CN103845340B - Alisol A 24-acetas prevents and treats the application in arterial disease medicine in preparation - Google Patents
Alisol A 24-acetas prevents and treats the application in arterial disease medicine in preparation Download PDFInfo
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- CN103845340B CN103845340B CN201210520840.1A CN201210520840A CN103845340B CN 103845340 B CN103845340 B CN 103845340B CN 201210520840 A CN201210520840 A CN 201210520840A CN 103845340 B CN103845340 B CN 103845340B
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Abstract
The invention discloses Alisol A 24-acetas and prevent and treat the application in arterial disease medicine in preparation, animal experiment proves, Alisol A 24-acetas is to ApoE-/-The Atherosclerosis Model that mice is caused through high lipid food nursing associating injury of carotid artery art has significant therapeutic effect, the medicine of the present invention, and toxicity is less, is suitable for long-term taking.The utilization modern medicine of the present invention is theoretical, it is provided that a kind of determined curative effect, definite ingredients, the atherosclerotic medicine of quality controllable treatment, it is possible to meet the needs of clinical practice.
Description
Technical field
The present invention relates to Alisol A 24-acetate at a kind of new opplication pharmaceutically.
Background technology
Cardiovascular disease has become as the number one killer threatening human health, and according to World Health Organization's report of 2004, the cause of the death just having an example in every three example death is cardiovascular disease, and atherosclerosis is the main cause of the cardiovascular event such as cerebral infarction, myocardial infarction.
Generation and the disappearing of promotion artery plaque of atherosclerosis are to reduce cardiovascular and cerebrovascular vessel morbidity example and the essential measure of mortality rate.At present, treat atherosclerotic medicine, such as atorvastatin, the clinical study results announced shows, atorvastatin is uniquely to be proved to reduce cardiovascular event to be better than the Antiatherosclerosis medicine of blood vessel double-fold eyelid operation, its to the inhibitory action of vascellum endometrial hyperplasia independent of effect for reducing blood fat outside, be antiatherogenic key agents.
Beijing College of Traditional Chinese Medicine's journal discloses entitled Rhizoma Alismatis anti-tremulous pulse medicated porridge induration series of studies (two) Rhizoma Alismatis to experimental rat, the effect for reducing blood fat of rabbit and suppression Atherosclerosis in Rabbits effect (the 6th phase of volume 14 in 1991), literary composition reports Rhizoma Alismatis crude extract (every 1ml contains Rhizoma Alismatis crude drug 4 grams), there is the nucleus formation of certain suppression Rabbit Aorta inner membrance speckle, but the concrete active component of test medicine is described in detail by Wen Zhongwei.Owing to the extract component difference that Chinese medicine ingredients is complicated, various extracting conditions obtains is huge, therefore have no way of knowing the active component suppressing aortic tunica intima speckle to generate in Rhizoma Alismatis from the document.
Blood lipid-lowering medicine is different according to the mechanism of action, is broadly divided into 1. HMG-CoA reductase inhibitor (Statins), 2. PPAR alpha activators (fibrates), 3. nicotinic acid class, the most alkenes (fish oil preparation) 5. Hongqu extract (Xuezhikang etc.).These medicine effect for reducing blood fat are clear and definite; but the function difference of its protection blood vessel endothelium, suppression aortic tunica intima hypertrophy is huge; even if being all statins antilipemic drugs, atorvastatin is uniquely to be proved to reduce cardiovascular event to be better than the blood lipid-lowering medicine of reconstructive vascular operation.And part blood lipid-lowering medicine to vascellum endometrial hyperplasia entirely without inhibitory action.It is thus impossible to the blood fat reducing characteristic of certain compound of direct basis infers that it has tunica intima protective effect and antiatherogenic function.
