CN105796764A - Preparation method and purpose of negundo chastetree fruit total lignans - Google Patents
Preparation method and purpose of negundo chastetree fruit total lignans Download PDFInfo
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- CN105796764A CN105796764A CN201610274653.8A CN201610274653A CN105796764A CN 105796764 A CN105796764 A CN 105796764A CN 201610274653 A CN201610274653 A CN 201610274653A CN 105796764 A CN105796764 A CN 105796764A
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- Prior art keywords
- fructus viticis
- total lignans
- viticis negundo
- rheumatoid arthritis
- medicine
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/85—Verbenaceae (Verbena family)
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/55—Liquid-liquid separation; Phase separation
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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
- A61K31/11—Aldehydes
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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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
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- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Alternative & Traditional Medicine (AREA)
- Biotechnology (AREA)
- Botany (AREA)
- Medical Informatics (AREA)
- Medicinal Chemistry (AREA)
- Microbiology (AREA)
- Mycology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to the technical field of medicine, and relates to negundo chastetree fruit total lignans and application of the negundo chastetree fruit total lignans to preparation of medicine for resisting rheumatoid arthritis and prostatic cancer. Through a type II collagen induced rat rheumatoid arthritis model, the effect that the negundo chastetree fruit total lignans can obviously relieve the symptoms of the rat rheumatoid arthritis, and the good rheumatoid arthritis resisting function is proved; through a tumor-bearing mice model, the effect that the negundo chastetree fruit total lignans can obviously inhibit the growth of the prostatic cancer tumor and the good prostatic cancer resisting function is proved. The negundo chastetree fruit total lignans disclosed by the invention can be used for preparing medicine for resisting rheumatoid arthritis and prostatic cancer. A novel resource is provided for seeking safe and effective medicine for resisting rheumatoid arthritis and prostatic cancer.
Description
Technical field
The present invention relates to pharmaceutical technology field, being specifically related to is Fructus Viticis Negundo total lignans and preparation method thereof, be used for prepare prevention or treatment rheumatoid arthritis and carcinoma of prostate medicine in purposes.
Background technology
Rheumatoid arthritis (RA) is current one of most important diseases endangering human health, is referred to as " not dead cancer ".RA be a kind of get involved with multi-joint, chronic generalized autoimmune inflammatory disease that synovial membrane inflammation, bone and cartilage destruction etc. are principal character, its pathogeny not yet illustrates so far completely, generally believe with heredity, infect and the factor disorder closely related (ImbodenJB.Theimmunopathogenesisofrheumatoidarthritis.Ann uRevPatholMechDis2009,4:417-434.) such as immunomodulating.nullThe prevalence of China RA is about 0.3%-0.4%，There are about 4,000,000 patients，Course of disease 5-10 disability rate is 60%，Late period 90%, patient lost social labor power and self care ability，It is the adult one of the main reasons (DaiSM that dies of labour force,HanXH,ZhaoDB,ShiYQ,LiuY,MengJM.Prevalenceofrheumaticsymptoms,rheumatoidarthritis,ankylosingspondylitis,andgoutinShanghai,China:aCOPCORDstudy.JRheumatol2003,30:2245-2251.)，A lot of domestic problem and huge burden on society are thus resulted in.The method of Current treatments rheumatoid arthritis mainly has the treatment of operative treatment, chemotherapy and cytokine class biological preparation.It is generally acknowledged that surgical operation is only applicable to late deformity case and somewhat expensive, body wound is bigger；The prolonged application of chemicals such as NSAID (non-steroidal anti-inflammatory drug), antirheumatic and glucocorticoid etc. can cause the serious untoward reaction such as gastrointestinal upset, bone marrow depression, hepatic injury, hypertension；Biological preparation is while intervening sick cell, normal cell can be produced too certain effect, the inherent immunity of interference body and adaptive immunity, thus producing bigger toxicity and destroying a risk (1. adopted creek of body defenses effect, Liu Zhimin, Xiong Lingshuan. rheumatoid arthritis pathogenesis and Therapeutic Method progress thereof. cell and molecular immunology magazine, 2005, 21 (supplementary issue): 88-94.2.DoanT, MassarottiE.RheumatoidArthritis:AnOverviewofNewandEmergi ngTherapies.JClinPharmacol2005, 45:751-762.).Therefore, the medicine of the preventing and treating RA seeking high-efficiency low-toxicity is still a challenge and the difficult problem that world medical circle faces.
