CN100528179C - Application of chrysanthemum indicum extract in the preparation of medicine for preventing and curing alcoholic liver disease - Google Patents
Application of chrysanthemum indicum extract in the preparation of medicine for preventing and curing alcoholic liver disease Download PDFInfo
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- CN100528179C CN100528179C CN 200710025576 CN200710025576A CN100528179C CN 100528179 C CN100528179 C CN 100528179C CN 200710025576 CN200710025576 CN 200710025576 CN 200710025576 A CN200710025576 A CN 200710025576A CN 100528179 C CN100528179 C CN 100528179C
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- liver
- liver disease
- chrysanthemum indicum
- indicum extract
- alcoholic
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Abstract
The present invention relates to a novel use of wild chrysanthemum ethanol extract, that is an application in the preparation of the drugs for the prevention and treatment of alcoholic liver disease. The present invention explores a new medical use of the wild chrysanthemum ethanol extract and also develops a new application field. The wild chrysanthemum ethanol extract can not only cure the symptoms, but can also cure the disease permanently, which is safe, non-toxic, strong in pharmacological effects and indicates the good medicinal prospect; the invention has rich sources of the raw materials, low price and mature preparation process, which can be made into various preparations for oral administration and is easy to use.
Description
Technical field
The present invention relates to the purposes of chrysanthemum indicum extract, relate in particular to the application of chrysanthemum indicum extract in the medicine of preparation control alcoholic liver disease.
Background technology
Flos Chrysanthemi Indici is the head inflorescence of feverfew Herba Dendranthematis indici Chrysanthemum indicum L..Spend in autumn, two seasons of winter and pluck when just open, dry or steam after dry and be used as medicine, be one of China's most of area Chinese herbal medicine commonly used among the people.Be distributed widely in ground such as China northeast, North China, northwest, East China, southwest, mainly be distributed in ground such as Wan Dong, Wan Nan in Anhui Province.Wild resource is abundanter, is born in stone matter hillside, meadow, limit, field, roadside etc. more and locates.
Flos Chrysanthemi Indici nature and flavor hardship, suffering are slightly cold, and return liver, heart channel, have dispelling wind and heat pathogens, subduing swelling and detoxicating, infection, antiviral effect, the furuncle carbuncle that cures mainly among the people, and conjunctival congestion and swelling pain, it is dizzy to have a headache.Clinically, Flos Chrysanthemi Indici is widely used in acute and chronic infectious diseases such as preventing cold, epidemic cerebrospinal meningitis, also is used for the treatment of carbuncle poison furuncle and phyma, hypertension and hyperlipemia, tumor etc.Domestic research is confined to the extraction and the evaluation aspect of Flos Chrysanthemi Indici chemical constituent more, and pharmacodynamic study also concentrates on antibiotic and the antiviral activity aspect.
The Flos Chrysanthemi Indici chemical constituent:
Chemical constituent is more in the Flos Chrysanthemi Indici, for example contains multiple compositions such as flavone compound, terpenoid, volatile oil, Palmic acid, polysaccharide, beta-carotene, protein, aminoacid, purine, choline, tannin, vitamin, chlorophyll.
Flavone compound is an active ingredient important in the Flos Chrysanthemi Indici, just isolates flavone compound sweet-scented osmanthus flavonoid glycoside (luteolin glucoside) as far back as the nineteen forty-two people from Flos Chrysanthemi Indici.Under country's great basic research early-stage Study special fund is subsidized, my school pharmaceutical college carries out extraction separation from Flos Chrysanthemi Indici, and select for use the inductive mice ear model of dimethylbenzene that several effective sites and dosage are carried out orthogonal design, through repeatedly experiment repeatedly, filter out anti-inflammatory activity position and dosage.And identify through crude drug teaching and research room of pharmaceutical college, determined that Flos Chrysanthemi Indici antiinflammatory effective site is chrysanthemum indicum extract, wherein general flavone content is up to more than 60%, thus be called again mother chrysanthemum total flavone (Total flavonoids ofChrysanthemum indicum, TFC).Learn that by thin layer chromatography, high performance liquid chromatography TFC mainly contains luteolin, linarin, luteolin-flavone compounds such as 7-glucoside.
