CN1843353A - Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases - Google Patents

Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases Download PDF

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CN1843353A
CN1843353A CN 200610035364 CN200610035364A CN1843353A CN 1843353 A CN1843353 A CN 1843353A CN 200610035364 CN200610035364 CN 200610035364 CN 200610035364 A CN200610035364 A CN 200610035364A CN 1843353 A CN1843353 A CN 1843353A
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mptp
neuron
preventing
test
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CN100475205C (en
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王文雅
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Southern Medical University
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Southern Medical University
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Abstract

The invention relates to the use of AR-AO14418 in preparing medicament for preventing and treating nerve retrogression diseases, wherein the medicament comprises AR-AO14418 and medically acceptable auxiliary materials, wherein the AR-AO14418 can be bonded with the ATP bonding points of the GSK-3 beta, inhibiting GSK-3 beta activity, and preventing hepatocyte nerve.

Description

The application of AR-A014418 in preparation control neurodegenerative diseases medicine
Technical field:
The present invention relates to a kind of medicine of preventing and treating neurodegenerative diseases, be specifically related to the application of AR-A014418 in preparation control neurodegenerative diseases medicine.
Background technology:
Neurodegenerative diseases is meant that the neuron generation degeneration of human body changes and a series of diseases of causing are mainly in elderly population, has influenced people's quality of life greatly.Wherein parkinson disease (Parkinson ' s disease, PD) and senile dementia (Alzheimer ' s disease AD) is two kinds of the most common neurodegenerative diseases.Because of Neuron Apoptosis causes neuron loss is the main pathological characters of neurodegenerative diseases, but for a long time, owing to can not find clear and definite drug target, people can only adopt the method for " taking stopgap measures " to treat this class disease, replenish the material of patient's cerebral neuron scarcity by the chemicals of taking or intravenous injection is specific.For example the sings and symptoms of PD can be enhanced the agents alleviate of dopamine function, and wherein the most effective medicine is a levodopa.But levodopa can not be controlled the natural pathological changes process of PD effectively, and also has bad side effect, for example the on-off phenomenon and the dyskinesia.More disappointed is that the therapeutical effect of levodopa can only be kept about 2 years.If life-time service, levodopa also can damage neuron, the apoptosis of accelerator nerve unit; And for example, at acetylcholine deficiency in the AD brain, improve its concentration with cholinesterase inhibitor.But, similarly, owing to can not stop neuronic losing, so also uncontrollable advancing of disease.Therefore, aspect the control neurodegenerative diseases, finding a kind of action target spot medicine clear and definite, that can effectively stop neuron loss, effective control disease to develop is the target that people are pursued for a long time.
AR-A014418 is that N-(4-Methoxybenzyl)-N '-(its chemical structural formula is for 5-nitro-1,3-thiazol-2-yl) urea (N-(4-methoxybenzyl)-N '-(5-nitro-1,3-thiazoles-2-hydrocarbon)) AR-A014418 is a kind of 1,3-sulfur pyrrole compounds, room temperature is white solid down, be slightly soluble in water, dissolubility in dimethyl sulfoxine is 5mg/ml, the interior specific inhibitor as glycogen synthase kinase-3 β (GSK-3 β) of the laboratory of being everlasting at present is applied to the research of apoptotic signal transduction path, also makes the research work for the treatment of depression on animal model.
Summary of the invention:
GSK-3 β is the convergent point (convergence site) of mediation Neuron Apoptosis multi-path, it shows as activity level and raises in multiple neurodegenerative diseases, being the key kinases of Neuron Apoptosis, is the ideal drug target of neurodegenerative diseases treatment.The present inventor discovers that AR-A014418 can effectively suppress the activity of glycogen synthase kinase-3 β (GSK-3 β) in the neuron, has the effect that stops Neuron Apoptosis.
Therefore, the object of the present invention is to provide the application of AR-A014418 in pharmacy.
The present invention relates to the application of AR-A014418 in preparation control neurodegenerative diseases medicine.
The present invention is specifically related to AR-A014418 and prevents and treats application in parkinson disease or the alzheimer disease disease drug in preparation.
Application of the present invention is to contain the AR-A014418 and the pharmaceutical composition of acceptable pharmaceutical adjunct medically.
