JP3769036B2 - Inhibitor against excessive human body - Google Patents
Inhibitor against excessive human body Download PDFInfo
- Publication number
- JP3769036B2 JP3769036B2 JP18024094A JP18024094A JP3769036B2 JP 3769036 B2 JP3769036 B2 JP 3769036B2 JP 18024094 A JP18024094 A JP 18024094A JP 18024094 A JP18024094 A JP 18024094A JP 3769036 B2 JP3769036 B2 JP 3769036B2
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- Prior art keywords
- acid
- human body
- therapeutic agent
- nucleotides
- active
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- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
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Description
【０００１】
【産業上の利用分野】
本発明は、人体過剰対応抑制剤、アレルギー性疾患治療薬及び自己免疫疾患治療薬に関し、詳しくは、ヌクレオチド及び／又は生理的に許容されるその塩と活血薬を有効成分とする人体過剰対応抑制剤、アレルギー性疾患治療薬及び自己免疫疾患治療薬に関する。
【０００２】
【従来の技術】
近年、食生活を中心とするライフスタイルの変化に伴い、全身性エリテマトーデス、結節性動脈周囲炎、強皮症、皮膚筋炎、慢性関節リューマチ等の自己免疫疾患、あるいは、花粉症、枯草熱、アトピー性皮膚炎、遅延型接触皮膚炎等のアレルギー性疾患の罹患者が急増している。特に、花粉症については、３人に１人が罹患しているといわれる程、患者数は増大している。また、花粉症の原因となる植物についても、春の杉に留まらず、椚、楢、ブタクサ、セイタカアワダチソウと種類も増え、従って、季節も通年に亘るようになってきた。
【０００３】
これらのアレルギー性疾患や自己免疫疾患は、抗体産生細胞が過剰に活発化する等による人体の外部刺激に対する過剰対応がその原因であるとされている。例えば、自己免疫疾患には、多彩な自己抗体、自己抗原感作リンパ球の存在が確認されており、自己抗体単独、補体依存性、食細胞抗体性、キラー細胞依存性の反応のもとに組織障害を起こしていることも実験的に確かめられている。また、アレルギー性疾患も外部抗原に対する生体側の過剰防衛反応であり、抗体産生細胞等の過剰対応が原因であるとされている。
【０００４】
この様なアレルギー性疾患や自己免疫疾患の治療には、従来より抗ヒスタミン剤やステロイド剤等の投与が対症療法的に行われてきた。しかしながら、これらの薬剤を用いても十分な効果は得られず、副作用が強いため、又、長期連続投与できないため、その使用には大きな制限があった。そこで、アレルギー性疾患や自己免疫疾患に対する根本的治療の手段として、生体側の過剰対応を抑制する、例えば、抗体産生細胞の増殖を抑制する薬剤やそれを用いた治療方法の開発が強く望まれていた。
【０００５】
また、花粉症など発症のタイミングが明かな疾患に対しては、生体の過剰対応を予防的に抑制することで発症を防ぐことも可能であり、このための有効な予防的治療手段の開発も望まれていた。
【０００６】
一方、イノシン酸の様なヌクレオチドやその塩と活血薬の組み合わせが人体の過剰対応を著しく抑制することは全く知られていなかった。
【０００７】
【発明が解決しようとする課題】
本発明は、上記観点からなされたものであり、アレルギー性疾患や自己免疫疾患の原因となる生体の過剰対応反応を十分に抑制する薬剤を提供すると共に、これを用いた、安全性が高く、十分な薬効を有するアレルギー性疾患治療薬、並びに自己免疫疾患治療薬を提供することを課題とする。
【０００８】
【課題を解決するための手段】
本発明者らは、上記課題を解決するために、過剰対応反応を抑制する物質を求めて、種々の物質を対象として抗体産生細胞抑制作用を指標にスクリーニングを重ねた結果、イノシン酸等のヌクレオチド類や漢方で活血作用を有する薬剤がその作用を有することを見出した。更に、この様な抗体産生細胞抑制作用を有する物質の効果的運用の検討を重ねた結果、前記ヌクレオチド類と活血薬を組み合わせることにより、抗体産生細胞抑制作用が相乗的に増大することを見出し本発明を完成させた。
【０００９】
すなわち本発明は、ヌクレオチド及び／又は生理的に許容されるその塩と活血薬を有効成分として含有する人体過剰対応抑制剤、及びこの人体過剰対応抑制剤からなるアレルギー性疾患治療薬、自己免疫疾患治療薬である。
【００１０】
ここで、本明細書に用いるアレルギー性疾患治療薬、自己免疫疾患治療薬中の「治療」とは、症状を抑制もしくは低減させるための治療の他に、症状の発症を防ぐいわゆる予防的治療を含む概念として用いられる。
【００１１】
以下、本発明を詳細に説明する。
【００１２】
＜１＞ヌクレオチド及び／又は生理的に許容されるその塩
本発明の人体過剰対応抑制剤は、ヌクレオチド及び／又はその塩（以下、総称してヌクレオチド類という）と活血薬とを有効成分として含有する。
【００１３】
上記ヌクレオチドは、核酸を構成する成分のひとつであり、具体的には、アデニル酸、イノシン酸、チミジル酸、シチジル酸、ウリジル酸、グアニル酸等が好ましく挙げられるが、本発明では、これらのうちでもイノシン酸がより好ましく用いられる。
【００１４】
これらのヌクレオチドは、例えば、アデノシン、イノシン、チミジン、シチジン、ウリジン、グアノシン等のヌクレオシドの糖鎖の水酸基がリン酸とエステル結合したものであるが、これらヌクレオシドにおいてリン酸化される水酸基は、２’位、３’位、５’位の３箇所にあるので、上述のそれぞれのヌクレオチドについて３種類の異性体が存在する。イノシン酸を例に挙げれば、これらは、２’−イノシン酸、３’−イノシン酸、５’−イノシン酸の３種である。
【００１５】
また、ヌクレオチドには、上記エステル結合したリン酸に更にリン酸が結合したものもありヌクレオシドに結合したリン酸の数により、一リン酸化物、二リン酸化物、三リン酸化物等のヌクレオチドがある。例えば、上記イノシン酸とは、イノシン一リン酸のことであるが、そのイノシン酸のひとつイノシン−５’−一リン酸（５’−イノシン酸）に更にリン酸が結合したイノシン−５’−二リン酸、イノシン−５’−三リン酸等がある。
【００１６】
