KR20160013512A - A pharmaceutical composition for preventing or treating Graves orbitopathy comprising statin - Google Patents
A pharmaceutical composition for preventing or treating Graves orbitopathy comprising statin Download PDFInfo
- Publication number
- KR20160013512A KR20160013512A KR1020150104947A KR20150104947A KR20160013512A KR 20160013512 A KR20160013512 A KR 20160013512A KR 1020150104947 A KR1020150104947 A KR 1020150104947A KR 20150104947 A KR20150104947 A KR 20150104947A KR 20160013512 A KR20160013512 A KR 20160013512A
- Authority
- KR
- South Korea
- Prior art keywords
- present
- statin
- composition
- pharmaceutical composition
- thyroid
- Prior art date
Links
Images
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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
Abstract
Description
The present invention relates to a pharmaceutical composition for preventing or treating thyroid ophthalmopathy comprising statin as an active ingredient.
Graves' disease is a well-known thyroid autoimmune disease. An autoantibody that binds to the thyroid stimulating hormone receptor present in the endothelial cells of the thyroid follicles is a pathologic factor. It activates the function of the thyroid gland and causes excessive production and secretion of thyroid hormones. About 50% of Graves 'patients develop symptoms in the eye, which is referred to as Graves' orbitopathy or thyroid associated orbitopathy. The most common symptoms of thyroid ophthalmopathy include upper eyelid retraction, swelling of the orbital tissue, redness, and exophthalmos. About 3 to 5% of patients with ophthalmopathy can cause severe pain, inflammation, diplopia, and compression optic neuropathy, which threatens vision.
The pathophysiology of thyroid ophthalmopathy is not clear. Although autoantibodies to thyroid stimulating hormone receptors are one of the major pathologies in thyroid ophthalmopathy, thyroid ophthalmopathy has been reported in 10% of patients with thyroid ophthalmoplegia even if thyroid function is normal. The pathology revealed to date is summarized as inflammation, hyaluronic acid accumulation and localization can be divided into. In patients with severe active thyroid ophthalmopathy, the connective / adipose tissue present in the osseous bone tissue increases. The expansion of these tissues is characterized by the accumulation of hydrophilic glucosaminoglycans, mainly hyaluronan, as well as the pronounced infiltration of immune cells, mainly T-, B-lymphocytes and mast cells. In addition, the orbital cells contain a higher proportion of progenitor cells capable of differentiating into adipocytes. As the fat volume is increased by promoting the lipid differentiation thereof, the eyeballs are pushed forward to protrude the cosmetic and functional problems .
Thyroid ophthalmopathy is a disease that often causes social life because it can lead to an unseemly appearance. High dose of glucocorticoids have been used for decades in severe active group of ophthalmopathy and have been applied as the first treatment of thyroid ophthalmopathy due to antiinflammatory and immunosuppressive effects. However, in patients with low activity of thyroid ophthalmopathy, drugs that can prevent or reverse disease progression to date have not yet been identified unless indicated for steroid therapy.
Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.
The present inventors have made efforts to develop an effective therapeutic agent for thyroid ophthalmopathy. As a result, the present inventors have completed the present invention by confirming that statin inhibits lipogenesis of orbital fibroblast, which is a pathogen of thyroid ophthalmopathy without cytotoxicity, and shows anti-inflammatory effect.
Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating thyroid ophthalmopathy.
Other objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.
According to one aspect of the present invention, there is provided a pharmaceutical composition for preventing or treating thyroid ophthalmopathy comprising statin or a pharmaceutically acceptable salt thereof as an active ingredient.
The present inventors have made efforts to develop an effective therapeutic agent for thyroid ophthalmopathy. As a result, the present inventors confirmed that statin inhibits lipogenesis of orbital fibroblast, which is a pathogen of thyroid ophthalmopathy without cytotoxicity, and shows anti-inflammatory effect.
As used herein, the term "statin " is also referred to as a reductase inhibitor of HMG-CoA reductase and refers to a drug class that lowers the level of cholesterol by inhibiting the activity of HMG-CoA reductase.
According to one embodiment of the present invention, statins that can be used in the present invention include, but are not limited to, rosuvastatin, atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin Mevastatin, Pitavastatin, Pravastatin and Simvastatin.
In one particular example, the statin is fluvastatin or rosuvastatin, more particularly rosuvastatin.
