WO2023115294A1 - 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用 - Google Patents

脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用 Download PDF

Info

Publication number
WO2023115294A1
WO2023115294A1 PCT/CN2021/139878 CN2021139878W WO2023115294A1 WO 2023115294 A1 WO2023115294 A1 WO 2023115294A1 CN 2021139878 W CN2021139878 W CN 2021139878W WO 2023115294 A1 WO2023115294 A1 WO 2023115294A1
Authority
WO
WIPO (PCT)
Prior art keywords
preparation
naoxintong
liver
alcoholic fatty
fatty liver
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2021/139878
Other languages
English (en)
French (fr)
Inventor
吴灏
张伟健
苏薇薇
王永刚
姚宏亮
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sun Yat Sen University
Original Assignee
Sun Yat Sen University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Sun Yat Sen University filed Critical Sun Yat Sen University
Publication of WO2023115294A1 publication Critical patent/WO2023115294A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/481—Astragalus (milkvetch)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/62—Leeches; Worms, e.g. cestodes, tapeworms, nematodes, roundworms, earth worms, ascarids, filarias, hookworms, trichinella or taenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/646—Arachnids, e.g. spiders, scorpions, ticks or mites
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/21—Amaranthaceae (Amaranth family), e.g. pigweed, rockwort or globe amaranth
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/232—Angelica
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/23—Apiaceae or Umbelliferae (Carrot family), e.g. dill, chervil, coriander or cumin
    • A61K36/236—Ligusticum (licorice-root)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/28—Asteraceae or Compositae (Aster or Sunflower family), e.g. chamomile, feverfew, yarrow or echinacea
    • A61K36/286—Carthamus (distaff thistle)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/324—Boswellia, e.g. frankincense
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/32—Burseraceae (Frankincense family)
    • A61K36/328—Commiphora, e.g. mecca myrrh or balm of Gilead
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/48—Fabaceae or Leguminosae (Pea or Legume family); Caesalpiniaceae; Mimosaceae; Papilionaceae
    • A61K36/486—Millettia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
    • A61K36/537—Salvia (sage)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/54—Lauraceae (Laurel family), e.g. cinnamon or sassafras
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/60—Moraceae (Mulberry family), e.g. breadfruit or fig
    • A61K36/605—Morus (mulberry)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/65—Paeoniaceae (Peony family), e.g. Chinese peony
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/71—Ranunculaceae (Buttercup family), e.g. larkspur, hepatica, hydrastis, columbine or goldenseal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/736—Prunus, e.g. plum, cherry, peach, apricot or almond
    • A—HUMAN NECESSITIES
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/04—Anorexiants; Antiobesity agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics

Definitions

  • the invention relates to a new medicine application of Naoxintong preparation, especially the application in preparing medicine for treating non-alcoholic fatty liver.
  • Non-alcoholic fatty liver disease refers to the clinical chronic liver disease caused by excluding alcohol and other liver damage factors, with excessive fat deposition in liver cells as the key pathological feature, including simple fatty liver , nonalcoholic steatohepatitis, liver fibrosis, cirrhosis, and hepatocellular carcinoma.
  • NAFLD Non-alcoholic Fatty Liver Disease
  • the global incidence of NAFLD is as high as 18-30%, and the risk of complications such as cardiovascular and cerebrovascular diseases and type 2 diabetes is increasing year by year, which seriously threatens human health.
  • the pathogenesis of NAFLD is complex and there are multiple pathogenic factors, which have a serious impact on the quality of life and life expectancy of patients.
  • Naoxintong preparation is developed on the basis of the ancient prescription Buyang Huanwu Decoction by adding insect medicine.
  • the compound Chinese patent medicine preparation composed of 16 medicinal materials such as blood vine, cow vine, cinnamon twig, mulberry branch, earthworm, scorpion and leech has the effects of nourishing qi, activating blood circulation, removing blood stasis and dredging collaterals.
  • various cardiovascular and cerebrovascular diseases such as stroke and coronary heart disease, mainly through anticoagulation and thrombolysis, protection of vascular endothelium, stabilization and regression of atherosclerosis, protection of nerve cells, and prevention of ischemic regeneration. It plays a therapeutic role in perfusion injury and other aspects.
  • the capsules of Naoxintong preparations have been on the market since 1993, and the clinical efficacy has been remarkable, bringing great social and economic benefits.
  • the purpose of the present invention is to disclose a new medicinal application of Naoxintong preparation, in particular to the application of Naoxintong preparation in the treatment of non-alcoholic fatty liver.
  • Naoxintong preparation in preparation of medicine for reducing serum low-density lipoprotein level in non-alcoholic fatty liver diseased body.
  • Naoxintong preparation can significantly reduce the body weight, liver weight/body mass index, and liver lipid deposition of nonalcoholic fatty liver model animals, and significantly improve liver function indicators, including aspartate aminotransferase (AST), alanine aminotransferase (ALT ), while significantly reducing the levels of serum triglyceride (TG), cholesterol (TC) and low-density lipoprotein (LDL-C) in the body, which has a significant effect on the treatment of non-alcoholic fatty liver. Further expand the medicinal scope of Naoxintong preparation.
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • TG serum triglyceride
  • TC cholesterol
  • LDL-C low-density lipoprotein
  • Figure 1 is H&E staining and Oil Red O staining of mouse liver in each group
  • Figure 2 is a histogram of the statistical results of the lipid droplet area percentage of the liver oil red O staining quantification results of mice in each group;
  • Fig. 3 is the bar graph of the experimental results of the serum aspartate aminotransferase (AST) content of APOE -/- mice fed with high fat in the embodiment of the present invention
  • Fig. 4 is the bar graph of the experimental results of APOE -/- mice serum alanine aminotransferase (ALT) content in the embodiment of the present invention
  • Fig. 5 is a broken line graph of the experimental results of the body weight of APOE -/- mice fed with high fat in the embodiment of the present invention
  • Fig. 6 is a histogram of experimental results of liver/body mass index of APOE -/- mice fed high-fat diet according to the embodiment of the present invention.
  • Fig. 7 is the histogram of the experimental results of serum triglyceride (TG) content in APOE -/- mice fed with high fat in the embodiment of the present invention
  • Fig. 8 is a histogram of the experimental results of the serum cholesterol (TC) content of APOE -/- mice fed with high fat in the embodiment of the present invention
  • Fig. 9 is a bar graph of the experimental results of the serum low-density lipoprotein (LDL-C) content of APOE -/- mice fed high-fat diet according to the embodiment of the present invention.
  • LDL-C serum low-density lipoprotein
  • APOE -/- mice are given high-fat feed for 24 weeks to establish a non-alcoholic fatty liver animal model, and the curative effect is verified by intragastric administration of Naoxintong capsules.
  • Fatty liver induced by high-fat diet is recognized as one of the classic models of NAFLD. Rodents fed high-fat diet for a long time will naturally develop hepatic steatosis.
  • APOE -/- mice are prepared by homologous recombination technology. Mice with homozygous deletion of exon 3, fed with high-fat diet can show more severe symptoms of hyperlipidemia and fat accumulation in organs than ordinary rodents.
  • the APOE -/- mice were randomly divided into 3 groups, namely the model control group, the atorvastatin group (10mg/kg), the Naoxintong capsule group (624mg/kg), Fifteen rats in each group were fed with high-fat feed and gavaged with corresponding drugs every day.
  • C57BL/6J mice were given normal diet every day as the blank control group, and the same volume of normal saline was given by intragastric administration.
  • liver tissues of the mice in each group were taken out, and the wet weight of the liver was weighed. Part of the liver tissues were soaked in 4% paramethanol for fixation, and paraffin sections were made for hematoxylin-eosin staining ( Hematoxylin-eosin, HE) staining, observed under a light microscope. Some liver tissues were directly embedded in OCT, and frozen sections were made for Oil Red O staining.
  • HE staining and Oil red O staining were performed on the liver of experimental mice to observe the changes in liver morphology and lipid deposition. It can be seen from Figure 1 that the results of HE staining showed that the hepatic cord structure of the mice in the normal control group was clear, the hepatocytes were closely arranged, and no obvious fatty degeneration, necrosis, inflammation and other pathological changes were seen in the tissue.
  • Severe fatty degeneration of hepatocytes was widely seen in the model control group mice, the cells were swollen, and the cytoplasm was filled with round vacuoles (black arrows), multiple small focal infiltrations of inflammatory cells were seen in the lobules (red arrows), and oval cells hyperplasia in the portal area (yellow arrow).
  • the degree of ballooning degeneration of liver cells, the area of fatty degeneration and the degree of inflammation were significantly reduced.
  • the oil red O staining results showed that compared with the blank group, the positive area of red lipid droplets in the liver cells of high-fat-fed mice was significantly increased, and the percentage of lipid droplet area was significantly increased, indicating that the model group was small.
  • the lipid deposition in the liver of the mice was significantly aggravated, while the red positive area of lipid droplets in liver cells in the Naoxintong Capsules administration group was significantly reduced, and the percentage of lipid droplet area was significantly reduced (see Figure 2), indicating that Naoxintong Capsules significantly inhibited liver lipid deposition .
  • the results of the above pathological sections all indicated that Naoxintong Capsules had a significant protective effect on the damage of non-alcoholic fatty liver.
  • ALT Alanine aminotransferase
  • AST aspartate aminotransferase

