Theophylline: Mechanism of action and use in asthma and chronic obstructive pulmonary disease

Drugs of Today

Volumn 40, Issue 1, 2004, Pages 55-69

  Hansel, Trevor T ^a   Tennant, Rachel C ^a   Tan, Andrew J ^a   Higgins, Lorna A ^a   Neighbour, Helen ^a   Erin, Edward M ^a   Barnes, Peter J ^a  

^a NATIONAL HEART AND LUNG INSTITUTE   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ALLOPURINOL; ANTICONVULSIVE AGENT; CIMETIDINE; CIPROFLOXACIN; CORTICOSTEROID; ERYTHROMYCIN; KETOCONAZOLE; PHENOBARBITAL; RIFAMPICIN; THEOPHYLLINE; ZAFIRLUKAST;

ABDOMINAL PAIN; ANOREXIA; ANTIINFLAMMATORY ACTIVITY; ANXIETY DISORDER; ASTHMA; CHRONIC OBSTRUCTIVE LUNG DISEASE; DIARRHEA; DRUG BLOOD LEVEL; DRUG EFFICACY; DRUG MECHANISM; EPILEPSY; GASTROESOPHAGEAL REFLUX; GASTROINTESTINAL SYMPTOM; HEADACHE; HEART ARRHYTHMIA; HEART PALPITATION; HEMATEMESIS; HUMAN; IMMUNOMODULATION; INSOMNIA; LOW DRUG DOSE; NAUSEA; OXIDATIVE STRESS; RESTLESSNESS; REVIEW; SEIZURE; SIDE EFFECT; TACHYCARDIA; TREATMENT OUTCOME; TREMOR; VOMITING;

ASTHMA; CLINICAL TRIALS; HUMANS; PULMONARY DISEASE, CHRONIC OBSTRUCTIVE; THEOPHYLLINE;

EID: 1442326051     PISSN: 16993993     EISSN: 16994019     Source Type: Journal    
DOI: 10.1358/dot.2004.40.1.799438     Document Type: Review

References (89)

