CN109864987A - Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property - Google Patents
Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property Download PDFInfo
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- CN109864987A CN109864987A CN201910204043.4A CN201910204043A CN109864987A CN 109864987 A CN109864987 A CN 109864987A CN 201910204043 A CN201910204043 A CN 201910204043A CN 109864987 A CN109864987 A CN 109864987A
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- quercetin
- paracetamol
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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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
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- 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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- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Gastroenterology & Hepatology (AREA)
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Abstract
The invention belongs to biomedicine technical fields, are related to medical usage of the Quercetin in protection and therapeutic agent acute liver damage, and in particular to application of the Quercetin in the liver injury medicament caused by preparation protection and treatment paracetamol.The present invention passes through zoopery, it was demonstrated that the Quercetin improves the abnormal raising and the change of pathologic structure for the liver function related biochemical indicator that paracetamol induces, and improves the content of internal antidote GSH in the hepatic tissue of paracetamol induction；The Quercetin is oral preparation or ejection preparation, and dosage can be administered according to patient age, weight, the intake variations such as paracetamol deal and course for the treatment of arrangement, and referrer is 40mg/kg/d with dosage, recommends Oral administration；The Quercetin can effectively antagonize the effect of hepatic injury caused by paracetamol, can be used for the therapeutic agent of hepatic injury caused by preparing paracetamol.
Description
Technical field
The invention belongs to biomedicine technical fields, are related to Quercetin in protection and therapeutic agent acute liver damage
Medical usage, and in particular to application of the Quercetin in the liver injury medicament caused by preparation protection and treatment paracetamol.
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 (Acetaminophen, APAP),
Referred to as paracetamol and N-acethyl-p-aminophenol are a kind of widely used antalgesics of clinic.In therapeutic dose < 4g/d
Under, APAP can cause of short duration serum amino transferase to increase, especially in malnutrition, dyshepatia, indulge in excessive drinking or take
In the crowd of certain CYP450 induced drugs, when overdose, people be greater than 4g/d, minor be greater than 50-75mg/
When kgd, serious hepatic injury or even acute liver failure (ALF) may all occur.It is estimated that annual in American-European countries
There are about 2000 people to undergo ALF, wherein nearly 50% is the drug induced hepatic injury as caused by APAP, in the seemingly use of 61% case
Position dosage, i.e. caused by 34g/3d.
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 radicals, i.e. hydrogen peroxide
H2O2 and peroxynitric acid salt ONOO- isoreactivity oxygen (ROS) lead to oxidative stress and protein nitration, and then generate cell toxicant
Property.Acetylcysteine (N-acetylcysteine, NAC) is to be ratified to draw for treating paracetamol by FDA for 2011
Unique antidote of the own type DILI risen.However, the half-life short of acetylcysteine, only early treatment is effective, generally
Being excessively used in paracetamol 8-12h hours has good therapeutic effect using NAC, main adverse reaction Wei Pi Shen, nausea, vomits
It spits, generate heat.Therefore its therapeutic effect is unsatisfactory, another main cause is to be that paracetamol causes the machine of hepatic injury
It manages sufficiently complex.In consideration of it, it is very urgent and necessary that research and development, which have the drug induced hepatic injury drug of good therapeutic effect,
's.
Quercetin (quercetin, 3,3 ', 4 ', 5,7- pentahydroxyflavone) and its derivative are that plant kingdom's distribution is most wide
Flavone compound, is widely present in the flower, leaf, fruit of plant and most important bioflavonoid in human diet, tool
There are the multiple efficacies such as expansion blood vessel blood pressure lowering, prevention and treatment of coronary heart disease, prevention and treatment myocardial ischemia/reperfusion injury, antithrombus formation, removes this
In addition, also there is Quercetin powerful oxidation resistant biological activity to form resonance stabilized so that toxic free radicals be made to be quenched
Phenoxyl radicals achieve the effect that protection and treatment liver oxidative damage.As a kind of nontoxic to the human body, without three-induced effect
Natural drug, Quercetin have good inside and outside antioxidant activity, are expected to be applied to clinical treatment and aoxidize related series
Disease.In consideration of it, present inventor will provide Quercetin in the drug that preparation is protected and treatment paracetamol induces
The purposes in Drug acute liver damage drug based on property hepatic injury.