Landscapes

  • Health & Medical Sciences (AREA)
  • Natural Medicines & Medicinal Plants (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Botany (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Medical Informatics (AREA)
  • Biotechnology (AREA)
  • Alternative & Traditional Medicine (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Insects & Arthropods (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

一种脑心通制剂的药物用途，尤其是在制备治疗非酒精性脂肪肝药物中的应用。经实验证明，脑心通制剂能显著降低非酒精性脂肪肝模型动物的体重、肝重/体重指数、肝脏脂质沉积，显著改善肝功能指标，包括谷草转氨酶（AST）、谷丙转氨酶（ALT），同时显著降低体内血清甘油三酯（TG）、胆固醇（TC）和低密度脂蛋白（LDL-C）水平，对于治疗非酒精性脂肪肝具有显著的效果，进一步拓展了脑心通制剂的药用范围。

Description

脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用 技术领域
本发明涉及脑心通制剂的药物新用途，尤其是在制备治疗非酒精性脂肪肝药物中的应用。
背景技术
非酒精性脂肪性肝病(Non-alcoholic Fatty Liver Disease，NAFLD)是指排除酒精和其他肝损伤因素所导致的，以肝细胞内脂肪过度沉积为关键病理特征的临床慢性肝病，包括单纯性脂肪肝、非酒精性脂肪性肝炎、肝纤维化、肝硬化和肝细胞癌。目前，伴随全球人口肥胖率的增长，NAFLD全球发病率高达18-30％，并伴随心脑血管疾病、二型糖尿病等并发症的风险逐年上升，严重威胁人类健康。同时，NAFLD的发病机制复杂，存在多致病因素，对患者的生活质量和预期寿命产生严重影响。
目前，现代医学多以运动、减肥等作为NAFLD的主要治疗手段，化学药物如降脂、降血糖药物等，需长期服用，容易出现肝肾损伤等不良反应，临床应用受到限制。而中药复方具有多途径、多靶点的药理效应，副作用少，已经成为脂肪肝防治研究的一种重要策略。
脑心通制剂是在古方补阳还五汤的基础上加虫类药发展而来的，是由黄芪、赤芍、丹参、当归、川芎、桃仁、红花、制乳香、制没药、鸡血藤、牛藤、桂枝、桑枝、地龙、全蝎和水蛭等16味药材组成的复方中成药制剂，具有益气活血，化瘀通络的功效。临床治疗上，主要用于治疗各种心脑血管疾病，如中风和冠心病等，主要是通过抗凝溶栓、保护血管内皮、稳定和消退动脉粥样硬化、保护神经细胞以及防止缺血再灌注损伤等方面起到治疗作用。脑心通制剂的胶囊剂自1993年上市后，临床用药效果显著，带来了很大的社会效益和经济效益。
发明内容
本发明的目的是公开一种脑心通制剂新的药物用途，具体涉及脑心通制剂在治疗非酒精性脂肪肝中的应用。
