Onset of action of loratadine/montelukast in seasonal allergic rhinitis subjects exposed to ragweed pollen in the Environmental Exposure Unit.

Onset of action is recognized as an important pharmacologic property of allergic rhinitis (AR) medications. This study was designed to evaluate the onset of action of loratadine/montelukast (L/M; 10 mg/10 mg) versus placebo in subjects with ragweed-induced seasonal AR (SAR). A single-center, double-blind, parallel-group study of ragweed-sensitive AR subjects (n = 310) was performed in the Environmental Exposure Unit (EEU). Subjects were exposed to ragweed pollen in the EEU and symptoms were recorded at 30, 60, 90, and 120 minutes before a single dose of L/M or placebo. After dosing, symptoms were recorded for 4 hours, at 15-minute intervals for the first 2 hours and at 30-minute intervals for the final 2 hours. The primary end point was time to onset of action of L/M, defined as the first time point at which the mean change from baseline in total symptom score (TSS) for L/M became and remained significantly better than placebo. Secondary end points included nasal congestion scores and peak nasal inspiratory flow (PNIF). The onset of action of L/M for TSS was 1 hour and 15 minutes (p = 0.005 versus placebo). L/M reduced nasal congestion as indicated by significant improvements in both the nasal congestion score (p = 0.011) and the PNIF measurements (p = 0.007) within 1 hour and 15 minutes postdose. The incidence of treatment-emergent adverse events was similar between groups. The onset of action after treatment with L/M was 1 hour and 15 minutes for TSS, as well as nasal congestion. L/M was well tolerated.

Efficacy of loratadine-montelukast on nasal congestion in patients with seasonal allergic rhinitis in an environmental exposure unit.

BACKGROUND: Nasal congestion is considered to be one of the most bothersome symptoms of allergic rhinitis (AR) and often the most difficult to treat. Oral therapies providing safe, effective, and reliable relief of AR symptoms, including nasal congestion, are limited. OBJECTIVE: To evaluate the efficacy of a single dose of loratadine-montelukast (10 mg/10 mg) vs placebo and phenylephrine (10 mg) in relieving nasal congestion over 6 hours after ragweed pollen exposure in the environmental exposure unit at the Kingston General Hospital. METHODS: After a screening visit and up to 6 priming visits, patients who met minimum symptom requirements during ragweed pollen exposure were randomized to receive loratadine-montelukast, phenylephrine, or placebo. Patients evaluated nasal congestion and other symptoms of AR and measured peak nasal inspiratory flow before dosing and at 20-minute intervals during the subsequent 8 hours of pollen exposure. RESULTS: During the first 6 hours after treatment (primary end point), loratadine-montelukast treatment resulted in greater improvement in the mean nasal congestion score vs placebo (P = .007) and phenylephrine (P < .001). Loratadine-montelukast was more effective than placebo (P < or = .02) and phenylephrine (P < or = .002) in relieving total symptoms, nasal symptoms, and nonnasal symptoms and in improving peak nasal inspiratory flow. There were no statistically significant differences between phenylephrine and placebo for any measures. Fewer patients in the loratadine-montelukast group (3.9%) reported adverse events than in the phenylephrine (7.9%) and placebo (7.1%) groups; most adverse events were mild or moderate. CONCLUSIONS: Loratadine-montelukast was more effective than placebo and phenylephrine in relieving nasal congestion and other nasal and nonnasal symptoms resulting from ragweed pollen exposure. There was no statistically significant difference between phenylephrine and placebo.

Efficacy of levocetirizine compared with montelukast in subjects with ragweed-induced seasonal allergic rhinitis in the Environmental Exposure Unit.

