CN1056997C - Application of theaflavine for prepn. of medicine for lowering endotheliotoxin - Google Patents

Abstract

The present invention discloses a new use of tea pigments preparing medicine, namely that the tea pigments have the function of reducing blood serum endothelin and hormones relevant to calcium.

Description

The application of tea pigment in the medicine of preparation reduction Endothelin

The present invention relates to the new medicine use of tea pigment, be specifically related to the application of tea pigment in the medicine of preparation reduction Endothelin, belong to the field of Chinese medicines.

Tea pigment is the natural plant pigment that extracts from Folium Camelliae sinensis, is a kind of active pigment complex that catechin forms through peroxidating in the tea polyphenols.Tea pigment is made up of theaflavin, thearubigins and abrownin.For the existing bibliographical information of the research of tea pigment.CN1074618A discloses tea pigment and production method thereof.This production process is, Folium Camelliae sinensis is to decoct extracting juice, and alkalization concentrates, and acidify adds alcohol reflux, and alcohol reflux liquid alkalizes and obtains tea pigment crystallization product, through vacuum drying, promptly obtains this tea pigment.Theaflavin, thearubigins and abrownin three have constant ratio in the tea pigment that makes with this method, can be used as medicinal.Medical value report for tea pigment may be summarized to be reduction blood viscosity, blood fat reducing, cholesterol reducing, prevention and treatment cardiovascular disease.But up to the present, the relevant tea pigment of Shang Weijian is used to reduce the report of Endothelin.

A kind of new pharmaceutical applications that the purpose of this invention is to provide tea pigment, i.e. the application of tea pigment in the medicine of preparation reduction Endothelin.

In recent years, serum endothelin (ET) is subjected to people's extensive attention in the developing effect of the generation of cardiovascular disease.Confirmed that endothelium have intensive vasoconstrictive effect, zoopery shows that the Endothelin antiserum can make myocardial infarction area dwindle.And bibliographical information coronary heart disease of hypertension patients serum Endothelin raises, and therefore, seeks a kind of medicine that can reduce serum endothelin, will help the treatment of cardiovascular disease.Tea pigment has the effect of obvious reduction serum endothelin.

The extracting method of tea pigment of the present invention can extract according to known extraction process, preferably the tea pigment that extracts according to following method:

(1), with Folium Camelliae sinensis by 1: after 15-30 multiple proportions example added water, through once or the decoction extracting juice once, fried liquid is used in the aqueous solution can produce OH ^-Ionic chemical compound alkalizes, and regulates PH8-10, at the 1/4-1/10 that heats concentrated this alkaline solution to the original volume amount down less than 70 ℃, gets concentrated solution then; (2) concentrated solution transfers to PH3-6 with acid, and acidifying solution adds ethanol 1-10 volume doubly to be measured, and backflow 0.5-2 hour, gets alcohol reflux liquid; (3) alcohol reflux liquid is used in aqueous solution and can produces OH ^-Ionic chemical compound is regulated PH7-10, and post precipitation filters, and gets the tea pigment crystallization, and tea pigment crystallization vacuum drying promptly gets the tea pigment product.

Tea pigment of the present invention is a kind of active constituents of medicine, preparation process according to routine, can be main active constituent with tea pigment, add conventional excipient, flavoring agent, disintegrating agent, antiseptic, lubricant, wetting agent,, excipient substances such as binding agent, solvent, thickening agent, solubilizing agent, make any dosage form that is suitable for using clinically, as tablet, capsule, granule, oral liquid, injection etc.

Because the present invention discloses the pharmacologic action that tea pigment reduces serum endothelin first, therefore, tea pigment cooperated separately or with other active constituents or adjuvant make medicament, so long as this medicament is used to reduce Endothelin, all belong to protection scope of the present invention.

Tea pigment of the present invention all has the effect that reduces Endothelin when making any dosage form.Any medicament; if contain tea pigment in its component or only prepare patent medicine with the tea pigment single component; on signs such as its packing or description or on other any propaganda materials,, then fall within protection scope of the present invention as long as indicate or prompting has the effect that reduces Endothelin.

Tea pigment of the present invention is the natural plants Folium Camelliae sinensis that derives from medicine-food two-purpose.Therefore, also tea pigment can be made health food or health care medicine.Health food or health care medicine with tea pigment is made have the effect that reduces Endothelin if indicate or point out on signs such as its packing or description, also fall within protection scope of the present invention.

