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Renate Engelstätter - One of the best experts on this subject based on the ideXlab platform.
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efficacy and safety of three Ciclesonide doses vs placebo in children with asthma the rainbow study
2010Co-Authors: Søren Pedersen, Paul Potter, Svetoslav Dachev, Miroslava Bosheva, Jadwiga Kaczmarek, Ewa Springer, Jochen Dunkel, Renate EngelstätterAbstract:Summary Objective: To evaluate the efficacy and safety of three doses of Ciclesonide (with or without spacer) in children with persistent asthma. Patients and methods: This was a multicentre, double-blind, placebo-controlled, 12-week study of Ciclesonide 40, 80 or 160 mg (once daily pm). Children (6e11 years) were randomised 1:1 to treatment via a metered dose inhaler (MDI) or MDI plus spacer. The primary variable was change from baseline in mean morning peak expiratory flow (PEF). Secondary variables included: time to first lack of efficacy (LOE), asthma control, forced expiratory volume in 1s( FEV1), asthma symptom score and quality of life (QoL). Safety assessments included: adverse events (AEs), urinary cortisol excretion and body height. Results: In total, 1073 children received treatment. At endpoint, mean morning PEF significantly improved with all doses of Ciclesonide vs. placebo. There was no difference over placebo in time to first LOE, but Ciclesonide was superior to placebo on asthma control, symptom score, FEV1 and QoL. There were no differences between the spacer or non
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efficacy and safety of Ciclesonide once daily and fluticasone propionate twice daily in children with asthma
2009Co-Authors: Søren Pedersen, Renate Engelstätter, Heinrich C Weber, Hansjochen Weber, Sabine Hirsch, Laszlo Barkai, Andrej Emeryk, Jan VermeulenAbstract:Abstract Background Ciclesonide is a new inhaled corticosteroid (ICS). Information about its clinical efficacy and safety in relation to other ICS in children is needed for clinical positioning. Objective This 12-week, randomized, double-blind, double-dummy, three-arm, parallel-group study compared the efficacy and safety of Ciclesonide with fluticasone propionate in children with mainly moderate and severe persistent asthma. Methods Seven hundred and forty-four patients (aged 6–11 years) were randomized to Ciclesonide (80 or 160 μg once daily) or fluticasone propionate (88 μg twice daily), following a 2–4-week run-in. Efficacy measurements included forced expiratory flow in 1 s (FEV 1 ), morning peak expiratory flow (PEF), asthma symptom scores, rescue medication use and quality of life. Systemic effect was assessed by 24-hour urine free cortisol adjusted for creatinine. Results FEV 1 and morning PEF increased from baseline in all groups ( p 1 ( p = 0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved ( p p p = 0.0103), but not with Ciclesonide. Conclusion Once-daily Ciclesonide has a clinical effect similar to that of fluticasone propionate, but does not suppress cortisol excretion, in children with moderate and severe asthma.
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rapid effect of inhaled Ciclesonide in asthma a randomized placebo controlled study
2008Co-Authors: Edward M Erin, Renate Engelstätter, Peter J Barnes, Michael Hellwig, Angela Zacharasiewicz, Grant C Nicholson, Andrew J Tan, Helen Neighbour, Onn Min Kon, Trevor T HanselAbstract:Background Ciclesonide is a novel inhaled corticosteroid for the treatment of asthma, and it is important to measure the onset of effect of this therapy on airway hyperresponsiveness (AHR), exhaled nitric oxide (NO), and levels of eosinophils in induced sputum. Methods In a randomized, double-blind, crossover study, 21 patients with mild asthma inhaled Ciclesonide 320 μg (ex-actuator) qd, Ciclesonide 640 μg (ex-actuator) bid, and placebo for 7 days. Exhaled NO and AHR to adenosine monophosphate (AMP), measured as the provocative concentration of AMP producing a 20% reduction in FEV 1 (PC 20 FEV 1 ), were assessed after inhalation on days 1, 3 and 7. Eosinophil levels in induced sputum were also measured. Results Ciclesonide 320 μg qd and 640 μg bid produced significantly greater improvements in PC 20 FEV 1 compared with placebo on day 1 (within 2.5 h), and on days 3 and 7 (all p Conclusions A single dose of Ciclesonide decreased AHR to AMP and exhaled NO within 3 h, while FEV, improved at 3 days and 7 days. Trial registration ClinicalTrials.gov Study ID Number BY9010/M1-125.
