CN108295052A - 红茴香苷醚及组合物在痛风性关节炎中的应用 - Google Patents
红茴香苷醚及组合物在痛风性关节炎中的应用 Download PDFInfo
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Abstract
本发明涉及一种红茴香脂醚、红茴香苷醚、红茴香总苷及其制备方法、在痛风性关节炎中的应用。其优点表现在：本发明得到了红茴香新木脂素成分5,5'‑二烯丙基‑2,2',3'‑三甲氧基联苯醚(红茴香脂醚)，并发现红茴香脂醚具有抗炎活性。本发明得到了一种红茴香总苷，红茴香总苷中含红茴香脂醚、地枫皮素、槲皮苷，具有抗炎活性；并经动物实验验证，对痛风性关节型具有治疗作用。
Description
技术领域
本发明涉及药物技术领域，具体地说，是红茴香苷醚及组合物在痛风性关节炎中的应用。
背景技术
八角科八角属植物披针叶茴香(I.lanceolatum)又名狭叶茴香，红毒茴，莽草，为我国特有植物，分布于我国南方，始载于《神农本草经》，列为下品，其根或根皮入药，果实有剧毒。红茴香具有祛风通络，散瘀止痛的功效；用于跌打损伤，风湿痹痛，痈疽肿毒，肠道寄生虫病。临床使用的中成药红茴香注射液也是经披针叶茴香(I.lanceolatum)根皮提取制成的，有消肿散瘀,活血止痛的功效，用于腰肌劳损，关节或肌肉韧带伤痛及风湿痛等。
八角科(Illiciaceae DC.)仅有八角属(Illicium Linn.)一个单属，为常绿乔木或灌木，全世界近50种，我国约有28种，2变种，主要分布在西南部、南部至东部，其中21种为我国特有。
目前，从该属植物中分离鉴定出大约三百种化学成分，主要类型有萜类(主要含倍半萜类)，苯丙素及木脂素类、黄酮类和挥发油类等成分，其中结构新颖的倍半萜类是该属植物的特征性成分。药理实验表明八角属植物的初提物和化学成分具有神经营养性，抗炎镇痛，抗肿瘤，抗氧化和抑菌等作用。
1.八角属植物化学成分研究概况
八角属植物多含有挥发油类成分，还有一些结构新颖的倍半萜类成分，它们大多以内酯的形式普遍存在于八角属植物中。另外还含有较为丰富的苯丙素及木脂素类和黄酮类成分。其中结构新颖的倍半萜类是该属植物的特征性成分。
1.1挥发油
八角茴香果实的挥发油含量2.35％-7.48％，主要成分为反式茴香脑(trans-anethole)，胡椒酚甲醚(estragole,methyl chavicol)，柠檬烯(limonene)，顺式茴香脑(cis-anethole)，α-蒎烯(α-pinene)，β-水芹烯(β-phellandrene)，芳樟醇(linalool)和α-水芹烯(α-phellandrene)，其中反式茴香脑在挥发油中的含量高达70％-94％。
地枫皮的干燥树皮挥发油含量约0.5％左右，主要成分有黄樟脑(safrole)，芳樟醇(linalool)，1,8-桉油醇(1,8-cineol)，樟脑(camphor)，吉马烯D(germacrene D)，α-松油醇(α-terpineol)，其中黄樟脑在挥发油中的含量(约21％-29％)最高。红茴香树皮的挥发油主要含σ-杜松烯(σ-cadinene)；野八角树皮的挥发油主要含芳樟醇。
在我们以前的研究工作中，对披针叶茴香根的挥发油进行了分析，结果表明根挥发油主要含肉豆蔻醚(17.63％),α-细辛脑(α-asarone，17.23％),甲基异丁香酚(methylisoeugenol，11.19％),洋芹醚(apiol，8.82％)和异长叶醇(isolongifolol，5.94％)。
1.2倍半萜类