Embodiment 1

Prescription

Tea pigment 125 grams

Medical starch 875 grams

Above-mentioned component is gone into blender, and fully stirring and evenly mixing is encapsulated with capsule machine, and every filling 1 gram makes 1000 of tea pigment capsules, and every capsules contains 125 milligrams of tea pigments.

Embodiment 2

Tea pigment 250 grams

2000 milliliters of distilled water

Stevioside 1 gram

Tea pigment is dissolved in the distilled water, and fully mixing adds stevioside, and stirring and evenly mixing is once more packed in the vial with can packing machine, and every bottled 10 milliliters, sterilization makes the tea pigment oral liquid.

Experimental example 1 tea pigment is to the influence of Endothelin and calcium associated hormone

In recent years, ET is subjected to people's extensive attention in the developing effect of the generation of cardiovascular disease, has confirmed that ET has intensive vasoconstrictive effect, and zoopery shows that the ET antiserum can make myocardial infarction area dwindle.

Calcium ion content and metabolism have great significance for cardiovascular system, and relevant calcium associated hormone does not appear in the newspapers as yet in the change of cardiovascular system.

Tea pigment is the natural plant pigment that extracts from green tea, and through a series of pharmacology, toxicological study and clinical practice are confirmed that it is a kind of comparatively ideal new drug of preventing and treating cardiovascular and cerebrovascular disease.

This paper uses tea pigment treatment hypertension, and patients with coronary heart disease is observed its influence to Endothelin and calcium associated hormone, and its treatment mechanism is inquired into, and the research of relevant this respect does not appear in the newspapers as yet.

Data and method

1, object: 32 people of observation group, coronary heart disease 21 people wherein, hypertension 11 people, male 20 people wherein, women 12 people, age 45.6 ± 5.8; Matched group 36 people are the healthy personnel of having a medical check-up, male 20 people, women 16 people, age 41.6 ± 4.8.

2, method: in the oral tea pigment capsule of observation group 3 * 4 weeks of every day, all its Endothelin and BGP, HCT, CGRP are measured and write down to patients' venous blood samples before and after treatment, adopts radio immunoassay.

3, date processing: experimental data adopts mean ± standard deviation, and (X ± S) expression, significance test adopt T check and the T check relatively of two sample means relatively of pairing measurement data, are the significant difference value with P＜0.05.

The result:

One, each index of matched group and observation group relatively sees Table 1, therefrom as seen except that HCT each index of observation group all be higher than matched group p＜0.001.

Each index comparison sheet of table 1 observation group and matched group

Each index relatively saw Table 2, all more preceding decline of each index of back of as seen taking medicine before and after example number ET BGP hCT CGRP matched group 36 60.7 ± 15.9 1.69 ± 0.8 82.4 ± 17.6 84.48 ± 18.4 observation groups 32 180.09 ± 50.04 Δs, 18.8 ± 17.3 Δs 86.4 ± 45.5 241.67 ± 90.7 Δs=P＜0.001 two, observation group took medicine

Each index comparison sheet before and after table 2 observation group takes medicine

Preceding 180.09 ± 50.64 18.8 ± 17.3 86.4 ± 45.5 241.67 ± 90.7 treatment back 96.6 ± 30.54 Δs, 7.49 ± 3.8 Δs 41.77 ± 14.5 105 ± 30.13 Δs of ET BGP hCT CGRP treatment

Δ＝P＜0.001

Discuss:

One, the variation of the ET of observation group

This paper result shows that coronary heart disease of hypertension patient ET raises, and is similar to bibliographical information.Its mechanism is: (1) atherosclerosis and spontaneous spasm make vascular endothelial cell impaired, impaired vascular endothelial cell makes the synthetic of ET and discharges and takes place unusually, cause the especially lasting contraction of arteria coronaria of blood vessel, endotheliocyte is further impaired after the vasospasm, forms vicious cycle.ET is the excretory 21 peptide vasoconstrictor substances of vascular endothelial cell, blockage effect for blood vessel, ET may be mediated by conducting system in two kinds of cells, it is the open and phosphide enzyme activation of calcium channel, after ET stimulates the phospholipase activation, promote InsP3 to generate, the latter promotes calcium to be released into endochylema from the calcium deposit; Activatory ET receptor is stimulation voltage dependent calcium channel and receptor operability calcium channel also, promotes stream in the extracellular Ca2, increases intracellular free calcium and causes vasoconstriction.ET activates phospholipase A ₂The TXA that the back produces ₂Can further strengthen the vasoconstriction effect Deng material.ET is to the contraction intensity difference of different blood vessel in the body, and is the strongest to arteria coronaria, and inferior is limb artery.

