CN113476447A - Application of meflonizone in preparation of acute liver injury medicine - Google Patents
Application of meflonizone in preparation of acute liver injury medicine Download PDFInfo
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- CN113476447A CN113476447A CN202110777560.8A CN202110777560A CN113476447A CN 113476447 A CN113476447 A CN 113476447A CN 202110777560 A CN202110777560 A CN 202110777560A CN 113476447 A CN113476447 A CN 113476447A
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- 206010067125 Liver injury Diseases 0.000 title claims abstract description 50
- 231100000439 acute liver injury Toxicity 0.000 title claims abstract description 41
- 239000003814 drug Substances 0.000 title claims abstract description 28
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims description 9
- 238000011282 treatment Methods 0.000 claims description 7
- 210000003494 hepatocyte Anatomy 0.000 claims description 4
- 210000005228 liver tissue Anatomy 0.000 claims description 4
- 230000017074 necrotic cell death Effects 0.000 claims description 4
- 230000006907 apoptotic process Effects 0.000 claims description 3
- QQIYZFHTOAXUGX-UHFFFAOYSA-N 1-[[4-[3-(4-methylpiperazin-1-yl)propylamino]phenyl]methyl]-5-(trifluoromethyl)pyridin-2-one Chemical group C1CN(C)CCN1CCCNC(C=C1)=CC=C1CN1C(=O)C=CC(C(F)(F)F)=C1 QQIYZFHTOAXUGX-UHFFFAOYSA-N 0.000 claims description 2
- 230000005856 abnormality Effects 0.000 claims description 2
- 208000019423 liver disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 241000699670 Mus sp. Species 0.000 description 23
- 210000004185 liver Anatomy 0.000 description 12
- 239000002158 endotoxin Substances 0.000 description 11
- 229920006008 lipopolysaccharide Polymers 0.000 description 11
- 108090000340 Transaminases Proteins 0.000 description 7
- 102000014898 transaminase activity proteins Human genes 0.000 description 6
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 210000004369 blood Anatomy 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 230000006378 damage Effects 0.000 description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 4
- 231100000234 hepatic damage Toxicity 0.000 description 4
- 230000008818 liver damage Effects 0.000 description 4
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- MSWZFWKMSRAUBD-GASJEMHNSA-N 2-amino-2-deoxy-D-galactopyranose Chemical compound N[C@H]1C(O)O[C@H](CO)[C@H](O)[C@@H]1O MSWZFWKMSRAUBD-GASJEMHNSA-N 0.000 description 3
- 206010028851 Necrosis Diseases 0.000 description 3
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- MSWZFWKMSRAUBD-UHFFFAOYSA-N beta-D-galactosamine Natural products NC1C(O)OC(CO)C(O)C1O MSWZFWKMSRAUBD-UHFFFAOYSA-N 0.000 description 3
- 238000005056 compaction Methods 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 3
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- 238000000034 method Methods 0.000 description 3
- 102100036475 Alanine aminotransferase 1 Human genes 0.000 description 2
- 108010082126 Alanine transaminase Proteins 0.000 description 2
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- 238000002560 therapeutic procedure Methods 0.000 description 2
- 238000002054 transplantation Methods 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- 208000007788 Acute Liver Failure Diseases 0.000 description 1
- 206010000804 Acute hepatic failure Diseases 0.000 description 1
- 108010003415 Aspartate Aminotransferases Proteins 0.000 description 1
- 102000004625 Aspartate Aminotransferases Human genes 0.000 description 1
- 108010062580 Concanavalin A Proteins 0.000 description 1
- 206010014950 Eosinophilia Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
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- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
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- 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
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Abstract
The invention discloses an application of meflufenidone in preparation of an acute liver injury medicament, wherein the meflufenidone is used as a raw material for preparing the acute liver injury medicament, or the medicament comprises a meflufenidone component. The invention discovers that the meflufenidone has the characteristic of treating acute liver injury, so that the application of the meflufenidone in preparing the acute liver injury medicament provides a new medicament for treating the acute liver injury, and has better market value and clinical application prospect.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to application of meflonization in preparation of a medicine for treating acute liver injury.
Background
Acute Liver Injury (ALI) is a Liver Injury caused by various causes, and its condition progresses rapidly. Studies have shown that exogenous substances, such as viral infections, abuse of alcohol or drugs, and exposure to toxins, can lead to ALI. The first cause of acute liver injury in China is virus infection, and the second cause is medicine. Because chronic liver injury can cause chronic liver inflammation and fibrosis reaction, the necrotizing cirrhosis caused by ALI is not cured. This not only seriously affects the quality of life of the patient, but also imposes a heavy medical burden on the country. Prevention of acute, chronic plus acute and/or chronic liver injury is therefore of great importance to public health. Liver transplantation is one of the most effective treatments for severe ALI, but statistics indicate that fewer than 10% of patients receiving liver transplantation therapy. At present, the treatment of acute liver failure at home and abroad is very limited, and the death rate is very high. Therefore, finding alternative therapies for ALI is an urgent medical need.
