CN114306299A - Application of belinostat in preparation of medicine for relieving and/or treating cerebral arterial thrombosis - Google Patents
Application of belinostat in preparation of medicine for relieving and/or treating cerebral arterial thrombosis Download PDFInfo
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- CN114306299A CN114306299A CN202011057176.2A CN202011057176A CN114306299A CN 114306299 A CN114306299 A CN 114306299A CN 202011057176 A CN202011057176 A CN 202011057176A CN 114306299 A CN114306299 A CN 114306299A
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Abstract
The invention belongs to the technical field of medicines, and particularly discloses application of belinostat in preparation of medicines for relieving and/or treating cerebral arterial thrombosis. On a rat cerebral ischemia reperfusion model, belinostat shows a good therapeutic effect, and can effectively prevent and treat pathological changes of diseases and progression of diseases.
Description
Technical Field
The invention relates to application of belinostat in preparation of a medicine for relieving and/or treating cerebral arterial thrombosis, and belongs to the technical field of medicines.
Background
Cerebral apoplexy is an acute onset cerebral blood circulation disorder disease, is caused by the stenosis, occlusion or rupture of internal cerebral arteries induced by various factors, and is clinically divided into ischemic stroke and hemorrhagic stroke, wherein the ischemic stroke accounts for 80% of stroke. Stroke is a refractory disease which seriously harms human health and life, and has the characteristics of high morbidity, high disability rate and high mortality. Epidemiological data show that stroke becomes the second most common cause of death worldwide, and cardiovascular diseases are combined in China to become the first cause of death, so that the treatment and prognosis rehabilitation of stroke are the key points of stroke research at present. Tissue-plasminogen activator (t-PA) is the only drug approved by the FDA in the United states for treating cerebral stroke, but clinical studies show that the treatment time window of t-PA is narrow, only one third of patients use t-PA to be effective, and two thirds of patients do not have effect or have deteriorated disease after t-PA treatment, thereby limiting the wide use of the t-PA.
After the failure of the shift from a number of preclinical studies to human clinical trials, the National Institute of Neurological Diseases and Stroke (NINDS) listed post-Stroke nerve repair as the primary research item in 2006 and 2011 (Front Hum neurosci.2014Jun 27; 8: 382.). In the subacute and chronic phases of the ischemic stroke, the restorative treatment can stimulate the intrinsic restoration route by remolding the residual nerve tissues, promote the remolding of the brain and spinal cord processes, the angiogenesis of the injured part and the recovery of the function of glial cells. Cell and drug based restorative therapies can significantly improve neural function after stroke by promoting one or several events in the neural restoration process.
The Middle Cerebral Artery Occlusion Model (MCAO) cuts off the lateral collateral blood flow from extracranial sources by blocking the external carotid Artery and its branches, and blocking the pterygopalatine Artery. The cerebral middle artery ischemia model is established by inserting a plug wire from an external carotid artery to the anterior cerebral artery through an internal carotid artery and mechanically blocking blood supply at the emergence of the cerebral middle artery. The middle cerebral artery ischemia reperfusion (MCAO/R) model only needs to pull out the wire plug to recover the cerebral blood supply. The model is a classic animal model of cerebral apoplexy, and a rat infarct area is relatively stable. When the model is made, male Wistar rats are selected, and female rats secrete estrogen to protect heart and cerebral vessels, so that the model is more stable when the male rats are selected to establish the model.
Belinostat (Belinostat, trade name: Beleodaq, also known as PXD101) is an inhibitor of Histone Deacetylase (HDAC), which promotes the removal of acetyl groups from lysine residues of histones and certain non-histones, together with histone acetyltransferases, and controls chromatin structure and gene expression by regulating histone acetylation and deacetylation in vivo. Belinostat was approved by the FDA in the united states for the treatment of relapsed or refractory peripheral T-cell lymphoma in 2014. The medicine has stronger toxic effect on tumor cells than normal cells, can inhibit HDAC activity at nanomolar concentration (< 250nM) in vitro tests, can induce accumulation of acetylated histone and other proteins, and induces cell cycle arrest or apoptosis of certain transformed cells. The safety and efficacy of belinostat is currently being evaluated and clinical studies have found that the most common side effects of treating subjects include nausea, vomiting, weakness, fever and anemia.