For cardiac muscle, Kramer thinks that ET may be the strongest positive inotropic material of mammal heart, tends at present think that positive inotropic effect realizes by following mechanism.(1) improve the sensitivity of muscle fiber to calcium, (2) promote to alkalize in the cell and cause sodium to increase, and then activate sodium, calcium exchange, cause calcium to increase and the myocardial contraction enhancing, and (3) promote the myocardial cell hypertrophy.But too high ET may increase vascular resistance, and makes calcium overload in the myocardial cell, thereby the injury of myocardium cell brings out or increases the weight of heart failure.

Reports such as Salvati, ET can cause that chamber speed and chamber quiver, its arrhythmogenic effect is not to be secondary to myocardial ischemia, but to the direct effect of cardiac muscle.In a word, ET has epochmaking effect for generation, the development of cardiovascular system diseases.

Two, the result of this group mensuration represents, after taking tea pigment, the content of ET obviously descends, and tea pigment makes the endotheliocyte secretion, and the mechanism that ET reduces may be that (1) tea pigment can make the generation of ischemic myocardium oxygen-derived free radicals reduce, improve the content of SOD, thereby alleviate endothelial cell damage, after (2) inner skin cell function improved, the synthetic and release active relaxing factor of endothelium (EDRF) increased, the latter is the physiology antagonist of ET, can make the synthetic minimizing of ET.

Originally discover hypertension, coronary heart disease patient, three kinds of calcium associated hormone content all are higher than normally, and there is abnormal calcium metabolism in prompting.Hypertension, coronary heart disease patient ET content are apparently higher than normally, and human body calcitonin gene-correlation peptide content compensatory increases, and expresses with the mRNA that suppresses ET, correspondingly cause increasing of calcitonin and Bone Gla protein.Tea pigment can reduce ET content by number of mechanisms, thus also can corresponding reduction calcitonin-gene-related peptide and corresponding hormone-content, and its mechanism remains further to be inquired into.

Conclusion:

(1) cardiovascular system diseases patient ET content obviously raises, and is roughly the same with bibliographical information.

(2) observation group's calcium associated hormone content obviously raises, and its mechanism remains further to be inquired into.

(3) tea pigment can make ET and calcium associated hormone reduce, and the protection endothelial tissue alleviates its damage, functional rehabilitation, thus confirm that tea pigment obviously is of value to the recovery of cardiovascular disease, is worth clinical application.

Experimental example 2 tea pigment lipidemias reduce Endothelin and strengthen the clinical observation that the tumour immunity function is improved hemorheology

We find that to the clinical observation of tea pigment tea pigment is to reducing TC, TG, LDL-C, Apo-B, Endothelin and increasing HDL-C, Apo-A, HDL ₃-ch improves hemorheology, regulates trace element, and raise immunity is received promising result.

1 object method

1.1 case is selected the dyslipidemia person, refers to individual event or multinomial rising person among four of TC, TG, LDL-C, the Apo-B, or HDL-C, Apo-A reduction person, totally 214 examples; To the observation of 132 routine Apo-A, Apo-B, to 63 routine diabetes HDL-ch subgroup HDL ₂-ch, HDL ₃-ch, HDL ₂-ch/HDL ₃-ch observes, to the observation of 76 routine myocardial ischemia heart infarction Endothelins, 30 routine tumor blood Zn, Se and T cell subsets observed, and to the observation of 98 routine coronary heart disease or hyperlipemia hemorheology, 45～84 years old age, sex man 390 people, women 161 people.

Blood fat normal value: TC＜5.70MMol/L, TG＜1.60mmol/L, LDL＜3.1mmol/L, HDL man＞1.04, woman＞1.17mmol/L.

1.2 medication is all observed inactive other of case history and is transferred fat agent, takes the each 250mg of tea pigment capsule (2) that the green pharmaceutical Co. Ltd in Chinese-foreign joint Jiangxi provides, every day 3 times, 30 days courses of treatment.Get blood before and after taking medicine and survey observed project.Person under inspection's dinner the previous day of taking a blood sample can not be advanced high fat diet and drunk, and plays extracting vein blood on an empty stomach morning.Adopt self-controlled method.Testing result takes statistics to learn and handles.

1.3 efficacy determination (1) produce effects: reach following any one person, TC drop to normal or 〉=20%, TG drop to normal or 〉=40%, LDL-C drop to normal or 〉=20%, HDL-C rises to normal Ji a word used in person's names aster .257mmol/L.(2) effective: TC descends 10%～20%, and TG descends 20%～40%, and LDL descends 10%～20%, the HDL 0.103～0.25mmol/L that rises.(3) invalid: as not reach effective standard person.(4) worsen: reach following any one, TC rises 〉=10%, TG rises 〉=10%, the HDL 0.103～0.157mmol/L that descends, LDL rising 〉=10%.

