Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma.
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.
Belvisi
Maria G
MG
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
Bundschuh
Daniela S
DS
Stoeck
Michael
M
Wicks
Sharon
S
Underwood
Stephen
S
Battram
Clifford H
CH
Haddad
El-Bdaoui
el-B
Webber
Stephen E
SE
Foster
Martyn L
ML
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
D000730:Androstadienes; D018927:Anti-Asthmatic Agents; D001798:Blood Proteins; D003911:Dextrans; D011282:Pregnenediones; D011987:Receptors, Steroid; C025614:sephadex; D000068298:Fluticasone; C120481:ciclesonide