Described AR-A014418 can pass through gastrointestinal absorption, be easy to pass through blood brain barrier, thereby can adopt peroral dosage form as making tablet, granule, capsule, and also can make injection, can also make transdermal absorption formulation such as membrane, Emulsion, suspending agent etc.AR-A014418 and acceptable pharmaceutical adjunct medically make above-mentioned various preparation according to the formulation method of routine, can also make compound preparation with levodopa, to alleviate the infringement of levodopa to the nigrostriatum dopaminergic neuron.Described AR-A014418 can directly buy from Calbiochem company, purity 〉=95%.
Described injection can restrain with 0.9~1.1 in AR-A014418 and water for injection: the ratio uniform mixing of 90~110ml makes, preferred proportion 1.0 gram: 100ml.
Described capsule can be made by the AR-A014418 of 36~44 weight portions and the adjuvant uniform mixing of following weight portion:
Calcium hydrogen phosphate 36~44
HPMC4000cp 7.2~8.8
HPMC100cp 7.2~8.8
EC100cp 1.8~2.2
Magnesium stearate 0.9~1.1
Pulvis Talci 0.9~1.1
Described capsule optimum ratio (weight portion) is:
AR-A014418 40
Calcium hydrogen phosphate 40
HPMC4000cp 8
HPMC100cp 8
EC100cp 2
Magnesium stearate 1
Pulvis Talci 1
Described tablet can get by following component (weight portion) is mixed:
AR-A014418 18~22
Starch 5.4~6.6
Citric acid 0.18~0.22
10% starch slurry is an amount of
1% magnesium stearate is an amount of
The optimal proportion of described tablet (weight portion) is:
AR-A014418 20
Starch 6
Citric acid 0.2
10% starch slurry is an amount of
1% magnesium stearate is an amount of
Described cutaneous permeable agent can be made by following component (weight portion):
AR-A014418 45~55
Stearic acid 135~165
White vaseline 90~110
Glyceryl monostearate 77~93
Glycerol 68~82
Tween 80 27~33
Ethylparaben 0.9~1.1
Distilled water is an amount of
The content that makes AR-A014418 in the last preparation is 4~6%
Optimal proportion (weight portion) is:
AR-A014418 50
Stearic acid 150
White vaseline 100
Glyceryl monostearate 85
Glycerol 75
Tween 80 30
Ethylparaben 1
Distilled water is an amount of
The content that makes AR-A014418 in the last preparation is 5%
Described AR-A014418 can also make compound preparation with levodopa, and component (weight portion) is:
AR-A014418 18~22
Levodopa 36~44
Starch 5.4~6.6
Citric acid 0.18~0.22
10% starch slurry is an amount of
1% magnesium stearate is an amount of
Optimal proportion (weight portion) is:
AR-A014418 20
Levodopa 40
Starch 6
Citric acid 0.2
10% starch slurry is an amount of
1% magnesium stearate is an amount of
The using dosage of AR-A014418 of the present invention is: oral dose 1~10mg/kg every day body weight; Injected dose reduces half.
The mechanism of action of control neurodegenerative diseases medication medication of the present invention is: adenosine triphosphate (ATP) competition of AR-A014418 and GSK-3 β, tied up the binding site of ATP, thereby make GSK-3 β lose the energy supply, the activity that has suppressed GSK-3 β, stop Neuron Apoptosis, reach the purpose of control neurodegenerative diseases.
AR-A014418 involved in the present invention is preparing the application that prevents and treats in the neurodegenerative diseases medicine, can not only suppress the activity of GSK-3 β effectively, stop Neuron Apoptosis, and action target spot is clear and definite, so determined curative effect and remarkable.
Description of drawings:
Fig. 1 for AR-A014418 to the resistant function design sketch of losing of the inductive midbrain veutro of MPP+ dopaminergic neuron (amplify: 40 *), wherein a is the solvent control group, b is 10 μ M MPP+ processed group, c is that 10nM AR-A014418 does not have influence to the toxicity of MPP+, d and e are 0.1,1.0 μ M AR-A014418 has saved the TH positive cell, f is that 10 μ MAR-A014418 have certain toxicity (* 200) to neuron;
Fig. 2 is the amount effect curve figure of AR-A014418 to the protective effect of TH-positive cell.
