JPH0774160B2 - Autoimmune enteropathy treatment - Google Patents
Autoimmune enteropathy treatmentInfo
- Publication number
- JPH0774160B2 JPH0774160B2 JP62052188A JP5218887A JPH0774160B2 JP H0774160 B2 JPH0774160 B2 JP H0774160B2 JP 62052188 A JP62052188 A JP 62052188A JP 5218887 A JP5218887 A JP 5218887A JP H0774160 B2 JPH0774160 B2 JP H0774160B2
- Authority
- JP
- Japan
- Prior art keywords
- steroid
- disease
- steroids
- crohn
- water
- Prior art date
- 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.)
- Expired - Fee Related
Links
Description
【発明の詳細な説明】 イ．利用分野 本発明は、ステロイドの併用において用いられるトリプ
シン阻害剤を有効成分とする自己免疫性腸疾患治療剤に
関する。Detailed Description of the Invention a. Field of Use The present invention relates to a therapeutic agent for autoimmune enteropathy, which contains a trypsin inhibitor used in combination with steroids as an active ingredient.
ロ．従来技術 非特異的炎症性腸疾患（クローン病、潰瘍性大腸炎）並
びに腸型エーチェット病は、自己免疫疾患と考えられ、
主として、腸管に多発潰瘍を合併する疾患である。B. Prior art Non-specific inflammatory bowel disease (Crohn's disease, ulcerative colitis) and intestinal Acet's disease are considered to be autoimmune diseases,
It is a disease mainly associated with multiple ulcers in the intestinal tract.
従来、この疾患のなかで、潰瘍性大腸炎の病変支配動脈
にプレドニン（水浴性）20〜30mgの動注療法を行い、約
80％に有効性が認められている。しかし、クローン病、
腸型ベーチェット病には無効と考えられ、治療が行われ
ていない。また、有効と考えられる潰瘍性大腸炎でも、
初回には有効であるが慢性持続期には、有効例が多い。Conventionally, in this disease, arterial injection therapy of 20 to 30 mg of predonin (water bathing) was performed on the lesion-controlling artery of ulcerative colitis.
Efficacy is recognized in 80%. But Crohn's disease,
Intestinal Behcet's disease is considered ineffective and is untreated. Also, in ulcerative colitis, which is considered to be effective,
It is effective at the first time, but it is often effective in the chronic continuation period.
ハ．本発明が解決しようとする問題点 今回この自己免疫性腸疾患の治療を目的として研究を進
めた結果、ステロイドとトリプシン阻害剤を併用するこ
とにより、治療効果が増強されることを見出して本発明
を完成した。C. Problems to be Solved by the Present Invention As a result of advancing research for the purpose of treating this autoimmune bowel disease, it was found that the combined use of a steroid and a trypsin inhibitor enhances the therapeutic effect. Was completed.
ニ．問題点を解決するための手段 本発明のステロイドとしては、抗炎症活性を有するステ
ロイドまたはその誘導体が挙げられる。また、その態様
としては、水溶性ステロイド、ステロイド含有脂肪乳
剤、ステロイド含有リポソーム、ステロイド含有直腸投
与製剤などが挙げられる。D. Means for Solving Problems The steroids of the present invention include steroids having anti-inflammatory activity or derivatives thereof. Further, examples thereof include water-soluble steroids, steroid-containing fat emulsions, steroid-containing liposomes, steroid-containing rectal preparations and the like.
水溶性ステロイドは、水に可溶性であれば特に限定され
ない。例えば、ステロイド（プレゾニゾロン、デキサメ
サゾン、ハイドロコルチゾン、ベタメタゾンなど）の有
機酸塩または鉱酸塩などが挙げられる。The water-soluble steroid is not particularly limited as long as it is soluble in water. Examples thereof include organic acid salts or mineral acid salts of steroids (prezonisolone, dexamethasone, hydrocortisone, betamethasone, etc.).
有機酸としてはコハク酸、メタンスルホン安息香酸な
ど、鉱酸としては硫酸、リン酸など、塩としてはナトリ
ウム塩、カリウム塩などが挙げられる。Examples of the organic acid include succinic acid and methanesulfonic benzoic acid, examples of the mineral acid include sulfuric acid and phosphoric acid, and examples of the salt include sodium salt and potassium salt.
