WO2010064434A1 - Prophylactic agent for hepatic function disorders - Google Patents

Prophylactic agent for hepatic function disorders Download PDF

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Publication number
WO2010064434A1
WO2010064434A1 PCT/JP2009/006588 JP2009006588W WO2010064434A1 WO 2010064434 A1 WO2010064434 A1 WO 2010064434A1 JP 2009006588 W JP2009006588 W JP 2009006588W WO 2010064434 A1 WO2010064434 A1 WO 2010064434A1
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Prior art keywords
kefir
group
chemotherapy
administration
radiation therapy
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PCT/JP2009/006588
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French (fr)
Japanese (ja)
Inventor
岡本哲治
谷亮治
徳丸浩一郎
徳丸千之助
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国立大学法人広島大学
日本ケフィア株式会社
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Priority to JP2010541239A priority Critical patent/JP5823695B2/en
Publication of WO2010064434A1 publication Critical patent/WO2010064434A1/en

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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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a preventive agent for liver dysfunction containing kefir as an active ingredient, and particularly to a preventive agent for liver dysfunction associated with cancer treatment.
  • Proposals for trying to prevent liver function disorders include, for example, “a hepatoprotectant composition comprising a black cohosh plant or an extract thereof as an active ingredient” (Patent Document 1: Japanese Patent Application Laid-Open No. 2007-55929), “phosphatidylserine or A liver function improving agent characterized by using the salt as an active ingredient "(Patent Document 2: Japanese Patent Application Laid-Open No. 2005-112731) has been made. However, no clinical effects have been confirmed, and no preventive effect on the impairment of liver function that occurs as a side effect of administration of an anticancer agent for cancer treatment and irradiation with radiation has not been confirmed.
  • 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 3 discloses a food product obtained by adding nattokinase to kefir.
  • kefir has not been confirmed to have a preventive effect on hepatic dysfunction, in particular, on a hepatic dysfunction caused as a side effect of administration of an anticancer drug for cancer treatment and radiation irradiation.
  • an object of the present invention is to provide a novel drug for preventing hepatic function disorder, particularly a cancer treatment chemotherapy and radiation therapy, which is a side effect of cancer therapy, which has been confirmed clinically effective.
  • a novel drug for preventing hepatic function disorder particularly a cancer treatment chemotherapy and radiation therapy, which is a side effect of cancer therapy, which has been confirmed clinically effective.
  • the present inventors have found that when kefir is administered to patients undergoing chemotherapy and / or radiation therapy for cancer treatment, the effect of preventing the impairment of liver function as a side effect is statistically significant. Thus, the present invention has been completed.
  • the present invention includes the following [1] to [4].
  • kefir has an excellent effect in preventing and also improving an improvement in liver function disorders caused as a side effect by chemotherapy and / or radiation therapy for cancer treatment. Met.
  • the present invention also includes the following [5] to [8].
  • the improving agent according to any one of [5] to [7], wherein the chemotherapy is superselective intra-arterial chemotherapy.
  • the present invention also includes the following [9] to [14].
  • [9] A method of preventing liver function disorder by administering kefir.
  • [10] A method for preventing impaired liver function, which is a side effect of chemotherapy and radiation therapy for cancer treatment, by administering kefir.
  • [11] A method of improving impaired liver function by administering kefir.
  • [12] A method for improving impaired liver function, which is a side effect of chemotherapy and radiation therapy for cancer treatment, by administering kefir.
  • Use of kefir for producing a preventive or ameliorating agent for liver dysfunction Use of kefir for producing a preventive or ameliorating agent for liver dysfunction, which is a side effect of chemotherapy and radiation therapy for cancer treatment.
  • the present invention also resides in an inhibitor of liver dysfunction comprising kefir as an active ingredient.
  • the present invention also resides in a method for suppressing impairment of liver function by administering kefir.
  • the present invention also lies in the use of kefir for producing a liver dysfunction inhibitor.
  • the preventive agent for hepatic dysfunction according to the present invention is used, it is possible to prevent hepatic dysfunction, in particular, hepatic dysfunction which is a side effect of chemotherapy and radiotherapy for cancer treatment. This is a statistically significant effect that has been confirmed clinically, and the present invention makes it possible for the first time to prevent liver function disorders, which are side effects of chemotherapy and radiotherapy for cancer treatment.
  • patients undergoing chemotherapy and / or radiation therapy for cancer treatment can significantly prevent the side effect of liver function disorder and minimize interruption or change of cancer treatment plan due to liver function disorder. be able to.
  • the cancer treatment plan can be completed to ensure the survival of the patient, and side effects can be avoided to improve the quality of life.
  • the present invention enables not only prevention of liver dysfunction but also improvement of liver dysfunction that has already occurred. That is, by using the liver dysfunction-improving agent according to the present invention, it is possible to improve hepatic dysfunction, particularly amelioration of hepatic dysfunction, which is a side effect of cancer treatment chemotherapy and radiotherapy. Therefore, the present invention improves the liver function disorder which is a side effect of cancer treatment chemotherapy and / or radiation therapy, and cancer treatment plan due to liver function disorder in patients receiving cancer treatment chemotherapy and / or radiation therapy. Interruptions and changes can be minimized. Thereby, the cancer treatment plan can be completed to ensure the survival of the patient, and side effects can be avoided to improve the quality of life.
  • kefir according to the present invention Since the kefir according to the present invention has been used for human consumption during historical years, there are no side effects or safety concerns in itself, and continuous administration over a long period of time, Can be done with confidence. Since chemotherapy for cancer treatment and / or radiation therapy is often extended over a long period of several weeks to several months, it is a great advantage of the present invention that continuous administration over a long period of time can be performed with confidence. .
  • the kefir according to the present invention since the kefir according to the present invention has been used for human consumption during historical years, it is excellent in palatability and easy to use. When receiving chemotherapy for cancer treatment and / or radiation therapy, nausea or the like often appears as a side effect thereof, and thus excellent palatability and ease of internal use are great advantages of the present invention.
  • the preventive and ameliorating agent for liver dysfunction comprises 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 preferably can be produced by adding kefir grains to milk and fermentation.
  • soy milk kefir and plant kefir produced by adding kefir grains and fermenting soy milk or other plant-derived raw materials as starting materials can also be used.
  • 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). ).
  • the preventive and ameliorating agent for liver dysfunction according to the present invention contains kefir as an active ingredient.
  • the preventive and ameliorating agent for hepatic dysfunction of the present invention may be various forms of kefir itself, or may contain components other than kefir.
  • the preventive and ameliorating agent for liver dysfunction of the present invention can be in various forms suitable for the administration method.
  • Examples of the preventive and ameliorating agent for liver dysfunction according to the present invention include capsules, tablets, granules, powders, syrups, troches, sprays, emulsions, suppositories, injections, ointments, tapes and the like. It can be.
  • oral administration it can be processed into tablets, capsules, troches, syrups, granules, powders, etc. and taken orally.
  • Administration of the preventive and ameliorating agent for hepatic dysfunction of the present invention includes, for example, oral administration and parenteral administration, preferably oral administration or enteral administration, and particularly preferably oral administration.
  • the preventive and ameliorating agent for hepatic dysfunction of the present invention can also be administered in combination with food and drink or feed.
  • the preventive and ameliorating agent for liver dysfunction according to the present invention can be in the form of food and drink. That is, this invention exists also in the functional food for the prevention or improvement of liver dysfunction. 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 preventive agent and ameliorating agent for liver dysfunction of the present invention can be in the form of a food additive. That is, this invention exists also in the food additive for the prevention or improvement of liver dysfunction.
  • the preventive and ameliorating agent for hepatic dysfunction 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 and ameliorating agent for hepatic dysfunction of the present invention includes auxiliary components commonly used in the fields of medicine and food, for example, lactose, sucrose, liquid sugar, honey, magnesium stearate, hydroxy, if necessary.
  • auxiliary components commonly used in the fields of medicine and food, for example, lactose, sucrose, liquid sugar, honey, magnesium stearate, hydroxy, if necessary.
  • Propyl 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.
  • Administration of the preventive and ameliorating agent for hepatic dysfunction of the present invention is usually at least 1 day before the start of chemotherapy or radiotherapy, preferably at least 2 days before, more preferably at least 3 days before, more preferably 1 Held for over a week. Since kefir is a traditional food that has been eaten and eaten for historical years, there is no problem no matter how long it has been administered before the start of chemotherapy or radiation therapy. In a preferred embodiment, it is administered during the period during which chemotherapy or radiation therapy is taking place. In addition, kefir does not have any problem even if it continues to be administered after the end of the treatment period by chemotherapy or radiation therapy.
  • prevention of liver dysfunction refers to improving the decrease in liver function when the probability of causing liver dysfunction is causing liver damage, In particular, in cancer patients undergoing chemotherapy or radiation therapy for cancer treatment, it refers to preventing the occurrence of impaired liver function.
  • “improving liver dysfunction” Reducing the degree of functional impairment occurring in the liver under the external causes that may cause functional impairment, especially in cancer patients undergoing chemotherapy or radiation therapy for cancer treatment, It means improving.
  • AST aspartate aminotransferase
  • GOT glutamate oxaloacetate transaminase
  • ALT alanine aminotransferase
  • GPT glutamate pyruvate transaminase
  • kefir which is an active ingredient according to the present invention, has the effect of preventing and improving liver dysfunction
  • kefir is prevented or improved by oral administration, that is, systemic administration.
  • oral administration that is, systemic administration.
  • the effect is not limited to oral cancer, and the same effect of preventing and improving the cancer in any part of the whole body. Is shown.
  • the effect of prevention and improvement of liver dysfunction by kefir which is an active ingredient according to the present invention, may be statistically significant by clinical trials, particularly in cancer patients undergoing chemotherapy or radiotherapy in cancer treatment. It has been confirmed that it is effective in preventing and improving liver dysfunction caused by other external causes.
  • Chemotherapy includes all types of chemotherapy that administer drugs that can cause liver dysfunction, including all types of administration, especially at high concentrations. It is effective in administration methods such as hyperselective intra-arterial chemotherapy.
  • Radiation therapy includes any radiation therapy that can cause liver dysfunction.
  • [Target] Group A (patients AE, superselective intra-arterial chemotherapy + kefir administration group)
  • Patient A Male, 50s, squamous cell carcinoma of the tongue, superselective intra-arterial chemotherapy (CDDP 180mg)
  • Patient B Female, 60s, squamous cell carcinoma of the buccal mucosa, superselective intra-arterial chemotherapy (CDDP 280mg)
  • Patient C Female, 50s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 200mg)
  • Patient D Male, 50s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 200mg)
  • Patient E Female, 60s, squamous cell carcinoma of tongue, superselective intraarterial chemotherapy (CDDP 40mg) and external radiation (30Gy)
  • Group B Patients K to N, radiation therapy + kefir administration group
  • Patient K Female,
  • kefir The administration of kefir was carried out by taking a granular preparation of kefir dry powder, 2 capsules at a time, once after each meal (6 capsules per day).
  • One sachet contained 4 g of a granular preparation, and the dry kefir equivalent amount was 25 mg / 1 sachet.
  • Grades 0 to 4 The degree of stomatitis was classified into Grades 0 to 4 as follows according to the side effect description format of the Japanese Cancer Treatment Society. Grade 0: None Grade 1: Pain, erythema Grade 2: Erosion, ulcer Grade 3: Ingestion of ulcer and liquid food only Grade 4: With ulcer and bleeding
  • Table 1 shows blood data in group A (patients AE, superselective arterial chemotherapy plus kefir administration group) and group C (patients FJ, superselective arterial chemotherapy group, no kefir administration) It is the table
  • Table 2 shows blood data (ALT) values in Group B (patients K to N, radiation therapy + kefir administration group) and Group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started. It is the table
  • Table 3 shows blood data in group A (patients AE, superselective intraarterial chemotherapy plus kefir administration group) and group C (patients FJ, superselective intraarterial chemotherapy group, no kefir administration) (AST) is a table summarizing values before the start of chemotherapy (week 0) to week 9.
  • Table 4 shows blood data (AST) values in Group B (patients K to N, radiation therapy + kefir administration group) and Group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started. It is the table
  • Table 5 shows the degree of stomatitis in group A (patients AE, superselective intraarterial chemotherapy plus kefir) and group C (patients FJ, superselective intraarterial chemotherapy, no kefir) Is a table summarizing the grade evaluation from before the start of chemotherapy (week 0) to week 9.
  • Table 6 shows the Grade evaluation of the degree of stomatitis in the group B (patients K to N, radiation therapy + kefir administration group) and the group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started ( It is the table put together from the 0th week) to the 9th week.
  • ALT was the highest during the treatment period for each patient. Compare the value showing high value with the ALT value before administration, calculate the value of ALT difference for each patient according to the following formula, and based on this, between the two groups of kefir administration group and non-administration group, A t-test was performed.
  • ALT difference (maximum ALT value during treatment)-(ALT value before administration)
  • AST was the highest during the treatment period for each patient. Compare the AST value before administration with the value showing high value, calculate the value of AST difference for each patient according to the following formula, and based on this, between the two groups of kefir administration group and non-administration group, A t-test was performed.
  • AST difference (maximum AST value during treatment)-(AST value before administration)
  • AST% 100% ⁇ (AST difference) / (AST value before administration)
  • oral administration of kefir has the effect of preventing the occurrence of liver dysfunction in cancer patients (especially oral cancer patients) undergoing chemotherapy (especially hyperselective arterial chemotherapy) and radiation therapy. It was. Furthermore, no side effects were observed and the safety was high. At the same time, no interruption was observed in all patients, and oral administration was easy.
  • the preventive agent for hepatic dysfunction according to the present invention has an effect of preventing hepatic dysfunction, particularly prevention of hepatic dysfunction which is a side effect of chemotherapy and radiotherapy for cancer treatment. is there.
  • the present invention provides for the first time a clinically confirmed prophylactic agent having a statistically significant effect.

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Abstract

Disclosed is a prophylactic agent for hepatic function disorders, of which the clinical efficacy has been confirmed, and which has high safety and is free from the concerns about adverse side effects.  The prophylactic agent comprises kefir as an active ingredient.

