Intranasal ciclesonide coadministration with inhaled fluticasone propionate-salmeterol does not suppress cortisol in allergic rhinitis patients.

Intranasal and inhaled corticosteroid administration concurrently in comorbid allergic rhinitis (AR) and asthma may potentially enhance cortisol suppression. This study determined whether intranasal ciclesonide 200 micro g once daily has an additional effect on cortisol suppression when coadministered with inhaled fluticasone propionate-salmeterol (FP-SAL) 500 to 50 micro g twice daily. Adults (N = 150) with perennial AR received FP-SAL and placebo nasal spray during the run-in period. Patients were randomized to ciclesonide or placebo and FP-SAL (43 days). A single 2-mg dose of dexamethasone was administered on the last treatment day. Plasma cortisol decreased during run-in period (p < 0.001), indicating cortisol suppression by FP-SAL. After ciclesonide was added to FP-SAL, plasma cortisol was similar in both groups. Dexamethasone decreased mean plasma cortisol (p < 0.001), demonstrating that further suppression was possible. Ciclesonide coadministered with FP-SAL did not have an additive effect on cortisol suppression compared with FP-SAL.     

Intranasal Ciclesonide Coadministration with Inhaled Fluticasone Propionate-Salmeterol does not Suppress Cortisol in Allergic Rhinitis Patients

Intranasal and inhaled corticosteroid administration concurrently in comorbid allergic rhinitis (AR) and asthma may potentially enhance cortisol suppression. This study determined whether intranasal ciclesonide 200 μ g once daily has an additional effect on cortisol suppression when coadministered with inhaled fluticasone propionate-salmeterol (FP-SAL) 500 to 50 μ g twice daily. Adults (N = 150) with perennial AR received FP-SAL and placebo nasal spray during the run-in period. Patients were randomized to ciclesonide or placebo and FP-SAL (43 days). A single 2-mg dose of dexamethasone was administered on the last treatment day. Plasma cortisol decreased during run-in period (p < 0.001), indicating cortisol suppression by FP-SAL. After ciclesonide was added to FP-SAL, plasma cortisol was similar in both groups. Dexamethasone decreased mean plasma cortisol (p < 0.001), demonstrating that further suppression was possible. Ciclesonide coadministered with FP-SAL did not have an additive effect on cortisol suppression compared with FP-SAL.     

Effects of inhaled ciclesonide and fluticasone propionate on cortisol secretion and airway responsiveness to adenosine 5'monophosphate in asthmatic patients

The efficacy and systemic effects of ciclesonide, a novel glucocorticosteroid, inhaled via pressurized metered-dose inhaler (pMDI) were compared with fluticasone propionate pMDI in 26 patients with asthma, using a randomized, double blind, placebo-controlled, double dummy, 6-period crossover study design. Treatments were placebo, ciclesonide 320 microg (ex-actuator dose) once daily (o.d.), ciclesonide 640 microg o.d., ciclesonide 640 microg twice daily (b.i.d.), fluticasone propionate 440 microg (ex-actuator dose) b.i.d., and fluticasone propionate 880 microg b.i.d. The primary variable was area under the plasma cortisol concentration-time curve over 24 h (plasma cortisol AUC(0-24), relative to placebo) derived from samples taken every 2 h, on the 9th day of treatment. Secondary variables were 24-h urinary cortisol excretion and PC20 for adenosine 5'-monophosphate (AMP) (relative to placebo and expressed in doubling concentrations). Ciclesonide did not affect 24-h cortisol secretion. Fluticasone propionate suppressed cortisol secretion as demonstrated by a decrease in plasma cortisol AUC(0-24), relative to placebo, by 29% (95% CI 15-41) and 59% (95% CI 51-66) with 440 and 880 microg b.i.d., respectively. PC20 more than doubled with each active treatment, but no statistically significant dose-response effect could be established. It was concluded that moderate to high doses of fluticasone propionate suppressed cortisol secretion, that ciclesonide did not suppress cortisol secretion, and that all active treatments decreased hyperresponsiveness to AMP.     

