In vitro and in vivo anti-inflammatory activity of the new glucocorticoid ciclesonide.
The glucocorticoid ciclesonide is the 2'R-epimer of 2'-cyclohexyl-11beta-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-alpha into the bronchoalveolar lavage fluid of ovalbumin-sensitized and -challenged Brown Norway rats with an ED(50) 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 (ED(50):= of 2 microg/pellet), whereas budesonide and des-CIC were 15- and 20-fold less active; thymus involution was induced with an ED(50) of 303, 279, and 154 microg/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.
Stoeck
Michael
M
ALTANA Pharma AG, Byk-Gulden-Strasse 2, 78467 Konstanz, Germany. michael.stoeck@altanapharma.com
Riedel
Richard
R
Hochhaus
Günther
G
Häfner
Dietrich
D
Masso
José M
JM
Schmidt
Beate
B
Hatzelmann
Armin
A
Marx
Degenhard
D
Bundschuh
Daniela S
DS
D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001665:Binding Sites; D001920:Bradykinin / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003208:Concanavalin A / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D005938:Glucocorticoids / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D006099:Granuloma / Q000517:prevention & control; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism; D015848:Interleukin-5 / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects; D008168:Lung / Q000378:metabolism; D008297:Male; D009368:Neoplasm Transplantation; D009374:Neoplasms, Experimental / Q000517:prevention & control; D011282:Pregnenediones / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000187:drug effects / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D014132:Trachea / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000970:Antineoplastic Agents; D017252:CD3 Complex; D016207:Cytokines; D005938:Glucocorticoids; D015848:Interleukin-5; D011282:Pregnenediones; D011965:Receptors, Glucocorticoid; D003208:Concanavalin A; D015847:Interleukin-4; C120481:ciclesonide; D001920:Bradykinin