CN1272004C - Use of Chinese medicinal Bamatin in treatment of diabetes II - Google Patents
Use of Chinese medicinal Bamatin in treatment of diabetes II Download PDFInfo
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- CN1272004C CN1272004C CN 200410026226 CN200410026226A CN1272004C CN 1272004 C CN1272004 C CN 1272004C CN 200410026226 CN200410026226 CN 200410026226 CN 200410026226 A CN200410026226 A CN 200410026226A CN 1272004 C CN1272004 C CN 1272004C
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Abstract
The present invention relates to a palmatine chloride ingredient from a raw material medicine of traditional Chinese medicines, and the application of the ingredient in the treatment for non-insulin dependent diabetes diseases. The palmatine chloride is from the alkaloid extract of the raw material medicine of golden thread or amur cork-tree. The present invention has the advantages of simple and practical extracting method, excellent purifying effect and accurate ingredient treating effect. Parmacodynamics research shows that the plmatine chloride of the present invention can be used as the medicine for treating the non-insulin dependent diabetes.
Description
Technical field
The present invention relates to a kind of composition, relate in particular to from palmatine hydrochloride composition in Rhizoma Coptidis and the Cortex Phellodendri crude drug extract from the raw material of Chinese medicine medicine.The invention still further relates to the application of palmatine hydrochloride in preparation treatment type ii diabetes disease medicament in the extract.
Background technology
(diabetes mellitus is the clinical syndrome that causes owing to the h and E factor interaction DM) to diabetes, is one of prevailing endocrinopathy.Absolute or relative deficiency and target tissue reduce insulin sensitivity because of insulin secretion, cause a series of metabolism disorders such as sugar, albumen, fat, power and water Xie Zhi.(polyphagia, polydipsia, polyuria) more than three, few (weight loss), a hyperglycemia symptom appear clinically.According to the difference of the cause of disease, diabetes can be divided into insulin dependent diabetes mellitus (IDDM) (IDDM, 1 type) and non-insulin-dependent diabetes mellitus (NIDDM, 2 types).
At present there is diabetic 300,000,000 in the whole world, in state-owned 6,000 ten thousand.86%-89% is a type 2 diabetes mellitus in these patients, shows as the excessive generation and the low utilization ratio of glucose, thereby causes hyperglycemia symptom rapidly.Diabetes are higher than the rural area at the sickness rate in city, and old, fat, living standard is improved by difference and falls ill easily.Severe complications such as coronary heart disease, ischemic or hemorrhagic apoplexy, blind, acromelic gangrene take place in diabetic population all apparently higher than non-diabetic people.Therefore, diabetes have become the Chronic Non-Communicable Diseases of the 3rd serious harm human body health after tumor, cardiovascular and cerebrovascular disease in the world.Just for above-mentioned situation, people we can say with a long history to the research of diabetes, in the ascendant so far.
Treatment of diabetes mainly contains psychotherapy, dietetic therapy, exercise therapy, insulin treatment and Drug therapy (oral antidiabetic drug).In general, if oral antidiabetic drug can not better controlled blood glucose, will be treated with insulin so.Insulin is the unique effective Therapeutic Method of treatment type 1 diabetes.The medicine of the treatment type 2 diabetes mellitus of having thrown in in the market has: the short secretion of (1) insulin medicine, as sulfonylureas: glyburide (glyburide, glibenclamide), glipizide (glipizide, glipizide), diamicron (gliclazide, gliclazide), gliquidone (gliquidone, gliquidone), also have ockers Nateglinide (nateglinide), the repaglinide (repaglinide) that upgrades; (2) biguanides is as metformin (metformin hydrochloride); (3) α-sugared sweet enzyme inhibitor is as acarbose (acarbose); (4) glitazone (glitazones) is as pioglitazone (pioglitazone), rosiglitazone (rosiglitazone).
