CN108771662A - 紫檀芪在制备防治高尿酸肾病的药物中的用途 - Google Patents
紫檀芪在制备防治高尿酸肾病的药物中的用途 Download PDFInfo
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Abstract
本发明涉及紫檀芪在制备防治高尿酸肾病的药物中的用途，属于医药领域。本发明提供了紫檀芪或其药学上可接受的盐在制备治疗和/或预防高尿酸肾病的药物中的用途。实验结果表明，紫檀芪能够明显降低血尿酸水平，还具有抑制肾间质纤维化的作用，能够显著降低α‑SMA、collagen I、collagen IV、fibronectin等纤维化相关蛋白的表达量，对高尿酸肾病的治疗作用确切，为临床用药提供了一种新的选择。
Description
技术领域
本发明涉及紫檀芪在制备防治高尿酸肾病的药物中的用途，属于医药领域。
背景技术
高尿酸肾病是嘌呤代谢异常，血尿酸升高所引起的肾脏损害，早期可表现为尿浓缩功能减退，其后逐步出现肾小球滤过率下降，血肌酐升高，导致慢性肾功能不全。近年来，随着高尿酸血症发病率的日益提高，高尿酸肾病发病率显著逐年增高。因此，寻求高尿酸肾病的有效治疗药物，具有重要意义。
既往的研究证实，降低血尿酸水平可以延缓肾脏疾病的进展，因此，治疗高尿酸肾病重在降低血尿酸水平，防止尿酸盐沉积在肾脏。目前，临床上用于降尿酸的一线药物是别嘌呤醇，但其可引起皮肤过敏、骨髓抑制等不良反应，尤其是Stevens-Johnson综合征和中毒性表皮坏死松解，其死亡率达10％～40％，这些不良反应在一定程度上限制了别嘌呤醇的临床应用。而且，别嘌呤醇经肾脏代谢，对于肾功能不全患者往往需要根据肾小球滤过率调整剂量，否则患者不易耐受。鉴于别嘌呤醇存在的上述缺陷，亟需开发出新的替代药物。
紫檀芪是一种广泛存在于天然产物中的二苯乙烯类化合物，化学名为3，5-二甲氧基-4'-羟基反式二苯乙烯，分子式为C16H16O3，分子量为256.11，化学结构如下：
紫檀芪最初从檀香中分离得到，故得以命名，其后在蓝莓、葡萄等水果中均有发现。现代药理研究表明，紫檀芪具有多种药理活性，如抗肿瘤、抗氧化、抗衰老等，且具有较高的生物利用度，是当前研究的热点化合物之一。
发明内容
本发明的目的在于提供紫檀芪在制备防治高尿酸肾病的药物中的用途。
本发明提供了紫檀芪或其药学上可接受的盐在制备治疗和/或预防高尿酸肾病的药物中的用途。
进一步地，所述药物通过降低血尿酸水平防治高尿酸肾病。
进一步地，所述药物通过抑制肾间质纤维化防治高尿酸肾病。
本发明提供了紫檀芪或其药学上可接受的盐在制备治疗和/或预防肾间质纤维化的药物中的用途。
进一步地，所述药物降低α-平滑肌肌动蛋白、I型胶原、IV型胶原、纤连蛋白中一种或几种蛋白的表达。
本发明提供了紫檀芪或其药学上可接受的盐在制备降低血尿酸水平的药物中的用途。
进一步地，所述药物是以紫檀芪或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
进一步地，所述制剂为口服制剂。
进一步地，每单位制剂含有紫檀芪2.75～5.5mg。
动物实验证明，紫檀芪在给药剂量为25～50mg/kg/d时对小鼠高尿酸肾病能够发挥显著的治疗作用。按成人体重70kg计算，换算出成人每天给药剂量范围为2.75mg～5.5mg。本发明所述每单位制剂对应成人每天给药剂量。
本发明提供了防治高尿酸肾病的药物组合物，它是以紫檀芪或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
术语“药学上可接受的”是指某载体、运载物、稀释剂、辅料，和/或所形成的盐、酯通常在化学上或物理上与构成某药物剂型的其它成分相兼容，并在生理上与受体相兼容。
术语“药学上可接受的盐”是指本发明化合物与无机和/或有机酸和碱形成的酸式和/或碱式盐，也包括两性离子盐(内盐)，还包括季铵盐，例如烷基铵盐。这些盐可以是在化合物的最后分离和纯化中直接得到。也可以是通过将上述化合物与一定数量的酸或碱适当(例如等当量)进行混合而得到。这些盐可能在溶液中形成沉淀而以过滤方法收集，或在溶剂蒸发后回收而得到，或在水介质中反应后冷冻干燥制得。本发明中所述盐可以是化合物的盐酸盐、硫酸盐、枸橼酸盐、苯磺酸盐、氢溴酸盐、氢氟酸盐、磷酸盐、乙酸盐、丙酸盐、丁二酸盐、草酸盐、苹果酸盐、琥珀酸盐、富马酸盐、马来酸盐、酒石酸盐或三氟乙酸盐。
