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The majority of patients with seasonal allergic rhinitis (SAR) suffer from nasal congestion. Desloratadine, a nonsedating H1-receptor antagonist, has given decongestant relief to patients with mild-to-moderate nasal congestion associated with SAR. The following study was undertaken to show that a once-daily formulation of desloratadine/pseudoephedrine would provide greater decongestant relief to patients experiencing moderate-to-severe nasal congestion compared with component monotherapy. A total of 1018 patients were assigned randomly to receive desloratadine/pseudoephedrine (5 mg/240 mg), desloratdine (5 mg), or pseudoephedrine (240 mg) daily for 15 days. Over the 15-day study period, patients receiving desloratadine/pseudoephedrine combination tablets had a significant reduction in mean A.M./P.M. reflective nasal congestion scores compared with patients receiving desloratadine or pseudoephedrine (p0.01); this reduction reached significance by day 2. Desloratadine/pseudoephedrine combination tablets also produced a greater reduction in A.M. instantaneous nasal congestion scores compared with component monotherapy (p0.01), indicating not only superior efficacy but also a full 24-hour effect. Desloratadine monotherapy reduced all mean nasal congestion scores to a similar degree as compared with pseudoephedrine monotherapy (p = NS). No unusual or unexpected adverse events were reported in any group. It was concluded that desloratadine/pseudoephedrine offers additional benefit to patients with moderate-to-severe SAR-associated nasal congestion compared with pseudoephedrine therapy alone.

Better treatment options should reduce symptoms, enhance quality of life, improve the course of disease, reverse pathogenetic and physiologic changes, have few side effects, and be cost effective. Because of the heterogeneous nature of asthma, specific agents will probably work best for selected types of patients. However, regardless of the obstacles, ongoing research into the wide range of therapeutic possibilities will provide new insights into the pathogenesis of allergic respiratory diseases.

Pharmacologic treatment of asthma should be done with a stepwise approach recommended in treatment guidelines. If inhaled corticosteroids (ICSs) alone are not adequate, ICSs in combination with long-acting β-agonists (LABAs) are now established and widely used as the next step in effective controller therapy. Fixed-dose ICS/LABA combinations in a single device are the preferred form of delivery and improve compliance by enabling patients to get symptom relief from the LABA while receiving the anti-inflammatory benefits of ICSs. Fluticasone propionate/formoterol fumarate is one of the newest fixed-dose combinations. It has been in use in Europe in 2012, but is still under regulatory review in the US. Fluticasone is a synthetic ICS with potent anti-inflammatory effects, while formoterol is a selective β2-adrenergic receptor agonist with a rapid onset of bronchodilation within 5-10 minutes and a 12-hour duration of action. Fluticasone/formoterol has shown superior efficacy when compared to fluticasone or formoterol alone in multiple well-designed studies. The combination has shown comparable or "noninferior" benefits in lung function, clinical symptoms, and asthma control when compared with fluticasone and formoterol administered concurrently in separate inhalers. Fluticasone/formoterol provides similar efficacy with fluticasone/salmeterol, but with more rapid symptom relief. It has been compared directly with budesonide/formoterol with comparable results. Fluticasone/formoterol is well tolerated, with no unusual or increased safety concerns versus each individual component or other available ICS/LABA combinations. Fluticasone/formoterol is the latest entry into a relatively crowded market of branded fixed-dose preparations. Upcoming generic fixed-dose combinations and once-daily agents pose significant market challenges. In clinical practice, most practitioners consider all the currently available fixed-dose preparations to be of comparable efficacy and safety.

