1L and post-bronchodilator (200 mcg salbutamol) FEV1<90% of predicted, with FEV1 reversibility (to 80 mcg inhaled ipratropium bromide and 400 mcg salbutamol) of at least 12% or 200 mL over baseline. The study was divided into two parts. In Part A, each patient received in a random order, four-way crossover manner, single doses of ondansetron placebo (oral) plus ipratropium bromide placebo (inhaled), ondansetron placebo plus ipratropium bromide 40 mcg inhaled via MDI, ondansetron 24 mg oral plus ipratropium bromide placebo and ondansetron 24 mg plus ipratropium bromide 40 mcg. In Part B, each patient received in a random order, two-way crossover manner, ipratropium bromide 40 mcg tid via MDI plus ondansetron 8 mg oral, qid, for 2 days; on day 3 patients received a single dose of ipratropium bromide 40 mcg plus 8 mg oral ondansetron. Alternatively, patients received ipratropium bromide via MDI and oral ondansetron placebo, as described above. Statistically significant differences in weighted mean FEV1 (0-6h), peak FEV1 and FEV1 determined 6h post-dose were noted comparing ipratropium bromide to placebo. Similar positive results were observed for sGaw and FVC. Addition of ondansetron to ipratropium bromide did not significantly modify values obtained with ipratropium alone. Ipratropium bromide induced a marked bronchodilation, compared to placebo. Addition of ondansetron (single or repeated doses) did not significantly increase the degree or duration of bronchodilation induced by ipratropium alone. sGaw was consistently more sensitive than FEV1 in measuring extent and duration of bronchodilation.     

Efficacy and Safety of a 12-week Treatment with Twice-daily Aclidinium Bromide in COPD Patients (ACCORD COPD I)

Abstract

Background: This Phase III study evaluated the efficacy and safety of twice-daily aclidinium 200 μg and 400 μg versus placebo in the treatment of moderate-to-severe COPD. Methods: In this 12-week, double-blind, multicenter trial, patients were randomized (1:1:1) to inhaled twice-daily aclidinium 200 μg, aclidinium 400 μg, or placebo. Primary and secondary endpoints were changes from baseline in trough FEV1 and peak FEV1 at Week 12, respectively. Health status (St. George's Respiratory Questionnaire [SGRQ]), COPD symptoms (Transitional Dyspnea Index [TDI], night and early morning symptoms), and safety were also assessed. Results: A total of 561 patients (mean age, 64 ± 9 years) with a mean baseline FEV1 of 1.36 ± 0.54 L (47.2% of predicted value) were randomized. At Week 12, aclidinium 200 μg and 400 μg showed significant improvements from baseline in mean (95% CI) trough FEV1 compared with placebo by 86 (45, 127) mL and 124 (83,164) mL, respectively, and in peak FEV1 by 146 (101, 190) mL and 192 (148, 236) mL, respectively (p ≤ 0.0001 for all). Both aclidinium doses also provided significant improvements in SGRQ, TDI and almost all COPD symptom scores compared with placebo (p < 0.05 for all). Incidences of adverse events (AEs) were similar across treatment groups. The incidence of anticholinergic AEs was low and similar across groups (dry mouth: 0.5%–1.6%; constipation: 0%-1.1%). Conclusions: Treatment of moderate-to-severe COPD patients with twice-daily aclidinium 200 μg and 400 μg was associated with significant improvements in bronchodilation, health status, and COPD symptoms. Both doses were well tolerated and had safety profiles similar to placebo.

Trial Registration: This ACCORD I study (AClidinium in Chronic Obstructive Respiratory Disease I) was registered on clinicaltrials.gov (NCT00891462) as “Efficacy and Safety of Aclidinium Bromide for Treatment of Moderate to Severe Chronic Obstructive Pulmonary Disease (COPD)”.     