本发明化合物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性化合物与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和***胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、和碳酸钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性化合物或化合物的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性化合物也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性化合物外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性化合物外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明化合物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明所述药学上可接受的辅料，是指除活性成分以外包含在剂型中的物质。
本发明所述药学上可接受的辅助性成分，它具有一定生理活性，但该成分的加入不会改变上述药物组合物在疾病治疗过程中的主导地位，而仅仅发挥辅助功效，这些辅助功效仅仅是对该成分已知活性的利用，是医药领域惯用的辅助治疗方式。若将上述辅助性成分与本发明药物组合物配合使用，仍然应属于本发明保护的范围。
本发明提供了紫檀芪在制备防治高尿酸肾病的药物中的用途。实验结果表明，紫檀芪能够明显降低血尿酸水平，还具有抑制肾间质纤维化的作用，能够显著降低α-SMA、collagen I、collagen IV、fibronectin等纤维化相关蛋白的表达量，对高尿酸肾病的治疗作用确切，为临床用药提供了一种新的选择。
附图说明
图1为紫檀芪抑制小鼠肾间质纤维化的染色及评分结果图；
图2为α-平滑肌肌动蛋白α-SMA、I型胶原col I、IV型胶原col IV、纤连蛋白FN等纤维化标志蛋白的表达情况图；
图3为血尿酸水平检测结果图；
图4为高尿酸肾病小鼠肾脏组织MASSON染色图。
具体实施方式
本发明具体实施方式中使用的原料、设备均为已知产品，通过购买市售产品获得。
本发明提供了紫檀芪或其药学上可接受的盐在制备治疗和/或预防高尿酸肾病的药物中的用途。
目前，已报道紫檀芪所具有的药理活性为降血脂、抑制真菌、抗氧化、保护脑缺血/再灌注损伤和抗肿瘤，但尚无研究表明其对高尿酸肾病具有治疗作用。本发明创造性地发现了紫檀芪能够降低血尿酸水平、抑制肾间质纤维化，对高尿酸肾病具有确切的治疗作用，开发出了紫檀芪新的制药用途。
实施例1紫檀芪抑制肾间质纤维化的作用
实验动物：野生C57BL/6J小鼠。实验前至少1周恒温环境下标准化实验日粮饲养，饮水不限。
动物分组：将小鼠24只分为4组：①假手术组12只；②单侧输尿管结扎肾间质纤维化(UUO)模型组12只；③紫檀芪不同浓度治疗组(25mg/kg/d、50mg/kg/d)每组各6只。
造模方法：对小鼠进行麻醉。麻醉后判断肾脏大致体表投影位置后于小鼠左侧腹部剪开皮肤，钝性分离皮下组织及肌层，暴露左肾，沿肾蒂向肾下极方向寻找输尿管，在输尿管上段行双线结扎，两结扎点之间剪断输尿管，逐层缝合皮下组织及皮肤。造模后于术后第7天处死假手术组、UUO模型组、紫檀芪治疗组一半的小鼠，14天后处死另一半小鼠，抽取心脏血并留取肾脏组织收集标本。
给药方法：紫檀芪不同浓度治疗组于造模后第1天开始采用口服给药方式给予紫檀芪，连续14天；UUO模型组造模后在相同时间灌喂同等剂量生理盐水；假手术组在相同时间灌喂同等剂量生理盐水。
实验结果：
1、紫檀芪抑制小鼠肾间质纤维化的染色及评分结果(见图1)
HE染色和MASSON染色：显微镜下发现，假手术组的染色图片具有完整的肾脏结构，没有明显的肾小管变性、坏死，管状萎缩，没有炎性细胞浸润和纤维化。UUO模型组在第7天时可见肾小管有明显的扩张，MASSON染色蓝色区域明显(蓝色区域表示纤维化病变的程度)，14天后病变更加明显。使用紫檀芪治疗后，虽然肾小管仍有明显扩张，但MASSON染色蓝色区域明显少于UUO模型组。
以上结果表明，在UUO模型组中，小鼠肾间质明显纤维化；使用紫檀芪进行治疗后，可以显著抑制肾间质纤维化的程度。
肾间质纤维化评分：评分标准：对每组MASSON涂片显微镜200倍视野下随机不同位置选取10个视野进行统计分析。根据肾小管变性和坏死、管状萎缩、炎性细胞浸润和纤维化的程度从无、轻度、中度到重度分别评分为0/1/2和3分。
评分结果：UUO组评分较假手术组显著增高，紫檀芪治疗组评分显著低于UUO组评分，且呈一定剂量依赖性。