Inhaled corticosteroids are established as maintenance therapy for persistent asthma. A new aerosol formulation of flunisolide delivers a small particle size by using a hydrofluoroalkane (HFA) propellant with a built-in spacer.To compare efficacy and safety of two different flunisolide formulations, HFA and chlorofluorocarbon (CFC), with placebo treatment over a range of doses.The multicenter, randomized, double-blind, placebo-controlled trial consisted of a 2-week, active run-in phase with CFC flunisolide 500 microg, twice daily, followed by 12 weeks of double-blind treatment with placebo, HFA flunisolide (85, 170, or 340 microg, twice daily), or CFC flunisolide (250, 500, or 1,000 microg, twice daily). Patients (N = 669) were nonsmokers, at least 12 years of age, with mild to moderate asthma who were being treated with inhaled corticosteroids. Outcome measures were change from baseline in forced expiratory volume in 1 second (FEV1), peak expiratory flow rate, as needed albuterol use, nocturnal awakenings, and asthma symptoms.After 12 weeks of treatment, patients receiving 170 microg, twice daily, and 340 microg, twice daily, of HFA flunisolide showed a significant (P0.01) improvement in percentage increase in FEV1 (12.22% at 170 microg, twice daily, and 14.69% at 340 microg, twice daily) compared with the placebo group (5.35%). At one-third the dose of CFC flunisolide, HFA flunisolide provided similar improvement in pulmonary function versus placebo. Both formulations demonstrated comparable linear dose dependency for the change from baseline in FEV1 without any evidence of cortisol suppression. Outcome values for all seven secondary efficacy measures were numerically superior in patients receiving HFA flunisolide compared with the CFC formulation. Both formulations seemed to be safe and well tolerated.HFA flunisolide provides comparable efficacy and safety at one-third the dose of CFC flunisolide.

Background Leukotriene receptor antagonists have been shown to attenuate physiologic changes in the upper and lower airways induced by allergen challenge. However, it is unknown whether these drugs modulate airway inflammation after exposure to allergen in a natural setting. Objective To determine the effects of the oral leukotriene receptor antagonist zafirlukast upon symptoms, changes in pulmonary function, and indices of inflammation in the upper and lower airways induced by natural exposure to cats. Methods Zafirlukast, 20 mg twice daily, or placebo was administered to 18 cat-allergic asthmatic patients in this randomized, double-blind, crossover study. Cat room challenges were performed after a 1-week period of each treatment. Upper and lower airway symptoms were measured and spirometry performed before and at regular intervals during each challenge. Nasal lavage and sputum induction were performed 24 hours before and after each challenge. Results Zafirlukast significantly improved the prechallenge baseline FEV 1 ( P = 0.001) and attenuated the decrease in FEV 1 induced by cat challenge ( P = 0.019). Zafirlukast also significantly reduced lower airway symptoms associated with cat challenge ( P = 0.005) but had no effects on nasal symptoms. Although zafirlukast did not significantly differ from placebo in its effects on sputum inflammatory cells or eosinophil cationic protein, it significantly reduced the absolute counts of total white cells, lymphocytes, neutrophils, and basophils in nasal lavage fluid. Conclusions Zafirlukast, 20 mg twice daily for 1 week, demonstrated a significant protective effect on symptoms of asthma and alterations in pulmonary function induced by natural cat exposure, whereas nasal symptoms and markers of sputum inflammation were not affected by the medication.

A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma.The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma.In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period.Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo.The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy.We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG.In 3 of 4 protocols (A, B, and C), MSG was administered without food. A positive response was scored if the subject reported 2 or more symptoms from a list of 10 symptoms reported to occur after ingestion of MSG-containing foods within 2 hours. In protocol A 130 self-selected reportedly MSG-reactive volunteers were challenged with 5 g of MSG and with placebo on separate days (days 1 and 2). Of the 86 subjects who reacted to MSG, placebo, or both in protocol A, 69 completed protocol B to determine whether the response was consistent and dose dependent. To further examine the consistency and reproducibility of reactions to MSG, 12 of the 19 subjects who responded to 5 g of MSG but not to placebo in both protocols A and B were given, in protocol C, 2 challenges, each consisting of 5 g of MSG versus placebo.Of 130 subjects in protocol A, 50 (38. 5%) responded to MSG only, 17 (13.1%) responded to placebo only (P. 05), and 19 (14.6%) responded to both. Challenge with increasing doses of MSG in protocol B was associated with increased response rates. Only half (n = 19) of 37 subjects who reacted to 5 g of MSG but not placebo in protocol A reacted similarly in protocol B, suggesting inconsistency in the response. Two of the 19 subjects responded in both challenges to MSG but not placebo in protocol C; however, their symptoms were not reproducible in protocols A through C. These 2 subjects were challenged in protocol D 3 times with placebo and 3 times with 5 g of MSG in the presence of food. Both responded to only one of the MSG challenges in protocol D.The results suggest that large doses of MSG given without food may elicit more symptoms than a placebo in individuals who believe that they react adversely to MSG. However, neither persistent nor serious effects from MSG ingestion are observed, and the responses were not consistent on retesting.

