WO2005034974A1 - 血栓症の予防または改善のための健康食品及び血栓症の予防または治療用医薬組成物 - Google Patents
血栓症の予防または改善のための健康食品及び血栓症の予防または治療用医薬組成物 Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/06—Fungi, e.g. yeasts
- A61K36/07—Basidiomycota, e.g. Cryptococcus
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
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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
- A61K31/33—Heterocyclic compounds
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
Definitions
- the present invention relates to a health food for preventing or improving thrombosis and a pharmaceutical composition for preventing or treating thrombosis.
- Patent document 1 JP-A-2000-159683
- Patent Document 2 JP 2003-155249A
- Shiitake mushrooms have attracted attention as pharmacologically active ingredients so far, mainly because of water-soluble components such as polysaccharides, and other pharmacologically active ingredients other than the polysaccharides of Shitake mushrooms, for example, organic solvents. No pharmacological effects of the extract components or the extract components, especially the essential oil components, by the mixture of organic solvent and water have been reported. In addition, the effect of shiitake mushrooms on the inhibition of platelet aggregation has also been reported.
- the present inventors have found that among the mushroom components, components extracted with an organic solvent or a mixture of an organic solvent and water, particularly those extracted into an organic solvent after a certain period of enzymatic reaction, inhibit platelet aggregation. And completed the present invention.
- the components include the following formulas I, II, III, IV, V and Z or VI: [0004] [Formula 3]
- lentionin 1,2,3,5,6-pentachepan
- Lentizonin is known as an aroma component of shiitake mushroom, and the ⁇ -daltamyl group of the precursor lentic acid is eliminated by the action of ⁇ -daltamyltransferase to produce des daltamyl lentinic acid, which is converted to C Sulfenic acid or thiosulfinate is generated by the action of —S lyase, and an io-containing fragment generated by non-enzymatic cleavage of thiosulfinate is generated by repeating polycondensation.
- an y-containing compound represented by the above formula II-VI is also produced.
- the present invention relates to an extract of shiitake mushroom in an organic solvent or a mixture of an organic solvent and water (hereinafter sometimes referred to as “extract of shiitake mushroom of the present invention” or simply “extract of shiitake mushroom”), shiitake mushroom A compound of the formulas I, II, III, IV, V and ⁇ or VI or a derivative thereof (hereinafter sometimes referred to as “the active ingredient of Shiitake mushroom of the present invention” or simply “the active ingredient of Shiitake mushroom” And a pharmaceutical composition for preventing or treating thrombosis or a pharmaceutical composition for preventing or treating thrombosis.
- the present invention relates to the following health food.
- a health food for preventing or ameliorating thrombosis comprising as an active ingredient an extract of shiitake mushrooms using an organic solvent or a mixture of an organic solvent and water.
- the extract is an extract obtained by using an organic solvent of shiitake mushroom body or a mixture of an organic solvent and water.
- the extract is obtained by crushing shiitake mushrooms, preferably shiitake mushroom fruit bodies, and then leaving the mixture at a temperature of 3-70 ° C for 1 minute or more, and then extracting the extract. , Health food described in any of the above.
- a health food for preventing or ameliorating thrombosis comprising a compound represented by the following formula I, II, III, IV, V and Z or VI or a derivative thereof as an active ingredient.
- R 1 — R 13 represent a hydrogen atom, a hydroxyl group, a halogen atom, an unsubstituted or substituted alkyl group having 1-20 carbon atoms, an unsubstituted or substituted Aryl group, unsubstituted or substituted alkoxy group, unsubstituted or substituted aryl group having 6 to 20 carbon atoms, unsubstituted or substituted alkyl aryl group having 7 to 20 carbon atoms Represents a group)
- the health food according to (5) which contains a compound represented by the above formulas I, II, III, IV, V and Z or VI as an active ingredient.
- the present invention also relates to the following pharmaceutical compositions.
- a pharmaceutical composition for preventing or treating thrombosis comprising, as an active ingredient, an extract of shiitake mushroom with an organic solvent or a mixture of an organic solvent and water.
- a pharmaceutical composition for preventing or treating thrombosis comprising a compound represented by the above formulas I, II, III, IV, V and Z or VI or a derivative thereof as an active ingredient.
