Suppression of hypothalamic-pituitary-adrenal axis activity with inhaled flunisolide and fluticasone propionate in adult asthma patients.

BACKGROUND: Suppression of the hypothalamic-pituitary-adrenal (HPA) axis, a potential systemic effect of inhaled corticosteroid therapy, can be quantified by monitoring serum, urinary, and salivary cortisol levels. OBJECTIVES: 1) Compare the effects on HPA axis of the inhaled corticosteroids flunisolide and fluticasone propionate versus placebo and oral prednisone. 2) Estimate dose-potency ratio for HPA-axis suppression. METHODS: Multicenter, randomized, placebo-controlled, open-label, 21-day trial. Active regimens were flunisolide 500 and 1,000 microg, twice daily; fluticasone propionate 110, 220, 330, and 440 microg, twice daily; and prednisone, 7.5 mg daily. Enrolled patients were nonsmokers, 18 to 50 years of age, with persistent mild-to-moderate asthma and had not used oral, nasal, or inhaled corticosteroids for 6 months before study. Main outcome measures were area under serum cortisol concentration curve for 22 hours (AUC(0-22h)); 24-hour urinary cortisol level; and 8 AM salivary cortisol level. RESULTS: One hundred fifty-three patients were randomly assigned to active treatment or placebo; 125 patients completed the study and were at least 80% compliant with their regimens. Both fluticasone propionate and flunisolide caused dose-dependent suppression of HPA axis, which was statistically greater for fluticasone propionate (P = 0.0003). Dose-potency ratio showed 4.4 times more serum-cortisol suppression/microgram increase in dose with fluticasone propionate than with flunisolide. Diurnal pattern of serum cortisol suppression was persistent with fluticasone propionate and "remitting" with flunisolide. Salivary and urinary cortisol data were qualitatively similar to serum cortisol results. CONCLUSIONS: Fluticasone caused significantly more suppression of HPA axis than flunisolide. Flunisolide may provide a safe option for patients with asthma requiring long-term inhaled corticosteroid therapy.     

Efficacy and safety of fluticasone propionate 250 microg administered once daily in patients with persistent asthma treated with or without inhaled corticosteroids.

BACKGROUND: Studies have shown fluticasone propionate (FP) 100, 200, and 500 microg administered once daily to be effective in the treatment of asthma. The efficacy of a once daily regimen of FP 250 microg has not been evaluated previously. OBJECTIVE: We sought to evaluate the efficacy and safety of inhaled FP 250 microg administered once daily in patients currently receiving inhaled short-acting beta-agonists (SABA) alone or inhaled corticosteroids (ICS). METHODS: In two separate studies, 408 patients in the SABA study and 401 patients in the ICS study were randomly assigned to receive FP 250 microg or placebo for 12 weeks through the Diskus device (GlaxoSmithKline, Research Triangle Park, NC) each morning. RESULTS: At the study endpoint, SABA patients treated with FP and placebo had mean increases in forced expiratory volume in 1 second from baseline of 0.23 +/- 0.03 L and 0.10 +/- 0.03 L, respectively (P < 0.001). ICS patients treated with FP had a mean increase of 0.08 +/- 0.02 L compared with a decrease in forced expiratory volume in 1 second of -0.08 +/- 0.03 L with placebo (P < 0.001). Changes of similar magnitude in morning peak expiratory flow rates were seen with FP in both the SABA and ICS studies. Fewer FP-treated ICS study patients were withdrawn from the study as a result of predetermined asthma stability criteria and, therefore, those patients had a greater probability of remaining in the study than placebo-treated patients (P < 0.001). CONCLUSIONS: FP 250 microg, once daily, produced greater improvements in pulmonary function and asthma symptom control than placebo. This new treatment regimen provides clinicians with an additional therapeutic option for patients with asthma previously treated with either beta2-agonists alone or ICS.     

Low-dose inhaled fluticasone propionate versus oral zafirlukast in the treatment of persistent asthma