Description

肝機能障害予防剤Liver dysfunction preventive
　本発明は、ケフィアを有効成分として含有する肝機能障害予防剤に関し、特に癌治療に伴う肝機能障害の予防剤に関する。 The present invention relates to a preventive agent for liver dysfunction containing kefir as an active ingredient, and particularly to a preventive agent for liver dysfunction associated with cancer treatment.
　癌治療の重要な手段として、化学療法や放射線療法がある。化学療法で行われる抗ガン剤の投与は、その副作用が問題とされている。重大な副作用の一つとして、肝臓の機能障害の発生が挙げられる。肝機能の障害が発生した場合には、これを放置すれば生命が脅かされる事態もあり得るために、何らかの対処が必要である。やむを得ず、抗ガン剤の投与の中止となることもあるが、副作用によって癌治療の中止や変更を余儀なくされることによる患者にとっての不利益は極めて重大である。放射線療法においても、その副作用は問題とされ、重大な副作用の一つとして、肝臓の機能障害の発生が挙げられ、同様に重大な問題がある。 There are chemotherapy and radiation therapy as important means for cancer treatment. Side effects of anticancer drugs administered by chemotherapy are a problem. One serious side effect is the occurrence of liver dysfunction. If a liver function disorder occurs, it may be life threatening if left untreated, so some measures are necessary. Although it is unavoidable that administration of anticancer drugs is unavoidable, the disadvantages to patients caused by the side effects of discontinuing or changing the cancer treatment are extremely serious. In radiation therapy, the side effects are a problem, and one of the serious side effects is the occurrence of liver dysfunction, which is also a serious problem.
　このような副作用、特に肝機能の障害に対しては、臨床的に行われる数少ない対応手段として、グリチロン錠や強力ミノファーゲンシーの投与が知られているが、これらは既に発生した機能障害に対して、これを改善するために投与されるが、肝機能障害を予防するものではない。 For such side effects, especially liver function disorders, the administration of glycylone tablets and strong minophagency is known as one of the few clinically available countermeasures. Administered to improve this, but does not prevent liver dysfunction.
　肝機能の障害の予防を試みる提案として、例えば、「ブラックコホシュ植物体又はその抽出物を有効成分とする肝保護剤組成物」（特許文献１：特開２００７－５５９２９号公報）、「ホスファチジルセリン又はその塩を有効成分とすることを特徴とする肝機能改善剤」（特許文献２：特開２００５－１１２７３１号公報）などがなされている。しかし、いずれも、臨床的な効果は確認されておらず、癌治療のための抗ガン剤の投与及び放射線の照射の副作用として生じる肝機能の障害に対する予防効果は確認されていない。 Proposals for trying to prevent liver function disorders include, for example, “a hepatoprotectant composition comprising a black cohosh plant or an extract thereof as an active ingredient” (Patent Document 1: Japanese Patent Application Laid-Open No. 2007-55929), “phosphatidylserine or A liver function improving agent characterized by using the salt as an active ingredient "(Patent Document 2: Japanese Patent Application Laid-Open No. 2005-112731) has been made. However, no clinical effects have been confirmed, and no preventive effect on the impairment of liver function that occurs as a side effect of administration of an anticancer agent for cancer treatment and irradiation with radiation has not been confirmed.
　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３（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 3 (WO2002 / 076240) discloses a food product obtained by adding nattokinase to kefir.
　しかし、ケフィアについて、肝機能障害の予防作用、特に、癌治療のための抗ガン剤の投与及び放射線の照射の副作用として生じる肝機能の障害に対する予防効果は確認されていない。 However, kefir has not been confirmed to have a preventive effect on hepatic dysfunction, in particular, on a hepatic dysfunction caused as a side effect of administration of an anticancer drug for cancer treatment and radiation irradiation.
特開２００７－５５９２９号公報JP 2007-55929 A 特開２００５－１１２７３１号公報JP 2005-112731 A ＷＯ２００２／０７６２４０号　国際公開公報WO2002 / 076240 International Publication
　このような状況のもとで、臨床的な効果が確認された、肝機能の障害を予防する新規な薬剤、特に癌治療の化学療法及び放射線療法の副作用である肝機能の障害を予防する新規な薬剤が求められていた。 Under such circumstances, a novel drug for preventing the impairment of liver function, which has been confirmed clinically effective, in particular, for preventing the impairment of liver function, which is a side effect of chemotherapy and radiation therapy for cancer treatment There was a need for a new drug.
　従って、本発明の目的は、臨床的な効果が確認された、肝機能の障害を予防する新規な薬剤、特に癌治療の化学療法及び放射線療法の副作用である肝機能の障害を予防する新規な薬剤を提供することにある。 Accordingly, an object of the present invention is to provide a novel drug for preventing hepatic function disorder, particularly a cancer treatment chemotherapy and radiation therapy, which is a side effect of cancer therapy, which has been confirmed clinically effective. To provide a drug.
　本発明者等は、癌治療の化学療法及び／又は放射線療法を受ける患者に対して、ケフィアを投与すると、副作用として生じる肝機能の障害の予防効果が、統計的に有意に認められることを発見して、本発明を完成するに至った。 The present inventors have found that when kefir is administered to patients undergoing chemotherapy and / or radiation therapy for cancer treatment, the effect of preventing the impairment of liver function as a side effect is statistically significant. Thus, the present invention has been completed.
　すなわち、本発明は、次の［１］～［４］にある。
［１］
　ケフィアを有効成分として含有してなる、肝機能障害の予防剤。
［２］
　肝機能障害が、癌の治療のための化学療法及び／又は放射線療法の副作用による肝機能障害である、［１］に記載の予防剤。
［３］
　癌が口腔癌である、［１］～［２］の何れかに記載の予防剤。
［４］
　化学療法が、超選択的動注化学療法である、［１］～［３］の何れかに記載の予防剤。 That is, the present invention includes the following [1] to [4].
[1]
A preventive agent for liver dysfunction, comprising kefir as an active ingredient.
[2]
The preventive agent according to [1], wherein the liver dysfunction is liver dysfunction due to side effects of chemotherapy and / or radiation therapy for cancer treatment.
[3]
The prophylactic agent according to any one of [1] to [2], wherein the cancer is oral cancer.
[4]
The prophylactic agent according to any one of [1] to [3], wherein the chemotherapy is superselective intra-arterial chemotherapy.
　さらに、ケフィアは、癌治療の化学療法及び／又は放射線療法により副作用として生じる肝機能の障害に対して、その予防に優れた効果が認められると同時に、その改善にも優れた効果が認められるものであった。 In addition, kefir has an excellent effect in preventing and also improving an improvement in liver function disorders caused as a side effect by chemotherapy and / or radiation therapy for cancer treatment. Met.
　すなわち、本発明は、次の［５］～［８］にもある。
［５］
　ケフィアを有効成分として含有してなる、肝機能障害の改善剤。
［６］
　肝機能障害が、癌の治療のための化学療法及び／又は放射線療法の副作用による肝機能障害である、［５］に記載の改善剤。
［７］
　癌が口腔癌である、［５］～［６］の何れかに記載の改善剤。
［８］
　化学療法が、超選択的動注化学療法である、［５］～［７］の何れかに記載の改善剤。 That is, the present invention also includes the following [5] to [8].
[5]
An agent for improving liver dysfunction, comprising kefir as an active ingredient.
[6]
The improving agent according to [5], wherein the liver dysfunction is liver dysfunction due to side effects of chemotherapy and / or radiation therapy for cancer treatment.
[7]
The improving agent according to any one of [5] to [6], wherein the cancer is oral cancer.
[8]
The improving agent according to any one of [5] to [7], wherein the chemotherapy is superselective intra-arterial chemotherapy.
　さらに、本発明は、次の［９］～［１４］にもある。
［９］
　ケフィアを投与することによって、肝機能の障害を予防する方法。
［１０］
　ケフィアを投与することによって、癌治療の化学療法及び放射線療法の副作用である肝機能の障害を予防する方法。
［１１］
　ケフィアを投与することによって、肝機能の障害を改善する方法。
［１２］
　ケフィアを投与することによって、癌治療の化学療法及び放射線療法の副作用である肝機能の障害を改善する方法。
［１３］
　肝機能障害の予防剤又は改善剤を製造するための、ケフィアの使用。
［１４］
　癌治療の化学療法及び放射線療法の副作用である肝機能障害の予防剤又は改善剤を製造するための、ケフィアの使用。 Furthermore, the present invention also includes the following [9] to [14].
[9]
A method of preventing liver function disorder by administering kefir.
[10]