Alcoholic liver disease and Drug therapy present situation thereof
Secular excessive drinking, can make hepatocyte that steatosis takes place repeatedly by ethanol itself and its derivant acetaldehyde, necrosis and regeneration, and cause alcoholic liver disease (Alcoholic liver disease, ALD), comprise alcoholic fatty liver (Alcoholic fatty liver), alcoholic hepatitis (Alcoholic hepatitis), hepatic fibrosis (Alcoholic fibrosis) and liver cirrhosis multiple performances such as (Alcoholic cirrhosis).Its histodiagnosis is divided into alcoholic fatty liver, alcoholic hepatitis, alcoholic fibrosis and alcoholic cirrhosis 4 types.In American-European countries, alcoholic liver disease is one of young and middle-aged main causes of death.The U.S. in 1993 has 1,530 ten thousand people excessive drinking approximately according to estimates, and the alcoholic liver patient has more than 200 ten thousand people, has every year 20000 6 thousand people to die from liver cirrhosis, and at least 40% perhaps reaches 90% patient the excessive drinking history.In China, along with living condition's improvement, alcoholic has the trend of increasing, and is although the incidence rate of alcoholic liver disease does not still have accurate statistics, much.Because domestic hepatopathy mainly causes by hepatitis virus, hepatitis virus carrier more may cover being actually the hepatopathy of ethanol as the cause of disease.Therefore the hepatic injury that correct understanding ethanol causes is in time diagnosed and control has great importance.
The treatment of alcoholic liver disease is primarily aimed at: (1) alleviates the severity of alcoholic liver disease; (2) prevention or reverse hepatic fibrosis; (3) improve already present secondary malnutrition; (4) treatment of alcoholic cirrhosis.In recent years, the medicine of treatment alcoholic liver disease has:
1. inflammatory reaction is arranged, swelling of liver cell necrosis and collagenation and deposition in the liver during glucocorticoid alcoholic liver disease; Evidence suggests that the initial sum development of alcoholic liver disease has immune factor to participate in.Glucocorticoid can suppress the lipoxygenase of arachidonic acid metabolic and the approach of cyclooxygenase, thereby suppresses the short inflammatory effect of leukotrienes and prostaglandin, can promote that still albumin is synthetic and stop type i collagen to generate.Therefore have the people to propose to can be used to treat alcoholic liver disease, but present many results of study are inconsistent.Many factors comprise sex, the hepatopathy severity, and renal function, different final results can be caused in nutritional status even region.It is generally acknowledged that hormone does not have positive effect to light medium-sized case, and only serious case could be benefited from hormone.Whether influential as for hormone to patient's long term survival rate, or whether the long-range hormone therapy can stop and develop into liver cirrhosis, still lacks research.
2. quiet of insulin and glucagon insulin and glucagon have certain curative effect to alcoholic liver disease, but should detect blood glucose in therapeutic process, prevent mortality hypoglycemia.
3. the curative effect of propylthiouracil propylthiouracil treatment is mainly seen in serious case, and is the less relatively person of ethanol amount.
4. antioxidant reduced glutathion, taurine, carotene, vitamin E, the r-Radix Oenotherae erythrosepalae, selenium organic compound etc. might reduce the hepatic fibrosis that oxidative stress infringement and lipid peroxidation are led to, and can remove the toxicity of exogenous noxious substance.
5. how unsaturated lecithin is the agent of hepatic sinusoidal endothelium regulating liver-QI cell membrane stability, can reduce lipid peroxidation, but because of being rich in unsaturated fatty acid, to can not abstainer Ying Shenyong.
