CN101318020B - Anti-anxiety or/and dumps medicament composition and uses thereof - Google Patents
Anti-anxiety or/and dumps medicament composition and uses thereof Download PDFInfo
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- CN101318020B CN101318020B CN2007100748309A CN200710074830A CN101318020B CN 101318020 B CN101318020 B CN 101318020B CN 2007100748309 A CN2007100748309 A CN 2007100748309A CN 200710074830 A CN200710074830 A CN 200710074830A CN 101318020 B CN101318020 B CN 101318020B
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Abstract
The invention provides a use of Alpha2 adrenergic receptor agonist with efficient dosage in preparing a medicament which is given together with 5-HT 1A receptor agonist with efficient dosage and is used for anti-anxiety or/and anti-depression. The invention also provides an anti-anxiety or/and anti-depression drug combination, which is a medicament prepared by the raw materials of Alpha2 adrenergic receptor agonist with efficient dosage and 5-HT 1A receptor agonist with efficient dosage, wherein, the weight proportion of Alpha2 adrenergic receptor agonist and 5-HT 1A receptor agonist is: 0.2-125 shares of Alpha2 adrenergic receptor agonist and 5-16 shares of 5-HT 1A receptor agonist. In the invention, the two drugs are used together, especially the optional tizanidine hydrochloride and tandospirone citrate are used together so as to have the function of increasing effect, and the side effect is low, effect taking is stable, thus solving the problem which can not be overcome presently and providing a new choice for clinic.
Description
Technical field
The present invention relates to a kind of α
2Adrenoceptor agonists and 5-HT
1AThe purposes of receptor stimulating agent the invention still further relates to a kind of anxiety or/and antidepressant pharmaceutical composition.Belong to drug world.
Background technology
Existing anxiety be or/and antidepressant medicine by to the neurotransmitter systematic influence, can be divided into four big classes: (1) is blocked the medicine of norepinephrine, serotonin and dopamine reuptake (as: tricyclic antidepressants [TCAs] is as clomipramine; Selectivity serotonin reuptake inhibitors [SSRIs] is as fluoxetine, fluvoxamine, paroxetine etc.; And selectivity norepinephrine and serotonin reuptake inhibitors [SNRIs] are as venlafaxine, duloxetine etc.; (2) irreversible or reversibly suppress monoamine oxidase, MAO (MAO) the active medicine of metabolism monoamine neurotransmitter (oxidase inhibitor [MAOIs] is as isocarbossazide, phenelzine etc.; Reversibility oxidase inhibitor [RIMAs] is as moclobemide); (3) α
2Adrenoceptor antagonists (norepinephrine energy and specificity serotonin can antidepressant [NaSSA] as: mirtazapine); (4) 5-HT
1AReceptor stimulating agent is as tandospirone and buspirone.The adrenoreceptor theory is proposed in 1948 by Ahlquist the earliest, will be positioned on the effector cell film that the sympathetic nerve postganglionic fibers arranged can with epinephrine and the bonded receptor of norepinephrine, be called adrenoreceptor.Adrenoceptor can be divided into α and Beta-3 adrenergic receptor again.Langer in 1974 is divided into α according to the region of anatomy and physiological function with alpha adrenergic receptor
1And α
22 hypotypes.α
2Receptor is present in presynaptic and postsynaptic, it by excitement after main release and the neuronic excitement that suppresses norepinephrine.Tizanidine hydrochloride is by exciting presynaptic membrane α
2Receptor has suppressed the release of norepinephrine, can cause calmness and anxiety to be alleviated; 5-HT
1AReceptor mainly concentrate on Hippocampus, in cerebral limbic system such as, interpeduncular nucleus, corpus amygdaloideum and seam gland nuclear.It occupies important status in ergasia, be the receptor of most important mediation anxiety.Tandospirone belongs to spiral shell ketone medicine, is the 5-HT receptor stimulating agent, the 5-HT of the exciting postsynaptic membrane of its high selectivity
1AReceptor suppresses hyperfunction 5-hydroxy tryptamine energy neural activity, makes the 5-HT of 5-HT and postsynaptic membrane
1AAnd 5-HT
2AThe combination of the receptor state that restores balance, active when superfluous when 5-hydroxy tryptamine, can suppress its active and performance angst resistance effect; But when the active reduction of 5-hydroxy tryptamine, can improve its activity again and the performance antidepressant effect.No of flaccid muscles, side effect that maincenters such as anesthesia enhancing, convulsion and autonomic movement inhibition etc. suppress, dependency that no benzodiazepine has and withdrawal reaction.