Fig. 3 for AR-A014418 to the resistant function design sketch of losing of the inductive substantia nigra dopaminergic neuron of MPTP (amplify: 40 *), wherein (a) is the solvent control group, (b) be the MPTP processed group, (c) be MPTP and 3mg/kg AR-A014418 processed group, (d) being MPTP and 10mg/kg AR-A014418 processed group, (e) is MPTP and 30mg/kg AR-A014418 processed group;
The protective effect design sketch of dopaminergic neuron in Fig. 4 is AR-A014418 in the experiment of parkinson model mouse to substantia nigra of midbrain.
Fig. 5 is the amount effect curve figure of AR-A014418 to the substantia nigra dopaminergic neuron protective effect.
Fig. 6 is the test result figure of behavioristics the tenth day Mus that experimentizes in MPTP last injection back.
The specific embodiment:
Below by pharmacology and effect experiment further specify AR-A014418 to the control neurodegenerative diseases beneficial effect.
Test the resistant function of an AR-A014418 to the outer dopaminergic neuron apoptosis of MPP+ inductor
MPP+ is 1-methyl-4-phenyl-pyridinium ion, to be MPTP have a toxic metabolite through what monoamine oxidase-B was transformed into to MPP+, to the DOPA aminergic neuron, it has the effect of high-affinity, selectivity murder by poisoning to substantia nigra dopaminergic neuron through the dopamine carrier transport.
1. get pregnant 14 days rat, use CO 2The back cervical vertebra dislocation that suffocates causes death.Aseptic condition takes out the uterus down, cleans with ice D-Hank balanced salt solution (Hyclone company), again through 75% ethanol bathing 30s, places the plate that fills ice D-Hank liquid.Take out the embryo, check down that in anatomic microscope the top buttocks of tire Mus is 10-12mm apart from (CRL), place the plate that fills ice D-Hank liquid stand-by.Pass through the midbrain chirring partial application of face with dissecting knife from eyes up to veutro; The rolling fetus makes it dorsad down, dispels forebrain from brain stem, and exposed side ventricular system and it are as the extension at brain stem of ventriculus tertius and cerebral aqueduct; Cut the ventricles of the brain that cut off both sides to the back side with separation, then caudad is cut a cutter, cuts a cutter again in the bottom of midbrain gauffer; (ventralmesencephalon, remnants VM) have just separated with other parts of brain the veutro midbrain.After with tweezers top meninges being removed isolating VM being put into another is equipped with cold dissection liquid (500ml contains sodium chloride 36.25g, potassium chloride 2g, NaH 2PO 42H 2O0.91g, glucose 13g, phenol red 50mg, HEPES 29.7g, pH 7.4) ware in.Peel off meninges, add 0.1% pancreatin solution (must preheating in 37 ℃ of baths) 20ml, 37 ℃ of DNA enzyme and pancreatin inhibitor cessation reactions that add the 10ml preheating down behind the digestion 15min with histotome chopping tissue back.Inhale behind the centrifugal 5min of 1500rpm and remove supernatant, add broken liquid 15ml (contain 1.2mg DNase I, the 7.8mg pancreatin inhibitor, 15ml dissects liquid, 150 μ l 3.82%MgSO 4); Blow and beat gently 10 times with suction pipe, make cell suspension.Leave standstill 15min, supernatant (be about cumulative volume 9/10) is drawn in another test tube.The centrifugal 5min of 1500rpm is with culture medium diluting cells suspension to 5 * 10 5Individual/ml.With cell suspension inoculation in 24 orifice plates (every hole 0.5ml) with poly-D-lysine bag quilt in advance.Put 37 ℃, 5%CO 2Cultivate in the incubator, in culture fluid, add 5 μ M cytosine arabinosides (Ara-C) after 24 hours to suppress the glial cell growth.Changed culture fluid one time, and under inverted phase contrast microscope, dynamic observed the cell growing state in per 3 days.So related preparations is all available from Sigma company.
