CN110507646A - Application of the artemisinin derivative in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder - Google Patents
Application of the artemisinin derivative in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder Download PDFInfo
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- CN110507646A CN110507646A CN201910868551.2A CN201910868551A CN110507646A CN 110507646 A CN110507646 A CN 110507646A CN 201910868551 A CN201910868551 A CN 201910868551A CN 110507646 A CN110507646 A CN 110507646A
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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Abstract
The invention discloses application of the artemisinin derivative in the drug of preparation antianxiety disease or the food for alleviating anxiety disorder, and the artemisinin derivative includes at least one of Artemether, Artesunate and dihydroartemisinine.The present invention has found that Artemether can adjust excitability on hippocampus of mice cone neurone/inhibitory synapse transmitting balance by record neuronal synapse activity.For the present invention by above-mentioned Artemether in the mechanism of action of central nervous system, discovery artemisinin derivative Artemether, Artesunate and dihydroartemisinine can effectively improve normal or Anxiety Model mouse anxiety sample symptom.Show that above-mentioned artemisinin derivative can play angst resistance effect by adjusting the excitability on forebrain cone neurone/inhibitory synapse transmitting balance, can be used for preparing anxiolytic drugs or help to alleviate the food of anxiety, it is safe and efficient, cheap.
Description
Technical field
The present invention relates to the new applications of artemisinin derivative more particularly to artemisinin derivative in the medicine for preparing antianxiety disease
Application in object or the food of alleviation anxiety disorder.
Background technique
The anxiety symptom that anxiety disorder and mental disease occur together is a kind of ictal or lasting sexual anxiety and intense strain is
The neuropsychiatric disease of main feature.The disease incidence of anxiety disorder rises year by year in recent years, seriously affects the life quality of patient.Mesh
Before, the treatment of anxiety disorder mainly uses drug and psychotherapy.And the breaking-out of anxiety disorder and central nervous system related neural ring
The dysfunction on road is closely related.
Intracerebral excitability/inhibitory synapse transmitting balance (E/I balance) refers to excitatory neuron in central nervous circuitry
Or excitatory neurotransmitter activity and inhibitory neuron or inhibitory neurotransmitter activity between dynamic equilibrium, be brain just
The important foundation that Chang Gongneng and plasticity are formed and maintained.The exception of E/I balance can induce anxiety disorder, depression, epilepsy, pa gold
A variety of neurological diseases such as gloomy, sleep disturbance.Modern neuro scientific research is mostly used it and evaluates excitability and suppression in local nerve loop
Dynamic between property cynapse transfer function processed changes, further prompt excitability and inhibitory neuron quantity in local circuit,
The variation such as form or function, these variations are closely related with specific behavior, emotion or cognitive activities.
Sweet wormwood, alias grass wormwood artemisia belong to that composite family class is annual or biennial herb plant, and qinghaosu (Artemisinin) is for I
A kind of sesquialter for structure containing peroxy radicals that state's Pharmacists are extracted from compositae plant chrysanthemum mugwort the 1970s
Terpene lactones compound.Its derivative mainly includes Artesunate, dihydroartemisinine, Artemether, arteether etc., is a kind of extensive
The anti-malaria medicaments of utilization.Artemether (Artemether, ART) is the Methyl ether derivatives of qinghaosu.Artemether is antimalarial
Effect is 6 times of its lead compound qinghaosu, is currently widely used for preparing anti-malaria medicaments, and with high security, poison is secondary
Act on the advantages that small.In addition, Artemether is there are also anti-inflammatory and antitumor and other effects, and maincenter mind can be distributed to by blood-brain barrier
Through in system.Clinical tests prove that Artemether has the characteristics that water-soluble and fat-soluble simultaneously, chemical property is than other derivatives
Object is more stable, clinically commonly uses the method that intramuscular injection treats malaria as it.Dihydroartemisinine
The artemisinin derivative that (Dihydroartemisinin, DHA) is developed as the first has efficient antimalarial, low toxicity and rises
Imitate the advantages that rapid.At present in anti-tumor activity, anti-immunity inhibits such as lupus erythematosus, anti parasitic etc. to have more good effect
Fruit.Artesunate (Artesunate, AS) is the sweet wormwood water solubility derivative that esterification formation is carried out on the basis of dihydroartemisinine
Object, bioavilability is high, also has good efficacy in the fields such as anti-inflammatory, antitumor.
