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Background: Nasal H(3) receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis., Objective: This study explored the effect of the potent oral H(3) receptor antagonist PF-03654746 in combination with an oral H(1) receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge., Methods: Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (A(min)) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF-03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), A(min) (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods., Results: The following symptom scores were significantly (P ≤ .05) reduced by active treatments versus placebo: group 1, congestion of -0.7 (SE, 0.3), itching of -1.0 (SE, 0.3), rhinorrhea of -1.3 (SE, 0.3), and sneeze of -8.8 (SE, 1.5); group 2, itching of -0.6 (SE, 0.3), rhinorrhea of -0.8 (SE, 0.3), and sneeze of -9.1 (SE, 1.5); and group 3, rhinorrhea of -0.7 (SE, 0.3) and sneeze of -7.0 (SE, 1.5). There was no significant effect of any treatment on mean A(min) proportion or nasal volume proportion after nasal allergen challenge., Conclusions: In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H(3) receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Intercellular adhesion molecules (ICAMs), in particular ICAM-1, appear to play a crucial role in the recruitment and migration of inflammatory cells to the site of an allergic reaction. Glucocorticoids and allergen-specific immunotherapy have been shown to exert effects on selected components of this system, both in vitro and in vivo, but further research is required to better understand the effects of these therapies. Nasal and conjunctival challenge models (including natural and experimental allergen exposure) represent useful and safe tools for studying the activity of antiallergy drugs in vivo. These tests allow the investigation of a wide variety of parameters including inflammatory infiltrate, ICAM-1 expression, and changes in the concentration of soluble inflammatory mediators. With these tools, anti-inflammatory activity related to the modulation of epithelial cell adhesion molecules has been demonstrated in vivo for several H(1)-receptor antagonists (azelastine, cetirizine, loratadine, levocabastine, oxatomide, and terfenadine). Fexofenadine is a nonsedating, long-acting antihistamine with highly selective H(1)-receptor antagonist activity and a particularly favorable safety profile. In addition, fexofenadine has proven anti-inflammatory activity and has been shown to inhibit a number of mediators at clinically relevant concentrations, including in vitro inhibition of ICAM-1 expression on conjunctival and nasal epithelial cells.

There is renewed interest in antihistamines for the treatment of allergic asthma. A growing body of literature has shown that the newer compounds can affect inflammatory cell accumulation and cytokine/chemokine production. In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the ability of fexofenadine to affect these outcomes was tested in a primary sensitization and challenge model and after treatment of donor mice before the adoptive transfer of T cells into recipients receiving limited allergen exposure. Mice were sensitized and challenged with allergen (ovalbumin). Airway function after inhaled methacholine was monitored in parallel to the assessment of tissue and airway inflammation and cytokine production. In further experiments, lung T lymphocytes from sensitized/challenged donor mice were transferred into naive recipients before limited airway challenge with the allergen. Administration of fexofenadine before challenge but after sensitization was effective in preventing tissue eosinophilia and airway hyperresponsiveness. Moreover, the treatment of donor mice with fexofenadine before transfer of lung T cells effectively prevented airway hyperresponsiveness and eosinophilia in naive mice exposed to limited airway challenge. These data therefore support the potential for fexofenadine in the treatment of allergen-induced airway hyperresponsiveness and inflammation.

Results of head-to-head comparative trials suggest that fexo-fenadine might offer distinct advantages compared with other antihistamines. Fexofenadine is highly selective for peripheral H(1)-receptors and does not cross the blood-brain barrier, as shown by positron emission tomography. These data support findings that fexofenadine is nonsedating and does not impair performance or driving ability, even at very high doses. In addition, fexofenadine does not interact with muscarinic receptors, which might offer a potential advantage compared with desloratadine, the recently approved active metabolite of loratadine. Fexofenadine is devoid of adverse cardiac effects, and changes in electrocardiogram parameters are not significantly different from those observed with placebo. Fexofenadine has also been shown to have a favorable effect on nasal congestion. This therapeutic advantage might be related to its significant antiallergic properties, ie, the demonstrated ability of fexofenadine to blunt the inflammatory effects of preformed and de novo synthesized mediators at clinically relevant doses in vivo and in vitro. Cumulatively, these benefits distinguish fexofenadine from other antihistamines and make it an optimum therapeutic option for treating allergy-mediated respiratory and dermatologic diseases.

