CN107875164A - A kind of medicine for treating liver fibrosis - Google Patents
A kind of medicine for treating liver fibrosis Download PDFInfo
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- CN107875164A CN107875164A CN201711170911.9A CN201711170911A CN107875164A CN 107875164 A CN107875164 A CN 107875164A CN 201711170911 A CN201711170911 A CN 201711170911A CN 107875164 A CN107875164 A CN 107875164A
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- China
- Prior art keywords
- liver
- neohesperidin
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- medicine
- liver fibrosis
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
Abstract
The invention discloses neohesperidin prevention or treatment liver fibrosis, atherosclerosis, the purposes of hepatic sclerosis.
Description
Technical field
The present invention relates to pharmaceutical technology field, and in particular to a kind of medicine for treating liver fibrosis.
Background technology
Liver fibrosis is secondary to the generation in various chronic pathogenic factor process of tissue reparation as caused by damage, inflammation etc.
Repay reaction.During damaged liver, due to the increasing of extracellular matrix (extracellular matrixc, ECM) secretion
The reduction for being subject to and degrading, causes ECM largely to deposit, and ultimately results in liver fibrosis, influences the function of liver.As treated not in time
It may then be in progress as hepatic sclerosis, liver failure even liver cancer.
Liver fibrosis is early stage in the reversible stage of hepatic sclerosis, promotees removal or some anti-fibrosis that fibrosis generation stimulates
Therapeutic strategy be expected to reverse liver fibrosis.Urso (Ursodesoxycholic Acid, UDCA) is to treat at present
The active drug of unique FDA approvals of primary liver cirrhosis, but urso is only used for the initial stage of hepatic sclerosis, Er Qiegao
The administration of dosage is harmful.Therefore, reverse the discovery of this process medicine of liver fibrosis that there is important clinical meaning.
Neohesperidin (Neohesperidin, CAS 13241-33-3) is a kind of natural flavonoid compound, usual and shaddock
Skin glycosides (Naringin, CAS 10236-47-2), aurantiamarin (Hesperidin, CAS520-26-3) are present in Rutaceae together
And in madder wort.Neohesperidin and its derivative NHDC (Neohesperidin
Dihydrochalcone Food Science and medical science etc.) are widely used in.
The content of the invention
Application of the neohesperidin in Antiatherosclerosis medicine is prepared is provided regarding to the issue above, with neohesperidin system
The medicine of standby improvement liver fibrosis, has the effect of preferable.
Medicine new opplication field provided by the invention is：Neohesperidin is preparing the effect in improving hepatic fibrosis medicines.
The present invention improvements hepatic fibrosis medicines auxiliary material refer to solvent, disintegrant, flavouring, preservative, colouring agent, glue
The conventional excipients such as mixture.The present invention improves other combination drug things of hepatic fibrosis medicines, refers to the new orange of effective dose
Skin glycosides is certain medicine material, compatibility other allow the Chinese medicine or chemicals that share.
Brief description of the drawings
The liver morphology of accompanying drawing 1. changes
The MTT cytotoxicities of the neohesperidin of accompanying drawing 2. administration
Embodiment
Embodiment 1
Influenceed to study alleviation of the neohesperidin on bile duct ligation mouse fibrosis model, using body weight in 18- 20g
Between male C57BL/6 wild-type mices.First day mouse carries out bile duct ligation operation, during animal is anesthetized fixation and carried out
Section laparotomy ventrotomy.Then, bile duct is exposed from abdominal cavity, and with surgical thread ligation twice, finally by wound suture.Sham-operation group
The same anesthetized mice and stage casing laparotomy ventrotomy is carried out with operation group, but do not ligature bile duct, finally by wound suture.Second day to small
Mouse is grouped at random.One is divided into six groups, and first group is sham-operation group (sham groups), and remaining five groups are BDL modeling groups, are given respectively
With PBS, low middle and high concentration medicine (being 15mg/kg, 30mg/kg, 60mg/kg respectively) and positive drug urso
(UDCA, 24mg/kg).Successive administration 14 days.
Observation index：
The ordinary circumstance of a animals
Experimental animal, illumination 12h nights 12h, free diet drinking-water, animal state is normal during experiment.
B records mouse weight daily during being administered
As a result such as following table：
The mouse weight of table 1. changes
Interpretation of result：
As shown in table 1, sham groups mouse weight slowly rises over time, and the body weight of BDL-PBS modeling groups
Then slowly decline, prompt mouse bile duct ligation modeling success.Low middle dose group same model of changes of weight trend in administration process
Group is the same, but the changes of weight trend of high dose group and positive drug group has been gone up, and prompts neohesperidin and urso
Body weight caused by equally alleviating liver fibrosis reduces.