Levocetirizine dihydrochloride, a potent H1-receptor antagonist, and montelukast sodium, a selective leukotriene receptor antagonist, have been approved for the treatment of seasonal allergic rhinitis (SAR), but target two different pathways that cause SAR symptoms. The study objective was to compare the efficacy of levocetirizine (LCTZ), 5 mg, and montelukast (MLKT), 10 mg, in reducing SAR symptoms in ragweed-sensitive adults exposed to ragweed pollen in the Environmental Exposure Unit (EEU). This randomized, double-blind, placebo-controlled, parallel-group study of 418 adult subjects with SAR to ragweed compared the efficacy of LCTZ, MLKT, and placebo administered once daily (11:00 A.M.) for 2 consecutive days in the EEU. There were three evaluation periods: period I, 0-5 hours after first dose; period II, 22.5-24 hours after first dose; and period III, 0-4.5 hours after second dose. The primary efficacy variable was the Major Symptom Complex (MSC) score (six symptoms) over period I. Both active drugs significantly improved the MSC score compared with placebo in all periods. The adjusted mean MSC score difference between LCTZ and MLKT was -0.93 (p = 0.100) in period I, -3.11 (p < 0.001) in period II, -2.42 (p < 0.001) in period III, and -1.88 (p < 0.001) over the total treatment period. The same trends were observed for the Total Symptom Complex score (10 symptoms) and most individual symptoms. Subject-reported global satisfaction was greater for LCTZ compared with MLKT and placebo. All treatments had a favorable safety profile. LCTZ, 5 mg, was more effective than MLKT, 10 mg, in subjects with SAR and had better subject-reported global satisfaction.

Experimental models for the evaluation of treatment of allergic rhinitis.

OBJECTIVE: To review the experimental models used for the clinical evaluation of treatments for allergic rhinitis. DATA SOURCES: Peer-reviewed clinical studies and review articles were selected from the PubMed database using the following relevant keywords: allergic rhinitis in combination with efficacy, wheal and flare, nasal challenge, park, cat room, or exposure unit. Regulatory guidance documents on allergic rhinitis were also included. STUDY SELECTION: The authors' knowledge of the field was used to limit references with emphasis on recent randomized and controlled studies. References of historical significance were also included. RESULTS: Traditional outpatient studies are universally accepted in the evaluation of treatment for allergic rhinitis. Experimental models provide ancillary information on efficacy at different stages of treatment development. Skin histamine and allergen challenge, as well as direct nasal challenge with histamine and allergen, are often used as early steps in assessing drug efficacy. Exposure units, park settings, and cat rooms better approximate real life by drawing on the natural mode of allergen exposure and delivering the sensitizing allergen to allergic individuals in the ambient air. Park studies make use of allergens in the outdoors, whereas cat rooms and exposure units present the sensitizing allergens indoors, with the latter providing consistent predetermined allergen levels. Exposure unit and park studies are acknowledged for the determination of onset of action and are also suited to the measurement of duration of effect and other measures of efficacy. Onset and duration of effect are 2 important pharmacodynamic properties of antihistamines and nasal corticosteroids as determined by the Allergic Rhinitis and Its Impact on Asthma and the European Academy of Allergology and Clinical Immunology workshop group. CONCLUSIONS: All challenge models serve as important instruments in the evaluation of antiallergic medications and provide additional information to complement traditional studies.

Comparative efficacy of cetirizine and fexofenadine for seasonal allergic rhinitis, 5-12 hours postdose, in the environmental exposure unit.

In a previous study, cetirizine and fexofenadine similarly relieved seasonal allergic rhinitis symptoms in the first 5 hours, but cetirizine was more effective at 21-24 hours postdose. This randomized, double-blind, placebo-controlled study compared the response to treatment between 5 and 12 hours. Eligible ragweed allergic subjects were exposed to pollen in the Environmental Exposure Unit and randomized (n = 599) to a single dose of cetirizine, 10 mg; fexofenadine, 180 mg; or placebo (2.5:2.5:1). The primary efficacy end point was the change from baseline in total symptom severity complex (TSSC) score at 12 hours postdose. TSSC score was the sum of self-rated scores (0 = absent to 3 = severe) for runny nose, sneezing, itchy nose/palate/throat, and itchy/watery eyes, recorded half-hourly. Mean baseline TSSC scores were similar: 9.2, cetirizine and fexofenadine; 8.9, placebo. Reductions in TSSC scores from baseline were 4.3 at 12 hours and 5.0 overall (i.e., average over 5-12 hours postdose) for cetirizine and 3.4 and 4.4, respectively, for fexofenadine. Cetirizine produced a 26% greater reduction in TSSC at 12 hours (p = 0.001) and 14% greater reduction in TSSC overall (p = 0.006) compared with fexofenadine. Cetirizine and fexofenadine reduced TSSC scores (p < 0.001) and individual symptoms (p < 0.05) more than placebo. However, cetirizine was more effective than fexofenadine (p < 0.05) for runny nose and sneezing (12 hours and overall), itchy/watery eyes (12 hours), and itchy nose/throat/palate (overall). Incidence of treatment-emergent adverse events and somnolence were similar among groups: cetirizine, 25.3 and 0.8%, respectively; fexofenadine, 29.6 and 0%, respectively; placebo, 35.0 and 0%, respectively. In conclusion, cetirizine produced greater relief of seasonal allergic rhinitis symptoms than fexofenadine at 12 hours postdose and over the 5- to 12-hour postdose period.

