CN109893537A - The purposes of chitosan oligosaccharide protection and the hepatic injury of medicine physical property - Google Patents
The purposes of chitosan oligosaccharide protection and the hepatic injury of medicine physical property Download PDFInfo
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- CN109893537A CN109893537A CN201910354734.2A CN201910354734A CN109893537A CN 109893537 A CN109893537 A CN 109893537A CN 201910354734 A CN201910354734 A CN 201910354734A CN 109893537 A CN109893537 A CN 109893537A
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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
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/716—Glucans
- A61K31/722—Chitin, chitosan
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- 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 the purposes of the chitosan oligosaccharide of molecular weight≤1000 (COST) a kind of, are used to prepare the composition of protection and medicine physical property hepatic injury.Particularly for the composition of hepatic injury caused by preparation protection and treatment paracetamol.A kind of and method of protection and the hepatic injury of medicine physical property, comprising: give hepatic injury object a effective amount of COST.Test confirms that COST adjusts the exception of the liver function biochemical indicator of paracetamol induction, significantly reduces the abnormal of ALT, AST in the mice serum of paracetamol induction and increases;Improve the liver tissue injury of paracetamol induction;Improve antidote glutathione (GSH) content in the hepatic tissue of paracetamol induced liver injury;Improve the oxidation resistance of the oxidative damage liver of paracetamol induction;Reduce malonaldehyde (MDA) content in the liver oxidative damage of paracetamol induction.It is expected to development and application and provides better choice in the drug-induced hepatic injury of clinical treatment, for patient.
Description
Technical field
The invention belongs to biomedicine technical fields, and in particular to the chitosan oligosaccharide of molecular weight≤1000 is in protection and medicine
Medical usage in physical property hepatic injury.
Background technique
Drug induced hepatic injury (drug-induced liver injury, DILI) refer to Human body package in routine dose or
After high dose medicament, because drug itself or its metabolite to the direct toxicity or human body of liver to drug or its metabolite
It generates allergy or is metabolized hepar damnification caused by idiosyncratic reaction.Paracetamol (APAP) is that a kind of clinic is widely used
Antalgesic, at therapeutic dose (< 4g/d), APAP can cause of short duration serum amino transferase to increase, especially in nutrition
In bad, dyshepatia, the crowd for indulging in excessive drinking or taking certain CYP450 induced drugs, when overdose, (adult is greater than 4g/
D, minor are greater than 50-75mg/kgd), serious hepatic injury or even acute liver failure (Acute may all occur
Liver failure, ALF).It is estimated that in American-European countries, there are about 2000 people to undergo ALF every year, wherein nearly 50% is by APAP
Caused drug induced hepatic injury.Caused by 61% case seemingly uses median doses (34g/3d).In it was discovered by researchers that
The Annual occurence rate of the drug induced hepatic injury of state is up to 23.80/10 ten thousand people.Wherein, acute drug hepatic injury accounting is 87%,
13% patient is chronic drug hepatic injury.In the drug for causing hepatic injury, the drug categories that China ranks the first are each
Class health care product and traditional Chinese medicine, accounting are up to 26.81%, are secondly anti-tubercular drug, accounting 21.99%, as caused by APAP
Although hepatic injury only accounts for the 3.8% of all DILI, the 50.8% of the DILI that all anodyne and anti-inflammatory agent cause is accounted for.It is domestic
It is still mainly faced with paracetamol bring hepatic injury in application analgesic and anti-inflammatory aspect, the situation is tense.
Most of APAP in blood pass through UDP-glucoronosyl/transferase (UGT) and sulfotransferase in liver
(SULT) effect makes it with glucuronic acid and sulfate ining conjunction with, forms conjugation metabolin and on a small quantity hydroxylating and deacetylated
The metabolin of change is discharged in urine.Under normal circumstances, the APAP of about 5-9% undergoes liver metabolism by different approach,
That is cytochrome P 450 enzymes (CYP450), mainly CYP2E1 and lesser degree of CYP1A2, CYP2A6 and CYP3A4 metabolism, shape
At toxicity mesostate N- acetyl group -1,4-benzoquinone imines (NAPQI) of high activity.Then, the sulfydryl of glutathione (GSH)
Convert NAPQI to the harmless metabolin drained in urine.However, when II phase metabolic enzyme is saturated after APAP excess, it is excessive
NAPQI exhaust GSH, lead to the covalent bond of sulfydryl in NAPQI and cell protein, especially mitochondrial protein.This leads to line
Plastochondria oxidative stress and dysfunction, eventually lead to necrosis of liver cells.NAPQI also interferes mitochondrial electron transport chain (ETC)
Complicated composite I and II causes electronics from ETC leakage in conjunction with oxygen, to form a large amount of superoxide radical (hydrogen peroxide
H2O2 and peroxynitric acid salt ONOO-) isoreactivity oxygen (ROS) and active nitrogen (RNS), lead to oxidative stress and protein nitration,
And then generate cytotoxicity.