2. the dopaminergic neuron with In vitro culture is divided into 3 experimental grouies (MPP+ group, AR-A014418 group and matched group), the AR-A014418 experimental group is divided into 6 concentration groups again, add 1000 times of AR-A014418 storage liquid of 0.5 μ l respectively, make final concentration be respectively 10nM, 100nM, 1 μ M, 5 μ M, 10 μ M and 20 μ M; MPP+ group and matched group add the dimethyl sulfoxide (DMSO) of equal-volume (0.5 μ l).After 2 hours, MPP+ group and AR-A014418 group add the MPP+ (final concentration is 10 μ M) of 0.5 μ l 10mM, and matched group adds in the equal-volume solvent.After 48 hours, cell fixation is made the immunocytochemical stain of tyrosine hydroxylase (TH), observes the quantity of dopaminergic neuron.Found that there are 12 TH-positive cells in every high power (20 *) visual field in the matched group, dopaminergic neuron quantity significantly reduces in the MPP+ group, and there are 6 TH-positive cells in every high power (20 *) visual field; In the AR-A014418 group, 100nM, 1 μ M, 5 μ M and 10 μ M concentration group TH-positive cell showed increased illustrate that AR-A014418 has very strong resistant function (see figure 1) to the outer dopaminergic neuron apoptosis of MPP+ inductor.Amount effect curve shows that AR-A014418 presents tangible dose dependent to neuronic protective effect, the r=0.9918 (see figure 2).
Fig. 1 a and b are compared as can be seen: after MPP+ used, black substance TH positive cell obviously reduced, and can find out from Fig. 1 f: but AR-A014418 concentration dependent ground increases black substance TH-positive cell number.
Test two AR-A014418 to the inductive parkinsonian therapeutical effect of MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) are a kind of white powder neurotoxins, can destroy dopaminergic nerve cell specifically, thereby nigrostriatum path in the infringement brain makes people and animal symptoms of Parkinson's Disease occur.
1. choose male C 57100 of BL type black rats are divided into normal saline group (NS group), MPTP group and three AR-A014418+MPTP groups (AR group, branch 3,10, three dosage groups of 30mg/kg), 20 every group at random.Be made into the MPTP solution that concentration is 6mg/ml with normal saline.Tested first day, the AR group is lumbar injection 0.3mg/ml, 1mg/ml, 3mg/mlAR-A01441810ml/kg respectively, and NS group and MPTP organize equal lumbar injection 3%DMSO 10ml/kg; AR organized first lumbar injection AR-A014418 (dosage is all with first day) in second day, all the other group lumbar injection 3%DMSO 10ml/kg.AR group and MPTP organize lumbar injection 6mg/ml MPTP 5ml/kg together behind the 30min, the normal saline of capacity such as NS group lumbar injection, continuous 5 days (totally 6 days).
2. injected the back the 7th day at the MPTP last, every experimental group is got two mices, uses 10% chloral hydrate anesthesia, goes into aorta from the left ventricle inserting needle, pours into each 50ml of blood vessel flushing liquor and 4%PFA successively.Blood vessel flushing liquor composition is: PBS 1000ml, 1%NaNO 22ml, heparin 0.02g and NaCl9g;
3 mices broken end is got full brain, and soaking at room temperature is 2 hours in 4%PFA, is transferred in 30% sucrose solution, leaves standstill 12 hours under 4 ℃ of conditions;
4. cut the brain sheet of 35 μ m with freezing microtome in the black substance compact part, be suspended in the PBS liquid in 24 orifice plates.Get the SABC that a slice is tyrosine hydroxylase (TH), the situation of remaining dopaminergic neuron in the observation black substance every 5.Injected the back the 10th day at the MPTP last, the mice of each experimental group is after having finished ethological detection, and the cervical vertebra dislocation causes death.Get full brain, boil in the boiling water after 2 minutes and peel off striatum carefully, weigh, be stored in-70 ℃, prepare to utilize DOPAMINE CONTENT IN RABBIT in the high-efficient liquid phase analysis striatum.
Observation index: the remaining dopaminergic neuron counting of black substance, striatum DOPAMINE CONTENT IN RABBIT and ethological scoring.
