CN109045022A - It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease - Google Patents
It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease Download PDFInfo
- Publication number
- CN109045022A CN109045022A CN201810715924.8A CN201810715924A CN109045022A CN 109045022 A CN109045022 A CN 109045022A CN 201810715924 A CN201810715924 A CN 201810715924A CN 109045022 A CN109045022 A CN 109045022A
- Authority
- CN
- China
- Prior art keywords
- calais
- prevention
- purposes according
- macular degeneration
- retinal
- 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.)
- Pending
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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Landscapes
- Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Ophthalmology & Optometry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Epidemiology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease, especially I type Stargardt macular degeneration disease.Ah Calais must not only play a protective role to retinal pigment epithelium, also play a protective role to photosensory cell, and for whole body organ function without influence, hereditary-less toxicity is highly-safe, and administration is easy.
Description
Technical field
The present invention relates to the technical field of pharmaceuticals of Stargardt macular degeneration disease, and in particular to Ah Calais must prepare
Purposes in the drug of Stargardt macular degeneration disease.
Background technique
Stargardt macular degeneration is the most common Inherited retinal macular degeneration disease, wherein I type Stargardt
Macular degeneration (Stargardt disease type 1, STGD1) is that a kind of Early onset as caused by Abca4 gene mutation often contaminates
Colour solid recessive inheritance eye disease was most reported, disease incidence is about early in 1909 by German ophthalmologist Karl Stargardt
1 people's illness, accounts for 7% of macular degeneration or so in every 8000~10000 people.It is reported at present to cause STGD1
Abca4 be mutated more than 900 or more, the age of onset and severity of patient shows huge heterogeneity.STGD1 patient
Mostly in the morbidity of juvenile or nonage, but also there are some patientss to fall ill after adult, it is considered that the more early view of disease time
Film degeneration is more serious, and treatment prognosis is poorer.ABCA4 is retinal specific expression ATP combination cassette transporter protein, for feeling
N-retinylidene-phosphatidylethanolamine (N-ret-PE) is transported in photo-cell acromere disk film, its function
Can lack causes visual cycle by-product such as A2E lipofuscin largely to accumulate in retinal pigment epithelium, clinical manifestation
It is denaturalized for the decline of bilateral central vision, dyschromatopsia, central vision blind spot, macular degeneration, macular area pigment epithelial cell, is photosensitive
There is yellow-white spot deposition etc. in cell degradation, retina Posterior pole pigment epithelial cell.
STGD1, which still lacks, at present generally acknowledges feasible treatment method, but since such disease is for children and labour year
The irreversibility of age population eyesight influences, and the exploitation of clinical treatment drug and therapy is the emphasis of research, and having put on record, it is more to carry out
Item preclinical study.Gene replacement therapy, stem cell therapy and pharmaceutical intervention are focused primarily upon for the treatment method of STGD1:
1., gene replacement therapy: normal Abca4 gene integration entered into adenovirus vector be sent into patient and intraocularly express, but Abca4
Gene contains 50 exons, mrna length 6.8kb, more than the adenovirus that can deliver foreign gene and enter retina cell
The bearing capacity (4.7kb) of carrier, existing research at present by Abca4 gene integration enter have the slow virus carrier of bigger bearing capacity into
Row gene delivery, but its therapeutic effect is still not clear；2, it stem cell therapy: is generated using human embryo stem cell vitro differentiation mature
Retinal pigment epithelium and by transplantation substitute degenerated cell to achieving the purpose that treatment.But it is similar with phenotype
Local Electroretinogram compare, feel while STGD1 patient is denaturalized with retinal pigment epithelium
The death of photo-cell and choroid are degenerated, therefore the retinal pigment epithelium after transplanting is due to lacking choroidal nutrition supplying