Sulfonylureas is one of medicine of the most frequently used treatment diabetes.This type of medicine has multiple, and its common structure is R
1-SO
4N-HCONH-R
2Sulfo group and urea acyl group are in conjunction with its blood sugar reducing function of decision, and the change of prothetic group determines the intensity and the time of different sulfonylurea hypoglycemic agent effects.
This type of medicine promotes insulin to discharge by the receptor that acts on the beta Cell of islet surface, and its hypoglycemic activity depends on and remains the beta Cell of islet tissue that function is arranged at a great deal of (more than 30%).In addition, sulfonylureas treatment patient NIDDM can improve Insulin receptor INSR and postreceptor defects, and the intensifier target tissue is to the sensitivity of insulin, so think to have the outer hypoglycemic activity of pancreas.At this moment or add with other class antidiabetic drugs but along with decline and some other factor of insulin secretion function, the effect of sulfonylurea hypoglycemic agent also can descend, and, or adds and uses insulin.
The main indication of sulfonylureas is patient NIDDM with Diet Therapy and physical training is invalid and light, moderate diabetes patient that islet function remains.This class medicine is not suitable for patient IDDM, and NIDDM merges severe infections, ketoacidosis, and hyperosmolar coma is carried out major operation, with hepatic and kidney function obstacle, and the patient who merges gestation.
Significant side effects of sulfonylureas is that consumption hypoglycemia can occur when excessive.Therefore, the problem of rational use of drug should be noted during medication, Rhizoma Coptidis (Rhizoma Coptidis) should be before drink, taken
This product is the dry rhizome of ranunculaceae plant Rhizoma Coptidis Coptis chinensis Franch., Coptis deltoidea C.Y.Cheng et Hsiao Coptis deltoidea C.Y.Cheng et Hsiao or Coptis Teeta Wall Coptis teeta Wall..More than three kinds practise to claim " flavor connects ", " refined company ", " Coptis Teeta Wall " respectively.Excavate autumn, removes fibrous root and silt, and drying is hit residual fibrous root.According to " it is cold in nature that Chinese pharmacopoeia was put down in writing Rhizoma Coptidis in the version in 2000, bitter in the mouth.GUIXIN, spleen, stomach, liver, gallbladder, large intestine channel.Has heat clearing and damp drying, eliminating fire and detoxication.Be used for damp and hot feeling of fullness, vomiting, dysentery, jaundice, unconsciousness due to high fever, hyperactivity of heart-fire, dysphoria and insomnia, heat in blood is told nosebleed, the conjunctival congestion acid regurgitation, the carbuncle furuncle is quenched one's thirst in toothache; External treatment eczema, eczema, auditory meatus is suppurated.The kind clear part of the body cavity above the diaphragm housing the heart and lungs of Rhizoma Coptidis (processed with wine) is burning hot.Be used for conjunctival congestion, aphtha.Prepared RHIZOMA COPTIDIS with rhizoma zingiberis recens juice clearing stomach stomach function regulating preventing or arresting vomiting.Be used for cold and heat and tie mutually, damp and hot middle resistance, feeling of fullness vomiting.Cornel Rhizoma Coptidis soothing liver-QI stomach function regulating preventing or arresting vomiting.Be used for incoordination between the liver and stomach, diseases such as vomiting acid regurgitation.
The main alkaloid that contains in the Rhizoma Coptidis, all contain in " flavor connects ", " refined company ", " Coptis Teeta Wall " three kinds of Rhizoma Coptidis berberine (berberine), palmatine (palmatine, palmatine), coptisine alkaloids such as (Coptisine).Also contain inorganic elementss such as Cu, Mn, Zn, Fe, Co, Se, Sr, Ti, Al, Mg, K, Ca in addition
Cortex Phellodendri (Cortex Phellodendri)
This product is the dry bark of rutaceae wampee Phellodendron chinense Schneid..Practise and claim " Cortex Phellodendri ".According to " it is cold in nature that Chinese pharmacopoeia was put down in writing Cortex Phellodendri in the version in 2000, and bitter in the mouth is returned kidney, urinary bladder channel.Have heat clearing and damp drying, pathogenic fire purging removes steams, and skin ulcer is treated in detoxifcation.Be used for damp-heat dysentery, jaundice, leukorrhagia, pyretic stranguria, beriberi, flaccidity, hectic fever due to YIN-deficiency consumptive fever, night sweat, seminal emission, sore swollen toxin, eczema pruritus.Salt Cortex Phellodendri (processed) nourishing YIN to lower pathogenic fire is used for hyperactivity of fire caused by deficiency of YIN, diseases such as night sweat hectic fever due to YIN-deficiency.
