CN101007009B - A drug for preventing and treating liver injury and lowering blood fat - Google Patents
A drug for preventing and treating liver injury and lowering blood fat Download PDFInfo
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- CN101007009B CN101007009B CN200710063401A CN200710063401A CN101007009B CN 101007009 B CN101007009 B CN 101007009B CN 200710063401 A CN200710063401 A CN 200710063401A CN 200710063401 A CN200710063401 A CN 200710063401A CN 101007009 B CN101007009 B CN 101007009B
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention discloses a medicament for preventing and treating liver injury, wherein the effective constituents comprise (by weight ratio) the following raw materials: ferulaic acid 4.5-35.0 parts, red sage root extract 4.9-30.0 parts, and cryptotanshinone 30.0-380.0 parts.
Description
Technical field
The present invention relates to the medicine of a kind of prevention and treatment hepatic injury and blood fat reducing.
Background technology
Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong are China tradition conventional Chinese medicine, have activating blood circulation to dissipate blood stasis, mediation blood vessels, an effect such as logically stagnate, inducing menstruation to relieve menalgia, removing heat from blood detumescence, relieving restlessness clear away heart-fire of becoming silted up of dispelling.Radix Salviae Miltiorrhizae and Rhizoma Chuanxiong distribute wide in the China's Mainland, the active constituent content height, and quality can be controlled, and now is usually used in the treatment of clinical cardiovascular and cerebrovascular disease.The effective ingredient of Radix Salviae Miltiorrhizae, Rhizoma Chuanxiong (tanshinone liposoluble constituent, danshensu class water soluble ingredient and ferulic acid etc.) has the effect of tangible anti-inflammation, free radical resisting and anti peroxidation of lipid, blood fat reducing, anticoagulation, antithrombotic formation, atherosclerosis and coronary artery dilating.It is synthetic that Radix Salviae Miltiorrhizae suppresses collagen in addition, promotes proliferative lesion to transform and Absorption.The above-mentioned pharmacologically active of comprehensive utilization red sage and chuanxiong rhizome effective ingredient carries out reasonable development, is a up-and-coming research direction.
Summary of the invention
The medicine that the purpose of this invention is to provide a kind of prevention and treatment hepatic injury and blood fat reducing.
The medicine of prevention provided by the present invention and treatment hepatic injury and blood fat reducing, its effective ingredient is made up of following substances in parts by weight:
Ferulic acid 4.5-35.0 part,
Danshensu 4.9-30.0 part,
Cryptotanshinone 30.0-380.0 part.
In actual applications, the effective ingredient of described medicine can be for being made up of following substances in parts by weight:
5.52 parts of ferulic acids,
10.15 parts of danshensus,
90.1 parts of cryptotanshinones; Or
7.90 parts of ferulic acids,
29.59 parts of danshensus,
183.8 parts of cryptotanshinones; Or
11.28 parts of ferulic acids,
7.11 parts of danshensus,
375 parts of cryptotanshinones; Or
16.12 parts of ferulic acids,
20.71 parts of danshensus,
63 parts of cryptotanshinones; Or
23.02 parts of ferulic acids,
4.97 parts of danshensus,
128.6 parts of cryptotanshinones; Or
32.88 parts of ferulic acids,
14.50 parts of danshensus,
260.5 parts of cryptotanshinones;
During with aforementioned pharmaceutical compositions prevention and treatment hepatic injury and blood fat reducing, calculate by the accumulative total effective ingredient, the referrer is the 10mg/kg body weight with dosage; General using dosage is 7～45mg/kg body weight.
Aforementioned pharmaceutical compositions can be directly oral or injection, also can add carrier auxiliary material or cosolvent, mixes and make any pharmaceutically useful dosage form, and adjuvant comprises sodium carboxymethyl cellulose, and starch etc., cosolvent comprise tween 80, propylene glycol etc.The addition of described adjuvant can be effective ingredient quality 2-10% in the described medicine, and the weight portion of described cosolvent can be the 1-5% of effective ingredient quality in the described medicine.The preparation that said medicine can be made into comprises: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, soft capsule, hard capsule, oral liquid, syrup, buccal tablet, granule, crude drug, pill, powder, unguentum, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, cream, spray, drop, patch, slow releasing preparation, controlled release preparation etc.
The crude drug of drug oral administration of the present invention, tablet, capsule are generally a kind of unit dose, and contain excipient commonly used, such as binding agent, filler, diluent, profit agent alive, disintegrating agent, coloring agent flavoring agent etc., and can carry out coating to tablet.
Form for oral liquid can be aqueous or oily suspensions, solution, Emulsion, syrup or tincture, perhaps can be a kind of before use can water or the composite dry products of other appropriate carrier.These liquid preparations can contain conventional additive, such as suspending agent (for example sorbitol, Polysorbate, syrup, methylcellulose, gelatin, hydroxy methocel, hydroxyethyl-cellulose aluminium stearate or hydrogenation edible fat), emulsifying agent (for example lecithin, anhydro sorbitol-olein or arabic gum), non-aqueous carrier (for example almond oil, propylene glycol or ethanol), antiseptic (for example p-Hydroxybenzoate, propyl p-hydroxybenzoate, sorbic acid) etc., and if desired, can contain conventional flavouring agent or coloring agent.
For injection, the liquid unit dosage forms of preparation contains effective ingredient of the present invention and sterile carrier.According to carrier and concentration, this chemical compound can be suspended or dissolving.
Medicine of the present invention is to adopt statistical methods such as optimizing Latin square and uniform Design to carry out again reasonable formula and the optimization of effective ingredient dosage ratio the main fat-soluble active ingredient of Radix Salviae Miltiorrhizae (cryptotanshinone) and main water-soluble active ingredient (danshensu) and the main effective ingredient of Rhizoma Chuanxiong (ferulic acid), prevention that obtains and treatment hepatic injury with good curative effect with the medicine of blood fat reducing.Drug effect of the present invention is fast, and effective ingredient is clear, and is quality controllable, and impurity is few, and toxic and side effects is little.
Pharmaceutical composition of the present invention has significant anti-inflammation, free radical resisting and anti peroxidation of lipid, blood fat reducing, liver protection function, can be used for the prevention and the treatment of the hepatic injury that multiple reason (as exogenous chemical poisonous substance and drug induced injury, microorganism such as virus damage and endogenous damage as fatty liver etc.) causes.Experiment shows that medicine of the present invention not only has excellent prevention and therapeutic effect to the hepatic injury disease, and on the curative effect He on the pharmacokinetics tangible function optimization is all being arranged with its arbitrary effective ingredient than single.The white mice toxicity test shows, each prescription medicine is not seen mice dying in the week, according to the toxicity assessment standard under the dosage of oral absorption total amount 4230～7867mg/kg body weight, toxicity dose is 18～45 times of clinical recommended drug amount, and this product is considered as nontoxic or low toxicity.The result shows that this prescription medicine clinical application amount is safe and reliable.Sampling Detection through 1 year shows that (1～2 year) main active stable content is controlled in the certain hour of medicine of the present invention.
Description of drawings
Fig. 1 is that No. 4 sides, red rhizome of chuanxiong side are high, medium and low, small dose group and each one pack system to the medication of hepatic injury mice after the pathology of livers photo.
The specific embodiment
Method described in the following embodiment is conventional method if no special instructions.
