WO2010116425A1 - Inhibitor of premalignant lesion in colon, and prophylactic agent for colorectal cancer - Google Patents

Inhibitor of premalignant lesion in colon, and prophylactic agent for colorectal cancer Download PDF

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Publication number
WO2010116425A1
WO2010116425A1 PCT/JP2009/005019 JP2009005019W WO2010116425A1 WO 2010116425 A1 WO2010116425 A1 WO 2010116425A1 JP 2009005019 W JP2009005019 W JP 2009005019W WO 2010116425 A1 WO2010116425 A1 WO 2010116425A1
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kefir
colorectal
colorectal cancer
inhibitor
colon
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PCT/JP2009/005019
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French (fr)
Japanese (ja)
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渡邊敦光
徳丸浩一郎
徳丸千之助
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日本ケフィア株式会社
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A61K35/741—Probiotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/06—Fungi, e.g. yeasts
    • A61K36/062—Ascomycota
    • A61K36/064—Saccharomycetales, e.g. baker's yeast
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

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  • the present invention relates to a precancerous colorectal lesion suppressant containing kefir as an active ingredient, and a colorectal cancer preventive agent.
  • a lesion known as a colorectal precancerous lesion becomes colon cancer at a certain rate after a lapse of a certain period. It is known that if this precancerous lesion of the large intestine is suppressed, the occurrence of colorectal cancer is also suppressed.
  • Patent Document 1 Japanese Patent Laid-Open No. 2006-290856 discloses that glycosphingolipid derived from rice bran suppresses precancerous lesions of the large intestine and exhibits a colorectal cancer preventive action.
  • Kefir is fermented milk native to the Caucasus region of Russia, and is produced by fermenting animal milk such as cow milk using kefir grains (kefir grains, kefir bacteria) derived from the Caucasus region as inoculum (starter). Kefir grains behave as if they were a single organism, but scientifically, various microorganisms have become natural symbiotic organisms, such as Lactobacillus kefiri, and various species of the genus Leuconostoc, Lactococcus and Acetobacter.
  • lactose fermenting yeast eg Kluyveromyces marxianus
  • non-lactose fermenting yeast eg Saccharomyces unisporus, Saccharomyces cerevisiae, Saccharomyces exiguus.
  • lactose fermenting yeast eg Kluyveromyces marxianus
  • non-lactose fermenting yeast eg Saccharomyces unisporus, Saccharomyces cerevisiae, Saccharomyces exiguus.
  • kefir has been pointed out for various health maintenance and promotion functions, and is becoming popular as a healthy food.
  • Patent Document 2 discloses a food product obtained by adding nattokinase to kefir.
  • an object of the present invention is to provide a preventive agent (inhibitor) that can prevent the occurrence of colorectal cancer and the prevention (suppression) of the occurrence of precancerous colorectal lesions.
  • the present invention includes the following [1] to [2].
  • [1] A preventive agent for colorectal cancer comprising kefir as an active ingredient.
  • [2] A pre-colon cancer lesion inhibitor comprising kefir as an active ingredient.
  • the present invention also includes the following [3] to [4].
  • the present invention is also present in a colorectal cancer preventive agent, a colorectal cancer inhibitor, a colorectal precancerous lesion preventive agent, and a colorectal precancerous inhibitor, and is used for oral administration of a colorectal cancer preventive and oral
  • a colorectal cancer preventive agent a colorectal cancer inhibitor
  • a colorectal precancerous lesion preventive agent a colorectal precancerous lesion preventive agent
  • a colorectal precancerous inhibitor a colorectal precancerous inhibitor
  • kefir which is an active ingredient of the present invention, can be safely taken for a long time as a result of traditional eating experience. Therefore, this invention exists also in the said preventive agent and inhibitor for long-term taking, long-term administration, and long-term intake.
  • the present invention also includes the following [5] to [9].
  • [5] A method of preventing colorectal cancer by administering kefir.
  • [6] A method of suppressing precancerous colorectal lesions by administering kefir.
  • [7] The method according to [5] or [6], wherein kefir is orally administered.
  • Ingestion as a preventive or suppressor must be taken daily for a long time before symptoms occur, so even if it is a drug with a strong effect, there are concerns about its side effects and safety. Is not suitable for ingestion as a prophylactic or inhibitor.
  • kefir which is an active ingredient of the inhibitor (preventive agent) of the present invention, is a food that has been used for human consumption during historical years, high safety is ensured, Long-term daily intake can also be performed with confidence. That is, it is a great advantage of the present invention that it is possible to suppress (prevent) colorectal precancerous lesions and prevent (suppress) colorectal cancer without worrying about long-term daily intake.
  • FIG. 1A shows a photomicrograph of a HE-stained section of normal colon.
  • FIG. 1B shows a photomicrograph of a HE-stained section of the large intestine with ACF.
  • FIG. 1C is a view showing a micrograph of a section of a normal large intestine stained with Alcian blue-PAS.
  • FIG. 1D is a photomicrograph of a section of the large intestine with ACF stained with Alcian blue-PAS.
  • FIG. 2 is a view showing a photomicrograph of the large intestine having ACF stained with methylene blue.
  • the present invention resides in a preventive agent for colon cancer and a precancerous lesion inhibitor for colon, which contain kefir as an active ingredient.
  • the kefir used in the present invention can be manufactured based on a known manufacturing method.
  • Kefir can be produced by fermenting milk of animal milk, that is, cows, horses, sheep, goats, etc., but can preferably be produced by adding kefir grains to milk and fermentation.
  • soymilk kefir and plant kefir produced by adding kefir grains and fermenting them with soymilk or other plant-derived raw materials as starting materials can also be used.
  • production methods reference can be made, for example, to JP-A-62-83842 and JP-A-2006-75176.
  • Examples of the kefir used in the present invention include liquid and fluid kefir, and solids such as freeze-dried products thereof. These can be in the form of powder, granules, capsules containing them, and the like. What is obtained by formulating by a known method is also included.