To maintenance function that cannot be permanent, the caused visual impairment of photosensory cell degeneration can not also restore, and influence its therapeutic effect；3,
Pharmaceutical intervention: ABCA4 is that all-trans-retinal (all-trans-retinaldehye, atRAL) is regenerated as 11- in view circulation
The crucial transport protein of cis retinal (11-cis-retinaldehyde, 11-cis-RAL), pathogenesis are mainly thought
It is a large amount of accumulations in retina such as view circulation by-product such as A2E, therefore visual cycle regulator is the exploitation of STGD1 therapeutic agent
The main direction of development.(a) ALK-001 (C20-D3-vitamin A): replacing with deuterium for C20 in vitamin A hydrogen,
Abca4-/-It can effectively reduce the deposition of A2E in mouse, I clinical trial phase be completed at present, into II phase clinical stage；(b)
Fenretinide (N- (4-hydroxyphenyl) retinamide, 4-HRP): the synthesis of derivatives of vitamin A, it can be with dimension
Raw element A competitive binding RBP ELISA (retinol binding protein), and form stable compound with RBP and lead to
Renal metabolism discharge is crossed, so that the generation of A2E be effectively reduced.But display Fenretinide, which has been reported, can induce view
Membranochromic pigments Epithelial Cell Apoptosis, the formation of induction of vascular sarcoma in mouse model, and may have teratogenesis, while it is right
Also lack the result of long-term evaluation in the effect of visual cycle, it is therefore desirable to further further investigation；(c)A1120(2-(4-
(2- (trifluoromethyl) phenyl) piperidine-1-carboxamido) benzoic acid): it can effectively tie
Retinol-binding proteins (RBP4) is closed to reduce the formation of A2E, it is similar with Fenretinide action principle, but its
Therapeutic effect in STGD1 still lacks data support.
Ah Calais must (Arglabin), be parthenolide derivative, CAS No.:84692-91-1, molecular formula:
C15H18O3, molecular weight: 246.3.Its structural formula is as shown in above formula.Ah Calais must be a kind of natural production purified from brilliant green wormwood artemisia
Object.Ah Calais, which must initially be purified screening, becomes anti-tumor drug.Toxicologic study be shown in maximum tolerated dose it for
Peripheral blood composition and marrow do not influence, while not influencing liver, kidney, cardiovascular system, Respiratory ft tive resistance, using vein
Injection, intraperitoneal injection, intramuscular injection and subcutaneous injection will not cause local stimulation to be reacted, and allergic reaction and body temperature increase,
There is no embryotoxicity, teratogenesis and mutagenesis.Pharmacokinetic shows that retention time is up to 22 hours in vivo for it,
Blood can be moved quickly through and enter perienchyma, initially accumulated in kidney and lungs, be transferred into liver and bone in 3 hours
Flesh.Compared with each internal organs of whole body, which accumulates maximum dose level in liver and stops maximum duration, can penetrate blood-brain barrier.
Ah Calais must be the competitive inhibitor of RAS proto-oncogene farnesylation, and the expression and ATP for reducing RAS downstream gene contain
Amount, inducing apoptosis of tumour cell.Simultaneously also have researches show that Ah Calais must derivative have inflammation regulatory function, antibacterium and
Fungi function.In the ApoE2 atherosclerosis mouse model of High-fat diet, the continuous Ah Calais that is injected intraperitoneally must can be with
By inhibiting NLRP3 inflammation corpusculum that atherosclerosis phenotype is effectively relieved.Newest research, which also shows Ah Calais, can press down
The activation of T cell receptor processed is to alleviate the inflammation and autoimmune disease that T cell mediates.But the not Calais You A so far
It must be used for the report of Stargardt macular degeneration disease.
Summary of the invention
It must be in preparation Stargardt it is an object of the invention in place of overcome the deficiencies in the prior art, provide Ah Calais
Purposes in the drug of macular degeneration disease.
The technical solution adopted by the present invention to solve the technical problems is:
It Ah Calais must be in the purposes in the prevention and/or therapeutic agent for preparing Stargardt macular degeneration disease.
In one embodiment: the Stargardt macular degeneration disease is I type Stargardt macular degeneration disease.
In one embodiment: the prevention and/or treatment refer to protection retinal pigment epithelium, prevent retinal pigment
Epithelial cell degeneration or death.
