CN116898830A - Application of Yi Li Simo in preparation of medicine for promoting skin wound healing - Google Patents
Application of Yi Li Simo in preparation of medicine for promoting skin wound healing Download PDFInfo
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- CN116898830A CN116898830A CN202311017193.7A CN202311017193A CN116898830A CN 116898830 A CN116898830 A CN 116898830A CN 202311017193 A CN202311017193 A CN 202311017193A CN 116898830 A CN116898830 A CN 116898830A
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- Prior art keywords
- skin wound
- simo
- wound healing
- illitemo
- medicament
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- 206010072170 Skin wound Diseases 0.000 title claims abstract description 34
- 230000029663 wound healing Effects 0.000 title claims abstract description 29
- 239000003814 drug Substances 0.000 title claims abstract description 24
- 230000001737 promoting effect Effects 0.000 title claims abstract description 16
- 238000002360 preparation method Methods 0.000 title claims description 8
- 230000000694 effects Effects 0.000 claims abstract description 16
- 102100021453 Histone deacetylase 5 Human genes 0.000 claims abstract description 15
- 101000899255 Homo sapiens Histone deacetylase 5 Proteins 0.000 claims abstract description 15
- 239000004480 active ingredient Substances 0.000 claims abstract description 6
- 239000000126 substance Substances 0.000 claims abstract description 5
- 238000002347 injection Methods 0.000 claims description 13
- 239000007924 injection Substances 0.000 claims description 13
- 230000035876 healing Effects 0.000 claims description 12
- 150000003384 small molecules Chemical class 0.000 claims description 6
- 230000004913 activation Effects 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 102000003964 Histone deacetylase Human genes 0.000 claims description 3
- 108090000353 Histone deacetylase Proteins 0.000 claims description 3
- 239000012190 activator Substances 0.000 claims description 3
- 201000010099 disease Diseases 0.000 claims description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 3
- 230000008685 targeting Effects 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000004615 ingredient Substances 0.000 claims description 2
- 239000007788 liquid Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000009467 reduction Effects 0.000 claims description 2
- 238000013268 sustained release Methods 0.000 claims description 2
- 239000012730 sustained-release form Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims 2
- 239000000203 mixture Substances 0.000 claims 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 230000003213 activating effect Effects 0.000 abstract 1
- 206010052428 Wound Diseases 0.000 description 24
- 208000027418 Wounds and injury Diseases 0.000 description 24
- 238000000034 method Methods 0.000 description 12
- 241000699670 Mus sp. Species 0.000 description 9
- 230000007547 defect Effects 0.000 description 6
- 102000004127 Cytokines Human genes 0.000 description 5
- 108090000695 Cytokines Proteins 0.000 description 5
- 239000003102 growth factor Substances 0.000 description 5
- 210000001519 tissue Anatomy 0.000 description 5
- 239000000463 material Substances 0.000 description 4
- 238000003556 assay Methods 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 238000009168 stem cell therapy Methods 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 206010020751 Hypersensitivity Diseases 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- 208000002847 Surgical Wound Diseases 0.000 description 2
- 208000026935 allergic disease Diseases 0.000 description 2
- 230000007815 allergy Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000001952 enzyme assay Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 230000036542 oxidative stress Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- 231100000241 scar Toxicity 0.000 description 2
- -1 small molecule compound Chemical class 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 1
- 208000032544 Cicatrix Diseases 0.000 description 1
- 206010063560 Excessive granulation tissue Diseases 0.000 description 1
- 102000016182 Histone deacetylase 5 Human genes 0.000 description 1
- 108050004676 Histone deacetylase 5 Proteins 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229930012538 Paclitaxel Natural products 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 206010043275 Teratogenicity Diseases 0.000 description 1
- 206010048038 Wound infection Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000006907 apoptotic process Effects 0.000 description 1
- 229940098773 bovine serum albumin Drugs 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 229940044683 chemotherapy drug Drugs 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000005284 excitation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 210000001126 granulation tissue Anatomy 0.000 description 1
- 230000036074 healthy skin Effects 0.000 description 1
- 229910052900 illite Inorganic materials 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000005012 migration Effects 0.000 description 1
- 238000013508 migration Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- VGIBGUSAECPPNB-UHFFFAOYSA-L nonaaluminum;magnesium;tripotassium;1,3-dioxido-2,4,5-trioxa-1,3-disilabicyclo[1.1.1]pentane;iron(2+);oxygen(2-);fluoride;hydroxide Chemical compound [OH-].[O-2].[O-2].[O-2].[O-2].[O-2].[F-].[Mg+2].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[Al+3].[K+].[K+].[K+].[Fe+2].O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2.O1[Si]2([O-])O[Si]1([O-])O2 VGIBGUSAECPPNB-UHFFFAOYSA-L 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229960001592 paclitaxel Drugs 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000037387 scars Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 238000002660 stem cell treatment Methods 0.000 description 1
- 238000009580 stem-cell therapy Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- RCINICONZNJXQF-MZXODVADSA-N taxol Chemical compound O([C@@H]1[C@@]2(C[C@@H](C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3([C@H]21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-MZXODVADSA-N 0.000 description 1
- 231100000211 teratogenicity Toxicity 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P17/00—Drugs for dermatological disorders
- A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of illitemo in preparing a medicament for promoting skin wound healing, wherein the illitemo has a chemical formula of C 19 H 20 N 4 O 2 S 2 The structure is shown in formula 1. The invention provides an application of I Li Simo (elemclomol) in preparing a medicament for promoting skin wound healing, in particular a micromolecular medicament taking illitemol as an active ingredient, achieves the effect of promoting skin wound healing by activating HDAC5 in an targeted manner through I Li Simo, has high safety, stable medicament, can treat large-area skin wound, has low synthesis cost, provides a new way for clinically treating skin wound healing, and has important clinical application value.
Description
Technical Field
The invention belongs to the field of biological medicine, and in particular relates to application of illitemol in preparing a medicine for promoting skin wound healing.
Background
Trauma, the first disease of global morbidity and teratogenicity, accounts for 12% of all diseases. Among the lesions caused by wounds, skin wounds are the most common, with new cases over ten million per year. When the skin defect is too large, the wound infection is serious or the basic condition of the patient is poor, the wound is difficult to heal, and the living quality of the individual patient and the national medical expense are greatly influenced. In the united states alone, refractory wounds require approximately $ 500 million healthcare costs per year, with surgical incisions and wounds resulting in refractory wounds of approximately $ 120 hundred million and burns resulting in refractory wounds of approximately $ 75.
At present, various methods for promoting the healing of skin wound surfaces exist, but the methods have obvious limitations, and the main methods are as follows: 1. wound surface covering wet dressing: only provides a closed wet environment for the wound surface, is beneficial to wound surface healing, but cannot directly activate the proliferation, migration and other capacities of wound surface cells to accelerate the healing process, and has limited effect. 2. Negative pressure sealing drainage: the method indirectly provides good environment for wound healing, but does not directly promote wound growth, has limited clinical curative effect and inaccurate treatment target spot. 3. Growth factors/cytokines: can promote granulation tissue proliferation to a certain extent, thereby accelerating wound healing, but the growth factors/cytokines belong to biological products, are easy to generate safety problems such as allergy and the like, have unstable activity, are easy to inactivate and limit clinical application. 4. Surgical treatment: skin grafting/skin flap grafting is carried out by cutting off the wound surface, and cutting healthy skin from other parts of the patient to cover the wound surface, so that the treatment process of the method is very painful, can cause damage to the skin supply area and leave large-area scars, and cannot be suitable for patients with large-area skin wound surfaces. 5. Stem cell treatment: is an emerging treatment technology, but has the risk of generating tumors and poor safety. In conclusion, the common methods such as wet dressing and negative pressure closed drainage all indirectly promote the healing by providing good environment for the wound healing, but can not directly promote the wound growth, and the growth factors, cytokines, stem cell therapies and the like are all biological products, have poor safety and stability, have higher preparation cost and limit the clinical application of the biological products. Thus, there is currently a lack of convenient and effective methods for promoting healing of skin wounds.
Histone deacetylase 5 (HDAC 5) plays an important role in the skin wound healing process, the reduction of the activity of the HDAC5 can cause the blockage of the wound healing process and the delay of wound healing, and if an effective drug can be found to target and activate the HDAC5, a new accurate and effective clinical treatment method can be possibly provided for promoting the skin wound healing.
