Use of psoralen and its derivatives in the preparation of drugs for preventing and treating kidney cell death, inflammation, fibrosis associated with stones

Abstract

The application discloses application of psoralen and derivatives thereof in preparation of drugs for preventing and treating kidney cell death, inflammation and fibrosis caused by calculi. It is found through pharmacodynamic and pharmacological experiments that psoralen and derivatives thereof have strong anti-calculus effect, and can protect kidney cells, and improve kidney inflammation and fibrosis. Psoralen and derivatives thereof have small side effects, long-lasting effect and low price in preventing and treating calculi, and therefore, can be used in preparation of drugs for preventing and treating calculi, and have wide application prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the application of psoralen and its derivatives in the preparation of drugs for the prevention and treatment of kidney stones accompanied by renal cell death, inflammation, and fibrosis. Background Technology

[0002] Kidney stones seriously endanger human life and health. A kidney stone (Calculi) is a solid mass that forms in the ducts or cavities of hollow organs (such as the kidneys, ureters, gallbladder, or bladder) of the human or animal body. They are mainly found in the gallbladder, bladder, and renal pelvis, and can also be found in the pancreatic duct, salivary gland duct, etc. Calcium-containing stones are the most common type of urinary tract stone. Calcium-containing stones can be classified as: simple calcium oxalate, calcium oxalate and calcium phosphate, and stones containing a small amount of uric acid in addition to calcium oxalate. The incidence rate is relatively high, about 5-6%, and has been increasing year by year in recent years.

[0003] Psoralen (Formula I) has a relative molecular mass of 186.16 and is a colorless needle-like crystal (in ethanol). Its melting point is 189–190 °C. It is soluble in ethanol and chloroform, and slightly soluble in water, ether, and petroleum ether. Derivatives of psoralen refer to substances that can be modified at the positions of the five-membered ring and double bonds, including various halogenated compounds (modified with chlorine, bromine, etc.), and different chains of aliphatic, ether, lipid, and oxygen bridges, such as isopsoralen (Formula II) and imperatorin (Formula III). Similarly, the two double bond positions of the middle six-membered ring can be modified to synthesize substances containing hydroxyl, hydroxymethyl, methyl, and cyano groups, such as 8-hydroxypsoralen (Formula IV), bergapten lactone (Formula V), and 5-(4-phenoxybutoxy)psoralen (Formula VI). The double bond positions of the lactone ring of the six-membered ring can also be modified to synthesize different chains of aliphatic, ether, lipid, oxygen bridges, and halogenated compounds, such as rutin (Formula VII).

[0004]

[0005] The China National Research Center for Traditional Chinese Medicine points out that psoralen and its derivatives are all photosensitive compounds. Clinically, they can be used to treat vitiligo, psoriasis, and alopecia areata; they have hemostatic effects on bleeding from the uterus, nose, and gums; they have significant inhibitory effects on S180, Ehrlich ascites carcinoma, and H-22 liver cancer; they have a bronchodilatory effect; they increase melanin production; and under ultraviolet light irradiation, they can produce a phototoxic reaction, selectively inhibiting the synthesis of epidermal cell DNA. Psoralen has low toxicity, with an LD50 (mg / kg): 615 mg / kg for mice (oral administration) and 480 mg / kg (subcutaneous injection); and 1330 mg / kg for rats (oral administration) and 810 mg / kg (subcutaneous injection). Summary of the Invention

[0006] The purpose of this invention is to address the shortcomings of existing technologies by providing the application of psoralen and its derivatives in the preparation of drugs for the prevention and treatment of gallstones.

[0007] This invention, through pharmacodynamic and pharmacological experiments, has found that psoralen and its derivatives effectively inhibit the formation of calcium oxalate. In the calcium oxalate monohydrate crystallization experiment, compared with the control group, the addition of psoralen significantly reduced the density of calcium oxalate crystals, as well as the crystal size and total crystal area. In in vivo experiments in rats, compared with the litholytic group, the psoralen treatment group showed a significant decrease in crystal levels in the kidneys and urine; the levels of renal fibrosis and inflammation in rats were also significantly reduced. These experimental results indicate that psoralen and its derivative solutions have a strong anti-lithiasis effect and can protect kidney cells, exerting anti-fibrotic and anti-inflammatory effects. Experimental studies have confirmed that the drug for preventing and treating stones of this invention can effectively reduce the formation of stone crystals, has few toxic side effects, long-lasting effects, and is inexpensive.

