JPH0331178B2 - - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an ischemic brain disease ameliorating agent comprising as a main component a protein polysaccharide derived from a basidiomycete belonging to the genus Corsicolor, and more particularly to an ischemic brain disease ameliorating agent comprising crestin. Krestin has already been provided to society as an antitumor agent, has extremely low toxicity, and can be administered for a long period of time without worrying about disturbance of intestinal flora. Furthermore, it has no effect on mutagenicity or allergic reactions, and is therefore extremely safe, with no risk of teratogenicity or allergic reactions in healthy people. The present inventors have discovered that the protein polysaccharide of the present invention has not only an antitumor effect but also a pharmacological effect as an ischemic brain disease ameliorating agent, which led to the present invention. The protein polysaccharide which is the active ingredient of the ischemic brain disease improving agent of the present invention is disclosed in, for example, Japanese Patent Publication No. 46-17149,
It is a known substance described in Japanese Patent Publication No. 51-36322, Japanese Patent Publication No. 14274, Japanese Patent Publication No. 14276, Japanese Patent Publication No. 39288, etc. An extract of mycelium, broth, or fruiting body obtained by culturing with hot water or alkaline aqueous solution, about 18 to 38
% protein and has a molecular weight of 5,000 to 300,000 (ultracentrifugation measurement method). Among the protein polysaccharides of the present invention, Corsiella versicolor mycelium [FERM-
P2412 (ATCC20547)] is commercially available under the trade name Krestin (Recent New Drugs Vol. 28, pp. 14-16, 1977 and Vol. 29, pp. 96-101). , 1978,
Pharmaceutical Handbook No. 1346, May 1976 6th edition,
Published by Yakugyo Jihosha, Medical Drugs Japan Pharmaceutical Collection 7th Edition
240 pages, 1983, published by Yakugyo Jihosha), PS-K
Some of its properties are as follows. The sugar moiety of the main fraction is β-D-glucan, and the structure of this glucan moiety is 1→3, 1→4 and 1→
It has a branched structure containing 6 bonds, and the amino acids that make up the protein are mostly acidic amino acids such as aspartic acid and glutamic acid, and neutral amino acids such as valine and leucine, and few basic amino acids such as lysine and arginine. Soluble in water, almost insoluble in methanol, pyridine, chloroform, benzene, and hexane. Gradually decomposes from about 120℃. In the red blood cells of animals administered with the protein polysaccharide, which is the active substance of the present invention, a decrease in the rate of hemolysis against mechanical hemolysis, that is, an improvement in deformability was observed. Blood flow in cerebral ischemic conditions is microcirculation, and it has been revealed that the active substance of the present invention can facilitate blood circulation by improving the deformability of red blood cells. It also has the effect of suppressing thrombotic death caused by arachidonic acid. The protein polysaccharide of the present invention is known to be an extremely safe substance for living organisms, having extremely low toxicity and causing almost no side effects. The acute toxicity values of the protein polysaccharide of the present invention are shown in Table 1 below. [Table] The acute toxicity values shown in Table 1 above were determined using the following test method. Mice are ICR-JCL strain, 4-5 weeks old, weight 21~
A 24 g sample was used, and the rats were 4- to 5-week-old, weighing 100 to 150 g. The protein polysaccharide of the present invention was administered through four routes: intravenous, subcutaneous, intraperitoneal, and oral. The protein polysaccharide of the present invention was dissolved in physiological saline and administered, and the animals were observed for general symptoms, death, and body weight for 7 days, and after the observation period, they were sacrificed and autopsied. As shown in Table 1, no cases of death were observed in both rats and mice even at the maximum dose that could be administered, and the protein _{polysaccharide} of the present invention is extremely safe for living organisms. That is, the protein polysaccharide of the present invention has extremely low acute toxicity, is a safe drug, and is useful as an agent for improving ischemic brain disease since it exhibits effects such as improving red blood cell deformity and inhibiting thrombotic death. The ischemic brain disease ameliorating agent of the present invention is effective for ischemic diseases accompanied by cerebral infarction due to cerebral thrombosis or arteriosclerosis. The protein polysaccharide of the present invention can be made into any dosage form when used as an ischemic brain disease improving agent. Moreover, administration is also performed by each route. In the case of oral administration, the tablets applied thereto;