As used herein, the term "rosuvastatin" refers to (3R, 5S, 6E) -7- [4- (4-fluorophenyl) -2- (N-methylmethanesulfonamido) (Propan-2-yl) pyrimidin-5-yl] -3,5-dihydroxyhept-6-enoic acid.
The active ingredient of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, acid addition salt formed by a pharmaceutically acceptable free acid is useful. As the free acid, inorganic acid and organic acid can be used.
In particular, pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, hydrochloride, bromate, sulfate, phosphate, citrate, acetate, trifluoroacetate, lactate, tartrate, maleate, fumarate, But are not limited to, methanesulfonate, glycolate, succinate, 4-toluenesulfonate, gluturonate, ebonate, glutamate, or aspartate salts, And salts formed using various inorganic acids and organic acids. The compounds of the present invention may also exist in the form of solvates (e.g., hydrates).
The composition of the present invention may be provided in the form of a pharmaceutical composition for the prevention or treatment of autoimmune thyroid disease.
As used herein, the term "treatment" means (a) inhibiting the development of a disease, disease or condition; (b) relief of the disease, disorder or condition; Or (c) eliminating the disease, disease or condition. The term "treatment" or "therapeutic agent ", as used herein, refers to a therapeutic or prophylactic treatment of " therapeutic adjuvant" or "therapeutic adjuvant" It includes meaning.
As used herein, the term "prophylactic " means to inhibit the occurrence of a disease or disease in a subject who has never been diagnosed as having a disease or disease, but is likely to suffer from such disease or disease.
As used herein, the term "Graves ophthalmopathy" refers to a disease in which the ocular hypertrophy of the orbital fibroblast due to autoimmune thyroid disease results in increased inflammatory response and lipid differentiation.
According to one embodiment of the present invention, the composition of the present invention inhibits lipogenesis of orbital fibroblast cells. For example, the inhibition of lipogenesis is achieved by inhibiting the differentiation of lipoprotein cells.
According to one embodiment of the present invention, the composition of the present invention exhibits an anti-inflammatory effect.
According to the present invention, statin, which is an active ingredient of the composition of the present invention, significantly inhibits lipid differentiation of the extraocular muscles and soft tissues around the eyes due to autoimmune phenomenon, which is one of the most important pathological mechanisms of thyroid ophthalmopathy, Which significantly reduces fat formation of the parent cells. Statins also have anti-inflammatory effects. With this multilateral experimental evidence, the present inventors have found that the composition of the present invention can be usefully used as an effective therapeutic agent for thyroid ophthalmopathy.
According to one embodiment of the present invention, the ophthalmopathy which is treated or prevented by the composition of the present invention is a disease in which an autoimmune reaction is an etiologic.
According to one embodiment of the present invention, the administration concentration of statin, which is an active ingredient of the present invention, is 0.1 to 100 μM or 5 to 10 μM in vitro .
The pharmaceutical composition of the present invention may comprise a pharmaceutically acceptable carrier. The pharmaceutically acceptable carriers to be contained in the pharmaceutical composition of the present invention are those conventionally used in the present invention and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia rubber, calcium phosphate, alginate, gelatin, But are not limited to, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrups, methylcellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil. It is not. The pharmaceutical composition of the present invention may further contain a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, etc. in addition to the above components. Suitable pharmaceutically acceptable carriers and formulations are described in detail in Remington ' s Pharmaceutical Sciences (19th ed., 1995).
The pharmaceutical composition of the present invention can be administered orally or parenterally, and in the case of parenteral administration, it can be administered by intravenous injection, subcutaneous injection, muscle injection, intraperitoneal injection, transdermal administration or the like. It may also be administered topically in the form of eye drops.
The appropriate dosage of the pharmaceutical composition of the present invention may vary depending on factors such as the formulation method, administration method, age, body weight, sex, pathological condition, food, administration time, administration route, excretion rate, . The daily dosage of the pharmaceutical composition of the present invention is, for example, 0.001-100 mg / kg.
The pharmaceutical composition of the present invention may be formulated into a unit dose form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Or by intrusion into a multi-dose container. The formulations may be in the form of solutions, suspensions, syrups or emulsions in oils or aqueous media, or in the form of excipients, powders, powders, granules, tablets or capsules, and may additionally contain dispersing or stabilizing agents.
