CN114469956B - Application of halofuginone in medicines for treating and preventing atherosclerosis diseases - Google Patents
Application of halofuginone in medicines for treating and preventing atherosclerosis diseases Download PDFInfo
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- CN114469956B CN114469956B CN202210110328.3A CN202210110328A CN114469956B CN 114469956 B CN114469956 B CN 114469956B CN 202210110328 A CN202210110328 A CN 202210110328A CN 114469956 B CN114469956 B CN 114469956B
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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
- A61K31/33—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
- A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Abstract
The invention provides an application of halofuginone in preparing medicines for treating and preventing atherosclerosis and related diseases. The invention also provides application of the halofuginone-modified compound in preparing medicines for treating and preventing atherosclerosis and related diseases and a pharmaceutical composition.
Description
Technical Field
The invention relates to the technical field of biological medicines, in particular to application of halofuginone in medicines for treating and preventing atherosclerosis diseases.
Background
Cardiovascular disease has become the leading cause of death worldwide. According to WHO data, it was shown that over 1700 tens of thousands of people die from cardiovascular disease in 2015, accounting for 31% of deaths worldwide. Atherosclerosis is a major cause of cardiovascular disease, including myocardial infarction and stroke, as well as peripheral arterial disease. It is a slowly evolving inflammatory disease characterized by the accumulation of modified lipid and fiber components in the arteries. Atherosclerotic lesions begin with endothelial cell activation, and monocytes migrate to the subendothelial space and differentiate into macrophages under the action of endothelial adhesion factor. Macrophages take up modified low density lipoproteins, forming foam cells, which participate in the formation of lipid cores. The microenvironment within the plaque induces smooth muscle cells to proliferate and migrate to the lipid core, forming a fibrous atheromatous plaque. Whereas as plaque progresses to a later stage, apoptotic and necrotic cells within the plaque increase and local inflammatory reactions activate. Later in the disease progression, plaque becomes more and more complex, calcification and thrombosis occur. Although advanced lesions may grow large enough to block blood flow, the most important clinical complication is acute occlusion due to thrombus or clot formation, resulting in myocardial infarction or stroke.
Among therapeutic drugs for the treatment of atherosclerotic diseases, statin lipid-lowering drugs are the first drugs. Although lipid-lowering therapy is a cornerstone for management of atherosclerotic diseases, statin intensive therapy has increased benefits and increases the cost and potential hazard of therapy, and patients are prone to myopathy and liver injury, as well as symptoms such as gastrointestinal reactions, skin flushing, headache, and the like. Newly emerging drugs such as PCSK9 small interfering RNAs and PCSK9 monoclonal antibodies are extremely costly, and their clinical safety and the presence or absence of other side effects still require further validation.
Therefore, finding a safer and more effective therapeutic agent has become a technical problem to be solved in the field of atherosclerosis.
Disclosure of Invention
In view of this, the present invention provides, in order to be able to solve at least partially the above problems, the use of halofuginone and a compound based on halofuginone modification for the preparation of a medicament for the treatment and prevention of atherosclerosis and related diseases.
In order to achieve the above object, an aspect of the present invention provides an application of halofuginone in preparing a medicament for treating and preventing atherosclerosis and related diseases.
In another aspect, the invention provides the use of a halofuginone-modified compound in the manufacture of a medicament for the treatment and prophylaxis of atherosclerotic and related diseases.
Wherein the halofuginone modification comprises at least one of: salt formation modification, ester formation modification, amide formation modification, carbamation modification, etherification modification, ring opening modification and cyclization modification.
According to an embodiment of the invention, the related diseases comprise at least one of: restenosis of blood vessel, hyperlipidemia.
According to an embodiment of the present invention, the drug comprises a pharmaceutical formulation formed by dissolution with a drug co-solvent.
In yet another aspect, the invention provides a pharmaceutical composition.
Wherein, the medicine composition comprises halofuginone or a compound based on halofuginone modification and an anti-atherosclerosis medicine, which are taken together as active ingredients, and one or more pharmaceutically acceptable carriers and/or medicine auxiliary materials.
According to an embodiment of the invention, the carrier comprises a nanoemulsion or a microemulsion.
According to an embodiment of the invention, the pharmaceutical excipients comprise at least one of the following: polyethylene glycol, sodium carboxymethyl cellulose, beta-cyclodextrin.
According to an embodiment of the invention, the anti-atherosclerosis drug comprises a statin lipid-lowering drug.
According to the embodiment of the invention, in the application of the halofuginone, the halofuginone can reduce the total Triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) content in serum, improve the formation of atherosclerosis plaques induced by high-cholesterol diet, and has good prevention and treatment effects on atherosclerosis and other acute cardiovascular events caused by rupture of the atherosclerosis plaques.
