CN102125567B - Medicinal composition for preventing and treating atherosclerosis - Google Patents
Medicinal composition for preventing and treating atherosclerosis Download PDFInfo
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- CN102125567B CN102125567B CN2011100735729A CN201110073572A CN102125567B CN 102125567 B CN102125567 B CN 102125567B CN 2011100735729 A CN2011100735729 A CN 2011100735729A CN 201110073572 A CN201110073572 A CN 201110073572A CN 102125567 B CN102125567 B CN 102125567B
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- atorvastatin
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
The invention discloses a medicinal composition for preventing and treating atherosclerosis. The medicinal composition comprises tanshinone II-A and atorvastatin, wherein the weight part ratio of the tanshinone II-A to the atorvastatin is preferably 10:(2-10); the tanshinone II-A is combined with the atorvastatin as a statin drug for use, so that the curative effect of high dosage of the tanshinone II-A or the atorvastatin can be achieved by a small dosage of the combined tanshinone II-A and atorvastatin, and the synergistic effect is obvious after drug combination; thus the areas of a lipid core and plaques can be obviously reduced, macrophage infiltration is reduced, collagen content in the plaques is increased, conditions of activation of NF-kB (Nuclear Factor-kappa B) are reduced, production of active oxygen in arterial plaques is inhibited, and the like. The medicinal composition for preventing and treating atherosclerosis has broad application prospect.
Description
Technical field
The present invention relates to a kind of atherosclerotic pharmaceutical composition that is used for preventing and treating.
Background technology
Atherosclerosis (Atherosclerosis As) is the common type of cardiovascular disease, the change of Along with people's growth in the living standard and life style, and the cardiovascular disease especially evidence of coronary heart diseases due to the As rises year by year.At present, become one of main disease of threatening human health and life by the heart due to the As, cerebrovascular disease.Great deal of research results shows that As is not only lipidosis property disease, also is inflammation and immune disease.Inflammatory reaction plays an important role in the formation and development of As speckle.The formation of As speckle, break and the thrombosis of secondary be cause clinically the main pathological basis of acute cardiovascular event (unstable angina pectoris, apoplexy, sudden sudden death etc.) (2002, Nature).Yet reducing also, the medicine of stabilize plaque still lacks.Therefore, develop new As medicine and drug regimen and very important meaning (2008, Nature Medicine) is arranged for the As clinical patients.
The mechanism of action of statins is the biosynthesis that suppresses cholesterol, can effectively reduce the endogenous cholesterol source.Owing to hypercholesterolemia concentration in the blood and in arterial blood tube wall inner membrance deposition is the main cause of disease that causes As, and therefore, statins has become the main flow medicine of treating As clinically at present.But the long-term heavy dose of application of statins can bring serious adverse effects clinically, like liver toxicity, muscle poison property etc., has limited the clinical practice of statins.In addition, statins can not influence the absorption of exogenous cholesterol, and statins is invalid to the normal patients with coronary heart disease of blood fat, and therefore simple use statins can not obtain ideal therapeutic effect.Have result of study to show, the statins intensive treatment still had the patient of 20 % that acute cardiovascular event (2005, New Engl J Med) still possibly take place after 2 years.In view of this, statins and other related drugs therapeutic alliances (Combination Pharmacotherapy) in recent years become a new focus in As treatment field.
Mainly contain following several types of medicines and statins at present and unite use: (1) and rising HDL-C drug combination, like nicotinic acid class medicine; (2) with reduction LDL-C drug combination, like cholesterol absorption inhibitor (Ezetimibe); (3) share with anti-inflammatory agent, like aspirin; (4) with the depressor coupling, like amlodipine etc.The big drugmaker in the world such as Pfizer and Merck has gone out a plurality of combination formulations listings according to these therapeutic alliance strategy Development, and clinical efficacy is good, but does not still have the drug combination of statins and Chinese medicine activated monomer.
