CN111973593A - Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer - Google Patents
Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer Download PDFInfo
- Publication number
- CN111973593A CN111973593A CN202010388532.2A CN202010388532A CN111973593A CN 111973593 A CN111973593 A CN 111973593A CN 202010388532 A CN202010388532 A CN 202010388532A CN 111973593 A CN111973593 A CN 111973593A
- Authority
- CN
- China
- Prior art keywords
- nitazoxanide
- pharmaceutically acceptable
- bladder cancer
- cells
- acceptable salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of nitazoxanide or pharmaceutically acceptable salt thereof in preparing a medicament for treating bladder cancer, wherein the nitazoxanide or pharmaceutically acceptable salt thereof can inhibit the proliferation and the clone formation capability of different bladder tumor cell lines; leading to a decrease in mitochondrial membrane potential and increased ROS production, leading to apoptosis of bladder cancer cells; simultaneously, the dryness maintenance of bladder cancer cells can be effectively inhibited; the nitazoxanide and the pharmaceutically acceptable salt thereof still have the effect of inhibiting the growth of bladder tumors in vivo, and the nude mice do not have the phenomena of activity, reduced feeding and the like under the treatment dosage, and the nude mice do not have the phenomena of obvious emaciation or death and the like, indicating that the nitazoxanide and the pharmaceutically acceptable salt thereof have better treatment and application prospects on the bladder cancer.
Description
Technical Field
The invention relates to the field of new medicines of nitazoxanide, in particular to the application of nitazoxanide and pharmaceutically acceptable salts thereof in preparing medicines for treating bladder cancer.
Background
Nitazoxanide (NTZ) belongs to the nitrosalicylic acid amide derivative, which is chemically known as 2-acetoxy-N- (5-nitro-2-thiazolyl) benzamide and was originally approved by the FDA in the united states for the treatment of various intestinal protozoal diseases. NTZ is a prodrug and pharmacokinetic studies have shown that in blood, NTZ is deacetylated by plasma esterase and hydrolyzed to the active product Tizoxanide (TIZ). Research finds that the mechanism of action of NTZ is probably that it inhibits a key metabolic enzyme in anaerobic energy metabolism, namely pyruvate: the iron redox protease PFOR. PFOR can catalyze the oxidative dehydrogenation of pyruvate to produce acetyl-CoA and CO2. Structurally, NTZ has certain similarity with PFOR cofactor thiamine pyrophosphate TPP, so that NTZ blocks the combination of pyruvate and TPP, further inhibits the energy metabolism of anaerobe, protozoan and the like, and plays the role of resisting protozoan and anaerobe. In addition, nitazoxanide and its active metabolite have been reported to be equally effective against viral infections, but the mechanism of action is not yet definite, and may be closely related to the influence of such compounds on the maturation and transport of key viral glycoproteins.
Bladder cancer is the most common malignant tumor of the urinary system, has the characteristic of easy relapse and drug resistance in clinical practice, and is treated by periodical cystoscopy and multiple operations, so that the bladder cancer becomes one of cancers with the highest treatment cost. The vast majority of patients with bladder cancer are urothelial cancer, mainly consisting of muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC), with the former patients having an overall 5-year survival rate of less than 50%. Currently, transurethral cystectomy (TUBRT) is often used for non-muscle invasive bladder cancer, but 50% -70% of patients still have recurrence within two years after the operation, and the recurrence rate is not improved significantly over the last two decades. Clinical studies find that postoperative bladder perfusion treatment is one of the main ways to effectively reduce postoperative recurrence of bladder cancer. At present, the curative effect of the conventional bladder perfusion chemotherapeutic drugs such as vinblastine, cisplatin, BCG and the like is not very ideal, and the clinical problems of large toxic and side effects, multi-drug resistance and the like generally exist. Therefore, there is a high need to develop a candidate drug for bladder cancer therapy that is effective in preventing recurrence and progression of bladder cancer.
Disclosure of Invention
In view of the defects of the prior art, the invention aims to provide the application of nitazoxanide and pharmaceutically acceptable salts thereof in preparing a medicament for treating bladder cancer, and aims to solve the problems of poor curative effect and large toxic and side effects of the existing medicament for treating bladder cancer.
The technical scheme of the invention is as follows:
the invention aims to provide a new medical application of nitazoxanide or pharmaceutically acceptable salts thereof, namely an application in preparing a medicament for treating bladder cancer.