Drawings
FIG. 1 schematically shows the APOE induced by halofuginone in high cholesterol diet in accordance with an embodiment of the invention -/- Schematic of experimental procedure for atherosclerosis in mice;
FIG. 2 shows the body weight change curve of mice during experiments in accordance with embodiments of the present invention;
FIG. 3 (a) shows the dichroa febrifuga ketone treatment versus APOE in an embodiment of the invention -/- Influence of triglyceride content in atherosclerosis mice;
FIG. 3 (b) shows the dichroa febrifuga ketone treatment versus APOE in an embodiment of the invention -/- Effects of cholesterol content in atherosclerosis mice;
FIG. 3 (c) shows the dichroa febrifuga ketone treatment versus APOE in an embodiment of the invention -/- Influence of high density lipoprotein content in atherosclerosis mice;
FIG. 3 (d) shows the dichroa febrifuga ketone treatment versus APOE in an embodiment of the invention -/- Influence of low density lipoprotein content in atherosclerosis mice;
FIG. 4 (a) shows the results of the rat aortic arch oil red O staining in accordance with the examples of the present invention;
FIG. 4 (b) shows the quantitative plaque area results after the aortic arch part of the mice is stained with oil red O in the examples of the present invention;
FIG. 5 (a) shows the results of staining the mouse aorta Dou Yougong O in the examples of the present invention;
fig. 5 (b) shows plaque area quantification results after staining of the mouse aorta Dou Yougong O in accordance with the embodiment of the invention.
Detailed Description
The present invention will be further described in detail below with reference to specific embodiments and with reference to the accompanying drawings, in order to make the objects, technical solutions and advantages of the present invention more apparent.
Dichroa febrifuga, a traditional Chinese medicine, has been used for the treatment of malaria. Antifebrile (Febrifugine) is a quinazolinone alkaloid present in the roots and leaves of antifebrile, with antimalarial activity. Halofuginone is a halogenated derivative of Febrifugine. Researchers have found that halofuginone has many physiological and pharmacological effects. Halofuginone has been reported to have antimalarial, anti-inflammatory, anti-cancer, anti-fibrosis effects, which specifically inhibit type I collagen gene expression and matrix metalloproteinase 2 (MMP-2) gene expression.
The invention provides a new therapeutic drug for treating the atherosclerosis diseases and related diseases, and has good popularization and application values.
The invention provides an application of halofuginone in preparing medicines for treating and preventing atherosclerosis and related diseases.
Wherein, the chemical structural formula of the halofuginone is shown in the following formula (1):
the invention also provides application of the halofuginone-modified compound in preparing medicines for treating and preventing atherosclerosis and related diseases.
According to embodiments of the present invention, the related diseases may include at least one of: restenosis of blood vessel, hyperlipidemia.
The drug may include a pharmaceutical formulation formed by dissolution using a drug co-solvent. Wherein, the medicine cosolvent can be pharmaceutically acceptable, and the solvent which does not damage the active ingredients of the halofuginone is not particularly limited.
The modified compounds based on halofuginone can be modified for functional groups in halofuginone by methods known in the art, and are included in the present invention as long as they are still pharmaceutically acceptable and do not destroy the active ingredient of halofuginone. Wherein, the halofuginone modification may include, but is not limited to, at least one of: salt formation modification, ester formation modification, amide formation modification, carbamation modification, etherification modification, ring opening modification and cyclization modification.
The application of the halofuginone or the halofuginone modified compound in preparing medicines for treating and preventing atherosclerosis diseases and related diseases is also provided.
Wherein, the medicine composition comprises halofuginone or a compound based on halofuginone modification and an anti-atherosclerosis medicine, which are taken together as active ingredients, and one or more pharmaceutically acceptable carriers and/or medicine auxiliary materials. The content of each component in the pharmaceutical composition is not particularly limited as long as the pharmaceutical composition is still pharmaceutically acceptable and does not destroy the active ingredient of the pharmaceutical composition, which is included in the present invention. The pharmaceutical composition can be applied to medicines for treating and preventing atherosclerosis and related diseases.
According to an embodiment of the invention, the carrier comprises a nanoemulsion or a microemulsion.
According to an embodiment of the invention, the pharmaceutical excipients comprise at least one of the following: polyethylene glycol, sodium carboxymethyl cellulose, beta-cyclodextrin.
According to embodiments of the present invention, the anti-atherosclerosis drug may include statin lipid-lowering drugs.
In the present invention, the effective dose of the pharmaceutical co-solvent, carrier or pharmaceutical adjuvant may be specifically determined according to the pharmaceutically acceptable dose.
The dosage of halofuginone or halofuginone-modified-based compounds or pharmaceutical compositions may be determined based on the route of administration, pharmacokinetic parameters of halofuginone, the grade of atherosclerotic disease, the health of the subject, and the like.
