Biology Reference
In-Depth Information
2.7 Other Substances
2.7.1 Theophylline
The xanthine theophylline has been in use as a remedy for respiratory disorders for
many decades. It was already known in 1957 that theophylline inhibits PDE
activities, along with the discovery of cAMP by Earl Sutherland and Ted Rall.
While the xanthine (together with caffeine as one pharmacologically active ingre-
dient in coffee, described by Dr Hyde Salter in 1859 to alleviate asthma) was the
first PDE inhibitor described, from our current perspective in 2010, it is a very weak
(IC
50
at PDE4 of 660
m
M) and unselective PDE inhibitor. Indeed, perhaps the only
PDE component that may add to therapeutic effects of theophylline is inhibition of
PDE3 (IC
50
of 110
m
M) that accounts in part for bronchodilation.
At therapeutic plasma levels theophylline primarily diminishes the activity of
phosphatidylinositol 3-kinase (PI3K)-
d
following its cellular activation by reactive
oxygen species (ROS), thus maintaining the activity of histone deacetylase-2
(HDAC2), which then supports to restore anti-inflammatory effectiveness of
glucocorticoids (To et al.
2010
). Steroid effectiveness is impaired in COPD proba-
bly as the result of the burden of ROS that prevails in this ailment (Barnes
2009
).
While ample affirmative evidence for this concept has been accumulated in cellular
and animals studies, clinical investigations with the objective of defining whether
theophylline, for example, reverses the resistance of sputum neutrophil accumula-
tion to glucocorticoids in COPD are not yet conclusive (Cosio et al.
2009
; Ford
et al.
2010
). At least in vitro, in alveolar macrophages from patients with COPD,
theophylline at only 1
m
M (a concentration at which none of the PDEs is inhibited)
that is ineffective alone was shown to partly restore the impaired inhibition of
LPS-induced interleukin-8 (IL-8) release by budesonide.
Another well-characterized mechanism of theophylline is the antagonism at
adenosine A1 as well as A2A and A2B receptors. In this context, endogenous
adenosine released from neutrophils when acting via A2A receptors on neutrophils
may serve to prevent their activation (Cronstein et al.
1985
). When released from
bronchial epithelial cells, endogenous adenosine acting via A2B receptors may
increase ciliary motility and cystic fibrosis transmembrane conductance regulator
(CFTR) activity by elevating cAMP (Rollins et al.
2008
). As a corollary, antago-
nism by theophylline may favor proinflammatory effects in neutrophils or impair
mucociliary functions of bronchial epithelial cells.
In clinical studies conducted with oral theophylline in COPD, this xanthine
improved lung function to a variable extent, however, by primarily acting as a
bronchodilator. For example, in a large trial the FEV
1
increase was comparable at
day 1 and 12 weeks after daily theophylline intake (ZuWallack et al.
2001
).
For theophylline, numerous side effects have been reported. Among them
are arrhythmias, seizures, palpitations, tremor, nausea, headache, and insomnia. In
addition, a considerable number of drug-drug interactions were described. For
example, allopurinol, cimetidine, and erythromycin increase, whereas phenobarbital,