In one embodiment: the prevention and/or treatment refer to the integrality for maintaining retinal pigment epithelium.
In one embodiment: the prevention and/or treatment refer to protection retinal photoreceptor cells, prevent retinal photoreceptor cells
It degenerates or dead.
In one embodiment: the prevention and/or treatment refer to maintenance retinal photoreceptor cells outer segment length.
In one embodiment: the prevention and/or treatment refer to maintenance outer nuclear layer thickness.
In one embodiment: the prevention and/or treatment refer to inhibition retinal inflammation.
In one embodiment: the prevention and/or treatment refer to the accumulation for reducing A2E, atRAL in retina cell.
In one embodiment: the Ah Calais must administration mode include intravenously administrable, it is subcutaneous administration, oral administration, intracavitary
Administration.
STGD1 still not general treatment method at present, with the treatment method and drug phase for entering preclinical study at present
Than Ah Calais must have the advantage that
1, highly-safe: compared with the gene therapy of viral vectors carrying, existing Preclinical Drug, Ah Calais must toxicity
, pharmacokinetic data are perfect, and for whole body organ function without influence, hereditary-less toxicity is highly-safe.
2, administration mode is convenient: Ah Calais retention time must be up to 22 hours in vivo, quickly can penetrate blood from blood
Brain, blood retina barrier reach retina target tissue, therefore can reach therapeutic effect by the way of being administered systemically.It is thin with doing
Born of the same parents' transplanting compares that administration mode is easier, and safety coefficient is higher with gene therapy.
3, block protection retinal photoreceptor cells and pigment epithelial cell from downstream: existing therapeutic agent targets blocking more
The generation of visual cycle by-product such as A2E etc. is to reach therapeutic effect, but the mutation of ABCA4 causes tiring out for atRAL simultaneously
Product.AtRAL contains active aldehyde radical, will also result in the degeneration and death of photosensory cell and retinal pigment epithelium, blocks secondary
The generation of product can not block the toxic effect of atRAL itself.Cell death can must be blocked from downstream using Ah Calais, from
And more comprehensively protective effect is played, it not only plays a protective role to retinal pigment epithelium, also photosensory cell is risen
To protective effect.
4, regulation retinal inflammation microenvironment protects retina: in STGD1 pathogenesis, inflammation is also to retinal degeneration
Facilitation is played, but existing treatment method and drug do not have regulating and controlling effect to inflammation.Ah Calais must be able to suppress inflammation
Reaction, to achieve the purpose that protect retina by regulating and controlling retinal microenvironment.
Detailed description of the invention
Present invention will be further explained below with reference to the attached drawings and examples.
Fig. 1 is that Ah Calais must Abca4 in injection process-/-Rdh8-/-It is double to strike mouse weight variation.
Fig. 2 is that Ah Calais must handle Abca4 after 8 weeks-/-Rdh8-/-It is double to strike Mouse Retina paraffin section haematoxylin dyeing knot
Fruit.
Fig. 3 is that Ah Calais must handle 8 weeks maintenance Abca4-/-Rdh8-/-Double integralities for striking Mouse Retina pigment epithelium
As a result.
Specific embodiment
The contents of the present invention are illustrated below by embodiment:
Embodiment
The therapeutic agent exploitation of STGD1 mostly uses Abca4 knock out mice at present.But it is different from STGD1 patient, in list
In knock out mice, the catagen speed of retina is slow, and more apparent pathology table is generally just shown after August age
Type, it is inconsistent with the phenotype of STGD1 juvenile onset.Therefore, it is reported in the laboratory Krzysztof Palczewski in 2008
Road has made Abca4-/-Rdh8-/-It is double to strike mouse, occur apparent photosensory cell acromere at 4 monthly age and shortened, outer nuclear layer becomes
Thin, the STGD1 pathological change such as A2E accumulation can be used as the animal model of STGD1 disease.The present embodiment uses Abca4-/-Rdh8-/-
It is double to strike mouse progress.