Carcinoma of prostate is one of modal malignant tumor of male genitourinary system, M & M is high, serious harm human health (AhmedinJemal, RebeccaSiegel, JiaquanXuandElizabethWard.Cancerstatistics, 2010.CACancerJClin2010,60:277-300.).The sickness rate of China's prostate cancer presents the trend of maintaining sustained and rapid growth in recent years, sickness rate increases ratio every year and is about 12%, Chinese male prostate-cancer incidence alreadys more than 11.00/10 ten thousand, carcinoma of prostate is just becoming the Urinary system tumor (Han Sujun having a strong impact on China's men's health, Zhang Siwei, Chen Wanqing, Li Changling. China's carcinoma of prostate disease currency and Analysis on Epidemic Trend. Journal of Clinical Oncology, 2013,8 (4): 330-334.).nullAnti-androgen therapy is one of effective Therapeutic Method of advanced prostate cancer，But through nearly all patient's pathological changes after a period of time by continuing advances，It is changed into castration-resistant prostate cancer (castration-resistantprostatecancer,CRPC)，Prognosis is not good enough，CRPC life in patients is poor，12～20 months (ThompsonI of median survival interval,ThrasherJB,AusG,etal.Guidelineforthemanagementofclinicallylocalizedprostatecancer:2007update.Urology2007,177(6):2106-2131.).At present, the mechanism of CRPC still imperfectly understands, and clinic still lacks effective medicine.Therefore, one of the main direction that the Drug therapy CRPC of high-efficiency low-toxicity is carcinoma of prostate research is sought.
Fructus Viticis Negundo is the dry mature fruit of Verenaceae Vitex species five-leaved chaste tree VitexnegundoL., originates in provinces and cities of China more than 20, and resource is extremely abundant.Warm in nature, acrid in the mouth, hardship；Return lung, stomach, Liver Channel；There is effect of expelling wind and removing dampness and promoting the circulation of QI to relieve pain, be used for treating migratory arthralgia, asthma etc. (the new medical college in Jiangsu. Chinese medicine voluminous dictionary. Shanghai science tech publishing house, 1986:2057.).At present, pharmacology activity research about Fructus Viticis Negundo is concentrated mainly on the aspects such as anti-inflammatory and antalgic, antitumor and antioxidation, the chemical composition main Types therefrom reported has (the Li Chunzheng such as lignanoids, terpenoid (iridoid, sesquiterpene, diterpene and triterpene), flavonoid, plant steroid class, Su Yanfang, Jin Xianjun. Vitex species chemical composition and bioactivity research progress. Chinese herbal medicine [J], 2005,36 (6): 930-938).nullWherein，Arylnaphthalene type lignan component is one of principal character composition in Fructus Viticis Negundo，Including 6-hydroxyl-4 β-(4-hydroxy 3-methoxybenzene base)-3 alpha-hydroxymethyl-7-methoxyl group-3,4-dihydro-2-naphthaldehyde、VitedoinA、VitedoamineA、VitrofolalsE-F、Remove tetrahydrochysene Juniperus oxycedrus lignan (detetrahydroconidendrin)、VitedoamineB、With (OnoM such as VitexdoinsA-I,NishidaY,MasuokaC,LiJC,OkawaM,IkedaT,NoharaT.LignanderivativesandanorditerpenefromtheseedsofVitexnegundo.J.Nat.Prod.,2004,67(12):2073–2075；ZhengCJ,HuangBK,HanT,ZhangQY,ZhangH,RahmanK,QinLP.NitricoxidescavenginglignansfromVitexnegundoseeds.J.Nat.Prod.,2009,72(9):1627–1630；ZhengCJ,ZhangXW,HanT,JiangYP,TangJY,D,QinLP.Anti-inflammatoryandanti-osteoporoticlignansfromVitexnegundoseeds.Fitoterapia2014,10.1016/j.fitote.2013.12.006.).nullModern pharmacology test shows，Arylnaphthalene type Lignanoids compounds in Fructus Viticis Negundo has multiple biological activity，Wherein 6-hydroxyl-4 β-(4-hydroxy 3-methoxybenzene base)-3 alpha-hydroxymethyl-7-methoxyl group-3,4-dihydro-2-naphthaldehyde has analgesic activities (ZhengCJ,TangWZ,HuangBK,HanT,ZhangQY,ZhangH,QinLP.Bioactivity-guidedfractionationforanalgesicpropertiesandconstituentsofVitexnegundoL.seeds.Phytomedicine.2009,16:560–567)；6-hydroxyl-4 β-(4-hydroxy 3-methoxybenzene base)-3 alpha-hydroxymethyl-7-methoxyl group-3,4-dihydro-2-naphthaldehyde and VitexdoinsA-E have anti-inflammatory activity (ZhengCJ, HuangBK, HanT, ZhangQY, ZhangH, RahmanK, QinLP.NitricoxidescavenginglignansfromVitexnegundoseeds. J.Nat.Prod., 2009,72 (9): 1,627 1630；ChawlaAS,SharmaAK,HandaSS.AlignanfromVitexnegundoseeds.Phytochemistry,1992,31(12):4378–4379)；null6-hydroxyl-4 β-(4-hydroxy 3-methoxybenzene base)-3 alpha-hydroxymethyl-7-methoxyl group-3,4-dihydro-2-naphthaldehyde、VitedoinA、VitedoamineA、VitrofolalsE-F、Tetrahydrochysene Juniperus oxycedrus lignan (detetrahydroconidendrin) is gone to have antioxidant activity (OnoM,NishidaY,MasuokaC,LiJC,OkawaM,IkedaT,NoharaT.LignanderivativesandanorditerpenefromtheseedsofVitexnegundo.J.Nat.Prod.,2004,67 (12): 2,073 2075) etc..
