CN106177962B - 含沙格雷酯的药物组合物用于治疗或预防脂肪肝、肝纤维化和/或肝损伤的用途 - Google Patents
含沙格雷酯的药物组合物用于治疗或预防脂肪肝、肝纤维化和/或肝损伤的用途 Download PDFInfo
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- CN106177962B CN106177962B CN201610806932.4A CN201610806932A CN106177962B CN 106177962 B CN106177962 B CN 106177962B CN 201610806932 A CN201610806932 A CN 201610806932A CN 106177962 B CN106177962 B CN 106177962B
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Abstract
本发明属于医药技术领域，公开了一种含沙格雷酯的药物组合物用于治疗或预防脂肪肝、肝纤维化和/或肝损伤的用途。从实验中证明，通过使用该药物组合物，高脂肪高胆固醇导致的脂肪肝被明显逆转，高脂肪高胆固醇结合链脲佐菌素刺激导致的肝纤维化及肝损伤被明显逆转。
Description
技术领域
本发明属于医药领域，涉及一种含沙格雷酯的药物组合物用于治疗或预防脂肪肝、肝纤维化和/或肝损伤的用途，具体涉及5-羟色胺2受体拮抗剂沙格雷酯和5-羟色胺合成抑制剂组合的复方药物组合物用于治疗或预防脂肪肝、肝纤维化和/或肝损伤的用途。
背景技术
脂肪肝，直接表现是肝脏产生明显的脂质沉积，可检测到肝组织甘油三酯(TG)含量明显升高，组织切片观察可见肝细胞出现明显脂滴。肝脏的进一步病变可发展为肝纤维化及肝损伤。肝纤维化可通过组织切片经特殊染色观察肝脏纤维组织的形成及检测肝组织羟脯氨酸含量(一种纤维组织中特有的氨基酸)来确定，而肝损伤可通过检测血液谷草转氨酶(AST)及谷丙转氨酶(ALT)来确定。多种原因可导致脂肪肝、肝纤维化及肝损伤。生活方式，如长期摄食过多的高热量、高脂肪食物，长期饮酒等不良饮食习惯及缺乏体力活动、精神紧张、生活不规律等，被认为是重要的原因，而某些继发性因素，如糖尿病、肾病综合症，或遗传因素被认为可与生活方式相互作用导致脂肪肝、肝纤维化及肝损伤。
5-羟色胺(5-hydroxy tryptamine,5-HT)也叫血清素，是一种存在于外周和中枢的小分子物质，5-HT的生理功能复杂，至今未完全弄清。
Ⅰ.5-HT的合成分两步，第一步：色氨酸在色氨酸羟化酶(tryptophanhydroxylase,TPH)的催化下转变为5-羟色氨酸(TPH可分为两个亚型：TPH1和TPH2，TPH1存在于外周，TPH2存在于中枢)；第二步：5-羟色氨酸在芳香族氨基酸脱羧酶(aromaticaminoacid decarboxylase,AADC)的催化下转变为5-HT。因此，可分别通过抑制TPH或AADC实现对5-HT合成的抑制。
对氯苯丙氨酸(parachlorophenylalanine或p-chlorophenylalanine,pCPA)，别名:DL-4-氯苯丙氨酸、DL-对氯苯丙氨酸等，分子式：C9H10ClNO2，是TPH抑制剂，无临床应用报导。
卡比多巴(Cabidoba,CDP)，分子式：C10H14N2O4。
苄丝肼(Benserazide,BSA)，别名：三羟基丝氨酰肼、色拉肼、丝氯酰肼、羟苄丝肼，分子式：C10H15N3O5。
CDP和BSA都是AADC抑制剂，临床用于帕金森氏病的辅助治疗，它们的共同作用特点是外周脱羧酶抑制剂，不易进入中枢，仅抑制外周左旋多巴转化为多巴胺，使循环中左旋多巴含量增加，也可抑制5-羟色氨酸转化为5-HT，使合成5-HT的细胞产生5-HT减少。CDP和BSA也没有用于改善血脂异常的研究报导。
