The Nitro Kr fte In vitro SB 203580 3-Methyladenine and VX 745 evaluated for p38 and inhibition of cytokines in vitro prior to the test in the rat iodoacetate model of cartilage degeneration. Both SB 203580 and VX 745 were potent inhibitors of p38 with an IC50 of 136 nM and 64 nM, 35 14, 50 ??????? ATP concentrations. Similar SB 203 580 and VX 745, the release of TNF LPS stimulated human THP 1 cells inhibited with IC 50 s of 15 nM and 72 nM 29 14. TNF release from LPS stimulated peripheral mononuclear Ren cells was 16th with IC50 June 8 nM and 14 nM inhibited was SB 203580 and VX 745 and IL-1 inhibited with IC50 of 20 nM and 8 nM 15 4, respectively.
P38 inhibitors reduce Gelenkverschlei iodoacetate in the rat model, oral administration of SB 203580 or VX 745 rats had, again U a single injection of sodium iodoacetate was entered in the left knee joint Born a statistically significant inhibition of the degeneration of the knee by 45% and 31%, compared with the vehicle animals embroidered treated. SB 230580 was also evaluated AZ 960 in the rat iodoacetate model in an experiment of dose-response relationship. SB 203580 administered orally inhibits degeneration induced iodoacetate common in rats 30, 25, 12 and 8% at 50, 25, 10 and 5 mg / kg as compared to animals treated with vehicle. P38 inhibitors attenuator Chen hyperalgesia in rats, the p38 inhibitors were for their F Ability, reaction hyperalgesic rats with model Hargraeves inhibit evaluated. The rats were again U sp an oral dose of vehicle, SB 203580 or VX 745 and 30 minutes Ter re one paw of each rat U intraplantar injection of carrageenan.
Time of paw withdrawal to a source of infrared Warmth was sp four hours Measured ter. Both SB 203580 and VX 745 erh Fa ht Significant time to paw withdrawal compared to animals with the vehicle in a manner to the dose, when administered orally at 30, 10 and 3 mg / kg treated proportionally. Discussion of cartilage degeneration in osteoarthritis occurs is the result of mechanical and biochemical factors. Proinflammatory cytokines play an r Important in the induction of proteinases, which is capable of degrading collagen and aggrecan components of cartilage. Cytokines such as IL 1ave also shown to inhibit the synthesis of the cartilage matrix. The result is an imbalance in favor of anabolism and catabolism over a net loss of cartilage matrix.
Zus Tzlich inflammatory cytokines such as IL 1 TNF and It has been shown to modulate pain responses in animal models. Therefore, the inhibition of entz??ndungsf Rdernden cytokines provide important therapeutic approach for the treatment of osteoarthritis. Clinical trial data on cytokine inhibitors for the treatment of osteoarthritis is limited. Diacerein is a compound which inhibits IL 1roduction in vitro and has been evaluated in several clinical trials for the treatment of osteoarthritis. Diacerein has been shown to reduce fa Symptoms are clearly Osteoarthritis and my adversely Chtigen structural Changes in the composition. A pilot study of 3 months of adalimumab-TNF in 12 patients with erosive arthritis has not significantly improved the signs and symptoms My disease, but this study was not controlled EEA and little short. P38 MAPK has been widely used as a target for the inhibition of the cytokines in the treatment of inflammatory diseases.