" sacred disease and mental health " 2006 the 6th the 1st phases of volume, " Clinical advances of antidepressants ", the 73rd page discloses a class antidepressants SNRI, it can block the reuptake of 5-HT and NE simultaneously, venlafaxine for example, can suppress the reuptake of presynaptic membrane, strengthen the function of maincenter 5-HT and NE neurotransmitter 5-HT and NE." venlafaxine is a kind of effective antidepressants, also is a kind of effective antianxiety drugs (comprising the treatment of panic disorder) " simultaneously.Selectivity norepinephrine and serotonin reuptake inhibitors [SNRIs] are as venlafaxine, duloxetine etc.Its main pharmacological mechanism is the reuptake of inhibition presynaptic membrane to 5-HT and NE, thereby the 5-HT of synaptic space and the concentration of NE are increased, and reaches the function of enhancing maincenter 5-HT and NE neurotransmitter, performance anxiety and depressed acting on.
Application number: 99811132.5, denomination of invention: the pharmaceutical agent of treatment parkinson, ADHD and little adenoma, the method for treatment ADHA (noting short superactivity disease), and the pharmaceutical composition of treatment ADHD, said composition comprises a, α
2Adrenoreceptor part (receptor stimulating agent or antagonist) b, D2 receptor stimulating agent or its pharmaceutically acceptable salt; C, 5-HT
1AReceptor stimulating agent, or they are at pharmaceutically acceptable salt; With the pharmaceutically acceptable carrier of d.This pharmaceutical composition is the compositions that contains above-mentioned three kinds of active agents, at be the treatment ADHA (noting short superactivity disease).
Still no-trump α at present
2Adrenoceptor agonists and 5-HT
1AThe receptor stimulating agent compatibility is united and is used for anxiety or/and antidepressant, also not with α
2Adrenoceptor agonists and 5-HT
1AThe receptor stimulating agent compatibility is used for anxiety or/and the report of antidepressant medicine.
Summary of the invention
The invention provides a kind of α
2Adrenoceptor agonists and 5-HT
1AThe new purposes that the receptor stimulating agent compatibility uses the invention still further relates to a kind of anxiety or/and antidepressant pharmaceutical composition.
The invention provides the α of effective dose
2Adrenoceptor agonists is used for 5-HT with effective dose in preparation
1AReceptor stimulating agent together administration be used for anxiety or/and the purposes of antidepressant medicament.
Wherein, described α
2Adrenoceptor agonists and 5-HT
1AThe weight proportion of receptor stimulating agent is: α
2Adrenoceptor agonists 0.2-125 part, 5-HT
1A5～16 parts of receptor stimulating agents.
Wherein, described α
2Adrenoceptor agonists is tizanidine's or derivatives thereof, methyldopa, guanabenz, clonidine, MPV-1440, mivazerol, Azepexol., rilmenidine; Described 5-HT
1AReceptor stimulating agent is tandospirone or derivatives thereof, buspirone.
Further preferably, described tizanidine's derivant is a tizanidine hydrochloride; Described tandospirone derivant is a SM-3997, and its weight proportion is: 1～4 part of tizanidine hydrochloride, 5～40 parts of SM-3997.Further preferably, its weight proportion is: 1～4 part of tizanidine hydrochloride, 10 parts of SM-3997.
Still more preferably, the weight proportion of described tizanidine hydrochloride and SM-3997 is: 2: 10.In raw material weight of the present invention, tizanidine hydrochloride is all in the tizanidine.
A kind of anxiety also is provided in the present invention or/and antidepressant pharmaceutical composition, and it is the α by effective dose
2The 5-HT of adrenoceptor agonists and effective dose
1AReceptor stimulating agent is the medicament that feedstock production forms, wherein, and α
2Adrenoceptor agonists and 5-HT
1AThe weight proportion of receptor stimulating agent is: α
2Adrenoceptor agonists 0.2-125 part, 5-HT
1A5～16 parts of receptor stimulating agents.
