CN108771662A - Purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis - Google Patents
Purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis Download PDFInfo
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- CN108771662A CN108771662A CN201810644954.4A CN201810644954A CN108771662A CN 108771662 A CN108771662 A CN 108771662A CN 201810644954 A CN201810644954 A CN 201810644954A CN 108771662 A CN108771662 A CN 108771662A
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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
- A61K31/075—Ethers or acetals
- A61K31/085—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon
- A61K31/09—Ethers or acetals having an ether linkage to aromatic ring nuclear carbon having two or more such linkages
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
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Abstract
The present invention relates to purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis, belong to field of medicaments.The present invention provides the purposes of pterostilbene or its pharmaceutically acceptable salt in preparing treatment and/or preventing the drug of high lithemia nephrosis.The experimental results showed that, pterostilbene can be substantially reduced serum uric acid level, also have the function of inhibiting kidney region fibrosis, the expression quantity of the fibrosis GAP-associated protein GAP such as α-SMA, collagen I, collagen IV, fibronectin can be significantly reduced, it is definite to the therapeutic effect of high lithemia nephrosis, provide a kind of new selection for clinical application.
Description
Technical field
The present invention relates to purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis, belong to field of medicaments.
Background technology
High lithemia nephrosis is purine metabolic disturbance, and blood uric acid increases caused kidney damage, can behave as urinating in early days dense
Gradually there is thereafter glomerular filtration rate decline in contracting hypofunction, and serum creatinine increases, and leads to chronic renal insufficiency.In recent years,
With the increasingly raising of hyperuricemia incidence, high lithemia nephropathy significantly increases year by year.Therefore, seek high lithemia kidney
Effective medicine of disease, is of great significance.
The research of the past confirms that the progress of kidney trouble can be delayed by reducing serum uric acid level, therefore, treats high lithemia kidney
It is seriously ill to reduce serum uric acid level, prevent lithate to be deposited on kidney.Currently, the first-line drug for being clinically used for anti-trioxypurine is other
Purine alcohol, but it can cause the adverse reactions such as skin allergy, bone marrow suppression, especially Stevens-Johnson syndromes in
Lyell disease, for the death rate up to 10%~40%, these adverse reactions limit allopurinol to a certain extent
Clinical application.Moreover, allopurinol generally requires according to glomerular filtration rate potential renal insufficiency patient through renal metabolism
Dosage is adjusted, otherwise patient is not easy-tolerated.In view of drawbacks described above existing for allopurinol, there is an urgent need for develop new alternative medicine.
Pterostilbene is a kind of diphenylethylene compounds being widely present in natural products, entitled 3, the 5- dimethoxies of chemistry
Base -4'- Hydroxy -- trans talan, molecular formula C16H16O3, molecular weight 256.11, chemical constitution is as follows：
Pterostilbene is initially isolated from santal, therefore is named, and has hair in the fruit such as blueberry, grape thereafter
It is existing.Modern pharmacological studies have shown that pterostilbene have a variety of pharmacological activity, such as antitumor, anti-oxidant, anti-aging, and have compared with
High bioavilability is one of hot spot compound of current research.
Invention content
The purpose of the present invention is to provide purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis.
The present invention provides pterostilbenes or its pharmaceutically acceptable salt to prepare treatment and/or prevent high lithemia nephrosis
Purposes in drug.
Further, the drug prevents high lithemia nephrosis by reducing serum uric acid level.
Further, the drug is by inhibiting kidney region fibrosis to prevent high lithemia nephrosis.
The present invention provides pterostilbenes or its pharmaceutically acceptable salt to prepare treatment and/or prevent kidney region fibrosis
Drug in purposes.
Further, the drug reduces a kind of in α-smooth muscle actin, type i collagen, IV Collagen Type VIs, fibronectin
Or the expression of several albumen.
The present invention provides pterostilbenes or its pharmaceutically acceptable salt in preparing the drug for reducing serum uric acid level
Purposes.
Further, the drug is added pharmaceutically using pterostilbene or its pharmaceutically acceptable salt as active constituent
Acceptable auxiliary material or complementary ingredient, the preparation being prepared.