并进一步公开脑心通制剂在以下方面的药物应用：
脑心通制剂在制备降低非酒精性脂肪肝患病机体肝脏内脂质沉积药物中的应用。
脑心通制剂在制备降低非酒精性脂肪肝患病机体血清肝功能指标AST和ALT水平药物中的应用。
脑心通制剂在制备降低非酒精性脂肪肝患病机体体重药物中的应用。
脑心通制剂在制备降低非酒精性脂肪肝患病机体血清甘油三脂水平药物中的应用。
脑心通制剂在制备降低非酒精性脂肪肝患病机体血清胆固醇水平药物中的应用。
脑心通制剂在制备用于降低非酒精性脂肪肝患病机体血清低密度脂蛋白水平药物中的应用。
经实验证明，脑心通制剂能显著降低非酒精性脂肪肝模型动物的体重、肝重/体重指数，肝脏脂质沉积，显著改善肝功能指标，包括谷草转氨酶(AST)、谷丙转氨酶(ALT)，同时显著降低体内血清甘油三脂(TG)、胆固醇(TC)和低密度脂蛋白(LDL-C)水平，对于治疗非酒精性脂肪肝具有显著的效果。进一步拓展了脑心通制剂的药用范围。
附图说明
图1是各组小鼠肝脏H&E染色和油红O染色情况；
图2是各组小鼠肝脏油红O染色量化结果脂滴面积百分比统计结果柱状图；
图3是本发明实施例高脂饲喂APOE -/-小鼠血清谷草转氨酶(AST)含量的实验结果柱状图；
图4是本发明实施例高脂饲喂APOE -/-小鼠血清谷丙转氨酶(ALT)含量的实验结果柱状图；
图5是本发明实施例高脂饲喂APOE -/-小鼠体重的实验结果折线图；
图6是本发明实施例高脂饲喂APOE -/-小鼠肝脏/体重指数的实验结果柱状图；
图7是本发明实施例高脂饲喂APOE -/-小鼠血清甘油三酯(TG)含量实验结果柱状图；
图8是本发明实施例高脂饲喂APOE -/-小鼠血清胆固醇(TC)含量的实验结果柱状图；
图9是本发明实施例高脂饲喂APOE -/-小鼠血清低密度脂蛋白(LDL-C)含量的实验结果柱状图。
具体实施方式
下面结合实施例对本发明作进一步说明。
实施例1体内动物模型实验
1.实验材料
1.1受试药物：脑心通胶囊(NXT)
1.2对照药物：阿托伐他汀(ATO)
1.3高脂饲料：含21％脂肪和1.5％胆固醇
2.实验动物
APOE -/-小鼠45只，SPF级，雄性，体重20～25g，C57BL/6J小鼠15只，SPF级，雄 性，体重20～25g，实验动物质量合格证号：SCXK(粤)2018-0002由广东省医学实验动物中心提供。
3.实验方法
本发明采用APOE -/-小鼠给予高脂饲料24周的方法建立非酒精性脂肪肝动物模型，通过灌胃给予脑心通胶囊方式验证其疗效。
高脂饲料诱导的脂肪肝被公认为是NAFLD的经典模型之一，长期喂食高脂饲料的啮齿类动物将自然进展为肝脏脂肪变性，APOE -/-小鼠是通过同源重组技术制备的具有3号外显子纯合缺失的小鼠，高脂饲喂能表现出较普通啮齿类动物更为严重的高血脂症状和器官的脂肪堆积。
具体过程：动物适应环境一周后，将APOE -/-小鼠随机分为3组，分别为模型对照组、阿托伐他汀组(10mg/kg)、脑心通胶囊组(624mg/kg)，每组15只，每天给予高脂饲料喂养并进行相应药物的灌胃给药。C57BL/6J小鼠每天给予正常饲料为空白对照组，灌胃给予同体积生理盐水。