As it can be seen that the safety of artemisinin derivative is higher, toxic side effect is small, has very in the research for expanding Other diseases direction
Good application prospect.Currently, there is not been reported, artemisinin derivative is flat by acting on central excitatory/inhibitory synapse transmitting
It weighs to reach anxiolytic effect or alleviate the related mechanism research of anxiolytic effect.
Although disclosing artemisine compounds in 107149601 A of Chinese patent application CN has treatment europathology
Property pain and pain induce anxiety symptom effect.But it take the analgesic effect of artemisinin-based drug as primary see that the patent application, which is,
It examines, and anxiety symptom caused by pain can be effectively relieved because of the mitigation of pain.Therefore, involved in the patent application
Anxiolytic phenotype is only limitted to the pain affection symptom that neurogenic pain occurs together, not with the cause of disease of anxiety symptom according to the present invention
Together, those skilled in the art are difficult to associate its antianxiety work based on effect of the artemisinin-based drug to neurogenic pain
With.Secondly, the patent application is using single spacious field Germicidal efficacy artemisinin-based drug to neuropathic pain model mouse
There is increasing action in the central area residence time, however spacious field experiment is not the classical index for examining anxiety behavior, it thus can not be
Judge that artemisinin-based drug has angst resistance effect.And the present invention is the tune balanced in discovery artemisinin derivative to maincenter E/I
On the basis of section effect, two classical animal anxiety behavior evaluation indexs, including Elevated plus-maze and light and shade case have been used
Experiment, specifies the angst resistance effect of artemisinin derivative for the first time, and specifies that artemisinin derivative balances maincenter E/I for the first time
Adjustment effect.
Summary of the invention
To solve above-mentioned shortcoming and defect existing in the prior art, it is anti-in preparation that the present invention provides artemisinin derivatives
Application in the drug of anxiety disorder or the food of alleviation anxiety disorder.The anxiety disorder include it is spontaneous or by heredity, disease, drug and
Generalized anxiety disorder caused by adverse events etc..
Artemisinin derivative of the present invention includes at least one of Artemether, Artesunate and dihydroartemisinine.
The present invention also provides the artemisinin derivatives as a kind of excitability/inhibition for adjusting central nervous system
Application of the agent of cynapse transmitting balance in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder.
After the present invention also provides the artemisinin derivatives as the inhibitory synapse on a kind of raising cone neurone
Application of the agent of electric current in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder.
Secondly, the present invention also provides a kind of drugs of antianxiety disease, the qinghaosu containing effective dose is derivative
Object and its pharmaceutical salts and pharmaceutically acceptable carrier.
In said medicine, the artemisinin derivative individually can be used directly, and can also form compound with other drugs makes
With.
Preferably, the dosage form of the anti anxiety agent object is oral preparation or ejection preparation.
Preferably, the oral preparation be selected from tablet, capsule, soft capsule, granule, suspension, dripping pill, pill,
At least one of oral liquid.
Preferably, the tablet is conventional tablet, dispersible tablet, oral disnitegration tablet or sustained release tablets.
Preferably, the ejection preparation is injection or powder-injection.
In addition, the present invention also provides a kind of food for alleviating anxiety disorder, it is derivative containing a effective amount of qinghaosu
Acceptable carrier and/or auxiliary material on object and food.
