PT  - JOURNAL ARTICLE
AU  - Michael Stoeck
AU  - Richard Riedel
AU  - Günther Hochhaus
AU  - Dietrich Häfner
AU  - José M. Masso
AU  - Beate Schmidt
AU  - Armin Hatzelmann
AU  - Degenhard Marx
AU  - Daniela S. Bundschuh
TI  - In Vitro and in Vivo Anti-Inflammatory Activity of the New Glucocorticoid Ciclesonide
AID  - 10.1124/jpet.103.059592
DP  - 2004 Apr 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 249--258
VI  - 309
IP  - 1
4099  - http://jpet.aspetjournals.org/content/309/1/249.short
4100  - http://jpet.aspetjournals.org/content/309/1/249.full
SO  - J Pharmacol Exp Ther2004 Apr 01; 309
AB  - The glucocorticoid ciclesonide is the 2′R-epimer of 2′-cyclohexyl-11β-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; and 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 concanavalin A-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 tumor necrosis factor-α into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED50 value 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:= of 2 μg/pellet), whereas budesonide and des-CIC were 15- and 20-fold less active; thymus involution was induced with an ED50 of 303, 279, 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. The American Society for Pharmacology and Experimental Therapeutics