In addition, the pharmaceutical composition of the present invention can be manufactured as a sustained-release preparation so as to maintain the therapeutically effective amount continuously, thereby reducing the number of times the medicament is used to increase the compliance of the medicament. The sustained-release preparation may be formulated to include a sustained-release carrier and other adjuvants in addition to the active ingredient of the present invention. The sustained release carrier used in the present invention may be any of various sustained release carriers known in the art, and specifically a hydrophilic polymer.
The features and advantages of the present invention are summarized as follows:
(a) The present invention provides a pharmaceutical composition for preventing or treating thyroid ophthalmopathy comprising statin or a pharmaceutically acceptable salt thereof as an active ingredient.
(b) The statin of the present invention has no cytotoxicity, inhibits lipid formation in the orbital region and exhibits an anti-inflammatory effect, and thus can be usefully used for prevention and treatment of thyroid ophthalmopathy.
Figure 1 shows the toxicity test results of rosuvastatin (RSV) against fibroblasts.
Fig. 2 shows an image of orbital fibroblast showing the effect of inhibiting fat formation on orbital fibroblast by staining with oil-red O stain.
FIG. 3 shows the result of quantitative analysis of images observed after oil-red O staining of orbital fibroblasts showing the effect of inhibiting fat formation on orbital fibroblast of suvastatin by concentration.
Figure 4 shows the anti-inflammatory effect of rosuvastatin.
Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .
Example
Example 1. Cytotoxicity test of rosuvastatin
The cytotoxicity test of rosuvastatin (RSV) was performed using MTT (3- (4,5-Dimethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide) analyzer (Cell Titer 96 Aqueous nonreactive cell proliferative assay, Promega) Respectively. MTT assays were performed by culturing orbital fibroblasts in each well and treating rosuvastatin by concentration (0.1-100 [mu] M) for 24 hours. After incubation for 48 hours, 20 μl of MTT solution was administered. After 4 hours, the optical density (OD) was measured at 490 nm wavelength in an ELISA plate reader to compare cell growth inhibition. The dehydrogenase enzyme found in intact metabolized cells converts MTS to formazan and the degree of absorbance measured at 490 nm ultraviolet light is directly proportional to the number of living cells in culture. The experiment was repeated 3 times and the average values were compared. The experimental results are shown in Fig.
As shown in Fig. 1, rosuvastatin was not toxic to orbital fibroblasts.
Example 2 Isolation and Fertilization of Orbital Fibroblasts in orbital fat tissue of thyroid ophthalmopathy
Orbital decompression was performed in patients with thyroid ophthalmopathy and primary orbital fibroblasts were cultured from orbital fat tissue. In the culture method, tissues were finely cut with a wescott scissor, and then treated with collagenase II (3 mg / ml, 1.5% BSA dissolved in HBSS) for 1 hour at 37 ° C, Centrifugation at 300 g for 5 minutes removed floating fat cells and fat globules. After washing twice with PBS, the cells were placed in DMEM (Dulbecco's Modified Eagle's Medium) supplemented with 10% fetal bovine serum (FBS), and cultured in a CO 2 incubator (5% CO 2 , 37 ° C). The fused cells were detached with trypsin-EDTA solution and subcultured while the culture medium was changed at intervals of 2-3 days.
After orbital fibroblasts were divided into 6 well plates, when the cells reached confluence to some degree, lipid differentiation of lipid precursor cells was induced. As the inducer, PPARγ agonist, rosiglitazone (10 mM, Cayman, Ann Arbor, MI, USA), 33 mM biotin (Dulbecco's Modified Eagle's Medi um) supplemented with 10% fetal bovine serum Calbiochem, La Jolla, Calif.), 17 mM pantothenic acid, 10 mg / ml transferrin, 0.2 nM T3, 1 mM insulin (Boehringer-Mannheim, Mannheim, Germany) and 0.2 mM carbaprostaglandin (cPGI2, USA), 1 mM dexamethasone, and 0.1 mM isobutylmethylxanthine. The lipid differentiation lasted for 10 days and the medium and drug were replaced every 2-3 days.
