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Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease
  1. P M A Calverley1,
  2. A Lee3,
  3. L Towse3,
  4. J van Noord2,
  5. T J Witek4,
  6. S Kelsen4
  1. 1Department of Medicine, University of Livepool, Liverpool, UK
  2. 2Atrium Medisch Centrum, Heerlen, The Netherlands
  3. 3Boehringer Ingelheim Ltd, Bracknell, Berkshire, UK
  4. 4Boehringer Ingelheim Pharmaceuticals, Ridgefield, Connecticut, USA
  1. Correspondence to:
    Professor P M A Calverley
    Pulmonary and Rehabilitation Research Group, Department of Medicine, University Hospital Aintree, Liverpool L9 7AL, UK;


Background: In chronic obstructive pulmonary disease (COPD), the degree of circadian variation in forced expiratory volume in 1 second (FEV1) and the influence of anticholinergic blockade is not known. Tiotropium is a long acting inhaled anticholinergic bronchodilator that increases daytime FEV1 in COPD. We hypothesised that tiotropium would modify the overnight change in FEV1, and this would be unaffected by the timing of drug administration.

Methods: A double blind, randomised, placebo controlled trial was conducted with tiotropium 18 mg once daily in the morning (09.00 hours), evening (21.00 hours), or an identical placebo. Patients with stable COPD (n=121, FEV1=41% predicted) underwent spirometric tests every 3 hours for 24 hours at baseline and after 6 weeks of treatment.

Results: There were no significant differences at baseline between the groups. Tiotropium improved mean (SE) FEV1 (over 24 hours) in the morning (1.11 (0.03) l) and evening (1.06 (0.03) l) groups compared with placebo (0.90 (0.03) l), and nocturnal FEV1 (mean of 03.00 and 06.00 hours) in the morning (1.03 (0.03) l) and evening (1.04 (0.03) l) groups compared with placebo (0.82 (0.03) l) at the 6 week visit (p<0.01). FEV1 before morning or evening dosing was similar, while the peak FEV1 moved later in the day with active treatment. The mean percentage change in FEV1 from 09.00 hours to 03.00 hours (the nocturnal decline in FEV1) was −2.8% in the morning group, −1.0% in the evening group, and −12.8% in the placebo group. The magnitude of the peak to trough change in FEV1 was not statistically different.

Conclusions: Tiotropium produced sustained bronchodilation throughout the 24 hour day without necessarily abolishing circadian variation in airway calibre.

  • tiotropium
  • chronic obstructive pulmonary disease
  • circadian rhythm
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    Publisher Correction

    Please note that there is an error in the author list, The name of the senior author, Dr Kesten, was spelt incorrectly.

    The correct author list is shown here:
    PMA Calverley, A Lee, L Towse, J van Noord, TJ Witek, and S Kesten

    The error is much regretted.


    • PMAC contributed patients to the study,helped develop the data analysis plan and wrote the manuscript together with SK. JvN contributed patients, LT organised the study implementation and AL undertook the statistical analysis. All authors contributed to development of the study protocol, data interpretation, and to the final manuscript.

    • The study was supported by Boehringer Ingelheim Pharmaceuticals Inc.

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