CN104188974B - 二甲氧基雌二醇在治疗系统性红斑狼疮中的用途 - Google Patents
二甲氧基雌二醇在治疗系统性红斑狼疮中的用途 Download PDFInfo
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Abstract
本发明公开了二甲氧基雌二醇用于治疗系统性红斑狼疮的用途。包含二甲氧基雌二醇作为治疗药物或者治疗药物所含成分。系统性红斑狼疮包含皮肤狼疮、狼疮肾炎、狼疮脑病及其他系统或/和器官的狼疮疾病。二甲氧基雌二醇的给药方式为尾静脉注射、给药剂量为0.75uM/kg/次，或灌胃、给药量100uM/kg/次。治疗用于B6.MRL‑Fas(lpr)小鼠。本发明有益之处是将2ME2用于红斑狼疮模型小鼠MRL‑Fas(lpr)鼠，可降低系统性红斑狼疮自身抗体水平，减少狼疮相关肾炎症状，缓解狼疮症状。
Description
技术领域
本发明属于生物医药领域，涉及二甲氧基雌二醇在治疗系统性红斑狼疮中的用途。
背景技术
系统性红斑狼疮(SLE)是以致病性自身抗体为特征的自身免疫性疾病，其直接的致病因子是多克隆自身抗体，并以免疫复合物的形式造成多种组织器官损伤。目前临床上治疗SLE的主导措施是使用激素和非特异性免疫抑制剂，如糖皮质激素、环磷酰胺等，这些药物能广泛地抑制免疫活性细胞，可有效控制疾病病程，但毒副作用明显，如破坏胃黏膜形成胃炎、诱发机体感染、导致骨质疏松等。由于血清中大量自身抗体的存在是SLE的基本病理特征，提示抑制系统性红斑狼疮患者自身抗体水平是治疗SLE的方向，但目前还无能直接抑制自身抗体产生的药物和制剂。
发明内容
本发明提供了二甲氧基雌二醇用于治疗系统性红斑狼疮的用途。
本发明的特点还在于二甲氧基雌二醇作为治疗药物或者治疗药物所含成分。系统性红斑狼疮包含皮肤狼疮、狼疮肾炎、狼疮脑病及其他系统或/和器官的狼疮疾病。二甲氧基雌二醇的给药方式为尾静脉注射、给药剂量为0.75uM/kg/次，或灌胃、给药量100uM/kg/次。治疗用于B6.MRL-Fas(lpr)小鼠。
本发明有益之处是将2ME2用于红斑狼疮模型小鼠MRL-Fas(lpr)鼠，可降低系统性红斑狼疮自身抗体水平，减少狼疮相关肾炎症状，缓解狼疮症状。
附图说明
图1是抗ds-DNA抗体水平对比图；
图2是患病肾小球病理图；
图3是2ME2治疗后肾小球病理图。
具体实施方式
本发明提供了二甲氧基雌二醇用于治疗系统性红斑狼疮的用途及二甲氧基雌二醇作为治疗药物或者治疗药物所含成分。系统性红斑狼疮包含皮肤狼疮、狼疮肾炎、狼疮脑病及累及其他系统或/和器官的狼疮疾病。二甲氧基雌二醇的给药方式为尾静脉注射、给药剂量为0.75uM/kg/次，或灌胃、给药量100uM/kg/次。治疗用于B6.MRL-Fas(lpr)小鼠。
本研究小组发现，系统性红斑狼疮小鼠尾静脉注射二甲氧基雌二醇(2ME2)，四周后，可降低红斑狼疮小鼠外周血中自身抗体水平，狼疮肾炎症状减轻，肾脏炎症缓解。二甲氧基雌二醇即2ME2，最早发现于妊娠妇女的尿液中，先前多认为它是雌二醇的代谢终产物，对其研究不多。体外实验表明二甲氧基雌二醇具有多种抗癌活性，包括乳腺癌、肝癌、胃癌、造血系统肿瘤等，对其药理作用进行了深入的研究发现2ME2能够抑制肿瘤生长和转移，具有广谱的抗肿瘤作用。本发明还发现二甲氧基雌二醇在治疗自身免疫病有好的效果，其中自身免疫病包含系统性自身免疫病(系统性红斑狼疮、类风湿性关节炎、系统性脉管炎、硬皮病、皮肌炎、甲状腺自身免疫病等)及器官特异性自身免疫病(慢性淋巴性甲状腺炎、甲状腺功能亢进、肺出血肾炎综合征等)。
