![]() Recently novel mechanisms of action that may account for the effectiveness of theophylline in severe asthma have been elucidated. Despite the fact that theophylline has been used in asthma therapy for over 70 years, there is still considerable uncertainty about its molecular mode of action in asthma and its logical place in therapy. The frequency of side-effects at the previously recommended doses and the relatively low efficacy of theophylline have recently led to reduced usage, since inhaled β 2-agonists are far more effective as bronchodilators and inhaled corticosteroids have a greater anti-inflammatory effect. Some have even questioned whether theophylline is indicated in any patients with asthma, although others have emphasized the special beneficial effects of theophylline which still give it an important place in management of asthma. ![]() This has been reinforced by various national and international guidelines on asthma and COPD therapy. In many industrialized countries, however, theophylline has become a third-line treatment that is only used in poorly controlled patients as an add-on therapy. Theophylline remains one of the most widely prescribed drugs for the treatment of asthma and COPD world-wide, since it is inexpensive and widely available. Side effects are related to plasma concentrations and include nausea, vomiting and headaches due to PDE inhibition and at higher concentrations to cardiac arrhythmias and seizures due to adenosine A 1-receptor antagonism. Theophylline is now usually used as an add-on therapy in asthma patients not well controlled on inhaled corticosteroids and in COPD patients with severe disease not controlled by bronchodilator therapy. Theophylline is given systemically (orally as slow-release preparations for chronic treatment and intravenously for acute exacerbations of asthma) and blood concentrations are determined mainly by hepatic metabolism, which may be increased or decreased in several diseases and by concomitant drug therapy. Through this mechanism theophylline also reverses corticosteroid resistance and this may be of particular value in severe asthma and COPD where HDAC2 activity is markedly reduced. The molecular mechanism of bronchodilatation is inhibition of phosphodiesterase(PDE)3 and PDE4, but the anti-inflammatory effect may be due to histone deacetylase (HDAC) activation, resulting in switching off of activated inflammatory genes. More recently it has been shown to have anti-inflammatory effects in asthma and COPD at lower concentrations. It was originally used as a bronchodilator but the relatively high doses required are associated with frequent side effects, so its use declined as inhaled β 2-agonists became more widely used. Theophylline (3-methyxanthine) has been used to treat airway diseases for over 70 years. ![]()
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