连续高脂饲喂并给药24周，每隔2周称重一次，给药结束当天，禁食12h，次晨以1％戊巴比妥钠、50mg/kg、体积50μL/10g腹腔注射麻醉小鼠，并进行眼眶采血，采用普通采血管收集血液样品，3000rpm离心10min，取血清进行脂质代谢(TC、TG、LDL-C)，肝功能(AST、ALT)检测，上述生化指标检测操作均严格按照各类试剂盒(南京建成生物工程研究所)使用说明书进行。取血后，立即对动物进行解剖，取出各组小鼠肝脏组织，进行肝湿重称量，部分肝脏组织浸泡于4％多聚甲醇固定，制作石蜡切片，进行苏木精-伊红染色(Hematoxylin-eosin,HE)染色，在光学显微镜下进行观察。部分肝脏组织直接进行OCT包埋，制作冰冻切片，用于油红O染色。
数据处理：各组结果分别以平均值±标准差(Mean±SD)表示，各组数据的比较采用SPSS 21.0进行单因子方差分析(One-Way ANOVA)，P<0.05为显著性差异，P<0.01为非常显著性差异。
4.实验结果：
4.1脑心通胶囊对高脂饮食诱导的小鼠非酒精性脂肪肝病理改变的影响。
对实验小鼠肝脏进行HE染色和油红O染色以观察肝脏形态改变以及脂质沉积情况。由图1可知，HE染色结果显示：正常对照组小鼠的肝索结构清晰，肝细胞排列紧密，组织未见明显脂肪变性，坏死、炎症等病理改变。模型对照组小鼠广泛见肝细胞重度脂肪变性，细胞肿胀，胞浆充满圆形空泡(黑色箭头)，小叶可见多处炎性细胞小灶性浸润(红色箭头)，汇管区卵圆形细胞增生(黄色箭头)。阿托发他汀组与脑心通胶囊组肝细 胞气球样变性程度、脂肪变性面积以及炎症程度明显减轻。与肝脏HE染色结果一致，油红O染色结果表明：与空白组相比，高脂饲喂小鼠肝细胞内红色脂滴阳性面积明显升高，脂滴面积百分比明显升高，表明模型组小鼠的肝脏脂质沉积显著加重，而脑心通胶囊给药组肝细胞脂滴红色阳性面积明显减少，脂滴面积百分比明显降低(见图2)，表明脑心通胶囊显著抑制肝脏脂质沉积。上述病理切片结果均表明脑心通胶囊对非酒精性脂肪肝的损伤具有显著的保护作用。
4.2脑心通胶囊给药对高脂饮食诱导的小鼠肝脏损伤的影响
NAFLD的特征之一是肝脏损伤。谷丙转氨酶(alanine aminotransferase，ALT)、谷草转氨酶(aspartate aminotransferase，AST)是反映肝细胞损伤的酶，ALT主要存在于肝细胞浆中，AST主要存在于肝细胞浆的线粒体中。当肝细胞出现损伤或坏死时，ALT以及AST活力会显著升高。我们对实验小鼠血清中ALT、AST进行了检测。结果表明：与空白组相比，模型组小鼠血清ALT和AST活力显著性上升，而脑心通胶囊给药显著抑制ALT和AST活力的升高(见图3，图4)，说明脑心通胶囊能够减轻高脂饮食诱导的肝损伤，具有显著的肝脏保护作用。
4.3脑心通胶囊给药对高脂饮食诱导的小鼠体重的影响。
结果见图5，表明：与空白组相比，模型组小鼠体重显著上升，脑心通胶囊给药能够显著抑制高脂饮食诱导小鼠体重的上升。
4.4脑心通胶囊给药对高脂饮食诱导的小鼠肝重/体重系数的影响
结果见图6，表明：与空白组相比，模型组小鼠肝重/体重系数显著增大，脑心通胶囊给药能够显著降低肝重/体重系数。
4.5脑心通胶囊给药对高脂饮食诱导的小鼠血脂水平的影响
结果见图7、图8和图9，表明：与空白组相比，模型组小鼠血清中TG、TC和LDL-C水平显著上升，而脑心通胶囊给药能够显著降低TG、TC和LDL-C水平，说明脑心通胶囊对高脂饮食诱导的小鼠血脂紊乱有显著的改善作用。

