CN103610681A - Pharmaceutical composition capable of treating alzheimer's disease - Google Patents
Pharmaceutical composition capable of treating alzheimer's disease Download PDFInfo
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- CN103610681A CN103610681A CN201310637561.8A CN201310637561A CN103610681A CN 103610681 A CN103610681 A CN 103610681A CN 201310637561 A CN201310637561 A CN 201310637561A CN 103610681 A CN103610681 A CN 103610681A
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- galantamine
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- meclofenoxane
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Abstract
本发明公开了一种复方药物对阿尔茨海默病的治疗作用。此复方药物由加兰他敏和氯酯醒组成，2药联用配伍的剂量比例为（0.5-4）∶（17.5-70），最佳的配伍比例为2∶35，在此配伍情况下，加兰他敏和氯酯醒合用对记忆获得障碍、记忆巩固障碍和记忆再现障碍具有明显的改善作用。同时此复方药物可以通过延缓脑老化、减少脑内淀粉样沉积以及保护胆碱能神经元等多方面达到预防和治疗阿尔茨海默病的作用。提示加兰他敏和氯酯醒合用能够改善学习记忆以及预防和治疗阿尔茨海默病。The invention discloses the therapeutic effect of a compound medicine on Alzheimer's disease. This compound drug is composed of galantamine and chlorpheniramine. The dosage ratio of the combination of the two drugs is (0.5-4): (17.5-70), and the best compatibility ratio is 2:35. In this case, The combined use of galantamine and chlorpheniramine can significantly improve the impairment of memory acquisition, memory consolidation and memory reproduction. At the same time, the compound drug can prevent and treat Alzheimer's disease by delaying brain aging, reducing amyloid deposition in the brain and protecting cholinergic neurons. It is suggested that the combined use of galantamine and chlorpheniramine can improve learning and memory as well as prevent and treat Alzheimer's disease.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that can prevent and treat Alzheimer.More specifically, relate to the pharmaceutical composition that formed by galantamine and meclofenoxane.
Background technology
Alzheimer (Alzheimer ' disease, AD) is senile dementia, be a kind of the geratic period occur take the neuron degenerative disease that progressive dementia is principal character.Its main clinical manifestation is carrying out property cognitive dysfunction and hypomnesis, personality and behavior change, judgment declines, human communication disorders, self care ability is lost, final dead, be the fourth-largest killer after cardiovascular disease, cancer and apoplexy, old people's healthy and quality of life in serious harm.World Health Organization (WHO) has been decided to be AD one of five large focal diseases of 21 century.Although the definite cause of disease of AD still imperfectly understands, but cholinergic nerve damage hypothesis is widely accepted at present, in AD patient's brain obviously there is cholinergic neuron loss in Hippocampus and neopallium, acetylcholine (the cholinesterase that causes synapse position, Ach) level declines, affect people's short-term attention and memory, research shows that Ach plays an important role in AD morbidity.
Galantamine is acetylcholine esterase (acetylcho1inesterase, AChE) inhibitor, is used for the treatment of light, moderate AD, and clinical effective rate is 50%～60%.Result of study shows, as the galantamine of second filial generation cholinesterase inhibitor in nerve synapse by with acetylcholine competition in conjunction with acetylcholinesterase, block the degraded of this enzyme to acetylcholine, and then increase the concentration of acetylcholine in brain.
Meclofenoxane is central nervous stimulant.There is scholar to think to can be used as after the acid of meclofenoxane main component dimethylaminoethanol enters in body the synthesis material of choline and acetylcholine, increase the content of acetylcholine in brain.Research shows, meclofenoxane recovers, improves the safety with pharmacological action widely and long-term prescription of the aspects such as senile dementia in brain functional rehabilitation, memory, and these all point out it for the treatment of AD, to have good prospect.
The effect on treatment AD based on galantamine and meclofenoxane, herein two medicine compatibilities are used, the decomposition of AchE to Ach in not only can antagonism brain, can also increase the content of Ach in brain, to slow down aging, to improve old people cognitive significant with dysmnesia.At present, the medicine that not yet discovery can be treated AD in these a plurality of links both at home and abroad.This compound preparation belongs to national drug registration minute apoplexy due to endogenous wind chemical drugs one class medicine, will fill up domestic and international blank in AD treatment field, and its exploitation will produce good Social benefit and economic benefit.
