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Molecular metal complexes catalyze aerobic oxidation reactions via redox cycling at the metal center to effect sequential activation of O 2 and the substrate. Metal surfaces can catalyze the same transformations by coupling independent half-reactions for oxygen reduction and substrate oxidation mediated via the exchange of band-electrons. Metal- and nitrogen-doped carbons (MNCs) are promising catalysts for aerobic oxidation that consist of molecule-like active sites embedded in conductive carbon hosts. Owing to their combined molecular and metallic features, it remains unclear whether they catalyze aerobic oxidation via the sequential redox cycling pathways of molecules or band-mediated pathways of metals. Herein, we simultaneously track the potential of the catalyst and the rate of turnover of aerobic hydroquinone oxidation on a cobalt-based MNC catalyst in contact with a carbon electrode. By comparing operando measurements of rate and potential with the current-voltage behavior of each constituent half-reaction under identical conditions, we show that these molecular materials can display the band-mediated reaction mechanisms of extended metallic solids. We show that the action of these band-mediated mechanisms explains the fractional reaction orders in both oxygen and hydroquinone, the time evolution of catalyst potential and rate, and the dependence of rate on the overall reaction free energy. Selective poisoning experiments suggest that oxygen reduction proceeds at cobalt sites, whereas hydroquinone oxidation proceeds at native carbon-oxide defects on the MNC catalyst. These findings highlight that molecule-like active sites can take advantage of band-mediated mechanisms when coupled to conductive hosts.

Two-electron, one-proton reactions of a family of [CoCp(dxpe)(NCCH 3 )] 2+ complexes (Cp = cyclopentadienyl, dxpe = 1,2-bis(di(aryl/alkyl)phosphino)ethane) form the corresponding hydride species [HCoCp(dxpe)] + (dxpe = dppe (1,2-bis(diphenylphosphino)ethane), depe (1,2-bis(diethylphosphino)ethane), and dcpe (1,2-bis(dicyclohexylphosphino)ethane)) through a stepwise proton-coupled electron transfer process. For three [CoCp(dxpe)(NCCH 3 )] 2+ complexes, peak shift analysis was employed to quantify apparent proton transfer rate constants from cyclic voltammograms recorded with acids ranging 22 p K a units. The apparent proton transfer rate constants correlate with the strength of the proton source for weak acids, but these apparent proton transfer rate constants curiously plateau ( k pl ) as the reaction becomes increasingly exergonic. The absolute apparent proton transfer rate constants across both these regions correlate with the steric bulk of the chelating diphosphine ligand, with bulkier ligands leading to slower kinetics ( k plateau,depe = 3.5 × 10 7 M -1 s -1 , k plateau,dppe = 1.7 × 10 7 M -1 s -1 , k plateau,dcpe = 7.1 × 10 4 M -1 s -1 ). Mechanistic studies were conducted to identify the cause of the aberrant k PT app -Δp K a trends. When deuterated acids are employed, deuterium incorporation in the Cp ring is observed, indicating protonation of the CoCp(dxpe) species to form the corresponding hydride proceeds via initial ligand protonation. Digital simulations of cyclic voltammograms show ligand loss accompanying initial reduction gates subsequent PCET activity at higher driving forces. Together, these experiments reveal the details of the reaction mechanism: reduction of the Co(III) species is followed by dissociation of the bound acetonitrile ligand, subsequent reduction of the unligated Co(II) species to form a Co(I) species is followed by protonation, which occurs at the Cp ring, followed by tautomerization to generate the stable Co(III)-hydride product [HCoCp(dxpe)] + . Analysis as a function of chelating disphosphine ligand, solvent, and acid strength reveals that the ligand dissociation equilibrium is directly influenced by the steric bulk of the phosphine ligands and gates protonation, giving rise to the plateau of the apparent proton transfer rate constant with strong acids. The complexity of the reaction mechanism underpinning hydride formation, encompassing dynamic behavior of the entire ligand set, highlights the critical need to understand elementary reaction steps in proton-coupled electron transfer reactions.

The proton-coupled electron transfer (PCET) oxidation of p-aminophenol in acetonitrile was initiated via stopped-flow rapid-mixing and spectroscopically monitored. For oxidation by ferrocenium in the presence of 7-(dimethylamino)quinoline proton acceptors, both the electron transfer and proton transfer components could be optically monitored in the visible region; the decay of the ferrocenium absorbance is readily monitored (λmax = 620 nm), and the absorbance of the 2,4-substituted 7-(dimethylamino)quinoline derivatives (λmax = 370-392 nm) red-shifts substantially (ca. 70 nm) upon protonation. Spectral analysis revealed the reaction proceeds via a stepwise electron transfer-proton transfer process, and modeling of the kinetics traces monitoring the ferrocenium and quinolinium signals provided rate constants for elementary proton and electron transfer steps. As the pKa values of the conjugate acids of the 2,4-R-7-(dimethylamino)quinoline derivatives employed were readily tuned by varying the substituents at the 2- and 4-positions of the quinoline backbone, the driving force for proton transfer was systematically varied. Proton transfer rate constants (kPT,2 = (1.5-7.5) × 10(8) M(-1) s(-1), kPT,4 = (0.55-3.0) × 10(7) M(-1) s(-1)) were found to correlate with the pKa of the conjugate acid of the proton acceptor, in agreement with anticipated free energy relationships for proton transfer processes in PCET reactions.