A method for preventing impaired liver function, which is a side effect of chemotherapy and radiation therapy for cancer treatment, by administering kefir.
[11]
A method of improving impaired liver function by administering kefir.
[12]
A method for improving impaired liver function, which is a side effect of chemotherapy and radiation therapy for cancer treatment, by administering kefir.
[13]
Use of kefir for producing a preventive or ameliorating agent for liver dysfunction.
[14]
Use of kefir for producing a preventive or ameliorating agent for liver dysfunction, which is a side effect of chemotherapy and radiation therapy for cancer treatment.
　また、本発明は、ケフィアを有効成分として含有してなる、肝機能障害の抑制剤にもある。本発明は、ケフィアを投与することによって、肝機能の障害を抑制する方法にもある。本発明は、肝機能障害の抑制剤を製造するための、ケフィアの使用にもある。 The present invention also resides in an inhibitor of liver dysfunction comprising kefir as an active ingredient. The present invention also resides in a method for suppressing impairment of liver function by administering kefir. The present invention also lies in the use of kefir for producing a liver dysfunction inhibitor.
　本発明に係る肝機能障害の予防剤を使用すれば、肝機能の障害の予防、特に癌治療の化学療法及び放射線療法の副作用である肝機能の障害の予防が可能である。これは統計的に有意な効果が臨床的に確認されたものであり、癌治療の化学療法及び放射線療法の副作用である肝機能の障害の予防は、本発明によって初めて可能となった。 If the preventive agent for hepatic dysfunction according to the present invention is used, it is possible to prevent hepatic dysfunction, in particular, hepatic dysfunction which is a side effect of chemotherapy and radiotherapy for cancer treatment. This is a statistically significant effect that has been confirmed clinically, and the present invention makes it possible for the first time to prevent liver function disorders, which are side effects of chemotherapy and radiotherapy for cancer treatment.
　本発明によれば、癌治療の化学療法及び／又は放射線療法を受ける患者は、副作用である肝機能の障害が有意に予防され、肝機能障害による癌治療計画の中断や変更を最小限に抑えることができる。これによって、癌治療計画を完遂して患者の生存をより確実なものとし、さらに副作用を回避して生活の質を高めることができる。 According to the present invention, patients undergoing chemotherapy and / or radiation therapy for cancer treatment can significantly prevent the side effect of liver function disorder and minimize interruption or change of cancer treatment plan due to liver function disorder. be able to. Thereby, the cancer treatment plan can be completed to ensure the survival of the patient, and side effects can be avoided to improve the quality of life.
　さらに、本発明は、肝機能障害の予防のみならず、既に発生した肝機能障害の改善をも可能としている。すなわち、本発明に係る肝機能障害の改善剤を使用すれば、肝機能の障害の改善、特に癌治療の化学療法及び放射線療法の副作用である肝機能の障害の改善が可能である。従って、本発明は、癌治療の化学療法及び／又は放射線療法の副作用である肝機能の障害を改善して、癌治療の化学療法及び／又は放射線療法を受ける患者において肝機能障害による癌治療計画の中断や変更を最小限に抑えることができる。これによって、癌治療計画を完遂して患者の生存をより確実なものとし、さらに副作用を回避して生活の質を高めることができる。 Furthermore, the present invention enables not only prevention of liver dysfunction but also improvement of liver dysfunction that has already occurred. That is, by using the liver dysfunction-improving agent according to the present invention, it is possible to improve hepatic dysfunction, particularly amelioration of hepatic dysfunction, which is a side effect of cancer treatment chemotherapy and radiotherapy. Therefore, the present invention improves the liver function disorder which is a side effect of cancer treatment chemotherapy and / or radiation therapy, and cancer treatment plan due to liver function disorder in patients receiving cancer treatment chemotherapy and / or radiation therapy. Interruptions and changes can be minimized. Thereby, the cancer treatment plan can be completed to ensure the survival of the patient, and side effects can be avoided to improve the quality of life.
　本発明に係るケフィアは、歴史的な年月の間、ヒトの飲食に供されていたものであるために、それ自体に副作用や安全性の懸念はなく、長期間にわたる継続的な投与も、安心して行うことができる。癌治療の化学療法及び／又は放射線療法は、数週間から数ヶ月の長期にわたるものとなる場合が多いために、長期間にわたる継続的な投与が安心して行えることは、本発明の大きな利点である。 Since the kefir according to the present invention has been used for human consumption during historical years, there are no side effects or safety concerns in itself, and continuous administration over a long period of time, Can be done with confidence. Since chemotherapy for cancer treatment and / or radiation therapy is often extended over a long period of several weeks to several months, it is a great advantage of the present invention that continuous administration over a long period of time can be performed with confidence. .
　また、本発明に係るケフィアは、歴史的な年月の間、ヒトの飲食に供されていたものであるために、嗜好性に優れ、内服も容易である。癌治療の化学療法及び／又は放射線療法を受けた場合には、その副作用として吐き気等が現れることも多いために、優れた嗜好性と内服の容易さは、本発明の大きな利点である。 Moreover, since the kefir according to the present invention has been used for human consumption during historical years, it is excellent in palatability and easy to use. When receiving chemotherapy for cancer treatment and / or radiation therapy, nausea or the like often appears as a side effect thereof, and thus excellent palatability and ease of internal use are great advantages of the present invention.
　本発明の実施の形態を、以下に詳細に説明する。本発明は、以下の実施の形態に限定されるものではない。 Embodiments of the present invention will be described in detail below. The present invention is not limited to the following embodiments.
　本発明に係る肝機能障害の予防剤及び改善剤は、ケフィアを有効成分として含有してなるものである。 The preventive and ameliorating agent for liver dysfunction according to the present invention comprises 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 preferably can be produced by adding kefir grains to milk and fermentation. Furthermore, as kefir used in the present invention, soy milk kefir and plant kefir produced by adding kefir grains and fermenting soy milk 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）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). ).
　本発明の肝機能障害の予防剤及び改善剤は、ケフィアを有効成分として含有してなるものである。本発明の肝機能障害の予防剤及び改善剤は、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。 The preventive and ameliorating agent for liver dysfunction according to the present invention contains kefir as an active ingredient. The preventive and ameliorating agent for hepatic dysfunction of the present invention may be various forms of kefir itself, or may contain components other than kefir.
　本発明の肝機能障害の予防剤及び改善剤は、投与方法に適した種々の形態とすることができる。本発明の肝機能障害の予防剤及び改善剤は、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。本発明の肝機能障害の予防剤及び改善剤の投与は、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。本発明の肝機能障害の予防剤及び改善剤は、飲食品や飼料等に配合して投与することもできる。 The preventive and ameliorating agent for liver dysfunction of the present invention can be in various forms suitable for the administration method. Examples of the preventive and ameliorating agent for liver dysfunction according to the present invention include capsules, tablets, granules, powders, syrups, troches, sprays, emulsions, suppositories, injections, ointments, tapes and the like. It can be. In the case of oral administration, it can be processed into tablets, capsules, troches, syrups, granules, powders, etc. and taken orally. Administration of the preventive and ameliorating agent for hepatic dysfunction of the present invention includes, for example, oral administration and parenteral administration, preferably oral administration or enteral administration, and particularly preferably oral administration. The preventive and ameliorating agent for hepatic dysfunction of the present invention can also be administered in combination with food and drink or feed.