The main alkaloid, content about 1%～3% of containing in the Cortex Phellodendri.It is mainly formed berberine (berberine), palmatine (palmatine, palmatine), jateorhizine (jatrorrhizine), magnoflorine (magnoflorine) etc., other contains phellodendrine (phelldendrine), Dauricine (meruspermine), candicine (candicine, candicine), guanidine (guanidine) etc.; The amaroid composition mainly contains obakulactone (obakulactone), obacunone (obakunone), limonin (limonin); The steroidal composition has cupreol (β-sitosterol), clionasterol (γ-sitosterol), campesterol (campesterol), 7-Dehydrostigmaslerol (7-dehydrostigmasterol).Dictamnolide (dictamnolide), obacunonic acid (obacunonic acid), lumicaeruleic acid (lumicaeruleic acid), 24-methylene cycloartenol (24-methyleneoycloartenol), γ-hydroxyl butylene lactone derivatives I, II, Fici hispidae alcohol (hispiol), berberrubine (berberrubine).Still contain the single glycoside of chlorogenic acid compounds, lignanoid in addition, to single glycoside of the N-methyl four oxygen benzoyl isoquinolin of oxybenzene ethanol celery acyl glycoside and 3 phenolic hydroxyl groups of a kind of tool.Berberine generally contains 1.6%～4.0% in Cortex Phellodendri, the approaching more tree base portion of content of berberine is high more in the bark, and high more near magnoflorine and palmatine equal size in the treetop portion skin more.Outside the Herb disleaf, fruit and xylem also all contain berberine.Place of production difference, content of berberine is variant.Root bark also contains berberine, jateorhizine, phellodendrine, candicine.Woody part contains berberine.
Wampee contains berberine, magnoflorine, phellodendrine, palmatine and lactone, sterol, phlegmatic temperament etc.
Bald leaf wampee contains N-1 (tetrahydroberberine), tetrahydropalmatine (tetrapalmatine), tetrahydrojatrorrhizine (tetrahydrojatrorrhizine), phellodendrine, magnoflorine and cupreol.
Taiwan is produced Cortex Phellodendri (P.wilsonii Hay-et kane) and is contained berberine, Columbamine (columbamine), jateorhizine, magnoflorine, palmatine, phellodendrine, thalifendine (thalifendine), thalictrinine (thaloiphenine).
The applicant is surprised to find that producing effect in the diabetes treatment of diseases, thereby has finished content of the present invention in the berberine hydrochloride in Rhizoma Coptidis and the Cortex Phellodendri and palmatine hydrochloride composition are studied.
Summary of the invention
The invention provides a kind of palmatine hydrochloride composition from the raw material of Chinese medicine medicine, this composition can be used for preparing the medicine of treatment type ii diabetes disease.
The present invention especially provides the composition from the palmatine hydrochloride of Chinese medicine Rhizoma Coptidis and Cortex Phellodendri, and then has proposed the new medical usage of effective ingredient in Rhizoma Coptidis and the Cortex Phellodendri.
Composition of the present invention can be from any crude drug that contains palmatine hydrochloride and berberine hydrochloride, preferably from alkaloid effective ingredient in Rhizoma Coptidis and the Cortex Phellodendri crude drug.Can obtain by any feasible method.
By pharmacodynamic study, prove that palmatine hydrochloride of the present invention can be used for the type ii diabetes treatment of diseases.
