CN104208063B - Insulin-like growth factor acceptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine - Google Patents
Insulin-like growth factor acceptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine Download PDFInfo
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Abstract
The present invention relates to insulin-like growth factor acceptor inhibitor PQ401 technical field, be a kind of insulin-like growth factor acceptor inhibitor PQ401 application as preparation treatment echinococcosis granulosa medicine.Insulin-like growth factor acceptor inhibitor PQ401 of the present invention is a kind of novel anti-treating echinococcosis；Internal and external both sides pharmacodynamic experiment data, all show that PQ401 is a kind of efficient anti-treating echinococcosis molecule, it is possible to destroy Echinococcus Granulosus Cysts vesicle organizational structure, cause vesicle Echinococcus Granulosus Cysts follicle cell the most downright bad；Internal pharmacodynamic experiment data show that the drug effect of the Albendazole In Treatment echinococcosis granulosa that this medicine is conventional with clinic is suitable；In view of clinical patients with hydatidosis long-term taking albendazole can cause drug resistance, therefore this medicine can carry out treating echinococcosis as the succedaneum of albendazole.
Description
Technical field
The present invention relates to insulin-like growth factor acceptor inhibitor PQ401 technical field, be a kind of Insulin-like Growth
Factor receptor inhibitor PQ401 is as the application of preparation treatment echinococcosis granulosa medicine.
Background technology
Echinococcosis granulosa harm is serious, the effective medicine of clinical shortage
Echinococcosis (Echinococcosis) is to be parasitized a kind of serious people caused by human body by the larva of a tapeworm or the cercaria of a schistosome worm of echinococcus
Poultry suffers from parasitic disease altogether, and 95% case is the larva of a tapeworm or the cercaria of a schistosome worm vesicle of Echinococcus Granulosus Cysts (Echinococcus granulosus, Eg),
At echinococcosis granulosa caused by people's endobiosis (Cystis Echinococcosis, CE).This disease is distribution on global, and China is western
Seven provinces and regions (Xinjiang, Qinghai, Ningxia, Gansu, Tibet, Sichuan, the Inner Mongol) are high Endemic Area, and compromised population reaches 66,000,000, often
Year cause economic loss to exceed 3,000,000,000 yuan, be the one of the main reasons " driven into poverty by medical crises, back into poverty by medical crises " of western peasants and herdsmen, be also extremely
The serious public health problem paid close attention to, within 2006, this disease is put into the free bailout package of country.
The main path of echinococcosis clinical treatment is excision focus, postoperative for prevention of recurrence or cannot surgical operation CE
Patient, uses oral albendazole tablets or liposome to treat more, but owing to Drug therapy exists absorption difference, focal zone
The defects such as drug level is low and curative effect is not good enough, therefore find new drug target and non-surgical treatment, for preventing and treating Echinococcus hydatid cyst
Disease has great importance.
Insulin-like growth factor acceptor inhibitor PQ401 has antineoplastic drug effect, and there is not been reported, and it can be applicable to
Treat the disease of non-tumor；As a member of receptor type protein tyrosine kinase family, insulin-like growth factor 1 receptor (IGF-
IR) inhibitor can serve as the inhibitor of antitumor cell growth.In recent years, the small molecule kinase suppression with IGF-IR as target spot
Agent Yi Beiduojia pays close attention in international well-known pharmaceutical factory, and enters clinical I-III experimental stage phase.
At present insulin-like growth factor 1 receptor (IGF-IR) inhibitor be roughly divided into benzimidazole, Pyrrolopyrimidine,
Seven classes such as pyrroles's-5-formaldehydes, Pyridopyrimidine class, miaow Pyrazine, natural origin micromolecular inhibitor and diaryl urea
Compound.Above inhibitor all can block PI3K/Akt signal path, suppression tumor cell diffusion, reduces tumor tissues volume
Effect, the tumor types such as carcinoma of prostate, breast carcinoma, nonsmall-cell lung cancer are respectively provided with preferable curative effect.