水溶性ステロイドは市販の医薬品を用いることができ
る。A commercially available drug can be used as the water-soluble steroid.
また、ステロイド含有脂肪乳酸としては、例えば、新油
性にしたステロイド（好ましくはステロイドの脂肪酸エ
ステル）を大豆油、リン脂質、水とともに乳化して得ら
れた水中油型乳剤が挙げられる。Examples of the steroid-containing fatty lactic acid include an oil-in-water emulsion obtained by emulsifying a lipophilic steroid (preferably a fatty acid ester of steroid) with soybean oil, phospholipid, and water.
ステロイド脂肪酸エステルとしては、メチルプレドニゾ
ロン、パラメタゾン、フルランドレロン、フルオシノロ
ン、ベクロメタゾン、その他のステロイド（例えは、ハ
イドロコルチゾン、プレドニゾロン、デキサメサゾン、
ベタメタゾン、トリアムシノロン、パラメタゾン、ベフ
ロメタゾン、フルオロメソロンなど）の炭素数６〜22の
脂肪酸（例えば、パルミチン酸、ミリスチン酸、ステア
リン酸など）のエステル体（モノエステル、ジエステル
を含む）などが挙げられる。Examples of steroid fatty acid esters include methylprednisolone, parameterzone, flulandrelone, fluocinolone, beclomethasone, and other steroids (for example, hydrocortisone, prednisolone, dexamethasone,
Examples thereof include esters (including monoesters and diesters) of fatty acids (for example, palmitic acid, myristic acid, stearic acid, etc.) having 6 to 22 carbon atoms such as betamethasone, triamcinolone, parameterzone, beflomethasone and fluoromesolone.
当該乳剤は主にステロイド、大豆油、リン脂質、水から
なり、これらを乳化して得られるが、その調製方法は、
例えば、登録No.1289054に記載されている。The emulsion mainly consists of steroids, soybean oil, phospholipids, and water, which can be obtained by emulsifying these.
For example, it is described in Registration No. 1289054.
ステロイド含有リポソームとしては、通常のステロイド
または、親油性にしたステロイド（例えば、ステロイド
の脂肪酸エステル）のいずれもが利用できる。当該リポ
ソームは、主としてステロイド、リン脂質、水からなる
製剤であるが、製法としては公知の方法（例えば、特開
昭56−16137、同60−208910等）により得られる。As the steroid-containing liposome, either a normal steroid or a lipophilic steroid (for example, a fatty acid ester of steroid) can be used. The liposome is a preparation mainly composed of steroids, phospholipids, and water, and can be obtained by a known method (for example, JP-A-56-16137 and JP-A-60-208910).
一方、トリプシン阻害剤は、トリプシン阻害活性を有す
るものであれば特に限定されない。On the other hand, the trypsin inhibitor is not particularly limited as long as it has a trypsin inhibitory activity.
例えば、人尿由来トリプシン阻害剤、アプロチニンなど
が例示される。For example, human urine-derived trypsin inhibitor, aprotinin and the like are exemplified.
人尿由来トリプシン阻害剤は人尿より分離精製された分
子量約65,000〜70,000糖蛋白質である。The human urine-derived trypsin inhibitor has a molecular weight of about 65,000 to 70,000 glycoproteins separated and purified from human urine.
製法としては特開昭51−123810に開示されており、ま
た、市販の医薬品（一般名ウリナスタチン）を用いるこ
ともできる。The production method is disclosed in JP-A-51-123810, and a commercially available drug (generic name ulinastatin) can also be used.
アプロチニンはウシの肺または耳下腺から抽出して得ら
れた糖蛋白質であるが、市販の医薬品を用いることもで
きる。Aprotinin is a glycoprotein obtained by extraction from bovine lung or parotid gland, but a commercially available drug can also be used.
（用法・用量） 用法としては、１日１〜数回経口または非経口による併
用投与（好ましくは動脈内投与または性脈内投与）が例
示される。経口投与の場合、薬物は腸溶性製剤とするこ
とが好ましい。(Dosage / Dose) Examples of administration include oral or parenteral combined administration (preferably intraarterial administration or intravascular administration) once to several times a day. For oral administration, the drug is preferably an enteric-coated preparation.
