CN108514568A - The preparation method and its medical usage of thiazides compounds in the achene of Siberian cocklebur - Google Patents
The preparation method and its medical usage of thiazides compounds in the achene of Siberian cocklebur Download PDFInfo
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Abstract
The present invention relates to the preparation method of thiazides compounds in the achene of Siberian cocklebur and its medical usages, the present invention, which screens to have obtained in cocklebur fruit ethanol extract to have, prevents and/or treats rheumatism, the active component of rheumatoid arthritis, the wherein ethyl acetate component of 50 90% ethanol extract of the achene of Siberian cocklebur, n-butanol component, with significant rheumatism, the therapeutic effect of rheumatoid arthritis, the n-butanol component of 50 90% ethanol extract of the achene of Siberian cocklebur is isolated and purified, 11 particular compounds are obtained, the compound shows the effect of the apparent RAFLS cell Proliferations for inhibiting TNF α inductions, it is wherein especially the most apparent with xanthiside effects, it is suitable for rheumatism, the prevention and treatment of rheumatoid arthritis.
Description
Technical field
The invention belongs to drug fields, are specifically related to a kind of medicine prevented and/or treat rheumatism, rheumatoid arthritis
Compositions and its preparation method and application, i.e., the preparation method and its medical usage of thiazides compounds in the achene of Siberian cocklebur.
Background technology
Rheumatism, rheumatoid arthritis (Rheumatoid arthritis, RA) are mainly carried out with synovitis and joint
Property destroy be main clinical manifestation chronic auto-immune disease, early stage joint part present red and swollen heat pain, it is serious to make
At the dysfunction in joint, the strong and deformation that late period can cause joint different degrees of has very high disability rate, specifically
Pathogenesis is still unclear at present.The treatment of rheumatism and rheumatoid arthritis is directed in addition to physical exercise and function at present
Nursing generally uses non-steroidal anti-inflammatory drugs, glucocorticoid, immunosuppressor etc. to control symptom, mitigate patient suffering, but non-
Non-steroidal anti-inflammatory drug will increase cardiovascular risk, cause the side effects such as injury of gastrointestinal tract, lesions of liver and kidney, and glucocorticoid
The serious side effects such as central obesity, half a month face, caput femoris necrosis can then be led to, there is also gastrointestinal tract damages for immunosuppressor
The serious side effects such as wound, alopecia, bone marrow suppression, Neuroleptic Leukocytopenia, liver renal toxicity, the serious pair present in the above drug
Effect limits their applications when rheumatism and rheumatoid are treated.
The achene of Siberian cocklebur also known as azure water, are the drying and ripening of composite family cocklebur Siberian cocklebur (Xanthium sibiricum)
Fruit with involucre is distributed on Hebei, Liaoning, Heilungkiang, the Jilin Inner Mongol and other places, is common Chinese herbal medicine, has and dissipate
Wind, dehumidifying, sensible effect, are usually used in the treatment of the diseases such as flu, arthralgia pain due to rheumatism, rubella itch.Come from《Prescriptions for Succouring the Sick》It is grey
The ears or side handles of a utensil dissipate, and are exactly for rhinitis chronic, the classics recipe of nasosinusitis and allergic rhinitis.
Chinese medicine think rheumatism, rheumatoid arthritis mainly with cold, heat, the stasis of blood, it is wet, empty based on, achene of Siberian cocklebur relieve heat dehumidifies
Effect makes it that can be possible to the treatment suitable for rheumatism, rheumatoid arthritis from theory of traditional Chinese medical science angle, is reported if explaining Jianping
It can be used for the treatment of rheumatoid arthritis using achene of Siberian cocklebur external application, but chemical composition contained by the achene of Siberian cocklebur is extremely complex, including
Volatile oil, aliphatic acid, glycoside, phenolic acid class, thiazine diketone class, sequiterpene, anthraquinone, flavones, alkaloid etc., variety classes ingredient
Therapeutic effect it is different so that the achene of Siberian cocklebur and its crude extract for rheumatism, the therapeutic effect of rheumatoid arthritis and are paid no attention to
Think, and the active component of achene of Siberian cocklebur antirheumatic, rheumatoid arthritis has not yet to see report.