Once-daily ciclesonide 80 or 320 microg for 12 weeks is safe and effective in patients with persistent asthma

The efficacy and safety of ciclesonide was assessed in this randomized, placebo-controlled study in patients with persistent asthma (randomized n=360) maintained on low to moderate doses of inhaled corticosteroids. Patients were randomized to receive ciclesonide 80 or 320 microg (ex-actuator doses, equivalent to 100 and 400 microg ex-valve, respectively) or placebo once daily in the morning via metered-dose inhaler for 12 weeks. Morning peak expiratory flow was maintained throughout the treatment period in patients treated with ciclesonide and decreased significantly in patients treated with placebo (P=0.0003). Ciclesonide (80 and 320 microg) significantly increased forced expiratory volume in 1s from baseline (0.13 and 0.19 L increases, respectively; P<0.01); improvements were superior versus placebo (P=0.0044 for 80 microg ciclesonide; P<0.0001 for 320 microg ciclesonide). The probability of losing efficacy decreased in a dose-dependent manner (55% for placebo, 38% for ciclesonide 80 microg, 23% for ciclesonide 320 microg). Asthma symptom scores and rescue medication use were unchanged with ciclesonide and significantly worsened with placebo. The incidence of adverse events was comparable in all treatment groups and no cortisol suppression was observed. Therefore, ciclesonide 80 and 320 microg administered once daily was a safe and effective maintenance treatment for patients with persistent asthma.     

Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide

The new inhalative glucocorticoid ciclesonide which is activated in lung to a more potent metabolite was hypothesized to have low risk for systemic and local side-effects in man. Therefore, a placebo-controlled, randomized, double-blind, four-period, change-over equivalence study in 12 healthy male volunteers (age 21-28 yr, body weight 62-90 kg) was conducted to assess the influence of three dosage regimens (800 microg in the morning, 800 microg in the evening, 400 microg twice daily for 7 d, metered inhalers) on the circadian time serum cortisol rhythm. RESULTS: Serum cortisol showed the typical circadian rhythm. The geometric mean of the 24-h mesor (AUC((0-24 h))/24 h) was 7.22 microg/dl for placebo, 6.75 microg/dl for the 800 microg ciclesonide morning dose, 7.08 microg/dl for the 800 microg evening dose, and 6.75 microg/dl for 400 microg ciclesonide inhaled twice daily. Because there was also no influence on cortisol amplitude and acrophase (time of maximum), the profiles after ciclesonide were equivalent to the placebo control. The small differences were considered not to be of clinical significance. In conclusion, inhaled ciclesonide in daily doses of 800 microg for 7 d is without clinically relevant effects on the hypothalamic-pituitary-adrenal axis independent of the time of administration.     

Comparison of hydrofluoroalkane-beclomethasone dipropionate Autohaler with budesonide Turbuhaler in asthma control.

BACKGROUND: Hydrofluoroalkane-beclomethasone dipropionate Autohaler (HFA-BDP AH) is a breath-actuated chlorofluorocarbon (CFC)-free metered dose inhaler in which BDP is in a solution of HFA propellant. Budesonide Turbuhaler (BUD TH) is a breath-dependent dry powder inhaler. OBJECTIVES: To test the hypothesis that half the daily dose of HFA-BDP AH would provide an equivalent control of asthma symptoms to the BUD TH. METHODS: This was an 8-week open study in patients with symptomatic moderate-to-severe asthma, previously on BUD 500-1,000 microg x day(-1), or an equivalent. After 5-14 days' run-in, patients were randomized to HFA-BDP AH 800 microg x day(-1) or BUD TH 1,600 microg x day(-1). The intent-to-treat population consisted of 111 patients on HFA-BDP AH and 98 patients on BUD TH. RESULTS: Mean change from baseline in PEF in the morning (AM PEF) at week 8 was 23.95 liters x min(-1) for HFA-BDP AH and 24.46 liters x min(-1) for BUD TH. A two-sided equivalence test using the 0.51 liter x min(-1) difference gave 95% confidence intervals within a defined equivalence interval of (-infinity, 25 liters x min(-1)) indicating that the mean change in AM PEF was equivalent for the two groups. There were no significant differences in the mean change from baseline in FEV1 or beta-agonist use. Patients using HFA-BDP AH had a significantly greater mean change from baseline in the percentage of days free from shortness of breath (p = 0.05), chest tightness (p = 0.02) and nights without sleep disturbance (p = 0.04) at week 3, and wheeze (p = 0.01), shortness of breath (p = 0.02), chest tightness (p < 0.01) and daily asthma symptoms (p = 0.03) at week 8. The incidence, type and severity of adverse events were similar in each group. At week 8, the mean change from baseline in corrected urine cortisol/creatinine ratio in a subgroup of patients was -0.36 for HFA-BDP and -4.88 for BUD TH (p < 0.01). CONCLUSIONS: HFA-BDP 800 microg x day(-1) provided control of moderate-to-severe asthma with efficacy and safety at least similar to BUD TH 1,600 microg x day(-1).     

