CN1426782A - Tanshinone 11A used in preparing medicine for preventing and treating atherosclerosis - Google Patents
Tanshinone 11A used in preparing medicine for preventing and treating atherosclerosis Download PDFInfo
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- CN1426782A CN1426782A CN 01130086 CN01130086A CN1426782A CN 1426782 A CN1426782 A CN 1426782A CN 01130086 CN01130086 CN 01130086 CN 01130086 A CN01130086 A CN 01130086A CN 1426782 A CN1426782 A CN 1426782A
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- 229930183118 Tanshinone Natural products 0.000 title claims abstract description 65
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- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 2
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- HYXITZLLTYIPOF-UHFFFAOYSA-N Tanshinone II Natural products O=C1C(=O)C2=C3CCCC(C)(C)C3=CC=C2C2=C1C(C)=CO2 HYXITZLLTYIPOF-UHFFFAOYSA-N 0.000 description 1
- KNDHRUPPBXRELB-UHFFFAOYSA-M [4-[3-(4-ethylphenyl)butyl]phenyl]-trimethylazanium;chloride Chemical compound [Cl-].C1=CC(CC)=CC=C1C(C)CCC1=CC=C([N+](C)(C)C)C=C1 KNDHRUPPBXRELB-UHFFFAOYSA-M 0.000 description 1
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- Medicines Containing Plant Substances (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
An application of tanshinone 11A to preparing the medicines for preventing and treating atherosclerosis and its related diseases is disclosed. The tanshinone 11A can reduce the deposit of cholesterol on the inner surface of artery.
Description
Technical field
The present invention relates to the new medical use of the tanshinone of single component in the Radix Salviae Miltiorrhizae extract.Be specifically related to tanshinone be used to prepare prevention and treatment atherosclerosis and with the purposes of atherosclerosis relevant disease medicine.
Technical background
Atherosclerosis is a kind of systemic disease relevant with lipidosis, and its lesion characteristic is the liposome in the blood, and particularly cholesterol wherein causes arteriosclerosis at arterial blood tube wall inner membrance formation of deposits atheromatous plaque.When atherosclerosis betides vitals such as the heart, brain, to cause that tissue ischemia sexually revises, cause serious consequence, for example angina pectoris, myocardial infarction, cerebral infarction, nephridial tissue infarction and artery of extremity gangrene etc., be commonly encountered diseases (pharmacology, Li Yuling chief editor, the People's Health Publisher of current serious harm human health, 2000, p82-88).
The atherosclerotic cause of disease is very complicated, and pathogenesis is not clear fully as yet yet.Clearly relevant with atherosclerosis factor comprises at present:
1. hyperlipidemia: owing to pathological changes or diet reason cause that blood fat is too high, particularly (it is maximum to contain cholesterol for low density lipoprotein, LDL LDL too high levels, and the lipoprotein molecule is less, easily intravasation wall inner membrance), cause the deposition of cholesterol easily at arterial blood tube wall inner membrance.
2. hypertension: vascular hypertension patient's blood vessel wall damages easily, helps lipoprotein intravasation wall inner membrance, causes the deposition of cholesterol at arterial blood tube wall inner membrance.
3. diabetes: hyperglycemia can cause hyperlipidemia, helps LDL intravasation wall inner membrance.
This shows hypercholesterolemia concentration and be to cause the atherosclerotic main cause of disease in the blood in arterial blood tube wall inner membrance deposition.If the atherosclerotic drug main of treatment reduces the concentration of cholesterol in the blood by the biosynthesis of cholesterol reducing or the decomposition of increased excretions of cholesterol at present.For example: the effect of lifibrate (Lifibrate) is reduce cholesterol synthetic, and the effect of simvastatin (Simvastatin) and cholestyramine resin (Colestyramine) is the decomposition that promotes cholesterol.If internal metabolism is movable to be realized because this class drug main is by influence, so pronounced side effects all arranged.And therapeutic effect is also undesirable, and general cholesterol reducing deposition is [medicine, Wang Rulong, former just flat chief editor, Chemical Industry Press, the third edition (1999), p544-559] below 30%.
Radix Salviae Miltiorrhizae is the dry root and rhizome of labiate Radix Salviae Miltiorrhizae (Salvia miltiorrhiza Bunge), the property hardship, is slightly cold GUIXIN, Liver Channel.As Chinese medicine, in clinical side's medicine, be widely used.Be mainly used in stasis-dispelling and pain-killing, promoting blood circulation to restore menstrual flow, relieving restlessness etc. clears away heart-fire.Tanshinone (tanshinone IIA) is one of Radix Salviae Miltiorrhizae main component [Okumura, Y., et al., Bull.Chem.Soc. (Japan) 1961,34,895].Up to the present, also do not prevent and treat atherosclerotic report about tanshinone with single component.
