CN104095981A - New drug application of scutellaria baicalensis georgi and schisandra chinensis composition - Google Patents
New drug application of scutellaria baicalensis georgi and schisandra chinensis composition Download PDFInfo
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Abstract
The invention relates to the new drug application of a scutellaria baicalensis georgi and schisandra chinensis composition. The ingredients of scutellaria baicalensis georgi and schisandra chinensis are scutellaria baicalensis georgi flavonoid and schisandra chinensis lignans respectively which are used to extract crude drugs of the scutellaria baicalensis georgi and the schisandra chinensis as effective medicinal ingredients at the weight ratio of 1/(0.2-5), and used for preparing drugs used for treating pulmonary fibrosis. A testing result shows that the composition has an obvious synergistic interaction effect on preventing pulmonary fibrosis.
Description
Technical field
The present invention relates to a kind of new pharmaceutical applications of the compositions to Radix Scutellariae and Chemical composition of Wuweizi, is specifically to prevent and treat the new purposes aspect pulmonary fibrosis medicine in preparation.
Background technology
Lungs stroma is made up of collagen protein, elastoidin and proteoglycans, collagen protein is main cell epimatrix (the extracellular matrix of lung tissue, ECM) albumen, collagen protein in lungs and other types ECM composition form tridimensional network, become the main skeleton of lung tissue structure, these protein ingredients keep the integrity of lung tissue structure.And to maintaining lung epithelial and endothelial cell differentiation state plays a very important role.In the time that lung fibroblast is subject to chemical (as bleomycin, abnormal source etc.) or physical property (as dust, lonizing radiation etc.) injury, can secretes collagen protein and carry out the repairing of interstitial tissue of lung, and then cause lungs fibrosis.Statistics shows, only 2 ~ 5 years intermediate value time-to-live of idiopathic pulmonary fibrosis after disease is examined out, 5 annual survival rates only have 20%.The process of pulmonary fibrosis is roughly divided into 3 stages: the first stage, lungs sustain damage or other destructive stimuluses, and fibroblastic extracellular matrix produces cell and is activated.Second stage, the extracellular matrix of activation produces the change of cell recurring structure and phenotype, produces a large amount of extracellular matrixs (ECM).The former activated protein kinase of mitogen (MAPK) and nuclear factor (NF-κ B) path in born of the same parents is activated simultaneously, promotes to produce a large amount of cytokines.By paracrine, the inflammatory cell of mediation including macrophage moves to irriate position.T cell is activated, and the short fibrotic growth factor of secretion, as interleukin (IL) and tumor necrosis factor α (TNF-α) etc.Macrophage promotes fibroblast proliferation and differentiation, simultaneously the cytokine profiles of secretion including transforming growth factor β (TGF-β) and IL-1.Phase III, impairment factor sustainable existence, causes damage repeatedly.Fibroblast continues to be activated, and produces more ECM.Cytokine is continual causes tissue inflammation and collagen overexpression, and ECM constantly deposits, and pulmonary fibrosis forms gradually, and the final special position pulmonary function of sending out is lost.
Current research shows, many cytokines have participated in formation and the degraded of pulmonary fibrosis.Wherein TNF-α, platelet derived growth factor (PDGF), TGF-β, IL-1, IL-2, IL-4, IL-6, IL-10 and IL-18 are the most significant fibrosis cytokines at present.Research is found, IL-18 and IL-18R all have certain expression at normal person's bronchovesicular epithelial cell, pulmonary alveolar macrophage and little vascular endothelial cell, and IL-18 mostly is high expressed in IPF patient's lung cells, especially form region in fibrosis at IPF Patients with Lung Interstitial cell and be high expressed, and Fibrotic Zonal expression is little, and tissue fibering integration is obviously relevant to fibrosis formation region IL-18 RA expression.IL-18 not only participates in the inflammatory process of IPF, also participates in process of reconstruction after lung injury as interstitial pulmonary fibrosis, vessel wall thickening and epithelial cell regeneration.
Pulmonary fibrosis is the terminal stage of many pulmonary disease development, and serious harm patient's health and postoperative rehabilitation, still lack effective Therapeutic Method.Main therapeutic strategy has at present: antiinflammatory, fibrosis and antioxidation etc.