The present invention has found artemisinin derivative wormwood artemisia by synaptic activity on patch-clamp whole cell recording hippocampal pyramidal neurons
Methyl ether can improve the spontaneous inhibitory postsynaptic current (sIPSCs) on the cone neurone of CA 1 Zone of Hippocampus in Mouse, without influencing
Spontaneous excitatory postsynaptic currents (sEPSCs), so that it is flat to reduce central nervous system stimulant/inhibitory synapse transmitting
The effect of weighing apparatus (E/I).The present invention further examined on normal mouse and Anxiety Model mouse artemisinin derivative Artemether,
The curative effect of medication of Artesunate and dihydroartemisinine passes through mouse elevated plus-maze experiment and the experiment discovery of light and shade case, wormwood artemisia
Methyl ether, Artesunate and dihydroartemisinine can effectively improve the coke of Anxiety Model mouse caused by normal or chlorobenzene piperazine (mCPP)
Consider sample symptom.It is above-mentioned the experimental results showed that, artemisinin derivative (Artemether, Artesunate and dihydroartemisinine) can pass through adjusting
Central nervous system stimulant/inhibitory synapse transmitting balance has the phase to become newly to reach safe and effective angst resistance effect
Anxiolytic drugs or the food for alleviating anxiety disorder.As it can be seen that the present invention for clinical anxiety patient provide it is a kind of it is safe and efficient,
Cheap therapeutic agent or functional food.
Detailed description of the invention
Fig. 1 is to find Artemether to E/I on the area hippocampal slices CA1 cone neurone using patch-clamp whole cell recording technique
The adjustment effect of balance.A is the example diagram of two groups of representative sIPSCs (upper two rows) and sEPSCs (lower two rows)；B and C are respectively
Influence of the Artemether to the area CA1 cone neurone sEPSCs frequency and amplitude；D is Artemether to the area CA1 cone neurone
The influence of the sEPSCs quantity of electric charge；E and F is respectively influence of the Artemether to the area CA1 cone neurone sIPSCs frequency and amplitude；G
Influence for Artemether to the area the CA1 cone neurone sEPSCs quantity of electric charge；H is that Artemether balances the area CA1 cone neurone E/I
The influence of ratio.
Fig. 2 is that Artemether induces anxiety-like behavior of the Anxiety Model mouse in the experiment of light and shade case to normal mouse and mCPP
Improvement result.A is activity trajectory figure of the mouse in light and shade case；B is residence time of each group mouse in camera-lucida；C is each
Activity distance of the group mouse in camera-lucida；D is the shuttle number of each group mouse camera-lucida and camera bellows in the experiment of light and shade case.
Fig. 3 is that Artemether induces anxiety of the Anxiety Model mouse in elevated plus-maze test to normal mouse and mCPP
The improvement result of sample behavior.A is activity trajectory figure of the mouse in Elevated plus-maze；B is time that each group mouse enters open arms
Number；C is each group mouse in open arms residence time.
Fig. 4 is changing for the spontaneous anxiety-like behavior of Artesunate and dihydroartemisinine to normal mouse in the experiment of light and shade case
Kind result.A is activity trajectory figure of the mouse in light and shade case；B is activity distance of each group mouse in camera-lucida；C is that each group is small
Residence time of the mouse in camera-lucida；D is the shuttle number of each group mouse camera-lucida and camera bellows in the experiment of light and shade case.
Fig. 5 is the spontaneous anxiety sample row of Artesunate and dihydroartemisinine to normal mouse in elevated plus-maze test
For improvement result；A is activity trajectory figure of the mouse in Elevated plus-maze；B is each group mouse in open arms residence time；
C is the number that each group mouse enters open arms.
Fig. 6 is the chemical structural drawing of artemisinin derivative (Artemether, Artesunate and dihydroartemisinine).
Specific embodiment
To better illustrate the object, technical solutions and advantages of the present invention, the present invention passes through the following example furtherly
It is bright.Obviously, the following example is only a part of the embodiments of the present invention, instead of all the embodiments.It should be understood that the present invention is real
It applies example and is merely to illustrate technical effect of the invention, protection scope and is not intended to limit the present invention.In embodiment, method therefor
It unless otherwise instructed, is conventional method.
