metabolism (less than 15% is excreted in the urine unchanged) (Undem and Lichtenstein 2001). There is wide variation in the rate of elimination of theophylline. The half-life of elimination is on average 8 to 9 hours in adults and about 3.5 hours in children (Undem and Lichtenstein 2001). The half-life is increased in heart or liver failure, viral infections, in the elderly and with concomitant administration of some drugs such as cimetidine, ciprofloxacin, erythromycin, fluvoxamine, and oral con- traceptives. The half-life of elimination of theophylline is decreased in smokers and in chronic alcoholics, and with concomitant administration of drugs such as phenytoin, carbamazepine, rifampicin, and barbiturates (RS 2003). In addition to bronchodilation, theophylline may increase cardiac contractility, have a psychostimulant or diuretic effect, and increase diaphragmic contractility. A possible therapeutic importance for COPD has been attributed to this last effect. However, theophylline has some dis- advantages including its low therapeutic index which limits its administration. For this reason, and because of the large interindividual variability in its bioavail- ability, therapeutic monitoring of plasma theophylline concentrations is required. This involves taking regular blood samples after the theophylline concentrations reach a steady-state to ensure that the plasma theophylline concentration is within the therapeutic range for plasma theophylline concentrations for which the majority of patients obtain therapeutic effects without toxic effects, even though side effects are found with therapeutic concentrations. The therapeutic range for theophylline is between 10–20 μg/ml. Toxic side effects are associated with theophylline concentrations of more than 25 μg/ml. The risk of serious toxic effects, such as arrhythmias and convulsions, is high with theophylline concentrations of more than 40 μg/ml. At therapeutic plasma concentrations the main side effects of theophylline include anorexia, nausea, vomiting, insomnia, agitation, palpitation, and hypotension (Undem and Lichtenstein 2001). Glucocorticoids Inhaled glucocorticoids currently available include beclomethasone dipropionate, budesonide, ﬂunisolide, ﬂuticasone propionate and triamcinolone acetonide. There are no signiﬁcant differences between these drugs in terms of their efﬁcacy and tolerability (Undem and Lichtenstein 2001; RS 2003). Mometasone and ciclesonide, two new glucocorticoids in advanced clinical trials, seem to have a longer duration of action with the possibility of once International Journal of COPD 2006:1(4) Pharmacological treatment of COPD a day administration. Ciclesonide is a prodrug which is activated by a pulmonary esterase, with the possibility of increased selectivity of action and reduced systemic side effects resulting from glucocorticoid absorption. Glucocorticoids do not cause relaxation of the airway smooth muscle and therefore have no effect on acute bronchoconstriction. Glucocorticoids bind to specific cytoplasmic receptor proteins, which, in turn bind to regulatory proteins such as heat shock proteins and an immunophyllin (Undem and Lichtenstein 2001). The glucocorticoid–receptor interaction causes a receptor conformational change which leads to regulatory protein detachment, dimerization of the glucocorticoid receptor complexes and translocation to the nucleus where the drug-receptor complex binds to speciﬁc regulatory DNA sequences (glucocorticoid response elements, GRE), which modulate the expression of the adjacent genes. The time required for gene expression and protein synthesis explains the delayed effect of glucocorticoids which generally occurs several hours after administration. The anti-inﬂammatory mechanisms of action of glucocorticoids are largely due to the inhibition of gene expression which encodes for proinﬂammatory cytokines in the airway in- ﬂammatory cells (Undem and Lichtenstein 2001). Part of the anti-inﬂammatory effect of glucocorticoids may be due to the induction of lipocortin. Lipocortin is a protein which inhibits phospholipase A2. Phospholipase A2 enzymes cause cleavage of arachidonic acid from phospholipids in the plasma membrane. The arachidonic acid is the substrate for the synthesis of leukotrienes, prostaglandins, and thromboxane A2, which are important inﬂammatory mediators. Although glucocorticoids are generally effective in asthma, the anti-inﬂammatory effect of glucocorticoids in COPD patients remains controversial and seems to be very limited (Pauwels et al 1999; Vestbo et al 1999; Burge et al 2000; LHSRG 2000). This seems to reﬂect a pathophysiological difference between COPD and asthma. It has been suggested, on the basis of in vitro studies, that oxidative stress and cigarette smoke, which both play an important role in the pathophysiology of COPD, induce resistance to the action of glucocorticoids through mechanisms which involve the acetylation of histones. Histones are nucleic proteins that are important regulators in gene expression (Barnes 2000, 2003). Furthermore, the variable effects of glucocorticoids on airway inﬂammation may be due to the heterogeneity of the disease and the limited reproducibility of markers of inflammation (Keatings et al 1997; Confalonieri et al 1998). What is 413