Conjunctivitis in dupilumab clinical trials.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4 and IL-13. It is approved in the U.S.A. for patients aged ≥ 12 years with moderate-to-severe atopic dermatitis (AD) uncontrolled by topical prescription medicines or who cannot use topical medicines, for patients in Japan whose AD is uncontrolled with existing therapies, for patients with moderate-to-severe AD in Europe who are candidates for systemic therapy and for patients aged ≥ 12 years for maintenance treatment of moderate-to-severe asthma uncontrolled with their current medicines. AD trials have reported increased incidence of conjunctivitis for dupilumab vs. placebo. OBJECTIVES: To characterize further the occurrence and risk factors of conjunctivitis in dupilumab clinical trials. METHODS: We evaluated randomized placebo-controlled trials of dupilumab in AD (n = 2629), asthma (n = 2876), chronic rhinosinusitis with nasal polyps (CRSwNP) (n = 60) and eosinophilic oesophagitis (EoE) (n = 47). RESULTS: In most AD trials, dupilumab-treated patients had higher conjunctivitis incidence than placebo controls. Higher baseline AD severity and previous history of conjunctivitis were associated with increased conjunctivitis incidence. Conjunctivitis was mostly mild to moderate. Most cases recovered or resolved during the treatment period; two patients permanently discontinued dupilumab due to conjunctivitis or keratitis. Common treatments included ophthalmic corticosteroids, antibiotics, and antihistamines or mast cell stabilizers. Most cases were diagnosed by the investigators. In asthma and CRSwNP trials, the incidence of conjunctivitis was lower for both dupilumab and placebo than in AD trials; dupilumab did not increase the incidence compared with placebo. In the EoE trial, no patients had conjunctivitis. CONCLUSIONS: Conjunctivitis was more frequent with dupilumab treatment in most AD trials. In dupilumab trials in other type 2 diseases, incidence of conjunctivitis was overall very low, and was similar for dupilumab and placebo. In AD, the incidence of conjunctivitis was associated with AD severity and prior history of conjunctivitis. The aetiology and treatment of conjunctivitis in dupilumab-treated patients require further study. What's already known about this topic? Ocular disorders, including allergic conjunctivitis, are common in patients with atopic dermatitis (AD). In most dupilumab AD trials, dupilumab-treated patients had higher conjunctivitis incidence than those receiving placebo. Most cases were mild to moderate and recovered or were recovering during study treatment; study treatment discontinuation due to conjunctivitis was rare. Conjunctivitis incidence was very low and similar for dupilumab and placebo in clinical trials in asthma, chronic rhinosinusitis with nasal polyps and eosinophilic oesophagitis. What does this study add? This analysis confirms and extends the results of the individual clinical trials. Baseline disease-related factors, including AD severity, prior conjunctivitis history and certain biomarkers (thymus and activation-regulated chemokine, IgE, eosinophils), were associated with increased incidence of conjunctivitis. Patients who responded well to dupilumab had reduced incidence of conjunctivitis. Further study is needed to elucidate the aetiology and treatment of conjunctivitis in dupilumab-treated patients with AD.

Safety and tolerability of omalizumab.

BACKGROUND: Omalizumab (Xolair) is a recombinant humanized monoclonal anti-IgE antibody with proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. OBJECTIVE: To review clinical study data to assess the safety profile of omalizumab. METHODS: We analysed the safety of omalizumab using data from completed clinical studies (up to 1 year) involving more than 7500 patients with asthma, rhinitis or related conditions and up to 4 years in one study of patients with severe allergic asthma, as well as post-marketing safety data. Analysis focuses on the risk of immune-system effects, hypersensitivity reactions, malignant neoplasia, parasitic infections and thrombocytopenia. RESULTS: Omalizumab exhibited a good safety and tolerability profile that was maintained up to 4 years in one study. The incidence of anaphylaxis was 0.14% in omalizumab-treated patients and 0.07% in control patients. No omalizumab-treated patient developed measurable anti-omalizumab antibodies. Post-marketing, based on estimated exposure of 57,300 patients (June 2003-December 2006), the frequency of anaphylaxis attributed to omalizumab use was estimated to be at least 0.2% of patients. Current clinical trial data do not support an increased risk of malignant neoplasia or thrombocytopenia with omalizumab. CONCLUSION: Data indicate that the proven efficacy of add-on omalizumab in patients with moderate-to-severe or severe allergic asthma is accompanied by a favourable safety and tolerability profile.

Comparison of once-daily mometasone furoate versus once-daily budesonide in patients with moderate persistent asthma.

