CN112755011A - 一种用于预防或治疗肝病的组合物 - Google Patents
一种用于预防或治疗肝病的组合物 Download PDFInfo
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- CN112755011A CN112755011A CN202110287235.3A CN202110287235A CN112755011A CN 112755011 A CN112755011 A CN 112755011A CN 202110287235 A CN202110287235 A CN 202110287235A CN 112755011 A CN112755011 A CN 112755011A
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Abstract
本发明提供一种用于预防或治疗肝病的组合物,具体提供了一种含有秋水仙碱(colchicine)和DPP‑4(dipeptidyl peptidase‑4)抑制剂作为有效成分的用于预防或治疗肝病的药学组合物。本发明涉及的药学组合物,通过对往常用于治疗其他疾病的药物—秋水仙碱和DPP‑4抑制剂的联合给药,可以显著减少肝细胞或肝组织中的纤维化、脂肪堆积、炎症等肝损伤,并利用其更有效地预防或治疗肝病。
Description
技术领域
本发明涉及一种用于预防或治疗肝病的组合物,具体涉及一种含有秋水仙碱(colchicine)和二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂作为有效成分的用于预防或治疗肝病的药学组合物。
背景技术
肝脏(liver)是一种在来自体外的物质及体内的物质代谢中起到中枢作用并持续发生酶反应和能量代谢的生物器官。事实上,目前在韩国国内的慢性疾病中,肝炎(hepatitis)、肝硬化(liver cirrhosis)及肝癌(liver cancer)与循环系统疾病一样占比最高,在因疾病而导致死亡的病因中也占着很大的比重。特别是与发达国家相比,饮酒人数相对较多,酗酒是引起肝脏损伤的较大原因,从而对其的关注度也很高。
所述肝病中的非酒精性脂肪性肝炎(Nonalcholic steatohepatitis,NASH或Non-alcoholic fatty liver disease,NAFLD)是由肥胖、糖尿病、高脂血症、药物等非饮酒引起的疾病,从而导致肝细胞内脂肪堆积、肝细胞变性/坏死,由此引发的炎症和肝纤维化(liver fibrosis)发展为肝硬化和肝癌,因此是全球公认的重疾。
特别是,肝纤维化是肝炎等慢性肝病伴随的生物适应反应的一部分,是指受损的肝组织不能恢复为正常的肝细胞,而是转变为胶原蛋白等纤维组织的状态。肝纤维化是组织损伤修复过程中发生的生物反应,但肝被完全不能执行体内物质代谢、胆汁分泌等肝固有功能的纤维组织所代替,因此肝功能下降是必然的。肝纤维化现象持续反复时,会发展为肝硬化并导致死亡。因此,研发合适的治疗剂一直是药物研发的重要课题。但是到目前为止,肝纤维化的机制本身尚不明确,因此尚未开发出合适的治疗药物。
于是,持续的肝组织损伤具有发展为肝硬化或肝癌的疾病特征,考虑到肝组织的生理特性和重要性,肝病的治疗和预防非常重要,需要开发能够减少肝组织损伤并最终提高疗效的肝病治疗剂。
另一方面,秋水仙碱已广泛用作与痛风相关的关节炎治疗剂,急性痛风和复发性痛风的治疗病例也有报告。另外,秋水仙碱的药物动力学特性也有报告,具有可口服的特性。10多年前就形成了秋水仙碱对多种适应症的病例报告和机制研究,据报道,对风湿性和非风湿性关节炎、家族性地中海热伴发的淀粉样变(amyloidosis)的预防、预防发烧、白塞病(Behcet)等也有疗效。
此外,二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂是选择性地抑制阻止控制血糖的胰高血糖素样肽1(glucagon like peptide-1,GLP-1)产生作用的DPP-4,是众所周知的提高2型糖尿病患者血糖水平控制的抗糖尿病治疗剂。虽然有很多使用所述DPP-4抑制剂的与治疗肝病相关的研究和先行技术的相关报告,但由于改善肝纤维化的效果等并不完善,所以以治疗上述疾病为目的而给药是有限的,目前还没有联合使用这些药物的肝病治疗技术的相关报告。
现有技术文献:
(专利文献)大韩民国公开专利第10-2009-0059017号(2009.06.10.公开)。
发明内容
【待解决的课题】
