fluticasone and ciclesonide

Topics: Administration, Inhalation; Adolescent; Asthma; Beclomethasone; Body Height; Budesonide; Child; Child Development; Child, Preschool; Fluticasone; Glucocorticoids; Humans; Infant; Mometasone Furoate; Pregnenediones

Eosinophilic esophagitis (EoE) is defined as a chronic, immune-medicated or antigen-mediated, esophageal disease, characterized clinically by symptoms related to esophageal dysfunction and histologically by eosinophil-predominant inflammation. Food allergens are identified in most patients. Treatment strategies include elimination diets, drugs, and esophageal dilation. This article focuses on pharmacologic treatment. Currently, there is no pharmacologic treatment that has been approved by regulatory authorities. Established pharmacologic options to treat EoE include proton pump inhibitors and swallowed topical steroids. Several biologic therapies are currently under evaluation and some of them have shown promising results in improving biologic endpoints and patient-reported outcomes.

Topics: Administration, Topical; Anti-Allergic Agents; Anti-Inflammatory Agents; Antibodies, Monoclonal; Budesonide; Eosinophilic Esophagitis; Fluticasone; Histamine Antagonists; Humans; Pregnenediones; Proton Pump Inhibitors

Many trials have been published comparing inhaled corticosteroid (ICS) treatments in asthma. However, mixed results necessitate the summarization of available evidence to aid in decision-making. Areas covered: This systematic review evaluated randomized controlled trials (RCTs) that compared the efficacy and safety of inhaled fluticasone propionate (FP) with other ICS including beclomethasone dipropionate (BDP), budesonide (BUD) and ciclesonide (CIC). PubMed was searched and 54 RCTs that fit pre-determined criteria were included. Endpoints evaluated included lung function, asthma symptom control, exacerbation frequency, reliever use, quality of life and steroid-related side effects. Expert commentary: Across all studies, FP was associated with either more favorable or at least similar efficacy and safety, in comparison with BDP or BUD. This observation may be related to FP's higher relative potency and almost negligible oral bioavailability. FP was comparable to CIC for efficacy. However, CIC appeared to have a smaller impact on cortisol levels than FP, which is likely due to CIC's incomplete conversion to active metabolite (des-CIC) and the lower potency of des-CIC compared with FP. Although there were no significant differences in evaluated outcomes after treatment with different ICS in the majority of studies, some observed differences could be explained by their respective pharmacodynamic and pharmacokinetic properties.

Topics: Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Fluticasone; Glucocorticoids; Humans; Nebulizers and Vaporizers; Pregnenediones; Randomized Controlled Trials as Topic

Because of its burden on patient's lives and its impact on asthma, allergic rhinitis must be treated properly with more effective and safer treatments. According to guidelines by Allergic Rhinitis and Its Impact on Asthma (ARIA), the classification, pathogenesis, and treatment of allergic rhinitis are well defined. Currently, second-generation antihistamines and inhaled steroids are considered the cornerstone of first-line therapy. However, new formulations of available drugs (e.g., loratadine and rupatadine oral solution, ebastine fast-dissolving tablets, and the combination of intranasal fluticasone propionate and azelastine hydrochloride), recently discovered molecules (e.g., ciclesonide, bilastine, and phosphodiesterase-4 inhibitors), immunologic targets (e.g., omalizumab), and unconventional treatments (e.g., homeopathic treatments) are currently under investigation and represent a new frontier in modern medicine and in allergic rhinitis management. The aim of this review is to provide an update on allergic rhinitis treatment, paying particular attention to clinical trials published within the past 20 months that assessed the efficacy and safety of new formulations of available drugs or new molecules.

Topics: Administration, Intranasal; Androstadienes; Anti-Allergic Agents; Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Benzimidazoles; Butyrophenones; Cyproheptadine; Fluticasone; Histamine H1 Antagonists; Humans; Omalizumab; Phthalazines; Piperidines; Pregnenediones; Rhinitis, Allergic; Rhinitis, Allergic, Perennial

Treatment guidelines for asthma recommend inhaled corticosteroids (ICS) as first-line therapy for children with persistent asthma. Although ICS treatment is generally considered safe in children, the potential systemic adverse effects related to regular use of these drugs have been and continue to be a matter of concern, especially the effects on linear growth.. To assess the impact of ICS on the linear growth of children with persistent asthma and to explore potential effect modifiers such as characteristics of available treatments (molecule, dose, length of exposure, inhalation device) and of treated children (age, disease severity, compliance with treatment).. We searched the Cochrane Airways Group Specialised Register of trials (CAGR), which is derived from systematic searches of bibliographic databases including CENTRAL, MEDLINE, EMBASE, CINAHL, AMED and PsycINFO; we handsearched respiratory journals and meeting abstracts. We also conducted a search of ClinicalTrials.gov and manufacturers' clinical trial databases to look for potential relevant unpublished studies. The literature search was conducted in January 2014.. Parallel-group randomised controlled trials comparing daily use of ICS, delivered by any type of inhalation device for at least three months, versus placebo or non-steroidal drugs in children up to 18 years of age with persistent asthma.. Two review authors independently performed study selection, data extraction and assessment of risk of bias in included studies. We conducted meta-analyses using the Cochrane statistical package RevMan 5.2 and Stata version 11.0. We used the random-effects model for meta-analyses. We used mean differences (MDs) and 95% CIs as the metrics for treatment effects. A negative value for MD indicates that ICS have suppressive effects on linear growth compared with controls. We performed a priori planned subgroup analyses to explore potential effect modifiers, such as ICS molecule, daily dose, inhalation device and age of the treated child.. We included 25 trials involving 8471 (5128 ICS-treated and 3343 control) children with mild to moderate persistent asthma. Six molecules (beclomethasone dipropionate, budesonide, ciclesonide, flunisolide, fluticasone propionate and mometasone furoate) [corrected] given at low or medium daily doses were used during a period of three months to four to six years. Most trials were blinded and over half of the trials had drop out rates of over 20%.Compared with placebo or non-steroidal drugs, ICS produced a statistically significant reduction in linear growth velocity (14 trials with 5717 participants, MD -0.48 cm/y, 95% CI -0.65 to -0.30, moderate quality evidence) and in the change from baseline in height (15 trials with 3275 participants; MD -0.61 cm/y, 95% CI -0.83 to -0.38, moderate quality evidence) during a one-year treatment period.Subgroup analysis showed a statistically significant group difference between six molecules in the mean reduction of linear growth velocity during one-year treatment (Chi² = 26.1, degrees of freedom (df) = 5, P value < 0.0001). The group difference persisted even when analysis was restricted to the trials using doses equivalent to 200 μg/d hydrofluoroalkane (HFA)-beclomethasone. Subgroup analyses did not show a statistically significant impact of daily dose (low vs medium), inhalation device or participant age on the magnitude of ICS-induced suppression of linear growth velocity during a one-year treatment period. However, head-to-head comparisons are needed to assess the effects of different drug molecules, dose, inhalation device or patient age. No statistically significant difference in linear growth velocity was found between participants treated with ICS and controls during the second year of treatment (five trials with 3174 participants; MD -0.19 cm/y, 95% CI -0.48 to 0.11, P value 0.22). Of two trials that reported linear growth velocity in the third year of treatment, one trial involving 667 participants showed similar growth velocity between the budesonide and placebo groups (5.34 cm/y vs 5.34 cm/y), and another trial involving 1974 participants showed lower growth velocity in the budesonide group compared with the placebo group (MD -0.33 cm/y, 95% CI -0.52 to -0.14, P value 0.0005). Among four trials reporting data on linear growth after treatment cessation, three did not describe statistically significant catch-up growth in the ICS group two to four months after treatment cessation. One trial showed accelerated li. Regular use of ICS at low or medium daily doses is associated with a mean reduction of 0.48 cm/y in linear growth velocity and a 0.61-cm change from baseline in height during a one-year treatment period in children with mild to moderate persistent asthma. The effect size of ICS on linear growth velocity appears to be associated more strongly with the ICS molecule than with the device or dose (low to medium dose range). ICS-induced growth suppression seems to be maximal during the first year of therapy and less pronounced in subsequent years of treatment. However, additional studies are needed to better characterise the molecule dependency of growth suppression, particularly with newer molecules (mometasone, ciclesonide), to specify the respective role of molecule, daily dose, inhalation device and patient age on the effect size of ICS, and to define the growth suppression effect of ICS treatment over a period of several years in children with persistent asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Child, Preschool; Fluocinolone Acetonide; Fluticasone; Growth; Growth Disorders; Humans; Mometasone Furoate; Patient Dropouts; Pregnadienediols; Pregnenediones