In the invention, the nitazoxanide and the pharmaceutically acceptable salt thereof can cause the proliferation inhibition and mitochondrial function damage of bladder cancer cells, induce the apoptosis of the bladder cancer cells and inhibit the dryness maintenance of the bladder cancer cells; the compound also has the effect of obviously inhibiting the growth of bladder tumors in vivo, and no obvious toxic or side effect is observed under the treatment dosage.
Further, the pharmaceutically acceptable salts include inorganic acid salts, organic acid salts, such as hydrochloride, acetate, and the like.
The invention also provides application of a pharmaceutical composition in preparing a medicament for treating bladder cancer, wherein the pharmaceutical composition comprises nitazoxanide or pharmaceutically acceptable salts thereof and pharmaceutically acceptable auxiliary materials.
In the invention, the pharmaceutically acceptable auxiliary materials are one or more of medicinal solvents, adhesives, disintegrants, flavoring agents, coloring agents and preservatives.
In the invention, the pharmaceutical composition is one of a solid preparation, an injection, an external preparation, a spray, a liquid preparation and a compound preparation.
Has the advantages that: the invention explores the new medical application of the nitazoxanide and the pharmaceutically acceptable salt thereof, namely the application in preparing the medicaments for treating the bladder cancer, and expands the application direction of the nitazoxanide and the pharmaceutically acceptable salt thereof; the nitazoxanide and the pharmaceutically acceptable salt thereof can inhibit the proliferation and the cloning formation capability of different bladder tumor cell lines; leading to a decrease in mitochondrial membrane potential and increased ROS production, leading to apoptosis of bladder cancer cells; simultaneously, the dryness maintenance of bladder cancer cells can be effectively inhibited; the nitazoxanide and the pharmaceutically acceptable salt thereof still have the effect of inhibiting the growth of bladder tumors in vivo, and the nude mice do not have the phenomena of activity, reduced feeding and the like under the treatment dosage, and the nude mice do not have the phenomena of obvious emaciation or death and the like, indicating that the nitazoxanide and the pharmaceutically acceptable salt thereof have better treatment and application prospects on the bladder cancer.
Drawings
FIG. 1a is a graph showing the effect of nitazoxanide on the proliferation of bladder tumor cell T24.
FIG. 1b is a graph showing the effect of nitazoxanide on the proliferation of bladder tumor cells UMUC-3.
FIG. 1c is a graph showing the effect of nitazoxanide on the proliferation of bladder tumor cells 5637.
FIG. 1d is a graph showing the effect of nitazoxanide on the proliferation of bladder tumor cell MGHU 3.
FIG. 2 is a graph showing the effect of nitazoxanide on the formation of MGHU3 clone in bladder tumor cells by crystal violet staining.
FIG. 3 is a graph showing the results of JC-1 staining in combination with flow cytometry analysis of the effect of nitazoxanide on mitochondrial membrane potential.
FIG. 4 is a graph showing the results of MitoSox staining combined with flow cytometry analysis of the regulation effect of nitazoxanide on mitochondrial ROS production.
FIG. 5 is a schematic diagram showing the analysis of early apoptosis and late apoptosis of cells after nitazoxanide treatment by Annexin V-FITC/PI double staining in combination with flow cytometry.
FIG. 6 is a diagram showing the results of western blot method for detecting the cleavage activation of apoptosis-related proteins (PARP, caspase 3).
FIG. 7a is a graph showing the effect of nitazoxanide on the balling capacity of bladder cancer cells (MGHU3, T24) in tumor cell suspension balling experiments.
Fig. 7b is a graph of the tumor cell formation of T24 bladder cancer cells as a result of varying concentrations of nitazoxanide, wherein ns. indicated no significant difference, P <0.01vs control.
Fig. 7c is a graph of tumor cell formation of MGHU3 as a result of tumor spheres formed at different concentrations of nitazoxanide, wherein ns. indicated no significant difference as P <0.01vs control.
FIG. 8a is a graph showing the sizes of tumors in the control group and the administration group in example 5.
FIG. 8b is a graph showing the results of the mean volume of tumors in each group as a function of time in example 5.
FIG. 8c is a graph showing the results of the change of the average body weight of the groups of nude mice in example 5 with time.
