JPH0656684A - Antidement agent - Google Patents
Antidement agentInfo
- Publication number
- JPH0656684A JPH0656684A JP4356551A JP35655192A JPH0656684A JP H0656684 A JPH0656684 A JP H0656684A JP 4356551 A JP4356551 A JP 4356551A JP 35655192 A JP35655192 A JP 35655192A JP H0656684 A JPH0656684 A JP H0656684A
- Authority
- JP
- Japan
- Prior art keywords
- weight
- parts
- granules
- activity
- dementia
- 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
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Landscapes
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Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は漢方を基本とする新規な
抗痴呆剤に関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a novel anti-dementia drug based on Kampo.
【０００２】[0002]
【従来の技術】痴呆症特に老人性痴呆症に対する医薬の
開発は高齢化社会の到来と共に重要な課題となってい
る。生薬または漢方を基本とする抗痴呆剤としては、特
公平３−２７５３０に生薬五味子の有機溶剤抽出物中に
含まれる化合物を有効成分とする脳機能改善薬が記載さ
れており、特開昭６３−２８７７２４には呉茱萸（ゴシ
ュ）から有機溶剤抽出により得られるエポジアミン又は
ルタエカルピンを有効成分とする脳機能改善剤、並びに
芍薬、求（ジュツ）、タンシャ、ブクリョウ、センキュ
ウ及び当帰を有効成分とする抗痴呆剤が知られている。2. Description of the Related Art The development of medicines for dementia, particularly senile dementia, has become an important issue with the advent of an aging society. As an anti-dementia agent based on crude drugs or Chinese herbs, Japanese Patent Publication No. 3-27530 describes a brain function improving drug containing as an active ingredient a compound contained in an organic solvent extract of crude drug Gomiza. -287724 contains a brain function improving agent containing epodiamine or rutaecarpine obtained by organic solvent extraction from gosh as an active ingredient, and peony, gut (jutsu), tansha, bukyou, senkyu and toki as active ingredients. Anti-dementia drugs are known.
【０００３】[0003]
【発明が解決しようとする課題】本発明は、すでに広く
使用され安全が十分に確認されている漢方薬を基礎とす
る新規な抗痴呆剤を提供しようとするものである。DISCLOSURE OF THE INVENTION The present invention is intended to provide a novel anti-dementia drug based on a herbal medicine which has been widely used and whose safety has been sufficiently confirmed.
【０００４】[0004]
【課題を解決するための手段】本発明者らは、漢方を基
礎とする薬用成分を広く検討した結果、センキュウ、芍
薬、紅花、木香、香附子、及び丹参の６種類の漢方材料
の混合物、並びにこの混合物に他の漢方成分を加えたも
のが抗痴呆作用を有することを見出し、本発明を完成し
た。[Means for Solving the Problems] As a result of extensive investigations on medicinal ingredients based on Chinese medicine, the present inventors have found that a mixture of six kinds of Chinese medicine materials, such as senkyu, peony, safflower, woody incense, Kafuzi, and Danshen. The present invention has been completed by discovering that the mixture of this mixture and other Kampo ingredients has an anti-dementia effect.
【０００５】[0005]
【具体的な説明】本発明において使用する抽出物の原料
である丹参（タンジン）はシソ科（Ｌａｂｉａｔａｅ）
の多年草Ｓａｌｖｉａ ｍｉｌｔｉｏｒｒｈｉｚａ Ｂ
ｕｎｇｅの根および根茎である。香附子（コウブシ）は
カヤツリグサ科（Ｃｙｐｅｒａｃｅａｅ）の多年草ハマ
スゲ（Ｃｙｐｅｒｕｓ ｒｏｔｕｎｄｕｓ Ｌ．の根茎
である。木香（モッコウ）はキク科（Ｃｏｍｐｏｓｉｔ
ａｅ）の多年草Ａｕｃｋｌａｎｄｉａ ｌａｐｐａ Ｄ
ｅｃｎｅ（Ｓａｕｓｓｕｒｅａ ｌａｐｐａ Ｃｌａｒ
ｋｅ）の根である。[Detailed Description] Danshen, a raw material of the extract used in the present invention, is a Labiatae family.
Perennial of Salvia miltiorrhiza B
Unge roots and rhizomes. Kabushi is the rhizome of the perennial Cyperus rotundus L. of the family Cyperaceae, while the incense is a composit.
ae) perennial Aucklandia lappa D
ecne (Saussurea lapa Clar
ke) is the root.
【０００６】紅花（コウカ）はキク科（Ｃｏｍｐｏｓｉ
ｔａｅ）の１〜２年草木ベニバナ（Ｃａｒｔｈａｍｕｓ
ｔｉｎｃｔｏｒｉｕｓ Ｌｉｎｎｅ）の管状花であ
る。芍薬（シャクヤク）はボタン科（Ｐａｅｏｎｉａｃ
ｅａｅ）の多年草シャクヤク（Ｐａｅｏｎｉａ ｌａｃ
ｔｉｆｌｏｒａ Ｐａｌｌａｓ）の根である。センキュ
ウはセリ科の（Ｕｍｂｅｌｌｉｆｅｒａｅ）の多年草セ
ンキュウ（Ｃｎｉｄｉｕｍ ｏｆｆｉｎａｌｅ Ｍａｋ
ｉｎａ）の根茎である。黄耆（オウギ）はマメ科（Ｌｅ
ｇｕｍｉｎｏｓａｅ）の多年草（Ａｓｔｒａｇａｌｕｓ
Ｂａｎｇｅ又はＡｓｔｒａｇａｌｕｓ ｍｏｎｇｈｏ
ｌｉｃｕｓ Ｂｕｎｇｅ）の根である。牛膝（ゴシツ）
はヒユ科（Ａｍａｒａｎｔｈａｃｅａｅ）の多年草ヒナ
タイノコズチＡｃｈｙｒａｎｔｈｅｓ ｆａｕｒｉｅｉ
Ｌｅｖｅｉｌｌｅ ｅｔ Ｖａｎｉｏｔ又はＡｃｈｙ
ｒａｎｔｈｅｓ ｂｉｄｅｎｔａｔａ Ｂｌｕｍｅの根
である。[0006] Safflower (comb)
1-2 years old plant safflower (Carthamus)
It is a tubular flower of tinctorius Linne. Peony is a peony family.
eae perennial peony (Paeonia lac)
(tiflora Pallas). The perennial herb of the Umbelliferae (Cumbium officinale Mak)
ina) rhizome. Beetle (Lepidoptera) is a legume (Le
Guminosae perennial (Astragalus)
Bange or Astragalus mongho
licus bunge). Beef knee
Is a perennial plant of Amaranthaceae, Achyranthes fauriei.
Leveille et Vaniot or Achy
It is the root of the ranses bidententa Blume.
【０００７】当帰（トウキ）はセリ（Ｕｍｂｅｌｌｉｆ
ｅｒａｅ）トウキ（Ａｎｇｅｌｉｃａ ａｃｕｔｉｌｏ
ｂａ Ｋｉｔａｇａｗａ）ホッカイトウキ（Ａ．ａｃｕ
ｔｉｌｏｂａ Ｋｉｔａｇａｗａ Ｖａｒ．Ｓｕｇｉｙ
ａｍａｅ Ｈｉｋｉｎｏ 又はＡ．Ｓｉｎｅｎｓｉｓ
Ｄｉｅｌｓ）の根である。人参（ニンジン）はウコギ科
（Ａｒａｌｉａｃｅａｅ）の多年草オタネニンジン（Ｐ
ａｎａｘ ｇｉｎｓｅｎｇ Ｃ．Ａ．Ｍｅｙｅｒ）の根
である。龍眼肉（リュウガンニク）はムクロジ科（Ｓａ
ｐｉｎｄａｃｅａｅ）の常緑小高木リュウガン（Ｅｕｐ
ｈｏｒｉａ Ｌｏｎｇａｎａ Ｌａｍａｒｃｋ）の果肉
である。鹿茸（ロクジヨウ）はシカ科（Ｃｅｒｖｉｄａ
ｅ）マンシュウカジカ（Ｃｅｒｖｕｓ ｅｌａｐｈｕｓ
Ｘａｎｔｈｏｐｙｇｕｓ Ｍｉｌｉｅ−Ｅｄｗａｒｄ
ｓ）、又はマンシュウジカ（Ｃ．ｎｉｐｐｏｎ ｍａｎ
ｔｈｕｒｉｃｕｓ Ｓｗｉｎｈｏｅ）の角質化していな
い幼角である。Toki is a Umbellif
erae) Touki (Angelica acutilo)
ba Kitagawa A. acu
tiloba Kitagawa Var. Sugiy
amae Hikino or A. Synesis
Diels). Carrot is a perennial ginseng (Pear ginseng) of the Araliaceae family.
anax ginseng C. A. Meyer) is the root. Long-eye meat (Ryuganiku) is a sectaceae (Sa
Pindaceae) Evergreen Otakagi Longan (Eup
This is the pulp of Horia Longana Lamarck). Deer mushrooms (Cervidae)
e) Manju deer (Cervus elaphus)
Xanthopygus Mileie-Edward
s), or C. nippon man
non-keratinized larvae of Thuricus Swinhoe).
【０００８】杜仲（トチュウ）はトチュウ科（Ｅｕｃｏ
ｍｍｉａｃｅａｅ）の落葉高木トチュウ（ Ｅｕｃｏｍ
ｍｉａ ｕｌｍｏｉｄｅｓ Ｏｌｉｖｅｒ）の樹皮であ
る。巴戟天（ハゲキテン）はアカネ科（Ｒｕｂｉａｃｅ
ａｅ）の蔓性低木ハゲキテン（Ｍｏｒｉｎｄａｅ ｏｆ
ｆｉｃｉｒａｌｉｓ Ｈｏｗ）の根である。地黄（ジオ
ウ）はゴマノハグサ科（Ｓｃｒｏｐｈｕｌａｒｉａｃｅ
ａｅ）の多年草アカヤジオウ（Ｒｅｈｍａｎｎｉａ ｇ
ｌｕｔｉｎｏｓａ Ｌｉｂｏｓｃｈｉｔｚ ｖａｒ．ｐ
ｕｒｐｕｒｅａ）の根である。茯苓（フクリョウ）はサ
ルノコシカケ科（Ｍａｋｉｎｏ）又はＲ．ｇｌｕｔｉｎ
ｏｓａ Ｌｉｂｏｓｃｈｉｔｚ）のマツホド（Ｒｏｒｉ
ａ ｃｏｃｏｓ Ｗｏｌｆ）の菌核である。牡丹皮（ボ
タンピ）はボタン科（Ｐａｅｏｒｉａｃｅａｅ）の落葉
低木ボタン（Ｐａｅｏｒｉａ ｓｕｆｆｒｕｔｉｃｏｓ
ａ Ａｎｄｒｅｗｓ）の根皮である。Eucommia is a eucommia family (Euco)
deciduous tree eucommia (Eucom)
Mia ulmoides Olive) bark. The vulture family (Rubiace)
ae) vine shrub vulture (Morindae of)
(Ficiralis How). Jiou is a Scrophulariaceae (Scrophulariaceae).
ae) perennial herb (Rehmannia g)
lutinosa Liboschitz var. p
urpurea). Fukuryo is a moss family (Makino) or R. glutin
Rosa Liboschitz's Matsuhodo (Rori)
a cocos Wolf). Peony skin is a deciduous shrub button (Paeoria suffruticos) of the family Boeoriaceae.
a Andrews).
【０００９】沢瀉（タクシャ）はオモダカ科（Ａｌｉｓ
ｍａｔａｃｅａｅ）の多年草サジオモダカ（Ａｌｉｓｍ
ａ Ｏｒｉｅｎｔａｌｅ Ｊｕｚｅｐｃｚｕｋ）の塊茎
である。サンシュユ（Ｃｏｒｎｕｓ ｏｆｆｉｃｉｎａ
ｌｉｓ Ｓｉｅｂｏｌｄ ｅｔ Ｚｕｃｃａｒｉｎｉ）
はミズキ科（Ｃｏｒｎａｃｅａｅ）の落葉小高木の偽果
の果肉である。山薬（サンヤク）はヤマノイモ科（Ｄｉ
ｏｓｃｏｒｅａｃｅａｅ）の多年草ナガイモ（ Ｄｉｏ
ｓｃｏｒｅａ ｂａｔａｔａｓ Ｄｅｃａｉｓｎｅ）又
はヤマノイモ（Ｄ．ｊａｐｏｎｉｃａ Ｔｈｕｎｂｅｒ
ｇ）の根茎根である。[0009] Takusha is a family of the
mataceae perennial herb (Alism)
a Orienteal Juzepczuk) tuber. Sanshuyu (Cornus officina
lis Siebold et Zuccarini)
Is a false pulp of a deciduous small tree of the Cornaceae family. Sanyaku is a Japanese yam family (Di
oscoreaceae perennial herb (Dio
score batatas Decaisne or yam (D. japonica Thunber)
g) rhizome root.
【００１０】本発明の抗痴呆剤の必須有効成分はセンキ
ュウ３．４〜１．１重量部、芍薬３．４〜１．１重量
部、紅花３．４〜１．１重量部、木香１．７〜０．６重
量部、香附子１．７〜０．６重量部、及び丹参６．８〜
２．６重量部からの熱水抽出物〔組成物（Ａ）〕であ
り、好ましくはセンキュウ２．２５重量部、芍薬２．２
５重量部、紅花２．２５重量部、木香１．１３重量部、
及び香附子１．１３重量部及び丹参４．５０重量部から
の熱水抽出物の乾燥物であり、これの顆粒状品を特に冠
元顆粒と称される。The essential active ingredients of the anti-dementia agent of the present invention are 3.4 to 1.1 parts by weight of Senkyu, 3.4 to 1.1 parts by weight of peony, 3.4 to 1.1 parts by weight of safflower, and 1 incense of wood. 0.7-0.6 parts by weight, Kafuzi 1.7-0.6 parts by weight, and Danshen 6.8-
A hot water extract [composition (A)] from 2.6 parts by weight, preferably 2.25 parts by weight of Senkyu, and peony 2.2.