Formoterol (Foradil) and medium-high doses of inhaled corticosteroids are more effective than high doses of corticosteroids in moderate-to-severe asthma

This double-blind, randomised, multi-centre, parallel-group study compared the effect of adding Foradil (formoterol fumarate) to existing medium-high doses of inhaled corticosteroids (ICS) with that of doubling the dose of ICS in patients with sub-optimally controlled asthma.After a run-in period, 203 patients with moderate-to-severe asthma who remained symptomatic despite treatment with 500 microg beclomethasone twice daily, were randomised to receive either 12 microg formoterol twice daily (Foradil Aerolizer), Novartis) in addition to beclomethasone 500 microg twice daily, or beclomethasone 1000 microg twice daily and placebo for 12 weeks. The primary efficacy variable was mean morning pre-medication peak expiratory flow (PEF) during the last seven days of treatment.The difference in PEF between treatments was 27.78 l/min in favour of the formoterol/beclomethasone combination (95% CI 13.42, 42.14 l/min, p=0.0002, intention-to-treat population). Significant differences in the urinary cortisol/creatinine ratio between treatment groups at 12 weeks (p=0.001) indicated suppression of the hypothalamic-pituitary-adrenal axis in the patients on beclomethasone 1000 microg twice daily.The addition of formoterol 12 microg twice daily to beclomethasone in patients with asthma who were poorly controlled with beclomethasone 500 microg twice daily was more effective than doubling the ICS dose and resulted in less suppression of the hypothalamic-pituitary-adrenal axis.     

Efficacy and safety of beclomethasone dipropionate extrafine aerosol in childhood asthma: a 12-week,randomized, double-blind,placebo-controlled study

BACKGROUND: Beclomethasone dipropionate (BDP) has been formulated as an extrafine aerosol (hydrofluoroalkane-134a [HFA]-BDP) [QVAR; 3M Pharmaceuticals; St Paul, MN], which gives improved lung deposition compared with chlorofluorocarbon (CFC)-BDP. The clinical efficacy of HFA-BDP has been established in adult asthma at a required dose below that of CFC-BDP, but has not been evaluated in children. OBJECTIVE: To examine the efficacy and safety of HFA-BDP in childhood asthma. DESIGN: A 12-week, multicenter, randomized, double-blind, placebo-controlled, parallel-group study involving 353 children aged 5 to 12 years with moderate, symptomatic asthma. After a 2-week run-in period, patients were randomized to HFA-BDP, 80 micro g/d (n = 120); HFA-BDP, 160 micro g/d (n = 117); or HFA-placebo (n = 116) administered twice daily. SETTING: Hospital outpatient. RESULTS: HFA-BDP, 80 micro g/d and 160 micro g/d, produced a significant, dose-related increase from baseline in FEV(1) percent predicted compared with placebo. At week 12, mean changes from baseline in FEV(1) percent predicted were 9.2% (p < or = 0.01 vs placebo), 10% (p < or = 0.01 vs placebo), and 3.9% for the HFA-BDP 80 micro g/d, HFA-BDP 160 micro g/d, and placebo groups, respectively. There was also a significant decrease in daily beta-agonist use, improvement in peak expiratory flow, and increase [correction] in the percentage of days free from asthma symptoms (p < or = 0.05 for HFA-BDP, 160 micro g/d, vs placebo at weeks 11 to 12). HFA-BDP was well tolerated, with no significant differences in the incidence or nature of adverse events between HFA-BDP and placebo groups. Neither were there significant differences between groups in mean percentage change from baseline in the morning plasma cortisol level at week 12 or in the percentage of patients with morning plasma cortisol levels below the reference range at baseline and week 12. In a subgroup tested, the percentage of patients with an abnormal response to low-dose adrenocorticotropic hormone stimulation at week 12 was low and similar among all groups. CONCLUSIONS: HFA-BDP, 80 to 160 micro g/d, is effective and safe in childhood asthma.     