- R 1 -R 13 are a hydrogen atom, a hydroxyl group, a halogen atom, an unsubstituted or substituted alkyl group having 1 to 20 carbon atoms, an unsubstituted or substituted alkoxy group having 1 to 20 carbon atoms
- composition according to (14) comprising a compound represented by the above formulas I, II, III, IV, V and Z or VI as an active ingredient.
- the present invention also relates to the following methods for preventing or treating thrombosis.
- a method for preventing or treating thrombosis which comprises administering an extract of Shiitake mushroom in an organic solvent or a mixture of an organic solvent and water.
- the present invention provides a health food effective for preventing or improving thrombosis and a pharmaceutical composition for preventing or treating thrombosis.
- the health food and the pharmaceutical composition of the present invention have a platelet aggregation inhibitory effect by an action mechanism different from that of cyclooxygenase inhibition. Conceivable.
- the active ingredient of the shiitake mushroom of the present invention particularly lentonin, does not participate in the platelet aggregation cascade due to the signal transduction substance in platelets, and causes morphological changes such as platelet adhesion and release reaction, and the accompanying phosphorylation of proteins. It is thought that the suppression suppresses platelet aggregation. Therefore, when used together with other antithrombotic agents, thrombosis can be more effectively prevented or treated by the effect of a different mechanism of action.
- FIG. 1 is a view showing the result of GC-MS analysis of a shiitake extract of the present invention.
- FIG. 2 is a graph showing the effect of lentonin on inhibiting platelet aggregation.
- FIG. 3 is a graph showing the effect of lentonin on inhibiting platelet aggregation.
- FIG. 4 is a graph showing the platelet aggregation inhibitory effect of the shiitake extract of the present invention.
- FIG. 5 is a graph showing the platelet aggregation inhibitory effect of the shiitake extract of the present invention.
- FIG. 6 is a graph showing the effect of lentonin on inhibiting platelet aggregation.
- FIG. 7 is a view showing an action mechanism of platelet aggregation.
- FIG. 8 is a graph showing platelet aggregation inhibitory effects of lentionine, 1,2-dichepan, and 1,2-dithiane.
- FIG. 9 is a graph showing platelet aggregation inhibitory effects of lentionine, 1,2-dicepan, and 1,2-dithiane.
- the shiitake mushroom as a raw material may be a raw shiitake mushroom or a dried shiitake mushroom.
- the dried shiitake is manufactured by, for example, solar drying or mechanical drying using a drying oven.
- Shiitake may be either a fruit body or a mycelium, but preferably a fruit body.
- the extraction solvent is an organic solvent or a mixture of an organic solvent and water, preferably an organic solvent.
- organic solvents include methanol, ethanol, n- or isopropanol, n-, iso, secondary or tertiary butanol, n-, iso, secondary or tertiary pentanol, n-, iso, secondary or Alcohols such as tertiary hexanol; ketones such as acetone and methyl ethyl ketone; esters such as methyl acetate, ethyl acetate and propyl acetate; halogenated hydrocarbons such as chloroform, methylene chloride; Ethers Examples thereof include aliphatic hydrocarbons such as sun and pentane, aromatic hydrocarbons such as benzene, toluene and xylene, and mixtures thereof, and are preferably, but not limited to, acetyl ether.
- the extraction temperature is preferably 70 ° C or lower, more preferably 40 ° C or lower, for example, 5-30 ° C. (Because heating for a long time at a temperature higher than 70 ° C may decompose the components to be extracted.)
- the extraction method may be cold immersion in an organic solvent or a mixture of water and an organic solvent, digestion, heating under reflux cooling, and the like.
- the extraction may be performed in a continuous manner or in a batch manner, for example, at a temperature in the range of room temperature to the boiling point of the solvent under increased pressure, normal pressure or reduced pressure.
- the extraction time can be appropriately determined depending on the extraction method, extraction solvent, and the like. For example, in the case of extraction at 5-30 ° C, the time is 1 hour to 24 hours, preferably 15 minutes to 30 minutes.
- a pretreatment such as crushing of shiitake mushroom and a constant temperature treatment. This is for the purpose of efficiently proceeding the enzymatic reaction for producing an iodinated compound such as lentonin starting from lentinic acid contained in shiitake mushroom.
- the crushing is performed, for example, by crushing using a device such as a homogenator in a pH 3-12 buffer solution.
