Ginkgetin, a biflavone from Ginkgo biloba leaves, was previously reported to be a phospholipase A2 inhibitor and this compound showed the potent antiarthritic activity in rat adjuvant-induced arthritis as well as analgesic activity. This investigation was carried out to find effects on cyclooxygenase (COX)-1 and -2 including an in vivo effect. Ginkgetin (1 - 10 microM) and the biflavonoid mixture (10 - 50 microg/ml), mainly a 1 : 1 mixture of ginkgetin and isoginkgetin, from G. biloba leaves, inhibited production of prostaglandin E2 from lipopolysaccharide-induced RAW 264.7 cells. This inhibition was mediated, at least in part, by down-regulation of COX-2 expression, but not by direct inhibition of COX-1 or COX-2 activity. Down-regulation of COX-2 by ginkgetin was also proved in the dorsal skin of ICR mouse treated by 12-O-tetradecanoylphorbol 13-acetate (TPA). At total doses of 1,000 microg/site on the dorsal skin (15 mm x 15 mm), ginkgetin inhibited prostaglandin E2 production by 65.6 % along with a marked suppression of COX-2 induction. In addition, ginkgetin and the biflavonoid mixture (100 - 1,000 microg/ear) dose-dependently inhibited skin inflammation of croton oil induced ear edema in mice by topical application. The present study suggests that ginkgetin from G. biloba leaves down-regulates COX-2 induction in vivo and this down-regulating potential is associated with an anti-inflammatory activity against skin inflammatory responses.
A new triterpenoid saponin, loniceroside C was isolated from the aerial parts of Lonicera japonica. Its structure was established to be 3-O-beta-D-glucopyranosyl hederagenin 28-O-alpha-L-rhamnopyranosyl (1-->2)-[beta-D-xylopyranosyl(1-->6)]-beta-D-glucopyranosyl ester by spectroscopic techniques and chemical transformations. Loniceroside C showed in vivo antiinflammatory activity against mouse ear edema provoked by croton oil.
The efficacy and safety of SKI306X, an herbal anti-arthritic agent, was compared with that of diclofenac sodium for the treatment of osteoarthritis of the knee. In a randomized, double-blind, active comparator-controlled trial, a total of 249 patients were randomly assigned to receive either 200 mg of SKI306X three times daily or 100 mg of diclofenac sustained release (SR) once daily. Clinical efficacy variables (visual analog scale, Lesquesne index and global satisfaction score) and adverse events were monitored at baseline and 2nd and 4th weeks of treatment. SKI306X demonstrated efficacy statistically comparable to that of diclofenac, as assessed by the VAS and patients' and investigators' global satisfaction score. Both treatments were well tolerated, however, the SKI306X treatment group experienced less heartburn (4.0% versus 13.7%, p = 0.015, chi-square test). In this four-week trial, SKI306X was well tolerated and demonstrated clinical efficacy comparable to that of diclofenac SR.
SKI306X was previously reported to have good anti-inflammatory and analgesic efficacy in various studies. To determine its mode of action, an investigation was carried out for some representative mediators. Arachidonic acid metabolism and its products are particularly important in inflammation and pain. The pro-inflammatory cytokines, especially interleukin-1 (IL-1) and tumor necrosis factor (TNF-a a), and induced nitric oxide (NO) appear to be most involved in the inflammatory process such as osteoarthritis (OA). Thus SKI306X was tested to determine the effects on enzymes related to arachidonic acid metabolism and the release or synthesis of inflammatory mediators. SKI306X did inhibit the expression of cyclooxygenase-2 (COX-2) enzyme without affecting COX-1 and COX-2 activity. Leukotriene B 4 (LTB 4 ) production also was inhibited by SKI306X (IC 50 62.4؎7.89؍ m mg/ml). SKI306X inhibited significantly TNF-a a release (IC 50 8.71؎6.79؍ m mg/ml) and NO production (IC 50 ؍ 280؎17.8 m mg/ml). But IL-1a a release was not attenuated by SKI306X. This study suggests that inhibition of these mediators by SKI306X may be one of the mechanisms responsible for its anti-inflammatory effects.
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