Summary of the invention
Technical problem solved by the invention is to have proposed a kind of pharmaceutical composition, and this pharmaceutical composition can prevent and treat Alzheimer.
Pharmaceutical composition of the present invention is comprised of galantamine and meclofenoxane; the dose ratio of galantamine and meclofenoxane is (0.5-4): in the time of (17.5-70); it can obviously improve learning and memory, delays brain aging, reduce amyloid deposition and protection cholinergic neuron in brain, points out pharmaceutical composition of the present invention to have better preventive and therapeutic action to Alzheimer.Preferably (0.5-2): (17.5-70), more preferably (1-2): (35-70), optimal proportion is 2:35.
Because meclofenoxane can be used as the synthesis material of choline and acetylcholine after entering in body, increase the content of acetylcholine in brain, and galantamine is second filial generation cholinesterase inhibitor, therefore two medicines share and can increase from too many levels the content of acetylcholine in brain, and then reach the object for the treatment of AD.We adopt the orthogonal of two factor 3,4 levels (3 horizontal factors are meclofenoxane, and 4 horizontal factors are galantamine), and with method of analysis of variance, each factor and level are analyzed, to investigate the primary and secondary of each factor and the quality of each level.Adopt algebraical sum additive process, the Q-value of take is determined best proportioning as index simultaneously.Set dosage is 7 folk prescription groups, be galantamine 4,2,1,0.5mg/kg, meclofenoxane 70,35,17.5mg/kg, 12 compound recipe groups are galantamine/meclofenoxane 4/70,4/35,4/17.5,2/70,2/35,2/17.5,1/70,1/35,1/17.5,0.5/70,0.5/35,0.5/17.5mg/kg, successive administration 7 days.20min after last administration, adopt the modeling of lumbar injection scopolamine, by diving tower method and darkness avoidance test, observe the effect of each folk prescription and compound recipe, result shows, there is synergism (F < 0.01) in galantamine and meclofenoxane, two factors are main factor (F < 0.01), under 12 groups of mix proportion schemes, be Q>1, best proportioning at galantamine and meclofenoxane is 2:35mg/kg, its Q>1, and Q-value is maximum, show that galantamine and meclofenoxane share the maximum synergism of generation under this mix proportion scheme.Therefore, pharmaceutical composition of the present invention to memory acquisition disturbance, obstacle is consolidated in memory and memory represents obstacle tool improves significantly.This compositions can reach the effect that prevents and treat Alzheimer by delaying the many-side such as amyloid deposition and protection cholinergic neuron in brain aging, minimizing brain simultaneously.Prompting galantamine and meclofenoxane share and can improve learning and memory and prevention and treatment Alzheimer.
Pharmaceutical composition of the present invention can be prepared into the preparation such as acceptable tablet, capsule, granule, oral liquid clinically with pharmaceutically acceptable carrier.
The specific embodiment
Embodiment 1
What the present embodiment designed is a kind of pharmaceutical composition that can treat Alzheimer, and this compositions is comprised of galantamine and meclofenoxane.The proportion compatibility of galantamine and meclofenoxane is (0.5-4): (17.5-70).
1.1 mice diving tower methods determine that compound recipe galantamine is to the action effect of Alzheimer and proportion compatibility
Get healthy male Kunming kind white mice, be divided into immediately 21 groups, be respectively 12 compound recipe groups, 7 folk prescription groups, Normal group and model group, Normal group and model group gavage isometric distilled water, all the other each groups gavage respectively galantamine 4,2,1,0.5mg/kg, meclofenoxane 70,35,17.5mg/kg, galantamine/meclofenoxane 4/70,4/35,4/17.5,2/70,2/35,2/17.5,1/70,1/35,1/17.5,0.5/70,0.5/35,0.5/17.5mg/kg, successive administration 7 days.20min after last administration, except Normal group intraperitoneal injection of saline, all the other respectively organize equal lumbar injection scopolamine 5mg/kg, carry out the training of diving tower method after 10min.Test after 24 hours, records jumping off incubation period of the interior mice of 5min.