The present invention is dedicated to screening in the determining achene of Siberian cocklebur for wind on the basis of country actively pushes forward original new drug research and development
Wet, rheumatoid arthritis has the extract or particular compound of therapeutic effect, makes every effort to provide a kind of therapeutic effect excellent
The medicine composition of rheumatism, rheumatoid arthritis.
Invention content
The present invention provides a kind of prevention and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis and its preparations
Method and purposes.
On the one hand, preventing and/or treat rheumatism, the pharmaceutical composition of rheumatoid arthritis the present invention provides a kind of,
It is characterized in that described pharmaceutical composition is with the ethyl acetate component of cocklebur fruit ethanol extract or n-butanol component or its mixing
Object is active constituent.
Preferably, the cocklebur fruit ethanol extract is achene of Siberian cocklebur 50-90% ethanol extracts, it is furthermore preferred that described grey
Ears or side handles of a utensil ethanol extract is achene of Siberian cocklebur 60-80% ethanol extracts；The most preferred cocklebur fruit ethanol extract is the achene of Siberian cocklebur
70% ethanol extract.
Preferably, the prevention and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, with the achene of Siberian cocklebur 70%
The n-butanol group of ethanol extract is divided into active constituent, includes in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur
Compound is one or more as follows：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione；
(2)3-[(2'-hydroxyacetic acid)amino]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-
2-sulfhydryl-cyclohexa-2,5-dienone；
(4)3-[(2'-hydroxyacetic acid)methanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(6)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-[(β-D-
glucopyranosyl)hydroxymethyl]-2-sulfhydryl-cyclohexa-2,5-dienone；
(7)2-β-D-glucopyranosyl-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzo
[1,4]thiazine-3,5-dione；
(8)xanthiazone；
(9)xanthiside；
(10)2-Hydroxy-xanthiazone；
(11)2-Hydroxy-xanthiside。
Preferably, in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur content of xanthiside account for it is described grey
At least the 10% of the n-butanol component of 70% ethanol extract of the ears or side handles of a utensil, it is furthermore preferred that 70% ethanol extract of the achene of Siberian cocklebur
The content of xanthiside accounts for the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur at least in n-butanol component
20%；Most preferably, in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur content of xanthiside account for it is described grey
At least the 30% of the n-butanol component of 70% ethanol extract of the ears or side handles of a utensil.
In another aspect, the present invention provides a kind of prevention and/or the pharmaceutical compositions for the treatment of rheumatism, rheumatoid arthritis
Object, it is characterised in that the active constituent of described pharmaceutical composition is selected from the one or more of following compound：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione；
(2)3-[(2'-hydroxyacetic acid)amino]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-
2-sulfhydryl-cyclohexa-2,5-dienone；
(4)3-[(2'-hydroxyacetic acid)methanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(6)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-[(β-D-
glucopyranosyl)hydroxymethyl]-2-sulfhydryl-cyclohexa-2,5-dienone；
(7)2-β-D-glucopyranosyl-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzo
[1,4]thiazine-3,5-dione；
(8)xanthiazone；
(9)xanthiside；
(10)2-Hydroxy-xanthiazone；
(11)2-Hydroxy-xanthiside。
Preferably, the active constituent of described pharmaceutical composition is selected from the one or more of following compound：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione；
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-
2-sulfhydryl-cyclohexa-2,5-dienone；
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(8)xanthiazone；
(9)xanthiside。
It is furthermore preferred that the active constituent of described pharmaceutical composition is selected from or mixtures thereof xanthiazone, xanthiside
Most preferably, the active constituent of described pharmaceutical composition is xanthiside.
It is of the present invention to prevent and/or treat rheumatism, the dosage form of the pharmaceutical composition of rheumatoid arthritis selected from external application
Topical formulations, gastrointestinal administration composition, parenteral administration composition.