Glucocorticoid is the leading medicine of traditional treatment pulmonary fibrosis, and it can inflammation-inhibiting reaction, alleviates alveolitis, thereby delays the process of pulmonary fibrosis.But at present research finds that it is only effective to 20% IPF patient, and there is obvious side effect in long-term taking glucocorticoid, tends to merge antibacterial or the fungal infection of pulmonary.The immunoreation that immunosuppressant can alleviate body as cyclophosphamide, azathioprine, ciclosporin A etc.But not only there is potential serious side effects in use often, and substantially invalid to IPF treatment.It is the recommendation therapeutic scheme of U.S.'s thoracic cavity association/European pneumatology meeting (ATS/ERS) to IPF patient that glucocorticoid and immunosuppressant are combined use, has certain effect for early stage pulmonary fibrosis.There is no so far perspective, random, double blinding, controlled trial is fully proved.Need clinical multicenter study.
Colchicine is from liliaceous plant Colchicum autumnale, to separate a kind of breast cancer of obtaining, can suppress tubulin set and suppresses collagen and produce emiocytosis precollagen.External and Research of Animal Model for Study shows, it can suppress, and collagen forms and ECM gathers.To hormone therapy nonresponder, can be alone or share with immunosuppressant/cell toxicity medicament.It is synthetic that INF-γ INF can suppress collagen, accelerates the degraded of ECM simultaneously, thereby play the effect of pulmonary fibrosis resistant.Antioxidation Treatment glutathion (GSH) can be in conjunction with unnecessary oxygen-derived free radicals.Cysteine prodrug NAC is the precursor substance of GSH, can effectively improve GSH level in lung tissue, improves patient's lung functions.In Japan, one only shows by the multicenter prediction random contrast clinical trial that sucks NAC single therapy patient IPF, for early stage patient IPF, only treats without immunosuppressant or other fibrosis medicines the continuous decline that can stablize patient IPF FVC with NAC.But to the IPF patient in other stages, also need further clinical research.
Along with the development of Protocols in Molecular Biology and perfect, cytokine profiles medium or its inhibitor have been had to more deep understanding to the mechanism of action of pulmonary fibrosis, cytokine and inhibitor thereof become the new direction of pulmonary fibrosis treatment.
Monoclonal antibody TGF-β is the important target spot of pulmonary fibrosis treatment.In the Model of Bleomycin-induced Pulmonary Fibrosis of bleomycin induction, give TGF-β monoclonal antibody TB21, after two weeks, put to death, lung tissue is carried out biochemical analysis after processing.The interstitial lung inflammatory cell of finding monoclonal antibody group obviously reduces, and pulmonary fibrosis degree alleviates compared with matched group.Show that TGF-β monoclonal antibody has certain inhibitory action to pulmonary fibrosis.In addition, monoclonal antibody CAT-192, CAT-152, the in vitro study of GC1008 shows, these antibody capables alleviate Pulmonary Fibrosis in Rats degree effectively.Enter at present the clinical research of I phase.
People also wish that the synthetic and function by suppressing TNF-α alleviates or regulates pulmonary fibrosis process.Lung fibrosis in rats gives the treatment of TNF-alpha-2 antagonists, finds that the TNF-of rat pulmonary alpha expression amount obviously declines, and pulmonary fibrosis degree alleviates.At present, TNF-alpha inhibitor has infliximab (infliximab), Embrel (etanercept) and adalimumab (adalimumab).Wherein, the II clinical trial phase of Embrel completes, and result shows, for lung function index and be not improved, but can delay to enter pulmonary fibrosis acute stage.
The combination of PDGF inhibitor blocking-up PDGF and tyrosine kinase receptor, makes it cannot bring into play short pulmonary fibrosis effect.Imatinib mesylate is the protein tyrosine kinase inhibitor playing an important role in tumor cell and Interstitial cell (as lung fibroblast) hypertrophy, and it can suppress the activation of PDGF precursor.Its II clinical trial phase well afoot.