1952年，Lane等人从有毒植物日本莽草中提取得到莽草素(anisatin)，并且在1958年日本学者Kawano和Matsuo证明了莽草素具有毒性。近几十年来，大量结构特异的倍半萜类成分从八角属植物中分离得到。日本学者Fukuyama Y.和中国学者Huang J.对这些倍半萜类成分结构进行分析总结，共分成九大类：secoprezizaane型、anislactone型、allohimachalane型、secoallohimachalane型、himachalane型、allocedrane型、campherenane型、santalane型和muurolane型。其中以secoprezizaane型最为常见。
1.3苯丙素及木脂素类
八角属植物含有苯丙素及木脂素类成分，多具有烯丙基或异戊烯基结构，如：threo-Anethole glycol，erythro-Anethole glycol，Verimol A-K,地枫皮素(difengpin),新地枫皮素(Neodifengpin)等。
1.4其它类成分
尚含有abietane型二萜类化合物如：(+)-Abieta-8,11,13,15-tetraene，Epipalustric acid，Angustanoic acid A-I，Angustanal，Angustanol，4-epi-Palustricacidα,13-endoperoxide，4-epi-Sandaracopimaric acid，Geraniol benzoyl ester。环波罗烷三萜(triterpene)类化合物如:Schizandronic acid，Schizandrolic acid，Magniferolic acid，Secocycloartane methyl ester，Secocycloartanedioic acid 26-methyl ester。另外，八角属植物中还含有黄酮以及一些甾醇和小分子酸类化合物。
2.药理活性
2.1神经营养活性
八角属植物可能被认为是神经营养活性物质的重要来源。一些化合物如倍半萜类成分：异红花八角素(isodunnianin)，假地枫皮素(Jiadifenin)可促进原代培养中胎鼠脑半球神经元细胞轴突的生长，并且可以提高乙酰胆碱转移酶的活性。
2.2抗炎镇痛活性
2009年，Song等人报道了化合物10-hydroxyacoronene和acoradiepoxide可以抑制LPS诱导巨噬细胞RAW264.7细胞NO的生成，IC50分别为82.4和76.5μg/mL。热板法、烫尾法、扭体法和电刺激法进行实验表明红花八角中提取毒八角酸在剂量50-l00mg/kg时具显著镇痛作用。从八角茴香中提取出的莽草酸也能减少小鼠扭体的次数，对小鼠疼痛反应有显著的抑制作用。另外八角茴香的甲醇和乙酸乙酯提取物具有镇痛作用。
2.3抗肿瘤活性
化合物(2S,4S)-illicinone D对人结肠癌细胞HCT-8、人胃癌细胞Bgc-823、人肺腺癌细胞A549和人卵巢癌细胞A2780四种癌细胞均有显著的细胞毒性效果(IC50 0.30-2.57μM)，化合物4R-illicinone C有一定的选择性，只对敏感的人卵巢癌细胞A2780有毒性效果(IC501.38μM)。化合物Illicaborin B对人喉癌细胞Hep-2、髓母细胞瘤细胞Daoy、人乳腺癌细胞Mcf-7、人大肠癌细胞WiDr四种肿瘤细胞均有一定的细胞毒性(IC50 10-20μM)。
2.4抗氧化活性
2012年，Yang等人评估了八角茴香各种提取物的抗氧活性，八角茴香乙醇提取物萃取得到的乙醚和乙酸乙酯部位具有清除DPPH自由基的活性，IC50值分别为57.43和38.60ppm，乙醇提取物，正己烷，乙醚，氯仿，乙酸乙酯和水萃取部位也具有清除2'-azino-bis-3-ethylbenz-thiazoline-6-sulfonic acid(ABTS)的活性,IC50值分别为15.82,0.12,26.75,25.73,26.95和18.24mmol trolox/100g DW。
2.5抗微生物活性