Randomized comparison of the efficacy and safety of ciclesonide and budesonide in adolescents with severe asthma

BACKGROUND: The aim of the study was to investigate the efficacy and safety of ciclesonide compared with budesonide in adolescents with severe asthma. METHODS: In this randomized, double-blind, double-dummy, parallel-group study, patients aged 12-17 years with severe asthma were treated with budesonide 400 microg once daily (QD) in a 2-week run-in period. At randomization, eligible patients were assigned 2:1 to ciclesonide 320 microg QD (ex-actuator) or budesonide 800 microg QD (metered dose), respectively, in the evening. Forced expiratory volume in 1s (FEV(1)) was the primary variable. Patients recorded asthma symptom score and rescue medication use in diaries. Safety assessments included adverse events (AEs) and 24-h urine cortisol. RESULTS: Four hundred and three patients were randomized. Ciclesonide 320 microg QD and budesonide 800 microg QD significantly increased FEV(1) (least-squares mean: 505 and 536 mL, respectively; both p<0.0001 versus baseline) in the intention-to-treat (ITT) population. Lower limits of the 95% confidence intervals (ITT: -138 mL; per-protocol: -122 mL) were above the non-inferiority limit (-150 mL). Median percentage of days without asthma symptoms and without rescue medication use was 84% with ciclesonide and 85% with budesonide. AEs were unremarkable, with no cases of confirmed candidiasis. Median creatinine-adjusted urine cortisol significantly decreased with budesonide treatment (15.9-13.7 nmol cortisol/mmol creatinine; p=0.0086 versus baseline), but not with ciclesonide (p=0.1125). CONCLUSIONS: Ciclesonide 320 microg QD showed similar efficacy to budesonide 800 microg QD in adolescents with severe asthma. Ciclesonide was well tolerated and, unlike budesonide, had no effect on urine cortisol levels. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT No.: 2004-001233-41.     

Concurrent use of intranasal and orally inhaled fluticasone propionate does not affect hypothalamic-pituitary-adrenal-axis function.

Two double-blind, randomized, placebo-controlled, parallel group safety and efficacy studies included evaluation of the hypothalamic-pituitary-adrenal (HPA)-axis effects of concurrent treatment with intranasal and orally inhaled fluticasone propionate (FP). In the first study, patients with asthma who were > or =12 years of age were assigned randomly to receive twice-daily doses (either 88 or 220 microg) of orally inhaled FP delivered from a metered-dose inhaler (MDI). In the second study, patients were assigned randomly to receive either orally inhaled FP 250 microg or orally inhaled FP 250 microg/salmeterol 50 microg delivered via the Diskus device. In both studies, patients with rhinitis were allowed to continue the use of intranasal FP at their usual dosing. Treatment periods were 26 weeks and 12 weeks for the MDI and Diskus studies, respectively. HPA-axis effects were assessed using response to short cosyntropin stimulation testing. The number and percentage of patients with an abnormal cortisol response, defined as a morning plasma cortisol of <5 microg/dL, a poststimulation peak of <18 microg/dL, or a poststimulation rise of <7 microg/dL, were summarized in two subgroups: patients who used intranasal FP and those who did not. The concurrent administration of intranasal FP and orally inhaled FP via an MDI or Diskus or via Diskus with salmeterol was not associated with HPA-axis effects compared with orally inhaled FP alone. The results of these two studies suggest that concurrent use of intranasal FP with orally inhaled FP administered via MDI or Diskus for treatment of comorbid rhinitis and asthma does not increase the risk of HPA-axis abnormalities.     