Experimental result: with matched group comparison, each administration group can obviously extend the incubation period that mice jumps off diving tower, compound recipe group is better than folk prescription group, and two medicines share and have synergism (F < 0.01), and two factors are main factor (F < 0.01).This result shows, galantamine and meclofenoxane coupling can improve the memory acquisition disturbance of mice, and effect is greater than folk prescription effect sum (Q>1).The proportion compatibility of galantamine and meclofenoxane is (0.5-4): (17.5-70).
1.2 mice darkness avoidance tests are determined best proportioning
Laboratory animal and method are with 1.1.Each organizes mice successive administration 7 days, 20min after last administration, and except Normal group intraperitoneal injection of saline, all the other respectively organize equal lumbar injection scopolamine 5mg/kg, carry out darkness avoidance test training after 10min.Test after 24 hours, records the incubation period that the interior mice of 3min enters darkroom.
Experimental result: with matched group comparison, each administration group can obviously extend the incubation period that mice enters darkroom, compound recipe group is better than folk prescription group, and two medicines share, and to have synergism (F < 0.01), galantamine be main factor (F < 0.01).This result shows, galantamine and meclofenoxane coupling can improve the memory acquisition disturbance of mice, and effect is greater than folk prescription effect sum (Q>1).The proportion compatibility of galantamine and meclofenoxane is (0.5-4): (17.5-70).
Embodiment 2
Galantamine and meclofenoxane share the screening of best proportioning.
2.1 mice diving tower methods are determined best proportioning
Laboratory animal and method are with 1.1.
Adopt Orthogonal Experiment and Design and Q
50method is carried out dosage design and is adopted method of analysis of variance to analyze experimental result, and galantamine and meclofenoxane exist synergism (F < 0.01), and two factors are main factor (F < 0.01).Adopt algebraical sum additive process (Q
50method), the effect that Q-value is greater than after 1 expression formula share is greater than folk prescription effect sum.The maximum Q=1.77 of Q-value when result shows that the optimal dose ratio of galantamine/meclofenoxane is 2/35mg/kg.
2.2 mice darkness avoidance tests are determined best proportioning
Laboratory animal and method are with 1.2.
Adopt Orthogonal Experiment and Design and Q
50method is carried out dosage design and is adopted method of analysis of variance to analyze experimental result, and galantamine and meclofenoxane exist synergism (F < 0.01), and galantamine is main factor (F < 0.01).Adopt algebraical sum additive process (Q
50method), the effect that Q-value is greater than after 1 expression formula share is greater than folk prescription effect sum.The maximum Q=1.20 of Q-value when result shows that the optimal dose ratio of galantamine/meclofenoxane is 2/35mg/kg.
Above result shows that the optimum dose proportion scheme of galantamine and meclofenoxane is 2:35mg/kg, and under this mix proportion scheme, galantamine and meclofenoxane share the maximum synergism of generation.
Embodiment 3
What the present embodiment related to is the improvement effect that compound recipe galantamine is consolidated obstacle and memory represents obstacle to memory acquisition disturbance, memory.。
3.1 compound recipe galantamines cause the improvement effect (diving tower method) of mouse memory acquired disturbance to scopolamine
Get healthy male Kunming kind white mice, be divided into immediately 7 groups, be i.e. Normal group, model group, compound recipe galantamine (COG) 4/70,2/35,1/17.5mg/kg group, meclofenoxane 35mg/kg group and galantamine 2mg/kg group.Remove Normal group and model group and gavage isometric distilled water, all the other each groups gavage respectively relative medicine, successive administration 7 days.20min after last administration, except Normal group intraperitoneal injection of saline, all the other respectively organize equal lumbar injection scopolamine 5mg/kg, carry out the training of diving tower method after 10min.
Mice is put into reaction chamber endoadaptation 3min, then lead to immediately 36V alternating current.Animal is shocked by electricity, and its normal reaction is that rebound platform is to hide noxious stimulation.So training 5min, records the number of times that every Mus is shocked by electricity, and as errors number (number of errors), usings this as school grade.The test of reforming after 24h, this remember and keep test.Record mice and jump off for the first time the incubation period of platform and the errors number in 5min.