Wherein, described α
2Adrenoceptor agonists is tizanidine's or derivatives thereof, methyldopa, guanabenz, clonidine, MPV-1440, mivazerol, Azepexol., rilmenidine; Described 5-HT
1AReceptor stimulating agent is tandospirone or derivatives thereof, buspirone.
Wherein, described tizanidine's derivant is a tizanidine hydrochloride; Described tandospirone derivant is a SM-3997, and its weight proportion is: 1～4 part of tizanidine hydrochloride, 5～40 parts of SM-3997.
Further preferably, its weight proportion is: 1～4 part of tizanidine hydrochloride, 10 parts of SM-3997.
Still more preferably, the weight proportion of described tizanidine hydrochloride and SM-3997 is: 2: 10.
Wherein, described pharmaceutical preparation is: tablet, capsule, granule, oral liquid, packaged preparation, gastric retention agent.
Wherein, described pharmaceutical preparation is the gastric retention agent, and this gastric retention agent is to be prepared from by following weight proportion raw material and adjuvant:
The ratio range of crude drug and adjuvant is: 5～60:40～500, wherein adjuvant is: the mixture of one or more of starch, dextrin, magnesium stearate, microcrystalline Cellulose, polysaccharide chitosan, hydroxypropyl emthylcellulose HPMC, hydroxypropyl cellulose HPC, hydroxyethyl-cellulose HEC, methylcellulose MC, ethyl cellulose EC, carboxymethyl starch sodium CMC-Na, carbomer carbopol, carbopol polycarboxyviny1 etc., wherein said crude drug is: the weight proportion of tizanidine hydrochloride and SM-3997 is: 2: 10.
Wherein, described gastric retention agent is to be prepared from by following weight proportion raw material and adjuvant:
The ratio range of crude drug and adjuvant is: 12: 188.
α among the present invention
2Adrenoceptor agonists is by exciting presynaptic membrane α
2Receptor has suppressed the release of norepinephrine, thereby the concentration of the NE of synaptic space is reduced, and causes calmness and anxiety to be alleviated; 5-HT
1AThe 5-HT of the exciting postsynaptic membrane of receptor stimulating agent high selectivity
1AReceptor suppresses hyperfunction 5-hydroxy tryptamine energy neural activity, makes the 5-HT of 5-HT and postsynaptic membrane
1AAnd 5-HT
2AThe combination of the receptor state that restores balance, active when superfluous when 5-hydroxy tryptamine, can suppress its active and performance angst resistance effect; But when the active reduction of 5-hydroxy tryptamine, can improve its activity again and the performance antidepressant effect.Compare with disclosed technology in the document " sacred disease and mental health, 2006 the 6th the 1st phases of volume, the Clinical advances of antidepressants, the 73rd page ", the compatibility of drugs mechanism of action is different fully.
Because 5-HT
1AThe receptor stimulating agent onset is slower, α
2The adrenoceptor agonists onset is very fast, but certain side effect is arranged, and as calm, hypotensive effect, is not suitable for independent medication.The present invention uses two class compatibility of drugss, and especially preferred tizanidine hydrochloride and SM-3997 reached the effect of Synergistic, and side effect are low, and onset is steady, has solved to be difficult to the problem that overcomes at present, provides a kind of new selection for clinical.
The specific embodiment
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
The preparation of [embodiment 1] medicine of the present invention
Tizanidine 1g (1000 capsules or 1000)
SM-3997 5g
Starch 200g
Magnesium stearate 2g
Tizanidine, SM-3997 and adjuvant by behind the equivalent incremental method mixing, are granulated, and tabletting or direct compression promptly get tablet; Or encapsulated, promptly get capsule.
The preparation of [embodiment 2] medicine of the present invention
Tizanidine 2g (1000 capsules or 1000)
SM-3997 10g
Starch 186g
Magnesium stearate 2g
Tizanidine, SM-3997 and adjuvant by behind the equivalent incremental method mixing, are granulated, and tabletting or direct compression promptly get tablet; Or encapsulated, promptly get capsule.
The preparation of [embodiment 3] medicine of the present invention
Tizanidine 1g (1000 bags of granules)
SM-3997 10g
Starch 400g
Dextrin 400g
Correctives 2g
Tizanidine, SM-3997 and adjuvant by behind the equivalent incremental method mixing, are granulated, promptly get granule.