Inhaled corticosteroids (ICS) are the first-line treatment for children with persistent asthma. Their potential for growth suppression remains a matter of concern for parents and physicians.. To assess whether increasing the dose of ICS is associated with slower linear growth, weight gain and skeletal maturation in children with asthma.. We searched the Cochrane Airways Group Specialised Register of trials (CAGR) and the ClinicalTrials.gov website up to March 2014.. Studies were eligible if they were parallel-group randomised trials evaluating the impact of different doses of the same ICS using the same device in both groups for a minimum of three months in children one to 17 years of age with persistent asthma.. Two review authors ascertained methodological quality independently using the Cochrane Risk of bias tool. The primary outcome was linear growth velocity. Secondary outcomes included change over time in growth velocity, height, weight, body mass index and skeletal maturation.. Among 22 eligible trials, 17 group comparisons were derived from 10 trials (3394 children with mild to moderate asthma), measured growth and contributed data to the meta-analysis. Trials used ICS (beclomethasone, budesonide, ciclesonide, fluticasone or mometasone) as monotherapy or as combination therapy with a long-acting beta2-agonist and generally compared low (50 to 100 μg) versus low to medium (200 μg) doses of hydrofluoroalkane (HFA)-beclomethasone equivalent over 12 to 52 weeks. In the four comparisons reporting linear growth over 12 months, a significant group difference was observed, clearly indicating lower growth velocity in the higher ICS dose group of 5.74 cm/y compared with 5.94 cm/y on lower-dose ICS (N = 728 school-aged children; mean difference (MD)0.20 cm/y, 95% confidence interval (CI) 0.02 to 0.39; high-quality evidence): No statistically significant heterogeneity was noted between trials contributing data. The ICS molecules (ciclesonide, fluticasone, mometasone) used in these four comparisons did not significantly influence the magnitude of effect (X(2) = 2.19 (2 df), P value 0.33). Subgroup analyses on age, baseline severity of airway obstruction, ICS dose and concomitant use of non-steroidal antiasthmatic drugs were not performed because of similarity across trials or inadequate reporting. A statistically significant group difference was noted in unadjusted change in height from zero to three months (nine comparisons; N = 944 children; MD 0.15, 95% CI -0.28 to -0.02; moderate-quality evidence) in favour of a higher ICS dose. No statistically significant group differences in change in height were observed at other time points, nor were such differences in weight, bone mass index and skeletal maturation reported with low quality of evidence due to imprecision.. In prepubescent school-aged children with mild to moderate persistent asthma, a small but statistically significant group difference in growth velocity was observed between low doses of ICS and low to medium doses of HFA-beclomethasone equivalent, favouring the use of low-dose ICS. No apparent difference in the magnitude of effect was associated with three molecules reporting one-year growth velocity, namely, mometasone, ciclesonide and fluticasone. In view of prevailing parents' and physicians' concerns about the growth suppressive effect of ICS, lack of or incomplete reporting of growth velocity in more than 86% (19/22) of eligible paediatric trials, including those using beclomethasone and budesonide, is a matter of concern. All future paediatric trials comparing different doses of ICS with or without placebo should systematically document growth. Findings support use of the minimal effective ICS dose in children with asthma.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Dose-Response Relationship, Drug; Fluticasone; Growth; Growth Disorders; Humans; Mometasone Furoate; Pregnadienediols; Pregnenediones; Randomized Controlled Trials as Topic

Inhaled corticosteroids (ICS) are the cornerstone of asthma maintenance treatment in children. Particularly among parents, there is concern about the safety of ICS as studies in children have shown reduced growth. Small-particle-size ICS targeting the smaller airways have improved lung deposition and effective asthma control might be achieved at lower daily doses.Ciclesonide is a relatively new ICS. This small-particle ICS is a pro-drug that is converted in the airways to an active metabolite and therefore with potentially less local (throat infection) and systemic (reduced growth) side effects. It can be inhaled once daily, thereby possibly improving adherence.. To assess the efficacy and adverse effects of ciclesonide compared to other ICS in the management of chronic asthma in children.. We searched the Cochrane Airways Group Register of trials with pre-defined terms. Additional searches of MEDLINE (via PubMed), EMBASE and Clinical study results.org were undertaken. Searches are up to date to 7 November 2012.. Randomised controlled parallel or cross-over studies were eligible for the review. We included studies comparing ciclesonide with other corticosteroids both at nominally equivalent doses or lower doses of ciclesonide.. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials.. Six studies were included in this review (3256 children, 4 to 17 years of age). Two studies were published as conference abstracts only. Ciclesonide was compared to budesonide and fluticasone.Ciclesonide compared to budesonide (dose ratio 1:2): asthma symptoms and adverse effect were similar in both groups. Pooled results showed no significant difference in children who experience an exacerbation (risk ratio (RR) 2.20, 95% confidence interval (CI) 0.75 to 6.43). Both studies reported that 24-hour urine cortisol levels showed a statistically significant decrease in the budesonide group compared to the ciclesonide group.Ciclesonide compared to fluticasone (dose ratio 1:1): no significant differences were found for the outcome asthma symptoms. Pooled results showed no significant differences in number of patients with exacerbations (RR 1.37, 95% CI 0.58 to 3.21) and data from a study that could not be pooled in the meta-analysis reported similar numbers of patients with exacerbations in both groups. None of the studies found a difference in adverse effects. No significant difference was found for 24-hour urine cortisol levels between the groups (mean difference 0.54 nmol/mmol, 95% CI -5.92 to 7.00).Ciclesonide versus fluticasone (dose ratio 1:2) was assessed in one study and showed similar results between the two corticosteroids for asthma symptoms. The number of children with exacerbations was significantly higher in the ciclesonide group (RR 3.57, 95% CI 1.35 to 9.47). No significant differences were found in adverse effects (RR 0.98, 95% CI 0.81 to 1.14) and 24-hour urine cortisol levels (mean difference 1.15 nmol/mmol, 95% CI 0.07 to 2.23).The quality of evidence was judged 'low' for the outcomes asthma symptoms and adverse events and 'very low' for the outcome exacerbations for ciclesonide versus budesonide (dose ratio 1:1). The quality of evidence was graded 'moderate' for the outcome asthma symptoms, 'very low' for the outcome exacerbations and 'low' for the outcome adverse events for ciclesonide versus fluticasone (dose ratio 1:1). For ciclesonide versus fluticasone (dose ratio 1:2) the quality was rated 'low' for the outcome asthma symptoms and 'very low' for exacerbations and adverse events (dose ratio 1:2).. An improvement in asthma symptoms, exacerbations and side effects of ciclesonide versus budesonide and fluticasone could be neither demonstrated nor refuted and the trade-off between benefits and harms of using ciclesonide instead of budesonide or fluticasone is unclear. The resource use or costs of different ICS should therefore also be considered in final decision making. Longer-term superiority trials are needed to identify the usefulness and safety of ciclesonide compared to other ICS. Additionally these studies should be powered for patient relevant outcomes (exacerbations, asthma symptoms, quality of life and side effects). There is a need for studies comparing ciclesonide once daily with other ICS twice daily to assess the advantages of ciclesonide being a pro-drug that can be administered once daily with possibly increased adherence leading to increased control of asthma and fewer side effects.

Topics: Adolescent; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Budesonide; Child; Child, Preschool; Fluticasone; Humans; Pregnenediones; Randomized Controlled Trials as Topic

During the last few years, fixed combinations of intranasal antihistamines and corticosteroids have been introduced for treatment of allergic rhinitis. The aim of this systematic review was to assess recent patents and clinical evidence for fixed combinations of intranasal antihistamines and intranasal corticosteroids in allergic rhinitis. Data base searches revealed that intranasal combinations of the antihistamine azelastine with the corticosteroids mometasone furoate, ciclesonide and fluticasone propionate, respectively, have been patented. Four randomized, double-blinded, parallel-group, placebo-controlled, multicenter trials sponsored by the manufacturer evaluated the fixed combination of intranasal azelastine 125 µg and fluticasone propionate 50 µg administered as one dose per nostril b.i.d. in patients with moderate-to-severe symptomatic allergic rhinitis ≥ 12 years of age. Three of the studies were published as a meta-analysis which found the fixed combination of azelastine and fluticasone propionate statistically significantly more efficacious in reducing baseline total nasal symptom score by 5.7 as compared to azelastine (4.4; P < 0.001), fluticasone propionate (5.1; P < 0.001) and placebo (3.0; P < 0.001). The findings were supported by secondary assessments of scores of specific nasal and ocular symptoms. Pharmacokinetic studies have revealed no drug-drug interactions but a discrete increase in bioavailability of fluticasone propionate which was considered clinically unimportant. Further efficacy and quality-of-life studies of combination products of nasal antihistamines and corticosteroids are needed, especially, in primary care settings and in children before fixed combination treatment can be considered first line therapy in allergic rhinitis. Fixed combination treatment of azelastine and fluticasone propionate may offer additional benefit to selected populations of adolescents and adults with moderate-to-severe symptoms.

