JPH04210642A - Antidement agent - Google Patents

Abstract

PURPOSE:To obtain an antidement agent, containing an extract of Hypericum erectum Thunb. as an active ingredient, having cerebral protective action due to protection of the respiratory center, useful for treating senile dementia and having ultrahigh safety. CONSTITUTION:An antidement agent is obtained by, as necessary, drying the whole herb or any of a leaf, a stem, a root, a fruit, a seed and a flower of Hypericum erectum Thunb., pulverizing the whole herb or any of the leaf, stem, root, fruit, seed and flower and then extracting the pulverized substance with water and/or a water-soluble polar solvent (e.g. an alcohol or a polyhydric alcohol) at ordinary temperature or by heating, directly including the resultant extract or fractionating a fraction having high activity using a suitable separating means and including the prepared fraction as an active ingredient. The aforementioned antidement agent is useful for treating dysmnesia such as Alzheimer type dementia and cerebrovascular dementia.

Description

[Detailed description of the invention]

[00011

[Industrial Application Field] The present invention is an anti-dementia agent, more specifically, it contains an extract of Hypericum perforatum as an active ingredient, has a brain protective effect by protecting the respiratory center, and is effective against scopolamine-induced amnesia. The present invention relates to an anti-dementia agent that exhibits activity and is useful for the treatment of senile dementia such as cerebrovascular dementia and Alzheimer's dementia. [0002] BACKGROUND OF THE INVENTION As society ages, the number of patients suffering from senile dementia is increasing, and it has become a major social problem today. [0003] Senile dementia is generally classified into Alzheimer's type dementia, which is accompanied by organic lesions of the brain, and cerebrovascular dementia, which is caused by cerebrovascular injury. Currently, various cerebral metabolism improving agents and cerebral circulation improving agents are used for the treatment of senile dementia. For example, the cause of Alzheimer's senile dementia is still unknown, but since the theory that it is due to a decline in the function of the cholinergic nervous system has been proposed, many attempts have been made to treat it with drugs that activate the cholinergic system. has been done. For example, there is a report that investigated using physostigmine, a typical acetylcholinesterase (AChE) inhibitor [Neuro
logy, 8°397 (1978)). [00041 Furthermore, Journal of Medicine
inal Chemistry. 31, 1278 (1988); 32.1805 (1
989) reports that aminoacridine derivatives have an acetylcholinesterase inhibitory effect and are effective in treating Alzheimer's type senile dementia. [0005]

[Problems to be Solved by the Invention] However, although these conventional anti-dementia drugs improve peripheral symptoms of senile dementia, they still do not have sufficient therapeutic effects and have the problem of causing side effects such as liver damage. It had [0006] Therefore, it has been desired to develop an anti-dementia agent with fewer side effects and excellent therapeutic effects on senile dementia. [0007]

