CN110169976A - Medicine composition for treating depression and its application containing adenosine a1 receptor agonists - Google Patents
Medicine composition for treating depression and its application containing adenosine a1 receptor agonists Download PDFInfo
- Publication number
- CN110169976A CN110169976A CN201910582825.1A CN201910582825A CN110169976A CN 110169976 A CN110169976 A CN 110169976A CN 201910582825 A CN201910582825 A CN 201910582825A CN 110169976 A CN110169976 A CN 110169976A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- atp
- chloro
- adenosine
- body weight
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Abstract
The present invention relates to a kind of medicine composition for treating depression containing adenosine a1 receptor agonists and its applications.The medicine composition for treating depression has an antidepression characteristic, and onset time quickly, therapeutic effect it is definite, significant, and side effect is smaller, has great application value for treatment depression.
Description
Technical field
The invention belongs to antidepressant technical fields, are related to a kind of antidepressant containing adenosine a1 receptor agonists
Composition and its application.
Background technique
Depression is also known as depressive disorder, low for main clinical characteristics with significant and lasting mental state, is mood disorder
Main Types.Clinical visible mental state is low unbecoming with its situation, and the downhearted of mood can be from depressed to extremely grieved, very
It is extremely pessimistic and worldweary, can there are conamen or behavior；Even occur numb；Some cases have apparent anxiety and motility intense；
Serious person may occur in which the psychotic symptoms such as illusion, vain hope.Even breaking-out continues at least 2 weeks or more, elder's several years every time, most
Case has the tendency that recurrent exerbation, and breaking-out is most of every time to alleviate, and can partially have residual symptoms or switch to chronic.
Antidepressants (antidepressive drugs) refer to that one group is mainly used to treatment to be in a very depressed state as herniation
The psychotropic agent of the mental disease of shape.Antidepressants come out the 1950s, have no suitably in depressive illness before this
Drug therapy.After the 1950s, antidepressants become the preferred treatment means of depressed patient.Currently, nearly all anti-
The mechanism of action of depressed drug relates generally to the transmitting of monoamine neurotransmitter, and side effect is relatively more, and curative effect is clear, but not to the utmost
Such as people's will, if some patientss are invalid to nearly all antidepressant, the onset time of nearly all antidepressants compares
It is long, take just action etc. at least 2 weeks.
Therefore, presently, there are the problem of be need to research and develop it is a kind of it is rapid-action, therapeutic effect is definite, significant, and secondary make
With lesser antidepressant.
Summary of the invention
The purpose of the present invention is to provide a kind of medicine composition for treating depression containing adenosine a1 receptor agonists and its answer
With.The medicine composition for treating depression is rapid-action, therapeutic effect is definite, significant for treating depression, and side effect is smaller.
For this purpose, first aspect present invention provides a kind of medicine composition for treating depression comprising the gland as active constituent
Glycosides A1 receptor stimulating agent, the adenosine a1 receptor agonists are 2-Chloro-N6-cyclopentyl adenosine.
According to the present invention, other active components are also contained in described pharmaceutical composition, the other active components are ATP.
According to certain embodiments of the present invention, in described pharmaceutical composition, the ATP and the chloro- N6- cyclopenta gland of 2-
Glycosides mass ratio is (0-3): 1, preferably (1-3): 1, further preferably 3: 1.
In some embodiments of the invention, the effective dose of described pharmaceutical composition is per kg body weight per day
The 2-Chloro-N6-cyclopentyl adenosine of 0.0015-0.03mg, the further preferably 2- of per kg body weight per day 0.015-0.03mg
Chloro- n6-cyclopentyl adenosine.
In some embodiments of the invention, the effective dose of described pharmaceutical composition is per kg body weight per day 0-
The ATP of 0.09mg, the preferably ATP of per kg body weight per day 0.0045-0.09mg, further preferably per kg body weight per day
The ATP of 0.045-0.09mg.
In some embodiments of the invention, antidepressant effect is generated in 8-12h after described pharmaceutical composition administration.
In some embodiments of the invention, continuous and effective time >=36h after described pharmaceutical composition administration, it is preferably described
Continuous and effective time >=48h after pharmaceutical composition administration.
Second aspect of the present invention provides pharmaceutical composition as described in the first aspect of the invention and is being used to prepare antidepression
Application in medicament.
