WO2016121892A1 - Composé formant un agent d'amélioration de l'infertilité - Google Patents

Composé formant un agent d'amélioration de l'infertilité Download PDF

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Publication number
WO2016121892A1
WO2016121892A1 PCT/JP2016/052548 JP2016052548W WO2016121892A1 WO 2016121892 A1 WO2016121892 A1 WO 2016121892A1 JP 2016052548 W JP2016052548 W JP 2016052548W WO 2016121892 A1 WO2016121892 A1 WO 2016121892A1
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Prior art keywords
infertility
activity
extract
fruit
administration
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PCT/JP2016/052548
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English (en)
Japanese (ja)
Inventor
正雄 神野
道生 山田
祥子 竹下
知広 上村
Original Assignee
正雄 神野
林兼産業株式会社
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Priority claimed from JP2015088110A external-priority patent/JP6077045B2/ja
Application filed by 正雄 神野, 林兼産業株式会社 filed Critical 正雄 神野
Priority to US15/126,331 priority Critical patent/US20170165313A1/en
Priority to AU2016213061A priority patent/AU2016213061B2/en
Priority to EP16743495.0A priority patent/EP3251681B1/fr
Publication of WO2016121892A1 publication Critical patent/WO2016121892A1/fr

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    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • 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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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 a composition for improving infertility that is safe and highly active and applicable to a wide range of symptoms related to infertility.
  • infertility refers to “a state in which pregnancy is not achieved for more than 12 months even though there is sufficient sex without contraception.” Infertility has both a cause on the male side and a cause on the female side. The former is called male infertility and the latter is called female infertility. As a cause of male infertility, for example, the following factors can be considered. (1) Impaired spermatogenic function: azoospermia, oligospermia, asthenozoospermia, etc., and is said to account for about 90% of male infertility.
  • Ovulation disorder Central ovulation disorder (endocrine failure), ovarian dysfunction, ovarian cyst, luteal unruptured follicle, hyperprolactinemia, etc.
  • Fallopian tube failure fallopian tube adhesion, fallopian tube stenosis, fallopian tube Obstruction, fallopian tube edema, etc.
  • Cervical disorders Cervical mucus failure, anti-sperm antibody formation, cervical stenosis, etc.
  • Endometriosis Chocolate cyst, uterine adenomyosis, etc.
  • Implantation disorder Uterus Myoma, uterine malformation, luteal dysfunction, endometrial polyp, etc.
  • Treatment methods for male infertility include sperm collection from semen, vas deferens, and testis and drug therapy such as artificial insemination, microinsemination, and hormone replacement therapy.
  • examples of treatment methods for female infertility include administration of an ovulation inducer, ovulation disorders, cervical mucus insufficiency, hyperprolactinemia, etc., advanced reproductive medicine such as artificial insemination and in vitro fertilization.
  • an ovulation inducer clomiphene (for example, refer to Patent Document 1), an internal medicine such as cyclophenyl, and an injection such as gonatotropin are widely used.
  • Dopaminergic drugs such as bromocriptine, terguride and cabergoline are used for pharmacotherapy for hyperprolactinemia. Moreover, it has been reported that the pregnancy rate of polycystic ovary syndrome and non-polycystic ovary syndrome improves by administering the insulin sensitizer metformin (see Non-Patent Document 1).
  • infertility may involve multiple factors in addition to the above factors, such as glycation stress due to lifestyle-related diseases and allergic diseases (for example, Shinji Komori, “Clinical Conference”). (Reproductive endocrine region): 1.
  • the present invention has been made in view of such circumstances, and an object thereof is to provide a composition for improving infertility that is safe and has high activity and can be applied to a wide range of symptoms related to infertility.
  • the present invention that meets the above-described object provides a composition for improving infertility, which comprises, as an active ingredient, one or more compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae.
  • the present invention solves the above problems.
  • the active ingredient contains one or a plurality of compounds separated from the extract of one or both of the fruit skin and the fruit or the extract.
  • the infertility improving composition of the present invention preferably has an activity to inhibit one or more reactions related to the production of a terminal glycation product from protein and sugar.