5 parts by weight, safflower 2.25 parts by weight, wood incense 1.13 parts by weight,
And 1.13 parts by weight of Kafuzi and 4.50 parts by weight of Danshen, which is a dried product of a hot water extract, and a granular product thereof is particularly referred to as a crown granule.
【００１１】上記組成物（Ａ）にはさらに、地黄２．２
〜６．６重量部、フクリョウ０．８〜２．６重量部、牡
丹皮０．８〜２．６重量部、タクシャ０．８〜２．６重
量部、山 黄１．１〜３．３重量部及び山薬１．１〜
３．３重量部からなる〔組成物（Ｂ）〕を追加の有効成
分として加えることができる。この追加の有効成分
（Ｂ）の具体例として、地黄４．４重量部、ブクリョウ
１．７重量部、牡丹皮１．７重量部、タクシャ１．７重
量部、サンシュユ２．２重量部及び山薬２．２重量部か
らなる丸剤が挙げられ、これは六味地黄丸と称される。
従って、本発明の抗痴呆剤の１つの態様においては、冠
元顆粒と六味地黄丸とを有効成分として併用する。The composition (A) further includes ground yellow 2.2.
~ 6.6 parts by weight, Fukurou 0.8 to 2.6 parts by weight, peony skin 0.8 to 2.6 parts by weight, Takusha 0.8 to 2.6 parts by weight, Yamahuang 1.1 to 3.3. Parts by weight and mountain medicine 1.1-
3.3 parts by weight of [composition (B)] can be added as an additional active ingredient. As a specific example of the additional active ingredient (B), 4.4 parts by weight of ground yellow, 1.7 parts by weight of Bukryou, 1.7 parts by weight of peony skin, 1.7 parts by weight of Takusha, 2.2 parts by weight of saussure, and mountain. A pill consisting of 2.2 parts by weight of the drug can be mentioned, which is called Rokumi-jiogan.
Therefore, in one embodiment of the anti-dementia agent of the present invention, crown-shaped granules and Rokumi-jio-gan are used together as active ingredients.
【００１２】本発明の他の態様においては、前記組成物
（Ａ）にはさらに、オウギ４．３〜１２．８重量部、ゴ
シツ４．３〜１２．８重量部、当帰４．３〜１２．８重
量部、人参２．２〜６．７重量部、龍眼肉４．３〜１
２．８重量部、鹿茸１．９〜５．５重量部、杜仲４．３
〜１２．８重量部及びハゲキテン４．３〜１２．８重量
部からなる丸剤〔組成物（Ｃ）〕を追加の有効成分とし
て加えることができる。この追加の有効成分（Ｃ）の具
体例として、オウギ８．６重量部、ゴシツ８．５重量
部、当帰８．６重量部、人参４．５重量部、龍眼肉８．
６重量部、鹿茸３．６重量部、杜仲８．６重量部及びハ
ゲキテン８．６重量部からなる丸剤を挙げることがで
き、これは参茸補血丸と称される。従って本発明の抗痴
呆剤の１つの好ましい態様においては、冠元顆粒と参茸
補血丸とを併用する。[0012] In another embodiment of the present invention, the composition (A) further comprises 4.3 to 12.8 parts by weight of ougi, 4.3 to 12.8 parts by weight of gojitsutsu, and 4.3 to 10% of the present time. 12.8 parts by weight, carrot 2.2 to 6.7 parts by weight, longan meat 4.3 to 1
2.8 parts by weight, shiitake mushrooms 1.9 to 5.5 parts by weight, Tochu 4.3
A pill [composition (C)] consisting of ˜12.8 parts by weight and bald octene 4.3 to 12.8 parts by weight can be added as an additional active ingredient. Specific examples of the additional active ingredient (C) include 8.6 parts by weight of ougi, 8.5 parts by weight of goshitsu, 8.6 parts by weight of toki, 4.5 parts by weight of carrot, and 8.
Pills composed of 6 parts by weight, 3.6 parts by weight of shiitake mushrooms, 8.6 parts by weight of Tochu and 8.6 parts by weight of vulture kiten can be mentioned. Therefore, in one preferred embodiment of the anti-dementia agent of the present invention, the crown granules and the ginseng supplemented blood are used in combination.
【００１３】追加の組成物（Ｂ）を使用する場合、その
使用量は組成物（Ａ）１００重量部に対して組成物
（Ｂ）を１０〜１５０重量部使用するのが好ましい。ま
た、追加の組成物（Ｃ）を使用する場合、組成物（Ａ）
１００重量部に対して組成物（Ｃ）を１０〜１５０重量
部使用するのが好ましい。When the additional composition (B) is used, the amount of the composition (B) used is preferably 10 to 150 parts by weight based on 100 parts by weight of the composition (A). When using the additional composition (C), the composition (A)
It is preferable to use 10 to 150 parts by weight of the composition (C) per 100 parts by weight.
【００１４】本発明の医薬の成分である組成物Ａの製造
においては、原料であるセンキュウ、芍薬、紅花、木
香、香附子及び丹参を所定の重量比で混合し、この混合
物を混合物全重量の５〜３０倍、好ましくは１０〜２０
倍の熱水により抽出し、抽出液を濃縮さらに乾燥する。
濃縮及び乾燥は常用手段、例えば減圧蒸発濃縮、スプレ
イドライ、凍結乾燥等により行うことができる。こうし
て得られた固形物はそれ自体、散剤又は粉剤として使用
されるが、適当な賦形剤、基剤、乳化剤、溶剤、安定剤
などの添加剤と共に顆粒剤、錠剤、カプセル剤、丸剤、
坐剤、液剤、注射剤等として使用することもできる。In the production of the composition A, which is a component of the pharmaceutical composition of the present invention, the raw materials senkyu, peony, safflower, woody incense, scented radish and danshen are mixed in a predetermined weight ratio, and this mixture is added to the total weight of the mixture. 5 to 30 times, preferably 10 to 20 times
Extract with double hot water, concentrate the extract and dry.
Concentration and drying can be carried out by a conventional means such as evaporative concentration under reduced pressure, spray drying or freeze drying. The solid thus obtained is itself used as a powder or powder, but granules, tablets, capsules, pills, together with suitable excipients, bases, emulsifiers, solvents, stabilizers and other additives.
It can also be used as a suppository, solution, injection, etc.
【００１５】本発明の任意成分である組成物Ｂは次のよ
うにして製造される。原料であるオウギ、ゴシツ、当
帰、人参、龍眼肉、鹿茸、杜仲及びハゲキテンの所定量
を粉砕した後、均等に混合し、さらにハチミツなどの常
用の添加剤を加え、球状に成型する。本発明の任意成分
である組成物Ｃは次のようにして製造される。原料であ
る地黄、ブクリョウ、牡丹皮、タクシャ、サンシュユ及
び山薬の所定量を粉砕した後、均等に混合し、さらにハ
チミツなどの常用の添加剤を加え、球状に成型する。ま
た、前記必須組成物Ａと任意成分である組成物Ｂ又はＣ
とを含む製剤の製造においては、それらの成分全体を一
緒に例えば熱水抽出することができる。The composition B, which is an optional component of the present invention, is manufactured as follows. After crushing a predetermined amount of raw materials, such as ougi, goshitsu, toki, carrot, dragon eye meat, antler mushroom, eucommia, and hagekiten, mix them evenly, and add a commonly used additive such as honey to form a spherical shape. Composition C, which is an optional component of the present invention, is manufactured as follows. After crushing a predetermined amount of raw materials, ground yellow, butterbur, peony skin, taksha, saury, and mountain herbs, they are mixed evenly, and commonly used additives such as honey are added to form a spherical shape. In addition, the essential composition A and the optional composition B or C
In the preparation of formulations containing and, the entire components can be extracted together, for example with hot water.
【００１６】本発明の抗痴呆剤は特に、老人性痴呆症に
対して有効である。これは次の動物実験により証明され
る。老化促進モデルマウス（ＳＡＭ）による実験 中枢神経系の老化による痴呆は神経細胞の脱落及び、機
能低下に起因すると考えられるが、一般の実験動物では
その寿命が短いために死の直前までそのような痴呆症状
は観察されない。老化促進モデルマウス（ＳＡＭ）は、
京都大学胸部疾患研の竹田らによりＡＫＲの飼育中に発
見され新たな系統として確立され、老化促進モデル動物
として注目されているものである。ＳＡＭは促進老化を
主徴とし、活動性の低下、脱毛、被毛光沢の減退消失、
被毛粗雑、眼周囲病変、白内障、脊椎前後弯増強、寿命
短縮などの促進老化現象を示す老化促進モデルマウス
Ｐ系（ＳＡＭ−Ｐ）と正常老化を示すと考えられる老化
促進モデルマウス Ｒ系（ＳＡＭ−Ｒ）から成る。ＳＡ
Ｍ−Ｐのうち、特にＳＡＭ−Ｐ／８系は、加齢に伴って
脳幹部での神経細胞の脱落を伴った著しい学習・記憶障
害を示すことが知られ、中枢の老化を研究する上での格
好な実験動物と考えられている。The anti-dementia agent of the present invention is particularly effective for senile dementia. This is proved by the following animal experiments. Experiments with aging-promoting model mice (SAM) Dementia due to aging of the central nervous system is thought to be caused by neuronal loss and functional decline. No dementia symptoms are observed. The aging-promoting model mouse (SAM)
It was discovered during the breeding of AKR by Takeda et al. Of the Chest Disease Research Institute of Kyoto University, was established as a new strain, and is attracting attention as a model animal for promoting aging. SAM has accelerated aging as a main symptom, decreased activity, hair loss, loss and disappearance of hair gloss,
Aging-promoting model mouse showing accelerated aging phenomena such as rough coat, periocular lesions, cataract, spinal anterior-posterior curvature, shortened life span
It consists of the P system (SAM-P) and the aging-promoting model mouse R system (SAM-R) which is considered to show normal aging. SA
Among the M-Ps, the SAM-P / 8 system is known to exhibit remarkable learning and memory deficits accompanied by loss of nerve cells in the brain stem with aging. It is considered to be a good experimental animal in.
【００１７】本実験では、冠元顆粒単独投与及び六味地
黄丸又は参茸補血丸との併用によるＳＡＭ−Ｐ／８系で
の学習・記憶障害改善効果をモーリスの水迷路を用い、
対照系であるＳＡＭ−Ｒ／１系と比較検討した。なお迷
路学習終了後、生化学的側面からの検討をするために老
化の指標としてスーパーオキシディスムターゼ（ＳＯ
Ｄ）活性、過酸化脂質量を記憶学習にもっとも関係の深
い神経系と考えられているアセチルコリン系の機能の指
標としてコリンアセチルトランスフェラーゼ（ＣｈＡ
Ｔ）活性を測定した。In this experiment, using the Morris water maze, the effect of improving learning and memory deficits in the SAM-P / 8 system by the single administration of crown root granules and the combined use with Rokumiji-ogan or ginseng supplemented blood,
A comparative study was conducted with the SAM-R / 1 system, which is a control system. After completion of maze learning, superoxydismutase (SO
D) Choline acetyltransferase (ChA) is used as an indicator of the function of the acetylcholine system, which is considered to be the nervous system most closely related to memory learning in terms of activity and lipid peroxide content.
T) Activity was measured.
【００１８】Ａ．実験方法 実験動物及び薬物投与 ＳＡＭ−Ｐ／８系及びＳＡＭ−Ｒ／１系マウスを、常用
の条件下、気温２２±２℃、湿度５０±１０％、１２時
間明暗サイクルの飼育室で飼育した。実験開始時に２２
−２３週齢のＳＡＭを用い、六味地黄丸及び冠元顆粒を
１．２％、２．２５％となるように水に溶かし、参茸補
血丸は９．５ｇ／１００ｇとなるように飼料中に混ぜ、
６週間、自由摂取させた。学習・記憶実験にはモーリス
の水迷路を使用し、試行は週に一度４回からなるセッシ
ョンを行った。迷路実験終了後、大脳皮質と線条体のＣ
ｈＡＴ活性、肝臓、小脳のＳＯＤ活性、肝臓、小脳、血
清中の過酸化脂質量を測定した。A. Experimental method Experimental animal and drug administration SAM-P / 8 strain and SAM-R / 1 strain mice were bred in a breeding room under a normal condition of temperature 22 ± 2 ° C., humidity 50 ± 10%, and a 12-hour light-dark cycle. . 22 at the start of the experiment
-23-week-old SAM was used to dissolve Rokumichi-ogan and Gangen-granule in water to 1.2% and 2.25%, respectively, and to supplement ginseng supplemented blood to 9.5 g / 100 g in the feed. Mix with
The animals were allowed to freely ingest for 6 weeks. Morris' water maze was used for learning and memory experiments, and the trials consisted of four sessions once a week. After completion of the maze experiment, C of cerebral cortex and striatum
The hAT activity, SOD activity in the liver and cerebellum, and the amount of lipid peroxide in the liver, cerebellum, and serum were measured.