Ⅱ.5-HT受体5-HT受体(5-HT receptor,5-HTR)存在于细胞膜上，属于膜受体，5-HT受体亚型复杂，现已发现有7大类受体存在，即5-HT1-7R，5-HT1,4,5R主要分布在中枢，5-HT2,3,6,7R主要分布在外周。这7类受体又被进一步分为若干个亚型。5-HT2R可被分为5-HT2AR、5-HT2BR和5-HT2CR。外周和中枢均有分布的是5-HT2A,2BR，5-HT2CR主要存在于中枢神经系统，肝脏、骨骼肌、内脏脂肪组织分布有5-HT2A,2BR。具有选择性阻断5-HT2R的药物不多，已知沙格雷酯属于选择性5-HT2R拮抗剂。
沙格雷酯(Sarpogrelate,SAR)是一种专一性5-HT2R阻断剂，分子式：C24H31NO6。临床应用中，SAR可抑制由5-HT增强的血小板凝集及抑制血管收缩作用等，临床用于改善慢性动脉闭塞症所引起的溃疡、疼痛以及冷感等缺血性诸症状。临床有SAR治疗糖尿病性并发症下肢动脉硬化闭塞症的报导。
目前还未有5-羟色胺2受体拮抗剂沙格雷酯和/或5-羟色胺合成抑制剂用于治疗或预防脂肪肝、肝纤维化、肝损伤的用途的报道。
发明内容
本发明公开了以5-羟色胺2受体拮抗剂沙格雷酯和5-羟色胺合成抑制剂为药物活性成分，沙格雷酯和5-羟色胺合成抑制剂组合的复方药物组合物具有协同治疗或预防脂肪肝、肝纤维化和/或肝损伤的作用。可有效用于治疗与脂肪肝、肝纤维化及肝损伤相关的疾病。
上述沙格雷酯和5-羟色胺合成抑制剂的重量比为15:1～1:15，优选9:1～1:7。
所述的沙格雷酯为沙格雷酯或沙格雷酯衍生物，优选沙格雷酯衍生物为沙格雷酯药学上可接受的盐。该沙格雷酯药学上可接受的盐优选为沙格雷酯盐酸盐。所述的5-羟色胺合成抑制剂优选为对氯苯丙氨酸、卡比多巴或苄丝肼。
其中，对氯苯丙氨酸为对氯苯丙氨酸或对氯苯丙氨酸衍生物，对氯苯丙氨酸衍生物优选氯苯丙氨酸药学上可接受的盐，卡比多巴为卡比多巴或卡比多巴衍生物，卡比多巴衍生物优选为卡比多巴药学上可接受的盐，苄丝肼为苄丝肼或苄丝肼衍生物，苄丝肼衍生物优选为苄丝肼药学上可接受的盐。
上述沙格雷酯和对氯苯丙氨酸的重量比更优选为7:1～1:5。进一步优选2:1。
上述沙格雷酯和卡比多巴的重量比更优选为9:1～1:5。进一步优选2:1。
上述沙格雷酯和苄丝肼的重量比更优选为6:1～1:7。进一步优选1:1。
所述的沙格雷酯和5-羟色胺合成抑制剂组合的复方药物组合物通过添加药学上可接受的辅料制备成适合临床使用的剂型，优选口服制剂或注射剂。口服制剂可以为固体制剂或液体制剂，固体制剂优选片剂、胶囊剂、颗粒剂、微丸剂、滴丸剂等。
所述的辅料可以为崩解剂、稀释剂、黏合剂、润滑剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、填充剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、等渗调节剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、絮凝剂与反絮凝剂、助滤剂、阻滞剂、抗氧剂、抑菌剂等。
优选崩解剂包括淀粉及其衍生物、纤维素类表面活性剂、泡腾混合物以及琼脂、海藻酸、皂土等，如羧甲基淀粉钠，羧甲基纤维素钠、交联羧甲基纤维素钠、羟丙基纤维素、交联聚维酮，阻滞剂乙基纤维素、羟丙甲纤维素等；增稠剂包括甲基纤维素钠等，助溶剂包括有机酸及其钠盐(如苯甲酸钠、水杨酸钠、对氨基苯甲酸等)、酰胺类化合物(如乌拉坦、尿素、烟酰胺、乙酰胺等)、无机盐、多聚物、脂类、多元醇、丙二醇、甘油；乳化剂包括天然乳化剂(如阿拉伯胶、磷脂、明胶)，半合成或合成乳化剂(如阴离子型乳化剂、非离子型乳化剂)，辅助乳化剂(如海藻酸钠、阿拉伯胶、黄原胶、果胶、HPC、MC、CMC-Na等)，固体粉末乳化剂(如氢氧化镁、氢氧