CN107375280A - Nitazoxanide and its pharmaceutically acceptable salt are preparing the application in being used to treat the medicine of Alzheimer disease - Google Patents
Nitazoxanide and its pharmaceutically acceptable salt are preparing the application in being used to treat the medicine of Alzheimer disease Download PDFInfo
- Publication number
- CN107375280A CN107375280A CN201610329100.8A CN201610329100A CN107375280A CN 107375280 A CN107375280 A CN 107375280A CN 201610329100 A CN201610329100 A CN 201610329100A CN 107375280 A CN107375280 A CN 107375280A
- Authority
- CN
- China
- Prior art keywords
- nitazoxanide
- pharmaceutically acceptable
- acceptable salt
- medicine
- purposes
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/426—1,3-Thiazoles
Landscapes
- Health & Medical Sciences (AREA)
- 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)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses Nitazoxanide and its pharmaceutically acceptable salt to prepare the purposes in being used to treat the medicine of Alzheimer disease, and for treating to increasing the nerve degenerative diseases that A β are removed and/or suppression Tau protein phosphorylations are related, such as the purposes of the medicine of Parkinson's etc..In the purposes, Nitazoxanide and its pharmaceutically acceptable salt can be removed by increasing A β and/or suppress Tau protein phosphorylations and play related drug effect.Nitazoxanide and its pharmaceutically acceptable salt have the obvious scavenging action for promoting Deiter's cells exogenous A β, the phosphorylation level of Tau albumen in nerve cell can significantly be suppressed, and can significantly reverse the memory injury of APP/PS1 transgenosis AD mouse to act on.
Description
Technical field
The present invention relates to pharmacotherapeutics field, and in particular to prepared by Nitazoxanide and its pharmaceutical composition
The purposes in medicine for treating Alzheimer disease, more particularly it relates to Nitazoxanide and
There is increase A β to remove and/or suppress Tau albumen phosphorus for its pharmaceutically acceptable salt or its pharmaceutical composition
It is acidified and is used to prepare the purposes in the medicines of nerve degenerative diseases such as treatment Alzheimer disease.
Background technology
Alzheimer disease (Alzheimer's Disease, AD) is a kind of progressive nervus retrogression disease
Disease, with the outer Amyloid deposition of nerve caused by A beta peptide aggregations, god caused by Protein tau Hyperphosphorylationof
It is its outstanding feature through fibre matting and neuronal apoptosis etc..AD has height age-dependent,
With age, the AD incidence of disease can be also increased sharply, and ended the whole world in 2011 and had more than 3000
With dementia, and as population in the world is aging, annual AD patient numbers' ten thousand populations are growing at top speed.
China has been enter into aged society at present, and AD, which also turns into one, to be caused life of elderly person Quality Down and cause
Dead major reason.At present, the illness of patient can only be slowed down by clinically treating AD medicine, and
AD process, therefore the hair of the new anti-AD medicines to AD pathogenesis can be blocked can not be blocked
Existing urgent demand.With progress of research, AD pathogenesis just peeps clue, A Er
Ci Haimo patient's postmortems show that obvious atrophy occurs in its brain tissue, and death extensively occurs in brain cell, when
The lesion such as visible obvious senile plaque expelling, neurofibrillary tangles at these positions.Therefore current AD hair
Interpretation of the cause, onset and process of an illness system mainly proposes two kinds of hypothesis：Amyloid beta (A β) hypothesis and Protein tau hypothesis, at present
Research think that the anti-AD medicines for this two kinds of hypothesis may have the function that blocking AD pathogenesis.
