CN101804046A - Application of myricetin for Janus kinase inhibitor medicines - Google Patents
Application of myricetin for Janus kinase inhibitor medicines Download PDFInfo
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- CN101804046A CN101804046A CN 201010167105 CN201010167105A CN101804046A CN 101804046 A CN101804046 A CN 101804046A CN 201010167105 CN201010167105 CN 201010167105 CN 201010167105 A CN201010167105 A CN 201010167105A CN 101804046 A CN101804046 A CN 101804046A
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- ampelopsin
- chemical compound
- medicine
- tyrosine kinase
- treatment
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Abstract
The invention relates to an application of myricetin for Janus kinase inhibitor medicines, more particularly an application of myricetin in the field of biomedicine, the invention further provides different forms of myricetin, and physical and chemical tests related thereto are conducted.
Description
Technical field
The present invention relates to the application that ampelopsin is used for the medicine of tyrosine kinase (JAK enzyme) inhibitor, is exactly the application of ampelopsin at biomedicine field specifically.
Background technology
Ampelopsin (Myricetin) is a flavonols native compound shown in (I), yellow acicular crystal, fusing point is 324.0～325.5 ℃, is dissolved in methanol, ethanol, acetone or ethyl acetate, is slightly soluble in water, be insoluble in chloroform, petroleum ether, place the easy oxidation of air to turn green.
At present ampelopsin has been carried out pharmacological research comparatively widely, the flavonoid natural product is natural drug and human health product research hot of research and development in recent years, ampelopsin has multiple efficacies such as removing free radical, antioxidation, antithrombotic, antitumor, antiphlogistic antibacterial, and scientist's ampelopsin that begins one's study is used for medicine, food, health product and cosmetics.External health product U.S. health product medicine FYI prevents ampelopsin from arthritis and various inflammation as additive as treatment, especially more suitable to gestation and women breast-feeding their children and baby, ampelopsin is expected to further be developed as the antiinflammatory medication of special population thus, thereby alleviates the toxic and side effects of Western medicine antibiotic to human body.Along with the further research of ampelopsin pharmacological action, market will sharply increase the demand of ampelopsin, and the research and development of ampelopsin have a extensive future.The patent of disclosed relevant ampelopsin has: denomination of invention is the CN101181261A of " application of ampelopsin in the preparation medicament for restraining uric acid transportor URAT 1 "; Disclosing as gynecological inflammation and denomination of invention is the CN10150175A of " preparation method of ampelopsin, pharmaceutical preparation and new medical use "; Disclose as preventing and treat senile dementia and denomination of invention CN101297900A for " new medical use of Caulis seu folium ampelopsis brevipedunculatae (Caulis Ampelopsis Brevipedunculae) stem leaf total flavones and single component ampelopsin ".
But still undiscovered about the more efficient and definite action target spot of ampelopsin, mechanism etc. up to now, the accurate application of ampelopsin requires study, so that treat disease better, more accurately, and reduces untoward reaction.
Ischemia/reperfusion (Ischemia/Reperfusion) is a kind of emergency rating that body local organization or organ circulating system are taken place when temporary blood supply disorder occurring, usually occurs together in the generation and evolution of various ischemic angiocardiopathy and cerebrovascular systemic diseases.Ischemia/reperfusion (I/R) process can be divided into two stages.Phase I is instantaneity ischemia (Ischemia), and promptly hypoxia and the own deficiency of nutrition confession appear in local organization, cause tissue or organ ischemia injury.Second stage is perfusion (Reperfusion) again, is meant the process that blood circulation is dredged after of short duration stagnation again in the ischemic tissue.In refilling process, damaged tissues is inner owing to the blood circulation reconstruction has triggered a series of locality emergency reactions.The tissue that is activated in the I/R process comprises blood vessel cell, blood complement system and lymphocyte.The lymphocyte that is activated not only discharges various strong oxidative free radicals (NO, H to perienchyma
2O
2, NO
3) and various inflammatory factor (interferon, interleukin, tumor necrosis factor and macrophage stimulation factor), also cause neutrophilic granulocyte to inflammatory reaction such as perienchyma's gathering, infiltrations.In addition, thereby the lymphocyte that is activated simultaneously also towards periphery the multiple factor that influences cell growth of tissue secretion induce peripheral cell to enter improper apoptosis and downright bad process (referring to Hilfiker-Kleiner et al.Journal of American College of Cardiology.2006,48:56-66).Therefore the intensity of the secondary damage that is caused by perfusion again is considerably beyond because the damage that ischemia causes, it is the main pathological process in the multiple ischemic angiocardiopathy and cerebrovascular system trauma disease progression process, and lymphocytic superpower activation is that one of principal element of reperfusion injury is (referring to Kaminski KA et al.International Journal of Cardiology.2002,86:41-59).Modern medicine study shows, lymphocytic activation then mainly is to finish by the activation of the signal transduction system (JAK/STAT) under the component cloth cell membrane, and appropriate excessively together drug molecule disturbs the activation of JAK/STAT signal transduction system, can reach adjustment or suppress lymphocytic overactive purpose.The various albumen of therefore, participation formation JAK/STAT signal transduction system become explores the up-to-date research and development target spot of various ischemic angiocardiopathy and cerebrovascular system trauma disease specific drugs for the treatment of of new generation (referring to Murray PJ.Journal ofImmunology.2007,178:2623-2629).