  • the infertility improving composition of the present invention preferably has an activity of promoting one or more reactions related to the degradation of the terminal glycation product.
  • the infertility improving composition of the present invention preferably has an activity of reducing allergic symptoms.
  • the active ingredient of the composition for improving fertility of the present invention is one or a plurality of compounds contained in one or both of the skin and the fruit of a plant belonging to the family Chinaceae with dietary experience. Therefore, safety has been confirmed, and it has a high infertility improving activity.
  • a safe and highly active fertility improving composition is provided.
  • 3 is a graph showing measurement results of ⁇ -dicarbonyl bond cleavage activity. It is a graph which shows the measurement result of AGE bridge
  • infertility improving composition according to an embodiment of the present invention (hereinafter, also referred to as “infertility improving composition” or simply “composition”) may be used for the pericarp and fruit of the Chinaceae plants.
  • infertility improving composition may be used for the pericarp and fruit of the Chinaceae plants.
  • One or more compounds contained in one or both are included as active ingredients.
  • pericarp and fruit of the Chinaceae plant which is an active ingredient
  • pulverized or finely divided pericarp and fruit In the case of production of a composition used as an injection, for example, fruit juice and one or both of fruit and fruit peel extracts are preferably used.
  • the one or more compounds contained in one or both of the pericarp and fruit of the Chestnut plant are preferably one or both of the pericarp and fruit extract or one or more compounds separated from the extract.
  • the preparation method of the extract of one or both of a fruit skin and a fruit is explained in full detail.
  • the fruits and pericarps of the Chinaceae plants may be raw fruits or those collected from raw fruits, dried after collection, dried fruits or those collected from dried fruits.
  • pretreatment such as crushing or pulverization may be performed using any method before solvent extraction.
  • Chrysanthemum plant used for extraction there are no particular restrictions on the Chrysanthemum plant used for extraction, but specific examples include horsetail (Trapa japonica), sea bream (Trapa natans L. ver. It is done.
  • water, an aqueous solution, a mixed solvent (aqueous solvent) obtained by mixing water in an arbitrary ratio with any one or more solvents miscible with water can be used.
  • Water, methanol, ethanol, and an aqueous solvent in which any two or more of these are mixed in an arbitrary ratio, and particularly preferable extraction solvents are water, ethanol and water which are organic solvents recognized as food additives, and water. It is the aqueous solvent mixed in the ratio.
  • the temperature of the extraction solvent may be any temperature that exceeds room temperature and is not higher than the boiling point of the extraction solvent, but is preferably determined in consideration of extraction efficiency, heat resistance and volatility of the extraction target, and the like.
  • an acid, a base, a salt, and the like may be appropriately included as necessary in order to improve extraction efficiency.
  • the temperature and pH of water used for extraction are not particularly limited, but the pH is preferably near neutral, more specifically pH 4-9, more preferably 6-8, considering use in living organisms. More preferably. If necessary, a heated extraction solvent may be used in order to improve the extraction efficiency.
  • Hot water extraction can be performed by any known method. For example, after mixing one or both of pericarp and fruit of a Chinaceae plant in a solvent for a predetermined time, it is separated from a solid content by filtration, centrifugation, decantation, or the like. Or a continuous extraction method such as a Soxhlet extraction method can be used.
  • Pre-treatment by dialysis, ultrafiltration, filtration, column chromatography, etc. to remove high molecular weight components and insolubles before separating one or more compounds from the solvent extract of persimmon skin May be performed.
  • an adsorbent such as activated carbon, bentonite, or celite or a filter aid may be added as necessary to remove impurities.
  • an adsorbent such as activated carbon, bentonite, or celite or a filter aid
  • Separation of the hot water extract subjected to the pretreatment as described above as necessary can be performed using any known method such as column chromatography, reverse phase chromatography, ion chromatography, and the like, which will be described later. It can be carried out by fractionating various highly active fractions that seem to be related to the improvement of infertility.
  • AGEs Advanced glycation end products
  • Maillard reaction products are protein derivatives with various structures that are generated by non-enzymatic reactions between reducing sugars such as glucose and amino groups of proteins. It is.
