【発明の詳細な説明】
技術分野
本發明はウリジンを有效成分とする關節炎治療劑に關
し，更に詳しくは，ヌクレオシドであるウリジンの新規
な藥效である關節炎治療效果としての用途及びこれを含
有する藥劑に關するものである．
背景技術
ウリジンはRNAを構成するのに必要な４個のリボヌク
レオシド中の一つとして自然界で廣範圍に分布されてい
る物質として，その分子量は244.20であり，分子式はC9
H12N2O6で10あり，その構造式は次の通りだ．
今まで知られたいるウリジンの藥理作用はウリジンが投
與されると體内でウリジンキナゼ酵素の觸媒作用によっ
てウリジン5'−ホスヌァートへ直ちに轉換されるので，
酵素の缺乏またはピリミジンヌクレオチジト缺乏と核酸
合成の缺乏に有用してオルチク酸尿症（HEREDITARY OR
OTIC ACIDURIA）を輕減させる藥劑として使われた報告
（MATINDALE,1989,1627）があり，實際，大韓民國内に
ても複合製劑の成分としているいるの藥效のため使用さ
れたことがありますが，ウリジン自體が關節炎に效果を
有することと報告されることはない．本發明者は生藥と
して使用されている成分を研究する中，單一成分として
分離精製された各種物質の藥效スクリニングした結果，
該植物より分離された成分中の一が優れた關節炎治療效
果を有することが發見して，物質に對する分子構造を糾
明した結果，ウリジンであることを確認して本發明を完
成した．
ウリジンが今まで醫藥品に使用された場合は他の藥效
物質とともに複合製劑として血管性腦疾患，肝腸保護，
末梢神腦症，組經織低酸素症等に使われることが知られ
ているが，その關節炎治療效果は知られていない．
發明の開示
本發明の目的は，式
で表されるウリジンを有效成分とする關節炎改善劑を提
供するものである．
圖面の簡單な説明
圖１は對照群と，ウリジンを投與した群の關節炎發生
部位の浮腫が拔けるの腦時推移を表わされるグラフであ
る．
發明を實施するための最良の形態
本發明はウリジンを有效成分とする關節炎改善劑を提
供することでウリジン0.6−60mg/kgを投與する場合，關
節炎に對する優れた效果を表わされる．それの有效成分
を腦口投與するにあっては錠劑，藥劑，カプセル劑等の
投與製劑とすることができ，これらは通常用いられる方
法に從い製造することができる．これらの製劑を製造す
るために乳糖，とうもろこし澱粉，ステアリン酸マグネ
シウム等の賦形劑を添加することができる．
本發明者は實驗によってウリジンが軟骨形成を促進
し，骨吸收（BONE RESORPTION）を抑制させて關節で組
織の炎症を低下させ，再生を促進する作用が有ることを
確認した．
即ち，ウリジンの關節炎の治療效果を確認するために
リューマチ性關節炎の動物實驗のモデルであるコラーゲ
ン誘發−關節炎實驗（COLLAGEN−INDUCED ARTHRITIS）
を施行して對照群に比べて關節炎部位の浮腫が拔ける速
度が早い，犠牲される前までの最終浮腫の拔ける程度も
有意の差を表わされる效果が有るのでウリジンがコラー
ゲン關節炎が生ずる組織の炎症を低減させ，再生を促進
することを確認した．また，コラーゲン關節炎は自己免
疫疾患の範疇として，ウリジンがほかの自己免疫疾患の
治療にも效果が有ることと考える．ウリジンに對する毒
性實驗の結果，元氣なラット及びマウスにウリジン0.0
1,0.1,10,100mg/Kgずつ投與し,1週日以上觀察した所，
とんなの異状も發見かることができなが」ったことを確
認した．
實施例
以下，實施例により本發明をさらに具體的に説明する
が，本發明はこれらにより限定されるものではない．
實施例1.コラーゲン關節炎に對する藥效實驗
（１）コラーゲン關節炎の誘導と觀察
天然牛型IIコラーゲン（Native bovine type II coll
agen）を2mg/mlなるように溶解した後，未完成のプロイ
ント（Freund）坐藥とを1:1で混合してエマルジョンを
調製した．このエマルジョンをルイスラットの尾根で1m
lずつ皮下注射した.8日後，同一な方法だエマルジョン
を調製した後,1mlずつ腹腔内注射した．以後，關節炎が
發生したラット對照群と，ウリジンを投與した群（ウリ
ジン群１は10μｇずつ一日あたり２回，ウリジン群２は
1mgずつ一日あたり２回）にてわけて觀察し，適當な間
隔で關節炎が發生した足の厚さと廣さを測定した．ま
た，コラーゲンタイプIIに對する抗體力價の腦時變化を
觀察するために一定間隔で尾の靜脈で血清を準備した．
（２）コラーゲンタイプIIに對する抗體力價の腦時變化
の觀察