Example 3. Oil Red O staining and quantitative analysis of differentiated adipocytes
A 0.5% (w / v) Oil Red O solution was prepared and diluted with sterilized distilled water at a ratio of 3: 2 and used as a staining reagent for adipocytes. After orbital fibroblasts were divided into 6 well plates, the lipid differentiation of the fat precursor cells was induced for 10 days when the cells reached a certain degree of density. After the lipid differentiation was completed, the medium was removed, washed twice with PBS, and fixed with 3.7% (w / v) formalin for 1 hour.
Following cell fixation, the Oil Red O working solution was treated for 1 hour and washed twice with distilled water. This was confirmed using a microscope (Olympus, Melville, NY, USA). The experimental results are shown in Fig.
FIG. 2 shows the effect of rosuvastatin on lipid differentiation, which is one of the pathological mechanisms of thyroid ophthalmopathy, through Oil Red O staining. As shown in Fig. 2, fat formation of orbital fibroblasts was inhibited (magnification: X40, lower left X400) with increasing concentration of rosuvastatin.
Quantitative analysis using Oil Red O staining method was performed by adding 400 μl of isopropanol to a dyed 6-well plate, dissolving the oil Red O in the cells, transferring 100 μl / well to a 96-well plate, Absorbance was measured and shown. Fat accumulation (percentage of control) was calculated using differentiated fat cells that were not treated with the drug as a control. The experimental results are shown in Fig.
As shown in FIG. 3, when isopropanol was added to a plate stained with Oil Red O to dissolve and quantitatively analyzed, rosuvastatin at a concentration of 5 μM was significantly inhibited lipid differentiation compared to the control without the drug .
Example 4. RNA isolation and real-time RT-PCR analysis
Orbital fibroblasts were divided into 10 cm dishes, and when the cells reached confluence, the cells were replaced with serum-free medium. Human thyroid stimulating monoclonal antibody M22 (RSR, Ltd.; 30 ng / Ml) together with
The synthesized cDNA was amplified by ABI 7300 real-time PCR thermocycler (Applied Biosystems, Carlsbad, California, USA) using CYBER Green universal PCR master mix. The primer sequences used were as follows.
ICAM1 Forward, 5'-GGC CTC AGC ACG TAC CTC TA-3 '(SEQ ID No. 1), Reverse, 5'-TGC TCC TTC CTC TTG GCT TA-
3 '(SEQ ID No. 4), Reverse, 5'-GTC CAC CAC CCT GTT GCT GTA-3' (SEQ ID No. 4), GAPDH Forward, 5'- GCC AAG GTC ATC CAT GAC AAC-
Relative GAPDH relative gene expression was analyzed by calculating the 2 -ΔΔCt using the Ct method. The experimental results are shown in Fig.
As shown in FIG. 4, when the human thyroid stimulating antibody, which is a pathogen of thyroid ophthalmopathy, was treated for 24 hours, the expression of ICAM1 was increased about 3 times, but when rosuvastatin (2 or 20 μM) Expression was decreased. These results show anti-inflammatory effects of rosuvastatin.
While the present invention has been particularly shown and described with reference to exemplary embodiments thereof, it is to be understood that the same is by way of illustration and example only and is not to be construed as limiting the scope of the present invention. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.
