CN106667981A - Application of Fingolimod hydrochloride in preparation of drugs for treating drug-induced liver injury - Google Patents
Application of Fingolimod hydrochloride in preparation of drugs for treating drug-induced liver injury Download PDFInfo
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- CN106667981A CN106667981A CN201710032575.5A CN201710032575A CN106667981A CN 106667981 A CN106667981 A CN 106667981A CN 201710032575 A CN201710032575 A CN 201710032575A CN 106667981 A CN106667981 A CN 106667981A
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- China
- Prior art keywords
- fty720
- apap
- liver injury
- liver
- fingolimod hydrochloride
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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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
Abstract
The invention relates to application of Fingolimod hydrochloride in preparation of drugs for treating drug-induced liver injury. The Fingolimod hydrochloride (FTY720) can be used for remarkably lowering the level of alanine transaminase and aspartate transaminase in APAP-induced liver injury, reducing the area of necrosis of liver tissue, lowering the mouse death rate induced by fatal dose of APAP and reducing the expression level of inflammatory factors and chemotactic factors during the drug-induced liver injury.
Description
Technical field
The invention belongs to field of medicaments, and in particular to fingolimod hydrochloride is in curative physical property liver injury medicament is prepared
Using.
Background technology
Liver is easily damaged as the important removing toxic substances organ of human body by toxicant.In China, hepatopathy is a kind of morbidity
Rate is high, it is difficult to which the disease of radical cure, is also one of common difficult treatment in the world today.The % of China HBV carrier rate about 10,
It is very big to human health damage.Hepatic injury is universal susceptible in crowd, and incubation period is short, and the process of pathological changes is direct with the dosage of infection
Correlation, can cause the different degrees of hepatic necrosis of liver, fat deformation, liver cirrhosis and hepatocarcinoma.Multi-medicament can cause liver
Damage, such as antineoplastic chemotherapeutic, antitubercular agent, antipyretic analgesic, immunosuppressant, hypoglycemic medicine, antibacterium, antifungal
And antiviral agents etc..Various the liver protecting and ALT lowering medicament categories are various, such as antiviral therapy medicine, immunoregulation medicament, and really have
The liver protecting and ALT lowering medicine of effect is few in number, and side effect is very big, to use with caution over the course for the treatment of.
Fingolimod hydrochloride（FTY720）It is a kind of neotype immunosuppressant newfound in recent years, is used for treatment many more
The property sent out sclerosiss.The medicine selectivity reduces peripheral circulation lymphocyte number, significantly extends the existence of laboratory animal transplant organ, together
When do not damage immunne response and immunological memory function to virus, toxic and side effects are low.
The content of the invention
The technical problem of solution：The present invention is carried for the problem of large side effects during existing the liver protecting and ALT lowering medicine use
For a kind of application of fingolimod hydrochloride in curative physical property liver injury medicament is prepared.
Technical scheme：Fingolimod hydrochloride（FTY720）Application in curative physical property liver injury medicament is prepared.
Curative physical property liver injury medicament, effective ingredient is fingolimod hydrochloride（FTY720）.
Fingolimod hydrochloride（FTY720）Application in preventive drug physical property liver injury medicament is prepared.
Preventive drug physical property liver injury medicament, effective ingredient is fingolimod hydrochloride（FTY720）.
Beneficial effect：Fingolimod hydrochloride（FTY720）Acetaminophen can be significantly reduced（APAP）The hepatic injury of induction
The level of middle glutamate pyruvate transaminase and glutamic oxaloacetic transaminase, GOT, reduces necrosis of liver tissue area, reduces the mice of fatal dose APAP inductions
Mortality rate, the expression of inflammatory factor and chemotactic factor when reducing drug induced hepatic injury.