6. lipid lowerers has objection, and need wait to explain.Many hypolipidemics may become to making blood fat more to concentrate on liver to carry out metabolism, impel lipid to store up on the contrary and damage liver function.
7. the Chinese medicine that suppresses hepatic fibrosis is with a long history at China's application blood-activating and stasis-removing treatment chronic hepatopathy, as Semen Persicae, and Radix Salviae Miltiorrhizae, Radix Angelicae Sinensis, tetrandrine, Radix Polygoni Multiflori, Fructus Crataegi, Rhizoma Curcumae Longae, Fructus Lycii, Rhizoma Chuanxiong, Rhizoma Alismatis, Radix Scutellariae, Rhizoma Polygonati, Radix Et Rhizoma Rhei etc. have the liver microcirculation of improvement respectively, prevent the hepatocellular degeneration necrosis, effects such as the generation of minimizing collagen fiber or enhancing collagenase activity help the treatment of alcoholic hepatitis hepatic fibrosis.
Summary of the invention
The object of the present invention is to provide the new purposes of chrysanthemum indicum extract, i.e. new application in pharmacy.
In fact, the present invention relates to the application of chrysanthemum indicum extract in the medicine of preparation control alcoholic liver disease.
The chrysanthemum indicum extract physical behavior: be the dark-brown powder, the easy moisture absorption, water solublity is relatively poor, is soluble in the lipotropy organic solvent, has peat-reek.
General flavone content is 50～65% (HPLC methods in the chrysanthemum indicum extract; Colorimetry).Also have in addition saponin (15～20%, colorimetry), caffeic acid (1～2%, HPLC) and chlorogenic acid (1～3%, HPLC).Chrysanthemum indicum extract obtains luteoloside, luteolin and linarin through further separating.Measure through the HPLC method, three kinds of content of flavonoids are respectively luteoloside (10～15%), luteolin (2～4%), linarin (8～12%).
Chrysanthemum indicum extract (TFC, 250,500mgkg
-1) can significantly reduce the MDA content that raises in TG, AST, ALT level and the liver homogenate that raises in the acute alcoholic liver disease mice serum (with model group relatively, p＜0.05), the activity that obviously improves SOD, GSH, GSH-Px in the liver homogenate (compares with model group, p＜0.05), TNF-α that remarkable inhibition alcoholic liver disease causes and the too high generation of IL-1 β (comparing p＜0.05) with model group; Simultaneously, and the results suggest TFC of histopathologic examination (250,500mgkg
-1) can obviously improve the liver fat denaturation degrees, alleviate the liver tissues inflammatory reaction.
In order to understand essence of the present invention better, will its new purposes in pharmaceutical field be described with the pharmacological testing and the result of chrysanthemum indicum extract below.
Chrysanthemum indicum extract is as follows to the preventive and therapeutic effect test of acute alcoholic liver disease:
(1) material
The animal Kunming mouse, male, body weight 22 ± 2g; Provide (the quality certification number: real moving accurate No. 02 of Anhui doctor) by Medical University Of Anhui's Experimental Animal Center.
Main medicine and reagent chrysanthemum indicum extract (TFC; self-control); tiopronin tablets (Xinyi Pharmaceutical Co., Ltd., Henan; lot number: 060716); dehydrated alcohol (Shanghai chemical reagent company limited; lot number: 200610206); ALT; AST measures test kit, and (bio-engineering research institute is built up in Nanjing; lot number: 20070118; 20070115); TG measures test kit (east, Zhejiang bowl biological engineering company limited; production number: AO-10017); SOD; MDA; (bio-engineering research institute is built up in Nanjing to the Coomassie brilliant blue protein determination kit; lot number: 20070123; 20070122; 20061010); GSH; GSH-Px measures test kit, and (bio-engineering research first branch is built up in Nanjing; lot number: 20070123; 20070122), TNF-α; IL-1 β radioimmunoassay determination box (Beijing North biotechnology research institute, lot number: 070120; 070120).
