CN105560224A - Application of salinomycin to preparation of angiogenesis inhibiting medicine - Google Patents
Application of salinomycin to preparation of angiogenesis inhibiting medicine Download PDFInfo
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- CN105560224A CN105560224A CN201410848769.9A CN201410848769A CN105560224A CN 105560224 A CN105560224 A CN 105560224A CN 201410848769 A CN201410848769 A CN 201410848769A CN 105560224 A CN105560224 A CN 105560224A
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Abstract
The invention provides application of salinomycin to preparation of an angiogenesis inhibiting medicine. The salinomycin can inhibit tumor angiogenesis, arthritis lesion tissue angiogenesis, neovascular eye disease, hemangiomas lesion tissue angiogenesis, psoriasis lesion tissue angiogenesis, solid tumor lesion tissue angiogenesis, hemangiomas, Kaposi's sarcoma lesion tissue angiogenesis, leukemia, lymphoma, myeloma blood cancer and Paget's disease angiogenesis. The invention further provides a composition containing the salinomycin with the effective dose and pharmaceutically acceptable components, and application of the composition to preparation of an angiogenesis inhibiting medicine. The invention further provides application of salinomycin to preparation of a medicine for treating stomach cancer by inhibiting tumor angiogenesis.
Description
Technical field
The present invention relates to biomedicine technical field, relate to the novelty teabag of monocarboxylic acid polyethers animal specific antibiotics salt mycin, be specifically related to Salinomycin and preparing the application in anti-angiogenic drugs.
Background technology
Angiogenesis refers to that the mature blood endothelial cell previously Already in organized forms the process of new filial generation blood vessel by propagation and migration in the mode of germinateing or embed.Angiogenesis all plays a key effect in tens kinds of diseases such as cancer, rheumatoid arthritis, diabetic retinopathy, endometritis, psoriasis, leiomyoma of uterus, benign prostatauxe and inflammatory reaction and wound healing.Under normal circumstances, angiogenesis is regulated jointly by angiogenesis promotive factor and Angiostatin, and in human homergy, the two balance in order, regulates and controls mutually.In specific period, as embry ogenesis, repair in trauma and menstrual cycle etc. angiogenesis just can occur.But, when disease occurs, somatomedin is unbalance, the promotive factor of angiogenesis is expressed or acts on to be better than inhibitive factor, cause vascular remodeling, angiogenesis phenotype is formed, thus causes blood vessel undue growth thus result in pathologic angiogenesis, comprises tumor, cardiovascular disease, diabetes etc.
Tumor-blood-vessel growth, also known as neonate tumour blood vessel, refers in Tumor Growth, forms new blood vessel structure in top set of Ji Cun vascular tissue.Within 1971, Folkman proposes tumor-blood-vessel growth concept first, and thinks " tumor generates and transfer all depends on the formation of new vessels ".This theory of tumor-blood-vessel growth is confirmed by lot of experiments institute gradually.At present, how Tumor suppression angiogenesis has become study hotspot in oncotherapy and brand-new therapeutic strategy.Research finds, under the supply of nonnutritive composition and oxygen, tumor can only grow to 2-3 cubic millimeter, once there be new vessels coupled, tumor will with geometrical progression ramp, and tumor vessel is simultaneously also for tumor cell provides the path of transfer.Therefore, tumor growth all depends on new vessels with transfer.Than traditional therapeutic modality, anti-angiogenesis therapy target schedules capillary endothelium instead of the tumor itself of tumor stove, vascular endothelial cell inheritance stability, mutation probability is little, not easily develop immunity to drugs, and have the anti-tumor activity of wide spectrum, so target vascular therapy new life becomes the tempting Therapeutic Method of Therapeutic cancer and other angiogenesis dependence diseases already.Current FDA approved has gone on the market multiple anti-angiogenic drugs to treat tumor.
