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Received for publication September 9, 2003.
Revised December 15, 2003.
Accepted for publication December 22, 2003.
The glucocorticoid ciclesonide is the 2'R-epimer of 2'-cyclohexyl-11
-hydroxy-21-isobutyryloxy-16bH-dioxolo[5',4':16,17] pregna-1,4-diene-3,20-dione. The active metabolite desisobutyryl-ciclesonide (des-CIC) is derived from ciclesonide by esterase cleavage of isobutyrate at the C21 position. The relative binding affinities at the rat glucocorticoid receptor were: dexamethasone 100; ciclesonide 12; des-CIC 1212; budesonide 905. Des-CIC potently inhibited the activation of murine and human lymphocytes in a series of different in-vitro systems. With the exception of ConA-stimulated rat spleen cells, des-CIC was more potent than the parent compound. Des-CIC compared well with budesonide in all in-vitro systems. Furthermore, the respective 2'S-epimers were always significantly less potent than the 2'R-epimers. In-vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and TNF-
into the bronchoalveolar fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED50 ranging from 0.4 to 1.3 mg/kg, indicating similar potency, which suggests in-vivo activation of the parent compound. Ciclesonide and budesonide inhibited the bradykinin-induced protein leakage into the rat trachea. In the rat cotton pellet model ciclesonide inhibited granuloma formation (ED50: 2 µg/pellet), whereas budesonide and des-CIC were 15-fold and 20-fold less active; thymus involution was induced with an ED50 of 303 µg/pellet, 279 µg/pellet, and 154 µg/pellet, respectively. When applied orally to rats for 28 days, ciclesonide showed low potency in reducing weight of thymus and adrenals, suggesting low oral bioavailability. The in-vivo data on ciclesonide highlight its effective local action and a reduced potential for side effects.
Key words:
animal model, asthma, ciclesonide, immunopharmacology, in vitro, inflammation
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