The preparation of embodiment 1, prevention and treatment hepatic injury and blood lipid-lowering medicine
Under Chinese medical theory instructs, and on existing pharmacological action basis, main active component danshensu with Chinese medicine Radix Salviae Miltiorrhizae and Rhizoma Chuanxiong, ferulic acid, cryptotanshinone adopts optimization Latin square and uniform Design method to carry out reasonable formula, recipe ingredient is divided into 6 dosage that vary in size, again these dosage are distributed to equably 6 compatibility groups, form 6 red rhizome of chuanxiong compound recipes (shown in the table 1), raw materials used danshensu (lot number 050114), ferulic acid (lot number 030401) and cryptotanshinone (lot number 050315), all, be up to the standards through chromatograph and spectrum (wave spectrum) qualitative, quantitative available from Xi'an Honson Biotechnology Co., Ltd..
The preparation method of prevention and treatment hepatic injury and blood lipid-lowering medicine: (1) crude drug: accurately take by weighing danshensu, ferulic acid and cryptotanshinone respectively by the proportioning of weight portion shown in the table 1, pulverize, (200 order) sieves, mix, the crude drug of No. 1 side, red rhizome of chuanxiong side, No. 2 sides, red rhizome of chuanxiong side, No. 3 sides, red rhizome of chuanxiong side, No. 4 sides, red rhizome of chuanxiong side, No. 5 sides, red rhizome of chuanxiong side or No. 6 sides, red rhizome of chuanxiong side is made in packing.(2) hard capsule: accurately take by weighing danshensu, ferulic acid and cryptotanshinone respectively by the proportioning of weight portion shown in the table 1, adding is that the adjuvant (starch) of described danshensu, ferulic acid and cryptotanshinone gross mass 2-10% is made uniform powder, press different size (250mg/ grain, 500mg/ grain) filling and in capsulae vacuus, make the hard capsule of No. 1 side, red rhizome of chuanxiong side, No. 2 sides, red rhizome of chuanxiong side, No. 3 sides, red rhizome of chuanxiong side, No. 4 sides, red rhizome of chuanxiong side, No. 5 sides, red rhizome of chuanxiong side or No. 6 sides, red rhizome of chuanxiong side.(3) injection: accurately take by weighing danshensu, ferulic acid and cryptotanshinone respectively by the proportioning of weight portion shown in the table 1, after adding is cosolvent (propylene glycol) hydrotropy of described danshensu, ferulic acid and cryptotanshinone gross mass 1-5%, get final product with the sealing sterilization behind the 5mg/ml of water for injection dissolving standardize solution.Make crude drug, hard capsule or the injection of prevention and treatment hepatic injury and No. 1 side, medicine-Dan rhizome of chuanxiong side of blood fat reducing, No. 2 sides, red rhizome of chuanxiong side, No. 3 sides, red rhizome of chuanxiong side, No. 4 sides, red rhizome of chuanxiong side, No. 5 sides, red rhizome of chuanxiong side, No. 6 sides, red rhizome of chuanxiong side respectively.
The pharmaceutical formulation of the red rhizome of chuanxiong side of table 1. is formed
| The compatibility of drugs group | Ferulic acid (weight portion) | Danshensu (weight portion) | Cryptotanshinone (weight portion) |
| No. 1, red rhizome of chuanxiong side | 5.52 | 10.15 | 90.1 |
| No. 2, red rhizome of chuanxiong side | 7.90 | 29.59 | 183.8 |
| No. 3, red rhizome of chuanxiong side | 11.28 | 7.11 | 375 |
| No. 4, red rhizome of chuanxiong side | 16.12 | 20.71 | 63 |
| No. 5, red rhizome of chuanxiong side | 23.02 | 4.97 | 128.6 |
| No. 6, red rhizome of chuanxiong side | 32.88 | 14.50 | 260.5 |
| On average | 16.12 | 14.50 | 183.83 |
| Maximum | 32.88 | 29.59 | 375 |
| Minima | 5.52 | 4.97 | 63 |
The drug effect of embodiment 2, prevention and treatment hepatic injury and blood lipid-lowering medicine detects:
(1) the effect experiment of No. 4 sides, red rhizome of chuanxiong side prevention hepatic injury
CCl is adopted in this experiment
4The acute liver damage model that single intraperitoneal injection causes carries out the pharmacodynamic study of chemoprophylaxis hepatic injury.CCl
4Enter in the body through hepatomicrosome cytochrome P 450 enzymes metabolism generation chloroform free radical CCl
3, CCl
3Phospholipid molecule causes lipid peroxidation on the attack liver plasma membrane, in addition, and CCl
3Speed that can also be the fastest and oxygen form trichloromethyl peroxy radical (CCl in vivo
3O
2), the latter has stronger lipid peroxidation, causes the destruction of liver plasma membrane 26S Proteasome Structure and Function, finally causes the infringement of membrane structure and function.The unsaturated fatty acid oxidation Decomposition can discharge malonaldehyde, and (Maleic Dialdehyde MDA) wait aldehyde material, but the heavy damage membrane structure causes cellular swelling, necrosis.(SuperoxideDismutase SOD) is the scavenger of ultra-oxygen anion free radical to superoxide dismutase, can suppress the lipid peroxidation that free radical starts.Therefore can reflect the degree of body lipid peroxidation injury and the ability of body anti-oxidative damage by the content that detects SOD and MDA.Hepatocyte injury, cause the liver plasma membrane structural deterioration, permeability of cell membrane increases, serum glutamic pyruvic transminase (glutamic pyruvic transaminase in the hepatocyte, ALT) hepatocyte of can overflowing enters in the blood circulation, (glutamic oxaloacetic transaminase, AST) the active prompting cell mitochondrial damage that raises is so the mensuration of serum AST and ALT is the Sensitive Detection index of reflection hepatic injury to serum glutamic oxalacetic transaminase.
1. the zoopery processing method of No. 4 sides, red rhizome of chuanxiong side prevention hepatic injury
100 (18-22g) are divided into 10 groups with mice, are respectively dosage group, No. 4 square low dose group in red rhizome of chuanxiong side, No. 4 square small dose group in red rhizome of chuanxiong side, danshensu group, TANSHINONES group, ferulic acid group, normal control group, hepatic injury matched group in No. 4 square high dose group in red rhizome of chuanxiong side, No. 4 sides, red rhizome of chuanxiong side; Every group 10 (healthy ICR mice, male and female half and half, available from Capital University of Medical Sciences's Experimental Animal Center, lot number SCXK (capital) 2005-0006).With the crude drug of normal saline with No. 4 sides, red rhizome of chuanxiong side of embodiment 1 preparation, dissolve respectively according to the dosage shown in the table 2 and to give four groups of (dosage group, No. 4 square low dose group in red rhizome of chuanxiong side, No. 4 square small dose group in red rhizome of chuanxiong side in No. 4 square high dose group in red rhizome of chuanxiong side, No. 4 sides, red rhizome of chuanxiong side) mouse stomaches behind the suspendible, irritate stomach danshensu (danshensu group), cryptotanshinone (cryptotanshinone group), ferulic acid (ferulic acid group), the drop pill (bifendate group) of bifendate, the normal saline (normal control group and liver injury model group) of equal volume according to the dosage shown in the table 2 simultaneously; Successive administration 7 days, 1 time/day.Wherein, the drop pill of bifendate, available from Beijing XieHe medicine Factory's product, lot number 04050116.Ferulic acid, danshensu, cryptotanshinone are all available from Xi'an Honson Biotechnology Co., Ltd.'s product, and lot number is respectively 030401,050114,041208.