  • Kefirs that can be suitably used are commercially available products such as NKG Kefir-D (manufactured by Nippon Kefir), NKG Kefir-P (manufactured by Nippon Kefir), NKG soybean milk kefir-SD (manufactured by Nippon Kefir). ), NKG Kefir YD-01 (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir YL-01 (manufactured by Nippon Kefir Co., Ltd.), and NKG Kefir G-07 (manufactured by Nippon Kefir Co., Ltd.).
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention comprise kefir as an active ingredient.
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention may be various forms of kefir itself, or may contain components other than kefir.
  • the kefir may be a kefir containing live bacteria or a kefir containing dead bacteria.
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be in various forms suitable for the administration method.
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention are, for example, capsules, tablets, granules, powders, syrups, troches, sprays, emulsions, suppositories, injections, ointments, tapes. It can be in the form of an agent or the like. In the case of oral administration, it can be processed into tablets, capsules, troches, syrups, granules, powders, etc. and taken orally.
  • Administration of the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention includes, for example, oral administration and parenteral administration, preferably oral administration or enteral administration, particularly preferably oral administration. .
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can also be administered in combination with food and drink, feed, and the like.
  • the colon cancer preventive agent and colon precancerous lesion inhibitor of the present invention can be in the form of food and drink. That is, this invention exists also in the functional food for colon cancer prevention and colon precancerous lesion suppression. As a shape suitable for a functional food, a tablet-like supplement can be exemplified. This makes it possible to accurately grasp the intake amount of active ingredients. Furthermore, the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be in the form of food additives. That is, this invention exists also in the food additive for colon cancer prevention and colon precancerous lesion suppression.
  • the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be produced, for example, by formulating kefir with any additive such as a pharmaceutically acceptable excipient.
  • a pharmaceutically acceptable excipient In the case of formulation, the content of kefir in the formulation is usually 0.01 to 50% by mass, preferably 0.1 to 25.0% by mass.
  • known pharmaceutically acceptable excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, injection solvents and the like can be used.
  • a known production method can be used for formulation.
  • the preventive agent for colorectal cancer and the inhibitor for precancerous colorectal lesion of the present invention include auxiliary components commonly used in the field of medicine and food, for example, lactose, sucrose, liquid sugar, honey, stearin, as necessary.
  • auxiliary components commonly used in the field of medicine and food for example, lactose, sucrose, liquid sugar, honey, stearin, as necessary.
  • Magnesium acid, hydroxypropyl cellulose, various vitamins, citric acid, malic acid, amino acids, fragrances, inorganic salts and the like can be added.
  • the dose and frequency of administration of kefir which is an active ingredient according to the present invention, vary depending on the administration method, treatment period, age, weight, etc., but the dose can be appropriately selected from the range of usually 1 mg to 50 g per day for an adult. The number of times can be appropriately selected from a range of once to several times a day.
  • Kefir is a traditional food that has been eaten and consumed for historical years, so there are no side effects and high safety. There is no.
  • colorectal precancerous lesions become colorectal cancer at a certain rate after a certain period of time. What are the environmental factors that cause this colorectal precancerous lesion, and among the precancerous colorectal lesions, what are the environmental factors that may or may not become colon cancer? It still has not been clarified as to whether or not to branch off. However, it is known that if this colorectal precancerous lesion is suppressed, the occurrence of colorectal cancer is also suppressed. In the present invention, as demonstrated by the experiment described in the examples, the effect is exhibited by suppressing the precancerous lesion of the large intestine in the large intestine.
  • the bait used was an oriental yeast MF powder bait.
  • Nippon Kefir Co., Ltd. freeze-dried NKG Kefir YD-01 (sterilized at 90 ° C for 20 minutes, killed), NKG Kefir YL-01 (viable) and NKG Kefir G-07 (doubled cells, viable) ) was mixed in the feed to 2% and given to the animals.
  • Food and drinking water were ad libitum. The intake of food and drinking water was measured. From 6 weeks of age, 15 mg / kg of azoxymethane (Azoxymethane) (AOM, Amagasaki Laboratories Co., Ltd.) was subcutaneously administered three times at weekly intervals.
  • the animals were necropsied, the large intestine was removed from the anus to the cecum (approximately 20cm), opened to the long axis, the feces were removed, the folds were spread flat, and sandwiched between paper towels, 10% neutral formalin solution Fixed for more than a day. Labeled and washed with water for more than 2 hours. Thereafter, the cells were stained at room temperature for 30 minutes while shaking in 0.1% methylene blue solution. Immediately, from the anus to the cecum was carefully observed with a stereomicroscope at a magnification of 1 or more times, and the number of ACFs was counted.
  • ACF Aberrant crypt foci
  • FIG. 2 An example of the ACF morphology observed in this way is shown in FIG. 2 (stereomicroscope ⁇ 2). Based on observation with a stereomicroscope as shown in FIG. 2, sections of the cross section were further stained and observed with a microscope.
  • 1A to 1D are micrographs ( ⁇ 200) stained by comparing sections of normal and ACF-containing sections.
  • ACF was 74.8 ⁇ 15.1 in the MF group, 40.9 ⁇ 19.2 and 41.2 ⁇ 18.8 in the YD group and YL group, and 52.3 ⁇ 26.0 in the G group, respectively, and significantly decreased in any kefir group compared to the MF group (Table). 1).
  • the total number of AC in the MF group is 136.7 ⁇ 32.3, while the YD group is 76.5 ⁇ 34.1, the YL group is 74.4 ⁇ 32.8, and the G group is 89.2 ⁇ 51.4. It was.
  • the average number of AC per ACF was 1.82 ⁇ 0.16 in the MF group, 1.92 ⁇ 0.20 in the YD group, 1.87 ⁇ 0.21 in the YL group, and 1.65 ⁇ 0.16 in the G group, and no significant difference was observed in all groups (Table 1).
  • FIG. 1A, FIG. 1B, FIG. 1C, and FIG. 1D are photomicrographs showing a comparison between normal colon and ACF, and sections stained with HE staining and Alcian blue-PAS staining, respectively. ⁇ 200).
  • 1A and 1C are photographs of a normal large intestine
  • FIGS. 1B and 1D are photographs of a large intestine having ACF.
  • 1A and 1B are photographs by HE staining
  • FIGS. 1C and 1D are photographs by Alcian blue-PAS staining.
  • the arrows in the photographs of FIGS. 1B and 1D indicate typical ACF locations.
  • FIG. 2 is a photomicrograph taken with a stereomicroscope ( ⁇ 2) showing the large intestine with ACF stained with methylene blue.
  • the arrows in the photograph of FIG. 2 indicate typical ACF positions.
  • kefir was found to significantly suppress colon precancerous lesions by oral administration.
  • the efficacy of this kefir was exhibited by any form of kefir, and was exhibited by both live and dead bacteria.
  • the efficacy of this kefir was effectively exerted on animals, particularly mammals.
  • the present invention provides an agent for inhibiting (preventing) colorectal precancerous lesions and an agent for preventing (suppressing) colorectal cancer.
  • the inhibitor and the preventive agent of the present invention are particularly suitable for ingestion as a prophylactic or inhibitory agent because daily ingestion over a long period can be performed with peace of mind.
  • the present invention is an industrially useful invention.

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Abstract

Disclosed are a prophylactic agent for colorectal cancer and an inhibitor of a premalignant lesion in the colon.  Each of the prophylactic agent and the inhibitor comprises kefir as an active ingredient.

Description

大腸前がん病変抑制剤及び大腸がん予防剤Precancerous colorectal lesion inhibitor and colorectal cancer preventive agent
　本発明は、ケフィアを有効成分として含有する大腸前がん病変抑制剤、及び大腸がん予防剤に関する。 The present invention relates to a precancerous colorectal lesion suppressant containing kefir as an active ingredient, and a colorectal cancer preventive agent.
　日本における大腸がんによる死亡率は増加しつつある。ヒト大腸癌についての癌遺伝子や発癌抑制遺伝子の解析が積極的に行われているが、長い年月を要する大腸癌の発生機構の解明は現在なお困難であり、大腸癌の発生に関わる環境要因の様式の解明は容易ではない。 The death rate from colorectal cancer in Japan is increasing. Analysis of oncogenes and tumor suppressor genes for human colorectal cancer has been actively conducted, but it is still difficult to elucidate the mechanism of colorectal cancer that takes a long time, and environmental factors related to the occurrence of colorectal cancer The elucidation of the style is not easy.
　一方、大腸前がん病変として知られる病変が、一定期間の経過後に一定割合で大腸がんとなってゆくことが知られている。そして、この大腸前がん病変を抑制すれば、大腸がんの発生もまた抑制されることが知られている。 On the other hand, it is known that a lesion known as a colorectal precancerous lesion becomes colon cancer at a certain rate after a lapse of a certain period. It is known that if this precancerous lesion of the large intestine is suppressed, the occurrence of colorectal cancer is also suppressed.
　例えば、特許文献１（特開２００６－２９０８５６号公報）には、米糠由来のスフィンゴ糖脂質が、大腸前がん病変を抑制し、大腸がん予防作用を示すことが開示されている。 For example, Patent Document 1 (Japanese Patent Laid-Open No. 2006-290856) discloses that glycosphingolipid derived from rice bran suppresses precancerous lesions of the large intestine and exhibits a colorectal cancer preventive action.
　ケフィアは、ロシアのコーカサス地方原産の発酵乳であり、コーカサス地方に由来するケフィアグレイン（ケフィア粒、ケフィア菌）を種菌（スターター）として牛乳等の獣乳を発酵させて製造される。ケフィアグレインは、それ自体があたかも一つの生体として振る舞うものであるが、学術的には各種微生物が天然の共生体となったものであり、Lactobacillus kefiri、並びにLeuconostoc属, Lactococcus属 及び Acetobacter属の各種微生物の１種以上、さらに、乳糖発酵性酵母（例えばKluyveromyces marxianus）及び非乳糖発酵性酵母（例えばSaccharomyces unisporus, Saccharomyces cerevisiae, Saccharomyces exiguus）を含んでいる。ケフィアは、発酵乳として美味である点に加えて、各種の健康維持増進機能が指摘されており、健康によい食品として普及しつつある。 Kefir is fermented milk native to the Caucasus region of Russia, and is produced by fermenting animal milk such as cow milk using kefir grains (kefir grains, kefir bacteria) derived from the Caucasus region as inoculum (starter). Kefir grains behave as if they were a single organism, but scientifically, various microorganisms have become natural symbiotic organisms, such as Lactobacillus kefiri, and various species of the genus Leuconostoc, Lactococcus and Acetobacter. It contains one or more microorganisms, as well as lactose fermenting yeast (eg Kluyveromyces marxianus) and non-lactose fermenting yeast (eg Saccharomyces unisporus, Saccharomyces cerevisiae, Saccharomyces exiguus). In addition to being delicious as fermented milk, kefir has been pointed out for various health maintenance and promotion functions, and is becoming popular as a healthy food.
　このケフィアの優れた特性を生かすために、ケフィアに種々の食品成分を添加して、さらに健康維持増進機能に優れた食品を創り出す試みが行われてきた。例えば、特許文献２（ＷＯ２００２／０７６２４０）は、ケフィアにナットウキナーゼを添加した食品を開示している。 In order to make use of the excellent properties of kefir, attempts have been made to add various food ingredients to kefir to create foods with even better health maintenance and promotion functions. For example, Patent Document 2 (WO2002 / 076240) discloses a food product obtained by adding nattokinase to kefir.
　しかし、ケフィアについて、大腸前がん病変に対する抑制効果、及び大腸がんの予防効果は確認されていない。 However, kefir has not been confirmed to have an inhibitory effect on colorectal precancerous lesions and a preventive effect on colorectal cancer.
特開２００６－２９０８５６号　公開特許公報JP 2006-290856 A Published Patent Gazette ＷＯ２００２／０７６２４０号　国際公開公報WO2002 / 076240 International Publication
　このように、大腸がんの発生の予防（抑制）と、大腸前がん病変の発生の予防（抑制）とが求められていた。 Thus, prevention (suppression) of the occurrence of colorectal cancer and prevention (suppression) of the occurrence of precancerous colorectal lesions have been demanded.
