Application of tanshinol or pharmaceutically acceptable salt thereof in preparation of drugs or health care products for preventing and treating hyperuricemia, gout and uric acid nephropathy
Tanshinone improves glomerular function and promotes uric acid excretion, inhibiting kidney inflammation and fibrosis, thus solving the problem of large adverse reactions of existing drugs and providing a safe and effective treatment for hyperuricemia and uric acid nephropathy.
Patent Information
- Application Number
- CN202410514638.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-04-26
- Publication Date
- 2025-11-04
AI Technical Summary
Existing medications for treating hyperuricemia and uric acid nephropathy have significant adverse reactions and require long-term use, resulting in a lack of safe and effective treatment options.
Tanshinone or its drug-acceptable salts can be used to prepare drugs or health products to lower blood uric acid levels and prevent and treat hyperuricemia and uric acid nephropathy by improving glomerular function, promoting uric acid excretion, and inhibiting inflammation and fibrosis.
Tanshinone significantly reduces serum uric acid levels, improves renal tubular dilation and necrosis, reduces urate deposition, and inhibits renal inflammation and fibrosis, providing a safe and effective new drug option for the treatment of hyperuricemia and uric acid nephropathy.
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Figure CN120884571A_ABST
Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of medicinal chemistry related to Danshensu, and particularly relates to application of Danshensu or a pharmaceutically acceptable salt thereof in preparation of a medicine or health care product for preventing and treating hyperuricemia, gout and uric acid nephropathy. BACKGROUND
[0002] Hyperuricemia (HUA) refers to that under normal purine diet, the fasting serum uric acid level is greater than 7.0 mg / dl (420 μmol / L) for males and greater than 6.0 mg / dl (360 μmol / L) for females in two consecutive measurements. Hyperuricemia is a chronic metabolic disease caused by purine and uric acid metabolism disorder, and is an important biochemical basis for diseases such as gout and uric acid nephropathy. At present, the prevalence rate of HUA in adults in China is 14.1%, and the prevalence rate is increasing year by year and tends to be younger. Due to the large population base in China, the number of HUA patients reaches 190 million, and at present, it has become the "fourth high disease" after hypertension, hyperglycemia and hyperlipidemia, and is the second largest metabolic disease only next to diabetes, which seriously threatens human life and health safety, and brings huge economic and spiritual burden to society and family. HUA is also the initial factor of many diseases in the body, and participates in the occurrence and development of metabolic diseases (diabetes, metabolic syndrome, hyperlipidemia, etc.), chronic kidney disease, cardiovascular and cerebrovascular diseases.
[0003] At present, the conventional drugs for treating gout mainly include colchicine, non-steroidal anti-inflammatory drugs, allopurinol, febuxostat and benzbromarone, etc. These drugs inhibit the formation of uric acid or promote the excretion of uric acid to achieve the purpose of relieving and treating gout and hyperuricemia, but are limited in clinical application due to adverse reactions. For example, colchicine has great toxicity and the therapeutic dose is very close to the toxic dose, allopurinol has a serious adverse reaction of exfoliative dermatitis with a mortality rate of 20% to 25%, febuxostat increases adverse cardiovascular events and mortality and has been black-boxed by the US Food and Drug Administration (FDA), and benzbromarone has serious liver and kidney toxicity and has been prohibited by FDA. The current clinical guidelines recommend that the uric acid-lowering drugs need to be taken for a long time or even for a lifetime. Therefore, it has become a hot issue to be solved in this field to find a safe and effective drug for treating hyperuricemia with small adverse reactions.
[0004] Traditional Chinese medicine Danshen (Salvia miltiorrhiza Bunge.) has the effects of removing blood stasis and relieving pain, promoting blood circulation and unblocking channels and collaterals, and clearing heart and relieving distress. Modern pharmacological studies have shown that Danshen has the effects of resisting atherosclerosis, improving blood circulation, resisting platelet adhesion and aggregation, removing oxygen free radicals in the body, improving the ability to resist hypoxia, improving coronary artery blood supply, and protecting the damage of heart and brain cells. Studies have shown that Danshen extract can significantly reduce the uric acid level of hyperuricemic mice and promote the excretion of uric acid in urine, and is the main component of Chinese medicine clinical application of anti-uric acid nephropathy, such as Spleen-Yang and Kidney-Yang Decoction, Shensu Decoction, Shensu Decoction, and Modified Siwu Decoction. Danshensu (Salvianic acid A) is the most important water-soluble component in Danshen, which can reduce the damage of inflammatory factors and free radicals to cells through antioxidant, anti-inflammatory and anti-apoptotic effects, maintain the stability of endothelial cells and protect cells. However, there is no relevant report that Danshensu has the effects of reducing uric acid, preventing and treating gout and uric acid nephropathy. SUMMARY
[0005] The present application relates to Danshensu or its pharmaceutically acceptable salt, and also relates to the application of a pharmaceutical composition containing Danshensu and its pharmaceutically acceptable salt in the preparation of a medicine for preventing and / or treating hyperuricemia, gout and uric acid nephropathy. In addition, the application of Danshensu and its pharmaceutically acceptable salt in the preparation of a medicine or health care product for reducing the uric acid level in blood. The application can provide a new drug selection for the clinical treatment of hyperuricemia and hyperuricemic nephropathy caused by hyperuricemia.
