CN115518132A - Chinese medicinal compound composition for preventing and treating hyperuricemia - Google Patents
Chinese medicinal compound composition for preventing and treating hyperuricemia Download PDFInfo
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- CN115518132A CN115518132A CN202211306001.XA CN202211306001A CN115518132A CN 115518132 A CN115518132 A CN 115518132A CN 202211306001 A CN202211306001 A CN 202211306001A CN 115518132 A CN115518132 A CN 115518132A
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- 229960004555 rutoside Drugs 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- GSZUGBAEBARHAW-UHFFFAOYSA-N sophoraflavone B Natural products OC1C(O)C(O)C(CO)OC1OC1=CC=C(C=2OC3=CC(O)=CC=C3C(=O)C=2)C=C1 GSZUGBAEBARHAW-UHFFFAOYSA-N 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 239000012192 staining solution Substances 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 210000004926 tubular epithelial cell Anatomy 0.000 description 1
- 230000036269 ulceration Effects 0.000 description 1
- 230000002477 vacuolizing effect Effects 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- QFRYQWYZSQDFOS-UHFFFAOYSA-N verbascoside Natural products CC1OC(COC2C(O)C(COC3OC(C(O)C(O)C3O)C(=O)O)OC(Oc4cc(O)cc5OC(=CC(=O)c45)c6ccc(O)c(O)c6)C2O)C(O)C(O)C1O QFRYQWYZSQDFOS-UHFFFAOYSA-N 0.000 description 1
- 210000001835 viscera Anatomy 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
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Abstract
A traditional Chinese medicine compound composition for preventing and treating hyperuricemia comprises chicory root, poria cocos, dandelion, corn stigma, sophora flower and liquorice, wherein the chicory root comprises the following components in parts by weight: 3-6 parts; poria cocos: 1.5-3.5 parts; dandelion: 1.5-3.5 parts; corn silk: 2.5-4.5 parts; flos sophorae: 1.5-3.5 parts; and licorice root: 1 part. The composition provided by the invention, which is prepared from medicinal and edible medicinal materials serving as raw materials, can effectively prevent and treat hyperuricemia.
Description
Technical Field
The invention relates to a Chinese medicinal compound composition for preventing and treating hyperuricemia.
Background
For humans and other primates, uric acid is the end product of the metabolism of dietary and endogenous purines, and therefore uric acid levels are closely related to purine metabolism in the body. Excessive uric acid production in vivo is often caused by two reasons, (1) abnormal purine metabolism; (2) ingestion of high amounts of high purine food in vivo.
Approximately 10% of primary hyperuricemia is the result of increased uric acid production. In purine metabolism, various catalytic enzymes are involved in purine metabolic processes in the human body. The current research results show that the abnormal enzyme activity is the main cause of the increase of uric acid production, including the increase of Xanthine Oxidase (XOD) and phosphoribosyl pyrophosphate synthetase (PRS) activities, and the decrease of hypoxanthine-guanine phosphoribosyl transferase (HGPRT) and adenine phosphoribosyl transferase (APRT) activities, which all cause hyperuricemia and gout.
Research shows that hyperuricemia is also related to metabolic diseases, nephropathy, cardiovascular and cerebrovascular diseases, nervous and respiratory diseases, psoriasis and the like.
The traditional Chinese medicine compound preparation has unique advantages in the aspect of preventing and treating hyperuricemia, but the search for a more accurate and efficient traditional Chinese medicine formula is always the direction of efforts in the field.
Disclosure of Invention
The invention aims to provide a universal and efficient traditional Chinese medicine compound composition for preventing and treating hyperuricemia.
According to the first aspect of the invention, the invention provides a traditional Chinese medicine compound composition for preventing and treating hyperuricemia, which comprises chicory root, tuckahoe, dandelion, corn stigma, sophora flower and liquorice, wherein the chicory root comprises the following components in parts by weight: 3-6 parts; tuckahoe, poria cocos: 1.5-3.5 parts; dandelion: 1.5-3.5 parts; corn silk: 2.5-4.5 parts; and (3) flos sophorae: 1.5-3.5 parts; and licorice root: 1 part.
The compound effect of the invention is as follows: clearing away heat and toxic material, inducing diuresis to remove turbid pathogen, inducing diuresis to alleviate edema, cooling blood and alleviating pain. The solution is as follows:
chicory root (monarch) has the effects of clearing away heat and toxic materials, inducing diuresis and relieving swelling; poria cocos (minister) strengthens the spleen and excretes dampness, induces diuresis and reduces edema; the dandelion (assistant) has the functions of clearing away heat and toxic materials, promoting diuresis and reducing edema; corn stigma (assisted) induces diuresis to alleviate edema, induces diuresis to excrete turbid; flos Sophorae Immaturus (flos Sophorae Immaturus) has effects of clearing liver-fire, cooling blood; licorice root, radix Glycyrrhizae is used to clear away heat and toxic materials, relieve spasm and pain, and harmonize the effects of the other drugs in the recipe.
The main pathogenesis of gout is stagnation of damp turbidity and blood stasis, and the damp turbidity is not affected by the exterior but produced in the interior. Patients mostly feel the phlegm-dampness of the food with abundant physique, and have good drinking and eating, which results in dysfunction of viscera and no right to ascend the clear and descend the turbid, because phlegm-dampness stagnation is obstructed in blood vessels, difficult to purge and transform, combined with blood to become turbid blood stasis, which is retained in channels and collaterals, and then, bone and joint swelling and pain, nodular malformation and even ulceration occur. The main treatment principle of the invention is to purge and resolve turbidity and stasis: since gout occurs as turbid blood, by using the treatment of discharging turbid blood stasis, turbid blood can be gradually discharged and transformed, and blood uric acid is reduced, so that the functions of separating clear and bleeding turbid are recovered and the health is recovered.
The modern pharmacological research and analysis of the compound recipe of the invention are as follows:
heat-clearing herbs: herba Cichorii contains acteoside, and has effects of promoting uric acid excretion, and increasing excretion of uric acid in intestinal tract; the dandelion, the aqueous extract of which has protective effect on kidney damage caused by persistent hyperuricemia; flos Sophorae Immaturus, its flavone extract such as rutin, quercetin, kaempferol and sophoricidin A, etc., has good therapeutic effect on hyperuricemia.
