CN116747226A - 黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用 - Google Patents
黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用 Download PDFInfo
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- RBBVPNQTBKHOEQ-KKSFZXQISA-O Phellodendrine Chemical compound C1CC2=CC(OC)=C(O)C=C2[C@H]2[N@+]1(C)CC(C=C(C(=C1)O)OC)=C1C2 RBBVPNQTBKHOEQ-KKSFZXQISA-O 0.000 title claims abstract description 48
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 title claims abstract description 32
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 20
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 10
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 10
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 10
- 239000000463 material Substances 0.000 claims description 6
- 239000000203 mixture Substances 0.000 claims description 6
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 6
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 6
- 235000012000 cholesterol Nutrition 0.000 claims description 5
- 230000007863 steatosis Effects 0.000 claims description 5
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 claims description 4
- 108010082126 Alanine transaminase Proteins 0.000 claims description 4
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- 102000004625 Aspartate Aminotransferases Human genes 0.000 claims description 4
- 206010067125 Liver injury Diseases 0.000 claims description 4
- 230000004761 fibrosis Effects 0.000 claims description 4
- 231100000753 hepatic injury Toxicity 0.000 claims description 4
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- 239000004480 active ingredient Substances 0.000 claims description 3
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- 239000003085 diluting agent Substances 0.000 claims description 3
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- 235000003599 food sweetener Nutrition 0.000 claims description 3
- 238000002347 injection Methods 0.000 claims description 3
- 239000007924 injection Substances 0.000 claims description 3
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- 235000020357 syrup Nutrition 0.000 claims description 3
- 235000013599 spices Nutrition 0.000 claims description 2
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 7
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- 230000005856 abnormality Effects 0.000 abstract description 4
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 abstract description 3
- 229930182817 methionine Natural products 0.000 abstract description 3
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- 210000002216 heart Anatomy 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
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- 210000004072 lung Anatomy 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 210000000952 spleen Anatomy 0.000 description 2
- 210000004003 subcutaneous fat Anatomy 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000011746 C57BL/6J (JAX™ mouse strain) Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101100154912 Mus musculus Tyrp1 gene Proteins 0.000 description 1
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- 239000003153 chemical reaction reagent Substances 0.000 description 1
- OEYIOHPDSNJKLS-UHFFFAOYSA-N choline Chemical compound C[N+](C)(C)CCO OEYIOHPDSNJKLS-UHFFFAOYSA-N 0.000 description 1
- 229960001231 choline Drugs 0.000 description 1
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- 230000005802 health problem Effects 0.000 description 1
- 231100000283 hepatitis Toxicity 0.000 description 1
- 206010073071 hepatocellular carcinoma Diseases 0.000 description 1
