JP2007297304A - Brain fatigue relieving agent - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for relieving brain fatigue such as the lowering of numeric ability caused by brain fatigue. <P>SOLUTION: The agent for relieving the fatigue of human brain comprises (a) one or more compounds selected from chlorogenic acids, caffeic acid, ferulic acid and their pharmacologically allowable salts and (b) proanthocyanidin. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a drug and a food for recovering fatigue, that is, cerebral fatigue caused by advanced mental activities (eg, computational ability) inherent in humans.

  Fatigue is usually broadly classified into mental fatigue and physical fatigue. In modern society, the effects of mental fatigue are more serious than physical fatigue. Nutritional supplements such as various vitamins and minerals are used as fatigue recovery agents, but the purpose is practically nutritional supplementation during physical fatigue. On the other hand, a fatigue recovery agent having an effect on mental fatigue is not yet known.

For chlorogenic acids, for example, antihypertensive action and vascular endothelial function improving action have been reported (see, for example, Patent Documents 1 and 2), but the action on cerebral fatigue is not known. As an example, there is no report on the effect of recovering cerebral fatigue (decrease in thinking ability) caused by long-term computer use or continuous thinking.
JP 2002-53464 A JP 2003-261444 A

  An object of the present invention is to provide an agent for recovering fatigue caused by mental activities inherent in humans (for example, computational ability, continuous thinking, etc.), that is, a cerebral fatigue recovery agent.

  Therefore, the present inventors combined a flicker test that evaluates the degree of cerebral fatigue through visual fatigue and a calculation load task that causes cerebral fatigue, and reduced the calculation ability etc. due to continued work, that is, a component that recovers cerebral fatigue. As a result of the search, it was found that there is an excellent cerebral fatigue recovery effect when proanthocyanidins are combined with at least one selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof.

  That is, the present invention relates to a human cerebral fatigue recovery agent and cerebrum comprising (a) one or more selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof and (b) proanthocyanidins. It provides food for fatigue recovery.

  According to the present invention, after using a computer for a long time, it is possible to recover a decrease in ability due to mental fatigue (cerebral fatigue) due to calculations or other thoughts. Moreover, cerebral fatigue can be reduced by taking 30 to 40 minutes before cerebral fatigue is assumed.

  The chlorogenic acids, caffeic acid, and ferulic acid used in the present invention can be extracted from natural products containing them, particularly plants, and can be industrially produced by chemical synthesis.

  The chlorogenic acids, caffeic acid, and ferulic acid in the present invention have stereoisomers, and in the present invention, pure stereoisomers or a mixture thereof can be used. Specific examples of the chlorogenic acids in the present invention include 3-caffeylquinic acid, 4-caffeylquinic acid, 5-caffeylquinic acid, 3,4-dicaffeylquinic acid, 3,5-dicaffeylquinic acid, 4,5- Dicaffeylquinic acid, 3-ferrylquinic acid, 4-ferrylquinic acid, 5-ferrylquinic acid, 3-ferryl-4-caffeylquinic acid, etc. (Nakabayashi et al., Chemistry and Technology of Coffee Roasting, Kogaku Publishing Co., Ltd.) , P166-167).

  Chlorogenic acids, caffeic acid, and ferulic acid can improve water solubility and increase physiological effectiveness by making them into salts. These salts may be pharmaceutically acceptable salts. Examples of such basic substances for salt formation include hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide and potassium hydroxide; hydroxides of alkaline earth metals such as magnesium hydroxide and calcium hydroxide. Ammonia; basic amino acids such as arginine, lysine, histidine, ornithine; organic bases such as monoethanolamine, diethanolamine, and triethanolamine are used, and alkali metal or alkaline earth metal hydroxides are particularly preferable. In the present invention, these salts may be prepared and then added to the composition comprising other components, or chlorogenic acids and the salt-forming component may be separately added to the composition, In this, a salt may be formed.