用量としては、患者の症状、体重、年齢等に応じてステ
ロイドとして１日あたり0.1〜100mg程度、トリプシン阻
害剤として同じく１〜100万単位程度が例示される。The dose is, for example, about 0.1 to 100 mg per day as a steroid and about 1 to 1,000,000 units per day as a trypsin inhibitor, depending on the patient's symptoms, body weight, age and the like.
〔単位はMethod in Enzymology 19,844（1970）に準じ
た。特開昭55−160724〕 適応症である自己免疫性腸疾患としては、好ましくは潰
瘍性大腸炎、クローン病（限局性回腸炎）、腸型ベーチ
ェット病などが例示される。[Units conform to Method in Enzymology 19 , 844 (1970). JP-A-55-160724] Preferred examples of the autoimmune enteropathy, which is an indication, include ulcerative colitis, Crohn's disease (localized ileitis), and intestinal Behcet's disease.
ホ．効 果 ステロイドとトリプシン阻害剤を併用することにより、
自己免疫性腸疾患（例えば、潰瘍性大腸炎、クローン
病、腸型ベーチェット病など）に対する治療効果が増強
する。この効果はステロイド単独療法に比べて顕著なも
のである。E. By combining steroids and trypsin inhibitors,
The therapeutic effect on autoimmune enteropathy (for example, ulcerative colitis, Crohn's disease, intestinal Behcet's disease, etc.) is enhanced. This effect is more pronounced than steroid monotherapy.
また、このことから、ステロイドがある程度、有効と考
えられている自己免疫疾患に対してもトリプシン阻害剤
の併用による治療効果の増強が期待できる。Further, from this, it can be expected that the therapeutic effect can be enhanced by the combined use of trypsin inhibitors even for autoimmune diseases in which steroids are considered effective.
従って、本発明は臨床上極めて有用と考えられる。Therefore, the present invention is considered to be extremely useful clinically.
ヘ．実施例 臨床例１ 52才、♂、慢性持続型の全大腸炎型の潰瘍性大腸炎、下
血１日７〜８回の症例に下腸間膜動脈及び上腸間膜動脈
のそれぞれに人尿由来トリプシンインヒビター10万単位
（５万単位/ml）と水溶性プレドニン15mg（１％溶液）
をone shot動注療法を施行し、以後１週間で正常便（１
日１回）に快復した。F. Example Clinical Example 1 52-year-old, ♂, ulcerative colitis of chronic persistent type colitis, melena 7 to 8 times a day in humans with inferior mesenteric artery and superior mesenteric artery respectively Urine-derived trypsin inhibitor 100,000 units (50,000 units / ml) and water-soluble predonin 15 mg (1% solution)
One shot intraarterial therapy was performed, and within 1 week thereafter, normal stools (1
Recovered once a day).
臨床例２ 21才、♂、全大腸炎型の亜急性持続型のクローン病症例
（下血、下痢８〜10回）に上記と同様の治療を行い、１
週間後に下血は消失し下痢も消失した。Clinical example 2 21-year-old, ♂, colitis-type subacute persistent Crohn's disease case (melena, diarrhea 8 to 10 times) was treated as described above.
After a week, the melena disappeared and the diarrhea disappeared.
臨床例３ 腸型ベーチェット病患者（38才男性）に水溶性プレドニ
ゾロン（コハク酸プレドニゾロンナトリウム）40mg、人
尿由来トリプシンインヒビター20万単位を支配動脈より
動注し、寛解期に導入することができた。Clinical example 3 Intestinal Behcet's disease patient (38-year-old male) was infused with 40 mg of water-soluble prednisolone (sodium prednisolone succinate) and 200,000 units of human urinary trypsin inhibitor from the main artery, and could be introduced during remission. .
以上、クローン病患者５例に対する、プレドニゾロンと
ウリナスタチンの併用効果を評価した。 As described above, the combined effect of prednisolone and ulinastatin was evaluated on 5 patients with Crohn's disease.
なお、Dutch A.I.（Dutch Activity Index）およびC.D.