Experimental result is in Table 1
Table 1 compound recipe galantamine causes the improvement effect (diving tower method) of mouse memory acquired disturbance to scopolamine
##p ﹤ 0.01 and matched group comparison; * P ﹤ 0.05 and model group comparison
Result is as shown in table 1.Compare with Normal group, model group can make the memory of mice obtain and suffer obvious damage, and showing as errors number increases, and shorten incubation period.With model group comparison, the middle and high dosage of COG group can make mouse wrong times obviously reduce, and obviously extend incubation period.
3.2 compound recipe galantamines are consolidated the improvement effect of obstacle to mouse memory
3.2.1 compound recipe galantamine causes mouse memory to sodium nitrite and consolidates the improvement effect of obstacle (diving tower method)
Get healthy male Kunming kind white mice and be divided at random blank group, model control group, COG4/70,2/35,1/17.5mg/kg, galantamine 2mg/kg, meclofenoxane 35mg/kg group.Administration group gavages respectively the COG of galantamine, meclofenoxane and various dose, and blank group and model control group gavage isometric(al) distilled water, gavages continuously 7 days.After administration in the 7th day, 30min carries out the training of diving tower method.After training finishes, except blank group intraperitoneal injection of saline, all the other respectively organize equal lumbar injection sodium nitrite 125mg/kg.After 24 hours, test, record mice and jump off for the first time the incubation period of platform and the errors number in 5min.Experimental result is in Table 2
Table 2 compound recipe galantamine causes to sodium nitrite the improvement effect that mouse memory is consolidated obstacle
#p ﹤ 0.05, with matched group comparison; * P ﹤ 0.05, with model group comparison
Result is as shown in table 2.Compare with Normal group, model group can make the memory of mice consolidate and suffer obvious damage, and showing as errors number increases, and shorten incubation period.With model group comparison, the middle and high dosage of COG group can make mouse wrong times obviously reduce, and obviously extend incubation period.
3.2.2 compound recipe galantamine causes to galvanic shock the improvement effect (darkness avoidance test) that mouse memory is consolidated obstacle
The same 2.2.1 of laboratory animal and medication, after administration in the 7th day, 30min keeps away dark training, and after training finishes, except blank group, all the other each groups all impose 7mA electric current, switch on and within 1 second, cause mice galvanic shock, after 24 hours, test.
This experiment is carried out in darkroom.The 60cm place, top, bright chamber that keeps away camera bellows settles the bulb of a 100W.During experiment, lamp is opened to the copper grid indirect current of bottom, darkroom.During training, the mice back of the body is put into bright chamber towards the hole that is communicated with light and shade two Room, mice one enters darkroom and shuts immediately portal, electric shock 1sec(38V) after animal is taken out, the test of reforming after 24h, record animal and enter the time in darkroom by bright chamber, this is the errors number in incubation period and 3min.Experimental result is in Table 3
Table 3 compound recipe galantamine causes to galvanic shock the improvement effect (darkness avoidance test) that mouse memory is consolidated obstacle
##p ﹤ 0.01, with matched group comparison; * P ﹤ 0.05, with model group comparison
Result is as shown in table 3.Compare with Normal group, model group can make the memory of mice consolidate and suffer obvious damage, and showing as errors number increases, and shorten incubation period.With model group comparison, the middle and high dosage of COG group can make mouse wrong times obviously reduce, and obviously extend incubation period.
3.3 compound recipe galantamines cause to 30% ethanol the improvement effect (diving tower method) that mouse memory reproduces obstacle
The same 2.2.1 of laboratory animal and medication, after administration in the 7th day, 30min carries out diving tower training.Within the 8th day, except blank group, all the other gavage to 30% ethanol 0.1ml/10g after respectively organizing administration 10min, and Normal group gavages isometric distilled water, after 20min, tests, and that records mice in 5min jumps off incubation period and errors number.Experimental result is in Table 4
Table 4 compound recipe galantamine causes to ethanol the improvement effect (diving tower method) that mouse memory reproduces obstacle
#p ﹤ 0.05, with matched group comparison; * P ﹤ 0.05, with model group comparison
Result is as shown in table 4.Compare with Normal group, model group can make the memory represents of mice suffer obvious damage, and showing as errors number increases, and shorten incubation period.With model group comparison, the middle and high dosage of COG group can make mouse wrong times obviously reduce, and obviously extend incubation period.
