CN100488498C - Application of turmeric extract in preparation of medicine for preventing and postponing chronic kidney function failure - Google Patents
Application of turmeric extract in preparation of medicine for preventing and postponing chronic kidney function failure Download PDFInfo
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Abstract
The invention relates to an application of curcumin in drug preparation, wherein test has proves that curcumin can increase the food intake of renal failure mouse, increase weight and improve health, it can improve Hb, RBC, and reduce NO, TNF-a contents, improve SOD level and release the renal failure condition.
Description
Technical field
The present invention relates to a kind of new medical usage of total curcumin.
Technical background
Rhizoma Curcumae Longae is the dry rhizome of zingiberaceous plant Rhizoma Curcumae Longae (Curcuma longa L.).In tcm field, its be acknowledged as have removing blood stasis, the effect of circulation of qi promoting, inducing menstruation to relieve menalgia.Be mainly used in the twinge of treatment costa sternales, amenorrhea, rheumatism shoulder arm pain, treating swelling and pain by traumatic injury.The medicinal active ingredient of Rhizoma Curcumae Longae mainly is curcumin (curcumin, 1), demethoxycurcumin (demethoxy-curcumin, 2), Bisdemethoxycurcumin (bisdemethoxy-curcumin, 3), in pharmaceutical field, be referred to as total curcumin usually.The chemical structural formula of curcumin is:
R wherein
1=R
2=Ome is curcumin (curcumin) R
1=H, R
2=OMe is demethoxycurcumin (demethoxy-curcumin) R
1=R
2=H is Bisdemethoxycurcumin (bisdemethoxy-curcumin).
There is scholar's research to find abroad, total curcumin has multiple pharmacological effect, comprise antiinflammatory, suppress cell proliferation (as human smooth muscle cell, endotheliocyte, lymphocyte, the propagation of fibrocyte and various tumor cells), also has the inductive mononuclear cell of the inflammation-inhibiting factor simultaneously, become the fibroid cell, mesangial cell and other cellular expression transforming growth factors TGF-β, mononuclear cell MCP-1, TNF, interleukin I L-1, inducing property nitric oxide synthetase iNOS, the effect of matrix metalloproteinase MMP etc., reduce extracellular matrix such as fibronectin, the generation of collagen protein etc.Plurality of advantages such as it is strong to it is found that in clinical practice total curcumin has a pharmacologically active, and toxic and side effects is little are so many research and development institutions are all at the further new medical usage of research and development total curcumin.
Summary of the invention
Purpose of the present invention is exactly that the new purposes of a kind of total curcumin in the pharmacy application will be provided, and is the clinical medicine that a kind of effective prevention and postponing chronic kidney function failure are provided simultaneously.
Chronic renal failure (hereinafter to be referred as chronic kidney hypofunction) is to occur in a various chronic renal disease clinical syndrome in late period.It is the nephron heavy damage that causes by a variety of causes, and the substantive irreversible functional lesion of kidney, thereby produce clinically with the retention of protein metabolism product, a series of poisoning symptoms of whole body appear in various poisonous substance acatharsias in water, electrolyte and acid base imbalance and the body.Chronic impaired renal function is not still had special effective way at present make it to cure, but can slow down the development speed of its state of an illness by taking some ways.In recent years both at home and abroad the medical expert all tend to adopt early prevention, strict blood pressure lowering, fall albuminuria, blood fat reducing, correction electrolyte disturbance, acidosis, improve anemia, the integrated comprehensive therapeutic plan that reduces complication such as cardiovascular and cerebrovascular vessel and renal osteodystrophy prevents, delaying chronic kidney hypofunction.But regrettably, these therapeutic schemes normally different clinical symptoms occurs and adopt corresponding medicine to carry out symptomatic treatment according to the patient.As except that keeping on a diet, controlling blood pressure mainly relies on depressor; Blood fat reducing, correction lipid metabolic disorder need be used blood lipid-lowering medicine; Control nephron hypermetabolism need be aided with the medicine that reduces methylguanidine level in the body, reduces the oxygen-derived free radicals generation.As everyone knows, chronic renal failure all is simultaneously with the various clinical symptom usually, so the patient often needs to take simultaneously multiple medicine in therapeutic process, this can further increase patient's kidney burden undoubtedly.Moreover many untoward reaction of chemicals also are unfavorable for patient's long-term prescription.Thereby at present the clinicist urgently wishes to invent and a kind ofly has multi-target effect and the little medicine of toxic and side effects is used for prevention, delaying chronic kidney hypofunction.Many pharmacologically actives that the inventor finds total curcumin through studying for a long period of time all have corresponding target effect to many pathology characteristics of chronic kidney hypofunction, have invented the application of total curcumin in preparation prevention and postponing chronic kidney function failure medicine in view of this.