- the isothermal treatment is carried out, for example, at a temperature of about 3 to 70 ° C, preferably 15 to 50 ° C, more preferably 25 to 40 ° C, for 1 minute to 24 hours, preferably 10 minutes to 12 hours, more preferably 30 minutes. This is done by holding for 13 minutes per minute.
- the extract used in the health food or the pharmaceutical composition of the present invention may be further purified by an extraction operation with an organic solvent, followed by a treatment such as filtration, drying and fractionation. Filtration, drying and fractionation can be performed by conventional methods well known to those skilled in the art.
- the extract used in the health food or pharmaceutical composition of the present invention may be one which has been extracted, purified if necessary, concentrated or dried or lyophilized, and further sterilized if desired. Good.
- the concentration or drying is performed under normal pressure or reduced pressure, preferably at a temperature of 150 ° C or lower, more preferably 30 ° C or lower. If the temperature exceeds 150 ° C, the components to be extracted may be decomposed.
- the health food and the pharmaceutical composition of the present invention can be obtained by the above-mentioned extraction / purification method.
- the extract is not limited to the extract containing the extract, but may be any extract containing essential oil components of shiitake mushrooms such as lentonine.
- the health food or pharmaceutical composition of the present invention may contain the compound represented by the above formula I-VI as an active ingredient. These compounds may be contained as components in the extract, or may be conjugates obtained by synthesis.
- the compound (lentonin) represented by the above formula I can be prepared, for example, by the method described in Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Cemistry (1972-1999), (3), 509-514; 1990. Can be synthesized.
- the reaction consists of reacting at room temperature.
- Lentons can be produced, for example, by the method described in Tetrahedron Vol. 41, No. 22, pp. 5145-5158.
- the method comprises reacting a metal halide and a metal tetrathiopercarbonate.
- the compound represented by the above formula II is, for example, Phosphorus and Sulfor and the Related Elements, 15 (1), 27-32; 1983, Phosphorus and Sulfur and the Related Elements, 8 (2), 157-9; It can be synthesized by the method described in 1980 and the like.
- the health food or pharmaceutical composition of the present invention may contain a derivative of the compound represented by the above formula I, II, III, IV, V and / or VI as an active ingredient.
- Such derivatives are, for example, compounds of the above formulas VII, VIII, IX, X, XI and Z or ⁇ .
- the shiitake extract or active ingredient of the shiitake mushroom of the present invention has high activity and low toxicity, so that it can be safely used for medical treatment.
- the ⁇ health food '' of the present invention includes extracts (soft extracts, dried extracts), capsules, granules, powders, and tablets containing the shiitake extract or the active ingredient of the shiitake mushroom of the present invention as an active ingredient. Liquid, dip, decoction, troche, fluid extract, tincture and the like. These can be formulated by methods known in the art. Health foods in the form of these preparations can contain the auxiliaries listed below for the pharmaceutical compositions. The amount of the extract of shiitake mushroom or the active ingredient of the shiitake mushroom of the present invention varies depending on the dosage form.
- the dose of the active ingredient per day may be, for example, 11 to 15 g, preferably 2 to 5 g, in the case of a compound or a derivative thereof, for example, 0.1 to 1.5 g, as the freeze-dried weight of the organic solvent extraction component.
- the amount is preferably 0.2-0.5 g.
- the health food of the present invention may be a food in which the active ingredient of shiitake mushroom of the present invention is added to a food such as a general processed food, that is, a so-called functional food.
- a food such as a general processed food, that is, a so-called functional food.
- Such foods include candies, gums, jellies, biscuits, cookies, rice crackers, bread, ⁇ , fish meat, animal meat products, tea, soft drinks, coffee drinks, and milk to which the above-mentioned active ingredient of the present invention has been added. Beverages, whey drinks, lactic acid bacteria drinks, yogurt, ice cream, pudding and the like.
- the healthy food of the present invention also includes the healthy mushroom obtained by soaking the shiitake mushroom and optionally other ingredients in drinking alcohol.
- the amount of the shiitake mushroom extract or the active ingredient of the shiitake mushroom of the present invention varies depending on the food to be added.
- the freeze-dried weight of the organic solvent extract of shiitake mushroom for example, 0.001 to 10% by weight, It is preferably 0.1-1% by weight.
- the amount is, for example, 0.0001 to 10% by weight, preferably 0.01 to 0.1% by weight.