　本発明の肝機能障害の予防剤及び改善剤は、飲食品の形態とすることができる。すなわち、本発明は、肝機能障害の予防又は改善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、本発明の肝機能障害の予防剤及び改善剤は、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、肝機能障害の予防又は改善のための食品添加剤にもある。 The preventive and ameliorating agent for liver dysfunction according to the present invention can be in the form of food and drink. That is, this invention exists also in the functional food for the prevention or improvement of liver dysfunction. 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 preventive agent and ameliorating agent for liver dysfunction of the present invention can be in the form of a food additive. That is, this invention exists also in the food additive for the prevention or improvement of liver dysfunction.
　本発明の肝機能障害の予防剤及び改善剤は、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、本発明の肝機能障害の予防剤及び改善剤には、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 preventive and ameliorating agent for hepatic dysfunction 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. Further, the preventive and ameliorating agent for hepatic dysfunction of the present invention includes auxiliary components commonly used in the fields of medicine and food, for example, lactose, sucrose, liquid sugar, honey, magnesium stearate, hydroxy, if necessary. Propyl 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.
　本発明の肝機能障害の予防剤及び改善剤の投与は、通常は化学療法又は放射線療法の開始の１日以上前、好ましくは２日以上前、さらに好ましくは３日以上前、さらに好ましくは１週間以上前から行われる。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、化学療法又は放射線療法の開始のどれほど前から投与されていても何ら問題はない。好ましい実施の態様において、化学療法又は放射線療法が行われている期間の間、投与される。また、ケフィアは、化学療法又は放射線療法による治療期間の終了の後に、投与されて続けていても何ら問題はない。 Administration of the preventive and ameliorating agent for hepatic dysfunction of the present invention is usually at least 1 day before the start of chemotherapy or radiotherapy, preferably at least 2 days before, more preferably at least 3 days before, more preferably 1 Held for over a week. Since kefir is a traditional food that has been eaten and eaten for historical years, there is no problem no matter how long it has been administered before the start of chemotherapy or radiation therapy. In a preferred embodiment, it is administered during the period during which chemotherapy or radiation therapy is taking place. In addition, kefir does not have any problem even if it continues to be administered after the end of the treatment period by chemotherapy or radiation therapy.
　本発明における「肝機能障害の予防」とは、肝機能障害を起こす蓋然性が肝障害を起こしている場合の肝機能の低下を改善すること、肝臓の機能に障害を引き起こすであろう外因のもとで、特に癌治療における化学療法又は放射線療法の行われている癌患者において、肝臓の機能の障害の発生を予防することをいい、本発明における「肝機能障害の改善」とは、肝臓の機能に障害を引き起こすであろう外因のもとで、特に癌治療における化学療法又は放射線療法の行われている癌患者において、肝臓に発生している機能の障害の程度を和らげ、肝臓の機能を改善することをいう。 In the present invention, “prevention of liver dysfunction” refers to improving the decrease in liver function when the probability of causing liver dysfunction is causing liver damage, In particular, in cancer patients undergoing chemotherapy or radiation therapy for cancer treatment, it refers to preventing the occurrence of impaired liver function. In the present invention, “improving liver dysfunction” Reducing the degree of functional impairment occurring in the liver under the external causes that may cause functional impairment, especially in cancer patients undergoing chemotherapy or radiation therapy for cancer treatment, It means improving.
　このような肝機能障害は、臨床的には、血液中のマーカーの値、例えばＡＳＴ及びＡＬＴ等を使用して、確認することができる。ＡＳＴ（アスパラギン酸アミノトランスフェラーゼ）は、かつてＧＯＴ（グルタミン酸オキサロ酢酸トランスアミナーゼ）と呼ばれ、ＡＬＴ（アラニンアミノトランスフェラーゼ）は、かつてＧＰＴ（グルタミン酸ピルビン酸トランスアミナーゼ）と呼ばれていたものである。血液中のＡＳＴ及びＡＬＴは、いずれも肝細胞の破壊に伴って増大するとされており、ＡＳＴ及びＡＬＴの上昇は、肝機能の障害の発生又は進行を意味している。 Such liver dysfunction can be confirmed clinically by using marker values in blood, such as AST and ALT. AST (aspartate aminotransferase) was once called GOT (glutamate oxaloacetate transaminase), and ALT (alanine aminotransferase) was once called GPT (glutamate pyruvate transaminase). Both AST and ALT in blood increase with hepatocyte destruction, and an increase in AST and ALT means the occurrence or progression of impaired liver function.
　本発明に係る有効成分であるケフィアが、どのようなメカニズムによって肝機能障害の予防及び改善の効果をもたらすかは不明であるが、ケフィアは、経口投与すなわち全身投与によって肝機能障害の予防及び改善の効果を示しているので、例えば癌患者における肝機能障害の予防及び改善の効果においても、その効果は口腔癌に限られず、全身の如何なる部位での癌についても、同様の予防及び改善の効果を示すものである。 Although it is unclear by what mechanism kefir, which is an active ingredient according to the present invention, has the effect of preventing and improving liver dysfunction, kefir is prevented or improved by oral administration, that is, systemic administration. For example, in the effect of preventing and improving liver dysfunction in cancer patients, the effect is not limited to oral cancer, and the same effect of preventing and improving the cancer in any part of the whole body. Is shown.
　本発明に係る有効成分であるケフィアによる肝機能障害の予防及び改善の効果は、特に癌治療における化学療法又は放射線療法の行われている癌患者において、臨床試験によって統計的に有意であることが確認されたものであるが、その他の外因によって生じる肝機能障害に対しても予防及び改善に有効なものである。化学療法には、肝機能障害を発生する可能性のある薬剤を投与するあらゆる種類の化学療法が含まれ、その投与方法もあらゆる種類の投与方法が含まれるが、特に高濃度の薬剤を投与する投与方法、例えば超選択的動注化学療法において有効なものである。放射線療法には、肝機能障害を発生する可能性のあるあらゆる放射線療法が含まれる。 The effect of prevention and improvement of liver dysfunction by kefir, which is an active ingredient according to the present invention, may be statistically significant by clinical trials, particularly in cancer patients undergoing chemotherapy or radiotherapy in cancer treatment. It has been confirmed that it is effective in preventing and improving liver dysfunction caused by other external causes. Chemotherapy includes all types of chemotherapy that administer drugs that can cause liver dysfunction, including all types of administration, especially at high concentrations. It is effective in administration methods such as hyperselective intra-arterial chemotherapy. Radiation therapy includes any radiation therapy that can cause liver dysfunction.
　以下に実施例を示して本発明を詳細に説明する。本発明は以下の実施例に限定されるものではない。 Hereinafter, the present invention will be described in detail with reference to examples. The present invention is not limited to the following examples.
［臨床試験］
　癌治療の化学療法及び放射線療法の副作用に対するケフィアの効果が、次のような癌患者に対する臨床試験によって確認された。 [Clinical trial]
The effect of kefir on the side effects of chemotherapy and radiation therapy for cancer treatment has been confirmed by the following clinical trials for cancer patients.
［対象］
Ａ群（患者Ａ～Ｅ、超選択的動注化学療法＋ケフィア投与群）
患者Ａ：男性、５０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 180mg)
患者Ｂ：女性、６０歳代、頬粘膜の扁平上皮癌、超選択的動注化学療法（CDDP 280mg)
患者Ｃ：女性、５０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 200mg)
患者Ｄ：男性、５０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 200mg)
患者Ｅ：女性、６０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 40mg)及び放射線外照射(30Gy)

