CN102462772A - Application of extract of total glucosides of picrorhiza in preparing medicines for preventing and treating fatty liver - Google Patents
Application of extract of total glucosides of picrorhiza in preparing medicines for preventing and treating fatty liver Download PDFInfo
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- CN102462772A CN102462772A CN2010105436451A CN201010543645A CN102462772A CN 102462772 A CN102462772 A CN 102462772A CN 2010105436451 A CN2010105436451 A CN 2010105436451A CN 201010543645 A CN201010543645 A CN 201010543645A CN 102462772 A CN102462772 A CN 102462772A
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- fatty liver
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- fatty
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- DHRLEVQXOMLTIM-UHFFFAOYSA-N phosphoric acid;trioxomolybdenum Chemical compound O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.O=[Mo](=O)=O.OP(O)(O)=O DHRLEVQXOMLTIM-UHFFFAOYSA-N 0.000 description 1
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- 210000001995 reticulocyte Anatomy 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 231100000161 signs of toxicity Toxicity 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
The invention provides an application of an extract of total glucosides of picrorhiza in preparing medicines for preventing and/or treating fatty liver and other related diseases. A preparation method of the extract of total glucosides of picrorhiza comprises the following steps: extracting picrorhiza by using a C1-C5 fatty alcohol solution having a concentration of 0-95 (v/v), removing C1-C5 fatty alcohol from the extracting solution, and then filtering; letting the filtrate pass through macroporous adsorption resin, and eluting the filtrate by using a C1-C5 fatty alcohol solution having a concentration of 0-30 (v/v), and discarding the eluent; eluting by using a C1-C5 fatty alcohol solution having a concentration of 40-100 (v/v), and removing the solvent in the eluent. The extract of total glucosides of picrorhiza prepared by the invention can be prepared into medicines for preventing and/or treating alcoholic and non-alcoholic fatty liver, acute fatty liver or chronic fatty liver, and further can prevent the formation of hepatic fibrosis.
Description
Technical field
The invention belongs to the field of Chinese medicines, relate to a kind of purposes of picrorhiza rhizome total glycoside extract, be specifically related to a kind of picrorhiza rhizome total glycoside extract is used for preventing and/or treating the fatty liver medicine in preparation purposes.
Background technology
Liver is lipometabolic vitals.Under the normal condition, fat weight accounts for 3%～5% of liver gross weight, and the every 100g liver of normal person weight in wet base contains 4～5g lipid, and wherein phospholipid accounts for more than 50%, and triglyceride accounts for 20%, and free fatty accounts for 20%, and cholesterol is about 7%, and all the other are cholesterol ester etc.When the hepatocyte inner lipid is accumulated above 5% of liver weight in wet base, or the histology is called fatty liver when going up the above liver parenchyma fatization of per unit area visible 1/3.The pathogenesis of fatty liver is not clear and definite fully as yet so far, it is generally acknowledged that the imbalance between hepatocyte synthetic glycerine three esters and the secretion low density lipoprotein, LDL is the main cause that forms fatty liver.
Fatty liver is the No.1 killer who destroys liver function; So far still disable and the dead primary cause of disease for developed country's hepatopathys such as America and Europes; Also become first hepatopathy, the patient is up to about 100,012,000, and it is as a kind of global commonly encountered diseases, frequently-occurring disease; Physical and mental health and quality of life that serious harm is human, and influence people and bring into play work efficiency.
Clinical emergency degree according to morbidity is divided into acute and chronic two big types with fatty liver.Acute fatty liver is shown in drug intoxication, late trimester of pregnancy, Reye syndrome etc., and its clinical manifestation and prognosis are similar to acute or subacute severe viral hepatitis, if sequela is not in time generally stayed in treatment; The formation of chronic fatty liver is general relevant with metabolism syndrome (diabetes, hyperlipemia and obesity etc.) with ethanol, therefore can be divided into alcoholic fatty liver and non-alcoholic fatty liver disease again.
Previously think that fatty liver is merely benign lesion, make slow progress or do not make progress.But discovering in recent years, the sickness rate of fat hepatitis is about 40% among the alcohol fatty hepatopath, the sickness rate of fatty cirrhosis reaches more than 50%; In addition, 20% non-alcoholic fatty liver disease develops into the fatty liver fibrosis, and then worsens and to be liver cirrhosis, and it is diseases related that wherein 30%～40% patient dies from these livers, and subacute liver failure and hepatocellular carcinoma take place part.
At present, still there is not the specific medicament of special for treating fatty liver both at home and abroad, many clinically employing blood fat reducing class medicines and the medication combined medication of type of protecting the liver.Mostly these medicines are to work to the pathogeny of certain link of fatty liver or part, lack the specificity of treatment fatty liver.Though some lipid regulating agent has short term efficacy to fatty liver, influences liver function, make blood fat more concentrate on liver and carry out metabolism, increase burden of liver, take for a long time and have potential liver toxicity, the state of an illness that on the contrary can the weight fat liver.In view of the specific medicament that lacks the treatment fatty liver, therefore from Chinese medicine, seeking new fatty liver medicine has become one of focus of study of tcm new drug in recent years.
