CN116270634B - Application of Zhongwuning in preparing medicine for preventing and treating liver diseases - Google Patents
Application of Zhongwuning in preparing medicine for preventing and treating liver diseases Download PDFInfo
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Classifications
-
- A—HUMAN NECESSITIES
- 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
- A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
-
- 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
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of Zhongwuning in preparing a medicine for preventing and treating liver diseases. The invention discloses an application of Zhongwuning in preparing a medicine for preventing and/or treating liver diseases, in particular to a medicine for treating hepatitis, liver fibrosis or liver insufficiency. The medicine is Zhongwuning or pharmaceutically acceptable salt, ester or solvate thereof, and is a preparation prepared by taking the medicine as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients. Experimental researches show that the medicine has a certain protection effect on liver diseases, and can effectively prevent or slow down liver cell injury, liver inflammation, fibrosis and liver insufficiency.
Description
Technical Field
The invention belongs to the field of medicines, and in particular relates to application of Zhongwuning in preparing medicines for preventing and treating liver diseases.
Background
The liver is an organ of the human body with a variety of important physiological functions, which is both the center of metabolism of substances and important secretory, excretory, bioconversion and barrier organs. The various complex functions of the liver are mainly performed by hepatic parenchymal cells. Liver injury factors cause serious damage to hepatocytes (including liver parenchymal cells and cumic cells), which cause morphological and structural destruction of the liver and cause serious disorders of metabolism, secretion, synthesis, detoxification and immune function, which are called liver dysfunction. In general, hepatic parenchymal cells are dysfunctional, with secretory function impaired first, synthetic function impaired second, and detoxification function impaired last.
The sustainable development of liver disease patients mainly consists in the persistence and aggravation of pathological changes such as liver cell injury, inflammatory reaction, fibrous tissue hyperplasia and the like. Liver fibrosis is a pathological process in which extracellular genes such as collagen in the liver are proliferated and degraded out of balance when necrosis and inflammatory stimulation of liver cells occur, resulting in abnormal deposition of fibrous connective tissue in the liver. The preparation is the best treatment choice for reducing the occurrence and development of severe liver diseases by effectively protecting liver cells, inhibiting the development of inflammation and liver fibrosis and controlling the liver dysfunction as early as possible before or during the occurrence of liver dysfunction. Therefore, the research of the medicine capable of protecting liver cell injury, reducing liver inflammatory reaction and fibrosis development has practical application value for clinical prevention and treatment of severe liver diseases.
The invention provides a Chinese black-bone (mesonine; CAS No.:6792-09-2; formula:
C 24 H 39 NO 9 ) The alkaloid has a novel medicinal value, a clear chemical structure, can be obtained by extracting raw materials, and can also be chemically synthesized. The research of the invention shows that the Zhongwuning has the obvious functions of reducing the damage of liver cells and the development of liver inflammatory reaction and fibrosis. The use of Zhongwuning for the treatment of liver diseases has not been reported before this application.
Disclosure of Invention
The invention discloses an application of Chinese wuning in preparing a medicament for treating liver diseases, and aims to provide the Chinese wuning in the medicament, which has a certain effect on liver diseases including acute and chronic hepatitis, nonalcoholic fatty liver disease, liver fibrosis, liver insufficiency and liver injury.
The invention discloses application of Zhongwuning or pharmaceutically acceptable salt, ester or solvate thereof in preparing a medicament for treating liver diseases.
Further, the liver disease includes chronic hepatitis, nonalcoholic steatohepatitis, liver failure, liver fibrosis and liver injury.
Furthermore, the medicine for treating liver diseases is a preparation prepared by taking the Chinese black-bone tannin or pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
The invention discloses application of Zhongwuning or pharmaceutically acceptable salt, ester or solvate thereof in preparing a medicament for preventing and/or treating hepatic fibrosis.
Furthermore, the medicine for preventing and/or treating liver fibrosis is a preparation prepared by taking the Chinese black-bone tannin or pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
The invention also discloses application of the Zhongwuning or the pharmaceutically acceptable salt, ester or solvate thereof in preparing medicaments for preventing and/or treating liver injury.
Furthermore, the medicine for preventing and/or treating liver injury is a preparation prepared by taking the Zhongwuning or pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
The preparation is liquid, solid or semisolid.
Advantageous effects
The invention discloses application of Chinese wuning in preparing a medicament for preventing and/or treating liver diseases, in particular a medicament for treating liver diseases with pathological features of liver cell injury, liver inflammation and fibrosis. The preparation taking the Chinese wuning as the active ingredient has certain effects on liver diseases including acute and chronic hepatitis, nonalcoholic fatty liver disease, liver fibrosis, liver insufficiency and liver injury. Experimental study shows that the medicine disclosed by the invention can obviously relieve the effects of liver cell injury, protecting liver function, relieving liver inflammatory reaction and fibrosis development, and improves the clinical prevention and treatment effects on severe liver diseases.