Description of the drawings
Fig. 1 is the hepatic injury result schematic diagram that FTY720 mitigates APAP inductions.A diagram datas show APAP induced liver injuries
After 6 hours, mice serum glutamic oxaloacetic transaminase, GOT（AST）Level substantially rises；And mice serum AST levels show in FTY720 treatment groups
Write and be less than non-treatment group；After 24 hours, AST levels steeply rise the bright APAP induced liver injuries of B charts in mice serum；And
Mice serum AST levels remain at relatively low level compared with non-treatment group in FTY720 treatment groups；C diagram datas show APAP
After induced liver injury 6 hours, glutamate pyruvate transaminase in mice serum（ALT）Level substantially rises；And mice in FTY720 treatment groups
Serum ALT levels are substantially less than non-treatment group；The bright APAP induced liver injuries of D charts are after 24 hours, ALT levels urgency in mice serum
Play rises；And mice Serum ALT levels are remarkably decreased compared with non-treatment group in FTY720 treatment groups.
Fig. 2 can reduce APAP for FTY720 causes necrosis of liver tissue result schematic diagram.A figures are contaminated with histopathology HE
Come necrosis of liver tissue region after detecting APAP and processing 6 hours and 24 hours, matched group and the mono- treatment groups of FTY720 color do not occur
There is necrosis of liver tissue in necrosis of liver tissue, APAP treatment groups after 6 hours, and in FTY720 treatment groups mice hepatic necrosis region
Area substantially reduce（A figures left side quantifies figure for necrosis area）；APAP treatment groups after 24 hours necrosis of liver tissue region it is notable
Increase；Equally, the area in the hepatic necrosis region of mice is substantially reduced in FTY720 treatment groups.B figures be with TUNEL stainings come
Detection necrosis of liver tissue region.After APAP treatment groups 24 hours, murine liver tissue necrotic zone substantially increases, and APAP processes half
Lumbar injection FTY720 is given after hour, the area in hepatic necrosis region is significantly reduced.
Fig. 3 can reduce APAP for FTY720 causes the infiltration result schematic diagram of liver tissues inflammatory cell.Matched group and
There are less neutrophilic granulocyte and macrophages infiltration in the mono- treatment groups of FTY720 around the lobules of liver of mice, APAP treatment groups are little
The a large amount of neutrophilic granulocytes of lobules of liver center dispersivity necrotic zone appearance of Mus and macrophage, and mice in FTY720 treatment groups
Necrosis of liver tissue region in neutrophilic granulocyte and macrophage numbers substantially reduce.
Fig. 4 is the mortality results schematic diagram that FTY720 can reduce fatal dose APAP inducing mouses.Fatal dose
After APAP process, mice is all dead in 24 hours, and the survival rate of the mice in FTY720 treatment groups is 36.364%, with
Fatal dose APAP groups are compared, and difference has statistical significance.
Specific embodiment
The following examples can make those skilled in the art that the present invention is more fully understood, but limit this never in any form
Invention.
Embodiment 1
FTY720 mitigates the hepatic injury of APAP inductions
1st, method：Test kit source needed for experiment：AST and ALT test kits build up Bioengineering Research Institute, FTY720 purchased from Nanjing
Purchased from Cayman Chemical companies.Experiment is divided into 4 groups：The mono- place of the mono- treatment group of C57BL/6 Normal groups, FTY720, APAP
Reason group, FTY720 and APAP coprocessing groups.Mice starved overnight, lumbar injection phosphate buffer or APAP (250 mg/kg
) after 0.5 hour, lumbar injection FTY720 (5 mg/kg), respectively mice is put to death in anesthesia behind 6 hours and 24 hours, takes blood.
2nd, result：See Fig. 1, give mouse peritoneal injection APAP (250 mg/kg), can be observed at 6 hours and 24 hours
AST and ALT expressions are significantly raised in serum；And FTY720 (5 mg/kg) and APAP coprocessing groups, AST and ALT in serum
Level is significantly reduced.
Embodiment 2
FTY720 can reduce necrosis of liver tissue caused by APAP
1st, method：Mice is by packet, mice starved overnight, lumbar injection phosphate buffer or APAP described in embodiment 1
After (250 mg/kg) 0.5 hour, lumbar injection FTY720 (5 mg/kg), respectively anesthesia is put to death behind 6 hours and 24 hours
Mice, taking hepatic tissue carries out H ＆ E dyeing and TUNEL dyeing.