JAK/STAT be in recent years scientist when the interferon-induced gene expression mechanism of research signal transduction system serendipitous (referring to Schindler CW.J Clin Invest.2002,109:1133-1137).Whole system is made up of tyrosine protein kinase (JAK) under the receptor that is distributed in cell membrane (R), the cell membrane and the signal of combining closely with it transmission activator protein (STAT).The JAK tyrosine protein kinase belongs to the non-receptor type protein kinase, is distributed under the cell membrane.Up to now, JAK tyrosine protein kinase family has four members and is identified out: JAK1, JAK2, JAK3 and TYK2.Identified in addition simultaneously that with JAK (signal conducts and transcription activating albumen the kinase substrate STAT that structurally links to each other closely with JAK, Signal Transducer and Activator of Transcription, STAT) (referring to Murray PJ.Journal ofImmunology.2007,178:2623-2629).In relevant tissue and cell, receptor activation thing-receptor-kinase signal transmission system is common to form an exquisiteness, orderly information analysis processing center, make the various stimulus signals of outside be passed to cell interior rapidly, make cell make various actively, emergency reaction accurately.Therefore, JAK tyrosine kinase signal transmission system plays and important effect at the normal physiological function that maintains various tissues, cell.Yet under abnormal conditions, because JAK tyrosine kinase signal transduction path activates and out of controlly also plays pivotal role (referring to Schindler CW.J Clin Invest.2002,109:1133-1137) in the generation of multiple disease, evolution.
As the main active of multiple resisting cardiovascular damage disease Chinese medicine, the natural flavone compounds becomes one of emphasis of state's giving drugs into nose circle research and development already.In the world because the structurally superpower antioxidation characteristics of natural flavone compounds, and illustrated one by one about the formation of oxyradical and the internal relation mechanism of many diseases generation in the recent period, the intervention of discussion use natural flavone compounds is various excessively synthesizes relevant disease disease with superoxides, particularly activated again (referring to Akhlaghi et al.Journal of molecular and cellular cardiology.2009 with the closely-related diseases of cardiovascular and cerebrovascular systems treatment of I/R theory, 46:309-317 and Larson A.J.et al.Pharmaceuticals.2010,3:237-250).At present to the cognition of the internal relation of JAK/STAT signal transduction pathway excessive activation and I/R damage, we use the medicine of two up-to-date establishments to select platform (enzyme modeling type and cell model) that ampelopsin has been carried out screening system and research based on people.We have the anti-JAK inhibition activity of highly significant by the unexpected ampelopsin of finding.The catalator analysis of data shows that ampelopsin can be to the effect of JAK tyrosine protein kinase generation strong inhibition, and its zymetology binding characteristic is a competitive inhibition.Use cell model to inquire into ampelopsin studies show that to lymphocytic function effect, this chemical compound permeate through cell membranes effectively exhausts JAK/STAT signal transduction pathway activation generation resistance, thereby suppresses the ability of lymphocyte to perienchyma's secrete cytokines such as interferon.The cell model result also points out Fructus Myricae rubrae to have higher biological absorption simultaneously.Therefore, ampelopsin is expected to develop at specially good effect new drug various and JAK/STAT signal transduction pathway activation imbalance relevant disease.
Summary of the invention
Based on above-mentioned cognition, we are through creationary design and discover that it is activated effect that ampelopsin has the above-mentioned signal transduction of intensive blocking-up.Experimental results show that further (I) can directly combine with this specific JAK tyrosine protein kinase generation specificity, and inhibitory action is formidably taken place the enzyme molecule.Therefore, we infer that the JAK tyrosine protein kinase of one of important composition in the above-mentioned signal transduction system is the attack target spot of ampelopsin.Based on this discovery we further successfully set up one accurately, medicine identification enzyme sieve platform efficiently, ampelopsin is screened.We have invented in screening process:
Can be effectively as chemical compound---the ampelopsin (Myricetin of JAK enzyme inhibitor, I), inhibitory action with very strong JAK enzyme, and effectively permeate through cell membranes makes a difference to lymphocyte immunologic function, and immunocyte is to the attack of damaged tissues in the reduction I/R process.Further pharmaceutical research also proves, ampelopsin not only rabbit platelet is assembled and coagulation function has certain inhibitory action, and to the diastole effect highly significant of isolated rat arteria coronaria and brain basilar artery contractile response (may by suppressing ACE mechanism).Thus, show that ampelopsin has great application value reducing the I/R damage and improve on the blood circulation.
According to research, invented ampelopsin and can be made into the upward acceptable preparation that is used as oral formulations, injection and other route of administration of JAK enzyme inhibitor of medical treatment the ampelopsin preparation.Be used for the treatment of under abnormal conditions this system and activate the multiple disease of also often bringing out out of control, perhaps in generation, the evolution of these diseases., treatment brand-new as probably becoming is various to damage the specific drug of related disease with cardiovascular and cerebrovascular vessel.
Description of drawings
Fig. 1 is the analysis of the anti-tyrosine kinase activity 50 3nhibitory dose of ampelopsin.
Fig. 2 is the regulating action of ampelopsin to the peripheral blood lymphocyte immunologic function.
The specific embodiment
The inventor utilizes ampelopsin and baicalin 50 3nhibitory dose (IC50) enzymatic analysis at the JAK2 tyrosine protein kinase.Selected ten different compound concentrations (ampelopsin to be measured and the baicalin of 0 to 0.3 mM) in the experiment altogether, add ATP cause kinase reaction before earlier with chemical compound and JAK2 equality of temperature 5 minutes, undertaken by above-mentioned experimental arrangement afterwards.Independent once three meansigma methodss (referring to Fig. 1) of experiment of measuring, error is used relative standard deviation (%CV).
