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WO2003035091A1 - Preparation ai et son utilisation pour prevenir et traiter une infection par le virus de l'immunodeficience humaine - Google Patents

Preparation ai et son utilisation pour prevenir et traiter une infection par le virus de l'immunodeficience humaine Download PDF

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Publication number
WO2003035091A1
WO2003035091A1 PCT/JP2002/009481 JP0209481W WO03035091A1 WO 2003035091 A1 WO2003035091 A1 WO 2003035091A1 JP 0209481 W JP0209481 W JP 0209481W WO 03035091 A1 WO03035091 A1 WO 03035091A1
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Prior art keywords
hiv
indigo
solution
cells
preparation
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PCT/JP2002/009481
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English (en)
Japanese (ja)
Inventor
Osami Aki
Shinobu Matsuda
Naoki Yamamoto
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Matsuda, Tasuku
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Application filed by Matsuda, Tasuku filed Critical Matsuda, Tasuku
Priority to JP2003537657A priority Critical patent/JP4121957B2/ja
Publication of WO2003035091A1 publication Critical patent/WO2003035091A1/fr

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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
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
    • A61K36/704—Polygonum, e.g. knotweed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention shows an anti-HIV effect that is effective for prevention of human immunodeficiency virus (HIV) infection and suppression of the development of acquired immunodeficiency syndrome (AIDS) caused by an increase in HIV-infected cells in the body of an infected person.
  • HIV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • the present invention relates to the indigenous plants of the Polygonum tinctrium Aiton (Polygonaceae J), the Ryukyu indigo (Strobilanthes flaccidifolium Nees), and the spurge Among the three species of Sanai (Mercuria Us leiocarpa Siebold), an indigo preparation prepared from the Polygonaceae plant Tateai, especially water from Sukumo derived from Tateino, using water as the extraction solvent.
  • the present invention relates to the use of the extracted "sukumo" water extract or the anti-HIV active ingredient contained in the "sukumo" water extract in preventing or treating human immunodeficiency virus infection. Background technology
  • HIV Human Immunodeficiency Virus
  • HIV is one of the special viruses, and its genomic mutations in clinically isolated mutants are extremely diverse. Therefore, development of an accurate vaccine that can protect the infection of these various mutants showing various genomic gene mutations in general has not yet been predicted.
  • the characteristic of the propagation process of this retrovirus, the HIV virus is that when the virus is infected to host cells, the virus and genomic RNA are converted into type II, and the virus-derived reverse transcriptase is used in the host.
  • a reverse transcriptase inhibitor that inhibits the process of replicating the corresponding DNA chain, that is, the reverse transcription process specific to the HIV virus has been developed, and multiple species have been put to practical use.
  • nucleotide reverse transcriptase inhibitors or non-nucleotide reverse transcriptase inhibitors used in this reverse transcriptase inhibitor have serious side effects, such as reduced production of leukocytes and erythrocytes, It has been shown that side effects such as inducing neuropathy and, in addition, the gene mutation of the virus itself in patients can relatively easily develop resistance to these reverse transcription-inhibiting drugs. .
  • virus-derived poly'proteins that are produced using the transcription and translation machinery of the host cell from viral genes that have been integrated into the genomic DNA of the host cell once through the reverse transcription process are: Through the cutting process by virus-derived HIV protease, it becomes various mature viral proteins. For example, inhibition of the cleavage process by the HIV protease inhibits the maturation of the reverse transcriptase derived from the above-mentioned virus, or the maturation of the outer coat protein of the virus. Production of viral molecules is suppressed. An HIV protease inhibitor targeting this HIV protease has also been developed, and several types have been put to practical use.
  • HIV protease inhibitors have been reported to exhibit side effects such as psychiatric disorders, convulsions, and kidney stones.
  • side effects such as psychiatric disorders, convulsions, and kidney stones.
  • resistance is quickly acquired due to the gene mutation of the virus itself, and the therapeutic effect is high. Is attenuated.
  • cocktail therapy In order to alleviate the shortcomings such as emergence of resistance and side effects of these HIV drugs, an administration method called cocktail therapy was developed.
  • two types of HIV drugs The above is, for example, a method of simultaneously administering a reverse transcriptase inhibitor and an HIV protease inhibitor.
  • one HIV protease inhibitor is administered in addition to two reverse transcriptase inhibitors, such as a combination of nucleotide reverse transcriptase inhibitors of different types of purine bases and pyrimidine bases. It is a method of simultaneously blocking different processes.