Acetylcysteine (N-acetylcysteine, NAC) is to be ratified by FDA for treating acetparaminosalol for 2011
Unique antidote of own type DILI caused by phenol.However, the half-life short of acetylcysteine, only early treatment is effective,
Main adverse reaction Wei Pi Shen, Nausea and vomiting, fever, therapeutic effect is unsatisfactory, another main cause is to second
Acylamino- phenol causes the mechanism of hepatic injury sufficiently complex.In consideration of it, research and development have the liver lesion induced by drugs of good therapeutic effect
Vulnerary object is very urgent and necessary.
Chitin (chitin) is the most abundant biomass after cellulose, is common in the shell of shellfish, insect
In epidermis and fungal cell wall.Chitosan is translated into alkaline solution treatment chitin: complete or partial deacetylated form
Chitin.Chitosan can be defined as natural nontoxic biological polymer, and linear polysaccharide is by β-Isosorbide-5-Nitrae-GlcNAc and β-Isosorbide-5-Nitrae-
GlcN composition.Chitosan contains rather unstable glycosidic bond, this, which makes it that can be hydrolyzed agent cutting, has variable gather to generate
The chitosan oligomer of right (degree of polymerization, DP).DP is less than 20 and average MW is less than 3.9kDa's
Chitosan is referred to as chitosan oligosaccharide (COS), and COS has extensive bioactivity, and in medicine, cosmetics, food and agricultural etc. are multiple
Field is with a wide range of applications, and also has the report applied to liver-protecting medicine, as CN201610639820.4 discloses one kind
For chitosan oligosaccharide in preparation for the purposes in Soboring-up liver-protecting drug, the drug is common peroral dosage form, including tablet, capsule,
Grain, oral solution, suspension.New purposes is increased for chitosan oligosaccharide, is efficiently solved the problems, such as the Soboring-up liver-protecting of drunk personnel, to the greatest extent may be used
Energy avoids alcohol from causing harm to the human body.But the problems such as being cut there are uncertain therapeutic efficacy.
Summary of the invention
The technical problem to be solved in the present invention is to provide the methods of a kind of protection and the hepatic injury of medicine physical property, give Drug
Mostly a kind of selection of DILI patient caused by patients with liver deficiency, especially paracetamol.
In order to solve the above technical problems, the invention discloses a kind of specified molecular weight chitosan oligosaccharide (molecular weight≤1000), letter
The referred to as purposes of COST is used to prepare the composition of protection and medicine physical property hepatic injury, protects and treats particularly for preparation
The composition of drug induccd acute liver damage is especially used to prepare protection and treats the combination of hepatic injury caused by paracetamol
Object.The composition is used for: Formulations for systemic administration or parenteral administration, preferably intravenous injection administration.
COST derives from natural products, and preparation step is easy, at low cost, and pollution is small, is conducive to large-scale production.The present invention is ground
Study carefully personnel to find as the COST with good inside and outside antioxidant activity nontoxic to the human body, without three-induced effect, it can be effective
It fights hepatic injury caused by paracetamol to act on, test confirms that the liver function of the adjustable paracetamol induction of COST is raw
Change the exception of index, significantly reduces the abnormal of ALT, AST in the mice serum of paracetamol induction and increase;Improve to acetyl
The liver tissue injury of amino phenols induction;Improve internal antidote GSH content in the hepatic tissue of paracetamol induced liver injury;
Improve the oxidation resistance of the oxidative damage liver of paracetamol induction;Reduce the liver oxidation of paracetamol induction
Property damage in MDA content.It is expected to development and application and provides better choosing in the drug-induced hepatic injury of clinical treatment, for patient
It selects.It may be the oxidisability hepatic injury that chitosan oligosaccharide can effectively antagonize paracetamol that it, which plays the mechanism of action protected and treated,
Effect, and AST and ALT activity is reduced, liver oxidation resistance is improved, protects liver cell from oxidativestress damage and confrontation
The powerful oxidation of paracetamol mesostate N- acetyl -1,4-benzoquinone imines (NAPQI), is answered by anti-oxidant
The hepatotoxicity wind agitation that function influence paracetamol generates is swashed to play its protection and therapeutic effect to hepatic injury.
The method of protection and the hepatic injury of medicine physical property disclosed in this invention, comprising: give hepatic injury object effective quantity
COST, the effective quantity be 8~13mg/kg/, preferably 11mg/kg/.
