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The safety of twice-daily treatment with
fluticasone propionate and salmeterol in
pediatric patients with persistent asthma
Randolph Malone, MD*; Craig LaForce, MD†; Sai Nimmagadda, MD‡; Lynne Schoaf, RN§;
Karen House, MS§; Anna Ellsworth, BS§; and Paul Dorinsky, MD§
Background: For children older than 5 years with asthma who remain symptomatic despite inhaled corticosteroid (ICS)
therapy, the preferred treatment is to add an inhaled long-acting ␤ -agonist vs increasing the ICS dose.
Objective: To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting
␤ -agonist salmeterol with that of fluticasone propionate used alone in children aged 4 to 11 years with persistent asthma.
Methods: A randomized, multicenter, double-blind, active-controlled, parallel-group study in 203 children with persistent
asthma who were symptomatic during ICS therapy. Patients received fluticasone propionate–salmeterol (100/50 ␮g) orfluticasone propionate (100 ␮g) alone twice daily for 12 weeks.
Results: The safety profile of fluticasone propionate–salmeterol was similar to that of fluticasone propionate alone. The overall
incidence of adverse events was 59% for fluticasone propionate–salmeterol and 57% for fluticasone propionate. Both treatmentswere well tolerated. Two patients receiving fluticasone propionate–salmeterol and 5 receiving fluticasone propionate withdrewfrom the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent andwere similar between treatments. No patients had clinically significant abnormal electrocardiographic findings during treatment.
Geometric mean 24-hour urinary cortisol excretion at baseline and after 12 weeks of treatment was comparable within andbetween groups; no patient in either group had abnormally low 24-hour urinary cortisol excretion after 12 weeks of treatment.
The incidence of withdrawals due to asthma exacerbations was 2% in the fluticasone propionate–salmeterol group and 5% in thefluticasone propionate group.
Conclusions: In pediatric patients with persistent asthma, fluticasone propionate–salmeterol twice daily was well tolerated,
with a safety profile similar to that of fluticasone propionate used alone.
Ann Allergy Asthma Immunol. 2005;95:66–71.
INTRODUCTION
the preferred treatment for initiating therapy in children of all Asthma is the most common chronic disorder in children and ages with persistent asthma.3 For children older than 5 years adolescents.1 In 1999, more than 3.1 million children younger who remain symptomatic despite treatment with low-dose than 15 years in the United States had an episode of asthma ICSs, the guidelines indicate that the preferred treatment is or an asthma attack in the preceding 12 months.2 During this the addition of an inhaled long-acting ␤ -agonist to the ICS same period, asthma was responsible for 190,000 hospital- rather than an increase in the dose of ICS.3 This therapeutic izations and 658,000 emergency department visits.2 Asthma approach helps ensure use of the lowest effective dose of ICS, also has a considerable effect on school attendance, account- thereby minimizing the potential for systemic adverse effects.
ing for 14 million missed school days from 1994 to 1996.2 Given the substantial morbidity of pediatric asthma and the The substantial morbidity of asthma in children suggests that current treatment guideline recommendations, this study was additional therapies and treatment strategies are needed.
conducted to compare the safety of twice-daily fluticasone Expert panel guidelines by the National Heart, Lung, and propionate–salmeterol (100/50 ␮g) with that of twice-daily Blood Institute recognize inhaled corticosteroids (ICSs) as fluticasone propionate (100 ␮g) alone in children 4 to 11years of age with persistent asthma. Safety measures includedadverse events, clinical laboratory tests, 24-hour urinary cor-tisol excretion, 12-lead electrocardiograms (ECGs), vital * Southeast Asthma and Allergy Center, Tallahassee, Florida.
signs, oropharyngeal examinations, and asthma exacerbations † North Carolina Clinical Research, Raleigh, North Carolina.
‡ Associated Allergists and Asthma Specialists Ltd, Hoffman Estates, Illi- nois.
§ GlaxoSmithKline, Research Triangle Park, North Carolina.
This study was funded by GlaxoSmithKline, Research Triangle Park, NC.