Pirfenidone (pirfenidone) pirfenidone (5-methyl isophthalic acid-phenyl-1 h-pyridin-2-ketone, PFD), developed by American I nterMune company, not only suppress the generation of a large amount of fibrogenic factors including PDGF and TGF-β, also suppress the fibrosis albumen such as HSP47.Pirfenidone has inhibitory action to the multiple organ fibrosis including lungs, liver, heart and kidney.At present, in Japan, India and European Union's listing.Be used for the treatment of mild to moderate idiopathic pulmonary fibrosis.
Although pirfenidone is the active drug of existing treatment IPF, as a kind of oral medicine, there is more side effect clinical, as gastrointestinal upset (as felt sick, vomiting, dyspepsia, diarrhoea), weak and heliosensitivity erythra etc.Pharmacokinetic studies result shows, the plasma half-life of oral pirfenidone is very short, can and get rid of to external by promptly metabolism in vivo.In order to maintain in the body of pirfenidone effectively plasma concentration, high dose has just become essential treatment scheme with altofrequency medication.Present stage, people can only be by reducing dosage or stopping the side effect that treatment alleviates pirfenidone.This just requires us further improve and optimize pirfenidone, effectively treats disease and alleviates its side effect.
The traditional Chinese medical science, according to the clinical manifestation of pulmonary fibrosis, is attributed to " pulmonary fistula ".Chinese medicine monomer, compound preparation and the Effective Component of Chinese Medicine of many effects with activating blood circulation to dissipate blood stasis, invigorating the lung and benefiting vital QI is for the experimentation of pulmonary fibrosis animal model.Current much Chinese medicine all has the effect of certain pulmonary fibrosis resistant, as tectorigenin (tectorigenin), Quercetin (quercetin), baicalin baicalin), breviscapine (breviscapine), puerarin (puerarin), curcumin (curcumin), epigallocatechin gallate (EGCG), ferulic acid (ferulic acid), resveratrol (resveratrol), (-)-Neferine (neferine), ligustrazine (tetramethylpyrazine), glycyrrhizin, emodin (emodin), diallyl monosulfide and schisandrin B.But the clinical efficacy of these medicines need further checking.Other have the Chinese medicine compound of certain effect to comprise that the fine health of anti-fine soup, compound recipe Carapax Trionycis, tonifying YIN blood activating decoction, lung, the logical fluid-retention in the lung of QI invigorating, Zaocys are loose etc. to pulmonary fibrosis.These medicines have the advantages such as toxicity is low, few side effects, although treatment mechanism it be unclear that, demonstrate the gratifying prospect of Chinese medicine pulmonary fibrosis.
Summary of the invention
Can be found out the research of pulmonary fibrosis resistant at present by above-mentioned, there is very large defect in the single control strategy for a certain cytokine, and for preventing certain effect, all effect reliability being used for the treatment of need further to be confirmed.Also can find out on the other hand, mainly to launch according to the formation mechanism of pulmonary fibrosis for the control strategy of pulmonary fibrosis at present, owing to will curing pulmonary fibrosis, except stoping the formation of fibrosis tissue, the fibrous tissue that also should degrade and form, but also do not have system to illustrate to the mechanism of pulmonary fibrosis tissue degradation at present.There are some researches show, part inflammatory factor will be conducive to the degraded of fibrosis tissue, scar tissue as TNF α, IL-1 maintain certain level at fibrosis tissue.
For above-mentioned situation, the invention provides and a kind of the compositions of Radix Scutellariae and Chemical composition of Wuweizi is prevented and treated to the new purposes aspect pulmonary fibrosis medicine in preparation.
The compositions of Radix Scutellariae of the present invention and Chemical composition of Wuweizi is that the applicant reported as the pharmaceutical composition of control hepatic injury in Granted publication CN101933973B.Wherein said Radix Scutellariae and Chemical composition of Wuweizi, respectively skullcapflavone and Fructus Schisandrae Chinensis lignanoid, extract by the ratio of the weight portion of raw material crude drug Radix Scutellariae and Fructus Schisandrae Chinensis as 1/ (0.2 ~ 5) as active drug composition taking it respectively in skullcapflavone and Fructus Schisandrae Chinensis lignanoid, assist adding ingredient jointly to form with acceptable in medicine.On this basis, skullcapflavone and Fructus Schisandrae Chinensis lignanoid are 1/ (0.5 ~ 2) in its extraction by the better ratio of the weight portion of raw material crude drug Radix Scutellariae and Fructus Schisandrae Chinensis respectively, preferred ratio 1/1.
