WO2013027245A1 - インフルエンザウイルス感染抑制剤 - Google Patents
インフルエンザウイルス感染抑制剤 Download PDFInfo
- Publication number
- WO2013027245A1 WO2013027245A1 PCT/JP2011/004701 JP2011004701W WO2013027245A1 WO 2013027245 A1 WO2013027245 A1 WO 2013027245A1 JP 2011004701 W JP2011004701 W JP 2011004701W WO 2013027245 A1 WO2013027245 A1 WO 2013027245A1
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- WO
- WIPO (PCT)
- Prior art keywords
- influenza virus
- extract
- virus infection
- daisies
- poppy
- Prior art date
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Images
Classifications
-
- 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)
- A61K36/66—Papaveraceae (Poppy family), e.g. bloodroot
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- A—HUMAN NECESSITIES
- A21—BAKING; EDIBLE DOUGHS
- A21D—TREATMENT, e.g. PRESERVATION, OF FLOUR OR DOUGH, e.g. BY ADDITION OF MATERIALS; BAKING; BAKERY PRODUCTS; PRESERVATION THEREOF
- A21D2/00—Treatment of flour or dough by adding materials thereto before or during baking
- A21D2/08—Treatment of flour or dough by adding materials thereto before or during baking by adding organic substances
- A21D2/36—Vegetable material
-
- 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
- A23L2/00—Non-alcoholic beverages; Dry compositions or concentrates therefor; Their preparation
- A23L2/52—Adding ingredients
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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
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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
- 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
- A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
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- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
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- A—HUMAN NECESSITIES
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- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
Definitions
- Provision of a composition having an influenza virus infection-suppressing effect is provided.
- influenza virus Infection with influenza virus may cause clinical symptoms such as high fever, headache, joint pain, general malaise, and may die.
- Influenza virus is highly infectious and is characterized by causing an explosive epidemic in a short period of time unlike a common cold.
- prevention / treatment methods for influenza vaccination prevention and treatment with drugs such as neuraminidase inhibitors are generally known.
- vaccines are not all-purpose because their effects vary greatly depending on the type of influenza virus, and drugs have problems such as side effects and the emergence of resistant viruses.
- Non-patent Document 1 Kakachi (Non-patent Document 1), lactoferrin and lactoperoxidase (Non-patent Document 2), spore-forming lactic acid bacteria ( Patent document 1), cromoglycic acid (patent document 2), protein fraction derived from mammalian colostrum (patent document 3), sialo-glycan-containing polymer (patent document 4), buckwheat (patent document 5), cassis (patent document) 6)
- Patent Documents 7 and 8 are disclosed as components exhibiting an influenza virus infection-suppressing effect. However, these components still cannot be said to exhibit a sufficient inhibitory effect on influenza virus infection, and further development of prevention and treatment methods is required.
- the poppy (Papaver rhoeas L.), which has been confirmed to have an influenza virus infection-suppressing effect in the present invention, is a plant belonging to the poppy family. It is used as an antitussive and sedative, but it is not known at all about the virus infection-suppressing effect.
- the present invention is to provide a composition having an influenza virus infection-suppressing effect.
- the present invention relates to an anti-influenza virus agent characterized by comprising an extract of daisies as an active ingredient. Furthermore, the present invention relates to an anti-influenza virus agent characterized in that an extract obtained by extracting daisies using water and lyophilizing and purifying the extract is used as an active ingredient. Furthermore, this invention relates to the food / beverage products which have an anti-influenza virus effect
- the corn poppy extract of the present invention is a new material that has an IgA secretion promoting effect and an influenza virus infection suppressing effect, and is considered to produce a constitution that is difficult to be infected with influenza, and can enhance the function of a throat candy.
- the present inventors focused on a poppy extract, and the same amount of influenza was administered to mice fed and administered with this poppy extract.
- the mice administered with the dairy beet extract had a moderate weight loss due to influenza virus infection and the survival rate was also improving.
- specific examples will be described in Examples. In addition, this invention is not limited to the following specific examples.