A.I.（Crohn′s Disease Activity Index）はGastroint
erology,70（３）:439−444,1976およびGut,21:279−28
6,1980に準じて測定した。 In addition, Dutch AI (Dutch Activity Index) and CD
AI (Crohn's Disease Activity Index) is Gastroint
erology, 70 (3): 439-444,1976 and Gut, 21: 279-28.
It was measured according to 6,1980.
［実験例１］ 慢性持続型の潰瘍性大腸炎、下血を１日４〜５回起こす
ビーグル犬（♂、３月齢、4kg）に対し、人尿性トリプ
シンインヒビター１万５千単位（５万単位/ml溶液）と
デキサメタゾン−パルミチン酸エステル含有脂肪乳剤
（リメタゾン 、0.1ml、デキサメタゾン0.25mgに相
当）を１回静注した。その後１週間で下血は消失し、快
複した。[Experimental Example 1] Chronic persistent ulcerative colitis and melena 4 to 5 times a day
Beagle dog (♂, 3 months old, 4 kg), human urinary tryp
Synthin inhibitor 15,000 units (50,000 units / ml solution)
Fat emulsion containing dexamethasone-palmitate
(Limethasone , 0.1 ml, dexamethasone 0.25 mg
Was injected once. One week thereafter, the melena disappeared
Duped.
［実験例２］ 亜急性持続型のクローン病で下血を起し、下痢頻繁のビ
ーグル犬（♂、４月齢、5kg）に対し、アプロチニン２
万単位（１万単位/ml溶液）とプレドニゾロン2.5mg含有
リポソームを１回静注し、５日間観察した結果、下血及
び下痢共に消失し、快復した。[Experimental Example 2] Aprotinin-2 was administered to beagle dogs (♂, 4 months old, 5 kg) with frequent diarrhea caused by subacute persistent Crohn's disease and diarrhea.
10,000 units (10,000 units / ml solution) and liposomes containing 2.5 mg of prednisolone were intravenously injected once and observed for 5 days. As a result, both melena and diarrhea disappeared, and recovery was recovered.
Claims (3)
リプシン阻害剤を有効成分とする自己免疫性腸疾患治療
剤。1. A therapeutic agent for autoimmune bowel disease containing a trypsin inhibitor used in combination with a steroid as an active ingredient.
ドまたはその誘導体である特許請求の範囲第（１）項記
載の治療剤。2. The therapeutic agent according to claim 1, wherein the steroid is a steroid having anti-inflammatory activity or a derivative thereof.
ン病または腸型ベーチェット病である特許請求の範囲第
（１）項記載の治療剤。3. The therapeutic agent according to claim 1, wherein the autoimmune bowel disease is ulcerative colitis, Crohn's disease or intestinal Behcet's disease.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62052188A JPH0774160B2 (en) | 1987-03-09 | 1987-03-09 | Autoimmune enteropathy treatment |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62052188A JPH0774160B2 (en) | 1987-03-09 | 1987-03-09 | Autoimmune enteropathy treatment |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP8227351A Division JPH09183736A (en) | 1996-08-12 | 1996-08-12 | Therapeutic agent for autoimmune enteropathy |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS63218626A JPS63218626A (en) | 1988-09-12 |
| JPH0774160B2 true JPH0774160B2 (en) | 1995-08-09 |
Family
ID=12907827
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62052188A Expired - Fee Related JPH0774160B2 (en) | 1987-03-09 | 1987-03-09 | Autoimmune enteropathy treatment |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0774160B2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH09183736A (en) * | 1996-08-12 | 1997-07-15 | Green Cross Corp:The | Therapeutic agent for autoimmune enteropathy |
| KR20020069239A (en) * | 2000-11-07 | 2002-08-29 | 가부시끼가이샤 하야시바라 세이부쓰 가가꾸 겐꾸조 | Mucosal immunomodulator and use thereof |
| JP6645737B2 (en) * | 2012-09-05 | 2020-02-14 | 漂太 高松 | Biomarkers for autoimmune diseases |
-
1987
- 1987-03-09 JP JP62052188A patent/JPH0774160B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS63218626A (en) | 1988-09-12 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |