CN101703617B - Medicinal composition for treating diabetic nephropathy and preparation method thereof - Google Patents
Medicinal composition for treating diabetic nephropathy and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a medicinal composition for treating diabetic nephropathy and a preparation method thereof. The medicinal composition comprises the following raw materials in part by weight: 200 to 400 parts of radix astragali, 50 to 200 parts of rehmanniae praeparatum, 6 to 60 parts of sanchi, 20 to 100 parts of prepared rhubarb, 80 to 280 parts of euonymus alatus, 40 to 150 parts of fructus corni and 30 to 180 parts of bitter orange. The preparation method comprises the following steps: adding water into the raw materials for decoction for 1 to 4 times, adding water in an amount which is 8 to 12 times of raw materials each time; decocting the mixture for 0.5 to 2 hours, merging decoction, filtering the decoction, and decompressing and concentrating the decoction to prepare thick paste; and adding conventional auxiliary materials to prepare dosage forms such as pilula, pulvis, syrup, tablets, granules, capsules, plaster, mixtures, pills, suppositories, aerosols, ointment and the like. The medicinal composition has the effects of supplementing qi and nourishing yin, and promoting blood circulation by removing blood stasis, and has the excellent curative effect on diabetic nephropathy.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition and preparation method thereof, particularly relate to a kind of treatment diabetic nephropathy drugs composition and method of making the same.
Background technology
Diabetic nephropathy (diabetic nephropathy, DN) be diabetes (diabetes mellitus, DM) common microvascular complication, it is the main cause that causes end stagerenaldisease (ESRD), also be that diabetes cause dead principal element, become the first cause that causes end stagerenaldisease the America and Europe.In China, diabetics reaches 4,000 ten thousand, and wherein about 20～30% progress are for DN, the serious harm human health, and in recent years along with the increased popularity of diabetes, the DN sickness rate also is and increases rapidly, becomes one of present research focus.(extraeellular matrix, ECM) to gather the nodositas or the diffuse mesangial sclerosis that cause be its main characteristic pathological change to carrying out property, therefore claims the diabetes glomerulosclerosis again for glomerular basement membrane thickening and mesangial region extracellular matrix.Discover DN generation may with biochemical metabolism disorder (polyol pathway, protein nonenzymatic glycosylation and abnormalities of sugar/lipid metabolism etc.), Protein kinase C activation, glycosylation dead end product deposition, multiple factors such as various kinds of cell factor abnormal secretion, glomerular hemodynamics are unusual, oxidative stress and heredity are closely related.But, the DN pathogeny is still imperfectly understood,
The western medical treatment diabetic nephropathy mainly takes medicines such as blood sugar lowering, blood fat reducing, angiotensin-convertion enzyme inhibitor and angiotensin receptor blocker to treat, though these medicines have certain curative effect to DN, can delay PD, but curative effect is not very good, and the untoward reaction of medicine is more, the patient still can be developed to chronic kidney hypofunction inevitably, causes dialysis or dead.Chinese medicine in the treatment of DN according to Traditional Chinese medical theory, carry out determination of treatment based on pathogenesis obtained through differentiation of symptoms and signs according to the concrete state of an illness of patient, have obvious characteristic and advantage, extract of the present invention is with supplementing QI and nourishing YIN, blood circulation promoting and blood stasis dispelling is the main rule of treatment, absorb and summary distinguished veteran doctors of TCM experience, develop, good efficacy is arranged for DN by long-term clinical practice.
Summary of the invention
The object of the invention is to provide a kind of treatment diabetic nephropathy drugs compositions.
The object of the invention is to provide a kind of treatment diabetic nephropathy drugs preparation of compositions method.
The present invention seeks to be achieved through the following technical solutions:
A kind of diabetic nephropathy drugs compositions for the treatment of of the present invention is made by following crude drug:
Radix Astragali 200-400 weight portion, Radix Rehmanniae 50-200 weight portion, Radix Notoginseng 6-60 weight portion, Radix et Rhizoma Rhei (processed) 20-100 weight portion, Ramulus Euonymi 80-280 weight portion, Fructus Corni 40-150 weight portion, Fructus Aurantii 30-180 weight portion.
Above-mentioned treatment diabetic nephropathy drugs compositions is preferably as follows that crude drug makes:
Radix Astragali 250-350 weight portion, Radix Rehmanniae 80-160 weight portion, Radix Notoginseng 10-50 weight portion, Radix et Rhizoma Rhei (processed) 30-90 weight portion, Ramulus Euonymi 100-200 weight portion, Fructus Corni 60-120 weight portion, Fructus Aurantii 50-150 weight portion.
More preferably, pharmaceutical composition of the present invention is made by following crude drug:
The Radix Astragali 300 weight portions, the Radix Rehmanniae 120 weight portions, Radix Notoginseng 30 weight portions, Radix et Rhizoma Rhei (processed) 60 weight portions, Ramulus Euonymi 150 weight portions, Fructus Corni 90 weight portions, Fructus Aurantii 100 weight portions.
More preferably, pharmaceutical composition of the present invention is made by following crude drug:
The Radix Astragali 260 weight portions, the Radix Rehmanniae 150 weight portions, Radix Notoginseng 20 weight portions, Radix et Rhizoma Rhei (processed) 80 weight portions, Ramulus Euonymi 120 weight portions, Fructus Corni 110 weight portions, Fructus Aurantii 60 weight portions.
More preferably, pharmaceutical composition of the present invention is made by following crude drug:
The Radix Astragali 340 weight portions, the Radix Rehmanniae 90 weight portions, Radix Notoginseng 50 weight portions, Radix et Rhizoma Rhei (processed) 40 weight portions, Ramulus Euonymi 180 weight portions, Fructus Corni 70 weight portions, Fructus Aurantii 140 weight portions.
Ramulus Euonymi is recorded in one one of pharmacopeia in 1963.
