ciclesonide and Inflammation

Ciclesonide is delivered as a small-particle inhaled corticosteroid and improves lung function and airway hyperresponsiveness. The objective of the present study was to assess whether ciclesonide can specifically improve small airway function in asthma. A total of 16 mild-to-moderate asthma patients (seven males; median (range) age 39 (19-56) yrs and forced expiratory volume in one second (FEV(1)) 89 (62-120)% predicted) were randomised to 5 weeks' treatment with placebo or 320 mug ciclesonide once daily. The following small airway parameters were assessed: mean forced expiratory flow between 25 and 75% of forced vital capacity (FVC), percentage fall in FVC at provocative dose of adenosine-5'-monophosphate and of methacholine (MCh) causing a 20% fall in FEV(1), expiratory lung volume on computed tomography (CT) scan after MCh challenge, single-breath nitrogen closing volume and alveolar exhaled nitric oxide (eNO). Seven subjects received placebo and nine received ciclesonide. Both alveolar eNO and CT measurements of expiratory lung volume after MCh challenge decreased significantly with ciclesonide (median (range) decrease 4.4 (54.8-1.4) ppb and 59 (1,569- -117) mL, respectively), and compared with placebo (-0.4 (7.3- -3.4) ppb and -121 (20- -236) mL respectively). Ciclesonide did not significantly improve other small airways parameters. Inflammation and patency of small airways, reflected by alveolar exhaled nitric oxide and air trapping on computed tomography scan, both improve with ciclesonide even in this small number of patients. This indicates that ciclesonide exerts anti-inflammatory effects on small airways.

Topics: Administration, Inhalation; Adult; Anti-Inflammatory Agents; Asthma; Breath Tests; Bronchi; Bronchial Provocation Tests; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Inflammation; Male; Middle Aged; Pilot Projects; Pregnenediones; Vital Capacity

To assess the efficacy of ciclesonide, a novel corticosteroid pro-drug, we compared its effect on lung function, airway responsiveness to inhaled AMP, the composition of induced sputum, and the level of exhaled nitric oxide (NO) with the effect of budesonide in patients with asthma. Fifteen non-smoking steroid-naive patients (mean FEV(1), 94%pred) inhaled either 400 microg ciclesonide or 400 microg budesonide as a single morning dose for two weeks each separated by a > or =3 week wash-out period. The study was performed in a double-observer, randomized, cross-over design. FEV(1)increased significantly during treatment with budesonide (3.38 vs. 3.64 l P=0,003), but not after ciclesonide (3.60 vs. 3.69 l). PC(20)FEV(1)of AMP increased (P<0,001, each) after both budesonide (4.59 vs. 32.48 mg/ml, 2.8 doubling doses) and ciclesonide (3.92 vs. 20.00 mg/ml, 2.4 doubling doses). The percentage of sputum eosinophils was significantly reduced after ciclesonide (7.9 vs. 3.4% P=0.01), but not budesonide (6.0 vs. 4.3%). After both budesonide and ciclesonide, a significant (P<0.001) reduction in the level of exhaled NO occurred. In none of the parameters studied, the changes differed significantly between treatment with budesonide or ciclesonide. These data suggest that ciclesonide is equi-effective to budesonide with regard to its potency to reduce the airway responsiveness to inhaled AMP as well as airway inflammation in patients with mild asthma.

Topics: Adenosine Monophosphate; Administration, Inhalation; Adult; Airway Resistance; Anti-Asthmatic Agents; Asthma; Breath Tests; Female; Humans; Inflammation; Male; Middle Aged; Nitric Oxide; Pregnenediones; Respiratory Function Tests; Sputum

Topics: Administration, Intranasal; Anti-Allergic Agents; Child; Evidence-Based Medicine; Female; Humans; Inflammation; Male; Practice Guidelines as Topic; Pregnenediones; Rhinitis, Allergic, Seasonal

Ciclesonide, a new inhaled corticosteroid, is administered as a parent compound and converted in the airway mucosa into the active metabolite, desisobutyryl-(des-)ciclesonide. A study was designed to evaluate the ability of ciclesonide to modulate pro-inflammatory functions of human bronchial epithelial cell (HBEC) primary cultures being converted into des-ciclesonide. HBECs were stimulated with interleukin (IL)-4 and tumour necrosis factor (TNF)-alpha (20 ng/mL) in the presence of ciclesonide and intercellular adhesion molecule (ICAM)-1 expression, granulocyte-macrophage colony stimulating factor (GM-CSF) and IL-8 release evaluated respectively by FACS and ELISA. Ciclesonide (3 microM) significantly inhibited ICAM-1 expression by stimulated HBECs, already after 3h and still after 48 h culture (p < 0.01). At all the concentrations tested ciclesonide inhibited ICAM-1 expression (p < 0.05). GM-CSF and IL-8 release by stimulated HBECs was also downregulated by ciclesonide (p < 0.05). All the ciclesonide activities tested appeared to be mainly due to a partial inhibition of the 'IL-4 + TNF-alpha-induced' and little or no involvement of the 'constitutive' cell functions. Des-ciclesonide was detected in 24 h culture HBEC supernatants using high-performance liquid chromatography, while no parental compound ciclesonide was present. These results show at cellular level the fast and prolonged activity of ciclesonide on pro-inflammatory functions of HBECs, a selective target of asthma therapy, involved in the activation of this new inhaled corticosteroid.

Topics: Adrenal Cortex Hormones; Bronchi; Cell Survival; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Down-Regulation; Epithelial Cells; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Inflammation; Intercellular Adhesion Molecule-1; Interleukin-4; Interleukin-8; Pregnenediones; Tumor Necrosis Factor-alpha

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