CN103655545B - 棕矢车菊素在制备治疗或预防慢性肾损伤的药物中的应用 - Google Patents
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Abstract
本发明涉及棕矢车菊素在制备治疗或预防慢性肾损伤的药物中的应用，具体涉及棕矢车菊素在制备治疗或预防慢性肾功能衰竭，肾纤维化及糖尿病肾病的药物中的应用。在上述应用中，棕矢车菊素使用剂量范围是10mg～500mg；优选10～250mg。棕矢车菊素以片剂、丸剂、颗粒剂、胶囊、糖浆等形式存在，优选为片剂。
Description
技术领域
本发明涉及棕矢车菊素在制备治疗或预防慢性肾损伤的药物中的应用，具体涉及棕矢车菊素在制备治疗或预防慢性肾功能衰竭，肾纤维化及糖尿病肾病的药物中的应用。
背景技术
艾叶(FoliumArtemisiaeArgyi)来源于菊科蒿属植物艾(ArtemisiaargyiLevl.etVant.)的干燥叶，为临床常用中药。棕矢车菊素是从艾叶中提取获得的单一化合物[唐生安，孙亮，翟慧媛，段宏泉，张彦文.艾叶化学成分的研究.天津医科大学学报，2011，17(4)：461-463.]，棕矢车菊素具有抗炎作用[ClavinM，GorzalczanyS，MachoA，E，FerraroG，AcevedoC，MartinoV.Anti-inflammatoryactivityofflavonoidsfromEupatoriumamottianum.JEthnopharmaco1.2007；112(3)：585-589.]，但棕矢车菊素在制备预防或治疗慢性肾损伤和肾纤维化的药理作用未见报道。本发明人通过大量的实验研究，发明了棕矢车菊素在制备治疗或预防慢性肾功能衰竭、肾纤维化及糖尿病肾病的药物中的应用。
发明内容：
本发明提供了棕矢车菊素在制备治疗或预防慢性肾损伤的药物中的应用
本发明提供了棕矢车菊素在制备治疗或预防慢性肾功能衰竭的药物中的应用。
本发明提供了棕矢车菊素在制备治疗或预防肾纤维化的药物中的应用。
本发明提供了棕矢车菊素在制备治疗或预防糖尿病肾病的药物中的应用。
本发明提供的棕矢车菊素在用于慢性肾功能衰竭、肾纤维化及糖尿病肾病时，其使用剂量范围是10mg～500mg；优选10～250mg。
本发明提供的棕矢车菊素可以根据制剂需要，加入相应辅料，以、片剂、丸剂、颗粒剂、胶囊、糖浆等形式存在，优选为片剂。本发明提供的各种剂型均可以采用药学常规方法制备而成。
本发明人进行了下列试验来证实治疗或预防慢性肾功能衰竭、肾纤维化及糖尿病肾病的药物中的应用，但药理作用不限于此。
具体实施实例：
制备例1：制备棕矢车菊素
1kg干燥的艾叶粉碎，用6倍量95％的乙醇加热回流提取3次，每次6h，过滤，合并滤液，减压浓缩至浸膏状，得提取物，加适量蒸馏水混悬后，于10L的分液漏斗中以乙酸乙酯萃取，收集萃取物以硅胶柱层析(硅胶600g，300-400目)分离，依次用CH2C12→CH2C12：EtoAc(5：1→2：1)→EtoAc→MeOH梯度洗脱，通过TLC合并类似组分，过硅胶柱常压柱，得棕矢车菊素460mg。
实施例2棕矢车菊素片剂制备
称取10.0g棕矢车菊素、55.0g糖粉、110.0g乳糖和23.0g羧甲基淀粉钠充分混合均匀后过100目筛，加入适量的3％PVPK30水溶液适量制软材，20目筛制粒，60℃干燥3小时，18目筛整粒，加入2.0g硬脂酸镁，混合均匀后浅凹冲压，调节片重约200mg，即得。
具体实施例
试验1棕矢车菊素对肾切除导致大鼠慢性肾衰的影响
1.1药品与试剂
棕矢车菊素按制备例1制备
谷胱甘肽(山东绿叶制药有限公司，规格：300mg/支，批号：20120706)
肌酐和尿素氮试剂盒(北京中生科技公司，批号：120606)
