WO2014163152A1 - Agent promoteur de sommeil non-rem, agent promoteur de sommeil profond et agent somnifère naturel - Google Patents

Agent promoteur de sommeil non-rem, agent promoteur de sommeil profond et agent somnifère naturel Download PDF

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Publication number
WO2014163152A1
WO2014163152A1 PCT/JP2014/059869 JP2014059869W WO2014163152A1 WO 2014163152 A1 WO2014163152 A1 WO 2014163152A1 JP 2014059869 W JP2014059869 W JP 2014059869W WO 2014163152 A1 WO2014163152 A1 WO 2014163152A1
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sleep
deep
rem
natural
promoter
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PCT/JP2014/059869
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English (en)
Japanese (ja)
Inventor
中村　好孝
上林　博明
朋美 瀬古
物井　則幸
辰行 翠川
裏出　良博
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ライオン株式会社
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Priority to JP2015510135A priority Critical patent/JP6226962B2/ja
Publication of WO2014163152A1 publication Critical patent/WO2014163152A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/20—Hypnotics; Sedatives

Definitions

  • the present invention relates to a non-REM sleep promoter, a deep sleep promoter, and a natural sleep inducer.
  • REM sleep is classified into two types, REM sleep and non-REM sleep, according to the electroencephalogram pattern.
  • REM sleep the whole body is weak, but part of the brain is actively active, and is a sleep state with rapid eye movement.
  • NREM sleep is a sleep state in which the cerebrum is hardly active and does not involve rapid eye movement.
  • Non-REM sleep is further divided into four stages of layer I, layer II, layer III, and layer IV in order of shallow sleep according to the depth of sleep. Sleep in which the depth of sleep is in the III layer and the IV layer among the I layer to the IV layer is particularly referred to as “deep sleep” (or slow wave sleep) (FIG. 1).
  • Examples of dissatisfaction with sleep include poor sleep, nightmares, sleepiness when waking up in the morning, no feeling of a good night's sleep, fatigue remaining after waking up in the morning, and sleepiness in the daytime. These can reduce work efficiency and lead to unexpected accidents. These causes include not only short sleep time but also poor quality sleep. That is, it is because the time from sleep to the appearance of non-REM sleep (sleeping latency) is long, the time of non-REM sleep is short, or deep non-REM sleep is not obtained.
  • sleeping pills For these symptoms, it is possible to use medicinal sleeping pills. However, when using sleeping pills, a doctor's diagnosis is required. In addition, sleeping pills may have side effects such as poor awakening, memory impairment, and dependence. As described above, sleeping pills as pharmaceuticals are often difficult to use easily and safely. Some medicines, such as benzodiazepine hypnotics and barbituric acid sedative anesthetics, reduce non-REM sleep, and if not used correctly, the quality of sleep may be reduced. The present situation is that it is difficult to obtain a natural and comfortable sleep by the use of pharmaceutical sleep induction.
  • Patent Document 1 describes that 5'-deoxy-5'-methylthioadenosine was used in combination with pentobarbital, which is a barbituric sedative anesthetic. Patent Document 1 describes that the period of sleep induced by pentobarbital in mice was increased by 87% by intramuscular administration of 5'-deoxy-5'-methylthioadenosine.
  • This invention makes it a subject to provide the new agent which promotes natural sleep.
  • the present invention provides the following means for solving the above problems.
  • deep sleep can be promoted in natural sleep, and good natural sleep can be induced.
  • FIG. 1 is a sleep progress diagram showing a general pattern of REM sleep and non-REM sleep.
  • the deep sleep promoter of the present invention contains methylthioadenosine or a salt thereof as an active ingredient.
  • methylthioadenosine means 5′-deoxy-5′-methylthioadenosine.
  • the 5′-deoxy-5′-methylthioadenosine may be in either the anti-type or the syn-type.
  • methylthioadenosine or a salt thereof may be abbreviated as MTA.
  • MTA which is an active ingredient of the deep sleep promoter of the present invention, can promote non-REM sleep, particularly deep sleep in natural sleep.
  • Non-REM sleep is a sleep state in which the cerebrum is hardly active and does not involve rapid eye movement.
  • humans periodically repeat REM sleep and non-REM sleep about 4-5 times throughout the night.
  • Non-REM sleep can be determined by polysomnograph analysis (electroencephalogram, electrooculogram, electromyogram).