According to the present invention, the dosage form of the antidepression medicament includes oral preparation or ejection preparation.
According to certain embodiments of the present invention, the oral preparation is selected from tablet, granule, capsule and pill.
In some embodiments of the invention, the content of 2-Chloro-N6-cyclopentyl adenosine is 0.035- in each preparation unit
0.7mg, preferably 0.35-0.7mg；In each preparation unit the content of ATP be 0-2.1mg, preferably 0.105-2.1mg, into
One step is preferably 1.05-2.1mg.
According to certain embodiments of the present invention, the ejection preparation is pulvis or injection.
In some embodiments of the invention, the ejection preparation is pulvis or injection；The ejection preparation is to inject
Liquid total weight, the content of 2-Chloro-N6-cyclopentyl adenosine are 0.007-0.14mg/mL, preferably 0.07-0.14mg/mL；Institute
Ejection preparation is stated with injection total weight, the content of ATP is 0-0.42mg/mL, preferably 0.021-42mg/mL, further
Preferably 0.21-0.42mg/mL.
In the present invention, the 2- that the effective dose of the antidepression medicament is per kg body weight per day 0.0001-0.03mg is chloro-
N6-cyclopentyl adenosine, the preferably 2-Chloro-N6-cyclopentyl adenosine of per kg body weight per day 0.00015-0.03mg；And/or institute
The effective dose for stating antidepression medicament is the ATP of per kg body weight per day 0-0.09mg, preferably per kg body weight per day
The ATP of 0.0045-0.09mg, the further preferably ATP of per kg body weight per day 0.045-0.09mg.
In some embodiments of the invention, the antidepression medicament further includes pharmaceutically acceptable auxiliary element.
Medicine composition for treating depression provided by the present invention containing adenosine a1 receptor agonists has antidepression characteristic, and
Onset time quickly, therapeutic effect it is definite, significant, and side effect is smaller, has great application value for treatment depression.
Detailed description of the invention
It is next with reference to the accompanying drawing that invention is further described in detail:
Fig. 1 shows CUS rat model and gives different time points after the various dose of medicine composition for treating depression of the invention
Syrup preference value (%).
Different time points after the various dose of medicine composition for treating depression of the invention are given Fig. 2 shows CUS rat model
Forced swimming tests dead time (s).
Specific embodiment
To be readily appreciated that the present invention, below in conjunction with attached drawing, the present invention will be described in detail.But before describing the present invention in detail,
It should be understood that the present invention is not limited to the specific embodiments of description.It is also understood that term used herein is only for description
Specific embodiment, and be not offered as restrictive.
Unless otherwise defined, all terms used herein and those skilled in the art's is usual
Understand meaning having the same.Although similar or equivalent any method and material can also with method described herein and material
To use in implementation or test of the invention, but preferred method and material will now be described.
I. term
Heretofore described " water " word, water for pharmaceutical purposes is referred in the case where being not particularly illustrated or limiting, including pure
Change water, water for injection or sterilized water for injection.
Heretofore described term " depression " is also known as depressive disorder, low for Major Clinical with significant and lasting mental state
Feature is the main Types of mood disorder.Clinical visible mental state is low unbecoming with its situation, and the downhearted of mood can be from bored
Do not find pleasure in extremely grieved, depression of feeling oneself inferior or even pessimistic and worldweary can have conamen or behavior；Even occur numb；Some cases
There are apparent anxiety and motility intense；Serious person may occur in which the psychotic symptoms such as illusion, vain hope.Breaking-out continues at least every time
Even 2 weeks or more, elder's several years, majority of cases have the tendency that recurrent exerbation, breaking-out is most of every time to alleviate, and can partially have
Residual symptoms switch to chronic.
Heretofore described depression includes depression in general sense and the depression by psychological social factor initiation
Disease, or the depression induced by other any Physical factors, can be by making in brain trauma, cardiovascular and cerebrovascular disease, treatment of cancer
With interferon etc. is drug-induced, life or social rhythm disorder causes, chronic sleep obstacle causes, be also possible to chronic ache,
The Chronic Somatic Diseases such as diabetes initiation, etc..