Radix Salviae Miltiorrhizae be the labiate Radix Salviae Miltiorrhizae (
Salvia miltiorrhizaBunge) dry root and rhizome, property is bitter, be slightly cold GUIXIN, Liver Channel.As Chinese medicine, in clinical side's medicine, be widely used in stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, relieving restlessness etc. clears away heart-fire.Tanshinone I I-A is a fat-soluble monomer component main in the Radix Salviae Miltiorrhizae.Our early-stage Study results suggest (Tang et al., 2007, Vasc Pharmacol.; Tang et al., 2011, Eur J Pharmacol.) Tanshinone I I-A can suppress generation and the development of As through following mechanism: free radical is removed in (1), suppresses lipid peroxidation; (2) anti-LDL oxidation reduces oxLDL level in the serum; (3) suppress sticking of mononuclear cell-endotheliocyte; (4) suppressing macrophage foam cell formationization assembles with cholesterol; (5) release of inhibition macrophage inflammatory factor; (6), reduce and remove the deposition etc. of cholesterol with the deposition site of cholesterol competition blood vessel wall inner membrance.Tanshinone I I-A can prevent and treat the As effect, in the animal model tests such as rat, rabbit and ApoE genetic flaw mice of high lipid food feed, is confirmed.Up to the present, still haveing nothing to do is used for stablizing the report of As speckle in Tanshinone I I-A, also do not have the research of Tanshinone I I-A drug combination.
Chinese patent " Tanshinone I I-A is used for the preparation prevention and treats atherosclerotic the medicine " (patent No. 01130086.8; Open day on July 2nd, 2003) disclosing Tanshinone I I-A can be used for the deposition of cholesterol reducing at the arterial blood tube wall; Avoid forming atheromatous plaque, prevent that As from taking place.But still there is not the report that this medicine and statins are united use.
Summary of the invention
The objective of the invention is to according to above-mentioned deficiency of the prior art, provide a kind of and be used for prevention and treat atherosclerotic pharmaceutical composition.
The present invention realizes above-mentioned purpose through following technical scheme:
A kind ofly be used for prevention and treat atherosclerotic pharmaceutical composition, comprise Tanshinone I I-A and atorvastatin, wherein the structural formula of Tanshinone I I-A is suc as formula I, and the structural formula of atorvastatin is suc as formula II:
The ratio of weight and number of said Tanshinone I I-A and atorvastatin is 10:2 ~ 10.
Said Tanshinone I I-A is the activated monomer that separation and purification obtains from the natural Chinese medicine Radix Salviae Miltiorrhizae, and atorvastatin is the merchandise resources chemical compound.
Wherein the method for the separation and purification of Tanshinone I I-A is: get dry Radix Salviae Miltiorrhizae, and with 95% ethanol extracting 3 times, each 24 hours; Add entry behind the extract concentrating under reduced pressure, divide 4 extractions, extract concentrating under reduced pressure with chloroform; Column chromatography for separation, silica gel are the 100-200 order, and eluent is the petrol ether/ethyl acetate mixed solution that contains 1 %-10 % ethyl acetate; Carry out gradient elution, obtain Tanshinone I I-A activated monomer.
Aforementioned pharmaceutical compositions also comprises pharmaceutically acceptable adjuvant except that comprising Tanshinone I I-A, atorvastatin, wherein adjuvant is one or more in emulsifying agent, solubilizing agent, excipient or the stabilizing agent.
The dosage form of said pharmaceutical composition is injection, tablet, pill, capsule, solution, suspending agent or Emulsion.
The route of administration of aforementioned pharmaceutical compositions is oral, percutaneous, vein or intramuscular injection, and dosage is 10 ~ 20 mg/kg/day.