The present invention also provides the preparation method of above-mentioned Chinese medicinal composition preparation, this method is: crude drug adds the pharmacy acceptable auxiliary according to the above ratio and makes the acceptable any conventional dosage form of pharmaceutics after conventional process is extracted, comprise capsule, tablet, granule, gel, slow releasing agent, oral liquid or drop pill; Described common process method comprises water extraction or alcohol extraction or first water extraction water extraction again after alcohol extraction or the first alcohol extraction again, and it is further active constituent-enriched to cross macroporous resin column after above-mentioned conventional the extraction; Above-mentioned common process water extracting method can for: extract 1-4 time, each 0.5-3 hour, add water 8-30 times of weight at every turn; Above-mentioned common process alcohol extraction method can for: extract 1-4 time, extracted 0.5-2 hour at every turn, add 5-100% ethanol 4-15 times of weight at every turn; The described macroporous resin column method of crossing is: water extraction or alcohol extract filter, filtrate is passed through macroporous resin, first ethanol elution with 4-6 times of water gaging or 20% following concentration, eluent discards, 1-10 times of eluting of reuse 10-90% ethanol, the collection eluent, decompression recycling ethanol gets the purification extracting solution to there not being the alcohol flavor.
Preferably, the invention provides this preparation of pharmaceutical compositions method is: the Radix Astragali, the Radix Rehmanniae, Radix Notoginseng, Radix et Rhizoma Rhei (processed), Ramulus Euonymi, Fructus Corni, Fructus Aurantii seven flavor medicine decoct with water 1-3 time, add water 8-12 at every turn and doubly measure, decocted 0.5-2 hour, merge decoction liquor, filter, concentrating under reduced pressure gets thick paste; According to common process, add conventional adjuvant and make dosage forms such as pill, powder, syrup, tablet, granule, capsule, emplastrum, mixture, drop pill, suppository, aerosol, ointment, injection.
More preferably, preparation of pharmaceutical compositions method of the present invention is: the Radix Astragali, the Radix Rehmanniae, Radix Notoginseng, Radix et Rhizoma Rhei (processed), Ramulus Euonymi, Fructus Corni, Fructus Aurantii seven flavor medicine decoct with water 2 times, add 10 times of amounts of water at every turn, decoct 1 hour, merge decoction liquor, filter, and concentrating under reduced pressure gets thick paste.According to common process, add conventional adjuvant and make dosage forms such as pill, powder, syrup, tablet, granule, capsule, emplastrum, mixture, drop pill, suppository, aerosol, ointment, injection.
Above-mentioned pharmacy acceptable auxiliary is: filler, disintegrating agent, lubricant, suspending agent, binding agent, sweeting agent, correctives, antiseptic, substrate etc.Filler comprises: starch, pregelatinized Starch, lactose, mannitol, chitin, microcrystalline Cellulose, sucrose etc.; Disintegrating agent comprises: starch, pregelatinized Starch, microcrystalline Cellulose, carboxymethyl starch sodium, crospolyvinylpyrrolidone, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose etc.; Lubricant comprises: magnesium stearate, sodium lauryl sulphate, Pulvis Talci, silicon dioxide etc.; Suspending agent comprises: polyvinylpyrrolidone, microcrystalline Cellulose, sucrose, agar, hydroxypropyl emthylcellulose etc.; Binding agent comprises, starch slurry, polyvinylpyrrolidone, hydroxypropyl emthylcellulose etc.; Sweeting agent comprises: saccharin sodium, Aspartane, sucrose, cyclamate, enoxolone etc.; Correctives comprises: sweeting agent and various essence; Antiseptic comprises: parabens, benzoic acid, sodium benzoate, sorbic acid and its esters, benzalkonium bromide, fixed, the Folium eucalypti globueli (Eucalyptus globulus Labill.) wet goods of acetic acid chloroethene; Substrate comprises: PEG6000, PEG4000, insect wax etc.
The present invention also provides the application of above-mentioned Chinese medicine composition in preparation treatment medicine for treating diabetic nephropathy.Described treatment diabetes are treatment 1 type or type 2 diabetes mellitus.
Following experimental example and embodiment do further explanation to the present invention, but do not constitute restriction of the present invention.
The effectiveness study of experimental example 1 medicine composite for curing type 1 diabetes nephropathy of the present invention
One, material and method
1 laboratory animal
60 of Wistar rats, the SPF level, male, 8 ages in week, body weight 180～220g, Beijing Vital River Experimental Animals Technology Co., Ltd. provides, credit number: SCXK (capital) 2007-0001.Raise barrier system, credit number: SYXK (capital) 2005-0019 in animal housing of China-Japan Friendship Hospital.Experimental session, rat give normal diet (Institute of Experimental Animals, Chinese Academy of Medical Sciences provides), freely drink water, take food.
2 experiment medicines
Preparation of pharmaceutical compositions of the present invention for the method for extract of the present invention is: Radix Astragali 300g, Radix Rehmanniae 120g, Radix Notoginseng 30g, Radix et Rhizoma Rhei (processed) 60g, Ramulus Euonymi 150g, Fructus Corni 90g, Fructus Aurantii 100g decocts with water 3 times, add 10 times of amounts at every turn, decocted merge extractive liquid, 1 hour, concentrating under reduced pressure gets thick paste, drying is pulverized, and gets dry powder; Be mixed with the solution of two kinds of variable concentrations with distilled water by the dosage of 1.33g/kg and 2.67g/kg, 4 ℃ of preservations, are taken out before the gastric infusion and are placed to room temperature at 3 days effect duration.
Monopril Tablets (fosinopril sodium sheet, expensive precious pharmaceutical Co. Ltd is executed in sino-america joint-venture Shanghai, 10mg/ sheet * 14 slice/box, lot number: 0704091), when using tablet ground and be fine powder, be mixed with the suspension of desired concn, 4 ℃ of preservations by the dosage of 0.833mg/kg with distilled water, 3 days effect duration, take out before the gastric infusion and be placed to room temperature.
3 main agents
Blood sugar test paper: Johson ﹠ Johnson, lot number: 2846475
Coomassie brilliant blue G250: Sigma company, lot number: 128K1109
Chloral hydrate: Beijing chemical reagents corporation, analytical pure, lot number: T20070725
Formalin: Chemical Reagent Co., Ltd., Sinopharm Group, analytical pure, lot number: 20080203
Creatinine reagent box: the safe clinical reagent of Beijing northization company, lot number: 20071108
Streptozotocin: U.S. Sigma company, lot number: 060326
The foundation of 4 experimental animal models
60 animals are bought the back adaptability and fed for 1 week, carry out base state and measure, and reject 3 of the unusual animals of blood glucose and urine protein, and all the other animals are divided into sham operated rats and operation group by body weight, 10 of sham operated rats, 47 of operation groups earlier at random.
