Effects of ciclesonide and fluticasone on cortisol secretion in patients with persistent asthma.

We compared the systemic and clinical effects of ciclesonide (CIC) and fluticasone propionate (FP) administered, in addition to CIC 160 microg x day(-1) and salmeterol 50 microg twice daily, in 32 patients with persistent asthma using a randomised double-blind, placebo-controlled, double-dummy, five-period crossover design. All patients exhibited a provocative concentration leading to a 20% decrease in forced expiratory volume in 1 s (PC(20)) methacholine <8 mg x mL(-1) and a PC(20) adenosine <60 mg x mL(-1). Primary outcome was 24-h serum cortisol suppression after 7 days. Secondary outcomes were changes in PC(20) methacholine and adenosine after 9 days. FP 500 microg x day(-1) and 1,000 microg x day(-1) significantly suppressed cortisol secretion versus placebo by -46.2 (95% confidence interval (CI) -83.8- -8.5) nmol x L(-1) and by -76.1 (95% CI -112.9- -39.3) nmol x L(-1), respectively. Neither dose of CIC (320 nor 640 microg x day(-1)) had a significant suppressive effect (-28.2 (95% CI -65.5-9.2) nmol x L(-1) and -37.3 (95% CI -74.7-0.0) nmol x L(-1), respectively). Differences between FP 1,000 microg x day(-1) and both CIC treatments were statistically significant (CIC 320 microg x day(-1): -48.0 (95% CI -84.8- -11.1) nmol x L(-1); CIC 640 microg x day(-1): -38.8 (95% CI -75.7- -1.9) nmol x L(-1)). Compared with placebo, the increase in PC(20) adenosine after the four treatments was small, but significant. Greater improvements in PC(20) adenosine were seen with FP 500 microg x day(-1) (1.8 (95% CI 1.0-2.6) doubling concentrations) compared with CIC 320 microg x day(-1) (0.9 (95% CI 0.1-1.7) doubling concentrations). No significant difference was seen between CIC 640 microg x day(-1) and FP 1,000 microg x day(-1). For a similar decrease in hyperresponsiveness, cortisol secretion was suppressed significantly with moderate-to-high doses of fluticasone propionate, but not with ciclesonide.

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.

A comparative study of inhaled ciclesonide 160 microg/day and fluticasone propionate 176 microg/day in children with asthma.

Ciclesonide (CIC) is an inhaled corticosteroid (ICS) with high anti-inflammatory activity and low incidence of local and systemic adverse effects. The objective of this study was to compare the efficacy and safety of CIC with fluticasone propionate (FP) in children and adolescents with persistent asthma. This was a 12-week, randomized, double blind, parallel-group study. After a 2-to 4-week baseline period, a total of 556 children (ages 6-15 years) with asthma (forced expiratory volume in 1 sec [FEV(1)], 50% to 90% predicted) were treated twice daily with CIC 80 microg (ex-actuator, equivalent to 100 microg ex-valve) or FP 88 microg (ex-actuator, equivalent to 100 microg ex-valve) administered via a hydrofluoroalkane-propelled metered-dose inhaler. A statistically significant increase from baseline was observed in FEV(1) for both CIC (285 +/- 16 ml) and FP (285 +/- 15 ml) (P < 0.0001 for both) and in morning and evening peak expiratory flow (P < 0.0001 for both). Significant improvements were seen in asthma symptoms, use of rescue medication, and asthma symptom-free days in both treatment groups, without any differences between the treatment groups in changes from baseline. Two FP-treated patients experienced oral candidiasis and one patient experienced voice alteration. Creatinine-adjusted 24-hr urine cortisol levels increased from baseline levels by 10% in the CIC group (P < 0.05) and by 6% in the FP group (not significant). The efficacy and safety of CIC 160 microg/day were comparable to those of FP 176 microg/day in children with asthma.

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.

Processing of noise by single units of the inferior colliculus of the bar Rhinolophus ferrumequinum.

For inferior colliculus units the response patterns and the thresholds for pure tones and noise of variable bandwidth were determined. In a threshold-bandwidth plot the noise thresholds usually fell along two regression lines whose point of intersection established the size of the neuronal critical bandwidth (nCB). The relevance of the small nCBs (0.2-0.4 kHz) obtained for the frequency range of the constant frequency part of the orientation call is discussed. No fixed relation was found either between the nCBs and the neuronal critical ratios or between the size of nCB and the width of the tuning curve 3 dB above threshold of the best frequency.

