CN104208063A - Application of insulin growth factor acceptor inhibitor PQ401 in as medicine for treating echinococcosis granulosa - Google Patents
Application of insulin growth factor acceptor inhibitor PQ401 in as medicine for treating echinococcosis granulosa Download PDFInfo
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Abstract
The invention relates to the technical filed of an insulin growth factor acceptor inhibitor PQ401, and concretely relates to an application of the insulin growth factor acceptor inhibitor PQ401 as a medicine for treating echinococcosis granulosa. The insulin growth factor acceptor inhibitor PQ401 is a novel echinococcosis resistance medicine; in vivo and in vitro pharmacodynamic experiment data show that the PQ401 is an efficient echinococcosis resistance medicine molecule, can destroy the tissue structure of the Echinococcus granulosus vesicles and causes necrosis of a large amount of cells of the Echinococcus granulosus vesicles; in vivo pharmacodynamic experiment data show that the medicine has same echinococcosis granulose treatmetn effect with clinically commonly used albendazole; and the long term administration of albendazole by clinic echinococcosis granulosa patients causes medicine resistance, so the medicine can substitute albendazole to be used in the treatment of the echinococcosis granulosa.
Description
Technical field
the present invention relates to insulin-like growth factor acceptor inhibitor PQ401 technical field, is the application of a kind of insulin-like growth factor acceptor inhibitor PQ401 as preparation treatment echinococcosis granulosa medicine.
Background technology
echinococcosis granulosa harm is serious, the effective medicine of clinical shortage
echinococcosis (Echinococcosis) parasitizes a kind of serious infecting both domestic animals and human parasitic disease caused by human body by the larva of a tapeworm or the cercaria of a schistosome worm of echinococcus, 95% case is Echinococcus Granulosus Cysts (Echinococcus granulosus, Eg) larva of a tapeworm or the cercaria of a schistosome worm vesicle, echinococcosis granulosa (Cystis Echinococcosis, CE) caused by people's endobiosis.This disease is distribution on global, western seven provinces and regions (Xinjiang, Qinghai, Ningxia, Gansu, Tibet, Sichuan, the Inner Mongol) of China are high Endemic Area, compromised population reaches 6,600 ten thousand, economic loss is caused to exceed 3,000,000,000 yuan every year, being the one of the main reasons that western peasants and herdsmen " drive into poverty by medical crises; back into poverty by medical crises ", is also the serious public health problem received much attention, and within 2006, this disease is put into the free bailout package of country.
the main path of echinococcosis clinical treatment is excision focus, postoperative is prevention of recurrence or cannot surgical operation patient CE, many employings oral albendazole tablet or liposome are treated, but owing to there is the defects such as absorption difference, focal zone drug level be low and curative effect is not good enough in Drug therapy, therefore finding new drug target and non-surgical treatment, having great importance for preventing and treating echinococcosis.
insulin-like growth factor acceptor inhibitor PQ401 has antineoplastic drug effect, and there is not been reported, and it can be applicable to the disease for the treatment of non-tumor; As a member of receptor type protein tyrosine kinase family, insulin-like growth factor 1 receptor (IGF-IR) inhibitor can be used as the inhibitor of antitumor cell growth.In recent years, be that the international well-known pharmaceutical factory of small molecule kinase inhibitors Yi Beiduojia of target spot is paid close attention to IGF-IR, and enter clinical I-III experimental stage phase.
current insulin-like growth factor 1 receptor (IGF-IR) inhibitor is roughly divided into seven compounds such as benzimidazole, Pyrrolopyrimidine, pyrroles-5-formaldehydes, Pyridopyrimidine class, miaow Pyrazine, natural origin micromolecular inhibitor and diaryl urea.Above inhibitor all can block PI3K/Akt signal path, and inhibition tumor cell spreads, and reduces the effect of tumor tissues volume, all has good curative effect to tumor types such as carcinoma of prostate, breast carcinoma, nonsmall-cell lung cancers.