Health-related quality of life in moderate asthma: 400 microg hydrofluoroalkane beclomethasone dipropionate vs 800 microg chlorofluorocarbon beclomethasone dipropionate. The Study Group

OBJECTIVE: To compare the effect of hydrofluoroalkane-134a (HFA) beclomethasone dipropionate (BDP; 400 microg/d) with that of chlorofluorocarbon (CFC) BDP (800 microg/d) on asthma health-related quality of life in a 12-week, parallel-group, multicenter study. BACKGROUND: HFA-BDP is a new CFC-free preparation of BDP, which was developed as a result of CFCs being phased out from metered dose inhalers. METHODS: Following 7 to 12 days of prednisone, 30 mg/d, 347 adults with moderate asthma were randomized to receive either 400 microg/d HFA-BDP, 800 microg/d CFC-BDP, or HFA placebo for 12 weeks (all other oral and inhaled steroids were withdrawn). Patients completed the Asthma Quality of Life Questionnaire (AQLQ), and clinical asthma status was measured at the end of a run-in period, at randomization (after oral steroid treatment), and at the end of the study treatment. RESULTS: Sixty-one patients withdrew, 43 due to worsening asthma (33 placebo; 5 HFA-BDP; 5 CFC-BDP). There was a deterioration in the AQLQ score (- 0.81) in the placebo group, and the difference between this and the stability observed in both the HFA-BDP group (+ 0.13) and the CFC-BDP group (- 0.03) was statistically significant (p 相似文献   

Hydrofluoroalkane-134a beclomethasone dipropionate, 400 microg, is as effective as chlorofluorocarbon beclomethasone dipropionate, 800 microg, for the treatment of moderate asthma

OBJECTIVE: The improved lung deposition of hydrofluoroalkane-134a beclomethasone dipropionate (HFA-BDP) extrafine aerosol compared with chlorofluorocarbon beclomethasone dipropionate (CFC-BDP) suggests that lower doses of HFA-BDP may be required to provide equivalent asthma control. The present study was undertaken to test this hypothesis. DESIGN: A 10- to 12-day run-in period confirmed that patients met established criteria of at least moderate asthma and the asthma was inadequately controlled by current therapy (inhaled beta-agonist and CFC-BDP [< or = 400 microg/d]). A short course of oral prednisone, 30 mg/d for 7 to 12 days, was followed to establish the patients were steroid responsive and to provide an "in-study" baseline of "optimal" asthma control. PATIENTS: A total of 347 patients were then randomized to HFA-BDP 400 microg/d, CFC-BDP 800 microg/d, or HFA-placebo for 12 weeks. RESULTS: Morning peak expiratory flow (AM PEF) measurements showed that HFA-BDP 400 microg/d achieved equivalent control of asthma to CFC-BDP 800 microg/d at all time intervals after oral steroid treatment. All other efficacy variables supported the AM PEF results and both active treatments were more effective than placebo. The safety profile of HFA-BDP compared favorably with that of CFC-BDP with no unexpected adverse events reported. CONCLUSIONS: These findings demonstrate that HFA-BDP provides equivalent control of moderate or moderately severe asthma as CFC-BDP in the population studied, but at half the total daily dose.     

Equivalent asthma control after dose reduction with HFA-134a beclomethasone solution aerosol. Comparative Inhaled Steroid Investigation Group (CISIG)

AIM: The replacement of chlorofluorocarbon (CFC) by hydrofluoroalkane has the potential to improve airway deposition of BDP. We investigated whether HFA-BDP extra-fine solution aerosol 400 microg day(-1) is as effective as CFC-BDP 1000 micro day(-1) in patients with stable, moderate asthma, having persistent bronchial hyperresponsiveness. PATIENTS AND METHODS: One hundred and fifty patients with moderate asthma from 20 centres, on inhaled steroids for < or = 3 months, entered a 4-week run-in period with 1000 microg day(-1) CFC-BDP. Patients were then allocated to a 10-week study phase, receiving CFC-BDP 1000 microg day(-1) or HFA-BDP 400 microg day(-1). Symptom score and PEF were measured daily and recorded as biweekly means. Spirometry, PC20FEV1, blood eosinophils and serum ECP were determined on days 15, 29, 43 and 71, and compared to the last visit of the run-in period. All group members were trained in a quality control centre. RESULTS: Treating the population of the HFA-BDP group (n = 72) and the CFC-BDP group (n = 78) did not show significant differences in terms of symptoms, lung function, airway hyperresponsiveness and serum markers of inflammation at the end of the run-in period and the end of the study phase. CONCLUSION: Using HFA instead of a CFC metered dose inhaler, containing less than half the daily dose of BDP, allows control of symptoms and lung function parameters, without changes in bronchial hyperresponsiveness.     