  • electroencephalogram As an electroencephalogram, non-REM sleep can be determined by a decrease in alpha waves (8-13 Hz in humans) and an increase in delta waves (0.5-4.5 Hz in humans).
  • the measured electroencephalogram can also be determined using automatic analysis software such as SleepSign.
  • “Deep sleep” refers to sleep in which the depth of sleep is a certain level or more in humans, and is at the depth of layers III and IV when non-REM sleep is classified into four stages of I to IV layers. It means sleeping state. During sleep in layers III and IV, the occupancy of the delta wave (0.5-4.5 Hz) to the entire electroencephalogram (0.5-20 Hz) is above a certain level. It is known that the power value is high. Therefore, deep sleep can also be defined as sleep with a high delta power value. The delta power value can be measured using, for example, a polysomnography inspection apparatus.
  • the “depth of sleep”, which is the sum of sleep depth and time, is defined as a value obtained by multiplying the delta power value by time.
  • Non-REM sleep can be determined by polysomnograph analysis (electroencephalogram, electrooculogram, electromyogram). As an electroencephalogram, non-REM sleep can be determined by a decrease in alpha waves and an increase in delta waves. The measured electroencephalogram can also be determined using automatic analysis software such as SleepSign (registered trademark).
  • “Promoting non-REM sleep” means that 1) the state of non-REM sleep is observed for a longer period of time compared to the state to be compared (for example, the state before ingestion of the internal use composition of the present invention), 2) It means that the effect of either deeper non-REM sleep or 3) the smooth transition to non-REM sleep is observed.
  • “Promoting deep sleep” means that 1) the state of deep sleep is observed for a longer period of time compared to the state to be compared (for example, the state before administration of the deep sleep promoter), 2) It means that the effect of either deepening the depth or 3) the smooth transition to deep sleep is observed. In the case of an experimental system using a mouse or guinea pig, it means that the value obtained by multiplying the delta power value by time increases.
  • Natural sleep refers to sleep that does not cause loss of direct reflex.
  • Direct reflection is a reflection motion that restores the head to a normal position with respect to the direction of gravity, and is also referred to as bounce reflection.
  • the disappearance of the direct reflex in the mouse or rat can be confirmed, for example, as a state where the mouse or rat placed in the supine position or the dorsal position does not return to the abdominal position within 30 seconds. If a sleeping mouse or rat is placed in a supine or dorsal position and immediately wakes up from sleep or quickly returns to the prone position, the sleep disappears from the positive reflex. There is no sleep. In humans, there is no equivalent of “direct reflection” as defined by animals. However, in humans, a state in which the “direct reflex does not disappear” corresponds to sleep that can be easily awakened, such as waking up immediately when the shoulder is hit, and can be defined as natural sleep.
  • Anesthesia causes the loss of right-angle reflexes against natural sleep. Loss of direct reflex in mice or rats is known as an evaluation index of anesthetic effect. The effect of anesthesia with anesthetics such as pentobarbital or other agents can be assessed by the increase in the number of animals that have lost the right reflex.
  • anesthesia or conventional Both sleep with hypnotics (also called hypnosis) and sleep without anesthesia or conventional hypnotics increase delta-wave (0.5-4.5 Hz) EEG, but anesthesia or conventional In sleep (also referred to as hypnosis) when using other sleeping pills, an increase in EEG in a frequency band not observed during anesthesia or sleep without using conventional sleeping pills is observed at 15 to 20 Hz.
  • the origin of the EEG in the frequency band that cannot be seen during sleep without anesthesia or conventional hypnotics is not clear at present, but there is a relationship with the poor awakening of anesthesia or conventional hypnotics It is estimated.
  • MTA methylthioadenosine or a salt thereof
  • MTA may be used alone or in combination of two or more. “Use in combination” can include mixing and using as a mixture, or combining the individual components in individual form (eg, combined use of individual pills, tablets, capsules, etc.).
  • the salt of methylthioadenosine is not particularly limited as long as it is a pharmacologically acceptable salt, and can be selected according to, for example, the dosage form and dosage.