Ｂ群（患者Ｋ～Ｎ、放射線療法＋ケフィア投与群）
患者Ｋ：女性、７０歳代、下顎歯肉の扁平上皮癌、術後外照射(55Gy)
患者Ｌ：男性、５０歳代、舌部の扁平上皮癌、術後外照射（50Gy)
患者Ｍ：女性、８０歳代、下顎歯肉の扁平上皮癌、根治的外照射(36Gy)
患者Ｎ：女性、８０歳代、下顎歯肉の扁平上皮癌、根治的外照射(66Gy)

Ｃ群（患者Ｆ～Ｊ、超選択的動注化学療法群、ケフィア非投与）
患者Ｆ：男性、６０歳代、上顎歯肉の扁平上皮癌、超選択的動注化学療法(CDDP 240mg)
患者Ｇ：男性、６０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 260mg)
患者Ｈ：女性、７０歳代、上顎歯肉の扁平上皮癌、超選択的動注化学療法(CDDP 220mg)
患者Ｉ：男性、５０歳代、口腔底の扁平上皮癌、超選択的動注化学療法(CDDP 240mg)
患者Ｊ：男性、２０歳代、舌部の扁平上皮癌、超選択的動注化学療法（CDDP 180mg)

Ｄ群（患者Ｏ～Ｑ、放射線療法群、ケフィア非投与）
患者Ｏ：女性、８０歳代、下顎歯肉の扁平上皮癌、術前 外照射(30Gy)
患者Ｐ：男性、６０歳代、口腔底の扁平上皮癌、術後 外照射(50Gy)
患者Ｑ：男性、５０歳代、口腔底の扁平上皮癌、術後 外照射(40Gy) [Target]
Group A (patients AE, superselective intra-arterial chemotherapy + kefir administration group)
Patient A: Male, 50s, squamous cell carcinoma of the tongue, superselective intra-arterial chemotherapy (CDDP 180mg)
Patient B: Female, 60s, squamous cell carcinoma of the buccal mucosa, superselective intra-arterial chemotherapy (CDDP 280mg)
Patient C: Female, 50s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 200mg)
Patient D: Male, 50s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 200mg)
Patient E: Female, 60s, squamous cell carcinoma of tongue, superselective intraarterial chemotherapy (CDDP 40mg) and external radiation (30Gy)

Group B (patients K to N, radiation therapy + kefir administration group)
Patient K: Female, 70s, squamous cell carcinoma of the lower gingiva, postoperative external irradiation (55Gy)
Patient L: male, 50s, squamous cell carcinoma of tongue, postoperative external irradiation (50Gy)
Patient M: Female, 80s, squamous cell carcinoma of the lower gingiva, radical external irradiation (36Gy)
Patient N: Female, 80s, squamous cell carcinoma of the lower gingiva, radical external irradiation (66Gy)

Group C (Patient FJ, Superselective intra-arterial chemotherapy group, Kefir non-administration)
Patient F: Male, 60s, squamous cell carcinoma of maxillary gingiva, superselective intra-arterial chemotherapy (CDDP 240mg)
Patient G: Male, 60s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 260mg)
Patient H: Female, 70s, squamous cell carcinoma of maxillary gingiva, superselective intra-arterial chemotherapy (CDDP 220mg)
Patient I: Male, 50s, squamous cell carcinoma of the floor of the mouth, superselective intra-arterial chemotherapy (CDDP 240mg)
Patient J: Male, 20s, squamous cell carcinoma of tongue, superselective intra-arterial chemotherapy (CDDP 180mg)