タナテクイムロン４プレート（Danatech Immulon 4 p
late）に各ウェル（well）當50μｌのコラーゲンタイプ
II溶液（10μg/ml）を添加し，一夜，コティングした
後，また一夜３％BSA−PBS（bovine serum albumin−ph
osphate buffered saline）溶液でブロキングした．こ
のプレートをまずPBSで４回洗滌し，上記のルイスラッ
トより得た血清を添加した後，一夜，反應させた．その
後PBSで４回洗滌し，過酸化酵素を標識したヤギのアン
ティ−ラットイムノグロブリンＧ（IgG）抗體を添加し
た．一夜後,PBSで４回洗滌しＯ−フェニレンジアミンを
基質として發色させた後,ETAプレート判讀器（ETA plat
e reader）にて405nmで吸光度を測定した．
（３）3H−チミジン吸收分析
２つの群のラットを犠牲させて得た脾臓でメッシュを
利用して脾臓細胞を得た．各各のウェルに0.5％の同一
群の血清を含むDulbecco修正イグルス培地に浮遊させた
2.5x106程度の脾臓細胞を入れて，コラーゲンタイプII
を０μg/ml,0.01μg/ml,0.1μg/ml,1μg/ml,10μg/mlな
るようにいれた.CO2インキュベータの中で56時間放置し
た後,0.5μCiの3H−チミジンを添加した.16時間後，自
動收穫器にて收穫し，シンチレーション計数管（scinti
llation counter）にて放射能を測定した．
（４）病理組織學的檢査
3H−チミジン吸收分析のためにルイスラットを犠牲す
る時，關節炎が發生した後足をホルマリンで固定し，無
機物を除去してスライドを製作して病理組織學的所見を
觀察した．
本實驗に對する結果は關節炎が發生した後，一日２回
ずつウリジンを投與したルイスラット群と蒸溜水たけを
投與した群とのあいたには圖１で表わされるように關節
炎が發生した足の浮腫（edema）が拔ける程度と速度で
有意の差が有することを認められる．しかし表１と表２
で示めしたように２つの群のあいたに抗體力價の變化や
脾臓細胞の3H−チミジン吸收の差はほどんとなかった．
病理組織學的の所見で，ウリジンを投與したルイスラッ
トは蒸溜水を投與したラットの場合とは違く硝子軟骨
（hyaline cartilage）がたくさん殘ていり，纎維軟骨
の形成ももっと活溌することとした示めた．また，炎症
の所見は２つの群で，すべての部位によって程度の差を
示めしたいるが，骨吸收の所見は蒸溜水を投與した群の
たけで示めることを確認される．
實施例2.藥劑學的錠劑の製造
（１）通常の方法に從ってウリジンの藥效にさしつかえ
ない賦形劑を下記の組成に依って添加し，混合して錠劑
を製造した．
（２）通常の方法に從って下記の組成に依って錠劑を製
造した．
Description: TECHNICAL FIELD The present invention relates to a therapeutic agent for the treatment of common sores that contains uridine as an active ingredient. More specifically, the use of uridine, which is a nucleoside, is a novel therapeutic effect for the treatment of common sores and its effects. It is the one that is contained in the garbage. Background Art Uridine is one of the four ribonucleosides necessary for constructing RNA and is distributed in nature in a wide range. Its molecular weight is 244.20 and its molecular formula is C 9
H 12 N 2 O 6 is 10, and its structural formula is as follows. The known pharmacological action of uridine is that when uridine is thrown, it is immediately converted into uridine 5'-phosphate by the catalytic action of uridine quinase enzyme in the body.
