CN105078947A - Purpose of nolvadex - Google Patents

Purpose of nolvadex Download PDF

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CN105078947A
CN105078947A CN201510481096.2A CN201510481096A CN105078947A CN 105078947 A CN105078947 A CN 105078947A CN 201510481096 A CN201510481096 A CN 201510481096A CN 105078947 A CN105078947 A CN 105078947A
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tamoxifen
medicine
fragile
syndrome
pharmaceutically acceptable
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王红兵
任建华
李轩
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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
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine

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  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The invention discloses the purpose of nolvadex and belongs to the technical field of biological medicine. In vitro cell culture tests prove that the nolvadex can inhibit mGluR1/5 and Gq-mAChR receptor activity or intracellular signal transduction caused by mGluR1/5 and Gq-mAChR receptor activation, reduce or stop the overactivity of the two receptors, and eliminate or weaken the adverse effect caused by the overactivity on cell functional changes. Meanwhile, autism and fragile X syndrome animal model tests prove that the nolvadex can correct hyperactivity behaviors and repeated behaviors, recover passive escape memory ability and contextual fear memory ability and correct the cognition ability defects of autism and fragile X syndrome animal models. The nolvadex can be made into medicine for preventing and treating autism and fragile X syndrome, and the medicine has potential clinical application value.

Description

The purposes of tamoxifen
Technical field
The present invention is specifically related to a kind of purposes of tamoxifen, belongs to biomedicine technical field.
Background technology
Along with the increase of new drug development difficulty and development cost, the large drugmaker in countries in the world progressively payes attention to the secondary development to drug products, and the new indication that there is medicine as expanded, exploitation novel form etc., to obtaining new effective medicine.The clinical observation of old medicine long a large amount of case after listing, its safety is guaranteed, untoward reaction understanding comprehensively, and chemistry or biosynthesis pathway ripe, develop its new indication purposes, the cost that pre-clinical assay expends also can be saved relatively.Therefore, to the old medicine of clinical practice, expand the indication purposes that it is new, can greatly promote that clinical treatment develops, save health resources, extend old medicine life cycle commercially simultaneously.
Tamoxifen (Tamoxifen), also known as tamoxifen, chemical name: (Z)-N, N-dimethyl-2-[4-(1,2-diphenyl-1-butylene base) phenoxy group] ethamine, molecular formula: C 26h 29nO, molecular weight: MW371, character: white or faint yellow brilliant end, odorless, its citrate crystalline melt point is 142 DEG C.The main salt of tamoxifen is Tamoxifen Citrate and TAMOXIFEN CITRATE.After taking, its main effectively metabolic derivative is that (afimoxifene, namely A Fei former times is fragrant, molecular formula: C for 4-hydroxyl-tamoxifen 26h 29nO 2) and N-demethyl tamoxifen (endoxifen).Other chemical synthetic derivatives such as cis-tamoxifen (cis-tamoxifen) also has the chemism similar to tamoxifen.Shown in the following formula I of chemical constitution of tamoxifen:
Tamoxifen (ICI46474) is researched and developed by ICI company (nowAstraZeneca) at first, have and block estrogen functions of hormones in human body, it is the important drugs for the treatment of women and male breast carcinoma, its direct effect target spot is estrogen receptor, the intracellular molecules physiological behavior caused with estrogen capable of blocking after receptors bind, T suppression cell is mitogenetic, thus controls developing of breast carcinoma.
After the oral 20mg of tamoxifen, 4 ~ 7h reaches blood peak concentration of drug, is 0.14 μ g/ml.Administration 4 days or longer time after due to enterohepatic circulation occur second time peak.Half-life β phase is greater than 7 days, and α phase is 7 ~ 14h.Tamoxifen is at intrahepatic metabolism, and major metabolite is N-demethyl tamoxifen and 4-OHT, and major part is discharged by feces with conjugate form, discharges on a small quantity from urine.It is 5 ~ 7 days that its parent compound removes the half-life, and metabolite nitrogen-demethyl tamoxifen is 14 days.Because the tamoxifen half-life is longer, cerebral tissue can be entered through blood brain barrier, and can long-term taking, explore its new indication purposes and can not only save clinical trial cost, also help and promote clinical treatment development, extend its market clusters.
