JP6583787B2 - Food, nausea / vomiting inhibitor and quasi drug - Google Patents

Description

The present invention relates to food, nausea and vomiting inhibitor and quasi-drugs.

  Cancer chemotherapy is effective for actively dividing cancer cells, but there are normal tissues and cells that are rapidly metabolized and actively divided in the same way as cancer cells. Since chemotherapeutic agents also act on normal tissues and cells where such divisions are actively performed, in some cases, serious side effects occur. In such cases, it is difficult to continue chemotherapy, the treatment is discontinued and the amount of anticancer drugs is reduced, and the therapeutic effects of chemotherapy (such as reduction of cancer and reduction of the risk of cancer recurrence) are obtained sufficiently. I can't.

  The side effects of cancer chemotherapy vary depending on the type of chemotherapeutic agent, but the main adverse events include, for example, anorexia, nausea, vomiting, diarrhea, stomatitis, myelotoxicity, skin disorders, hair loss. , Neuropathy, interstitial pneumonia, liver disorder, kidney disorder, heart disorder and the like. In order to obtain the maximum effect of chemotherapy, it is important to suppress these side effects. Currently, several supportive therapies to reduce side effects are being implemented.

Among the side effects in cancer chemotherapy, nausea, vomiting, and anorexia are the most common side effects and are typical side effects that patients complain about. These side effects may lead to a reduction in patient quality of life (QOL) and may hinder continued treatment.
Excellent nausea and vomiting suppression effects lead to improvement of QOL and continuation of chemotherapy for patients receiving cancer chemotherapy, and can contribute to the transition to outpatient chemotherapy and improvement of cancer chemotherapy results.

  Vomiting is controlled at the emetic center located in the medulla oblongata. Supportive measures such as antiemetics according to the vomiting induction pathway and the onset time are used as a measure to suppress vomiting due to cancer chemotherapy. However, supportive care is symptomatic treatment, which is given after side effects occur, and does not prevent the side effects associated with cancer chemotherapy itself.

  Nausea and vomiting induced by cancer chemotherapy includes acute nausea and vomiting that occurs within 24 hours after the start of cancer chemotherapy, and delayed nausea and vomiting that occurs 24 hours after the start of cancer chemotherapy. It is classified as predictive nausea / vomiting, which occurs when patients are conscious of receiving cancer chemotherapy. The frequency of expression varies depending on the type of anticancer drug, the dose, the administration route, and the like. Anticancer drugs are classified into high emetic, moderate emetic, and low emetic depending on the frequency of nausea and vomiting.

Serotonin (5-HT) has been shown to be involved in acute nausea and vomiting. Currently, for the acute nausea and vomiting, sufficient control by combining a 5-HT receptor is one 5-HT ₃ receptor antagonist (5-HT ₃ receptor antagonist) and steroids Is possible.

On the other hand, antiemetic therapy for delayed nausea and vomiting is not sufficient. It has been reported that tachykinin (tachykinin family), a group of peptide neurotransmitters including substance P, is involved in late-onset nausea and vomiting. In recent years, selective receptors for substance P have been reported. Clinical introduction of an antagonist of a neurokinin-1 (NK-1) receptor (NK-1 receptor antagonist) has been promoted, and it has been utilized in actual clinical practice.
However, since the NK-1 receptor antagonist is metabolized by the drug metabolizing enzyme CYP3A4 in the liver, it must be carefully administered when used in combination with anticancer drugs or steroid drugs that are similarly metabolized by this drug metabolizing enzyme. It is said that.

The onset mechanism of vomiting in the acute phase by anticancer drugs is that gastrointestinal mucosal intestinal chromaffin cells (EC cells) are stimulated by the drug to release 5-HT and exist in the abdominal afferent meditation nerve terminal Via the 5-HT ₃ receptor, the excitement is directly transmitted to the emesis center via the chemoreceptor trigger zone (CTZ), and the drug directly stimulates CTZ and is transmitted to the emesis center. And there is a route. For late-onset vomiting, 5-HT is thought to be less involved, but cannot be completely denied.

  On the other hand, in order to improve appetite loss caused by side effects or stress of anticancer drugs, Chinese medicines such as Rikkunshito may be used in combination. Rikkunshito is commonly used to recover symptoms such as loss of appetite and stomach upset in patients with weak physical strength and reduced gastrointestinal function, and has also been shown to be effective against functional dyspepsia. . Rikkunshito has been confirmed to have effects such as increased appetite, increased gastrointestinal motility, improved gastric adaptive relaxation, and improved gastric emptying. As an action mechanism of increased appetite and gastrointestinal motility, it is also involved in the promotion of secretion and degradation of ghrelin, a peptide hormone, and the enhancement of ghrelin signal.