- Example 1 Preparation of corn poppy hot water extract After pulverizing 100 g of corn poppy (flower), 10 times the amount of water was added to the weight of the sample and extracted at 70 ° C. for 2 hours. After filtering the insoluble matter, the extract obtained was freeze-dried to obtain 37.5 g of dairy hot water extract.
- Example 2 Influenza virus infection suppression effect by repeated sublingual administration to mice
- mice Thirty 7-week-old mice (BALB / c strain) were divided into control group (14 mice) and administration group (16 mice), normal feed (MF, Oriental yeast ).
- dairy (flower) hot water extract was sublingually administered daily as an aqueous solution at a dose of 4 mg / day, and the control group was administered only the same amount of water sublingually.
- influenza virus was intranasally inoculated (100 pfu / 50 ⁇ l PBS / animal) under anesthesia, and body weight was measured up to 16 days after inoculation.
- a / PR / 8/34 (H1N1) strain was used as the influenza virus, and sublingual administration of daisy (flower) hot water extract was performed after virus infection.
- the weight of each animal at the time of virus inoculation is as shown in Table 1 below, and no significant difference was observed between the two groups.
- FIG. 1 is a plot of the survival rate of mice in the corn poppy extract administration group and the control group up to 16 days after influenza virus inoculation.
- the number of days indicates the number of days elapsed after inoculation with influenza virus
- the change in body weight indicates the amount of change from the body weight at the time of virus inoculation.
- X in Table 2 and Table 3 indicates that the mouse died.
- tablets, chewing gum, candy, chocolate, biscuits, gummy jelly, tablet confectionery, ice cream, sorbet, and beverages were prepared in a conventional manner using the corn poppy extract of the present invention that showed an influenza virus infection inhibitory effect.
- the prescription is shown below.
- Example 3 Tablets were prepared according to the following formulation. D-mannitol 33.6% Lactose 33.6 Crystalline cellulose 8.5 Hydroxypropylcellulose 4.3 Daisies extract 20.0 100.0%
- Chewing gum was prepared according to the following formulation. Gum base 20.0% Sugar 54.7 Glucose 15.0 Minamata 9.5 Fragrance 0.5 Daisies extract 0.3 100.0%
- Example 5 Candy was prepared according to the following formulation. Sugar 50.0% Minamata 33.0 Citric acid 1.0 Fragrance 0.2 L-Menthol 1.0 Daisies extract 0.5 Water 14.3 100.0%
- Example 6 Chocolate was prepared according to the following formulation. Cocoa bitter 20.0% Whole milk powder 20.0 Cocoa butter 17.0 Powdered sugar 41.85 Lecithin 0.45 Fragrance 0.1 Daisies extract 0.6 100.0%
- Example 8 Gummy jelly was prepared according to the following formulation. Polydextrose aqueous solution 40.0% Sorbitol aqueous solution 8.0 Palatinose aqueous solution 9.0 Maltose aqueous solution 20.0 Trehalose aqueous solution 11.0 Gelatin 10.0 Tartaric acid 1.0 Daisies extract 1.0 100.0%
- Example 9 Tablet confectionery was prepared according to the following formulation. 76.1% sugar Glucose 19.0 Sucrose fatty acid ester 0.2 Fragrance 0.2 Daisies extract 0.5 Water 4.0 100.0%
- Example 10 Tablets were prepared according to the following formulation. 35.85% sugar Sucrose fatty acid ester 0.15 Daisies extract 60.0 Water 4.0 100.0%
- Ice cream was prepared according to the following formulation. Yolk 11.0% Sugar 14.0 Milk 37.0 Fresh cream 37.0 Vanilla beans 0.5 Daisies extract 0.5 100.0%
- Example 12 A sherbet was prepared according to the following formulation. Orange juice 16.0% Sugar 31.0 Daisies extract 3.0 Water 50.0 100.0%
- Example 13 A beverage was prepared according to the following formulation. Orange juice 30.0% Isomerized sugar 15.33 Citric acid 0.1 Vitamin C 0.04 Fragrance 0.1 Daisies extract 0.01 Water 54.42 100.0%
- the corn poppy extract of the present invention exhibits an influenza virus infection suppressing effect, and thus can be applied to various pharmaceuticals and foods and drinks for suppressing influenza virus.
