JPS6045526A - Improver for ischemic heart desease - Google Patents
Improver for ischemic heart deseaseInfo
- Publication number
- JPS6045526A JPS6045526A JP58147233A JP14723383A JPS6045526A JP S6045526 A JPS6045526 A JP S6045526A JP 58147233 A JP58147233 A JP 58147233A JP 14723383 A JP14723383 A JP 14723383A JP S6045526 A JPS6045526 A JP S6045526A
- Authority
- JP
- Japan
- Prior art keywords
- protein
- ischemic heart
- heart disease
- improver
- protein polysaccharide
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000302 ischemic effect Effects 0.000 title 1
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 23
- 102000004169 proteins and genes Human genes 0.000 claims abstract description 23
- 150000004676 glycans Chemical class 0.000 claims abstract description 18
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 18
- 239000005017 polysaccharide Substances 0.000 claims abstract description 18
- 208000031225 myocardial ischemia Diseases 0.000 claims abstract description 15
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- 108010001062 polysaccharide-K Proteins 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 238000005199 ultracentrifugation Methods 0.000 claims abstract description 3
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- FYGDTMLNYKFZSV-WFYNLLPOSA-N (2s,3r,4s,5s,6r)-2-[(2r,4r,5r,6s)-4,5-dihydroxy-2-(hydroxymethyl)-6-[(2r,3s,4r,5r,6s)-4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxan-3-yl]oxy-6-(hydroxymethyl)oxane-3,4,5-triol Chemical group O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1[C@@H](CO)O[C@@H](O[C@@H]2[C@H](O[C@H](O)[C@H](O)[C@H]2O)CO)[C@H](O)[C@H]1O FYGDTMLNYKFZSV-WFYNLLPOSA-N 0.000 abstract description 2
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- 208000010125 myocardial infarction Diseases 0.000 abstract description 2
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Landscapes
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Abstract
Description
【発明の詳細な説明】
本発明はカワラタケ属に属する担子菌由来の蛋白多糖体
を主成分とする虚血性心疾患改善剤に係り、詳しくはク
レスチンよりなる虚血性心疾患改善剤に関づる。該クレ
スチンは、抗肝瘍剤として既に社会に提供されており、
極めて低毒性で、且つ腸内菌叢撹乱などの心配がなく、
長期投与が可能である。また、変異原性やアレルギー反
応などにも影響を与えＪ”、したがって、健康な人に対
重る催奇形成や、アレルギー反応の危険もなく、極めて
安全な物質である。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 comprising crestin. Krestin has already been provided to society as an anti-liver tumor agent,
It has extremely low toxicity and there is no need to worry about disrupting the intestinal flora.
Long-term administration is possible. It also affects mutagenicity and allergic reactions, so it is an extremely safe substance with no risk of teratogenicity or allergic reactions compared to healthy people.
本発明者等は、本発明の前記蛋白多糖体が抗腫瘍効果に
加えて虚血性心疾患改善剤としての薬理効果をも有して
いることを知見し、本発明に至ったものである。The present inventors have discovered that the protein polysaccharide of the present invention has, in addition to its antitumor effect, a pharmacological effect as an agent for improving ischemic heart disease, leading to the present invention.
本発明虚面性心疾患改善剤の活性成分である蛋白多糖体
は、例えば特公昭４６−１７１４９号公報、特公昭５１
−３６３２２号公報、特公昭５６−１４２７４号公報、
特公昭５６−１４２７６号公報、特公昭５６−３９２８
８号公報などに記載されている公知の物質であり、カワ
ラタケ属に属する担子菌を培養して得られる菌糸体培養
物（［３ｒｏｔｈ）又は子実体の熱水又はアルカリ溶液
による抽出物であって、約１８〜３８％の蛋白質を含み
、５ 、００’０〜３００，０００ （超゛遠心分離測
定法）の分子量を有づるものである。本発明の蛋白多糖
体のうち、カワラタク菌糸体［ＦＥＲＭ−Ｐ２４’１２
（ＡＴＣＣ２０５４７） ］由来の蛋白多糖体は、前記
したとおり、クレスチンという商品名で市販されている
ものであり（最近の新薬 第２８集１４〜１６ページ、
１９７７年及び第２９集９６〜１０１ページ、 １９
７８年、医薬品要覧第１３４６ページ、昭和５４年５月
第６版、薬業時報社発行、医療薬 日本医薬品集用７版
第２４０ページ。The protein polysaccharide which is the active ingredient of the present invention improving agent for ischemic heart disease 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 No. Sho 56-14276, Special Publication No. Sho 56-3928
It is a known substance described in Publication No. 8, etc., and is a mycelium culture ([3roth) obtained by culturing basidiomycetes belonging to the genus Corsicolor or an extract of the fruiting body with hot water or an alkaline solution. It contains about 18-38% protein and has a molecular weight of 5,00'0-300,000 (ultracentrifugation measurement). Among the protein polysaccharides of the present invention, Kawarataku mycelium [FERM-P24'12
(ATCC20547)] is commercially available under the trade name Krestin (Recent New Drugs Vol. 28, pp. 14-16), as mentioned above.