<110> INDUSTRY-ACADEMIC COOPERATION FOUNDATION, Yonsei University <120> A pharmaceutical composition for preventing or treating Graves orbitopathy comprising statin <130> PN140383P <160> 4 <170> Kopatentin 2.0 <210> 1 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> forward primer for ICAM1 <400> 1 ggcctcagca cgtacctcta 20 <210> 2 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> reverse primer for ICAM1 <400> 2 tgctccttcc tcttggctta 20 <210> 3 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> forward primer for GAPDH <400> 3 gccaaggtca tccatgacaa c 21 <210> 4 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> reverse primer for GAPDH <400> 4 gtccaccacc ctgttgctgt a 21
Claims (5)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR20140094539 | 2014-07-25 | ||
| KR1020140094539 | 2014-07-25 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR20160013512A true KR20160013512A (en) | 2016-02-04 |
| KR101686881B1 KR101686881B1 (en) | 2016-12-20 |
Family
ID=55356213
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020150104947A KR101686881B1 (en) | 2014-07-25 | 2015-07-24 | A pharmaceutical composition for preventing or treating Graves orbitopathy comprising statin |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR101686881B1 (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070003636A1 (en) * | 2003-01-22 | 2007-01-04 | Francois Mach | Statins (HMG-COA reductase inhibitors) as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
| CN101790376A (en) * | 2007-08-31 | 2010-07-28 | 欧加农股份有限公司 | The 3,4-tetrahydroquinoline compounds of Tsh receptor antagonizing |
| KR20130020788A (en) * | 2010-04-16 | 2013-02-28 | 큠버랜드 파마슈티컬즈 인코포레이티드 | Stabilized statin formulations |
| KR20140065442A (en) * | 2011-09-15 | 2014-05-29 | 크로마덱스 아이엔씨. | Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation |
-
2015
- 2015-07-24 KR KR1020150104947A patent/KR101686881B1/en active IP Right Grant
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20070003636A1 (en) * | 2003-01-22 | 2007-01-04 | Francois Mach | Statins (HMG-COA reductase inhibitors) as a novel type of immunomodulator, immunosuppressor and anti-inflammatory agent |
| CN101790376A (en) * | 2007-08-31 | 2010-07-28 | 欧加农股份有限公司 | The 3,4-tetrahydroquinoline compounds of Tsh receptor antagonizing |
| KR20130020788A (en) * | 2010-04-16 | 2013-02-28 | 큠버랜드 파마슈티컬즈 인코포레이티드 | Stabilized statin formulations |
| KR20140065442A (en) * | 2011-09-15 | 2014-05-29 | 크로마덱스 아이엔씨. | Pterostilbene and statin combination for treatment of metabolic disease, cardiovascular disease, and inflammation |
Also Published As
| Publication number | Publication date |
|---|---|
| KR101686881B1 (en) | 2016-12-20 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6258266B2 (en) | Methods and compositions for treating disorders | |
| JP5956664B2 (en) | Treatment of lipodystrophy | |
| US9539259B2 (en) | Compounds and methods of use thereof for treating neurodegenerative disorders | |
| JP6250671B2 (en) | Treatment of immune-related and inflammatory diseases | |
| US11534442B2 (en) | Treatment of adipocytes | |
| KR20150144679A (en) | Composition for preventing or treating immune disease comprising mesenchymal stem cell treated stat3 inhibitor | |
| JPH02502020A (en) | Metabolic anti-aging agent containing melatonin or its congeners | |
| WO2001060370A1 (en) | Remedies for endothelin-induced diseases | |
| KR101686881B1 (en) | A pharmaceutical composition for preventing or treating Graves orbitopathy comprising statin | |
| KR20080015789A (en) | Novel triglyceride reducing agent | |
| Hughes et al. | Asciminib provides durable molecular responses in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with the T315I mutation: updated efficacy and safety data from a phase I trial | |
| KR101680834B1 (en) | A pharmaceutical composition for preventing or treating Graves orbitopathy comprising -lipoic acid | |
| TW201618776A (en) | A treating agent for dyslipidemia | |
| US8785491B2 (en) | Pharmaceutical compositions and methods for treating age-related macular degeneration with melatonin analogues | |
| KR101558477B1 (en) | Compositions for Prevention or Treating Autoimmune Thyroid Diseases | |
| US10646466B2 (en) | Uses of gallocatechin | |
| US20130203811A1 (en) | Thalidomide and thalidomide analogues for the prevention and treatment of sarcopenia | |
| US8969378B2 (en) | Inhibitor of the differentiation of T cells into Th1 cells | |
| MX2013010371A (en) | Compositions of opioid antagonists and their use for treating scleroderma. | |
| KR20230000792A (en) | Use of sd282 as therapeutic agents for immunosuppressant refractory autoimmune disease | |
| WO2008015763A1 (en) | Drug formulation containing fibrate medicament and process for producing the same | |
| JP2009051796A (en) | Precursor adipocyte differentiation inhibitor | |
| JP2023527942A (en) | Enhancer of particulate guanylyl cyclase receptor A | |
| JP5707137B2 (en) | Rebamipide treatment for osteoporosis | |
| Yin et al. | Angiopoietin 1 Relieves Osteolysis by Promoting Macrophage Mitophagy Through the TBK1-SQSTM1 Pathway to Inhibit AIM2 Inflammasome-Mediated Pyroptosis |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E701 | Decision to grant or registration of patent right | ||
| GRNT | Written decision to grant | ||
| FPAY | Annual fee payment |
Payment date: 20191203 Year of fee payment: 4 |