本发明旨在提供一种包含对肝病具有良好疗效的联合制剂的药学组合物。
【课题的解决手段】
为了达到所述目的,本发明提供了一种含有秋水仙碱(colchicine)和DPP-4(dipeptidyl peptidase-4)抑制剂作为有效成分的用来预防或治疗肝病的药学组合物。此外,本发明还提供了一种含有秋水仙碱(colchicine)和DPP-4(dipeptidyl peptidase-4)抑制剂作为有效成分的用来预防或治疗肝病的联合给药药学组合物。
【发明的效果】
本发明涉及往常用于其他疾病治疗的药物秋水仙碱及DPP-4抑制剂的一种新的联合疗法,所述两种制剂的联合给药可使肝细胞或肝组织中的纤维化、脂肪堆积、炎症等肝损伤显著减少。
本发明涉及的药学组合物中含有一定含量的秋水仙碱和DPP-4抑制剂,因此可显示出比传统技术更好的肝病预防或治疗效果,从而利用其可以更有效地预防或治疗肝病。
附图说明
图1是本发明的一个实验例涉及的诱导肝纤维化小鼠肝细胞中I型胶原蛋白表达变化的观察结果。
图2是本发明的一个实验例涉及的诱导脂肪堆积的小鼠肝细胞中SREBP1表达变化的观察结果。
图3是本发明的一个实验例涉及的诱导炎症的小鼠肝细胞中IL-1β表达变化的观察结果。
图4是本发明一个实验例涉及的诱导非酒精性脂肪性肝炎(NASH)大鼠模型的肝组织变化通过苏木精-曙红染色法(hematoxylin-eosin staining,H&E)进行解剖学观察的结果。
图5是本发明的一个实验例涉及的诱导NASH大鼠模型的肝组织中羟脯氨酸(hydroxyproline)变化的观察结果。
图6是本发明的一个实验例涉及的诱导NASH大鼠模型的肝组织纤维化相关基因的表达变化的观察结果。
图7是本发明的一个实验例诱导NASH大鼠模型的肝组织炎症相关基因的表达变化的观察结果。
图8是本发明的一个实验例涉及的诱导NASH大鼠模型的肝组织脂肪堆积相关基因的表达变化的观察结果。
图9是本发明的一个实验例涉及的诱导NASH大鼠模型的肝组织中超氧化物(superoxide)生成变化的观察结果。
具体实施方式
以下将对本发明进行详细说明。
本发明人确认,在联合给药痛风药物秋水仙碱和降糖药DPP-4抑制剂时,在高脂饮食下诱导非酒精性脂肪性肝炎(NASH)的动物模型中对肝细胞或肝组织纤维化、脂肪堆积、炎症等肝损伤的抑制效果,从而完成了本发明。
本发明提供了含有秋水仙素(colchicine)和DPP-4(dipeptidyl peptidase-4)抑制剂作为有效成分的用于预防或治疗肝病的药学组合物。
在本说明书中,“秋水仙碱(colchicine)”是百合科植物秋水仙(Colchicumautumnale)的种子或球茎中含有的生物碱成分,用下述化学式1表示,如上所述,是被广泛用作痛风相关关节炎治疗剂的纯口服药物。
<化学式1>
本说明书中,“DPP-4(dipeptidyl peptidase-4)抑制剂”如上所述,选择性地抑制阻止控制血糖的GLP-1作用的DPP-4,具体来说可以是抑制DPP-4核苷酸的表达或DPP-4蛋白的表达或活性。
在本发明中,抑制所述DPP-4核苷酸的表达可以是相对于DPP-4的mRNA的反义核苷酸、App Tamer、小干扰RNA(siRNA)、短发夹RNA(shRNA)、微RNA(miRNA)和RNA干扰(RNAi)组成的群中选择的一个或两个以上,但不限于此。
抑制所述DPP-4蛋白的表达或活性是与DPP-4特异性结合的抗体,可以是肽、胃蛋白酶、App Tamer、化合物或天然物,所述化合物可以是由西他列汀(sitagliptin)、阿格列汀(alogliptin)、阿拉格列汀(anagliptin)、杜拓格利普汀(Dutogliptin)、依格列汀(Evogliptin)、戈索格列汀(gosogliptin)、吉格列汀(gemigliptin)、利拉利汀(linagliptin)、奥格列汀(omarigliptin)、沙格列汀(saxagliptin)、特力利汀(teneligliptin)、曲格列汀(trelagliptin)、维达列汀(vildagliptin)、黄连素(berberine)、抑二肽素(diprotin)、羽扇豆醇(lupeol)组成的群中一个或两个以上,优选西他格列汀、阿格列汀、依格列汀、吉格列汀、利拉利汀、沙格列汀、特力列汀或维达列汀,最优选的可以是西他列汀,但不限于此。
所述秋水仙碱或DPP-4抑制剂化合物可以在药学上可接受的盐的任意形式下使用,只要是在与其具有同等功效的范围内。
本说明书中,“药学上可接受”是指对暴露在所述组合物中的细胞或人类无毒,并且具有适合人类服用的安全性和有效性的盐。
