piperidines and Nasal-Obstruction

A therapeutic role for histamine H(3) receptor antagonism in allergic rhinitis has been proposed and may be complimentary to the well-known benefits of H(1) receptor antagonism. Combined H(1)/H(3) blockade has therefore been investigated as a novel therapeutic approach that may enhance symptom relief, particularly nasal blockage.. Two novel H(1)/H(3) dual receptor antagonists were investigated in phase I and II safety and efficacy studies. One molecule (GSK1004723) was designed for intranasal administration as a suspension or solution and the other molecule (GSK835726) for oral administration. In phase I and II studies, both molecules were compared with an active control and/or placebo in randomised studies. In phase II studies, efficacy was assessed in an environmental allergen challenge chamber (ECC). Subjects with seasonal allergic rhinitis were exposed to allergen to induce symptoms. Efficacy and safety was measured over 4, 7 and 20-24 h post-dose. The endpoints included total nasal symptom score and nasal blockage.. Intranasal suspension of GSK1004723 and oral GSK835726 were well tolerated. Single-dose intranasal suspensions of GSK1004723 (220, 1,100 μg) failed to demonstrate clinically significant attenuation of symptoms of allergic rhinitis induced in the ECC. Single (10, 50, 100 mg) and 3-day repeat (10 mg) dose oral GSK835726 demonstrated clinically significant attenuation of symptoms in the ECC comparable to cetirizine 10 mg. Three-day repeat dosing of the intranasal solution GSK1004723 1,000 μg also demonstrated a statistically significant attenuation of nasal symptoms, but was less than seen with cetirizine and GSK835726 and caused initial nasal discomfort.. Combined H(1)/H(3) antagonism did not show differentiation from H(1) antagonism in reducing total nasal symptom score or nasal blockage.

Topics: Administration, Intranasal; Anti-Allergic Agents; Cetirizine; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Female; Histamine H1 Antagonists; Histamine H3 Antagonists; Humans; Male; Naphthalenes; Nasal Obstruction; Phthalazines; Piperidines; Rhinitis, Allergic, Seasonal

H1 antihistamines constitute one of the main references for the treatment of allergic rhinitis. Classically, these drugs have been considered effective in controlling sneezing, rhinorrhea and itching, though they have not been regarded as particularly effective in application to nasal obstruction. The most recent studies, involving second-generation H1 antihistamines (desloratadine, fexofenadine, levocetirizine, rupatadine), have shown these drugs to offer effects upon nasal obstruction significantly superior to those of placebo. The present review examines the effect of bilastine, a new, potent and highly specific H1 antihistamine without sedative effects or cardiac toxicity, upon nasal obstruction. The analysis of the data from the different clinical trials indicates that in patients with allergic rhinitis, the effect of bilastine upon nasal obstruction is superior to that of placebo and similar to that of other second-generation H1 antihistamines, manifesting within 24 hours after the start of treatment.

Topics: Benzimidazoles; Clinical Trials as Topic; Histamine H1 Antagonists; Humans; Nasal Obstruction; Piperidines; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal

Bepotastine besilate is a selective histamine1-receptor antagonist and mast cell stabilizer with inhibitory effects on eosinophilic activity.. To evaluate the safety and efficacy of 1.5% bepotastine besilate ophthalmic solution in alleviating nonocular symptoms induced by a conjunctival allergen challenge (CAC), a clinical model of allergic conjunctivitis.. This was a single-center, double-masked, randomized, placebo-controlled clinical trial performed from March 1 to April 4, 2007. Patients 10 years or older with a history of allergic conjunctivitis and a reproducible, positive, clinical response to a CAC were eligible. Patients received either placebo or 1.5% bepotastine besilate, 1 drop in each eye. After 15 minutes, 8 hours, or 16 hours after dosing, a CAC was performed and patients evaluated nonocular symptoms using standardized grading scales.. Seventy-one patients were enrolled in the study, and 66 comprised the per protocol population. A clinically meaningful reduction (> or = 1.0 unit) compared to placebo was achieved for rhinorrhea and nasal congestion at most time points after 1.5% bepotastine besilate instillation at 8 hours before a CAC test. Significant reductions (P < or = .05) in mean values were seen with 1.5% bepotastine besilate at 15 minutes and 8 hours after dosing for CAC-induced nasal congestion, rhinorrhea, ear or palate pruritus, nasal pruritus, and summed nonocular composite symptom (NOCS) scores and also at 16 hours after dosing for nasal congestion and rhinorrhea.. The 1.5% bepotastine besilate formulation produced statistically significant reductions after a CAC in individual nonocular symptoms and NOCS scores at onset of allergic response and for at least 8 hours after instillation, with the greatest reduction seen for nasal congestion and rhinorrhea.

