title: Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma.
abstract: 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.
authors.affiliation: Respiratory Pharmacology, Department of Cardiothoracic Surgery, Imperial College School of Medicine at the National Heart and Lung Institute, Dovehouse Street, London SW3 6LY, UK. m.belvisi@imperial.ac.uk
authors.forename: Maria G
authors.initials: MG
authors.lastname: Belvisi
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Bundschuh
authors.forename: Michael
authors.initials: M
authors.lastname: Stoeck
authors.forename: Sharon
authors.initials: S
authors.lastname: Wicks
authors.forename: Stephen
authors.initials: S
authors.lastname: Underwood
authors.forename: Clifford H
authors.initials: CH
authors.lastname: Battram
authors.forename: El-Bdaoui
authors.initials: el-B
authors.lastname: Haddad
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Webber
authors.forename: Martyn L
authors.initials: ML
authors.lastname: Foster
mesh_terms: D000311:Adrenal Glands / Q000187:drug effects; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001851:Bone Diseases, Metabolic / Q000139:chemically induced / Q000473:pathology; D003911:Dextrans; D004804:Eosinophils / Q000187:drug effects / Q000473:pathology; D005269:Femur / Q000187:drug effects / Q000254:growth & development; D005270:Femur Head / Q000187:drug effects / Q000254:growth & development; D000068298:Fluticasone; D006132:Growth Plate / Q000187:drug effects; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D011282:Pregnenediones / Q000493:pharmacokinetics / Q000494:pharmacology*; D011485:Protein Binding; D011654:Pulmonary Edema / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D011914:Rats, Inbred BN; D017207:Rats, Sprague-Dawley; D011987:Receptors, Steroid / Q000187:drug effects; D013950:Thymus Gland / Q000187:drug effects / Q000254:growth & development
chemical_list: D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D001798:Blood Proteins; D003911:Dextrans; D011282:Pregnenediones; D011987:Receptors, Steroid; C025614:sephadex; D000068298:Fluticasone; C120481:ciclesonide