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randomized comparison of the efficacy and safety of Ciclesonide and budesonide in adolescents with severe asthma
2007Co-Authors: J H Vermeulen, K Gyurkovits, H Rauer, Renate EngelstätterAbstract:Summary 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 400mg once daily (QD) in a 2-week run-in period. At randomization, eligible patients were assigned 2:1 to Ciclesonide 320mg QD (ex-actuator) or budesonide 800mg QD (metered dose), respectively, in the evening. Forced expiratory volume in 1 s (FEV1) 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 320mg QD and budesonide 800mg QD significantly increased FEV1 (least-squares mean: 505 and 536 mL, respectively; both po0.0001 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 ¼ 0.0086 versus baseline), but not with Ciclesonide (p ¼ 0.1125).
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similar efficacy of Ciclesonide once daily versus fluticasone propionate twice daily in patients with persistent asthma
2007Co-Authors: Helgo Magnussen, Jerzy Hofman, Pawel Staneta, Johnphilip Lawo, Michael Hellwig, Renate EngelstätterAbstract:This 12-week, double-blind, parallel-group study compared the efficacy and safety of once daily Ciclesonide and twice daily fluticasone propionate in patients aged 12–75 years with persistent asthma. Patients were randomized to once-daily Ciclesonide 80 μg (n = 278) or 160 μ g (n = 271), or twice daily fluticasone propionate 88 μ g (n = 259) (all ex-actuator). Significant improvements from baseline were seen in all three treatment groups for forced expiratory volume in 1 second, asthma symptom scores and rescue medication use (all p < 0.0001). Asthma exacerbation rates were low (each Ciclesonide group, n = 2; fluticasone group, n = 1). Adverse event reporting indicated good tolerability. Once daily Ciclesonide 80 μg or 160 μg showed comparable efficacy and tolerability to twice daily fluticasone propionate 88 μg in persistent asthma.
Ruediger Nave - One of the best experts on this subject based on the ideXlab platform.
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REVIEW Metabolism of Ciclesonide in the upper and lower airways: review of available data
2013Co-Authors: Ruediger Nave, Nigel Mccracken, Nycomed Gmbh KonstanzAbstract:Abstract: Ciclesonide is a novel corticosteroid (CS) for the treatment of asthma and allergic rhinitis. After administration, the parent compound Ciclesonide is converted by intracellular airway esterases to its pharmacologically active metabolite desisobutyryl-Ciclesonide (des-CIC). We investigated the in vitro activation of Ciclesonide and further esterification of des-CIC to (mainly) des-CIC oleate in several human target organ test systems. Human precision-cut lung slices, alveolar type II epithelial cells (A549), normal bronchial epithelial cells (NHBE), and nasal epithelial cells (HNEC) were incubated with Ciclesonide. Enzymes characterization and the determination of the reversibility of fatty acid esterification was investigated in HNEC and NHBE. Ciclesonide was taken up and converted to des-CIC in all cellular test systems. Intracellular concentrations of des-CIC were maintained for up to 24 h. Formation of des-CIC oleate increased over time in HNEC, A549 cells, and lung slices. The formed des-CIC fatty acid conjugates were reconverted to des-CIC. Increasing concentrations of carboxylesterase and cholinesterase inhibitors progressively reduced the formation of metabolites. The results derived from these studies demonstrate the activation of Ciclesonide to des-CIC in the upper and lower airways. The reversible formation of des-CIC fatty acid conjugates may prolong the anti-inflammatory activity of des-CIC and may allow for once-daily dosing