Randomized double-blind comparison of cetirizine and fexofenadine after pollen challenge in the Environmental Exposure Unit: duration of effect in subjects with seasonal allergic rhinitis.

There is published evidence that cetirizine has a longer duration of effect than fexofenadine. This study compared duration of effect and other measures of efficacy of cetirizine, 10 mg; fexofenadine, 180 mg; and placebo in allergic subjects exposed to pollen in the Environmental Exposure Unit. Eligible subjects (n = 575) were exposed to ragweed pollen (day 1, 7 hours; day 2, 5 hours) and randomized in double-blind fashion to once-daily cetirizine, 10 mg; fexofenadine, 180 mg; or placebo. The total symptom severity complex (TSSC) score, the primary efficacy variable, was based on four rhinoconjunctivitis symptoms rated at 20-minute intervals. Treatment evaluation was divided into three periods: period 1 TSSC, average of 15 scores obtained 0-5 hours after the first dose; period 2 TSSC, average of 9 scores obtained 21-24 hours after the first dose; and period 3 TSSC, average of 6 scores obtained 0-2 hours after the second dose. The primary efficacy end point was the change from baseline TSSC at period 2. Baseline TSSC was the final pretreatment score on day 1 and was 9.7 for cetirizine, 9.8 for fexofenadine, and 9.7 for placebo. For the primary efficacy end point, the reduction in baseline TSSC at period 2 was greater for cetirizine (-3.6) compared with fexofenadine (-2.7; p < 0.001) and placebo (-2.0; p < 0.001), representing a 33% greater reduction for cetirizine versus fexofenadine. Cetirizine continued to reduce TSSC more than fexofenadine (-5.2 versus -4.6; p = 0.017) and placebo (-3.9; p < 0.001) (period 3). Similar efficacy was observed in period 1 for both active treatments. Treatment-related adverse events were similar in all groups with an incidence of somnolence of 1.3% for both active medications. In conclusion, cetirizine produced a 33% greater reduction in SAR symptoms over the 21- to 24-hour interval after the first dose and for 40 minutes after the second dose, indicating a superior and longer duration of effect, which is relevant because both are once-daily medications. Onset of action was comparable and both treatments were safe and well tolerated.

A comparison of the effect of diphenhydramine and desloratadine on vigilance and cognitive function during treatment of ragweed-induced allergic rhinitis.

BACKGROUND: Decrements in cognitive performance are associated with the use of sedating antihistamines. Most, but not all, second-generation antihistamines have been found to be nonsedating. OBJECTIVE: To examine the central nervous system (CNS) profile of a new second-generation antihistamine, desloratadine. METHODS: Subjects with ragweed-induced allergic rhinitis (aged 18-60 years) who demonstrated a predetermined severity of symptoms after priming with ragweed pollen in the Environmental Exposure Unit were randomized to receive a single dose of desloratadine, 5 mg; diphenhydramine, 50 mg; or placebo. A comprehensive battery of repeatable, automated neuropsychological tests was administered to subjects before treatment (symptomatic baseline) and 90 minutes after taking study medication. RESULTS: Both desloratadine (P = .04) and diphenhydramine (P < .01) alleviated the symptoms of allergic rhinitis compared with placebo, but treatment with diphenhydramine was associated with clinically meaningful decrements on all vigilance parameters (P < .05 for desloratadine-diphenhydramine contrasts). Also, subjects treated with diphenhydramine performed significantly worse than subjects given desloratadine or placebo across all cognitive domains evaluated. Most effect sizes for the mean desloratadine and diphenhydramine differences were between 0.4 and 0.8 (moderate to high). Stanford Sleepiness Scale scores also indicated significantly more somnolence with diphenhydramine vs desloratadine or placebo (P < .001). There were no significant differences on any of the cognitive parameters between subjects treated with desloratadine and those given placebo. CONCLUSIONS: Desloratadine improved ragweed-induced allergic rhinitis symptoms without adversely affecting performance. Diphenhydramine improved allergic rhinitis symptoms but caused significant decrements in vigilance and cognitive functioning. Thus, efficacy of antihistamine treatment must be balanced against the associated effects on CNS functioning.