Ah Calais must be dissolved in production 25ng/ μ L mother liquor in DMSO.Select 2 monthly age Abca4-/-Rdh8-/-It is double to strike mouse, 6
Mouse must handle group as Ah Calais, and mother liquor is diluted in physiological saline according to 1:200, daily according to 2.5ng/g weight
It is injected intraperitoneally, the DMSO of equivalent is diluted in physiological saline while being injected intraperitoneally by control group, after continuous injection 8 weeks
Mouse collection eyeball is put to death to be analyzed.
(1) drug safety
In 8 weeks injection process, apparent toxic reaction is not observed, it is dead that processing group and control group do not occur mouse
It dies, mouse weight keeps stablizing (Fig. 1).
(2) Ah Calais must be handled in Abca4-/-Rdh8-/-Double strike plays the role of protecting retinal photoreceptor cells in mouse
In Abca4-/-Rdh8-/-It is double to strike in mouse, since atRAL to be regenerated as to two key proteins of 11-cis-RAL
The missing of ABCA4 and RDH8 causes to regard dyshaemia, shows atRAL and its by-product A2E with the age and largely accumulate in retina
Poly-, photosensory cell is degenerated, and acromere shortens, the STGD1 Pathology such as photoreceptor cell nuclei stratum nucleare number decline, after processing 8 weeks, observation
Photosensory cell acromere and outer nuclear layer thickness must can be maintained to Ah Calais, illustrates that it plays protective effect to photosensory cell degeneration
(Fig. 2).
(3) Ah Calais must be handled in Abca4-/-Rdh8-/-Double strike plays protection retinal pigment epithelium work in mouse
With
In STGD1 patient, cell death is caused to move back since the lipofuscins such as A2E gather in retinal pigment epithelium
Change, shows as the expression decline of intercellular tight junction ZO-1, be observed that and compareed using ZO-1 immunofluorescence dyeing
Fragmentary expression is presented in group RPE cellular layer (dashed lines labeled) ZO-1, extracellular matrix distribution compared with Ah Calais must handle group
It is decreased obviously.Meanwhile Western blots detection also shows Ah Calais and must handle can effectively maintain layer of retina,pigment epithelium
The expression of middle ZO-1 plays a protective role (Fig. 3) for the integrality of retinal pigment epithelium.In addition, asterisk marks retina
The inflammatory cell of damage location is moved to after damage, it has also been discovered that there are a large amount of inflammatory cell migrations to enter retina in control group
Acromere, and Ah Calais must handle group since view film integrality maintains preferably, not observing cell migration phenomena (Fig. 3).
The above is only the preferred embodiment of the present invention, the range implemented of the present invention that therefore, it cannot be limited according to, i.e., according to
Equivalent changes and modifications made by the invention patent range and description, should still be within the scope of the present invention.
Claims (10)
1. Ah Calais must be in the purposes in the prevention and/or therapeutic agent for preparing Stargardt macular degeneration disease.
2. purposes according to claim 1, it is characterised in that: the Stargardt macular degeneration disease is I type
Stargardt macular degeneration disease.
3. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to protection retinal pigment
Epithelial cell prevents retinal pigment epithelium degeneration or dead.
4. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to maintenance retinal pigment
The integrality of epithelium.
5. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to protection retinal photoreceptor
Cell prevents retinal photoreceptor cells degeneration or dead.
6. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to maintenance retinal photoreceptor
Cell outer segment length.
7. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to maintenance retina outer core
Thickness degree.
8. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to inhibition retinal inflammation.
9. purposes according to claim 1, it is characterised in that: the prevention and/or treatment refer to that reducing A2E, atRAL exists
Accumulation in retina cell.