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the role of esterases in the metabolism of Ciclesonide to desisobutyryl Ciclesonide in human tissue
2007Co-Authors: Elaine Mutch, Ruediger Nave, Nigel Mccracken, Karl Zech, Faith M WilliamsAbstract:Ciclesonide (CIC) is an inhaled glucocorticosteroid. This study aimed to identify esterases involved in the metabolism of CIC to the active metabolite desisobutyryl-Ciclesonide (des-CIC), and to measure hydrolysis rates in human liver, lung and plasma and normal human bronchial epithelial (NHBE) cells in vitro. Ciclesonide (5 microM and 500 microM) was incubated with microsomal or cytosolic fractions from liver, lung and plasma (n=4 for each) and des-CIC formation was determined by reverse-phase high-performance liquid chromatography with U.V. detection. The roles of carboxylesterase, cholinesterase and A-esterase in CIC hydrolysis were determined using a range of inhibitors. Inhibitor concentrations for liver and NHBE cells were 100 microM and 5 microM, respectively. Liver tissue had a higher activity for 500 microM CIC hydrolysis (microsomes: 25.4; cytosol: 62.9 nmol/g tissue/min) than peripheral lung (microsomes: 0.089; cytosol: 0.915 nmol/g tissue/min) or plasma (0.001 nmol/mL plasma/min), corresponding with high levels of carboxylesterase and cholinesterase in the liver compared with the lung. CIC (5 microM) was rapidly hydrolyzed by NHBE cells (approximately 30% conversion at 4h), with almost complete conversion by 24h. In liver and NHBE cells, major involvement of cytosolic carboxylesterases, with some contribution by cholinesterases, was indicated. The highest level of conversion was found in the liver, the site of inactivation of des-CIC through rapid oxidation by cytochrome P450. Carboxylesterases in bronchial epithelial cells probably contribute significantly to the conversion to des-CIC in the target organ, whereas low systemic levels of des-CIC are a result of the high metabolic clearance by the liver following CIC inhalation.
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in vitro metabolism of Ciclesonide in human lung and liver precision cut tissue slices
2006Co-Authors: Ruediger Nave, Robyn Fisher, Karl ZechAbstract:Ciclesonide is a new-generation inhaled corticosteroid developed to treat the inflammation associated with persistent asthma. In order to identify the properties of Ciclesonide responsible for anti-inflammatory activity, Ciclesonide metabolism was investigated in human lung and liver precision-cut tissue slices. Three human lung and three human liver tissue slices were incubated with 25 µM [14C]-Ciclesonide for 2, 6 and 24 h. Cellular viability was assessed using adenosine 5′-triphosphate content and protein synthesis in lung slices and adenosine 5′-triphosphate content and potassium retention in liver slices. Ciclesonide and Ciclesonide metabolites were analysed in tissue samples using high-performance liquid chromatography with ultraviolet and radiochemical detection. Metabolite identity was confirmed using mass spectrometry. In lung slices, the inactive parent compound, Ciclesonide, was initially converted to the active metabolite, desisobutyryl-Ciclesonide, and subsequently converted to fatty acid conjugates. The reversible formation of fatty acid conjugates was a major pathway of Ciclesonide metabolism in human lung slices. The primary conjugate was identified as desisobutyryl-Ciclesonide oleate. Ciclesonide was metabolized to at least five polar metabolites in the liver. Dihydroxylated desisobutyryl-Ciclesonide was the major polar metabolite in liver slices. Activation and fatty acid esterification in the lung followed by rapid inactivation in the liver may explain the improved safety profile and prolonged anti-inflammatory activity of Ciclesonide. Copyright © 2006 John Wiley & Sons, Ltd.
