JPH0753371A - Anticonvulsant - Google Patents
AnticonvulsantInfo
- Publication number
- JPH0753371A JPH0753371A JP5199381A JP19938193A JPH0753371A JP H0753371 A JPH0753371 A JP H0753371A JP 5199381 A JP5199381 A JP 5199381A JP 19938193 A JP19938193 A JP 19938193A JP H0753371 A JPH0753371 A JP H0753371A
- Authority
- JP
- Japan
- Prior art keywords
- liquid
- anticonvulsant
- bilobalide
- administration
- convulsion
- 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.)
- Pending
Links
Landscapes
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines Containing Plant Substances (AREA)
Abstract
Description
【0001】[0001]
【産業上の利用分野】本発明は抗痙攣薬に関し、詳しく
は、イチョウ葉抽出物の一種であるビロバリドを有効成
分とする抗痙攣薬に関するものである。TECHNICAL FIELD The present invention relates to an anticonvulsant, and more particularly to an anticonvulsant containing bilobalide, which is a kind of ginkgo biloba extract, as an active ingredient.
【0002】[0002]
【従来の技術及び発明が解決しようとする課題】イチョ
ウ葉抽出物は、フラボン配糖体やギンコライド等のテル
ペノイドを多く含み、脳機能低下、末梢血流障害、動脈
硬化、糖尿病、めまい、頭痛、知的能力の低下、記憶喪
失、耳鳴り、集中力低下、しびれ、冷感、皮膚血行障
害、視力低下、種々の痴呆症候等の治療に効果があるた
め、西欧諸国で広く医薬品として用いられている。BACKGROUND OF THE INVENTION Ginkgo biloba extract contains a large amount of terpenoids such as flavone glycosides and ginkgolides, and has decreased brain function, peripheral blood flow disorder, arteriosclerosis, diabetes, dizziness, headache, It is widely used in Western countries as a drug because it is effective in treating intellectual impairment, memory loss, tinnitus, concentration loss, numbness, cold sensation, skin circulation disorder, visual acuity, various dementia symptoms, etc. .
【0003】従って、これまでに、イチョウ葉抽出物に
ついて、低酸素耐性の強化、低酸素状態及び虚血下のエ
ネルギー代謝の維持、脳及び末梢血流の増大、血液流動
性の改善、浮腫の軽減、ラジカル補足作用、PAF拮抗
作用、脳波や短期記憶の改善、コリン性ムスカリンレセ
プター数の増加、脳内ノルアドレナリン代謝回転の増加
など、様々な薬理作用が調べられている。Therefore, so far, ginkgo biloba extract has been enhanced in hypoxic tolerance, maintenance of energy metabolism under hypoxia and ischemia, increase in brain and peripheral blood flow, improvement in blood fluidity, and edema. Various pharmacological actions such as alleviation, radical scavenging action, PAF antagonizing action, improvement of electroencephalogram and short-term memory, increase in the number of cholinergic muscarinic receptors, increase in brain noradrenaline turnover have been investigated.
【0004】しかしながら、上記作用のほとんどは西欧
において標準化された抽出物について実施されたもので
あり、更に精製されたものや単一の化合物に関するもの
は少ない。また、抗痙攣作用についても知られていな
い。However, most of the above-mentioned actions were carried out on the standardized extract in Western Europe, and few were further purified or a single compound. Also, no anticonvulsant effect is known.
【0005】イチョウ葉抽出物から抽出単離された、分
子式 C15H13O8 のラクトン化合物であるビロバリドにつ
いては、マウスのMCA結紮による梗塞を縮小したり、
抗浮腫作用を示したりすることが知られており(特開昭
60−109522号)、作用機構は不明であるが、脳神経保護
作用を有することが示されている。しかし、抗痙攣作用
については報告されていない。Bilovalide, which is a lactone compound of the molecular formula C 15 H 13 O 8 extracted and isolated from Ginkgo biloba extract, reduces infarct due to MCA ligation in mice,
It is known to have an anti-edema effect (Japanese Patent Application Laid-Open
60-109522), the mechanism of action is unknown, but it has been shown to have a cranial nerve protective action. However, no anticonvulsant effect has been reported.
