Real-World Efficacy and Safety of Extended-Release Methylphenidate (PRC-063) in the Treatment of ADHD in Pediatric and Adult Subjects: Results of a Phase IV Multicenter Comparison With Lisdexamfetamine Dimesylate.

OBJECTIVE: To evaluate the real-world efficacy, safety, and functional outcomes of PRC-063 (multilayer-release methylphenidate) versus lisdexamfetamine (LDX) in ADHD subjects in a phase IV, open-label study. METHOD: The primary endpoint was the change in the ADHD-DSM-5 Rating Scale (ADHD-5-RS) total score from baseline to Month 4. Secondary endpoints included a non-inferiority comparison between PRC-063 and LDX and measures of functioning and evening behavior. RESULTS: One hundred forty-three pediatric and 112 adult subjects were enrolled. Mean ADHD-5-RS scores (standard deviation) were reduced in pediatric (-16.6 [10.4]) and adult (-14.8 [10.6]) subjects treated with PRC-063 (p < .001). PRC-063 was non-inferior to LDX in the pediatric population but not in the adult population. Significant improvements were demonstrated in quality of life and functionality. Both medications were well-tolerated; more adverse events led to study discontinuation in pediatric subjects treated with LDX versus PRC-063. CONCLUSION: PRC-063 and LDX significantly improved ADHD symptomatology and functioning and were well-tolerated.

Factors that affect the allergic rhinitis response to ragweed allergen exposure.

BACKGROUND: People with seasonal allergic rhinitis (SAR) respond to allergen exposure differently. OBJECTIVE: To determine the factors that affect the rate and degree of symptom development upon controlled allergen exposure. METHODS: Study participants underwent skin prick testing (SPT) to selected aeroallergens, completed the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) and the 36-Item Short Form Health Survey, and provided a detailed allergy and exposure history. Nasal eosinophil counts and late-phase responses to SPT were measured. Eligible participants underwent a 3-hour ragweed pollen exposure in the Environmental Exposure Unit, rating rhinoconjunctivitis symptoms every 30 minutes. Data were analyzed using a mixed-effects model for repeated measures. RESULTS: One hundred twenty-three participants completed the study. Skin test reactivity to ragweed was not correlated with the rate of symptom development or with severity. Participants with positive SPT reactions to dust mite, dog, or grass and those with self-reported symptoms to dog or cat exposure tended to develop symptoms earlier and to a greater degree by 90 minutes. Self-report of SAR symptoms during the ragweed or grass season and RQLQ scores were positively associated with the rate and degree of symptom development. No other significant associations were detected. CONCLUSIONS: The rate of symptom development upon ragweed exposure was related to concomitant hypersensitivity to perennial allergens and grass pollen as determined by SPT and clinical history. The RQLQ was a powerful predictor of the priming response to ragweed, showing a dose-response-type association. These data suggest that a "prepriming" phenomenon is present in patients with SAR. No correlation was shown between symptomatic responses and degree of SPT reactivity.

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.

Effect of in vivo nitrate tolerance on hypersensitivity to NO donors after NO-synthase blockade.

Animals treated with nitric oxide synthase (NOS) inhibitors exhibit marked hypersensitivity to the blood pressure lowering effects of exogenous nitric oxide (NO) donors. We used this model as a sensitive index to evaluate the relative importance of reduced biotransformation of glyceryl trinitrate (GTN) to NO in the development of nitrate tolerance. NOS-blockade hypertension using N(G)-nitro-L-arginine methyl ester (L-NAME) caused a marked enhancement of the mean arterial pressure (MAP) decrease mediated by GTN in nontolerant rats. However, even large doses of GTN were unable to change the MAP in GTN-tolerant, NOS-blockade hypertensive animals. In contrast, the MAP responses to the spontaneous NO donor sodium nitroprusside (SNP) were completely unaltered in either tolerant rats or tolerant NOS-blockade hypertensive animals, indicating that NO-dependent vasodilatory mechanisms remain intact despite the development of GTN tolerance. The MAP-lowering effects of GTN in NOS-blockade hypertensive animals were restored 48 h after cessation of chronic GTN exposure. These alterations in the pharmacodynamic response to GTN during tolerance development and reversal were associated with parallel changes in the pattern of GTN metabolite formation, suggesting that the activity of one or more enzymes involved in nitrate metabolism was altered as a consequence of chronic GTN exposure. These findings suggest that the vasodilation resulting from the vascular biotransformation of GTN to NO (or a closely related species) is severely compromised in nitrate-tolerant animals, and that although other mechanisms may contribute to the vascular changes observed following the development of GTN tolerance, decreased GTN bioactivation is likely the most important.

Neuroprotection against ischemic brain injury conferred by a novel nitrate ester.

Nitrates exhibit a selectivity of action in different tissue types not fully recognized: in particular, the neuromodulatory and cardiovascular properties can be dissociated. A novel nitrate showed relatively weak systemic effects, but in the middle cerebral artery occlusion rat model of focal ischemia, reduced the cerebral infarct by 60-70% when administered 4 h after the onset of ischemia.