CN106138046B - Application of isoquinoline alkaloid in prevention or treatment of diabetic nephropathy - Google Patents
Application of isoquinoline alkaloid in prevention or treatment of diabetic nephropathy Download PDFInfo
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Abstract
The invention relates to an application of isoquinoline alkaloid in preventing or treating diabetic nephropathy.
Description
Technical Field
The invention relates to the field of natural medicines, relates to an application of isoquinoline alkaloid in prevention or treatment of diabetic nephropathy, and particularly relates to an application of phellodendrine in prevention or treatment of diabetic nephropathy.
Background
Diabetes is a metabolic disease which is characterized by hyperglycemia and is caused by insulin secretion defect and/or biological action disorder thereof, is a genetic susceptibility disease with environmental factors participating on the basis of heredity, is a chronic systemic metabolic disease, seriously harms human health, and has become a main social public health problem by actively carrying out the prevention and treatment work of diabetes.
The pathogenesis of type I diabetes is mainly due to the absolute lack of insulin secretion, while type II diabetes is a pathological process from insulin resistance with a major insulin deficiency to insulin hyposecretion with a major insulin resistance. It is currently recognized that type II diabetes is a complex genetic disease caused by multiple genes or interactions under the influence of environmental factors, lifestyle changes, etc., but the etiology of type II diabetes has not yet been fully elucidated.
Western medicine currently adopts diets and exercise therapy sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, repaglinide, insulin and the like to treat type II diabetes, and only thiazolidinediones can improve insulin resistance. When a patient is treated by western medicines, complications such as arteriosclerosis, coronary heart disease, hypertension and the like continuously appear, and the complex mechanism of type II diabetes and the general pathological changes caused by the complex mechanism are weak links of western medicine treatment. Neither the suaves secretagogues nor the thiazolidinedione sensitizers have obvious weight-losing efficacy in experiments and clinical researches, and the obesity is the important pathological basis of the type 2 diabetes mellitus and even the metabolic syndrome.
Type II diabetes is not only a disorder of glucose metabolism but also a disorder of fat metabolism. Type II diabetics who are caused by obesity often have a high sugar and high fat diet, often accompanied by hyperlipidemia. There are studies that suggest that obese patients with "normal" blood glucose have abnormal beta cell secretory function. However, most obese people do not develop diabetes, indicating that the body's own condition plays an important role. With the same toxic effects, susceptible people are susceptible to developing type II diabetes, while non-susceptible people may have no or delayed onset for life. Modern medicine can not change the susceptibility of the body, but can reduce early causes as much as possible and prolong the compensation period as much as possible by means of changing life style, losing weight and the like, thereby delaying the occurrence of type II diabetes and even avoiding the occurrence of the type II diabetes.
The modern treatment view of the type II diabetes is changed from the traditional simple blood sugar control into multi-link treatment such as blood sugar reduction, blood fat reduction, blood pressure reduction, insulin resistance improvement and the like. However, for type II diabetics, the dosage needs to be gradually increased, and the administration types are also gradually changed from single administration to combined administration, which inevitably considers the side effect of drug metabolism on liver and kidney. Therefore, the search of natural medicines with low toxicity and definite curative effect from the traditional Chinese medicines for treating diabetes is one of the hot spots in the current research on diabetes.
The classification standard formulated by the ministry of health in the published clinical research guidelines of new traditional Chinese medicines for treating diabetes (diabetes) is the most widely adopted classification method at present, namely the four types of yin deficiency and heat excess, qi and yin deficiency, yin and yang deficiency and blood fatigue and qi stagnation.
Diabetic Nephropathy (DN) is one of the most important complications of diabetes, the incidence of disease in our country is also on the rise, and has become the second place of end-stage nephropathy at present, and is second only to glomerulonephritis, because of the existence of complex metabolic disorders, diabetes has renal damage, especially once entering clinical proteinuria stage, the disease condition is generally irreversible, and often develops progressively until the end-stage nephropathy, which is often more difficult to treat than other kidney diseases, and is one of the main causes of diabetes death, and the research of the pathogenesis and therapeutic drugs of DN is greatly regarded by the medical community. Modern medicine mostly starts from the aspects of diet control, blood sugar control, blood pressure reduction, lipid metabolism regulation and the like, or adopts treatment means such as dialysis, kidney transplantation and the like, and no western medicine with definite curative effect can prevent the process of DN renal function damage. The main clinical diagnostic features are albumin excretion rate and albumin creatinine ratio.