【００１９】モーリス水迷路課題 学習・記憶実験として、モーリスの水迷路を使用した。
直径８０cm、深さ４０cmの円形プールに、ゴールとして
円形プラットホーム（直径１２cm、深さ３０cm）をお
き、プラットホーム面が水面下１cmとなるように水を満
たし、水迷路を作成した（図１）。マウスをプールの辺
より水中にいれ、プラットホームまで泳がせた。１２０
秒以内にプラットホームを見つけられなかった場合、プ
ラットホームに誘導し乗せて終了し、１２０秒をゴール
への到達時間記録した。各試行終了後、マウスをプラッ
トホーム上に１分間放置した。試行は、週に一度、４回
の試行からなるセッションを行った。スタート地点及び
ゴール地点は、それぞれ４ヶ所（図示）から、２地点の
距離が等しくなるように任意に１ヶ所ずつ選択し、１セ
ッションは固定した。行動はビデオトレーサーにより収
録し、室町機械社製のソフト（ＣＨＡＳＥＲ）によりコ
ンピュータを用いて解析した。 Morris Water Maze The Morris water maze was used as a learning and memory experiment.
A circular platform (diameter 12 cm, depth 30 cm) was placed as a goal in a circular pool with a diameter of 80 cm and a depth of 40 cm, and water was filled so that the platform surface was 1 cm below the water surface to create a water maze (Fig. 1). The mouse was put into the water from the side of the pool and allowed to swim to the platform. 120
If the platform could not be found within the second, it was guided to the platform, put on, and finished, and 120 seconds was recorded as the time to reach the goal. After each trial, the mice were left on the platform for 1 minute. The trial consisted of a session consisting of four trials once a week. The starting point and the goal point were arbitrarily selected from four points (illustrated) so that the distance between the two points would be equal, and one session was fixed. The behavior was recorded by a video tracer and analyzed by a computer using software (CHASER) manufactured by Muromachi Kikai Co., Ltd.
【００２０】ＣｈＡＴ活性測定 迷路実験に使用した動物の大脳皮質と線条体のＣｈＡＴ
活性を以下の方法に基づき測定した。大脳皮質と線条体
をそれぞれ１００μｌ及び５０μｌの５０mMＴｒｉｓ−
ＨＣｌ（トリス−塩酸緩衝液pH７．６）中で超音波粉砕
し、同量の１０mM ＥＤＴＡと１／５量の２．５％ Ｔ
ｒｉｔｏｎ Ｘ−１００（商品名）を加えた後、１５分
間攪拌してエンザイム溶液とした。 ChAT of animal cerebral cortex and striatum used in the maze experiment for measuring ChAT activity
The activity was measured according to the following method. The cerebral cortex and striatum are 100 μl and 50 μl of 50 mM Tris-, respectively.
Ultrasonic pulverization in HCl (Tris-HCl buffer pH 7.6), same volume of 10 mM EDTA and 1/5 volume of 2.5% T.
After adding Ritton X-100 (trade name), the mixture was stirred for 15 minutes to prepare an enzyme solution.
【００２１】インキュベーション液の組成は以下の通り
である：０．２mM〔 3Ｈ〕ａｃｅｔｙｌ−ＣｏＡ（Ａｍ
ｅｒｓｈａｍ，社３．２５Ci／mmol＝１２０GBq ／mmo
l），３００mM ＮａＣｌ，５０mM ｓｏｄｉｕｍ ｐ
ｈｏｓｐｈａｔｅ ｂｕｆｆｅｒ（pH７．４），８mM
ｃｈｏｌｉｎｅ ｃｈｌｏｒｉｄｅ，２０mM ＥＤＴＡ
（pH７．４），０．１mM ｐｈｙｓｏｓｔｉｇｍｉｎ
ｅ。〔 3Ｈ〕ａｃｅｔｙｌ−ＣｏＡはラベルされていな
いａｃｅｔｙｌ−ＣｏＡで希釈して１２，５００dpm ／
nmolまで比活性を下げて使用した。カウンティングミニ
バイアルに８μｌのエンザイム溶液と２０μｌのインキ
ュベーション液を入れ、１５分間、３７℃でインキュベ
ートした。１mlの冷１０mM ｓｏｄｉｕｍ ｐｈｏｓｐ
ｈａｔｅ ｂｕｆｆｅｒで反応を停止させ、氷上におい
た。２mgのＫａｌｉｇｎｏｓｔ（商品名）を含む０．４
mlのアセトニトリルと２mlのトルエンシンチレーション
カクテル（トルエン１ｌ中にＰＰＯ（２，５ジフェニー
ルオキサザール）４ｇとＰＯＰＯＰ〔１，４−ビス−２
−（４−メチル ５−フェニルオキサゾイル）ベンゼ
ン〕０．１ｇを含む）を加え、ゆっくり振り混ぜた。ト
ルエンシンチレーションカクテルに抽出されてきた放射
活性を測定した。The composition of the incubation solution is as follows: 0.2 mM [ 3 H] acetyl-CoA (Am
ersham, company 3.25 Ci / mmol = 120 GBq / mmo
l), 300 mM NaCl, 50 mM sodium p
phosphate buffer (pH 7.4), 8 mM
choline chloride, 20 mM EDTA
(PH 7.4), 0.1 mM physostigmin
e. [ 3 H] acetyl-CoA was diluted with unlabeled acetyl-CoA at 12,500 dpm /
The specific activity was lowered to nmol before use. 8 μl of enzyme solution and 20 μl of incubation solution were placed in a counting mini vial and incubated at 37 ° C. for 15 minutes. 1 ml cold 10 mM sodium phosp
The reaction was stopped with a hate buffer and placed on ice. 0.4 including 2 mg of Kalignost (trade name)
ml of acetonitrile and 2 ml of toluene scintillation cocktail (4 g of PPO (2,5 diphenyl oxazal) in 1 l of toluene) and POPOP [1,4-bis-2
-(4-Methyl 5-phenyloxazoyl) benzene] (including 0.1 g) was added thereto, and the mixture was shaken slowly. The radioactivity extracted in the toluene scintillation cocktail was measured.
【００２２】ＳＯＤ活性測定 迷路実験で使用したマウスの小脳のＳＯＤ活性を、亜硝
酸変法を用いて測定した。脳組織は１mM ＥＤＴＡ（pH
７．４）と１０mM Ｔｒｉｓ−ＨＣｌ（pH７．４）を含
む０．３２Ｍ ｓｕｃｒｏｓｅ（１：９Ｗ／Ｖ）中で、
超音波粉砕した。その後４℃で、１５００ｇ、１０分の
遠心分離をし、上清をさらに４℃で５０００ｇ、１０分
間遠心分離をして得られた上清とペレット分画について
測定を行った。脳サンプル及び上記のバッファー（ブラ
ンクとして）０．１mlに、基質試薬（組成：１mM ｈｙ
ｄｒｏｘｙｌａｍｉｎｅ，１mM ｈｙｐｏｘａｎｔｈｉ
ｎｅ）０．２ml及びＨ2 Ｏ又はＣｕ，Ｚｎ−ＳＯＤを阻
害できる２mM ＫＣＮを０．５mlを加えて攪拌し、酵素
試薬（組成：１００mU／ml ＸＯＤ、キサンチンオキシ
ターゼ（ベーリンガーマンハイム社 ２０Ｕ／ml），１
０４mM ＫＨ2 ＰＯ4 ，Ｎａ2 Ｂ4 Ｏ7 ，０．５mM Ｅ
ＤＴＡ）０．２mlを加えて３７℃で３０分間、インキュ
ベートした。その後、発色試薬（０．４５mg／ml ｓｕ
ｌｆａｎｉｌｉｃ ａｃｉｄと１０．４μｇ／ml Ｎ−
１−ｎａｐｈｔｈｙｌｅｔｈｙｌｅｎｅｄｉａｍｉｎｅ
を含む０．２５％酢酸溶液）２．０mlを加えて、２０分
間、室温で放置した。５５０nmの波長で吸光度を測定し
た。 SOD activity measurement The SOD activity of the cerebellum of the mice used in the maze experiment was measured using the modified nitrite method. Brain tissue contains 1 mM EDTA (pH
7.4) and 0.3 mM M sucrose (1: 9 W / V) containing 10 mM Tris-HCl (pH 7.4),
It was ultrasonically ground. Thereafter, centrifugation was performed at 1500 g for 10 minutes at 4 ° C., and the supernatant was further centrifuged at 5000 g for 10 minutes at 4 ° C. The supernatant and pellet fraction obtained were measured. To a brain sample and 0.1 ml of the above buffer (as a blank), a substrate reagent (composition: 1 mM hy)
droxylamine, 1 mM hypoxanthi
ne) 0.2 ml and 0.5 ml of 2 mM KCN capable of inhibiting H 2 O or Cu, Zn-SOD were added and stirred, and an enzyme reagent (composition: 100 mU / ml XOD, xanthine oxidase (Boehringer Mannheim Co., 20 U / ml)) was added. , 1
04 mM KH 2 PO 4 , Na 2 B 4 O 7 , 0.5 mM E
0.2 ml of DTA) was added and the mixture was incubated at 37 ° C. for 30 minutes. After that, coloring reagent (0.45 mg / ml su
lfanilic acid and 10.4 μg / ml N-
1-naphtylethylenediamine
2.0 ml of a 0.25% acetic acid solution containing) was added and left at room temperature for 20 minutes. Absorbance was measured at a wavelength of 550 nm.
【００２３】ＳＯＤ活性量は亜硝酸単位NU：１NU（亜硝
酸単位）＝５０％阻害率を示すときの希釈度で表した。過酸化脂質量測定法 過酸化脂質の測定は、ｔｈｉｏｂａｒｂｉｔｕｒｉｃ
ａｃｉｄ（ＴＢＡ）を用いて、三原らの方法で行った。The amount of SOD activity was represented by the dilution degree when the nitrite unit NU: 1NU (nitrite unit) = 50% inhibition rate was shown. Lipid peroxide amount measurement method The measurement of lipid peroxide is thiobarbituric
It was carried out by the method of Mihara et al. using acid (TBA).
【００２４】１）肝臓 サンプル調製：肝臓を９倍量の氷冷した１．１５％ＫＣ
ｌ溶液中で、テフロングラスホモジナイザーでホモジナ
イズし、サンプル溶液とした。 測定法：サンプル０．５mlに０．３mlの１％リン酸溶
液、１．０mlの０．６７％ＴＢＡ溶液を加えて混和し
た。反応チューブにビー玉で栓をして、９５℃で、４５
分間加熱した。その後、直ちに冷却して反応を停止し
た。４mlのｎ−ブタノールを添加して、振盪抽出した
後、３０００rpm 、１０分間遠心分離した。上層（ブタ
ノール層）の吸光度を５３５nmと５２０nmの２箇所で測
定し、その差を求めた。標準として１，１，３．３−ｔ
ｅｔｒａｅｔｈｏｘｙｐｒｏｐａｎｅを、対照には生理
食塩水を使用して同様に行った。1) Liver sample preparation: 9 times the amount of liver-cooled 1.15% KC
1 solution was homogenized with a Teflon glass homogenizer to obtain a sample solution. Measurement method: 0.3 ml of 1% phosphoric acid solution and 1.0 ml of 0.67% TBA solution were added to 0.5 ml of the sample and mixed. Cap the reaction tube with marbles and place at 95 ° C for 45
Heated for minutes. Then, the reaction was stopped immediately by cooling. After adding 4 ml of n-butanol and extracting by shaking, the mixture was centrifuged at 3000 rpm for 10 minutes. The absorbance of the upper layer (butanol layer) was measured at two points, 535 nm and 520 nm, and the difference was determined. 1,1,3.3-t as standard
Etraethoxypropane was performed in the same manner using saline as a control.
【００２５】２）小脳 サンプル調製：小脳を９倍量の氷冷した１．１５％ＫＣ
ｌ溶液中で、テフロングラスホモジナイザーでホモジナ
イズし、サンプル溶液とした。 測定法：サンプル０．２５mlに０．１５mlの１％リン酸
溶液、０．５mlの０．６７％ＴＢＡ溶液を加えて混和し
た。反応チューブにビー玉で栓をして、９５℃で、４５
分間加熱した。その後、直ちに冷却して反応を停止し
た。２mlのｎ−ブタノールを添加して、振盪抽出した
後、３０００rpm 、１０分間遠心分離した。上層（ブタ
ノール層）の吸光度を５３５nmと５２０nmの２箇所で測
定し、その差を求めた。標準として１，１，３．３−ｔ
ｅｔｒａｅｔｈｏｘｙｐｒｏｐａｎｅを、対照には生理
食塩水を使用して同様に行った。2) Cerebellar sample preparation: 9 volumes of cerebellum ice-cooled 1.15% KC
1 solution was homogenized with a Teflon glass homogenizer to obtain a sample solution. Measurement method: To 0.25 ml of the sample, 0.15 ml of 1% phosphoric acid solution and 0.5 ml of 0.67% TBA solution were added and mixed. Cap the reaction tube with marbles and place at 95 ° C for 45
Heated for minutes. Then, the reaction was stopped immediately by cooling. After adding 2 ml of n-butanol and extracting with shaking, the mixture was centrifuged at 3000 rpm for 10 minutes. The absorbance of the upper layer (butanol layer) was measured at two points, 535 nm and 520 nm, and the difference was determined. 1,1,3.3-t as standard
Etraethoxypropane was performed in the same manner using saline as a control.