[0008] Therefore, the object of this invention is to provide the use of psoralen and its derivatives in the preparation of medicaments for the prevention and / or treatment of gallstones.

[0009] The psoralen derivatives can be modified at the positions of the five-membered ring and double bonds of psoralen, including various halogenated derivatives (modified with chlorine, bromine, etc.), and different chains of aliphatic, ether, lipid, oxygen bridge, etc.; similarly, they can also be modified at the two double bond positions of the middle six-membered ring to synthesize substances containing hydroxyl, hydroxymethyl, methyl, and cyano groups; the double bond positions of the lactone ring of the six-membered ring can also be modified to synthesize different chains of aliphatic, ether, lipid, oxygen bridge, and halogenated derivatives.

[0010] Preferably, the drug for preventing and / or treating stones contains 0.1% to 99.9% by weight of psoralen or its derivatives.

[0011] Preferably, the dosage form of the drug is a liquid dosage form or a solid dosage form.

[0012] Preferably, the liquid dosage form is an injection, solution, suspension, emulsion, or aerosol.

[0013] Preferably, the solid dosage form is a tablet, capsule, pill, powder for injection, sustained-release preparation, or microparticle delivery system.

[0014] Preferably, the stone can be a urinary stone or a kidney stone.

[0015] The pharmaceutical products of the present invention can be prepared according to methods known in the art. For this purpose, if desired, the active ingredient can be combined with one or more solid or liquid pharmaceutical excipients and / or adjuvants to form a suitable administration or dosage form for human use.

[0016] The drug of the present invention can be administered in unit dose form, and the route of administration can be intestinal or non-intestinal, such as oral, intramuscular, subcutaneous, nasal, oral mucosa, skin, peritoneum or rectum, etc.

[0017] The drug of the present invention can be administered via injection. Injection includes intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection, and acupoint injection.

[0018] The dosage form of this invention can be a liquid dosage form or a solid dosage form. For example, liquid dosage forms can be solutions, colloids, microparticles, emulsions, or suspensions. Solid dosage forms can be tablets, capsules, pellets, aerosols, pills, powders, solutions, suspensions, emulsions, granules, suppositories, lyophilized powder injections, etc.

[0019] The drug of the present invention can be formulated as a conventional preparation, or as a sustained-release preparation, a controlled-release preparation, a targeted preparation, or various microparticle delivery systems.

[0020] To formulate unit-dose dosage forms into tablets, a wide variety of carriers known in the art can be used. Examples of carriers include: diluents and absorbents: starch, dextrin, calcium sulfate, lactose, mannitol, sucrose, sodium chloride, glucose, urea, calcium carbonate, kaolin, microcrystalline cellulose, aluminum silicate, etc.; humectants and binders: water, glycerin, polyethylene glycol, ethanol, propanol, starch paste, dextrin, syrup, honey, glucose solution, gum arabic paste, gelatin paste, sodium carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone, etc.; disintegrants, such as dried starch, alginate, agar powder, brown algae starch, etc. Sodium bicarbonate, citric acid, calcium carbonate, polyoxyethylene sorbitol fatty acid esters, sodium lauryl sulfonate, methylcellulose, ethylcellulose, etc.; disintegration inhibitors, such as sucrose, tristearate, cocoa butter, ammoniacal oil, etc.; absorption promoters, such as quaternary ammonium salts, sodium lauryl sulfate, etc.; lubricants, such as talc, silica, corn starch, stearates, boric acid, liquid paraffin, polyethylene glycol, etc.; tablets can also be further processed into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or bilayer and multilayer tablets.

