Pharmacology: Pharmacodynamics: It is now well accepted that the cytokine interleukin-1β (IL-1β) plays a crucial role in triggering the cascade of cartilage degrading events by inducing the production of catabolic factors such as TNF-α, matrix metalloproteinases (MMPs) and nitric oxide (NO). In OA, excessive IL-1β production and activity can enhance catabolic and anti-anabolic processes, resulting in a reduction in cartilage synthesis, an increase in cartilage degradation and subchondral bone remodeling. IL-1β also indirectly stimulates chondrocyte and synoviocyte apoptosis and plays a key role in inflammation, both of which contribute to the loss of cartilage. In addition, by acting in an autocrine or paracrine manner within cartilage, IL-1β can stimulate its own production and thus perpetuate cartilage damage. Blocking IL-1β or its activity has been shown to be effective in preventing cartilage destruction.
In vitro studies show that diacerein and rhein, the active moiety, inhibit the production and activity of the pro-inflammatory and pro-catabolic cytokine IL-1β both in the superficial and deep layers of the cartilage and in the synovial membrane from OA patients.
Diacerein and rhein reduced IL-1β-induced MMP levels and NO by chondrocytes. They also reduced the synthetic activities of OA osteoblasts which could be responsible for the abnormal subchondral bone remodeling occurring during the course of OA. In addition, Boileau et al. (2008) showed that diacerein and rhein reduced, in a dose-dependent manner, IL-1β-induced MMP-13 production in OA subchondral bone. In osteoclasts, they significantly reduced the activity of MMP-13 and cathepsin K. Moreover, these drugs effectively blocked the IL-1β effect on the osteoclast differentiation process and the survival of mature osteoclasts. Altogether, these data suggest that diacerein/rhein could impact the abnormal subchondral bone metabolism in OA by reducing the synthesis of resorptive factors and osteoclast formation.
ARTRODAR has a unique mode of action and influences both the anabolism and catabolism of chondrocytes by down-regulating the production of pro-inflammatory cytokines, and thus inflammation and cartilage degradation, while stimulating cartilage repair.
Anti-catabolic effects: By inhibiting IL-1β production and activity at pre- and post-cell membrane levels, ARTRODAR down-regulates IL-1β-induced cartilage degrading events such as the production of pro-catabolic cytokines e.g. TNF-α, MMPs, NO, and other proteases which cause cartilage degradation and also counteracts NO-mediated down-regulation of cartilage repair process.
Anti-inflammatory effects: By inhibiting IL-1β, ARTRODAR acts at an earlier stage in the inflammatory cascade than non-steroidal anti-inflammatory drugs (NSAIDs) or corticosteroids, down-regulating the key mediators responsible for the propagation and exacerbation of inflammation in OA and leading to a reduction in the pain experienced in OA. As ARTRODAR does not negatively affect the arachidonic acid cascade and the synthesis of prostaglandins, unlike NSAIDs, it does not cause gastric damage, cardiovascular side effects, or renal problems. Studies have shown that ARTRODAR does not have a negative effect on the gastric mucosa and may have a gastroprotective effect when taken with an NSAID.
Pro-anabolic effects: ARTRODAR also has pro-anabolic properties. It has been shown to stimulate production of cartilage growth factors such as transforming growth factor-β (TGF-β), even in the presence of IL-1β. This stimulates chondrocyte proliferation, consequently increasing the synthesis of cartilage components such as hyaluronan, collagen and proteoglycans leading to cartilage repair. TGF-β is also an inhibitor of several IL-1β-induced catabolic processes. In addition, TGF-β stimulates the production of tissue inhibitor of metalloproteinases (TIMP), thus inhibiting MMP activity.
In clinical trials, ARTRODAR significantly improved OA symptoms such as pain, joint dysfunction and inflammation. The effect was comparable to that obtained with NSAIDs but with better safety profile. The results from a study in a Thai population found that 90% of patients treated with ARTRODAR reported high satisfaction with treatment, and pain showed a decrease of 70% compared to baseline after 16 weeks of treatment. The beneficial effects of ARTRODAR are observed after 2-4 weeks of treatment, with significant improvements appearing after about 4-6 weeks of treatment, and are still present for at least 2-3 months after treatment has stopped (carry-over effect).
ARTRODAR also has shown disease-modifying properties in animal models and in a clinical study in patients with hip osteoarthritis. Daily treatment with ARTRODAR for 3 years significantly reduced radiographic progression of OA with a cartilage sparing effect of 32% compared with placebo. Moreover, the results from this long-term study showed that requirement for total hip replacement during the study and during the 3 months following treatment discontinuation was lower in the ARTRODAR group (14.5%) compared with the placebo group (19.8%). It also had a good safety profile during this continuous, 3-year treatment period.
Pharmacokinetics: After oral administration of ARTRODAR, diacerein is rapidly converted to rhein, the active moiety. Clinical pharmacokinetics studies carried out in healthy adults (40 to 60 years) and elderly volunteers (over 60 years of age), showed that peak levels of rhein were reached 2.6 hours after multiple oral dose administration of 50 mg diacerein twice a day with an elimination half-life of 7 to 8 hours. Therefore, no change in the usual recommended dose is necessary in elderly patients. In patients with severe renal insufficiency, a significant increase in the elimination half-life, AUC and renal clearance were observed. A dose reduction is recommended in these patients. No changes in plasmatic or urinary parameters of diacerein were observed in patients with compensated or decompensated mild or moderate hepatic insufficiency and no changes in the posology are required in these cases. However, ARTRODAR is contraindicated in patients with severe liver disease.