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Abstract
Description
インフルエンザの予防・治療法としては、ワクチン接種による予防やノイラミニダーゼ阻害剤等の薬剤による治療が一般的に知られている。しかし、ワクチンはインフルエンザウイルスのタイプによって効果が著しく異なるため万能ではなく、薬剤は副作用や耐性ウイルスの出現といった問題がある。
ヒナゲシ(ポピー)の薬理作用に関し、ハーブを含む免疫賦活剤に関する特許(特許文献9)にハーブの一例としてポピーの記載があるものの、発明の具体性に欠ける文献であり、ポピーのウイルス感染抑制効果に関する記載も示唆もない。
さらに、本発明は、ヒナゲシを水を用いて、抽出し、その抽出液を凍結乾燥して精製することにより得た抽出物を有効成分とすることを特徴とする抗インフルエンザウイルス剤に関する。
さらにまた、本発明は、ヒナゲシ抽出物を含有する抗インフルエンザウイルス作用を有する飲食品に関する。
以下、具体例を実施例で説明する。なお、本発明は以下の具体例に限定されるものではない。
ヒナゲシ熱水抽出物の調製
ヒナゲシ(ポピー)(花)100gを粉砕した後、試料の重量に対して10倍量の水を加え、70℃で2時間抽出した。不溶物を濾過した後、得られた抽出液を凍結乾燥してヒナゲシ熱水抽出物37.5gを得た。
マウスへの反復舌下投与によるインフルエンザウイルス感染抑制効果
7週齢のマウス(BALB/c系)30匹を対照群(14匹)と投与群(16匹)に分け、普通飼料(MF, オリエンタル酵母)で飼育した。投与群には飼育開始時からヒナゲシ(花)熱水抽出物を4mg/dayの用量で水溶液として毎日舌下投与し、対照群は同量の水のみを舌下投与した。4週目にインフルエンザウイルスを麻酔下で経鼻接種(100pfu/50μl PBS/匹)し、接種後16日までの体重を測定した。インフルエンザウイルスはA/PR/8/34(H1N1)株を用い、ヒナゲシ(花)熱水抽出物の舌下投与はウイルス感染後も行った。ウイルス接種時の各動物の体重は以下の表1の通りであり、両群間に有意差を認めなかった。
表2及び表3は、インフルエンザウイルス接種後16日までのマウスの体重変化をグラムで示したものであり、ポピー抽出物投与群と対照群の個別データと平均データを示す。
図1は、インフルエンザウイルス接種後16日までの、ヒナゲシ抽出物投与群と対照群とのマウス生存率をプロットしたものである。
表2及び表3において、日数はインフルエンザウイルス接種後の経過日数、体重変化はウイルス接種時の体重からの変化量を示した。表2及び表3中の×はマウスが死亡したことを示す。
また、体重変化については、t-検定の結果、3日目から7日目までの期間は対照群に比べて投与群の体重減少が有意に抑えられており、投与群のほうがウイルス感染による体重減少が緩やかと考えられた。
下記処方にしたがって錠剤を調製した。
D-マンニトール 33.6%
乳糖 33.6
結晶セルロース 8.5
ヒドロキシプロピルセルロース 4.3
ヒナゲシ抽出物 20.0
100.0%
下記処方にしたがってチューインガムを調製した。
ガムベース 20.0%
砂糖 54.7
グルコース 15.0
水飴 9.5
香料 0.5
ヒナゲシ抽出物 0.3
100.0%
下記処方にしたがってキャンディを調製した。
砂糖 50.0%
水飴 33.0
クエン酸 1.0
香料 0.2
L-メントール 1.0
ヒナゲシ抽出物 0.5
水 14.3
100.0%
下記処方にしたがってチョコレートを調製した。
カカオビター 20.0%
全脂粉乳 20.0
カカオバター 17.0
粉糖 41.85
レシチン 0.45
香料 0.1
ヒナゲシ抽出物 0.6
100.0%
下記処方にしたがってビスケットを調製した。
砂糖 31.7%
小麦粉 26.8
片栗粉 26.8
バター 3.2
卵 10.2
重曹 0.3
ヒナゲシ抽出物 1.0
100.0%
下記処方にしたがってグミゼリーを調製した。
ポリデキストロース水溶液 40.0%
ソルビトール水溶液 8.0
パラチノース水溶液 9.0
マルトース水溶液 20.0
トレハロース水溶液 11.0
ゼラチン 10.0
酒石酸 1.0
ヒナゲシ抽出物 1.0
100.0%
下記処方にしたがって錠菓を調製した。
砂糖 76.1%
グルコース 19.0
ショ糖脂肪酸エステル 0.2
香料 0.2
ヒナゲシ抽出物 0.5
水 4.0
100.0%
下記処方にしたがってタブレットを調製した。
砂糖 35.85%
ショ糖脂肪酸エステル 0.15
ヒナゲシ抽出物 60.0
水 4.0
100.0%
下記処方にしたがってアイスクリームを調製した。
