CN115611916B - 一种治疗IgA肾病的中药提取物和组合物及其医药用途 - Google Patents
一种治疗IgA肾病的中药提取物和组合物及其医药用途 Download PDFInfo
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Abstract
本发明涉及一种治疗IgA肾病的中药提取物和组合物及其医药用途,所述中药提取物为含有下式所示化合物(exo,anti)‑2,9‑二羟基‑1,8‑桉油精的白豆蔻挥发油及白豆蔻乙醇提取物。
Description
技术领域
本发明属于医药领域，涉及一种治疗IgA肾病的中药提取物和组合物及其医药用途，用于治疗IgA增多而引起的原发性和继发性IgA肾病。
背景技术
IgA是人体一种正常的免疫球蛋白，在健康人体中具有一定的含量。而IgA肾病指的是人体IgA免疫球蛋白，出现糖基化缺陷，从而导致的一类慢性肾脏疾病，在我国为常见的慢性肾脏疾病。IgA肾病多表现为血尿、蛋白尿、高血压，并可以伴有肾功能不全，该类患者通过肾活检可以明确诊断，并且进行病理分级，根据其病因可以分为原发性IgA肾病和继发性IgA肾病：
1)原发性IgA肾病：一般由遗传因素或自身免疫调节异常所致，使体内糖基化异常的IgA增多，沉积于肾小球的系膜区，从而引发原发性IgA肾病；
2)继发性IgA肾病：一般继发于过敏性紫癜、病毒性肝炎、肝硬化、系统性红斑狼疮、强直性脊柱炎、类风湿关节炎、混合性结缔组织疾病、结节性多动脉炎、结节性红斑、银屑病、溃疡性结肠炎、克罗恩病、肿瘤、艾滋病等，在疾病发生发展过程中，引起不同程度的肾脏损害，从而诱发IgA增多，而引起的继发性IgA肾病。
原发性IgA肾病和继发性IgA肾病可以根据不同的临床及病理分级表现，进行相应对症治疗，尚无有效的治疗药物，患者经常因为治疗药物的缺乏而引起病情加重，出现肾功能衰竭，从而可能需要进行血液透析、肾脏移植等肾脏替代治疗。对症治疗常用的药物治疗方案包括ACEI(血管紧张素转化酶抑制剂)或ARB(血管紧张素转换酶受体抑制剂)类降压药，部分患者需要使用激素和免疫抑制剂。ACEI类药物有雷米普利、贝那普利、利达普利等；ARB药物有替米沙坦、氯沙坦、厄贝沙坦。
爪哇白豆蔻，(学名Amomum compactum Soland ex Moton),姜科豆蔻属多年生草本植物。我国广东、海南有引种。原产印度尼西亚(爪哇)。果实供药用。主要成分为d-龙脑、d-樟脑。有行气、暖胃、消食、化湿、止吐等功效。
白豆蔻(拉丁学名：Amomum kravanh Pierre ex Gagnep.)为姜科植物。主产于越南、泰国等地，广东、广西、云南等地亦有栽培。原植物生于气候温暖潮湿，富含腐殖质的林下，味辛、性温，归肺、脾、胃经，功效化湿，行气，温中，止呕，临床用名白豆蔻。
本发明在对爪哇白豆蔻和白豆蔻研究的基础上，首次从其果实中提取出一种新化合物，命名为(exo,anti)-2,9-二羟基-1,8-桉油精。
本发明进一步对爪哇白豆蔻和白豆蔻的挥发油或乙醇提取物进行了研究，发现其中均含化合物(exo,anti)-2,9-二羟基-1,8-桉油精，并意外发现含有该化合物的挥发油和乙醇提取物可以有效治疗各种原因引起的IgA肾病。该发现在国内外未见报道，其成果对开发IgA肾病治疗药物具有重大的现实意义。
发明内容
本发明提供一种下式所示的化合物，命名为：(exo,anti)-2,9-二羟基-1,8-桉油精。
本发明进一步包括含有(exo,anti)-2,9-二羟基-1,8-桉油精化合物的组合物。
本发明所述的组合物，包括含有(exo,anti)-2,9-二羟基-1,8-桉油精化合物的中药提取物，以及(exo,anti)-2,9-二羟基-1,8-桉油精化合物加药用辅料做成的药物制剂。
本发明所述的组合物，其中所述中药提取物，为白豆蔻果实的挥发油和/或乙醇提取物。
