WO2011078323A1 - Active oxygen production inhibitor and anti-hypertensive agent - Google Patents
Active oxygen production inhibitor and anti-hypertensive agent Download PDFInfo
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- WO2011078323A1 WO2011078323A1 PCT/JP2010/073341 JP2010073341W WO2011078323A1 WO 2011078323 A1 WO2011078323 A1 WO 2011078323A1 JP 2010073341 W JP2010073341 W JP 2010073341W WO 2011078323 A1 WO2011078323 A1 WO 2011078323A1
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- ergosterol
- active oxygen
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- oxygen production
- blood pressure
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- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to an active oxygen production inhibitor and an oxidative stress ameliorating agent that suppress active oxygen production.
- the present invention also relates to a blood pressure lowering agent useful for prevention or improvement of hypertension symptoms and the like.
- Active oxygen produced in the body is used to maintain the homeostasis of the body such as biological regulation, antibacterial activity, antiviral activity, etc., but if its production becomes excessive due to stress, ultraviolet exposure, etc., nucleic acid degradation, protein denaturation It causes lipid peroxidation, damages cells and contributes to various pathological conditions.
- Non-patent Document 1 Non-patent Document 1
- Non-Patent Document 2 The Health Organization / International High Pressure Society (WHO / ISH) Guidelines (Non-Patent Document 2) have been established, and antihypertensive measures are being taken not only in Japan but worldwide. In this guideline, blood pressure is classified according to level into mild hypertension, moderate hypertension, severe hypertension, etc.
- Non-pharmacological therapy that summarizes the improvement of the above is considered as a method for effectively reducing the risk of developing hypertension, preventing it, or improving the constitution.
- a prevention or improvement method using a material having a blood pressure lowering action that can be taken as food.
- ergosterol is a kind of sterol contained in fungi such as mushrooms and yeasts.
- This ergosterol or glycoside thereof has a hyaluronic acid degradation inhibitory effect (Patent Document 1), a hair growth / hair growth effect (Patent Document 2), a wrinkle improvement effect that appears due to photoaging (Patent Document 3), an adiponectin secretion promoting effect It is known to have (Patent Document 4).
- Patent Document 5 it has been reported that the plant sterol which has a structure similar to ergosterol has superoxide elimination ability
- the present invention relates to an active oxygen production inhibitor containing ergosterol as an active ingredient.
- the present invention also relates to an antioxidant stress improving agent containing ergosterol as an active ingredient.
- the present invention also relates to a method for suppressing active oxygen production, characterized by administering or ingesting ergosterol.
- the present invention also relates to a method for improving antioxidant stress, characterized by administering or ingesting ergosterol.
- the present invention also relates to the use of ergosterol for producing an active oxygen production inhibitor.
- the present invention also relates to the use of ergosterol for producing an oxidative stress ameliorating agent.
- the present invention also relates to ergosterol for use in suppressing active oxygen production.
- the present invention also relates to ergosterol for use in improving oxidative stress.
- the present invention also relates to a blood pressure lowering agent containing ergosterol as an active ingredient.
- the present invention also relates to an agent for reducing, preventing and / or improving the risk of developing hypertension, which contains ergosterol as an active ingredient.
- the present invention also relates to a method for lowering blood pressure, characterized by administering or ingesting ergosterol.
- the present invention also relates to a method for reducing, preventing and / or improving the risk of developing hypertension, characterized by administering or ingesting ergosterol.
- the present invention also relates to the use of ergosterol for producing a blood pressure lowering agent.
- the present invention also relates to the use of ergosterol for producing an agent for reducing, preventing and / or improving the risk of developing hypertension.
- the present invention also relates to ergosterol for use in lowering blood pressure.
- the present invention also relates to ergosterol for use in reducing, preventing and / or improving the risk of developing hypertension.
- concentration of ergosterol, sitosterol, and stigmasterol is shown.
- the active oxygen production amount in the control (no addition) was set to 0% for the active oxygen production inhibition rate. It shows an erasing action on superoxide production by xanthine oxidase at each concentration of ergosterol, sitosterol, and stigmasterol.
- the superoxide production amount in the control (no addition) was defined as a superoxide production inhibition rate of 0%.
- the present invention is to provide an active oxygen production inhibitor or an oxidative stress ameliorating agent that suppresses excessive oxygen produced in the body.
- Another object of the present invention is to provide a blood pressure lowering agent having high safety and an excellent blood pressure lowering action.
- the present inventor examined a substance having an active oxygen production inhibitory action, and found that ergosterol had a significantly superior active oxygen production inhibitory action than plant sterols similar in structure to ergosterol such as sitosterol and stigmasterol.
- the present invention has been found by finding that the present invention is effective as a pharmaceutical, food, beverage, etc. that exhibits an active oxygen production inhibitory effect or as a material for these.
- the present inventor examined a substance having a blood pressure lowering action, and found that, when ergosterol was orally administered, the blood pressure rapidly decreased and this action lasted for a long time, thereby completing the present invention.
- the active oxygen production inhibitor or oxidative stress ameliorating agent of the present invention can suppress active oxygen produced in the body, it is induced by excessive production of active oxygen such as cardiovascular diseases, allergic diseases, aging / senile diseases, etc.
- active oxygen such as cardiovascular diseases, allergic diseases, aging / senile diseases, etc.
- it is useful as a material used in combination with foods, beverages, pharmaceuticals, etc. that exerts a reduction, prevention, treatment or improvement effect of symptoms and diseases that are promoted.
- the blood pressure lowering agent of the present invention is highly safe and has an action of rapidly reducing blood pressure, it is effective in reducing, preventing and / or improving the risk of developing hypertension and the like.
- Ergosterol used in the present invention is It is a compound represented by these.
- the ergosterol is a kind of sterol and is contained in fungi such as basidiomycetes such as shiitake mushrooms and maitake mushrooms and ascomycetes such as yeast.
- the ergosterol may be an ergosterol glycoside produced by dehydration condensation of the hydroxyl group at the 3-position of ergosterol and a hemiacetal or hemiketal hydroxyl group of 1 to 5 sugars.
- an ergosterol fatty acid ester in which a fatty acid is ester-bonded to the hydroxyl group at the 3-position of ergosterol may be used.
- the fatty acid having an ester bond is not particularly limited as long as it is a fatty acid contained in fungi such as basidiomycetes and ascomycetes, and examples thereof include saturated or unsaturated linear fatty acids having 14 to 22 carbon atoms. .
- the ergosterol used in the present invention includes those obtained by a known chemical synthesis method and those obtained by extraction or purification from fungi containing ergosterol (see Patent Documents 1 to 5). Commercially available products, chemically synthesized products, extracts and purified products thereof can also be used as ergosterol.
- any of polar and nonpolar solvents may be used.
- water water-soluble organic solvents such as methanol, ethanol, butanol, and ethyl acetate; hexane
- a hydrophobic organic solvent such as diethyl ether, and among them, it is preferable to use a hydrophobic organic solvent from the viewpoint of improving the recovery rate.
- the extraction means is, for example, an active oxygen production inhibitor or an oxidative stress improver
- 1 to 50 parts by mass of a solvent is used per 1 part by mass of fungi containing ergosterol, and 0 (preferably 20 ° C.) It is preferable to immerse in the range of the boiling point of the solvent for 1 hour to 3 days or to reflux for 5 minutes to 2 hours.
- an antihypertensive agent 2 to 100 parts by weight of a solvent is used per 1 part by weight of fungi containing ergosterol, and the temperature ranges from 0 (preferably 20 ° C.) to the boiling point of the solvent for 1 hour to It is preferable to immerse for 3 days or to heat and reflux for 5 minutes to 2 hours, and to extract for 0.1 to 12 hours, particularly 0.5 to 5 hours.
- separation and purification means examples include activated carbon treatment, liquid-liquid distribution, column chromatography, liquid chromatography, gel filtration chromatography, and precision distillation.
- the ergosterol of the present invention has an action of strongly suppressing active oxygen produced from leukocytes to ergosterol as compared to plant sterols such as sitosterol and stigmasterol, that is, an excellent inhibitory action of active oxygen production, as shown in Examples below. Therefore, it can be used as an active oxygen production inhibitor or an oxidative stress improver (hereinafter referred to as “active oxygen production inhibitor, etc.”), and further used for producing this preparation. Can do.
- the active oxygen production inhibitor, etc. the ergosterol used alone or in addition to this is allowed in the later-described object to be blended, such as a carrier appropriately selected as necessary. May be.
- the said formulation can be manufactured by a conventional method according to the target object which should be mix
- the active oxygen production inhibitor or oxidative stress ameliorating agent reduces or prevents the onset risk of diseases caused by active oxygen in the living body such as arteriosclerosis, diabetes, hyperlipidemia and cancer. It can be used as an active ingredient in foods for improvement or treatment, functional foods, quasi drugs, pharmaceuticals, feeds and the like.
- active oxygen production inhibitors and the like are also useful for lifestyle-related disease reserve armies (groups that have not reached lifestyle-related disease but are close to that state (boundary region)).
- the food is based on the concept of suppression of active oxygen production, risk of onset of lifestyle-related diseases, prevention, improvement and treatment, foods that indicate that if necessary, functional foods, foods for the sick, Applicable to food for specified health use.