本発明に用いるヌクレオチドとして、これらの何れの化合物をも用いることができるが、入手のしやすさとコストの低さの点からイノシン−５’−一リン酸が最も好ましい。なお、上記ヌクレオチドは、生体内に広く存在する化合物であると共に、何れも古くより食品添加物として市販されており、その入手及び安全性については全く問題がない。
【００１７】
また、ヌクレオチドの塩としては生理的に許容されるものであれば特に限定はされないが、例えば、ヌクレオチドとナトリウム、カリウム等のアルカリ金属との塩、カルシウム、マグネシウム等のアルカリ土類金属との塩、アンモニウム、トリエチルアミン等のアミンとの塩、アルギニン、リジン等の塩基性アミノ酸との塩等が例示できる。
【００１８】
上記ヌクレオチド及び／又はヌクレオチドの塩は、抗体産生細胞抑制作用を有しており、本発明の人体過剰対応抑制剤に以下の活血薬と共に用いられるが、本発明においては、これらの１種を単独で用いてもよいし、２種以上を組み合わせて用いてもよい。
【００１９】
＜２＞活血薬
本発明の人体過剰対応抑制剤には、上記ヌクレオチド類の他に活血薬が有効成分として配合される。
【００２０】
ここで、活血とは漢方の概念であり、血の流れの停滞で起こるとされている鬱血性疼痛、狭心症や心筋梗塞などの際に現れる真心痛等を血流を改善して治療する作用のことをいう。具体的には、以下の漢方薬にその作用があることが知られており、本発明においては、この様な漢方薬を活血薬として用いることができる。
【００２１】
セリ科センキュウ（Ligusticum wallichii）の根茎の乾燥物であるセンキュウ、シソ科タンジン（Salvia miltiorrhiza）の根の乾燥物であるタンジン、マメ科コンメイケイケットウ（Millettia reticulata）又は白花油麻藤（Mucuna birdwoodiana Tutcher）の茎の乾燥物であるケイケットウ、モチノキ科モウヒジュ（Irex pubescens Hook. et Arn）の根の乾燥物であるモウトウセイ、ケシ科エンゴサク（Corydalis bulbosa DC.）の塊茎を乾燥させたエンゴサク、ショウガ科キョウオウ（Curcuma longa L.）又はウコン（Curcuma aromatica Salisb.）の塊根を乾燥させたウコン、ショウガ科キョウオウ（Curcuma longa L.）の塊根を乾燥させたキョウオウ、シソ科ヤクモソウ（Leonurus heterophillus Sweet）の全草を乾燥させたヤクモソウ、シソ科ヤクモソウ（Leonurus heterophillus Sweet）の果実を乾燥させたジュウイシ、シソ科シロネ（Lycopus lucidus Turcz）の茎根を乾燥させたタクラン、ノウゼンカズラ科リョウショウ（Camsis gradiflora(Thunb.)Loisel）の花の乾燥物であるリョウショウカ、バラ科ゲッキ（Rosa chinensis Jacq.）の花ライ又は花びらの乾燥物であるゲッキカ、ロウバイ科ロウバイ（Chimonanthus praecox(L.)Link.）のガク付きの花の乾燥物であるサクバイカ、ウリ科ヘチマ（Luffa cylindria(L.)Roem）の網状繊維束の乾燥物であるシカラク、ボタン科シャクヤク（Paeonia latiflora Pall）の根の乾燥物であるセキシャク、バラ科モモ（Prunus persica(L.)Batsch.）の種子中の仁の乾燥物であるトウニン、キク科紅花（Carthumus tinctorius L.）の花冠の乾燥物であるコウカ、アヤメ科サフラン（Crocus sativus L.）の柱頭又は花柱の上部を乾燥させたバンコウカ、ショウガ科ガジュツ（Curcuma zedoria Rosc.）の根茎の乾燥物であるガジュツ、カヤツリグサ科ウキヤガラ（Scirpus yagara Ohwi.）の塊根の乾燥物であるサンリョウ、カンラン科ニュウコウジュ（Boswellia carterii Birdwood）の膠質物質であるニュウコウ、カンラン科モツヤクジュ（CVommiphora myrrha Engl.(C. molmol Engl.)）の油膠質物質であるモツヤク、ヒユ科ゴシツ（Achyranthes bidentata Blume）又はカワゴシツ（Cyathula capitata Miq.）の根の乾燥物であるゴシツ、ナデシコ科ドウカンソウ（Vaccaria pyramidata Medic.）の種子又はクワ科オオイタビ（Ficus pumila L.）の果殻の乾燥物であるオウフルギョウ、マンサク科フウ（Liquidambar Taiwaniana Hance）の果実の乾燥物であるロロツウ、キク科キコウ（Artemisia anomala S Moore）又はゴマノハグサ科ヒキヨモギ（Sinphonostegia chnensis Benth.）の全草の乾燥物であるリュウキド、スイカズラ科のリクエイ（Sambucus javanica Rein.）の全草の乾燥物であるラクトクダ、黄鉄鉱の硫化鉄鉱石である自然銅、ヤシ科キリンケツ（Daemonorops draco Bl.）の樹脂であるケッケツ、マメ科スオウ（Caesalpinia sappan L.）の茎木の乾燥物であるソボク、ツリフネソウ科ホウセンカ（Impatiens balsamina L.）の種子の乾燥物であるキュウセイシ、オオコウモリ科オオコウモリ（Petaurista xanthotis Milne-Edwards）の糞の乾燥物であるゴレイシ、ビヨウブガイ科ハイガイ（Arca granosa L.）の貝殻の粉砕物であるガリョウシ、センザンコウ科センザンコウ（Manis pentadactyla L.）の甲羅片の粉砕物であるセンザンコウ、ヒルド科ウマビル（Whitmania pigra Whitman）の乾燥物であるスイテツ、ゴキブリ科シナゴキブリ（Eupolyphaga sinensis Walk.）の雄の乾燥物であるシャチュウ、ウシ科ハイイロヒマラヤカモシカ（Naemorhedus goral Hardwicke）の血の乾燥物であるサンヨウケツ、ウシ科黄牛（Bas taurus domesticus Gmelin）の胆石の乾燥物であるゴオウ、クマ等の動物の胆嚢の乾燥物であるユウタン等である。
【００２２】
この様な活血作用を有する漢方薬を活血薬として、本発明の人体過剰対応抑制剤に有効成分として配合するが、その場合、上記漢方薬をそのまま活血薬として用いることも可能であるが、これらを適宜水や有機溶媒など適当な抽出溶媒で抽出し、溶媒除去等したものを活血薬として用いてもよい。また、抽出物等を更に液液抽出やカラムクロマトグラフィーによって分画することで、上記漢方薬から活性の高い画分のみを取り出して活血薬としてもよい。また、上記漢方薬が生薬由来のものである場合には、その生薬が由来する植物等を原料として得られる抽出物、濃縮物、分画物等を同様にして活血薬として用いることもできる。
【００２３】
