JP6190211B2 - PDE3 inhibitor - Google Patents

Description

  The present invention relates to a PDE3 (phosphodiesterase 3) inhibitor.

  3 ', 5'-cyclic adenosine monophosphate (cAMP) and 3', 5'-cyclic guanosine monophosphate (cGMP) act as second messengers when cells receive hormone and neurotransmitter signals It is known that when the intracellular concentration increases, a signal is transmitted downstream and the cell responds. For example, when prostaglandins and adrenaline act on cell surface receptors, adenylate cyclase is activated, increasing intracellular cAMP concentration and causing various cellular responses such as smooth muscle relaxation.

  Cyclic phosphate diesters typified by cAMP and cGMP are used as substrates, and the enzyme that hydrolyzes them is called phosphodiesterase (PDE). When the activity of PDE increases, the concentration of intracellular cAMP and cGMP decreases. Accordingly, since the activity of PDE greatly affects the concentration of intracellular cAMP and cGMP, PDE plays an extremely important role in the activation of the intracellular signal transduction system and the function of cells and tissues.

  PDE is known to have about 11 subtypes, of which PDE3 has a higher affinity for cAMP than cGMP, also known as cGMP-inhibited PDE, and is known to specifically reduce the intracellular concentration of cAMP. It has been. PDE3 is expressed mainly in the heart, vascular smooth muscle, ovary, kidney, adipose tissue, hepatocyte, bronchial smooth muscle and the like.

  Inhibiting the activity of PDE3 present in the lungs, heart and peripheral blood vessels prevents the decrease in cAMP concentration, leading to contraction and relaxation in the lungs, heart and peripheral blood vessels, increasing myocardial strength, and inhibiting platelet aggregation . Therefore, the PDE3 inhibitor is effective in preventing and improving heart failure, chronic arterial occlusion, and thrombosis.

  Inhibiting PDE3 present in bronchial smooth muscles relaxes bronchial smooth muscles, so PDE3 inhibitors can improve bronchial function by expanding bronchi contracted by asthma and the like.

  As such PDE3 inhibitors, for example, amrinone and milrinone are known, and preemptive therapy of these drugs reduces the risk of low cardiac output and low oxygen supply after cardiac surgery. be able to. However, there is a demand for materials derived from natural products that are less active and easy to use.

  On the other hand, licorice is a plant belonging to the genus Lizoaceae, and the licorice is used as it is or as an extract or powder as a sweetener, and is anti-obesity (Patent Document 1), anti-visceral obesity (Patent Document 2), cGMP-specific. It has been reported that it has an effect of improving sexual dysfunction by inhibiting phosphodiesterase (Patent Document 3) and can be used as a basic component of slimming cosmetics (Patent Document 4).

  Marjoram is a plant belonging to the genus Lamiaceae, and is used as an herb for various uses, and the marjoram or an extract thereof has been reported to have an anti-obesity effect (Patent Documents 5 and 6).

  Parsley is a plant belonging to the family Apiaceae, and it is reported that the parsley or an extract thereof is used as an anti-obesity (Patent Documents 7 and 8) effect or a slimming skin cosmetic (Patent Document 9).

  It is a vitamin A precursor (-carotene is a kind of pigment that is contained abundantly in green-yellow vegetables and seaweeds, and (-carotene improves metabolic syndrome (patent document 10), anti-obesity (patent documents 11 to 13) effect It has been reported to have

  However, the relationship between marjoram, parsley, licorice and β-carotene and PDE3 inhibition is not known.

JP 2009-292805 A International Publication No. 2002/047699 JP 2000-319191 A JP 2009-249340 A JP 2006-36788 A JP 2006-16312 A JP 2006-273788 A JP 2005-8572 A JP 2004-59520 A International Publication No. 2007/037438 JP 2009-161443 A JP 2008-280281 A JP 2003-95930 A

  The present invention relates to providing pharmaceuticals, quasi-drugs, foods, feeds, and materials that can be blended in them, having a PDE3 inhibitory action and high safety.

