JPH0930976A - Improver for reduction in memory - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject new improver comprising purine nucleoside and pyrimidine nucleoside as active ingredients, improving reduction in memory caused by senile dementia, having no adverse action. SOLUTION: This improver for reduction in memory comprises (A) a compound selected from purine nucleosides and (B) a compound selected from pyrimidine nucleosides as active ingredients. Inosine is used as the component A and cytidine and uridine are used as the component B. Thymidine and guanosine 5'-monophosphate disodium salt (5'-GMP-2Na) are preferably used as other nucleic acid constituent components. The components are preferably blended in the molar ratio of inosine/cytidine/uridine/5'GMP2NA/thymidine of 4:4:3:4:1. The objective improver is preferably made into an injection form suitable for intravenous dosage. The concentration of the active ingredients in the improver is preferably 2-8w/v%. A dose is preferably 1-20ml (30-620mg of the amount of the active ingredients) per adult daily in the case of an infection.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an agent for improving memory deterioration, and more particularly to a new agent for improving memory deterioration due to senile dementia and the like.

[0002]

BACKGROUND OF THE INVENTION Dementia refers to an acquired, non-recoverable, intellectually deficient condition caused by various organic diseases of the brain. In other words, dementia, which once reached an extraordinary stage, then became obsolete, and is different from mental retardation, which is a natural cessation of intellectual development.

The above dementia can be classified into the following various types. That is, memory dementia with a loss of memory function, such as senile dementia, as the main symptom, mistaken judgment such as that seen in advanced paralysis, constructive dementia that acts unfit for purpose, epilepsy or traumatic dementia. The dementia, etc., has a markedly impaired take-up force as shown in FIG.

Of these, senile dementia has become one of the major social problems as the average life expectancy has been extended in recent years, and research on agents for improving senile dementia and the like has been earnestly studied. However, a drug with sufficient efficacy has not been developed or provided yet, and it is desired in the art to provide a new drug of this kind.

[0005]

SUMMARY OF THE INVENTION Therefore, an object of the present invention is to provide a novel memory-improving agent.

[0006]

The above object can be achieved by the memory-improving agent of the present invention having the following constitution.

[0007] That is, according to the present invention, there is provided a memory-reduction improving agent comprising at least two compounds selected from purine nucleosides (or purine bases) and pyrimidine nucleosides as active ingredients. To be done.

Particularly, according to the present invention, the above-mentioned memory-improving agent, wherein the purine nucleoside (or base) is inosine and the pyrimidine nucleosides are cytidine and uridine, (1) inosine, (2) cytidine, and (3) uridine. , (4) a compound selected from guanosine, guanosine 5′-1 phosphate (hereinafter referred to as “5′GMP”) and salts thereof, and (5) the above-described memory-improving agent containing thymidine as an active ingredient, inosine, Cytidine, uridine,
A compound selected from the above-mentioned memory-improving agent containing a salt of 5'GMP and thymidine as an active ingredient, (1) inosine, (2) cytidine, (3) uridine, (4) guanosine, 5'GMP and salts thereof. And (5) the memory-improving agent containing thymidine in a molar ratio of 4: 4: 3: 4: 1, and inosine, cytidine, uridine,
The above-mentioned memory-improving agents containing guanosine, 5'GMP and a salt thereof, and thymidine in a molar ratio of 4: 4: 3: 4: 1 are provided, respectively.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the memory lowering improving agent of the present invention,
The compound selected from purine nucleosides (or purine bases) as one of the active ingredients may be any of the conventionally known purine nucleosides or purine bases, including adenine, inosine and guanosine (pharmacologically acceptable salts). The same shall apply hereinafter) are included, and these may be used alone or in combination of two or more. Inosine is particularly preferred among others. The compound selected from pyrimidine nucleosides as the other active ingredient may be any of the commonly known compounds, and includes cytidine and uridine. These may be used alone, but it is more preferable to use two or more in combination. The combined ratio of both active ingredient compounds is not particularly limited, but usually purine: pyrimidine = 1: 0.2 to 5
(Molar ratio, the same applies hereinafter), preferably within the range of 1: 0.5 to 2.

