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.

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Phosphodiesterase type 4 (PDE4) is involved in the hydrolysis of cAMP in pulmonary vascular smooth muscle (PA-SMC) and immune inflammatory cells. Given that intracellular cAMP accumulation inhibits contraction and growth of PA-SMCs as well as inflammatory cell functions, we investigated the effects of the PDE4 inhibitor 3-cyclopropylmethoxy-4-difluoromethoxy-N- [3,5-di-chloropyrid-4-yl]-benzamide (roflumilast), on pulmonary hypertension (PH) in rats. Treatment with roflumilast (0.5 or 1.5 mg ⅐ kg Ϫ1 day Ϫ1 ) from day 1 to day 21 after monocrotaline (MCT) injection (60 mg ⅐ kg Ϫ1 s.c.) attenuated PH development: pulmonary artery pressure, right ventricular hypertrophy, and muscularization of distal vessels on day 21 were decreased compared to control MCT-treated rats. Roflumilast (1.5 mg ⅐ kg Ϫ1 day Ϫ1 ) also reduced the increases in interleukin-6 and monocyte chemotactic protein-1 mRNAs observed in lung tissue on day 21 without affecting the rise in interleukin-1␤ mRNA on days 1 and 21. Roflumilast (1.5 mg ⅐ kg Ϫ1 day Ϫ1 ) from day 21 to day 42 after MCT reversed established PH, almost normalizing pulmonary artery pressure and structure, and suppressing proliferating cell nuclear antigen-positive cells in pulmonary vascular walls. Treatment with roflumilast similarly attenuated PH development due to chronic hypoxia. Treatment of human PA-SMCs with roflumilast N-oxide, the active metabolite of roflumilast, at concentrations up to 10 Ϫ6 M, potentiated PA-SMC growth inhibition induced by prostacyclin (10 Ϫ6 M) or interleukin-1␤ (10 ng ⅐ ml Ϫ1 ) but was inactive on its own. In conclusion, the PDE4 inhibitor roflumilast significantly attenuates pulmonary vascular remodeling and hypertension induced by chronic hypoxia or MCT and reverses established PH after MCT administration.Pulmonary hypertension (PH) is characterized by an increase in pulmonary vascular resistance that impedes ejection of blood by the right ventricle and subsequently leads to right ventricular failure. The most common form of PH occurs in patients with chronic hypoxemic lung disease such as chronic obstructive pulmonary disease (COPD). Although PH is usually mild to moderate in this condition and stabilized with long-term oxygen therapy, it remains the strongest prognostic factor, independent from the severity of air flow limitation or hypoxemia (Burrows et al., 1972). Among the many other causes of PH, idiopathic pulmonary hypertension and PH associated with inflammatory conditions such as connective tissue diseases are severe and often fatal diseases, although new treatments help to prolong survival and quality of life.Persistent vasoconstriction and structural remodeling of pulmonary vessels with proliferation of vascular smooth muscle cells (SMCs) are cardinal features of PH. An imbalance between vasoactive factors such as endothelin and serotonin, which exhibit constrictor and mitogenic properties on pulmonary vascular smooth muscle, and endogenous vasodilator substances such as prostacyclin, which not only relax pulmonary vascular sm...

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