Carlson R P, Hartman D A, Tomchek L A, Walter T L, Lugay J R, Calhoun W, Sehgal S N, Chang J Y
Wyeth-Ayerst Research, Princeton, New Jersey.
J Pharmacol Exp Ther. 1993 Aug;266(2):1125-38.
Rapamycin (RAPA), a potent immunosuppressive agent that prevents organ graft rejection in animal models of transplantation, possesses a mechanism of action different than that of cyclosporin A and FK-506. In this study, the pharmacological activity of RAPA in a variety of immune and inflammatory models was assessed in order to define better its potential utility as an antiarthritic agent. RAPA inhibited T cell-mediated inflammation in mouse methylated bovine serum albumin-induced delayed-type hypersensitivity (ED40 = 4.7 mg/kg p.o.) and produced oral ED50 of 2.0 mg/kg against developing adjuvant arthritis in rats (3-day dosing schedule) and 9.5 mg/kg in established adjuvant arthritis in rats (daily dosing schedule). In both models of adjuvant arthritis, effects of RAPA were maintained even after cessation of drug dosing. In contrast, after discontinuation of cyclosporin A (5- and 10-mg/kg doses), disease activity returned. RAPA was also effective in another T cell-mediated model, experimental allergic encephalomyelitis (ED50 approximately 5 mg/kg p.o.). At higher doses, RAPA significantly inhibited carrageenan paw edema in rats, a model of acute inflammation (ED40, 56 mg/kg p.o.), without increasing serum corticosterone levels. In this model, doses approximately 10 to 20 times greater than active doses in T cell-mediated models were required. RAPA at 1 to 50 microM did not inhibit in vitro human synovial phospholipase A2 or 5-lipoxygenase and cyclo-oxygenase activity in the human blood leukocyte assay. The total profile of RAPA suggests that it may be effective in the treatment of rheumatoid arthritis, multiple sclerosis and other autoimmune diseases.
雷帕霉素（RAPA）是一种强效免疫抑制剂，可在移植动物模型中预防器官移植排斥，其作用机制与环孢素A和FK - 506不同。在本研究中，评估了RAPA在多种免疫和炎症模型中的药理活性，以便更好地确定其作为抗关节炎药物的潜在效用。RAPA抑制小鼠甲基化牛血清白蛋白诱导的迟发型超敏反应中T细胞介导的炎症（口服ED40 = 4.7 mg/kg），对大鼠佐剂性关节炎的发展产生口服ED50为2.0 mg/kg（3天给药方案），对大鼠已建立的佐剂性关节炎产生口服ED50为9.5 mg/kg（每日给药方案）。在两种佐剂性关节炎模型中，即使停药后RAPA的作用仍得以维持。相比之下，停用环孢素A（5和10 mg/kg剂量）后，疾病活动恢复。RAPA在另一种T细胞介导的模型——实验性变态反应性脑脊髓炎中也有效（口服ED50约为5 mg/kg）。在较高剂量时，RAPA显著抑制大鼠角叉菜胶足肿胀，这是一种急性炎症模型（口服ED40，56 mg/kg），且不增加血清皮质酮水平。在该模型中，所需剂量比T细胞介导模型中的有效剂量大约高10至20倍。在体外人滑膜磷脂酶A2或人血白细胞试验中的5 - 脂氧合酶和环氧化酶活性测定中，1至50 microM的RAPA没有抑制作用。RAPA的总体情况表明，它可能对类风湿性关节炎、多发性硬化症和其他自身免疫性疾病的治疗有效。