Alisol A 24-acetate (AlisolA24-acetate) is triterpenes components in Chinese medicine Rhizoma Alismatis, has had document report Alisol A 24-acetate to have diuresis, blood sugar lowering, treatment lithangiuria and blood fat reducing isoreactivity.But have no that Alisol A 24-acetate has atherosclerosis, the document of suppression vascellum endometrial hyperplasia effect is published.
Summary of the invention
It is an object of the invention to provide the application in preparing Antiatherosclerosis medicine of a kind of Alisol A 24-acetate, with the drawbacks described above overcoming prior art to exist, meet the needs of clinical practice.
The invention still further relates to a kind of pharmaceutical composition, including pharmaceutically acceptable carrier and the Alisol A 24-acetate of therapeutically effective amount, Alisol A 24-acetate can share to increase curative effect with other Antiatherosclerosis medicine.
In described pharmaceutical composition, the weight content of described A24-acetas is 1～99.9%, preferably 50% ~ 99.9%；
Described carrier includes filler, and such as starch, microcrystalline Cellulose or Icing Sugar, excipient, such as mannitol, lactose or calcium sulfate, disintegrating agent, such as carboxymethyl starch sodium, modified starch or low-substituted hydroxypropyl cellulose；Method well known in the art can be used, the preparation of described pharmaceutical composition is become oral formulations, such as tablet, hard capsule, soft capsule, drop pill or granule etc..
In the present invention, described Alisol A 24-acetate source can be to extract to obtain from Waterplantain plant, and preferably Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep. is more preferably the dry tuber of Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep..Additionally, Alisol A 24-acetate can be obtained by the method such as semi-synthetic and (or) complete synthesis；
Described extraction separation method can refer to the method that document Biological-ActiveTriterpenesofAlismatisRhizoma.I.Isolati onoftheAlisols [Chem.Pharm.Bull.18 (7) 1347-1353 (1970)] reports.
The chemical structure of general formula of described Alisol A 24-acetate is as follows:
Animal experiment proves, Alisol A 24-acetate is to ApoE-/-The Atherosclerosis Model that mice is caused through high lipid food nursing associating injury of carotid artery art has significant therapeutic effect, this medicine can be put on by oral route needs the patient for the treatment of, dosage is 20～550mg/ days people, specifically can determine by doctor according to the state of an illness of patient, age etc..
The medicine of the present invention, toxicity is less, is suitable for long-term taking.
The utilization modern medicine of the present invention is theoretical, it is provided that a kind of determined curative effect, definite ingredients, the atherosclerotic medicine of quality controllable treatment, it is possible to meet the needs of clinical practice.The creativeness of the present invention is: make public for the first time the ApoE that Alisol A 24-acetate suppression high fat diet causes-/-Vascellum endometrial hyperplasia effect after mouse carotid arterial injury, shows it to have significantly and treats Atherosclerosis.
Detailed description of the invention
Embodiment 1
The extraction of medical material:
Method 1: take the dry tuber 1 kilogram of Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep., make decoction pieces, with 7500ml ethyl acetate backflow extract 2 times, each 0.5 hour.United extraction liquid, decompression and solvent recovery, obtain dark brown extractum 40g.
Method 2: take the dry tuber 3 kilograms of Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep., be ground into coarse granule, by 75% ethanol seepage, merges effusion, decompression and solvent recovery, obtains dark brown extractum 110g.
Method 3: take the dry tuber 2 kilograms of Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep., be ground into coarse granule, be placed in CO2In supercritical extraction instrument, extraction conditions: CO2Pressure is 24～35MPa, and extraction temperature is 41～55 DEG C, and extraction time is 1.5h, obtains dark brown extractum 65g.
Method 4: take the dry tuber 1 kilogram of Notes On Alism At Aceae Rhizoma Alismatis Alismaorientalis (Sam.) Juzep., make decoction pieces, by 80% methanol 8000ml reflux, extract, 3 times, 1.0h every time, united extraction liquid liquid, decompression and solvent recovery, obtain dark brown extractum 50g.
