JPH0331176B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an ischemic heart disease ameliorating agent containing as a main component a protein polysaccharide derived from a basidiomycete belonging to the genus Corsicolor, and more particularly to an ischemic heart disease ameliorating agent consisting of 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 heart disease ameliorating agent, which led to the present invention. The protein polysaccharide which is the active ingredient of the ischemic heart disease ameliorating agent of the present invention is disclosed in, for example, Japanese Patent Publication No. 17149/1983, Japanese Patent Publication No. 36322/1982, Japanese Patent Publication No. 14274/1989,
It is a known substance described in Japanese Patent Publication No. 56-14276, Japanese Patent Publication No. 56-39288, etc., and is a mycelium, a broth, or a fruiting body obtained by culturing a basidiomycete belonging to the genus Corsicolor. Extract with hot water or alkaline aqueous solution of about 18-38%
It has a molecular weight of 5,000 to 300,000 (according to ultracentrifugation measurement). 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℃. The protein polysaccharide of the present invention has an effect of increasing coronary blood flow and is useful as an agent for improving ischemic heart disease. That is, when a heart-lung specimen was prepared using a normal beagle dog and the protein polysaccharide was injected through the superior aorta, an increase in coronary blood flow was observed, demonstrating its effectiveness as an agent for improving ischemic heart disease. 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 heart disease since it exhibits an effect of increasing coronary blood flow. The drug of the present invention can be used to treat coronary artery sclerosis, acute or chronic myocardial infarction, stable or unstable angina, arrhythmia,
It is effective for various types of heart failure. When the protein polysaccharide of the present invention is used as an agent for improving ischemic heart disease, it can be made into any dosage form. 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 agent for improving ischemic heart disease 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 dosage of the ischemic heart disease ameliorating 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, an amount 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. In addition, the ischemic heart disease improving agent of the present application can be used in combination with amyl nitrite, nitroglycerin, etc. during attacks, or when used in non-attacks with nitrites, xanthine preparations, papaverine, dipyridamoleprenylamine, benziodarone, carbochromene, etc. , Efloxate, MAO inhibitor, 2,6-pyridine dimethanol-bis(N-methylcarbamate),
A combined effect can be expected when used in combination with coronary dilators such as beta receptor blockers, verapamil, and nicotinic acid, and sedatives such as phenobarbital, meprobamate, chlordiazepoxide, reserpine, and chlorpromazine. Moreover, it can also be used in combination with an anti-arteriosclerotic agent. Example 1 Measurement of Coronary Blood Flow Increase Effect Cardiopulmonary specimens were prepared using three normal beagle dogs in each group. Coronary blood flow was recorded using an electromagnetic flowmeter (Statham SP-2202) using a Morawity cannula inserted into the coronary sinus from the right atrium. After dissolving Krestin in physiological saline, 1-100mg/Kg
was injected through the superior vena cava. The results were expressed as the percentage increase in the average blood flow after administration relative to the average blood flow before administration, as shown in Table 2.

[Table] Example 2 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 heart disease improving agent containing a protein polysaccharide as an active ingredient. 2. The agent for improving ischemic heart disease according to claim 1, characterized in that the protein polysaccharide is obtained from Coriolus versicolor.