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Objective: A new epinephrine hydrofluoroalkane (HFA) asthma metered-dose inhaler (MDI) was reformulated to replace the previously marketed epinephrine chlorofluorocarbon (CFC) MDI. In addition to the HFA propellant change, several enhanced modifications (i.e. changed from solution to suspension, 43% dose reduction, etc.) were made to the formulation of epinephrine HFA MDI. This study evaluates the 6-month long-term safety and efficacy profile of the new epinephrine HFA MDI. Method: The long-term safety study consists of two 3-month, multi-center, double- or evaluator-blinded, parallel-group, placebo, and active controlled stages. In each stage, subjects aged ≥12 years with intermittent or mild-to-moderate persistent asthma were randomized to receive epinephrine HFA (2 × 125 mcg/inhalation), placebo HFA, or epinephrine CFC (2 × 220 mcg/inhalation). Bronchodilator efficacy was assessed in Stage 1 and was determined primarily by the change in the forced expiratory volume in 1 s (ΔFEV1) at Week 12, relative to the same day baseline. Results: The primary efficacy endpoint (AUC0-6hrs of %ΔFEV1 at Week 12) for epinephrine HFA (47.3 ± 54.2) closely paralleled those for the active control, epinephrine CFC (41.0 ± 43.4). Both groups were found to be overall comparable in bronchodilator efficacy. Both also showed low incidence rates of AEs with tremor being most commonly reported for epinephrine HFA. All AEs found were non-serious and non-significant. The observed changes in vital signs, ECG, serum glucose, and potassium were minimal and not clinically relevant. Conclusion: This study demonstrated that the new epinephrine HFA is overall comparable, in both safety and efficacy, to the previous epinephrine CFC.

Background Nasal, noninhaled carbon dioxide (CO 2 ) was shown to be effective for the treatment of symptoms of seasonal allergic rhinitis (SAR) and perennial allergic rhinitis in single application studies. Objective To assess the efficacy of as-needed treatment with nasal, noninhaled CO 2 in patients with SAR. Methods Fifty-six ragweed-allergic patients were enrolled at 3 sites in this study. After a 3- to 7-day run-in, 32 eligible patients who had an instantaneous total nasal symptom score of 8 or more out of a maximum of 12 in at least 2 SAR episodes per day were randomized to the CO 2 group (n = 19) or to the placebo group (n = 13). A 10-second/nostril application was used as needed for 14 days (maximum 6 times/d). Patients evaluated their symptoms before and 30 minutes after each application. All symptoms were scored on a 0 to 3 scale. Results Analysis of all treated episodes (CO 2 = 816, placebo = 516) showed a statistically significant beneficial change in total nasal symptom score from baseline (effect size = −0.51; P P 2 was well tolerated, with transient nasal discomfort as the most common adverse event reported. There were no serious adverse events, serious adverse device effects, or early discontinuations. Conclusions Nasal, noninhaled CO 2 is effective for the as-needed treatment of SAR symptoms. The effect is rapid and the effect size is large. It represents a novel potential option for the as-needed treatment of rhinitis symptoms.

Summary Background In phase 2 trials, lebrikizumab, an anti-interleukin-13 monoclonal antibody, reduced exacerbation rates and improved FEV 1 in patients with uncontrolled asthma, particularly in those with high concentrations of type 2 biomarkers (eg, periostin or blood eosinophils). We undertook replicate phase 3 studies to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite inhaled corticosteroids and at least one second controller medication. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV 1 40–80% predicted, and stable background therapy were randomly assigned (1:1:1) with an interactive voice–web-based response system to receive lebrikizumab 37·5 mg or 125 mg, or placebo subcutaneously, once every 4 weeks. Randomisation was stratified by screening serum periostin concentration, history of asthma exacerbations within the last 12 months, baseline asthma medications, and country. The primary efficacy endpoint was the rate of asthma exacerbations over 52 weeks in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells per μL), analysed with a Poisson regression model corrected for overdispersion with Pearson χ 2 that included terms for treatment group, number of asthma exacerbations within the 12 months before study entry, baseline asthma medications, geographic region, screening periostin concentration, and blood eosinophil counts as covariates. Both trials are registered at ClinicalTrials.gov, LAVOLTA I, number NCT01867125, and LAVOLTA II, number NCT01868061. Findings 1081 patients were treated in LAVOLTA I and 1067 patients in LAVOLTA II. Over 52 weeks, lebrikizumab reduced exacerbation rates in biomarker-high patients in the 37·5 mg dose group (rate ratio [RR] 0·49 [95% CI 0·34–0·69], p vs 80% [576 of 716 patients] for placebo), serious adverse events (8% [115 patients] for both lebrikizumab doses vs 9% [65 patients] for placebo), and adverse events leading to study drug discontinuation (3% [49 patients] for both lebrikizumab doses vs 4% [31 patients] for placebo) were similar between lebrikizumab and placebo. The following serious adverse events were reported in the placebo-controlled period: one event of aplastic anaemia and five serious adverse events related to raised concentrations of eosinophils in patients treated with lebrikizumab and one event of eosinophilic pneumonia in the placebo group. Interpretation Lebrikizumab did not consistently show significant reduction in asthma exacerbations in biomarker-high patients. However, it blocked interleukin-13 as evidenced by the effect on interleukin-13-related pharmacodynamic biomarkers, and clinically relevant changes could not be ruled out. Funding F Hoffmann-La Roche.