The role of halofuginone in atherosclerotic diseases and related diseases is illustrated schematically below in connection with FIGS. 1-5. It should be noted that the examples are only specific embodiments of the present invention and are not intended to limit the scope of the present invention.
Preparation of experimental mice: SPF-grade APOE -/- Mice (8 weeks old, male) were purchased from Jiangsu Jiyaokang biotechnology Co., ltd, raised in China university of science and technology animal center, replaced sterile litter once a week, and food and water were freely obtained.
FIG. 1 shows the APOE induced by halofuginone in high cholesterol diet of an example of the invention -/- Schematic of experimental procedure for atherosclerosis in mice.
As shown in fig. 1, the animals were dosed and treated as follows: apoE -/- Mice were randomized into two groups (vehicle control group and halofuginone experimental group) after one week of adaptation in the animal house, and were given intraperitoneal injections, with vehicle or halofuginone doses of 250 μg/kg/day for 10 weeks. Halofuginone hydrobromide is purchased from Shanghai Tao Shu Biotechnology Inc. The medicine is prepared into mother liquor of 2mg/ml in dimethyl sulfoxide and stored in a refrigerator at-20 ℃. A concentration of 0.05mg/ml was formulated in 0.5% sodium carboxymethylcellulose prior to administration.
During the dosing period, mice were weighed once a week. The mice were harvested after 14 weeks and subjected to subsequent molecular and pathological experiments.
It should be noted that in this example, all data were processed and statistically analyzed using Graphpad Prism 8.0 software, and the mean value of all samples was compared using One-way ANOVA analysis. p <0.05 indicates a statistical difference. * : p <0.05; * *: p <0.01; * **: p <0.001.
Example 1: halofuginone pair APOE -/- Influence of mouse body weight
During the 14 week period of the experiment, mice were weighed once a week.
Figure 2 shows the body weight change profile of mice during experiments in accordance with embodiments of the present invention.
As shown in FIG. 2, the experimental group APOE was compared with the Vehicle (Vehicle) control group -/- The mice had significantly reduced body weight.
Experimental results show that the halofuginone can effectively reduce the APOE -/- Body weight of mice.
Example 2: halofuginone pair APOE -/- Influence of blood lipid level in atherosclerosis mice
The detection of four blood lipid items (cholesterol, triglyceride, low density lipoprotein and high density lipoprotein) was delegated to the detection of wuhansaiweil biotechnology limited.
FIG. 3 (a) shows the effect of halofuginone treatment on triglyceride content of APOE-/-atherosclerosis mice in accordance with an embodiment of the present invention; FIG. 3 (b) shows the effect of halofuginone treatment on cholesterol levels in APOE-/-atherosclerosis mice in accordance with an embodiment of the invention; FIG. 3 (c) shows the effect of halofuginone treatment on high density lipoprotein content in APOE-/-atherosclerosis mice according to embodiments of the invention; FIG. 3 (d) shows the effect of halofuginone treatment on the low density lipoprotein content of APOE-/-atherosclerosis mice according to embodiments of the invention.
As shown in fig. 3 (a) and 3 (d), the halofuginone experimental group was able to significantly down-regulate serum triglyceride and low density lipoprotein levels compared to the Vehicle (Vehicle) control group.
As shown in fig. 3 (b), the halofuginone test group was able to reduce serum cholesterol levels compared to the Vehicle (Vehicle) control group.
As shown in fig. 3 (c), the halofuginone test group was able to raise high density lipoprotein compared to the Vehicle (Vehicle) control group, but the statistical result was not significant.
In conclusion, the experimental results show that the halofuginone can effectively improve the APOE -/- Problems of lipid disorders in atherosclerosis mice.
Example 3: halofuginone pair ApoE -/- Influence of aortic arch lesions in mice
Fig. 4 (a) shows the results of the aortic arch oil red O staining of the mice according to the example of the present invention.
In this example of the invention, after 14 weeks of corresponding treatment on each group of mice, the aorta (including aortic arch and thoracic aorta) was removed, the fresh aortic specimen was removed, peripheral excess fat and tissue was peeled off under a stereoscopic microscope, and the resultant was fixed in paraformaldehyde overnight, taken out the next day, washed with PBS, longitudinally dissected, and placed in PBS. Then, the mixture was placed in a 0.3% oil red O staining solution for 10min, taken out and placed in 60% isopropanol for 10s, rinsed with PBS, and photographed by a microscope, as shown in FIG. 4 (a).
Fig. 4 (b) shows the quantitative results of plaque area after the aortic arch oil red O staining of the mice according to the example of the present invention (the percentage of aortic arch plaque area in% of total aortic arch area is represented by the ordinate).
In this embodiment of the invention, plaque deposition in the aorta was analyzed using Image J, and the plaque area ratio was calculated as the ratio of plaque deposition area to total aortic area. As shown in fig. 4 (b), the aortic arch plaque area of the experimental group was significantly reduced compared to the vehicle control group.