卵黄 11.0%
砂糖 14.0
牛乳 37.0
生クリーム 37.0
バニラビーンズ 0.5
ヒナゲシ抽出物 0.5
100.0%
下記処方にしたがってシャーベットを調製した。
オレンジ果汁 16.0%
砂糖 31.0
ヒナゲシ抽出物 3.0
水 50.0
100.0%
下記処方にしたがって飲料を調製した。
オレンジ果汁 30.0%
異性化糖 15.33
クエン酸 0.1
ビタミンC 0.04
香料 0.1
ヒナゲシ抽出物 0.01
水 54.42
100.0%
Claims (3)
- ヒナゲシの抽出物を有効成分とすることを特徴とする抗インフルエンザウイルス剤。
- ヒナゲシを水を用いて、抽出し、その抽出液を凍結乾燥して精製することにより得た抽出物を有効成分とすることを特徴とする抗インフルエンザウイルス剤。
- ヒナゲシ抽出物を含有する抗インフルエンザウイルス作用を有する飲食品。
Priority Applications (5)
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CN201180073004.7A CN103764157A (zh) | 2011-08-24 | 2011-08-24 | 流感病毒感染抑制剂 |
PCT/JP2011/004701 WO2013027245A1 (ja) | 2011-08-24 | 2011-08-24 | インフルエンザウイルス感染抑制剤 |
KR1020147007135A KR101765995B1 (ko) | 2011-08-24 | 2011-08-24 | 인플루엔자 바이러스 감염 억제제 |
EP11871336.1A EP2749287A4 (en) | 2011-08-24 | 2011-08-24 | INHIBITOR OF INFLUENZA VIRUS INFECTION |
BR112014004159A BR112014004159A2 (pt) | 2011-08-24 | 2011-08-24 | inibidor da infecção por vírus influenza |
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CN (1) | CN103764157A (ja) |
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Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002370993A (ja) | 2001-06-13 | 2002-12-24 | Bussan Biotech Kk | ハーブを含む免疫賦活剤 |
JP2004059463A (ja) | 2002-07-26 | 2004-02-26 | Lotte Co Ltd | 抗インフルエンザウイルス剤及びそれを含む組成物並びに飲食物 |
EP1468677A2 (en) * | 2003-04-03 | 2004-10-20 | D.M.G. Italia Srl | An antireflux syrup |
JP2004352712A (ja) | 2003-05-08 | 2004-12-16 | Fujisawa Pharmaceut Co Ltd | インフルエンザの予防または治療剤 |
JP2005343836A (ja) | 2004-06-04 | 2005-12-15 | Lotte Co Ltd | 抗インフルエンザウイルス剤及びこれを含有する感染抑制用品及び飲食物 |
JP2008013543A (ja) | 2006-06-07 | 2008-01-24 | Daiichi Sankyo Healthcare Co Ltd | 有胞子性乳酸菌含有抗感冒ウイルス又は抗インフルエンザウイルス用組成物 |
JP2008024695A (ja) * | 2006-06-19 | 2008-02-07 | Morishita Jintan Kk | シームレスカプセル |
JP2008031156A (ja) | 2006-07-07 | 2008-02-14 | National Univ Corp Shizuoka Univ | 抗ウイルス剤 |
JP4185996B2 (ja) | 2002-04-02 | 2008-11-26 | 島根県 | 抗インフルエンザウイルス剤 |
JP2009190994A (ja) | 2008-02-13 | 2009-08-27 | Kitasato Institute | 抗インフルエンザウイルス剤、及びその有効成分の製造方法 |