Radix Scutellariae is the dry root of labiate Radix Scutellariae Scutellaria baicalensis Georgi, for conventional Chinese medicine, there is heat clearing and damp drying, eliminating fire and detoxication, hemostasis, the effect such as antiabortive, be widely used in hygropyrexia, heat-damp in summer, vomiting and nausea uncomfortable in chest, damp and hot feeling of fullness, jaundice dysentery, cough due to lung-heat, high hot excessive thirst, heat in blood are told nosebleed, the disease such as carbuncle sore tumefacting virus, frequent fetal movement, obtains good result.Radix Scutellariae is mainly containing flavones ingredient, as baicalin, baicalin, wogonoside, wogonin, neobaicalein etc., modern pharmacological research shows that Radix Scutellariae and extract thereof have antibacterial, antiallergic, bacillus, Bacillus proteus, staphylococcus aureus, Hemolytic streptococcus, Diplococcus pneumoniae, meningococcus, vibrio cholera etc. are had to inhibitory action in various degree, baicalin, baicalin shrink and whole animal allergic asthma guinea-pig isolated trachea anaphylaxis, all have mitigation.Radix Scutellariae antipyretic, blood pressure lowering, calmness in addition, protect the liver, the effect such as function of gallbladder promoting, inhibition intestinal tube wriggling, blood fat reducing, antioxidation, adjusting cAMP level, antitumor.Radix Scutellariae extract records in " Chinese Pharmacopoeia " 2010, must not be less than 85.0% containing baicalin.Experimentation shows that Radix Scutellariae total flavones and effective monomer baicalin thereof have good preventive effect to pulmonary fibrosis, thought thing, baicalin has good pulmonary fibrosis resistant effect in the time of low dose, significantly increases the degree of pulmonary fibrosis in the time of larger dose.Does this just give the clinical very scabrous difficult problem that proposed: under which kind of dosage, can effectively prevent and treat pulmonary fibrosis, instead of increase pulmonary fibrosis?
Fructus Schisandrae Chinensis can have dividing of Radix Schisandrae Bicoloris and Fructus Schisandrae Sphenantherae.Practising the Radix Schisandrae Bicoloris claiming is the dry mature fruit of magnoliaceae schisandra Schisandra chinesis (Turcz.) Baill; Fructus Schisandrae Sphenantherae is the dry mature fruit of Magnoliacea plant schisandra chinensis Schisandra sphenanthera Rehd. et Wils..The two all records in current edition " Chinese Pharmacopoeia ", have identical function with cure mainly, restrain astringent or styptic treatment for spontaneous sweating, supplementing QI for promoting the production of body fluid, kidney calming, can be used for chronic cough dyspnea due to deficiency, spontaneous perspiration, night sweat, seminal emission, spermatorrhea, incessant chronic diarrhea, Tianjin wound thirsty, quench one's thirst, cardiopalmus, insomnia, dreaminess etc.Research at present shows; two kinds of Fructus Schisandrae Chinensis contain same or analogous chemical composition; as lignanoid, volatile oil, organic acid etc.; energy function of gallbladder promoting, reduces serum transaminase, and hepatocyte is had to protective effect; can increase cellular immune function; make brain, liver, the active obviously enhancing of spleen SOD, therefore there is the immunity of raising, antioxidation, anti-aging effects.Therefore, generally no longer distinguish in the present invention and be referred to as Fructus Schisandrae Chinensis.There are some researches show that schisandrin B has significant inhibitory action to pulmonary fibrosis.
Result of the test shows, in the above-mentioned pharmaceutical composition of the present invention, said active drug composition skullcapflavone replaces with the Radix Scutellariae extract that contains said amount skullcapflavone, and/or said active drug composition Fructus Schisandrae Chinensis lignanoid replaces with the Fructus Schisandrae Chinensis extrat that contains said amount Fructus Schisandrae Chinensis lignanoid, can not produce significant adverse effect to effect of said pharmaceutical composition and effect.Wherein, said Radix Scutellariae extract can be conventional water extract, and said Fructus Schisandrae Chinensis extrat can be the ethanol extraction that has been reported and use.