上記抽出に用いる抽出溶媒としては、水やアルコール、アセトン等の極性溶媒が好ましい。更に、上記漢方薬類は何れも熱安定性がよいため、抽出に際して加熱操作を加えてもよい。また、この様にして得られる活血薬のうちでも、上記漢方薬類の水抽出物を凍結乾燥したものが本発明には好ましく用いられる。
【００２４】
上記活血薬は、抗体産生細胞抑制作用を有しており、本発明の人体過剰対応抑制剤の構成成分として、上記ヌクレオチド類と共に用いられるが、これら活血薬の１種を単独で用いても、２種以上を組み合わせて用いてもよい。
【００２５】
一方、これらの漢方薬は古くから用いられているので、安全性に関しての懸念は極めて少ない。
【００２６】
＜３＞本発明の人体過剰対応抑制剤、アレルギー性疾患治療薬及び自己免疫疾患治療薬
本発明の人体過剰対応抑制剤は、上記ヌクレオチド及び／又はその塩と活血薬を有効成分として含有する。ここでヌクレオチド類及び活血薬は、それぞれに抗体産生細胞抑制作用を有するが、これらの物質を組み合わせて用いることにより、その作用は、相乗的に大きくなる。
【００２７】
本発明の人体過剰対応抑制剤におけるヌクレオチド類の配合量は、薬剤全量に対して１〜５０重量％であることが好ましく、更に好ましい配合量は５〜３０重量％である。また、活血薬の好ましい配合量も同様に、薬剤全量に対して１〜５０重量％であり、更に好ましくは５〜３０重量％である。更に、人体過剰対応抑制剤中のヌクレオチド類と活血薬の配合比は、重量比で１０：１〜１：１００が好ましい。
【００２８】
本発明の人体過剰対応抑制剤の剤型は、特に限定されないが、一般に製剤上許容される無害の一種、あるいは数種のベヒクル、担体、賦形剤、結合剤、防腐剤、安定剤、矯味矯臭剤、コーティング剤、着色剤、糖衣剤、崩壊剤、増量剤、滑沢剤等と共に混和して、錠剤、散剤、顆粒剤、カプセル剤、水薬等の経口投与剤、軟膏剤、クリーム、ローション剤等の経皮投与剤、無菌溶液剤、懸濁液剤等の注射剤とすることができる。これらは、上記ヌクレオチド類及び活血薬を配合する以外は、従来公知の技術を用いて製造することができる。
【００２９】
例えば、上記ヌクレオチド類及び活血薬とコーンスターチ、ゼラチン等の結合剤、微晶性セルロース等の賦形剤、馬鈴薯デンプン、アルギン酸ナトリウム等の膨化剤、乳糖、ショ糖等の甘味剤等を、配剤して散剤、錠剤、顆粒剤、カプセル剤等の経口投与剤とすることができる。また、注射剤とする場合は、溶媒として注射用蒸留水、又はポリエチレングリコール等が使用され、あるいはこれに分散剤、緩衝剤、溶解補助剤、等張剤、安定剤、防腐剤、抗酸化剤等を必要に応じて添加してもよい。
【００３０】
経皮投与剤とする場合には、ワセリン、流動パラフィン等の炭化水素類、ホホバ油、ミツロウ等のエステル類、オリーブ油、牛脂等のトリグリセライド類、セタノール、ベヘニルアルコール等の高級アルコール類、ステアリン酸、ベヘン酸等の脂肪酸類、ＰＯＥ硬化ヒマシ油、ステアリン酸モノグリセライド等のノニオン界面活性剤類、石鹸、ラウリル硫酸ナトリウム等のアニオン性界面活性剤、ステアリルアンモニウムクロライド等のカチオン性界面活性剤、グリセリン、１，３−ブタンジオール等の多価アルコール類、ポリエチレングリコール、ヒアルロン酸等の保湿剤、パラベン類、グルコン酸クロルヘキシジン等の防腐剤、紫外線吸収剤、抗酸化剤等の安定剤等の任意成分と共にヌクレオチド類及び活血薬を配剤すれば、軟膏、クリーム、ローション剤等を得ることができる。
【００３１】
また、同様にして上記ヌクレオチド類及び活血薬を、通常、化粧料、医薬部外品等に配合される任意成分と共に配合して、過剰対応抑制作用を有する化粧料、医薬部外品等として用いることも可能である。
【００３２】
更に、これらの薬剤には、生体過剰対応反応に併発しがちな炎症、発赤を抑える消炎鎮痛剤等、他の薬効成分を各種目的に合わせて加えることも可能である。
本発明の人体過剰対応抑制剤は、アレルギー性疾患、例えば、花粉症、枯草熱、アトピー性皮膚炎、遅延型接触皮膚炎等及び自己免疫疾患、例えば、全身性エリテマトーデス、結節性動脈周囲炎、強皮症、皮膚筋炎、慢性関節リューマチ等の治療及び予防的治療に有効であり、これをアレルギー性疾患治療薬及び自己免疫疾患治療薬として用いることもできる。
【００３３】
この様な本発明のアレルギー性疾患治療薬あるいは自己免疫疾患治療薬の好適な適用量は、疾患の種類、症状、患者の年令、性別、体重等により異なるが、成人１人１日当たり、皮膚外用剤ではヌクレオチド類を１〜３００ｍｇ、活血薬を１〜５０００ｍｇ、注射剤ではヌクレオチド類を１〜２００ｍｇ、活血薬を１〜２５００ｍｇ、経口投与剤ではヌクレオチドを１〜１０００ｍｇ、活血薬を１〜５０００ｍｇ投与するのが適当である。注射剤の投与方法としては、静脈内投与、動脈内投与、門脈内投与、腹腔内投与、筋肉内投与、皮下投与等が例示できる。また、経皮投与剤の適応部位については、顔、手、足の露出部分にとどまらず、頭皮等の全身の皮膚に適用可能である。
【００３４】
【作用】
本発明においては、ヌクレオチド類と活血薬を組み合わせることで、これを含む人体過剰対応抑制剤に、抗体産生細胞の増殖を十分に抑制して、生体の過剰対応反応を抑制する作用を十分に持たせたものである。以下に、各種活血薬とイノシン−５’−一リン酸ナトリウムを用いて抗体産生細胞抑制作用を評価した実験について述べる。
【００３５】
なお、評価に用いた活血薬は、表１に示す各種漢方薬に水を１０倍量加え３時間煮沸させて冷却し、濾過により不溶物を取り除いた後、凍結乾燥したものである。但し、ゴオウとユウタンについては原料粉末をそのまま活血薬とした。表１に、漢方薬名と共に、上記抽出に用いた仕込み量及び収量を示す。
【００３６】
【表１】
＜抗体産生細胞抑制作用の評価＞
抗体産生細胞抑制作用の評価は、ジェルン（Ｊｅｒｎ）らが開発した溶血プラーク法（Science,140,405,1963）に従って、脾細胞の抗体産生細胞数を計数する方法を用いた。
【００３８】
１群６匹づつ６０週齢の老齢ｄｄｙ系雄性マウスの各２群に、上記で得られた各活血薬を１ｇ／ｍＬの濃度で含有する生理食塩水溶液を０．５ｍＬづつ腹腔内投与した。これらのマウスの他に、２群のマウスには、活血薬を含有しない生理食塩水を０．５ｍＬづつ腹腔内投与した。その後、更に、各活血薬投与群の１群と上記で生理食塩水のみを投与された群の１群には、イノシン−５’−一リン酸ナトリウムを１ｇ／ｍＬの濃度で含有する生理食塩水溶液を０．５ｍＬづつ腹腔内投与し、残りの各群にはイノシン−５’−一リン酸ナトリウムを含有しない生理食塩水溶液を０．５ｍＬづつ腹腔内投与した。ここで、活血薬とイノシン−５’−一リン酸ナトリウムの両方の投与を受けなかったマウス群をコントロール群とした。
【００３９】
その後、全マウスに４×１０8個／ｍＬの羊赤血球（ＳＲＢＣ）を０．２５ｍＬづつ投与し、感作させた。感作後１日目、２日目、３日目の計３回、全マウスに、感作前に投与したものと同じ試験液を、感作前の投与と同様にして腹腔内投与した。
【００４０】