  • AGEs can be produced in various ways as a result of cellular functions caused by glycation modification of extracellular matrix proteins, membrane proteins, and intracellular proteins, as well as the breakdown of the functions of these proteins and their dependent cellular functions, or by receptors using AGEs as ligands. Involved in the onset and exacerbation of lesions.
  • AGEs are recognized by RAGE, one of the AGEs receptors, the production of intracellular oxidative stress substances by intracellular NADPH oxidase is enhanced, and this changes the gene expression in epithelial cells, thereby causing various diabetic properties. Vascular disorders are thought to develop.
  • AGEs have been developed in addition to diabetic vascular disorders, cardiovascular disorders such as myocardial infarction and arteriosclerosis, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis, and brains caused by alcoholism.
  • diabetic nephropathy, diabetic retinopathy, diabetic complications such as diabetic neuropathy, bone metabolism abnormalities such as osteoporosis, aging phenomenon, insulin resistance, tumor growth and metastasis It is suggested that
  • Diabetes is known to be one of the causes of infertility and irregular menstruation. Although the mechanism is not always clear, insulin resistance plays an important role in the mechanism of ovulation due to insulin resistance, and damage to the ovaries, fallopian tubes, cervix, endometrium by AGEs, etc. Conceivable. Gestational diabetes is a risk factor such as premature detachment of the placenta, premature birth and stillbirth, abnormal growth of the fetus due to excessive carbohydrate supply, and hypoglycemia after birth.
  • the reactions to be inhibited by the infertility improver composition are the generation of Schiff bases by the reaction of protein amino groups and reducing sugars, 1,2-enaminol by 2, Amadori rearrangement, or 2, It may be any one or more reactions such as the production of 3-enediol, degradation of the Amadori transfer product and the polymerization product of the degradation product with amino acids, peptides or proteins.
  • the activity of inhibiting one or more reactions related to the generation of AGEs from proteins and sugars is, for example, AGEs produced by reacting serum proteins such as human serum albumin with glucose (for example, 60 ° C., 40 hours).
  • activities that may be related to the improvement of infertility include activities that promote one or more reactions related to the degradation of advanced glycation end products (AGEs).
  • Reactions related to the degradation of AGEs include the production of Schiff bases by the reaction of protein amino groups with reducing sugars, the production of 1,2-enaminol or 2,3-enediol by Amadori rearrangement, and the degradation of Amadori transfer products. And a reaction that cleaves a bond formed by the formation of a polymerization product of the degradation product and an amino acid, peptide, or protein.
  • reaction used for evaluating the activity that promotes the reaction related to the degradation of AGEs include And a reaction that cleaves an ⁇ -dicarbonyl bond peculiar to AGEs, a reaction that cleaves a crosslink formed by a reaction between a protein such as collagen and AGEs, and the like.
  • Allergic diseases such as atopic dermatitis, allergic rhinitis, and hay fever have been pointed out to be associated with endometriosis and are also said to cause infertility due to the immune system.
  • the mechanism by which one or more compounds contained in one or both of the pericarp and the fruit of the Chinaceae plant alleviate allergic symptoms and its relationship with improvement of infertility are not necessarily clear, but contain such compounds as active ingredients It has been confirmed that an infertility improving composition can reduce allergic symptoms and improve infertility.
  • the composition for improving infertility By mixing the composition for improving infertility with a carrier or the like, it can be used as a pharmaceutical composition having one or both of a therapeutic effect and a preventive effect for diabetes and related diseases and symptoms.
  • the dosage form of the pharmaceutical composition for humans or animals include oral, rectal, parenteral (for example, intravenous administration, intramuscular administration, subcutaneous administration, etc.), and the dosage is the formulation of the pharmaceutical composition.
  • the active ingredient generally contained in the formulation is difficult to determine and uniquely determined depending on the administration method, purpose of use, and age, weight, and symptoms of the subject to be applied.
  • the amount is preferably 0.1 to 2000 mg / day per day for an adult.
  • an amount smaller than the above dosage may be sufficient or may be necessary beyond the above range.
  • the above-mentioned desired dosage form can be prepared by blending an infertility improving composition with a pharmaceutically acceptable carrier or diluent, a stabilizer, and other desired additives.