We conducted this study to compare the efficacy and safety of once-daily mometasone furoate (MF) administered by dry powder inhaler (DPI) with once-daily budesonide (BUD)-DPI and placebo in patients with moderate persistent asthma previously using twice-daily inhaled corticosteroids. A total of 262 patients (> or = 12 years of age) with moderate persistent asthma were randomised to once-daily morning treatment with MF-DPI 440 microg (metered dose), BUD-DPI 400 microg (metered dose), or placebo in an eight-week, multicentre, placebo-controlled, double-blind, double-dummy study. The primary efficacy variable was percent change in FEV1 from baseline to endpoint (last evaluable visit). At endpoint, the percent change in FEV1 was significantly greater (p < 0.01) following treatment with MF-DPI 440 microg (8.9%) than with both BUD-DPI 400 microg (2.1%) and placebo (-3.9%). Secondary efficacy variables, including morning and evening peak expiratory flow rates, albuterol use, percentage of asthma symptom-free days, and physician-evaluated response to therapy were also significantly improved at endpoint in the MF-DPI group compared with both the placebo and BUD-DPI groups (p < 0.05). Both active treatments were well tolerated. In conclusion, once-daily treatment in the morning with MF-DPI 440 microg significantly improved pulmonary function and asthma control compared with morning administration of BUD-DPI 400 microg and placebo.

Effective control of asthma with hydrofluoroalkane flunisolide delivered as an extrafine aerosol in asthma patients.

BACKGROUND: 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. OBJECTIVE: To compare efficacy and safety of two different flunisolide formulations, HFA and chlorofluorocarbon (CFC), with placebo treatment over a range of doses. METHODS: 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. RESULTS: After 12 weeks of treatment, patients receiving 170 microg, twice daily, and 340 microg, twice daily, of HFA flunisolide showed a significant (P < 0.01) 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. CONCLUSIONS: HFA flunisolide provides comparable efficacy and safety at one-third the dose of CFC flunisolide.

Effects of zafirlukast upon clinical, physiologic, and inflammatory responses to natural cat allergen exposure.

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 FEV1 (P = 0.001) and attenuated the decrease in FEV1 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.

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: 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. RESULTS: 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. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.

Efficacy of soluble IL-4 receptor for the treatment of adults with asthma.

BACKGROUND: IL-4 mediates important proinflammatory functions in asthma, including induction of the IgE isotype switch, increased expression of vascular cell adhesion molecule 1 and promotion of eosinophil transmigration across the endothelium, stimulation of mucus production, and T(H)2 lymphocyte differentiation, leading to release of IL-4, IL-5, IL-9, and IL-13. OBJECTIVE: The current study evaluated the therapeutic potential of inhaled recombinant human soluble interleukin-4 receptor (IL-4R) as an IL-4 antagonist. METHODS: This study was a randomized, double-blind, placebo-controlled study in 62 subjects involving 12 once weekly nebulizations of 0.75, 1.5, or 3.0 mg of IL-4R or placebo. During screening, subjects documented dependence on inhaled corticosteroids by an exacerbation in asthma induced by one or two 50% dose reductions at 2-week intervals. After restabilization for 2 weeks on the dose above which their asthma flared, inhaled steroids were discontinued, patients were randomized, and study medication was started on day 0. RESULTS: IL-4R was well tolerated. Efficacy was demonstrated by a decline in FEV(1) observed in the placebo group (-0.4 L and -13% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -2% predicted; P =.05 over the 3-month treatment period). Daily patient-measured morning FEV(1) also demonstrated a significant decline in the placebo group (-0.5 L and -18% predicted), which did not occur in the group receiving 3.0 mg of IL-4R (-0.1 L and -4% predicted; P =.02 over the 3-month treatment period). The efficacy of IL-4R was further confirmed by the absence of increase in asthma symptom scores in the group receiving 3.0 mg of IL-4R (Delta 0.1) compared with that seen in the placebo group (Delta 1.4 over 1 month; P =.07). Study discontinuation for asthma exacerbation was not significantly different between groups (placebo, 56%; 3.0 mg of IL-4R, 47%; P = not significant). CONCLUSION: These promising data suggest that IL-4R is safe and effective in the treatment of moderate persistent asthma.

Multicenter, double-blind, placebo-controlled, multiple-challenge evaluation of reported reactions to monosodium glutamate.

BACKGROUND: The frequency of reactions reported to occur after the consumption of monosodium glutamate (MSG) is the subject of controversy. OBJECTIVE: We conducted a multicenter, multiphase, double-blind, placebo-controlled study with a crossover design to evaluate reactions reportedly caused by MSG. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Allergic rhinitis: treating the adult.