实验动物：普通级Wistar大鼠，雄性，体重280g-350g，山东绿叶制药有限公司动物实验中心提供。合格证号：鲁动质字200906005号。
1.2试验方法与结果
大鼠140只，体重150-200g，动物喂养1周，将动物分为7组，每组20只，即正常组，模型组，谷胱甘肽静脉注射(150mg/kg)组，棕矢车菊素1mg/kg组，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组，除正常组外，大鼠用5/6肾切除方法制成慢性肾衰模型，第一次手术切除左肾2/3，一周后行第二次手术切除右肾，第二次手术后5周开始给药，棕矢车菊素给药方式为灌胃给药，给药后4周、8周分别大鼠眼框取血，测定血清肌酐和尿素氮，给药后4周处死10只，试验结束处死10只，作病理切片，观察肾功能的病理改变。
从表1、表2结果可以看出，棕矢车菊素1mg/kg组降低大鼠慢性肾衰血清肌酐和尿素氮(与模型组比较，p＜0.05)；谷胱甘肽静脉注射(150mg/kg)组，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组明显降低大鼠慢性肾衰血清肌酐和尿素氮(与模型组比较，p＜0.01)；棕矢车菊素25mg/kg组降低大鼠慢性肾衰血清肌酐和尿素氮与棕矢车菊素50mg/kg组比较，无显著性差异。
病理改变：给药第4周模型组光镜下见肾小球有不同程度代偿性肥大，系膜细胞增生，系膜基质增多，肾小球毛细血管襻呈分叶状，部分肾小球囊腔消失，毛细血管管壁增厚，肾小管肿胀、扩张，管腔内有蛋白沉积，部分小管萎缩，间质有炎性细胞浸润，各给药组亦见上述改变，但病变程度较轻，随剂量增大，病变程度减轻；给药第8周模型组光镜下见系膜细胞增生，基质明显增多，毛细血管管壁塌陷，毛细血管节段性硬化，硬化区多在血管壁附近硬化的肾小球内可见均质圆形PAS染色深红色的沉积物，个别肾小球有局灶球囊粘连，局灶新月体形成，间质可见炎细胞浸润，纤维组织增生，各组肾小球硬化程度不等，随剂量增大，病变程度减轻。
表1棕矢车菊素对肾切除慢性肾衰大鼠给药4周血清肌酐和尿素氮的影响
*，p＜0.05，**，p＜0.01，与模型组比较
表2棕矢车菊素对肾切除慢性肾衰大鼠给药8周血清肌酐和尿素氮的影响
*，p＜0.05，**，p＜0.01，与模型组比较
试验2棕矢车菊素对单侧输尿管结扎大鼠肾间质纤维化的影响
2.1材料
棕矢车菊素按制备例1制备
实验动物：普通级Wistar大鼠，雄性，体重280g-350g，山东绿叶制药有限公司动物实验中心提供。合格证号：鲁动质字200906005号。
依那普利，北京诺华制药有限公司生产，批号：040306；羟脯氨酸试剂盒，南京建成生物公司，批号：050906。
2.2试验方法与结果
大鼠70只，体重200-230g，动物喂养1周，各大鼠以10％水合氯醛3.0mL/kg腹腔注射麻醉后，将大鼠右侧卧位固定于手术台上，剪毛后用碘酒、75％酒精消毒手术区，行左侧腹切口，逐层切开皮肤、肌肉及腹壁各层，暴露并分离左侧输尿管，其中10只大鼠仅切开腹腔并游离左侧输尿管，但不结扎和剪断，作为假手术组，其余60大鼠用4-0丝线结扎两道，上一道结扎点位于左肾下极水平，然后在两道结扎点间剪断输尿管，逐层缝合，60只造模大鼠随机分为6组，即模型组、依那普利(4mg/kg)组，棕矢车菊素1mg/kg组，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组，各组给药21天后，10％水合氯醛麻醉后处死各组动物，生理盐水反复灌洗后留取左侧肾脏，肾组织经4％的多聚甲醛缓冲液固定。切取适量肾组织，按羟脯氨酸试剂盒测定说明测定羟脯氨酸。