Examples of natural product extracts containing chlorogenic acids and caffeic acid include coffee, cabbage, lettuce, arch chalk, tomato, eggplant, potato, carrot, apple, pear, plum, peach, apricot, cherry, sunflower, morohaya, What was extracted from plants, such as a sweet potato, a southern leaf, a blueberry, and wheat, is preferable.
For example, chlorogenic acids are preferably extracted from plants such as green coffee beans, southern leaves, and unripe apples. Further, ascorbic acid and citric acid acidic aqueous solution from seeds of coffee arabica LINNE Or what was obtained by extracting with hot water is more preferable.

  Specifically, Hasegawa Fragrance Co., Ltd. “Flavor Folder” as raw coffee bean extract, Nikka Whiskey Co., Ltd. “Applephenon” as apple extract, Dainippon Ink Chemical Co., Ltd. as sunflower seed extract Industrial Co., Ltd. “Heliant” and the like.

  As a natural product extract containing ferulic acid, in particular, a plant extract, for example, coffee, onion, radish, lemon, nematode, toki, pine, auren, agi, sweet potato, corn, barley, wheat, rice and the like are preferable, Rice is particularly preferable. The rice in the present invention means raw or dried products such as seeds of Oryza sativa LINNE.

  As a method for extracting ferulic acid from plants, for example, rice bran oil obtained from rice bran was distributed with hydrous ethanol and hexane under slightly alkaline at room temperature, and then ferulic acid ester obtained in the hydrous ethanol fraction May be obtained by hydrolyzing and purifying with sulfuric acid under heat under pressure. In addition, bacteria (Pseudomonas) are cultured in a culture solution containing clove oil obtained by steam distillation from buds and leaves of Syzygium aromaticum MERRILL et PERRY, or eugenol obtained by purification from clove oil. The culture solution can also be obtained by separation and purification.

  Ferulic acid can also be produced by chemical synthesis, for example, a condensation reaction between vanillin and malonic acid (Journal of American Chemical Society, 74, 5346, 1952).

  The content of one or more (component (a)) selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof in the food and pharmaceutical preparations of the present invention is the form of the food or pharmaceutical preparation. Depending on the desired amount of intake, it is appropriately determined, but in the case of powders or granules, it is preferably 0.1 to 60% by mass, more preferably 0.5 to 55% by mass, and particularly preferably 5 to 50% by mass. In the case of liquids and beverages, 0.001 to 10% by mass, more preferably 0.05 to 1% by mass is preferable. 0.1-0.6 mass% is especially preferable.

  Proanthocyanidins used in the present invention are a compound group in which condensed tannins existing in various plant bodies, that is, flavan-3-ols or flavan-3,4-diols are combined as constituent units by condensation or polymerization. These are given this name because they produce anthocyanidins such as cyanidin, delphinidin, pelargonidin, etc. by acid treatment, and they are dimers, trimers, tetramers and even 10-mers or more of the above structural units. These polymers include proanthocyanidins such as procyanidins, prodelphinidins, and propelargonidins, and stereoisomers thereof. Examples of raw materials include various plant bodies, such as grape seeds, grape skins, cranberry fruits, apple fruits, strawberries, red beans, cedars, strawberries, pine barks, etc. Synthetic materials are also known. There are no restrictions on the origin of the raw materials, the use of the raw materials, the production method, or the purification method, but high purity proanthocyanidins can be easily obtained due to the high content and the low content of saccharides and other contaminants. As a raw material, grape seeds are suitable.

These proanthocyanidins are also commercially available. For example, “Grabinol” (Kikkoman Co., Ltd.) made from grape seeds, “Applephenon” (Nikka Whiskey Co., Ltd.) made from unripe apples, and bark of coastal pine It is “Pycnogenol” (Hofer Research (UK)) as a raw material, and is generally in a powdery form.
Grape seed extract is attracting attention as a substance contributing to health in red wine, and is used as a pharmaceutical in France, as a dietary supplement in the United States, and as a health food material and food additive in Japan. In addition, safety has been confirmed by various tests, and it is extremely safe. Proanthocyanidins can be obtained by known methods [for example, the method described in Japanese Patent Publication No. 3-7232 or the method of extraction from pine bark; RW Hemingway et al., Phytochemistry, 1983, Volume 22, p. 275-281] or a method based thereon can be easily obtained from the above-mentioned various plants.