  • this cocktail therapy the mechanism of acquiring resistance to each of the HIV drugs used is different, and the infections of resistant strains to each drug are mutually suppressed, thereby compensating for the above-mentioned disadvantages of monotherapy. be able to.
  • the present invention exerts a very clear effect in the prevention of HIV infection, the suppression of AIDS development after infection and the treatment of HIV infection, and has no adverse effects even when administered for a long period of time.
  • the present invention provides an indigo preparation and its composition as a novel anti-HIV active ingredient that has a low resistance acquisition rate, is robust, can be obtained at low cost, and can be used for a long time.
  • Polygonum tinctrium Aiton Polygonum tinctrium Aiton
  • Polygonaceae plant and Ryukyu Ai (Strobilanthes flaccidifolium Nees), Poaceae plant, which have been used for medicinal purposes such as antipyretic and detoxifying for a long time.
  • Ryukyu Ai Strobilanthes flaccidifolium Nees
  • indigo preparations using “Tateai” of the Polygonaceae plant as a raw material in particular, a component that is remarkably resistant to components extracted with water from “Sukumo” prepared from “Tatei”. I found that it has HIV action.
  • the indigo preparation which is an aqueous extract of Sukumo, and the active ingredients contained therein are extremely low in toxic “I” life, and are suitable for the prevention of HIV infection, as well as for humans. Confirmed that it can be used with confidence.
  • the first aspect of the present invention relates to an indigo preparation
  • the indigo preparation according to the present invention is an indigo preparation derived from Polygonum tinctorium Aiton belonging to the Polygonaceae family,
  • An indigo preparation characterized by being an aqueous extract of "Sukumo" prepared from the leaves and stems of the indigo plant in the indigo production process.
  • the second aspect of the present invention relates to an active ingredient which provides an anti-HIV activity of an indigo preparation derived from Polygonum tinctorium Aiton belonging to the above-mentioned Polygonaceae, and thus the anti-HIV according to the present invention.
  • the active ingredients are:
  • a third aspect of the present invention relates to the use of the indigo preparation in the prevention or treatment of human immunodeficiency virus infection,
  • the first use of the indigo preparation according to the present invention is the use of the indigo preparation as one of the active ingredients in the production of a health food
  • the health food is a use of the indigo preparation, characterized by comprising, as an active ingredient, the indigo preparation derived from the indigo plant belonging to the Polygonaceae plant according to the present invention. Also, the second use of the indigo preparation according to the present invention,
  • the pharmaceutical composition according to the present invention is obtained by blending, as one of active ingredients having an anti-HIV activity, the indigo preparation derived from the above-mentioned fruit belonging to the Polygonaceae plant according to the present invention. Use of things. BRIEF DESCRIPTION OF THE FIGURES
  • Figure 1 shows the use of the HTLV-III B strain as HIV-1, infection of MT-4 cells derived from human and lymphocytes, and HIV in cells infected with the HTLV-III B virus. 1 shows the results of evaluating the inhibitory effect on the growth process by the "Sukumo solution" derived from Tateai added to the culture solution. The graph shown in FIG.
  • FIG. 2 shows a cell culture of MOLT-4 cells (MOLT-4 ⁇ B) with persistent infection of HTLV-IIIB strain, using a “squid solution” derived from Tateai added to the culture.
  • FIG. 9 shows the results of evaluating the effect of suppressing the concentration of the P-24 antigen protein derived from the HIV-1 virus contained in the supernatant.
  • Fig. 4 shows that MOLT-4 cells were cultured for 24 hours in a culture solution supplemented with a squid solution derived from Tateai at various ratios and expressed CD4 antigen molecules on the cell surface. The result of evaluating the cell number ratio is shown.
  • Fig. 5 shows that four kinds of "Sukumo solution” derived from Tateai were prepared in a culture solution containing the "Sukumo solution” at a ratio of 20%, respectively, and cultured for 24 hours in the medium containing the "Sukumo solution". After treating the treated MOLT-4 cells with the HIV-1 virus, the cells are cultured in a new culture medium and cultured from the HIV-1 virus replicated and produced in the cells. The result of measuring the P24 antigen protein concentration in the supernatant is shown.
