CN111888348A - Application of glucose transporter 1 inhibitor WZB117 in preparation of drugs for treating cystic echinococcosis - Google Patents
Application of glucose transporter 1 inhibitor WZB117 in preparation of drugs for treating cystic echinococcosis Download PDFInfo
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- CN111888348A CN111888348A CN202010733537.4A CN202010733537A CN111888348A CN 111888348 A CN111888348 A CN 111888348A CN 202010733537 A CN202010733537 A CN 202010733537A CN 111888348 A CN111888348 A CN 111888348A
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- albendazole
- echinococcus granulosus
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- FRSWCCBXIHFKKY-UHFFFAOYSA-N [3-fluoro-2-(3-hydroxybenzoyl)oxyphenyl] 3-hydroxybenzoate Chemical compound OC1=CC=CC(C(=O)OC=2C(=C(F)C=CC=2)OC(=O)C=2C=C(O)C=CC=2)=C1 FRSWCCBXIHFKKY-UHFFFAOYSA-N 0.000 title claims abstract description 177
- 201000003808 Cystic echinococcosis Diseases 0.000 title claims abstract description 118
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- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
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- 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
- A61K31/4164—1,3-Diazoles
- A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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Abstract
The invention relates to the technical field of echinococcosis drugs, in particular to an application of a glucose transporter 1 inhibitor WZB117 in preparing a drug for treating cystic echinococcosis; the invention discloses the application of WZB117 in preparing a medicament for treating cystic echinococcosis for the first time; pharmacodynamic experimental data in vivo and in vitro indicate that the WZB117 is a high-efficiency echinococcosis resisting drug molecule, has obvious treatment effect on cystic echinococcosis, and has better effect than albendazole sulfoxide serving as a metabolite; the combination of the WZB117 and the albendazole sulfoxide has better synergistic treatment effect, and the effect is obviously better than that of the single administration of the WZB117 and the single administration of the albendazole sulfoxide; meanwhile, the dosage of the WZB117 combined with albendazole sulfoxide is reduced by 1/3-1/2 compared with the dosage of the albendazole sulfoxide alone, so that the dosage and the drug resistance problem are greatly reduced, a good treatment effect is achieved, and the albendazole compound can be used as an effective substitute for the existing albendazole.
Description
Technical Field
The invention relates to the technical field of echinococcosis drugs, in particular to application of a glucose transporter 1 inhibitor WZB117 in preparation of a drug for treating cystic echinococcosis.
Background
Cystic Echinococcosis (CE) is caused by Echinococcus granulosus (Echinococcus granulosus)Echinococcus granulosus) The larva parasitizes chronic parasitic diseases caused by livestock such as cattle and sheep or human bodies. The disease is distributed globally, China is mainly concentrated in northwest farming and animal husbandry areas, the number of threatened people reaches 6600 ten thousand, economic loss exceeds 30 million yuan each year, the disease is a serious public health problem which is concerned, and the disease is listed in a national free rescue plan in 2006.
The treatment means of cystic echinococcosis mainly comprises surgical treatment and drug therapy, but the surgical treatment has the problems of high risk and recurrence rate and the like, and the drug therapy becomes the first choice for some patients who are not suitable for surgical treatment. The first drug recommended by WHO for treating echinococcosis is albendazole, which is rapidly absorbed in gastrointestinal tract, metabolized in liver to albendazole sulfoxide and albendazole sulfone, and then permeates back to intestine and stomach, wherein albendazole sulfone has no insecticidal effect and plays a main role in albendazole sulfoxide. Because albendazole sulfoxide is easily oxidized to albendazole sulfone, the clinically applied drug is albendazole instead of albendazole sulfoxide. Years of clinical use and animal in-vivo and in-vitro culture experiments prove that the medicament is effective to the echinococcosis. Albendazole sulfoxide can inhibit the activity of malate dehydrogenase, cause the obstruction of glycolysis pathway of insect body and reduce energy storage. Simultaneously influences the structure and the function of the tubulin, and the microstructure and the function of the tubulin are lost due to high affinity and irreversible property in the process of combining the tubulin. However, the benzimidazole drugs have the problems of low blood concentration, poor intestinal absorption, large individual difference, long-term administration, possible echinococcus granulosus drug resistance and the like, and the treatment effect is still unsatisfactory. Therefore, the research and development of new echinococcosis drugs are of great significance.