Claims (8)

  1. 脑心通制剂在制备降低非酒精性脂肪肝患病机体肝脏内脂质沉积药物中的应用。
  2. 脑心通制剂在制备降低非酒精性脂肪肝患病机体血清肝功能指标AST和ALT水平药物中的应用。
  3. 脑心通制剂在制备降低非酒精性脂肪肝患病机体体重药物中的应用。
  4. 脑心通制剂在制备降低非酒精性脂肪肝患病机体血清甘油三脂水平药物中的应用。
  5. 脑心通制剂在制备降低非酒精性脂肪肝患病机体血清胆固醇水平药物中的应用。
  6. 脑心通制剂在制备用于降低非酒精性脂肪肝患病机体血清低密度脂蛋白水平药物中的应用。
  7. 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用。
  8. 如权利要求1到7任一权利要求所述的应用，其特征在于所述的脑心通制剂是脑心通胶囊。
PCT/CN2021/139878 2021-12-20 2021-12-21 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用 Ceased WO2023115294A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202111551308.1 2021-12-20
CN202111551308.1A CN114129626A (zh) 2021-12-20 2021-12-20 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用

Publications (1)

Publication Number Publication Date
WO2023115294A1 true WO2023115294A1 (zh) 2023-06-29

Family

ID=80382965

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/139878 Ceased WO2023115294A1 (zh) 2021-12-20 2021-12-21 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用

Country Status (2)

Country Link
CN (1) CN114129626A (zh)
WO (1) WO2023115294A1 (zh)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1406609A (zh) * 2001-08-20 2003-04-02 赵步长 一种可用于治疗中风和胸痹的中药胶囊剂及其制法
CN1615958A (zh) * 2004-09-30 2005-05-18 咸阳步长医药科技发展有限公司 用于治疗中风和胸痹的中药制剂及其制备方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1406609A (zh) * 2001-08-20 2003-04-02 赵步长 一种可用于治疗中风和胸痹的中药胶囊剂及其制法
CN1615958A (zh) * 2004-09-30 2005-05-18 咸阳步长医药科技发展有限公司 用于治疗中风和胸痹的中药制剂及其制备方法

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
LI HONGFAN, KUANG YUEHUAI, YANG GUANGXUN: "87 Cases of Hyperlipidemia Treated by Naoxintong Capsule", JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 54, no. 20, 31 October 2013 (2013-10-31), pages 1783 - 1784, XP093073823, DOI: 10.13288/j.11-2166/r.2013.20.019 *
LYU YING: "92 Cases of Hyperlipidemia Treated by Naoxintong Capsule", ZHEJIANG JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 44, no. 2, 28 February 2009 (2009-02-28), pages 147 - 147, XP093073826 *
TAN HUILING, LI QIANG: "Observation on Therapeutic Effect of Buchang Naoxintong Capsules in Treating 152 Cases of Hyperlipidemia", CHINESE AND FOREIGN MEDICAL RESEARCH, vol. 10, no. 10, 30 April 2012 (2012-04-30), pages 117 - 118, XP093073822, ISSN: 1674-6805, DOI: 10.14033/j.cnki.cfmr.2012.10.011 *
WANG JIANQIN, LIANG HAIFENG: "Clinical Observation of Naoxintong in Treating Metabolic Syndrome", CHINESE JOURNAL OF INTEGRATIVE MEDICINE ON CARDIO-/CEREBROVASCULAR DISEASE, vol. 9, no. 1, 30 September 2003 (2003-09-30), pages 546 - 547, XP093073816, ISSN: 1672-1349 *
WANG YAN, ET AL.: "Clinical Observation on Lipid-regulating Effect of Buchang Naoxintong Capsule", PRACTICAL JOURNAL OF CARDIAC CEREBRAL PNEUMAL AND VASCULAR DISEASE, vol. 20, no. 3, 31 March 2012 (2012-03-31), pages 510 - 510, XP093073820, ISSN: 1008-5971 *
WU FUMING: "Clinical Observation on Buchang Naoxintong in Treating Endothelial Injury in Metabolic Diseases", ZHEJIANG JOURNAL OF INTEGRATED TRADITIONAL CHINESE AND WESTERN MEDICINE, vol. 17, no. 12, 31 December 2007 (2007-12-31), pages 757 - 758, XP093073813 *
YANG MING: "Observation on 40 Cases of Fatty Liver Treated by Naoxintong Capsule", GUIDE OF CHINA MEDICINE, ZHONG GUO YI YAO ZHI NAN BIAN JI BU, CN, 30 June 2011 (2011-06-30), CN , pages 134 - 135, XP093073810, ISSN: 1671-8194, DOI: 10.15912/j.cnki.gocm.2011.17.146 *
ZHONG YING: "Naoxintong combined with Lipitor in the treatment of 40 cases of hyperlipidemia complicated with fatty liver", ZHEJIANG JOURNAL OF TRADITIONAL CHINESE MEDICINE, vol. 52, no. 12, 31 December 2017 (2017-12-31), pages 927 - 927, XP093073815, DOI: 10.13633/j.cnki.zjtcm.2017.12.048 *