II. embodiment
As previously mentioned, the mechanism of action of nearly all antidepressant relates generally to the transmitting of monoamine neurotransmitter,
Side effect is relatively more, and curative effect is clear, but not fully up to expectations, and some patientss are invalid to nearly all antidepressant, several
The onset time of all antidepressants is all relatively long, takes at least 2 weeks and just works.In consideration of it, the present inventor is for antidepression
Drug has carried out a large amount of research.
The present inventor is the study found that adenosine a1 receptor agonists 2-Chloro-N6-cyclopentyl adenosine (CCPA) has preferable resist
The adenosine a1 receptor agonists of certain dosage and concentration are used to treat depression by anti-depressant, rapid-action, therapeutic effect is true
It cuts, significantly, and side effect is smaller.The present invention is based on what above-mentioned discovery was made.
Therefore, medicine composition for treating depression involved in first aspect present invention mainly includes the adenosine as active constituent
A1 receptor stimulating agent, the adenosine a1 receptor agonists are 2-Chloro-N6-cyclopentyl adenosine (CCPA).
Shown in the molecular structural formula of the 2-Chloro-N6-cyclopentyl adenosine such as formula (I).
2-Chloro-N6-cyclopentyl adenosine (CCPA) is a kind of potent and selective adenosine A1 receptor stimulating agent, usually as
Cardiovascular disease treating medicine is used as heart protective agent, is also used for treatment myocardial ischemia.Up to the present medical field is not still by adenosine A 1
Receptor stimulating agent is used to treat the precedent of depression.But the present inventor is the study found that by the adenosine A 1 of certain dosage and concentration
Receptor stimulating agent can work, therapeutic effect is definite, significant, and side effect is smaller for treating depression in 12 hours.
Heretofore described 2-Chloro-N6-cyclopentyl adenosine (CCPA) can be obtained by artificial synthesized, can also direct quotient
It purchases (for example, abcam company) to obtain, and purity >=98% of the 2-Chloro-N6-cyclopentyl adenosine (CCPA).
The present inventor further study show that, using ATP as other active components and 2-Chloro-N6-cyclopentyl adenosine
(CCPA) compound constituted pharmaceutical composition can reduce 2-Chloro-N6-cyclopentyl adenosine for treating depression
(CCPA) while dosage, shorten onset time, and further increase the duration of curative effect, and further decrease side effect.
Result of study shows that in described pharmaceutical composition, the ATP is with 2-Chloro-N6-cyclopentyl adenosine mass ratio
(0-3): 1, preferably (1-3): 1, further preferably 3: 1, it can achieve more significant therapeutic effect, and by onset time
It shortens within 8 hours, and side effect is minimum.
Effective dose reference " pharmacological experimental methodology " (Xu Shuyun religion of the heretofore described pharmaceutical composition for the mankind
Award chief editor, P1861 table 11-8) in " between humans and animals by body surface area conversion equivalent dose ratio ", be based on the agent of rat drug effect
Amount is estimated.
" ATP " is primarily referred to as adenosine triphyosphate (abbreviation atriphos or adenosine triphosphate from the meaning of a word
Acid).Heretofore described " ATP " actually refers to atriphos class medicament comprising atriphos and/or atriphos
The salt of the atriphos such as disodium.
In some embodiments of the invention, the effective dose of described pharmaceutical composition is per kg body weight per day
The 2-Chloro-N6-cyclopentyl adenosine of 0.0015-0.03mg, the further preferably 2- of per kg body weight per day 0.015-0.03mg
Chloro- n6-cyclopentyl adenosine.
In other embodiments of the invention, the effective dose of described pharmaceutical composition is per kg body weight per day 0-
The ATP of 0.09mg, the preferably ATP of per kg body weight per day 0.0045-0.09mg, further preferably per kg body weight per day
The ATP of 0.045-0.09mg.
In the present invention, antidepressant effect is generated in 8-12h after described pharmaceutical composition administration.
Result of study shows continuous and effective time >=36h after pharmaceutical composition administration of the invention, the preferably described medicine group
Close continuous and effective time >=48h after object is administered.
In second aspect of the present invention, the pharmaceutical composition being related to as described in the first aspect of the invention is being used to prepare antidepression
Application in medicament.
In the present invention, the dosage form of the antidepression medicament can be oral preparation or ejection preparation.