Compared with prior art, the present invention has following beneficial effect:
Through analyzing relatively Tanshinone I I-A and statins treatment As mechanism of action; We find to have good complementarity between the two; Be embodied in: (1) Tanshinone I I-A can effectively reduce low density lipoprotein, LDL (LDL) oxidation; Reduce serum OxLDL ELISA (oxLDL) level, statins is to this not influence; (2) statins reduces blood plasma LDL-C, rising HDL-C, Tanshinone I I-A does not have obvious influence to blood fat, but it is as novel plant steroid medicine, because of structure similar with cholesterol, can the competitive inhibition cholesterol in the deposition of blood vessel wall; (3) can the inflammation-inhibiting transcription factor NF-KB in a large amount of body and then bring into play it and imitate antiinflammatory action by force with in vitro study report Tanshinone I I-A, and the anti-inflammatory effect of Statins a little less than; (4) statins is widely applied for a long time and can be produced serious adverse reaction, especially Liver and kidney toxicity and musclar toxicity, and Tanshinone I I-A is in the news and has good hepatic and renal function protective effect; (5) Tanshinone I I-A has slight hypotensive effect in renal hypertensive rat and spontaneously hypertensive rat model, and Statins is not had a hypotensive effect.In view of above analysis, we unite use with Tanshinone I I-A and statins atorvastatin, can effectively suppress the generation and the development of As disease, and are expected to develop and have traditional Chinese medicine characteristic and the good combination formulations medicine of clinical efficacy.This kind administering drug combinations mode is based on the reasonable administering drug combinations scheme that the research of As pathogenesis and drug mechanism is set up, and helps to reduce the clinical risk that his spit of fland of independent use high dose causes.
Our experimental result shows; Tanshinone I I-A and statins atorvastatin are united use; Can be issued to the Tanshinone I I-A and the individually dosed curative effect of atorvastatin of high dose at low dosage; And collaborative facilitation is obvious after the coupling, significantly reduces lipid core and plaque area size, reduce macrophages infiltration, increase collagen content in the speckle, reduce NF-kB activation situation, suppresses tremulous pulse active oxygen generation etc.
Description of drawings
Fig. 1. embodiment 3 respectively organize medicine to ApoE knock out mice aortic sinus plaque area influence interpretation of result figure, wherein, * * *
P<0.001 the vs normal group, $
P<0.05 vs model group ， $$
P<0.01 vs model group ， $$$
P<0.001 vs model group;
Fig. 2. embodiment 4 respectively organizes medicine influences interpretation of result figure, wherein * * * to ApoE knock out mice whole blood pipe plaque area
P<0.001 vs normal group;
Fig. 3. embodiment 5 respectively organizes medicine influences interpretation of result figure, wherein * * * to ApoE knock out mice innominate artery plaque area
P<0.001 the vs normal group, $
P<0.05 vs model group ， $$
P<0.01 vs model group ， $$$
P<0.001 vs model group;
Fig. 4. embodiment 6 respectively organizes the macrophage content interpretation figure of medicine to ApoE knock out mice artery plaque, wherein ###
P<0.001 the vs normal group, *
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group;
Fig. 5. embodiment 6 respectively organize medicine to the inner collagen content of ApoE knock out mice artery plaque influence interpretation of result figure, wherein, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group;
Fig. 6. embodiment 6 respectively organizes medicine to NF-kB activation situation interpretation figure, wherein * in the ApoE knock out mice artery plaque
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group;
Fig. 7. embodiment 7 respectively organizes the coordinate repression interpretation figure that medicine produces ApoE knock out mice tremulous pulse active oxygen, wherein ###
P<0.001 the vs normal group, *
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group.
The specific embodiment
Extraction, separation and the purification of embodiment 1 Tanshinone I I-A
Dry Radix Salviae Miltiorrhizae 1 kg was with 95% ethanol extracting 3 times (each 1000 ml), each 24 hours; Extract is evaporated to 500 ml, adds 500 ml water then, divides four extractions with 1000 ml chloroform; The extract concentrating under reduced pressure, column chromatography for separation, silica gel is the 100-200 order; Eluent is the petrol ether/ethyl acetate mixed solution that contains 1 %-10 % ethyl acetate, carries out gradient elution.Can obtain purity and be 98% about 1.8 g of Tanshinone I I-A.
