Airway and systemic effects of hydrofluoroalkane formulations of high-dose ciclesonide and fluticasone in moderate persistent asthma. Effect of ciclesonide on allergen challenge in subjects with bronchial asthma Treatment of asthma by the inhaled corticosteroid ciclesonide given either in the morning or evening. Maintenance of asthma control by once‐daily inhaled ciclesonide in adults with persistent asthma Comparison of the oropharyngeal deposition of inhaled ciclesonide and fluticasone propionate in patients with asthma. Lower oropharyngeal deposition of inhaled ciclesonide via hydrofluoroalkane metered-dose inhaler compared with budesonide via chlorofluorocarbon metered-dose inhaler in healthy subjects Effects of hydrofluoroalkane formulations of ciclesonide 400 microg once daily vs fluticasone 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma. Pharmacokinetics of [14C]Ciclesonide After Oral and Intravenous Administration to Healthy Subjects Circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid ciclesonide. A dose-dependent effect of the novel inhaled corticosteroid ciclesonide on airway responsiveness to adenosine-5'-monophosphate in asthmatic patients. Lung deposition of hydrofluoroalkane-134a beclomethasone is greater than that of chlorofluorocarbon fluticasone and chlorofluorocarbon beclomethasone : a cross-over study in healthy volunteers. Effect of inhaled ciclesonide on airway responsiveness to inhaled AMP, the composition of induced sputum and exhaled nitric oxide in patients with mild asthma.
BACKGROUND There are no data comparing the relative effects of high-dose ciclesonide ( CIC ) and fluticasone propionate ( FP ) on airway and systemic outcomes in patients with moderate persistent asthma . OBJECTIVE We elected to evaluate the relative effects of CIC and FP on the plasma cortisol response to stimulation with human corticotropin-releasing factor ( hCRF ) and bronchial hyperresponsiveness to methacholine as the primary outcome variables , in addition to secondary outcomes of overnight 10-h urinary cortisol ( OUC ) levels , exhaled nitric oxide levels , lung function , symptoms , and quality of life . METHODS Fourteen patients with moderate persistent asthma ( mean FEV(1 ) , 67 % predicted [ prior to each r and omized treatment ] ) completed the study , which had a r and omized , double-blind , double-dummy , crossover design , per protocol . Patients stopped receiving their usual inhaled corticosteroids for the duration of the study and instead began receiving salmeterol , 50 mug twice daily , and montelukast , 10 mg once daily , for the 2-week washout periods prior to each r and omized treatment , in order to prevent dropouts after withdrawal from inhaled corticosteroid therapy . Patients received 4 weeks of either CIC , 200 microg ex-valve ( 160 microg ex-actuator ) four puffs twice daily , plus FP-placebo , four puffs twice daily , or FP , 250 microg ex-valve ( 220 microg ex-actuator ) four puffs twice daily , plus CIC-placebo , four puffs twice daily . Salmeterol and montelukast were withheld for 72 h prior to each postwashout baseline visit , and CIC or FP was withheld for 12 h prior to each posttreatment visit . RESULTS FP , but not CIC , when compared to respective baseline values , significantly suppressed ( p < 0.05 ) plasma cortisol levels as follows : FP prior to receiving hCRF : geometric mean fold difference , 1.2 ; 95 % confidence interval ( CI ) , 1.1 to 1.3 ; CIC prior to receiving hCRF : geometric mean fold difference , 0.9 ; 95 % CI , 0.8 to 1.0 ; FP 30 min after receiving hCRF : geometric mean fold difference , 1.2 ; 95 % CI , 1.1 to 1.3 ; CIC 30 min after receiving hCRF : geometric mean fold difference , 1.0 ; 95 % CI , 0.9 to 1.2 ; OUC after FP administration : geometric mean fold difference , 1.9 ; 95 % CI , 1.4 to 2.6 ; OUC after CIC administration : geometric mean fold difference , 1.2 ; 95 % CI , 0.9 to 1.5 . There was also a significantly lower ( p < 0.05 ) mean value for OUC levels after FP administration than after CIC administration ( geometric mean fold difference , 1.5 ; 95 % CI , 1.1 to 2.0 ) . Therapy with CIC and FP , compared to respective baselines , significantly increased ( p < 0.05 ) the provocative concentration of methacholine causing a 20 % fall in FEV(1 ) , as follows : CIC : doubling dilution difference , 0.8 ; 95 % CI , 0.1 to 1.6 ; FP : doubling dilution difference , 1.0 ; 95 % CI , 0.1 to 2.0 . It also significantly reduced ( p < 0.05 ) exhaled nitric oxide levels , as follows : CIC : geometric mean fold difference , 1.2 ; 95 % CI , 1.1 to 1.3 ; FP : geometric mean fold difference , 1.9 ; 95 % CI , 1.3 to 2.8 . There was no effect on other secondary efficacy outcomes . CONCLUSION FP , 2,000 microg daily , but not CIC , 1,600 microg daily , significantly suppressed hypothalamic-pituitary-adrenal axis outcomes , with OUC levels being lower after FP administration than after CIC administration . Both drugs