CN114209708A - Application of alendronic acid in preparation of medicine for treating hepatic fibrosis - Google Patents

Application of alendronic acid in preparation of medicine for treating hepatic fibrosis Download PDF

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CN114209708A
CN114209708A CN202111586548.5A CN202111586548A CN114209708A CN 114209708 A CN114209708 A CN 114209708A CN 202111586548 A CN202111586548 A CN 202111586548A CN 114209708 A CN114209708 A CN 114209708A
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mice
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alendronate
hepatic fibrosis
acid
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崔文浩
赵成江
王猛
武佳琦
郑智
田欢栋
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Youjia Hangzhou Biomedical Technology Co ltd
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • A—HUMAN NECESSITIES
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Abstract

The invention relates to application of alendronic acid in treating hepatic fibrosis, liver injury and the like. Aiming at the current situation that no effective means for treating acute liver injury and hepatic fibrosis exists at present, the inventor of the invention finds that the alendronate can play a role in treating the carbon tetrachloride-induced acute liver injury and chronic hepatic fibrosis models and can obviously relieve the acute liver injury and the hepatic fibrosis through deep research. During the experiment, no obvious toxicity is found.

Description

Application of alendronic acid in preparation of medicine for treating hepatic fibrosis
Technical Field
The invention relates to the field of medical application, in particular to application of alendronate in treating hepatic fibrosis.
Background
Hepatic fibrosis is the result of liver injury, is the abnormal proliferation of connective tissue in the liver caused by various pathogenic factors, may cause liver dysfunction, and is the main process of liver injury developing into other chronic diseases. It causes the accumulation of extracellular matrix in response to the recruitment of inflammatory cells of chronic injury and the activation of Hepatic Stellate Cells (HSCs). Steatosis (steatosis) is commonly associated with hepatitis and hepatocellular damage. Regardless of its etiology, increased oxidative stress is a common factor that causes fibrosis in all chronic liver diseases. Damaged hepatocytes, HSCs and infiltrating inflammatory cells are the major sources of Reactive Oxygen Species (ROS). Indeed, oxidative stress will induce the recruitment of inflammatory cells and the activation of HSCs. Thus, in the context of chronic liver injury, a vicious cycle of hepatocyte injury, ROS production, HSC activation, and inflammatory cell recruitment will occur, amplifying the fibrotic response to the injury. At present, the medicines for treating liver injury and hepatic fibrosis are relatively lack.
Allenic acid (Arundic acid, ONO-2506) was developed by the Min Ye pharmaceutical industries, Inc. as a drug for treating stroke, Alzheimer's disease, Parkinson's disease. Currently, it is widely believed that the alendronic acid is mainly used in the field of cerebral neuropathy, is an astrocyte regulator, and delays the expansion of cerebral infarction by inhibiting the synthesis of S100 beta and regulating the activation of astrocytes. At present, no research report of Arundic acid for treating hepatic fibrosis is found.
Disclosure of Invention
The invention aims to provide application of alendronate in treating hepatic fibrosis.
The technical scheme of the invention is as follows:
use of alendronate in preparing medicine for treating hepatic fibrosis is provided.
Further, the liver fibrosis is liver fibrosis caused by toxic substances or drugs.
Further, the liver fibrosis is caused by a high fat diet.
The other technical scheme provided by the invention is as follows:
use of alendronate in the preparation of a medicament for the treatment of liver injury.
Further, the liver injury is acute liver injury.
Further, the liver damage is caused by a toxic substance or a drug.
Further, the liver injury is caused by a high fat diet.
The other technical scheme provided by the invention is as follows:
use of alendronate in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis.
Further, the non-alcoholic steatohepatitis is caused by high-fat diet.
Further, the non-alcoholic steatohepatitis is caused by a choline-methionine deficiency diet.
The other technical scheme provided by the invention is as follows:
use of alendronate in the preparation of a medicament for the treatment of cholestatic hepatitis.
Further, the hepatic cholestatic hepatitis is acute cholestatic hepatitis.
The other technical scheme provided by the invention is as follows:
use of alendronic acid in the preparation of a medicament for the treatment of pulmonary fibrosis.
Further, the pulmonary fibrosis is pulmonary fibrosis or idiopathic pulmonary fibrosis caused by toxic substances or medicaments.