各試験液の腹腔内投与終了の翌日、各群のマウスの脾臓を摘出し、脾細胞中の抗体産生細胞をジェルンらの方法に準じて検出し、その細胞数を計測した。この計測結果を用いて、コントロール群の抗体産生細胞数から、それぞれ活血薬＋ヌクレオチド類投与群、活血薬投与群、ヌクレオチド類投与群の抗体産生細胞数を引いた値をコントロール群の抗体産性細胞数で除した値に１００をかけた値を求め、これを抗体産生細胞抑制率として評価に用いた。尚、抗体産生細胞抑制率の計算に用いた各群の抗体産性細胞数は、各群６匹のマウスの平均値であった。結果を表２に示す。
【００４１】
【表２】
この結果より、ヌクレオチド類のみ、活血薬のみを投与した群においては、ある程度抗体産生細胞の増殖が抑制されているが、この両者を組み合わせて投与した群では、抗体産生細胞の増殖が著しく抑制されていることがわかり、これにより、本発明の人体過剰対応抑制剤が生体の過剰対応反応を抑制する作用に優れるといえる。
【００４３】
更に、上記実験では、マウス１匹当たりの、ヌクレオチド類及び活血薬の投与量が極めて多かったにもかかわらず、異常を起こしたマウスは全くなく、これらの安全性が高いことがわかる。
【００４４】
また、この様な人体過剰対応抑制剤からなるアレルギー性疾患治療薬や自己免疫疾患治療薬は、その有効成分である上記ヌクレオチド及び／又はその塩と活血薬の組合せによる優れた抗体産性細胞増殖抑制作用により、生体の過剰対応反応を抑制し、上述のような生体の過剰対応反応が原因とされる様々なアレルギー性疾患や自己免疫疾患の治療に対して有効に働くものである。
【００４５】
更に、アレルギー性疾患や自己免疫疾患のうちでも、特に花粉症など発症のタイミングが明かな疾患に対しては、上記薬剤の投与により、予め抗体産性細胞の増殖を抑制しておくことで、アレルギー原に対する生体の過剰対応を抑制することができ、結果としてその発症を防ぐという予防的治療の効果を持たせることも可能である。
【００４６】
【実施例】
以下に、ヌクレオチド類、活血薬を含有する本発明の人体過剰対応抑制剤、アレルギー性疾患治療薬及び自己免疫疾患治療薬の実施例を説明する。尚、実施例に用いた活血薬は上記作用の実験に用いたものと同様の方法で得られた活血薬である。また、以下に用いる配合量は全て重量部とする。
【００４７】
【実施例１】
クリーム
表３に示すＡ成分、Ｂ成分をそれぞれ８０℃に加熱し溶解させ、Ａ成分にＢ成分を徐々に加え乳化し冷却してクリームを得た。
【００４８】
【表３】
【実施例２】
顆粒剤
表４に示す成分をグラッド造粒器に入れ水を加えて加湿しながら造粒し、その後４０℃で２４時間送風乾燥し、整粒して顆粒剤を得た。
【００５０】
【表４】
＜本発明のアレルギー性疾患治療薬の評価＞
上記実施例で得られた各種薬剤について、アトピー性皮膚炎の罹患者及び花粉症の罹患者にそれぞれ実使用テストをしてもらい、また、モルモットを用いて遅延型アレルギー反応に対する実験を行い、アレルギー性疾患治療薬としての効果を評価した。
【００５２】
（１）アトピー性皮膚炎に対する効果
アトピー性皮膚炎の患者５名に、上記実施例１で得られたクリームを２週間、朝夕２回毎日連続して使用してもらい、使用開始から２週間後に皮膚炎の改善度を、改善した、無変化、悪化の３段階評価で評価してもらった。結果は全員が改善と答えており、これより、本発明のアレルギー性疾患治療薬がアトピー性皮膚炎に有効であることがわかる。
【００５３】
（２）花粉症に対する効果
杉花粉症の羅患者７名に、上記実施例２で得られた顆粒剤を杉花粉の飛散が始まる前に１回１ｇ、１日３回の割合で１４日間連続して飲んでもらった。杉花粉症の季節が終了した後、前年との比較で花粉症の症状が改善したかどうかを、改善した、無変化、悪化の３段階で評価してもらった。結果は改善が３名、無変化が４名であった。これより本発明のアレルギー性疾患治療薬が花粉症の予防的治療にも有効であることがわかる。
【００５４】
（３）遅延型アレルギー反応に対する効果
ハートレー系雄性モルモットを用いたマキシマイゼーションテスト法によるホルマリンに対する遅延型接触皮膚炎の発現を指標に、本発明のアレルギー性疾患治療薬の遅延型アレルギー反応に対する抑制作用を見た。
【００５５】
５０匹のモルモットを１０匹づつ第１群から第５群の５群に分けた。第１群には、実施例１のクリームを０．０５ｍＬ／日、５日間背部に投与し、第２群には実施例２の顆粒剤を１ｇづつ５日間経口投与した。他の３群にはこの５日間は何も投与しなかった。その後、全てのモルモットにフロイントの完全アジュバント（ＦＣＡ）存在下、１重量％のホルマリンの生理食塩水溶液を経皮及び皮内投与によりインダクションした。
【００５６】
インダクション後、第３群には実施例１のクリームを０．０５ｍＬ／日、５日間背部に投与し、第４群には実施例２の顆粒剤を１ｇづつ５日間経口投与した。第１群、第２群、第５群にはこの５日間何も投与しなかった。
【００５７】
インダクション終了後１４日目に、全てのモルモットに０．０１重量％のホルマリン水溶液をクローズドパッチにより経皮投与して、陽性率を調べた。陽性率の判定基準はドレーズの基準を用いた。結果を表５に示す。
【００５８】
【表５】
この結果から、本発明のアレルギー性疾患治療薬は、遅延型アレルギー反応を予防的に治療する効果（第１群、第２群）及び、治療する効果（第３群、第４群）に優れていることがわかる。
【００６０】
【発明の効果】
本発明の人体過剰対応抑制剤は、抗体産生細胞の増殖を抑制する作用に優れ、生体過剰対応反応をよく抑制する上、安全性も高い。また、これを用いたアレルギー性疾患治療薬、自己免疫疾患治療薬は、これらの疾患を治療する効果、あるいは、これらの疾患を予防的に治療する効果に優れると共に、長期連続使用が可能である。[0001]
[Industrial application fields]
More particularly, the present invention relates to a human excess response inhibitor, an allergic disease therapeutic agent and an autoimmune disease therapeutic agent. More specifically, the present invention relates to suppression of excess human response comprising nucleotides and / or physiologically acceptable salts and active agents as active ingredients. The present invention relates to agents, therapeutic agents for allergic diseases and therapeutic agents for autoimmune diseases.