2 results

2.1 214 routine high fat patients treat the efficacy analysis (table 1) of back TC, TG, HDL-C, LDL-C with tea pigment

Table 1 tea pigment is treated the effective percentage (%) of 214 routine dyslipidemia

Example digital display effect (n) effectively (n) invalid (n) worsens result's (table 2) that (n) total effective rate (n) TC 115 35.65 (41) 31.30 (36) 29.56 (34) 3.47 (4) 66.95 (77) TG 165 35.15 (58) 32.72 (54) 28.48 (47) 3.63 (6) 67.87 (112) HDL 93 38.7 (36) 38.7 (36) 18.27 (17) 4.3 (4) 77.41 (72) LDL 128 45.31 (58) 15.62 (20) 33.59 (43) 5.46 (7) 60.93 (78) 2.2 132 routine hyperlipidemia patients take Tea Pigment

Table 2 changes (X ± s, mmol/L) group example number TC TG LDL-C HDL-C Apo-A with the level of blood fat before and after the tea pigment and apolipoprotein

Apo-B 132 5.97±0.25 1.82±0.18 3.78±0.16 1.26±0.27 0.47±0.19 0.81±0.16 132 5.89±0.23** 1.77±0.16* 3.72±0.19** 1.34±0.12** 0.59±0.17*** 0.69±0.1***：*P＜0.05 **P＜0.01 ***P＜0.012.3 63HDL-ch （ 3 ） 3 HDL-ch （ X±s （ mg／dl ） ，n＝63 ） HDL-ch HDL2-ch HDL3-ch HDL2-ch／HDL3-ch 47.91±9.45 17.10±7.03 30.81±6.14 0.56±1.14 51.90±4.78 25.00±6.31 26.90±7.02 0.93±0.90P＞0.05＜0.001＜0.01＜0.012.4 34 （ 4 ）。

The table 4 rheol comparison of tea pigment front and back blood flow (X ± s)

(n=34) whole blood contrast viscosity after (u=34) takes medicine before taking medicine

Height is cut 7.112 ± 1.488 5.458 ± 0.347*

Low 13.151 ± 3.247 7.357 ± 1.234 whole blood reduced viscosities of cutting

Height is cut 12.875 ± 1.925 10.486 ± 1.042*

Low 23.97 ± 4.148 14.852 ± 2.081 plasma viscosity 1.96 ± 0.157 1.745 ± 0.086 of cutting

Erythrocyte sedimentation rate mm/h 21.232 ± 14.876 22.684 ± 12.374 packed cell volume % 48.585 ± 6.754 41.924 ± 4.107* Fibrinogen g/l, 4.86 ± 1.31 3.55 ± 0.73*t check * P＜0.0564 example is taken the influence (table 5) of tea pigment to hemorheology

The variation that table 5 is learned with hemorheology before and after the tea pigment treatment

X ± s (mmol/L) project rate of change (%) t value P value

Before the administration after the administration whole blood viscosity height cut that rate 5.22 ± 1.42 4.73 ± 1.16 9.38 2.14＜0.05 whole blood viscosity are low cuts rate 6.89 ± 2.48 6.15 ± 1.54 10.74 2.03＜0.05 plasma viscosities 1.82 ± 0.18 1.72 ± 0.16 5.49 3.32＜0.01 Fibrinogen (g/l), 3.92 ± 1.11 3.20 ± 1.02 18.36 3.82＜0.012.5,30 routine tumor people and take tea pigment bleeding from anus zinc, selenium, variation (table 6) table 6 of T cell subsets is taken tea pigment front and back tumour patient zinc, the comparison that selenium and T cell subsets change (X ± s)

T cell subsets (%) trace element (ng/ml)

In the blood plasma in the cell

CD ₃ CD ₄ CD ₈ CD ₄/CD8

Zinc selenium zinc selenium take medicine front 51.00 ± 1.57 35.75 ± 1.93 26.98 ± 1.23 1.33 ± 0.10 0.91 ± 0.28 0.0021 ± 0.0019 8.21 ± 2.47 0.021 ± 0.001 take medicine after 51.00 ± 1.58 35.85 ± 1.90 26.92 ± 1.22 1.36 ± 0.11 0.91 ± 0.27 0.0022 ± 0.027 8.21 ± 2.46 0.031 ± 0.001P value-＜0.05＜0.05＜0.05-＜0.05-＜0.052.6 76 examples observation (table 7) of taking Tea Pigment front and back serum endothelin

