CN101829218B - New medical application of fructus evodiae total alkaloid - Google Patents
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- CN101829218B CN101829218B CN2010101717386A CN201010171738A CN101829218B CN 101829218 B CN101829218 B CN 101829218B CN 2010101717386 A CN2010101717386 A CN 2010101717386A CN 201010171738 A CN201010171738 A CN 201010171738A CN 101829218 B CN101829218 B CN 101829218B
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Abstract
The invention relates to new medical application of a fructus evodiae total alkaloid, namely, the application of the fructus evodiae total alkaloid in the preparation of a medicament for preventing and treating hepatic fibrosis. The fructus evodiae total alkaloid is a general name of indole-quinoline and quinolone alkaloids extracted and separated from fructus evodiae, and the content of the total alkaloid is between 20 and 60 percent. The fructus evodiae total alkaloid shows a certain treating effect in a therapeutic action experiment on rat hepatic fibrosis induced by carbon tetrachloride and has an excellent clinical application prospect. The fructus evodiae total alkaloid has an exact anti-hepatic fibrosis function and can be combined with auxiliary materials for preparing an anti-hepatic fibrosis medicament.
Description
One, technical field
The present invention relates to the medicinal usage of active component in a kind of vegetable Chinese herbal medicine of extraction, the new medical usage of specifically a kind of Fructus Evodiae total alkaloids.
Two, background technology
Fructus Evodiae is the dry almost ripe fruit of rutaceae Fructus Evodiae Evodia rutaecarpa (Juss.) Benth., thin hair Fructus Evodiae Evodiarutarecarpa (Juss.) Benth.vat.bodinieri (Dode) Huang, Shi Hu Evodia rutaecarpa (Juss.) Benth.var.officinalia (Dode) Huang.Acrid in the mouth, hardship, hot in nature, slightly poisonous.Return liver, spleen, stomach, kidney channel.Have effects such as warming the liver and stomach, dispersing cold for relieving pain, sending down the abnormal ascending QI, dampness.Be distributed in provinces and regions such as Anhui, Zhejiang, Fujian, Hunan, Hubei, Guangdong, Guangxi, Yunnan, Guizhou.
At present, from the Fructus Evodiae fruit, isolated 100 surplus kind of chemical compound, comprise alkaloid, bitter principle, volatile oil, aminoacid etc.(1) alkaloid: be the main active component of Fructus Evodiae; Can be divided into indole quinoline alkaloid and quinolone alkaloid according to structure, the former mainly contains rutaecarpin, rutaecarpine, wuchuyine, Hydroxyevodiamine, dihydro rutaecarpine, nor-Fructus Evodiae amide, 14-formyl dihydro rutaecarpine etc.; The latter has evocarpine, dihydro evocarpine, 1-methyl-2-pentadecyl-4-quinolinones etc., and Fructus Evodiae total alkaloids has important medical value, and some is widely used clinical.(2) bitter principle class: comprise that mainly evodine, evodol, obacunone, limonin, evodine acetas, lattice sieve bitter principle are first-class, the bitter principle compounds can reduce gastric acid secretion, improve functions such as local blood circulation.(3) volatile oil: from Fructus Evodiae, isolate myrcene, limonene, caryophyllene, alloaromadendrene etc. through gas chromatogram.(4) aminoacid: 18 seed amino acids such as aspartic acid, tryptophan, threonine, serine.In addition, also contain a spot of flavone compound, steroidal class, fatty acid and trace element in the Fructus Evodiae.
Fructus Evodiae has multiple pharmacological activity, has higher medical value and application prospect.Data shows that the Fructus Evodiae alkaloid can strengthen crystal and stop the rich liquid protective effect dirty to guinea-pig heart, and has strong effect blood pressure lowering and vasodilator effect; Fructus Evodiae extract, rutaecarpin, obaculactone have good analgesic activity to rabbit; Fructus Evodiae decoct and water logging agent are inhibited to vibrio cholera, acrothesium floccosum and the dermatophytes of causing a disease etc.; Rutaecarpine has anti-platelet activity, suppress the formation of thromboxane, the motion of intracellular Ca2+ when suppressing platelet aggregation that agonist causes; The Fructus Evodiae water extract has antagonism to the isolated rat uterus by the contraction that 5-hydroxy tryptamine causes, its excited uterus composition is dehydroevodiamine, rutaecarpine and rutamine; Rutaecarpin also has the bronchoconstriction effect; Experiment shows that also the Fructus Evodiae alkaloid has significant cytotoxic activity to kinds of tumor cells in addition.