【0006】[0006]
【課題を解決するための手段】本発明者等は、イチョウ
葉抽出物の中枢作用成分を明らかにし、その有効利用を
図るべく鋭意研究の結果、イチョウ葉中の一成分である
ビロバリドが抗痙攣作用を有することを見い出し、本発
明を完成するに至った。すなわち、本発明は、ビロバリ
ドを有効成分として含有することを特徴とする抗痙攣薬
を提供するものである。[Means for Solving the Problems] The inventors of the present invention clarified the centrally acting component of ginkgo biloba extract, and as a result of diligent research aimed at effective utilization thereof, as a result, bilobalide, which is one of the components of ginkgo biloba leaves, has anticonvulsant properties. They found that they have an effect, and completed the present invention. That is, the present invention provides an anticonvulsant comprising bilobalide as an active ingredient.
【0007】本発明において、抗痙攣作用とは、上記有
効成分を経口、腹腔、静注などの方法で哺乳動物に投与
した場合に、間代性痙攣及び強直性痙攣の発現回数や持
続時間を短縮する等の抗痙攣作用を言う。本発明の抗痙
攣薬の有効成分は、MPN(4−O−メチルピリドキシ
ン)誘発痙攣、PTZ(ペンチレンテトラゾール)誘発
痙攣、及び最大電撃痙攣に対して抗痙攣作用を示す。In the present invention, the anticonvulsant action means the number and duration of onset of clonic convulsions and ankylosing convulsions when the above-mentioned active ingredient is administered to a mammal by a method such as oral, intraperitoneal or intravenous injection. It is an anticonvulsant effect such as shortening. The active ingredient of the anticonvulsant of the present invention exhibits an anticonvulsant action against MPN (4-O-methylpyridoxine) -induced convulsions, PTZ (pentylenetetrazole) -induced convulsions, and maximum electric shock convulsions.
【0008】本発明の抗痙攣薬の抗痙攣作用は、痙攣誘
発因子、投与経路、投与期間、投与回数によって異なる
が、例えば、マウスでのMPN誘発痙攣において、MP
N投与の4日前より本発明の抗痙攣薬の30mg/kg/day を
連続経口投与した場合、全例痙攣を抑制することができ
る。本発明の抗痙攣薬の投与量は、ビロバリドとして1
mg〜50mg/kg が望ましい。The anticonvulsant action of the anticonvulsant of the present invention varies depending on the convulsion inducing factor, the route of administration, the period of administration, and the number of administrations.
When 30 mg / kg / day of the anticonvulsant of the present invention is continuously orally administered from 4 days before N administration, convulsion can be suppressed in all cases. The dose of the anticonvulsant of the present invention is 1 as bilobalide.
mg to 50 mg / kg is desirable.
【0009】MPNは、銀杏(ぎんなん)中毒の原因物
質であり、γ−アミノ酪酸(GABA)の欠乏とグルタ
ミンの増加をもたらすものと考えられている。また、P
TZもGABA受容体に対する競合的阻害作用により痙
攣を誘発する。これらのことから、本発明の抗痙攣薬の
抗痙攣作用には少なくともGABA作動系が関係してい
ると考えられる。MPN is a causative agent of ginkgo addiction, and is considered to cause deficiency of γ-aminobutyric acid (GABA) and increase of glutamine. Also, P
TZ also induces convulsions by its competitive inhibitory effect on GABA receptors. From these, it is considered that at least the GABAergic system is involved in the anticonvulsant action of the anticonvulsant of the present invention.
【0010】なお、本発明に用いるビロバリドは、例え
ば特開昭60−109522号に記載されている方法でイチョウ
葉から単離できる。該公報によれば、ビロバリドはイチ
ョウの葉から、例えばJustus Liebigs Ann. Chem., 724
(1969)、214-216 記載の方法で単離することができ、毒
性試験の結果、所定の範囲となり、使用に際し、何ら問
題はなかったとされている。本発明者等によるビロバリ
ドの単離方法の例を図1にフローで概略を示す。The bilobalide used in the present invention can be isolated from ginkgo biloba by the method described in, for example, JP-A-60-109522. According to the publication, bilobalide is derived from ginkgo leaves, for example Justus Liebigs Ann. Chem., 724.