When dosage form this using oral preparation, can choose using tablet, granule, capsule or pill.
In some embodiments of the invention, the content of 2-Chloro-N6-cyclopentyl adenosine is 0.035- in each preparation unit
0.7mg, preferably 0.35-0.7mg；In each preparation unit the content of ATP be 0-2.1mg, preferably 0.105-2.1mg, into
One step is preferably 1.05-2.1mg.
When dosage form this using injection, can choose using pulvis or injection.
In some embodiments of the invention, the ejection preparation is with injection total weight, the chloro- N6- cyclopenta gland of 2-
The content of glycosides is 0.007-0.14mg/mL, preferably 0.07-0.14mg/mL；The ejection preparation with injection total weight,
The content of ATP is 0-0.42mg/mL, preferably 0.021-42mg/mL, further preferably 0.21-0.42mg/mL.
In the present invention, the effective dose of the antidepression medicament are as follows:
(1) 2-Chloro-N6-cyclopentyl adenosine of per kg body weight per day 0.0001-0.03mg, preferably daily every kilogram of body
The 2-Chloro-N6-cyclopentyl adenosine of weight 0.00015-0.03mg, the further preferably 2-Chloro-N6-cyclopentyl adenosine of 0.03mg；
(2) ATP of per kg body weight per day 0-0.09mg, preferably per kg body weight per day 0.0045-0.09mg's
ATP, the further preferably ATP of 0.045-0.09mg.
Content based on CCPA and ATP in above-mentioned injection, it is readily appreciated that, the effective dose of above-mentioned antidepression medicament is to infuse
It penetrates liquid and is calculated as per kg body weight per day 0.107-0.214mL, be daily 7.5-15mL by 70kg batheroom scale, divide 1-3 injection.
In some specific preferred embodiments, the effective dose of above-mentioned antidepression medicament is calculated as daily every thousand with injection
Gram weight 0.107-0.214mL, by 70kg batheroom scale, daily 7.5-15mL, point 3 injections, each 2.5-5mL.
In some further embodiments of the invention, the antidepression medicament further includes pharmaceutically acceptable auxiliary
Ingredient.
Pharmaceutically acceptable auxiliary element is not particularly limited in the present invention, this field routine medicine can be used
Acceptable auxiliary element on.
For example, the pharmaceutically acceptable auxiliary element includes filler (diluent, absorption for tablet
Agent), wetting agent, binder, disintegrating agent, lubricant and other surfaces activating agent.
The filler includes starch, Icing Sugar, dextrin, lactose, pregelatinized starch, microcrystalline cellulose, inorganic salts and sweet
Reveal one or more of alcohol.
The wetting agent and binder include water, ethyl alcohol, starch slurry, sodium carboxymethylcellulose, hydroxypropyl cellulose, methyl
Cellulose, ethyl cellulose, hydroxypropyl methyl cellulose and other binder (gelatin solution, sucrose solution, polyethylene pyrroles
One or more of the aqueous solution or alcoholic solution of pyrrolidone).
The disintegrating agent includes that dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crosslinked polyethylene ratio cough up alkane
One or more of ketone and croscarmellose sodium.
The lubricant includes magnesium stearate, talcum powder, hydrogenated vegetable oil, superfine silica gel powder and polyethylene glycols and the moon hanging alcohol
One or more of magnesium sulfate.
The other surfaces activating agent includes the lauryl sodium sulfate etc. for improving dissolution rate.
For another example pharmaceutically acceptable auxiliary element mainly includes Vehicle Composition for injection comprising steam
Distilled water and/or physiological saline.
Those skilled in the art should understand that be for powder-type injection, by antidepressant of the invention when use
Composition pulvis is dissolved or dispersed in distilled water and/or injection is made in physiological saline.
Be readily appreciated that, injection type injection be scattered in by medicine composition for treating depression of the invention water for injection and/
Or physiological saline is made.
III. embodiment
The present invention is specifically described below by way of specific embodiment.Experimental method described below, such as without special theory
It is bright, it is laboratory conventional method.Experimental material described below can be obtained unless otherwise instructed by commercial channel.
Quantitative test in following embodiment is respectively provided with three repeated experiments, and all results are with average value ± standard error
(Mean ± S.E.M) is indicated.Data analysis uses two-way analysis of variance (Two-Way ANOVA)；All post hoc points
Analysis is all made of Turkey and has inspected.Using p < 0.05 as significance of difference standard.