  • Suitable salts of methylthioadenosine include, for example, acid addition salts.
  • the acid addition salt may be either an inorganic acid addition salt or an organic acid addition salt.
  • hydrochloride, sulfate, nitrate, carbonate, phosphate, formate, oxalate, citrate , Ascorbate, methanesulfonate, 1,4-butanedisulfonate, 1,5-pentanesulfonate and p-toluenesulfonate for example, hydrochloride, sulfate, nitrate, carbonate, phosphate, formate, oxalate, citrate , Ascorbate, methanesulfonate, 1,4-butanedisulfonate, 1,5-p
  • MTA can be obtained by a known method, and a commercially available product can be used.
  • the content of MTA in the deep sleep promoter of the present invention is not particularly limited, and can be appropriately adjusted according to various conditions such as an effective amount that can exert an effect.
  • the deep sleep promoter of the present invention may be mixed or used in combination with a component capable of promoting deep sleep in sleep in addition to MTA.
  • the deep sleep promoter of the present invention may be mixed with other sleeping drugs other than MTA as long as the effects of the present invention are not essentially impaired.
  • other sleeping drugs what is called a sleep improving agent, a sleep inducer, etc. may be contained, for example.
  • a mixed or combined form with a kind or amount of anesthetic that causes the disappearance of the direct reflex is excluded.
  • the deep sleep promoter of the present invention can be a preparation substantially consisting of only MTA, or a preparation containing one or more components other than MTA and MTA.
  • Components other than MTA contained in the deep sleep promoter of the present invention are not particularly limited as long as the effects of the present invention are not essentially impaired.
  • optional components other than MTA that can be blended in the deep sleep promoter of the present invention include excipients, disintegrants, binders, lubricants, coating agents, colorants, color formers, corrigents, and flavoring agents.
  • Pharmacologically acceptable additives such as antioxidants, preservatives, flavoring agents, sour agents, sweeteners, fortifiers, vitamins, swelling agents, thickeners, surfactants and the like.
  • the effect of promoting deep sleep in natural sleep various properties necessary for the preparation (for example, preparation stability) are not impaired, and the final product (for example, food and drink, pharmaceuticals, quasi drugs, nutrition
  • One or more additives may be selected depending on the dosage form of an auxiliary product (supplement).
  • the components other than MTA contained in the deep sleep promoter of the present invention may be one type or a combination of two or more types.
  • the dosage form of the deep sleep promoter of the present invention is not particularly limited as long as MTA can be used as an active ingredient.
  • dosage forms for oral administration include liquid (liquid), syrup (syrup), solid (tablet), capsule (capsule), powder (granule, fine granule), soft capsule ( Soft capsules), semi-liquid, cream, and paste.
  • dosage forms for parenteral administration include liquids (injections, nasal drops), mists (sprays, inhalants) and the like. These formulations can be prepared by mixing MTA with a pharmacologically acceptable medium.
  • the dosage of the deep sleep promoter of the present invention is not particularly limited as long as the effects of the present invention are not impaired, and can be appropriately adjusted depending on factors such as the age and condition of the administered living body to which it is applied.
  • the preferable dose for obtaining the desired effect is the dose of MTA per day (mg / day), and the lower limit thereof is preferably 0.01 mg or more, more preferably 0.1 mg or more, and further preferably 1 mg.
  • the upper limit is preferably 1000 mg or less, more preferably 500 mg or less, and still more preferably 100 mg or less.
  • the administration form of the deep sleep promoter of the present invention is not particularly limited.
  • oral administration eg, oral administration, sublingual administration, etc.
  • parenteral administration intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, nasal administration, pulmonary administration, etc.
  • a less invasive dosage form is preferable, and oral administration is more preferable.
  • the time of administration of the deep sleep promoter of the present invention is not particularly limited, it is usually administered before bedtime, preferably administered from 3 hours before bedtime to bedtime, and from 2 hours before bedtime to bedtime. It is more preferable to administer, more preferably 1 hour before bedtime to bedtime, and particularly preferably 1 hour before bedtime.