Allergic rhinitis is now recognized as a chronic medical condition that markedly affects patient quality of life and is a cause of substantial medical care expenditures. Effective treatment of adults with allergic rhinitis usually requires an integrated regimen that combines allergen avoidance measures, pharmacotherapy, and possible specific-allergen immunotherapy. This approach can control bothersome symptoms with minimal adverse effects in most patients. New medications, such as anti-immunoglobulin E therapy and cytokine antagonists, may provide relief to patients who are refractory to or do not tolerate currently available treatments.

Once-daily mometasone furoate dry powder inhaler in the treatment of patients with persistent asthma.

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 microg and 400 microg 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 FEV1 was the primary efficacy variable. RESULTS: At endpoint, both doses of MF DPI were significantly more effective than placebo (P < or = .05) in improving FEV1. Based on morning peak expiratory flow rate, once-daily MF DPI 400 microg was more effective than placebo (P < or = .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 microg 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.

Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study.

Monosodium glutamate (MSG) has a long history of use in foods as a flavor enhancer. In the United States, the Food and Drug Administration has classified MSG as generally recognized as safe (GRAS). Nevertheless, there is an ongoing debate exists concerning whether MSG causes any of the alleged reactions. A complex of symptoms after ingestion of a Chinese meal was first described in 1968. MSG was suggested to trigger these symptoms, which were referred to collectively as Chinese Restaurant Syndrome. Numerous reports, most of them anecdotal, were published after the original observation. Since then, clinical studies have been performed by many groups, with varying degrees of rigor in experimental design ranging from uncontrolled open challenges to double-blind, placebo controlled (DBPC) studies. Challenges in subjects who reported adverse reactions to MSG have included relatively few subjects and have failed to show significant reactions to MSG. Results of surveys and of clinical challenges with MSG in the general population reveal no evidence of untoward effects. We recently conducted a multicenter DBPC challenge study in 130 subjects (the largest to date) to analyze the response of subjects who report symptoms from ingesting MSG. 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, the frequency of the responses was low and the responses reported were inconsistent and were not reproducible. The responses were not observed when MSG was given with food.

Treating asthma in the new millennium.

As the pathophysiologic process of asthma has become better defined, new molecular targets for treating asthma have emerged. Resident airway cells, circulating leukocytes, and various cell-derived mediators and cytokines contribute to the inflammatory events of asthma. New therapeutic approaches to moderate to severe asthma currently in clinical development include antibodies to IgE and interleukin-5, a soluble receptor that would sequester interleukin-4, cytokine and chemokine receptor antagonists, and phosphodiesterase type 4 inhibitors. Adhesion molecules, which are involved in the migration of inflammatory cells into lung tissue, are also important targets for new antiasthma therapies. Because of researchers' focus on specific pathologic processes and molecular targets, the adverse effects of new agents may be minimized. Also, the longer duration of action of some of the new agents allows weekly to monthly dosing, which may well enhance patient compliance.

Intranasal corticosteroids for allergic rhinitis: how do different agents compare?

Intranasal steroids have proved to be an effective and safe form of therapy for allergic rhinitis. However, as the number of new glucocorticoid compounds has increased over the past decade, it has become important to consider whether significant differences exist between these agents. Pharmacologically, newer drugs such as mometasone furoate and fluticasone propionate appear to have substantially higher topical potencies and lipid solubilities and lower systemic bioavailabilities than do older compounds. In clinical use, however, all the available drugs appear to be equally effective in controlling symptoms of seasonal and perennial allergic rhinitis. With respect to adverse effects, emerging data suggest that mometasone furoate and fluticasone propionate may have less potential for systemic effects during prolonged use, particularly in children. Newer intranasal steroids appear to have practical advantages over older agents that may favor their use in some groups of patients with allergic rhinitis.

Onset and duration of action of levocabastine nasal spray in atopic patients under nasal challenge conditions.