In conclusion, the experimental result shows that the halofuginone can effectively reduce ApoE -/- Aortic arch plaque area in aortic arch lesions in mice.
Example 4: halofuginone pair ApoE -/- Influence of aortic sinus lesions in mice
Fig. 5 (a) shows the results of staining the mouse aorta Dou Yougong O in the examples of the present invention.
In this example of the invention, after each group of mice was treated for 14 weeks, hearts were taken out and put into paraformaldehyde overnight, washed with PBS the next day and dehydrated in 30% sucrose, and the hearts were embedded in a frozen embedding medium the third day, and the embedded hearts were serially sectioned in a frozen microtome to obtain sections of aortic sinus portions. The slices are stored at-80 ℃, and are taken out and rewarmed for 20min at room temperature when in use.
The specific steps of dyeing may include, but are not limited to, the following steps:
the first step: the sections were washed 2-3 times with PBS for 5min each, lifted up with filter paper to dryness, and then circled with a histochemical pen.
And a second step of: the sections were set up and blotted with filter paper after washing with 60% isopropanol for 10s and decanting.
And a third step of: 0.3% oil red O staining solution submerges the tissue sections for 1min.
Fourth step: the supernatant was removed by washing with 60% isopropyl alcohol for 10 s.
Fifth step: washing with PBS was performed once (slow washing was performed), the supernatant was decanted and blotted with paper.
Sixth step: glycerogelatin (preheated at 60-70 ℃) is sealed, dropped on a glass slide and covered with a cover slip.
After completion of staining, a photograph of the microscope was taken, as shown in fig. 5 (a).
Fig. 5 (b) shows the plaque area quantification result (the percentage of the aortic sinus plaque area in% of the total area of the lumen in terms of the ordinate) after staining the aorta Dou Yougong O of the mice according to the embodiment of the invention.
In this example of the present invention, plaque deposition in the aortic sinus was analyzed using Image J, and the plaque area ratio was calculated as the ratio of the aortic sinus atherosclerosis plaque area to the total area of the lumen. As shown in fig. 5 (b), the aortic sinus plaque area of the experimental group was significantly reduced compared to the vehicle control group.
In conclusion, the experimental result shows that the halofuginone can effectively reduce ApoE -/- Aortic sinus plaque area in aortic sinus lesions of mice.
According to an embodiment of the invention, in the application of the halofuginone provided by the invention, the halofuginone induces ApoE on high-cholesterol feed diet -/- The blood lipid of the mice has the regulation effect, can reduce the weight of the mice, can obviously improve the formation of atherosclerosis plaques induced by high cholesterol diet, and has good prevention and treatment effects on atherosclerosis and other acute cardiovascular events caused by the rupture of the atherosclerosis plaques.
The foregoing description of the embodiments has been provided for the purpose of illustrating the general principles of the invention, and is not meant to limit the invention thereto, but to limit the invention thereto, and any modifications, equivalents, improvements and equivalents thereof may be made without departing from the spirit and principles of the invention.
Claims (3)
1. Application of halofuginone in preparing medicine for treating hyperlipidemia is provided.
2. Use of a compound based on halofuginone modification in the manufacture of a medicament for the treatment of hyperlipidemia, wherein the halofuginone modification is: salt-forming modification or ester-forming modification.
3. The use according to claim 1 or 2, wherein the medicament comprises a pharmaceutical formulation formed by dissolution with a pharmaceutical co-solvent.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL110831A (en) * | 1994-08-31 | 1998-12-27 | Hadasit Med Res Service | Pharmaceutical compositions containing quinazolinone derivatives for preventing restenosis |
| US5891879A (en) * | 1994-08-31 | 1999-04-06 | Hadasit Medical Research Services & Development Co., Inc. | Quinazolinone-containing pharmaceutical compositions and methods for the use thereof |
| IL112125A (en) * | 1994-12-22 | 1998-02-08 | Hadasit Med Res Service | Quinazolinone-containing pharmaceutical compositions |
| JP2008531697A (en) * | 2005-02-28 | 2008-08-14 | ニトロメッド インコーポレーティッド | Cardiovascular compounds containing nitric oxide enhancing groups, compositions and methods of use |
| EP2830628A4 (en) * | 2012-03-29 | 2016-05-25 | Halo Therapeutics Llc | Dosage forms of halofuginone and methods of use |
| CN109820855A (en) * | 2019-03-21 | 2019-05-31 | 重庆赛拜欧生物医药科技有限公司 | Halofuginone hydrobromide is in preparation for treating and preventing the application in ischemic heart medicine |
| WO2022040566A1 (en) * | 2020-08-21 | 2022-02-24 | The Regents Of The University Of California | Methods and uses of halofuginone |
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