  • the subject who takes the deep sleep promoter of the present invention is not particularly limited.
  • people who are ingested may have a subjective sleep sensation such as light sleep, poor sleep, poor sleep, lack of deep sleep (not able to sleep deeply), bad dreams, and fatigue after sleep.
  • Examples include subjects who are dissatisfied and subjects who feel fatigue and want to improve their subjective sleep feeling.
  • the subject who does not have a special problem can be ingested on a daily basis for the purpose of maintaining good sleep, preventing sleep disorders, and promoting deep sleep more naturally during sleep.
  • the deep sleep promoter of the present invention may be used as an additive for food and drink, a pharmaceutical additive, and an additive for quasi drugs. Thereby, the effect which promotes deep sleep in natural sleep can be provided to food-drinks, a medicine, and a quasi drug.
  • the deep sleep promoter of the present invention is food and drink related, for example, health foods, functional foods, nutritional supplements (supplements), foods for specified health use, medical foods, foods for the sick, foods for infants, foods for nursing care It can be used in combination with foods for elderly people.
  • beverages soft drinks, carbonated drinks, nutritional drinks, powdered drinks, fruit drinks, milk drinks, jelly drinks, etc.
  • confectionery confectionery
  • cakes gum, candy, tablet, gummy, bun, sheep gourd, pudding, jelly, ice cream, sherbet, etc.
  • processed fishery products kamaboko, chikuwa, hanpen, etc.
  • processed livestock products hamburger, ham, sausage, winner, Cheese, butter, yogurt, fresh cream, margarine, fermented milk, etc.
  • soups powder soup, liquid soup, etc.
  • staple foods rice, noodles (dried noodles, raw noodles), bread, cereals, etc.
  • seasonings Mayonnaise, shortening, dressing, sauce, sauce, soy sauce, etc.
  • the deep sleep promoter of the present invention can increase the non-REM sleep time during sleep as compared to the case where the deep sleep promoter of the present invention is not administered, as shown in the following examples. Therefore, application to the prevention and treatment of diseases associated with a decrease in sleep quality due to a shortening of deep sleep time and / or a decrease in deep sleep depth is also expected.
  • the present invention further provides a natural sleep inducer. Since the deep sleep promoter can promote deep sleep under natural sleep, it can also be used as a natural sleep inducer. “Inducing natural sleep” refers to inducing sleep without loss of direct reflex. Since the natural sleep inducer of the present invention can promote deep sleep under natural sleep, it can contribute to maintaining a good sleep pattern or restoring a disturbed sleep pattern to a good sleep pattern, etc. . The dose of the natural sleep inducer of the present invention can be adjusted as appropriate within the range of an effective amount capable of inducing natural sleep. In addition, the embodiment of the deep sleep promoter of the present invention may be applied to the deep sleep promoter of the present invention.
  • the deep sleep promoter or natural sleep inducer of the present invention can be combined with one or more components suitable for internal use to form an internal use composition.
  • the internal use composition of this invention can obtain easily the component which has the effect which promotes deep sleep in natural sleep by oral ingestion.
  • the form is not particularly limited as long as it is a form suitable for internal use, and it can be obtained by mixing with a pharmacologically acceptable medium capable of internal use.
  • the optional components described above with respect to the deep sleep promoter can be similarly applied.
  • this invention can provide the following embodiment in other aspects.
  • a method for promoting deep sleep or a method for inducing natural sleep wherein methylthioadenosine or a salt thereof is administered.
  • Electroencephalogram and myoelectric electrodes were attached to 8-week-old male C57BL / 6 mice purchased from Japan SLC. After the electrodes were mounted, they were recovered for 10 days in a recovery chamber. Then, it moved to the recording chamber and the cable was connected. Mice that could be discriminated by electroencephalogram using SleepSign (registered trademark) Ver 3.0 (Kissei Comtech Co., Ltd.), an electroencephalogram analysis software, were acclimated for 3 days. Furthermore, brain waves were measured for 24 hours, and administration groups were performed on mice in which sleep / wake rhythm was maintained.