(1) AR-A014418 induces losing of substantia nigra dopaminergic neuron to have very strong antagonism to MPTP
Inject the back the 7th day at the MPTP last, detect the number of remaining dopaminergic neuron in the black substance with the ABC method.The result shows: contrast with group of solvents; after the MPTP injection; black substance TH positive cell obviously reduces; illustrate that MPTP causes the losing in a large number of dopaminergic neuron in the black substance (being Fig. 3 (a) and (b) contrast); about only 57.06 ± 6.35 (P<0.01) (seeing Fig. 1 f) of residual matched group; and AR-A014418 has obviously reduced losing because of the caused dopaminergic neuron of MPTP toxicity; and but concentration dependent ground increase black substance TH-positive cell number (is seen Fig. 3 (c); (d); (e)); the protective effect that AR-A014418 is described is typical dose dependent, the r=0.9857 (see figure 5).In the 30mg/kg of AR-A014418 dosage group, the number of dopaminergic neuron and normal saline group is close in the black substance, has promptly reached normal level (seeing Fig. 3 (e)).Fig. 4 show AR-A014418 10 and can obviously protect during the concentration of 30mg/kg MPTP induce dead TH-positive cell ( *P<0.01, the AR-A014418 group is compared with the MPTP group).
(2) AR-A014418 has improved the striatum levels of dopamine that is reduced by MPTP
Inject the back the tenth day at the MPTP last, detect the concentration of dopamine in the striatum.(0.70 ± 0.22ng/mg) compares, and MPTP has caused the decline significantly of striatum dopamine concentration, has only 0.21 ± 0.06ng/mg (P<0.01) with the normal saline group; And AR-A014418 can concentration dependent ground improves the content (table 1) of striatum dopamine, and AR-A014418 3,10,30mg/kg make dopamine concentration rise to 0.33 ± 0.05 (P<0.01), 0.40 ± 0.14 (P<0.05) and 0.54 ± 0.12 (P<0.01) respectively.r=0.9857。
AR-A014418 has improved the striatum dopamine concentration that MPTP reduces
Handle The example number Striatum dopaminergic concentration (ng/mg)
Normal saline group MPTP 30mg/kg AR-A0144183mg/kg AR-A01441810mg/kg AR-A01441830mg/kg 15 6 6 6 6 0.70±0.22 0.21±0.06 * 0.33±0.05 ** 0.40±0.14 *** 0.54±0.12 ***
Injected the back the tenth day at the MPTP last, measure the striatum dopamine concentration with high performance liquid chromatogram, data are compared with the solvent control group with the formal representation of meansigma methods ± standard error, *P<0.01; Compare with the MPTP processed group, *P<0.01, * *P<0.05.
(3) it is unusual that AR-A014418 has improved the behavioristics of PD mice
Injected the back the tenth day at the MPTP last, the PD mice is implemented behavioristics check.The scope of examination is pole-jump test (pole test) and hangs experiment (traction test).
1. pole-jump test (pole test):
Purpose: detect the mice limb motion and coordinate situation.
Method: with a diameter is the rod top that 2.5 centimetres cork bead is fixed in 1 centimetre of long 50 cm diameter, be wrapped with gauze on the rod with anti-slip, then tested mice is put on the bead, and writes down the following time: the time that mice stops in heading; Mice has climbed the used time of the first half of pole; Mice has climbed the used time of the latter half of pole.Then by the score of following standard: the note 3 minutes of finishing above-mentioned a certain action in 3 seconds; The note of finishing in 6 seconds 2 minutes; Note above 6 seconds 1 minute.Calculate three cumulative score situations at last, and the credit that takes statistics is analysed.The enforcement of pole-climbing experiment and scoring are according to the carrying out of methodology introduction, and data are represented with the form of meansigma methods ± standard error.Compare with the solvent control group: *P<0.01; Compare with the MPTP experimental group: *P<0.01.
2. hang experiment (traction test):
Purpose: detect the mice limb motion and coordinate situation.
Method: will be tried mice two fore paws and be suspended from the horizontal wire, and catch electric wire then to remember 3 fens with two rear solid ends as mice; As catching electric wire then to remember 2 fens with a rear solid end.If mice two rear solid ends are all grabbed incessantly electric wire then are remembered 1 fen, the situation that counts the score at last, and the credit that takes statistics is analysed.
Experimental result: in pole-jump test, the first half and used time of the latter half that control group mice has been climbed pole were respectively 2.61 seconds and 3.94 seconds; MPTP group mice has then been used 7.21 seconds respectively and 8.63 seconds (P<0.01).Compare with the MPTP group, three groups of AR-A014418+MPTP obviously will lack the used time, wherein the used time very close with matched group (seeing Table 2) of 10mg/kg dosage group.In hanging test, control group mice is caught electric wire with extremity, and MPTP group mice can only catch electric wire with fore paw, and rear solid end is unable; Though the rear solid end that the mice that AR-A014418 handles has still moves and is obstructed, and can catch electric wire with a rear solid end at least, show that the hind leg motion makes moderate progress.