[0021] To formulate the drug delivery unit into pills, a wide variety of carriers known in the art can be used. Examples of carriers include, for instance, diluents and absorbents such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, polyvinylpyrrolidone, gelucire, kaolin, talc, etc.; binders such as gum arabic, tragacanth, gelatin, ethanol, honey, liquid sugar, rice paste, or flour paste, etc.; and disintegrants such as agar powder, dried starch, alginate, sodium dodecyl sulfate, methylcellulose, ethylcellulose, etc.

[0022] To formulate the drug delivery unit into a suppository, a wide variety of carriers known in the art can be used, such as polyethylene glycol, lecithin, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

[0023] To formulate suppositories into capsules, the active ingredient is mixed with the various carriers described above, and the resulting mixture is placed in hard gelatin capsules or soft capsules. Alternatively, the active ingredient can be formulated into microcapsules, suspended in an aqueous medium to form a suspension, or filled into hard capsules or formulated into injectable preparations for use.

[0024] For example, the drug of the present invention can be formulated into injectable preparations, such as solutions, suspension solutions, emulsions, and lyophilized powder injections. These preparations can be aqueous or non-aqueous and may contain one or more pharmacodynamically acceptable carriers, diluents, binders, lubricants, preservatives, surfactants, or dispersants. For example, diluents may be selected from water, ethanol, polyethylene glycol, 1,3-propanediol, ethoxylated isostearyl alcohol, polyoxyethylene isostearyl alcohol, polyoxyethylene sorbitan fatty acid esters, etc. Furthermore, to prepare isotonic injections, appropriate amounts of sodium chloride, glucose, or glycerol can be added to the injectable preparations. In addition, conventional solubilizers, buffers, pH adjusters, etc., can also be added. These excipients are commonly used in the art.

[0025] In addition, colorants, preservatives, flavorings, tasters, sweeteners or other materials may be added to pharmaceutical preparations if necessary.

[0026] The dosage of the drug of the present invention can vary within a certain range taking into account individual differences, such as the nature and severity of the disease to be prevented or treated, the sex, age, weight, personality and individual response of the patient or animal, the route of administration, the frequency of administration, etc.

[0027] A second object of the present invention is to provide a medicament for the prevention and / or treatment of stones, comprising an effective amount of psoralen or a derivative thereof as an active ingredient.

[0028] The medication for the prevention and / or treatment of stones also includes pharmaceutically acceptable carriers.

[0029] The pharmaceutically acceptable carrier is a conventional drug excipient or adjuvant.

[0030] This invention, through pharmacological and pharmacodynamic experiments, has discovered that psoralen and its derivatives have a strong anti-calculi effect. Psoralen and its derivatives have few toxic side effects, long-lasting effects, and low cost in preventing and treating calculi. Therefore, psoralen and its derivatives can be used to prepare drugs for the prevention and treatment of calculi, which has broad application prospects. Attached Figure Description

[0031] Figure 1This is a microscopic image taken during the crystallization experiment of psoralen calcium oxalate monohydrate.

[0032] Figure 2 This is a statistical graph showing the inhibition rate of psoralen on crystal formation in the crystallization experiment of calcium oxalate monohydrate.

[0033] Figure 3 This is a statistical graph showing the effect of calcium oxalate monohydrate crystallization experiment on the density of psoralen crystals;

[0034] Figure 4 This is a statistical graph showing the effect of psoralen on crystal size in the crystallization experiment of calcium oxalate monohydrate;

[0035] Figure 5 This is a statistical graph showing the effect of psoralen on the total crystal area in the crystallization experiment of calcium oxalate monohydrate.

[0036] Figure 6 This is a microscope image taken during the crystallization experiment of isopsoralen calcium oxalate monohydrate.

[0037] Figure 7 This is a statistical graph of the crystal density from the crystallization experiment of isopsoralen calcium oxalate monohydrate;

[0038] Figure 8 This is a statistical chart of crystal size from the crystallization experiment of isopsoralen calcium oxalate monohydrate;

[0039] Figure 9 This is a statistical chart of the total crystal area in the crystallization experiment of isopsoralen calcium oxalate monohydrate;

[0040] Figure 10 This is a microscopic image taken during the crystallization experiment of the calcium oxalate monohydrate of imperatorin.

[0041] Figure 11 This is a statistical graph of the crystal density of the crystallization experiment of the calcium oxalate monohydrate of imperatorin;

[0042] Figure 12 This is a statistical chart of crystal size from the crystallization experiment of purslane calcium oxalate monohydrate;

[0043] Figure 13 This is a statistical chart of the total crystal area in the crystallization experiment of purslane calcium oxalate monohydrate;

[0044] Figure 14 These are microscopic images taken during the crystallization experiment of bergapten, 8-hydroxypsoralen, and PAP-1 calcium oxalate monohydrate.

[0045] Figure 15 This is a statistical graph of the crystallization density of bergapten, 8-hydroxypsoralen and PAP-1 calcium oxalate monohydrate in a crystallization experiment.

[0046] Figure 16 This is a statistical chart of crystal sizes from crystallization experiments of bergapten, 8-hydroxypsoralen, and PAP-1 calcium oxalate monohydrate.

[0047] Figure 17 This is a statistical chart of the total crystal area in the crystallization experiments of bergapten, 8-hydroxypsoralen, and PAP-1 calcium oxalate monohydrate.

[0048] Figure 18 This is a microscope image taken during the crystallization experiment of rutin calcium oxalate monohydrate.

[0049] Figure 19 This is a statistical graph of the crystal density from the crystallization experiment of rutin calcium oxalate monohydrate;

[0050] Figure 20 This is a statistical chart of crystal size from the crystallization experiment of rutin calcium oxalate monohydrate;

[0051] Figure 21 This is a statistical chart of the total crystal area in the crystallization experiment of rutin calcium oxalate monohydrate;

[0052] Figure 22 This is a crystallography image of urine from SD rats in a rat stone model.

[0053] Figure 23 This is a statistical graph showing the inhibition rate of psoralen on urinary liquid crystals in a rat stone model.

[0054] Figure 24 This is a statistical graph showing the number of liquid crystals in the urine of SD rats in a rat stone model.

[0055] Figure 25 This is a statistical chart of 24-hour urine volume in SD rats in a rat stone model.

[0056] Figure 26 This is a statistical chart of kidney weight in SD rats in a rat stone model;

[0057] Figure 27 This is an image of silver nitrate staining of the kidneys of SD rats in a rat stone model.

[0058] Figure 28 This is an HE staining image of the kidney of an SD rat in a rat stone model.

[0059] Figure 29 The inhibition rate of psoralen on renal crystals in SD rats in a rat stone model;

[0060] Figure 30 It is the area of ​​the kidney lens in SD rats in a rat stone model;

[0061] Figure 31These are transcriptome sequencing results of rat kidney tissue from a rat stone model;

[0062] Figure 32 This refers to the level of renal fibrosis in a rat model of kidney stones.

[0063] Figure 33 This is a statistical graph showing the level of renal fibrosis in a rat stone model.

[0064] Figure 34 This is a statistical chart showing the effect of psoralen on the survival rate of kidney cells;

[0065] Figure 35 This is a statistical graph showing the effect of psoralen on the expression of interleukin-6 in renal cells;

[0066] Figure 36 This is a statistical graph showing the effect of psoralen on the expression of interleukin-10 in renal cells. Detailed Implementation

[0067] The following embodiments are further illustrations of the present invention, but not limitations thereof.

[0068] Example 1:

[0069] The following embodiments are further illustrations of the present invention, but not limitations thereof.

[0070] The following detailed description, in conjunction with specific embodiments, will introduce in detail the application of psoralen and its derivatives in the prevention and treatment of gallstones, as well as drugs containing psoralen for the prevention and treatment of gallstones.