IntroductionIn a subset of patients with asthma, standard-of-care treatment does not achieve disease control, highlighting the need for novel therapeutic approaches. Lebrikizumab is a humanised, monoclonal antibody that binds to and blocks interleukin-13 activity.MethodsLUTE and VERSE were replicate, randomised, double-blind, placebo-controlled studies, evaluating multiple doses of lebrikizumab in patients with uncontrolled asthma despite the use of medium-to-high-dose inhaled corticosteroid and a second controller. Patients received lebrikizumab 37.5, 125, 250 mg or placebo subcutaneously every four weeks. The primary endpoint was the rate of asthma exacerbations during the placebo-controlled period. Analyses were performed on prespecified subgroups based on baseline serum periostin levels. Following the discovery of a host-cell impurity in the study drug material, protocols were amended to convert from phase III to phase IIb. Subsequently, dosing of study medication was discontinued early as a precautionary measure. The data collected for analysis were from a placebo-controlled period of variable duration and pooled across both studies.ResultsThe median duration of treatment was approximately 24 weeks. Treatment with lebrikizumab reduced the rate of asthma exacerbations, which was more pronounced in the periostin-high patients (all doses: 60% reduction) than in the periostin-low patients (all doses: 5% reduction); no dose–response was evident. Lung function also improved following lebrikizumab treatment, with greatest increase in FEV1 in periostin-high patients (all doses: 9.1% placebo-adjusted improvement) compared with periostin-low patients (all doses: 2.6% placebo-adjusted improvement). Lebrikizumab was well tolerated and no clinically important safety signals were observed.ConclusionsThese data are consistent with, and extend, previously published results demonstrating the efficacy of lebrikizumab in improving rate of asthma exacerbations and lung function in patients with moderate-to-severe asthma who remain uncontrolled despite current standard-of-care treatment.Trial registration numbersThe LUTE study was registered under NCT01545440 and the VERSE study under NCT01545453 at http://www.clinicaltrials.gov

Consistent medication delivery is critical for disease control including symptom management of allergic rhinitis (AR). Available aqueous intranasal corticosteroid devices lack an accurate dose (actuation) counter, which may lead patients to prematurely discard a unit or use a unit beyond its labeled number of actuations, therefore impacting patient adherence. Beclomethasone dipropionate (BDP) nasal aerosol, a nonaqueous hydrofluoroalkane formulation in a device with a novel integrated dose counter and an established efficacy/safety profile, was approved to treat AR-associated nasal symptoms in adolescent and adult patients. This study was designed to evaluate performance of the BDP nasal aerosol device with an integrated dose counter in perennial AR (PAR) patients. In a 6-week, double-blind, placebo-controlled study in PAR patients (≥12 years), patients were randomized to receive once-daily BDP nasal aerosol at 320 micrograms or placebo. In addition to assessing the primary efficacy end point, patients evaluated the performance of the device and reliability, accuracy, and functionality of the dose counter. Concordance between daily patient-reported actuations and dose counter readings was assessed by classifying discrepancies into four categories: "fire not count," "count not fire," "count unknown fire," and "count up unknown fire." Analysis was performed for the total device completer population (n = 374), which included all randomized patients completing ≥80% of actuations during the last 4 weeks of treatment. Low discrepancy rates were shown for all discrepancy categories. Of 41,891 patient-reported actuations, only 159 discrepancies (diary versus counter) were noted, resulting in an overall discrepancy rate of 0.38 per 100 actuations. The medically important discrepancy rate of "fire not count" was low (0.09 per 100 actuations). Overall, 79.1% of patients reported zero discrepancies, 9.4% reported one discrepancy, and 6.4% reported two discrepancies. These results showed the functionality and reliability of the BDP nasal aerosol device with an integrated dose counter in a clinical setting. (ClinicalTrials.gov identifier: NCT01134705.).

Introduction In Phase II trials, lebrikizumab, an anti-IL-13 mAb, improved exacerbation rates and FEV1 in patients with uncontrolled asthma, particularly in patients with higher levels of Type 2 biomarkers. Aims LAVOLTA I ([NCT01867125][1]) and II ([NCT01868061][2]) are replicate Phase III studies designed to assess the efficacy and safety of lebrikizumab in patients with uncontrolled asthma despite ICS and at least a second controller. Methods Adult patients with uncontrolled asthma, pre-bronchodilator FEV1 40–80% predicted, and stable background therapy were randomized to receive lebrikizumab 37.5 mg or 125 mg, or placebo SC, Q4W. The primary efficacy endpoint was rate of asthma exacerbations during the 52-week placebo-controlled period in biomarker-high patients (periostin ≥50 ng/mL or blood eosinophils ≥300 cells/µL). Secondary endpoints included change in FEV1 and ACQ-5. Results 1081 and 1067 patients were randomized and treated in LAVOLTA I and II. Over 52 weeks, lebrikizumab treatment reduced exacerbation rates in biomarker-high patients by 51% for the 37.5 mg dose ( p

Many patients with asthma have uncontrolled disease despite treatment with inhaled glucocorticoids. One potential cause of the variability in response to treatment is heterogeneity in the role of interleukin-13 expression in the clinical asthma phenotype. We hypothesized that anti-interleukin-13 therapy would benefit patients with asthma who had a pretreatment profile consistent with interleukin-13 activity.We conducted a randomized, double-blind, placebo-controlled study of lebrikizumab, a monoclonal antibody to interleukin-13, in 219 adults who had asthma that was inadequately controlled despite inhaled glucocorticoid therapy. The primary efficacy outcome was the relative change in prebronchodilator forced expiratory volume in 1 second (FEV(1)) from baseline to week 12. Among the secondary outcomes was the rate of asthma exacerbations through 24 weeks. Patient subgroups were prespecified according to baseline type 2 helper T-cell (Th2) status (assessed on the basis of total IgE level and blood eosinophil count) and serum periostin level.At baseline, patients had a mean FEV(1) that was 65% of the predicted value and were taking a mean dose of inhaled glucocorticoids of 580 μg per day; 80% were also taking a long-acting beta-agonist. At week 12, the mean increase in FEV(1) was 5.5 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.02). Among patients in the high-periostin subgroup, the increase from baseline FEV(1) was 8.2 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.03). Among patients in the low-periostin subgroup, the increase from baseline FEV(1) was 1.6 percentage points higher in the lebrikizumab group than in the placebo group (P = 0.61). Musculoskeletal side effects were more common with lebrikizumab than with placebo (13.2% vs. 5.4%, P = 0.045).Lebrikizumab treatment was associated with improved lung function. Patients with high pretreatment levels of serum periostin had greater improvement in lung function with lebrikizumab than did patients with low periostin levels. (Funded by Genentech; ClinicalTrials.gov number, NCT00930163 .).