Glucose transporter 1 (GLUT 1) inhibitors are in a wide variety, and common GLUT1 inhibitors include WZB117, STF-31, BAY-876, and some small molecule inhibitors of natural origin. The inhibitor can be combined with GLUT1 to inhibit glucose transport function of GLUT1, and has good therapeutic effect on breast cancer, colon cancer, lung cancer, etc.
WZB117 (glucose transporter 1 inhibitor WZB 117) is capable of inhibiting glucose transport in human erythrocytes and reducing the expression of GLUT1 in cancer cells, resulting in decreased intracellular ATP and glycolytic enzyme levels. Animal experiments show that the medicine has good therapeutic effect on the growth of tumors such as colon cancer, breast cancer, lung cancer and the like, and has low toxicity; however, no report is available about WZB117 (glucose transporter 1 inhibitor WZB 117) as a drug for treating cystic echinococcosis.
Disclosure of Invention
The invention provides application of a glucose transporter 1 inhibitor WZB117 in preparation of a drug for treating cystic echinococcosis, which can effectively solve the problem that no glucose transporter 1 inhibitor WZB117 is used as a drug for treating cystic echinococcosis at present; meanwhile, the benzimidazole medicine has the problems of poor intestinal absorption, long-term administration and easy generation of drug resistance, so that the treatment effect is unsatisfactory.
The technical scheme of the invention is realized by the following measures: an application of glucose transporter 1 inhibitor WZB117 in preparing the medicines for treating cystic echinococcosis is disclosed.
The following is further optimization or/and improvement of the technical scheme of the invention:
the above also includes albendazole, the glucose transporter 1 inhibitor WZB117 and albendazole in combination.
The mass ratio of the glucose transporter 1 inhibitor WZB117 to the albendazole is 1: 8 to 1: 1.
the invention discloses the application of a glucose transporter 1 inhibitor WZB117 in preparing a medicament for treating cystic echinococcosis for the first time; pharmacodynamic experimental data in vivo and in vitro indicate that the glucose transporter 1 inhibitor WZB117 is a high-efficiency echinococcosis drug molecule, can destroy the echinococcus granulosus vesicle tissue structure, causes massive necrosis of echinococcus granulosus vesicle cells, has a remarkable treatment effect on cystic echinococcosis, and has an effect superior to that of albendazole sulfoxide which is a metabolite of albendazole; the glucose transporter 1 inhibitor WZB117 combined with albendazole sulfoxide has better synergistic treatment effect, and the effect of the glucose transporter 1 inhibitor WZB117 combined with albendazole sulfoxide is obviously better than that of the glucose transporter 1 inhibitor which is singly administered and the albendazole sulfoxide which is singly administered; meanwhile, the dosage of the glucose transporter 1 inhibitor WZB117 combined with albendazole sulfoxide is reduced by 1/3-1/2 compared with the dosage of the albendazole sulfoxide alone, so that the dosage and the drug resistance problem are greatly reduced, a good treatment effect is achieved, and the glucose transporter 1 inhibitor WZB combined with albendazole sulfoxide can be used as an effective substitute and combined medicament of the existing albendazole.
Drawings
FIG. 1 is a graph of the survival rate (viatility) of Echinococcus granulosus (PSCs) in vitro intervention with WZB 117.
FIG. 2 is a scanning electron micrograph of Echinococcus granulosus metacercaria of DMSO group.
FIG. 3 is a scanning electron micrograph of Echinococcus granulosus metacercaria by ABZSO group.
FIG. 4 is a scanning electron micrograph of Echinococcus granulosus metacercaria in the WZB117 dried group 1.
FIG. 5 is a scanning electron micrograph of Echinococcus granulosus metacercaria in the WZB117 dried group 2.
FIG. 6 is a scanning electron micrograph of Echinococcus granulosus metacercaria in the WZB117 dried group 3.
FIG. 7 is a graph of the survival (viatility) of Echinococcus granulosus vesicles (Cysts) following in vitro intervention with WZB 117.