pQ401 belongs to diaryl urea compound, and this compounds reduces the Phosphorylation events in the activation path of caspase apoptosis pathway thus the apoptosis mediated while suppressing the activity of IGF-IR.Zoopery shows that this medicine has good therapeutical effect for the growth of the tumors such as breast carcinoma, head and neck cancer, nonsmall-cell lung cancer, and toxicity is lower.At present, Insulin-Like acceptor inhibitor is only for the Therapy study of tumor, and in parasite field, there is not been reported.
treating echinococcosis Recent Progresses In The Development
the choice drug of current treatment echinococcosis is benzimidazoles residues, and it represents medicine mebendazole and albendazole.All prove that such medicine is effective to echinococcosis with In vitro culture experiment in Clinical practice and animal body for many years.Mebendazole and albendazole are that WHO recommends the only two kinds of medicines for the treatment of echinococcosis.Benzimidazoles residues (comprising mebendazole and albendazole) can optionally combine with nematicide and the intracytoplasmic tubulin of cestode, affect the formation of microtubule, intracytoplasmic microtubule is caused to disappear, block the transhipment of secretory vacuole, affect the conveying of nutrient substance, absorption and digestion, suppress polypide ingestion of glucose, polypide hair growth promoting is made to become cell glycogen depletion, the degeneration of endoplasmic reticulum corpusculum, lysosome increases, and finally causes polypide dead.But because it exists intestinal absorption difference, blood medicine, liver concentration are lower, and chemotherapy effect is still unsatisfactory; After chemotherapy, follow up a case by regular visits to one be only and have the patient of 30% to be cured, 30% to 50% improves, and all the other are invalid, and curative effect is also very unstable, there is individual difference.The scholar even had points out: for most of cases of alveolar hydatid disease, and the effectiveness master of albendazole is pressing down worm (parasitistatic) but not parasite killing (parasiticidal activity).In addition, zoopery and case report all show, long-term taking albendazole medicine, and Echinococcus Granulosus Cysts worm can be caused to produce drug resistance.Therefore, the research and development of echinococcosis new drug are extremely important.
Summary of the invention
the invention provides the application of a kind of insulin-like growth factor acceptor inhibitor PQ401 as preparation treatment echinococcosis granulosa medicine, it is a kind of efficient anti-treating echinococcosis molecule, Echinococcus Granulosus Cysts vesicle organizational structure can be destroyed, cause vesicle Echinococcus Granulosus Cysts follicle cell downright bad in a large number; Suitable with clinical conventional albendazole drug effect.
one of technical scheme of the present invention is realized by following measures: a kind of insulin-like growth factor acceptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine.
insulin-like growth factor acceptor inhibitor PQ401 of the present invention is a kind of novel anti-treating echinococcosis; With the pharmacodynamic experiment data of external two aspects in body, all show that PQ401 is a kind of efficient anti-treating echinococcosis molecule, Echinococcus Granulosus Cysts vesicle organizational structure can be destroyed, cause vesicle Echinococcus Granulosus Cysts follicle cell downright bad in a large number; In body, pharmacodynamic experiment data show that the drug effect of this medicine and clinical conventional Albendazole In Treatment echinococcosis granulosa is suitable; In view of clinical patients with hydatidosis long-term taking albendazole can cause drug resistance, the succedaneum that therefore this medicine can be used as albendazole carries out treatment echinococcosis.
Accompanying drawing explanation
accompanying drawing 1 is the survival rate figure of Echinococcus Granulosus Cysts vesicle through the external intervention of PQ401.
accompanying drawing 2 is the negative group of Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
accompanying drawing 3 is the Electronic Speculum figure of DMSO group to Echinococcus Granulosus Cysts vesicle.
accompanying drawing 4 is the Electronic Speculum figure of PQ401 intervention group 1 pair of Echinococcus Granulosus Cysts vesicle.
accompanying drawing 5 is the Electronic Speculum figure of PQ401 intervention group 2 pairs of Echinococcus Granulosus Cysts vesicles.
accompanying drawing 6 is the Electronic Speculum figure of PQ401 intervention group 3 pairs of Echinococcus Granulosus Cysts vesicles.
accompanying drawing 7 is the Electronic Speculum figure of PQ401 intervention group 4 pairs of Echinococcus Granulosus Cysts vesicles.