The combination of budesonide and formoterol administered in one hydrofluoroalkane pressurized metered-dose inhaler (pMDI) is approved in the United States in two dosage strengths (budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations [160/9 microg] or 160/4.5 microg x 2 inhalations [320/9 microg]) in a fixed-dose, twice-daily regimen for the treatment of patients > or =12 years old with persistent asthma not adequately controlled with an inhaled corticosteroid (ICS) alone. This article reviews the clinical profile of budesonide/formoterol pMDI in patients with persistent asthma, including information on pharmacogenetics, efficacy, and tolerability. Studies of budesonide/formoterol pMDI in patients with asthma were identified through PubMed and respiratory meeting abstract databases. Budesonide/formoterol pMDI 160/9 microg has shown a rapid onset (within 15 minutes) of clinically significant bronchodilation that is faster than fluticasone propionate/salmeterol dry powder inhaler (DPI) 250/50 microg (within 30 minutes). The efficacy and tolerability profile of budesonide/formoterol pMDI 320/9 microg was similar to fluticasone propionate/salmeterol DPI 250/50 microg and budesonide/formoterol DPI 320/9 microg in adults and adolescents with persistent asthma. Short-term (12-week) and long-term (6- to 12-month) studies have established greater efficacy and similar tolerability of budesonide/formoterol pMDI compared with its monocomponents and placebo in patients with mild/moderate or moderate/severe persistent asthma. Studies evaluating patient-reported outcomes, including health-related quality of life and patient satisfaction with treatment, further support the benefits of budesonide/formoterol pMDI in patients with persistent asthma. In summary, budesonide/formoterol pMDI is an effective, well-tolerated treatment option for patients with persistent asthma for whom ICS/long-acting beta2-adrenergic agonist combination therapy is appropriate.

Antileukotriene drugs have been studied for more than 15 years. In this review we examine the role of leukotrienes in rhinitis and rhinosinusitis, and explore the clinical literature supporting the use of anti-leukotriene agents in these diseases. Although these medications clearly are efficacious in rhinitis, it is unclear where in the armamentarium they should be used. The evidence for use in sinusitis has not been well studied except in sinusitis-associated aspirin-exacerbated respiratory disease. In this circumstance there is information that allows use of antileukotriene agents to be considered efficacious. We provide our rationale for use and await future clinical studies to answer this important question.

Context: Acute asthma causes nearly 2 million hospital emergency department (ED) visits in the United States annually, and hospitalization after an ED visit and relapse after ED discharge are common. Objective: To evaluate the adding of therapy with zafirlukast to standardized care for patients with acute asthma in the ED and a 28-day follow-up period. Design and patients: A total of 641 patients presenting to the ED with acute asthma were randomized to receive either single-dose zafirlukast, 160 mg (Z160) [162 patients], zafirlukast, 20 mg (Z20) [158 patients]), or placebo (321 patients) as adjunct treatment to standard care in this double-blind, multicenter trial. Assessments, including spirometry and symptom scores, were obtained before each albuterol treatment and at 4 h. Patients who were discharged from the ED after 4 h continued outpatient therapy over a 28-day period and received either Z20 bid (276 patients) or placebo (270 patients) in addition to prednisone, albuterol, and their previous asthma medications. FEV1 was measured at clinic visits on days 10 and 28. Patients recorded outpatient clinical data twice daily on a home diary card. Main outcome measures: the effect of zafirlukast on relapse after ED discharge. Other assessments were the rate of extended care (ie, ED stay for > 4 h or hospitalization), FEV1, and symptoms. Results: At the end of the outpatient period, 65 of 276 patients (23.6%) treated with zafirlukast and 78 of 270 patients (28.9%) treated with placebo relapsed (p = 0.047; absolute reduction, 5.3%; relative reduction, 18.3%). At the end of the ED period, 16 of 162 patients (9.9%) treated with Z160, 26 of 158 patients (16.5%) treated with Z20, and 48 of 321 patients (15.0%) treated with placebo required extended care (p = 0.052; absolute reduction with Z160 compared to placebo, 5.1%; relative reduction, 34%). These findings were supported by a significant improvement in FEV1 and dyspnea in the ED with the use of Z160 therapy, and by greater improvement in FEV1 and symptoms during the outpatient period for patients treated with Z20. Conclusions: When added to standardized care, therapy with Z20 bid reduced the risk of relapse compared with placebo over a 28-day treatment period. One dose of Z160 in the ED also reduced the rate of extended care.