For the checking palmatine hydrochloride composition of the present invention medicinal effects, except composition detection, the inventor also to this composition carried out further cell membrane chromatography (Cell MembraneChromatography, CMC).The cell membrane chromatograph is a kind of bionic biological affinity chromatography method, and the specificity that can measure between medicine and compound molecule and cell membrane and membrane receptor interacts.With islet cells membrane chromatography model, be contrast in the experiment of the present invention, the effective ingredient in Rhizoma Coptidis and the Cortex Phellodendri crude drug total effective parts is screened with the glibenclamide.
Result of the test shows, under the CMC screening conditions, contain the effective ingredient similar to the glibenclamide effect and berberine hydrochloride and palmatine hydrochloride in Rhizoma Coptidis of the present invention and the Cortex Phellodendri total effective parts, wherein the action intensity of berberine hydrochloride and palmatine hydrochloride and islet cells film and membrane receptor is greater than positive control drug.
In a word, the inventor is surprised to find that in the medicinal research to Rhizoma Coptidis and Cortex Phellodendri mentioned component is effective to the type ii diabetes treatment of diseases, and determine wherein contain dative be listed as this ureas like the effect active component.Further the test of pesticide effectiveness confirms, effective ingredient is to not influence of euglycemia in Rhizoma Coptidis and the Cortex Phellodendri.The alloxan induced hyperglycemia there is the reduction effect.
The specific embodiment
Below be the inventor provide about concrete enforcement of the present invention and therapeutic effect, and further elaborating of carrying out in conjunction with the preferred embodiments.
1. the extraction of Rhizoma Coptidis and Cortex Phellodendri effective site
Rhizoma Coptidis or Cortex Phellodendri medical material are measured 85% alcohol heating reflux 2 times with 8 times, each 2h.Merge extractive liquid, reclaims ethanol, and concentrated aqueous liquid makes into thick.The water that adds 1/2 medical material amount stirs, the multilamellar filtered through gauze, and filtrate adds proper C a (OH)
2, stir, leave standstill 24h, filter.Filtrate concentrates, and puts coldly, regulates pH1～pH2 with hydrochloric acid, leaves standstill, and has precipitation to separate out, and filters drying precipitated Cortex Phellodendri or the Rhizoma Coptidis extract of promptly getting.
2. the thin layer chromatography qualitative analysis of Rhizoma Coptidis or Cortex Phellodendri extract
Get this product powder 10.0mg, add hydrochloric acid-methanol (1: 100) solution 10mL, sonic oscillation 20min filters, and filtrate is replenished methanol to 10mL, as need testing solution.Other gets berberine hydrochloride and palmatine hydrochloride reference substance, adds methanol and makes the solution that every 1mL contains 0.5mg, in contrast product solution.According to thin layer chromatography (" appendix VIB of Chinese pharmacopoeia version in 2000) test, draw each 1 μ L of above-mentioned three kinds of solution, put respectively on same silica gel g thin-layer plate, with benzene-ethyl acetate-isopropyl alcohol-methanol-strong ammonia solution (6: 3: 1.5: 1.5: 0.5) is developing solvent, put in the expansion cylinder of ammonia saturated with vapor, launch, take out, dry, put under the ultra-violet lamp (365nm) and inspect.In the test sample chromatograph, with the corresponding position of reference substance chromatograph on, show the yellow fluorescence speckle of same color.
The result shows, contains berberine hydrochloride and palmatine hydrochloride in this extract.
3. chromatograph screening conditions
With rabbit islet cells film immobile phase dress post (50mm * 2mm, I.D.);
Mobile phase: 25mmol/L ammonium sulfate buffer (pH7.4);
Flow velocity: 0.5ml/min;
Detect wavelength: 270nm;
Column temperature: 37 ℃.