Amyloid beta (A β) hypothesis thinks that aβ protein is one of main component of senile plaque expelling, by forming sediment
Powder sample precursor protein (APP) shears generation successively through beta-secretase and gamma-secretase, and it is in cerebral tissue
Excessively increase cause nervous system produce oxidative stress, inflammatory reaction etc. ultimately result in Neuron Apoptosis and
AD generation.Therefore the generation by suppressing A β or promotion A β removing are generally believed to reduce entirety
AD can effectively be prevented or be treated to A β content in brain, and this is also current anti-AD newtype drugs
One of main R＆D direction (Yamin G, Ono K, Inayathullah M, Teplow D B.Amyloid
beta-protein assembly as a therapeutic target of Alzheimer’s disease.Current Pharmaceutical
Design,2008,14:3231-3246；Kurz A,Perneczky R.Amyloid clearance as a treatment target
against Alzheimer’s disease.Journal of Alzheimer's disease,2011,24[Suppl 2]:61-73.)。
Tau albumen hypothesis think that the neurofibrillary tangles formed by Protein tau hyperphosphorylation is finally same
The transmission of neuron mediator can be caused to damage, apoptosis of neuron etc. ultimately results in AD.Tau albumen
It is a kind of microtubule associated protein, tubulin can be promoted to be assembled into micro-pipe and maintain the structure of micro-pipe, in god
Through wide expression in tissue, and by different Hyperphosphorylationof (D.N.Drechsel, A. in AD patient's brain tissue
A.Hyman,M.H.Cobb,M.W.Kirschner.Modulation of the dynamic instability of tubulin
assembly by the microtubule-associated protein tau.Molecular biology of the cell,1992,
3,:1141).Under normal circumstances, the phosphorylation of Protein tau and dephosphorylation are in dynamic equilibrium, but abnormal feelings
Under condition, Protein tau meeting peroxophosphoric acid, the function of maintaining micro-tubular structure is lost, triggers AD, op parkinson's
The diseases such as syndrome.
Nitazoxanide, which has, suppresses acetonate, the enzyme dependence electricity of ferrodoxins oxidoreducing enzyme
The effect of son transfer, to a variety of enterozoons, such as Amoeba, Ascaris lumbricoides, hookworm, Trichuris trichiura
Etc. being respectively provided with obvious activity.In addition some researchs find Nitazoxanides also to anaerobism and microaerobion, such as
Helicobacter pylori etc. is active, also has pertinent literature to report that it has antiviral and antineoplastic action.
Nitazoxanide is clinically mainly used in the medicine of anti parasitic at present.Increase A β for it at present to remove
And/or suppress Tau protein phosphorylations, so as to play anti-Alzheimer disease (Alzheimer ' s disease,
AD effect) has no report.The present invention is further discovered that there is Nitazoxanide increase A β to remove and/or press down
The effect of Tau protein phosphorylations processed, and with the note for the transgenosis AD model mices for improving APP/PS1
Recall the effect of power damage, therefore the present invention is it has further been discovered that the potentiality that it is treated to new indication.
The content of the invention
It is an object of the present invention to provide the new pharmaceutical of Nitazoxanide and its pharmaceutically acceptable salt
On the way, i.e., it is preparing the purposes in being used to treat the medicine of Alzheimer disease.
In the purposes, Nitazoxanide and its pharmaceutically acceptable salt can suppress the phosphorus of Tau albumen
Acidifying and/or the micromolecular compound for promoting A β to remove.
The pharmaceutically acceptable salt, including inorganic acid salt, acylate, such as malate etc..
It is a further object to provide Nitazoxanide and its pharmaceutically acceptable salt as suppression
The phosphorylation of Tau albumen and/or promote the micromolecular compound that A β are removed prepare treatment removed with A β and
/ or the medicine of the related nerve degenerative diseases of Tau protein phosphorylations in purposes.
It is described to remove to A β and/or nerve degenerative diseases that Tau protein phosphorylations are related include but unlimited
In Parkinson's etc..
It is a further object of the present invention to provide the medicine group for including Nitazoxanide or its pharmaceutically acceptable salt
Purposes of the compound in preparation is used to treat the medicine of Alzheimer disease, described pharmaceutical composition include nitre
Azoles nit or its pharmaceutically acceptable salt and pharmaceutically acceptable various auxiliary materials.
The invention also discloses the pharmaceutical composition to prepare and A β removings and/or Tau protein phosphorylation phases
Purposes in the medicine of the nerve degenerative diseases of pass.
Present invention finds the new mechanism of action and drug effect of Nitazoxanide, has the phosphorus for suppressing Tau albumen
Acidifying and/or the effect for promoting A β to remove.The compound can be used for treatment Alzheimer disease and with A β
And/or the disease treatment that Tau albumen is related.
Brief description of the drawings
Fig. 1 Nitazoxanides can substantially increase removing of the BV2 cells to A β.* * represent P<0.001.
