62 Thorax 1995;50:62-66 Comparative dose-response study of three anticholinergic agents and fenoterol using a Thorax: first published as 10.1136/thx.50.1.62 on 1 January 1995. Downloaded from metered dose inhaler in patients with chronic obstructive pulmonary disease Akihiko Ikeda, Koichi Nishimura, Hiroshi Koyama, Takateru Izumi Abstract either ipratropium bromide or flutropium Background - Inhaled anticholinergics bromide when used at doses of less than and P agonists are widely used in the treat- six puffs, without apparent side effects. ment of patients with chronic obstructive There were, however, no differences in pulmonary disease (COPD). However, maximal response between these drugs. dosage requirements have not been thor- Fenoterol may have a greater peak bron- oughly evaluated and comparative dose- chodilator effect than the anticholinergic response data for these agents are limited. agents but it causes more adverse effects, Methods - Twenty men with stable COPD even at lower doses. Depending upon the ofmean (SD) age 69-4 (5.8) years and FEVy balance between efficacy and side effects, 0 93 (0.38) litres were studied in ran- oxitropium bromide may be preferred in domised, double blind, crossover, placebo the treatment of patients with COPD. controlled experiments. All ofthe patients (Thorax 1995;50:62-66) received two, four, eight, and 16 puffs of ipratropium bromide (20 tgIpuff), flu- Keywords: chronic obstructive pulmonary disease, ip- ratropium bromide, oxitropium bromide, flutropium tropium bromide (30 tgIpuff), oxitropium bromide, fenoterol. bromide (100 sgIpuff), fenoterol (200 dgi puff), or placebo in random order on five separate days. Doses were administered by a metered dose inhaler at intervals of http://thorax.bmj.com/ 60 minutes to give cumulative doses oftwo, The appropriate use of bronchodilator drugs six, 14, and 30 puffs. Five mg of nebulised improves airflow limitation and reduces dys- salbutamol was administered 60 minutes pnoea in patients with chronic obstructive pul- after the patient had received the final 16 monary disease (COPD). Two classes of puffs of each regimen. Forced expiratory inhaled bronchodilators - anticholinergics and volume in one second (FEVI), forced vital 02 agonists - are available for the management capacity (FVC), heart rate, and blood of COPD. Anticholinergic agents show fewer pressure were measured five minutes be- side effects and often greater efficacy in elderly on September 24, 2021 by guest. Protected copyright. fore each treatment and 30 minutes after patients.'`6 Despite the extensive use of these treatment with nebulised salbutamol. agents, the dosage requirements for patients Results - FEV1 and FVC reached a plateau with COPD have not been clearly established after administration of a cumulative dose and most recommended dosages result in less of 14 puffs ofipratropium bromide (280 tg) than maximal bronchodilation.7-'0 Ipratropium or flutropium bromide (420 tg), and after bromide and oxitropium bromide are widely six puffs of oxitropium bromide (600 ,sg). used, but few reports compare the effects There were no differences with respect to of these drugs in the treatment of COPD. maximum increases in FEVy and FVC Flutropium bromide is a quatemary anti- amongst the three anticholinergic agents. cholinergic derived from atropine and has a However, after six puffs oxitropium brom- pharmacological profile closely related to that ide produced a greater increase in FEVy ofipratropium bromide.'" Flutropium bromide Chest Disease than either ipratropium bromide or flu- also possesses some antihistaminic and anti- Research Institute, tropium bromide. Fenoterol caused a 2 and has been used in Kyoto University, allergic activity Japan 53 Kawara-machi greater increase in both FEV, and FVC for the relief of symptoms of bronchial asthma Shogoin Sakyo-ku, than the three anticholinergic agents after and COPD. There are, however, few controlled Kyoto 606-01, Japan six puffs, as well as a greater increase in studies either assessing the clinical efficacy of A Ikeda bromide or it with other K Nishimura pulse rate. Oxitropium bromide produced flutropium comparing H Koyama a greater increase in pulse rate than the anticholinergic agents. T Izumi other anticholinergics after 14 puffs. The To determine the dosage which produced Reprint requests to: incidence of side effects was dose-related optimal bronchodilation, a cumulative dose- Dr A Ikeda. and notable adverse effects were reported response study comparing the currently avail- Received 11 March 1994 after 30 puffs of ipratropium bromide, 14 able anticholinergic agents (ipratropium brom- Returned to authors 16 June 1994 puffs ofoxitropium bromide, and two puffs ide, flutropium bromide, and oxitropium Revised version