Leukotriene modifiers have been shown to be efficacious in the treatment of asthma. Because of this success, and the fact that leukotrienes can be recovered not only from bronchoalveolar lavage fluid but also nasal lavage fluid, some researchers have suggested that these medications may also be useful for treating allergic rhinitis. Because the upper and lower airways are linked physically, there has been an assumption that therapy for upper and lower airway disease should be similar. This critical appraisal examines available data both supporting and refuting the emerging role of leukotriene modifiers in the treatment of allergic rhinitis. Although many studies have shown an improvement in nasal symptoms when comparing a leukotriene modifier with placebo, few studies have conclusively shown that a leukotriene modifier is any more effective in treating allergic rhinitis than an antihistamine. Results from several reported studies suggest that the addition of a leukotriene antagonist to an antihistamine is no more efficacious than antihistamine alone. However, many of these studies were small and/or primarily designed to examine the asthmatic response, with nasal symptoms being a lesser endpoint. To better understand how, where, and when leukotriene modifiers should be used in the armamentarium of therapies for allergic rhinitis, larger clinical investigations designed specifically to study allergic rhinitis need to be undertaken. We conclude that currently, the data do not support widespread use of a leukotriene modifier with or without an antihistamine in place of an intranasal corticosteroid with or without an antihistamine in the treatment of allergic rhinitis.

To summarize recent advances in IL-4 and IL-13 blockade in the treatment of asthma.Historically, anticytokine therapies have historically been unsuccessful in the treatment of asthma because of the heterogeneity of its pathogenesis. Recent advances in our understanding of asthma pathophysiology and our increased ability to phenotype patients have led to the identification of asthmatic subsets (endotypes) that are most likely to respond to anticytokine therapy. Several new biologic therapies targeting IL-13 or both IL-4 and IL-13 signaling are currently in clinical trials and both types of therapies have demonstrated therapeutic benefit.Anti-IL-4/13 therapies, guided by knowledge of an individual's underlying pathophysiology, are a promising class of therapies for treatment of asthma.

Background The Accolate Clinical Experience and Pharmacoepidemiology Trial (ACCEPT), evaluated zafirlukast in a wide spectrum of patients from a variety of clinical practices. Objective To determine the effect of age on the response to zafirlukast 20 mg twice daily in 3759 patients with mild, moderate, or severe asthma. Methods Patients received open-label administration of zafirlukast 20 mg twice daily (bid) for 4 weeks. Pulmonary function was measured twice daily, and overall asthma symptom scores, number of nighttime awakenings, severity of morning asthma symptoms, and β 2 -agonist use were recorded daily. Trial results were analyzed to compare the efficacy of zafirlukast in 263 adolescent (12 to 17 years old), 2602 adult (18 to 65 years old), and 321 elderly (66 years old and older) patients (the evaluable population). Results After 4 weeks of zafirlukast therapy, improvements in pulmonary function decreased with age and were significant for all measures in adolescents and adults and for morning peak expiratory flow in elderly patients. Improvements in symptom response were statistically significant across age groups. Reduction in β 2 -agonist rescue was similar in adolescents and adults but significantly less in elderly patients. Conclusions Zafirlukast is an effective treatment for asthma in all patients, regardless of age. In elderly patients, improvement in asthma symptoms rather than pulmonary function may represent a primary marker for efficacy with zafirlukast.

Fluticasone propionate is a glucocorticoid with negligible oral bioavailability and very low intranasal bioavailability that is used as an intranasal spray for the treatment of rhinitis.The purpose of this study was to evaluate the hypothalamic-pituitary-adrenal (HPA)axis effects of fluticasone propionate aqueous nasal spray (FP ANS) compared with oral prednisone and placebo by using a 6-hour cosyntropin infusion test.In a 4-week, randomized, double-blind, double-dummy, placebo-controlled parallel-group study, 105 adult patients with allergic rhinitis were randomly assigned to receive FP ANS 200 microg once daily, FP ANS 400 microg twice daily, oral prednisone 7.5 mg once daily, oral prednisone 15 mg once daily, or placebo. HPA-axis function was assessed at the screening visit and after 4 weeks of treatment by measuring morning plasma cortisol concentrations and poststimulation concentrations of plasma and urinary cortisol.There was no evidence of altered HPA-axis response to cosyntropin by the end of treatment with FP ANS 200 microg once daily or FP ANS 400 microg twice daily when compared with placebo. In contrast, 4 weeks of treatment with oral prednisone 7.5 or 15 mg once daily was associated with significant (p0.05 vs placebo) reduction in HPA-axis function, as evidenced by lower plasma cortisol concentrations (area under the plasma concentration-time curve and peak concentrations) after cosyntropin stimulation and reduced mean 24-hour urinary cortisol excretion. FP ANS 400 microg twice daily and both prednisone regimens were associated with a significant (p0.05 vs placebo) reduction in mean morning plasma cortisol concentrations.These results indicate that a 4-week course of FP ANS at four times the recommended dose does not suppress adrenal function in response to a 6-hour cosyntropin stimulation test.

