CN109846863B - Application of honokiol - Google Patents
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- CN109846863B CN109846863B CN201910185064.6A CN201910185064A CN109846863B CN 109846863 B CN109846863 B CN 109846863B CN 201910185064 A CN201910185064 A CN 201910185064A CN 109846863 B CN109846863 B CN 109846863B
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Abstract
The invention relates to a new application of honokiol, in particular to an application of honokiol in preparing a product for preventing or treating hashimoto's thyroiditis and/or complications thereof.
Description
Technical Field
The invention belongs to the technical field of medicines, relates to an application of honokiol, and particularly relates to an application of honokiol in preparation of a product for preventing or treating hashimoto's thyroiditis and/or complications thereof.
Background
The incidence of thyroid diseases in China is quite high, the total incidence is estimated to be about 20% according to data of each party, and more than 2 hundred million people are expected to suffer from the diseases in China. According to the results published by 2010, epidemiological investigation of thyroid diseases of residents of ten urban communities for the first time in China, the prevalence rate of hyperthyroidism reaches 1.3%, the prevalence rate of hypothyroidism reaches 6.5%, and the prevalence rate of thyroid nodules reaches 18.6%. In addition, 5% to 15% of thyroid nodules are malignant, i.e., thyroid cancer. The knowing rate and the treatment rate of thyroid diseases in China are very low, and the overall treatment rate of thyroid diseases is less than 5 percent at present.
Hashimoto's thyroiditis is an autoimmune disease which is characterized by chronic lymphocytic infiltrates of the thyroid gland and is caused by the attack of thyroid gland functional cells by a series of cells or antibody-mediated immune functional cells or molecules, and is mostly seen in middle-aged 30-50 years old women, with the proportion of diseased men and women being 1:5.7-1: 6. In hashimoto's thyroiditis, approximately 5% of patients develop a mild hypothyroidism or hyperthyroidism to a dominant hypothyroidism or hyperthyroidism each year; some patients with hashimoto's thyroiditis may be self-healed, and some patients may become cancerous with a cancer rate of 5% -15%.
Hashimoto's thyroiditis has a certain genetic predisposition, 10% -15% of patients have family history, and the genetic factors which are currently confirmed include the expression of HLA-DR5, the expression of HLA-DR3 and the down-regulation of cytotoxic T lymphocyte-associated antigen-4 (CTLA-4). Meanwhile, the incidence of hashimoto's thyroiditis is higher in people with other autoimmune diseases (such as rheumatoid arthritis, type 1 diabetes, lupus erythematosus). Environmental factors also play a role, including iodine, selenium, and certain viruses and bacteria, which are associated with the development of this disease.
The pathogenesis of hashimoto's thyroiditis is very complex and is the result of participation of multiple factors, including genetic, immune, pathogenic microorganisms, diet, environmental and social factors and the like. The causative factors and pathogenesis of thyroid disorders are still poorly understood.
In view of the complex pathogenesis of hashimoto's thyroiditis, no clearly effective drug is currently available, and the disease usually does not heal spontaneously, and if left unchecked, can lead to permanent hypothyroidism, requiring lifelong administration of thyroid hormone. The current view of western medicine is that hashimoto's thyroiditis can not be treated, and only when the disease develops hypothyroidism, thyroid hormone is taken for symptomatic treatment.
The magnolia officinalis is a traditional Chinese medicine with wide drug effect, and is used for treating various diseases at home and abroad. Honokiol (Honokiol) is one of the two main active components of magnolia officinalis, and has the chemical formula of C18H18O2Structural formula is
In recent years, various pharmacodynamics researches on honokiol are more intensive, and the action mechanism of honokiol is clearer. A great number of scientific researches report that honokiol has the functions of resisting bacteria, viruses, oxidation, inflammation, tumors, angiogenesis, spasm and depression and the like. Meanwhile, the toxicology experiment, the pharmacokinetics experiment, the drug metabolism experiment and other researches of honokiol prove that the honokiol is suitable for developing patent drugs.
At present, no report on the use of honokiol for preventing or treating hashimoto's thyroiditis and/or its complications exists.