  As a result of intensive studies to solve the above problems, the present inventors have found that marjoram, parsley, licorice and β-carotene have a PDE3 inhibitory action.

That is, the present invention relates to the following.
(1) A PDE3 inhibitor comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene.
(2) A circulatory function improver comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene.
(3) A bronchial function improving agent comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene.
(4) A non-therapeutic PDE3 inhibition method comprising administering or ingesting one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene to humans or animals.
(5) A method for improving non-therapeutic circulatory function, wherein one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene are administered or ingested to humans or animals.
(6) A non-therapeutic method for improving bronchial function, wherein one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene are administered or ingested to humans or animals.

  The PDE3 inhibitor and the like of the present invention have excellent PDE3 inhibitor action and are highly safe even when ingested for a long period of time. It is useful as an external product, food and feed, or a material or preparation for blending them.

In the present invention, “PDE3 inhibition” refers to reducing or eliminating the enzyme activity of PDE3. Specifically, it acts on the active center of PDE3 to prevent reaction initiation, and forms a covalent bond with a specific moiety to make it irreversible. Binding, inhibition of reaction catalysis by PDE3, PDE3 molecule alone, enzyme-substrate complex, or both, inhibiting reaction progress, competitively binding to the same site as substrate to initiate reaction Competitive inhibition that prevents or non-competitive inhibition of the enzyme or enzyme-substrate complex that binds to a different site from the substrate and prevents the progress of the reaction. Also included are those in which the enzyme activity of PDE3 is suppressed by acutely or chronically reducing the expression level of PDE3 gene or protein.
Moreover, although it is known that there are two types of PDE3, 3A and 3B, both are included in the present invention.

  “Improvement of circulatory function” refers to relaxation and expansion of vascular smooth muscles in the lungs, heart and periphery, suppression of platelet aggregation, increase in myocardial strength, heart failure, failure of vascular function, chronic arterial occlusion, thrombus formation or thrombus It means to prevent and improve the disease.

  “Bronchial function improvement” means relaxation of bronchial smooth muscle, bronchodilation, prevention and improvement of bronchial asthma, relaxation of bronchial smooth muscle, dilation of bronchus contracted by asthma and the like, and improvement of accompanying cardiac function.

(A) Marjoram, parsley, licorice In the present invention, marjoram refers to Origanum majorana belonging to the genus Lamiaceae.
Parsley refers to Carum Petroselinum and Petroselium crispum, which belong to the genus Dutchis.
Licorice refers to Glycyrrhiza uralensis FISCHER, Glycyrrhiza inflata BATALIN, or Glycyrrhiza glabra LINNE.

(B) β-carotene In the present invention, β-carotene can be extracted and purified from various plants, and examples thereof include those obtained from Dunaliella bardawil, Dunaliella salina and the like. .

  Such a plant can be any arbitrary part, for example, whole plant, leaf (leaf blade, petiole, etc.), bark, woody part, branch, fruit, seed, flower (petal, ovary, etc.), root, rhizome, etc. Or a combination thereof, but marjoram preferably uses whole grass, parsley uses whole grass, and licorice uses root or rhizome.

  Such plants can be used by crushing, pulverizing or exploiting them as they are, or they can be used after drying or pulverizing those treated from now on, or using them as extracted extracts. Is preferred.

  The plant may be subjected to an extraction process as it is, or may be subjected to an extraction process after being pulverized, cut or dried to obtain an extract.

  As the above extract, commercially available ones may be used, or various solvent extracts obtained by a conventional method, or diluted solutions thereof, concentrated solutions thereof, dried powders thereof, pastes or activated carbon treatments thereof. There may be. As an example, an extract can be obtained by extraction means, such as extracting the said plant under fixed temperature (low temperature, normal temperature, or warming), or extracting using extraction tools, such as a Soxhlet extractor.