The Chinese medicine Rhizoma Picrorhizae is the dry rhizome of Scrophulariaceae (Scrophulariaceae) Rhizoma Picrorhizae (Picrorhiza scrophulariiflora Pennell).Chemical research to Rhizoma Picrorhizae finds that Rhizoma Picrorhizae mainly contains iridoids, phenolic glycoside class, organic aromatic acid constituents.Pharmacology and clinical research show, Rhizoma Picrorhizae with the iridoids be main glycoside composition have clear and definite protect the liver, the anti-liver injury effect.In recent years research shows that also Picroside II Amphicoside 6-Vanilloylcatalpol can be through improving liver function, suppress lipid peroxidation, reducing the formation that TGF-β 1 and type i collagen mRNA and protein expression suppress hepatic fibrosis.
Summary of the invention
Therefore, the objective of the invention is to provide a kind of newtype drug of effective treatment fatty liver based on the Chinese medicine picrorhiza rhizome total glycoside extract.
Be used to realize that the technical scheme of above-mentioned purpose is following:
A kind of picrorhiza rhizome total glycoside extract is used for preventing and/or treating the purposes of fatty liver or its relevant disease medicine in preparation, and the method for preparing of wherein said picrorhiza rhizome total glycoside extract may further comprise the steps:
(1) with concentration is the C of 0～95% (volume)
1-C
5Fatty alcohol aqueous solution extracts Rhizoma Picrorhizae, removes the C in the extracting solution
1-C
5The aliphatic alcohol after-filtration;
(2) filtrating is the C of 0～30% (volume) through macroporous adsorbent resin and with concentration
1-C
5The fatty alcohol aqueous solution eluting, eluent discards;
(3) with concentration be the C of 40～100% (volume)
1-C
5The fatty alcohol aqueous solution eluting is removed the solvent in the eluent.
In such use, preferably, the C that adopts in the step (1)
1-C
5The concentration of fatty alcohol aqueous solution is 0～30% (volume).Preferably, the C that adopts in the step (2)
1-C
5Fatty alcohol aqueous solution is 0～20% (volume).Preferably, the C that adopts in the step (3)
1-C
5Fatty alcohol aqueous solution is 40～60% (volume).
In such use, macroporous adsorbent resin can be selected from one or more in styrene, divinylbenzene, acrylic ester and methacrylate type polarity or the nonpolar macroporous adsorption resin.
In such use, the method for extraction can be selected from one or more in percolation, backflow and the immersion, is preferably percolation.
In such use; Gross weight by picrorhiza rhizome total glycoside extract; In the said picrorhiza rhizome total glycoside extract; The content of Rhizoma Picrorhizae total glucosides is not less than 60% (w/w), and the content of picroside is not less than 21% (w/w), and the content of picroside is not less than 13% (w/w).Preferably, said picrorhiza rhizome total glycoside extract also comprises picroside III, kutkin I V, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
In such use, medicine can be peroral dosage form or injection type.Peroral dosage form can be tablet, pill, capsule, granule or oral liquid.Injection type can be aqueous injection or injectable powder.
In such use, fatty liver can be alcoholic fatty liver or non-alcoholic fatty liver disease; Also can be acute fatty liver or chronic fatty liver.The relevant disease of fatty liver is specially the hepatic fibrosis that fatty liver causes.
The present invention finds that after deliberation Rhizoma Picrorhizae total glucosides content wherein is rich in effective ingredient such as iridoids up to more than 60% (w/w) in the picrorhiza rhizome total glycoside extract that method for distilling of the present invention makes.Adopt the research of acute and chronic fatty liver model to show, this picrorhiza rhizome total glycoside extract has liver heat removing fat, blood fat reducing, transaminase lowering, removing free radical, anti peroxidation of lipid, enhance immunity, liver-protective effect.Therefore, can process medicine, be used to prevent and/or treat treatment ethanol property and non-alcoholic fatty liver disease, and acute fatty liver or chronic fatty liver, and then prevent the formation of hepatic fibrosis with the picrorhiza rhizome total glycoside extract of method for distilling of the present invention preparation.