Salinomycin is a kind of polyethers monocarboxylic acid antibiotic, and being fermented by streptomyces albus produces, and is the medicine being used for the treatment of poultry coccidiosis of a class FDA approval.Recent study shows that Salinomycin can kill the mankind and comprise gastric cancer, the Several Kinds of Malignancy stem cell such as pulmonary carcinoma, and by the propagation of Tumor suppression stem cell, migration, infiltrate the object reaching Therapeutic cancer, but whether Salinomycin as a kind of inhibiting angiogenesis inhibitor, or can reach the object for the treatment of gastric cancer by Tumor suppression angiogenesis, there is not been reported.
Summary of the invention
The present invention's innovation proposes the application of Salinomycin in the medicine preparing angiogenesis inhibiting.
Salinomycin (Salinomycin, Sal) has another name called Salinomycin, be streptomyces albus fermentation produce polyethers monocarboxylic acid, white or light yellow crystalline powder, micro-have special smelly, fusing point 140-142 DEG C.Be soluble in acetone, chloroform, benzene, ethyl acetate, ether and methanol, water-soluble hardly.Molecular formula: C
42h
69naO
11, molecular weight: 772.9804.Molecular structural formula is such as formula shown in (I):
Salinomycin of the present invention is being prepared in the application in anti-angiogenic drugs, and described medicine includes but not limited to the medicine suppressing animal blood vessels new life.Wherein, described animal includes but not limited to vertebrates etc.Wherein, described animal includes but not limited to people, Mus, other mammals, other animals etc.Described angiogenesis includes but not limited to neonate tumour blood vessel, pathological tissues angiogenesis etc.
Described medicine comprises the medicine for the treatment of neonate tumour blood vessel, comprises the medicine for the treatment of hemangioma, solid tumor pathological tissues angiogenesis.Wherein, hemangioma comprises angiomatosis, hemangioblastoma and some other non-malignant vascular proliferative disease, solid tumor comprises constitutional and insecondary solid tumor, comprises Kaposi ' s sarcoma, the medicine of leukemia, lymphoma, myeloma blood cancer and Paget ' s disease; The medicine of the angiogenesis for the treatment of rheumatoid arthritis and inflammatory arthritis pathological tissues; The medicine for the treatment of neovascular eye diseases, comprise treatment neovascular keratopathy, diabetic retinopathy, retinal vein occlusion, retinopathy of prematurity, retinal arterial obstruction, angiogenic Iris diseases, neovascular glaucoma, neovascular optic nerve disease, neovascular vitreous body oculopathy, neovascular conjunctiva oculopathy and the cataractous medicine of generation vascular type; The medicine for the treatment of psoriatic lesions tissue blood vessel new life.Refer to that Salinomycin is preparing the application in the neovascularization diseases such as Tumor suppression angiogenesis, ophthalmic diseases, rheumatoid arthritis, hemangioma, psoriasis, duodenal ulcer especially.
The invention allows for Salinomycin to suppress the cell proliferation of human umbilical vein of VEGF induction, migration in preparation and/or become the application in the medicine of pipe.Described Salinomycin can be used as the inhibitor suppressing the cell proliferation of human umbilical vein of VEGF induction, migration and/or become pipe.The invention allows for the cell proliferation of human umbilical vein, the migration that suppress VEGF induction and/or become the method for pipe.
The invention allows for the application of Salinomycin in the medicine of new vessels formation preparing mouse stromal glue bolt.Described Salinomycin can be used as the inhibitor suppressing the new vessels of mouse stromal glue bolt to be formed.The invention allows for the method suppressing mouse stromal glue bolt new vessels to be formed.
The invention allows for Salinomycin and to be treated application in the medicine of gastric cancer in preparation by angiogenesis inhibiting.