significantly improved airway outcomes in terms of methacholine bronchial hyperresponsiveness and exhaled nitric oxide levels . The present results would therefore suggest that CIC might confer a better therapeutic ratio than FP when used at higher doses 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 The study addressed the question whether the novel inhaled prodrug corticosteroid ciclesonide is equally effective when inhaled in the morning compared to the evening . For this purpose a double-blind , r and omized , parallel group study was initiated in which 209 asthmatic patients ( forced expiratory volume in one second = 50 - 90 % predicted ) inhaled either 200 microg ciclesonide in the morning or in the evening , for 8 weeks . Efficacy was assessed by means of spirometry as well as daily recordings of morning and evening peak expiratory flow ( PEF ) , symptoms and use of rescue medication . The 24-h urinary cortisol excretion was measured to evaluate any effect on hypothalamic-pituitary-adrenol axis . Ciclesonide significantly improved asthma control . Morning and evening administration was shown to be equally effective for the different spirometry variables , evening PEF , symptoms , use of rescue medication and number of asthma exacerbations . Regarding morning PEF , the improvements after evening dosing were more prominent and equivalence of morning and evening administration could not be demonstrated . No relevant influence on cortisol excretion was found . Overall , the study indicates that ciclesonide can be given either in the morning or in the evening to meet the patients ' preference and individual medical needs , although evening administration may lead to a more pronounced improvement in morning peak expiratory flow 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 , r and omized , parallel‐group , placebo‐controlled study evaluated the efficacy and safety of ciclesonide in adults with persistent asthma Ciclesonide is a novel inhaled corticosteroid that is converted in the lungs to its active metabolite , desisobutyryl-ciclesonide ( des-CIC ) . The aim of this study was to compare the deposition of ciclesonide , as well as its conversion to des-CIC , in the oropharyngeal cavity with fluticasone propionate ( FP ) following inhalation via hydrofluoroalkane-propelled metered-dose inhalers ( HFA-MDIs ) . Eighteen asthmatics inhaled ciclesonide 800 microg followed by FP 1000 microg or vice versa in an open , r and omized , 2-treatment , 2-sequence study design . The oropharynx was washed out immediately and at 15 , 30 , 45 , and 60 minutes after inhalation . Sample s were analyzed for ciclesonide , des-CIC , and FP using liquid chromatography with t and em mass-spectrometric detection . Concentration-time curves and area under the concentration-time curve ( AUC ) were calculated for each drug . Ciclesonide and FP were recovered in almost all sample s. Within 60 minutes after inhalation , the amounts of both ciclesonide and FP decreased sharply , and low residual levels were detected after 30 minutes . des-CIC was detected in relatively low concentrations , with maximum concentration 30 minutes following inhalation . The AUC(0 - 60 min ) for ciclesonide ( 250.4 nmol x h/L ) and des-CIC ( 37.8 nmol x h/L ) were found to be significantly lower compared with FP ( 636.2 nmol.h/L , P < .001 ) . Approximately 50 % less ciclesonide and 90 % less metabolite were present in the oropharynx compared with FP . Less than 20 % of the residual ciclesonide in the oropharynx was metabolized to des-CIC . These findings indicate that oropharyngeal deposition of ciclesonide is only half that of FP following inhalation from an HFA-MDI . Furthermore , there is little activation of ciclesonide to its active metabolite in the oropharynx , suggesting a decreased likelihood of inhaled ciclesonide-associated oropharyngeal side effects Objective Inhaled corticosteroids may cause  oropharyngeal side effects  if deposited in the oropharynx in active form . Ciclesonide , an inhaled corticosteroid with low glucocorticoid receptor affinity , is activated primarily in the lung by esterases to an active metabolite , desisobutyryl-ciclesonide ( des-CIC ) , with high glucocorticoid receptor affinity . We studied oropharyngeal deposition of ciclesonide , des-CIC , and budesonide . Methods In an open-label , r and omized , two-treatment ( administered in sequence ) , five-period study , 18 healthy subjects received 800 μg ( ex-valve ) inhaled ciclesonide via a hydrofluoroalkane-pressurized , metered-dose inhaler followed by 800 μg budesonide ( Pulmicort ) by a chlorofluorocarbon-pressurized , metered-dose inhaler ( four puffs of 200 μg each , ex-valve ) or vice versa . Oropharyngeal cavity rinsing was performed immediately , or 15 , 30 , 45 , or 60 min after inhalation ( one rinsing per study period ) , and the solutions were analyzed using liquid chromatography with t and em mass spectrometric detection . Results Ciclesonide and budesonide were detected in most oropharyngeal wash sample s. Maximal concentration of each inhaled corticosteroid was reached immediately post-inhalation ; maximal concentrations of ciclesonide and des-CIC were 30 % and 0.67 % , respectively , of budesonide . Oropharyngeal deposition of ciclesonide and budesonide decreased rapidly within 15 min post-inhalation , and less rapidly thereafter . Less than 10 % of the residual ciclesonide in the oropharynx was converted to des-CIC . The molar dose-adjusted amount of des-CIC was 4 % of budesonide ( P < 0.0001 ) . There were no significant adverse events . Conclusion Oropharyngeal deposition of des-CIC was more than one order of magnitude lower than that of budesonide when administered by the respective metered-dose inhalers . This may explain the low frequency of oropharyngeal side effects of ciclesonide in clinical studies AIMS There are no data comparing the relative efficacy of hydrofluoroalkane ( HFA ) formulations of ciclesonide ( CIC ) and fluticasone propionate ( FP ) on airway hyper-responsiveness , in mild-to-moderate persistent asthma . We therefore elected to evaluate the comparative efficacy of HFA pressurized metered-dose inhaler formulations of CIC and FP , assessing methacholine challenge , in addition to exhaled nitric oxide , lung function , diary cards and quality of life . METHODS Nineteen mild-to-moderate asthmatic patients completed the study per protocol in r and omized , double-blind , double-dummy , crossover fashion . Patients were required to stop their usual inhaled corticosteroid therapy for the duration of the study . Patients were commenced instead on salmeterol ( SM ) 50 microg one puff twice daily + montelukast ( ML ) 10 mg once daily for 2-week washout periods prior to each r and omized treatment , in order to prevent dropouts . Patients received 4 weeks of either CIC 200 microg two puffs once daily ( 08.00 h ) + CIC-placebo ( PL ) two puffs once daily ( 20.00 h ) + FP-PL two puffs twice daily ( 08.00 h and 20.00 h ) , or FP 125 microg two puffs twice daily ( 08.00 h and 20.00 h ) + CIC-PL two puffs twice daily ( 08.00 h and 20.00 h ) . SM + ML were withheld for 72 h prior to post-washout visits and CIC or FP was withheld for 24 h prior to study visits . RESULTS There was no significant difference between CIC vs. FP for the primary outcome of methacholine PC20 as doubling dilution ( dd ) shift from respective baseline ; mean difference : 0.4 dd ( 95 % CI -0.4 , 1.2 ) . Moreover , there was no difference between treatments for the sequence of CIC first vs FP second ; mean difference : 0.2 dd ( 95 % CI -1.3 , 1.7 ) or FP first vs CIC second ; mean difference : 0.9 dd ( 95 % CI -0.1 , 1.8 ) . There were also no differences for other secondary outcomes between treatments , either respective or irrespective of sequence , as change from baseline . CONCLUSIONS There were no differences between 4 weeks of CIC 400 microg once daily and FP 250 microg twice daily on methacholine hyper-responsiveness in mild-to-moderate persistent asthma . Longer-term studies are indicated to evaluate their relative efficacy on asthma exacerbations Background Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma . Objective To investigate the extent of oral absorption and bioavailability of ciclesonide referenced to an intravenous infusion . This information provides an estimate for the contribution of the swallowed fraction to systemic exposure to ciclesonide after oral inhalation . Methods In a r and omised crossover study , six healthy male subjects ( age range 19–40 years ) received single doses of 6.9 mg ( oral administration ) and 0.64 mg ( intravenous administration ) of [14C]ciclesonide , separated by a washout period of at least 14 days . Total radioactivity was determined in whole blood , plasma , urine and faeces . Serum concentrations of ciclesonide and its major metabolite , the pharmacologically active desisobutyryl-ciclesonide ( des-CIC ) , were determined in serum by high-performance liquid chromatography with t and em mass spectrometry detection . Results After a 10-minute intravenous infusion , the mean half-life for total radioactivity was 45.2 hours . Elimination of des-CIC was fast with a mean elimination half-life of 3.5 hours . After oral administration , the mean half-life for total radioactivity was 27.5 hours . On the basis of a comparison of dose-normalised areas under the curve of total plasma radioactivity versus time , 24.5 % of orally administered [14C]ciclesonide was absorbed . The parent compound ciclesonide was not detected in any of the serum sample s after oral administration ; serum concentrations of des-CIC were mostly near or below the lower limit of quantification . Thus , systemic bioavailability for des-CIC is < 1 % and the absolute bioavailability of ciclesonide is even less than this . [14C]Ciclesonide showed no retention in red blood cells . The mean