- “diseases induced or promoted by active oxygen in the living body” include cardiovascular diseases, cranial nervous system diseases, digestive system diseases, kidney diseases, respiratory system diseases, metabolic / endocrine diseases, allergic diseases, ocular diseases And aging / senile diseases (Non-patent Document 1). Accordingly, examples of subjects who are administered or ingested with the oxygen production inhibitor or oxidative stress ameliorating agent of the present invention include patients with these diseases, persons with a high risk of developing these diseases, and the like.
- Oxidative stress refers to a state unfavorable for a living body in which the active oxygen production system and the elimination system in the living body are out of balance and excessive active oxygen is produced. “Improving oxidative stress” mainly refers to returning this broken balance to a normal state. Examples of indicators of oxidative stress include lipid peroxide, 8-OHdG, isoplastane, hydroperoxide and the like, and these are considered to be increased in vivo in the oxidative stress state. Accordingly, examples of subjects who are administered or ingested with the oxygen production inhibitor or oxidative stress improving agent of the present invention include those whose oxidative stress index is higher than that of healthy people.
- the ergosterol of the present invention has an action of rapidly lowering the blood pressure of SHR, which is a spontaneously hypertensive model rat, as shown in Examples below, and has the action of maintaining this blood pressure lowering effect for a long time.
- ergosterol can be used as an antihypertensive agent and can be used to produce this agent.
- a carrier that is appropriately selected as necessary such as a carrier that is allowed in the object to be described later, may be used.
- the said formulation can be manufactured by a conventional method according to the target object which should be mix
- the blood pressure lowering agent is a food or drink that reduces or prevents, improves, or treats the risk of developing various lifestyle-related diseases that are closely related to hypertension or hypertension. It can be used as an active ingredient for products, pharmaceuticals, feeds and the like.
- the antihypertensive agent is effective for patients satisfying the hypertension diagnostic criteria such as mild patients, moderate patients and severe patients, or subjects who are expected to develop hypertension, and mild hypertension. It is also effective for people with normal high blood pressure who are considered to have high blood pressure, those with a high risk of developing hypertension due to lifestyle, and those with normal blood pressure who have a history of high blood pressure in their families and who are likely to have high blood pressure in the future.
- the antihypertensive agent is a food, a function, and a function indicating the necessity of reducing, preventing, improving, or treating the risk of developing various lifestyle-related diseases that are closely related to hypertension or hypertension as necessary. It can be applied to food, food for the sick, food for specified health use, etc.
- the active oxygen production inhibitor or oxidative stress ameliorating agent of the present invention is used as an active ingredient of a pharmaceutical product
- the pharmaceutical product can be administered in any dosage form.
- the blood pressure lowering agent of the present invention When used as an active ingredient of a pharmaceutical product, it can be administered in any dosage form.
- the dosage form include oral, enteral, transmucosal, transdermal, and injection.
- the dosage form of the preparation for oral administration include tablets, capsules, granules, powders, and syrups.
- parenteral administration include intravenous injections, intramuscular injections, suppositories, inhalants, transdermal absorption agents, eye drops, and nasal drops.
- the active oxygen production inhibitor, oxidative stress ameliorating agent or blood pressure lowering agent of the present invention may be used alone or in appropriate combination with other pharmaceutically acceptable carriers.
- Such carriers include, for example, excipients, binders, disintegrants, lubricants, diluents, osmotic pressure regulators, pH regulators, emulsifiers, preservatives, stabilizers, antioxidants, colorants, ultraviolet rays.
- Absorber moisturizer, thickener, brightener, activity enhancer, anti-inflammatory agent, bactericidal agent, corrigent, flavoring agent, extender, surfactant, dispersant, buffer, preservative, fragrance, coating agent Etc.
- the content of the ergosterol of the present invention which is an active ingredient in the above preparation when used as an active ingredient of an oral administration agent, is usually the total mass of the preparation in terms of dry matter. It is preferably 0.01 to 100% by mass, more preferably 0.05 to 50% by mass, still more preferably 0.1 to 30% by mass, and 0.5 to 20% by mass. Is even more preferable.
- the dosage of the above formulation may vary according to the patient's condition, body weight, sex, age or other factors, but the daily dosage per adult for oral administration is usually effective on a dry matter basis
- the component ergosterol is preferably 3 to 300 mg, more preferably 10 to 200 mg, and even more preferably 20 to 100 mg.
- the preparation can be administered according to an arbitrary administration schedule, but is preferably administered once to several times a day, and the administration interval is preferably 3 to 18 hours, more preferably 4 to 6 hours.
- the form of the food may be solid, semi-solid or liquid.
- foods include breads, noodles, confectionery, jelly, dairy products, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, beverages, soups, seasonings, dietary supplements, etc. , And their raw materials.
- a tablet form, a pill form, a capsule form, a liquid form, a syrup form, a powder form, a granule form etc. may be sufficient.
- the active oxygen production inhibitor, oxidative stress-improving agent, or blood pressure-lowering agent of the present invention alone or in combination with foods, such as other food materials and solvents , Softeners, fats and oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, antioxidants, humectants, thickeners, and the like may be used in appropriate combinations.
- the content of the ergosterol of the present invention in the food is preferably 0.001 to 10% by mass in the beverage, usually 0.01 to 10% by mass in the case of a liquid form such as a beverage as a dry product. Is more preferably 0.05 to 2% by mass, and still more preferably 0.1 to 0.5% by mass.
- the total composition is preferably 0.01 to 50% by mass, more preferably 0.05 to 25% by mass, and The content is more preferably 1 to 10% by mass, and still more preferably 0.3 to 5% by mass.
- the feed is for livestock used for cattle, pigs, chickens, sheep, horses, etc.
- livestock used for cattle, pigs, chickens, sheep, horses examples include feeds for small animals used for feeds, rabbits, rats, mice, etc., feeds for seafood used for tuna, eel, Thailand, Hamachi, shrimp, etc., pet foods used for dogs, cats, small birds, squirrels, and the like.
- feed in addition to the content of ergosterol, meat such as cattle, pigs, sheep, protein, grains, bran, potatoes, sugars, vegetables, vitamins, minerals, etc.
- meat such as cattle, pigs, sheep, protein, grains, bran, potatoes, sugars, vegetables, vitamins, minerals, etc.
- the feed ingredients used, and gelling agents, shape-preserving agents, pH adjusters, seasonings, preservatives, nutritional supplements, etc., which are generally used in feeds, are blended as necessary. Can be processed and manufactured.
- the content of ergosterol in the feed varies depending on the use form, but is usually 0.001 to 50% by mass, preferably 0.01 to 10% by mass, more preferably 0.05 to 1% by mass. .
- Ergosterol manufactured by Tokyo Chemical Industry Co., Ltd. was used as a sample.
- the animals used were SD rats (10-16 weeks old, male). From the SD rat, carotid artery blood was collected under isoflurane (Abbott Japan) anesthesia. This blood sample was layered on a blood cell separation reagent (manufactured by SIGMA) and centrifuged, and then the leukocyte fraction was collected.
- ergosterol, sitosterol, and stigmasterol were added to 1 ⁇ g / mL, 10 ⁇ g / mL, and 100 ⁇ g / mL, respectively, and reacted at room temperature for 1 hour. Thereafter, the fluorescent reagent 10 ⁇ M 5- (and 6-) chloromethyl-2 ′, 7′-dichlorodihydrofluorescein diacetate, acetyl ester (5,6-CM-H2DCFDA) (manufactured by Invitrogen) is allowed to act at room temperature for 20 minutes.
- the intracellular active oxygen was measured in the same manner as described above with no sample added, and the amount of active oxygen produced without addition (control) was defined as the active oxygen production inhibition rate of 0%.
- the active oxygen production inhibition rates when sitosterol and stigmasterol were added were 8.5% and 6.7%, respectively, at 1 ⁇ g / mL; ⁇ 5.5% and 3.3 at 10 ⁇ g / mL, respectively. 3%; at 100 ⁇ g / mL, they were 11.2% and 8.0%, respectively.
- Ergosterol, sitosterol, and stigmasterol were dispensed into a 96-well plate in an amount of 20 ⁇ L each in 200 ⁇ L of the reaction solution so that the final concentrations were 1 ⁇ g / mL, 10 ⁇ g / mL, 100 ⁇ g / mL, and 200 ⁇ g / mL.
- ergosterol was recognized to have a much stronger active oxygen production inhibitory effect than plant sterols such as sitosterol and stigmasterol, which have similar structures.
- plant sterols such as sitosterol and stigmasterol, which have similar structures.
- ergosterol, stigmasterol, and sitosterol only ergosterol showed a strong ability to suppress the production of active oxygen. It was considered to have an effect over plant sterols under conditions reflecting biological reactions such as
- ergosterol is highly safe because it is contained in foods such as mushrooms with abundant dietary experience, and the formulation containing this as an active ingredient contributes to the development of excessive active oxygen. It can be used as an active ingredient or as a raw material for foods and drinks, quasi-drugs, pharmaceuticals, etc. for preventing, ameliorating or treating many diseases and symptoms such as ischemic heart disease, kidney disease and aging. it can.
- Example 3 Blood pressure lowering effect by single administration of ergosterol
- the administered ergosterol solution (the ergosterol concentration in the solution is 0.1% by mass) is 10 mg / kg body weight (kg) of ergosterol (manufactured by Tokyo Chemical Industry Co., Ltd.).
- a methylcellulose 400cP aqueous solution (Wako Pure Chemical Industries, Ltd.) It was suspended in.
- only a 400 mL aqueous solution of methylcellulose was administered to the control group.