1. Barnes, P.J. Theophylline: New perspectives for an old drug. Am J Respir Crit Care Med 2003, 167: 813-8.
2. Lam, A., Newhouse, M.T. Management of asthma and chronic airflow limitation. Are methylxanthines obsolete? Chest 1990, 98: 44-52.
3. Giembycz, M.A. Phosphodiesterase 4 inhibitors and the treatment of asthma: Where are we now and where do we go from here? Drugs 2000, 59: 193-212.
4. Giembycz, M.A. 4D or not 4D - the emetogenic basis of PDE4 inhibitors uncovered? Trends Pharmacol Sci 2002, 23: 548.
5. Robichaud, A., Stamatiou, P.B., Jin, S.L. et al. Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis. J Clin Invest 2002, 110: 1045-52.
6. Sakula A. A history of asthma. The FitzPatrick lecture 1987. J Royal Coll Physicians London 1988, 22: 36-44.
7. Persson, C.G. On the medical history of xanthines and other remedies for asthma: A tribute to HH Salter. Thorax 1985, 40: 881-6.
8. Weinberger, M., Hendeles L. Theophylline in asthma. N Engl J Med 1996, 334: 1380-8.
9. Weinberger, M., Hendeles, L., Bighley L. The relation of product formulation to absorption of oral theophylline. N Engl J Med 1978, 299: 852-7.
10. Rennard, S.I. Combination bronchodilator therapy in COPD. Chest 1995, 107(5 Suppl): 171S-5S.
11. Pauwels R. The use of theophylline in chronic obstructive pulmonary disease. Clin Exp Allergy 1996, 26 Suppl 2: 55-9.
12. Cazzola, M., Donner, C.F., Matera, M.G. Long acting beta(2) agonists and theophylline in stable chronic obstructive pulmonary disease. Thorax 1999, 54: 730-6.
13. Finney, M.J., Karlsson, J.A., Persson, C.G. Effects of bronchoconstrictors and bronchodilators on a novel human small airway preparation. Br J Pharmacol 1985, 85: 29-36.
14. Rabe, K.F., Magnussen, H., Dent G. Theophylline and selective PDE inhibitors as bronchodilators and smooth muscle relaxants. Eur Respir J 1999, 8: 637-42.
15. Miura, M., Belvisi, M.G., Stretton, C.D., Yacoub, M.H., Barnes, P.J. Role of potassium channels in bronchodilator responses in human airways. Am Rev Respir Dis. 1992, 146: 132-6.
16. Guillot, C., Fornaris, M., Badier, M., Orehek J. Spontaneous and provoked resistance to isoproterenol in isolated human bronchi. J Allergy Clin Immunol 1984, 74: 713-8.
17. Wanner A. Effects of methylxanthines on airway mucociliary function. Am J Med 1985, 79 (6A): 16-21.
18. Cushley, M.J., Holgate, S.T. Bronchodilatoractions of xanthine derivatives administered by inhalation in asthma. Thorax 1985, 40: 176-9.
19. Aubier, M., De Troyer, A., Sampson, M., Macklem, P.T., Roussos C. Aminophylline improves diaphragmatic contractility. N Engl J Med 1981, 305: 249-52.
20. Moxham J. Aminophylline and the respiratory muscles: An alternative view. Clin Chest Med. 1988, 9: 325-36.
21. Barnes, P.J., Pauwels, R.A. Theophylline in the management of asthma: Time for reappraisal? Eur Respir J 1994, 7: 579-91.
22. Pauwels, R., Van Renterghem, D., Van der Straeten, M., Johannesson, N., Persson, C.G. The effect of theophylline and enprofylline on allergen-induced bronchoconstriction. J Allergy Clin Immunol 1985, 76: 583-90.
23. Ward, A.J., McKenniff, M., Evans, J.M., Page, C.P., Costello, J.F. Theophylline - an immunomodulatory role in asthma? Am Rev Respir Dis 1993, 147: 518-23.
24. Mapp, C., Boschetto, P., dal Vecchio, L. et al. Protective effect of antiasthma drugs on late asthmatic reactions and increased airway responsiveness induced by toluene diisocyanate in sensitized subjects. Am Rev Respir Dis. 1987, 136: 1403-7.
25. Sullivan, P., Bekir, S., Jaffar, Z., Page, C., Jeffery, P., Costello, J. Antiinflammatory effects of low-dose oral theophylline in atopic asthma. Lancet 1994, 343(8904): 1006-8.
26. Jaffar, Z.H., Sullivan, P., Page, C., Costello, J. Low-dose theophylline modulates T-lymphocyte activation in allergen-challenged asthmatics. Eur Respir J 1996, 9: 456-62.