化铝、二氧化硅、硅皂土、白陶土、氢氧化钙、氢氧化锌、硬脂酸镁等)，助悬剂包括低分子助悬剂(如甘油、糖浆等)，高分子助悬剂(如天然助悬剂阿拉伯胶、淀粉浆，合成助悬剂甲基纤维素、羟丙基纤维素、羧甲基纤维素钠、卡波普和硅皂土等)；矫味剂包括芳香剂(如天然香料柠檬、樱桃、薄荷、茴香挥发油、麝香等)和人工香料(醇、醛、酮、胺、酯、醚、酸、酚、內酯、萜、缩醛等以及香精)，甜味剂(如蔗糖、甜菊甙、阿司帕坦、糖精钠)，胶浆剂(如羧甲基纤维素钠、琼酯、明胶、阿拉伯胶、海藻酸钠等)，泡腾剂(如碳酸氢盐与有机酸：枸橼酸、酒石酸)；防腐剂包括羟苯酯类、有机酸及其盐类、季铵化合物类，醋酸氯己定类；着色剂包括天然色素和人工合成色素；抗氧剂包括水溶性抗氧剂(如亚硫酸盐类、抗坏血酸类、硫代化合物、氨基酸类、胺类、有机酸类、酚类)和油溶性抗氧剂(如没食子酸丙酯类、生育酚类)；pH值调节剂包括酸类(如盐酸、硫酸、醋酸)，碱类(如氢氧化钠、碳酸氢钠、浓氨溶液等)，缓冲溶液(如磷酸盐缓冲液、硼酸缓冲液、硼酸盐缓冲液等)；等渗调节剂包括无机等渗调节剂(如硼砂、氯化钠)和有机等渗调节剂(如葡萄糖、果糖等)；抑菌剂包括季铵化合物(如苯扎溴铵、苯扎氯铵)、中性化合物类(如苯甲醇、三氯叔丁醇、苯氧乙醇等)、汞化合物类(如硝酸苯汞、硫柳汞)、羟苯酯类(如尼泊金类)、酸及其盐类(如苯甲酸及其盐、山梨酸及其盐)、酚类(如苯酚、甲酚)；稀释剂包括水溶性稀释剂(如乳糖、甘露醇)和水不溶性稀释剂(如微晶纤维素、淀粉)；黏合剂包括天然黏合剂(如淀粉浆、蔗糖、明胶浆、阿拉伯胶浆)和人工黏合剂(如PVP、MCC、MC、CMC-Na等)，润滑剂包括水溶性和水不溶性润滑剂，如硬脂酸、硬脂酸镁、硬脂酸钙、滑石粉、聚乙二醇、硼酸、苯甲酸钠；增塑剂包括多元醇类、聚醇类、酯类、醇酯类、聚酯类。
我们在研究中发现：
Ⅰ.在高脂肪高胆固醇饲料(高脂饲料)喂养建立小鼠脂肪肝的动物模型中，用SAR+pCPA、SAR+CDP、SAR+BSA按两种药物不同的重量配比组成不同的复方对模型进行治疗。结果表明，高脂饲料导致的脂肪肝被明显逆转，表现为：药物治疗使模型动物肝组织TG含量明显降低，肝组织切片素木精伊红染色(HE染色)观察到肝细胞内脂滴明显减少。并且，SAR+pCPA、SAR+CDP、SAR+BSA三种复方按药物一定的重量配比，对治疗脂肪肝显示出明显的协同作用，联合用药能明显提高药物疗效。
Ⅱ.在高脂肪高胆固醇饲料(高脂饲料)喂养结合链脲佐菌素(STZ)刺激建立小鼠肝纤维化及肝损伤的动物模型中，用SAR+pCPA、SAR+CDP、SAR+BSA按两种药物不同的重量配比组成不同的复方对模型进行治疗。结果表明，肝纤维化及肝损伤被明显逆转，表现为：药物治疗使模型动物肝组织羟脯氨酸含量明显减少，肝组织切片MASSON染色观察到肝组织纤维化明显减轻，血清ASL、ALT活性明显降低。并且，SAR+pCPA、SAR+CDP、SAR+BSA三种复方按药物一定的重量配比，对治疗肝纤维化及肝损伤显示明显的协同作用，联合用药能明显提高药物疗效。
综上所述，用沙格雷酯与5-羟色胺合成抑制剂如对氯苯丙氨酸或卡比多巴或苄丝肼在一定的重量比范围内组成复方，对治疗脂肪肝、肝纤维化及肝损伤有明显的协同作用，用于脂肪肝、肝纤维化和/或肝损伤的治疗具有显著的效果。
下面通过试验例及实施例对本发明的复方药物组合物做进一步的药效学实验的阐述。
附图说明
图1为药物组合物治疗对高脂饲料喂养诱导的脂肪肝模型肝细胞内脂滴含量的影响图。
HR染色，图片放大倍数为200倍。
图2为药物组合物治疗对高脂饲料喂养结合链脲佐菌素刺激致肝纤维化的治疗作用观察图。MASSON染色，图片放大倍数为200倍，示汇管区周围肝纤维化。
具体实施方式
以下通过具体试验例及实施例对本发明进行进一步阐述：
试验例1
药物对高脂饲料喂养致小鼠脂肪肝模型的治疗作用