The present inventor is devoted to negundo chastetree fruit extract always, including the research of monomeric compound.
The present inventor has applied for Chinese invention patent with regard to negundo chastetree fruit extract and the application in prevention or treatment medicine for treating rheumatoid arthritis or food thereof, and patented power, the patent No. is CN201110186425.2, denomination of invention is " negundo chastetree fruit extract and application thereof ", and Authorization Notice No. is CN102258633B.
The present inventor has applied for Chinese invention patent with regard to benzene for naphthalene type Lignanoids compounds (including VNL, VitedoinA, VitedoamineA or VitrofolalF) application in preparing antiradiation drug, and patented power, the patent No. is CN201110186436.0, denomination of invention is " benzene is for the application in preparing antiradiation drug of the naphthalene type Lignanoids compounds ", Authorization Notice No. CN102349886B.
The present inventor has applied for Chinese invention patent with regard to benzene for naphthalene type Lignanoids compounds Fructus Viticis Negundo element VNL application in preparing antiprostate cancer, application number is CN201410025746.8, denomination of invention is " application in preparing antiprostate cancer of a kind of arylnaphthalene type lignanoid ", and application publication number is CN103860528A.
The present inventor has applied for Chinese invention patent with regard to benzene for naphthalene type Lignanoids compounds Fructus Viticis Negundo element VNL application in preparing resisting rheumatoid arthritis medicine, application number is CN201510278639.0, denomination of invention is " a kind of benzene is for the application in preparing resisting rheumatoid arthritis medicine of the Nai Xing lignanoid ", and application publication number is CN105030740A.
In modernization of cmm, one of Chinese medicine effect special advantage is exactly that Chinese medicine is made up of active substance group, active substance group plays integration (Cao Junling by Mutiple Targets, too many levels, multipath, Li Zulun, Fu Qiang, Xiao little He. the research of Chinese medicine and compound recipe integration. Chinese herbal medicine, 2007,38 (1): I0002-I0004).Every taste Chinese medicine is equivalent to a little compound recipe, and containing multiple chemical composition, each effective ingredient is respectively provided with again many-sided biological activity, can mutually work in coordination with, integrates onset between them.
So far there are no, and Fructus Viticis Negundo total lignans is used for treating rheumatoid arthritis and the report of carcinoma of prostate aspect.
Summary of the invention
It is an object of the invention to provide a kind of Fructus Viticis Negundo total lignans and new medical usage thereof.
Although, it has been found that negundo chastetree fruit extract has the activity of resisting rheumatoid arthritis；Have also discovered the monomeric compound Fructus Viticis Negundo element VNL extracting acquisition in Fructus Viticis Negundo and there is the activity of anti-prostate cancer and resisting rheumatoid arthritis.But, the separating-purifying of Fructus Viticis Negundo element VNL is extremely difficult, and is only capable of in the Fructus Viticis Negundo medical material of 10 kilograms extracting the Fructus Viticis Negundo element VNL obtaining about 2 grams, greatly wastes raw medicinal material；And Fructus Viticis Negundo total extract does not report the activity of anti-prostate cancer at present, it addition, the other benzene extracted in Fructus Viticis Negundo does not all report the activity whether with good anti-prostate cancer and resisting rheumatoid arthritis for naphthalene type lignanoids monomeric compound such as VitedoinA, VitedoamineA, VitexdoinA, VitrofolalF, VitrofolalE etc..Inventors have contemplated that and whether can obtain Fructus Viticis Negundo total lignans, it is also possible to there is the activity of good anti-prostate cancer and resisting rheumatoid arthritis.
In consideration of it, the lignan component in Fructus Viticis Negundo has been enriched with by we, it is thus achieved that Fructus Viticis Negundo total lignans.
Fructus Viticis Negundo total lignans mainly contains following four benzene for naphthalene type Lignanoids compounds, and including VNL, VitedoinA, VitedoamineA and VitexdoinA, respective structural formula is as follows:
The invention provides the application in prevention or treatment rheumatoid arthritis and/or carcinoma of prostate medicine of the Fructus Viticis Negundo total lignans.
The preparation method that present invention also offers Fructus Viticis Negundo total lignans.