[0071] Example 1:

[0072] Experiments on efficacy and pharmacological effects:

[0073] 1. Crystallization experiment of calcium oxalate monohydrate

[0074] 1.1 Experimental Procedure: Jihae Chung et al. proposed this experiment in their 2016 research on kidney stones; they found that anti-stone drugs can effectively inhibit the density and crystal structure of calcium oxalate crystals. Adding drugs during the crystallization process of calcium oxalate can be applied to the research of anti-stone drugs. The specific steps are: add 5 mL of sodium chloride (300 mM) solution, then add 0.7 mL of calcium chloride (10 mM) solution. Place a clean glass slide (approximately 1.3 × 1.3 cm) on the slide. 2Place the slide at the bottom of a glass bottle to collect calcium oxalate crystals for microscopic observation. Then, place the glass bottle in a 60°C incubator to ensure the solution reaches the crystallization temperature. Add 0.7 mL of sodium oxalate (10 mM) dropwise while continuously shaking at 400 rpm. To explore the effect of the inhibitor, an appropriate amount of inhibitor was added to the solution before the sodium oxalate. The final solution contained 0.7 mM calcium chloride; 0.7 mM sodium oxalate; 150 mM sodium chloride; x μg / mL inhibitor (x = 0-100, x = 0 being the control group), and added pure water to a total volume of 10 mL. Incubate at 60°C under stable conditions. After three days, remove the slide, gently rinse with ultrapure water, and air dry at room temperature for analysis.

[0075] 1.2 Experimental Materials: All reagents required for the experiment were purchased from Sigma-Aldrich.

[0076] 1.3 Experimental Results: Figure 1-5 The image shows the crystallization result of psoralen monohydrate. For example... Figure 1 and Figure 2 As shown, psoralen has a significant inhibitory effect on crystal formation, and this effect is dose-dependent (p < 0.05). *** <0.001); such as Figure 3 As shown, psoralen significantly reduced the number of crystals in a dose-dependent manner (p0.05). * <0.05; p *** <0.001); In the analysis of crystal volume size, it was found that, as Figure 1 and Figure 4 As shown, the crystal size decreased significantly after the addition of psoralen (p < 0.05). *** <0.001), the crystal structure undergoes significant changes; such as Figure 5 As shown, psoralen significantly reduced the total crystal area (p0.05). *** <0.001). The above results indicate that psoralen can inhibit crystal formation, reduce the number of calcium oxalate crystals, and alter their structure, thereby achieving an anti-stone effect.

[0077] Figure 6-9 The image shows the results of an experiment on the crystallization of calcium oxalate monohydrate by isopsoralen. Figure 6 and Figure 7 As shown, isopsoralen (100 μg / mL) significantly reduced the number of crystals (p0.05). * <0.05); Crystal size analysis revealed that, for example... Figure 6 and Figure 8 As shown, isopsoralen significantly reduced crystal size (p0.05). ** <0.01); such as Figure 9 As shown, isopsoralen significantly reduces the total crystal area (pc). ** <0.01; p ***<0.001). The above results indicate that isopsoralen can inhibit crystal formation, reduce the number of calcium oxalate crystals, and alter their structure, thereby achieving an anti-stone effect.

[0078] Figure 10-13 The image shows the results of an experiment involving the crystallization of calcium oxalate monohydrate by imperatorin. Figure 10 and Figure 11 As shown, imperatorin significantly reduced the number of crystals (p). *** <0.001); In crystal size analysis, it was found that, as Figure 10 and Figure 12 As shown, purslane did not have a significant effect on crystal size; as Figure 13 As shown, purslane significantly reduces the total crystal area (pc). *** <0.001). The above results indicate that imperatorin can inhibit crystal formation and reduce the amount of calcium oxalate crystals, thereby achieving an anti-stone effect.