Compared with prior art, there is following beneficial effect at least in the present invention:
1, the present invention adopts water or low alcohol extraction, and adopts Amberlyst process to carry out purification, and the composition of the total glycosides extractive that obtains and content are different with prior art; In the picrorhiza rhizome total glycoside extract of the present invention; Total glycosides content >=60% (w/w), picroside >=21% (w/w), picroside >=13% (w/w); In addition, also contain picroside III, kutkin I V, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol; Prior art is mainly the picrorhiza iridoid total glycosides extractive, and wherein, picroside and picroside HPLC content amount to >=20% (w/w);
2, the origin cause of formation of liver fat bulk deposition comprises that the output of liver fat output relative deficiency regulating liver-QI fat is absolute not enough in the fatty liver.Liver fat output relative deficiency is to be increased or liver self synthetic fatty acid increases, quickens due to the synthetic TG of liver by fatty acid in the blood that gets into liver, the chronic fatty liver model that brings out of employing high lipid food usually in the drug efficacy study; Compared with prior art, the present invention carries out the drug efficacy study picrorhiza rhizome total glycoside extract except selecting above-mentioned model, and also to another origin cause of formation of fatty liver, i.e. liver fat output is absolute not enough, has designed acute fatty liver model and CCl that ethionine brings out
4Fatty liver/the Liver Fibrosis Model of bringing out has reflected respectively that liver VLDL is synthetic, paracrisis and fatty liver oxidation suppress.The multiple origin cause of formation according to pathogenesis of fatty liver has designed several animal models, thus integrated survey the therapeutical effect of picrorhiza rhizome total glycoside extract to fatty liver.
3, the present invention is in the chmice acute fatty liver model that ethionine brings out, and continuous 3 filling stomaches give picrorhiza rhizome total glycoside extract 15,30,60mg/kg; Other test dosages 20,40,80mg/kg, the onset dosage of the rat of picrorhiza rhizome total glycoside extract treatment fatty liver is 20mg/kg/ days, effective dosage ranges is 40～80mg/kg/ days.
Although have in 4 prior aries Rhizoma Picrorhizae extract is used to treat and the report of prevention of liver disease; But wherein the composition of Rhizoma Picrorhizae extract is different with the present invention with content; And because the kind of hepatopathy is a lot, and the formation mechanism difference of different hepatopathys is very big, the hepatopathy that forms mechanism for difference needs specific aim to use different drug; The present invention is through discover in a large number, and the Rhizoma Picrorhizae extract of the specific composition of the present invention's preparation has better effect in the treatment fatty liver.
The specific embodiment
Below in conjunction with the specific embodiment the present invention is further described in detail, the embodiment that provides has been merely and has illustrated the present invention, rather than in order to limit scope of the present invention.
Embodiment 1
20 kilograms of Rhizoma Picrorhizae pulverizing medicinal materials are become coarse powder, steeped 2 hours with the 60L water logging, the percolator of packing into the water percolation, is collected the 240L percolate, is concentrated into the concentrated solution that is equivalent to 1g medical material/mL.Through the D101 macroporous adsorbent resin, with the washing decontamination, again with 60% (volume) ethanol water eluting; Concentrate eluant, drying under reduced pressure make 2.8 kilograms of picrorhiza rhizome total glycoside extracts, and wherein total glycosides content reaches 70% (w/w); Picroside is 22.5% (w/w); Picroside is 13.9% (w/w), in addition, also contains picroside III, picroside IV, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
Get 1.2 kilograms of above-mentioned picrorhiza rhizome total glycoside extracts, add 1.6 kilograms of starch, microcrystalline Cellulose 400g granulates, and encapsulated, every contains total glycosides 30mg.
Embodiment 2
20 kilograms of Rhizoma Picrorhizae pulverizing medicinal materials are become coarse powder; 30% (volume) ethanol water with 60L soaked 12 hours, and the percolator of packing into is with 30% (volume) ethanol water percolation; Collect the 240L percolate, be concentrated into the concentrated solution that is equivalent to 1g medical material/mL.Through the AB-8 macroporous adsorbent resin, with the washing decontamination, again with 50% (volume) ethanol water eluting; Concentrate eluant, drying under reduced pressure make 2.6 kilograms of picrorhiza rhizome total glycoside extracts, and wherein total glycosides content reaches 75% (w/w); Picroside is 22.8% (w/w); Picroside is 14.6% (w/w), in addition, also contains picroside III, picroside IV, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
Get 1.1 kilograms of above-mentioned picrorhiza rhizome total glycoside extracts, add 1.6 kilograms of starch, microcrystalline Cellulose 400g granulates, tabletting, and every contains total glycosides 30mg.