Key instrument BP211D electronic balance (German Saftarius produces), DL-5M low speed refrigerated centrifuge (Hunan, Changsha instrument centrifuge instrument company limited product), TGL-16H high speed centrifuge (Heima Medical Instrument Co., Ltd., Zhuhai City's product), 722S spectrophotometer (Shanghai exact science instrument company product), GSY-8 electric-heated thermostatic water bath (Beijing Medical Equipment Plant anticipates into company's product), Multiskan MK3 microplate reader (Dutch Lei Bo company product), SW-CJ-IF type superclean bench (SuZhou Antai Air Tech Co., Ltd. of Jiangsu Su Jing group product) etc.
(2) method
Model preparation, grouping and specimen are taked
Kunming mouse after normal one week of nursing,
, body weight 22 ± 2g is divided into 6 groups at random, 10 every group.If normal control group (Normal), model group (Model), TFC low dose group (125mgkg
-1), middle dosage group (250mgkg
-1), high dose group (500mgkg
-1) and tiopronin tablets (TP) positive controls (20mgkg
-1).
During experiment, irritate stomach (ig) administration (20mlkg according to body weight
-1), every day 1 time, continuous 7 days, irritate the stomach medicine with 5gL
-1Sodium carboxymethyl cellulose make suspension, irritate the decision of weighing before the stomach every day and irritate the stomach amount, model group and normal control group give the solvent of respective volume.6h begins fasting (can't help drink) before the last administration, 1h after the last administration, and except that normal control group mice ig respective volume normal saline, all the other respectively organize the disposable ig 50% ethanol 6gkg of mice
-1, behind continuation fasting (the can't help drink) 6h, the eyeball of mouse blood sampling, separation of serum is done index of correlation and is detected.Simultaneously, crane one and put to death animal, the taking-up liver is also weighed, and gets the fritter hepatic tissue of leftlobe of liver apart from edge 0.5cm place, row histopathologic examination, and conventional preparation liver homogenate.
Serum biochemistry index determining serum alanine aminotransferase (ALT), aspartate amino transferase (AST), triglyceride (TG) are measured and are pressed the test kit standard operation.
The same area that is determined at of liver biochemical indexes and cytokine is got liver and is accurately taken by weighing 0.5g, in frozen water, make 10% liver homogenate, 4 ℃ of centrifugal 10min of 3000rpm, extract supernatant, press kit method and measure superoxide dismutase (SOD), malonaldehyde (MDA), glutathion (GSH), glutathion peroxidase (GSH-Px) content, and measure tumor necrosis factor-alpha (TNF-α) and interleukin-1 ' beta ' (IL-1 β) content in the homogenate with radio immunoassay.
Liver organization pathological examination liver organization is fixed with 10% neutral formalin, and specimens paraffin embedding slices is carried out conventional H E dyeing, observes hepatic tissue steatosis and inflammation active situation under light microscopic.The alcoholic liver disease diagnostic criteria that the liver histological diagnostic criteria is worked out with reference to Chinese Medical Association's hepatology branch fatty liver and alcoholic liver disease group.
(3) result
1. chrysanthemum indicum extract is to the influence of acute alcoholic liver disease mice serum AST, ALT, TG level
By table 1 as seen, chrysanthemum indicum extract (TFC, 250,500mgkg
-1) can significantly reduce ALT, AST in the acute alcoholic liver disease mice serum, TG level, show that it has stable liver plasma membrane and mitochondrial membrane, improve the lipid metabolism of liver, reduce the absorption of liver, alleviate the cytotoxic effect of free fatty liver to lipid.
