Badger A M, Dimartino M J, Talmadge J E, Picker D H, Schwartz D A, Dorman J W, Mirabelli C K, Hanna N
Department of Immunology, Smith Kline and French Laboratories, King of Prussia, PA 19406-0939.
Int J Immunopharmacol. 1989;11(7):839-46. doi: 10.1016/0192-0561(89)90138-0.
SK&F 105685 (N,N-dimethyl-8,8-dipropyl-2-azaspiro[4.5]decane-2-propanamine+ ++ dihydrochloride), administered orally to adjuvant arthritic (AA) rats inhibited immune-mediated hindpaw inflammation with an ED50 of 20 mg/kg/day. Both prophylactic and therapeutic administration were effective in this model. In addition, SK&F 105685 inhibited skin wheal responses to purified protein derivative (PPD) of tuberculin in AA rats and the development of hindleg paralysis associated with experimental allergic encephalomyelitis (EAE). Spleens of normal rats treated with SK&F 105685 were found to contain a population(s) of suppressor cells (SC) which inhibited the response of normal cells to Concanavalin A (Con A) in co-culture assays. The association between SC induction and anti-arthritic activity was determined by evaluating a series of chemically related azaspiranes in the AA rat model and for SC induction in normal rats. A statistically significant correlation was demonstrated (r = 0.79, P less than 0.001), indicating that SC induction may be responsible for the therapeutic activity of these compounds.
SK&F 105685（N，N - 二甲基 - 8，8 - 二丙基 - 2 - 氮杂螺[4.5]癸烷 - 2 - 丙胺二盐酸盐）口服给予佐剂性关节炎（AA）大鼠，可抑制免疫介导的后爪炎症，半数有效剂量（ED50）为20毫克/千克/天。预防性给药和治疗性给药在该模型中均有效。此外，SK&F 105685可抑制AA大鼠对结核菌素纯蛋白衍生物（PPD）的皮肤风团反应以及与实验性变态反应性脑脊髓炎（EAE）相关的后腿麻痹的发展。发现用SK&F 105685处理的正常大鼠脾脏含有一群抑制细胞（SC），在共培养试验中，这些抑制细胞可抑制正常细胞对刀豆球蛋白A（Con A）的反应。通过在AA大鼠模型中评估一系列化学相关的氮杂螺环烷并检测其在正常大鼠中诱导SC的情况，确定了SC诱导与抗关节炎活性之间的关联。结果显示存在统计学上的显著相关性（r = 0.79，P小于0.001），表明SC诱导可能是这些化合物发挥治疗活性的原因。