accompanying drawing 8 is the Electronic Speculum figure of PQ401 intervention group 5 pairs of Echinococcus Granulosus Cysts vesicles.
accompanying drawing 9 is capsule weight in wet base statistical analysis figure.
accompanying drawing 10 is Echinococcus Granulosus Cysts vesicle number statistical analysis figure.
accompanying drawing 11 is the transmission electron microscope picture of PQ401 high dose group to Echinococcus Granulosus Cysts vesicle.
accompanying drawing 12 is the bubble transmission electron microscope of PQ401 low dose group to Wall of Echinococcus.
accompanying drawing 13 is the transmission electron microscope picture of positive drug group to Echinococcus Granulosus Cysts vesicle.
accompanying drawing 14 is the transmission electron microscope picture of model group to Echinococcus Granulosus Cysts vesicle.
accompanying drawing 15 is the transmission electron microscope picture of group of solvents to Echinococcus Granulosus Cysts vesicle.
Detailed description of the invention
the present invention by the restriction of following embodiment, can not determine concrete embodiment according to technical scheme of the present invention and practical situation.
embodiment 1, this insulin-like growth factor acceptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine.
this insulin-like growth factor acceptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine, and its application test is as follows:
one. insulin-like growth factor acceptor inhibitor PQ401 experiment in vitro (insulin-like growth factor acceptor inhibitor PQ401 is called for short PQ401)
1.1 PQ401 experiment in vitro
1.1.1 experiment purpose: the explorative experiment cycle is PQ401 external intervention Echinococcus Granulosus Cysts vesicle mortality rate under each concentration of 2 days.
1.1.2 grouping (overview) is tested:
this experiment is divided into 7 groups, is respectively PQ401 intervention group 1, PQ401 intervention group 2, PQ401 intervention group 3, PQ401 intervention group 4, PQ401 intervention group 5, negative group and DMSO group; Often group does 3 secondary orifices; Experimental period arranges 2 days altogether.
1.1.3 mother solution configuration
take 2mgPQ401 be dissolved in 200ulDMSO obtain 10mg/ml mother solution 1.; The mother solution of 2.5 mg/ml is obtained 2. after 1. mother solution is diluted 4 times with DMSO; The mother solution of 1.25mg/ml is obtained 3. after 2. mother solution is diluted 2 times with DMSO; The mother solution of 0.625 mg/ml is obtained 4. after 3. mother solution is diluted 2 times with DMSO; The mother solution of 0.3125mg/ml is obtained 5. after 4. mother solution is diluted 2 times with DMSO; The mother solution of 0.15625mg/ml is obtained 6. after 5. mother solution is diluted 2 times with DMSO.
1.1.4 the configuration of Echinococcus Granulosus Cysts culture fluid
obtain Echinococcus Granulosus Cysts culture fluid by hyclone and the dual anti-RPMI1640 of joining culture medium after mixing, hyclone is 10% in the percent by volume of Echinococcus Granulosus Cysts culture fluid, and the dual anti-percent by volume at Echinococcus Granulosus Cysts culture fluid is 1%.
1.1.5 the preparation of Echinococcus Granulosus Cysts vesicle
from the sheep liver of the fresh collection natural infection in slaughterhouse, Xinjiang Urumqi city Echinococcus Granulosus Cysts.Aseptically, gather protoscolex, and wash 3 times with the aseptic PBS liquid (pH7.3) containing mycillin, add 1%pepsin(pH 2.0), 37 DEG C of digestion 30 min, period is every 5 min, jog, upset test tube, make protoscolex shed from brood capsule, simultaneously with aseptic PBS liquid rinsing 3 times.The protoscolex that the vigor of getting is greater than 95%, cultivates after 2 months to 3 months and forms the Echinococcus Granulosus Cysts vesicle that diameter is 2mm to 3 mm in Echinococcus Granulosus Cysts culture fluid.Condition of culture is 37 DEG C, the cell culture incubator of 5%CO2, changes Echinococcus Granulosus Cysts culture fluid 1 time every 5 days.