Fructus Viticis Negundo total lignans is extract separation from the fruit of Verenaceae Vitex species five-leaved chaste tree to obtain, and concrete preparation method is as follows:
1) preparing extracting solution: after being pulverized by five-leaved chaste tree fruit, carrying 2～3 times by the ethanol heat of 50～80%, Extracting temperature is 50～80 DEG C, each solvent consumption is made a living 8～10 times of dose, and each extraction time is 1～2 hour, united extraction liquid；
2) refining concentrate drying: said extracted liquid carries out concentrating under reduced pressure, recycling design, concentrated solution (0.15g/mL), after petroleum ether (1:1, v/v) defat, is extremely the solution of 0.1g/mL containing extractum amount with 70% ethanol dilution；3) separate purification: by above-mentioned be the solution of 0.1g/mL containing extractum amount, after mixing sample with polycaprolactam resin 1.5:1w/w, be splined on polycaprolactam resin column 2:1w/w, after washing, collect 35% alcohol elution；35% ethanol elution is through concentrating under reduced pressure, with water dissolution after recycling design, above-mentioned solution is splined on D-101 macroporous adsorbent resin, after water elution, collect 35% alcohol elution, with water suspendible after recycling design, be extracted with ethyl acetate, by acetic acid ethyl acetate extract concentrating under reduced pressure, obtain Fructus Viticis Negundo total lignans.
Preferably, in the Fructus Viticis Negundo total lignans of the present invention, VNL, VitedoinA, VitedoamineA and VitexdoinA summation account for more than the 40% of Fructus Viticis Negundo total lignans.
More excellent, wherein VNL content be more than 20%, VitedoinA content be more than 20%, VitedoamineA content be more than 0.1%, VitexdoinA content be more than 4%.
Optimum, wherein VNL content be more than 23%, VitedoinA content be more than 25%, VitedoamineA content be more than 0.2%, VitexdoinA content be more than 4%.(aforementioned proportion is W/W)
Described medicine is: Fructus Viticis Negundo total lignans, or comprises the pharmaceutical composition of Fructus Viticis Negundo total lignans.
In described medicine, the content of Fructus Viticis Negundo total lignans is 1-99wt%, it is preferable that content is 40-90wt%.
Described pharmaceutical composition can make pharmaceutical preparation with the conventional pharmaceutical adjuvants on pharmaceutics.
Described pharmaceutical preparation can be tablet, granule, dispersible tablet, capsule, soft capsule, drop pill, injection, injectable powder, or aerosol etc..
The present invention adopts rheumatoid arthritis animal model (TrenthamDE, TownesAS, KangAH.AutoimmunitytotypeIIcollagenanexperimentalmodelof arthritis.JExpMed1977,146:857 868；VijiV, KavithaSK, HelenA.Bacopamonniera (L.) WettstinhibitstypeIIcollagen-inducedarthritisinrats.Phyt otherRes2010,24:1377 1383), observe the therapeutical effect of Fructus Viticis Negundo total lignans gastric infusion provided by the invention.
Experimental result shows, after Fructus Viticis Negundo total lignans (40mg/kg) gastric infusion, can significantly reduce RA rat arthritis index, it is suppressed that ankle swelling degree.The studies above shows, Fructus Viticis Negundo total lignans has good anti-RA activity.
The present invention adopts carcinoma of prostate bearing mouse model (ZhanY, CaoB, QiYF, LiuS, ZhangQ, ZhouWD, XuD, LuH, SartorO, KongW, ZhangHT, DongY.MethylselenolprodrugenhancesMDV3100efficacyfortrea tmentofcastration-resistantprostatecancer.IntJCancer.201 3November；133 (9): 2,225 2233.), the inhibitory action that prostate cancer is grown by Fructus Viticis Negundo total lignans gastric infusion provided by the invention is observed.
Experimental result shows, after Fructus Viticis Negundo total lignans (40mg/kg) gastric infusion, can significantly inhibit the prostate cancer growth of non-hormone dependant.The studies above shows, Fructus Viticis Negundo total lignans has good anti-prostate cancer activity.
Adopt its safety of acute toxicity test preliminary assessment further, result shows that the maximum tolerated dose of Fructus Viticis Negundo total lignans is 16.0g/kg (8000g crude drug amount/kg, be equivalent to 6400 times of people's quantity), without animal dead during test, animal spontaneous activity, body weight are all had no significant effect, to mice main organs without overt toxicity, it was shown that Fructus Viticis Negundo total lignans has higher safety.
Fructus Viticis Negundo total lignans, compared to Fructus Viticis Negundo element VNL, it is advantageous that:
1) Fructus Viticis Negundo element total lignans extracts, purifying process is better than Fructus Viticis Negundo element VNL, and solvent for use and chromatographic column filler meet new drug requirements of customs declaration, are more suitable for industrialized production；
2) Fructus Viticis Negundo total lignans yield is about 0.2%, and Fructus Viticis Negundo element VNL yield < 0.02%, can more make full use of Fructus Viticis Negundo herb resource；
3) Fructus Viticis Negundo total lignans maximum tolerated dose is 16.0g/kg (8000g crude drug amount/kg is equivalent to 6400 times of people's quantity), points out its safety higher；
4) in the experiment of internal resisting rheumatoid arthritis, the total lignans of same dose 30mg/kg is suitable with VNL effect, but animal more tolerates for total lignans, model is relatively decreased obviously by the weight of animals according to group nothing, and model is relatively decreased obviously by VNL the weight of animals during being administered according to group.