Useful for enzyme deficiency or pyrimidine nucleotidite deficiency and nucleic acid synthesis deficiency.
There is a report (MATINDALE, 1989,1627) that was used as a pottery to reduce OTIC ACIDURIA), and it was used as a component of a composite sardine even in the Republic of Korea. Uridine itself is not reported to have any effect on sores. While studying the components used as raw herbs, the present researcher screened various substances that were separated and purified as a single ingredient,
It was found that one of the components isolated from the plant had an excellent therapeutic effect on scabitis, the molecular structure of the substance was revealed, and as a result, it was confirmed that it was uridine and the present study was completed. ． When uridine has been used in medical supplies, it is used as a compound iron with other drugs to treat vascular disease, hepatointestinal protection,
It is known to be used for peripheral dementia, brachyplasty hypoxia, etc., but its curative effect on arthritis is not known. Disclosure disclosure The purpose of this disclosure is to formula The present invention provides a swelling-improving syrup containing uridine as an effective ingredient. A simple explanation of the face. Rake 1 is a graph showing the time course of edema at the swelling site of the swelling of the swelling of the urateru group and the group receiving uridine. This is the best mode for the treatment of glaucoma. This glaucoma has an excellent effect of treating glaucoma when uridine of 0.6-60 mg / kg is provided by providing an improving ingredient of glaucoma containing uridine. ． In the case of poaching the active ingredient thereof, it can be made into a pot-making product such as tablets, porridges, capsules, etc., which can be manufactured according to a commonly used method. In order to produce these shavings, lactose, corn starch, and shaping syrups such as magnesium stearate can be added. The present authors have confirmed that uridine promotes cartilage formation and suppresses bone resorption (BONE RESORPTION), and reduces inflammation of the tissues in the spinal joint, and promotes regeneration by the bone marrow. That is, in order to confirm the therapeutic effect of uridine on scabitis, COLLAGEN-INDUCED ARTHRITIS, which is a model of animal disease of rheumatoid arthritis.
The edema of the swelling part of the arthralitis is faster than that of the sera group, and the extent of the final edema before the sacrifice is significantly different. It was confirmed that the resulting tissue inflammation was reduced and regeneration was promoted. In addition, we believe that uridine is effective in the treatment of other autoimmune diseases, as collagen scabitis is a category of autoimmune diseases. As a result of the toxicity of uridine, uridine was 0.0% in the original rats and mice.
1,0.1,10,100mg / Kg each, and observed for more than 1 week,
I couldn't detect any abnormalities. " Examples Hereafter, the present invention will be explained more concretely by the following examples, but the present invention is not limited thereto. Example 1. Collagen scabitis and its effects (1) Induction and observation of collagen scabitis. Native bovine type II coll (Native bovine type II coll)
agen) was dissolved to 2 mg / ml and mixed with unfinished Proint (Freund) zabuta 1: 1 to prepare an emulsion. 1m of this emulsion on a Lewis rat ridge
8 days later, an emulsion was prepared by the same method, and then 1 ml was intraperitoneally injected. After that, a group of rats with scabitis and a group with uridine (Uridine group 1 10 μg twice a day, Uridine group 2
1 mg each twice a day), and the thickness and height of the foot on which the arthritis was caused were measured at appropriate intervals. Serum was prepared at regular intervals in the veins of the tail to observe the anti-hypertensive changes in collagen type II. (2) Observation of the anti-hypertensive effect of collagen type II on the swelling time Tanatech Immulon 4 p
late) 50μl of each well type collagen type
After adding II solution (10 μg / ml) and coating overnight, 3% BSA-PBS (bovine serum albumin-ph) was added overnight.
