JPH06234649A - Anticonvulsant - Google Patents

Abstract

PURPOSE:To obtain an anticonvulsant containing a persimmon calyx extract as active ingredient. CONSTITUTION:This anticonvulsant contains, a persimmon calyx extract as active ingredient. Specifically, the active ingredient can be obtained by the following process: dried persimmon calyxes are extracted with water, a hydrophilic organic solvent or a mixture thereof under heating and the resultant extract is concentrated into a concentrate or dried to a solid. Combined use of this extract (the concentrate or solid) with a barbituric acid-based anticonvulsant potentiates the anticonvulsant activity of the latter synergistically, resulting in reducing the dose of the latter and mitigating side effects.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to an anticonvulsant based on persimmon extract.

[0002]

BACKGROUND OF THE INVENTION Various anticonvulsants have been used for the treatment of convulsive diseases such as epilepsy, but many of them have drawbacks and none are completely satisfactory. . For example, barbituric acid hypnotics used as anticonvulsants are apt to form psychological and physical dependence. Those of the hydantoin system strongly antagonize electric shock seizures but are ineffective against drug seizures, and conversely enhance clonic seizures. Oxazolidine-type compounds are effective for absent seizures but ineffective for other types, and conversely enhance major seizures. Succinimides are effective for absent seizures but ineffective for major seizures. Phenylacetylureas are effective for all types but have many side effects. Therefore, there is a need for an anticonvulsant drug with few side effects and unlimited use.

[0003]

Means for Solving the Problems As a result of searching for active ingredients or extracts of crude drugs which are considered to have few side effects and having anticonvulsant action, the present inventor has found that the persimmon extract itself has anticonvulsant action. In addition, they have found that they have synergistically enhancing the anticonvulsant action of barbituric acid hypnotics and have completed the present invention.

That is, the present invention provides: (1) an anticonvulsant containing persimmon extract as an active ingredient, (2) an anticonvulsant containing (b) persimmon extract and (b) a barbituric acid anticonvulsant as an active ingredient. The present invention provides a convulsive agent, and (3) a side effect reducing agent for a barbituric acid-based anticonvulsant drug containing a persimmon extract as an active ingredient.

Persimmon oysters are dried oysters and have been used as a medicine for hiccups since ancient times. It is explained that this action is a physical action due to the coagulation of hemicellulose contained in persimmon in the stomach (Primary color Makino Kazuhan Encyclopedia (October 31, 1988, published by Hokuryukan)) 389), no pharmacological effect on seizure itself. In the present invention, the "persimmon extract" means an extract obtained by extracting oyster mushroom (dry product). Here, oysters include all kinds of oysters regardless of varieties, such as sweet persimmon, astringent persimmon and blister. Extracts include extracts, concentrates thereof and dry solids (eg freeze-dried powder). The extraction is usually performed with water, a hydrophilic organic solvent (eg, lower dialkyl ketone such as acetone or methyl ethyl ketone, lower alkanol such as methanol or ethanol, lower cyclic ether such as tetrahydrofuran or dioxane), or a mixture thereof. In the extraction, persimmon (whole form, cut product, powder, etc.) may of course be extracted alone, or may be extracted in the form of a mixture with other crude drug. Such a mixture includes a mixture referred to as Kakikakito. Typical Kakikaze hot water is clove 1-1.5, Kakikama 5.0, ginger 4.
It is obtained with a mixture in a ratio of 0. The persimmon extract according to the present invention includes all solutions, suspensions, solids and the like containing the components obtained by extracting persimmons alone or as a mixture.

The "barbituric acid anticonvulsant" used in the present invention includes compounds represented by the following formula and salts thereof.