The invention allows for a kind of compositions.Described compositions comprises pharmaceutical composition.Described compositions comprises Salinomycin containing effective dose and pharmaceutically acceptable composition.Comprise pharmaceutically acceptable carrier and/or adjuvant etc.In a particular embodiment, such as, described compositions is respectively: in 0.5%FBS culture medium, add final concentration is 50ng/mLVEGF, then adds 0.5,1,2.5,5 μm of ol/L Salinomycin respectively, forms the compositions containing variable concentrations Salinomycin.In a specific embodiment, described compositions comprises 100ngVEGF and 15 μ g Salinomycins; In another embodiment, described compositions comprises 100ngVEGF and 30 μ g Salinomycins.In mice experiments in vivo embodiment, described compositions comprises 3mg/kg//2 days Salinomycins; In another embodiment, described compositions comprises 5mg/kg//2 days Salinomycins.
The Salinomycin that the present composition comprises treatment effective dose and any one or the multiple auxiliary materials that pharmaceutically allow.The present composition can also comprise and adds other anti-angiogenic drugs that other and Salinomycin do not have antagonism.One or more pharmaceutically acceptable carriers can be added in the compositions/medicine of angiogenesis inhibiting of the present invention.The preparation of described compositions can be any one dosage form pharmaceutically, includes but not limited to last agent, powder, tablet, pill, drop, granule, suspending agent, solution, capsule, sugar-coat agent, oral liquid, injection, liposome, sublingual lozenge etc.Its use approach comprises but does not limit local topical, subcutaneous, vein, lumbar injection and the mode such as oral.
In a particular embodiment, Salinomycin all has obvious inhibitory action in Human umbilical vein endothelial cells (HUVEC) proliferation experiment, the migration of external cut experiment, micro-tube formation assay, the experiment of matrigel bolt etc., and experiment shows that Salinomycin can be applicable to prepare the medicine of angiogenesis inhibiting.In a particular embodiment, the Salinomycin growth of gastric cancer and angiogenesis of tumor in the experiment of bare mouse different species lotus tumor all have obvious inhibitory action, and experiment shows that Salinomycin can be applicable to be treated by angiogenesis inhibiting the medicine of gastric cancer.
Accompanying drawing explanation
Figure 1 shows that Salinomycin suppresses Human umbilical vein endothelial cells (HUVEC) propagation of VEGF induction.
Figure 2 shows that Salinomycin suppresses Human umbilical vein endothelial cells (HUVEC) migration of VEGF induction.
Figure 3 shows that Salinomycin suppresses the Human umbilical vein endothelial cells (HUVEC) of VEGF induction to become pipe.
Figure 4 shows that Salinomycin suppresses the new vessels of mouse stromal glue bolt to be formed.
Figure 5 shows that Salinomycin suppresses the growth of gastric cancer.
Figure 6 shows that Salinomycin suppresses the angiogenesis of gastric cancer.
All represent that there were significant differences with p<0.05 in each accompanying drawing, *, p<0.05; *, p<0.01; * *, p<0.001.
Detailed description of the invention
In conjunction with following specific embodiments and the drawings, the present invention is described in further detail, and protection content of the present invention is not limited to following examples.Under the spirit and scope not deviating from inventive concept, the change that those skilled in the art can expect and advantage are all included in the present invention, and are protection domain with appending claims.Implement process of the present invention, condition, reagent, experimental technique etc., except the following content mentioned specially, be universal knowledege and the common practise of this area, the present invention is not particularly limited content.In the present invention, used salt mycin is purchased from sigma company.
Embodiment 1: Salinomycin suppresses Human umbilical vein endothelial cells (HUVEC) propagation of VEGF induction
Object and principle: endothelial cell proliferation experiment adopts MTSassay.MTSassay is a kind of assay method using colorimetry indirect inspection living cells quantity.CellTiter
the mono-solution reagent of Aqueous comprises a kind of tetrazole compound (inner salt; MTS) and one electronics coupled reagent (second sulfur azophenlyene; PES).MTS can be had dehydrogenase effect in metabolic active cells to generate the granule dissolving in tissue culture medium (TCM), and the light absorption value measuring product at 490nm is directly proportional to the quantity of living cells in culture.