　従って、本発明の目的は、大腸がんの発生の予防と、大腸前がん病変の発生の予防（抑制）を可能とする予防剤（抑制剤）を提供することにある。 Therefore, an object of the present invention is to provide a preventive agent (inhibitor) that can prevent the occurrence of colorectal cancer and the prevention (suppression) of the occurrence of precancerous colorectal lesions.
　本発明者は、鋭意研究の結果、ケフィアを経口投与すると大腸前がん病変が抑制され、大腸がんが予防されることを見出して、本発明に到達した。 As a result of intensive studies, the present inventor has found that when kefir is orally administered, precancerous lesions of the large intestine are suppressed and colon cancer is prevented, and the present invention has been reached.
　すなわち、本発明は、次の［１］～［２］にある。
［１］
　有効成分としてケフィアを含有してなる、大腸がん予防剤。
［２］
　有効成分としてケフィアを含有してなる、大腸前がん病変抑制剤。 That is, the present invention includes the following [1] to [2].
[1]
A preventive agent for colorectal cancer comprising kefir as an active ingredient.
[2]
A pre-colon cancer lesion inhibitor comprising kefir as an active ingredient.
　さらに、本発明は、次の［３］～［４］にもある。
［３］
　経口投与用である、［１］に記載の大腸がん予防剤。
［４］
　経口投与用である、［２］に記載の大腸前がん病変抑制剤。 Furthermore, the present invention also includes the following [3] to [4].
[3]
The preventive agent for colorectal cancer according to [1], which is for oral administration.
[4]
The colon precancerous lesion inhibitor according to [2], which is for oral administration.
　このように、本発明は、大腸がん予防剤、大腸がん抑制剤、大腸前がん病変予防剤、大腸前がん抑制剤にもあり、経口投与用大腸がん予防剤、経口投与用大腸がん抑制剤、経口投与用大腸前がん病変予防剤、経口投与用大腸前がん抑制剤にもあり、大腸がん予防用経口投与剤、大腸がん抑制用経口投与剤、大腸前がん病変予防用経口投与剤、大腸前がん抑制用経口投与剤にもある。 As described above, the present invention is also present in a colorectal cancer preventive agent, a colorectal cancer inhibitor, a colorectal precancerous lesion preventive agent, and a colorectal precancerous inhibitor, and is used for oral administration of a colorectal cancer preventive and oral There are also colon cancer suppressants, preventive agents for colorectal precancerous lesions for oral administration, and colonic cancer inhibitors for oral administration. There are also oral administration agents for preventing cancer lesions and oral administration agents for suppressing colon precancer.
　また、本発明の有効成分であるケフィアは、伝統的な食経験の結果、長期にわたる日常的な摂取も安心して行うことができるものである。従って、本発明は、長期服用用、長期投与用、及び長期摂取用の、上記予防剤及び抑制剤にもある。 Moreover, kefir, which is an active ingredient of the present invention, can be safely taken for a long time as a result of traditional eating experience. Therefore, this invention exists also in the said preventive agent and inhibitor for long-term taking, long-term administration, and long-term intake.
　さらに、本発明は、次の［５］～［９］にもある。
［５］
　ケフィアを投与することによって、大腸がんを予防する方法。
［６］
　ケフィアを投与することによって、大腸前がん病変を抑制する方法。
［７］
　ケフィアを経口投与する、［５］又は［６］に記載の方法。
［８］
　大腸がん予防剤を製造するための、ケフィアの使用。
［９］
　大腸前がん病変抑制剤を製造するための、ケフィアの使用。 Furthermore, the present invention also includes the following [5] to [9].
[5]
A method of preventing colorectal cancer by administering kefir.
[6]
A method of suppressing precancerous colorectal lesions by administering kefir.
[7]
The method according to [5] or [6], wherein kefir is orally administered.
[8]
Use of kefir to produce a colorectal cancer preventive.
[9]
Use of kefir to produce a colorectal precancerous lesion inhibitor.
　本発明によれば、大腸前がん病変を抑制（予防）し、大腸がんを予防（抑制）することができる。 According to the present invention, it is possible to suppress (prevent) colorectal precancerous lesions and prevent (suppress) colorectal cancer.
　予防剤又は抑制剤としての摂取は、症状が発生する以前からの長期にわたる日常的な摂取とする必要があるために、強力な効能効果がある薬剤であっても、その副作用や安全性に不安がある場合には、予防剤又は抑制剤としての摂取には適さない。しかし、本発明の抑制剤（予防剤）の有効成分であるケフィアは、歴史的な年月の間、ヒトの飲食に供されてきた食品であるために、高い安全性が担保されており、長期にわたる日常的な摂取も、安心して行うことができる。すなわち、長期にわたる日常的な摂取にも不安なく、大腸前がん病変を抑制（予防）し、大腸がんを予防（抑制）することができることが、本発明の大きな利点である。 Ingestion as a preventive or suppressor must be taken daily for a long time before symptoms occur, so even if it is a drug with a strong effect, there are concerns about its side effects and safety. Is not suitable for ingestion as a prophylactic or inhibitor. However, since kefir, which is an active ingredient of the inhibitor (preventive agent) of the present invention, is a food that has been used for human consumption during historical years, high safety is ensured, Long-term daily intake can also be performed with confidence. That is, it is a great advantage of the present invention that it is possible to suppress (prevent) colorectal precancerous lesions and prevent (suppress) colorectal cancer without worrying about long-term daily intake.
図１Ａは、正常大腸のＨＥ染色した切片の顕微鏡写真を示す図である。FIG. 1A shows a photomicrograph of a HE-stained section of normal colon. 図１Ｂは、ＡＣＦを有する大腸のＨＥ染色した切片の顕微鏡写真を示す図である。FIG. 1B shows a photomicrograph of a HE-stained section of the large intestine with ACF. 図１Ｃは、正常大腸のアルシアンブルーパス（Ａｌｃｉａｎ　ｂｌｕｅ－ＰＡＳ）染色した切片の顕微鏡写真を示す図である。FIG. 1C is a view showing a micrograph of a section of a normal large intestine stained with Alcian blue-PAS. 図１Ｄは、ＡＣＦを有する大腸のアルシアンブルーパス（Ａｌｃｉａｎ　ｂｌｕｅ－ＰＡＳ）染色した切片の顕微鏡写真を示す図である。FIG. 1D is a photomicrograph of a section of the large intestine with ACF stained with Alcian blue-PAS. 図２は、ＡＣＦを有する大腸をメチレンブルー染色した顕微鏡写真を示す図である。FIG. 2 is a view showing a photomicrograph of the large intestine having ACF stained with methylene blue.
