Maesen F P, Smeets J J, Sledsens T J, Wald F D, Cornelissen P J
Department of Respiratory Diseases, De Wever Hospital, Heerlen, The Netherlands.
Eur Respir J. 1995 Sep;8(9):1506-13.
The objective of the present study was to investigate the dose-dependent bronchodilator efficacy and duration of action of the newly developed antimuscarinic agent tiotropium bromide in patients with chronic obstructive pulmonary disease (COPD). In a randomized, double-blind, placebo-controlled, crossover design, patients inhaled single doses of 10-80 micrograms tiotropium bromide and placebo, formulated in lactose powder capsules. The washout period between test doses was 72 h. Thirty five patients were enrolled in the trial (32 males and 3 females; mean age 64 yrs). Baseline forced expiratory volume in one second (FEV1) (mean 1.34 L) was less than 65% of predicted and was < 70% of forced vital capacity (FVC). All subjects had a smoking history of more than 10 pack-years. The mean reversibility of FEV1 after inhalation of 40 micrograms ipratropium bromide was 28%. Pulmonary function testing was performed before and at regular time intervals for up to 32 h after test drug administration. Compared to placebo, tiotropium bromide produced significant improvements in FEV1, FVC, peak expiratory flow rate (PEFR) and forced mid-expiratory flow (FEF25-75%). The bronchodilator response was almost immediate; peak improvement in FEV1 was reached 1-4 h after test drug inhalation, and the duration of action extended to 32 h after the 20, 40 and 80 micrograms doses. A clear dose-response relationship was seen for peak FEV1 and for the average FEV1 over differing time periods during the 32 h observation period, 80 micrograms of test drug being superior to the 10 micrograms dose. Peak improvement in FEV1 ranged 19-26% of test-day baseline for tiotropium bromide doses compared to 16% for placebo. The large improvement for placebo is probably due to carry-over effect which was significant. After excluding carry-over effect, the peak response to placebo decreased to 11%, whilst for tiotropium bromide doses it ranged 20-25%; standard error for mean difference was about 4%. There was no evidence of systemic anticholinergic effects. In this population of patients with COPD, tiotropium bromide was found to be a safe and long-acting bronchodilator, demonstrating a clear dose-response relationship following single dose administration.
本研究的目的是调查新开发的抗胆碱能药物噻托溴铵在慢性阻塞性肺疾病（COPD）患者中的剂量依赖性支气管扩张疗效及作用持续时间。在一项随机、双盲、安慰剂对照的交叉设计中，患者吸入单剂量10 - 80微克的噻托溴铵及乳糖粉胶囊剂型的安慰剂。试验剂量之间的洗脱期为72小时。35名患者参与了该试验（32名男性和3名女性；平均年龄64岁）。一秒用力呼气容积（FEV1）基线值（平均1.34升）低于预测值的65%，且低于用力肺活量（FVC）的70%。所有受试者的吸烟史均超过10包年。吸入40微克异丙托溴铵后FEV1的平均可逆性为28%。在给予试验药物前及给药后长达32小时的定期时间间隔进行肺功能测试。与安慰剂相比，噻托溴铵使FEV1、FVC、呼气峰值流速（PEFR）和用力呼气中期流速（FEF25 - 75%）有显著改善。支气管扩张反应几乎是即时的；吸入试验药物后1 - 4小时达到FEV1的峰值改善，20、40和80微克剂量后的作用持续时间延长至32小时。在32小时观察期内，FEV1峰值及不同时间段的平均FEV1均呈现明确的剂量 - 反应关系，80微克试验药物优于10微克剂量。与安慰剂相比，噻托溴铵剂量使FEV1的峰值改善幅度为试验日基线的19 - 26%，而安慰剂为16%。安慰剂的较大改善可能是由于显著的残留效应。排除残留效应后，安慰剂的峰值反应降至11%，而噻托溴铵剂量的峰值反应范围为20 - 25%；平均差异的标准误差约为4%。没有证据表明存在全身性抗胆碱能效应。在这群COPD患者中，发现噻托溴铵是一种安全且长效的支气管扩张剂，单次给药后呈现明确的剂量 - 反应关系。