At this time, no placebo-controlled studies in the clinical literature compare the efficacy and safety of the most widely prescribed oral inhaled corticosteroids when dosed at their recommended daily doses. This study compared the efficacy and safety of beclomethasone dipropionate (BDP) 336 μg/day administered by metered dose inhaler (MDI) alone, and triamcinolone acetonide (TA) 800 μg/day by MDI with a built-in tube extender in adults with persistent asthma. Methods This 56-day, randomized, double-blind, double-dummy, placebo-controlled, multicenter trial was conducted in 328 adults with mild to moderately severe asthma (FEV 1 50% to 90% of predicted while maintained on inhaled corticosteroids). Patients were seen at a baseline visit and on study days 28 and 56. Efficacy variables included pulmonary function tests, physician and patient assessments of asthma condition, and use of rescue medication. Results Statistically significant improvements from baseline in most efficacy measures were demonstrated for both active treatments versus placebo, and with the following exception were the same between active treatments: mean increase in FEV 1 in the beclomethasone dipropionate group was statistically significantly greater than in the triamcinolone acetonide group on day 28. Throughout the sudy, BDP was statistically superior to TA with respect to mean change from baseline in total asthma symptom scores and for 3 of 8 weeks in reducing the mean average weekly use of rescue albuterol (the two active treatments were comparable for this variable at all other time points). Beclomethasone dipropionate and TA were comparable in safety. Conclusion In adult patients with mild to moderately severe persistent asthma, treatment with BDP consistnetly conferred greater improvement from baseline in mean FEV 1 than TA. This difference achieved statistical significance after 28 days of therapy but was not maintained to endpoint. Decreases in overall asthma symptom scores and in the use of rescue albuterol were statistically significantly greater for the BDP group compared with the TA group. Based on these findings, we conclude that BDP is at least as effective as TA in the treatment of persistent asthma in adults, and judged by some measures, may be superior.

The second reported case of common variable immunodeficiency (acquired agammaglobulinemia) after renal transplantation is presented. Agammaglobulinemia presumably resulted from long-standing immunosuppression. This case and our review of the literature indicate that agammaglobulinemia is a rare event after transplantation but can be treated successfully with intravenous immunoglobulin. Additionally, hypogammaglobulinemia occurs frequently after transplantation and should be monitored and treated in appropriate clinical situations. The treatment of our patient with intravenous immunoglobulin also suggests that patients with common variable immunodeficiency can undergo renal transplantation.

Background Brief nasal carbon dioxide insufflation has previously been shown to provide rapid relief of the symptoms of allergic rhinitis. Objective To examine the safety and efficacy of nasal carbon dioxide on the symptoms of perennial allergic rhinitis. Methods This was a randomized, double-blind, placebo-controlled, multicenter, in-clinic study that evaluated 2 flow rates (5 or 10 mL/s) and 2 administration durations (10 or 30 seconds per nostril) for nasal carbon dioxide vs placebo. Study participants rated their symptoms in clinic for 4 hours after administration and then through 24 hours outside the clinic. A total of 348 symptomatic patients with a minimum 2-year history of perennial allergic rhinitis requiring pharmacotherapy were randomized and treated. Results The mean change in total nasal symptom score from baseline at 30 minutes (the primary end point) showed greater improvement in the nasal carbon dioxide–treated groups compared with placebo. This change was statistically significant in the group treated with 10 mL/s for 10 seconds per nostril: −4.69 carbon dioxide vs −2.00 placebo ( P = .03). The effect of a single dose lasted approximately 4 to 6 hours. The mean change from baseline at 30 minutes in total nonnasal symptom score was also statistically significant (−4.06 carbon dioxide vs −2.25 placebo, P = .029) for this group. The most common adverse events were nasal discomfort, lacrimation, and headache. Conclusion The study provides further evidence that nasal carbon dioxide is a potentially efficacious treatment for the symptoms of allergic rhinitis.

The efficacy of oral montelukast has been well established in asthma and allergic rhinitis in adults and children. The purpose of this study was to evaluate dose-related bronchodilation and tolerability of inhaled montelukast.Randomized, double-blind, crossover, adaptive-design study comparing single-dose administration of inhaled montelukast versus placebo in patients age 15-65 years with chronic asthma (n = 68). Montelukast was delivered as a witnessed dose through dry powder inhaler at doses of 25, 250, or 1000 μg, and doses of 50, 100, and 500 μg could be used if needed based on a prespecified dose-response algorithm. Each administration was followed by a 4- to 7-day washout period before crossing over to the next treatment. The primary endpoint was the change from baseline in a forced expiratory volume in 1 second (FEV₁) over the first 4 hours after administration, calculated as a time-weighted average (ΔFEV₁ [0-4 hours]). Other endpoints included the onset and duration of bronchodilation and the effect of albuterol when added to inhaled montelukast.Over 4 hours postdose, and compared with placebo (least-squares [LS] mean 0.03 L), inhaled montelukast 100 μg (0.13 L; p ≤ .001), 250 μg (0.10 L; p.01), and 1000 μg (0.12 L; p ≤ .001) had significantly greater ΔFEV₁ (0-4 hours). At 24 hours postdose, inhaled montelukast 100 μg (0.10 L) and 1000 μg (0.09 L) had significantly greater bronchodilation compared with placebo (0.02 L; p.05 vs. montelukast). Montelukast 1000 μg provided significant bronchodilation versus placebo within 20 minutes of administration (0.03 L vs. -0.05 L), whereas montelukast 100 μg provided significant bronchodilation relative to placebo within 2 hours of dosing (0.09 L vs. 0.01 L). Montelukast (pooled doses) plus albuterol was significantly more effective than montelukast plus placebo for ΔFEV₁ (0-90 minutes) (0.34 L vs. 0.15 L; p = .015). The tolerability of inhaled montelukast was similar to that of placebo. No serious adverse experiences were reported.Inhaled montelukast provided significant bronchodilation compared with placebo as early as 20 minutes after the administration that persisted for 24 hours and provided additive bronchodilation to albuterol.