  In addition, several nutritional agents have been clinically studied for the purpose of preventing and ameliorating the side effects of cancer chemotherapy through nutritional intervention. For example, Elental (trade name), a component nutrient, has a mucosal protective effect on glutamine, a component, and is known to reduce the onset of stomatitis when taken during chemotherapy for digestive organ cancer. . In addition, Racol (trade name), which is a semi-digested nutrient, has functions such as anti-inflammatory action in the omega-3 fatty acid contained therein, leukopenia, neutropenia, stomatitis during chemoradiotherapy, It has been reported to have an alleviating effect on diarrhea. In addition, it has been reported that Prosure (trade name) containing ω-3 fatty acids and zinc as well as Racoal reduces side effects during chemotherapy.

  On the other hand, glycolipids are known to have many physiological effects. Glycolipid is a general term for substances containing both water-soluble sugar chains and fat-soluble groups in the molecule. Glycolipids are roughly classified into a sphingoglycolipid having sphingosine in a fat-soluble group and a glyceroglycolipid having a glycerol skeleton such as acylglycerol in the fat-soluble group.

Glycosphingolipids are one of the components of cell membranes, and are present on the cell surface in the form that the lipid portion is embedded in the membrane and the sugar chain portion is exposed outside the cell. Glycosphingolipids are thought to be involved in cell recognition mechanisms due to their structural features. As a physiological action of glycosphingolipid, it is known that GM1 ganglioside has a protective action against gastric mucosal damage caused by ethanol.
Regarding glycosphingolipids, for example, Patent Document 1 describes that ganglioside, which is a glycosphingolipid containing sialic acid, inhibits the adhesion of Helicobacter pylori to gastric mucosa.

On the other hand, glyceroglycolipids are mainly present in microorganisms and plants. As physiological actions of glyceroglycolipid, lipase activity inhibitory action, antiallergic action, colon cancer preventive effect, apoptosis inducing action, etc. have been clarified.
Regarding glyceroglycolipids, for example, Patent Document 2 describes that glyceroglycolipids extracted from seaweed and terrestrial plants have DNA synthase inhibitory activity, cancer cell growth inhibitory activity, and antitumor activity. .
Furthermore, regarding glyceroglycolipid, for example, Patent Document 3 describes that glyceroglycolipid has a gastrointestinal mucosa protective action, a caveolin gene expression promoting action, and an anti-stress action.

Japanese Patent Laid-Open No. 10-45602 Japanese Patent No. 4744297 Japanese Patent No. 4839436

  As described above, side effects in cancer chemotherapy, particularly nausea, vomiting, and loss of appetite are the most common side effects that patients complain about, causing a reduction in the patient's QOL and hindering continued treatment. Therefore, if functional foods such as pharmaceuticals, special-purpose foods, foods for specified health use, health supplements, etc., which have excellent nausea / vomiting prevention and suppression effects, can be achieved, improvement of QOL and chemotherapy in cancer chemotherapy patients This leads to continuation and contributes to the transition to outpatient chemotherapy and the improvement of cancer chemotherapy results. However, there are still few food ingredients that have such an action, and many have not been scientifically proven to be effective.

  In addition, as described above, many physiological actions have been reported for glycolipids such as sphingoglycolipids and glyceroglycolipids, but it is thought that there are many actions that have not yet been elucidated. For example, glyceroglycolipids have not been reported to have nausea / vomiting suppression effects during cancer chemotherapy. In addition, glyceroglycolipid is a gene that expresses a synthase that synthesizes serotonin (a serotonin synthase gene) that induces nausea and vomiting, and a gene that expresses substance P (a substance P gene) that also induces nausea and vomiting. It has not been reported to have an expression-inhibiting action.

The present invention has been made in view of the above circumstances, food that can of suppressing nausea and vomiting, and to provide a nausea and vomiting inhibitor and quasi-drugs.

  The present inventor has conducted research in view of the above problems, and as a result, (a) a glycolipid-containing composition obtained from spinach has an anti-nausea / nausea-inhibiting action by an anticancer agent, (b) gastrointestinal mucosal cells The inventors have found that the expression of serotonin synthase gene and substance P gene that are secreted more is suppressed, and the present invention has been completed.