Summary of the invention
It is an object of the invention to overcome the deficiencies of the prior art and provide Quercetins in protection and therapeutic agent Acute Hepatic
New medical usage in damage, and in particular to Quercetin liver injury medicament caused by preparation protection and treatment paracetamol
In application.
To achieve the above object, the present invention adopts the following technical scheme:
Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property, the structural formula of the Quercetin
Are as follows:
The present invention induces acute hepatic injury model, pathogenic process using BABL/C mouse peritoneal injection paracetamol
It is similar to clinic, the experimental results showed that, Quercetin can significantly weaken the liver function related biochemical indicator of paracetamol induction
Glutamic-pyruvic transaminase (ALT), the abnormal of glutamic-oxalacetic transaminease (AST) increase (as shown in Figure 1), and pathological examination significantly improves (such as Fig. 2 institute
Show)；Quercetin can significantly improve the liver tissue lesions (as shown in Figure 3) of paracetamol induction, and have dose dependent；
Meanwhile Quercetin also significantly increases the content (as shown in Figure 4) of liver polyphenoils glutathione (GSH).Quercetin is being made
In application in liver injury medicament caused by standby paracetamol, the mechanism of action for playing protection and treatment is that Quercetin can have
The oxidisability hepatic injury effect of effect confrontation paracetamol, and AST and ALT activity is reduced, liver oxidation resistance is improved,
Protect liver cell from oxidativestress damage and confrontation paracetamol mesostate N- acetyl -1,4-benzoquinone imines
(NAPQI) powerful oxidation, mainly by oxidative stress function influence paracetamol generate hepatotoxicity wind agitation to
Play its protection and therapeutic effect to hepatic injury.
Preferably, the Quercetin is oral preparation or ejection preparation.
Preferably, the dosage of the Quercetin can be according to patient age, weight, intake paracetamol deal
And the variations such as course for the treatment of arrangement are administered, referrer is 40mg/kg/d with dosage.
Preferably, the Quercetin recommends Oral administration using oral or injection system medication.
Beneficial effects of the present invention:
(1) the new purposes the present invention provides Quercetin in preparation protection Drug acute liver damage drug, especially
It is purposes of the Quercetin in the drug induced hepatic injury drug of preparation protection paracetamol induction；Quercetin can effectively antagonize
The effect of hepatic injury caused by paracetamol, can be used for the therapeutic agent of hepatic injury caused by preparing paracetamol, for disease
People provides better choice；
(2) Quercetin derives from natural products, and preparation step is easy, at low cost, and pollution is small, is conducive to large-scale production, and
As a kind of natural drug nontoxic to the human body, without three-induced effect, Quercetin has good inside and outside antioxidant activity, is expected to
Development and application are in the drug of the drug-induced hepatic injury series of disease of clinical treatment；
(3) present invention oral administration can play significant curative effect, on the one hand improve safety, on the other hand reduce
Drug administration by injection gives patient bring pain, convenient to take, curative effect is accurate, and patient compliance is high.
Detailed description of the invention
Fig. 1 shows the exception of the BABL/C Mouse Liver functional biochemistry index of paracetamol induction, BABL/C mouse
After the paracetamol of 300mg/kg is given in intraperitoneal injection, the morbidity of acute liver damage is induced, wherein serum AST is being given
Paracetamol 2h occur it is apparent increase trend (p < 0.05 *), ALT be then 4h occur preferable significant difference (* * p <
0.01), and subsequent AST and ALT are persistently increased.
Fig. 2 shows the different of the BABL/C mouse liver function related biochemical indicator of Quercetin protection paracetamol induction
Often, give intraperitoneal injection 300mg/kg paracetamol 2h after, give N-acetylcystein (NAC, 300mg/kg),
Continue to feed after for 24 hours after the treatment of Quercetin (100mg/kg, 200mg/kg, 400mg/kg) gastric infusion, compared to model
AST, ALT of each treatment group of group are substantially reduced, NAC, p < 0.001 * * *；Que (100mg/kg), ALT*p < 0.05,
AST***p<0.001；P < 0.001 Que (200mg/kg, 400mg/kg), * * *.