One-way analysis of variance.
The Tau protein phosphorylations that Fig. 2 Nitazoxanides can substantially suppress BV2 cells are horizontal, have no effect on
The expression of Tau albumen.
Fig. 3 Nitazoxanides can be obviously improved the memory injury of APP/PS1 transgenosis AD model mices.
* P is represented<0.05, compared with TV (transgenosis solvent group) group.One-way analysis of variance.Fig. 3 a are 8
Every group of preclinical Line Chart of mouse of its time；Fig. 3 b are the 8th day three groups of preclinical block diagrams of mouse；
Fig. 3 c are that the 8th day three groups of mouse wear the block diagram of platform number.
Embodiment
With reference to specific embodiment, the present invention is further elaborated, but these embodiments should not be construed as
The limitation present invention.
Test example
Test example 1：Nitazoxanide (Nitazoxanide, NTZ) increase A β are removed.
The present invention carries out experiment that cell exogenous A β remove to detect Nitazoxanide in BV2 cells
The influence removed to A β, experiment show that NTZ has the function that significantly to increase A β removings.
1st, experimental principle
This experiment the effect such as can be gulped down based on BV2 cells by intracellular and exogenous A β are transferred into cell
It is interior, then exogenous A β are degraded by relational approach.The present inventor is by exogenous A β
, then will be thin and the Nitazoxanide of various concentrations adds common incubation certain time in BV2 cell culture fluids
Born of the same parents' broth out, clean cell and crack, obtain and determine the A β contents of intracellular.Final intracellular A β
The reduction of content shows Scavenging activity [Jiang Q.ApoE promotes the of the Nitazoxanide to A β
proteolytic degradation of Abeta.Neuron,2008；58:681-693].
A β are by ELISA method detection, its principle in this experimental cell：It is intracellular after cracking
The orifice plate of white clear 96 that A β have A β antibody with coupling is incubated, and another site for then adding A β resists
Body is incubated simultaneously, identifies combination principle by antigen and antibody specific, by A β and its antibody simultaneously
It is specific to be adsorbed on 96 orifice plates；Then with the secondary antibody and its colour developing bottom for being coupled horseradish peroxidase
Thing (Tetramethylbenzidine, TMB) is incubated, and the coloured product depth and A β contents of generation are into just
Than, the absorbance (OD450) of difference bioassay standard pipe and sample tube, calculating A β content.
2nd, experiment material and method
1) A beta determinations kit is purchased from invitrogen companies, and cell culture reagent is purchased from Gibico public affairs
Department, A β peptide are purchased from Sigma companies, and BV2 cell deriveds are in ATCC.
2) BV2 cells A β remove experiment：After BV2 cell culture to 70% density, add different
The Nitazoxanide (20,10,1,0 μM) of concentration is incubated 18 hours jointly, then adds 2 μ g/mL
A β continue to be incubated 3 hours, then cell PBS 3 times, adds cell pyrolysis liquid (50mM
Tris, 1%SDS) cracked in 37 DEG C 15 minutes and collect supernatant, then 12,000g is centrifuged 15 minutes,
A β in supernatant are determined by ELISA method.
3) supernatant of cell cracking is subjected to 80 times of dilutions with standard dilution, then according to kit institute
Offer method is detected.The supernatant after dilution, A β antibody and lotus root are joined into A β another kinds at room temperature
96 orifice plates of antibody are incubated 3 hours jointly, then carry out board-washing 4 with the rinsing liquid provided in kit
It is secondary, add lotus root and be associated with the secondary antibody of horseradish peroxidase and be incubated at room temperature 30 minutes, then washed with rinsing liquid
Plate five times, nitrite ion is then added in incubation at room temperature 30 minutes, is eventually adding stopping of reaction liquid.With
Bio-Rad ELIASAs read OD values at 450nm.
3rd, experimental result
As a result as shown in figure 1, Nitazoxanide can concentration dependent reduce the intracellular A β contents of BV2,
The increase A β that showing Nitazoxanide has the function that obvious concentration dependent are removed.
Test example 2：Nitazoxanide (Nitazoxanide, NTZ) suppresses the phosphorylation of Tau albumen.