Sprague-Dawley (SD) rat: Beijing Vital River Experimental Animals Technology Co., Ltd..
Effect of the chloro- n6-cyclopentyl adenosine of embodiment 1:2- (CCPA) in antidepression
Experimental animal: male Sprague-Dawley (SD) rat (weight 260-280g).
1, it is divided into 5 experimental groups as follows after rat adaptive feeding 1 week to be raised:
Experimental group 1 (control+solvent group): 2- is injected intraperitoneally in normal raising 28 days (do not give any stress), the 29th day when
The solvent (2%DMSO and physiological saline mixed solution) of chloro- n6-cyclopentyl adenosine (CCPA), injection dosage 2ml/kg, totally 10
Rat；
Experimental group 2 (CUS+ solvent group) (Stress Depression Model+solvent group): being carried out continuously 28 days chronic stresses, and the 29th day
When screen depressed modeling success rat, solvent (2%DMSO and the physiology salt of 2-Chloro-N6-cyclopentyl adenosine (CCPA) is injected intraperitoneally
Water mixed solution), injection dosage 2ml/kg, totally 10 rats；
Experimental group 3 (CUS+2- chloro- n6-cyclopentyl adenosine (CCPA) 0.002mg/kg group): it is carried out continuously 28 days and chronic answers
Swash, depressed modeling success rat is screened at the 29th day, is injected intraperitoneally 2-Chloro-N6-cyclopentyl adenosine (CCPA), injection dosage is
2ml/kg, totally 10 rats；
Experimental group 4 (CUS+2- chloro- n6-cyclopentyl adenosine (CCPA) 0.02mg/kg group): it is carried out continuously 28 days and chronic answers
Swash, depressed modeling success rat is screened at the 29th day, is injected intraperitoneally 2-Chloro-N6-cyclopentyl adenosine (CCPA), injection dosage is
2ml/kg, totally 10 rats；
Experimental group 5 (CUS+2- chloro- n6-cyclopentyl adenosine (CCPA) 0.2mg/kg group): being carried out continuously 28 days chronic stresses,
Depressed modeling success rat is screened at the 29th day, is injected intraperitoneally 2-Chloro-N6-cyclopentyl adenosine (CCPA), injection dosage 2ml/
Kg, totally 10 rats.
Chronic stress follows random, Unpredictability principle, gives two kinds of stimulations at unfixed time point daily.
Continuous 28 days chronic stress concrete schemes arrange as shown in table 1；
The continuous 28 days chronic stress concrete schemes of 1 rat of table
It is various stress method it is specific as follows:
(1) fasting: feed is not provided in 24 hours；
(2) vibrate: rat is put in oscillation shaking table together with rearging cage instrument, 130 revs/min, continues 1 hour；
(3) it presss from both sides tail: using binder clip clamp rat root of the tail portion, continue 1 minute；
(4) empty cage: the padding in rat breeding cage is taken out, continues 24 hours；
(5) tilt: mouse cage is in 45 degree of slant settings, continues 24 hours；
(6) it swims: animal is put into in the bucket for filling 4 DEG C of water (45 centimetres of the depth of water), rat tail point can just touch a barrel bottom,
It is put back in cage after animal is taken out, dried after five minutes；
(7) 4 degree: rat being put in 4 DEG C of refrigerators, continues 1 hour；
(8) crowded: large size normal rat rearging cage (CP4) places 10-15 rat, continues 12 hours or more；
(9) fetter: rat is fitted into dedicated restraint device, continues 1 hour；
(10) moist: padding water being drenched, is subject to completely moist but does not have ponding, continue 24 hours；
(11) stroboscopic: rat is exposed to stroboscopic light irradiation, continues 6 hours；
(12) prohibit water: cutting off the water supply within 24 hours；
(13) noise: rat is exposed to the white noise of 120dB, continues 1 hour.
2, it has carried out after the injection of step 1 12 hours, syrup preference test has been carried out to rat, test method is as follows:
(1) the syrup laundering period (time laundering period be 48 hours): single cage raising rat, place in cage one bottle of pure water and
One bottle of 1% sucrose water (1g sucrose/100mL pure water) the 24th hour, exchanges the position of pure water and syrup.
