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WO2006051997A1 - Agent inducteur de cystéine dioxygénase - Google Patents

Agent inducteur de cystéine dioxygénase Download PDF

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Publication number
WO2006051997A1
WO2006051997A1 PCT/JP2005/020985 JP2005020985W WO2006051997A1 WO 2006051997 A1 WO2006051997 A1 WO 2006051997A1 JP 2005020985 W JP2005020985 W JP 2005020985W WO 2006051997 A1 WO2006051997 A1 WO 2006051997A1
Authority
WO
WIPO (PCT)
Prior art keywords
cystine
dioxygenase
chain amino
cysteine
metabolism
Prior art date
Application number
PCT/JP2005/020985
Other languages
English (en)
Japanese (ja)
Inventor
Makoto Shimizu
Hideo Satsu
Asami Kawakami
Kenji Takehana
Original Assignee
Toudai Tlo, Ltd.
Ajinomoto Co., Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toudai Tlo, Ltd., Ajinomoto Co., Inc. filed Critical Toudai Tlo, Ltd.
Publication of WO2006051997A1 publication Critical patent/WO2006051997A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES, NOT OTHERWISE PROVIDED FOR; PREPARATION OR TREATMENT THEREOF
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/175—Amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to an inducer of cysteine dioxygenase (CDO) containing a branched chain amino acid, a pharmaceutical composition containing the same, and a food or drink containing the branched chain amino acid.
  • CDO cysteine dioxygenase
  • Cystin dioxygenase is mainly expressed in the liver and is one of the major enzymes in cystine metabolism and plays an important role in the quantitative regulation of sulfur-containing amino acids in vivo. It is known to fulfill. Chronically elevated cysteine levels are known to function as neurotoxins that are excitable for neurons (McFadden et al., “Toxicology”, Ireland), 1 9 9 6th, 1 1 1st, P. 4 3— 6 5). On the other hand, Parkinson's disease (Steventon et al., “Neurology”, (USA), 1 9 8 9th, Vol. 39, P.
  • Tumor growth factor] 3 (TG F ⁇ ), one of the inflammatory site ins, is also associated with multiple sclerosis, Parkinson's disease, AIDS dementia, Alach It has been suggested that neurodegenerative diseases such as Imah's disease are related to the progression of the disease, but the details are not clear (Pratt et al., “Site Force In & Growth Factor Leviuse (Cytokine Growth Factor Rev.) ", (UK), 1 997, 8th (4), P. 2 6 7-2 9 2).
  • An object of the present invention is to provide an excellent cysteinoxygenase (CDO) inducer.
  • the object of the present invention is to treat a disease caused by a cystine metabolism disorder (a neurological disease such as Parkinson's disease or Hallervorden-Spatz disease) and a drug for preventing or preventing cysteine metabolism abnormalities.
  • a cystine metabolism disorder a neurological disease such as Parkinson's disease or Hallervorden-Spatz disease
  • a drug for preventing or preventing cysteine metabolism abnormalities to provide ingredients.
  • the present inventors have found that branched-chain amino acids have an excellent CDO gene expression-inducing action, and further, the pathogenesis of various diseases. It was also found that the inflammatory cytokine TGF] 3 involved in the progression suppresses the expression of CDO, and that branched-chain amino acids release the suppression, thereby completing the present invention. That is, the present invention provides a branched chain buffer. Provided is a CDO inducer comprising a mino acid.
  • the present invention also provides a pharmaceutical product for treating and / or preventing a disease caused by an abnormal cystine metabolism (a neurological disease such as Parkinson's disease or Hal lervorden-Spatz disease) characterized by containing the above-mentioned CDO inducer.
  • the present invention provides an active ingredient of a food or drink for improving metabolic disorders.