At present, Chinese infantile autism patient, more than 1,300 ten thousand, accounts for 1/100 of population, and about have in worldwide tens million of to 100,000,000 ASD and FXS Disease.Fragile X syndrome (FragileXsyndrome, FXS) also claims Martin's Bayer syndrome, and being a kind of intelligence amentia disease caused by inherited genetic factors, is the most pandemic infantile autism caused by term single gene.The a little higher than women of sickness rate in male.FXS lacks FMRP (FragileXMentalRetardationProtein) protein due to the sudden change of gene Fmr1 (fragileXmentalretardation1) to cause.Fmr1 gene is positioned at " the fragile sites Xq27.3 " of X chromosome.FXS patient has excessive CGG repeated fragment (mutant has more than 200 repeated fragments) in 5 end untranslated regions of Fmr1 gene, normal human is then about 30.This sudden change causes Fmr1 genetic transcription to stop, thus causes the expression of FMRP albumen to reduce.Because FMRP albumen is translated by suppressing it with the specific binding of mRNA, it is expressed and reduces and will cause the excessive synthesis of some specific proteinses, thus affects the normal physiological function of brain cell.
FXS shows the different dysnoesia defect of series, and has manifest symptom in ontogeny.The neuroethology main manifestations of patient FXS is (being not limited only to): intellectual deficiency, moves more, repeated stereotyped action, epilepsy, doings anxiety, communication disorder etc.; Cytology shows as the exception of dendritic spine; In formalness, main manifestations is (being not limited only to): face longitudinal tensile strain, and external ear is bigger than normal or excessively outstanding, and after adolescence, male testical is excessive, flatfoot and muscular tension etc. on the low side.
Research display, knocks out the homogenic mice of mankind Fmr1 consistent with the clinical symptoms height of mankind FXS patient and infantile autism patient with physiological performance in behavioristics.Such as Fmr1 knock out mice shows cognitive defect, is easy to epilepsy, hyperkinetic syndrome, human communication disorders and repeated behavior etc. occur, and the huge testis disease similar with male patient appears in male mice.Histological research finds the spinous process increase in density of Fmr1 knock out mice, and has the spinous process of developmental immaturity in brain, and mice also shows typical infantile autism feature in addition, as occurred human communication disorders, repeated behavior and linking up defect etc.At present, Fmr1 knock out mice is used for the treatment of in the test of infantile autism and FXS medicine in research and development is used widely, and some compounds utilizing Fmr1 knock out mice to research and develop have gone through to enter human clinical trial.
Owing to understanding limited to the pathomechanism of FXS and infantile autism, up to now still not for the specific medicament of this kind of disease.Early diagnosis early intervention, specific education and behavior healing training are the major ways preventing and treating FXS and infantile autism at present, and therefore developing the new medicine effectively preventing and treating above-mentioned nervous system disease will have far-reaching social meaning.
Summary of the invention
The object of this invention is to provide a kind of purposes of tamoxifen.
Meanwhile, the present invention also provides a kind of pharmaceutical composition containing tamoxifen effective ingredient.
In order to realize above object, the technical solution adopted in the present invention is:
The purposes of tamoxifen, be specially tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism be 4-hydroxyl-tamoxifen, N-demethyl tamoxifen compound for the preparation of the application in control infantile autism, fragile X syndrome and related indication medicine thereof.
Described tamoxifen pharmaceutically acceptable salt, fat, solvate and can metabolism is 4-hydroxyl-tamoxifen in vivo, the concrete kind of the compound of N-demethyl tamoxifen and structure be prior art, such as tamoxifen pharmaceutically acceptable salt is selected from Tamoxifen Citrate, TAMOXIFEN CITRATE etc., repeats no more herein.
Described infantile autism, fragile X syndrome refer to that being diagnosed as performance according to clinical symptoms has one or more above-mentioned disease feature; Related symptoms can be one or more related secondary clinical symptoms showed due to infantile autism and/or fragile X syndrome.The core symptom of infantile autism is human communication disorders, communication disorder and repeated behavior etc.The cardinal symptom of FXS comprises dysnoesia obstacle, human communication disorders, communication disorder, repeated behavior and hyperkinetic syndrome and epilepsy etc.Related secondary clinical symptom comprises epilepsy, dysnoesia etc.