5) in extracorporeal anti-inflammatory experiment (RAW264.7 cell), total lignans (IC500.20 μ g/mL) suppress NO generation effect to be better than VNL (IC500.80μg/mL)。
6) (DU145 cell), total lignans (IC in In Vitro Anti prostate cancer experiment500.30 μ g/mL) suppress cell proliferation effect to be better than VNL (IC503.0μg/mL)。
The present invention has searched out safely and effectively preventing and treating RA and CRPC medicine.
Accompanying drawing explanation
Fig. 1: II Collagen Type VI is induced impact (* vs model group, the p < 0.05 of the left back podarthritis index of RA rat model by Fructus Viticis Negundo total lignans and VNL；* vs model group, p < 0.01)；
Fig. 2: II Collagen Type VI is induced inhibitory action (mean ± SD, n=10) (* vs model group, the p < 0.05 of the left back whole swelling of RA rat model by Fructus Viticis Negundo total lignans and VNL；* vs model group, p < 0.01)；Fig. 3: II Collagen Type VI is induced impact (mean ± SD, n=10) (* vs model group, the p < 0.05 of RA rat model body weight by Fructus Viticis Negundo total lignans and VNL；* vs model group, p < 0.01)；
Fig. 4: Fructus Viticis Negundo total lignans and VNL impact (mean ± SD, n=10) (* vs model group, p < 0.05 on carcinoma of prostate nude mouse tumor weight；* vs model group, p < 0.01)；
Detailed description of the invention
In conjunction with embodiment, the present invention is described in detail, but the enforcement of the present invention is not limited only to this.
Embodiment 1: the preparation of Fructus Viticis Negundo total lignans
1) preparing extracting solution: after being pulverized by five-leaved chaste tree fruit, carrying 2～3 times by the ethanol heat of 50～80%, Extracting temperature is 50～80 DEG C, each solvent consumption is made a living 8～10 times of dose, and each extraction time is 1～2 hour, united extraction liquid；
2) refining concentrate drying: said extracted liquid carries out concentrating under reduced pressure, recycling design, concentrated solution (0.15g/mL), after petroleum ether (1:1, v/v) defat, is extremely the solution of 0.1g/mL containing extractum amount with 70% ethanol dilution；
3) separate purification: by above-mentioned be the solution of 0.1g/mL containing extractum amount, be splined on polycaprolactam resin column (2:1, w/w) after mixing sample (1.5:1, w/w) with polycaprolactam resin, after washing, collect 35% alcohol elution；35% ethanol elution is through concentrating under reduced pressure, with water suspendible after recycling design, it is extracted with ethyl acetate, by acetic acid ethyl acetate extract concentrating under reduced pressure, with water dissolution (1.5mg/mL) after recycling design, above-mentioned solution is splined on D-101 macroporous adsorbent resin, after water elution, collect 35% alcohol elution, obtain said medicine Fructus Viticis Negundo total lignans TOV, through HPLC assay, VNL content is 23.14%, VitedoinA content is 25.17%, VitedoamineA content is 0.23%, VitexdoinA content is 4.63%, and can survey component content is 53.17%.
Embodiment 2: the resisting rheumatoid arthritis pharmacodynamic experiment of Fructus Viticis Negundo total lignans
2.1 experiment materials
Bull 180～220gSD rat (The 2nd Army Medical College Experimental Animal Center provides) 40.Key instrument: toes capacity measurer (YLS-7A, Shandong Academy of Medical Sciences's equipment station), microplate reader (BIO-RAD550), centrifuge (Labofuge400R, Heraeus company), electronic balance (FA110A type, Shanghai Precision Scientific Apparatus Co., Ltd).
2.2 experiment modeling and administrations
By 40 rat weight before experiment, it is randomly divided into 4 groups by weight, often group 10, free diet, water inlet.It is divided into blank group, model group, positive drug group and Fructus Viticis Negundo total lignans group.
Blank group: not any process；
Model group: cattle II collagen type acetum is mixed with the incomplete Freund's adjuvant waiting capacity, fully emulsified.0th day, SD rat root of the tail carried out intradermal injection (1mg/ml), every 0.1ml；After 7 days, booster immunization, rat root of the tail is injected as booster injection with 0.1ml/ solution, within about the 15th day, causes RA animal model；
Positive drug group: dexamethasone, 0.05mg/kg, gastric infusion, every day 1 time；
Fructus Viticis Negundo total lignans group: from modeling success, giving rat Fructus Viticis Negundo total lignans, gastric infusion, every day 1 time, dosage is 30mg/kg, successive administration 30d.
2.3 observation index
(1) rat articular swelling degree carrying out arthritis index scoring, scoring in every 3 days is once.