Inhaled corticosteroids (ICSs) are recommended as first-line treatment for persistent asthma. This study was designed to evaluate the ability of ciclesonide (CIC) in subjects with stable asthma previously receiving another ICS or ICS/long-acting beta(2)-agonist (LABA) to maintain asthma disease control. In this 12-week, multicenter, double-blind, parallel-group study, subjects agedor =12 years with stable mild-to-moderate persistent asthma were switched at randomization from an ICS or ICS/LABA to CIC, 80 microg twice daily (CIC80 b.i.d.; n = 149); CIC, 160 microg once daily (CIC160 q.d.; n = 150); or placebo (n = 147). Change in forced expiratory volume in 1 second (FEV(1); primary end point), morning peak expiratory flow (PEF), rescue albuterol use, total asthma symptom score, nighttime awakenings, and safety were evaluated. FEV(1) improved from baseline to week 12 after CIC80 b.i.d. treatment (+0.07 L; p = 0.0232), and was maintained after CIC160 q.d. (+0.01 L; p = 0.6217). FEV(1) declined from baseline after placebo (-0.12 L; p0.0001) and significantly versus CIC treatments (p0.001). At week 12, morning PEF maintained baseline values after CIC80 b.i.d. (-4.43 L/minute; p = 0.1272) and decreased after CIC160 q.d. (-5.77 L/minute; p = 0.0490) and placebo (-12.82 L/minute; p0.0001); the difference between CIC80 b.i.d. and placebo was significant (p = 0.035). Baseline albuterol use, total daily asthma score, and nighttime awakenings were maintained after CIC treatments (p0.25), but increased after placebo (por = 0.002); the difference between CIC80 b.i.d. and placebo was significant (p0.02). Incidence of adverse events was similar among treatment groups (range, 52.0-57.9%). In this study, CIC80 b.i.d. maintained asthma control in subjects with stable mild-to-moderate asthma previously treated with ICS or ICS/LABA, was well tolerated, and, in general, was better than CIC160 q.d. in maintaining disease control.

Ten patients with systemic mastocytosis (SM) were evaluated for their metabolic bone disease (4 men and 6 women; mean +/- SD, 59 +/- 13 yr). All patients presented with generalized osteopenia and/or atraumatic vertebral compression fractures. Three patients had long-standing urticaria pigmentosa; in these, the diagnosis of cutaneous mastocytosis had been established by skin biopsy. One of the 3 and 2 of the other 7 individuals had symptoms suggestive of SM. Although six patients had previously undergone decalcified bone marrow trephine core biopsy (DBMB), findings were consistent with SM in only 2 of them. X-Ray survey revealed generalized osteopenia in all 10 patients and vertebral compression fractures in 9. No patient had sclerotic bone lesions. Histological findings of undecalcified transiliac crest biopsy (UTBB) specimens from 9 patients (5 patients underwent both DBMB and UTBB, 4 underwent only UTBB, and 1 had only DBMB) disclosed bone marrow that contained nodules characteristic of mast cell granulomas and numerous scattered oval- and spindle-shaped mast cells. The trabecular bone contained abundant newly synthesized bone matrix and a significant increase in osteoblastic, osteoclastic, and resorptive surfaces. Dynamic histomorphometric parameters revealed a significantly increased mineral apposition rate. Our study suggests that SM may be a more frequent cause of osteoporosis than previously recognized. Generalized osteopenia with compression fractures may be the only presentation of SM. Undecalcified bone biopsy is useful in the diagnosis of SM. Accelerated bone remodeling is a characteristic histomorphometric feature of SM with diffuse osteopenia.

The addition of the long-acting beta(2)-adrenergic agonist formoterol to low- to moderate-dose budesonide has shown clinical efficacy in patients with persistent asthma. Combination therapy with budesonide/formoterol in 1 pressurized metered-dose inhaler (pMDI) has been found to have greater efficacy than its monocomponents in patients with moderate to severe persistent asthma, but it has not been assessed in patients with mild to moderate persistent asthma.The aim of this study was to compare the efficacy and tolerability of budesonide and formoterol delivered via 1 pMDI (budesonide/formoterol pMDI), budesonide pMDI, formoterol dry powder inhaler (DPI), and placebo.This 12-week, multicenter, double-blind, randomized, placebo-controlled, double-dummy study was conducted at 56 centers across the United States. Patients agedor =12 years with mild to moderate persistent asthma treated with inhaled corticosteroids (ICSs) foror =4 weeks before screening and who had a forced expiratory volume in 1 second (FEV(1)) ofor =60% toor =90% of predicted normal at screening were eligible. After 2 weeks (current asthma therapy discontinued), patients received twice-daily budesonide/formoterol pMDI 80/4.5 microg x 2 inhalations (160/9 microg), budesonide pMDI 80 microg x 2 inhalations (160 microg), formoterol DPI 4.5 microg x 2 inhalations (9 microg), or placebo. The coprimary efficacy variables were changes from baseline in morning predose FEV(1) and 12-hour mean FEV(1) (from serial spirometry) after administration of the morning dose of study medication. Tolerability was assessed based on adverse events (AEs); routine laboratory assessments; electrocardiography; 24-hour Holter monitor assessments; and physical examinations, including vital signs (eg, systolic and diastolic blood pressure and heart rate). AEs were recorded manually by the patient in paper notebooks and reviewed at each clinic visit by the investigator and during a final follow-up phone call.A total of 480 patients were randomized (299 females, 181 males; mean age, 36 years; mean FEV(1), 2.4 L; budesonide/formoterol pMDI, 123 patients; budesonide pMDI, 121; formoterol DPI, 114; placebo, 122). At end of treatment, the mean increases from baseline in predose FEV(1) were greater with budesonide/formoterol pMDI versus budesonide pMDI, formoterol DPI, and placebo (0.37 vs 0.23, 0.17, and 0.03 L, respectively; all, P0.005). 0.005). After administration of the first dose and at weeks 2 and 12, mean increases in 12-hour mean FEV(1) were significantly greater with budesonide/formoterol pMDI (0.41, 0.47, and 0.50 L, respectively) versus budesonide pMDI (0.17, 0.30, and 0.32 L) and placebo (0.15, 0.12, and 0.12 L) (all, P0.001). Fewer patients receiving budesonide/formoterol pMDI met criteria for (18.7%; P0.001) or withdrew because of (7.3%; Por = 0.010) worsening asthma versus formoterol DPI (42.1% and 18.4%, respectively) and placebo (56.6% and 32.8%); results were similar between budesonide pMDI (21.5% and 6.6%, respectively) and budesonide/formoterol pMDI. Three patients experienced serious AEs; none was considered related to study medication. The proportions of withdrawals due to worsening asthma were not significantly different between the budesonide/formoterol pMDI and budesonide pMDI groups.In this population of adults and adolescents with mild to moderate persistent asthma previously treated with ICSs, twice-daily budesonide/formoterol pMDI was associated with significantly increased pulmonary function versus its monocomponents. All study drugs were generally well tolerated.