I Li Simo is a small molecule compound, and has the chemical formula C 19 H 20 N 4 O 2 S 2 The molecular weight is 400.52, the structure is shown as formula 1, the molecular weight is fat-soluble, the molecular weight is insoluble in water and ethanol, the molecular weight is an oxidative stress inducer, the oxidative stress inducer can cause pro-apoptosis in tumor cells, the molecular weight does not have anticancer activity, but can enhance the curative effect of chemotherapeutic drugs (such as paclitaxel). However, no report is currently made on the effect of illitemo in promoting skin wound healing.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide the application of the ilo Li Simo in preparing the medicines for promoting the healing of the skin wound, researches show that the ilo can activate the HDAC5 activity so as to promote the healing of the skin wound, solve the problems that the conventional wet dressing, negative pressure closed drainage and other methods can not directly promote the growth of the wound, but the biological products such as growth factors, cytokines, stem cell therapies and the like are poor in safety and stability, and provide a new way for promoting the healing of the skin wound.
In order to achieve the above purpose, the invention adopts the following technical scheme:
the invention provides an application of Yi Li Simo in preparing a medicament for promoting skin wound healing, wherein the chemical formula of Yi Li Simo is C 19 H 20 N 4 O 2 S 2 The structural formula is
Preferably, the agent comprises a targeting agent that targets HDAC 5.
Preferably, illitemo acts as an HDAC5 activator to promote healing of skin wounds by targeted activation of HDAC5 activity.
Preferably, the dosage form of the medicine comprises tablets, powder, granules, capsules, oral liquid, injection or sustained release agent.
Preferably, the promotion of skin wound healing means that the skin wound formed by treatment is completely healed or the area of the skin wound is reduced.
The invention also provides a small molecule injection preparation, which takes the Yi Li Simo as an active ingredient, and the concentration of the small molecule injection preparation is 1-100 mu M.
Preferably, the micromolecule injection preparation takes illitemo as the only active ingredient and also comprises pharmaceutically acceptable auxiliary materials or auxiliary ingredients, wherein the concentration of the illitemo Li Simo is 1-100 mu M.
The invention provides a medicament for promoting skin wound healing by taking illitemo as an HDAC5 activator, in particular to a small molecule medicament which takes illitemo as an active ingredient. Compared with the prior art, the invention has the beneficial effects that:
(1) Through the activation of the HDAC5 by the illite Mo Ba, the effect of promoting the healing of the skin wound surface is achieved.
(2) Compared with stem cell therapy, the medicine provided by the invention has the advantages of definite therapeutic target, high safety, stable medicine and the like, and effectively avoids the defects of poor safety, possibility of tumor generation and the like.
(3) Compared with the operation treatment, the medicine can treat a large-area skin wound surface, and effectively avoids the defects of small treatment range, damage to the skin supply area, large-area scar left and the like.
(4) Compared with the wound surface covered wet dressing and negative pressure closed drainage, the medicine provided by the invention effectively avoids the defects of no definite treatment target, low efficiency, poor effectiveness and the like.
(5) Compared with growth factors/cytokines, the invention can overcome the defects of easy allergy generation, poor safety of biological products, unstable activity, easy inactivation and the like.
(6) Compared with the existing medicines, the preparation has obvious advantages in cost, low synthesis cost, provides a new potential way for clinically treating skin wound healing, and has important clinical application value.
Drawings
FIG. 1 shows the results of an in vitro enzyme activity assay for the activation of HDAC5 deacetylase by i Li Simo in the examples.
Fig. 2 is a graph showing wound healing of different groups of mice recorded on days 0, 3, 7, 10 and 14 after the establishment of the wound healing model in the example.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present invention more clear, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings of the embodiments of the present invention. It will be apparent that the described embodiments are some, but not all, embodiments of the invention. All other embodiments, which can be made by a person skilled in the art without creative efforts, based on the described embodiments of the present invention fall within the protection scope of the present invention.
Example 1
1. Experimental materials
Illitemo (CAS 488832-69-5) was purchased from shanghai sieve biomedical limited. I Li Simo is a small molecule compound with chemical formula C 19 H 20 N 4 O 2 S 2 The molecular weight is 400.52, the structure is shown in formula 1, and after the injection into wound surface edge tissue, the hydrophilic tissue can not be absorbed and diffused into capillary blood vessels to enter body circulation due to good fat solubility, so that the effect of local action can be achieved, and the hydrophilic tissue can not act on other tissue organs except skin wound surface tissue.