本发明所述的组合物，其中所述白豆蔻为爪哇白豆蔻(Amomum compactum Solandex Maton)或白豆蔻(Amomum kravanhPierre ex Gagnep.)。
本发明所述的组合物，其中所述白豆蔻果实的挥发油的制备方法为：水蒸气直接通过白豆蔻干燥的药材或药材粉末，收集馏出液，冷却油水分离、分离出上层挥发油，即得。
本发明所述的组合物，其中所述白豆蔻果实的挥发油的制备方法为：白豆蔻药材或药材粉末加入5-30倍量水，加热蒸出馏出液，冷却油水分离、分离出上层挥发油，即得；或，白豆蔻药材或药材粉末加入5-30倍量水，利用挥发油提取器，加热蒸出馏出液，冷却油水分离、分离出上层挥发油，即得。
本发明所述的组合物，其中所述白豆蔻果实的乙醇提取物的制备方法为：用乙醇作为溶剂对白豆蔻药材或药材粉末进行提取，提取后回收溶剂，干燥即得。
本发明所述的化合物或组合物在制备治疗IgA肾病的药物中的用途。其中所述IgA肾病包括：1)由遗传因素或自身免疫调节异常所致，使体内糖基化异常的IgA增多，沉积于肾小球的系膜区，从而引发原发性IgA肾病；2)继发于过敏性紫癜、病毒性肝炎、肝硬化、系统性红斑狼疮、强直性脊柱炎、类风湿关节炎、混合性结缔组织疾病、结节性多动脉炎、结节性红斑、银屑病、溃疡性结肠炎、克罗恩病、肿瘤、艾滋病等，在疾病发生发展过程中，引起不同程度的肾脏损害，从而诱发IgA增多，而引起的继发性IgA肾病。
本发明进一步提供(exo,anti)-2,9-二羟基-1,8-桉油精的制备方法，其中包括以下步骤：
(1)提取：白豆蔻干燥果实7.3Kg捣碎，用5倍体积95％乙醇浸泡24h，加热60℃提取3h，滤液蒸发浓缩，重复4次，得浸膏250g。
(2)萃取：将上述提取物溶解于纯净水，超声助溶混悬后，用乙酸乙酯萃取5次，回收溶剂浓缩乙酸乙酯层，得乙酸乙酯层浸膏30.3g。
(3)分离：乙酸乙酯浸膏30.3g，经MCI柱层析，MeOH-H 2O系统(M:W)统梯度(0:100,20:80,40:60,60:40,80:20,100:0)洗脱，得到B1(2.35g)，B2(4.12g)，B3(6.24g)，B4(8.35g)，B5(8.59g)，5个组分。B1组分经葡聚糖凝胶(Sephadex LH-20)MeOH系统洗脱，得B1.1-B1.5五个组分。B1.1组分经硅胶柱层析，石油醚-乙酸乙酯(P:E)系统1:3洗脱，得到4个组分B1.1.1，B1.1.2，B1.1.3，B1.1.4。B1.1.1组分经ODS柱色谱M:W系统2:3洗脱得到(exo,anti)-2,9-二羟基-1,8-桉油精(9.0mg)。
本发明进一步提供(exo,anti)-2,9-二羟基-1,8-桉油精或以其作为药物活性成分的组合物，其具有治疗IgA肾病的用途。
本发明所述含有(exo,anti)-2,9-二羟基-1,8-桉油精的组合物，包括本发明所述的中药提取物或者药物组合物。也包括任意一种以(exo,anti)-2,9-二羟基-1,8-桉油精化合物作为药物活性成分的药物制剂组合物。
附图说明
图1(exo,anti)-2,9-二羟基-1,8-桉油精的化学结构
图2(exo,anti)-2,9-二羟基-1,8-桉油精的1H-NMR图谱
图3(exo,anti)-2,9-二羟基-1,8-桉油精的13CNMR图谱
图4(exo,anti)-2,9-二羟基-1,8-桉油精的1H-NMR和13CNMR数据归属
图5HE染色(200X)(A空白；B模型；C挥发油低剂量；D挥发油中剂量；E挥发油高剂量；F(exo,anti)-2,9-二羟基-1,8-桉油精；G雷公藤；H泼尼松.)
图6PASM染色(200X)(A空白；B模型；C挥发油低剂量；D挥发油中剂量；E挥发油高剂量；F(exo,anti)-2,9-二羟基-1,8-桉油精；G雷公藤；H泼尼松.)
图7IgA荧光染色(A空白；B模型；C挥发油低剂量；D挥发油中剂量；E挥发油高剂量；F(exo,anti)-2,9-二羟基-1,8-桉油精；G雷公藤；H泼尼松.)