  • a therapeutic or prophylactic agent for diseases caused by abnormal cystine metabolism comprising the cystine dioxygenase inducer according to any one of [1] to [4];
  • the disease caused by abnormal cysteine metabolism is selected from the group consisting of Parkinson's disease, Al-Haima disease, and rheumatoid arthritis [5]
  • a food and drink for improving cystine metabolism disorder characterized by containing a branched chain amino acid
  • a method for inducing cysteine dioxygenase comprising administering an effective amount of a branched chain amino acid to an administration subject;
  • a method for treating or preventing a disease caused by abnormal cysteine metabolism comprising administering an effective amount of a cysteine dioxygenase-inducing agent containing a branched chain amino acid to a subject of administration;
  • FIG. 1 shows the suppression of mRNA expression of CDO gene by TGF] 3.
  • Figure 2 shows the induction of mRNA expression of CDO gene by branched chain amino acids. It is a figure.
  • FIG. 3 is a diagram showing the mRNA expression induction action of a branched chain amino acid-specific CDO gene.
  • FIG. 4 is a diagram showing (A) enhancement of CDO gene promoter activity by branched chain amino acids, (B) suppression of CDO gene promoter activity by TGF and enhancement effect by BCAA.
  • FIG. 5 is a diagram showing the mRNA expression induction effect of CDO gene by branched chain amino acids in a cirrhosis model rat.
  • the branched chain amino acid in the present invention refers to those containing at least one of isoleucine, valine, and oral isocyanic branched chain amino acids, each of which may be used alone or in combination of two or more. It may be a combination of these, or may include all three types.
  • Induction of CDO in the present invention refers to an action of increasing the amount of CDO in vivo, particularly CDO in the liver, and is not particularly limited in its mechanism, but induces the expression of CDO gene and / or It is preferably an action that enhances or activates transcription of the CD O gene promoter. Furthermore, since TGF i3 suppresses the expression of the CDO gene or suppresses transcription from the CDO gene promoter, suppression of the action of TGF / 3 is also included in the induction of CDO.
  • the CDO gene is a gene having a base sequence represented by ⁇ -001801 or its equivalent (for example, a variant including SNP and haplotype) in NCBI Reference Sequences (RefSeq) in humans, for example. Or a mammalian ortholog, etc., which encodes a protein with an Enzyme Commission Number force S, EC 1 ⁇ 13.11.20, as defined by the International Biochemical Union.
  • the branched chain amino acid which is an active ingredient of the CDO inducer of the present invention, is always used. It is not necessary to be used as a free amino acid, and it may be used in the form of a salt or an ester that can be hydrolyzed in vivo (for example, an ester with an alcohol that can be used as a prodrug of a pharmaceutical product). Good.
  • the salt form include acid addition salts and salts with bases, and it is preferable to select a salt of a branched chain amino acid that is acceptable as a pharmaceutical or a food or drink.
  • acids that are added to branched chain amino acids to form salts that are acceptable as pharmaceuticals or foods and drinks include inorganic salts such as hydrogen chloride, hydrogen bromide, sulfuric acid, and phosphate, acetic acid, lactic acid, citrate, Organic acids such as tartaric acid, maleic acid, fumaric acid or monomethyl sulfuric acid can be mentioned.
  • bases acceptable as pharmaceuticals or foods and drinks of branched chain amino acids include, for example, metal hydroxides or carbonates such as sodium, potassium and calcium, salts with inorganic bases such as ammonia, ethylenediamine And salts with organic bases such as propylenediamine, ethanolamine, monoalkyl / reethanolamine, dialkylethanolamine, diethanolamine, and triethanolamine.
  • branched chain amino acids or peptides in which a branched amino acid other than a branched chain amino acid and a branched chain amino acid are peptide-bonded (eg, dipeptide, tripeptide, oligopeptide, etc.)
  • peptides are also branched chain amino acids as referred to in the present invention.
  • the branched chain amino acid is in the form of a peptide
  • the content of the branched chain amino acid in the peptide is preferably 10% or more, more preferably 25% or more, and still more preferably 50% or more.
  • amino acids other than branched chain amino acids include glycine, alanine, serine, threonine, aspartate, glutamate, asparagine, gnoretamine, lysine, hydroxylysine, arginine, cysteine, cystine, methionine, Examples include phenylalanine, tyrosine, tryptophan, histidine, proline, and 4-hydroxyproline.
  • any of L-integral, D-form, and DL-form can be used. However, L integration is desirable from the viewpoint of natural existence.
  • the C D O inducer of the present invention may be composed only of a branched chain amino acid, but may contain a pharmaceutical carrier described later, or may be contained in a general food or drink.
  • the CDO inducer of the present invention preferably contains about 0.1 1 to 10 g of branched chain amino acids, more preferably about 0.1 to 10 g, and even more preferably 1 to 10 g. Degree.
  • the C D O inducer of the present invention can be administered orally, intravenously, subcutaneously, or intramuscularly, but oral administration is preferred because of its simplicity.
  • the dose varies depending on the subject to be administered, but is usually 0.1 to 30 g Z k g Z days.
  • parenteral administration such as infusion administration, injection administration (intravenous administration), etc.
  • the preferred dosage (ingestion amount) for oral administration is as follows. About 10 to 20 times of the range can be administered.
  • the CDO inducer of the present invention can be formulated by a conventional method.
  • the form of the preparation is tablets, granules, fine granules, powders, capsules, solids such as chupuls, solutions such as solutions and syrups, or creams, suppositories, injections, sprays , Etc.
  • Examples of the carrier for the preparation include lactose, glucose, D-mannitol, starch, crystalline cellulose, calcium carbonate, kaolin, starch, gelatin, hydroxypropyl senorelose, hydroxypropinoremethizolecenorelose, polyvinyl pyrrolopyrrole Don, Ethanol / Les, Canolepoxymethyl senorelose, Canolepoxy methinolece Norellose chanoleum salt, Magnesium stearate, Talc, Acetinole Cellulose, Sucrose, Titanium oxide, Benzoic acid, Paraoxybenzoate ester, De Sodium hydroacetate, gum arabic, tragacanth, methylsenololose, egg yolk, surfactant, sucrose, simple syrup, citrate, distilled water, ethanolate, glycerin.
  • Propyleneglycone, macrogonore, phosphate There are sodium monohydrogen, sodium dihydrogen phosphate, sodium phosphate, bud sugar, sodium chloride, phenol, thimerosal, paraoxybenzoate, sodium hydrogen sulfite, etc. Used in combination with CDO inducers.
  • the C D O inducer of the present invention is useful for mammals (eg, mice, rats, hamsters, rabbits, cats, dogs, sushi, Hedges, monkeys, humans, etc.).
  • mammals eg, mice, rats, hamsters, rabbits, cats, dogs, sushi, Hedges, monkeys, humans, etc.
  • the administration form to animals other than humans may be addition to feed.
  • the C D O inducer of the present invention can be formulated into various pharmaceutical preparations to be developed in the future. Methods that will be developed in the future can be used as appropriate.
  • the C D O inducer of the present invention in the preparation form exemplified above should contain an effective amount of the above-mentioned components to exert a medicinal effect.
  • an effective amount of the above-mentioned ingredients should be contained to have a medicinal effect is also applicable to the use in medicines and foods and drinks described below.
  • the C D O inducer of the present invention is useful for patients with diseases caused by abnormal cysteine metabolism.
  • diseases caused by abnormal cysteine metabolism include neurological diseases such as Parkinson's disease, Alzheimer's disease, Hal lervorden- Spatz disease, rheumatoid arthritis, motor neuron diseases (for example, amyotrophic lateral cords). Sclerosis) and delayed food hypersensitivity.
  • the C D O inducer of the present invention can be used as a pharmaceutical product. Since the active ingredient is an amino acid, it is excellent in safety and can be used easily. When used as a medicine, the form is not particularly limited, and the above preparation may be used as it is.
  • the present invention provides a therapeutic or prophylactic agent for diseases caused by abnormal cystine metabolism, which contains a CDO inducer.
  • the treatment and / or prevention of a disease caused by abnormal cysteine metabolism also includes suppressing the occurrence / progress of the disease caused by abnormal cysteine metabolism.
  • a therapeutic or prophylactic agent or other pharmaceutical composition for diseases caused by abnormalities in cystine metabolism such as Parkinson's disease or Hallervorden-Spatz disease
  • cystine metabolism such as Parkinson's disease or Hallervorden-Spatz disease
  • 1 preparation it is preferable to contain about 0.1 to 10 g of branched chain amino acids, more preferably about 0.1 to 10 g, and still more preferably about 1 to 10 g.
