In Vitro and in Vivo Anti-Inflammatory Activity of the New Glucocorticoid Ciclesonide

Abstract

The glucocorticoid ciclesonide is the 2ЈR-epimer of 2Ј-cyclohexyl-11␤-hydroxy-21-isobutyryloxy-16bH-dioxolo [5Ј,4Ј:16,17]pregna-1,4-diene-3,20-dione. The active metabolite desisobutyrylciclesonide (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 2ЈS-epimers were always significantly less potent than the 2ЈR-epimers. In vivo, ciclesonide (intratracheal administration), des-CIC, and budesonide inhibited antigen-induced accumulation of eosinophils, protein, and tumor necrosis factor-␣ 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 :ϭ of 2 g/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 g/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.

Preclinical Profile of Ciclesonide, a Novel Corticosteroid for the Treatment of Asthma

“…In both models, the efficacy of ciclesonide was identical to that of fluticasone, and the ED 50 for ciclesonide was less than 10-fold higher than that of fluticasone. These data are consistent with a recent report describing the activity of ciclesonide in a similar Brown Norway rat model of allergic inflammation (ED 50 ϭ 0.7 mg/kg for inhibition of BAL eosinophilia compared with 0.75 mg/kg in this study) (Stoeck et al, 2004). These investigations used an acute treatment with ciclesonide, although inhaled corticosteroids are administered on a chronic basis for optimal anti-inflammatory therapy in clinical practice.…”

In vitro metabolism of ciclesonide in human nasal epithelial cells

“…Desisobutyryl-ciclesonide subsequently undergoes reversible fatty acid conjugation at the carbon-21 position [9]. Desisobutyryl-ciclesonide has a high affinity for the glucocorticoid receptor (relative glucocorticoid receptor binding affinities of des-CIC and ciclesonide are 1200 and 12, respectively; the dexamethasone reference being 100) and exhibits substantial in vitro and in vivo antiinflammatory activity [10]. Low oral bioavailability (1%) [11], high protein binding (99%) [12] and high hepatic clearance (396 l/h for des-CIC) [13] contribute to the low systemic bioavailability of ciclesonide and des-CIC.…”

Ciclesonide is more effective than budesonide in the treatment of persistent asthma

“…[25,26] Furthermore, the active metabolite of ciclesonide (des-CIC) has a high relative glucocorticoid receptor affinity (1200 versus 900 for budesonide; dexamethasone reference is 100) and possesses substantial anti-inflammatory activity. [24,27] …”