【００２６】蛋白定量 蛋白濃度は、標準液には、ｂｏｖｉｎｅ ｓｅｒｕｍ
ａｌｂｍｉｎ（牛血清アルブミン）を用い、Ｂｉｏ−Ｒ
ａｄ蛋白定量キットで測定した。 Ｂ．結果 水迷路学習ではＳＡＭ−Ｐ／８系、Ｒ／１系共に、薬物
投与群は対照群と比較して各セッションのプラットホー
ムにたどり着くまでのｇｏａｌ ｌａｔｅｎｃｙの有意
な減少を示した。その作用強度の比較は冠元顆粒単独投
与（図２）＜六味地黄丸併用（図３）＜参茸補血丸併用
（図４）であった。ＳＯＤ活性は六味地黄丸併用ではＳ
ＡＭ−Ｐ／８系で薬物投与群が対照群と比較して有意に
高値を示し、ＳＡＭ−Ｒ／１系とほぼ同程度にまで回復
した（図５）。 Quantitative protein concentration: bovine serum
Bio-R using albmin (bovine serum albumin)
It was measured with an ad protein quantification kit. B. Results In the water maze learning, in both the SAM-P / 8 system and the R / 1 system, the drug administration group showed a significant reduction in the goal latency until reaching the platform of each session, as compared with the control group. The comparison of the action strengths was that administration of crown granules alone (Fig. 2) <combination of Rokumiji-ogan (Fig. 3) <combination of ginseng supplemented blood circles (Fig. 4). SOD activity is S when combined with Rokumichi yellow circle
In the AM-P / 8 system, the drug-administered group showed a significantly higher value as compared with the control group, and recovered to almost the same level as the SAM-R / 1 system (FIG. 5).
【００２７】冠元顆粒単独投与においても肝臓小脳共に
薬物投与群が対照群と比較して高値を示したが、六味地
黄丸併用と比較するとその程度は少なかった（図６，
７）。参茸補血丸併用では強いＳＯＤ活性の増加が観察
されたが、その作用は肝臓においてより顕著であった
（図８，９）。冠元顆粒単独投与で過酸化脂質量はＳＯ
Ｄ活性の上昇に伴い減少した（図１０）。参茸補血丸併
用ではＳＯＤ活性の上昇が顕著に見られた肝臓におい
て、過酸化脂質量が減少した（図１１）。Even in the administration of Guangyuan granules alone, the drug-administered group showed a higher value in both liver cerebellum as compared with the control group, but the level was lower than that in the case of combined use with Rokumiji-ogan (FIG. 6, FIG.
7). A strong increase in SOD activity was observed with the combined use of Ginseng Bamboo Pills, but the effect was more prominent in the liver (Figs. 8 and 9). The amount of lipid peroxide is SO when administered alone
It decreased with the increase of D activity (Fig. 10). The amount of lipid peroxide was decreased in the liver in which the SOD activity was remarkably increased when the ginseng supplemented blood was used together (FIG. 11).
【００２８】六味地黄丸併用では線条体におけるＣｈＡ
Ｔ活性はＳＡＭ−Ｐ／８系の薬物投与群で低下の抑制傾
向が見られた（図１２）。冠元顆粒単独投与では有意な
変化は見られなかった（図１３）。冠元顆粒単独投与で
は体重の薬物投与による変化はみられなかった（図１
４）。六味地黄丸併用時にはＳＡＭ−Ｒ／１系での体重
変化が無かったが、ＳＡＭ−Ｐ／８系ではその体重減少
が有意に回復した（図１５）。参茸補血丸併用では対照
系のＳＡＭ−Ｒ／１で薬物投与により体重の減少傾向が
見られた（図１６）。Chroma in the striatum when used together with the Rokumijiogan
A decrease in T activity tended to be suppressed in the SAM-P / 8 system drug-administered group (FIG. 12). No significant change was observed in administration of coronal granules alone (Fig. 13). Administration of coronal granules alone showed no change in body weight due to drug administration (Fig. 1).
4). There was no change in body weight in the SAM-R / 1 system when combined with Rokumijiogan, but the weight loss was significantly recovered in the SAM-P / 8 system (FIG. 15). In the case of combined use of Ginseng Bamboo Blood Companion Pill, a decrease in body weight due to drug administration was observed in SAM-R / 1 as a control system (FIG. 16).
【００２９】以上より、これらの薬物は、老化によるＳ
ＯＤとＣｈＡＴ活性の低下、過酸化脂質の増加の抑制を
示し、学習・記憶障害改善効果を持つ可能性が示唆され
る。六味地黄丸併用時には体重減少抑制による体力維持
効果の関与も考えられるが、参茸補血丸併用時には体重
減少が表れているにもかかわらず、迷路実験でよい成績
を得ていることから、この実験系における体重減少抑制
による体力維持効果の関与は少ないと思われる。From the above, these drugs are
It shows a decrease in OD and ChAT activities and an increase in lipid peroxides, suggesting that it may have a learning / memory disorder improving effect. Although it is possible that the physical strength maintenance effect due to the suppression of body weight loss may be involved when using Rokumiji-ogan, this experiment shows good results in the maze experiment despite the fact that weight loss appears when using ginseng supplemented blood. Involvement of physical strength maintenance effect by suppressing weight loss in the system seems to be small.
【００３０】また水迷路課題においては薬物の投与によ
り、データは示してないが個体の遊泳速度や外見的特徴
を変化は見られなかったが、プラットホームに到達する
までのｇｏａｌ ｌａｔｅｎｃｙを有意に減少させ、線
条体においてはＳＡＭ−Ｐ／８系におけるＣｈＡＴ活性
をＳＡＭ−Ｒ／１系と差がなくなるまで増加させるな
ど、記憶学習作用の改善効果も示された。この時、大脳
皮質でＣｈＡＴ活性に変化がみられなかったのは、線条
体ではコリン作動性神経が豊富でＣｈＡＴも多量に存在
するが、大脳皮質では線条体と比べてＣｈＡＴの全体量
が少ないのでＣｈＡＴ活性の変化が検出しにくかったも
のと考えられる。In the water maze task, administration of the drug did not show any change in the swimming speed or the appearance characteristics of the individual, although the data are not shown, but it significantly decreased the goal latency until reaching the platform. In the striatum, ChAT activity in the SAM-P / 8 system was increased until there was no difference from that in the SAM-R / 1 system. At this time, no change was observed in ChAT activity in the cerebral cortex because the striatum is rich in cholinergic nerves and a large amount of ChAT is present, but in the cerebral cortex, the total amount of ChAT is higher than that in the striatum. It is considered that the change in ChAT activity was difficult to detect because the amount of ChAT was small.
【００３１】老化は細胞や組織に生じるラジカルが起こ
す連続的な有害反応による障害の蓄積であるという老化
のフリーラジカル説が１９５６年Ｈａｒｍａｎにより唱
えられた。ラジカルの連続反応には生体内の不飽和脂質
を非特異的に過酸化し、過酸化脂質を生成するものがあ
る。不飽和脂質は生体膜の成分であるから、この脂質過
酸化反応は全身的にまた非特異的に障害を起こし、この
障害が老化につながっていくと考えられる。The free radical theory of aging was proposed by Harman in 1956 that aging is an accumulation of disorders due to continuous adverse reactions caused by radicals generated in cells and tissues. Some of the continuous radical reactions non-specifically peroxidize unsaturated lipids in the body to produce lipid peroxides. Since unsaturated lipids are components of biological membranes, it is considered that this lipid peroxidation reaction causes systemic and nonspecific damage, which leads to aging.
【００３２】スーパーオキサイドラジカル（Ｏ2 - ）を
過酸化水素（Ｈ2 Ｏ2 ）と酸素分子（Ｏ2 ）に変える酵
素、スーパーオキサイドディスムターゼ（ＳＯＤ）とい
う酵素が多くの生体内過酸化反応を阻害することが明か
となっている。ＳＯＤは生体内で生じるスーパーオキサ
イドラジカルを消去することにより生体防御に役立って
いると考えられる。The superoxide radical (O 2 -) inhibits the enzyme turned into hydrogen peroxide (H 2 O 2) and oxygen molecules (O 2), the enzyme superoxide dismutase (SOD) Many vivo peroxidation of It is clear to do. SOD is considered to be useful for biological defense by eliminating superoxide radicals generated in the body.
【００３３】本実験で用いたＳＡＭ−Ｐ／８系は、脳幹
や脊髄の海綿化が４〜８ヶ月齢にかけて進むことが知ら
れており、ＳＡＭ−Ｒ／１系と比べてＣｕ，Ｚｎ−ＳＯ
ＤやＭｎ−ＳＯＤが低下しているという報告や、学習や
記憶の能力が劣っているという報告がある。今回、冠元
顆粒と他の薬物の併用により有意にＳＯＤが増加し、そ
れに伴って過酸化脂質量が低下したことは、ＳＯＤが生
体で老化に関係の深い脂質過酸化反応を抑える酵素の一
つであることから、用いた漢方薬がこの観点からの老化
の進行を遅らせる働きを有することが示唆される。The SAM-P / 8 system used in this experiment is known to cause spongiformation of the brain stem and spinal cord over the age of 4 to 8 months, and compared with the SAM-R / 1 system, Cu, Zn- SO
There are reports that D and Mn-SOD are lowered, and that learning and memory abilities are inferior. This time, when SOD increased significantly due to the combined use of Guangyuan granules and other drugs, and the amount of lipid peroxide decreased accordingly, SOD is one of the enzymes that suppress lipid peroxidation reaction deeply related to aging in the living body. Therefore, it is suggested that the Kampo medicine used has a function of delaying the progress of aging from this viewpoint.
【００３４】また、冠元顆粒は血液の粘度を低下させる
ことにより、微小循環を促進して全身の老廃物を除去
し、いろいろな酵素の活性を上昇させていると考えられ
る。またこの微小循環の改善作用が、神経細胞の活動に
必要なグルコースの供給を増加させて、学習、記憶障害
の改善につながっている可能性も考えられる。It is also considered that the crown granules reduce the viscosity of blood to promote the microcirculation, remove wastes from the whole body, and increase the activities of various enzymes. It is also possible that this improving effect on the microcirculation increases the supply of glucose required for nerve cell activity, leading to improvement in learning and memory disorders.
【００３５】ｄｄＹ系マウスによる実験 アルツハイマー型痴呆ではポジトロンエミッションモグ
ラフィー（ＰＥＴ）による解析で脳血流量の低下に伴っ
たグルコース代謝の低下が報告されている。このことは
その部位での神経活動の低下を意味しており、この低下
を改善することで痴呆症状の改善が期待される。一方、
冠元顆粒の薬理作用は脳血液循環量を増進することでグ
ルコースなどの栄養物の運搬効率を改善し神経細胞の活
動を増すことにあると考えられる。そこで冠元顆粒投与
によりこのグルコース代謝の増加が得られるか否かの検
討を行った。In experimental Alzheimer-type dementia using ddY mice, a decrease in glucose metabolism accompanying a decrease in cerebral blood flow has been reported by analysis by positron emission tomography (PET). This means a decrease in nerve activity at that site, and improvement of this decrease is expected to improve dementia symptoms. on the other hand,
It is thought that the pharmacological action of Gongen granules is to improve the cerebral blood circulation and thereby improve the efficiency of delivering nutrients such as glucose and increase the activity of nerve cells. Therefore, it was examined whether or not administration of coronal granules could increase this glucose metabolism.
【００３６】脳神経はその活動に必要とする大部分のエ
ネルギーをグルコースから生成している。そこでどのく
らいのグルコースが代謝されたかを調べれば神経活動の
程度が明かとなる。２−デオキシグルコースはグルコー
スと同様に神経細胞内に取り込まれるが１段階代謝され
るとその時点で代謝が止まり神経細胞内に蓄積する。こ
の現象を利用して２−デオキシグルコースを放射性同位
元素で標識しておけばその放射性同位元素の細胞内蓄積
量で神経活動を測ることができる。この原理は先に述べ
たＰＥＴでも用いられているが、ＰＥＴでは解像力が低
いために実験動物の脳内変化を捉えることが出来ない。
そこで本実験ではオートラジオグラフィ法を用いた。Cranial nerves produce most of the energy needed for their activity from glucose. The extent of neural activity can be revealed by examining how much glucose is metabolized. Similar to glucose, 2-deoxyglucose is taken into the nerve cells, but when it is metabolized in one step, the metabolism stops at that point and accumulates in the nerve cells. If 2-deoxyglucose is labeled with a radioisotope using this phenomenon, nerve activity can be measured by the intracellular accumulation amount of the radioisotope. This principle is used in the PET described above, but PET cannot detect changes in the brain of experimental animals because of its low resolution.
Therefore, the autoradiography method was used in this experiment.
【００３７】方法 動物は体重２０±２ｇのｄｄＹ系雄性マウスを用いた。
冠元顆粒は３ｇを１mlの精製水に解かした。この冠元顆
粒溶液を６０ｇ／kgとなるように経口的に投与した。ｄ
ｅｏｘｙ−Ｄ−ｇｌｕｃｏｓｅ，２−〔14Ｃ（Ｕ）〕−
（２ＤＧ：比放射能１１．８ギガベクレル（ＧＢｑ）／
mmol，ＮＥＮ）は０．５１８MBq ／mlとなるように生理
食塩水で希釈し、５．１８MBq ／kg尾静脈より冠元顆粒
投与３０分後に注入した。２ＤＧ投与４０分後に頚椎脱
臼によりマウスを殺し、全脳を摘出した。 Method As the animal, a male ddY mouse having a body weight of 20 ± 2 g was used.
3 g of the crown granules were dissolved in 1 ml of purified water. This crown granule solution was orally administered at a dose of 60 g / kg. d
eoxy-D-glucose, 2- [ 14 C (U)]-
(2DG: Specific activity 11.8 Gigabecquerel (GBq) /
(mmol, NEN) was diluted with physiological saline to a concentration of 0.518 MBq / ml, and injected from the tail vein of 5.18 MBq / kg 30 minutes after administration of coronal granules. 40 minutes after 2DG administration, the mouse was killed by cervical dislocation and the whole brain was removed.
