JPH0326173B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to an anti-rheumatic agent containing a protein polysaccharide derived from a basidiomycete belonging to the genus Corsicolor as a main component, and more particularly to an anti-rheumatic agent comprising PSK. Applicable
PSK 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 disruption 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 anti-rheumatic pharmacological effects in addition to anti-tumor effects, leading to the present invention. The protein polysaccharide which is the active ingredient of the anti-rheumatic agent of the present invention is disclosed in, for example, Japanese Patent Publication No. 46-17149, Japanese Patent Publication No. 51
-36322 Publication, Special Publication No. 56-14274, Special Publication Sho
It is a known substance described in Japanese Patent Publication No. 56-14276, Japanese Patent Publication No. 56-39288, etc., and is a heat-generating mycelium, broth, or fruiting body obtained by culturing basidiomycetes belonging to the genus Coriolis. It is a water or alkaline aqueous extract containing about 18-38% protein and has a molecular weight of 5,000-300,000 (ultracentrifugation measurement). Among the protein polysaccharides of the present invention, C. versicolor mycelium [FERM-P2412
(ATCC20547)], as mentioned above, is commonly called PSK or is commercially available under the trade name Krestin (Recent New Drugs Vol. 28, pages 14-16, 1977 and Volume 29, pages 96-101, 1978, Pharmaceutical Directory No.
1346 pages, May 1974 6th edition, published by Yakugyo Jihosha, Medical Drugs Japan Pharmaceutical Collection 7th Edition 240 pages,
(Published by Yakugyo Jihosha in 1983), and some of its properties are as follows. The sugar moiety of the main fraction is β-D-glucan, and the structures of this glucan moiety are 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℃. When the protein polysaccharide of the present invention is administered to rheumatism patients, as shown in the Examples below, improvement in pain, improvement in grip strength, etc. have been observed, and animal experiments using rats have shown that it also has anti-adjuvant arthritis effects. It was found that the protein polysaccharide of the present invention has activity as an antirheumatic agent. 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 anti-rheumatic agent since it exhibits adjuvant arthritis suppressive effects, pain, and improvement in grip strength. The protein polysaccharide of the present invention can be made into any dosage form when used as an anti-rheumatic agent. or,
Administration is also carried out by each route. Further, other anti-rheumatic agents that can be used in combination with other anti-rheumatic agents include chloroquine, a gold preparation, and penicillamine. 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. For injection, the compositions may contain additives such as stabilizers, 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 antirheumatic 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 dosage of the anti-rheumatic agent of the present invention depends on whether it is an animal or a human, and is influenced by age, individual differences, medical conditions, etc., and in some cases, doses outside the following range may be administered. If applicable,
The active substance of the present invention is orally administered at a dose of 10 to 1000 mg, preferably 20 to 600 mg, divided into 1 to 3 doses per kg of body weight per day. Example 1 Adjuvant arthritis suppressive effect Mycobacterium tuberculosis suspended in liquid paraffin was subcutaneously placed in the right hind foot pad of a rat according to the method of Fujiwara (1971) et al.
On the 14th day, rats with similar hindlimb volumes were selected, and from the 15th day, 1000 mg/Kg of Crestin was orally administered continuously for 7 days.
The hindlimb volume was measured, and the inhibition rate was calculated using the following formula. (1-T/C) x 100 = IR (%) T: Average footpad volume of the administration group C: Average footpad volume of the control group (no Krestin administration) As a result, the suppression rate was 35.9% in the Krestin administration group. , showed remarkable medicinal efficacy against adjuvant arthritis. Example 2 Rheumatoid arthritis (diagnosis name: Classical Stage)
A 62-year-old woman who had been diagnosed with the disease (Class 3) for 25 years took Crestin at a dose of 3 g per day for about 30 days, and as a result, her pain improved and the number of active joints decreased, and the patient was very impressed. The improvement effect was confirmed. Before administration 1 month after administration Morning stiffness 10 10 Degree of pain 1.5 0.5 Grip strength ^*1 - 82/100 Blood sedimentation ^*2 47 54 CRT ^*3 ± ± Number of active joints ^*4 4 1 Patient's impression - Very good Doctor's impression Judgment - Improvement ^* 1 Grip strength: Measured with a blood pressure monitor (mmHg) Fluctuations in grip strength in rheumatoid arthritis (RA) are used as a practical parameter to determine the presence or absence of pain and stiffness. The level of measurement values before and after treatment serves as an indicator and can be used to evaluate drug efficacy. ^* 2 Blood sedimentation, Westergren method (adds sodium citrate to the collected blood and measures the blood sedimentation rate (1 hour value)) During the active phase of RA, CRP (inflammatory protein), fibrinogen increase, albumin decrease, platelets Blood sedimentation increases due to an increase in blood pressure and anemia.The degree of increase correlates with clinical symptoms, so it is an indicator of RA activity. 100 mm/hour or more; intensity, 50-99 mm/hour; moderate, 21 ~49 mm/hour; mildly increased, 21 mm/hour or less; inactive ^* 3CRT; inflammatory protein, measured by capillary sedimentation method.
It is a protein that is mainly produced in the liver and increases in the blood when inflammation or tissue destruction lesions appear. RA produces various types of sediment that reflect its activity, so it is used as an indicator of activity. Sediment 0; (-), 〃 1 mm or less; (±) 〃 1 mm to less than 2 mm; (+1) 〃 2 mm to less than 3 mm; (+2) 〃 3 mm to less than 4 mm; (+3) Sediment 4 mm to less than 5 mm; ( +4) 〃 5 mm to less than 6 mm; (+5) 〃 6 mm or more; (+6) ^* 4 Number of active joints; counted by interview and palpation Arthritis (2 or more symptoms of pain, redness, fever, swelling) This is the number of joints that have Used as an indicator for drug efficacy evaluation. Example 3 Rheumatoid arthritis (diagnosis: Classical Stage)
A 47-year-old woman diagnosed with Class 2) who had been suffering from the disease for 4 years was treated with the conventional treatment drugs Bluehen 6 tablets/day, Indamine suppositories 2 tablets/day, and Crestin 3g/day, and an improvement effect was confirmed. Morning stiffness before and 6 months after combination use 60 0 Pain level 2 1 Grip strength 90/60 93/138 Number of active joints 5 5 Patient's impression - Good Doctor's judgment - Improvement example 4 Using a pressure-type automatic filling machine, A No. 0 hard capsule was filled with 330 mg of Crestin to prepare a capsule.

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 anti-rheumatic agent whose active ingredient is a protein polysaccharide. 2. The anti-rheumatic agent according to claim 1, wherein the protein polysaccharide is obtained from Corsicolor versicolor.