Known extraction methods include, for example, solid-liquid extraction, liquid-liquid extraction, immersion, decoction, leaching, reflux extraction, ultrasonic extraction, microwave extraction, stirring, and the like. In order to shorten the extraction time, solid-liquid extraction with stirring is desirable. Examples of suitable conditions for this solid-liquid extraction include stirring at 10 to 100 ° C. and 100 to 400 rpm / min for 1 to 30 minutes. As a suitable example of immersion, the immersion for 1 hour-14 days is mentioned at 10-50 degreeC. Moreover, when shortening extraction time, solid-liquid extraction with stirring is desirable.
In order to prevent oxidation of the extract, a means for extraction under a so-called non-oxidizing atmosphere while removing dissolved oxygen by bubbling degassing or inert gas such as nitrogen gas may be used in combination.

  As the solvent for extraction, either a polar solvent or a nonpolar solvent can be used. Examples of the extraction solvent include water; alcohols such as methanol, ethanol, propanol and butanol; polyhydric alcohols such as propylene glycol and butylene glycol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate and ethyl acetate. Linear or cyclic ethers such as tetrahydrofuran and diethyl ether; polyethers such as polyethylene glycol; hydrocarbons such as squalene, hexane, cyclohexane and petroleum ether; aromatic hydrocarbons such as benzene and toluene; dichloromethane And halogenated hydrocarbons such as chloroform, dichloroethane and carbon tetrachloride; pyridines; carbon dioxide, supercritical carbon dioxide; organic solvents such as fats, waxes and other oils; and mixtures thereof. These solvents can be used alone or in combination as a mixture.

  Among these solvents, one or more selected from water, alcohols (more preferably having 1 to 5 carbon atoms), ketones, and hydrocarbons are preferable. Among these, water, ethanol, a water-ethanol mixed solution, acetone, and hexane are more preferable. When a water-ethanol mixed solution is used, the ethanol concentration (V / V) in the mixed solution is preferably 0.01% by volume or more, more preferably 20% by volume or more, still more preferably 40% by volume or more, Preferably it is less than 100 volume%, More preferably, it is 99.5 volume% or less. Moreover, 0.01 volume% or more and less than 100 volume% are preferable, 20 volume% or more and less than 100 volume% are more preferable, and 40-99.5 volume% is still more preferable.

As a usage-amount of a solvent, 1-50 mass parts is preferable with respect to 1 mass part of the said plants (dry mass conversion), and 2-30 mass parts is more preferable. As extraction temperature, 0-100 degreeC is preferable, 4-85 degreeC is more preferable, and 4-60 degreeC is still more preferable. The extraction time is preferably 1 minute to 150 days, more preferably 5 minutes to 50 days, and even more preferably 10 minutes to 30 days.
In the case of marjoram and parsley, it is preferable to extract at 10 to 30 ° C. for 3 to 10 days. In the case of licorice, it is preferable to extract at 10-30 ° C. for 1-24 hours.

  Specifically, the marjoram and / or parsley extract uses a solvent of 5 to 15 parts by mass of a 20 to 80% by volume ethanol-water mixture with respect to 1 part by mass of the plant, and a temperature of 4 to 85 ° C ( Preferably, it can be obtained by extraction at 15 to 85 ° C. for 1 hour to 30 days (preferably 3 hours to 25 days). The extract of licorice uses a solvent of 5-15 parts by mass of acetone or hexane with respect to 1 part by mass of the plant, and a temperature of 4 to 85 ° C. (preferably 15 to 85 ° C.) for 1 hour to 30 days ( (Preferably 3 hours to 25 days).