[0079] Figure 14-17 The results show the effects of bergapten, 8-hydroxypsoralen, and PAP-1 in the crystallization experiment of calcium oxalate monohydrate. Figure 14 and Figure 15 As shown, bergamot lactone (10 μg / mL) and PAP-1 (100 μg / mL) significantly reduced the number of crystals (p). * <0.05; p *** <0.001), while 8-hydroxypsoralen significantly increased the number of crystals (p <0.001). *** <0.001); In crystal size analysis, it was found that, as Figure 14 and Figure 16 As shown, bergamot lactone (10 μg / mL) significantly increased crystal size (p *** <0.001), bergapten (100 μg / mL), 8-hydroxypsoralen and PAP-1 (100 μg / mL) significantly reduced crystal size (p *** <0.001); such as Figure 14 and Figure 17 As shown, bergapten, 8-hydroxypsoralen (10 μg / mL), and PAP-1 (100 μg / mL) significantly reduced the total crystal area (pc). * <0.05; p *** <0.001). The above results indicate that bergapten, 8-hydroxypsoralen, and PAP-1 can inhibit crystal formation, reduce the number of calcium oxalate crystals, and alter their structure, thereby achieving an anti-stone effect.

[0080] Figure 18-21 The image shows the results of an experiment involving the crystallization of calcium oxalate monohydrate by rutin. Figure 18 and Figure 19 As shown, rutin significantly reduced the number of crystals (p). *** <0.001); In crystal size analysis, it was found that, as Figure 18 and Figure 20 As shown, rutin did not have a significant effect on crystal size; as Figure 13 As shown, rutin significantly reduces the total crystal area (pc). *** <0.001). The above results indicate that rutin can inhibit crystal formation and reduce the amount of calcium oxalate crystals, thereby achieving an anti-stone effect.

[0081] 2. Rat stone model experiment:

[0082] 2.1 Experimental Materials: All drugs required for the experiment were of analytical grade and purchased from Sigma-Aldrich. SPF-grade adult male SD rats were purchased from the Experimental Animal Center of Southern Medical University. They were allowed free access to food and water and were housed in an environment with light and dark cycles every 12 hours.

[0083] 2.2 Experimental grouping: SD rats weighing approximately 220g were used in the experiment and divided into 4 groups. (1) Blank control group: No treatment was given, n=4 rats; (2) Model group: Stone induction model, n=6 rats; (3) Low-dose psoralen treatment group: Stone model combined with drug treatment (psoralen 50mg / kg), n=5 rats; (4) High-dose psoralen treatment group: Stone model combined with drug treatment (psoralen 100mg / kg), n=5 rats.

[0084] 2.3 Rat Stone Model Establishment Method: From day 1 to 5, rats were fed drinking water containing 0.75% (w / v) ethylene glycol and 1% (w / v) ammonium chloride. Starting from day 6, rats were fed drinking water containing only 0.75% ethylene glycol. The entire modeling process lasted 21 days. On day 22, 2-hour morning urine and 24-hour urine were collected from the rats, and the number of stone crystals in the urine was counted using a hemocytometer. Compared with the blank control group, the number of crystals in the model group was significantly increased, indicating successful modeling.

[0085] 2.4 Experimental Procedure: (1) Modeling and Drug Treatment. The blank control group was not treated. The modeling group used ethylene glycol and ammonium chloride to create a stone model according to the above modeling method. The treatment group rats were treated with psoralen or derivative 2 in drinking water at the same time as the stone model was created. The treatment lasted for 21 days. (2) Urine Collection and Crystal Counting. On day 22, 2h morning urine and 24h urine of rats were collected in the metabolic cage. The volume of 24h urine was measured and the number of stone crystals in 2h morning urine was counted using a hematology counter. (3) Kidney Sampling and Staining Counting. Fresh rat kidney tissue was taken for transcriptome sequencing. After rat perfusion, the kidneys were weighed and pathological sections were prepared. After staining with silver nitrate and HE, the slides were taken and the crystal level was calculated. (4) At the end of the experiment, the rat carcasses were handed over to the Experimental Animal Carcass Recycling Center of Southern Medical University for unified disposal.