PQ401 belongs to diaryl urea compound, and this compounds reduces while the activity by suppression IGF-IR
Phosphorylation events in the activation path of caspase apoptosis pathway thus the apoptosis that mediates.Zoopery shows this medicine
Thing has preferable therapeutical effect for the growth of the tumors such as breast carcinoma, head and neck cancer, nonsmall-cell lung cancer, and toxicity is relatively low.Mesh
Before, Insulin-Like acceptor inhibitor is only used 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 for the treatment of echinococcosis is benzimidazoles residues at present, and it represents medicine has mebendazole and acetysalicylic acid phenobarbital to reach
Azoles.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 is that WHO recommends the treatment only two kinds of medicines of echinococcosis.Benzimidazoles residues (includes mebendazole and acetysalicylic acid phenobarbital
Reach azoles) can optionally combine by tubulin intracytoplasmic with nematicide and cestode, affect the formation of micro-pipe, cause Cytoplasm
Interior micro-pipe disappears, and blocks the transhipment of secretory vacuole, affects the conveying of nutrient substance, digests and absorb, suppression polypide picked-up Fructus Vitis viniferae
Sugar, makes polypide hair growth promoting become cell glycogen depletion, endoplasmic reticulum corpusculum degeneration, and lysosome increases, and ultimately results in polypide dead.But due to
It is poor to there is intestinal absorption in it, and blood medicine, liver concentration are relatively low, and chemotherapy effect is the most unsatisfactory；Follow up a case by regular visits to 1 year only have after chemotherapy
The patient of 30% is cured, and 30% to 50% improves, and remaining is invalid, and curative effect is the most unstable, there is individual difference.Very
Point out to the scholar having: for most of cases of alveolar hydatid disease, the effectiveness master of albendazole press down worm (
Parasitistatic) rather than parasite killing (parasiticidal activity).It addition, zoopery and case report
All show, long-term taking albendazole medicine, Echinococcus Granulosus Cysts worm can be caused to produce drug resistance.Therefore, the grinding of echinococcosis new drug
Sending out is to be extremely important.
Summary of the invention
The invention provides a kind of insulin-like growth factor acceptor inhibitor PQ401 as preparation treatment echinococcosis granulosa
The application of medicine, is a kind of efficient anti-treating echinococcosis molecule, it is possible to destroy Echinococcus Granulosus Cysts vesicle organizational structure, cause capsule
Bubble Echinococcus Granulosus Cysts follicle cell is the most downright bad；The albendazole drug effect conventional with clinic is suitable.
One of technical scheme is realized by following measures: a kind of insulin-like growth factor receptor presses down
Preparation 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；Internal and
External both sides pharmacodynamic experiment data, all show that PQ401 is a kind of efficient anti-treating echinococcosis molecule, it is possible to destroy thin
Grain echinococcus vesicle organizational structure, causes vesicle Echinococcus Granulosus Cysts follicle cell the most downright bad；Internal pharmacodynamic experiment tables of data
The drug effect of the Albendazole In Treatment echinococcosis granulosa that this medicine bright is conventional with clinic is suitable；In view of clinical patients with hydatidosis takes for a long time
Can cause drug resistance with albendazole, therefore this medicine can carry out treating echinococcosis as the succedaneum of albendazole.
Accompanying drawing explanation
Accompanying drawing 1 is the Echinococcus Granulosus Cysts vesicle survival rate figure through the external intervention of PQ401.
Accompanying drawing 2 is the negative group Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 3 is the DMSO group Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 4 is the PQ401 intervention group 1 Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 5 is the PQ401 intervention group 2 Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 6 is the PQ401 intervention group 3 Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 7 is the PQ401 intervention group 4 Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 8 is the PQ401 intervention group 5 Electronic Speculum figure to Echinococcus Granulosus Cysts vesicle.