  • Polygonum tinctrium Lour (Polygonum tinctrium Lour) has been reported to have some medicinal properties in Kampo medicine. For example, fresh juice and decoction of indigo leaves, dried leaves, and seeds, when taken orally or externally, are effective against anti-inflammatory, detoxifying, antipyretic, hemostatic, insecticide, hemorrhoidal, tonsillitis, laryngitis, etc. Have been reported.
  • Indigo also has the action of removing active oxygen from the body as a physiologically active substance.It has the properties of gallic acid, caffeic acid, kaemperol, It has been reported that it contains trybotanthrin, indimbin, and flavonoids having a platelet aggregation inhibitory action, which exhibit a cancer action and an antiallergic action.
  • sukumo water extract contains HIV: the process by which human immunodeficiency virus enters healthy lymphocyte cells, specifically HIV
  • HIV In the process of binding to the CD4 antigen molecule and the chemokine 'receptor expressed on the surface of T cells via (gP120) and invading the T cells, HIV has the effect of inhibiting the binding process.
  • HIV causes mutations in infected cells, and repeats replication of virus particles and infection of other cells, resulting in the growth and infection of infected individuals.
  • the water extract of Sukumo has a strong anti-HIV effect and is expected to play an important role in the prevention and treatment of HIV infection.
  • the “indigo preparation” is usually a Polygonum tinctrium Aiton (Polygonum tinctrium Aiton),
  • Plants and tissues of the Euphorbiaceae plant “Yamaai” (Mercurialis leiocarpa Siebold) include all processed products that have been subjected to physical or chemical treatment. In this case, the site used as a raw material and its preparation The processing method used for the process does not matter.
  • the fermented material looks like red-black humus, and is called “sukumo”.
  • This "sukumo” can be used as an indigo preparation in the present invention.
  • the outline of the method for preparing the “indigo preparation” and the “indigo composition” used in the present invention is as follows.
  • the above-mentioned “spring solution” is further heat-treated at 121 ° C. for 15 minutes to sterilize it.
  • the heat-sterilized “spider solution” is particularly called “heat spider solution”.
  • the mixture is centrifuged, and the soluble component eluted by the heating and boiling treatment is collected as a supernatant.
  • the supernatant obtained by filtering the supernatant with a Millipore filter 1 is referred to as a “heated indigo solution”.
  • indigo dried leaf, stem, root, seed, fruit powder
  • Indigo composition Compounds derived from plants with anti-HIV activity have already been reported, but plants containing such compounds with anti-HIV activity, such as plants containing HIV, have already been shown to be somewhat effective in preventing and treating HIV infection.
  • a composition in which a seed plant is mixed with, for example, the above-described “dried indigo leaf / stalk 'root' seed 'fruit” is referred to as “indigo composition”.
  • the active ingredient exhibiting an anti-HIV activity derived from the Polygonaceae plant “Tateai” according to the present invention is usually obtained by extracting water from a fermented indigo product called “Sukumo” by water extraction.
  • a fermented indigo product called “Sukumo”
  • the present invention will be described more specifically using specific examples.
  • the filtrate subjected to the sterilization treatment is referred to as a ⁇ scoop solution '', and is usually used as the heat-sterilized ⁇ spark solution ''.
  • Heated spider solution when distinguishing from the solution before the heat sterilization treatment, Heated spider solution ".
  • the harvested indigo leaves, stems, roots, seeds, and fruits are dried once, and the dried product is ground into a fine powder having a particle size of about 50 microns or less.Pressing is performed at 121 ° C for 15 minutes. And sterilize.
  • the dried fine powder that has been sterilized by pressurization and heating is referred to as “blue-dried leaves, stems, roots, seeds, and fruit powder” depending on the location.
  • the verification method used in the anti-HIV activity verification experiment described below is described below.
  • human lymphocyte-derived MT-4 cells (HTLV-I transformed T4-cell line) were used as host cells for infection with HIV.
  • culture in a PRM I-1640 medium supplemented with 10% fetal serum, 100 ⁇ s 1 streptomycin and 100 U / ml penicillin G under the conditions of 5% CO 2 was used.
  • HIV-1 virus solution is obtained from the culture supernatant of MOL T-14 cells (MOLT-4 / IIIB) that have been persistently infected with HTLV-IIIB as the source of HIV-1 used for infection. did.
  • the amount of virus in such HIV-1 virus fluid is the indicator TCID 5 .