　以下に本発明の実施の態様を挙げて、本発明を詳細に説明する。本発明は以下に例示する具体的な実施の態様に限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to embodiments of the present invention. The present invention is not limited to the specific embodiments illustrated below.
　上述のように、本発明は、有効成分としてケフィアを含有してなる、大腸がん予防剤、及び大腸前がん病変抑制剤にある。 As described above, the present invention resides in a preventive agent for colon cancer and a precancerous lesion inhibitor for colon, which contain kefir as an active ingredient.
　本発明において使用されるケフィアは、公知の製造方法に基づいて製造することができる。ケフィアは、獣乳すなわち牛、馬、羊、山羊などの乳を発酵させて製造することができるが、好ましくは牛乳へのケフィアグレインの添加、発酵によって製造することができる。さらに、本発明において使用されるケフィアとして、豆乳その他の植物由来原料を出発材料として、これにケフィアグレインを添加して発酵させて製造された豆乳ケフィア及び植物性ケフィアを使用することもできる。これらの製造方法としては、例えば特開昭６２－８３８４２号公報、特開２００６－７５１７６号公報などを参照することができる。本発明において使用されるケフィアとしては、液体及び流動状のケフィア、さらにこれらの凍結乾燥品等の固体が含まれ、これらは粉末、顆粒、これらを内包するカプセル等の形態とすることもでき、公知の方法によって製剤して得られるものも含まれる。 The kefir used in the present invention can be manufactured based on a known manufacturing method. Kefir can be produced by fermenting milk of animal milk, that is, cows, horses, sheep, goats, etc., but can preferably be produced by adding kefir grains to milk and fermentation. Furthermore, as kefir used in the present invention, soymilk kefir and plant kefir produced by adding kefir grains and fermenting them with soymilk or other plant-derived raw materials as starting materials can also be used. For these production methods, reference can be made, for example, to JP-A-62-83842 and JP-A-2006-75176. Examples of the kefir used in the present invention include liquid and fluid kefir, and solids such as freeze-dried products thereof. These can be in the form of powder, granules, capsules containing them, and the like. What is obtained by formulating by a known method is also included.
　好適に使用可能なケフィアとしては、市販品として、例えば、ＮＫＧケフィア－Ｄ（日本ケフィア株式会社製）、ＮＫＧケフィア－Ｐ（日本ケフィア株式会社製）、ＮＫＧ豆乳ケフィア－ＳＤ（日本ケフィア株式会社製）、ＮＫＧケフィアＹＤ－０１（日本ケフィア株式会社製）、ＮＫＧケフィアＹＬ－０１（日本ケフィア株式会社製）、ＮＫＧケフィアＧ－０７（日本ケフィア株式会社製）を挙げることができる。 Kefirs that can be suitably used are commercially available products such as NKG Kefir-D (manufactured by Nippon Kefir), NKG Kefir-P (manufactured by Nippon Kefir), NKG soybean milk kefir-SD (manufactured by Nippon Kefir). ), NKG Kefir YD-01 (manufactured by Nippon Kefir Co., Ltd.), NKG Kefir YL-01 (manufactured by Nippon Kefir Co., Ltd.), and NKG Kefir G-07 (manufactured by Nippon Kefir Co., Ltd.).
　本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、ケフィアを有効成分として含有してなるものである。本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、種々の形態のケフィアそれ自体であってもよく、ケフィア以外の成分を含有したものとすることもできる。また、ケフィアは生菌を含有するケフィアであっても良く、死菌を含有するケフィアであってもよい。 The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention comprise kefir as an active ingredient. The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention may be various forms of kefir itself, or may contain components other than kefir. The kefir may be a kefir containing live bacteria or a kefir containing dead bacteria.
　本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、投与方法に適した種々の形態とすることができる。本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、例えば、カプセル剤、錠剤、顆粒剤、散剤、シロップ剤、トローチ剤、噴霧剤、乳剤、座剤、注射剤、軟膏、テープ剤等の形態とすることができる。経口投与をする場合には、錠剤、カプセル剤、トローチ剤、シロップ剤、顆粒剤、散剤等に加工して経口摂取することができる。本発明の大腸がん予防剤及び大腸前がん病変抑制剤の投与は、例えば、経口投与、非経口投与が挙げられ、好ましくは経口投与又は経腸投与であり、特に好ましくは経口投与である。本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、飲食品や飼料等に配合して投与することもできる。 The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be in various forms suitable for the administration method. The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention are, for example, capsules, tablets, granules, powders, syrups, troches, sprays, emulsions, suppositories, injections, ointments, tapes. It can be in the form of an agent or the like. In the case of oral administration, it can be processed into tablets, capsules, troches, syrups, granules, powders, etc. and taken orally. Administration of the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention includes, for example, oral administration and parenteral administration, preferably oral administration or enteral administration, particularly preferably oral administration. . The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can also be administered in combination with food and drink, feed, and the like.
　本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、飲食品の形態とすることができる。すなわち、本発明は、大腸がん予防及び大腸前がん病変抑制のための機能性食品にもある。機能性食品とした場合に好適な形状として、タブレット状のサプリメントを例示することができる。これによって有効成分の摂取量を正確に把握することができる。さらに、本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、食品添加剤の形態とすることができる。すなわち、本発明は、大腸がん予防及び大腸前がん病変抑制のための食品添加剤にもある。 The colon cancer preventive agent and colon precancerous lesion inhibitor of the present invention can be in the form of food and drink. That is, this invention exists also in the functional food for colon cancer prevention and colon precancerous lesion suppression. As a shape suitable for a functional food, a tablet-like supplement can be exemplified. This makes it possible to accurately grasp the intake amount of active ingredients. Furthermore, the colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be in the form of food additives. That is, this invention exists also in the food additive for colon cancer prevention and colon precancerous lesion suppression.