Preferably, local external use's preparation is selected from：Plaster, cataplasm, ointment, cream, tincture, gelling agent, gas
Mist agent, spray；The gastrointestinal administration composition is selected from：Tablet, capsule, granule, powder, solution etc.；The stomach
Parenteral administration composition is selected from：Injection, freeze drying powder injection etc..
The content of active constituent accounts for the 5-80% of pharmaceutical composition total weight in pharmaceutical composition of the present invention, preferably
, the content of active constituent accounts for the 10-60% of pharmaceutical composition total weight in described pharmaceutical composition, it is furthermore preferred that the medicine
The content of active constituent accounts for the 15% of pharmaceutical composition total weight in compositions.
Another aspect, the present invention provides the ethyl acetate component of cocklebur fruit ethanol extract or n-butanol component or its
Mixture is preparing prevention and/or treatment rheumatism, the purposes of the pharmaceutical composition of rheumatoid arthritis.
Preferably, the cocklebur fruit ethanol extract is achene of Siberian cocklebur 50-90% ethanol extracts, it is furthermore preferred that described grey
Ears or side handles of a utensil ethanol extract is achene of Siberian cocklebur 60-80% ethanol extracts；The most preferred cocklebur fruit ethanol extract is the achene of Siberian cocklebur
70% ethanol extract.
Preferably, the present invention provides the n-butanol components of 70% ethanol extract of the achene of Siberian cocklebur prevents and/or controls preparing
Treat rheumatism, the purposes of the pharmaceutical composition of rheumatoid arthritis.
Preferably, one kind or more of following compound is included in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur
Kind：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione；
(2)3-[(2'-hydroxyacetic acid)amino]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-
2-sulfhydryl-cyclohexa-2,5-dienone；
(4)3-[(2'-hydroxyacetic acid)methanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone；
(6)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-[(β-D-
glucopyranosyl)hydroxymethyl]-2-sulfhydryl-cyclohexa-2,5-dienone；
(7)2-β-D-glucopyranosyl-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzo
[1,4]thiazine-3,5-dione；
(8)xanthiazone；
(9)xanthiside；
(10)2-Hydroxy-xanthiazone；
(11)2-Hydroxy-xanthiside。
The content of xanthiside accounts for described in the n-butanol component of 70% ethanol extract of the preferred achene of Siberian cocklebur
At least the 10% of the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur, it is furthermore preferred that 70% ethanol extract of the achene of Siberian cocklebur
N-butanol component in the content of xanthiside account for the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur at least
20%；Most preferably, in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur content of xanthiside account for it is described grey
At least the 30% of the n-butanol component of 70% ethanol extract of the ears or side handles of a utensil.
On the other hand, the present invention also provides a kind of prevention and/or treatment rheumatism, the medicine groups of rheumatoid arthritis
Close the preparation method of object comprising following steps：
(1) it stocks up：The achene of Siberian cocklebur is weighed, is crushed, 10-30 mesh sieve is crossed, obtains Siberian Cocklebur Fruit；
(2) preparation of cocklebur fruit ethanol extract：Siberian Cocklebur Fruit obtained by step (1) is added 5-10 times and measures 50-90%
Ethyl alcohol extracts 1-3h using heat reflow method, and dry cream is obtained after being concentrated after filtered fluid recycling ethyl alcohol after filtering；
(3) it extracts：Step (2) is got dry extract and is extracted successively using petroleum ether, ethyl acetate, n-butanol respectively,
And obtain opposed polarity position, i.e. petroleum ether component (petroleum ether, PE), ethyl acetate component (ethyl
Acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water), select ethyl acetate group
Point, or mixtures thereof n-butanol component, add manufacturing cost invention after pharmaceutically acceptable auxiliary material and prevent and/or treatment wind
Wet, rheumatoid arthritis pharmaceutical composition.
Preferably, the achene of Siberian cocklebur is weighed in step (1), crushed, cross 20 mesh sieve；Step (2) is by the achene of Siberian cocklebur obtained by step (1)
Powder adds 8 times of 70% ethyl alcohol of amount, and 2h is extracted using heat reflow method, is done after being concentrated after filtered fluid recycling ethyl alcohol after filtering
Cream.