  The extract thus obtained may be used as it is, alone or mixed with the extract or fraction, and may be used as a diluted solution diluted with an appropriate solvent, or may be a concentrated extract or a dry powder. A paste prepared may be used. In addition, when lyophilized and used, a solvent usually used for extraction, such as water, ethanol, propylene glycol, butylene glycol, water-ethanol mixed solution, water-propylene glycol mixed solution, water-butylene glycol mixed solution, etc. It can also be used after diluting. It can also be used by encapsulating in vesicles such as liposomes or microcapsules.

  The extract may be a crude product as long as it conforms to food and pharmaceutical acceptable standards and exhibits the effects of the present invention, and the obtained crude product is further purified by a known separation and purification method. These purities may be combined appropriately to remove inactive impurities and increase their purity. Examples of the purification means include organic solvent precipitation, centrifugation, ultrafiltration membrane, high performance liquid chromatograph and column chromatograph, liquid-liquid distribution, gel filtration separation, activated carbon treatment and the like.

β-carotene can be obtained, for example, by extraction from dried whole plant of Dunaliella Dunaliella (Dunaliella bardawil, Dunaliella salina) with hot oil or with room temperature to hot hexane or carbon dioxide under pressure. it can.
Specifically, β-carotene uses a solvent of 5 to 15 parts by mass of hexane with respect to 1 part by mass of the plant, and a temperature of 4 to 85 ° C. (preferably 15 to 85 ° C.) for 1 hour to It can be obtained by extracting for 30 days (preferably 3 hours to 25 days).

  As shown in Examples below, marjoram, parsley and licorice extracts and β-carotene have an action of suppressing the activity of PDE3. Therefore, the above (A) marjoram, parsley, licorice or their extract and (B) β-carotene are useful for PDE3 inhibition, and they can be expected to have an effect of improving circulatory function and bronchial function.

  Therefore, the above plants or their extracts and β-carotene used in the present invention should be used as PDE3 inhibitors, circulatory function improvers, bronchial function improvers (hereinafter referred to as “PDE3 inhibitors, etc.”). And can be used to produce these agents.

  The PDE3 inhibitor, etc. itself, when ingested or administered to animals including humans, exhibits the effects of PDE3 inhibition, circulatory function improvement, bronchial function improvement, human or animal drugs, quasi drugs, It may be a food or a feed, or may be a material or a preparation used in combination with the drug, quasi drug, food or feed.

The use of the PDE3 inhibitor or the like when administered to humans or animals may be therapeutic use or non-therapeutic use.
Here, “non-therapeutic” is a concept that does not include medical practice, that is, does not include a method of operating, treating, or diagnosing a human by a doctor or a person who has received instructions from a doctor.

  In addition, the food includes the concept of PDE3 inhibition, circulatory function improvement, bronchial function improvement in middle-aged and elderly people, etc., food, health food, functional food, sick food, specified health Food products are included. Since these foods are foods whose function is permitted, they can be distinguished from general foods.

  The above (A) marjoram, parsley, licorice or their extract, and (B) β-carotene-containing pharmaceutical products (including quasi-drugs) are tablets, capsules, granules, powders, syrups Agents, ointments, lotions, creams, poultices, poultices, intravenous injections, intramuscular injections, infusions, infusions, suppositories, inhalants, transdermal absorption agents, eye drops, nasal drops, etc. It may be. The administration form may be either oral administration (internal use) or parenteral administration (transdermal, enteral, transmucosal external use, injection). Of these dosage forms, the preferred form is oral administration. In addition, the said formulation can be manufactured by a conventional method according to the target object which should be mix | blended.

  In addition, in order to prepare pharmaceutical preparations of such various dosage forms, the above (A) marjoram, parsley, licorice or their extracts, and (B) β-carotene, either alone or pharmaceutically acceptable You may use it in combination with the support | carrier used. 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., and other medicinal components can be prepared by appropriately combining them.