Background: This is the first prospective, randomized, double-blind, placebo-controlled study showing statistical improvement of an H(1)-antihistamine in children with seasonal allergic rhinitis in all symptoms throughout the entire treatment period., Objective: This randomized, placebo-controlled, parallel-group, double-blind study was performed to assess the efficacy and safety of fexofenadine in children with seasonal allergic rhinitis., Methods: This study was conducted at 148 centers in 15 countries. Nine hundred thirty-five children (aged 6-11 years) were randomized and treated with either fexofenadine HCl 30 mg (n = 464) or placebo (n = 471) tablets twice a day for 14 days. Individual symptoms (sneezing; rhinorrhea; itchy nose, mouth, throat, and/or ears; itchy, watery, and/or red eyes; and nasal congestion) were assessed at baseline and then daily at 7:00 AM and 7:00 PM (+/-1 hour) during the double-blind treatment period. Each total symptom score was the sum of all symptoms, excluding nasal congestion. The primary efficacy variable was the change from baseline in the average of the daily 12-hour evening reflective total symptom scores throughout the double-blind treatment. Safety was evaluated from adverse-event reporting, vital signs, physical examinations, and clinical laboratory data at screening and study end point., Results: Fexofenadine was significantly superior to placebo in the primary efficacy analysis (P

Background: Modern H(1)-antihistamines differ in their in vitro binding affinity, but their comparative in vivo bioactivity in asthmatic airways is unknown., Objectives: We compared clinically recommended doses of 3 H(1)-antihistamines on airway hyperresponsiveness to AMP challenge (the primary outcome variable)., Methods: Sixteen atopic patients with mild-to-moderate asthma of whom 10 were receiving inhaled corticosteroid therapy (all had positive results to house dust mite on skin prick testing) were randomized in a double-blind, placebo-controlled, cross-over fashion to receive single doses of 5 mg of desloratadine, 180 mg of fexofenadine hydrochloride (FEX), 5 mg of levocetirizine dihydrochloride (LEV), or placebo, with AMP challenge performed 12 hours after dosing., Results: All H(1)-antihistamines demonstrated significantly greater (P <.05) geometric mean +/- SEM AMP PC(20) values compared with that of placebo (86 +/- 29 mg/mL): desloratadine, 189 +/- 54 mg/mL; FEX, 176 +/- 57 mg/mL; and LEV, 163 +/- 48 mg/mL. Prechallenge forced expiratory flow at 25% to 75% of maximal lung volume (percent predicted) but not FEV(1) was significantly higher (P <.05) for all H(1)-antihistamines compared with that of placebo (53% +/- 4%): desloratadine, 62% +/- 4%; FEX, 62% +/- 4%; and LEV, 59% +/- 3%. There were no significant differences in either AMP PC(20) or lung function values among the H(1)-antihistamines., Conclusion: Single doses of H(1)-antihistamines improved airway hyperresponsiveness and small-airways caliber to a similar degree. Data for in vitro binding affinity do not therefore translate into commensurate differences in in vivo bioactivity at clinically recommended doses.