所述盐可以用药学上可接受的碱性盐或酸性盐中的任何一种形式使用。碱性盐可以在有机碱盐、无机碱盐中的任何一种形态下使用,可以从钠盐、钾盐、钙盐、锂盐、镁盐、铯盐、氨基盐、铵盐、三乙胺盐和吡啶盐组成的群中选择。
酸性盐是由游离酸(free acid)形成的酸附加盐有用。游离酸可以使用无机酸和有机酸,无机酸可使用盐酸、溴酸、硫酸、亚硫酸、磷酸、双磷酸、硝酸等,有机酸可使用枸橼酸、醋酸、顺丁烯二酸、苹果酸、浮石酸、葡萄糖酸、甲磺酸、苯磺酸、樟脑磺酸、草酸、丙二酸、戊二酸、乙酸、葡糖酸、丁二酸、酒石酸、4-甲苯磺酸、半乳糖醛酸、琥珀酸、谷氨酸、柠檬酸、天冬氨酸碳酸、硬脂酸等,但并不限于此,用该行业中常规使用的各种无机酸和有机酸形成的盐都可以包括在内。
此外,所述化合物不仅包括所述盐,还可以包括通过常规方法制备的所有盐、水合物、溶剂、衍生物等。附加盐可以用常规方法制备,也可以溶于丙酮、甲醇、乙醇或乙酰唑等有机溶剂-水混合溶剂,加入过量的有机碱或无机碱的碱水溶液,然后沉淀或结晶制备而成。也可以在该混合物中蒸发溶剂或过量的碱,使其干燥后获得附加盐,也可以将析出的盐抽吸和过滤进行制备。
在本发明中,所述组合物所含有的秋水仙碱和DPP-4抑制剂的重量比为1:(100到10000),优选1:(100至6000),更优选的重量比为1:(200至3000),但不限于此。
例如,以西他列汀为例,所述组合物含有的秋水仙碱和西他列汀的重量比为1:(100到3000),优先为1:(250至2000),更优选的重量比为1:(500至1500),但不限于此。
在本发明中,所述组合物可含有所述秋水仙碱0.01至300μg/kg,所述DPP-4抑制剂可能含有0.01至300mg/kg;优选的是,所述秋水仙碱可含有10至100μg/kg,所述DPP-4抑制剂可含有5至120mg/kg,但不限于此。
例如,以西他列汀为例,所述组合物可含有所述秋水仙碱10至100μg/kg,可含有所述西他列汀5至120mg/kg,优选含有所述秋水仙碱可为20至80μg/kg,所述西他列汀可为10至80mg/kg,更优选的是含有的所述秋水仙碱可为30至50μg/kg,所述西他列汀可为20至50mg/kg,但不限于此。
当所述秋水仙碱或DPP-4抑制剂的含量低于所述范围时,其功效几乎无法发挥;当其含量超过所述范围时,服用时可能会引起肠胃障碍等副作用,因此所述范围是理想的。
特别地,根据本发明的一个实验例,当所述秋水仙碱为40μg/kg、所述的西他列汀为20mg/kg时,可以确认对肝纤维化、脂肪堆积或炎症的抑制有着最显著的效果。
在本发明中,所述组合物可以抑制肝细胞或肝组织的纤维化、脂肪堆积或炎症等。
根据本发明的一个实验例,所述组合物显著降低了小鼠肝细胞AML12中TGF-β1(转化生长因子β1,transforming growth factor beta 1)诱导的I型胶原蛋白的表达,显著降低了由棕榈酸酯(palmitate)诱导的SREBP1(甾醇调节元件结合转录因子1,Sterolregulatory element-binding transcription factor 1)或IL-1β(白细胞介素1β,interleukin 1beta)的表达。
特别是,所述秋水仙碱与所述DPP-4抑制剂中的西他列汀并用处理时,根据本发明的一个实验例,所述组合物在小鼠肝细胞AML12中由TGF-β1诱导的I型胶原蛋白的表达降低与其他DPP-4抑制剂并用处理时相比更为显著,高脂肪饮食诱导的NASH大鼠模型中纤维化相关因子TGF-β1,可以确定其显著降低了I型胶原蛋白(collagen I)、α-平滑肌动素(α-smooth muscle actin,α-SMA)的表达,并且显著抑制了胶原蛋白指标羟脯氨酸(hydroxyproline)的积累。
此外,还可以确认小鼠肝细胞AML12中棕榈酸酯诱导的SREBP1和IL-1β的表达比与其他DPP-4抑制剂并用处理显著降低,高脂膳食诱导的NASH大鼠模型中脂肪堆积相关因子SREBP1、甘油二酯酰基转移酶(Dgat,Diglyceride acyltransferase)、载脂蛋白A1(ApoA1,Apolipoprotein A1)的表达以及胆固醇和中性脂肪的数值也显著降低,还可以确认炎症相关因子肿瘤坏死因子-α(TNF-α,tumor necrosis factor-α)、IL-1β、白细胞介素6(IL-6,interleukin 6)的表达也显著降低。
在本发明中,所述组合物可减少由胆红素(bilirubin)、丙氨酸转氨酶(alarnineaminotransferase,ALT)和天冬氨酸转氨酶(aspartate aminotransferase,AST)组成的群组中选择的一个或两个以上肝细胞损伤因子。