The invention is a new discovery obtained by a large number of animal experimental researches. The new invention relates to a medicine for treating cerebral apoplexy, which is provided for clinic. At present, no report is provided about the direct or indirect treatment effect of belinostat on cerebral apoplexy.
Disclosure of Invention
The invention aims to solve the technical problem of providing the application of belinostat in preparing medicines for relieving and/or treating cerebral arterial thrombosis.
In order to solve the technical problem, the invention provides the following technical scheme:
the first aspect of the technical scheme of the invention provides the application of belinostat shown in formula (I) in preparing the medicine for relieving and/or treating stroke,
preferably, the stroke is ischemic stroke. The drug effect is observed after 24 hours of drug administration to show the protective effect of the belinostat on the acute cerebral ischemia-reperfusion rats; and the drug effect is observed in 14 days after the drug is administered once a day after 24 hours of reperfusion, which shows the nerve function recovery effect of the belinostat on cerebral ischemia-reperfusion rats. The experimental procedure was divided into two sections.
1. Protective effect of belinostat on acute cerebral ischemia-reperfusion rats
A male Wistar rat is adopted to establish an MCAO/R model, and the influence of belinostat on animal neurological function scores is detected. The effect of belinostat on the volume of cerebral infarction was examined using TTC staining.
2. Belinostat promotes nerve function recovery of cerebral ischemia reperfusion rats
A male Wistar rat is adopted to establish an MCAO/R model, and the influence of the belinostat on the survival rate of animals, the scoring of the nerve function and the function of forelimbs is detected.
The second aspect of the technical scheme of the invention provides application of a pharmaceutical composition in preparing a medicine for relieving and/or treating cerebral apoplexy, which is characterized in that the pharmaceutical composition contains an effective dose of belinostat shown in formula (I) and a medicinal excipient,
wherein, the pharmaceutical composition contains other active ingredients besides the belinostat serving as a pharmaceutical active ingredient. The pharmaceutical composition comprises the following dosage forms: solutions, suspensions, lyophilized powders, emulsions, pills, capsules, powders, controlled release, sustained release formulations and microsomal delivery systems. The medicinal excipient comprises starch, dextrin, sodium carboxymethylcellulose, magnesium stearate and talcum powder. Preferably, the stroke is ischemic stroke.
The invention also relates to application of a pharmaceutical composition taking the compound belinostat as an active ingredient in preparing a medicine for relieving and/or treating cerebral arterial thrombosis. The pharmaceutical composition may be prepared according to methods well known in the art. The compounds of the present invention may be formulated into any dosage form suitable for patient use by combining them with one or more pharmaceutically acceptable solid or liquid excipients and/or adjuvants.
In the present application, a patient includes a mammal, including bovine, equine, ovine, porcine, canine, feline, rodent, primate, wherein the mammal is preferably a human, cat, dog, or pig, more preferably a human.
The compounds of the present invention or pharmaceutical compositions containing them may be administered in unit dosage form by enteral or parenteral routes, such as oral, intravenous, intramuscular, subcutaneous, nasal, oromucosal, ophthalmic, pulmonary and respiratory, dermal, vaginal, rectal, and the like. The dosage form for administration may be a liquid dosage form, a solid dosage form, or a semi-solid dosage form. The liquid dosage forms can be solution (including true solution and colloidal solution), emulsion (including o/w type, w/o type and multiple emulsion), suspension, injection (including water injection, powder injection and infusion), eye drop, nose drop, lotion, liniment, etc.; the solid dosage form can be tablet (including common tablet, enteric coated tablet, buccal tablet, dispersible tablet, chewable tablet, effervescent tablet, orally disintegrating tablet), capsule (including hard capsule, soft capsule, and enteric coated capsule), granule, powder, pellet, dripping pill, suppository, pellicle, patch, aerosol (powder), spray, etc.; semisolid dosage forms can be ointments, gels, pastes, and the like. The compound can be prepared into common preparations, sustained release preparations, controlled release preparations, targeting preparations and various particle drug delivery systems.