　本発明の大腸がん予防剤及び大腸前がん病変抑制剤は、例えば、ケフィアを薬学的に許容され得る賦形剤等の任意の添加剤を用いて製剤化することにより製造できる。製剤化する場合、製剤中のケフィアの含有量は、通常０．０１～５０質量％、好ましくは０．１～２５．０質量％である。製剤化にあたっては、薬学的に許容されうる公知の賦形剤、結合剤、崩壊剤、滑沢剤、安定剤、矯味矯臭剤、希釈剤、注射剤用溶剤等の添加剤を使用できる。製剤化にあたっては、公知の製造方法を使用することができる。また、本発明の大腸がん予防剤及び大腸前がん病変抑制剤には、必要に応じ、薬品及び食品の分野において慣用されている補助成分、例えば乳糖、ショ糖、液糖、蜂蜜、ステアリン酸マグネシウム、ヒドロキシプロピルセルロース、各種ビタミン類、クエン酸、リンゴ酸、アミノ酸、香料、無機塩等を添加することができる。 The colorectal cancer preventive agent and colorectal precancerous lesion inhibitor of the present invention can be produced, for example, by formulating kefir with any additive such as a pharmaceutically acceptable excipient. In the case of formulation, the content of kefir in the formulation is usually 0.01 to 50% by mass, preferably 0.1 to 25.0% by mass. In the formulation, known pharmaceutically acceptable excipients, binders, disintegrants, lubricants, stabilizers, flavoring agents, diluents, injection solvents and the like can be used. A known production method can be used for formulation. In addition, the preventive agent for colorectal cancer and the inhibitor for precancerous colorectal lesion of the present invention include auxiliary components commonly used in the field of medicine and food, for example, lactose, sucrose, liquid sugar, honey, stearin, as necessary. Magnesium acid, hydroxypropyl cellulose, various vitamins, citric acid, malic acid, amino acids, fragrances, inorganic salts and the like can be added.
　本発明に係る有効成分であるケフィアの投与量及び投与回数は、投与方法、治療期間、年齢、体重等により異なるが、投与量は、成人１日当たり通常１ｍｇ～５０ｇの範囲から適宜選択でき、投与回数は、１日１回から数回の範囲から適宜選択できる。ケフィアは、伝統的な食品として歴史的な年月の間、飲食に供されていたものであるために、副作用の心配がなく、安全性が高いために、投与量がさらに多くても何ら問題はない。 The dose and frequency of administration of kefir, which is an active ingredient according to the present invention, vary depending on the administration method, treatment period, age, weight, etc., but the dose can be appropriately selected from the range of usually 1 mg to 50 g per day for an adult. The number of times can be appropriately selected from a range of once to several times a day. Kefir is a traditional food that has been eaten and consumed for historical years, so there are no side effects and high safety. There is no.
　大腸前がん病変は、一定期間の経過後に一定割合で大腸がんとなってゆくことが知られている。この大腸前がん病変がどのような環境要因によって発生し、大腸前がん病変のうちで、大腸がんとなってゆく病変と大腸がんとなってゆかない病変が、どのような環境要因によって分岐するかについては、未だ解明されていない。しかし、この大腸前がん病変を抑制すれば、大腸がんの発生もまた抑制されることが知られている。本発明では、実施例に記載の実験によって実証されているように、大腸における大腸前がん病変を抑制することによって、その効果を発揮するものとなっている。 It is known that colorectal precancerous lesions become colorectal cancer at a certain rate after a certain period of time. What are the environmental factors that cause this colorectal precancerous lesion, and among the precancerous colorectal lesions, what are the environmental factors that may or may not become colon cancer? It still has not been clarified as to whether or not to branch off. However, it is known that if this colorectal precancerous lesion is suppressed, the occurrence of colorectal cancer is also suppressed. In the present invention, as demonstrated by the experiment described in the examples, the effect is exhibited by suppressing the precancerous lesion of the large intestine in the large intestine.
　以下に実施例によって本発明をより具体的に説明する。本発明は以下に例示する実施例に限定されるものではない。 Hereinafter, the present invention will be described in more detail with reference to examples. The present invention is not limited to the examples illustrated below.
［材料並びに方法］
　動物は5週齢雄ラットF344/DuCrlCrljを日本チャールスリバーより購入し実験に用いた。室温24±2℃並びに湿度55±10%の条件下で、12時間明暗サイクルの部屋で飼育した。餌並びに飲料水は自由に摂取させた。摂餌量並びに摂水量を測定した。 [Materials and methods]
For animals, 5-week-old male rat F344 / DuCrlCrlj was purchased from Japan Charles River and used for experiments. The animals were housed in a room with a 12-hour light-dark cycle under conditions of room temperature 24 ± 2 ° C. and humidity 55 ± 10%. Food and drinking water were freely available. Food intake and water intake were measured.
　餌はオリエンタル酵母のMF粉末餌を用いた。日本ケフィア(株)製の凍結乾燥したNKGケフィアYD－01（90℃　20分殺菌、死菌）、NKGケフィアYL－01（生菌）並びにNKGケフィアG-07（2倍の菌体、生菌）を2%になるように餌に混入し、動物に与えた。餌並びに飲料水は自由摂取させた。餌並びに飲料水の摂取量を測定した。6週齢より15mg/kgのazoxymethane (アゾキシメタン)（AOM, ナード研究所製　尼崎）を皮下に1週間間隔で3回投与した。 The bait used was an oriental yeast MF powder bait. Nippon Kefir Co., Ltd. freeze-dried NKG Kefir YD-01 (sterilized at 90 ° C for 20 minutes, killed), NKG Kefir YL-01 (viable) and NKG Kefir G-07 (doubled cells, viable) ) Was mixed in the feed to 2% and given to the animals. Food and drinking water were ad libitum. The intake of food and drinking water was measured. From 6 weeks of age, 15 mg / kg of azoxymethane (Azoxymethane) (AOM, Amagasaki Laboratories Co., Ltd.) was subcutaneously administered three times at weekly intervals.
