Montelukast protects against nasal lysine-aspirin challenge in patients with aspirin-induced asthma

Abstract

Aspirin-induced asthma (AIA) is associated with increased production of cysteinyl leukotrienes (CysLT). Although leukotriene CysLT 1 -receptor antagonists improve lower airway outcomes in AIA, their effects and dose-response in the upper airway is less well documented.The present study evaluated the dose-response for montelukast (ML) against nasal lysine-aspirin challenge in patients with AIA.A total of 12 patients with a clear-cut history of AIA were randomised in double-blind cross-over fashion to receive single doses of ML 10 mg, ML 40 mg, or placebo (PL), with nasal lysine-aspirin challenge performed 12 h after dosing. Measurements of peak nasal inspiratory flow (PNIF), nasal blockage visual analogue scale (VAS) and forced expiratory volume in one second (FEV1) were made over 120 min after nasal lysineaspirin challenge.Prechallenge values for mean¡SEM PNIF (L?min -1 ) were not significantly different comparing all groups: ML 10 mg (132¡10), ML 40 mg (125¡12) and PL (132¡11). There was no significant difference comparing the maximum % PNIF fall from baseline between screening (46¡6) and PL (45¡6). The maximum % PNIF fall from baseline was significantly greater with PL (45¡6) compared to either ML 10 mg (34¡6) or ML 40 mg (32¡5). There was also a significantly greater mean % PNIF response over 120 min after lysine-aspirin challenge for PL (26¡7) compared to either ML 10 mg (14¡6) or ML 40 mg (17 ¡ 6). There were no significant differences for the maximum or mean % PNIF fall from baseline comparing ML 10 mg and ML 40 mg. A significant increase in nasal blockage VAS score was observed between baseline and 60 min or 120 min with PL but not with ML 10 mg or ML 40 mg. There were no significant differences for either the maximum or mean % FEV1 over 120 min as change from baseline comparing all groups.A single 10 mg dose of montelukast partially protected against the local effects of nasal lysine-aspirin challenge, with no further benefit at 40 mg. Nasal lysine-aspirin challenge appeared to be a reproducible and safe method in assessing patients with aspirin-induced asthma.

Nasal Blockage Induced by Oral Administration of Non-steroidal Anti-inflammatory Drugs in a Guinea-Pig Model of Allergic Rhinitis

“…It has been reported by researchers in the laboratories of the manufacturer of pranlukast that 10 -30 mg/ kg pranlukast caused potent inhibition in in vivo experiments of CysLT-mediated allergic reactions (21,22). The present result is different from clinical findings, in which not only the CysLT antagonist montelukast (18,19), but also the 5-lipoxygenase inhibitor zileuton (23) improved nasal function after aspirin administration in aspirin-sensitive asthmatics. However, from the present findings, we have to consider that CysLTs are not substantially involved in the indomethacin-induced nasal blockage.…”

“…In contrast to these results, various NSAIDs including aspirin and indomethacin cause upper and lower airway obstructive responses in a certain population of AIAR patients (2, 4 -6). Although a CysLT 1 -receptor antagonist effectively improved nasal responses to aspirin in such patients (18,19), the indomethacin-induced nasal blockage in the present study was not affected by a high dose of pranlukast. Therefore, the nasal blockage induced by indomethacin and diclofenac in the present study may not be an identical phenomenon to airway symptoms in clinical settings.…”

International Union of Basic and Clinical Pharmacology. LXXXIV: Leukotriene Receptor Nomenclature, Distribution, and Pathophysiological Functions

“…Although a definite explanation for this syndrome is not yet available, a large body of evidence supports the possibility that patients with AIA are particularly dependent on the bronchoprotective and anti-inflammatory properties of prostaglandin E 2 (Stevenson and Szczeklik, 2006) and that inhibition of COX-1 in these patients triggers MC activation and release of LTs as well as histamine and tryptase (Picado et al, 1992). In addition to the already discussed high levels of cysteinyl LTs and the localization of CysLT 1 R in nasal mucosa and leukocytes of patients with AIA (Sousa et al, 2002), the clinical relevance of the cysteinyl LTs in AIA has been supported by studies demonstrating that patients with AIA respond favorably to clinical treatment with LT modifiers (Dahlén et al, 1998Israel, 2000;Mastalerz et al, 2002a,b Obase et al, 2002Lee et al, 2004a;Micheletto et al, 2004;Park et al, 2010).…”

An update on the management of aspirin-exacerbated respiratory disease

“…31 Leukotriene-receptor antagonists also modify upper airway symptoms in AERD, as montelukast has been shown to decrease nasal symptoms during lysine aspirin challenge. 32 In a prospective study of the effect of montelukast on nasal polyposis, 3 months of montelukast therapy improved subjects' nasal symptom scores and decreased the nasal polyp tissue eosinophilia. The improvement was most significant in patients with perennial allergies.…”