比较SAR(沙格雷酯)与对氯苯丙氨酸(pCPA)、卡比多巴(CDP)或苄丝肼(BSA)联合给药，及各自单独给药对高脂饲料喂养致大鼠血脂异常模型的治疗作用，从而验证SAR与pCPA、CDP或BSA联合给药对血脂异常治疗的协同效应。
2.1实验方法
(1)动物处理
180只雄性ICR小鼠除对照组(10只，喂以普通饲料)外，其他动物均喂以高脂饲料(高脂饲料中含脂肪23％，胆固醇2.6％，蛋白质17.5％)，连续喂养12周建立脂肪肝动物模型。然后，高脂饲料喂养动物随机分为17组(每组10只)：脂肪肝模型组，脂肪肝模型SAR治疗组，脂肪肝模型SAR+pCPA复方治疗组(SAR:pCPA按不同重量配比的4种复方)，脂肪肝模型pCPA治疗组，脂肪肝模型SAR+CDP复方治疗组(SAR:CDP按不同重量配比的4种复方)，脂肪肝模型CDP治疗组，脂肪肝模型SAR+BSA复方治疗组(SAR:BSA按不同重量配比的4种复方)，脂肪肝模型BSA治疗组。动物笼养于普通鼠笼，保持室温24±2℃、光照控制保证12h明、暗条件，普通水喂养。连续给药4周，给药期间，除对照组喂以普通饲料外，各组仍喂以高脂饲料。最后一次给药后各组动物禁食(不禁水)12小时后，动物经麻醉后处死，取肝脏检测TG含量及肝组织福尔马林固定后作组织切片HE染色观察肝细胞内脂滴含量。
实验中，SAR+pCPA复方按不同重量配比的四种复方为：
SAR+pCPA-1—SAR:pCPA＝1:5；SAR+pCPA-2—SAR:pCPA＝1:2；
SAR+pCPA-3—SAR:pCPA＝2:1；SAR+pCPA-4—SAR:pCPA＝7:1。
实验中，SAR+CDP复方按不同重量配比的四种复方为：
SAR+CDP-1—SAR:CDP＝1:5；SAR+CDP-2—SAR:CDP＝1:2；
SAR+CDP-3—SAR:CDP＝2:1；SAR+CDP-4—SAR:CDP＝9:1。
实验中，SAR+BSA复方按不同重量配比的四种复方为：
SAR+BSA-1—SAR:BSA＝1:7；SAR+BSA-2—SAR:BSA＝1:3；
SAR+BSA-3—SAR:BSA＝1:1；SAR+BSA-4—SAR:BSA＝6:1。
(2)给药剂量
对照组—经口给药(p.o.)0.5％羧甲基纤维素钠(CMC-Na)溶液0.20ml/10g体重/次；
血脂异常模型组—p.o.0.5％CMC-Na 0.20ml/10g体重/次；
血脂异常模型药物治疗组—p.o.各组药物，所有给药组给药剂量均相同为：30.0mg/kg/次。
各药物用0.5％CMC-Na混悬，浓度相同均为：1.50mg/ml，各组药物p.o.给药容积为0.20ml/10g体重/次；每天给药两次，上下午各给药一次。
2.2实验指标检测方法
试剂盒、分光光度法检测肝组织TG含量，肝组织切片后HE染色观察肝细胞内脂滴含量。
2.3实验结果
所有数据统计学检测用单因素方差分析LSD检测，p<0.05表示有明显统计学差异，p<0.01表示有非常明显统计学差异。表中数据用均值±标准差(X±SD)表示,N＝10；$p<0.05,$$p<0.01与对照组比较；*p<0.05,**p<0.01与血脂异常模型组比较；#p<0.05,##p<0.01复方组与SAR单方组比较；&p<0.05,&&p<0.01复方组与pCPC或CDP或BSA单方组比较。
(1)SAR+pCPA复方对高脂饲料喂养致脂肪肝的治疗作用研究结果