Disclosure of Invention
Aiming at the clinical dilemma of the hashimoto thyroiditis, the inventor utilizes a mouse suffering from the hashimoto thyroiditis to make clinical prodrug effect evaluation based on deep understanding and comprehension of the drug effect and the pharmacology of the honokiol and the pathogenesis of the hashimoto thyroiditis, aims to apply the honokiol to the prevention or treatment of the hashimoto thyroiditis and/or the complications of the hashimoto thyroiditis, greatly improves the current treatment dilemma of the hashimoto thyroiditis, namely, the situation that no drug is available, and provides a reference way for the development of new drugs and the new application of old drugs.
The present invention relates in a first aspect to the use of honokiol in the manufacture of a product for the prevention or treatment of hashimoto's thyroiditis and/or its complications in a subject.
In a preferred embodiment, the prevention or treatment is reducing lymphocyte infiltration in thyroid tissue of the subject.
In a preferred embodiment, the prevention or treatment is the repair of pathological damage caused by hashimoto's thyroiditis in thyroid tissue of the subject.
In a preferred embodiment, the subject is a human.
In a preferred embodiment, the product comprises a medicament.
In a preferred embodiment, the product is administered in an amount of 20-800mg/kg, preferably 40-600mg/kg, more preferably 80-400mg/kg, most preferably 160-250mg/kg of the active ingredient honokiol based on the subject's weight.
In a preferred embodiment, the medicament is administered in unit dosage form, either enterally or parenterally, such as orally, intramuscularly, subcutaneously, intravenously, rectally, or the like. When administered, the concentration of the neutralized honokiol is 2-100mg/ml, preferably 5-60mg/ml, more preferably 10-40mg/ml, and most preferably 15-25 mg/ml.
In a preferred embodiment, the medicament comprises the active ingredient honokiol and one or more pharmaceutically acceptable adjuvants. Wherein the auxiliary materials comprise diluent and absorbent, wetting agent and adhesive, disintegrating agent, disintegration inhibitor, absorption enhancer, lubricant, injection diluent, isotonic agent, cosolvent, buffering agent, pH regulator, solvent, osmotic pressure regulator, antioxidant, preservative and flavoring agent. The administration form of the drug may be tablets, capsules, injections or the like, and may be a general formulation, a sustained-release formulation, a controlled-release formulation or the like. Various excipients well known in the art, including diluents and absorbents such as starch, dextrin, calcium sulfate, mannitol, aluminum silicate, etc., can be widely used in order to formulate the drug into tablets; wetting agents and binders such as water, glycerin, polyethylene glycol, propanol, dextrin, syrup, methyl cellulose, potassium sulfate, etc.; disintegrating agents, such as dried starch, alginate, agar powder, calcium carbonate, polyoxyethylene, methyl cellulose, ethyl cellulose, etc.; disintegration inhibitors such as sucrose, cacao butter, hydrogenated oil and the like; absorption accelerators such as quaternary ammonium salts, sodium lauryl sulfate, and the like; lubricants such as talc, silica, corn starch, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, or double-layer and multi-layer tablets. To encapsulate a drug, the drug may be mixed with any one or more of the above-mentioned adjuvants, and the resulting mixture placed in a hard or soft capsule. The medicine can also be made into microcapsule, suspended in aqueous medium to make suspension, or filled into hard capsule to make injection. In order to prepare the drug into injections such as solutions, emulsions, lyophilized powders, suspensions, etc., various diluents known in the art, such as water, ethanol, polyethylene glycol, 1, 3-propanediol, etc., may be used. In addition, to prepare an isotonic injection, an appropriate amount of sodium chloride, glucose or glycerol may be added to the injection; in addition, conventional cosolvents, buffers, pH adjusters, and the like may also be added.
In a preferred embodiment, the medicament further comprises other active ingredients for preventing or treating hashimoto's thyroiditis and/or its complications.
In a preferred embodiment, the honokiol can also be replaced by a structural analogue of honokiol having the same reactive group as the honokiol, the structural analogue of honokiol having the following structural formula (see, for details, chinese patent application "honokiol derivatives and methods of preparation and use thereof" (CN106278829A), incorporated herein by reference):
the second aspect of the invention relates to a pharmaceutical composition comprising or consisting of the active ingredient honokiol and one or more adjuvants.
Preferably, a pharmaceutical composition comprising honokiol, having the following composition:
0.005-0.02 weight part of honokiol, preferably 0.009-0.015 weight part
0.01-0.04 part by weight of ethanol, preferably 0.015-0.025 part by weight
PEG-4000.05-0.22 weight portion, preferably 0.08-0.18 weight portion
The balance being water.
