Use of Theophylline and Sodium Cromoglycate in Adult Asthma

  • Hironori Sagara
  • Kenya Kouyama
  • Takeshi Fukuda
  • Sohei Makino
Part of the Allergy Frontiers book series (ALLERGY, volume 5)

Sustained-release theophylline is frequently used in Japan to treat asthma. Theophylline has a long history as a therapeutic drug. In the early twentieth century, Plavec et al. reported that theophylline has a positive inotropic action on the myocardium. Since 1937, when Herrman et al. confirmed its effectiveness for asthma attacks, theophylline has been primarily considered a bronchodilator. In the 1970s and 1980s, theophylline was mainly used for the long-term management of asthma in the United States.

Since the 1990s, the mainstay of treatment for asthma in the United States shifted to inhaled corticosteroids or inhaled corticosteroids plus long-acting inhaled β 2 agonists (LABAs). The clinical positioning of theophylline was thus negatively affected. Since the latter part of the 1990s, however, evidence has accumulated that theophylline inhibits the airway inflammation characteristically found in asthma and can be used with inhaled corticosteroids to treat asthma. In this paper, we describe the clinical significance of sustained-release theophylline for the long-term management of asthma.


Severe Asthma Respir Crit Sodium Cromoglycate Serum Drug Concentration Adult Asthma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Fawett L, Baxedale R, Stacy R, et al. Molecular cloning and characterization of a distinct human phosphodiesterase gene family. PDE11A. Proc Natl Acad Sci USA 2000; 97: 3702–3707CrossRefGoogle Scholar
  2. 2.
    De Boer J, Philpott AJ, van Amesterdam RG, et al. Human bronchial cyclic nucleotide phos-phodiesterase isoenzymes Biochemical and pharmacological analysis using selective inhibitors. Br J Pharmacol 1992; 106: 1028–1034PubMedGoogle Scholar
  3. 3.
    Lipworth B. Phosphodiesterase type 4 inhibitors for asthma: a real Allergy. Asthma Immunol 2006; 96: 640–642Google Scholar
  4. 4.
    itenko PA, Ogilvie RI. Rational intravenous doses of theophylline. N Engl J Med 1973; 289: 600–603CrossRefGoogle Scholar
  5. 5.
    Rossing TH, Fanta CH, Goldstein DH, et al. Emergency therapy of asthma: Comparison of the acute effects of parenteral and inhaled sympathomimetics and infused aminophylline. Ame Rev Respir Dis 1980; 122: 365–371Google Scholar
  6. 6.
    Rossing TH, Fanta CH, McFadden ER. A controlled trial of the use of single versus combined-drug therapy in the treatment of acute episodes of asthma. Am Rev Respir Dis 1981; 123: 190–194PubMedGoogle Scholar
  7. 7.
    Fanta CH, Rossing TH, McFadden ER, Treatment of acute asthma. Is combination therapy with sympathomimetics and methylxanthines indicated? Am J Med 1986; 80: 5–l0CrossRefPubMedGoogle Scholar
  8. 8.
    Sullivan P, Bekir S, Jaffar Z, et al. Anti-inflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994; 343: 1006–1008CrossRefPubMedGoogle Scholar
  9. 9.
    Ito K, Sam Lim S, Caramori G, et al. A molecular mechanism of action of theophylline: induction of histone deacetylase activity to decrease inflammatory gene expression. PNAS 2002; 55: 8921–8926CrossRefGoogle Scholar
  10. 10.
    Ohta K, Sawamoto S, Nakajima M, et al. The pro-longed survival of human eosinophils with inter-leukin-5 and its inhibition by theophylline via apoptosis. Clin Exp Allergy 1996; 26: 10–15CrossRefPubMedGoogle Scholar
  11. 11.
    Spoeltsra FM, Berends C, Dijkhuizen B, et al. Effect of theophylline on CD1lb and L-selectin expression and density of eosinophils and neutrophils in vitro. Eur Respir J 1998; 12: 585–591CrossRefGoogle Scholar
  12. 12.
    Choo JH, Nagata M, et al. Theophylline attenuates the adhesion of eosinophils to endothelial cells. Int Arch Allergy Immunol 2003; 131: 40–45CrossRefPubMedGoogle Scholar
  13. 13.
    Nagata M. Differential effect of corticosteroids and theophylline on the adhesive interaction between eosinophils and endothelial cells. Allergol Int 2004; 53: 33–36CrossRefGoogle Scholar
  14. 14.
    Kaiser J, Bickel CA, Bochner BS, et al. The effects of the potent glucocorticoid budesonide on adnesion of eosinophils to human vascular endothelial cells and endothelial expression of adhesion molecules. J Pharmacol Exp Ther 1993; 267: 45–49Google Scholar
  15. 15.
    Sutani A, Nagata M, et al. Dexamethasone does not modulate eosinophil adhesion to endothe-lial cells. Int Arch Allergy Immunol 2001; 125: 2–6CrossRefGoogle Scholar
  16. 16.
    Minoguchi K, et al. Effect of theophylline with-drawl on airway inflammation in asthma. Clin Exp Allergy 1998; 28: 57–63PubMedGoogle Scholar
  17. 17.
    Aizawa H, et al. Once-daily theophylline reduces serum eosinophil cationic protein and eosinophil levels in induced sputum of asthmatics. Int Arch Allergy Immunol 2000; 121: 123–128CrossRefPubMedGoogle Scholar
  18. 18.
