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. 2003 Oct;58(10):855–860. doi: 10.1136/thorax.58.10.855

Effect of tiotropium bromide on circadian variation in airflow limitation in chronic obstructive pulmonary disease

P Calverley 1, A Lee 1, L Towse 1, J van Noord 1, T Witek 1, S Kelsen 1
PMCID: PMC1746483  PMID: 14514937

Abstract

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.

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Selected References

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  1. Ballard R. D., Clover C. W., Suh B. Y. Influence of sleep on respiratory function in emphysema. Am J Respir Crit Care Med. 1995 Apr;151(4):945–951. doi: 10.1164/ajrccm.151.4.7697271. [DOI] [PubMed] [Google Scholar]
  2. Barnes P. J., Belvisi M. G., Mak J. C., Haddad E. B., O'Connor B. Tiotropium bromide (Ba 679 BR), a novel long-acting muscarinic antagonist for the treatment of obstructive airways disease. Life Sci. 1995;56(11-12):853–859. doi: 10.1016/0024-3205(95)00020-7. [DOI] [PubMed] [Google Scholar]
  3. Beam W. R., Weiner D. E., Martin R. J. Timing of prednisone and alterations of airways inflammation in nocturnal asthma. Am Rev Respir Dis. 1992 Dec;146(6):1524–1530. doi: 10.1164/ajrccm/146.6.1524. [DOI] [PubMed] [Google Scholar]
  4. Becker H. F., Piper A. J., Flynn W. E., McNamara S. G., Grunstein R. R., Peter J. H., Sullivan C. E. Breathing during sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med. 1999 Jan;159(1):112–118. doi: 10.1164/ajrccm.159.1.9803037. [DOI] [PubMed] [Google Scholar]
  5. Borsboom G. J., van Pelt W., van Houwelingen H. C., van Vianen B. G., Schouten J. P., Quanjer P. H. Diurnal variation in lung function in subgroups from two Dutch populations: consequences for longitudinal analysis. Am J Respir Crit Care Med. 1999 Apr;159(4 Pt 1):1163–1171. doi: 10.1164/ajrccm.159.4.9703106. [DOI] [PubMed] [Google Scholar]
  6. Brand P. L., Postma D. S., Kerstjens H. A., Koëter G. H. Relationship of airway hyperresponsiveness to respiratory symptoms and diurnal peak flow variation in patients with obstructive lung disease. The Dutch CNSLD Study Group. Am Rev Respir Dis. 1991 May;143(5 Pt 1):916–921. doi: 10.1164/ajrccm/143.5_Pt_1.916. [DOI] [PubMed] [Google Scholar]
  7. Casale R., Pasqualetti P. Cosinor analysis of circadian peak expiratory flow variability in normal subjects, passive smokers, heavy smokers, patients with chronic obstructive pulmonary disease and patients with interstitial lung disease. Respiration. 1997;64(4):251–256. doi: 10.1159/000196682. [DOI] [PubMed] [Google Scholar]
  8. Cochrane G. M., Clark J. H. A survey of asthma mortality in patients between ages 35 and 64 in the Greater London hospitals in 1971. Thorax. 1975 Jun;30(3):300–305. doi: 10.1136/thx.30.3.300. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Coe C. I., Barnes P. J. Reduction of nocturnal asthma by an inhaled anticholinergic drug. Chest. 1986 Oct;90(4):485–488. doi: 10.1378/chest.90.4.485. [DOI] [PubMed] [Google Scholar]
  10. Dawkins K. D., Muers M. F. Diurnal variation in airflow obstruction in chronic bronchitis. Thorax. 1981 Aug;36(8):618–621. doi: 10.1136/thx.36.8.618. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Di Stefano A., Lusuardi M., Braghiroli A., Donner C. F. Nocturnal asthma: mechanisms and therapy. Lung. 1997;175(1):53–61. doi: 10.1007/pl00007556. [DOI] [PubMed] [Google Scholar]
  12. Disse B. Antimuscarinic treatment for lung diseases from research to clinical practice. Life Sci. 2001 Apr 27;68(22-23):2557–2564. doi: 10.1016/s0024-3205(01)01052-9. [DOI] [PubMed] [Google Scholar]
  13. Disse B., Speck G. A., Rominger K. L., Witek T. J., Jr, Hammer R. Tiotropium (Spiriva): mechanistical considerations and clinical profile in obstructive lung disease. Life Sci. 1999;64(6-7):457–464. doi: 10.1016/s0024-3205(98)00588-8. [DOI] [PubMed] [Google Scholar]
  14. Guberan E., Williams M. K., Walford J., Smith M. M. Circadian variation of F.E.V. in shift workers. Br J Ind Med. 1969 Apr;26(2):121–125. doi: 10.1136/oem.26.2.121. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hetzel M. R. The pulmonary clock. Thorax. 1981 Jul;36(7):481–486. doi: 10.1136/thx.36.7.481. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Higgins B. G., Britton J. R., Chinn S., Cooper S., Burney P. G., Tattersfield A. E. Comparison of bronchial reactivity and peak expiratory flow variability measurements for epidemiologic studies. Am Rev Respir Dis. 1992 Mar;145(3):588–593. doi: 10.1164/ajrccm/145.3.588. [DOI] [PubMed] [Google Scholar]
  17. Maesen F. P., Smeets J. J., Sledsens T. J., Wald F. D., Cornelissen P. J. Tiotropium bromide, a new long-acting antimuscarinic bronchodilator: a pharmacodynamic study in patients with chronic obstructive pulmonary disease (COPD). Dutch Study Group. Eur Respir J. 1995 Sep;8(9):1506–1513. [PubMed] [Google Scholar]