Hepatic fibrosis is that the common pathological of multiple chronic hepatopathy is basic, shows as fibrous connective tissue paraplasm in the liver, also is simultaneously the early stage only stage which must be passed by that reaches to the liver cirrhosis transformation of liver cirrhosis.Think on the etiology that the generation of hepatic fibrosis is the result of many different factor effects with development; Comprising chemicals and medicine (like ethanol, methotrexate, arsenide isoniazid, oxybenzene indole, methyldopa, polrvinyl chloride and thorium anhydride etc.), the various infection of liver (like virus, antibacterial, spirillum and parasitic infection) etc. all can be induced the improper deposition of exogenous and endogenous material in the liver.The existing all types of hepatopaths of China have reached more than 200,000,000 people; And hepatitis, fatty liver, alcoholic liver etc. all possibly cause the generation of hepatic fibrosis in interior most of hepatopathy; Bring huge misery not only for countless patients and family, also society is caused heavy financial burden.
In recent years, the synthetic regulation and control with degraded of pair cell epimatrix have had more understanding along with the understanding to the hepatic fibrosis mechanism deepens continuously particularly.People recognize gradually because the genesis mechanism of hepatic fibrosis is very complicated, are difficult to reach the purpose that suppresses hepatic fibrosis with the medicine of single action target spot.At present, the anti-hepatic fibrosis chemicals and the biological preparation that use clinically mainly contain following several types:
1, suppresses the liver inflammation: mainly contain colchicine, interferon, glucocorticoid, lamivudine, Malotilate, PGE, IL-10, specific receptor antagonistic (like IL-receptor antagonist, soluble TNF-α receptor) etc.
2, suppress hepatic stellate cell activation and propagation: the hepatic stellate cell activation is the key factor that hepatic fibrosis takes place; Activated hepatic stellate cell has propagation, fiber generates, causes functions such as inflammation and contraction; Therefore, suppress the activation of this kind cell and the Critical policies that propagation just becomes the inhibition hepatic fibrosis.At present, silibinin, phosphatidylcholine, vitamin E and S-ademetionine etc., in zoopery, all demonstrating has an inhibitory action to the activation of hepatic stellate cell and collagen are synthetic.
3, fibrosis cytokine: interleukin 10 can promote thymocyte cell and B cell proliferation, and in the rat liver fibrosis experiment of tetrachloro-methane induction, interleukin 10 can be blocked inflammatory reaction, promotes the dissolving of collagen, makes hepatic fibrosis take a turn for the worse.Hepatocyte growth factor can synthesize by cell cultured supernatant DNA, promotes hepatocyte growth, reduces hepatocellular necrosis and damage, and the stimulation that reduces inflammation suppresses even reverse the development of hepatic fibrosis.
4, induce the hepatic stellate cell apoptosis: data demonstration aspergillin and gliotoxin can be induced the hepatic stellate cell apoptosis in various degree, reduce the synthetic of collagen, thereby play the effect of blocking or delaying hepatic fibrosis.
5, promote extracellular matrix degradation: study comparatively sophisticated have unsaturated lecithin and relaxin; Experiment in vitro confirms that its unsaturated lecithin can suppress stellate cells and change fibroblast into; Thereby suppress the extracellular matrix secretion, impel the collagen decomposition that has formed.All can impel the synthetic minimizing of collagen during relaxin is tested in vivo and in vitro, extracellular matrix degradation increases.
Although research worker has been carried out deep research to the formation mechanism of hepatic fibrosis, up to the present, also lack determined curative effect, side reaction is little, toxicity is low anti-hepatic fibrosis Western medicine clinically.Because chemicals and the biological preparation all deficiencies in the anti-hepatic fibrosis treatment, domestic and international in recent decades research worker also is devoted to the Chinese medicine research of anti-hepatic fibrosis.The effective site of Chinese medicine, single preparation and compound recipe complicated component can carry out multi-faceted, many target treatments to hepatic fibrosis, demonstrate remarkable advantages than other drug.