JP2009269861A (ja) | 2008-05-08 | 2009-11-19 | Tama Seikagaku Kk | カシス果実由来のウィルス感染予防・治療剤 |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2011108275A1 (ja) | 2010-03-04 | 2011-09-09 | 株式会社ロッテ | イムノグロブリンa分泌促進剤 |
-
2011
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- 2011-08-24 WO PCT/JP2011/004701 patent/WO2013027245A1/ja unknown
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Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2002370993A (ja) | 2001-06-13 | 2002-12-24 | Bussan Biotech Kk | ハーブを含む免疫賦活剤 |
JP4185996B2 (ja) | 2002-04-02 | 2008-11-26 | 島根県 | 抗インフルエンザウイルス剤 |
JP2004059463A (ja) | 2002-07-26 | 2004-02-26 | Lotte Co Ltd | 抗インフルエンザウイルス剤及びそれを含む組成物並びに飲食物 |
EP1468677A2 (en) * | 2003-04-03 | 2004-10-20 | D.M.G. Italia Srl | An antireflux syrup |
JP2004352712A (ja) | 2003-05-08 | 2004-12-16 | Fujisawa Pharmaceut Co Ltd | インフルエンザの予防または治療剤 |
JP2005343836A (ja) | 2004-06-04 | 2005-12-15 | Lotte Co Ltd | 抗インフルエンザウイルス剤及びこれを含有する感染抑制用品及び飲食物 |
JP2008013543A (ja) | 2006-06-07 | 2008-01-24 | Daiichi Sankyo Healthcare Co Ltd | 有胞子性乳酸菌含有抗感冒ウイルス又は抗インフルエンザウイルス用組成物 |
JP2008024695A (ja) * | 2006-06-19 | 2008-02-07 | Morishita Jintan Kk | シームレスカプセル |
JP2008031156A (ja) | 2006-07-07 | 2008-02-14 | National Univ Corp Shizuoka Univ | 抗ウイルス剤 |
JP2009190994A (ja) | 2008-02-13 | 2009-08-27 | Kitasato Institute | 抗インフルエンザウイルス剤、及びその有効成分の製造方法 |
JP2009269861A (ja) | 2008-05-08 | 2009-11-19 | Tama Seikagaku Kk | カシス果実由来のウィルス感染予防・治療剤 |
Non-Patent Citations (4)
Title |
---|
KULTUR, SUKRAN: "Medicinal plants used in Kirklareli Province (Turkey)", JOURNAL OF ETHNOPHARMACOLOGY, vol. 111, no. 2, 4 May 2007 (2007-05-04), pages 341 - 364, XP022021930 * |
KUROKAWA M. ET AL., ANTIVIRAL RESEARCH, vol. 56, 2002, pages 183 - 188 |
See also references of EP2749287A4 * |
SHIN K. ET AL., JOURNAL OF MEDICAL MICROBIOLOGY, vol. 54, 2005, pages 717 - 723 |
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BR112014004159A2 (pt) | 2017-03-01 |
EP2749287A4 (en) | 2015-05-13 |
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