Embodiment 2 Tanshinone I I-A and atorvastatin drug combination are to the influence of ApoE knock out mice blood fat
5 the week age male ApoE knock-out mice (ApoE
-/-) (introduce a fine variety laboratory, the animal quality certification number: SCXK (capital) 2006-0008) available from Department Of Medicine, Peking University's laboratory animal portion from U.S. Jackson.With strain with age in week the C57BL/6J male mice available from Nanfang Medical Univ's Experimental Animal Center (5 ages in week, SPF level, the animal quality certification number: SCXK (Guangdong) 2006-0015).After buying back, laboratory animal raises in HSPH of Zhongshan University experimental center SPF environment (temperature 25 ± 0.5 degree; Humidity 60%-70%; The dark 12h of illumination 12h/), first adaptability raised for 1 week, beginning of inferior week (6 week) feed high lipid food (normal feedstuff+10% Adeps Sus domestica+1.25% cholesterol).Experiment is divided into groups as follows: (A) the C57BL/6J group is the normal control group, gives equal-volume 0.5% sodium carboxymethyl cellulose (CMC-Na); (B) ApoE
-/-Group is model group (ApoE KO), gives equal-volume 0.5% CMC-Na; (C) Tanshinone I I-A low dose group (Tan 10) is irritated the Tanshinone I I-A that stomach gives 10 mg/kg/day, and capacity is 0.1ml/10g; (D) Tanshinone I I-A high dose group (Tan 30) is irritated the Tanshinone I I-A that stomach gives 30 mg/kg/day, and capacity is 0.1 ml/10g; (E) Atorvastatin calcium low dose group (Ato 3) is irritated the medicine that stomach gives 3 mg/kg/day, and capacity is 0.1 ml/10g; (F) Atorvastatin calcium high dose group (Ato 10) is irritated the medicine that stomach gives 10 mg/kg/day, and capacity is 0.1 ml/10g; (G) administering drug combinations I group (T/A 3), gastric infusion Tanshinone I I-A 10 mg/kg/day+ Atorvastatin calciums 3 mg/kg/day.(H) administering drug combinations II group (T/A 10), gastric infusion Tanshinone I I-A 10 mg/kg/day+ Atorvastatin calciums 10 mg/kg/day.Afternoon every day, 14:00 divided into groups and 16 weeks of dosage continuous irrigation stomach according to last table.The used test kit of lipid determination is bought the Zhong Shengbei control Bioisystech Co., Ltd from Beijing; Detect content and comprise T-CHOL (TC), triglyceride (TG), low density lipoprotein, LDL (LDL-C), high density lipoprotein (HDL-C), experimental result sees the following form 1.
Table 1
| ? | B.W.(g) | TC (mM) T-CHOL | TG (mM) triglyceride | HDL-C(mM) | LDL-C(mM) |
| C57BL/6J | 25.9±2.8 | 2.6±0.4 | 1.1±0.2 | 0.62±0.02 | 1.0±0.3 |
| ApoE KO | 30.0±1.6 | 29.4±3.2 | 13.9±2.4 | 0.99±0.06 | 13.3±1.2 |
| Tan 30 | 31.5±2.3 | 26.5±4.0 | 12.8±1.9 | 0.97±0.14 | 11.2±2.8 |
| Tan 10 | 30.7±1.2 | 27.5±4.9 | 14.2±2.6 | 0.89±0.04 | 12.4±1.5 |
| Ato 10 | 30.8±2.0 | 19.2±5.3*** | 6.4±3.1*** | 1.06±0.05 | 8.6±3.0*** |
| Ato 3 | 29.3±3.3 | 22.2±2.5** | 9.8±1.9** | 0.86±0.02 | 9.8±1.3** |
| T/A10 | 30.45±1.11 | 18.9±1.1*** | 11.3±4.0 | 1.27±0.02 | 8.9±1.4*** |
| T/A3 | 31.5±0.6 | 23.1±4.8** | 13.2±1.6 | 1.03±0.11 | 9.9±1.4** |
Annotate: same compared with normal, * *
P<0.01, * * *
P<0.001.