For tableting the compounds of the invention, a wide variety of excipients known in the art may be used, including diluents, binders, wetting agents, disintegrants, lubricants, glidants. The diluent can be starch, dextrin, sucrose, glucose, lactose, mannitol, sorbitol, xylitol, microcrystalline cellulose, calcium sulfate, calcium hydrogen phosphate, calcium carbonate, etc.; the humectant can be water, ethanol, isopropanol, etc.; the binder can be starch slurry, dextrin, syrup, Mel, glucose solution, microcrystalline cellulose, acacia slurry, gelatin slurry, sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, ethyl cellulose, acrylic resin, carbomer, polyvinylpyrrolidone, polyethylene glycol, etc.; the disintegrant may be dry starch, microcrystalline cellulose, low-substituted hydroxypropyl cellulose, crosslinked polyvinylpyrrolidone, crosslinked sodium carboxymethylcellulose, sodium carboxymethyl starch, sodium bicarbonate and citric acid, polyoxyethylene sorbitol fatty acid ester, sodium dodecyl sulfate, etc.; the lubricant and glidant may be talc, silicon dioxide, stearate, tartaric acid, liquid paraffin, polyethylene glycol, and the like. The tablets may be further formulated into coated tablets, such as sugar-coated tablets, film-coated tablets, enteric-coated tablets, or double-layer and multi-layer tablets. To encapsulate the administration units, the active ingredient of the compounds of the invention can be mixed with diluents and glidants and the mixture can be placed directly into hard or soft capsules. Or the effective component of the compound of the invention can be prepared into granules or pellets with diluent, adhesive and disintegrating agent, and then placed into hard capsules or soft capsules. The various diluents, binders, wetting agents, disintegrants, glidants used to prepare the compound tablets of the present invention may also be used to prepare capsules of the compound of the present invention. In order to prepare the compound of the invention into injection, water, ethanol, isopropanol, propylene glycol or a mixture thereof can be used as a solvent, and a proper amount of solubilizer, cosolvent, pH regulator and osmotic pressure regulator which are commonly used in the field can be added. The solubilizer or cosolvent can be poloxamer, lecithin, hydroxypropyl-beta-cyclodextrin, etc.; the pH regulator can be phosphate, acetate, hydrochloric acid, sodium hydroxide, etc.; the osmotic pressure regulator can be sodium chloride, mannitol, glucose, phosphate, acetate, etc. For example, mannitol and glucose can be added as proppant for preparing lyophilized powder for injection. In addition, colorants, preservatives, flavors, or other additives may also be added to the pharmaceutical preparation, if desired. For the purpose of administration and enhancing the therapeutic effect, the drug or pharmaceutical composition of the present invention can be administered by any known administration method.
Advantageous technical effects
1. The compound of the invention can relieve and/or treat cerebral ischemic stroke. This use is disclosed for the first time. The clinical application field of the compound is widened, and the compound provides medicine selection for clinical application.
2. At present, the application of the compound in the product for relieving and/or treating the cerebral arterial thrombosis is disclosed for the first time in China and China. No relevant papers and patents are published.
3. The compound of the invention can achieve the treatment and prevention effects by being taken in a small amount. The medicine is safe and reliable. The compound is developed as a medicament and has obvious advantages.
Drawings
FIG. 1. effect of belinostat on cerebral infarct volume in MCAO/R rats. In the experiment, the cerebral ischemia reperfusion injury part of the rat after the model building has obvious cerebral infarction, and compared with a model group, the cerebral infarction volume of a middle and high dose treatment group of belinostat is obviously reduced after the drug administration. And # P is less than 0.01vs. normal control group, P is less than 0.01vs. model group, and n is 7-11.
Figure 2. effect of belinostat on rat neurological score (mNSS), in this experiment, rats in the model group had a significantly higher mns score than the normal control group, while after administration, the mNSS score in the belinostat medium and high dose treatment group was significantly lower than the model group. And # P is less than 0.01vs. normal control group, P is less than 0.01vs. model group, and n is 7-11.
FIG. 3. Effect of belinostat on survival of MCAO/R rats. In the experiment, the survival rate of the model group rats is lower, the survival rate of the administration group rats is obviously increased, and n is 9-18.
FIG. 4. Effect of belinostat on recovery of neurological function in MCAO/R rats. In the experiment, the motor function of the rat nerve after modeling is obviously damaged, after administration, along with the increase of administration time, the motor function of the rat nerve of an administration group is recovered, and the mNSS score is obviously lower than that of a model group from the third day. And # P is less than 0.01vs. normal control group, P is less than 0.05, P is less than 0.01vs. model group, and n is 6-9.