结果见表1及图1。高脂饲料喂养致脂肪肝模型中，肝组织TG含量大幅升高及肝细胞中出现大量脂滴，提示出现明显脂肪肝。用相同给药剂量的SAR，pCPA，SAR+pCPA四种复方：SAR+pCPA-1、SAR+pCPA-2、SAR+pCPA-3、SAR+pCPA-4对脂肪肝进行治疗，均能明显降低肝组织TG并使肝细胞内脂滴明显减少；复方SAR+pCPA-3治疗显示其降低肝组织TG含量效果明显好于SAR或pCPA单独治疗，提示产生明显的协同效应(注：复方组与单方组为等剂量给药，因此只要复方组疗效好于单方组就表明有协同效应)；复方SAR+pCPA-1、SAR+pCPA-2、SAR+pCPA-4治疗的降低肝组织TG含量作用好于或等于pCPA及SAT单独治疗。各组HE染色肝细胞内脂滴含量观察结果与肝组织TG含量测量结果一致。结果提示，SAR与pCPA组成一定比例的复方，对治疗脂肪肝有明显的协同作用，按重量配比，SAR:pCPA的比例范围为：7:1～1:5，本实验中以SAR:pCPA＝2:1复方(SAR+pCPA-3)疗效最好。
表1 SAR+pCPA复方药物对小鼠高脂饲料喂养致脂肪肝模型肝组织内TG含量的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$:P<0.05,$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与pCPA组比较
(2)SAR+CDP复方对高脂饲料喂养致脂肪肝的治疗作用研究结果
结果见表2、图1。用相同给药剂量的CDP，SAR+CDP四种复方：SAR+CDP-1、SAR+CDP-2、SAR+CDP-3、SAR+CDP-4对高脂饲料喂养致脂肪肝进行治疗，均能明显降低肝组织TG含量、减少肝细胞内脂滴数量；复方SAR+CDP-2、SAR+CDP-3治疗均显示降低肝组织TG含量疗效明显好于SAR或CDP单独治疗，提示产生明显的协同效应(注：复方组与单方组为等剂量给药，因此只要复方组疗效好于单方组就表明有协同效应)；复方SAR+CDP-1、SAR+CDP-4治疗效果好于或等于CDP、SAR单独治疗。各组HE染色肝细胞内脂滴含量观察结果与肝组织TG含量测量结果一致。结果提示，SAR与CDP组成一定比例的复方，对治疗脂肪肝有明显的协同作用，按重量配比，SAR:CDP的比例范围为：9:1～1:5，本实验中以SAR:CDP＝2:1复方(SAR+CDP-3)疗效最好。
表2 SAR+CDP复方药物对小鼠高脂饲料喂养致脂肪肝模型肝组织TG含量的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$:P<0.05,$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与CDP组比较
(3)SAR+BSA复方对高脂饲料喂养致脂肪肝的治疗作用研究结果
结果见表3及图1。用相同给药剂量的BSA，SAR+BSA四种复方：SAR+BSA-1、SAR+BSA-2、SAR+BSA-3、SAR+BSA-4对高脂饲料喂养致脂肪肝进行治疗，均能明显降低肝组织TG含量并减少肝细胞内脂滴数量；复方SAR+BSA-2、SAR+BSA-3治疗均显示降低肝组织内TG含量疗效明显好于SAR或BSA单独治疗，产生明显的协同效应；复方SAR+BSA-1、SAR+BSA-4治疗效果好于或等于BSA、SAR单独治疗。各组HE染色肝细胞内脂滴含量观察结果与肝组织TG含量测量结果一致。结果提示，SAR与BSA组成一定比例的复方，对治疗脂肪肝有明显的协同作用，按重量配比，SAR:BSA的比例范围为：6:1～1:7，本实验中以SAR:BSA＝1:1复方(SAR+BSA-3)疗效最好。
表3 SAR+BSA复方药物对小鼠高脂饲料喂养致脂肪肝模型肝组织TG含量的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$:P<0.05,$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与BSA组比较
试验例2
药物对高脂饲料喂养结合链脲佐菌素刺激致小鼠高血糖、肝纤维化、肝损伤模型的治疗作用
比较SAR与pCPA、CDP、BSA联合给药，及各自单独给药对DEX致大鼠血脂异常模型的治疗作用(模拟人长期精神紧张或慢性应激的情形)，从而再次验证SAR与pCPA、CDP、BSA联合给药对血脂异常治疗的协同效应。