(2) syrup has a preference for test phase: prohibiting Rat Fast water 4 hours after completing step (1), then in cage
Appearance the same one bottle of pure water and one bottle of 1% sucrose water (1g sucrose/100mL pure water) are placed, drinks rat freely
Water 1 hour (position of pure water and syrup was exchanged at the 30th minute), weighing two water bottles in test front and back calculated big in 1 hour
The intake and syrup preference value of 1% syrup of mouse and pure water.Syrup preference value=syrup intake/(syrup intake+pure water is taken the photograph
Enter amount) × 100%.
As a result as shown in Figure 1.In Fig. 1, Con is that the syrup of 1 rat of experimental group has a preference for test result, and CUS+CCPA (0) is
The syrup of 2 rat of experimental group has a preference for test result, and CUS+CCPA (0.002) is that the syrup of 3 rat of experimental group has a preference for test result,
CUS+CCPA (0.02) is that the syrup of 4 rat of experimental group has a preference for test result, and CUS+CCPA (0.2) is the sugar of 5 rat of experimental group
Water has a preference for test result.The result shows that the syrup preference value of 2 rat of experimental group is significant compared with the syrup preference value of 1 rat of experimental group
It reduces (p < 0.05), shows behavior depression.12 hours to 36 hours after giving CCPA or solvent, single factor test variance point
Analysis shows that experimental group 3,4,5 has significant raising compared with the syrup preference value of 2 rat of experimental group, and difference is statistically significant
(F3,28=3.599, p < 0.05；F3,28=3.165, p < 0.05；F3,28=4.534, p < 0.05), show antidepression sample row
For.
3, after completing step 2, forced swimming test is carried out to rat, forced swimming is tested in diameter 24cm, high 50cm's
It is carried out in organic glass cylinder, depth of water 35cm, 25 ± 2 DEG C of water temperature.When rats'swimming, guarantee that it cannot lean on four limbs or tail barrel support
Bottom, and nose is kept to expose the surface breathing.15min swimming is carried out when experiment starts first to adapt to, carries out 5min's after 24 hours
Forced swimming test, records the floating dead time of rat in 5min, the index as desperate behavior.
As a result as shown in Figure 2.In Fig. 2, Con is the forced swimming test result of 1 rat of experimental group, and CUS+CCPA (0) is
The test result of 2 rat of experimental group, CUS+CCPA (0.002) are the test result of 3 rat of experimental group, and CUS+CCPA (0.02) is
The test result of 4 rat of experimental group, CUS+CCPA (0.2) are the test result of 5 rat of experimental group.The result shows that experimental group 2 is big
The dead time of mouse significantly extends (p < 0.05) compared with the dead time of 1 rat of experimental group, shows behavior depression；It is giving
12 to 48 hours after CCPA or solvent, one-way analysis of variance shows the dead time phase of experimental group 3,4,5 with 2 rat of experimental group
Than having significant decrease, the statistically significant (F of difference3,28=4.758, p=0.0084；F3,28=9.693, p=0.0001；F3,36
=22.09, p < 0.0001), show reverse behavior depression.
The above result shows that rats by intraperitoneal injection 2-Chloro-N6-cyclopentyl adenosine (CCPA) significant reverse in 12-36 hours afterwards
The preference of syrup caused by chronic stress reduces (F3,28=3.599, p < 0.05；F3,28=3.165, p < 0.05；F3,28=
4.534, p < 0.05) and forced swimming in the dead time increase (F3,28=4.758, p=0.0084；F3,28=9.693, p=
0.0001；F3,36=22.09, p < 0.0001).Wherein, 2-Chloro-N6-cyclopentyl adenosine (CCPA) 0.2mg/kg is to reverse rat
The optimal dose of antidepression sample behavior.
Test result show the antidepressant medicament in the present invention for treating depression, quick, significant effect, and
Almost without systemic toxic side effect, side effect is smaller.
With the dosage (quality of ATP and CCPA of 2-Chloro-N6-cyclopentyl adenosine (CCPA) 0.1mg/kg, ATP 0.3mg/kg
Than being 3: 1) to rat carry out intraperitoneal injection test the result shows that, combine ATP with 2-Chloro-N6-cyclopentyl adenosine (CCPA)
For treating depression, onset time was shortened within 8 hours, and effect is more significant, and side effect is minimum.