Adrenal suppression with dry powder formulations of fluticasone propionate and mometasone furoate

Mometasone furoate (MF) and fluticasone propionate (FP) are high potency inhaled corticosteroids. The systemic bioavailability of MF is claimed to be negligible, leading to a minimal potential for systemic adverse effects. We assessed the overnight urinary cortisol/creatinine as the primary outcome of adrenal suppression in 21 patients with persistent asthma (mean FEV1 = 91%). Patients were randomized in a crossover fashion to receive 2 weekly consecutive doubling incremental doses of either FP Accuhaler (500, 1,000, and 2,000 microg/day) or MF Twisthaler (400, 800, and 1,600 microg/day). For the 21 per protocol completed patients, there was significant suppression of overnight urinary cortisol/creatinine with high and medium doses of both drugs-as geometric mean fold suppression (95% confidence interval) from baseline: FP 2,000 microg, 1.85 (1.21-2.82, p = 0.002); FP 1,000 microg, 1.45 (1.07-1.96, p = 0.02); MF 1,600 microg, 1.92 (1.26-2.93, p = 0.001); and MF 800 microg, 1.39 (1.04-1.88, p = 0.02). For secondary outcomes of 8:00 A.M. plasma cortisol, serum osteocalcin, and early morning urinary cortisol/creatinine, there was significant suppression with MF and FP at the highest dose. Our data refute the assertion that MF has negligible systemic bioavailability and a lower potential for systemic adverse effects compared with FP.     

Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma

BACKGROUND: The aim of this study was to compare the efficacy and safety of once-daily ciclesonide, a new-generation, on-site-activated, inhaled corticosteroid, with once-daily budesonide in persistent asthma. METHODS: Eligible patients requiring budesonide or equivalent 320-640 microg (ex-mouthpiece, equivalent to 400-800 microg; Turbohalertrade mark) daily entered a 2-week baseline, and then a 2- to 4-week pretreatment period (budesonide 1280 microg/day; ex-mouthpiece, equivalent to 1600 microg/day). Patients with an increase in forced expiratory volume in 1s (FEV1) of 7% or 0.15 L were randomised to ciclesonide 320 microg (ex-actuator, equivalent to 400 microg ex-valve) via a hydrofluoroalkane-metered dose inhaler (HFA-MDI) without a spacer or budesonide 320 microg once daily in the morning for 12 weeks. Change in FEV1 was the primary endpoint. RESULTS: In all, 359 patients were randomised. The FEV1 and forced vital capacity (FVC) decreased by 0.18 and 0.12L, respectively, in the ciclesonide group, and by 0.23 and 0.21L in the budesonide group. For FEV1, ciclesonide was noninferior and numerically superior to budesonide. For FVC, ciclesonide was statistically superior to budesonide (P=0.010). Asthma symptom scores were comparable; the median percentage of symptom-free days was significantly higher for ciclesonide (43.6%) versus budesonide (25.8%) (P=0.017). Rescue medication use decreased significantly only for ciclesonide patients (P=0.009). Frequency of adverse events was low in both groups. CONCLUSION: Ciclesonide 320 microg once daily by HFA-MDI without a spacer was at least as effective as budesonide 320 microg once daily in persistent asthma.     

Randomized comparison of ciclesonide 160 and 640 microg/day in severe asthma

OBJECTIVE: Demonstrating clinical benefit of higher doses of inhaled corticosteroids in asthma is frequently problematic owing to their relatively flat dose-response curve in this condition. In this study we compared the efficacy and safety of a fourfold difference in the dose of ciclesonide-ciclesonide 320 microg twice daily (CIC640) versus ciclesonide 160 microg once daily (CIC160)-in patients with severe persistent asthma. METHODS: Patients with bronchial asthma (6 months) were included in this randomized, double-blind study. After receiving fluticasone propionate 250 microg twice daily during run-in, patients were randomized to CIC160 (n=339) or CIC640 (n=341) for 12 weeks. Primary endpoints were time to first asthma exacerbation and forced expiratory volume in 1s (FEV(1)). Secondary endpoints included other lung function variables, asthma symptom scores and rescue medication use (RMU). RESULTS: Asthma exacerbations occurred in 12.7% of patients receiving CIC160 and 6.7% receiving CIC640. CIC640 was superior for time to first exacerbation (p=0.0050, one-sided). FEV(1) increased significantly with CIC160 and CIC640 (least squares mean+/-SE of mean: 269+/-31 and 332+/-31 mL, respectively; p<0.0001), with no significant difference between groups. Change in % predicted FEV(1) and morning peak expiratory flow (PEF) were significantly higher with CIC640 (p<0.05). Asthma symptom score sums and RMU decreased in both groups; CIC640 was statistically superior (p=0.0108 and 0.0005, respectively). No unexpected adverse events were reported in either group and the majority of the events reported were mild or moderate in intensity. No significant changes in serum cortisol were observed from the baseline to the study end. Small decreases in creatinine-adjusted 24h urine cortisol levels from baseline were seen in both the treatment groups, which, due to the large patient numbers, were statistically significant (p<0.05); however, no dose-response effect was seen and the difference between groups was not significant (p=0.7892). CONCLUSION: CIC640 was superior to CIC160 for time to first exacerbation, % predicted FEV1, morning PEF, asthma symptom score sum and RMU in patients with severe asthma; both doses had similar tolerability profiles and no significant changes in serum cortisol were seen in either treatment group.     