FIG. 8 is a scanning electron micrograph of Echinococcus granulosus vesicles from the set of DMSO groups.
FIG. 9 is a scanning electron micrograph of an ABZSO group versus Echinococcus granulosus vesicle.
FIG. 10 is a scanning electron micrograph of Echinococcus granulosus vesicles from WZB117 dried group 1.
FIG. 11 is a scanning electron micrograph of Echinococcus granulosus vesicles from WZB117 dried group 2.
FIG. 12 is a scanning electron micrograph of Echinococcus granulosus vesicles from WZB117 dried group 3.
FIG. 13 is an electron micrograph of Echinococcus granulosus vesicles from the solvent set.
FIG. 14 is an electron micrograph of an ABZ set of Echinococcus granulosus vesicles.
FIG. 15 is an electron micrograph of WZB117 high dose panels versus Echinococcus granulosus vesicles.
FIG. 16 is an electron micrograph of Echinococcus granulosus vesicles at low dose set of WZB 117.
FIG. 17 is a graph of the survival rate (viatility) of Echinococcus granulosus (PSCs) in vitro intervention with WZB117, ABZSO, WZB117 in combination with ABZSO.
Detailed Description
The invention is not limited by the following examples, and the specific implementation manner can be determined according to the technical scheme and the actual situation of the invention; in the invention, the glucose transporter 1 inhibitor WZB117, albendazole sulfoxide and dimethyl sulfoxide are all known and used in the prior art; in the invention, the glucose transporter 1 inhibitor WZB117 is abbreviated as WZB117, albendazole is abbreviated as ABZ, albendazole sulfoxide is abbreviated as ABZSO, and dimethyl sulfoxide is abbreviated as DMSO.
Example 1 use of the glucose transporter 1 inhibitor WZB117 for the preparation of a medicament for the treatment of cystic echinococcosis.
Example 2, which is an optimization of the above examples, further comprises albendazole, the glucose transporter 1 inhibitor WZB117, and albendazole in combination.
Example 3, as an optimization of the above example, the mass ratio of the glucose transporter 1 inhibitor WZB117 to albendazole was 1: 8 to 1: 1.
the application of the glucose transporter 1 inhibitor WZB117 in preparing the medicine for treating the cystic echinococcosis is tested as follows:
in vitro assay for glucose transporter 1 inhibitor WZB117
1.1 WZB117 in vitro assay
1.1.1 Experimental purposes: explore the survival rate of the echinococcus granulosus protozoon and the vesicle at each concentration of the WZB117 with the experimental period of 4 days
1.1.2 Experimental groups (overview)
The experiment is divided into 9 groups, namely a WZB117 intervention group 1, a WZB117 intervention group 2, a WZB117 intervention group 3, a WZB117 intervention group 4, a WZB117 intervention group 5, a WZB117 intervention group 6, an ABZSO group, a negative group and a DMSO group; each group is provided with 3 multiple holes; the experimental period was set for 4 days.
1.1.3 mother liquor preparation
1.8416mg of WZB117 is weighed and dissolved in 500 mul of DMSO, and mother liquor (i) is prepared (the concentration is 10 mM) by mixing evenly; taking 50 mul of mother liquor, adding 50 mul of DMSO to obtain mother liquor II; taking 50 mu l of mother liquor, adding 50 mu l of DMSO to obtain mother liquor; taking 50 mu l of mother liquor, adding 50 mu l of DMSO to obtain mother liquor; taking 50 mul of mother liquor, adding 50 mul of DMSO to obtain mother liquor; taking 50 mul of mother liquor, adding 50 mul of DMSO to obtain mother liquor; 0.2110mg albendazole sulfoxide is weighed and dissolved in 500 mul DMSO, and the albendazole sulfoxide suspension mother solution (the concentration is 1.5 mM) is prepared by mixing evenly.
1.1.4 preparation of Echinococcus granulosus culture solution
Adding fetal bovine serum and double antibodies into an RPMI1640 culture medium, and uniformly mixing to obtain an echinococcus granulosus culture solution, wherein the volume percentage of fetal bovine serum in the echinococcus granulosus culture solution is 25%, and the volume percentage of the double antibodies in the echinococcus granulosus culture solution is 1%.