Ipratropium bromide hydrofluoroalkane inhalation aerosol is safe and effective in patients with COPD

STUDY OBJECTIVE: To compare the efficacy and safety of ipratropium bromide reformulated with the chlorofluorocarbon (CFC)-free propellant hydrofluoroalkane (HFA)-134a (ipratropium bromide HFA) to that of the marketed ipratropium bromide inhalation aerosol (containing CFC) in patients with COPD. DESIGN: This was a randomized, double-blind, parallel-group, placebo-controlled, multicenter trial. The primary efficacy parameter was acute bronchodilator response. The primary end points were peak change in FEV(1) from baseline and area under the response-time curve. SETTING: Thirty-one clinical centers in the United States participated in this project. PATIENTS: A total of 507 patients with moderate-to-severe COPD were randomized, and 444 patients completed the trial. INTERVENTIONS: Twelve weeks of treatment four times daily with one of the following: ipratropium bromide HFA, 42 microg; ipratropium bromide HFA, 84 microg; HFA placebo; ipratropium bromide inhalation aerosol, 42 microg; or CFC placebo. Measurements and results: Patients in all active treatment groups had significant bronchodilator responses as shown by increases in mean FEV(1) from baseline of at least 15%. Bronchodilator response in all active treatment groups was also significantly more than their respective placebo treatments based on FEV(1), area under the time-response curve from 0 to 6 h, and peak response. FVC results were similar to those seen with FEV(1). There were no significant differences in adverse events, laboratory findings, or ECG findings among the treatment groups. CONCLUSIONS: Ipratropium bromide HFA, 42 and mgr;g, provided bronchodilation comparable to the marketed ipratropium bromide CFC, 42 and mgr;g, over 12 weeks of regular use.     

异丙托溴铵对COPD并发呼吸衰竭BiPAP患者的影响

目的分析异丙托溴铵对慢性阻塞性肺疾病(COPD)并发呼吸衰竭双水平气道正压力通气(BiPAP)辅助通气患者免疫功能、血清降钙素原(PCT)表达、活动耐量的影响。 方法选择2019年1月至2021年4月我院收治的86例COPD并发呼吸衰竭患者,随机分为对照组44例和观察组42例,对照组在常规治疗基础上给予BiPAP辅助通气,观察组在对照组基础上采用异丙托溴铵治疗,比较两组治疗前后T淋巴细胞亚群、免疫球蛋白、PCT水平、肺功能、病情严重程度及活动耐量差异,并分析PCT与肺功能、CAT评分、mMRC评分、6MWD相关性。 结果治疗后两组CD4⁺、CD4⁺/CD8⁺、IgA、IgM、IgG均升高,CD8⁺均降低(P>0.05);治疗后两组PCT、CAT评分、mMRC评分均下降,FEV₁、FEV₁/FVC均升高,且观察组改善优于对照组(P<0.05);治疗后观察组6MWD高于对照组(P<0.05);Pearson相关性分析显示,PCT与FEV₁、FEV₁/FVC、6MWD呈负相关(r<0,P<0.05),与CAT评分、mMRC评分呈正相关(r>0,P<0.05)。 结论异丙托溴铵可能通过抗炎作用提高COPD并发呼吸衰竭BiPAP辅助通气患者肺功能及活动耐量,降低PCT表达。     

Respimat (a new soft mist inhaler) delivering fenoterol plus ipratropium bromide provides equivalent bronchodilation at half the cumulative dose compared with a conventional metered dose inhaler in asthmatic patients

BACKGROUND: Respimat, a possible alternative to the conventional metered dose inhaler (MDI), is a novel, reusable, propellant-free, multidose soft mist inhaler. Respimat slowly releases a metered dose of active substance as a soft mist with a high proportion of the dose in the fine particle fraction, leading to improved lung deposition following inhalation when compared with the conventional MDI. OBJECTIVES AND METHODS: The equipotent bronchodilating efficacy and safety of a combination of fenoterol hydrobromide and ipratropium bromide (F/I) in cumulative doses delivered by either Respimat or pressurised MDI was assessed in a randomised, controlled, double-blind (within device) 4-way crossover study. Forty-three patients with stable asthma (mean FEV(1) 62% predicted) responsive to F/I inhaled cumulatively 16 puffs on each of 4 test days (1 + 1 + 2 + 4 + 8 puffs at 50-min intervals) via Respimat delivering 50/20, 25/20 or 25/10 microg F/I per puff or via MDI delivering 50/20 microg F/I per puff. RESULTS: Cumulative doses of 400/160 and 400/320 microg F/I via Respimat produced bronchodilation (evaluated by average increase in FEV(1) 45-245 min after first inhalation) equivalent to that achieved with a cumulative 800/320 microg F/I via MDI (mean increase in FEV(1) above baseline 0.76, 0.73 and 0.71 litres, respectively). The tolerability of the F/I combination via Respimat was also comparable to that of twice the dose delivered via MDI. CONCLUSION: Therefore, a fenoterol hydrobromide/ipratropium bromide combination delivered by Respimat is as safe and effective as the MDI at half the cumulative dose, on acute administration to patients with asthma.     

