CN103816172B - The application of eleutheroside E in preparation treatment medicine for treating rheumatoid arthritis - Google Patents
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Abstract
The present invention relates to the novelty teabag of eleutheroside E, be specifically related to eleutheroside E and treat medicine for treating rheumatoid arthritis compositions in the application prepared in treatment medicine for treating rheumatoid arthritis and one.Treatment medicine for treating rheumatoid arthritis compositions is by purity 98%(mass percent) more than eleutheroside E add general medicinal auxiliary element, make tablet, capsule, electuary, drop, granule, ointment or injection.The pharmacological results shows, eleutheroside E obviously can improve rheumatoid arthritis arthroncus situation, reduces arthritis index, reverse the change of arthritis rationality, and without the critical defect of clinical common medicine, show that eleutheroside E has the effect of potent low toxicity resisting rheumatoid arthritis.Therefore, eleutheroside E can be used for the medicine preparing treatment rheumatoid arthritis.The present invention is that the treatment of rheumatoid arthritis provides new medicament sources.
Description
Technical field
The present invention relates to medical art, is the application of eleutheroside E in preparation treatment medicine for treating rheumatoid arthritis.
Background technology
Rheumatoid arthritis (Rheumatoidarthritis, RA) is a kind of periarticular that involves is main multisystem inflammatory autoimmune disease, and the cause of disease is not bright.Rheumatoid arthritis is modal inflammatory joint diseases clinically, has a strong impact on the function status of patient, quality of life and life expectancy, because of its chronic feature, related complication and long-term dysfunction, causes tremendous influence to society and economy.Based on Drug therapy, (common medicine is NSAID (non-steroidal anti-inflammatory drug) in the current treatment to rheumatoid arthritis, new listing biological preparation is as TNF-a inhibitor), but neither one medicine can the development of real complete symptom management, and have serious side effect, therefore urgently research and develop novel resisting rheumatoid arthritis medicine.Natural drug is the important rarity of China, and due to its wide material sources, composition is abundant, untoward reaction is few, is developed to new drug and is easy to the feature that human body accepts, more and more receive the concern of domestic and international researcher.The focus that the novelty for the treatment of RA is found in current trial from natural drug, effective active pharmaceutical substance has become research.
Eleutheroside E (EleutherosideE) is colorless needle crystals in dilute methanol, and fusing point 269-271 DEG C is the principle active component of Chinese medicine Radix Et Caulis Acanthopanacis Senticosi, and this composition all has existence in the position such as root, stem, leaf, flower of Radix Et Caulis Acanthopanacis Senticosi.It dissolves in methanol or ethanol, and all unstable to soda acid, structural formula is as follows.
Eleutheroside E is as a kind of known monomers compound, although have definite molecular formula and structural formula, but the activity of its research is not high, pharmacological action report at present about eleutheroside E is considerably less, its pharmaceutical research report is mainly reduction blood glucose, anti-central fatigue, improves the myocardiac mechanics change caused by pituitrin, reduce the effect of myocardial infarction incidence rate, clinical being mainly used in prevents and treats cardiovascular and cerebrovascular disease aspect.So far, eleutheroside E yet there are no research report as the application of monomer in preparation treatment medicine for treating rheumatoid arthritis.
Summary of the invention
The technical problem that the present invention will solve first aspect is, provides the novelty teabag of eleutheroside E, i.e. the application of eleutheroside E in preparation treatment medicine for treating rheumatoid arthritis.
For solving the problem, the technical scheme that first aspect present invention provides is: the application of eleutheroside E in preparation treatment medicine for treating rheumatoid arthritis compositions.Described pharmaceutical composition comprises inertia, the excipient that nontoxic, pharmacology is suitable.
Second aspect present invention provides a kind of pharmaceutical composition for the treatment of rheumatoid arthritis, and said composition contains the eleutheroside E active component for the treatment of effective dose.
Preferably, described pharmaceutical composition also comprises the medicine of one or more inertia, nontoxic, that pharmacology is suitable excipient.
