JP3988014B2 - Antiviral agent - Google Patents

Antiviral agent Download PDF

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Publication number
JP3988014B2
JP3988014B2 JP2000025148A JP2000025148A JP3988014B2 JP 3988014 B2 JP3988014 B2 JP 3988014B2 JP 2000025148 A JP2000025148 A JP 2000025148A JP 2000025148 A JP2000025148 A JP 2000025148A JP 3988014 B2 JP3988014 B2 JP 3988014B2
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Japan
Prior art keywords
infection
virus
cystine
influenza virus
active ingredient
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JP2000025148A
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JP2001213774A (en
Inventor
進 柴原
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Ajinomoto Co Inc
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Ajinomoto Co Inc
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Priority to JP2000025148A priority Critical patent/JP3988014B2/en
Priority to PCT/JP2001/000569 priority patent/WO2001056561A1/en
Publication of JP2001213774A publication Critical patent/JP2001213774A/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12Antivirals
    • A61P31/14Antivirals for RNA viruses
    • A61P31/16Antivirals for RNA viruses for influenza or rhinoviruses

Description

【0001】
【発明の属する技術分野】
本発明は、ウイルス感染症の予防剤に関する。
【0002】
【従来の技術】
ウイルス感染症は肝炎やHIVを原因とするAIDSなどをはじめとし、多数知られている。そのうち、インフルエンザウイルス、ライノウイルス、コロナウイルス、パラインフルエンザウイルス、RSウイルス、アデノウイルス、レオウイルスなどの呼吸器感染性ウイルスは鼻腔から咽頭、気管、気管支、肺の上皮系細胞で増殖し、かぜ症状を呈する日常で多くみられる疾患の原因ウイルスである。多くは軽い鼻炎や咽頭炎などの症状で回復するが、肺炎などの重篤な合併症を併発し死の帰転に至る場合もあり、注意を要する疾患である。ストレスなどによって免疫力が低下し生体側が感染を防御しきれなくなった時、症状として現われる。現状における治療方法は対症療法が一般的で、アセトアミノフェン等の解熱鎮痛薬、マレイン酸クロルフェニラミン等アレルギ−症状を抑える薬剤、塩酸メチルエフェドリン等の鎮咳薬等が配合された感冒薬などを非処方箋薬として服用する場合が多い。また、症状が比較的重くなりだした際、病院にて医師から上記感冒薬や細菌の二次感染の併発に対処した抗菌剤の服用やビタミン剤の摂取が行われているのが現状である。
【0003】
一方、予防的な処方としてはこれら原因ウイルスのうち最も重要なインフルエンザに対する不活化ワクチンの予防接種が流行期前に用いられる。インフルエンザウイルスはその表面抗原の違いにより多くの株が存在し、しかも抗原変異を起こし易いことから、ワクチン株と流行株との抗原構造の一致が重要な問題となり、予測により接種したワクチンと異なった株が流行した場合には有効性が発揮できない。また、呼吸器感染性ウイルスは前述のように多くの種類が知られており、しかもそれぞれのウイルスごとに多くの亜型が存在する為、ウイルスのタイプに選択的な予防法ではあたり外れがあり流行のウイルス型(亜型)が的中しない場合もある。
【0004】
また、呼吸器感染性ウイルス感染症の予防法としてヨウ素製剤によるうがい液が用いられているが、特有の苦味を有するという欠点がある。また、抗インフルエンザウイルスA型作用を有するアマンタジンあるいはリマンタジンが米国で感染予防の目的で用いられているが(MMWR,44,RR-3,1995)、耐性株出現の危険性の問題、あるいは副作用出現の可能性など一般的な普及という点では制約も多い。
【0005】
このように現状では呼吸器感染性ウイルス感染症に対する予防法は必ずしも十分で無く、解決すべき問題点を残している。一方、PCT/US98/00380においてグルタチオン、グルタチオンジスルフィド、アスコルビン酸、N−アセチルシステインが細胞培養による感染抑制効果を有することが報告されているが、そのin vivoにおける効果は不明である。また、ビタミンEの老齢マウスにおけるインフルエンザウイルスの感染抑制効果が報告されているが、6週間以上の極めて長期摂取が必要である。また、セレノシスチンがマウスにおいてインフルエンザウイルス感染抑制効果を有することが報告されている(Ho et al、Antimicrobial Agents and Chemotherapy, 1967年)。
【0006】
【発明が解決しようとする課題】
本発明は満足な予防手段の無いウイルス感染症に対し予防する有効成分を提供すること、特に呼吸器感染ウイルス感染症に対し、流行の時期に服用することにより罹患を予防する有効成分を提供することにある。
【0007】
【課題を解決するための手段】
本発明者は、前記記載の課題を解決すべく鋭意研究を行った結果、シスチンがインフルエンザウイルス感染症に対し予防効果を有することを見出し本発明を完成するに至った。即ち、本出願に係る発明は、シスチンを有効成分として含有することを特徴とするインフルエンザウイルスの感染症の予防剤である。
【0008】
【発明の実施の形態】
本発明の予防剤が適応できるウイルス感染症として、ヘルペスウイルスを原因とする帯状疱疹、ロタウイルスを原因とする下痢、ウイルス性肝炎、AIDS、などが挙げられるが、特に呼吸器感染性ウイルスに対して効果的である。呼吸器感染性ウイルスの標的となる生物として、ヒト以外にシチメンチョウ、ニワトリなどの家禽類やブタやウマなどの家畜に適用できる。これら経済動物への利用は家畜の経済的損失を軽減するのみならず、それらを食用とする場合も多いため、ヒトへの感染予防という点からも重要な用途になる。
【0009】
用いる予防剤の投与量は有効成分であるシスチンを1日あたり200μg/kg~300mg/kg好ましくは500μg/kg~100mg/kgの範囲で投与すれば良く、1日あたりの量を一度にもしくは数回に分けて投与することができる。また投与期間は特に問わない。
【0010】
この有効成分であるシスチンは、例えば錠剤、顆粒剤、散剤、カプセル剤、エリキシル剤、マイクロカプセル剤あるいは懸濁液剤の形で使用してもよく、粉ミルクなどの粉末飲料や飲料、菓子などの食品の中に添加して用いることもできる。また、家禽類や家畜においては、飼料に添加して経口で与えることができる。食前あるいは食後経口的に投与することもできる他、有効成分の溶液を点鼻噴霧することもできる。
本発明の有効成分として使用するシスチンは、L−シスチンが好ましく、生理学的に認められる塩の化合物または混合物として用いることができ、また担体、賦形剤、結合剤、防腐剤、安定剤、などとともに一般に認められた製剤実施に要求される単位用量形態で用いることができる。これらの組成物または製剤における活性物質の量は指示された範囲の適当な用量が得られるようにすればよい。
錠剤、カプセル剤などに混和することができる具体的な成分の例は次に示すものである。トラガント、アラビアゴム、コーンスターチまたはゼラチンのような結合剤;微晶性セルロースのような賦形剤;コーンスターチ、前ゼラチン化デンプン、アルギン酸のような膨化剤;ステアリン酸マグネシウムのような潤滑剤;ショ糖、乳糖またはアスパルテームののような甘味剤;ペパーミント、アカモノ油またはチェリーのような香味剤、調剤単位形態がカプセルである場合には上記のタイプの材料にさらに油脂のような液状担体を含有することができる。種々の他の材料は被服剤としてまたは調剤単位の物理的形態の別の方法で変化させるために存在させることができる。例えば、錠剤はシェラック、砂糖またはその両方で被服することができる。シロップまたはエリキシルは活性化合物、甘味剤としてショ糖、防腐剤としてメチルおよびプロピルパラベン、色素およびチェリーまたはオレンジ香味を含有することができる。その他、各種ビタミン類、各種アミノ酸類を含有しても良い。
【0011】
腸溶製剤とするときは、例えばヒドロキシルフェニルメチルセルロースの水溶液を被服前処理剤とし、またはヒドロキシプロピルメチルセルロースフタレートの水溶液およびポリアセチンの水溶液を被服剤とし、それぞれ使用し常法により腸溶製剤とすればよい。
以下、実施例によりその有効性を示す。
【0012】
【実施例】
成長期にある6週齡のBALB/c雌性マウスをタンパク質源としてカゼインを20%含む飼料(基本食)で1週間飼育後、同飼料にL−シスチンを0.5%添加した飼料に切り換え更に2週間飼育した。また基本食のまま継続して飼育したものを対照群とした。各群とも10匹を試験に用いた。次いで10PFUのインフルエンザウイルスA/Aichi/2/68(H3N2)を経鼻接種した。ウイルス接種5日目に、マウスの肺を摘出し、そのウイルス量をMDCK細胞(イヌの腎臓由来)を用いたプラック形成による感染価として求めた。また感染前後の体重を測定した。
その結果を図1、図2に示す。 L−シスチンを添加しない基本食飼料摂取群を対照としたところ、肺のウイルス量は6.11 ±0.21log10PFU/gであったのに対し、L−シスチン添加群では5.72 ±0.25log10PFU/gであり、有意に(P<0.05)感染抑制効果を示した。一方、対照群が感染により5日間で0.90%の体重減少を示したのに対し、 L−シスチン添加群では逆に3.48%の体重増加を示した。従って、0.5% L−シスチン添加群はインフルエンザウイルス感染によって惹起される体重減少障害を克服していることが示された。