The behavioristics that table 2. AR-A014418 has improved MPTP processing Mus is unusual
Handle The example number The pole-jump test scoring The hanging test scoring
Matched group MPTP 30mg/kg AR-A0144183mg/kg AR-A01441810mg/kg AR-A01441830mg/kg 7 7 7 7 7 7.6±0.7 4.8±1.3 * 6.8±1.2 ** 7.4±0.9 ** 7.6±1.4 ** 3.0±0.0 1.4±0.3 * 2.1±0.8 ** 2.6±0.5 ** 2.5±0.5 **
Inject behavioristics's test of back ten days Mus that experimentize at the MPTP last.The enforcement of pole-jump test and hanging test and scoring are according to the carrying out of methodology introduction, and data are represented with the form of meansigma methods ± standard error.Compare with matched group *P<0.01; Compare with the MPTP experimental group, *P<0.01 (see figure 6).
Test the acute toxicity testing of three AR-A014418:
By national medicine management regulation, with Kunming kind closed colony healthy mice, body weight 20.0 ± 0.5g, each 25 of male and female, Zhongshan Medical Univ.'s animal center provides.Be divided into five groups at random, each 5 of male and female, oral administration is irritated the disposable administration of stomach, and dosage is respectively 1,10,100,1000,5000mg/kg, and record mouse toxicity response situation and dead animal distribute, and measure LD with the Bliss statistic law 50Value.LD 50Be about 2200mg/kg, 95% credibility interval is 1943~2457mg/kg; Therapeutic index is about 90.Experimental result shows: AR-A014418 toxicity is low, and safety is good.
Test the long term toxicity test of four AR-A014418:
Laboratory animal: Wistar rat, 6 ages in week, 100~120g, 80, male and female half and half.
Experimental technique: rat is divided into 4 groups at random, every group each 20, male and female half and half are divided into matched group and three experimental grouies (30mg/ day, 90mg/ day 270mg/ day, irritating stomach).The disposable celiac injection was observed 90 days continuously.
Detection method: (1) animal generally shows.(2) routine blood test and blood biochemistry index.Hemoglobin, erythrocyte, leukocyte and classification.The transaminase, blood urea nitrogen, creatinine, cholesterol, triglyceride, blood glucose, total protein, albumin.(3) pathological examination: liver, kidney, stomach, testis, ovary.
Experimental result:
(1) rat appetite, growth promoter are not had influence, the same with matched group, weight increase, growth curve are for increasing progressively state, and hair is bright and clean, do not have depilation, and skin health is movable normal, with matched group relatively, no group difference, P value>0.05.
(2) every prescriptions such as rat urine, blood, biochemistry all in range of normal value, compare no group difference, P value>0.05 with matched group.
(3) each organ such as the heart of rat, liver, spleen, lung, kidney is not caused organic change.
Long term toxicity test is the result show: AR-A014418 toxicity is little, and is safe in utilization.
Below be specific embodiment, but the present invention is limited only within these scope of embodiments with AR-A014418 preparation control neurodegenerative diseases medicine.
The preparation of embodiment one injection
Take by weighing 10 gram AR-A014418, be dissolved in 1000 milliliters of waters for injection, dissolving, supermicro filtration membrane filter, and promptly making concentration is the injection of 1 gram/100 milliliters (1%), sterilization, packing.
To Parkinsonian and senile dementia patient: the dosage of subcutaneous injection, intramuscular injection, slow quiet notes is all identical, a 50~100mg, 2~3 times on the one.
The preparation of embodiment two tablets
Prescription: AR-A014418 20g
Starch 6g
Citric acid 0.2g
10% starch slurry is an amount of
1% magnesium stearate is an amount of
The 0.2g citric acid is dissolved in 10% starch slurry of 20ml.Get proportional quantity AR-A014418, starch mix homogeneously, add the 10% starch slurry system soft material that contains citric acid in right amount, cross 16 mesh sieves and granulate, with wet granular in 40-60 ℃ of drying; 16 mesh sieve granulate, add an amount of 1% magnesium stearate after tabletting form every tablet of tablet that contains 100mg AR-A014418.
