Treatments in Respiratory Medicine

, Volume 4, Issue 6, pp 447–455 | Cite as

Clinical Efficacy and Safety of Transdermal Tulobuterol in the Treatment of Stable COPD: An Open-Label Comparison with Inhaled Salmeterol

  • Yoshinosuke Fukuchi
  • Atsushi Nagai
  • Kuniaki Seyama
  • Masaharu Nishimura
  • Kazuto Hirata
  • Keishi Kubo
  • Masakazu Ichinose
  • Hisamichi Aizawa
  • the BAREC Research Group
Original Research Article


Background: Long-acting bronchodilators are recommended for the management of stable COPD to relieve symptoms and improve quality of life. The tulobuterol patch (Hokunalin®) is a transdermal patch preparation of the β2-adrenoceptor agonist (β2-agonist) tulobuterol designed to yield sustained β2-agonistic effects for 24 hours when applied once daily.

Objective: To compare the effectiveness of tulobuterol patch and inhaled salmeterol (Serevent® Diskus) in the treatment of stable COPD.

Study design: Clinically stable COPD patients (age ≥40 years, postbronchodilator FEV1/FVC <70%, and postbronchodilator FEV1 <80% predicted) were enrolled in a multicenter, open-label randomized study. After a 2-week run-in period, patients were administered either tulobuterol (2mg once-daily applied as a patch) or salmeterol (50μg per inhalation, twice a day) for 12 weeks.

Results: Data for 92 patients (46 each for each treatment group) were analyzed. There were no significant differences in baseline characteristics in the tulobuterol versus salmeterol groups: age, 69.2 ± 7.4 vs 71.6 ± 7.3 years; male, 91% versus 96%; and patients with stage II (III) COPD, 32.6% (67.4%) versus 50% (50%). FEV1, FVC, and PEF improved during treatment in both groups compared with baseline, with no significant between group differences. The total St George’s Respiratory Questionnaire (SGRQ) score was significantly improved relative to baseline in the tulobuterol group at 8 weeks (−4.7 units [U]), but not in the salmeterol group at all timepoints. Domain analysis of the SGRQ scores revealed significant improvement in the symptom score relative to baseline in the tulobuterol group at weeks 4 (−6.9U), 8 (−12.0U), and 12 (−11.7U), but not in the salmeterol group in any of the domains tested. Medical Research Council dyspnea scale score improved during treatment in both groups, with no significant differences between groups. Compliance with the treatment regimen was significantly better in the tulobuterol than in the salmeterol group (98.5% vs 94.1%; p < 0.05).

Conclusion: These findings indicate that once-daily transdermal sustained-release tulobuterol is as effective or better than the inhaled long-acting β2-agonist salmeterol in the management of stable COPD, with significant effects on quality of life.



The BAREC Research Group consists of the following investigators: Yoshinosuke Fukuchi, Department of Respiratory Medicine, Juntendo University School of Medicine; Atsushi Nagai, Tokyo Women’s Medical University Respiratory Center; Masaharu Nishimura, First Department of Internal Medicine, Hokkaido University; Hiromasa Ogawa, Department of Internal Medicine, Tohoku University Graduate School of Medicine; Keishi Kubo, First Department of Internal Medicine, Shinshu University School of Medicine; Yukihiko Sugiyama, Division of Pulmonary Medicine, Department of Medicine, Jichi Medical School; Takayuki Kuriyama, Department of Respirology, Chiba University School of Medicine; Kazuhiro Yamaguchi, Department of Medicine, Keio University School of Medicine; Ken Matsuoka, Kasumigaura Hospital, Tokyo Medical University; Ken Ohta, Department of Internal Medicine, Teikyo University School of Medicine; Shoji Kudoh, Fourth Department of Internal Medicine, Nippon Medical School; Shu Hashimoto, First Department of Internal Medicine, Nihon University School of Medicine; Kuniaki Seyama, Department of Respiratory Medicine, Juntendo University School of Medicine; Keiji Takahashi, Department of Respiratory Medicine, Kanazawa Medical University; Hirohisa Toga, Department of Respiratory Medicine, Kanazawa Medical University; Michiaki Mishima, Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University; Masakazu Ichinose, Third Department of Internal Medicine, Wakayama Medical University; Kazuto Hirata, Division of Respiratory Medicine, Osaka City University; and Hisamichi Aizawa, First Department of Internal Medicine, Kurume University School of Medicine.