Preferably, described excipient is carrier, solvent, emulsifying agent, dispersant, wetting agent, binding agent, stabilizing agent, coloring agent, spice.
Preferably, described pharmaceutical composition is tablet, capsule, electuary, drop, lyophilized products, granule, ointment or injection.
In technique scheme, described treatment medicine for treating rheumatoid arthritis compositions adds general medicinal auxiliary element by eleutheroside E more than purity 98% (mass percent), makes tablet, capsule, electuary, drop, lyophilized products, granule, ointment or injection.
Can whole body and/or work partly according to pharmaceutical composition of the present invention, for this reason, can in an appropriate manner, such as, be taken by the approach of mouth, parenteral, lung or nose, the form of taking that can be suitable for these route of administration according to compositions of the present invention is taken.
Being suitable for oral is to work according to prior art level and promptly and/or discharge the form of medication of pharmaceutical composition of the present invention with improved procedure, and comprise with crystallization and/or unbodied and/or dissolved form, such as tablet is (without coating or cated tablet, it such as has and resists gastric juice or delayed dissolved or undissolved coating, compositions according to the present invention discharges), tablet broken rapidly in mouth, or diaphragm, film/lyophilized products, capsule (such as hard or soft capsule), coated tablet, granule, piller, powder, Emulsion, suspension, aerosol or solution according to pharmaceutical composition of the present invention.
Parenteral admistration can avoid absorption step (such as intravenous, intra-arterial, intracardiac, in spinal column or in waist or intraarticular) or comprise absorption (such as intramuscular, subcutaneous, Intradermal, percutaneous or intraperitoneal) simultaneously and carry out.Be suitable for the suitable form of taking of parenteral admistration method in particular for injecting and injecting with solution, suspension, Emulsion, the preparation of lyophilized products or sterilized powder form.
What be suitable for another route of administration is medicament forms such as sucking, and such as powder sucks seven or nebulizer, or can the medicament forms taken of nose, typing drop, solution or spray.
Can be converted into according to pharmaceutical composition of the present invention and described take form.This can in a way known by carrying out with inertia, nontoxic, that pharmacology is suitable mixed with excipients.These excipient comprise carrier (such as microcrystalline Cellulose, lactose, mannitol especially, starch), solvent (such as liquid macrogol), emulsifying agent and dispersant or wetting agent (such as sodium lauryl sulphate, oleic acid polyoxy sorbitan esters, propylene glycol), binding agent (such as polyvinylpyrrolidone), synthesis and natural polymer (such as albumin), stabilizing agent (such as antioxidant, as ascorbic acid), coloring agent (such as inorganic pigment, as iron oxides) and masking property spice and abnormal smells from the patient.
The effective dosage of eleutheroside E can change according to the age body weight of administering mode, patient, coincident with severity degree of condition and other relevant factor, and during oral administration, recommended dose is 20-70mg/ time, every day 1-2 time; Parenteral recommended dose is 10-30mg/ time, every day 1 time.
Technical scheme of the present invention is: by collagen-induced method establishment rheumatoid arthritis mice (CIA) model, select eleutheroside E as medicine first, study the impact that it changes CIA mice serum related immunological index and arthropathology, observe eleutheroside E to the preventive and therapeutic effect of rheumatoid arthritis mice (CIA) animal model, thus for eleutheroside E control rheumatoid arthritis experimental basis is provided.
The invention has the advantages that: (1) provides eleutheroside E to have the purposes of Effective Anti rheumatoid arthritis: can remarkable mitigation symptoms, as arthroncus, arthritis index, and reverse joint pathology damages, reduces anti-CII antibody horizontal, " treating both the principal and secondary aspects of a disease ".Overcome the defect that prior art " is cured the symptoms, not the disease " as NSAID (non-steroidal anti-inflammatory drug).