Get above-mentioned Rhizoma Coptidis respectively and Cortex Phellodendri total effective extractive part, glibenclamide, berberine hydrochloride and palmatine hydrochloride are an amount of, add pyridine 100 μ l and make dissolving, centrifugal 5min (6000r/min) draws supernatant 5 μ l sample introductions and measures, the positive contrast medicine of glibenclamide, record CMC screening chromatogram.Under the CMC screening conditions, contain the effective ingredient similar to the glibenclamide effect and berberine hydrochloride and palmatine hydrochloride in this Rhizoma Coptidis and the Cortex Phellodendri total effective parts, wherein the action intensity of berberine hydrochloride and palmatine hydrochloride and islet cells film and membrane receptor is greater than positive control drug.
4. palmatine hydrochloride and berberine hydrochloride are to normal mouse blood sugar and the pharmacology that stimulates insulin secretion
Some can promote secretion of insulin by stimulating beta Cell of islet in the antidiabetic medicine; Some can suppress glyconeogenesis, promotes the glucose utilization in the peripheral tissues or suppresses the picked-up of glucose at small intestinal, and some can improve peripheral tissues the sensitivity of insulin is reached hypoglycemic purpose.So some hypoglycemic drug not only can make the blood sugar level of hyperglycemia animal reduce, and normal blood sugar level is reduced.Sulfonylureas such as glibenclamide, glipizide, gliquidone and gliclazide, the metformin of biguanides, and berberine is the hypoglycemic drug of using always.This experiment is made the experiment object with healthy mice, has compared the pharmacological action intensity that reduces euglycemia and stimulate insulin secretion.
5. experiment material
Medicine and reagent glibenclamide (Tianjin Lisheng Pharmaceutical Co., Ltd., lot number 0301003), metformin (Shenzhen China Associated Pharmaceutical Co., Ltd., lot number 0203068), berberine hydrochloride, palmatine hydrochloride (self-control), glucose oxidase enzyme reagent kit (Zhongsheng Beikong Biological Science ﹠ Technology Co., Ltd.), I
125-insulin test kit.
Animal Kunming kind male white mouse, body weight 18g～22g is provided by Xi'an Communications University's Experimental Animal Center.
6. method and result
84 of mices are divided into 5 groups by the body weight layering, and 12 every group is negative control group, glibenclamide, metformin, berberine hydrochloride and palmatine hydrochloride successively.Raised 3 days under experimental situation, eye socket is got blood, and is centrifugal, gets serum 10 μ L, and determination of glucose oxidase blood glucose is designated as the preceding blood glucose value of medicine.Ig gives corresponding medicine, and once a day, continuous 7 days, the last administration was after 2 hours, and eye socket is got blood, measures blood glucose once more, is designated as blood glucose value behind the medicine, all needs fasting (can't help water) 10 hours before the blood sugar detection.In addition, get the mensuration of serum 100 μ L as serum insulin levels.Experimental result adopts the analysis of t inspection statistics.
Table 1 berberine hydrochloride and palmatine hydrochloride are to the influence of mice euglycemia and insulin level
| Group | Dosage (g/kg) | Blood glucose value (mgdL -1) | Serum insulin levels | ||
| Before the medicine | Behind the medicine | Difference (anterior-posterior) | |||
| Blank group | - | 6.4±0.8 | 6.4±1.3 | 0.0±1.1 | 25.7±10.3 |
| Glibenclamide | 0.028 | 6.4±1.3 | 4.7±1.0 | 1.7±1.2** | 28.4±13.6 |
| Metformin | 0.500 | 6.4±1.0 | 5.0±1.1 | 1.3±1.2* | 20.2±11.5 |
| Berberine hydrochloride | 0.500 | 6.5±1.0 | 6.3±1.0 | 0.2±1.4 | 24.5±8.7 |
| Palmatine hydrochloride | 0.500 | 6.4±1.0 | 6.0±1.3 | 0.4±1.2 | 24.7±7.3 |
With the blank group than * P＜0.05, * * P＜0.01
Data can draw from table, and glibenclamide has the reduction effect to the mice euglycemia, and metformin reduces serum insulin levels when reducing euglycemia.The two influence there are no significant meaning of palmatine hydrochloride and berberine hydrochloride.