另外,所述组合物可以减少活性氧簇(reactive oxygen species,ROS)的生成。
所述组合物可以作为预防或治疗肝病的药学组合物,以达到这种效果。将通过后面的实验例做进一步阐述。
在本发明中,所述肝病可以是由肝纤维化、肝硬化、肝癌及炎症性肝病组成的群体中选择的一种或两种以上疾病,但不限于此,可以包括本行业广为知晓的所有相关疾病。
在本说明书中,“炎症性肝病”一般称为肝炎,是指由肝细胞及肝组织炎症引起的所有疾病。
所述炎症性肝病可能是由肝炎、急性肝炎、慢性肝炎、酒精性肝炎、非酒精性脂肪肝炎、亚急性肝炎、病毒性肝炎、毒性肝病、肝脓肿、肉芽肿性肝炎、自身免疫性肝炎和狼疮样肝炎组成的群中选择的一种或两种以上,优选的是非酒精性脂肪肝炎,但不限于此,可以包括本行业广为知晓的所有相关疾病。
此外,本发明还提供了一种用于预防或治疗肝病的联合用药的药学组合物,其中含有秋水仙碱(colchicine)和DPP-4(dipeptidyl peptidase-4)抑制剂作为有效成分。
根据本发明的一个实验例,在所述秋水仙素及DPP-4抑制剂联合用药处理时,肝细胞或肝组织的纤维化、脂肪堆积、炎症等肝损伤受到更显著的抑制,从而进一步提高肝病的预防或治疗效果。
与此相应的特征可以在所述部分替换。
本发明涉及的药学组合物可以按照药学领域的常规方法制备。所述药学组合物可根据剂型与药学上允许的合适的载体配合,并可以根据需要加入赋形剂、稀释剂、分散剂、乳化剂、缓冲剂、稳定剂、结合剂、崩解剂、溶剂等进行制备。所述合适的载体不降低本发明涉及的秋水仙碱或DPP-4抑制剂,或其药学上可接受的盐的活性和特性,可根据给药形式和剂型进行不同的选择。
所述药学组合物中可能包含的载体,用作赋形剂、稀释剂等的有乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、海藻酸钠、明胶、磷酸钙、硅酸钙、纤维素、纤维素甲醚、微晶质纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、苯甲酸羟基酯、滑石、硬脂酸镁、矿物油等。当所述组合物制成制剂时,可以使用常规使用的填充剂、增量剂、结合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂进行制备。
本发明涉及的药学组合物可适用于任何剂型,具体来说可以根据常规方法制备为散剂、冲剂、片剂、胶囊剂、悬浮液、乳液、糖浆、气溶胶等口服剂型以及外用剂、栓剂和注射液等剂型使用,优选配制为适合口服的单位剂型服用。
具体来说,所述口服剂型中的固体剂型有片剂、丸剂、散剂、冲剂、胶囊等形式,至少与一种以上赋形剂混合制备,例如淀粉、碳酸钙(calcium carbonate)、蔗糖、乳糖、山梨醇、甘露醇、纤维素、明胶等。除单纯的赋形剂以外,还可包括硬脂酸镁、滑石等润滑剂。另外,当剂型为胶囊时,除所述提到的物质外,还可以包括脂肪油等液体载体。
所述口服剂型中的液体剂型包括悬浮剂、内用液剂、乳剂、糖浆等,除了常用的纯稀释剂水、液体石蜡外,还可以包括各种赋形剂,如润湿剂、甜味剂、芳香剂、保水剂等。
所述非口服剂型可以包括灭菌水溶液、非水性溶剂、悬浮剂、乳剂、注射剂、冷冻干燥制剂、栓剂等。非水性溶剂、悬浮剂可以是丙二醇(propylene glycol)、聚乙二醇、橄榄油等植物油,乙烯油酸等可注射的酯等。栓剂的基质可以使用合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)61、可可籽脂、月桂碱酯、甘油醇明胶等。但不限于此,可以使用本行业内广为人知的所有合适的制剂。
此外,本发明涉及的药学组合物可以进一步添加抗氧化剂,以增进疗效。所述抗氧化剂可使用硫胺(thiamin,维生素B1)、核黄素(riboflavin,维生素B2)、烟酸(niacin,维生素B3)、泛酸(pantothenic acid,维生素B5)、吡哆醇(pyridoxine,维生素B6)、钴胺素(Cobalamin,维生素B12)等维生素B群的化合物以及维生素C、维生素D、维生素E等,但并不限于此,本行业广为人知的合适的制剂都可以使用。
本发明涉及的药学组合物可以用药学上有效的量给药。
在本说明书中,“药学上有效的量”是指适用于医学治疗的合理的受益率/风险率、足以治疗疾病且不会引起副作用的量。