(2) eleutheroside E provided by the invention has the purposes of Effective Anti rheumatoid arthritis, there is potential great economy effect: current global rheumatoid arthritis treatment medicine market is huge: have data to show, patient with rheumatoid arthritis in life branched go out expense be approximately 61000-122000 dollar.Preparation prepared by eleutheroside E or its pharmaceutically acceptable carrier has the application prospect for the treatment of medicine for treating rheumatoid arthritis, develop according to national original new drug drug approval law procedure, be expected to become the country 1 class high-efficiency low-toxicity treatment rheumatoid arthritis new drug with the independent intellectual property of China, industrialization prospect is clear and definite.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the invention will be further described:
Figure 1A is each group of CIA mice rear solid end picture substantially; Figure 1B is the impact of eleutheroside E on CIA mice Joint scores; Fig. 1 C is the impact of eleutheroside E on CIA Mouse Weight; Fig. 1 D is the impact of eleutheroside E on CIA mice claw thickness;
Fig. 2 A is each group of mice rear solid end mammography picture; Fig. 2 B is each group of mice rear solid end micro-CT picture; Fig. 2 C is the impact that eleutheroside E is marked on the bone destruction of CIA mice;
Fig. 3 A is that each group of mice joint part pathological tissue changes picture; Fig. 3 B is the impact that eleutheroside E is marked on CIA mice arthropathology;
Fig. 4 is the impact of eleutheroside E on C II antibody horizontal anti-in Mice Body.
Wherein, Vehicle is excipient; TG is positive control drug; EE is eleutheroside E; EE-15 is 15mg/kg gavage group; EE-30 is 30mg/kg gavage group, and EE-60 is 60mg/kg gavage group.
Detailed description of the invention
Below in conjunction with accompanying drawing, the specific embodiment of the invention is described.
One, material
1. laboratory animal
DBA/1J mice, 30, male, in 8 week age, body weight 18 ~ 25g, cleaning grade, is provided by Shanghai Slac Experimental Animal Co., Ltd..Laboratory animal production licence number (SCXK (Shanghai) 2012-0002).Duration of test receptacle temperature 20 ± 3.2 DEG C, relative humidity is 65 ~ 75%, freely ingests and drinks water.
2, medicine and reagent:
2.1 medicine
Eleutheroside E, white powder, content is >=98%, is provided by Sigma-Aldrich (Louis, MO, USA) company, 4 DEG C of Refrigerator stores.Facing the used time adds 1% sodium carboxymethyl cellulose (CMC-Na) and makes suspension, matching while using; Tripterygium wilfordii Polyglycosidium Tablets, Xieli Pharmaceutical Co., Ltd., Hunan produces, the accurate word of traditional Chinese medicines: Z43020138.
2.2 reagent
Cattle II Collagen Type VI, complete Freund's adjuvant and incomplete Freund's adjuvant, Chondrex company of the U.S. produces; Hyclone, Gibco company produces, lot number: 948573; RPMI-1640 cultivates powder, and Gibco company produces, lot number: 984716; THP-1 cell line, is so kind as to give by University Of Suzhou's hematopathy institute; Penicillin (1000U/ml), streptomycin (10mg/ml), produces by Beijing Solarbio company, lot number: 20121025; Horseradish peroxidase sheep anti-mouse antibody, is produced by Abgent company, lot number: 130318.
2.3 instrument
Electronic balance scale, EL104 type, Shanghai Yue Ping scientific instrument company limited produces; Slide gauge (HAMILTION); 3K15 type tabletop refrigerated centrifuge, German Sigma company produces; CO2 incubator, electrical machinery of Japanese sanyo Co., Ltd. manufactures; Sunrise microplate reader, is produced by Tecan company of Switzerland; FACSCanto II flow cytometer, U.S. company BD production; DK-8AD type electric heating constant temperature tank, the permanent Science and Technology Ltd. in Shanghai one produces.