从表3结果可以看出，棕矢车菊素1mg/kg组，依那普利(4mg/kg)组，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组明显降低大鼠羟脯氨酸水平(与模型组比较，p＜0.05或0.01)，棕矢车菊素25mg/kg组降低羟脯氨酸水平与棕矢车菊素50mg/kg组比较，无显著性差异。常规病理学检查①肉眼检查：假手术组肾脏颜色鲜红，表面光滑，包膜光泽，无粘连。其他各组肾脏体积增大，颜色苍白，表面呈颗粒状，类似人体大白肾，少数区域肾包膜粘连。②光镜检查：假手术组肾单位结构清晰，肾小球囊无扩张或缩小，肾小管上皮细胞无明显变性及坏死，管腔内无脱落上皮细胞或管型，间质中无血管扩张或炎细胞浸润。模型对照组大片肾小管坏死，肾间质纤维细胞增生，肾小管扩张，内有大量棕黄色折光物质或坏死脱落的上皮细胞，肾小球数目减少，部分肾小球纤维化并与包曼氏囊壁粘连，囊腔消失。给药各组病变与模型对照组类似，但均有不同程度的形态学改善，尤以棕矢车菊素大剂量各组显著，与模型对照组比较，差异明显。
表3棕矢车菊素对单侧输尿管结扎大鼠肾组织羟脯氨酸含量的影响
p＜0.05，**，p＜0.01，与模型组比较
试验3棕矢车菊素对糖尿病肾病大鼠的影响
3.1材料
棕矢车菊素按制备例1制备
依那普利，北京诺华制药有限公司生产，批号：110306；链脲佐菌素(Sigma公司)，血糖测定试剂盒(北京中生试剂有限公司批号：120503)；肌酐和尿素氮试剂盒(北京中生科技公司，批号：120606)。
实验动物：普通级Wistar大鼠，雄性，体重280g-350g，山东绿叶制药有限公司动物实验中心提供。合格证号：鲁动质字200906005号。
3.2试验方法与结果
雄性SD大鼠100只，适应性喂养1周后，所有的大鼠在10％水合氯醛(0.35mL/100g，ip)麻醉，行左肾摘除术，一周后单次静脉注射1％的链脲佐菌素溶液60mg/kg，链脲佐菌素以0.1mol/L、pH为4.5枸椽酸缓冲溶液溶解，72h后眼眶采血，血糖测定试剂盒测定，血糖≥16.7mmol/L确定为造模成功，4周后随机分为6组，即模型组、依那普利(2mg/kg)组，棕矢车菊素1mg/kg组，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组，另外取10只作为正常对照组大鼠。各组连续给药4周，眼眶采血测定血清肌酐和尿素氮及各组大鼠24h尿蛋白排泄量。再连续给药4周后取血，测定血清肌酐和尿素氮及各组大鼠24h尿蛋白排泄量，同时对肾脏作病理切片进行显微检查。
血液生化指标测定：表4、表5结果表明棕矢车菊素1mg/kg组，依那普利(2mg/kg)组，，棕矢车菊素5mg/kg组，棕矢车菊素25mg/kg组，棕矢车菊素50mg/kg组给药4周和8周明显降低血清肌酐和尿素氮及24h尿蛋白排泄量(与模型对照组比较，p＜0.05或0.01)；棕矢车菊素25mg/kg组降低血清肌酐和尿素氮及24h尿蛋白排泄量与棕矢车菊素50mg/kg组比较，无显著性差异。
病理检查：正常对照组大鼠肾小球基底膜正常，未见增宽，足突排列整齐。模型对照组大鼠肾小球基底膜显著增宽，足突排列紊乱、融合，系膜细胞和基质轻度节段性增生。棕矢车菊素各给药组较模型组病变轻，且随剂量的增加病理逐步减轻。
表4棕矢车菊素给药4周对糖尿病肾病大鼠的影响(n＝10)
*，p＜0.05，**，p＜0.01，与模型组比较
表5棕矢车菊素给药8周对糖尿病肾病大鼠的影响(n＝10)
*，p＜0.05，**，p＜0.01，与模型组比较。
Claims (1)
1.棕矢车菊素在制备治疗肾纤维化的药物中的应用，其中棕矢车菊素治疗或预防肾纤维化时口服用药为250mg。
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