The application of Rhizoma Curcumae Longae extract in preparation prevention and postponing chronic kidney function failure medicine, wherein said Rhizoma Curcumae Longae extract is to extract in accordance with the following methods:
The Rhizoma Curcumae Longae pulverizing medicinal materials is become powder, cross the 40-80 mesh sieve; Curcuma powder carries out supercritical CO
2Extraction, extracting pressure is 30-35Mpa, extraction temperature is 50-60 ℃, extracts time 2-5 hour; Curcuma powder and CO
2Weight ratio be 1:3-6, separate obtain Rhizoma Curcumae Longae volatile oil and deoil after Rhizoma Curcumae Longae A; The ethanol or the acetone that Rhizoma Curcumae Longae A after deoiling are added 2-10 times of weight reflux 3 times, and each 0.5-2 hour, filter, get Rhizoma Curcumae Longae liquid B; Reclaim ethanol or acetone among the Rhizoma Curcumae Longae extracting solution B, drying under reduced pressure gets Rhizoma Curcumae Longae extract.
Beneficial effect
Useful result of the present invention is confirmed by following experiment.
The test of pesticide effectiveness of the chronic kidney hypofunction rat that total curcumin brings out adenine
Medicine: test used medicine for to make the total curcumin dried powder according to embodiment 1, total curcumin content is counted 50-95% with curcumin;
1, experimental technique
1.1 animal and reagent
1. animal: the SD rat, male and female half and half, about body weight 180.6 ± (SD) 18.0g, provide credit number by the laboratory animal department of the Chinese Academy of Sciences of Tongji Medical College, Huazhong Science and Technology Univ.: SCXK (Hubei Province) is (2004-0007).
2. reagent: adenine (Adenine, C
5H
5N
5, FW:135.13), purchase extensive and profound in meaning biological import packing in Shanghai.
1.2 grouping and modeling:
1. grouping: after 40 SD rats are selected for use commercially available solid speech material to feed 7d to conform, be divided into 4 groups at random, i.e. (1) normal group, (2) model group, 1 group of (3) administration, 2 groups of (4) administrations.
2. modeling: from testing for the 1st date, set time modeling in morning every day, all the other are respectively organized rat and irritate stomach 51d with adenine 250mg/ (kgd) except that normal group, and normal group is irritated stomach with the equivalent normal saline, and all animals all freely absorbs feedstuff and drinking-water.
3. method: 1 group of administration: from the experiment beginning to the 51d off-test, 1 time/d, irritate stomach with 54mg/ (kgd) total curcumin, purpose is the preventive administration drug effect of observing total curcumin; 2 groups of administrations: the experiment beginning is to 21d, and 1 time/d, normal saline is irritated stomach, tests the 22-51d off-test, and 1 time/d, irritate stomach with 54mg/ (kgd) total curcumin, purpose is the therapeutic administration drug effect of observing at total curcumin.
1.3 detection index: 1. general state, 2. urine detection: twenty-four-hour urine albumen, 3. hematological indices: erythrocyte (RBC), hemoglobin (Hb), serum urea nitrogen (BUN), serum creatinine (Scr), total protein (TB), albumin (Alb), tumor necrosis factor (TNF-α), serum levels of nitric oxide (NO), serum superoxide dismutases (SOD), 4. pathologic finding: kidney.