27. Kraft, M., Torvik, J.A., Trudeau, J.B., Wenzel, S.E., Martin, R.J. Theophylline: Potential antiinflammatory effects in nocturnal asthma. J Allergy Clin Immunol 1996, 97: 1242-6.
28. Kidney, J., Dominguez, M., Taylor, P.M., Rose, M., Chung, K.F., Barnes, P.J. Immunomodulation by theophylline in asthma. Demonstration by withdrawal of therapy. Am J Respir Crit Care Med 1995, 151: 1907-14.
29. Lim, S., Tomita, K., Carramori, G. et al. Low-dose theophylline reduces eosinophilic inflammation but not exhaled nitric oxide in mild asthma. Am J Respir Crit Care Med 2001, 164: 273-6.
30. Culpitt, S.V., De Matos, C., Russell, R.E., Donnelly, L.E., Rogers, D.F., Barnes, P.J. Effect of theophylline on induced sputum inflammatory indices and neutrophil chemotaxis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2002, 165: 1371-6.
31. Culpitt, S.V., Maziak, W., Loukidis, S., Nightingale, J.A., Matthews, J.L., Barnes, P.J. Effect of high dose inhaled steroid on cells, cytokines, and proteases in induced sputum in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1999, 160(5 Pt 1): 1635-9.
32. Polson, J.B., Krzanowski, J.J., Goldman, A.L., Szentivanyi, A. Inhibition of human pulmonary phosphodiesterase activity by therapeutic levels of theophylline. Clin Exp Pharmacol Physiol 1978, 5: 535-9.
33. Pauwels, R.A., Joos, G.F. Characterization of the adenosine receptors in the airways. Arch Int Pharmacodyn Ther 1995, 329: 151-60.
34. Bjorck, T., Gustafsson, L.E., Dahlen, S.E. Isolated bronchi from asthmatics are hyperresponsive to adenosine, which apparently acts indirectly by liberation of leukotrienes and histamine. Am Rev Respir Dis. 1992, 145: 1087-91.
35. Feoktistov, I., Polosa, R., Holgate, S.T., Biaggioni, I. Adenosine A2B receptors: A novel therapeutic target in asthma? Trends Pharmacol Sci 1998, 19: 148-53.
36. Cushley, M.J., Tattersfield, A.E., Holgate, S.T. Adenosine-induced bronchoconstriction in asthma. Antagonism by inhaled theophylline. Am Rev Respir Dis. 1984, 129: 380-4.
37. Ezeamuzie, C.I. Involvement of A(3) receptors in the potentiation by adenosine of the inhibitory effect of theophylline on human eosinophil degranulation: Possible novel mechanism of the antiinflammatory action of theophylline. Biochem Pharmacol 2001, 61: 1551-9.
38. Barnes, P.J. IL-10: A key regulator of allergic disease. Clin Exp Allergy 2001, 31: 667-9.
39. Mascali, J.J., Cvietusa, P., Negri, J., Borish, L. Antiinflammatory effects of theophylline: modulation of cytokine production. Ann Allergy Asthma Immunol 1996, 77: 34-8.
40. Oliver, B., Tomita, K., Keller, A. et al. Low-dose theophylline does not exert its antiinflammatory effects in mild asthma through upregulation of interleukin-10 in alveolar macrophages. Allergy 2001, 56: 1087-90.
41. Tomita, K., Chikumi, H., Tokuyasu, H. et al. Functional assay of NF-kappaB translocation into nuclei by laser scanning cytometry: Inhibitory effect by dexamethasone or theophylline. Naunyn Schmiedebergs Arch Pharmacol 1999, 359: 249-55.
42. Ichiyama, T., Hasegawa, S., Matsubara, T., Hayashi, T., Furukawa, S. Theophylline inhibits NF-kappa B activation and I kappa B alpha degradation in human pulmonary epithelial cells. Naunyn Schmiedebergs Arch Pharmacol 2001, 364: 558-61.
43. Yasui, K., H.u., B., Nakazawa, T., Agematsu, K., Komiyama, A. Theophylline accelerates human granulocyte apoptosis not via phosphodiesterase inhibition. J Clin Invest 1997, 100: 1677-84.
44. Chung, I.Y., Nam-Kung, E.K., Lee, N.M. et al. The downregulation of Bcl-2 expression is necessary for theophylline-induced apoptosis of eosinophil. Cell Immunol 2000, 203: 95-102.
45. Yasui, K., Agematsu, K., Shinozaki, K. et al. Theophylline induces neutrophil apoptosis through adenosine A2A receptor antagonism. J Leukoc Biol 2000, 67: 529-35.
46. Ohta, K., Yamashita N. Apoptosis of eosinophils and lymphocytes in allergic inflammation. J Allergy Clin Immunol 1999, 104: 14-21.