The described medicine for preventing and treating above-mentioned disease and symptom, it contains tamoxifen or its pharmaceutically acceptable salt, fat, the solvate of pharmacy effective dose, also or in vivo metabolism is the compound of 4-hydroxyl-tamoxifen, N-demethyl tamoxifen, and one or more pharmaceutically acceptable carriers (i.e. pharmaceutically useful adjuvant).Described medicine is prepared by conventional pharmaceutical method, dosage form is not limit, as made with the tablet of administered in oral forms, capsule, granule, powder, syrup etc., or with the injection of non-oral mode administration, and import body as muscle, Intradermal, subcutaneous, vein, mucosal tissue etc. by the mode of the physics such as oral (tablet, capsule, powder etc.), injection or chemistry mediation.
Described carrier comprises the excipient of pharmaceutical field routine, binding agent, disintegrating agent, lubricant, stabilizing agent, correctives, diluent or solvent, filler, wetting agent, absorption enhancer, surfactant, absorption carrier, lubricant etc.Excipient comprises carbohydrate derivative as lactose, sucrose, glucose, mannitol and Sorbitol, starch derivatives is as corn starch, potato starch, dextrin and carboxymethyl starch, cellulose derivative is as crystalline cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, carboxymethylcellulose calcium, sodium carboxymethyl cellulose, arabic gum, dextran, silicate derivative is as Neusilin US2, phosphate derivative is as calcium phosphate, carbonate derivative is as calcium carbonate, and sulfate-derivatives is as calcium sulfate etc.; Described binding agent comprises gelatin, polyvinylpyrrolidone, Polyethylene Glycol etc.; Described disintegrating agent comprises cellulose derivative as carboxymethyl cellulose, polyvinylpyrrolidone etc.; Described lubricant comprises Talcum, magnesium stearate, spermaceti, boric acid etc.; Described stabilizing agent comprises methyl parahydroxybenzoate, propyl p-hydroxybenzoate etc.; Described correctives comprises conventional sweeting agent, acidic flavoring agent and spice etc.; Diluent or injection solvent comprise water, ethanol and glycerol, etc.
The purposes of tamoxifen, also comprise tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism be 4-hydroxyl-tamoxifen, the compound of N-demethyl tamoxifen for the preparation of the application suppressed in mGluR1/5 and Gq-mAChR receptor active or the medicine of intracellular signal transduction that caused by mGluR1/5 and Gq-mAChR receptor activation, and for the preparation of the application of correcting in the medicine of hyperactivity behavior, repeated behavior, dysnoesia (or learning and remembering ability decline); Or for the preparation of the application suppressed in mGluR1/5 and Gq-mAChR receptor active in infantile autism or fragile X syndrome or the medicine of intracellular signal transduction that caused by mGluR1/5 and Gq-mAChR receptor activation, and for the preparation of the application of correcting in the medicine of the hyperactivity behavior caused by infantile autism or fragile X syndrome, repeated behavior, dysnoesia (or learning and remembering ability decline).
For preventing and treating infantile autism, fragile X syndrome and related indication pharmaceutical composition thereof, it contains tamoxifen or its pharmaceutically acceptable salt, fat, the solvate of pharmacy effective dose, also or in vivo metabolism is the compound of 4-hydroxyl-tamoxifen, N-demethyl tamoxifen, and pharmaceutically acceptable carrier (i.e. pharmaceutically useful adjuvant).
Described tamoxifen pharmaceutically acceptable salt, fat, solvate and can metabolism is 4-hydroxyl-tamoxifen in vivo, the concrete kind of the compound of N-demethyl tamoxifen and structure be prior art, with above-mentioned.
Described carrier comprises the excipient of pharmaceutical field routine, binding agent, disintegrating agent, lubricant, stabilizing agent, correctives, diluent or solvent, filler, wetting agent, absorption enhancer, surfactant, absorption carrier, lubricant etc., with above-mentioned.