The above-mentioned problem according to the present invention is solved by the following means.
(1) The glyceroglycolipid containing as an active ingredient, the food is for nausea and vomiting suppressed with is for suppressing the expression of at least one gene selected from the group consisting of serotonin synthase gene and substance P gene.
(2) The glyceroglycolipid is at least one selected from the group consisting of monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and sulfoquinovosyldiacylglycerol (SQDG) . food.
(3) the glyceroglycolipid is, food according to the derived from at least one of the seaweed and terrestrial plants (1) or (2).
(4) the terrestrial plants, food according to the a spinach (3).
(5) A nausea / vomiting inhibitor which contains glyceroglycolipid as an active ingredient and suppresses the expression of at least one gene selected from the group consisting of a serotonin synthase gene and a substance P gene.
(6) The glyceroglycolipid is at least one selected from the group consisting of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG). Nausea and vomiting inhibitor.
(7) The nausea / vomiting inhibitor according to (5) or (6), wherein the glyceroglycolipid is derived from at least one of seaweed and terrestrial plants.
(8) The nausea / vomiting inhibitor according to (7), wherein the terrestrial plant is spinach.
(9) A quasi-drug containing glyceroglycolipid as an active ingredient, for suppressing the expression of at least one gene selected from the group consisting of a serotonin synthase gene and a substance P gene, and for suppressing nausea and vomiting.
(10) The (9), wherein the glyceroglycolipid is at least one selected from the group consisting of monogalactosyldiacylglycerol (MGDG), digalactosyldiacylglycerol (DGDG) and sulfoquinovosyldiacylglycerol (SQDG). of pharmaceuticals and quasi drugs.
(11) The glyceroglycolipid is the derived from at least one of the seaweed and terrestrial plants (9) or a pharmaceutical quasi according to (10).
(12) the terrestrial plants, pharmaceuticals quasi according to the a spinach (11).

According to the present invention, it is possible to provide food that can of suppressing nausea and vomiting, nausea and vomiting inhibitor and quasi-drugs.

It is a graph which shows the inhibitory effect of the spinach-derived glycolipid containing composition with respect to the kaolin intake increase (pica action) by cyclophosphamide administration. In the figure, the vertical axis represents the kaolin intake (g). It is a graph which shows the inhibitory effect of the spinach derived glycolipid containing composition with respect to small intestine serotonin synthetase mRNA induction by 5-FU. In the figure, the vertical axis represents the relative expression level of small intestine serotonin synthase mRNA. It is a graph which shows the inhibitory effect of the spinach-derived glycolipid containing composition with respect to small intestine alpha-tachykinin mRNA induction by 5-FU. In the figure, the vertical axis represents the relative expression level of small intestine α-tachykinin mRNA.

  Hereinafter, embodiments for carrying out the nausea / vomiting inhibitor, gene expression inhibitor food, quasi drug and cosmetic according to the present invention will be described in detail.

  The nausea / vomiting inhibitor and the gene expression inhibitor according to the present invention each contain an amount having a medicinal effect with glyceroglycolipid as an active ingredient.

(Glyceroglycolipid)
As the glyceroglycolipid that can be contained in the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention, all compounds generally referred to as glyceroglycolipids, derivatives or derivatives thereof may be used. it can.

Specific examples of such glyceroglycolipids include monogalactosyl diacylglycerol (MGDG), monogalactosyl monoacylglycerol (MGMG), digalactosyl diacylglycerol (DGDG), sulfoquinovosyl diacylglycerol (SQDG), sulfoxino. Examples thereof include bosyl monoacylglycerol (SQMG). In addition, these glyceroglycolipid can be used individually by 1 type or in combination of 2 or more types as appropriate. Preferably, at least one selected from the group consisting of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG) is used.
As a derivative of glyceroglycolipid, for example, a part of the molecular structure such as MGDG, MGMG, DGDG, SQDG, and SQMG is substituted with a functional group such as a hydroxy group, a formyl group, a carboxyl group, a carbonyl group, and an amino group. Things can be mentioned.
Derivatives of glyceroglycolipids include, for example, those in which one or more long-chain fatty acids that are constituents such as MGDG, MGMG, DGDG, SQDG, SQMG are added, deleted, or substituted.

  These glyceroglycolipids can be extracted and purified from plants, microorganisms or animals, and can be chemically synthesized. However, natural glycerolipids containing a large amount of glyceroglycolipids such as seaweeds and terrestrial plants can be used. It is preferably used after extraction, separation and purification by a known method.

  Such seaweeds include, for example, cyanobacteria such as spiruna, green algae such as aonori, aosa, and mill, brown algae such as wakame, hijiki, macomb, mozuku, and akamoku; Although algae etc. can be mentioned, it is not limited to these.

  Examples of such terrestrial plants include, but are not limited to, vegetables such as Japanese mustard spinach, spinach, carrots, broccoli, and onions, and monocotyledons such as barley and rice. Of these, spinach is preferably used.

  Moreover, as a method for extracting / separating / purifying glyceroglycolipids from seaweed and terrestrial plants as described above, for example, the method described in WO2005 / 027937 can be used, but it is not limited thereto. In addition, according to this extraction method, glyceroglycolipids having a useful physiological function efficiently and easily from seaweed and terrestrial plants are converted into monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfo. An extract containing high purity as a mixture of quinovosyl diacylglycerol (SQDG) can be obtained. In the present invention, the extract can be directly contained in a drug or food as a glyceroglycolipid, and further, a product obtained by separating and purifying the extract is contained in a drug, food, quasi drug or cosmetic as a glyceroglycolipid. It can also be made.

