CN110652511A - Application of Zhongwuning in preparation of medicine for preventing and treating renal failure - Google Patents
Application of Zhongwuning in preparation of medicine for preventing and treating renal failure Download PDFInfo
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- CN110652511A CN110652511A CN201910582911.2A CN201910582911A CN110652511A CN 110652511 A CN110652511 A CN 110652511A CN 201910582911 A CN201910582911 A CN 201910582911A CN 110652511 A CN110652511 A CN 110652511A
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- renal failure
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- kidney
- renal
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/439—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom the ring forming part of a bridged ring system, e.g. quinuclidine
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Abstract
The invention discloses a medicine for preventing and treating renal failure. The medicine is the Chinese wuning or acceptable salt, ester or solvate thereof. The medicine is taken as an effective component, and can be prepared into a preparation with corresponding functions together with acceptable auxiliary materials or auxiliary components in the medicine. Research shows that the Chinese wuning has obvious effect on preventing and/or treating kidney failure.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of Zhongwuning in preparation of medicines and health-care products for treating acute and chronic renal failure.
Background
The renal failure is a condition that renal function declines to enter a uremia stage, and is divided into acute renal failure and chronic renal failure, wherein the acute renal failure refers to a condition that physiological functions of kidneys are sharply reduced or even lost due to various reasons, and then a series of physiological changes are caused. Chronic Renal Failure (CRF), also known as Chronic Renal insufficiency, has become one of the major diseases affecting the global human health, and the incidence and prevalence of Chronic Renal Failure are on the rise year by year. Chronic renal insufficiency is a syndrome of a series of clinical symptoms such as azotemia, metabolic disorders, and various systemic diseases, which is caused by chronic progressive renal parenchymal damage due to various chronic kidney diseases or systemic diseases involving the kidney, resulting in chronic renal hypofunction, and the kidney cannot maintain basic functions such as excretion of metabolic waste, regulation of water-salt and acid-base balance, secretion, and regulation of various hormone metabolism. The serum urea nitrogen and creatinine of patients with acute and chronic renal failure rise rapidly, and renal failure gradually results.
At present, no document or patent indicates that the Chinese medicine Wuning has the effect of resisting renal failure, and the Chinese medicine Wuning (mesaconine; Cas No.: 6792-09-2; molecular formula: C) is separated from monkshood and aconitum carmichaeli24H39NO9) The traditional Chinese medicine composition has the advantages that the traditional Chinese medicine composition has a remarkable effect of resisting renal failure, the traditional Chinese medicine composition has rich raw material sources and a clear chemical structure, can be synthesized, overcomes the problem that the traditional Chinese medicine compound substance is complex and difficult to clarify, and is expected to become an innovative medicine through research and development according with modern pharmaceutical rules.
The pharmacological experiments of the invention research the effects of Wuning chronic and acute renal failure, and the results show that the Wuning can effectively reduce the content of Blood Urea Nitrogen (BUN) and creatinine (Cr) in serum, relieve proteinuria, obviously improve chronic renal failure and acute renal failure, and can be used for preparing health products and medicines for preventing and/or treating acute and chronic renal failure. The invention relates to an application of Zhongwuning in preparing a medicine for preventing and/or treating acute and chronic renal failure, which is disclosed for the first time.
Disclosure of Invention
The invention provides a Chinese medicine Wuning or a pharmaceutically acceptable salt, ester or solvate thereof, and application thereof in preparing a medicine or a health-care product for preventing and/or treating renal failure, wherein the structural formula of the Chinese medicine Wuning is shown as follows.
In the invention, the renal failure is partial or total loss of renal function caused by development of various primary or secondary renal diseases to a later stage.
Further, the various primary or secondary kidney inducing factors are drugs, diabetes, hypertension, gout, viruses, bacterial infections, or kidney transplants.
In the invention, the medicine for preventing and/or treating renal failure is a preparation prepared by taking the Chinese wuning or the pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient and adding pharmaceutically common auxiliary materials or auxiliary ingredients.
Wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt; the inorganic salt is sulfate, nitrate, hydrochloride, hydrobromide or phosphate; the organic salt is acetate, propionate, maleate, oxalate, malate, glycolate, pyruvate, malonate, succinate, citrate, benzoate, fumarate, tartrate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate or salicylate; the preparation is in a liquid preparation, a solid preparation or a semisolid preparation.