Described tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism be 4-hydroxyl-tamoxifen, N-demethyl tamoxifen the dosage of compound different with differences such as patient age, sex, the state of an illness, general dosage is 1 ~ 40mg/ day.
Beneficial effect of the present invention:
The overacfivity of the mAChR of metabotropic glutamate receptor 1/5 and Gq coupling is a kind of important cells mechanism causing infantile autism and Fragile X syndrome.The present invention proves by Cell culture invitro test the intracellular signal transduction that tamoxifen can suppress mGluR1/5 and Gq-mAChR receptor active or be caused by mGluR1/5 and Gq-mAChR receptor activation, reduce or block the overacfivity of these two kinds of receptors, eliminating or weaken its cellular function and change the harmful effect brought.
Fmr1 knock out mice shows the clinical symptoms identical with mankind FXS and infantile autism patient in behavioristics with physiology, such as, occur hyperkinetic syndrome, repeated behavior and cognitive disorder etc.By infantile autism and Fragile X syndrome animal model (i.e. Fmr1 gene knock-out mice model) test, the present invention proves that tamoxifen can correct hyperactivity behavior and repeated behavior, recover its passive escape memory ability and scene fear memory ability, correct the cognitive competence defect of infantile autism and Fragile X syndrome animal model.
The present invention has the following advantages: 1) at present infantile autism and FXS disease mainly rely on behavioral intervention and specific education to guide, and there is no specific treatment medicine, tamoxifen be first potential in infantile autism and the pathogenetic medicine of FXS disease; 2) for some clinical severity of infantile autism and FXS disease, current clinical application is only treated for single symptom usually, and tamoxifen then can correct multiple symptom on the whole simultaneously; 3) tamoxifen can pass through blood brain barrier, and then plays the prevention effect for nervous system disease.
Accompanying drawing explanation
Fig. 1 be in test example tamoxifen on the impact of phosphorylated CREB 1/2 and overall ERK1/2 level;
Fig. 2 is the impact of tamoxifen on the behavior of Fmr1 knock out mice hyperactivity;
Fig. 3 is the impact of tamoxifen on the behavior of Fmr1 knock out mice repeatability;
Fig. 4 is the impact of tamoxifen on the passive escape memory ability of Fmr1 knock out mice;
Fig. 5 is the impact of tamoxifen on Fmr1 knock out mice scene fear memory ability.
Detailed description of the invention
Following embodiment is only described in further detail the present invention, but does not form any limitation of the invention.
Embodiment 1
The purposes of tamoxifen in the present embodiment, be specially tamoxifen for the preparation of control infantile autism, fragile X syndrome and related indication medicine in application, the preparation method of medicine is prior art, repeats no more herein.
Embodiment 2
The purposes of tamoxifen in the present embodiment, be specially Tamoxifen Citrate for the preparation of control infantile autism, fragile X syndrome and related indication medicine in application, the preparation method of medicine repeats no more herein.
Embodiment 3
The purposes of tamoxifen in the present embodiment, be specially TAMOXIFEN CITRATE for the preparation of control infantile autism, fragile X syndrome and related indication medicine in application, the preparation method of medicine repeats no more herein.
Embodiment 4
The purposes of tamoxifen in the present embodiment, be specially cis-tamoxifen for the preparation of control infantile autism, fragile X syndrome and related indication medicine in application, the preparation method of medicine repeats no more herein.
Test example
Tamoxifen is on the clinical of model mice and mechanism impact test:
(1) tamoxifen suppresses the intracellular signalling pathways that mGluR1/5 and Gq-mAChR receptor activation causes
Basic Mechanism: by finding the research of Fmr1 knock out mice neuronal cell function, the excessive activation of the mAChR (Gq-mAChR) of metabotropic glutamate receptor 1/5 (mGluR1/5) and Gq coupling is a kind of important cells mechanism causing infantile autism and Fragile X syndrome.Therefore, any medicine that effectively can hinder the activity of mGluR1/5 and Gq-mAChR two kinds of receptors or the Cellular Signaling Transduction Mediated by their mediations, can reach certain effect of curing the disease.