Neurofibrillary tangles is morbidity important in AD pathology caused by Protein tau Hyperphosphorylationof
One of factor.Therefore the present invention tests further research compound Nitazoxanide pair by Western blot
The adjustment effect of Protein tau phosphorylation level.As a result show, in BV2 cells, NTZ can be notable
Ground reduces by 396 phosphorylation levels of Protein tau.
1st, experimental principle
Western blot are tested:There is wide expression in Tau albumen, in nervous system in BV2 cells
Same to have expression, its phosphorylation level height will directly influence tubulin and be assembled into micro-pipe and maintenance
The important function of the structure of micro-pipe, therefore directly detect cell using 396 phospho-ABs of Protein tau
The phosphorylation level of Protein tau after cracking, glyceraldehyde 3-phosphate dehydro-genase (GAPDH) and Tau eggs
It is not to influence its expression as increase of the control test compound on Tau phosphorylation in vain.
2nd, experiment material and method
1) cell culture reagent is purchased from Gibico companies, and BV2 cell deriveds are in ATCC, Tau albumen
396 phospho-ABs, Tau protein antibodies, GAPDH antibody are purchased from Cell signaling companies.
2) Western blot test major parameter：Primary antibody：p-Tau(1:1000, Cell signaling are public
Department), Tau (1:1000, Cell signaling companies), GAPDH (1:10,000, Kang Cheng biologies)；
Secondary antibody：Rabbit-anti (anti-Rabbit) (1:5,000, Jackson companies), mouse resists (anti-mouse) (1:10,000,
AbCam Co., Ltds).
3) experimental method：In cell experiment, BV2 cell culture treats cell density in six orifice plates
For 70% when add various concentrations Nitazoxanide (20,10,1,0 μM), cultivate 24 hours, with
After draw nutrient solution, and with PBS 3 times, subsequent cell receives sample buffer solution with SDS-PAGE
(25%SDS, 62.5mM Tris, 25% glycerine, 0.1% bromine is fragrant blue, pH6.8) is collected in 1.5mL's
In EP pipes, heat in 98 DEG C 15 minutes, then centrifuged 10 minutes with 10,000g in 4 DEG C.
Supernatant carries out SDS-PAGE electrophoresis, is then walked around film 90 minutes using semidry method electricity, then by film in
Closing 30 minutes in TBST confining liquids (TBS, 0.5% polysorbas20,5% skimmed milk power).Will closing
Film afterwards corresponding to 4 DEG C with being incubated overnight.Second day with TBST buffer solutions (TBS, 0.5% polysorbas20)
Wash film 3 times (every time 15 minutes), then carry out being incubated 2 hours with secondary antibody.Then equally use TBST
Buffer solution washes film 3 times (every time 15 minutes).Finally it is incubated with horseradish peroxidase (HRP) substrate
5 minutes, then using the optical signal collection instrument (imagequant LAS4000mini) of AM General
Collect signal.
3rd, experimental result：
As a result as shown in Fig. 2 compared with compareing DMSO treatment groups, Nitazoxanide can be with concentration dependent
Suppression Tau albumen phosphorylation (P-Tau), but its total protein (T-Tau) is not influenceed, shown
Nitazoxanide can substantially suppress the phosphorylation of Tau albumen.
Test example 3：Nitazoxanide (Nitazoxanide, NTZ) reverses Alzheimer disease to turn base
Because of the effect of model mice memory injury.
For the anti-Alzheimer disease (Alzheimer ' s disease, AD) of further clear and definite Nitazoxanide
Drug effect, the present invention give APP/PS1 double transgenic AD model mice Nitazoxanides by gastric infusion,
Then determine Nitazoxanide by water maze laboratory improves work to transgenosis AD model mices memory injury
With.As a result show that Nitazoxanide can reverse the memory injury of AD model mices.
1st, experimental principle
This experiment use for APP/PS1 double transgenic AD model mices (APPswe, PS1dE9).
This kind of transgenic mice can high expression is embedding and the swedish mutant APP of mouse/people (Mo/HuAPP695swe) and
People deletes in source the albumen of presenilin 1 (presenilin, PS1-dE9) of the 9th extron, this kind of transgenosis
Mouse can occur obvious A β when 6 months and deposit and can occur sky when 7 months
Between memory infringement.