  When (A) marjoram, parsley, licorice or their extract (dry matter equivalent), (B) β-carotene is used in a preparation for oral administration, its content is usually within the total mass of the preparation. Preferably it is 0.001 mass% or more, More preferably, it is 0.01 mass% or more, More preferably, it is 0.1 mass% or more, Preferably it is 50 mass% or less, More preferably, it is 10 mass% or less, More preferably, it is 5 mass% It is as follows. Moreover, Preferably it is 0.001-50 mass%, More preferably, it is 0.01-10 mass%, More preferably, it is 0.1-5 mass%.

  The form of the food containing (A) marjoram, parsley, licorice or an extract thereof and (B) β-carotene includes breads, noodles, confectionery, jellys, dairy products, frozen foods, and instant foods. , Starch processed products, processed meat products, other processed foods, beverages, soups, seasonings, nutritional supplements, soft drinks, tea-based beverages, coffee beverages, fruit juice beverages, carbonated beverages, juices, wafers, biscuits, sausages, etc. Any of various foods such as foods and beverages and nutritional foods and their raw materials may be used. Furthermore, a nutritional supplement composition in the same form (tablet, pill, capsule, liquid, syrup, powder, granule, etc.) as the above-mentioned oral administration preparation can be mentioned.

  Various forms of food include (A) marjoram, parsley, licorice or their extracts, (B) β-carotene alone, or other food ingredients, solvents, softeners, oils, emulsifiers, preservatives , Fragrances, stabilizers, colorants, ultraviolet absorbers, antioxidants, humectants, thickeners, active ingredients other than the present invention, and the like can be prepared as appropriate.

In the food, the content of (A) marjoram, parsley, licorice or their extract (in terms of dry matter), (B) β-carotene varies depending on the form of use, but is usually preferred in the form of a beverage. Is 0.001% by mass or more, more preferably 0.01% by mass or more, further preferably 0.1% by mass or more, preferably 50% by mass or less, more preferably 5% by mass or less, and further preferably 1% by mass or less. It is. Moreover, Preferably it is 0.001-50 mass%, More preferably, it is 0.01-5 mass%, More preferably, it is 0.1-1 mass%.
In the form of solid foods such as tablets and processed foods, the content of (A) marjoram, parsley, licorice or extract thereof (in terms of dry matter), (B) β-carotene is preferably 0.005% by mass Above, more preferably 0.05% by mass or more, still more preferably 0.1% by mass or more, preferably 50% by mass or less, more preferably 5% by mass or less, and further preferably 1% by mass or less. Moreover, Preferably it is 0.005-50 mass%, More preferably, it is 0.05-5 mass%, More preferably, it is 0.1-1 mass%.

  Examples of the feed include feed for livestock used for cattle, pigs, chickens, sheep, horses, pet food used for dogs, cats, and the like, and can be prepared in the same form as the above food.

  When producing feed, in addition to (A) marjoram, parsley, licorice or extracts thereof, (B) β-carotene, meat such as cattle, pigs and sheep, protein, grains, bran Commonly used feed raw materials such as potatoes, potatoes, sugars, vegetables, vitamins, minerals, etc. Furthermore, gelling agents, shape-preserving agents, pH adjusters, seasonings, preservatives, nutritional reinforcements commonly used in feeds A combination of agents can be used.

  The content of the above-mentioned (A) marjoram, parsley, licorice or their extract (in terms of dry matter) and (B) β-carotene in the feed varies depending on the form of use, but is usually preferably 0.001% by mass More preferably, it is 0.01% by mass or more, more preferably 0.1% by mass or more, preferably 50% by mass or less, more preferably 10% by mass or less, and further preferably 5% by mass or less. Moreover, 0.001-50 mass% is preferable, 0.01-10 mass% is more preferable, 0.1-5 mass% is still more preferable.