This experimental result shows: after (1) high lipid food was fed, the normal C57 mice of model group mice body weight obviously increased, individually dosed group of each dosage of Tanshinone I I-A and atorvastatin and administering drug combinations group to body weight do not have obvious influence (
P>0.05).(2) model group mice TC, TG and LDL-C obviously increase (
P<0.001), Statins significantly reduces these blood lipid levels, but the high low dose group of Tanshinone I I-A does not have obvious influence to these indexs, and administering drug combinations group blood fat and improving does not have obvious synergism.This experimental result shows: Tanshinone I I-A and atorvastatin administering drug combinations do not have tangible improvement effect to the rising of ApoE knock out mice blood fat.
Experiment is divided into groups with embodiment 2.Take off the heart after the perfusion; Residual blood is removed in the PBS rinsing; Cut with blade with the straight line that is parallel to left and right sides auricle place or perpendicular to the direction of aortic root (aortic root); Stay the first half heart tissue (being with 1 mm aorta), encapsulate in the mould that contains OCT (Tissue-Tek), liquid nitrogen flash freezer is placed on-80 ℃ of refrigerators preservations immediately.Frozen section on the Leica freezing microtome, first serial section occurs beginning collecting section until three valves of aortic sinus part fully, and thickness is 8 μ m, and every interval 50 μ m paste a sheet, every anticreep slide (the clean sharp company in Guangzhou) 6 sections in shop.Section is placed-80 ℃ of preservations after cutting sheet.The slice row oil red O stain is taken pictures with Leica Qwin Plus analysis software (Leica Microsystems), and double-blind method is analyzed plaque area, and the result sees Fig. 1, wherein * * *
P<0.001 the vs normal group, $
P<0.05 vs model group ， $$
P<0.01 vs model group ， $$$
P<0.001 vs model group.Fig. 1 shows that Tanshinone I I-A and atorvastatin are individually dosed and can suppress the aortic sinus plaque area in dose dependent ground; The administering drug combinations group has synergism, and the administering drug combinations low dose group can reach the curative effect of individually dosed group of Tanshinone I I-A and the atorvastatin of high dose.
Embodiment 4 Tanshinone I I-A and atorvastatin drug combination are to the influence of ApoE knock out mice whole blood pipe plaque area
Experiment is divided into groups with embodiment 2.Breast is taken a blood sample, fixed, opens to mice with pentobarbital sodium (100 mg/kg) anesthesia posterior orbit, exposes heart, and (naked eyes are separating blood vessel substantially for 0.01mM, pH7.4) 10ml for row left ventricular cannulation perfusion PBS.The isolating whole piece blood vessel of warp cardinal principle places the capsule of ice-cold PBS, at connective tissue and the fat of operating microscope bearing segmentation from clean blood vessel periphery.Vascular strip is vertically cut open, made aortic arch and iliac artery bifurcated be " Y " font.The row oil red O stain places slide on the green background, makes that normal blood vessels inner membrance, speckle and background contrast are clear, with digital camera (Canon IXUS110) fixed-distance shooting, adopts Image J computed in software plaque area/whole blood pipe area.Result of calculation such as Fig. 2, wherein * * *
P<0.001 vs normal group; The result shows that Tanshinone I I-A and atorvastatin are individually dosed and can suppress whole blood pipe plaque area in dose dependent ground; The administering drug combinations group has synergism, and the administering drug combinations low dose group can reach the curative effect of individually dosed group of Tanshinone I I-A and the atorvastatin of high dose.