Sham operated rats: rat is with 3.3ml/kg lumbar injection 10% chloral hydrate anesthesia, and preoperative preserved skin is carried out at the back, routine disinfection, and back otch 1～1.5cm fully exposes right kidney, peels off kidney fat peplos, sews up the incision.1 week of postoperative is with the dosage lumbar injection 0.1mmol/L citric acid-sodium citrate buffer of 4ml/kg.
The operation group: rat anesthesia, preserved skin and disinfect same sham operated rats, back otch 1～1.5cm exposes right kidney, peels off kidney fat and adrenal gland, and the right hilus renalis blood vessel of ligation excises right kidney, sews up the incision.After the postoperative animal recovered for 1 week, press the streptozotocin of 40mg/kg lumbar injection 1%, blood glucose is surveyed in the blood sampling of tail point after 72 hours, is higher than 16.7mmol/L as model success standard with blood glucose.
5 grouping and administrations
40 of modeling success animals are divided into model group at random by body weight and blood glucose, the heavy dose of group of invention extract, and invention extract small dose group and MENGNUO group, concrete grouping is as follows with dosage regimen:
Each organizes the rat sub-cage rearing, free diet water inlet, and administering mode is a gastric infusion, carries out 20 weeks of successive administration every day 1 time the morning.
6 collections of specimens
After the modeling the 0th, 4,8,12, in 16,20 weeks, blood glucose is surveyed in the blood sampling of rat tail point, simultaneously rat is changed in the metabolic cage, and water is can't help in fasting, collects the 24h urine.Can't help water 12h in fasting at 20 weekends, chloral hydrate anesthesia animal with the dosage lumbar injection 10% of 3.3ml/kg, abdominal aortic blood is divided into two parts, and is a with the preservation of EDTA anticoagulant tube, get serum after a centrifugal, take out left kidney simultaneously, peel off kidney peplos, vertical profile is two, get a slice and be fixed in 10% neutral formalin solution to carry out histopathological examination, another sheet is put in the liquid nitrogen and is preserved.
7 indexs detect
7.1 general state: animal is weighed weekly, the close observation animal mental status, reactivity, chroma of hair, diet and drainage situation.
7.2 blood biochemistry index: measure each time point blood glucose value with blood glucose meter, get serum, measure total serum protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (Scr), serum total cholesterol (TC), triglyceride (TG) with full-automatic blood biochemistry analyzer.
7.3 hemorheology index: measure whole blood viscosity (height is cut), whole blood viscosity (low cutting) and plasma viscosity with the hemorheology instrument with the blood plasma that the EDTA anticoagulant tube is preserved.
7.4 urine protein/creatinine: the urine that each time point is collected is drawn supernatant with 3000 rev/mins of centrifugal 10min, detects urine protein concentration with the Coomassie brilliant blue method; Picric acid does not remove protein method and detects concentration of urinary creatinine, calculates urine protein/creatinine.
7.5 histopathology index: nephridial tissue is behind 10% formalin fixed 24h, and routine is dewatered, and is transparent, paraffin embedding is cut to the thick section of 3 μ m respectively through microtome, carries out PAS, Masson dyeing, light microscopic is observed the nephridial tissue pathology down and is changed, and adopts point system that it is carried out semi-quantitative analysis.
Glomerular sclerosis index: these 40 glomerule of random observation under 400 times of optical microscopes of every increment, carry out the sxemiquantitative scoring according to the glomerule extent of damage, normal glomerule is designated as 0 fen, slight glomerule infringement, sclerosis pathological changes such as local proliferation mesentery substrate and/or hyalinosis account for whole bead and are designated as 1 fen below 25%, and the sclerosis pathological changes accounts for whole bead 26～50% and counts 2 fens, and 51～75% are designated as 3 fens, 76～100% are designated as 4 fens, and the glomerular sclerosis index is calculated as follows:
Glomerular sclerosis index=(1 * N
1+ 2 * N
2+ 3 * N
3+ 4 * N
4)/(N
0+ N
1+ N
2+ N
3+ N
4) Nx is the number of the corresponding glomerule of glomerular sclerosis score.
1. renal tubules interstitial fibrosis index]: the matter visual field between discontinuous 10 renal tubules of random observation under 100 times of mirrors of every part of specimen, according to matter inflammatory cell infiltration between renal tubules, fibrosis, the extent of damage such as tubular ectasia or atrophy and protein cast, according to document (1, Thallas-bonke V, Thorpe S R, Coughlan M T, et al.Inhibition of NADPH oxidase prevents advanced glycation end product-mediated damage in diabetic nephropathy through a protein kinase C-alpha-dependent pathway.[J] .Diabetes, 2008,57 (2): 460-469; 2, Sebekova K, Eifert T, Klassen A, et al.Renal effects of S18886 (Terutroban), a TP receptor antagonist, in an experimental model of type 2 diabetes.[J] .Diabetes, 2007,56 (4): 968-974.) carry out the sxemiquantitative scoring, be between tubule the anosis loss on transmission of matter to hinder be 0 minute, above-mentioned pathological changes is slight or corresponding area of visual field＜25% are 1 minute, moderate or corresponding area of visual field are 26%～50% to be 2 minutes, extensively or severe, corresponding area of visual field＞50% are 3 minutes.Renal tubules interstitial fibrosis index is calculated as follows:
Renal tubules interstitial fibrosis index=(1 * N
1+ 2 * N
2+ 3 * N
3)/(N
0+ N
1+ N
2+ N
3) Nx is the corresponding area of visual field number of renal tubules interstitial fibrosis score.
All measurement datas of 8 date processing are with mean ± standard deviation
Expression, applied statistics software SPSS13.0 carries out One-Way ANOVA one factor analysis of variance, relatively adopts the LSD check between group in twos, and P＜0.05 expression group difference has statistical significance.
