Modulation of inflammatory responses by diterpene acids from Helianthus annuus L.

Fractionation of a petroleum ether extract of Helianthus annuus L. led to the isolation of three diterpene acids: grandiflorolic, kaurenoic and trachylobanoic acids. These compounds were studied for potential anti-inflammatory activity on the generation of inflammatory mediators in lipopolysaccharide (LPS)-activated RAW 264.7 macrophages. At non-toxic concentrations, these compounds reduced, in a concentration-dependent manner nitric oxide (NO), prostaglandin E(2) (PGE(2)) and tumor necrosis factor (TNF-alpha) production, as well as expression of inducible nitric oxide synthase (NOS-2) and cyclooxygenase-2 (COX-2). All diterpenoids displayed significant in vivo anti-inflammatory activity and suppressed the 12-O-tetradecanoylphorbol-13-acetate (TPA)-mouse ear edema. In addition, inhibition of myeloperoxidase (MPO) activity, an index of cellular infiltration, was observed. In summary, our results suggest that the inhibition of the expression of NOS-2, COX-2 and the release of inflammatory cytokines, is responsible for the anti-inflammatory effects of the diterpenoids isolated from H. annuus L. which likely contributes to the pharmacological action of sunflower.

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.