The invention realizes the technical effects that:
aiming at the current situation that no effective means for treating acute liver injury and hepatic fibrosis exists at present, the inventor of the invention finds that the alendronate can play a therapeutic role in tests of carbon tetrachloride-induced acute liver injury and chronic hepatic fibrosis models, alpha-naphthalene isothiocyanate (ANIT) -induced acute cholestatic hepatitis of mice, bleomycin-induced pulmonary fibrosis of mice and high-fat diet-induced nonalcoholic steatohepatitis of mice through deep research, can obviously relieve the acute liver injury, the hepatic fibrosis, the cholestatic hepatitis or the nonalcoholic steatohepatitis, and plays an obvious therapeutic role. During the experiment, no obvious toxicity is found.
Drawings
FIG. 1 example 1 groups of CCl4Induced acute liver injury model mouse ALT influence contrast map;
FIG. 2 example 1 pairs of CCl4Induced acute liver injury model mouse AST influence contrast chart;
FIG. 3 example 1 pairs of CCl4Comparing induced acute liver injury model mouse liver HE slices;
wherein, the Arundic acid group is an Allenic acid medium dosage group;
FIG. 4 example 2 pairings CCl4Induced chronic liver fibrosis model mouse ALT influence contrast map;
FIG. 5 example 2 pairings CCl4Induced chronic liver fibrosis model mouse AST influence contrast chart;
FIG. 6 example 2 pairings CCl4Induced chronic liver fibrosis model mouse ALT/AST influence contrast map;
FIG. 7 example 2 pairings CCl4Induced chronic liver fibrosis model mouse TBIL influence contrast chart;
FIG. 8 example 2 pairings CCl4Comparing the induced chronic liver fibrosis model mouse liver sirius red slices;
wherein, the Arundic acid group is an alendronic acid middle dose group.
Detailed Description
The following examples serve to illustrate the invention in further detail, but without restricting it in any way.
Example 1: effect of Allenic acid on carbon tetrachloride-induced acute liver injury in mice, and comparison with the Positive drug Silibinin
1. Materials and methods
56 male C57BL/6 mice (Viton-Li-Hua) were testedInitial mouse weight 24+1g of the total weight of the composition. The breeding is carried out adaptively for one week under the culture conditions of 24-26 ℃ of temperature, 60% of humidity and 12h of light and shade. Mixing CCl with a volume ratio of 1:34And olive oil, 0.05mL/10g (body weight) CCl was intraperitoneally injected once into each male C57BL/6 mouse except for the control group4Olive oil solution, control group was injected with an equal volume of olive oil intraperitoneally. After 24h of molding, the alendronic acid and the silybin are subjected to intervention according to the following groups, after 48h, the samples are killed, and the serum and the liver of the mouse are respectively frozen and fixed by 4 percent paraformaldehyde.
2. Method of administration
The alendronate was dissolved using physiological saline containing 0.1% v/v Tween 80.
3. Grouping design
Figure DEST_PATH_IMAGE002
4. Test results
(1) Allen acid p CCl4Effect of ALT in induced acute liver injury model mice
As shown in FIG. 1, mice were injected intraperitoneally with CCl4After 48 hours later, the ALT level in the serum of the model mice was significantly elevated compared to that of the normal control group (. about.P)<0.01); compared with the model group, the positive control medicament silybin group can reduce ALT level in serum, but has no statistical difference; the ALT level (# # P) in serum can be obviously reduced by the dose group in the alendronic acid<0.01), ALENIC ACID LOW, HIGH DOSE GROUP also can reduce ALT LEVEL (# P)<0.05), the effect is weaker than that of the dose group in the alendronate.
(2) Allen acid p CCl4Effect of AST in induced acute liver injury model mice
As shown in FIG. 2, mice were injected intraperitoneally with CCl4After 48 hours later, the AST levels in the serum of the model group mice increased significantly compared to the normal control group (. about.p)<0.01); the positive control drug silibinin group was able to reduce AST levels in serum compared to the model group, but had no statistical difference; the alendronic acid middle and high dose groups can obviously reduce serumAST levels (# # P)<0.01), the low-dose group of alendronic acid was also able to reduce AST levels (# P)<0.05), the effect is weaker than that of the dose group in the alendronate.