【００３８】脳は直ちにドライアイスにて凍結、包埋剤
（Ｏ．Ｃ．Ｔ．コンパウンド、マイルス三共）にて凍結
包埋標本とした。この凍結包埋脳標本をクリオスタット
ミクロトーム（ＯＴ／ＳＥＡ、ブライト）を用いて−２
０℃下で厚さ２０μｍの水平連続切片とした。この連続
切片標本を常温下、フィルムカセット内で14Ｃの標準線
源（Ａｕｔｏｒａｄｉｏｇｒａｐｈｉｃ（14Ｃ）ｍｉｃ
ｒｏ−ｓｃａｌｅｓ、アマシャム）と共にＸ線フィルム
に２週間暴露の後、そのＸ線フィルムを現像処理した。The brain was immediately frozen with dry ice and frozen with an embedding agent (OCT compound, Miles Sankyo) to prepare a frozen-embedded specimen. Using a cryostat microtome (OT / SEA, Bright), this frozen-embedded brain specimen was -2.
A horizontal serial section having a thickness of 20 μm was prepared at 0 ° C. Room temperature The continuous section sample, 14 C standard ray source in a film cassette (Autoradiographic (14 C) mic
After exposure to X-ray film for 2 weeks with ro-scales, Amersham), the X-ray film was processed.
【００３９】現像したＸ線フィルム上の脳標本と14Ｃの
標準線源の像のデジタルデータをスキャナー（ＥＰＳＯ
Ｎ ＧＴ−８００）を用いてマイクロコンピューター
（Ｍａｃｉｎｔｏｓｈ Ｑｕａｄｒａ９００、アップ
ル）に取込み、ＮＩＨ Ｉｍａｇｅ Ｖｅｒｓｉｏｎ
１．４１で擬似カラー化及び定量の画像処理をした。な
お、マウスの脳の解剖学はＳＩｄｍａｎらの脳図譜（ハ
ーバード大学出版１９７１）によった。この結果を図１
７に示す。The digital data of the image of the brain specimen on the developed X-ray film and the standard radiation source of 14 C was scanned with a scanner (EPSO).
NGT-800) was used to load into a microcomputer (Macintosh Quadra900, Apple), and NIH Image Version was used.
In 1.41, pseudo-coloring and quantitative image processing were performed. The anatomy of the mouse brain was based on the brain diagram of SIdman et al. (Harvard University Press 1971). This result is shown in Figure 1.
7 shows.
【００４０】結果 冠元顆粒の投与により、脳全体でのグルコースの取込み
が増加した。その増加の程度は均一ではなく、線条体、
視床、大脳皮質前頭葉、小脳の一部で特に強く、続いて
大脳皮質側頭葉、海馬で強い増加が見られた。このよう
にその増強作用に部位特異性が見られることから、冠元
顆粒の作用は脳血流量の増加のみではなく、何らかの神
経細胞活動に対する直接作用が有ると思われる。 Results Administration of crown granules increased glucose uptake in the whole brain. The degree of increase is not uniform, the striatum,
It was particularly strong in the thalamus, frontal lobe of the cortex, and part of the cerebellum, followed by a strong increase in the temporal lobe of the cortex and hippocampus. Since site-specificity is observed in its enhancing action, it is considered that the action of coronal granules has not only an increase in cerebral blood flow but also a direct action on some nerve cell activity.
【００４１】またそのグルコースの取込みが増加した部
分を詳細に検討すると特にコリン作動性神経の多く分布
する部位でありコリン作動性神経系に対する受容体刺激
などに代表される直接作用の存在が示唆される。このこ
とはコリン作動性神経系に対する作用と共にｃ−ＡＭＰ
量の増加を起こしている可能性を示唆する。今回の結果
から冠元顆粒はその投与により脳内グルコース代謝の増
加、つまり神経活動の増進を行うことで今までに行って
来た実験動物モデルでの記憶障害の改善ひいてはヒトで
の痴呆症状の改善を行う可能性が示唆された（図１
７）。Further, a detailed examination of the part where the glucose uptake is increased suggests the existence of a direct action represented by receptor stimulation on the cholinergic nervous system, which is a site where a large number of cholinergic nerves are distributed. It This is due to the action on the cholinergic nervous system and c-AMP
It suggests that the amount may be increasing. From these results, the administration of coronal granules improves the glucose metabolism in the brain by its administration, that is, the improvement of the memory deficits in the experimental animal models that have been carried out up to now by enhancing the nerve activity, and consequently the dementia symptoms in humans. The possibility of improvement was suggested (Fig. 1
7).
【００４２】雄性Ｓｐｒａｇｕｅ−Ｄａｗｌｅｙ系ラッ
トによる実験 アルツハイマー病（ＡＤ）は、脳での萎縮変化と学習記
憶機能の障害を特徴とする病気である。そして学習や記
憶といった事柄は、中枢神経系（ＣＮＳ）のコリン作動
性神経系の機能と深く関連していることは広く知られて
いる。前脳基底部（ＢＦ）は、新皮質や海馬へのコリン
作働性神経系の投射の源であり、特にマイネルト基底核
（ｎｂｍ）のコリン作働性神経はＡＤにおいて顕著に障
害されている。 Male Sprague-Dawley system rat
Experiment by Toh Alzheimer's disease (AD) is a disease characterized by atrophy changes in the brain and impaired learning and memory function. It is widely known that matters such as learning and memory are deeply related to the function of the cholinergic nervous system of the central nervous system (CNS). The basal forebrain (BF) is the source of the projection of the cholinergic nervous system to the neocortex and hippocampus, and the cholinergic nerve of the basal ganglia (nbm) of Meinert is markedly impaired in AD. .
【００４３】またヒトｎｂｍはラットでのｎｂｍに相当
していることから、ｎｂｍを破壊したラットは、ＡＤ患
者の大脳皮質でみられるコリン作動性神経系の機能低下
を示す動物モデルであると考えられている。ｎｂｍを破
壊したラットは、大脳皮質でのアセチルコリン（ＡＣ
ｈ）遊離量やコリンアセチルトランスフェアーゼ（Ｃｈ
ＡＴ）活性といったコリンマーカーの減少を示し、また
学習や記憶の障害も示す。Since human nbm corresponds to that in rat, it is considered that the rat in which nbm has been destroyed is an animal model showing the hypofunction of the cholinergic nervous system found in the cerebral cortex of AD patients. Has been. nbm-disrupted rats showed acetylcholine (AC) in the cerebral cortex.
h) Release amount and choline acetyltransferase (Ch
It also shows a decrease in choline markers such as AT) activity and also impairs learning and memory.
【００４４】本実験では冠元顆粒が、ｎｂｍ破壊に伴い
ラット大脳皮質でみられるコリンマーカーの低下を改善
する作用を有するかどうかを検討した。実験開始時、体
重２３０〜２６０ｇの雄性Ｓｐｒａｇｕｅ−Ｄａｗｌｅ
ｙ系ラットを用いた。ラットは、２２±２℃に保った１
２時間の明暗サイクルを有する飼育室のケージの中で飼
育した。ラットは、自由に飼育用の餌（日本クレア；Ｃ
Ｅ２）を摂取できるようにした。手術に先だって、ペン
トバルビタール酸ナトリウム（５０mg／kg；腹腔内投
与）麻酔下に脳固定器（Ｄａｖｉｄ ｋｏｐｈ）に固定
した。In this experiment, it was examined whether crown granules had an action of improving the decrease of choline marker observed in rat cerebral cortex upon nbm destruction. At the start of the experiment, a male Sprague-Dawle weighing 230-260 g
Y rat was used. Rats were kept at 22 ± 2 ° C 1
They were housed in cages in a breeding room with a 2 hour light / dark cycle. Rats are allowed to freely feed (Clea Japan; C
E2) was made available. Prior to surgery, it was fixed to a brain fixator (David koph) under anesthesia with sodium pentobarbitalate (50 mg / kg; intraperitoneal administration).
【００４５】ブレグマから後方２．３mm、正中線より左
側３．７mm、深さ７．５mmのｎｂｍの位置にイボテン酸
（１０μｇ／μｌ）を注入してｎｂｍを破壊した。ＫＡ
Ｎは５％（ｗ／ｖ）となるように精製水に溶かした。手
術の影響から回復するために数日必要であったので、手
術後２日間は、１日２回、１回に２．５mlのＫＡＮを経
口ゾンデを用いてラットに強制的に投与した。それから
ラットには、５％のＫＡＮ溶液を自由に飲めるようにし
た。Ibotenic acid (10 μg / μl) was injected at a position of 2.3 mm rearward from the bregma, 3.7 mm left of the midline and 7.5 mm deep to inject ibotenic acid (10 μg / μl) to destroy the nbm. KA
N was dissolved in purified water so as to be 5% (w / v). Since it took several days to recover from the effects of surgery, the rats were gavaged with 2.5 ml of KAN twice a day, once a day, using an oral probe for 2 days after surgery. Rats were then allowed to drink 5% KAN solution ad libitum.
【００４６】手術から２週間目にラットを断頭し、脳を
素早く取り出して、予め９５％Ｏ2、５％ＣＯ2 の混合
ガスを通気し氷冷しておいたクレブス緩衝液（Ｋｒｅｂ
ｓ−Ｒｉｎｇｅｒ 炭酸緩衝液；pH７．４）中に入れ
た。クレブス緩衝液の組成は、ＮａＣｌ １１８mM，Ｋ
Ｃｌ ４．７０mM，ＭｇＳＯ4 １．５０mM，ＫＨ2 ＰＯ
4 １．１５mM，ＣａＣｌ2 １．２５mM，ＮａＨＣＯ3 ２
５．０mM，グルコース１１．１mMである。大脳はＭｃＩ
ＬＷＡＩＮティシューチョッパー（Ｂｒｉｎｋｍａｎ）
で厚さ４００μｍの切片とした。Two weeks after the operation, the rat was decapitated, the brain was taken out quickly, and a Krebs buffer solution (Kreb) (Kreb buffer) (Kreb) which had been previously ice-cooled with a gas mixture of 95% O 2 and 5% CO 2 was aerated.
s-Ringer carbonate buffer; pH 7.4). The composition of Krebs buffer is NaCl 118 mM, K
Cl 4.70 mM, MgSO 4 1.50 mM, KH 2 PO
4 1.15 mM, CaCl 2 1.25 mM, NaHCO 3 2
It is 5.0 mM and glucose is 11.1 mM. The brain is McI
LWAIN tissue chopper (Brinkman)
To obtain a 400 μm thick section.
【００４７】切片は、ブレグマの前後２mmの位置から採
取し、前から後ろにかけて大脳皮質の部分をそれぞれ
Ｃ．Ｃ．−１〜Ｃ．Ｃ．−５と名付けた。ＡＣｈ遊離量
とＣｈＡＴ活性の測定は、一枚おきの連続切片を用いて
行った。内径２mmのステンレス管を用いてそれぞれの大
脳半球から、大脳皮質のみを繰り抜いてマイクロパンチ
サンプルを作製した。マイクロパンチサンプルは１枚お
きに全部で１０枚の連続切片から取り、一枚の切片の片
側の半球から３ヶ所、両側の半球で６ヶ所ずつ、合計６
０個を取り出した。The slices were collected from a position 2 mm before and after the bregma, and the cerebral cortex part from C. C. -1 to C. C. It was named -5. The measurement of ACh release amount and ChAT activity was performed using every other serial section. A micropunch sample was prepared by pulling out only the cerebral cortex from each cerebral hemisphere using a stainless steel tube having an inner diameter of 2 mm. Micropunch samples were taken every other sheet from a total of 10 serial sections, 3 sections from one hemisphere on one side and 6 sections on each side of the hemisphere for a total of 6 sections.
0 pieces were taken out.
【００４８】この内３０個は、ＣｈＡＴ活性の測定に用
いるので、測定まで−８０℃の超低温庫に保存した。残
りの３０個は以下に示すＡＣｈ遊離量の測定実験に用い
た。マイクロパンチサンプルを、０．１μＭの〔 3Ｈ〕
−塩化コリン（８０Ci／mmol、アマシャム）を含むクレ
ブス緩衝液中で３０分間インキュベートした後、ブラン
デールの貫流装置に移し、１個のチャンバーにつき３個
の割合でマイクロパンチサンプルを入れた。Since 30 of these were used for measuring ChAT activity, they were stored in an ultralow temperature chamber at -80 ° C until the measurement. The remaining 30 were used in the measurement experiment of ACh release amount shown below. The micro punch sample was added with 0.1 μM [ 3 H].
-Incubated for 30 minutes in Krebs buffer containing choline chloride (80 Ci / mmol, Amersham), then transferred to a Brander flow-through and loaded with 3 micropunch samples per chamber.
【００４９】そして、予め９５％Ｏ2 、５％ＣＯ2 の混
合ガスを通気しておいた１０μＭのヘミコリニウムを含
むクレブス緩衝液を連続的に貫流させた。貫流速度は、
０．６ml／min とし、２．５min 毎に分画した。４０分
間の貫流の後に、４０mMＫ+を含むクレブス緩衝液で組
織を５分間刺激した。実験終了後、マイクロパンチサン
プルを取り出し、組織溶解剤（Ｓｏｌｕｅｎ−３５０）
を加えて８０℃で３０分間インキュベートしてサンプル
を溶かした。Then, a Krebs buffer solution containing 10 μM hemicolinium, which had been previously gassed with a mixed gas of 95% O 2 and 5% CO 2 , was continuously flowed through. Once-through velocity is
The volume was adjusted to 0.6 ml / min, and fractionation was performed every 2.5 min. After 40 minutes of flow-through, the tissues were stimulated with Krebs buffer containing 40 mM K + for 5 minutes. After the experiment was completed, the micro punch sample was taken out and a tissue lysing agent (Soluen-350) was used.
