JPH07291864A - Therapeutic agent for obstructive jaundice - Google Patents
Therapeutic agent for obstructive jaundiceInfo
- Publication number
- JPH07291864A JPH07291864A JP11018694A JP11018694A JPH07291864A JP H07291864 A JPH07291864 A JP H07291864A JP 11018694 A JP11018694 A JP 11018694A JP 11018694 A JP11018694 A JP 11018694A JP H07291864 A JPH07291864 A JP H07291864A
- Authority
- JP
- Japan
- Prior art keywords
- therapeutic agent
- leucovorin
- obstructive jaundice
- jaundice
- calcium
- 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.)
- Ceased
Links
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は閉塞性黄疸治療剤に関
し、更に詳細には、ロイコボリンを有効成分として含有
する閉塞性黄疸治療剤に関する。FIELD OF THE INVENTION The present invention relates to a therapeutic agent for obstructive jaundice, and more particularly to a therapeutic agent for obstructive jaundice containing leucovorin as an active ingredient.
【０００２】[0002]
【従来の技術】術後あるいは悪性腫瘍の肝／リンパ節転
移を契機に、または肝疾患もしくは胆道系疾患にともな
い、閉塞性黄疸症状が発現する場合がある。このような
黄疸症状が見られる場合、これを放置すれば肝不全や腎
不全を招来し死に至るそれがあるため、速やかに減黄処
置を採る必要がある。2. Description of the Related Art Occurrence of obstructive jaundice may occur postoperatively or as a result of liver / lymph node metastasis of a malignant tumor, or with liver disease or biliary tract disease. If such jaundice is observed, it may lead to liver failure or renal failure leading to death if left untreated, so it is necessary to promptly reduce the yellowing.
【０００３】従来、上記閉塞性黄疸の症状を緩和する手
段としては、経皮経肝胆道ドレナージ（ＰＴＢＤ）が第
一選択処置として行われている。しかしながら、かかる
ＰＴＢＤは外科的処置であるため、この処置自体が患者
の苦痛を招くものである。また、医師にとっても手技に
熟練を要し、しかも術前及び術後の管理が必要であるな
ど、負担が大きい。さらに、ＰＴＢＤでは黄疸症状が改
善しない閉塞性黄疸もしばしばみられるため、ＰＴＢＤ
は必ずしも完全な処置法であるとはいいがたい。Conventionally, percutaneous transhepatic biliary drainage (PTBD) has been used as a first-line treatment as a means for alleviating the symptoms of obstructive jaundice. However, since such PTBD is a surgical procedure, the procedure itself causes patient distress. In addition, it requires a great deal of skill for a doctor, and also requires management before and after surgery, which is a heavy burden. In addition, PTBD often causes obstructive jaundice, which does not improve jaundice symptoms.
Is not always a complete treatment.
【０００４】一方、黄疸症状を緩和するものとして催胆
剤、排胆剤が知られているが、かかる薬剤は、肝内胆汁
うっ滞には奏功しても閉塞性黄疸には効果が少ないこと
が知られている。[0004] On the other hand, a bile-producing agent and a bile-creating agent are known to alleviate the symptoms of jaundice. Such agents are effective for obstructive cholestasis but have little effect on obstructive jaundice. It has been known.
【０００５】以上のとおり、閉塞性黄疸に対して、患者
及び医師の双方に負担の大きいＰＴＢＤに代わって、負
担の少ないより有効な減黄処置、例えば内科的治療法が
強く要望されている。しかしながら、これまで、臨床上
有効性の認められる薬剤が皆無であった。As described above, for occlusive jaundice, there is a strong demand for a more effective yellowing treatment with less burden, for example, a medical treatment method, in place of PTBD, which burdens both patients and doctors. However, until now, there have been no drugs that are clinically effective.