(Applicable disease)
The nausea / vomiting inhibitor according to the present invention described above is used for nausea / vomiting caused by emesis supplementation by transvenous infusion after surgery for gastrointestinal resection. It can be used as a prophylactic / inhibitory agent. For example, when performing treatment with anticancer agents having strong side effects such as gastrointestinal mucosal disorders, side effects caused by anticancer agents can be prevented by taking the nausea / vomiting inhibitor according to the present invention in advance. it can. In the case of gastrointestinal mucosal atrophy caused by nutritional supplementation by transvenous infusion after surgery for gastrointestinal resection, the nausea / vomiting inhibitor according to the present invention can be administered before surgery or simultaneously with transvenous infusion. Can prevent nausea and vomiting. Furthermore, the nausea / vomiting inhibitor according to the present invention can be applied to emesis disorders due to stress, alcohol, drugs, inflammatory diseases and the like.

As described above, serotonin and substance P are inducers of nausea and vomiting.
The gene expression inhibitor according to the present invention contains glyceroglycolipid as an active ingredient and contains an amount that suppresses the expression of at least one gene selected from the group consisting of a serotonin synthase gene and a substance P gene.

  Therefore, the gene expression inhibitor according to the present invention can suppress gene expression of an enzyme that synthesizes serotonin, which is a substance that induces nausea and vomiting, and substance expression of substance P. Therefore, the gene expression inhibitor according to the present invention can suppress nausea and vomiting.

  In particular, in the case of a gene expression inhibitor that suppresses gene expression of serotonin synthase (serotonin synthase gene expression inhibitor), since it can be expected to suppress gastrointestinal peristalsis, the mechanism of action of serotonin in the gastrointestinal tract It can be applied as a useful substance for various studies such as elucidation. In addition, the serotonin synthase gene expression inhibitor can be used to prevent or improve symptoms such as diarrhea caused by increased gastrointestinal peristalsis because it can be expected to suppress gastrointestinal peristalsis as described above. It is.

  On the other hand, substance P is synthesized as a substance P precursor called α-tachykinin (α-preprotachykinin A), and substance P is cut out from this precursor. Substance P not only acts on nerves as a neuropeptide, but also acts on vascular endothelial cells, enhances vasodilation and vascular permeability, acts on immune cells, promotes secretion of inflammatory cytokines, The effect of promoting the reaction is known.

  Therefore, in the case of a gene expression inhibitor that suppresses the expression of substance P (substance P gene expression inhibitor), an inhibitory effect on vasodilation and increased vascular permeability and an anti-inflammatory effect can be expected. It can be applied as a useful substance in various studies to clarify the role of P. In addition, in the case of a substance P gene expression inhibitor, as described above, since it can be expected to have an inhibitory effect on vasodilation and increased vascular permeability and an anti-inflammatory effect, it prevents inflammatory reactions and symptoms caused by various pathologies. Can be used for improvement.

  The nausea / vomiting inhibitor and the gene expression inhibitor according to the present invention are animals other than humans, for example, livestock in the veterinary field, pet animals, laboratory animals, etc., such as mice, rats, rabbits, dogs, horses, cows, It can also be used for diseases corresponding to or similar to human diseases as described above in monkeys and the like.

(Method of administration)
The nausea / vomiting inhibitor and gene expression inhibitor according to the present invention can be administered by a known administration method such as oral, transdermal, intradermal, subcutaneous, intravenous, intramuscular, etc., but it is safe and effective. However, it is not limited to these as long as it can be administered.

(Types of anticancer drugs)
Examples of anticancer agents used in cancer chemotherapy include anticancer antibiotics, platinum preparations, alkylating agents, antimetabolites, plant alkaloids, molecular target therapeutics, hormonal agents, and the like. However, it is not limited to these.

(Formulation)
Regarding the formulation and form of the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention, glyceroglycolipids such as plant-derived glyceroglycolipids may be used as they are, but usually fillers, binders, increasing amounts A known pharmaceutical carrier such as an agent, a disintegrant, a dispersant, and an excipient can be added to prepare a preparation by a conventional method.

  As the physical properties of the preparation, liquid, paste, solid, spray (gas) and the like can be adopted. In the case of oral preparations, solid preparations such as tablets, capsules, granules, powders, liquids, pills, troches, chewables, liquids such as syrups, elixirs, emulsions, suspensions, etc., pastes in tubes It can be formulated in the form of In the case of a parenteral preparation, it can be formulated into a form such as an injection, a drop, an instillation, an external preparation, a coating agent, a suppository and the like.