图8TGF-β1检测结果(200X)(A空白；B模型；C挥发油低剂量；D挥发油中剂量；E挥发油高剂量；F(exo,anti)-2,9-二羟基-1,8-桉油精；G雷公藤；H泼尼松.)
图9western blot检测白豆蔻挥发油对Caspase-3，IgA表达的影响(n＝3)(A空白；B模型；C挥发油低剂量；D挥发油中剂量；E挥发油高剂量；F(exo,anti)-2,9-二羟基-1,8-桉油精；G雷公藤.)
具体实施方式
下面仅以实施例的方式结合附图对本发明作进一步的说明。
实施例1白豆蔻乙醇提取物的制备和(exo,anti)-2,9-二羟基-1,8-桉油精的分离和结构确证
(1)提取：白豆蔻干燥果实7.3Kg捣碎，用5倍体积95％乙醇浸泡24h，加热60℃提取3h，滤液蒸发浓缩，重复4次，得浸膏250g。
(2)萃取：将上述提取物溶解于纯净水，超声助溶混悬后，用乙酸乙酯萃取5次，回收溶剂浓缩乙酸乙酯层，得乙酸乙酯层浸膏30.3g。
(3)分离：乙酸乙酯浸膏30.3g，经MCI柱层析，MeOH-H 2O系统(M:W)统梯度(0:100,20:80,40:60,60:40,80:20,100:0)洗脱，得到B1(2.35g)，B2(4.12g)，B3(6.24g)，B4(8.35g)，B5(8.59g)，5个组分。B1组分经葡聚糖凝胶(Sephadex LH-20)MeOH系统洗脱，得B1.1-B1.5五个组分。B1.1组分经硅胶柱层析，石油醚-乙酸乙酯(P:E)系统1:3洗脱，得到4个组分B1.1.1，B1.1.2，B1.1.3，B1.1.4。B1.1.1组分经ODS柱色谱M:W系统2:3洗脱得到(exo,anti)-2,9-二羟基-1,8-桉油精(9.0mg)。
(4)化学结构确证：
无色针状结晶，1％茴香醛/硫酸显蓝色，254nm波长下无暗斑点。ESI-MS给出m/z187[M+H]+准分子离子峰，结合1H-NMR、13C-NMR推测化合物分子式为C10H18O3，计算不饱和度为2。1H-NMR(600MHz,DMSO-d6)谱图中，高场区给出两个单峰甲基质子信号δ0.92(3H,s)，δ1.06(3H,s)，提示结构中存在两个分别与季碳相连的甲基；低场区给出三个氧质子信号δ3.07(1H,dd,J＝11.2,6.0Hz)，δ3.43(1H,m)和δ3.46(1H,m)；δ4.57(1H,t,J＝6.0Hz)，δ4.74(1H,d,J＝4.8Hz)处为羟基质子信号,由此推测存在两个羟基，一个连氧亚甲基和一个连氧次甲基；δ1.26～2.29之间给出七个烷基质子信号。13C-NMR(150MHz,DMSO-d6)谱图中共给出10个碳信号，其中δ25.0,24.7处为两个甲基碳信号；δ68.8处给出一个连氧亚甲基碳信号；δ70.1处给出一个连氧次甲基碳信号；δ70.1,75.3处给出两个连氧季碳信号；其余均为烷基碳信号。与相关文献[Australian Journal of Chemistry,1994,47:1509-1521.]对比，鉴定其化学结构为(exo,anti)-2,9-二羟基-1,8-桉油精。
实施例2含(exo,anti)-2,9-二羟基-1,8-桉油精的爪哇白豆蔻乙醇提取物的制备和(exo,anti)-2,9-二羟基-1,8-桉油精的确证
(1)提取：爪哇白豆蔻干燥果实1.0Kg捣碎，用5倍体积70％乙醇浸泡24h，用30倍体积70％乙醇渗漉提取，渗漉液蒸发浓缩，得浸膏59.2g。
(2)(exo,anti)-2,9-二羟基-1,8-桉油精的确证：利用实施例1得到的对照品，GC测定含有1.5％的(exo,anti)-2,9-二羟基-1,8-桉油精。
实施例3含(exo,anti)-2,9-二羟基-1,8-桉油精的白豆蔻挥发油提取物的制备和(exo,anti)-2,9-二羟基-1,8-桉油精的确证
(1)提取：水蒸气直接通过爪哇白豆蔻果实药材粉末1.0Kg，收集馏出液，冷却油水分离、分离出上层挥发油，得挥发油51.4ml。
(2)(exo,anti)-2,9-二羟基-1,8-桉油精的确证：利用实施例1得到的对照品，GC测定含有1.5％的(exo,anti)-2,9-二羟基-1,8-桉油精。