Two, experimental technique
1, modeling and administration
DBA/1J mice 30, male, weigh, numbering, is divided into 5 groups, i.e. CIA model group at random, eleutheroside E low (15mg/kg), in (30mg/kg) and high (60mg/kg) dosage group and positive control drug Radix Tripterygii Wilfordii (TG15mg/kg) group, often organize 6.The mice of model group and each treatment group all induces rheumatoid arthritis to fall ill.Concrete operation step is as follows: by cattle II Collagen Type VI acetic acid solution (2mg/ml) and Freund's complete adjuvant (containing 5mg/mlBCG) mixed in equal amounts and emulsifying, forms Emulsion.In one glass of clear water, instill an Emulsion, emulsion droplet maintains the original state, and that does not disperse is considered to qualified stability.Every experiment mice back is got 4-6 point and is carried out subcutaneous injection, 200 μ l altogether.With incomplete Freund's adjuvants and cattle II Collagen Type VI acetic acid solution (2mg/ml) mixed in equal amounts and emulsifying after three weeks, every mouse tail root gets 3-5 point subcutaneous injection, 100 μ l altogether.Each treated animal starts from every morning per os gastric infusion 1 time in 2 second days of exempting from, successive administration 35 days.Every other day Joint scores carried out to mice, weigh and survey rear solid end thickness once.
2, collection of specimens
The process in joint: at the end of experiment, each group mice is all plucked eyeball through eye socket and gets blood, and gets the rear solid end (comprising rear solid end and joint part) of mice.The paraformaldehyde respectively rear solid end being placed in 10% is fixed for more than 24 hours, and wherein a rear solid end is used for pathological study, and another rear solid end is used for imaging observation (molybdenum target and microCT).
The preparation of serum: each group mice is plucked after eyeball gets blood through eye socket, and 4 DEG C are spent the night, the centrifugal 20min of 4000r/min, carefully get the centrifuge tube that supernatant is placed in 0.5ml.The serum prepared-20 DEG C of Refrigerator stores, to measure the level of Anti-type Ⅱcollagen antibody in serum.
3, Joint scores
Mouse arthritis disease is as follows with scoring: 0: without obviously changing; 1: one toe head obvious tumefaction and rubescent; 2: the swelling of slight swelling and the erythema of limbs or two toe heads; There is the erythema of obvious swelling and limbs in 3: three toe heads; 4: swelling and rubescent, even joint stiffness appear in whole joint.
4, pathological study:
Rear solid end (rear solid end and the joint part) formaldehyde with 10% of mice is fixed, then within two days, carries out decalcification through the EDTA solution soaking of 10%, and by paraffin embedding, tissue slice 5 μm, rear row HE dyes.According to organizing the change of microcosmic as neutrophilic granulocyte in the infiltration of synovial membrane and periarticular tissue and monocytic infiltration (inflammation), the pannus (pannus) of boundary zone, the damage (loss of proteoglycan, the death of chondrocyte and the destruction of collagen stroma) of osteoclasia and cartilage is marked.Parameter according to sufficient pawl, knee joint and joint carries out overall scoring.Be divided into five grades: 0: without changing; 1: the change of minimum degree; 2: slightly change; 3: medium change; 4: obviously change; 5: severe changes.
5, the mensuration of serumanti-typeⅡcollagenantibody
With cattle II Collagen Type VI (10 μ g/ml) bag by 96 orifice plates, put 4 DEG C and spend the night.Then PBST(phosphate Tween buffer is used) clean three times, every hole adds 200ul sealer (0.01mol/LPBS and 5% skim milk), hatches 2 hours for 37 DEG C.With sample buffer (0.01MPBST, 5% skim milk), serum is carried out 1:32000 dilution, join every hole (100 μ l) and hatch 1 hour at 37 DEG C.In every hole, add 100 μ l horseradish peroxidases sheep anti-mouse antibody (1:2000) after cleaning 3 times, hatch 1 hour for 37 DEG C.Clean 3 times again, add tmb substrate solution, ambient temperatare puts 10min colour developing, and then every hole adds the sulphuric acid color development stopping of 50ul2M.Under 450nm wavelength, the OD value in every hole is read by automatic microplate reader.