Table 2, No. 4 sides, red rhizome of chuanxiong side are to CCl
4The drug dose of hepatic injury mice protective effect
| Dosage (mg/kg body weight) | Ferulaic acid content (mg/kg body weight) | Content of Danshensu (mg/kg body weight) | Cryptotanshinone content (mg/kg body weight) | |
| The normal control group | 0 | 0 | 0 | 0 |
| The liver injury model group | 0 | 0 | 0 | 0 |
| The bifendate group | 25.6 | 0 | 0 | 0 |
| The ferulic acid group | 16.12 | 16.12 | 0 | 0 |
| The danshensu group | 20.7 | 0 | 20.7 | 0 |
| Dosage (mg/kg body weight) | Ferulaic acid content (mg/kg body weight) | Content of Danshensu (mg/kg body weight) | Cryptotanshinone content (mg/kg body weight) | |
| The cryptotanshinone group | 12.6 | 0 | 0 | 12.6 |
| No. 4 high dose group in red rhizome of chuanxiong side | 247.1 | 80.6 | 103.5 | 63 |
| Dosage group in No. 4, the red rhizome of chuanxiong side | 49.42 | 16.12 | 20.7 | 12.6 |
| No. 4 low dose group in red rhizome of chuanxiong side | 9.88 | 3.22 | 4.14 | 2.52 |
| No. 4 small dose group in red rhizome of chuanxiong side | 1.97 | 0.64 | 0.83 | 0.50 |
After the administration the 7th day, except that the normal control group, all the other each groups all give CCl
4Induce hepatic injury, concrete grammar is: mouse peritoneal injection 0.1%CCl
4Behind the peanut oil solution 10ml/kg, overnight fasting.After 16 hours, mice is weighed, breaks end and get blood, and 3000 leave the heart collected blood plasma in 10 minutes, used the Beckman automatic biochemical analyzer and detected serum glutamic pyruvic transminase (ALT), glutamic oxaloacetic transaminase, GOT (AST), blood plasma total protein, albumin.Cut open and get liver and weigh, get a part of liquid nitrogen freezing cryogenic refrigerator and preserve and be used to detect liver SOD, MDA.Other get the part hepatic tissue with 10% formalin fixed after, histopathology is carried out in HE dyeing.Wherein serum glutamic pyruvic transminase (ALT) (IFCC continuous monitoring method), glutamic oxaloacetic transaminase, GOT (AST) (IFCC continuous monitoring method), blood plasma total protein (biuret end-point method), albumin (bromocresol green end-point method) detection kit are available from the BeiJing ShouYi clinical Medicine Science Center.SOD (chemical colorimetry), MDA (thiobarbituricacid method) detection kit is built up bio-engineering research institute available from Nanjing.
2, the zoopery experimental result of No. 4 sides, red rhizome of chuanxiong side prevention hepatic injury:
2.1 medicine of the present invention is to the influence of ALT, AST, total protein, albumin and globulin ratio in the hepatic injury mice serum
The result is as shown in table 3, gives CCl from table 3 data as can be seen
4The serum glutamic pyruvic transminase of modeling mice (ALT), serum glutamic oxalacetic transaminase (AST) level significantly raise, and histopathology changes obviously, and the modeling success is described.
The serum alanine transaminase (ALT) of bifendate group, ferulic acid group, danshensu group and TANSHINONES group and the expression of serum glutamic oxalacetic transaminase (AST) all decrease (p＜0.05), No. 4 high doses in red rhizome of chuanxiong side of the present invention, middle dosage, the low dose of administration group of low dosage also can obviously reduce serum glutamic pyruvic transminase (ALT) and serum glutamic oxalacetic transaminase (AST) expression (p＜0.05), and have certain dose dependent.And, the degree that No. 4 high doses in the red rhizome of chuanxiong side of prescription, middle dosage, the low dose of administration group of low dosage reduce serum alanine transaminase (ALT) and serum glutamic oxalacetic transaminase (AST) expression all is higher than other each administration groups, and the curative effect of having optimized drug component after the compound recipe medication (No. 4 high doses in red rhizome of chuanxiong side, middle dosage, low dosage, low dose of administration group) is described.
The total serum protein of liver injury model matched group, albumin and white/globulin ratio there was no significant difference of comparing with the normal control group, when this may be acute or FHL, to total protein, albumin, in vain/the globulin ratio do not have obvious influence.In contrast to this, total protein of each administration group mice and albumin all have obvious rising (p＜0.05), illustrate that this type of medicine has the synthetic effect of the hepatic protein of promotion.And the normal matched group of albumins/globulins ratio reduces (p＜0.05), illustrates that medicine promotes that the effect of globulin rising is more remarkable than albumin.In each administration group, the total protein and the albuminous elevated levels of No. 4 sides, red rhizome of chuanxiong side are the most obvious, are higher than each folk prescription administration group (bifendate group, ferulic acid group, danshensu group, cryptotanshinone group) and illustrate that No. 4 sides, red rhizome of chuanxiong side have the effect of stronger promotion protein synthesis than folk prescription.
Each administration group of table 3. is to CCl
4The influence of damage mice plasma index (x ± sd)
| Group | ALT (U/L) | AST (U/L) | Total protein content (g/L) | Albumin (g/L) | Albumins/globulins |
| The normal control group | 42.20±9.64 * | 129.80±19.33 * | 47.25±2.95 | 35.77±1.01 | 3.07±0.36 |
| The liver injury model group | 305.64±140.64 | 264.00±82.35 | 47.8±6.78 | 35.41±1.12 | 3.29±1.08 |
| The bifendate group | 57.80±23.37 * | 188.60±73.15 * | 53.98±3.73 *△ | 37.2±0.92 *△ | 2.29±0.42 *△ |
| The ferulic acid group | 68.10±20.38 * | 172.1±42.91 * | 55.61±4.01 *△ | 38.02±0.72 *△ | 2.18±0.40 *△ |
| Radix Salviae Miltiorrhizae rope group | 47.50±13.35 * | 158.8±22.08 * | 57.734.32 *△ | 38.23±0.97 *△ | 2.02±0.34 *△ |
| The cryptotanshinone group | 66.80±25.14 * | 173.2±32.22 * | 58.81±7.21 *△ | 37.75±1.33 *△ | 1.86±0.51 *△ |
| No. 4 square high dose group in red rhizome of chuanxiong side | 35.60±12.07 * | 150.4±43.08 * | 62±4.25 *△ | 39.28±1.08 *△ | 1.74±0.25 *△ |
| Dosage group in No. 4 sides, red rhizome of chuanxiong side | 50.80±12.08 * | 164.70±40.75 * | 60.92±6.58 *△ | 38.10±1.36 *△ | 1.81±0.38 *△ |
| No. 4 square low dose group in red rhizome of chuanxiong side | 102.90±70.81 * | 209.20±49.01 * | 63.57±4.06 *△ | 38.72±1.03 *△ | 1.62±0.22 *△ |
| No. 4 square small dose group in red rhizome of chuanxiong side | 70.50±35.28 * | 195.7±55.46 * | 62.11±3.89 *△ | 38.92±1.60 *△ | 1.73±0.21 *△ |
△Expression is compared p＜0.05 with the normal control group; * expression is compared p＜0.05 with the liver injury model group;
2.2 medicine of the present invention is to the influence of SOD, MDA regulating liver-QI coefficient in the hepatic injury mouse liver.