化合物simonin A，dunnianol,macranthol,isodunnianol和manolol对粘性放线菌(Actinomyces viscosus)，变异链球菌(Streptococcus mutans),血链球菌(Streptococcus sanguis)和内氏放线菌(Actinomyces naeslundii)有一定的抑制作用,最小抑制浓度(MIC)在1.95-31.25μg/mL范围内。2012年，Liu等人报道了化合物东亚八角素(tashironin)对乙型肝炎病毒表面抗原(HBsAg)和e抗原(HBeAg)都具有较好的抑制活性，IC50分别为0.48mM和0.15mM。
我国八角属植物资源丰富，大量的化学成分被分离鉴别，其中倍半萜类化合物约160个左右，苯丙素和木脂素类化合物约140个左右。现代药理学研究表明这些化合物具有神经营养性，抗氧化，抑菌，抗炎镇痛和抗肿瘤等多种药理活性。但是这些研究主要集中在白花八角(I.anisatum)，台湾八角(I.arborescens)，八角茴香(I.verum)，粤中八角(I.tsangii)，滇西八角(I.merrillianum)，大屿八角(I.angustisepalum)，红花八角(I.dunnianum)这七种八角属植物上，而对八角属其它植物的化学成分与生物活性有待于进一步深入研究。同时，八角属大部分植物具有毒性，因此，还需要对其毒理学进行研究，包括毒性成分，毒性大小，安全范围及毒性作用机制等。
中国专利文献CN102940685A公开了一种红茴香提取液：将红茴香根皮或茎皮粗粉用药材2～3倍量浓度为70～90％的乙醇浸泡后，渗漉，收集药材3～5倍量的药液为初漉液，另存；继续收集药材4～5倍量的药液为续漉液，减压回收乙醇，浓缩至干，所得续漉液的浓缩干膏转溶于初漉液中，得到的红茴香提取液的药液比为1:3～5；具有消肿、散瘀、活血、止痛的功能。中国专利文献CN102302555A公开了一种治疗痛风性关节炎的中药提取物，由原料药红茴香根皮、红茴香根、红茴香茎叶、地枫皮、假地枫皮或合欢花制备得到，所述的提取物中总黄酮的含量为20-80％。但是关于本发明的红茴香苷醚及组合物在痛风性关节炎中的应用目前还未见报道。
发明内容
本发明的第一个目的是，针对现有技术中的不足，提供一种红茴香脂醚及其药学可接受的盐。
本发明的第二个目的是，提供一种红茴香脂醚及其药学可接受的盐的应用。
本发明的第三个目的是，提供一种红茴香脂醚的制备方法。
本发明的第四个目的是，提供一种红茴香苷醚。
本发明的第五个目的是，提供一种红茴香总苷的制备方法。
本发明的第六个目的是，提供一种红茴香总苷。
本发明的第七个目的是，提供一种红茴香总苷的用途。
为实现上述第一个目的，本发明采取的技术方案是：一种红茴香脂醚及其药学可接受的盐，所述的红茴香脂醚为5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚。
在本发明中，药学上可接受的盐是指活性成分与酸生成的任何盐，其不会产生不希望的毒性或副作用。这些酸是本技术领域人员熟知的，适宜的盐包括但不限于：盐酸盐、硫酸盐、硝酸盐、甲烷磺酸盐、富马酸盐、柠檬酸盐、酒石酸盐、富马酸盐、氯化物、溴化物等。
为实现上述第二个目的，本发明采取的技术方案是：红茴香脂醚及其药学可接受的盐在制备预防或治疗炎症性疾病的药物组合物中的应用。
在本发明中，药物组合物可以按照本领域熟知的方法配制，可以将有效治疗量的活性成分与常规的药用辅料混合制成适合临床上使用的剂型。
常规的药用辅料包括赋形剂、调味剂、崩解剂、防腐剂、润滑剂、湿润剂、粘合剂、溶剂、增稠剂、增溶剂等。
药物剂型可以是粉剂、片剂、胶囊剂、颗粒剂、注射剂、口服液体制剂等。
炎症性疾病包括关节炎症、炎性肠病、关节炎、类风湿性关节炎、类风湿性脊椎炎、痛风性关节炎、创伤性关节炎、风疹性关节炎、牛皮癣关节炎、哮喘、骨关节炎等。
进一步地，所述的炎症性疾病为痛风性关节炎。