Background: Few studies have compared the efficacy of inhaled corticosteroids and leukotriene modifiers for the treatment of persistent asthma. Objective: Our purpose was to compare the efficacy of a low dose of inhaled fluticasone propionate (FP) with that of oral zafirlukast in the treatment of persistent asthma previously treated with short-acting β₂-agonists alone. Methods: A 12-week, randomized, double-blind, double-dummy, multicenter study was conducted in 451 patients aged 12 years and older with asthma who were symptomatic on short-acting β₂-agonists alone. After an 8- to 14-day run-in period, patients were randomized to treatment with FP 88 μg twice daily or zafirlukast 20 mg twice daily. Results: Treatment with FP was more effective than treatment with zafirlukast in increasing morning FEV₁ (by 0.42 L vs 0.20 L over baseline, P < .001), morning peak expiratory flow (by 49.94 L/min vs 11.68 L/min over baseline, P < .001), and evening PEF (by 38.91 L/min vs 10.50 L/min over baseline, P < .001). Statistically significant differences between the two treatments in FEV₁ were noted after the first observation (week 4) and in morning and evening peak expiratory flow by week 2. Mean change in percentage of symptom-free days was greater with FP than with zafirlukast (28.5% of days vs 15.6% of days, P < .001) and FP significantly increased the percentage of rescue-free days by 40.4% of days compared with 24.2% of days with zafirlukast (P < .001). Treatment with FP significantly reduced albuterol use by 2.39 puffs per day compared with 1.45 puffs per day (P < .001) and increased the percentage of nights with no awakenings by 21.2% of nights compared with 8.0% of nights with zafirlukast (P < .001). Conclusion: The clinical effectiveness of a low dose of FP as first-line therapy in patients with persistent asthma who are symptomatic on β₂-agonists alone is superior to that of zafirlukast. (J Allergy Clin Immunol 2000;105:1123-9.)     

The addition of salmeterol to fluticasone propionate versus increasing the dose of fluticasone propionate in patients with persistent asthma. Salmeterol Study Group.

BACKGROUND: Current treatment guidelines define inhaled corticosteroids such as fluticasone propionate (FP) as the cornerstone of anti-inflammatory therapy for asthma. OBJECTIVE: The objective was to evaluate the efficacy and safety of adding salmeterol therapy to patients who remain symptomatic while receiving FP as compared with increasing the dose of FP. METHODS: In a multicenter, double-blind study conducted over 24-weeks, 437 patients aged 12 years and older and receiving FP 88 microg twice daily for 2 to 4 weeks were randomly assigned to receive either salmeterol (42 microg twice daily) or FP 220 microg twice daily. The primary efficacy endpoint was morning peak expiratory flow. Secondary measures included FEV1, symptom scores, nighttime awakenings, and supplemental albuterol use. Safety was assessed by reported adverse events and asthma exacerbations. RESULTS: The addition of salmeterol resulted in significantly greater improvements in lung function and symptom control as compared with increasing the dose of FP. Over weeks 1 to 24, morning peak expiratory flow was increased by 47 L/min from baseline with salmeterol treatment as compared with 24 L/min with FP 220 microg twice daily (P < .001) while the percent of symptom-free days increased from baseline by 26% of days as compared with 10% of days (P < .001). The adverse event profiles were similar between groups and fewer exacerbations were reported with salmeterol treatment. CONCLUSIONS: The addition of salmeterol therapy to patients who remain symptomatic while using a low dose of FP was clinically and statistically superior to increasing the dose of FP.     

Efficacy and safety of dry powder fluticasone propionate in children with persistent asthma.

BACKGROUND: Flovent Diskus is a powder formulation of the inhaled corticosteroid fluticasone propionate (FP) delivered via a breath-actuated, multidose inhaler. OBJECTIVE: To determine the efficacy and safety of dry powder FP administered once or twice daily (200 microg per day) to children with persistent asthma. METHODS: Twelve-week, randomized, double-blind, placebo-controlled, multicenter trial with a 52-week, open-label extension. Children aged 4 to 11 were required to have pulmonary function 50% to 85% of predicted values. The population was stratified for baseline therapy (inhaled corticosteroid/cromolyn or bronchodilators only). After a 2-week placebo run-in, 242 patients received dry powder FP 200 microg each morning, dry powder FP 100 microg BID, or placebo for 12 weeks; 192 were rerandomized to the QD or BID regimen for an additional 52 weeks of open-label treatment. Primary endpoints were mean changes in FEV1 and morning PEF recorded at clinic visits. RESULTS: Both dry powder FP regimens significantly improved FEV1, evening PEF, and asthma symptoms at the double-blind phase endpoint (P < or = .017 compared with placebo). The BID regimen also significantly improved morning PEF and nighttime awakenings due to asthma (P < or = .005). Among patients previously treated with inhaled corticosteroids/cromolyn, improvements observed with the QD and BID regimens were similar. Patients switched from BID to open-label QD treatment showed additional improvements at week 52 generally comparable to patients who received the BID regimen during both phases. Fluticasone propionate was well tolerated for up to 64 weeks with few reports of drug-related adverse events or morning plasma cortisol abnormalities. CONCLUSIONS: Once daily dosing of dry powder FP 200 microg is an effective and convenient alternative for children whose asthma is controlled with a more frequent dosing regimen of inhaled corticosteroids.     