The preparation of [embodiment 4] medicine of the present invention
Tizanidine 2g (1000 gastric residential tablets)
SM-3997 10g
Hydroxypropyl emthylcellulose 80g
Starch 103g
Magnesium stearate 5g
Preparation technology: with SM-3997, tizanidine's crude drug and hydroxypropyl emthylcellulose, methylcellulose mix homogeneously, sieve, the system granule, oven dry in about 50 ℃, 20 mesh sieve granulate add magnesium stearate, tabletting behind the mix homogeneously, promptly.
The preparation of [embodiment 5] medicine of the present invention
Tizanidine 1g (1000 gastric residential tablets)
SM-3997 5g
Ethyl cellulose EC 100g
Starch 20g
Polysaccharide 60g
Tizanidine and ethyl cellulose EC are passed through equivalent incremental method mixing, and with SM-3997 and other auxiliary materials and mixing, tabletting promptly again.
The preparation of [embodiment 6] medicine of the present invention
The many 125g of methyl (1000 capsules or 1000)
SM-3997 10g
Starch 200g
Magnesium stearate 2g
SM-3997, methyldopa and adjuvant by behind the equivalent incremental method mixing, are granulated, and tabletting or direct compression promptly get tablet; Or encapsulated, promptly get capsule.
The preparation of [embodiment 7] medicine of the present invention
Rilmenidine 1g (1000 capsules or 1000)
SM-3997 10g
Starch 200g
Magnesium stearate 2g
SM-3997, rilmenidine and adjuvant by behind the equivalent incremental method mixing, are granulated, and tabletting or direct compression promptly get tablet; Or encapsulated, promptly get capsule.
The preparation of [embodiment 8] medicine of the present invention
Dexmedetomidine 1g (1000 capsules or 1000)
Buspirone 10g
Starch 200g
Magnesium stearate 2g
Buspirone, dexmedetomidine and adjuvant by behind the equivalent incremental method mixing, are granulated, and tabletting or direct compression promptly get tablet; Or encapsulated, promptly get capsule.
The preparation of [embodiment 9] medicine of the present invention
Clonidine 2g (1000 pills)
SM-3997 10g
Correctives 3g
Starch 80g
Dextrin 80g
By behind the equivalent incremental method mixing, again with SM-3997, dextrin, correctives mixing, weary ball is drying to obtain with clonidine and starch.
The preparation of [embodiment 10] medicine of the present invention
Press the selection and the consumption preparation of the method for embodiment 5 and adjuvant, tizanidine 1g wherein, SM-3997 40g.
The preparation of [embodiment 11] medicine of the present invention
Press the selection and the consumption preparation of the method for embodiment 5 and adjuvant, tizanidine 4g wherein, SM-3997 5g.
The preparation of [embodiment 12] medicine of the present invention
Press the method for embodiment 9 and selection and consumption preparation, wherein clonidine 2g, the tandospirone 160g of adjuvant.
The preparation of [embodiment 13] medicine of the present invention
Press the method for embodiment 9 and selection and consumption preparation, wherein clonidine 16g, the tandospirone 5g of adjuvant.
The preparation of [embodiment 14] medicine of the present invention
Press the selection and the consumption preparation of the method for embodiment 8 and adjuvant, dexmedetomidine 4g wherein, buspirone 10g.
Below prove beneficial effect of the present invention by pharmacodynamics test.
For exploring the α of effective dose
2The 5-HT of adrenoceptor agonists and effective dose
1AReceptor stimulating agent is preparing anxiety or/and the purposes in the associating medicament of antidepressant and tranquilizing soporific, and the best of breed of this drug combination and best proportioning, carried out the research of interactional experimental study of this drug combination and compatibility respectively, obtained the mass efficient reliable test data, conclusion is as follows:
Discover by compatibility multiple medicine, calmness, antidepressant or antianxity using tangible enhancing is arranged all behind the two class drug combinations, compatibility optimization experiment result of study shows that the best compatibe drug in the two class medicines is tizanidine hydrochloride and SM-3997 compatibility, its compatibility mass ratio is all effective to 4:10 at 1:10, and its best proportion compatibility is 2:10.