(3) Allen acid p CCl4Effect of induced acute liver injury model mice on HE sections of the liver
As shown in FIG. 3, mice were injected intraperitoneally with CCl4After 48 hours later, the HE staining result of the liver tissue shows that compared with a control group, the cell degeneration and necrosis of the model group are increased, the cell necrosis can be reduced by all the groups of the alendronate and the positive control medicament silybin group, and the treatment effect of the dose group in the alendronate is obvious.
Example 2: effect of Allenic acid on carbon tetrachloride-induced chronic liver fibrosis models in mice, and comparison with the positive drug Silibinin
1. Materials and methods
56 male C57BL/6 mice (Wittingle) weighed 20% at the beginning of the experiment+1g of the total weight of the composition. The breeding is carried out adaptively for one week under the culture conditions of 24-26 ℃ of temperature, 60% of humidity and 12h of light and shade. Mixing CCl with a volume ratio of 2:54And olive oil, administered by intraperitoneally injecting 0.02ml/10g (body weight) CCl every three days to each male C57BL/6 mouse except for the control group4Olive oil solution, control group was injected with an equal volume of olive oil intraperitoneally for 6 weeks of molding. The test drug administration was started 2 weeks after molding for 4 weeks (28 days), and the administration was terminated 6 weeks later.
2. Method of administration
The same as in example 1.
3. Grouping design
Figure DEST_PATH_IMAGE004
4. Test results
(1) Allen acid p CCl4Effect of ALT in induced Chronic hepatic fibrosis model mice
As shown in FIG. 4, mice were injected intraperitoneally with CCl4The ALT level in the serum of the model group mice is very obvious compared with that of a normal control group after the model is molded for 2 weeks and the drug administration is continued for 4 weeks and after 6 weeks, the model is molded and the drug administration is finishedRising of (c) P<0.01); compared with the model group, the positive control medicament silybin group can obviously reduce ALT level (# # P) in serum<0.01); the low, medium and high dose groups of the alendronic acid can obviously reduce ALT level (# # P) in serum<0.01), the effect of the dose group in the alendronate is most obvious.
(2) Allen acid p CCl4Effect of AST in induced Chronic hepatic fibrosis model mice
As shown in FIG. 5, mice were injected intraperitoneally with CCl4After 2 weeks of molding and 4 weeks of continuous administration, and 6 weeks of molding and end of administration, the AST level in the serum of the model mice was significantly increased compared with that of the normal control group (. about.P)<0.05); compared with the model group, the dose group of the alendronic acid and the positive control medicament silybin group can obviously reduce the AST level in serum (# P)<0.05); the low, high dose group of alendronate was also able to reduce AST levels in serum, but with no statistical difference.
(3) Allen acid p CCl4Effect of induced ALT/AST in Chronic liver fibrosis model mice
As shown in FIG. 6, mice were injected intraperitoneally with CCl4After 2 weeks of modeling and 4 weeks of continuous administration, and 6 weeks of modeling and end of administration, the ALT/AST level in the serum of the model mice was significantly increased compared with that of the normal control group (P)<0.01); compared with the model group, the positive control medicament silybin group can obviously reduce ALT/AST level (# # P) in serum<0.01); the ALT/AST level (# # P) in serum can be obviously reduced in low, medium and high dose groups of the alendronic acid<0.01）。
(4) Allen acid p CCl4Effect of induced TBIL in Chronic hepatic fibrosis model mice
As shown in FIG. 7, mice were injected intraperitoneally with CCl4After 2 weeks of modeling and 4 weeks of continuous administration, and 6 weeks of modeling and end of administration, the levels of TBIL in serum of model mice increased significantly compared to normal control group (. about.P)<0.01); compared with the model group, the positive control medicament silibinin group and the low-dose and high-dose groups of the alendronic acid can reduce the TBIL level in serum, but have no statistical difference, and the middle dose of the alendronic acid isThe group was also able to reduce TBIL levels (# P) in serum<0.05）。
(5) Allen acid p CCl4Influence of liver sirius red section of induced chronic liver fibrosis model mouse
As shown in FIG. 8, mice were injected intraperitoneally with CCl4After 2 weeks of molding, the drug is continuously administered for 4 weeks, and after 6 weeks of molding and drug administration, the liver tissue sirius red staining shows that the type I collagen in the model group manifold area is obviously deposited and extended and is mutually crosslinked to form a false lobular structure compared with a control group. The alendronate group and the silibinin group serving as a positive control medicament can reduce the type I collagen deposition in the zone of the sink, and the effect of the dosage group in the alendronate is more obvious.
