Acute Evect of Pretreatment with Single Conventional Dose Of
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Thorax 1999;54:1083–1086 1083 Acute eVect of pretreatment with single conventional dose of salmeterol on dose-response Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from curve to oxitropium bromide in chronic obstructive pulmonary disease Mario Cazzola, Felice Di Perna, Stefano Centanni, Clara Califano, Claudio Ferdinando Donner, Maria D’Amato, Gennaro D’Amato Abstract Keywords: salmeterol; oxitropium bromide; combina- Background—An earlier study docu- tion therapy; chronic obstructive pulmonary disease mented that, in patients with chronic obstructive pulmonary disease (COPD), addition of ipratropium bromide at the Recent British Thoracic Society guidelines for clinically recommended dose (40 µg) does the management of stable chronic obstructive not produce any further bronchodilation pulmonary disease (COPD) state that bron- than that achieved with salmeterol 50 µg chodilators are the cornerstone of symptomatic treatment for the reversible component of alone. However, the dose of ipratropium airways obstruction.1 Short acting â agonists bromide needed to produce near maximal 2 used as required should be tried first in view of bronchodilation is several times higher their more rapid relief of symptoms. If these do than the customary dosage. The full not control symptoms adequately or if regular therapeutic potential of combined sal- maintenance therapy is desired, an anticholin- meterol plus an anticholinergic drug can ergic agent can be added. This recommen- therefore only be established using doses dation is based on the fact that anticholinergic higher than those currently recommended and â adrenergic agents, which are distinct in the marketing of these agents. A study classes of drugs with diVerent mechanisms of was undertaken to examine the possible 23 action, are additive when used together. acute eVects of higher than conventional Long acting â agonist bronchodilators such doses of an anticholinergic agent on the as formoterol and salmeterol are a new single dose salmeterol induced bronchodi- 4–6 interesting therapeutic option for COPD. lation in patients with stable and partially A. Cardarelli Hospital, However, their impact on combinations is still http://thorax.bmj.com/ reversible COPD. Division of unclear. Methods—Thirty two outpatients received Pneumology and A combination of ipratropium with 50 µg salmeterol or placebo. Two hours 7 8 Allergology, Naples, salmeterol or formoterol in their normal dos- Italy after inhalation a dose-response curve to ages does not appear to improve pulmonary M Cazzola inhaled oxitropium bromide (100 µg/puV) function, but this lack of improvement with the FDiPerna or placebo was constructed using one puV, C Califano combination should not in itself prevent imple- one puV,twopuVs, and two puVs—that is, a M D’Amato mentation of further therapeutic steps in G D’Amato total cumulative dose of 600 µg oxitropium patients responsive to ipratropium and/or on September 23, 2021 by guest. Protected copyright. bromide. Dose increments were given at 20 salmeterol or formoterol administered singly. University of Milan, minute intervals with measurements being In the present study we have investigated the Medical School, San made 15 minutes after each dose. On four possible acute eVects of higher than normal Paolo Hospital, separate days all patients received one of Respiratory Diseases doses of an anticholinergic agent on the single the following: (1) 50 µg salmeterol + 600 µg Unit, Milan, Italy dose salmeterol induced bronchodilation in oxitropium bromide; (2) 50 µg salmeterol S Centanni patients with stable and partially reversible + placebo; (3) placebo + 600 µg oxitropium COPD. S Maugeri Foundation, bromide; (4) placebo + placebo. Institute of Care and Results—Salmeterol induced a good bron- Research, Medical chodilation (mean increase 0.272 l; 95% CI Methods Centre of Thirty two outpatients with moderate to severe Rehabilitation, 0.207 to 0.337) two hours after its inhala- Division of tion. Oxitropium bromide elicited an evi- COPD but in a stable phase of the disease and Pneumology, Veruno, dent dose-dependent increase in forced with partially reversible airway obstruction Italy expiratory volume in one second (FEV1) were assessed. They gave their informed C F Donner and this occurred also after pretreatment consent to participate in the study. All fulfilled with salmeterol with a further mean the criteria proposed by the American Tho- Correspondence to: 9 Dr M Cazzola, Via del Parco maximum increase of 0.152 l (95% CI of racic Society —that is, they were >50 years of Margherita 24, 80121 diVerences 0.124 to 0.180). age, current or former smokers (>10 pack Napoli, Italy Conclusions—This study shows that acute years) without a history of asthmatic attacks, reporting chronic cough with or without Received 16 April 1999 pretreatment with 50 µg salmeterol does Returned to authors not block the possibility of inducing more sputum production and/or dyspnoea when 14 July 1999 bronchodilation with an anticholinergic