This study was presented in part at the American College of Asthma, Allergy and Immunology 2003 Annual Meeting; November 8 and 9, 2003; New Boys and premenarchal girls aged 4 to 11 years were eligible Orleans, LA; and at the American College of Chest Physicians Annual for this study if they had asthma, as defined by the American Meeting; October 27, 2004; Seattle, WA.
Thoracic Society criteria,4 for at least 2 months and were Received for publication December 6, 2004.
Accepted for publication in revised form February 9, 2005.
receiving ICS therapy (beclomethasone dipropionate, 252– ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY 336 ␮g/d; triamcinolone acetonide, 600 –1,000 ␮g/d; fluni- tom score of at least 1 (on a scale from 0 to 5) on 3 or more solide, 1,000 ␮g/d; fluticasone propionate, 88 –250 ␮g/d; or days or the use of albuterol on 3 or more days during the 7 budesonide, 200 – 400 ␮g/d) at a consistent dose for at least 1 days before the randomization visit, and (3) adequate com- month before screening. At the screening visit, patients aged pliance, defined as 70% or greater compliance with diary card 6 to 11 years were required to have a forced expiratory volume in 1 second (FEV ) of 50% to 95% of the Polgar Patients returned to the clinic after 1, 2, 4, 8, and 12 weeks predicted value5; patients aged 4 to 5 years were required to of treatment. In addition, each patient’s parent or guardian have a morning peak expiratory flow rate (PEFR) of 50% to was contacted 3 to 5 days after the final visit for evaluation of 95% of the Polgar predicted value.5 Patients were also re- posttreatment adverse events. Parents or guardians recorded quired to demonstrate an increase in FEV (for patients aged morning and evening PEFRs, use of albuterol for relief of 6 –11 years) or morning PEFR (for patients aged 4 –5 years) symptoms, and daytime asthma symptom scores on a daily of 12% or more within 30 minutes of inhalation of 2 to 4 diary card. Symptom scores were based on a Likert scale actuations of albuterol (180 –360 ␮g) or to have historical from 0 (no symptoms) to 5 (severe symptoms that prevented documentation of 12% or greater reversibility within the normal daily activities). Morning and evening PEFRs were measured before taking a dose of study medication or albu- Exclusion criteria consisted of a history of life-threatening asthma; hospitalization due to asthma twice or more in the previous year; a significant concurrent disease (eg, cysticfibrosis, malignancy, or immunologic compromise); recent At the end of the run-in period, eligible patients discontinued upper or lower respiratory tract infection; current chickenpox their current ICS therapy and were randomly assigned to or recent exposure to chickenpox in a nonimmune patient; receive 1 of the following blinded treatments twice daily for severe milk protein allergy; hypersensitivity to ␤ -agonist, 12 weeks: fluticasone propionate–salmeterol, 100/50 ␮g (Ad- sympathomimetic, or corticosteroid therapy; clinically signif- vair Diskus; GlaxoSmithKline, Research Triangle Park, NC), icant abnormal laboratory test results; a history or present use or fluticasone propionate, 100 ␮g (Flovent Diskus; Glaxo- of tobacco; and a history or current presence of glaucoma or SmithKline). Patients were assigned to treatment in accor- posterior subcapsular cataracts. Patients were required not to dance with a predetermined randomization schedule and ad- have used oral or parenteral corticosteroids for at least 1 ministered 1 inhalation from the Diskus each morning and month before screening, cromolyn or nedocromil for at least evening, approximately 12 hours apart.