3.1实验方法
(1)动物处理
实验用雄性ICR小鼠235只。除对照组(10只，喂以普通饲料)外，其他动物首先用高脂饲料喂养(高脂饲料配方同试验例1)喂养4周建立高脂血症及脂肪肝动物模型，然后腹腔注射链脲佐菌素(STZ)(80mg/kg)，72h后测定空腹血糖(FBG)，选择FBG≥11.1mM作为为造模成功标准，随机分为17组(每组10只)：肝纤维化、肝损伤模型组，模型SAR治疗组，模型SAR+pCPA复方治疗组(SAR:pCPA按不同重量配比的4种复方)，模型pCPA治疗组，模型SAR+CDP复方治疗组(SAR:CDP按不同重量配比的4种复方)，模型CDP治疗组，模型SAR+BSA复方治疗组(SAR:BSA按不同重量配比的4种复方)，模型BSA治疗组。动物笼养于普通鼠笼，保持室温24±2℃、光照控制保证12h明、暗条件，普通水喂养。给药期间模型组及各治疗组继续喂以高脂饲料，对照组喂以普通饲料。连续给药21天后，动物于实验前4h最后一次给药，并禁食12h后处死动物取血、取脏器，检测指标，肝组织福尔马林固定后作组织切片MASSON染色观察肝组织纤维化情况。
实验中，SAR+pCPA、SAR+CDP、SAR+BSA三种复方形式按不同重量配比的四种复方配伍同试验例1。
(2)给药剂量
对照组—经口给药(p.o.)0.5％羧甲基纤维素钠(CMC-Na)溶液5.0ml/kg/次；
模型组—p.o.CMC-Na 5.0ml/kg/次；
模型药物治疗组—p.o.各组药物，所有给药组给药剂量均相同为：30.0mg/kg/次；
各药物用0.5％CMC-Na混悬，浓度相同均为：1.50mg/ml，各组药物p.o.给药容积为0.20ml/10g体重/次；每天给药两次，上下午各给药一次。
3.2实验结果
肝组织羟脯氨酸含量用ELISA方法检测，血清AST、ALT检测用试剂盒分光光度法，肝组织切片后MASSON染色观察肝组织纤维化情况。统计学处理同试验例1。
(1)SAR+pCPA复方对肝纤维化、肝损伤的治疗作用研究结果
结果见表4及图2。高脂饲料喂养结合STZ刺激使动物出现明显的肝纤维化，可检测到肝组织羟脯氨酸含量大幅升高、MASSON染色可见肝组织内纤维组织形成明显增多(图中染色成兰色条纹状结构)，主要分布在汇管区周围；另外，血清AST、ALT活力检测表明，模型组AST、ALT活力明显升高，提示出现肝损伤。用相同给药剂量的SAR，pCPA，SAR+pCPA四种复方：SAR+pCPA-1、SAR+pCPA-2、SAR+pCPA-3、SAR+pCPA-4对模型进行治疗，均能明显降低肝组织羟脯氨酸含量、减少肝组织纤维生成，并降低血清AST、ALT活力，提示均具有明显的抑制肝纤维化、降低肝损伤疗效；复方SAR+pCPA-2、SAR+pCPA-3治疗均显示其降低肝组织羟脯氨酸含量及血清AST活力好于SAR或pCPA单独治疗，复方SAR+pCPA-3治疗降低血清ALT活力也明显好于SAR或pCPA单独治疗，提示产生协同效应；复方SAR+pCPA-1、SAR+pCPA-4治疗降低肝组织羟脯氨酸含量及血清AST、ALT活力的疗效好于或等于pCPA及SAR单独治疗。各组MASSON染色肝纤维化的观察结果与肝组织羟脯氨酸的测量结果一致。结果提示，SAR与pCPA组成一定比例的复方，对治疗肝纤维化及肝损伤有明显的协同作用，按重量配比，SAR:pCPA的比例范围为：7:1～1:5，本实验中以SAR:pCPA＝2:1复方(SAR+pCPA-3)疗效最好。
表4 SAR+pCPA复方药物对小鼠肝纤维化、肝损伤的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$:P<0.05,$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与pCPA组比较