  • the food containing the infertility improving agent composition can take any form commonly used for foods or supplements, such as those obtained by blending the infertility improving composition with food, or capsules, tablets, and the like.
  • the type of food to be blended for example, liquid (fluid) foods such as coffee, fruit juice, soft drinks, beer, milk, miso soup, soup, tea, tea, nutrients, syrup, margarine, jam, etc.
  • it may be formed into a powder, granule, tablet or the like.
  • an improving agent composition can also be added and administered to feed. That is, a food containing an infertility improving composition as an active ingredient can be safely added to livestock such as pigs, cows, horses, sheep, and feed such as pets (dogs, cats). It can be used as a functional feed having activity to improve infertility.
  • the present invention relates to a method for improving human infertility by administering a composition for improving infertility containing one or more compounds contained in one or both of the pericarp and fruits of Chinaceae as an active ingredient and non-human It also provides a method for improving infertility in other mammals.
  • Example 1 Preparation of an extract of persimmon pericarp and oral administration containing the same
  • a hot water extract of a Coriaceae plant hereinafter abbreviated as "Hoshi pericarp extract” bispinosa
  • the extract was concentrated at a predetermined concentration rate that was determined in advance so as to be 25% by weight or more.
  • Example 2 Effect of continuous administration of Hoshi peel extract on blood glucose level, blood AGEs concentration, blood cholesterol concentration 50 female subjects were divided into Hishi peel extract administration group and placebo administration group (25 each), For 12 weeks, the former contains an extract of persimmon peel (referred to as “Hishi extract” in Tables 1 to 6 and FIGS. 1 and 2), a placebo for the latter, The dose described in Example 1 (2) above was administered in a double-blind manner. Every 4 weeks, blood tests (blood HbA1c concentration, blood neutral lipid concentration, blood cholesterol concentration (total cholesterol concentration, HDL-cholesterol concentration and LDL-cholesterol concentration), blood pentosidine concentration measurement) are measured. went. The respective measurement results are shown in Tables 1 to 6.
  • 0W”, “4W”, “8W” and “12W” represent the results of the 0th, 4th, 8th and 12th weeks, respectively, and “Mean” is the average value. “SD” represents standard deviation, “SE” represents standard error, and “Wilcoxon” represents the result of Wilcoxon's sign rank test.
  • Example 3 Effect of administration of an extract of persimmon peel on postprandial blood glucose level For 4 subjects (average age 28.7 years old, 1 male, 3 females) whose fasting blood glucose level was 70 to 110 mg / dL The test was conducted according to the following protocol.
  • fasting blood glucose was measured at 8:00 on the day of the study, and then an oral preparation containing placenta extract or placebo was administered (double blind) The test method was used.) After 5 minutes, eat 200g of cooked rice + 2.5g of sprinkles (total calorie 308kcal, carbohydrate amount 70.2g) as a loaded meal, 15 minutes, 30 minutes, 45 minutes, 60 minutes, 90 minutes and 120 minutes after eating The blood glucose level was measured.
  • Example 4 Measurement of ⁇ -Dicarbonyl Bond Cleavage Activity
  • the dicarbonyl bond cleavage activity was determined by measuring the benzoic acid concentration obtained by decomposing 1-phenyl-1,2-propanedione (PPD), which is a dicarbonyl compound, by HPLC. It calculated by measuring by. Dissolve 4.2 ⁇ L of 98% PPD solution in 25 mL of 50 mM phosphate buffer (pH 7.4) / 50% methanol (methanol buffer), and prepare the PPD solution so that the concentration in the final reaction solution is 1.0 mM. did.
  • PPD 1-phenyl-1,2-propanedione
  • the analysis column used was TSKgel ODS-80T, 150 ⁇ 6.0 mm (ID) (Tosoh).
  • the eluent was 50 mM phosphate buffer (pH 2.2), the flow rate was 1.0 mL / min, and the detection wavelength was 230 nm.