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safety tolerability and exposure of Ciclesonide nasal spray in healthy and asymptomatic subjects with seasonal allergic rhinitis
2006Co-Authors: Ruediger Nave, Mark A Wingertzahn, Sheldon Brookman, Shigenori Kaida, Takashi MatsunagaAbstract:Ciclesonide is an intranasal corticosteroid in development for the treatment of allergic rhinitis. To assess the safety, tolerability, and pharmacokinetics of Ciclesonide, adult healthy volunteers and asymptomatic subjects with seasonal allergic rhinitis were randomized to receive intranasal Ciclesonide or placebo for 14 days. Serum concentrations of Ciclesonide and its active metabolite, desisobutyryl-Ciclesonide, were measured using high-performance liquid chromatography assay with tandem mass spectrometric detection, with lower limits of quantification of 25 and 10 pg/mL, respectively. Adrenal function was monitored by diurnal serum free and 24-hour urine cortisol concentrations. Despite the use of a sensitive assay and a high Ciclesonide dose (800 microg/d), serum levels of Ciclesonide and desisobutyryl-Ciclesonide were below the lower limits of quantification for the majority of samples assayed. Ciclesonide was well tolerated and did not appear to affect serum or urine free cortisol levels. The low systemic exposure and favorable safety profile support the continued clinical development of Ciclesonide nasal spray.
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high lung deposition of 99mtc labeled Ciclesonide administered via hfa mdi to patients with asthma
2006Co-Authors: Steve Newman, Ruediger Nave, Andrew Salmon, Anton DrollmannAbstract:Summary Objective To examine the deposition and pharmacokinetics of Ciclesonide administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) in patients with asthma. Methods Twelve patients with mild asthma (FEV 1 , 95% predicted) inhaled a single dose of 99m technetium (Tc)-Ciclesonide 320μg ex-actuator (400μg ex-valve). Deposition of Ciclesonide in the lung and oropharynx was quantified using two-dimensional (2D)-gamma scintigraphy. Three-dimensional single photon emission computed tomography (3D SPECT) was used to assess the regional distribution of Ciclesonide in the lung. The pharmacokinetics of Ciclesonide and its active metabolite, desisobutyryl-Ciclesonide (des-CIC), were determined by liquid chromatography-tandem mass spectrometry. Ciclesonide and des-CIC concentrations were determined in mouth-rinsing solutions. Results 2D-gamma scintigraphy indicated that Ciclesonide deposition was higher in the whole lung (52%) than in the oropharynx (32.9%). Furthermore, 3D SPECT revealed that Ciclesonide deposition within the lungs was highest in the peripheral regions that contain the small airways and alveoli. The pharmacokinetic profile of Tc-labeled Ciclesonide and des-CIC was similar to that obtained after inhalation of non-labeled formulations in previous studies. Des-CIC accounted for 14.9% of the total molar concentration of Ciclesonide/des-CIC in mouth-rinsing solutions obtained between 7 and 12min after inhalation. Conclusion Inhalation of Ciclesonide via HFA-MDI results in high pulmonary deposition, especially in the peripheral regions of the lung. High pulmonary deposition contributes to Ciclesonide's ability to maintain lung function and control symptoms in patients with asthma. Deposition and activation of Ciclesonide in the oropharynx is low, consistent with previous reports of low oropharyngeal deposition and a reduced incidence of local side effects in patients receiving Ciclesonide therapy.
Tushar P Shah - One of the best experts on this subject based on the ideXlab platform.