Test example 1 α
2Adrenoceptor agonists and 5-HT
1AReceptor stimulating agent is united the experiment of use
The two class medicines that this patent relates to are respectively α
2Adrenoceptor agonists and 5-HT
1AReceptor stimulating agent, two classes are medication combined to be used in anxiety or/and the effect of antidepressant and tranquilizing soporific aspect in order to probe into, with tizanidine, methyldopa as α
2The representative medicine of adrenoceptor agonists, with SM-3997, buspirone as 5-HT
1AThe representative medicine of receptor stimulating agent is estimated by calmness, antidepressant and anxiety animal model experiment.Used medicine that organon is carried out prescription research to two class medicines on the research method, utilization improvement B ü rgiShi formula, if A, B two the prescriptions solely effect of effect are respectively EA, EB, q=E (A/2+B/2)/(EA+EB)/2, if q〉1.15 for strengthening, q〉0.85 be antagonism, between 0.85～1.15, be addition.
The result shows: the representative medicine (α of two class medicines
2Adrenoceptor agonists methyldopa and tizanidine hydrochloride, 5-HT
1AReceptor stimulating agent buspirone and SM-3997) calm, antidepressant using tangible enhancing is arranged all after the coupling.
1, to the influence of spontaneous activity in mice (calm experiment)
Select 80 Kunming mouses for use, male and female half and half, in Mus 8 weeks of age, body weight 20～22g is divided into 8 groups at random by sex and body weight, and 10 every group, male and female half and half, fasting be can't help water 12 hours before the test, and test arrangement carried out night, and laboratory temperature is controlled at 24～26 ℃.0.5h after the administration measures spontaneous activity in mice.Assay method: after mice put into the complete behavioral activity analyzer of ZL-1 computer control toy and adapt to 1min, measure the movable number of times in its 3min, result's T inspection statistics sees Table 1.
Table 1 shows that methyldopa group, tizanidine hydrochloride group and drug combination group respectively can be obviously or significantly reduced spontaneous activity in mice (P＜0.05 or P＜0.01), have the abirritative effect.
Calculating is 1.24 with the q value that it is right that methyldopa and buspirone are medicine, with tizanidine hydrochloride and the right q value of SM-3997 medicine is 1.42, greater than 1.15, show that methyldopa and buspirone unite to use and have obvious synergistic potentiation, and action intensity all obviously is better than both and uses separately.By contrast, tizanidine hydrochloride and SM-3997 medicine are to being better than methyldopa and the buspirone medicine is right.
The influence of table 1 pair spontaneous activity in mice (x ± SD)
2, the acquired desperate depression model test of mouse tail suspension method
Choose 80 Kunming mouses, be all malely, in 9～10 ages in week of Mus age, body weight 22～24g is divided into 8 groups at random by body weight, presses the listed medicine gastric infusion of table 2 once.30min after each treated animal administration, use rubberized fabric adhere on the pvc pipe of diameter 1cm apart from sharp 1cm place mouse tail, do not make the mouse tail distortion folding, built on stilts then pvc pipe is mice and hangs shape by the feet, head is apart from table top 5cm, separate with dividing plate between per two mices, it is not disturbed mutually, observe the motionless time (stationarity indices is that animal all limbs except that breathing are all motionless) of accumulative total in every animal 6min, result's T inspection statistics the results are shown in Table 2.
Table 2 shows, list all can obviously shorten the interior motionless time (P＜0.05) of accumulative total of mouse tail suspension 6min with tizanidine hydrochloride, SM-3997 and buspirone, (methyldopa/2+ buspirone/2) group and (tizanidine hydrochloride/2+ SM-3997/2) all can significantly shorten the motionless time (P＜0.01) of accumulative total in the mouse tail suspension 6min, and its action intensity and fluoxetine are suitable.
Calculating is 1.43 with the q value that it is right that methyldopa and buspirone are medicine, with tizanidine hydrochloride and the right q value of SM-3997 medicine is 1.69, all greater than 1.15, show that tizanidine hydrochloride and tandospirone unite to use and have obvious synergistic potentiation, and action intensity all obviously is better than both and uses separately.By contrast, tizanidine hydrochloride and SM-3997 medicine are to being better than methyldopa and the buspirone medicine is right.