[Chemical 1] [Wherein R ₁ is lower alkyl or lower alkenyl, R ₂
Represents lower alkyl, lower alkenyl or aryl having one benzene ring, R ₃ represents hydrogen atom or lower alkyl, X represents O, S or 2 hydrogen atoms. The lower alkyl includes alkyl having 1 to 6 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, 1-methylbutyl, isopentyl, hexyl and the like. Lower alkenyl includes groups having 1 to 6 carbon atoms having an unsaturated bond, such as allyl, butenyl, cyclohexenyl and the like. The aryl having one benzene ring includes phenyl, tolyl and the like.

Representative barbituric acid hypnotic sedatives are:

[Table 1] Nominal R ₁ R ₂ R ₃ X barbital C ₂ H ₅ -C ₂ H ₅ -H- O alobarbital CH ₂ = CHCH ₂ -CH ₂ = CHCH ₂ -H- O phenobarbital C ₂ H ₅ -C ₆ H ₅ -H- O Primidone C ₂ H ₅ -C ₆ H ₅ -H- H, H Mephobarbital C ₂ H ₅ -C ₆ H ₅ -CH ₃ -O Amobarbital C ₂ H _5- ( CH ₃ ) ₂ CH (CH ₂ ) ₂ -H- O Butabarbital C ₂ H ₅ -C ₂ H ₅ CH (CH ₃ )-H- O Cyclobarbital C ₂ H ₅ -C ₆ H ₉ -H- O Pento Barbital C ₂ H ₅ -C ₃ H ₇ CH (CH ₃ )-H- O Secobarbital CH ₂ = CHCH ₂ -C ₃ H ₇ CH (CH ₃ )-H- O Hexobarbital CH ₃ -C ₆ H ₉ -CH ₃ -O thiopental C ₂ H ₅ -C ₃ H ₇ CH (CH ₃ )-H- S thialaminol CH ₂ = CHCH ₂ -C ₃ H ₇ CH (CH ₃ )-H- S talbutal CH ₂ = CHCH ₂ -s-Bu H- O Metalbital C ₂ H ₅ -C ₂ H ₅ -CH ₃ -O Aprobarbital CH ₂ = CHCH ₂ -i-Pr H- O Methohexital C ₂ H ₅ -C ₃ H ₇ CH (CH ₃₎ - CH ₃ - as O R ₃ Those having Eniru are preferred. Salts include alkali metal salts and alkaline earth metal salts. Representative salts are sodium phenobarbital, sodium amobarbital, calcium cyclobarbital, calcium pentobarbital, sodium secobarbital and the like.

According to the present invention, it was revealed that the persimmon extract as described above has an anticonvulsant action and enhances the anticonvulsant activity of the barbituric acid anticonvulsant. Therefore, by administering both of them in parallel, the dose of the barbituric acid anticonvulsant can be reduced and side effects can be reduced. When the persimmon extract and the barbituric acid anticonvulsant are concurrently administered, both may be administered simultaneously by the same or different administration routes, but may be administered at different times. When the administration is not simultaneous, it is desirable that the administration times are close to each other. The dose varies depending on the method of extracting persimmons or the chemical structure of the barbituric acid anticonvulsant, the route of administration, the patient's age, body weight, symptom and the type of intended treatment. Here, the treatment includes all management of diseases such as prevention, treatment, alleviation of symptoms, prevention of deterioration and the like. Generally, persimmon extract is 0.
5 to 10 g, preferably 2 to 6 g is used. Barbituric acid anticonvulsants are used at the usual doses or lower doses of the respective compounds, but are commonly used 1
The daily dose is generally within the range of 30 to 300 mg.

Upon administration, the persimmon extract and the barbituric acid anticonvulsant can be formulated into a dosage form suitable for administration. Such dosage forms include solutions (including injectable solutions), liquids such as suspensions, powders, granules,
Includes solids such as tablets and capsules. Such a preparation is manufactured by a conventional method using a liquid or solid excipient such as water, alcohol, starch, lactose, glucose, dextrin, cellulose, aluminum silicate and the like. Also,
The formulation may optionally include adjuvants, stabilizers, binders, emulsifiers,
Lubricants and other active ingredients can be included.
In addition, the persimmon extract preparation and the barbituric acid anticonvulsant may be contained in the same preparation, or a combination of separate preparations may be packaged and administered together with instructions for use. According to this invention, an anticonvulsant with few side effects is provided. In other words, persimmon extract has almost no side effects, and when it is used together with a barbituric acid anticonvulsant drug, the activity of the barbituric acid anticonvulsant drug is improved, and therefore the dose can be reduced, resulting in less side effects. . The seizures referred to here are mainly systemic seizures.