[Means for Solving the Problems] Under such circumstances, the present inventors conducted intensive research and found that an extract of Hypericum perforatum has an excellent effect on the treatment of senile dementia. completed. [0008] That is, the present invention provides an anti-dementia agent containing an extract of Hypericum perforatum as an active ingredient. [0009] The extract of Hypericum perforatum, which is the active ingredient of the anti-dementia agent of the present invention, can be used, for example, from Hypericum perforatum (Hyperiraceae)
pericum erectum Thunb,)
The whole plant, or any one or more parts of leaves, stems, roots, fruits, seeds, and flowers (hereinafter referred to as "raw material") are dried or crushed without drying, and then dried at room temperature or It can be obtained by extraction with a solvent under heating or by extraction using an extractor such as a Soxhlet extractor. [00103 Solvents used here include water and/or water-soluble polar solvents. Specific examples of these solvents include water; glycerin, polyethylene glycol,
Polyhydric alcohols such as propylene glycol; a mixture of these polyhydric alcohols and water (preferably 5 to 30%
aqueous solution); anionic surfactant aqueous solution, nonionic surfactant aqueous solution, amphoteric surfactant aqueous solution; alcohols such as methanol, ethanol, butanol; mixed solution of these alcohols and water (10 to 90%, preferably 20 to
80% aqueous solution). [00113 Specific examples of preferable extraction methods from the raw material include (1) a method in which the raw material is pulverized, extracted with a solvent such as a hydrous lower alcohol, and the solvent is distilled off; (2) the raw material obtained in (1) The extract was treated with activated carbon, polyamide resin, H
A method of treating with one or more selected from polystyrene resin such as P-20 and polyethylene methacrylate resin; (3) After crushing the raw material, extracting with a solvent such as anhydrous or water-containing lower alcohol, and then extracting the extract. Subjected to liquid-liquid extraction using water and a water-immiscible solvent such as ethyl acetate,
Further, a method of distilling off the solvent from the aqueous phase; (4) subjecting the aqueous phase obtained in (3) above to liquid-liquid extraction using butanol and water;
Further, a method of distilling off the solvent from the butanol phase; (5) In (3) or (4) above, before or after liquid-liquid extraction, the aqueous phase is treated with activated carbon, polyamide resin, HP-20
A method of treating with one or more selected from polystyrene resins and polyethylene methacrylate resins such as;
6) After pulverizing the raw material, it is extracted with a suitable solvent, and then the extracted phase is treated with one or more selected from activated carbon, polyamide resin, polystyrene resin such as HP-20, and polyethylene methacrylate resin to make the active material Examples include methods of adsorbing components, then extracting active components with methanol, ethanol, or a mixture of these and water, and distilling off the solvent, which can be appropriately selected and used depending on the purpose. [0012] Although these extracts of Hypericum perforatum can be used as they are as an active ingredient of the anti-dementia agent of the present invention,
The extract can be further used after fractionating the highly active components by appropriate separation means, such as gel filtration, silica gel column chromatography, or reversed phase or normal phase high performance liquid chromatography. [0013] [Effect 1] Next, the results of testing the pharmacological effects of the Hypericum perforatum extract in the present invention are shown. [0014] (1) Central cholinergic effect (test method) Hypericum perforatum extract (sample 5) has a central cholinergic effect.
In order to examine the presence or absence of agonism, oxotremorine [o
The effect of [otremorine: 1-(2-oxopyrrolidino)-4-pyrrolidino-butyne-2] on the vibration frequency induced by stimulation of muscarinic receptors was investigated. (0015) That is, ddV male mice (body weight 20
-2ig) and oxotremorine at 0.15■/k.
intraperitoneally (i,
p,) was administered, and behavior was observed every 5 minutes for 30 minutes from 1 post-administration. At 6 o'clock, the maximum action onset time of the test drug (sample 5) (p, o, 1 hour after administration, i, p, 3 hours after administration)
0 minutes) is the onset time of action of oxotremorine (10 minutes).
The drug should be pre-administered at a dose of 500 mg/kg
Oral (p, o,) administration and 250 mg/kg, 500 m
g/kg intraperitoneal (i, p,) administration), and the presence or absence of enhancement of vibration frequency was observed. Measurement of abnormal behavior induced by oxotremorine was based on the following scoring method. 0: Abnormal behavior does not appear at all (normal) 1: Intermittent weak vibrations appear 2: In addition to intermittent weak vibrations, occasional moderate vibrations appear 3: Continuous moderate vibrations Number appears 4: Continuously significant vibration appears [0016] (Result) 500 mg/kg p of Hypericum perforatum extract (sample 5)
