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OBJECTIVE: The efficacy of ciclesonide 160 mug QD (given either in the morning or evening) was compared with budesonide 200 mug BID in adults with stable asthma that was pretreated with inhaled corticosteroids. METHODS: This was a randomized, 3-arm, parallel-group study comparing ciclesonide (given in a double-blind, double-dummy regimen) with open-label budesonide. After 2 to 2.5 weeks, during which patients were treated with budesonide 200 microg BID, patients (n = 405) were randomly assigned to receive ciclesonide 160 microg QD AM or 160 microg QD pm, or budesonide 200 microg BID (all administered by metered-dose inhaler) for 12 weeks. All patients received 2 puffs of medication (or placebo) in the morning and evening. The primary efficacy variable was the difference in spirometric forced expiratory volume in 1 second (FEV(1) in liters) from randomization to study end. Secondary efficacy end points were forced vital capacity, peak expiratory flow by spirometry, and diary assessments of peak expiratory flow, asthma symptoms, and rescue medication use. Adverse events were assessed by patient report, investigator observation, physical examination, and laboratory testing; events were classified as mild, moderate, or severe. RESULTS: Baseline demographic characteristics with regard to sex, age, weight, smoking status, baseline medication use, and FEV(1) were balanced among the treatment groups. Over the course of treatment, both ciclesonide and budesonide maintained FEV(1) compared with baseline. Both ciclesonide regimens were as effective as budesonide 200 microg BID in maintaining FEV(1) during the treatment period versus baseline (ciclesonide 160 microg QD am: 95% CI, -0.120 to 0.045 vs budesonide; P = NS; ciclesonide 160 microg QD pm: 95% CI, -0.061 to 0.105 vs budesonide; P = NS). Ciclesonide 160 microg QD (morning or evening) was comparable with budesonide 200 microg BID for maintaining pulmonary function, asthma symptom scores, and rescue medication use. The incidence of adverse events was not significantly different among the treatment groups, and most adverse events were not related to study medication. CONCLUSIONS: In this study, ciclesonide 160 microg QDwas as effective as budesonide 200 microg BID (400 microg total daily dose) in these adults with persistent asthma. Both treatments were well tolerated. [ABSTRACT FROM AUTHOR]

Ciclesonide is an onsite-activated inhaled corticosteroid (ICS) for the treatment of asthma. This study compared the efficacy, safety and effect on quality of life (QOL) of ciclesonide 160 microg (ex-actuator; nominal dose 200 microg) vs. budesonide 400 microg (nominal dose) in children with asthma. Six hundred and twenty-one children (aged 6-11 yr) with asthma were randomized to receive ciclesonide 160 microg (ex-actuator) once daily (via hydrofluoroalkane metered-dose inhaler and AeroChamber Plus spacer) or budesonide 400 microg once daily (via Turbohaler) both given in the evening for 12 wk. The primary efficacy end-point was change in forced expiratory volume in 1 s (FEV1). Additional measurements included change in daily peak expiratory flow (PEF), change in asthma symptom score sum, change in use of rescue medication, paediatric and caregiver asthma QOL questionnaire [PAQLQ(S) and PACQLQ, respectively] scores, change in body height assessed by stadiometry, change in 24-h urinary cortisol adjusted for creatinine and adverse events. Both ciclesonide and budesonide increased FEV1, morning PEF and PAQLQ(S) and PACQLQ scores, and improved asthma symptom score sums and the need for rescue medication after 12 wk vs. baseline. The non-inferiority of ciclesonide vs. budesonide was demonstrated for the change in FEV1 (95% confidence interval: -75, 10 ml, p = 0.0009, one-sided non-inferiority, per-protocol). In addition, ciclesonide and budesonide showed similar efficacy in improving asthma symptoms, morning PEF, use of rescue medication and QOL. Ciclesonide was superior to budesonide with regard to increases in body height (p = 0.003, two-sided). The effect on the hypothalamic-pituitary-adrenal axis was significantly different in favor of ciclesonide treatment (p < 0.001, one-sided). Both ciclesonide and budesonide were well tolerated. Ciclesonide 160 microg once daily and budesonide 400 microg once daily were effective in children with asthma. In addition, in children treated with ciclesonide there was significantly less reduction in body height and suppression of 24-h urinary cortisol excretion compared with children treated with budesonide after 12 wk.

Background: Ciclesonide is an investigational corticosteroid under development for treatment of allergic rhinitis. Ciclesonide is converted to active metabolite, desisobutyryl-ciclesonide (des-CIC), by upper and lower airway esterases. In vitro studies in human nasal epithelial cells and bronchial epithelial cells have demonstrated a long duration of anti-inflammatory activity of des-CIC., Objective: To evaluate the dose-dependent efficacy and safety of a hypotonic intranasal formulation of ciclesonide in patients with seasonal allergic rhinitis (SAR)., Methods: This was a phase 2, randomized, parallel-group, double-blind, placebo-controlled study. Adults (n = approximately 145 per treatment group) with a minimum 2-year history of SAR received placebo or ciclesonide (25, 50, 100, or 200 microg/d) for 14 days. The primary end point was change in the sum of morning and evening reflective total nasal symptom scores (TNSSs) over 2 weeks. Safety was monitored throughout the study., Results: Ciclesonide, 100 microg/d (P = .04) and 200 microg/d (P = .003), significantly improved the sum of morning and evening reflective TNSS vs placebo at more than 2 weeks of treatment. Baseline values for morning and evening reflective TNSS ranged from 17.80 to 18.82 across treatment groups. The average change from baseline in reflective TNSS was -4.2 for placebo and -4.8, -4.8, -5.3, and -5.8 for ciclesonide, 25, 50, 100, and 200 microg/d, respectively. There were no dose-related differences in the incidence of adverse events among treatment groups., Conclusions: Results from this study indicate that 100-microg and 200-microg daily doses of ciclesonide are effective in the treatment of SAR. Ciclesonide, 200 microg/d, appears to be the optimal dose studied for reducing the symptoms of SAR while maintaining an acceptable safety profile.

The CD95 (APO-1/Fas) receptor has attracted great interest in recent years because it transduces an apoptotic signal in a variety of different tissues. CD95 belongs to the NGF/TNF-receptor superfamily, members of which need to be trimerized by specific protein ligands in order to generate a signal. This review focuses on recent advances in the understanding of the proximal signal transduction mechanism of CD95. The cloning of numerous proteins that interact with CD95 and other members of this receptor family and the in vivo identification of several proteins that associate with CD95 in a ligand-dependent fashion opens the way to delineate the death pathway and to explain crosstalk among these receptors on a molecular basis.

Certain B and T cell lines respond to activation signals, e.g. through the antigen receptor, by undergoing apoptotic cell death. In T cells it has been recently shown that TCR-mediated apoptosis involves APO-1/Fas(CD95) receptor-ligand interaction. To investigate whether the TCR-CD3 complex can trigger alternative apoptosis pathways we generated subclones of the T cell line Jurkat which were completely resistant towards APO-1-mediated apoptosis. These JurkatR cells differed phenotypically from sensitive parental JurkatS cells only by the lack of APO-1 protein expression. Although JurkatR cells responded normally to anti-CD3 stimulation by expression of APO-1 ligand they failed to undergo anti-CD3-induced apoptosis. Thus, in Jurkat cells APO-1-mediated apoptosis was the main, and might be the only, mechanism for anti-CD3-induced cell death. However, BL-60 B cells, highly sensitive to anti-IgM-induced apoptosis, did not use the APO-1 receptor-ligand system because they failed to express APO-1 ligand mRNA. Taken together, our results suggest that malignant T and B cell lines may use APO-1 receptor-ligand-dependent and -independent antigen receptor-induced apoptosis pathways respectively. Similarly, differential pathways may be used by T and B cell subsets.

APO-1/Fas(CD95), a member of the tumour necrosis factor (TNF)/nerve growth factor (NGF) receptor superfamily transduces apoptotic signals into apoptosis sensitive cells. In metabolic labelling experiments using the highly APO-1 positive cell lines HUT78 (adultT cell leukemia) and SKW6.4 (Blymphoblastoid cell line) APO-1 was characterised as a long living protein with a complex glycosylation pattern involving terminal sialic acid groups which account for 8-kDa of its apparent molecular weight on SDS-PAGE. APO-1 expression and the degree of sialylation were determined in additionalT and B cell lines. On the group I Burkitt's lymphoma cell line BL60 transfected with human APO-1 (K50) low sialylated species were detected only on the cell surface, suggesting that sialylation might be functionally important. Removal of terminal sialic acid groups by treatment of B and T cell lines with Vibrio cholerae neuraminidase (VCN) augmented sensitivity towards anti-APO-1 and human APO-1 ligand induced apoptosis. Similarly, VCN-treated U937 cells were rendered more sensitive to TNFalpha-induced cell death. Thus, sialylation may be one mechanism to regulate sensitivity towards ligand-mediated cell death in this receptor family.