Embodiment 2
The preparation of Alisol A 24-acetate:
Weigh embodiment 1 extractum 10g, upper D101 type macroporous adsorbent resin, after 10 column volumes of 20% ethanol elution, use 5 column volumes of 70% ethanol elution instead, collect 70% ethanol elution, decompression and solvent recovery, obtain yellow oil 2g；2g yellow oil is dissolved in 65% methanol, uses preparation scale HPLC isolating target compound.Separation condition is: C18 post, and flowing is 65% methanol mutually, and flow velocity is 50ml/min, detects wavelength 208nm.Obtaining purity is 95%(weight) Alisol A 24-acetate 100mg.
High resolution mass spectrum: m/z:555.36561, C32H52O6Na+[M+Na], its molecular formula is C32H52O6。
C13nullNMR (δ): 223.76、172.845、139.75、136.463、81.127、74.064、70.006、58.442、49.831、49.794、48.291、41.946、41.361、38.340、35.534、35.194、34.801、32.129、31.788、30.367、30.019、29.582、27.390、26.798、26.183、24.584、24.458、21.230、20.734、20.638、20.608，With the C of AlisolA24-acetate in document StabilityandStructureStudiesonAlisolA24-acetate [Chem.Pharm.Bull.56 (1) 41 45 (2008)]13NMR coincide, and determines that this compound is Alisol A 24-acetate.
Embodiment 3
Weigh Alisol A 24-acetate 10g in embodiment 2, add starch 8g, microcrystalline Cellulose 2g, magnesium stearate 0.2g, mix homogeneously, use method well known in the art, make tablet, capsule or granule.
Embodiment 4
Weighing embodiment 2 Alisol A 24-acetate 10g, be dissolved in 10ml ethanol, add hydroxypropyl methyl cellulose (HPMC) 4g, in water-bath, solvent is flung in stirring, and 60 DEG C of dry 2h in vacuum drying oven pulverize, and cross 20 mesh sieves, fill capsule, it is thus achieved that capsule.
Embodiment 5
Alisol A 24-acetate is referred to the condition isolated that document Biological-ActiveTriterpenesofAlismatisRhizoma.I.Isolati onoftheAlisols [Chem.Pharm.Bull.18 (7) 1347-1353 (1970)] reports.
I.e. Rhizoma Alismatis, extracts with methanol heat, adds water after solvent concentration, extracts with ethyl acetate, separating ethyl acetate layer, adds sodium bicarbonate, collects ethyl acetate layer, through activated carbon adsorption, upper silica gel column chromatography, obtains Alisol A 24-acetate after eluting.
Embodiment 6
The pharmacodynamic study of the present invention is as follows:
1, animal and packet: ApoE-/-Mice left carotid artery blood vessel is performed the operation, and damages 7 days and 28 days and is respectively divided into 7 groups: high fat diet operation group (VI group, n=10)
High fat diet operation+low concentration Alisol A 24-acetate group (prevention group gives to be administered 10mg/kg, n=10 during high fat diet)
High fat diet operation+middle concentration Alisol A 24-acetate group (prevention group gives to be administered 30mg/kg, n=10 during high fat diet)
High fat diet operation+high concentration Alisol A 24-acetate group (prevention group gives to be administered 90mg/kg, n=10 during high fat diet)
High fat diet operation+low concentration Alisol B monoacetate group (prevention group gives to be administered 10mg/kg, n=10 during high fat diet)
High fat diet operation+middle concentration Alisol B monoacetate group (prevention group gives to be administered 30mg/kg, n=10 during high fat diet)
High fat diet operation+high concentration Alisol B monoacetate group (prevention group gives to be administered 90mg/kg, n=10 during high fat diet)
High fat diet operation+atorvastatin group (prevention group gives to be administered during high fat diet, n=10)
High fat diet group feeding WesterntypeDiet formula forage (protein: 15.8%, fat: 40%, carbohydrate: 44.2%), low fat diet group feeding AIN-76A formula forage (protein: 18.8%, fat: 12.4%, carbohydrate: 68.8%).
