CN108785321A - Purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor - Google Patents
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Abstract
The invention belongs to drug or field of health care products, and in particular to purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor.The present invention is had found by studying, periplocoside L and periplocoside H is superior to inhibitory activity of the positive control drug 1- methyl tryptophans (1-MT) to intracellular IDO to the inhibitory activity of intracellular IDO, inhibitory activity with significant IDO can be used for treating cancer, Alzheimer disease, autoimmune disease, ankylosing spondylitis, bacterium infection, cataract, mood disorder, depressive and anxiety neurosis.
Description
Technical field
The invention belongs to drug or field of health care products, and in particular to Heiguteng exract C21 steroids are preparing IDO inhibitor
In purposes.
Background technology
The entitled indoleamine 2 of IDO (indoleamine-2,3-dioxygenase) Chinese, 3- is bis- to add oxidizing ferment, be liver with
The rate-limiting enzyme that outer unique catalysis tryptophan is metabolized along kynurenine pathway (kynurenine pathway, KP), can be by color ammonia
Acid is decomposed into a variety of metabolins such as L- kynurenins, pyridine carboxylic acid and quinolinic acid.L-Trp maintains cell to live as in human body
Amino acid necessary to changing and being proliferated, and the indispensable ingredient of protein is constituted, its shortage can cause some important thin
The dysfunction of born of the same parents.Since 1967 are found, IDO inhibits the mechanism of pathogenic microorganism proliferation, IDO by tryptophan of degrading
Relationship between the nervous system disease is gradually elucidated with;And thering is research to confirm, IDO also participates in the reaction of regulatory T-cell, can
Proliferation and activation to T cell generate inhibiting effect, and this inhibiting effect has then mediated expression the immune of IDO tumour cells to escape
Ease phenomenon.Therefore, the expression of IDO or active exception increase, closely related with the pathogenesis of a variety of diseases, be cause it is a variety of
An important factor for disease, such as the tumour, Alzheimer disease, depression and the cataract of old people that have been found, AIDS etc. are sick
Bacterium infections such as poison infection, Lyme disease and streptococcal infection etc. (can refer to following document:The progress of IDO inhibitor, Kong Ling
Thunder etc.,《Chinese journal of Medicinal Chemistry》, 2009,19 (2):147-154;Chinese patent literature CN101429151A one kind containing (E)-
The IDO inhibitor and preparation method thereof of 4- (Β-bromo vinyl) benzene oxygen acyl group structure, May 13 2009 publication date).Cause
This, IDO inhibitor becomes the medicine of great potential, causes the concern of numerous scholars.
As a kind of completely new target spot, IDO becomes the cancer immunotherapy target of great potential.The IDO of screening efficiently, less toxic
Inhibitor/antibody, and use it for treating above-mentioned disease, become the common demand of researcher.1978, there is researcher
Non-selective competitive IDO inhibitor has been isolated in research, but it inhibits effect faint.In the early 1990s, closing for the first time
(i.e. at tryptophan derivative 1-MT:Indoximod), as with the immediate inhibitor of substrate tryptophan structure, cause
People are for IDO inhibitor more widely concern and interest.The research and development of IDO inhibitor are still in the initial stage of drug development,
Only 2 compounds (epacadostat and indoximod) enter II phase clinic at present, and 1 compound (GDC-0919) enters
I phase is clinical.
Initially the work of searching IDO inhibitor is mainly using chemical synthesis as means, using the substrate tryptophan of IDO as template,
Structural modification is carried out to it on the basis of studying structure-activity relationship, the patent of the article and registration delivered almost covers all energy
The group of modification, but produce little effect.From 2006, domestic and foreign scholars, which attempt to find from natural products, had new construction
The IDO inhibitor of the high activity of skeleton, such as:Brastianos etc. is extracted to obtain from sponge Neopetrosiaexigua
Exiguamine A (value=0.21 μM Ki);Alban Pereir etc. extracted from seawater Xi obtain Annulin C (Ki values=
0.14μM);The natural products Brassinin (value=97.7 μM Ki) that the discoveries such as Caspari business can be sold has medium activity;In
State patent document CN101843618A is disclosed:Jamaicin and its derivative also have IDO inhibiting effect.