Ciclesonide, a novel inhaled steroid, does not affect hypothalamic-pituitary-adrenal axis function in patients with moderate-to-severe persistent asthma

BACKGROUND: Inhaled corticosteroids (ICSs) reduce local airway inflammation, which is an underlying cause of asthma symptoms. However, potential systemic side effects associated with ICS use are a major concern for asthmatic patients. METHODS: Adult patients (n = 60; > or = 18 years of age) with moderate-to-severe asthma were randomized to receive 4 weeks of treatment with ciclesonide (CIC), 320 microg bid (CIC 640), CIC, 640 microg bid (CIC 1280), fluticasone propionate (FP), 440 microg bid (FP 880), FP 880 microg bid (FP 1760), or placebo (PBO) [all doses expressed as ex-actuator; comparable to ex-valve doses of 800 and 1,600 microg/d for CIC and 1,000 and 2,000 microg/d for FP, respectively]. RESULTS: After 29 days of treatment, CIC 640, CIC 1280, and FP 880 had no significant effect on the mean serum cortisol area under the curve for 0 to 24 h (AUC0-24h). FP 1760 produced a statistically significant suppression in mean serum cortisol AUC0-24h compared to PBO (p = 0.0009; 95% confidence interval [CI] -117.5 [corrected] to -32.1). Results obtained with cosyntropin stimulation revealed no statistically significant differences among the groups. The CIC 640 group demonstrated a significant increase compared to the PBO group in 24-h urinary cortisol levels from baseline at week 4 (p = 0.0224; 95% CI, 0.0023 to 0.0283), while the other treatment groups revealed no change in this parameter. The incidence of treatment-emergent adverse events was similar in all groups, and all adverse events were mild or moderate in severity. CONCLUSION: Treatment with moderate and high doses of CIC does not result in hypothalamic-pituitary-adrenal-axis suppression as compared with PBO.     

Dose-response evaluation of the therapeutic index for inhaled budesonide in patients with mild-to-moderate asthma

PURPOSE: Inhaled corticosteroids have beneficial effects on pulmonary function and inflammation in patients with asthma, but they also cause systemic adverse effects, such as adrenal suppression. We evaluated the therapeutic index of inhaled corticosteroids in asthmatic patients by comparing their dose-response effects on lung function, surrogate markers of airway inflammation, and tests of adrenal function. SUBJECTS AND METHODS: After a 10-day placebo run-in, we evaluated the effects of 200 microg, 400 microg, and 800 microg of inhaled budesonide, each dose given twice daily sequentially for 3 weeks in 26 patients, aged 35 +/- 12 years (mean +/- SD), with mild-to-moderate asthma. Measurements were made of bronchial reactivity, exhaled nitric oxide (a marker of airway inflammation), spirometry, serum eosinophilic cationic protein concentration, and 10-hour overnight urinary cortisol excretion. Plasma cortisol levels were measured at 8 AM and after stimulation with human corticotropin releasing factor. RESULTS: For measurements of pulmonary function and exhaled nitric oxide, there was a plateau in the mean response to budesonide between 400 microg (low dose) and 800 microg (medium dose) per day, whereas for eosinophilic cationic protein and bronchial challenge, maximal benefits occurred between 800 and 1,600 microg (high dose) per day. Effects on plasma cortisol levels showed maximal suppression at 1,600 microg of budesonide per day. The proportion of patients with an optimal therapeutic index, in terms of a good airway response (fourfold decrease in bronchial hyperreactivity) and minimal systemic response (overnight urinary cortisol greater than 20 nmol), was similar at low-dose (46%) and at high-dose (52%) budesonide. The proportion of patients with a suboptimal therapeutic index, a good airway response with a marked systemic response (overnight urinary cortisol greater than 20 nmol), increased from 4% at low dose to 38% at high dose. CONCLUSIONS: In patients with mild-to-moderate atopic asthma, there were dose-related effects of budesonide on surrogate markers of inflammation (bronchial hyperreactivity and serum eosinophilic cationic protein), although higher doses were associated with adrenal suppression and a decrease in the therapeutic index.     