Table 1 chrysanthemum indicum extract to ethanol cause acute liver damage mice serum ALT, AST, TG influence (x ± s, n=10)
##Compare with normal group P＜0.01;
*P＜0.01,
*Compare with model group P＜0.05
2. chrysanthemum indicum extract is to the influence of alcoholic liver disease mouse liver even slurry SOD, MDA, GSH, GSH-Px content
By table 2,3 as seen, chrysanthemum indicum extract (TFC, 250,500mgkg
-1) can significantly reduce MDA content in the acute alcoholic liver disease mouse liver even slurry, improve SOD, GSH and GSH-in the liver homogenate
PXActivity, illustrate that chrysanthemum indicum extract may have certain inhibition peroxidating material and form and promote the effect that antioxidant generates, and can be by improving hepatic tissue SOD, GSH and GSH-Px vigor, the development of checking alcoholic fatty liver with lapse to.
Table 2 chrysanthemum indicum extract to ethanol cause acute liver damage murine liver tissue SOD, MDA influence (x ± s, n=10)
##Compare with normal group P＜0.01;
*P＜0.01,
*Compare with model group P＜0.05
Table 3 chrysanthemum indicum extract to ethanol cause acute liver damage mouse liver GSH, GSH-Px influence (x ± s, n=10)
##Compare with normal group P＜0.01;
*P＜0.01,
*Compare with model group P＜0.05
3. chrysanthemum indicum extract is to the influence of acute alcoholic liver disease mouse liver even slurry TNF-α and IL-1 β content
By table 4 as seen and normal group relatively, give ethanol (50%, 6mgkg
-1) after all murine liver tissue in TNF-α and IL-1 β content significantly raise, illustrate that under the stimulation of ethanol, the hepatic tissue of mice all has damage to a certain degree, cause a large amount of secretions of TNF-α and IL-1 β.And give chrysanthemum indicum extract (TFC, 250,500mgkg
-1) after, TNF-α, IL-1 β content significantly reduce in the hepatic tissue, and the regulating action of pointing out its pair cell factor may be the important mechanisms of its treatment alcoholic liver disease.
Table 4 chrysanthemum indicum extract to ethanol cause acute liver damage mouse liver TNF-α and IL-1 β influence (x ± s, n=10)
##P＜0.01,
#Compare with normal group P＜0.05
*P＜0.01,
*Compare with model group P＜0.05
4. chrysanthemum indicum extract is to the influence of acute alcoholic liver disease mouse liver histopathology variation
Histopathologic examination: normal group mouse liver cell form is normal, lobules of liver clear in structure, hepatic cords marshalling, the hepatocyte size is consistent, and karyon is placed in the middle, the kytoplasm pale red, be dispersed in fat in the visible minority of central vein district idol and drip, hepatic sinusoid is normal, does not have obvious degeneration, necrosis (Fig. 1).Typical fatty live lesions appears in the model group mice: the hepatic cords arrangement disorder, swelling of liver cell, being full of fat not of uniform size in the cell drips, piecemeal necrosis and the point-like that is dispersed in or the necrosis of kitchen range type appear in the lobule, there is cell infiltration the portal area, sinus hepaticus narrows down, and endochylema, karyon is light dyes, but does not see hepatic fibrosis (Fig. 2).Chrysanthemum indicum extract (TFC, 125mgkg-1) group acts on not obvious (Fig. 3) to alleviating of acute alcoholic liver disease model mice liver fat denaturation degrees regulating liver-QI tissue inflammation reaction, chrysanthemum indicum extract (TFC, 250mgkg-1,500mgkg-1) group obviously alleviates model mice liver fat denaturation degrees, the inflammatory reaction of hepatic tissue also significantly alleviates (Fig. 4, Fig. 5), positive control drug tiopronin tablets (TP) (20mgkg
-1) group also obviously alleviate model mice liver fat denaturation degrees, the inflammatory reaction of hepatic tissue also significantly alleviates (Fig. 6).
From above result, can draw beneficial effect of the present invention and be:
A, the present invention have excavated new medical application to chrysanthemum indicum extract, have opened up a new application.