One-year claims analysis comparing inhaled fluticasone propionate with zafirlukast for the treatment of asthma

BACKGROUND: Randomized clinical trials have demonstrated that fluticasone propionate (FP) has better objective as well as subjective clinical outcomes than zafirlukast (ZA) in the treatment of asthma. OBJECTIVE: The goal of this study was to determine whether the superiority of FP over ZA observed in clinical trials is supported under actual practice conditions. METHODS: A retrospective cohort analysis of pharmacy and medical claims for asthma was performed. Patients were identified who had at least 1 ICD-9 (493.XX) claim for asthma and were recently prescribed inhaled FP or ZA. Subjects could not have had a claim for any inhaled corticosteroid or oral leukotriene modifier in the 9 months before initiation of FP or ZA. They were subsequently observed for 12 months. RESULTS: A total of 725 persons were new users of FP and 309 of ZA. FP was associated with a 70% reduced risk for hospitalization (P =.0232), a 49% lower risk for an emergency department event (P =.0546), and a 51% reduction in combined emergency department events and hospitalizations (P =.0268) when compared with ZA. Adjusted annual asthma care costs declined significantly for FP and increased for ZA. The adjusted mean difference in annual asthma costs was $215 less per patient for FP (P <.0001). CONCLUSION: Asthma care costs decreased for patients treated with FP and increased for patients treated with ZA. Furthermore, FP-treated patients had significantly lower risks of asthma-related hospitalization than ZA patients. This study supports results seen in clinical trials comparing these two medications.     

Efficacy and safety of fluticasone propionate 44 microg/salmeterol 21 microg administered in a hydrofluoroalkane metered-dose inhaler as an initial asthma maintenance treatment.

BACKGROUND: We wanted to evaluate whether treatment with an inhaled corticosteroid and an inhaled long-acting beta2-agonist is more effective than an inhaled corticosteroid alone for patients using as-needed albuterol who are initiating maintenance treatment. OBJECTIVE: To compare the efficacy and safety of twice-daily fluticasone propionate (FP) 88 microg and salmeterol 42 microg combined in a chlorofluorocarbon (CFC)-free (hydrofluoroalkane 134a) metered-dose inhaler (MDI) with the individual agents alone, each delivered through an MDI containing CFC propellants, in patient with persistent asthma previously uncontrolled with as-needed short-acting beta2-agonists alone. METHODS: Patients with asthma (n = 283) were randomized to twice-daily treatment for 12 weeks with FP 88 microg combined with salmeterol 42 microg (FSC) in a CFC-free MDI or the individual components alone from CFC-containing MDIs. RESULTS: At endpoint, mean change from baseline in morning predose forced expiratory volume in 1 second was significantly (P < or = 0.016) greater with FSC (0.69 L) compared with FP (0.51 L) or salmeterol (0.47 L). Fewer patients treated with FSC withdrew due to worsening asthma (1%) compared with FP (3%) or salmeterol (8%; P = 0.024). FSC significantly increased (P < or = 0.002) morning and evening peak expiratory flow rate at endpoint (66.5 and 51.5 L/min, respectively) compared with FP (43.0 and 29.9 L/min, respectively) and salmeterol (29.2 and 21.6 L/min, respectively). In addition, asthma symptom scores were reduced, and percentages of days with no asthma symptoms increased in all treatment groups. CONCLUSIONS: Treatment with FSC in a CFC-free MDI is more effective than FP or salmeterol alone in asthma patients who are symptomatic taking short-acting beta2-agonists alone.     

Steroid-sparing effects of fluticasone propionate 100 microg and salmeterol 50 microg administered twice daily in a single product in patients previously controlled with fluticasone propionate 250 microg administered twice daily