No sources of funding were used to assist in the preparation of this manuscript. The authors have no potential conflicts of interest that are directly relevant to the contents of this manuscript.


  1. 1.
    Global Initiative for Chronic Obstructive Lung Disease. Global strategy for the diagnosis, management, and prevention of COPD [online]. National Heart Lung and Blood Institute/World Health Organization; 2003. Available from URL: [Accessed 2005 Jun 6]
  2. 2.
    Celli BR, MacNee W, ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J 2004; 23: 932–46PubMedCrossRefGoogle Scholar
  3. 3.
    3. The Japan Respiratory Society COPD Guideline Development Committee. The guidelines for diagnosis and treatment of chronic obstructive pulmonary disease (COPD) [in Japanese]. 2nd ed. Osaka: Medical Review Sha, 2004: 69–70Google Scholar
  4. 4.
    Uematsu T, Nakashima M, Nakano M, et al. The pharmacokinetics of the β2-adrenoceptor agonist, tulobuterol, given transdermally and by inhalation. Eur J Clin Pharmacol 1993; 44: 361–4PubMedCrossRefGoogle Scholar
  5. 5.
    Iikura Y, Ebisawa M, Saito H. Pharmacokinetics and pharmacodynamics of the tulobuterol patch, HN-078, in childhood asthma. Ann Allerg Asthma Immunol 1995; 74: 147–51Google Scholar
  6. 6.
    Miyamoto T, Takishima T, Makino S, et al. Clinical study of salmeterol xinafoate (SN408) aerosol: double blind parallel study between procaterol tablet in patients with bronchial asthma [in Japanese]. J Clin Ther Med 2002; 18: 411–36Google Scholar
  7. 7.
    Urik CS. Efficacy of inhaled salmeterol in the management of smokers with chronic obstructive pulmonary disease: a single centre randomized, double blind, placebo controlled, crossover study. Thorax 1995; 50: 750–4CrossRefGoogle Scholar
  8. 8.
    Boyd G, Morice AH, Pounsford JC, et al. An evaluation of salmeterol in the treatment of chronic obstructive pulmonary disease (COPD). Eur Respir J 1997; 10: 815–21PubMedGoogle Scholar
  9. 9.
    Cazzola M, Matera MG, Santangelo G, et al. Salmeterol and formoterol in partially reversible severe chronic obstructive pulmonary disease: a dose-response study. Respir Med 1995; 89: 357–62PubMedCrossRefGoogle Scholar
  10. 10.
    Miyamoto T, Takishima T, Takahashi T, et al. Clinical evaluation of HN-078, a patch formulation of tulobuterol, in patients with bronchial asthma in a phase III study: a multicenter double-blind parallel study between procaterol hydrochloride tablet [in Japanese]. J Clin Ther Med 1995; 11: 783–807Google Scholar
  11. 11.
    Donohue JF, van Noord JA, Bateman ED, et al. A 6-month, placebo-controlled study comparing lung function and health status changes in COPD patients treated with tiotropium or salmeterol. Chest 2002; 122: 47–55PubMedCrossRefGoogle Scholar
  12. 12.
    Mahler DA, Donohue JF, Barbee RA, et al. Efficacy of salmeterol xinafoate in the treatment of COPD. Chest 1999; 115: 957–65PubMedCrossRefGoogle Scholar
  13. 13.
    Rennard SI, Anderson W, Zu Wallack R, et al. Use of a long-acting inhaled β2-adrenergic agonist, salmeterol xinafoate, in patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2001; 163: 1087–92PubMedGoogle Scholar
  14. 14.
    Patakas D, Andreadis D, Mavrofridis E, et al. Comparison of the effects of salmeterol and ipratropium bromide on exercise performance and breathlessness in patients with stable chronic obstructive pulmonary disease. Respir Med 1998; 92: 1116–21PubMedCrossRefGoogle Scholar
  15. 15.
    Ayers ML, Mejia R, Ward J, et al. Effectiveness of salmeterol versus ipratropium bromide on exertional dyspnoea in COPD. Eur Respir J 2001; 17: 1132–7PubMedCrossRefGoogle Scholar
  16. 16.