Topics: Administration, Intranasal; Adolescent; Adrenal Cortex Hormones; Adult; Androstadienes; Animals; Drug Combinations; Evidence-Based Medicine; Fluticasone; Histamine Antagonists; Humans; Mometasone Furoate; Patents as Topic; Phthalazines; Pregnadienediols; Pregnenediones; Randomized Controlled Trials as Topic; Rhinitis, Allergic, Perennial; Rhinitis, Allergic, Seasonal; Treatment Outcome

Inhaled corticosteroids (ICS) are an integral part of asthma management, and act as an anti-inflammatory agent in the airways of the lung. These agents confer both significant benefit in terms of symptom management and improvement in lung function, but may also cause harm in terms of local and systemic side-effects. Ciclesonide is a novel steroid that is metabolised to its active component in the lung, making it a potentially useful for reducing local side effects.. To assess the efficacy and adverse effects of ciclesonide relative to those of other inhaled corticosteroids in the management of chronic asthma.. We searched the Cochrane Airways Group register of trials with pre-defined terms. Additional searches of PubMed and Clinicalstudyresults.org were undertaken. The literature searches for this review are current up to June 2007.. Randomised parallel or crossover studies were eligible for the review. We included studies comparing ciclesonide with other steroids both at nominally equivalent dose or lower doses of ciclesonide.. Two review authors independently assessed trial quality and extracted data. Study authors were contacted for additional information. Adverse effects information was collected from the trials.. Twenty one trials involving 7243 participants were included. Equal daily doses of ciclesonide and beclomethasone (BDP) or budesonide (BUD) gave similar results for peak expiratory flow rates (PEF), although forced vital capacity (FVC) was higher with ciclesonide. Data on forced expired volume in one second (FEV1) were inconsistent. Withdrawal data and symptoms were similar between treatments. Compared with the same dose of fluticasone (FP), data on lung function parameters (FEV1, FVC and PEF) did not differ significantly. Paediatric quality of life score favoured ciclesonide. Candidiasis was less frequent with ciclesonide, although other side-effect outcomes did not give significant differences in favour of either treatment. When lower doses of ciclesonide were compared to BDP or BUD, the difference in FEV1 did not reach significance but we cannot exclude a significant effect in favour of BDP/BUD. Other lung function outcomes did not give significant differences between treatments. Paediatric quality of life scores did not differ between treatments. Adverse events occurred with similar frequency between ciclesonide and BDP/BUD. Comparison with FP at half the nominal dose was undertaken in three studies, which indicated that FEV1 was not significantly different, but was not equivalent between the treatments (per protocol: -0.05 L 95% confidence intervals -0.11 to 0.01).. The results of this review give some support to ciclesonide as an equivalent therapy to other ICS at similar nominal doses. The studies assessed low doses of steroids, in patients whose asthma required treatment with low doses of steroids. At half the dose of FP and BDP/BUD, the effects of ciclesonide were more inconsistent The effect on candidiasis may be of importance to people who find this to be problematic. The role of ciclesonide in the management of asthma requires further study, especially in paediatric patients. Further assessment against FP at a dose ratio of 1:2 is a priority.

Topics: Administration, Inhalation; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Chronic Disease; Fluticasone; Humans; Pregnenediones; Randomized Controlled Trials as Topic

Inhaled corticosteroids (ICSs) are the most potent anti-inflammatory choice for patients with asthma. Selecting the most appropriate ICS for a patient requires a thorough understanding of the pharmacologic properties of each drug.. This review details the pharmacologic properties of ciclesonide (CIC) and fluticasone propionate (FP) and reviews the available data on suppression of the hypothalamic-pituitary-adrenal axis as a measure of systemic exposure and safety profile.. Clinical studies and case reports were identified through a MEDLINE and EMBASE search of English-language articles. The databases were searched for the years 1990 to April 2005 using the terms ciclesonide, fluticasone, ICS, and adrenal suppression. All studies were clinical trials of pharmacologic properties of the ICSs in humans.. A total of 1082 articles were identified. CIC and FP are 2 of the most potent ICSs. Both have high receptor-binding affinities (12 times and 18 times that of dexamethasone, respectively), and both may provide enhanced respiratory effects through a prolonged pulmonary residence time. The CIC metered dose inhaler dispenses smaller and more highly respirable particles than FP (1.1-2.1 pm vs 2.8-3.2 microm, respectively). Therefore, a greater percentage of administered CIC is topically deposited in the lungs (52% vs 12% to 13% for FP). CIC is delivered as an inactive parent compound, which is converted to its active metabolite, desisobutyryl-CIC (des-CIC), by esterases in the airways. More than 50% of a dose of CIC is deposited and distributed evenly throughout the lungs of healthy adults; lipid conjugation in the lung also may increase lung residence time. On entering the systemic circulation, both corticosteroids are rapidly cleared by the liver (elimination half-life of 3.5 hours for CIC vs 7.8 hours for FP). However, plasma protein binding is greater with CIC/des-CIC (99%/ approximately 99%) than FP (90%), resulting in reduced amounts of des-CIC (660 pg/d) may result in adrenal suppression. CIC has not been reported to produce any significant adrenal suppression throughout its studied dose range (up to 1280 micro/d).. A review of the literature suggests that CIC, as compared with FP, achieves greater pulmonary deposition, causes fewer adverse oropharyngeal effects, deposits less biologically active drug in the systemic circulation, and has less potential for adrenal suppression.

Topics: Adrenal Cortex Hormones; Androstadienes; Asthma; Fluticasone; Half-Life; Humans; Hypothalamo-Hypophyseal System; Metered Dose Inhalers; Pituitary-Adrenal System; Pregnenediones

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 aimed to systematically review published randomised controlled trials of the effectiveness and safety of ciclesonide compared to alternative inhaled corticosteroids in people with asthma.. We performed literature searches on MEDLINE, EMBASE, PUBMED, the COCHRANE LIBRARY and various Internet evidence sources for randomised controlled trials or systematic reviews comparing ciclesonide to beclomethasone or budesonide or fluticasone in adult humans with persistent asthma. Data was extracted by one reviewer.. Five studies met the inclusion criteria. Methodological quality was variable. There were no trials comparing ciclesonide to beclomethasone. There was no significant difference between ciclesonide and budesonide or fluticasone on the following outcomes: lung function, symptoms, quality of life, airway responsiveness to a provoking agent or inflammatory markers. However, the trials were very small in size, increasing the possibility of a type II error. One trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 47% of that of budesonide while another trial demonstrated that the combined deposition of ciclesonide (and its active metabolite) in the oropharynx was 53% of that of fluticasone. One trial demonstrated less suppression of cortisol in overnight urine collection after ciclesonide compared to fluticasone (geometric mean fold difference = 1.5, P < 0.05) but no significant difference in plasma cortisol response.. There is very little evidence comparing CIC to other ICS, restricted to very small, phase II studies of low power. These demonstrate CIC has similar effectiveness and efficacy to FP and BUD (though equivalence is not certain) and findings regarding oral deposition and HPA suppression are inconclusive. There is no direct comparative evidence that CIC causes fewer side effects since none of the studies reported patient-based outcomes.