Further, the preparation is oral preparation.
Further, per unit preparation contains 2.75~5.5mg of pterostilbene.
Zoopery proves that pterostilbene can send out mouse high lithemia nephrosis when dosage is 25~50mg/kg/d
Wave significant therapeutic effect.By adult body weight 70kg calculate, converse adult daily administration dosage range be 2.75mg~
5.5mg.Per unit preparation of the present invention corresponds to adult's daily administration dosage.
The present invention provides the pharmaceutical compositions of prevention high lithemia nephrosis, it is with pterostilbene or its is pharmaceutically acceptable
Salt is active constituent, and pharmaceutically acceptable auxiliary material or complementary ingredient, the preparation being prepared is added.
Term " pharmaceutically acceptable " refers to certain carrier, load, diluent, auxiliary material, and/or is formed by salt, ester
Usually in chemistry or physically with constitute the other compatible at split-phase of certain pharmaceutical dosage form, and physiologically mutually compatible with receptor.
Term " pharmaceutically acceptable salt " refers to the acid that the compounds of this invention is formed with inorganic and/or organic bronsted lowry acids and bases bronsted lowry
And/or basic salt, also include amphoteric ion salt (inner salt), further includes quaternary ammonium salt, such as alkylammonium salt.These salt can changed
Close being finally separating and being directly obtained in purifying for object.Can also be by the way that above compound and a certain number of acid or alkali is appropriate
(such as equivalent) is obtained by mixing.These salt may be formed precipitation and be collected with filter method in the solution, or molten
It recycles and obtains after agent evaporation, or be freeze-dried and be made after being reacted in aqueous medium.Heretofore described salt can be compound
Hydrochloride, sulfate, citrate, benzene sulfonate, hydrobromate, hydrofluoride, phosphate, acetate, propionate, fourth two
Hydrochlorate, oxalates, malate, succinate, fumarate, maleate, tartrate or trifluoroacetate.
The method of application of the compounds of this invention or pharmaceutical composition is not particularly limited, and representative method of application includes
(but being not limited to)：Oral, parenteral (intravenous, intramuscular or subcutaneous) and local administration.
Solid dosage forms for oral medication includes capsule, tablet, pill, powder and granule.In these solid formulations
In type, reactive compound is mixed at least one conventional inert excipients (or carrier), such as sodium citrate or Dicalcium Phosphate, or with
Following compositions mix：(a) filler or bulking agent, for example, starch, lactose, sucrose, glucose, mannitol and silicic acid；(b) it bonds
Agent, for example, hydroxymethyl cellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and Arabic gum；(c) moisturizer, example
Such as, glycerine；(d) disintegrant, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain composition silicates,
And sodium carbonate；(e) retarding solvent, such as paraffin；(f) absorbsion accelerator, for example, quaternary ammonium compound；(g) wetting agent, such as spermaceti
Alcohol and glycerin monostearate；(h) adsorbent, for example, kaolin；(i) lubricant, for example, talcum, calcium stearate, tristearin
Or mixtures thereof sour magnesium, solid polyethylene glycol, lauryl sodium sulfate,.In capsule, tablet and pill, dosage form also may include
Buffer.
Solid dosage forms such as tablet, sugar-pill, capsule, pill and granule can be used coating and shell material and prepare, such as casing and
Other materials well known in the art.They may include opacifying agent, also, reactive compound or compound in this composition
Release can discharge in certain part in the digestive tract in a delayed fashion.The example of adoptable embedding component is polymeric material
And wax material.When necessary, reactive compound also can be with one or more formation microencapsulation forms in above-mentioned excipient.
Liquid formulation for oral administration includes pharmaceutically acceptable lotion, solution, suspension, syrup or tincture.
In addition to active compounds, liquid dosage form may include the inert diluent routinely used in this field, such as water or other solvents, increase
Solvent and emulsifier, example know, ethyl alcohol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1,3-BDO, dimethyl formyl
The mixture of amine and oil, especially cottonseed oil, peanut oil, maize germ, olive oil, castor oil and sesame oil or these substances
Deng.