The result is as shown in table 4, and the result shows, gives CCl
4After the liver of liver injury model mice in MDA significantly raise, SOD reduces.Compare with the liver injury model group, each administration group all can obviously reduce the MDA (p＜0.05) in the mouse liver, increased SOD (p＜0.05).Wherein the effect of No. 4 prescription increased SOD in prescription medicine rhizome of chuanxiong side is better than bifendate and each folk prescription group (single with ferulic acid, danshensu or cryptotanshinone), and it is the strongest that No. 4 prescriptions in red rhizome of chuanxiong side reduce the effect of MDA.Give CCl
4The liver coefficient of mice after the modeling does not have significant change, and liver coefficient significantly raise (p＜0.05) of each group of administration.The above results shows that these No. 4 prescription medicines in red rhizome of chuanxiong side are alleviating by CCl
4The better effects if of the tissue oxidizing damage effect that poisoning causes.
Each administration group of table 4. is to CCl
4The influence of SOD, the MDA regulating liver-QI coefficient of damage mice (x ± sd)
| Group | SOD (U/mgprot) | MDA (mol/mgprot) | Liver coefficient (g liver weight/10g body weight) |
| The normal control group | 156.43±11.23 * | 6.43±1.51 * | 0.434±0.115 |
| The liver injury model group | 139.05±15.55 | 10.34±2.21 | 0.452±0.070 |
| Group | SOD (U/mgprot) | MDA (mol/mgprot) | Liver coefficient (g liver weight/10g body weight) |
| The bifendate group | 143.12±7.97 △ | 7.65±1.01 * | 0.598±0.046 △* |
| The ferulic acid group | 125.55±13.16 △ | 8.72±0.94 △* | 0.548±0.034 △* |
| The danshensu group | 139.20±8.99 △ | 8.20±0.76 △* | 0.575±0.036 △* |
| The TANSHINONES group | 152.96±9.87 * | 8.13±1.38 △* | 0.587±0.052 △* |
| No. 4 high dose group in red rhizome of chuanxiong side | 156.96±28.67 * | 9.18±1.40 △ | 0.583±0.023 △* |
| Dosage group in No. 4, the red rhizome of chuanxiong side | 139.13±13.65 △ | 8.93±0.98 △* | 0.548±0.043 △* |
| No. 4 low dose group in red rhizome of chuanxiong side | 145.30±13.03 * | 8.54±1.70 * | 0.537±0.024 △* |
| No. 4 small dose group in red rhizome of chuanxiong side | 149.55±17.86 * | 7.65±1.12 * | 0.571±0.081 * |
△Expression is compared p＜0.05 with the normal control group; * expression is compared p＜0.05 with the hepatic injury matched group;
2.3 medicine of the present invention is to the influence of hepatic injury mouse liver pathological change.See Fig. 1.
With the mice and the control group mice thereof of step 1 administration post processing in 7 days, get liver with formalin fixed after, tissue section strain carries out the pathology of hepatic tissue and detect to observe under light microscopic, the result as shown in Figure 1.The result shows, the normal control group, and the lobules of liver structure is normal, and hepatic cords, sinus hepaticus, central vein and portal area are high-visible, and structure is normal.The visible lobules of liver structure disturbance of liver injury model group, hepatocyte is filled the air puffing and severe steatosis.Visible local hepatocyte puffing of bifendate administration group and slight steatosis, slight puffing of ferulic acid administration group and steatosis, danshensu administration group diffusivity puffing and steatosis, red rhizome of chuanxiong side's No. 4 high dose administrations group administration group shows as normally, accidental slight puffing of dosed administration group administration group and steatosis in No. 4, the red rhizome of chuanxiong side, red rhizome of chuanxiong side's No. 4 institutes slight puffing of low dosage administration group and steatosis, No. 4 low dose of administration group hepatocyte in red rhizome of chuanxiong side are gently to severe diffusivity puffing.
Combine and above-mentioned steps 1,2,3 described experiments, the result shows that No. 4 sides, red rhizome of chuanxiong side have significant antagonism CCl
4Hepatic injury, the synthetic effect of promotion hepatic protein.(single with ferulic acid, danshensu or cryptotanshinone) relatively, has tangible pharmacodynamics potentiation behind the composition compound recipe with each independent component.
(2) 1-6 side, red rhizome of chuanxiong side is to the C57BL/6J mice effect for reducing blood fat that gives high lipid food and the experimentation of prophylactic treatment hepatic injury:
Adopt the most frequently used high lipid food to feed and bring out C57BL/6J mice hyperlipemia, and give red rhizome of chuanxiong side each prescription medicine in the high lipid food of feeding, the Changing Pattern of mice blood fat is observed in blood sampling.
1, experimental technique
Inbred line 9 all C57BL/6J mice in age (available from Military Medical Science Institute of PLA animal center) totally 90, male and female half and half.Be divided into the normal diet matched group, the high lipid food model group, (medicine of feeding is an Xuezhikang to the Xuezhikang matched group, purchase in the Beijing WBL Peking University Biotech Co., Ltd, lot number is crossed the accurate word Z10950029 of medicine), No. 1 side's group in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation), No. 2 side's groups in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation), No. 3 side's groups in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation), No. 4 side's groups in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation), No. 5 side's groups in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation), totally nine groups of No. 6 side's groups in red rhizome of chuanxiong side (irritating the crude drug of No. 1 side, red rhizome of chuanxiong side of stomach embodiment 1 preparation).After all mice normal diet adaptabilities were raised a week, except that the normal diet matched group continues to give the normal diet, it all fed high lipid food in each group.
Feed formula is: normal diet: 50% corn, 20% wheat bran, 15% Semen Glycines, 10% flour, 5% fish flour, an amount of Sal; High lipid food: normal diet+3% cholesterol, 10% fat, 0.5% sodium cholate, 0.2% propylthiouracil.
After high lipid food was fed 20 days, begin administration simultaneously, respectively to medicine with physiological saline solution after, press dosage shown in the table 5 and irritate stomach, once a day, 5 weeks of successive administration, the broken end blood sampling detects total plasma cholesterol (totalcholesterol, TC, cholesterol oxidase end-point method) then, triglyceride (triglyceride, TG, phosphoglycerol oxidase end-point method), highdensity lipoprotein-cholesterol (high density lipoprotein, HDL, direct algoscopy), low-density lipoprotein cholesterol (low density lipotrotein, LDL, direct algoscopy) serum glutamic pyruvic transminase (glutamic pyruvic transaminase, ALT) (IFCC continuous monitoring method), albumin (serumalbumin, bromocresol green end-point method), blood urea nitrogen (blood urea nitrogen, the glutamte dehydrogenase two-point method) the These parameters used kit is used the Beckman automatic biochemical analyzer and is detected all available from the BeiJing ShouYi clinical Medicine Science Center.