Method: be that 5000/hole is inoculated in 96 orifice plates according to density by cell, every hole 100 μ L, at the 5%CO of 37 DEG C
2cell attachment is cultured in case.Leave standstill cell pellet overnight by the culture medium of 1%FBS, make cell major part be in G
0phase.Next day, change fresh culture (culture medium of 1%FBS), test is set up separately: matched group (culture medium of 0.5%FBS), VEGF group (adding the VEGF that final concentration is 50ng/mL in the culture medium of 0.5%FBS) and Salinomycin medicine group (adding the Salinomycin that final concentration is 0.5,1,2.5 and 5 μm of ol/L on the basis of VEGF group), often organize repetition 5 hole.After 72 hours, utilize MTS method, operate in strict accordance with test kit (being purchased from Promega company of the U.S.) description.Using control group cell survival rate as 100%, press for all the other each group: survival rate percentage ratio=(each concentration group light absorption value/matched group light absorption value) × 100% compares with it, mapping.
Result and evaluation: as shown in Figure 1, compared with matched group, the multiplication capacity of the Human umbilical vein endothelial cells under VEGF induction is suppressed, and shows under angiogenesis state, and Salinomycin suppresses the propagation of Human umbilical vein endothelial cells.
Embodiment 2: Salinomycin suppresses Human umbilical vein endothelial cells (HUVEC) migration of VEGF induction
Object and principle: under the effect of vascular endothelial cell growth factor (VEGF), Human umbilical vein endothelial cells can be moved to scored area.By observing the endotheliocyte amount in cut district of moving into, evaluating Salinomycin and whether there is the ability suppressing Human umbilical vein endothelial cells migration.
Method: HUVEC cell is inoculated in 6 orifice plates of 0.1% gelatin bag quilt, treats that cell reaches 90% coverage rate, leave standstill cell pellet overnight by the culture medium of 0.1%FBS, make cell major part be in G
0phase.The aseptic rifle head of secondary daily 1mL, at hole central authorities mark signature reticule, then, sucks culture medium, with aseptic PBS cleaning twice.Test is set up separately: matched group (culture medium of 1%FBS), VEGF group (adding the VEGF that final concentration is 50ng/mL in the culture medium of 1%FBS) and Salinomycin medicine group (adding 2.5 and 5 μm of ol/L Salinomycins respectively on the basis of VEGF group).At 37 DEG C, 5%CO
2cultivate 8-10h, treat that VEGF group dashed part heals.Abandon original fluid, PBS cleans, and with 4% paraformaldehyde fixed cell 20min, observes under inverted microscope.At decussation immediate vicinity, taking pictures in random selecting 3 visuals field, carries out cell counting.Using cellular control unit mobility as 100%, all the other are respectively organized migration percentage ratio=(each drug level group migrating cell number/matched group migrating cell number) × 100% and compare with it, mapping.
Result and evaluation: examine under a microscope and take pictures, as shown in Figure 2, result display is compared with VEGF group, and the migration of Human umbilical vein endothelial cells is obviously suppressed, and shows the migration of the Human umbilical vein endothelial cells that Salinomycin can suppress VEGF to induce.
Embodiment 3: Salinomycin suppresses Human umbilical vein endothelial cells (HUVEC) to become pipe
Object and principle: Matrigel is the basement membrane extract of the solubility that extracting obtains from murine sarcoma.Be rich in extracellular matrix protein, Human umbilical vein endothelial cells can attach into pipe on Matrigel, and this one-tenth pipe characteristic of Human umbilical vein endothelial cells on Matrigel can be utilized to carry out drugs to angiopoietic impact.