BACKGROUND: Although prior studies have documented the rapid onset of action of topical intranasal levocabastine (LEV), little is known about its duration of action under nasal challenge conditions. OBJECTIVES: We sought to assess the onset and duration of action of escalating doses of LEV nasal spray by using a nasal allergen challenge (NAC) model. METHODS: Eighteen asymptomatic subjects with histories of seasonal allergic rhinitis were enrolled into a randomized, single-blind, placebo-controlled, dose-ranging crossover study. Each patient was randomly assigned to receive single doses of placebo and intranasal LEV 0.1, 0.2, and 0.4 mg during 2 parts of the study. In part 1 (onset of action), NAC consisted of a single dose of allergen administered 5 minutes after study drug treatment. In part 2 (duration of action), NAC consisted of increasing doses of allergen administered 0.5, 6, 12, and 24 hours on separate days after study drug treatment. Nasal symptom scores (NSSs) and nasal peak expiratory flow rates were measured after NAC in both phases of the study. Blood samples for plasma LEV concentrations were drawn after each NAC. RESULTS: In part 1, NSSs were significantly lower after the administration of LEV 0.1, 0.2, and 0.4 mg compared with placebo (P <.05). In part 2, NSSs were significantly lower after LEV doses of 0.2 and 0.4 mg compared with placebo at 0.5, 6, 12, and 24 hours after treatment (P <.05). The mean provocative dose of allergen required to elicit a positive nasal reaction was increased after LEV doses of 0.2 and 0.4 mg at 0.5, 6, and 12 hours after treatment. Nasal peak expiratory flow rates demonstrated no significant differences between LEV and placebo for any doses at any time points. Mean plasma LEV concentrations were low (range, 0 to 3. 7 ng/mL) after all doses and did not correlate with drug efficacy. CONCLUSIONS: Single intranasal LEV doses of 0.1, 0.2, and 0.4 mg significantly reduced the severity of the immediate nasal response to allergen when administered 5 minutes before NAC. This protective effect against NAC continued to be present 24 hours after administration of LEV doses of 0.2 and 0.4 mg. Efficacy in blocking the reaction to NAC did not correlate with plasma LEV levels, suggesting that the inhibitory effect was due largely to topical rather than systemic effects.

The relationship between allergic rhinitis and bronchial asthma.

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.

Salmeterol improves quality of life in patients with asthma requiring inhaled corticosteroids. Salmeterol Quality of Life Study Group.

BACKGROUND: Traditional clinical outcomes have demonstrated that salmeterol improves pulmonary function and reduces asthma symptoms. However, they do not evaluate how patients perceive the effect of therapeutic intervention on day-to-day functioning and well-being. OBJECTIVE: We sought to evaluate the impact of salmeterol on disease-specific quality of life with the Asthma Quality-of-Life Questionnaire, as well as the efficacy and safety of salmeterol in patients with stable asthma who were symptomatic despite daily use of inhaled corticosteroids. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study of 506 patients. Patients were treated with 42 microg salmeterol or placebo twice daily for 12 weeks delivered through a metered dose inhaler. RESULTS: Mean change from baseline in asthma quality-of-life scores was significantly greater (p < or = 0.006) after 12 weeks of treatment with salmeterol compared with placebo ("as-needed" albuterol) in global scores (1.08 vs 0.61) and individual domains (activity limitations, 0.91 vs 0.54; asthma symptoms, 1.28 vs 0.71; emotional function, 1.17 vs 0.65; and environmental exposure, 0.84 vs 0.47). Patients treated with salmeterol experienced significantly greater improvements from baseline to week 12 compared with placebo in FEV1 (0.42 L vs 0.15 L, p < 0.001), morning peak expiratory flow (47 L/min vs 14 L/min, p < 0.001), evening peak expiratory flow (29 L/min vs 11 L/min, p < 0.001), and asthma symptom scores (daytime scores reduced by 0.55 vs 0.30, p < 0.001). Patients treated with salmeterol used significantly less supplemental albuterol (reduced by 3 puffs/day vs 1 puff/day, p < 0.001). CONCLUSION: Salmeterol provided significantly greater improvement in quality-of-life outcomes in patients whose asthma symptoms are not well controlled with inhaled corticosteroids. These results demonstrate that the benefits of salmeterol are not limited to conventional clinical measures of efficacy.

The effectiveness of once-daily dosing of inhaled flunisolide in maintaining asthma control.

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 microg) twice daily, each patient was randomized into one of four 12-week flunisolide treatment groups: group 1, 2 inhalations (500 microg) bid; group 2, 4 inhalations (1000 microg) qd in the morning; group 3, 4 inhalations (1000 microg) qd in the evening; or group 4, 2 inhalations (500 microg) 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), FEV1, and methacholine PC20. 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 microg 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 microg 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 PC20 or 24-hour urinary cortisol levels in any group. CONCLUSIONS: For patients with asthma that was stabilized by 2 inhalations of flunisolide (500 microg) bid, switching to 4 inhalations (1000 microg) qd in either the morning or evening is effective in maintaining asthma control. Reducing the dose to 2 inhalations (500 microg) qd in the morning, however, leads to a deterioration in asthma control.