Group D (patients O to Q, radiation therapy group, kefir non-administration)
Patient O: Female, 80s, squamous cell carcinoma of the lower gingiva, preoperative external irradiation (30Gy)
Patient P: Male, 60s, squamous cell carcinoma of the oral floor, postoperative external irradiation (50Gy)
Patient Q: Male, 50s, Squamous cell carcinoma of the oral floor, Postoperative external irradiation (40Gy)
［方法］
　上記のように、超選択的動注化学療法または放射線療法を施行した１７名の口腔癌患者（患者Ａ～Ｑ）をＡ～Ｄ群の４群に分けて、Ａ群及びＢ群をケフィア投与群とし、Ｃ群及びＤ群をケフィア非投与群（対照群）として、治療中の口内炎の程度、血液データ（ＡＳＴ、ＡＬＴ）を１週間ごとに測定した。 [Method]
As described above, 17 oral cancer patients (patients A to Q) who underwent superselective intra-arterial chemotherapy or radiation therapy were divided into groups A to D, and groups A and B were administered with kefir. Group C and group D were not treated with kefir (control group), and the degree of stomatitis during treatment and blood data (AST, ALT) were measured every week.
　ケフィアの投与は、ケフィア乾燥粉末の顆粒状製剤を１回２包ずつ毎食後１回（１日あたり６包）を内服することによって行った。１包中には顆粒状製剤４ｇが含まれ、乾燥ケフィア相当量２５ｍｇ／１包であった。 The administration of kefir was carried out by taking a granular preparation of kefir dry powder, 2 capsules at a time, once after each meal (6 capsules per day). One sachet contained 4 g of a granular preparation, and the dry kefir equivalent amount was 25 mg / 1 sachet.
　口内炎の程度は、日本癌治療学会の副作用記載様式に準じて以下のようにGrade ０から４に分類した。
　Ｇｒａｄｅ０：　無
　Ｇｒａｄｅ１：　疼痛、紅斑
　Ｇｒａｄｅ２：　びらん、潰瘍
　Ｇｒａｄｅ３：　潰瘍、流動食のみ摂取
　Ｇｒａｄｅ４：　潰瘍、出血を伴う The degree of stomatitis was classified into Grades 0 to 4 as follows according to the side effect description format of the Japanese Cancer Treatment Society.
Grade 0: None Grade 1: Pain, erythema Grade 2: Erosion, ulcer Grade 3: Ingestion of ulcer and liquid food only Grade 4: With ulcer and bleeding
　口内炎の程度に対してはMann-WhitneyのＵ検定、血液データ（ＡＳＴ、ＡＬＴ）に対してはｔ検定を用いて２群間の統計処理を行った。 Statistical processing between two groups was performed using Mann-Whitney U test for the degree of stomatitis and t test for blood data (AST, ALT).
［結果］
　表１は、Ａ群（患者Ａ～Ｅ、超選択的動注化学療法＋ケフィア投与群）及びＣ群（患者Ｆ～Ｊ、超選択的動注化学療法群、ケフィア非投与）における血液データ（ＡＬＴ）の値を、化学療法開始前（第０週）から第９週までまとめた表である。 [result]
Table 1 shows blood data in group A (patients AE, superselective arterial chemotherapy plus kefir administration group) and group C (patients FJ, superselective arterial chemotherapy group, no kefir administration) It is the table | surface which put together the value of (ALT) from the chemotherapy start (week 0) to the 9th week.
Figure JPOXMLDOC01-appb-T000001
Figure JPOXMLDOC01-appb-T000001
　表２は、Ｂ群（患者Ｋ～Ｎ、放射線療法＋ケフィア投与群）及びＤ群（患者Ｏ～Ｑ、放射線療法群、ケフィア非投与）における血液データ（ＡＬＴ）の値を、放射線療法開始前（第０週）から第９週までまとめた表である。 Table 2 shows blood data (ALT) values in Group B (patients K to N, radiation therapy + kefir administration group) and Group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started. It is the table | surface summarized from the (week 0) to the 9th week.
Figure JPOXMLDOC01-appb-T000002
Figure JPOXMLDOC01-appb-T000002
　表３は、Ａ群（患者Ａ～Ｅ、超選択的動注化学療法＋ケフィア投与群）及びＣ群（患者Ｆ～Ｊ、超選択的動注化学療法群、ケフィア非投与）における血液データ（ＡＳＴ）の値を、化学療法開始前（第０週）から第９週までまとめた表である。 Table 3 shows blood data in group A (patients AE, superselective intraarterial chemotherapy plus kefir administration group) and group C (patients FJ, superselective intraarterial chemotherapy group, no kefir administration) (AST) is a table summarizing values before the start of chemotherapy (week 0) to week 9.
Figure JPOXMLDOC01-appb-T000003
Figure JPOXMLDOC01-appb-T000003
　表４は、Ｂ群（患者Ｋ～Ｎ、放射線療法＋ケフィア投与群）及びＤ群（患者Ｏ～Ｑ、放射線療法群、ケフィア非投与）における血液データ（ＡＳＴ）の値を、放射線療法開始前（第０週）から第９週までまとめた表である。 Table 4 shows blood data (AST) values in Group B (patients K to N, radiation therapy + kefir administration group) and Group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started. It is the table | surface summarized from the (week 0) to the 9th week.
Figure JPOXMLDOC01-appb-T000004
Figure JPOXMLDOC01-appb-T000004
　表５は、Ａ群（患者Ａ～Ｅ、超選択的動注化学療法＋ケフィア投与群）及びＣ群（患者Ｆ～Ｊ、超選択的動注化学療法群、ケフィア非投与）における口内炎の程度のＧｒａｄｅ評価を、化学療法開始前（第０週）から第９週までまとめた表である。 Table 5 shows the degree of stomatitis in group A (patients AE, superselective intraarterial chemotherapy plus kefir) and group C (patients FJ, superselective intraarterial chemotherapy, no kefir) Is a table summarizing the grade evaluation from before the start of chemotherapy (week 0) to week 9.
Figure JPOXMLDOC01-appb-T000005
Figure JPOXMLDOC01-appb-T000005
　表６は、Ｂ群（患者Ｋ～Ｎ、放射線療法＋ケフィア投与群）及びＤ群（患者Ｏ～Ｑ、放射線療法群、ケフィア非投与）における口内炎の程度のＧｒａｄｅ評価を、放射線療法開始前（第０週）から第９週までまとめた表である。 Table 6 shows the Grade evaluation of the degree of stomatitis in the group B (patients K to N, radiation therapy + kefir administration group) and the group D (patients O to Q, radiation therapy group, kefir non-administration) before radiation therapy started ( It is the table put together from the 0th week) to the 9th week.
Figure JPOXMLDOC01-appb-T000006
Figure JPOXMLDOC01-appb-T000006
［ＡＬＴデータの分析］
　ケフィア投与群（Ａ群及びＢ群）と、ケフィア非投与群（Ｃ群及びＤ群）とについての上記データ（表１及び表２）に対して、各患者について、治療期間中においてＡＬＴが最も高値を示した値と投与前のＡＬＴ値を比較し、下記の式に従って各患者ごとにＡＬＴ差の値を算出して、これをもとにケフィア投与群と非投与群の２群間で、ｔ検定を行った。 [Analysis of ALT data]
Compared to the above data (Tables 1 and 2) for the kefir-administered group (Groups A and B) and the non-kefir-administered group (Groups C and D), ALT was the highest during the treatment period for each patient. Compare the value showing high value with the ALT value before administration, calculate the value of ALT difference for each patient according to the following formula, and based on this, between the two groups of kefir administration group and non-administration group, A t-test was performed.
　ＡＬＴ差　＝（治療期間中のＡＬＴの最高値）－（投与前のＡＬＴの値） ALT difference = (maximum ALT value during treatment)-(ALT value before administration)