Diuresis-inducing herbs: poria has effects of promoting urination, relieving pain, and reducing uric acid synthesis; the flavone extract of the corn stigma has the following functions: the signal channel is regulated and controlled by inhibiting the expression of inflammatory factors such as interleukin and the like, so that edema and inflammatory cell infiltration are relieved, and inflammatory symptoms caused by gouty arthritis are relieved.
Deficiency tonifying medicine: licorice root, its flavonoid compounds such as liquiritigenin, can inhibit AQP4/NF-kB signal transduction pathway and NLRP3 inflammatory body activation of HUA rat, so as to reduce and improve kidney inflammation.
The traditional Chinese medicine compound composition disclosed by the invention is proved to be capable of effectively preventing and treating hyperuricemia. In addition, the composition provided by the invention is prepared from medicinal and edible medicinal materials serving as raw materials, so that the composition is particularly suitable for production and sale as functional food.
The invention also provides a preparation for preventing and treating hyperuricemia, which comprises an aqueous extract of the composition. The preparation of the invention can be in any suitable form, such as oral liquid or capsule, and the recommended daily dose for an adult (in 60 kg) corresponds to the following composition: 10g of chicory root, 5g of tuckahoe, 10g of dandelion, 10g of corn stigma, 10g of sophora flower and 3g of liquorice.
Description of the drawings:
FIG. 1 shows the results of blood uric acid level measurements under different treatments of a first pharmacodynamic experiment;
FIG. 2 shows the results of urea nitrogen determination for different treatments of the first pharmacodynamic experiment;
FIG. 3 shows the measurement of the serum creatinine content for the first pharmacodynamic experiment with different treatments;
FIG. 4 shows the measurement of xanthine oxidase content in different treatments of the first pharmacodynamic experiment;
FIG. 5 shows graphs of HE section damage scores for rat liver under different treatments for the first pharmacodynamic experiment;
figure 6 shows graphs showing the damage scores of HE sections from rat kidney under different treatments for the first pharmacodynamic experiment;
FIG. 7 shows the results of blood uric acid level determination under different treatments for a second pharmacodynamic experiment;
FIG. 8 shows the results of the urea nitrogen determination for different treatments of the second pharmacodynamic experiment;
FIG. 9 shows the measurement of serum creatinine levels for a second pharmacodynamic experiment with different treatments;
FIG. 10 shows a graph of lesion scores of rat liver sections at different treatments of a second pharmacodynamic experiment;
FIG. 11 shows graphs of HE slice injury scores of rat kidneys at different treatments for a second pharmacodynamic experiment;
FIG. 12 shows the results of blood uric acid assay with different treatments for the third pharmacodynamic experiment;
FIG. 13 shows the results of the measurement of urea nitrogen content for different treatments of the third pharmacodynamic experiment;
FIG. 14 shows the measurement of creatinine blood content for the third pharmacodynamic experiment;
figure 15 shows graphs of HE sections from rat kidneys and their damage scores for different treatments of the third pharmacodynamic experiment;
FIG. 16 shows the results of blood uric acid level measurements under different treatments of prophylactic administration regimes;
FIG. 17 shows the results of urea nitrogen determination for different treatments of the prophylactic dosing regime;
FIG. 18 shows the results of the determination of the serum creatinine content for different treatments of the prophylactic dosing regimen; and
figure 19 shows graphs of rat kidney HE sections and their injury scores for different treatments with prophylactic dosing regimes.
In the above figures: p < 0.05 compared to blank; * P < 0.01; * P < 0.001; * P < 0.0001 (same # compared to model group)
Detailed Description
The present invention is further described below in conjunction with specific experimental examples and figures, it being understood by those skilled in the art that these examples and figures are only for the purpose of better understanding of the present invention and are not intended to be limiting in any way.
Laboratory apparatus
HWS26 type electric heating thermostat water bath (shanghai henkou instruments ltd);
model AL204 electronic analytical balance (mettler-toledo instruments (shanghai) ltd);
GZX-GF101-3-BS type electric heating constant temperature air blast drying oven (Shanghai leap-in medical appliances Co., ltd.);
MPR-414F-PC type medicine refrigerator freezer storage box (Panasonic);
multiskan MK3 microplate reader (Thermo Scientific);
AU480 type fully automatic biochemical analyzer (beckmann coulter ltd., usa);
an Epoch vortex mixer (BioTek);
RE-3000 type rotary evaporator (Shanghai Yanrong Biochemical apparatus factory);
model DZF-6020 vacuum drying oven (Shanghai sperm macro laboratory Equipment Co., ltd.);
KH-500DE model numerical control ultrasonic cleaner (Kunshan Seama ultrasonic Instrument Co., ltd.);
a cooling water circulation device model CA-1116A (shanghai elan instruments ltd);
SHB-B95A TYPE MULTIPURPOSE VACUUM PUMP WITH CIRCULATION WATER (Zhengzhou great wall CERTH. CORPORATION CO., LTD.)
Experimental Material
A molding agent: acetyl butanol hydrochloride (Hangzhou folk pharmaceutical Co., ltd., lot number: T21C068, T21D 024); potassium Oxonate (Shanghai Maxin Biochemical technologies, inc., batch Nos. C12677304, C12677411); yeast extract (Shanghai Maxin Biochemical technology, inc., batch No. C12434523); adenine (Shanghai Maxin Biochemical technologies, inc., lot: C12642922); sodium carboxymethylcellulose (Shanghai Michelin Biochemical technology, inc., batch No. C12286568).
Chinese herbal pieces: purchased from beijing herbal medicine group ltd, GMP license BJ20190426, production license: and 3, beijing 20150136. Purchasing according to the formula requirement.
Positive drugs: (1) benzbromarone tablets, hemman pharmaceutical factory, germany, lot number: 1914725; (2) Allopurinol tablets, shanghai xin yi wangxiang pharmaceutical industry gmbh, lot number 07130806.
Kit and reagent: a urea nitrogen determination kit (Zhongsheng Bei Zhi Biotechnology GmbH, batch number: 100020070); uric acid and blood creatinine determination kits (Nanjing institute of bioengineering, lot Nos. 20200911, 20220111: 20201106, 20220111; absolute ethanol (beijing chemical plant, lot number 201909412); 10% neutral formalin solution (beijing solibao science and technology ltd, 20210817); physiological saline (Shandong Hualu pharmaceutical Co., ltd., batch No. H19010913); xylene (Beijing chemical plant, lot number: 20190113); neutral gums (Shanghai Instrument plant, lot number: 201901208); hematoxylin stain (Kyoto Biotechnology, inc., lot number 718072); eosin staining solution (Zhuhai Becable Biotech Co., ltd., lot No. 718091); ethambutol hydrochloride tablets (Hangzhou folk medicine Co., ltd., batch No. T21C068, T21D 024); potassium Oxonate (Shanghai Maxin Biochemical technologies, inc., batch No. C12677304); yeast extract (Shanghai Michelin Biochemical technology Co., ltd., batch No. C12434523); adenine (Shanghai Michelin Biochemical technology Ltd., lot: C12642922); sodium carboxymethylcellulose (Shanghai Michelin Biochemical technology Ltd., batch No. C12286568).
Laboratory animal
SPF SD male rat with body mass of 180-220 g, purchased from Beijing Wittingle laboratory animal technology Limited company, license number: SCXK (Jing) 2017-0020. The research is approved by the ethical committee of the experimental animal center of the medicinal plant institute of Beijing cooperative and medical college, and the experimental ethical examination number is as follows: SLXD-20210826005. The animal houses are raised in the institute of medicinal plants of Beijing cooperative medical college, and can drink and eat water freely every day.
TABLE 1 Experimental formulation design and drug composition optimization iterative Process Table
Hyperuricemia pathogenic model modeling method
Preparing a molding agent dissolving solution: 0.5% CMC-Na configuration: 5g of CMC-Na powder is weighed, dissolved in 1000mL of distilled water and mixed evenly to prepare a transparent solution, and the solution is stored at 4 ℃. Before use, the stomach is irrigated after the temperature is increased to 30-35 ℃ by warm water bath.
Preparing a model I molding agent: preparing an oteracil potassium normal saline intraperitoneal injection solution: 3g of Potassium Oxonate crystals were dissolved in 100ml of physiological saline solution. Preparing a yeast extract solution (1 g/100 g): weighing 100g of yeast extract, dissolving in 100mL of 0.5% of CMC-Na, preparing homogenate by a high-speed homogenizer, storing at 4 ℃, and performing intragastric lavage after the temperature is increased to 30-35 ℃ by warm water bath before use. Preparing an adenine solution: 6.7g adenine was weighed and dissolved in 100ml 5% CMC-Na, homogenized in a high speed homogenizer, stored at 4 ℃ and perfused into the stomach after being heated to 30-35 ℃ in warm water bath before use.
Preparing a model II molding agent: preparing oteracil potassium + ethambutol intragastric solution: 5g of Potassium Oxonate and 1.67g of ethambutol are weighed and dissolved in 0.5 percent of CMC-Na solution to prepare 100mL of potassium Oxonate solution, homogenate is prepared by a high-speed homogenizer and stored at 4 ℃. Before use, the stomach is irrigated after the temperature is increased to 30-35 ℃ by warm water bath.
Preparing a model III molding agent: preparing a yeast extract, adenine and oteracil potassium intragastric solution: 66.7g of yeast extract, 0.667g of adenine powder and 2g of Potassium Oxonate powder were dissolved in 100ml of 0.5% CMC-Na, and a homogenate was prepared by a high speed homogenizer and stored at 4 ℃. Before use, the stomach is irrigated after the temperature is increased to 30-35 ℃ by warm water bath.
The animal molding method comprises the following steps: after the animals are adaptively raised for 7 days, the modeling agent is continuously administered for 14 days under the aseptic principle, and the specific operation is as follows:
model I group: intragastric gavage 3ml of yeast extract 0.5% CMC-Na solution in the morning, intragastric gavage 3ml of adenine 0.5% CMC-Na solution 2h later, and intraperitoneal injection of 2ml of oteracil potassium physiological saline solution on days 1,3,7, 11, 14.
Model II, gavage 1 time every day 3ml potassium oxonate + ethambutol 0.5% CMC-Na mixed solution.
Model group III, intragastric administration 1 time per day in the morning of 3ml mix of Potassium Oxonate + adenine + Yeast extract 0.5% CMC-Na solution.
Each group was fed with water for two weeks.
Preparation and experimental treatment method of traditional Chinese medicine to be tested
Decocting the Chinese medicinal decoction pieces: according to the experimental requirements, determining the experimental formula and purchasing the traditional Chinese medicine decoction pieces. The amount of the decoction pieces is calculated and weighed by adopting the formulas 2-1 and 2-2. Decocting with water (reflux extraction method) twice at a ratio of 1: 8 for 40min and 30min, filtering the decoctions with 8 layers of gauze, mixing the decoctions, rotary evaporating for concentration, and accurately measuring volume T of the concentrated solution Shrinking device (requirement: T) Shrinking device V is less than or equal to V multiplied by N multiplied by X, see formula 2-4).
Preparing traditional Chinese medicine test liquid: calculating by adopting formulas 2-3 and 2-4, and mixing the decoction (T) Shrinking device ) Adding distilled water to a constant volume to prepare total medicinal liquid (T) for animal administration, wherein the concentration of the medicinal liquid is (C/V) calculated according to the amount of the decoction pieces. Sealing and storing in refrigerator at 4 deg.C for use, and sucking to administer medicine according to daily requirement (V) of each animal during experimental treatment.
A = CxNxX formula 2-2
V =15 XM formula 2-3
T = V × N × X formula 2-4
Formula 2-1: c is the total amount (g) of the Chinese medicinal decoction pieces required to be fed to the rat every day; r is the total amount (g) of the decoction pieces of the human beings per day in the formula; 60 is the average human body weight (Kg); m is rat body weight (Kg); 7 is a parameter, and the dosage of the rat per unit weight is 7 times of the dosage of the human.