所述药学成分的有效容量水平可以根据使用目的、患者的年龄、性别、体重和健康状况、疾病类型、重症率、药物的活性、对药物的敏感度、给药方法、给药时间、给药途径和排出率、治疗时间、配方或同时使用的药物等因素和其他医学领域熟知的因素而做出不同的决定。例如,虽然不一定,但一般为0.001至100mg/kg,优选每天可一次或多次给药0.01至10mg/kg。所述给药剂量并不以任何方式对本发明的范围进行限制。
本发明涉及的药学组合物可以用到任何可能发生肝病的动物身上,所述动物不仅可以包括人类和灵长类动物,还可包括牛、猪、马、狗等家畜。
所述药学组合物可以根据制剂形态通过适当的给药途径给药,只要能到达目的组织,就可以通过口服或非口服的多种途径给药。给药方法不需特别限定,可采用口服、直肠或静脉、肌肉、皮肤涂抹、呼吸道吸入、子宫内硬膜或脑血管内(intracerebroventricular)注射等常规方法给药。
本发明涉及的药学组合物可以单独用于肝病的预防或治疗,也可以与手术或其他药物治疗等联合使用。
此外,本发明还为需要肝病治疗的个体提供了用于预防或治疗肝病的联合用药方法,其中包括处理秋水仙碱(colchicine)和DPP-4(dipeptidyl peptidase-4)抑制剂的步骤。
所述个体可以是除人类以外的任何动物。
所述秋水仙碱和DPP-4抑制剂可以同时(simultaneous)、分别(separate)或依次(sequential)处理,以预防或治疗肝病。
与其相应的特征可以在所述部分替换。
以下,为了帮助理解本发明,决定举例进行详细说明。但是,以下实施例只是举例说明本发明的内容,本发明的范围并不仅限于实施例。本发明的实施例是为在业内拥有基本知识的人提供的,用以更完整地对本发明进行说明。
<实验例1>
<实验方法>
1.实验材料
AML12细胞(CRL-2254)购自美国模式培养物保藏所(ATCC)。秋水仙碱(C9754)、棕榈酸钠(Sodium palmitate;P9767)、超氧化物阴离子荧光探针(dihydroethidium,DHE;D7008)购自西格玛奥德里奇公司。阿洛格列汀(品牌名:Nesina)购自韩国武田制药,依格列汀(品牌名:Suganon)购自东亚ST公司,吉格列汀(品牌名:Zemiglo)购自LG生命科学,沙格列汀(品牌名:Onglyza)购自百时美施贵宝公司,西他列汀(品牌名:Januvia)购自默克制药,特力列汀(品牌名:Ziten)购自格伦马克制药公司,维达列汀(品牌名:Galvus)购自诺华制药。
2.细胞培养和药物处理
小鼠肝细胞-AML12细胞在37℃、95%的空气和5%的C02环境下,在包含5μg/ml的胰岛素(insulin)、5μg/ml的转铁蛋白(transferrin)、5ng/ml的硒(selenium)、40ng/ml的地塞米松(dexamethasone)、10%的胎牛血清(fetal bovine serum,FBS)以及1%的青霉素(penicillin)/链霉素(streptomycin)的DMEM/F12培养液中培养。经5nM的秋水仙碱(colchicine)和30μg/ml二肽基肽酶-4(dipeptidyl peptidase-4,DPP-4)抑制剂预处理的AML12细胞在8小时后进行TGF-β1(5ng/ml)或棕榈酸盐(palmitate)0.2mM处理,再培养16小时。
3.动物实验
每个群组分8只C57BL/6J雄性大鼠,使它们稳定7天后,进行6周的正常饮食(ND)或高脂饮食(HFD)。之后,每日一次口服给药秋水仙素40μg/kg或西他列汀(sitagliptin)5、10、20mg/kg,再进行24周正常饮食或高脂饮食。共30周后,用异氟醚(isoflurane)吸入麻醉后,利用大鼠心脏采血法获取血液后,将3,000rpm转速、4℃的温度离心分离15分钟后获取的血清用于血液生化检查。此外,利用肝组织进行了羟基脯氨酸(hydroxyproline)分析、超氧化物(superoxide)生成分析、mRNA表达分析及H&E染色法。
4.胆红素(Bilirubin)分析法
利用胆红素测定试剂盒(Bilirubin assay kit)(细胞性生物多分子实验室公司)测定了大鼠的胆红素。将准备好的血清在96孔板非每个孔中分装50μl,并添加了50μl的50%二甲亚砜(dimethyl sulfoxide,DMSO)。然后,分别添加了125μl的反应混合物(reaction mix),在常温下使其反应30分钟。在添加75μl的总胆红素探针(totalbilirubin probe)后,遮光并在常温下进一步反应20分钟,用全自动定量绘图酶标仪(microplate reader)测定600nm的吸光度。