实施例4含(exo,anti)-2,9-二羟基-1,8-桉油精的爪哇白豆蔻挥发油提取物的制备和(exo,anti)-2,9-二羟基-1,8-桉油精的确证
(1)提取：爪哇白豆蔻药材粉末1.0Kg加入30L水，加热蒸出馏出液，冷却油水分离、分离出上层挥发油，得挥发油35.3ml。
(2)(exo,anti)-2,9-二羟基-1,8-桉油精的确证：利用实施例1得到的对照品，GC测定含有1.5％的(exo,anti)-2,9-二羟基-1,8-桉油精。
实施例5含(exo,anti)-2,9-二羟基-1,8-桉油精的白豆蔻挥发油提取物的制备和(exo,anti)-2,9-二羟基-1,8-桉油精的确证
(1)提取：白豆蔻药材1.0Kg加入5.0L水，利用挥发油提取器，加热蒸出馏出液，冷却油水分离、分离出上层挥发油，得挥发油55.2ml。
(2)(exo,anti)-2,9-二羟基-1,8-桉油精的确证：利用实施例1得到的对照品，GC测定含有1.5％的(exo,anti)-2,9-二羟基-1,8-桉油精。
实施例6(exo,anti)-2,9-二羟基-1,8-桉油精和含(exo,anti)-2,9-二羟基-1,8-桉油精的白豆蔻挥发油提取物治疗大鼠IgA肾病的作用评价
实验动物模型的建立
运用牛血清白蛋白(BSA)+脂多糖(LPS)+四氯化碳(CCl4)方法造就IgA肾病模型：以蒸馏水配制免疫原BSA，隔天早晨灌胃4ml/kg，持续8周；皮下注射蓖麻油0.3ml+CCl40.1ml，每周1次，持续9周；以生理盐水配制0.025％LPS，于第6、8、10、12周尾静脉注射0.2ml/只；于此同时造就瘀热模型，复合为IgA肾病大鼠模型：于第9周开始隔天灌服25％干姜水10ml/kg，持续4周。空白组以等量蒸馏水灌胃，等量生理盐水皮下或尾静脉注射，生存温度为正常室温(常年22℃)。第12周末造模结束。
实验分组
所有大鼠适应性喂养l周，造模前两次尿蛋白定性试验均呈阴性(试纸条法)。将入选的70只SD大鼠以随机数字表法分为空白组、模型组、中药阳性对照组(雷公藤多苷)、西医药阳性对照组(泼尼松)、含(exo,anti)-2,9-二羟基-1,8-桉油精的白豆蔻挥发油提取物的低中高剂量给药组、(exo,anti)-2,9-二羟基-1,8-桉油精给药组。
给药方法
模型组、对照组及给药组均运用复合造模法建立IgA肾病实验动物模型，白豆蔻组和阳性对照组自第13周起灌胃，每天早1次，连续5周；空白组及模型组在第13周起给予相应等量溶剂灌胃。给药期间所有大鼠均予标准饮食及标准室温。
标本采集
在实验结束后，用代谢笼收集24h内大鼠尿液，收集24h内大鼠尿液，分装后新鲜尿液一部分用于送检测定尿生化指标；腹主动脉收集大鼠血液4000r/min离心15min，取上清液血清放在-20℃，供测血生化指标。处死大鼠，取其两侧肾脏，生理盐水冲洗干净后，滤纸擦干，拍照称重；一部分右肾固定在10％中性福尔马林中，固定供病理变化(HE染色、PAS染色、IgA免疫荧光)组织切片及免疫荧光、免疫组化石蜡切片用；另一部分放入液氮速冻后，放入-80℃，为PCR、WB实验用。
评价结果：
1)尿液检测结果
对所得24h尿液进行检测发现，IgA肾病大鼠，24小时尿蛋白含量增高，尿肌酐，和尿素氮含量也明显增高。经过白豆蔻治疗后发现其尿蛋白、尿素氮、尿肌酐含量有所下降。结果见表1。
表1各组大鼠尿蛋白、血清尿素氮及血清肌酐测定结果
Table 1 urine protein,serum urea nitrogen and serum
注：与模型组相比**p<0.01,*p<0.05；与正常组相比##P<0.01。
2)肾体指数
IgA肾病大鼠模型组肾体指数与空白对照组没有显著性区别，各治疗组与模型组大鼠比较亦没有显著性差异，表IgA肾病模型对大鼠的肾脏大小没有明显改变。结果见表2
表2肾体指数
Table 2kidney index
3)血清常规检测结果
血清检测结果表明，IgA肾病模型大鼠血清CR，BUN，ALT，AST，CHO相较于空白对照组均有所增加，治疗后均有所改善(P<0.05)。各结果见表3。