The memory-improving agent of the present invention contains at least two kinds of compounds selected from the above-mentioned purine nucleoside or purine base and a compound selected from pyrimidine nucleosides as an active ingredient, and thus is excellent in the intended purpose of the present invention. In addition to the above two purine and pyrimidine components, other nucleic acid constituents or salts thereof can be used in combination, and the desired effects can also be achieved. You can Among the combined components, particularly preferable ones are, for example, thymidine and 5 '.
GMP or its salt can be illustrated. The 5'GMP salts include pharmacologically acceptable alkali metal salts such as sodium and potassium, and particularly disodium salt (5'GMP
-2Na) is preferred because of its high solubility. It is preferable that the combination components are usually selected in a range of about 0.2 to 5 times mol, and particularly about 0.2 to 2 times mol of thymidine, relative to 1 mol of the purine and / or pyrimidine. In the case of'GMP and its salt, it is suitable to be selected from the range of 0.5 to 2 times mol.

[0011] Preferable combinations containing the above-mentioned two types of nucleosides constituting the memory-improving agent of the present invention include, for example, (1) adenine / cytidine, (2) adenine / uridine, (3) inosine / cytidine, (4). Inosine / uridine, (5) guanosine / uridine, (6) guanosine / cytidine, (7) adenosine / cytidine / uridine, (8) inosine / cytidine / uridine, (9) guanosine / cytidine / uridine, (10) adenosine / Inosine / cytidine, (11) adenosine / guanosine /
Uridine, (12) adenosine / inosine / cytidine /
Uridine, (13) adenosine / inosine / guanosine / cytidine, (14) cytidine / 5′GMP / uridine / inosine / thymidine, (15) cytidine / 5′GMP
-2Na / uridine / inosine / thymidine, (16) cytidine / 5'GMP-2Na / uridine / adenosine /
Thymidine, (17) cytidine / 5'GMP-2Na / uridine / guanosine / thymidine, (18) adenosine /
5'GMP-2Na / uridine / guanosine / thymidine, (19) cytidine / adenosine / 5'GMP-2N
Examples include a / uridine / inosine / thymidine and the like.

Among the above, especially (15) cytidine / 5 '
A combination of GMP-2Na / uridine / inosine / thymidine is preferable, and the mixing ratio (molar ratio) of each component constituting the combination is preferably, for example, 4: 4: 3: 4: 1.

The drug of the present invention can be prepared into an appropriate pharmaceutical preparation form suitable for its application by weighing the respective components in the above composition and according to a conventional method. The form is not particularly limited and may be the same as a usual drug, but it is particularly preferably an injection form suitable for intravenous administration. The injection form can be prepared by mixing and dissolving the above-mentioned predetermined components in distilled water for injection according to a conventional method, and if necessary, various additives commonly used, such as hydrochloric acid, acetic acid, malic acid, and citric acid. It can be prepared by adding a pH adjusting agent such as acid, sodium hydroxide or potassium hydroxide, a stabilizer and the like to adjust the pH of the aqueous solution to usually about 6 to 9 and then sterilizing the resulting aqueous solution by heating or sterilizing it. The concentration of all the active ingredients in the thus prepared injectable form of the memory-improving agent of the present invention is not particularly limited, but is generally about 0.5 to 10 w / v%, preferably about 2 It is suitable to be about 8 w / v%.

The memory lowering improving agent of the present invention exerts an excellent ability to improve memory lowering and is very unlikely to cause side effects when it is applied to a patient in various forms as described above. The dose applied to the patient is not particularly limited and can be appropriately determined according to the pathological state of the patient to which it is to be administered, age, sex, body weight, degree of disease, etc. About 0.5-50m per adult per day
An amount of 1 or preferably about 1 to 20 ml (about 30 to 620 mg of active ingredient) can be used as a standard.

[0015]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a new agent for improving memory deterioration, which is particularly effective in improving memory deterioration due to senile dementia and the like and which is substantially free of side effects.

[0016]

[Examples] In order to explain the present invention in more detail, preparation examples of the preparation of the present invention will be given below as Examples, followed by pharmacological test examples.