Test method: adopt the Hippocampal Neuron Cells of original cuiture as test material, with activator DHPG (100 micromoles of mGluR1/5, process in 30 minutes) and activator carbachol (100 micromoles of Gq-mAChR, CCH, process in 30 minutes) activate this two kinds of receptors respectively.Phosphorylation due to ERK1/2 is that the direct signal after these two kinds of receptor activations conducts result, the phosphorylation level (p-ERK1/2) of ERK1/2 is as measurement target, and the level of overall ERK1/2 (comprising the comprehensive of phosphorylation and non-phosphorylating ERK/2) is as standardized index.Except matched group and activator processed group, other two groups of cells accept tamoxifen (TAMOXIFEN CITRATE or tetrahydroxy tamoxifen respectively, TAM, 5 micromoles), tamoxifen (TAMOXIFEN CITRATE or tetrahydroxy tamoxifen, TAM, 5 micromoles) add activator process.Cell lysis after process in 30 minutes, protein component in electrophoretic isolated cell, and by electrotransfer on nitrocellulose filter, adopt WesternBlot method to detect phosphorylated CREB 1/2 and overall ERK1/2 level, result of the test is shown in A, B in Fig. 1.
Result of the test: phosphorylated CREB 1/2 level significantly increases after DHPG (in see Fig. 1 A) and carbachol (in see Fig. 1 B) process; Tamoxifen effectively can reduce the impact (p < 0.05) of DHPG and carbachol on phosphorylated CREB 1/2 level.Result of the test shows that tamoxifen and effective metabolite (tetrahydroxy tamoxifen) thereof effectively can hinder mGluR1/5 and Gq-mAChR two kinds of receptor-mediated Cellular Signaling Transduction Mediateds, has potential therapeutic effect to infantile autism and Fragile X syndrome.
(2) tamoxifen corrects the hyperactivity behavior of Fmr1 knock out mice
Basic Mechanism: hyperactivity is a typical clinical phenotype of infantile autism and Fragile X syndrome patient, and Fmr1 knock out mice also shows hyperactivity behavior.If tamoxifen can correct the hyperactivity behavior of Fmr1 knock out mice, then show that tamoxifen has the drug effect of hyperkinetic syndrome in treatment infantile autism and Fragile X syndrome.
Test method: the moving situation of test mice in spacious field.Wild type (WT) or Fmr1 knock out mice be lumbar injection solvent (VC, 2 percent ethanol) or tamoxifen (TMF, citrate) first, and injection volume is 1 milligram/every kilogram Mouse Weight.Inject after 12 hours and mice is placed in spacious field case (40cm length, 40cm is wide, 40cm is high) in, adopt the movement time of automatic measurement system detection mice, move distance, the movement time in spacious center court region, the move distance in spacious center court region and enter the number of times in spacious center court region, Measuring Time is 2 hours, the every 10min of above data adds up 1 time, and the summation effect of 2 hours every data is shown in A, B, C, D, E in Fig. 2.
Result of the test: the hyperkinetic syndrome performance of Fmr1 knock out mice significantly, is specially: the dynamic motion time increases (see A in Fig. 2), dynamic motion distance increases (see B in Fig. 2), increases (see C in Fig. 2) to the time of central area, place, obviously increases (see E in Fig. 2) to the number of times that the move distance of central area increases (see D in Fig. 2), enter central area.Compared with the matched group of injection solvent, in tamoxifen treatment group, the activeness of the different index of Fmr1 knock out mice all significantly reduces.Show that tamoxifen can be used for the hyperactivity behavior of correcting hyperkinetic syndrome or being caused by infantile autism or Fragile X syndrome.
(3) tamoxifen corrects the repeated behavior of Fmr1 knock out mice
Basic Mechanism: repeated behavior is one of typical clinical symptom of infantile autism and Fragile X syndrome patient, Fmr1 knock out mice also shows significant repeated behavior.If tamoxifen can correct Fmr1 knock out mice repeated behavior, then show that tamoxifen has the drug effect of repeated behavior in treatment infantile autism and Fragile X syndrome.