(1969), 214-216, it was isolated, and the result of the toxicity test was within the prescribed range, and it is said that there was no problem in use. An example of the method for isolating bilobalide by the present inventors is schematically shown in the flow chart of FIG.
【0011】[0011]
【実施例】以下に本発明の実施例を示すが、本発明はこ
れらの実施例に限定されるものではない。EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited to these examples.
【0012】実施例1 <実験動物>動物は体重25〜30gのddY系の雄性マウ
スを使用し、1群は9匹以上とした。 <投与方法>ビロバリドは表1に記載した用量を2%ア
ラビアゴム溶液に懸濁してMPN投与の5日前から1日
1回連続4日間経口投与した。MPNは生理食塩水に溶
解し、30mg/kg を腹腔内投与した。陽性対照群としてフ
ェノバルビタール50mg/kg をMPN投与1時間前に腹腔
内投与した。 Example 1 <Experimental animals> As the animals, male ddY mice having a body weight of 25 to 30 g were used, and one group consisted of 9 or more animals. <Administration method> Vilovalide was suspended in a 2% gum arabic solution at the dose shown in Table 1 and orally administered from 5 days before MPN administration once a day for 4 consecutive days. MPN was dissolved in physiological saline and intraperitoneally administered at 30 mg / kg. As a positive control group, 50 mg / kg of phenobarbital was intraperitoneally administered 1 hour before MPN administration.
【0013】<活性の検定方法>MPN投与後90分にわ
たって間代性痙攣の回数、間代性痙攣の持続時間、筋痙
攣の回数、筋痙攣の持続時間を測定した。有意差検定に
は、Scheffe の比較検定を用いた。 <結果>結果を表1に示す。<Activity Assay Method> The number of clonic convulsions, the duration of clonic convulsions, the number of muscle cramps, and the duration of muscle cramps were measured over 90 minutes after MPN administration. Scheffe's comparison test was used for the significance test. <Results> The results are shown in Table 1.
【0014】[0014]
【表1】 [Table 1]
【0015】表1から明らかなように、ビロバリドは10
mgおよび20mgの投与で痙攣の発現回数と持続時間を短縮
し、30mgの投与では全例痙攣を抑制した。As is clear from Table 1, bilobalide is 10
The number and duration of seizures were shortened by administration of mg and 20 mg, and convulsion was suppressed in all cases by administration of 30 mg.
【0016】実施例2 <実験動物>動物は体重25〜30gのddY系の雄性マウ
スを使用し、1群は9匹以上とした。 <投与方法>ビロバリドは表2に記載した用量を2%ア
ラビアゴム溶液に懸濁してPTZ投与の5日前から1日
1回連続4日間またはPTZ投与の24時間前に1回経口
投与した。PTZは生理食塩水に溶解し、90mg/kg を腹
腔内投与した。なお、陽性対照群にはフェノバルビター
ル50mg/kg をPTZ投与の1時間前に腹腔内投与した。 Example 2 <Experimental animals> As the animals, male ddY mice having a body weight of 25 to 30 g were used, and one group consisted of 9 or more animals. <Administration method> Bilovalide was suspended in a 2% gum arabic solution at the doses shown in Table 2 and orally administered from 5 days before PTZ administration to once a day for 4 consecutive days or once 24 hours before PTZ administration. PTZ was dissolved in physiological saline and 90 mg / kg was intraperitoneally administered. In addition, 50 mg / kg of phenobarbital was intraperitoneally administered to the positive control group 1 hour before the administration of PTZ.
【0017】<活性の検定方法>PTZ投与後20分にわ
たって最小痙攣(MF)、強直性屈曲痙攣および強直性
伸展痙攣の持続時間を測定した。抗痙攣作用の判定には
MF以上の持続時間を使用した。ビロバリドの有意差検
定には、Student's t-testを用い、フェノバルビタール
の有意差検定にはAS. WELCH 法を用いた。 <結果>結果を表2に示す。<Method of assaying activity> The duration of the minimum spasm (MF), tonic flexion spasm and tonic extension spasm was measured over 20 minutes after PTZ administration. A duration of MF or more was used to determine the anticonvulsant effect. Student's t-test was used for the significant difference test of bilobalide, and AS. WELCH method was used for the significant difference test of phenobarbital. <Results> The results are shown in Table 2.