　その後2週目に動物を剖検し、大腸を肛門から盲腸まで（約20cm）を取り出し、長軸にそり開き、糞を除き、襞を平たく広げて、ペーパータオルに挟み、10%中性フォルマリン液で一日以上固定した。ラベルを付け2時間以上水洗した。その後0.1%のメチレンブルー液中でシェイクしながら室温で30分染色した。直ちに実体顕微鏡の一倍以上の倍率で丁寧に肛門から盲腸までを実体顕微鏡で観察して、ACFの個数を計数した。Aberrant crypt foci (ACF)一カ所が複数のAberrant crypt focusから構成されている場合も多いので、ACF一カ所当たりのAC個数をあわせて計数した。この観察と計数を一群10匹に対して行った。これらの計数の結果から、ACFの個数(表の左から2番目：ACF)、全AC数(表の左から3番目:Total AC)、並びにACF一カ所当たりのAC個数の平均(表の右端：Mean AC)を算出した。算出された結果を次の表１に示す。実験群はMF+AOM(MF群)、YD＋AOM （YD群）、YL＋AOM （YL群）、ケフィアG＋AOM（G群）の4群とし、各群10匹を用いた。統計検定はDunnett法を用いた。さらに、その一部を切り出し、アルコールで脱水し、パラフィンに包埋し、3μｍに薄切し、今度は水まで戻し、ヘマトキシリン・エオシン（ＨＥ）染色、アルシアンブルーパス染色等を行い、再度脱水して、オイキットで封入し、顕微鏡で観察し、ACFの形態を観察した。このようにして観察されたＡＣＦの形態の一例を図２（実体顕微鏡　×２）に示す。図２に示すような実体顕微鏡での観察に基づいて、さらに断面の切片を染色して顕微鏡で観察した。図１Ａ～Ｄは正常及びＡＣＦを含む断面の切片を比較して染色した顕微鏡写真（×２００）である。 Then, at the second week, the animals were necropsied, the large intestine was removed from the anus to the cecum (approximately 20cm), opened to the long axis, the feces were removed, the folds were spread flat, and sandwiched between paper towels, 10% neutral formalin solution Fixed for more than a day. Labeled and washed with water for more than 2 hours. Thereafter, the cells were stained at room temperature for 30 minutes while shaking in 0.1% methylene blue solution. Immediately, from the anus to the cecum was carefully observed with a stereomicroscope at a magnification of 1 or more times, and the number of ACFs was counted. In many cases, one Aberrant crypt foci (ACF) is composed of multiple Aberrant crypt focus, so the number of ACs per ACF was counted together. This observation and counting was performed on 10 animals per group. From these counting results, the number of ACFs (second from the left: ACF), the total number of ACs (third from the left: Total AC), and the average number of ACs per ACF (right end of the table) : Mean AC). The calculated results are shown in Table 1 below. The experimental groups were MF + AOM (MF group), YD + AOM (YD group), YL + AOM (YL group), and Kefir G + AOM (G group). The Dunnett method was used for the statistical test. Further, a part of the sample was cut out, dehydrated with alcohol, embedded in paraffin, sliced into 3 μm, returned to water, hematoxylin / eosin (HE) staining, Alcian blue pass staining, etc., and again dehydrated. Then, it was enclosed with an oy kit, observed with a microscope, and the morphology of ACF was observed. An example of the ACF morphology observed in this way is shown in FIG. 2 (stereomicroscope × 2). Based on observation with a stereomicroscope as shown in FIG. 2, sections of the cross section were further stained and observed with a microscope. 1A to 1D are micrographs (× 200) stained by comparing sections of normal and ACF-containing sections.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
［結果］
　摂水量は一日一匹当たりYL群で17.8±2.4mlと減少の傾向が、G群で19.0±2.4mlと増加の傾向があったが、YD群の18.0±2.1ml、MF群の18.3±2.8mlで何れの群間で差は認めなかった。摂餌量は一日一匹当たりG群では11.9±2.1gで、YD群で11.6±5.1gと僅かに増加したが、YL群11.2±2.2g並びにMF群の11.2±2.7gと統計学的に差は認めなかった。屠殺時の体重はG群で209gと増加の傾向が、YD群で200gと減少の傾向があったが、その他の群では206g程度で、群間には有意の差は認められなかった。 [result]
Water consumption was 17.8 ± 2.4 ml in the YL group per animal per day, and the trend was an increase of 19.0 ± 2.4 ml in the G group, but 18.0 ± 2.1 ml in the YD group, 18.3 ± in the MF group There was no difference between any groups at 2.8ml. Food intake per day was 11.9 ± 2.1 g in group G and slightly increased to 11.6 ± 5.1 g in group YD, but 11.2 ± 2.2 g in YL group and 11.2 ± 2.7 g in MF group. There was no difference. The body weight at the time of slaughter was 209 g in the G group, and the decrease was 200 g in the YD group, but it was about 206 g in the other groups, and there was no significant difference between the groups.
　ACFはMF群で74.8±15.1個に対しYD群、YL群でそれぞれ40.9±19.2、41.2±18.8、G群では52.3±26.0で、何れのケフィア群でもMF群に比べて有意に減少した(表１)。しかしケフィア群間では統計的な有意差は認められなかった。全ACの数はMF群で136.7±32.3であるのに対し、YD群で76.5±34.1、YL群で74.4±32.8、並びにG群で89.2±51.4と同様にMF群に比べて有意差を示した。ACF当たりの平均AC数はMF群で1.82±0.16、YD群で1.92±0.20、YL群で1.87±0.21、G群で1.65±0.16と全ての群で有意差は認めなかった(表１)。 ACF was 74.8 ± 15.1 in the MF group, 40.9 ± 19.2 and 41.2 ± 18.8 in the YD group and YL group, and 52.3 ± 26.0 in the G group, respectively, and significantly decreased in any kefir group compared to the MF group (Table). 1). However, there was no statistically significant difference between the kefir groups. The total number of AC in the MF group is 136.7 ± 32.3, while the YD group is 76.5 ± 34.1, the YL group is 74.4 ± 32.8, and the G group is 89.2 ± 51.4. It was. The average number of AC per ACF was 1.82 ± 0.16 in the MF group, 1.92 ± 0.20 in the YD group, 1.87 ± 0.21 in the YL group, and 1.65 ± 0.16 in the G group, and no significant difference was observed in all groups (Table 1).