Wherein the daily administration dosage of the Chinese medicine Wuning is 0.0001-80 mg/Kg. Furthermore, the daily administration dosage of the Chinese medicine Wuning is 0.0005-80 mg/Kg. Furthermore, the daily administration dosage of the Chinese medicine Wuning is 0.001-50 mg/Kg.
The chronic renal failure refers to a pathological state of partial or complete loss of renal function caused by development of various primary or secondary renal diseases to later stages, is a common homing state of the development of the renal diseases at the later stages, and is a group of clinical comprehensive groups characterized by excretion function, homeostasis function and endocrine function disorder of kidneys caused by progressive nephron damage. The main pathological manifestations are glomerular sclerosis, renal interstitial fibrosis and renal vascular injury, and the main clinical manifestations are renal hypofunction, retention of metabolic waste and imbalance of the environment in the organism. It is understood that the partial or complete loss of renal function due to various factors (e.g., drugs, diabetes, hypertension, chronic kidney disease, viral/bacterial infections, kidney transplantation, etc.) is within the scope of the present application.
The term "prevention" refers to the prevention or reduction of the occurrence of acute or chronic renal failure after use in the presence of possible factors of acute or chronic renal failure. The term "treatment" refers to reducing the degree of acute or chronic renal failure, or delaying the progression of acute or chronic renal failure, or curing acute or chronic renal failure to normalize it.
As used herein, the term "pharmaceutically acceptable" means having no long term deleterious effects on the general health of the subject being treated.
In the present invention, the term "pharmaceutically acceptable salt" refers to a salt that retains the biological effectiveness of the free base in mexicanin and has no biological or other adverse effects. Pharmaceutically acceptable salts refer to salts formed by converting a base group of a parent compound into a salt, such as inorganic or organic acid salts of a base group (e.g., an amine group), typically prepared by reacting the parent compound with a conventional acid in a solvent system, typically an inorganic acid such as sulfuric, nitric, hydrochloric, hydrobromic, or phosphoric acid; organic acids typically include acetic, propionic, maleic, oxalic, malic, glycolic, pyruvic, malonic, succinic, citric, benzoic, fumaric, tartaric, cinnamic, mandelic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic, and the like.
In the present invention, the term "pharmaceutically acceptable solvate" refers to a combination of wuning and solvent molecules formed by solvation, and may include stoichiometric or non-stoichiometric amounts of solvent, and solvent molecules in the solvent may exist in ordered or non-ordered arrangements.
In the present invention, the term "pharmaceutically acceptable ester" refers to a pharmaceutically acceptable ester of mexicanin, typically under biological conditions in vitro or in vivo, wherein the ester linkage may be cleaved or otherwise reacted from the compound to provide mexicanin. Said ester may be inactive or less active than the meonin itself, such that the meonin does not exert its activity until cleaved from said upper ester. The esterified meonine generally improves the properties of the parent compound (i.e., meonine) in terms of histocompatibility or pharmacokinetics, etc.
In the present invention, the "medicament for preventing and/or treating chronic kidney failure" may include mexicanin or a pharmaceutically acceptable salt, ester or solvate thereof, and a pharmaceutically acceptable excipient, which may be prepared according to a conventional method in the art, and is generally prepared by mixing mexicanin or a pharmaceutically acceptable salt, ester or solvate thereof, with one or more pharmaceutically conventional excipients (which may be solid excipients or liquid excipients) and/or adjuvants, and making into a dosage form suitable for human or animal use, such as a common preparation (such as capsules, tablets, granules or injections, etc.), a sustained release preparation, a controlled release preparation, a targeted preparation, and various microparticle delivery systems. The content of the Chinese wuning in the medicine for treating chronic kidney failure can be 5-99% by weight.
The "drug for preventing and/or treating chronic kidney failure" can be administered by any known administration method, and the administration route can be intestinal tract or parenteral tract, such as oral administration, intravenous injection, intramuscular injection, subcutaneous injection, nasal cavity, oral mucosa, lung and respiratory tract, skin, vagina, rectum, eye, etc. The dosage form for administration may be a solid dosage form, a semi-solid dosage form, or a liquid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet, enteric coated tablet, buccal tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, aerosol (powder), spray suppository, pellicle, patch, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like.
When the "medicament for preventing and/or treating chronic kidney failure" is a tablet, various excipients which are conventional in the art can be used, including diluents, disintegrants, binders, wetting agents, lubricants and glidants. The diluent can be starch, dextrin, sucrose, glucose, calcium carbonate, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the disintegrant may be pregelatinized starch, low-substituted hydroxypropyl cellulose, cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch, microcrystalline cellulose, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the binder can be starch slurry, dextrin, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like. The above tablet can be further made into coated tablet, such as sugar-coated tablet, film-coated tablet, enteric-coated tablet, or double-layer tablet and multi-layer tablet.
When the medicine for preventing and/or treating chronic kidney failure is a capsule, the effective component (the Chinese wuning) can be mixed with a diluent and a glidant, and the mixture is directly placed into a hard capsule or a soft capsule. Or mixing the effective components with diluent, binder, and disintegrating agent, making into granule or pellet, and placing into hard capsule or soft capsule. The various diluents, binders, wetting agents, disintegrants and glidants of the above tablets may also be used to prepare the capsules.
When the medicine for preventing and/or treating chronic kidney failure is an injection, water, ethanol, isopropanol, propylene glycol or a mixture of the water, the ethanol, the isopropanol and the propylene glycol can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator or osmotic pressure regulator which is commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol, glucose, lactose, etc. can be added as proppant for preparing lyophilized powder for injection.
The dosage of the "drug for preventing and/or treating chronic kidney failure" to be administered may vary depending on the nature and severity of the disease to be prevented and/or treated, the individual condition of the patient or animal, the route and dosage form of administration, and the like. Generally, the daily clinical dosage of Zhongwuning may range from 0.0001 to 100mg/Kg body weight, preferably from 0.0005 to 80mg/Kg body weight, more preferably from 0.001 to 50mg/Kg body weight. The above-described dosage may be administered in one dosage unit or divided into several dosage units, depending on the clinical experience of the physician and the dosage regimen including the use of other therapeutic means.
The medicine or health product for preventing and/or treating chronic kidney failure can be taken alone or combined with other treatment medicines or symptomatic medicines. When the compounds of the present invention act synergistically with other therapeutic agents, the dosage to be used should be adjusted according to the actual circumstances.
In the application of the invention, the product comprises but is not limited to drugs and health care products. The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
Drawings
Figure 1 pathological h.e staining of rat kidney for blank and model groups.
Figure 2 h.e staining pathogram of rat kidney in low and high dose groups.
Detailed Description
The present invention will be described in further detail with reference to the following examples, but the scope of the present invention is not limited to the specific examples, but is defined by the claims. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
Example 1 study of the effects of wuning on the treatment of acute renal failure in rats
1. Experimental Material
Experimental animals: SD rats, SPF grade, were supplied by Somogul Biotech, Inc. Producing license numbers: SCXK 2015-030, raised in cages with complete nutrition in an artificial 12h day/night circulating illumination environment at the room temperature of 18-25 ℃ and the relative humidity of 50-60%, the cages are cleaned regularly every day, and rats freely eat and drink water.
Main raw materials and reagents: zhongwuning (provided by Hao doctor pharmaceutical group Co., Ltd., ZWN for short); kits for quantification of blood creatinine (SCr), Blood Urea Nitrogen (BUN), 24-hour urine protein, etc. were purchased from tokyo bio-corporation.
2. Experimental methods
2.1 animal groups: after the SD rats are bred adaptively for 3 days, the SD rats are randomly divided into a blank control group, a model group, a positive group, a ZWN high-dose group, a ZWN low-dose group and a ZWN injection group according to body weights. (10 pieces per group)
2.2, a molding method: gentamicin was administered intraperitoneally at a dose of 100mg/kg for 1 dose/day for 10 consecutive days to create a rat kidney injury model.