本发明将2ME2用于红斑狼疮模型小鼠MRL-Fas(lpr)鼠，可降低系统性红斑狼疮自身抗体水平，减少狼疮相关肾炎症状，缓解狼疮症状，该发现为寻求治疗系统性红斑狼疮的新药物提供了方向。将为开发治疗SLE的新药奠定基础，还可为治疗其它自身免疫性疾病及浆细胞相关疾病的药物设计提供新策略。
下面列举具体实施例来进行说明：
实施例1：模型小鼠：SPF级SLE模型B6.MRL-Fas(lpr)雌性小鼠(购自中国南京大学模式动物研究所)，均为18-20g，随机分为实验组及对照组，饲养至18周龄，期间观测小鼠的精神状态、行为及体态，并触摸检查各部位淋巴结情况。用乙醚麻醉法处死小鼠，解剖并肉眼观察淋巴结、肾脏及脾脏变化，然后取淋巴结、肾脏、脾脏、甲状腺、肝脏组织。二甲氧基雌二醇(2ME2)给药方式(溶入二甲基亚砜)：(1)在小鼠15周时，尾静脉注射0.75uM/kg/次，每天一次，连续注射三周；或(2)在小鼠15周时，灌胃100uM/kg/次，每天一次，连续灌胃三周；
结果：(1)2ME2可控制狼疮鼠抗ds-DNA抗体水平：
为研究2ME2是否影响自身抗体水平，我们每三周检测一次MRL-Fas(lpr)狼疮鼠抗ds-DNA抗体水平。狼疮鼠的抗ds-DNA抗体水平随小鼠周龄逐渐上升，15周龄时实验组注入2ME2，对照组注入DMSO，注入后，对照组抗ds-DNA抗体水平继续上升，而实验组抗ds-DNA抗体水平保持稳定，在18周时明显低于对照组，对比结果如图1所示(C组为对照组，B组为实验组)。
(2)2ME2可下降狼疮鼠24小时蛋白尿水平：
在15周、18周用代谢笼收集狼疮鼠24h尿液，测定尿液中蛋白含量。结果显示，实验组在注入2ME2三周后，小鼠24h尿蛋白下降，明显低于对照组。
表1：尿液蛋白含量(g/L)
| 组别 | 15W | 18W |
| 对照组 | 0.42 | 0.63 |
| 实验组 | 0.43 | 0.40 |
(3)2ME2可缓解小鼠肾脏病理学改变：
狼疮鼠肾脏病理改变为肾小球系膜细胞增生，体积增大，球囊壁增厚，肾小球囊与球内细胞间隙减少如图2所示。经2ME2治疗后，肾小球病理学变化减轻，肾小球囊与球内细胞间隙基本恢复正常，如图3所示为2ME2治疗后肾小球病理图。
结论：静脉注射或灌胃方式导入2ME2，可降低系统性红斑狼疮鼠外周血自身抗体水平，降低蛋白尿水平，改善肾小球病理改变，缓解狼疮症状。该发现为寻求治疗系统性红斑狼疮的新药物提供了方向。将为开发治疗SLE的新药奠定基础，还可为治疗其它自身免疫性疾病的药物设计提供新策略。
以上所述仅是本发明的较佳实施方式，故凡依本发明专利申请范围所述的构造、特征及原理等所做的各种修改或改动，均作为等价形式同样落于本申请所附的权利要求书所限定的范围之内。
Claims (1)
1.二甲氧基雌二醇在制备用于治疗系统性红斑狼疮药物的用途，其特征在于：所述系统性红斑狼疮为狼疮肾炎。
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| CN102952168A (zh) * | 2012-12-12 | 2013-03-06 | 中国药科大学 | 一类作为血管抑制剂的雌甾衍生物、其制备方法和医药用途 |
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