Topics: Administration, Inhalation; Adult; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Bronchodilator Agents; Budesonide; Chronic Disease; Fluticasone; Humans; Pregnenediones; Randomized Controlled Trials as Topic

Review the molecular mechanisms of action, efficacy, and potential side effects associated with inhaled corticosteroids (ICS) in children with persistent asthma.. Articles in English from MEDLINE. The following terms were used: corticosteroids, inhaled corticosteroids, asthma, children, beclomethasone, fluticasone, budesonide, ciclesonide, growth, adrenal insufficiency, bone mineral density, and oral candidiasis. Treatment guidelines, review articles, controlled trials, meta-analyses, and systematic reviews evaluating the efficacy and the adverse events of treatment with ICS were selected.. In vivo and in vitro studies show that the available ICS have different pharmacokinetic and pharmacodynamic properties that result in different action potentials. ICS also differ as to the systemic and local side effects. The bioavailability of these products is essential in order to determine the incidence of side effects. In general, ICS are capable of controlling asthma, reducing the number of exacerbations, medical consultations, hospitalizations, and the need of oral corticosteroid (applications) bursts. Improvement can also be seen in pulmonary function, especially in patients with recent onset asthma. The most documented adverse effect is transitory decrease of growth rate.. ICS are the main anti-inflammatory agent used to treat persistent asthma. When administered in low doses, they seem to be safe and effective. Patient monitoring allows for early detection of possible side effects associated with ICS.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Allergic Agents; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Biological Availability; Bone and Bones; Bone Density; Budesonide; Child; Child Development; Fluticasone; Humans; Pregnenediones; Treatment Outcome

The pathology of asthma has clarified that the inflammatory process in the pulmonary airways of the asthmatic patients determines asthma symptom activity primarily. Among the anti-inflammatory agents currently available to treat asthma, glucocorticoids are the most effective, and the topically active agents, inhaled corticosteroids (ICS) are the most efficient. In Japan, two ICS are commercially available: beclomethasone dipropionate (BDP) and fluticasone propionate(FP). Both agents have been widely used and their clinical efficacy (BDP vs FP at half the microgram dose of the BDP) are largely comparable. In order to bring asthmatic patients maximal benefits of the ICS, enhancing treatment compliance and giving educations (including how to use the ICS) are mandatory. New ICS, which have better drug delivery and be topically more potent, will be available.

Topics: Administration, Inhalation; Administration, Topical; Androstadienes; Anti-Asthmatic Agents; Anti-Inflammatory Agents; Asthma; Beclomethasone; Budesonide; Clinical Trials as Topic; Fluticasone; Glucocorticoids; Humans; Hydrocarbons, Fluorinated; Patient Education as Topic; Pregnenediones

Patients with mild persistent asthma constitute about 70% of the asthma population; thus, it is important to know which first-line treatment is best for the management of mild asthma. We compared benefits of first-line treatment with ciclesonide and a combination of fluticasone and salmeterol in patients with mild asthma.. Patients aged 12 to 75 years with mild persistent asthma were enrolled in a randomized, double-blind, placebo-controlled study. After run-in, patients were randomized to ciclesonide 160 μg once daily (CIC160), fluticasone propionate/salmeterol 100/50 μg bid (FP200/S100), or placebo for 52 weeks. The primary variable was time to first severe asthma exacerbation; the coprimary variable was the percentage of poorly controlled asthma days. Patients recorded asthma symptoms and salbutamol use in electronic diaries and completed a standardized version of the Asthma Quality of Life Questionnaire.. Compared with placebo, the time to first severe asthma exacerbation was prolonged, and lung function was improved with FP200/S100 treatment (P = .0002) but not with CIC160. Both CIC160 and FP200/S100 provided significantly fewer poorly controlled asthma days than placebo (P ≤ .0016 for both active treatments). Moreover, both active treatments provided significantly more asthma symptom-free days (P ≤ .0001), rescue medication-free days (P = .0005, one-sided), and days with asthma control (P ≤ .0033). Overall Asthma Quality of Life Questionnaire scores were significantly higher in both active treatment groups than placebo (P ≤ .0017).. In mild asthma, FP200/S100 prolonged time to first severe asthma exacerbation, and CIC160 and FP200/S100 were clinically equieffective for most measures of asthma control.. ClinicalTrials.gov; No.: NCT00163358; URL: www.clinicaltrials.gov.

Topics: Adolescent; Adult; Aged; Albuterol; Androstadienes; Anti-Allergic Agents; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Double-Blind Method; Female; Fluticasone; Humans; Male; Middle Aged; Placebos; Pregnenediones; Quality of Life; Respiratory Function Tests; Salmeterol Xinafoate; Statistics, Nonparametric; Surveys and Questionnaires; Treatment Outcome

Measurement of short-term lower-leg growth rate in children by knemometry has become established as an integral part of the available measures of systemic activity of inhaled corticosteroids (ICS) in children. The aim of this study was to compare the effects of the novel ICS ciclesonide (CIC) and the ICS fluticasone propionate (FP) on lower-leg growth rate and hypothalamic-pituitary-adrenal-axis function in children with mild asthma. In a double-blind, placebo-controlled, three-period crossover study, 28 children, aged 6-12 yr, sequentially received daily doses of CIC 320 μg, FP 375 μg (330 μg ex-actuator) and placebo via a spacer in a randomized order. Each 2-wk treatment period was followed by a 2-wk washout period. Knemometry was performed at the beginning and end of each treatment period. Cortisol levels in 12-h overnight urine were measured at the end of each treatment period. No statistically significant differences were seen in lower-leg growth rates between CIC (0.30 mm/wk) and placebo (0.43 mm/wk) treatments. Lower-leg growth rate during FP treatment (0.08 mm/wk) was significantly reduced compared with both placebo [least squares (LS) mean: -0.35 (95% CI: -0.53, -0.18; p = 0.0002)] and CIC [LS mean: -0.23 (95% CI: -0.05, -0.40; p = 0.0137)]. Cortisol levels in 12-h overnight urine were significantly lower in the FP group when compared with CIC (p < 0.05); however, there were no statistically significant differences between each of the active treatments and placebo. CIC had no significant effect on lower-leg growth rate in children aged 6-12 yr with mild asthma. In contrast, a similar dose of FP significantly reduced lower-leg growth rate compared with placebo and CIC.

Topics: Androstadienes; Asthma; Child; Disease Progression; Double-Blind Method; Female; Fluticasone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Leg Bones; Male; Pituitary-Adrenal System; Pregnenediones; Time Factors

Inhaled corticosteroids (ICS) are the mainstay of asthma treatment, but conventional ICS may have limited effectiveness in inflammation and patency of small airways. Ciclesonide is delivered and deposited in the peripheral region of the lung as a small particle corticosteroid. The aim of the study is to compare the effects of ciclesonide with fluticasone propionate on small airway function in asthma.. Thirty mild persistent asthma patients treated with 200 microg of fluticasone propionate were randomized to receive either ciclesonide 200 microg once daily or fluticasone propionate 100 microg twice daily for 8 weeks. Small airway function was assessed by impulse oscillometry (IOS) and percentage of eosinophil induced sputum.. We observed that ciclesonide significantly improved IOS measured resistance of small airways (R5-R20; p<0.05), distal reactance (X5; p<0.01), reactance area (AX; p<0.01), and decreased late-phase sputum eosinophil level (p<0.01) compared with fluticasone propionate. There were no significant changes in spirometry indices in either group during the study.. These findings suggest that ciclesonide improves small airway function and inflammation compared with fluticasone propionate in mild asthma. This study provides evidence that IOS and late-phase induced sputum allows detection of changes in the small airways that can not be detected by spirometry.

Topics: Adult; Airway Resistance; Androstadienes; Asthma; Cell Count; Cell Movement; Eosinophils; Female; Fluticasone; Humans; Male; Middle Aged; Oscillometry; Pregnenediones; Spirometry; Sputum

Inhaled corticosteroids, such as fluticasone propionate (FP) and ciclesonide (CIC), are commonly used for the treatment of asthma. The objectives of this study were to characterize pharmacokinetics (PK) and pharmacodynamics (PD) of FP and a pharmacologically active metabolite of CIC (desisobutyryl-ciclesonide [Des-CIC]) using a nonlinear mixed-effects modeling approach, to investigate selected covariate effects on PK and PD parameters of FP and Des-CIC, and to assess the systemic effects of FP and CIC on serum cortisol suppression in patients with persistent asthma. This was a randomized, double-blind, placebo-controlled, double-dummy, 5-period, crossover, multicenter clinical study. A total of 32 patients were enrolled and given basic asthma medication (salmeterol 50 µg twice per day [BID] and CIC 160 µg daily in the evening) through the entire study. During crossover periods, patients were given placebo or CIC 160 µg BID (ex actuator), CIC 320 µg BID (ex actuator), FP 220 µg BID (ex actuator), or FP 440 µg BID (ex actuator). The FP and Des-CIC PK were described using a 1-compartment and a 2-compartment linear model with first-order absorption process. The FP population PK parameter estimates of the first-order rate constant, relative clearance, and volume of distribution were 4.07 1/h, 890 L/h, and 9800 L, respectively. The Des-CIC PK parameter estimates of the first-order absorption rate constant were 2.63 1/h, clearance 202 L/h (non-CIC treatment) or 271 L/h (CIC treatment), and volume of distribution 947 L. Gender was a significant covariate on the maximum cortisol release rate (male, 3440 µg/h; female, 4310 µg/h). The CIC showed the least serum cortisol suppression of the tested dosing regimens.