A great deal of research has been carried out worldwide to find effective drugs for the prevention and treatment of ALI, some of which have been used clinically for a long time, but the therapeutic effects of these drugs are still unsatisfactory.
Disclosure of Invention
The invention provides an application of meflofenidone in preparation of an acute liver injury medicament, which is used for solving the technical problem of deficiency of the existing medical field in the treatment of acute liver injury medicaments.
In order to solve the technical problems, the invention adopts the following technical scheme:
an application of meflufenidone in preparing a medicine for treating acute liver injury, wherein the meflufenidone is used as a raw material for preparing the medicine for treating the acute liver injury, or the medicine comprises a meflufenidone component.
Mefenidone is 1- (4- ((3- (4-methylpiperazin-1-yl) propyl) amino) benzyl) -5- (trifluoromethyl) pyridin-2 (1H) -one.
Acute liver injury is manifested by rapid loss and abnormality of hepatocyte function, necrosis and apoptosis of a large number of hepatocytes in liver tissue in patients with or without liver disease.
When the meflufenidone is used for treating acute liver injury, the administration dosage is 5.5-16.5 mg/kg.
Compared with the prior art, the invention has the advantages that:
the invention discovers that the meflufenidone has the characteristic of treating lipopolysaccharide/D-galactosamine and canavalin A induced acute liver injury, so that the application of the meflufenidone in preparing the acute liver injury medicament provides a new medicament for treating the acute liver injury, and has better market value and clinical application prospect.
Drawings
FIG. 1 is a (200-fold) graph of HE staining of liver of each group of mice in a lipopolysaccharide/D-galactosamine induced acute liver injury model;
FIG. 2 is a graph (200-fold) showing HE staining of liver of each group of mice in a concanavalin A-induced acute liver injury model.
Detailed Description
The invention is described in further detail below with reference to the figures and specific examples.
Example 1:
in this example, applying meflufenidone to the preparation of drugs for acute liver injury, the therapeutic effect of meflufenidone will be demonstrated below:
1. experimental methods
(1) Preparing an experimental animal model of lipopolysaccharide/D-galactosamine (LPS/D-GaIN) for inducing Acute Liver Injury (ALI) to observe the curative effect of meflufenidone on ALI:
SPF grade C57BL/6 mice (8-10 weeks old, male, 25-28g weight) 33 in total, were divided into 5 groups, control, model and experimental groups, respectively, and the experimental group was further divided according to the dosage of meflonizone: 50mg/kg, 100mg/kg and 150mg/kg of meflufenidone, wherein each group comprises 5, 9, 5, 7 and 7 respectively. The normal saline or the meflufenidone with different dosages is administered by intragastric administration half an hour before the molding. Injecting 0.3ml of normal saline into the abdominal cavity of each mouse in the control group; model group and Meflufenidone-treated mice were molded by intraperitoneal injection at a dose of 100. mu.g/kg LPS and 700mg/kg D-GaIN. Mice were anesthetized 6h after intraperitoneal injection molding and blood was collected to leave serum, followed by sacrifice of the mice.
(2) Experimental animal models of canavalin a (ConA) induced Acute Liver Injury (ALI) were prepared to observe the efficacy of mefenidone to treat ALI:
SPF grade C57BL/6 mice (8-10 weeks old, male, 25-28g weight) were divided into 5 groups, control, model and experimental groups, and the experimental group was further divided according to the dosage of meflonizone: 50mg/kg, 100mg/kg and 150mg/kg of meflufenidone, wherein each group comprises 4, 8, 6, 5 and 6 respectively. The normal saline or the meflufenidone with different dosages is administered by intragastric administration half an hour before the molding. Injecting 0.3ml of normal saline into the abdominal cavity of each mouse in the control group; model group and meflufenidone-treated mice were post-spheronized for intravenous injection molding at a dose of 15mg/kg ConA. Mice were anesthetized 8h after molding and blood was collected to leave serum, and then the mice were sacrificed.
And (3) separating the mouse livers of the step (1) and the step (2), reserving the left outer leaf for preparing a paraffin section, and placing the remaining liver tissue in a liquid nitrogen tank. Liver functions of mice in each group are detected by a continuous monitoring method, and the liver damage condition is observed by HE staining of paraffin sections.
The LPS/D-GaIN model liver tissue damage scoring standard refers to CARLOS A. and the like, and the semi-quantitative analysis is carried out on the pathological damage of the liver by the method. Grading standard: level 0: little or no evidence of injury; level 1: mild injury, vacuolation of the cytoplasm, focal nuclear compaction; and 2, stage: moderate to severe injury with extensive nuclear compaction, cytoplasmic eosinophilia, and loss of intercellular borders; and 3, level: with severe necrosis of the liver with loss of liver cords, hemorrhage and neutrophil infiltration. Each section was scored by randomly selecting 5 fields of 200 x field, and the average was the sample score value for this example.