Example 3: pharmacodynamic effect of alendronate in alpha-naphthalene isothiocyanate (ANIT) induced mouse acute cholestatic hepatitis model
Reagent and apparatus
ANIT (available from sigma, usa, lot No. N4525), soybean oil (goldfish, Q/BBAH 0019S), alenic acid (apextio B); glutamic-pyruvic transaminase (ALT) detection kit, glutamic-oxalacetic transaminase (AST) detection kit, Total Bilirubin (TB) detection kit, Direct Bilirubin (DB) detection kit, bile acid (TBA) detection kit and alkaline plum phosphate (ALP) detection kit (Zhongsheng Bei-controlled Biotechnology GmbH).
Experimental methods
Normal male C57 mice were used in this experiment, 40 mice (vindolite) were divided into 5 groups by weight. Modeling and dosing were as follows:
Figure DEST_PATH_IMAGE006
model group animals were sacrificed 48 hours after administration of ANIT (i.e., day 6, fasted for more than 6 hours) on day 4 with 75mg/kg of naphthyl isothiocyanate (ANIT, dissolved in soybean oil); the low, medium and high dose groups of alendronate were administered on day 4 with 75mg/kg ANIT (dissolved in soybean oil) and the animals were sacrificed 48 hours after administration of the drug and ANIT (i.e. day 6, fasted for more than 6 hours).
After the test is finished, collecting serum samples for detecting each corresponding index to evaluate the drug effect. Biochemical blood tests, AST, ALT, Total Bilirubin (TB), Direct Bilirubin (DB), Total Bile Acid (TBA), ALP;
data analysis
After the experimental data are sorted and analyzed, Office Excel 2019 is used for data analysis and table making, independent samples are tested by t, P is less than 0.01, the difference is extremely obvious compared with a blank control group, and P # is less than 0.01, the difference is extremely obvious compared with a model group, and the statistical significance is achieved.
The results are shown in attached tables 4 and 5, and ANIT can cause significant elevation of ALT, AST, ALP, TBA, TB and DB in mouse serum, which indicates successful modeling. Allenic acid was able to reduce ALT, ALP and TBA levels in serum at high doses (0.25 mg/kg), with significant statistical differences compared to the model group. The results show that the alendronic acid has good protective effect on the ANIT-induced cholestasis model.
Figure DEST_PATH_IMAGE008
Figure DEST_PATH_IMAGE010
Example 4: effect of alendronic acid on improvement of pulmonary fibrosis of mice induced by bleomycin
Reagent and apparatus
Bleomycin (Zhejiang Haizian drug industry, national drug standard H20055883, 15 mg); hydroxyproline (HYP) kit (a030-2-1), alenic acid (apextio, B7676).
Experimental methods
Animal grouping and model preparation BALB/c mice were randomly divided into control, model and low, medium and high alendronate groups, 12 per group, according to the random number table method. Carrying out intraperitoneal injection anesthesia by using 1.5% sodium pentobarbital (2.5mL/kg), fixing on a table in a supine manner, cutting off neck hair, disinfecting by ethanol, separating layer by layer and exposing an air pipe, penetrating the air pipe into an injector through the annular gap of the air pipe cartilage towards the centripetal end, slowly injecting 0.3 mL of bleomycin physiological saline solution (5mg/kg), continuously injecting 0.3 mL of air, immediately standing the animal after injection, rotating the animal left and right to uniformly distribute the liquid medicine in the lung. Wherein the lungs of sham operated rats were injected with an equal volume of saline. After 24h, the mice in the low, medium and high groups of the alendronate are subjected to intraperitoneal injection administration according to the set dose, and the control group and the model group are injected with the same volume of normal saline. Followed by once daily dosing. After 21 days, the mice were sacrificed, lung tissues were snap frozen in liquid nitrogen and placed in a freezer at-80 ℃ for future use.