Detailed description of the invention
Fig. 1 is ALT, AST situation of change in intraperitoneal injection paracetamol (APAP) afterwards mice serum;
Fig. 2 is each group Mouse Liver functional biochemistry index comparison after administration for 24 hours;
Fig. 3 is the hepatic tissue H&E dyeing pathologic structure figure of each group mouse after administration for 24 hours;
Fig. 4 is that GSH content balance in rear each group mouse liver for 24 hours is administered;
Fig. 5 is each group mouse liver total antioxidative abilities (T-AOC) comparison after administration for 24 hours;
Fig. 6 is each group mouse liver tissue MDA content balance after administration for 24 hours;
Fig. 7 is each group mouse liver tissue GSH-Px content balance after administration for 24 hours;
Fig. 8 is each group mouse liver tissue SOD content balance after administration for 24 hours;
Fig. 9 is each group mouse liver tissue CAT content balance after administration for 24 hours;
Figure 10 is that ALT, AST situation of change in rear 02 cell supernatant of each group liver L for 24 hours is administered.
Specific embodiment
Above content of the invention is described in further detail again below by way of specific embodiment.But this should not be managed
Solution is limited only to embodiment below for the range of the above-mentioned theme of the present invention.The case where not departing from above-mentioned technical idea of the invention
Under, the various replacements or change made according to ordinary skill knowledge and customary means, should all include in model of the invention
In enclosing.
To illustrate the present invention, we are using its pathogenic process and clinical similar BABL/C mouse peritoneal injection to acetyl ammonia
Base phenol induction acute hepatic injury model and external APAP induction people's liver cell L02 damage model come to disclosed in this invention
Method is further described.
1. the exploration of the pathologic process of the mouse liver injury of paracetamol induction
Male BALB/C mice 6-8 weeks 25, adaptable fed 3 days, it is randomly divided into paracetamol (APAP) effect
0h group, 2h group, 4h group, 6h group, 8h group, every group each 5, paracetamol is injected intraperitoneally in fasting 12 hours before experimental administration
300mg/kg puts to death the mouse of corresponding group every 2h since 0 moment, takes blood, is stored at room temperature 1h, 4500 revs/min of centrifugations
15min, takes supernatant i.e. serum, carries out ALT, AST detection, the results show that ALT in the mice serum of paracetamol induction,
Since AST significantly increase 2-4h is administered, and wherein serum AST is giving paracetamol 2h appearance apparent raising trend (*
P < 0.05), ALT is then more significant sex differernce (p < 0.01 * *) occur in 4h, and subsequent AST and ALT are persistently increased.Thus may be used
To find out that the disease time of paracetamol induction acute liver damage is 2-4h upon administration.I.e. to acetyl ammonia after modeling administration
Base phenol, which induces acute liver damage, is fallen ill since 2-4h, and concrete outcome is shown in Table 1 and attached drawing 1:
Table 1
Mean±SEM | APAP-0h group | APAP-2h group | APAP-4h group | APAP-6h group |
ALT(U/L) | 15.7±2.3 | 59.2±7.7 | 236.9±62.1 | 565.7±72.7 |
AST(U/L) | 25.6±1.5 | 98.9±19.1 | 123.3±30.1 | 231.3±21.3 |
2.COST adjusts the exception of the Mouse Liver functional biochemistry index of paracetamol induction
BABL/C mouse 60, fasting 12 hours, is randomly divided into Normal group (CON), model group before testing
(APAP300mg/kg), COST senior middle school low dosage (L-25mg/kg, M-50mg/kg and H-100mg/kg) administration group, half Guang of acetyl
Propylhomoserin (NAC) 300mg/kg positive controls give 2 hour intraperitoneal injection paracetamol before COST and positive drug NAC
300mg/kg, administration are put to death after 24 hours, take serum and hepatic tissue, ALT, AST testing result are shown, each compared to model group
AST, ALT for the treatment of group are substantially reduced (* p < 0.05, * * p < 0.01, * * * p < 0.001, vs APAP), and show certain
Concentration dependent, as the higher therapeutic effect of the administration concentration of COSM is more obvious.Substantially do not occur significant difference (#p <
0.05, ##p < 0.01, ###p < 0.001vs NAC).That is the mice serum of paracetamol induction can be significantly reduced in COST
The abnormal of middle ALT, AST increases, and concrete outcome is shown in Table 2 and attached drawing 2:
Table 2
3.COST improves the liver tissue injury of paracetamol induction
Take the hepatic tissue of each group mouse in 4% paraformaldehyde it is fixed overnight, using being sliced after paraffin embedding and carry out H&E
Dyeing in observation pathologic structure and is taken pictures using microscope, and experimental result is shown, COST treatment group weakens acetparaminosalol point
The hepar damnification (H&E dyeing) of induction, and certain dose dependent is presented, the COST therapeutic effect of 100mg/kg is even more positive
Property drug effect fruit is good.COST can significantly improve the liver tissue lesions of paracetamol induction, and concrete outcome is shown in attached drawing 3.