Fig. 3 shows that Quercetin treatment group weakens the hepar damnification of paracetamol induction, wherein shows H&E
Dyeing.
Fig. 4 shows that quercitrin extract for treating significantly improves the content of liver glutathion inside GSH.
Specific embodiment
The present invention is made with specific embodiment with reference to the accompanying drawings of the specification and further being elaborated, the embodiment
It is served only for explaining the present invention, be not intended to limit the scope of the present invention.
Paracetamol in following embodiments is purchased from Dalian Meilun Biological TechnologyCo.,
Ltd, purity are greater than 98.5%, are dissolved in sterile PBS, 40 degree of water-bath dissolutions；Quercetin and acetylcysteine are purchased from Sigma-
Aldrich；Experimental animal chooses the SPF grade male C57BL/6 from Nanfang Medical Univ's Experimental Animal Center weight in 18-22g
Mouse.The rearing conditions of mouse are the sunshine of 23 ± 2 DEG C of temperature, humidity 55 ± 5% and 12h, while giving and meeting rodent
The diet and water of animal feeding standard.
The exception of embodiment 1, the Mouse Liver functional biochemistry index of paracetamol induction
Male BALB/C mice 6-8 weeks adaptable fed 3 days, is divided into paracetamol effect 0h group, acetparaminosalol
Phenol acts on 2h group, paracetamol effect 4h group, paracetamol effect 6h group, paracetamol and acts on 8h group, real
It tests administration first fasting 12 hours, paracetamol 300mg/kg is injected intraperitoneally, put to death corresponding group every 2h since 0 moment
Mouse, take blood, be stored at room temperature 1h, 4500 revs/min of centrifugation 15min, take supernatant i.e. serum, carry out ALT, AST detection, as a result
It shows, since ALT, AST significantly increase 2-4h is administered in the mice serum of paracetamol induction, i.e., right after modeling administration
Paracetamol induction acute liver damage is the morbidity (as shown in Figure 1) since 2-4h.
Embodiment 2, Quercetin adjust the exception of the Mouse Liver functional biochemistry index of paracetamol induction
Fasting 12 hours before BABL/C mouse experiment are divided into Normal group, model group (APAP, 300mg/kg), quercitrin
Plain administration group (100mg/ kg, 200mg/kg and 400mg/kg) and positive drug processing group (NAC, 300mg/kg), give Quercetin
Paracetamol 300mg/kg is injected intraperitoneally with the preceding 2-4 hour of positive drug NAC gastric infusion, puts to death, takes after 24 hours
Serum and hepatic tissue, ALT, AST testing result show that the mice serum of paracetamol induction can be significantly reduced in Quercetin
The abnormal of middle ALT, AST increases；Compared with positive drug NAC, the Quercetin of 200mg/kg is shown and its comparable therapeutic effect,
The Quercetin treatment group of 400mg/kg shows the AST and ALT (##p < 0.01) being substantially reduced with positive NAC, shows than sun
The property better effect of medicine (as shown in Figure 2).
Embodiment 3, Quercetin improve the liver tissue injury of paracetamol induction
Take the hepatic tissue of mouse in 4% paraformaldehyde it is fixed overnight, using being sliced after paraffin embedding and carry out H&E dye
Color in observation pathologic structure and is taken pictures using microscope, and experimental result is shown, Quercetin can significantly improve paracetamol and lure
The liver tissue lesions led, and certain dose dependent is presented, the Quercetin therapeutic effect of 400mg/kg is even up to than positive
The better effect of medicine (as shown in Figure 3).
Embodiment 4, Quercetin improve internal antidote GSH content in the hepatic tissue of paracetamol induction
The appropriate 50mg of hepatic tissue for weighing 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 GSH, can significantly improve liver compared to model group Quercetin as the result is shown
The content of dirty GSH achievees the effect that removing toxic substances (as shown in Figure 4) to increase oxidation resistant ability.