To Parkinsonian and senile dementia patient: oral 1 day 0.5~1.0g, divide to give for 2~4 times.
The preparation of embodiment three slow releasing capsulees
Prescription: AR-A014418 10g
Calcium hydrogen phosphate 10g
HPMC4000cp 2g
HPMC100cp 2g
EC100cp 0.5g
Magnesium stearate 0.25g
Pulvis Talci 0.25g
Composition that capsule comprises and percentage by weight are: AR-A01441840%, and calcium hydrogen phosphate 40%, HPMC-4000cp 8%, and HPMC100cp 8%, and EC100cp 2%, magnesium stearate 1%, Pulvis Talci 1%.Its preparation method is: proportional quantity AR-A014418, calcium hydrogen phosphate, HPMC4000cp, HPMC 100cp and EC 100cp are crossed 60 orders~100 mesh sieves respectively, put the mixer mixing, adding concentration is that 50%~75% alcohol is made soft material as wetting agent and stirring, crossing 14 orders~20 mesh sieves granulates, 50 ℃~60 ℃ dryings of granule, 14 orders~20 mesh sieve granulate add magnesium stearate and Pulvis Talci again, and mixing, encapsulated, packing promptly get each capsule that contains 100mg AR-A014418.
To Parkinsonian and senile dementia patient: oral 1 day 0.5~1.0g, divide to give for 2~4 times.
The preparation of embodiment four Emulsions
Prescription:
AR-A014418 50g
Stearic acid 150g
White vaseline 100g
Glyceryl monostearate 85g
Glycerol 75g
Tween 80 30g
Ethylparaben 1g
Distilled water is an amount of
Make 1000g
AR-A014418, stearic acid, white vaseline and glyceryl monostearate are put the fusing of container internal heating, in addition glycerol, tween 80, ethylparaben and distilled water are heated to whole dissolvings.Keeping about 70 ℃ of temperature, biphase mixing is stirred to condensation, promptly gets the Emulsion of content 5%.
To Parkinsonian and senile dementia patient: external, an amount of, every day 2~4 times.
Embodiment five makes compound preparation with the levodopa compatibility
Prescription: AR-A014418 20g
Levodopa 40g
Starch 6g
Citric acid 0.2g
10% starch slurry is an amount of
1% magnesium stearate is an amount of
The 0.2g citric acid is dissolved in 10% starch slurry of 20ml.Get recipe quantity AR-A014418, levodopa, starch mix homogeneously, add the 10% starch slurry system soft material that contains citric acid in right amount, cross 16 mesh sieves and granulate, with wet granular in 40-60 ℃ of drying; 16 mesh sieve granulate, add an amount of 1% magnesium stearate after tabletting form every tablet of tablet that contains 50mg AR-A014418 and 100mg levodopa.
To Parkinsonian and senile dementia patient: oral 1 day 0.75~1.5g, divide to give for 2~4 times.

Claims (4)

1, the application of AR-A014418 in preparation control neurodegenerative diseases medicine.
2, the described application of claim 1 is characterized in that AR-A014418 prevents and treats application in the parkinson disease medicine in preparation.
3, the described application of claim 1 is characterized in that AR-A014418 prevents and treats application in the alzheimer disease disease drug in preparation.
4, claim 1,2 or 3 described application is characterized in that containing the AR-A014418 and the pharmaceutical composition of acceptable pharmaceutical adjunct medically.
CNB2006100353649A 2006-05-08 2006-05-08 Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases Expired - Fee Related CN100475205C (en)

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Application Number Priority Date Filing Date Title
CNB2006100353649A CN100475205C (en) 2006-05-08 2006-05-08 Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases

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Application Number Priority Date Filing Date Title
CNB2006100353649A CN100475205C (en) 2006-05-08 2006-05-08 Use of AR-A014418 in preparing medicine for preventing and treating nerve degenerative diseases

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107519166A (en) * 2017-08-29 2017-12-29 贵州医科大学附属医院 A kind of application of beta inhibitors of GSK 3 on the medicine for the treatment of atherosclerosis

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107519166A (en) * 2017-08-29 2017-12-29 贵州医科大学附属医院 A kind of application of beta inhibitors of GSK 3 on the medicine for the treatment of atherosclerosis

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