Drawings
FIG. 1 is a hematoxylin-eosin (HE) staining pattern of thyroid gland of unmodeled mouse (normal mouse) observed under a microscope. The thyroid follicles in the thyroid tissues of the mice were intact, and were not seen for epithelial cell proliferation and lymphocyte infiltration.
Fig. 2 is a graph of HE staining of mouse thyroid after seven weeks of modeling observed under a microscope. The thyroid epithelial cells in the thyroid tissue of the mouse are hyperplastic and have the phenomenon of lymphocyte infiltration, and the thyroid follicle is gradually destroyed.
The Tpo antibody (TpoAb) levels (U/ml) in serum of normal mice, mice after successful modeling of hashimoto's thyroiditis, mice treated for 4 weeks with placebo (clear water) and mice treated for 4 weeks with HK (honokiol) are shown in figure 3. As can be seen from the figure, the level of Tpo antibody (TpoAb) in serum (U/ml) was significantly reduced in the HK (honokiol) -treated mice compared to the placebo group.
Fig. 4 is a graph of HE staining of the thyroid of mice given rinsing water treatment for 4 weeks b after successful modeling observed under the microscope. The thyroid epithelial cells in the thyroid tissue of the mouse are hyperplastic, the lymphocyte infiltration is obvious, the thyroid follicular fluid is gradually destroyed, and no good transition sign appears.
FIG. 5 is a graph of HE staining of the thyroid gland of mice that were stimulated with NaI for 4 weeks following successful modeling by microscopic observation. Wherein, the thyroid gland epithelial cells in the thyroid gland tissue of the mouse are increased in proliferation, the lymphocyte infiltration is more obvious, and the thyroid gland follicle is damaged.
Figure 6 is a graph of HE staining of the thyroid of mice given honokiol treatment for 4 weeks after successful modeling observed under the microscope. Wherein the proliferation of thyroid gland epithelial cells in the thyroid gland tissue of the mouse is improved, the infiltration condition of lymphocytes is obviously reduced, and the lymphocytes in the thyroid gland follicular cell gaps are absorbed and gradually replaced by fibrous tissues.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation and explanation of the invention, but is not intended to limit the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
EXAMPLE 1 determination of the Effect of Honokiol on the treatment of Hashimoto's thyroiditis
1. Material
1.1 drugs and reagents
The honokiol used in the present example was obtained by the inventor through self-extraction and purification (purity greater than 99.0%), and the specific extraction method is described in the applicant's patent application "method for preparing mixture of honokiol and magnolol by hydroxyapatite assisted filtration" (CN106588578A), which is incorporated herein by reference. In addition, other methods known to those skilled in the art can be used for extraction and purification of honokiol, such as macroporous adsorbent resin method, silica gel chromatography, gradient pH separation method, and countercurrent chromatography. In addition, honokiol with purity of more than 99.0% can also be obtained commercially.
Sodium iodide (NaI): dalian Melam Biotechnology Ltd
Ethanol: chemical reagents of national drug group Co Ltd
PEG-400: tianjin chemical reagent Limited of Kemiou Mi
1.2 instruments
A liquid transfer device: eppendorf;
a water purifier: product of Milli-Q company, USA, FTSN97007
Vortex mixer: type 16700Mixer, Thermolyne
An electronic balance: sartorius scientific instruments (Beijing) Inc., Sartorius BT125D
An upright research grade microscope: olympus BX51TRF
1.3 laboratory mice
Cg-H2H4/DilTacUmmJ strain mice, purchased from Jackson laboratories, USA.
Cg-H2H4/DilTacUmmJ was used as a pharmacodynamic test model in this example. The Cg-H2H4/DilTacUmmJ mouse model is the most recognized model in the field of hashimoto's thyroiditis as the disease closest to human hashimoto's thyroiditis, and the majority (60-70%) of the mice develop spontaneous hashimoto's thyroiditis at 7-10 months of age and produce auto-IgG antibodies. 100% of mice develop hashimoto's thyroiditis at around 4 months of age if fed with 0.05% NaI by drinking water (see Braley-Mullen H; Sharp GC; Medling B; Tang H.1999.Spontaneous automimutus thyroiditis in NOD.H-2H 4. J. automimutum 12(3): 157-65), which is incorporated herein by reference in its entirety). One of the important uses of this model is in pharmacodynamic testing. In this example, the mouse model for Hashimoto's thyroiditis used was a human-like Hashimoto's thyroiditis mouse model induced by NaI in NOD.Cg-H2H4/DilTacUmmJ mice.