Detailed Description
The invention provides the application of nitazoxanide and pharmaceutically acceptable salts thereof in preparing medicaments for treating bladder cancer, and the invention is further detailed in the following for making the purpose, the technical scheme and the effect of the invention clearer and more clear. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
The discovery of new functions from the existing 'old medicine' is one of the important ways of drug development, and the chemical structural formula of Nitazoxanide (NTZ) is as follows:
the existing research shows that nitazoxanide inhibits the energy metabolism of anaerobic microorganisms, protozoa and the like, thereby playing the role of resisting protozoa and anaerobic bacteria. However, at present, the inhibition effect and the regulation mechanism of NTZ on bladder cancer are not reported, and the potential of NTZ as a substitute drug for bladder cancer perfusion chemotherapy is worth exploring.
The invention carries out systematic research on the in vivo and in vitro anti-bladder tumor activity of nitazoxanide, and finds that nitazoxanide or pharmaceutically acceptable salt thereof can inhibit the proliferation and the clone formation capability of different bladder tumor cell lines; leading to a decrease in mitochondrial membrane potential and increased ROS production, leading to apoptosis of bladder cancer cells; meanwhile, nitazoxanide or pharmaceutically acceptable salt thereof can effectively inhibit dryness maintenance of bladder cancer cells; the experiment of nude mice subcutaneous transplantation tumor shows that nitazoxanide or pharmaceutically acceptable salt thereof can obviously inhibit the growth of bladder cancer subcutaneous transplantation tumor.
The invention is further illustrated by the following specific examples:
nitazoxanide used in the examples of the present invention was purchased from MCE, and contained in an amount of more than 98%, and was prepared as 100mM mother liquor using DMSO, and stored at-20 ℃.
Example 1
Detecting the killing effect of nitazoxanide on bladder cancer cells
1) And in vitro bladder tumor cell culture: the bladder cancer cells used in the experiment mainly comprise UMUC-3, T24, 5637 and MGHU3 cells, wherein the UMUC-3 and T24 cells are cultured by DMEM (DMEM) culture solution containing 10% fetal calf serum and 1% double antibody, and the 5637 and MGHU3 cells are cultured by RPMI1640 culture solution containing 10% fetal calf serum and 1% double antibody at 37 ℃ and 5% CO2Cultured in an incubator. When the cells grow to 80% density, the cells are digested by pancreatin, collected by centrifugation and resuspended in culture solution, and a proper amount of cell suspension is taken for passage.
2) In vitro proliferation inhibition experiment: taking a certain number of cells (0.6X 10)4One well) was inoculated in a 96-well plate, 6 multiple wells were set for each of the control group and the experimental group, and the bladder tumor cells were treated with nitazoxanide at different concentrations after 12 hours of culture. After further incubation for 24h, 48h, 72h, 10ul CCK-8 solution was added to each well and incubated for 1h at 37 ℃. The microplate reader detects the light absorption value at the wavelength of 450 nm. Cell viability was calculated as follows: the cell viability ratio = average OD value of experimental group/average OD value of control group × 100%, and the experimental results are shown in fig. 1 a-fig. 1 d.
As can be seen from FIGS. 1a to 1d, nitazoxanide has significant inhibitory effect on various bladder tumor cell lines, and the inhibitory rate is significantly increased in a time-dependent and dose-dependent manner, wherein the inhibitory effect on 5637 and MGHU3 cell proliferation is significant. MGHU3 cells were selected for further examination of nitazoxanide for anti-bladder tumor activity.
3) Clone formation experiment: taking a certain number of cells (4X 10)5One hole) is inoculated in a 6-hole plate, a control group and an experimental group are arranged, after 12 hours of culture, MGHU3 cells are treated by nitazoxanide with different concentrations, and the culture is continued for 48 hours; the pancreas digests and digestsSuspending to obtain single cell suspension, counting the single cell suspension, re-inoculating the single cell suspension into a 6-well plate according to the cell density of 2000 cells per well, and continuously culturing for about 2 weeks. The culture solution was discarded and washed with pre-cooled PBS, fixed with 4% paraformaldehyde for 30min, stained with 1% crystal violet for 5min, and the number of cell clones formed per well was counted, with the results shown in fig. 2.
As can be seen from FIG. 2, nitazoxanide at different concentrations was able to inhibit clonogenic capacity of MGHU3 cells, and its inhibitory effect was gradually increased as the drug concentration increased.