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long term safety and efficacy of intranasal Ciclesonide in adult and adolescent patients with perennial allergic rhinitis
2007Co-Authors: Paul Chervinsky, Sudeesha Kunjibettu, Nancy Hall, David L Miller, Bruce M Prenner, Gordon D Raphael, Tushar P ShahAbstract:Background Ciclesonide is a corticosteroid in development for allergic rhinitis that has been shown to be safe and effective in seasonal allergic rhinitis and perennial allergic rhinitis (PAR) trials of up to 6 weeks in duration. However, the long-term safety and efficacy of Ciclesonide are unknown. Objective To demonstrate the long-term safety of intranasal Ciclesonide, 200 μg once daily, in patients with PAR. Methods Patients (≥12 years old) with a 2-year or longer history of PAR were randomized in a double-blind fashion to receive Ciclesonide, 200 μg, or placebo once daily in the morning for up to 52 weeks. Spontaneous and elicited adverse events were monitored throughout the study. Ear, nose, and throat examinations were performed to evaluate local tolerability. Additionally, 24-hour urinary free cortisol level, morning plasma cortisol level, intraocular pressure, and lens opacification were monitored to evaluate the systemic safety of intranasal Ciclesonide. Ciclesonide efficacy was determined by measuring 24-hour reflective total nasal symptom scores. Results No clinically relevant differences were observed between the Ciclesonide and placebo groups in adverse events, ear, nose, and throat examinations, or 24-hour urinary free or morning plasma cortisol levels. Similarly, no clinically relevant differences were found between treatment groups in intraocular pressure, visual acuity, or lens opacification. With regard to efficacy, Ciclesonide achieved a significantly greater reduction in 24-hour reflective total nasal symptom score compared with placebo over more than 52 weeks ( P Conclusion In this study, intranasal Ciclesonide, 200 μg once daily, was safe and effective for the long-term treatment of PAR, with no evidence of tachyphylaxis.
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efficacy and safety of Ciclesonide nasal spray for the treatment of seasonal allergic rhinitis
2006Co-Authors: Paul H Ratner, Mark A Wingertzahn, Julius Van Bavel, Frank C Hampel, Patrick F Darken, Tushar P ShahAbstract:Background Allergic rhinitis (AR), an inflammatory disease of the nasal mucosa, affects approximately 25% of adults and 40% of children in the United States. Ciclesonide nasal spray is a corticosteroid being developed as a hypotonic formulation for AR. Objective We sought to evaluate the efficacy, safety, and tolerability of Ciclesonide nasal spray in adult and adolescent patients with seasonal AR (SAR). Methods In this double-blind study patients (age, ≥12 years) were randomized to receive 200 μg of intranasal Ciclesonide (n = 164) or placebo (n = 163) once daily for 28 days. The primary measure was morning and evening patient-assessed reflective total nasal symptom score (TNSS). Additionally, instantaneous TNSSs, physician-assessed overall nasal signs and symptoms severity, and the results of the Rhinoconjunctivitis Quality of Life Questionnaire were evaluated. Adverse events were monitored throughout the study. Results Ciclesonide significantly improved average morning and evening reflective and instantaneous TNSSs compared with placebo over days 1 to 14 ( P P P = .011). Ciclesonide was well tolerated. Conclusion Intranasal Ciclesonide was superior to placebo in relieving nasal symptoms in adult and adolescent patients with SAR. These results confirm the dose range–finding study in patients with SAR and support the efficacy of Ciclesonide in AR. Clinical implications In a clinical setting Ciclesonide was shown to be safe and effective in the treatment of SAR in adolescent and adult patients.
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efficacy and safety of Ciclesonide nasal spray for the treatment of seasonal allergic rhinitis
2006Co-Authors: Paul H Ratner, Mark A Wingertzahn, Frank C Hampel, Patrick F Darken, Julius Van Bavel, Tushar P ShahAbstract:BACKGROUND: Allergic rhinitis (AR), an inflammatory disease of the nasal mucosa, affects approximately 25% of adults and 40% of children in the United States. Ciclesonide nasal spray is a corticosteroid being developed as a hypotonic formulation for AR. OBJECTIVE: We sought to evaluate the efficacy, safety, and tolerability of Ciclesonide nasal spray in adult and adolescent patients with seasonal AR (SAR). METHODS: In this double-blind study patients (age, >or=12 years) were randomized to receive 200 microg of intranasal Ciclesonide (n = 164) or placebo (n = 163) once daily for 28 days. The primary measure was morning and evening patient-assessed reflective total nasal symptom score (TNSS). Additionally, instantaneous TNSSs, physician-assessed overall nasal signs and symptoms severity, and the results of the Rhinoconjunctivitis Quality of Life Questionnaire were evaluated. Adverse events were monitored throughout the study. RESULTS: Ciclesonide significantly improved average morning and evening reflective and instantaneous TNSSs compared with placebo over days 1 to 14 (P < .001). Improvements were also noted over days 1 to 28 (P < .001) and over days 15 to 28 (P = .011). Ciclesonide was well tolerated. CONCLUSION: Intranasal Ciclesonide was superior to placebo in relieving nasal symptoms in adult and adolescent patients with SAR. These results confirm the dose range-finding study in patients with SAR and support the efficacy of Ciclesonide in AR. CLINICAL IMPLICATIONS: In a clinical setting Ciclesonide was shown to be safe and effective in the treatment of SAR in adolescent and adult patients.