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.

Comparison of twice-daily inhaled ciclesonide and fluticasone propionate in patients with moderate-to-severe persistent asthma.

OBJECTIVE: To investigate the relative efficacy of ciclesonide and fluticasone propionate (FP) administered at comparable microgram doses in maintaining asthma control in patients with moderate-to-severe persistent asthma. METHODS: This randomized, open-label, parallel-group study enrolled patients aged 12-75 years with a 6-month history of bronchial asthma. To enter a 2-week run-in period, patients had to have received FP 500-1000 microg/day or equivalent at a stable dose for 4 weeks and have a forced expiratory volume in 1s (FEV 1) 80% of predicted. To enter the treatment period, patients had to have the following during run-in: FEV 1 80% of predicted; reversibility of Delta FEV 1 12% after 200-400 microg salbutamol; and 1 day without asthma symptoms during the last 7 days. Patients were randomized to twice-daily ciclesonide 320 microg (ex-actuator) or twice-daily FP 330 microg (ex-actuator) for 6 months. Efficacy was assessed by lung function, asthma exacerbations, asthma symptoms and rescue medication use. Patients completed the standardized version of the Asthma Quality of Life Questionnaire (AQLQ[S]). Adverse events (AEs), including local oropharyngeal AEs, were recorded. RESULTS: 528 patients were randomized (ciclesonide, n=255; FP, n=273). In both groups, FEV 1 was maintained from baseline to study end (mean increase: ciclesonide 11 mL, FP 24 mL; intention-to-treat [ITT] analysis). The least squares mean+/-standard error of the mean for the treatment difference was -13+/-29 (95% confidence interval [CI]: -70, 44) in the ITT analysis and -27+/-34 (95% CI: -93, 40) in the per-protocol (PP) analysis, demonstrating non-inferiority of ciclesonide to FP. Morning, evening and site-measured PEF improved significantly with both treatments (ITT and PP analyses: p<0.05). Six patients receiving ciclesonide and seven receiving FP (ITT analysis) experienced an asthma exacerbation requiring treatment with oral corticosteroids. Both treatments significantly decreased asthma symptom score sum (ITT and PP analyses: p0.0001) and rescue medication use (ITT and PP analyses: p<0.05), with no significant difference between treatments. Both treatments significantly improved overall AQLQ(S) score (ITT and PP analyses: p<0.05). Significantly more patients experienced candidiasis and dysphonia with FP compared with ciclesonide (p=0.0023). CONCLUSION: Ciclesonide 320 microg and FP 330 microg administered twice daily over 6 months provided similar efficacy in patients with moderate or severe persistent asthma previously well-controlled by high doses of ICS at baseline. Ciclesonide was associated with fewer local AEs than FP.

Maintenance of asthma control by once-daily inhaled ciclesonide in adults with persistent asthma.

BACKGROUND: Inhaled corticosteroids (ICS) are recommended therapy for persistent asthma, although side effects can limit appropriate use. Ciclesonide, a novel ICS, is activated in the lung, thereby reducing systemic activity and side effects. This 12-week, double-blind, randomized, parallel-group, placebo-controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma. METHODS: After a 2-week baseline period in which current ICS treatment was continued, 329 patients were randomized to receive ciclesonide 160 microg (n = 107) or 640 microg (n = 112) (ex-actuator doses, equivalent to 200 and 800 microg ex-valve, respectively), or placebo (n = 110) once daily in the morning. Efficacy was monitored by asthma symptom scores, rescue medication use, morning and evening peak expiratory flow (PEF) measurements, spirometry, and probability of study completion without experiencing lack of efficacy. RESULTS: Morning PEF remained stable with either ciclesonide dose but decreased with placebo; the differences were significant (P < 0.0001) for both ciclesonide doses vs placebo. The forced expiratory volume in 1 s and forced vital capacity decreased significantly with placebo (P < 0.005), but were unchanged with ciclesonide. Lack of efficacy was significantly greater for patients switched to placebo (63%) than it was for those treated with ciclesonide 160 microg (30%) (P < 0.0001 vs placebo) or ciclesonide 640 microg (31%) (P < 0.0001 vs placebo). There were no significant differences between the two tested doses of ciclesonide with respect to efficacy and safety. Serum and 24-h urine cortisol were unaffected by ciclesonide treatment. Both doses of ciclesonide were well tolerated with no cases of oral candidiasis. CONCLUSION: Ciclesonide (160 or 640 microg) once daily in the morning effectively maintains asthma control, does not affect cortisol levels, and has an adverse event profile comparable with placebo in adults with primarily mild to moderate asthma.