Summary of the invention
The purpose of this invention is to provide a kind of tanshinone or its pharmaceutical compositions as shown in Equation 1 and be used to prevent and treat the atherosclerosis that causes in the deposition of arterial blood tube wall inwall because of cholesterol in manufacturing, and with the medicine of atherosclerosis relevant disease in application.
The inventor finds after deliberation, the tanshinone that extracts from Radix Salviae Miltiorrhizae can enter in the blood, by with the competition effect of cholesterol, minimizing and removing cholesterol are in the deposition of blood vessel wall inner membrance, avoid forming atheromatous plaque, show that tanshinone has prevention and treatment atherosclerosis, reaches the good prospect with the atherosclerosis relevant disease.
The present invention has the mechanism of action that combines (deposition) site that can compete arterial blood tube wall inner membrance with cholesterol according to tanshinone, and it is used for preparation prevention and treatment atherosclerosis, reaches the newtype medicine with the atherosclerosis relevant disease.
The structure of the said tanshinone of the present invention is suc as formula shown in the I.
Formula I
We studies show that, tanshinone is in planform, physical property, aspects such as the character of water soluble group and hydrophobic group and the distribution in molecule and cholesterol have good similarity, by with the competition effect of cholesterol, minimizing and removing cholesterol avoid forming atheromatous plaque in the deposition of blood vessel wall inner membrance, reach prevention and treatment atherosclerosis and and atherosclerosis relevant disease purpose.
The said tanshinone of the present invention can extract from Radix Salviae Miltiorrhizae, makes through separation and purification.
The present invention tests by animal pharmacology, determine tanshinone can cholesterol reducing in the deposition of blood vessel wall inner membrance, avoid forming atheromatous plaque, demonstration can become be used to prevent and treat atherosclerosis and with the active drug of atherosclerosis relevant disease.
The present invention also provide a kind of be used for the prevention and treat atherosclerotic medicine, wherein contain the tanshinone shown in the formula I, and with pharmaceutically acceptable adjuvant.This medicine can be made into the form of injection, tablet, pill, capsule, solution, suspending agent, Emulsion.That the route of administration of this medicine can be is oral, percutaneous, vein or muscle.
The present invention tests by animal pharmacology, and the using dosage scope of determining tanshinone or its pharmaceutical compositions is 50-200mg (tanshinone)/kg (body weight)/sky.
The present invention tests by animal toxicology, determines that tanshinone has no side effect in the dose therapeutically effective scope, the medicine that can take for a long time.
The present invention will be further described by the following examples.Embodiment 1: the extraction of tanshinone, separation and purification in the Radix Salviae Miltiorrhizae
Dry Radix Salviae Miltiorrhizae 1kg, with 95% ethanol extracting 3 times, each 24 hours, extract was evaporated to 500mL, added 500mL water then, divide four extractions with the 1000mL 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 the 1%-10% ethyl acetate, carries out gradient elution.Can get the about 0.85g of tanshinone.Embodiment 2: tanshinone reduces the experiment of hyperlipemia animal model (rat) arterial blood tube wall inner membrance cholesterol deposits
Animal for research is 48 of bull rats (Sprague-Dawley), and body weight is 150-200g.Divide the normal control group, hyperlipidemia model control group, positive drug cholestyramine (500mg/kg) matched group, tanshinone high dose (300mg/kg), middle dosage (100mg/kg), low dosage (30mg/kg) administration group.Except that the normal control group, all the other each groups all adopt hypercholesterolemia and lipid forage feed, feed continuously 45 days.
Hypercholesterolemia and lipid feed formula: 3% cholesterol, 10% Adeps Sus domestica, 0.2% methylthiouracil and 88% normal feedstuff.
Arterial blood tube wall cholesterol level assay method: isopropyl alcohol extracting, high ferro-acetic acid-sulphuric acid development process.Experimental result sees Table 1.
Reduction rate computational methods in table 1 and following each table: reduction rate=[1-(treatment group concentration-normal control group concentration)/hyperlipidemia model control group concentration-normal control group concentration)] * 100%.
Table 1. tanshinone influences hyperlipidemia rats arterial blood tube wall cholesterol level
| Group | Ductus arteriosus wall cholesterol level (mg/g dry weight tissue) | Reduction rate (%) |
| The normal control group | ????2.4±1.1 | ??????--- |
| The hyperlipidemia model control group | ????8.9±2.7 | ??????--- |
| Positive drug cholestyramine matched group | ????6.6±2.1 | ??????35 |
| The tanshinone low dose group * | ????7.6±2.8 | ??????20 |
| Dosage group in the tanshinone | ????5.9±2.2 | ??????47 |
| The tanshinone high dose group | ????3.9±3.5 | ??????77* |
*High dose has certain influence to rat appetite, and determination data has than mistake.Embodiment 3: tanshinone is to the influence of hyperlipemia animal model (rat) serum cholesterol concentration
Animal for research is 48 of bull rats (Sprague-Dawley), and body weight is 150-200g.Divide the normal control group, hyperlipidemia model control group, positive drug cholestyramine (500mg/kg) matched group, tanshinone high dose (300mg/kg), middle dosage (100mg/kg), low dosage (30mg/kg) administration group.Except that the normal control group, all the other each groups all adopt hypercholesterolemia and lipid forage feed, feed continuously 45 days.