Embodiment 3
20 kilograms of Rhizoma Picrorhizae pulverizing medicinal materials are become coarse powder, reflux 3 times with 20% (volume) ethanol water of 60L, each 2 hours, each 80L, merge extractive liquid, is concentrated into the concentrated solution that is equivalent to 1g medical material/mL.Through the HPD100 macroporous adsorbent resin; With water and 20% (volume) ethanol aqueous wash decontamination, again with 40% (volume) ethanol water eluting, concentrate eluant; Drying under reduced pressure makes 3 kilograms of picrorhiza rhizome total glycoside extracts, and wherein total glycosides content reaches 60% (w/w).Picroside is 21.6% (w/w), and picroside is 13.5% (w/w), in addition, also contains picroside III, picroside IV, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
Embodiment 4
20 kilograms of Rhizoma Picrorhizae pulverizing medicinal materials are become coarse powder, soaked 24 hours with 10% (volume) ethanol water of 240L, the concentrating under reduced pressure soak is to 1g medical material/mL.Through the NKA macroporous adsorbent resin, with 10% (volume) ethanol aqueous wash decontamination, again with 50% (volume) ethanol water eluting; Concentrate eluant, drying under reduced pressure make 1 kilogram of picrorhiza rhizome total glycoside extract, and wherein total glycosides content reaches 65% (w/w); Picroside is 21.9% (w/w); Picroside is 13.7% (w/w), in addition, also contains picroside III, picroside IV, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
Test Example
The purpose of test is to verify the effect of picrorhiza rhizome total glycoside extract in preventing and/or treating fatty liver.For therapeutic effect and the safety that proves picrorhiza rhizome total glycoside extract of the present invention, its pharmacodynamics, pharmacology, toxicologic study process and result are following:
One, Pharmacodynamic test of active extract
1. the influence of the acute fatty liver model that ethionine is brought out
70 of ICR mices, male, body weight 20.3 ± 1.2 (18.2～22.5) g is divided into 7 groups at random, 10 every group.Adopt ethionine to prepare the acute fatty liver model, ethionine can suppress the synthetic apolipoprotein of liver, obstacle occurs thereby make triglyceride in the lipid metabolism (TG) transport liver, causes TG to accumulate in liver and forms fatty liver.Behind the mice overnight fasting, except that the normal control group was irritated the clothes distilled water, all the other each groups were irritated clothes DL-ethionine (250mg/kg; 20mL/kg) modeling; Behind the 1h, normal control group and model control group are irritated clothes 0.5% (g/ml) CMC, receive the reagent group to irritate the picrorhiza rhizome total glycoside extract of clothes embodiment 1 preparation; Dosage is respectively 15,30,60mg/kg/ time; The positive drug group is irritated clothes strong liver granule or tiopronin tablets respectively, and dosage is respectively 1700,100mg/kg/ time (all be equivalent to clinical consumption per day 3 times), and the administration volume is 10ml/kg.Administration every day 2 times, administration is 3 times altogether.1h puts to death mice after the last administration, wins liver, takes by weighing lobus sinister edge 200mg; Grind preparation homogenate with 2ml acetone-alcohol mixeding liquid (volume ratio=1: 1); The extracting lipid, centrifugal after, get supernatant with colorimetric method for determining triglyceride (TG), T-CHOL (TC).The result is as shown in table 1.
Table 1 picrorhiza rhizome total glycoside extract is to the influence
of liver TG, TC
Annotate: 1. compare with normal group,
△ △P＜0.01,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Conclusion; In the chmice acute fatty liver model that ethionine brings out; After continuous 3 filling stomaches give picrorhiza rhizome total glycoside extract 15,30,60mg/kg treatment; Can significantly reduce liver TG, the TG that liver is raise descended respectively 15.7% (P＞0.05), 24.7% (P＜0.05), 29.6% (P＜0.01).Picrorhiza rhizome total glycoside extract 15mg/kg is suitable with the effect of strong liver granule 1700mg/kg; Picrorhiza rhizome total glycoside extract 30mg/kg and Kai Xi come the effect of 100mg/kg suitable.
2. the influence of the chronic fatty liver model that high lipid food is brought out
70 of SD rats, male, body weight 211 ± 5 (202～221) g.Except that the normal control group is fed the normal diet, all the other rats high lipid food of feeding prepares chronic fatty liver model.Through the acid of a large amount of absorption ectogenous fat the fatty acid that gets into liver is increased, cause that the slow fat of hepatocyte becomes, the final formation fatty liver model similar with the fatty liver due to the clinical hyperlipoproteinemia.The high lipid food prescription is 5% (w/w) Adeps Sus domestica, 2% (w/w) cholesterol, 0.5% (w/w) cholate, 0.2% (w/w) methylthiouracil and 92.3% (w/w) normal diet.After 8 weeks of moulding, animal pattern is divided into 6 groups at random, 10 every group.Begin administration subsequently, normal control group and model control group are irritated clothes 0.5% (g/ml) CMC; Receive the reagent group to irritate the picrorhiza rhizome total glycoside extract of clothes embodiment 1 preparation, dosage is respectively 20,40,80mg/kg; The positive drug group is irritated stomach respectively and is given strong liver granule or tiopronin tablets, and dosage is respectively 2300,140mg/kg (all be equivalent to clinical dosage 3 times), and the administration volume is 5ml/kg.Administration every day 1 time, administration is 30 days altogether.
1h animal eye socket is got blood 1ml after reaching the last administration before the administration, and preparation serum is measured serum triglycerides (TG), T-CHOL (TC), HDL-C (HDL-C), low-density lipoprotein cholesterol (LDL-C).The result is shown in table 2 and table 3.
Put to death animal, win liver, take by weighing lobus sinister edge 200mg, grind preparation homogenate with 2ml acetone-alcohol mixeding liquid (volume ratio=1: 1), the extracting lipid, centrifugal after, get supernatant with colorimetric method for determining TG, TC.The result is as shown in table 4.
