CN103211832A - Medicine composition containing myricetrin or/and myricetin and application of medicine composition in preparation of medicine used for treating Parkinson - Google Patents
Medicine composition containing myricetrin or/and myricetin and application of medicine composition in preparation of medicine used for treating Parkinson Download PDFInfo
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- CN103211832A CN103211832A CN2013101470508A CN201310147050A CN103211832A CN 103211832 A CN103211832 A CN 103211832A CN 2013101470508 A CN2013101470508 A CN 2013101470508A CN 201310147050 A CN201310147050 A CN 201310147050A CN 103211832 A CN103211832 A CN 103211832A
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- myricetrin
- levodopa
- ampelopsin
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- myricetin
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- DCYOADKBABEMIQ-OWMUPTOHSA-N myricitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=C(O)C=2)OC2=CC(O)=CC(O)=C2C1=O DCYOADKBABEMIQ-OWMUPTOHSA-N 0.000 title claims abstract description 79
- DCYOADKBABEMIQ-FLCVNNLFSA-N myricitrin Natural products O([C@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](C)O1)C1=C(c2cc(O)c(O)c(O)c2)Oc2c(c(O)cc(O)c2)C1=O DCYOADKBABEMIQ-FLCVNNLFSA-N 0.000 title claims abstract description 77
- 239000003814 drug Substances 0.000 title claims abstract description 25
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- 229940079593 drug Drugs 0.000 title claims description 7
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- IKMDFBPHZNJCSN-UHFFFAOYSA-N Myricetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC(O)=C(O)C(O)=C1 IKMDFBPHZNJCSN-UHFFFAOYSA-N 0.000 title abstract 7
- 229940116852 myricetin Drugs 0.000 title abstract 7
- PCOBUQBNVYZTBU-UHFFFAOYSA-N myricetin Natural products OC1=C(O)C(O)=CC(C=2OC3=CC(O)=C(O)C(O)=C3C(=O)C=2)=C1 PCOBUQBNVYZTBU-UHFFFAOYSA-N 0.000 title abstract 7
- 235000007743 myricetin Nutrition 0.000 title abstract 7
- WTDRDQBEARUVNC-LURJTMIESA-N L-DOPA Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-LURJTMIESA-N 0.000 claims abstract description 56
- WTDRDQBEARUVNC-UHFFFAOYSA-N L-Dopa Natural products OC(=O)C(N)CC1=CC=C(O)C(O)=C1 WTDRDQBEARUVNC-UHFFFAOYSA-N 0.000 claims abstract description 56
- 229960004502 levodopa Drugs 0.000 claims abstract description 49
- IVTMXOXVAHXCHI-YXLMWLKOSA-N (2s)-2-amino-3-(3,4-dihydroxyphenyl)propanoic acid;(2s)-3-(3,4-dihydroxyphenyl)-2-hydrazinyl-2-methylpropanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(O)=C1.NN[C@@](C(O)=O)(C)CC1=CC=C(O)C(O)=C1 IVTMXOXVAHXCHI-YXLMWLKOSA-N 0.000 claims abstract description 18
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- KQILIWXGGKGKNX-UHFFFAOYSA-N dihydromyricetin Natural products OC1C(=C(Oc2cc(O)cc(O)c12)c3cc(O)c(O)c(O)c3)O KQILIWXGGKGKNX-UHFFFAOYSA-N 0.000 claims description 70
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- YCIMNLLNPGFGHC-UHFFFAOYSA-N catechol Chemical compound OC1=CC=CC=C1O YCIMNLLNPGFGHC-UHFFFAOYSA-N 0.000 description 2
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- MIQPIUSUKVNLNT-UHFFFAOYSA-N tolcapone Chemical compound C1=CC(C)=CC=C1C(=O)C1=CC(O)=C(O)C([N+]([O-])=O)=C1 MIQPIUSUKVNLNT-UHFFFAOYSA-N 0.000 description 2
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention relates to a medicine composition of myricetrin or/and myricetin aglycone thereof and levodopa or of levodopa and carbidopa and an application of myricetrin or/and myricetin aglycone thereof as a synergist in preparation of a medicine used for treating Parkinson. In vitro activity determination finds that IC50 of myricetrin and myricetin inhibiting catechol-O-methyltransferase (COMT) can be a micromole-nanomole scale. Rat overall pharmacokinetic study finds that blood concentration of levodopa can be increased after myricetrin and myricetin aglycone thereof and levodopa are used jointly; and myricetrin and myricetin aglycone thereof are high in safety, no obvious toxicity is produced to main visceral organ cells of a human body, and no active intermediate is produced by virtue of metabolism activation and further no damage done to organs such as liver and kidney is initiated, so that the myricetrin and myricetin aglycone thereof have a good application prospect in adjuvant therapy of Parkinson.