Formula 2-2: a is the total amount of decoction pieces required by N rats in a certain treatment group in a certain planned time period of X days (7 days). In order to prevent operation loss, the daily dosage (5C) of 5 rats needs to be increased, and the total weight of the actual decoction pieces is A +5C.
The weight of the rat is 200g on average, 3mL of the gavage liquid is used for gavage every day, 3mL of the gavage liquid is used for each rat every day, and the amount of the traditional Chinese medicine decoction pieces to be extracted is calculated according to a formula 2-1. The results of calculating the crude drug amount required by each formula in 3 drug effect experiments in this study are shown in table 2.
Table 2 Chinese medicine formula 3 times medicinal effect experiment rat daily administration decoction piece amount
Positive drug test drug preparation and experimental treatment method
Two positive drugs are selected for experiments, and the specific preparation and experimental treatment methods are as follows.
Benzbromarone tablets: dissolving in distilled water by ultrasonic wave, converting into rat dosage according to the instruction dosage, intragastrically administering, and storing at 4 deg.C.
Allopurinol tablets: dissolving in distilled water by ultrasonic wave, converting into rat dosage according to the instruction dosage, intragastrically administering, and storing at 4 deg.C.
Collection of Experimental samples
The collection of experimental samples is divided into two main categories, one being blood samples and the other being liver and kidney tissue samples.
(1) Collecting a serum sample: collecting blood from orbit at a specified time point with blood collection amount of 0.5mL, standing at 4 deg.C for 30min, and collecting blood at 3500 rpm/min -1 Centrifuging for 15min, collecting serum, and storing in refrigerator at-80 deg.C.
(2) Collecting organ tissues: taking materials at the end of an experiment, anesthetizing with 7% chloral hydrate, dissecting the experimental animal, quickly picking the liver and the kidney of the experimental animal, rinsing in precooled normal saline for a plurality of times, then sucking the normal saline on the surface of an organ by using filter paper, and weighing; then, the organ is fixed for one day by using 10% neutral formalin solution, and then the sample is sent out to a company with related qualification to be made into an HE staining section.
Detection index and measurement method
(1) Serum sample determination: serum was tested for blood uric acid (SUA), blood creatinine (Cre), urea nitrogen (BUN) and Xanthine Oxidase (XOD). The determination method adopts a kit, and content detection is carried out on a microplate reader according to the kit instructions.
(2) Preparing and observing liver and kidney tissue HE slices: the preparation of the HE section of the liver and kidney tissues is detailed in 1.3.3.5 (preparation of the HE stained section of the liver and kidney). And entrusts Beijing Xinnuojia scientific and technological development company Limited to detect. Evaluation rule of damage degree of HE section of kidney tissue: (1) vacuolation of renal tubular epithelial cells; (2) renal tubular atrophy, dilation; (3) tubular protein casts, cell casts within the kidney tubules; (4) intratubular crystalline deposition; (5) interstitial inflammatory cell infiltration (lymphocyte infiltration, macrophage accumulation, foreign body granuloma reaction, etc.); (6) renal interstitial fibrosis. The scoring criteria were: no obvious pathological changes, score 0; the lesion range is not more than 1/4, and 1 point is marked; the range of pathological changes is 1/4 to 1/2, and 2 points are marked; the range of pathological changes is 1/2 to 3/4, and 3 points are marked; the lesion size exceeded 3/4, and was scored 4.
Efficacy analysis of primary selection formula for treating hyperuricemia (first efficacy experiment)
The experimental set-up was divided into 5 treatment groups, respectively: blank group, model II group, and 3 formula groups (formula group code numbers are AC1, AC2, and AC3 respectively), and the formula and dosage are described above. The experimental groups and dosing regimen are shown in table 3 below. The experiment period is 28 days, blood samples are collected for 12 times, and liver and kidney tissue detection samples are collected after the experiment is finished.
Table 3: preliminary matching efficacy evaluation experiment grouping and administration treatment scheme
Effect of different formulations on the blood Uric Acid (UA) content
The results of blood Uric Acid (UA) determination by sampling at each time node of model 4-28 days are shown in figure 1, the blood uric acid content difference between the model and the blank group is obvious, the blood uric acid content difference between the model and the model group is extremely obvious on the AC2 and AC3 days 6-22, and some measuring points are reduced to the level of the blank group, which shows that the two formulas have good regulation and reduction effects on the blood uric acid content of rats. AC1 exhibited an earlier uric acid lowering effect than AC2 and AC3, a stronger effect during the administration of the molding agent, and a significantly reduced effect after the cessation of the administration of the molding agent (day 15), always with a significant difference from the blank content, at the same level as the model by day 22. And the uric acid reducing effects of the AC2 and the AC3 are stable and remarkable, and have no difference from the blank group after the 18 th day.
Effect of different formulations on Urea Nitrogen (BUN) content
Figure 2 shows that the effect of molding on urea nitrogen content appeared later, with the model making a clear difference from the blank only on day 11 of molding and from the model group only on days AC2 and AC3 15. The 3 formulas have a certain effect of regulating and reducing the nitrogen content of urea, and the best AC2 and the worst AC1 are comprehensively analyzed from the aspects of action strength, duration, stability and the like.
Effect of different formulations on serum Creatinine (Cre) content
The influence trend of the experimental treatment on the blood creatinine content is basically the same as that of urea nitrogen, and the differences between the model group and the blank group and between the 3 formula groups and the model group are only obviously appeared after the detection of 14 days after the model is made. And the effect was slightly different between the 3 formula groups, the content could be reduced to the empty level at some of the measurement nodes, but no significant difference was made between the 3, as shown in fig. 3.
Effect of different formulations on Xanthine Oxidase (XOD) content
FIG. 4 shows that the xanthine oxidase content in rats is somewhat unstable, and the model group and the blank group have different degrees only at days 11-20, and only 2 contents of 3 formulas and model groups are obviously reduced in 12 detection points. Since the important index of particular interest in this study is the serum uric acid index, which is unstable in the xanthine oxidase index according to a large number of research results, the xanthine oxidase index is not detected in later experiments.