As above-mentioned, at present research shows that two kinds of Fructus Schisandrae Chinensis contain same or analogous chemical composition and identical function and cure mainly, therefore said Fructus Schisandrae Chinensis extrat in the present invention, can derive from Radix Schisandrae Bicoloris and/or Fructus Schisandrae Sphenantherae and without differentiation, at least in the pharmaceutical composition that can realize the object of the invention its without special differentiation.
Said two class active drug compositions, or said its corresponding extract, all can be by the method preparation of at present existing bibliographical information.For example, Fructus Schisandrae Chinensis extrat can be by the mode in " Traditional Chinese medicine historical preparation " the 11st, decocts with water 1 hour with crude drug Fructus Schisandrae Chinensis, filters, and discards filtrate, medicinal residues are dried, pulverize, and with 70% alcohol reflux 2 times, each 1.5 hours, filter, merging filtrate, concentrated, to obtain final product; Or according to the mode in " Traditional Chinese medicine historical preparation " the 19th, adopt Fructus Schisandrae Chinensis dry, after pulverizing, with 75% alcohol reflux three times, add for the first time 4 times of amount 75% ethanol, reflux 3 hours, add for the second time 3 times of amount 75% ethanol, reflux 2 hours, add for the third time 3 times of amount 75% ethanol, reflux 1 hour, merge extractive liquid,, leaves standstill 48 hours, draws supernatant, decompression recycling ethanol, then add 90% alcohol reflux 2 hours, filter, collect filtrate, decompression recycling ethanol, to obtain final product.
Radix Scutellariae extract can be with reference to [method for making] under the 391st page " Radix Scutellariae extract " item of " Chinese Pharmacopoeia " version in 2010, decocted with water by Radix Scutellariae, collecting decoction, be concentrated into appropriate, with salt acid for adjusting pH value to 1.0～2.0, 80 DEG C of insulations, leave standstill, filter, precipitate adds suitable quantity of water and stirs evenly, regulate pH value to 7.0 with 40% sodium hydroxide, add equivalent ethanol, be stirred to dissolve, filter, filtrate is used salt acid for adjusting pH value to 1.0～2.0, 60 DEG C of insulations, leave standstill, filter, precipitation is washed till pH value to 7.0 with the ethanol of suitable quantity of water and variable concentrations successively, wave most ethanol, drying under reduced pressure, obtain.
The pharmaceutical composition that the present invention is above-mentioned, according to using needs, can be by current usual manner, by the corresponding auxiliary adding ingredient of acceptable in said drug effect ingredient and medicine, as disintegrating agent, excipient, lubricant, binding agent, filler etc., be jointly prepared into operational oral type pharmaceutical preparation including the common formulations such as tablet, drop pill, capsule, micropill.
Inventor shows that through large quantity research and experiment the Radix Scutellariae that the present invention is above-mentioned and the compositions of Chemical composition of Wuweizi not only can significantly suppress TGF β
1in the expression of fibrosis tissue, also can significantly suppress the expression of IL-18 at lungs tissue, make TNF α maintain normal level, and showing significant synergistic function in prevention with treating aspect pulmonary fibrosis, prevent and treat aspect pulmonary fibrosis medicine and have a good application prospect and be worth in preparation.
Detailed description of the invention is by the following examples described in further detail foregoing of the present invention again.But this should be interpreted as to the scope of the above-mentioned theme of the present invention only limits to following example.Without departing from the idea case in the present invention described above, various replacements or the change made according to ordinary skill knowledge and customary means, all should comprise within the scope of the invention.
Detailed description of the invention
embodiment 1
Skullcapflavone: get Radix Scutellariae 10kg, decoct with water, collecting decoction, be concentrated in right amount, with salt acid for adjusting pH value to 1.0～2.0,80 DEG C of insulations, leave standstill, filter, precipitate adds suitable quantity of water and stirs evenly, and regulates pH value to 7.0 with 40% sodium hydroxide, add equivalent ethanol, be stirred to dissolve, filter, filtrate regulates batch pH value to 1.0～2.0 with hydrochloric acid, 60 DEG C of insulations, leave standstill, filter, precipitation is washed till pH value to 7.0 with the ethanol of suitable quantity of water and variable concentrations successively, wave most ethanol, drying under reduced pressure, obtains skullcapflavone, wherein content of baicalin >=90.0%.