Beneficial effects of the present invention：
The present invention, which screens to have obtained in the achene of Siberian cocklebur to have in ethanol extract, prevents and/or treats rheumatism, rheumatoid pass
Scorching active component, wherein the ethyl acetate component, n-butanol component of achene of Siberian cocklebur 50-90% ethanol extracts are saved, is had notable
Rheumatism, the therapeutic effect of rheumatoid arthritis, can obviously inhibit TNF-α induce RAFLS cells proliferation, hence it is evident that subtract
The redness and swelling of joints situation of light RA rat models, reduces RA rat arthritis indexes, it is obviously good that RA rat articular synovial membranes thicken situation
Turn, inflammatory cell infiltration is reduced in synovium of joint, and it is scorching can effectively to reduce TNF-α in RA rat blood serums, PGE2 and IL-1 β etc.
The content of property molecule.
The present invention also further isolates and purifies the n-butanol component of achene of Siberian cocklebur 50-90% ethanol extracts, obtains
To 11 particular compounds, which shows the RAFLS cells of excellent inhibition TNF-α induction
The effect of proliferation, wherein it is especially the most apparent with xanthiside effects, it can be used for the prevention of rheumatism, rheumatoid arthritis
With treatment.
Description of the drawings
Attached drawing 1：Influence of the achene of Siberian cocklebur opposed polarity position to rat toes swelling；
Attached drawing 2：Influence of the achene of Siberian cocklebur opposed polarity position to RA rat arthritis indexes；
Attached drawing 3：Influence of the achene of Siberian cocklebur opposed polarity position to RA rat articular synovial membranes；
Attached drawing 4：Influence of the achene of Siberian cocklebur opposed polarity position to RA rat blood serum TNF-α；
Attached drawing 5：Influence of the achene of Siberian cocklebur opposed polarity position to RA rat blood serum IL-1 β；
Attached drawing 6：Influence of the achene of Siberian cocklebur opposed polarity position to RA rat blood serums PEG2.
Specific implementation mode
Following embodiment is intended to illustrate invention rather than the present invention further limits, and the present invention can be by invention content
The either type is implemented.
Embodiment 1：A kind of tablet prevented and/or treat rheumatism, rheumatoid arthritis
It prepares according to the following steps：
(1) it stocks up：The achene of Siberian cocklebur is weighed, is crushed, 20 mesh sieve is crossed, obtains Siberian Cocklebur Fruit；
(2) preparation of cocklebur fruit ethanol extract：Siberian Cocklebur Fruit obtained by step (1) is added into 8 times of 70% ethyl alcohol of amount, is made
2h is extracted with heat reflow method, dry cream is obtained after being concentrated after filtered fluid recycling ethyl alcohol after filtering；
(3) it extracts：Step (2) is got dry extract and is extracted successively using petroleum ether, ethyl acetate, n-butanol respectively,
And obtain opposed polarity position, i.e. petroleum ether component (petroleum ether, PE), ethyl acetate component (ethyl
Acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water), select n-butanol component,
The invention of tabletting manufacturing cost prevents and/or treats the piece of rheumatism, rheumatoid arthritis after adding pharmaceutically acceptable auxiliary material
Agent.
Embodiment 2：A kind of capsule prevented and/or treat rheumatism, rheumatoid arthritis
It prepares according to the following steps：
(1) it stocks up：The achene of Siberian cocklebur is weighed, is crushed, 20 mesh sieve is crossed, obtains Siberian Cocklebur Fruit；
(2) preparation of cocklebur fruit ethanol extract：Siberian Cocklebur Fruit obtained by step (1) is added into 8 times of 70% ethyl alcohol of amount, is made
2h is extracted with heat reflow method, dry cream is obtained after being concentrated after filtered fluid recycling ethyl alcohol after filtering；
(3) it extracts：Step (2) is got dry extract and is extracted successively using petroleum ether, ethyl acetate, n-butanol respectively,
And obtain opposed polarity position, i.e. petroleum ether component (petroleum ether, PE), ethyl acetate component (ethyl
Acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water), select ethyl acetate component
With n-butanol component, add filling after pharmaceutically acceptable auxiliary material prevent to manufacturing cost invention after gelatine capsule shell and/or
Treat the capsule of rheumatism, rheumatoid arthritis.