Description
Technical field
The present invention relates to a kind of medical composition and its use, relate in particular to and a kind ofly contain myricetrin or/and the pharmaceutical composition of aglycon ampelopsin and the purposes in the medicine of preparation treatment Parkinson's disease thereof.
Background technology
Parkinson's disease (PD) is a kind of chronic central nervous system's degenerative deficiency disorder that the dopamine deficiency causes in the brain, and the sickness rate in the old people is up to 1.7% (Neurology.2000; 54:S24-7).China is the maximum country of PD patient in the world, and along with the arriving of China's aging society, problems such as the medical treatment that PD brings, family, society are extensive all the more and severe, and patient's quality of life is subjected to tremendous influence.
At present, the most effective treatment means of treatment Parkinson's disease (PD) is the dopamine alternative medicine, promptly changes dopamine by prodrug levodopa (L-dopa) in patient's brain, to replenish insufficient dopamine in patient's brain.But since L-dopa in peripheral tissues very easily by metabolism, almost there is not drug effect when using separately, its need with catechol O-methyltransferase (Catechol-O-methyltransferase, COMT) inhibitor can be brought into play effect (Eur Neurol.2009 in vivo with clothes; 62:1-8).Yet the COMT enzyme inhibitor that has gone on the market as Tolcapone, Entacapone etc., uses continuously and easily causes serious toxic and side effects such as hepatic injury (Neurology2004; 62:39-46).And PD patient needs frequent medication, and the existing medicine of life-time service can cause severe liver injury.Therefore developing safely and efficiently, novel C OMT inhibitor becomes one of the focus in Parkinson's disease Drug therapy field.
The COMT enzyme is a kind of magnesium ion dependent form enzyme, and it is SAM as the methylating of methyl donor catalysis pyrocatechol substrate with the S-ademetionine, generates the corresponding O-catechol that methylates.At present, have many reporting both at home and abroad, a lot of natural catechols all are the substrates of COMT enzyme, and COMT suppresses active but the part substrate has also shown efficiently, and promptly it can be by slowing down in the body COMT enzyme to the metabolite clearance of levodopa with levodopa competition COMT enzyme.
Myricetrin and aglycon ampelopsin thereof are the natural polyhydroxy flavone compound, and wide material sources have resources advantage in the research of medicine and purposes.Myricetrin is present in other multiple medicinal plants leaves such as fruit, bark, leaves and Ampelopsis grossedentata, ampelopsis and Folium Longan of Myruca ceas plant Fructus Myricae rubrae, have vasoconstrictive, blood sugar lowering, antioxidation, protect the liver, effect such as function of gallbladder promoting, antiinflammatory, mutation, antitumor, have researching value (Food Research and Development, 2007; 28 (2): 185-188).Ampelopsin is the bark of Myruca ceas plant Fructus Myricae rubrae and the main chemical compositions of leaf, also be present in the natural plants such as Bulbus Allii Cepae, berry and tea, it is one of main component of flavonols in the red wine, ampelopsin has pharmacologically active widely, multiple efficacies such as have antiinflammatory, analgesia, antitumor, blood sugar lowering simultaneously and protect the liver, especially preventing and treating aspect the cardiovascular disease effect obviously (Inpharm research magazine, 2012; 39(6): 483-487).
Summary of the invention
The inventor treats and finds in the studying for a long period of time of Parkinson's disease that myricetrin and aglycon ampelopsin thereof have the activity of potent inhibition COMT enzyme and good safety, have good antiinflammatory and antioxidant activity simultaneously concurrently.It can unite the treatment that is used for Parkinson's disease with Parkinson's disease medicine levodopa.
One of purpose of the present invention is to provide a kind of pharmaceutical composition, contains myricetrin or/and its aglycon ampelopsin and levodopa.For example be the pharmaceutical composition that myricetrin and levodopa are formed, or be the pharmaceutical composition that ampelopsin and levodopa are formed, or be the pharmaceutical composition of myricetrin and its aglycon ampelopsin and levodopa composition.