Statistical method
The Office Excel 2019 is used for data analysis and table making, independent samples are tested by t, P is less than 0.01, the difference is extremely obvious compared with a blank control group, P is less than 0.01, the difference is extremely obvious compared with a model group, and the statistical significance is achieved.
The results are shown in the attached table 6, the alexanic acid in the three dose groups can obviously reduce the bleomycin-induced increase of the hydroxyproline content in the lung tissue, and the dose-effect relationship is shown, which indicates that the drug has the effect of resisting pulmonary fibrosis.
Figure DEST_PATH_IMAGE012
Example 5: effect of alendronic acid on improving non-alcoholic fatty liver disease of high-fat diet-induced mice
Reagent and apparatus
High-fat feed (Research Diets type: D12492, containing 60% milk fat), fructose, sucrose, enzyme-linked immunosorbent assay, analytical balance, injector, surgical instrument
Model group mice were fed with 42g/L sugar (fructose: sucrose = 55%: 45%) in the drinking water, example: 1L of water was supplemented with 23.1g fructose +18.9g sucrose. The control mice were given normal water.
Allenic acid was dissolved using physiological saline containing 0.1% v/v Tween 80.
Experimental methods
50 male C57BL/6J mice (SPF grade) with age of 8-10 weeks, weight 20+1g of the total weight of the composition. The breeding conditions are as follows: the temperature is 24-26 ℃, the humidity is 60%, and the brightness is 12h each.
After one week of acclimatization, 10 control groups were fed with normal feed, 50 molding mice, and male C57BL/6J mice were fed with HFHF, while maintaining free diet, for 16 weeks. Mice were observed daily for survival during the period and body weights were recorded weekly. The test drug is administered starting after 12 weeks for 4 weeks and ending after 16 weeks.
Group design and drug administration treatment
Figure DEST_PATH_IMAGE014
Statistical method
The Office Excel 2019 is used for data analysis and table making, independent samples are tested by t, P is less than 0.01, the difference is extremely obvious compared with a blank control group, P is less than 0.01, the difference is extremely obvious compared with a model group, and the statistical significance is achieved.
As shown in table 8, high-fat high-sugar diet can significantly increase TC, TG content in liver tissue of mice, suggesting lipid deposition in liver tissue. The alendronate in the medium and high dose groups can reduce the TC content of the liver tissue, and has a significant difference (P < 0.05) compared with the model group. The alendronate in the low, medium and high dose groups can obviously reduce the TG content of the liver tissue (P < 0.01).
As shown in Table 9, the high-fat and high-sugar diet can significantly increase ALT and AST in mouse serum, which indicates that hepatic cells are damaged, and the TC and TG content in the serum increase, which indicates that the lipid metabolism capability of liver exceeds load, and indicates that the model is successfully constructed. The alendronate can reduce ALT content in serum, and the medium and high dose groups have significant difference compared with the model group (# # P < 0.01). The alendronate in the low, medium and high dose groups can reduce the AST and TG contents in serum. Allenic acid has no statistical significance for the down-regulation of TC content in serum.
Figure DEST_PATH_IMAGE016
Figure DEST_PATH_IMAGE018

Claims (9)

1. Use of alendronate in preparing medicine for treating hepatic fibrosis is provided.
2. Use according to claim 1, characterized in that: the hepatic fibrosis is caused by toxic substances, medicines or high fat diet.
3. Use of alendronate in the preparation of a medicament for the treatment of liver injury.
4. Use according to claim 3, characterized in that: the liver damage is caused by toxic substances, drugs or high fat diet.
5. Use of alendronate in the preparation of a medicament for the treatment of non-alcoholic steatohepatitis.
6. Use according to claim 5, characterized in that: the non-alcoholic steatohepatitis is caused by high-fat diet.
7. Use of alendronate in the preparation of a medicament for the treatment of cholestatic hepatitis.
8. Use of alendronic acid in the preparation of a medicament for the treatment of pulmonary fibrosis.
9. Use according to claim 8, characterized in that: the pulmonary fibrosis is pulmonary fibrosis or idiopathic pulmonary fibrosis caused by toxic substances or medicaments.
CN202111586548.5A 2020-12-23 2021-12-23 Application of alendronic acid in preparation of medicine for treating hepatic fibrosis Pending CN114209708A (en)

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