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effectiveness of Ciclesonide nasal spray in the treatment of seasonal allergic rhinitis
2006Co-Authors: Paul H Ratner, Mark A Wingertzahn, Sheldon Brookman, S Hellbardt, Julius Van Bavel, Frank C Hampel, Patrick F Darken, Tushar P ShahAbstract:Background Ciclesonide is an investigational corticosteroid under development for treatment of allergic rhinitis. Ciclesonide is converted to active metabolite, desisobutyryl-Ciclesonide (des-CIC), by upper and lower airway esterases. In vitro studies in human nasal epithelial cells and bronchial epithelial cells have demonstrated a long duration of anti-inflammatory activity of des-CIC. Objective To evaluate the dose-dependent efficacy and safety of a hypotonic intranasal formulation of Ciclesonide in patients with seasonal allergic rhinitis (SAR). Methods This was a phase 2, randomized, parallel-group, double-blind, placebo-controlled study. Adults (n = approximately 145 per treatment group) with a minimum 2-year history of SAR received placebo or Ciclesonide (25, 50, 100, or 200 μg/d) for 14 days. The primary end point was change in the sum of morning and evening reflective total nasal symptom scores (TNSSs) over 2 weeks. Safety was monitored throughout the study. Results Ciclesonide, 100 μg/d ( P = .04) and 200 μg/d ( P = .003), significantly improved the sum of morning and evening reflective TNSS vs placebo at more than 2 weeks of treatment. Baseline values for morning and evening reflective TNSS ranged from 17.80 to 18.82 across treatment groups. The average change from baseline in reflective TNSS was −4.2 for placebo and −4.8, −4.8, −5.3, and −5.8 for Ciclesonide, 25, 50, 100, and 200 μg/d, respectively. There were no dose-related differences in the incidence of adverse events among treatment groups. Conclusions Results from this study indicate that 100-μg and 200-μg daily doses of Ciclesonide are effective in the treatment of SAR. Ciclesonide, 200 μg/d, appears to be the optimal dose studied for reducing the symptoms of SAR while maintaining an acceptable safety profile.
T D Bethke - One of the best experts on this subject based on the ideXlab platform.
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comparison of the efficacy and safety of Ciclesonide 160 μg once daily vs budesonide 400 μg once daily in children with asthma
2007Co-Authors: Andrea Von Berg, Renate Engelstätter, Predrag Minic, Miodrag Sreckovic, Maria Luz Garcia Garcia, Tadeusz Latoś, Jan Vermeulen, Stefan Leichtl, S Hellbardt, T D BethkeAbstract:Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of Ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive Ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both Ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of Ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, Ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of Ciclesonide treatment (p < 0.001, one-sided). Both Ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with Ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk.
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two dimensional and three dimensional imaging show Ciclesonide has high lung deposition and peripheral distribution a nonrandomized study in healthy volunteers
2006Co-Authors: Chet L Leach, Anton Drollmann, T D Bethke, R J Boudreau, Bruce E Hasselquist, Patricia J Davidson, Wilhelm WurstAbstract:Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of Ciclesonide. Technetium-99m (99mTc)-labeled Ciclesonide (where the 99mTc-label is physically dissolved in the Ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) Ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg Ciclesonide for 2-D and 3-D imaging. The Ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of Ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that Ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of Ciclesonide produced no drug-related side effects. In conclusion, Ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.