Background: A previous study with azelastine nasal spray in patients with seasonal allergic rhinitis (SAR) demonstrated that increasing the azelastine concentration from 0.1% to 0.15% allowed for once-daily dosing without increasing the incidence of adverse effects. This study evaluated the efficacy of azelastine 0.15% nasal spray administered once daily for treating symptoms of SAR., Methods: In this 14-day, randomized, double-blind, placebo-controlled study, patients with moderate-to-severe SAR were randomized to azelastine 0.15% (n = 251) or placebo (n = 255), both at a dosage of 2 sprays/nostril once daily. The primary efficacy variable was change from baseline in the 12-hour reflective Total Nasal Symptom Score (TNSS). Key secondary variables were change from baseline in 24-hour instantaneous TNSS, to establish the dosing interval, and change from baseline in the Total Ocular Symptom Score (TOSS)., Results: The mean improvement (3.57) and percentage improvement (19.3%) in 12-hour reflective TNSS was significant (p < 0.012) with azelastine 0.15% compared to placebo (2.14 and 11.4%, respectively). The mean improvement in 24-hour instantaneous TNSS was also significant (p < 0.001) for azelastine 0.15% compared to placebo, indicating efficacy with once-daily dosing. The overall improvement and percentage improvement in TOSS was significant (p ≤ 0.012) with azelastine 0.15% (2.21 and 16.7%, respectively) compared to placebo (1.28 and 6.0%, respectively). The overall score for the Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) was significantly (p < 0.001) improved from baseline in the azelastine group compared with the placebo group. Nasal discomfort (3.6%) and bitter taste (2.4%) were the most common adverse events. There were no reports of somnolence with azelastine., Conclusion: Azelastine 0.15% was effective and well tolerated with once-daily dosing. Azelastine 0.15% nasal spray significantly improved a complex of eye symptoms compared to placebo., (Copyright © 2011 American Rhinologic Society-American Academy of Otolaryngic Allergy, LLC.)

Azelastine nasal spray is commercially available as a 0.1% w/v solution and is recommended for twice-daily dosing. Increasing the azelastine concentration to 0.15% may be effective with once-daily dosing without increasing the incidence of adverse events. This study evaluated the efficacy and safety of azelastine 0.15% nasal spray at a dosage of 2 sprays/nostril once daily. This randomized, double-blind, placebo-controlled study was conducted in subjects with moderate-to-severe seasonal allergic rhinitis (SAR) during the 2007/2008 Texas Mountain Cedar season. In total, 536 subjects were randomized to 2 sprays/nostril once daily (A.M.) of azelastine 0.15% or placebo. The primary efficacy variable was change from baseline in a 12-hour reflective Total Nasal Symptom Score (TNSS), consisting of nasal congestion, runny nose, itchy nose, and sneezing. The key secondary variable was change from baseline in 24-hour instantaneous TNSS, which determines the duration of action and effective dosing interval. After 2 weeks, the mean improvement in 12-hour reflective TNSS and percentage improvement in 12-hour reflective TNSS were significant (p < 0.001) with azelastine 0.15% (19%) compared with placebo (10%). The improvement in 24-hour instantaneous TNSS also was significant (p < 0.001) for azelastine 0.15% compared with placebo, supporting efficacy with once-daily dosing. All individual TNSS symptoms were significantly (p < 0.01) improved with azelastine 0.15% compared with placebo. With the exception of bitter taste (4.5%) and nasal discomfort (4.5%), adverse events with azelastine 0.15% were reported with an incidence similar to placebo. Azelastine 0.15% nasal spray was effective and well tolerated in subjects with SAR with once-daily dosing.

Background: The safety and efficacy of intranasal corticosteroids for the treatment of allergic rhinitis is well documented in the literature. Additionally, an expert panel has concluded that intranasal corticosteroids are the first line of therapy when obstruction is a major component of rhinitis. Montelukast is a leukotriene receptor antagonist recently approved for the treatment of seasonal allergic rhinitis (SAR)., Objective: This randomized, double-blind, double-dummy, parallel-group study was conducted to compare the effectiveness of a 15-day course of intranasal fluticasone propionate 200 microg, once daily (FP200QD), to oral montelukast 10 mg, once daily (MON10QD), in relieving daytime and nighttime nasal symptoms associated with SAR., Methods: The intent-to-treat (ITT) analysis population consisted of 705 eligible males and females (> or = 15 years) with SAR randomized to either FP200QD (N = 353) or MON10QD (N = 352). The primary efficacy endpoint was the mean change from baseline in subject-rated daytime total nasal symptom scores (the sum of four individual scores: nasal congestion, itching, rhinorrhea, and sneezing), evaluated via visual analog scales, and averaged over weeks 1 to 2. Secondary endpoints included the four daytime individual nasal symptom scores, the nighttime total, and individual nasal symptom scores (each evaluated on a four-point scale from 0 to 3)., Results: Statistically significant differences favoring FP200QD over MON10QD were observed for the mean change from baseline in daytime total nasal symptom scores (P < 0.001), daytime individual nasal symptom scores (P < 0.001), nighttime total (P < 0.001), and all individual nasal symptom scores (P < or = 0.002) over the 15-day treatment period. FP200QD and MON10QD were both well tolerated., Conclusions: The results of this well controlled study demonstrated that FP200QD was consistently superior to MON10QD with regard to every efficacy endpoint evaluated, including daytime and nighttime nasal congestion, in subjects with SAR.