Was added and incubated at 80 ° C. for 30 minutes to dissolve the sample.
【００５０】集めたそれぞれの分画と溶解させた組織中
の放射活性を液体シンチレーションカウンターを用いて
測定した。ＣｈＡＴ活性の測定では、それぞれのマイク
ロパンチサンプルに５０mMのトリス塩酸緩衝液（pH７．
４）５０μｌを加えて、超音波破砕器で懸濁溶液とし
た。この懸濁溶液２０μｌに１０mM ＥＤＴＡ・２Ｎａ
溶液２０μｌと２．５％トライトンＸ−１００溶液８μ
ｌを加えて、室温で１５分間インキュベートして酵素溶
液とした。The radioactivity in each collected fraction and the lysed tissue was measured using a liquid scintillation counter. For measurement of ChAT activity, 50 mM Tris-HCl buffer (pH 7.
4) 50 μl was added and a suspension was prepared with an ultrasonic crusher. 20 μl of this suspension solution was added to 10 mM EDTA · 2Na
20 μl of solution and 8 μ of 2.5% Triton X-100 solution
1 was added and incubated at room temperature for 15 minutes to prepare an enzyme solution.
【００５１】この酵素溶液のタンパク質濃度は、ＢＩＯ
−ＲＡＤのプロテインアッセイキットを用いて測定し
た。酵素溶液８μｌに、０．１μＭ〔 3Ｈ〕−アセチル
ＣｏＡ（ＮＥＮ，１μCi／mmol）を含む５０mMナトリウ
ムリン酸緩衝液（組成：ＥＤＴＡ・２Ｎａ ２０mM，Ｎ
ａＣｌ ３００mM、塩化コリン８mM、サリチル酸フィゾ
スチグミン０．１mM；pH７．４）２０μｌをシンチレー
ションミニバイアル中で混合し、３７℃で１５分間イン
キュベートした。The protein concentration of this enzyme solution is
-Measured using the RAD protein assay kit. 50 mM sodium phosphate buffer solution (composition: EDTA.2Na 20 mM, N) containing 0.1 μM [ 3 H] -acetyl CoA (NEN, 1 μCi / mmol) in 8 μl of enzyme solution
20 μl of aCl 300 mM, choline chloride 8 mM, physostigmine salicylate 0.1 mM; pH 7.4) were mixed in a scintillation mini vial and incubated at 37 ° C. for 15 minutes.
【００５２】その後、シンチレーションミニバイアルを
氷浴中に入れ、さらに氷冷した１０mMリン酸ナトリウム
緩衝液を加えて反応を停止させた。これに２mgのカリグ
ノストを含むアセトニトリル４００μｌを加えた。生合
成された〔 3Ｈ〕−ＡＣｈを２mlのトルエンシンチレー
ションカクテル（ＰＰＯ ４ｇ／ｌ，ＰＯＰＯＰ ０．
１ｇ／ｌ）に抽出してその放射活性をシンチレーション
カウンターで測定した。統計処理にはステューデントの
ｔ−検定を用いた。Then, the scintillation mini-vial was placed in an ice bath, and an ice-cooled 10 mM sodium phosphate buffer was added to stop the reaction. To this was added 400 μl of acetonitrile containing 2 mg of calignost. The biosynthesized [ 3 H] -ACh was mixed with 2 ml of toluene scintillation cocktail (PPO 4 g / l, POPOP 0.
1 g / l) and its radioactivity was measured with a scintillation counter. Student's t-test was used for statistical processing.
【００５３】データは示してないがｎｂｍ破壊に伴っ
て、それぞれのマイクロパンチサンプルの間の基礎的な
〔 3Ｈ〕−塩化コリン取り込み量と〔 3Ｈ〕−ＡＣｈ遊
離量には顕著な差はなかった。この結果は、ｎｂｍ破壊
後でも大脳皮質に存在するコリン作働性神経の大部分
は、まだ生き残っていることを示している。しかしなが
ら、ｎｂｍ破壊後２週間目では、カリウム刺激に伴う〔
3Ｈ〕−ＡＣｈ遊離量とＣｈＡＴ活性がラット大脳皮質
で有意に低下していた（図１８及び１９）。[0053] Data with the but nbm destruction not shown, a basic [3 H] between each micro punch samples - significant difference in the [3 H] -ACh free amount choline chloride uptake is There wasn't. This result indicates that most of the cholinergic nerves existing in the cerebral cortex still survive after nbm destruction. However, two weeks after the nbm destruction, potassium stimulation was involved [
The amount of 3 H] -ACh released and ChAT activity were significantly decreased in rat cerebral cortex (FIGS. 18 and 19).
【００５４】またこの時コントロール群のＣｈＡＴ活性
は０．７６４−０．８４０（nmol／mg蛋白質／分）であ
り、ｎｂｍ破壊群でのそれは０．４７３−０．５５１
（nmol／mg蛋白質／分）であった。この神経の機能低下
は、ｎｂｍから大脳皮質へのコリン作働性神経の投射が
なくなることによって生じる脳血流の低下により一部説
明できるかもしれない。At this time, the ChAT activity of the control group was 0.764-0.840 (nmol / mg protein / min), and that of the nbm-disrupted group was 0.473-0.551.
(Nmol / mg protein / min). This decrease in nerve function may be explained in part by the decrease in cerebral blood flow caused by the loss of cholinergic projections from the nbm to the cerebral cortex.
【００５５】ｎｂｍを電気的に刺激すると大脳皮質での
血流量が増加し、ｎｂｍを破壊すると脳血流量が低下す
ることが分かっている。さらに、コリン作働性神経の脳
血管への支配も報告されている。これらの発見は、ｎｂ
ｍからのコリン作働性神経の投射が、脳血流の制御に関
与していることを示している。It has been known that electrical stimulation of nbm increases blood flow in the cerebral cortex, and destruction of nbm decreases cerebral blood flow. Furthermore, the control of cholinergic nerves to cerebral blood vessels has been reported. These findings are nb
It has been shown that the projection of cholinergic nerves from m is involved in the control of cerebral blood flow.
【００５６】また脳血流の低下は、脳への酸素の供給を
減らすかもしれない。そして神経は、活動を維持するた
めに酸素が必要であるから、酸素の不足が結果的に大脳
皮質での神経機能低下を引き起こしているかもしれな
い。冠元顆粒は、ｎｂｍを破壊したラットの大脳皮質の
広い部分でカリウム刺激に伴う〔 3Ｈ〕−ＡＣｈ遊離量
（図１８）とＣｈＡＴ活性（図１９）の低下を防いだ。
この結果は、冠元顆粒の投与によってｎｂｍ破壊後に大
脳皮質でのコリン作働性神経系を維持できることを示し
ている。冠元顆粒はｎｂｍを破壊した後で大脳皮質での
コリンマーカーの低下を防ぐことから、抗痴呆薬として
使用できる。Also, a decrease in cerebral blood flow may reduce the supply of oxygen to the brain. And because nerves need oxygen to maintain activity, lack of oxygen may result in reduced neuronal function in the cerebral cortex. Coronal granules prevented a decrease in [ 3 H] -ACh release (FIG. 18) and ChAT activity (FIG. 19) associated with potassium stimulation in a wide area of the cerebral cortex of nbm-disrupted rats.
This result indicates that administration of coronal granules can maintain the cholinergic nervous system in the cerebral cortex after nbm disruption. Coronal granules can be used as an anti-dementia drug because they prevent the reduction of choline markers in the cerebral cortex after nbm destruction.
【００５７】ヒトにおける臨床観察 観察対象者 観察対象患者として、本人の同意が得られたものの中か
ら次の条件に合うものを選んだ。（１）年齢が４６才以
上である者、（２）臨床及びＣＴ（コンピューター・サ
ーモグラフィー）による診断が脳梗塞である者、（３）
Ｈａｃｈｉｎｓｋｉ局部虚血の評価点数が７点以下であ
る者、（４）ＤＳＭIII 四項目診断標準に合う者、
（５）長谷川式知的機能検査スケールが７点以下である
者、（６）精神認識能力（ＣＣＳＥ）が２０点以下であ
る者、（７）発病後、１ヵ月経過した者。但し、（ａ）
心臓、肝臓、腎臓に重篤な疾患を持つ者、（ｂ）発病
後、１ヵ月未満の者を除く。総計４０名の患者を対象と
して本実験を実施した。その内に、男性２１名、女性１
９名であった。年齢は４７才から７８才までである。平
均年齢は６８．４±７．１才である。 Clinical observation in humans Observed patients As patients to be observed, those who met the following conditions were selected from among the patients who had their consent. (1) Aged 46 years or older, (2) Cerebral infarction diagnosed by clinical and CT (Computer Thermography), (3)
Hachinski local ischemia with a score of 7 or less, (4) DSMIII four-item diagnostic standard,
(5) Hasegawa-type intellectual function test scale is 7 points or less, (6) Psychological cognitive ability (CCSE) is 20 points or less, (7) One month after the onset of illness. However, (a)
Excludes persons with serious heart, liver, or kidney diseases, and (b) persons who have been ill for less than 1 month. This experiment was conducted on a total of 40 patients. Among them, 21 men and 1 woman
There were 9 people. The age ranges from 47 to 78. The average age is 68.4 ± 7.1 years.
【００５８】方法 ダブルブラインド（二重盲検法）、随意法、プラシーボ
（偽薬）などを乱数表に基づいて、患者を治療群と対照
群とに分類した。治療群と対照群の年齢、性別、用量な
どを下記の表に示す。 Method Double blind (double blind method), voluntary method, placebo (placebo) etc. were used to classify patients into treatment group and control group based on a random number table. The age, sex, dose, etc. of the treatment group and the control group are shown in the table below.
【００５９】[0059]
【表１】 [Table 1]
【００６０】治療群と対照群の年齢には著しい相違がな
い（Ｐ＞０．０５）。また、治療群及び対照群への割り
ふり比率は男女間で実質的に同じである。治療群には１
日３回毎日９グラムの冠元顆粒を１２週間投与した。対
照群の服用法と期間は治療群と同様とした。投与前、専
門の主治医が一人一人の患者に対して、健康診断、病歴
聴取を行うと共に観察表を記入した。There is no significant difference in age between the treatment and control groups (P> 0.05). In addition, the ratio of allocation to the treatment group and the control group is substantially the same between men and women. 1 for treatment group
9 grams of crown granules were administered three times daily for 12 weeks. The dosage and duration of the control group were the same as those of the treatment group. Before administration, a specialist doctor performed a health checkup and a medical history for each patient and filled in an observation table.
【００６１】楊蜀蓮氏、Ｈｅｒｓｈｅｙ．Ｌなどが引用
した認識能力テスト（ＣＣＳＥ）と効能活動調査（ＦＡ
Ｑ）を用いて、神経心理学の専門医による高次神経機能
検査を行った。上記二つのテストは静かな普通の部屋で
行った。一つのテストの所要時間が１５分間であった。
ＣＣＳＥテストには患者に関する見当識力、注意力、集
中力、逆行記憶などの測定が含まれている。ＣＣＳＥの
評点は３０点から０点までであるため、２０以下なら
ば、痴呆症と診断される。Mr. Yang Lotus, Hershey. Cognitive ability test (CCSE) and efficacy activity survey (FA
Q) was used to perform a higher-order nerve function test by a neuropsychologist. The above two tests were done in a quiet, ordinary room. The time required for one test was 15 minutes.
The CCSE test includes measurements of patient orientation, attention, concentration, and retrograde memory. The CCSE score ranges from 30 to 0, so if it is 20 or less, dementia is diagnosed.
【００６２】ＦＡＱテストとは患者の身体に対する質問
であり、内容が十項目ある。例えば、収支均等、好み、
食事の用意などである。患者の能力によって、評価を下
す。項目ごとに四等級に分けられる。０点が正常であ
る；１点が単独にやれるが難しい；２点が単独にやれる
が、部分的に人に依頼する；３点が完全に人に依頼す
る。１０項目を評価する際、３０点が完全に異常であ
り、０点が正常であるとされる。治療終了後、再度患者
のＦＡＱとＣＣＳＥを測定した。The FAQ test is a question about the patient's body and has 10 items. For example, balance of income, preference,
For example, preparing meals. It is evaluated according to the patient's ability. Each item is divided into four grades. 0 point is normal; 1 point is difficult to do alone; 2 points can be done independently but partially asks a person; 3 points completely asks a person. When evaluating 10 items, 30 points are completely abnormal and 0 point is normal. After the treatment was completed, the patient's FAQ and CCSE were measured again.
【００６３】治療後に、それぞれ下記実験指標を測定し
た。脳波、血流指数…血漿粘度（ηｐｌａｓ）、高交換
率の全血比粘度（ηＨ）、低交換率の全血比粘度（η
Ｌ）、ヘマトクリット値（赤血球容積率、Ｈｃｔ）、赤
血球電気泳動率（ＲＥＭ）及び繊維蛋白濃度（Ｆｉｂ）
などである。また、患者に現れた不良反応を記録した。
治療群と対照群の投与前後のＣＣＳＥの比較（Ｍ±Ｓ
Ｄ）は次の表２に示す通りであった。After the treatment, the following experimental indexes were measured. EEG, blood flow index ... Plasma viscosity (ηplasm), high exchange rate whole blood specific viscosity (ηH), low exchange rate whole blood specific viscosity (η
L), hematocrit value (red blood cell volume ratio, Hct), red blood cell electrophoresis rate (REM) and fiber protein concentration (Fib)
And so on. In addition, the adverse reactions that appeared in the patient were recorded.