[0006] The present application provides the application of Danshensu or its pharmaceutically acceptable salt in the preparation of a medicine or health care product for preventing and treating hyperuricemia, gout and uric acid nephropathy.
[0007] Further, the Danshensu has a structure as shown in formula (1):
[0008]
[0009] Further, the Danshensu or its pharmaceutically acceptable salt reduces the blood creatinine level by improving the glomerular function.
[0010] Further, the Danshensu or its pharmaceutically acceptable salt reduces the blood uric acid level by promoting the excretion of uric acid.
[0011] Further, the Danshensu or its pharmaceutically acceptable salt improves the glomerular basement membrane, improves the glomerular filtration, and reduces the urine protein creatinine ratio.
[0012] Further, the Danshensu or its pharmaceutically acceptable salt improves the renal tubular expansion and / or necrosis by reducing the blood uric acid level, reducing the deposition of uric acid, inhibiting inflammation and fibrosis.
[0013] Furthermore, the tanshinone or its drug-acceptable salt can reduce kidney inflammation by inhibiting the TLR4 / NF-κB signaling pathway, inhibiting the activation of the NLRP3 inflammasome, and thus reducing kidney inflammation.
[0014] Furthermore, the tanshinone or its drug-acceptable salts improve renal fibrosis by inhibiting renal tubular epithelial-mesenchymal transition, inhibiting the renin-angiotensin system, inhibiting vascular smooth muscle cell proliferation, inhibiting oxidative stress, and inhibiting autophagy.
[0015] Furthermore, the effective dose of the tanshinone or its pharmaceutically acceptable salt is 1–1000 mg / kg.
[0016] Furthermore, the aforementioned pharmaceutical or health product is a clinically acceptable formulation made by mixing tanshinone or its pharmaceutically acceptable salt as the active ingredient with a pharmaceutically acceptable excipient or carrier.
[0017] Furthermore, the preparation is an oral preparation or an injectable preparation.
[0018] Furthermore, the oral preparation is an oral tablet.
[0019] In this invention, tanshinone or its pharmaceutically acceptable salts refer to acidic and / or basic salts formed by tanshinone with inorganic bases and / or acids, organic bases and / or acids, including zwitterionic salts (internal salts), and quaternary ammonium salts, such as alkyl ammonium salts. The salts described in this invention are selected from: sodium tanshinone, potassium tanshinone, calcium tanshinone, lithium tanshinone, magnesium tanshinone, ammonium tanshinone, meglumine tanshinone, amine tanshinone, arginine tanshinone, and lysine tanshinone.
[0020] The advantages of this invention compared to the prior art are as follows:
[0021] This invention provides the use of tanshinone or its salts in the preparation of drugs for lowering serum uric acid levels and preventing and treating uric acid nephropathy. Animal experiments have demonstrated that tanshinone can significantly reduce serum uric acid levels while improving the degree of renal tubular dilation, necrosis, and renal fibrosis in hyperuricemic mice. The application of this invention can provide new drug options for the clinical treatment of hyperuricemia and its resulting hyperuricemic nephropathy. Attached Figure Description
[0022] Figure 1 The image shows the results of serum uric acid level detection in rats in Example 1 (Note: *** vs. normal group P<0.001). # vs model group P<0.05, ### vs model group P<0.001);
[0023] Figure 2 The image shows the results of serum creatinine level detection in rats in Example 1 (Note: *** vs normal group P<0.001, ##vs model group P<0.01, ### vs model group P<0.001);
[0024] Figure 3 The graph shows the results of the urine protein-to-creatinine ratio test in rats in Example 1 (Note: *** vs normal group P<0.001). ## vs model group P<0.01, ### vs model group P<0.001);
[0025] Figure 4 This is a PAS staining image of rat kidney tissue from Example 1;
[0026] Figure 5 This is a Masson staining image of rat kidney tissue from Example 2;
[0027] Figure 6 This is a quantitative map of collagen volume in rat kidneys obtained by Masson staining in Example 2 (Note: *** vs. normal group P<0.001). ### vs model group P<0.001);
[0028] Figure 7 Immunohistochemical staining of rat kidney α-SMA in Example 2;
[0029] Figure 8 The percentage of the area of the rat kidney α-SMA immunohistochemically positive region in Example 2;
[0030] Figure 9 This is from Example 2, where Western blot analysis was performed to determine the expression of renal α-SMA protein.
