ISS conjugate attenuates the allergic symptoms in experimental allergic rhinitis sensitized to house dust mites

Abstracts S127

J ALLERGY CLIN IMMUNOL VOLUME 115, NUMBER 2

Intranasal Application of HDM/ISS Conjugate Attenuates the Allergic Symptoms in Experimental Allergic Rhinitis Sensitized to House Dust Mites C. Rhee1, J. Mo1, K. Takabayashi2, S. Quan1, J. Park1, I. Kim1, E. Raz2, C. Lee1; 1Otorhinolaryngology-Head and Neck Surgery, Seoul National University Hospital, Seoul, REPUBLIC OF KOREA, 2Medicine, University of California San Diego, San Diego, CA. RATIONALE: Because currently available medications for allergic rhinitis (AR) do not reverse allergen specific responses, pharmacotherapeutics are not curative and their daily use is often required for years. This study was conducted to determine whether intranasal delivery of Dermatophagoides farinae (Der f)/immunostimulatory sequence oligodeoxynucleotide (ISSODN) conjugate protects AR hypersensitivity responses and modulates allergen specific immune profiles in previously house dust mite sensitized mice. METHODS: C57BL/6 mice were systemically and then locally sensitized with crude extract of Der f. After injection of ISS-ODN or intranasal instillation of Der f/ISS-ODN conjugate, several parameters of allergic response were evaluated. RESULTS: Symptoms including scratching and sneezing, and eosinophilic infiltration into nasal mucosa were attenuated by ISS-ODN only or Der f/ ISS-ODN conjugate. Decreased IL-5 level and elevated IFN-gamma level by Der f/ ISS-ODN conjugate were observed in nasal lavage fluid. Der f-specific IgE was decreased by ISS-ODN or Der f/ ISSODN. In the supernatant of spleen cell culture, TGF-beta was significantly increased in Der f/ ISS-ODN conjugate group. CONCLUSIONS: The present results suggest that Der f/ISS-ODN conjugate delivery rapidly attenuated effecter cell responses in experimental AR model sensitized to Der f. and that intranasal therapy with this conjugate may be an effective alternative for the clinical management of AR. Funding: Seoul National University

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A Proof of Concept Trial Demonstrating Decongestant Activity of an Alpha2 Adrenergic Receptor Agonist in Patients With Seasonal Allergic Rhinitis (SAR) R. Berkowitz 1 , F. McCafferty 1 , M. E. Dato 2 ; 1 Atlanta Allergy & Asthma Clinic, Marietta, GA, 2Proctor & Gamble Pharmaceuticals, Mason, OH. RATIONALE: This study was conducted to determine the onset of action, efficacy, and safety of PG-118415 (PG) in subjects with moderate-to-severe SAR to ragweed allergen in an allergen exposure unit (AEU). PG has been shown to be a full alpha2 adrenergic receptor agonist. In preclinical work, PG caused a significant decrease in nasal airway resistance. METHODS: This single-center, double-blind, placebo-controlled, parallel-group AEU study evaluated a single oral dose of PG (24ug/kg) or pseudoephedrine liquid 60 mg (PS) or placebo (P). Open label oxymetazoline (OXY) was administered to subjects 6.25 hours post treatment as an internal control. Primary endpoints included nasal congestion change from baseline and time to onset of nasal congestion relief. RESULTS: Of 210 randomized subjects, 70 were to PG, 71 to PS and 69 to P. When compared to P, both PG (p=0.0273) and PS (p=0.0014) demonstrated statistically significant relief of nasal congestion. The onset of relief of nasal congestion was achieved significantly faster in the PS treatment group. PS decreased symptom scores and individual symptoms of itchy nose, sneezing, and itchy, watery, and red eyes to a significantly greater degree than did PG subjects. The OXY dose confirmed that this is an environment in which decongestant effect can be measured. The incidence of drug-related adverse events was 62.9% for PG, 18.3% for PS, and 21.7% for P; no serious AEs were reported. CONCLUSIONS: Both PS and PG demonstrated clinically and statistically significant relief of nasal congestion when compared to P. The effect of PS was more favorable than that of PG. Funding: Proctor & Gamble Pharmaceuticals