Two, experimental result
1 general state
The blank group rat mental status is good during the whole test, and activity is quick on the draw freely, and hair is glossy, and body weight is with the experimental period steady-state growth; Polydipsia polyuria, polyphagia, listlessness, bradykinesia appear in the model group rat, slow movement, hair tarnish at random, build symptom such as become thin, local ulcer also appears in the part animal, pathological manifestations such as edema of scrotum and cataract, body weight has significant difference from modeling success the 0th week beginning with the blank group than promptly, P＜0.01 is further strengthened with prolonging difference experimental period, body weight difference reaches peak when experiment finished for the 20th week, 3 animals is arranged because of depleted dead; Each administration group mental status, activity and the degree that is quick on the draw all obviously are better than model group, and invention extract small dose group rat body weight is from testing for the 4th week to the 20th week comparing remarkable increase with model group, except that the 8th when week P＜0.05, all the other time points are P＜0.01, the heavy dose of group of invention extract is compared body weight with the MENGNUO group with model group have increase trend, but not statistically significant, the present composition is heavy dose of dead 1 in the experimentation, low dose of dead 2, dead 1 of MENGNUO group.Body weight the results are shown in accompanying drawing 1 in detail.
2. the variation of rat blood sugar:
After the modeling success, promptly test the 0th all model group rat blood sugars and compare remarkable rising (P＜0.01) with the blank group, after the 4th, 8,12,16,20 week each time point all organize utmost point significant difference arranged with blank, be P＜0.01; Large and small dosage group of the present composition and MENGNUO group are compared with model group, and blood sugar level has reduction trend, but not statistically significant, experimental result is seen accompanying drawing 2.
The variation of 3 rat fat levels
By table 1 as seen, compare model group serum TC (T-CHOL) and all significantly risings (P＜0.01) of TG (triglyceride) level with the blank group.The large and small dosage group of the present composition can significantly reduce the TC and the TG level of model group, and MENGNUO group TG level has been compared significant difference with model group, P＜0.05.And the TC level compares with model group reduction trend only arranged, and there was no significant difference, shows that effect is better than MENGNUO to the present composition aspect the blood fat disorder that DN (diabetic nephropathy) occurs together improving.
The variation of table 1 rat fat level
With model group ratio, * P＜0.05, * * P＜0.01
The variation of 4 hemorheology of rat indexs
Each experimental group rat whole blood viscosity height is cut and the low difference of cutting that there are no significant; The model group plasma viscosity is compared remarkable rising with the blank group, P＜0.01, the heavy dose of group of the present composition can significantly reduce the plasma viscosity level of model group rat, P＜0.05, present composition small dose group is compared not statistically significant with MENGNUO group plasma viscosity level with model group, the results are shown in Table 2.
The variation of table 2 hemorheology of rat index
With model group ratio, * P＜0.05, * * P＜0.01
5. the variation of rat urine protein/creatinine
From accompanying drawing 3 as can be seen, compare with the blank group, model group urine protein/creatinine is from testing significantly rising (P＜0.01) of the 12nd week beginning, prolongation difference with experimental period further strengthens, heavy dose of group of the present composition and MENGNUO group can significantly reduce the urine protein creatinine ratio of model group from the 16th week, be P＜0.01, the urine protein creatinine ratio had been compared significant difference with model group, P＜0.01 when present composition small dose group finished for the 20th week in experiment.
6. the variation of rat blood serum total protein, albumin and renal function
Each experimental group total serum protein, albumin and creatinine level there was no significant difference, model group serum urea nitrogen level are compared remarkable rising (P＜0.01) with the blank group, each administration group does not have the significance influence to model group rat serum urea nitrogen levels, the results are shown in Table 3.
The variation of table 3 rat blood serum albumen and renal function
With model group ratio, * P＜0.05, * * P＜0.01
7. kidney of rats histo pathological change
Blank group glomerule clear in structure is not seen mesentery substrate hypertrophy and basement membrane thickened, and cortex and medullary substance renal tubules structure are normal, marshalling, matter NIP and fibrosis.The model group rat kidney obviously increases, and cortex narrows down, medullary substance broadening.The Bowman cyst wall obviously thickens, the adhesion of glomerule sacculus part, and blister cavities increases, mesentery substrate moderate is diffusivity or nodositas, basement membrane thickened to the severe hypertrophy in the glomerule, focal glomerular sclerosis appears in the subregion, and the glomerular capillary clump has the leaflet phenomenon; Cortex renal cells glass drop sample and vacuolar degeneration, visible protein-like substance or protein cast in the part tubular ectasia, part tube chamber, renal cells comes off, and microvillus comes off, and the renal tubules atrophy appears in the subregion.As seen expansion of medullary substance tubular segment or atrophy, a matter are dispersed in or lymphocyte in blocks and monocyte infiltration and fibrosis.The heavy dose of group of invention extract glomerule changes slight, the slight hypertrophy of mesentery, and minority cortex renal tubules is slightly expanded, and cortex renal cells glass drop sample and vacuolar degeneration obviously alleviate than model group.Minority is dispersed in slight expansion of medullary substance renal tubules or atrophy, a small amount of inflammatory cell infiltration of individual areas, and accidental protein cast does not see that obvious fibrosis forms.Invention extract small dose group and the mild to moderate hypertrophy of MENGNUO group glomerular mesangium, the slight adhesion of part glomerule sacculus, the minority glomerule has blood capillary leaflet phenomenon.Cortex and medullary substance tubular segment are obviously expanded, slight kitchen range shape inflammatory cell infiltration, and renal cells glass drop sample and vacuolar degeneration degree circle are between model group and the heavy dose of group of invention extract, and as seen a few regions has little shrink tube.The interstitial fibrosis zone is compared to some extent with model group and is alleviated, but the heavy dose of group of invention extract does not change obviously (seeing accompanying drawing 4).
8. nephridial tissue pathological score result
Model group kidney of rats bead hardenability value and renal tubule fibrosis index are compared remarkable rising with the blank group, be P＜0.01, large and small dosage group of the present composition and MENGNUO group all can significantly reduce glomerular sclerosis index and the renal tubule fibrosis index of model group rat, P＜0.01; The results are shown in Table 4.
Table 4 kidney of rats histopathology appraisal result
With the model group ratio, * * P＜0.01
The effectiveness study of experimental example 2 medicine composite for curing type 2 diabetes mellitus nephropathy of the present invention
One, material and method
1. experiment material
1.1 animal
Male OLETF and LETO rat, the SPF level, 4 ages in week, body weight 90-110g, the big tomb pharmaceutical Co. Ltd of Japan Tokushima institute is so kind as to give; Raise barrier system, credit number: SYXK (capital) 2005-0019 in animal housing of China-Japan Friendship Hospital.Experimental session, rat give normal diet (Institute of Experimental Animals, Chinese Academy of Medical Sciences provides), freely drink water, take food.
1.2 medicine and reagent
Preparation of pharmaceutical compositions of the present invention for the method for pharmaceutical composition extract of the present invention is: Radix Astragali 300g, Radix Rehmanniae 120g, Radix Notoginseng 30g, Radix et Rhizoma Rhei (processed) 60g, Ramulus Euonymi 150g, Fructus Corni 90g, Fructus Aurantii 100g decocts with water 2 times, adds 10 times of amounts at every turn, decocts 1 hour, merge extractive liquid,, concentrating under reduced pressure gets thick paste.Drying is pulverized, and gets dry powder; Be mixed with solution with distilled water by the dosage of 1.60g/kg, 4 ℃ of preservations, are taken out before the gastric infusion and are placed to room temperature at 3 days effect duration.
Monopril Tablets (fosinopril sodium sheet, expensive precious pharmaceutical Co. Ltd is executed in sino-america joint-venture Shanghai, 10mg/ sheet * 14 slice/box, lot number: 0704091), when using tablet ground and be fine powder, be mixed with the suspension of desired concn, 4 ℃ of preservations by the dosage of 1.00mg/kg with distilled water, 3 days effect duration, take out before the gastric infusion and be placed to room temperature.
1.3 main agents
With experimental example 1.
1.4 the preparation of main solution
With experimental example 1.
1.5 instrument
With experimental example 2.
2. experimental technique
2.1 grouping and administration
The rat adaptability carries out base state mensuration after feeding for 2 weeks, the OLETF rat is divided into 3 groups at random, and the LETO rat is as the blank group, and specifically grouping and dosage are as follows, each treated animal carried out gastric infusion, 24 weeks and 44 weeks of successive administration respectively from 12 ages in week.The free diet drinking-water of experimental session rat.
Grouping of table 5 animal and administration situation
2.2 collection of specimens
Animal begins per 4 all rat tail points blood samplings from administration, surveys blood glucose value; Rat is changed in the metabolic cage, collect the 24h urine and write down the urine amount, carry out the twenty-four-hour urine protein quantification.24 weeks of administration, blank group was got 10, and all the other each groups are got 7, and execution is drawn materials, and carries out every index determining; Administration 44 during week each group residue animal again row put to death and draw materials, water 12h is can't help in the rat fasting before drawing materials, with 3.33ml/kg dosage lumbar injection 10% chloral hydrate anesthesia animal, abdominal aortic blood divides two parts, the a EDTA of using anticoagulant tube is preserved, and gets serum after portion is centrifugal, and is standby; Getting left kidney is 2 from hilus renalis vertical profile, and a slice is fixed in 10% neutral formalin solution, and another sheet is put in the liquid nitrogen and preserved.
2.3 index detects
2.3.1 general state
Animal is weighed weekly, the close observation animal mental status, reactivity, chroma of hair, diet and drainage situation.
2.3.224h urine protein quantitation
With the urine mixing that each time point is collected, get the centrifugal 10min of about 1ml 3000r/min, get supernatant, measure urine protein concentration with the Coomassie brilliant blue method; And carry out the 24h urine protein quantitation according to animal 24h urine amount.
2.3.3 blood biochemistry
Measure each time point blood glucose with blood glucose meter; The serum of drawing materials is measured total serum protein (TP), albumin (ALB), blood urea nitrogen (BUN), creatinine (Scr), serum total cholesterol (TC), triglyceride (TG) with automatic blood biochemistry analyzer.
2.3.4 hemorheology index
Measure whole blood viscosity and plasma viscosity with the blood plasma that the EDTA anticoagulant tube is preserved with the hemorheology instrument.
2.3.5 histopathology
Nephridial tissue is behind 10% formalin fixed 24h, and routine is dewatered, and is transparent, paraffin embedding is cut to the thick section of 3 μ m respectively through microtome, carries out PAS, Masson dyeing, light microscopic is observed the nephridial tissue pathology down and is changed, and adopts point system that it is carried out semi-quantitative analysis (with experimental example 1).
3. statistical procedures
All measurement datas are with mean ± standard deviation
Expression, applied statistics software SPSS13.0 carries out One-Way ANOVA one factor analysis of variance, relatively adopts the LSD check between group in twos, and P＜0.05 expression group difference has statistical significance.
Two, experimental result
1. general state
The model group animal is since 6 ages in week, body weight is compared with the blank group promptly significant difference, carries out with experiment, and polyphagia appears in animal, amount of drinking water increases, obesity, the movable minimizing, hair jaundice, body weight reaches maximum with blank group difference when 40 ages in week, model group reduces with blank group body weight difference subsequently, two groups of body weight difference not statistically significants during to 52 ages in week, but that model group animal state is compared early stage is poorer, hair is at random, diet and amount of drinking water continue to increase, and the urine amount increases, and be few moving, there are 2 animals ulcer to occur, 3 animal deads are arranged, and invention extract group is compared body weight with model group and is significantly reduced when 40,44 and 48 ages in week.Invention extract and MENGNUO treated animal state obviously improve than model group, dead 2 of invention extract group, and dead 3 of MENGNUO group the results are shown in accompanying drawing 5.
2. rat blood sugar changes
The model group blood sugar level promptly significantly raises from 6 ages in week with the model group ratio, continue to increase with blood glucose difference between two groups of the prolongations of experimental period, difference reaches the highest during to 52 ages in week, the invention extract 52 ages in week and 56 weeks during ages to the model group blood sugar level by remarkable reduction effect, be P＜0.01, and the MENGNUO group only can significantly reduce the model group blood sugar level, P＜0.05 when 52 ages in week, show that glycometabolic improvement effect is better than MENGNUO to the invention extract to rat model, the results are shown in accompanying drawing 6.
3. rat 24h urine protein changes
Compare with the blank group, model group rat 24h urine protein level is from 6 week remarkable risings in age, and pass constantly in time and raise, peak when experiment finishes to 56 ages in week, invention extract group all can significantly reduce model group rat 24h urine protein from each time point in 36 ages in week, and the MENGNUO group is in 24 ages in week, 36 ages in week with 44 weeks remarkable reduction effect was arranged during ages, and other times point only has reduction trend and no difference of science of statistics the results are shown in accompanying drawing 7.