2、WesternBlot检测α-平滑肌肌动蛋白(α-SMA)、I型胶原(col I)、IV型胶原(colIV)、纤连蛋白(FN)等纤维化标志蛋白的表达情况(见图2)
α-SMA、collagen I、collagen IV、fibronectin蛋白的表达量能够反映肾间质纤维化的程度。从图2可以看出，紫檀芪能显著抑制α-SMA、collagen I、collagen IV、fibronectin蛋白的表达，治疗肾间质纤维化的作用非常明显。
实施例2紫檀芪治疗高尿酸肾病的作用
实验动物：SPF级雄性C57BL/6J小鼠。实验前至少1周恒温环境下标准化实验日粮饲养，饮水不限。
动物分组：将小鼠40只分为4组：①正常对照组10只；②高尿酸肾病模型组10只；③紫檀芪治疗组(50mg/kg/d)10只；④阳性对照别嘌呤醇治疗组(5mg/kg/d)10只。
造模方法：根据小鼠体重以腺嘌呤100mg/kg、氧嗪酸钾1500mg/kg的比例，用蒸馏水将两者混合后制成终浓度为80g/L的混悬液，每日早晚灌胃，连续21天，建立高尿酸血症肾损害动物模型。21天后处死小鼠，腹主动脉取血，留取肾脏组织。
给药方法：紫檀芪和别嘌呤醇治疗组于造模后第1天开始采用口服给药方式给药，连续21天；模型组造模后在相同时间灌喂同等剂量生理盐水；正常对照组在相同时间灌喂同等剂量生理盐水。
实验结果：
1、血尿酸
实验动物取血后离心保留血清，使用Beckman全自动生化分析仪检测血尿酸含量，检测结果见图3。从图3可以看出，紫檀芪能显著降低血尿酸水平，效果与临床降尿酸一线药物别嘌呤醇相当。
2、MASSON染色
从图4可以看出，正常对照组的染色图片具有完整的肾脏结构，没有明显的肾小管变性、坏死，管状萎缩，没有炎性细胞浸润和纤维化。高尿酸肾病模型组可见肾小管有明显的扩张，MASSON染色蓝色区域明显(蓝色区域表示纤维化病变的程度)。使用紫檀芪治疗后，虽然肾小管仍有扩张，但MASSON染色蓝色区域明显少于模型组。
以上结果表明，紫檀芪可以显著抑制高尿酸肾病小鼠肾间质纤维化的程度。
Claims (10)
1.紫檀芪或其药学上可接受的盐在制备治疗和/或预防高尿酸肾病的药物中的用途。
2.如权利要求1所述的用途，其特征是：所述药物通过降低血尿酸水平防治高尿酸肾病。
3.如权利要求1所述的用途，其特征是：所述药物通过抑制肾间质纤维化防治高尿酸肾病。
4.紫檀芪或其药学上可接受的盐在制备治疗和/或预防肾间质纤维化的药物中的用途。
5.如权利要求4所述的用途，其特征是：所述药物降低α-平滑肌肌动蛋白、I型胶原、IV型胶原、纤连蛋白中一种或几种蛋白的表达。
6.紫檀芪或其药学上可接受的盐在制备降低血尿酸水平的药物中的用途。
7.如权利要求1～6任意一项所述的用途，其特征是：所述药物是以紫檀芪或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
8.如权利要求7所述的用途，其特征是：所述制剂为口服制剂。
9.如权利要求7所述的用途，其特征是：每单位制剂含有紫檀芪2.75～5.5mg。
10.防治高尿酸肾病的药物组合物，其特征是：它是以紫檀芪或其药学上可接受的盐为活性成分，加入药学上可接受的辅料或者辅助性成分，制备而成的制剂。
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN110772516A (zh) * | 2019-12-02 | 2020-02-11 | 四川大学华西医院 | 异紫堇定碱或其盐在制备降低血尿酸水平、防治尿酸性肾病的药品中的用途 |
| CN113209060A (zh) * | 2021-06-17 | 2021-08-06 | 迈迪唯希科技(天津)有限公司 | 一种紫檀芪在制备预防和/或治疗肠上皮屏障损伤药物中的应用 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110772516A (zh) * | 2019-12-02 | 2020-02-11 | 四川大学华西医院 | 异紫堇定碱或其盐在制备降低血尿酸水平、防治尿酸性肾病的药品中的用途 |
| CN110772516B (zh) * | 2019-12-02 | 2022-10-04 | 四川大学华西医院 | 异紫堇定碱或其盐在制备降低血尿酸水平、防治尿酸性肾病的药品中的用途 |
| CN113209060A (zh) * | 2021-06-17 | 2021-08-06 | 迈迪唯希科技(天津)有限公司 | 一种紫檀芪在制备预防和/或治疗肠上皮屏障损伤药物中的应用 |
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