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The use of β2 agonists for the control of symptoms is central to the treatment of patients with asthma. However, there is controversy surrounding the regular use of this drug class as numerous studies have demonstrated a variety of changes that can be considered unwanted attributes, particularly when these drugs are used regularly as monotherapy. These include increased bronchial hyper-responsiveness (BHR) to inhaled contractile agents1 and an increase in the allergen-induced early2 and late asthmatic response3 following regular treatment with short-acting β2 agonists (SABAs). Furthermore, a number of studies have suggested that regular treatment with inhaled SABAs and long-acting β2 agonists (LABAs) by inhalation leads to a loss of bronchoprotection4 5 and with salmeterol treatment an excess mortality in patients with asthma,6 a trend also observed with regular treatment with formoterol.7 This has led the Food and Drug Administration (FDA) to post black-box warnings on all medicines containing these LABAs.
Christian Virchow and colleagues from Rostock have provided data (see page 763) on a potential mechanism as to how regular treatment with salmeterol can paradoxically increase BHR.8 Eighteen patients with mild allergic asthma inhaled standard doses of salmeterol xinafoate for 2 weeks, followed by 2 weeks of treatment with the combination of fluticasone and salmeterol xinafoate. There was no overall statistically significant change in BHR for the whole group receiving monotherapy with salmeterol. However, 67% of the patients showed a modest increase in BHR as measured by a lowered PC20 (provocative concentration of histamine causing a 20% fall in the forced expiratory volume in 1 s) following monotherapy with salmeterol compared with baseline. This contrasted with a statistically significant improvement in BHR following the combination therapy. The levels of brain-derived neurotrophic factor (BDNF) were elevated in both serum and platelets obtained from patients receiving monotherapy with salmeterol, and the changes in BDNF levels correlated with the changes in PC20, although the levels of BDNF decreased significantly and there was no such correlation with changes in PC20 in the patients receiving the combination therapy. The changes in PC20 following monotherapy with inhaled salmeterol did not show a correlation with known β2 receptor polymorphisms.
A number of other investigators have suggested a role for BDNF in BHR as this is a mediator that is increased in subjects with asthma, both in the lung9 and in platelets,10 and which at least in animal models can induce BHR associated with changes in neuronal activity.11 In patients with asthma, the systemic levels of BDNF are also elevated, whilst they correlate with BHR.9 Increases in BDNF levels in the lung following allergen challenge of patients with asthma can be reduced by glucocorticosteroids.12 Airway sensory nerves have also been implicated in the pathogenesis of BHR induced by a number of stimuli,13 including treatment with regular β2 agonists,14 and it is of particular interest that platelet activation has also been observed to play a central role in allergen-induced BHR experimentally,15 16 supporting the observations of Virchow and colleagues in the present study. Interestingly, salmeterol enhanced the secretion of BDNF from tumour necrosis factor α (TNFα)-stimulated human peripheral blood mononuclear cells, whilst BDNF secretion was inhibited by fluticasone.
Clearly it would be of interest to see if salmeterol also caused an increase in BDNF secretion from platelets, thus allowing a clearer link between platelet activation, BDNF and the exacerbation of BHR observed following monotherapy with regular inhaled salmeterol. Whilst the acute benefits of β2 agonist therapy are well accepted, the worsening of asthma control with chronic β2 agonist treatment is not as well accepted, with a recent study reinforcing the safety of regular β2 agonists use.17 Nonetheless, a number of mechanisms have been put forward to explain worsening asthma control with regular β2 agonist treatment, including increased antigen burden,18 increased BHR induced by the (+) enantiomer14 and loss of bronchoprotection.4 Recently, the role of β2 receptors in asthma has become more complicated with the recognition that β-blockers, which have traditionally been contraindicated in the treatment of patients with asthma, can improve BHR when administered chronically to patients with mild asthma.19 This research has many parallels with the use of β-blockers in the treatment of patients with heart failure where this class of drug was once contraindicated as acute dosing produced adverse effects in such patients.20 It was then subsequently recognised that chronic dosing with β-blockers was beneficial in patients with heart failure, and the use of this drug class is now considered a central part of standard treatment guidelines. So-called “paradoxical pharmacology”,21 where there may be differential effects of acute versus chronic dosing of a given class of drug, would seem to be a very important issue when considering the use of drugs that recognize the β2 receptor.
Furthermore, given that it has been recently suggested that some β-blockers act as inverse agonists at the β2 receptor and activate novel signalling pathways that are required for the full asthma phenotype in mice,22 it would seem time to challenge the dogma that activation of β2 receptors chronically is a good thing. If nothing else, the study by Virchow and colleagues provides further support for why monotherapy with β2 receptor agonists has no role in the treatment of patients with asthma.
Competing interests CP is a co-founder of Verona Pharma which has an interest in developing novel drugs for treating respiratory diseases.
Provenance and Peer review Commissioned; not externally peer reviewed.
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