Blocking was performed with an osphate buffered saline) solution. The plate was first washed with PBS four times, and the serum obtained from the Lewis rat was added to the plate, which was then reacted overnight. Then, the cells were washed 4 times with PBS, and anti-rat immunoglobulin G (IgG) anti-rat of goat labeled with peroxidase was added. After overnight, washing with PBS four times, and using O-phenylenediamine as a substrate, and then bleaching, ETA plate reading device (ETA plat
The absorbance was measured at 405 nm with an e reader). (3) 3 H-thymidine absorption analysis Spleen cells were obtained by using a mesh with the spleen obtained by sacrificing two groups of rats. Suspended in Dulbecco's modified Igls medium containing 0.5% of the same serum in each well
Put about 2.5x10 6 spleen cells, collagen type II
Was added to 0 μg / ml, 0.01 μg / ml, 0.1 μg / ml, 1 μg / ml, 10 μg / ml. After standing in a CO 2 incubator for 56 hours, 0.5 μCi of 3 H-thymidine was added. .16 hours later, harvested with an automatic harvester, scintillation counter (scinti
Radioactivity was measured using an llation counter). (4) Histopathological Examination When Lewis rats were sacrificed for 3 H-thymidine uptake analysis, the hindpaw, which suffered from osteoarthritis, were fixed with formalin, and inorganic substances were removed to prepare slides for histopathology. I observed the findings. The result of this study was that after the necrotizing outbreak, Lewis rats fed twice daily with uridine and the group fed with distilled water were treated with glaucoma as indicated by 圖 1. It is recognized that there is a significant difference in the degree and speed at which the edema of the foot in which the swelling occurs occurs. But Tables 1 and 2
As shown in Fig. 4, there was little difference between the two groups in the change in anti-tumor activity and in the 3 H-thymidine absorption of spleen cells.
From histopathological findings, Lewis rats fed with uridine had more hyaline cartilage than the rats fed with distilled water, and the formation of fibrous cartilage was more active. I showed you that. In addition, the findings of inflammation were shown to be different to all extent in the two groups, but the findings of bone resorption were confirmed to be shown only in the group to which distilled water was poured. Example 2 Production of Chinese medicine tablets (1) According to the usual method, a tablet which could not be effective against the effect of uridine was added according to the following composition and mixed to produce tablets. (2) Tablets were produced according to the following composition according to a conventional method.
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フロントページの続き
(56)参考文献 特開 平４−243830（ＪＰ，Ａ)
特開 平２−25425（ＪＰ，Ａ)
特開 昭60−136515（ＪＰ，Ａ)
特開 昭62−145019（ＪＰ，Ａ)
ＦＯＸ， Ｒ． Ｉ．， ｅｔ ａ
ｌ．， ＴＲＥＡＴＭＥＮＴ ＯＦ Ｒ
ＨＥＵＭＡＴＯＩＤ ＡＲＴＨＲＩＴＩ
Ｓ（ＲＡ） ＷＩＴＨ ＴＨＥ ＰＹＲ
ＩＭＩＤＩＮＥ ＳＹＮＴＨＥＳＩＳ
ＩＮＨＩＢＩＴＯＲ ＴＲＩＡＣＥＴＹ
Ｌ−６−ＡＺＡＵＲＩＤＩＮＥ， Ａｒ
ｔｈｒｉｔｉｓ Ｒｈｅｕｍ．，
1992， 35（Ｓｕｐｐｌ． ９），
ｐ． Ｓ203
(58)調査した分野(Int.Cl.7，ＤＢ名)
A61K 31/70 - 31/713
A61P 1/00 - 43/00
C07H 19/00 - 19/067
ＣＡ（ＳＴＮ)
ＲＥＧＩＳＴＲＹ（ＳＴＮ)
ＷＰＩ（ＤＩＡＬＯＧ)─────────────────────────────────────────────────── --- Continuation of the front page (56) References JP-A-4-243830 (JP, A) JP-A-2-25425 (JP, A) JP-A 60-136515 (JP, A) JP-A 62- 145019 (JP, A) FOX, R.A. I. , Et al. , TREATMENT OF R HEUMATOID ARTHRITIS (RA) WITH THE PYR IMIDINE SYNTHESIS INHIBITOR TRIACETY L-6-AZAURIDINE, Ar thresholds Rheum. , 1992, 35 (Suppl. 9), p. S203 (58) Fields investigated (Int.Cl. 7 , DB name) A61K 31/70-31/713 A61P 1/00-43/00 C07H 19/00-19/067 CA (STN) REGISTRY (STN) WPI (DIALOG)