Budesonide inhalation powder via the dry-powder multidose inhaler Turbuhaler (budesonide Turbuhaler) has been shown to improve lung function and symptoms in adults with asthma. In this double-blind, placebo-controlled, multicenter trial, we evaluated the effects of once-daily budesonide Turbuhaler on health-related quality of life (HRQL) in 177 adults (aged 18-70 years) with non-steroid-dependent asthma. Patients were randomized to receive budesonide Turbuhaler (400 micrograms) once daily or placebo for 12 weeks. HRQL was assessed at baseline and weeks 4 and 12 using the Asthma Quality of Life Questionnaire (AQLQ). In addition to assessment based on the four AQLQ domains (activity limitations, asthma symptoms, emotional function, and response to exposure to environmental stimuli), AQLQ overall scores were analyzed for both treatment groups. Compared with placebo, patients using budesonide Turbuhaler once daily had statistically significant (p < 0.001) improvements from baseline to weeks 4 and 12 in AQLQ overall scores. Statistically significant improvements from baseline to weeks 4 and 12 in all four individual domains also were observed in the budesonide Turbuhaler group compared with placebo. Differences between the two treatment groups in mean changes from baseline in AQLQ overall, asthma symptoms, and emotional function reached the level required for patients to achieve a minimal important difference of change (> or = 0.5 U) at week 12. A retrospective analysis of the data showed that approximately 70% of patients treated with budesonide Turbuhaler experienced a minimal important difference of change in AQLQ overall scores. Overall, improvements in AQLQ correlated significantly (p < or = 0.04) with improvements in forced expiratory volume in 1 second, morning peak expiratory flow measurements, asthma symptoms, and breakthrough bronchodilator use at the study end. Thus, patients with corticosteroid-naïve asthma can experience improved HRQL when using budesonide Turbuhaler.

Objective: The AERx insulin Diabetes Management System (AERx iDMS) (Aradigm, Hayward, CA) delivers an aerosol of liquid human insulin to the deep lung for systemic absorption. This study examined the effects on pulmonary function, pharmacokinetics, and pharmacodynamics of inhaled insulin in asthmatic and nonasthmatic subjects without diabetes., Research Design and Methods: A total of 28 healthy and 17 asthmatic (forced expiratory volume during the first second [ FEV(1)] 50-80% of predicted value) subjects were enrolled in a two-part, open-label trial. To assess insulin pharmacokinetics and pharmacodynamics, a single inhalation dose of 1.57 mg (45 IU) was given on each of the 2 dosing days in part 1. A dose of 4.7 mg (135 IU) of insulin was inhaled in part 2 to assess effects on pulmonary function., Results: Inhaled insulin showed area under the curve (AUC)((0-360 min)) values that were significantly greater for healthy subjects than for asthmatic subjects (P = 0.013), whereas no difference was observed for maximum concentration (C(max)) in the two groups. A greater reduction of serum glucose as indicated by area over the curve (AOC)((0-360 min)) was observed in healthy subjects (P = 0.007). Asthmatic subjects had greater intrasubject variations in insulin AUC((0-360 min)) and C(max) values than healthy subjects, but similar variations in glucose AOC((0-360 min)). No significant changes in FEV(1), forced vital capacity (FVC), and FEV(1)/FVC were observed from pre- to postdose times, and there were no observed safety issues., Conclusions: After inhaling insulin using the AERx iDMS, asthmatic subjects absorbed less insulin than healthy subjects, resulting in less reduction of serum glucose. No effects on airway reactivity were observed. Diabetic patients with asthma may need to inhale more insulin than patients with normal respiratory function in order to achieve similar glycemic control.

Although allergic rhinitis is commonly associated most with symptoms of nasal congestion, rhinorrhea, sneezing, and itching, the symptom of sinus pain and pressure often prompts the patient to seek medical attention. The effect of fluticasone propionate on this symptom has not been studied. The purpose of this study was to compare the efficacy and safety of fluticasone propionate aqueous nasal spray to placebo vehicle in the treatment of patients with sinus pain and pressure arising from allergic rhinitis. A multicenter, double-blind, parallel-group trial was conducted in 206 symptomatic patients > or = 12 years with seasonal or perennial allergic rhinitis. Patients were treated for 14 days with either fluticasone propionate aqueous nasal spray, 200 mcg once daily, or placebo vehicle. Patients attended clinic visits and kept diary cards rating sinus pain and pressure (measured as one symptom) and nasal congestion symptoms during the study. Treatment with fluticasone propionate provided significantly greater relief of symptoms of sinus pain and pressure compared with placebo over the entire 14-day treatment period. Nasal congestion scores also were significantly reduced compared with placebo at each time point. Treatments were well tolerated, and the incidence of adverse events attributable to study treatments was similar between groups. Our data indicate that symptoms of sinus pain and pressure and nasal congestion can be significantly reduced in patients with allergic rhinitis when treated with fluticasone propionate aqueous nasal spray, 200 mcg once daily.