BACKGROUND: Concurrent use of an inhaled corticosteroid (ICS) and an inhaled long-acting beta2-agonist provides better overall asthma control than the use of higher doses of ICS alone. OBJECTIVE: The purpose of this investigation was to determine whether fluticasone propionate (FP) combined with salmeterol in the Diskus device can be used to reduce the dose of ICS in patients currently stable on medium-dose ICS while maintaining asthma control. METHODS: This was a randomized, double-blind, parallel-group, 12- to 24-week trial consisting of a 3-part run-in period. The run-in period was designed to first establish FP 250 microg administered twice a day (bid) via Diskus as the minimum effective dose. During run-in period 1, patients received FP 220 microg bid or the equivalent for 10 to 14 days. Controlled patients moved to run-in period 2 (5-28 days), which assessed asthma stability on FP 100 microg bid administered via Diskus. Only patients who became unstable on FP 100 microg bid were eligible to enter run-in period 3 (26-30 days), during which they were placed on FP 250 microg bid and those regaining asthma control were eligible for randomization. The primary efficacy endpoint was the proportion of patients who remained in the study with no evidence of worsening asthma. Secondary efficacy measures included FEV1, morning peak expiratory flow, percent of symptom-free days, and daily albuterol use. RESULTS: Only 5% of patients treated with FP100/salmeterol withdrew because of worsening asthma in the first 12 weeks; this compared with 7% in the FP250 group. All patients from a subset of sites continued in the study for an additional 12 weeks; only an additional 1% of patients treated with either FP100/salmeterol or FP250 withdrew because of worsening asthma. Secondary efficacy measures confirmed primary efficacy results. CONCLUSION: In patients requiring FP250 bid for asthma stability, FP100/salmeterol bid was steroid-sparing, allowing a 60% reduction in the FP dose while maintaining overall asthma control.     

Treatment with 400 microg of inhaled budesonide vs 200 microg of inhaled budesonide and oral montelukast in children with moderate persistent asthma: randomized controlled trial.

BACKGROUND: Montelukast is reported to be beneficial in asthma as add-on therapy to inhaled corticosteroids and may reduce the need for the latter. OBJECTIVE: To evaluate whether a combination of oral montelukast and 200 microg of inhaled budesonide has comparable efficacy to 400 microg of inhaled budesonide alone in children with moderate persistent asthma. METHODS: In this prospective, blinded, hospital-based randomized controlled trial, 71 children with moderate persistent asthma were randomized to receive either montelukast, 5-mg chewable tablet, with 200 microg of inhaled budesonide or only 400 microg of inhaled budesonide daily for 12 weeks. Baseline and serial measurements of forced expiratory volume in 1 second, peak expiratory flow rate, and Asthma Symptom Score were performed; the frequency and severity of exacerbations were also recorded. RESULTS: Measurements of forced expiratory volume in 1 second, peak expiratory flow rate, and Asthma Symptom Score showed no significant differences between the 2 groups at baseline, during the serial follow-up visits, and at the end of the study. However, children who received montelukast had a greater frequency of exacerbations vs those who did not (33.3% vs 9.1%; P < .01). CONCLUSION: The overall control of asthma with 5 mg of oral montelukast and 200 microg of inhaled budesonide is inferior to that with 400 microg of inhaled budesonide in children with moderate persistent asthma.     

Comparison of once- and twice-daily dosing of fluticasone propionate 200 micrograms per day administered by Diskus device in patients with asthma treated with or without inhaled corticosteroids

Background: There are limited published data regarding the efficacy of once- versus twice-daily administration of flutica-sone propionate. Objective: Our purpose was to evaluate the effectiveness of fluticasone propionate powder 200 μg/d administered as a once- or twice-daily dosage regimen in patients who were currently being treated with bronchodilators only (BD patients) and in patients who required inhaled corticosteroids for maintenance treatment of asthma (ICS patients). Methods: Five hundred seventy patients were randomly assigned to receive one of the following inhaled treatments through the Diskus device (Glaxo Wellcome, Research Triangle Park, NC) for 12 weeks: fluticasone propionate 100 μg twice daily (FP100BID) or 200 μg once daily (FP200QD) or placebo. Results: BD patients treated with FP100BID, FP200QD, and placebo had mean increases in FEV₁ from baseline to end point of 0.49 L, 0.37 L, and 0.21 L, respectively (P < .001, FP100BID vs placebo; P = .05, FP200QD vs placebo). ICS patients treated with FP100BID and FP200QD had mean increases in FEV₁ of 0.27 L and 0.11 L, respectively, compared with a decrease in FEV₁ of –0.08 L with placebo (P < .001, FP100BID vs placebo; P = .023, FP200QD vs placebo). BD patients treated with FP100BID and FP200QD had mean increases in morning peak expiratory flow from baseline to end point of 31 L/min and 27 L/min, respectively, compared with a 1 L/min increase in patients treated with placebo. ICS patients treated with FP100BID had a mean increase in morning peak expiratory flow (from baseline to end point) of 18 L/min compared with mean decreases of –3 L/min and –12 L/min in the FP200QD and placebo groups, respectively. More patients were withdrawn from placebo (26% and 48%, in BD and ICS patients, respectively) than from fluticasone propionate (7%-9% [BID-QD] and 18%-32% [BID-QD], in BD and ICS patients, respectively) because of failure to meet predetermined asthma stability criteria. Conclusion: The efficacies of FP100BID and FP200QD were comparable with regard to improvement in pulmonary function and asthma stability in BD patients. In ICS patients, asthma control was maintained with FP200QD, whereas FP100BID provided greater improvements in pulmonary function and asthma stability. (J Allergy Clin Immunol 2000;105:1153-61.)     