(2)SAR+CDP复方对肝纤维化、肝损伤的治疗作用研究结果
结果见表5、图2。用相同给药剂量的CDP，SAR+CDP四种复方：SAR+CDP-1、SAR+CDP-2、SAR+CDP-3、SAR+CDP-4对肝纤维化、肝损伤模型进行治疗，均能明显降低肝组织羟脯氨酸含量、减少肝组织纤维化，并且降低血清AST、ALT活力；复方SAR+CDP-2、SAR+CDP-3的疗效明显好于SAR或CDP单独治疗，产生明显的协同效应；复方SAR+CDP-1、SAR+CDP-4治疗效果好于或等于CDP、SAR单独治疗。各组MASSON染色肝纤维化的观察结果与肝组织羟脯氨酸的测量结果一致。结果提示，SAR与CDP组成一定比例的复方，对治疗肝纤维化、肝损伤有明显的协同作用，按重量配比，SAR:CDP的比例范围为：9:1～1:5，本实验中以SAR:CDP＝2:1复方(SAR+CDP-3)疗效最好。
表5 SAR+CDP复方药物对小鼠肝纤维化、肝损伤的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$:P<0.05,$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与CDP组比较
(6)SAR+BSA复方对肝纤维化、肝损伤的治疗作用研究结果
结果见表6和图2。用相同给药剂量的BSA，SAR+BSA四种复方：SAR+BSA-1、SAR+BSA-2、SAR+BSA-3、SAR+BSA-4对肝纤维化、肝损伤模型进行治疗，均能明显降低肝组织羟脯氨酸含量、抑制肝纤维化，并且降低血清AST、ALT活力；复方SAR+BSA-2、SAR+BSA-3治疗效果明显好于SAR或BSA单独治疗，产生明显的协同效应；复方SAR+BSA-1、SAR+BSA-4治疗效果好于或等于BSA、SAR单独治疗。各组MASSON染色肝纤维化的观察结果与肝组织羟脯氨酸的测量结果一致。结果提示，SAR与BSA组成一定比例的复方，对治疗肝纤维化、肝损伤有明显的协同作用，按重量配比，SAR:BSA的比例范围为：6:1～1:7，本实验中以SAR:BSA＝1:1复方(SAR+BSA-3)疗效最好。
表6 SAR+BSA复方药物对小鼠肝纤维化、肝损伤的影响
注：各给药组给药剂量相同，均为30.0mg/kg.次，一天两次，上下午各一次
$$:P<0.01,与对照组比较；*:P<0.05,**:P<0.01,与模型组比较；
#:P<0.05,##:P<0.01,与SAR组比较；&:P<0.05,&&:P<0.01,与BSA组比较
实施例1
沙格雷酯1重量份，对氯苯丙氨酸5重量份，与糊精等颗粒剂常用的辅料采用常规技术制成颗粒剂。
实施例2
沙格雷酯1重量份，对氯苯丙氨酸2重量份，与微晶纤维素等片剂常用辅料压制成片剂。
实施例3
沙格雷酯2重量份，对氯苯丙氨酸1重量份，与糊精等颗粒剂常用的辅料采用常规技术制成颗粒剂，再灌入硬胶囊皮中制成胶囊剂。
实施例4
盐酸沙格雷酯7重量份，对氯苯丙氨酸1重量份，与药学可接受的辅料采用常规技术制成滴丸剂。
实施例5
沙格雷酯1重量份，卡比多巴5重量份，与药学可接受的辅料采用常规技术制成微丸剂。
实施例6
沙格雷酯1重量份，卡比多巴2重量份，与药学可接受的辅料采用常规技术制成口服溶液剂。实施例7
沙格雷酯2重量份，卡比多巴1重量份，与药学可接受的辅料采用常规技术制成注射剂。
实施例8
盐酸沙格雷酯9重量份，卡比多巴1重量份，与糊精等颗粒剂常用的辅料采用常规技术制成颗粒剂。
实施例9
沙格雷酯1重量份，苄丝肼7重量份，与淀粉等片剂常用辅料采用常规技术压制成片剂。
实施例10
沙格雷酯1重量份，苄丝肼3重量份，与药学可接受的辅料采用常规技术制成微丸剂
实施例11
沙格雷酯1重量份，苄丝肼1重量份，与药学可接受的辅料采用常规技术制成乳剂。
实施例12