Topics: Administration, Inhalation; Adult; Albuterol; Androstadienes; Anti-Allergic Agents; Area Under Curve; Asthma; Bronchodilator Agents; Cross-Over Studies; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; Half-Life; Humans; Hydrocortisone; Male; Middle Aged; Pregnenediones; Salmeterol Xinafoate; Sex Factors

To compare the efficacy of ciclesonide (80 microg/day) with fluticasone propionate (200 microg/day) in mild to moderate persistent asthma.. Patients aged 12-75 years and previously treated with low doses of inhaled corticosteroid (fluticasone propionate 250 microg/day or equivalent) entered a 2-4 week run-in period during which only rescue medication was permitted. For inclusion into the double-blind, 24-week treatment period, patients had to show a forced expiratory volume in 1s (FEV(1)) of 61-90% predicted and a decrease in FEV(1) during run-in of >or=10%. Patients (n = 480) were randomized to ciclesonide 80 microg (ex-actuator) once daily in the evening or fluticasone propionate 100 microg (ex-valve) twice daily. The primary efficacy variable was the change from baseline in FEV(1). Secondary efficacy variables included asthma control and asthma-specific quality of life.. Both treatments significantly increased FEV(1) and other lung function variables from baseline (p < 0.0001, both groups, all variables). The least squares mean increases in FEV(1) were 0.46L (ciclesonide) and 0.52L (fluticasone propionate); non-inferiority of ciclesonide to fluticasone propionate was demonstrated (p = 0.0002, per-protocol analysis). Five patients in each group experienced asthma exacerbations. Improvements in the percent of days with asthma control (days with no asthma symptoms and no use of rescue medication) and asthma-specific quality of life were comparable between treatments.. The study confirmed similar efficacy of ciclesonide 80 microg once daily and fluticasone propionate 100 microg twice daily in mild to moderate persistent asthma. The low dose of ciclesonide was efficacious during long-term treatment. EudraCT number: 2004-001072-39.

Topics: Adolescent; Adult; Aged; Androstadienes; Asthma; Bronchodilator Agents; Child; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pregnenediones; Quality of Life; Respiratory Function Tests; Surveys and Questionnaires; Treatment Outcome; Young Adult

Patient-reported outcomes provide new insights into the dynamics of asthma management. Further to asthma control and quality of life, self-reported side effects of treatment can be assessed with the validated Inhaled Corticosteroid Questionnaire (ICQ).. To compare patient-reported side effects between the inhaled corticosteroids ciclesonide and fluticasone propionate.. Patients with moderate or moderate-to-severe asthma, pre-treated with a constant dose and type of medication, were randomized in three separate studies: 1) once daily ciclesonide 320 μg (n = 234) or twice daily fluticasone propionate 200 μg (n = 240); 2) twice daily ciclesonide 320 μg (n = 255) or twice daily fluticasone propionate 375 μg (n = 273); and 3) twice daily ciclesonide 320 μg (n = 259) or twice daily fluticasone propionate 500 μg (n = 244). Patients rated the side effect questions of the 15 domain ICQ on a 7-point Likert scale (0 = not at all, 6 = a very great deal) during scheduled visits.. The majority of side effect scores remained similar with ciclesonide but worsened statistically significantly with fluticasone propionate from baseline to the end of the study in within-treatment analyses. In between-treatment analyses of studies 1 and 3 ciclesonide significantly improved total side effect scores (p < 0.025) and 14 out of 30 individual local and systemic domain scores (p < 0.025) compared with fluticasone propionate. In Study 2, although ciclesonide improved the majority of scores compared with fluticasone propionate only 'oropharyngeal itching' reached statistical significance (p < 0.025, one-sided).. Patient-perceived side effects differ depending on the type of inhaled corticosteroids used. Patients with moderate-to-severe asthma report less intense side effects assessed with ICQ with ciclesonide than with fluticasone propionate.. The reported trials were completed before July 1 2005 and, therefore, are not registered.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchoconstrictor Agents; Child; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pregnenediones; Quality of Life; Surveys and Questionnaires; Treatment Outcome; Young Adult

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.. 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.. Seven hundred and forty-four patients (aged 6-11 years) were randomized to ciclesonide (80 or 160 microg once daily) or fluticasone propionate (88 microg twice daily), following a 2-4-week run-in. Efficacy measurements included forced expiratory flow in 1s (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.. FEV(1) and morning PEF increased from baseline in all groups (p<0.0001). Ciclesonide 160 microg was not inferior to fluticasone propionate 176 microg for FEV(1) (p=0.0030, one-sided). In all groups, asthma symptom score sums and rescue medication use significantly improved (p<0.0001). The percentages of asthma symptom-, rescue medication- and nocturnal awakening-free days were high, with no significant differences between treatments. Quality of life scores improved with all treatments (p<0.0001). A significant dose-response occurred between low and higher doses of ciclesonide for exacerbations and asthma control definitions. The incidences of adverse events were comparable across treatments. Urine free cortisol levels decreased significantly with fluticasone propionate (p=0.0103), but not with ciclesonide.. 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.

Topics: Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchoconstrictor Agents; Child; Chronic Disease; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocortisone; Lung; Male; Methacholine Chloride; Pregnenediones; Quality of Life; Treatment Outcome

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.

Topics: Adenosine; Adolescent; Adult; Aged; Albuterol; Analysis of Variance; Androstadienes; Anti-Allergic Agents; Area Under Curve; Asthma; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocortisone; Least-Squares Analysis; Male; Methacholine Chloride; Middle Aged; Placebos; Pregnenediones; Salmeterol Xinafoate; Spirometry; Treatment Outcome

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.. 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.. 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).. 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.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Androstadienes; Asthma; Bronchodilator Agents; Child; Drug Administration Schedule; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pregnenediones; Quality of Life; Recurrence; Treatment Outcome

To compare the effects of once-daily ciclesonide and twice-daily fluticasone propionate in patients with moderate persistent asthma.. Patients aged 12-75 years with moderate bronchial asthma entered a 1-4 week run-in period. For inclusion into the 12-week, randomized, open-label treatment period, patients had to have a forced expiratory volume in 1s (FEV1) of either 60-80% of predicted or 80% of predicted and a defined use of rescue medication and asthma symptoms, depending on previous treatment. Patients received ciclesonide 320 microg once daily (ex-actuator) or fluticasone propionate 200 microg twice daily. Primary efficacy endpoint was change from baseline in FEV1.. In total, 474 patients were randomized. FEV1 increased significantly from baseline with ciclesonide and fluticasone propionate in the intention-to-treat (ITT) and per-protocol (PP) analyses (all p < 0.0001). Treatment difference was -31 mL (95% confidence interval [CI]: -121, 59) in the PP analysis, demonstrating non-inferiority of ciclesonide. Similar findings were seen for other measures of lung function. In the ITT population, asthma symptom scores and rescue medication use decreased with both treatments (all p < 0.0001). Improvement in health-related quality of life (HRQoL) from baseline was significantly greater with ciclesonide than fluticasone (p = 0.005; one-sided). There were no cases of oral candidiasis in patients receiving ciclesonide and nine cases (3.8%) in those receiving fluticasone propionate (p = 0.002; one-sided).. Treatment with once-daily ciclesonide and twice-daily fluticasone propionate resulted in similar improvements in lung function in patients with moderate persistent asthma. Ciclesonide showed significant improvements in oral candidiasis and HRQoL over fluticasone.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Androstadienes; Asthma; Bronchodilator Agents; Child; Drug Administration Schedule; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pregnenediones; Respiratory Function Tests

To compare a step-down approach in well-controlled asthma patients, as recommended by treatment guidelines, from fluticasone propionate 250 microg twice daily (FP250 BID), or equivalent, to ciclesonide 160 microg once daily (CIC160 OD) with continued FP250 BID treatment.. Patients with well-controlled asthma prior to study entry were included in two identical, randomized, double-blind, double-dummy, parallel-group studies. After a 2-week run-in period with FP250 BID, patients were randomized to CIC160 OD (n = 58) or FP250 BID (n = 53) for 12 weeks. Primary endpoints were percentage of days with asthma control, asthma symptom-free days, rescue medication-free days and nocturnal awakening-free days. Secondary endpoints included lung function variables, asthma symptom scores, rescue medication use and asthma exacerbations. Safety variables were also recorded.. Patients had >or= 97% of days with asthma control, 98% asthma symptom-free days and 100% of days free from rescue medication use and nocturnal awakenings in both treatment groups (median values). There were no significant between-treatment differences for any of the primary or secondary efficacy variables. Overall, 42 treatment-emergent adverse events (TEAEs) were reported in the CIC160 OD group and 49 TEAEs were reported in the FP250 BID group. There were no clinically relevant changes from baseline in the safety variables in either treatment group.. Patients well controlled on FP250 BID, or equivalent, who were stepped down to CIC160 OD, maintained similar asthma control compared with patients who received continued treatment standardized to FP250 BID.

