BackgroundOsteoarthritis (OA) is the most common joint disorder worldwide and one of the leading causes of disability in the elderly. We have investigated the novel sodium hyaluronate derivative chemically linked with diclofenac (DF), diclofenac etalhyaluronate (SI-613), which is a potentially safer and more effective treatment for OA knee pain. In this study, we evaluated the pharmacological effects of SI-613 in experimental arthritis models.MethodsWe compared the analgesic and anti-inflammatory effects of intra-articularly administered SI-613, hyaluronic acid (HA), and of orally administered diclofenac sodium (DF-Na) in rat silver nitrate-induced arthritis model and rabbit antigen-induced arthritis model.ResultsA single intra-articular (IA) administration of SI-613 significantly suppressed pain responses in rats in a dose-dependent manner. The analgesic effects were greater than those of HA, a mixture of DF-Na and HA, or an oral once-daily administration of DF-Na. In the rabbit arthritis model, SI-613 significantly reduced knee joint swelling compared with that in the control group on day 1 after a single IA injection. This significant anti-inflammatory effect was observed until day 28. In the pharmacokinetic study, the DF concentration in the synovium after SI-613 administration reached its maximum concentration of 311.6 ng/g on day 1, and gradually declined to 10 ng/g by day 28. It fell below the lower limit of quantification on day 35. Thus, a clear correlation was found between pharmacokinetics and pharmacodynamics. These results demonstrate that SI-613 exerts its long-lasting and potent anti-inflammatory effect by sustainable release of DF in the knee joint tissues.ConclusionA single IA injection of SI-613 was shown to exert analgesic and anti-inflammatory effects for 28 days in non-clinical pharmacological studies, suggesting that SI-613 will be a promising candidate in the treatment of osteoarthritis pain.

A single-dose IA injection of Gel-200 exerts chondroprotective and anti-inflammatory effects in the experimental OA model, and long-lasting analgesia in the joint pain model, suggesting the beneficial multimodal function of Gel-200 against symptomatic OA patients.

Background We have reported that a single intra-articular injection of diclofenac etalhyaluronate (SI-613) exerted a potent and long-lasting analgesic effect in experimental arthritis models. In the present study, we investigated the effect of SI-613 on the production of high molecular weight hyaluronic acid (HMW-HA) in synoviocytes from osteoarthritis (OA) patients and compared its efficacy with that of hyaluronic acid (HA). Methods We compared the effect of SI-613, HA, and diclofenac sodium (DF-Na) on high molecular weight HA production by human synoviocytes. Results SI-613 and exogenous HA induced the production of high molecular weight HA in synoviocytes from OA patients, whereas DF-Na had no effect. The molecular weight of newly produced HA was about 1000 kDa in the HA-treated synoviocytes and much higher than 2400 kDa in the SI-613-treated cells. The effect of the mixture of HA and DF-Na was similar to that of HA alone in that the molecular weight of newly produced HA was around 1000 kDa. SI-613 significantly suppressed hyaluronidase 2 (HYAL2) mRNA expression and significantly enhanced hyaluronan synthase 2 (HAS2) mRNA expression. HA had no effect on the expression levels of HYAL and HAS. Conclusion The present results clearly demonstrate that SI-613 induces the production of high molecular weight HA in synoviocytes from OA patients, suggesting the long-lasting analgesic and disease modifying effect of SI-613 for OA. Taken together with the anti-inflammatory and analgesic effects we recently reported for the intra-articular administration of SI-613 to experimental animal models, SI-613 holds great promise for the treatment of knee osteoarthritis.