【発明の効果】
本発明のウイルス感染症予防剤により、ウィルス感染を抑制することができ、感染に伴う体重減少を軽減できる。
【図面の簡単な説明】
【図1】実施例における、感染5日目のマウスの肺のインフルエンザウイルス量を示す。
【図2】実施例における、感染後5日間でのマウスの体重変化率を示す。
[0001]
BACKGROUND OF THE INVENTION
The present invention relates to a preventive agent for viral infections.
[0002]
[Prior art]
Many viral infections are known, including AIDS caused by hepatitis and HIV. Among them, respiratory infectious viruses such as influenza virus, rhinovirus, coronavirus, parainfluenza virus, RS virus, adenovirus, reovirus, etc. grow in epithelial cells from the nasal cavity, pharynx, trachea, bronchus and lung, and cold symptoms It is a causative virus that causes many diseases in daily life. Most of them recover with symptoms such as mild rhinitis and pharyngitis, but serious complications such as pneumonia may result in death. Appears as a symptom when the immune system is weakened due to stress, etc., and the living body cannot fully defend the infection. Symptomatic treatment is common as the current treatment method, such as antipyretic analgesics such as acetaminophen, allergic symptoms such as chlorpheniramine maleate, cold medicines combined with antitussives such as methylephedrine hydrochloride, etc. Often taken as a non-prescription drug. In addition, when the symptoms start to become relatively severe, doctors are taking antibacterial agents and taking vitamins to deal with the above-mentioned common cold and bacterial secondary infections at hospitals. .
[0003]
On the other hand, as a preventive prescription, inoculation of an inactivated vaccine against the most important influenza among these causative viruses is used before the epidemic period. Influenza virus has many strains due to the difference in surface antigens, and is susceptible to antigenic mutation. Therefore, matching the antigen structure between vaccine strains and epidemic strains is an important issue, and it differs from the vaccine inoculated by prediction. Effectiveness cannot be demonstrated when a stock is prevalent. In addition, many types of respiratory infectious viruses are known as described above, and there are many subtypes for each virus. In some cases, the epidemic virus type (subtype) is not right.
[0004]
In addition, gargle solution based on iodine preparations is used as a preventive method for respiratory infectious virus infection, but has a disadvantage of having a peculiar bitter taste. Amantadine or rimantadine, which has anti-influenza virus type A action, is used in the United States for the purpose of preventing infection (MMWR, 44, RR-3, 1995). There are many restrictions in terms of general dissemination, such as the possibility of
[0005]
Thus, at present, the preventive method for respiratory infectious virus infection is not always sufficient, and there remains a problem to be solved. On the other hand, it has been reported in PCT / US98 / 00380 that glutathione, glutathione disulfide, ascorbic acid, and N-acetylcysteine have an infection-suppressing effect by cell culture, but the effect in vivo is unknown. Moreover, although the inhibitory effect of the influenza virus in the old mouse | mouth of vitamin E is reported, the very long-term ingestion for 6 weeks or more is required. It has also been reported that selenocystine has an inhibitory effect on influenza virus infection in mice (Ho et al, Antimicrobial Agents and Chemotherapy, 1967).
[0006]
[Problems to be solved by the invention]
The present invention provides an active ingredient for preventing viral infections without satisfactory preventive measures, and particularly provides an active ingredient for preventing morbidity by taking it at the time of epidemic against respiratory infection virus infections. There is.
[0007]
[Means for Solving the Problems]
As a result of intensive studies to solve the above-mentioned problems, the present inventor has found that cystine has a preventive effect against influenza virus infection and has completed the present invention. That is, the invention according to the present application is a preventive agent for influenza virus infection characterized by containing cystine as an active ingredient.
[0008]
DETAILED DESCRIPTION OF THE INVENTION
Examples of viral infections to which the preventive agent of the present invention can be applied include herpes zoster caused by herpes virus, diarrhea caused by rotavirus, viral hepatitis, AIDS, etc., especially for respiratory infectious viruses And effective. In addition to humans, it can be applied to poultry such as turkeys and chickens and livestock such as pigs and horses as the target organisms for respiratory infectious viruses. Utilization of these economic animals not only reduces the economic loss of livestock, but is often used as food, so it becomes an important use from the viewpoint of preventing infection to humans.