The influence of table 2 pair mouse tail suspension test
Annotate: each administration group and distilled water group are relatively
*P＜0.05
Test example 2 α
2Adrenoceptor agonists and 5-HT
1AThe medicine of receptor stimulating agent drug combination is to optimization experiment
Unite the optimal drug combination of use in order to probe into α 2 adrenoceptor agonists (tizanidine's or derivatives thereof, methyldopa, clonidine, MPV-1440, mivazerol, rilmenidine etc.) and 5-HT1A receptor stimulating agent (tandospirone or derivatives thereof, buspirone), study by the acquired desperate depression model test of mice forced swimming method, result of study shows, it is right for best compatibility drug that tizanidine hydrochloride and SM-3997 compatibility use, and method and result are as follows:
Choose 140 Kunming mouses, be all malely, in 9～10 ages in week of Mus age, body weight 22～24g is divided into 14 groups at random by body weight, press the listed medicine of table 3 and distinguishes gastric infusion once.30min after each treated animal administration, with the single 2500ml large beaker of only putting into of mice, 25 ℃ of water temperatures, depth of water 10cm, the high 20cm of walls of beaker, diameter 14cm observes the motionless time (stationarity indices is that animal all limbs except that breathing are all motionless) of accumulative total in the back 4min in every animal 6min, and calculates the inhibition percentage rate of respectively organizing medicine.Result's T inspection statistics the results are shown in Table 3.
The result shows that each administration group all can extremely significantly, significantly or obviously reduce the accumulative total dead time (P＜0.001, P＜0.01 or P＜0.05) of forced swimming depression model mice, shows that two class drug combinations all have tangible antagonism.Wherein best with the effect of tizanidine hydrochloride+SM-3997 group, suppress percentage rate and reach 76.09, right far above other compatibility drug, and notable difference (P＜0.05) is arranged.
The influence of table 3 pair mice forced swimming test
Annotate: each administration group and distilled water group are relatively
*P＜0.05
*P＜0.01
* *P＜0.001
Tizanidine hydrochloride and SM-3997 proportioning test in test example 3 medicines of the present invention
For seeking the best proportion compatibility that tizanidine hydrochloride and SM-3997 compatibility use, carried out following test, according to clinical using dosage, safety range and the pertinent literature of two medicines, determined that by the test of pesticide effectiveness tizanidine hydrochloride and SM-3997 proportion research are grouped into 5 proportioning groups such as 1: 20 group, 1: 10 group, 2: 10 groups, 4: 10 groups and 8: 10 groups.Result of study shows 2: 10 groups of most pronounced effects in 5 proportioning groups, so be at 2: 10 best compatibility program.The result is as follows:
1, reserpine causes motion and can not test
Choose 80 Kunming mouses, be all malely, in 8～9 ages in week of Mus age, body weight 18～22g is divided into 8 groups at random by body weight, presses listed medicine of table 4 and dosage gastric infusion every day once, continuous 5 days.Each treated animal is 60min after the last administration, lumbar injection reserpine injection 2.5mg/kg.Injection back 60min is put in the circular filter paper central authorities of diameter 7.5cm with mice, observes the number that still stays in each treated animal in the 30sec in the filter paper.The result the results are shown in Table 4 with Fisher Precision Test statistics.
The result shows that 2: 10 groups, 4: 10 groups and 1: 10 group cause motion to the mice reserpine and can not have remarkable or tangible antagonism (P＜0.01 or P＜0.05), wherein 2: 10 groups of most pronounced effects respectively.
Table 4 pair mice reserpine causes akinetic influence
Annotate: each administration group and distilled water group are relatively
*P＜0.05
*P＜0.01
2, the behavioristics of chronic stress rat depression model test
Orphan of the whole every cages of modeling animal supports, accept 21 days various stress, comprise frozen water swimming (4 ℃, 5min), folder tail (3min), prohibit water (40h), fasting (40h), pairing is raised and moist, constraint and illumination all night stimulate, average every kind stimulates 2～3 times.5 raisings of the every cage of normal rats will not any stimulation.Each administration group is pressed the gastric infusion of medicine shown in the table 5 simultaneously in modeling, continuous 21 days.Adopt the observed behavior of Open-field method.This tests used spacious case is cube, and 25 of being equated by area of high 40cm, length and width 80cm, perisporium, bottom surface form, and divide with white line.Passing through the bottom surface block number with animal is horizontal anomalous movement (crossing) score, serves as vertical movable (rearing) score with upright number of times.Observed in the 22nd day, every zoometry 1 time, each minute is 3min, count level activity score and vertical activity score.Result's T inspection statistics the results are shown in Table 5.