【０００６】かかる現状のもと、外科的処置によること
なく内科的に投与することにより閉塞性黄疸を改善でき
る治療剤を開発すべく検討した結果、本発明者らは、抗
葉酸代謝拮抗剤として知られているロイコボリンが閉塞
性黄疸患者の黄疸症状を著しく改善することを見出し、
かかる知見に基づいて本発明を完成するに至った。Under the present circumstances, as a result of studies to develop a therapeutic agent capable of improving obstructive jaundice by administering it medically without surgical treatment, the present inventors have found that it is an antifolate antimetabolite. It was found that known leucovorin significantly improves jaundice symptoms in patients with obstructive jaundice,
The present invention has been completed based on these findings.
【０００７】[0007]
【課題を解決するための手段】すなわち本発明は、ロイ
コボリンを有効成分として含有する閉塞性黄疸治療剤を
提供するものである。本発明の治療剤によれば、ＰＴＢ
Ｄ等の外科的手術を行うことなく閉塞性黄疸患者の黄疸
症状を著しく改善することができる。また、上記ＰＴＢ
Ｄにより黄疸の改善が見られなかった症例にも、著しい
改善効果が認められる。そのため、本発明の治療剤は、
臨床上極めて有用な薬剤である。That is, the present invention provides a therapeutic agent for obstructive jaundice containing leucovorin as an active ingredient. According to the therapeutic agent of the present invention, PTB
The jaundice symptom of the obstructive jaundice patient can be remarkably improved without performing surgical operation such as D. Also, the above PTB
Even in the case where the improvement of jaundice was not observed due to D, a remarkable improvement effect is recognized. Therefore, the therapeutic agent of the present invention,
It is a clinically extremely useful drug.
【０００８】本発明で有効成分として用いられるロイコ
ボリンは、化学名がＮ−［４−［［（２−アミノ−５−
ホルミル−１，４，５，６，７，８−ヘキサハイドロ−
４−オキソ−６−プテリジニル）メチル］アミノ］ベン
ゾイル］−Ｌ−グルタミン酸として知られる化合物であ
るが、本発明では、さらに該化合物の薬理学的に許容し
うる塩、例えばカルシウム塩及びマグネシウム塩をも包
含する。さらに、当該化合物にはｄ体及びｌ体の光学異
性体が存在するが、これらの混合物及びｌ体のいずれも
が、本発明のロイコボリンに含まれる。Leucovorin used as an active ingredient in the present invention has a chemical name of N- [4-[[(2-amino-5-
Formyl-1,4,5,6,7,8-hexahydro-
A compound known as 4-oxo-6-pteridinyl) methyl] amino] benzoyl] -L-glutamic acid is used in the present invention, but in the present invention, a pharmacologically acceptable salt of the compound, for example, a calcium salt or a magnesium salt is further added. Also includes. Furthermore, although the compound has optical isomers of d-form and l-form, both the mixture and the 1-form are included in the leucovorin of the present invention.
【０００９】本発明の閉塞性黄疸治療剤としてのロイコ
ボリンの投与量は特に厳密に制限されるものではなく、
投与方法及び対照となる患者の黄疸の程度によって異な
るが、一般に、ｄｌ−ロイコボリン若しくはｌ−ロイコ
ボリンとして１ｍｇないし２００ｍｇ／日、好ましくは
２０ｍｇないし１００ｍｇ／日の範囲内で適宜選択する
ことができる。The dose of leucovorin as a therapeutic agent for obstructive jaundice of the present invention is not particularly limited,
Although it varies depending on the administration method and the degree of jaundice of a control patient, in general, it can be appropriately selected as dl-leucovorin or 1-leucovorin within the range of 1 mg to 200 mg / day, preferably 20 mg to 100 mg / day.