Analysis of liver and kidney injury degree by modeling
As can be seen from fig. 5 and 6, the modeling has certain damage effect on the liver and the kidney, and 3 formulas have certain protection effect on the liver and kidney tissues. In comparison, the liver is slightly damaged, the liver is only slightly affected by the modeling, and the damage effect on the kidney is extremely remarkable. The 3 formulations had slightly different damage-reducing effects on the kidney, with AC1 and AC2 being significantly stronger and AC3 being relatively weaker.
In comparison, the liver is slightly damaged, the liver is only slightly affected by the modeling, and the damage effect on the kidney is extremely remarkable. The 3 formulations had slightly different damage-reducing effects on the kidney, with AC1 and AC2 being significantly stronger and AC3 being relatively weaker.
The experimental results of the initially selected formula show that 3 Chinese medicinal formula test objects can reduce the content of uric acid, urea nitrogen and serum creatinine in blood to different degrees and can reduce the damage of the uric acid in the blood to the kidney, wherein the AC2 has the best effect, the AC3 is used, the two formulas are improved in the later stage to further verify the efficacy, and the AC1 gives up continuous research. In addition, the detection result shows that the content of xanthine oxidase is unstable, and the molding can cause the increase of xanthine oxidase to a certain extent, but the xanthine oxidase is not enough to be used for evaluating the efficacy of the traditional Chinese medicine compound. Therefore, the blood uric acid content, the urea nitrogen content, the blood creatinine content and the damage degree of the kidney HE slice are used as detection indexes for comprehensively evaluating the prevention and treatment of hyperuricemia by the traditional Chinese medicine compound.
Second, the analysis of the therapeutic effect of hyperuricemia (second pharmacodynamic experiment)
Referring to the efficacy experiment analysis result of the initially selected formula, the efficacy of AC1 is relatively poor, the experiment is abandoned and continued, and AC2 and AC3 are continued to be improved; according to the demonstration of earlier clinical experience, the medicine flavor and compatibility of a newly designed formula of a project are improved, 6 formulas are newly designed, the improved formulas of AC2 and AC3 are added, 8 improved formulas are determined in a second batch of efficacy experiments for efficacy experiments, the composition and the code number of each formula are detailed in table 1, and the code numbers are respectively: BC2, BC3, BC4, BC5, BC6, BC7, BC8, BC9. According to the analysis of the previous experiment, benzbromarone is selected as a positive drug, and the preparation method and the administration dosage of the tested drug are the same as those of the previous experiment.
Animal modeling and grouping administration
Modeling by adopting a model II method, and setting a blank group, a model II group, a positive medicine group and 8 traditional Chinese medicine formula groups in total to 11 treatment groups. After adaptive feeding, the medicine is administrated in groups, and the grouping and experimental treatment are shown in table 4.
Table 4 experimental grouping and dosing treatment protocol
Efficacy analysis for regulating blood Uric Acid (UA) content by improved formula
Fig. 7 shows that at 5 sampling time points, the blood uric acid content of the model group and that of the blank group are obviously different, which shows that the model is successfully made and can be used for evaluating the efficacy of the formula. The 8 formulas showed a certain blood uric acid lowering effect to different degrees overall. Comprehensive analysis shows that BC7 and BC9 are poor in performance, BC2 and BC3 are best in performance, and then BC4, BC5 and BC8 are adopted, and blood uric acid is reduced to a blank level at 4 time points in 14-21 days; the positive drug (benzbromarone) also showed efficacy in reducing blood uric acid, but its efficacy in reducing uric acid after stopping molding was not as good as BC2 and BC 3.
Effect of improved formula on reducing urea nitrogen (BUN) content
The urea nitrogen content detection result is shown in fig. 8, the urea nitrogen content is obviously increased by the model group, and each traditional Chinese medicine formula group has the function of reducing the urea nitrogen content to different degrees, but in comparison, the BC7 group and the BC9 group are still at the same level with the model group at part of time points, other formulas are obviously reduced compared with the model group at most of time points, and the respective reduction degrees are different due to different time nodes. The curative effect of the positive drug benzbromarone is not obviously different from most traditional Chinese medicine formulas on the whole, and the content of some traditional Chinese medicine formulas is better than that of benzbromarone at different measuring points.
Effect of improved formula on reducing serum creatinine (Cre) content
The measurement results of the treatment groups on the content of the serum creatinine are shown in fig. 9, and the results show that the content of the model group is slightly increased at each time point, but no significant difference is generated compared with the blank group; compared with the model group, each traditional Chinese medicine formula group does not show obvious down-regulation effect, the content of some formulas is obviously reduced only in the detection of 14 th, 16 th and 18 th days, and the model group and the blank group have no difference in the detection of 21 st day, but all the formulas are greatly reduced compared with the model group and the blank group. The detection result of the positive medicine group is basically the same as the formula. From the results of multiple experiments of the project, the results of the experiments are somewhat abnormal, the reasons for the abnormal results need to be researched, and the abnormal results are not suitable to be used as the basis for evaluating the efficacy of the formula.
Improved formula for relieving liver and kidney injury (HE slice)
The analysis results of the treatment of each group on HE sections of the liver and the kidney are shown in FIGS. 10-11, and the analysis results on liver injury show that modeling has certain influence on liver tissues; each traditional Chinese medicine formula group has the function of reducing liver injury, the effect is better than that of a positive medicine, and the obvious difference degree is not achieved through statistical analysis compared with the positive medicine group. The analysis result of the kidney injury shows that each traditional Chinese medicine formula shows extremely obvious reduction effect and embodies the protection effect on the kidney; compared with the positive medicines, the reduction effect of BC9 is only weak, the rest 7 traditional Chinese medicine formula groups are at the same level with the positive medicines, but the positive medicines and all the traditional Chinese medicine formula groups do not reach the blank level in the research time.