1.1.5 preparation of Echinococcus granulosus metacercaria and vesicles
Echinococcus granulosus metacercaria was obtained aseptically from the liver of a sheep naturally infected with Echinococcus granulosus in the Uygur woodii Hualing slaughterhouse of Xinjiang. After being digested by 1% pepsin for 30min, the mixture is washed for a plurality of times by sterile normal saline added with 2% streptomycin, and after the mixture is naturally precipitated, the supernatant is sucked off and is cultured aseptically. The prototheca miracidium is cultured in vitro aseptically for 4 months, and vesicles with the diameter of about 2mm to 3mm can be obtained. The culture conditions were 37 ℃ and 5% CO2The cell culture chamber (2) was further filled with the culture solution 1 time every 5 days.
1.1.6 configurations of WZB117 intervention group 1, WZB117 intervention group 2, WZB117 intervention group 3, WZB117 intervention group 4, WZB117 intervention group 5, WZB117 intervention group 6, ABZSO group, negative group and DMSO group
The echinococcus granulosus protocoenurus is prepared in groups: mu.l of mother liquor (r) is added to 198. mu.l of Echinococcus granulosus culture solution and mixed to obtain a dry group 1 of WZB117 (100. mu. mol/L WZB 117); mu.l of mother liquor (2 mu.l) is added into 198 mu.l of echinococcus granulosus culture solution and mixed evenly to obtain a WZB117 dry group 2 (50 mu mol/L WZB 117); mu.l of mother solution (2. mu.l) is added into 198. mu.l of echinococcus granulosus culture solution and mixed evenly to obtain a WZB117 dry group 3 (25. mu. mol/L WZB 117); mu.l of mother liquor (4) of WZB117 dry group (12.5. mu. mol/L WZB 117) is obtained after adding 2. mu.l of mother liquor (r) into 198. mu.l of Echinococcus granulosus culture solution and mixing uniformly; adding 2 mul of mother liquor into 198 mul of echinococcus granulosus culture solution, and mixing to obtain WZB117 dry group 5 (6.25 mul mol/LWZB 117); adding 2 mul of mother solution into 198 mul of echinococcus granulosus culture solution, and mixing to obtain WZB117 dried group 6 (3.125 mul/L WZB 117); mu.l (with the concentration of 1.5 mM) albendazole sulfoxide suspension is added into 198 mu.l of echinococcus granulosus culture solution, and after uniform mixing, albendazole sulfoxide group (ABZSO group) (15 mu mol/L ABZSO) is obtained; obtaining a negative group by taking 200 mu L of echinococcus granulosus culture solution; mu.l of Echinococcus granulosus culture solution was added to 2. mu.l of DMSO and mixed to obtain a DMSO group.
The echinococcus granulosus vesicles are arranged in groups: mu.l of mother liquor (r) is added to 1980. mu.l of Echinococcus granulosus culture solution and mixed to obtain WZB117 dry group 1 (100. mu. mol/L WZB 117); mu.l of mother liquor (20. mu.l) is added to 1980. mu.l of Echinococcus granulosus culture solution and mixed to obtain a WZB117 dry group 2 (50. mu. mol/L WZB 117); mu.l of mother liquor (20. mu.l) is added to 1980. mu.l of Echinococcus granulosus culture solution and mixed to obtain a WZB117 dry group 3 (25. mu. mol/L WZB 117); adding 20 mul of mother liquor (R) into 1980 mul of Echinococcus granulosus culture solution, and mixing to obtain WZB117 dry group 4 (12.5 mul/LWZB 117); adding 20 μ L of mother liquor to 1980 μ L of Echinococcus granulosus culture solution, and mixing to obtain WZB117 dry group 5 (6.25 μmol/L WZB 117); adding 20 mul of mother solution into 1980 mul of echinococcus granulosus culture solution, and mixing to obtain WZB117 dry pre-group 6 (3.125 mul/L WZB 117); adding 20 μ l (1.5 mM) albendazole sulfoxide suspension into 1980 μ l echinococcus granulosus culture solution, and mixing to obtain albendazole sulfoxide group (ABZSO group) (15 μmol/LABZSO); obtaining a negative group by taking 2000 mu L of echinococcus granulosus culture solution; mu.l of DMSO was added to 1980. mu.l of Echinococcus granulosus culture medium and mixed to give a DMSO group.