Background Although inhaled glucocorticoids are recommended for all stages of persistent asthma, compliance with long-term therapy is often poor, leading to significant morbidity and mortality. A simplified, once-daily dosing regimen may foster improved compliance. Objective To compare the efficacy and safety of once-daily (am) administration of mometasone furoate dry powder inhaler (MF DPI) 200 μg and 400 μg with placebo in patients with asthma previously maintained only on short-acting inhaled beta-adrenergic receptor agonists. Methods This was a 12-week, double-blind, placebo-controlled, parallel group study. The mean change from baseline to endpoint (last treatment visit) for FEV 1 was the primary efficacy variable. Results At endpoint, both doses of MF DPI were significantly more effective than placebo ( P ≤ .05) in improving FEV 1 . Based on morning peak expiratory flow rate, once-daily MF DPI 400 μg was more effective than placebo ( P ≤ .001) at endpoint. Both active treatments also demonstrated improvement at endpoint in asthma symptom scores, physician-evaluated response to therapy and use of rescue medication. Although both MF DPI dosages were efficacious, MF DPI 400 μg provided additional improvement in some measures of pulmonary function (eg, morning PEFR) when these agents were administered once daily in the morning. Both doses of MF DPI were well tolerated and treatment-related adverse events occurred at a similar incidence among the three treatment groups. Conclusions The results of this study indicate that once-daily (am) MF DPI provides a convenient and effective treatment option for patients with mild or moderate persistent asthma.

Background: Antihistamines have been shown to have a variety of therapeutic effects in asthma. Although nasal obstruction may play an important role in modulating lower airway function, no prior trial has used a decongestant in combination with an antihistamine in patients with allergic rhinitis and concomitant asthma. Objective: We sought to determine the efficacy and safety of loratadine (5 mg) plus pseudoephedrine (120 mg) (L/P) twice daily in patients with seasonal allergic rhinitis and mild asthma. Methods: We conducted a randomized, double-blind, placebo-controlled trial of L/P in 193 subjects during the fall allergy season. Nasal and chest symptoms, albuterol use, and peak expiratory flow rates were recorded daily for 6 weeks. Spirometry was measured at baseline and after 1, 2, 4, and 6 weeks of therapy, and health-related quality of life was rated at the beginning and end of the study. Results: Total rhinitis and asthma symptom severity scores were significantly reduced in patients receiving active therapy compared with those receiving placebo throughout the 6-week study. Peak expiratory flow rates improved significantly in patients treated with L/P during weeks 2 through 6 (peak effect [mean ± SEM]: L/P, 26.23 ± 4.64 L/min vs placebo, 8.52 ± 3.53 L/min, p = 0.002) as did FEV 1 (peak effect [mean ± SEM]: L/P, 170 ± 53 ml vs placebo, 20 ± 40 ml, p = 0.01) at all clinic visits. In addition, select measures of asthma-specific quality of life improved significantly relative to placebo. Conclusions: L/P significantly improved nasal and asthma symptoms, pulmonary function, and quality of life in patients with seasonal allergic rhinitis and concomitant mild asthma. (J Allergy Clin Immunol 1997;100:781-8)