By combining the analysis, the improved 8 formulas have certain treatment efficacy on hyperuricemia, can obviously reduce the content of the blood uric acid, and can obviously reduce the damage to the kidney tissues and functions caused by the hyperuricemia. Overall analysis shows that the BC9 has lower efficacies in all aspects, the BC2, BC3, BC4, BC5 and BC8 are relatively better, the blood uric acid content of the BC2 and BC3 formula at a plurality of detection time points is reduced to a blank level, and the curative effect is better than that of the positive drug benzbromarone. In order to select the optimal curative effect formula, the BC2, BC4, BC5 and BC8 traditional Chinese medicine formulas are selected, optimized, subjected to pharmacodynamic experiments, and further evaluated and verified.
Third, efficacy verification analysis (third efficacy experiment) for preventing and treating hyperuricemia by optimizing formula
According to the pharmacodynamic experiment result of the improved formula and project requirements, BC6, BC7 and BC9 with poor efficacy are eliminated, and the experiment of BC3 is stopped. Finally, efficacy verification research is carried out on 4 formulas, the codes of the formulas are ZC2, ZC4, ZC5 and ZC8, and detailed adjustment processes and formulas are shown in a table 1; the positive medicine is benzbromarone; the preparation method and the administration dose of the tested medicine are the same as the above.
Grouping and grouping administration scheme for experimental animals
The experiment designs two modes of treatment administration and prevention administration, and the experimental period is 28 days. The treatment administration mode is as follows: giving the modeling agent and the tested medicine at the same time in 7-21 days, and only giving the tested medicine in 22-28 days; the preventive administration mode is as follows: the test drug is given for 1-6 days, the modeling agent and the test drug are given for 7-21 days, and the modeling agent is not given any more but the test drug is continuously given for 22-28 days. The experiment is provided with a blank group and a positive drug group, and a model group and ZC2, ZC4, ZC5 and ZC8 formula groups are respectively arranged in a treatment group and a prevention group, and the total number of the treatment groups is 12. The model group adopts a model II molding method. The rats to be tested were fed adaptively and then administered randomly in groups, and the groups and experimental treatments are shown in Table 5.
Table 5 experimental grouping and dosing treatment protocol
The experimental design cycle is 21 days, and animals are grouped after being fed adaptively, and are divided into a model group, a positive medicine group and a treatment group. The model group is administered with the modeling agent on days 1-14, the formulation group and the positive drug group are administered with the formulation extract or the positive drug while the modeling agent is administered on days 1-14, and the formulation is stopped on days 15-21, but the formulation extract or the positive drug is continuously administered. The sampling time points are: dynamic blood sampling tests were started on days 7, 14, 17, and 21 of the model making, and kidney samples were collected on day 21 to make HE sections.
Efficacy analysis for reducing blood Uric Acid (UA) content by optimizing formula of treatment administration mode
The results of measuring the blood uric acid content by 4 dynamic blood-taking of rats in each experimental treatment group are shown in fig. 12. It can be seen from this that: (1) compared with the blank group, the UA level of the model group is obviously higher than that of other groups (P is less than 0.01) in 7-21 days, which indicates that the molding is successful; experimental observation shows that on the 7 th day of experimental treatment, the blood uric acid value of the model rat is obviously higher than that of the blank group, reaches the highest value on the 14 th day and is improved by 64.50 percent compared with that of the blank group. After stopping the administration of the molding agent on day 14, the blood uric acid level of the rat slowly declined, but there was still a significant difference (15.24% higher) between day 21 and the blank group; (2) compared with the model group, each optimized formula group can obviously reduce the blood uric acid level of rats (P is less than 0.01) according to the results of continuous 4-time sampling measurement, the phase difference reaches the maximum value on the 14 th day, and the formulas ZC2, ZC4, ZC5 and ZC8 are respectively reduced by 32.37 percent, 27.85 percent, 31.78 percent and 26.19 percent compared with the model group; (3) compared with the blank group, the blood uric acid content of rats fed with the formulation extract can be restored to the level of the blank group by taking samples for detection on 7 th and 14 th days, the blood uric acid content of the formulations such as ZC2 and the like is consistent with the level of the control group, and the blood uric acid content of each optimized formulation group is restored to the control level after the administration of the formulation is stopped (on 17 th and 21 th days). (4) Compared with the positive medicine group, the optimized formula groups have basically the same function of controlling the blood uric acid of rats as the positive medicine, the test result of the ZC2 formula at some points shows that the efficacy of the ZC2 formula is better than that of the positive medicine, if the blood uric acid of the positive medicine group is tested at the 7 th day, the blood uric acid of the positive medicine group is obviously higher than that of the blank group, and the ZC2 formula group and the blank group are at the same level. By combining the analysis, several formulas optimized by two experiments have good effects on treating hyperuricemia, can remarkably control the hyperuricemia symptoms of rats induced by the modeling agent, and the regulation and control capabilities of the optimized formulas are ordered as follows: ZC2> positive drug > ZC5> ZC4= ZC8.
Efficacy analysis of optimized formulation for reducing urea nitrogen (BUN) content in therapeutic dosing regimen
Experimental treatment groups of rats were bled 4 times dynamically to determine the urea nitrogen (BUN) content as shown in fig. 13. It can be seen from this that:
(1) compared with the blank group, the urea nitrogen level of the model group is obviously increased (P is less than 0.01) in 7-17 days, which indicates that the model is successfully molded, the urea nitrogen value of the rat is obviously higher than that of the blank group in 7 days of molding treatment, the urea nitrogen value reaches the highest value in 14 days, and is increased by 58.36 percent compared with the blank group. The urea nitrogen levels of rats declined after the cessation of the model-making agent on day 14, with no significant difference between day 21 and the blank group;
(2) compared with the model group, each optimized formula group can obviously reduce the urea nitrogen level of rats (P is less than 0.01) by continuously sampling and determining for 4 times, and the maximum value is 14 days. The formulation of ZC2, ZC4, ZC5 and ZC8 is still reduced by 37.69%, 41.47%, 37.52% and 37.69% compared with the model group on the day of stopping the feeding of the molding agent for 3 days, namely on the day of 17;
(3) compared with the blank group, the urea nitrogen content of the rats which take the formula extract simultaneously with the molding agent can be restored to the level of the blank group; (4) compared with the positive medicine group, the optimized formula groups have basically the same function of controlling the urea nitrogen of the rats as the positive medicine. In 4 formulas, ZC2 and ZC4 have the strongest effect of reducing urea nitrogen, the urea nitrogen content is at the same level as blank on days 7, 14 and 17, and the level is obviously lower than that of the blank and the model on day 21.