1.1.7 Experimental procedures
Taking the metacercaria cultured in vitro for 2d, and paving the metacercaria on a 96-well plate according to 250-300 heads/well, wherein each group is provided with 3 multiple wells. Then, WZB117 run-on 1 (100. mu. mol/L WZB 117), WZB117 run-on 2 (50. mu. mol/L WZB 117), WZB117 run-on 3 (25. mu. mol/L WZB 117), WZB117 run-on 4 (12.5. mu. mol/L WZB 117), WZB117 run-on 5 (6.25. mu. mol/LWZB 117), WZB117 run-on 6 (3.125. mu. mol/L WZB 117), ABZSO (15. mu. mol/L ABZSO), Negative (NC) and DMSO groups were added and mixed, respectively.
Echinococcus granulosus vesicles 2mm to 3mm in diameter were added to 6-well plates, 20 to 30 Echinococcus granulosus vesicles per well, and WZB117 dry run 1 (100. mu. mol/L WZB 117), WZB117 dry run 2 (50. mu. mol/L WZB 117), WZB117 dry run 3 (25. mu. mol/LWZB 117), WZB117 dry run 4 (12.5. mu. mol/L WZB 117), WZB117 dry run 5 (6.25. mu. mol/L WZB 117), WZB117 dry run 6 (3.125. mu. mol/L WZB 117), ABZSO group (15. mu. mol/L ABZSO), negative group (DMSO), and 3 duplicate wells were set up for each experimental group, and the time to change the well plate design for this experiment (0 day is calculated for convenience). On the 4 th day, the experiment period is 4 days, and the in-hole photographic experiment observation is carried out, and then the metacercaria and the vesicle ultrastructure are observed by a scanning electron microscope and a transmission electron microscope.
The survival rate (viatility) of Echinococcus granulosus (PSCs) after day 4 in vitro intervention with WZB117 is shown in FIG. 1; the scanning electron micrograph of Echinococcus granulosus metacercaria by DMSO group after day 4 is shown in FIG. 2; the scanning electron micrograph of the ABZSO group on Echinococcus granulosus metacercaria after day 4 is shown in FIG. 3; the scanning electron micrograph of WZB117 dried control group 1 against Echinococcus granulosus metacercaria after day 4 is shown in FIG. 4; the scanning electron micrograph of WZB117 dried control group 2 against Echinococcus granulosus metacercaria after day 4 is shown in FIG. 5; the scanning electron micrograph of WZB117 dried control group 3 against Echinococcus granulosus metacercaria after day 4 is shown in FIG. 6; the survival (viatility) of echinococcus granulosus vesicles (Cysts) following WZB117 in vitro intervention is shown in figure 7; a scanning electron micrograph of the echinococcus granulosus vesicles from the DMSO group after day 4 is shown in fig. 8; a scanning electron micrograph of the ABZSO group of echinococcus granulosus vesicles after day 4 is shown in fig. 9; scanning electron micrographs of WZB117 dried group 1 on Echinococcus granulosus vesicles after day 4 are shown in FIG. 10; scanning electron micrographs of WZB117 dried group 2 on Echinococcus granulosus vesicles after day 4 are shown in FIG. 11; scanning electron micrographs of echinococcus granulosus vesicles from WZB117 dried group 3 after day 4 are shown in fig. 12.
It can be seen from fig. 1 to fig. 12 that after the in vitro intervention for 4 days, the terminal hooks of the ABZSO group metacercaria are irregularly and incompletely arranged, the sucking discs are invaginated, the polypide is wrinkled, and the surface of the vesicle is damaged; the WZB117 intervention group 1 all died of the protozoan coenuruses and vesicles, and electron microscope results show that the WZB117 intervention group had incomplete parasite acrosin structure, irregular or disappeared acrosin grabs, outward sinking of suckers, decreased or even disappeared of parasite body microvilli and calcium particles, parasite body injury, vesicle collapse, and positive correlation of vesicle collapse degree and WZB117 administration concentration, which indicates that the glucose transporter 1 inhibitor WZB117 is a good echinococcus granulosus in vitro pesticide, and the effect is superior to albendazole sulfoxide.