1 week before screening, or long-acting ␤ -agonists within 48 hours of screening and throughout the study. In addition, the Adverse events were monitored throughout the study, and use of medications that could affect the course of asthma or investigators were responsible for the detection, documenta- interact with study medications (eg, anticholinergics, anticon- tion, intensity evaluation, and causality evaluation of all vulsants, or ␤-adrenergic blockers) was prohibited through- adverse events. Routine clinical laboratory evaluations were performed after an overnight fast at screening and after 12 weeks of treatment or at study discontinuation. Threshold This randomized, multicenter, double-blind, active-con- ranges for each laboratory variable were defined a priori as a trolled, parallel-group study was conducted on an outpatient measure of abnormalities of potential clinical concern. A basis at 66 sites in the United States and 13 sites in Canada timed 24-hour urine collection for cortisol excretion was between April 2002 and January 2003. An institutional re- conducted within 7 days of randomization and within 7 days view board approved the study protocol, and informed con- of the week 12 visit. A 12-lead ECG was also recorded at sent was obtained for all patients before enrollment. Eligible screening, randomization, and after 12 weeks of treatment or patients underwent physical examinations, pulmonary func- at study discontinuation. An independent cardiologist, tion testing, and other screening procedures and then entered blinded to treatment assignment, interpreted all ECGs at- a 2-week run-in period, during which their baseline ICS tained in the study. Vital signs (ie, systolic and diastolic blood therapy was continued. All patients were also supplied with pressure) and physical examination findings were recorded at an albuterol metered-dose inhaler for rescue use. During this screening and after 12 weeks of treatment or at study discon- period, we evaluated the patient’s eligibility for randomiza- tinuation. An oropharyngeal examination for clinical evi- tion and compliance with the study procedures and attained a dence of infection (eg, Candida albicans) was conducted at baseline for safety measures. Patients who completed the all study visits. If evidence of infection was found, a culture run-in period and met all the randomization criteria pro- was taken and appropriate therapy was instituted.
ceeded to the double-blind treatment period. Randomization Asthma exacerbations or worsening asthma was also eval- criteria included (1) a morning FEV of 50% to 95% of the uated throughout the study. Patients were withdrawn from the Polgar predicted value for patients 6 to 11 years of age or a study because of worsening asthma if they experienced a morning PEFR of 50% to 95% of the Polgar predicted value clinical exacerbation or at the investigator’s discretion. A for patients 4 to 5 years of age, (2) a daytime asthma symp- clinical exacerbation was defined as worsening asthma that required emergency intervention, hospitalization, or treat- failure to meet FEV or PEFR percent predicted entry criteria ment with an asthma medication prohibited by the protocol.
at the screening visit. Randomization resulted in comparable The following criteria were used to aid the investigator in treatment groups at baseline with respect to patient demo- determining asthma stability: a 20% or greater decrease from graphics and pulmonary function (Table 1). Fluticasone pro- the best FEV obtained at the randomization visit for patients pionate was the most commonly used ICS before randomiza- aged 6 to 11 years, more than 3 of 7 days immediately tion in each treatment group (Table 1).
preceding a study visit in which the morning or evening Mean overall compliance with study medication was 93% PEFR decreased 20% or more from the mean morning base- for the fluticasone propionate–salmeterol group and 89% for line PEFR calculated for the 7 days before the randomizationvisit, or more than 2 of 7 days immediately preceding a studyvisit in which 12 or more puffs per day of albuterol were Table 1. Patient Characteristics at Baseline (Treatment Day 1) used. These criteria were used as a guideline but did not Fluticasone
require that a patient be withdrawn from the study. Compli- Fluticasone
propionate–
ance with study medication was calculated for each patient propionate
salmeterol
based on the dose counter on the Diskus.
(n؍102)
(n؍101)
Although this study was a safety study and was not designed to evaluate efficacy differences between treatment groups, the following assessments were performed: 2-hour serial postdose FEV (for patients aged 6 –11 years) or 2-hour serial postdose PEFR (for patients aged 4 –5 years) after the first dose of study medication on treatment day 1, FEV (for patients aged 6 –11 years only), morning and evening PEFRs, and daytime asthma symptom scores and 24-hour albuterol use.
Because this was a safety study, no primary end point was identified; thus, no power calculations were performed. How- ever, it was estimated that approximately 100 patients in each treatment arm was sufficient to evaluate the safety of fluti- casone propionate–salmeterol compared with fluticasone pro- pionate. The intent-to-treat population, which included all patients who were randomized and received at least 1 dose of study drug, was the primary population used for all demo- graphic and safety measures except for cortisol excretion. For patients who withdrew from the study prematurely, all avail- able data up to the time of discontinuation were included in the intent-to-treat population. The cortisol population, the primary population for urinary cortisol analyses, was defined as the intent-to-treat population excluding patients with 1 or more of the following: urine volume less than 300 mL (for patients aged 4 –5 years) or less than 400 mL (for patients aged 6 –11 years) and 24-hour creatinine excretion below a predefined threshold range; a collection time that was not less than 24 Ϯ 4 hours in duration; oral, parenteral, or topical (Ն1% hydrocortisone) corticosteroid use within 30 days of visit 1 or during the study; not taking the study drug for more than 1 day before the start of urine collection; and failure to have both a baseline and a posttreatment urine collection.