- the blood pressure of each rat was measured with a non-invasive blood pressure measuring device for rats (manufactured by Softron Co., Ltd.) before administration and at 1 hour, 3 hours and 6 hours after administration.
- FIG. 3 shows the systolic blood pressure change rates of the rats in the ergosterol administration group and the control group.
- the blood pressure in the ergosterol administration group rapidly decreased by 5% or more in 1 hour after oral administration and decreased by 10% or more in 6 hours compared with the blood pressure before oral administration.
- the decrease in blood pressure was significant at 1 hour and 6 hours after administration, and was sustained for a long time.
- almost no reduction in blood pressure was observed in the control group. Therefore, ergosterol was found to have an effect of rapidly reducing blood pressure by 5% or more in a short time after oral administration, and an effect of maintaining its efficacy for a long time.
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Abstract
Disclosed is an active oxygen production inhibitor or an oxidative stress ameliorating agent, which can inhibit active oxygen produced in vivo excessively; and an anti-hypertensive agent having high safety and an excellent anti-hypertensive activity. Specifically disclosed are an active oxygen production inhibitor, an oxidative stress ameliorating agent, an anti-hypertensive agent, and an agent for reducing the risk of hypertension and/or preventing and/or ameliorating hypertension, each of which comprises ergosterol as an active ingredient.
Description
本発明は、活性酸素産生を抑制する活性酸素産生抑制剤及び酸化ストレス改善剤に関する。また本発明は、高血圧症状等の予防又は改善に有用な血圧低下剤に関する。
The present invention relates to an active oxygen production inhibitor and an oxidative stress ameliorating agent that suppress active oxygen production. The present invention also relates to a blood pressure lowering agent useful for prevention or improvement of hypertension symptoms and the like.
生体内で産生される活性酸素は、生体調節、抗菌活性、抗ウイルス活性等の生体の恒常性維持に利用されるが、ストレス、紫外線被爆等によってその産生が過剰となると、核酸分解、タンパク質変性、脂質過酸化等を引き起こして細胞にダメージを与え、様々な病態を誘引する一因となってしまう。
Active oxygen produced in the body is used to maintain the homeostasis of the body such as biological regulation, antibacterial activity, antiviral activity, etc., but if its production becomes excessive due to stress, ultraviolet exposure, etc., nucleic acid degradation, protein denaturation It causes lipid peroxidation, damages cells and contributes to various pathological conditions.
体内で過剰な活性酸素が産生されることが発症や症状の進展に関与していると考えられている疾患には、循環器疾患、脳神経系疾患、消化器系疾患、腎疾患、呼吸器系疾患、代謝・内分泌疾患、アレルギー疾患、眼疾患、老化・老人性疾患等がある(非特許文献1)。
Diseases that are thought to be associated with the onset and development of symptoms due to excessive production of active oxygen in the body include cardiovascular disease, cranial nervous system disease, digestive system disease, kidney disease, respiratory system There are diseases, metabolic / endocrine diseases, allergic diseases, eye diseases, aging / senile diseases and the like (Non-patent Document 1).
このため、過剰な活性酸素産生を抑制することは、上記のような疾患の予防、改善や治療につながると考えられ、活性酸素産生を抑制する物質に関する研究開発が進められている。
For this reason, suppression of excessive active oxygen production is thought to lead to prevention, improvement and treatment of the above-mentioned diseases, and research and development relating to substances that suppress active oxygen production are underway.
また、近年、人口の約20~25%が高血圧に該当している。高血圧者は、高血圧によって生じる動脈硬化の結果、脳卒中、心筋梗塞、心不全、腎不全等の脳血管障害、心臓疾患、腎臓疾患、血管疾患等の各種生活習慣病も発症するリスクが高まるため、世界保健機構/国際高圧学会(WHO/ISH)ガイドライン(非特許文献2)が設けられ、日本国のみならず世界的に高血圧対策がなされている。このガイドラインでは、血圧をレベル別に、軽症高血圧、中等症高血圧、重症高血圧等と分類している。
In recent years, about 20-25% of the population falls under high blood pressure. People with high blood pressure are at risk of developing various lifestyle-related diseases such as stroke, myocardial infarction, heart failure, renal failure, and other lifestyle-related diseases such as heart disease, kidney disease, and vascular disease as a result of arteriosclerosis caused by high blood pressure. The Health Organization / International High Pressure Society (WHO / ISH) Guidelines (Non-Patent Document 2) have been established, and antihypertensive measures are being taken not only in Japan but worldwide. In this guideline, blood pressure is classified according to level into mild hypertension, moderate hypertension, severe hypertension, etc.
そして、軽症高血圧とみなされる以前の正常高値者や家族に高血圧の既往歴があり将来血圧が高くなる可能性のある正常血圧者に対しては、食事、運動、飲酒・喫煙の制限など生活習慣の改善を総括する非薬物療法(生活療法)が、高血圧症の有効な発症リスクの低下や予防又は体質改善法とされている。また、医食同源の観点から、食品として摂取可能な血圧降下作用を有する素材を使用した予防又は改善法にも関心が寄せられている。
For those with normal high blood pressure prior to being considered mild hypertension and those with a history of high blood pressure who have a history of high blood pressure and who may have a higher blood pressure in the future, lifestyle habits such as restrictions on diet, exercise, drinking and smoking Non-pharmacological therapy (life therapy) that summarizes the improvement of the above is considered as a method for effectively reducing the risk of developing hypertension, preventing it, or improving the constitution. In addition, from the viewpoint of the same source of medical food, there is an interest in a prevention or improvement method using a material having a blood pressure lowering action that can be taken as food.
一方で、高血圧診断基準を満たす患者もしくは高血圧症の発症が予想される対象者に対しては、上記生活療法と共に、神経因子による調節系に作用する各種神経遮断薬、液性因子に関わる調節系に作用するACE阻害薬、AT受容体拮抗薬、血管内皮由来物質による調節系に関わるCa拮抗薬、腎臓での体液調節系に関わる血圧低下利尿薬などの高血圧症の治療薬の投与が、慢性的疾患の発症を予防する点からも、行なわれている。
On the other hand, for patients who meet the diagnostic criteria for hypertension or for subjects who are expected to develop hypertension, various neuroleptic agents that act on the regulatory system by neural factors, and the regulatory system related to humoral factors, along with the above life therapy Administration of anti-hypertensive drugs such as ACE inhibitors that act on the body, AT receptor antagonists, Ca antagonists related to the regulation system by vascular endothelium-derived substances, and antihypertensive diuretics related to the body fluid regulation system in the kidney It is also performed from the viewpoint of preventing the onset of common diseases.
しかしながら、現状において使用されている高血圧症治療薬は少なからず頻脈・徐脈等の副作用等が存在するため、患者の負担が大きい場合がある。また、血圧低下作用を有する食品素材は、その血圧低下の効果が必ずしも満足できるものではなく、効果の発現までに長期間を要するものが多い。従って、安全性が高く、短時間で薬理効果を発揮するような有用な血圧低下剤が求められている。
However, since there are many side effects such as tachycardia and bradycardia, there are cases where the burden on the patient is heavy because there are many side effects such as tachycardia and bradycardia. In addition, food materials having a blood pressure lowering effect do not always satisfy the blood pressure lowering effect, and many food materials require a long time before the effect is exhibited. Accordingly, there is a need for a useful anti-hypertensive agent that is highly safe and exhibits a pharmacological effect in a short time.
ところで、エルゴステロールは、キノコや酵母などの菌類に含有されるステロールの一種である。このエルゴステロール又はその配糖体は、ヒアルロン酸分解阻害効果(特許文献1)、発毛・育毛効果(特許文献2)、光老化により出現するシワ改善効果(特許文献3)、アディポネクチン分泌促進効果(特許文献4)を有することが知られている。また、エルゴステロールと類似の構造を持つ植物ステロールに、スーパーオキシド消去能があることが報告されている(特許文献5)。
By the way, ergosterol is a kind of sterol contained in fungi such as mushrooms and yeasts. This ergosterol or glycoside thereof has a hyaluronic acid degradation inhibitory effect (Patent Document 1), a hair growth / hair growth effect (Patent Document 2), a wrinkle improvement effect that appears due to photoaging (Patent Document 3), an adiponectin secretion promoting effect It is known to have (Patent Document 4). Moreover, it has been reported that the plant sterol which has a structure similar to ergosterol has superoxide elimination ability (patent document 5).
しかしながら、エルゴステロールが、活性酸素産生抑制能を有することについては全く知られていない。また、アディポネクチンと血圧との関係は様々な報告があるが、アディポネクチン濃度が高まると血圧が上昇するとの報告もあり(非特許文献2)、その関連性は未だ不明である。このように、エルゴステロールが、血圧低下効果を発揮することについては全く知られていない。
However, it is not known at all that ergosterol has an ability to suppress active oxygen production. Moreover, although there are various reports on the relationship between adiponectin and blood pressure, there is also a report that blood pressure increases when the adiponectin concentration increases (Non-Patent Document 2), and the relationship is still unclear. Thus, it is not known at all that ergosterol exerts a blood pressure lowering effect.
本発明は、エルゴステロールを有効成分とする活性酸素産生抑制剤に関する。
The present invention relates to an active oxygen production inhibitor containing ergosterol as an active ingredient.
また本発明は、エルゴステロールを有効成分とする抗酸化ストレス改善剤に関する。
The present invention also relates to an antioxidant stress improving agent containing ergosterol as an active ingredient.