Embodiment 3：A kind of granule prevented and/or treat rheumatism, rheumatoid arthritis
It prepares according to the following steps：
(1) it stocks up：The achene of Siberian cocklebur is weighed, is crushed, 20 mesh sieve is crossed, obtains Siberian Cocklebur Fruit；
(2) preparation of cocklebur fruit ethanol extract：Siberian Cocklebur Fruit obtained by step (1) is added into 8 times of 70% ethyl alcohol of amount, is made
2h is extracted with heat reflow method, dry cream is obtained after being concentrated after filtered fluid recycling ethyl alcohol after filtering；
(3) it extracts：Step (2) is got dry extract and is extracted successively using petroleum ether, ethyl acetate, n-butanol respectively,
And obtain opposed polarity position, i.e. petroleum ether component (petroleum ether, PE), ethyl acetate component (ethyl
Acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water), select ethyl acetate group
Point, add of manufacturing cost invention prevention and/or treatment rheumatism, rheumatoid arthritis after pharmaceutically acceptable auxiliary material
Granula.
Effect example 1：The inhibited proliferation for the RAFLS cells that achene of Siberian cocklebur opposed polarity position induces TNF-α
1.1 experimental drug
The petroleum ether component (petroleum ether, PE) of the 1 gained achene of Siberian cocklebur of embodiment, 70% ethanol extract, acetic acid
Components (ethyl acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water),
Compound：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione
(2)3-[(2'-hydroxyacetic acid)amino]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-
2-sulfhydryl-cyclohexa-2,5-dienone
(4)3-[(2'-hydroxyacetic acid)methanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-
hydroxymethyl-2-sulfhydryl-cyclohexa-2,5-dienone
(6)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-[(β-D-
glucopyranosyl)hydroxymethyl]-2-sulfhydryl-cyclohexa-2,5-dienone
(7)2-β-D-glucopyranosyl-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzo
[1,4]thiazine-3,5-dione
(8)xanthiazone
(9)xanthiside
(10)2-Hydroxy-xanthiazone
(11)2-Hydroxy-xanthiside
1.2 experimental method
The RAFLS cell models of TNF-α induction are established, wherein RAFLS cells use tissue mass cell culture, and rheumatoid is closed
The scorching patient's synovial membrane of section shreds under aseptic condition, digests 4h in 37 DEG C using the collagenase type I (Gibco BRL) of 1.0mg/mL,
Cell is collected by centrifugation, 20%FBS DMEM (Gibco BRL) culture solution is added, is placed in 37 DEG C, 5%CO2It is cultivated to thin in incubator
Intracellular growth is to had digestive transfer culture when 85%.
By the petroleum ether component of 70% ethanol extract of the achene of Siberian cocklebur, ethyl acetate component, n-butanol component and water layer component
And 11 compounds are formulated as being added to the RAFLS cells of TNF-α induction after gradient concentration, continue after cultivating 48h, detection is each
The growth inhibition effect for the RAFLS cells that component and compound induce TNF-α calculates what each component induced TNF-α
The half-inhibition concentration (IC50) of RAFLS cells, specific experiment the results are shown in Table 1.
1.3 data processing
Experimental data using 19.0 statistical softwares of SPSS it is for statistical analysis, each group of data withIt indicates.Institute's total
According to making t inspections, P after making homogeneity of variance experiment<0.05 is statistically significant.