2.3 administration method: respectively intragastrically administering ZWN 4 mg/kg-d and 2 mg/kg-d liquid medicines at high and low doses of ZWN, and intraperitoneally injecting 0.1mg/kg in ZWN injection group; the positive control group is administered with SHENSHUAINING tablet (360 mg/kg. d), and the blank group and model group are administered with equal volume of normal saline by intragastric administration for 1 time per day for 15 days.
2.4 specimen collection: firstly, collecting a blood sample, administering for 24 hours at the last time, anesthetizing a rat by using 20% urethane, placing the rat on a sterile operating table, opening the abdominal cavity, exposing the abdominal aorta, collecting the blood of the abdominal aorta by using a sterile blood collector and a No. 7 needle, centrifuging at 3500rpm/min, and separating serum by using centrifugation for 10 min. Freezing at-80 deg.C for use. Collecting urine specimen, placing the animal in a metabolism cage after last administration, collecting urine, and detecting urine protein content. All detection indexes are detected according to the kit instructions. Tissue material taking: the kidney of the rat is dissected out, and after being fully fixed by 10% neutral formaldehyde, the pathological change of the kidney of the model rat is observed by adopting HE staining and Masson staining.
2.5 statistical methods: metering data adoption
Showing that the data obtained from each group are compared with the model control groupAnd (4) according with normal distribution, adopting SPSS 21.0 single-factor variance analysis, and adopting non-parameter check rank sum method for the non-conforming person to analyze.
3 results of the experiment
(1) Effect of ZWN on weight Change in rats
During the experiment, the 1d, 7d, 14d and 25d were weighed. In the experimental process, the weight of the rats in the blank group is constantly in a stable increasing state, and the weights of the rats in the other groups are reduced in different degrees in the molding period, so that the influence of the intraperitoneal injection of the gentamicin on the weight of the rats is prompted. After the modeling is finished, the weight of each group of rats begins to gradually increase in the administration period, wherein the weight increase of the ZWN high-dose group of rats is more remarkable than that of the model group. Suggesting that high doses of ZWN improve the overall condition of rats with acute renal injury. The body weight changes of the rats in each group are shown in Table 1.
TABLE 1 Effect of ZWN on mean change in mean body weight of rats (g)
| Time of day | Blank group | Model set | Kidney failure treating group | ZWN high dose group | ZWN Low dose group | ZWN injection group |
| 1d th | 200.00 | 199.20 | 200.30 | 200.10 | 200.20 | 198.70 |
| 7d th | 249.00 | 249.80 | 236.50 | 237.80 | 243.50 | 241.70 |
| 17 th d | 288.90 | 230.10 | 215.10 | 227.50 | 231.90 | 223.90 |
| 25d th | 312.05 | 238.70 | 236.70 | 260.90 | 248.70 | 254.60 |
(2) Effect of ZWN on Kidney index in rats
Compared with the blank group, the weight of the model group rats is reduced, the change of the kidney weight is small, and the kidney index is obviously increased (p is less than 0.01); compared with the model group, the kidney index of the ZWN high-dose group and the ZWN injection group is obviously reduced; the kidney index was decreased in both ZWN low dose group and positive group, and the results are shown in Table 2.
TABLE 2 Effect of ZWN on rat Kidney index
| Group of | Renal index |
| Blank group | 0.0031±0.0015** |
| Model set | 0.0049±0.0013△△ |
| Kidney failure treating group | 0.0047±0.0013△△ |
| ZWN high dose group | 0.0035±0.00110* |
| ZWN Low dose group | 0.0042±0.00080△ |
| ZWN injection group | 0.0037±0.00020* |
Note: comparison with blank group△△P＜0.01△P is less than 0.05; comparison with model group**P＜0.01*P＜0.05；
(3) Effect of ZWN on rat 24h urine volume and urine protein
Compared with the blank group, the 24h urine volume and the urine protein content of the model group rats are obviously increased (p is less than 0.01), which indicates that the model rats have impaired glomerular reabsorption function and filtration function. Compared with the model group, 24h urine volume and urine protein content of rats in the ZWN high dose group, the injection group and the positive group are obviously reduced (p is less than 0.01), and 24h urine volume and urine protein content of rats in the ZWN low dose group tend to be reduced, and the results are shown in a table 3.