Background: Previous studies have demonstrated the efficacy and safety of twice-daily budesonide Turbuhaler (Pulmicort Turbuhaler, AstraZeneca, Wilmington, DE) for the treatment of mild to severe asthma., Objective: To compare the efficacy and safety of budesonide Turbuhaler administered once daily each morning with placebo in inhaled corticosteroid-naive adults with persistent asthma., Methods: In this randomized, double-blind, placebo-controlled, multicenter study, 177 adults (aged 18 to 70 years) received placebo or once-daily budesonide Turbuhaler (400 microg) for 12 weeks. Efficacy variables included mean changes from baseline in forced expiratory volume in 1 second (FEV1) and AM/PM peak expiratory flow rate (PEFR), and nighttime/daytime asthma symptom scores, patient discontinuations, use of breakthrough medication (albuterol), forced vital capacity (FVC), forced expiratory flow between 25% and 75% of FVC (FEF25%-75%), and quality of life assessments. Safety was evaluated based on adverse events, physical examinations, vital signs, and laboratory tests., Results: Demographic and baseline characteristics were comparable between study groups. The mean percentages of predicted FEV1 at baseline were 71.9 +/- 9.8 in patients receiving budesonide Turbuhaler and 70.6 +/- 11.0 in patients receiving placebo. Mean changes from baseline over the 12-week treatment period in FEV1 were significantly (P = 0.007) improved in patients receiving once-daily budesonide Turbuhaler compared with placebo (0.31 L and 0.17 L, respectively). Significant (P < or = 0.037) improvements over placebo also were observed in AM PEFR, nighttime/daytime asthma symptoms, and albuterol use with budesonide Turbuhaler treatment. Adverse events were generally mild or moderate in intensity and similar between study groups., Conclusions: Budesonide Turbuhaler 400 microg administered once daily in the AM is efficacious and safe for inhaled corticosteroid-naive asthmatic adults.

Background: The proportion of older adults in the US population will increase dramatically in the near future, yet the frequency and nature of care furnished to older adults by Allergy/Immunology practitioners has not been described., Objective: To determine the extent and nature of care being provided to adults and older adults by Allergy/Immunology practitioners., Methods: ACAAI members and fellows were surveyed to obtain information regarding certification and training as well as their practice patterns., Results: The distribution of diagnoses among patients aged 40 to 54 years were very similar to distributions found among adults age 55 to 69 years and > or = 70 years of age. Virtually all respondents indicated they provide inhalant allergen immunotherapy for patients age 40 to 54 years with asthma and/or allergic rhinitis; administration of inhalant allergen immunotherapy for asthma and allergic rhinitis was also frequently reported for adults > or = 55 years. The proportions of respondents providing venom immunotherapy for adults aged 40 to 54, 55 to 69, and > or = 70 years were 82%, 70%, and 39%, respectively., Conclusion: ACAAI members and fellows commonly provide care to older adults. Our survey findings highlight the need to develop strategies for successful management of Allergy/Immunology conditions specifically pertaining to older adults, including studies to determine the therapeutic utility of inhalant allergen and venom immunotherapy in this age group.

Background: Consensus asthma guidelines recommend antileukotriene agents as alternative therapy to existing anti-inflammatory medications; however, the full therapeutic potential of these medications has not yet been determined., Objective: The purpose of this study was to assess the efficacy and safety of the oral leukotriene receptor antagonist zafirlukast (20 mg twice daily) in subgroups of patients who have asthma with the use of integrated data from four 13-week trials., Methods: The trials had comparable designs, entry criteria, and clinical assessments. Patient subgroups were characterized by demographic and baseline asthma characteristics. Analysis of covariance models were tested for overall treatment effect and for interactions between treatment and subgroup characteristics., Results: Patients with mild-to-moderate asthma (12 to 76 years old) who were treated with albuterol alone were randomized (nZ = 879; nP = 605) and included in subset analyses. Significant overall treatment effects, favoring zafirlukast, were noted for measures of daytime and nighttime symptoms, beta2 -agonist use, and pulmonary function (P <.05). A significant, quantitative, treatment-by-age interaction was noted for beta2 -agonist use (P <. 03), suggesting greater reductions in rescue medication use with increasing patient age. Compared with placebo, similar size and/or direction of response was noted with zafirlukast in the various subgroups, indicating a benefit with zafirlukast regardless of subgroup. Significant treatment-by-strata interactions (P <.05), favoring zafirlukast, were noted for various outcome measures in subgroups with the greatest amount of baseline beta2 -agonist use (>8 puffs/day) and with greater baseline peak flow variability (>/=20%) and baseline airflow obstruction (FEV1 /forced vital capacity ratio, <0.70). The overall treatment failure rate was significantly lower in the zafirlukast group compared with the placebo group (P <.003). No associations were observed between any adverse events and subgroups defined by demographic characteristics., Conclusions: Exploratory subset analyses showed that zafirlukast is similarly efficacious in patients with asthma who have differing demographic characteristics and degrees of subjective symptoms. Additionally, zafirlukast appears to be incrementally beneficial in patients with more moderate disease, defined by a greater requirement for as-needed rescue medication and more abnormal pulmonary function at baseline. Over 13 weeks, zafirlukast was well tolerated and demonstrated a safety profile clinically indistinguishable from placebo.