(2) measure rat toes swelling degree with toes capacity measurer, within every 3 days, measure once.
(3) experiment end weighed rat body weight the same day.
2.4 experimental results
Adopting SPSS14.0 that experimental data carries out t test statistics analysis, P < thinks when 0.05 that difference is statistically significant.
(1) rat arthritis index score
As shown in Figure 1, it is administered the 30th day, the left back podarthritis index of Fructus Viticis Negundo total lignans group is 0.2 ± 0.4, the left back podarthritis index of model group is 2.6 ± 0.5, prompting Fructus Viticis Negundo total lignans can significantly reduce the left back podarthritis index of RA rat of II Collagen Type VI induction, there is significant difference compared with model group, it was shown that rat model of rheumatoid arthritis is had good antiinflammatory action by Fructus Viticis Negundo total lignans, effect is suitable with VNL.
(2) rat toes swelling
As in figure 2 it is shown, the blank group left back toes of rat are without obvious change, model group has obvious swelling, there is significant difference, prompting modeling success with blank group；It is administered the 30th day, the left back sufficient volume of Fructus Viticis Negundo total lignans group is 1357.0 ± 319.4, the left back sufficient volume of model group is 2297.1 ± 177.2, the prompting Fructus Viticis Negundo left back toes swelling lesser extent of total lignans administration group rat, significant difference is there is compared with model group, showing that rat model of rheumatoid arthritis is had good antiinflammatory action by negundo chastetree fruit extract, effect is suitable with VNL.
(3) rat body weight
As it is shown on figure 3, be administered the 30th day, compared with model control group, positive drug group and VNL group rat body weight are decreased obviously, and Fructus Viticis Negundo total lignans group rat body weight is without significant change, and prompting animal is to the tolerance of Fructus Viticis Negundo total lignans better.
Embodiment 3: the anti-prostate cancer pharmacodynamic experiment of Fructus Viticis Negundo total lignans
3.1 experiment materials
The male BALB/c nude mice of SPF level 60, is provided (laboratory animal production licence: SCXK (Soviet Union) 2011-0003) by this laboratory animal company limited of Cavan, Changzhou；Laboratory animal occupancy permit: SCXK (Soviet Union) 2011-0003), 4-6 week during buying, 9-10 week, body weight 16-18g during buying, body weight 19-20g when starting to be administered when starting to be administered.C4-2 Human Prostate Cancer Cells (hormone refractory), cell is cultivated in the RPMI1640 culture medium containing 10% hyclone.ChemBaseCBS-CJ-1FD superclean bench, MCO-15AC CO2 gas incubator, SANYO GS SANYOXD-202 fluorescence inverted biological microscope microscope (Nanjing Jiangnan Yongxin Optical Co., Ltd.), 0-150 type slide gauge (Southwest Taiwan Jia Hua fine measuring instrument company limited).
3.2 experiment modeling and administrations
Human prostata cancer C4-2 Nude Mice, is inoculated in nude mouse axillary fossa by human prostata cancer C4-2 null cell strain subcutaneous and set up.Inoculation uses after passing for 3 generations after forming transplanted tumor again in nude mouse.
Taking the tumor cell of growth animated period, aseptically, inoculate axillary fossa on the right side of 60 nude mouses subcutaneous, cell inoculum concentration is 1 × 106.Nude Mice vernier caliper measurement transplanted tumor diameter, treats that tumor growth is to 70-100mm3Select during left and right that growth conditions is good and the good tumor bearing nude mice of tumor size homogeneity 40, it is randomly divided into 4 groups, often group 10, namely model group, TOV group 40mg/kg, VNL group 40mg/kg, positive drug MDV3100 group 20mg/kg, TOV20mg/kg combine MDV310010mg/kg group.The equal gastric infusion of each group, every day is administered once, and administration volume is 0.2ml/2Lg body weight.After being administered 21 times, de-neck puts to death nude mice, and operation strips tumor block and weighs.
3.3 observation index
(1) administration processes the impact on nude mouse tumor weight
3.4 experimental results
As it is shown on figure 3, TOV group, VNL group, positive drug MDV3100 group and drug combination group all can significantly inhibit tumor growth, alleviate tumor weight.It is suitable that TOV and VNL organizes drug effect, and with positive drug MDV3100 group quite, both TOV and MDV3100 drug combination best results, not only can reduce drug administration amount, and individually dosed with both compared with, effect is obviously improved.
Embodiment 4: the acute toxicity test of Fructus Viticis Negundo total lignans
4.1 laboratory animals
18～22gICR mice (The 2nd Army Medical College Experimental Animal Center provides) 50, male and female half and half.