1.4 statistical analysis: adopt SPSS to carry out statistical analysis, all (X ± S) expression relatively adopts variance analysis between many groups to test data, and enumeration data adopts X 2 test with mean ± standard deviation.
2, result:
2.1, ordinary circumstance: rat obviously shows growth inhibited with feed adenine feedstuff time lengthening, and the model group rat ingests and obviously reduces, the movable minimizing, bradykinesia, sparse withered by hair, abdominal part has depilation in various degree, amount of drinking water increases, hydrouria; 1,2 groups of above-mentioned situations of administration are obviously lighter, and height and body weight all have in various degree to be increased.
2.2 total curcumin is to the influence of adenine chronic renal failure rat 24h urine protein, RBC and Hb.(seeing Table 1)
Table 1 51d respectively organize rat 24h urine protein, RBC and Hb statistical result (x ± s, n=10)
As can be seen from Table 1: model group twenty-four-hour urine protein content highly significant is higher than normal group, and RBC, Hb value highly significant is lower than normal group (P＜0.01), and the modeling success is described; The twenty-four-hour urine protein content, RBC, 1,2 groups of Hb administrations and model group relatively have highly significant difference (P＜0.01); The relatively more equal zero difference of each treatment group and model group (P〉0.05), but the mean statistics shows that 1 group of twenty-four-hour urine protein content of administration is lower than 2 groups of administrations, RBC, and the Hb value is higher than 2 groups of administrations.
When renal failure,, can cause complication such as hyperlipemia because GCBM to the permeability increase of plasma proteins, causes serious albuminuria to cause hypoalbuminemia thereupon.This experiment shows total curcumin prevention group and treatment group, and the 24h urine protein content obviously reduces, and the former reduces more obvious, and the albumin elevated levels also is that the prevention group is comparatively remarkable, and the prompting total curcumin is having synergism aspect reduction urine protein and the rising blood albumin.
This zoopery shows that also total curcumin can significantly improve the hemoglobin of chronic kidney hypofunction rat, so can partly correct anemia problem common in the chronic kidney hypofunction disease progression.
2.3 total curcumin is to the influence (seeing Table 2) of adenine chronic renal failure kidney of rats merit index
Table 2 51d respectively organize kidney of rats merit indicator-specific statistics result (x ± s, n=10)
Compare with normal group: "
*" P＜0.05, "
*" P＜0.01.Compare with model group: " △ " P＜0.05, " △ △ " P＜0.01
By table 2 as can be seen, through the adenine modeling, BUN, Scr content have had remarkable rising (P＜0.01) than normal group in the animal pattern blood, show that this modeling is successful.51d, administration 1,2 groups of BUN, Scr, TB, Alb indexs all are better than model group contrast, illustrates that total curcumin can obviously suppress the progress of renal failure, do not have significant difference between 1,2 groups of the administrations, and 1 group of administration makes progress for 2 groups than administration the trend of slowing down.
Scr is the metabolite of creatine in the human body, and the drainage of creatinine is the Excretion by glomerule mainly.BUN is the metabolic dead end product of body protein, and it is all from glomerular filtration.Total curcumin prevention administration all can make chronic kidney hypofunction rat serum creatinine descend with treatment administration group; blood urea nitrogen reduces; point out this medicine can protect the glomerule function; alleviate the glomerule pathological changes; increase the glomerular filtration function; quicken chronic kidney hypofunction rat vivotoxin and drain, alleviate azotemia, and the effect of the turbid toxin expelling of toolization.And total curcumin prevention group has the trend of slowing down the chronic kidney hypofunction process than treatment group.