Background: Intranasal corticosteroids and oral antihistamines are both effective in the treatment of seasonal allergic rhinitis, although the therapeutic value of administering the two types of agents concurrently has rarely been evaluated. This study was designed to compared the efficacy, safety, and impact on quality of life of fluticasone propionate aqueous nasal spray (FP ANS), loratadine, FP ANS plus loratadine, and placebo (an aqueous nasal spray plus tablet) in the treatment of seasonal allergic rhinitis during the mountain cedar allergy season in south central Texas., Methods: Six hundred patients with seasonal allergic rhinitis were treated for 2 weeks with either FP ANS 200 microgram once daily, loratadine 10 mg once daily, the FP ANS and loratadine regimens combined, or placebo in a multicenter, randomized, double-blind, double-dummy, parallel-group study., Results: Clinician- and patient-rated total and individual nasal symptom scores after 7 and 14 days of therapy and overall evaluations were significantly lower (P < .001) in the FP ANS and FP ANS plus loratadine groups compared with the loratadine only and placebo groups. Loratadine was not statistically different from placebo in clinician and patient symptom score ratings nor in overall clinician and patient evaluations. FP ANS plus loratadine and FP ANS monotherapy were comparable in efficacy in almost all evaluations; for some patient-rated symptoms the combination was found superior. Mean score changes in the Rhinoconjunctivitis Quality of Life Questionnaire from baseline to day 14 showed significantly greater improvement (P < .001) in quality of life in the FP ANS group than in the group of patients receiving loratadine only or placebo and no significant benefit was demonstrated in the FP ANS plus loratadine group over the FP ANS monotherapy group. No serious or unusual drug-related adverse events were reported. Combining loratadine with FP ANS did not alter the adverse events profile or frequency.

Objective: The objective of this study was to develop, pretest, and validate a questionnaire to measure quality of life in children with seasonal allergic rhinoconjunctivitis (SAR)., Methods (development Study): Thirty-four children with SAR were enrolled from summer camps, notices in the media, and an allergy clinic (Southern Ontario). After generating a pool of 48 potentially important quality of life items, the children identified the ones that they experienced with their SAR and scored each for bother (1 = a little bothered to 4 = extremely bothered). Items identified most frequently and with the highest bother score were included in the Paediatric Rhinoconjunctivitis Quality of Life Questionnaire (PRQLQ). The PRQLQ was pretested for ease completion and accuracy of understanding., Results (development Study): The PRQLQ has 23 items in five domains (nose symptoms, eye symptoms, practical problems, other symptoms, and activities). Responses are given on a seven-point scale, and children are asked to score their experiences during the previous 7 days., Methods (validation Study): Seventy-five children with symptomatic SAR were enrolled from notices in the media and a pediatric allergy clinic (Austin, Tex.). A single cohort design was used, with children assessed at 0, 1, and 3 weeks. The PRQLQ was administered to the children by a trained interviewer at 1 and 3 weeks. A conventional nasal symptom daily diary was completed for 1 week before each of these clinic visits. Global ratings were completed at the final visit., Results (validation Study): In patients who were stable between clinic visits, the PRQLQ demonstrated good reliability (intraclass correlation coefficient = 0.93). The questionnaire was very responsive to change (p < 0.001) and was able to differentiate between patients who were in a stable clinical state and those whose clinical state changed between visits (p = 0.005). Correlations between the PRQLQ and diary scores were close to predicted and supported both the cross-sectional and longitudinal validity of the PRQLQ., Conclusions: The PRQLQ measures the quality of life impairments important to children with SAR. Children provide reliable and accurate responses, the measurement properties are strong, and the questionnaire can be used with confidence in clinical trials, clinical practice, and surveys.