2nd, result：See Fig. 2, after APAP process, Mouse Liver centrilobular dispersivity apoptosis necrotic zone substantially increases, Jing
After FTY720 is treated 6 hours and 24 hours, murine liver tissue necrotic zone is substantially reduced.
Embodiment 3
FTY720 can reduce the infiltration of liver tissues inflammatory cell caused by APAP
1st, method：Mice is by packet, starved overnight, lumbar injection phosphate buffer or APAP (250 described in embodiment 1
Mg/kg) after 0.5 hour, lumbar injection FTY720 (5 mg/kg), respectively the anesthetized mice behind 6 hours and 24 hours, takes out
Liver, liver organization is cut into slices after fixing 72 hours at 4 degree with 4% formalin, and groupization is dyeed using MPO and CD68.
2nd, result：See Fig. 3, after APAP process, the neutrophilic granulocyte of Mouse Liver centrilobular dispersivity necrotic zone and huge
Phagocyte number substantially increases, compared with the mono- treatment groups of APAP, in FTY720 and APAP coprocessing group necrosis of liver tissue region
Neutrophilic granulocyte and macrophage numbers are substantially reduced.
Embodiment 4
FTY720 can reduce the mortality rate of fatal dose APAP inducing mouses
1st, method：Mice is grouped as described in embodiment 1, starved overnight, lumbar injection APAP (700 mg/kg), after 30 minutes
Intraperitoneal administration FTY720 (5 mg/kg), in 48 hours The dead quantity is counted.
2nd, result：See Fig. 3, it is all dead in 24 hours after injected in mice fatal dose APAP；And FTY720 treatment groups
In mice 48 hours survival rate be 36.364%.
Claims (4)
1. fingolimod hydrochloride（FTY720）Application in curative physical property liver injury medicament is prepared.
2. curative physical property liver injury medicament, effective ingredient is fingolimod hydrochloride（FTY720）.
3. fingolimod hydrochloride（FTY720）Application in preventive drug physical property liver injury medicament is prepared.
4. preventive drug physical property liver injury medicament, effective ingredient is fingolimod hydrochloride（FTY720）.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710032575.5A CN106667981B (en) | 2017-01-16 | 2017-01-16 | Fingolimod hydrochloride is preparing the application in medicine physical property liver injury medicament |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710032575.5A CN106667981B (en) | 2017-01-16 | 2017-01-16 | Fingolimod hydrochloride is preparing the application in medicine physical property liver injury medicament |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106667981A true CN106667981A (en) | 2017-05-17 |
| CN106667981B CN106667981B (en) | 2019-05-14 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN201710032575.5A Expired - Fee Related CN106667981B (en) | 2017-01-16 | 2017-01-16 | Fingolimod hydrochloride is preparing the application in medicine physical property liver injury medicament |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010077741A1 (en) * | 2008-12-09 | 2010-07-08 | The Trustees Of Columbia University In The City Of New York | Diagnosis and therapy of organ dysfunction using sphinganine-1-phosphate |
| CN102209705A (en) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | Crystalline forms of fingolimod hcl |
-
2017
- 2017-01-16 CN CN201710032575.5A patent/CN106667981B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102209705A (en) * | 2008-11-11 | 2011-10-05 | 诺瓦提斯公司 | Crystalline forms of fingolimod hcl |
| WO2010077741A1 (en) * | 2008-12-09 | 2010-07-08 | The Trustees Of Columbia University In The City Of New York | Diagnosis and therapy of organ dysfunction using sphinganine-1-phosphate |
Non-Patent Citations (2)
| Title |
|---|
| 何景华等: "FTY720 对免疫性肝损伤保护作用的研究", 《中国药理学通报》 * |
| 李新中: "《住院医师实用药物手册》", 28 February 2009, 科学技术文献出版社 * |
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| CN106667981B (en) | 2019-05-14 |
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Granted publication date: 20190514 Termination date: 20210116 |