[Effect of ebrantil, a new antihypertensive agent, on lipid metabolism and electrolyte balance]. / Fettstoffwechsel und Elektrolyt-Haushalt unter Ebrantil, einem neuen Antihypertonikum.

The influence of Ebrantil on serum electrolytes, lipids, and lipoproteins was studied in 8 normotensives and 10 hypertensives. For this purpose, Ebrantil sustained-release capsules were administered after a 7-10 day diet phase concomitantly with the diet for a period of 2 weeks. Before and after the diet phase, as well as subsequent to the treatment period, laboratory parameters were determined in fasting blood. The serum levels of sodium, potassium, calcium, and magnesium were identical at all measuring times. The concentrations of triglycerides, phospholipids, total cholesterol, VLDL-, LDL-, HDL-cholesterol, and of the apolipoproteins AI, AII and B measured in all patients at the end of the treatment period deviated only slightly from those determined in the diet phase. The mean value for the arteriosclerosis index LDL/HDL decreases significantly during treatment. The results reveal that Ebrantil has no negative influence on electrolyte balance and lipometabolism.

Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma.

Zardaverine is a newly developed selective phosphodiesterase III and IV inhibitor. This study investigates the bronchodilatory properties of zardaverine, administered by inhalation. Twelve patients with reversible bronchial obstruction (increase in forced expiratory volume in one second (change FEV1 % predicted) at least 15% after 200 micrograms salbutamol, median age 31 yrs, range 21-54 years) entered the double-blind, crossover study. Four puffs of either zardaverine (total dose 6 mg) or placebo were inhaled at 15 min intervals. Pulmonary function (specific airway conductance (sGaw) and FEV1 was measured by body plethysmography at regular intervals (5 and 12 min after each puff and, in addition, 30, 60, 120, 180 and 240 min after the last puff). Compared to placebo, sGaw and FEV1 increased significantly during the first hour of repeated inhalations, but not during the entire observation period of almost 5 h. The maximum mean difference between zardaverine and placebo for FEV1 was 0.3 l or 12% and occurred approximately 1 h after inhalation of the first puff. In seven patients FEV1 increased by > 15%. The duration of action varied considerably between patients. Three patients complained of side-effects (headache, drowsiness, vertigo, nausea), and one of these dropped out of the study due to vomiting. We conclude that inhalational administration of zardaverine has a modest and short-lasting bronchodilating activity.

The muscarinic M1-receptor-selective antagonist, telenzepine, had no bronchodilatory effects in COPD patients.

In a double-blind, placebo-controlled, randomized, cross-over trial, we studied the effects of the muscarinic M1-receptor-selective antagonist (+/-)-telenzepine (3 mg orally at 6 p.m. for 5 days) in 21 patients with chronic obstructive pulmonary disease (COPD). At enrollment all patients showed at least a 50% decrease in airway resistance (Raw) after inhalation of 400 micrograms fenoterol or 200 micrograms oxitropium bromide. Telenzepine did not have a significant effect on forced expiratory volume in one second (FEV1) or forced vital capacity (FVC). Also, no significant changes could be detected in daily spirometric profiles or Raw. The results indicate that short-term treatment with the M1-selective antagonist, telenzepine, does not improve airway function in COPD patients, at least after administration by the oral route.

Effect of ciclesonide on allergen challenge in subjects with bronchial asthma.

BACKGROUND: The aim of this clinical trial was to investigate whether repeated inhalation of the new inhaled steroid ciclesonide reduces the early-phase (EAR) and late-phase (LAR) reactions after allergen challenge in patients with mild allergic asthma. Also, this study provides further data on safety and tolerance of ciclesonide. METHODS: The study was designed as a double-blind placebo-controlled randomized crossover trial. Following a baseline period, patients were randomized to either of two treatment sequences (ciclesonide/placebo, placebo/ciclesonide) each of which lasted for one week and were separated by 3-5 weeks from the alternate treatment sequence. Patients received 800 micro g ciclesonide twice daily by means of a Cyclohaler. At the end of each treatment patients were subjected to an allergen challenge. RESULTS: Thirteen asthmatic patients (mean FEV1 of 91% predicted) who experienced an EAR and LAR after allergen challenge participated in the study. The time-average FEV1 decreases 0-2 h (2-12 h) after allergen challenge as measure of the EAR (LAR) were significantly reduced (P < 0.05, one-sided) from 0.426 L to 0.233 L (EAR) and from 0.443 L to 0.213 L (LAR), respectively. Thus, the study results suggest that ciclesonide significantly lowered the extent of EAR and LAR compared to placebo. Ciclesonide was well tolerated and no drug-related adverse events were reported. Cortisol excretion in 24-h urine showed no significant difference between ciclesonide and placebo. CONCLUSIONS: The study supports the efficacy and safety of ciclesonide.