The safety of twice-daily treatment with fluticasone propionate and salmeterol in pediatric patients with persistent asthma.

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 beta2-agonist vs increasing the ICS dose. OBJECTIVE: To compare the safety of twice-daily treatment with inhaled fluticasone propionate plus the inhaled long-acting beta2-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 microg) or fluticasone propionate (100 microg) 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 treatments were well tolerated. Two patients receiving fluticasone propionate-salmeterol and 5 receiving fluticasone propionate withdrew from the study because of worsening asthma. Changes in heart rate, blood pressure, and laboratory variables were infrequent and were 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 and between 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 the fluticasone 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.     

Diskus and diskhaler: efficacy and safety of fluticasone propionate via two dry powder inhalers in subjects with mild-to-moderate persistent asthma.

BACKGROUND: Fluticasone propionate is a topically active glucocorticoid with potent antiinflammatory activity in the treatment of asthma. OBJECTIVE: This study evaluated the safety and efficacy of fluticasone propionate administered via the Diskus and Diskhaler powder delivery devices in subjects with mild-to-moderate asthma. METHODS: Fluticasone propionate (500 microg twice daily) or placebo was administered via the Diskus and Diskhaler to 213 adolescent and adult asthma subjects in a randomized, double-blind, double-dummy, parallel-group study for 12 weeks. Subjects were stratified according to baseline therapy of inhaled corticosteroids or beta2-agonists alone. Subjects were dropped from the study if they met predefined criteria for lack of efficacy. RESULTS: Fluticasone propionate improved pulmonary function both in subjects previously treated with inhaled corticosteroids or beta2-agonists alone. At endpoint, fluticasone propionate significantly improved forced expiratory volume in 1 second (P < .001), morning and evening peak expiratory flow (P < .001), and asthma symptom scores (P < or = .016), and significantly reduced nighttime awakenings (P = .016; Diskhaler group only) and rescue albuterol use (P < .001). Overall, efficacy measurements for the Diskus and Diskhaler were similar. More placebo-treated subjects (34%) withdrew from the study due to lack of efficacy than subjects in the Diskus (5%) or Diskhaler (5%) groups. The incidence and severity of adverse events were similar across groups. Measurement of plasma fluticasone propionate and cortisol concentrations showed no apparent influence of device on systemic exposure. CONCLUSION: Fluticasone propionate powder, administered via the Diskus or Diskhaler inhalation devices, was well tolerated and effective in the treatment of mild-to-moderate persistent asthma.     

Effects of low doses of inhaled fluticasone propionate on inflammation and remodelling in persistent-mild asthma

In asthma a dysregulation of eosinophil apoptosis and an imbalance of metalloproteinase-9 (MMP-9) and tissue inhibitor metalloproteinase-1 (TIMP-1) play an important role in airway inflammation and remodelling. We evaluated the effects of a low dose of inhaled fluticasone proprionate (FP) (100 microg bid by Diskus) for 4 weeks in 24 steroid naive patients with mild persistent asthma, symptomatic and with a sputum eosinophilia >or=3% on clinical outcomes and inflammatory markers such as the induced sputum eosinophils, the induced sputum apoptotic eosinophils, the levels of MMP-9 and TIMP-1 and their molar ratio in the induced sputum supernatants. After FP treatment forced expiratory volume (FEV1) and FEV1/forced vital capacity values, PEF (L/min), sputum apoptotic eosinophils, and MMP-9/TIMP-1 molar ratio in sputum supernatants of asthmatic subjects were significantly increased in comparison with baseline, while sputum eosinophils significantly decreased. Change (Delta) in FEV1 after treatment with FP negatively correlated with the Delta in sputum eosinophils, while the Delta in MMP-9 values positively correlated with Delta in TIMP-1 values. This study shows that the clinical improvement achieved by the use of low doses of FP in asthmatics is related, at least in part, to the resolution of eosinophilic inflammation and the downregulation of remodelling markers.     