The result shows, the horizontal movement of chronic stress depression model rat and all significantly minimizings (P＜0.01) that moves both vertically, 1: 10 group, 4: 10 groups and 2: 10 groups respectively can be obviously or significantly resist horizontal movement and reduce (P＜0.05 and P＜0.01), obviously or significantly resist the minimizing (P＜0.05 and P＜0.01) that moves both vertically, wherein with 2: 10 groups of most pronounced effects.
The influence of table 5 pair chronic stress depression model rat Open-field judicial act
Annotate: 1. model group matched group and normal control group are relatively
▲ ▲P＜0.01
2. each administration group and normal control group are relatively
*P＜0.05
*P＜0.01
3, elevated plus-maze test (anxiety test)
80 healthy mices are divided into 8 groups at random, and 10 every group, each administration group is pressed the continuous gastric infusion 5d of medicine shown in the table 5,1 time/d, behind the last administration 60min, mice is placed overhead cross labyrinth open portion of central authorities, (overhead cross labyrinth comprises that two are opened arm (long 30cm to head towards closing arm, wide 6cm) closes arm (long 30cm with two, wide 6cm, high 10cm), close the arm opened upper end, there is the open portion of one 5 * 5cm in central authorities, and the labyrinth is high 50cm far from ground).By DigBehv animal behavior analytical system 2.0 automatically in the record 5min animal enter out arm and the number of times that closes arm and opening arm with close in the arm and the labyrinth central area in movement time and move distance.With enter out arm number of times and the percentage of always going into the arm number of times when in opening arm movement time with open the percentage ratio that arm closes the total time in the arm and represent the angst resistance effect index.
The result shows, the diazepam group can be obviously or is significantly increased number of times that mice enters out arm, opens arm holdup time and percentage ratio (P＜0.05 or P＜0.01) thereof, 2: 10 groups and 4: 10 groups respectively can be significantly or obviously increase number of times, the mice that mice enters out arm and opening arm holdup time and percentage ratio thereof (P＜0.01 or P＜0.05), and, has significant angst resistance effect with 2: 10 groups of most pronounced effects.
4, to the influence (anxiety test) of mice cat ladder (the staircase test) behavior
When mice is introduced into a new environment, anxiety reaction can occur, increase as the Vigilance behavior.The index of cat ladder behavior evaluation exploratory behavior or activeness, upright then as the parameter of anxiety state, antianxiety drug makes the number of standing reduce under the dosage that does not reduce the cat ladder number.
70 of mices, male and female half and half are divided into 7 groups at random by body constitution amount, sex equilibrium, press the gastric infusion of medicine shown in the table 6, and 30min places the bottom of case with mice after the administration, and the back of the body is taken the mice behavior towards stair with DV, and the experimenter leaves to reduce and disturbs.The mice cat ladder number (all climbing up stair with extremity is as the criterion) and the number of standing in the record 3min.Experimentize under the 18:00～21:00 point red light every day, and every zoopery finishes back cleaning experimental box rapidly, to get rid of the interference of olfactory sensation hint to next animal.
The result shows, though each administration group cat ladder number reduces but does not have significant difference, and 1: 10,2: 10 groups and 4: 10 groups can obviously, significantly and obviously reduce the number (P＜0.05, P＜0.01 and P＜0.05) of standing respectively, and with 2: 10 groups of most pronounced effects, prompting has significant angst resistance effect.
The influence of table 7 pair mice cat ladder behavior
Annotate: each administration group and normal control group are relatively
*P＜0.05
*P＜0.01
To sum up, the present invention uses two class compatibility of drugss, especially preferred tizanidine hydrochloride and SM-3997, all can reach the effect of Synergistic at 1: 10 to 4: 10, and best results during with 2: 10 weight proportions, and side effect is low, and onset is steady, solved and be difficult to the problem that overcomes at present, provide a kind of new selection for clinical.
Claims (7)
1. the α of effective dose
2Adrenoceptor agonists is used for 5-HT with effective dose in preparation
1AReceptor stimulating agent together administration be used for anxiety or/and the purposes of antidepressant medicament, wherein, described α
2Adrenoceptor agonists and 5-HT
1AThe weight proportion of receptor stimulating agent is: α
2Adrenoceptor agonists 0.2-125 part, 5-HT
1A5～16 parts of receptor stimulating agents;
Described α
2Adrenoceptor agonists is tizanidine hydrochloride, methyldopa, clonidine, MPV-1440, mivazerol, rilmenidine; Described 5-HT
1AReceptor stimulating agent is SM-3997, buspirone.