Example 2
Detection of injury of nitazoxanide to mitochondria of bladder cancer cells
1) JC-1 staining to detect changes in cell membrane potential (MMP): taking a certain number of cells (4X 10)5One well) was inoculated in a 6-well plate, control and experimental groups were set, MGHU3 cells were treated with 60 μ M nitazoxanide after 12h of culture, and culture was continued for 6, 12, 24 h; digesting and collecting cells, washing the cells with precooled PBS, resuspending the cells with JC-1 solution (PBS preparation) with the concentration of 5 mu M, and dyeing the cells at the constant temperature of 37 ℃ for 15min in a dark place; after filtering through a 300-mesh sieve, the change of mitochondrial membrane potential MMP was detected by a Guava easyCyte type flow cytometer (JC-1 is polymer state: Ex 488nm, Em 575 nm, JC-1 is monomer state: Ex 488nm, Em 525 nm). The data were analyzed using FlowJo software and the results are shown in figure 3.
And detecting the change of mitochondrial membrane potential in the cells after nitazoxanide treatment by using a flow cytometer. The results show that, as can be seen from fig. 3, the proportion of cells with higher mitochondrial membrane potential in the drug-treated group was gradually decreased (from 96.8% to 16.2%) and showed better time dependence than the control group, indicating that the nitazoxanide treatment caused mitochondrial damage to MGHU3 cells and the mitochondrial membrane potential was decreased.
2) Detecting mitochondrial ROS production by using a mitochondrial specific fluorescent dye MitoSox: taking a certain number of cells (4X 10)5One well) was inoculated in a 6-well plate, control and experimental groups were set, MGHU3 cells were treated with 60 μ M nitazoxanide after 12h of culture, and culture was continued for 6, 12, 24 h; the cells were collected by digestion and washed with a pre-chilled HBSS/Ca/Mg solution,resuspending the cells using a final concentration of 5. mu.M MitoSox solution (HBSS/Ca/Mg configuration), and staining at 37 ℃ in the dark for 10 min; after washing the cells with the buffer solution for 2 times, the cells were filtered through a 300-mesh screen, and ROS production by the cells after nitazoxanide treatment was measured using a Guava easyCyte model flow cytometer (where Ex is 510nm and Em is 580 nm). The data were analyzed using FlowJo software and the results are shown in figure 4.
As can be seen from fig. 4, the treatment with 60 μ M nitazoxanide at different times resulted in a significant increase in red fluorescence in MGHU3 cells and a time-dependent increase, indicating that nitazoxanide caused an increase in mitochondrial ROS production in MGHU3 cells.
Example 3
Detection of nitazoxanide induced bladder cancer cell apoptosis
1) Detecting apoptosis by Annexin V-FITC/PI double staining method: taking a certain number of cells (4X 10)5One hole) is inoculated in a 6-hole plate, a control group and an experimental group are arranged, after 12 hours of culture, MGHU3 cells are treated by nitazoxanide with different concentrations, and the culture is continued for 48 hours; the cells were collected by digestion and washed with pre-cooled PBS, resuspended in PBS containing 5. mu.L Annexin V-FITC and 3. mu.L PI (500. mu.L), and stained at 37 ℃ in the dark for 15 min; after filtering through a 300-mesh screen, apoptosis was detected by a Guava easyCyte-type flow cytometer (wherein Annexin V-FITC: Ex ═ 488nm, Em ═ 525nm, PI: Ex ═ 488nm, Em ═ 620 nm). The data were analyzed using FlowJo software and the results are shown in figure 5.
As can be seen from FIG. 5, the nitazoxanide-treated group showed early apoptosis (Annexin V/PI) after double staining with Annexin V-FITC/PI, compared with the control group+/PI-) And late apoptosis (Annexin V)+ /PI+) The apoptosis rate of the cells is increased from 15.65% (30. mu.M) to 38.6% (120. mu.M) with the increase of the drug concentration.
2) And a western blot experiment is used for detecting the regulation and control effect of nitazoxanide on apoptosis-related protein: taking a certain number of cells (4X 10)5One hole) is inoculated in a 6-hole plate, a control group and an experimental group are arranged, after 12 hours of culture, MGHU3 cells are treated by nitazoxanide with different concentrations, and the culture is continued for 48 hours; digesting and collecting cells with protease and phosphatase inhibitorThe RIPA lysate is used for cracking cells to obtain total protein; after protein quantification by a BCA method, taking an equal amount of protein samples to perform SDS-PAGE gel electrophoresis and membrane transfer; after blocking, incubation with primary antibody (anti-PARP, anti-caspase3) and secondary antibody, ECL chemiluminescence was used for determination. GAPDH was chosen as the experimental internal control and the results are shown in fig. 6.