Background: Antihistamines have been evaluated for usefulness in the treatment of asthma for more than 50 years. Interest was limited until the introduction of newer compounds that were free of much of the dose-limiting sedation associated with the earlier drugs., Objective: In a murine model of allergen-induced airway inflammation and hyperresponsiveness, the efficacy of an H1 receptor antagonist to prevent allergic inflammation and altered airway function was evaluated., Methods: Mice were sensitized and challenged to an allergen, ovalbumin, which elicited marked airway and tissue eosino-philia and airway hyperresponsiveness. Fexofenadine was administered before challenge, and airway responsiveness to inhaled methacholine, airway and tissue eosinophilia, bronchoalveolar lavage fluid cytokine levels, and serum IgE levels were assayed. In a second group of experiments, sensitized and challenged mice were treated or not treated with fexofenadine before challenge. T cells were isolated from the lungs and adoptively transferred into naive recipients before exposure to limited airway allergen challenge, and lung function and inflammation were evaluated., Results: Fexofenadine treatment of sensitized mice prevented the development of airway hyperresponsiveness in both the primary sensitization and challenge, as well as in the adoptive transfer experiments. These changes were accompanied by decreases in bronchoalveolar lavage and tissue eosinophilia, lymphocyte numbers, and T(H)2 cytokine production., Conclusion: The results demonstrate the efficacy of an H1 receptor antagonist in preventing allergen-induced alterations in pulmonary inflammation and airway function. The data support the evaluation of drugs such as fexofenadine in the treatment of allergic asthma.

Background: H1-receptor antagonists are widely used in the treatment of allergic skin disorders., Objective: We sought to evaluate the extent of fexofenadine and diphenhydramine distribution into the skin concomitantly with their peripheral H1-receptor antagonist activity., Methods: In a prospective, randomized, double-blind, parallel-group study, 7 men received 120 mg of fexofenadine, and 7 received 50 mg of diphenhydramine. Before dosing; at 1, 3, 6, 9, and 24 hours after the first dose; and at 168 hours (steady-state), 12 hours after the seventh and last daily dose, blood samples and skin punch biopsy specimens were obtained, and epicutaneous tests with histamine phosphate, 1 mg/mL, were performed., Results: Fexofenadine penetrated the skin to a significantly greater extent than diphenhydramine at 6, 9, 24, and 168 hours (P < or = .05). Maximum skin/plasma ratios of both the H1-antagonists (41.3 +/- 7.8 for fexofenadine and 8.1 +/- 4.4 for diphenhydramine) were obtained at 24 hours. Fexofenadine also produced significantly greater suppression of wheals at 3, 6, and 9 hours and of flares at 3, 6, 9, and 168 hours compared with diphenhydramine (P < or = .05)., Conclusion: In disorders in which the presence and the effects of H1-receptor antagonists in the skin are clinically relevant, our results support the use of fexofenadine and indicate the need to re-examine the role of diphenhydramine.

Background: Terfenadine is a selective, nonsedative, H(1)-blocker antihistamine used for a variety of allergic conditions. The widespread popularity of terfenadine and its use by many women in their reproductive age raises concerns regarding its safety during pregnancy. Presently, no prospective controlled study has addressed its safety during gestation., Objective: We sought to determine whether terfenadine use during pregnancy is associated with an increased risk of major malformations, decreased birth weight, perinatal complications, or developmental delays., Methods: A multicenter, prospective controlled study was performed. Pregnant women exposed to terfenadine during gestation were matched with control subjects exposed to drugs not known to adversely affect pregnancy outcome. The primary end point was the incidence of major malformations. Secondary outcomes of interest were pregnancy outcome, rates of preterm delivery, birth weight, and developmental milestones., Results: One hundred eighteen women were exposed to terfenadine during pregnancy. Among those exposed during the first trimester (n = 65), rates of major malformations in the terfenadine group did not differ from rates in their matched control subjects (0% vs 2%; relative risk, 0.57; 95% confidence interval, 0.06-5.39; P =.53). The birth weight in the terfenadine-exposed newborns was significantly lower compared with that in their matched control subjects (3335 +/- 582 vs 3499 +/- 617 g; P =.04). However, the rates of birth weight below 2500 g and birth weight below the 10th percentile for gestational age were not different between the groups. Univariate and multiple regression analysis revealed that none of the terfenadine therapy-related factors (daily dose, duration of therapy, and trimester of exposure) had a significant predictive effect on birth weight. Gestational age at delivery, rates of preterm deliveries, and developmental milestones were comparable between the groups., Conclusions: On the basis of the limited sample size of this study, it appears that terfenadine is not associated with a 6-fold or greater increased incidence of major malformations. Terfenadine use during gestation was not associated with increased rates of prematurity or developmental delays. Further studies will be needed to confirm the finding of lower birth weight in newborns exposed to terfenadine.

