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J Pharmacol Exp Ther. 2005 Aug;314(2):568-74. Epub 2005 May 5.

Preclinical profile of ciclesonide, a novel corticosteroid for the treatment of asthma.

Author information

1
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

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.

PMID:
15878996
DOI:
10.1124/jpet.105.085217
[Indexed for MEDLINE]

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