Asthma is a common airway disease found in people of all ages, although most studies of asthma therapies are focused on adolescent and young adults. Little information exists on the use of asthma therapeutics in the older patient (>65 years of age). The newest therapeutic class to be released in the US for the treatment of asthma is the leukotriene modifiers. These medications (either receptor antagonists or enzyme inhibitors) have been found to be beneficial in younger patients with asthma, but their potential role in older patients is less clear. In this review, the data regarding the use of these medications in older patients are examined, as are the epidemiological and pathophysiological issues regarding asthma in this growing patient population. On the basis of the two published reports of leukotriene modifiers in the older patient, we conclude that leukotriene modifiers are useful in this population, but like other controller therapies for asthma, they are less effective in the older population.

Acute asthma causes nearly 2 million hospital emergency department (ED) visits in the United States annually, and hospitalization after an ED visit and relapse after ED discharge are common.To evaluate the adding of therapy with zafirlukast to standardized care for patients with acute asthma in the ED and a 28-day follow-up period.A total of 641 patients presenting to the ED with acute asthma were randomized to receive either single-dose zafirlukast, 160 mg (Z160) [162 patients], zafirlukast, 20 mg (Z20) [158 patients]), or placebo (321 patients) as adjunct treatment to standard care in this double-blind, multicenter trial. Assessments, including spirometry and symptom scores, were obtained before each albuterol treatment and at 4 h. Patients who were discharged from the ED after 4 h continued outpatient therapy over a 28-day period and received either Z20 bid (276 patients) or placebo (270 patients) in addition to prednisone, albuterol, and their previous asthma medications. FEV(1) was measured at clinic visits on days 10 and 28. Patients recorded outpatient clinical data twice daily on a home diary card.the effect of zafirlukast on relapse after ED discharge. Other assessments were the rate of extended care (ie, ED stay for4 h or hospitalization), FEV(1), and symptoms.At the end of the outpatient period, 65 of 276 patients (23.6%) treated with zafirlukast and 78 of 270 patients (28.9%) treated with placebo relapsed (p = 0.047; absolute reduction, 5.3%; relative reduction, 18.3%). At the end of the ED period, 16 of 162 patients (9.9%) treated with Z160, 26 of 158 patients (16.5%) treated with Z20, and 48 of 321 patients (15.0%) treated with placebo required extended care (p = 0.052; absolute reduction with Z160 compared to placebo, 5.1%; relative reduction, 34%). These findings were supported by a significant improvement in FEV(1) and dyspnea in the ED with the use of Z160 therapy, and by greater improvement in FEV(1) and symptoms during the outpatient period for patients treated with Z20.When added to standardized care, therapy with Z20 bid reduced the risk of relapse compared with placebo over a 28-day treatment period. One dose of Z160 in the ED also reduced the rate of extended care.

The precise amount of epinephrine needed to reverse severe symptomatology due to an anaphylactic reaction is unknown. We tried to determine how frequently more than one injection of epinephrine is required to treat an anaphylactic reaction. A retrospective review of patient charts with anaphylactic reactions requiring epinephrine, in response to inhalant allergen and hymenoptera venom immunotherapy as well as live hymenoptera stings, examined type of reaction; number, doses, and timing of epinephrine administered; and ancillary treatment. A total of 105 anaphylactic reaction events of varying severity (Ring's classification) were recorded (54--Grade I, 29--Grade II, 18--Grade III, 0--Grade IV, 4--unknown). The median epinephrine dose administered was 0.3 cc (range 0.1 to 0.8 cc, 1:1000). The timing of the first epinephrine injection wasor = 5 minutes in 27, 6-10 minutes in 13, 11-30 minutes in 16,or = 30 minutes in 32, 31-60 minutes in 12, and60 minutes in five epinephrine treated patients. Overall, 38 patients (35.5%; CI95, 26.4-44.6%) required1 epinephrine injection. Of these, 11 experienced Grade I (11/54-20.3%; CI95, 9.6-31.0%), 12--Grade II (12/29-41.5%, CI95, 23.5-59.3%), and 13--Grade III (13/18-72.2%, CI95, 51.5-92.9%); reactivity was unknown in 2 patients. Forty-four patients also received an antihistamine, 10 received corticosteroids, and 30 received both medications and/or other ancillary therapy. A significant number of patients (35%) with anaphylactic reactions received greater than one epinephrine dose to manage events for the three classes of severity. Patients at risk for anaphylaxis and their caregivers need to recognize that more than one dose of epinephrine may be required for treatment of anaphylaxis.