  • MTA used was a product (trade name: 5′-Deoxy-5 ′-(methylthio) adenosine) commercially available from Sigma-Aldrich.
  • As the control solution a 0.5 mass% methylcellulose aqueous solution was used.
  • the methyl cellulose used was a product commercially available from Sigma-Aldrich (trade name: Methyl cellulose, 2% aqueous solution, 20 ° C., viscosity of 25 cP).
  • MTA solution 5 mg, 10 mg, 15 mg, and 30 mg were suspended in 10 mL of a 0.5 mass% methylcellulose aqueous solution to prepare an MTA solution.
  • MTA solution or control solution was forcibly orally administered to each group of mice at 10 mL / kg, and brain waves were recorded for 24 hours.
  • the electroencephalogram was automatically analyzed by SleepSign (registered trademark) Ver 3.0, and the evaluator confirmed the result of the automatic analysis and classified it into sleep stages of wakefulness, REM sleep and non-REM sleep.
  • the MTA-containing yeast culture was prepared as follows.
  • Commercially available S-adenosylmethionine-containing yeast culture powder (manufacturer name: Mitsubishi Gas Chemical Co., Ltd., trade name: SAMe-containing dry yeast) was heat-treated at 120 ° C. for 20 minutes.
  • the methylthioadenosine content in the obtained yeast culture was 320 mg
  • the dry weight of the yeast culture (including MTA) was 5000 mg
  • the dry weight of the yeast cultures other than MTA was 4680 mg. That is, the mass ratio of the methylthioadenosine content to the yeast culture was 6.4% by mass.
  • Example 5 tablets containing the above MTA-containing yeast (methylthioadenosine content in 4 tablets: 21 mg) were prepared.
  • a placebo tablet containing no MTA-containing yeast was prepared. Details of each composition are as shown in Table 2.
  • Example 5 Six subjects were ingested 4 sample tablets of the above Example 5 one hour before bedtime and equipped with a two-electrode portable electroencephalograph (“Sleepscope, EEG Meter Sleep Scope”). Then, the electroencephalogram during the sleep of the subject was measured. Similarly, the same six subjects were orally ingested 4 tablets of the above comparative sample one hour before going to bed. A two-electrode portable electroencephalograph (Sleepwell Corp. A scope ”) was worn, and the brain waves during the sleep of the subject were measured. For each subject, administration and electroencephalogram measurement were performed four times for each of the sample of Example 5 and the sample of Comparative Example 2.
  • each sample was orally ingested by the same six subjects, and after the subject went to bed, the subject's shoulder was beaten. As a result, it was confirmed for each subject that the subject woke up easily, that is, the sleep after each sample was orally ingested by each subject was natural sleep.
  • the electroencephalogram was analyzed by requesting Sleepwell.
  • the depth of sleep can be known from the delta power value of the electroencephalogram during sleep. The greater the delta power value, the deeper the sleep depth.
  • non-REM sleep appears immediately after going to bed, and REM sleep appears thereafter.
  • the delta power value during non-REM sleep that appeared immediately after going to bed was taken as the delta power value in the early stage of sleep. .
  • Delta power values vary from person to person. Therefore, the delta power value in the early stage of sleep after ingesting the example sample or the comparative example sample was measured four times for each subject, and the average value of the four measured values was calculated. For each subject, the change rate (%) of the delta power value after ingestion of the MTA-containing yeast culture (Example sample) relative to the delta power value after ingestion of the placebo (comparative sample) was calculated by the following equation (1).
  • Formula (1): Delta power value change rate (%) ⁇ (Average value of delta power after ingestion of MTA-containing yeast) / (Average value of delta power after taking placebo) ⁇ ⁇ 100
  • Table 3 shows the rate of change of the delta power value.
  • the rate of change of the delta power value is an average value of six subjects.
  • Example 5 in which a tablet of an MTA-containing yeast culture was orally ingested as a sample, the delta power value in the early stage of sleep was larger than that in Comparative Example 2 in which a placebo tablet was orally ingested. This indicates that the MTA of the present invention can sufficiently deepen non-REM sleep in the early stages of sleep, thereby promoting sleep and inducing good natural sleep.