また本発明は、エルゴステロールを投与又は摂取することを特徴とする、活性酸素産生抑制方法に関する。
The present invention also relates to a method for suppressing active oxygen production, characterized by administering or ingesting ergosterol.
また本発明は、エルゴステロールを投与又は摂取することを特徴とする、抗酸化ストレス改善方法に関する。
The present invention also relates to a method for improving antioxidant stress, characterized by administering or ingesting ergosterol.
また本発明は、エルゴステロールの、活性酸素産生抑制剤を製造するための使用に関する。
The present invention also relates to the use of ergosterol for producing an active oxygen production inhibitor.
また本発明は、エルゴステロールの、酸化ストレス改善剤を製造するための使用に関する。
The present invention also relates to the use of ergosterol for producing an oxidative stress ameliorating agent.
また本発明は、活性酸素産生抑制のために使用するためのエルゴステロールに関する。
The present invention also relates to ergosterol for use in suppressing active oxygen production.
また本発明は、酸化ストレス改善のために使用するためのエルゴステロールに関する。
The present invention also relates to ergosterol for use in improving oxidative stress.
また本発明は、エルゴステロールを有効成分とする血圧低下剤に関する。
The present invention also relates to a blood pressure lowering agent containing ergosterol as an active ingredient.
また本発明は、エルゴステロールを有効成分とする高血圧症の発症リスク低下、予防及び/又は改善剤に関する。
The present invention also relates to an agent for reducing, preventing and / or improving the risk of developing hypertension, which contains ergosterol as an active ingredient.
また本発明は、エルゴステロールを投与又は摂取することを特徴とする、血圧低下方法に関する。
The present invention also relates to a method for lowering blood pressure, characterized by administering or ingesting ergosterol.
また本発明は、エルゴステロールを投与又は摂取することを特徴とする、高血圧症の発症リスク低下、予防及び/又は改善方法に関する。
The present invention also relates to a method for reducing, preventing and / or improving the risk of developing hypertension, characterized by administering or ingesting ergosterol.
また本発明は、エルゴステロールの、血圧低下剤を製造するための使用に関する。
The present invention also relates to the use of ergosterol for producing a blood pressure lowering agent.
また本発明は、エルゴステロールの、高血圧症の発症リスク低下、予防及び/又は改善剤を製造するための使用に関する。
The present invention also relates to the use of ergosterol for producing an agent for reducing, preventing and / or improving the risk of developing hypertension.
また本発明は、血圧低下のために使用するためのエルゴステロールに関する。
The present invention also relates to ergosterol for use in lowering blood pressure.
また本発明は、高血圧症の発症リスク低下、予防及び/又は改善のために使用するためのエルゴステロールに関する。
The present invention also relates to ergosterol for use in reducing, preventing and / or improving the risk of developing hypertension.
本発明は、体内に過剰に産生される活性酸素を抑制する活性酸素産生抑制剤又は酸化ストレス改善剤を提供することにある。
The present invention is to provide an active oxygen production inhibitor or an oxidative stress ameliorating agent that suppresses excessive oxygen produced in the body.
また本発明は、安全性が高く、優れた血圧降下作用を有する血圧低下剤を提供することにある。
Another object of the present invention is to provide a blood pressure lowering agent having high safety and an excellent blood pressure lowering action.
本発明者は、活性酸素産生抑制作用を有する物質の検討を行なったところ、エルゴステロールがシトステロールやスティグマステロールなどエルゴステロールと構造が類似した植物ステロール類よりも際だって優れた活性酸素産生抑制作用を示し、活性酸素産生抑制効果を発揮する医薬品、食品、飲料等として又はこれらのための素材として有効であることを見出し、本発明を完成した。
The present inventor examined a substance having an active oxygen production inhibitory action, and found that ergosterol had a significantly superior active oxygen production inhibitory action than plant sterols similar in structure to ergosterol such as sitosterol and stigmasterol. The present invention has been found by finding that the present invention is effective as a pharmaceutical, food, beverage, etc. that exhibits an active oxygen production inhibitory effect or as a material for these.
また本発明者は、血圧降下作用を有する物質の検討を行なったところ、エルゴステロールを経口投与すると、速やかに血圧が低下すると共にこの作用が長時間持続することを見出し、本発明を完成した。
Further, the present inventor examined a substance having a blood pressure lowering action, and found that, when ergosterol was orally administered, the blood pressure rapidly decreased and this action lasted for a long time, thereby completing the present invention.
本発明の活性酸素産生抑制剤又は酸化ストレス改善剤は、体内で産生される活性酸素を抑制することができるので、循環器疾患、アレルギー疾患、老化・老人性疾患等の活性酸素過剰産生によって誘発又は助長される症状及び疾患の発症リスクの低下、予防、治療又は改善効果を発揮する食品、飲料、医薬品等に配合して用いる素材等として有用である。
Since the active oxygen production inhibitor or oxidative stress ameliorating agent of the present invention can suppress active oxygen produced in the body, it is induced by excessive production of active oxygen such as cardiovascular diseases, allergic diseases, aging / senile diseases, etc. Alternatively, it is useful as a material used in combination with foods, beverages, pharmaceuticals, etc. that exerts a reduction, prevention, treatment or improvement effect of symptoms and diseases that are promoted.
本発明の血圧低下剤は、安全性が高く、速やかに血圧を低下させる作用があるため、高血圧症等の発症リスクの低下、予防及び/又は改善に有効である。
Since the blood pressure lowering agent of the present invention is highly safe and has an action of rapidly reducing blood pressure, it is effective in reducing, preventing and / or improving the risk of developing hypertension and the like.
本発明に用いるエルゴステロールは、
で表される化合物である。当該エルゴステロールは、ステロールの一種であり、シイタケやマイタケ等の担子菌類や酵母等の子嚢菌類などの菌類に含まれるものである。また、当該エルゴステロールは、エルゴステロールの3位の水酸基と1~5糖のヘミアセタール又はヘミケタール性水酸基との脱水縮合で生成されたエルゴステロール配糖体であってもよい。さらに、エルゴステロールの3位の水酸基に脂肪酸がエステル結合したエルゴステロール脂肪酸エステルであってもよい。ここで、エステル結合した脂肪酸としては、担子菌類や子嚢菌類などの菌類に含まれる脂肪酸であれば特に制限されず、炭素数14~22の飽和又は不飽和の直鎖の脂肪酸等が挙げられる。
Ergosterol used in the present invention is
It is a compound represented by these. The ergosterol is a kind of sterol and is contained in fungi such as basidiomycetes such as shiitake mushrooms and maitake mushrooms and ascomycetes such as yeast. The ergosterol may be an ergosterol glycoside produced by dehydration condensation of the hydroxyl group at the 3-position of ergosterol and a hemiacetal or hemiketal hydroxyl group of 1 to 5 sugars. Furthermore, an ergosterol fatty acid ester in which a fatty acid is ester-bonded to the hydroxyl group at the 3-position of ergosterol may be used. Here, the fatty acid having an ester bond is not particularly limited as long as it is a fatty acid contained in fungi such as basidiomycetes and ascomycetes, and examples thereof include saturated or unsaturated linear fatty acids having 14 to 22 carbon atoms. .
本発明に用いるエルゴステロールには、公知の化学合成法により得られるものや、エルゴステロールを含有する菌類等から抽出や精製により得られるもの等も包含される(特許文献1~5参照)。また、エルゴステロールとして、市販品、化学合成品、抽出物やその精製物を使用することもできる。
The ergosterol used in the present invention includes those obtained by a known chemical synthesis method and those obtained by extraction or purification from fungi containing ergosterol (see Patent Documents 1 to 5). Commercially available products, chemically synthesized products, extracts and purified products thereof can also be used as ergosterol.
菌類等からエルゴステロールを抽出するための抽出溶剤としては、極性や非極性溶剤の何れを用いてもよいが、例えば、水;メタノール、エタノール、ブタノール、酢酸エチル等の水溶性有機溶剤;ヘキサン、ジエチルエーテル等の疎水性有機溶剤等を用いるのが好ましく、このうち疎水性有機溶剤を用いるのが回収率向上の点から好ましい。これらを単独で又は2種以上組み合わせて用いてもよい。また、煮沸脱気や窒素ガス等の不活性ガスを通気して溶存酸素を除去しつつ、いわゆる非酸化的雰囲気下で抽出する方法を併用してもよい。
As an extraction solvent for extracting ergosterol from fungi and the like, any of polar and nonpolar solvents may be used. For example, water; water-soluble organic solvents such as methanol, ethanol, butanol, and ethyl acetate; hexane, It is preferable to use a hydrophobic organic solvent such as diethyl ether, and among them, it is preferable to use a hydrophobic organic solvent from the viewpoint of improving the recovery rate. You may use these individually or in combination of 2 or more types. Moreover, you may use together the method of extracting in so-called non-oxidative atmosphere, ventilating inert gas, such as boiling deaeration and nitrogen gas, and removing dissolved oxygen.
抽出手段は、例えば活性酸素産生抑制剤又は酸化ストレス改善剤とする場合は、エルゴステロールを含有する菌類等1質量部に対して1~50質量部の溶剤を用い、0(好ましくは20℃)~溶媒の沸点の範囲で1時間~3日間浸漬又は5分~2時間加熱還流するのが好ましい。
When the extraction means is, for example, an active oxygen production inhibitor or an oxidative stress improver, 1 to 50 parts by mass of a solvent is used per 1 part by mass of fungi containing ergosterol, and 0 (preferably 20 ° C.) It is preferable to immerse in the range of the boiling point of the solvent for 1 hour to 3 days or to reflux for 5 minutes to 2 hours.
あるいは、血圧低下剤とする場合は、エルゴステロールを含有する菌類等1質量部に対して2~100質量部の溶剤を用い、0(好ましくは20℃)~溶媒の沸点の範囲で1時間~3日間浸漬又は5分~2時間加熱還流、0.1時間~12時間、特に0.5~5時間抽出するのが好ましい。
Alternatively, in the case of an antihypertensive agent, 2 to 100 parts by weight of a solvent is used per 1 part by weight of fungi containing ergosterol, and the temperature ranges from 0 (preferably 20 ° C.) to the boiling point of the solvent for 1 hour to It is preferable to immerse for 3 days or to heat and reflux for 5 minutes to 2 hours, and to extract for 0.1 to 12 hours, particularly 0.5 to 5 hours.
分離精製手段としては、例えば、活性炭処理、液液分配、カラムクロマトグラフィー、液体クロマトグラフィー、ゲルろ過クロマトグラフィー、精密蒸留等が挙げられる。
Examples of the separation and purification means include activated carbon treatment, liquid-liquid distribution, column chromatography, liquid chromatography, gel filtration chromatography, and precision distillation.
本発明のエルゴステロールは、後記実施例に示すとおりエルゴステロールに、シトステロール、スティグマステロールなどの植物ステロール類よりも、白血球から産生される活性酸素を強く抑制する作用、すなわち優れた活性酸素産生抑制作用が認められたことから、活性酸素産生抑制剤又は酸化ストレス改善剤(以下、「活性酸素産生抑制剤等」とする。)として使用することができ、更にこの製剤を製造するために使用することができる。このとき、当該活性酸素産生抑制剤等には、当該エルゴステロールを単独で、又はこれ以外に、必要に応じて適宜選択した担体等の、配合すべき後述の対象物において許容されるものを使用してもよい。なお、当該製剤は配合すべき対象物に応じて常法により製造することができる。
The ergosterol of the present invention has an action of strongly suppressing active oxygen produced from leukocytes to ergosterol as compared to plant sterols such as sitosterol and stigmasterol, that is, an excellent inhibitory action of active oxygen production, as shown in Examples below. Therefore, it can be used as an active oxygen production inhibitor or an oxidative stress improver (hereinafter referred to as “active oxygen production inhibitor, etc.”), and further used for producing this preparation. Can do. At this time, as the active oxygen production inhibitor, etc., the ergosterol used alone or in addition to this is allowed in the later-described object to be blended, such as a carrier appropriately selected as necessary. May be. In addition, the said formulation can be manufactured by a conventional method according to the target object which should be mix | blended.
当該活性酸素産生抑制剤又は酸化ストレス改善剤は、生体内において活性酸素によって誘発又は助長される疾患、例えば動脈硬化、糖尿病、高脂血症及び癌等の生活習慣病の発症リスクの低下、予防、改善又は治療のための食品、機能性食品、医薬部外品、医薬品、飼料等の有効成分として配合して使用可能である。また、活性酸素産生抑制剤等は、生活習慣病予備軍(生活習慣病には至っていないがその状態に近い(境界領域)の集団)に対しても有用である。更に、当該食品は、活性酸素産生抑制、生活習慣病等の発症リスクの低下、予防、改善や治療をコンセプトとして、必要に応じてその旨を表示した食品、機能性食品、病者用食品、特定保健用食品に応用できる。
The active oxygen production inhibitor or oxidative stress ameliorating agent reduces or prevents the onset risk of diseases caused by active oxygen in the living body such as arteriosclerosis, diabetes, hyperlipidemia and cancer. It can be used as an active ingredient in foods for improvement or treatment, functional foods, quasi drugs, pharmaceuticals, feeds and the like. In addition, active oxygen production inhibitors and the like are also useful for lifestyle-related disease reserve armies (groups that have not reached lifestyle-related disease but are close to that state (boundary region)). In addition, the food is based on the concept of suppression of active oxygen production, risk of onset of lifestyle-related diseases, prevention, improvement and treatment, foods that indicate that if necessary, functional foods, foods for the sick, Applicable to food for specified health use.
ここで、「生体内において活性酸素によって誘発又は助長される疾患」としては循環器疾患、脳神経系疾患、消化器系疾患、腎疾患、呼吸器系疾患、代謝・内分泌疾患、アレルギー疾患、眼疾患、老化・老人性疾患等が挙げられる(非特許文献1)。従って、本発明の酸素産生抑制剤又は酸化ストレス改善剤の投与又は摂取対象者としては、これらの疾患の患者、これらの疾患の発症リスクの高い人等が挙げられる。
Here, “diseases induced or promoted by active oxygen in the living body” include cardiovascular diseases, cranial nervous system diseases, digestive system diseases, kidney diseases, respiratory system diseases, metabolic / endocrine diseases, allergic diseases, ocular diseases And aging / senile diseases (Non-patent Document 1). Accordingly, examples of subjects who are administered or ingested with the oxygen production inhibitor or oxidative stress ameliorating agent of the present invention include patients with these diseases, persons with a high risk of developing these diseases, and the like.
また、「酸化ストレス」とは、生体内の活性酸素産生系と消去系とのバランスが崩れ、過剰な活性酸素が産生されるようになった、生体にとって好ましくない状態を云う。「酸化ストレスを改善する」と云うのは、この崩れたバランスを正常の状態に戻すことを主として云う。酸化ストレスの指標の例には、過酸化脂質、8-OHdG、イソプラスタン、ヒドロペルオキシドなどがあり、酸化ストレス状態においては、生体内でこれらが上昇していると考えられている。従って、本発明の酸素産生抑制剤又は酸化ストレス改善剤の投与又は摂取対象者としては、これらの酸化ストレスの指標が、健常人より高い人が挙げられる。
“Oxidative stress” refers to a state unfavorable for a living body in which the active oxygen production system and the elimination system in the living body are out of balance and excessive active oxygen is produced. “Improving oxidative stress” mainly refers to returning this broken balance to a normal state. Examples of indicators of oxidative stress include lipid peroxide, 8-OHdG, isoplastane, hydroperoxide and the like, and these are considered to be increased in vivo in the oxidative stress state. Accordingly, examples of subjects who are administered or ingested with the oxygen production inhibitor or oxidative stress improving agent of the present invention include those whose oxidative stress index is higher than that of healthy people.
更に、本発明のエルゴステロールは、後記実施例に示すとおり、高血圧自然発症モデルラットであるSHRの血圧を速やかに低下させる作用を有し、しかもこの血圧低下効果を長時間持続する作用を有する。
Furthermore, the ergosterol of the present invention has an action of rapidly lowering the blood pressure of SHR, which is a spontaneously hypertensive model rat, as shown in Examples below, and has the action of maintaining this blood pressure lowering effect for a long time.
従って、エルゴステロールは血圧低下剤として使用することができ、更にこの剤を製造するために使用することができる。このとき、当該血圧低下剤には、当該エルゴステロールを単独で、又はこれ以外に、必要に応じて適宜選択した担体等の、配合すべき後述の対象物において許容されるものを使用してもよい。なお、当該製剤は配合すべき対象物に応じて常法により製造することができる。
Therefore, ergosterol can be used as an antihypertensive agent and can be used to produce this agent. At this time, as the blood pressure lowering agent, the ergosterol alone or in addition to this, a carrier that is appropriately selected as necessary, such as a carrier that is allowed in the object to be described later, may be used. Good. In addition, the said formulation can be manufactured by a conventional method according to the target object which should be mix | blended.
当該血圧低下剤は、上述のとおり(非特許文献2)、高血圧症又は高血圧症に密接に関係する各種生活習慣病の発症リスクの低下や予防、改善又は治療するような飲食品、医薬部外品、医薬品、飼料等のための有効成分として配合して使用可能である。
As described above (Non-Patent Document 2), the blood pressure lowering agent is a food or drink that reduces or prevents, improves, or treats the risk of developing various lifestyle-related diseases that are closely related to hypertension or hypertension. It can be used as an active ingredient for products, pharmaceuticals, feeds and the like.
ここで、当該血圧降下剤は、上述のとおり、軽症患者、中等症患者及び重症患者等の高血圧診断基準を満たす患者若しくは高血圧症の発症が予想される対象者に有効であり、また、軽症高血圧とみなされる以前の正常高値者、生活習慣の関係で高血圧症発症リスクの高い者や家族に高血圧の既往歴があり将来血圧が高くなる可能性の高い正常血圧者にも有効である。
Here, as described above, the antihypertensive agent is effective for patients satisfying the hypertension diagnostic criteria such as mild patients, moderate patients and severe patients, or subjects who are expected to develop hypertension, and mild hypertension. It is also effective for people with normal high blood pressure who are considered to have high blood pressure, those with a high risk of developing hypertension due to lifestyle, and those with normal blood pressure who have a history of high blood pressure in their families and who are likely to have high blood pressure in the future.
そして、当該血圧低下剤は、高血圧症又は高血圧症に密接に関係する各種生活習慣病の発症リスクの低下や予防、改善又は治療をコンセプトとして、必要に応じてその旨を表示した食品、機能性食品、病者用食品、特定保健用食品等に応用できる。
The antihypertensive agent is a food, a function, and a function indicating the necessity of reducing, preventing, improving, or treating the risk of developing various lifestyle-related diseases that are closely related to hypertension or hypertension as necessary. It can be applied to food, food for the sick, food for specified health use, etc.
本発明の活性酸素産生抑制剤又は酸化ストレス改善剤を、医薬品の有効成分として用いる場合、当該医薬品は任意の投与形態で投与され得る。
When the active oxygen production inhibitor or oxidative stress ameliorating agent of the present invention is used as an active ingredient of a pharmaceutical product, the pharmaceutical product can be administered in any dosage form.
本発明の血圧低下剤を、医薬品の有効成分として用いる場合、任意の投与形態で投与され得る。投与形態としては、例えば、経口、経腸、経粘膜、経皮、注射等が挙げられる。経口投与のための製剤の剤型としては、例えば錠剤、カプセル剤、顆粒剤、散剤、シロップ剤等が挙げられる。また非経口投与のものとしては、例えば、静脈内注射剤、筋肉注射剤、座剤、吸入剤、経皮吸収剤、点眼剤、点鼻剤等が挙げられる。
When the blood pressure lowering agent of the present invention is used as an active ingredient of a pharmaceutical product, it can be administered in any dosage form. Examples of the dosage form include oral, enteral, transmucosal, transdermal, and injection. Examples of the dosage form of the preparation for oral administration include tablets, capsules, granules, powders, and syrups. Examples of parenteral administration include intravenous injections, intramuscular injections, suppositories, inhalants, transdermal absorption agents, eye drops, and nasal drops.
また、斯かる製剤では、本発明の活性酸素産生抑制剤、酸化ストレス改善剤又は血圧低下剤を単独で、又は他の薬学的に許容され得る担体と適宜組み合わせて使用してもよい。
In such a preparation, the active oxygen production inhibitor, oxidative stress ameliorating agent or blood pressure lowering agent of the present invention may be used alone or in appropriate combination with other pharmaceutically acceptable carriers.
斯かる担体としては、例えば、賦形剤、結合剤、崩壊剤、滑沢剤、希釈剤、浸透圧調整剤、pH調整剤、乳化剤、防腐剤、安定剤、酸化防止剤、着色剤、紫外線吸収剤、保湿剤、増粘剤、光沢剤、活性増強剤、抗炎症剤、殺菌剤、矯味剤、矯臭剤、増量剤、界面活性剤、分散剤、緩衝剤、保存剤、香料、被膜剤等が挙げられる。
Such carriers include, for example, excipients, binders, disintegrants, lubricants, diluents, osmotic pressure regulators, pH regulators, emulsifiers, preservatives, stabilizers, antioxidants, colorants, ultraviolet rays. Absorber, moisturizer, thickener, brightener, activity enhancer, anti-inflammatory agent, bactericidal agent, corrigent, flavoring agent, extender, surfactant, dispersant, buffer, preservative, fragrance, coating agent Etc.
これらの投与形態のうち、経口投与が好ましく、経口投与剤の有効成分として用いる場合の上記製剤中の有効成分である本発明のエルゴステロールの含有量は、通常乾燥物換算で、製剤全質量の0.01~100質量%であるのが好ましく、0.05~50質量%であるのがより好ましく、0.1~30質量%であるのが更に好ましく、0.5~20質量%であるのがより更に好ましい。
Of these dosage forms, oral administration is preferred, and the content of the ergosterol of the present invention, which is an active ingredient in the above preparation when used as an active ingredient of an oral administration agent, is usually the total mass of the preparation in terms of dry matter. It is preferably 0.01 to 100% by mass, more preferably 0.05 to 50% by mass, still more preferably 0.1 to 30% by mass, and 0.5 to 20% by mass. Is even more preferable.
上記製剤の投与量は、患者の状態、体重、性別、年齢又はその他の要因に従って変動し得るが、経口投与の場合の成人1人当りの1日の投与量は、通常乾燥物換算で、有効成分エルゴステロールとして3~300mgであるのが好ましく、10~200mgであるのがより好ましく、20~100mgであるのが更に好ましい。また、上記製剤は、任意の投与計画に従って投与させ得るが、1日1回~数回投与するのが好ましく、その投与間隔は3~18時間が好ましく、4~6時間がより好ましい。
The dosage of the above formulation may vary according to the patient's condition, body weight, sex, age or other factors, but the daily dosage per adult for oral administration is usually effective on a dry matter basis The component ergosterol is preferably 3 to 300 mg, more preferably 10 to 200 mg, and even more preferably 20 to 100 mg. The preparation can be administered according to an arbitrary administration schedule, but is preferably administered once to several times a day, and the administration interval is preferably 3 to 18 hours, more preferably 4 to 6 hours.
本発明の活性酸素産生抑制剤、酸化ストレス改善剤又は血圧低下剤を、食品の有効成分として用いる場合、当該食品の形態は、固形、半固形又は液状でもよい。食品の例としては、パン類、麺類、菓子類、ゼリー類、乳製品、冷凍食品、インスタント食品、澱粉加工製品、加工肉製品、その他加工食品、飲料、スープ類、調味料、栄養補助食品等、及びそれらの原料が挙げられる。また、上記経口投与製剤と同様のように、錠剤形態、丸剤形態、カプセル形態、液剤形態、シロップ形態、粉末形態、顆粒形態等であってもよい。
When the active oxygen production inhibitor, oxidative stress improver or blood pressure lowering agent of the present invention is used as an active ingredient of food, the form of the food may be solid, semi-solid or liquid. Examples of foods include breads, noodles, confectionery, jelly, dairy products, frozen foods, instant foods, processed starch products, processed meat products, other processed foods, beverages, soups, seasonings, dietary supplements, etc. , And their raw materials. Moreover, like the said oral administration formulation, a tablet form, a pill form, a capsule form, a liquid form, a syrup form, a powder form, a granule form etc. may be sufficient.
種々の形態の食品を調製するには、本発明の活性酸素産生抑制剤、酸化ストレス改善剤又は血圧低下剤を単独で、またはこれと食品に許容され得るもの、例えば他の食品材料や、溶剤、軟化剤、油脂、乳化剤、防腐剤、香料、安定剤、着色剤、酸化防止剤、保湿剤、増粘剤等を適宜組み合わせて使用してもよい。
In preparing various forms of food, the active oxygen production inhibitor, oxidative stress-improving agent, or blood pressure-lowering agent of the present invention alone or in combination with foods, such as other food materials and solvents , Softeners, fats and oils, emulsifiers, preservatives, fragrances, stabilizers, colorants, antioxidants, humectants, thickeners, and the like may be used in appropriate combinations.
また、食品中の本発明のエルゴステロールの含有量は、通常乾燥物として、飲料等の液状形態の場合、飲料中0.001~10質量%であるのが好ましく、0.01~10質量%であるのがより好ましく、0.05~2質量%であるのが更に好ましく、0.1~0.5質量%であるのがより更に好ましい。また、錠剤や加工食品等の固形又は半固形形態の場合、全組成物中、0.01~50質量%であるのが好ましく、0.05~25質量%であるのがより好ましく、0.1~10質量%であるのが更に好ましく、0.3~5質量%であるのがより更に好ましい。
Further, the content of the ergosterol of the present invention in the food is preferably 0.001 to 10% by mass in the beverage, usually 0.01 to 10% by mass in the case of a liquid form such as a beverage as a dry product. Is more preferably 0.05 to 2% by mass, and still more preferably 0.1 to 0.5% by mass. In the case of a solid or semi-solid form such as a tablet or processed food, the total composition is preferably 0.01 to 50% by mass, more preferably 0.05 to 25% by mass, and The content is more preferably 1 to 10% by mass, and still more preferably 0.3 to 5% by mass.
また、本発明の活性酸素産生抑制剤、酸化ストレス改善剤又は血圧低下剤を飼料の有効成分として用いる場合には、当該飼料としては、例えば牛、豚、鶏、羊、馬等に用いる家畜用飼料、ウサギ、ラット、マウス等に用いる小動物用飼料、マグロ、ウナギ、タイ、ハマチ、エビ等に用いる魚介類用飼料、犬、猫、小鳥、リス等に用いるペットフード等が挙げられる。
In addition, when the active oxygen production inhibitor, oxidative stress improving agent or blood pressure lowering agent of the present invention is used as an active ingredient of feed, the feed is for livestock used for cattle, pigs, chickens, sheep, horses, etc. Examples include feeds for small animals used for feeds, rabbits, rats, mice, etc., feeds for seafood used for tuna, eel, Thailand, Hamachi, shrimp, etc., pet foods used for dogs, cats, small birds, squirrels, and the like.
尚、飼料を製造する場合には、エルゴステロールの含有量の他に、牛、豚、羊等の肉類、蛋白質、穀物類、ぬか類、粕類、糖類、野菜、ビタミン類、ミネラル類等一般に用いられる飼料原料、更に一般的に飼料に使用されるゲル化剤、保型剤、pH調整剤、調味料、防腐剤、栄養補強剤等を必要に応じて配合し、常法により当該飼料を加工製造することができる。
In addition, when producing feed, in addition to the content of ergosterol, meat such as cattle, pigs, sheep, protein, grains, bran, potatoes, sugars, vegetables, vitamins, minerals, etc. The feed ingredients used, and gelling agents, shape-preserving agents, pH adjusters, seasonings, preservatives, nutritional supplements, etc., which are generally used in feeds, are blended as necessary. Can be processed and manufactured.
また、飼料中におけるエルゴステロールの含有量は、その使用形態により異なるが、通常0.001~50質量%であり、0.01~10質量%が好ましく、0.05~1質量%がより好ましい。
Further, the content of ergosterol in the feed varies depending on the use form, but is usually 0.001 to 50% by mass, preferably 0.01 to 10% by mass, more preferably 0.05 to 1% by mass. .
以下、本発明を実施例に基づき更に詳細に説明するが、本発明はこれに限定されるものではない。
Hereinafter, the present invention will be described in more detail based on examples, but the present invention is not limited thereto.
実施例1:エルゴステロールの活性酸素産生抑制試験
Example 1: Ergosterol active oxygen production inhibition test
試料として、エルゴステロール(東京化成工業社製)を用いた。比較試料として、植物ステロール類のシトステロール(ACROS社製)、スティグマステロール(SIGMA社製)を用いた。
Ergosterol (manufactured by Tokyo Chemical Industry Co., Ltd.) was used as a sample. Plant sterols sitosterol (manufactured by ACROS) and stigmasterol (manufactured by SIGMA) were used as comparative samples.
動物は、SDラット(10~16週齢、雄)を使用した。当該SDラットから、イソフルラン(アボットジャパン社製)麻酔下で、頚動脈採血を行った。この血液サンプルを、血球分離用試薬(SIGMA社製)に重層して遠心分離した後、白血球画分を回収した。
The animals used were SD rats (10-16 weeks old, male). From the SD rat, carotid artery blood was collected under isoflurane (Abbott Japan) anesthesia. This blood sample was layered on a blood cell separation reagent (manufactured by SIGMA) and centrifuged, and then the leukocyte fraction was collected.
回収した白血球画分に、エルゴステロール、シトステロール、スティグマステロールをそれぞれ1μg/mL、10μg/mL、100μg/mLとなるよう加え、室温で1時間反応させた。その後、蛍光試薬10μM 5-(および6-)クロロメチル-2’,7’-ジクロロジヒドロフルオレセイン・ジアセテート、アセチルエステル(5,6-CM-H2DCFDA)(Invitrogen社製)を室温で20分作用させてから、10容量%(v/v)固定試薬(BECKMAN COULTER社製)を添加し室温で20分作用させた。蛍光試薬添加から固定試薬添加までの間に白血球細胞内で産生された活性酸素量を、Flowcytemetory(フローサイトメーター:機種名 FACSCalibur、Becton Dickinson社製)にて測定した。
To the collected leukocyte fraction, ergosterol, sitosterol, and stigmasterol were added to 1 μg / mL, 10 μg / mL, and 100 μg / mL, respectively, and reacted at room temperature for 1 hour. Thereafter, the fluorescent reagent 10 μM 5- (and 6-) chloromethyl-2 ′, 7′-dichlorodihydrofluorescein diacetate, acetyl ester (5,6-CM-H2DCFDA) (manufactured by Invitrogen) is allowed to act at room temperature for 20 minutes. Then, 10% by volume (v / v) fixing reagent (BECKMAN manufactured by COULTER) was added and allowed to act at room temperature for 20 minutes. The amount of active oxygen produced in the white blood cells from the addition of the fluorescent reagent to the addition of the fixing reagent was measured with a flow cytometer (flow cytometer: model name: FACSCalibur, manufactured by Becton Dickinson).
試料無添加にて上記と同様にして細胞内の活性酸素を測定し、無添加(コントロール)における活性酸素産生量を、活性酸素産生抑制率0%とした。白血球から産生される活性酸素の抑制能について検討することにより、SOD様活性のようにスーパーオキシドを直接消去するだけでなく、活性酸素産生酵素の発現を抑制する、活性酸素消去酵素の発現を亢進する、活性酸素産生酵素の構造に作用し活性を抑制する、活性酸素消去酵素の構造に作用し活性を亢進するような素材も検出することが可能である。
The intracellular active oxygen was measured in the same manner as described above with no sample added, and the amount of active oxygen produced without addition (control) was defined as the active oxygen production inhibition rate of 0%. By studying the ability to inhibit active oxygen produced from leukocytes, not only superoxide is directly eliminated as in the case of SOD-like activity, but also the expression of reactive oxygen-producing enzyme is suppressed and the expression of active oxygen-eliminating enzyme is enhanced. It is also possible to detect materials that act on the structure of the active oxygen producing enzyme to suppress the activity and act on the structure of the active oxygen scavenging enzyme to enhance the activity.
図1に示すように、エルゴステロールを1μg/mL、10μg/mL、100μg/mLで白血球画分に添加したとき、いずれも産生される活性酸素を抑制した。これら各濃度の活性酸素産生抑制率は、コントロールの活性酸素産生抑制率を0%とした場合、1μg/mLで16.5%、10μg/mLで30.6%、100μg/mLで29.7%であり、何れの濃度でも産生される活性酸素が有意に抑制された。これに対し、シトステロール、スティグマステロールを添加したときの活性酸素産生抑制率は、1μg/mLでは、それぞれ8.5%、6.7%;10μg/mLでは、それぞれ-5.5%、3.3%;100μg/mLでは、それぞれ11.2%、8.0%であった。
As shown in FIG. 1, when ergosterol was added to the leukocyte fraction at 1 μg / mL, 10 μg / mL, and 100 μg / mL, all of the active oxygen produced was suppressed. The active oxygen production inhibition rates at these concentrations are 16.5% at 1 μg / mL, 30.6% at 10 μg / mL, and 29.7 at 100 μg / mL when the active oxygen production suppression rate of the control is 0%. The active oxygen produced at any concentration was significantly suppressed. On the other hand, the active oxygen production inhibition rates when sitosterol and stigmasterol were added were 8.5% and 6.7%, respectively, at 1 μg / mL; −5.5% and 3.3 at 10 μg / mL, respectively. 3%; at 100 μg / mL, they were 11.2% and 8.0%, respectively.
実施例2:エルゴステロールのスーパーオキシド産生抑制試験
Example 2: Superoxide production inhibition test of ergosterol
エルゴステロール、シトステロール、スティグマステロールを反応液200μL中で終濃度1μg/mL、10μg/mL、100μg/mL、200μg/mLとなるようにそれぞれ20μLずつ96wellプレートに分注した。50μM Lucigenin(SIGMA社製)を20μL(終濃度5μM)添加し、37℃で10分間静置後、22mU/mLキサンチンオキシダーゼ(WAKO社製)を20μL(終濃度2.2mU/mL)加えた。反応は500μMXantine-100μM EDTA/PBS溶液中で行い、5分間のスーパーオキシド産生量を測定した(BERTHOLD centro LB960、ベルトールドジャパン株式会社製)。結果は、コントロールに対するスーパーオキシド産生抑制率(%)で示した。
Ergosterol, sitosterol, and stigmasterol were dispensed into a 96-well plate in an amount of 20 μL each in 200 μL of the reaction solution so that the final concentrations were 1 μg / mL, 10 μg / mL, 100 μg / mL, and 200 μg / mL. 20 μL of 50 μM Lucigenin (manufactured by SIGMA) (final concentration: 5 μM) was added and allowed to stand at 37 ° C. for 10 minutes, and then 20 μL (final concentration: 2.2 mU / mL) of 22 mU / mL xanthine oxidase (manufactured by WAKO) was added. The reaction was carried out in a 500 μM Xantine-100 μM EDTA / PBS solution, and the amount of superoxide produced for 5 minutes was measured (BERTHOLD centro LB960, manufactured by Bertoled Japan KK). The results are shown as the superoxide production inhibition rate (%) relative to the control.
図2に示すように、いずれの剤においても1μg/mL、10μg/mL、100μg/mLではスーパーオキシドを抑制しなかった。エルゴステロールとスティグマステロール200μg/mLでは、コントロールと比べてスーパーオキシドを15.5%、6.1%抑制した。
As shown in FIG. 2, superoxide was not suppressed in any agent at 1 μg / mL, 10 μg / mL, and 100 μg / mL. Ergosterol and stigmasterol 200 μg / mL suppressed superoxide by 15.5% and 6.1% compared to control.
よって、エルゴステロールには、構造が類似しているシトステロール及びスティグマステロールなどの植物ステロールよりも、はるかに強い活性酸素産生抑制作用が認められた。エルゴステロール、スティグマステロール、シトステロールのうち、エルゴステロールのみが強い活性酸素産生抑制能を示したが、この濃度付近におけるスーパーオキシド産生抑制活性についてはそれぞれ同程度であったことから、エルゴステロールは白血球細胞を用いるような生体反応を反映した条件で植物ステロールよりも効果を有すると考えられた。しかも、エルゴステロールは、食経験の豊富なキノコ類等の食品に含まれているので安全性が高く、これを有効成分とする製剤は、過剰な活性酸素の産生が発症の一因であるといわれている虚血性心疾患、腎疾患や老化等の多くの疾病や症状等を予防、改善又は治療するための飲食品、医薬部外品、医薬品等の有効成分として又は素材として使用することができる。
実施例3:エルゴステロール単回投与による血圧低下作用 Therefore, ergosterol was recognized to have a much stronger active oxygen production inhibitory effect than plant sterols such as sitosterol and stigmasterol, which have similar structures. Among ergosterol, stigmasterol, and sitosterol, only ergosterol showed a strong ability to suppress the production of active oxygen. It was considered to have an effect over plant sterols under conditions reflecting biological reactions such as In addition, ergosterol is highly safe because it is contained in foods such as mushrooms with abundant dietary experience, and the formulation containing this as an active ingredient contributes to the development of excessive active oxygen. It can be used as an active ingredient or as a raw material for foods and drinks, quasi-drugs, pharmaceuticals, etc. for preventing, ameliorating or treating many diseases and symptoms such as ischemic heart disease, kidney disease and aging. it can.