(Dose)
The dosage of the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention varies depending on the age, weight, administration method, target disease, symptom, etc. of the recipient, but in the case of oral administration, usually a child or an adult (Mg glyceroglycolipid / kg body weight / day) is 1 to 800 mg / kg / day, preferably 2 to 200 mg / kg / day, more preferably 5 to 100 mg / kg / day. In the case of parenteral administration, the dose (mg glyceroglycolipid / kg body weight / day) is 1 to 400 mg / kg / day, preferably 2 to 100 mg / kg / day, more preferably 5 to 50 mg / kg. / Day. Each dose described above can be administered once a day or divided into several doses.

(Food)
The glyceroglycolipid that can be contained in the present invention is obtained from natural products such as plants (specifically, obtained from vegetables that are eaten daily such as spinach), and has high safety. It can be provided as a food that produces nausea / vomiting inhibitory action and gene expression inhibitory action (serotonin synthase gene expression inhibitory action and substance P gene expression inhibitory action). Examples of such foods include foods for specified health use, functional indication foods, nutritional supplements, special-purpose foods, health foods, and the like. Such a food form is very useful because it can be easily ingested on a daily basis.

(Type of food)
The food product according to the present invention can be produced by adding glyceroglycolipid to a common food product by mixing, mixing, coexistence and the like. As the glyceroglycolipid to be added, it is possible to use an extract from a plant as described above as it is or further separated and purified as necessary. Common foods containing glyceroglycolipid include, for example, cooked rice products such as cooked rice, noodles, bread and tofu, processed meat products such as ham and sausage, marine products such as kamaboko and chikuwa, cookies, chocolate and candy. Beverages such as confectionery, juice, tea and coffee (that is, the food in the present invention is a concept including beverages), dairy products such as yogurt and butter, seasonings such as soy sauce, sauces and dressings, rich for medical use Examples include liquid foods, but are not limited to these as long as nausea / vomiting suppression and gene expression suppression (serotonin synthase gene expression suppression and substance P gene expression suppression) are exhibited.

(Food form)
The food according to the present invention is ingested as a supplement by mixing the glyceroglycolipid as it is or mixed with excipients, extenders, binders, thickeners, emulsifiers, coloring agents, flavoring agents, food additives, seasonings, etc. can do. Examples of the form include powders, granules, pellets, tablets, capsules, drinks, pastes and the like.

(Intake by food)
The amount of glyceroglycolipid to be ingested by the food according to the present invention is the same as the oral dose of the above-mentioned therapeutic agent, and varies depending on the age, weight, disease, and symptoms of the ingestor, but is usually ingested by children or adults (Mg glyceroglycolipid / kg body weight / day) is 1 to 800 mg / kg / day, preferably 2 to 200 mg / kg / day, more preferably 5 to 100 mg / kg / day. The above intake can be taken once a day or divided into several times.

(Quasi-drugs, cosmetics)
Since the glyceroglycolipid that can be contained in the present invention is obtained from natural products such as plants and has high safety, the pharmaceutical composition containing the above-described nausea / vomiting inhibitor and gene expression inhibitor according to the present invention described above. It can be provided as a quasi-drug or cosmetic. Such quasi-drugs and cosmetics can be ingested or used on a daily basis and are very useful.

(Form of quasi drug)
When the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention are used as quasi-drugs, glyceroglycolipids such as plant-derived glyceroglycolipids may be used as they are. Forms, fillers, binders, thickeners, emulsifiers, colorants, fragrances, food additives, seasonings etc. mixed with powders, granules, pellets, tablets, drinks, etc. Provided in.
Further, when the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention are used as quasi-drugs, medicinal cosmetics such as creams, emulsions, lotions, lotions, gels, cosmetics, packs, and hand creams It can also be provided in the form of parenteral intake such as medicinal body cosmetics such as leg creams, body lotions and bath preparations.
For such medicinal cosmetics and medicinal body cosmetics, in addition to glyceroglycolipid, which is an active ingredient, raw materials commonly used in the production of medicinal cosmetics, such as surfactants, oils, water, moisturizers, alcohols , Thickeners, stabilizers, preservatives, antioxidants, chelating agents, pH adjusters, fragrances, pigments, pigments, various vitamins, various amino acids, and the like.
In order to produce such medicinal cosmetics and medicinal body cosmetics, an appropriate amount of glyceroglycolipid may be added at an arbitrary stage in the production process according to a conventional method.

(Intake from quasi drugs)
The amount of glyceroglycolipid to be ingested by the quasi-drug according to the present invention is the same as the oral dose of the above-mentioned therapeutic agent in the case of oral ingestion, and varies depending on the age, weight, disease, and symptoms of the ingestor, In general, the intake amount (mg glyceroglycolipid / kg body weight / day) for a child or adult is 1 to 800 mg / kg / day, preferably 2 to 200 mg / kg / day, more preferably 5 to 100 mg. / Kg / day. The above intake can be taken once a day or divided into several times.