[0031] Figure 10 For the quantitative analysis of renal α-SMA protein in Example 2 (Note: *** vs normal group P<0.001, ### vs model group P<0.001);
[0032] Figure 11 The urinary uric acid excretion in mice in Example 2 is 24h (Note: *** vs normal group P<0.001, # vs model group P<0.05, ### vs model group P<0.001). Detailed Implementation
[0033] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0034] As used herein, the term "danshensu or pharmaceutically acceptable salts thereof" refers to acid and / or base salts of danshensu with inorganic bases and / or acids, organic bases and / or acids, and also to zwitterionic salts (inner salts), and also to quaternary ammonium salts, such as alkylammonium salts. The salts of the present application are selected from the group consisting of danshensu sodium salt, danshensu potassium salt, danshensu calcium salt, danshensu lithium salt, danshensu magnesium salt, danshensu ammonium salt, danshensu meglumine salt, danshensu amine salt, danshensu arginine salt, danshensu lysine salt.
[0035] The danshensu of the present application can be administered to a patient in the form of a pharmaceutically acceptable salt or pharmaceutical composition. The compound is combined with appropriate carriers or excipients to form a pharmaceutical composition in a manner that allows the desired dosage to be delivered to the patient. The "effective therapeutic dosage" is the dosage of danshensu or pharmaceutically acceptable salts thereof that is necessary to achieve a therapeutic effect.
[0036] Danshensu or pharmaceutically acceptable salts thereof can be formulated into various dosage forms including solid dosage forms, semi-solid dosage forms, liquid dosage forms, and aerosol dosage forms (Remington's Pharmaceutical Sciences, Mack Publishing Company (1995), Philadelphia, PA, 19th ed). Specific examples of these dosage forms include tablets, pills, lozenges, granules, gels, pastes, solutions, suppositories, injections, inhalers, and sprays. These dosage forms can be used for both local or systemic administration and for immediate or sustained release.
[0037] When danshensu or pharmaceutically acceptable salts thereof are administered by injection, the compounds can be formulated into solutions, suspensions, and emulsions using water-soluble or fat-soluble solvents. Fat-soluble solvents include vegetable oils and similar oils, synthetic fatty acid glycerides, higher fatty acid esters, and proylene glycol. The compounds are more soluble in ethanol solutions and in small amounts of DMSO.
[0038] When danshensu or pharmaceutically acceptable salts thereof are administered orally, they can be combined with pharmaceutically acceptable excipients using conventional techniques. These excipients can be used to formulate the compounds into various dosage forms that can be taken by patients, such as tablets, pills, suspensions, gels, and the like. Oral formulations can be prepared in a variety of ways, such as by mixing the compounds with solid excipients, thoroughly grinding the mixture, and adding appropriate auxiliary agents and processing into granules. Auxiliary agents that can be used to make oral dosage forms include sugars such as lactose, sucrose, mannitol, or sorbitol; cellulose derivatives such as corn starch, wheat starch, potato starch, gelatin, xanthan gum, methylcellulose, hydroxymethylcellulose, carboxymethylcellulose sodium, polyvinylpyrrolidone, and the like.
[0039] The Danshensu or pharmaceutically acceptable salt thereof according to the present application can also be prepared into a spray. Such a dosage form is realized by a pressurizer and a sprayer or a dry powder inhalation device. Suitable propellants for use in the sprayer include dichlorodifluoromethane, fluorotrichloromethane, dichlorotetrafluoroethane, carbon dioxide, dimethyl ether, and the like. The dosage of the aerosol can be adjusted by the valve of the sprayer.