In vivo assay for glucose transporter 1 inhibitor WZB117
Pharmacodynamic experiments in WZB117 mice
1.1 purpose of experiment: obtaining pharmacodynamic data of different dosages of WZB117 on a cystic echinococcosis mouse animal model in an intraperitoneal injection administration mode.
1.2 contents of the experiment
1.2.1 establishing an echinococcosis mouse animal model:
(1) the Echinococcus granulosus is cultured in vitro for 5 to 6 days, and the Echinococcus granulosus activity is detected by the eosin exclusion method. Around 2000 Echinococcus granulosus were placed in 1mL of physiological saline and inoculated intraperitoneally to each mouse. Kunming white mice, 6 to 8 weeks old, weigh 18 to 22 g.
(2) Molding time: the molding period of the cystic echinococcosis mouse animal model is 6 months.
(3) And (3) judging the success of molding: after 6 months of inoculation, the mice are subjected to ultrasonic B-ultrasonic detection molding, and the molding success is determined when the focus with the diameter exceeding about 0.5cm exists.
② mouse model: the intraperitoneal injection is divided into a solvent group, a positive drug group (ABZ group, namely albendazole group) and a treatment group (WZB 117 high dose group and WZB117 low dose group), and the total number of the groups is 4, and 5 to 8 groups are respectively prepared.
1.2.2 echinococcosis mouse animal model drug intervention:
(1) and selecting a mouse cystic echinococcosis animal model which is successfully modeled, and performing pharmacodynamic experiments.
(2) The experimental groups are WZB117 high dose group, WZB117 low dose group, positive drug group (ABZ group is albendazole group), solvent group; the dosage of the WZB117 high-dose group is 10mg/kg, the dosage of the WZB117 low-dose group is 5mg/kg, the dosage of the positive drug group is 50mg/kg, the solvent group is injected with phosphate buffer solution/DMSO solution (1: 1, v/v), 5 to 8 mice per group are subjected to cyst type echinococcosis animal model, and the injection amount is 0.1ml/10g by intraperitoneal injection and is administered for 28 days 1 time per day.
(3) The drugs were formulated at each concentration according to the test schedule: (same group is given according to different dosages with same concentration)
WZB117 high dose group: 31.12mg of WZB117 was precisely weighed and dissolved in 31.12ml of phosphate buffered saline/DMSO solution (1: 1, v/v) to obtain a 10mg/kg dose.
WZB117 low dose group: 15.78mg of WZB117 was weighed out precisely and dissolved in 31.56ml of phosphate buffered saline/DMSO solution (1: 1, v/v) to give a 5mg/kg dose.
Positive drug group: 160.62mg of ABZ was precisely weighed and dissolved in 32.12ml of phosphate buffered saline/DMSO solution (1: 1, v/v) to give a 50mg/kg dose.
Solvent group: phosphate buffered saline/DMSO solution (1: 1, v/v).
Sterilizing the liquid medicine prepared in the step 4; after sterilization, the mixture is stored in a refrigerator at 4 ℃ for later use in experiments.
(4) The cystic echinococcosis mouse animal model was sacrificed after 28 days of intraperitoneal injection, and the echinococcus granulosus vesicles from 2 mice were randomly selected for transmission electron microscopy in each experimental group to observe the microstructure. An electron micrograph of the solvent group versus the echinococcus granulosus vesicle is shown in fig. 13, an electron micrograph of the ABZ group versus the echinococcus granulosus vesicle is shown in fig. 14, an electron micrograph of the WZB117 high dose versus the echinococcus granulosus vesicle is shown in fig. 15, and an electron micrograph of the WZB117 low dose versus the echinococcus granulosus vesicle is shown in fig. 16.