6, imaging evaluation
X-ray mammography is carried out to the rear solid end of mice, marks according to destruction of joint and bone erosion degree: 0: not damage; 1: find that there is slight osteoclasia at a place; 2: moderate change, there is 2-4 point to destroy at a place; 3: have 2-4 point significantly to destroy in many places; 4: the destruction that joint part is serious; 5: joint part is completely destroyed.
7, the assessment of Micro-CT scanning (micro-CT)
The mice rear solid end fixed with formaldehyde is placed on the scanning bed enterprising line scanning of micro-CT, has scanned rear NRecon software and carried out three-dimensional reconstruction, then with CT analysis software, image has been processed further.
8, statistical method
Adopt SPSS16.0 statistical software processing system, experimental data with
represent, statistical analysis adopts Mann – WhitneyU inspection, and P<0.05 has statistical significance.
Three, result of implementation
Embodiment 1 eleutheroside E is on the impact of mice joint, body weight and sufficient volume
Experiment mice eleutheroside E carries out gavage treatment, add up its Joint scores, body weight and rear solid end thickness, result shows: model group mice rear solid end has significantly red and swollen and joint stiffness, and the mice lesion degree of eleutheroside E and TG treatment group obviously reduces (Figure 1A).Compared with model group, 15mg/kgTG treatment group, 30mg/kg and 60mg/kg eleutheroside E treatment group small mouse Joint scores and the degree lost weight obviously reduce (P<0.01).The mice Joint scores of 15mg/kg eleutheroside E treatment group also reduces compared with model group with the degree lost weight, but significant difference is not significantly (P>0.05), sees Figure 1B and 1C.The thickness of 30mg/kg and 60mg/kg eleutheroside E treatment group small mouse rear solid end obviously declines after exempting from one for 42 days to 56 days, but 15mg/kg eleutheroside E treatment group does not demonstrate obvious therapeutic effect, sees Fig. 1 D.
The impact of embodiment 2 eleutheroside E treatment on joint bone destruction
Molybdenum target X-ray plain film and micro-CT inspection are carried out to the rear solid end of mice, molybdenum palladium X-ray film display model group mice hind paw joint obviously destroys, the hypertrophy of displacement and irregular bone, and the bone destruction degree of eleutheroside E (30mg/kg, 60mg/kg) and TG(15mg/kg) treatment group small mouse obviously lowers, see Fig. 2 A.Correspondingly eleutheroside E (30mg/kg, 60mg/kg) and TG(15mg/kg) the bone destruction degree for the treatment of group small mouse score also obviously reduce (P<0.01), see Fig. 2 C.And the mice of 15mg/kg eleutheroside E treatment group is compared with model group, do not show obvious improvement (P>0.05).Scan the rear solid end of mice with micro-CT, same discovery model group mice has obvious destruction of joint, and eleutheroside E (30mg/kg, 60mg/kg) and TG(15mg/kg) treatment group small mouse joint and osteoclasia degree obviously reduce, and see Fig. 2 B.
Embodiment 3 eleutheroside E is on the impact of synovial tissue of joint
At the end of experiment, get mice rear solid end and ankle joint, to walk abreast HE dyeing through paraffin section, observed result display under light microscopic: in the mice synovial membrane of CIA model group, have that obvious cell infiltration, pannus are formed, cartilage destruction and bone erosion, see Fig. 3 A.Eleutheroside E (30mg/kg, 60mg/kg) and TG(15mg/kg) treatment group small mouse cell infiltration degree alleviate, pannus quantity obviously reduces, the degree of cartilage destruction and bone erosion also significantly suppressed (P<0.001), and eleutheroside E 15mg/kg treatment group is compared with model group, change and not obvious (P>0.05) is shown in Fig. 3 B.