    Di Lorenzo G, Morici G, Drago A, et al. Efficacy, tolerability and effects on quality of life of inhaled salmeterol and oral theophylline in patients with mild-to-moderate chronic obstructive pulmonary disease. Clin Ther 1998; 20: 1130–48PubMedCrossRefGoogle Scholar
  17. 17.
    van Noord JA, de Munck DR, Bantje TA, et al. Long-term treatment of chronic obstructive pulmonary disease with salmeterol and the additive effect of ipratropium. Eur Respir J 2000; 15: 878–85PubMedCrossRefGoogle Scholar
  18. 18.
    Matera MG, Caputi M, Cazzola M. A combination with clinical recommended dosages of salmeterol and ipratropium is not more effective than salmeterol alone in patients with chronic obstructive pulmonary disease. Respir Med 1996; 90: 497–9PubMedCrossRefGoogle Scholar
  19. 19.
    Sasaki H, Nakamura M, Kida K, et al. Standard values of spirogram and arterial blood gas analysis in Japanese population [in Japanese]. Nihon Kokyuki Gakkai Zasshi 2001; 39: 1–17Google Scholar
  20. 20.
    Jones PW, Bosh TK. Quality of life changes in COPD patients treated with salmeterol. Am J Respir Crit Care Med 1997; 155: 1283–9PubMedGoogle Scholar
  21. 21.
    Laube BL, Swift DL, Wagner Jr HN, et al. The effect of bronchial obstruction on central airway deposition of a saline aerosol in patients with asthma. Am Rev Respir Dis 1986; 133: 740–3PubMedGoogle Scholar
  22. 22.
    Pauwels RA, Lofdahl CG, Postma DS, et al. Effect of inhaled formoterol and budesonide on exacerbations of asthma. N Engl J Med 1997; 337: 1405–11PubMedCrossRefGoogle Scholar
  23. 23.
    Ullman A, Hedner J, Svedmyr N. Inhaled salmeterol in asthmatic patients: an evaluation of asthma symptoms and the possible development of tachyphylaxis. Am Rev Respir Dis 1990; 142: 571–5PubMedCrossRefGoogle Scholar
  24. 24.
    Kume H, Kondo M, Ito Y, et al. Effects of sustained-release tulobuterol on asthma control and β-adrenoceptor function. Clin Exp Pharmacol Physiol 2002; 29: 1076–83PubMedCrossRefGoogle Scholar
  25. 25.
    Kume H. Clinical use of beta2-adrenergic receptor agonists based on their intrinsic efficacy. Allergology Int 2005; 54: 89–97CrossRefGoogle Scholar
  26. 26.
    Tamura G, Yamauchi K, Honma M, et al. Long-term study of NH-078, a patch formulation of tulobuterol, in adult bronchial asthma [in Japanese]. J Clin Ther Med 1995; 11: 1067–80Google Scholar
  27. 27.
    Horiguchi T, Kondo R, Miyazaki J, et al. Clinical evaluation of a transdermal therapeutic system of the β2-agonist tulobuterol in patients with mild or moderate persistent bronchial asthma. Arzneimittel Forschung 2004; 54: 280–5PubMedGoogle Scholar
  28. 28.
    Eguchi Y, Hirata K. Clinical long-term efficacy of tulobuterol patch (long acting β2-agonist) in patients with chronic obstructive pulmonary disease [abstract]. Proc Am Thorac Soc 2005; 2: A543Google Scholar

Copyright information

© Adis Data Information BV 2005

Authors and Affiliations

  • Yoshinosuke Fukuchi
    • 1
  • Atsushi Nagai
    • 2
  • Kuniaki Seyama
    • 1
  • Masaharu Nishimura
    • 3
  • Kazuto Hirata
    • 4
  • Keishi Kubo
    • 5
  • Masakazu Ichinose
    • 6
  • Hisamichi Aizawa
    • 7
  • the BAREC Research Group
  1. 1.Department of Respiratory MedicineJuntendo University School of MedicineBunkyo-Ku, TokyoJapan
  2. 2.First Department of MedicineTokyo Women’s Medical University School of MedicineShinguku, TokyoJapan
  3. 3.First Department of Internal MedicineHokkaido UniversitySapporoJapan
  4. 4.Division of Respiratory MedicineOsaka City UniversityOsakaJapan
  5. 5.First Department of Internal MedicineShinshu University School of MedicineMatsumoto, NaganoJapan
  6. 6.Third Department of Internal MedicineWakayama Medical UniversityWakayamaJapan
  7. 7.First Department of Internal MedicineKurume University School of MedicineKurume City, FukuokaJapan

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