Embodiment 2
The compound method of neohesperidin：Dissolved with 0.5% CMC-Na solution.The compound method of urso：With nothing
Bacterium PBS dissolves.
Successive administration is drawn materials after 14 days, and sample includes blood, liver.Liver form will take pictures simultaneously, record liver weight, kidney weight
Amount.
Animal's liver is fixed on 10% formalin solution, dehydration, FFPE, section (4 microns of thickness), HE dyeing, light
Learn micro- Microscopic observation：(1) liver cell whether there is denaturation, necrosis；(2) sinus hepaticus whether there is extravasated blood, and there is no inflammation lobuli hepatis and portal area；
(3) the small bile duct in portal area whether there is hyperplasia and surrounding whether there is proliferation of fibrous tissue (fibroplasia), whether there is the pathology such as cell infiltration
Change.
Animal blood, which is stored at room temperature after 1h, to be transferred to 4 DEG C and continues to stand, and is centrifuged after serum precipitation, centrifugal condition is
3500-4000rpm, 10min.The faint yellow serum in upper strata is drawn after centrifugation, with reference to measure kit specification measure Serum ALT
(glutamic-pyruvic transaminase), AST (glutamic-oxalacetic transaminease), T-Bil (total bilirubin).
As a result：
The change of 2.1 liver index and renal index
As a result such as following table：
The mouse renal index of table 2.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
The mouse liver index of table 3.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
Interpretation of result：
As shown above, the liver renal index of model group has obvious significant difference compared with sham-operation group, prompts mouse
Bile duct ligation modeling success.Administration group reduces with the increase of dosage, the liver index of mouse in dose dependent, and in 30mg/
Conspicuousness reduces liver index under kg administration concentration, and liver index is less than positive drug group under 60mg/kg administration concentration, and positive
There was no significant difference with high dose administration group for the liver index of medicine group, prompts neohesperidin to play the role of well to reduce liver index.Separately
Outside, administration group also has conspicuousness reduction with the increase of dosage, the renal index of mouse, and kidney refers under 60mg/kg administration concentration
Number reduction degree is slightly below positive drug group.Find out that neohesperidin can effectively reduce liver fibrosis mouse from the change of liver renal index
Liver renal index, it is better than existing medicine urso in terms of liver index is reduced.
2.2 liver pathologies detect
Experimental result：
The hepatic fibrosis in mice result of table 4.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
The Mouse Liver bile duct proliferation result of table 5.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
The Mouse Liver inflammatory consequences of table 6.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
Analysis of experimental results：
As shown in figure 1, sham-operation group liver surface is smooth, and in normal cerise, and modeling group liver surface is thick
Rough, color is in yellow.Administration group is with the increase of dosage, and liver surface tends to smooth, and color also switchs to normal red.
Under 15mg/kg administration concentration, liver surface is slightly yellow, but under 30mg/kg administration concentration, liver surface has turned to red,
And under 60mg/kg administration concentration, liver surface color almost recovers to normal level, and than positive drug group liver surface more
It is smooth.
Accompanying drawing 1B is the result of hepatic tissue HE dyeing.Sham group liver cell polygons, endochylema enrich, and core is big and justifies, and liver is thin
Born of the same parents are in individual layer radial arrangement around central vein.Model group liver cell shape is still visible, karyopyknosis or dissolving, and endochylema is light
So, it is matt；The cell infiltration of volume is seen around the liver cell of necrosis；Small bile duct severe hyperplasia is seen in portal area, illustrates bile duct
Ligature model copy success.Administration group is with the increase of dosage, and fibrosis lesion degree gradually mitigates, especially in 60mg/kg
Administration concentration under lesion degree with positive drug UCDA groups, slight hepatic cell necrosis, see very small amount bleeding around downright bad liver cell
And cell infiltration, the small bile duct mild hyperplasia in portal area.
Table 4/5/6 is HE section appraisal results.Either in fibrosis, bile duct proliferation or aspect of inflammation, model group with
Sham-operation group has obvious significant difference, again shows that the success of bile duct ligation model.With the increase of administration concentration, fiber
Change degree is gradually alleviated, and bile duct proliferation degree reduces level of inflammation and significantly reduced.Lesion of the high dose administration group with positive drug group
Degree does not have significant difference, prompts effect of the neohesperidin in terms of liver fibrosis is alleviated obvious.
2.3 Serum Indexes detect
Experimental result：
The mouse ALT results of table 7.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
The mouse AST results of table 8.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
The mouse T-BIL results of table 9.