Background: Symptoms of chronic idiopathic urticaria (CIU) include relentless itching and painful wheals, which can be physically and psychologically debilitating. Half of all patients with urticaria have angioedema, which is often disfiguring., Objective: To evaluate the safety and efficacy of fexofenadine HCl for the treatment of CIU symptoms., Methods: In this 4-week, multicenter, placebo-controlled study, 439 patients with moderate to severe pruritus and urticaria received 1 of 4 oral doses of fexofenadine HCl (20, 60, 120, or 240 mg twice a day) or placebo. Patients reflectively assessed (over the previous 12 hours) the severity of pruritus, the number of wheals, and the interference with sleep (7 AM) and normal activities (7 PM) due to urticaria. Efficacy measures included a change from baseline of daily mean pruritus score (MPS), daily mean number of wheals (MNW) score, daily mean total symptom score (MTSS) (ie, the sum of the wheal and pruritus scores), and mean interference with sleep and daily activities due to urticaria., Results: All 4 doses of fexofenadine were statistically superior to placebo (P

Background: Fexofenadine hydrochloride (HCl) is a new H(1) antihistamine used twice daily in some countries., Objective: A multicenter, double-blind, parallel-group, placebo-controlled trial compared the efficacy and safety of fexofenadine HCl (120 and 180 mg administered once daily) and cetirizine (10 mg once daily) in the treatment of seasonal allergic rhinitis., Methods: After a 3- to 5-day run-in period, patients meeting entrance criteria were randomized to receive placebo, fexofenadine HCl 120 mg once daily, fexofenadine HCl 180 mg once daily, or cetirizine 10 mg once daily (active control) for 2 weeks. Eight hundred twenty-one patients comprised the intention-to-treat population and 722 patients completed the study. Symptom assessments were conducted 12 hours after the dose for the previous 12 hours and again at 24 hours after the dose for the previous 12 hours. In addition, assessment was made immediately before dosing in the morning for the previous 30 minutes. Total symptom score was calculated as the sum of scores for the 4 individual symptoms: (1) sneezing, (2) rhinorrhea, (3) itchy nose, palate, or throat, and (4) itchy, watery, or red eyes; the nasal congestion score was also recorded., Results: Both doses of fexofenadine HCl were superior to placebo in reducing the total symptom score. Efficacy was maintained for the entire dosing interval (ie, for 24 hours). There were no differences in efficacy between the 2 doses of fexofenadine HCl or between either dose of fexofenadine HCl and cetirizine. There was no major side effect, but the combined incidence of drowsiness or fatigue was greater with ce-tirizine (9%) than with placebo (4%) (P =.07) or fexofenadine (4%) (P =.02)., Conclusions: Once-daily fexofenadine is thus a valuable addition to the nonsedating group of H(1) receptor antagonists currently available for the treatment of seasonal allergic rhinitis.

Background: Fexofenadine is the hydrochloride salt of terfenadine's active metabolite., Objective: Fexofenadine's effects on performance were assessed in this study for the purpose of determining its safety of use by patients who engage in potentially dangerous activities, especially car driving., Methods: Fexofenadine was administered in daily doses of 120 or 240 mg, each in single and divided units given over 5 days. Two milligrams of clemastine given twice daily and placebo were given in similar series. Twenty-four healthy volunteers (12 men, 12 women; age range, 21 to 45 years) participated in a double-blind six-way crossover study. Psychomotor tests (critical tracking, choice reaction time, and sustained attention) and a standardized actual driving test were undertaken between 1.5 to 4 hours after administration of the morning dose on days 1, 4, and 5 of each series. On day 5, subjects were challenged with a moderate alcohol dose before testing., Results: Fexofenadine did not impair driving performance. On the contrary, driving performance was consistently better during twice daily treatment with 120 mg fexofenadine than during treatment with placebo, significantly so on day 4. Both of the 240 mg/day regimens significantly attenuated alcohol's adverse effect on driving on day 5. Effects in psychomotor tests were not significant, with the exception of the critical tracking test in which the first single doses of fexofenadine, 120 and 240 mg, had significantly impairing effects., Conclusion: It was concluded that fexofenadine has no effect on performance after being taken in the recommended dosage of 60 mg twice daily.

