Maksymowych Walter P, Jhangri Gian S, Aspeslet Launa, Abel Mark D, Trepanier Daniel J, Naicker Selvaraj, Freitag Derrick G, Cooper Bobbi-Lynn, Foster Robert T, Yatscoff Randall W
Department of Medicine, University of Alberta, Edmonton, Canada.
J Rheumatol. 2002 Aug;29(8):1646-52.
To examine the efficacy and toxicity of ISA(TX)247, a novel calcineurin inhibitor, in comparison to cyclosporine (cyclosporin A, CSA) and placebo in established collagen induced arthritis. ISA(TX)247 has up to 3-fold greater potency than CSA in an in vitro whole blood calcineurin inhibition assay and in in vivo solid organ and cell transplantation models. Phase I clinical trials show no discernible nephrotoxicity.
Type II collagen immunized DBA/Lac J mice with established arthritis were randomized to treatment with ISA(TX)247 (125/250/500 microg/mouse), CSA (250/500 microg/mouse), or drug vehicle, by daily intraperitoneal injection for 10 days from the onset of clinical arthritis.
A significant dose dependent reduction in clinical severity was observed in ISA(TX)247 treated but not in CSA treated animals 10 days after the onset of established arthritis, and when examined by area under the curve analysis during the treatment period. Significant improvement in paw swelling (p < 0.001), synovial histology (p < 0.001), and articular cartilage damage scores (p = 0.002) was also noted in ISA(TX)247 treated animals, even in the 125 pg dose group (p = 0.03 for paw swelling and synovial histology). By comparison, CSA had no significant effect on either synovial inflammation or articular cartilage damage. ISA(TX)247 (500 microg dose group) was the only treatment to significantly decrease the development of proximal interphalangeal joint erosions (p < 0.05). A significant reduction in Type II collagen antibody titer was noted in ISA(TX)247 animals in both 250 microg (p = 0.02) and 500 microg (p = 0.004) dosage groups, but only in the 500 microg group for CSA (p = 0.004). Treatment was well tolerated, with no significant toxicity in ISA(TX)247 groups.
ISA(TX)247 demonstrates efficacy and safety in the treatment of established collagen induced arthritis. Together with its improved potency and nephrotoxicity profile in comparison to CSA, this agent warrants further clinical investigation in autoimmune disease. Phase II studies in rheumatoid arthritis have been initiated.
在已建立的胶原诱导性关节炎模型中，对比新型钙调神经磷酸酶抑制剂ISA(TX)247与环孢素（环孢素A，CSA）及安慰剂的疗效和毒性。在体外全血钙调神经磷酸酶抑制试验以及体内实体器官和细胞移植模型中，ISA(TX)247的效力比CSA高3倍。I期临床试验显示其无明显肾毒性。
将已患有关节炎的经II型胶原免疫的DBA/Lac J小鼠随机分为三组，分别用ISA(TX)247（125/250/500微克/小鼠）、CSA（250/500微克/小鼠）或药物赋形剂进行治疗，从临床关节炎发作起每天腹腔注射，持续10天。
在已建立关节炎发作10天后，观察到ISA(TX)247治疗组的临床严重程度有显著的剂量依赖性降低，而CSA治疗组则无此现象，在治疗期间通过曲线下面积分析也得到同样结果。在ISA(TX)247治疗的动物中，即使是125微克剂量组，爪肿胀（p < 0.001）、滑膜组织学（p < 0.001）和关节软骨损伤评分（p = 0.002）也有显著改善（爪肿胀和滑膜组织学p = 0.03）。相比之下，CSA对滑膜炎症或关节软骨损伤均无显著影响。ISA(TX)247（500微克剂量组）是唯一能显著减少近端指间关节侵蚀发展的治疗方法（p < 0.05）。在250微克（p = 0.02）和500微克（p = 0.004）剂量组的ISA(TX)247治疗动物中，II型胶原抗体滴度显著降低，但CSA仅在500微克组有此现象（p = 0.004）。治疗耐受性良好，ISA(TX)247组无明显毒性。
ISA(TX)247在治疗已建立的胶原诱导性关节炎中显示出疗效和安全性。与CSA相比，其效力提高且肾毒性改善，该药物值得在自身免疫性疾病中进行进一步临床研究。类风湿关节炎的II期研究已启动。
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