Fructus Schisandrae Chinensis lignanoid: get Fructus Schisandrae Sphenantherae or Radix Schisandrae Bicoloris 10kg, decoct with water 1 hour, filter, discard filtrate, medicinal residues are dried, pulverize, with 70% alcohol reflux 2 times, each 1.5 hours, filter, merging filtrate, reclaim ethanol extremely without alcohol taste, add water appropriate, fully stir, hold over night, incline and supernatant, lower floor's oily precipitation separates through silica gel column chromatography, first use the remove impurity of petroleum ether-ethyl acetate (10:1) eluting, use again petroleum ether-ethyl acetate (10:4) eluting, thin layer chromatography checks, merge containing lignanoid's part, remove solvent, Ji get Fructus Schisandrae Chinensis lignanoid, total lignans content >=95.0%.
Get above-mentioned skullcapflavone (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis lignanoid (being equivalent to 1kg Fructus Schisandrae Chinensis), add in the Polyethylene Glycol dissolving, stir evenly, make drop pill, obtain described drop pills oral medicine.
embodiment 2
Radix Scutellariae extract: get Radix Scutellariae 10kg, decoct with water, collecting decoction, is concentrated in right amount, with salt acid for adjusting pH value to 1.0～2.0,80 DEG C of insulations, leaves standstill, and filters, and drying precipitate, obtains Radix Scutellariae extract, wherein content of baicalin >=50.0%.
Fructus Schisandrae Chinensis extrat: get Fructus Schisandrae Sphenantherae or Radix Schisandrae Bicoloris 10kg, decoct with water 1 hour, filter, discard filtrate, medicinal residues are dried, pulverize, with 70% alcohol reflux 2 times, each 1.5 hours, filtration, merging filtrate, concentrated, obtain Fructus Schisandrae Chinensis extrat, total lignans content >=10.0%.
Get above-mentioned Radix Scutellariae extract (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis extrat (being equivalent to 1kg Fructus Schisandrae Chinensis), mix, add starch appropriate, mix homogeneously, granulates, and incapsulates, and makes 1000, obtains described capsule oral drugs.
embodiment 3
Get above-mentioned skullcapflavone (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis extrat (being equivalent to 2kg Fructus Schisandrae Chinensis), mix, add starch and Icing Sugar appropriate, mix homogeneously, granulates, and tabletting, makes 2000, obtains described tablet oral drugs.
embodiment 3
By above-mentioned Radix Scutellariae extract (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis lignanoid (being equivalent to 0.5kg Fructus Schisandrae Chinensis), mix, add right amount of auxiliary materials, mix homogeneously, extruding pill, obtains described pill oral drugs.
embodiment 4
Get above-mentioned Radix Scutellariae extract (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis extrat (being equivalent to 0.2kg Fructus Schisandrae Chinensis), mix homogeneously, granulates, and tabletting, makes 1000, obtains described tablet oral drugs.
embodiment 5
Get above-mentioned skullcapflavone (being equivalent to 1kg Radix Scutellariae) and Fructus Schisandrae Chinensis lignanoid (being equivalent to 5kg Fructus Schisandrae Chinensis), add in the Polyethylene Glycol dissolving, stir evenly, make drop pill, obtain described drop pills oral medicine.
Carry out following experiment using Radix Scutellariae extract and Fructus Schisandrae Chinensis extrat as the pharmaceutical composition of the different proportion composition form of effective medicinal ingredient as trial drug.
1
material
1.1
experimental agents
Radix Scutellariae extract (hereinafter to be referred as Radix Scutellariae): this test dose is pressed crude drug in whole g/kg and calculated.
Fructus Schisandrae Chinensis extrat (hereinafter to be referred as Fructus Schisandrae Chinensis): this test dose is pressed crude drug in whole g/kg and calculated.