Hypercholesterolemia and lipid feed formula: 3% cholesterol, 10% Adeps Sus domestica, 0.2% methylthiouracil and 88% normal feedstuff.
Serum cholesterol content assay method: high ferro-acetic acid-sulphuric acid development process.Experimental result sees Table 2.
This experimental result shows that tanshinone does not influence the metabolism of cholesterol basically.Show that it is that promptly competition mechanism realizes by a kind of new mechanism of action that tanshinone reduces arterial blood tube wall inner membrance cholesterol deposits.
Table 2. tanshinone is to the influence of hyperlipidemia rats serum cholesterol concentration
| Group | Serum cholesterol concentration (mg/dL) | Reduction rate (%) |
| The normal control group | ????37.5±10.8 | ???????--- |
| The hyperlipidemia model control group | ????574.6±95.3 | ???????--- |
| Positive drug cholestyramine matched group | ????379.2±88.5 | ???????37 |
| The tanshinone low dose group | ????564.7±91.8 | Reduce not obvious |
| Dosage group in the tanshinone | ????552.8±84.6 | Reduce not obvious |
| The tanshinone high dose group | ????418.9±104.7 | ???????29* |
*High dose has certain influence to rat appetite, and determination data has than mistake.Embodiment 4: tanshinone reduces the experiment of hyperlipemia animal model (rabbit) arterial blood tube wall inner membrance cholesterol deposits
Animal for research is 36 of healthy regular grade new zealand rabbits, and male and female half and half, body weight are 2.0-2.5kg.Divide the normal control group, hyperlipidemia model control group, positive drug cholestyramine (500mg/kg) matched group, tanshinone high dose (300mg/kg), middle dosage (100mg/kg), low dosage (30mg/kg) administration group.Except that the normal control group, all the other each groups all adopt hypercholesterolemia and lipid forage feed, feed continuously 45 days.
Hypercholesterolemia and lipid feed formula: 3% cholesterol, 10% Adeps Sus domestica, 0.2% methylthiouracil and 88% normal feedstuff.
Arterial blood tube wall cholesterol level assay method: isopropyl alcohol extracting, high ferro-acetic acid-sulphuric acid development process.Experimental result sees Table 3.
Table 3. tanshinone influences hyperlipemia rabbit arterial blood tube wall cholesterol level
| Group | Ductus arteriosus wall cholesterol level (mg/g dry weight tissue) | Reduction rate (%) |
| The normal control group | ????1.8±0.7 | ???????--- |
| The hyperlipidemia model control group | ????7.2±2.3 | ???????--- |
| Positive drug cholestyramine matched group | ????5.1±1.8 | ???????39 |
| The tanshinone low dose group | ????6.0±3.1 | ???????33 |
| Dosage group in the tanshinone | ????3.8±2.0 | ???????63 |
| The tanshinone high dose group | ????3.3±1.6 | ???????73* |
*High dose has certain influence to rat appetite, and determination data has than mistake.Embodiment 5: tanshinone is to the influence of hyperlipemia animal model (rabbit) serum cholesterol concentration
Animal for research is 36 of healthy regular grade new zealand rabbits, and male and female half and half, body weight are 2.0-2.5kg.Divide the normal control group, hyperlipidemia model control group, positive drug cholestyramine (500mg/kg) matched group, tanshinone high dose (300mg/kg), middle dosage (100mg/kg), low dosage (30mg/kg) administration group.Except that the normal control group, all the other each groups all adopt hypercholesterolemia and lipid forage feed, feed continuously 45 days.Hypercholesterolemia and lipid feed formula: 3% cholesterol, 10% Adeps Sus domestica, 0.2% methylthiouracil and 88% normal feedstuff serum cholesterol content assay method: high ferro-acetic acid-sulphuric acid development process.Experimental result sees Table 4.
Table 4. tanshinone is to the influence of hyperlipemia rabbit anteserum cholesterol concentration
| Group | Serum cholesterol concentration (mg/dL) | Reduction rate (%) |
| The normal control group | ????107.5±34.2 | ??????--- |
| The hyperlipidemia model control group | ????724.3±124.5 | ??????--- |
| Positive drug cholestyramine matched group | ????478.0±120.5 | ???????40 |
| The tanshinone low dose group | ????674.6±104.6 | Reduce not obvious |
| Dosage group in the tanshinone | ????662.3±117.5 | Reduce not obvious |
| The tanshinone high dose group | ????644.2±112.7 | ??????13* |
*High dose has certain influence to rat appetite, and determination data has than mistake.