  18. Man G. C., Champman K. R., Ali S. H., Darke A. C. Sleep quality and nocturnal respiratory function with once-daily theophylline (Uniphyl) and inhaled salbutamol in patients with COPD. Chest. 1996 Sep;110(3):648–653. doi: 10.1378/chest.110.3.648. [DOI] [PubMed] [Google Scholar]
  19. Martin R. J., Banks-Schlegel S. Chronobiology of asthma. Am J Respir Crit Care Med. 1998 Sep;158(3):1002–1007. doi: 10.1164/ajrccm.158.3.9712132. [DOI] [PubMed] [Google Scholar]
  20. Martin R. J., Pak J. Overnight theophylline concentrations and effects on sleep and lung function in chronic obstructive pulmonary disease. Am Rev Respir Dis. 1992 Mar;145(3):540–544. doi: 10.1164/ajrccm/145.3.540. [DOI] [PubMed] [Google Scholar]
  21. Nisar M., Walshaw M., Earis J. E., Pearson M. G., Calverley P. M. Assessment of reversibility of airway obstruction in patients with chronic obstructive airways disease. Thorax. 1990 Mar;45(3):190–194. doi: 10.1136/thx.45.3.190. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. O'Connor B. J., Towse L. J., Barnes P. J. Prolonged effect of tiotropium bromide on methacholine-induced bronchoconstriction in asthma. Am J Respir Crit Care Med. 1996 Oct;154(4 Pt 1):876–880. doi: 10.1164/ajrccm.154.4.8887578. [DOI] [PubMed] [Google Scholar]
  23. Pincus D. J., Szefler S. J., Ackerson L. M., Martin R. J. Chronotherapy of asthma with inhaled steroids: the effect of dosage timing on drug efficacy. J Allergy Clin Immunol. 1995 Jun;95(6):1172–1178. doi: 10.1016/s0091-6749(95)70073-0. [DOI] [PubMed] [Google Scholar]
  24. Postma D. S., Keyzer J. J., Koëter G. H., Sluiter H. J., De Vries K. Influence of the parasympathetic and sympathetic nervous system on nocturnal bronchial obstruction. Clin Sci (Lond) 1985 Sep;69(3):251–258. doi: 10.1042/cs0690251. [DOI] [PubMed] [Google Scholar]
  25. Postma D. S., Koëter G. H., vd Mark T. W., Reig R. P., Sluiter H. J. The effects of oral slow-release terbutaline on the circadian variation in spirometry and arterial blood gas levels in patients with chronic airflow obstruction. Chest. 1985 May;87(5):653–657. doi: 10.1378/chest.87.5.653. [DOI] [PubMed] [Google Scholar]
  26. Quanjer P. H., Tammeling G. J., Cotes J. E., Pedersen O. F., Peslin R., Yernault J. C. Lung volumes and forced ventilatory flows. Report Working Party Standardization of Lung Function Tests, European Community for Steel and Coal. Official Statement of the European Respiratory Society. Eur Respir J Suppl. 1993 Mar;16:5–40. [PubMed] [Google Scholar]
  27. Rivington R. N., Calcutt L., Hodder R. V., Stewart J. H., Aitken T. L. Safety and efficacy of once-daily Uniphyl tablets compared with twice-daily Theo-Dur tablets in elderly patients with chronic airflow obstruction. Am J Med. 1988 Jul 29;85(1B):48–53. doi: 10.1016/0002-9343(88)90242-2. [DOI] [PubMed] [Google Scholar]
  28. Smolensky M. H., McGovern J. P., Scott P. H., Reinberg A. Chronobiology and asthma. II. Body-time-dependent differences in the kinetics and effects of bronchodilator medications. J Asthma. 1987;24(2):91–134. doi: 10.3109/02770908709070926. [DOI] [PubMed] [Google Scholar]
  29. Tashkin D. P., Ashutosh K., Bleecker E. R., Britt E. J., Cugell D. W., Cummiskey J. M., DeLorenzo L., Gilman M. J., Gross G. N., Gross N. J. Comparison of the anticholinergic bronchodilator ipratropium bromide with metaproterenol in chronic obstructive pulmonary disease. A 90-day multi-center study. Am J Med. 1986 Nov 14;81(5A):81–90. doi: 10.1016/0002-9343(86)90468-7. [DOI] [PubMed] [Google Scholar]
  30. Turner-Warwick M. Nocturnal asthma: a study in general practice. J R Coll Gen Pract. 1989 Jun;39(323):239–243. [PMC free article] [PubMed] [Google Scholar]
  31. Tweeddale P. M., Alexander F., McHardy G. J. Short term variability in FEV1 and bronchodilator responsiveness in patients with obstructive ventilatory defects. Thorax. 1987 Jul;42(7):487–490. doi: 10.1136/thx.42.7.487. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. van Noord J. A., Bantje T. A., Eland M. E., Korducki L., Cornelissen P. J. A randomised controlled comparison of tiotropium nd ipratropium in the treatment of chronic obstructive pulmonary disease. The Dutch Tiotropium Study Group. Thorax. 2000 Apr;55(4):289–294. doi: 10.1136/thorax.55.4.289. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. van Noord J. A., de Munck D. R., Bantje T. A., Hop W. C., Akveld M. L., Bommer A. M. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J. 2000 May;15(5):878–885. doi: 10.1034/j.1399-3003.2000.15e11.x. [DOI] [PubMed] [Google Scholar]

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