As can be seen from fig. 13 to 16, the echinococcus granulosus vesicle ultrastructure of the WZB117 high dose group and the ABZ group significantly changed, and the echinococcus granulosus vesicle cells largely necrose; the hair between the horny layer and the hair growing layer of the ABZ group disappears, the cell form of the hair growing layer is unclear, and the endoplasmic reticulum is obviously expanded to form large vacuoles; the WZB117 high-dose group has fewer germinal cells, damaged germinal cells, incomplete structures, disappeared microvilli, incomplete synaptosome band structures, necrotized cortex thinned cells, obvious necrotic medullary structures, vacuole phenomenon in cytoplasm, stratum corneum swelling and vesicle fusion, loose germinal layer structures, disordered conditioning, unclear cell structures, disappeared vacuole-like structures and nucleoplasm shrinkage; the glucose transporter 1 inhibitor WZB117 can well treat the mouse cystic echinococcosis by the intraperitoneal injection, and the effect is better than that of albendazole.
1.1 WZB117 in vitro assay with albendazole sulfoxide
1.1.1 Experimental purposes: exploring the WZB117 combined with albendazole sulfoxide in-vitro intervention echinococcus granulosus vesicle mortality with an experimental period of 4 days
1.1.2 experimental groups (overview):
the total 5 groups of the experiment are respectively a WZB117 dry group (3.125 mu mol/L WZB 117), an albendazole sulfoxide group (15 mu mol/L ABZSO), a WZB117 combined albendazole sulfoxide group (3.125 mu mol/L WZB117+15 mu mol/L ABZSO), a negative group and a solvent group (DMSO); each group is provided with 3 multiple holes; the experimental period was set for 4 days.
1.1.3 mother liquor preparation
Weighing 0.211mg albendazole sulfoxide, dissolving in 500 μ l DMSO, and mixing to obtain (2 mM) albendazole sulfoxide suspension; 57.5484. mu.g of WZB117 were dissolved in 500. mu.l of DMSO and mixed well to prepare a suspension of WZB117 (concentration 0.3125 mM).
1.1.4 preparation of Echinococcus granulosus culture solution
Adding fetal bovine serum and double antibodies into an RPMI1640 culture medium, and uniformly mixing to obtain an echinococcus granulosus culture solution, wherein the volume percentage of fetal bovine serum in the echinococcus granulosus culture solution is 25%, and the volume percentage of the double antibodies in the echinococcus granulosus culture solution is 1%.
1.1.5 preparation of Echinococcus granulosus
Echinococcus granulosus metacercaria was obtained aseptically from the liver of a sheep naturally infected with Echinococcus granulosus in the Uygur woodii Hualing slaughterhouse of Xinjiang. After being digested by 1% pepsin for 30min, the mixture is washed for a plurality of times by sterile normal saline added with 2% streptomycin, and after the mixture is naturally precipitated, the supernatant is sucked off and is cultured aseptically.
1.1.6 configurations of the WZB117 Dry run group (3.125. mu. mol/L WZB 117), the Albendazole sulfoxide group (15. mu. mol/LABZSO), the WZB117 Combined Albendazole sulfoxide group (3.125. mu. mol/L WZB117+ 15. mu. mol/L ABZSO), the negative group and the solvent group (DMSO)
Mu.l of the suspension of WZB117 (concentration 0.3125 mM) was added to 198. mu.l of Echinococcus granulosus culture solution and mixed to obtain a dry group of WZB117 (3.125. mu. mol/L WZB 117); adding 2 mu L (the concentration is 2 mM) albendazole sulfoxide suspension into 198 mu L of echinococcus granulosus culture solution, and uniformly mixing to obtain albendazole sulfoxide group (15 mu mol/L ABZSO); samples were taken in 198. mu.l of culture medium at a ratio of 1: 5, adding 2 mul of WZB117 and albendazole sulfoxide, and uniformly mixing to obtain the WZB117 combined albendazole sulfoxide group (3.125 mul/L WZB117+15 mul/L ABZSO); obtaining a negative group by taking 200 mu L of echinococcus granulosus culture solution; mu.l of Echinococcus granulosus culture solution was added to 2. mu.l of DMSO and mixed to obtain a DMSO group.