Urinary cortisol excretion values were not corrected for cre- Abbreviations: CFC, chlorofluorocarbon; FEV , forced expiratory vol- ume in 1 second; HFA, hydrofluoroalkane; ICS, inhaled corticosteroid;NA, not applicable; PEFR, peak expiratory flow rate.
* Reversibility was evaluated at screening.
Of 421 children screened, 203 (48%) were randomly assigned † The toal daily dose of ICS was calculable in 93 patients in the to receive treatment. The most common reasons for excluding fluticasone propionate–salmeterol group and in 89 patients in the patients before randomization were lack of reversibility and ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY the fluticasone propionate group. The mean number of days gastrointestinal discomfort and pain, nausea and vomiting, that patients received treatment was 74.8 and 78.8 in the and fever. Thirteen percent of patients treated with flutica- fluticasone propionate–salmeterol and fluticasone propionate sone propionate–salmeterol and 9% treated with fluticasone groups, respectively. A total of 81% and 84% of patients in propionate experienced at least 1 adverse event during the the fluticasone propionate–salmeterol and fluticasone propi- study that was considered by the investigator to be potentially onate groups, respectively, completed the study.
related to treatment (drug related). The most common drug- related adverse events for the fluticasone propionate–salme-terol and fluticasone propionate groups included headaches One patient experienced a serious adverse event (asthmaexacerbation) during the run-in period. This patient was dis- (Ͻ1% and 4%), candidiasis of the mouth or throat (4% and continued from the study and was not randomized to receive 0%), throat irritation (3% and 2%), dizziness (2% and Ͻ1%), double-blind study medication. Both treatments were well tolerated during the 12-week study. The overall incidence of Three patients treated with fluticasone propionate–salmet- adverse events was similar in the 2 groups (59% for flutica- erol experienced adverse events that led to premature with- sone propionate–salmeterol and 57% for fluticasone propi- drawal from the study. One of these patients experienced onate) (Table 2). The most common adverse events included angioedema and hives that were not considered to be drug headache, upper respiratory tract infection, throat irritation, related. Another patient experienced chest pain, which wasconsidered to be drug related, and shortness of breath, whichwas not considered to be drug related. The third patient Table 2. Adverse Events During Treatment* experienced sleeplessness (for 38 days) during treatment thatwas considered to be drug related. None of the patients Fluticasone Fluticasone
propionate–
treated with fluticasone propionate were withdrawn from the propionate
salmeterol
study prematurely because of adverse events.
(n؍102)
(n؍101)
For most patients treated with fluticasone propionate–salme- terol or fluticasone propionate, hematology and chemistry values were normal and fell within the predefined threshold ranges for the following analytes: hemoglobin, hematocrit, red blood cells, white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, basophils, platelets, alkaline phos- phatase, alanine aminotransferase, aspartate aminotransfer- ase, total bilirubin, creatinine, glucose, calcium, potassium, sodium, urea nitrogen, total protein, and albumin. Three patients in each treatment group had clinical laboratory val- ues that were outside the threshold ranges. For the fluticasone propionate–salmeterol group, 1 patient had a decrease in elevation in glucose level (from 112 to 155 mg/dL), and 1 had an elevation in potassium level (from 4.6 to 6.8 mEq/L, which normalized on repeated measurement to 4.4 mEq/L).