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Abstract

La présente invention vise à fournir un nouveau médicament destiné à promouvoir le sommeil naturel. La présente invention concerne par conséquent un agent promoteur de sommeil non-REM, un agent promoteur de sommeil profond ou un agent somnifère naturel qui a de la méthylthioadénosine ou un de ses sels en tant qu'ingrédient actif.
PCT/JP2014/059869 2013-04-05 2014-04-03 Agent promoteur de sommeil non-rem, agent promoteur de sommeil profond et agent somnifère naturel WO2014163152A1 (fr)

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JP2015510135A JP6226962B2 (ja) 2013-04-05 2014-04-03 ノンレム睡眠促進剤、深睡眠促進剤、自然睡眠誘発剤、および睡眠初期デルタパワー向上剤

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JP2013079403 2013-04-05

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56166117A (en) * 1980-04-22 1981-12-21 Bioresearch Srl Antiinflammatory and analgesic adenosine derivative and therapeutical composition containing it as effective component
WO2008122054A1 (fr) * 2007-04-02 2008-10-09 University Of Southern California Utilisation de la s-adénosylméthionine et de la méthylthioadénosine dans la chimioprévention et le traitement des polypes et du cancer du côlon
JP2012184177A (ja) * 2011-03-03 2012-09-27 Cci Corp ５’−デオキシ−５’−メチルチオアデノシンを含むエキスの製造方法
JP2012529477A (ja) * 2009-06-11 2012-11-22 プロイェクト デ ビオメディシーナ シマ，ソシエダー．リミターダ． ５’−メチルチオアデノシンの神経保護特性

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IT1229477B (it) * 1989-03-13 1991-09-03 Bioresearch Spa Impiego di 5' deossi - 5' metiltioadenosina, s adenosilmetionina e dei loro sali per la preparazione di composizioni farmaceutiche atte a ridurre la seborrea e composizioni farmaceutiche relative

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Publication number Priority date Publication date Assignee Title
JPS56166117A (en) * 1980-04-22 1981-12-21 Bioresearch Srl Antiinflammatory and analgesic adenosine derivative and therapeutical composition containing it as effective component
WO2008122054A1 (fr) * 2007-04-02 2008-10-09 University Of Southern California Utilisation de la s-adénosylméthionine et de la méthylthioadénosine dans la chimioprévention et le traitement des polypes et du cancer du côlon
JP2012529477A (ja) * 2009-06-11 2012-11-22 プロイェクト デ ビオメディシーナ シマ，ソシエダー．リミターダ． ５’−メチルチオアデノシンの神経保護特性
JP2012184177A (ja) * 2011-03-03 2012-09-27 Cci Corp ５’−デオキシ−５’−メチルチオアデノシンを含むエキスの製造方法

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Title
MAGGINI, C. ET AL.: "A Polygraph Evaluation of the Effects of S-Adenosyl-L-Methionine(SAMe) or All-Night Sleep", MONOGRAPHIEN AUS DEM GESAMTGEBIETE DER PSYCHIATRIE, vol. 18, 1978, pages 151 - 169 *
MAKOTO TADENUMA ET AL.: "Seishu no Jukusei ni yoru Komi no Henka ni Kansuru Kenkyu (the 3rd report", JOURNAL OF THE BREWING SOCIETY OF JAPAN, vol. 70, no. 8, 1975, pages 581 - 584 *
RAVONA, JO 50MG, October 2009 (2009-10-01) *

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