Other than these inert diluents, composition also may include auxiliary agent, such as wetting agent, emulsifier and suspending agent, sweet taste
Agent, corrigent and fragrance.
In addition to active compounds, suspension may include suspending agent, for example, ethoxylation isooctadecane alcohol, polyoxyethylene
The mixture etc. of sorbierite and Isosorbide Dinitrate, microcrystalline cellulose, aluminium methoxide and agar or these substances.
Composition for parenteral injection may include physiologically acceptable sterile, aqueous or anhydrous solution, dispersion liquid,
Suspension or lotion, and the aseptic powdery for re-dissolving into sterile Injectable solution or dispersion liquid.It is suitable aqueous and
Nonaqueous carrier, diluent, solvent or excipient include water, ethyl alcohol, polyalcohol and its suitable mixture.
The dosage form of the compounds of this invention for local administration includes ointment, powder, patch, propellant and inhalant.
Active constituent aseptically with physiologically acceptable carrier and any preservative, buffer, or when necessary may need
Propellant be mixed together.
Pharmaceutically acceptable auxiliary material of the present invention refers to the substance being included in addition to the active ingredient (s in dosage form.
Pharmaceutically acceptable complementary ingredient of the present invention, it has certain physiological activity, but the addition of the ingredient
Leading position of the aforementioned pharmaceutical compositions in treatment of diseases will not be changed, and only play auxiliary effect, these auxiliary
Effect is only the utilization to the ingredient known activity, is the usual adjuvant treatment modality of field of medicaments.If by above-mentioned complementary
Ingredient is used cooperatively with pharmaceutical composition of the present invention, still should belong to the scope of protection of the invention.
The present invention provides purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis.The experimental results showed that purple
Wingceltis stilbene can be substantially reduced serum uric acid level, also have the function of inhibit kidney region fibrosis, can significantly reduce α-SMA,
The expression quantity of the fibrosis GAP-associated protein GAP such as collagen I, collagen IV, fibronectin, the treatment to high lithemia nephrosis
Effect is definite, and a kind of new selection is provided for clinical application.
Description of the drawings
Fig. 1 is dyeing and the appraisal result figure that pterostilbene inhibits mice renal interstitial fibrosis；
Fig. 2 is the fibres such as α-smooth muscle actin α-SMA, type i collagen col I, IV Collagen Type VIs col IV, fibronectin FN
The expression figure of dimensionization marker protein；
Fig. 3 is serum uric acid level testing result figure；
Fig. 4 is high lithemia nephrosis mouse kidney tissue MASSON colored graphs.
Specific implementation mode
The raw material that is used in the specific embodiment of the invention, equipment are known product, pass through and buy commercial product and obtain.
The present invention provides pterostilbenes or its pharmaceutically acceptable salt to prepare treatment and/or prevent high lithemia nephrosis
Purposes in drug.
Currently, reported pharmacological activity possessed by pterostilbene be reducing blood lipid, inhibit fungi, it is anti-oxidant, protection cerebral ischemia/
Reperfusion injury and antitumor, but there is no research shows that it has therapeutic effect to high lithemia nephrosis.The present invention is creatively sent out
Serum uric acid level can be reduced, inhibit kidney region fibrosis by having showed pterostilbene, have exact therapeutic effect to high lithemia nephrosis,
Have developed the new pharmaceutical applications of pterostilbene.
1 pterostilbene of embodiment inhibits the effect of kidney region fibrosis
Experimental animal：Wild C57BL/6J mouse.Standardization experiment diet feeding under at least 1 week isoperibol before experiment,
It drinks water unlimited.
Animal packet：Mouse 24 is only divided into 4 groups：1. sham-operation group 12；2. unilateral ostruction renal interstitial fiber
Change (UUO) model group 12；3. each 6 of every group of pterostilbene various concentration treatment group (25mg/kg/d, 50mg/kg/d).