4.COST improves internal antidote GSH content in the hepatic tissue of paracetamol induced liver injury
The hepatic tissue 50mg for weighing each group mouse, after physiological saline is added according to 1:9, progress homogenized, 10000 turns/
Minute centrifuging and taking supernatant, carries out the measurement of liver organization glutathione (GSH), the results show that COST group is compared to APAP mould
Type group significantly increases the content of GSH, and certain concentration dependent is presented, and COST high dose group (COST-H) and NAC
Effect is suitable.(* p < 0.05, * * p < 0.01, * * * p < 0.001vs APAP;#p < 0.05, ##p < 0.01, ###p < 0.001vs
NAC).Compared to the content that model group COST can significantly improve liver GSH, to achieve the effect that removing toxic substances, concrete outcome is shown in Table 3
With attached drawing 4:
Table 3
5.COST improves the oxidation resistance of the liver oxidative damage of paracetamol induction
The hepatic tissue 50mg for weighing each group mouse, after extracting solution is added according to 1:9, progress homogenized, 10000 revs/min
Clock centrifuging and taking supernatant carries out the measurement of liver organization total antioxidant capacity (T-AOC), the results show that COST middle dosage
(COST-M) it is significantly increased with high dose (COST-H) compared to APAP model group total antioxidant capacity (T-AOC), and is presented one
Fixed concentration dependent.And T-AOC and the NAC effect of COST high dose group (COST-H) are suitable.(* p < 0.05, * * p <
0.01,***p<0.001vs APAP;#p < 0.05, ##p < 0.01, ###p < 0.001vs NAC).Compared to model group COST-H
The content of liver GSH can be significantly improved with COST-M, so that concrete outcome is shown in Table 4 and attached drawing 5 up to the effect for improving hepatic injury:
Table 4
6.COST reduces MDA content in the liver oxidative damage of paracetamol induction
The hepatic tissue 50mg for weighing each group mouse, after extracting solution is added according to 1:9, progress homogenized, 10000 revs/min
Clock centrifuging and taking supernatant, carrying out liver organization malonaldehyde, (measurement of MDA content, as the result is shown COST treatment significantly reduce liver
Dirty fatty acid product MDA in conjunction with ROS, improves liver oxidative damage, and COST senior middle school low dose group is equal compared to APAP model group MDA
It significantly reduces, and certain concentration dependent is presented, COSM reduces (* p < 0.05, the * * of the liver oxidative damage of APAP induction
p<0.01,***p<0.001vs APAP;), senior middle school's administration group is suitable with the effect of positive drug NAC, and concrete outcome is shown in Table 5 and attached
Fig. 6:
Table 5
7.COST improves GSH-Px content in the liver oxidative damage of paracetamol induction
The hepatic tissue 50mg for weighing each group mouse, after extracting solution is added according to 1:9, progress homogenized, 10000 revs/min
Clock centrifuging and taking supernatant carries out the measurement of liver organization glutathione peroxidase (GSH-Px) content, as the result is shown COST
Treatment significantly improves the content of liver GSH-Px, improves liver oxidative damage, COST senior middle school low dose group is compared to APAP model
Group GSH-Px is significantly increased, and certain concentration dependent is presented, and COST reduces liver oxidative damage (the * p of APAP induction
< 0.05, * * p < 0.01, * * * p < 0.001vs APAP;) concrete outcome is shown in Table 6 and attached drawing 7:
Table 6
8.COST improves SOD content in the liver oxidative damage of paracetamol induction
The hepatic tissue 50mg for weighing each group mouse, after extracting solution is added according to 1:9, progress homogenized, 10000 revs/min
Clock centrifuging and taking supernatant carries out the measurement of liver organization superoxide dismutase (SOD) content, and COST treatment is significant as the result is shown
The content of liver SOD is improved, liver oxidative damage is improved, COST senior middle school low dose group is significant compared to APAP model group SOD
It increases, COST reduces liver oxidative damage (* p < 0.05, * * p < 0.01, * * * p < 0.001vs APAP of APAP induction;), it is high
In low administration group it is suitable with the effect of positive drug NAC, concrete outcome is shown in Table 7 and attached drawing 8:
Table 7
9.COSM improves SOD content in the liver oxidative damage of paracetamol induction
The hepatic tissue 50mg for weighing each group mouse, after extracting solution is added according to 1:9, progress homogenized, 10000 revs/min
