mk-0524 and Rhinitis--Allergic--Seasonal

Prostaglandin D(2) is a proinflammatory mediator believed to be important in asthma and allergic rhinitis (AR). Allelic variants in the prostaglandin D(2) receptor type 1 (DP1) gene (PTGDR) have been suggested to be associated with asthma susceptibility.. We sought to investigate the efficacy of the DP1 antagonist laropiprant (alone or with montelukast) in asthma and seasonal AR and explore whether sequence variations in PTGDR are associated with asthma severity.. For asthma, in a double-blind crossover study, 100 patients with persistent asthma were randomized to placebo or laropiprant, 300 mg/d for 3 weeks, followed by addition of montelukast, 10 mg/d for 2 weeks. PTGDR promoter haplotypes were categorized as high, medium, or low transcriptional efficiency. The primary efficacy end point was FEV(1). For AR, in a double-blind parallel-group study, 767 patients sensitized to a regionally prevalent fall allergen with symptomatic fall rhinitis were allocated to laropiprant, 25 mg/d or 100 mg/d; cetirizine, 10mg/d; or placebo for 2 weeks. The primary end point was the Daytime Nasal Symptoms Score.. For asthma, no significant differences in FEV(1) or asthma symptoms were noted for laropiprant versus placebo or laropiprant plus montelukast vs montelukast (differences between montelukast and placebo: P

Topics: Acetates; Adolescent; Adult; Aged; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Cetirizine; Cross-Over Studies; Cyclopropanes; Double-Blind Method; Female; Genetic Predisposition to Disease; Haplotypes; Humans; Indoles; Male; Middle Aged; Promoter Regions, Genetic; Quinolines; Receptors, Prostaglandin; Rhinitis, Allergic, Seasonal; Sulfides; Young Adult

Nasal congestion in allergic rhinitis results from tissue edema and vasodilatation in the nasal mucosa. Of the mediators released by mast cells in response to allergens, prostaglandin (PG) D(2) is regarded as the most potent inducer of nasal congestion. Intranasal administration of PGD(2) reproduces the nasal blockade experienced by patients with seasonal allergic rhinitis (SAR) via its action on the PGD(2) (DP) receptor to induce nasal vasodilatation. Intranasal challenge with PGD(2) can be a useful tool for evaluating DP-receptor antagonists.. The main purpose of this study was to examine the ability of MK-0524, a DP receptor antagonist in development for the treatment of SAR, to block PGD(2) induced nasal congestion in healthy volunteers.. To this end, a double-blind, placebo-controlled, randomized, 3-period study was performed in 15 healthy subjects. During each period, subjects received MK-0524 25 mg, MK-0524 100 mg or placebo qd for 3 days. Twenty-four hours following the last dose, nasal provocations with PGD(2) were performed to determine the PD(75), which is the intranasal dose of PGD(2) that provokes a 75% increase in baseline total nasal airway resistance as performed by active anterior rhinomanometry.. Following treatment with MK-0524, the PD(75) (mean+/-SD) was significantly shifted from 15.8 +/- 18.3 mug/nostril during the placebo period to more than 512 mug/nostril both following the 25- and 100-mg (maximum challenge dose tested) dose regimen.. Whether this >45 fold increase in PD(75) will induce a clinically meaningful effect of MK-0524 will require clinical study in participants with SAR.

Topics: Administration, Oral; Adult; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Indoles; Male; Nasal Obstruction; Prostaglandin D2; Receptors, Immunologic; Receptors, Prostaglandin; Rhinitis, Allergic, Seasonal; Rhinomanometry