1977 and Volume 29, pp. 96-101, 19
1978, Pharmaceutical Handbook, page 1346, May 1978, 6th edition, published by Yakugyo Jihosha, Medical Drugs Japan Pharmaceutical Dictionary, 7th edition, page 240.
１９８３年、薬業時報社発行）、ＰＳ−にとも呼称され
ているものであって、その性状の一端を示せば次のとお
りである。(Published by Yakugyo Jihosha in 1983) and is also called PS-, and some of its properties are as follows.
主要画分の糖部分はβ−Ｄ−グルカンで、このグルカン
部分の構造は１→３，１→４および１→６結合を含む分
校構造であり、蛋白質の構成アミノ酸は、アスパラギン
酸、グルタミン酸等の酸性アミノ酸とバリン、ロイシン
等の中性アミノ酸が多く、リジン、アルギニン等の塩基
性アミノ酸は少ない。水に可溶で、メタノール、ピリジ
ン、クロロホルム、ベンゼン、ヘキリーンには殆／Ｖど
溶（）ない。約１２０℃から徐々に分Ｍする。The sugar moiety of the main fraction is β-D-glucan, and the structure of this glucan moiety is a branched structure containing 1→3, 1→4, and 1→6 bonds, and the amino acids that constitute the protein include aspartic acid, glutamic acid, etc. There are many acidic amino acids and neutral amino acids such as valine and leucine, and there are few basic amino acids such as lysine and arginine. It is soluble in water, but hardly soluble in methanol, pyridine, chloroform, benzene, and hexylene. The temperature is gradually increased from about 120°C.
本発明の前記蛋白多糖体は、冠血流用増加作用を有して
おり、虚血性心疾患改善剤として有用である。即ち、正
常ピーグル大を用いて心肺標本を作製し、前記蛋白多糖
体を上人動脈より注入したところ冠面流量の増加がみら
れ、虚血性心疾患改善剤としての有効性が示された。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 Pegle-sized animal and the protein polysaccharide was injected through the superior human artery, an increase in coronary flow rate was observed, indicating its effectiveness as an agent for improving ischemic heart disease.
本発明の蛋白多糖体は、その毒性が極めて低く且つ副作
用も殆んど生起しないなど、生体に対して非常に安全な
物質であると知られている。本発明の蛋白多糖体の急性
毒性値を下記表−１に示す。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.
表−１
なお、上掲表−１に示される急性毒性値は、下記試験法
により調べたものである。Table 1 The acute toxicity values shown in Table 1 above were determined using the following test method.
マウスはＩ ＣＲ−Ｊ ＣＬ系、４〜５週令、体重２１
〜２４（Ｉのものを、ラットは６竜系、４へ・５週令、
体重１００〜１５０ｇのものを用いた。本発明蛋白多糖
体の投与経路は、静脈内、皮下、腹腔内おＪ、び経口の
四経路の投与を実施した。本発明の蛋白多糖体を生理食
塩水に溶解して投与し、 ７日間にわたり、一般症状、
死亡ならびに体重について観察し、観察期間終了後に虐
殺剖検した。Mice are I CR-J CL strain, 4-5 weeks old, weight 21
~24 (for I, rats are 6 dragons, 4 to 5 weeks old,
Those weighing 100 to 150 g were used. 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 to treat general symptoms,
Mortality and body weight were observed, and a slaughter autopsy was performed after the observation period.
表−１に示されるように、ラツ１〜、マウスとｂ投与可
能な最大投与量においてもまったく死亡例は認められず
、［−Ｄ５ｏ値の粋定が事実上不可１ｊシな程に、本発
明の蛋白多糖体は生体に対しＣ極めて安全である。As shown in Table 1, no deaths were observed even at the maximum doses that could be administered to rats and mice, and the results of this study are so great that it is virtually impossible to determine the [-D5o value]. The protein polysaccharide of the invention is extremely safe for living organisms.
すなわち、本発明の蛋白多糖体は急性毒性も極めて低く
、安全な医薬品であり、冠血流量増加作用等を示すこと
より虚血性心疾患改善剤として有用である。本発明の薬
剤は冠動脈硬化、急性又は慢性心筋梗塞、安定又は不安
定狭心症、不整脈。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 is used for coronary artery sclerosis, acute or chronic myocardial infarction, stable or unstable angina, and arrhythmia.