4.2 maximum tolerated doses (MTD) measure
Mice is randomly divided into by body weight matched group and administration group.Water 12h is can't help in two groups of mice fasting before gastric infusion, administration group to the molten concentration of maximum energy containing total lignans 0.4g/ml for reagent liquid according to gavage volume gastric infusion 2 times in 24h of 0.4ml/10g weight, matched group gives equivalent 0.5%CMC-Na gavage 2 times with method.The situation of mice Continuous Observation 2 weeks is observed at once, the two groups of mices of 1h, 1d to 14d itemized record upon administration general situation of change in weight, coat color, breathing, eye mucosa and oral cavity place secretions, defecation, activity, extraneous reaction etc. and death condition after administration.If there being dead mouse, dissecting and performing an autopsy on sb., main internal organs are observed, the pathological changes situation of the main organs such as all mices brain, the heart, spleen, liver, kidney and lung is put to death, if the pathological examination making tissue slice is sent in the change that perusal has obvious pathology at once after testing and terminating.
4.3 observation index
(1) the total lignans TOV impact on mice general status
(2) the total lignans TOV impact on Mouse Weight
(3) the total lignans TOV impact on mice main organs
4.4 experimental results
In the experiment of maximum tolerated dose, the maximum volume 0.4ml/10g that total lignans TOV can bear with maximum suspendible mass concentration 0.4g/ml and mice is in 1d after gastric infusion 2 times, major part mice is the same with matched group, crawler behavior, reaction all normal, only least a portion of mice occurs in that slightly weakening of activity and reaction, the critical conditions such as do not occur mice to tremble in experimentation, to topple over.Do not have, after gavage maximum and during observing, the situation that mice appearance is dead.
As shown in Table 1, after male and female mouse stomach total lignans TOV, experimental group and control group mice do not have significant difference (P > 0.05) in body weight growth.
After observing 2 weeks, sacrifice being dissected the situation of change of each internal organs of perusal: liver surface is smooth, and the pathological change such as focus, lump does not occur, its size, shape are all normal, after liver crosscut, the color and luster of tangent plane and the equal gloss of quality, matter are close, without loose wait abnormal；Checking mouse spleen situation with method, there is not the pathological phenomenon such as tuberosity, enlargement in spleen surface, and the size of spleen, shape, surface, tangent plane and quality are all normal；Checking mouse kidney situation with method, kidney is every all acts normally；The size of the heart and color are by the naked eye all less than abnormal；Stomach size, shape are normal, and the situations such as hemorrhage, downright bad do not occur gastric mucosa, also without petechia on coat of the stomach.The coefficient record of the internal organs percentage of liveweight ratio of mice is with table 2, and Main Organ Coefficients shows that the internal organs of mice are not had overt toxicity by total lignans TOV.
It is shown that Fructus Viticis Negundo total lignans maximum tolerated dose is 16.00g/kg (8000g crude drug amount/kg is equivalent to 6400 times of people's quantity).Each group dosage is all without animal dead, and animal spontaneous activity, body weight are all had no significant effect by Fructus Viticis Negundo total lignans, and mice main organs is had no significant effect, and prompting Fructus Viticis Negundo total lignans has higher safety.
Impact that Mouse Weight is changed by table 1. total lignans TOV (N=10)
Table 2. total lignans TOV on the impact of mice organs coefficient (N=10)
Embodiment 5: the extracorporeal anti-inflammatory activity of Fructus Viticis Negundo total lignans: suppress nitric oxide (NO) in the LPS RAW264.7 cell stimulated to generate
5.1 cells are cultivated
RAW264.7 cell culture system is DMDE culture medium (HyClone), containing 10% hyclone (FBS, HyClone), 100U/ml penicillin, 100U/ml streptomycin in 37 DEG C, 5%CO2Cultivate when saturated humidity.
5.2NO burst size is tested
RAW264.7 cell, with 1 × 105Individual/hole is inoculated in 96 orifice plates.Put into adherent 4h in incubator.Add variable concentrations compound, add LPS (final concentration 10 μ g/ml), separately set corresponding cell controls and stimulate comparison (RAW264.7 cell adds above-mentioned concentration LPS).37 DEG C, 5%CO2Incubator is cultivated 24 hours.Terminate to cultivating, supernatant is carefully sucked in 1.5ml centrifuge tube, 5000rpm, 10min, again suck 1.5ml centrifuge tube, frozen to be detected.The burst size of NO adopts the detection of Griess method.
5.3 experimental results
It is shown that Fructus Viticis Negundo total lignans TOV and VNL can significantly inhibit the generation of nitric oxide (NO), IC in the LPS RAW264.7 cell stimulated50Respectively 0.20 μ g/mL and 0.80 μ g/mL, it is shown that good extracorporeal anti-inflammatory effect, TOV effect is better than VNL.
Embodiment 6: the In Vitro Anti carcinoma of prostate activity of Fructus Viticis Negundo total lignans: the impact that Human Prostate Cancer Cells (DU145) is bred
6.1 cells are cultivated
DU145 cell culture system is RPMI1640 culture medium (Gibco), containing 10% hyclone (hyclone), 100U/ml penicillin, 100U/ml streptomycin in 37 DEG C, 5%CO2Cultivate when saturated humidity.