  When used as an external medicine, quasi-drug or cosmetic including the natural product or extract or purified product thereof according to the present invention, it may be a skin external preparation, a cleaning agent, a bath agent, a makeup cosmetic, etc. Yes, depending on how you use it, serum, lotion, massage agent, lotion, emulsion, gel, cream, ointment, powder, pack, poultice, granule, foundation, lipstick, shampoo, conditioner, hair tonic, It can be provided in various dosage forms such as tablets, capsules, absorbent articles, and sheet products. Such external pharmaceuticals, quasi-drugs or cosmetics in various dosage forms are the above-mentioned natural products of the present invention or extracts, purified products, etc., alone or externally-used pharmaceuticals, quasi drugs or skin cosmetics. Oils or oily substances, moisturizers, powders, pigments, emulsifiers, solubilizers, cleaning agents, UV absorbers, thickeners, medicinal ingredients, fragrances, resins, antibacterial and antifungal agents, It can be prepared by combining other plant extracts (herbal medicine, herbal medicine, herbs), alcohols, polyhydric alcohols, inorganic acids, organic acids, vitamins, water-soluble polymers, surfactants and the like.

  The above-mentioned natural product of the present invention or an extract or purified product thereof in the total amount of the external medicine, quasi-drug, and cosmetic is usually 0.0001 to 30% by mass in terms of dry matter, 0.001 10 mass% is preferable, 0.01-5 mass% is more preferable, 0.1-3 mass% is further more preferable.

  Moreover, in the total amount of the bath agent, the natural product of the present invention or an extract or purified product thereof is usually 0.0001 to 30% by mass, preferably 0.001 to 10% by mass in terms of dry matter, 0.01-5 mass% is more preferable, and 0.1-3 mass% is further more preferable.

  The intake of a PDE3 inhibitor, etc. of the present invention may vary according to the subject's species, weight, sex, age, condition or other factors. The dose, route, interval of administration, and the amount and interval of ingestion can be appropriately determined by those skilled in the art, but the above (A) marjoram, parsley, licorice or extract thereof per day for an adult (60 kg) (In terms of dry matter), (B) β-carotene is preferably preferably 0.01 mg or more, more preferably 0.1 mg or more, still more preferably 1 mg or more, preferably 5000 mg or less, more preferably 1000 mg or less, still more preferably 500 mg or less. Moreover, Preferably it is 0.01-5000 mg, More preferably, it is 0.1-1000 mg, More preferably, it is 1-500 mg. Moreover, although the said formulation can be administered according to arbitrary administration schedules, it is preferable to administer once to several times per day.

The subject of administration or ingestion is not particularly limited as long as it is a person who needs or desires it regardless of whether it is sick or healthy, but middle-aged and elderly are preferred. In addition, the PDE3 inhibitor of the present invention is not affected by not only patients with circulatory function diseases such as heart failure, chronic arterial occlusion and thrombosis and bronchial function diseases such as bronchial asthma, but also circulatory function diseases and bronchial function diseases. Target person, for example
It can be applied to subjects who suffer from coldness, swelling, stiff shoulders, cough and tan caused by circulatory function decline and want to improve these.

With respect to the above-described embodiment, the following aspects are disclosed in the present invention.
<1> A PDE3 inhibitor comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene.
<2> A circulatory function improver comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene.
<3> A bronchial function improving agent comprising as an active ingredient at least one selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene.
<4> One or more uses selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene for producing a PDE3 inhibitor.
<5> Use of one or more selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene for producing a circulatory function improving agent.
<6> Use of one or more selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene for producing a bronchial function improving agent.
<7> One or more selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene for use in inhibiting PDE3.
<8> One or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene, for use in improving circulatory function.
<9> One or more selected from the group consisting of (A) marjoram, parsley, licorice and extracts thereof, and (B) β-carotene for use in improving bronchial function.
<10> One or more types selected from the group consisting of (A) plants or their extracts according to <7> to <9> and (B) β-carotene for non-therapeutic use.
<11> A method for inhibiting PDE3, wherein one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene are administered or ingested to humans or animals.
<12> A method for improving circulatory function, wherein one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene are administered or ingested to humans or animals.
<13> A method for improving bronchial function, wherein one or more selected from the group consisting of (A) marjoram, parsley, licorice and their extracts, and (B) β-carotene are administered or ingested to humans or animals.
<14> The method according to <11> to <13>, which is a non-therapeutic method.
<15><2>,<5>,<8>,<10>,<12>,<14> The circulatory function improvement described in <14> is preferably selected from heart failure improvement, chronic arterial occlusion improvement and thrombosis improvement One or more types.
<16><3>,<6>,<9>,<10>,<13>,<14> The bronchial function improvement described in <14> is preferably bronchial asthma improvement.
<17> In any one of <1> to <16>, the extract is preferably an aqueous ethanol solution extract.