The cleavage activation form of PARP protein as cleavage substrate of Caspase as cell apoptosis core member is considered as an important index of cell apoptosis. As can be seen from FIG. 6, after nitazoxanide treatment, the levels of PARP and caspase3 in cells are decreased in a dose-dependent manner, while the amounts of the shear-activated forms, namely clear-PARP and clear-caspase 3, are increased in a dose-dependent manner, which indicates that nitazoxanide can induce the apoptosis of bladder tumor cells.
Example 4
And (3) detecting the inhibition effect of nitazoxanide on the balling capacity of the bladder cancer cells:
1) and the test method comprises the following steps: taking a certain number of cells (4X 10)5One/well) are inoculated in a 6-well plate, a control group and an experimental group are arranged, cells MGHU3 and T24 are treated by nitazoxanide with different concentrations after being cultured for 12 hours, and the cells are continuously cultured for 48 hours; trypsinizing and resuspending in serum-free medium (containing 2% B27, 20ng/ml human bFGF), and counting the cell suspension; inoculating the cells into an ultra-low adhesion cell culture plate with 6 holes according to the density of 2000 cells in each hole, and culturing for 7-10 days to form tumor cell spheres; centrifugally collecting the tumor balls, digesting by pancreatin, and re-suspending into a single cell suspension by using a serum-free culture medium; each group of cells was re-inoculated in an ultra-low adhesion 6-well plate and cultured for 7-10 days to form tumor spheres (passage 2). Images were taken under the microscope and the number of tumor spheres (greater than 30 μm) formed in each group was counted, with at least 3 replicates per group, and the results are shown in FIGS. 7a-7 c.
From fig. 7a-7c, it can be seen that in MGHU3 and T24 cells, the number of tumor cells formed in the different concentration nitazoxanide treated group was significantly reduced compared to the control group, indicating that nitazoxanide can inhibit the self-renewal ability of bladder tumor cells, i.e., inhibit the dry maintenance of bladder tumor cells.
Example 5
And (3) detecting the inhibition effect of nitazoxanide on subcutaneous transplanted bladder tumor:
1) and the test method comprises the following steps: female BALB/c nude mice used were purchased from Guangdong provincial medical laboratory animal center, and randomly divided into control and administration groups, and at least 5 nude mice per treatment group. After the mouse cells are aged 4-5 weeks, MGHU3 cells are collected by digestion, resuspended in PBS buffer, counted, and inoculated subcutaneously at the left axillary region of nude mice at a rate of about 0.8X 107And (4) cells. Tumor volume (0.5X length X width)2) Up to about 50mm3In this case, the drug was administered by the gavage method, and a solvent control group (0.2% sodium carboxymethylcellulose, hydrochloric acid adjusted to pH 2-3) and an administration group (200mg/kg nitazoxanide) were provided. The administration was performed once a day for three weeks, during which the weight of nude mice and the length and width of tumor were measured every two days. Nude mice were sacrificed 1 day after the last dose, and tumor masses were removed from each group and weighed, and the results are shown in fig. 8a-8 c.
As can be seen from FIGS. 8a-8c, the in vivo experiment in nude mice showed that in MGHU3 tumor model, the tumor volume of nitazoxanide treated group was significantly reduced to 54.2% of that of the control group, compared with the solvent control group. More importantly, the weight of the nude mice in the treatment group is not significantly different from that of the control group, and no abnormal behavior occurs, which indicates that nitazoxanide has better tolerance in vivo. These results indicate that nitazoxanide still has significant effect on bladder tumor growth in vivo.
It is to be understood that the invention is not limited to the examples described above, but that modifications and variations may be effected thereto by those of ordinary skill in the art in light of the foregoing description, and that all such modifications and variations are intended to be within the scope of the invention as defined by the appended claims.
Claims (5)
1. Use of nitazoxanide or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating bladder cancer.
2. The use according to claim 1, wherein the pharmaceutically acceptable salt comprises an inorganic acid salt, an organic acid salt.
3. The application of a pharmaceutical composition in preparing a medicament for treating bladder cancer is characterized in that the pharmaceutical composition comprises nitazoxanide or pharmaceutically acceptable salt thereof and pharmaceutically acceptable auxiliary materials.
4. The use according to claim 3, wherein the pharmaceutically acceptable excipient is one or more of a pharmaceutically acceptable solvent, a binder, a disintegrant, a flavoring agent, a coloring agent, and a preservative.
