Biol. Pharm. Bull. 28(9) 1615—1620 (2005)

toid arthritis (RA) are the most common inflammatory diseases. Inasmuch as OA and RA afflict more than 80% of all patients suffering from arthritis, they are major public concerns. Although OA and RA differ fundamentally in several respects, they share some final pathway leading to cartilage degradation, characterized by the gradual and progressive loss of articular cartilage, resulting in erosions to subchondral bone. Symptoms include joint pain, tenderness, limited movement, crepitus and variable degrees of joint inflammation. Current therapeutic strategies for OA alleviate symptoms, particularly pain and inflammation. SKI306X is an extract purified from a mixture of three Oriental herbal medicines, Clematis mandshurica, Trichosanthes kirilowii and Prunella vulgaris which have been widely used for the treatment of inflammatory diseases such as lymphadenitis and arthritis in Far East Asia. In previous studies, the anti-inflammatory and analgesic activities of this herbal extract were reported in various in vitro and in vivo experimental models. SKI306X had been reported to have protective effects in articular cartilage. The double blind, placebo-controlled study also confirmed the clinical efficacy and good tolerability of SKI306X in patients with OA in the knee and in another clinical study, this herbal extract was well tolerated and demonstrated clinical efficacy comparable to that of diclofenac SR (slow released). Another clinical study is underway to determine the efficacy of SKI306X in RA patients. But, its mode of action is still to be determined. Cartilage in OA is a site of the prodigious production of mediators classically associated with inflammation, namely prostaglandins (PGs), nitric oxide (NO) and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF)-a . These mediators, produced by activated chondrocytes, act in an autocrine/paracrine fashion to exert profound effects on cartilage metabolism in OA. Recent studies showed that IL1b , TNF-a and inducible nitric oxide synthase (iNOS) are highly expressed in synovial cells, infiltrating leukocytes and endothelial cells in RA. IL-1 and TNF-a play a central role in many inflammatory processes and appear most involved in the catabolic process of OA. These cytokines also enhances the production of 5-lipoxygenase (5-LOX) products and prostaglandin E2 (PGE2). It is clearly established that pro-inflammatory cytokines, mainly IL-1 and TNF-a , can activate chondrocytes to enter a catabolic condition and prime a matrix-degrading activity, including protease secretion, radical species production, down-regulation of matrix and protease inhibitor synthesis, inhibition of chondrocyte proliferation and cell death. And NO production by iNOS may reflect the degree of inflammation and provides a measure to assess the effect of drugs on the inflammatory process. NO, free radical generated from L-arginine by NOS, has been recognized to be an important mediator of cellular communication in several preparation. Several studies have demonstrated that induction of iNOS produces a large amount of NO during endotoxemia and under inflammatory conditions. Therefore, drugs that inhibit iNOS expression and/or enzyme activity resulting in decreased NO generation may have beneficial therapeutic effects in the treatment of diseases due to overproduction of NO. Other studies also have suggested that inhibition of NO production may ameliorate arthritis. Furthermore, cytokine-induced degenerative activities in synovial joint tissues can be potentialized via the biosynthesis of inflammatory eicosanoids by cyclooxygenase (COXs) and 5-LOX. Arachidonic acid is a polyunsaturated fatty acid covalently bound in esterified form in the cell membranes of most body cells. Following irritation or injury, arachidonic acid is released and oxygenated by enzyme systems to the formation of an important group of inflammatory mediators, the eicosanoids “PGs, thromboxanes (TXs) and leukotrienes (LTs)”. The PGs, products of the COXs enzyme pathway, have potent inflammatory properties and PGE2 is readily detectable in equine acute inflammatory exudates. PGE2 and PGI2 markedly enhance edema formation and leukocyte infilSeptember 2005 Biol. Pharm. Bull. 28(9) 1615—1620 (2005) 1615