cumulative excretion of total radioactivity was almost complete by 120 hours after oral and intravenous administration . Faecal excretion was the predominant route of excretion for total radioactivity after both routes of administration . Single oral and intravenous administration of ciclesonide was well tolerated . Conclusions Because of an almost complete first-pass metabolism , ciclesonide is undetectable in serum after oral administration . Thus , any ciclesonide swallowed after oral inhalation does not contribute to systemically available ciclesonide or to its active metabolite . Drug-related metabolites are excreted mainly via the faeces , and overall recovery of administered radioactivity is virtually complete after an extended sample collection period UNLABELLED 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 , r and omized , 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 clinical ly relevant effects on the hypothalamic-pituitary-adrenal axis independent of the time of administration 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 , r and omized , 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 STUDY OBJECTIVES To compare the lung deposition of radiolabeled hydrofluoroalkane-134a beclomethasone dipropionate ( HFA-BDP ) with chlorofluorocarbon fluticasone propionate ( CFC-FP ) and chlorofluorocarbon beclomethasone ( CFC-BDP ) . DESIGN Six-day , open-label , nonr and omized , crossover study . SETTING Clinical research laboratory . PARTICIPANTS Nine healthy , nonsmoking , adult volunteers . INTERVENTIONS On each study day , participants inhaled one or two puffs of 99mTc-labeled HFA-BDP , CFC-FP , or CFC-BDP . All products delivered 50 micro g per puff ex-valve . Subjects used a respiratory training and monitoring device to meet predefined , st and ardized inhalation patterns . Immediately after inhalation of radiolabeled study drug , planar gamma camera images were obtained . MEASUREMENTS AND RESULTS Radiolabeled HFA-BDP had a higher deposition in the lungs ( 53 % ex-actuator ) compared with CFC-FP ( 12 to 13 % ) and CFC-BDP ( 4 % ) . Conversely , CFC-FP and CFC-BDP had a much higher distribution to the oropharynx ( 72 to 78 % , and 82 % , respectively ) than HFA-BDP ( 29 % ) . HFA-BDP was deposited evenly throughout the lungs , while CFC-FP and CFC-BDP deposition was primarily in the large central and intermediate airways . And ersen particle size sampling gave mass median aerodynamic diameters for HFA-BDP , CFC-FP , and CFC-BDP of 0.9 micro m , 2.0 micro m , and 3.5 micro m , respectively . CONCLUSIONS Lung deposition was greater with HFA-BDP compared with CFC-FP and CFC-BDP . Deposition values appeared to be related to the particle size distribution of each inhaler , with the smaller particles of HFA-BDP providing the greatest lung deposition and least oropharyngeal deposition To assess the efficacy of ciclesonide , a novel corticosteroid pro-drug , we compared its effect on lung function , airway responsiveness to inhaled AMP , the composition of induced sputum , and the level of exhaled nitric oxide ( NO ) with the effect of budesonide in patients with asthma . Fifteen non-smoking steroid-naive patients ( mean FEV(1 ) , 94%pred ) inhaled either 400 microg ciclesonide or 400 microg budesonide as a single morning dose for two weeks each separated by a > or =3 week wash-out period . The study was performed in a double-observer , r and omized , cross-over design . FEV(1)increased significantly during treatment with budesonide ( 3.38 vs. 3.64 l P=0,003 ) , but not after ciclesonide ( 3.60 vs. 3.69 l ) . PC(20)FEV(1)of AMP increased ( P<0,001 , each ) after both budesonide ( 4.59 vs. 32.48 mg/ml , 2.8 doubling doses ) and ciclesonide ( 3.92 vs. 20.00 mg/ml , 2.4 doubling doses ) . The percentage of sputum eosinophils was significantly reduced after ciclesonide ( 7.9 vs. 3.4 % P=0.01 ) , but not budesonide ( 6.0 vs. 4.3 % ) . After both budesonide and ciclesonide , a significant ( P<0.001 ) reduction in the level of exhaled NO occurred . In none of the parameters studied , the changes differed significantly between treatment with budesonide or ciclesonide . These data suggest that ciclesonide is equi-effective to budesonide with regard to its potency to reduce the airway responsiveness to inhaled AMP as well as airway inflammation in patients with mild asthma
Background Ciclesonide is a new inhaled corticosteroids licensed for the prophylactic treatment of persistent asthma in adults .
Currently beclomethasone dipropionate , budesonide and fluticasone propionate are the most commonly prescribed inhaled corticosteroids for the treatment of asthma but there has been no systematic review comparing the effectiveness and safety ciclesonide to these agents .
We therefore aim ed to systematic ally review published r and omised controlled trials of the effectiveness and safety of ciclesonide compared to alternative inhaled corticosteroids in people with asthma .