2.4 total curcumin is to the influence (seeing Table 3) of adenine chronic renal failure rat Endothelin blood fat
Table 3 51d respectively organize the rat fat level (x ± s, n=10)
Compare with normal group: "
*" P＜0.05, "
*" P＜0.01.Compare with model group: " △ " P＜0.05, " △ △ " P＜0.01
Table 3 as can be seen, administration 51d administration is compared with model group for 1,2 groups, rat Endothelin blood fat ET, UHO, LDL there is the reduction effect (P＜0.01) of highly significant, 1,2 groups of comparisons of administration no significant difference (P〉0.05), but the mean statistics shows that 1 group of blood fat reducing trend of administration is better than 2 groups of administrations.
Lipid metabolic disorder is to promote one of key factor that glomerular sclerosis takes place and chronic kidney hypofunction makes progress.TNF-α assembles and adhesion inflammatory cell, the circulation Marjoram Extract, and permeability strengthens, and has participated in glomerule tissue injury.Curcumin prevention group and treatment group all can reduce the TNF-alpha levels, and the prevention group reduces more remarkable than the treatment group.ET can stimulate mesangial cell to shrink, breed, and discharges inflammatory mediator and produces extracellular medium, promotes glomerule inflammation and sclerosis.Total curcumin prevention and treatment group have remarkable reduction effect to ET, infer that improving blood capillary with it stops up, blood fat reducing level, and blood viscosity, and it is relevant to improve the kidney hemoperfusion.Total curcumin has highly significant reduction effect to low density lipoprotein, LDL (LDL), and LDL becomes the OX-LDL latter after being modified by active oxygen and is considered to have more cytotoxicity than LDL, thinks that at present hyperlipemia causes one of main pathomechanism of kidney damage.
2.5 total curcumin detects (seeing Table 4) to adenine chronic renal failure rat TNF-α, SOD, NO
Table 4 51d respectively organize rat serum TNF-α, SOD, NO detection statistics result relatively (x ± s, n=10)
Compare with normal group: "
*" P＜0.05, "
*" P＜0.01.Compare with model group: " △ " P＜0.05, " △ △ " P＜0.01
Table 4 is 51d as can be seen, and 1,2 groups of administrations and model group comparison can significantly reduce TNF-a value, SOD and NO value (P＜0.01); 1,2 groups of administrations do not have significant difference (P〉0.05), but the mean statistics shows that 1 group of TNF-a value of administration, SOD and NO value are lower than 2 groups of administrations.
2.6 total curcumin the results are shown in Table 5 to the influence of chronic kidney hypofunction free radicals in rats.
Table 5 total curcumin is to the influence of chronic kidney hypofunction free radicals in rats (%, x ± s)
Compare with normal group: "
*" P＜0.01, compare with model group: " △ △ " P＜0.01
Adenine brings out chronic kidney hypofunction model nephridial tissue SOD significantly to be reduced, supposition may be the adenine of high concentration under the effect of nephridial tissue xanthine oxidase, when being converted into xanthine and uric acid with O
2-With the generation of lipid peroxide, cause the functional lesion and the forfeiture of nephron.In addition, renal tubules hypermetabolism during chronic kidney hypofunction, the inflammatory cell oxygen consumption of renal cells and infiltration increases, and brings out " respiratory burst ", also is a large amount of another reasons that produce of oxygen-derived free radicals.
When originally experimental results show that chronic kidney hypofunction in the nephridial tissue SOD vigor far below normal group animal (P＜0.01).After total curcumin prevention or treatment, the remarkable improvement (P＜0.01) arranged than animal pattern.Studies show that, total curcumin is when improving renal function, can obviously improve chronic kidney hypofunction kidney of rats tissue SOD vigor, illustrate that this medicine can alleviate the infringement of oxygen-derived free radicals to renal tissue, can suppress the ability of nephridial tissue lipid peroxidation and raising kidney anti peroxidation of lipid simultaneously.