(Cosmetic form)
When the nausea / vomiting inhibitor and gene expression inhibitor according to the present invention are used as cosmetics, the forms include basic cosmetics such as creams, emulsions, lotions, lotions, gels, cosmetics, packs, and makeup bases. Examples include makeup cosmetics such as creams, powder foundations, liquid foundations, and lipsticks, and body cosmetics such as hand creams, leg creams, body lotions, and bath preparations.

  For the cosmetics as described above, in addition to the glyceroglycolipid which is an active ingredient, raw materials generally used in the production of cosmetics, such as surfactants, oils, water, humectants, alcohols, thickeners , Stabilizers, preservatives, antioxidants, chelating agents, pH adjusters, fragrances, dyes, pigments, various vitamins, various amino acids, and the like can also be blended. In order to produce such a cosmetic, an appropriate amount of glyceroglycolipid may be added at an arbitrary stage in the production process according to a conventional method.

Next, examples of the present invention will be described.
[1] Extraction of Glycolipid-Containing Composition As a raw material, commercially available spinach is used, and after chopping 100 g of the dried product, in order to remove water-soluble components as much as possible, 1 L of hot water at 60 ° C. Washed twice. Next, filtration was performed using filter paper, 1 L of ethanol was added to the solid (residue) obtained by removing water, and reflux extraction was performed twice at 60 ° C. with stirring. The obtained extract was filtered and then concentrated under reduced pressure to obtain 20.5 g of spinach oily extract.

  Next, the obtained extract was dissolved in a 70% ethanol solution (a solution having a volume ratio of ethanol and water of 70:30, the same applies hereinafter), and then 500 g of a resin for hydrophobic chromatography (Diaion HP-20, Mitsubishi Chemical). Injected into the company). Thereafter, the unadsorbed substance was washed with a 70% ethanol solution, and eluted fraction I (water-soluble fraction, 13.6 g), fraction II eluted with 90% ethanol (glycolipid fraction, 6.5 g). The fraction was fractionated into three fractions III (a pigment fraction containing chlorophyll (chlorophyll), 1.0 g) eluted with chloroform.

  The components of the glycolipid fraction of fraction II were analyzed by thin layer chromatography. As a result, 250 mg of the glycolipid fraction contained 87.4 mg (33.9%) of MGDG and 35.0 mg (14.0) of DGDG. %) And 92.3 mg (36.9%) of SQDG. That is, it was found that the glycolipid fraction of fraction II (hereinafter referred to as “glycolipid-containing composition”) contains at least 84.8% glyceroglycolipid.

Furthermore, as a result of confirming the structure and purifying the purity of purified MGDG, DGDG, and SQDG using ¹ H-NMR and ¹³ C-NMR, the chemical structure of MGDG, DGDG, and SQDG can be confirmed. Was 95% or more.

  From the above, it was confirmed that at least one glyceroglycolipid selected from the group consisting of MGDG, DGDG, and SQDG can be obtained from spinach. In addition, since these glyceroglycolipids are widely contained not only in spinach but also in terrestrial plants including seaweed and spinach, it is considered that they can be obtained from at least one of seaweed and terrestrial plants.

[2] Anti-emetic action of glycolipid-containing composition The anti-emetic action of the glycolipid-containing composition obtained in [1] was examined as follows. As test animals, SD (Sprague Dawley) rats were used, and “cyclophosphamide + glycolipid-containing composition administration group (7 animals)”, “cyclophosphamide administration group (7 animals)”, and “control group” (5 animals) ”.

MF (oriental yeast) was administered to all groups as a standard feed, and daily food intake was measured. The glycolipid-containing composition is dissolved in ultrapure water and is 20 mg / kg from 5 days before cyclophosphamide administration to 3 days after administration for “cyclophosphamide administration + glycolipid-containing composition administration group”. / Day was forcibly administered with a sonde.
In the “cyclophosphamide administration + glycolipid-containing composition administration group” and “cyclophosphamide administration group”, cyclophosphamide was administered at a dose of 120 mg / kg with a sonde.
Rats do not have a vomiting reflex, but exhibit pica behavior (taste symptom) equivalent to vomiting. The evaluation of pica behavior is based on the amount of food consumed by a foreign substance called kaolin. In this test, kaolin pellets containing kaolin and MF were administered to all groups over the entire test period, and their food intake was evaluated.

(result)
FIG. 1 is a graph showing the inhibitory effect of a spinach-derived glycolipid-containing composition on the increase in kaolin intake (pica behavior) by cyclophosphamide administration. In the figure, the vertical axis represents the kaolin intake (g). As shown in FIG. 1, in the “cyclophosphamide administration group”, the kaolin intake was significantly increased after cyclophosphamide administration compared to the “control group”, but “cyclophosphamide + glycolipid-containing group” In the "composition administration group", the kaolin intake was significantly reduced.
From this, it was confirmed that the glycolipid-containing composition has an anti-vomiting effect.