- the “pharmaceutical composition” of the present invention contains, as an active ingredient, the active ingredient of the shiitake mushroom of the present invention.
- the dosage form is not particularly limited, for example, extracts (soft extract, dry extract), capsules, granules, solutions, emulsions, suspensions, powders, tablets, liquids, dips, decoctions, troches Fluid extract, tincture, eye drops, nasal drops, ointments, creams, lotions, injections, suppositories and the like.
- the amount of the mushroom extract or the active ingredient thereof in the pharmaceutical composition of the present invention varies depending on the dosage form.
- the daily dose of the active ingredient is, for example, 11 to 15 g, preferably 2 to 5 g, as the freeze-dried weight of the organic solvent extracted component.
- the amount is, for example, 0.1 to 1.5 g, preferably 0.2 to 0.5 g.
- preparations are prepared according to a conventional method using a pharmaceutical agent such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a flavoring agent, a solubilizer, a suspending agent, a coating agent, a diluent, etc. It is formulated using known adjuvants which can be usually used in the art of formulation.
- a pharmaceutical agent such as an excipient, a binder, a disintegrant, a lubricant, a stabilizer, a flavoring agent, a solubilizer, a suspending agent, a coating agent, a diluent, etc. It is formulated using known adjuvants which can be usually used in the art of formulation.
- the pharmaceutical composition containing the active ingredient of shiitake mushroom of the present invention is usually prepared according to a conventional method, and is formulated into a form suitable for the purpose.
- the pharmaceutical composition may contain the active ingredient of the shiitake mushroom of the present invention and an auxiliary agent known to be usable in the technical field of pharmaceutical formulation.
- Solid preparations include, for example, powders, granules, tablets, capsules, dragees and the like, and a compound of the present invention as an active ingredient and a diluent (eg, lactose, dextrose, sucrose, cellulose, corn starch).
- a diluent eg, lactose, dextrose, sucrose, cellulose, corn starch.
- lubricants eg, silica, talc, stearic acid, magnesium stearate, calcium stearate, polyethylene glycol, etc.
- Binders eg, starches, gum arabic, gelatin, methinoresenorelose, canoleboxymethylcellulose, polybutylpyrrolidone, etc.
- discrete agents eg, starch, alginic acid, alginate, etc.
- saturants coloring agents
- sweeteners Wetting agents (eg, lecithin, polysorbate, lauryl sulfate, etc.) and the like can be included.
- These can be formulated by known methods such as mixing, granulation, tableting, sugar coating and the like.
- Liquid preparations can be in the form of, for example, syrups, solutions, emulsions and suspensions.
- the suspensions and emulsions may contain as carrier, for example, natural gums, agar, sodium alginate, pectin, methinoresenolerose, carboxymethylcellulose, polyvinyl alcohol and the like.
- the suspension or solution for intramuscular injection may be a pharmacologically acceptable carrier such as sterile water, olive oil, ethyl oleate, glycols such as propylene glycol, and if necessary, an appropriate amount of lidocaine hydrochloride. Salts can be included.
- the solutions for intravenous injection or infusion are preferably in the form of a sterile isotonic saline solution which can contain, for example, sterile water as a carrier.
- the health food and the pharmaceutical composition of the present invention are used for prevention, amelioration or treatment of diseases caused by platelet aggregation, for example, cerebral infarction and myocardial infarction.
- the present invention also relates to a method for preventing or treating thrombosis, which comprises administering the above-described extract or active ingredient of shiitake mushroom of the present invention together with another antiplatelet drug, if desired.
- antiplatelet drugs examples include ticlovidine hydrochloride, cilostazol, ethyl icosapentate, beraprost sodium, salpodalate hydrochloride, aspirin'dialuminate combination agent, aspirin and the like. It can be administered in combination with one or more platelet agents.
- Example 1 Preparation of shiitake extract 500 ml of 0.2 MTris-HC1 buffer (pH 3.0, 5.0, 7.0 or 9.0) was added to 300 g of raw shiitake fruit body, and homogenized with a homogenizer (Matsubara) for 3 minutes. Then, it was incubated at 37 ° C for 30 minutes.
- a homogenizer Matsubara
- the obtained oily substance was analyzed by GC-MS.
- the components obtained when incubated at pH 3.0, 5.0, 7.0 and 9.0 are shown in Table 1 below.