心不全等の開型に有効である。It is effective for open cases such as heart failure.
本発明の蛋白多糖体は、虚血性心疾患改善剤として用い
る場合、任意の剤型にすることができる。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.
又、投与も各経路で行なわれる。Moreover, administration is also performed by each route.
経口投与の場合には、それに適用される錠剤、顆粒剤、
散剤、カブレル剤などは、それらの組成物中に製剤上一
般に使用される結合剤、包含剤、賦形剤、潤滑剤、崩壊
剤、湿潤剤のような添加物を含有し【いてもよく、又経
日用液体製剤として用いる場合は、内用水剤、振とう合
剤、懸濁液剤、乳剤、シロップ剤の形態であってもよく
、又使用りる前に再溶解させる乾燥生成物の形態であつ
−Ｃもよい。さらに、このような液体製剤は普通用いら
れる添加剤、保存剤のいずれを含有してもよい。In the case of oral administration, tablets, granules,
Powders, Cabrel agents, etc. may contain additives such as binders, inclusion agents, excipients, lubricants, disintegrants, and wetting agents commonly used in pharmaceutical formulations in their compositions. When used as a liquid preparation for daily use, it may be in the form of an oral solution, a shaken mixture, a suspension, an emulsion, or a syrup, or it may be in the form of a dry product that is redissolved before use. Deatsu-C is also good. Additionally, such liquid formulations may contain any commonly used additives and preservatives.
注射用の場合には、その組成物は安定剤、緩衝剤、保存
剤、等張化剤などの添加剤を含／ｖでい（もＪ、く、単
位投与間アンプル、又は多投与量容器中Ｃ提供される。When used for injection, the composition may contain additives such as stabilizers, buffers, preservatives, tonicity agents, etc., in unit-dose ampoules, or in multi-dose containers. Middle C provided.
なお、上記組成物は水溶液、懸濁液、溶液、油性または
水性ビヒクル中の乳液のＪ、うな形態であってもよく、
一方活性成分は使用づる前に適当なビヒクルたとえば発
熱物質不含の滅菌した水で再溶解させる粉末であっても
よい。The composition may be in the form of an aqueous solution, suspension, solution, emulsion in an oily or aqueous vehicle,
Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.
本発明の虚血性心疾患改善剤は人間及び動物に経口的ま
たは非経口的に投与されるが経口投与が好ましい。経口
的投与は舌下投与を包合する。非経口的投与は注射、例
えば皮下、筋肉、静脈注射、点滴などを含む。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.
本発明の虚血性心疾患改善剤の投、！″ｉｍは動物か人
間により、また年齢、個人差、病状などに影響されるの
で、場合によっては下記範囲外のωを投与する場合も生
ずるが、一般に人間をり・ｊ象とする場合、本発明活性
物質の経口投与量は体重１ｋｇ、１０当り１０〜１００
０ｍｇ、’Ｍ？ましくは２０〜６０（１ｍｇを １回か
ら ３回に分【プで投与する。Administration of the ischemic heart disease improving agent of the present invention! ``Im is influenced by animals and humans, as well as by age, individual differences, medical conditions, etc., so in some cases it may be necessary to administer ω outside the range below, but in general, when humans are considered as animals, The oral dosage of the active substance of the invention is 10 to 100 per 10 kg of body weight.
0mg, 'M? Preferably 20 to 60 mg (administer 1 mg in 1 to 3 divided doses).
また、本願の虚血性心疾患改善剤は、発作時に亜硝酸ア
ミル、二１−口グリレリン等と併用り−ることにより、
或いは非発作時に亜硝酸剤、キ４〕−ンチン製剤、パバ
ベリン、ジピリダモールプレニルアミン、ペンツイＡダ
ロン、カルボクロメン、エフロキセー１−、ＭＡＯＩＩ
ＩＩ害剤、２．６−ピリシンシメタノール−ビス（Ｎ−
メチルカルバメ−１へ）、β受容体遮断剤、ベラパミー
ル、ニコチン酸等の冠拡張剤やフエノバルビタール、メ
プロバメ−１・、クロルジアゼポキシド、レセルピン。In addition, the ischemic heart disease improving agent of the present application can be used in combination with amyl nitrite, 21-glyrelin, etc. during an attack.
Or, during non-seizures, nitrites, quintin preparations, pababerine, dipyridamole prenylamine, Penzi A Daron, carbochromene, efloxe 1-, MAOII
II harmful agent, 2,6-pyricinsimethanol-bis(N-
methylcarbame-1), beta receptor blockers, verapamil, coronary dilators such as nicotinic acid, phenobarbital, meprobame-1, chlordiazepoxide, reserpine.