The red rhizome of chuanxiong side of table 5. anti-C57BL/6J mice hyperlipemia experiment drug dose
| Dosage (mg/kg body weight) | Ferulic acid (mg/kg body weight) | Danshensu (mg/kg body weight) | TANSHINONES (mg/kg body weight) | |
| The normal diet matched group | 0 | 0 | 0 | 0 |
| The high lipid food model group | 0 | 0 | 0 | 0 |
| The Xuezhikang matched group | 4 | 0 | 0 | 0 |
| No. 1 side, red rhizome of chuanxiong side | 105.77 | 5.52 | 10.15 | 90.1 |
| No. 2 sides, red rhizome of chuanxiong side | 220.89 | 7.5 | 29.59 | 183.8 |
| No. 3 sides, red rhizome of chuanxiong side | 393.39 | 11.28 | 7.11 | 375 |
| No. 4 sides, red rhizome of chuanxiong side | 99.82 | 16.12 | 20.7 | 63 |
| No. 5 sides, red rhizome of chuanxiong side | 138.18 | 4.79 | 4.79 | 128.6 |
| No. 6 sides, red rhizome of chuanxiong side | 309.88 | 32.88 | 14.5 | 262.5 |
2, experimental result
2.1 the influence that the C57BL/6J mice mice blood fat of feeding to high lipid food in red rhizome of chuanxiong side is four
According to the described method of step 1, fed for 8 weeks with high lipid food and each medicine after, blood sampling detects four of blood fat, the results are shown in Table 6.Mice plasma TC, LDL all significantly raise after giving high lipid food as can be seen from Table 6, illustrate that model is more successful.Mice plasma TG raises not obvious, belongs to normal condition.1,2,3,4, No. 6 crude drug in red rhizome of chuanxiong side of Xuezhikang and embodiment 1 preparation all can significantly reduce TC and LDL.After giving high lipid food, the HDL of mice plasma has certain rising, and TG decreases.
Table 6: the influence that the C57BL/6J mice blood fat of feeding to high lipid food in red rhizome of chuanxiong side is four
| Grouping | TC(mmol/L) | TG(mmol/L) | LDL(mmol/L) | HDL(mmol/L) |
| The normal diet matched group | 2.73±035 * | 1.47±0.18 * | 0.63±0.19 * | 1.42±0.29 * |
| The high lipid food model group | 8.05±0.90 △ | 0.96±0.10 △ | 4.56±0.71 △ | 2.24±0.21 △ |
| The Xuezhikang matched group | 6.35±0.88 △* | 1.12±0.17 △* | 3.23±0.83 △* | 2.58±0.23 △ |
| No. 1 side's group in red rhizome of chuanxiong side | 7.00±0.39 △* | 0.94±0.12 △ | 3.86±0.58 △* | 2.44±0.34 △* |
| No. 2 side's groups in red rhizome of chuanxiong side | 6.56±0.84 △* | 1.02±0.07 △ | 3.54±0.76 △* | 2.53±0.27 △* |
| No. 3 side's groups in red rhizome of chuanxiong side | 5.33±0.70 △* | 0.95±0.11 △ | 2.52±0.81 △* | 2.09±0.28 △ |
| No. 4 side's groups in red rhizome of chuanxiong side | 6.79±0.59 △* | 0.97±0.13 △ | 3.92±0.61 △* | 2.50±0.29 △ |
| No. 5 side's groups in red rhizome of chuanxiong side | 7.75±0.66 △ | 0.95±0.07 △ | 4.24±0.54 △ | 2.74±0.21 △* |
| No. 6 side's groups in red rhizome of chuanxiong side | 6.03±1.47 △* | 0.83±0.15 △ | 3.43±1.39 △* | 2.43±0.60 △ |
△ represents to compare p＜0.05 with normal group; * expression is compared p＜0.05 with the hyperlipidemia model group
2.2 the influence of the C57BL/6J mice plasma transaminase who feeds to high lipid food in red rhizome of chuanxiong side, albumin, blood urea nitrogen
The C57BL/6J mice plasma transaminase that the red rhizome of chuanxiong side 1-6 crude drug of embodiment 1 preparation is fed to high lipid food, albumin, blood urea nitrogen to influence the result as described in Table 7, the result shows.Give the high lipid food blood plasma transaminase that can significantly raise, illustrate that the hyperlipidemia that continues can cause the liver cell damage, thereby the blood plasma transaminase is increased, and Xuezhikang, 1-6 side, red rhizome of chuanxiong side all can significantly reduce the blood plasma transaminase, and the performance hepatoprotective effect.High fat diet is to not influence of plasma albumin; but can raise the plasma urea nitrogen level; illustrate that the remarkable rising of blood fat has caused certain renal dysfunction, Xuezhikang and red rhizome of chuanxiong side obviously do not reduce plasma urea nitrogen in this research, and illustrating does not have obvious protecting renal function effect.
The influence of the C57BL/6J mice plasma transaminase who feeds to high lipid food in the red rhizome of chuanxiong side of table 7., albumin, blood urea nitrogen
| Grouping | ALT(U/L) | Albumin (g/L) | Blood urea nitrogen (mmol/L) |
| The normal diet matched group | 43.50±5.91 * | 45.06±2.70 | 7.79±0.81 * |
| The high lipid food model group | 513.83±98.63 △ | 46.25±3.00 | 10.65±2.26 △ |
| Grouping | ALT(U/L) | Albumin (g/L) | Blood urea nitrogen (mmol/L) |
| The Xuezhikang matched group | 279.83±129.67 △* | 45.53±2.50 | 10.69±2.24 △ |
| No. 1 side's group in red rhizome of chuanxiong side | 311.67±119.85 △* | 44.01±1.90 | 10.20±1.30 △ |
| No. 2 side's groups in red rhizome of chuanxiong side | 287.83±111.65 △* | 44.24±2.84 | 10.22±1.22 △ |
| No. 3 side's groups in red rhizome of chuanxiong side | 360.57±71.92 △* | 43.06±2.20 * | 9.88±1.02 △ |
| No. 4 side's groups in red rhizome of chuanxiong side | 309.22±118.86 △* | 47.77±3.55 △ | 11.19±2.90 △ |
| No. 5 side's groups in red rhizome of chuanxiong side | 336.00±7108.33 △* | 49.05±6.55 △* | 11.66±2.83 △ |
| No. 6 side's groups in red rhizome of chuanxiong side | 323.60±171.07 △* | 44.17±1.57 | 10.62±1.26 △ |
△ represents to compare p＜0.05 with normal group; * expression is compared p＜0.05 with the hyperlipidemia model group
(3) No. 1 side, red rhizome of chuanxiong side the serum lipids in rats that high lipid food is brought out and the prevention and the curative effect of hepatic injury
On the basis of above-mentioned experiment, select for use red rhizome of chuanxiong side to proceed rat blood fat reducing experimentation for No. 1, with the lipid-lowering effect of the red rhizome of chuanxiong side of further affirmation.
1. experimental technique
1.1 laboratory animal and reagent
70 of Wistar rats, male and female half and half, (available from Beijing Vital River Experimental Animals Technology Co., Ltd., quality certification SCXK (capital) 2002-0003).Ferulic acid, danshensu, TANSHINONES crude drug are identical with previous experiments.Lovastatin is available from the BeiJing WanSheng Pharmacy Co., Ltd, lot number 20060715.Colestyramine is available from the Nanjing pharmaceutcal corporation, Ltd that improves people's living condition, lot number 040501.
Total plasma cholesterol (total cholesterol, TC, the cholesterol oxidase end-point method), triglyceride (triglyceride, TG, phosphoglycerol oxidase end-point method), highdensity lipoprotein-cholesterol (high densitylipoprotein, HDL, directly algoscopy), low-density lipoprotein cholesterol (low density lipotrotein, LDL, directly algoscopy), serum glutamic pyruvic transminase (glutamic pyruvic transaminase, ALT) (IFCC continuous monitoring method), albumin (serum albumin, bromocresol green end-point method) detection kit is all available from the BeiJing ShouYi clinical Medicine Science Center.
1.2 animal processing method
After all mices are raised 2 days with the normal diet adaptability, be divided into 7 groups, every group 10, be respectively normal control group, model group with hyperlipemia, lovastatin, examine LaCie amine, the large, medium and small dosage group in No. 1 side, red rhizome of chuanxiong side, except that the normal control group gives the normal diet, all the other animals give high lipid food.
Feed formula is: normal diet: 50% corn, 20% wheat bran, 15% Semen Glycines, 10% flour, 5% fish flour, an amount of Sal; High lipid food: normal diet+3% cholesterol, 10% fat, 0.5% sodium cholate, 0.2% propylthiouracil.
High lipid food is fed the beginning administration of 4 weeks, and normal control group and hyperlipidemia model group are irritated stomach and given normal saline, and all the other each administration groups give corresponding medicine.All animal eye sockets of back are got blood examination and are surveyed every index all around.
The drug dose of the red rhizome of chuanxiong side of table 8. blood fat reducing research
| Dosage (mg/kg body weight) | Ferulic acid (mg/kg body weight) | Danshensu (mg/kg body weight) | Cryptotanshinone (mg/kg body weight) | |
| The normal control group | 0 | 0 | 0 | 0 |
| Model group with hyperlipemia | 0 | 0 | 0 | 0 |
| Lovastatin | 7 | 0 | 0 | 0 |
| Examine LaCie amine | 1300 | 0 | 0 | 0 |
| No. 1 high dose group in red rhizome of chuanxiong side | 330 | 9 | 32.5 | 287.5 |
| Dosage group in No. 1, the red rhizome of chuanxiong side | 66 | 1.8 | 6.5 | 57.7 |
| No. 1 low dose group in red rhizome of chuanxiong side | 13 | 0.36 | 1.3 | 11.5 |
2. experimental result
2.1 the influence of the rat fat of feeding to high lipid food in red rhizome of chuanxiong side
According to preceding method, give four of high lipid food and 8 week of each medicine back blood sampling detection blood fat, the results are shown in Table 9.Come hyperlipidemia model treated animal TC, LDL, TG all than normal control group p＜0.05 that significantly raises as can be seen from Table 9, illustrate that model is extremely successful.No. 1 high dose in red rhizome of chuanxiong side can be reduced to TC 50% of hyperlipidemia model group, LDL is reduced to 30% of model group, with the blood fat reducing therapeutic equivalence of colestyramine.Optimizing aspect the atherogenic index can significantly raise HDL-C/TC and reduce LDL-C/HDL-C of No. 1 heavy dose in red rhizome of chuanxiong side, p＜0.05, curative effect and colestyramine are suitable.Lovastatin, colestyramine, No. 1 high, medium and low dosage in side in red rhizome of chuanxiong side all can significantly reduce the plasma triglyceride level.
The influence of the rat fat that the red rhizome of chuanxiong side of table 9. brings out high lipid food
△Compare p＜0.05 with the saline group,
*Compare p＜0.05 with model group.
2.2 the rat transaminase who feeds to high lipid food in red rhizome of chuanxiong side, the influence of plasma albumin (treatment hepatic injury effect)
According to preceding method, give high lipid food and 8 week of each medicine back blood sampling detection blood plasma transaminase, albumin content, the results are shown in Table 10, give high lipid food as can be seen after the rat transaminase significantly raise, illustrate that the liver of rat in the process of high lipid food of feeding sustains damage.Lovastatin, colestyramine, No. 1 high, medium and low dosage in side in red rhizome of chuanxiong side is remarkable transaminase lowering all, and p＜0.05 illustrates that this medicine can alleviate the hepatic injury that hyperlipemia causes.
The influence of the rat fat that the red rhizome of chuanxiong side of table 10. brings out high lipid food
| Group | Dosage (mg/kg body weight) | ALT(U/L) | Albumin (g/L) |
| The normal control group | 0 | 49.8±27.58 * | 38.93±1.39 * |
| Model group with hyperlipemia | - | 163.22±69.06 △ | 40.73±0.75 △ |
| Lovastatin | 7 | 61.56±6.25 * | 43.33±0.83 △* |
| Examine LaCie amine | 1300 | 72.89±21.84 * | 42.36±1.10 △* |
| No. 1 square high dose group in red rhizome of chuanxiong side | 330 | 82.43±16.17 * | 41.26±1.97 △ |
| Dosage group in No. 1 side, red rhizome of chuanxiong side | 66 | 62.00±20.61 * | 42.43±0.90 △* |
| No. 1 square low dose group in red rhizome of chuanxiong side | 13 | 103.25±50.76 △* | 42.10±0.92 △* |
△With saline group p＜0.05 mutually,
*Compare p＜0.05 with model group.
See that from The above results red rhizome of chuanxiong side can obviously reduce the blood fat of the rat that high lipid food brings out for No. 1, and have that tangible prevention of arterial is atherosis, the effect of serious disease that hepatic injury etc. is brought out by hyperlipidemia.
Three, the pharmacokinetic study of prevention and treatment hepatic injury and blood lipid-lowering medicine
1, test grouping and mensuration
8 of healthy rabbits are intersected at random, and own control is divided into 4 groups, after each test through 15 day off-drug period.First group: every rabbit is through auricular vein single dose (10.15mg/kg) injection danshensu; Second group: every rabbit is through auricular vein single dose (5.52mg/kg) injection ferulic acid; The 3rd group: every rabbit is through auricular vein single dose (90.1mg/kg) injection TANSHINONES; The 4th group: every No. 1 square injection in red rhizome of chuanxiong side (injected dose is danshensu (10.15mg/kg), ferulic acid (5.52mg/kg), TANSHINONES (90.1mg/kg)) that rabbit prepares through auricular vein injection embodiment 1.Adopt reversed phase high-performance liquid chromatography (high performance liquid chromatograph 1100 types (U.S. Agilent company product) then respectively, comprise the online degasser of G1379A, G1312A double base pump, G1313A automatic sampler, diode array detector (DAD), HP Chemistation chem workstation; AgilentZORBAX SB-C
18Chromatographic column (150mm * 4.6mm, id.5 μ m, U.S. Agilent company product).Chromatographic condition: mobile phase is methanol and 0.5% glacial acetic acid aqueous solution, adopts gradient elution, elution program such as table 1, flow velocity 1mL/min, detecting wavelength is the maximum absorption wavelength (danshensu 281nm, ferulic acid 320nm, cryptotanshinone and tanshinone are 254nm) of each material.Column temperature is a room temperature.Sample size is 10 μ l) measure the blood drug level of danshensu, ferulic acid and TANSHINONES in folk prescription (danshensu group, ferulic acid group, cryptotanshinone group) and the compound recipe (No. 1 side, red rhizome of chuanxiong side) respectively, determination data is through the processing of 3P87 calculation procedure and carry out the model differentiation, its pharmacokinetic parameter shown in table 11, table 12, table 13, t in table 11, table 12, the table 13
1/2 αExpression distribution half-life, t
1/2 βHalf-life, K are eliminated in expression
10Elimination rate constant, the K of expression central compartment
12Expression is by transport velocity constant, the K of central compartment to periphery compartment
21Expression is by transport velocity constant, the V of periphery compartment to the central compartment
(c)Expression apparent volume of distribution, AUC represent that area under the drug-time curve, CLs represent the medicine clearance rate.
2, experimental result
Danshensu is as shown in table 11 at the intravital pharmacokinetics comparative result of rabbit, the result shows, danshensu is separately or after compound recipe (injection of No. 1 side, red rhizome of chuanxiong side of the embodiment 1 preparation) intravenous injection, its in the body of rabbit through the time change and meet the intravenously administrable one-level and absorb two-compartment model.The main pharmacokinetic parameters such as the t of danshensu
1/2 α, t
1/2 β, V
(c), parameter does not more all have statistical significant difference (P＞0.05) in AUC and CLs etc. and the compound recipe, and average is also more approaching, illustrates that compound recipe (No. 1 square injection in red rhizome of chuanxiong side) administration disposes pharmacokinetics in the body of danshensu and do not have the significance influence.The result shows, wait the administration of dosage compound recipe after, in the prescription other compositions to danshensu in the basic not influence of the intravital pharmacokinetics process of rabbit (as distributing and draining).
Danshensu is at the intravital pharmacokinetics of rabbit (x ± sd) relatively in table 11. folk prescription and the compound recipe
| Parameter | Unit | Danshensu (individually dosed) | Danshensu (No. 4 square injections in red rhizome of chuanxiong side) |
| V(c) | (mg/kg)/(μg/ml) | 0.27±0.08 | 0.26±0.04 |
| t 1/2α | min | 2.84±2.00 | 2.33±1.13 |
| t 1/2β | min | 20.95±10.18 | 24.86±21.30 |
| K 21 | 1/min | 0.21±0.23 | 0.19±0.22 |
| K 10 | 1/min | 0.09±0.04 | 0.12±0.05 |
| K 12 | 1/min | 0.24±0.32 | 0.14±0.13 |
| AUC | (μg/ml)min | 154.98±88.45 | 116.85±49.97 |
| CL(s) | mg/kg/min/(μg/ml) | 0.02±0.01 | 0.03±0.02 |
Ferulic acid is as shown in table 12 at the intravital pharmacokinetics comparative result of rabbit in folk prescription and the compound recipe, the result shows, ferulic acid is after independent or compound recipe (No. 1 square injection in red rhizome of chuanxiong side of embodiment 1 preparation) intravenous injection, and its physiological disposition rabbit all meets the intravenously administrable two-compartment model.The main pharmacokinetic parameters of individually dosed back ferulic acid is (as t
1/2 α, t
1/2 β, V
(c), AUC and CLs etc.) with compound recipe (No. 1 square injection in red rhizome of chuanxiong side) administration after the pharmacokinetic parameters of ferulic acid more all do not have statistical significant difference (P＞0.05), and its average is also more approaching, illustrates that compound recipe (No. 1 square injection in red rhizome of chuanxiong side) administration does not have the significance influence to pharmacokinetics process in the body of ferulic acid.The blood drug level time lengthening that ferulic acid can measure after compound recipe (No. 1 square injection in the red rhizome of chuanxiong side) administration, the ferulic acid list time spent, generally can only in 240 minutes, detect ferulic acid original shape medicine, and can in 360 minutes, detect ferulic acid after No. 1 square injection administration in red rhizome of chuanxiong side.AUC after ferulic acid list usefulness and No. 1 square injection administration in red rhizome of chuanxiong side is respectively 94.33 ± 27.65 and 122.05 ± 48.92, single time spent of AUC that compound recipe (No. 1 square injection in red rhizome of chuanxiong side) administration ferulic acid is described has on average increased by 22%, ferulic acid increased in the intravital body storage of rabbit after compound recipe (No. 1 square injection in red rhizome of chuanxiong side) administration was described, eliminated and slowed down relatively.
Table 12. ferulic acid is at the intravital pharmacokinetics of rabbit (x ± sd) relatively
| Parameter | Unit | Ferulic acid (individually dosed) | Ferulic acid (No. 1 square injection in red rhizome of chuanxiong side) |
| V(c) | (mg/kg)/(μg/ml) | 0.20±0.06 | 0.19±0.05 |
| t 1/2α | min | 1.47±1.30 | 1.68±1.06 |
| t 1/2β | min | 19.28±10.21 | 20.61±9.96 |
| K 21 | 1/min | 0.28±0.35 | 0.22±0.27 |
| K 10 | 1/min | 0.19±0.09 | 0.16±0.07 |
| K 12 | 1/min | 0.80±1.32 | 0.25±0.20 |
| AUC | (μg/ml)*min | 94.33±27.65 | 122.05±48.92 |
| CL(s) | mg/kg/min/(μg/ml) | 0.03±0.01 | 0.03±0.02 |
It is more as shown in table 13 in the intravital pharmacokinetics of rabbit to reach the compound recipe cryptotanshinone separately, the result shows, after reaching compound recipe (No. 1 square injection in red rhizome of chuanxiong side of embodiment 1 preparation) intravenous administration separately, cryptotanshinone all meets the intravenously administrable two-compartment model in the intravital disposal process of rabbit.Some pharmacokinetic parameters of two kinds of administering modes are (as t
1/2 αAnd t
1/2 β) do not demonstrate significant difference, both t
1/2 αAverage is very approaching, is about 2.3min, illustrates that cryptotanshinone distributes comparatively fast in vivo.The t of cryptotanshinone after the compound recipe administration
1/2 βAverage is more individually dosed to have improved 22%, the compound recipe administration is described after cryptotanshinone slow down but t in the intravital elimination of rabbit
1/2 βValue does not demonstrate evident difference after learning by statistics and handling, and this may be the bigger result who causes of individual variation of animal.Analysis result finds, some other pharmacokinetic parameters behind two kinds of drug administrations such as clearance rate (Cls) and area under the drug-time curve (AUC) have all demonstrated statistical significant difference (P＜0.05).After compound recipe (No. 1 square injection in red rhizome of chuanxiong side of the embodiment 1 preparation) administration, single time spent of the Cls of cryptotanshinone obviously reduces, and shows to eliminate and slows down.Its AUC value is because t
1/2 βProlongation and slowing down of Cls and obviously increasing, the body storage increase of cryptotanshinone be described with compound recipe (No. 1 square injection in red rhizome of chuanxiong side of embodiment 1 preparation) administration.The distribution speed constant alpha of cryptotanshinone behind two kinds of drug administrations of comparison, the distribution speed of cryptotanshinone slows down after as can be seen red rhizome of chuanxiong side (No. 1 square injection in red rhizome of chuanxiong side of the embodiment 1 preparation) administration.From the central compartment to periphery compartment transport velocity constant K
12As can be seen, in red rhizome of chuanxiong side (embodiment 1 preparation No. 1 square injection in red rhizome of chuanxiong side) cryptotanshinone the distribution speed to the peripheral compartment also slows down from the central compartment.
From The above results as can be seen, after red rhizome of chuanxiong side (No. 1 square injection in red rhizome of chuanxiong side of embodiment 1 preparation) administration, cryptotanshinone slows down in the intravital elimination of rabbit, retain time lengthening in the body, other chemical constituents after the administration of prompting compound recipe in the red rhizome of chuanxiong side are disposed pharmacokinetics in the body of cryptotanshinone and have been produced certain influence.But from integral body, the interior pharmacokinetics of the body of cryptotanshinone is disposed and is improved after the compound recipe administration, helps clinical practice.