  Hereinafter, examples and test examples will be given to specifically describe the present invention, but the present invention is not limited to these examples.

Example 1
10 mL of 99.5 vol% ethanol-water mixed solution was added to 0.1 g of oil-soluble licorice extract PT (40) obtained from Maruzen Pharmaceutical Co., Ltd. to obtain a licorice extract of 1% of the dried extract.

Example 2
To 10 g of dried marjoram whole plant (Tochimoto Tenkaidou), 10 L of 50 volume% ethanol-water mixed solution 0.1 L was added, insoluble matter was filtered off at about 20 ° C. for 7 days, and the resulting filtrate was obtained. Was extracted with a flask while stirring with a magnetic stirrer to obtain a marjoram extract with a solids concentration of 2.2%.

Example 3
To 100 g of dried parsley leaves (Shinwa Bussan), add 1 L of 10 volumes of 50 volume% ethanol-water mixed solution, and extract in a flask while stirring with a magnetic stirrer at about 20 ° C. for 7 days. The insoluble matter in the extract was filtered off to obtain a parsley extract having a solid content concentration of 3.0%.

Example 4
0.1 g of biocarotene 30MCT obtained from Kyowa Hakko was dissolved in 10 mL of 99.5% ethanol to obtain a β-carotene solution having a solid concentration of 1%.

Test example
Using PDE-Glo Phosphodiesterase Assay (Promega), after mixing 10 μL of the solution prepared in the PDE-Glo reaction solution so that human recombinant phosphodiesterase 3B is 0.8 μg / mL, and 2.5 μL of the solution of the above example. The enzyme reaction was carried out by adding a cAMP solution prepared to a concentration of 2 μM. The obtained reaction solution was reacted at 37 ° C. for 10 minutes, and then 12.5 μL of PDE-Glo Termination Buffer was added to stop the reaction. Thereto, 12.5 μL of PDE-Glo detection solution was added, and after 10 minutes, 50 μL of Kinase-Glo solution was added, and the amount of chemiluminescence was measured. The PDE3 activity was determined from the measured luminescence amount by the following formula, and the results are shown in Table 1.
PDE3 activity (%) = (light emission amount of any of Examples 1 to 4 and Comparative Example 2 / light emission amount of Comparative Example 1) × 100
In Comparative Example 1, the PDE-Glo reaction solution was not added with the solution of the above example, and in Comparative Example 2, caffeine was added to the prepared solution instead of the above example. .

As shown in Table 1, in Examples 1 to 4 and Comparative Example 2 using caffeine, PDE3 activity was suppressed compared to Comparative Example 1. It is clear that marjoram, parsley, licorice and β-carotene have an excellent PDE3 inhibitory action.
Caffeine is a known material having a PDE3 inhibitory action.

Claims (5)

  A PDE3 inhibitor containing β-carotene as an active ingredient.   A bronchial function improving agent containing β-carotene as an active ingredient. The bronchial function improving agent according to claim 2 , which is a bronchial asthma improving agent.   A food for inhibiting PDE3 containing β-carotene as an active ingredient.   Food for improving bronchial function, containing β-carotene as an active ingredient.