1.4 experimental result
The inhibited proliferation for the RAFLS cells that 1 achene of Siberian cocklebur opposed polarity position of table induces TNF-α
1 experimental result of table shows the petroleum ether component of 70% ethanol extract of the achene of Siberian cocklebur, ethyl acetate component, n-butanol group
Point, water layer component and 11 particular compounds show certain inhibition to RAFLS cell Proliferations, wherein positive fourth
The RAFLS cyto-inhibitions that the specific compound of alkoxide component, ethyl acetate component and 11 induces TNF-α are more notable,
And the inhibition conduct for the RAFLS cells that n-butanol component induces TNF-α in extract is the most notable, and 11 specific chemical combination
The inhibition conduct for the RAFLS cells that compound 9 (xanthiside) induces TNF-α in object is the most notable.
Effect example 2：Internal anti-RA activity research of the achene of Siberian cocklebur opposed polarity position to RA rats
2.1 experimental drug
The petroleum ether component (petroleum ether, PE) of the 1 gained achene of Siberian cocklebur of embodiment, 70% ethanol extract, acetic acid
Components (ethyl acetate, EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water),
Using normal saline at 0.25%, 0.5% and 1% basic, normal, high dose suspension, dexamethasone use physiological saline
It is configured to 0.1% solution, it is spare.
II collagen types are dissolved in 0.1% acetum, are configured to the solution of a concentration of 2mg/mL, in 4 DEG C of ice
Case is stood overnight.Experiment mixes II collagen types acetum with the Freund's complete adjuvant of equivalent 2mg/mL before starting,
Under condition of ice bath by its it is homogeneous turn to emulsion, it is spare.
2.2 experimental method
Male SD rat 75, weight 180-220g, is randomly divided into 15 groups, every group 5, specially：Blank group, model
Group, positive drug group, basic, normal, high group of petroleum ether component, basic, normal, high group of ethyl acetate component, basic, normal, high group of n-butanol component
With basic, normal, high group of water layer component.After all rat adaptability raising 1d, blank group rat is in Rat Right metapedes bottom, root of the tail portion
With 3 points of hypodermic injection physiological saline 0.25mL of back portion, model group, positive drug group, petroleum ether group, ethyl acetate group, positive fourth
Alcohol group and water layer group rat in 3 points of Rat Right metapedes bottom, root of the tail portion and back portion be subcutaneously injected comprising II collagen types with
The emulsion 0.25mL of Freund's complete adjuvant, each group rat repeats that physiological saline is subcutaneously injected or includes II collagen types after 7 days
With the emulsion 0.25mL of Freund's complete adjuvant.
After second is subcutaneously injected 1d, blank group rat is normally raised, every rat oral gavage 2mL physiological saline of model group,
Positive drug group gavage dexamethasone solution 2mL, the relative medicine suspension of other each group gavages 2mL, successive administration 21d, with
8d after primary immunization, 14d, it is within the 21st, the 28th day reference index, records the arthritis index of each group rat；Last dose
Each group rat immunity position shape metamorphosis is observed after 1h；Rat eye socket takes blood after last dose 2h, is surveyed using ELISA method
Determine TNF-α in each group rat blood serum, the content of PGE2 and IL-1 β；Rat is put to death using cervical dislocation after eye socket takes blood, is taken
Left back ankle joint, is put into 10% neutral formalin solution and fixes 2d, reuses 8% formic acid decalcification 14d, stone after dehydration
Wax embeds, slice, after HE dyeing, observes synovial tissue's pathological change, specific experiment the result is shown in Figure 1-4.
2.3 data processing
Experimental data using 19.0 statistical softwares of SPSS it is for statistical analysis, each group of data withIt indicates.Institute's total
According to making t inspections, P after making homogeneity of variance experiment<0.05 is statistically significant.