【００１０】しかして、本発明の閉塞性黄疸治療剤は、
医薬品の製剤において慣用されている無機もしくは有機
の固体または液体の製剤用担体もしくは希釈剤、例え
ば、でんぷん、乳糖、白糖、結晶セルロース、リン酸水
素カルシウム等の賦形剤；アカシア、ヒドロキシプロピ
ルセルロース、アルギン酸、ゼラチン、ポリビニルピロ
リドン等の結合剤；ステアリン酸、ステアリン酸マグネ
シウム、ステアリン酸カルシウム、タルク、水添植物油
等の滑沢剤；加工でんぷん、カルシウムカルボキシメチ
ルセルロース、低置換ヒドロキシプロピルセルロース等
の崩壊剤；非イオン性界面活性剤、アニオン性界面活性
剤等の溶解補助剤等と共に、経口的、非経口的または局
所的投与に適した剤形に製剤化することができる。Therefore, the therapeutic agent for obstructive jaundice of the present invention is
Inorganic or organic solid or liquid pharmaceutical carriers or diluents that are commonly used in pharmaceutical formulations, for example, starch, lactose, sucrose, crystalline cellulose, excipients such as calcium hydrogen phosphate; acacia, hydroxypropyl cellulose, Binders such as alginic acid, gelatin and polyvinylpyrrolidone; Lubricants such as stearic acid, magnesium stearate, calcium stearate, talc and hydrogenated vegetable oils; disintegrants such as processed starch, calcium carboxymethyl cellulose and low-substituted hydroxypropyl cellulose; non- It can be formulated into a dosage form suitable for oral, parenteral or topical administration together with a solubilizing agent such as an ionic surfactant and an anionic surfactant.
【００１１】経口投与に適した剤形には、錠剤、コーテ
ィング剤、カプセル剤、トローチ剤、散剤、細粒剤、顆
粒剤、ドライシロップ剤等の固体製剤、あるいはシロッ
プ剤等の液体製剤が挙げられ、非経口投与に適した剤形
としては、例えば注射剤、点滴剤、坐剤等が包含され
る。また、局所投与に適した剤形には軟膏、チンキ、ク
リーム、ゲル等が挙げられる。これらの製剤は製剤学の
分野でそれ自体周知の方法で調製することができる。Suitable dosage forms for oral administration include solid preparations such as tablets, coatings, capsules, troches, powders, fine granules, granules and dry syrups, or liquid preparations such as syrups. Suitable dosage forms for parenteral administration include, for example, injections, drops, suppositories and the like. Further, dosage forms suitable for topical administration include ointments, tinctures, creams, gels and the like. These preparations can be prepared by a method known per se in the field of pharmaceutics.
【００１２】本発明の閉塞性黄疸治療剤は、他の薬剤、
例えば抗癌剤、肝疾患治療剤、利胆剤と同時に、組み合
わせて用いることもできる。The therapeutic agent for obstructive jaundice of the present invention comprises other agents,
For example, they can be used in combination with an anticancer agent, a liver disease therapeutic agent, and a choleretic agent, in combination.
【００１３】[0013]
【実施例】以下に、本発明の閉塞性黄疸治療剤の有用性
を、薬理試験の結果、安全性及び具体的製剤例によって
明らかにする。EXAMPLES The usefulness of the therapeutic agent for obstructive jaundice of the present invention will be clarified below based on the results of pharmacological tests, safety, and specific formulation examples.
【００１４】［薬理試験］ Ｉ ラットにおける胆汁***促進効果 １．試験方法 体重約２５０ｇのｗｉｓｔａｒ系雄性ラット４匹の総胆
管にポリエチレンチューブをカニュレーションし総胆管
外瘻を作成する。ラットは２群に分け、１群には外瘻作
成から１２時間後にｄｌ−ロイコボリンカルシウム塩・
五水和物１ｍｇ／ｋｇを腹腔内投与し、他の１群には対
照として同量の生理食塩水を腹腔内投与して、経時的に
各ラットの胆汁***量を測定した。[Pharmacological test] Bile excretion promoting effect in I rat 1. Test method A polyethylene tube is cannulated into the common bile duct of four male Wistar rats having a body weight of about 250 g to prepare a common bile duct. Rats were divided into 2 groups, and 1 group contained dl-leucovorin calcium salt 12 hours after the external fistula was created.
The pentahydrate 1 mg / kg was intraperitoneally administered, and the other group was intraperitoneally administered with the same amount of physiological saline as a control, and the bile excretion amount of each rat was measured over time.