为实现上述第三个目的，本发明采取的技术方案是：一种红茴香脂醚的制备方法，所述的制备方法包括以下步骤：红茴香药材粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏，取浸膏均匀分散于水中，分别用等体积的石油醚、二氯甲烷、乙酸乙酯和正丁醇萃取，合并二氯甲烷部位与乙酸乙酯部位；采用湿法装柱干法上样，以两倍量硅胶H拌样，经反复硅胶柱层析，洗脱剂为石油醚：乙酸乙酯＝50:1～1:1，合并流分Fr36～Fr58，再经Sephadex LH-20凝胶柱层析得到红茴香脂醚。
为实现上述第四个目的，本发明采取的技术方案是：一种治疗痛风性关节炎的组合物，所述的组合物由红茴香脂醚：地枫皮素：槲皮苷＝0～1:0～5:1～10组成，所述的红茴香脂醚为5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚。
为实现上述第五个目的，本发明采取的技术方案是：一种红茴香总苷的制备方法，所述的制备方法包括以下步骤：红茴香药材粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏，取浸膏均匀分散于水中，分别用等体积的石油醚、乙酸乙酯萃取，合并乙酸乙酯部位减压浓缩得浸膏，分别过聚酰胺柱、AB-8大孔树脂柱，合并流分浓缩得红茴香总苷。
为实现上述第六个目的，本发明采取的技术方案是：前述制备方法制得的红茴香总苷。
进一步地，所述的红茴香总苷中含红茴香脂醚：地枫皮素：槲皮苷＝0～1:0～5:1～10。
更进一步地，所述的红茴香总苷中含槲皮苷32.1％，地枫皮素5.6％，红茴香脂醚0.41％。
为实现上述第七个目的，本发明采取的技术方案是：红茴香总苷在制备治疗炎症性疾病的药物中的应用。
进一步地，所述的炎症性疾病为痛风性关节炎。
本发明优点在于：
1、本发明得到了红茴香新木脂素成分5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚(5,5'-diallyl-2,2',3'-trimethoxydiphenyl ether)(红茴香脂醚)，并发现红茴香脂醚具有抗炎活性。
2、本发明得到了一种红茴香总苷，红茴香总苷中含红茴香脂醚、地枫皮素、槲皮苷，具有抗炎活性；并经动物实验验证，对痛风性关节型具有治疗作用。
附图说明
附图1：红茴香脂醚的1H NMR图。
附图2：红茴香脂醚的13C NMR图。
附图3：红茴香脂醚的DEPT图。
附图4：红茴香脂醚的COSY图。
附图5：红茴香脂醚的NOESY图。
附图6：红茴香脂醚的HMQC图。
附图7：红茴香脂醚的HMBC图。
附图8：红茴香脂醚的IR图。
附图9：红茴香苷醚对二甲苯致小鼠耳肿胀程度的影响(x±SD，n＝10)。与对照组相比，*P<0.05，**P<0.01，***P<0.001。
附图10：红茴香总苷对尿酸钠晶体诱导小鼠关节肿胀度的影响(x±s)(n＝10)。与对照组相比，**P<<0.01；与模型组相比，*P<0.05。
附图11：红茴香总苷对GA模型小鼠血清尿酸水平的影响(x±s)(n＝10)。与模型组相比，*P<0.05；与对照组相比，**P<0.01。
具体实施方式
下面结合实施例对本发明提供的具体实施方式作详细说明。
实施例1红茴香脂醚的制备
1仪器和试剂
红外(IR)光谱仪：Nicolet 5700FT-IR spectrometer
紫外(UV)光谱仪：Shimadzu UV-210A spectrophotometer
核磁(NMR)共振仪：Bruker AC-300or DRX-600spectrometers with TMS as aninternal standard
质谱(MS)仪：API QSTAR Pulsar 1spectrometer(HR-ESI-MS)
半制备(semipreparative)HPLC仪：Agilent 1100liquid chromatograph with aZorbax SB-C18,9.4mm×25cm
