JPH0640901A - Agent for suppressing toxicity of acetaldehyde - Google Patents

Abstract

PURPOSE:To provide the truly effective drunken sickness-preventing agent capable of neutralizing or inhibiting the action of acetaldehyde-in-blood produced with the intake of alcohol to suppress a drunken sickness symptom caused by the acetaldehyde. CONSTITUTION:The acetaldehyde toxicity-suppressing agent contains L-theanine as an active ingredient. In more detail, a medicine preventing a living body from the toxicity of the acetaldehyde produced in blood with the intake of an alcoholic beverage.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an acetaldehyde toxicity inhibitor containing L-theanine as an active ingredient, and more particularly to a drug which protects the living body from the toxicity caused by acetaldehyde produced in blood when an alcoholic beverage is ingested. .

[0002]

2. Description of the Related Art Alcohols, especially ethyl alcohol, are converted into acetaldehyde mainly by oxidation in the liver by alcohol dehydrogenase. In addition, a part of it is microsomal ethanol oxidation system (microsomal ethanol oxidizi
ng system: MEOS) and peroxidosomal catalase also oxidize to acetaldehyde (LJ Kricka and PMS Cleark, Biochemistry of a
lcohol and alcoholism, Ellis Horwood Ltd., Chichest
er, 1979). Acetaldehyde is further converted to acetic acid by aldehyde dehydrogenase. About 75% of the alcohol taken up by the liver is released to the circulatory system as acetic acid (Lundquist, E. et al., J. Clin. Invest., Vol. 4
1, 955-961, 1962). In general, the blood alcohol level of healthy people after drinking is 0.01-0.1% (Lundquist, E., The m
etabolism of alcohol, 1-52, Biological basis of al
coholism, Wiley-interscience, Toronto, 1971). On the other hand, the blood concentration of acetaldehyde is 1/100 that of alcohol.
It is about 0.

Acetaldehyde is an unavoidable product in terms of alcohol metabolism, and is considered to form the main cause of acute poisoning and so-called "sickness" when an alcoholic beverage is excessively ingested. The following side effects of acetaldehyde are also being clarified.

(1) Inhibition of oxidative phosphorylation and suppression of coenzyme A activity in brain and liver. (Beer, CT and Quastel, JH, Can. J. Biochem.
Physiol., Vol.36,531-541, 1958) (2) Accelerated release of catecholamines and accompanying decline in cardiac function. (McCloy, RB et al., Cardiovasc. Res., Vol.8, 21
6, 1974) (3) Formation of tetrahydroisoquinolines. There is a theory that this substance is produced by the condensation of norepinephrine or epinephrine with acetaldehyde and forms the main cause of alcoholism. (Sandler, M. et al., Nature (London), Vol. 241, 439
-443, 1973) (4) Formation of tetrahydro-β-carbolines. This substance is formed by the condensation of acetaldehyde and indoleamines and is also said to be involved in alcoholism. (Rahwan, RG, Toxicol. Appl. Pharmacol., Vol.3
4, 3-27, 1975). (5) Increased heart rate, ventilation, dead space. (Asmussen, E. et al., Acta Pharmacol.Toxicol., Vo
l.4, 311-320, 1948) (6) Mutagenicity and chromosomal aberration induction (Obe, G. and Ristow, H., Mutation Res., Vol.65, 2
29-259, 1979).

Therefore, in order to taste alcoholic beverages in a healthy manner, it is desirable to reduce the adverse effects of acetaldehyde on the living body and prevent unwanted side effects. Especially in Japanese and other Mongoloids, aldehyde dehydrogenase (ALDH) is genetically
The defect 2) is found in about 50% of people. And, it was pointed out that the blood acetaldehyde concentration after alcohol intake in a person deficient in this enzyme was remarkably higher (about 17 times) than that in a person not deficient (Harada, S., Lanc.
et, 11, 982, 1981). Thus, reducing the toxicity of acetaldehyde is absolutely necessary for the healthy taste of alcoholic beverages.

[0006] As substances that serve such purpose, L-cysteine, L-2-methylthiazoline-4-carboxylic acid and thiamine hydrochloric acid (Sprince, H. et al.
l., Agents and Actions. Vol.4 / 2, 125-130, 1974),
Sodium bisulfite, D-penicillamine (Nagasawa, H.
T., et al., Life Sci., Vol.20, 187-194, 1977),
Nicotinamide (Eriksson, CJP, FEBS Lett., Vo
l.40, 317, 1974).

However, regarding the effectiveness of compounds having an SH group such as L-cysteine, thiamine hydrochloride, and D-penicillamine, there is no effect on the blood concentration of acetaldehyde within the clinically acceptable dose range of D-penicillamine. There is also a negative opinion because it does not reach the target (Inoue, K. et al., Jpn. J. Alcohol & Drug Depende
nce, Vol. 19 (1), 74-82, 1984). Further, L-cysteine is relatively toxic, and other thiol compounds also have a pharmacological action different from the purpose of the present invention, and thus it cannot be said to be an ideal acetaldehyde toxicity reducing agent.