Efficacy analysis for reducing serum creatinine (Cre) content by optimized formula of treatment administration mode
The results of the measurement of creatinine content in blood samples taken 4 times dynamically for each treatment of the experiment are shown in FIG. 14. It can be seen from this that:
(1) compared with the blank group, the blood creatinine level of the model group is obviously increased (P is less than 0.01) in 7-17 days, which indicates that the model building is successful. On the 7 th day of experimental treatment, the blood creatinine value of the model-making rat is obviously higher than that of the blank group, the value reaches the highest on the 14 th day and is increased by 29.92 percent compared with that of the blank group, the blood creatinine content is in a descending trend after the model-making agent is stopped on the 14 th day, the higher level can be maintained on the third day after the model-making agent is stopped, and the level of the blank group is recovered on the 21 st day.
(2) Each optimized formulation group was significantly reduced in rat serum creatinine levels (P < 0.01) by 4 consecutive samplings compared to the model group, and on the third day (day 17 from the start of the experiment) when the administration of the molding agent was stopped and the test drug was administered, formulation ZC2, ZC4, ZC5 and ZC8 were reduced by 15.74%, 12.94%, 13.35% and 12.87%, respectively, compared to the model group.
(3) Compared with the blank group, the blood creatinine content of the rats which take the formula extract simultaneously with the modeling agent can be restored to the level of the blank group, and the blood creatinine content and the blank of all the formulas have no obvious difference on the 17 th day of experimental treatment.
(4) Compared with the positive medicine group, each optimized formula group has basically the same function of controlling rat serum creatinine and the positive medicine, the overall analysis shows that the action of ZC2 is slightly stronger than that of the positive medicine, and the action of ZC5 and ZC8 takes effect slightly later than that of the positive medicine, ZC2 and ZC4, but the sustained time is longer.
Optimized formulation for therapeutic dosing regimen renal injury mitigation (HE slice) efficacy analysis
At the end of the experiment (day 21), the results of the rat kidney HE slice assay are shown in FIG. 15. From the slicing and quantitative analysis results, it can be seen that:
(1) compared with the blank group, the model group has obvious kidney injury, the injury is mainly in renal tubules, severe renal tubular dilatation is generated, the renal tubules have large-area tubular shapes, the renal tubules are large in size, the epithelium is thinned, the cavity area is increased by multiple times, and inflammatory cell infiltration and renal tissue fibrosis symptoms exist around the renal tubules.
(2) Compared with the model group, each optimized formula group obviously improves the kidney injury, and is specifically characterized in that only a small amount of inflammatory cell infiltration and renal tubule type are visible in a section, and the formulas ZC2, ZC4, ZC5 and ZC8 are respectively reduced by 33.93%, 32.14%, 35.71% and 25.00% compared with the model group.
(3) Compared with the positive medicine group, each optimized formula group is basically the same as the positive medicine group in terms of the protective effect of kidney injury caused by the modeling agent, the damage degree of hyperuricemia to the kidney is obviously reduced, but each group does not recover to the blank group level, and relatively speaking, the protective effect of the ZC8 formula is weakest.
Analysis of prevention effect of optimized formula on hyperuricemia
The experiment of the round designs two ways of treatment administration and prevention administration at the same time, and the difference is that the prevention group continuously injects the gastric lavage formulation test object for the first 6 days before the model forming agent is administered, and the administration at other times, the model forming agent and the sampling time are completely the same. The results of the experiment were analyzed as follows.
Analysis of blood uric acid content reduction by optimized formula of preventive administration mode
The results of the measurement of blood uric acid content based on 4 dynamic blood draws are shown in FIG. 16, from which it can be seen that: (1) compared with the blank group, the UA content of the model group is obviously increased (P is less than 0.01) in 7-21 days after the model is made, the blood uric acid value of the rat in 7 days is obviously higher than that of the blank group, the maximum value is reached in 14 days, and the UA content is increased by 45.33 percent compared with that of the blank group. The blood uric acid level of the rats tended to decrease after the cessation of the administration of the modeling agent on day 14, and there was still a significant difference between day 21 and the blank group; (2) compared with the model group, the measurement values of the optimized formula groups after 4 times of continuous sampling are obviously reduced (P is less than 0.01), and on the 17 th day, the formulas ZC2, ZC4, ZC5 and ZC8 are respectively reduced by 24.58%, 15.40%, 19.09% and 13.77% compared with the model group; (3) compared with the blank group, the blood uric acid content of the rats taking the formula extract together with the modeling agent can be restored to the level of the blank group, and the blood uric acid content of each formula group and the blank group are at the same level by sampling and detecting on the 7 th day, the 14 th day and the 17 th day. By combining the analysis, several formulas optimized by two experiments have good effects on preventing hyperuricemia, and the effects of the formulas are sequenced as follows: ZC2= ZC5> ZC4> ZC8.
Optimized formulation reduced urea nitrogen (BUN) content analysis for prophylactic dosing regimens
The results of measuring urea nitrogen content by 4 dynamic blood sampling in each experimental treatment group are shown in fig. 17, from which it can be seen that:
(1) compared with the blank group, the urea nitrogen level of the model group is obviously increased in 7-17 days (P is less than 0.01), which indicates that the model is successfully manufactured. On the 7 th day of experimental treatment, the urea nitrogen value of the model-making rats is obviously higher than that of the blank group, reaches the highest value on the 14 th day, is increased by 37.98 percent compared with the blank group, and recovers to the blank level on the 21 st day.