Table 2 picrorhiza rhizome total glycoside extract is to the influence
of serum TG, TC
Annotate: 1. compare with normal group,
△ △P＜0.01;
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05;
*P＜0.01.
Table 4 picrorhiza rhizome total glycoside extract is to the influence
of liver TG, TC
Annotate: 1. compare with normal group,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05.
Conclusion: the chronic fatty liver rat model that the high lipid food of feeding brings out can effectively be removed in the liver in 30 days and the fat in the blood through picrorhiza rhizome total glycoside extract 20,40,80mg/kg treatment, the TG that liver is raise descended respectively 15.2% (P＞0.05), 37.8% (P＜0.05), 72.8% (P＜0.01); The TC that liver is raise descended respectively 21.7% (P＞0.05), 24.1% (P＜0.05), 24.8% (P＜0.05); The TC that serum is raise descended respectively 45.3% (P＞0.05), 66.5% (P＜0.05), 77.1% (P＜0.01); The LDL-C that serum is raise descended respectively 39.5% (P＜0.05), 55.4% (P＜0.01), 57.3% (P＜0.01); The HDL-C/LDL-C that serum is descended risen respectively 0.7% (P＞0.05), 30.1% (P＜0.05), 30.8% (P＜0.01); And can alleviate the hepatic cell fattydegeneration degree.Picrorhiza rhizome total glycoside extract 40mg/kg is suitable with the effect of strong liver granule 2300mg/kg; The effect of picrorhiza rhizome total glycoside extract 40mg/kg and tiopronin tablets 140mg/kg is suitable.
3. the influence of the chronic fatty liver model that ethanol+high fat is brought out
70 of SD rats, male, body weight 212 ± 6 (200～223) g.Except that the normal control group was irritated clothes 0.5% (g/ml) CMC, all the other rats were irritated clothes moulding emulsion 15ml/kg every day, in order to make and the human similar chronic fatty liver model of dietary structure.Ethanol has liver toxicity, can suppress the fatty acid beta-oxidation, and high fat can strengthen the damage of ethanol to liver.Moulding emulsion ratio is 60% (volume) ethanol 10ml/kg, cholesterol 1g/kg, Adeps Sus domestica 5g/kg.After the 8th week of moulding, animal pattern is divided into 6 groups at random, 10 every group.Begin administration subsequently, normal control group and model control group are irritated clothes 0.5% (g/ml) CMC; Receive the reagent group to irritate the picrorhiza rhizome total glycoside extract of clothes embodiment 1 preparation, dosage is respectively 20,40,80mg/kg; The positive drug group is irritated stomach respectively and is given strong liver granule or tiopronin tablets, and dosage is respectively 2300,140mg/kg (all be equivalent to clinical dosage 3 times), and the administration volume is 5ml/kg.Administration every day 1 time, administration is 30 days altogether.
The animal eye socket is got blood 1ml before administration, and preparation serum is measured TG, TC.1h gets hematometry TG, TC, glutamic oxaloacetic transaminase, GOT (AST), glutamate pyruvate transaminase (ALT) after the last administration.The result is shown in table 5 and table 6.
Put to death animal, win liver, take by weighing lobus sinister edge 200mg, grind preparation homogenate with 2ml acetone-alcohol mixeding liquid (volume ratio=1: 1), the extracting lipid, centrifugal after, get supernatant with colorimetric method for determining TG, TC.The result is as shown in table 7.Other gets hepatic tissue, measures SOD with xanthine oxidase, measures MDA with the TBA method, measures hydroxyproline content with the sample alkali hydrolysis method.The result is as shown in table 8.
Table 5 picrorhiza rhizome total glycoside extract is to the influence
of serum TG, TC
Annotate: 1. compare with normal group,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05;
*P＜0.01;
* *P＜0.001.
Table 6 picrorhiza rhizome total glycoside extract is to the influence
of Serum ALT, AST
Annotate: 1. compare with normal group,
△P＜0.05;
△ △P＜0.01; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Table 7 picrorhiza rhizome total glycoside extract is to the influence
of liver TG, TC
Annotate: 1. compare with normal group,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Table 8 picrorhiza rhizome total glycoside extract is to the influence
of liver SOD, MDA
Annotate: 1. compare with normal group,
△ △ △P＜0.01; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Conclusion; The chronic fatty liver rat model that ethanol+high fat brings out can be removed in the liver in 30 days and the fat in the blood through picrorhiza rhizome total glycoside extract 20,40,80mg/kg treatment, the TG that liver is raise descended respectively 13.3% (P＞0.05), 40.2% (P＜0.05), 76.1% (P＜0.01); The TC that liver is raise 2.3% (P＞0.05,22.6% (P＞0.05), 60.5% (P＜0.05) that descended respectively; The TG that serum is raise descended respectively 79.2% (P＜0.05), 77.8% (P＜0.05), 93.1% (P＜0.01); The TC that serum is raise descended respectively 47.7% (P＞0.05), 56.8% (P＜0.05), 81.2% (P＜0.05); Can improve liver function, transaminase lowering, the ALT that serum is raise descended respectively 69.4% (P＞0.05), 77.6% (P＜0.05), 83.6% (P＜0.05); The AST that serum is raise descended respectively 82.9% (P＜0.05), 97.9% (P＜0.01), 95.7% (P＜0.01); SOD activity improving reduces MDA content.Picrorhiza rhizome total glycoside extract 20～40mg/kg is suitable with the effect of strong liver granule 2300mg/kg; The effect of picrorhiza rhizome total glycoside extract 40mg/kg and tiopronin tablets 140mg/kg is suitable.
