JPH0753371A - Anticonvulsant - Google Patents

Abstract

PURPOSE:To provide an anticonvulsant containing bilobalide which is a component of ginkgo leaf extract, as the active component and useful for the treatment of convulsion, etc., such as 4-O-methylpyridoxine-induced convulsion, pentylenetetrazole-induced convulsion and electroconvulsion. CONSTITUTION:This anticonvulsant is produced by extracting ginkgo leaf with a lower alcohol or ketone, concentrating the extracted liquid, subjecting to liquid-liquid partition with methanol/hexane, concentrating the methanol layer, subjecting the concentrate to liquid-liquid partition with water/chloroform, collecting the chloroform layer, separating and purifying by silica get column chromatography to obtain bilobalide which is a lactone compound having the molecular formula of C15H13O8, compounding the bilobalide as the active component with conventional inorganic or organic solid or liquid carrier for pharmaceutical preparation and forming in the form of solid preparation (e.g. tablet, capsule, troche, granule and powder) or liquid preparation (e.g. solution and syrup).

Description

Detailed Description of the Invention

[0001]

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]

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. .

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.

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.

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]

[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.

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.

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.

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.

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]

EXAMPLES Examples of the present invention will be shown below, but the present invention is not limited to these examples.

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.

<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]

[Table 1]

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.

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.

<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]

[Table 2]

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.

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.

<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.

<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]

[Table 3]

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]

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.

[Brief description of drawings]

1 (A) and 1 (B) are schematic diagrams showing the flows of two examples of the method for isolating bilobalide.

 ─────────────────────────────────────────────────── ─── 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)

[Claims] 1. An anticonvulsant comprising bilobalide as an active ingredient.