For the fluticasone propionate group, 1 patient had a low neutrophil count at baseline that further decreased after treat- ment (from 1.3 to 0.78 ϫ 103/␮L), 1 had a high eosinophil count at baseline that further increased after treatment (from ϫ 103/␮L), and 1 had an increase in glucose level 24-Hour Urinary Cortisol Excretion A total of 48 and 57 patients in the fluticasone propionate– salmeterol and fluticasone propionate groups, respectively, were included in the cortisol population. Geometric meanurinary cortisol excretion at baseline was comparable be- Abbreviation: FEV , forced expiratory volume in 1 second.
tween treatment groups (fluticasone propionate–salmeterol * Data are given as percentage of patients.
† Includes all events (whether considered drug related or not drug ␮g/24 hours; fluticasone propionate group: 7.82 related by the investigator) that occurred at a rate of 3% or greater in ␮g/24 hours). At treatment week 12, geometric mean urinary cortisol excretion was 10.29 ␮g/24 hours in the fluticasone propionate–salmeterol group compared with 7.37 ␮g/24 improvements in FEV 6 and in morning and evening PEFRs hours in the fluticasone propionate group. The geometric during treatment with fluticasone propionate–salmeterol mean ratio for urinary cortisol excretion (week 12– baseline) compared with fluticasone propionate alone.
was 1.26 for patients treated with fluticasone propionate–salmeterol compared with 0.94 for those treated with flutica- DISCUSSION
sone propionate alone. Although all patients were receiving The results of this clinical study demonstrate that treatment ICS on study entry, none in either group had urinary cortisol with fluticasone propionate–salmeterol for 12 weeks had a excretion values that were below the reference range (1.4 –18 safety profile similar to that of treatment with fluticasone ␮g/24 hours for patients aged 4–6 years, 1.6–21 ␮g/24 hours propionate alone. Both treatments were well tolerated, with for patients aged 7–10 years, and 2.1–38 ␮g/24 hours for no serious drug-related adverse events reported in either patients aged 11 years) after 12 weeks of treatment in this group. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were similar between treatmentgroups, and no patient had a clinically significant abnormal ECG finding during treatment. No patient in either group had For all patients in both treatment groups, all baseline ECGs evidence of hypothalamic-pituitary-adrenal axis suppression were within the reference limits or were not considered as evaluated by 24-hour urinary cortisol excretion. Specifi- clinically significantly abnormal. After 12 weeks of treatment cally, geometric mean urinary cortisol excretion at baseline or premature study discontinuation, none of the patients in and after 12 weeks of treatment was comparable within and either treatment group had clinically significant abnormal between groups. Furthermore, none of the patients in either ECG findings. In addition, mean heart rate and QTc intervals treatment group had a value for 24-hour urinary cortisol were similar between the treatment groups after 12 weeks of excretion that was below the lower limit of the reference treatment and were comparable to baseline values. After 12 range after 12 weeks of treatment in this study. Finally, the weeks of treatment, the mean heart rate was 79.3/min in the incidence of withdrawals due to asthma exacerbations was fluticasone propionate–salmeterol group and 78.7/min in the lower in the fluticasone propionate–salmeterol group than in fluticasone propionate group. The mean QTc interval was the fluticasone propionate group (2% vs 5%).
313.8 milliseconds in the fluticasone propionate–salmeterol Current guidelines in children and adults recommend the group and 327.3 milliseconds in the fluticasone propionate use of inhaled long-acting ␤ -agonists plus ICS as the pre- ferred therapy for patients with persistent asthma who remain Mean systolic and diastolic blood pressures were compa- symptomatic while receiving ICS treatment, thus helping to rable between treatment groups at screening and throughout ensure that the lowest effective dose of ICS is used.3 For the study. Mean changes from baseline in systolic or diastolic pediatric patients who remain symptomatic while receiving blood pressure were small and comparable within and be- an ICS, treatment options are limited and include increasing the dose of ICS, adding an agent such as salmeterol, oradministering oral corticosteroids. In this regard, salmeterol has been previously shown to be effective in patients older Oropharyngeal candidiasis occurred in 4 patients treated with than 4 years with asthma.7,8 In addition, treatment with flu- fluticasone propionate–salmeterol and in none treated with ticasone propionate–salmeterol, 100/50 ␮g, twice daily via Diskus has been previously shown to be as safe and effective Asthma Exacerbations and Worsening Asthma as fluticasone propionate, 100 ␮g, and salmeterol, 50 ␮g, The incidence of asthma exacerbations and withdrawals due administered concurrently twice daily in patients aged 4 to 11 to worsening asthma were lower in the group treated with fluticasone propionate–salmeterol vs fluticasone propionate The addition of salmeterol to an ICS represents a treatment alone. Asthma exacerbations occurred in 3 patients (3%) option for patients who remain symptomatic while taking an treated with fluticasone propionate–salmeterol and in 8 pa- ICS that minimizes the risk of systemic effects that can occur tients (8%) treated with fluticasone propionate. Two patients when either higher doses of ICSs or oral corticosteroids are (2%) treated with fluticasone propionate–salmeterol and 5 administered. Unlike all other potential treatment options for patients (5%) treated with fluticasone propionate were with- patients who remain symptomatic while receiving an ICS, the drawn from the study because of asthma exacerbations.