Topics: Adolescent; Adult; Aged; Androstadienes; Anti-Allergic Agents; Anti-Inflammatory Agents; Asthma; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone; Humans; Male; Middle Aged; Pregnenediones; Treatment Outcome

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 micro g (n = 278) or 160 micro g (n = 271), or twice daily fluticasone propionate 88 micro 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 micro g or 160 micro g showed comparable efficacy and tolerability to twice daily fluticasone propionate 88 micro g in persistent asthma.

Topics: Adolescent; Adult; Aged; Androstadienes; Anti-Allergic Agents; Asthma; Child; Double-Blind Method; Drug Administration Schedule; Female; Fluticasone; Humans; Male; Middle Aged; Pregnenediones; Respiratory Function Tests

Inhaled corticosteroids are the mainstay of therapy in asthma, but local and systemic side effects and adherence remain a concern. Ciclesonide is an inhaled corticosteroid with on-site lung activation that provides potent anti-inflammatory activity and has been shown to have a good safety profile, even at high doses.. The aim of this study was to compare the efficacy and safety of once-daily ciclesonide versus twice-daily fluticasone propionate at comparable daily doses in patients with asthma.. In this multicenter, randomized, double-blind, double-dummy, parallel group study, 529 patients were randomized to ciclesonide 160 microg once daily or fluticasone propionate 88 microg twice daily for 12 weeks. The primary endpoint was change in lung function.. Both ciclesonide and fluticasone propionate significantly improved forced expiratory volume in 1s, forced vital capacity, and morning peak expiratory flow compared with baseline (p<0.0001 for all variables). Both medications reduced asthma symptoms and rescue medication use within the first 24 h. At the tested dose, both medications were equally safe and well tolerated.. Ciclesonide 160 microg once daily was as effective as fluticasone propionate 88 microg twice daily in improving lung function and asthma symptoms, and in reducing rescue medication use in patients with asthma.

Topics: Adolescent; Adult; Aged; Androstadienes; Anti-Asthmatic Agents; Asthma; Bronchodilator Agents; Child; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Pregnenediones; Respiratory Function Tests; Vital Capacity

Ciclesonide is a novel, lung-activated, inhaled corticosteroid with once-daily efficacy and potent anti-inflammatory activity. The aim of the study was to compare the effect of ciclesonide and fluticasone propionate on exhaled nitric oxide (FENO), pulmonary function, and other parameters used in clinical evaluation of patients with mild allergic asthma. The study indicates that ciclesonide (in a daily dose of either 80 or 160 microg) induces both a faster and stronger decrease of FENO in comparison with fluticasone (100 microg twice daily). In both groups of patients treated with ciclesonide, the highest decrease in FENO levels was observed after 2 weeks of treatment. In the group of patients treated with fluticasone, this maximum effect was not observed till 8 weeks. An improvement in spirometric indices was observed in all groups studied. Statistical differences between the groups were not found; however, there was a trend toward higher increase in the group receiving 160 microg of ciclesonide. In all groups studied we observed clinical improvement (asthmatic symptoms and consumption of rescue medication were reduced), but there were no significant differences between these groups. Our results indicate that ciclesonide, compared with fluticasone, has stronger anti-inflammatory activity in patients with mild allergic asthma.

Topics: Adult; Androstadienes; Anti-Allergic Agents; Asthma; Breath Tests; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Male; Middle Aged; Nitric Oxide; Pregnenediones; Treatment Outcome

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.

Topics: Administration, Inhalation; Adolescent; Androstadienes; Anti-Inflammatory Agents; Asthma; Child; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocortisone; Male; Pregnenediones; Respiratory Function Tests

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, randomized, 2-treatment, 2-sequence study design. The oropharynx was washed out immediately and at 15, 30, 45, and 60 minutes after inhalation. Samples were analyzed for ciclesonide, des-CIC, and FP using liquid chromatography with tandem 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 samples. 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.

Topics: Administration, Inhalation; Adult; Androstadienes; Area Under Curve; Asthma; Chromatography, Liquid; Cough; Drug Administration Schedule; Ethanol; Female; Fluticasone; Humans; Male; Mass Spectrometry; Metered Dose Inhalers; Oropharynx; Pregnenediones; Solutions; Therapeutic Irrigation; Time Factors

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.. 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.. Fourteen patients with moderate persistent asthma (mean FEV(1), 67% predicted [prior to each randomized treatment]) completed the study, which had a randomized, 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 randomized 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.. 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.. 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.

Topics: Administration, Inhalation; Androstadienes; Asthma; Breath Tests; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchodilator Agents; Corticotropin-Releasing Hormone; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Humans; Hydrocortisone; Male; Methacholine Chloride; Middle Aged; Nitric Oxide; Peak Expiratory Flow Rate; Pregnenediones; Quality of Life; Spirometry

Despite their proven efficacy in the treatment and prevention of asthma exacerbations, current inhaled corticosteroids carry safety concerns, especially adrenal suppression. Ciclesonide (hydrofluoroalkane propellant) is a novel inhaled corticosteroid with few, if any, clinical adverse events.. To evaluate the potential effects of ciclesonide therapy on the dynamic cortisol response to sequential low- and high-dose cosyntropin stimulation in adults with mild-to-moderate persistent asthma.. This was a double-blind, randomized, placebo-controlled, 12-week study in adults with mild-to-moderate asthma. One hundred sixty-four patients were randomized and treated; 148 patients completed the study. Fluticasone propionate (chlorofluorocarbon propellant) was used as an active comparator. The doses administered were 320 microg of ciclesonide once daily, 320 microg of ciclesonide twice daily, and 440 microg of fluticasone propionate twice daily, all doses ex-actuator.. For both ciclesonide groups, changes in mean low- and high-dose peak serum cortisol levels and in 24-hour urinary free cortisol levels corrected for creatinine were small vs baseline and comparable with placebo. For the fluticasone propionate group, significant reductions vs placebo in serum cortisol levels in response to high-dose cosyntropin stimulation and in 24-hour urinary free cortisol levels were observed. Oral candidiasis rates were 2.5% for 320-microg/d ciclesonide, 2.4% for 640-microg/d ciclesonide, and 22.0% for 880-microg/d fluticasone propionate.. These findings confirm the safety of ciclesonide therapy, demonstrating that at doses up to 640 microg/d, the drug does not affect sensitive markers of adrenal function.

Topics: Adolescent; Adult; Aged; Androstadienes; Anti-Asthmatic Agents; Asthma; Cosyntropin; Double-Blind Method; Female; Fluticasone; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Patient Compliance; Pituitary-Adrenal System; Pregnenediones

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

Topics: Adenosine Monophosphate; Administration, Inhalation; Adolescent; Adult; Androstadienes; Area Under Curve; Asthma; Bronchial Hyperreactivity; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Drug Therapy, Combination; Female; Fluticasone; Humans; Hydrocortisone; Lung; Male; Middle Aged; Pregnenediones; Spirometry; Treatment Outcome

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

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Androstadienes; Anti-Inflammatory Agents; Asthma; Cosyntropin; Dose-Response Relationship, Drug; Double-Blind Method; Female; Fluticasone; Hormones; Humans; Hydrocortisone; Hypothalamo-Hypophyseal System; Male; Middle Aged; Pituitary-Adrenal System; Pregnenediones

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.. Nineteen mild-to-moderate asthmatic patients completed the study per protocol in randomized, 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 randomized 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.. 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.. 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.

Topics: Administration, Inhalation; Androstadienes; Asthma; Bronchial Hyperreactivity; Bronchial Provocation Tests; Bronchoconstrictor Agents; Bronchodilator Agents; Cross-Over Studies; Double-Blind Method; Female; Fluticasone; Forced Expiratory Volume; Humans; Hydrocarbons, Fluorinated; Male; Methacholine Chloride; Middle Aged; Pregnenediones; Vital Capacity

Particle inhalation is an effective and rapid delivery method for a variety of pharmaceuticals, particularly bronchodilation drugs used for treating asthma and COPD. Conditions of relative humidity and temperature inside the lungs are generally very different from the outside ambient air, with the lung typically being warmer and more humid. Changes in humidity, from inhaler to lung, can cause hygroscopic phase transitions and particle growth. Increasing particle size and mass can negatively affect particle deposition within the lung leading to inefficient treatment, while deliquescence prior to impaction is liable to accelerate drug uptake. To better understand the hygroscopic properties of four pharmaceutical aerosol particles; pharmaceutical particles from four commercially available pressurised metered dose inhalers (pMDIs) were stably captured in an optical trap, and their composition was examined online via Raman spectroscopy. Micron-sized particles of salbutamol sulfate, salmeterol xinafoate, fluticasone propionate and ciclesonide were levitated and examined over a range of relative humidity values inside a chamber designed to mimic conditions within the respiratory tract. The effect of temperature upon hygroscopicity was also investigated for salbutamol sulfate particles. Salbutamol sulfate was found to have significant hygroscopicity, salmeterol xinafoate showed some hygroscopic interactions, whilst fluticasone propionate and ciclesonide revealed no observable hygroscopicity. Thermodynamic and structural modelling is used to explain the observed experimental results.