The inventor utilizes ampelopsin that the regulating action of peripheral blood T-lymphocyte immunologic function is carried out the analysis file experiment.Plant in 12-porocyte culture plate through the complete blood cell of carrying out washing treatment in the experiment, revolve at specified culture hole cell afterwards and add ampelopsin, myricetrin or baicalin (final concentration is 100 micromoles) in the supernatant liquid, 37C incubator equality of temperature 60 minutes.In each hole, add isodose IL-2 afterwards with T-lymphocytic emiocytosis interferon in the stimulation of whole cell.Repeatedly (with reference to figure 2) once measured in experiment, and error is used relative standard deviation (%CV).The analysis file experiment shows that ampelopsin and baicalin have remarkable inhibitory action to the lymphocytic secretion interferon of T-ability, but a little less than the effect very of myricetrin.
By the enforcement of the technical program, find that ampelopsin has powerful kinase inhibiting activity.Further enzyme dynamics shows that this specific JAK tyrosine protein kinase inhibition strength of ampelopsin and specificity are all high.End user's peripheral body T-LS model tentative confirmation Fructus Myricae rubrae have the ability of regulating immune system activity, and the various inflammatory factors of T-emiocytosis are had the strong inhibition effect.Further pharmaceutical research proves, ampelopsin not only rabbit platelet is assembled and coagulation function has certain inhibitory action, and to the diastole effect highly significant of isolated rat arteria coronaria and brain basilar artery contractile response.Judge from present data, the clinical indication of ampelopsin will comprise ischemic cardio cerebrovascular diseases, damaging cardiovascular and cerebrovascular disease, tumor, and indication such as skin-whitening, ampelopsin get a good chance of becoming a kind of brand-new, treatment is various damages the specific drug etc. of related disease with cardiovascular and cerebrovascular vessel.
Embodiment 1: ampelopsin is to the inhibitory action of JAK enzyme
Enzyme modeling type measuring principle: the enzyme choosing method be according to Abukhalaf etc. at the classical way of report in 1993 (referring to Abukhalaf IK et al.J Biochem Biophys Methods.1993,26:95-104) through suitably revising and setting up.The measuring principle is: when having ATP to exist in reaction system, JAK can be transferred to the γ phosphorus on the ATP on the tyrosine specific on the peptide substrate.Because the part γ phosphorus of the ATP that uses in the reaction is label isotope 32, can discharge the β ray.And the intensity that participates in the γ phosphorus of polypeptide can accurately be measured by the liquid scintiloscope, thereby is determined substrate polypeptide molecular phosphorus acidizing degree and protein tyrosine kinase activity.Two kinds of used tyrosine protein kinase of catalysis experiment are that baculovirus is infected insect cell and expresses synthetic fusion rotein, and expressing protein is able to purification through affinity chromatograph, and purity reaches more than 90%.Substrate in the kinase reaction is one section artificial synthetic polypeptide that is made of 13 aminoacid, and its sequence is as follows: NH2-lysine-lysine-lysine-lysine-valine-leucine-glutamic acid-phenylalanine-tyrosine-glutamic acid-glutamic acid-glutamic acid-glutamic acid-glutamic acid-glycine-COOH
Experimental implementation:
Step 1: reagent and solution allocation: chemical reagent that all use among the present invention and ampelopsin and baicalin are purity and surpass 99% pure product.Ampelopsin, Fructus Myricae rubrae is sweet and baicalin provides by Kumin Longjin Medicine Co., Ltd.Sample dissolves with DMSO, is configured to 25 mM liquid storages, with 50%DMSO ampelopsin and baicalin liquid storage is diluted to desired concentration afterwards.Substrate and ATP then with deionized water be configured to respectively 0.25 mM and 0.05 mM (
32P-ATP specific activity: liquid storage 225 μ Ci/ μ mol).
Step 2: the final volume of standard enzyme reaction is 50 microlitres, and comprises following various reacted constituent: 20ng tyrosine protein kinase, 15 μ M ATP, 50 μ M substrate polypeptide, 20mM Hepes, pH 7.5,10mM MgCl
2, 1mM EGTA, 0.02%Brij35,0.02mg/ml BSA, 0.1mM Na
3VO
4, 2mM DTT, 0.5%DMSO.Measure if carry out IC50, then also should comprise in the reaction and the sweet and baicalin of ampelopsin to be measured, Fructus Myricae rubrae of 0 to 0.3 mM.
Step 3: after treating that above various composition joins 1.5 milliliters reaction tube,, add the ATP liquid storage at last to start the reaction of phosphorylation zymetology room temperature pre-reaction 5 minutes.Allowing this be reflected at room temperature carried out 60 minutes.
Step 4: in reaction tube, add 2% phosphoric acid of 25 microlitres, and mixing immediately, to stop enzyme reaction.Get 10 microlitre response sample points to P81 phosphoric acid fiber consider film (P81, Disc, Waterman) on, air drying 5 minutes.
Step 5: P81 phosphoric acid fiber worry film is moved to porous filter device (Millipore), filter washing with two milliliters 150mM phosphoric acid solutions and consider film four times, filter washing with reuse two ml methanol and consider film once.To move to the liquid scintillation vial afterwards through the worry film of washing dry 5 minutes, add two milliliters scintillation solution again at air at room temperature.
Step 6: use the liquid scintiloscope to measure and remain in and consider isotope intensity on the film, use the CPM value representation.