1 Artemether of embodiment is to the influence of the area hippocampal slices CA1 cone neurone excitability/inhibitory synapse transmitting ratio
1. experimental animal feeding: SPF grades of C57BL/6 mouse: male, the age 6 weeks, pleasing experimental animal breeding by Jinan friend had
Limit company provides.SPF grades of animal center raisings, raise area's temperature generally between 24-26 DEG C, humid control is in 40%-70%
Between, micro computer control fluorescent lamp illuminating system, 12h light and shade replaces automatically.The regular cleaning of animal center, replacement animal pad
Material, addition feed, can freely absorb SPF grades of breeding grade feeds and drinking-water.
2. drug and main agents: cesium chloride, methanesulfonic acid caesium, HEPES, EGTA, ATP-Mg, GTP-Na, sodium chloride, chlorination
Potassium, sodium dihydrogen phosphate, magnesium sulfate, calcium chloride, sodium bicarbonate, glucose, sucrose be purchased from Sigma-Aldrich company (China,
Shanghai)；Artemether is purchased from Shanghai Aladdin biochemical technology limited liability company；Dimethyl sulfoxide is purchased from the auspicious easypro biological section in Guangzhou
Skill Co., Ltd.
3. the Artemether solution that the preparation of Artemether is 10 μM with dmso solution compound concentration.
4. medication: brain piece records the Artemether solution that perfusion concentration is 10 μM in liquid.
5. Patch-clamp techniques method:
(1) mouse hippocampal slices are prepared: with 1% yellow Jackets (50mg/kg) intraperitoneal injection of anesthesia mouse, being breaked end rapidly
Brain is taken, the brain tissue of taking-up is put into preparatory prepared 4 DEG C of slices liquid.Brain tissue is fixed on slice machine base, is made
Cut hippocampal slices with vibration slicer (LEICA VT1200S, Germany), slice with a thickness of 300 μm.The hippocampus brain scaled off
Piece is placed in 32-34 DEG C of incubation slot and is incubated for 30 minutes, is then incubated at room temperature 1 hour.It is i.e. recordable after the completion of being incubated for
Brain piece electrical activity.Using Axon digidata 1550A digital analog converter (Molecular Devices, the U.S.) and
Multiclamp 700B (Molecular Devices, the U.S.) amplifier.
(2) excitability/inhibitory synapse transmitting ratio (E/I balance): Axon digidata 1550A digital-to-analogue conversion is used
Device (Molecular Devices, the U.S.) and Multiclamp 700B (Molecular Devices, the U.S.) amplifier.Note
Record Hippocampal CA 1 cone neurone minute inhibitory postsynaptic current, under the mode of voltage clamp, voltage clamp down on respectively-
60mV and 10mV records the spontaneous excitatory postsynaptic currents of the area hippocampal slices CA1 cone neurone in perfusion artificial cerebrospinal fluid
And spontaneous inhibitory postsynaptic current (sEPSCs and sIPSCs).
(3) data are analyzed: counting the frequency and amplitude of sEPSCs and sIPSCs respectively, it is corresponding to calculate sEPSCs and sIPSCs
Charge figureofmerit, excitement/inhibition cynapse transmitting ratio is the ratio of the total charge dosage of sEPSCs and the total charge dosage of sIPSCs.
6. experimental result: Artemether can improve the frequency and the quantity of electric charge of hippocampus CA1 cone neurone sIPSC, without changing
Become sEPSC, to reduce the ratio of E/I (see Fig. 1).
2 Artemether of embodiment is spontaneous to mouse and mCPP induces the improvement result that Anxiety Model mouse anxiety sample shows
One, experimental animal feeding (with embodiment 1).
Two, drugs and main agents
Artemether is purchased from Shanghai Aladdin biochemical technology limited liability company；Between chlorobenzene piperazine, be purchased from Sigma-
Aldrich (China, Shanghai)；Methylcellulose (Methyl cellulose, MC) is purchased from Sigma-Aldrich company
(China, Shanghai)；NaCl, purchased from Sigma-Aldrich company (China, Shanghai).
Three, experimental methods
1. animal packet: animal is divided into 4 groups, every group 11, respectively control group (solvent group), Artemether intervention group,
MCPP model group and Artemether in Treatment group.