クロルプロマジン等の鎮静剤などと併用することにより
ｖ１用効果が期待できる。また、抗動脈硬化剤と併用覆
ることもできる。V1 effects can be expected when used in combination with sedatives such as chlorpromazine. It can also be used in combination with an anti-arteriosclerotic agent.
実施例１
冠血流ｍ増加作用の測定
各市３匹の正常ピーグル大を用いて心肺標本を作製し７
ｊ ｏ冠血流帛は、右心房Ｊ、り冠状静脈側に挿入した
Ｍ ０ｒａＷｉ ｔｙのカニコーレにＪ、り電磁流量匹
１（スタリームＳ Ｆ’ −２２０２）を用い−Ｃ記録
した。クレスチンを生理食塩水に溶Ｍ後、 １〜１００
ｍ！Ｊ／ｋＧを−Ｌ大静脈より注入した。結果は表−
２に承り如く、投与並平均血流■に対づる投与後平均血
流１１１の増加パーレン１〜で表わした。Example 1 Measurement of the effect of increasing coronary blood flow m Cardiopulmonary specimens were prepared using three normal peagles from each city.
Coronary blood flow patterns were recorded using an electromagnetic flowmeter 1 (Starim SF'-2202) inserted into the right atrium and into the coronary vein side of the M0raWity canicule. After dissolving Krestin in physiological saline, 1-100
m! J/kG was injected from the -L vena cava. The results are in the table-
2, the increase in the mean blood flow after administration (111) relative to the mean blood flow (2) before administration was expressed as perlen 1.
裏瀝」し乙
カプセル剤の作製
圧力式自動充填機を用い、０号硬カブレルにクレスチン
を３３０ｍｇ充填し、カプセルを作製した。Preparation of Capsules Using a pressure-type automatic filling machine, 330 mg of Crestin was filled into a No. 0 hard cabrel to prepare capsules.
代理人弁理士今 村 元Representative Patent Attorney Hajime Imamura
Claims (1)
る菌糸体又は子実体の熱水又はアルカリ溶液による抽出
物であって、約１８〜３８％の蛋白質を含み、分子量が
５，０００〜３００，０００ （超遠心分離測定法）で
ある蛋白多糖体を活性成分とする虚血性心疾患改善剤。 （２＝） 前記蛋白多糖体がクレスチンであることを特
徴とする特許請求の範囲第１項に記載の虚血性心疾患改
善剤。(1) A hot water or alkaline solution extract of mycelia or fruiting bodies obtained by culturing Basidiomycetes belonging to the genus Corsicolor, containing approximately 18 to 38% protein and having a molecular weight of 5,000 to 300. ,000 (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, wherein the protein polysaccharide is Krestin.
Priority Applications (14)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58147233A JPS6045526A (en) | 1983-08-11 | 1983-08-11 | Improver for ischemic heart desease |
| DE3448153A DE3448153C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448152A DE3448152C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448155A DE3448155C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448148A DE3448148C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448150A DE3448150C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448144A DE3448144C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448149A DE3448149C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448145A DE3448145C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE3448154A DE3448154C2 (en) | 1983-08-11 | 1984-08-10 | |
| DE19843429551 DE3429551A1 (en) | 1983-08-11 | 1984-08-10 | PHARMACEUTICAL PREPARATION CONTAINING A GLYCOPROTEIN |
| DE3448151A DE3448151C2 (en) | 1983-08-11 | 1984-08-10 | |
| US06/898,900 US4820689A (en) | 1983-08-11 | 1986-08-22 | Pharmaceutical composition containing a glycoprotein |
| US07/285,664 US5008243A (en) | 1983-08-11 | 1988-12-16 | Pharmaceutical composition containing a glycoprotein |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP58147233A JPS6045526A (en) | 1983-08-11 | 1983-08-11 | Improver for ischemic heart desease |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6045526A true JPS6045526A (en) | 1985-03-12 |
| JPH0331176B2 JPH0331176B2 (en) | 1991-05-02 |
Family
ID=15425579
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP58147233A Granted JPS6045526A (en) | 1983-08-11 | 1983-08-11 | Improver for ischemic heart desease |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS6045526A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5693610A (en) * | 1994-08-25 | 1997-12-02 | Kureha Chemical Industry Co., Ltd. | Binding agent for growth factor |
-
1983
- 1983-08-11 JP JP58147233A patent/JPS6045526A/en active Granted
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5693610A (en) * | 1994-08-25 | 1997-12-02 | Kureha Chemical Industry Co., Ltd. | Binding agent for growth factor |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0331176B2 (en) | 1991-05-02 |
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