  The content of proanthocyanidins in the food and pharmaceutical preparations of the present invention is appropriately determined according to the form of the food and pharmaceutical preparations and the amount of intake to be desired, but in the case of powders or granules, 0.02 to 20 mass%, further 0.1-15 mass%, especially 1-14 mass% are preferable. In the case of liquids and beverages, 0.0002 to 3% by mass, more preferably 0.01 to 0.3% by mass is preferable. Especially 0.03-0.2 mass% is preferable.

  In the cerebral fatigue recovery agent or cerebral fatigue recovery food of the present invention, (a) a content mass ratio of chlorogenic acids, caffeic acid, ferulic acid and the like to (b) proanthocyanidins, ((a) / (b)) Is preferably 8/1 to 1/1, and more preferably 6/1 to 2/1, from the viewpoint of cerebral fatigue recovery effect and cerebral fatigue reduction effect. 5/1 to 3/1 is particularly preferable.

  The human cerebral fatigue recovery agent of the present invention recovers cerebral fatigue based on human mental activity and reduces cerebral fatigue. Human mental activity refers to mental activity accompanied by human logical understanding. Specific contents of human mental activities include thought work, calculation work, computer work, and the like. Moreover, although said cerebral fatigue accompanying human mental activity has individual differences, about a personal computer work etc., it means the state after 1-2 hours.

Cerebral fatigue associated with mental activity can be evaluated by performing a flicker test or the like on mental fatigue caused by the Kraepelin test, ATMT, computational load work, or the like.
The Kraepelin test is a continuous addition task that is originally used for mental examinations. Specifically, it is a task of adding one-digit numbers next to each other side by side, and it is an advanced mental activity. It can be positioned as the work of generating cerebral fatigue accompanying this work. Here, the Kraepelin test can be used for quantification as a model system for computing power, computer work, continuous thinking and the like.

  ATMT is originally used as a mental function test method. It is a visual search task that pushes the target numbers presented on the touch panel in order, and the search reaction time for each target can be recorded. It can be arranged or newly generated. Therefore, it is also possible to measure the working memory and the degree of fatigue during the task.

  The calculation load task gives the subject an alphanumeric detection task, a numerical addition task, and a short-term memory task. The alphanumeric detection task is a task in which a mouse is left-clicked when a fixed number or English character is presented, and right-clicked otherwise. The number addition task is a task in which a value obtained by adding all the presented two-digit and two-stage numbers is input from the keyboard. The short-term memory task is a task that left-clicks when a number that matches the first four numbers presented on the left side is presented on the right side, and right-clicks when they do not match. It can be positioned as the work of generating cerebral fatigue accompanying this work.

  The flicker test is a method for measuring a visual response to a light source flashing at an arbitrary interval, but directly evaluates an activity state (fatigue state) of the cerebral cortex through a visual instrument.

  In order to measure the fatigue recovery effect of the cerebrum, a flicker test is performed, and it is preferable to measure fingertip volume pulse wave measurement (chaos analysis) in order to measure a mental response. Fingertip volume pulse wave measurement (chaos analysis) can quantify the state of the whole body from the fingertip because the pulse dynamics are chaotic. Chaos is caused by the entanglement of multiple chaos, and has the characteristic of forming one chaos locally. Therefore, if the analysis using this theory is performed, it is considered that the state of the whole body can be grasped as a numerical value from information from only a part of the body.