2. purposes according to claim 1 is characterized in that: described tizanidine hydrochloride and SM-3997, its weight proportion is: 1～4 part of tizanidine hydrochloride, 5～40 parts of SM-3997.
3. purposes according to claim 2 is characterized in that: the weight proportion of described tizanidine hydrochloride and SM-3997 is: 2: 10.
4. an anxiety is or/and antidepressant pharmaceutical composition, and it is the α by effective dose
2The 5-HT of adrenoceptor agonists and effective dose
1AReceptor stimulating agent is the medicament that feedstock production forms, wherein, and α
2Adrenoceptor agonists and 5-HT
1AThe weight proportion of receptor stimulating agent is: α
2Adrenoceptor agonists 0.2-125 part, 5-HT
1A5～16 parts of receptor stimulating agents;
Described α
2Adrenoceptor agonists is tizanidine hydrochloride, methyldopa, clonidine, MPV-1440, mivazerol, rilmenidine; Described 5-HT
1AReceptor stimulating agent is SM-3997, buspirone.
5. anxiety according to claim 4 or/and antidepressant pharmaceutical composition it is characterized in that: described tizanidine hydrochloride, SM-3997, its weight proportion is: 1～4 part of tizanidine hydrochloride, 5～40 parts of SM-3997.
6. anxiety according to claim 5 or/and antidepressant pharmaceutical composition it is characterized in that: the weight proportion of described tizanidine hydrochloride and SM-3997 is: 2: 10.
According to any described anxiety of claim 4-6 or/and antidepressant pharmaceutical composition it is characterized in that: described pharmaceutical preparation is: tablet, capsule, granule, oral liquid, packaged preparation, gastric retention agent.
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| CN2007100748309A CN101318020B (en) | 2007-06-06 | 2007-06-06 | Anti-anxiety or/and dumps medicament composition and uses thereof |
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| CN101318020B true CN101318020B (en) | 2011-09-28 |
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| CN101780075B (en) * | 2009-01-16 | 2013-10-30 | 四川科瑞德制药有限公司 | Combined drug for treating insomnia |
| PT3160464T (en) * | 2014-06-26 | 2018-10-12 | Contera Pharma Aps | 6-hydroxybuspirone for use in the treatment of movement disorders |
| RU2736713C1 (en) * | 2019-12-02 | 2020-11-19 | Общество С Ограниченной Ответственностью "Валента - Интеллект" | Combination of mirtazapine and tizanidine for use in pain disorders |
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| US4788189A (en) * | 1988-02-29 | 1988-11-29 | Glazer Howard I | Method to treat smoking withdrawal symptoms by potentiated central noradrenergic blocking |
| CN1284066A (en) * | 1997-12-04 | 2001-02-14 | 阿勒根销售公司 | Substituted inidazole derivatives having agonist-like activity at alpha 2B or 2B/2C adrenergic receptors |
| CN1319013A (en) * | 1998-09-21 | 2001-10-24 | 辉瑞产品公司 | Pharmaceutical agents for treatment of parkinson's diseae, ADHD and microadenomas |
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| US4788189A (en) * | 1988-02-29 | 1988-11-29 | Glazer Howard I | Method to treat smoking withdrawal symptoms by potentiated central noradrenergic blocking |
| CN1284066A (en) * | 1997-12-04 | 2001-02-14 | 阿勒根销售公司 | Substituted inidazole derivatives having agonist-like activity at alpha 2B or 2B/2C adrenergic receptors |
| CN1319013A (en) * | 1998-09-21 | 2001-10-24 | 辉瑞产品公司 | Pharmaceutical agents for treatment of parkinson's diseae, ADHD and microadenomas |
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Address after: 646000 national high tech Zone, Sichuan, Luzhou Province Pharmaceutical Industrial Park Patentee after: Sichuan Keruide pharmaceutical Limited by Share Ltd Address before: 646106 Industrial Park, Fu Zhen Town, Luzhou, Sichuan, Luxian County Patentee before: Keruide Pharmaceutical Co., Ltd., Sichuan |