Innominate artery is also claimed the brachiocephalic trunk tremulous pulse, starts from aortic arch, extends upward and tells RCCA and right subclavian artery, is that the research arteriosclerosis plaque forms, speckle constitutes and a generally acknowledged position of plaques stabilize property.Breast is taken a blood sample, fixed, opens to mice with pentobarbital sodium (100 mg/kg) anesthesia posterior orbit, exposes heart, and (naked eyes are separating blood vessel substantially for 0.01 mM, pH7.4) 10 ml for row left ventricular cannulation perfusion PBS.Between heart and aortic arch infall to brachiocephalic trunk tremulous pulse, cut the heart of band portion blood vessel; Put into 10% formalin soaked overnight after the rinsing; Under operating microscope, take off the brachiocephalic trunk tremulous pulse, place the OCT embedding medium immediately, be put in-80 ℃ of preservations behind the liquid nitrogen flash freezer.When drawing materials, under operating microscope, isolate RCCA and right subclavian artery with the ophthalmology microscissors, black line ligation right subclavian artery is as identification marking.Cut innominate artery, its plaque area dyeing is dyeed with aortic sinus among the embodiment 3 (aortic sinus).Take pictures with Leica Qwin Plus analysis software, double-blind method is analyzed plaque area, every group of 6 mices, and every mice is got 3 sections, interval 50 μ m, result of calculation such as Fig. 3, wherein * * *
P<0.001 the vs normal group, $
P<0.05 vs model group ， $$
P<0.01 vs model group ， $$$
P<0.001 vs model group.
The result shows that Tanshinone I I-A and atorvastatin are individually dosed and can suppress the innominate artery plaque area in dose dependent ground; The administering drug combinations group has synergism, and the curative effect of administering drug combinations low dose group obviously is superior to the Tanshinone I I-A and the individually dosed curative effect of atorvastatin of high dose.The administering drug combinations group effect of high dose is particularly evident.
Embodiment 6 Tanshinone I I-A and atorvastatin drug combination are to the Stabilization of ApoE knock out mice artery plaque
Research plaques stabilize property is mainly analyzed through the formation of speckle at present, relates generally to following four aspects: the size of (1) lipid core; (2) infiltration of macrophage; (3) content of smooth muscle cell and collagen content; (4) degree of inflammatory reaction in the speckle.We have analyzed the speckle formation through SABC and specific stain, to set forth the Stabilization of administering drug combinations to speckle.Wherein the size of lipid core is seen the mensuration of embodiment 3 plaque area.Visible by example 3: Tanshinone I I-A and atorvastatin are individually dosed can to suppress the aortic sinus plaque area in dose dependent ground; Reduce lipid core; The administering drug combinations group has synergism, and the administering drug combinations low dose group can reach the curative effect of individually dosed group of Tanshinone I I-A and the atorvastatin of high dose.
The collaborative infiltration that suppresses macrophage of Tanshinone I I-A associating atorvastatin
:Through the specific stain (Mac-3 is positive) that frozen section is carried out macrophage; And adopt computer-aided image analysis system (Image Pro-Plus Software 6.0) to analyze the positive staining area of macrophage in the speckle; Analysis result is as shown in Figure 4, wherein ###
P<0.001 the vs normal group, *
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group.
The collaborative inner collagen content of speckle that increases of Tanshinone I I-A associating atorvastatin: through frozen section being carried out the specific stain (Masson Trichrome) of collagen; And adopt computer-aided image analysis system (Image Pro-Plus Software 6.0) to analyze the positive staining area of collagen in the speckle; Analysis result such as Fig. 5; Wherein, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group.
The collaborative NF-kB activation that suppresses of Tanshinone I I-A associating atorvastatin: through frozen section being carried out the specific stain of NF-κ B; And adopt the situation of NF-kB activation in computer-aided image analysis system (Image Pro-Plus Software 6.0) the analysis speckle and calculate the positive staining area; Analysis result such as Fig. 6, wherein *
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group.