1.1.6 the configuration of PQ401 intervention group 1, PQ401 intervention group 2, PQ401 intervention group 3, PQ401 intervention group 4, PQ401 intervention group 5, negative group and DMSO group
pQ401 intervention group 1 is obtained after 2. the mother solution adding 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l mixes; PQ401 intervention group 2 is obtained after 3. the mother solution adding 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l mixes; PQ401 intervention group 3 is obtained after 4. the mother solution adding 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l mixes; PQ401 intervention group 4 is obtained after 5. the mother solution adding 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l mixes; PQ401 intervention group 5 is obtained after 6. the mother solution adding 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l mixes; Get 1000 μ L Echinococcus Granulosus Cysts culture fluid and obtain negative group; DMSO group is obtained add the DMSO mixing of 10 μ l in the Echinococcus Granulosus Cysts culture fluid of 990 μ l after.
1.1.7 experimental procedure
be that the Echinococcus Granulosus Cysts vesicle of 2 mm to 3 mm adds on 24 well culture plates respectively by diameter, 15 to 20 Echinococcus Granulosus Cysts vesicles in each hole, then on 24 well culture plates that Echinococcus Granulosus Cysts vesicle is housed, PQ401 intervention group 1(25 μ g/ml PQ401 is added respectively), PQ401 intervention group 2 (12.5 μ g/ml PQ401), PQ401 intervention group 3 (6.25 μ g/ml PQ401), PQ401 intervention group 4(3.125 μ g/ml PQ401), PQ401 intervention group 5(1.5625 μ g/ml PQ401), negative group (NC) and DMSO group (DMSO) are cultivated, the multiple hole of each experimental group 3, for orifice plate basis (designing the 0th day is the time of conveniently changing liquid and counting) is carried out in this experiment.Not very the 0th day, this experimental period was 2 days, within the 2nd day, carried out photographic experiment in hole and observed, then use the microstructure of transmission electron microscope observing vesicle; After 2nd day Echinococcus Granulosus Cysts vesicle through the external intervention of PQ401 survival rate figure as shown in Figure 1; Negative group Fig. 2 is shown in the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle after 2nd day; After 2nd day, the Electronic Speculum figure of DMSO group to Echinococcus Granulosus Cysts vesicle is shown in Fig. 3; After 2nd day, the Electronic Speculum figure of PQ401 intervention group 1 pair of Echinococcus Granulosus Cysts vesicle is shown in Fig. 4; After 2nd day, the Electronic Speculum figure of PQ401 intervention group 2 pairs of Echinococcus Granulosus Cysts vesicles is shown in Fig. 5; After 2nd day, the Electronic Speculum figure of PQ401 intervention group 3 pairs of Echinococcus Granulosus Cysts vesicles is shown in Fig. 6; After 2nd day, the Electronic Speculum figure of PQ401 intervention group 4 pairs of Echinococcus Granulosus Cysts vesicles is shown in Fig. 7; After 2nd day, the Electronic Speculum figure of PQ401 intervention group 5 pairs of Echinococcus Granulosus Cysts vesicles is shown in Fig. 8.
can find out that external intervention is after 2 days by Fig. 1 to Fig. 8, Echinococcus granulosus vesicle in PQ401 intervention group 1 and PQ401 intervention group 2 is all dead, the cell membrane of Electronic Speculum result display Echinococcus Granulosus Cysts vesicle is destroyed, and structure is imperfect, and cortical cell is downright bad, nucleus swelling, nuclear matrix density is extremely low, mitochondrial swelling, and endoplasmic reticulum height is expanded, microtriche structure does not almost have, and syncytium band structure is also imperfect; Illustrate in vitro under experiment condition, the PQ401 of low concentration at short notice (2 days) namely has higher toxic action to Echinococcus Granulosus Cysts vesicle, and prompting PQ401 is the external insecticide of a kind of Echinococcus Granulosus Cysts worm.
two. insulin-like growth factor acceptor inhibitor PQ401 experiment in vivo (insulin-like growth factor acceptor inhibitor PQ401 is called for short PQ401)
1. PQ401 Mouse Acute Toxicity experiment
1.1 experiment purposes: obtain intraperitoneal injection mode various dose PQ401 to the acute toxicity data of Kun ming white mouse.