[0008]

In view of the above situation, it is possible to neutralize or suppress the action of blood acetaldehyde produced by alcohol intake, and to suppress the sickness symptoms caused by acetaldehyde.
A truly effective anti-sickness agent has been desired.

[0009]

[Means for Solving the Problems] The present inventors have conducted a thorough screening for a substance that effectively suppresses the acute toxicity of acetaldehyde, using the reduction of acute toxicity when acetaldehyde is administered to mice as an index. It was found that L-α-alanine, which is one of the amino acids, effectively suppresses the acute toxicity of acetaldehyde, and a patent application was filed (see Japanese Patent Laid-Open No. 59-255252).

In order to find a more effective inhibitor of acetaldehyde acute toxicity, the inventors of the present invention conducted an intensive screening using a survival rate when a lethal dose of acetaldehyde was administered to mice as a result, and as a result, L-theanine was identified. The present invention was completed by discovering that it effectively protects the living body from the toxicity of acetaldehyde in blood and produced a composition containing this as an active ingredient. That is, the present invention provides a sickness preventive agent containing L-theanine as an active ingredient for the purpose of preventing or treating acute alcohol toxicity and sickness.

L-Theanine (L-Glutam used in the present invention
ic acid-γ-monoethylamide) is a glutamic acid derivative contained in tea leaves and is the main component of umami. Its content in tea leaves is higher than other amino acids, 2466 mg% gyokuro (top), 2007 mg% gyokuro (normal), 1496 mg% sencha (top), 652 mg sencha (normal) % (Tea Kenkyubo No.40, 65, 1973). Further, it is used as a food additive for taste, and its use standard is not limited.

The pharmacological action of L-theanine is as follows:
In experiments using mice, it has been reported to antagonize caffeine-induced spastic death and increase in motor activity (Chem. Pharm. Bull. Vol. 19, 1257-
1261, 1971, Pharmaceutical Journal, Vol.95, 892-895, 1975), L
-Theanine is considered to moderate the action of caffeine contained in tea, but there is no report that L-theanine reduces the toxicity of acetaldehyde.

L- which is the active ingredient of the toxicity suppressor of the present invention
Theanine is a pharmaceutically acceptable salt, for example, in the form of a hydrochloride, an excipient, a carrier, etc., and auxiliary components commonly used in the field of food such as lactose, sucrose, liquid sugar, honey, magnesium stearate, It can be formulated into capsules, tablets, powders, granules, drinks, injections, infusions, etc. together with oxypropylcellulose, various vitamins, citric acid, malic acid, flavors, inorganic salts and the like. Furthermore,
It may be a readily soluble preparation that is added to alcoholic beverages and mineral water before use.

In the case of drinks, if necessary, other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients,
By mixing a flavoring agent or the like, it is possible to give the beverage a personal taste.

L-theanine is a very attenuated or harmless substance in an acute toxicity test using mice, with no death of 2 g / kg oral administration, no abnormalities in general symptoms and body weight. .

In order to use the L-theanine of the present invention as a prophylactic or therapeutic agent for hangover or sickness, the toxicity-reducing effect of L-theanine when a lethal dose of acetaldehyde is administered to mice in Examples described later, and Average blood acetaldehyde concentration during human sickness (about 20
μmol / l) and L-theanine may be administered in an amount of 0.3 mg / kg or more in consideration of the absorption rate in the case of oral administration. There is no particular upper limit to the dose of L-theanine, but considering the unique taste and economy of L-theanine,
Generally, it is preferable not to exceed about 300 mg / kg. Therefore, in order for the anti-sickness agent of the present invention to fully exert its effect, 0.02 to 2 g of L-theanine per single dose
It is preferable to contain. The anti-sickness agent of the present invention is taken before, during or after ingestion of an alcoholic beverage,
It is possible to prevent or treat hangover caused by acetaldehyde.

The L-theanine used in the present invention improves the survival rate when a lethal dose of acetaldehyde (11 mmol / kg) is administered to mice, as will be apparent from the examples described below. Further, the drink preparation of the present invention prevents drunkenness in an acetaldehyde dehydratase deficient paneler, which is considered to be susceptible to drunkenness, as shown in the evaluation examples described below.

It is not yet known how L-theanine suppresses the toxicity of acetaldehyde, but as the physiological action of acetaldehyde, it stimulates the adrenal medulla and sympathetic nerves to promote the release of catecholamines, thereby promoting cardiac release. Since it has been known that the heart rate is increased via the β-receptor, it is considered that when the animal is administered with a large amount of acetaldehyde, this effect is strengthened, causing arrhythmia and death. Therefore, it is considered that the mechanism of L-theanine for suppressing the toxicity of acetaldehyde is to antagonize the action of catecholamine whose release is promoted by acetaldehyde.

[0019]

The present invention will be further described with reference to examples, but the scope of the present invention is not limited to these.