Topics: Aerosols; Albuterol; Fluticasone; Humidity; Metered Dose Inhalers; Models, Structural; Particle Size; Pregnenediones; Salmeterol Xinafoate; Spectrum Analysis, Raman; Temperature; Wettability

Most randomised clinical trials typically exclude a significant proportion of asthma patients, including those at higher risk of adverse events, with comorbidities, obesity, poor inhaler technique and adherence, or smokers. However, these patients might differentially benefit from extrafine-particle inhaled corticosteroids (ICS). This matched cohort, database study, compared the effectiveness of extrafine-particle with fine-particle ICS in a real-life population initiating ICS therapy in the Netherlands.. Data were from the Pharmo Database Network, comprising pharmacy and hospital discharge records, representative of 20 % of the Dutch population. The study population included patients aged 12 - 60, with a General Practice-recorded diagnosis for asthma (International Classification of Primary Care code R96), when available, ≥2 prescriptions for asthma therapy at any time in their recorded history, and receiving first prescription of ICS therapy as either extrafine-particle (ciclesonide or hydrofluoroalkane beclomethasone dipropionate [BDP]) or fine-particle ICS (fluticasone propionate or non-extrafine-particle-BDP). Patients were matched (1:1) on relevant demographic and clinical characteristics over 1-year baseline. Primary outcomes were severe exacerbation rates, risk domain asthma control and overall asthma control during the year following first ICS prescription. Secondary outcomes, treatment stability and being prescribed higher versus lower category of short-acting β2 agonists (SABA) dose, were compared over a 1-year outcome period using conditional logistic regression models.. Following matching, 1399 patients were selected in each treatment cohort (median age: 43 years; males: 34 %). Median (interquartile range) initial ICS doses (fluticasone-equivalents in μg) were 160 (160 - 320) for extrafine-particle versus 500 (250 - 500) for fine-particle ICS (p < 0.001). Following adjustment for residual confounders, matched patients prescribed extrafine-particle ICS had significantly lower rates of exacerbations (adjusted rate ratio [95 % CI], 0.59 [0.47-0.73]), and significantly higher odds of achieving asthma control and treatment stability in the year following initiation than those prescribed fine-particle ICS, and this occurred at lower prescribed doses. Patients prescribed extrafine-particle ICS had lower odds of being prescribed higher doses of SABA (0.50 [0.44-0.57]).. In this historical, matched study, extrafine-particle ICS was associated with better odds of asthma control than fine-particle ICS in patients prescribed their first ICS therapy in the Netherlands. Of importance, this was reached at significantly lower prescribed dose.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Adult; Anti-Asthmatic Agents; Asthma; Beclomethasone; Cohort Studies; Databases, Factual; Female; Fluticasone; Humans; Logistic Models; Male; Middle Aged; Netherlands; Particle Size; Pregnenediones; Treatment Outcome

Assessing the dissolution behavior of orally inhaled drug products (OIDs) has been proposed as an additional in vitro test for the characterization of innovator and generic drug development. A number of suggested dissolution methods (e.g., commercially available Transwell or Franz cell systems) have in common a membrane which provides the separation between the donor compartment, containing nondissolved drug particles, and an acceptor (sampling) compartment into which dissolved drug will diffuse. The goal of this study was to identify and overcome potential pitfalls associated with such dissolution systems using the inhaled corticosteroids (ICS), viz., budesonide, ciclesonide, and fluticasone propionate, as model compounds. A respirable fraction (generally stage 4 of a humidity, flow, and temperature controlled Andersen Cascade Impactor (ACI) or a Next Generation Impactor (NGI)) was collected for the tested MDIs. The dissolution behavior of these fractions was assessed employing the original and an adapted Transwell system using dissolution media which did or did not contain surfactant (0.5% sodium dodecyl sulfate). The rate with which the ICS transferred from the donor to the acceptor compartment was assessed by HPLC. Only a modified system that incorporated faster equilibrating membranes instead of the original 0.4 μm Transwell membrane resulted in dissolution and not diffusion being the rate-limiting step for the transfer of drug from the donor to the acceptor compartment. Experiments evaluating the nature of the dissolution media suggested that the presence of a surfactant (e.g., 0.5% SDS) is essential to obtain rank order of dissolution rates (e.g., for budesonide, fluticasone propionate, and ciclesonide) that is in agreement with absorption rates of these ICS obtained in studies of human pharmacokinetics. Using the optimized procedure, the in vitro dissolution behavior of budesonide, ciclesonide, and fluticasone propionate agreed approximately with descriptors of in vivo absorption. The optimized procedure, using membranes with increased permeability and surfactant containing dissolution medium, represents a good starting point to further evaluate in vitro/in vivo correlations.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Budesonide; Cells, Cultured; Drugs, Generic; Fluticasone; Humans; Membranes; Oral Sprays; Pregnenediones; Respiratory Therapy; Respiratory Tract Absorption; Solubility; Surface-Active Agents; Tissue Culture Techniques

The choice among the different treatments available can have a great impact on the costs of asthma,. The objective of this study was to estimate the incremental cost-utility ratio of three inhaled corticosteroids (ICs): budesonide (BUD), fluticasone propionate (FP), and ciclesonide, compared to beclomethasone dipropionate (BDP) (the only IC included in the Compulsory Health Insurance Plan of Colombia),. A Markov-type model was developed to estimate costs and health outcomes of a simulated cohort of patients less than 18 years of age with persistent asthma treated over a 12-month period. Effectiveness parameters were obtained from a systematic review of the literature. Cost data were obtained from a hospital´s bills and from the national manual of drug prices. The study assumed the perspective of the national healthcare in Colombia. The main outcome was the variable "quality-adjusted life years" (QALY), RESULTS: While treatment with BDP was associated with the lowest cost (£106.16 average cost per patient during 12 months), treatment with FP resulted in the greatest gain in QUALYs (0.9325 QALYs). FP was associated with a greater gain in QALYs compared to BUD and ciclesonide (0.9325 vs. 0.8999 and 0.9051 QALYs, respectively) at lower costs (£231.19 vs. £309.27 and £270.15, respectively), thus leading to dominance. The incremental cost-utility ratio of FP compared to BDP was £19,835.28 per QALY, CONCLUSIONS: BDP is the most cost-effective therapy for treating pediatric patients with persistent asthma when willingness to pay (WTP) is less than £21,129.22/QALY, otherwise, FP is the most cost-effective therapy.

Topics: Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Beclomethasone; Budesonide; Child; Cohort Studies; Colombia; Computer Simulation; Cost-Benefit Analysis; Drug Costs; Female; Fluticasone; Humans; Male; Markov Chains; Models, Economic; Pregnenediones; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic

Recent developments concerning pressurized metered dose inhalers (pMDIs) with inhaled corticosteroids (ICS) are the introduction of ciclesonide and the replacement of propellants. As the results of in vivo studies depend on pMDIperformance, it is necessary to evaluate pMDIs in vitro for delivered dose and particle size distributions under different conditions.. Fluticasone 125microg, budesonide 200microg, beclomethasone HFA100microg, and ciclesonide 160microg were compared for delivered dose and particle size using laser diffraction analysis with inspiratory flow rates of 10, 20 and 30l/s.. The volume median diameter of budesonide was 3.5microm, fluticasone 2.8microm, beclomethasone and ciclesonide both 1.9microm. The mouthpiece retention was up to 30% of the nominal dose for beclomethasone and ciclesonide, 11-19% for the other pMDIs. Lifespan, flow rate, and air humidity had no significant influence on particle size distribution. The delivered dose of beclomethasone, budesonide, and ciclesonide remained constant over the lifespan. The delivered dose of fluticasone 125 decreased from 106% to 63%; fluticasone 250 also decreased whereas fluticasone 50 remained constant.. There is a significant difference in median particle size distribution between the different ICS pMDIs. Air humidity and inspiratory flow rate have no significant influence on particle size distribution. Ciclesonide 160 and beclomethasone 100 deliver the largest fine particle fractions of 1.1-3.1microm. The changes in delivered dose during the lifespan for the fluticasone 125 and 250 may have implications for patient care.