,0. ．． 250■/kg i, p, , 500■
No enhancement of the frequency induced by oxotremorine was observed at either /kgi or p (Figure 1
). [0017] This result shows that the extract of Hypericum perforatum has no central cholinergic effect. [0018] (2) Effect on scopolamine-induced amnesia (test method) A step-through passive avoidance learning device was used as the experimental device. It consisted of a dark room (30 x 30 x 30 cm) with 15 grids on the floor and a bright room (20 x 10 x 12 cm) illuminated with 6W white light. The two rooms are separated by a guillotine door (8X8cXl). Also, the darkroom grid is 5HOCK SCRAMBL
3 by AR (MODEL 5GS-002 Muromachi equipment)
A foot shock is generated by applying a current of mA for 5 seconds.
5 hock). [0019] The experimental animals used were Wistar male rats (weight 210-250 g), and each rat was housed in a metal cage (5 rats) at a room temperature of 23 ± 2°C and an absolute humidity of 6.
0 ± 2% and 12 hour dark/light cycle (7:00a, I
The animals were kept in an animal room with lights on. In addition, food and water were provided ad libitum. After placing the rat in the passive avoidance device for 1 minute to acclimate to the device, the door was closed, the rat was taken out and placed in the light room, and 30 seconds later, the guillotine door was opened and the rat's limbs were completely moved into the dark room, and the rat was placed in the foot 5hock. was given as an acquisition attempt. [24 hours after the 00201 acquisition trial, the rats were placed in the light room again, and the time it took to enter the dark room (response latency) was measured. Note that the reaction latency was measured up to a maximum of 600 seconds. [00211 In addition, scopolamine has a reaction latency of 30
The test drug [Hypericum extract (sample 5)] was administered intraperitoneally (i, p) at 3 kg/kg 1 minute before the reaction latency window.
2 mg/kg, 20 mg/kg, 200 mg before hours
/kg orally (p, o, ). Effects can be determined using Mann-Whit measurement results of response latency.
Determined by ney's U-test test. [0022] (Results) Rats that have adapted to the passive avoidance device and have not undergone passive avoidance learning move to the dark room in about 4 seconds, but rats that have acquired passive avoidance learning have a response latency of over 600 seconds. acknowledged. [0023] Furthermore, after passive avoidance learning, the response latency of the group administered scopolamine was 110 seconds on average;
A significant (E)<0.01) shortening of the response latency was observed compared to the vehicle-administered group. However, the group in which Hypericum perforatum extract (sample 5) was administered (2 mg/kg, 20 mg/kg, all orally (p, o,) administration) 30 minutes before scopolamine administration (1 hour before reaction latency measurement) , response latency was significantly prolonged compared to the scopolamine-administered group (p<0, 05, respectively). The action of this Hypericum extract (sample 5) was almost equivalent to that of THA (tetrahydroaminoacridine), a cholinesterase inhibitor used as a positive control (FIG. 2). [00241From the above results, the extract of Hypericum perforatum,
It is found to be effective against scopolamine-induced amnesia. However, from the test results in (1) above, it is presumed that this effect is not based on activation of the central cholinergic nervous system. [0025] On the other hand, in learning and memory, in addition to the acetylcholinergic nervous system, hyperfunction of the adrenergic nervous system is also thought to enhance memory; for example, blockade of α receptors may cause learning injury [RetrOgrade amne
sia produced byseveral t
reatments:evidence for a
common neurobi. logical mechanics, 5cienc
E, 28, 367-369 (1978)), it has been reported that blocking β receptors in addition to muscarinic receptors enhances learning damage [Michal W,
Decker, T., Michael Gill: Co.
current muscarinic and β
-adrenergic blockade in r
ats impairS place-1earni
ng ina water maZeand reta
tion of 1nhibitory avoid
ance, Brain Research, 51
381-85. (1990)). [0026] Therefore, it is inferred that the extract of Hypericum perforatum has an activation effect on the adrenergic nervous system. [0027] (3) Cerebral protective effect against hypoxemia (
Test method) For the purpose of examining the presence or absence of cerebral protective effect against hypoxemia, the extract of Hypericum perforatum (sample 5) was tested for its effect on brain dysfunction caused by a rapid decrease in intracerebral ATP caused by hypoxic conditions. was investigated by examining its protective effect on the respiratory center. [0028] That is, C3H mice (body weight 30-40
Using g), 9 mice were used in group I, and the mice were placed in an environment of 100% carbon dioxide, and the time until the final breath was measured to determine the survival effect. [0029] The extract of Hypericum perforatum (sample 5) is I