  In order to examine subjective feeling of fatigue, it is preferable to use a multifaceted emotional state scale, a subjective symptom check, and a questionnaire regarding fatigue. The shortened version of the multifaceted emotional state scale is a questionnaire for measuring the subjective state of multiple emotions at the same time. Depression / anxiety (worried, anxious, worried, unconfident, clunky), malaise (Boring, tired, boring, dull, lethargic), active pleasure (lively, energetic, energetic, energetic, cheerful), inactive pleasure (loose, slow 4 levels (1. I don't feel at all) 2) How much do you feel about 5 items: tranquil, tranquil, carefree) and concentration (careful, polite, polite, thoughtful, careful) Not 3) I feel a little 4) I feel it clearly)). In addition, in the fatigue analogy (VAS (Visual Analog Scale)), overall fatigue, mental fatigue, physical fatigue, subjective stress, tension, sleepiness, boredom, motivation, hunger throat For the 12 items of thirst, irritability, and exhilaration, the current state is entered as a vertical line on a 10 cm line segment. There was no 0 cm for that condition and 10 cm was the maximum that could be experienced. However, the center of the line segment is not necessarily “normal”.

As the fatigue recovery effect of the present invention, the decrease in flicker test value indicated as mental fatigue (cerebral fatigue) is recovered by ingestion of chlorogenic acids, caffeic acid, ferulic acid, etc. and proanthocyanidins, and the decrease in flicker test value Is alleviated by ingestion of chlorogenic acids, caffeic acid, ferulic acid, etc. and proanthocyanidins.
The cerebral fatigue that can be recovered by the human cerebral fatigue recovery agent of the present invention is mainly fatigue caused by desk work or the like performed by a human at work or study.

  Chlorogenic acids, caffeic acid, ferulic acid, etc. and proanthocyanidins, which are the active ingredients of the human cerebral fatigue recovery agent of the present invention, may be taken in combination with each other, but preferably include excipients, carriers, etc. Auxiliary ingredients commonly used in the pharmaceutical and food fields, such as lactose, sucrose, liquid sugar, honey, magnesium stearate, hydroxypropylcellulose, various vitamins, citric acid, malic acid, fragrance, inorganic salts, capsules, tablets , Powders, granules, drinks, injections, drops, etc.

  In the case of drinks and foods, other physiologically active ingredients, minerals, vitamins, hormones, nutritional ingredients, flavoring agents, and the like can be mixed as necessary. Moreover, it can also be set as a green tea type | system | group drink, a oolong tea type | system | group drink, a black tea type | system | group drink, and an isotonic type | system | group drink.

  The human cerebral fatigue recovery agent of the present invention is useful for recovering a decrease in cerebral function such as a decrease in calculation ability mainly due to computer use, and the dosage is chlorogenic acids, caffeic acid, ferulic acid per day for an adult. Or 30-14000 mg as those pharmaceutically acceptable salt, More preferably, it is 50-10000 mg, More preferably, it is 200-7600 mg, Especially 250-3000 mg is preferable. The dose of proanthocyanidins is preferably 13 to 800 mg, more preferably 26 to 270 mg per day for an adult. In order to more effectively develop the cerebral fatigue recovery effect, it is considered preferable to take the medicine continuously every day.

Three healthy people entered a room with a constant temperature and humidity and acclimated for 10 minutes, and then performed a resting flicker test. Next, after performing a calculation load task (alphanumeric detection task 3 minutes, number addition task 5 minutes, short-term memory task 3 minutes, ATMT), the flicker test was performed again. After the final flicker test, we asked about the mental state and feeling of fatigue at that time using a subjective questionnaire (Visual Analog Scale (VAS) related to fatigue). After a 5-minute break, the test was performed again in the order of flicker test, calculation load work, and flicker test.
Thereafter, any one of the following three types of test samples (1.25 g each) was drunk with 190 mL of water, and the flicker test was performed again.

(Test sample)
A) Oblate inclusion containing proanthocyanidins (160 mg) and chlorogenic acids (600 mg),
B) Oblate inclusion containing proanthocyanidins (160 mg),
C) Oblate containing agent containing oblate as placebo.
Here, raw coffee bean extract (chlorogenic acids 47.9%, caffeine 1.1%) was used as chlorogenic acids.

After taking each test sample, at the time of 15 minutes, 30 minutes, and 120 minutes, the flicker test, calculation load work, flicker test, and subjective questionnaire are conducted in the same manner as described above. The change of flicker test and subjective questionnaire score was evaluated. As subjective questionnaires, fatigue and refreshment were measured.
The above test was performed for all three subjects by A), B), and C). However, A), B), C) The order of taking each test sample was arbitrary.