[0002]
[Prior art]
In recent years, with lifestyle changes centered on eating habits, autoimmune diseases such as systemic lupus erythematosus, nodular periarteritis, scleroderma, dermatomyositis, rheumatoid arthritis, hay fever, hay fever, atopy The number of patients with allergic diseases such as atopic dermatitis and delayed contact dermatitis is rapidly increasing. In particular, with regard to hay fever, the number of patients is increasing as it is said that one in three is affected. In addition, plants that cause hay fever are not limited to spring cedar, but are also increasing in variety, such as camellia, camellia, ragweed, and stilt.
[0003]
These allergic diseases and autoimmune diseases are said to be caused by excessive response to external stimuli of the human body due to excessive activation of antibody-producing cells. For example, various autoantibodies and autoantigen-sensitized lymphocytes have been confirmed in autoimmune diseases, and are based on autoantibodies alone, complement-dependent, phagocytic antibody-dependent, and killer cell-dependent reactions. It has also been experimentally confirmed that it causes tissue damage. In addition, allergic diseases are an excessive defense reaction on the living body side against external antigens, and are considered to be caused by excessive responses such as antibody-producing cells.
[0004]
In the treatment of such allergic diseases and autoimmune diseases, the administration of antihistamines, steroids and the like has been conventionally performed symptomatically. However, even if these drugs are used, sufficient effects cannot be obtained, and the side effects are strong. Further, since these drugs cannot be administered continuously for a long period of time, their use is greatly limited. Therefore, as a means of fundamental treatment for allergic diseases and autoimmune diseases, development of a drug that suppresses excessive response on the living body side, for example, suppresses proliferation of antibody-producing cells and a treatment method using the same is strongly desired. It was.
[0005]
In addition, for diseases with clear onset timing such as hay fever, it is possible to prevent the onset by prophylactically suppressing excessive responses to the living body, and development of effective preventive treatment means for this is also possible. It was desired.
[0006]
On the other hand, it has not been known at all that a combination of a nucleotide such as inosinic acid or a salt thereof and an active blood agent remarkably suppresses excessive correspondence of the human body.
[0007]
[Problems to be solved by the invention]
The present invention has been made from the above viewpoint, and provides a drug that sufficiently suppresses the excessive response of the living body that causes allergic diseases and autoimmune diseases, and using this, it is highly safe, It is an object of the present invention to provide a therapeutic agent for allergic diseases and a therapeutic agent for autoimmune diseases having sufficient medicinal effects.
[0008]
[Means for Solving the Problems]
In order to solve the above-mentioned problems, the present inventors have sought a substance that suppresses an excessive response, and as a result of repeated screening using various substances as a target for inhibiting antibody-producing cells, nucleotides such as inosinic acid It has been found that a drug having an active blood effect in a kind or Chinese medicine has the action. Furthermore, as a result of repeated studies on the effective operation of such substances having antibody-producing cell inhibitory action, it has been found that the antibody-producing cell inhibitory action is synergistically increased by combining the nucleotides and active agents. Completed the invention.
[0009]
That is, the present invention relates to a human excess response inhibitor containing nucleotides and / or physiologically acceptable salts thereof and active blood agents as active ingredients, an allergic disease therapeutic agent comprising this excess response inhibitor, and an autoimmune disease It is a therapeutic drug.
[0010]
Here, the term “treatment” in the therapeutic agents for allergic diseases and autoimmune diseases used in this specification refers to so-called prophylactic treatment for preventing the onset of symptoms in addition to the treatment for suppressing or reducing the symptoms. Used as a concept to include.
[0011]
Hereinafter, the present invention will be described in detail.
[0012]
<1> Nucleotides and / or physiologically acceptable salts thereof The human body excess response inhibitor of the present invention contains nucleotides and / or salts thereof (hereinafter collectively referred to as nucleotides) and active agents as active ingredients. To do.
[0013]
The above nucleotide is one of the components constituting the nucleic acid, and specifically, adenylic acid, inosinic acid, thymidylic acid, cytidylic acid, uridylic acid, guanylic acid and the like are preferably mentioned. However, inosinic acid is more preferably used.
[0014]
These nucleotides are, for example, those in which the hydroxyl group of a sugar chain of a nucleoside such as adenosine, inosine, thymidine, cytidine, uridine, guanosine and the like is ester-bonded with phosphoric acid. The hydroxyl group phosphorylated in these nucleosides is 2 ′ There are three types of isomers for each of the above-mentioned nucleotides because of the three positions, 3 'and 5'. Taking inosinic acid as an example, these are 3 kinds of 2′-inosinic acid, 3′-inosinic acid, and 5′-inosinic acid.
[0015]
Some nucleotides such as monophosphate, diphosphate, and triphosphate depend on the number of phosphate bound to the nucleoside. is there. For example, the inosinic acid is inosine monophosphate, and inosine-5′-inosin-5′-monophosphate (5′-inosinic acid) is further bound to inosine-5′-monophosphate. Examples include diphosphate, inosine-5′-triphosphate.
[0016]
Any of these compounds can be used as the nucleotide used in the present invention, but inosine-5′-monophosphate is most preferred from the viewpoint of availability and low cost. The above nucleotides are compounds widely present in the living body, and all of them have been commercially available as food additives for a long time, and there is no problem with respect to their availability and safety.
[0017]
The salt of the nucleotide is not particularly limited as long as it is physiologically acceptable. For example, a salt of a nucleotide and an alkali metal such as sodium or potassium, or a salt of an alkaline earth metal such as calcium or magnesium. And salts with amines such as ammonium and triethylamine, and salts with basic amino acids such as arginine and lysine.
[0018]
The nucleotide and / or nucleotide salt has an antibody-producing cell inhibitory action, and is used together with the following active blood in the human body excess response inhibitor of the present invention. In the present invention, one of these is used alone. Or may be used in combination of two or more.
[0019]
<2> Liver Active Agent In addition to the above nucleotides, a live active agent is blended as an active ingredient in the inhibitor against excessive human body of the present invention.
[0020]
Here, live blood is a concept of Kampo, which treats congestive pain, true heart pain, etc. that appear in the event of angina or myocardial infarction by improving blood flow. It refers to the action. Specifically, the following Kampo medicines are known to have the action, and in the present invention, such Kampo medicines can be used as active agents.
[0021]
A cucumber that is a dried rhizome of Ligusticum wallichii, a tangin that is a dried root of Salvia miltiorrhiza, a milletia reticulata or a white flower oil Mito ) Stem dried cereals, Irex pubescens Hook. Et Arn Root dried mullet, Corydalis bulbosa DC. (Curcuma longa L.) or turmeric (Curcuma aromatica Salisb.) Dried turmeric, ginger (Curcuma longa L.) dried tuber, Leonurus heterophillus Sweet , Dried jukushi, dried fruit of Leonurus heterophillus Sweet, From the dried stem of the stem root of Lycopus lucidus Turcz, the dried flower of the flower of Camellia glandae (Camsis gradiflora (Thunb.) Loirel) A dried net of flower rye or petals, vaccinia (Chimonanthus praecox (L.) Link.) Shikaku, which is a dried product of fiber bundles, peony, which is a dried product of the roots of Paeonia latiflora Pall, and Tonin, a dried product of seeds in the seeds of the Rosaceae peach (Prunus persica (L.) Batsch.) , Kouka which is a dried product of the corolla of the asteraceae (Carthumus tinctorius L.), Banchouka which dried the top of the head of the saffron (Crocus sativus L.) or the top of the style, Curcuma zedoria Rosc. The dried rhizomes of the roots, the dried root of the tuber of Scirpus yagara Ohwi. (C. molmol Engl.)) Oily colloid, Achyranthes bidentata Blume or Cyathula capitata Miq. Root dry matter, Vaccaria pyramidata Medic. ) Seeds or dried crustaceae (Ficus pumila L.) fruit husks, Liquidambar Taiwaniana Hance berries dried crustaceae, Artemisia anomala S Moore or Ryukiddo, a honeysuckle family, which is a dried product of the whole plant of Sinphonostegia chnensis Benth. Lactocuda, which is a dried product of Sambucus javanica Rein., Natural copper, which is pyrite iron sulfide ore, Kaketsu, which is a resin of Daemonorops draco Bl., And Caesalpinia sappan L. ) Stalks of dried stalks, Impatiens balsamina L. seeds of dried cucumbers, flying foxtails of Peteurista xanthotis Milne-Edwards It is a dry product of Whitmania pigra Whitman which is a ground product of shellfish of Arca granosa L., Papaver which is a ground product of shellfish of Manis pentadactyla L. Sweets, the male dry product of the cockroach, Eupolyphaga sinensis Walk. These include, butterfly, which is a dried product of the blood of the antelope (Naemorhedus goral Hardwicke), a dried product of the gallstones of the bovine cattle (Bas taurus domesticus Gmelin), and a dried product of the gallbladder of animals such as bears.
[0022]
Such a traditional Chinese medicine having an active blood effect is used as an active ingredient in the inhibitor against excessive human body according to the present invention, and in that case, the above-mentioned traditional Chinese medicine can be used as an active blood drug as it is, but these are appropriately used. A product obtained by extracting with a suitable extraction solvent such as water or an organic solvent and removing the solvent may be used as the active blood. Further, the extract or the like may be further fractionated by liquid-liquid extraction or column chromatography, whereby only the highly active fraction may be taken out from the above-mentioned Chinese medicine and used as a live blood drug. In addition, when the herbal medicine is derived from a herbal medicine, extracts, concentrates, fractions, and the like obtained from plants and the like from which the herbal medicine is derived can be used as active blood agents in the same manner.
[0023]
The extraction solvent used for the extraction is preferably a polar solvent such as water, alcohol, or acetone. Furthermore, since all of the above Chinese herbal medicines have good thermal stability, a heating operation may be added during extraction. Among the active blood drugs obtained in this manner, a product obtained by freeze-drying the water extract of the above Chinese herbal medicine is preferably used in the present invention.
[0024]
The active blood agent has an antibody-producing cell inhibitory action and is used together with the nucleotides as a component of the human body excess response inhibitor of the present invention. Even if one of these active blood agents is used alone, Two or more kinds may be used in combination.
[0025]
On the other hand, since these traditional Chinese medicines have been used for a long time, there are very few concerns about safety.
[0026]
<3> Suppressive agent for excessive human body, therapeutic agent for allergic disease and therapeutic agent for autoimmune disease of the present invention The excessive inhibitor for human body according to the present invention contains the nucleotide and / or a salt thereof and an active blood agent as active ingredients. Here, nucleotides and active blood agents each have an antibody-producing cell inhibitory action, but the action is synergistically increased by using these substances in combination.
[0027]
The compounding amount of nucleotides in the inhibitor against excessive human body of the present invention is preferably 1 to 50% by weight, more preferably 5 to 30% by weight, based on the total amount of the drug. Moreover, the preferable compounding quantity of an active agent is 1-50 weight% with respect to the chemical | medical agent whole quantity similarly, More preferably, it is 5-30 weight%. Furthermore, the mixing ratio of nucleotides and active blood in the inhibitor against excess human body is preferably 10: 1 to 1: 100 by weight.
[0028]
The dosage form of the inhibitor against excessive human body of the present invention is not particularly limited, but generally one kind of harmless pharmaceutically acceptable vehicle or several kinds of vehicles, carriers, excipients, binders, preservatives, stabilizers, taste masking Blended with flavoring agents, coating agents, coloring agents, sugar coatings, disintegrating agents, bulking agents, lubricants, etc., orally administered tablets, powders, granules, capsules, liquid medicines, ointments, creams, Transdermal administration agents such as lotions and injections such as sterile solutions and suspensions can be used. These can be produced using a conventionally known technique except that the nucleotides and the active blood are blended.