　このようにして、ＡＬＴ差についての群情報及びｔ検定（対応なし）の結果を得た。これによって得られたＡＬＴ差についての群情報を次の表７に、ｔ検定（対応なし）による結果を次の表８に示す。 In this way, group information on the ALT difference and the result of t-test (no correspondence) were obtained. The group information on the ALT difference thus obtained is shown in Table 7 below, and the result of t-test (no correspondence) is shown in Table 8 below.
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000007
Figure JPOXMLDOC01-appb-T000008
Figure JPOXMLDOC01-appb-T000008
　以上のように、ケフィア投与群（Ａ群及びＢ群）においては、対照群（Ｃ群及びＤ群）と比較して、超選択的動注化学療法や放射線治療中の肝機能障害の発生を示すＡＬＴの上昇は、有意に減少していた。（ｔ検定　p＜0.05） As described above, in the kefir administration group (Group A and Group B), compared with the control group (Group C and Group D), the occurrence of liver dysfunction during superselective intraarterial chemotherapy or radiotherapy The indicated increase in ALT was significantly reduced. (T test p <0.05)
［ＡＳＴデータの分析］
　ケフィア投与群（Ａ群及びＢ群）と、ケフィア非投与群（Ｃ群及びＤ群）とについての上記データ（表３及び表４）に対して、各患者について、治療期間中においてＡＳＴが最も高値を示した値と投与前のＡＳＴ値を比較し、下記の式に従って各患者ごとにＡＳＴ差の値を算出して、これをもとにケフィア投与群と非投与群の２群間で、ｔ検定を行った。 [Analysis of AST data]
Compared to the above data (Tables 3 and 4) for the kefir-administered group (Groups A and B) and the non-kefir-administered group (Groups C and D), AST was the highest during the treatment period for each patient. Compare the AST value before administration with the value showing high value, calculate the value of AST difference for each patient according to the following formula, and based on this, between the two groups of kefir administration group and non-administration group, A t-test was performed.
　ＡＳＴ差　＝（治療期間中のＡＳＴの最高値）－（投与前のＡＳＴの値） AST difference = (maximum AST value during treatment)-(AST value before administration)
　このようにして、ＡＳＴ差についての群情報及びｔ検定（対応なし）の結果を得た。これによって得られたＡＳＴ差についての群情報を次の表９に、ｔ検定（対応なし）による結果を次の表１０に示す。 In this way, group information on the AST difference and the result of t-test (no correspondence) were obtained. The group information regarding the AST difference obtained in this way is shown in Table 9 below, and the result of t test (no correspondence) is shown in Table 10 below.
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000009
Figure JPOXMLDOC01-appb-T000010
Figure JPOXMLDOC01-appb-T000010
　以上のように、ケフィア投与群（Ａ群及びＢ群）においては、対照群（Ｃ群及びＤ群）と比較して、超選択的動注化学療法や放射線治療中の肝機能障害の発生を示すＡＳＴの上昇は、有意傾向に減少していた。（t検定　p＜0.05）
　なお、同じ群に対して、次の式によって計算して、投与前のＡＳＴの値を基準とした百分率に換算した値を用いてｔ検定を行ったところ、ケフィア投与群（Ａ群及びＢ群）においては、対照群（Ｃ群及びＤ群）と比較して、超選択的動注化学療法や放射線治療中の肝機能障害の発生を示すＡＳＴの上昇は、有意に減少していた。（t検定　p＜0.05） As described above, in the kefir administration group (Group A and Group B), compared with the control group (Group C and Group D), the occurrence of liver dysfunction during superselective intraarterial chemotherapy or radiotherapy The increase in AST shown decreased significantly. (T test p <0.05)
For the same group, a t-test was performed using the value calculated by the following formula and converted into a percentage based on the AST value before administration, and the kefir administration group (Group A and Group B) ), The increase in AST indicating the occurrence of liver dysfunction during hyperselective arterial chemotherapy or radiotherapy was significantly reduced as compared to the control group (Group C and Group D). (T test p <0.05)
　ＡＳＴ％　＝　100％　×　（ＡＳＴ差）／（投与前のＡＳＴの値） AST% = 100% × (AST difference) / (AST value before administration)
［口内炎データの分析］
　表５及び表６に見られるように、ケフィア投与群（Ａ群及びＢ群）においては、対照群（Ｃ群及びＤ群）と比較して、口内炎の出現が遅くなる傾向が見られた。 [Analysis of stomatitis data]
As seen in Tables 5 and 6, in the kefir-administered group (Group A and Group B), there was a tendency for the appearance of stomatitis to be delayed as compared to the control group (Group C and Group D).
［結果のまとめ］
　１．ケフィア投与群（Ａ群及びＢ群）においては、対照群（Ｃ群及びＤ群）と比較して、超選択的動注化学療法や放射線治療中の肝機能障害（ＡＳＴ、ＡＬＴの上昇）の発生は、有意に減少していた。（t検定　p＜0.05）
　２．ケフィア投与群は、非投与群と比較し、口内炎の出現が遅くなる傾向が見られた。
　３．ケフィアを投与した患者群でケフィアが原因と考えられるアレルギーや副作用は全くみられなかった。また、内服指示のコンプライアンスは良好であった。 [Summary of results]
1. In the kefir-administered group (Group A and Group B), compared with the control group (Group C and Group D), liver dysfunction (increased AST and ALT) during hyperselective arterial chemotherapy and radiotherapy Outbreaks were significantly reduced. (T test p <0.05)
2. The kefir-administered group tended to delay the onset of stomatitis compared to the non-administered group.
3. There were no allergies or side effects thought to be caused by kefir in the group of patients receiving kefir. The compliance with the internal use instructions was good.
　このように、ケフィアの経口投与は、化学療法（特に超選択的動注化学療法）や放射線治療中の癌患者（特に口腔癌患者）における肝機能障害の発生を、予防する効果を有していた。さらに、いかなる副作用も見られず、安全性が高いものであると同時に、全ての患者において服用の中断は見られず、内服が容易なものであった。 Thus, oral administration of kefir has the effect of preventing the occurrence of liver dysfunction in cancer patients (especially oral cancer patients) undergoing chemotherapy (especially hyperselective arterial chemotherapy) and radiation therapy. It was. Furthermore, no side effects were observed and the safety was high. At the same time, no interruption was observed in all patients, and oral administration was easy.
　本発明に係る肝機能障害の予防剤は、肝機能の障害の予防、特に癌治療の化学療法及び放射線療法の副作用である肝機能の障害の予防の効果を有しており、有用なものである。本発明は、臨床的に確認された統計的に有意な効果を有する予防剤を、初めて提供するものである。 The preventive agent for hepatic dysfunction according to the present invention has an effect of preventing hepatic dysfunction, particularly prevention of hepatic dysfunction which is a side effect of chemotherapy and radiotherapy for cancer treatment. is there. The present invention provides for the first time a clinically confirmed prophylactic agent having a statistically significant effect.