Detailed Description
The invention is further illustrated by the following examples, but the scope of the invention is not limited by the specific examples, but by the claims. The experimental methods, in which specific conditions are not noted in the following examples, were selected according to conventional methods and conditions, or according to the commercial specifications.
Example 1
1. Experimental materials
1.1 samples and reagents
Sample: the Zhongwuning is white powder, which is provided by the good doctor pharmaceutical company.
Reagent: concanavalin A, sigma, lot #SLBL3798V,100 mg/bottle; bifendate dripping pill, mo Bangde pharmaceutical group Co., ltd., specification: 1.5 mg/pellet, 250 pellets/bottle, lot number: a02J180112;0.9% sodium chloride injection, sichuan Korea pharmaceutical Co., ltd., specification: 100mL, 0.9g, product lot: w217071904; ALT detection kit (batch No. 20181228), AST detection kit (batch No. 20181228), alkaline phosphatase (AKP) detection kit (batch No. 20190829), total Bilirubin (TBIL) detection kit (batch No. 20190824), direct Bilirubin (DBIL) detection kit (batch No. 20190905) are all from Nanjing's institute of biological engineering; total Bile Acid (TBA) detection kit, lot number 2019006, vinca Huoli Biotechnology Co., ltd; hematoxylin dye liquor (batch number 170220) supplied by Duke's dragon chemical reagent factory; eosin dye liquor (lot number 170220), supplied by the Chengkolong chemical reagent plant; basic fuchsin (lot number 101112), shanghai reagent three factories; periodic acid (lot number 180425), MIEuro chemical reagent Co., ltd; sodium thiosulfate (lot 160723), a large-scale chemical reagent plant in Tianjin; PAS staining solution is prepared according to PAS staining method of the main code of pathology technology of Wang Ba, li Yusong, etc.; other reagents are commercially available, analytically pure.
1.2 laboratory animals and environmental conditions
Kunming mice, SPF grade qualified animals, production license number: SCXK (Chuan) No. 2018-19. Provided by the experimental animal center of the academy of Chinese medicine of Sichuan province;
test environmental conditions: the application meets the SPF-level standard, license number: SYXK (Chuan) 2018-100. The indoor temperature is 19-21 ℃ and the relative humidity is 40-70%. The experimental animals are fed in separate cages, each cage does not exceed 5, water is freely drunk, and the experimental animals are fed with conventional complete feed at fixed time and fixed quantity.
1.3 test instruments
VARIOSKAN FLASH multifunction scanner, company Thermo Scientific, usa; TSJ-Q type full-automatic closed tissue dehydrator, changzhongwei electronic instrument factory; BMJ-III type embedding machine, changzhongwei electronic instruments factory; rotary microtomes, LEICA, germany; CX31 optical microscope, OLYMPUS; JA1003 electronic balance, shanghai precision balance, d=1 mg; EB-3200D electronic balance, manufactured by Shimadzu, japan, d=0.01 g; YB electronic balance, produced by Shanghai ocean electronics instruments works, d=0.1 g; disposable syringes, lavage needles, etc.
2. Experimental method
2.1 Effect on liver injury in mice caused by Canavalia ectenes A
60 mice with the weight of 18-22 g are taken, the male and female halves are randomly divided into 6 groups according to the sex and the weight, the different Chinese Wuning samples and positive control drugs of the administration group ig are taken, and the normal control group and the model control group are filled with equal volumes of NS (10 ml/kg BW). Each group was given 1 time daily for 7 times, 30 minutes after the last administration, and each sample group was given with Canavalia gladiata (10 ml/kg BW) at a dose of 18mg/kg by tail vein injection, normal control group iv was 0.9% physiological saline in equal volume. Blood is collected through a retroorbital venous plexus after 6 hours of fasted food, and centrifugation is carried out at 3000rpm for 10 minutes after standing for 1 hour, and serum is taken for measuring ALT, AST, AKP, TBA and TBIL and DBIL levels; mice were sacrificed by cervical vertebrae removal after blood collection, livers were dissected, fixed with formalin after weighing, cross sections along the liver left She were harvested, gradient ethanol dehydrated, paraffin embedded, sectioned, HE stained, and liver tissue morphology was observed under an optical microscope and classified into 5 grades according to the degree of liver morphology damage.
Level 0: the liver morphological structure is not abnormal; stage 1: a small amount of liver apoptosis cell foci are distributed in the liver section, and the area of liver apoptosis is less than one tenth of that of the liver section; 2 stages: more liver apoptosis cell foci are distributed in the liver section, and the area of liver apoptosis is less than two tenth of the liver section; 3 stages: a large number of liver apoptosis cell foci can be distributed in the liver section, and the area of liver apoptosis is less than four tenths of a liver section; 4 stages: the distribution of large-area liver apoptosis cells can be seen in the liver section, and the area of liver apoptosis of the liver cells is more than four tenths.