1.1.7 Experimental procedures
Taking the in vitro cultured metacercaria, paving the metacercaria on a 96-well plate according to 200-300 heads/well, and arranging 3 multiple wells in each group; then adding the medicines respectively and adding equal volume of 0.9% physiological saline into the edge holes uniformly. Placing at 37 ℃ in CO2Culturing in a constant temperature incubator. Collecting 1d, 2d, 3d and 4d of protocercaria with drug-dry prognosis respectively, adding the protocercaria into a 1.5mL EP tube, discarding the culture solution, washing 3 times by using 0.9% physiological saline, adding 1% eosin for dyeing for 5min, absorbing the protocercaria, performing flaking, observing the rejection of the protocercaria under a microscope, counting the survival number of the protocercaria, and performing data statistical analysis; the survival rate (viatility) of Echinococcus granulosus (PSCs) following in vitro intervention with WZB117, ABZSO, WZB117 in combination with ABZSO is shown in FIG. 17.
As can be seen from fig. 17, WZB117, ABZSO, and WZB117 in combination with ABZSO all inhibited the growth of protozoan larvae to different degrees, and the effect of WZB117 in combination with ABZSO was significantly better than that of WZB117 alone and that of ABZSO alone, indicating that the glucose transporter 1 inhibitor WZB117 in combination with albendazole sulfoxide had better synergistic therapeutic effect, and the effect of glucose transporter 1 inhibitor WZB117 in combination with albendazole sulfoxide was significantly better than that of glucose transporter 1 inhibitor WZB117 alone and that of albendazole sulfoxide alone; experiments also prove that the dosage of the glucose transporter 1 inhibitor WZB117 combined with albendazole sulfoxide is reduced by 1/3-1/2 compared with the dosage of the albendazole sulfoxide alone, so that the dosage and the drug resistance problem are greatly reduced, a good treatment effect is achieved, and the glucose transporter 1 inhibitor WZB combined with albendazole sulfoxide can be used as an effective substitute for the existing albendazole.
In conclusion, the invention discloses the application of the glucose transporter 1 inhibitor WZB117 in preparing the medicine for treating the cystic echinococcosis for the first time; pharmacodynamic experimental data in vivo and in vitro indicate that the glucose transporter 1 inhibitor WZB117 (WZB 117) is a high-efficiency echinococcosis drug molecule, can destroy the echinococcus granulosus vesicle tissue structure, causes a large amount of necrosis of the echinococcus granulosus vesicle cells, has a remarkable treatment effect on cystic echinococcosis, and has an effect superior to that of albendazole sulfoxide which is a metabolite of albendazole; the glucose transporter 1 inhibitor WZB117 (WZB 117) is combined with albendazole sulfoxide to have better synergistic treatment effect, and the effect of the glucose transporter 1 inhibitor WZB117 (WZB 117) combined with albendazole sulfoxide is obviously better than that of the glucose transporter 1 inhibitor (WZB 117) and the albendazole sulfoxide which are separately administered; meanwhile, the dosage of the glucose transporter 1 inhibitor WZB117 (WZB 117) combined with albendazole sulfoxide is reduced by 1/3-1/2 compared with the dosage of the albendazole sulfoxide alone, so that the dosage and the drug resistance problem are greatly reduced, a good treatment effect is achieved, and the glucose transporter 1 inhibitor WZB combined with albendazole sulfoxide can be used as an effective substitute for the existing albendazole.
The technical characteristics form an embodiment of the invention, which has strong adaptability and implementation effect, and unnecessary technical characteristics can be increased or decreased according to actual needs to meet the requirements of different situations.
Claims (3)
1. An application of glucose transporter 1 inhibitor WZB117 in preparing the medicines for treating cystic echinococcosis is disclosed.
2. The use of the glucose transporter 1 inhibitor, WZB117, as described in claim 1, for the manufacture of a medicament for the treatment of cystic echinococcosis, further comprising albendazole, wherein the glucose transporter 1 inhibitor, WZB117, and albendazole are used in combination.
3. The use of the glucose transporter 1 inhibitor WZB117 as a medicament for the treatment of cystic echinococcosis according to claim 2, wherein the mass ratio of the glucose transporter 1 inhibitor WZB117 to albendazole is 1: 8 to 1: 1.
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