Hydroxyproline (HyP) detection kit (alkali hydrolysis method): Nanjing is built up Bioengineering Research Institute and produced;
TGF-β 1, IL-18, TNF-α ELISA detection kit, produce purchased from R & D System.
N,N'-dimethyl-.gamma..gamma.'-dipyridylium liquid: mass concentration is 20%, is purchased from pesticide company limited of Rising of Weifang City of Shandong Province.
1.2
laboratory animal
mice: Kunming kind, SPF level, is provided by Sichuan Provincial Academy of Traditional Chinese Medicine Experimental Animal Center, producing the quality certification number is SCXK(river) 2013-19.
2
method and result
2.1
n,N'-dimethyl-.gamma..gamma.'-dipyridylium is caused to therapeutical effect and the mechanism research thereof of mouse pulmonary fibrosis model
52 of male mices getting body weight and be 20 ~ 22g, are divided into matched group (10) and model group (42) at random, and once, matched group gives isopyknic normal saline to model group gavage N,N'-dimethyl-.gamma..gamma.'-dipyridylium 80mg/kg.After moulding 21 days, put to death two animals and do pathology detection and confirm, after its pulmonary fibrosis, animal pattern to be pressed to table 1 random packet, gastric infusion, every day 1 time, continuous 1 month.After last administration 24 hours, put to death mice, get lungs alkali hydrolysis method and measure its hydroxyproline content (Hyp), measure the cytokine content such as its tumor necrosis factor (TNF α), transforming growth factor (TGF β 1) and interleukin (IL-18) by euzymelinked immunosorbent assay (ELISA) (ELISA).The results are shown in Table 1.
As seen from Table 1, mice is giving N,N'-dimethyl-.gamma..gamma.'-dipyridylium latter two month, and its lungs hydroxyproline significantly increases, and its lungs TGF β 1 and IL-18 protein expression significantly raise, and its TNF alpha expression significantly reduces, and relatively has significant difference with matched group.Combine and use the treatment of Radix Scutellariae and Fructus Schisandrae Chinensis within one month, can significantly reduce pulmonary fibrosis mice lungs to organize hydroxyproline content, significantly reduce its lungs TGF β 1 and IL-18 protein expression, but its lungs TNF alpha expression that significantly raises, has statistical significance with model group comparing difference; And use separately baicalin, schisandrin B, Fructus Schisandrae Chinensis and Radix Scutellariae all to organize hydroxyproline content, lungs TGF β 1, IL-18 and TNF alpha expression all to have no significant effect to pulmonary fibrosis mice lungs, with relatively no difference of science of statistics of model group.
2.2
bleomycin is caused to the preventive effect research of mouse pulmonary fibrosis model
Get body weight and be 42 of the male mices of 20 ~ 22g, be divided at random matched group (10) and model group (32), model group, with after urethane anesthesia, is lain on the back and is fixed in laboratory table, after cervical region unhairing, routine disinfection, cuts skin, successively exposes trachea, 1 mL syringe is entered to trachea through two tracheal cartilages czermak spaces towards heart terminal spine, pumpback non-resistance, Injecting Bleomycin after Retaining 6 mg/kg, matched group injects the normal saline of equivalent.After operation, rapidly by upright animal, rotation, medicinal liquid is evenly distributed in lung, conventional raising after animal is clear-headed.After operation, model group animal was pressed to table 2 random packet, gastric infusion in the 3rd, every day 1 time, continuous 1 month.After last administration 24 hours, put to death mice, get lungs alkali hydrolysis method and measure its hydroxyproline content (Hyp).The results are shown in Table 2.
As seen from Table 2, mice is giving after bleomycin 1 month, and its lungs hydroxyproline significantly increases, and relatively has significant difference with matched group.In the time of modeling, give all embodiment samples of the present invention simultaneously and prevent and treat, all can significantly reduce each mice lungs hydroxyproline content, relatively there is statistical significance with model group.Preventatively give baicalin and schisandrin B also can reduce bleomycin mice lungs hydroxyproline content, similar to the action intensity of positive drug prednisone, there is statistical significance with model group comparing difference, but it is evident in efficacy lower than various embodiments of the present invention sample.