2.4 experimental result
(1) the observation result that achene of Siberian cocklebur opposed polarity position changes RA rat immunities position mode of appearance
There is the red and swollen phenomenon in joint in model group and administration each group rat after immune.Compared with blank group, model group
Rat toes redness and swelling of joints is apparent, includes the redness of small articulations digitorum manus, the redness in entire toe face, while rat is slow in action；With
Model group is compared, and positive drug dexamethasone is substantially reduced rat articular redness phenomenon；The high, medium and low dosage group rat of n-butanol is closed
The red and swollen situation of section gradually mitigates, and is reduced with dosage, acts on and gradually weakening.The high dose component of water layer and ethyl acetate layer also may be used
Partly to mitigate rat articular redness phenomenon, but function and effect are markedly less than n-butanol component, and petroleum ether group is grouped rat in reality
It is red and swollen apparent to test the entire toe position of process rat, and does not show the sign being relieved in whole experiment process, shows
The petroleum ether extraction component of cocklebur fruit ethanol extract alleviates the redness and swelling of joints of rheumatism, rheumatoid arthritis rat
Effect is weaker (as shown in Fig. 1).
(2) observation result of the achene of Siberian cocklebur opposed polarity position to RA rat arthritis index (AI)
After modeling, since the 5th day, each modeling group rat immunity joint started red and swollen phenomenon occur, the about the 8th day each group
There is apparent red and swollen phenomenon in rat immunity joint.Experimental result shows that the high, medium and low dosage group of n-butanol was since the 8th day
AI is integrated and the significant difference (P of model group<0.05), and over time, difference becomes larger, and conspicuousness also increases
Greatly, illustrate that n-butanol component can obviously inhibit the redness and swelling of joints of rat.The AI integrals of positive drug Dexamethasone group rat are apparent low
In model group, there is pole significant difference (P<0.01).Compared with model group, water layer high dose group and ethyl acetate high dose
Group had significant difference (P since 14 days<0.05).And in water layer and ethyl acetate layer, low dose group and petroleum ether
The each dosage group of layer is contrasted with model group, difference that there are no significant (as shown in Figure 2).
(3) pathological observation of the achene of Siberian cocklebur opposed polarity position to RA rat articulars
Compared with model group, water layer component and ethyl acetate component intrasynovial cell arrangement are irregular, there is concave-convex phenomenon, sliding
Film thicken situation have it is a little take a turn for the better, in synovium of joint inflammatory cell infiltration reduce.And petroleum ether component is then to joint tissue, pass
The lesions of synovium contributed is saved almost without effect.N-butanol component and positive drug group intrasynovial cell arrangement slightly restore neatly, clearly may be used
See, synovial membrane thickens situation and obviously takes a turn for the better, and inflammatory cell infiltration is reduced in synovium of joint.Illustrate achene of Siberian cocklebur n-butanol component to class
Rheumatoid arthritis disease change improves significantly (as shown in Figure 3).
(4) influence of the achene of Siberian cocklebur opposed polarity position to inflammatory factor in RA rat blood serums
Experimental result shows, in model group rats serum TNF-α, PGE2 and IL-1 β contents obviously higher than blank group, and
Positive drug dexamethasone significantly reduces TNF-α in model group rats serum, the content of PGE2 and IL-1 β, 70% second of the achene of Siberian cocklebur
Petroleum ether component, ethyl acetate component, n-butanol component and the water layer component of alcohol extracting thing show certain reduction RA rats
TNF-α, the effect of PGE2 and IL-1 β contents in serum, it is shown that certain antiphlogistic effects, wherein n-butanol component effect are most
To be apparent, and with significant difference compared with model group, the n-butanol group to show cocklebur fruit ethanol extract is divided into
The active component (as Figure 4-Figure 6) of the anti-RA of the achene of Siberian cocklebur.
Above example is only enumerating for the present invention, is prevented with Chinese medicine composition of the present invention and/or treatment polycystic ovary is comprehensive
The technical solution of simulator sickness and its relevant disease is each fallen in protection scope of the present invention.
Claims (10)
1. a kind of prevention and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, it is characterised in that the pharmaceutical composition
Object is with or mixtures thereof the ethyl acetate component of cocklebur fruit ethanol extract or n-butanol component for active constituent.
2. prevention according to claim 1 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that the cocklebur fruit ethanol extract is achene of Siberian cocklebur 50-90% ethanol extracts.
3. prevention according to claim 2 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that the cocklebur fruit ethanol extract is achene of Siberian cocklebur 60-80% ethanol extracts.