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lower oropharyngeal deposition of inhaled Ciclesonide via hydrofluoroalkane metered dose inhaler compared with budesonide via chlorofluorocarbon metered dose inhaler in healthy subjects
2005Co-Authors: Ruediger Nave, Karl Zech, T D BethkeAbstract: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. In an open-label, randomized, 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 tandem mass spectrometric detection. Ciclesonide and budesonide were detected in most oropharyngeal wash samples. 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. 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.
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lower oropharyngeal deposition of inhaled Ciclesonide via hydrofluoroalkane metered dose inhaler compared with budesonide via chlorofluorocarbon metered dose inhaler in healthy subjects
2005Co-Authors: Ruediger Nave, Karl Zech, T D BethkeAbstract: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.
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pharmacokinetics of 14c Ciclesonide after oral and intravenous administration to healthy subjects
2004Co-Authors: Ruediger Nave, T D Bethke, Sjoerd P Van Marle, Karl ZechAbstract:Ciclesonide is a novel inhaled corticosteroid developed for the treatment of asthma. 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. In a randomised crossover study, six healthy male subjects (age range 19–40 years) received single doses of 6.9mg (oral administration) and 0.64mg (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 tandem mass spectrometry detection. 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 samples 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. 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.
Anton Drollmann - One of the best experts on this subject based on the ideXlab platform.
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two dimensional and three dimensional imaging show Ciclesonide has high lung deposition and peripheral distribution a nonrandomized study in healthy volunteers
2006Co-Authors: Chet L Leach, Anton Drollmann, T D Bethke, R J Boudreau, Bruce E Hasselquist, Patricia J Davidson, Wilhelm WurstAbstract:Drug deposition is an important factor that contributes to safety and efficacy outcomes of inhaled steroid therapy. Ciclesonide is a nonhalogenated, inhaled corticosteroid under investigation for the treatment of asthma. Therefore, this study was performed to assess lung deposition of Ciclesonide. Technetium-99m (99mTc)-labeled Ciclesonide (where the 99mTc-label is physically dissolved in the Ciclesonide-hydrofluoroalkane [HFA] solution aerosol) inhaled by healthy volunteers was analyzed by two-dimensional (2-D) and three-dimensional (3-D) imaging to determine lung deposition. Six healthy volunteers inhaled one puff of 40 microg (exactuator, equivalent to 50 microg ex-valve) Ciclesonide for 2-D imaging, and two healthy volunteers inhaled 10 puffs of 40 microg Ciclesonide for 2-D and 3-D imaging. The Ciclesonide aerosol was administered via metered-dose inhaler (MDI) containing HFA-134a as propellant. The ex-actuator mean (+/- standard deviation) deposition of Ciclesonide in the lungs was higher (52% +/- 11%) than in the mouth/pharynx (38% +/- 14%). Two-dimensional and 3-D imaging showed that Ciclesonide reached all regions of the lung. Mean percent deposition in peripheral regions (47% and 34%) was higher than in lower central regions (17% and 30%), as revealed by 3-D and 2-D imaging, respectively. Inhalation of up to 400 microg of Ciclesonide produced no drug-related side effects. In conclusion, Ciclesonide administered via metered-dose inhaler using HFA-134a as a propellant provided high lung deposition (>50%), greater distribution throughout peripheral regions of the lungs, and relatively low oropharyngeal deposition.
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comparative efficacy of once daily Ciclesonide and budesonide in the treatment of persistent asthma
2006Co-Authors: L P Boulet, Renate Engelstätter, Anton Drollmann, P Magyar, M Timar, A Knight, Leonardo M FabbriAbstract:Summary 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 320–640μg (ex-mouthpiece, equivalent to 400–800μg; Turbohaler™) daily entered a 2-week baseline, and then a 2- to 4-week pretreatment period (budesonide 1280μg/day; ex-mouthpiece, equivalent to 1600μg/day). Patients with an increase in forced expiratory volume in 1s (FEV 1 ) of ⩾7% or ⩾0.15L were randomised to Ciclesonide 320μg (ex-actuator, equivalent to 400μg ex-valve) via a hydrofluoroalkane-metered dose inhaler (HFA-MDI) without a spacer or budesonide 320μg once daily in the morning for 12 weeks. Change in FEV 1 was the primary endpoint. Results In all, 359 patients were randomised. The FEV 1 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 FEV 1 , 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 320μg once daily by HFA-MDI without a spacer was at least as effective as budesonide 320μg once daily in persistent asthma.