超声波清洗器：KQ-501E型，昆山市超声仪器有限公司
柱色谱填料：柱层层析硅胶H(试剂级，100～200目，200～300目)，山东青岛海洋化工厂；Sephadex LH-20，GE Healthcare Bio-Science AB公司(瑞士)
薄层层析硅胶板：HSGF254(20×20cm，5×20cm)，山东烟台芝罘黄务硅胶开发试验厂
色谱溶剂系统：石油醚：乙酸乙酯(不同比例)，石油醚：丙酮(不同比例)，二氯甲烷：甲醇(不同比例)，氯仿：甲醇(不同比例)，氯仿：丙酮(不同比例)，乙酸乙酯：甲醇(不同比例)，BAW(n-BuOH：H2O：HAc＝4:1:5，上层)
TLC显色：香兰素-10％H2SO4乙醇溶液；紫外灯(254nm)
试剂：提取用乙醇(EtOH)为工业试剂；石油醚(PE)、二氯甲烷(CH2Cl2)、氯仿(CHCl3)、乙酸乙酯(EtOAc)、正丁醇(n-BuOH)、甲醇(MeOH)、乙酸(HAc)等均为分析纯，购买自国药集团化学试剂有限公司以及上海禾汽化工有限公司；制备高效液相用的甲醇和乙腈为色谱纯购买自Merck KgaA公司(德国)
2药材
红茴香药材2015年10月购自毫州药材市场，经黄宝康教授鉴定为八角科八角属植物披针叶茴香的干皮及根皮。
3提取与分离
红茴香药材15kg，粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏(0.87kg)，取浸膏均匀分散于水中，分别用等体积的石油醚、二氯甲烷、乙酸乙酯和正丁醇萃取，合并二氯甲烷部位与乙酸乙酯部位(112g)。
采用湿法装柱干法上样，以两倍量硅胶H(100～200目)拌样，经反复硅胶柱层析(Φ6×L 100cm,200～300目,石油醚：乙酸乙酯＝50:1-1:1)，合并流分Fr36～Fr58，再经Sephadex LH-20凝胶柱层析(氯仿－甲醇；甲醇)得到红茴香脂醚。
红茴香脂醚为新化合物5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚，无色油状物。1H-and13C-NMR等数据如下表及附图1～8。
表1红茴香脂醚的1H-and 13C-NMR数据
a Measured in CDCl3at 600MHz for 1H and at 600MHz for 13C.Chemicalshift as ppm.
按质量比，红茴香脂醚：地枫皮素：槲皮苷0～1:0～5:1～10混合得红茴香苷醚。
实施例2红茴香总苷的制备
红茴香药材30kg，粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏(1.52kg)，取浸膏均匀分散于水中，分别用等体积的石油醚、乙酸乙酯萃取，合并乙酸乙酯部位减压浓缩得浸膏(251.6g)，分别过聚酰胺柱、AB-8大孔树脂柱，合并流分浓缩得红茴香总苷TG-IL 32.5g，经HPLC法测定，其中槲皮苷含32.1％，地枫皮素5.6％，红茴香脂醚0.41％。
实施例3红茴香苷醚抗炎活性
红茴香脂醚及TG-IL对二甲苯致小鼠耳肿胀程度的影响
1动物、试剂和材料
实验动物：ICR雄性小鼠(18～22g)购买自上海斯莱克实验动物有限公司；小鼠在室温条件下饲养，可自由摄取食物和水；实验前12个小时开始禁食不禁水
阳性对照药物：醋酸地塞米松片(Dexamethasone)，上海医药(集团)有限公司信谊制药总厂
致炎剂：二甲苯，分析纯，国药集团化学试剂有限公司，批号F20100303
红茴香脂醚ZM-IL给药剂量均为20mg/kg，80mg/kg，红茴香总苷TG-IL，槲皮苷Q-IL给药剂量均为100mg/kg，400mg/kg，临用前以0.5％CMC-Na水溶液分别配成2mg/ml，10mg/ml混悬液，摇匀。
阳性对照：醋酸地塞米松给药剂量5mg/kg。临用前以0.5％CMC-Na水溶液配成0.5mg/ml悬液。