2nd, experiment material and method
1) the Jackson Laboratory that APP/PS1 double transgenics AD model mices are bought in the U.S. are public
Department, then breeds.The transgenic of generation mice is identified, by using tail is cut to mouse, then PCR
Identify the APP/PS1 of mouse gene order.Negative control in using nontransgenic mice as experiment is small
Mouse.Mouse raise at the standard conditions (circulation of 12/12 hour light and shade, enough water and food, 22 DEG C
Constant temperature, 60% humidity).
2) AD model mices are administered：In mouse size in June, 20 transgenic mices are randomly divided into
2 groups (transgenosis solvent group, transgenosis Nitazoxanide 30mg/kg dosage groups), 10 non-transgenics are small
Mouse is as negative control group.Nitazoxanide is dissolved in 3 percent Tween 80, then starts continuously to fill
Nitazoxanide is administered in stomach, and Behaviors survey detection (Morris water maze laboratories) is carried out after 100 days.
3) Morris water maze laboratories：Reference literature of the present invention carries out water maze laboratory, is simply described below：
Morris water mazes instrument is one a diameter of 1.5 meters, deep 60 centimetres round pool；We are by pond
It is divided into four quadrants, lower 1.5 centimetres of the pond liquid level of one of quadrant there are one a diameter of 10 centimetres
Platform, we train mouse to find and remember platform position；We allow mouse to be instructed three times daily
Practice, continue the time of eight days；Mouse is removed platform by us towards pool wall in three respectively in training three times
It is placed in water in the quadrant at place, then looks for position of platform to the seconds of mouse 90, if 90
Platform can not be found in second, mouse can be placed on platform by we；Station is arrived regardless of in the case of
Mouse on platform can all allow it to place 15 seconds on platform to help it to remember position of platform；
Record mouse searches out evaluation index of the time of platform as mouse memory power, takes what is trained three times daily
Results averaged, 8 day time, every group of preclinical Line Chart of mouse was shown in Fig. 3 a.At the 8th day, three
After secondary training, mouse can carry out platform and find experiment；In current experiment, dive in the platform of underwater
Removed, then allow mouse to continue to look within 90 seconds platform, record mouse spanning platform institute in pond
Index of the number equally as evaluation mouse memory power, the 8th day three groups of preclinical columns of mouse in position
Figure is shown in Fig. 3 b, and the block diagram that the 8th day three groups of mouse wear platform number is shown in Fig. 3 c.
3rd, experimental result
Experimental result during the training of the first eight day is as shown in Figure 3 a, 3 b：AD transgenic mice
Incubation period is apparently higher than nontransgenic mice, and the incubation period of the transgenic mice of 30mg/kg/day administrations
It is substantially shorter than the transgenic mice of solvent group；These results illustrate APP/PS1 transgenic models mouse
There is obvious damage in memory, and Nitazoxanide can significantly reverse this memory injury.Last
Secondary platform finds the result of experiment as shown in Figure 3 c：The number of transgenic mice spanning platform position
Considerably less than nontransgenic mice, and the spanning platform position of the transgenic mice of Nitazoxanide administration
Number substantially than solvent processing transgenic mice it is more；These result further instructions APP/PS1's
There is obvious damage in the memory of transgenic models mouse, and Nitazoxanide can significantly reverse it is this
Memory injury.
Claims (7)
1. Nitazoxanide and its pharmaceutically acceptable salt are preparing the medicine for treating Alzheimer disease
In purposes.
2. purposes according to claim 1, wherein, Nitazoxanide and its pharmaceutically acceptable salt
A β can be increased and remove and/or suppress Tau protein phosphorylations.
3. Nitazoxanide and its pharmaceutically acceptable salt are being prepared for treating and A β removings and/or Tau
Purposes in the medicine of the related nerve degenerative diseases of protein phosphorylation.
It is described to be removed with A β and/or Tau protein phosphorylation phases 4. purposes according to claim 3
The nerve degenerative diseases of pass include Parkinson's.
5. a kind of pharmaceutical composition is preparing the purposes in being used to treat the medicine of Alzheimer disease, described
Pharmaceutical composition includes Nitazoxanide or its pharmaceutically acceptable salt and pharmaceutically acceptable auxiliary material.