4. the variation of rat fat level
Model group serum TC level is compared there was no significant difference with the blank group during 36 ages in week, and invention extract group and MENGNUO group do not have obvious influence to model group TC, and model group serum TC level is compared remarkable rising with the blank group, P＜0.01 during 56 ages in week; The invention extract can significantly reduce model group TC level, P＜0.01, and the MENGNUO group does not have reduction trend; 36 the week ages and 56 the week ages two time points, model group rat blood serum TG all significantly raises, P＜0.01, the MENGNUO group 36 age in week the TG level with model group than significantly reducing, but 56 the week age not statistically significant, invention extract group only has reduction trend to model group rat TG level, and no difference of science of statistics the results are shown in Table 6.
The variation of each experimental group rat fat of table 6
With the model group ratio,
*P＜0.05,
*P＜0.01
5. the hemorheology of rat index changes:
Each experimental group whole blood viscosity height when 36 ages in week is cut and the low there was no significant difference of cutting of whole blood viscosity, during 56 ages in week, model group whole blood viscosity height is cut, low the cutting with the blank group of whole blood viscosity compared remarkable rising, be P＜0.01, invention extract group can significantly reduce model group rat whole blood viscosity height cuts with whole blood viscosity is low and cuts level, and the MENGNUO group does not have obvious improvement to these two indexs.The model group plasma viscosity all is significantly higher than blank group in 36 ages in week and 56 ages in week, is P＜0.01, and invention extract group has remarkable reduction effect to the model group plasma viscosity, be respectively P＜0.05, P＜0.01, MENGNUO group plasma viscosity and model group the results are shown in Table 7 than no significant difference.
Each experimental group hemorheology of rat index of table 7 changes
With the model group ratio,
*P＜0.05,
*P＜0.01
6. rat blood serum total protein and albuminous variation
Experimental result shows, each experimental group rat 36 age in week total serum protein and albumin level no difference of science of statistics, but these two indexs of model group have reduction trend.When 56 ages in week, model group rat rat blood serum total protein is compared remarkable reduction with albumin level with the blank group, difference P＜0.01, P＜0.05; Invention extract group is elevation model group rat blood serum total protein and albumin level significantly, is P＜0.01, and the MENGNUO group only has reduction trend, but not statistically significant sees Table 8.
Each experimental group rat blood serum total protein of table 8 and albumin change
With the model group ratio,
*P＜0.05,
*P＜0.01
7. the kidney of rats merit changes
As can be seen from Table 9, each experimental group rat blood serum BUN no significant difference during 36 ages in week, model group BUN level has been compared significant difference with the blank group during 56 ages in week, P＜0.01, invention extract group only has reduction trend to model group rat BUN, the MENGNUO group is compared with model group, the horizontal zero difference of BUN.The model group serum creatinine level all significantly is lower than blank group in 36 ages in week and 56 ages in week, and each administration group is compared the serum creatinine level there was no significant difference with model group.
Each experimental group kidney of rats merit of table 9 changes
With the model group ratio,
*P＜0.05,
*P＜0.01
8. the rat pathomorphology changes
Blank group glomerule clear in structure, the renal tubules structure is normal, marshalling, matter NIP and fibrosis.Model group rat Bowman cyst wall when 36 ages in week obviously thickens, mesentery substrate moderate hypertrophy in the glomerule, be diffusivity or nodositas, basement membrane thickened, focal glomerular sclerosis appears in the subregion, cortex renal cells glass drop sample and vacuolar degeneration, part tubular ectasia or atrophy, visible protein-like substance or protein cast in the tube chamber, as seen a matter is dispersed in lymphocyte and monocyte infiltration and fibrosis.Invention extract group and MENGNUO group glomerule change slight, the slight hypertrophy of mesentery, and minority cortex renal tubules is slightly expanded, and minority is dispersed in slight expansion of medullary substance renal tubules or atrophy, a small amount of inflammatory cell infiltration of individual areas, accidental protein cast.Model group glomerular mesangium substrate severe hypertrophy during 56 ages in week, the diffuse type glomerular sclerosis occurs, Bowman thickens highly significant, and the glomerule fibrin cap forms, most zones renal tubules occurs and obviously expand, atrophy, severe patient occurs downright bad, and protein cast is seen more, inflammatory cell infiltration and fibrosis in blocks appear, compare with 36 ages in week, the nephridial tissue pathological changes increases the weight of obviously, and invention extract group is compared obviously with model group with MENGNUO group pathological changes and alleviated (seeing accompanying drawing 8).
9. kidney of rats histopathology appraisal result
Compare with the blank group, model group kidney of rats bead hardenability value has significant difference when 36 ages in week, P＜0.01, and difference further strengthens during to 56 ages in week, invention extract group, MENGNUO group significantly reduce than glomerular sclerosis index with model group, are P＜0.01; Model group renal tubules interstitial fibrosis index 36 the week ages and 56 the week ages all apparently higher than the blank group, and the difference during 56 ages in week was greater than for 36 ages in week, compare all significantly reduction in 36 ages in week with model group with 56 week invention in age extract group glomerular sclerosis indexes, P＜0.05, the MENGNUO group only has reduction trend, but not statistically significant.
Each experimental group kidney of rats histopathology appraisal result of table 10
With the model group ratio,
*P＜0.05,
*P＜0.01
Description of drawings:
Fig. 1: the result of variations of treatment type 1 diabetes rat body weight, with model group ratio, * P＜0.05, * * P＜0.01
Fig. 2: the variation of treatment type 1 diabetes rat blood sugar, with the model group ratio, * * P＜0.01
Fig. 3: the variation of rat urine protein/creatinine and model group ratio, * P＜0.05, * * P＜0.01
Fig. 4: each experimental group kidney pathological change (renal tubules ID reason changes), first group of 4 photo is PAS, 400 times; Second group of 4 photo is PAS, 200 times;
Fig. 5: the result of variations and model group ratio of treatment type 2 diabetes mellitus rat body weight, * P＜0.05, * * P＜0.01
Fig. 6: the variation and model group ratio of treatment type 2 diabetes mellitus rat blood sugar,
*P＜0.05,
*P＜0.01
Fig. 7: the rat urine protein changes, * P＜0.05, * * P＜0.01
Fig. 8: each experimental group kidney pathological change (renal tubules ID reason changes), first group of 4 photo is glomerule pathology change in 36 ages in week PAS, 400 times; Second group of 4 photo is renal tubules ID reason change in 36 ages in week PAS, 200 times; The 3rd group of 4 photos are glomerule pathology change in 56 ages in week PAS, 400 times; The 4th group of 4 photos are renal tubules ID reason change in 56 ages in week PAS, 200 times.