Modeling method：Mouse is anaesthetized.The abdomen on the left of mouse is judged behind kidney substantially body surface projection position after anesthesia
Cut off skin, blunt separation subcutaneous tissue and muscle layer, the left kidney of exposure, along the kidney base of a fruit to inferior pole of kidney direction finding ureter, defeated in portion
Urinary catheter epimere row two-wire ligatures, and ureter, layer-by-layer suture subcutaneous tissue and skin are cut between 2 ligation points.In postoperative after modeling
The 7th day mouse for putting to death sham-operation group, UUO model groups, pterostilbene treatment group half, puts to death the other half mouse after 14 days, extract
Cardiac blood simultaneously leaves and takes renal tissue and makes a collection of specimens.
Medication：Pterostilbene various concentration treatment group starts to give purple using Oral administration on the 1st day after modeling
Wingceltis stilbene, continuous 14 days；After UUO model group modelings Isodose physiological saline is fed in same time；Sham-operation group is when identical
Between feed Isodose physiological saline.
Experimental result：
1, pterostilbene inhibits dyeing and the appraisal result of mice renal interstitial fibrosis (see Fig. 1)
HE is dyed and MASSON dyeing：It being found under microscope, the dyeing picture of sham-operation group has complete Renal Structure,
There is no apparent tubular degeneration, necrosis, tubulose atrophy, without inflammatory cell infiltration and fibrosis.UUO model groups were at the 7th day
Shi Kejian renal tubules have apparent expansion, MASSON to dye the apparent (journey of blue region expression fibrosis lesion of blue region
Degree), lesion is more obvious after 14 days.After being treated using pterostilbene, although renal tubule still has apparent expansion, MASSON dyeing blue
Color region is considerably less than UUO model groups.
The above result shows that in UUO model groups, mouse renal interstitial obvious fibrosis；After being treated using pterostilbene,
The degree of kidney region fibrosis can be significantly inhibited.
Kidney region fibrosis scores：Standards of grading：To random difference position under 200 times of visuals field of every group of MASSON smear microscopy
It is for statistical analysis to set 10 visuals field of selection.According to tubular degeneration and necrosis, tubulose atrophy, inflammatory cell infiltration and fibrosis
Degree from without, slight, moderate to severe score respectively is 0/1/2 and 3 point.
Appraisal result：The scoring of UUO groups is significantly increased compared with sham-operation group, and the scoring of pterostilbene treatment group is substantially less than UUO groups and comments
Point, and be in doses dependence.
2, WesternBlot detects α-smooth muscle actin (α-SMA), type i collagen (col I), IV Collagen Type VIs (col
IV), the expression of the markers of fibrosis albumen such as fibronectin (FN) (see Fig. 2)
α-SMA, collagen I, collagen IV, fibronectin albumen expression quantity can reflect renal interstitial fibre
The degree of dimensionization.Figure it is seen that pterostilbene can significantly inhibit α-SMA, collagen I, collagen IV,
The expression of fibronectin albumen treats the effect of kidney region fibrosis clearly.
2 pterostilbene of embodiment treats the effect of high lithemia nephrosis
Experimental animal：SPF grades of male C 57 BL/6 J mouses.Standardization experiment daily ration under at least 1 week isoperibol before experiment
Raising, drinking-water are unlimited.
Animal packet：Mouse 40 is only divided into 4 groups：1. Normal group 10；2. high lithemia nephropathy model group 10；③
Pterostilbene treatment group (50mg/kg/d) 10；4. positive control allopurinol treatment group (5mg/kg/d) 10.
Modeling method：According to mouse weight with the ratio of adenine 100mg/kg, Oteracil Potassium 1500mg/kg, with distillation
The suspension of final concentration of 80g/L is made in water after mixing the two, daily morning and evening gavage, continuous 21 days, establishes hyperuricemia
Renal damage animal model.Mouse is put to death after 21 days, abdominal aortic blood leaves and takes renal tissue.
Medication：Pterostilbene and allopurinol treatment group start to be administered using Oral administration for the 1st day after modeling,
Continuous 21 days；After model group modeling Isodose physiological saline is fed in same time；Normal group is fed in same time
Isodose physiological saline.