6. the pharmaceutical composition containing Nitazoxanide or its pharmaceutically acceptable salt prepare be used for treat with
Purposes in the medicine for the nerve degenerative diseases that A β are removed and/or Tau protein phosphorylations are related.
It is described to be removed with A β and/or Tau protein phosphorylation phases 7. purposes according to claim 6
The nerve degenerative diseases of pass include Parkinson's.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610329100.8A CN107375280B (en) | 2016-05-17 | 2016-05-17 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparing medicament for treating Alzheimer disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610329100.8A CN107375280B (en) | 2016-05-17 | 2016-05-17 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparing medicament for treating Alzheimer disease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN107375280A true CN107375280A (en) | 2017-11-24 |
| CN107375280B CN107375280B (en) | 2021-03-05 |
Family
ID=60338185
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610329100.8A Expired - Fee Related CN107375280B (en) | 2016-05-17 | 2016-05-17 | Application of nitazoxanide and pharmaceutically acceptable salt thereof in preparing medicament for treating Alzheimer disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN107375280B (en) |
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109364067A (en) * | 2018-11-17 | 2019-02-22 | 王海玲 | A kind of drug and application thereof improving blood-brain barrier permeability |
| WO2019097050A1 (en) * | 2017-11-17 | 2019-05-23 | Köster | [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl]ethanoate for use in lymphangioleiomyomatosis and other diseases |
| WO2019241376A1 (en) * | 2018-06-14 | 2019-12-19 | The Trustees Of Columbia University In The City Of New York | Treatment of cognitive disorders using nitazoxanide (ntz), nitazoxanide (ntz) analogs, and metabolites thereof |
| CN110650958A (en) * | 2017-03-21 | 2020-01-03 | 诺瓦莱德制药公司 | Therapeutic agents for phosphodiesterase inhibition and related disorders |
| CN111012778A (en) * | 2018-10-10 | 2020-04-17 | 北京市农林科学院 | Application of Nitazoxanide in inhibiting canine parvovirus |
| CN113277994A (en) * | 2021-05-18 | 2021-08-20 | 杜心赟 | Thiazole compound and preparation method and application thereof |
| CN115197164A (en) * | 2021-04-12 | 2022-10-18 | 杜心赟 | Novel thiazole compound and preparation method and application thereof |
Citations (2)
| 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 |
| CN104520325A (en) * | 2012-05-21 | 2015-04-15 | 霍夫曼-拉罗奇有限公司 | Methods for improving safety of blood-brain barrier transport |
-
2016
- 2016-05-17 CN CN201610329100.8A patent/CN107375280B/en not_active Expired - Fee Related
Patent Citations (2)
| 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 |
| CN104520325A (en) * | 2012-05-21 | 2015-04-15 | 霍夫曼-拉罗奇有限公司 | Methods for improving safety of blood-brain barrier transport |
Non-Patent Citations (1)
| Title |
|---|
| CHIA-WEN HSU: "Identification of HDAC Inhibitors Using a Cell-Based HDAC I/II Assay", 《JOURNAL OF BIOMOLECULAR SCREENING》 * |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110650958A (en) * | 2017-03-21 | 2020-01-03 | 诺瓦莱德制药公司 | Therapeutic agents for phosphodiesterase inhibition and related disorders |
| WO2019097050A1 (en) * | 2017-11-17 | 2019-05-23 | Köster | [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl]ethanoate for use in lymphangioleiomyomatosis and other diseases |
| US11547699B2 (en) | 2017-11-17 | 2023-01-10 | Hubert Köster | [2-[(5-nitro-1,3-thiazol-2-yl)carbamoyl]phenyl]ethanoate for use in lymphangioleiomyomatosis and other diseases |
| WO2019241376A1 (en) * | 2018-06-14 | 2019-12-19 | The Trustees Of Columbia University In The City Of New York | Treatment of cognitive disorders using nitazoxanide (ntz), nitazoxanide (ntz) analogs, and metabolites thereof |
| CN111012778A (en) * | 2018-10-10 | 2020-04-17 | 北京市农林科学院 | Application of Nitazoxanide in inhibiting canine parvovirus |
| CN111012778B (en) * | 2018-10-10 | 2022-06-24 | 北京市农林科学院 | Application of Nitazoxanide in inhibiting canine parvovirus |