Example 3: Blood pressure lowering effect by single administration of ergosterol
実施例3:エルゴステロール単回投与による血圧低下作用 Therefore, ergosterol was recognized to have a much stronger active oxygen production inhibitory effect than plant sterols such as sitosterol and stigmasterol, which have similar structures. Among ergosterol, stigmasterol, and sitosterol, only ergosterol showed a strong ability to suppress the production of active oxygen. It was considered to have an effect over plant sterols under conditions reflecting biological reactions such as In addition, ergosterol is highly safe because it is contained in foods such as mushrooms with abundant dietary experience, and the formulation containing this as an active ingredient contributes to the development of excessive active oxygen. It can be used as an active ingredient or as a raw material for foods and drinks, quasi-drugs, pharmaceuticals, etc. for preventing, ameliorating or treating many diseases and symptoms such as ischemic heart disease, kidney disease and aging. it can.
Example 3: Blood pressure lowering effect by single administration of ergosterol
高血圧自然発症モデルラットSHR(16週齢、雄:n=6)に対して、エルゴステロール溶液3mLをゾンデにより経口投与した。投与したエルゴステロール溶液(溶液中のエルゴステロール濃度0.1質量%)は、エルゴステロール(東京化成工業社製)10mg/体重(kg)となるようメチルセルロース400cP水溶液(和光純薬工業(株))に懸濁した。また、コントロール群には、メチルセルロース400cP水溶液のみを投与した。各ラットの血圧を、投与前、投与後1時間、3時間、6時間に、ラット用非観式血圧測定装置(ソフトロン社製)にて測定した。
3 mL of ergosterol solution was orally administered to a spontaneous hypertensive model rat SHR (16 weeks old, male: n = 6) by means of a sonde. The administered ergosterol solution (the ergosterol concentration in the solution is 0.1% by mass) is 10 mg / kg body weight (kg) of ergosterol (manufactured by Tokyo Chemical Industry Co., Ltd.). A methylcellulose 400cP aqueous solution (Wako Pure Chemical Industries, Ltd.) It was suspended in. In addition, only a 400 mL aqueous solution of methylcellulose was administered to the control group. The blood pressure of each rat was measured with a non-invasive blood pressure measuring device for rats (manufactured by Softron Co., Ltd.) before administration and at 1 hour, 3 hours and 6 hours after administration.
図3に、エルゴステロール投与群のラット及びコントロール群のラットの収縮期血圧変化率を示した。エルゴステロール投与群の血圧は、経口投与前の血圧に比し、経口投与後1時間で速やかに5%以上低下し、6時間では10%以上低下した。血圧低下は、投与後1時間、6時間で有意であり、長時間持続していた。これに対し、コントロール群には、ほとんど血圧低下は認められなかった。従って、エルゴステロールには、経口投与後血圧を短時間で速やかに5%以上低下させる作用、且つその効能が長時間持続する作用が認められた。
FIG. 3 shows the systolic blood pressure change rates of the rats in the ergosterol administration group and the control group. The blood pressure in the ergosterol administration group rapidly decreased by 5% or more in 1 hour after oral administration and decreased by 10% or more in 6 hours compared with the blood pressure before oral administration. The decrease in blood pressure was significant at 1 hour and 6 hours after administration, and was sustained for a long time. In contrast, almost no reduction in blood pressure was observed in the control group. Therefore, ergosterol was found to have an effect of rapidly reducing blood pressure by 5% or more in a short time after oral administration, and an effect of maintaining its efficacy for a long time.
Claims (16)
- エルゴステロールを有効成分とする活性酸素産生抑制剤。 An active oxygen production inhibitor containing ergosterol as an active ingredient.
- エルゴステロールを有効成分とする酸化ストレス改善剤。 An oxidative stress remedy containing ergosterol as an active ingredient.
- エルゴステロールを投与又は摂取することを特徴とする、活性酸素産生抑制方法。 A method for suppressing active oxygen production, which comprises administering or ingesting ergosterol.
- エルゴステロールを投与又は摂取することを特徴とする、酸化ストレス改善方法。 Oxidative stress improvement method characterized by administering or ingesting ergosterol.
- エルゴステロールの、活性酸素産生抑制剤を製造するための使用。 Use of ergosterol for producing an active oxygen production inhibitor.
- エルゴステロールの、酸化ストレス改善剤を製造するための使用。 ¡Use of ergosterol to produce an oxidative stress-improving agent.
- 活性酸素産生抑制のために使用するためのエルゴステロール。 Ergosterol for use in suppressing active oxygen production.
- 酸化ストレス改善のために使用するためのエルゴステロール。 Ergosterol for use in improving oxidative stress.
- エルゴステロールを有効成分とする血圧低下剤。 An antihypertensive agent containing ergosterol as an active ingredient.
- エルゴステロールを有効成分とする高血圧症の発症リスク低下、予防及び/又は改善剤。 An agent for reducing, preventing and / or improving the risk of developing hypertension, which contains ergosterol as an active ingredient.
- エルゴステロールを投与又は摂取することを特徴とする、血圧低下方法。 A method for lowering blood pressure, characterized by administering or ingesting ergosterol.
- エルゴステロールを投与又は摂取することを特徴とする、高血圧症の発症リスク低下、予防及び/又は改善方法。 A method for reducing, preventing and / or improving the risk of developing hypertension, comprising administering or ingesting ergosterol.
- エルゴステロールの、血圧低下剤を製造するための使用。 ¡Use of ergosterol to produce antihypertensive agent.
- エルゴステロールの、高血圧症の発症リスク低下、予防及び/又は改善剤を製造するための使用。 使用 Use of ergosterol to produce an agent for reducing, preventing and / or improving the risk of developing hypertension.
- 血圧低下のために使用するためのエルゴステロール。 Ergosterol for use in lowering blood pressure.
- 高血圧症の発症リスク低下、予防及び/又は改善のために使用するためのエルゴステロール。
Ergosterol for use in reducing, preventing and / or improving the risk of developing hypertension.
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JP2009-294726 | 2009-12-25 | ||
JP2009-294727 | 2009-12-25 | ||
JP2009294727 | 2009-12-25 | ||
JP2009294726 | 2009-12-25 |
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WO2011078323A1 true WO2011078323A1 (en) | 2011-06-30 |
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PCT/JP2010/073341 WO2011078323A1 (en) | 2009-12-25 | 2010-12-24 | Active oxygen production inhibitor and anti-hypertensive agent |
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Cited By (3)
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CN104434927A (en) * | 2014-12-16 | 2015-03-25 | 吉林农业大学 | Application of bicyclopentanoperhydrophenanthrene malonate B in preparing hypotensive drugs |
CN104523702A (en) * | 2014-12-17 | 2015-04-22 | 吉林农业大学 | Application of phenylalanine cyclopentanoperhydro-phenanthrene ester in preparation of hypotensor |
CN107519183A (en) * | 2017-07-28 | 2017-12-29 | 贵州源熙生物研发有限公司 | Application of the ergosterol in anti-oxidation stress |
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JP2005068132A (en) * | 2003-08-06 | 2005-03-17 | Enkaku Iryo Kenkyusho:Kk | Adiponectin secretion promoter, and anti-arteriosclerosis agent, anti-obesity agent, antidiabetic mellitus agent, food additive, functional food and feed additive containing adiponectin secretion promoter |
JP2006347929A (en) * | 2005-06-15 | 2006-12-28 | Gunma Prefecture | Active oxygen scavenger and method for using the same |
WO2009138583A2 (en) * | 2008-04-29 | 2009-11-19 | Am Phyto-Conseil | Use of a composition containing ergosterol or a natural extract of a vegetable or animal microorganism |
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JP2005068132A (en) * | 2003-08-06 | 2005-03-17 | Enkaku Iryo Kenkyusho:Kk | Adiponectin secretion promoter, and anti-arteriosclerosis agent, anti-obesity agent, antidiabetic mellitus agent, food additive, functional food and feed additive containing adiponectin secretion promoter |
JP2006347929A (en) * | 2005-06-15 | 2006-12-28 | Gunma Prefecture | Active oxygen scavenger and method for using the same |
WO2009138583A2 (en) * | 2008-04-29 | 2009-11-19 | Am Phyto-Conseil | Use of a composition containing ergosterol or a natural extract of a vegetable or animal microorganism |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
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CN104434927A (en) * | 2014-12-16 | 2015-03-25 | 吉林农业大学 | Application of bicyclopentanoperhydrophenanthrene malonate B in preparing hypotensive drugs |
CN104523702A (en) * | 2014-12-17 | 2015-04-22 | 吉林农业大学 | Application of phenylalanine cyclopentanoperhydro-phenanthrene ester in preparation of hypotensor |
CN107519183A (en) * | 2017-07-28 | 2017-12-29 | 贵州源熙生物研发有限公司 | Application of the ergosterol in anti-oxidation stress |
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