Comparison of CCSE before and after treatment (M ± S
D) was as shown in Table 2 below.
【００６４】[0064]
【表２】 [Table 2]
【００６５】冠元顆粒投与前後のＣＣＳＥでは顕著な相
違があるのに対して、対照群には著しい変化が見られな
かった。治療群と対照群の投与前後のＦＡＱの比較（Ｍ
±ＳＤ）は次の表３に示す通りであった。There was a significant difference in CCSE before and after the administration of coronal granules, whereas no significant change was observed in the control group. Comparison of FAQ before and after administration of the treatment group and the control group (M
(± SD) was as shown in Table 3 below.
【００６６】[0066]
【表３】 [Table 3]
【００６７】冠元顆粒投与後、患者のＦＡＱ点数が著し
く減少した（Ｐ＞０．０１）。それに対して、対照群の
ＦＡＱは特に変化はなかった。次に治療群と対照群の血
流学的指数の比較（Ｍ±ＳＤ）の結果を表４に示す。After administration of coronal granules, the patient's FAQ score decreased significantly (P> 0.01). In contrast, the FAQ of the control group did not change. Next, Table 4 shows the results of comparison (M ± SD) of hemodynamic indexes of the treatment group and the control group.
【００６８】[0068]
【表４】 [Table 4]
【００６９】冠元顆粒投与前後で、ηｐｌａｓの相違が
著しい。Ｐ値の相違はあまりない。対照群の血流指数は
投与前後無変化であった。治療群と対照群の脳波の比較
を次の表５に示す。The difference in ηplas is remarkable before and after administration of Guangyuan granules. There is not much difference in P value. The blood flow index of the control group was unchanged before and after administration. A comparison of the electroencephalogram between the treatment group and the control group is shown in Table 5 below.
【００７０】[0070]
【表５】 [Table 5]
【００７１】副作用については、治療群では３例に胃の
不快感が出現した。対照群でも、３例に胃の不快感が出
現した。１例は皮疹が出たが、皆一過性であって、治療
せずに完治した。本研究は冠元顆粒が血漿粘度を低下さ
せ、局部脳流量（ＣＢＦ）を高め、虚血及び無酸素状態
を改善することができることを示唆した。そのため、脳
波活動が改善されるに従って、患者の高次神経機能、例
えば、記憶力、見当識力、注意力、集中力、及び社会活
動の能力を高めることができ、副作用が少なかった。Regarding side effects, gastric discomfort appeared in 3 cases in the treatment group. Also in the control group, stomach discomfort appeared in 3 cases. One patient had a skin rash, but all of them were transient and healed completely without treatment. This study suggested that basal granules could reduce plasma viscosity, enhance regional cerebral flow (CBF), and improve ischemia and anoxia. Therefore, as the electroencephalogram activity is improved, the higher nerve function of the patient, for example, the memory ability, the orientation ability, the attention ability, the concentration ability, and the ability of social activity can be enhanced, and the side effects are reduced.
【００７２】本発明の抗痴呆剤の有効成分はすでに使用
され、その安全性が確認されている漢方成分である。抗
痴呆剤は有効成分を抽出乾燥物として１〜２０ｇ／日、
好ましくは９ｇ／日を１日３回にわけて投与される。製剤例 センキュウ２２５ｇ、芍薬２２５ｇ、紅花２２５ｇ、木
香１１３ｇ、香附子１１３ｇ、及び丹参４５０ｇに２０
倍量の熱水中で１時間抽出し、抽出液を得た。これをス
プレイドライヤーにより乾燥し、乾燥エキス４５０ｇを
得た。これに乳糖を加え顆粒剤とし、３ｇずつ分包し、
本発明の抗痴呆剤を得た。The active ingredient of the anti-dementia agent of the present invention is a Kampo ingredient which has been used and whose safety has been confirmed. The anti-dementia agent has 1 to 20 g / day of the active ingredient extracted and dried,
Preferably, 9 g / day is administered in three divided doses per day. Formulation Example 20 to 225 g of Senkyu, 225 g of peony, 225 g of safflower, 113 g of wooden incense, 113 g of Kazushi, and 450 g of ginseng
Extraction was performed for 1 hour in double volume of hot water to obtain an extract. This was dried with a spray dryer to obtain 450 g of a dried extract. Lactose was added to this to make a granule, and 3 g each was packaged.
An anti-dementia agent of the present invention was obtained.
【図１】図１は水迷路課題実験に用いた装置の平面図を
模式的に示す。FIG. 1 schematically shows a plan view of an apparatus used for a water maze task experiment.
【図２】図２は冠元顆粒単独投与の場合の水迷路課題実
験の結果を示す。FIG. 2 shows the results of a water maze task experiment in the case of single administration of crown granules.
【図３】図３は冠元顆粒と六味地黄丸併用の場合の水迷
路課題実験の結果を示す。[Fig. 3] Fig. 3 shows the results of a water maze task experiment in the case of combined use of crown root granules and Rokumijiogan.
【図４】図４は冠元顆粒と参茸補血丸併用の場合の水迷
路課題実験の結果を示す。FIG. 4 shows the results of a water maze task experiment in the case of combined use of crown granules and ginseng supplemented blood.
【図５】図５は冠元顆粒と六味地黄丸併用の場合の小脳
におけるＳＯＤ活性を示す。FIG. 5 shows SOD activity in the cerebellum in the case of combined use of crown granules and Rokumi-jio-gan.
【図６】図６は冠元顆粒単独投与の場合の肝臓における
ＳＯＤの活性を示す。FIG. 6 shows the activity of SOD in the liver in the case of single administration of crown granules.
【図７】図７は冠元顆粒単独投与の場合に小脳における
ＳＯＤの活性を示す。FIG. 7 shows the activity of SOD in the cerebellum in the case of single administration of crown granules.
【図８】図８は冠元顆粒と参茸補血丸併用の場合の肝臓
におけるＳＯＤ活性を示す。FIG. 8 shows SOD activity in the liver in the case of combined use of crown granules and ginseng supplemented blood.
【図９】図９は冠元顆粒と参茸補血丸併用の場合の小脳
におけるＳＯＤ活性を示す。FIG. 9 shows SOD activity in the cerebellum in the case of combined use of coronal root granules and ginseng supplemented blood.
【図１０】図１０は冠元顆粒単独投与の場合の肝臓及び
小脳における過酸化脂質量を示す。FIG. 10 shows the amount of lipid peroxide in the liver and cerebellum in the case of single administration of coronal granules.
【図１１】図１１は冠元顆粒と参茸補血丸を併用した場
合の肝臓及び小脳における過酸化脂質量を示す。FIG. 11 shows the amount of lipid peroxides in the liver and cerebellum when the crown granules and the ginseng supplemented blood were used together.
【図１２】図１２は冠元顆粒と六味地黄丸を併用した場
合の線条体におけるＣｈＡＴ活性を示す。FIG. 12 shows the ChAT activity in the striatum when the crown granules and the Rokumi-jio-gan were used in combination.
【図１３】図１３は冠元顆粒単独投与の場合の脳内各部
位におけるＣｈＡＴ活性を示す。FIG. 13 shows ChAT activity in each site in the brain in the case of single administration of crown granules.
【図１４】図１４は冠元顆粒単独投与の場合の体重の変
化を示す。FIG. 14 shows changes in body weight in the case of single administration of crown granules.
【図１５】図１５は冠元顆粒と六味地黄丸併用の場合の
体重の変化を示す。FIG. 15 shows changes in body weight in the case of combined use of crown root granules and Rokumi-jio-gan.
【図１６】図１６は冠元顆粒と参茸補血丸の併用の場合
の体重の変化を示す。[Fig. 16] Fig. 16 shows changes in body weight in the case of combined use of coronal root granules and ginseng supplemented blood.
【図１７】図１７は冠元顆粒投与及び非投与における、
放射性標識された２−デオキシグルコースの脳への取込
みを比較した写真であり、生物の形態を表わす図面に代
る写真である。FIG. 17 shows administration and non-administration of crown granules,
FIG. 3 is a photograph comparing the uptake of radiolabeled 2-deoxyglucose into the brain, and is a photograph instead of a drawing showing the morphology of organisms.
【図１８】図１８はマイネルトン基底核（ｎｂｍ）の除
去により減少したアセチルコリン（ＡＣｈ）の遊離が冠
元顆粒の投与により回復することを示すグラフである。FIG. 18 is a graph showing that the release of acetylcholine (ACh), which was decreased by the removal of Meinerton basal ganglia (nbm), was restored by the administration of Guangyuan granules.
【図１９】図１９はｎｂｍの除去により低下したコリン
アセチルトランスフェラーゼ（ＣｈＡＴ）活性が冠元顆
粒の投与により回復することを示すグラフである。FIG. 19 is a graph showing that choline acetyltransferase (ChAT) activity decreased by nbm removal is restored by administration of crown granules.
─────────────────────────────────────────────────────
─────────────────────────────────────────────────── ───
【手続補正書】[Procedure amendment]
【提出日】平成５年２月９日[Submission date] February 9, 1993
【手続補正１】[Procedure Amendment 1]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】請求項３[Name of item to be corrected] Claim 3
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【手続補正２】[Procedure Amendment 2]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００２[Name of item to be corrected] 0002
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００２】[0002]
【従来の技術】痴呆症特に老人性痴呆症に対する医薬の
開発は高齢化社会の到来と共に重要な課題となってい
る。生薬または漢方を基本とする抗痴呆剤としては、特
公平３−２７５３０に生薬五味子の有機溶剤抽出物中に
含まれる化合物を有効成分とする脳機能改善薬が記載さ
れており、特開昭６３−２８７７２４には呉茱萸（ゴシ
ュ）から有機溶剤抽出により得られるエポジアミン又は
ルタエカルピンを有効成分とする脳機能改善剤、並びに
芍薬、朮（ジュツ）、タクシャ、ブクリョウ、センキュ
ウ及び当帰を有効成分とする抗痴呆剤が知られている。2. Description of the Related Art The development of medicines for dementia, particularly senile dementia, has become an important issue with the advent of an aging society. As an anti-dementia agent based on crude drugs or Chinese herbs, Japanese Patent Publication No. 3-27530 describes a brain function improving drug containing as an active ingredient a compound contained in an organic solvent extract of crude drug Gomiza. the -287724 Wu Fructus (Ghosh) brain function improving agent comprising as an active ingredient Epojiamin or Rutaekarupin obtained by organic solvent extraction from, and peony, Atractylodes (below), the active ingredient data click Shah, Bukuryou Sinensis and Dang The anti-dementia drug is known.
【手続補正３】[Procedure 3]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００６[Correction target item name] 0006
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００６】紅花（コウカ）はキク科（Ｃｏｍｐｏｓｉ
ｔａｅ）の１〜２年草木ベニバナ（Ｃａｒｔｈａｍｕｓ
ｔｉｎｃｔｏｒｉｕｓ Ｌｉｎｎｅ）の管状花であ
る。芍薬（シャクヤク）はボタン科（Ｐａｅｏｎｉａｃ
ｅａｅ）の多年草シャクヤク（Ｐａｅｏｎｉａ ｌａｃ
ｔｉｆｌｏｒａ Ｐａｌｌａｓ）の根である。センキュ
ウはセリ科の（Ｕｍｂｅｌｌｉｆｅｒａｅ）の多年草セ
ンキュウ（Ｃｎｉｄｉｕｍ ｏｆｆｉｎａｌｅ Ｍａｋ
ｉｎａ）の根茎である。黄耆（オウギ）はマメ科（Ｌｅ
ｇｕｍｉｎｏｓａｅ）の多年草（Ａｓｔｒａｇａｌｕｓ
ｍｅｍｂｒａｎａｃｅｕｓ Ｂｕｎｇｅ又はＡｓｔｒ
ａｇａｌｕｓ ｍｏｎｇｈｏｌｉｃｕｓＢｕｎｇｅ）の
根である。牛膝（ゴシツ）はヒユ科（Ａｍａｒａｎｔｈ
ａｃｅａｅ）の多年草ヒナタイノコズチＡｃｈｙｒａｎ
ｔｈｅｓ ｆａｕｒｉｅｉ Ｌｅｖｅｉｌｌｅ ｅｔ
Ｖａｎｉｏｔ又はＡｃｈｙｒａｎｔｈｅｓ ｂｉｄｅｎ
ｔａｔａ Ｂｌｕｍｅの根である。[0006] Safflower (comb)
1-2 years old plant safflower (Carthamus)
It is a tubular flower of tinctorius Linne. Peony is a peony family.
eae perennial peony (Paeonia lac)
(tiflora Pallas). The perennial herb of the Umbelliferae (Cumbium officinale Mak)
ina) rhizome. Beetle (Lepidoptera) is a legume (Le
Guminosae perennial (Astragalus)
membranaceus B u nge or Astr
agalus mongholicus Bunge). Beef knees (Amaranth)
aceae) perennial herb Achyran
the fauriei Leverelet et
Vaniot or Achyranthes biden
It is the root of data Blume.