FIG. 5. Effect of belinostat on the rate of foot failure in MCAO/R rats. In the experiment, compared with a normal control group, the probability of foot faults of rats in the model group is high; compared with the model group, the rats of the administration group have obviously reduced foot error rate from the seventh day. And # P is less than 0.01vs. normal control group, P is less than 0.05, P is less than 0.01vs. model group, and n is 6-9.
Detailed Description
The pharmacological effects of belinostat in the alleviation and/or treatment of ischemic stroke are further described below in connection with the present invention.
The following examples illustrate the invention in more detail and are not intended to limit the invention in any way.
Example 1: protective action of belinostat on acute cerebral ischemia-reperfusion rats 1.1 establishment of Experimental cerebral ischemia-reperfusion model and administration conditions
Principle of experiment
Wistar rats were selected and, after 3% isoflurane anesthesia, a plug wire was inserted from the external carotid artery to the anterior cerebral artery via the internal carotid artery, mechanically blocking the blood supply at the site of the middle cerebral artery emergence. After blocking for 1.5 hours, the wire plug is pulled out, and a middle cerebral artery ischemia-reperfusion (MCAO/R) model is established.
Experimental methods
Male Wistar rats weighing 280-320g were adapted and 3 days later, MCAO/R model was established, and animals were divided into normal control group, model group, belinostat low dose group (10mg/kg), medium dose group (30mg/kg) and high dose group (50 mg/kg). The normal control group was treated with the same treatment as the other groups except that no plug was inserted. The medicine is injected into the abdominal cavity at the same time of reperfusion, and the normal control group and the model group are injected into the abdominal cavity with 10 percent of L-arginine as the medicine solvent. After 24 hours, neurological scores were performed and brains were taken for TTC staining.
Results of the experiment
After the model is made, the cerebral ischemia reperfusion injury part of the rat is infarcted, and the nerve function is affected. 1.2 Bellistat Effect on MCAO/R rat infarct volume
Experimental methods
The infarct volume of rats was observed by TTC staining, and after staining, the non-ischemic part was stained red and the ischemic part was still white.
Results of the experiment
In the experiment, the cerebral infarction volume of the rats in the model group is the largest, and compared with the model group, the belinostat can reduce the infarction volume of the MCAO/R rats. The results are shown in Table 1 and FIG. 1.
TABLE 1 Belinostat effect on cerebral infarct volume in MCAO/R rats
Mean ± standard deviation (n ═ 7 to 11) ## # P < 0.01vs. normal control group,. × P < 0.01vs. model group.
1.3 Effect of Bellistat on the neurological Scoring (mNSS) of rats
Experimental methods
The neurological scores of the animals were determined 24 hours after cerebral ischemia-reperfusion in rats and were determined according to the following criteria:
results of the experiment
In this experiment, the neuromotor functional score of the model group rats was significantly higher than that of the normal control group. The neuromotor function score of the animals in the belinostat-administered group was significantly reduced compared to the model group. The results are shown in Table 2 and FIG. 2.
TABLE 2 Effect of belinostat on MCAO/R rat neurological score (mNSS)
Mean value ± standard deviation (n is 7 to 11).
Normal control group, # P < 0.01vs. model group.
Example 2: belinostat promotes nerve function recovery of cerebral ischemia reperfusion rats
2.1 establishment of MCAO/R rat model and administration conditions
Principle of experiment
Wistar rats were selected and, after 3% isoflurane anesthesia, a plug wire was inserted from the external carotid artery to the anterior cerebral artery via the internal carotid artery, mechanically blocking the blood supply at the site of the middle cerebral artery emergence. After blocking for 1.5 hours, the wire plug is pulled out, and a middle cerebral artery ischemia-reperfusion (MCAO/R) model is established.
Experimental methods
Male Wistar rats weighing 280-320g were adapted and 3 days later, MCAO/R model was established, and animals were divided into normal control group, model group, belinostat low dose group (10mg/kg), medium dose group (30mg/kg) and high dose group (50 mg/kg). The normal control group was treated with the same treatment as the other groups except that no plug was inserted. And carrying out mNSS scoring and grouping 24 hours after reperfusion, and carrying out administration, wherein the normal control sham operation group and the model group are subjected to intraperitoneal injection of 10% L-arginine, and the administration is carried out once a day for 14 days continuously. The mNSS score, behavioral assessment were performed 1,3,7,14 days after reperfusion, and brains were harvested on day 14 for further study.