Fluticasone furoate nasal spray: effective monotherapy for symptoms of perennial allergic rhinitis in adults/adolescents.

Intranasal corticosteroids are widely prescribed for the treatment of perennial allergic rhinitis (PAR). The purpose of this study was to evaluate the efficacy and tolerability of intranasal fluticasone furoate, a novel enhanced-affinity glucocorticoid, in patients > or =12 years of age with PAR in a global, randomized, double-blind, placebo-controlled, 6-week study. Patients (n = 302) received fluticasone furoate nasal spray (FFNS) 110 microg or vehicle placebo once daily (q.d.). The primary efficacy measure was mean change from baseline over the 6-week treatment period in daily reflective total nasal symptom score (TNSS). Secondary end points included mean change from baseline in total and individual reflective nasal and ocular symptom scores and in daily peak nasal inspiratory flow (PNIF). FFNS was significantly more effective than placebo in reducing daily reflective TNSS over the treatment period (least square [LS] mean difference, -1.256; p < 0.001). Significant improvements were also established in total ocular symptom score (LS mean difference, -0.506; p = 0.004 versus placebo) and in all individual nasal (p < 0.001) and ocular (p < 0.03) symptoms assessed in a reflective manner. Improvements in daily PNIF were significantly greater with FFNS than placebo (LS mean difference, 8.376 L/minute; p = 0.004). FFNS was well tolerated. In this study, FFNS 110 microg q.d. was well tolerated and effective in reducing the nasal and ocular symptoms of PAR in adult and adolescent patients > or =12 years of age.     

Does vitamin D administered to children with asthma treated with inhaled glucocorticoids affect short‐term growth or bone turnover?

Our objective was to assess whether administration of 25-OH-vitamin D to children with asthma treated with inhaled dry-powder budesonide 400 microg daily affects short-term growth or markers of bone turnover. We utilized a randomized, double-blind, two-period crossover trial with run-in and washout periods of 2 weeks and treatment periods of 4 weeks duration. The setting was an Outpatient clinic in a secondary referral center. Subjects included 14 boys and 3 girls with a mean age of 11.7 (range, 6.1-14.4) years. Interventions included 15 microg (600 IU) 25-OH-vitamin D (cholecalciferol) in one tablet ABCDin(R) once daily in the morning. Primary outcome measures were: lower leg growth rate, serum osteocalcin, and serum markers of type I collagen turnover, i.e., the amino terminal propeptide of type I procollagen (PINP), the carboxy terminal propeptide of type I procollagen (PICP) (formation markers), and the carboxy terminal pyridinoline cross-linked telopeptide of type I collagen (ICTP) (degradation markers). Secondary outcome measures were parameters of asthma control and serum 25-OH-vitamin D. Lower leg growth rate was 0.22 mm/week during vitamin D and 0.25 mm/week during placebo treatment (NS). Osteocalcin was 59.9 and 57.8 microg/l during vitamin D and placebo treatment, respectively, PINP 574 and 565 microg/l, PICP 381 and 382 microg/l, and ICTP 11.5 and 11.1 microg/l, respectively (NS). Serum 25-OH-vitamin D was 76.3 nmol/l and 48.2 nmol/l, respectively (P < 0.001). There were no statistically significant differences in measures of pulmonary function. In conclusion, administration of 25-OH-vitamin D does not affect short-term growth or markers of bone turnover in children with asthma treated with inhaled dry-powder budesonide 400 microg daily.