Clock centrifuging and taking supernatant carries out the measurement of liver organization catalase (CAT) content, and COST treatment as the result is shown significantly improves
The content of liver CAT improves liver oxidative damage, and COST high dose group is significantly increased compared to APAP model group CAT, COST high
Dosage reduces liver oxidative damage (* p < 0.05, * * p < 0.01, * * * p < 0.001vs APAP of APAP induction;), height administration
Group is suitable with the effect of positive drug NAC, and concrete outcome is shown in Table 8 and attached drawing 9:
Table 8
10.COST adjusts the protective effect and improvement of external people's liver cell L02 damage of paracetamol induction
The exception of biochemical indicator
In vitro culture Human normal hepatocyte LO2, cell are laid on 96 orifice plates according to 15000-20000, every hole cells/well, after
Continuous culture 8-12h;It is grouped into COST high, medium and low (1.0mg/mL, 0.5mg/mL, 0.25mg/mL) according to toxicity test early period,
Normal group and every group of 6 multiple holes of model group, each group is added after COS cultivate 12 hours after the APAP of 8mM be added continue culture 12h;
After microscopically observation pathological state and therapeutic effect, culture solution, centrifuging and taking supernatant are collected, kit surveys the release of AST, ALT
Amount, remaining cell are added CCK-8 reagent and survey cell survival rate.COST can significantly inhibit the liver of APAP induction as the result is shown
The damage or death of cell, the COST of high middle dosage significantly increases the survival rate of liver cell and changes compared with model group
It has been apt to the exception (* p < 0.05, * * p < 0.01, * * * p < 0.001, vs APAP) of AST, ALT hepatic injury index of APAP induction, tool
Body the results are shown in Table 9, table 10 and attached drawing 10:
Table 9
Table 10
Claims (8)
1. a kind of purposes of the chitosan oligosaccharide of molecular weight≤1000 (COST), is used to prepare the group of protection and medicine physical property hepatic injury
Close object.
2. purposes as described in claim 1, which is characterized in that be used to prepare protection and treat the group of the impatient property hepatic injury of medicine source
Close object.
3. purposes as described in claim 1, which is characterized in that be used to prepare liver caused by protection and treatment paracetamol and damage
The composition of wound.
4. purposes as claimed in claim 1 or 2, which is characterized in that the composition is used for: Formulations for systemic administration or parenteral to
Medicine.
5. purposes as claimed in claim 4, which is characterized in that the composition is for being injected intravenously administration.
6. a kind of method of protection and the hepatic injury of medicine physical property, comprising: give hepatic injury object a effective amount of COST.
7. method as claimed in claim 6, which is characterized in that the effective quantity is 8~13mg/kg/ days.
8. the method for claim 7, which is characterized in that the effective quantity is 11mg/kg/ days.
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CN111671719A (en) * | 2020-06-18 | 2020-09-18 | 广东药科大学 | Chitosan oligosaccharide composition and preparation method and application thereof |
WO2020220607A1 (en) * | 2019-04-29 | 2020-11-05 | 广东药科大学 | Use of chitooligosaccharides for protecting against and treating drug-induced liver injury |
CN112402444A (en) * | 2019-08-21 | 2021-02-26 | 天津大学 | Application of chitosan oligosaccharide biguanide derivative in preparation of liver injury inhibiting medicine |
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CN106943424A (en) * | 2017-05-23 | 2017-07-14 | 哈尔滨工业大学 | A kind of application of chitosan oligosaccharide |
CN109893537A (en) * | 2019-04-29 | 2019-06-18 | 广东药科大学 | The purposes of chitosan oligosaccharide protection and the hepatic injury of medicine physical property |
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WO2020220607A1 (en) * | 2019-04-29 | 2020-11-05 | 广东药科大学 | Use of chitooligosaccharides for protecting against and treating drug-induced liver injury |
CN112402444A (en) * | 2019-08-21 | 2021-02-26 | 天津大学 | Application of chitosan oligosaccharide biguanide derivative in preparation of liver injury inhibiting medicine |
CN111671719A (en) * | 2020-06-18 | 2020-09-18 | 广东药科大学 | Chitosan oligosaccharide composition and preparation method and application thereof |
WO2021253545A1 (en) * | 2020-06-18 | 2021-12-23 | 广东药科大学 | Chitosan oligosaccharide composition, preparation method therefor, and application thereof |
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Application publication date: 20190618 |