This experimental result shows that tanshinone does not influence the metabolism of cholesterol basically.Show that it is that promptly competition mechanism realizes by a kind of new mechanism of action that tanshinone reduces arterial blood tube wall inner membrance cholesterol deposits.Embodiment 6: the tanshinone toxicological test
Acute toxicity test in mice: animal for research is a healthy male mice.Adopt and irritate the stomach method test.Dosage does not find for the examination mice poisoning symptom and death are arranged during to 25g/kg yet.Test shows, cryptotanshinone LD
50＞25g/kg.
30 days toxicity tests of mice: animal for research is a healthy male mice.Adopt and irritate the stomach method test, dosage is 100mg/kg/day, continuous 30 days.Test shows, is tried Mus and does not have death, and growth promoter, hemopoietic function, biochemical indicator etc. all do not have tangible ANOMALOUS VARIATIONS or toxic reaction; The dissection inspection of important organ and organize microscopy not find pathological change.Embodiment 7: tanshinone enters the test of blood
Animal for research is healthy male rat.Adopt and irritate the stomach method test.Dosage is 100mg/kg/ days.Continuous 5 days.After administration in the 5th day 2 hours, put to death and get blood, use chloroform extraction, application HPLC can detect the significant quantity tanshinone.Practicality pharmaceutically
Above-mentioned experiment of the present invention shows: (1) tanshinone shows the experiment of hyperlipemia animal model arterial blood tube wall inner membrance cholesterol deposits influence, tanshinone can reduce and remove the deposition of cholesterol at arterial blood tube wall inner membrance, shows that tanshinone can effectively suppress cholesterol at arterial blood tube wall inner membrance formation of deposits speckle.(2) tanshinone shows that to the experiment of hyperlipemia animal model serum cholesterol concentration influence tanshinone does not influence the metabolism of cholesterol basically.Illustrate that it is that promptly competition mechanism realizes by a kind of new mechanism of action that tanshinone reduces arterial blood tube wall inner membrance cholesterol deposits.(3) use tanshinone shown in the formula 1 of the present invention, the using dosage scope is 50-200mg/kg body weight/day.(4) use tanshinone shown in the formula 1 of the present invention, under normal dose, it is safe as medicinal application.(5) compare with existing clinical treatment hyperlipidemia commonly used, it is better that chemical compound of the present invention has therapeutic effect, the littler and wider characteristics of range of application of side effect.(6) tanshinone shown in the formula I of the present invention can enter in the blood, by with the competition effect of cholesterol, reduce and remove the deposition of cholesterol at arterial blood tube wall inner membrance, avoid forming atheromatous plaque.Can be used for preparing prevention and treatment atherosclerosis and with the medicine of atherosclerosis relevant disease.
Claims (6)
1, the tanshinone shown in the formula I is used for prevention and treatment atherosclerosis in preparation, and with the medicine of atherosclerosis relevant disease in application.
Formula I
2. purposes according to claim 1 is characterized in that the tanshinone shown in the formula 1 is the chemical compound that separation and purification obtains from natural Radix Salviae Miltiorrhizae.
3. one kind is used for prevention and treats atherosclerotic medicine, wherein contains the tanshinone shown in the formula I of claim 1, and with pharmaceutically acceptable adjuvant.
4. medicine according to claim 3 is characterized in that described medicine is a form of making injection, tablet, pill, capsule, solution, suspending agent, Emulsion.
5. according to claim 3 or 4 described medicines, the route of administration that it is characterized in that described medicine is oral, percutaneous, vein or muscle.
6. according to claim 3 or 4 described medicines, the oral dose that it is characterized in that described medicine is the 50-200mg/kg body weight/day.
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| CN 01130086 CN1245970C (en) | 2001-12-17 | 2001-12-17 | Tanshinone 11A used in preparing medicine for preventing and treating atherosclerosis |
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| Application Number | Priority Date | Filing Date | Title |
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| CN 01130086 CN1245970C (en) | 2001-12-17 | 2001-12-17 | Tanshinone 11A used in preparing medicine for preventing and treating atherosclerosis |
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| Publication Number | Publication Date |
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| CN1426782A true CN1426782A (en) | 2003-07-02 |
| CN1245970C CN1245970C (en) | 2006-03-22 |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100362993C (en) * | 2005-01-07 | 2008-01-23 | 四川思达康药业有限公司 | Tanshinone emulsion and its making method |
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2001
- 2001-12-17 CN CN 01130086 patent/CN1245970C/en not_active Expired - Fee Related
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100362993C (en) * | 2005-01-07 | 2008-01-23 | 四川思达康药业有限公司 | Tanshinone emulsion and its making method |
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