- 231100000844 hepatocellular carcinoma Toxicity 0.000 description 1
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- 201000007270 liver cancer Diseases 0.000 description 1
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- 235000021590 normal diet Nutrition 0.000 description 1
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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Abstract
本发明公开了黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用,所述黄柏碱具有改善非酒精性脂肪肝炎,降低血脂,改善肝纤维化的作用。本发明首次发现黄柏碱对蛋氨酸及胆碱缺乏饮食诱导的非酒精性脂肪肝炎的改善作用,为脂质代谢异常相关疾病的治疗提供了更多的选择。
Description
技术领域
本发明涉及医药的新应用,具体涉及黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用。
背景技术
非酒精性脂肪性肝病(Non-alcoholic fatty liver disease,NAFLD)是以肝内脂质堆积为特征,包含一系列组织学改变的疾病,主要有单纯性脂肪肝、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、肝纤维化、肝硬化和肝癌。研究表明,全球约25%的人群患有非酒精性脂肪肝病(NAFLD),这已成为不容忽视的健康问题。NAFLD被认为是一种从脂肪变性到肝脏炎症和纤维化的代谢疾病,约20%的患者会发展成为更严重的NASH,并可进一步发展为肝硬化和肝细胞癌,严重威胁人类健康。然而,目前还没有一种有效药物被批准用于治疗NASH。
黄柏碱(Phellodendrin),CAS号为6873-13-8,分子式为C20H24NO4+,分子量为342.41,化学结构式如下:
发明内容
发明目的:本发明的目的在于提供一种改善非酒精性脂肪肝炎,降低血脂,改善肝纤维化作用的黄柏碱在制备治疗和/或预防脂质代谢异常相关性疾病药物中的应用。
技术方案:黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用。
含有黄柏碱的组合物在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用。
所述组合物是以黄柏碱作为活性成分,加上药学上可接受的载体或辅料所制成的药物制剂。
所述药物制剂为片剂、胶囊、糖浆、悬浮剂或注射剂。
所述辅料为香料、甜味剂、液体/固体填料或稀释剂。
所述黄柏碱是从植物中提取或化学合成。
所述黄柏碱CAS号为6873-13-8。
黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎导致的肝脂肪变性、肝损伤及纤维化药物中的应用。
黄柏碱在制备降低非酒精性脂肪肝炎的胆固醇、甘油三酯、谷草转氨酶、谷丙转氨酶含量的药物中的应用。
黄柏碱在制备改善非酒精性脂肪肝炎导致的脂肪变性的药物中的应用。
发明人在对黄柏碱的药理活性研究中发现,黄柏碱能有效的降低蛋氨酸及胆碱缺乏饮食诱导的非酒精性脂肪肝炎小鼠血清和肝脏中胆固醇、甘油三酯的水平,改善肝纤维化。
黄柏碱在制备治疗和/或预防脂质代谢异常相关性疾病药物中的应用。
优选地,脂质代谢异常相关性疾病为非酒精性脂肪肝炎。
本发明的含有黄柏碱的组合物在制备治疗和/或预防脂质代谢异常相关性疾病药物中的应用。
进一步地,组合物是以黄柏碱作为活性成分,加上药学上可接受的载体或辅料所制成的药物制剂。药物制剂为片剂、胶囊、糖浆、悬浮剂或注射剂。辅料为香料、甜味剂、液体/固体填料或稀释剂。
有益效果:本发明与现有技术相比,具有如下优点:(1)黄柏碱可以有效改善非酒精性脂肪肝炎模型小鼠的肝脂肪变性、肝损伤、肝炎症及纤维化,并且降低了非酒精性脂肪肝炎模型小鼠血清和肝脏中中的胆固醇、甘油三酯、谷草转氨酶、谷丙转氨酶的含量。(2)黄柏碱和药物组合物应用广泛,针对其在动物体内的活性,有望开发成为治疗非酒精性脂肪肝炎的生物医药制剂。
附图说明
图1是小鼠体重的实验结果;
图2是血清中甘油三酸酯(TG)的实验结果;
图3是血清中总胆固醇(TC)的实验结果;
图4是血清中谷丙转氨酶(ALT)的实验结果;
图5是血清中谷草转氨酶(AST)的实验结果;
图6是肝脏中甘油三酸酯(TG)的实验结果;
图7是肝脏中总胆固醇(TC)的实验结果;
图8是小鼠肝脏的病理切片;
图9是小鼠棕色脂肪、附睾脂肪和皮下脂肪的病理切片;
图10是小鼠心、肌、脾、肺和肾的病理切片。
具体实施方式
下面结合实施例对本发明的技术方案作进一步说明。实施例中所述实验方法,如无特殊说明,均为常规方法;所述试剂和材料,如无特殊说明,均可从商业途径获得。实验所用黄柏碱购于成都普菲德对照品科技有限公司,CAS:6873-13-8。
实施例:黄柏碱对非酒精性脂肪肝炎的作用。
1、实验方法
正常组(Control):取8周大的C57BL/6J雄性小鼠,喂养普通饲料。4周后每天在同一时间通过灌胃,给药0.1%CMC-Na,持续4周,每周记录体重。
模型组(MCD):取8周大的C57BL/6J雄性小鼠,喂养MCD饮食(MCD,蛋氨酸及胆碱缺乏饲料)。4周后每天在同一时间通过灌胃,给药0.1%CMC-Na,持续4周,每周记录体重。
给药组:取8周大的C57BL/6J雄性小鼠,喂养MCD饮食。4周后每天在同一时间通过灌胃,黄柏碱低剂量给药(15mg/kg)组、高剂量给药组(30mg/kg),持续4周,每周记录体重。
2、实验结果
与正常饮食喂养的小鼠相比,MCD模型组的体重显著下降,降低了7.72g(图1)。另外,黄柏碱低、高剂量给药组小鼠的血清TG相比MCD模型组分别降低了0.43和0.50mM/L(图2)。与上述结果一致,黄柏碱低、高剂量给药组小鼠的血清TC相比MCD模型组分别降低了0.71和0.50mM/L(图3)。随后,对临床肝脏损伤的常用指标ALT和AST进一步检测发现,黄柏碱给药组的ALT和AST含量显著降低(图4-5)。此外,黄柏碱低、高剂量给药组小鼠的肝脏TG相比MCD模型组分别降低了49.91和61.35mM/gprot(图6)。黄柏碱低、高剂量给药组小鼠的肝脏TC相比MCD模型组分别降低了12.02和14.54mM/gprot(图7)。肝脏HE、天狼猩红病理切片染色显示,与MCD模型组小鼠相比,用化合物黄柏碱治疗的小鼠肝脏中脂肪变性得到改善,肝纤维化减弱(图8)。随后,组织学分析表明,化合物黄柏碱改善了小鼠棕色脂肪细胞组织(BAT)、附睾白色脂肪细胞组织(eWAT)和皮下脂肪组织(sWAT)的脂肪变性(图9)。而心、肌、脾、肺和肾的HE切片显示,化合物黄柏碱没有明显的毒副作用(图10)。
综上所述,化合物黄柏碱改善了C57BL/6J小鼠的MCD饮食诱导的非酒精性脂肪肝炎,并且具有优异的安全性。
Claims (10)
1.黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用。
2.含有黄柏碱的组合物在制备治疗和/或预防非酒精性脂肪肝炎药物中的应用。
3.根据权利要求2所述的应用,其特征在于:所述组合物是以黄柏碱作为活性成分,加上药学上可接受的载体或辅料所制成的药物制剂。
4.根据权利要求3所述的应用,其特征在于:所述药物制剂为片剂、胶囊、糖浆、悬浮剂或注射剂。
5.根据权利要求3所述的应用,其特征在于:所述辅料为香料、甜味剂、液体/固体填料或稀释剂。
6.根据权利要求1所述的应用,其特征在于:所述黄柏碱是从植物中提取或化学合成。
7.根据权利要求1所述的应用,其特征在于:所述黄柏碱CAS号为6873-13-8。
8.黄柏碱在制备治疗和/或预防非酒精性脂肪肝炎导致的肝脂肪变性、肝损伤及纤维化药物中的应用。
9.黄柏碱在制备降低非酒精性脂肪肝炎的胆固醇、甘油三酯、谷草转氨酶、谷丙转氨酶含量的药物中的应用。
10.黄柏碱在制备改善非酒精性脂肪肝炎导致的脂肪变性的药物中的应用。
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