CN113456636A - Application of flufenidone in preparation of acute liver injury medicine - Google Patents
Application of flufenidone in preparation of acute liver injury medicine Download PDFInfo
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- CN113456636A CN113456636A CN202110777586.2A CN202110777586A CN113456636A CN 113456636 A CN113456636 A CN 113456636A CN 202110777586 A CN202110777586 A CN 202110777586A CN 113456636 A CN113456636 A CN 113456636A
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- 206010067125 Liver injury Diseases 0.000 title claims abstract description 51
- 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 description 6
- 229940079593 drug Drugs 0.000 claims abstract description 12
- 239000002994 raw material Substances 0.000 claims abstract description 3
- 238000011282 treatment Methods 0.000 claims description 9
- 210000005228 liver tissue Anatomy 0.000 claims description 5
- 230000017074 necrotic cell death Effects 0.000 claims description 5
- 210000003494 hepatocyte Anatomy 0.000 claims description 4
- JDZYVVUJIQYGRX-UHFFFAOYSA-N 1-(3-fluorophenyl)-5-methylpyridin-2-one Chemical group C1=C(C)C=CC(=O)N1C1=CC=CC(F)=C1 JDZYVVUJIQYGRX-UHFFFAOYSA-N 0.000 claims description 2
- 230000005856 abnormality Effects 0.000 claims description 2
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- 208000019423 liver disease Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 2
- 241000699670 Mus sp. Species 0.000 description 21
- 210000004185 liver Anatomy 0.000 description 14
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 10
- 239000002158 endotoxin Substances 0.000 description 10
- 229920006008 lipopolysaccharide Polymers 0.000 description 10
- 241000699666 Mus <mouse, genus> Species 0.000 description 7
- 102000003929 Transaminases Human genes 0.000 description 7
- 108090000340 Transaminases Proteins 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 208000029618 autoimmune pulmonary alveolar proteinosis Diseases 0.000 description 6
- 210000004027 cell Anatomy 0.000 description 6
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- 230000003902 lesion Effects 0.000 description 6
- 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 5
- 206010028851 Necrosis Diseases 0.000 description 4
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- 238000007490 hematoxylin and eosin (H&E) staining Methods 0.000 description 3
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- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000011740 C57BL/6 mouse Methods 0.000 description 2
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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 2
- 230000001684 chronic effect Effects 0.000 description 2
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- 238000011156 evaluation Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 231100000234 hepatic damage Toxicity 0.000 description 2
- 238000001746 injection moulding Methods 0.000 description 2
- 230000008818 liver damage Effects 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 229960005489 paracetamol Drugs 0.000 description 2
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010016654 Fibrosis Diseases 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- 206010040742 Sinus congestion Diseases 0.000 description 1
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- 231100000836 acute liver failure Toxicity 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
- A61K31/435—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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
-
- 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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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
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- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
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Abstract
The invention discloses an application of flufenidone in preparing a drug for treating acute liver injury, wherein the flufenidone is used as a raw material for preparing the drug for treating acute liver injury, or the drug comprises a flufenidone component. The invention discovers that the flufenidone has the characteristic of treating acute liver injury, so that the application of the flufenidone 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 in particular relates to application of flufenidone 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 application of flufenidone 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 flufenidone in preparing the medicine for treating acute liver injury, wherein the flufenidone is used as raw material for preparing the medicine for treating acute liver injury, or the medicine contains flufenidone component.
The flufenidone is 1- (3-fluorophenyl) -5-methyl-2- (1H) pyridone.
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 flufenidone is used for treating acute liver injury, the administration dosage is 11-55 mg/kg.
Compared with the prior art, the invention has the advantages that:
the invention discovers that the flufenidone has the characteristic of treating acute liver injury, so that the application of the flufenidone 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) HE staining pattern of liver of each group of mice in a model of acetaminophen-induced acute liver injury;
FIG. 2 is a graph (200-fold) showing HE staining of liver of each group of mice in a lipopolysaccharide/D-galactosamine 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, flufenidone is applied to the preparation of drugs for acute liver injury, and the therapeutic effect of flufenidone is demonstrated below:
1. experimental methods
(1) Preparing an acetaminophen (APAP) induced Acute Liver Injury (ALI) experimental animal model to observe the curative effect of the flufenidone on the ALI:
SPF grade C57BL/6 mice (7-8 weeks old, male, 20-22g in weight) were prepared and divided into 6 groups, namely a control group, a model group and an experimental group, wherein the experimental group is further divided into the following groups according to the dosage of flufenidone: the flufenidone is 100mg/kg, 150mg/kg, 200mg/kg and 250mg/kg, and each group comprises 5, 9, 5 and 9 respectively. Normal saline or flufenidone 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 flufenidone-treated mice were injected intraperitoneally with APAP at a dose of 300 mg/kg. Mice were anesthetized 6h after intraperitoneal injection molding and blood was collected to leave serum, followed by sacrifice of the mice.