4. to CCl
4The influence of the fatty liver/Liver Fibrosis Model of bringing out
70 of SD rats, male, body weight 154 ± 10 (141～177) g.Except that the neutral vegetable oil of normal control group cervical region subcutaneous injection, all the other rat skin lower injection 40% (volume) CCl
4Neutral vegetable oil solution.CCl
4In liver, activating through microsome cytochrome oxidase P450 is free radical CCl
3 -, cause the lipid peroxidation of hepatomicrosome, destroy liver cell mitochondria structure and function, its oxidability to fat is reduced, damage hepatocyte endoplasmic reticulum makes the synthetic minimizing of lipoprotein.Injecting first dosage is the 0.5ml/kg body weight, later 0.2ml/100g body weight, 2 times/week.After 7 weeks of moulding, animal pattern is divided into 6 groups at random, 10 every group.Begin administration subsequently, normal control group and model control group are irritated clothes 0.5% (g/ml) CMC; Tried drug group and irritate the picrorhiza rhizome total glycoside extract of clothes by embodiment 1 preparation, dosage is respectively 20,40,80mg/kg; The positive drug group is irritated stomach respectively and is given strong liver granule or tiopronin tablets, and dosage is respectively 2300,140mg/kg (all be equivalent to clinical dosage 3 times), and the administration volume is 5ml/kg.Administration every day 1 time, administration is 30 days altogether.
1h animal eye socket is got blood 1ml after reaching the last administration before the administration, and preparation serum is measured serum glutamic oxalacetic transaminase (AST), glutamate pyruvate transaminase (ALT).The result is as shown in table 9.
Put to death animal, win liver, take by weighing lobus sinister edge 200mg, grind preparation homogenate with 2ml acetone-alcohol mixeding liquid (volume ratio=1: 1), the extracting lipid, centrifugal after, get supernatant with colorimetric method for determining TG, TC.The result is as shown in table 10.
Other gets hepatic tissue, measures superoxide dismutase (SOD) with xanthine oxidase, measures malonaldehyde (MDA) with the TBA method, measures hydroxyproline content with the sample alkali hydrolysis method.The result is as shown in table 11.
Get again in 1cm * 1cm * 0.5cm right lobe of liver immersion formalin solution and fix HE dyeing.The Masson trichrome stain is observed rat liver collagen tissue (the dyeing collagen fiber are blue) deposition and is waited variation.Collagen fiber area percentage=collagen fiber area/hepatic tissue area * 100%, the result is as shown in table 12.
Table 9 picrorhiza rhizome total glycoside extract is to the influence
of serum transaminase
Annotate: 1. compare with normal group,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05;
*P＜0.01.
Table 10 picrorhiza rhizome total glycoside extract is to the influence
of liver TG, TC
Annotate: 1. compare with normal group,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05.
Table 11 picrorhiza rhizome total glycoside extract is to the influence
of liver SOD, MDA
Annotate: 1. compare with normal group,
△ △P＜0.01,
△ △ △P＜0.001; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Table 12 picrorhiza rhizome total glycoside extract is to the influence
of hepatic fibrosis
Annotate: 1. compare with normal group,
△ △ △P＜0.01; 2. compare with model group,
*P＜0.05,
*P＜0.01.
Conclusion: CCl
4The fatty liver that brings out/Liver Fibrosis Model rat can be removed intrahepatic fat in 30 days through picrorhiza rhizome total glycoside extract 20,40,80mg/kg treatment, the TG that liver is raise descended respectively 7.0% (P＞0.05), 35.8% (P＜0.05), 38.5% (P＜0.05); Can improve liver function, transaminase lowering, the ALT that serum is raise descended respectively 14.0% (P＞0.05), 23.4% (P＜0.05), 42.0% (P＜0.01); The AST that serum is raise descended respectively 29.6% (P＞0.05), 47.0% (P＜0.05), 59.1% (P＜0.01); And the ability SOD activity improving, reduce MDA content.Picrorhiza rhizome total glycoside extract 20～40mg/kg is suitable with the effect of strong liver granule 2300mg/kg; The effect of picrorhiza rhizome total glycoside extract 40～80mg/kg and tiopronin tablets 140mg/kg is suitable.
In sum, the onset dosage of the rat of picrorhiza rhizome total glycoside extract treatment fatty liver is 20mg/kg/ days, and effective dosage ranges is 40～80mg/kg/ days.Pharmacological action comprises effects such as liver heat removing fat, blood fat reducing, transaminase lowering, anti peroxidation of lipid, removing free radical, the liver protecting, enhance immunity, can treat ethanol property and non-alcoholic fatty liver disease effectively through a plurality of links, prevents hepatic fibrosis.