Experimental result：
1, blood uric acid
Centrifugation retains serum after experimental animal takes blood, and Uric Acid Content is detected using Beckman automatic clinical chemistry analyzers,
Testing result is shown in Fig. 3.From figure 3, it can be seen that pterostilbene can significantly reduce serum uric acid level, effect and one line medicine of clinical anti-trioxypurine
Object allopurinol is suitable.
2, MASSON is dyed
From fig. 4, it can be seen that the dyeing picture of Normal group has complete Renal Structure, without apparent renal tubule
Denaturation, necrosis, tubulose atrophy, without inflammatory cell infiltration and fibrosis.The visible renal tubule of high lithemia nephropathy model group has obviously
Expansion, it is apparent (blue region indicates the degree of fibrosis lesion) that MASSON dyes blue region.After being treated using pterostilbene,
Although renal tubule still has expansion, MASSON dyeing blue regions to be considerably less than model group.
The above result shows that pterostilbene can significantly inhibit the degree of high lithemia nephrosis mice renal interstitial fibrosis.
Claims (10)
1. the purposes of pterostilbene or its pharmaceutically acceptable salt in preparing treatment and/or preventing the drug of high lithemia nephrosis.
2. purposes as described in claim 1, it is characterized in that：The drug prevents high lithemia kidney by reducing serum uric acid level
Disease.
3. purposes as described in claim 1, it is characterized in that：The drug is by inhibiting kidney region fibrosis to prevent high lithemia kidney
Disease.
4. the use of pterostilbene or its pharmaceutically acceptable salt in preparing treatment and/or preventing the drug of kidney region fibrosis
On the way.
5. purposes as claimed in claim 4, it is characterized in that：The drug reduces α-smooth muscle actin, type i collagen, IV
The expression of one or more of albumen in Collagen Type VI, fibronectin.
6. the purposes of pterostilbene or its pharmaceutically acceptable salt in preparing the drug for reducing serum uric acid level.
7. the purposes as described in claim 1~6 any one, it is characterized in that：The drug be with pterostilbene or its pharmaceutically
Acceptable salt is active constituent, and pharmaceutically acceptable auxiliary material or complementary ingredient, the preparation being prepared is added.
8. purposes as claimed in claim 7, it is characterized in that：The preparation is oral preparation.
9. purposes as claimed in claim 7, it is characterized in that：Per unit preparation contains 2.75~5.5mg of pterostilbene.
10. the pharmaceutical composition of high lithemia nephrosis is prevented, it is characterized in that：It is to be with pterostilbene or its pharmaceutically acceptable salt
Pharmaceutically acceptable auxiliary material or complementary ingredient, the preparation being prepared is added in active constituent.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810644954.4A CN108771662A (en) | 2018-06-21 | 2018-06-21 | Purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201810644954.4A CN108771662A (en) | 2018-06-21 | 2018-06-21 | Purposes of the pterostilbene in the drug for preparing prevention high lithemia nephrosis |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110772516A (en) * | 2019-12-02 | 2020-02-11 | 四川大学华西医院 | Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy |
| CN113209060A (en) * | 2021-06-17 | 2021-08-06 | 迈迪唯希科技(天津)有限公司 | Application of pterostilbene in preparation of medicine for preventing and/or treating intestinal epithelial barrier injury |
-
2018
- 2018-06-21 CN CN201810644954.4A patent/CN108771662A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110772516A (en) * | 2019-12-02 | 2020-02-11 | 四川大学华西医院 | Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy |
| CN110772516B (en) * | 2019-12-02 | 2022-10-04 | 四川大学华西医院 | Application of isocorydine or salt thereof in preparing medicine for reducing blood uric acid level and preventing and treating uric acid nephropathy |
| CN113209060A (en) * | 2021-06-17 | 2021-08-06 | 迈迪唯希科技(天津)有限公司 | Application of pterostilbene in preparation of medicine for preventing and/or treating intestinal epithelial barrier injury |
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Application publication date: 20181109 |