Three, summary of the invention
The present invention aims to provide a kind of medicine of anti-hepatic fibrosis, and technical problem to be solved is in vegetable Chinese herbal medicine, to select determined curative effect, toxicity is low, side reaction is little active component.
Qi Hebin etc. think that based on Traditional Chinese medical theory the main diseases of hepatic fibrosis is invaded and positive QI-insufficiency because of being that epidemic disease caused by damp-heat pathogen is malicious; Liver blood stasis of blood resistance is its pathologic basis, and this disease belongs to the card of deficiency in origin and excess in superficiality, and sick position is liver, shows as wet, hot, malicious, the stasis of blood, void.The applicant combines secular Chinese herbal medicine basic research; Utilize attributes such as warming the liver that Fructus Evodiae has, cold expelling, pain relieving, sending down the abnormal ascending QI, dampness; Deep research has been carried out in the control hepatic fibrosis, and the result finds that Fructus Evodiae has excellent prevention and therapeutical effect, has good potential applicability in clinical practice.
The alleged new medical usage of Fructus Evodiae total alkaloids of the present invention is exactly the application of Fructus Evodiae total alkaloids in the preparation anti-hepatic fibrosis medicines.
Described Fructus Evodiae total alkaloids is in Fructus Evodiae, to extract, separate alkaloidal general names such as the indole quinolines that obtains and quinolones, in alkaloid, and total alkaloid content 20～60%.
The extraction of described Fructus Evodiae total alkaloids, separate as follows:
Get the Fructus Evodiae crude drug, the acidic ethanol reflux, extract,, extracting solution merges, resin column on the adjustment pH value behind the recovery section ethanol, 40-95% ethanol elution part is collected in the washing back, reclaims ethanol, and concentrating under reduced pressure, the extract that obtains after the drying promptly are Fructus Evodiae total alkaloids.Its main component total alkaloid content is in alkaloid 20～60%.
Total alkaloids can add pharmaceutically the corresponding adjuvant that allows, and processes tablet, capsule, slow releasing tablet, drop pill, electuary, microgranule, and is further purified and processes injection.
According to zooperal result, the clinical RD 300～1200mg/ of Fructus Evodiae total alkaloids days, oral, three times on the one.
The present invention has following advantage and effect:
1, the present invention has excavated the new prospect in medicine of Fructus Evodiae total alkaloids, has opened up a new medicinal field;
2, Fructus Evodiae total alkaloids of the present invention adopts oral administration, taking convenience, and toxic and side effects is little, takes medicine for a long time and does not have harm;
3, the former medicine resource of Fructus Evodiae total alkaloids of the present invention is very abundant, has good society and economic benefit;
4, Fructus Evodiae total alkaloids of the present invention is to the determined curative effect of hepatic fibrosis;
5, the present invention provides strong basis for Fructus Evodiae total alkaloids is developed further into new drug.
Four, description of drawings
Tried liver tissues of rats section light microscopic figure, wherein
Fig. 1 is 10 * 10 times of matched group (normal group) HE dyeing.
Fig. 2 is 10 * 10 times of model group HE dyeing.
Fig. 3 is Fructus Evodiae total alkaloids 100mgkg
-110 * 10 times of HE dyeing.
Fig. 4 is Fructus Evodiae total alkaloids 50mgkg
-110 * 10 times of HE dyeing.
Fig. 5 is 10 * 10 times of positive drug group HE dyeing.
Five, the specific embodiment
Below in conjunction with embodiment the present invention is done to describe further.
(1) preparation of Fructus Evodiae total alkaloids
Get Fructus Evodiae crude drug 6kg, with acidic ethanol reflux, extract, 4 times, each 1.5h; Extracting solution merges, cationic resin column on the adjustment pH to 2 behind the recovery section ethanol, and 80% ethanol elution part is collected in the washing back; Reclaim ethanol, concentrating under reduced pressure is drying to obtain Fructus Evodiae total alkaloids.In total alkaloids, alkaloid is 20～60%.
(2) zoopery
Experimental result is following:
1, experiment purpose:
Adopt volume fraction than being 40%CCl
4Salad oil solution gives rat back or the extremity injected prepares Liver Fibrosis Model, and test Fructus Evodiae total alkali is to the therapeutical effect of hepatic fibrosis.