5.AST酶活性分析法
用AST的活性分析工具包(AST activity assay kit,Abcam公司)测定了大鼠的天冬氨酸转氨酸(aspartate aminotransferase,AST)活性。将准备好的血清在96孔板的每个孔中中分装50μl,并添加了150μL反应试剂(Reaction Reagent),在遮光状态下,并在37℃的温度下进一步反应60分钟,利用全自动定量绘图酶标仪测定450nm的吸光度。
6.ALT酶活性分析法
用Alt活性测定试剂盒(Alt Activity Assay Kit)(西格玛奥德里奇公司)测定了大鼠的丙氨酸转氨酶(alarnine aminotransferase,ALT)活性。将准备好的血清在96孔板的每个孔中分装50μl,并添加了100μl的反应试剂,在遮光状态下并在37℃的温度下进一步反应60分钟,利用全自动定量绘图酶标仪测定570nm的吸光度。
7.胆固醇(cholesterol)分析法
用总胆固醇测定试剂盒(Total cholesterol assay kit,细胞性生物多分子实验室公司)测定了大鼠的总胆固醇量。将老鼠血清在1倍测定稀释溶液中以1:100的比例稀释,在96孔板的每个孔中分装50μl。然后,添加50μl胆固醇反应试剂,并在37℃的温度下将遮光反应45分钟。反应结束的样品利用全自动定量绘图酶标仪设备测定540-570nm的吸光度。
8.甘油三酯(Triglyceride)分析法
用EZ-甘油三酯定量测定试剂盒(EZ-Trigly Ceride quantification AssayKit,多根生物技术公司)测定了大鼠的中性脂肪数值。在大鼠的血清样本中加入了1毫升的5%NP-40,在冰中均质化,然后在室温下充分冷却。再次加热溶解所有甘油三酯后将该样品在13,000rpm转速下离心分离2分钟后,去除不溶物质,分析前样品用蒸馏水稀释10倍。在96孔板的每个孔中分装90μl,在该样品中添加2μl的脂肪酶(lipase),并使其在室温下反应20分钟,然后分别加入50μl反应混合物,在遮光的室温下进一步反应30分钟。然后,使用全自动定量绘图酶标仪设备测定570nm的吸光度。
9.苏木精(Hematoxylin)和曙红(EOSIN)(H&E)染色法
为了进行H&E染色,脱石蜡的组织用50%苏木精(Hematoxylin)在常温下反应20分钟,在1%HCl中反应1秒后,直接转移到0.5%的曙红溶液(EOSIN)中染色20分钟。然后,组织被蒸馏水冲洗,并用各浓度的酒精进行反应,最后用二甲苯脱水。脱了水的组织用封片(permount)固定在盖玻片(coverslip)上。
10.羟脯氨酸(Hydroxyproline)分析法
将100毫克的肝组织与生理盐水均质化,然后分离出肝组织上层液。在分离的上层液中加入等量的12N HCl,在120℃下水解3个小时。冷却的样品经过电压(voltexing)后,在10,000g下离心分离3分钟并使用羟脯氨酸测定试剂盒(hydroxyproline assay kit),最后用全自动定量绘图酶标仪测定550nm的吸光度。
11.定量PCR(Quantitative PCR)法
整个RNA用RNeasy迷你套件(RNeasy mini kit,德国快而精公司)提取,然后用高容量cDNA逆转录试剂盒(High-Capacity cDNA Reverse Transcription Kit,赛默飞世尔公司)合成为cDNA。等量的cDNA利用嵌合荧光法(SYBRTM green PCR master mix)以及各基因分别对应的10pM引物组得到扩增。扩增过程在95℃的温度下进行5分钟的初始变性过程,95℃下10秒、58.5℃下10秒、72℃下10秒,共反复复制了40次。
12.超氧化物(Superoxide)分析法
为了测定小鼠肝组织内的超氧化物(superoxide)生成,使用了超氧化物荧光指标二氢乙酸钠(dihydroethidium,DHE)。综上所述,脱石蜡的肝组织滑片在遮光且调好湿度的腔室内与10μMDHE一起在37℃的温度下反应了30分钟。反应后,体现DHE的荧光在OlympusFV1000荧光显微镜下通过580nm波长的过滤器进行了测量。
<实验结果>
1.确认秋水仙碱和DPP-4抑制剂联合用药处理对肝细胞中纤维化的抑制作用
图1是根据本发明的一个实验例观察纤维化诱导的小鼠肝细胞中I型胶原蛋白(Collagen I)的表达变化的结果,参照该结果,确认了小鼠肝细胞AML12中TGF-β1增加的I型胶原蛋白表达因为秋水仙碱的单独处理而减少。
此外,为了了解秋水仙碱和DPP-4抑制剂的联合用药效果,使用了多种DPP-4抑制剂[(阿洛格列汀(Alogliptin)、依格列汀(Evogliptin)、吉格列汀(Gemigliptin)]、利格列汀(Linagliptin)、沙格列汀(Saxagliptin)、西他列汀(Sitagliptin)、特力列汀(Teneligliptin)、维达列汀(Vildagliptin)]与秋水仙碱一起处理试剂,从结果可以确认除了阿洛格列汀、沙格列汀以外的其他DPP-4抑制剂与秋水仙素一起,在抑制I型胶原蛋白表达时出现了一些相加作用,其中西他列汀与秋水仙碱抑制纤维化的相加作用尤为突出。
2.确认秋水仙碱和DPP-4抑制剂联合用药处理对肝细胞脂肪堆积的抑制效果
图2是根据本发明的一个实验例观察脂肪堆积诱导的小鼠肝细胞中SREBP1的表达变化,参照该变化,确认了在小鼠肝细胞AML12中由棕榈酸酯(palmitate)诱导的脂肪堆积指标SREBP 1(STEROL regulatory Element-binding traing)的表达因为秋水仙碱单独处理而降低。
此外,为了了解秋水仙碱和DPP-4抑制剂的联合用药效果,将多种DPP-4抑制剂与秋水仙碱一起进行试剂处理,从结果可以确认,除了利格列汀、阿洛格列汀和特力列汀之外,其余DPP-4抑制剂与秋水仙碱一起抑制SREBP1的表达方面还会出现一些相加作用,其中西他列汀的和秋水仙碱抑制SREBP1表达的作用尤为突出。
3.确认秋水仙碱和DPP-4抑制剂联合处理对肝细胞抗炎的效果
图3根据本发明的一个实验例观察炎症诱导的小鼠肝细胞中IL-1β的表达变化,参照此结果,确认了小鼠肝细胞AML12中由棕榈酸酯诱导的炎症指标IL-1β(Interleukin1beta)的表达因为秋水仙碱的单独处理而降低。
此外,为了了解秋水仙碱和DPP-4抑制剂的联合用药效果,将多种DPP-4抑制剂与秋水仙碱一起进行试剂处理后,确认所有DPP-4抑制剂与秋水仙碱一起在抑制IL-1β表达方面还存在一定的相加作用,其中西他列汀和秋水仙碱抑制IL-1β表达的作用尤为突出。
4.确认秋水仙碱或西他力挺联合用药对肝组织脂肪堆积的抑制效果
图4是本发明的一个实验例中,通过苏木精(Hematoxylin)和曙红(EOSIN)(H&E)染色法对非酒精性脂肪肝炎(NASH)诱导模型大鼠肝组织的变化进行解剖学观察,参照此结果,可以确认通过30周的高脂饮食方式诱导的肝组织脂肪堆积通过秋水仙碱单独用药略有减少。另外还可以确认,通过与不同浓度西他列汀的联合用药,秋水仙碱的减脂效果与西他列汀一同呈现了相加作用。
5.确认秋水仙碱或西他列汀联合用药对肝组织的胶原蛋白抑制效果
图5是在本发明一个实验例中,观察NASH诱导模型大鼠肝组织中羟脯氨酸(hydroxyproline)的变化,参照该结果,可以确认30周高脂饮食诱导的胶原蛋白指标羟脯氨酸(hydroxyproline)的堆积通过秋水仙素的单独用药而减少。此外还可以确认,通过与不同浓度的西他格列汀的联合用药,秋水仙素的羟脯氨酸的的抑制效果与西他列汀一同呈现了相加作用。
6.确认秋水仙碱或西他列汀联合用药对肝组织纤维化的抑制效果
图6是通过本发明的一个实验例观察NASH诱导模型大鼠肝组织纤维化相关基因的表达变化,参照这一结果,可以确认30周内由高脂饮食诱导的纤维化指标基因TGF-β1、I型胶原蛋白(collagen I)、α-SMA(α-Smooth Muscluscluse)的表达通过秋水仙碱的单独用药而减少。另外,可以确认通过与不同浓度的西他列汀联合用药,秋水仙碱的纤维化相关基因表达的减少效果与西他列汀一同呈现相加作用。
7.确认秋水仙碱或西他列汀联合给药处理对肝组织的抗炎效果
图7是根据本发明的一个实验例观察NASH诱导模型大鼠肝组织炎症相关基因的表达变化的结果,参照该结果,可以确认30周高脂方式诱导的炎症指标基因TNF-α、IL-1β、IL-6的表达因秋水仙碱的单独用药而减少。另外,可以确认通过与不同浓度的西他列汀联合用药,秋水仙碱的炎症相关基因表达减少效果与西他列汀一同呈现相加作用。
8.确认秋水仙碱或西他列汀联合给药处理对肝组织的脂肪堆积抑制效果
图8是根据本发明的一个实验例观察NASH诱导模型大鼠肝组织脂肪堆积相关基因的表达变化,参照这一结果,可以确认30周高脂饮食诱导的脂肪堆积指标基因SREBP1、二脂酰甘油脂酰基转移酶(DGAT,Diglyceride Acyltransferase)、APOA 1(APOLIPIPE)的表达因秋水仙碱的单独给药而减少。另外,可以确认通过与不同浓度的西他列汀联合用药,秋水仙素的脂肪堆积相关基因表达减少效果与西他列汀一同呈现相加作用。