use of a long-acting ␤ -agonist with an ICS in a single device eliminates the possibility that patients can selectively discon- This study was a safety study and was not designed to Therapy with an ICS and a long-acting ␤ -agonist ad- evaluate efficacy differences between treatment groups.
dresses inflammation and smooth muscle dysfunction (eg, However, as noted previously, some measures of efficacy bronchoconstriction), the 2 main components of asthma. In were obtained in this study. In this regard, although daytime addition, salmeterol possesses several nonbronchodilator asthma symptom scores and albuterol use improved to a properties that may contribute to its therapeutic effects. For similar degree in both groups, there were numerically greater example, salmeterol has demonstrated inhibitory effects on ANNALS OF ALLERGY, ASTHMA & IMMUNOLOGY vascular permeability,10–12 platlet-activating factor–induced 2. Mannino DM, Homa DM, Akinbami LJ, Moorman JE, Gwynn eosinophil accumulation,8,13 and the release of mast cell me- C, Redd SC. Surveillance for asthma—United States, diators from the lung.10,14,15 Salmeterol has also demonstrated 1980 –1999. MMWR Surveill Summ. 2002;51:1–13.
the ability to prime the glucocorticoid receptor for activation 3. National Asthma Education and Prevention Program. Expert Panel Report: Guidelines for the Diagnosis and Management of by corticosteroids16; however, the clinical relevance of these Asthma. Update on Selected Topics—2002. J Allergy Clin in vitro observations is unclear. These findings suggest that Immunol. 2002;110:S141–S219.
using an ICS with a long-acting ␤ -agonists has a broad scope 4. American Thoracic Society. Standards for the diagnosis and of activity in the treatment of asthma.
care of patients with chronic obstructive pulmonary disease In summary, the results of this clinical trial demonstrate (COPD) and asthma. Am Rev Respir Dis. 1987;136:225–244.
that treatment for 12 weeks with fluticasone propionate– 5. Polgar G, Promadhat V. Pulmonary Function Testing in salmeterol, 100/50 ␮g, twice daily was well tolerated in Children: Techniques and Standards. Philadelphia, PA: WB children aged 4 to 11 years with persistent asthma and has a safety profile that is similar to that of fluticasone propionate, 6. House K, Dorinsky PM, Stauffer J, Schoaf L, Ellsworth A. The 100 ␮g, twice daily alone. In addition, the use of salmeterol safety of fluticasone propionate/salmeterol Diskus in pediatricpatients ages 4 –11 with asthma [abstract]. Chest. 2004;126: with an ICS represents a treatment option for patients who remain symptomatic while taking an ICS that minimizes the 7. Weinstein SF, Pearlman DS, Bronsky EA, et al. Efficacy of risk of systemic effects that can occur when either higher salmeterol xinafoate powder in children with chronic persistent doses of ICSs or oral corticosteroids are administered.
asthma. Ann Allergy Asthma Immunol. 1998;81:51–58.