    Lim S, et al. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001; 164: 273–276PubMedGoogle Scholar
  19. 19.
    Yano Y, Yoshida M, Hoshino S, et al. Anti-fibrotic effects of theophylline on lung fibroblasts. Biochem Biophys Res Comm 2006; 341: 684–690CrossRefPubMedGoogle Scholar
  20. 20.
    Kraft M, Torvik JA, Trudeau JB, et al. Theophylline: potential anti-inflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996; 97: 1242–1246CrossRefPubMedGoogle Scholar
  21. 21.
    Culpitt S V, de Matos C, Russell RE, et al. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002; 165: 1371–1376CrossRefPubMedGoogle Scholar
  22. 22.
    Wenzel SE, Schwartz LB, Langmack EL, et al. Evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics. Am J Respir Crit Care Med 1999; 160: 1001–1008PubMedGoogle Scholar
  23. 23.
    The ENFUMOSA Study Group. The ENFUMOSA cross-sectional European multicentre study of the clinical phenotype of chronic severe asthma. Eur Respir J 2003; 22: 470–477CrossRefGoogle Scholar
  24. 24.
    Kikuchi S, Nagata M, Kikuchi I, et al. Association between neutrophilic and eosinophilic inflammation in patients with severe persistent asthma. Int Arch Allergy Immunol 2005; 137: 7–11CrossRefPubMedGoogle Scholar
  25. 25.
    Kikuchi I, Kikuchi S, Kobayashi T, et al. Eosinophil trans-basement migration induced by IL-8 and neutrophils. Am J Respir Cell Mol Biol 2006; 34: 760–765CrossRefPubMedGoogle Scholar
  26. 26.
    Kikuchi I, Kikuchi S, Kobayashi K, et al. Theophylline Attenuates the Neutrophil-Dependent Augmentation of Eosinophil Trans-Basement Membrane Migration. Int Arch Allergy Immunol 2005; 137 (accepted for publication)Google Scholar
  27. 27.
    Ohta K, Fukuchi Y, Grouse L, et al. A prospective clinical study of theophylline safety in 3810 elderly with asthma or COPD. Respir Med 2004; 98: 1016–1024CrossRefPubMedGoogle Scholar
  28. 28.
    Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337: 1412–1418CrossRefPubMedGoogle Scholar
  29. 29.
    Ukena D, Harnest U, Sakalauskas R, et al. Comparison of addition of theophylline to inhaled steroid with doubling of the dose of inhaled steroid in asthma. Eur Respir J 1997; 10: 2754–2760CrossRefPubMedGoogle Scholar
  30. 30.
    Wang Y, Eang C, Lin K, et al. Comparison of inhaled corticosteroid combined with theophyl-line and double-dose inhaled corticosteroid in moderate to severe asthma. Respirology 2005; 10: 189–195CrossRefPubMedGoogle Scholar
  31. 31.
    Shah AR, Sharples LD, Solanki RN, et al. Double-blind, randomized, controlled trial assessing controller medications in asthma. Respiration 2006; 73: 449–456CrossRefPubMedGoogle Scholar
  32. 32.
    American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelnkast in patients with poorly controlled asthma. Am J Respir Crit Care Med 2007; 175: 235–242CrossRefGoogle Scholar
  33. 33.
    Yurdakul AS, Caliir HC, Tunctan B, et al. Comparison of second controller medications in addition to inhaled corticosteroid in patients with moderate asthma. Respir Med 2002; 96: 322–329CrossRefPubMedGoogle Scholar
  34. 34.
    Nassif EG, Weinberger M, Thompson R, et al. The value of maintenance theophylline in steroid-dependent asthma. N Eng J Med 1981; 304: 71–75Google Scholar
  35. 35.
    Brenner M, Berkowitz R, Marshall N, et al. Need for theophylline in severe steroid-requiring asthmatics. Clinical Allergy 1988; 18: 143–150CrossRefPubMedGoogle Scholar
  36. 36.
    Vatrella A, Ponticiello A, Pelaia G, et al. Bronchodilating effects of salmeterol, theophylline and their combination in patients with moderate to severe asthma. Pulm Pharmacol Ther 2005; 18: 89–92CrossRefPubMedGoogle Scholar
  37. 37.
    Wechsler ME, Lehman E, Lazarus SC, et al. National Heart, Lung, and Blood Institute's Asthma Clinical Research Network. beta-Adrener-gic receptor polymorphisms and response to salmeterol. Ame J Respir Crit Care Med 2006; 173: 519–526CrossRefGoogle Scholar
  38. 38.
    Martinez FD. Safety of long-acting beta-agonists -an urgent need to clear the air. N Engl J Med 2005; 353: 2637–2639CrossRefPubMedGoogle Scholar
  39. 39.
    Salpeter SR, Buckley NS, Ormiston TM, et al. Meta-analysis: effect of long-acting beta-ago-nists on severe asthma exacerbations and asthma-related deaths. Ann Int Med 2006; 144: 904–912PubMedGoogle Scholar
  40. 40.
    Weinberger M, Abu-Hasan M. Life-threatening asthma during treatment with salmeterol. N Engl J Med 2006; 355: 852–853CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2009

Authors and Affiliations

  • Hironori Sagara
    • 1
  • Kenya Kouyama
    • 1
  • Takeshi Fukuda
    • 2
  • Sohei Makino
    • 3
  1. 1.Department of Respiratory MedicineDokkyo Medical University Koshigaya HospitalJapan
  2. 2.Department of Pulmonary Medicine and Clinical ImmunologyDokkyo Medical University School of MedicineJapan
  3. 3.Jobu Hospital for Respiratory DiseasesJapan

Personalised recommendations