5. The use according to claim 3, wherein the pharmaceutical composition is one of a solid preparation, an injection, an external preparation, a spray, a liquid preparation and a compound preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010388532.2A CN111973593A (en) | 2020-05-09 | 2020-05-09 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010388532.2A CN111973593A (en) | 2020-05-09 | 2020-05-09 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN111973593A true CN111973593A (en) | 2020-11-24 |
Family
ID=73441805
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010388532.2A Pending CN111973593A (en) | 2020-05-09 | 2020-05-09 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN111973593A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114480562A (en) * | 2022-01-27 | 2022-05-13 | 西南医科大学附属医院 | PFOR enzyme activity guide-based FMT donor screening method and application thereof |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016062277A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Applications of anthelmintic in preparing anticancer pharmaceutical composition |
| US20160361298A1 (en) * | 2015-06-11 | 2016-12-15 | Globavir Biosciences, Inc. | Methods and compositions for treating cancer |
| CN108431017A (en) * | 2015-12-03 | 2018-08-21 | 拜欧赛特有限公司 | The salt of conjugate for cancer therapy |
-
2020
- 2020-05-09 CN CN202010388532.2A patent/CN111973593A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2016062277A1 (en) * | 2014-10-24 | 2016-04-28 | 朗齐生物医学股份有限公司 | Applications of anthelmintic in preparing anticancer pharmaceutical composition |
| US20160361298A1 (en) * | 2015-06-11 | 2016-12-15 | Globavir Biosciences, Inc. | Methods and compositions for treating cancer |
| CN108431017A (en) * | 2015-12-03 | 2018-08-21 | 拜欧赛特有限公司 | The salt of conjugate for cancer therapy |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114480562A (en) * | 2022-01-27 | 2022-05-13 | 西南医科大学附属医院 | PFOR enzyme activity guide-based FMT donor screening method and application thereof |
| CN114480562B (en) * | 2022-01-27 | 2023-09-19 | 西南医科大学附属医院 | FMT donor screening method based on PFOR enzyme activity guidance and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN117298104B (en) | Application of ELOVL6-IN-2 IN preparation of MYCN (MYCN-amplified neuroblastoma) drug | |
| CN111973593A (en) | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparation of medicines for treating bladder cancer | |
| GB2611905A (en) | Use of pyridoxal in preparation of drugs for treating ovarian cancer | |
| CN113143913A (en) | Application of eudesmane type sesquiterpene compound in preparation of anti-pancreatic cancer drugs | |
| CN115300521B (en) | Application of naringin in preparation of Sortase A sortase and PLY hemolysin inhibitor | |
| CN108295085B (en) | Application of protodioscin in preparation of drug-resistant osteosarcoma drug | |
| CN112618527B (en) | Application of small molecule in preparation of mutant type uveal melanoma medicine | |
| WO2022110568A1 (en) | Use of vitamin c and disulfiram in preparing anti-tumor combination drug | |
| CN111514133A (en) | Application of costunolide and/or dehydrocostuslactone in preparing medicine for treating melanoma | |
| CN107198685B (en) | Pharmaceutical composition for treating renal cell carcinoma and application thereof | |
| CN108186641B (en) | Application of GSK2193874 in preparing anti-glioma medicine | |
| CN115505022B (en) | Alkaloid glycoside and application thereof | |
| CN114903901A (en) | Medicine for treating intrahepatic bile duct cell cancer | |
| CN114907287B (en) | Compound for treating kidney injury | |
| CN115475166B (en) | Application, medicine and preparation method of revaprazan compound | |
| CN116211856B (en) | Application of small molecular compound Hesperadin in preparation of medicine for treating uveal melanoma | |
| CN111281872B (en) | Afatinib-containing pharmaceutical composition and application thereof | |
| CN118576606A (en) | Application of P-chiral benzophosphine cyclopentane phosphine oxide compound in preparation of medicine for preventing and/or treating polycystic kidney disease | |
| CN112142742B (en) | CTCF transcription factor inhibitor and application thereof | |
| CN114903884A (en) | Medicine for treating tumor | |
| CN114903888A (en) | Medicine for treating intrahepatic bile duct cell cancer | |
| CN114903899A (en) | Medicine for treating intrahepatic cholangiocellular carcinoma | |
| CN118178425A (en) | Application of cucurbitacin compound combined medication in treating triple negative breast cancer | |
| CN113461708A (en) | Ansamitocin P-3 derivative and application thereof in preparation of drugs for treating gastric cancer | |
| CN117618440A (en) | Application of cefradine monohydrate in preparation of cisplatin-resistant ototoxic drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201124 |