Topics: Adult; Allergens; Conjunctivitis, Allergic; Double-Blind Method; Female; Histamine Antagonists; Humans; Immunization; Male; Middle Aged; Nasal Obstruction; Ophthalmic Solutions; Piperidines; Pyridines

Patients with allergic rhinitis demonstrate hyperreactive response in distilled water nasal provocation, shown by significant increase in nasal airway resistance (NAR). Antihistamines, including topical antihistamine, levocabastine, reduce response in non-specific nasal provocation tests. Furosemide is a diuretic which reduces hyperreactivity in lower airways, but the mode of its action is not yet fully understood. In this study, we hypothesized that either levocabastine or furosemide pre-treatment in allergic rhinitis patients reduced response to nasal challenge with non-isotonic aerosol. To test the hypothesis, we measured the effect of pre-treatment with levocabastine and furosemide in topical application on suppression of hyperreactive response to distilled water nasal inhalation. Nasal resistance was measured, prior to and after the provocation, by active anterior rhinomanometry in two randomized groups of patients, according to pre-treatment, either by levocabastine or furosemide, 20 patients in each group, respectively. Nasal airflow resistance and level of hyperreactive response considering nasal eosinophilia were tested. Significant increase in nasal resistance following provocation was found at baseline conditions (without pre-medication); pre-treatment with levocabastine and furosemide has suppressed such response. Patients with positive nasal eosinophilia showed a significantly higher increase in nasal resistance compared to those with negative smears. Furosemide has shown significantly better protective effect on nasal resistance increase in patients with positive eosinophils nasal smears. Levocabastine and furosemide pre-treatment suppress hyperreactive response to distilled water nasal provocation. Comparison of resistances (pre-treatment vs. without) showed more protective effect of furosemide, measured on both better and worse patent side of nose, in contrast to levocabastine group for which it was shown only on better patent side prior to provocation. Protection of furosemide was significantly more pronounced in patients with significant nasal eosinophilia.

Topics: Administration, Intranasal; Adolescent; Adult; Diuretics; Female; Furosemide; Histamine H1 Antagonists, Non-Sedating; Humans; Male; Middle Aged; Nasal Obstruction; Nasal Provocation Tests; Piperidines; Rhinitis, Allergic, Perennial; Rhinomanometry; Saline Solution, Hypertonic; Time Factors; Young Adult

Three similarly designed, multicenter, double-blind, randomized, placebo-controlled, parallel-group comparative studies were carried out in the United States in a total of 1,881 patients to evaluate the efficacy of ebastine 20 mg (E20), ebastine 10 mg (E10), loratadine 10 mg (L10), and placebo (P), all given once daily, in controlling the symptoms of ragweed-induced rhinitis over a 4-week treatment period. Efficacy was assessed, among other means, by nasal congestion symptom scores entered by patients on diary cards in the morning and before bedtime over the previous 12-h period (reflective score, R) and at the time of recording (snapshot score, SS). Mean value of both morning and evening score changes from baseline were analyzed in each study and for each treatment. E20 was more effective than placebo in all studies, in both R and SS symptom scores (6 of 6 scores), while E10 was effective in 4 of 6 scores (2 R and 2 SS). In contrast, L10 was effective in only 1 of 6 scores (1 R). In conclusion, the comparative analysis of the results from these three trials shows that ebastine is efficacious in the reduction of nasal congestion associated with seasonal allergic rhinitis. This symptomatic effect of ebastine may be accounted for by its ability to reduce inflammatory markers, as shown in preclinical studies, in addition to its primary effect of antagonizing histamine H1 receptors.

Topics: Adult; Ambrosia; Butyrophenones; Dose-Response Relationship, Drug; Double-Blind Method; Female; Histamine H1 Antagonists; Histamine H1 Antagonists, Non-Sedating; Humans; Loratadine; Male; Nasal Obstruction; Piperidines; Rhinitis, Allergic, Seasonal

Nasal obstruction is one of the most bothersome symptoms of allergic rhinitis (AR) affecting sleep-related quality of life in AR patients. Although several treatments were tested to control nasal obstruction, some patients with moderate to severe AR do not respond to current treatments, including the combined administration of different types of anti-allergic medicine. Thus, new options for AR treatment are needed. This study aimed to evaluate the effects of combined treatment with a novel inhibitor of hematopoietic prostaglandin D synthase (HPGDS), TAS-205, and different types of anti-allergic medicine on nasal obstruction in AR. Firstly, we demonstrated that TAS-205 selectively inhibited prostaglandin D

Topics: Acetates; Animals; Anti-Allergic Agents; Cell Line; Cyclopropanes; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; Enzyme Inhibitors; Guinea Pigs; Humans; Intramolecular Oxidoreductases; Lipocalins; Male; Morpholines; Nasal Mucosa; Nasal Obstruction; Ovalbumin; Piperidines; Prostaglandin D2; Pyrroles; Quality of Life; Quinolines; Rats; Rhinitis, Allergic; Sulfides; Terfenadine