TABLE 3 Effect of ZWN on rat 24h urine volume and urine protein
| Group of | Urine volume (ml) | Urine protein (mg/ml) |
| Blank group | 1.96±0.49** | 157.82±65.20** |
| Model set | 9.25±3.42△△ | 401.06±262.74△△ |
| Kidney failure treating group | 2.95±1.51** | 242.02±56.04 |
| ZWN high dose group | 3.23±1.49** | 173.43±103.66** |
| ZWN Low dose group | 5.84±2.20△ | 233.87±88.49 |
| ZWN injection group | 4.17±1.53** | 183.42±112.66** |
Note: comparison with blank group△P＜0.05，△△P is less than 0.01; comparison with model group*P＜0.05，**P＜0.01
(4) Effect of ZWN on rat serum Urea Nitrogen (BUN), creatinine (Scr)
Compared with the blank group, the serum urea nitrogen content of the model group rats is obviously increased (p is less than 0.01), and the renal function of the model rats is suggested to be damaged. Compared with the model group, the BUN content of the ZWN high-dose group and the ZWN injection group is obviously reduced (p is less than 0.01), the SCr content is reduced to a certain extent, and no statistical difference is seen. The results show that ZWN has an effect of improving kidney function of rats at high dose, and are shown in Table 4.
TABLE 4 Effect of ZWN on rat SCr, BUN
| Group of | SCr(μmol/L) | BUN(mmol/L) |
| Blank group | 51.18±9.43 | 5.80±0.71** |
| Model set | 53.93±8.92 | 8.53±2.31△△ |
| Kidney failure treating group | 66.26±11.01△ | 8.06±2.49△ |
| ZWN high dose group | 48.14±7.74 | 5.90±0.90** |
| ZWN Low dose group | 63.82±9.46*△ | 7.12±1.59△ |
| ZWN injection group | 45.23±6.81 | 6.30±0.78* |
Note: comparison with blank group△P＜0.05，△△P is less than 0.01; comparison with model group*P＜0.05，**P＜0.01
(5) Pathological result analysis of H.E staining of rat kidney by ZWN
Each group of rats was assessed for nephrotoxic injury according to the pathological grading score of table 5. Compared with the blank group, the total renal component of the model group is obviously increased, and the statistical significance is achieved (P is less than 0.01); compared with the model group, the total renal component of each drug group of ZWN is remarkably reduced, and the statistical significance is achieved (P is less than 0.01), and the results are shown in Table 5.
TABLE 5 grading of renal toxicity Damage Pathology
TABLE 6 statistical results of ZWN on rat Kidney scores
| Grouping | Kidney score |
| Blank group | 0.00±0.00 |
| Model set | 9.00±1.15** |
| Kidney failure treating group | 4.00±1.90△△ |
| ZWN Low dose group | 3.10±1.64△△ |
| ZWN high dose group | 1.60±1.14△△ |
| ZWN injection | 2.00±1.79△△ |
Note: 0.01 < (R) > as compared with blank group*P<0.05，**P<0.01; 0.01 < compared with the model group△P<0.05，△△P<0.01。
HE pathological results show that most of the kidneys of the model group have renal tubular atrophy or disappearance, the volume is reduced, the peripheral gaps are widened, a small number of renal tubular cells have protein tube types, and most of adjacent parallel renal tubular epithelial cells are degenerated or necrotized; it is seen that there is much lymphocyte infiltration and there is a great amount of fibrous tissue proliferation in the renal interstitium. The structure of part of glomeruli in the cortical areas of the ZWN high-dose group and the injection group is complete and clear, no obvious atrophy is seen in renal tubules, vacuolar degeneration or necrosis of renal tubular epithelial cells and no obvious proliferation of fibrous tissues occur in a few cases, and the vacuolar degeneration or necrosis of the renal tubular epithelial cells and the proliferation of the fibrous tissues are relieved in the ZWN low-dose group as shown in the figure 1-2. By combining kidney index monitoring and observation under a light microscope, ZWN has a protective effect on acute renal failure caused by gentamicin.
Example 2 study of the effects of Wuning on the treatment of chronic renal failure in mice
1 materials of the experiment
Experimental animals: SPF-grade KM mice, male, weighing 30-35g, were purchased from Duoduoshu laboratory animals GmbH under the certification number SCXK 2015-030.