- a shiitake mushroom extract was prepared in the same manner as in Example 2 except that incubation was not performed at 37 ° C for 30 minutes.
- Dulbecco 'sPBS (-) solution 9.6 g of Dulbecco' sPBS (-) manufactured by Nissui Pharmaceutical Co., Ltd. It was used by dissolving it in distilled water so that the total amount was 1000 ml.
- Instruments All glass products (such as cuvettes) and metal instruments (such as steering rods) used for the measurement were treated with silicon (SIGMACOTE, manufactured by Sigma-Aldrich Japan) to prevent adsorption and coagulation caused by platelet foreign body contact stimulation. Silicone coating was used.
- Test Example 1 Inhibitory effect of lentonine on platelet aggregation by arachidonic acid
- Renchionin manufactured by Ogawa & Co., Ltd.
- L Asukorubin acid Pal Miteto to Etanonore containing 50ppm as Sani ⁇ inhibitor, final concentration force S respectively 3. 16 X 10- 4, 1. 0 X 10- 3. 16 X 10- 5, 1. 0 X 10- 5, 3. 16 X 10- 6, 1. 0 X 10- 6, 3. 16 X 10- 7, diluted to 1. 0 X 10 one 7
- a lentonine diluent was prepared.
- Arachidonic acid (manufactured by Sigma-Aldrich Japan) lOOmg is dissolved in 2.76 ml of 0.5N NaOH, dispensed in 50 ⁇ l aliquots into an eppendorf tube, and after adding nitrogen gas, freeze at -80 ° C and store. At the time of use, a solution diluted to a concentration of 1.5 mM in PRP in a PBS buffer solution was used as an aggregation-inducing substance solution.
- the obtained taenic acid blood was centrifuged at 1500 rpm for 10 minutes, and the upper layer was used as platelet rich plasma (hereinafter referred to as PRP).
- the lower layer was further centrifuged at 3000 rpm for 15 minutes, and the upper layer was used as platelet poor plasma (hereinafter referred to as PPP).
- PRP 300 1 of the PPP prepared above was dispensed into a cuvette, and PRP 300 1 prepared above was dispensed into another cuvette. This was set on an aggregometer (NKK HEMA TRACER 1 MODEL PAT-4A, SSR ENGINEERING), and the stirrer was rotated at 100 rpm to incubate at 37 ° C.
- the transmittance was recorded by a recorder (CHROMATOPAC C-R4A, manufactured by Shimadzu Corporation). First, set the cuvette containing PPP and adjust the recorder's transmittance to 40,000. Then, set the cuvette containing PRP and adjust the recorder's transmittance to 0. Adjusted PAN. This SPAN adjustment was performed for each measurement.
- CHROMATOPAC C-R4A manufactured by Shimadzu Corporation.
- the platelet aggregation inhibition rate was determined as follows.
- the change in PRP transmittance ( ⁇ %) associated with platelet aggregation was regarded as the change in platelet aggregation (Agg%), and the maximum value was defined as the maximum aggregation (Agg. Max%).
- T and T ' Determine the maximum agglutination rates (T and T ', respectively) for the PRP to which no sample was added and the PRP to which the sample was added.
- Test Example 2 Inhibitory effect of lentonine on platelet aggregation by U-46619
- a 10 mM U-46619 solution was prepared by diluting lmg U-46619 (U-46619 lmgZ methyl acetate 1001, manufactured by Funakoshi Co., Ltd.) with ethanol 185 1 as the coagulation-inducing substance solution.
- Lentonin was prepared in the same manner as in Test Example 1 above, except that a solution stored frozen at -20 ° C was used and diluted with PBS buffer to a final concentration of 1 ⁇ in PRP at the time of use. was examined for its production against platelet aggregation.
- Aspirin is known as a compound having a platelet aggregation inhibitory action.
- the inhibitory action of aspirin on platelet aggregation is due to cyclooxygenase inhibition. While inhibiting the production of xan ⁇ 2, It also inhibits the production of prostacyclin, which has a platelet aggregation inhibitory action produced by the mechanism.
- U-46619 which is an analogous conjugate of thromboxane A2
- thromboxane A2 is an unstable compound. Showed an effect.
- the inhibitory effect of lentonin on platelet aggregation is thought to be due to a different mechanism of action from cyclooxygenase inhibition. Therefore, it is considered that the present invention can solve the problems when aspirin is used as a platelet aggregation inhibitor.