[0086] 2.5 Experimental Results: Figure 22-30 The image shows the experimental results of the inhibitory effect of psoralen on stone formation in SD rats. Analysis of rat urine revealed that, as... Figure 22 , Figure 23 and Figure 24 As shown, compared with the model group, psoralen significantly inhibited crystal formation in urine, and the number of crystals in urine was significantly reduced (p<0.05). *** <0.001); such as Figure 25 As shown, compared with the control group, the 24-hour urine volume of rats in the model group and the psoralen treatment group was significantly increased (p < 0.05). ## <0.01); such as Figure 26 As shown, compared with the control group, the kidney weight of the model group and the treatment group was significantly increased (p < 0.05). ** <0.01, p *** <0.001); such as Figure 27 , Figure 28 , Figure 29 and Figure 30 As shown, compared with the control group, the formation of kidney stones and the total area of ​​the crystals were significantly increased in the model group rats; psoralen significantly inhibited crystal formation in the stone model rats (p < 0.05). ## <0.01), which significantly reduced its total crystallization area (p ## <0.01; p *** <0.001), and in a dose-dependent manner. These results indicate that psoralen can effectively inhibit the formation of kidney stones and reduce the number of stone crystals in the kidneys and urine.

[0087] like Figure 31 As shown, KEGG signaling pathway enrichment analysis after transcriptome sequencing revealed that psoralen can effectively reverse stone-induced inflammation-related signaling pathways, including Toll-like receptor, TNF, and NF-κB signaling pathways. Figure 32 and Figure 33 As shown, psoralen can effectively reverse the level of kidney fibrosis induced by kidney stones in a dose-dependent manner (p < 0.05). ** <0.01; p *** <0.001). For example... Figure 34 As shown, in vitro cultured kidney cells showed a significant decrease in cell viability after administration of exogenous CaOx; however, administration of 5 μg / mL psoralen effectively blocked CaOx-induced cell death (p < 0.05). * <0.05; p *** <0.001). For example... Figure 35 and 36 As shown, quantitative real-time PCR of collected kidney cells revealed that CaOx significantly increased the expression level of interleukin-6 and significantly decreased the expression level of interleukin-10 in kidney cells; however, administration of 5 μg / mL psoralen effectively reversed the changes in interleukin-6 and interleukin-10 induced by CaOx (p < 0.05). * <0.05; p ** <0.01). The above results indicate that psoralen can effectively inhibit the formation of kidney stones and urine stones, reduce the number of kidney stone crystals and urine stones, improve kidney inflammation and fibrosis, and protect kidney cells, thus achieving an anti-stone effect.

[0088] The above results indicate that psoralen and its derivatives can effectively inhibit the formation of kidney stones and urine stones, reduce the number of kidney stone crystals and urine stones, protect kidney cells, and improve kidney inflammation and fibrosis, thereby achieving an anti-stone effect.

[0089] The above results indicate that the drug of the present invention, comprising an effective amount of psoralen or its derivatives as an active ingredient, can effectively inhibit the formation of stones in the prevention and treatment of stones, with few toxic side effects, long-lasting effects, and low price.

[0090] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. The use of psoralen or its derivatives in the preparation of drugs that inhibit the formation of kidney stones and urine and reduce the number of kidney stone crystals and urine, wherein the derivatives are bergapten, rutin, or 5-(4-phenoxybutoxy)psoralen. Application of 2,8-hydroxypsoralen in the preparation of drugs that inhibit the formation of kidney and urine stones.

3. The application according to claim 1 or 2, characterized in that, The drug is in liquid or solid dosage form.

4. The application according to claim 3, characterized in that, The liquid dosage form is a solution, suspension, or emulsion.

5. The application according to claim 3, characterized in that, The liquid dosage form is either an injection or an aerosol.

6. The application according to claim 3, characterized in that, The solid dosage form is a sustained-release formulation.

7. The application according to claim 3, characterized in that, The solid dosage form is a tablet, capsule, pill, or powder for injection.

8. The application according to claim 1, characterized in that, The drug also includes pharmaceutically acceptable carriers.

9. The application according to claim 8, characterized in that, The pharmaceutically acceptable carrier is a pharmaceutical excipient.

10. The application according to claim 1 or 2, characterized in that, The stones mentioned are bladder stones, urethral stones, and kidney stones.

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