空白对照：按体重0.2ml/20g给0.5％CMC-Na水溶液。
2实验步骤
ICR雄性小鼠以体重为区组因素，采用随机区组设计分组，每组10只。在使用二甲苯致炎前60min按1所列剂量灌胃给药。移液器吸取二甲苯20μl均匀滴于鼠右耳的正反面，左耳作为对照。120min后将小鼠颈椎脱臼致死，沿耳廓基线剪下两耳，用直径为7mm的打孔器分别在左、右两耳同一部位打下圆耳片，随即称重。
3评判标准及数据处理
耳肿胀程度(Ear Edema,mg)：左右耳重量之差
受试组抑制率(Inhibition,％)：{(空白组肿胀度均数－受试组肿胀度均数)/空白组肿胀度均数}×100
数据处理：统计分析软件spss 18.0，one-way ANOVA(单因素多样本均数比较的方差分析)的Dunnett检验(各实验组肿胀度与空白组比较)
4结果
如附图9所示，红茴香总苷、槲皮苷、红茴香脂醚与空白对照组相比，对二甲苯致小鼠耳肿胀均有较好的抑制活性，尤其以红茴香总苷高剂量组为优，抑制率为49.6％。
实施例4红茴香苷醚对LPS诱导RAW264.7巨噬细胞NO生成的影响
1细胞、试剂和材料
仪器：全自动酶标仪(WellscanMK-2型，Labsystems公司)
实验细胞：小鼠巨噬细胞(RAW 264.7)，由本实验室课题组提供
试剂：脂多糖LPS(Escherichia coli 055:B5)和噻唑蓝MTT[3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide]购买自Sigma公司(USA)；培养基DMEM(dulbecco’s modified eagle‘s medium)和胎牛血清(foetal bovine serum,FBS)购买自Gibco公司(USA)；Griess试剂系统购买自普洛麦格(北京)生物技术有限公司
阳性对照药：氨基胍硫酸盐(aminoguanidine sulfate，AG)购买自百灵威(北京)化学技术有限公司
实验材料：红茴香脂醚，TG-IL，Q-IL
2供试品配制
受试样品：红茴香脂醚，TG-IL，Q-IL以少量DMSO溶解后用DMEM培养基配制成0.12,0.25,0.5,1和2mg/mL五个初始浓度(DMSO在样品中的浓度不大于0.1％)
阳性对照：氨基胍硫酸盐(AG)用DMEM培养基配制成0.12,0.25,0.5,1和2mg/mL五个初始浓度
阴性对照：A组仅加入LPS的细胞培养基；B组既不加LPS也不加样品的细胞培养基
MTT溶液的配制：用5ml磷酸缓冲液(PBS)溶解25mg MTT，配制成5mg/ml的MTT溶液，配制后-20℃避光保存
Griess试剂的配制：0.5％的磺胺溶液(用5％H3PO4配制)和0.1％的N-(1-萘基)乙二胺盐酸盐(用蒸馏水配制)等体积混合，临用前配制
3实验步骤
将RAW264.7细胞用0.25％胰酶消化，收集细胞，吹打均匀，加入含10％胎牛血清和0.25μg/mL L-谷氨酰胺的DMEM培养基将细胞浓度调整至3×104/mL，将细胞接种至96孔板，每孔200μL，于5％CO2和37℃培养箱内培养，加入10μL浓度为120,250,500,1000和2000μg/mL的样品(终浓度分别为6,12.5,25,50和100μg/mL)，培养2h后加入10μL浓度为20μg/mL诱导剂LPS(终浓度：1μg/mL)，于5％CO2和37℃条件下培养24h。吸取100μL培养上清液于96孔板，每孔再加入等体积的Griess试剂(重氮反应，产物为粉红色)，漩涡震荡使之混匀，室温避光静置10min，用全自动酶标仪于550nm波长处测吸光度值。然后再向每孔中加入10μL浓度为5mg/mL的MTT溶液(终浓度：0.5mg/mL)，于5％CO2和37℃培养箱内培养4h，小心吸去孔内培养液，加入100μL DMSO将紫色结晶甲臜(formazan)溶解(10min)，用全自动酶标仪于570nm波长处测吸光度值。
