JP3306459B2 - Amyloidosis preventive and therapeutic agent - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to an agent for preventing and treating amyloidosis.

[0002]

[Prior art and its problems] amyloidosis (amyloidosis)
)) Refers to a state in which a substance called amyloid is deposited on various organ tissues and the organ function is impaired.

[0003] Amyloidosis is classified into various types, all of which have a histopathologically unstructured substance resembling the vitreous, and which have a width of less than 10 nm under an electron microscope. It is seen as a collection of fibrils (amyloid fibrils). The place of deposition is exclusively interstitial, starting at the vessel wall, around the basement membrane, and the like. Amyloid is lightly stained with eosin on a tissue specimen, but its reaction to collagen staining is warm, which is different from general vitreous. Histochemically, Congo red stains orange-red, and under polarized light microscope, it shows green polarized light. By confirming these, it is identified as amyloid. The term amyloid (amyloid) is derived from a positive iodine reaction, which proves the presence of immunoglobulin-derived L-chain protein in the form of an immunoglobulin. It is presumed to be involved in the reaction. However, there are still many unclear points regarding the site of amyloid production and the mechanism of the production.

Conventionally, dimethyl sulfoxide (DMSO) has been used for the treatment of the amyloidosis described above (Clinical dermatology, Vol. 27, No. 8, p.
879-882 (1985), Journal of Geriatrics Society of Japan, V
ol. 19, no. 4, P370-374 (1982)
Etc.).

[0005] An object of the present invention is to provide a novel amyloidosis preventive and therapeutic agent containing as an active ingredient a compound completely different from conventional amyloidosis therapeutic agents. In particular,
An object of the present invention is to provide an amyloidosis preventive agent which has not existed conventionally.

[0006]

That is, according to the present invention,
A preventive and therapeutic agent for amyloidosis, comprising as an active ingredient a nucleic acid component comprising inosine, cytidine, guanosine 5'-phosphate , uridine, and thymidine and / or a pharmaceutically acceptable salt thereof. Is done.

[0007] The nucleic acid component used in the present invention is a compound which has been studied by the present applicant for a long time, and is already known. For example, JP-A-58-233142 describes a specific nucleic acid component developed as a nutritional supplement. JP-A-61-277619 discloses the same component developed as a therapeutic agent for liver disease.
Further, JP-A-3-135918 discloses the same component as an immunostimulant.

The present inventors have conducted further intensive studies thereafter, and as a result, surprisingly surprisingly, the above nucleic acid component is effective as a prophylactic and therapeutic agent for amyloidosis, which is different from the previously developed pharmaceutical use. We found the new fact that there is, and completed the present invention here.

The nucleic acid component used as the active ingredient in the present invention is based on the premise that the above five specific components are used in combination, and the combination ratio thereof is not particularly limited. The following relative molar ratio can be exemplified as a composition suitable for exhibiting the most excellent effect as an agent.

Nucleic acid constituent relative molar ratio Inosine 4 Cytidine 4 Guanosine 5′-phosphate 4 Uridine 3 Thymidine 1 The nucleic acid constituent as an active ingredient used in the present invention is:
It may be in the form of a pharmacologically acceptable salt. Pharmaceutically acceptable salts may be any of the usual types, especially guanosine.
5′-Phosphoric acid (hereinafter referred to as “5′-GMP”) is preferably used in the form of a highly soluble disodium salt or the like.

The dosage unit form of the prophylactic and therapeutic agent for amyloidosis of the present invention can be selected as appropriate, for example, in the form of a liquid such as an injection or an oral preparation such as tablets, granules, powders, solutions, suspensions and emulsions. It can be appropriately used in the form. Among them, the powder form is preferred.

The preparation into various forms can be carried out according to a conventional method. For example, the preparation of the present invention in the form of an injection can be prepared in the same manner as a usual injection, typically in distilled water for injection. Is mixed and dissolved, and if necessary, various commonly used additive components such as hydrochloric acid, acetic acid, lactic acid, malic acid, citric acid, sodium hydroxide, potassium hydroxide, etc. An appropriate amount of an agent or the like is added, and the resulting aqueous solution can be adjusted by aseptic sterilization by heat sterilization or aseptic filtration.

The thus prepared preventive and therapeutic agent for amyloidosis in the form of a liquid preparation can have the same pH as that of an injection such as an ordinary infusion. The preferred pH can be in the range from about 3.0 to 9.0, particularly preferably from about 5.0 to 8.0. The concentration of the nucleic acid component and / or a pharmaceutically acceptable salt thereof in the preparation is usually about 0.5 to 10 w / v%, preferably about 2 to 8 w / v%. Is appropriate.

The preparation of the present invention can also be in the form of a solid preparation such as a tablet. For example, when forming the tablet form, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, Excipients such as kaolin, crystalline cellulose, silicic acid, water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, binders such as carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinyl pyrrolidone, drying Starch, sodium alginate,
Agar powder, laminaran powder, sodium bicarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose sugar disintegrant, sucrose stearin, cocoa butter, hydrogenated oil, etc. Agents, quaternary ammonium bases, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and denbun, adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid, purified talc, stearate, borate Lubricants such as acid powder and polyethylene glycol can be used. Further tablets are tablets coated with ordinary skin as required, such as sugar-coated tablets,
Gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double tablets, and multilayer tablets can be used.

In the case of molding into a pill form, examples of the carrier include excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable fat, kaolin, talc, gum arabic powder, tragacanth powder, gelatin, ethanol and the like. Binder,
Disintegrant sugars such as laminaran and agar can be used. When molded into a suppository, the carrier may be, for example, polyethylene glycol, cocoa butter, higher alcohol,
Esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be used.