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 PQ401 high dose group transmission electron microscope picture to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 12 is the PQ401 low dose group bubble transmission electron microscope to Wall of Echinococcus.
Accompanying drawing 13 is the positive drug group transmission electron microscope picture to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 14 is the model group transmission electron microscope picture to Echinococcus Granulosus Cysts vesicle.
Accompanying drawing 15 is the group of solvents transmission electron microscope picture to Echinococcus Granulosus Cysts vesicle.
Detailed description of the invention
The present invention is not limited by following embodiment, can determine specifically according to technical scheme and practical situation
Embodiment.
Embodiment 1, this insulin-like growth factor acceptor inhibitor PQ401 is as preparation treatment echinococcosis granulosa medicine
Application.
This insulin-like growth factor acceptor inhibitor PQ401 treats the application of echinococcosis granulosa medicine as preparation, its
Application test is as follows:
One. (insulin-like growth factor receptor suppresses insulin-like growth factor acceptor inhibitor PQ401 experiment in vitro
Agent 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 under each concentration of 2 days
Mortality rate.
1.1.2 packet (overview) is tested:
This experiment is divided into 7 groups, and respectively PQ401 intervention group 1, PQ401 intervention group 2, PQ401 intervention group 3, PQ401 are dry
Pre-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
Weigh 2mgPQ401 to be dissolved in 200ulDMSO and obtain the mother solution of 10mg/ml 1.；1. mother solution is diluted 4 times with DMSO
After obtain the mother solution of 2.5 mg/ml 2.；The mother solution of 1.25mg/ml is obtained 3. after 2. mother solution is diluted 2 times with DMSO；By mother solution 3.
The mother solution of 0.625 mg/ml is obtained 4. after diluting 2 times with DMSO；0.3125mg/ml is obtained after 4. mother solution is diluted 2 times with DMSO
Mother solution 5.；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
Hyclone and the dual anti-RPMI1640 of joining culture medium will obtain Echinococcus Granulosus Cysts culture fluid, tire cattle after mixing
Serum 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
Sheep liver from the fresh collection in slaughterhouse, Xinjiang Urumqi city natural infection Echinococcus Granulosus Cysts.At aseptic condition
Under, gather protoscolex, and wash 3 times with the aseptic PBS liquid (pH7.3) containing mycillin, add 1%pepsin(pH 2.0),
37 DEG C digest 30 min, and period, every 5 min, jog, upset test tube, makes protoscolex shed from brood capsule, uses aseptic PBS simultaneously
Liquid rinses 3 times.Take the vigor protoscolex more than 95%, formed straight after cultivating 2 months to 3 months in Echinococcus Granulosus Cysts culture fluid
Footpath is the Echinococcus Granulosus Cysts vesicle of 2mm to 3 mm.Condition of culture was 37 DEG C, the cell culture incubator of 5%CO2, changed thin every 5 days
Grain echinococcus culture fluid 1 time.
1.1.6 PQ401 intervention group 1, PQ401 intervention group 2, PQ401 intervention group 3, PQ401 intervention group 4, PQ401 intervene
Group 5, negative group and the configuration of DMSO group
The Echinococcus Granulosus Cysts culture fluid of 990 μ l adds after 2. the mother solution of 10 μ l mixes and obtain PQ401 intervention group 1；?
The Echinococcus Granulosus Cysts culture fluid of 990 μ l adds after 3. the mother solution of 10 μ l mixes and obtain PQ401 intervention group 2；Particulate at 990 μ l
Echinococcus culture fluid adds after 4. the mother solution of 10 μ l mixes and obtain PQ401 intervention group 3；Echinococcus Granulosus Cysts at 990 μ l is cultivated
Liquid adds after 5. the mother solution of 10 μ l mixes and obtain PQ401 intervention group 4；10 μ are added in the Echinococcus Granulosus Cysts culture fluid of 990 μ l
The mother solution of l obtains PQ401 intervention group 5 after 6. mixing；Take 1000 μ L Echinococcus Granulosus Cysts culture fluid and obtain negative group；990 μ l's
DMSO group is obtained after Echinococcus Granulosus Cysts culture fluid adds the DMSO mixing of 10 μ l.