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high lung deposition of 99mtc labeled Ciclesonide administered via hfa mdi to patients with asthma
2006Co-Authors: Steve Newman, Ruediger Nave, Andrew Salmon, Anton DrollmannAbstract:Summary Objective To examine the deposition and pharmacokinetics of Ciclesonide administered via hydrofluoroalkane-metered dose inhaler (HFA-MDI) in patients with asthma. Methods Twelve patients with mild asthma (FEV 1 , 95% predicted) inhaled a single dose of 99m technetium (Tc)-Ciclesonide 320μg ex-actuator (400μg ex-valve). Deposition of Ciclesonide in the lung and oropharynx was quantified using two-dimensional (2D)-gamma scintigraphy. Three-dimensional single photon emission computed tomography (3D SPECT) was used to assess the regional distribution of Ciclesonide in the lung. The pharmacokinetics of Ciclesonide and its active metabolite, desisobutyryl-Ciclesonide (des-CIC), were determined by liquid chromatography-tandem mass spectrometry. Ciclesonide and des-CIC concentrations were determined in mouth-rinsing solutions. Results 2D-gamma scintigraphy indicated that Ciclesonide deposition was higher in the whole lung (52%) than in the oropharynx (32.9%). Furthermore, 3D SPECT revealed that Ciclesonide deposition within the lungs was highest in the peripheral regions that contain the small airways and alveoli. The pharmacokinetic profile of Tc-labeled Ciclesonide and des-CIC was similar to that obtained after inhalation of non-labeled formulations in previous studies. Des-CIC accounted for 14.9% of the total molar concentration of Ciclesonide/des-CIC in mouth-rinsing solutions obtained between 7 and 12min after inhalation. Conclusion Inhalation of Ciclesonide via HFA-MDI results in high pulmonary deposition, especially in the peripheral regions of the lung. High pulmonary deposition contributes to Ciclesonide's ability to maintain lung function and control symptoms in patients with asthma. Deposition and activation of Ciclesonide in the oropharynx is low, consistent with previous reports of low oropharyngeal deposition and a reduced incidence of local side effects in patients receiving Ciclesonide therapy.
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once daily Ciclesonide 80 or 320 μg for 12 weeks is safe and effective in patients with persistent asthma
2005Co-Authors: C G Langdon, M Adler, S Mehra, M Alexander, Anton DrollmannAbstract:Summary 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 μg (ex-actuator doses, equivalent to 100 and 400 μg 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 μg) significantly increased forced expiratory volume in 1 s from baseline (0.13 and 0.19 L increases, respectively; P 0.01 ); improvements were superior versus placebo ( P = 0.0044 for 80 μg Ciclesonide; P 0.0001 for 320 μg Ciclesonide). The probability of losing efficacy decreased in a dose-dependent manner (55% for placebo, 38% for Ciclesonide 80 μg, 23% for Ciclesonide 320 μg). 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 μg administered once daily was a safe and effective maintenance treatment for patients with persistent asthma.
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circadian rhythm of serum cortisol after repeated inhalation of the new topical steroid Ciclesonide
2002Co-Authors: Anita Weinbrenner, Wolfgang Timmer, Wilhelm Wurst, Anton Drollmann, T D Bethke, Dagny Huneke, Michael Zschiesche, Georg Engel, Volker Steinijans, Hans Joachim KaatzAbstract: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 μg in the morning, 800 μg in the evening, 400 μg 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 μg/dl for placebo, 6.75 μg/dl for the 800 μg Ciclesonide morning dose, 7.08 μg/dl for the 800 μg evening dose, and 6.75 μg/dl for 400 μg 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 dif...