[0029]
For example, the above nucleotides and active agents and binders such as corn starch and gelatin, excipients such as microcrystalline cellulose, leavening agents such as potato starch and sodium alginate, sweeteners such as lactose and sucrose are dispensed. Orally administered powders, tablets, granules, capsules and the like. In the case of an injection, distilled water for injection or polyethylene glycol is used as a solvent, or a dispersant, buffer, solubilizer, isotonic agent, stabilizer, preservative, antioxidant Etc. may be added as necessary.
[0030]
For transdermal administration, hydrocarbons such as petroleum jelly and liquid paraffin, esters such as jojoba oil and beeswax, triglycerides such as olive oil and beef tallow, higher alcohols such as cetanol and behenyl alcohol, stearic acid, behen Fatty acids such as acids, nonionic surfactants such as POE hydrogenated castor oil and stearic acid monoglyceride, anionic surfactants such as soap and sodium lauryl sulfate, cationic surfactants such as stearyl ammonium chloride, glycerin, 1, Nucleotides together with optional components such as polyhydric alcohols such as 3-butanediol, moisturizers such as polyethylene glycol and hyaluronic acid, parabens, preservatives such as chlorhexidine gluconate, ultraviolet absorbers, stabilizers such as antioxidants, etc. If a live blood agent is dispensed, ointment, chestnut Beam, it is possible to obtain a lotion or the like.
[0031]
Similarly, the above-mentioned nucleotides and active agents are usually blended together with optional ingredients blended in cosmetics, quasi drugs, etc., and used as cosmetics, quasi drugs, etc. having an inhibitory action against excess. It is also possible.
[0032]
Furthermore, other medicinal ingredients such as anti-inflammatory analgesics that suppress inflammation and redness that tend to occur in response to excessive biological responses can be added to these drugs in accordance with various purposes.
Inhibitors against excessive human body of the present invention are allergic diseases such as hay fever, hay fever, atopic dermatitis, delayed contact dermatitis and autoimmune diseases such as systemic lupus erythematosus, nodular periarteritis, It is effective for the treatment and preventive treatment of scleroderma, dermatomyositis, rheumatoid arthritis, etc., and can also be used as a therapeutic agent for allergic diseases and a therapeutic agent for autoimmune diseases.
[0033]
The suitable application amount of the therapeutic agent for allergic disease or autoimmune disease of the present invention varies depending on the type of disease, symptoms, patient age, sex, weight, etc. For external preparations, nucleotides are 1 to 300 mg, active agents are 1 to 5000 mg, injections are nucleotides are 1 to 200 mg, active agents are 1 to 2500 mg, oral administration agents are nucleotides are 1 to 1000 mg, and active agents are 1 to 5000 mg. It is appropriate to administer. Examples of the administration method of injections include intravenous administration, intraarterial administration, intraportal administration, intraperitoneal administration, intramuscular administration, and subcutaneous administration. In addition, the application site of the transdermal administration agent is applicable not only to the exposed portions of the face, hands and feet, but also to the whole body skin such as the scalp.
[0034]
[Action]
In the present invention, a combination of nucleotides and active blood agent, to a human body excess response inhibitor containing this, sufficiently suppresses the proliferation of antibody-producing cells and has a sufficient action of suppressing an excessive response in the living body. It is The following describes experiments in which the effect of inhibiting antibody-producing cells was evaluated using various active blood agents and inosine-5′-sodium phosphate.
[0035]
The active blood used in the evaluation was prepared by adding 10 times the amount of water to various Chinese herbal medicines shown in Table 1, boiling for 3 hours, cooling, removing insolubles by filtration, and then freeze-drying. However, for Goo and Yutan, the raw material powder was used as a live blood as it was. Table 1 shows the charge amount and yield used for the above extraction together with the names of Chinese medicines.
[0036]
[Table 1]
<Evaluation of antibody-producing cell inhibitory action>
The antibody-producing cell inhibitory action was evaluated by a method of counting the number of antibody-producing cells in splenocytes according to the hemolytic plaque method (Science, 140, 405, 1963) developed by Jern et al.
[0038]
Two groups of 60-week-old aged ddy male mice, each group of 6 mice, were intraperitoneally administered with 0.5 mL of a physiological saline solution containing each of the obtained active blood agents at a concentration of 1 g / mL. In addition to these mice, two groups of mice received 0.5 mL of physiological saline containing no active blood agent intraperitoneally. Thereafter, one group of each active blood drug administration group and one group of the group administered with only physiological saline as described above further contained physiological saline containing inosine-5′-sodium phosphate at a concentration of 1 g / mL. The aqueous solution was intraperitoneally administered at 0.5 mL, and the remaining groups were intraperitoneally administered with 0.5 mL of a physiological saline solution not containing sodium inosine-5′-monophosphate. Here, a group of mice that did not receive both the active blood drug and inosine-5′-sodium phosphate was used as a control group.
[0039]
Thereafter, 4 × 10 8 cells / mL of sheep erythrocytes (SRBC) were administered to all mice in increments of 0.25 mL for sensitization. On the 1st, 2nd, and 3rd day after sensitization, the same test solution as that administered before sensitization was intraperitoneally administered to all mice in the same manner as the administration before sensitization.
[0040]
The day after the intraperitoneal administration of each test solution was completed, the spleen of each group of mice was removed, antibody-producing cells in the spleen cells were detected according to the method of Jerun et al., And the number of cells was counted. Using this measurement result, the value obtained by subtracting the number of antibody-producing cells in the group in the active blood plus nucleotides administration group, the group in the active blood administration group, and the nucleotides administration group from the number of antibody-producing cells in the control group, respectively, A value obtained by multiplying the value divided by the number of cells by 100 was determined and used as an antibody-producing cell inhibition rate for evaluation. The number of antibody-producing cells in each group used for calculating the antibody-producing cell inhibition rate was the average value of 6 mice in each group. The results are shown in Table 2.
[0041]
[Table 2]
From this result, in the group administered with only nucleotides and only active agent, the proliferation of antibody-producing cells was suppressed to some extent, but in the group administered in combination of both, the proliferation of antibody-producing cells was remarkably suppressed. Thus, it can be said that the human body excessive response inhibitor of the present invention is excellent in the action of suppressing the excessive response of the living body.
[0043]
Furthermore, in the above experiment, it can be seen that, despite the extremely high doses of nucleotides and active blood per mouse, there were no abnormal mice and their safety was high.