7. palmatine hydrochloride and berberine hydrochloride are to the influence of alloxan induced hyperglycemia mice
80 of Kunming kind white mice, male and female half and half, under experimental situation, raise be 22 ~ 26g to body weight after, fasting (can't help water) 24 hours, tail vein iv alloxan 48gkg
-1After 4 days, observe each treated animal and tangible polydipsia, polyphagia symptom occur.Eye socket is got blood, get blood before, animal fasting (can't help water) 6 hours, glucose oxidase enzymatic determination blood glucose, note is made blood glucose value before the medicine.And be divided into 6 groups, administration every day 1 time, a continuous week according to blood glucose value.Fasting administration after 4 hours before the last administration, after the administration 2 hours, eye socket was got its blood glucose value of hematometry, with matched group relatively, the administration group causes the degree of blood sugar increasing to alloxan after the statistical analysis administration, observes simultaneously respectively to organize the per 12 hours drinking-water of mice and change.
Table 2 berberine hydrochloride and palmatine hydrochloride are to the influence of alloxan induced hyperglycemia mice
| Group | The example number | Dosage (gkg -1) | Blood glucose (mmolL before the medicine -1) | Blood glucose (mmolL behind the medicine -1) | Difference (back-preceding) (mmolL -1) |
| Model group | 12 | - | 30.3±7.7 | 30.4±9.5 | 0.1±4.3 |
| Metformin | 9 | 0.3 | 29.2±15.0 | 11.6±7.8 | -17.6±13.0** |
| Palmatine hydrochloride | 9 | 0.7 | 27.5±10.1 | 23.7±10.5 | -3.8±4.4* |
| Berberine hydrochloride | 12 | 0.5 | 26.6±10.4 | 21.6±10.7 | -5.0±6.0* |
" * * " represents P＜0.01, and " * " represents P＜0.05
Experimental result (seeing Table 3-1) shows that palmatine hydrochloride and berberine hydrochloride reduce alloxan induced hyperglycemia mice blood glucose and have significance meaning (P＜0.05), point out these two medicines to have certain hypoglycemic activity.
Claims (2)
1. the chemical substance palmatine hydrochloride that contains in the Chinese medicine extract is used to prepare the medicinal usage for the treatment of type ii diabetes.
2. purposes as claimed in claim 1 is characterized in that described chemical substance palmatine hydrochloride comes from the extract of Chinese medicine Rhizoma Coptidis and Cortex Phellodendri.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410026226 CN1272004C (en) | 2004-06-10 | 2004-06-10 | Use of Chinese medicinal Bamatin in treatment of diabetes II |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410026226 CN1272004C (en) | 2004-06-10 | 2004-06-10 | Use of Chinese medicinal Bamatin in treatment of diabetes II |
Publications (2)
| Publication Number | Publication Date |
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| CN1582930A CN1582930A (en) | 2005-02-23 |
| CN1272004C true CN1272004C (en) | 2006-08-30 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN 200410026226 Expired - Fee Related CN1272004C (en) | 2004-06-10 | 2004-06-10 | Use of Chinese medicinal Bamatin in treatment of diabetes II |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101153039B (en) | 2006-09-30 | 2010-12-01 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant and pharmaceutical composition |
| CN103288821A (en) * | 2012-03-01 | 2013-09-11 | 北京以岭药业有限公司 | Palmatine derivative and preparation method and application thereof |
| CN105497027A (en) * | 2015-12-15 | 2016-04-20 | 上海壹志医药科技有限公司 | Medical application of palmatine |
| CN116139134A (en) * | 2023-03-29 | 2023-05-23 | 首都医科大学附属北京同仁医院 | Application of berberine metabolite in preparation of medicine for stimulating GLP-1 secretion |
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