4. prevention according to claim 3 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that the cocklebur fruit ethanol extract is 70% ethanol extract of the achene of Siberian cocklebur.
5. prevention according to claim 4 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that the n-butanol group with 70% ethanol extract of the achene of Siberian cocklebur is divided into active constituent, 70% ethanol extract of the achene of Siberian cocklebur is just
Comprising one or more in following compound in butanol component：
(1)7-[(β-D-apiofuranosyl-(1→6)-β-D-glucopyranosyl)oxymethy]-8,8-
dimethyl-4,8-dihydrobenzo[1,4]thiazine-3,5-dione；
(2)3-[(2'-hydroxyacetic acid)amino]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(3)3-[(2'-hydroxyacetic acid)acetamide]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(4)3-[(2'-hydroxyacetic acid)methanamine]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(5)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-hydroxymethyl-2-
sulfhydryl-cyclohexa-2,5-dienone；
(6)3-[(2'-hydroxyacetic acid)ethanamine]-1,1-dimethyl-6-[(β-D-
glucopyranosyl)hydroxymethyl]-2-sulfhydryl-cyclohexa-2,5-dienone；
(7)2-β-D-glucopyranosyl-7-hydroxymethyl-8,8-dimethyl-4,8-dihydrobenzo[1,
4]thiazine-3,5-dione；
(8)xanthiazone；
(9)xanthiside；
(10)2-Hydroxy-xanthiazone；
(11)2-Hydroxy-xanthiside。
6. prevention according to claim 5 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that the content of xanthiside in the n-butanol component of 70% ethanol extract of the achene of Siberian cocklebur accounts for 70% second of the achene of Siberian cocklebur
At least the 10% of the n-butanol component of alcohol extracting thing.
7. preventing and/or treating the pharmaceutical composition of rheumatism, rheumatoid arthritis according to claim 1-6 any one of them
Object, it is characterised in that the dosage form of described pharmaceutical composition is selected from local external use's preparation, gastrointestinal administration composition, parenteral gives
Drug composition.
8. prevention according to claim 7 and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis, feature
It is that local external use's preparation is selected from：Plaster, cataplasm, ointment, cream, tincture, gelling agent, aerosol, spray；
The gastrointestinal administration composition is selected from：Tablet, capsule, granule, powder, solution；The parenteral administration combination
Object is selected from：Injection, freeze drying powder injection.
9. or mixtures thereof ethyl acetate component or n-butanol component of cocklebur fruit ethanol extract are prevented and/or are treated preparing
The purposes of rheumatism, the pharmaceutical composition of rheumatoid arthritis.
10. claim 1-9 any one of them is prevented and/or treatment rheumatism, the pharmaceutical composition of rheumatoid arthritis
Preparation method, it is characterised in that include the following steps：
(1) it stocks up：The achene of Siberian cocklebur is weighed, is crushed, 10-30 mesh sieve is crossed, obtains Siberian Cocklebur Fruit；
(2) preparation of cocklebur fruit ethanol extract：Siberian Cocklebur Fruit obtained by step (1) is added 5-10 times and measures 50-90% ethyl alcohol,
1-3h is extracted using heat reflow method, dry cream is obtained after being concentrated after filtered fluid recycling ethyl alcohol after filtering；
(3) it extracts：Step (2) is got dry extract and is extracted successively using petroleum ether, ethyl acetate, n-butanol respectively, and is obtained
Opposed polarity position, i.e., petroleum ether component (petroleum ether, PE), ethyl acetate component (ethyl acetate,
EA), n-butanol component (n-Butyl alcohol, BA) and water layer component (water) select ethyl acetate component, n-butanol group
Or mixtures thereof point, it adds and is prepared into prevention after pharmaceutically acceptable auxiliary material and/or treats rheumatism, rheumatoid arthritis
Pharmaceutical composition.
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| CN110038023B (en) * | 2019-04-19 | 2021-05-07 | 温州医科大学 | Anti-allergic pharmaceutical composition for replacing cocklebur fruit |
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