[0009]
The prophylactic agent used may be administered in an amount of 200 μg / kg to 300 mg / kg, preferably 500 μg / kg to 100 mg / kg of cystine as an active ingredient at a time or several times a day. Can be administered in divided doses. The administration period is not particularly limited.
[0010]
The active ingredient cystine may be used in the form of tablets, granules, powders, capsules, elixirs, microcapsules or suspensions, and powdered drinks such as powdered milk, beverages, foods such as confectionery, etc. It can also be used by adding to the inside. Moreover, in poultry and livestock, it can be added orally to feed. In addition to oral administration before meals or after meals, a solution of the active ingredient can be sprayed nasally.
The cystine used as the active ingredient of the present invention is preferably L-cystine, and can be used as a physiologically recognized salt compound or mixture, and can also be used as a carrier, excipient, binder, preservative, stabilizer, etc. And can be used in unit dosage forms required for accepted formulation practice. The amount of active substance in these compositions or formulations may be such that an appropriate dosage in the indicated range is obtained.
Examples of specific components that can be incorporated into tablets, capsules and the like are as follows. Binders such as tragacanth, gum arabic, corn starch or gelatin; excipients such as microcrystalline cellulose; leavening agents such as corn starch, pregelatinized starch, alginic acid; lubricants such as magnesium stearate; sucrose Sweeteners such as lactose or aspartame; flavoring agents such as peppermint, red oil or cherry; if the dispensing unit form is a capsule, the material of the type described above should further contain a liquid carrier such as fat Can do. Various other materials can be present as clothing or to alter the physical form of the dispensing unit in other ways. For instance, tablets may be taken with shellac, sugar or both. A syrup or elixir may contain the active compound, sucrose as a sweetening agent, methyl and propylparabens as preservatives, a dye and cherry or orange flavor. In addition, various vitamins and various amino acids may be contained.
[0011]
When an enteric preparation is used, for example, an aqueous solution of hydroxylphenylmethylcellulose is used as a pretreatment agent, or an aqueous solution of hydroxypropylmethylcellulose phthalate and an aqueous solution of polyacetin are used as an application agent, and they may be used as an enteric preparation by a conventional method. .
Hereinafter, the effectiveness is shown by an Example.
[0012]
【Example】
A 6-week-old BALB / c female mouse in the growth period is raised for 1 week on a diet containing 20% casein (basic diet) using protein as a protein source, then switched to a diet supplemented with 0.5% L-cystine. Reared for 2 weeks. In addition, a control group was continuously bred with a basic diet. Ten animals were used for the test in each group. Subsequently, 10 5 PFU of influenza virus A / Aichi / 2/68 (H3N2) was intranasally inoculated. On the fifth day after virus inoculation, the lungs of the mice were removed, and the amount of the virus was determined as the infectivity titer by plaque formation using MDCK cells (from dog kidney). The body weight before and after infection was measured.
The results are shown in FIGS. When the control group was a basic dietary intake group to which L-cystine was not added, the viral viral load was 6.11 ± 0.21 log 10 PFU / g, whereas in the L-cystine addition group, 5.72 ± It was 0.25 log 10 PFU / g, and showed a significant (P <0.05) infection suppression effect. On the other hand, the control group showed a weight loss of 0.90% after 5 days due to infection, whereas the L-cystine addition group showed a weight gain of 3.48%. Therefore, it was shown that the 0.5% L-cystine addition group overcomes the weight loss disorder caused by influenza virus infection.
【The invention's effect】
With the virus infection preventive agent of the present invention, virus infection can be suppressed, and weight loss associated with infection can be reduced.
[Brief description of the drawings]
FIG. 1 shows the amount of influenza virus in the lungs of mice on the fifth day of infection in Examples.
FIG. 2 shows the weight change rate of mice in 5 days after infection in Examples.