This was a 1-week study evaluating the safety and efficacy of two dosage regimens of salmeterol in children with asthma. A total of 243 children, aged 4-11 years, with mild-to-moderate asthma were enrolled in a randomized, double-blind, placebo-controlled, parallel-group, multicenter study evaluating salmeterol xinafoate 21 micrograms and 42 micrograms administered via metered-dose inhaler (MDI) twice daily for 1 week. Patients were allowed to use albuterol MDI as needed for relief of acute symptoms. Inhaled corticosteroids and/or cromolyn at fixed dosages could be continued during the study, but theophylline and oral beta-agonists were not allowed. Twelve-hour serial spirometry (for patients aged 6-11 years) and serial peak expiratory flow rate (PEFR) (all patients) were performed on days 1 and 8 of treatment; morning and evening PEFR were recorded each day prior to inhalation of the study drug. Safety was assessed by monitoring adverse events, clinical laboratory values, vital signs, electrocardiogram (ECG), and 24-hr ECG (Holter) monitoring. Both the 21-micrograms and 42-micrograms doses of salmeterol produced significantly greater bronchodilation, as measured by 12-hr serial forced expiratory volume in 1 sec (FEV1) (p < or = 0.02) and PEFR (p < or = 0.001), than did placebo on days 1 and 8. A small dose-response was observed, with the 42-micrograms dosage producing consistently higher serial FEV1 and PEFR than did the 21-micrograms dosage, although the differences were not statistically significant. Morning and evening PEFR increased significantly (p < or = 0.008) with both dosages of salmeterol compared with placebo. Twelve patients (5%) experienced potentially drug-related adverse events, with headache (4% in each salmeterol group) being the most common. There were no clinically significant changes in heart rate as measured by Holter monitoring, ECGs, vital signs, or clinical laboratory values following treatment with either dose of salmeterol. Salmeterol 21 micrograms or 42 micrograms twice daily was effective in producing bronchodilation in children aged 4-11 years, and both dosages had good safety profiles. Patients treated with salmeterol 42 micrograms twice daily showed a trend toward greater improvement in asthma control compared with those who received salmeterol 21 micrograms.

Fluticasone propionate aqueous nasal spray is an intranasal corticosteroid for the treatment of patients with allergic rhinitis. This double-masked, double-dummy, parallel-group study was conducted to confirm that the efficacy of fluticasone propionate nasal spray is attributable to topical rather than systemic effects. A total of 304 patients with documented seasonal allergic rhinitis were randomly assigned to receive fluticasone propionate nasal spray 200 micrograms once daily (n = 77), oral fluticasone propionate 5 mg once daily (n = 73), oral fluticasone propionate 10 mg once daily (n = 77), or placebo (n = 77) for 14 days. Plasma fluticasone propionate concentrations were determined at baseline and after 14 days of treatment (day 15). Nasal symptoms were recorded daily by patients and assessed weekly by clinicians. On day 15, more patients in the oral fluticasone propionate 5-mg or 10-mg groups, compared with patients in the fluticasone propionate nasal spray group or the placebo group, had detectable plasma fluticasone propionate concentrations, and mean concentrations were higher in the oral fluticasone propionate groups. Both clinician- and patient-rated total and individual nasal symptom scores for obstruction, rhinorrhea, sneezing, and itching were significantly lower in the fluticasone propionate nasal spray group compared with either of the oral fluticasone propionate groups or the placebo group. With few exceptions, oral fluticasone propionate (5 mg or 10 mg) was not significantly different from placebo on any measures of efficacy. These findings indicate that the efficacy of fluticasone propionate nasal spray (200 micrograms once daily) in the treatment of allergic rhinitis results from direct topical effects rather than from indirect effects after systemic absorption.

Background: The use of intranasally administered corticosteroid sprays is an established treatment option for seasonal allergic rhinitis., Methods: In this double-blind, placebo-controlled, multicenter study, 438 patients with moderate to severe symptoms of seasonal allergic rhinitis were treated for 4 weeks with double-strength beclomethasone dipropionate (BDP) aqueous nasal spray (84 micrograms/spray: BDP-ds), once daily; regular-strength BDP (42 micrograms/spray: BDP-rs), twice daily; high-strength BDP (336 micrograms/spray: BDP-hs), once daily; or placebo. BDP-hs was included as a safety comparison group. All treatments were given as two sprays per nostril., Results: Physician-rated nasal symptom scores were significantly improved in all three active treatment groups compared with those of the placebo group within the initial 3 days of treatment. Improvement was maintained throughout the 4-week treatment period. BDP-ds and BDP-rs were equivalent at all time points. The BDP-ds, BDP-rs, and BDP-hs groups had greater numbers of patients with a good or excellent therapeutic response at end point than the placebo group. All treatments were well-tolerated, and no unexpected adverse events were reported. No effects on laboratory evaluations or vital signs were evident for any treatment group., Conclusions: The results of this study show that BDP-ds given once a day and BDP-rs given twice a day in the same total daily dose are comparably safe and effective in the treatment of patients with seasonal allergic rhinitis.

Background: One of the risks associated with the use of oral corticosteroids is suppression of adrenocortical function. Triamcinolone acetonide (TAA) aqueous nasal spray administered once daily (110 micrograms and 220 micrograms) has been shown to reduce allergic rhinitis symptoms., Objective: This multicenter, placebo-controlled, double-blind study determined the effects of TAA aqueous nasal spray, placebo, and oral prednisone on adrenocortical function in patients with allergic rhinitis., Methods: Sixty-four patients received TAA aqueous nasal spray (220 micrograms or 440 micrograms), oral prednisone (10 mg), or placebo once daily for 6 weeks. Adrenocortical function was assessed after cosyntropin stimulation for 6 hours before treatment and after 6 weeks of treatment., Results: There was no statistically significant effect on adrenocortical function in patients who received either dose of TAA aqueous nasal spray compared with placebo. In contrast, prednisone produced statistically significant (p < 0.001) reductions in adrenocortical function compared with placebo; reductions occurred in both the mean 6-hour plasma cortisol levels and mean change in 6-hour plasma cortisol levels from pretreatment., Conclusion: This study demonstrated that, unlike oral prednisone, TAA aqueous nasal spray, in therapeutic doses, did not alter adrenocortical function and was comparable to treatment with placebo in its absence of measurable effects on adrenocortical function.