[0044]
In addition, the therapeutic agent for allergic diseases and the therapeutic agent for autoimmune diseases composed of such an inhibitor against excessive human body has excellent antibody-producing cell proliferation by a combination of the above-mentioned nucleotides and / or salts thereof as active ingredients and active agents. The inhibitory action suppresses the excessive response of the living body and effectively works for the treatment of various allergic diseases and autoimmune diseases caused by the excessive response of the living body as described above.
[0045]
Furthermore, among allergic diseases and autoimmune diseases, especially for diseases with clear onset timing such as hay fever, by suppressing the growth of antibody-producing cells in advance by administration of the above drug, It is possible to suppress the excessive response of the living body to the allergen, and as a result, it is possible to have a preventive treatment effect of preventing its onset.
[0046]
【Example】
Hereinafter, Examples of the present invention containing excessive inhibitors for human bodies, allergic disease therapeutic agents and autoimmune disease therapeutic agents containing nucleotides and active agents will be described. In addition, the active agent used for the Example is an active agent obtained by the method similar to what was used for the experiment of the said effect | action. Moreover, all the compounding quantities used below shall be a weight part.
[0047]
[Example 1]
Each of the A component and the B component shown in Table 3 was heated to 80 ° C. to dissolve, and the B component was gradually added to the A component and emulsified and cooled to obtain a cream.
[0048]
[Table 3]
[Example 2]
Granules The ingredients shown in Table 4 were placed in a grad granulator, granulated while adding water and humidified, then blown and dried at 40 ° C. for 24 hours, and granulated to obtain granules.
[0050]
[Table 4]
<Evaluation of Allergic Disease Treatment Drug of the Present Invention>
For the various drugs obtained in the above-mentioned examples, each of those suffering from atopic dermatitis and those suffering from hay fever conducts an actual use test, and experiments on delayed type allergic reactions are conducted using guinea pigs. The effect as a therapeutic drug for sexually transmitted diseases was evaluated.
[0052]
(1) Effect on atopic dermatitis Five patients with atopic dermatitis continuously use the cream obtained in Example 1 for 2 weeks, twice daily in the morning and evening, 2 weeks after the start of use. The degree of improvement of dermatitis was evaluated by a three-step evaluation of improved, unchanged, and worsened. All the results answered that the improvement was made, and this shows that the therapeutic agent for allergic diseases of the present invention is effective for atopic dermatitis.
[0053]
(2) Effect on hay fever For seven patients with cedar pollinosis, the granule obtained in Example 2 above was continuously applied for 14 days at a rate of 1 g once a day and 3 times a day before cedar pollen scattering began. I had you drink it. After the season of cedar pollinosis was over, we evaluated whether the symptoms of hay fever improved compared to the previous year, in three stages: improved, unchanged, and worsened. As a result, 3 people improved and 4 people remained unchanged. This shows that the therapeutic agent for allergic diseases of the present invention is also effective for preventive treatment of hay fever.
[0054]
(3) Effect on delayed-type allergic reaction The inhibitory action on the delayed-type allergic reaction of the therapeutic agent for allergic diseases of the present invention using as an index the development of delayed-type contact dermatitis to formalin by the maximization test method using Hartley male guinea pigs I saw.
[0055]
50 guinea pigs were divided into 5 groups of 1 group to 5 group of 10 animals. In the first group, the cream of Example 1 was administered at 0.05 mL / day on the back for 5 days, and in the second group, 1 g of the granule of Example 2 was orally administered for 5 days. The other 3 groups did not receive anything during these 5 days. Thereafter, all guinea pigs were induced by transdermal and intradermal administration of a 1% by weight formalin saline solution in the presence of Freund's complete adjuvant (FCA).
[0056]
After induction, the cream of Example 1 was administered to the back of the third group at 0.05 mL / day for 5 days, and 1 g of the granule of Example 2 was orally administered to the fourth group for 5 days. No administration was given to the first group, the second group, and the fifth group for these 5 days.
[0057]
On the 14th day after the end of induction, a 0.01% by weight formalin aqueous solution was transdermally administered to all guinea pigs by a closed patch, and the positive rate was examined. The criteria for the positive rate was the Draise standard. The results are shown in Table 5.
[0058]
[Table 5]
From these results, the therapeutic agent for allergic diseases of the present invention is excellent in the effect of prophylactically treating delayed type allergic reaction (Group 1 and Group 2) and the effect of treatment (Group 3 and Group 4). You can see that
[0060]
【The invention's effect】
The human body excess response inhibitor of the present invention is excellent in the action of suppressing the proliferation of antibody-producing cells, has a high safety in addition to well suppressing the biological excess response. In addition, therapeutic agents for allergic diseases and autoimmune diseases using these are excellent in the effect of treating these diseases or in the preventive treatment of these diseases, and can be used continuously for a long time. .
Claims (6)
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| JP18024094A JP3769036B2 (en) | 1994-08-01 | 1994-08-01 | Inhibitor against excessive human body |
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| JP18024094A JP3769036B2 (en) | 1994-08-01 | 1994-08-01 | Inhibitor against excessive human body |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH0899889A (en) * | 1994-08-02 | 1996-04-16 | Taisho Pharmaceut Co Ltd | Therapeutic agent for atopic dermatitis |
| ES2132855T3 (en) * | 1995-09-07 | 1999-08-16 | Oreal | EXTRACT OF IRIDACEAS AND COMPOSITIONS THAT CONTAIN IT. |
| JP2001199862A (en) * | 2000-01-14 | 2001-07-24 | Ichimaru Pharcos Co Ltd | Cosmetic composition containing moisture retention plant extract |
| JP5030366B2 (en) * | 2003-05-30 | 2012-09-19 | 株式会社武蔵野免疫研究所 | Composition for treatment of allergic diseases |
| JP5044957B2 (en) * | 2005-03-28 | 2012-10-10 | 大正製薬株式会社 | Copper compound composition |
| US8697152B2 (en) * | 2005-08-31 | 2014-04-15 | Johnson & Johnson Consumer Companies, Inc. | Anti-inflammatory compositions and personal care compositions comprising olive leaf (Olea europea) extract |
| JP6231895B2 (en) * | 2014-01-28 | 2017-11-15 | 宝珠 藍澤 | Cosmetic, method for producing cosmetic, external preparation for skin, and method for producing external preparation for skin |
| JP6038246B2 (en) * | 2015-07-27 | 2016-12-07 | 大塚製薬株式会社 | Erythema or edema improver |
| CN108210565A (en) * | 2018-04-17 | 2018-06-29 | 宁保发 | A kind of Chinese medicine preparation for solving numbness detoxification |
| CN112137932B (en) * | 2020-10-22 | 2021-07-06 | 佛山天韵化妆品科技有限公司 | Anti-allergy repairing composition and preparation method thereof |
-
1994
- 1994-08-01 JP JP18024094A patent/JP3769036B2/en not_active Expired - Fee Related
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