The mensuration of serum endothelin concentration before and after 4 groups of clothes of table 7 tea pigment

The old angina pectoris group 20 67.61 in rate of change (%) normal control 30 26.20 ± 3.4 20.38 ± 2.75 22.21 Elder Patients with Symptomatic Myocardial Ischemia group 14 38.32 ± 4.13 32.60 ± 3.9 16.02 ± 9.02 54.31 ± 5.8 19.67 senile myocardium stalks organize 12 115.75 ± 15.45 98.75 ± 12.04 14.68 after the front treatment of example number treatment

3 discuss

Tea pigment is a kind of polyatomic phenol speciality based on catechin of extracting from natural green tea, becomes a class water colo(u)r through the chemical constitution transformation.By our clinical observation, confirm dark brown have cholesterol reducing (TC), triglyceride (TG), low density lipoprotein, LDL (LDL-C), apolipoprotein B (Apo-B), high density lipoprotein increasing (HDL-C), the effect of ApoA (Apo-A).Statistical procedures all has significance, and the result is very satisfied.HDL-C has study of anti-atherogenic effect, so in the research of lipid lowerers, importantly find out and can reduce LDL-C and TG, HDL-C and its subgroup HDL that raises can raise again simultaneously ₂-ch reduces HDL ₃-ch increases its ratio.Clinical observation confirms that tea pigment meets this requirement.Many for many years fat regulation medicines come out, and clinical practice can not be satisfactory, as the superfluous compound of cholic acid, fibrate the accent blood fat is arranged, but side effect are also more obvious; The pantethin side effect is little but the effect of accent fat is also poor; Some lipid lowerers is taken the toxic and side effects that has hepatorenal damage for a long time.And tea pigment is not found any side effect by clinical observation, is the medicine that is worth of widely use.It has the atherosclerosis of delaying, and reduces the effect of Incidence of CHD.To account for the prevention of dead primary cardiovascular and cerebrovascular vessel in China, has epoch making significance.

Endothelin is a kind of peptide material, regulates the local vascular tensity with paracrine and autocrine formula, participates in the propagation of blood pressure regulation, promotion vascular smooth muscle, regulates myocardial metabolism and endocrine function.Burst size is very low under the physiological status, and at myocardial ischemia, myocardial ischemia states such as myocardial infarction discharge down to be increased.It is reported that the interior thrombosis of crown arteries and veins increases relevant with level of ET, we observe discovery to the art of facing that 76 examples are taken tea pigment, old silent ischemia group, old angina pectoris group, ACUTE MYOCARDIAL INFARCTION IN THE AGED group Endothelin all have obvious decline, and particularly all there is significant difference (P＜0.001) back for two groups.

To 98 routine observation on Hemorheology, before and after the clothes tea pigment whole blood viscosity height is cut rate, low rate, plasma viscosity ratio, the Fibrinogen cut of whole blood viscosity, obvious reduction is all arranged, statistical procedures (P＜0.05).Tea pigment can effectively reduce blood viscosity, mainly is by reduction fibrin source, improves function of plasma membrane and hematoblastic rheological characteristic, improves blood lipid metabolism, and blood fat reducing is relevant.

30 routine tumour patients are observed, and tumor patient is because multiple factor reduces the T cell function, and immunologic function fails, and tumor patient can make zinc drain for chronic instrumentality in the leukocyte of tissue necrosis reaction in addition increases, thereby makes patient's zinc deficiency.Some author thinks that selenic shortage may be the pathogenic factor of cancer.Selenium may influence the cell glycolysis by selectivity, the energy supply process of anticancer.It can promote to react with activate immunity.The T cell subsets is the reacting cells immunity, after taking tea pigment, finds that with contrast before the clothes suppressor T cell CD is on the rise, is higher than matched group P＜0.01.Clothes tea pigment bleeding from anus selenium and T cell CD ₈All have before the index ratio is taken medicine and increase, this shows that tea pigment regulates immunologic function by increasing in the body the selenic content of trace element, has suppressed the development of tumor.

Claims (3)

1, the application of tea pigment in the medicine of preparation reduction Endothelin.

2, the application of tea pigment in the medicine of preparation reduction calcium associated hormone.

3, according to the application of claim 2, wherein said calcium associated hormone comprises Bone Gla protein (BGP), calcitonin (HCT) and calcitonin-gene-related peptide (CGRP).