Intranasal corticosteroids have been shown to be more effective than oral antihistamines for the treatment of seasonal allergic rhinitis. However, there are some who question whether intranasally administered corticosteroids should be used due to potential systemic effects. Fluticasone propionate, a potent corticosteroid with high specificity for the glucocorticoid receptor, is available as an aqueous nasal spray for the treatment of allergic rhinitis. To determine whether the efficacy of fluticasone propionate aqueous nasal spray (FPANS) was due to direct topical effects on the nasal mucosa or to indirect systemic effects following absorption from the nasal mucosa or from the swallowed portion of an intranasal dose, FPANS 200 micrograms once daily was compared with oral fluticasone propionate 5 mg or 10 mg once daily or placebo for 2 weeks in patients with seasonal allergic rhinitis. These oral dosages were chosen to yield low but consistent plasma fluticasone propionate concentrations. Both clinician- and patient-rated scores for nasal obstruction, rhinorrhoea, sneezing, and nasal itching were significantly lower in the intranasal fluticasone propionate group compared with both oral fluticasone propionate groups. A separate placebo-controlled study was conducted in patients with perennial rhinitis to determine if administration of FPANS 200 micrograms once daily for 1 year was associated with adverse systemic effects. At the 1-year assessment, there were no significant effects on bone mineral density or on biochemical markers of bone turnover. Similarly, there was no evidence of posterior subcapsular cataracts nor of glaucoma. Furthermore, there were no significant effects on hypothalamic-pituitary adrenal axis function as assessed by plasma cortisol and 24-h urinary cortisol response to the 6-h cosyntropin stimulation test. These data confirm that the efficacy of FPANS for the treatment of allergic rhinitis results from direct topical effects, thus reducing the likelihood of adverse systemic effects.

Background: Astemizole, an H1-histamine-receptor antagonist prescribed for seasonal allergic rhinitis, has a slow onset of action and a strong suppressive effect on the wheal and flare reaction, which interferes with skin testing results. The newer antihistamine cetirizine appears to have a rapid onset of action and a low potential to interfere with posttreatment skin testing results., Objective: To compare the efficacy, safety, and skin test inhibition of astemizole and cetirizine in the treatment of seasonal allergic rhinitis., Methods: In a double-blind, parallel-group study conducted at six sites during ragweed pollination season, 263 subjects were randomized to receive 10 mg of astemizole, 5 mg of cetirizine, or 10 mg of cetirizine daily for 2 weeks. The subjects rated seven allergic rhinitis symptoms daily, the subjects and investigators provided global assessments of the responses to the treatments, and the subjects rated their satisfaction with the treatments. Thirty-nine subjects at one study site underwent quantitative skin testing before and after treatment., Results: As measured by reduction from baseline in total symptom severity score, which was the primary efficacy measure in the study, all three treatments significantly relieved the symptoms of allergic rhinitis (P less than .05). This finding was supported by the global ratings and the subject satisfaction ratings. There were no significant differences among the three treatments for reduction from baseline in total symptom severity score. The mean subject satisfaction score with 10 mg of cetirizine was significantly greater than that with astemizole (P less than .05). In the skin tests performed 3, 7, and 14 days after the end of antihistamine treatment, the subjects who had received the cetirizine doses had significantly greater mean sum of wheal and mean sum of erythema values than those who had received the astemizole dose (P less than .05). Sensitivity to ragweed pollen extract returned to 90% of baseline within three days of the end of cetirizine treatment. Both drugs were well tolerated and their adverse event profiles were similar., Conclusions: Astemizole and cetirizine are effective and well tolerated in alleviating the symptoms of ragweed-induced allergic rhinitis. Cetirizine inhibits skin test results to a much lesser extent than does astemizole. Physicians may wish to consider the potential for skin test inhibition when selecting an antihistamine for patients with allergic rhinitis.