| CN109364067A (en) * | 2018-11-17 | 2019-02-22 | 王海玲 | A kind of drug and application thereof improving blood-brain barrier permeability |
| CN109364067B (en) * | 2018-11-17 | 2020-07-28 | 王海玲 | Application of compound in preparation of medicine for improving blood brain barrier permeability |
| CN115197164A (en) * | 2021-04-12 | 2022-10-18 | 杜心赟 | Novel thiazole compound and preparation method and application thereof |
| CN113277994A (en) * | 2021-05-18 | 2021-08-20 | 杜心赟 | Thiazole compound and preparation method and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN107375280B (en) | 2021-03-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN107375280A (en) | Nitazoxanide and its pharmaceutically acceptable salt are preparing the application in being used to treat the medicine of Alzheimer disease | |
| Spilman et al. | Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-β levels in a mouse model of Alzheimer's disease | |
| Nie et al. | Porphyromonas gingivalis infection induces amyloid-β accumulation in monocytes/macrophages | |
| Hoey et al. | Synaptic NMDA receptor activation stimulates α-secretase amyloid precursor protein processing and inhibits amyloid-β production | |
| Kobayashi et al. | Behavioral phenotypes of amyloid‐based genetically modified mouse models of Alzheimer's disease | |
| Cogliati et al. | Bacillus subtilis delays neurodegeneration and behavioral impairment in the Alzheimer’s disease model Caenorhabditis elegans | |
| Ahmadi et al. | Effects of vanillic acid on Aβ1-40-induced oxidative stress and learning and memory deficit in male rats | |
| Hillen et al. | Generation and therapeutic efficacy of highly oligomer-specific β-amyloid antibodies | |
| Saura et al. | Conditional inactivation of presenilin 1 prevents amyloid accumulation and temporarily rescues contextual and spatial working memory impairments in amyloid precursor protein transgenic mice | |
| Landes et al. | OPA1 (dys) functions | |
| Gong et al. | S-propargyl-cysteine, a novel hydrogen sulfide-modulated agent, attenuates lipopolysaccharide-induced spatial learning and memory impairment: involvement of TNF signaling and NF-κB pathway in rats | |
| Benito-Cuesta et al. | Assessment of autophagy in neurons and brain tissue | |
| JP6755938B2 (en) | Utilization of PI4KIIIα protein and related membrane protein complexes in the treatment of Alzheimer's disease | |
| Chow et al. | Modeling an anti-amyloid combination therapy for Alzheimer’s disease | |
| Prediger et al. | Genetic deletion or antagonism of kinin B1 and B2 receptors improves cognitive deficits in a mouse model of Alzheimer's disease | |
| BRPI0613358A2 (en) | polyunsaturated fatty acids for the treatment of dementia and conditions related to pre-dementia | |
| Meng et al. | Tat-haFGF14–154 upregulates ADAM10 to attenuate the Alzheimer phenotype of APP/PS1 mice through the PI3K-CREB-IRE1α/XBP1 pathway | |
| CN107812004A (en) | The application of Desloratadine and its pharmaceutically acceptable salt in the medicine for preparing treatment Alzheimer disease | |
| Hou et al. | Tetrahydroxystilbene glucoside improves learning and (or) memory ability of aged rats and may be connected to the APP pathway | |
| Lekchand Dasriya et al. | Etiology and management of Alzheimer’s disease: Potential role of gut microbiota modulation with probiotics supplementation | |
| Geng et al. | Autophagic degradation deficit involved in sevoflurane-induced amyloid pathology and spatial learning impairment in APP/PS1 transgenic mice | |
| Yi et al. | The autophagy protein Atg9 functions in glia and contributes to parkinsonian symptoms in a Drosophila model of Parkinson’s disease | |
| Atlante et al. | Mitochondrial Complex I and β-Amyloid Peptide Interplay in Alzheimer’s Disease: A Critical Review of New and Old Little Regarded Findings | |
| Dai et al. | Dopaminergic antagonists inhibit bile chemotaxis of adult Clonorchis sinensis and its egg production | |
| Garcia et al. | Biochemical and histological responses of Rattus novergicus (Wistar) infected by Echinostoma paraensei (Trematoda: Echinostomatidae) |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20210305 |