It should be noted that embodiment described above for explaining only the invention, is not constituted to of the invention any
Limitation.By referring to exemplary embodiments, invention has been described, it should be appreciated that word used in it is descriptive
With explanatory vocabulary, rather than limited vocabulary.The present invention can be made within the scope of the claims by regulation
Modification, and the present invention is revised in without departing substantially from scope and spirit of the present invention.Although the present invention described in it relates to
And specific method, material and embodiment, it is not intended that the present invention is limited to particular case disclosed in it, on the contrary, this hair
It is bright to can be extended to other all methods and applications with the same function.
Claims (10)
1. a kind of medicine composition for treating depression comprising as the adenosine a1 receptor agonists of active constituent, the adenosine A 1 by
Body agonist is 2-Chloro-N6-cyclopentyl adenosine.
2. pharmaceutical composition according to claim 1, which is characterized in that also containing other activity in described pharmaceutical composition
Ingredient, the other active components are ATP.
3. pharmaceutical composition according to claim 2, which is characterized in that in described pharmaceutical composition, the ATP and 2-
Chloro- n6-cyclopentyl adenosine mass ratio is (0-3): 1, preferably (1-3): 1, further preferably 3:1.
4. pharmaceutical composition described in any one of -3 according to claim 1, which is characterized in that the medicine of described pharmaceutical composition
Imitate the 2-Chloro-N6-cyclopentyl adenosine that dosage is per kg body weight per day 0.0015-0.03mg, further preferably daily every thousand
The 2-Chloro-N6-cyclopentyl adenosine of gram weight 0.015-0.03mg；And/or the effective dose of described pharmaceutical composition is daily every
The ATP of kg body weight 0-0.09mg, the preferably ATP of per kg body weight per day 0.0045-0.09mg, further preferably daily
The ATP of every kg body weight 0.045-0.09mg.
5. pharmaceutical composition according to claim 4, which is characterized in that produced in 8-12h after described pharmaceutical composition administration
Raw antidepressant effect；And/or continuous and effective time >=36h after described pharmaceutical composition administration, preferably described pharmaceutical composition are given
Continuous and effective time >=48h after medicine.
6. pharmaceutical composition described in any one of -5 is in the application being used to prepare in antidepression medicament according to claim 1；
Preferably, the dosage form of the antidepression medicament includes oral preparation or ejection preparation.
7. application according to claim 6, which is characterized in that the oral preparation be selected from tablet, granule, capsule and
Pill；Preferably, the content of 2-Chloro-N6-cyclopentyl adenosine is 0.035-0.7mg, preferably 0.35- in each preparation unit
0.7mg；The content of ATP is 0-2.1mg, preferably 0.105-2.1mg, further preferably 1.05- in each preparation unit
2.1mg。
8. application according to claim 6, which is characterized in that the ejection preparation is pulvis or injection；The injection
Preparation is 0.007-0.14mg/mL, preferably 0.07- with injection total weight, the content of 2-Chloro-N6-cyclopentyl adenosine
0.14mg/mL；The ejection preparation is 0-0.42mg/mL, preferably 0.021- with injection total weight, the content of ATP
42mg/mL, further preferably 0.21-0.42mg/mL.
9. application according to claim 7 or 8, which is characterized in that the effective dose of the antidepression medicament is daily every
The 2-Chloro-N6-cyclopentyl adenosine of kg body weight 0.0001-0.03mg, preferably per kg body weight per day 0.00015-0.03mg
2-Chloro-N6-cyclopentyl adenosine；And/or the effective dose of the antidepression medicament is per kg body weight per day 0-0.09mg's
ATP, the preferably ATP of per kg body weight per day 0.0045-0.09mg, further preferably per kg body weight per day 0.045-
The ATP of 0.09mg.