As optimal technical scheme, pharmaceutical composition of the present invention also contains carbidopa.For example be the pharmaceutical composition that myricetrin and levodopa and carbidopa are formed, or the pharmaceutical composition that be ampelopsin form with levodopa and carbidopa, or be the pharmaceutical composition of myricetrin and its aglycon ampelopsin and levodopa and carbidopa composition.
Described myricetrin and aglycon ampelopsin thereof have following structure:
Chemical compound myricetrin of the present invention and aglycon ampelopsin thereof are that the COMT enzyme inhibitor of efficiency natural, safety has good antiinflammatory, antioxidant activity simultaneously concurrently, the number of drawbacks that current clinical Parkinson's disease medicine COMT enzyme inhibitors such as (especially) Tolcapone exists be can effectively improve, liver, nephrotoxicity etc. easily caused as continuous use.
As optimal technical scheme, myricetrin in the described pharmaceutical composition or/and its aglycon ampelopsin share with any ratio with levodopa, such as for myricetrin and levodopa arbitrarily than share, or be that ampelopsin and levodopa are any than share, or be that myricetrin is any than share with its aglycon ampelopsin and levodopa, preferred myricetrin or/and its aglycon ampelopsin and levodopa share with the mol ratio of 1:10～10:1, the mol ratio of myricetrin and levodopa wherein, or the mol ratio of ampelopsin and levodopa, or the mole sum of myricetrin and its aglycon ampelopsin and the mol ratio of levodopa can be 1:8,1:6,1:4,1:2,1:1,2:1,3.5:1,4:1,5:1,7:1,9:1 etc., further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
One of purpose of the present invention also be a kind of myricetrin is provided or/and its aglycon ampelopsin as the purposes of synergist in the medicine of preparation treatment Parkinson's disease.
As optimal technical scheme, medicine of the present invention is that levodopa or levodopa and carbidopa share.Myricetrin and aglycon ampelopsin thereof are as the levodopa synergist, it can be used for the auxiliary treatment of Parkinson's disease, myricetrin and aglycon ampelopsin thereof optional arbitrary and levodopa or levodopa and carbidopa share, also can mix the back use by arbitrary proportion, also can mix the back with carbidopa and use jointly as pharmaceutical composition with levodopa or levodopa.Myricetrin and aglycon ampelopsin thereof be as potent COMT enzyme inhibitor, slows down its internal metabolism with levodopa or levodopa and carbidopa when shared and then improve the effect of levodopa.
As optimal technical scheme, purposes of the present invention is a myricetrin or/and ampelopsin share with any ratio with levodopa, preferred myricetrin or/and ampelopsin and levodopa share with the mol ratio of 1:10～10:1, for example be 1:8,1:6,1:4,1:2,1:1,2:1,3.5:1,4:1,5:1,7:1,9:1 etc., further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
As optimal technical scheme, purposes of the present invention is a myricetrin or/and ampelopsin share with any ratio with levodopa/carbidopa, such as for myricetrin and levodopa and carbidopa arbitrarily than share, or be that ampelopsin is any than share with levodopa and carbidopa, or be that myricetrin and its aglycon ampelopsin are any than share with levodopa and carbidopa, preferred myricetrin or/and ampelopsin and levodopa share with the mol ratio of 1:10～10:1, for example be 1:8,1:6,1:4,1:2,1:1,2:1,3.5:1,4:1,5:1,7:1,9:1 etc., further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
As optimal technical scheme, of the present invention share to making pharmaceutical composition after the present invention's 4～7 each described combination with medication are mixed used.
Myricetrin of the present invention and aglycon ampelopsin thereof are the COMT enzyme inhibitor, and myricetrin and aglycon ampelopsin thereof are united use with Parkinson's disease medicine (levodopa, carbidopa/levodopa) after can becoming dosage form separately.Also can be mixed in proportion the back with Parkinson's disease medicine (levodopa, carbidopa/levodopa) uses as pharmaceutical composition.
The dosage form of pharmaceutical composition of the present invention is not limit, all dosage forms that is suitable for the levodopa administration all can be used for the present invention, for example can select the dosage form of suitable medicine performance functions of the present invention such as tablet, powder, granule, capsule, pill, injection, spray, aerosol.