Measure and date processing: all test triplicate at least, and data described in the patent is three independent meansigma methodss of measuring of wherein once testing, and error is used relative standard deviation (%CV).Unrestraint agent matched group comprises all compositions except that inhibitor in the experiment, and the test group contains the inhibitor of variable concentrations.And blank group does not add kinases and inhibitor, and other conditions are identical with the test group.Chemical compound suppresses the effect of active anti-JAK tyrosine protein kinase to tyrosine protein kinase and represents with the relative percentage suppression ratio.
The blank CMP of γ-phosphorus amount of participating in=actual measurement CPM-
Protein kinase relative activity=[the test group phosphorus amount of the participating in/unrestraint agent matched group phosphorus amount of participating in] * 100
Result and discussion: Fig. 1 shows is ampelopsin and baicalin 50 3nhibitory dose (IC50) the enzymatic determination experimental result at the JAK2 tyrosine protein kinase.50% of the anti-JAK2 tyrosine protein kinase of ampelopsin and baicalin suppresses dosage and is respectively 1.9 micromoles and 5.0 micromoles (seeing Table 1).The anti-JAK2 tyrosine protein kinase of ampelopsin suppresses about the strong approximately twice of specific activity baicalin.Whether another member JAK3 of tyrosine protein kinase is had depression effect in order to detect these two kinds of chromocor compounds, we have carried out at the 50 3nhibitory dose of JAK3 tyrosine protein kinase (IC50) enzymatic determination.Structure shows that ampelopsin and baicalin also have powerful inhibitory action to JAK3, and the 50 3nhibitory dose of the two (IC50) is respectively 1.4 micromoles and 6.3 micromoles' (table 2).But 50% sweet inhibition concentration of the Fructus Myricae rubrae after the saccharifying but rises to 500 micromoles' (table 2).Therefore, ampelopsin and baicalin have same intensity trend to the inhibitory action of tyrosine protein kinase, promptly ampelopsin suppresses activity and is higher than baicalin, and the existence of glycocide has weakened the inhibition activity of flavone molecule.
Table 1 ampelopsin suppresses dosage to 50% of JAK2
| Chemical compound | 50 3nhibitory dose (IC 50)??Mean±S.D.[μM] |
| Ampelopsin | ??2.1±0.3 |
| Fructus Myricae rubrae is sweet | Do not survey |
| Baicalin | ??4.7±0.4 |
Table 1 shows is ampelopsin and baicalin 50 3nhibitory dose (IC50) the enzymatic determination experimental result at the JAK2 tyrosine protein kinase.Each data is three independent meansigma methodss of measuring, and error is represented with standard deviation (SD).
Table 2 ampelopsin suppresses dosage to 50% of JAK3
| Chemical compound | 50 3nhibitory dose (IC 50)??Mean±S.D.[μM] |
| Ampelopsin | ??1.4±0.1 |
| Fructus Myricae rubrae is sweet | ??510±52 |
| Baicalin | ??6.3±0.5 |
Table 2 shows is ampelopsin and baicalin 50 3nhibitory dose (IC50) the enzymatic determination experimental result at the JAK3 tyrosine protein kinase.Each data is three independent meansigma methodss of measuring, and error is represented with standard deviation (SD).
Embodiment 2: raji cell assay Raji process and result
Cell model measuring principle: use the human peripheral blood T-lymphocyte of prepared fresh in the experiment as object of study.Because the peripheral blood lymphocyte film is distributed with intensive cytokine-2 receptor (IL2R), and the activation of IL2R is mainly passed on by the activation of JAK3.When IL2R by the cytokine-2 combination, activate bonded with it JAK immediately, and JAK further activates STAT5/STAT6.The nucleus that the further activation STAT5/STAT6 that is activated shifts immediately starts a plurality of destination gene expressions by its control.And interferon gamma is exactly one of controlled expression albumen, and it just is secreted into outside the lymphocyte immediately once synthetic.Can extrapolate the action intensity of drug molecule pair cell immunologic function (referring to Changelian PS et al.Blood.2008,111:2155-2157) by measuring whole blood medium-sized lymphocyte generation interferon gamma ability.
Experimental implementation:
Step 1: the healthy human body fresh blood of getting 20 milliliters is in two 10 milliliters of test tubes (100 microlitres, 0.3% sodium citrate is as anticoagulant).
Step 2: use and got rid of tack centrifuge phase 125G centrifugal 10 minutes.Carefully supernatant (blood plasma) is removed.Outstanding again the mixing in phosphoric acid of gained precipitation complete blood cell suffered from liquid (PBS), uses 125G centrifugal 10 minutes.So repeat pair cell and carry out PBS suspendible, centrifugal three times.Afterwards complete blood cell is suspended in (RPMI1640,10% human serum, 50 units per ml penbritin) in the culture fluid.
Step 3: measure cell concentration, cell concentration is adjusted to 1-2 * 10
6Cells/ml.
Step 4: use prepared lymphocyte to carry out the cytositimulation experiment.Cell (1 milliliter) is planted to planting in 12 porocyte culture plates, quantitatively add testing compound and cell mixing afterwards.(5%CO in 37 degree cell culture incubators
2) equality of temperature 60 minutes, add IL-2 (50ng/ml) irritation cell afterwards.
Step 5: measure the interferon expression level.Spend cell culture incubator (5%CO in cell 37
2) cultivate after 40 hours, get 100 microlitre cell culture supernatants and measure interferon content.Assay method uses the standard enzyme linked immunoassay reagent kit to carry out.
Step 6: measure and date processing: all test triplicate at least, and described data are three independent meansigma methodss of measuring of wherein once testing, and error is used relative standard deviation (%CV).Unrestraint agent matched group comprises all compositions except that inhibitor in the experiment, and the test group contains the inhibitor of variable concentrations.Chemical compound uses synthetic relatively percentage rate (% contrast) expression of interferon to interferon expression inhibitory action intensity:
Synthetic relatively percentage rate=[the test group interferon content/unrestraint agent matched group interferon content * 100] of interferon
The IC50 value is calculated and is utilized the SIGMAPLOT graphing method, with compound concentration the synthetic relatively percentage rate of corresponding interferon is tried to achieve as nonlinear regression.
Result and discussion: for further confirm in enzyme sieve model, to find several to JAK have active ampelopsin of strong inhibition and baicalin also can effective function in cell, and the function of interference cell has been selected whole blood T-lymphocyte model in the experiment.Figure 2 shows that three kinds of chromocor compounds (ampelopsin, myricetrin and baicalin) inhibitory action retaining case analysis to T-lymphocytic emiocytosis interferon ability when concentration is 100 micromoles.Ampelopsin produces the interferon inhibitory action to the T-lymphocyte and reaches more than 98% when 100 micromoles, baicalin also has tangible influence (T-lymphocytic emiocytosis interferon ability reduces about about 45%) in the ability to the lymphocytic emiocytosis interferon under the same concentration.And myricetrin does not have remarkable inhibitory action to lymphocyte function.
For the further action intensity of assessment ampelopsin on cell, we use peripheral blood T-lymphocyte model that the IC50 of ampelopsin and two kinds of chemical compounds of baicalin has been carried out measuring (table 3).50% inhibition concentration of ampelopsin and baicalin is respectively 2.8 micromoles and 57 micromoles.Therefore, cell model the analysis showed that ampelopsin far is better than baicalin to the inhibition activity of lymphocyte function.
Table 3 ampelopsin is to the synthetic 50% inhibitor quantitative determination of peripheral blood T-lymphocyte interferon
| Chemical compound | 50 3nhibitory dose (IC 50)??Mean±S.D.[μM] |
| Ampelopsin | ??2.8±0.5 |
| Myricetrin | ??n/a |
| Baicalin | ??57±10 |
Table 3 is that ampelopsin is summed up the inhibiting 50% inhibitor quantitative determination of peripheral blood T-lymphocyte immunologic function.Plant in 12-porocyte culture plate through the complete blood cell of carrying out washing treatment in the experiment, revolve in the supernatant liquid the sweet or baicalin (final concentration is by 0 to 100 micromole) of ampelopsin, Fructus Myricae rubrae that adds variable concentrations at specified culture hole cell afterwards, 37C incubator equality of temperature 60 minutes.In each hole, add isodose IL-2 afterwards with T-lymphocytic emiocytosis interferon in the stimulation of whole cell.Above-mentioned IC50 is three empirical average values, and error is represented with standard deviation (SD).Because the sweet effect extreme difference of Fructus Myricae rubrae is so its IC50 value can't be determined (n/a) under this research imposes a condition.
Embodiment 3: ampelopsin is to the influence of rabbit platelet gathering and coagulation function
Laboratory animal and raise the big ear rabbit of Japan is provided by unming Medical College's Experimental Animal Center, the animal quality certification number: the real moving card 2005-0008 in Yunnan, room temperature environment is raised.
Provide by Kumin Longjin Medicine Co., Ltd with sample ampelopsin, lamp-dish flower acetic (SCU) for test agent experiment, face with preceding and be mixed with the 1.4mg/ml suspension with physiological saline solution, then 2 times to be diluted to certain volume standby.
Reagent and test kit adenosine diphosphate (ADP) disodium (ADPNa
2) available from Solarbio company; Prothrombin time (PT), Fibrinogen (FB), thrombin time (TT), activated partial thromboplastin time (APTT) test kit are French STAGO company import matched reagent box.
Key instrument equipment four-way platelet aggregation instrument (LBY-NJ, Pulisheng Instruments Co., Ltd., Beijing); Automatic coagulation analyzer (STA-R, French STAGO company); Vacuum test tube (sodium citrate 9: 1, liuyang hunan medical apparatus factory).
Experimental technique
Healthy Japan large ear rabbit is selected in experiment grouping and administration for use, the male and female dual-purpose, and body weight 2-3kg divides cage to put the Animal Lab. room temperature and raises.Be divided into 5 groups at random: the normal saline matched group, the basic, normal, high dosage group of ampelopsin sample (3.5,7,14mg/kg, day), the lamp-dish flower acetic matched group (7mg/kg, day).Irritate stomach (ig.) every day except that the normal saline matched group and give the normal saline, each is organized every day ig and gives correspondingly to be subjected to test product once, gets in touch 7 days.Last administration finished after 1 hour, from clear-headed rabbit carotid artery blood sampling, measured accordingly.
Sample ampelopsin dosage mainly per sample the lamp-dish flower acetic that provides of the unit of providing appoint dosage (50mg * 3 time/day, by people 60kg weighing machine, promptly 2.5mg/kg is oral) be according to design, with human dosage is middle Rapid Dose Calculation, and dosage in the rabbit (7mg/kg) is 2.8 times of people's dosage approximately.
The platelet maximum agglutination rate measure with the rabbit whole blood blood sample respectively through 800 and the centrifugal 10min of 3000rpm get platelet rich plasma (PRP) and platelet poor plasma (PPP).With reference to the BornShi turbidimetry, according to the procedure operation of four-way platelet aggregation instrument, add ADP (10uM) induced platelet and assemble, record platelet maximum agglutination rate.