A comparison of fluticasone propionate 200 μg/day with beclomethasone dipropionate 400 μg/day in adult asthma

A total of 261 patients with symptomatic, mild to moderate asthma were randomized to treatment in this 4-week, double-blind, parallel-group comparison of fluticasone propionate 200 μg/d with beclomethasone dipropionate 400 μg/d. Improvements from both treatments were seen in diary card data. Morning peak expiratory flow rate (PEFR) improved from 375 to 390 and 371 to 382 1/min with fluticasone propionate and beclomethasone dipropionate, respectively. Symptom scores, percentage of symptom-free days and nights, and use of rescue (β₂-agonist medication also improved, as did clinical lung function. With the exception of percentage of rescue-free days, which was greater for beclomethasone dipropionate, none of the differences between the groups were statistically significant. There was a significant difference between treatments in the number of rescue-free days over days 1–28; however, there was no difference between treatments in the number of rescue-free days over days 1-14, nor was there any difference in the number of inhalations of rescue medication used throughout the study. Very few adverse effects were reported. Although all mean plasma cortisol values were within the normal range, they were significantly different between treatments, rising from 402 to 429 nmol/1 with fluticasone propionate, and falling from 435 to 394 nmol/1 with beclomethasone dipropionate (P= 0.006). Mean stimulated cortisol levels 30 min after tetracosactin injection were also significantly greater with fluticasone propionate (P = 0.024). In conclusion, fluticasone propionate 200 μg/d is as effective as beclomethasone dipropionate 400 μg/d with less effect on plasma cortisol levels.     

One-year efficacy and safety of inhaled formoterol dry powder in children with persistent asthma.

BACKGROUND: The long-term efficacy and safety of formoterol dry powder capsules for inhalation in pediatric asthma have not previously been evaluated. OBJECTIVE: We examined the effectiveness of inhaled formoterol over a period of 12 months in asthmatic children who were still symptomatic despite anti-inflammatory treatment. METHODS: After a run-in period, 518 patients (5 to 12 years old) were randomized in a double-blind manner to receive 12 or 24 microg formoterol dry powder (Foradil, Novartis Pharma AG, Basel, Switzerland) or placebo twice daily for 12 months. The drug was administered by inhaler (Aerolizer, Novartis Pharma AG) and was given in addition to their anti-inflammatory treatment. The primary variable was the area under the curve for forced expiratory volume in 1 second measured over 12 hours after the morning dose of study medication. RESULTS: The area under the curve for forced expiratory volume in 1 second after the first dose of treatment and after 3 and 12 months of treatment was significantly greater for patients receiving formoterol 12 microg and 24 microg than for patients receiving placebo (all P < or = 0.0062). Compared with placebo, both doses of formoterol significantly improved morning and evening premedication peak expiratory flow rate (all P < 0.001). In the group treated with formoterol 24 microg, median symptom score and median dose of rescue medication at night were lower than during the run-in period, whereas the opposite occurred in the placebo group. The incidence of hospitalizations for asthma was higher in the formoterol groups than in the placebo group. CONCLUSION: Our results indicate that, in asthmatic children who are still symptomatic despite anti-inflammatory therapy, the addition of formoterol consistently improves airflow obstruction and nocturnal symptoms and reduces the use of rescue medication. However, this treatment requires close disease monitoring to detect early signs of acute exacerbation.     

Advair: combination treatment with fluticasone propionate/salmeterol in the treatment of asthma

Several classes of medications are available for the treatment of asthma, and often they must be taken concurrently to achieve asthma control. Based on the understanding of asthma as an inflammatory disease, the National Heart Lung and Blood Institute guidelines provide a stepwise approach to pharmacologic therapy. Corticosteroid therapy, principally inhaled corticosteroid (ICS) therapy, is considered the most effective anti-inflammatory treatment. In cases of moderate-to-severe persistent asthma, the addition of a second long-term control medication to ICS therapy is one recommended treatment option. A combination-product inhaler (Advair, Seretide) was developed to treat both the inflammatory and bronchoconstrictive components of asthma by delivering a dose of the ICS, fluticasone propionate, and a dose of the long-acting beta2-adrenergic (LABA) bronchodilator, salmeterol. The Advair Diskus is available in 3 strengths of fluticasone propionate (100, 250, and 500 microg) and a fixed dose (50 microg) of salmeterol. Combination treatment with both ICS and LABA provides greater asthma control than increasing the ICS dose alone, while at the same time reducing the frequency and perhaps the severity of exacerbations. Furthermore, salmeterol added to ICS therapy provides superior asthma control compared with the addition of leukotriene modifiers or theophylline. The superior control is likely a consequence of the complementary actions of the drugs when taken together, including the activation of the glucocorticoid receptor by salmeterol. By combining anti-inflammatory treatment with a long-acting beta2-agonist in a single inhaler (1 inhalation twice daily), physicians can provide coverage for both the inflammatory and bronchoconstrictive aspects of asthma without introducing any new or unexpected adverse consequences. The most common drug-related adverse events were those known to be attributable to the constituent medications (ICS therapy and/or LABA therapy). Although the benefits of combined ICS plus LABA therapy can be achieved with separate inhalers, the convenience of the combination product may improve patient adherence and may therefore reduce the morbidity of asthma.     