1.2 experiment contents:
the drug dose of echinococcosis granulosa mouse model is treated, the experiment of design PQ401 Mouse Acute Toxicity in order to grope PQ401.This experiment lowest dose level adopts 1000 mg/kg, and increases progressively the dosage of PQ401 successively according to survival rate data.Each dosage choice 2 Kun ming white mouse, the observation cycle is 7 days to 14 days, and PQ401 Mouse Acute Toxicity experimental data is shown in Table 1; Initial guess 4000mg/Kg is safe dose, then adopts 10 Kun ming white mouse to repeat the acute toxicity testing of this dosage, only 1 Kun ming white mouse death.Illustrate that 4000mg/kg is the safe dose of PQ401, be 100mg/kg according to the medicine high dose group of PQ401 in this Rapid Dose Calculation pharmacodynamic experiment, low dose group is 50mg/kg.
2. PQ401 mouse pharmacodynamic experiment
2.1 experiment purposes: obtain intraperitoneal injection mode various dose PQ401 to the Pharmacodynamic Data of echinococcosis granulosa mouse model.
2.2 experiment content
2.2.1 echinococcosis mouse model is set up:
(1) select the uniform Echinococcus Granulosus Cysts vesicle that diameter is 2mm-to 3mm under aseptic condition, lumbar injection is inoculated in Mice Body.
kun ming white mouse, age week in 6 week age to 8, body weight 20g to 25g.Notice that operation wants steady, otherwise damage is larger; When injecting Echinococcus Granulosus Cysts vesicle, must guarantee do not have air to enter.
(2) the modeling time: echinococcosis granulosa mouse model becomes the mould cycle to be 3 months.
(3) the successful criterion of modeling: when infecting 89 days, echinococcosis granulosa mouse model is checked by Abdominal B type ultrasonography, there is the Kun ming white mouse of diameter more than the Echinococcus Granulosus Cysts vesicle of 0.5cm in abdominal part, is the successful echinococcosis granulosa mouse model of modeling.
2. mouse model: lumbar injection is divided into group of solvents, model group, positive drug group (ABZ group and albendazole group), treatment group (PQ401 high dose group, PQ401 low dose group), totally 5 groups, often organizes 10, calculates modeling 100 by modeling success rate.
2.2.2 echinococcosis mouse model pharmaceutical intervention:
(1) select modeling successful mice echinococcosis granulosa animal model, enter pharmacodynamic experiment.
(2) experiment is grouped into PQ401 high dose group, PQ401 low dose group, positive drug group (ABZ group and albendazole group), model group (being called for short M group) and group of solvents (being called for short R group), PQ401 high dose group dosage is 100 mg/kg, PQ401 low dose group dosage is 50 mg/kg, positive drug group administration albendazole, dosage is 50mg/kg, model group is injecting normal saline, group of solvents is the solvent of injection 8% Tween 80+8% ethanol, dosage is 20ml/kg, often organize 10 mice echinococcosis granulosa animal models, lumbar injection 3 times weekly, administration 3 weeks.(2) 50 mice echinococcosis granulosa animal models application " PEMS 3.1 for Windows ", software random packet, numbering, list, weigh, record, dye marker often organizes 1,2,3,4, No. 5.
(3) medicine of each concentration is prepared according to test plan: (same group gives by the different dose of same concentration)
the configuration of solvent (8% Tween 80+8% ethanol):
precision takes 24g Tween 80 (pharmaceutical grade), is settled to 150ml, shakes up with vortice with PBS, obtains 16% tween 150ml, with 0.22 Mm filter membrane filtration degerming 2 times.Precision measures 32ml 75% ethanol, is settled to 150ml with PBS, obtains the ethanol 150ml of 16%, with 0.22 Mm filter membrane filtration degerming 2 times.Get 16% Tween 80 after filtration sterilization and the mixing of 16% ethanol same volume respectively, obtain required concentration solvent 300ml for subsequent use.
pQ401 high dose group: precision takes 105mgPQ401, is placed in sterilized mortar, adds the fully grinding and mixing of above-mentioned solvent (8% ethanol+8% Tween 80) that 21ml configured, is 100mg/kg (5mg/ml) dosage.