[0017]

Example 1 Pure crystals of each component having the following composition (numerical values in parentheses indicate molar ratios, the same applies hereinafter) were added to distilled water for injection and dissolved by stirring to make a total amount of 1 liter. Then, the obtained aqueous solution is aseptically filtered and filled in an injection container, and after closing the container, this is sterilized in an autoclave at 105 ° C. for 40 minutes to prepare a book in the form of an injection (5 ml × 200 bottles). Inventive memory-improving agents were prepared. The total free nucleic acid concentration of this product is 3.35 w / v%.

Inosine 0.80 w / v% (4) Cytidine 0.73 w / v% (4) 5'GMP-2Na 1.22 w / v% (4) Uridine 0.55 w / v% (3) Thymidine 0. 18w / v% (1)

[0019]

Example 2 Adenine 60 mM (0.81 w / v%,
(1)) and uridine 60 mM (1.47 w / v%,
The two-component system memory-improving agent of the present invention was prepared in the same manner as in Example 1 except that the respective amounts of (1)) were used.

[0020]

Example 3 Inosine 53.3 mM (1.43 w / v
%, (4)), 5'GMP-2Na 53.3 mM (2.
17 w / v%, (4)) and thymidine 13.3 mM
The three-component system memory-improving agent of the present invention was prepared in the same manner as in Example 1 except that each component was used in an amount of (0.32 w / v%, (1)).

[0021]

Example 4 Inosine 2.4 with each component as pure crystals
g, cytidine 2.2 g, 5'GMP-2Na 3.7 g,
After uridine (1.7 g) and thymidine (0.5 g) were mixed by sieving each component with a 60-mesh sieve, starch (89.5 g) was added as an excipient and mixed evenly. The memory-improving agent of the present invention in powder form was prepared.

The molar ratio of each component in the obtained preparation is inosine: cytidine: 5'GMP-2Na: uridine: thymidine = 4: 4: 4: 3: 1.

[0023]

Example 5 A memory loss-improving agent of the present invention was obtained in the same manner as in Example 4, except that 3.7 g of guanosine was used instead of 5'GMP-2Na.

[0024]

[Pharmacological test example 1] Disease model animal (application to nutrition research, supervised by the Japanese Society of Nutrition and Food P196-213, Chapter 7
In the SAM-P / 8 learning / memory disorder mouse described in “Aging-promoting model mouse, 1994 Kenfusha edition”, from weaning period to C
RF-1 (manufactured by Oriental Yeast Co., Ltd.) was fed to the animals and they were bred as experimental animals.

At the age of 6 months, the above-mentioned experimental animals were screened by the following method to select experimental animals having uniform memory ability.

(Screening Method) A galvanic metal net was stretched over the entire floor surface of a suitable cage, a small wooden block was placed on the metal net in one corner of the cage, and a mouse was placed on the block. When the mouse descends from the block onto the metal net,
Electric shock (50V x 0.5se by energizing the metal net)
c) was given and this was repeated up to 10 times, and it was evaluated that the learning was achieved when the mouse was able to stay on the block for 5 minutes.

Regarding the mice that have achieved learning as described above, mice can be placed on the small blocks of the cage again and stayed for 5 minutes, 24 hours and 1 week later, respectively, in order to check the memory status. Was selected as the experimental animal.

The experimental animals screened above were
Group (control group and the memory-improving agent administration group of the present invention,
The present invention group) and was subjected to the following learning test and memory test.

The experimental animals used were 230.
They were in the range of 3 ± 6.7 days of age, and had a diet of the following composition ad libitum from the start of the learning test.

[0030]

[Table 1]

Further, in order to more accurately judge the results of the learning test and the memory test, normal mice of 8 weeks of age (the above CRF-1 diet was fed until 4 weeks of age, and 4 weeks after 4 weeks of age). The same learning and memory test was also carried out for those (bred that were fed with the same feed as the above control group).

(Learning test) A partition plate having an opening with a door through which a mouse can enter and exit is installed in the center of a breeding cage of an appropriate size, the cage is divided into two rooms, and one room is covered with a blackout curtain to darken the room. Then, a galvanic metal net was stretched on the floor of the dark room to prepare a test cage.

The other one chamber of the above test cage (bright chamber)
When I put the mouse in, the mouse felt anxious and tried to enter the dark room. At this time, the electric shock (50 V
X 0.5 sec) was given, and the number of electric shocks received until it became possible to stay in a bright room for 5 minutes (until learning was achieved) was measured.