2.2 Effect of Belinostat on survival in MCAO/R rats
Experimental methods
After dosing, the status of the rats was recorded and the survival rate was calculated.
Results of the experiment
In the experiment, the survival rate of the model group rats is lower, and the survival rate of the administration group rats is obviously increased. The results are shown in FIG. 3.
2.3 Effect of Belinostat on recovery of neurological function in MCAO/R rats
Experimental methods
mNSS scoring was performed on days 1,3,7, and 14 after molding, and recorded and counted. The scoring criteria were as in 1.3.
Results of the experiment
In the experiment, the motor function of the rat nerve after modeling is obviously damaged, after administration, along with the increase of the administration time, the motor function of the rat nerve of the administration group is recovered, and the mNSS score is obviously lower than that of the model group from the 3 rd day. The results are shown in Table 3 and FIG. 4.
TABLE 3 effects of Belinostat on recovery of neurological function in MCAO/R rats
Mean ± sd (n is 6 to 9).
Normal control group, # P < 0.01vs. model group, # P < 0.05, # P < 0.01vs. model group.
2.4 Effect of Belinostat on MCAO/R rat foot error test
Experimental methods
Rat forelimb function was assessed using a foot error experiment. The rats were evaluated for foot-fault on days 1,3,7 and 14 after molding, and in the test, the animals were placed on a grid plane (10X 110 cm) 100cm above the ground2) The diameter of the separation line is 1.0mm, and the mesh is 9cm2Grid end and platform (15X 20 cm)2) In conjunction, rats were encouraged in each experiment to cross the plane of the grid with sound or stimulation. The rate of foot error was determined by counting the total number of bilateral forelimb movements and the number of times the left forelimb toes slip into the interstitial spaces, as a percentage of the total number of steps compared to the total number of bilateral forelimb movements.
Results of the experiment
In the experiment, compared with a normal control group, the probability of foot faults of rats in the model group is high; compared with the model group, the rats of the administration group have obviously reduced foot error rate from the 7 th day. The results are shown in Table 4 and FIG. 5.
TABLE 4 effects of Belinostat on MCAO/R rat foot error test
Mean ± sd (n is 6 to 9).
Normal control group, # P < 0.01vs. model group, # P < 0.05, # P < 0.01vs. model group.
Claims (9)
1. The application of the belinostat shown in the formula (I) in preparing the medicine for relieving and/or treating the stroke of a patient;
2. use according to claim 1, characterized in that the stroke is selected from ischemic stroke.
3. Use according to claim 1 or 2, wherein the patient is a mammal, preferably a human.
4. The application of a pharmaceutical composition in preparing a medicine for relieving and/or treating cerebral apoplexy of a patient is characterized in that the pharmaceutical composition contains an effective dose of belinostat shown in formula (I) and optional pharmaceutically acceptable carriers and/or auxiliary materials;
5. use according to claim 3, characterized in that the pharmaceutical composition contains, in addition to belinostat as pharmaceutically active ingredient, further active ingredients.
6. The use according to claim 3, wherein said pharmaceutical composition comprises the following dosage forms: solutions, suspensions, lyophilized powders, emulsions, pills, capsules, powders, controlled release, sustained release formulations and microsomal delivery systems.
7. Use according to claim 3, characterized in that the pharmaceutically acceptable carriers and/or adjuvants comprise starch, dextrin, sodium carboxymethylcellulose, magnesium stearate, talc.
8. Use according to claim 3, characterized in that the stroke is selected from ischemic stroke.
9. Use according to any one of claims 4 to 8, wherein the patient is a mammal, preferably a human.
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| US20200179381A1 (en) * | 2016-04-08 | 2020-06-11 | Cereno Scientific Ab | Compounds and compositions for the treatment or prevention of pathological conditions associated with excess fibrin deposition and/or thrombus formation |
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| US20200179381A1 (en) * | 2016-04-08 | 2020-06-11 | Cereno Scientific Ab | Compounds and compositions for the treatment or prevention of pathological conditions associated with excess fibrin deposition and/or thrombus formation |
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| 张琛琛等: "组蛋白去乙酰化酶6抑制剂治疗缺血性脑卒中的研究进展" * |
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