2. The statistical method comprises the following steps: all metric data are expressed in ± s, and the comparisons between groups were analyzed using one-way variance (ANOVA): this statistical approach is the most common method in drug field experiments for comparison of differences in efficacy between such groups. After differences between groups were obtained, Turky test was used to further verify the differences within the groups, i.e. whether the differences between the model group and the control group and the differences between the dose-administered groups relative to the model group were statistically significant. Defining two sides p < 0.05 is considered statistically significant.
3. Results of the experiment
3.1HE staining results
The liver of the mouse has wide intercellular boundary deletion, hepatic cord loss and necrosis, hepatic sinus congestion and nuclear contraction after 6 hours after LPS/G-GaIN injury. In mice livers treated with mefenidone, the lesions were significantly reduced, the lesion size was reduced (as shown in figure 1), and the liver damage pathology score was significantly reduced (p < 0.05) compared to the model group. See table 1. The mouse liver showed extensive apoptosis, nuclear compaction and necrosis 8 hours after ConA injury. In the liver of mice treated with mefenidone, the lesions were significantly reduced and the extent of damage was reduced compared to the model group (as shown in figure 2).
In the table, p < 0.05 compared to control; p < 0.01 compared to control; p < 0.001 compared to control;#compared with the model group, p is less than 0.05;##compared with the model group, p is less than 0.01;###compared with the model group, p is less than 0.001.
3.2 measurement results of blood transaminases of mice in each group
Compared with a control group, the mean value of the aminotransferase in the mice of the LPS/D-GaIN model group is obviously increased compared with the average value of the aminotransferase in the mice of the normal group, and the difference has statistical significance (p is less than 0.001); after 100mg/kg and 150mg/kg of meflonizone, the blood transaminase of mice is obviously reduced, and the difference has statistical significance (p is less than 0.001), which is detailed in table 2-1. Compared with a control group, the mean value of the blood transaminase of the mice in the ConA model group is obviously increased compared with that of the mice in the normal group, and the difference has statistical significance (p is less than 0.001); after 100mg/kg of meflufenidone treatment, the glutamic-pyruvic transaminase of the mice is obviously reduced, the difference has statistical significance (p is less than 0.05), after 150mg/kg of meflufenidone treatment, the glutamic-pyruvic transaminase and the glutamic-oxaloacetic transaminase of the mice are obviously reduced, the difference has statistical significance (p is less than 0.05), and the details are shown in a table 2-2.
In the table, p < 0.05 compared to control; p < 0.01 compared to control; p < 0.001 compared to control;#compared with the model group, p is less than 0.05;##compared with the model group, p is less than 0.01;###compared with the model group, p is less than 0.001.
TABLE 2-2 serum transaminase levels (X. + -. S) in groups of mice with liver damage due to ConA
In the table, p < 0.05 compared to control; p < 0.01 compared to control; p < 0.001 compared to control;#p is less than 0.05 compared with the control group;##p is less than 0.01 compared with the control group;###p is less than 0.001 compared with the control group; .
4. And (4) experimental conclusion: mefenanib can effectively treat mice acute liver injury induced by LPS/D-GaIN and ConA.
The above description is only a preferred embodiment of the present invention, and the protection scope of the present invention is not limited to the above-described embodiments. Modifications and variations that may occur to those skilled in the art without departing from the spirit and scope of the invention are to be considered as within the scope of the invention.
Claims (4)
1. The application of meflufenidone in preparation of drugs for acute liver injury is characterized in that meflufenidone is used as a raw material for preparing drugs for acute liver injury or the drugs comprise a meflufenidone component.
2. The use of meflufenidone in the preparation of a medicament for treating acute liver injury according to claim 1, wherein the meflufenidone is administered at a dose of 5.5-16.5 mg/kg in a human body.
3. The use of meflufenidone for the manufacture of a medicament for treating acute liver injury according to claim 1, wherein meflufenidone is 1- (4- ((3- (4-methylpiperazin-1-yl) propyl) amino) benzyl) -5- (trifluoromethyl) pyridin-2 (1H) -one.
4. Use of meflofenidone according to claim 1 in the manufacture of a medicament for the treatment of acute liver injury characterized by rapid loss and abnormality of hepatocyte function, massive hepatocyte necrosis and apoptosis in liver tissue in patients with or without liver disease.
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CN108283639A (en) * | 2018-05-03 | 2018-07-17 | 中南大学 | Fluorofenidone is preparing the application in treating acute kidney injury drug |
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- 2021-07-09 CN CN202110777560.8A patent/CN113476447A/en active Pending
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