Combined mediator antagonism for allergic rhinitis.

The drug treatment for allergic rhinitis comprises the use of intranasal corticosteroids, as well as histamine and cysteinyl leukotriene antagonists. Current guidelines advocate the use of histamine receptor antagonists for the treatment of intermittent or persistent allergic rhinitis, particularly due to seasonal pollen exposure, as these drugs have a fast onset of action (1). These drugs tend to be more effective for histamine mediated type symptoms such as sneezing, itching and rhinorrhoea, rather than on nasal blockage, which tends to be better controlled on intranasal corticosteroid therapy (2, 3). The cysteinyl leukotrienes are considered to be more responsible for symptoms of nasal congestion in allergic rhinitis, although their current role remains to be clearly defined in the light of emerging data (1, 4). Given the potential role for using combined mediator blockade with both histamine and leukotriene antagonists in allergic rhinitis, this has resulted in a number of clinical studies looking at a variety of outcome measures. Moreover, as there is a recognized link between allergic inflammation in the upper and lower airways, the use of combined mediator antagonism offers the potential for treating the unified airways in patients who have concomitant allergic rhinitis and asthma, as an alternative to using topical intranasal plus inhaled corticosteroids (5). The relative roles of histamine and cysteinyl leukotrienes have been studied using various challenge models in the upper and lower airways. An in vitro study in sensitized human bronchus showed that blockade of mast cell-mediated contraction occurred to a greater degree with a combination of a histamine antagonist (chloropheniramine), and a leukotriene antagonist (MK571) when compared with either drug alone (6). In vivo allergen broncho provocation testing in asthmatics found zafirlukast to reduce the early asthmatic response to a greater degree than loratadine, while each drug conferred a similar degree of protection against the late response (7). However the combination of both drugs was significantly more effective than either drug alone, suggesting additive antagonism. Interestingly in the skin, two separate studies have shown that fexofenadine but not montelukast attenuates the cutaneous allergen response, with there being no additivity when both drugs are given together (8, 9). Nasal challenge studies have also been performed which are pertinent to allergic rhinitis. The response to nasal mannitol challenge, an indirect acting pro-inflammatory osmotic stimulus, in patients with persistent allergic rhinitis, was attenuated to a significant degree by single doses of either desloratadine 5 mg or montelukast 10 mg when compared with placebo (10). In a nasal challenge study using another indirect stimulus, adenosine monophosphate, which acts via priming and degranulation of airway mucosal mast cells, also in persistent allergic rhinitis, a significant degree of attenuation of response was seen with either fexofenadine 180 mg or montelukast 10 mg given for 1 week compared with placebo, although there was no additive effect when both drugs were given in combination (11). In the same study, total nasal symptom scores were also significantly improved by either drug given alone compared with placebo, but again no additivity of response was seen with the combination. In this issue of Allergy , Kurowski et al. (12) report on a parallel group trial evaluating the effects of prophylactic treatment with either montelukast 10 mg or cetirizine 10 mg alone or in combination, given for 6 weeks prior to the grass pollen season and for a further 6 weeks during the season to patients with seasonal allergic rhinitis. In a fourth comparator group patients were pretreated for C. M. Jackson, B. J. Lipworth Tayside Centre For General Practice, University of Dundee; Asthma and Allergy Research Group, Ninewells Hospital and Medical School, University of Dundee, Dundee, UK