2. Method of producing a composite material
2.1 establishment of mouse Hashimoto's thyroiditis model
(1) When the same batch of newborn mice born at the same time grows for 7-8 weeks, the drinking water of the mice is changed into water containing 0.05% NaI. After 7 weeks of induction 6 mice were randomly drawn and thyroid glands were taken for HE staining. The results of microscopic observation showed that 100% of mice had thyroid lymphocyte infiltration regardless of male and female, as shown in fig. 2, demonstrating successful modeling.
(2) The group administration was started 8 weeks after induction (HE staining experiment required one week for the results, and it was considered that the condition of thyroid lesions in mice was in an aggravated state during this one week).
2.2 treatment of thyroiditis in mice with honokiol
(1) The grouping method is as follows:
clear water group: the drinking water of the mice was changed to clear water.
NaI group: water containing 0.05% NaI was continued to be administered.
And the magnolol group: changing the drinking water of the mice into clear water, and simultaneously administering honokiol for treatment, wherein the mode of orally administering the honokiol solution is adopted.
(2) Preparing a honokiol solution: collecting honokiol powder 200mg, adding 500 μ l ethanol and 2ml PEG-400, dissolving with vortex, and adding double distilled water (ddH)2O) is diluted to 10ml, and the honokiol solution with the concentration of 20mg/ml is prepared, is used immediately and is preserved for no more than 3 days at the temperature of 4 ℃ in the dark.
(3) The administration mode comprises the following steps: orally administered five times a week
(4) Administration dose: the dosage is 200mg/kg per time, and is administered according to the weight of mice
2.3 evaluation method and result judgment
(1) Peripheral blood serum of each experimental group of mice was taken 4 weeks after the administration, and the level of Tpo antibody (TpoAb) in peripheral blood of the mice was measured. The mice are sacrificed, the thyroid glands of the mice are taken for HE staining, and the pathological changes of the thyroid glands of the mice are observed under a microscope.
(2) And (3) pathological detection indexes: and HE staining is used for observing the infiltration condition of thyroid lymphocytes and the repair condition of thyroid tissue fibers of the mice.
3. Results
The Tpo antibody (TpoAb) levels (U/ml) in serum of normal mice, mice after successful modeling of hashimoto's thyroiditis, mice treated for 4 weeks with placebo (clear water) and mice treated for 4 weeks with HK (honokiol) are shown in figure 3. As can be seen from the figure, the level of Tpo antibody (TpoAb) in serum (U/ml) was significantly reduced in the HK (honokiol) -treated mice compared to the placebo group.
As shown in fig. 4 to 6, the mice of both the clear water group and the NaI group had no improvement in the pathological condition of the thyroid gland tissue (clear water results are shown in fig. 3, in which the thyroid gland epithelial cells in the thyroid gland tissue of the mice were proliferated, the lymphocyte infiltration was significant, the thyroid follicle was gradually destroyed, and no improvement in the pathological condition was observed; NaI results are shown in fig. 4, in which the thyroid gland epithelial cells in the thyroid gland tissue of the mice were proliferated, the lymphocyte infiltration was more significant, and the thyroid follicle was destroyed); and the thyroid gland epithelial cell hyperplasia in the thyroid gland tissue of the mouse treated by honokiol for 4 weeks is improved, the lymphocyte infiltration condition is obviously reduced, and the lymphocyte in the thyroid gland follicular cell gap is absorbed and gradually replaced by fibrous tissue.
4. Conclusion
The overall pathological signs of the thyroid tissue of mice with hashimoto's thyroiditis show that honokiol has a therapeutic effect on hashimoto's thyroiditis and a repairing effect on pathological injuries caused by hashimoto's thyroiditis.
The research of the invention shows that the honokiol used alone has the activity of treating hashimoto's thyroiditis, and provides a new idea for the treatment of hashimoto's thyroiditis and the research and potential application of new pharmacological effects of the honokiol. In addition, the honokiol old medicine is newly used, so that time cost and labor cost for research on safety are saved, and the medicine development and clinical application of the honokiol for treating thyroid related diseases are accelerated.
Example 2
A pharmaceutical composition comprising honokiol, having the following composition:
0.01 part by weight of honokiol
0.02 part by weight of ethanol
PEG-4000.11 parts by weight
The balance being water.