Two, general pharmacological research
General pharmacological research is not found the overt toxicity of medicine to blood circulation and respiratory system.Do not see influence to animal balance exercise ability yet, but collaborative 30, under the 270mg/kg dosage with pentobarbital, sleep there is certain promotion.
Three, acute toxicity test
Behind the picrorhiza rhizome total glycoside extract of mice single intravenous injection various dose, of short duration at once signs of toxicity such as tic appear in medicine rear section animal, and symptoms such as prostrate and movable minimizing all appear behind the medicine in each dose groups mice.Except that lowest dose level group 0.70g/kg, death all appears in all the other each dose groups animals, and increases with dosage, and dead animal was distributed in 1 hour, and asexuality difference.Mice extremely dead and alive is cutd open the inspection organs and tissues and is not all seen obviously unusual.Surviving animals 24h symptom disappears basically behind the medicine, and toxic reaction degree and dosage are proportionate; Surviving animals body weight gain in the observation period is normal basically behind the medicine.Mice single vein gives to have tangible toxic reaction behind the picrorhiza rhizome total glycoside extract of doses, and causes animal dead, calculates LD with the Bliss method
50Be 1.09g/kg (95% fiducial limit: 0.98g/kg～1.21g/kg).
Behind the gastric infusion, 12.5g/kg dose groups animal is behind medicine in observation period of 14 days, and the animal average weight increases and is starkly lower than concurrent control group (p＜0.05 or p＜0.01), especially behind the medicine in 1 week individual animal the body weight negative growth appears; 10.0g/kg in observation period of 14 days, body weight gain is normal basically behind medicine for the dose groups animal, with matched group relatively there are no significant difference (p＞0.05).It is the maximal non-toxic amounts of reactants that results suggest, mouse stomach give 10.0g/kg.
Four, long term toxicity test
Rat continuous irrigation stomach gives 50,150 and the picrorhiza rhizome total glycoside extract of 450mg/kg 6 months; The body weight of the general reaction of observation animal in administration phase and convalescent period, feed situation, mensuration animal detects indexs such as hematological indices, blood parameters, system's postmortem, organ coefficient and histopathology when administration 3 months, 6 months and 1 month convalescent period finish.The result finds, high dose group, and slow, the STB of body weight gain male and jenny slightly raises during administration; In addition, the reticulocyte of high dose group jenny is slight rising and slight increase tendency appears in kidney device coefficient, and except that above-mentioned abnormal index, all the other each items detect index and all do not find the obvious change relevant with medicine.Middle dose groups, the body weight gain that removes buck during the administration is slow, and the STB that reaches jenny has outside the slight rising, and all the other detect indexs and all do not see the significant change relevant with medicine.Low dose group, the animal each item during the administration detect index and all do not find the toxic reaction relevant with medicine.Drug withdrawal recovered after 1 month, and above-mentioned have the detection index of ANOMALOUS VARIATIONS all to recover normal.The main organs of histopathological examination is not seen organic disease relevant with medicine and delayed toxicity reaction.Therefore, can think that rat oral gavage gives picrorhiza rhizome total glycoside extract 50mg/kg (being equivalent to clinical plan 30 times with dosage), is basic security dosage.
Beasle dog continuous oral picrorhiza rhizome total glycoside extract 320mg/kg, 80mg/kg, 20mg/kg dosage are established matched group, successive administration 180 days.Observe spirit, behavior, diet, the feces of animal behind the medicine every day, regularly carry out an inspection such as body weight, feces occult blood, urine biochemistry, electrocardiogram, hematology, blood biochemical, bone marrow, ophthalmology, pathological tissue.The result finds 320mg/kg, 80mg/kg dose groups animal, and at the gastrointestinal reaction (vomiting, loose stool) of the initial had slight of administration, the ERY inspection all has the part animal to present the positive after the administration, but does not increase the weight of with the administration process; Histopathologic examination's mucous membrane of urinary bladder, the slight congestion of gastrointestinal mucosa; 320mg/kg dose groups animal glutamic oxaloacetic transaminase, GOT slightly raises; These variations can disappear after drug withdrawal.The spirit of 20mg/kg dose groups animal, activity, diet, feces, body weight, anus temperature, hematology, blood biochemical, urine biochemistry, electrocardiogram all do not have obvious influence; This dosage is the dosage that do not observe toxic reaction (calculate 13 times that are equivalent to intend clinical dosage with every kg body weight, converting with body surface area is equivalent to intend 8.3 times of clinical dosage, 90mg/ people/sky, 60kg/ people).
