Zoja C, Corna D, Benedetti G, Morigi M, Donadelli R, Guglielmotti A, Pinza M, Bertani T, Remuzzi G
Mario Negri Institute for Pharmacological Research, Bergamo, Italy.
Kidney Int. 1998 Mar;53(3):726-34. doi: 10.1046/j.1523-1755.1998.00804.x.
As an alternative to classical immunosuppressants in experimental lupus nephritis, we looked at bindarit, 2-methyl-2-[[1-phenylmethyl)-1H-indazol-3-y1]methoxy]propanoic acid, a novel molecule devoid of immunosuppressive effects, which selectively reduces chronic inflammation in rat adjuvant arthritis. Two groups of NZB/W mice (N = 55 for each group) were given bindarit, (50 mg/kg/day p.o.) or vehicle starting at 2 months of age. Mice were sacrificed at 2, 6, 8 and 10 months or used for survival studies. Bindarit delayed the onset of proteinuria (% proteinuric mice, bindarit vs. vehicle, 6 months: 0 vs. 33% and 8 months: 7% vs. 60%, P < 0.005; 10 months: 53% vs. 80%) and significantly (P < 0.05) protected from renal function impairment (serum BUN, bindarit vs. vehicle: 8 months, 30 +/- 3 vs. 127 +/- 42; 10 months, 53 +/-5 vs. 140 +/- 37 mg/dl). Appearance of anti-DNA antibodies was retarded and survival significantly (P < 0.0001) prolonged by bindarit (% survival, bindarit vs. vehicle: 8 months, 100% vs. 80%; 10 months, 87% vs. 40%; 12 months, 27% vs. 20%). Bindarit significantly limited glomerular hypercellularity, interstitial inflammation and tubular damage. Renal expression of monocyte chemoattractant protein (MCP-1) mRNA (Northern blot) markedly increased (7 - 12-fold in 8- 10-month-old mice vs. 2-month-old) during the progression of nephritis in association with mononuclear cell infiltration. Bindarit completely prevented MCP-1 up-regulation. In another series of experiments, bindarit (0.25% and 0.5% medicated diet, N = 16 for each group) when started at 4.5 months of age in NZB/W mice improved survival in respect to untreated mice (N = 17) in a dose-dependent manner (% survival: 8 months, 94% and 100%, respectively, vs. 47%; 10 months, 75% and 100% vs. 35%; 12 months, 31% and 75% vs. 12%). Survival was even more prolonged when bindarit (0.5% medicated diet) was combined with a low dose of methylprednisolone (1.5 mg/kg i.p.), which that only partially modifies proteinuria and survival of lupus mice, in an additional group of animals (N = 16). Thus, at 14.5 months when all mice given bindarit alone died, 50% of mice on combined therapy were still alive (P < 0.023). Studies are needed to establish whether bindarit may function as a steroid sparing drug in human lupus.
作为实验性狼疮性肾炎中经典免疫抑制剂的替代药物，我们研究了苯达立特（2-甲基-2-[[(1-苯基甲基)-1H-吲唑-3-基]甲氧基]丙酸），一种没有免疫抑制作用的新型分子，它能选择性减轻大鼠佐剂性关节炎中的慢性炎症。两组NZB/W小鼠（每组N = 55）从2月龄开始分别给予苯达立特（50 mg/kg/天，口服）或赋形剂。在2、6、8和10个月时处死小鼠或用于生存研究。苯达立特延迟了蛋白尿的发生（蛋白尿小鼠百分比，苯达立特组与赋形剂组比较，6个月时：0%对33%，8个月时：7%对60%，P < 0.005；10个月时：53%对80%），并显著（P < 0.05）保护小鼠免受肾功能损害（血清尿素氮，苯达立特组与赋形剂组比较：8个月时，30±3对127±42；10个月时，53±5对140±37 mg/dl）。抗DNA抗体的出现延迟，苯达立特显著（P < 0.0001）延长了小鼠的生存期（生存率，苯达立特组与赋形剂组比较：8个月时，100%对80%；10个月时，87%对40%；12个月时，27%对20%）。苯达立特显著限制了肾小球细胞增多、间质炎症和肾小管损伤。在肾炎进展过程中，随着单核细胞浸润，单核细胞趋化蛋白（MCP-1）mRNA的肾表达（Northern印迹法）显著增加（8 - 10月龄小鼠相对于2月龄小鼠增加7 - 12倍）。苯达立特完全阻止了MCP-1的上调。在另一系列实验中，NZB/W小鼠在4.5月龄开始给予苯达立特（含药饲料0.25%和0.5%，每组N = 16），相对于未治疗小鼠（N = 17），以剂量依赖方式提高了生存率（生存率：8个月时，分别为94%和100%对47%；10个月时，75%和100%对35%；12个月时，31%和75%对12%）。当苯达立特（含药饲料0.5%）与低剂量甲基强的松龙（1.5 mg/kg，腹腔注射）联合使用时，在另一组动物（N = 16）中，生存期延长得更多，甲基强的松龙仅部分改善狼疮小鼠的蛋白尿和生存期。因此，在14.5个月时，所有单独给予苯达立特的小鼠均死亡，而联合治疗组50%的小鼠仍然存活（P < 0.023）。需要开展研究以确定苯达立特在人类狼疮中是否可作为一种激素节省药物发挥作用。