(2) Compared with the model group, the nitrogen level of urea measured by 4 times of continuous sampling of each formula group is significantly lower than that of the model group (P is less than 0.01), and the formulas ZC2, ZC4, ZC5 and ZC8 are respectively reduced by 22.96%, 16.19%, 19.20% and 13.53% compared with the model group on the 7 th day.
(3) The urea nitrogen content of each formula group can be restored to the blank level compared with the blank group.
Analysis of serum creatinine content reduction by optimized formula of preventive administration mode
The results of measuring the serum creatinine content by 4 dynamic blood sampling of rats treated in each experiment are shown in FIG. 18. The results show that: (1) compared with the blank group, the blood creatinine level of the model group is obviously increased (P is less than 0.01) in 7-17 days, the blood creatinine level is already obviously higher than that of the blank group on 7 days, the maximum value is reached on 14 days, the content begins to decrease after the feeding of the molding agent is stopped on 14 days, the difference is still obvious on 17 days, and the difference is not already obvious between the model group and the blank group on 21 days; (2) compared with a model group, each formula group can be obviously lower than the level of the model group (P is less than 0.01) after 3 times of continuous sampling and measurement, and the formulas ZC2, ZC4, ZC5 and ZC8 are respectively reduced by 16.38%, 9.85%, 9.91% and 12.07% compared with the model group on the 7 th day; (3) compared with the blank group, the blood creatinine content of rats which are simultaneously administered with the formulation extract by the formulation can be restored to the blank group level on the 21 st day except ZC 4.
Analysis of efficacy of optimized formula for preventing drug administration to reduce kidney injury
The kidney HE slices and their damage quantification index histograms of the experimental treatment groups are shown in fig. 19, from which it can be seen that: (1) the modeling can cause obvious kidney injury, the injury is mainly in renal tubules, severe renal tubular dilatation, large-area tubular renal tubules, large renal tubule size, thin epithelium, multiple-time increase of the area of a cavity, the cavity, inflammatory cell infiltration and renal tissue fibrosis around the renal tubules; (2) compared with a model group, each formula group has different degrees of improvement on kidney injury caused by the model-making agent, and is particularly characterized in that only a small amount of inflammatory cell infiltration and renal tubule tube types are visible in a section, and the injury degree can be reduced by 40-59% by other formulas except ZC8 from the quantitative statistical analysis result.
For 4 optimized formulations of ZC2, ZC4, ZC5 and ZC8, the following formulations are obtained through experiments with different administration modes:
(1) By adopting a treatment administration mode, the medicine has obvious treatment effect on the hyperuricemia caused by the model II, the treatment effect can reach an obvious degree on the 7 th day when the modeling agent and the formula medicine are taken simultaneously, and the blood uric acid content can be maintained at a blank level by most formulas. Compared with the positive drug of the bromobenzamanlone, the effect of each formula is at the same level. The formulas have good protection function on reducing kidney injury caused by the modeling agent, urea nitrogen and blood creatinine have two indexes, sampling is carried out 3 times in 7 th, 14 th and 17 th days, the content level of most formula groups is very different from that of a model group, and the difference from a blank group is not obvious, so that the damage degree of kidney tissues is reduced by nearly one time but does not reach the blank level. The comprehensive ranking of the efficacies of the formulas is as follows: ZC2> positive drug > ZC4= ZC5> ZC8.
(2) By adopting a prevention administration mode, the injection has obvious prevention and treatment effects on the hyperuricemia generated by the model II, and the content of the blood uric acid is remarkably reduced compared with that of a model group on the 7 th, 14 th, 17 th and 21 th days of the injection, so that the degree of no remarkable difference from that of a blank group is reached. Each formula group has a good protection function on kidney injury caused by the modeling agent, urea nitrogen and serum creatinine have two indexes, sampling is performed 3 times in 7 th, 14 th and 17 th days, the content of most of the formulas is obviously reduced compared with that of a model, and the content of the formulas such as ZC2 can be maintained at a blank level. Renal HE sections showed that prophylactic administration greatly reduced damage to renal tissue, but the extent of damage was significantly different from that of the blank.
(3) Through the experimental results of the prevention administration mode and the treatment administration mode, the two administration modes have different reduction action ranges on the contents of blood uric acid, urea nitrogen and blood creatinine and have different lightening action degrees on kidney injury, but the action onset time nodes are slightly different. The preventive administration has stronger effect in the early stage, and the treatment has higher effect in the later stage, which is probably the effect generated by the administration of the preventive group 6 days earlier. Therefore, the 4 formulations subjected to iterative optimization in the project have a certain preventive effect besides the obvious therapeutic effect. The optimized formulas have obvious effects of reducing the contents of blood uric acid, urea nitrogen and blood creatinine no matter in a prevention or treatment administration mode, and can also obviously relieve the kidney injury caused by model building. The efficacy of each formulation, both prophylactic and therapeutic, although shown to be slightly different at different time nodes, is not significantly different overall.
Through comprehensive analysis, 4 formulas subjected to twice optimization have the best ZC2 effect and the worst ZC8 effect. The blood uric acid and blood creatinine values of the ZC2 prevention and administration group on the 7 th day show obvious prevention effect, and the degree of kidney damage (HE slices) is obviously reduced compared with the prevention and treatment groups of the ZC2 treatment group and other 3 formulas.
Claims (3)
1. A traditional Chinese medicine compound composition for preventing and treating hyperuricemia comprises chicory root, tuckahoe, dandelion, corn stigma, sophora flower and liquorice, wherein the chicory root comprises the following components in parts by weight: 3-6 parts; tuckahoe, poria cocos: 1.5-3.5 parts; dandelion: 1.5-3.5 parts; corn silk: 2.5-4.5 parts; and (3) flos sophorae: 1.5-3.5 parts; and licorice root: 1 part.
2. A preventive and therapeutic agent for hyperuricemia comprising an aqueous extract of the composition according to claim 1.
3. The formulation according to claim 2, wherein the daily dosage for an adult corresponds to a composition of: 10g of chicory root, 5g of poria cocos, 10g of dandelion, 10g of corn stigma, 10g of sophora flower and 3g of liquorice.
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