2. Experimental method
2.1HDAC5 Activity assay
In each assay well, 5. Mu.L of HDAC5 substrate (20. Mu.M), 5. Mu.L of bovine serum albumin (1. Mu.g/mL), 30. Mu.L of LHDAC5 buffer were mixed. Adding 5 μl of diluted HDAC5 (0.6 ng/μl) and 5 μl of illicit Mo Yaowu solution to illicit assay wells; the control wells were then incubated with 10. Mu.L of buffer for 30 minutes at 37 ℃. After incubation, 50 μ LHDAC5 developer was added to each well and incubated at room temperature for 15 minutes, and fluorescence with excitation wavelength of 360nm and emission wavelength of 450nm was measured.
2.2 establishment of wound healing model of mice
The wound healing model is described in the prior art (The mouse excisional wound splinting model, including applications for stem cell transformation. Nature protocol.2013;8 (2): 302-9.). Briefly, 12 week old C57/BL6 mice were anesthetized and dorsal skin prepared. A full-thickness excision wound surface of the skin with the diameter of 8 mm is manufactured at the midline position of the back, and a meat membrane is cut off. The ring-shaped clamping plates made of the silica gel material are fixed on the skin around the wound surface by ring-stitching through 4-0 silk threads, so that the wound surface is prevented from being closed due to skin shrinkage. Mice were photographed and recorded immediately after surgery, day 3, 7, 10, 14, and the wound area was counted using ImageJ.
2.3 illicit Mo Zhenji injection
The day when the small wound healing model was established, i.e. the injection of illicit Mo Zhenji was started, and the injection was subcutaneously performed around the wound, and the mice were randomly divided into two groups of mice, i.e. a control group (solvent group) and an experimental group (illicit administration group), each group of 6 mice. Every other day, 8 points around each wound surface are injected, each point is injected with 10 mu L of medicine or control solvent, and is injected by connecting 10 mu L of NanoFil micro injector (World Precision Instruments) with a 34-gauge needle (World Precision Instruments, saraota, FL) until the materials are obtained, and the concentration of the I Li Simo in the injection is 100 mu M.
3. Experimental results
3.1I Li Simo can activate HDAC5 deacetylase Activity
In vitro enzyme activity assays showed that i Li Simo significantly activated HDAC5 deacetylase activity (P < 0.001) (fig. 1).
3.2 illitemo can promote healing of skin wound
The wound healing conditions of different groups of mice recorded by photographing on days 0, 3, 7, 10 and 14 after the wound healing model is established show that the wound area of the mice injected with the illitemo treatment group on days 7, 10 and 14 is obviously reduced (P < 0.001) compared with the control group (figure 2).
The foregoing is illustrative of a preferred embodiment of the present invention, but the present invention should not be limited to the disclosure of this embodiment. So that equivalents and modifications will fall within the scope of the invention, all within the spirit and scope of the invention as disclosed.
Claims (7)
1. Use of I Li Simo in preparing medicine for promoting skin wound healing, wherein the chemical formula of I Li Simo is C 19 H 20 N 4 O 2 S 2 The structural formula is
2. The use according to claim 1, wherein the medicament comprises a targeting medicament targeting HDAC 5.
3. The use according to claim 2, wherein i Li Simo acts as an HDAC5 activator to promote skin wound healing by targeted activation of HDAC5 activity.
4. The use according to claim 1, wherein the dosage form of the medicament comprises a tablet, powder, granule, capsule, oral liquid, injection or sustained release agent.
5. The use according to claim 1, wherein the promotion of skin wound healing means complete healing of skin wound formed by disease treatment or reduction of the area of skin wound.
6. A small molecule injection preparation characterized in that illitemo is used as an active ingredient, and the concentration of the illitemo is 1-100 mu M.
7. The small molecule injection formulation of claim 6, wherein the small molecule injection formulation comprises illitemo as the only active ingredient, and further comprises pharmaceutically acceptable excipients or auxiliary ingredients, wherein the concentration of i Li Simo is 1-100 μΜ.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017193.7A CN116898830A (en) | 2023-08-14 | 2023-08-14 | Application of Yi Li Simo in preparation of medicine for promoting skin wound healing |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202311017193.7A CN116898830A (en) | 2023-08-14 | 2023-08-14 | Application of Yi Li Simo in preparation of medicine for promoting skin wound healing |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116898830A true CN116898830A (en) | 2023-10-20 |
Family
ID=88363014
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202311017193.7A Pending CN116898830A (en) | 2023-08-14 | 2023-08-14 | Application of Yi Li Simo in preparation of medicine for promoting skin wound healing |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN116898830A (en) |
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2023
- 2023-08-14 CN CN202311017193.7A patent/CN116898830A/en active Pending
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