10. purposes according to claim 1, it is characterised in that: the Ah Calais must administration mode include intravenously administrable,
Subcutaneous administration, oral administration, intracavitary administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810715924.8A CN109045022A (en) | 2018-07-03 | 2018-07-03 | It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810715924.8A CN109045022A (en) | 2018-07-03 | 2018-07-03 | It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109045022A true CN109045022A (en) | 2018-12-21 |
Family
ID=64818989
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810715924.8A Pending CN109045022A (en) | 2018-07-03 | 2018-07-03 | It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109045022A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6242481B1 (en) * | 1997-03-18 | 2001-06-05 | The Children's Medical Center Corp. | Methods for the inhibition of angiogenesis with arglabin |
| CN102372723A (en) * | 2010-08-19 | 2012-03-14 | 石药集团中奇制药技术（石家庄）有限公司 | Method for extracting arglabin from artemisia myriantha |
| EP2865421A1 (en) * | 2013-10-28 | 2015-04-29 | Albert-Ludwigs-Universität Freiburg | Bitter taste receptor agonists for topical use |
-
2018
- 2018-07-03 CN CN201810715924.8A patent/CN109045022A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6242481B1 (en) * | 1997-03-18 | 2001-06-05 | The Children's Medical Center Corp. | Methods for the inhibition of angiogenesis with arglabin |
| CN102372723A (en) * | 2010-08-19 | 2012-03-14 | 石药集团中奇制药技术（石家庄）有限公司 | Method for extracting arglabin from artemisia myriantha |
| EP2865421A1 (en) * | 2013-10-28 | 2015-04-29 | Albert-Ludwigs-Universität Freiburg | Bitter taste receptor agonists for topical use |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI396532B (en) | Methods and compositions for treating ophthalmic conditions with retinyl derivatives | |
| Lu et al. | Human adult bone marrow-derived somatic cells rescue vision in a rodent model of retinal degeneration | |
| Kaneko et al. | Characteristics of bone marrow–derived microglia in the normal and injured retina | |
| JP6904570B2 (en) | How to treat brain tumors | |
| CN101507729B (en) | Use of ginsenoside Compound K in preparing medicine capable of preventing and treating atherosclerosis | |
| Wang et al. | Selective rod degeneration and partial cone inactivation characterize an iodoacetic acid model of Swine retinal degeneration | |
| RU2759916C2 (en) | Use of triacetyl-3-hydroxyphenyladenosine for the preparation of pharmaceutical drug for the prevention or treatment of non-alcoholic fatty liver disease | |
| CN109689083B (en) | Anti-angiogenic pharmaceutical composition containing cyclopentadepsipeptide as active ingredient | |
| CN109045022A (en) | It Ah Calais must be in the purposes in the drug for preparing Stargardt macular degeneration disease | |
| US20230302046A1 (en) | Methods of treating chronic inflammatory diseases | |
| CN112370496A (en) | Application of effective components of Lycii folium in preparing medicine for preventing or treating hepatic fibrosis | |
| US20130303611A1 (en) | Use of phenethyl caffeate derivatives in the preparation of a medicament against tumor angiogenesis | |
| US11419854B2 (en) | Medicament containing pemafibrate | |
| WO2020143332A1 (en) | Application of ilexgenin o in preparation of medication for preventing and treating alzheimer's disease | |
| TWI640310B (en) | Use of z-butylidenephthalide in activating autoimmune system | |
| CIBIS et al. | Ocular lesions produced by iodoacetate | |
| US20220184017A1 (en) | Compositions for improving eye health and methods of making and using thereof | |
| KR102633321B1 (en) | Pharmarceutical composition for preventing or treating of age-related macular degeneration | |
| CN104546828A (en) | Application of butylphthalide or derivative in preparation of medicine for treating or preventing diabetic complication | |
| EP3257518A1 (en) | A pharmaceutical composition for treating or alleviating autoimmune-related diseases and use of an acitive ingredient in the pharmaceutical composition | |
| CN117137902B (en) | Application of (-) -equitable edible phenol in preparing medicine for preventing and/or treating Alzheimer disease | |
| CN112569216B (en) | Use of pentanoic acid derivatives for the treatment of down syndrome | |
| KR102671857B1 (en) | Method and composition for treating hunter syndrome by administration of lateral ventricle of cerebrum | |
| US20210213109A1 (en) | Method and composition for treating hunter syndrome through cerebral lateral ventricle administration | |
| KR20170095850A (en) | Drug for treating disorders of corneal epithelium |
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 | ||
| WD01 | Invention patent application deemed withdrawn after publication | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20181221 |