As optimal technical scheme, the dosage form of pharmaceutical composition of the present invention is tablet, slow releasing tablet, capsule, drop pill.
Myricetrin of the present invention and aglycon ampelopsin thereof are as follows as the advantage of COMT enzyme inhibitor:
1, high security, myricetrin and aglycon ampelopsin toxicity thereof are very little, the LD after its mice is oral
50Greater than 2.0g/kg (nontoxic rank); Simultaneously it does not have overt toxicity to human body main organs cell yet, and can not produce reactive intermediate and cause visceral organ injury such as Liver and kidney through metabolic activation;
2, the COMT enzyme inhibition activity is remarkable, its half-inhibition concentration IC
50Can reach nanomole-micromole's level; After the body giving drugs into nose also showed myricetrin and aglycon ampelopsin and L-dopa drug combination for experiment, the AUC of L-dopa had remarkable increase;
3, myricetrin and aglycon ampelopsin thereof have good antioxidant activity concurrently, can slow down the hepatic and renal tissue oxidative damage that patient's long-term prescription causes;
4, myricetrin and aglycon ampelopsin thereof are difficult for penetrating blood brain barrier, can the interference maincenter in the metabolism that methylates of endogenous neurotransmitter.
Description of drawings
Fig. 1 myricetrin and aglycon ampelopsin thereof suppress IC to the COMT enzyme
50Figure;
Fig. 2 myricetrin and aglycon ampelopsin thereof are to COMT enzyme depression effect figure: the Dixon mapping of ampelopsin and myricetrin.
Fig. 3 myricetrin and aglycon ampelopsin thereof are to COMT enzyme depression effect figure: the Lineweaver-Burk mapping of ampelopsin and myricetrin.
The specific embodiment
For ease of understanding the present invention, it is as follows that the present invention enumerates embodiment.Those skilled in the art should understand that described embodiment helps to understand the present invention, should not be considered as concrete restriction of the present invention.
Embodiment
Embodiment 1 myricetrin and aglycon ampelopsin monomer thereof are to the inhibition determination of activity of people COMT enzyme
With the L-dopa methylation reaction is probe reaction, by the outer incubation system of human liver cell slurry, measures the IC that myricetrin and aglycon ampelopsin thereof suppress the COMT enzyme
50, concrete experiment flow is as follows:
In the external metabolic response system of (1) 200 microlitre, add 5mM MgCl
2, the 2mM dithiothreitol, DTT, 150 μ M substrate L-dopa, human liver cell slurry protein concentration is 1mg/ml, inhibitor final concentration scope is 0.05 μ M-50 μ M, incubates in advance 3 minutes under 37 ℃ of conditions;
(2) in reaction system, add S-ademetionine (final concentration is 0.2mM), initial action; Add 200 μ l acetonitriles in reaction under 37 ℃ of conditions after 30 minutes, behind the concuss, cessation reaction;
(3) adopt High speed refrigerated centrifuge, under the condition of 20,000 * g, the above-mentioned system of high speed centrifugation was got supernatant after 20 minutes, carried out the HPLC-MS/MS check and analysis; By detecting the L-dopa3-position metabolite ion pair [M-H] that methylates
+M/z212.2＞195.1, metabolite carries out detection by quantitative to methylating.
Fig. 1 is that myricetrin and aglycon ampelopsin thereof suppress IC to the COMT enzyme
50Figure, as can be seen from the figure myricetrin and aglycon ampelopsin thereof all present the dependent inhibition of substrate to the COMT enzyme, ampelopsin half-inhibition concentration (IC
50) be 0.45 μ M, the half-inhibition concentration (IC of myricetrin
50) be 1.0 μ M.This shows that myricetrin and aglycon ampelopsin thereof have the activity of stronger inhibition activity, especially ampelopsin (hydrolyzate in the myricetrin body) more remarkable to the COMT enzyme.In addition, find also that by suppressing dynamics research myricetrin and ampelopsin are the mixed type competitive inhibitors (Fig. 2 and Fig. 3) of COMT enzyme.