　図１Ａ、図１Ｂ、図１Ｃ、及び図１Ｄは、正常大腸とＡＣＦとを比較して、切片をＨＥ染色とアルシアンブルーパス（Ａｌｃｉａｎ　ｂｌｕｅ－ＰＡＳ）染色によってそれぞれ染色して示した顕微鏡写真（×２００）である。図１Ａと図１Ｃは正常大腸、図１Ｂと図１ＤはＡＣＦを有する大腸の写真である。また、図１Ａと図１Ｂは、ＨＥ染色による写真であり、図１Ｃと図１Ｄは、アルシアンブルーパス（Ａｌｃｉａｎ　ｂｌｕｅ－ＰＡＳ）染色による写真である。図１Ｂと図１Ｄの写真中の矢印は、典型的なＡＣＦの位置を示す。これらの観察は、図２に示すような実体顕微鏡での観察に基づいて行った。 FIG. 1A, FIG. 1B, FIG. 1C, and FIG. 1D are photomicrographs showing a comparison between normal colon and ACF, and sections stained with HE staining and Alcian blue-PAS staining, respectively. × 200). 1A and 1C are photographs of a normal large intestine, and FIGS. 1B and 1D are photographs of a large intestine having ACF. 1A and 1B are photographs by HE staining, and FIGS. 1C and 1D are photographs by Alcian blue-PAS staining. The arrows in the photographs of FIGS. 1B and 1D indicate typical ACF locations. These observations were made based on observations with a stereomicroscope as shown in FIG.
　図２は、ＡＣＦを有する大腸をメチレンブルー染色して示した実体顕微鏡（×２）による顕微鏡写真である。図２の写真中の矢印は、典型的なＡＣＦの位置を示す。 FIG. 2 is a photomicrograph taken with a stereomicroscope (× 2) showing the large intestine with ACF stained with methylene blue. The arrows in the photograph of FIG. 2 indicate typical ACF positions.
　以上のように、ケフィアは、大腸前がん病変を、経口投与によって有意に抑制することがわかった。また、このケフィアの効能は、いずれの形態のケフィアでも発揮され、生菌と死菌のいずれの場合でも発揮されるものであった。このケフィアの効能は、動物、特にほ乳類に対して有効に発揮された。 As described above, kefir was found to significantly suppress colon precancerous lesions by oral administration. In addition, the efficacy of this kefir was exhibited by any form of kefir, and was exhibited by both live and dead bacteria. The efficacy of this kefir was effectively exerted on animals, particularly mammals.
　本発明は、大腸前がん病変抑制（予防）剤及び大腸がん予防（抑制）剤を提供する。本発明の抑制剤及び予防剤は、長期にわたる日常的な摂取も、安心して行うことができるために、予防剤又は抑制剤としての摂取に、特に適したものである。このように本発明は、産業上有用な発明である。 The present invention provides an agent for inhibiting (preventing) colorectal precancerous lesions and an agent for preventing (suppressing) colorectal cancer. The inhibitor and the preventive agent of the present invention are particularly suitable for ingestion as a prophylactic or inhibitory agent because daily ingestion over a long period can be performed with peace of mind. Thus, the present invention is an industrially useful invention.

Claims (4)

  1. 　有効成分としてケフィアを含有してなる、大腸がん予防剤。 A colon cancer preventive agent comprising kefir as an active ingredient.
  2. 　有効成分としてケフィアを含有してなる、大腸前がん病変抑制剤。 An inhibitor of colorectal precancerous lesions, which contains kefir as an active ingredient.
  3. 　経口投与用である、請求項１に記載の大腸がん予防剤。 The preventive agent for colorectal cancer according to claim 1, which is for oral administration.
  4. 　経口投与用である、請求項２に記載の大腸前がん病変抑制剤。 The colon precancerous lesion inhibitor according to claim 2, which is for oral administration.
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Citations (4)

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JPS6283842A (en) * 1985-10-08 1987-04-17 Sennosuke Tokumaru Freeze-dried yogurt and production thereof
JPH0937711A (en) * 1995-07-28 1997-02-10 Sennosuke Tokumaru Health food
JP2000166467A (en) * 1998-12-10 2000-06-20 Nippon Kefia Kk Health food containing fermented milk product and herbs
WO2002076240A1 (en) * 2001-03-22 2002-10-03 Nihon Kefir Co., Ltd. Health foods containing natto kinase and fermented milk porducts

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Publication number Priority date Publication date Assignee Title
JPS6283842A (en) * 1985-10-08 1987-04-17 Sennosuke Tokumaru Freeze-dried yogurt and production thereof
JPH0937711A (en) * 1995-07-28 1997-02-10 Sennosuke Tokumaru Health food
JP2000166467A (en) * 1998-12-10 2000-06-20 Nippon Kefia Kk Health food containing fermented milk product and herbs
WO2002076240A1 (en) * 2001-03-22 2002-10-03 Nihon Kefir Co., Ltd. Health foods containing natto kinase and fermented milk porducts

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CENESIZ,S. ET AL.: "The effect of kefir on glutathione (GSH), malondialdehyde (MDA) and nitric oxide (NO) levels in mice with colonic abnormal crypt formation (ACF) induced by azoxymethane (AOM), DTW.", DEUTSCHE TIERARZTLICHE WOCHENSCHRIFT, vol. 115, no. 1, 2008, pages 15 - 19 *
HIROMITSU WATANABE ET AL.: "Hakko Nyuseihin Kefir ni yoru Daicho Zengan Byohen no Yokusei", THE JOURNAL OF JAPAN MIBYO SYSTEM ASSOCIATION, vol. 14, no. SUP.1, 2008, pages 58 *
MICHINORI KUBO ET AL.: "Caucasus-gata Hakkonyu Kefir no Yakuri Kassei Kenkyu (1st report) Ko Shuyo Kassei ni Tsuite Sono 1", JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 112, no. 7, 1992, pages 489 - 495 *
TORU NISHIZAKI, KENKO SHOKUHIN HYAKKA, 2003, pages 359 - 361 *

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