  In addition, it was confirmed that when a glycolipid-containing composition was administered to SD rats at 20 mg / kg / day, pica behavior corresponding to vomiting could be suppressed. It was inferred that the correct dose (intake) should be used. That is, in the case of oral administration, the dosage is usually 1 to 800 mg / kg / day, preferably 2 to 200 mg / kg / day, more preferably as the dosage for children or adults (mg glyceroglycolipid / kg body weight / day). Was estimated to be 5-100 mg / kg / day. In the case of parenteral administration, the dose (mg glyceroglycolipid / kg body weight / day) is 1 to 400 mg / kg / day, preferably 2 to 100 mg / kg / day, more preferably 5 to 50 mg. / Kg / day. The dose may vary depending on the age, weight, administration method, target disease, symptoms, etc. of the recipient.

[3] Gene expression inhibitory action of glycolipid-containing composition The glycolipid-containing composition obtained in [1] above is induced in the gastrointestinal tract induced by 5-FU (5-fluorouracil), which is an anticancer agent. The effect | action which suppresses the expression of a serotonin synthase gene and a substance P gene was examined.

(Test meal and 5-FU administration)
Seven-week-old male SD rats were divided into three groups of “control group”, “5-FU group”, and “5-FU + glycolipid-containing composition administration group”. “Control group” and “5-FU group” AIN93-G standard feed (standard purified feed for nutritional research for mice and rats published in 1993 by the American Institute of Nutrition), "5-FU + glycolipid-containing composition In addition to the standard feed, the “food administration group” was administered a 20 mg / day glycolipid-containing composition per kg of body weight.

  In the “5-FU group” and the “5-FU + glycolipid-containing composition administration group”, 300 mg of 5-FU per kg of body weight was administered on the fifth day after the start of the test. Three days later, dissection was performed, the jejunal mucosa and tissue samples were collected, and the effect of the glycolipid-containing composition on the expression of intestinal serotonin synthase gene and substance P gene by 5-FU (inhibition of gene expression) On the third day after administration of FU, a small intestine sample was collected and examined.

(result)
In the “5-FU group” and the “5-FU + glycolipid-containing composition administration group”, the amount of food intake and body weight during the test period tended to decrease after 5-FU administration. On the other hand, villous atrophy that was noticeably observed in the jejunal mucosa tissue of the “5-FU group” was significantly improved in the “5-FU + glycolipid-containing composition administration group”.
Furthermore, the inflammatory cytokine expression increased in the “5-FU group” also tended to be suppressed in the “5-FU + glycolipid-containing composition administration group”.

  In addition, the expression levels of the serotonin synthase gene (mRNA) in the small intestine and the α-tachykinin gene (mRNA), which is a substance P precursor, were examined over time (1 day, 3 days, and 5 days after the start of the test). The expression levels of these genes were examined by Real-time PCR (Polymerase Chain Reaction) method. The Real-time PCR method was performed under the following conditions.

<Primer>
(Serotonin synthase)
Forward primer: 5'-CAAGGAGAACAAAGACCATTC-3 '(SEQ ID NO: 1 in the sequence listing)
Reverse primer: 5'-ATTCAGCTGTTCTCGGTTGATG-3 '(SEQ ID NO: 2 in the sequence listing)
(Α-Takikinin)
Forward primer: 5'-TCCGACAGTGACCAAATCAA-3 '(SEQ ID NO: 3 in the sequence listing)
Reverse primer: 5'-AGCCTTTAACAGGGCCACTT-3 '(SEQ ID NO: 4 in the sequence listing)
(Β-actin)
Forward primer: 5'-CGACTTGGAGCAAGAGATGG-3 '(SEQ ID NO: 5 in the sequence listing)
Reverse primer: 5'-AGCACTGTGTTGGCGTACAG-3 '(SEQ ID NO: 6 in the sequence listing)

<PCR conditions>
The Real-time PCR method was performed using Step One Plus (TM) Real-time PCR System (Applied Biosystems).
First, cDNA was synthesized from total mRNA collected from the small intestine by an ordinary method using Oligo dT primer. Then, the forward primer, reverse primer, and Fast SYBR (R) Green Master Mix (Applied Biosystems) specific to the cDNA sequence of each gene are mixed, denatured at 95 ° C. for 10 seconds, and annealed at 60 ° C. for 15 seconds. Fifty cycles of extension reaction at 72 ° C. for 15 seconds were performed.