【手続補正４】[Procedure amendment 4]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００７[Correction target item name] 0007
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００７】当帰（トウキ）はセリ科（Ｕｍｂｅｌｌｉ
ｆｅｒａｅ）のトウキ（Ａｎｇｅｌｉｃａ ａｃｕｔｉ
ｌｏｂａ Ｋｉｔａｇａｗａ）ホッカイトウキ（Ａ．ａ
ｃｕｔｉｌｏｂａ Ｋｉｔａｇａｗａ Ｖａｒ．Ｓｕｇ
ｉｙａｍａｅ Ｈｉｋｉｎｏ又はＡ．Ｓｉｎｅｎｓｉｓ
Ｄｉｅｌｓ）の根である。人参（ニンジン）はウコギ
科（Ａｒａｌｉａｃｅａｅ）の多年草オタネニンジン
（Ｐａｎａｘ ｇｉｎｓｅｎｇ Ｃ．Ａ．Ｍｅｙｅｒ）
の根である。龍眼肉（リュウガンニク）はムクロジ科
（Ｓａｐｉｎｄａｃｅａｅ）の常緑小高木リュウガン
（Ｅｕｐｈｏｒｉａｌｏｎｇａｎａ Ｌａｍａｒｃｋ）
の果肉である。鹿茸（ロクジヨウ）はシカ科（Ｃｅｒｖ
ｉｄａｅ）マンシュウアカジカ（Ｃｅｒｖｕｓ ｅｌａ
ｐｈｕｓＬ．ｖａｒ Ｘａｎｔｈｏｐｙｇｕｓ Ｍｉｌ
ｎｅ−Ｅｄｗａｒｄｓ）、又はマンシュウジカ（Ｃ．ｎ
ｉｐｐｏｎ Ｔｏｍｍｉｎｃｋ ｖａｒ．ｍａｎｔｈｕ
ｒｉｃｕｓ Ｓｗｉｎｈｏｅ）の角質化していない幼角
である。[0007] angelica (Angelica) is Umbelliferae (Umbelli
Registration of ferae) (Angelica acuti
loba Kitagawa) Hokaitouki (A. a.
cutiloba Kitagawa Var. Sug
iyamae Hikino or A. Synesis
Diels). Carrot is a perennial ginseng (Panax ginseng CA Meyer) of the Araliaceae family.
Is the root of. Longan meat is a evergreen small Takagi longan from the Sapindaceae family.
Is the flesh of. Deer mushrooms (Cervaceae) are deer (Cervaceae)
idae) Manchuria A sculpin (Cervus ela
pus L. var Xanthopygus Mil
n e-Edwards), or Manshuujika (C.n
ippon Tomminck var . manthu
It is a non-keratinized larval horn of Ricus Swinhoe.
【手続補正５】[Procedure Amendment 5]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】０００８[Correction target item name] 0008
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【０００８】杜仲（トチュウ）はトチュウ科（Ｅｕｃｏ
ｍｍｉａｃｅａｅ）の落葉高木トチュウ（Ｅｕｃｏｍｍ
ｉａ ｕｌｍｏｉｄｅｓ Ｏｌｉｖｅｒ）の樹皮であ
る。巴戟天（ハゲキテン）はアカネ科（Ｒｕｂｉａｃｅ
ａｅ）の蔓性低木ハゲキテン（Ｍｏｒｉｎｄａ ｏｆｆ
ｉｃｉｎａｌｉｓ Ｈｏｗ）の根である。地黄（ジオ
ウ）はゴマノハグサ科（Ｓｃｒｏｐｈｕｌａｒｉａｃｅ
ａｅ）の多年草アカヤジオウ（Ｒｅｈｍａｎｎｉａ ｇ
ｌｕｔｉｎｏｓａ Ｌｉｂｏｓｃｈｉｔｚ ｖａｒ．ｐ
ｕｒｐｕｒｅａ Ｍａｋｉｎｏ又はＲ．ｇｌｕｔｉｎｏ
ｓａ Ｌｉｂｏｓｃｈｉｔｚ）の根である。茯苓（ブク
リョウ）はサルノコシカケ科（Ｐｏｌｙｐｏｒａｃｅａ
ｅ）ホド（Ｐｏｒｉａ ｃｏｃｏｓ Ｗｏｌｆ）の菌核
である。牡丹皮（ボタンピ）はボタン科（Ｐａｅｏｎｉ
ａｃｅａｅ）の落葉低木ボタン（Ｐａｅｏｎｉａ ｓｕ
ｆｆｒｕｔｉｃｏｓａ Ａｎｄｒｅｗｓ）の根皮であ
る。Eucommia is a eucommia family (Euco)
deciduous tree eucommia (Eucomm)
ia ulmoides Olive) bark. The vulture family (Rubiace)
vine shrub Hagekiten of ae) (Morind a o ff
It is the root of ici n alis How). Jiou is a Scrophulariaceae (Scrophulariaceae).
ae) perennial herb (Rehmannia g)
lutinosa Liboschitz var. p
urpurea Makino or R. glutino
sa Liboschitz) .茯苓(blanking click <br/> Ryo) is Polyporaceae (Polyporacea
It is a bacterial nucleus of e) groundnut (P oria cocos Wolf). Peony skin (moutan bark) is peony (Paeo n i
aceae) deciduous shrub button of (Paeo n ia su
ffruticosa Andrews).
【手続補正６】[Procedure correction 6]
【補正対象書類名】明細書[Document name to be amended] Statement
【補正対象項目名】００１１[Correction target item name] 0011
【補正方法】変更[Correction method] Change
【補正内容】[Correction content]
【００１１】上記組成物（Ａ）にはさらに、地黄２．２
〜６．６重量部、ブクリョウ０．８〜２．６重量部、牡
丹皮０．８〜２．６重量部、タクシャ０．８〜２．６重
量部、山茱萸（サンシュユ）１．１〜３．３重量部及び
山薬１．１〜３．３重量部からなる〔組成物（Ｂ）〕を
追加の有効成分として加えることができる。この追加の
有効成分（Ｂ）の具体例として、地黄４．４重量部、ブ
クリョウ１．７重量部、牡丹皮１．７重量部、タクシャ
１．７重量部、サンシュユ２．２重量部及び山薬２．２
重量部からなる丸剤が挙げられ、これは六味地黄丸と称
される。従って、本発明の抗痴呆剤の１つの態様におい
ては、冠元顆粒と六味地黄丸とを有効成分として併用す
る。The composition (A) further includes ground yellow 2.2.
-6.6 parts by weight, blanking Kuryou 0.8 to 2.6 parts by weight, peony skin from 0.8 to 2.6 parts by weight, Takusha 0.8 to 2.6 parts by weight, mountain Fructus (Cornus officinalis) 1.1 [Composition (B)] consisting of .about.3.3 parts by weight and mountain drug 1.1 to 3.3 parts by weight can be added as an additional active ingredient. As a specific example of the additional active ingredient (B), 4.4 parts by weight of ground yellow, 1.7 parts by weight of Bukryou, 1.7 parts by weight of peony skin, 1.7 parts by weight of Takusha, 2.2 parts by weight of saussure, and mountain. Medicine 2.2
There is a pill consisting of parts by weight, which is called Rokumi-jiogan. Therefore, in one embodiment of the anti-dementia agent of the present invention, crown-shaped granules and Rokumi-jio-gan are used together as active ingredients.
Claims (6)
３．４〜１．１重量部、紅花３．４〜１．１重量部、木
香１．７〜０．６重量部、香附子１．７〜０．６重量
部、及び丹参６．８〜２．３重量部を有効成分とする抗
痴呆剤。1. Senkyu 3.4 to 1.1 parts by weight, peony herb 3.4 to 1.1 parts by weight, safflower 3.4 to 1.1 parts by weight, wood incense 1.7 to 0.6 parts by weight, An anti-dementia agent containing 1.7-0.6 parts by weight of Kashiko and 6.8-2.3 parts by weight of Danshen as active ingredients.
剤。2. The anti-dementia agent according to claim 1, which is a crown granule.
０．８〜２．６重量部、牡丹皮０．８〜２．６重量部、
タクシャ０．８〜２．６重量部、サンシュ１．１〜３．
３重量部及び山薬１．１〜３．３重量部を有効成分とす
る請求項１又は２に記載の抗痴呆剤。3. Ground yellow 2.2 to 6.6 parts by weight, butterbur 0.8 to 2.6 parts by weight, peony skin 0.8 to 2.6 parts by weight,
0.8-2.6 parts by weight of Takusha, 1.1-3.
The anti-dementia agent according to claim 1 or 2, which comprises 3 parts by weight and 1.1 to 3.3 parts by weight of the mountain drug as an active ingredient.
請求項３に記載の抗痴呆剤。4. The anti-dementia agent according to claim 3, wherein the additional active ingredient is Rokumi-jiogan.
４．３〜１２．８重量部、当帰４．３〜１２．８重量
部、人参２．２〜６．７重量部、龍眼肉４．３〜１２．
８重量部、鹿茸１．９〜５．５重量部、杜仲４．３〜１
２．８重量部及びハゲキテン４．３〜１２．８重量部を
有効成分とする請求項１又は２に記載の抗痴呆剤。5. 4.3 to 12.8 parts by weight of Astragalus, 4.3 to 12.8 parts by weight of Goshitsu, 4.3 to 12.8 parts by weight of Toki, 2.2 to 6.7 parts by weight of ginseng, Longan meat 4.3-12.
8 parts by weight, shiitake mushroom 1.9 to 5.5 parts by weight, Tochu 4.3 to 1
The anti-dementia agent according to claim 1 or 2, which comprises 2.8 parts by weight and 4.3-12.8 parts by weight of hagekiten as an active ingredient.
請求項５に記載の抗痴呆剤。6. The anti-dementia agent according to claim 5, wherein the additional active ingredient is Ganoderma lucidum blood supplementation pill.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4356551A JPH0737392B2 (en) | 1992-06-12 | 1992-12-22 | Anti-dementia agent |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP4-153839 | 1992-06-12 | ||
| JP15383992 | 1992-06-12 | ||
| JP4356551A JPH0737392B2 (en) | 1992-06-12 | 1992-12-22 | Anti-dementia agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0656684A true JPH0656684A (en) | 1994-03-01 |
| JPH0737392B2 JPH0737392B2 (en) | 1995-04-26 |
Family
ID=26482341
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP4356551A Expired - Lifetime JPH0737392B2 (en) | 1992-06-12 | 1992-12-22 | Anti-dementia agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0737392B2 (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006076948A (en) * | 2004-09-10 | 2006-03-23 | Suzuka Univ Of Medical Science | Nerve trunk cell proliferation agent containing salvianolic acid b as active ingredient |
| US7083811B2 (en) * | 2001-02-08 | 2006-08-01 | Siloam Hightech Pharm. Co., Ltd. | Herbal composition for the prevention and treatment of dementia |
| JP2006206584A (en) * | 2004-12-27 | 2006-08-10 | Tohoku Univ | Aggregation inhibitor of amyloid β protein, degradation agent of aggregated amyloid β protein, anti-dementia drug and anti-dementia food |
| JP2006298896A (en) * | 2005-03-22 | 2006-11-02 | Iskra Ind Co Ltd | Hyperlipemia remedy, arteriosclerosis remedy and liver function remedy |
| JP2008013484A (en) * | 2006-07-05 | 2008-01-24 | Iskra Ind Co Ltd | Learning / memory disorder improving agent by cerebral ischemia |
| JP2008184448A (en) * | 2007-01-31 | 2008-08-14 | Iskra Ind Co Ltd | Psychotropic agent |
| JP2010126529A (en) * | 2008-12-01 | 2010-06-10 | Noevir Co Ltd | Alleviating agent for decline of cognitive-memory function |
| JP2010180250A (en) * | 2004-07-30 | 2010-08-19 | Iskra Ind Co Ltd | Final glycate-formation inhibitor |
| JP2012126716A (en) * | 2010-11-26 | 2012-07-05 | Kracie Seiyaku Kk | Composition effective for prevention and treatment of dementia, and chinese/crude medicine preparation containing the same |
| JP2013216633A (en) * | 2012-04-11 | 2013-10-24 | Saiseido Yakuhin Kk | Anti-dementia drug |
-
1992
- 1992-12-22 JP JP4356551A patent/JPH0737392B2/en not_active Expired - Lifetime
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US7083811B2 (en) * | 2001-02-08 | 2006-08-01 | Siloam Hightech Pharm. Co., Ltd. | Herbal composition for the prevention and treatment of dementia |
| JP2010180250A (en) * | 2004-07-30 | 2010-08-19 | Iskra Ind Co Ltd | Final glycate-formation inhibitor |
| JP2006076948A (en) * | 2004-09-10 | 2006-03-23 | Suzuka Univ Of Medical Science | Nerve trunk cell proliferation agent containing salvianolic acid b as active ingredient |
| JP2006206584A (en) * | 2004-12-27 | 2006-08-10 | Tohoku Univ | Aggregation inhibitor of amyloid β protein, degradation agent of aggregated amyloid β protein, anti-dementia drug and anti-dementia food |
| JP2006298896A (en) * | 2005-03-22 | 2006-11-02 | Iskra Ind Co Ltd | Hyperlipemia remedy, arteriosclerosis remedy and liver function remedy |
| JP2008013484A (en) * | 2006-07-05 | 2008-01-24 | Iskra Ind Co Ltd | Learning / memory disorder improving agent by cerebral ischemia |
| JP2008184448A (en) * | 2007-01-31 | 2008-08-14 | Iskra Ind Co Ltd | Psychotropic agent |
| JP2010126529A (en) * | 2008-12-01 | 2010-06-10 | Noevir Co Ltd | Alleviating agent for decline of cognitive-memory function |
| JP2012126716A (en) * | 2010-11-26 | 2012-07-05 | Kracie Seiyaku Kk | Composition effective for prevention and treatment of dementia, and chinese/crude medicine preparation containing the same |
| JP2013216633A (en) * | 2012-04-11 | 2013-10-24 | Saiseido Yakuhin Kk | Anti-dementia drug |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0737392B2 (en) | 1995-04-26 |
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