Theophylline has been relegated to a second- or even third-line
therapy in the treatment of
asthma and
chronic obstructive pulmonary disease (
COPD), behind glucocorticosteroids and beta2-agonists, although recent findings have suggested that
theophylline possesses anti-inflammatory and immunomodulatory effects in addition to its well-recognized effects as a
bronchodilator. In part,
theophylline has fallen out of favor because of its adverse side-effect profile, and this has led to the search for more effective and safer drugs based on the knowledge that
theophylline is orally active and that it is a nonselective
phosphodiesterase (PDE) inhibitor. This has led to the development of selective
PDE4 inhibitors, originally designed for depression, for the treatment of both
COPD and
asthma. Such drugs have shown clinical efficacy in the treatment of respiratory disease while having a considerably safer side-effect profile in comparison with
theophylline, particularly because there are no reported drug interactions with
PDE4 inhibitors, a feature that complicates the use of
theophylline. In addition, it is also becoming increasingly apparent that
theophylline is not working solely through PDE inhibition, as formerly assumed, and that this drug has other relevant pharmacologic activities that are likely to contribute to its efficacy, such as
adenosine receptor antagonism and induction of
histone deacetylase. Thus, the introduction of
PDE4 inhibitors represents an entirely new class of drugs for the treatment of respiratory disease.