Background: Few clinical trials have directly compared the efficacy of antihistamines with topical nasal corticosteroids., Objective: The study was performed to compare the efficacy and safety of triamcinolone acetonide nasal spray at a dose of 110 micro g in each nostril once daily with 10 mg of oral astemizole once daily for the treatment of seasonal allergic rhinitis., Methods: A multicenter, double-blind, parallel-group study was conducted in 239 patients who were randomized to receive either triamcinolone acetonide or astemizole. A 5-day, drug-free, lead-in period was followed by 4 weeks of double-blind treatment. One hundred four patients treated with triamcinolone acetonide and 105 patients treated with astemizole could be evaluated., Results: Overall, triamcinolone acetonide was more effective than astemizole in reducing total nasal symptoms, nasal stuffiness, nasal itching, and sneezing (p

This study was designed to determine whether lettuce treated with a commercially available sulfite-containing freshener prepared according to manufacturer's directions could provoke reactions in sulfite-sensitive subjects with asthma (SSAs). Five adult SSAs with stable asthma who had multiple prior reactions to double-blind, placebo-controlled, sulfite-capsule challenges were studied. Each patient ingested, in a double-blind, placebo-controlled fashion, four portions of lettuce (3 oz) pretreated with one of two commercially available, nearly identical vegetable fresheners. One freshener contained sodium bisulfite and was used on one portion of lettuce. The other freshener contained no sulfite and was used on three portions of lettuce. The fresheners were prepared and the lettuce was treated according to label instructions. After baseline spirometry, the SSAs consumed the lettuce samples with the same dressing of their choice, serial spirometry was performed, and a positive reaction was defined as a greater than 20% drop in FEV1 decreased 0% to 7%; mean, 3%. Two of the subjects experienced severe reactions to the sulfite-treated lettuce. One of these reactions was life threatening; the other reaction occurred despite placing only 30% of the usual sulfite dose on the lettuce. This study has demonstrated that sulfite-treated lettuce is capable of provoking bronchospasm in SSAs and suggests that such food is one cause of restaurant-provoked asthma in these individuals.

Purified human peripheral blood monocytes were stimulated with aggregated human myeloma proteins of different classes or the calcium ionophore A23187 and the release of leukotrienes C4 and B4 (LTC4, LTB4), and prostaglandin E2 (PGE2) into the supernatant was determined. The ionophore induced release of 10 +/- 5 ng LTC4/10(6) cells and 25 +/- 8 ng LTB4/10(6) cells. Aggregated IgG, IgA, and IgE, but not IgM or monomeric immunoglobulins (Ig), induced release of LTC4 and LTB4 that was approximately 10 to 20% of that induced by ionophore. In addition, IgG, IgA, and IgE, but not IgM, induced release of PGE2 (range 0.015 to 0.22 ng/10(6) cells). Aggregated Ig induced LTC4, LTB4, and PGE2 release in a dose-dependent manner; maximal leukotriene (LT) release was observed by 30 min, in contrast to PG release, which continued to increase up to 2.5 hr. Both ionophore- and Ig-induced LTC4 and LTB4 release were completely inhibited by removal of calcium from the media and by preincubation of cells with nordihydroguaiaretic acid. Indomethacin inhibited Ig-induced PGE2 release by 80%. Phagocytosis of the Ig aggregates was not required for LT or PGE2 release, since release was not inhibited by cytochalasin B. Release of LTC4, LTB4, and PGE2 induced by IgG, IgA, and IgE, but not IgM, correlated with the presence or absence of monocyte Fc receptors (FcR) as determined by rosette assays. The data suggest that IgG, IgA, and IgE immune complexes mostly likely induce monocyte arachidonic acid metabolism via cross-linking of FcR. The ability of monocytes to release eicosanoids in the absence of phagocytosis suggests that interaction of monocytes with immobilized immune complexes, such as those deposited in blood vessel walls or glomerular basement membranes, could initiate metabolism of arachidonic acid by monocytes. Such a mechanism could contribute to inflammatory reactions characterized by mononuclear cell infiltrates.

The levels of leukotriene C4 (LTC4), leukotriene B4 (LTB4), prostaglandin E2 (PGE2), and histamine were measured in nasal lavage fluids obtained from aspirin-sensitive, desensitized aspirin-sensitive, and aspirin-insensitive asthmatics and normal volunteers before and after ingestion of aspirin. Increased levels of LTC4 and histamine were associated with significant decreases in the FEV1 for 3 of 4 aspirin-sensitive asthmatics who had both naso-ocular and bronchospastic reactions to aspirin. In contrast, no increase in LTC4 or histamine release was detected in aspirin-sensitive asthmatics who had only bronchospastic reactions to aspirin. No significant decreases in PGE2 levels or increases in LTB4 levels were detected during these reactions to relatively low doses of aspirin regardless of the clinical symptoms, nor was any increase in mediator release apparent in lavage fluids from normal donors, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects before or after various doses of aspirin. Levels of PGE2 decreased in nasal secretions from normal volunteers, aspirin-insensitive asthmatics, and desensitized aspirin-sensitive subjects after ingestion of 650 mg of aspirin. These decreases were not associated with increased LTC4 or LTB4 or with histamine release, decreased FEV1, or naso-ocular symptoms. In addition, reductions of PGE2 release were similar for normal and desensitized aspirin-sensitive volunteers (63 +/- 11 versus 61 +/- 10%, respectively). The data demonstrate that LTC4 and histamine are released into nasal secretions of aspirin-sensitive asthmatics with naso-ocular and bronchospastic reactions after ingestion of low doses of aspirin without a decrease in the levels of PGE2 and suggest that LTC4 and histamine contribute to the naso-ocular and bronchospastic symptoms characteristic of reactions to aspirin.