The present invention will be described in more detail below with reference to production examples, formulation examples and test examples. Production Example 1 30 pieces of persimmon were placed in about 10 times the amount of hot water, heated under reflux for 1 hour, and filtered. The filtrate was concentrated under reduced pressure at 45 ° C., and the concentrate was freeze-dried. About 1000 mg of extract (hereinafter abbreviated as water extract) was obtained. In addition, an extract (hereinafter, referred to as 8
0% acetone extract or ethanol extract) was obtained. Formulation Example 1 (a) Persimmon extract 10 g Purified water 30 ml The above ingredients are mixed and uniformly dissolved. (B) Phenobarbital 30m
g Physiological saline 3 ml Mix the above and dissolve uniformly. Formulation example 2 Persimmon extract powder (50%) 10 g Primidone fine granules (99.5%) 200 mg The above are mixed to give a powder.

Test Example 1 1. Test animals As test animals, mature ddY male mice were used.
Animals are purchased at 24 ± 2 ℃ for 12 hours / 12 hours (7: 0
In an environment of a light-dark cycle of 0 to 19:00), an acrylic breeding box was laid with wood chips and preliminarily bred for one week or more was used. Solid feed (CLEA Japan CE-2) and water were available ad libitum. 2. Convulsive recordings: tonic flexor (TF), tonic extensor (TE) and clonic convulsion (clo)
The duration of nic convulsion (CL) was measured and recorded using a stopwatch. 3. Cramps Woodbury & Davenport as an electric shock device
(Woodbury and Davenport) The constant current electric shock device which improved a part was used. Apply Cardio Cream to both ears of the mouse and pass through both ears at 60Hz, 5
The current of 0mA was applied for 0.2 seconds, and the maximum electric shock convulsion was caused. Drug convulsion is pentotetrazole 80mg / kg
Or it was induced by the administration of 2.4 mg / kg of bicuculline. 4. Test substance Phenobarbital (5.0 mg / kg unless otherwise specified) was dissolved in physiological saline to prepare 0.1 ml per 10 g of body weight. Persimmon water extract, 80% acetone extract or ethanol extract (3 g / kg unless otherwise specified) was dissolved in purified water to prepare 0.1 ml per 10 g of body weight. 5. Experimental method Using an overnight fasted mouse, water extract, 80% acetone extract or ethanol extract or purified water was orally administered alone, or phenobarbital or physiological saline was intraperitoneally administered at the same time for a certain period of time (60 unless otherwise specified). Min) later induced drug or maximal electroconvulsive spasm.
(This time was regarded as the reaction evoked time, and it was set as 0 o'clock.) Immediately after that, the mouse was placed in a plastic cage, and the duration of each convulsion was measured and recorded. 6. Results The results for the various experiments are as follows. (1) The effect of each extract on the mortality of pentetrazole is shown in FIG. As is clear from the figure, for example, 8
Mortality is about 30% with 0% acetone extract (p <0.0
(Significantly 5). (2) The effect of water extract on convulsions caused by bicuculline is shown in FIGS. 2 and 3. The administration of the extract was 30, 60, 120, 240, 360, 480 after the administration of bicuculline.
I went after a minute. As is clear from the figure, there was a tendency to prolong the time until the onset of both convulsions, and a significant (p <0.05) prolongation was observed after 240 minutes of administration. (3) 2 effects of water extract on convulsions caused by bicuculline
The effect of continuous administration for 4 days ending 40 minutes before and 40 minutes before is shown in FIGS. 4 and 5. As is clear from the figure, there was a tendency to prolong the time until the onset of both convulsions, and it was significant (p <0.05) after single administration. (4) The effect of phenobarbital alone (A) and combined use with water extract (B) on the expression of seizures due to maximum electric shock is shown in FIG. As is clear from the figure, a significant (p <0.01) combined effect was observed in TE and TE / TF. (5) Phenobarbital alone (A) and water extract (dose B1: 0.
3 g / kg, B2: 1 g / kg, B3: 3 g / kg) shows the effect of combined use. As is clear from the figure, there is a tendency for suppression in TE and TE / TF, and there is a significant effect at 3 g / kg.
A combined effect of (p <0.01) was observed.

