Aceclofenac has an outstanding anti-inflammatory and analgesic profile, involving besides a classical inhibition of PGE2, a decrease in the expression of several cytokines including IL-1 and TNF-alpha. It also inhibits activated oxygen species production and influences cells adhesion [2]. Various pharmacological actions of Aceclofenac is listed below.
Aceclofenac had a faster and more potent effect than the other NSAID, mainly on the expression of cell adhesion molecules. It efficiently interferes with neutrophil adhesion to endothelium and this effect may represent an additional relevant mechanism in its anti-inflammatory activity [6]. 4'-Hydroxy Aceclofenac suppresses the IL-1 induced production of promatrix metalloproteinases and release of sulfated-glycosaminoglycans from rabbit articular chondrocytes [7].
4'-Hydroxy Aceclofenac, a main metabolite of aceclofenac in humans, down-regulated the production of pro-matrix metalloproteinase-1/procollagenase 1 and promatrix metalloproteinase-3/prostromelysin 1 along with a decrease in their mRNAs in rabbit articular chondrocytes and synoviocytes, and interfered with the release of sulfated-glycosaminoglycans (proteoglycan) from the chondrocytes. 4'-Hydroxy Aceclofenac also suppressed the proliferation of rabbit synoviocytes [7].
In contrast, Aceclofenac itself and its other metabolites, Diclofenac and 4'-hydroxy Diclofenac, did not exert obvious actions on cellular functions. Therefore, it is suggested that the therapeutic effects of Aceclofenac on rheumatoid arthritis and osteoarthritis are, at least in part, due to the novel chondro-protective effect of 4'-hydroxy Aceclofenac via the suppression of promatrix metalloproteinase production and proteoglycan release [7].
Aceclofenac at the concentrations found in synovial fluid both exert a favorable effect on the overall metabolism of Proteoglycan and HA in OA cartilage. Aceclofenac should not hamper the biomechanical properties of the articular tissue and might delay joint failure in OA. However Aceclofenac does not normalize the changes in cartilage metabolism seen in the OA tissue [17].
Proteoglycan synthesis and release of the cartilage are not affected by PGE2 alone. Addition of IL-1 & TNF-a to healthy cartilage resulted in inhibition of proteoglycan synthesis and increase in proteoglycan release. When PGE2 is added, in addition to IL-1 & TNF-a, proteoglycan release increased further, but proteoglycan synthesis is not influenced.
Inhibition of IL-1 & TNF-a production and consequent expression of growth factor activity have been recently proposed as possible stimulatory mechanisms [17]. Addition of a selective COX-2 inhibitor to IL-1 & TNF-a treated cartilage inhibited the enhanced PGE2 production & almost completely normalized proteoglycan release, whereas synthesis remained unaffected. Also, the enhanced NO-levels remained elevated. PGE2 levels correlated significantly with proteoglycan release, whereas NO levels correlated significantly with proteoglycan synthesis.
Aceclofenac reduces the loss labelled proteoglycan molecules from the articular tissue and concomitantly enhanced proteoglycan synthesis whereas Diclofenac unaffected the overall metabolism of sulphated glycosaminoglycans [17].
Aceclofenac, 4′-hydroxy-Aceclofenac and Diclofenac significantly decreased interleukin-6 production on concentration dependent gradient and fully blocked PGE2 synthesis by IL-1beta- or LPS-stimulated human chondrocytes. Aceclofenac and Diclofenac had no effect on interleukin-8 production while 4′-hydroxy Aceclofenac slightly decreased at the highest doses. Aceclofenac has no effect on IL-1beta- or LPS-stimulated nitric oxide production where as at higher concentration, 4′-hydroxy-Aceclofenac inhibited both IL-1beta or LPS-stimulated nitric oxide production while Diclofenac inhibited only the LPS-stimulated production. Finally, at higher concentration (30 microM), the three drugs significantly decreased IL-1beta mRNA [8].
Nitric oxide (NO) and PGE2 are two inflammatory mediators overproduced in arthritis-affected joints. The inducible isoform of nitric oxide synthase (iNOS) and COX-2 are found both in the synovial tissue and in the cartilage. Their expression is regulated by catabolic cytokines, such as interleukin-1beta and TNF-alpha. These inflammatory mediators play a profound role in the pathogenic processes that arise in the pannus of rheumatoid arthritis and also interfere with cartilage homeostasis in osteoarthritis [14]. Nitric Oxide can promote cellular injury and increase chondrocytes susceptibility to cytokine-induced apoptosis [15].
All menisci constitutively produced NO, and significant increases in NO production were observed in the presence of IL-1beta, TNF-alpha, or IL-17 . The combination of IL-17 and TNF-alpha significantly increased NO production compared with either cytokine alone. IL-1beta significantly increased PGE2 production. The combination of IL-1beta and TNF-alpha had an additive effect on PGE2 production, while addition of IL-17 to TNF-alpha or IL-1beta synergistically enhanced PGE2 production [16].
Pro-inflammatory stimuli induce (Interleukin 1 receptor antagonist) IL-1Ra synthesis in human articular chondrocytes. Aceclofenac may modulate PGE2 production by increasing IL-1Ra production and decreasing NO synthesis. IL-1Ra may play an important role in cartilage degradation by inhibiting IL-1 activity and therefore blocking IL-1 stimulation of PGE2 synthesis. Nitric oxide (NO) formation is increased during inflammation. High concentrations of NO exert negative effects on chondrocytes functions [5].