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Effect of Intranasal Corticosteroid Therapy for Perennial Nonallergic Rhinitis and Perennial Allergic Rhinitis J. Jung1, J. Lee2, J. Kim3, J. Choi1; 1Pediatrics, Dong-A University Hospital, Busan, DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA, 2Pediatrics, Masan Samsung Hospital, Masan, DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA, 3Pediatrics, Ulsan University Hospital, Ulsan, DEMOCRATIC PEOPLE’S REPUBLIC OF KOREA. RATIONALE: The efficacy of intranasal corticosteroids for the treatment of allergic rhinitis has been reported. But the efficacy of intranasal corticosteroids has not been compared between perennial nonallergic rhinitis(PNAR) and perennial allergic rhinitis(PAR). METHODS: 23 patients with PNAR and 19 patients PAR were enrolled in this study. Every patients received fluticasone propionate (FP) 200 g (100 g, bid) daily for 4weeks. Control group(n=16) was received only anti-histamin (Hydroxyzine, 0.6mg/kg/dose) intermittent. Efficacy of FP was evaluated by the mean change in nasal congestion, rhinorrhea, nasal itching, sneezing and total nasal symptom score (a sum of patient ratings of nasal congestion, rhinorrhea, nasal itching, sneezing). RESULTS: Both groups (PNAR and PAR) showed similar improvement of nasal symptom with FP 200 g compared with control(P<0.05). In the total population, both groups showed significant improvement from baseline in TNSS compared with control during each week of treatment(P<0.05). In PNAR and PAR, nasal congestion was significantly improved more than in control (P=0.001,P=0.000). Rhinorrhea and itching in PAR were improved more than in control(P=0.021, P=0.028). In sneezing, three groups showed no differences(P=1.00, P=0.31, P=0.29). CONCLUSIONS: Intranasal FP is an effective treatment for perennial nonallergic rhinitis as same as perennial allergic rhinitis.

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Short-Term Safety, Tolerability, and Pharmacokinetics of Desloratadine and Fexofenadine in Healthy Adults Identified as Desloratadine Slow Metabolizers (DSMs) R. A. Blum1, W. Kraft2, J. A. Stewart3, S. Meeves4, G. Georges4, S. J. Kovacs4; 1Buffalo Clinical Research Center, Buffalo, NY, 2Thomas Jefferson University, Philadelphia, PA, 3Aventis Pharmaceuticals, Laval, PQ, CANADA, 4Aventis Pharmaceuticals, Bridgewater, NJ. RATIONALE: Approximately 7-9% of the general population cannot metabolize desloratadine and are exposed to higher concentrations with recommended dosing. Prevalence is higher in the black population (2023%) with predominance in males. Safety and pharmacokinetics of desloratadine and fexofenadine were assessed in DSMs. METHODS: Randomized, double- blind, two-period, crossover study. DSMs received desloratadine 5 mg or fexofenadine HCI 180 mg QD for 7 Days during each period. Blood samples were collected on Days 1 and 7; trough samples on Days 5, 6, and 48, 72, 96, 120, and 144 hours after the last dose. 12-lead ECGs, vital signs, and AEs were recorded. RESULTS: Eighteen DSMs (15 males, 3 females) aged 32.2±7.3 years were enrolled. Desloratadine exposure increased with each dose; mean AUC(0-24) was 40±12 ng·hr/mL on Day 1 which increased to 196±53 ng·hr/mL on Day 7. Mean half-life was 112±56 hours. Steady state was not reached by Day 7. These data predict that desloratadine concentrations would increase 7.3±3.4-fold (range 4.1-18.6-fold) at steady state. Consistent with published reports in the general population, fexofenadine mean AUC(0-24) in DSM was 2095±1002 ng·hr/mL and 2357±909 ng·hr/mL on Days 1 and 7, respectively. Mean half-life was 17±7 hours. Both drugs were well tolerated. No changes from baseline were reported for ECGs, vital signs or AEs. CONCLUSIONS: No alteration of fexofenadine pharmacokinetics was apparent in DSMs. Substantial accumulation of desloratadine occurred with recommended dosing in DSMs. Although desloratadine was welltolerated in this healthy volunteer study, the long-term safety of increased desloratadine exposure in patients has yet to be established. Funding: Aventis Pharmaceuticals

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