2.7 pathological observation
Normal group: nephridial tissue is as usual, and the histology there is no change.Model group: the kidney volume all obviously increases.Each kidney all exists regional nephron atrophy, disappearance, and proliferation of fibrous tissue obviously reaches the necrosis of cell infiltration part renal cells, disappearance or expansion, and very the person is capsule.Excess of the kidney matter internal glomerulus number obviously reduces, and palm fibre as seen not of uniform size, that quantity is little etc. is taken off color knot product or foreign body granuloma formation and protein cast.1 group of administration: nephropathy becomes and obviously to alleviate than model group, and the kidney volume all slightly increases or near normal group except that individual animal, nephron atrophy, disappearance, and the proliferation of fibrous tissue area is less and be confined to the cortex part of nearly tunicle.Except that individual animal, the renal tubules of expansion and crystalline solid form all and alleviate, and the part nephridial tissue is more similar to the normal control group.2 groups of administrations: nephropathy becomes and obviously alleviates than model control group, and regional nephron atrophy, disappearance and proliferation of fibrous tissue area are little than model group; The renal tubules and the intraparenchymatous crystalline solid of kidney that enlarge are less.
Infringement is comprehensively to adenine to rat kidney, and infringement is based on matter between glomerule and kidney.Total curcumin treatment group and prevention treated animal its numbers of glomeruli are than the model group showed increased, and glomerule cyst wall counterdie thickens and alleviates, and matter inflammatory reaction etc. all has alleviating in various degree between renal tubules structure, kidney, and visible total curcumin has the effect that improves renal function.See Fig. 1, Fig. 2, Fig. 3, Fig. 4 for details.
Description of drawings
Fig. 1: normal group pathology picture.
Fig. 2: model group pathology picture.
Fig. 3: 1 group of pathology picture of administration.
Fig. 4: 2 groups of pathology pictures of administration
In sum, total curcumin has following multi-target effect to chronic kidney hypofunction, that is:
(1) can increase the food ration of renal failure rat, increase body weight, improve survival condition.
(2) can reduce renal failure rat serum creatinine, urea nitrogen, reduce albuminuria, improve the kidney merit.
(3) can improve renal failure rat Hb, RBC, improve the renal anemia symptom.
(4) total curcumin can reduce renal failure rat NO, and TNF-a content improves the SOD level, thereby delays The progress of renal failure.
(5) can obviously improve renal failure renal tissues of rats pathological change, the progress of delaying chronic kidney hypofunction.
Total curcumin has extensive and long-term application (such as falling as cardiovascular drugs at the other drug preparation The fat channel activating soft capsule), have no so far the relevant report that it has any serious toxic and side effect.
The result of the present invention by acute toxicity test shows that also having no side effect of this medicine (see total turmeric for details The anxious poison test of plain animal).
The anxious poison test of total curcumin animal:
The oral curcumin capsule preparations of reported in literature mouse 6g/kg (containing 20% total curcumin) can not survey half and causes Dead amount. 12 mouse gavage 40-100g/kg of curcumol immersion liquid (114-286 of suitable clinical application amount Doubly), observe none only death in three days. When rat oral take dosage up to the 5g/kg curcumin after, do not find Any obvious intoxication.
The inventor uses 30 of ICR mouse, be divided into high, medium and low 3 groups, every group of 10 animals, male and female half and half, every day gavage Turmeric P.E secondary, each 10mg, 5mg, 2.5mg total curcumin (be equivalent to human body [in a 60kg] consumption per day 200 times, 100 times and 50 times), one week of Continuous Observation, abnormal response do not occur, have no an animal dead, can not survey LD50 Therefore, adopt oral administration gavage and lumbar injection two The approach of kind carries out mtd test to mouse.
Test shows: the maximal tolerance dose of mouse oral administration gavage administration is the 60mg/0.8ml total curcumin, quite 563 times of people's one consumption per day; The maximal tolerance dose of mouse peritoneal drug administration by injection is the 20mg/0.5ml total curcumin, Quite 190 times of people's one consumption per day.
The application of total curcumin in preparation prevention and postponing chronic kidney function failure medicine, can be according to routine Formulation method is made various pharmaceutical dosage forms with total curcumin, such as tablet, dripping pill, capsule, powder, injection Agent, controlled release agent etc. pharmaceutical dosage form.