  • the therapeutic or prophylactic agent for diseases caused by cysteine metabolism abnormalities according to the present invention it can be administered orally, intravenously, subcutaneously, or intramuscularly. However, oral administration is preferred because of its simplicity.
  • the dose varies depending on the patient's symptoms, age, and method of administration, but is usually 0.1 to 3 0 ⁇ 1 ⁇ ⁇ "days.
  • parenteral administration such as infusion administration, injection administration (intravenous administration), etc.
  • the preferred dosage (ingestion amount) for oral administration is as follows. About 10 to 20 times of the range can be administered.
  • the present invention also provides a food or drink characterized by containing a branched chain amino acid.
  • the food / drink exhibits an effect of inducing cysteine dioxygenase, an effect of enhancing the expression of cysteine dioxygenase gene, and an effect of suppressing the action of TGF] 3, and is therefore effective as a food / drink for improving cystine metabolism abnormality.
  • Examples of the branched chain amino acids contained in the food / beverage products of the present invention include the same as those mentioned above for the C D O derivative.
  • the form is not particularly limited, and the food and drink may contain only the amount necessary to exert the CDO inducing effect of the branched chain amino acid.
  • the food and drink may include animal feed.
  • the intake is usually 0.1 to 30 g / kg Z days, although it varies depending on the type, age, and method of intake.
  • the food and drink of the present invention is useful for mammals (eg, mouse, rat, hamster, usagi, cat, inu, ushi, hidge, monkey, human etc.).
  • mammals eg, mouse, rat, hamster, usagi, cat, inu, ushi, hidge, monkey, human etc.
  • the active ingredient is an amino acid
  • it is excellent in safety and can be easily used in the form of food and drink.
  • foods and drinks can be mixed with juice, milk, confectionery, jelly and the like.
  • Such foods and drinks are also included.
  • These health functional foods are labeled foods and drinks that are used to improve cystine metabolism abnormalities, especially for specific health use. Foods etc. are also included.
  • the food-drinks of this invention when using the food-drinks of this invention as a food supplement etc., it can prepare in forms, such as a tablet, a capsule, a powder, a granule, a suspension agent, a chewable agent, a syrup agent, for example.
  • the expression level of CD ⁇ mRNA decreased depending on the concentration of TGF (Fig. 1).
  • Hep G 2 cells were seeded on a collagen-coated 60 mm dish and cultured overnight in DMEM medium containing 10% FBS until reaching about 70% confluence. The medium was removed, washed with PBS, replaced with serum-free DMEM medium containing 0.1% BSA, and cultured for 2 hours. Next, after removing the medium and washing with PBS, the medium was replaced with an amino acid-deficient medium in which only methionine was added to amino acid-free DMEM at a concentration of 3 O mg / L and cultured for 2 hours.
  • BCAA branched chain amino acid
  • B CAA enhances CDO mRNA expression by TGF] 3 treatment.
  • the CDO mRNA level which was also observed under physical conditions and decreased by TGF treatment, recovered to near the control level by adding BCAA (Fig. 2).
  • Example 3 Induction of mRNA expression of CD 0 gene by branched chain amino acid in human hepatoma cell line Hep G 2 cells
  • Hep G 2 cells are cultured under the same conditions as in Example 2.
  • 3 O mg / L methionine, 2 mM BCAA mixture, or any one of individual branched chain amino acids, phenylalanin, and cysteine The cells were cultured for 16 hours in an amino acid-deficient DMEM medium containing.
  • Activation of mT OR is via phosphorylation of S 6 K 1 and 4 E—B P 1: it accelerates the translation initiation stage of mRNA and enhances gene expression at the protein level. Therefore, we investigated the involvement of mT O R in the effect of B C A A observed in the regulation of CD0 gene expression.
  • Hep G 2 cells were cultured in a medium containing only methionine for 2 hours, they were treated with 25 ng / m 1 of rapamycin after 1 hour and a half, and 30 minutes later, 2 mM BCAA was added and cultured for 16 hours. As a result, the increase in the mRNA expression level of CDO by B CAA was not suppressed by rapamycin treatment (Fig. 3 (B)).