Effect of slow-release theophylline on nasal antigen challenge in subjects with allergic rhinitis.

It has been recognized recently that theophylline possesses anti-inflammatory effects that could be of clinical interest in patients with airway inflammatory diseases such as asthma and allergic rhinitis (AR). The aim of the present study was to explore the effect of theophylline on the nasal eosinophilic inflammatory response following allergen challenge in patients with AR. Fourteen subjects suffering from seasonal rhinitis with an early reaction after nasal allergen provocation were challenged outside the pollen season after pretreatment for 3 weeks with placebo or slow-release theophylline (Euphylong in a randomized double-blind, cross-over study. Nasal blocking index (NBI), nasal airway resistance and symptoms were recorded before, and 1 and 5 h after challenge; additionally, nasal lavage fluid was collected before, as well as 1 and 5 h after challenge. Eosinophil cationic protein (ECP) was measured in the lavage as well as the number of eosinophils before, and 1 h and 5 h after allergen challenge. After 3 weeks of treatment, baseline concentrations of ECP in nasal lavage amounted to 826+/-329 ng x L(-1) (placebo) and 936+/-351 ng x L(-1) (theophylline). The ECP levels did not increase during the early phase response. Five hours after challenge, ECP in the placebo group increased markedly (p<0.01), whereas no significant increase was observed during theophylline treatment. In parallel, the number of eosinophils in the nasal lavage fluid was lower during theophylline treatment. Additionally, theophylline therapy also significantly reduced the nasal symptoms and had some protective effect against nasal obstruction following allergen challenge. These results confirm the anti-inflammatory effects of theophylline and suggest that these effects may be of clinical benefit in patients with allergic rhinitis.

A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients.

Inhaled corticosteroids decrease airway responsiveness in asthma partly through suppression of airway inflammation. We have previously demonstrated that inhaled budesonide reduced airway responsiveness to the mast cell stimulus adenosine-5'-monophosphate (AMP) to a threefold greater extent than to methacholine and sodium metabisulfite, suggesting that AMP responsiveness may be a more sensitive marker of airway inflammation and steroid action in order to assess a dose-response relationship. To investigate this, we studied the effects of three doses of the novel corticosteroid ciclesonide (50 micrograms, 200 micrograms, and 800 micrograms) inhaled as a dry powder twice daily on airway responsiveness to AMP and inflammatory parameters in induced sputum. In a three-parallel-dose group, double-blind, placebo-controlled, randomized, crossover study, with a washout period of 3 to 8 wk, a total of 29 patients with mild to moderate allergic asthma underwent AMP challenge and sputum induction before and after 14 d of treatment with ciclesonide or matched placebo. Compared with placebo, ciclesonide 100 micrograms, 400 micrograms, and 1,600 micrograms daily reduced airway responsiveness to AMP by 1.6 (95% confidence interval [CI], -0.1 to 3.4, not significant [NS]), 2.0 (95% CI, 0.4 to 3.6, p < 0.05), and 3.4 (95% CI, 2.3 to 4. 4, p < 0.05) doubling doses, respectively, and this reduction in airway responsiveness was dose-dependent (p = 0.039). A significant reduction in the percentage of eosinophils in induced sputum was observed after 400 micrograms and 1,600 micrograms daily ciclesonide (p < 0. 05), but this was not dose-dependent. Sputum eosinophil cationic protein (ECP) was significantly reduced after 400 micrograms daily ciclesonide only (p < 0.05). Thus, in patients with mild to moderate asthma, assessment of airway responsiveness to AMP, rather than inflammatory parameters in induced sputum, represents a sensitive method to evaluate a dose-response relationship of an inhaled corticosteroid and may have applications in evaluating other novel inhaled corticosteroids.