Method: Matrigel4 DEG C is spent the night thaw in advance, then draw 100 μ L and be laid in bottom 48 orifice plates, be positioned over 37 DEG C, make it fully be polymerized and solidify.Digestion HUVECs cell, is resuspended in the culture medium of 1%FBS, with 8 × 10
4cell number is inoculated in plate.Test is set up separately: matched group and Salinomycin (2.5 μm of ol/L and 5 μm ol/L) group.This plate is put in 37 DEG C, 5%CO
2cultivate 8-10h, visible matched group endotheliocyte forms obvious little tubular structure.This structure 4% paraformaldehyde to be fixed, observation of taking pictures under being placed in inverted microscope, amplification is 100 ×.
Result and evaluation: as shown in Figure 3, Human umbilical vein endothelial cells grows in Matrigel, and individual cells extends in Matrigel, forms tridimensional network.Compared with matched group, endothelium becomes pipe process to be affected, and three-dimensional net structure is damaged, and shows that Salinomycin can suppress Human umbilical vein endothelial cells microtubule to be formed.
Embodiment 4: Salinomycin suppresses the new vessels of the mouse stromal glue bolt of VEGF induction to be formed
Object and principle: matrigel bolt (Matrigelplug) model is the screening model that ideal domestic and international screening angiogenesis class medicine is generally acknowledged at present.The matrigel of drug containing is placed in the subcutaneous avascular area of mouse web portion, can be observed the impact of medicine on new Angiogenesis.
Method: 6 week age male C57BL/6, be divided into 4 groups at random, often organize 5 (n=5), be respectively matched group (PBS), VEGF group (heparin containing 100ngVEGF and 20 unit) and Salinomycin group (adding 15 μ g and 30 μ g Salinomycins on the basis of VEGF group respectively).By the drug solution mix homogeneously on ice of 0.5mLMatrigel and various dose, inject on the left of mouse web portion subcutaneous.After 7d, intraperitoneal anesthesia mice, surgical incision abdominal cavity skin, separate subcutaneous complete matrix gel ball, PBS rinses well.Take pictures, and fix with 4% paraformaldehyde in time, specimens paraffin embedding slices.Carry out immunohistochemical staining with CD31, make a video recording (picture approach multiple is 200 ×) under microscope, quantitatively penetrate into the formation of neovascularity in matrix gel ball with LeicaQ550IW image analyzer.
Result and evaluation: as shown in Figure 4, experimental group compares with negative control group, and VEGF has the facilitation of strong Angiogenesis, compared with positive controls, new Angiogenesis is suppressed, and shows that Salinomycin can suppress the generation of the neovascularity of mouse stromal glue bolt.
Embodiment 5: Salinomycin suppresses the growth of gastric cancer and the angiogenesis of tumor
Object and principle: nude mice is Immune deficient mice, cancerous cell immune system of can escaping constantly is bred at nude mice by subcutaneous and is formed new tumor, is to study tumor growth and the ideal model of angiogenesis at present.Medication after the subcutaneous lotus tumor of mice, can observe the growth inhibited of tumor, and model can observe Agiogenesis inhibition after setting up.
Method: 6 week age, male BALB/C nude mice was purchased from Ningxia Experimental Animal Center, and body weight is about 20g.Nude mice is divided into 3 groups at random, often organizes 10.Cultivate SGC-7901 cells, get well-grown cell, after trypsinization, with counting chamber counting, concentration is adjusted to 3.5 × 10
6the every 100 μ L of individual cell, be placed on ice, and it are subcutaneous to be slowly inoculated in mouse back.Treating that entity tumor grows to size is 100mm
3time, start to carry out the treatment of various dose Salinomycin.According to dosage 3mg/kg/ and 5mg/kg/ lumbar injection administration every other day, continuous 28 days, and the change of periodic monitor Mouse Weight and entity tumor volume.The mensuration of tumor utilizes slide gauge, according to formula A × B
2× 0.52 calculates gross tumor volume, and wherein A represents most long portion position diameter (major diameter) of tumor, and B represents tumor the shortest position diameter (minor axis).Treat that medicine group gross tumor volume is greater than 1500mm
3time, nude mice anesthesia is put to death.After nude mice is put to death, the skin that peeling operation tumor and tumor depend on, takes pictures.