  • the evaluation of the anti-HIV activity of the test substance was based on the cytopathogenic effect of HIV-1 in MT-4 cells as an index, and the inhibitory effect was evaluated.
  • the cytopathogenic effect of HIV-1 on MT-4 cells was measured according to the method described in the literature: Harada, Koyanagi & Yamamoto, Science, Vol. 229 p.563-566 (1985).
  • MT-4 cells were contacted with a solution containing HIV-1 (0.001 / well TC ID 50 ) for 1 hour to infect the cells, and then unadsorbed virus was washed and removed. Then, the MT- 4 cells subjected to the infection process, RPMI-were resuspended at a concentration of 1. 5 X 1 0 5 eel 1 / m 1 in 1640. The cells were cultured for 5 days on a 96-well culture plate with 200 ⁇ l of 1-well cell suspension containing various concentrations of the test substance. As a control, a culture in which HIV-1 infected cells (positive control) or uninfected cells (negative control) were similarly cultured without adding a test substance to the medium was used.
  • a cell proliferation test in a medium to which the test substance was added at various concentrations was separately performed to determine a concentration at which the survival rate of MT-4 cells was reduced.
  • the survival rate of the cultured cells was evaluated using MT based on the reduction reaction of viable cells against 3- (4,5-dimethythithiazoi-2-yl-2,5-diphenylentetrazolium bromide (MTT).
  • the method is performed according to the T-Atsey method (J. Virol. Methods 20 (4), p. 309-21 (1988)).
  • the addition ratio of the "sparkling solution” to the medium is 100% for the “sparkling solution” itself, and 0% for the medium without the “sparkling solution”, and the addition ratio is determined by the volume ratio.
  • the “spider solution” itself had cytotoxicity.
  • MT-4 cells and MT-4 cells infected with the HIV-1 virus were cultured in a culture medium supplemented with various proportions of the "spider solution”, and the MTT assay was performed. Assess its survival.
  • the anti-HIV activity was verified in the range of the addition ratio of the “spin solution”, which was confirmed not to exhibit the cytotoxicity.
  • the evaluation of the suppression of the effect of HIV-1 on the cytopathogenic effect of MT-4 cells by the addition of a "steam solution" to the medium was evaluated.
  • P24 antigen test MOLT-4 / IIIB cells were cultured in a culture solution containing “Sukumo's solution” at various addition ratios, and 4 days later, the p24 antigen protein in the culture supernatant was cultured. The substance concentration was measured. Figure 2 shows the measurement results.
  • MOLT-4 cells MOLT-4 / IIIB
  • MOLT-4 IIB cells After culturing these MOLT-4 IIB cells at various ratios in a culture solution supplemented with the ⁇ spider solution '' for 4 days, the culture supernatant, which corresponds to the concentration of the HIV-1 virus contained in the culture solution, is used. P24 antigen protein concentration was measured.
  • the isolated peripheral blood mononuclear cells PBMC: Peripheral blood monocytes
  • PBMC peripheral blood mononuclear cells
  • PHA phytohemagglutinin
  • the HIV-1 virus culture supernatant of MOLT-4 iB cells
  • the infected PMBC was cultured for 12 days in the presence of T-cell growth factor IL-2 in a culture medium supplemented with various proportions of "Sukumotsu", and then the P24 antigen protein in the culture supernatant was Measure the concentration 1
  • FIG. 3 shows the measurement results of the P24 antigen protein concentration in the culture supernatant.
  • concentration of P24 antigen protein in the culture supernatant decreases along with the addition ratio ai of the "sparkle solution” added to the culture solution.
  • ai the addition ratio of the "sparkle solution” added to the culture solution.
  • P24 antigen was hardly detected in the culture supernatant, and almost 100% was suppressed.
  • the ratio of addition of the “scoop solution” a i was 20%, no P24 antigen was observed in the culture supernatant after culturing for 12 days.
  • Glycoprotein gp120 present on the surface of the HIV virus coat has the ability to form a complex with the CD4 surface antigen molecule, a leukocyte differentiation antigen of human T lymphocytes (receptor function).
  • the CD4 molecule which forms a complex with HIV gp120, plays a role as a receptor in the process of HIV infection of T cells.
  • the “spider solution” added to the culture solution reduced the surface expression of the CD4 antigen molecule, a receptor for HIV-1, in MOLT-4 cells in a concentration (addition ratio) -dependent manner.
