Yamamoto N, Sakai F, Yamazaki H, Kawai Y, Nakahara K, Okuhara M
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd., Ibaraki, Japan.
J Rheumatol. 1996 Oct;23(10):1778-83.
We evaluated the effect of FR133605, a novel inhibitor of interleukin 1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha), on bone and cartilage destruction in adjuvant arthritic rats and compared it to corticosteroid, nonsteroidal antiinflammatory drugs (NSAID), and disease modifying antirheumatic drugs (DMARD).
The antiinflammatory responses were evaluated by measurement of hind paw swelling, body weight, femoral bone mineral density, and glycosaminoglycan content (GAG) in femoral condyles in adjuvant arthritic rats.
FR133605 inhibited IL-1 and TNF-alpha production stimulated with lipopolysaccharide (LPS) in human monocytes. FR133605 also inhibited serum IL-1 and TNF-alpha concentrations in LPS treated mice. In contrast, among comparison antirheumatic drugs, only corticosteroid inhibited production at nontoxic concentrations. In adjuvant arthritis, FR133605 significantly inhibited paw swelling, bone and cartilage destruction, and increased body weight. On the other hand, indomethacin significantly inhibited paw swelling, but not bone and cartilage loss. Dexamethasone completely inhibited paw swelling and bone loss, but augmented cartilage breakdown. DMARD weakly restored the loss of GAG contents in articular cartilage.
FR133605 improved bone loss and articular cartilage destruction in adjuvant arthritic rats and the inhibitory effect was closely correlated with the suppressive activity of IL-1 and TNF-alpha production.
我们评估了新型白细胞介素1（IL-1）和肿瘤坏死因子-α（TNF-α）抑制剂FR133605对佐剂性关节炎大鼠骨骼和软骨破坏的影响，并将其与皮质类固醇、非甾体抗炎药（NSAID）和改善病情抗风湿药（DMARD）进行比较。
通过测量佐剂性关节炎大鼠的后爪肿胀、体重、股骨骨密度和股骨髁中的糖胺聚糖含量（GAG）来评估抗炎反应。
FR133605抑制人单核细胞中脂多糖（LPS）刺激产生的IL-1和TNF-α。FR133605还抑制LPS处理小鼠的血清IL-1和TNF-α浓度。相比之下，在比较的抗风湿药物中，只有皮质类固醇在无毒浓度下抑制产生。在佐剂性关节炎中，FR133605显著抑制爪肿胀、骨骼和软骨破坏，并增加体重。另一方面，吲哚美辛显著抑制爪肿胀，但不抑制骨骼和软骨损失。地塞米松完全抑制爪肿胀和骨质流失，但加剧软骨破坏。DMARD微弱地恢复关节软骨中GAG含量的损失。
FR133605改善了佐剂性关节炎大鼠的骨质流失和关节软骨破坏，且抑制作用与IL-1和TNF-α产生的抑制活性密切相关。