The diabetic nephropathy is a disease name of modern medicine, and an exact disease name corresponding to the diabetic nephropathy is not existed in ancient medical books, but the clinical manifestations of diabetes mellitus and nephropathy are similar to those of diabetes mellitus and nephropathy, such as unique urine, edema, renal failure, obstruction and the like which are caused after long-term treatment and mistreatment of diabetes mellitus and diabetes mellitus recorded in documents. For example, the book Sheng Ji Zong Lu says: diabetes is chronic, kidney qi is injured, kidney governs water, kidney qi is deficient, qi transformation is abnormal, opening and closing are not smooth, and edema is caused. Record of the source of miscellaneous diseases rhinoceros candle, three eliminants source of origin: the symptoms of swollen body after thirst, swollen feet and knees with thirst-quenching face and scanty urine. Therefore, this disease belongs to the category of diabetes, edema and consumptive disease in TCM.
The understanding of the pathogenesis of the diabetic nephropathy is consistent among Chinese medicine, the understanding of traditional Chinese medicine is more consistent, the principle of deficiency, the secondary aspect of excess and the mixture of deficiency and excess are mainly established, the pathogenesis of the diabetic nephropathy is characterized in that: based on the deficiency of kidney, spleen, liver, qi, blood, yin and yang; the excess marked by blood stasis, water-dampness and most phlegm. The traditional Chinese medicine has unique advantages in the aspect of preventing and treating diabetic nephropathy, and natural products which are found from the traditional Chinese medicine and are used for improving clinical symptoms, relieving proteinuria, reducing blood sugar and protecting kidney functions are hot spots of domestic and foreign researches.
Phellodendron bark is a traditional Chinese medicine commonly used in China, is recorded in Shennong Ben Cao Jing, is originally named as Berberis amurensis, is listed as the top grade, is bitter and cold in nature, mainly enters kidney and bladder meridians, has the effects of clearing heat and drying dampness, removing heat and steaming by Bay fire, detoxifying and treating epidemic, and is used for treating damp-heat dysentery, jaundice dark urine, pruritus vulvae, stranguria with heat, beriberi flaccidity , bone steaming and overexertion, night sweat, spermatorrhea, pyogenic infections and eczema. Modern pharmacological research shows that the phellodendron bark has the effects of resisting bacteria, fungi, inflammation, hepatitis, nephritis, ulcer, oxidation, gout, blood pressure, blood sugar, tumor, heart failure and cell immunity. At present, the phellodendron bark preparation is widely applied clinically, for example, the phellodendron bark preparation is used for treating nasosinusitis, acute and chronic suppurative otitis media, acute and chronic osteomyelitis, chronic colitis, skin erosion, pustular skin lesion, eczema dermatitis, ulcerative stomatitis, external hemorrhoid gall, anal pain, postoperative external washing, soft tissue contusion, swelling and other diseases. (research on extraction and purification process of phellodendrine in phellodendron amurense, university of southwest traffic university student's school paper, Luohong, 2012).
Phellodendrine (Phellodendrine) is an isoquinoline alkaloid extracted and separated from stem bark of phellodendron amurense (phellodendron chinensis) and phellodendron wilsonii belonging to Rutaceae, and has effects of lowering blood pressure, resisting nephritis, inhibiting cellular immune response, and inhibiting central nerve.
The pharmacological actions of phellodendrine mainly comprise: the antihypertensive effect is mainly shown in that the antihypertensive effect is caused by intravenous injection in cats, rats and dogs, the pressure-boosting reaction of adrenaline and noradrenaline can be enhanced, the artificial asphyxia is inhibited, the pressure-boosting reaction of the vagus nerve medial end is stimulated, and the contraction of the transient membrane of the cat caused by the stimulation of the preganglionic fiber is inhibited. The intensity and the duration of the antihypertensive effect are increased along with the increase of the dosage; the blocking effect of vegetative nerve is shown in that phellodendrine has an inhibiting effect on central nerve and can inhibit spontaneous activity and various reflexes of mice; muscle relaxation effect; has inhibitory effect on induction phase of cellular immune response phase.