1.1.7 experimental procedure
The Echinococcus Granulosus Cysts vesicle of a diameter of 2 mm to 3 mm is separately added on 24 well culture plates, in each hole 15
To 20 Echinococcus Granulosus Cysts vesicles, then equipped with being separately added into PQ401 intervention on 24 well culture plates of Echinococcus Granulosus Cysts vesicle
Group 1(25 μ g/ml PQ401), 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, carry out (the design the 0th of orifice plate basis for this experiment
For it is the time changing liquid and counting for convenience).Not very the 0th day, this experimental period was 2 days, shone within the 2nd day, carrying out hole
Phase laboratory observation, then with transmission electron microscope observing vesicle microstructure；After 2nd day, Echinococcus Granulosus Cysts vesicle is external dry through PQ401
Pre-survival rate figure is as shown in Figure 1；After 2nd day, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Fig. 2 by negative group；DMSO after 2nd day
The Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Fig. 3 by group；After 2nd day, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in by PQ401 intervention group 1
Fig. 4；After 2nd day, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Fig. 5 by PQ401 intervention group 2；After 2nd day, PQ401 intervention group 3 is to carefully
The Electronic Speculum figure of grain echinococcus vesicle is shown in Fig. 6；After 2nd day, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Fig. 7 by PQ401 intervention group 4；The
After 2 days, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Fig. 8 by PQ401 intervention group 5.
After can be seen that external intervention 2 days by Fig. 1 to Fig. 8, thin in PQ401 intervention group 1 and PQ401 intervention group 2
Grain echinococcus vesicle is the most dead, and the cell membrane of Electronic Speculum result display Echinococcus Granulosus Cysts vesicle is destroyed, and structure is imperfect, skin
Confluent monolayer cells is downright bad, nucleus swelling, and nuclear matrix density is extremely low, mitochondrial swelling, and endoplasmic reticulum height is expanded, and microtriche structure does not almost have
Having, syncytium band structure is the most imperfect；Illustrate that in vitro under experiment condition, the PQ401 of low concentration (2 days) at short notice is the most right
Echinococcus Granulosus Cysts vesicle has higher toxic action, and prompting PQ401 is the external insecticide of a kind of Echinococcus Granulosus Cysts worm.
Two. (insulin-like growth factor receptor suppresses insulin-like growth factor acceptor inhibitor PQ401 experiment in vivo
Agent PQ401 is called for short PQ401)
1. PQ401 Mouse Acute Toxicity experiment
1.1 experiment purposes: obtain the intraperitoneal injection mode various dose PQ401 acute toxicity to Kun ming white mouse
Data.
1.2 experiment contents:
In order to grope the drug dose of PQ401 treatment echinococcosis granulosa mouse model, design PQ401 chmice acute poison
Property experiment.This experiment lowest dose level uses 1000 mg/kg, and is incremented by the dosage of PQ401 successively according to survival rate data.Each
2 Kun ming white mouse of dosage choice, 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 uses 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, according in this Rapid Dose Calculation pharmacodynamic experiment
The medicine high dose group of PQ401 is 100mg/kg, and low dose group is 50mg/kg.
2. PQ401 mouse pharmacodynamic experiment
2.1 experiment purposes: obtain intraperitoneal injection mode various dose PQ401 to echinococcosis granulosa mouse model
Pharmacodynamic Data.
2.2 experiment content
2.2.1 echinococcosis mouse model is set up:
(1) selecting the uniform Echinococcus Granulosus Cysts vesicle of a diameter of 2mm-to 3mm under aseptic condition, lumbar injection connects
Plant in Mice Body.