- Test Example 3 Inhibition of platelet aggregation by arachidonic acid of shiitake organic solvent extract
- Test Example 4 Inhibition of platelet aggregation by U-46619 of Shiitake organic solvent extract
- Test Example 5 A23187, phorbol 12-myristate 13-acetate (hereinafter referred to as PMA), platelet activator (hereinafter referred to as PAF), and the inhibitory effect of lentonin on platelet aggregation when used as an inducer were investigated.
- PMA phorbol 12-myristate 13-acetate
- PAF platelet activator
- the lentonin diluent prepared in Test Example 1 was used to prepare a solution of each inducer as follows.
- A23187 manufactured by Wako Pure Chemical Industries, Ltd. was dissolved in DMSO, and refrigerated as an A23187 solution having a final concentration of 12.5 mM. When used, it was diluted with PBS buffer to a final concentration of 50 M in PRP.
- PMA manufactured by Funakoshi Co., Ltd. was dissolved in ethanol and stored refrigerated as a PMA solution having a final concentration of 90 ⁇ . When used, it was diluted with PBS buffer containing 4% ethanol to a final concentration of 5 M in PRP.
- PAF PAFlOmg manufactured by Funakoshi Co., Ltd. was dissolved in black-mouthed form and stored frozen at -20 ° C as a PAF solution of ImM. When used, dispense the used amount into an eppendorf tube, remove the pore form with nitrogen gas, add PBS buffer containing 0.25% BSA, sonicate, and terminate the PRP. Diluted to a concentration of 1 ⁇ .
- ADP ADP manufactured by Wako Pure Chemical Industries, Ltd. was diluted with PBS buffer so that the final concentration in PRP was 10 ⁇ .
- the following operations were performed at room temperature because blood is apt to spontaneously aggregate when cooled.
- the taenic acid blood obtained by the blood collection was centrifuged at 1500 rpm for 10 minutes, and the upper layer was used as platelet rich plasma (hereinafter referred to as PRP).
- the lower layer was further centrifuged at 3000 rpm for 15 minutes, and the upper layer was used as platelet poor plasma (hereinafter referred to as PPP). Platelets were used within 3 hours after blood collection, because platelet function declined about 3 hours after blood collection.
- the platelet aggregation ability was measured using an aggregometer (NKK HEMA TRACER 1 MODEL PAT-4A, SSR ENGINEERING).
- the cuvette was incubated at 37 ° C, and the rotation speed of the stirrer was set to 100 rpm.
- the transmittance was recorded by a recorder (CHROMATOPAC C-R4A, manufactured by Shimadzu Corporation).
- a cuvette containing a steering rod was prepared.
- One cuvette was filled with 300 ⁇ l of PPP, and the other cuvette was filled with 300 ⁇ l of PRP.
- set the cuvette filled with ⁇ to set the recorder's transmittance to 40,000, and then set the cuvette filled with PRP and set the recorder's transmittance to 0 to adjust the SPAN. went. This SPAN adjustment was performed for each measurement.
- a platelet aggregation inhibitory rate was used in which only a diluent solvent was added instead of the lentonine diluent, and the platelet aggregation inhibition rate was determined by the same method as in Test Example 1.
- A23187 causes platelet aggregation by increasing intracellular Ca ion concentration
- PMA and platelet activity induce platelet aggregation by activating protein kinase C.
- Lentionin suppresses platelet aggregation induced by any of the ADP-inducing substances that are released from PAF, which is the arsenical, and platelet-associated dense granules in platelets following platelet aggregation and affect other platelets showed that.
- Figure 7 summarizes the mechanism of action of each inducer.
- lentonin does not participate in the platelet aggregation cascade due to signal transduction substances in platelets, but suppresses morphological changes such as platelet adhesion and release reaction, and the accompanying phosphorylation of proteins. It is thought that there is.
- Test example 6 Lentionin's ability to inhibit platelet aggregation
- the IC of Lentisonin is lower than that of 1,2-Dichepan and 1,2-Dithiane.
- the present invention provides a health food effective for preventing or improving thrombosis and a pharmaceutical composition for preventing or treating thrombosis.