Separation, identification and insulinotropic activity screening of several alkaloids in phellodendron amurense (the Chinese medical guidance, 2011, 3 months, 9 th volume, 7 th period, pages 54-55, Zhongming Wei, Vanminbong, Jiyubin and Tangyi red) records: 3 compounds are separated from the alkaloid part of phellodendron amurense, which are berberine, jateorhizine and phellodendrine respectively. Researches find that when the concentration of glucose is 5.6mmol/L, 3 alkaloids in the total alkaloids of the phellodendron amurense have no obvious promotion effect on the secretion of insulin; when the concentration of glucose is 16.7mmol/L, berberine can obviously promote insulin secretion of cells. The positive drug glimepiride can promote insulin secretion at low sugar concentration and high sugar concentration.
So far, no report about the treatment effect of phellodendrine on diabetic nephropathy is available.
Disclosure of Invention
The invention discloses an application of isoquinoline alkaloid in preventing or treating diabetic nephropathy; in particular to a new application of phellodendrine in treating diabetic nephropathy,
the invention discloses an isoquinoline alkaloid used for preparing a composition for treating or preventing diabetic nephropathy.
In the composition disclosed by the invention, isoquinoline alkaloid is phellodendrine.
The composition disclosed by the invention is the phellodendrine or the medicinal salt, hydrate or anhydride thereof which is commercially available or prepared according to a known method.
The invention discloses a composition, wherein the phellodendrine medicinal salt comprises: inorganic acid salts such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate and phosphate; organic acid salts such as acetate, benzoate, maleate, fumarate, malate, citrate, oxalate, lactate, succinate, tartrate, alkylsulfonate or arylsulfonate, cysteine salt or other amino acid salts. Also included are basic salts such as sodium, potassium and calcium salts.
The hydrate contains n crystal water, and n is 1-12.
The composition disclosed by the invention is as follows: the medicine, health product, excipient or carrier is excipient or carrier commonly used in pharmaceutical field, such as diluent, disintegrant, lubricant, etc.
The effective amount of phellodendrine in the invention can be the common amount or dosage in the application field of phellodendrine at present.
The phellodendrine of the present invention can be used in oral or injectable form.
The isoquinoline alkaloids are used for preventing or treating type I diabetes.
The isoquinoline alkaloids are used for preventing or treating type II diabetes.
The isoquinoline alkaloids are used for preparing a composition for protecting kidney tissues of a diabetic kidney patient or repairing damaged kidney tissues of the diabetic kidney patient.
The Phellodendrine (phellandrine) has the CAS number of 6873-13-18 and the molecular formula of C20H24NO4Relative molecular mass 342, has the structure of formula:
in the pharmacological activity research of phellodendrine, the inventor unexpectedly finds that phellodendrine has a remarkable effect of treating diabetic nephropathy.
The invention develops diabetic nephropathy through (1) STZ modeled diabetic mice after 14 weeks, and the result shows that the treatment effect is obvious and the statistical difference is significant after the intragastric administration for 12 weeks
For the convenience of understanding, the use of phellodendrine according to the present invention for treating diabetic nephropathy is described in detail below with reference to the accompanying drawings and specific examples. It is to be expressly understood that the specific embodiments and figures are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the scope of the present invention.
Drawings
FIG. 1: HE staining of kidney
FIG. 2: PAS staining of kidney
Detailed description of FIG. 1
Figure 1 shows renal HE staining by upper, middle and lower three sections;
the upper part of fig. 1 shows normal group mouse kidney tissue;
the middle part of fig. 1 shows the kidney tissue of STZ group mice;
the lower part of figure 1 shows the kidney tissue of STZ + phellodendrine group mice.
Detailed description of FIG. 2
Figure 2 shows kidney PAS staining through the upper, middle and lower three sections;
the upper part of fig. 2 shows normal group mouse kidney tissue;
the middle part of fig. 2 shows the kidney tissue of STZ group mice;
the lower part of figure 2 shows the kidney tissue of STZ + phellodendrine group mice.
The invention relates to the following table
TABLE 1 Effect of phellodendrine on blood sugar of STZ-molded diabetic nephropathy
TABLE 2 Effect of phellodendrine on urine volume in STZ-modeled diabetic nephropathy
TABLE 3 Effect of phellodendrine on the UAE (24h urinary albumin excretion rate) of STZ-modeled diabetic nephropathy.
TABLE 4 Effect of phellodendrine on the UACR (ug urinary albumin/mg creatinine ratio) of STZ-modeled diabetic nephropathy.