Compared with model group, * P ＜ 0.05, * * P ＜ 0.01, * * * P ＜ 0.001
Analysis of experimental results：
As shown in table 7/8/9, compared with sham-operation group, ALT, AST and the T-Bil of model group serum have significantly significantly
Sex differernce, again show that the success of bile duct ligation model.With the increase of administration concentration, ALT, AST and T-Bil content are in
Existing dose dependent declines.And under 60mg/kg administration concentration, ALT, AST and T-Bil content and positive drug group are without aobvious
Sex differernce is write, prompts neohesperidin to have good clinical value in terms of liver function is alleviated.
Embodiment 3
Cell culture condition：Take the logarithm the HSC-T6 cells in growth period, with 3 × 105Density plant in 96 orifice plates,
It is incubated overnight.Next day, administration processing 24h, administration concentration is respectively 0.01,0.1,1,10,100 μM.10 μ L MTT are added per hole
Solution (0.5mg/mL), continue to cultivate 4h.After discarding culture medium, 150 μ L DMSO are added per hole, after shaking 10min, at 490nm
Absorbance is determined, calculates cell viability value.
As a result：
Such as accompanying drawing 2, neohesperidin administration concentration is respectively 0.01,0.1,1,10,100 μM, MTT cytotoxicity experiment tables
Bright, neohesperidin is to cytotoxic.
Claims (3)
1. neohesperidin is used to prepare the composition for treating or preventing treatment liver fibrosis.
2. neohesperidin is used to prepare the composition for treating or preventing hepatic sclerosis.
3. neohesperidin, which is used to prepare, treats or prevents the composition of any one or more in liver fibrosis, hepatic sclerosis, it is special
Sign is
For neohesperidin or its pharmaceutical salts that are commercially available or being prepared by known method, hydrate or anhydride；
Wherein neohesperidin pharmaceutical salts include basic salt, such as acid salt, sodium salt, sylvite and calcium salt, maleate, citrate；
Composition is made：Medicine, health products or functional food, excipient or carrier are to be commonly used in pharmacy or field of food
Excipient or carrier, such as diluent, disintegrant, lubricant etc..
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711170911.9A CN107875164A (en) | 2017-11-16 | 2017-11-16 | A kind of medicine for treating liver fibrosis |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711170911.9A CN107875164A (en) | 2017-11-16 | 2017-11-16 | A kind of medicine for treating liver fibrosis |
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| Publication Number | Publication Date |
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| CN107875164A true CN107875164A (en) | 2018-04-06 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201711170911.9A Pending CN107875164A (en) | 2017-11-16 | 2017-11-16 | A kind of medicine for treating liver fibrosis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117224558A (en) * | 2023-08-21 | 2023-12-15 | 中山大学附属第三医院 | Application of RNA editing enzyme inhibitor in preparation of medicines for preventing and/or treating hepatic fibrosis |
| CN117224558B (en) * | 2023-08-21 | 2024-05-17 | 中山大学附属第三医院 | Application of RNA editing enzyme inhibitor in preparation of medicines for preventing and/or treating hepatic fibrosis |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107028962A (en) * | 2017-04-14 | 2017-08-11 | 杭州禹正医药科技有限责任公司 | Application of the neohesperidin in preventing and treating tumour medicine is prepared |
| CN107188912A (en) * | 2016-03-15 | 2017-09-22 | 折改梅 | A kind of NHDC obtained from Oxytropis Species |
-
2017
- 2017-11-16 CN CN201711170911.9A patent/CN107875164A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107188912A (en) * | 2016-03-15 | 2017-09-22 | 折改梅 | A kind of NHDC obtained from Oxytropis Species |
| CN107028962A (en) * | 2017-04-14 | 2017-08-11 | 杭州禹正医药科技有限责任公司 | Application of the neohesperidin in preventing and treating tumour medicine is prepared |
Non-Patent Citations (2)
| Title |
|---|
| YK KIM等: "Cytoprotective effects of natural flavonoids on carbon tetrachloride-induced toxicity in primary cultures of rat hepatocytes", 《KOREAN SOCIETY OF PHARMACOGNOSY》 * |
| 张硕等: "4种黄酮类化合物对CCl4致小鼠肝纤维化的防治作用", 《华西药学杂志》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN117224558A (en) * | 2023-08-21 | 2023-12-15 | 中山大学附属第三医院 | Application of RNA editing enzyme inhibitor in preparation of medicines for preventing and/or treating hepatic fibrosis |
| CN117224558B (en) * | 2023-08-21 | 2024-05-17 | 中山大学附属第三医院 | Application of RNA editing enzyme inhibitor in preparation of medicines for preventing and/or treating hepatic fibrosis |
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Application publication date: 20180406 |