The toxicity assessment of embodiment 2 myricetrins and aglycon ampelopsin thereof
Choose kunming mice, body weight 178-22g.With the mice random packet, 20 every group, male and female half and half are carried out the oral acute toxicity test of mice of myricetrin and ampelopsin respectively.Myricetrin or ampelopsin are suspended in respectively among the 0.5%CMC-Na.Select various dose oral administration (0.1～2g/kg); And 0.5%CMC-Na group is set does negative control.Experimental result shows myricetrin and the oral LD of ampelopsin mice
50Value belongs to nontoxic rank greater than 2.0g/kg.In addition, cell in vitro experiment confirm myricetrin and ampelopsin do not have overt toxicity to human primary hepatocyte and nephrocyte.Simultaneously in the people's hepatomicrosome incubation system that adds cofactor NADPH or its generation structure, add this myricetrin and aglycon ampelopsin thereof (final concentration is 100 μ M) and reduced glutathion (final concentration is 1000 μ M) respectively, after hatching 120 minutes under 37 ℃, carry out adduct by AB Qtrap5500 and detect the formation of confirmation non-activity adduct, prompting myricetrin and ampelopsin can not have good safety because of metabolic activation causes liver, nephrotoxicity.
The pharmacokinetic of embodiment 3 myricetrins and aglycon ampelopsin thereof and levodopa coupling
Myricetrin has only when share with levodopa just meaningful or/and ampelopsin as the COMT enzyme inhibitor, is used separately for the readily good therapeutic effect of Parkinson's disease.
Select 24 Wistar rats, male and female half and half, body weight 180-220g, be divided into 4 groups at random: oral levodopa/carbidopa matched group, oral myricetrin/levodopa/carbidopa group (myricetrin and levodopa mol ratio are 5:1), oral ampelopsin/levodopa/carbidopa group (ampelopsin and levodopa mol ratio are 5:1), oral ampelopsin-myricetrin mixture/levodopa/carbidopa group (the mole sum of myricetrin and myricetrin and the mol ratio of levodopa are 5:1), 6/group are carried out the whole pharmacokinetics research of L-dopa.Oral dose is 2g/kg.Respectively before gathering administration after blood plasma and the administration about 5,10,15,30,60,120,180,240 minutes rat plasma sample 0.5ml, place the brown centrifuge tube in the 1.5ml point end of heparinization in advance, behind centrifugal 10 minutes of 4000 * g, add isopyknic methanol extraction albumen and high speed centrifugation (20 after the separated plasma, 000 * g), it is to be measured to get supernatant and be stored in-80 ℃ of refrigerators.Adopt UFLC-MS/MS to measure the blood drug level of levodopa in each sample, the blood drug level data are handled, and calculate pharmacokinetic parameter with DAS2.0 software.The result shows that with respect to independent oral levodopa/carbidopa matched group, myricetrin and aglycon ampelopsin thereof can both obviously improve the level of levodopa in the rat plasma and prolong its metabolic half life.Myricetrin group area under the drug-time curve (AUC) has increased 31%, and ampelopsin group AUC has increased 27%, and ampelopsin-myricetrin mixture group AUC has increased 30%.Above result shows that myricetrin and aglycon ampelopsin thereof all brought into play the effect of levodopa synergist.In addition, adopt COMT enzyme inhibitor ampelopsin or/and myricetrin and levodopa mol ratio are the ratio of 10:1 and carry out above-mentioned identical experiment, the AUC recruitment of administration group is more than 20%; Ampelopsin is or/and myricetrin and levodopa mol ratio are the ratio of 1:10 carries out above-mentioned identical experiment and find that the AUC recruitment of administration group is about 10%.
Applicant's statement, the present invention illustrates detailed process flow of the present invention by the foregoing description, but the present invention is not limited to above-mentioned detailed process flow, does not mean that promptly the present invention must rely on above-mentioned detailed process flow and could implement.The person of ordinary skill in the field should understand, any improvement in the present invention to the interpolation of the equivalence replacement of each raw material of product of the present invention and auxiliary element, the selection of concrete mode etc., all drops within protection scope of the present invention and the open scope.
Claims (9)
1. a pharmaceutical composition is characterized in that, contains myricetrin or/and its aglycon ampelopsin and levodopa.
2. pharmaceutical composition according to claim 1 is characterized in that, also contains carbidopa.
3. pharmaceutical composition according to claim 1 and 2, it is characterized in that, myricetrin in the described pharmaceutical composition or/and its aglycon ampelopsin share with any ratio with levodopa, preferred myricetrin or/and its aglycon ampelopsin and levodopa share with the mol ratio of 1:10～10:1, further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
A myricetrin or/and its aglycon ampelopsin as the purposes of synergist in the medicine of preparation treatment Parkinson's disease.