Granules, powders, capsules, etc. contain binders, encapsulating agents,
It may contain additives such as excipients, lubricants, disintegrants, and wetting agents, and when used as oral liquid preparations, oral solutions, shaken mixtures, suspensions, emulsions, It may be in the form of a syrup or as a dry product which is redissolved before use. Additionally, such liquid formulations may contain any commonly used additives and preservatives. When used for injection, the composition may include stabilizers,
They may also contain additives such as buffers, preservatives, tonicity agents, and are presented in unit-dose ampoules or multi-dose containers. It should be noted that the compositions may be in the form of aqueous solutions, suspensions, solutions, emulsions in oily or aqueous vehicles, wherein the active ingredient is dissolved in a suitable vehicle, e.g., a pyrogen-free, sterile vehicle, before use. It may also be a powder that is redissolved in water. The ischemic brain disease improving agent of the present invention can be administered orally or parenterally to humans and animals, but oral administration is preferred. Oral administration includes sublingual administration. Parenteral administration includes injections such as subcutaneous, intramuscular, intravenous, infusion, and the like. The dose of the ischemic brain disease improving agent of the present invention depends on whether it is an animal or a human being, and is influenced by age, individual differences, medical conditions, etc., so in some cases, doses outside the following range may be administered. In general, for humans, the oral dosage of the active substance of the present invention is 1 kg body weight,
10-1000mg, preferably 20-600mg per day
Administer in 3 to 3 divided doses. Furthermore, the ischemic brain disease improving agent of the present invention is CO ₂ ,
Papaverine, nyridrine, isoxsuprine, hexabendine, cyclanderate, ATP,
A combined effect can be expected when used in combination with cerebral vasodilators such as ADP, AMP, acetazolamide, hypertonic glucose solution, lauvacin, and pyrithioxine. Moreover, it can also be used in combination with an anti-arteriosclerotic agent. Example 1 Measurement of the effect of improving red blood cell deformability Krestin 10 to 5 Wistar rats in each group
10 ⁴ mg/Kg (mouse body weight) was administered intraperitoneally or orally, and blood was collected 3 hours later. Add this to 10 times the volume of physiological saline, stir with a mixer,
After mechanical hemolysis, the mixture was centrifuged and the amount of hemoglobin in the supernatant was determined colorimetrically. The hemolysis rate was calculated based on the hemolysis degree of 100 when the same operation was performed using distilled water instead of physiological saline. The results were expressed as a relative hemolysis rate, with the hemolysis rate of the control (physiological saline administered through each route instead of Krestin) set as 100, and the average values are shown in Table 2. By administering Krestin, a decrease in the relative hemolysis rate, that is, an improvement in the deformability of red blood cells was observed regardless of the administration route. [Table] [Table] Example 2 Measurement of thrombotic death inhibitory effect Furlow et al.'s method (Furlow et al., Science,
187, 658, 1975), 100 rats per group were given 100 mg/Kg of Krestin intraperitoneally (ip) or 1000 mg/Kg.
mg/Kg was administered orally (po), and 30 minutes later, 20 mg/Kg of arachidonic acid was injected antegrade into the left carotid artery and the mortality rate was observed. The results are shown in Table 3, and the lethality suppressing effect of Crestin administration was observed. [Table] Example 3 Production of Capsules Using a pressure-type automatic filling machine, 330 mg of Crestin was filled into No. 0 hard capsules to produce capsules.

Claims (1)

[Scope of Claims] 1. A hot water or alkaline aqueous extract of mycelia or fruiting bodies obtained by culturing Basidiomycetes belonging to the genus Corsicolor, containing about 18 to 38% protein and having a molecular weight of 5000. ~300000 (Ultracentrifugation measurement method)
An ischemic brain disease improving agent containing a protein polysaccharide as an active ingredient. 2. The agent for improving ischemic brain disease according to claim 1, characterized in that the protein polysaccharide is obtained from Coriolus versicolor.