Acute effects of higher than standard doses of salbutamol and ipratropium on tiotropium-induced bronchodilation in patients with stable COPD

Knowledge on the effects of the additive bronchodilatory effects of short-acting agents on the top of the effect of long-acting bronchodilators is limited. In this trial, we examined the influence of higher than conventional doses of the short-acting inhaled β₂-adrenergic agent salbutamol and the short-acting anticholinergic drug ipratropium bromide on bronchodilation induced by a regular treatment with the long-acting anticholinergic drug tiotropium 18 μg/day in 30 patients with stable COPD. On 3 separate days, a dose-response curve to inhaled salbutamol (100 μg puff-1), ipratropium bromide (20 μg puff-1) or placebo was constructed 3 h after inhalation of the last dose of tiotropium, using one puff, one puff, two puffs and two puffs, for a total cumulative dose of 600 μg salbutamol or 120 μg ipratropium bromide. Doses were given at 30-min intervals and measurements made 15 min after each dose. At the highest cumulative dose, salbutamol showed a trend to be more effective than ipratropium bromide in improving FEV₁ (0.157 L vs 0.125 L), and reducing sRaw (?4.52 kPa/s vs 3.57 kPa/s), although the differences between the two treatments were always not significant (p > 0.05), whereas there was no substantial difference between the two drugs in changing FVC (0.179 L vs 0.168 L), IC (0.254 L vs 0.240 L), TGV (?0.444 L vs ?0.441 L), TLC (?0.334 L vs ?0.318 L) and RV (?0.467 L vs ?0.498 L). Both drugs did not affect heart rate and SpO₂. Our results indicate that there is not much difference in bronchodilation between adding higher than conventional doses of salbutamol or ipratropium bromide to tiotropium in patients with stable COPD. Effective improvement of the pulmonary function may be achieved in such a type of patients by adding salbutamol 600 μg or ipratropium bromide 120 μg to regular tiotropium. These is an interesting finding mainly for those COPD patients suffering from cardiovascular co-morbidities that are at highest risk of myocardial infarction, congestive heart failure, cardiac arrest and sudden cardiac death when treated with elevated doses of a β₂-agonist (EudraCT number: 2007-001597-82).     

Survival of COPD patients using inhaled corticosteroids and long-acting beta agonists

We conducted a historical cohort study to examine the relationship between survival and use of inhaled corticosteroids (ICS) and/or long-acting beta agonists (LABA) in patients with chronic obstructive pulmonary disease (COPD). All COPD patients aged 40 years who were enrolled in one of two regional managed care organizations during 1995-2000, and who had 90 days use of an ICS and/or LABA (N=1288) or of a short-acting bronchodilator (N=397), were identified. Of patients treated with ICS and/or LABA, 14.4% died during the follow-up period, as compared to 28.2% of comparison patients (P<0.01). In a Cox proportional hazards model that controlled for age, sex, comorbidities, COPD severity, and asthma status, a reduced risk of death was found for ICS treatment (HR 0.59 [95% CI 0.46-0.78]), LABA (HR 0.55 [0.34-0.89]), and ICS plus LABA treatment (HR 0.34 [0.21-0.56]). A second model that excluded any patient who also had an ICD-9 code for asthma (N=840) still found improved survival among those using the combination of ICS plus LABA (HR 0.35 [CI 0.17-0.71]). Additional analyses that varied the exposure criteria also found a consistent treatment benefit. Inclusion of ICS or bronchodilator treatment during the follow-up period as a time-dependent function appears to negate the survival benefit; however, the underlying assumptions for valid time-dependent modeling are clearly violated in this situation. In conclusion, we found that COPD patients who used ICS alone or in combination with LABA had substantially improved survival even after adjustment for asthma and other confounding factors.