【0018】[0018]
【表2】 [Table 2]
【0019】表2から明らかなように、PTZ投与5日
前からの経口投与では、ビロバリド投与量30mgにおい
て、MF持続時間及び強直性痙攣持続時間を短縮する傾
向にあり、MF以上痙攣の持続時間を有意に短縮した。
またPTZ投与の24時間前経口投与では、ビロバリド投
与量10mgと30mgで、それぞれMF以上痙攣の持続時間を
有意に短縮した。As is clear from Table 2, in the oral administration from 5 days before PTZ administration, at the dose of bilobalide of 30 mg, the MF duration and the tonic convulsive duration tended to be shortened, and the duration of convulsions above MF was shortened. Significantly shortened.
Oral administration 24 hours before PTZ administration, the dose of bilobalide 10 mg and 30 mg, respectively, significantly shortened the duration of convulsions above MF.
【0020】実施例3 <実験動物>動物は体重25〜30gのddY系の雄性マウ
スを使用し、1群は9匹以上とした。 <投与方法>ビロバリドは表3に記載した用量を2%ア
ラビアゴム溶液に懸濁して電撃試験の5日前から1日1
回連続4日間経口投与した。なお、陽性対照群にはフェ
ノバルビタール50mg/kg を電撃試験の1時間前に腹腔内
投与した。 Example 3 <Experimental animals> As the animals, male ddY mice having a body weight of 25 to 30 g were used, and one group consisted of 9 or more animals. <Administration method> Bilovalide was suspended in the 2% gum arabic solution at the doses shown in Table 3 from 5 days before the electric shock test to 1 day per day.
Oral administration was carried out once a day for 4 consecutive days. In addition, 50 mg / kg of phenobarbital was intraperitoneally administered to the positive control group 1 hour before the electric shock test.
【0021】<電撃試験方法>マウスの左右耳をクリッ
プではさみ電気刺激装置(日本光電、SEN-3301およびss
-102J)にて刺激(所要時間 0.2秒、電圧 200V)を加え
電気刺激痙攣を生じさせた。<Electrical shock test method> The left and right ears of a mouse are clipped by clips and electrically stimulated (Nihon Kohden, SEN-3301 and ss
-102J) applied stimulation (time required 0.2 seconds, voltage 200V) to cause electrical stimulation convulsions.
【0022】<活性の検定方法>電気刺激による強直性
屈曲痙攣、強直性伸展痙攣および間代性痙攣の持続時間
を測定した。ビロバリドの有意差検定には、Student's
t-testを用い、フェノバルビタールの有意差検定にはA
S. WELCH 法を用いた。 <結果>結果を表3に示す。<Method of assaying activity> Durations of tonic flexion twitch, tonic extension twitch and clonic twitch caused by electrical stimulation were measured. Student's for the significance test of bilobalide
Using t-test, A for phenobarbital significance test
The S. WELCH method was used. <Results> The results are shown in Table 3.
【0023】[0023]
【表3】 [Table 3]
【0024】表3から明らかなように、ビロバリド20mg
と30mg投与では、強直性屈曲痙攣以上の持続時間を短縮
した。As is clear from Table 3, bilobalide 20 mg
Administration of 30 mg and 30 mg reduced the duration of tonic flexion convulsion or more.
【0025】[0025]
【発明の効果】本発明の抗痙攣剤の有効成分であるビロ
バリドはMPN、PTZ、および電撃によって誘発され
る痙攣に対し、表1〜3に示す如く、有意な抗痙攣作用
を示す。従って、本発明の有効成分であるビロバリド
は、その有効且つ非毒性量を含有する組成物の形で、抗
痙攣薬として用いることが出来、例えば経口剤として
は、錠剤、カプセル剤、トローチ剤、顆粒剤、散剤等の
固体製剤、あるいは水剤、シロップ剤等の液剤として用
いることができる。そしてこれら各種の製剤は、慣用の
無機又は有機のあるいは固体又は液体の医薬製剤用担体
を用いて公知の方法で製造することができる。As shown in Tables 1 to 3, bilobalide, which is an active ingredient of the anticonvulsant of the present invention, has a significant anticonvulsant action against convulsions induced by MPN, PTZ, and electric shock. Therefore, bilobalide, which is the active ingredient of the present invention, can be used as an anticonvulsant in the form of a composition containing an effective and nontoxic amount thereof. For example, as an oral preparation, tablets, capsules, troches, It can be used as solid preparations such as granules and powders, or as liquid preparations such as water preparations and syrup preparations. These various preparations can be produced by a known method using a conventional inorganic or organic or solid or liquid pharmaceutical preparation carrier.