Table 13. cryptotanshinone is at the intravital pharmacokinetics of rabbit (x ± sd) relatively
Comprehensive above-mentioned result of the test shows, improves significantly when the pharmacokinetics process is than the independent medication of each one matter in the body of each composition after red rhizome of chuanxiong compound recipe (No. 1 square injection in red rhizome of chuanxiong side of the embodiment 1 preparation) administration.
Four, the toxicity test of the medicine of prevention and treatment hepatic injury
1, ferulic acid, TANSHINONES and danshensu are through the acute toxicity test of mice lavage
Detect the acute toxicity of ferulic acid, TANSHINONES and danshensu respectively with white mice.Healthy ICR mice, body weight 18 ± 2g, male and female half and half (Capital University of Medical Sciences's Experimental Animal Center provides, quality certification 2000-0012).Experimental result is as described below:
(1) ferulic acid: white mice is divided into 5 groups at random, and 10 every group, observed 7 days by 2234,2390,2557,2736 and the 2928mg/kg gastric infusion every day respectively, write down death condition.After irritating stomach, occurred at that time rolling up that motionless, perpendicular hair, eyes close, abdominal discomfort, appetite depression phenomenon, disappear after 6-8 hour, it is normal that its spirit, appetite etc. are recovered.
The LD that white mice is oral
50For: 2421.57 ± 78.84mg/kg body weight.
(2) TANSHINONES: white mice is divided into 5 groups at random, and 10 every group, observed 7 days by 1981.1,2278.26,2620,3013 and the 3464.9mg/kg gastric infusion every day respectively, write down death condition.Occurred at that time rolling up that motionless, perpendicular hair, eyes close, abdominal discomfort, appetite depression phenomenon, disappear after 6-8 hour, it is normal that its spirit, appetite etc. are recovered.
The LD that white mice is oral
50For: 2574.52 ± 206.17mg/kg body weight.
(3) danshensu: white mice is divided into 5 groups at random, and 10 every group, observed 7 days by 3900,4175,4465 and the 4785mg/kg gastric infusion every day respectively, write down death condition.After irritating stomach, occurred at that time rolling up that motionless, perpendicular hair, eyes close, abdominal discomfort, appetite depression phenomenon, disappear after 6-8 hour, it is normal that its spirit, appetite etc. are recovered.
The LD that white mice is oral
50For: 4403.62 ± 237.75mg/kg body weight.
2,1-6 side, red rhizome of chuanxiong side is through the acute toxicity test of mice lavage
Detect the oral acute toxicity of prescription 1-6 respectively with white mice, experimental result is as described below:
The LD oral according to the white mice of ferulic acid, TANSHINONES and danshensu
50Result and actual mice are born the maximum volume of irritating stomach.Formulate acute toxicity test dosage respectively red rhizome of chuanxiong side 1-6 number through mice lavage.
With ICR mice (male and female half and half, available from Capital University of Medical Sciences's Experimental Animal Center, lot number SCXK (capital) 2005-0006) 60, be divided into 6 groups at random, every group 10, the prescription dosage is pressed ferulic acid respectively, total is compared in each assembly of TANSHINONES and danshensu, No. 1 square crude drug in red rhizome of chuanxiong side (4230.8mg/kg body weight) with embodiment 1 preparation, the red No. 2 square crude drug in rhizome of chuanxiong side (5089.7mg/kg), the red No. 3 square crude drug in rhizome of chuanxiong side (7867.8mg/kg), the red No. 4 square crude drug in rhizome of chuanxiong side (4491.9mg/kg), red No. 5 square crude drug in rhizome of chuanxiong side (7046.6mg/kg) and No. 66 square crude drug in red rhizome of chuanxiong side (5577.8mg/kg) all adopt gastric infusion, observed the record death condition 7 days.
After irritating stomach, all mices lethargy occurred, rolled up motionless, perpendicular hair at that time, eyes close, abdominal discomfort, appetite depression phenomenon, disappeared after 6-8 hour, and it is normal that its spirit, appetite etc. are recovered.No animal dead takes place in one week.
The white mice toxicity test shows that each medicine (has reached medicine dissolution and animal and irritated the maximum volume that stomach can tolerate), does not see mice dying in the week under the dosage of oral absorption total amount 4230～7867mg/kg body weight.According to the toxicity assessment standard, the animal tolerance dose is 18～45 times of actual dosage, and this product is considered as nontoxic or low toxicity.The clinical application recommended dose of this prescription only is 10mg/kg, and according to the toxicity assessment standard, clinical recommended drug dosage is safer.
Five, the stability of drug test of prevention and treatment hepatic injury
The preparation (ratio of weight and number of ferulic acid, danshensu, cryptotanshinone is 16.12: 20.71: 63) of 6 batches of No. 4 sides, red rhizome of chuanxiong side of embodiment 1 preparation put in 4 ℃ of refrigerators preserve, respectively at 7,15,30, sampling in 60,120,180,240,360 days, with its active component of high performance liquid chromatograph detection by quantitative, calculate the degree of variation of the peak area of the composition of surveying.The result shows that each constituent content content under preservation condition is relatively stable, and its relative standard deviation RSD is all less than 5%.Its appearance character does not have change in the preservation process.Its index content is relatively stable in 1 year.
Claims (9)
1. the medicine of a prevention and treatment hepatic injury and blood fat reducing, its effective ingredient is made up of following substances in parts by weight:
Ferulic acid 4.5-35.0 part,
Danshensu 4.9-30.0 part,
Cryptotanshinone 63.0-380.0 part.
2. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
5.52 parts of ferulic acids,
10.15 parts of danshensus,
90.1 parts of cryptotanshinones.
3. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
7.90 parts of ferulic acids,
29.59 parts of danshensus,
183.8 parts of cryptotanshinones.
4. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
11.28 parts of ferulic acids,
7.11 parts of danshensus,
375 parts of cryptotanshinones.
5. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
16.12 parts of ferulic acids,
20.71 parts of danshensus,
63 parts of cryptotanshinones.
6. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
23.02 parts of ferulic acids,
4.97 parts of danshensus,
128.6 parts of cryptotanshinones.
7. medicine according to claim 1 is characterized in that: the effective ingredient of described medicine is made up of following substances in parts by weight:
32.88 parts of ferulic acids,
14.50 parts of danshensus,
260.5 parts of cryptotanshinones.
8. according to the arbitrary described medicine of claim 1-7, it is characterized in that: also being added with in the described medicine is the adjuvant of described effective ingredient quality 2-10%.
9. according to the arbitrary described medicine of claim 1-7, it is characterized in that: also being added with in the described medicine is the cosolvent of described effective ingredient quality 1-5%.
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| CN1616064A (en) * | 2004-09-30 | 2005-05-18 | 北京正大绿洲医药科技有限公司 | Blood circulation promoting dripping pill for treating cardiocerebral vascular disease |
| CN1742793A (en) * | 2004-09-02 | 2006-03-08 | 山东绿叶天然药物研究开发有限公司 | Medicine composition and use thereof |
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| CN1742793A (en) * | 2004-09-02 | 2006-03-08 | 山东绿叶天然药物研究开发有限公司 | Medicine composition and use thereof |
| CN1616064A (en) * | 2004-09-30 | 2005-05-18 | 北京正大绿洲医药科技有限公司 | Blood circulation promoting dripping pill for treating cardiocerebral vascular disease |
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