Test method: the shuttle back and forth behavior of test mice between light-dark case.Wild type (WT) or Fmr1 knock out mice be lumbar injection solvent (VC, 2 percent ethanol) or tamoxifen (TMF, citrate) first, and injection volume is 1 milligram/every kilogram Mouse Weight.Inject and after 12 hours, mice to be placed in light-dark case (it is long that bright case, camera bellows are 20cm, 20cm is wide, 20cm is high, bright case has illumination, the opening that 5cm is wide and 5cm is high is had between bright case and camera bellows, can shuttle back and forth between bright case and camera bellows for mice), measure mice shuttling back and forth number of times and the time of staying in bright case between light-dark case, Measuring Time is 10 minutes.Relatively mice is at the behavioral data (in see Fig. 3 B) of first 5 minutes (in see Fig. 3 A) and whole 10 minutes.
Result of the test: the shuttle back and forth number of times of Fmr1 knock out mice between light-dark case is more, shows obvious repeated behavior, and inject the Fmr1 knock out mice of tamoxifen repeated behavior be improved significantly (see A1, B1 in Fig. 3).Fmr1 knock out mice and the time of staying of normal mouse in bright case do not have notable difference (in see Fig. 3 A2, B2).Show that tamoxifen can be used for the repeated behavior of correcting repeated behavior or being caused by infantile autism or Fragile X syndrome.
(4) tamoxifen corrects the passive escape memory ability of Fmr1 knock out mice
Basic Mechanism: dysnoesia is one of typical clinical symptom of infantile autism and Fragile X syndrome patient.Passive escape memory and learning behavior are the methods to intelligent test conventional in animal model.If tamoxifen can correct Fmr1 knock out mice passive escape memory impairment, then show that tamoxifen has the drug effect of dysnoesia in treatment infantile autism and Fragile X syndrome.
Test method: wild type (WT) or Fmr1 knock out mice be lumbar injection solvent (VC, 2 percent ethanol) or tamoxifen (TMF, citrate) first, and injection volume is 1 milligram/every kilogram Mouse Weight.(it is long that bright case, camera bellows are 20cm to inject the bright case side after 12 hours, mice being placed in the passive training box that escapes learning, 20cm is wide, and 20cm is high, and bright case has illumination, there is the opening that 5cm is wide and 5cm is high between bright case and camera bellows, can shuttle back and forth between bright case and camera bellows for mice).After mice enters camera bellows, the door connected between bright camera bellows is closed, and give electric shock stimulates (0.7 milliampere, 2 seconds stimulated) simultaneously, within 30 seconds, shifts mice afterwards and is back to rearging cage.Memorability test is carried out after 24 hours.During test, first mice is placed at bright case side, if mice remembers camera bellows side dangerous (electricity irritation), then mice can continue to rest on bright case side, and the time entering camera bellows will extend.The time of staying of mice before entering camera bellows in bright case is as the parameter measuring mice learning and memory power.
Result of the test: as shown in Figure 4, four groups of mices enter camera bellows side all very soon when learning training (Train).When testing learning effect and memory (Test), compared with wild-type mice, solvent injection Fmr1 knock out mice enters camera bellows side soon, shows that the passive escape memory ability of Fmr1 knock out mice significantly weakens.Passive escape memory ability and the wild-type mice of tamoxifen injection Fmr1 knock out mice are basically identical, illustrate that tamoxifen can improve the passive of Fmr1 type mice and escape learning and memory ability, the passive escape memory ability that tamoxifen can be used for correcting the decline of passive escape memory ability or being caused by infantile autism or Fragile X syndrome declines.
5, tamoxifen corrects the scene fear memory ability of Fmr1 knock out mice
Basic Mechanism: dysnoesia is one of typical clinical symptom of infantile autism and Fragile X syndrome patient.The frightened learning and memory of scene is the method to intelligent test conventional in animal model.If tamoxifen can correct the scene fear memory defect of Fmr1 knock out mice, then show that tamoxifen has the drug effect of dysnoesia in treatment infantile autism and Fragile X syndrome.