Coagulation function detects according to relevant test kit rule of operation, measures PT, TT, FB and APTT four indices on automatic coagulation analyzer.
The statistical method data are with mean ± standard error
Expression, date processing adopts SigmaStat3.1 statistics software, carry out homogeneity test of variance earlier, carry out one factor analysis of variance (One-way ANOVA) or rank test (One-way ANOVA on Rank) then and carry out the group difference analysis, test level is 0.05.
The result with discuss as shown in table 4, the ampelopsin sample (3.5,7,14mg/kg, day, ig), induce the normal rabbit platelet aggregation that certain inhibitory action trend is arranged, but do not have significant difference between each group of statistical test ADP.The trend that the ampelopsin sample of test dose has certain prolongation and increase to TT, APTT and the FB of normal rabbit coagulation function has the effect trend of certain shortening to PT, but does not have significant difference between each group on the statistics.
Isodose sample ampelopsin and lamp-dish flower acetic do not have notable difference.
In this experiment, do not observe notable difference between each group, analyze reason and mainly contain: 1) drug administration dosage is not enough; 2) drug oral filling stomach effect is not strong.These analyses are provided with back experimental design reference.
Table 4 is irritated stomach and is given the sample ampelopsin to normal rabbit platelet gathering and coagulation function influence
Annotate: platelet aggregation adopts adenosine diphosphate (ADP) (10uM) to induce.
Each is organized data and is expressed as
Adopt SigmaSata 3.1 statistics software analysis, carry out the homogeneity of variance analysis earlier, carry out one factor analysis of variance (One-way ANOVA) or rank test (One-way ANOVA onRank) then and carry out the group difference analysis, test level is 0.05.
Embodiment 4: ampelopsin is to the diastole effect of isolated rat arteria coronaria and brain basilar artery contractile response
Animal SD rat, body weight 250～300g, male, credit number: SYXK (Shan) 2007-003 purchases Xi'an Jiaotong University Medical College's Experimental Animal Center.
Medicine and reagent ampelopsin are provided by Kumin Longjin Medicine Co., Ltd, and it is stand-by to be mixed with variable concentrations with MOPS-PSS.NaCl, KCl, CaCl
2, MgSO
4, Na
2HPO
4, EDTA, D-glucose be all available from Tianjin chemical reagent three factories (analytical pure), 3-[N-morpholino]-propane sulfonic acid (MOPS) is available from ShangHaiMdmy Science ﹠amp; Technologies.Ltd.Thrombosis receptor stimulating agent (U46619) is available from Cayman company.
Equipment Wire Myograph System DMT, Danish Myo Technology Co, PowerLab data record and analytical system, Australian Adinstruments company; Motic SMZ168-TL anatomic microscope, Maike Aodi Industry Group Co Ltd; Venus's eye scissors, Jiangsu Su Ke medical apparatus and instruments company limited; Microforceps WA3010, Shanghai medical apparatus and instruments group; Mettler Toledo FE20 meter; Mettler Toledo AL104 electronic balance etc.
The configuration MOPS-PSS of working solution contains (mM): NaCl, 140.0; KCl, 4.7; CaCl
2, 1.6; MgSO
4, 1.2; 3-[N-morpholino]-propane sulfonic acid (MOPS), 1.2; Na
2HPO
4, 1.4; EDTA, 0.02; D-glucose transfers PH to 7.4 for 5.6,37 ℃.MOPS-KPSS contains (mM): NaCl, 84.7; KCl, 60.0; CaCl
2, 1.6; MgSO
4, 1.2; 3-[N-morpholino]-propane sulfonic acid (MOPS), 1.2; Na
2HPO
4, 1.4; EDTA, 0.02; D-glucose transfers PH to 7.4 for 5.6,37 ℃.
The preparation SD rat anesthesia of vascular ring is put to death, and takes out cerebral tissue and heart rapidly, immerses respectively in the cold MOPS-PSS liquid, isolates brain basilar artery and coronary artery under the anatomic microscope, peels off blood vessel and sticks tissue on every side.With the arterial ring section of vascular scissors into about 1mm length.At microscopically, steel wire with two diameter 60um passes arterial ring, is hung in 8 baths of DMT, and each bath has two fixed metal devices of rightabout, one of them connects tonotransducer, and another connects micromatic setting (regulating preload tension force).Bath contains MOPS-PSS liquid, and 37 ℃ of constant temperature continue the logical 95%O that contains
2And 5%CO
2Mist, pH keeps 7.4.The tranquillization load of regulating brain basilar artery and coronary artery ring is respectively 1.5mN and 1mN, every 20min changes liquid once, add MOPS-KPSS (containing K+60mM) vasoconstrictive after stablizing 1.5h, double, check arterial ring contractility, twice shrinkage amplitude differ＜and 10% vascular ring is used for experiment (referring to Zhang W et al.Basic ﹠amp; Clinical Pharmcaology ﹠amp; Toxicology.2007,101 (6): 401-406).
After the good detection of active of diastole effect experiment blood vessel balance of ampelopsin, add MOPS-KPSS (containing K+60mM) 5ml successively, U46619 (1uM) preshrinking blood vessel, wait to shrink peaking and when stable, with the concentration method of cumulative scale add be subjected to the reagent ampelopsin (10～100uM), the diastole amount effect curve of record ampelopsin.
The tension force of statistical analysis arterial ring is represented with the percent of its relative maximum collapse value, maps with Sigma Plot mapping software, and total data is expressed as mean ± standard error.
