Antiasthmatic Effects of Mediator Blockade versus Topical Corticosteroids in Allergic Rhinitis and Asthma

Abstract

To compare the antiasthmatic efficacy of inflammatory mediator blockade versus topical corticosteroid therapy in patients with seasonal allergic rhinitis (SAR) and asthma, 14 patients were enrolled into a single-blind, double-dummy, placebo-controlled crossover study comparing 2 wk therapy of ( 1 ) 400 g orally inhaled budesonide plus 200 g intranasal budesonide (BUD) or ( 2 ) 10 mg oral montelukast plus 10 mg oral cetirizine (ML ϩ CZ). Before each treatment period, patients received 7 to 10 d placebo washout. All treatments were given once daily in the morning. Throughout the study, patients recorded the following domiciliary measures: peak expiratory flow (PEF), rescue inhaler requirement, asthma symptoms, and daily activity score. Laboratory measurements were made at trough of adenosine monophosphate (AMP) bronchial challenge and exhaled nitric oxide (NO). Compared with pooled placebo (PL), there were significant (p Ͻ 0.05) improvements in all domiciliary measures with both treatments (mean PEF [L/min] PL: 463; BUD: 478; ML ϩ CZ: 483). For geometric mean AMP PC 20 (mg/ml), there was an improvement (p Ͻ 0.05), compared with PL (47), for ML ϩ CZ (133) but not for BUD (51); whereas for NO (ppb) there was significant suppression with BUD (7.6) but not ML ϩ CZ (11.5) compared with PL (13.6). In conclusion, both combined mediator blockade and combined topical corticosteroids are equally effective antiasthma therapy in patients with asthma and SAR.Asthma and allergic rhinitis are common conditions, occurring with increasing prevalence, and frequently coexisting (1). Both conditions occur in patients with underlying atopy and have a common etiology and pathophysiology. Untreated rhinitis can result in increased lower respiratory tract inflammation (2) due to a variety of possible mechanisms (3). There is good evidence to show that treating the upper airway inflammation in seasonal allergic rhinitis with intranasal corticosteroids alone has beneficial effect on lower airway inflammation in terms of an improvement in bronchial hyperreactivity (4).Topically delivered inhaled and intranasal corticosteroids are widely recognized as effective anti-inflammatory treatment for both conditions (5, 6). They work by altering gene transcription to increase or decrease a plethora of cytokines, inflammatory mediators and enzymes, and adhesion molecules (7). Histamine and cysteinyl leukotrienes are important inflammatory mediators in the pathogenesis of asthma and allergic rhinitis. With the introduction of leukotriene receptor antagonists it is now possible to selectively block the effects of both of these mediators. This may have a theoretical advantage over corticosteroid therapy as a result of a better adverse effect profile as well as the preference for taking tablets rather than inhalers and nasal sprays.The anti-inflammatory properties of leukotriene receptor antagonists have been shown to exhibit beneficial effects on asthma disease control (8). Antihistamines have been considered to be effective in the management of asthma ...

Response profiles to fluticasone and montelukast in mild-to-moderate persistent childhood asthma

“…These findings corroborate studies that also failed to identify patient characteristics predictive of response to montelukast treatment for outcomes similar to ACDs: days without asthma in 2-to 5-year-old children, 29 total daily as-needed bagonist use in children 6 to 14 years of age, 5 and daytime symptoms in adults. 30 eNO, a biomarker for airway inflammation, 31,32 was reduced significantly more with an ICS (48% reduction) than with a LTRA (28% reduction, Table I), findings previously reported in smaller comparative monotherapy studies in children 33 and adults. 34,35 The reductions in eNO levels in our trial are of similar magnitude to reductions in eNO levels with ICSs 36,37 and LTRAs 38 in steroidnaive school-aged children with persistent asthma reported earlier in smaller studies.…”

Leukotriene C4 synthase polymorphisms and responsiveness to leukotriene antagonists in asthma

“…This retrospective genotype analysis was of 8 randomised, placebo-controlled, crossover, chronic dosing trials in mild-to-moderate persistent asthmatics performed in our department (Table 1) [7][8][9][10][11][12][13][14]. References 9 and 10 were sponsored by MSD (who make montelukast) (Merck Inc., Whitehouse Station, New Jersey, USA) and reference 12 was sponsored by Aventis (who make triamcinolone) (Aventis Inc., Bridgewater, New Jersey, USA); all other studies received no funding from the pharmaceutical industry.…”

Montelukast exerts no acute direct effect on NO synthases

“…Taken together these assays clearly gave no evidence of any direct inhibitory effect of montelukast on NOS isoenzymes within the concentration range from 10 -7 to 10 -4 M, far exceeding that achieved during drug therapy (39). Therefore, alternative explanantions for the decreased NO levels measured in expired air from asthmatic subjects after treatment with montelukast should be considered (18)(19)(20)(21)(22)(23)(24)(25)(26)(27).…”

“…Since no acute inhibitory effect on NO synthesis, neither directly on the three NOS isoenzymes, nor a suppression of the expression of iNOS was found, alternative explanantions for the decreased NO levels measured in expired air from asthmatic subjects after treatment with montelukast must be considered (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). They may be explained by changes in quantities or sites of NO generation, binding or more distal processes.…”

“…A number of studies in asthmatic subjects treated with montelukast have shown that such LTD 4 receptor blockade is associated with lower levels of exhaled NO (18)(19)(20)(21)(22)(23)(24)(25)(26)(27). In a murine allergic asthma model in which inflammation was induced by injection of ovalbumin, no evidence for a change in inducible NOS (iNOS) mRNA levels following montelukast treatment was observed (28).…”