2. the preparation of Artemether (Art):
(1) it prepares 1% methocel solution (MC): with 0.9% physiological saline, being heated to 40 DEG C in water-bath, it is molten
MC powder is solved, is evenly stirred until and is completely dissolved, until no milky white precipitate.
(2) Artemether is prepared: the Art for being 50mg/kg with the 4 DEG C of 1%MC refrigerated dissolution configuration concentrations is mixed into suspension
Liquid, it is ready-to-use.
(3) chlorobenzene piperazine is prepared between: preparing the mCPP solution of 1mg/ml with 0.9% NaCl solution, dosage is
5mg/kg。
3. medication: Artemether 50mg/kg is injected intraperitoneally in 2h before Artemether intervention group Behaviors survey, and control group is simultaneously
Between inject 1%MC, mCPP model group 30 minutes injection mCPP 5mg/kg, Artemether in Treatment group before Behaviors survey are being injected
2h injects Artemether 50mg/kg before mCPP solution, and mCPP half an hour after has been injected intraperitoneally and has started Behaviors survey.
4. behaviouristics method: experimental animal used is familiar with adapting to behaviour daily to every mouse before carrying out behaviouristics detection
The hand of author and operation, daily 3 minutes.It tests and is carried out under quiet environment, every time with 75% alcohol wipe behavior after test
Case, in order to avoid the stool and urine of a upper mouse or odor impact test result next time.Mouse behavior acquisition uses high-definition camera, row
Software (Jiliang Software Sci-Tech Co., Ltd., Shanghai, China) is analyzed using lucky amount animal behavior for analysis.
(1) light and shade case is tested: mouse being put into camera bellows center, camera shooting and Timing synchronization when formal experiment, mouse when record
Can free shuttling in camera-lucida and camera bellows, record 10 minutes altogether.Mouse is statisticallyd analyze to move in camera-lucida residence time, in camera-lucida
Distance and shuttle in the number of light and shade case.
(2) elevated plus-maze test: mouse is placed on open arms when formal experiment and closes the intermediate region of arm intersection, head court
Arm, camera shooting and Timing synchronization are closed to side, is recorded 10 minutes altogether.Statistical analysis mouse enters the number of open arms and rests on
The time of open arms.
5. experimental result: the result shows that Artemether can effectively improve the spontaneous anxiety sample performance induced with mCPP of mouse, energy
Enough increase normal mouse and Anxiety Model mouse camera-lucida residence time and activity distance (see Fig. 2), energy in the experiment of light and shade case
Enough increase normal mouse and Anxiety Model mouse and open arms residence time and enters open arms in elevated plus-maze test
Number (see Fig. 3).
The improvement result that 3 dihydroartemisinine of embodiment and Artesunate show the spontaneous anxiety sample of normal mouse
One, experimental animal feeding (with embodiment 1).
Two, drugs and main agents
Dihydroartemisinine and Artesunate are purchased from Shanghai Aladdin biochemical technology limited liability company；Methylcellulose
(Methyl cellulose, MC), purchased from Sigma-Aldrich company (China, Shanghai)；NaCl is purchased from Sigma-Aldrich
Company (China, Shanghai).
Three, experimental methods
1. animal packet: animal is divided into 3 groups, every group 11, respectively control group (solvent group), dihydroartemisinine intervention
Group and Artesunate intervention group.
2. solution is prepared:
(1) it prepares 1% methocel solution (MC): with 0.9% physiological saline, being heated to 40 DEG C in water-bath, it is molten
MC powder is solved, is evenly stirred until and is completely dissolved, until no milky white precipitate.1%MC solvent injects solution as a control group.
(2) dihydroartemisinine is prepared: the dihydroartemisinine for being 5mg/ml with the 4 DEG C of 1%MC refrigerated dissolution configuration concentrations
Suspension, ready-to-use, effective dose is according to 50mg/kg intraperitoneal injection.
(3) Artesunate is prepared: with the suspension for the Artesunate that the 4 DEG C of 1%MC refrigerated dissolution configuration concentrations are 5mg/ml
Liquid, ready-to-use, effective dose is according to 5mg/kg intraperitoneal injection.