The diastole effect that mediation is shunk to MOPS-KPSS of sample ampelopsin
After the effect coronary artery detection of ampelopsin diastole rat coronary artery is qualified, add MOPS-KPSS (containing K+60mM) 5ml, wait to shrink peaking and when stable, be subjected to reagent ampelopsin (10～100uM) with the adding of concentration method of cumulative scale, because SCU diastole effect is not obvious, therefore adopting adding respective volume solvent is the solvent matched group.As shown in table 5, the relative shrinkage value of blood vessel reduces to 19.06 ± 4.72%.Ampelopsin can shrink due to the diastole KCl, and is concentration dependent.The EC50 value is 0.38 ± 0.05mM.
The amount effect curve that table 5 ampelopsin shrinks at MOPS-KPSS mediation coronary artery
Annotate:
(standard error), control (contrast): n=8; Ampelopsin: n=8.
Sample ampelopsin diastole rat brain basilar artery require mental skill basilar artery detect qualified after, add MOPS-KPSS and (contain K+60mmo1L
-1) 5ml, treat the vasoconstriction peaking and when stable, with cumulative concentration application of sample method give bathe add in the mortise ampelopsin (10～1000uM) because SCU diastole effect is not obvious, adopt therefore that to add the respective volume solvent be the solvent matched group.As shown in table 6, the relative shrinkage value of blood vessel reduces to 4.81 ± 1.43%.Ampelopsin can shrink due to the diastole KCl, and is concentration dependent.The EC50 value is 0.21 ± 0.02mM.
The amount effect curve that table 6 ampelopsin shrinks at MOPS-KPSS mediation brain basilar artery
Annotate:
(standard error), control (contrast): n=7; Ampelopsin: n=8.
The contractile response of sample ampelopsin diastole U46619 mediation
The effect of diastole rat arteria coronaria adds U46619 (1uM), and vasoconstriction peaking and stable adds ampelopsin and SCU with cumulative concentration application of sample method to bathing in the mortise.As shown in table 7, ampelopsin and SCU reduce to 9.93 ± 2.28% and 43.52 ± 6.97% to relative shrinkage value coronarius.Prompting ampelopsin and SCU all can shrink due to the diastole U46619, and are concentration dependent.The EC50 value is 0.18 ± 0.02mM and 0.39 ± 0.11mM, and the two has significant difference (P＜0.05).
The amount effect curve that table 7 ampelopsin, lamp-dish flower acetic shrink at U46619 mediation coronary artery
Annotate:
(standard error), control (contrast): n=7; Ampelopsin: n=8.
The effect of diastole rat brain basilar artery adds thromboxane receptor agonist U46619 (1uM), and vasoconstriction peaking and stable adds ampelopsin and SCU with cumulative concentration application of sample method to bathing in the mortise.As shown in table 8, the relative shrinkage value of blood vessel reduces to 5.62 ± 1.52% and 18.93 ± 5.39% respectively.Ampelopsin and SCU all can shrink due to the diastole U46619, and are concentration dependent.The EC50 value is 0.18 ± 0.03mM and 0.33 ± 0.05mM, and the two has significant difference (P＜0.05).Can shrink due to the diastole KCl, and be concentration dependent.The EC50 value is 0.21 ± 0.02mM.
The amount effect curve that table 8 ampelopsin shrinks at U46619 mediation brain basilar artery
Annotate:
(standard error), control (contrast): n=8; Ampelopsin: n=8.
Result and discussion
In this experiment, the sample ampelopsin all has the diastole effect to two kinds of isolated rat coronary artery that different contracting agent mediated, the contraction of brain basilar artery, almost can diastole 90% when high concentration, and its diastole effect obviously is better than SCU, and the prompting ampelopsin has the cardiovascular and cerebrovascular vessel dilating effect stronger than SCU.
Illustrate: the ampelopsin of 5-11 all is by Long John pharmacy self-control and provides among the following embodiment.
Embodiment 5: the ampelopsin granule
Prescription:
Ampelopsin 2000g
Sucrose 5000g
Dextrin 400g
Ethanol is an amount of
Granulate by common granulation, be distributed into 1000 bags (every bag of about 7.4g), every bag contains ampelopsin 2000mg.Each edible one bag, every day 1～3 time.
Embodiment 6: the ampelopsin soft gelatin capsule
Prescription:
Ampelopsin 75g
Polyethylene Glycol-400 300g
By the preparation of common soft gelatin capsule (soft capsule) agent preparation method, the tolerant heavy about 375mg of every intragranular can get 1000, and every contains ampelopsin 75mg.Each 1-2 grain, every day 1-3 time.
Embodiment 7: the ampelopsin freeze-dried powder
Prescription:
Ampelopsin 25g
Mannitol 100g
Be prepared into lyophilized formulations by common lyophilization, can make the ampelopsin freeze-dried powder of the specification of 1000 25mg.
Embodiment 8: the ampelopsin freeze-dried powder
Prescription:
Ampelopsin 100g
Lecithin 85g
Mannitol 100g
Be prepared into lyophilized formulations by common lyophilization, can make the ampelopsin freeze-dried powder of the specification of 1000 100mg.
Embodiment 9: compound recipe ampelopsin oral liquid
Prescription:
Ampelopsin 360g
Ferulic acid 155g
Mel 1000g
Distilled water adds to 10kg
By common oral liquor preparation, can get the oral liquid of 1000 (every nearly weighs 15g).
Embodiment 10: the ampelopsin drop pill
Prescription:
Ampelopsin 10g
PEG-6000????????????200g
By common drop pill preparation method preparation, the heavily about 22.8mg of every ball can be about 10000, and every ball contains the about 1mg of ampelopsin, takes the 1-20 ball at every turn.