Main raw materials and reagents: zhongwuning, offered by good physicians pharmaceutical group, ltd; jin Kui Shen Qi Wan (Tong Yao pharmaceutical group, Inc.), Xue Niao Ning (BUN) kit and Creatinine (Cr) kit were purchased from Nanjing Jiang Bio Inc.
2 Experimental methods and results
2.1 Experimental methods
95 SPF-grade KM mice with the weight of 30-35g are taken, after adaptive feeding for 3 days, the mice are randomly divided into 10 normal groups and 85 molding groups, the normal groups are perfused with physiological saline with the same volume as the normal groups every day, the other mice are perfused with adenine 0.2115mg/g every day, and the perfusion is continuously carried out for 14 days. Each of the molded mice has exhibited chronic renal failure symptoms such as emaciation, hunching, aversion to cold, cold limbs, loose and yellow body hair, lackluster, listlessness, slow response, polydipsia, polyuria, etc. 75 mice successfully modeled are randomly grouped into 15 groups, from the 15 th day, except for a normal group and a model group which are filled with normal saline with the same volume as the normal saline, a medium wuning low dose group (the administration dose is 2mg/kg), a medium wuning medium dose group (4mg/kg), a medium wuning high dose group (8mg/kg) and a Jinkui kidney qi pill group (2g/kg), the normal group and the model group are filled with liquid medicine with the corresponding volume, the stomach is continuously filled for 14 days, the orbital bleeding is obtained on the 2 nd day after the last administration, the method of taking the eyeball and the blood is not anticoagulated, the blood is placed in a common test tube, the blood is centrifuged at 3500rpm for 10min after the blood collection, the blood serum is separated from a centrifuge tube, and the serum is stored in a refrigerator at the temperature of-20 ℃. And detecting the renal function indexes of Blood Urea Nitrogen (BUN) and creatinine (Cr) in the serum according to the kit instruction. Isolated bilateral kidney tissues of mice were dissected out and weighed, and the renal index (renal bilateral kidney (mg)/body weight (g) was calculated.
2.2 results
2.2.1 general conditions and Kidney index levels
Before the experiment, the mouse normally moves, has smooth fur, luster and sensitive response, and is normally drunk by water. After one week of modeling, the mice have the conditions of loose and lusterless fur, reduced activity, emaciation, crouched and hunched back, aversion to cold, cold limbs, liking of bunching, somnolence, moist vulva, listlessness, slow reaction, increased water intake, decreased food intake and increased urine intake. During the treatment period, mice in various dose groups of Zhongwuning and Jinkui Shenqi pill groups have slightly improved cold intolerance and curling phenomena, slightly increased self activities and slightly increased body weight. The organ index is the percentage of organs and body weight, can reflect the influence of molding on animal organs, compared with a blank group, the kidney index of the model group is obviously increased, the kidney swelling caused after molding is proved, the kidney index can be obviously reduced in the middle and high dose groups of Zhongwuning, and the result shows that the kidney failure is improved, and the result is shown in a table 7.
TABLE 7 Effect of Wuning on Kidney index in Chronic renal failure mice
| Group of | Kidney index% |
| Blank control group | 1.65±0.17 |
| Model control group | 1.99±0.21** |
| Middle wuning low dose group | 1.83±0.23 |
| Medium dosage group of Zhongwuning | 1.75±0.26# |
| High dose group of Zhongwuning | 1.70±0.16# |
| Jinkui kidney qi pill group | 1.82±0.27 |
Note: (1) comparing model control group with blank control group<0.01. (2) Each administration group was compared with the model control group,#P<0.05，##P<0.01。
2.2.2 levels of BUN and Cr in mouse serum
The experimental result shows that compared with a blank group, the serum content of BUN and Cr of the model group mice is obviously increased (P < 0.01). Compared with a model group, each dose group of the Zhongwuning can reduce the content of BUN and Cr in the blood serum of mice, wherein the medium and high dose groups of the Zhongwuning have obvious effects (P <0.05 and P < 0.01). Zhongwuning has the function of improving the serum BUN and Cr of a chronic renal failure model mouse, has obvious treatment effect on chronic renal failure, and the result is shown in a table 8.