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Asthma; Beclomethasone; Budesonide; Drug Delivery Systems; Equipment Design; Fluticasone; Humans; Materials Testing; Metered Dose Inhalers; Particle Size; Pregnenediones

A new and very sensitive analytical method has been developed and validated to jointly determine the anti-inflammatory drug ciclesonide (CIC), its active principle metabolite M1 (CIC-M1) and fluticasone propionate (FP) in human serum, in the low concentration range from 10 to 1000 pg/mL. This was accomplished by high-performance liquid chromatography and tandem mass spectrometry using atmospheric pressure photo ionisation (HPLC-MS/MS with APPI) using 0.5 mL of serum. Serum was mixed with the internal standards (IS) D11-CIC and D11-CIC-M1 and extracted with diisopropylether. A gradient with acetonitrile (containing 10 mM of acetic acid and 10% of acetone) was used. HPLC-MS/MS of the acetic acid adducts of the analytes was performed in negative mode. The novel aspect of this method is that instead of the dopant being introduced directly into the source by means of an external HPLC pump, it was added to the mobile phase. This provided significantly better sensitivity than the usual method of in-source addition of the dopant, and with no loss in HPLC performance. Sensitivity for the analytes was about four times greater than with either APCI or ESI. Validation was performed in three batches. The inter-batch precision (CV) of the quality control samples in human serum ranged from 4.08% to 6.78% for CIC, from 2.57% to 7.74% for CIC-M1, and from 2.38% to 9.61% for FP. The inter-batch accuracy (with reference to the mean value) of the quality control samples in human serum ranged from 99.3% to 110.0% for CIC, from 101.8% to 104.7% for CIC-M1, and from 100.4% to 101.8% for FP. Calibration data and LLOQ data are also presented in this paper. The analytes were stable in human serum over three freeze/thaw cycles, or for 4h at room temperature, or for at least 18 months when stored at below -20 degrees C. This method was used for quantifying the analytes after inhalation of low-mug amounts of the drugs by patients.

Topics: Androstadienes; Anti-Inflammatory Agents; Atmospheric Pressure; Chromatography, High Pressure Liquid; Fluticasone; Humans; Pregnenediones; Reproducibility of Results; Tandem Mass Spectrometry

Topics: Administration, Inhalation; Adrenal Cortex Hormones; Androstadienes; Anti-Asthmatic Agents; Asthma; Drug Administration Schedule; Fluticasone; Humans; Metered Dose Inhalers; Pregnenediones; Treatment Outcome

The therapeutic effect of inhaled corticosteroids (ICS) may be affected by the metabolism of the drug in the target organ. We investigated the in vitro metabolism of beclomethasone dipropionate (BDP), budesonide (BUD), ciclesonide (CIC), and fluticasone propionate (FP) in human lung precision-cut tissue slices. CIC, a new generation ICS, is hydrolyzed by esterases in the upper and lower airways to its pharmacologically active metabolite desisobutyryl-ciclesonide (des-CIC).. Lung tissue slices were incubated with BDP, BUD, CIC, and FP (initial target concentration of 25 microM) for 2, 6, and 24 h. Cellular viability was assessed using adenosine 5'-triphosphate content and protein synthesis in lung slices. Metabolites and remaining parent compounds in the tissue samples were analyzed by HPLC with UV detection.. BDP was hydrolyzed to the pharmacologically active metabolite beclomethasone-17-monopropionate (BMP) and, predominantly, to inactive beclomethasone (BOH). CIC was hydrolyzed initially to des-CIC with a slower rate compared to BDP. A distinctly smaller amount (approximately 10-fold less) of fatty acid esters were formed by BMP (and/or BOH) than by BUD or des-CIC. The highest relative amounts of fatty acid esters were detected for BUD. For FP, no metabolites were detected at any time point. The amount of drug-related material in lung tissue (based on initial concentrations) at 24 h was highest for CIC, followed by BUD and FP; the smallest amount was detected for BDP.. The in vitro metabolic pathways of the tested ICS in human lung tissue were differing. While FP was metabolically stable, the majority of BDP was converted to inactive polar metabolites. The formation of fatty acid conjugates was confirmed for BMP (and/or BOH), BUD, and des-CIC.

Topics: Adult; Androstadienes; Anti-Allergic Agents; Beclomethasone; Budesonide; Cell Survival; Fluticasone; Glucocorticoids; Humans; In Vitro Techniques; Lung; Male; Middle Aged; Pregnenediones

Several topical corticosteroids are available as anti-inflammatory treatment for asthma. Their comparative effects on allergic inflammation and airway remodeling are unclear.. We compared the effects of ciclesonide with those of fluticasone propionate in a Brown Norway rat model of chronic allergic asthma.. Rats sensitized and exposed to ovalbumin (OVA) were treated with dry powder vehicle, ciclesonide, or fluticasone (0.01, 0.03, and 0.1 mg/kg administered intratracheally) 24 hours and 1 hour before each of 6 OVA exposures. In a second protocol we administered 0.1 mg/kg ciclesonide or fluticasone only after the third OVA exposure.. Ciclesonide at all doses inhibited the allergen-induced increase in airway eosinophils and T cells, reduced goblet cell hyperplasia, and decreased 5-bromo-2'-deoxyuridine-immunoreactive airway smooth muscle (ASM) and epithelial cells. At 0.03 and 0.1 mg/kg ciclesonide, bronchial hyperresponsiveness (BHR) was also inhibited. Fluticasone did not attenuate allergen-induced BHR, despite inhibiting airway eosinophils and T cells, goblet cell hyperplasia, and 5-bromo-2'-deoxyuridine-immunoreactive ASM and epithelial cells. Fluticasone (0.1 mg/kg) caused a significant reduction in body weight (9%) compared with ciclesonide (0.1 mg/kg). Ciclesonide did not change plasma corticosterone levels, whereas fluticasone (0.1 mg/kg) reduced them. In the second protocol both fluticasone and ciclesonide inhibited BHR, bronchial inflammation, goblet cell hyperplasia, and ASM proliferation.. Ciclesonide potently inhibited chronic allergic inflammation, remodeling, and BHR without having an effect on body weight and the hypothalamic-pituitary-adrenal axis. Fluticasone prevented airway inflammation but not BHR, but both fluticasone and ciclesonide are effective at reversal of BHR, inflammation, and remodeling features.

Topics: Administration, Inhalation; Allergens; Androstadienes; Animals; Anti-Allergic Agents; Body Weight; Corticosterone; Dose-Response Relationship, Drug; Eosinophils; Epithelial Cells; Fluticasone; Male; Muscle, Smooth; Ovalbumin; Pregnenediones; Rats; Rats, Inbred BN; Respiratory Hypersensitivity; Respiratory System; T-Lymphocytes

Ciclesonide is a novel, inhaled corticosteroid under development for the treatment of asthma. Ciclesonide is activated to desisobutyryl-ciclesonide (des-CIC) in the lungs to provide potent anti-inflammatory activity. The investigations herein compared the activity of ciclesonide with fluticasone in animal models to assess efficacy/potency as an airway anti-inflammatory and the comparative side effect potential to consider the therapeutic ratio of each compound. In radioligand binding assays, des-CIC and fluticasone exhibited comparable high-affinity binding to the glucocorticoid receptor, whereas ciclesonide exhibited 100-fold less binding affinity. In the Brown Norway rat model of antigen-induced airway eosinophilia and in a model of Sephadex-induced lung edema, ciclesonide and fluticasone exhibited comparable efficacy. Interestingly, following 7-day intratracheal administration, ciclesonide elicited adrenal involution with a potency that was 44-fold less than fluticasone. Furthermore, ciclesonide was 22-fold less active than fluticasone in eliciting hypoplasia of the femoral growth plate. These data support the concept that ciclesonide acts as a parent compound that, when delivered to the airways, can be transformed into the active metabolite des-CIC, resulting in local high anti-inflammatory activity. Furthermore, ciclesonide possesses equivalent anti-inflammatory efficacy through pulmonary activation with a significantly improved safety profile in preclinical animal models compared with fluticasone.

Topics: Adrenal Glands; Androstadienes; Animals; Anti-Asthmatic Agents; Binding, Competitive; Blood Proteins; Bone Diseases, Metabolic; Dextrans; Eosinophils; Femur; Femur Head; Fluticasone; Growth Plate; Inflammation; Pregnenediones; Protein Binding; Pulmonary Edema; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Receptors, Steroid; Thymus Gland