2.2 statistical analysis method
Metering data: the experimental data of each group of animals in the table are expressed by mean ± standard deviation (x±s), and the experimental data are described by mean ± standard deviation (x±s). (1) The normal and the multiple groups with uniform variance are compared by adopting single factor analysis of variance (ANOVA), when the overall difference has statistical significance (p is less than 0.05), the multiple comparison among the groups is further tested by adopting LSD; when the total difference has no statistical significance (p is more than or equal to 0.05), the statistical analysis is finished. (2) The normal distribution or variance is not satisfied, the analysis is carried out by using a Kruskal-Wallis H test (K-W method), when the total difference has statistical significance (p is less than 0.05), the inter-group multiple comparison is further carried out by using an uncorrected Dunn's method; when the test shows that the total difference has no statistical significance (p is more than or equal to 0.05), the statistical analysis is ended. p <0.05 is statistically significant for differences. The above statistical analysis was done using Graphpad prism8.0 software.
Counting data: using the Ridit analysis, p <0.05 is statistically significant for the differences.
3. Experimental results
3.1 Effect on liver injury in mice caused by Canavalia ectenes A
By the method, the results are obtained, after the concanavalin A is molded, serum ALT and AST levels of mice in a model group are obviously increased, and compared with the ALT and AST levels of normal control groups, the serum ALT and AST levels of mice in the model group are obviously different (P < 0.01). There was some decrease in ALT and AST levels in the low-dose group of Zhongwuning (2 mg/kg), the medium-dose group of Zhongwuning (4 mg/kg), the high-dose group of Zhongwuning (8 mg/kg) and the bifendate-administered group compared to the model group, wherein the high-dose group of Zhongwuning showed significant differences (P <0.01 or P < 0.05) compared to the model group, and the results are shown in Table 1 and Table 2.
Influence of Wuning on liver weight and ALT and AST levels in mice with acute liver injury in Table 1
Note that: * P <0.05, < P <0.01, compared to model group
The serum Total Bile Acid (TBA) and Total Bilirubin (TBIL) levels were significantly elevated in the mice of the model group, with significant differences (P < 0.01) compared to the TBA and TBIL levels of the normal control group. Both TBA and TBIL levels were reduced to different extents in the medium-and high-dose groups compared to the model group, and TBA levels in the medium-and high-dose groups were significantly different from those in the model group (P <0.01 or P < 0.05).
Influence of Wuning on serum AKP, total bile acid and bilirubin levels in liver injured mice in Table 2
Note that: * P <0.05, < P <0.01, compared to model group
Dissecting abdominal cavity, finding normal control group mouse liver to be reddish brown, soft and glossy; the model group mice have darker livers and appear dark red, the shape of the model group mice is slightly increased compared with the normal control group, and the liver weight and organ coefficients of the model group mice are obviously higher than those of the normal control group (P < 0.01).
The liver of the mice seen under the pathological section scope is composed of liver envelope and liver parenchyma. The normal control group has smooth liver capsule, evenly distributed liver lobules in liver parenchyma, orderly arrangement of hepatic cable cells, normal liver sinus morphology, even small amount of livers can also cause apoptosis of hepatic cells, no swelling of the hepatic cells, and no infiltration of inflammatory cells in a liver section; compared with a normal control group, the concanavalin A mainly causes apoptosis of liver cells, inflammatory cell infiltration and liver cell swelling to the liver of an experimental mouse; the model control group has smooth liver capsule, liver apoptosis in liver lobule and liver sinus, multifocal distribution of apoptotic liver cells, concentrated cytoplasmic staining of liver cells in apoptotic foci, shrinkage of cell nucleus, reduction of cell body, distending congestion of liver sinus, swelling of other liver cells, infiltration of lymphocyte, neutrophil and monocyte in hepatic necrosis zone, and fibrous tissue hyperplasia in manifold zone; compared with the model group, the hepatic cell apoptosis area, inflammatory cell infiltration and fibrous tissue proliferation of each administration group are reduced to different degrees, wherein the middle-and high-dose groups of the Chinese and the Chinese Wuning have the most remarkable effects.
Therefore, the medicine disclosed by the invention has a certain protection effect on mice liver injury caused by the concanavalin, and can effectively improve hepatocyte apoptosis, liver inflammation, liver fibrosis and liver function injury.
Claims (3)
1. Application of Zhongwuning or pharmaceutically acceptable salt thereof in preparing medicament for treating acute liver injury is provided.
2. The use according to claim 1, wherein the medicament for treating acute liver injury is a preparation prepared by taking the Chinese black-bone tannin or pharmaceutically acceptable salt thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
3. The use according to claim 1 or 2, wherein the formulation is in the form of a liquid, solid or semi-solid formulation.
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Non-Patent Citations (2)
| Title |
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| 寿折星 ; 范恒 ; .乌头原碱对非酒精性脂肪肝大鼠瘦素胰岛素抵抗的实验研究.山东中医药大学学报.2008,(第02期),全文. * |
| 郭尹玲 ; 扈晓宇 ; 钟森 ; 白松林 ; 谭小燕 ; 辜海英 ; 王德莉 ; .附子对免疫性肝损伤模型大鼠的影响及代谢组学研究.西部医学.2010,(第05期),全文. * |
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