  • benzoic acid concentration in each measurement sample is calculated from a calibration curve using benzoic acid at each concentration (manufactured by Wako Pure Chemical Industries, Ltd.), and 1.0 mM benzoic acid is obtained from 1.0 mM PPD. From this, the dicarbonyl bond cleavage activity in the PPD structure was determined using the following formula.
  • Dicarbonyl bond cleavage activity 100 ⁇ benzoic acid concentration (mM) / 1 mM
  • Example 5 Measurement of AGE cross-linking cleavage activity
  • the AGE cross-linking cleaving activity is obtained by measuring the cross-linking formed between type I collagen and AGE-BSA by the ELISA method, and calculating the cross-linking cleaving rate by adding the pericarp extract. It was evaluated by.
  • AGE-BSA 10 ⁇ g / mL solution (100 ⁇ L) was added to BD BioCoat Collagen I 96 well micro test plate and incubated at 37 ° C. for 4 hours. The plate was washed 5 times with 0.05% Tween20 / PBS ( ⁇ ), 100 ⁇ L of each concentration sample dissolved in PBS ( ⁇ ) was added, and reacted at 37 ° C. for 20 hours. Each well after the reaction was washed three times with 0.05% Tween 20 / PBS ( ⁇ ), and 1 ⁇ g / mL anti-bovine serum albumin (BSA) rabbit polyclonal antibody solution (ROCKLAND) was added to each well as a primary antibody.
  • BSA anti-bovine serum albumin
  • the AGE-BSA crosslinking residual ratio was calculated from the following formula.
  • Example 6 Test administration to refractory infertile patients (1) Five female patients with refractory infertility with repeated ART (Advanced Reproductive Assistance Medicine) were administered as subjects for oral administration containing Hishi peel extract over 3 months. After administration for 3 months, the blood HbA1c concentration decreased by 0.1 to 0.4 points for all of them. In addition, there was one subject who had a symptom of atopic dermatitis, one subject who had a symptom of allergic rhinitis (hay fever), and one subject who had improved makeup riding. Among the subjects, one woman in her 40s who had suffered from atopic dermatitis and diabetes and had previously failed 13 in vitro fertilizations succeeded in pregnancy by in vitro fertilization during the test period.
  • ART Advanced Reproductive Assistance Medicine
  • Example 7 Test administration to refractory infertile patients (2) From July 2014 to March 2015, 32 cases of refractory infertility (including 5 cases of Example 6) with unsuccessful repetitive ART (advanced assisted reproductive medicine) ART was performed while administering persimmon peel extract every day from 1 to 2 months in advance (once daily, taking 100 mg immediately before the start of breakfast).
  • ART advanced assisted reproductive medicine

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Abstract

La présente invention se rapporte à un composé formant un agent d'amélioration de l'infertilité sans danger et très efficace. Ce composé formant un agent d'amélioration de l'infertilité contient, en tant qu'ingrédient actif, un ou plusieurs composés qui sont présents dans l'écorce et/ou le fruit d'une plante de la famille des Trapaceae, ainsi que, de préférence, un extrait de l'écorce et/ou du fruit d'une plante de la famille des Trapaceae ou un ou plusieurs composés séparés de l'extrait. Ledit ou lesdits composés présentent, de préférence, une ou plusieurs des caractéristiques suivantes : une activité d'inhibition d'une ou de plusieurs réactions relatives à la production d'un produit final de glycation avancée à partir d'une protéine et d'un sucre ; une activité d'accélération d'une ou plusieurs réactions relatives à la dégradation du produit final de glycation avancée ; et une activité de réduction des symptômes allergiques.