Following embodiment all can realize the effect of above-mentioned experimental example.
The specific embodiment
Embodiment 1:
Radix Astragali 300g, Radix Rehmanniae 120g, Radix Notoginseng 30g, Radix et Rhizoma Rhei (processed) 60g, Ramulus Euonymi 150g, Fructus Corni 90g, Fructus Aurantii 100g decoct with water 3 times, add 8 times of amounts at every turn, decocted 0.5 hour, merge extractive liquid,, concentrating under reduced pressure gets thick paste, drying, pulverize, get dry powder, add the dextrin of 1.4 times of amounts, mixing adds 75% ethanol and granulates drying in right amount, make granule, an oral 8g, every day 2 times.
Embodiment 2:
Radix Astragali 260g, Radix Rehmanniae 150g, Radix Notoginseng 20g, Radix et Rhizoma Rhei (processed) 80g, Ramulus Euonymi 120g, Fructus Corni 120g, Fructus Aurantii 60g adds 12 times of water gagings and decocts 1 time, decocts merge extractive liquid, 1.5 hours, concentrating under reduced pressure gets thick paste, and drying is pulverized, get dry powder, add appropriate amount of auxiliary materials, make tablet, oral every day 3 times, each 3-6 sheet.
Embodiment 3:
Radix Astragali 350g, Radix Rehmanniae 90g, Radix Notoginseng 50g, Radix et Rhizoma Rhei (processed) 40g, Ramulus Euonymi 180g, Fructus Corni 60g, Fructus Aurantii 140g decocts with water 2 times, adds 10 times of amounts at every turn, decocts 1 hour, merge extractive liquid,, concentrating under reduced pressure gets thick paste, drying, pulverize, get dry powder, add suitable adjuvant, make soft capsule, oral each 2-4 grain, every day 3 times.
Embodiment 4:
Radix Astragali 250g, Radix Rehmanniae 80g, Radix Notoginseng 20g, Radix et Rhizoma Rhei (processed) 20g, Ramulus Euonymi 120g, Fructus Corni 60g, Fructus Aurantii 70g decoct with water 3 times, add 10 times of amounts at every turn, decocted 1 hour, merge extractive liquid,, concentrating under reduced pressure gets thick paste, drying, pulverize, get dry powder, add the dextrin of 1.4 times of amounts, mixing, add 75% ethanol and granulate in right amount, drying, encapsulated, make capsule, every day 3 times, each 3-6 grain.
Embodiment 5:
Radix Astragali 330g, Radix Rehmanniae 100g, Radix Notoginseng 40g, Radix et Rhizoma Rhei (processed) 50g, Ramulus Euonymi 180g, Fructus Corni 80g, Fructus Aurantii 120g according to common process, adds conventional adjuvant and makes pill.
Embodiment 6:
Radix Astragali 260g, Radix Rehmanniae 140g, Radix Notoginseng 50g, Radix et Rhizoma Rhei (processed) 70g, Ramulus Euonymi 190g, Fructus Corni 80g, Fructus Aurantii 140g according to common process, adds conventional adjuvant and makes the ball syrup.
Embodiment 7:
Radix Astragali 350g, Radix Rehmanniae 80g, Radix Notoginseng 40g, Radix et Rhizoma Rhei (processed) 40g, Ramulus Euonymi 160g, Fructus Corni 100g, Fructus Aurantii 130g according to common process, adds conventional adjuvant and makes drop pill.
Embodiment 8:
Radix Astragali 280g, Radix Rehmanniae 150g, Radix Notoginseng 60g, Radix et Rhizoma Rhei (processed) 80g, Ramulus Euonymi 120g, Fructus Corni 100g, Fructus Aurantii 150g according to common process, adds conventional adjuvant and makes aerosol.
Embodiment 9:
Radix Astragali 240g, Radix Rehmanniae 150g, Radix Notoginseng 20g, Radix et Rhizoma Rhei (processed) 80g, Ramulus Euonymi 120g, Fructus Corni 100g, Fructus Aurantii 60g according to common process, adds conventional adjuvant and makes granule.
Embodiment 10:
Radix Astragali 360g, Radix Rehmanniae 85g, Radix Notoginseng 40g, Radix et Rhizoma Rhei (processed) 40g, Ramulus Euonymi 180g, Fructus Corni 80g, Fructus Aurantii 70g according to common process, adds conventional adjuvant and makes granule.
Embodiment 11:
Radix Astragali 360g, Radix Rehmanniae 85g, Radix Notoginseng 40g, Radix et Rhizoma Rhei (processed) 40g, Ramulus Euonymi 180g, Fructus Corni 80g, Fructus Aurantii 70g,
50% ethanol, 5 times of weight are extracted 2 times, extract 1.5 hours at every turn, according to common process, add conventional adjuvant and make granule.
Embodiment 12:
Radix Astragali 240g, Radix Rehmanniae 150g, Radix Notoginseng 20g, Radix et Rhizoma Rhei (processed) 80g, Ramulus Euonymi 120g, Fructus Corni 100g, Fructus Aurantii 60g,
30% ethanol, 6 times of weight are extracted 2 times, extract 1.5 hours at every turn, according to common process, add conventional adjuvant and make granule.
Embodiment 13:
Radix Astragali 280g, Radix Rehmanniae 150g, Radix Notoginseng 60g, Radix et Rhizoma Rhei (processed) 80g, Ramulus Euonymi 120g, Fructus Corni 100g, Fructus Aurantii 150g,
Above-mentioned raw materials decocts with water 2 times, adds 10 times of amounts at every turn, decocts 1 hour, merge extractive liquid,, extracting solution filters, and filtrate is passed through macroporous resin, earlier with 5 times of water gaging eluting, eluent discards, and 3 times of eluting of reuse 30% ethanol are collected eluent, decompression recycling ethanol is to there not being the alcohol flavor, get the purification extracting solution,, add conventional adjuvant and make the ball syrup according to common process.
