Review
Novel bronchodilators for the treatment of chronic obstructive pulmonary disease

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Because of the central role of bronchodilators in the treatment of respiratory diseases, there is still considerable interest in finding novel classes of broncholytic drugs. It can be hypothesized that a longer duration of bronchodilation with a once-daily agent might be associated with superior and more consistent efficacy over a range of endpoints than is achieved with a twice-daily agent. Several novel β2-adrenoceptor (AR) agonists, antimuscarinic agents, new combination platforms such as dual-acting muscarinic antagonist–β2-AR agonist bronchodilators, xanthine drugs and phosphodiesterase inhibitors, and their combination with another bronchodilator class, or an inhaled corticosteroid are currently under development with the aim of achieving once-daily dosing and, therefore, increasing the likelihood of compliance with therapy. This review paper mainly focuses on recent results of preclinical studies that have used human tissue and clinical trials of new bronchodilators in patients with chronic obstructive pulmonary disease.

Section snippets

Bronchodilators in COPD

Inhaled bronchodilators are the mainstay of the current management of chronic obstructive pulmonary disease (COPD) [1] (Box 1). Three classes of broncholytic agents are currently available: β2-adrenoceptor (AR) agonists, antimuscarinic agents and methylxanthines. These can be used individually or in combination [1]. The use of short-acting bronchodilators is advocated for the rescue of symptoms, whereas inhaled long-acting bronchodilators are recommended as the treatment of choice for

β2-Adrenoceptor agonists

A variety of β2-AR agonists with long half-lives are currently under development with the aim of achieving once-daily dosing. To differentiate them from the currently used long-acting β2-AR agonists (LABAs, such as formoterol and salmeterol, which induce a bronchodilator that is limited to 12 h), these compounds are now called ultra-LABAs. These agents include indacaterol, which received European regulatory approval in November 2009 and has already been launched in some countries worldwide,

Long-acting antimuscarinic agents

The growing evidence of the importance of tiotropium bromide in the maintenance treatment of COPD has spurred further research to identify new long-acting antimuscarinic agents (LAMAs) with a potentially improved risk–benefit profile compared with current LAMAs 2, 3. Muscarinic M3 receptor antagonists with high selectivity for the M3 over the M2 receptor are anticipated to have minimal cardiac effects. Moreover, novel antimuscarinic agents should elicit their intended pharmacological effect at

Novel xanthine drugs

Theophylline is a methylxanthine similar in structure to the common dietary xanthines caffeine and theobromine. It has been widely used in the treatment of patients with COPD. Several studies have examined its efficacy in these patients, but results are conflicting and difficult to interpret owing to differences in patient populations, duration of therapy and measurements of outcome. Studies comparing theophylline with β2-agonists found comparable improvements in spirometry and symptoms in both

Phosphodiesterase inhibitors

Another class of drugs that has been discovered are the selective phosphodiesterase (PDE) 4 inhibitors. The PDE4 isoenzyme was identified as a major therapeutic target because it is the predominant isoenzyme in the majority of inflammatory cells, including neutrophils, which are implicated in the pathogenesis of COPD. PDE4 is also present in airway smooth muscle, but to date selective PDE4 inhibitors have not shown acute bronchodilator activity in a variety of clinical trials 41, 42.

It is

Combination therapy in COPD

Current guidelines for the treatment of COPD recommend the combination of bronchodilators that work through different mechanisms in patients with continuous symptoms [1]. They also recommend a LABA plus an inhaled corticosteroid (ICS) for symptomatic patients with a FEV1 of less than 50% of predicted value, particularly if there have been frequent exacerbations [1]. It is clear, therefore, that there is considerable interest in developing inhalers containing a combination of several classes of

New classes of bronchodilators (new targets)

Novel classes of bronchodilators have proved difficult to develop, but there is still a continued interest in developing novel classes of bronchodilators that act via new targets, although progress to date has been limited.

Potassium channel openers, although effective in relaxing human airways in vitro, were not effective in treating COPD because they were more potent as vasodilators; this limited the dose that could be administered [59].

The bronchodilatory effect of vasoactive intestinal

Concluding remarks

Bronchodilators are still central to the symptomatic treatment of COPD. Because it has been documented that COPD patients who initiated treatment with once-daily dosing had significantly higher adherence than other daily dosing frequencies [4], there is a real interest within the pharmaceutical industry in developing novel inhaled bronchodilators with an improved duration of action compared to drugs currently on the market 2, 3. However, it has proven difficult to discover novel classes of

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