47. Urnov, F.D., Wolffe, A.P. Chromatin remodeling and transcriptional activation: the cast (in order of appearance). Oncogene 2001, 20: 2991-3006.
48. Hart, L.A., Krishnan, V.L., Adcock, I.M., Barnes, P.J., Chung, K.F. Activation and localization of transcription factor, nuclear factor-kappaB, in asthma. Am J Respir Crit Care Med 1998, 158 (5 Pt 1): 1585-92.
49. Ito, K., Caramori, G., Barnes, P.J. et al. Expression and activity of histone deacetylases in human asthmatic airways. Am J Respir Crit Care Med 2002, 166: 392-6.
50. Ito, K., Watanabe, S., Kharitonov, S., Hanazawa, T., Adcock, I.M., Barnes, P.J. Histone deacetylase activity and gene expression in COPD patients. Eur Respir J 18, 316S. 2001.
51. Ito, K., Lim, S., Caramori, G., Chung, K.F., Barnes P.J., Adcock, I.M. Cigarette smoking reduces histone deacetylase 2 expression, enhances cytokine expression and inhibits glucocorticoid actions in alveolar macrophages. FASEB J 2001, 15: 1100-2.
52. Ito, K., Barnes, P.J., Adcock, I.M. Glucocorticoid receptor recruitment of histone deacetylase 2 inhibits interleukin-1beta-induced histone H4 acetylation on lysines 8 and 12. Mol Cell Biol 2000, 20: 6891-903.
53. Ito, K., 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, 99: 8921-6.
54. Ito, K., Lim, S., Chung, K.F., Barnes, P.J., Adcock, I.M. Theophylline enhances histone deacetylase activity and restores glucocorticoid function during oxidative stress. Am J Respir Crit Care Med 2002, 165, A625.
55. Global Initiative for Asthma (GINA). Global strategy for asthma management and prevention. NHLBI/WHO workshop report. www.ginasthma. com. NIH Publication 2002: 02-3659.
56. Fabbri, L.M., Hurd, S.S. Global Strategy for the Diagnosis, Management and Prevention of COPD (GOLD): 2003 update. www.goldcopd. Eur Respir J 2003, 22: 1-2.
57. Wilson, A.J., Gibson, P.G., Couglan, J. Long-acting beta agonists versus theophylline for maintenance treatment of asthma. Cochrane Data-base Syst Rev 2000: CD001281.
58. Evans, D.J., Taylor, D.A., Zetterstrom, O., Chung, K.F., O'Connor, B.J., Barnes, P.J. A comparison of low-dose inhaled budesonide plus theophylline and high-dose inhaled budesonide for moderate asthma. N Engl J Med 1997, 337: 1412-8.
59. 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: 2754-60.
60. Lim, S., Jatakanon, A., Gordon, D., Macdonald, C., Chung, K.F., Barnes, P.J. Comparison of high dose inhaled steroids, low dose inhaled steroids plus low dose theophylline, and low dose inhaled steroids alone in chronic asthma in general practice. Thorax 2000, 55: 837-41.
61. Markham, A., Faulds D. Theophylline. A review of its potential steroid sparing effects in asthma. Drugs 1998, 56: 1081-91.
62. Rivington, R.N., Boulet, L.P., Cote, J. et al. Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995, 151 (2 Pt 1): 325-32.
63. Brenner, M., Berkowitz, R., Marshall, N., Strunk, R.C. Need for theophylline in severe steroid-requiring asthmatics. Clin Allergy 1988, 18: 143-50.
64. Tinkelman, D.G., Reed, C.E., Nelson, H.S., Offord, K.P. Aerosol beclomethasone dipropionate compared with theophylline as primary treatment of chronic, mild to moderately severe asthma in children. Pediatrics 1993, 92: 64-77.
65. Reed, C.E., Offord, K.P., Nelson, H.S., Li, J.T., Tinkelman, D.G. Aerosol beclomethasone dipropionate spray compared with theophylline as primary treatment for chronic mild-to-moderate asthma. The American Academy of Allergy, Asthma and Immunology Beclomethasone Dipropionate-Theophylline Study Group. J Allergy Clin Immunol 1998, 101 (1 Pt 1): 14-23.
66. Dahl, R., Larsen, B.B., Venge P. Effect of long-term treatment with inhaled budesonide or theophylline on lung function, airway reactivity and asthma symptoms. Respir Med 2002, 96: 432-8.
67. Littenberg B. Aminophylline treatment in severe, acute asthma. A meta-analysis. JAMA 1988, 259: 1678-84.