  • a genomic sequence from about 2.5 kb upstream to about 2.3 kb downstream of the transcription start site of the human CDO gene is inserted into the commercially available luciferase reporter gene pGL 3 basicvector P romeg a
  • the reporter gene pGL3-CD04 integrated into the cloning site of Madison, Wis.) was constructed and transfected into Hep G2 cells.
  • C DO specific primer sense primer sequence: 5'-GAG AACGT CAG C CACACAG-3 '(SEQ ID NO: 1)
  • antisense primer sequence 5'-TTG CT GT GGAATGT CATGG-3' (SEQ ID NO: 2)
  • the CD O mRNA expression level was quantified. Quantitative results were expressed as a percentage, with the average value of normal rat being 100%, with the value corrected using GAP DH as an internal standard (Fig. 5). In the normal diet group of the cirrhosis model rat, the CD O mRNA mRNA expression level in the liver decreased to 50% or less of the normal rat, but in the BCAA diet group, it recovered to the normal level.
  • BC AA is effective in restoring the decreased CDO gene expression level in the liver of cirrhosis model rat.
  • the inducer of cystine dioxygenase (CDO) containing a branched chain amino acid provided by the present invention is useful for the treatment and / or prevention of diseases caused by abnormal cysteine metabolism.
  • this inducer since this inducer has an amino acid as an active ingredient, it is highly safe and has few side effects, so it is advantageous not only for pharmaceuticals but also for food and drink.
  • the inducer of cysteine dioxygenase comprising a branched chain amino acid provided by the present invention has excellent cysteine dioxygenase-inducing activity.
  • the pharmaceutical composition of the present invention contains amino acid as an active ingredient, it is highly safe and has few side effects. Therefore, it can be administered for a long period of time, and is a disease caused by abnormal cysteine metabolism (Parkinson's disease). Can be advantageously used for the treatment and prevention or prevention of neurological diseases such as Hallervorden-Spatz disease.
  • the food and drink for improving cystine metabolism abnormality of the present invention also uses amino acid as an active ingredient, it is highly safe and can be consumed over a long period of time. It is effective to prevent it.

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  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
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  • Biomedical Technology (AREA)
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  • Pain & Pain Management (AREA)
  • Hospice & Palliative Care (AREA)
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  • Psychology (AREA)
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Abstract

La présente invention a pour objet un excellent agent inducteur de cystéine dioxygénase, ainsi qu’un aliment ou une boisson susceptible de réparer une anomalie dans le métabolisme des cystéines. Ledit agent comprend un acide aminé ramifié. La présente invention a également pour objet une préparation thérapeutique incluant ledit agent. Ledit aliment ou ladite boisson contiennent un acide aminé ramifié.
PCT/JP2005/020985 2004-11-09 2005-11-09 Agent inducteur de cystéine dioxygénase WO2006051997A1 (fr)

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JP2004324700 2004-11-09
JP2004-324700 2004-11-09

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0276813A (ja) * 1988-05-06 1990-03-16 Ajinomoto Co Inc 神経変性疾患の治療薬
JPH05339148A (ja) * 1992-05-28 1993-12-21 T Knight Albert 血液脳関門を通過する物質
WO2002060431A1 (fr) * 2001-01-30 2002-08-08 Ajinomoto Co., Inc. Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires
JP2004292437A (ja) * 2003-03-10 2004-10-21 Masami Moriyama 異常プリオン蛋白質の増殖の抑制方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0276813A (ja) * 1988-05-06 1990-03-16 Ajinomoto Co Inc 神経変性疾患の治療薬
JPH05339148A (ja) * 1992-05-28 1993-12-21 T Knight Albert 血液脳関門を通過する物質
WO2002060431A1 (fr) * 2001-01-30 2002-08-08 Ajinomoto Co., Inc. Medicaments therapeutiques/prophylactiques contre des maladies inflammatoires
JP2004292437A (ja) * 2003-03-10 2004-10-21 Masami Moriyama 異常プリオン蛋白質の増殖の抑制方法

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