received of fenoterol. bromide) and the adrenergic agent fenoterol 2 September 1994 - a Accepted for publication Conclusions Oxitropium bromide pro- was undertaken using metered dose inhaler 10 October 1994 duced a greater bronchodilator effect than in patients with stable COPD. Dose-response study of three anticholinergic agents andfenoterol in stable COPD 63 Methods exhaled to functional residual capacity, the can- SUBJECTS ister was activated. Patients then inhaled very Twenty men with stable COPD were recruited slowly until total lung capacity was reached, at from the outpatient clinic at the Chest Disease which point the breath was held for at least 10 Thorax: first published as 10.1136/thx.50.1.62 on 1 January 1995. Downloaded from Research Institute, Kyoto University. All sub- seconds. To ensure that the trials were double jects fulfilled the following criteria: (1) a history blind, identical metered dose inhaler canisters of more than 20 pack-years of cigarette smok- containing either active drug or placebo were ing; (2) a forced expiratory volume in one prepared in advance, coded, and randomly second (FEV,) of <80% ofthe predicted value, selected. The treatment codes were not re- and a best post-bronchodilator FEVI/forced vealed until all 20 patients had completed the vital capacity (FVC) ratio of less than 0-7; (3) protocols. a history of chronic dyspnoea on exertion with Spirometric testing was performed according or without sputum production and radiological to the methods described in the American evidence of emphysema; (4) no history sug- Thoracic Society's 1987 update.14 Three con- gestive of asthma; (5) no exacerbation of air- secutive flow-volume curves were recorded ways obstruction in the preceding three months with a spirometer (AUTOSPIRO AS-600, Mi- and no heart disease or any other illness; nato Medical Science, Osaka, Japan), which and (6) no treatment with oral or inhaled was precalibrated with a 3-01 syringe before corticosteroids in the preceding four weeks, each day oftesting. The highest FEV, and FVC and no current treatment with any oral from the triplicate measurements were analysed bronchodilators, including theophylline. No and predicted FEV1 and FVC values were cal- patients were current smokers. The study was culated according to the 1993 proposal of the approved by the ethics committee of our in- Japan Society of Chest Diseases."5 stitute and written informed consent was ob- Pulmonary function tests were performed tained from each patient. within the three months preceding the study and at least 12 hours after the administration of bronchodilators had been suspended. In STUDY DESIGN addition to spirometric testing (CHESTAC- The study was performed in a randomised, 65V, Chest, Tokyo, Japan) the functional double blind, placebo controlled, crossover residual capacity was measured by ple- fashion. Testing was started at approximately thysmography (MBR-600, Nihon Kohden, the same time each morning on five separate Tokyo, Japan) and this was combined with the days during a two week period, and the interval inspiratory capacity measured spirometrically between testing ranged from two to four days. to calculate the total lung capacity. The static The patients received two, four, eight, or 16 compliance and airways resistance were also http://thorax.bmj.com/ puffs of: (1) ipratropium bromide (20 ,ug/puff); measured by plethysmography. The carbon (2) flutropium bromide (30 gg/puff); (3) oxi- monoxide diffusing capacity was measured tropium bromide (100 jg/puff); (4) fenoterol using the single breath technique (CHESTAC- (200 gg/puff); and (5) placebo in random 65V). order. Doses were administered by a metered dose inhaler at one hour intervals to give cu- mulative doses of two, six, 14, and 30 puffs. DATA ANALYSIS Five mg of nebulised salbutamol in 1 ml saline Friedman's two way analysis of variance was on September 24, 2021 by guest. Protected copyright. was administered 60 minutes after the patient used to compare differences between the five had received 16 puffs of each regimen. test regimens with respect to FEVy and FVC Spirometric testing was performed initially, 60 (expressed as absolute changes from the base- minutes after each dose (and just before line), and also with respect to pulse rate and the administration of the next dose), and 30 blood pressure (expressed as absolute differ- minutes after the administration of nebulised ences relative to the placebo). When a sig- salbutamol. Pulse rate and blood pressure were nificant difference existed among groups the also measured after at least five minutes of rest Wilcoxon signed rank test was used to identify before each spirometric measurement. Sim- specifically which differences were significant. ultaneously, patients were asked