TABLE 8 Effect of Wuning on serum BUN and Cr levels in mice with chronic renal failure
| Group of | Cr(μmol/L) | BUN(mmol/L) |
| Blank control group | 110.29±22.15 | 4.77±0.45 |
| Model control group | 152.43±23.46** | 8.72±2.67** |
| Middle wuning low dose group | 129.45±28.06 | 7.39±1.23 |
| Medium dosage group of Zhongwuning | 113.41±24.33## | 6.38±1.26# |
| High dose group of Zhongwuning | 107.74±19.71## | 5.33±2.03## |
| Jinkui kidney qi pill group | 112.45±27.11## | 7.22±1.34 |
Note: (1) comparing model control group with blank control group<0.01. (2) Each administration group was compared with the model control group,#P<0.05，##P<0.01。
example 3 study of the effects of Wuning on the treatment of chronic renal failure in rats
1 experimental materials:
1.1 Experimental animals: SD rats, SPF grade, were supplied by Somogul Biotech, Inc. Producing license numbers: SCXK 2015-030, raised in cages with complete nutrition in an artificial 12h day/night circulating illumination environment at the room temperature of 18-25 ℃ and the relative humidity of 50-60%, the cages are cleaned regularly every day, and rats freely eat and drink water.
1.2 main raw materials and reagents: zhongwuning (provided by Hao doctor pharmaceutical group Co., Ltd., ZWN for short); blood Urea Nitrogen (BUN) kit and creatinine (Cr) kit were purchased from tokyo bio-corporation.
2 method of experiment
2.1 animal groups: after the SD rats are bred adaptively for 3 days, the SD rats are randomly divided into a blank control group, a pseudo-operation group, a model group, a positive group, a ZWN high-dose group and a ZWN low-dose group according to the body weight, wherein the blank control group and the pseudo-operation group are respectively 10, and the other groups are respectively 15.
2.2, a molding method: the procedure establishes 5/6 a nephrectomy model. Fasting for 12 hours, weighing, carrying out intraperitoneal injection anesthesia fixation, preparing skin, sterilizing by 20% of urethane (100g/0.5ml), making a longitudinal incision on the skin 1.5cm away from the lower edge of a left rib and the side of the spine under aseptic conditions, separating fascia and intra-abdominal oblique muscle fascia layer by layer, entering a posterior peritoneal cavity, separating a fat layer, exposing a left kidney, carrying out blunt separation on a fat sac, carefully peeling a kidney envelope and adrenal gland, paying attention to avoid damaging the adrenal gland, ligating the left kidney pedicle, cutting off the upper and lower poles 2/3 kidney parenchyma of the left kidney, pressing a wound surface by gelatin sponge to stop bleeding, observing for 30-50 seconds after unfastening a ligature without continuous bleeding, bringing the residual kidney into the abdominal cavity, suturing the muscle layer, the subcutaneous layer and the skin layer by layer, and carrying out local sterilization. After 1 week, the right kidney was removed, and the anesthesia and surgical procedures were the same, i.e., 5/6 nephrectomy model was established. In the sham operation group, only the kidney capsule is separated and no nephrectomy is performed after 2 operations.
2.3 administration mode and time: 4 mg/kg.d and 2 mg/kg.d liquid medicines are respectively administered to the high and low dosage components of Zhongwuning (ZWN) by intragastric administration; enalapril solution is administered to the positive control group for intragastric administration (10 mg/kg. d), and equal volume of physiological saline is administered to the blank group, the model group and the sham operation group for continuous administration for 30d 1 time a day.
2.4 detection indexes and methods: counting the death condition of each group of animals, and calculating the survival protection rate; collecting blood sample 24h after last administration, anesthetizing rat with 20% urethane, placing on sterile operating table, opening abdominal cavity, exposing abdominal aorta, collecting blood from abdominal aorta at 3000rpm/min with sterile hemostix and 7-gauge needle, centrifuging for 10min, and separating serum. Freezing at-80 deg.C for use. All detection indexes are detected according to the kit instructions.
2.5 statistical methods: metering data adoption
The data obtained from each group are compared with the model control group, normal distribution is met, SPSS 21.0 single-factor variance analysis is adopted, and non-parameter check rank sum analysis is adopted for the non-conforming persons.