Claims (1)

シスチンを有効成分として含有することを特徴とするインフルエンザウイルス感染症の予防剤。An agent for preventing influenza virus infection, comprising cystine as an active ingredient.
JP2000025148A 2000-02-02 2000-02-02 Antiviral agent Expired - Lifetime JP3988014B2 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP2000025148A JP3988014B2 (en) 2000-02-02 2000-02-02 Antiviral agent
PCT/JP2001/000569 WO2001056561A1 (en) 2000-02-02 2001-01-29 Preventives for viral infection

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
JP2000025148A JP3988014B2 (en) 2000-02-02 2000-02-02 Antiviral agent

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JP3988014B2 true JP3988014B2 (en) 2007-10-10

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Publication number Priority date Publication date Assignee Title
US7767714B2 (en) 2002-02-18 2010-08-03 Ajinomoto Co., Inc. Method of preventing infectious diseases
JP3953031B2 (en) * 2002-02-18 2007-08-01 味の素株式会社 New preventive agent for infectious diseases
JP6814312B1 (en) * 2020-02-05 2021-01-13 株式会社タイショーテクノス How to impart antiviral properties to antiviral agents and articles
WO2021235494A1 (en) * 2020-05-20 2021-11-25 孝章 赤池 Medical agent containing active sulfur compound as main ingredient

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IL98310A (en) * 1990-06-08 1996-08-04 Astra Ab Pharmaceutical compositions comprising cystine derivatives
SE9602262D0 (en) * 1996-06-06 1996-06-06 Astra Ab New use of cystine derivatives
US6013632A (en) * 1997-01-13 2000-01-11 Emory University Compounds and their combinations for the treatment of influenza infection

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