5. purposes according to claim 4 is characterized in that, described medicine is that levodopa or levodopa and carbidopa share.
6. purposes according to claim 4, it is characterized in that, described purposes is a myricetrin or/and ampelopsin share with any ratio with levodopa, preferred myricetrin or/and ampelopsin and levodopa share with the mol ratio of 1:10～10:1, further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
7. purposes according to claim 4, it is characterized in that, described purposes is a myricetrin or/and ampelopsin share with any ratio with levodopa/carbidopa, preferred myricetrin or/and ampelopsin and levodopa share with the mol ratio of 1:10～10:1, further preferably share, especially preferably share with the mol ratio of 5:1 with the mol ratio of 3:1～6:1.
8. according to each described purposes of claim 4～7, it is characterized in that described share to making pharmaceutical composition after 4～7 each described combination with medication are mixed used.
9. purposes according to claim 8 is characterized in that, the dosage form of described pharmaceutical composition is tablet, slow releasing tablet, capsule, drop pill.
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| CN103919765A (en) * | 2014-04-24 | 2014-07-16 | 无锡艾德美特生物科技有限公司 | Application of hispidulin in preparing catechol drug synergist and pharmaceutical composition containing hispidulin |
| CN105315251A (en) * | 2014-06-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist |
| WO2016107579A1 (en) * | 2014-12-31 | 2016-07-07 | 广东药学院 | Preparation and application of flavonol as brain-targeting synergist |
| CN107721963A (en) * | 2017-10-19 | 2018-02-23 | 宁波金昉生物科技有限公司 | The method of extraction separation myricetin from Chinese waxmyrtle bark |
| CN108354941A (en) * | 2018-02-26 | 2018-08-03 | 南京工业大学 | application of natural product micromolecule α -arbutin (Arb) in medicine for preventing and treating Parkinson disease |
| CN110628840A (en) * | 2019-09-05 | 2019-12-31 | 宁波德康生物制品有限公司 | Method for extracting myricetin by microbial fermentation |
| CN111892566A (en) * | 2019-05-05 | 2020-11-06 | 首都医科大学 | Aqueous extract of A. chinensis, its preparation method and its application as acetylcholinesterase inhibitor |
| CN115804785A (en) * | 2021-09-12 | 2023-03-17 | 中国医学科学院药物研究所 | Application of myricitrin in preparing medicine for inhibiting cerebellar inflammatory reaction |
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| CN103919765A (en) * | 2014-04-24 | 2014-07-16 | 无锡艾德美特生物科技有限公司 | Application of hispidulin in preparing catechol drug synergist and pharmaceutical composition containing hispidulin |
| CN103919765B (en) * | 2014-04-24 | 2016-06-15 | 无锡艾德美特生物科技有限公司 | Dinatin application in preparation catechol medicament synergistic agent and comprise the pharmaceutical composition of dinatin |
| CN105315251A (en) * | 2014-06-24 | 2016-02-10 | 中国科学院大连化学物理研究所 | Application of oroxylin A and pro-drug thereof as catechol-type medicine synergist |
| WO2016107579A1 (en) * | 2014-12-31 | 2016-07-07 | 广东药学院 | Preparation and application of flavonol as brain-targeting synergist |
| CN107721963A (en) * | 2017-10-19 | 2018-02-23 | 宁波金昉生物科技有限公司 | The method of extraction separation myricetin from Chinese waxmyrtle bark |
| CN108354941A (en) * | 2018-02-26 | 2018-08-03 | 南京工业大学 | application of natural product micromolecule α -arbutin (Arb) in medicine for preventing and treating Parkinson disease |
| CN111892566A (en) * | 2019-05-05 | 2020-11-06 | 首都医科大学 | Aqueous extract of A. chinensis, its preparation method and its application as acetylcholinesterase inhibitor |
| CN110628840A (en) * | 2019-09-05 | 2019-12-31 | 宁波德康生物制品有限公司 | Method for extracting myricetin by microbial fermentation |
| CN115804785A (en) * | 2021-09-12 | 2023-03-17 | 中国医学科学院药物研究所 | Application of myricitrin in preparing medicine for inhibiting cerebellar inflammatory reaction |
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