B, chrysanthemum indicum extract of the present invention can take stopgap measures, can effect a permanent cure again, and safety non-toxic, pharmacological action is strong, is indicating well prospect in medicine.
C, abundant, inexpensive, the mature preparation process of chrysanthemum indicum extract raw material sources of the present invention can be made into various peroral dosage forms, and be easy to use.
D, chrysanthemum indicum extract of the present invention have good preventive and therapeutic effect to acute alcoholic liver disease, take medicine for a long time and do not have harm.
Description of drawings
Fig. 1 is normal group mouse liver cell form (HE * 200) figure,
Fig. 2 typical fatty live lesions (HE * 200) figure occurs for acute alcoholic liver disease model group mice,
Fig. 3 is acute alcoholic liver disease model mice+TFC 125mgkg
-1Medication group (HE * 200) figure,
Fig. 4 is acute alcoholic liver disease model mice+TFC 250mgkg
-1Medication group (HE * 200) figure,
Fig. 5 is acute alcoholic liver disease model mice+TFC 500mgkg
-1Medication group (HE * 200) figure,
Fig. 6 is acute alcoholic liver disease model mice+tiopronin tablets medication group (HE * 200) figure.
The specific embodiment
Below in conjunction with embodiment, the present invention is further described.
Embodiment:
Dry Flos Chrysanthemi Indici (5kg) is used 80% ethanol, 50L, reflux, extract, 2 times, each 3h, merge extractive liquid, reclaims solvent to not having alcohol flavor (10L), last AB-8 macroporous resin (5kg), use the 25L water elution, remove water-solubility impurity, reuse 50% ethanol 2L eluting merges alcohol eluen, reclaim solvent, get chrysanthemum indicum extract (500 ± 50g).General flavone content is 55% in the HPLC method mensuration chrysanthemum indicum extract; The colorimetric method for determining general flavone content is 65%.Also have in addition saponin (20%, colorimetry), caffeic acid (1.5%, HPLC) and chlorogenic acid (2.5%, HPLC).
Mother chrysanthemum total flavone obtains luteoloside, luteolin and linarin through further separating.Measure through the HPLC method, three kinds of content of flavonoids are respectively luteoloside (15%), luteolin (4%), linarin (12%).Above chemical compound is a flavone compound main in the chrysanthemum indicum extract.
Above chrysanthemum indicum extract faces with preceding and all is made into suspension with 0.5%CMC-Na, and used dosage all shows with the dry powder scale.
Chrysanthemum indicum extract is recommended clinical dosage: 62.5-125mg/ day, and oral, divide and take for three times.
Claims (1)
- The application of chrysanthemum indicum extract in pharmacy is characterized in that: the application of chrysanthemum indicum extract in the medicine of preparation control alcoholic liver disease.
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| CN102743424A (en) * | 2012-07-10 | 2012-10-24 | 郑州大学 | Flos chrysanthemi indici effective ingredient and application thereof |
| CN103301212A (en) * | 2013-07-10 | 2013-09-18 | 吴中区胥口精益生物医药研究所 | Liver cirrhosis resisting traditional Chinese medicine essence and extraction process thereof |
| CN112353792A (en) * | 2020-10-29 | 2021-02-12 | 南通大学 | Application of eupatilin in preparing medicament for preventing or treating alcoholic liver disease |
| CN114209728B (en) * | 2022-02-14 | 2023-08-25 | 郑州大学 | Wild chrysanthemum active site with function of regulating epigenetic expression balance and resisting liver cancer as well as preparation method and application thereof |
| CN114886906A (en) * | 2022-05-26 | 2022-08-12 | 广东药科大学 | Application of flavone glycoside composition in preparing medicament for preventing or treating lipid metabolism disorder diseases |
| CN116794330B (en) * | 2023-08-25 | 2023-11-14 | 中国人民解放军总医院第一医学中心 | Biomarker for diagnosing alcoholic liver disease and application thereof |
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