Kun ming white mouse, 6 week old to 8 week old, body weight 20g to 25g.Notice that operation wants steady, otherwise damage bigger；Inject
During 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, checks echinococcosis granulosa mouse species mould by Abdominal B type ultrasonography
, there is the Kun ming white mouse of the diameter Echinococcus Granulosus Cysts vesicle more than 0.5cm in type, for the successful echinococcosis granulosa of modeling in abdominal part
Mouse model.
2. mouse model: lumbar injection is divided into group of solvents, model group, positive drug group (ABZ group i.e. albendazole group), controls
Treatment group (PQ401 high dose group, PQ401 low dose group), totally 5 groups, often group 10, calculate 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 i.e. albendazole
Group), model group (be called for short M group) and group of solvents (abbreviation R group), PQ401 high dose group dosage is that 100 mg/kg, PQ401 are low
Dosage group dosage is 50 mg/kg, positive drug group is administered albendazole, and dosage is 50mg/kg, and model group is note
Penetrating normal saline, group of solvents is the solvent of injection 8% Tween 80+8% ethanol, and dosage is 20ml/kg, often 10 mice capsules of group
Type echinococcosis animal model, lumbar injection 3 times a week, is administered 3 weeks.(2) 50 mice echinococcosis granulosa animal model application
" PEMS 3.1 for Windows ", software random packet, numbering, to list, weigh, record, dye marker often organizes 1,2,3,4,5
Number.
(3) according to the medicine of the test plan each concentration of preparation: (same group is given by same concentration difference dose)
The configuration of solvent (8% Tween 80+8% ethanol):
Precision weighs 24g Tween 80 (pharmaceutical grade), is settled to 150ml with PBS, shakes up with vortice, 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 16%
Ethanol 150ml, with 0.22 Mm filter membrane filtration degerming 2 times.Take 16% Tween 80 after filtration sterilization and 16% second respectively
Alcohol same volume mixes, and obtains required concentration solvent 300ml standby.
PQ401 high dose group: precision weighs 105mgPQ401, is placed in sterilized mortar, adds 21ml configured good
Above-mentioned solvent (8% ethanol+8% Tween 80) be fully ground and mix, be 100mg/kg (5mg/ml) dosage.
PQ401 low dose group:
Precision weighs 54mgPQ401, is placed in sterilized mortar, adds the configured good above-mentioned solvent (8% of 21.6ml
Ethanol+8% Tween 80) it is fully ground and mixes, it is 50mg/kg (2.5mg/ml) dosage.
Positive drug group:
Precision weighs 57mg ABZ, is placed in sterilized mortar, adds configured good above-mentioned solvent (8% second of 22.8ml
Alcohol+8% Tween 80) it is fully ground and mixes, it is 50mg/kg (2.5mg/ml) dosage.
Model group: normal saline.
Group of solvents: solvent (8% Tween 80+8% ethanol).
Above-mentioned 5 medicinal liquids assembled, tighten and use sealed membrane good seal, are placed in liquid nitrogen cryogenics sterilizing (20min), and moment freezes
Form solid, be subsequently placed in the constant water bath box of 37 DEG C thawing, such repeatable operation 3 times, carry out sterilizing with this；Sterilizing is complete
Become to be placed on 4 DEG C of Refrigerator stores, standby for experiment.
(4) intraperitoneal injection puts to death echinococcosis granulosa mouse model after 3 weeks, collects the particulate of every mice respectively
Echinococcus vesicle weighs weight and the number of record Echinococcus Granulosus Cysts vesicle, the capsule weight in wet base of each experimental group of statistical analysis and particulate spine
Ball larva of a tapeworm or the cercaria of a schistosome vesicle number, as shown in Figure 9, Echinococcus Granulosus Cysts vesicle number statistical analysis figure is shown in Figure 10 institute to capsule weight in wet base statistical analysis figure
Showing, each experimental group randomly chooses the Echinococcus Granulosus Cysts vesicle of 2 mices for transmission electron microscope, observation microstructure.PQ401 height agent
The Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in that the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in figure by Figure 11, PQ401 low dose group by amount group
12, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Figure 13 by positive drug group, and the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in by model group
Figure 14, the Electronic Speculum figure of Echinococcus Granulosus Cysts vesicle is shown in Figure 15 by group of solvents.