10. application according to claim 8, which is characterized in that the antidepression medicament further includes pharmaceutically acceptable
Auxiliary element.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910582825.1A CN110169976A (en) | 2019-06-28 | 2019-06-28 | Medicine composition for treating depression and its application containing adenosine a1 receptor agonists |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910582825.1A CN110169976A (en) | 2019-06-28 | 2019-06-28 | Medicine composition for treating depression and its application containing adenosine a1 receptor agonists |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110169976A true CN110169976A (en) | 2019-08-27 |
Family
ID=67699578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910582825.1A Pending CN110169976A (en) | 2019-06-28 | 2019-06-28 | Medicine composition for treating depression and its application containing adenosine a1 receptor agonists |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110169976A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111789950A (en) * | 2019-10-15 | 2020-10-20 | 浙江大学 | Method and pharmaceutical composition for regulating fear memory consolidation |
| CN112656936A (en) * | 2021-01-05 | 2021-04-16 | 北京大学 | Application of immune cell factor interleukin-22 in preparation of antidepressant drugs |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103251951A (en) * | 2013-01-16 | 2013-08-21 | 南方医科大学 | Application of P2X2 receptor agonist or opening agent in preparation of anti-depression or anti-anxiety drugs |
-
2019
- 2019-06-28 CN CN201910582825.1A patent/CN110169976A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103251951A (en) * | 2013-01-16 | 2013-08-21 | 南方医科大学 | Application of P2X2 receptor agonist or opening agent in preparation of anti-depression or anti-anxiety drugs |
Non-Patent Citations (1)
| Title |
|---|
| D J HINES等: "Antidepressant effects of sleep deprivation require astrocyte-dependent adenosine mediated signaling", 《TRANSLATIONAL PSYCHIATRY》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111789950A (en) * | 2019-10-15 | 2020-10-20 | 浙江大学 | Method and pharmaceutical composition for regulating fear memory consolidation |
| CN112656936A (en) * | 2021-01-05 | 2021-04-16 | 北京大学 | Application of immune cell factor interleukin-22 in preparation of antidepressant drugs |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Hintzen et al. | The pharmacology of LSD | |
| ES2606041T3 (en) | Composition of low dose topiramate / phentermine and methods of use thereof | |
| Thomas et al. | ATP-sensitive potassium channels mediate contraction-induced attenuation of sympathetic vasoconstriction in rat skeletal muscle. | |
| Hall et al. | Cocaine abuse and its treatment | |
| US20210338603A1 (en) | Combinations of adrenergic receptor agonists for the treatment of type 2 diabetes | |
| Gillin et al. | The neuropharmacology of sleep and wakefulness | |
| CN108685935B (en) | A kind of food containing adenosine receptor excitement reagent | |
| TW200808324A (en) | Method for shortening hospital stay in patients with congestive heart failure and acute fluid overload | |
| CN109906077A (en) | The sublingual pharmaceutical composition of Edaravone and (+) -2- baras camphor | |
| CN110169976A (en) | Medicine composition for treating depression and its application containing adenosine a1 receptor agonists | |
| CN107951869A (en) | Pharmaceutical preparation and its application containing cannabidiol | |
| Martín et al. | Simultaneous effects of p‐chloroamphetamine, d‐fenfluramine, and reserpine on free and stored 5‐hydroxytryptamine in brain and blood | |
| JP3074519B2 (en) | Intestinal fluid absorption enhancer | |
| CN100415728C (en) | Alkylol piperazine derivative optical isomer or its salt and its application | |
| CN110327362A (en) | Application of the inosinic acid in preparation antidepressant | |
| Jones | Perspectives in drug development and clinical pharmacology: the discovery of histamine H1 and H2 antagonists | |
| CN105853479A (en) | Pharmaceutical composition for treating depression | |
| CATALANO et al. | Olanzapine overdose in an 18-month-old child | |
| CN108904516A (en) | Application of the inosine in prevention and treatment depression | |
| Chechani | Serotonin syndrome presenting as hypotonic coma and apnea: potentially fatal complications of selective serotonin receptor inhibitor therapy | |
| CN101172124A (en) | Novel uses of pennycress, pharmaceutical composition containing the pennycress and and preparation method thereof | |
| Hennig et al. | Tonic immobility and skin color in anoles: Effects of serotonin precursors and metabolites | |
| CN103550778A (en) | Pharmaceutical composition for treating affective disorder disease | |
| CN108210879A (en) | A kind of pharmaceutical composition for treating acute Cerebral bleeding and its application | |
| WO2020103889A1 (en) | Method and medicine for treating depressive disorders |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |