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WO2020066484A1 - Composition contenant de l'acide ellagique - Google Patents

Composition contenant de l'acide ellagique Download PDF

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Publication number
WO2020066484A1
WO2020066484A1 PCT/JP2019/034489 JP2019034489W WO2020066484A1 WO 2020066484 A1 WO2020066484 A1 WO 2020066484A1 JP 2019034489 W JP2019034489 W JP 2019034489W WO 2020066484 A1 WO2020066484 A1 WO 2020066484A1
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WO
WIPO (PCT)
Prior art keywords
composition
ellagic acid
cgmp
active ingredient
increasing
Prior art date
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Ceased
Application number
PCT/JP2019/034489
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English (en)
Japanese (ja)
Inventor
理夏子 石橋
史郎 田島
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Kobayashi Pharmaceutical Co Ltd
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Kobayashi Pharmaceutical Co Ltd
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Publication of WO2020066484A1 publication Critical patent/WO2020066484A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/116—Heterocyclic compounds
    • A23K20/121—Heterocyclic compounds containing oxygen or sulfur as hetero atom
    • A23K20/126—Lactones
    • 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
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • 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
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • 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
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/99—Enzyme inactivation by chemical treatment

Definitions

  • the present invention relates to a new use of ellagic acid based on a new action found for ellagic acid.
  • Ellagic acid is a polyphenol contained in nuts such as walnuts and cashew nuts; and eucalyptus leaves. It is known that it can also be obtained by hydrolysis of ellagitannin or heating of gallic acid. Ellagic acid has hitherto been used as an antioxidant in food additives and as a whitening component of cosmetics based on its antioxidant action. Further, in recent years, various effects including pharmacological effects have been found by research on ellagic acid, and various uses have been proposed based on the effects.
  • Such uses include, for example, glucosyltransferase inhibitors (Patent Document 1), antioxidants (Patent Document 2), agents for preventing or treating diseases caused by high blood lipid levels (Patent Document 3), apoptosis inducers (Patent Document 3).
  • Reference 4 an anti-H. Pylori composition (Patent Document 5), an agent for preventing or improving arthritis (Patent Document 6), a uric acid excretion promoter (Patent Document 7), and a polyphenol stabilizer (Patent Document 8).
  • ellagic acid has an activity of inhibiting the activity of phosphodiesterase (PDE).
  • Phosphodiesterase is an enzyme that hydrolyzes cyclic GMP (cGMP) and cyclic AMP (cAMP), and a plurality of families exist in mammals. Among them, phosphodiesterase 5 (hereinafter sometimes abbreviated as “PDE5” in the present specification) is mainly involved in cGMP degradation. cGMP acts as an intracellular second messenger, relaxing smooth muscle and increasing blood flow. Therefore, by suppressing the activity of PDE5, smooth muscle relaxes and blood flow increases.
  • PDPDE5 inhibitors have hitherto been known as drugs utilizing this action, and typical examples thereof include drugs containing sildenafil citrate as an active ingredient.
  • PDE5 inhibitors are used to improve symptoms such as decreased penile erectile function, reduced bladder and prostate function, and pulmonary hypertension by inhibiting PDE5 activity and suppressing cGMP degradation and increasing local blood flow. Have been.
  • the present invention aims to provide a new use of ellagic acid. Specifically, it is used as a PDE5 activity inhibitor, used as an agent for suppressing or degrading the degradation of cGMP, used as an agent for increasing penile pressure, used as an inhibitor for lowering penile erectile function, or used as an agent for reducing prostatic hypertrophy.
  • PDE5 activity inhibitor used as an agent for suppressing or degrading the degradation of cGMP
  • used as an agent for increasing penile pressure used as an inhibitor for lowering penile erectile function
  • the purpose is to provide the use of.
  • the present inventors have been studying the effects of ellagic acid, and as shown in the Examples described below, the PDE5 activity inhibitory effect, cGMP degradation suppression or concentration increasing effect, and penile pressure increasing effect were observed. It was found that ellagic acid was useful as an active ingredient for suppressing a decrease in penile erectile function and as an active ingredient for alleviating prostatic hypertrophy.
  • the present invention has been completed by further research based on such findings, and includes the following embodiments.
  • a composition for inhibiting PDE5 activity comprising ellagic acid as an active ingredient.
  • a composition for suppressing a decrease in penile erectile function comprising ellagic acid as an active ingredient.
  • a composition for alleviating prostatic hypertrophy comprising ellagic acid as an active ingredient.
  • composition for inhibiting PDE5 activity a composition for suppressing the degradation or increasing the concentration of cGMP, a composition for increasing the pressure in the penis, a composition for suppressing a decrease in penile erectile function, or a composition for alleviating prostatic hypertrophy Use of ellagic acid.
  • ellagic acid can be used for its production as an active ingredient of a composition for inhibiting PDE5 activity based on the PDE5 activity inhibiting action of ellagic acid.
  • ellagic acid can be used for its production as an active ingredient of a composition for suppressing cGMP decomposition or increasing its concentration, based on the action of suppressing or increasing the concentration of cGMP possessed by ellagic acid.
  • ellagic acid can be used for its production as an active ingredient of the composition for increasing penile pressure, based on the action of increasing the pressure inside the penis possessed by ellagic acid.
  • ellagic acid can be used for its production as an active ingredient of a composition for suppressing a decrease in penile erectile function, specifically a composition for preventing or improving a decrease in penile erectile function, based on the above action.
  • Ellagic acid can be used for its production as an active ingredient of a composition for alleviating prostatic hypertrophy, preferably a composition for preventing or improving prostatic hypertrophy, based on the above action.
  • compositions for inhibiting PDE5 activity a composition for suppressing the degradation or increasing the concentration of cGMP, a composition for increasing the pressure in the penis, a composition for suppressing a decrease in penile erectile function, and the prostate, which are the objects of the present invention.
  • All the compositions for alleviating hypertrophy are characterized by using ellagic acid as an active ingredient.
  • the ellagic acid used in the production of the composition of the present invention is preferably a purified product (pure product), but is not limited to this, as long as the effects of the present invention are exhibited, and may be a crude product.
  • the crudely purified product include an ellagic acid fraction prepared from a plant containing ellagic acid.
  • fruits of plants such as pomegranate, strawberry, raspberry, cranberry, blackberry, strawberry, grape, walnut, chestnut, and pecan are known (see Patent Documents 8 and 9).
  • ellagitannins such as punicalazine are known to generate ellagic acid by acid decomposition.
  • an ellagic acid fraction prepared from a plant containing ellagitannin by acid decomposition treatment or the like can be used as the partially purified product containing ellagic acid.
  • the ellagic acid fraction targeted by the present invention is extracted once from a plant part containing ellagic acid with one kind of solvent (water; alcohol of methanol or ethanol; hydrous alcohol, etc.), then filtered and concentrated.
  • solvent extraction may be repeated several times. , Molecular weight filtration, size exclusion chromatography, or ion exchange chromatography.
  • ellagic acid content in the ellagic acid fraction prepared from a plant is preferably 60% by mass or more, more preferably 70% by mass or more, further preferably 80% by mass or more, particularly preferably 90% by mass or more and 100% by mass. It is as follows.
  • the composition for inhibiting PDE5 activity of the present invention can inhibit PDE5 activity based on the PDE5 activity inhibitory action of ellagic acid as an active ingredient, as shown in Experimental Example 1 described later.
  • the activity of PDE5 is inhibited in smooth muscle tissue, the degradation of cGMP into 5'-GMP is inhibited, resulting in an increase in cGMP concentration as shown in Experimental Example 2.
  • ellagic acid has an effect of suppressing the degradation of cGMP or inducing an increase in the cGMP concentration through a PDE5 activity inhibiting effect.
  • the present invention also provides a composition for suppressing cGMP degradation or a composition for increasing cGMP concentration, which contains ellagic acid as an active ingredient.
  • ellagic acid has an action to increase penile pressure, and as described above, can be used as an active ingredient of a composition for increasing penile pressure, and further can be used as an active ingredient of a composition for suppressing a decrease in penile erectile function.
  • the present invention provides a composition for increasing penile pressure, a composition for suppressing a decrease in penile erectile function, and a composition for alleviating prostatic hypertrophy, comprising ellagic acid as an active ingredient. From these facts, the composition of the present invention can be preferably applied to a subject who is concerned about male function and a subject who is concerned about urination function, particularly for male subjects.
  • compositions of the present invention can be prepared and provided in the form of pharmaceuticals or quasi-drugs, or food and drink for humans, or be prepared and provided in the form of feed for animals. Can be.
  • composition of the present invention comprises, in addition to ellagic acid, a pharmaceutically acceptable carrier or additive depending on the preparation form (dosage form), if necessary, to prepare various agents. It can be prepared as a pharmaceutical or quasi-drug in form.
  • Pharmaceuticals or quasi-drugs preferably include oral dosage forms of pharmaceuticals or quasi-drugs. Examples of such pharmaceuticals or quasi-drugs include, but are not limited to, tablets (including coated tablets such as sugar-coated tablets), capsules (including hard capsules and soft capsules), granules, powders, syrups, and intestines.
  • composition such as a solvent, a troche and a drink.
  • formulations having various dosage forms can be carried out according to a conventional method, and the carriers and additives used are not particularly limited.
  • pharmaceutically acceptable excipients sorbitol, glucose, lactose, dextrin, sugars such as starch, inorganic substances such as calcium carbonate, crystalline cellulose, distilled water, sesame oil, corn oil, olive oil, rapeseed oil, etc.
  • liquid carriers Disistilled water, physiological saline, aqueous glucose solution, alcohols such as ethanol, propylene glycol, polyethylene glycol, etc.
  • oily carriers variousous animal and vegetable oils, white petrolatum, paraffin, waxes, etc.
  • stabilizers wetting agents, emulsifiers , Binders, isotonic agents, disintegrants, lubricants, bulking agents, surfactants, dispersants, suspending agents, diluents, osmotic agents, pH adjusters, preservatives, antioxidants, coloring Agents, ultraviolet absorbers, humectants, thickeners, brighteners, buffering agents, preservatives, flavoring
  • the drug or quasi-drug can be used for the above-mentioned applications (inhibition of PDE5 activity, suppression of cGMP degradation or increase in concentration, increase in penile pressure, suppression of decrease in penile erectile function, alleviation of prostatic hypertrophy).
  • a PDE5 activity inhibitor an agent for preventing or treating penile erectile dysfunction (dysfunction), or an agent for preventing or treating prostatic hypertrophy, especially for men, those who are concerned about male functions and those who are concerned about urination functions Can be applied.
  • the amount of ellagic acid (active ingredient) in the composition of the present invention in the form of a drug or a quasi-drug differs according to the obstacle to be applied, its degree, and the form of the drug, etc., it is not limited.
  • the solid content concentration can be selected from the range of 1 to 100% by mass, preferably the range of 10 to 60% by mass, more preferably the range of 25 to 55% by mass, as long as the effect of the above is exhibited.
  • the administration or intake of the composition of the present invention in the form of a drug or a quasi-drug depends on the condition, body weight, gender, age, type of ellagic acid to be incorporated as an active ingredient, or other factors of the subject (patient) Is appropriately selected and determined according to the above.
  • the daily administration or intake for humans can be appropriately set in the range of 0.15 to 85 mg / kg in terms of the administration or intake of ellagic acid.
  • the dose to humans or the amount of intake is generally the human equivalent dose (HED) 6.2 based on the body surface area in rats (see "Guidance for Industry Estimating the Maximum Safe Starting” Dose in Initial Clinical Clinical Trials for Therapeutics in Adult Healthy Volunteers). Can be calculated from It is preferably 0.5 to 50 mg / kg, and more preferably a range of 1 to 20 mg / kg.
  • the composition of the present invention can be taken and administered once to several times a day, or at any time and interval.
  • composition of the present invention is prepared as food and drink
  • its form is not particularly limited as long as it is a form suitable for food or drink.
  • tablets including coated tablets such as sugar-coated tablets
  • capsules including hard capsules and soft capsules
  • these preparations may be packaged in small portions.
  • additives such as sweeteners, coloring agents, antioxidants, vitamins, flavors, minerals, proteins, lipids, carbohydrates, carbohydrates, dietary fiber, etc.
  • the general food raw materials described above may be appropriately combined and blended.
  • the type and form of the obvious food are not particularly limited, and for example, processed flour foods represented by bread, noodles, etc .; porridge, processed rice foods such as cooked rice; biscuits, cakes, jellies, chocolate, rice crackers, Confectionery such as ice cream; processed soy foods such as tofu and processed foods; beverages such as soft drinks, fruit drinks, milk drinks, carbonated drinks; dairy products such as yogurt, cheese, butter, milk; soy sauce, sauces, Seasonings such as miso, mayonnaise and dressing; processed foods including meat storage such as ham, bacon and sausage; processed foods including seafood such as hampon and chikuwa and other prepared dishes such as processed foods.
  • processed foods including meat storage such as ham, bacon and sausage
  • processed foods including seafood such as hampon and chikuwa and other prepared dishes
  • These may be in the form of oral enteral nutritional foods such as concentrated liquid foods, natural liquid foods, semi-digestive nutritional foods, component nutritional foods, and drink nutritional foods.
  • composition of the present invention in the form of a food or drink is selected from the group consisting of PDE5 activity inhibitory action, cGMP degradation or concentration increasing action, penile pressure increase action, penile erectile function reduction inhibitory action, and prostate hypertrophy alleviating action. It has at least one function, and can be used for applications utilizing these functions.
  • the concept is to prevent or ameliorate penile erectile dysfunction or dysfunction based on these mechanisms of action, and / or to prevent or ameliorate urinary dysfunction due to prostatic hypertrophy. It can be in the form of a functional food or drink (functionally labeled food or food for specified health use) displayed as a functional claim or health claim.
  • the food and drink of the present invention can be applied to a subject who is concerned about a male function and a subject who is concerned about a urination function, particularly for a male.
  • the foods and drinks can be positioned as feed.
  • the amount of ellagic acid (active ingredient) in the composition of the present invention having the form of food and drink depends on the symptoms to be applied and its degree, and also on the form of food and drink, etc., and is not limited. As long as it plays, the solid content can be selected from the range of 1 to 100% by mass, preferably 10 to 60% by mass, more preferably 25 to 55% by mass.
  • the intake amount of the composition of the present invention in the form of food or drink is appropriately selected and determined according to the condition, weight, sex, age, or other factors of the subject (ingested individual).
  • the daily intake can be appropriately set in the range of 0.15 to 85 mg / kg in terms of the intake of ellagic acid. It is preferably 0.5 to 50 mg / kg, and more preferably a range of 1 to 20 mg / kg.
  • the composition of the present invention can be taken and administered once to several times a day, or at any time and interval.
  • Experimental methodElagic acid was previously mixed with dimethyl sulfoxide to make a 10 mM ellagic acid-containing solution, and then mixed with 5 ⁇ L of the ellagic acid-containing solution and 495 ⁇ L of sterilized water to prepare a sample solution (ellagic acid concentration of 100 ⁇ M) as follows. It was used for the experiment. First, 25 ⁇ L of the diluted and prepared FAM-Cyclic-3 ′, 5′-GMP was added to each well (Test, Substrate control, and Positive control wells) except for the blank well. On the other hand, 25 ⁇ L of the PDE assay buffer included in the kit was added to the blank wells.
  • ellagic acid was found to have a strong effect of inhibiting the activity of PDE5.
  • Test animals test samples For the main measurement, SD male rats (body weight: about 250 g / animal), cGMP ELISA kit (catalog number: ADI-900-014, manufactured by Enzo Life Science), PerkinElmer EnVision 2102 Multilabel Reader (PerkinElmer (Manufactured by Sharp Corporation).
  • the dispersed tissue was centrifuged at 600 G / 10 min, the supernatant was collected, dispensed into a microtube, and stored frozen at -80 ° C. until the experiment.
  • the amount of cGMP in penis tissue was measured by ELISA according to the method described in the cGMP ELISA kit.
  • the amount of cGMP in penile tissue was measured in the same manner as described above except that distilled water was administered into the rat stomach instead of the ellagic acid-containing solution.
  • the cGMP amount at the time of administration of the ellagic acid-containing solution was higher than the cGMP amount at the time of administration of distilled water.
  • test animals test samples Rats (SD rats, male, 250 g) were used as test animals, and evaluation was performed by measuring the maximum penile pressure after administering the test samples. Ellagic acid was used as a test substance, and sildenafil, which is known to have a penile pressure increasing effect, was used as a positive control. All the test substances dissolved in distilled water were used as test samples (see Table 2) for the following experiments.
  • an aqueous solution containing ellagic acid was intragastrically administered with a sonde after stirring.
  • the same test sample was intragastrically administered to the rats of each group again by the same procedure.
  • urethane anesthesia under shallow isoflurane anesthesia anesthesia was introduced with shallow isoflurane and then anesthesia with urethane was performed.
  • the penis of each group of rats is detached from the abdominal wall, and the dorsal nerve of the penis is identified.
  • a bipolar electrode was attached to the penile dorsal nerve, a 25G needle was inserted into the corpus cavernosum, and electrical stimulation (10-20 V, 20 pulse / s, pulse duration) was performed while saline was injected at a rate of 2 ml / h. 0.2 ms, train duration 30 s), and the penile pressure during electrical stimulation of the penile dorsal nerve was recorded.
  • FIG. 1 shows the experimental results . As shown in FIG. 1, in the ellagic acid administration group, it was confirmed that the pressure in the penis due to the electrical stimulation was extremely high. From this, it was confirmed that ellagic acid had a high penile pressure increasing effect.

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Abstract

Le problème est de fournir un nouvel usage de l'acide ellagique. La solution selon la présente invention consiste à utiliser l'acide ellagique en tant que principe actif d'une composition destinée à inhiber l'activité phosphodiestérase-5, d'une composition destinée à inhiber la décomposition du GMPc ou à augmenter la concentration de ce dernier, d'une composition destinée à augmenter la pression interne du pénis, d'une composition destinée à prévenir un dysfonctionnement érectile pénien et/ou d'une composition destinée à améliorer l'hypertrophie prostatique.
PCT/JP2019/034489 2018-09-28 2019-09-02 Composition contenant de l'acide ellagique Ceased WO2020066484A1 (fr)

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JP2018185807A JP7278734B2 (ja) 2018-09-28 2018-09-28 エラグ酸含有組成物

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JP7368340B2 (ja) * 2020-11-13 2023-10-24 金氏高麗人参株式会社 ホスホジエステラーゼ５阻害用組成物

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Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
"Clinical Guideline for Benign Prostatic Hyperplasia", THE JAPANESE UROLOGICAL ASSOCIATION, I. PHOSPHODIESTERASE-TYPE 5 INHIBITORS, 25 June 2011 (2011-06-25), pages 63, 64 *
OBOH, G. ET AL.: "Effects of water extractable phytochemicals of mahogany (Swietenia macrophylla) and axlewood (Anogeissus leiocarpus) stem bark on some enzymes implicated in erectile dysfunction and type-2 diabetes", JOURNAL OF FOOD BIOCHEMISTRY, vol. 41, 14 September 2017 (2017-09-14), pages 1 - 7, XP055700610 *
ODUBANJO, V. 0. ET AL.: "Seed extracts from Myristica fragrans (Nutmeg) and Moringa oleifera (Drumstick tree) inhibits enzymes relevant to erectile dysfunction and metal-induced oxidative damage in rats' penile tissues", JOURNAL OF FOOD BIOCHEMISTRY, vol. 42, 30 October 2017 (2017-10-30), pages e12452, XP055700612 *

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