Also Published As

Publication number Publication date
CN114129626A (zh) 2022-03-04

Similar Documents

Publication Publication Date Title
KR102676056B1 (ko) 비알코올성 지방간 질환의 치료 또는 예방용 의약의 제조에서의 트리아세틸-3-하이드록시페닐아데노신의 용도
CN115806574A (zh) 一种雪菊提取物的制备方法及其应用
CN106860482A (zh) 蜂胶乙醇提取物的应用
CN104557532A (zh) 二联苯衍生物及其应用
CN103054929A (zh) 一种红景天提取物、其药物组合物和治疗脂肪肝病的用途
US8927601B2 (en) Uses of N-butylidenephthalide in treating a liver injury and improving liver function
CN115006494B (zh) 一种显脉旋覆花复合解酒组合物、解酒护肝制剂及其应用
CN120732985A (zh) 一种治疗代谢相关脂肪性肝病的中药组合物及其制备方法
WO2017181857A1 (zh) 一种降脂保肝组合物及其用途
WO2023115294A1 (zh) 脑心通制剂在制备治疗非酒精性脂肪肝药物中的应用
US20240408162A1 (en) Use of Extract from Morus alba L. in the Preparation of a Medicament for Preventing and/or Treating a Hepatobiliary Disease
CN104825564A (zh) 中药组合物在制备治疗酒精性脂肪肝药物中的应用
Enogieru et al. Changes in biochemical markers of kidney function and antioxidant status of diabetic rats treated with aqueous leaf extracts of Ficus exasperata (Vahl)
CN112370496A (zh) 枸杞叶有效成分在制备预防或治疗肝纤维化药物中的应用
CN111346102A (zh) 黄芩苷在治疗和预防非酒精性脂肪肝中的应用
CN103108639A (zh) 一种中药活性成分组合物及其用途
CN107157983B (zh) 土木香内酯在制备防治肝脏损伤药物中的应用
CN107625796B (zh) 一种含白芷的药物组合物及其用途
CN117018010A (zh) 尿苷二磷酸葡萄糖在治疗肝脏糖脂代谢异常中的用途
CN116172993A (zh) 艾地苯醌在制备预防和/或治疗脑缺血再灌注损伤的药物中的应用
CN112972440B (zh) 麝香酮在制备防治抑郁症的药物中的用途
CN106924227B (zh) 桂皮醛在制备治疗动脉粥样硬化药物中的用途
CN102670672A (zh) 苦丁茶提取物在制备降低肝脏甘油三酯含量的药物中的用途
CN115677869A (zh) 一种金芝多糖的制备方法及其用途
CN117018117B (zh) 一种中药组合物及其中药制剂和应用

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 21968448

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 01/10/2024)

122 Ep: pct application non-entry in european phase

Ref document number: 21968448

Country of ref document: EP

Kind code of ref document: A1