Claims (6)

  1. 　ケフィアを有効成分として含有してなる、肝機能障害の予防剤。 A preventive agent for liver dysfunction, containing kefir as an active ingredient.
  2. 　肝機能障害が、癌の治療のための化学療法及び／又は放射線療法の副作用による肝機能障害である、請求項１に記載の予防剤。 The preventive agent according to claim 1, wherein the liver dysfunction is liver dysfunction due to side effects of chemotherapy and / or radiation therapy for cancer treatment.
  3. 　癌が口腔癌である、請求項１～２の何れかに記載の予防剤。 The preventive agent according to any one of claims 1 to 2, wherein the cancer is oral cancer.
  4. 　ケフィアを有効成分として含有してなる、肝機能障害の改善剤。 ∙ An agent for improving liver dysfunction, containing kefir as an active ingredient.
  5. 　肝機能障害が、癌の治療のための化学療法及び／又は放射線療法の副作用による肝機能障害である、請求項４に記載の改善剤。 The liver dysfunction is an improving agent according to claim 4, wherein the liver dysfunction is a liver dysfunction caused by side effects of chemotherapy and / or radiation therapy for cancer treatment.
  6. 　癌が口腔癌である、請求項４～５の何れかに記載の改善剤。 The improving agent according to any one of claims 4 to 5, wherein the cancer is oral cancer.
PCT/JP2009/006588 2008-12-03 2009-12-03 Prophylactic agent for hepatic function disorders WO2010064434A1 (en)

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