Detailed Description
Example 1
To investigate the effect of phellodendrine on blood glucose in diabetic nephropathy, C57BL mice were randomly assigned to 3 groups, a normal control group (10), and an STZ group (20). STZ group is continuously injected into abdominal cavity for 5 days, fasting blood sugar is measured after two weeks, and the success of diabetes molding is determined when the blood sugar is more than or equal to 13.8 mM. And then randomly dividing the STZ group into an STZ group and an phellodendrine treatment group, wherein the STZ group is only normally raised, the phellodendrine treatment group is orally intragastrically administrated (15mg/kg), after 12 weeks, the mice are placed in a mouse metabolism cage, free diet and drinking water are carried out, urine is used for analysis, the measured indexes are all clinical classic indexes for detecting diabetic nephropathy, the obvious increase of the STZ group is more than 10 times compared with a blank control group as shown in tables 2, 3 and 4, the serious injury of the renal function of the diabetic mice is shown, and the organ injury of the STZ group is obvious compared with a normal group as shown in figures 1 and 2. The success of the diabetic nephropathy model can be obtained by combining the table drawings.
Table 1. the results show that phellodendrine can effectively reduce the blood sugar rise caused by STZ, reverse the urine volume increase caused by diabetic nephropathy (Table 2), and effectively reduce the 24h protein excretion rate increase caused by diabetic nephropathy (Table 3). Renal function is routinely evaluated clinically from the ratio of protein to creatinine in urine, and the effective reduction of phellodendrine increases the ratio of albumin to creatinine resulting from diabetic nephropathy (table 4). The results of the ratio of urine volume, 24h protein excretion rate albumin and creatinine indicate that phellodendrine treatment improves renal function well.
To further assess changes in renal organotypic injury, the present invention performs PAS and HE staining of the kidney. Fig. 1 and 2 show: the phellodendrine can effectively repair the reversal of the organ injury of the diabetic nephropathy, as shown in the figure, the glomerular mesangial region of the STZ group is widened, the matrix is increased, the glomerular basement membrane is thickened, the tubular basement membrane is thickened and split, the typical characteristics of the diabetic nephropathy are shown, the modeling is good, the phellodendrine is repaired to a certain extent, the mesangial region is relatively reduced, the matrix hyperplasia and the tubular basement membrane are improved, and the obvious treatment effect is shown.
TABLE 1 Effect of phellodendrine on blood glucose in STZ-molded diabetic nephropathy (unit: mM).
Note: p < 0.05, P < 0.01, P < 0.001, compared to the STZ group.
TABLE 2 influence of phellodendrine on urine volume (unit: g) in STZ-molded diabetic nephropathy.
TABLE 3 Effect of phellodendrine on UAE (24h urinary albumin excretion rate in. mu.g) of STZ-molded diabetic nephropathy.
TABLE 4 Effect of phellodendrine on the UACR (μ g urinary albumin/mg creatinine ratio) of STZ-modeled diabetic nephropathy.
Note: p < 0.05, P < 0.01, P < 0.001, compared to the STZ group.
Example 2
Preparation of phellodendrine
Phellodendrine tablet
Phellodendrine 10mg, starch 88g, magnesium stearate 3g
The preparation process comprises the following steps: sieving phellodendrine with 100 mesh sieve, adding starch and magnesium stearate, mixing, granulating, drying, and tabletting.
Phellodendrine capsule
Phellodendrine 10mg, starch 88g, magnesium stearate 3g
The preparation process comprises the following steps: sieving phellodendrine with 100 mesh sieve, adding starch and magnesium stearate, mixing, granulating, drying, and making into capsule.
Phellodendrine injection
Phellodendrine 47mg, sodium chloride 7mg for injection
The preparation process comprises the following steps: taking phellodendrine, sieving with a 100-mesh sieve, adding 1.9mL of injection water for dissolving, adding sodium chloride for injection to be isotonic, adjusting the pH value to 7-7.1, filtering, refrigerating for 24 hours, adding the injection water to a specified amount, filtering, filling and sealing, and sterilizing to obtain the phellodendrine.
Example 3
Dissolving phellodendrine monomer (with purity of 91-92%) 100mg with 10mL chloroform, adding 10mL 0.1M HCl chloroform solution, precipitating, filtering and drying to obtain phellodendrine hydrochloride monomer, dissolving with 1mL ethanol, standing in refrigerator at 4 deg.C for 24h, crystallizing, filtering and drying to obtain phellodendrine hydrochloride monomer with purity of over 98%.
Dissolving phellodendrine monomer (with purity of 91-92%) 100mg with 10mL chloroform, adding 10mL 0.1M H2SO4 chloroform solution, precipitating, filtering and drying to obtain phellodendrine sulfate monomer, dissolving with 1mL ethanol, filtering, standing the filtrate in refrigerator at 4 deg.C for 24h, crystallizing, filtering and drying to obtain phellodendrine sulfate monomer with purity of over 98%.