pQ401 low dose group:
precision takes 54mgPQ401, is placed in sterilized mortar, adds the fully grinding and mixing of above-mentioned solvent (8% ethanol+8% Tween 80) that 21.6ml configured, is 50mg/kg (2.5mg/ml) dosage.
positive drug group:
precision takes 57mg ABZ, is placed in sterilized mortar, adds the fully grinding and mixing of above-mentioned solvent (8% ethanol+8% Tween 80) that 22.8ml configured, is 50mg/kg (2.5mg/ml) dosage.
model group: normal saline.
group of solvents: solvent (8% Tween 80+8% ethanol).
the medicinal liquid that above-mentioned 5 assembly are good, tightens and uses sealed membrane good seal, and be placed in liquid nitrogen cryogenics sterilizing (20min), flash frozen becomes solid, and the constant water bath box being then placed in 37 DEG C melts, and repeatable operation like this 3 times, carries out sterilizing with this; Sterilizing completes and is placed on 4 DEG C of Refrigerator stores, for subsequent use for testing.
(4) intraperitoneal injection put to death echinococcosis granulosa mouse model after 3 weeks, the Echinococcus Granulosus Cysts vesicle collecting every mice respectively takes the number of weight and record Echinococcus Granulosus Cysts vesicle, the capsule weight in wet base of each experimental group of statistical analysis and Echinococcus Granulosus Cysts vesicle number, capsule weight in wet base statistical analysis figure as shown in Figure 9, Echinococcus Granulosus Cysts vesicle number statistical analysis figure as shown in Figure 10, the Echinococcus Granulosus Cysts vesicle of each experimental group Stochastic choice 2 mices is used for transmission electron microscope, observes microstructure.The Electronic Speculum figure of PQ401 high dose group to Echinococcus Granulosus Cysts vesicle is shown in Figure 11, the Electronic Speculum figure of PQ401 low dose group to Echinococcus Granulosus Cysts vesicle is shown in Figure 12, the Electronic Speculum figure of positive drug group to Echinococcus Granulosus Cysts vesicle is shown in Figure 13, the Electronic Speculum figure of model group to Echinococcus Granulosus Cysts vesicle is shown in Figure 14, and the Electronic Speculum figure of group of solvents to Echinococcus Granulosus Cysts vesicle is shown in Figure 15.
can be found out by Fig. 9 to Figure 10, capsule weight in wet base and the Echinococcus Granulosus Cysts vesicle number of PQ401 high dose group and positive drug group all significantly reduce, and PQ401 high dose group and positive drug group have the drug effect of suitable treatment echinococcosis granulosa.Can be found out by Figure 11 to Figure 15, the Echinococcus Granulosus Cysts vesicle Change of Ultrastructure of PQ401 high dose group and positive drug group is remarkable, Echinococcus Granulosus Cysts follicle cell is downright bad in a large number, and the Echinococcus Granulosus Cysts vesicle tissue necrosis degree that PQ401 causes is high compared with the Echinococcus Granulosus Cysts vesicle degree of necrosis of positive drug group.PQ401 high dose group Echinococcus Granulosus Cysts vesicle, stratum corneum gets thinner or disappearance, the in disorder rare irregularity of microtriche; Cortical area is also thinning, occurs a large amount of transparent cavity, lysosome increasing simultaneously.Germinal layer cell or dissociate or disappear or degeneration necrosis (membranolysis), structural fuzzy is unclear, kernel or scatter or disappear, the bare nucleus cell of even visible apoptosis.Positive drug group Echinococcus Granulosus Cysts vesicle, horny layer loosens crack, and cortical area is thinning, and microtriche is rare, and in stratum germinativum, intercellular substance becomes large, the few and degeneration of cortical cell quantity, and kernel scatters or disappears, and core heterochromatin increases, and limit collection; In addition, disorderly, texture is unintelligible in cortical area myofibroblasts beam spreading.There is certain changing unit cell death, horny layer structure thin in PQ401 low dose group Echinococcus Granulosus Cysts vesicle ultrastructure, the rare irregularity arrangement of microtriche; Stratum germinativum is thinning, and cortical area content is few, occurs transparent marrow sample corpusculum or cavity, lysosome increasing, the cortical cell of the even visible damaged degeneration of fascicula distribution at random, karyomorphism irregularity, and kernel or disappearance or its cloud density reduce, and present canescence; Core heterochromatin increases, and limit collection, lysosome increasing.The Echinococcus Granulosus Cysts imitated vesicle structure of model group and group of solvents is normal, and cytoactive is higher; Horny layer and stratum germinativum homogeneous, clear in structure can be distinguished, the bright vesicle that cortical area has many compact size more homogeneous, and its surperficial microtriche densification is abundant, marshalling; The germinal layer cell of cortical area is regular, and nuclear structure is fine and close, and core is large and round, and the less one-tenth of the clear heterochromatin of nucleolar structure is reunited; In addition, myofibroblasts clear in structure in cortical area can be distinguished.Illustrate that show that the administration of PQ401 lumbar injection mode can treat mice echinococcosis granulosa, the therapeutic effect of its therapeutic effect and albendazole is suitable by the experiment of echinococcosis mouse model pharmaceutical intervention.
