Does theophylline have a role in COPD management

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Theophylline has been used for a long time in the management of COPD, but has not been formally studied in large randomized controlled trials [1]. Theophylline is used as a bronchodilator, with doses that give plasma concentrations of 10-20 mg/L. At these doses, theophylline results in reduced symptoms and a small improvement in lung function and exercise capacity [2,3]. In one study, theophylline improved dyspnoea by a reduction in hyperinflation, without significant changes in spirometry [4]. This may indicate an effect of the orally administered drug on small-airway function. Whether theophylline improves respiratory muscle function in patients with COPD is controversial, and there is little evidence that respiratory muscle weakness contributes to symptomatology in the chronic stable state.

There is increasing evidence that theophylline may have anti-inflammatory or immunomodulatory effects in asthma, and that these may be seen at lower doses than needed for bronchodilatation [5,6] (Fig. 11.1). The molecular basis for these effects is still uncertain, although some effects are mediated via a non-selective inhibition of phosphodiesterases (PDE) in inflammatory and immune cells. This has not yet been explored in COPD. In a recent study, theophylline (mean plasma level approximately 10mg/L) was

Bronchodilation (incl. small airways)

Bronchodilation (incl. small airways)

t Plasma t Mucociliary t Neutrophil t T-cell t Macrophage t Respirator exudation clearance function function function muscle strength

Fig. 11.1 Mechanisms of action of theophylline in chronic obstructive pulmonary disease (COPD).

t Plasma t Mucociliary t Neutrophil t T-cell t Macrophage t Respirator exudation clearance function function function muscle strength

Fig. 11.1 Mechanisms of action of theophylline in chronic obstructive pulmonary disease (COPD).

shown to decrease the proportion of neutrophils and the concentration of myeloperoxidase, an index of neutrophil activation, in induced sputum of patients with COPD [7]. This effect may be mediated by an inhibitory effect of theophylline on PDE4, the predominant PDE in neutrophils. However, the antiinflammatory effect of theophylline may be mediated by some other molecular mechanism, since the inhibitory effect on PDE activity is very small at these concentrations of theophylline. Interestingly, recent studies have demonstrated that therapeutic concentrations of theophylline decrease neu-trophil survival in vitro, whereas PDE4 inhibitors have the reverse effect [8]. An additional mechanism that might contribute to a beneficial effect of theophylline in COPD is an increase in interleukin-10 (IL-10) release, as has been demonstrated in asthmatic patients [9]. IL-10 is a potent anti-inflammatory cytokine that inhibits the release of inflammatory cytokines such as tumour necrosis factor-a (TNF-a) and IL-8, as well as increasing the expression of antiproteases. These studies suggest that theophylline might have an anti-inflammatory effect in COPD and that it may theoretically reduce the decline in lung function. However, it is unlikely that the necessary long-term randomized controlled trial will be conducted, as these drugs are cheap and pharmaceutical companies may be unwilling to invest in such expensive studies.

Side effects have been the main problem in the clinical use of theophylline in COPD patients. Side effects, particularly nausea, vomiting and headaches, occur increasingly as plasma concentrations rise from 10 to 20mg/L and may be commoner in elderly patients. Benefit may be obtained at concentrations below 10mg/L, so that aiming for a therapeutic concentration of 5-10mg/L, as in patients with asthma, may be adequate.

Overall, theophylline is a useful additional treatment for patients with COPD, improving symptoms and lung function and may have the additional benefit of reducing the inflammatory response. More long-term studies and further investigation of its anti-inflammatory effect are now indicated.

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