Above result shows, the memory acquisition disturbance that compound recipe galantamine causes a variety of causes, obstacle is consolidated in memory and memory represents obstacle tool improves significantly.
Embodiment 4
What the present embodiment related to is the improvement effect of compound recipe galantamine to D-galactose Aging mice learning and memory.
4.1 compound recipe galantamines are to the improvement effect of D-galactose Aging mice learning and memory (diving tower method)
Get healthy male mice in kunming and be divided at random blank group, model control group, COG4/70,2/35,1/17.5mg/kg group, galantamine 2mg/kg, meclofenoxane 35mg/kg group.Model group and blank group gavage isometric distilled water, and administration group gavages respectively the COG of galantamine, meclofenoxane and various dose.Simultaneously, model group and each administration group mice subcutaneous injection every day 10%D-galactose 0.25ml/ only, inject 6 weeks continuously in administration, the isometric normal saline of blank group subcutaneous injection.After 6 weeks, adopt diving tower method to carry out the mensuration of learning and memory.Experimental result is in Table 5
Table 5 compound recipe galantamine is to the improvement effect of D-galactose Aging mice learning and memory (diving tower method)
#p ﹤ 0.05,
##p ﹤ 0.01, with matched group comparison; * P ﹤ 0.05, with model group comparison
Result is as shown in table 5.Compare with Normal group, model group mouse memory obviously fails, and showing as errors number increases, and shorten incubation period.With model group comparison, the middle and high dosage of COG group can make mouse wrong times obviously reduce, and obviously extend incubation period.
The impact of 4.2 compound recipe galantamines on LPO, LF, MAO-B content in D-galactose Aging mice brain
Experimental technique is with 3.1.Administration Hou Qu animal brain, sucks residual blood with filter paper for the last time, is cut into small pieces, and makes homogenate.Check respectively the content of brain endoperoxides lipid (LPO), lipofuscin (LF) and monoamine oxidase-B (MAO-B).Experimental result is in Table 6
The impact of table 6 compound recipe galantamine on LPO, LF, MAO-B content in D-galactose Aging mice brain
#p < 0.05,
##p < 0.01 and matched group comparison; * P < 0.05, * * P < 0.01 and model group comparison.
Result is as shown in table 6.Compare with normal group, D-galactose significantly increases the content of mouse brain interior LPO, LF and MAO-B.With the comparison of D-galactose group, the high, medium and low dosage of COG group can make the content of mouse brain interior LF, LPO and MAO-B obviously reduce.
Embodiment 5
What the present embodiment related to is the therapeutical effect of compound recipe galantamine to Alzheimer.
5.1 compound recipe galantamines cause the improvement effect of Model of Dementia in Rats to KA (KA)
It is the nuclei originis of up cholinergic neuron to Basal Forebrain of Rats nbM(that this test adopts) inject micro-excitatory neuron toxin aminoacid KA, the cholinergic cell in this region of selective destruction, causes the AD animal model of maincenter choline system disorders.Get healthy Wistar rat and be divided at random blank group, model control group, COG2.8/49,1.4/24.5,0.7/12.3mg/kg group, galantamine 1.4mg/kg, meclofenoxane 24.5mg/kg group.By 1% pentobarbital sodium (40mg/kg for rat; Ip) after anesthesia, be fixed on brain solid positioner, along skull center line, cut off skin.Determine that Meynert basal nuclei (nbM) coordinate is: 2.4mm after bregma, 1.4mm is opened on side, dark 7.4mm. bores an aperture on skull, diameter 1.0mm, with microsyringe, respectively 2ul KA (containing 0.25ug) is injected to both sides nbM in 5min, blank group is injected the phosphate buffer (pH7.4) of equivalent, injects completely, stops pin 5min.Postoperative dental base acrylic resin powder sealing skull, skin suture, in 3 days, give penicillin (a 3.2 ten thousand u/ ip) every day, and second day after operation starts to gavage medicine, and blank group and model control group gavage isometric distilled water, gavage continuously 14 days.From the 9th day, start to carry out diving tower experiment, record the training achievement of every day, train continuously 5 days.