6.2 cell proliferation tests
Adopting CellCountingKit-8 test kit (CCK-8), the DU145 cell taking some exponentials phase of growth is inoculated in 96 orifice plates, and point blank group and administration group (0.1,1 and 10 μM) often group set 6 multiple holes.Continue after cell administration to hatch 48h, after being cultured to the stipulated time, add CCK-810 μ l, continue to hatch 2h, microplate reader detection 450nm place optical density (OD) value (630nm is with reference to wavelength), repeats experiment 3 times, calculates medicine IC50Value.
6.3 experimental results
It is shown that Fructus Viticis Negundo total lignans TOV and VNL can significantly inhibit the propagation of DU145 cell, IC50Respectively 0.30 μ g/mL and 3.00 μ g/mL, it is shown that good In Vitro Anti effect on prostate carcinoma, TOV effect is better than VNL.
In view of above-mentioned effect experiment and safety evaluatio result, the Fructus Viticis Negundo total lignans of the present invention has notable resisting rheumatoid arthritis and anti-prostate cancer activity, and safety is better, therefore can be used for preparing resisting rheumatoid arthritis and antiprostate cancer or food.
Below the preferred embodiment of the invention has been illustrated, but the invention is not limited to described embodiment, those of ordinary skill in the art also can make all equivalent modification or replacement, these equivalent modification or replacement under the premise without prejudice to the invention spirit and be all contained in the application claim limited range.
Claims (9)
1. Fructus Viticis Negundo total lignans in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food.
2. Fructus Viticis Negundo total lignans according to claim 1 in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterised in that the preparation method of described Fructus Viticis Negundo total lignans is as follows:
A, preparing extracting solution: after being pulverized by five-leaved chaste tree fruit, carrying 2～3 times by the ethanol heat of 50～80%, Extracting temperature is 50～80 DEG C, each solvent consumption is made a living 8～10 times of dose, and each extraction time is 1～2 hour, united extraction liquid；
B, refining concentrate drying: said extracted liquid carries out concentrating under reduced pressure, recycling design, concentrated solution, after petroleum ether 1:1v/v defat, is extremely the solution of 0.1g/mL containing extractum amount with 70% ethanol dilution；
C, separate purification: by above-mentioned be the solution of 0.1g/mL containing extractum amount, after mixing sample with polycaprolactam resin 1.5:1w/w, be splined on polycaprolactam resin column 2:1w/w, after washing, collect 35% alcohol elution；35% ethanol elution is through concentrating under reduced pressure, with water dissolution after recycling design, above-mentioned solution is splined on D-101 macroporous adsorbent resin, after water elution, collect 35% alcohol elution, with water suspendible after recycling design, be extracted with ethyl acetate, by acetic acid ethyl acetate extract concentrating under reduced pressure, obtain Fructus Viticis Negundo total lignans.
3. Fructus Viticis Negundo total lignans according to claim 1 in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterized in that, described Fructus Viticis Negundo total lignans Fructus Viticis Negundo total lignans at least contains structural formula four kinds of benzene as follows for naphthalene type Lignanoids compounds VNL, VitedoinA, VitedoamineA and VitexdoinA:
And four kinds of benzene for naphthalene type Lignanoids compounds VNL, VitedoinA, VitedoamineA and VitexdoinA weight sum account for Fructus Viticis Negundo total lignans gross weight more than 40%.
4. Fructus Viticis Negundo total lignans according to claim 3 in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterized in that, in described Fructus Viticis Negundo total lignans Fructus Viticis Negundo hammer butt fat, VNL content is more than 20%, VitedoinA content is more than 20%, VitedoamineA content is more than 0.1%, VitexdoinA content is more than 4%.
5. the Fructus Viticis Negundo total lignans according to Claims 1-4 any one in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterized in that, described medicine is using Fructus Viticis Negundo total lignans as sole active component, or comprises the pharmaceutical composition of Fructus Viticis Negundo total lignans.
6. the Fructus Viticis Negundo total lignans according to Claims 1-4 any one in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterised in that in described medicine, the content of Fructus Viticis Negundo total lignans is 1-99wt%.
7. the Fructus Viticis Negundo total lignans according to Claims 1-4 any one in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterised in that in described medicine, the content of Fructus Viticis Negundo total lignans is 1-90wt%.
8. Fructus Viticis Negundo total lignans according to claim 5 in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterised in that the conventional pharmaceutical adjuvants on described pharmaceutical composition and pharmaceutics makes pharmaceutical preparation.
9. Fructus Viticis Negundo total lignans according to claim 8 in preparation prevention or treats the application in rheumatoid arthritis and carcinoma of prostate medicine or food, it is characterized in that, described pharmaceutical preparation is tablet, granule, capsule, drop pill, injection or aerosol.
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| CN114306322A (en) * | 2021-12-15 | 2022-04-12 | 深圳大学 | Specific inhibitor and application thereof |
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