Videoendoscopy allows for close scrutiny of fine mucosal detail. Subtle lesions of the GI mucosa are being recognized with increasing frequency. We have previously identified many patients with whiteyellow mucosal speckling that resulted from accumulation of fat in foamy macrophages in the lamina propria adjacent to colonic neoplasms.1,2 During this study of “chicken skin mucosa,” other conditions were identified with a similar endoscopic appearance but investigation disclosed a different histopathology. In this report, 7 cases of speckling caused by focal mucin accumulation and 1 case of diffuse colonic lipid accumulation in macrophages are described.

Asthma is a disease with marked heterogeneity in its clinical course and response to treatment. IL-13 is central to type 2 inflammation, which contributes to many key features of asthma. Lebrikizumab is an anti-IL-13 mAb previously reported to significantly improve lung function in patients with inadequately controlled asthma despite inhaled corticosteroid therapy, especially in periostin-high patients.This phase II study investigated the efficacy and safety of IL-13 blockade with different doses of lebrikizumab in asthmatic patients not receiving inhaled corticosteroids.Patients were randomized to receive 125, 250, or 500 mg of lebrikizumab or placebo subcutaneously monthly for 12 weeks with an 8-week follow-up period. The primary efficacy end point was the relative change in prebronchodilator FEV1 from baseline to week 12.A total of 212 patients were randomized. The mean relative change in FEV1 was numerically higher in all lebrikizumab dose groups versus the placebo group, although the difference was neither statistically nor clinically significant. There were no meaningful differences in changes in FEV1 between the dose groups and the placebo group by the periostin subgroup. Lebrikizumab treatment was associated with a reduced risk of treatment failure at all doses versus placebo (P.001), and results were similar by the periostin subgroup, with no apparent differences between doses of lebrikizumab. Lebrikizumab was generally well tolerated.Blocking IL-13, a single cytokine, in this population of asthmatic patients is insufficient to improve lung function. There is evidence that IL-13 blockade may improve disease control, as measured by prevention of protocol-defined treatment failure in these patients.

Rationale Daclizumab (Zenapax®), a humanized monoclonal antibody directed against the IL-2 receptor α chain (CD25, Tac), is approved for prevention of renal allograft rejection and is under evaluation for treatment of patients with asthma and autoimmune diseases. Daclizumab inhibits Th1 and Th2 cytokine secretion and acts synergistically with dexamethasone in vitro (JACI, 2002, 109(1): S27). In this phase II trial, we studied the safety and efficacy of daclizumab in patients with moderate to severe chronic asthma. Methods Non-smoking asthmatics age 18-70 with baseline FEV1 50-80% predicted despite use of ≥1200 μg daily inhaled triamcinolone (TAA) or equivalent were enrolled in a randomized, multi-center, double-blind, placebo-controlled, parallel trial. Patients with demonstrated requirement for inhaled corticosteroids during run-in were randomized (3:1 active: placebo) to daclizumab (loading dose of 2 mg/kg i.v. followed by 1 mg/kg i.v. every 2 weeks) or placebo added to stable dose TAA. Starting at week 12, patients underwent 25% reduction of TAA every two weeks while continuing study drug. The primary efficacy endpoint was the change in FEV1 from baseline at week 12. Results Baseline characteristics of the 116 randomized patients included: (mean ± SD) age 42.6 ± 12.5 years, disease duration 22.9 ± 13.5 years, FEV1 (% predicted) pre-bronchodilator 68.8 ± 8.7 and post-bronchodilator 80.3 ± 10.8. Eight patients have reported serious adverse events, of which 3 patients had events assessed as related to (blinded) study drug. Conclusions Preliminary safety and efficacy will be assessed following completion of study follow up visits. Unblinded analysis will be presented.

Selection of medications most appropriate to improve both short-term and long-term quality of life remains a major challenge for clinicians caring for patients with asthma. Underlying the choice of medicines for an individual patient is knowledge of the role of inflammation in asthma, the mechanism of action of a medication, the likelihood of patient adherence, and studies of outcomes of medication use. Typical studies of medication effectiveness compare the response to a medicine with the response to a placebo—a necessary comparison, given the possibility of patient and investigator bias in evaluating response to therapy. These studies are essential to give clinicians guidance in medication choice. Studies comparing medicines that are known to be effective are also important. Too few studies done by the pharmaceutical industry accomplish this latter goal. The article by Israel et al1 in this issue of the Journal makes such a comparison: it looks at 2 medications known to be effective for asthma, an inhaled corticosteroid (ICS) and a leukotriene receptor antagonist (LRA). This head-to-head comparison is a useful contribution to our management of patients. In their article, the investigators have chosen as their primary outcome days of asthma control. This outcome is obviously relevant to patients and to clinicians who are caring for them. The outcome is clearly defined, relating as it does to need for albuterol, presence of nighttime awakenings, and absence of asthma exacerbations. Associated outcomes of asthma attacks, flare-ups, and sustained control are also clearly defined. The authors find that the percentage of days of asthma control was almost identical for the ICS (beclomethasone) arm and the LRA (montelukast) arm. Montelukast was at least equal to beclomethasone in terms of frequency of asthma attacks, asthma flare-ups, and corticosteroid rescue. Symptoms and other clinical outcomes are obviously important in medication selection and follow-up of effectiveness, but information concerning the effects of medications on airway function is also important, both for selecting a medication initially and for following its usefulness over the longer term. In the article by Israel et al, beclomethasone had a greater effect than montelukast on improving FEV1. How are clinicians to use this information in their practice? Whereas patient acceptance of a medication is determined in large part by control of symptoms, for determination of the long-term outcome from asthma— and therefore of the medication’s effectiveness—one must consider its effectiveness in improving and maintaining improvement of lung function—specifically, FEV1. FEV1 is a powerful predictor of pulmonary and cardiovascular morbidity and mortality.2-5 Low levels of FEV1 are associated with risk even for people without