Pharmacological effects of N-[2-[[2-[2-[(2,6-dichlorophenyl)amino]phenyl]acetyl]oxy]ethyl]hyaluronamide (diclofenac Etalhyaluronate, SI-613), a novel sodium hyaluronate derivative chemically linked with diclofenac.

BACKGROUND: Osteoarthritis (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. METHODS: We 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. RESULTS: A 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. CONCLUSION: A 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.

Interleukin-6 production by peritoneal mesothelial cells and its regulation by inflammatory factors in rats administered carbon tetrachloride intraperitoneally.

We previously reported that a high level of interleukin-6 (IL-6), which is protective against CCl(4)-induced hepatotoxicity, is produced in the peritoneal cavity in the early period after ip carbon tetrachloride (CCl(4)) administration. The objective of this study was to identify the tissues and cells involved in IL-6 production and clarify the mechanisms underlying its regulation. IL-6 mRNA levels increased significantly in the serous membranes of the mesentery and peritoneum, but not in the parenchymal organs including liver, kidney and spleen, 3 h after ip CCl(4) administration. Peritoneal mesothelial cells (PMCs), a major cell population in serous membranes, were isolated from rat peritoneal walls by trypsin digestion and cultured with peritoneal exudate fluid (PEF) from CCl(4)-administered rats. PMCs produced a high level of IL-6 in the presence of PEF recovered 0.5 h after ip CCl(4) administration. Analyses of PEF revealed that the levels of prostaglandin E(2) (PGE(2)), histamine, IL-1alpha, IL-1beta and tumor necrosis factor-alpha (TNF-alpha) increased immediately after ip CCl(4) administration. These inflammatory factors, except for histamine, stimulated IL-6 production to varying degrees, in the following order: IL-1alpha>IL-1beta>TNF-alpha>>PGE(2). In summary, the present study indicates that the high level of IL-6 observed in the rat peritoneal cavity after ip CCl(4) administration is at least partially produced by PMCs stimulated cooperatively with IL-1alpha, IL-1beta, TNF-alpha and PGE(2). These inflammatory factors may be released from tissues or cells either stimulated or injured directly by CCl(4).

Early induced, high-level interleukin-6 expression in the rat peritoneal cavity into which a hepatotoxicant carbon tetrachloride was administered.

IL-6 induction depending on the mode of carbon tetrachloride (CCl4) administration was investigated in rats. After the intraperitoneal (i.p.) administration of CCl4 in 50% corn oil at 1.0 ml/kg body weight, IL-6 level markedly increased in plasma and peaked at 4h. TNF-alpha and IL-1beta levels gradually increased, reaching the maximum at 24h. IL-10 level transiently peaked at 4h and then decreased, but later further increased, reaching the second peak at 24h. Plasma alanine aminotransferase (ALT) and sorbitol dehydrogenase (SDH) activities peaked at 24h. As the vehicle-to-CCl4 ratio increased, the level of IL-6 decreased and the activities of ALT and SDH increased. After oral CCl4 administration, IL-6 was not significantly detected. IL-6 level in peritoneal exudate fluid (PEF) increased simultaneously with plasma IL-6 level after i.p. CCl4 administration, but the total amount of PEF IL-6 was 37-fold as much as that of plasma IL-6, in contrast to the result that the total amount of plasma IL-6 was 19-fold as much as that of PEF IL-6 after i.p. lipopolysaccharide administration. These results suggest that i.p. administration of CCl4 dissolved in a small amount of vehicle selectively induces a high production of IL-6 in the peritoneal cavity early after the administration. Since IL-6 is a protective cytokine against hepatotoxicity, its induction should be taken into consideration during analysis of data obtained using the CCl4-induced liver injury model.