Rapid effect of inhaled fluticasone propionate on airway responsiveness to adenosine 5'-monophosphate in mild asthma

Inhaled adenosine 5'-monophosphate (AMP) has an "indirect" bronchoconstrictive effect through mast cell degranulation and mediator release, whereas inhaled histamine has a "direct" effect on smooth muscle. Prolonged treatment with inhaled glucocorticosteroids attenuates airway responsiveness (AR) to AMP and histamine. We investigated the early effects of inhaled fluticasone propionate (FP) therapy on AR in 3 consecutive double-blind, randomized, placebo-controlled crossover studies in steroid-naive subjects with mild asthma. In one study, each of 12 subjects received FP 1000 microg or matched placebo for 7 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 3rd and 7th inhalations. In a second study, each of 12 subjects received FP 100, 250, or 1000 microg or matched placebo for 3 inhalations at 12 hourly intervals; AR to AMP and FEV(1) were measured 2 hours after the 1st and 3rd inhalations. In a third study, each of 8 subjects received a single inhalation of FP 1000 microg or matched placebo; AR to histamine was measured 2 hours later. In the first study, FP 1000 microg significantly attenuated AR to AMP by 2.7 and 2.5 doubling doses after 3 and 7 inhalations, respectively (P < or =.0001). In the second study, FP 100, 250, and 1000 microg significantly attenuated AR to AMP by 1.9, 2.2, and 2.7 doubling doses, respectively, after 1 inhalation and by 2.4, 2.2, and 3.2 doubling doses, respectively, after 3 inhalations (P < or =.0001); a small but significant increase in FEV(1) (>0.15 L) was observed after 3 inhalations but not after 1 inhalation of FP irrespective of dose (P < or =.05). In the third study, a single inhalation of FP 1000 microg had no effect on AR to histamine. We have demonstrated a reduction in AR to AMP but not AR to histamine within 2 hours of a single inhalation of FP. This reflects a rapid, topical anti-inflammatory action of inhaled FP by a mechanism of action that remains unknown.     

Influence of different dosage schedules of inhaled fluticasone propionate on peripheral blood cytokine concentrations in childhood asthma

BACKGROUND: Asthma is characterized by eosinophilic airways inflammation with elevated levels of IL-4, IL-5 and sICAM-1, and reduced levels of IL-10 and IFN-gamma. Inhaled corticosteroids powerfully reduce airways inflammation. OBJECTIVE: To investigate if eosinophil counts, serum eosinophilic cationic protein (ECP) and sICAM-1 levels, as well as serum and production of cytokines (IL-4, IL-5, IL-10, IFN-gamma) by peripheral blood monocytes (PBMCs) are useful markers to monitor therapy with inhaled fluticasone propionate (FP) in asthmatic children. METHODS: In a double-blind, 1-year study, 55 asthmatic children (aged 6-10 years) stopped inhaled corticosteroids for a mean period of 24 days and were randomized to receive either FP 200 microg/day (constant dose group), or a starting dose of FP 1000 microg/day with two monthly reductions to 500, 200 and 100 microg/day (stepdown group). Hyper-responsiveness, symptom scores and blood sampling were performed at 2-month intervals. RESULTS: Symptoms and hyper-responsiveness improved significantly in both treatment groups after reintroduction of FP. Eosinophil counts decreased significantly more during the first 2 months of FP in the stepdown group than in the constant dose group (P = 0.03). We found a trend towards a dose-dependent response in changes of eosinophil counts and serum ECP levels during treatment. Serum IL-4 and IL-5 levels were undetectable in the majority of children. No significant effect of the dose of FP on the release of IL-4, IL-5, IL-10 or IFN-gamma by Con A stimulated PBMCs was found. sICAM-1 levels did not significantly differ at any time point between the two groups. CONCLUSION: Serum ECP as well as peripheral blood eosinophils, cytokine production by PBMCs and sICAM-1 levels are insensitive markers in titrating and monitoring therapy with inhaled corticosteroids over a wide dose range in childhood asthma.     