PCT/JP2016/052548 2015-01-29 2016-01-28 Composé formant un agent d'amélioration de l'infertilité WO2016121892A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
US15/126,331 US20170165313A1 (en) 2015-01-29 2016-01-28 Composition for ameliorating infertility
AU2016213061A AU2016213061B2 (en) 2015-01-29 2016-01-28 Composition for ameliorating infertility
EP16743495.0A EP3251681B1 (fr) 2015-01-29 2016-01-28 Composition d'amélioration de l'infertilité

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JP2015-014907 2015-01-29
JP2015014907 2015-01-29
JP2015088110A JP6077045B2 (ja) 2015-01-29 2015-04-23 不妊の改善剤組成物
JP2015-088110 2015-04-23

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11199500A (ja) * 1998-01-07 1999-07-27 Nissin Food Prod Co Ltd アトピー性皮膚炎治療剤
JP2001048766A (ja) * 1999-08-02 2001-02-20 Mikimoto Pharmaceut Co Ltd ヒスタミン遊離抑制剤
JP2010077123A (ja) * 2008-08-29 2010-04-08 Hayashikane Sangyo Kk メイラード反応阻害剤
JP2010202580A (ja) * 2009-03-03 2010-09-16 Fukuoka Prefecture 天然物由来α−グルコシダーゼ阻害剤
JP2014037399A (ja) * 2012-07-18 2014-02-27 Up Well:Kk 抗糖化剤およびその製造方法
WO2014126199A1 (fr) * 2013-02-18 2014-08-21 アークレイ株式会社 Agent augmentant l'activité protéine oxydée hydrolase

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH11199500A (ja) * 1998-01-07 1999-07-27 Nissin Food Prod Co Ltd アトピー性皮膚炎治療剤
JP2001048766A (ja) * 1999-08-02 2001-02-20 Mikimoto Pharmaceut Co Ltd ヒスタミン遊離抑制剤
JP2010077123A (ja) * 2008-08-29 2010-04-08 Hayashikane Sangyo Kk メイラード反応阻害剤
JP2010202580A (ja) * 2009-03-03 2010-09-16 Fukuoka Prefecture 天然物由来α−グルコシダーゼ阻害剤
JP2014037399A (ja) * 2012-07-18 2014-02-27 Up Well:Kk 抗糖化剤およびその製造方法
WO2014126199A1 (fr) * 2013-02-18 2014-08-21 アークレイ株式会社 Agent augmentant l'activité protéine oxydée hydrolase

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
JINNO, M. ET AL.: "Accumulation of advanced glycation endproducts (AGE) are novel markers to detect women with poor IVF/ICSI outcomes independently of age and day-3-FSH levels: Possible novel therapy for poor responders by decreasing AGE", JOURNAL FUR REPRODUKTIONSMEDIZIN UND ENDOKRINOLOGIE, vol. 7, no. 4, 2010, pages 275 - 276, XP055402759 *
MASAO JINNO ET AL.: "Shumatsu Toka Sanbutsu (AGE) ni yoru Nenrei, day-3-FSH to Dokuritsu shita Jusho Ranso Kino Shogai no Soki Shindan: Atarashii Funin Chiryoho no Kokoromi", OBSTETRICAL AND GYNECOLOGICAL PRACTICE, vol. 60, no. 3, 2011, pages 469 - 476, XP008185825 *
MASAO JINNO: "Ranso Yobino Teika no Atarashii Chiryo Senryaku: To Taisha to Shumatsu Toka Sanbutsu no Juyosei", JAPAN SOCIETY OF ASSISTED REPRODUCTION ZASSHI, vol. 16, no. 2, 2013, pages 58 - 60, XP008185856 *
NATSUKI UGAJIN ET AL.: "Seisho Allergy Kanja ni Taishi IVF-ET o Okonai Kyoji o Eta Shorei", JOURNAL OF JAPAN SOCIETY FOR REPRODUCTIVE MEDICINE, vol. 52, no. 4, 2007, pages 328, P222, XP008185816 *
SHINJI KOMORI ET AL.: "Clinical Conference (Seishoku Naibunpitsu Ryoiki); 1.Funin Shinryo no Mondaiten to Taisaku 3)Immunological Infertility", ACTA OBSTETRICA ET GYNAECOLOGIA JAPONICA, vol. 59, no. 9, 2007, pages N.437 - N.441, XP008185823 *
SHOKO TAKESHITA ET AL.: "Tobishi (Trapa bispinosa) Kahi Chushutsubutsu ni yoru Ko- Glycation Sayo", THE JAPANESE SOCIETY OF NUTRITION AND FOOD SCIENCE TAIKAI KOEN YOSHISHU, vol. 65th, 2011, pages 244, XP008185821 *

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