The above examples are illustrative of the present invention and do not represent the best administration and combination of the drug for treating hashimoto's thyroiditis, but the present invention is not limited to the above examples, and any other changes, modifications, substitutions, combinations and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and are intended to be included within the scope of the present invention.
Claims (10)
1. Use of honokiol in the manufacture of a medicament for preventing or treating hashimoto's thyroiditis and/or its complications in a subject.
2. Use according to claim 1 for reducing lymphocyte infiltration in thyroid tissue of a subject.
3. Use according to claim 1 for repairing pathological damage caused by hashimoto's thyroiditis in thyroid tissue of a subject.
4. The use according to any one of claims 1-3, wherein the subject is a human.
5. The use according to claim 1, wherein the medicament is administered in an amount of 20-800mg/kg of the active ingredient honokiol based on the subject's weight.
6. Use according to claim 5, wherein the medicament is administered in an amount of 40-600mg/kg of the active ingredient honokiol, based on the subject's weight.
7. Use according to claim 6, wherein the medicament is administered in an amount of 80-400mg/kg of the active ingredient honokiol, based on the subject's weight.
8. The use according to claim 7, wherein the medicament is administered in an amount of 160-250mg/kg of the active ingredient honokiol, based on the weight of the subject.
9. Use according to claim 1, wherein the medicament comprises the active ingredient honokiol and one or more pharmaceutically acceptable adjuvants; wherein the auxiliary materials comprise diluent and absorbent, wetting agent and adhesive, disintegrant, disintegration inhibitor, absorption enhancer, lubricant, injection diluent, isotonic agent, cosolvent, buffering agent, pH regulator, solvent, osmotic pressure regulator, antioxidant, preservative and flavoring agent; wherein the diluent and absorbent comprise starch, dextrin, calcium sulfate, mannitol, and aluminum silicate; wetting agents and binders including water, glycerin, polyethylene glycol, propanol, dextrin, syrup, methyl cellulose, potassium sulfate; disintegrating agent comprising dried starch, alginate, agar powder, calcium carbonate, polyoxyethylene, methylcellulose, and ethyl cellulose; a disintegration inhibitor comprising sucrose, cocoa butter, hydrogenated oil; absorption enhancer comprising quaternary ammonium salt, sodium dodecyl sulfate; a lubricant comprising talc, silica, corn starch, polyethylene glycol; an injection diluent comprising water, ethanol, polyethylene glycol, 1, 3-propanediol; an isotonic agent comprising sodium chloride, glucose or glycerol.
10. Use according to claim 1, wherein the medicament further comprises a further active ingredient for the prevention or treatment of hashimoto's thyroiditis and/or its complications.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178666A (en) * | 2011-03-21 | 2011-09-14 | 四川大学 | Application of Honokiol to preparing drugs for preventing or treating intracranial space occupying lesion and intracranial tissues and organs inflammation |
| WO2014124134A1 (en) * | 2013-02-07 | 2014-08-14 | The General Hospital Corporation | Methods for expansion or depletion of t-regulatory cells |
| CN105233002A (en) * | 2015-10-31 | 2016-01-13 | 菏泽海诺知识产权服务有限公司 | Traditional Chinese medicine composition for treating subacute thyroiditis |
| CN106278829A (en) * | 2015-05-28 | 2017-01-04 | 四川大学华西医院 | Honokiol derivant and preparative separation method thereof and purposes |
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- 2019-03-12 CN CN201910185064.6A patent/CN109846863B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102178666A (en) * | 2011-03-21 | 2011-09-14 | 四川大学 | Application of Honokiol to preparing drugs for preventing or treating intracranial space occupying lesion and intracranial tissues and organs inflammation |
| WO2014124134A1 (en) * | 2013-02-07 | 2014-08-14 | The General Hospital Corporation | Methods for expansion or depletion of t-regulatory cells |
| CN106278829A (en) * | 2015-05-28 | 2017-01-04 | 四川大学华西医院 | Honokiol derivant and preparative separation method thereof and purposes |
| CN105233002A (en) * | 2015-10-31 | 2016-01-13 | 菏泽海诺知识产权服务有限公司 | Traditional Chinese medicine composition for treating subacute thyroiditis |
Non-Patent Citations (1)
| Title |
|---|
| 厚朴酚与和厚朴酚的药理作用及提取合成研究进展;王颖 等;《陕西理工大学学报(自然科学版)》;20180430;第34卷(第2期);第58-64、78页 * |
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