Low-dose fluticasone propionate compared with montelukast for first-line treatment of persistent asthma: a randomized clinical trial

BACKGROUND: Both inhaled corticosteroids and leukotriene modifiers are used in the maintenance treatment of persistent asthma. OBJECTIVE: The goal was to compare the efficacy and safety of low-dose fluticasone propionate (FP) and montelukast as first-line maintenance therapy in symptomatic patients by using short-acting beta2-agonists alone to treat persistent asthma. METHODS: In this multicenter, randomized, double-blind, double-dummy, parallel-group study, 533 patients (>15 years old) with persistent asthma who remained symptomatic while taking short-acting beta2-agonists alone were treated with FP (88 microg [2 puffs of 44 microg] twice daily) or montelukast (10 mg once daily) for 24 weeks. RESULTS: Compared with treatment with montelukast, treatment with FP resulted in significantly greater improvements at endpoint in morning predose FEV(1) (22.9% vs 14.5%, P <.001), forced midexpiratory flow (0.66 vs 0.41 L/sec, P <.001), forced vital capacity (0.42 vs 0.29 L, P =.002), morning peak expiratory flow (PEF) (68.5 vs 34.1 L/min, P <.001), and evening PEF (53.9 vs 28.7 L/min, P <.001). Similar improvements in PEF were observed in patients with milder asthma (>70%-80% predicted FEV(1)). At endpoint, FP was more effective than montelukast at decreasing rescue albuterol use (3.1 puffs/day vs 2.3 puffs/day, P <.001), asthma symptom scores (-0.85 [48.6% decrease] vs -0.60 [30.5%], P <.001), and nighttime awakenings due to asthma (-0.64 awakenings/night [62% decrease] vs -0.48 awakenings/night [47.5%], P =.023), and FP increased the percentage of symptom-free days (32.0% vs 18.4% of days, P <.001) compared with montelukast. The adverse event and asthma exacerbation profiles for FP and montelukast were similar. CONCLUSIONS: Low-dose FP is more effective than montelukast as first-line maintenance therapy for patients with persistent asthma who are undertreated and remain symptomatic while taking short-acting beta2-agonists alone.     

Effect of fluticasone propionate and salmeterol in a single device, fluticasone propionate, and montelukast on overall asthma control, exacerbations, and costs.

BACKGROUND: Inhaled corticosteroids are the most effective class of anti-inflammatory agents and are recommended for patients with persistent asthma. OBJECTIVE: To compare the effectiveness of (1) fluticasone propionate, 100 microg, and salmeterol, 50 microg; (2) fluticasone propionate, 100 microg; and (3) montelukast, 10 mg, as first-line maintenance treatment for persistent asthma. METHODS: Combined analysis of 4 clinical trials, 2 that compared fluticasone propionate-salmeterol with montelukast and 2 that compared fluticasone propionate with montelukast as initial asthma therapy. RESULTS: The 4 studies had a total of 1,910 patients 15 years or older with symptomatic asthma previously treated with inhaled short-acting beta2-agonists alone. At the end point, there were significantly greater increases in forced expiratory volume in 1 second with fluticasone propionate-salmeterol (0.57 L; P < or = .004) vs fluticasone propionate (0.48 L) and montelukast (0.31 L) and significantly greater increases in morning peak expiratory flow rate (84.9 L/min; P < .001) vs fluticasone propionate (56.0 L/min) and montelukast (36.1 L/min). Fluticasone propionate-salmeterol significantly increased the percentage of symptom- and rescue-free days and significantly reduced albuterol use vs fluticasone propionate and montelukast (P < or = .04 for both). Patients treated with fluticasone propionate and montelukast had 2.6 and 3.6 greater risk, respectively, of having an asthma-related exacerbation vs fluticasone propionate-salmeterol users. In addition, mean daily exacerbation costs per treated patient were dollars 0.41 for fluticasone propionate-salmeterol, dollars 4.60 for fluticasone propionate, and dollars 7.57 for montelukast, whereas mean daily costs per patient exacerbation for fluticasone propionate-salmeterol, fluticasone propionate, and montelukast were dollars 29, dollars 128, and dollars 154, respectively. CONCLUSIONS: Patients with symptomatic asthma previously treated with short-acting beta2-agonists only who require maintenance therapy are likely to have greater clinical benefits, lower risk of an asthma exacerbation, and reduced exacerbation-related costs when initiating therapy with fluticasone propionate-salmeterol vs fluticasone propionate or montelukast.