The use of leukotriene receptor antagonists (LTRAs) as complementary therapy in asthma

The cysteinyl-leukotrienes (cysLTs: LTC4, LTD4 and LTE4) have an important pathophysiological role in asthma. They are not only extremely potent bronchoconstrictors, but are also involved in the central mechanisms of the asthmatic inflammation and the subsequent remodelling of the airways. Allergen-induced bronchoconstriction as well as spontaneous exacerbations of asthma are associated with increased secretion of LTE4 in urine. This increase does not seem to be affected by high doses of inhaled or systemic corticosteroids. On the contrary, both in vivo and in vitro experiments indicate that corticosteroids to a certain degree may even upregulate the cysLTs synthesis. Moreover, inhaled medication may not get as far as the small airways, which are affected by inflammatory changes in asthma. Hence, the combination of an oral leukotriene receptor antagonist (LTRA) with an inhaled corticosteroid (ICS) seems a rational therapeutic approach to achieve a more complete control of the inflammatory mechanisms in asthma. The additive effects by combining an LTRA with an ICS have been investigated in adults as well as in children from 6-14 years of age. The addition of LTRA improves lung function, and reduces day and night time symptoms in all age groups. More importantly, the combination has also been found to decrease the exacerbation rates in all age groups. More recently, a few studies have compared the effect of additive therapy with LTRA and ICS versus long-acting beta 2-agonists (LABAs) and ICS in asthmatics. Depending on the patient and outcome parameters preselection, some studies found that addition of LABA to ICS resulted in a better lung function and a better overall disease control. Yet one--unsponsored-study, comparing the protective effects of LABA versus LTRA on inflammatory outcome parameters in asthma, found a significant protection against airway hyperresponsiveness to adenosine monophosphate (AMP), together with significant decreases in exhaled nitric oxide (NO) and sputum eosinophils following one week treatment with LTRA, whereas the initial protection by LABA on the AMP responsiveness was lost after one week, and no anti-inflammatory effects could be observed. Similar beneficial effects from LTRA therapy are expected in patients with nocturnal asthma, in whom a decreased responsiveness to corticosteroids has been demonstrated. The choice of either combination therapy has clinical implications. It seems that especially patients with a suboptimal lung function and a significant beta 2-agonist reversibility will benefit from the addition of a LABA, whereas asthmatics with mainly exercise-induced asthma, nocturnal symptoms, or a frequent worsening due to low tolerance to provocative stimuli, may mostly benefit by adding an LTRA to ICS. However, it remains to be determined which combination has the most profound effect on the inflammatory process and the structural changes in asthma.