(Memory test) Further, with regard to the mice that achieved learning as described above, 1 week and 2 weeks after the achievement of learning,
Each was put in the same bright room and examined whether it could stay in the room for 5 minutes.

The results of the above learning test are shown in FIG. 1 (vertical axis: electric shock avoidance achievement rate (%), horizontal axis: number of electric shocks).
In addition, the results of the memory test are shown in FIG. 2 (vertical axis: electric shock avoidance achievement rate (%), horizontal axis: elapsed time (week) after learning test).
Are shown below.

In each figure, is the group of the present invention (n = 6), is the control group (n = 7), and is the normal mouse group (n =).
8) are respectively shown.

From each figure, the following is clear. That is, in a test using an aging-promoting model mouse, the group that is ingesting the drug of the present invention, compared to the control group that is not ingested, learning is faster and memory decline is slower. It can be seen that the drug of the present invention is effective in improving memory deterioration.

[0038]

[Pharmacological Test Example 2] (Memory Test) The same test cage as used for the learning test and the memory test in Pharmacological Test Example 1 (however, the opening door is closed) was used, and 272.3 ± 6. A 7-day-old mouse was placed in the bright room for 10 seconds. After that, the door was opened to wait until the mouse entered the dark room. When the mouse entered the dark room, the dark room was made to experience for 10 seconds, and then the mouse was returned to a normal breeding cage.

Then, the mouse was placed in the bright room of the test cage with the door closed again, the door was opened after 10 seconds, and the electric shock (50 V x 0.5 se) was entered when the mouse entered the dark room.
c) was given only once, and it was returned to a normal breeding cage (for learning).

After 24, 48 and 72 hours and 1 week later, the mice were placed in a bright room of the same test cage to examine whether or not they could stay there for 5 minutes.

The results are shown in FIG. 3 (vertical axis: electric shock avoidance achievement rate (%), horizontal axis: elapsed time (hours) after learning).
In the figure, represents the group of the present invention (n = 5) and represents the control group (n = 6).

From the figure, it is clear that the drug of the present invention has an effect of improving memory depression.

[0043]

[Pharmacological Test Example 3] The same test as in Pharmacological Test Example 2 was conducted using 329.3 ± 6.7-day-old mice.
The memory status of each mouse after 72 hours was examined.

The results are shown in FIG. 4 as in FIG.

From the figure also, it is clear that the drug of the present invention has an excellent memory-lowering improving action. From these facts, the drug of the present invention is particularly effective in improving memory-impairment in congenital dementia and aging. I understand.

[Brief description of drawings]

FIG. 1 is a graph showing the results of a learning test conducted according to Pharmacological Test Example 1.

FIG. 2 is a graph showing the results of a memory test conducted according to Pharmacological Test Example 1.

FIG. 3 is a graph showing the results of a memory test conducted according to Pharmacological Test Example 2.

FIG. 4 is a graph showing the results of a memory test conducted according to Pharmacological Test Example 3.

Claims (6)

[Claims] 1. A memory-reducing agent comprising at least two compounds selected from purine nucleosides and compounds selected from pyrimidine nucleosides as active ingredients. 2. The memory-improving agent according to claim 1, wherein the purine nucleoside is inosine and the pyrimidine nucleoside is cytidine and uridine. 3. (1) Inosine, (2) cytidine, (3)
The memory lowering improving agent according to claim 1, which comprises, as an active ingredient, a compound selected from uridine, (4) guanosine, guanosine 5'-1 phosphate and salts thereof, and (5) thymidine. 4. The memory-improving agent according to claim 3, which contains inosine, cytidine, uridine, a salt of guanosine 5'-1 phosphate and thymidine as active ingredients. 5. (1) Inosine, (2) cytidine, (3)
The compound selected from uridine, (4) guanosine, guanosine 5'-1 phosphate and salts thereof, and (5) thymidine in a molar ratio of 4: 4: 3: 4: 1. Memory-improving agent. 6. Inosine, cytidine, uridine, a salt of guanosine 5'-1 phosphate and thymidine in a molar ratio of 4: 4 :.
The memory deterioration improving agent according to claim 5, which is contained at a ratio of 3: 4: 1.