4数据处理
{1-[(给药组NO浓度均数)-(阴性对照B组NO浓度均数)]/[(阴性对照A组NO浓度均数)-(阴性对照B组NO浓度均数)]}×100作为受试组抑制率(inhibition,％)，根据样品各个浓度的抑制率计算化合物的IC50(半数抑制浓度)值。
5结果
一氧化氮(nitric oxide,NO)是细胞内重要的信使分子和神经递质，具有广泛的生理学和病理学作用。可以由一氧化氮合酶(nitric oxide synthase，NOS)：内皮型一氧化氮合酶(endothelial NOS，eNOS),神经元型一氧化氮合酶(neuronal NOS，nNOS)和诱导型一氧化氮合酶(inducible Ca2+-independent NOS，iNOS)催化L-精氨酸反应生成。在炎症因子刺激下，细胞核转录因子(nuclear factor-κB，NF-κB)信号转导通路被激活，iNOS在许多类型的细胞(包括巨噬细胞)内表达，随即NO及其反应产物亚硝基硫醇和过氧亚硝酸盐产生，参与机体免疫防御系统。但是在病理状态下，过量的过氧亚硝酸盐的产生可以导致各种炎症性疾病，如类风湿性关节炎，痛风性关节炎等。因此，抑制病理状态下过量NO的产生，对于多种炎症相关疾病具有治疗作用。
通过标准曲线计算NO浓度。如表2所示，红茴香脂醚，TG-IL，Q-IL对NO的抑制活性都呈剂量依赖关系，其中红茴香酯醚对NO的抑制活性较强(IC50＝27.5μg/mL)。
表2红茴香苷醚对LPS诱导RAW 264.7细胞NO生成的影响
AG：氨基胍硫酸盐，阳性对照。
实施例5红茴香总苷对急性痛风性关节炎小鼠的作用
1.1动物与试剂
ICR小鼠，雌雄各半，体重22-29g，购自上海斯莱克实验动物有限责任公司，许可证号：SCXK(沪)2012-0002。由第二军医大学药学院动物实验中心提供饲养环境，自由饮水、进食，饲养室温控制在22±2℃。
待测药物：红茴香总苷，以0.5％羧甲基纤维素钠(CMC-Na)配成终浓度分别为10mg/mL、20mg/mL、40mg/mL的混悬液，置于4℃冰箱中保存待用。
阳性对照药：秋水仙碱片，云南吴邦药业有限公司，批号140105。0.5％CMC-Na配成终浓度为0.15mg/mL的乳悬液，置于4℃冰箱中保存待用。
尿酸钠：美国sigma公司，批号：BCBH7155V
2实验方法
2.1动物分组及给药方法
实验前取400mg尿酸钠晶体，充分研磨，加18mL生理盐水，2mL聚山梨酯80，边加热边搅拌，配制成20mg/mL尿酸钠混悬液。
将60只小鼠适应性饲养三天后，随机分为6组，分别为对照组，模型组，秋水仙碱组，红茴香总苷低、中、高剂量组，每组10只，雌雄各半，分笼饲养，每笼5只。实验过程中，自由摄食、进水，定时清洁。各给药组分别按体重0.2ml/20g腹腔注射给药，对照组与模型组给予等量的0.5％CMC-Na，每天1次，连续8天。第6天给药后1h，称重，造模，继续每天给药直至处死。
(1)对照组
(2)模型组
(3)秋水仙碱组(1.5mg/kg)
(4)TG-IL-L：红茴香总苷低剂量组(100mg/kg)
(5)TG-IL-M：红茴香总苷中剂量组(200mg/kg)
(6)TG-IL-H：红茴香总苷高剂量组(400mg/kg)
2.2小鼠痛风性关节炎模型的建立
第6天给药1h后，小鼠腹腔注射4％水合氯醛(0.1mL/10g)麻醉，75％医用酒精消毒右后肢小腿踝关节，用1mL无菌注射针在模型组、秋水仙碱组、红茴香总苷低、中、高剂量组的小鼠右足踝关节背侧，斜插入胫骨肌腱内侧，将0.2mL(4mg)尿酸钠溶液注入踝关节腔，以关节囊对侧鼓起为成功标准，诱导急性痛风性关节炎模型。空白组小鼠关节腔注入0.2mL等量灭菌的生理盐水。
2.3指标测定
2.3.1一般情况
主要观察小鼠活动、饮食、排便情况、死亡等情况。