2, the foundation of blood vessel injury disease model: first give mice DIFFERENT FEED (NPERC-8501vehicle, low, high) feeding 2 weeks, carry out VI Post operation according to packet and continue same forage feed and give variable concentrations respectively, after 7 days and 28 days, mice end end draws materials.Use 1% pentobarbital sodium, 90mg/kg anesthetized mice, after row heart left ventricle takes blood, isolate mouse carotid arteries, make the tissue specimen for paraffin detection, mouse model is evaluated.
3, the narrow change of vessel lumen is evaluated
Testing the 28th day, mice is put to death in excess anesthesia, from left ventricle opening blood-letting, take carotid artery row 4% paraformaldehyde fixing after, paraffin embedding, 5 μm sections, row HE dyeing display luminal stenosis situation.Using Image-proplus6.0 image analysis software to measure tunica intima, media thickness, calculate tunica intima/middle film ratio, to evaluate blood vessel injury post-surgical vascular luminal stenosis, a situation arises.
4, result
Mouse carotid endarterium/media area ratio the statistical result of each group is shown in Table 1.
Table 1, mouse carotid endarterium/media area ratio (χ ± SD)
Note: * represents and compares P < 0.05 with model control group;* represents and compares P < 0.01 with model control group;
# represents and compares P < 0.05 with model control group
As can be seen from Table 1, the mouse carotid endarterium of Alisol A 24-acetate administration group/media area ratio is significantly less than model control group, and in dose-effect relationship, even, its high dose group drug effect, due to positive control drug atorvastatin group, illustrates that its suppression arterial intima proliferative effect is notable；And the effect having no any suppression endarterium blood vessel hyperplasia of Alisol B monoacetate administration group.
Conclusion: Alisol A 24-acetate has the effect significantly suppressing arterial intima hypertrophy, shows that its study of anti-atherogenic effect is obvious, and the Alisol B monoacetate equally with effect for reducing blood fat shows the curative effect having no to suppress vascellum endometrial hyperplasia.
Claims (4)
1. Alisol A 24-acetate application in preparing Antiatherosclerosis medicine.
Application the most according to claim 1, it is characterised in that described medicine, including Alisol A 24 and the pharmaceutically acceptable carrier of therapeutically effective amount.
Application the most according to claim 2, it is characterised in that described medicine is oral formulations.
Application the most according to claim 3, it is characterised in that described medicine is tablet, hard capsule, soft capsule, drop pill or granule.
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| CN103845340B true CN103845340B (en) | 2016-08-03 |
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| CN104434930B (en) * | 2014-11-14 | 2017-06-09 | 南京中医药大学 | Composition comprising 24 acetylalisol A and 23 acetylalisol B and its in Adjust-blood lipid, the application prepared on HMG CoA inhibitor |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872252A (en) * | 2005-06-03 | 2006-12-06 | 江苏省药物研究所 | Composition of active ingredients of alisma rhizome, and medical application |
| CN101411711A (en) * | 2008-11-24 | 2009-04-22 | 上海现代药物制剂工程研究中心有限公司 | Composition containing alisol A and alisol A 24-acetic ester and use |
| CN101602787A (en) * | 2009-07-03 | 2009-12-16 | 中国科学院昆明植物研究所 | Alisol A derivative, its pharmaceutical composition and its production and use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1872252A (en) * | 2005-06-03 | 2006-12-06 | 江苏省药物研究所 | Composition of active ingredients of alisma rhizome, and medical application |
| CN101411711A (en) * | 2008-11-24 | 2009-04-22 | 上海现代药物制剂工程研究中心有限公司 | Composition containing alisol A and alisol A 24-acetic ester and use |
| CN101602787A (en) * | 2009-07-03 | 2009-12-16 | 中国科学院昆明植物研究所 | Alisol A derivative, its pharmaceutical composition and its production and use |
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