Embodiment 11: the ampelopsin oral cavity quick disintegrating slice
Prescription (1000):
Ampelopsin (particle diameter＜35 μ m) 20g
Microcrystalline cellulose (100 order) 120g
Lactose (120 order) 54g
Carmethose (80 order) 10g
Polyethylene Glycol-10000 (60 order) 8g
Sorbitol (120 order) 40g
Strawberry essence 0.1g
Preparation technology: ampelopsin and above-mentioned various raw material are carried out super-refinement,, promptly get every oral cavity quick disintegrating slice that contains ampelopsin (specification) 20mg by direct compression behind the abundant mixing of prescription.
Product provided by the invention is through study of pharmacy, and its result is as follows:
The ampelopsin stability of formulation
Sample with embodiment 5,6,7,8,9 at room temperature keeps in Dark Place, and places respectively 1,2,3,6,12 month, checks that on time outward appearance is constant substantially, and the effective ingredient ampelopsin does not change through check yet.Therefore, the product that makes of the various prescriptions of this ampelopsin preparation all can reach the shelf-life in 1 year.
The stability test result: assay and discriminating etc. are with reference to working standard in the quality standard, and the result is as shown in table 9:
Table 9 sample stability result of the test
The result shows sample provided by the invention, and through the preliminarily stabilised investigation, product quality is basicly stable, can reach more than 1 year.
Though the present invention is described with exemplary embodiment and embodiment, disclosed system and method is not limited to these exemplary embodiment/embodiments.And, be understandable that those skilled in the art obviously can be from the above description, and under the situation that does not deviate from present disclosed spirit and scope, disclosed system and method modified, changed and improves.Therefore, the present invention comprises significantly and comprises above-mentioned all modifications, change and improvement in its scope.
Claims (8)
1. the purposes of the chemical compound shown in (I) is characterized in that the medicine that described chemical compound is used to prepare treatment or prevents to enliven because of tyrosine kinase the disease that causes
2. according to the described purposes of claim 1, it is characterized in that described chemical compound is used to prepare the medicine of treatment because of the active ischemic cardio cerebrovascular diseases that causes of tyrosine kinase.
3. purposes according to claim 1 is characterized in that described chemical compound is used to prepare the medicine of treatment because of the active damaging cardiovascular and cerebrovascular disease that causes of tyrosine kinase.
4. purposes according to claim 1 is characterized in that described chemical compound is used to prepare the medicine of treatment because of the active tumor disease that causes of tyrosine kinase.
5. purposes according to claim 1 is characterized in that described chemical compound is used to prepare the medicine of treatment because of the active dermatosis that causes of tyrosine kinase.
6. purposes according to claim 1 is characterized in that described chemical compound is used to prepare combination and/or the prescription of treatment because of the medicine of the active disease that causes of tyrosine kinase.
7. purposes according to claim 1, when it is characterized in that described chemical compound is used to prepare treatment because of the medicine of the active disease that causes of tyrosine kinase, the scope of effective dose is at 1mg-2000mg.
8. purposes according to claim 1 is characterized in that described chemical compound can be made into medical treatment and goes up acceptable preparation and the cosmetics that are used as oral formulations, injection, granule, pill, capsule, spray, lotion, suppository, drop pill, mixture, liniment, patch, membrane, paper preparation, suspensoid, tincture, dry syrup, effervescent tablet, plaster, ointment, syrup, Emulsion, powder, slow release, controlled release preparation, targeting preparation and other route of administration of tyrosine kinase inhibitor.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633762A (en) * | 2012-04-06 | 2012-08-15 | 昆明龙津药业股份有限公司 | Myricetin sulfonic acid compound and salt compound thereof and application of myricetin sulfonic acid and salt compound |
| CN103655540A (en) * | 2012-09-26 | 2014-03-26 | 四川大学华西医院 | Application of myricetin crystal compound in medicine of nerve inhibitor |
| CN108042524A (en) * | 2017-12-21 | 2018-05-18 | 南方医科大学 | The application of tanshin polyphenolic acid B and its analogue in anti-HPV viruse infection medicine is prepared |
-
2010
- 2010-05-10 CN CN 201010167105 patent/CN101804046A/en active Pending
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| 《FEBS Letters》 20091229 Tiziano M. Scarabelli et al. Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia/reperfusion-induced injury 第531-541页 2-3 第583卷, 2 * |
| 《Journal of Natural Products》 19891030 ROBERT L.GEAHLEN et al INHIBITION OF PROTEIN-TYROSINE KINASE ACTIVITY BY FLAVANOIDS AND RELATED COMPOUNDS 第982-986页 1，4，6-8 第52卷, 第5期 2 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102633762A (en) * | 2012-04-06 | 2012-08-15 | 昆明龙津药业股份有限公司 | Myricetin sulfonic acid compound and salt compound thereof and application of myricetin sulfonic acid and salt compound |
| CN103655540A (en) * | 2012-09-26 | 2014-03-26 | 四川大学华西医院 | Application of myricetin crystal compound in medicine of nerve inhibitor |
| CN103655540B (en) * | 2012-09-26 | 2015-12-02 | 四川大学华西医院 | Application of myricetin crystal compound in medicine of nerve inhibitor |
| CN108042524A (en) * | 2017-12-21 | 2018-05-18 | 南方医科大学 | The application of tanshin polyphenolic acid B and its analogue in anti-HPV viruse infection medicine is prepared |
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