  • Figure 4 shows the results of estimating the ratio of the number of cells expressing CD4 antigen molecules on the cell surface by culturing MOLT-4 cells for 24 hours in culture medium supplemented with various proportions of the Sukumotsu solution. Is shown. Relative evaluation based on the ratio of the number of cells expressing and expressing the CD4 antigen in the culture of unpolished sorghum (100%) When the ai 2.5% solution was added to ai 2.5%, 92%, ai 5%, 42%, ai 10%, 26%, and ai 20%, 10% The surface expression of the CD4 antigen molecule is suppressed in a concentration (addition ratio) -dependent manner.
  • the MOLT-4 cells treated with the “spider solution” are transferred to HIV-1 virus (MOLT-4 / IIIB cells). (Culture supernatant). Then, the cells were cultured in a new culture medium, and the concentration of the P24 antigen protein in the culture medium derived from the P24 antigen protein produced in the cultured cells was observed. In this experiment, a culture solution supplemented with “smooth solution” at a ratio of 20% was used.
  • each "splatter solution” was prepared in a culture solution supplemented with 20% of the "splatter solution”, and cultured for 24 hours in a medium containing the "splatter solution”.
  • Treated MOLT-4 cells were infected with HIV-1 virus. Then, the cells were cultured in a new culture medium, and the concentration of P24 antigen protein in the culture supernatant derived from the HIV-1 virus replicated and produced in the cells was measured.
  • FIG. 5 shows the measurement results of the P24 antigen protein concentration.
  • indicans glycosides of indoxyl
  • eyes Persicariatinctria
  • indigo the main component of natural indigo dyes produced by fermenting plants containing this indican
  • derivatives indigoca rmi ne (5, 5) '-Indigotine' diso-lenoic acid disodium salt
  • the active ingredient involved in the anti-HIV activity indicated by the “spider solution” was a component having the following characteristic properties.
  • the "spider solution” produces a precipitate upon treatment with 0.5N HC1, and the precipitate has anti-HIV activity, while the supernatant has no activity;
  • the "spider solution” is unchanged by the treatment with 0.5N NaOH, and the solution retains anti-HIV activity;
  • the “spider solution” is a blue precipitate formed by the addition of an aqueous solution of .l% FeCl 3 , 1% potassium ferricyanide (potassium hexacyanoferrate (III)) containing trivalent iron ions, Indicates the presence of a reducing, phenolic OH group.
  • “Sukumo solution” was evaporated to dryness processing, the dry product obtained, an organic solvent (methanol, pyridine, Asetonitoriru) can not be re-dissolved in, 0. IN NaHC 0 3 aqueous solution, 0. 5N N a OH It can be redissolved in aqueous solution or water.
  • the “heated spider solution” described in Experimental Example 2 described above was subjected to a heat sterilization treatment at 121 ° C for 15 minutes in the manufacturing process, but was further heated at 100 ° C for 1 hour. Even with the treatment, the anti-HIV activity remained to a considerable extent.
  • the "heated spider solution” is converted into a water-soluble component having a molecular weight of less than 10,000 and a water-soluble component having a molecular weight of 10,000 or more remaining on the ultrafiltration membrane by an ultrafiltration membrane having a molecular weight of 10,000.
  • No anti-HIV activity was found in the filtrate of a water-soluble component having a molecular weight of less than 10,000 that permeated the ultrafiltration membrane.
  • Ultrafiltration membrane in a liquid which is redissolved molecular weight 10, 000 or more soluble water-soluble components remain on only anti HI active '! 1 production was found.
  • the methanol-extracted residue and water extract obtained by extracting the water-soluble components remaining in the residue by reflux extraction with methanol after reflux extraction for 4 hours with methanol are also the same.
  • anti-HIV activity was evaluated, anti-HIV activity was found.
  • the components extracted in water after removing methanol-soluble and water-soluble components by methanol extraction in advance correspond to the active components contained in the “heated spider solution”. .
  • the evaluation of the anti-HIV activity was based on the measurement of the addition ratio (EC 5 ) that inhibited cell degeneration by 50% by using the MTT assay method. Separately, the total component contained in each test aqueous solution was measured as a dry weight, and the EC 5 was determined. Represents the weight of the dry matter (dry matter weight / ml unit) added per unit volume of the medium. Also measured simultaneously, the addition ratio to inhibit cell growth by 50% (50% cytotoxic ⁇ concentration:. CC 5) for were also expressed in (dry matter weight Zm l units). Table 3 below shows the evaluation results of anti-HIV activity. Table 3
  • the indigo preparation according to the present invention in particular, the water extract of "Sukumo" derived from Polygonum tinctorium Aiton belonging to the Polygonaceae family has anti-HIV virus activity, and particularly, non-infected cells of HIV virus.