Rat diving tower method, reflective box bottom is electric screen, has the platform of a high 10min in case.Conditional stimulus is the tinkle of bells, and unconditioned stimulus is foot shock.Its program is the tinkle of bells 5sec, succeeded by electric shock 10sec, interval 20sec.Rat is subject to electric shock and jumps onto platform and be referred to as passive avoidance response; Hear the tinkle of bells and jump onto platform and be referred to as active avoidance response before being shocked by electricity.Train every day 10 times, record the number of times of active avoidance response.
The results are shown in Table 7
Table 7 compound recipe galantamine causes the improvement effect (diving tower method) of Model of Dementia in Rats to KA (KA)
##p ﹤ 0.01, with matched group comparison; * P ﹤ 0.05, * * P ﹤ 0.01 and model group comparison
Shown in result table 7.Compare with blank group, the active avoidance response number of times of Model of Dementia group rat was not significantly improved in each day of training; Compare with Model of Dementia group, the active avoidance response number of times of the middle and high dosage group of COG rat all has remarkable rising in each day of training.Result shows, learning and memory process that can obvious damage rat at rat brain nbM micro-injection KA; The middle and high dosage of COG improves significantly to the learning memory disorder of Model of Dementia rat.
5.2 compound recipe galantamines cause the improvement effect of Model of Dementia in Rats to aluminum chloride
By the method for Chronic aluminum poisoning, setting up senility study memory disturbance model is one of model that research AD is comparatively desirable.Aluminum chloride can obviously reduce the avoidance response rate of rat, suppresses the reservation of avoidance response.Get healthy male Wistar rat and be divided at random blank group, model control group, COG2.8/49,1.4/24.5,0.7/12.3mg/kg group, galantamine 1.4mg/kg, meclofenoxane 24.5mg/kg group.Blank group gavages isometric distilled water, and all the other each groups gavage Alcl
3500mg.kg
-1.d
-1, in the time of the 30th day, with rat darkness avoidance test, investigate dull-witted formation degree, after model forms, administration group gavages Alcl
3time give galantamine, meclofenoxane and COG each dosage, continuous two first quarter moons.The 75th day starts to carry out diving tower experiment, records the training achievement of every day, trains continuously 5 days, trains every day 10 times, records the number of times of active avoidance response.The results are shown in Table 8
Table 8 compound recipe galantamine causes the improvement effect (diving tower method) of Model of Dementia in Rats to aluminum chloride
##p ﹤ 0.01, with matched group comparison; * P ﹤ 0.05, * * P ﹤ 0.01 and model group comparison
Result is as shown in table 8.Compare with pseudo-model group, the active avoidance response number of times of Model of Dementia group rat was not significantly improved in each day of training; Compare with Model of Dementia group, the active avoidance response number of times of the middle and high dosage group of COG rat all has remarkable rising in each day of training.Result shows, the learning and memory process that aluminum chloride can obvious damage rat; The middle and high dosage of COG improves significantly to the learning memory disorder of Model of Dementia rat.