Test method: wild type (WT) or Fmr1 knock out mice be lumbar injection solvent (VC, 2 percent ethanol) or tamoxifen (TMF, citrate) first, and injection volume is 1 milligram/every kilogram Mouse Weight.Inject the scene fear memory ability of to test after 12 hours each group of mice.When accepting scene fear learning training, (40cm is long first mice to be placed in the frightened training box of scene, 40cm is wide, 40cm is high), after 2 minutes, electricity irritation (0.7 milliampere, 2 seconds stimulated) is carried out to mice, after 60 seconds, mice is transferred in rearging cage, after 24 hours, carries out Memorability test.First mice is placed in scene frightened training box during test, if mice learns and remembers once to suffer electric shock in this scene, then can show frightened behavior, i.e. stiff behavior, and associated movement reduces.
Result of the test: as shown in Figure 5, four groups of mices all show similar kinematic parameter when learning training (Train).When testing learning effect and memory (Test), compared with wild-type mice, solvent injection Fmr1 knock out mice shows more motor behavior (in Fig. 5 A) and less stiff behavior (in Fig. 5 B), shows that the scene fear memory ability of Fmr1 knock out mice significantly weakens.Scene fear memory ability and the wild-type mice of tamoxifen injection Fmr1 knock out mice are basically identical, illustrate that tamoxifen can improve the scene fear note learning and memory ability of Fmr1 type mice.Tamoxifen can be used for the scene fear memory ability decline of correcting the decline of scene fear memory ability or being caused by infantile autism or Fragile X syndrome, show that tamoxifen can be used for treating the dysnoesia caused by infantile autism or Fragile X syndrome, there is potential clinical value.

Claims (7)

1. the purposes of tamoxifen, it is characterized in that: tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism be 4-hydroxyl-tamoxifen, N-demethyl tamoxifen compound for the preparation of the application in control infantile autism, fragile X syndrome and related indication medicine thereof.
2. purposes according to claim 1, it is characterized in that: tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism is 4-hydroxyl-tamoxifen, the compound of N-demethyl tamoxifen is for the preparation of the application suppressed in mGluR1/5 and Gq-mAChR receptor active or the medicine of intracellular signal transduction that caused by mGluR1/5 and Gq-mAChR receptor activation.
3. purposes according to claim 1, it is characterized in that: tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism be 4-hydroxyl-tamoxifen, N-demethyl tamoxifen compound for the preparation of the application of correcting in the medicine of hyperactivity behavior, repeated behavior.
4. purposes according to claim 1, it is characterized in that: tamoxifen or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism is 4-hydroxyl-tamoxifen, the compound of N-demethyl tamoxifen is for the preparation of the application of correcting in medicine that dysnoesia or learning and remembering ability decline.
5. the purposes according to any one of Claims 1 to 4, is characterized in that: tamoxifen pharmaceutically acceptable salt is Tamoxifen Citrate, TAMOXIFEN CITRATE.
6. for preventing and treating infantile autism, fragile X syndrome and related indication pharmaceutical composition thereof, it is characterized in that: the tamoxifen containing pharmacy effective dose in pharmaceutical composition or its pharmaceutically acceptable salt, fat, solvate, also or in vivo metabolism is the compound of 4-hydroxyl-tamoxifen, N-demethyl tamoxifen, and pharmaceutically acceptable carrier.
7. pharmaceutical composition according to claim 6, is characterized in that: tamoxifen pharmaceutically acceptable salt is Tamoxifen Citrate, TAMOXIFEN CITRATE.
CN201510481096.2A 2015-08-07 2015-08-07 Purpose of nolvadex Pending CN105078947A (en)

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Publication number Priority date Publication date Assignee Title
WO2008133884A2 (en) * 2007-04-23 2008-11-06 Combinatorx, Incorporated Methods and compositions for the treatment of neurodegenerative disorders
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Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
WO2008133884A2 (en) * 2007-04-23 2008-11-06 Combinatorx, Incorporated Methods and compositions for the treatment of neurodegenerative disorders
EP2724721A1 (en) * 2012-10-26 2014-04-30 Matentzoglu, Konstantin Composition for use in the treatment of Angelman syndrome and/or autism spectrum disorder, the use of such composition and a method for manufacturing a medicament for the treatment of Angelman syndrome and/or autism spectrum disorder

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