for the treatment of exacerbations. Furthermore, inhaled glucocorticoids are recommended for symptomatic COPD patients who have a documented spirometric response to these drugs or for patients with FEV1 ≤50% of the predicted value and frequent exacerbations (two or more per year), which require antibiotics or oral glucocorticoids, according to the GOLD guidelines (GISCOPD 2001). However, these recommendations are not universally agreed (Barnes 2000), as the effect of inhaled glucocorticoids at high doses on the frequency of exacerbations in patients with severe COPD is controversial (Paggiaro et al 1998; Burge et al 2000). Furthermore, the cost of glucocorticoids as well as their pharmacological proﬁle, as discussed above, does not justify indiscriminate administration of inhaled glucocorticoids in COPD. Fixed combinations of inhaled glucocorticoids and long-acting β2-agonists, namely ﬂuticasone–salmeterol (Dransﬁel and Bailey 2004) and budesonide–formoterol, were approved for use in COPD in the US and other countries based on clinical trials showing their effectiveness for health status and exacerbations of COPD (Calverley, Boonsawat, et al 2003; Calverley, Pauwels, et al 2003; Szafranski et al 2003). However, there were conﬂicting results when the different combination therapies were compared with the mono-component alone (Nannini et al 2004). More studies to deﬁnitively establish the effects of combination therapy in a single inhaler are required, including double-dummy trials on the comparative effects with separate adiministration of the two drugs (Nannini et al 2004). Other drugs Vaccines Vaccination can reduce severe complications and mortality from influenza in elderly patients, including those with COPD. Vaccination is recommended once in the autumn or, once in the autumn and once in the winter each year (Nichol et al 1994; Hak et al 1998). Pneumococcal vaccines have been used in COPD patients and can reduce complications of pneumonia in elderly patients, but there is no evidence to support its general use in COPD patients. Antibiotics Numerous large-scale controlled studies have shown that prophylactic antibiotics and chronic antibiotic administration have no effect on the frequency of exacerbations in COPD (MacNee and Calverley 2003). Prophylactic antibiotics are also ineffective in winter (MacNee and Calverley 2003). Current available data does not support the effectiveness International Journal of COPD 2006:1(4) Pharmacological treatment of COPD of prophylactic antibiotics against bacterial infections or exacerbations of COPD. Mucolytic agents Mucolytic agents such as ambroxol, erdosteine, carbocysteine, and iodinated glycerol produce a reduction in the frequency of exacerbations in chronic bronchitis compared with a placebo (Poole and Black 2000). Since these studies are of relatively short duration, between two to six months, and in patients with mild to moderate COPD (FEV1 >50% of the predicted value), the systematic administration of mucolytic drugs in COPD is not currently recommended. Antioxidants Oxidant stress plays an important role in the pathophysiology of COPD. Therefore, administration of antioxidant agents is an interesting treatment strategy. Although antioxidant and mucolytic drug N-acetylcysteine has been shown to reduce the frequency of exacerbations of COPD in most clinical trials (Grandjean et al 2000), a recent 3 year randomized placebo-controlled multicenter trial has shown that N- acetylcysteine is ineffective at prevention of deterioration in lung function and prevention of exacerbations in patients with COPD (Decramer et al 2005). On the basis of current data, N-acetylcysteine is not recommended for COPD (MacNee and Calverley). The details of various antioxidants trials are discussed elsewhere (Rahman 2006). Drugs in phase III of clinical development Phosphodiesterase-4 inhibitors Selective inhibitors of phosphodiesterase (PDE) type 4 increase intracellular concentrations of cyclic AMP by inhibiting its breakdown with consequent airway smooth muscle relaxation and anti-inﬂammatory effects on effector cells involved in the pathophysiology of COPD (Lipworth 2005). PDE4 enzymes include at least four isoenzymes (PDE4A, PDE4B, PDE4C, and PDE4D) (Soderling and Beavo 2000). Inhibition of PDE4B is mainly responsible for the anti-inﬂammatory effects of PDE4 inhibitors, whereas inhibition of PDE4D causes nausea which is one of the main adverse effects of these drugs (Lipworth 2005). Cilomilast and roﬂumilast, the two main orally active PDE4 inhibitors, are in the late phase III of clinical development for COPD (Lipworth 2005). Placebo-controlled studies for up to 6 months with cilomilast 15 mg twice daily and roﬂumilast 500 mg once daily have shown small, although signiﬁcant, improvements in lung function tests in patients with COPD (Compton et al 2001; Rabe et al 2005). PDE4 inhibitors 417