Background: Some clinical studies suggest that a combination of an H1- and H2-antagonist may be effective in the prophylaxis of allergic reactions., Objective: The efficacy of pretreatment with an H1/H2-antagonist combination, H1-antagonist alone, or placebo in the prophylaxis of local and systemic adverse reactions to specific immunotherapy with Hymenoptera venom was compared., Methods: In a prospective, randomized, double-blind, placebo-controlled study, 121 patients with Hymenoptera venom allergy were treated with rush immunotherapy and pretreatment with one of the following: 120 mg of terfenadine plus 300 mg of ranitidine, 120 mg of terfenadine alone, or placebo. The incidence of unwanted systemic adverse and local reactions was recorded for up to 50 weeks., Results: In seven patients (6%), six in the placebo group and one in the terfenadine group, systemic side effects required cessation of therapy (p = 0.005). Subjective symptoms occurred in four patients (10%) in the terfenadine plus ranitidine group and in three patients (7%) in the terfenadine group. Regarding local reactions, significantly fewer patients treated with a combination of terfenadine and ranitidine and with terfenadine alone as compared with placebo had severe local symptoms of erythema (29%, 29%, and 49%), edema (24%, 18%, and 41%), and pruritus (13%, 11%, and 31%) at week 1 (p < 0.05). This therapeutic benefit was limited to the first 4 weeks of treatment. Treatment with a combination of terfenadine and ranitidine was not superior to treatment with terfenadine alone., Conclusions: Pretreatment with H1-antihistamines with or without H2-antihistamines significantly reduced local and systemic adverse reactions to immunotherapy with Hymenoptera venom and may therefore be helpful in the management of immunotherapy.

Background: Drug selection for optimal treatment of common medical conditions may be difficult and involve many diverse factors., Objective: The efficacy, safety, quality of life, and cost of treatment of seasonal allergic rhinitis with cetirizine, chlorpheniramine, or terfenadine were compared in a prospective, two-phase, randomized, single-blind clinical trial conducted in a managed care setting., Methods: In phase I, which lasted 2 weeks, patients were randomized to receive one of the study drugs. In phase II, which lasted 4 weeks, the initial treatment was continued unless patients were dissatisfied, in which case they could be randomly assigned to receive another study drug. In both phases pseudoephedrine could be taken as needed. Patients kept daily diaries of symptoms and costs, and study drugs were evaluated at the end of each phase for efficacy, safety, and effect on quality of life by means of a validated questionnaire. A multiattribute outcomes assessment model for formulary decision making was used to rank the antihistamines., Results: Physicians' and patients' assessments in phases I and II indicated that cetirizine and chlorpheniramine were significantly more effective than terfenadine (p < 0.05). Incidence of sedation in phase I and phase II was 40.5% and 16.7% for chlorpheniramine, 11.6% and 9.8% for cetirizine, and 6.7% and 5.1% for terfenadine, respectively. At the end of phase I, 28.9% of the patients treated with chlorpheniramine, 50% of the patients treated with terfenadine, and 69.4% of the patients treated with cetirizine were satisfied with their therapy and chose not to switch their medication. Quality of life scores improved most after treatment with cetirizine and least after treatment with terfenadine., Conclusion: The result of this trial indicate that antihistamine selection is best made with the use of a multiattribute evaluation that includes quality of life. In this study cetirizine was favored by patients and physicians most often, followed by chlorpheniramine and then terfenadine.