Orally (p,o,) administered at C0mg,/kg, part 10
The experiment was performed after a minute. In addition, the same volume of water was administered orally (p, o,) to the control group. (00301 (Results) The average survival time of the control group was 38.5 seconds, but the average survival time of the group administered with Hypericum perforatum extract (sample 5) was 44.3 seconds, which was significantly prolonged. (Figure 3). [00311 These results show that the extract of Hypericum perforatum has the effect of protecting the respiratory center and therefore has a brain protective effect against hypoxemia. [0032] (4) Acute Toxicity test Hypericum perforatum extract (sample 5) was administered to mice at 10 g/kg.
No deaths were observed even after oral administration. Therefore, the extract of Hypericum perforatum, which is the active ingredient of the anti-dementia agent of the present invention, is extremely safe. [00331 The anti-dementia agent of the present invention can be administered orally or parenterally. [00341 When the anti-dementia agent of the present invention is used as an oral drug, the extract can be administered as it is, but the effect can be further enhanced by forming it into various dosage forms commonly used in oral preparations. I can do it. These dosage forms include solid preparations such as tablets, gunpowder, granules, fine granules, powders, and capsules; emulsions, solutions, suspensions, syrups,
Examples include liquid agents such as elixirs; inhalants such as sprays. [00351 When the anti-dementia agent of the present invention is a solid preparation, in addition to the active ingredients, inert substances such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, magnesium aluminate metasilicate, etc. A diluent; a lubricant such as magnesium stearate; a disintegrant such as cellulose calcium gluconate, and the like can be contained. In addition, in the case of tablets or gunpowder, white sugar, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose,
It can be coated with one or more layers of gastric or enteric films such as phthalate. Furthermore, in the case of liquid preparations, in addition to the active ingredients, the above-mentioned inert diluents; auxiliary agents such as wetting agents and suspending agents; sweeteners, flavoring agents, aromatics, preservatives, etc. can be contained. . [0036] Furthermore, when the anti-dementia agent of the present invention is used as a parenteral drug, typical preparations include injections. In this case, the extract of Hypericum perforatum may be dissolved in an aqueous medium such as distilled water for injection or physiological saline; a vegetable oil such as propylene glycol, polyethylene glycol, or olive oil; an alcohol such as ethanol; or a non-aqueous medium such as polysorbate 80; If it is made cloudy, an injection can be obtained. When the anti-dementia agent of the present invention is an injection, it may contain auxiliary agents such as preservatives, wetting agents, emulsifiers, and dispersants in addition to the active ingredients. Sterilization methods required for injections include a filtration method in which the drug is passed through a bacteria retention filter, a method in which a sterilizing agent is added, and an irradiation sterilization method. These injections can be prepared in the form of an injection from the beginning, but the active ingredient, Hypericum perforatum extract, is made into a sterile solid composition by an appropriate method, and immediately before use, it is mixed with sterile water or a sterile injection. It is also possible to use it by dissolving it in a solvent for use. [0037] Other preparations for use as parenteral drugs include coating agents such as suspensions and emulsions; academic regulations, pessaries, and the like. [0038] In addition to the above-mentioned active ingredients, these preparations also contain:
Furthermore, distilled water; lower alcohols such as ethanol; higher alcohols such as cetanol; polyethylene glycol,
Polyhydric alcohols such as propylene glycol; Celluloses such as hydroxypropyl cellulose; Animal fats and oils,
Vegetable oils, synthetic oils; vaseline, wax, silicone, surfactants; diluents such as zinc oxide; auxiliary agents such as wetting agents, suspending agents, fragrances, preservatives, etc. can be blended. [0039] The dosage of the anti-dementia agent of the present invention depends on age, body weight,
Although it varies depending on various factors such as gender, symptoms, therapeutic effects, administration method, and treatment time, the amount of the active ingredient Hypericum perforatum extract is usually 1 to 10 g per adult per dose when administered orally. In particular, it is preferable to administer a dose in the range of 20 to 2 g, divided into once to several times a day. In addition, in the case of parenteral administration, the dose is usually 100 μg per adult.