【図1】図1(A)、(B)はビロバリドの単離方法の
二つの例のフローを示す概略図である。1 (A) and 1 (B) are schematic diagrams showing the flows of two examples of the method for isolating bilobalide.
───────────────────────────────────────────────────── フロントページの続き (72)発明者 藤田 美智 北海道札幌市中央区北3条第2 405 (72)発明者 松本 武 姫路市余部区上余部500 (72)発明者 戸井 浤二 東京都千代田区東神田一丁目11−4 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Michi Fujita, Kita 3-2405, Kita-ku, Sapporo-shi, Hokkaido (72) Inventor Takeshi Matsumoto 500 Kamiobe-part, Yobu-ku, Himeji-shi 500 (72) Inventor Reiji Toi Chiyoda, Tokyo 11-4, Higashikanda, Ward
Claims (1)
とを特徴とする抗痙攣薬。1. An anticonvulsant comprising bilobalide as an active ingredient.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5199381A JPH0753371A (en) | 1993-08-11 | 1993-08-11 | Anticonvulsant |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP5199381A JPH0753371A (en) | 1993-08-11 | 1993-08-11 | Anticonvulsant |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH0753371A true JPH0753371A (en) | 1995-02-28 |
Family
ID=16406823
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP5199381A Pending JPH0753371A (en) | 1993-08-11 | 1993-08-11 | Anticonvulsant |
Country Status (1)
Country | Link |
---|---|
JP (1) | JPH0753371A (en) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001524528A (en) * | 1997-12-03 | 2001-12-04 | ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーション・シヤンテイフイツク・(エス.セー.エール.アー.エス) | Use of Ginkgo biloba extract for manufacturing pharmaceuticals |
JP2001526235A (en) * | 1997-12-19 | 2001-12-18 | ドクター.ヴィルマー シュワーベ ゲーエムベーハー ウント ツェーオー. | Ginkgo biloba leaf extract with reduced 4'-O-methylpyridoxine content and biflavone content |
CN107509997A (en) * | 2017-09-08 | 2017-12-26 | 南京林业大学 | A kind of product and the application of method and its preparation based on endogenous glycosidase enzymolysis binding resin adsorbing and removing gingko intoxicating composition |
CN107568567A (en) * | 2017-09-08 | 2018-01-12 | 南京林业大学 | A kind of product and the application of method and its preparation based on UF membrane removing gingko intoxicating composition |
-
1993
- 1993-08-11 JP JP5199381A patent/JPH0753371A/en active Pending
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2001524528A (en) * | 1997-12-03 | 2001-12-04 | ソシエテ・ド・コンセイユ・ド・ルシエルシエ・エ・ダアツプリカーション・シヤンテイフイツク・(エス.セー.エール.アー.エス) | Use of Ginkgo biloba extract for manufacturing pharmaceuticals |
JP2001526235A (en) * | 1997-12-19 | 2001-12-18 | ドクター.ヴィルマー シュワーベ ゲーエムベーハー ウント ツェーオー. | Ginkgo biloba leaf extract with reduced 4'-O-methylpyridoxine content and biflavone content |
CN107509997A (en) * | 2017-09-08 | 2017-12-26 | 南京林业大学 | A kind of product and the application of method and its preparation based on endogenous glycosidase enzymolysis binding resin adsorbing and removing gingko intoxicating composition |
CN107568567A (en) * | 2017-09-08 | 2018-01-12 | 南京林业大学 | A kind of product and the application of method and its preparation based on UF membrane removing gingko intoxicating composition |
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