Example 1. Acetaldehyde acute lethality control
As test animals, 7-week-old CDF ₁ male mice were purchased from Japan Charles River KK and used for experiments after 1-week preliminary breeding. As for the breeding conditions, the room temperature of the mouse is 23 ± 1 to 2 ° C., the humidity is 55 ± 5%, the ventilation rate is 12 to 15 times / hour (all fresh air method), the illumination time (12 hours / day, 7 am lighting, 7 pm Polyisopentene cage (Nippon Charles River, 235 × 325 × 170H) in the breeding room set to off when
6) were bred each. The solid feed CE-2 (CLEA Japan, Inc.) and drinking water were freely taken.

Acetaldehyde was diluted with distilled water, and the dose was adjusted to 11 mmol / kg. Also, L-
Theanine was dissolved in distilled water at the doses of 0.2 and 2 g / kg and used for the test. All injections are 10
It was set to ml / kg.

Each group consisted of 12 mice, and a prescribed amount of L-theanine or distilled water was intraperitoneally administered as a control, and 30 minutes later, acetaldehyde was intraperitoneally administered. The survival rate was observed 2 hours and 2 weeks after the administration of acetaldehyde, and a significant difference was determined by the χ ² test.

As a result, as shown in [Table 1], the survival rates of the control group after 2 hours and 2 weeks were 16.7 and 26.7, respectively.
However, the survival rates of the L-theanine 0.2 g / kg administration group were 33.3% and 25.0%, respectively, and the survival rates of the 2 g / kg administration group were 66.7% and 58.3%, respectively. In the / kg administration group, the risk rate was 5% or less, which was significant compared to the control group.

[0024]

[Table 1] Reduction of acetaldehyde acute toxicity by L-theanine ------------------------------------- -------------------------------- 2 hours after administration 2 weeks after administration Group survival / study (%) Survival Number / number of tests (%) ------------------------------------------- -------------------------- Control 2/12 16.7 2/12 16.7 (distilled water) L-theanine 0.2 g / kg 4/12 33.3 3/12 25.0 L-Theanine 2 g / kg 8/12 66.7 * 7/12 58.3 * ----------------------------- ---------------------------------------- *: Compared to the control group administered with distilled water There was a significant difference (P <0.05).

[0025] b. Manufacturing method L-theanine and lactose were mixed according to the recipe, and the mixture was crushed after tableting, and the prescribed amount of magnesium stearate was mixed. The mixture was filled in No. 2 capsules at 400 mg each to produce capsules containing 200 mg of L-theanine in one capsule.

[0026] b. Manufacturing method Mix L-theanine, lactose and oxypropylcellulose according to the recipe, add a small amount of water and knead with a kneader, and then size-adjust, dry and size again, and sift through 1000 mg each. Thus, a powder containing 200 mg of L-theanine per agent was produced.

Example 4. Manufacture of drink a. Prescription L-theanine 20 g DL-sodium tartrate 0.1 g Succinic acid 9 mg Liquid sugar 800 g Citric acid 12 g Vitamin C 10 g Flavor 15 ml Potassium chloride 1 g Magnesium sulfate 0.5 g b. Preparation method Dissolve the above components in 8 l of distilled water according to the recipe, add distilled water to make the total volume 10 l, sterilize with a 0.22 μm sterilization filter, and aseptically fill 100 ml amber bottles. A drink formulation containing 200 mg of L-theanine per day was prepared.

Evaluation example. Aldehyde dehydrogenase deficient panel
Evaluation of drinks by ethanol 5 healthy people (age 25-32 years old, male 3) determined to be aldehyde dehydrogenase deficient by ethanol patch test
(2 females) were used as panels, and the drink preparation prepared in Example 4 and the placebo drink preparation prepared by adding the same amount of L-glutamic acid in place of L-theanine in Example 4 were used.

20 minutes after taking the drink, drink 135 ml of beer (alcohol concentration about 4.5%), and
The participants were asked to answer their subjective symptoms in minutes. The panel test was conducted blindly in consideration of the order effect, and was conducted on different days in the same time period. The subjective symptom was evaluated on a scale of 1 to 5 (1: no symptom, 2: somewhat symptom, 3: symptom, 4: somewhat severe, 5: severe), and a significant difference was tested by Paired-t test. .

The results are shown in [Table 2]. It was revealed that the drink of the present invention improves the degree of sickness and hot flashes on the face at a risk rate of 5% and prevents sickness.

[0031]

[Table 2] Intoxication prevention effect (average value) of the drink of the present invention --------------------------------- ----------------------- Item Drink agent of Example 4 Placebo drink ------------------ -------------------------------------- Degree of sickness 2.4 * 3.4 of face Hot flash 2.2 * 3.6 Heartbeat 2.6 3.6 Drowsiness level 3.4 3.4 ------------------------ -------------------------------- *: Significantly different from placebo drink (P <0.05)

[0032]

INDUSTRIAL APPLICABILITY According to the present invention, there is provided a prophylactic and therapeutic agent for hangover or sickness containing L-theanine as an active ingredient.

Claims (3)

[Claims] 1. A toxicity inhibitor composition for acetaldehyde, which comprises L-theanine as an active ingredient. 2. A composition for preventing and treating hangover or sickness, which comprises L-theanine in an amount effective for suppressing the toxicity of acetaldehyde. 3. The composition according to claim 1, which is a drink.