3. medication: 1%MC, dihydroartemisinine intervention group is injected intraperitoneally in 1h before control group (solvent group) Behaviors survey
And Artesunate intervention group same time injection 50mg/kg corresponds to drug.
4. behaviouristics method: with embodiment 1.
5. experimental result: the result shows that dihydroartemisinine and Artesunate can effectively improve the spontaneous anxiety of normal mouse
Sample performance can increase mouse camera-lucida residence time and activity distance (see Fig. 4) in the experiment of light and shade case, can increase mouse
Open arms residence time and the number into open arms in elevated plus-maze test (see Fig. 5).
Finally it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than protects to the present invention
The limitation of range, although the invention is described in detail with reference to the preferred embodiments, those skilled in the art should be managed
Solution, can with modification or equivalent replacement of the technical solution of the present invention are made, without departing from technical solution of the present invention essence and
Range.
Claims (10)
1. application of the artemisinin derivative in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder.
2. application as described in claim 1, which is characterized in that the anxiety disorder includes generalized anxiety disorder.
3. application as described in claim 1, which is characterized in that the artemisinin derivative include Artemether, Artesunate and
At least one of dihydroartemisinine.
4. application as claimed in any one of claims 1 to 3, which is characterized in that the artemisinin derivative is as a kind of adjusting
Drug or alleviation anxiety of the excitability of central nervous system/inhibitory synapse transmitting balance agent in preparation antianxiety disease
Application in the food of disease.
5. application as claimed in any one of claims 1 to 3, which is characterized in that the artemisinin derivative is as a kind of raising
The agent of inhibitory postsynaptic current on cone neurone is in the drug of preparation antianxiety disease or the food of alleviation anxiety disorder
In application.
6. a kind of drug of antianxiety disease, which is characterized in that artemisinin derivative and its pharmaceutical salts and medicine containing effective dose
Acceptable carrier on.
7. the drug of antianxiety disease as claimed in claim 6, which is characterized in that the artemisinin derivative include Artemether,
At least one of Artesunate and dihydroartemisinine.
8. the drug of antianxiety disease as claimed in claims 6 or 7, which is characterized in that the dosage form of the anti anxiety agent object is
Oral preparation or ejection preparation；Preferably, the oral preparation be selected from tablet, capsule, soft capsule, granule, suspension,
At least one of dripping pill, pill, oral liquid；Preferably, the tablet is conventional tablet, dispersible tablet, Orally disintegrating
Piece or sustained release tablets；Preferably, the ejection preparation is injection or powder-injection.
9. a kind of food for alleviating anxiety disorder, which is characterized in that containing acceptable on a effective amount of artemisinin derivative and food
Carrier and/or auxiliary material.
10. alleviating the food of anxiety disorder as claimed in claim 9, which is characterized in that the artemisinin derivative includes Hao Jia
At least one of ether, Artesunate and dihydroartemisinine.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107149601A (en) * | 2017-05-25 | 2017-09-12 | 中国中医科学院中药研究所 | Application of the artemisine compounds in the medicine for the treatment of neurogenic pain and/or complication is prepared |
| CN114668758A (en) * | 2021-05-17 | 2022-06-28 | 澳门大学 | Application of artemisinin and derivatives thereof in preparation of ChAT activity enhancer |
| CN114042149B (en) * | 2021-12-03 | 2023-06-16 | 中国人民解放军空军军医大学 | D-Ala 2 Use of GIP for the preparation of a medicament for the treatment of anxiety disorders |
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| CN107149601A (en) * | 2017-05-25 | 2017-09-12 | 中国中医科学院中药研究所 | Application of the artemisine compounds in the medicine for the treatment of neurogenic pain and/or complication is prepared |
| CN114668758A (en) * | 2021-05-17 | 2022-06-28 | 澳门大学 | Application of artemisinin and derivatives thereof in preparation of ChAT activity enhancer |
| CN114042149B (en) * | 2021-12-03 | 2023-06-16 | 中国人民解放军空军军医大学 | D-Ala 2 Use of GIP for the preparation of a medicament for the treatment of anxiety disorders |
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