Result and evaluation: see shown in Fig. 5, Fig. 6.As shown in Figure 5, experimental group and matched group compare, and the volume of tumor obviously reduces.As shown in Figure 6, the vessel density around the tumor of experimental group is starkly lower than matched group.As shown in Figure 5, Figure 6, along with the increase of drug level, the volume of tumor and the density of blood vessel reduce.Show that Salinomycin can suppress the growth of gastric cancer and the angiogenesis of tumor.
Claims (10)
1. the application of Salinomycin in the medicine preparing angiogenesis inhibiting, is characterized in that, described Salinomycin is such as formula shown in (I):
2. application according to claim 1, is characterized in that, described medicine comprises the medicine suppressing animal blood vessels new life.
3. application according to claim 1, is characterized in that, described angiogenesis comprises neonate tumour blood vessel, pathological tissues angiogenesis.
4. application according to claim 1, it is characterized in that, described angiogenesis comprises: the angiogenesis of leukemia, lymphoma, myeloma blood cancer, Kaposi ' s sarcoma pathological changes tissue blood vessel new life, Paget ' s disease angiogenesis, hemangioma, hemangioma pathological changes tissue blood vessel new life, solid tumor pathological tissues angiogenesis, angiomatosis, hemangioblastoma, non-malignant vascular proliferative, arthritis pathological changes tissue blood vessel new life, angiogenic oculopathy, psoriatic lesions tissue blood vessel new life.
5. Salinomycin to treat the application in the medicine of gastric cancer by angiogenesis inhibiting in preparation.
6. the application of Salinomycin in the medicine preparing the cell proliferation of human umbilical vein of suppression VEGF induction, migration, one-tenth pipe.
7. the application of Salinomycin in the medicine of new vessels formation preparing mouse stromal glue bolt.
8. a compositions, is characterized in that, described compositions comprises Salinomycin containing effective dose and pharmacy can accept composition.
9. the application of compositions in the medicine preparing angiogenesis inhibiting as claimed in claim 7.
10. as claim 1 ~ 7,9 any one as described in application, it is characterized in that, the dosage form of described medicine comprises last agent, powder, tablet, pill, drop, granule, suspending agent, solution, capsule, sugar-coat agent, oral liquid, injection, liposome, sublingual lozenge.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2022234040A1 (en) * | 2021-05-05 | 2022-11-10 | Centre National De La Recherche Scientifique (Cnrs) | Nitrogen-containing analogs of salinomycin for use in multiple myeloma (mm) |
| CN116570584A (en) * | 2023-05-08 | 2023-08-11 | 广州白云山医药集团股份有限公司白云山制药总厂 | Application of salinomycin in preparing medicament for reducing uric acid and/or treating hyperuricemia |
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| CN102188418A (en) * | 2010-03-05 | 2011-09-21 | 王毅 | Application of salinomycin in preparing medicament for resisting various human malignant tumors |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN102188418A (en) * | 2010-03-05 | 2011-09-21 | 王毅 | Application of salinomycin in preparing medicament for resisting various human malignant tumors |
Non-Patent Citations (3)
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| TAO LI等: "Salinomycin exerts anti-angiogenic and anti-tumorigenic activities by inhibiting vascular endothelial growth factor receptor 2-mediated angiogenesis", 《ONCOTARGET》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022234040A1 (en) * | 2021-05-05 | 2022-11-10 | Centre National De La Recherche Scientifique (Cnrs) | Nitrogen-containing analogs of salinomycin for use in multiple myeloma (mm) |
| CN116570584A (en) * | 2023-05-08 | 2023-08-11 | 广州白云山医药集团股份有限公司白云山制药总厂 | Application of salinomycin in preparing medicament for reducing uric acid and/or treating hyperuricemia |
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Application publication date: 20160511 |