When being used for prevention and postponing chronic kidney function failure, the usage and dosage of oral formulations is that take every day Total curcumin 300-600mg. The consumption of other preparations can be with reference to this consumption. Drug usage consumption of the present invention, Also be not limited solely to this, the clinician also can determine according to patient's concrete condition the usage and dosage of medicine.
The specific embodiment
Embodiment 1: the total curcumin soft capsule
The Rhizoma Curcumae Longae pulverizing medicinal materials is become powder, cross the 40-80 mesh sieve; Curcuma powder carries out supercritical CO
2Extraction, extracting pressure is 30-35Mpa, extraction temperature is 50-60 ℃, extracts time 2-5 hour; Curcuma powder and CO
2Weight ratio be 1:3-6, separate obtain Rhizoma Curcumae Longae volatile oil and deoil after Rhizoma Curcumae Longae A; The ethanol or the acetone that Rhizoma Curcumae Longae A after deoiling are added 2-10 times of weight reflux 3 times, and each 0.5-2 hour, filter, get Rhizoma Curcumae Longae liquid B; Turn one's head ethanol or acetone among the Rhizoma Curcumae Longae extracting solution B, drying under reduced pressure, Rhizoma Curcumae Longae extract; Measure the content of Rhizoma Curcumae Longae extract dried powder, its total curcumin content is counted 50-95% with curcumin; The curcumin extraction that will meet content requirement adds 3-6 vegetable oil or Polyethylene Glycol doubly and mixes, and makes suspension, is soft capsule content; By weight being 40-60:10-30:50-30, take by weighing gelatin, glycerol, water; Be mixed and made into the softgel shell of soft capsule; The compacting soft capsule.
Usage and dosage: oral, take total curcumin 300-600mg every day.
Embodiment 2 total curcumin tablets
According to the total curcumin of the method for the foregoing description preparation, add appropriate amount of auxiliary materials, adopt the conventional method tabletting, make tablet.
Usage and dosage: oral, take total curcumin 300-600mg every day.
Embodiment 3 total curcumin granules
According to the total curcumin of the method for the foregoing description preparation, add appropriate amount of auxiliary materials, adopt the conventional method tabletting, make granule.
Claims (1)
1, the application of Rhizoma Curcumae Longae extract in preparation prevention and postponing chronic kidney function failure medicine, wherein said Rhizoma Curcumae Longae extract extracts in accordance with the following methods:
The Rhizoma Curcumae Longae pulverizing medicinal materials is become powder, cross the 40-80 mesh sieve; Curcuma powder carries out supercritical CO
2Extraction, extracting pressure is 30-35Mpa, extraction temperature is 50-60 ℃, extracts time 2-5 hour; Curcuma powder and CO
2Weight ratio be 1:3-6, separate obtain Rhizoma Curcumae Longae volatile oil and deoil after Rhizoma Curcumae Longae A; The ethanol or the acetone that Rhizoma Curcumae Longae A after deoiling are added 2-10 times of weight reflux 3 times, and each 0.5-2 hour, filter, get Rhizoma Curcumae Longae liquid B; Reclaim ethanol or acetone among the Rhizoma Curcumae Longae liquid B, drying under reduced pressure gets Rhizoma Curcumae Longae extract.
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| CN100571692C (en) * | 2007-11-15 | 2009-12-23 | 南京大学 | The application of curcumin in the preparation medicament for restraining uric acid transportor URAT 1 |
| CN105311004B (en) * | 2015-05-06 | 2018-12-11 | 江苏靶标生物医药研究所有限公司 | The application of curcumin and its pharmaceutical salts |
| CN107335026B (en) * | 2016-12-09 | 2020-09-11 | 中南大学湘雅二医院 | Medicine for treating focal segmental glomerulosclerosis |
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| 姜黄素的药理作用研究进展. 于冬青等.山东医药，第45卷第2期. 2005 |
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