表3血清CR，BUN，ALT，AST，CHO测定结果
Table 3Results of serum CR,BUN,ALT,AST,CHO
注：与模型组相比*P<0.05；与正常组相比#P<0.05。
4)IL-1β、IL-6、TNF-α、IgA检测结果
对血清中IL-1β、IL-6、TNF-α、IgA含量检测结果显示，IgA肾病模型大鼠IL-1β、IL-6、TNF-α、IgA含量均显著增高，而白豆蔻各组及阳性药组均有所下降。结果见4
表4 IL-1β、IL-6、TNF-α、IgA测定结果
注：与模型组相比**p<0.01,*p<0.05；与正常组相比##P<0.01。
5)MDA、SOD、NO、NOS测定
检测结果显示，IgA肾病模型大鼠，血清及组织中MDA、NO含量及NOS活性均显著增加，SOD活性显著降低。经白豆蔻及阳性药治疗后，IgA肾病模型大鼠血清及组织MDA、NO含量及NOS活性显著下降，SOD活性显著增加。白豆蔻能降低IgA肾病模型大鼠血清及组织MDA、NO含量及NOS活性的增高，改善SOD活性的下降。结果见5。
表5 MDA、NO含量及SOD、NOS活力测定结果
注：与模型组相比**p<0.01,*p<0.05；与正常组相比##P<0.01。
6)肾组织染色结果
HE染色：与空白对照组相比，模型组大鼠肾脏出炎性浸润，基底膜增厚，肾小管内皮细胞结构不完整。与模型组相比，其他各组均有所改善。
PASM染色：与空白对照组相比，模型组大鼠基底膜增厚，与模型组相比，其他各组均有所改善。
IgA荧光染色：与空白对照组相比，模型组肾小球出现的IgA沉积较严重，与模型组相比其他各组肾小球均有改善。
TGF-β1检测：与空白组相比，模型组TGF-β1表达显著增加，其他各组表达均有所降低。
western blot检测：与空白对照组相比，模型组IgA和Caspase-3的表达增加，治疗组与模型组相比其他各组有改善。
综合以上结果表明：含(exo,anti)-2,9-二羟基-1,8-桉油精的白豆蔻挥发油提取物和乙醇提取物可以显著地治疗IgA肾病。
Claims (3)
1.一种下式所示的化合物。
2.权利要求1所述的化合物在制备治疗IgA肾病的药物中的用途。
3.根据权利要求2的用途，其中所述IgA肾病包括：1)由遗传因素或自身免疫调节异常所致，使体内糖基化异常的IgA增多，沉积于肾小球的系膜区，从而引发原发性IgA肾病；2)继发于过敏性紫癜、病毒性肝炎、肝硬化、系统性红斑狼疮、强直性脊柱炎、类风湿关节炎、混合性结缔组织疾病、结节性多动脉炎、结节性红斑、银屑病、溃疡性结肠炎、克罗恩病、肿瘤、艾滋病，在疾病发生发展过程中，引起不同程度的肾脏损害，从而诱发IgA增多，而引起的继发性IgA肾病。
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| KR20160063716A (ko) * | 2014-11-27 | 2016-06-07 | 한림대학교 산학협력단 | 유칼립톨을 함유하는 신장 섬유증 예방 및 치료용 조성물 |
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| WO2011141108A2 (de) * | 2010-05-12 | 2011-11-17 | Maria Clementine Martin Klosterfrau Vertriebsgesellschaft Mbh | Neue darreichungsformen für cineol |
| KR20160063716A (ko) * | 2014-11-27 | 2016-06-07 | 한림대학교 산학협력단 | 유칼립톨을 함유하는 신장 섬유증 예방 및 치료용 조성물 |
| CN113908144A (zh) * | 2020-07-10 | 2022-01-11 | 肇庆民药生物科技有限公司 | 一种治疗肾炎的化学成分及其制备工艺、医药用途和组合物 |
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