walking quietly on level ground, or both; they Revised manuscript received agent when a higher than normal dosage had had no change in symptom severity or 29 July 1999 Accepted for publication of the muscarinic antagonist is used. treatment in the preceding four weeks, had 17 August 1999 (Thorax 1999;54:1083–1086) shown no signs of a respiratory tract infection 1084 Cazzola, Di Perna, Centanni, et al Table 1 Anthropometric data and pulmonary function of patients The study, which was conducted according to the rules of the declaration of Helsinki, was Reversibility 15 min after 200 µg salbutamol performed using a randomised, double blind, Thorax: first published as 10.1136/thx.54.12.1083 on 1 December 1999. Downloaded from FEV1 FVC (% increase in FEV1 crossover design. Patients received two puVsof Patient Sex Age (years) (% predicted) (% predicted) from baseline) salmeterol (25 µg/puV) or placebo inhaled 1 F 62 48 51 15 from matched metered dose inhalers (MDI) 2 M 66 30 45 18 and a holding chamber (AeroChamber) with a 3 M 73 36 39 17 4 M 55 48 55 18 mouthpiece. Although oxitropium bromide 5 M 61 29 34 31 and placebo could have been given by neb- 6 M 58 36 48 21 7 M 71 19 24 18 uliser, we chose MDI dosing for this study 8 F 70 55 69 17 because salmeterol is not available as a solution 9 M 65 42 60 25 and a double blind study would otherwise have 10M57374421 11M68586515 not been possible. 12F62202724 Spirometric testing was performed accord- 13M68333615 ing to the procedures described in the Ameri- 14M69445423 10 15M58293619 can Thoracic Society’s 1987 update. Three 16M61476116 acceptable forced expiratory manoeuvres were 17F73434417 18M67405815 performed in order to obtain two reproducible 19M64385327 results for FVC and FEV1. The higher of the 20M65253228 two FEV results was kept for analysis. 21F71506126 1 22M55333924 Measurements were performed immediately 23M63476019 before inhalation of treatment and after two 24M68555616 hours. 25F74455118 26M72434920 Two hours after the inhalation of salmeterol 27M68182918 or placebo spirometric tests were performed in 28M64222515 each patient, after which a dose-response curve 29F62333519 30F58495517 to inhaled oxitropium (100 µg/puV) or placebo 31M65212819 was constructed using one puV, one puV,two 32M64415728 puVs, and two puVs—that is, a total cumulative FEV1 = forced expiratory volume in one second; FVC = forced vital capacity. dose of 600 µg oxitropium. Oxitropium or pla- cebo were administered from an MDI and in the month preceding or during the trial, had holding chamber (AeroChamber) with a not been taking oral or inhaled corticosteroids mouthpiece. Dose increments were given at 20 for at least three months, and had a forced minute intervals with measurements being expiratory volume in one second (FEV1)of made 15 minutes after each dose. On four <65% of predicted normal and a forced vital non-consecutive days all patients received one capacity (FVC) of <70% after bronchodilators of the following: (1) 50 µg salmeterol + 600 µg http://thorax.bmj.com/ had been withheld for 24 hours and a best oxitropium bromide, (2) 50 µg salmeterol + post-bronchodilator FEV1/FVC of less than placebo, (3) placebo + 600 µg oxitropium bro- 0.7. Patients with allergic rhinitis, atopy, mide, or (4) placebo + placebo. positive skin test, or with a total blood eosino- The increases in the functional indices from –3 phil count over 400 mm were excluded. baseline after salmeterol or placebo were Patients were also excluded if they had any assessed. The FEV1 value induced by 600 µg co-existing cardiovascular or lung disorder. At oxitropium bromide or placebo (six puVs) was an initial screening visit patients were required chosen as the primary outcome variable. With on September 23, 2021 by guest. Protected copyright. to demonstrate an increase in FEV1 of at least an estimation of the within subject variability 15% from baseline to inhaled 200 µg salbuta- (residual standard deviation) of 0.10 l, this mol. Table 1 outlines the baseline characteris- crossover study with 32 patients had 80% tics of the population studied. power to detect a diVerence of at least 0.08 l No oral bronchodilators were permitted for between treatments. one week before and during the study while Analysis of spirometric data for each treat- inhaled short acting bronchodilator drugs and ment was performed using the Student’s t test inhaled long acting bronchodilator agents were for paired variables. Mean responses were also not permitted for at least 12 hours and 24 compared by multifactorial analysis of variance hours, respectively, before each test. Patients (ANOVA) to establish any significant overall were also asked to refrain from consumption of eVect between all four treatments. In the pres- cola drinks, coVee, tea, and smoking in the 12 ence of a significant overall ANOVA, Duncan’s hours before and during the investigation. multiple range testing with 95% confidence Table 2 Mean (95% CI) baseline values and changes in FEV1 and FVC two hours after placebo (P) or 50 µg salmeterol (S), and changes from values at 2 hours after 6 puVs of oxitropium bromide (OB) or placebo (P).