  The result of the flicker test is shown in FIG. When proanthocyanidins were taken, and when chlorogenic acids and proanthocyanidins were taken at the same time, the decrease in flicker value was suppressed as compared with the case of taking placebo. In particular, when chlorogenic acids and proanthocyanidins were taken at the same time, the decrease in flicker value was suppressed compared to when taking proanthocyanidins alone. 30 minutes after taking the sample, the difference in flicker value was the largest, with a 5.6% decrease with placebo, 3.7% with proanthocyanidins alone, and 0.8% with chlorogenic acids and proanthocyanidins taken at the same time Increased and maintained almost the state before drinking.

  In addition, as shown in FIGS. 2 and 3, in the subjective questionnaire, the fatigue (Watanabe et al., Fatigue Science, History of Medicine, Vol. 204 No. 5, p392-397 (2003)) was observed after 30 minutes of sample administration. The feeling decreased and the result of maintaining was obtained. 1.3 points (after 30 minutes), 1.7 points (after 120 minutes) increased fatigue when taking placebo, and 1.0 points (after 30 minutes) when taking proanthocyanidins alone, 1.3 points (after 120 minutes) increased fatigue, but when chlorogenic acids and proanthocyanidins were taken simultaneously, only 0.7 points (after 30 minutes) and 1.0 (after 120 minutes) increased fatigue The patient was able to maintain fatigue after taking 30 minutes. There is a difference between the samples 30 minutes after taking the sample in the feeling of exhilaration (easy phytoncide story, phytoncide dissemination center, p30-31 (1999)), and 2.0 points of exhilaration when taking placebo compared to before taking The 6.3 point refreshing feeling decreased when taking proanthocyanidins alone, but the 2.3 point refreshing feeling increased when chlorogenic acids and proanthocyanidins were taken simultaneously.

  Further, the results of the calculation load task are shown in FIGS. As shown in the figure, the change rate (%) of the correct answer rate in the alphanumeric detection task is almost unchanged when taking placebo and proanthocyanidin alone compared to before taking the sample, and when taking chlorogenic acids and proanthocyanidin at the same time After 15 minutes, the correct answer rate increased by about 10% and was maintained until 120 minutes later. In the short-term memory task, the percentage of correct answers decreases with the passage of time (30 minutes and 120 minutes) when taking placebo and proanthocyanidins, but when the chlorogenic acids and proanthocyanidins are taken simultaneously, the passage of time (after 30 minutes, 120 minutes) (After 30 minutes; placebo: 1.2% decrease, proanthocyanidin alone: 0.9% decrease, simultaneous use of chlorogenic acids and proanthocyanidins: 2.4% increase, 120 minutes later; Placebo: 0.3% decrease, proanthocyanidin simple substance: 2.8% decrease, chlorogenic acids and proanthocyanidin simultaneous drinking: 1.3% increase).

It is a figure which shows the variation | change_quantity of the flicker value after taking chlorogenic acids and proanthocyanidins simultaneously. It is a figure which shows the effect | action with respect to the fatigue after simultaneous administration of a chlorogenic acid and proanthocyanidins. It is a figure which shows the effect | action with respect to the refreshing feeling after taking chlorogenic acids and proanthocyanidins simultaneously. It is a figure which shows the effect | action with respect to the alphanumeric character detection task after simultaneous chlorogenic acid and proanthocyanidins. It is a figure which shows the effect | action with respect to the short-term memory task after simultaneous administration of chlorogenic acids and proanthocyanidins.

Claims (3)

  A human cerebral fatigue recovery agent comprising (a) one or more selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof and (b) proanthocyanidins.   The cerebral fatigue recovery agent according to claim 1, which reduces cerebral fatigue associated with mental activity.   A human cerebral fatigue recovery food containing (a) one or more selected from chlorogenic acids, caffeic acid, ferulic acid and pharmaceutically acceptable salts thereof and (b) proanthocyanidins.