8. Data on file. GlaxoSmithKline (SLGA3014).
ACKNOWLEDGMENTS
9. Van den Berg NJ, Ossip MS, Hederos CA, Anttila H, Riberio We thank Cynthia Toso, PharmD, and Laura Sutton, PharmD, BL, Davies PI. Salmeterol/fluticasone propionate (50/100 ␮g) for their assistance in preparing the manuscript and the fol- in combination in a Diskus Inhaler (Seretide) is effective and lowing investigators for their participation in this study: Rich- safe in children with asthma. Pediatr Pulmonol. 2000;30: ard Ahrens, MD, Iowa City, IA; Garrison Ayars, MD, Kirk- land, WA; Malik Baz, MD, San Antonio, TX; George 10. Johnson M. The preclinical pharmacology of salmeterol: non- Bensch, MD, Stockton, CA; Kathryn Blake, PharmD, Jack- bronchodilator effects. Eur Respir Rev. 1991;1:257–260.
11. Proud D, Reynolds CJ, Lichtenstein LM, et al. Intranasal sal- sonville, FL; Michael Blumberg, MD, Richmond, VA; Daniel meterol inhibits allergen-induced vascular permeability but not Brown, MD, Columbia, SC; John Condemi, MD, Rochester, mast cell activation or cellular infiltration. Clin Exp Allergy.
NY; Donald Ellenburg, MD, Knoxville, TN; Mark Ellis, MD, Orange, CA; Gilbert Friday Jr, MD, Pittsburgh, PA; Sandra 12. Birchall MA, O’Connell F, Henderson J, et al. Topical salme- Gawchik, DO, Upland, PA; Milton Gold, MD, Bramptom, terol reduces protein content of nasal lavage fluid in response to Ontario; Brad Goodman, MD, Savannah, GA; Sam Henein, allergen and histamine challenge: double-blind crossover study MD, Newmarket, Ontario; Eugene Hurwitz, MD, Carrollton, placebo-controlled studies in adults. Am J Rhinol. 1996;10: GA; Stacie Jones, MD, Little Rock, AK; Neil Kao, MD, Greenville, SC; Kevin Kelly, MD, Milwaukee, WI; Kenneth 13. Whelan CJ, Johnson M. Inhibition by salmeterol of increased Kim, MD, Signal Hill, CA; Burton Lesnick, MD, Atlanta, vascular permeability and granulocyte accumulation in guinea-pig lung and skin. Br J Pharmacol. 1992;105:831– 838.
GA; Robert Nathan, MD, Colorado Springs, CO; William 14. Butchers PR, Vardey CJ, Johnson M. Salmeterol: a potent and Nish, MD, Gainesville, GA; Michael Noonan, MD, Portland, long-acting inhibitor of inflammatory mediator release from OR; Grant Olson, MD, Lakewood, CA; Ashok Patel, MD, human lung. Br J Pharmacol. 1991;104:672– 676.
Pueblo, CO; David Pearlman, MD, Denver, CO; Paul Pi- 15. Chong LK, Cooper E, Vardey CJ, et al. Salmeterol inhibition of anosi, MD, Halifax, Nova Scotia; Jacob Pinnas, MD, Tuscon, AZ; Bruce Prenner, MD, San Diego, CA; William Rees, MD, ␤-adrenoceptor–dependent and independent mechanisms. Br J Burke, VA; Alan Resnick, MD, Highland Park, IL; Ned Pharmacol. 1998;123:1009 –1015.
Rupp, MD, Charleston, SC; Constantine Saadeh, MD, Am- 16. Eickelberg O, Roth M, Lorx R, et al. Ligand-independent acti- arillo, TX; Ronald Saff, MD, Tallahassee, FL; Gary Steven, vation of the glucocorticoid receptor by ␤ -adrenergic receptor MD, West Allis, WI; Randy Stoloff, MD, Plattsburgh, NY; agonists in primary human lung fibroblasts and vascular smoothmuscle. J Biol Chem. 1999;274:1005–1010.
Martha Tarpay, MD, Oklahoma City, OK; Russell Walker,MD, Chattanooga, TN; Steven Weinstein, MD, HuntingtonBeach, CA; Robert Wolfe, MD, Los Angeles, CA.
Requests for reprints should be addressed to:Randolph Malone, MD REFERENCES
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