By Fig. 9 to Figure 10 it can be seen that the capsule weight in wet base of PQ401 high dose group and positive drug group and Wall of Echinococcus
Bubble number all significantly reduces, and PQ401 high dose group and positive drug group have the drug effect of suitable treatment echinococcosis granulosa.Pass through
Figure 11 to Figure 15 it can be seen that the Echinococcus Granulosus Cysts vesicle Change of Ultrastructure of PQ401 high dose group and positive drug group is notable,
Echinococcus Granulosus Cysts follicle cell is the most downright bad, the Echinococcus Granulosus Cysts vesicle tissue necrosis degree relatively positive drug that PQ401 is caused
The Echinococcus Granulosus Cysts vesicle degree of necrosis of group is high.PQ401 high dose group Echinococcus Granulosus Cysts vesicle, horny layer is thinning or disappears, micro-
The in disorder rareness of hair is irregular；Cortical area is the most thinning, a large amount of transparent cavity, lysosome increasing occurs simultaneously.Germinal layer cell or solution
From or disappear or degeneration necrosis (membranolysis), structural fuzzy is unclear, kernel or scatter or disappears, even seen from the bare nucleus of apoptosis
Cell.Positive drug group Echinococcus Granulosus Cysts vesicle, horny layer loosens crack, and cortical area is thinning, and microtriche is rare, cell in stratum germinativum
Gap becomes big, and cortical cell quantity is few and degeneration, and kernel scatters or disappears, and core heterochromatin increases, and limit collection；It addition,
Disorderly, texture is unintelligible in cortical area myofibroblasts beam spreading.PQ401 low dose group Echinococcus Granulosus Cysts vesicle ultrastructure occurs certain
Changing unit cell death, horny layer structure thin, the rare irregular arrangement of microtriche；Stratum germinativum is thinning, cortical area content
Seldom, transparent marrow sample corpusculum or cavity, lysosome increasing, the cortex of the even visible damaged degeneration of fascicula distribution at random occur
Cell, karyomorphism is irregular, 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 life
Sending out layer homogeneous, clear in structure can be distinguished, there is the bright vesicle that many compact size are more uniform cortical area, and its surface microtriche is fine and close
Abundant, marshalling；The germinal layer cell of cortical area is regular, and nuclear structure is fine and close, and core is big and round, the clear heterochromatin of nucleolar structure
Less one-tenth is reunited；It addition, cortical area myofibroblasts clear in structure can be distinguished.Illustrate to be done by echinococcosis mouse model medicine
Preliminary experiment, shows that PQ401 lumbar injection mode is administered and can treat mice echinococcosis granulosa, its therapeutic effect and albendazole
Therapeutic effect is suitable.
In sum, insulin-like growth factor acceptor inhibitor PQ401 of the present invention is a kind of novel anti-echinococcosis medicine
Thing；Internal and external both sides pharmacodynamic experiment data, 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 the most downright bad；Internal pharmacodynamics
Experimental data shows that the drug effect of the Albendazole In Treatment echinococcosis granulosa that this medicine is conventional with clinic is suitable；In view of clinical packages parasitosis
Patient's long-term taking albendazole can cause drug resistance, and therefore this medicine can carry out treating Echinococcus hydatid cyst as the succedaneum of albendazole
Sick.
Table 1 PQ401 Mouse Acute Toxicity experimental data
| Dosage (mg/kg) | It is administered 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 in the application preparing treatment echinococcosis granulosa medicine.
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