[0040] The various dosage forms according to the present application are related to the effective therapeutic dosage of Danshensu or pharmaceutically acceptable salt thereof. The effective therapeutic dosage of the compound depends on the patient to be treated. In determining the appropriate dosage, the body weight, the condition of the patient, the mode of administration, and the subjective judgment of the prescribing physician are taken into account. The therapeutically effective amount of Danshensu or pharmaceutically acceptable salt thereof and the composition containing these compounds should be determined by the prescribing physician with the ability and experience.
[0041] Although the effective therapeutic dosage of Danshensu or pharmaceutically acceptable salt thereof varies depending on the patient, the appropriate dosage range is generally 1-1000 mg / kg.
[0042] Example 1: Danshensu reduces serum uric acid level and improves kidney injury
[0043] Animal modeling and grouping administration, the specific steps are as follows:
[0044] Experimental animals: 60 SPF male SD rats, randomly divided into 6 groups, 10 rats in each group, body weight 180-220 g, standardization of experimental diet feeding in constant temperature environment for at least 1 week before experiment. Rats were fed in cages, free water and food, room temperature (25±2)℃, relative humidity 50%-70%.
[0045] Animal grouping: 60 rats were divided into 6 groups: normal control group, hyperuricemia model group, Danshensu low dose group (5 mg / kg / d), Danshensu medium dose group (10 mg / kg / d), Danshensu high dose group (50 mg / kg / d), and positive control allopurinol group (50 mg / kg / d), 10 rats in each group.
[0046] Drugs and reagents: oxypurinol potassium salt (Sigma); adenine (Sigma); allopurinol (Shanghai Titan Technology Co., Ltd.); Danshensu (Shanghai Zhongshi Pharmaceutical Co., Ltd.).
[0047] Experimental method: establishment of hyperuricemia animal model, administration and sampling method. Except for the normal group, the rest of the groups were given intragastric administration of adenine 1.5 g / kg and oxypurinol 1.5 g / kg daily to establish a hyperuricemia model, for 21 consecutive days. Danshensu and allopurinol treatment groups were given Danshensu and allopurinol intervention treatment by intragastric administration every day for 21 consecutive days, and the normal group and the model group were given the same amount of normal saline.
[0048] Biochemical index determination: After the last administration, the rats were placed in metabolic cages, fasted and watered, and the urine of the rats was collected for 24 h. After the urine was collected, the eyeballs of the rats in each group were bled, and the serum was obtained after the blood samples were centrifuged at room temperature at 3000 r / min for 15 min, and the biochemical indexes were determined by using an automatic biochemical analyzer. The mouse urine samples were centrifuged at room temperature at 3500 r / min for 10 min, and the upper layer of urine was taken to determine the biochemical indexes by using an automatic biochemical analyzer. After the blood was taken, the double kidneys were removed, fixed with paraformaldehyde to prepare paraffin sections, and subjected to PAS staining to observe the structure of the kidneys, and the experimental results are shown in Figure 4 . MASSON staining was used to observe the renal fibrosis, and the experimental results are shown in Figure 5 .
[0049] As can be seen from Figure 1 , compared with the normal group, the uric acid of the model group was significantly increased, indicating that the combination of adenine and potassium oxonate could cause hyperuricemia in rats, and salvianin could significantly reduce the levels of blood uric acid, creatinine and urine protein creatinine ratio, and the effect of the high-dose treatment group was better than that of allopurinol.
[0050] As can be seen from Figure 2 , high and medium doses of salvianin could significantly reduce the level of blood creatinine, and the effect was better than that of allopurinol, indicating that salvianin had a protective effect on the kidney function of animals while reducing uric acid.
[0051] As can be seen from Figure 3 , salvianin had the effect of improving the kidney function, and the effect of reducing the urine protein creatinine ratio was better than that of allopurinol.
[0052] As can be seen from Figure 4 , compared with the normal group, the kidney structure of the model group was abnormal, the brush edge of the renal tubule was missing, the mesangial proliferation of the glomerulus was increased, and there were many inflammatory cell infiltrations in the renal tubular interstitium. After salvianin was administered, the deposition of renal glycogen was significantly reduced, and the damage to the glomerulus and the renal tubular interstitium was significantly reduced, and the effect was better than that of the allopurinol group, indicating that salvianin could improve the pathological damage of the kidney caused by hyperuricemia.
[0053] Example 2 Therapeutic effect of salvianin on renal fibrosis in hyperuricemic rats
[0054] The animals were grouped and administered as in Example 1, MASSON staining and α-SMA (α-smooth muscle actin) immunohistochemical staining were used to observe the expression of collagen fibers in the kidney, and the renal fibrosis was evaluated, and the experimental results are shown in Figures 5-10 .