2.3.2各阶段小鼠体重变化情况
第一次给药前称重一次，第6天建模之前，再次称重，观察体重变化情况。
2.3.3小鼠踝关节肿胀度测定
实验前在各组小鼠右后足踝关节上方作一记号，各组分别于造模前(0h)及造模后1h、6h、12h、24h、36h用缚线法测定右踝关节同一部位的周径，整个测量过程均由一人完成，比较肿胀度。
2.3.4血尿酸值的测定
最后一次量完踝关节周径后，各组动物摘眼球取血，静置1h后，3000r/min离心10min，取血清，测血尿酸值，比较组间差异性。
2.3.5受试关节周围组织的病理变化
各组取小鼠右踝关节组织，置于10％福尔马林液中固定，10％脱钙液(EDTA)脱钙，经乙醇脱水、石蜡包埋、切片，苏木精-伊红(HE)染色，光镜下观察受试关节及周围组织的炎症细胞浸润情况等。
3数据分析
统计学方法：计量资料数据以表示，采用spss 18.0统计软件进行数据分析，t检验比较组间差异，单因素方差分析(ANOVA)比较多组间均数。
4实验结果
4.1踝关节肿胀度
与对照组相比，小鼠在造模后各时间点的踝关节肿胀度均显著增加，在24h达到峰值，提示造模成功。与模型组相比，秋水仙碱组在24h时，红茴香总苷各剂量组对GA模型小鼠的踝关节肿胀度均具有显著地缓解作用。
4.2红茴香对小鼠血尿酸值的影响
与对照组比较，模型组小鼠的血尿酸值明显升高，具有统计学意义(P<0.01)。与模型组比较，秋水仙碱组能显著地降低小鼠的血清尿酸值(P<0.05)，红茴香总苷高剂量组能显著降低小鼠血清尿酸水平(P<0.05)。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员，在不脱离本发明方法的前提下，还可以做出若干改进和补充，这些改进和补充也应视为本发明的保护范围。
Claims (10)
1.一种红茴香脂醚及其药学可接受的盐，其特征在于，所述的红茴香脂醚为5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚。
2.根据权利要求1所述的红茴香脂醚及其药学可接受的盐在制备预防或治疗炎症性疾病的药物组合物中的应用。
3.根据权利要求2所述的应用，其特征在于，所述的炎症性疾病为痛风性关节炎。
4.一种红茴香脂醚的制备方法，其特征在于，所述的制备方法包括以下步骤：红茴香药材粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏，取浸膏均匀分散于水中，分别用等体积的石油醚、二氯甲烷、乙酸乙酯和正丁醇萃取，合并二氯甲烷部位与乙酸乙酯部位；采用湿法装柱干法上样，以两倍量硅胶H拌样，经反复硅胶柱层析，洗脱剂为石油醚：乙酸乙酯＝50:1～1:1，合并流分Fr36～Fr58，再经Sephadex LH-20凝胶柱层析得到红茴香脂醚。
5.一种预防或治疗痛风性关节炎的组合物，其特征在于，所述的组合物由红茴香脂醚：地枫皮素：槲皮苷＝0～1:0～5:1～10组成，所述的红茴香脂醚为5,5'-二烯丙基-2,2',3'-三甲氧基联苯醚。
6.一种红茴香总苷的制备方法，其特征在于，所述的制备方法包括以下步骤：红茴香药材粉碎，用80％乙醇加热回流提取，提取液过滤后减压浓缩成浸膏，取浸膏均匀分散于水中，分别用等体积的石油醚、乙酸乙酯萃取，合并乙酸乙酯部位减压浓缩得浸膏，分别过聚酰胺柱、AB-8大孔树脂柱，合并流分浓缩得红茴香总苷。
7.根据权利要求6所述的制备方法制得的红茴香总苷。
8.根据权利要求7所述的红茴香总苷，其特征在于，所述的红茴香总苷中含槲皮苷32.1％，地枫皮素5.6％，红茴香脂醚0.41％。
9.根据权利要求7或8所述的红茴香总苷在制备预防或治疗炎症性疾病的药物组合物中的应用。
10.根据权利要求9所述的应用，其特征在于，所述的炎症性疾病为痛风性关节炎。
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