Embodiment 6
What the present embodiment related to is that galantamine and meclofenoxane share the impact on neurotransmitter in Alzheimer brain
The impact of 6.1 compound recipe galantamines on Ach, AchE in KA Model of Dementia rat brain
In patient's AD brain, the cholinergic neuron of basal nuclei and forebrain is impaired the earliest neuron, when disease further develops, in basal nuclei, 90% cholinergic neuron all can be destroyed, causes the Ach level of its nerve fiber projection area-cerebral cortex and Hippocampus to reduce.Experimentation shows, the reduction of these regions Ach level and the reduction of patient's AD cognitive competence are remarkable dependency, and uses cholinergic drug can affect the cognitive competence of humans and animals.Therefore cholinergic hypothesis thinks that it is the main pathogenesis of AD that cholinergic nerve function reduces.We have investigated the impact of compound recipe galantamine on acetylcholine (Ach) in KA rat model brain and acetylcholine esterase (AchE), the results are shown in Table 9
The impact of table 9 compound recipe galantamine on Ach, AchE in KA Model of Dementia rat brain
##p ﹤ 0.01 and matched group comparison; * P ﹤ 0.05, * * P ﹤ 0.01 and model group comparison
Result is as shown in table 9.Result shows, can damage most of cholinergic nerve of centrum first at rat brain nbM micro-injection KA; Compare with pseudo-model group, Ach, AchE content in Model of Dementia group rat brain significantly reduce; Compare with Model of Dementia group, the AchE content in the middle and high dosage group of COG rat brain obviously reduces, and Ach content obviously raises.
The impact of 6.2 compound recipe galantamines on monoamine transmitters in KA Model of Dementia rat brain
AD patient occurs pathological change except cholinergic nerve of centrum system, other mediator system as norepinephrine (NE) can, 5-hydroxy tryptamine (5-HT) can, dopamine (DA) nervous system also has infringement.Many results of animals show, central cholinergic system function relies on the function that complete forebrain NE, 5-HT, DA can systems at least partly, and they and cholinergic nerve system reciprocal action, restrict joint effect learning and memory function mutually.We have investigated the impact of compound recipe galantamine on NE, DA and 5-HT in KA rat model brain, the results are shown in Table 10
The impact of table 10 compound recipe galantamine on monoamine transmitters in KA Model of Dementia rat brain
##p ﹤ 0.01 and matched group comparison; * P ﹤ 0.05 and model group comparison
Result is as shown in table 10.Compare with pseudo-model group, NE, DA and 5-HT content in Model of Dementia group rat brain significantly reduce; Compare with Model of Dementia group, the middle and high dosage of COG can obviously improve NE, DA, the 5-HT level in rat brain.
Embodiment 7
What the present embodiment related to is that galantamine and meclofenoxane share the impact on hippocampus of rats with Alzheimer disease district amyloid precursor protein
The main pathological characters of Alzheimer (AD) is the fibrin deposition in cerebral cortex Ji Nao district, and poly Tau proteinosis in the amyloid beta of ECS (A β) and cell, both can show as respectively senile plaque (SP) and neurofibrillary tangle (NFT) in pathomorphology.The A β and the AD onset relation that wherein participate in senile plaque formation receive much concern closely.The precursor of A β is amyloid precursor protein (β-APP), and increasing evidence shows that the apoptosis of neurocyte participates in the morbidity of AD, and the A β that β-APP sudden change produces plays an important role to apoptotic inspiring.β-APP can produce A β through secretase hydrolysis, so can reach by suppressing the generation of β-APP the object for the treatment of AD.The Model of Dementia that we cause by research rat Long-term Oral aluminum chloride, finds to compare with normal group, and aluminum chloride obviously increases β-App positive neuron in Dorsal Hippocampus of The Rat and dentate gyrus.With the comparison of aluminum chloride group, the middle and high dosage of compound recipe galantamine group can make β-APP positive neuron in rat Dorsal Hippocampus of The Rat and dentate gyrus obviously reduce.And galantamine and meclofenoxane folk prescription group all fail to make β-APP positive neuron in Rat Dentate Gyrus obviously to reduce.Show that this compound medicine can reach by suppressing the generation of β-APP the object for the treatment of AD
Embodiment 8
What the present embodiment related to is that galantamine and meclofenoxane share the neuronic protective effect to hippocampus of rats with Alzheimer disease district
The main neuropathological feature of AD has brain atrophy, neurocyte to reduce, occur neurofibrillary tangle and neuritis's speckle.The main brain district that the neurocyte of AD is lost is that cortical areas, Hippocampus etc. are located.Hippocampus and the mankind's learning and memory is closely related, and wherein Hippocampus loop is considered to the nerve basis of impermanent memory.Therefore in AD patient Hippocampus, the infringement of neurocyte provides good explanation for its recent memory obstacle.