Objective: The purpose of this study was to evaluate the feasibility of switching to once-daily (qd) administration of flunisolide in patients with asthma that was controlled by twice-daily (bid) dosing of this inhaled steroid. Methods: Three hundred sixty-six adults and children with bronchial asthma that was controlled with inhaled steroids were recruited for this prospective, double-blind, parallel-group study. After a 4-week, stable baseline period of flunisolide administration, 2 inhalations (500 μg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 μg) bid; group 2, 4 inhalations (1000 μg) qd in the morning; group 3, 4 inhalations (1000 μg) qd in the evening; or group 4, 2 inhalations (500 μg) qd in the morning. Outcome measures included morning and evening asthma symptoms (scale of 0 to 3), daytime and nighttime albuterol use, morning and evening peak expiratory flow rate (PEFR), FEV 1 , and methacholine PC 20 . In addition, a subset of patients in each group had 24-hour urinary cortisol levels measured before and after randomization. Results: Outcome measures in the four groups were not significantly different at baseline before randomization. The three groups that received maintenance therapy with flunisolide, 1000 μg daily, did not show significant changes from baseline values and remained comparable in all outcome areas. Asthma control in the group randomized to flunisolide 500 μg qd, however, deteriorated significantly: morning symptoms increased by 0.21 units (48%), evening symptoms increased by 0.15 units (31%), daytime albuterol use increased by 0.42 inhalations per day (37%), nighttime albuterol use increased by 0.48 inhalations per night (91%), morning PEFR decreased by 17.1 L/min (4%), and evening PEFR decreased by 12.6 L/min (3%). There were no significant changes in PC 20 or 24-hour urinary cortisol levels in any group. Conclusions: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 μg) bid, switching to 4 inhalations (1000 μg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 μg) qd in the morning, however, leads to a deterioration in asthma control. (J Allergy Clin Immunol 1997;99:278-85.)

Dysfunction of the upper and lower airways frequently coexist, and they appear to share key elements of pathogenesis. Data from epidemiologic studies indicate that nasal symptoms are experienced by as many as 78% of patients with asthma and that asthma is experienced by as many as 38% of patients with allergic rhinitis. Studies also have identified a temporal relation between the onset of rhinitis and asthma, with rhinitis frequently preceding the development of asthma. Patients with allergic rhinitis and no clinical evidence of asthma commonly exhibit nonspecific bronchial hyperresponsiveness. The observation that management of allergic rhinitis also relieves symptoms of asthma has heightened interest in the link between these diseases. Intranasal corticosteroids can prevent increases in nonspecific bronchial reactivity and asthma symptoms associated with seasonal pollen exposure. Similarly, among patients with perennial rhinitis, daily asthma symptoms, exercise-induced bronchospasm, and bronchial responsiveness to methacholine are reduced after administration of intranasal corticosteroids. Antihistamines, with or without decongestants, reduce seasonal rhinitis symptoms, asthma symptoms, and objective measurements of pulmonary function among patients with rhinitis and asthma. The mechanisms that connect upper and lower airway dysfunction are under investigation. They include a nasal-bronchial reflex, mouth breathing caused by nasal obstruction, and pulmonary aspiration of nasal contents. Nasal allergen challenge results in increases in lower airway reactivity within 30 minutes, suggesting a neural reflex. Improvements in asthma associated with increased nasal breathing may be the result of superior humidification, warming of inspired air, and decreased inhalation of airborne allergens. Postnasal drainage of inflammatory cells during sleep also may affect lower airway responsiveness. A link between allergic rhinitis and asthma is evident from epidemiologic, pathophysiologic, and clinical studies. Future research, however, is needed to determine whether nasal therapy can alter the natural history of asthma. (J Allergy Clin Immunol 1997; 99:S781-6.)

With aging, multiple physiological changes occur in the connective tissue and vasculature of the nose which may predispose or contribute to chronic rhinitis. Accurate differentiation of allergic from nonallergic causes of rhinitis requires skin testing or in vitro measures of specific IgE. Empiric treatment with over-the-counter first generation antihistamines and oral decongestants frequently results in CNS, anticholinergic and cardiovascular adverse effects. While newer second generation histamine antagonists do not cause these problems, selected drugs in this class may cause electrocardiographic QT prolongation and, in rare cases, ventricular arrhythmias. Topical therapies including sodium cromoglycate (cromolyn sodium), corticosteroids and ipratropium bromide are all well-tolerated with minimal adverse effects. Avoidance of allergens and/or irritants is an important adjunct in treating patients with allergic and vasomotor rhinitis. If all other therapies fail in patients with confirmed allergic rhinitis, immunotherapy can be safely instituted in most older patients.