68. Parameswaran, K., Belda, J., Rowe, B.H. Addition of intravenous aminophylline to beta2 agonists in adults with acute asthma. Cochrane Database Syst Rev 2000: CD002742.
69. ZuWallack, R.L., Mahler, D.A., Reilly, D. et al. Salmeterol plus theophylline combination therapy in the treatment of COPD. Chest 2001, 119: 1661-70.
70. Kirsten, D.K., Wegner, R.E., Jorres, R.A., Magnussen, H. Effects of theophylline withdrawal in severe chronic obstructive pulmonary disease. Chest 1993, 104: 1101-7.
71. Chrystyn, H., Mulley, B.A., Peake, M.D. Dose response relation to oral theophylline in severe chronic obstructive airways disease. Br Med J 1988, 297: 1506-10.
72. Murciano, D., Auclair, M.H., Pariente, R., Aubier, M. A randomized, controlled trial of theophylline in patients with severe chronic obstructive pulmonary disease. N Engl J Med 1989, 320: 1521-5.
73. Mahler, D.A., Matthay, R.A., Snyder, P.E., Wells, C.K., Loke, J. Sustained-release theophylline reduces dyspnea in nonreversible obstructive airway disease. Am Rev Respir Dis 1985, 131: 22-5.
74. Guyatt, G.H., Townsend, M., Pugsley, S.O. et al. Bronchodilators in chronic air-flow limitation. Effects on airway function, exercise capacity, and quality of life. Am Rev Respir Dis 1987, 135: 1069-74.
75. Thomas, P., Pugsley, J.A., Stewart, J.H. Theophylline and salbutamol improve pulmonary function in patients with irreversible chronic obstructive pulmonary disease. Chest 1992, 101: 160-5.
76. Ashutosh, K., Sedat, M., Fragale-Jackson, J. Effects of theophylline on respiratory drive in patients with chronic obstructive pulmonary disease. J Clin Pharmacol 1997, 37: 1100-7.
77. Murciano, D., Aubier, M., Lecocguic, Y., Pariente, R. Effects of theophylline on diaphragmatic strength and fatigue in patients with chronic obstructive pulmonary disease. N Engl J Med 1984, 311: 349-53.
78. Fink, G., Kaye, C., Sulkes, J., Gabbay, U., Spitzer, S.A. Effect of theophylline on exercise performance in patients with severe chronic obstructive pulmonary disease. Thorax 1994, 49: 332-4.
79. Tsukino, M., Nishimura, K., Ikeda, A., Hajiro, T., Koyama, H., Izumi, T. Effects of theophylline and ipratropium bromide on exercise performance in patients with stable chronic obstructive pulmonary disease. Thorax 1998, 53: 269-73.
80. Mulloy, E., McNicholas, W.T. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993, 148:1030-6.
81. Melani, A.S., Pirrelli, M., Di Gregorio, A. Effects of inhaled salmeterol and orally dose-titrated theophylline on exercise capacity of stable COPD patients. Eur Respir J 1996, 9 (Suppl. 23): 391s.
82. Berry, R.B., Desa, M.M., Branum, J.P., Light, R.W. Effect of theophylline on sleep and sleep-disordered breathing in patients with chronic obstructive pulmonary disease. Am Rev Respir Dis 1991, 143: 245-50.
83. 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, 110: 648-53.
84. Rossi, A., Kristufek, P., Levine, B.E. et al. Comparison of the efficacy, tolerability, and safety of formoterol dry powder and oral, slow-release theophylline in the treatment of COPD. Chest 2002, 121: 1058-69.
85. Powell, J.R., Vozeh, S., Hopewell, P., Costello, J., Sheiner, L.B., Riegelman, S. Theophylline disposition in acutely ill hospitalized patients. The effect of smoking, heart failure, severe airway obstruction, and pneumonia. Am Rev Respir Dis 1978, 118: 229-38.
86. Zhang, Z.Y., Kaminsky, L.S. Characterization of human cytochromes P450 involved in theophylline 8-hydroxylation. Biochem Pharmacol 1995, 50: 205-11.
87. Barnes, P.J. Current therapies for asthma. Promise and limitations. Chest 1997, 111 (2 Suppl.): 17S-26S.
88. Howell, R.E., Muehsam, W.T., Kinnier, W.J. Mechanism for the emetic side effect of xanthine bronchodilators. Life Sci 1990, 46: 563-8.
89. Nishimura, K., Koyama, H., Izumi, T. Is oral theophylline effective in combination with both inhaled anticholinergic agent and inhaled beta 2-agonist in the treatment of stable COPD? Chest 1993, 104: 179-84.