Claims (10)
1. a picrorhiza rhizome total glycoside extract is used for preventing and/or treating the purposes of fatty liver or its relevant disease medicine in preparation, and the method for preparing of wherein said picrorhiza rhizome total glycoside extract may further comprise the steps:
(1) with concentration is the C of 0～95% (volume)
1-C
5Fatty alcohol aqueous solution extracts Rhizoma Picrorhizae, removes the C in the extracting solution
1-C
5The aliphatic alcohol after-filtration;
(2) filtrating is the C of 0～30% (volume) through macroporous adsorbent resin and with concentration
1-C
5The fatty alcohol aqueous solution eluting, eluent discards;
(3) with concentration be the C of 40～100% (volume)
1-C
5The fatty alcohol aqueous solution eluting is removed the solvent in the eluent.
2. purposes according to claim 1 is characterized in that, the C that adopts in the said step (1)
1-C
5The concentration of fatty alcohol aqueous solution is 0～30% (volume).
3. purposes according to claim 1 and 2 is characterized in that, the C that adopts in the said step (2)
1-C
5Fatty alcohol aqueous solution is 0～20% (volume).
4. according to each described purposes in the claim 1 to 3, it is characterized in that the C that adopts in the said step (3)
1-C
5Fatty alcohol aqueous solution is 40～60% (volume).
5. according to each described purposes in the claim 1 to 4, it is characterized in that said macroporous adsorbent resin is selected from one or more in styrene, divinylbenzene, acrylic ester or methacrylate type polarity or the nonpolar macroporous adsorption resin.
6. according to each described purposes in the claim 1 to 5, it is characterized in that the method for said extraction is selected from one or more in percolation, backflow and the immersion, is preferably percolation.
7. according to each described purposes in the claim 1 to 6; It is characterized in that; By the gross weight of said picrorhiza rhizome total glycoside extract, in the said picrorhiza rhizome total glycoside extract, the content of Rhizoma Picrorhizae total glucosides is not less than 60% (w/w); The content of picroside is not less than 21% (w/w), and the content of picroside is not less than 13% (w/w);
Preferably, said picrorhiza rhizome total glycoside extract also comprises picroside III, kutkin I V, 6-feruloyl catalpol and the different Resina Ferulae acyl of 6-catalpol.
8. according to each described purposes in the claim 1 to 7, it is characterized in that said medicine is peroral dosage form or injection type.
9. purposes according to claim 8 is characterized in that, said peroral dosage form is tablet, pill, capsule, granule or oral liquid; Said injection type is aqueous injection or injectable powder.
10. according to each said injection type in the claim 1 to 9, it is characterized in that said fatty liver is alcoholic fatty liver or non-alcoholic fatty liver disease, perhaps said fatty liver is acute fatty liver or chronic fatty liver; The relevant disease of said fatty liver is the hepatic fibrosis that fatty liver causes.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105982998A (en) * | 2015-02-11 | 2016-10-05 | 天津药物研究院 | Medicine composition for treating fatty liver, and preparation method and purpose of medicine composition |
| CN111000856A (en) * | 2020-01-03 | 2020-04-14 | 吉林大学 | Application of picroside II in preparing medicine for treating hyperlipemia |
| CN112168834A (en) * | 2020-10-12 | 2021-01-05 | 上海中医药大学 | Application of picroside I in preparation of medicine for preventing and treating hepatic fibrosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1457794A (en) * | 2002-05-15 | 2003-11-26 | 成都博瑞医药科技开发有限公司 | New use of picrorhiza rhizome and its iridoid glycoside extract |
| CN1488637A (en) * | 2003-09-05 | 2004-04-14 | 北京深文医药科技开发有限公司 | Method for preparing total aglycone extract of radix picrorrhizae |
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| CN1457794A (en) * | 2002-05-15 | 2003-11-26 | 成都博瑞医药科技开发有限公司 | New use of picrorhiza rhizome and its iridoid glycoside extract |
| CN1488637A (en) * | 2003-09-05 | 2004-04-14 | 北京深文医药科技开发有限公司 | Method for preparing total aglycone extract of radix picrorrhizae |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105982998A (en) * | 2015-02-11 | 2016-10-05 | 天津药物研究院 | Medicine composition for treating fatty liver, and preparation method and purpose of medicine composition |
| CN105982998B (en) * | 2015-02-11 | 2019-03-05 | 天津药物研究院 | A kind of pharmaceutical composition and its preparation method and application for treating fatty liver |
| CN111000856A (en) * | 2020-01-03 | 2020-04-14 | 吉林大学 | Application of picroside II in preparing medicine for treating hyperlipemia |
| CN112168834A (en) * | 2020-10-12 | 2021-01-05 | 上海中医药大学 | Application of picroside I in preparation of medicine for preventing and treating hepatic fibrosis |
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Application publication date: 20120523 Assignee: TASLY PHARMACEUTICAL GROUP Co.,Ltd. Assignor: Tianjin Institute of Pharmaceutical Research Co.,Ltd. Contract record no.: X2020120000002 Denomination of invention: Application of extract of total glucosides of picrorhiza in preparing medicines for preventing and treating fatty liver Granted publication date: 20140312 License type: Exclusive License Record date: 20200203 |