2, receive the reagent thing:
Title: Fructus Evodiae total alkali
Source: Anhui Prov. Inst. of Pharmacology
Purity: total alkaloid content＞50%
Lot number: 20090121
Solution: dissolve with 5 ‰ CMC-Na solution suspendibles.
3, positive control drug:
Title: FUFANG BIEJIA RUANGAN PIAN
Source: the auspicious mongolian medicine of Inner Mongol good fortune Science and Technology Co., Ltd.
Lot number: 20080604
Specification: 0.5g/ grain
4, laboratory animal:
Strain: SD rat
Body weight: 180 ± 20g
Sex: female
Source: Medical University Of Anhui's Experimental Animal Center
The animal quality certification number: real moving accurate No. 01 of Anhui doctor
Every treated animal number: 12
5, experiment reagent:
CCl
4Solution: analytical pure, purity>=99.5%, chemical plant, Gansu Province, west, Shantou, Guangdong company limited
AST, ALT test kit: power Bioisystech Co., Ltd converges in Changchun
LN, HA and, the PCIII radioimmunological kit: Beijing China English biotechnology research institute
6, experimental technique:
The experiment establish the large and small dose groups of Fructus Evodiae total alkaloids (100,50mgkg
-1), model group, FUFANG BIEJIA RUANGAN PIAN group (600mg granule kg
-1) and matched group.
Adopt volume fraction than being 40%CCl
4Salad oil solution gives rat back or the extremity injected prepares Liver Fibrosis Model, 3mlkg
-1(initial dose doubles), a week 2 times, continuous 12 weeks; Normal group, subcutaneous injection equivalent salad oil; Positive drug with all dissolved by reagent with 5 ‰ CMC-Na solution suspendibles, every day, gastric infusion was 1 time, continuous 10 weeks.Normal group and model group give equivalent 5 ‰ CMC-Na solution.
Tested for 12 weekends (10 weeks of administration), 3.2% chloral hydrate (1ml100g
-1) the intraperitoneal injection of anesthesia rat, abdominal aortic blood is with 3500rmin
-1Centrifugal 10min gets supernatant and measures serum liver functional biochemistry index by the test kit explanation: AST and ALT active (reitman-frankel method); Hepatic fibrosis index: HA, LN, PC-III are put the method for exempting from and are measured.Put to death rat, claim liver, spleen weight in wet base, calculate liver, the heavy index of spleen.Perusal rat liver situation and scoring are got part lobus dexter liver with dipped into formalin, conventional dehydration, and FFPE, section, HE dyeing, light microscopic is observed down.
7, experimental result:
(1) Fructus Evodiae total alkaloids is to CCl
4The liver fibrosis due rats'liver is heavy, the heavy exponential influence of spleen
Administration 12 all model group rat body weights are starkly lower than normal group, and the heavy index of liver is significantly higher than normal group, heavy index of spleen and normal group no difference of science of statistics; Fructus Evodiae total alkaloids 100mgkg
-1The growth of group rat body weight is slightly faster than model group, and the heavy index of liver is starkly lower than model group (seeing table 1).
Table 1 Fructus Evodiae total alkaloids is to CCl
4The liver fibrosis due rats'liver is heavy, the heavy exponential influence of spleen
(2) Fructus Evodiae total alkaloids is to CCl
4The influence of liver fibrosis due rats'liver function
CCl
4During the modeling, model group rat blood serum ALT and AST are significantly higher than normal group (P＜0.01), prompting modeling success; During 2～10 weeks of administration, Fructus Evodiae total alkaloids high dose group ALT is the decline (P＜0.05～0.01) of carrying out property, and Fructus Evodiae low dose group and positive drug group are in 10 week of administration back ALT and all obviously decline (seeing table 2,3) of AST.
Table 2 Fructus Evodiae total alkaloids is to CCl
4The influence of liver fibrosis due rat blood serum ALT
Table 3 Fructus Evodiae total alkaloids is to CCl
4The influence of liver fibrosis due rat blood serum AST
(3) Fructus Evodiae total alkaloids is to CCl
4The influence of LN, HA and PCIII in the liver fibrosis due rat blood serum
Adopt CCl
4After 12 weeks of modeling, model group rat blood serum PCIII, HA and LN all are significantly higher than normal group (p＜0.01), and ECM deposits TAE 50,100mgkg in a large number in the prompting hepatic tissue
-1Group and above-mentioned three indexs of positive drug group are obviously decline (seeing table 4) all.