Background: Comparative studies with topical corticosteroids and antihistamines for treatment of allergic rhinitis have not always demonstrated clear distinctions between the two on the basis of therapeutic efficacy., Objective: This study was designed to compare the efficacy and tolerability of fluticasone propionate aqueous nasal spray with those of terfenadine in the treatment of seasonal allergic rhinitis., Methods: Three hundred forty-eight patients with allergic rhinitis were given fluticasone propionate aqueous nasal spray (200 micrograms once daily), terfenadine tablets (60 mg twice daily), or placebo for 4 weeks in a multicenter, randomized, double-blind, double-dummy, parallel-group study., Results: Clinician-rated total nasal symptom scores after 1, 2, 3, and 4 weeks of therapy and patient-rated total nasal symptom scores throughout treatment were significantly (p <0.05) lower in the fluticasone propionate group compared with the terfenadine group or the placebo group. Terfenadine was not statistically different from placebo on the basis of clinician-related nasal symptom scores, except for sneezing. Total nasal airflow, measured by rhinomanometry, significantly (p <0.05) improved in the fluticasone propionate group compared with the terfenadine group or the placebo group. More fluticasone propionate-treated patients compared with placebo-treated patients had reduced nasal mucosal eosinophil counts after 4 weeks of therapy (p <0.05). No serious or unusual drug-related adverse events were reported. Morning plasma cortisol concentrations after 4 weeks of therapy did not differ among groups., Conclusion: Fluticasone propionate aqueous nasal spray is more effective than terfenadine tablets for treatment of seasonal allergic rhinitis.

To investigate the role of H1 receptor-mediated effects in allergic rhinitis, we challenged 12 allergic volunteers with allergen 2 hours after administration of either placebo or 60 mg of terfenadine. Filter paper discs were used for the unilateral administration of allergen and the collection of nasal secretions. Secretion weights, levels of histamine in recovered nasal secretions, and nasal airway resistance (NAR) were measured for each nostril separately, and the number of sneezes was counted. After placebo treatment, allergen challenge led to significant increases in ipsilateral and contralateral secretion weights, ipsilateral histamine levels, ipsilateral NAR, and sneezing. Contralateral histamine levels were not elevated. H1 antagonism with terfenadine markedly reduced the number of sneezes and partially decreased ipsilateral and contralateral secretion weights, without affecting the increase in NAR. Terfenadine premedication also lowered the amount of histamine in ipsilateral secretions after allergen challenge. Performing identical nasal challenges with a 10-fold lower dose of antigen produced similar results. Previous studies showed that terfenadine had no effect on methacholine provocation and completely abolished ipsilateral and contralateral secretion weights after histamine challenge. We conclude that sneezing after allergen challenge is caused almost exclusively by a reflex initiated through H1 receptors and that H1 antagonism has no influence on allergen-induced increases in NAR. Unilateral allergen challenge leads to bilateral increases in secretion weights, which are only partially inhibited by terfenadine, suggesting the involvement of mediators other than histamine in the nasonasal reflex. As reported earlier, terfenadine also decreases allergen-induced histamine release after challenge with the highest dose of antigen.

Some of the second-generation H1 antihistamines reduce the bronchoconstrictor response after exercise and antigen challenge. For example, terfenadine causes a slight but significant increase in forced expiratory volume after 1 second. At doses of 120 and 240 mg, terfenadine has a protective effect against asthma induced by ultrasonic nebulized distilled water and cold air hyperventilation challenge. Certain other newer antihistamines, such as ketotifen, azelastine, and cetirizine, have additional antiallergy properties. These effects include inhibition of eosinophil, basophil, and neutrophil migration and platelet-activating factor-induced eosinophil accumulation in skin. The ability of cetirizine (and perhaps other antihistamines) to inhibit these responses at usual therapeutic doses may be useful in investigating the late allergic reaction.