Dissolving phellodendrine monomer (with purity of 91-92%) 100mg with 10mL of chloroform, adding 10mL of 0.1M phosphoric acid chloroform solution, precipitating, filtering and drying to obtain phellodendrine phosphate monomer, dissolving with 1mL of ethanol, filtering, placing the filtrate in a refrigerator at 4 ℃ for 24h, crystallizing, filtering and drying to obtain phellodendrine phosphate monomer with purity of more than 98%.
100mg of phellodendrine monomer (with the purity of 91-92 percent), firstly dissolving with 10mL of chloroform, adding 10mL of 0.1M tartaric acid chloroform solution, precipitating, filtering and drying to obtain the phellodendrine monomer, dissolving with 1mL of ethanol, filtering, placing the filtrate in a refrigerator at the temperature of 4 ℃ for 24 hours, crystallizing, filtering and drying to obtain the phellodendrine monomer with the purity of more than 98 percent.
Dissolving phellodendrine monomer (with the purity of 91-92%) 100mg by using 10mL of chloroform, adding 10mL of 0.1M oxalic acid chloroform solution, precipitating, filtering and drying to obtain the phellodendrine oxalate monomer, dissolving by using 1mL of ethanol, filtering, placing the filtrate in a refrigerator at the temperature of 4 ℃ for 24 hours, crystallizing, filtering and drying to obtain the phellodendrine oxalate monomer, wherein the purity of the phellodendrine oxalate monomer is more than 98%.
Dissolving phellodendrine monomer (with the purity of 91-92%) 100mg by using 10mL of chloroform, adding 10mL of 0.1M succinic acid chloroform solution, separating out precipitate, filtering and drying to obtain phellodendrine succinate monomer, dissolving by using 1mL of ethanol, filtering, placing filtrate in a refrigerator at the temperature of 4 ℃ for 24h, crystallizing, filtering and drying to obtain phellodendrine succinate monomer, wherein the purity of phellodendrine succinate monomer is more than 98%.
Dissolving phellodendrine monomer (with purity of 91-92%) 100mg with 10mL chloroform, adding 10mL 0.1M chloroform acetate solution, precipitating, filtering and drying to obtain phellodendrine acetate monomer, dissolving with 1mL ethanol, filtering, standing the filtrate in refrigerator at 4 deg.C for 24h, crystallizing, filtering and drying to obtain phellodendrine acetate monomer with purity of over 98%.
Dissolving phellodendrine monomer (with purity of 91-92%) 100mg with 10mL of chloroform, adding 10mL of 0.1M propionic acid chloroform solution, precipitating, filtering and drying to obtain phellodendrine propionate monomer, dissolving with 1mL of ethanol, filtering, standing the filtrate in a refrigerator at 4 ℃ for 24h, crystallizing, filtering and drying to obtain phellodendrine propionate monomer with purity of more than 98%.
Claims (1)
1. Application of phellodendrine in preparation of a medicine for reversing renal organopathy of diabetic nephropathy can reduce the increase of the ratio of albumin to creatinine caused by diabetic nephropathy.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510118942.4A CN106138046B (en) | 2015-03-17 | 2015-03-17 | Application of isoquinoline alkaloid in prevention or treatment of diabetic nephropathy |
| PCT/CN2016/074781 WO2016145983A1 (en) | 2015-03-17 | 2016-02-28 | Medical use of isoquinoline alkaloid |
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| CN201510118942.4A CN106138046B (en) | 2015-03-17 | 2015-03-17 | Application of isoquinoline alkaloid in prevention or treatment of diabetic nephropathy |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101153039A (en) * | 2006-09-30 | 2008-04-02 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant, pharmaceutical composition and uses of the same |
| CN102107006A (en) * | 2009-12-25 | 2011-06-29 | 奇复康药物研发(苏州)有限公司 | Coupling medicament for treating diabetes mellitus and medicinal application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101153039A (en) * | 2006-09-30 | 2008-04-02 | 中国科学院上海药物研究所 | 13, 13a- dihydro berberine derivant, pharmaceutical composition and uses of the same |
| CN102107006A (en) * | 2009-12-25 | 2011-06-29 | 奇复康药物研发(苏州)有限公司 | Coupling medicament for treating diabetes mellitus and medicinal application thereof |
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