Above-mentioned result of study prompting, although baicalin and schisandrin B have certain preventive effect to pulmonary fibrosis, but because in treatment, it has no significant effect cytokine-expressings such as lungs TGF β 1, IL-18 and TNF α, both weakened its impact that fibrosis tissue is generated, again to the degraded of pulmonary fibrosis tissue without obvious facilitation, cause its therapeutical effect faint.On the contrary, because Radix Scutellariae and Fructus Schisandrae Chinensis can either promote the expression of TNF α to make the enzyme of degradation of fibersization tissue remain on greater activity after share, thereby promote the degraded of fibrosis tissue; Simultaneously, because these two kinds of drug regimens also can significantly suppress to have the cytokine TGF β 1 of significantly short fibrosis effect and IL-18 in the expression of lungs tissue, make the generation minimizing of its fibrosis tissue, the summation of two kinds of effects will be conducive to the reverse of pulmonary fibrosis.
Claims (7)
1. the new pharmaceutical use of Radix Scutellariae and Chemical composition of Wuweizi compositions, it is characterized in that described Radix Scutellariae and Chemical composition of Wuweizi are respectively skullcapflavone and Fructus Schisandrae Chinensis lignanoid, extract by the ratio of the weight portion of raw material crude drug Radix Scutellariae and Fructus Schisandrae Chinensis as 1/ (0.2 ~ 5) as active drug composition taking it respectively in skullcapflavone and Fructus Schisandrae Chinensis lignanoid, prevent and treat the purposes aspect pulmonary fibrosis medicine in preparation.
2. purposes as claimed in claim 1, is characterized in that described active drug composition skullcapflavone and Fructus Schisandrae Chinensis lignanoid extract by the ratio of the weight portion of raw material crude drug Radix Scutellariae and Fructus Schisandrae Chinensis as 1/ (0.5 ~ 2) taking it respectively.
3. purposes as claimed in claim 1, is characterized in that described active drug composition skullcapflavone and Fructus Schisandrae Chinensis lignanoid extract by the ratio of the weight portion of raw material crude drug Radix Scutellariae and Fructus Schisandrae Chinensis as 1/1 taking it respectively.
4. the purposes as described in one of claims 1 to 3, it is characterized in that described active drug composition skullcapflavone allows to replace with the Radix Scutellariae extract that contains said amount skullcapflavone, this Radix Scutellariae extract, for the method for making by under the 391st page of Radix Scutellariae extract item of " Chinese Pharmacopoeia " version in 2010, is prepared by Radix Scutellariae.
5. the purposes as described in one of claims 1 to 3, it is characterized in that described active drug composition Fructus Schisandrae Chinensis lignanoid allows to replace with the Fructus Schisandrae Chinensis extrat that contains said amount Fructus Schisandrae Chinensis lignanoid, the mode of this Fructus Schisandrae Chinensis extrat for Fructus Schisandrae Chinensis decocting being boiled to rear medicinal residues ethanol extraction in " Traditional Chinese medicine historical preparation " the 11st, or in the 19th, the mode of Fructus Schisandrae Chinensis alcohol reflux is prepared.
6. the purposes as described in one of claims 1 to 3, is characterized in that described Fructus Schisandrae Chinensis is at least one in Radix Schisandrae Bicoloris or Fructus Schisandrae Sphenantherae.
7. the purposes as described in one of claims 1 to 3, is characterized in that described medicine is oral type pharmaceutical preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410365943.4A CN104095981A (en) | 2014-07-29 | 2014-07-29 | New drug application of scutellaria baicalensis georgi and schisandra chinensis composition |
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| CN101933973A (en) * | 2009-07-02 | 2011-01-05 | 四川省中医药科学院 | Medicament composition for preventing and treating liver damage |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101933973A (en) * | 2009-07-02 | 2011-01-05 | 四川省中医药科学院 | Medicament composition for preventing and treating liver damage |
Non-Patent Citations (1)
| Title |
|---|
| 廖应养等: "肝宝胶囊抗免疫性肝纤维化及其机制的研究", 《中药药理与临床》, vol. 30, no. 1, 15 February 2014 (2014-02-15) * |
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