(2) Preparing an experimental animal model of lipopolysaccharide/D-galactosamine (LPS/D-GaIN) for inducing Acute Liver Injury (ALI) to observe the curative effect of the flufenidone on the ALI:
SPF grade C57BL/6 mice (8-10 weeks old, male, 25-28g weight) were divided into 4 groups, control, model and experimental groups, and the experimental group was further divided according to the dose of flufenidone: and the flufenidone is 250/kg and 500mg/kg, and each group comprises 5, 10, 7 and 7 respectively. Normal saline or flufenidone 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 flufenidone-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.
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 liver tissue damage scoring standard in the APAP model refers to a method adopted by Zhang-Xu Liu and the like to carry out semi-quantitative analysis on the pathological damage of the liver. Grading standard: 0 minute: no damage is caused; 0.5 min: a single necrotic cell was seen on the first cell layer adjacent to the central layer, and there was subline degeneration; 1 minute: necrotic cells extend from the central vein in two to three cell layers; and 2, dividing: necrotic cells extend from the central vein in three to six cell layers, but are limited to being distributed circumferentially; and 3, dividing: same as 2, but necrosis extends from one central vein to the other; and 4, dividing: more severe than 3, the entire section necrosed extensively in the center of the leaflet. The evaluation standard of the liver tissue damage in the LPS/D-GaIN model 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 adopted by the people. 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 the measurement data are as followsThe inter-group comparisons were analyzed using one-way variance (ANOVA): the statistical method is a drug field experimentThe most common method for comparing the difference in therapeutic effect among 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. Definition of two sides p<0.05 was considered statistically significant.
3. Results of the experiment
3.1HE staining results
6 hours after APAP injury, the mouse liver showed extensive nuclear compaction, loss of intercellular borders, loss of hepatic cords and necrosis. In mice treated with flufenidone, the lesions were significantly reduced, lesion coverage was reduced (as shown in figure 1), and the liver lesion pathology score was significantly reduced (p <0.05) compared to the model group, as detailed in tables 1-1. The liver of the mouse has wide intercellular boundary deletion, hepatic cord loss and necrosis, and hepatic sinus congestion 6 hours after the LPS/G-GaIN injury. In mice livers treated with flufenidone, the lesions were significantly reduced, lesion coverage was reduced (as shown in figure 2), and the liver lesion pathology score was significantly reduced (p <0.05) compared to the model group, as detailed in tables 1-2.
In the table, p is compared with the control group<0.05; comparison with control group, p<0.01; comparison with control group, p<0.001;#In comparison with model group, p<0.05;##In comparison with model group, p<0.01;###Compared with the model group, p is less than 0.001.
In the table, p is compared with the control group<0.05; comparison with control group, p<0.01; comparison with control group, p<0.001;#In comparison with model group, p<0.05;##In comparison with model group, p<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 average value of the blood transaminase of the APAP model group mouse is obviously increased compared with that of a normal group mouse, and the difference has statistical significance (p is less than 0.05); after the flufenidone treatment, the blood transaminase of mice is obviously reduced, wherein the treatment effect is best when the dosage is 250mg/kg, and the difference has statistical significance (p is less than 0.001), and the detailed table is shown in table 2-1. The mean value of the blood transaminase of mice in the LPS/D-GalN model group is obviously higher than that of the mice in the normal group, and the difference has statistical significance (p is less than 0.001); after the flufenidone treatment, the blood transaminases of the mice are obviously reduced, wherein the treatment effect is best when the dosage is 500mg/kg, and the difference has statistical significance (p is less than 0.001), which is shown in a table 2-2.
In the table, p is compared with the control group<0.05; comparison with control group, p<0.01; comparison with control group, p<0.001;#In comparison with model group, p<0.05;##In comparison with model group, p<0.01;###Compared with the model group, p is less than 0.001.
TABLE 2-2 serum transaminase levels in various groups of mice with liver damage induced by LPS/D-GalN
In the table, p is compared with the control group<0.05; comparison with control group, p<0.01; comparison with control group, p<0.001;#In comparison with model group, p<0.05;##In comparison with model group, p<0.01;###Compared with the model group, p is less than 0.001.
4. And (4) experimental conclusion: flufenidone can effectively treat acute liver injury of mice induced by APAP and LPS/D-GaIN.
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. An application of flufenidone in preparing a drug for treating acute liver injury is characterized in that the flufenidone is used as a raw material for preparing the drug for treating acute liver injury, or the drug comprises a flufenidone component.
2. The use of flufenidone in the preparation of a medicament for treating acute liver injury as claimed in claim 1, wherein the dose of flufenidone administered to a human is from 11 mg/kg to 55 mg/kg.
3. The use of flufenidone in the manufacture of a medicament for treating acute liver injury as recited in claim 1, wherein the flufenidone is 1- (3-fluorophenyl) -5-methyl-2- (1H) pyridone.
4. Use of flufenidone 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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CN1846699A (en) * | 2005-04-13 | 2006-10-18 | 中南大学湘雅医院 | Application of 1- (substituted phenyl) -5-methyl-2- (1H) pyridone (I) compound in preparing medicines for resisting fibrosis of other organs or fibrosis of tissues except renal interstitial fibrosis |
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-
2021
- 2021-07-09 CN CN202110777586.2A patent/CN113456636A/en active Pending
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