Can find out that from Fig. 4-6 (1) aspect the minimizing lipid core, Tanshinone I I-A various dose group and atorvastatin therapeutic equivalence are worked in coordination with after the coupling and significantly reduced lipid core and plaque area size; (2) aspect antiinflammatory (macrophages infiltration) effect, the ability that Tanshinone I I-A various dose group suppresses free macrophage is better than atorvastatin, the collaborative macrophages infiltration that reduces after the coupling; (3) effect of collagen content is suitable in Tanshinone I I-A and the atorvastatin increase speckle, the collaborative interior collagen content of speckle that increases of administering drug combinations group; (4) owing to the inflammation transcription factor NF-KB is played an important role in arteriosclerosis formation and rupture process; Tanshinone I I-A can significantly suppress NF-kB activation in the speckle; Atorvastatin suppresses a little less than the effect of NF-kB activation, the collaborative NF-kB activation that reduces after the coupling.
The coordinate repression that embodiment 7 Tanshinone I I-A and atorvastatin drug combination produce ApoE knock out mice tremulous pulse active oxygen
Take out freezing not fixing (zymetology is complete) brachiocephalic trunk section (10 μ m) from-80 ℃ of refrigerators, room temperature is dried.In wet box, 37 ℃, hatch balance 30 min altogether with PBS.Then frozen section and DHE dyestuff lucifuge are hatched 30 min.Under the lucifuge condition, clean slide 3 times, with PBS 5 min/ time.Dry, with the glycerin gelatine mounting, (LSM 710, Carl Zeiss, Germany) intensity of observation red fluorescence to move to laser confocal microscope immediately.Select 488 nm as exciting light, observe blood vessel elastic layer (Elastic Lamella) AF (green); Select Ex 546 nm simultaneously, Em 610 nm observe original position active oxygen (ROS) production (redness).Adopt the analysis of Zeiss Axiovert image analysis software respectively to organize the active oxygen production, mapping analysis result such as Fig. 7, wherein ###
P<0.001 the vs normal group, *
P<0.05 the vs model group, * *
P<0.01 the vs model group, * * *
P<0.001 vs model group.
Experimental result shows: ROS produces obviously in the ApoE knock out mice brachiocephalic trunk artery plaque that high cholesterol diet is fed increases; Tanshinone I I-A and atorvastatin can suppress the increase that ROS produces in dose dependent ground; And the inhibitory action of Tanshinone I I-A obviously is better than atorvastatin; Can work in coordination with the increase that suppresses ROS after the two medicine couplings, it is one of mechanism of working in coordination with that prompting suppresses original position ROS generation.
Claims (6)
1. a compositions is prevented and treated the purposes in the atherosclerosis medicine in preparation, it is characterized in that: said composition comprises Tanshinone I I-A and atorvastatin, and wherein the structural formula of Tanshinone I I-A is suc as formula I, and the structural formula of atorvastatin is suc as formula II:
2. purposes according to claim 1, the ratio of weight and number that it is characterized in that said Tanshinone I I-A and atorvastatin is 10: 2 ~ 10.
3. purposes according to claim 1 is characterized in that said Tanshinone I I-A is the activated monomer that separation and purification obtains from the natural Chinese medicine Radix Salviae Miltiorrhizae.
4. purposes according to claim 3 is characterized in that the method for the separation and purification of said Tanshinone I I-A is: get dry Radix Salviae Miltiorrhizae, with 95% ethanol extracting 3 times; Each 24 hours, add entry behind the extract concentrating under reduced pressure, divide 4 extractions with chloroform; The extract concentrating under reduced pressure, column chromatography for separation, silica gel is 100 ~ 200 orders; Eluent carries out gradient elution for containing the petrol ether/ethyl acetate mixed solution of 1 % ~ 10 % ethyl acetate, obtains Tanshinone I I-A activated monomer.
5. purposes according to claim 1 is characterized in that said compositions also comprises pharmaceutically acceptable adjuvant, and said adjuvant is one or more in emulsifying agent, solubilizing agent, excipient or the stabilizing agent.
6. purposes according to claim 1, the dosage form that it is characterized in that said compositions is injection, tablet, pill, capsule, solution, suspending agent or Emulsion.
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