It is preferable to administer 1 g, especially 11 g to 200 mg, divided into once to several times a day. [00401] [Effect of the invention] The extract of Hypericum perforatum, which is the active ingredient of the anti-dementia agent of the present invention, has a brain-protective effect by protecting the respiratory center, and has been shown to be active in a scopolamine-induced amnesia model, and is safe. The sex is also extremely high. Therefore, the anti-dementia agent of the present invention is useful for treating memory disorders such as Alzheimer's dementia and cerebrovascular dementia. [00411] [00411] [00411] Next, the present invention will be explained with reference to Examples, but the present invention is not limited thereto. [0042] Reference Example 1 After pulverizing 500 g (dry weight) of a whole plant of Hypericum perforatum, 70% methanol aqueous solution 21 was added, heated to 50°C and shaken for one week, and the extract was filtered. The resulting filtrate was designated as Sample 1. [0043] Reference Example 2 After pulverizing 500 g (dry weight) of a whole plant of Hypericum perforatum, ethanol 21 was added and extraction was carried out by immersion at room temperature for one week. The solvent was distilled off, and 90% aqueous methanol solution was added to the residue.
After adding 51, the solvent was distilled off to obtain 35.8 g of a residue. Subsequently, 20 On+1 of water was added to this residue, liquid-liquid distribution was performed three times with 200 ml of ethyl acetate to remove the ethyl acetate transfer portion, and then 150 ml of n-butanol was added 3 times.
Liquid-liquid distribution was performed. The solvent was distilled off from the butanol layer to obtain 5.4 g of a butanol fraction, which was designated as sample 2. [0044] Reference Example 3 The solvent of Sample 1 obtained in Reference Example 1 was distilled off, leaving a residue of 45.3
I got g. After dissolving 20.0 g of this in 100 ml of 50% ethanol water, 4.5 g of activated carbon was added. After adding Og and stirring at room temperature for 5 hours, filtration was performed and the solvent was distilled off to obtain 17.0 g of a residue. Subsequently, 50 ml of water was added to this residue, and the synthetic adsorbent Diaion HP-20250 ml was passed through a column prepared with water to remove 13.3 g of unadsorbed area.
2.9 g of the adsorbed portion eluted with methanol was obtained. The non-adsorbed part was designated as Sample 3, and the adsorbed part was designated as Sample 4. [0045] Reference Example 4 After pulverizing 500 g (dry weight) of a whole plant of Hypericum perforatum, methanol 21 was added and extraction was carried out by immersion. The solvent was distilled off to obtain 53.6 g of residue. Then add 50% water to this residue.
0ml was added and aged for one week at room temperature. then 10
% activated carbon, and the unadsorbed portion was further passed through an ion exchange resin Amberlite IRA400, and then the unadsorbed portion was passed through a synthetic adsorbent Diaion HP-20, and the unadsorbed portion was passed through a synthetic adsorbent Diaion HP-20.
4 g and 7.1 g of methanol eluate were obtained. Sample 5 was the adsorption area eluted by methanol. [0046] Example 1 Tablet: Hypericum extract (sample 4) Crystalline cellulose Lactose Magnesium stearate Hydroxyprobyl cellulose 50■ 80■ 120■ 4■ 26■ Tablets were manufactured by a conventional method using the above ingredients. did. 280 ■ [0047] Example 2 Hard capsules: Hypericum perforatum extract (sample 4) Lactose starch magnesium stearate 50 ■ 168 ■ 50 ■ 2 ■ Hard capsules were manufactured by a conventional method using the above ingredients. . 270■ [0048] Example 3 Granules: Hypericum perforatum extract (sample 4) Lactose D-mannitol Sodium carboxymethyl cellulose Hydroxyprobyl cellulose 50■ 40mg 200■ 20■ 130■ Measurement Using the above ingredients, by a conventional method Granules were manufactured. 40 mg [0049] Example 4 Half open: Hypericum extract (sample 5) Lytepsol (H-15) Lytepsol (E-75) 10■ 745■ 745■ Total 1500■ Using the above ingredients, a conventional method A half-open one was manufactured by [00501 Example 5 Injection: Hypericum perforatum extract (sample 5) 0, IN benzyl hydrochloride alcohol Distilled water meter for injection An injection was prepared by a conventional method using the above ingredients. 0Ing 0.1ml m10O3 Appropriate amount 10 (ml)

[Brief explanation of the drawing]

FIG. 1 is a drawing showing the test results of the central cholinergic action of Hypericum extract (Sample 5).

FIG. 2 is a drawing showing the test results of the effect of Hypericum extract (Sample 5) on scopolamine-induced amnesia.

FIG. 3 is a drawing showing the test results of the cerebral protective effect against hypoxemia of Hypericum perforatum extract (sample 5).

[Figure 1]

[Figure 2]

[Figure 3]

Claims (2)

[Claims] Claim 1: An anti-dementia agent containing an extract of Hypericum perforatum as an active ingredient. 2. The anti-dementia agent according to claim 1, wherein the extract of Hypericum perforatum is extracted from Hypericum perforatum using water and/or a water-soluble polar solvent.