Embodiment 14:
Radix Astragali 300g, Radix Rehmanniae 120g, Radix Notoginseng 30g, Radix et Rhizoma Rhei (processed) 60g, Ramulus Euonymi 150g, Fructus Corni 90g, Fructus Aurantii 100g decoct with water 3 times, add 8 times of amounts at every turn, decocted 0.5 hour, merge extractive liquid,, extracting solution filters, filtrate is used 15% ethanol elution earlier by macroporous resin, and eluent discards, 3 times of eluting of reuse 40% ethanol are collected eluent, and decompression recycling ethanol is to there not being the alcohol flavor, get the purification extracting solution,, add conventional adjuvant and make the ball syrup according to common process.
Claims (12)
1. treat the diabetic nephropathy drugs compositions for one kind, it is characterized in that the raw material of this pharmaceutical composition consists of:
Radix Astragali 200-400 weight portion, Radix Rehmanniae 50-200 weight portion, Radix Notoginseng 6-60 weight portion, Radix et Rhizoma Rhei (processed) 20-100 weight portion, Ramulus Euonymi 80-280 weight portion, Fructus Corni 40-150 weight portion, Fructus Aurantii 30-180 weight portion.
2. pharmaceutical composition as claimed in claim 1 is characterized in that the raw material of this pharmaceutical composition consists of:
Radix Astragali 250-350 weight portion, Radix Rehmanniae 80-160 weight portion, Radix Notoginseng 10-50 weight portion, Radix et Rhizoma Rhei (processed) 30-90 weight portion, Ramulus Euonymi 100-200 weight portion, Fructus Corni 60-120 weight portion, Fructus Aurantii 50-150 weight portion.
3. pharmaceutical composition as claimed in claim 2 is characterized in that the raw material of this pharmaceutical composition consists of:
The Radix Astragali 300 weight portions, the Radix Rehmanniae 120 weight portions, Radix Notoginseng 30 weight portions, Radix et Rhizoma Rhei (processed) 60 weight portions, Ramulus Euonymi 150 weight portions, Fructus Corni 90 weight portions, Fructus Aurantii 100 weight portions.
4. pharmaceutical composition as claimed in claim 2 is characterized in that the raw material of this pharmaceutical composition consists of:
The Radix Astragali 260 weight portions, the Radix Rehmanniae 150 weight portions, Radix Notoginseng 20 weight portions, Radix et Rhizoma Rhei (processed) 80 weight portions, Ramulus Euonymi 120 weight portions, Fructus Corni 110 weight portions, Fructus Aurantii 60 weight portions.
5. pharmaceutical composition as claimed in claim 2 is characterized in that the raw material of this pharmaceutical composition consists of:
The Radix Astragali 340 weight portions, the Radix Rehmanniae 90 weight portions, Radix Notoginseng 50 weight portions, Radix et Rhizoma Rhei (processed) 40 weight portions, Ramulus Euonymi 180 weight portions, Fructus Corni 70 weight portions, Fructus Aurantii 140 weight portions.
6. as the arbitrary described preparation of drug combination method of claim 1-5, it is characterized in that this method comprises any one in the following method:
Method 1: water extraction 1-4 time, add water 8-30 times of weight at every turn, extracted 0.5-3 hour; Or,
Method 2: ethanol extraction 1-4 time, add 5-100% ethanol 4-15 times of weight at every turn, extracted 0.5-2 hour; Or,
Method 3: method 1 described water extraction or method 2 described alcohol extracts filter, filtrate is passed through macroporous resin, first ethanol elution with 4-6 times of water gaging or 20% following concentration, eluent discards, 1-10 times of eluting of reuse 10-90% ethanol, the collection eluent, decompression recycling ethanol gets the purification extracting solution to there not being the alcohol flavor.
7. as the arbitrary described preparation of drug combination method of claim 1-5, it is characterized in that this method is:
The Radix Astragali, the Radix Rehmanniae, Radix Notoginseng, Radix et Rhizoma Rhei (processed), Ramulus Euonymi, Fructus Corni, Fructus Aurantii seven flavor Chinese medicines decoct with water 1-4 time, add 8-12 at every turn and doubly measure, and decoct 0.5-2.0 hour, merge decoction liquor, filter, and concentrating under reduced pressure gets thick paste; According to common process, add conventional adjuvant and make pill, powder, syrup, tablet, granule, capsule, emplastrum, mixture, suppository, aerosol, ointment or injection.
8. preparation of drug combination method as claimed in claim 7 is characterized in that described pill is a drop pill.
9. preparation of drug combination method as claimed in claim 7 is characterized in that this method is:
The Radix Astragali, the Radix Rehmanniae, Radix Notoginseng, Radix et Rhizoma Rhei (processed), Ramulus Euonymi, Fructus Corni, Fructus Aurantii seven flavor Chinese medicines decoct with water 2 times, add 10 times of amounts at every turn, decoct 1 hour, merge decoction liquor, filter, and concentrating under reduced pressure gets thick paste; According to common process, add conventional adjuvant and make granule, pill, powder, syrup, tablet, capsule, emplastrum, mixture, suppository, aerosol, ointment.
10. preparation of drug combination method as claimed in claim 9 is characterized in that described pill is a drop pill.
11. as the application of the described arbitrary pharmaceutical composition of claim 1-5 in preparation treatment medicine for treating diabetic nephropathy.
12. application as claimed in claim 11 is characterized in that diabetes are 1 type or type 2 diabetes mellitus.
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| CN2009102413690A CN101703617B (en) | 2009-12-07 | 2009-12-07 | Medicinal composition for treating diabetic nephropathy and preparation method thereof |
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| CN102550916A (en) * | 2012-02-04 | 2012-07-11 | 王姗思 | Food for treating diabetic nephropathy (DN) |
| CN102743540A (en) * | 2012-06-14 | 2012-10-24 | 黄培光 | Combined blood sugar-reduction formula |
| CN103495066B (en) * | 2013-10-15 | 2015-03-11 | 王俊英 | Enema liquid for treating diabetic nephropathy |
| CN104027458B (en) * | 2014-05-16 | 2016-11-23 | 中日友好医院 | A kind of pharmaceutical composition is for preparing the new application of antihyperglycemic hepatoprotective agent |
| CN106138494B (en) * | 2015-04-07 | 2021-06-08 | 何世东 | Kidney nourishing composition and production method thereof |
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