Heiguteng exract (Periploca forrestii Schltr) is Asclepiadaceae (Asclepiadaceae) Periploca (Peri
Ploca) dry root of the black keel of plant or complete stool, are distributed mainly on the ground such as China Guangxi, Yunnan, Guizhou, Sichuan, Tibet, and one
The straight Chinese herbal medicine maximally efficient as treatment rheumatism.With deepening continuously to its pharmacological research, Heiguteng exract is in many sides
Face shows unique pharmacological activity, such as anti-inflammatory effect, anti rheumatism action, analgesic activity.In addition, also having document to black
Chemical composition and its drug effect contained by bone rattan are studied, such as:C21 steroids have been isolated in extraction from Heiguteng exract,
Effect experiment shows that it has the effects that certain antitumor, immunological regulation.
Currently, being used to prepare IDO inhibitor about Heiguteng exract C21 steroids there is no report.
Invention content
For this purpose, the technical problem to be solved by the present invention is to be used to prepare in the prior art without Heiguteng exract C21 steroids
The problem of IDO inhibitor, to provide purposes of the Heiguteng exract C21 steroids in preparing IDO inhibitor.
In order to solve the above technical problems, the present invention is achieved through the following technical solutions:
The present invention provides Heiguteng exract C21 steroids and its pharmaceutically acceptable derivates and is preparing IDO inhibitor
In purposes;
The IDO inhibitor is for treating cancer, Alzheimer disease, autoimmune disease, ankylosing spondylitis, thin
Bacterium infection, cataract, mood disorder, depressive and anxiety neurosis;The pharmaceutically acceptable derivates are selected from salt, ester, prodrug
Or solvate;
The Heiguteng exract C21 steroids have structure as follows:
R is selected fromAnd its acetyl derivatives,And its acetyl derivatives,And its at least one of acetyl derivatives are formed by glycosyl residue.
The present invention also provides Heiguteng exract C21 steroids and its pharmaceutically acceptable derivates to prepare treatment IDO
Purposes in the drug of the disease of the pathological characteristics of the tryptophan metabolic pathway of mediation, the disease are cancer, alzheimer '
Silent disease, autoimmune disease, ankylosing spondylitis, bacterium infection, cataract, mood disorder, depressive and anxiety neurosis;It is described
Pharmaceutically acceptable derivates are selected from salt, ester, prodrug or solvate;
The Heiguteng exract C21 steroids have structure as follows:
R is selected fromAnd its acetyl derivatives,And its acetyl derivatives,And its at least one of acetyl derivatives are formed by glycosyl residue.
Wherein, sugared acetyl derivatives refer to:Free hydroxyl group (- OH) in glycan molecule is protected by acetyl group (- Ac)
Sugar derivatives.
The pharmaceutically acceptable salt, for example, be the salt formed with inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, nitric acid, or
It is the salt formed with organic acids such as citric acid, succinic acid, tartaric acid, methanesulfonic acids.
According to document (" Structural revision of periplocosides and periperoxides,
Natural immunosuppressive agents from the genus Periploca ", Luo-Yi Wang et
Al., report Phytochemistry, 2011,72,2230-2236), in Heiguteng exract C21 steroids of the present invention, periploca spium
Glycosides L (Periploside L) former name is Periperoxide D, and periplocoside H (Periploside H) former name is
Periperoxide E。
Preferably, in such use,
R isWhen, the Heiguteng exract C21 steroids are thick stick
Willow glycosides L (Periploside L);Or
R isWhen, the Heiguteng exract C21 steroids are periploca spium
Glycosides H (Periploside H).
Preferably, in such use, customary adjuvant system is added according to common process in the Heiguteng exract C21 steroids
At clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup, emplastrum, suppository, aerosol,
Ointment or injection.
The customary adjuvant is:Filler, disintegrant, lubricant, suspending agent, adhesive, sweetener, corrigent, anti-corrosion
Agent, matrix etc..Filler includes:Starch, pregelatinized starch, lactose, mannitol, chitin, microcrystalline cellulose, sucrose etc.;It collapses
Solving agent includes:Starch, pregelatinized starch, microcrystalline cellulose, sodium carboxymethyl starch, crosslinked polyvinylpyrrolidone, low substitution hydroxyl
Third cellulose, cross-linked carboxymethyl cellulose are received;Lubricant includes:Magnesium stearate, lauryl sodium sulfate, talcum powder, dioxy
SiClx etc.;Suspending agent includes:Polyvinylpyrrolidone, microcrystalline cellulose, sucrose, agar, hydroxypropyl methyl cellulose etc.;Bonding
Agent includes starch slurry, polyvinylpyrrolidone, hydroxypropyl methyl cellulose etc.;Sweetener includes:Saccharin sodium, aspartame, sugarcane
Sugar, honey element, enoxolone etc.;Corrigent includes:Sweetener and various essence;Preservative includes:Parabens, benzoic acid,
Sodium benzoate, sorbic acid and its esters, benzalkonium bromide, the fixed, eucalyptus oil of acetic acid chloroethene etc.;Matrix includes:PEG6000,
PEG4000, insect wax etc..
Technical scheme of the present invention has the following advantages that:
The present invention passes through the study found that periplocoside L and periplocoside H are superior to the positive to the inhibitory activity of intracellular IDO
Comparison medicine 1- methyl tryptophans (1-MT) are to the inhibitory activity of intracellular IDO, the inhibitory activity with significant IDO, can be with
For treating cancer, Alzheimer disease, autoimmune disease, ankylosing spondylitis, bacterium infection, cataract, mental state barrier
Hinder, depressive and anxiety neurosis.
Specific implementation mode
In following embodiment of the present invention and experimental example, periplocoside L (Periploside L) and periplocoside H
(Periploside H) can be prepared according to the method for the embodiment of the present invention 1, can also be prepared according to following document
It obtains:
Immunosuppressive pregnane glycosides from Periploca sepium and
Periploca forrestii.Phytochemistry, 2008,69 (15), 2716-2723.
Structural revision of periplocosides and periperoxides,natural
Immunosuppressive agents from the genus Periploca.Phytochemistry, 2011,72 (17),
2230-2236.
Corrigendum to“Structural revision of periplocosides and
periperoxides,natural immunosuppressive agents from the genus Periploca”
[Phytochemistry72/17 (2011) 2230-2236] .Phytochemistry, 2013,95,445.
Embodiment 1The preparation of Heiguteng exract C21 steroids
The root of Heiguteng exract is taken, is crushed, the ethanol water that the volumetric concentration that 3 times of weight is added is 95% extracts 2 at room temperature
Secondary, extraction 7 days, merge extracting solution, are concentrated under reduced pressure into no alcohol taste, obtain Heiguteng exract medicinal extract every time;
Heiguteng exract medicinal extract is suspended in the water of 1 times of weight, then carries out extraction 2 times by extractant of chloroform, collects extraction
The organic phase for taking liquid, is then concentrated under reduced pressure, and Heiguteng exract chloroform extraction position medicinal extract is obtained;
Heiguteng exract chloroform extraction position medicinal extract is taken to be purified through silica gel column chromatography, using petroleum ether as mobile phase A, using acetone as stream
Dynamic phase B carries out gradient elution according to following procedure:First use A:B volume ratios are 10:1 mobile phase elution, then use A:B volume ratios
It is 5:1 mobile phase elution, then use A:B volume ratios are 2:1 mobile phase elution, then use A:B volume ratios are 1:1 mobile phase is washed
It is de-, it is detected by TLC detections or HPLC-MS, collection mobile phase is A:B volume ratios are 2:Then 1 eluent carries out depressurizing dense
Contracting obtains Heiguteng exract petroleum ether acetone elution position medicinal extract;
It is pure that C18 reverse phase of the Heiguteng exract petroleum ether acetone elution position medicinal extract through Agilent SD-1 is prepared into liquid phase separation
Change, using water as mobile phase C, using methanol as mobile phase D, gradient elution is carried out according to following procedure:First use C:D volume ratios are
50%:50% mobile phase elution, then use C:D volume ratios are 35%:65% mobile phase elution, then use C:D volume ratios are
25%:75% mobile phase elution, is detected by TLC detections or HPLC-MS, and it is C to collect mobile phase respectively:D volume ratios are
35%:65%, C:D volume ratios are 25%:Then 75% eluent is concentrated under reduced pressure, is dried respectively, obtain periplocoside respectively
L (Periploside L) and periplocoside H (Periploside H) (HPLC purity >=95%).
The above-mentioned compound being prepared is passed through respectively1H-NMR、13C-NMR and HPLC-MS carries out structural confirmation, passes through
With in existing literature1H-NMR、13C-NMR and HPLC-MS are compared respectively, it is known that preparation-obtained compound is respectively
Periplocoside L (Periploside L) and periplocoside H (Periploside H).
Experimental example 1Research of the Heiguteng exract C21 steroids of the present invention to the inhibitory activity of IDO
1, experiment purpose
Using plasmid pcDNA3.1-IDO transfected HEK 293s, makes its height expression IDO, then measure Heiguteng exract of the present invention
C21 steroids are in cellular level to the inhibitory activity of IDO.
2, experimental method
293 cells of HEK are inoculated in the density of 2.5X104 cells/wells in 96 orifice plates, DMEM medium cultures (contain
10% fetal calf serum, 50U/mL penicillin and 50mg/mL streptomysins), be placed in 37 DEG C, humidity 95%, 5%CO2Incubator in
Culture.After culture for 24 hours, pcDNA3.1-hIDO plasmid transfections are mediated using liposome Lipofectamin 2000, are divided into the positive
Control group and experimental group 1-2 groups.
Positive controls are with 1- methyl tryptophans (1-MT) for test sample, and experimental group 1-2 groups are respectively with the preparation of embodiment 1
Periplocoside L and periplocoside H is test sample.
After transfection for 24 hours, each group is separately added into corresponding test sample and is incubated.After being incubated 5h, take 140 μ L supernatants to another
In 96 orifice plates, 10 μ L 30% (w/v) trichloroacetic acids are added, 15min is heated at 65 DEG C, then 12000rpm centrifuges 10min, takes
The acetic acid solution mixing colour developing of isometric 2% (w/v) p- dimethylaminobenzaldehyde, finally uses microplate reader to be detected in 492nm and inhales
Light value, determination of activity result IC50Value indicates.
3, experimental result
The results are shown in Table 1 for specific experiment of each group to the inhibitory activity of IDO.
Specific experiment result of 1 each group of table to the inhibitory activity of cellular level IDO
Group | IC50(μM) |
Positive controls | 17.8 |
1 group of experimental group | 13.8 |
2 groups of experimental group | 12.2 |
As shown in Table 1:(1) experimental group 1-2 groups are superior to positive controls to cell to the inhibitory activity of intracellular IDO
The inhibitory activity of interior IDO, the inhibitory activity with significant IDO;
(2) experimental group 1-2 groups are suitable to the inhibitory activity of intracellular IDO, this shows Heiguteng exract C21 steroids
The difference of R substituent has no significant effect inhibitory activity.
4, experiment conclusion
Periplocoside L and periplocoside H is superior to positive control drug 1- methyl tryptophans to the inhibitory activity of intracellular IDO
(1-MT) has the inhibitory activity of significant IDO to the inhibitory activity of intracellular IDO.
Experimental example 2Therapeutic effect of the Heiguteng exract C21 steroids of the present invention to ankylosing spondylitis
1, experiment purpose
Mouse ankylosing spondylitis model is established using proteoglycans immunization method, then gavage Heiguteng exract C21 of the present invention
Steroid, ELISA method detection Inflammatory Mediators Serum TNF-α and NF- к B receptor activations factor ligands (RANKL) are horizontal,
And serum I DO activity (Kyn/Trp) is detected, verify treatment of the Heiguteng exract C21 steroids of the present invention for ankylosing spondylitis
Effect.
2, experimental method
2.1 experimental animal
Healthy male BALB/c mouse 32, weight (18 ± 2) g, age of mouse 4~5 weeks are purchased from Shanghai Si Laike.
2.2 for reagent object
The periplocoside L and periplocoside H prepared with embodiment 1 is for reagent object.
2.3 experiment packets and modeling
After mouse adaptable fed 1 week, wherein 8 are taken to be only used as blank control group.Remaining 24 are taken to gather only with albumen
Sugared immunization method establishes ankylosing spondylitis model, and proteoglycans emulsion 0.15mL (75 μ g+ Freund's adjuvants) is injected intraperitoneally in mouse, first
It is secondary it is immune after 7 days can booster immunization, 0.15mL emulsions, modeling totally 21 days is injected intraperitoneally;After modeling success, it is divided into 3 groups:Experimental group
1-2 groups and model control group.Experimental group 1-2 groups give the periplocoside L and periplocoside H gastric infusions of the preparation of embodiment 1 respectively, often
Day 1 time, each 0.2g/10g.Model control group and blank control group give normal saline gavage.Each group is administered 60
It, blood is taken in the 61st day eye socket.
2.4 inflammatory factors measure
Serum TNF-α and RANKL levels in animal peripheral blood are detected using ELISA, operated according to kit specification.
2.5 IDO Activity determinations
Detect Trp concentration and Kyn concentration in mice serum simultaneously using high-efficient liquid phase chromatogram technology.Because IDO can be catalyzed
Substrate Trp metabolism generates product Kyn, therefore Kyn/Trp ratios can reflect IDO activity.
Serum is stood overnight at 4 DEG C, and 3000rpm centrifuges 15min.Supernatant serum is taken, 5% isometric perchloric acid is added
Solution, in mixing 0.5-1min on whirlpool misfortune vortex mixer.It is stored at room temperature 10-15min, fully to precipitate the albumen in serum, then
10min is centrifuged with 12000rpm, takes supernatant that 1/2 volumes methanol (chromatographically pure) is added, vibrates 5min on whirlpool misfortune instrument, then
12000rpm centrifuges 10min, and last supernatant carries out loading after 0.45 μm of filter filters, detect kynurenin in serum/
Tryptophan (Kyn/Trp) ratio, to reflect the active variations of IDO.Chromatographic condition:C18 columns (250mm × 4.6mm, 5 μm);Stream
Dynamic phase:15mmol/L sodium acetate-acetic acids solution (acetonitrile for being 7% containing volume fraction, pH 3.5);Flow velocity:1mL/min;Detection
Wavelength:225nm;Sample size:20μL;25 DEG C of column temperature.
2.6 statistical procedures
It is analyzed using SPSS22.0 statistics softwares, continuous data mean ± standard deviation It indicates, row
T is examined;Enumeration data is expressed as a percentage, row chi-square criterion;P < 0.05 indicate that difference is statistically significant.
3, experimental result
The results are shown in Table 2 for the specific experiment of each group mouse.
2 each group mice serum TNF-α of table and RANKL are horizontal and to the active inhibiting effect of IDO
#The P < 0.05 compared with blank control group,*The P < 0.05 compared with model control group
As shown in Table 2, the Serum TNF-α of (1) model control group mouse and RANKL are horizontal significantly raised, this shows tetanic
Property rachitis model modeling success;(2) Serum TNF-α and RANKL levels of experimental group 1-2 groups mouse significantly reduce (P <
0.05), and IDO activity (P < 0.05) is significantly reduced;This shows that periplocoside L prepared by embodiment 1 and periplocoside H pass through inhibition
IDO activity plays the therapeutic effect to ankylosing spondylitis.
4, experiment conclusion
Periplocoside L and periplocoside H of the present invention can significantly reduce the Serum TNF-α and RANKL of ankylosing spondylitis model
Level, and there is significant inhibiting effect to IDO activity;Periplocoside L and periplocoside H of the present invention have ankylosing spondylitis aobvious
The therapeutic effect of work.
Experimental example 3Therapeutic effect of the Heiguteng exract C21 steroids of the present invention for streptococcal infection
1, experiment purpose
By to streptococcal infection intragastric administration on mice Heiguteng exract C21 steroids of the present invention, detecting it for streptococcus sense
The dead inhibiting rate for contaminating mouse, verifies its therapeutic effect to streptococcal infection.
2, experimental method
2.1 experimental animal
Healthy male mouse of kunming 40, weight (18 ± 2) g, age of mouse 4~5 weeks are purchased from Shanghai Si Laike.
2.2 for reagent object
The periplocoside L and periplocoside H prepared with embodiment 1 is for reagent object.
2.3 experiment packets and modeling
32171 reference cultures of hemolytic streptococcus CMCC (B) are inoculated with rabbit blood agar plate, cultivate and have been obtained obviously after scribing line
The single bacterium colony of zone of hemolysis.Single bacterium colony is taken to be inoculated in THY culture mediums (containing 5% calf serum) amplification overnight, OD600nm=0.6 is (about
109When CFU/ml), 4 DEG C save backup.(every liter contains 20 grams of tryptone, 3 grams of yeast extract, beef extract 5 to THY culture mediums
Gram, 2 grams of sodium chloride, 4 grams of glucose, 2.5 grams of sodium carbonate, 0.4 gram of disodium hydrogen phosphate, tune pH to 7.4.Solid medium:Again plus
Enter 1.5% agar powder, autoclaving 30min is placed in 4 DEG C of preservations).
10 mouse are taken, as blank control group.Remaining 30 mouse is divided into 3 groups:Experimental group 1-2 groups and model pair
According to group, every group of 10 mouse.Experimental group 1-2 groups give periplocoside L and periplocoside H gastric infusions, each 80mg/kg respectively.Mould
Type control group and blank control group give normal saline gavage.After experimental group 1-2 groups and model control group gavage 1h,
Tail vein injection OD600nm=0.6 micrococcus scarlatinae 322171PBS solution, injection dosage:0.4ml bacterium solutions/10g mouse, often
Be administered once every for 24 hours, every 6h observe 1 time, respectively record time 6h, 12h, for 24 hours, the death condition of the mouse of 48h.
3, experimental result
Influence of each group different time to streptococcal infection dead mouse is as shown in table 3.
Influence (n=10) of 3 each group of table to streptococcal infection dead mouse
As shown in Table 3, after (1) is administered 48 hours, the mouse survival rates of experimental group 1-2 groups is respectively 80% and 70%, and
The survival rate of model control group mouse is only 20%;This shows that periplocoside L prepared by embodiment 1 and periplocoside H can be carried significantly
The survival rate of high streptococcal infection mouse, has significant therapeutic effect to streptococcal infection.
4, experiment conclusion
Periplocoside L and periplocoside H of the present invention have significant therapeutic effect to streptococcal infection.
Obviously, the above embodiments are merely examples for clarifying the description, and does not limit the embodiments.It is right
For those of ordinary skill in the art, can also make on the basis of the above description it is other it is various forms of variation or
It changes.There is no necessity and possibility to exhaust all the enbodiments.And it is extended from this it is obvious variation or
It changes still within the protection scope of the invention.
Claims (4)
1. the purposes of Heiguteng exract C21 steroids and its pharmaceutically acceptable derivates in preparing IDO inhibitor;
The IDO inhibitor is for treating cancer, Alzheimer disease, autoimmune disease, ankylosing spondylitis, bacterium sense
Dye, cataract, mood disorder, depressive and anxiety neurosis;The pharmaceutically acceptable derivates are selected from salt, ester, prodrug or molten
Object is closed in agent;
The Heiguteng exract C21 steroids have structure as follows:
R is selected fromAnd its acetyl derivatives,And its acetyl derivatives,And its at least one of acetyl derivatives are formed by glycosyl residue.
2. Heiguteng exract C21 steroids and its pharmaceutically acceptable derivates are in the tryptophan generation for preparing treatment IDO mediations
Thank to the purposes in the drug of the disease of the pathological characteristics of approach, the disease is cancer, Alzheimer disease, autoimmune
Disease, ankylosing spondylitis, bacterium infection, cataract, mood disorder, depressive and anxiety neurosis;It is described pharmaceutically acceptable
Derivative is selected from salt, ester, prodrug or solvate;
The Heiguteng exract C21 steroids have structure as follows:
R is selected fromAnd its acetyl derivatives,And its acetyl derivatives,And its at least one of acetyl derivatives are formed by glycosyl residue.
3. purposes according to claim 1 or 2, which is characterized in that
R isWhen, the Heiguteng exract C21 steroids are periplocoside L;
Or
R isWhen, the Heiguteng exract C21 steroids are periplocoside H.
4. according to claim 1-3 any one of them purposes, which is characterized in that the Heiguteng exract C21 steroids according to
Common process is added customary adjuvant and clinically acceptable tablet, capsule, powder, mixture, pill, granule, syrup is made
Agent, emplastrum, suppository, aerosol, ointment or injection.
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CN110702813A (en) * | 2019-10-23 | 2020-01-17 | 贵州中医药大学 | Miao medicine caulis et folium periplocae HPLC fingerprint spectrum research and multi-component content determination method |
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