  The expression level of each gene was corrected with β-actin as a housekeeping gene as an internal standard, and expressed as a relative value based on the control group. The results are shown in FIGS. In addition, FIG. 2 is a graph which shows the inhibitory effect of the spinach origin glycolipid containing composition with respect to small intestine serotonin synthetase mRNA induction by 5-FU. In the figure, the vertical axis represents the relative expression level of small intestine serotonin synthase mRNA. FIG. 3 is a graph showing the inhibitory effect of the spinach-derived glycolipid-containing composition on the induction of small intestine α-tachykinin mRNA by 5-FU. In the figure, the vertical axis represents the relative expression level of small intestine α-tachykinin mRNA.

  As shown in FIG. 2 and FIG. 3, the expression of these mRNAs was significantly increased in the “5-FU group”, but in the “5-FU + glycolipid-containing composition administration group”, It was confirmed that expression was suppressed. The production of serotonin and substance P in the small intestine is a cause of nausea and vomiting at the time of anticancer drug administration, and suppressing the production indicates that adverse events caused by the anticancer drug can be reduced.

  Similar to the examination in [2] above, when 20 mg / kg / day of the glycolipid-containing composition was administered to SD rats, the expression suppressing action of small intestine serotonin synthase mRNA, the expression suppressing action of small intestine α-tachykinin mRNA, In view of species differences, it was speculated that the following dosage (intake) should be used for humans. That is, in the case of oral administration, the dosage is usually 1 to 800 mg / kg / day, preferably 2 to 200 mg / kg / day, more preferably as the dosage for children or adults (mg glyceroglycolipid / kg body weight / day). Was estimated to be 5-100 mg / kg / day. In the case of parenteral administration, the dose (mg glyceroglycolipid / kg body weight / day) is 1 to 400 mg / kg / day, preferably 2 to 100 mg / kg / day, more preferably 5 to 50 mg. / Kg / day. The dose may vary depending on the age, weight, administration method, target disease, symptoms, etc. of the recipient.

[4] Pharmaceutical composition or edible composition containing a glycolipid-containing composition About 150 mg of the glycolipid-containing composition obtained in the above [1], 125 mg of purified soybean oil, 15 mg of beeswax and 10 mg of vitamin E are obtained under a nitrogen gas atmosphere. Heated to 40 ° C. and mixed well to make a homogeneous liquid. This was supplied to a capsule filling machine, and a gelatin-coated capsule having an inner volume of 300 mg was made as a prototype. The preparation thus produced can be used as a pharmaceutical composition or an edible composition.

As described above, the present invention provides foods, pharmaceuticals, and pharmaceutical parts effective for the prevention and treatment of nausea and vomiting, which are side effects of cancer chemotherapy, and for the prevention and suppression of gastrointestinal mucosal damage and gastrointestinal mucosal atrophy. External goods and cosmetics can be provided.
The present invention can also be used as foods for specific health, functional foods, special-purpose foods, health supplements, nutritional supplements and the like that are effective in the prevention and treatment of nausea and vomiting.

Claims (12)

A food containing glyceroglycolipid as an active ingredient, and for suppressing the expression of at least one gene selected from the group consisting of a serotonin synthase gene and a substance P gene, and for suppressing nausea and vomiting. The glyceroglycolipid is mono galactosyl Luzia sill glycerol (MGDG), digalactosyldiacylglycerol (DGDG) and food according to claim 1 is at least one selected from the group consisting of sulfo Keno Bosi Luzia sill glycerol (SQDG). The glyceroglycolipid is, seaweed and claim 1 or 2 food according to derived from at least one of terrestrial plants. The terrestrial plants, food according to claim 3 is spinach.   A nausea / vomiting inhibitor which contains glyceroglycolipid as an active ingredient and is used for suppressing the expression of at least one gene selected from the group consisting of serotonin synthase gene and substance P gene.   The nausea / vomiting according to claim 5, wherein the glyceroglycolipid is at least one selected from the group consisting of monogalactosyl diacylglycerol (MGDG), digalactosyl diacylglycerol (DGDG) and sulfoquinovosyl diacylglycerol (SQDG). Inhibitor.   The nausea / vomiting inhibitor according to claim 5 or 6, wherein the glyceroglycolipid is derived from at least one of a seaweed and a terrestrial plant.   The nausea / vomiting inhibitor according to claim 7, wherein the terrestrial plant is spinach. Contains glyceroglycolipid as an active ingredient, serotonin synthase gene and quasi drugs is for nausea and vomiting suppressed with is for suppressing the expression of at least one gene selected from the group consisting of substance P gene. The glyceroglycolipid is mono galactosyl Luzia sill glycerol (MGDG), pharmaceuticals unit according to claim 9 is at least one selected from the group consisting of digalactosyldiacylglycerol (DGDG) and sulfo Kino Bosi Luzia sill glycerol (SQDG) Foreign goods. The glyceroglycolipid is, seaweed and pharmaceuticals quasi according to claim 9 or 10 derived from at least one of terrestrial plants. The terrestrial plants, pharmaceuticals quasi according to claim 11 is spinach.