Table 4 Fructus Evodiae total alkaloids is to the influence of LN, HA and PCIII in the CCl4 liver fibrosis due rat blood serum
(4) Fructus Evodiae total alkaloids is to CCl
4The influence of liver fibrosis due rat histopathology
It is smooth to be observed visually the normal rats liver surface, and color and luster is scarlet; The model group rat liver is faint in color, yellow partially; Even liver surface is graininess or tiny nodositas; Perusal was equally divided into 2.8 fens; Fructus Evodiae total alkaloids high dose group rat liver perusal pathological changes situation is lighter than model group, is equally divided into 1.8 fens, and each is organized rat liver perusal scoring and sees table 5.
Table 5 Fructus Evodiae total alkaloids is to CCl
4The influence of liver fibrosis due rat histopathology
Standards of grading: 0 minute: smooth surface, color and luster is scarlet; 1 minute: liver surface was smooth, and color and luster is light red;
2 minutes: liver surface was smooth, yellow;
3 minutes: liver surface was still smooth, sight be graininess, color and luster is yellow;
4 minutes: liver surface was rough, and tiny tuberosity is arranged, and color and luster is yellow.
Om observation shows: normal rats lobules of liver structural integrity, and the portal area structure is normal, and sinus hepaticus is obvious, and hepatocyte is strand and distributes, marshalling, volume is normal, fat-free degeneration necrosis, NIP cellular infiltration.As shown in Figure 1.Model group lobules of liver structure disturbance, hepatocyte are swelling cavity appearance steatosis, and there is inflammatory cell infiltration the portal area, and collagen fiber extend in lobules of liver along the portal area and around the central vein, the crosslinked RF that is, and the part rat forms complete pseudolobuli.As shown in Figure 2.Fructus Evodiae high dose group rats'liver leaflet structure obviously improves, and collagen fiber reduce at interval, and hepatic necrosis, inflammatory cell infiltration are rare, and the portal area connective tissue proliferation alleviates.As shown in Figure 3.Fructus Evodiae low dose group and positive drug group hepatic tissue kitchen range property destruction, hepatocellular degeneration, hepatic fibrosis also alleviate than model group.As shown in Figure 4.Explain that Fructus Evodiae total alkaloids can effectively alleviate CCl
4Inductive rat liver fibrosis.General effect is superior to the positive drug group.
(3) Fructus Evodiae total alkaloids preparation processing
The preparation of Fructus Evodiae total alkali tablet:
Embodiment one:
Fructus Evodiae total alkali 100mg
Starch 100mg
Starch slurry (10%) is an amount of
Magnesium stearate 1%
Technology:
With principal agent and auxiliary materials and mixing, with the granulation of 10% starch slurry, dry, granulate, add the magnesium stearate mixing, tabletting promptly gets.
Two: 1000 of embodiment
Fructus Evodiae total alkali 100g
Starch 100g
Starch slurry (10%) is an amount of
Magnesium stearate 1%
Technology is the same.
Claims (1)
1. the application of Fructus Evodiae total alkaloids in the preparation anti-hepatic fibrosis medicines.
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| CN103083677B (en) * | 2012-11-30 | 2015-07-08 | 甘肃中医学院 | Permeation accelerator and application thereof to permeation acceleration |
| CN111686112A (en) * | 2020-07-23 | 2020-09-22 | 昆明医科大学第一附属医院 | Application of evodiamine in preparation of antiplatelet drugs |
| CN114917283A (en) * | 2022-05-26 | 2022-08-19 | 南京中医药大学 | Application of Chinese medicinal compound preparation in preparing medicine for treating hepatic fibrosis |
| CN115252630B (en) * | 2022-09-02 | 2024-02-09 | 深圳技术大学 | Application of phellodendron ketone in preparing medicine for preventing, improving or treating non-alcoholic fatty liver disease |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096681A (en) * | 1993-06-22 | 1994-12-28 | 张俊才 | Hepatosis treating medicine powder |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1096681A (en) * | 1993-06-22 | 1994-12-28 | 张俊才 | Hepatosis treating medicine powder |
Non-Patent Citations (1)
| Title |
|---|
| 田光辉等.吴茱萸果实中脂溶性成分的研究.《中药材》.2008,第31卷(第03期),382-385. * |
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