9.确认秋水仙碱或西他列汀联合给药处理对肝组织的活性氧抑制效果
图9根据本发明的一个实验例观察NASH诱导模型大鼠肝组织中的超氧化物(superoxide)生成变化,参照该结果,可以确认30周高脂饮食诱导的活性氧指标“超氧化物生成”因秋水仙碱单独给药而减少。另外,可以确认通过与不同浓度的西他列汀联合用药,秋水仙碱的超氧化物生成减少效果与西他列汀一起呈现相加作用。
10.确认秋水仙碱或西他列汀联合给药处理后的血液生化变化
表1是根据本发明的一个实验例,对NASH诱导模型大鼠的血清进行血液生化检查的结果,可以确认30周高脂肪饮食的大鼠的血清中肝细胞损伤指标—胆红素(Bilirubin)、丙氨酸氨基转移酶(alarnine aminotransferase,ALT)、天冬氨酸氨基(aspartateaminotransferase,AST)和脂肪堆积指标胆固醇、甘油三酯(Triglyceride)大幅度提高,秋水仙碱单独给药后增加的数值减少。另外,不同浓度的西他列汀与秋水仙碱联合用药时,可以看到与秋水仙碱的单独用药效果相比,不同浓度下的相加作用进一步减少。
<表1>
以上对本发明内容的特定部分进行了详细阐述,对具有业界常规知识的人来说,这些具体技术只是优选的实施方式,因此,本发明的范围并不受限制,这一点是显而易见的。也就是说,本发明的实际范围由所附权利要求和其同等物定义。
Claims (9)
1.一种用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,含有秋水仙碱和DPP-4抑制剂作为有效成分,所述DPP-4抑制剂选自由西他列汀、阿格列汀、阿拉格列汀、杜拓格利普汀、依格列汀、戈索格列汀、吉格列汀、利拉利汀、奥格列汀、沙格列汀、特力利汀、曲格列汀、维达列汀、黄连素、抑二肽素、羽扇豆醇组成的群组中的一个或两个以上。
2.根据权利要求1所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物所含有的秋水仙碱和DPP-4抑制剂的重量比为1:(100至10000)。
3.根据权利要求1所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物所含有的秋水仙碱为0.01至300μg/kg,DPP-4抑制剂为0.01至300mg/kg。
4.根据权利要求1所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物抑制肝细胞或肝组织的纤维化、脂肪堆积或炎症。
5.根据权利要求1所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物使得由胆红素、丙氨酸氨基转移酶和天冬氨酸氨基转移酶组成的群组中的一个或两个以上的肝细胞损伤因子减少。
6.根据权利要求1至权利要求5中的任意一项所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,将所述组合物制备为选自由散剂、冲剂、片剂、胶囊剂、悬浮液、乳液、糖浆、气溶胶、外用剂、栓剂和注射液等组成的群组中的一种或两种以上剂型。
7.根据权利要求1至权利要求5中的任意一项所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物进一步包含选自由乳糖、葡萄糖、蔗糖、山梨醇、甘露醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、海藻酸钠、明胶、磷酸钙、硅酸钙、纤维素、纤维素甲醚、微晶质纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、苯甲酸羟基酯、滑石和硬脂酸镁组成的群组中的一种或两种以上成分。
8.根据权利要求1至权利要求5中的任意一项所述的用于治疗非酒精性脂肪肝炎的药学组合物,其特征在于,所述组合物包含选自由硫胺、核黄素、烟酸、泛酸、吡哆醇、钴胺素、维生素C、维生素D、维生素E组成的群组中的一种或两种以上成分。
9.一种用于治疗非酒精性脂肪肝炎的联合给药的药学组合物,其特征在于,含有秋水仙碱和DPP-4抑制剂作为有效成分,所述DPP-4抑制剂选自由西他列汀、阿格列汀、阿拉格列汀、杜拓格利普汀、依格列汀、戈索格列汀、吉格列汀、利拉利汀、奥格列汀、沙格列汀、特力利汀、曲格列汀、维达列汀、黄连素、抑二肽素、羽扇豆醇组成的群组中的一个或两个以上。
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