8.1 compound recipe galantamines are to the neuronic protective effect in aluminum chloride Model of Dementia rat hippocampus district
The Model of Dementia that we cause by research rat Long-term Oral aluminum chloride finds that aluminum chloride can cause rat hippocampus district neuronal necrosis, main manifestations is neuron axon distortion, in it, microtubule is partly dissolved, and in neuropil, synapse seldom, becomes cavity sample to change more.Neuron axon density of matrix increases, and mitochondrion such as increases at the phenomenon.And compound recipe galantamine can cause rat hippocampus district neuronal necrosis to have good protective effect to aluminum chloride, in the hippocampus neuron axon of its height, middle dosage group rat, micro-tubular structure is bordering on normally, and microfilament is clear, arranges more neat.In neuropil, there is more synapse, in it, have more synaptic vesicle and good mitochondrion.8.2 compound recipe galantamines are to the neuronic protective effect in KA Model of Dementia rat hippocampus district
We investigate KA and cause the neuronic variation of dementia rats hippocampus, and result shows that Basal Forebrain of Rats nbM injects after KA, occur that Hippocampus cell arrangement is disorderly, and cell is sparse, and pyramidal cell aixs cylinder is short, Leukopenia, the phenomenons such as the liquefaction community differing in size as seen.Compound recipe galantamine causes rat hippocampus district neuronal necrosis to have good protective effect to KA, and the hippocampus granular cell of its height, middle dosage group rat shows no obvious abnormalities, neuron marshalling, and kernel is clear, has no softening kitchen range and other pathological changes.
From the above results, the neuronal damage that compound recipe galantamine causes Alzheimer has protective effect.
Claims (9)
1. can prevent and treat a pharmaceutical composition for Alzheimer, it is characterized in that, described pharmaceutical composition is comprised of galantamine and meclofenoxane, and the dose ratio of galantamine and meclofenoxane is (0.5-4): (17.5-70).
2. pharmaceutical composition according to claim 1, is characterized in that, the preferred dose ratio of galantamine and meclofenoxane is (0.5-2): (17.5-70).
3. pharmaceutical composition according to claim 1, is characterized in that, the more preferably dose ratio of galantamine and meclofenoxane is (1-2): (35-70).
4. pharmaceutical composition according to claim 1, is characterized in that, the optimal dose ratio of galantamine and meclofenoxane is 2:35.
5. the preparation that the pharmaceutical composition of claim 1-4 described in any one and pharmaceutically acceptable carrier are prepared from, described preparation is selected from tablet, capsule, granule, oral liquid.
6. pharmaceutical composition or the claimed in claim 5 preparation application in preparation prevention or treatment Alzheimer medicine of claim 1-4 described in any one.
7. described in claim 1-4, the pharmaceutical composition described in any one or preparation claimed in claim 5 are consolidated the application in the learning and memory decline medicine that obstacle, memory represents obstacle, aging cause in preparation prevention or treatment memory acquisition disturbance, memory.
8. the pharmaceutical composition described in any one or preparation claimed in claim 5 application in protection brain Cholinergic Neurons described in claim 1-4.
9. the pharmaceutical composition described in any one or the preparation claimed in claim 5 application in amyloid deposition in reducing brain described in claim 1-4.
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| CN107847504A (en) * | 2015-05-18 | 2018-03-27 | 斯奈普泰克发展有限责任公司 | Galantamine clearance of amyloid beta |
| CN112569243A (en) * | 2019-09-30 | 2021-03-30 | 神农医药科技有限公司 | Preparation of medicine for treating Alzheimer disease |
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| 马玉奎: "复方加兰他敏改善阿尔茨海默病的药效学及机制研究", 《中国优秀硕士学位论文全文数据库 医药卫生科技辑》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107847504A (en) * | 2015-05-18 | 2018-03-27 | 斯奈普泰克发展有限责任公司 | Galantamine clearance of amyloid beta |
| CN112569243A (en) * | 2019-09-30 | 2021-03-30 | 神农医药科技有限公司 | Preparation of medicine for treating Alzheimer disease |
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