Background Multiple strengths of mometasone furoate/formoterol (MF/F) MDI combination therapy are under investigation as new treatments for asthma. We report efficacy/ safety findings from a 3-month MF/F study in subjects with severe asthma. Materials and methods This was a 3-month, randomized, double-blind, parallelgroup, multicenter study with a 2-3-week open-label, run-in period of mometasone furoate (MF) 400 μg twice-daily (BID). Subjects (≥12 years) were randomized to MF/F (200/10 μg or 400/10 μg BID) or MF (400 μg BID). The primary endpoint was the area under the curve (AUC) of the change in serial FEV1 (0-12 hours) for MF/F 400/10 μg vs MF 400 μg from baseline to Week 12. Adverse events (AEs) and other clinical safety measures were recorded. Results A total of 728 subjects (mean: age = 47.9 y, asthma duration = 14.0 y, FEV1 % predicted = 66.3, reversibility = 22.9%, Asthma Control Questionnaire [ACQ] score = 1.93) were randomized. Improvements in mean changes from baseline in FEV1 AUC0-12 h (L ×h ) at Week 12 were MF/F 200/10 μg = 3.59, MF/F 400/10 μg = 4.19, and MF 400 μg = 2.04, with both MF/F doses significantly better than MF (p < 0.001). These FEV1s correspond to average hourly increases of 0.30, 0.35, and 0.17 L, respectively. MF/F was associated with rapid (

Rationale To study effects of montelukast on lower and upper airway responses to controlled cat allergen challenge in patients with concomitant asthma and allergic rhinitis. Methods This randomized, cross-over study treated patients (n=58) with montelukast 10-mg vs placebo during two 2-week, double-blind treatment periods, separated by a 1-week washout. Following each treatment period, patients underwent ≤60-minute exposure to naturally-generated airborne cat allergen. Lower and upper airway reactions were measured by spirometry and symptom scores. Results Montelukast demonstrated protection (p≤0.001) against allergen challenge in the lower airway endpoint of AUC 0-60min (Area under the curve during challenge) for %-fall in FEV 1 : mean of 10.5% · hr [95%CI: 7.5, 13.4] and 14.7% · hr [11.8, 17.7] for montelukast and placebo, respectively. While the upper airway endpoint of AUC 0-60min for increased nasal symptoms score (NSS) on montelukast demonstrated a borderline (p=0.1) improvement, both the individual symptom of nasal congestion and the NSS during the recovery phase (30-min postchallenge) showed significant (p 0-60min –%Fall–FEV 1 >10%·hr (p=0.017) and similarly, against an upper airway reaction of AUC 0-60min -Increase-NSS >1.0 score · hr (p=0.039). Finally, montelukast demonstrated a simultaneous effect against lower and upper airway reactions, with significantly more patients (p=0.016) on montelukast (43.1%) vs placebo (25.5%) being protected from both asthma and rhinitis responses to cat allergen. Conclusion In patients exhibiting simultaneous lower and upper airway responses to acute cat allergen challenge, montelukast protected against both asthma and rhinitis responses.

Allergic rhinitis and bronchial asthma frequently coexist in the same patients. Many patients with rhinitis alone demonstrate nonspecific bronchial hyperresponsiveness, and prospective studies suggest that nasal allergy may be a predisposing risk factor for developing asthma. A growing body of literature has documented that the treatment of patients with allergic rhinitis may result in improvement of asthma symptoms, airway caliber, and bronchial hyperresponsiveness to methacholine and exercise. Finally, mechanistic studies of airway physiology have demonstrated that nasal disease may influence pulmonary function via both direct and indirect mechanisms. Nasal disease should be considered as a possible concomitant illness in all patients with asthma and treated appropriately when identified.