The above-described embodiments merely illustrate the principles and effects of the present invention, and is not intended to limit the present invention.It is any ripe
The personage for knowing this technology all without departing from the spirit and scope of the present invention, carries out modifications and changes to above-described embodiment.Cause
This, institute is complete without departing from the spirit and technical ideas disclosed in the present invention by those of ordinary skill in the art such as
At all equivalent modifications or change, should be covered by the claims of the present invention.
Claims (7)
1. application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property.
2. application of the Quercetin according to claim 1 in the drug of preparation protection and the hepatic injury of medicine physical property,
It is characterized in that, the Drug acute liver damage is the drug induced hepatic injury of paracetamol induction.
3. application of the Quercetin according to claim 2 in the drug of preparation protection and the hepatic injury of medicine physical property,
It is characterized in that, the Quercetin improves the abnormal of liver function related biochemical indicator ALT, AST of paracetamol induction and rises
High and pathologic structure change.
4. application of the Quercetin according to claim 2 in the drug of preparation protection and the hepatic injury of medicine physical property,
It is characterized in that, the Quercetin improves the content of internal antidote GSH in the hepatic tissue of paracetamol induction.
5. Quercetin according to claim 1 to 4 answering in the drug of preparation protection and the hepatic injury of medicine physical property
With, which is characterized in that the Quercetin is oral preparation or ejection preparation.
6. Quercetin according to claim 1 to 4 answering in the drug of preparation protection and the hepatic injury of medicine physical property
With, which is characterized in that the dosage of the Quercetin can be according to patient age, weight, intake paracetamol deal
And the variations such as course for the treatment of arrangement are administered, referrer is 40mg/kg/d with dosage.
7. Quercetin according to claim 1 to 4 answering in the drug of preparation protection and the hepatic injury of medicine physical property
With, which is characterized in that the Quercetin recommends Oral administration using oral or injection system medication.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910204043.4A CN109864987A (en) | 2019-03-18 | 2019-03-18 | Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property |
| PCT/CN2019/098902 WO2020186683A1 (en) | 2019-03-18 | 2019-08-01 | Application of quercetin in preparation of drug for prevention and treatment of drug-induced liver injury |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910204043.4A CN109864987A (en) | 2019-03-18 | 2019-03-18 | Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property |
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| CN109864987A true CN109864987A (en) | 2019-06-11 |
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| WO (1) | WO2020186683A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186683A1 (en) * | 2019-03-18 | 2020-09-24 | 广东药科大学 | Application of quercetin in preparation of drug for prevention and treatment of drug-induced liver injury |
| CN113209077A (en) * | 2021-05-15 | 2021-08-06 | 西北农林科技大学 | Application of quercetin compounds in protection of hepatotoxicity caused by acrylamide |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653267A (en) * | 2017-03-30 | 2018-10-16 | 复旦大学 | Dihydroquercetin is preparing the purposes in protecting drug induccd acute liver damage drug |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2015101749A4 (en) * | 2015-12-03 | 2016-01-14 | Macau University Of Science And Technology | Method of treating or preventing liver injury induced by acetaminophen |
| CN105998101B (en) * | 2016-06-22 | 2019-12-24 | 中央民族大学 | Application of Uygur medicine cumin Ougi extract in preparing liver protection medicine and health care product |
| CN109864987A (en) * | 2019-03-18 | 2019-06-11 | 广东药科大学 | Application of the Quercetin in the drug of preparation protection and the hepatic injury of medicine physical property |
-
2019
- 2019-03-18 CN CN201910204043.4A patent/CN109864987A/en active Pending
- 2019-08-01 WO PCT/CN2019/098902 patent/WO2020186683A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108653267A (en) * | 2017-03-30 | 2018-10-16 | 复旦大学 | Dihydroquercetin is preparing the purposes in protecting drug induccd acute liver damage drug |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2020186683A1 (en) * | 2019-03-18 | 2020-09-24 | 广东药科大学 | Application of quercetin in preparation of drug for prevention and treatment of drug-induced liver injury |
| CN113209077A (en) * | 2021-05-15 | 2021-08-06 | 西北农林科技大学 | Application of quercetin compounds in protection of hepatotoxicity caused by acrylamide |
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| Publication number | Publication date |
|---|---|
| WO2020186683A1 (en) | 2020-09-24 |
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