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Cited By (4)
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---|---|---|---|---|
WO2018135417A1 (ja) | 2017-01-23 | 2018-07-26 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-ペンタチエパンの製造方法 |
CN108456193A (zh) * | 2017-02-21 | 2018-08-28 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-五硫杂环庚烷的制造方法 |
WO2019181484A1 (ja) | 2018-03-22 | 2019-09-26 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-ペンタチエパンの製造方法 |
KR20190125632A (ko) * | 2018-04-30 | 2019-11-07 | 재단법인 경북바이오산업연구원 | 표고버섯 추출물의 에틸아세테이트 분획물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6272620A (ja) * | 1985-09-25 | 1987-04-03 | Res Dev Corp Of Japan | 播種性血管内凝固症候群予防・治療剤 |
JPH0881385A (ja) * | 1994-09-13 | 1996-03-26 | Asano Sangyo Kk | キノコ由来の抗血小板凝集物質 |
-
2004
- 2004-10-07 JP JP2005514608A patent/JP4877664B2/ja not_active Expired - Fee Related
- 2004-10-07 WO PCT/JP2004/014872 patent/WO2005034974A1/ja active Application Filing
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6272620A (ja) * | 1985-09-25 | 1987-04-03 | Res Dev Corp Of Japan | 播種性血管内凝固症候群予防・治療剤 |
JPH0881385A (ja) * | 1994-09-13 | 1996-03-26 | Asano Sangyo Kk | キノコ由来の抗血小板凝集物質 |
Non-Patent Citations (4)
Title |
---|
CHEN C-C ET AL.: "Identification of sulfurous compounds of Shiitake mushroom (Lentinus edodes sing.)", J. AGRIC. FOOD CHEM., vol. 34, no. 5, 1986, pages 830 - 833, XP002904555 * |
HATVANI N.: "Antibacterial effects of the culture fluid of Lentilus edodes mycelium growth in submerged liquid culture", J. ANTIMICROBIAL AGENTS, vol. 17, no. 1, 2001, pages 71 - 74, XP001051184 * |
HAYAKAWA M. ET AL.: "Shiitake to kesshoban gyoshu ni kansuru kenkyu", JAPANESE JOURNAL OF GERIATRICS, vol. 22, no. 2, 1985, pages 151 - 159, XP002988132 * |
OTSUKA M. ET AL.: "Jikkenteki haikessen rat ni taisuru shiitake-fructo-oligosaccharide kongobutsu(SK-204) no eikyo", JOURNAL OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 116, no. 2, 1996, pages 169 - 173, XP002988133 * |
Cited By (10)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2018135417A1 (ja) | 2017-01-23 | 2018-07-26 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-ペンタチエパンの製造方法 |
KR20180090901A (ko) | 2017-01-23 | 2018-08-13 | 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 | 1,2,3,5,6-펜타티에판의 제조방법 |
US10472343B2 (en) | 2017-01-23 | 2019-11-12 | Mitsubishi Gas Chemical Company, Inc. | Method for producing 1,2,3,5,6-pentathiepane |
CN108456193A (zh) * | 2017-02-21 | 2018-08-28 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-五硫杂环庚烷的制造方法 |
CN108456193B (zh) * | 2017-02-21 | 2022-04-08 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-五硫杂环庚烷的制造方法 |
WO2019181484A1 (ja) | 2018-03-22 | 2019-09-26 | 三菱瓦斯化学株式会社 | 1,2,3,5,6-ペンタチエパンの製造方法 |
KR20200135320A (ko) | 2018-03-22 | 2020-12-02 | 미쯔비시 가스 케미칼 컴파니, 인코포레이티드 | 1,2,3,5,6-펜타티에판의 제조방법 |
US11919877B2 (en) | 2018-03-22 | 2024-03-05 | Mitsubishi Gas Chemical Company, Inc. | Production method for 1,2,3,5,6-pentathiepane |
KR20190125632A (ko) * | 2018-04-30 | 2019-11-07 | 재단법인 경북바이오산업연구원 | 표고버섯 추출물의 에틸아세테이트 분획물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품 |
KR102120490B1 (ko) * | 2018-04-30 | 2020-06-09 | 재단법인 경북바이오산업연구원 | 표고버섯 추출물의 에틸아세테이트 분획물을 유효성분으로 함유하는 혈전증의 예방 또는 치료용 약학적 조성물 및 건강 기능 식품 |
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JPWO2005034974A1 (ja) | 2006-12-21 |
JP4877664B2 (ja) | 2012-02-15 |
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