(6) The effect of phenobarbital alone (A) and combined use with water extract (B) on the duration of seizures due to maximum electric shock is shown in FIG. As is clear from the figure, a significant (p <0.01) inhibitory effect by the combined use was observed. (7) The effect of 15 mg / kg phenobarbital alone (A) and the combination with water extract (B) on the duration of seizures due to maximum electric shock is shown in FIG. As is clear from the figure, a significant inhibitory effect was observed by the combined use with TF (p <0.01), TE (p <0.05) and CL (p <0.01). (8) Water extract alone (C) and phenobarbital alone (dose A on the TE / TF of convulsion due to maximum electric shock)
Fig. 1 shows the effect of 1: 5 mg / kg, A2: 15 mg / kg) or their combination (B4: C + A1, B5: C + A2).
It shows in 0. As is clear from the figure, a significant (p <0.01) inhibitory effect was observed in the combined use.

[Brief description of drawings]

FIG. 1 is a bar graph showing the effect of each extract on the mortality of pentetrazole.

FIG. 2 is a bar graph showing the effect of water extract on convulsions caused by bicuculline.

FIG. 3 is a bar graph showing the effect of water extract on convulsions caused by bicuculline.

FIG. 4 is a bar graph showing the effect of a single administration of water extract 240 minutes before on convulsions caused by bicuculline.

FIG. 5 is a bar graph showing the effect of continuous administration of water extract on convulsions caused by bicuculline for 4 days ending 240 minutes before.

FIG. 6: Phenobarbital alone (A) and combined use with water extract (B) on expression of convulsion due to maximum electric shock.
It is a bar graph which shows the influence by.

FIG. 7: Phenobarbital alone (A) and water extract (dose B1: 0.3 g / k) on maximal electric shock seizure development.
g, B2: 1 g / kg, B3: 3 g / kg).

FIG. 8 is a bar graph showing the effect of phenobarbital alone (A) and in combination with water extract (B) on the duration of seizures due to maximum electric shock.

FIG. 9 is a bar graph showing the effect of phenobarbital 15 mg / kg alone (A) and in combination with a water extract (B) on the duration of seizures due to maximum electric shock.

FIG. 10: Water extract alone (C), phenobarbital alone (dose A1: 5 mg / kg, A2: 15 mg / kg) or their combination (B4: C + A1, B5: C + A2) affecting TE / TF of convulsion due to maximum electric shock. ) Is a bar graph showing the effect of

[Explanation of symbols]

 A Phenobarbital alone A1 Phenobarbital 5 mg / kg A2 Phenobarbital 15 mg / kg BA + water extract B1 A + water extract 0.3 g / kg B2 A + water extract 1 g / kg B3 A + water extract 3 g / kg B4 C + A1 B5 C + A2 C water extract Alone

Claims (3)

[Claims] 1. An anticonvulsant containing a persimmon extract as an active ingredient. 2. An anticonvulsant containing (a) persimmon extract and (b) a barbituric acid anticonvulsant as active ingredients. 3. A side effect reducing agent for a barbituric acid anticonvulsant, which comprises persimmon extract as an active ingredient.