In order to form a powder, the active ingredient crystals of the present invention, which have been sieved through a sieve, may be used as a carrier, for example, lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystal. What is necessary is just to mix uniformly with an excipient, such as cellulose and silicic acid.

The dosage (dose) of the prophylactic and therapeutic agent for amyloidosis of the present invention to a patient is appropriately selected depending on the pathological condition, age, weight, sex, degree of disease, etc. of the patient to which the agent is administered, and is particularly limited. Usually, the amount can be about 0.5 to 5 g per adult per day, preferably about 1.5 to 2.5 g per day. . And the above dosage is 1 to 1 per day
It can be administered in four divided doses.

[0018]

EXAMPLES Hereinafter, in order to further clarify the present invention, production examples of the prophylactic and therapeutic agents for amyloidosis of the present invention will be described as examples, followed by test examples.

Example 1 Pure crystals of each component having the following composition were added to distilled water for injection, and dissolved by stirring to make the total volume 1 liter. Then, the obtained aqueous solution is aseptically filtered and filled into an injection container. After closing the container, the container is sterilized in an autoclave at 105 ° C. for 40 minutes to obtain an injection (× 200 in 5 ml). Inventive amyloidosis preventive and therapeutic agents (total free nucleic acid concentration 3.
(35 w / v%).

[0020] Example 2 2.4 g of inosine, 2.2 g of cytidine, 3.7 g of 5'-GMP.2Na, 1.7 g of uridine, and 0.5 g of thymidine as pure crystals of each nucleic acid component were sieved through a 60-mesh sieve. After mixing, 89.5 g of starch as an excipient was added and mixed evenly to prepare a prophylactic and therapeutic agent for amyloidosis of the present invention as a powder.

The ratio of each nucleic acid component in the obtained preparation is
The molar ratio of inosine: cytidine: 5′-GMP · 2Na:
Uridine: thymidine = 4: 4: 4: 3: 1.

Example 3 A prophylactic and therapeutic agent for amyloidosis of the present invention as a powder was prepared in the same manner as in Example 2 except that each component was adjusted as follows.

[0023] Example 4 A prophylactic and therapeutic agent for amyloidosis of the present invention as a powder was prepared in the same manner as in Example 2 except that each component was adjusted as follows.

[0024] Example 5 A prophylactic and therapeutic agent for amyloidosis of the present invention as a powder was prepared in the same manner as in Example 2 except that each component was adjusted as follows.

[0025] Pharmacological test 1 B6C3F1 mice were divided into three groups, and one group (27 animals) contained 0.5% by weight of the nucleic acid component obtained in Example 2 in AIN-76B-containing purified feed (manufactured by Oriental Corporation) having a clear amino acid composition. The other group (26 animals) was fed a diet (2.5% group) with the same nucleic acid component added to the same purified diet (2.5% group). Do)
Gave. Still another group (control, 31 animals) was fed only the above-mentioned compounded and purified food (0% group).

The mice in each of the above groups were bred one week before irradiation, and at the age of 6 weeks, ²⁵² Cf (Californium-
252) was irradiated once with whole body at 2 Gy (0.8 Gy / min). Each group of mice was kept on each diet after the irradiation, and sacrificed 13 months after the irradiation.

As a result of the above test, amyloidosis mainly in the spleen occurred at a high rate of 9 (29%) in the 0% group.
Two animals (7%) in the 0.5% group and four animals (1
5%), indicating that the nucleic acid component, which is the active ingredient of the present invention, is useful as an agent for preventing and treating amyloidosis.

Pharmacological Test 2 B6C3F1 mice were divided into three groups, and one group (31 cases) contained the nucleic acid component obtained in Example 2 in a commercially available standard feed (containing nucleic acid, manufactured by Oriental Yeast Co., Ltd.). The diet (M + 0.5% group) supplemented with 5% by weight was added to another group (29
For example), only the standard feed (M + 0% group) was given.

The mice in each group were bred one week before irradiation, and at the age of 6 weeks, ²⁵² Cf (Californium-
252) was irradiated once with whole body at 2 Gy (0.8 Gy / min). Each group of mice was kept on each diet after the irradiation, and sacrificed 13 months after the irradiation.

As a result of the above test, the incidence of amyloidosis of the spleen was 6 cases (21%) in the M + 0% group, but 4 cases (13%) in the M + 0.5% group.

Therefore, according to the utilization of the specific nucleic acid component which is the active ingredient of the present invention, ordinary diet (including nucleic acid)
It was found that the prevention and treatment of amyloidosis can be more effectively performed as compared with the case in which is taken.

────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-4-243830 (JP, A) JP-A-4-33092 (JP, A) JP-A-5-194580 (JP, A) JP-A-6-1994 192106 (JP, A) JP-A-3-135918 (JP, A) JP-A-61-277619 (JP, A) JP-A-4-505006 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 31/7042-31/708 A61P 43/00 CA (STN) CAOLD (STN) MEDLINE (STN) WPI (DIALOG)

Claims (2)

(57) [Claims] 1. Inosine, cytidine, guanosine 5'-li
A prophylactic and therapeutic agent for amyloidosis, comprising as an active ingredient a nucleic acid component composed of an acid , uridine and thymidine and / or a pharmaceutically acceptable salt thereof. 2. The prophylactic and therapeutic agent for amyloidosis according to claim 1, wherein the relative molar ratio of the nucleic acid components is the following molar ratio. Nucleic acid components Relative molar ratio Inosine 4 Cytidine 4 Guanosine 5'-phosphate 4 Uridine 3 Thymidine 1