[0055] As can be seen from Figures 5-6 , the expression of α-SMA in the model group was significantly increased, indicating that the model group had renal fibrosis. After salvianin was administered, the expression of α-SMA was significantly reduced, and the effect was better than that of the allopurinol group, indicating that salvianin could improve the renal fibrosis caused by hyperuricemia.It can be seen that compared with the normal group, the model group mice glomerulus and renal tubular interstitium appear obvious blue dyeing, indicating that the collagen deposition is more, fibrosis is obvious, compared with the model group, allopurinol and danshensu administration group is reduced in different degrees, danshensu high dose group effect is more significant.
[0056] Alpha-SMA is a fibrosis marker, from Figure 7 Immunohistochemistry can be seen that the model group alpha-SMA expression increases (brown dyeing), Figure 9 WB experiment in the model group alpha-SMA expression increases, indicating that high uric acid can cause renal fibrosis. After danshensu treatment, alpha-SMA expression is inhibited, and the degree of renal interstitial fibrosis in hyperuricemic mice is obviously improved. Alpha-SMA immunohistochemical staining shows that danshensu can effectively inhibit the expression of interstitial alpha-SMA. It shows that danshensu can improve the renal fibrosis of hyperuricemic rats.
[0057] Example 3 Danshensu reduces blood uric acid level by promoting renal uric acid excretion
[0058] On the 21st day of the experiment, 24-hour urine of mice was collected with metabolic cages and the urine volume was recorded. After centrifugation of mouse urine samples at room temperature at 800g / min for 10min, the upper layer of urine was taken and the urine uric acid level was determined by using a fully automatic biochemical instrument. 24-hour urine uric acid excretion = 24-hour urine volume x 24-hour urine uric acid concentration. The experimental results are shown in Figure 11 .
[0059] From Figure 11 It can be seen that the 24-hour urine uric acid excretion of the model group mice decreased significantly; after danshensu treatment, the urine uric acid excretion increased significantly, and the high dose group was better than the low dose group. The above results show that danshensu can reduce serum uric acid level by promoting renal uric acid excretion, and reduce the damage of urate deposition to kidney tissue, and play a protective role in kidney function.
[0060] The compounds of the present application, the preparation method and application thereof are described in combination with some specific embodiments and examples, and many details are also stated and explained. However, it should be understood that the specific embodiments and examples provided herein are only exemplary, and do not limit the protection scope of the present application. In fact, the present application can also be implemented by using other specific ways for those skilled in the art, and the corresponding modifications, changes or adjustments do not deviate from the spirit and essence of the present application, and thus should be considered as being included in the scope of the present application.
Claims
1. The use of tanshinone or its drug-acceptable salt in the preparation of drugs or health products for the prevention and treatment of hyperuricemia, gout and uric acid nephropathy.
2. The application according to claim 1, characterized in that: The tanshinone has the structure shown in formula (1):
3. The application according to claim 1, characterized in that: The tanshinone or its drug-acceptable salts reduce serum creatinine levels by improving glomerular function.
4. The application according to claim 1, characterized in that: The tanshinone or its drug can be used to promote uric acid excretion and lower blood uric acid levels.
5. The application according to claim 1, characterized in that: The tanshinone or its drug-acceptable salt improves glomerular basement membrane, enhances glomerular filtration, and reduces the urine protein-to-creatinine ratio.
6. The application according to claim 1, characterized in that: The tanshinone or its drug-acceptable salts improve renal tubular dilation and / or necrosis by lowering blood uric acid levels, reducing urate deposition, inhibiting inflammation and fibrosis.
7. The application according to claim 1, characterized in that: The tanshinone or its drug-acceptable salts reduce kidney inflammation by inhibiting the TLR4 / NF-κB signaling pathway, suppressing the activation of the NLRP3 inflammasome, and thus reducing kidney inflammation.
8. The application according to claim 1, characterized in that: The tanshinone or its drug-acceptable salts improve renal fibrosis by inhibiting renal tubular epithelial-mesenchymal transition, inhibiting the renin-angiotensin system, inhibiting vascular smooth muscle cell proliferation, inhibiting oxidative stress, and inhibiting autophagy.
9. The application according to claim 1, characterized in that: The effective dose of the tanshinone or its acceptable drug salt is 1–1000 mg / kg.
10. The application according to claim 1, characterized in that: The aforementioned medicine or health product is a clinically acceptable formulation made by mixing tanshinone or its pharmaceutically acceptable salt as the active ingredient with a pharmaceutically acceptable excipient or carrier.