盐酸沙格雷酯6重量份，苄丝肼1重量份，与药学可接受的辅料采用常规技术制成软胶囊。
Claims (10)
1.以沙格雷酯和5-羟色胺合成抑制剂为药物活性成分的复方药物组合物在制备治疗或预防脂肪肝、肝纤维化和/或肝损伤的药物中的应用，其中，5-羟色胺合成抑制剂为对氯苯丙氨酸或卡比多巴或苄丝肼，沙格雷酯和5-羟色胺合成抑制剂的重量比为9:1~1:7；所述的沙格雷酯为沙格雷酯或沙格雷酯盐酸盐。
2.根据权利要求1所述的应用，其特征在于所述的沙格雷酯和对氯苯丙氨酸的重量比为7:1~1:5。
3.根据权利要求2所述的应用，其特征在于所述的沙格雷酯和对氯苯丙氨酸的重量比为2:1。
4.根据权利要求1所述的应用，其特征在于所述的沙格雷酯和卡比多巴的重量比为9:1~1:5。
5.根据权利要求4所述的应用，其特征在于所述的沙格雷酯和卡比多巴的重量比为2:1。
6.根据权利要求1所述的应用，其特征在于所述的沙格雷酯和苄丝肼的重量比为6:1~1:7。
7.根据权利要求6所述的应用，其特征在于所述的沙格雷酯和苄丝肼的重量比为1:1。
8.根据权利要求1所述的应用，其特征在于所述的沙格雷酯和5-羟色胺合成抑制剂组合的复方药物组合物添加药学上可接受的辅料制备成适合临床使用的剂型。
9.根据权利要求8所述的应用，其特征在于所述的剂型为口服制剂或注射剂。
10.根据权利要求8所述的应用，其特征在于所述的辅料为崩解剂、稀释剂、黏合剂、
润滑剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、填充剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、包衣材料、芳香剂、抗黏合剂、整合剂、渗透促进剂、等渗调节剂、pH值调节剂、缓冲剂、增塑剂、表面活性剂、发泡剂、消泡剂、增稠剂、包合剂、保湿剂、吸收剂、絮凝剂与反絮凝剂、助滤剂、阻滞剂、抗氧剂、抑菌剂。
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| CN102657868A (zh) * | 2012-05-30 | 2012-09-12 | 中国药科大学 | 5-羟色胺2受体拮抗剂或转运体抑制剂治疗脂肪肝或高脂血症 |
| CN104667283A (zh) * | 2015-03-09 | 2015-06-03 | 中国药科大学 | 一种治疗血脂异常和动脉粥样硬化的复方药物组合 |
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| CN102657868A (zh) * | 2012-05-30 | 2012-09-12 | 中国药科大学 | 5-羟色胺2受体拮抗剂或转运体抑制剂治疗脂肪肝或高脂血症 |
| CN104667283A (zh) * | 2015-03-09 | 2015-06-03 | 中国药科大学 | 一种治疗血脂异常和动脉粥样硬化的复方药物组合 |
Non-Patent Citations (1)
| Title |
|---|
| 外周5-羟色胺在胰岛素抵抗中的作用研究进展;李涛等;《药学进展》;20151231;第39卷(第2期);113-118 |
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| CN110548150A (zh) * | 2019-08-27 | 2019-12-10 | 中国药科大学 | 一种复方药物组合物在制备治疗急性肾损伤药物中的应用 |
| CN110548150B (zh) * | 2019-08-27 | 2022-03-08 | 中国药科大学 | 一种复方药物组合物在制备治疗急性肾损伤药物中的应用 |
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