  • anti-HIV virus activity and particularly, non-infected cells of HIV virus.
  • the indigo preparation according to the present invention in particular, the water extract of Sukumo, which is derived from Tatsuai, has extremely low side effects, high safety, and can be provided at low cost. It is considered to be well tolerated for periodical administration.
  • the indigo preparation according to the present invention in particular, the "Sukumo" extract derived from Tatsuai, itself has a plurality of types of anti-HIV virus activities with different mechanisms of action. Even when used in combination with other drugs, it is possible to reduce the number of drugs administered to patients and consequently delay the onset of side effects and the acquisition of resistance of these concomitant drugs. Thus, it seems that it can have a positive effect on current drug treatment.
  • the indigo preparation according to the present invention in particular, the water extract of "Sukumo" derived from the indigo plant, is particularly useful in drug treatment aimed at preventing infection and preventing the onset of AIDS. Useful as an anti-HIV drug.

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Abstract

L'invention concerne une nouvelle préparation d'origine végétale efficace pour prévenir et traiter le virus de l'immunodéficience humaine (VIH). L'invention concerne essentiellement une préparation ai (polrgoum indigo) provenant de tadeai (Polygonum tinctorium Lour.) qui est une plante appartenant à Polygonaceae et , notamment, un composant possédant un effet anti-VIH remarquable contenu dans un extrait aqueux de sukumo (feuille fermentée de ai). Dans le procédé dans lequel un antigène CD4 se lie à un récepteur de chémokine via un antigène de surface gp120 et envahit des cellules, le composant contenu dans l'extrait aqueux de sukumo possède un effet inhibant la liaison de l'antigène. Ce composant inhibe également la réplication et la prolifération du VIH dans les cellules associées à l'infection. En outre, l'extrait aqueux de sukumo présente une faible toxicité et de ce fait est exempt d'effets secondaires même en cas d'administration prolongée pour traiter une infection par le VIH. On peut donc l'utiliser de manière sûre.
PCT/JP2002/009481 2001-10-23 2002-09-17 Preparation ai et son utilisation pour prevenir et traiter une infection par le virus de l'immunodeficience humaine WO2003035091A1 (fr)

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Cited By (4)

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Publication number Priority date Publication date Assignee Title
WO2006115202A1 (fr) * 2005-04-25 2006-11-02 Fuji Sangyo Co., Ltd. Composition pour diminuer la toxicite de la nicotine
JP2008019227A (ja) * 2006-07-14 2008-01-31 Toyokatsu Horikawa 生理活性物質及びその製造方法
WO2008062861A1 (fr) 2006-11-24 2008-05-29 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Poudre d'extrait de plante contenant de l'indigo, procédé de fabrication de celle-ci et utilisation de celle-ci
CN103623070A (zh) * 2013-04-02 2014-03-12 汕头市创美中药饮片有限公司 何首乌的炮制生产工艺

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JPH04124137A (ja) * 1990-09-13 1992-04-24 Higashimaru Shoyu Kk アンジオテンシン変換酵素阻害剤
JP2001031581A (ja) * 1998-06-30 2001-02-06 Hayashibara Biochem Lab Inc 生理活性抽出物
JP2001064131A (ja) * 1999-08-27 2001-03-13 Riaru Kagaku Kk 染毛剤およびそれを用いた染毛方法

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WO2006115202A1 (fr) * 2005-04-25 2006-11-02 Fuji Sangyo Co., Ltd. Composition pour diminuer la toxicite de la nicotine
JP2008019227A (ja) * 2006-07-14 2008-01-31 Toyokatsu Horikawa 生理活性物質及びその製造方法
WO2008062861A1 (fr) 2006-11-24 2008-05-29 Kabushiki Kaisha Hayashibara Seibutsu Kagaku Kenkyujo Poudre d'extrait de plante contenant de l'indigo, procédé de fabrication de celle-ci et utilisation de celle-ci
CN103623070A (zh) * 2013-04-02 2014-03-12 汕头市创美中药饮片有限公司 何首乌的炮制生产工艺

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