in sum, insulin-like growth factor acceptor inhibitor PQ401 of the present invention is a kind of novel anti-treating echinococcosis; With the pharmacodynamic experiment data of external two aspects in body, all show that PQ401 is a kind of efficient anti-treating echinococcosis molecule, Echinococcus Granulosus Cysts vesicle organizational structure can be destroyed, cause vesicle Echinococcus Granulosus Cysts follicle cell downright bad in a large number; In body, pharmacodynamic experiment data show that the drug effect of this medicine and clinical conventional Albendazole In Treatment echinococcosis granulosa is suitable; In view of clinical patients with hydatidosis long-term taking albendazole can cause drug resistance, the succedaneum that therefore this medicine can be used as albendazole carries out treatment echinococcosis.
table 1 PQ401 Mouse Acute Toxicity experimental data
| Dosage (mg/kg) | Administration volume number (ml) | Number of animals | Dead number of elements |
| 1000 | 0.6 | 2 | 0 |
| 2000 | 0.6 | 2 | 1 |
| 5000 | 0.6 | 2 | 1 |
| 4000 | 0.6 | 2 | 0 |
| 4000(repeats) | 0.6 | 10 | 1 |
Claims (1)
1. an insulin-like growth factor acceptor inhibitor PQ401 is as the application preparing treatment echinococcosis granulosa medicine.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN105012319A (en) * | 2015-07-27 | 2015-11-04 | 吕海龙 | Application of celecoxib in preparation of medicine for treatment of echinococcosis granulosa |
| CN105497898A (en) * | 2016-02-02 | 2016-04-20 | 新疆医科大学第一附属医院 | Application of MAPK signal pathway inhibitor to preparation of drugs for treating cystic echinococcosis |
| CN113398134A (en) * | 2021-07-08 | 2021-09-17 | 新疆医科大学第一附属医院 | Application of insulin-like growth factor 1 receptor inhibitor BMS536924 in preparation of medicine for treating cystic echinococcosis |
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2014
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| SARAH HEMER,ET AL.: "Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development", 《BMC BIOLOGY》, vol. 12, 27 January 2014 (2014-01-27), pages 5 - 26 * |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105012319A (en) * | 2015-07-27 | 2015-11-04 | 吕海龙 | Application of celecoxib in preparation of medicine for treatment of echinococcosis granulosa |
| CN105497898A (en) * | 2016-02-02 | 2016-04-20 | 新疆医科大学第一附属医院 | Application of MAPK signal pathway inhibitor to preparation of drugs for treating cystic echinococcosis |
| CN105497898B (en) * | 2016-02-02 | 2018-09-07 | 新疆医科大学第一附属医院 | MAPK signal pathway inhibitors are as the application for preparing treatment cystic echinococcosis drug |
| CN113398134A (en) * | 2021-07-08 | 2021-09-17 | 新疆医科大学第一附属医院 | Application of insulin-like growth factor 1 receptor inhibitor BMS536924 in preparation of medicine for treating cystic echinococcosis |
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