Embodiment 4 eleutheroside E resists the impact of II Collagen Type VI antibody horizontal
Get the detection that a serum of exempting from mice after 42 days carries out Anti-type Ⅱcollagen antibody level, interpretation of result finds: in model group mice serum, Anti-type Ⅱcollagen antibody level is very high, and in eleutheroside E (30mg/kg, 60mg/kg) and TG(15mg/kg) treatment group, Anti-type Ⅱcollagen antibody level obviously reduces (P<0.01).See Fig. 4.
Result of implementation brief summary
The continuous gavage of 1.CIA mice gives after eleutheroside E treats 35 days, and eleutheroside E (30mg/kg and 60mg/kg) can reduce the order of severity and the weight loss degree of the swelling of CIA mice rear solid end significantly.
2. molybdenum target X-ray plain film and micro-CT check display, and successive administration is after 35 days, and eleutheroside E (30mg/kg and 60mg/kg) can improve the degree of destruction of joint significantly.
3. pathologic examination result display, mice joint part cell infiltration after eleutheroside E treatment, pannus are formed, the erosion of cartilage destruction and bone obviously alleviates.
4. after eleutheroside E treatment, in model Mice Body, Anti-type Ⅱcollagen antibody level obviously reduces.
In sum, eleutheroside E corrodes have certain preventive and therapeutic effect to cell infiltration, bone destruction, articular cartilage in CIA mouse arthritis.
The present invention further illustrates by experimental example below.
Prepare the embodiment 1 of medicament:
Get eleutheroside E monomeric compound 20g, add medical starch 280g, the two fully mixes, and makes 1000 capsules, and every heavy 0.3g, containing eleutheroside E 20mg.
Prepare the embodiment 2 of medicament:
Get eleutheroside E monomeric compound 100g, add medical starch 200g, the two fully mixes, and makes 1000, and the heavy 0.3g of every sheet, containing eleutheroside E 100mg.
Prepare the embodiment 3 of medicament:
Get eleutheroside E monomeric compound 20g, add 1,2-PD 100m1, fully dissolve, add sterilized water for injection and be diluted to 1000m1, be dispensed into after mixing in 1000 ampullas, often prop up lml, containing eleutheroside E 20mg.
More than show and describe ultimate principle of the present invention, principal character and advantage of the present invention.The technical staff of the industry should understand; the present invention is not by the restriction of above-mentioned example; what describe in above-mentioned example and description just illustrates principle of the present invention; the present invention also has various changes and modifications without departing from the spirit and scope of the present invention, and these changes and improvements all fall in the claimed scope of the invention.Application claims protection domain is defined by appending claims and equivalent thereof.
Claims (4)
1. the application of eleutheroside E in preparation treatment medicine for treating rheumatoid arthritis compositions.
2. purposes according to claim 1, is characterized in that, described pharmaceutical composition comprises inertia, the excipient that nontoxic, pharmacology is suitable.
3. purposes according to claim 1, is characterized in that, described pharmaceutical composition is tablet, capsule, electuary, drop, lyophilized products, granule, ointment or injection.
4. purposes according to claim 2, is characterized in that, described excipient is carrier, solvent, emulsifying agent, dispersant, wetting agent, binding agent, stabilizing agent, coloring agent, spice.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102160869A (en) * | 2011-03-02 | 2011-08-24 | 中国人民解放军第二军医大学 | Application of eleutheroside E in preparing medicines for resisting central fatigue |
| WO2012101746A1 (en) * | 2011-01-24 | 2012-08-02 | 株式会社資生堂 | Tie-2 activator, agent for maturation, normalization, or stabilization of blood vessels, lymph vessel stabilizing agent, wrinkle prevention/improvement agent, and edema improvement/prevention agent |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2012101746A1 (en) * | 2011-01-24 | 2012-08-02 | 株式会社資生堂 | Tie-2 activator, agent for maturation, normalization, or stabilization of blood vessels, lymph vessel stabilizing agent, wrinkle prevention/improvement agent, and edema improvement/prevention agent |
| CN102160869A (en) * | 2011-03-02 | 2011-08-24 | 中国人民解放军第二军医大学 | Application of eleutheroside E in preparing medicines for resisting central fatigue |
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