3 results of the experiment
(1) Effect of ZWN on survival protection Rate in model rats
5/6 the mortality rate of rats in nephrectomy model group is 53%, the mortality rate of rats in model can be reduced by both high and low dose ZWN groups, and ZWN has protective effect on the rat model of chronic renal failure, as shown in Table 9.
TABLE 9 Effect of ZWN on survival protection Rate in model rats
| Group of | Survival protection Rate (%) |
| Blank group | 100(10/10) |
| Artificial operation group | 100(10/10) |
| Model set | 53％(8/15) |
| Positive control group | 60％(9/15) |
| ZWN high dose group | 80％(12/15) |
| ZWN Low dose group | 73％(11/15) |
(2) Effect of ZWN on serum Urea Nitrogen (BUN), creatinine (Scr) in model rats
Compared with the blank group and the sham operation group, the serum urea nitrogen and creatinine levels of the rats in the sham operation group have no statistical difference (P is more than 0.05), and compared with the blank group and the sham operation group, the serum urea nitrogen and creatinine levels of the rats in the model group are obviously increased (P is less than 0.01), which indicates that the model is successfully made, and 5/6 shows obvious chronic renal insufficiency after the kidney is cut off.
Compared with the model group, the ZWN high-dose group, the ZWN low-dose group and the positive drug group can reduce the serum urea nitrogen and creatinine level of the model rat, and the ZWN high-dose group and the ZWN low-dose group can obviously reduce the serum urea nitrogen and creatinine level of the model rat. The results of ZWN in the model rats are shown in Table 10.
TABLE 10 Effect of ZWN on serum Urea Nitrogen, Creatinine in model rats
| Group of | BUN(mmol/L) | Scr(μmol/L) |
| Blank group | 7.22±2.56** | 53.85±4.01** |
| Artificial operation group | 6.12±0.95** | 49.74±8.64** |
| Model set | 12.40±3.18△△ | 102.76±11.85△△ |
| Positive control group | 10.58±2.38△△ | 94.10±25.85△△ |
| High dose group | 6.34±0.52** | 58.61±16.21** |
| Low dose group | 7.29±0.72** | 65.23±11.75** |
Note: comparison with blank group△P＜0.05，△△P is less than 0.01; comparison with model group*P＜0.05，**P＜0.01
Claims (10)
1. Application of Zhongwuning or pharmaceutically acceptable salts, esters or solvates thereof in preparing medicines or health products for preventing and/or treating renal failure, wherein the structural formula of the Zhongwuning is shown as follows.
2. The use of claim 1, wherein the renal failure is partial or complete loss of renal function resulting from the progression to a later stage of various primary or secondary renal diseases.
3. The use of claim 2, wherein the various primary or secondary renal inducing factors are drugs, diabetes, hypertension, gout, viruses, bacterial infections, or kidney transplants.
4. The use of claim 3, wherein the drug is gentamicin or adenine.
5. The use of any one of claims 1-4, wherein the renal failure is acute renal failure or chronic renal failure.
6. The use according to claim 1, wherein the medicament for preventing and/or treating renal failure is a preparation prepared from mexicanin or a pharmaceutically acceptable salt, ester or solvate thereof as an active ingredient, together with pharmaceutically common adjuvants or auxiliary ingredients.
7. The use of claim 6, wherein the pharmaceutically acceptable salt is an inorganic salt or an organic salt.
8. The use of claim 7, wherein the inorganic salt is a sulfate, nitrate, hydrochloride, hydrobromide, or phosphate salt.
9. The use of claim 7, wherein the organic salt is an acetate, propionate, maleate, oxalate, malate, glycolate, pyruvate, malonate, succinate, citrate, benzoate, fumarate, tartrate, cinnamate, mandelate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, or salicylate salt.
10. The use of claim 6, wherein the formulation is in the form of a liquid, solid or semi-solid formulation.
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| CN105486775A (en) * | 2016-01-08 | 2016-04-13 | 首都医科大学 | Method for detecting content of various components in pills for treating kidney-yang deficiency |
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| CN105486775A (en) * | 2016-01-08 | 2016-04-13 | 首都医科大学 | Method for detecting content of various components in pills for treating kidney-yang deficiency |
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