【００１５】２．結果 薬剤投与後の胆汁***量の経時的変化を、１２時間毎の
累積***量の変化として下記表１に示す。2. Results The changes over time in bile excretion after drug administration are shown in Table 1 below as changes in cumulative excretion every 12 hours.
【００１６】[0016]
【表１】 [Table 1]
【００１７】以上の結果から、本発明の薬剤がラットの
胆汁***量の自然減少を３６時間以上にわたって防ぐこ
とが確認された。このことは、本発明の薬剤が胆汁***
促進作用及び胆汁産生促進作用を有することを示唆する
ものである。From the above results, it was confirmed that the drug of the present invention prevents the spontaneous decrease in the amount of biliary excretion in rats for 36 hours or longer. This suggests that the drug of the present invention has a bile excretion promoting action and a bile production promoting action.
【００１８】ＩＩ ヒトによる減黄効果 １．試験方法 食道癌の術後閉塞性黄疸患者にｄｌ−ロイコボリンカル
シウム塩・五水和物３０ｍｇ／日を連日静脈内投与し、
血清中総ビリルビン値を測定して、減黄効果を評価し
た。II Human yellowing effect 1. Test method A patient with postoperative obstructive jaundice of esophageal cancer was intravenously administered with dl-leucovorin calcium salt pentahydrate 30 mg / day every day,
The total bilirubin level in serum was measured to evaluate the yellowing effect.
【００１９】２．結果 本試験で得られた総ビリルビン値の変化を後記図１に示
す。図から明らかなとおり、ロイコボリン投与開始約１
週間後には総ビリルビン値の顕著な低下が認められた。
この状態は、その後の投与期間中も継続した。また、総
ビリルビン値の低下にともない、著しい減黄効果が認め
られた。その他、当該患者の臨床検査値の変動から、本
発明の治療剤には更にコレステロール上昇抑制作用、Ｇ
ＯＴ値及びＧＴＰ値の上昇抑制作用が認められ、肝機能
の改善効果も示唆された。2. Results Changes in the total bilirubin value obtained in this test are shown in FIG. 1 described later. As is clear from the figure, about 1 leucovorin administration was started.
A marked decrease in total bilirubin was observed after a week.
This state continued during the subsequent administration period. In addition, a marked yellowing effect was observed as the total bilirubin value decreased. In addition, from the fluctuation of the clinical test value of the patient, the therapeutic agent of the present invention further has an inhibitory effect on cholesterol elevation, G
The effect of suppressing the elevation of the OT value and the GTP value was observed, and the effect of improving liver function was also suggested.
【００２０】ＩＩＩ 他剤併用における減黄効果 １．試験方法 再発胃癌のため閉塞性黄疸症状を示す患者９名に対し
て、ロイコボリン２０ｍｇ／ｍ2 を急速静注し、この１
時間後から５−ＦＵ７００ｍｇ／ｍ2 を２時間点滴静注
する。この併用投与を４日間連続して行い、患者の血清
総ビリルビン値を測定して減黄効果を評価した。また、
当該９名のうち既にＰＴＢＤ（経皮経肝胆道ドレナー
ジ）を行っていた６名の患者について、薬剤投与前後の
胆汁***量を測定した。III Yellowing effect in combination with other agents 1. Test method Leucovorin 20 mg / m 2 was rapidly injected intravenously to 9 patients with obstructive jaundice due to recurrent gastric cancer.
After the lapse of time, 5-FU 700 mg / m 2 is intravenously infused for 2 hours. This combined administration was performed for 4 consecutive days, and the serum total bilirubin level of the patient was measured to evaluate the yellowing effect. Also,
Bile excretion before and after drug administration was measured in 6 patients who had already undergone PTBD (percutaneous transhepatic biliary drainage) among the 9 patients.
【００２１】２．結果 ９名の患者の、薬剤投与前の血清総ビリルビン平均値が
１３．８ｍｇ／ｄｌであったのに対して、薬剤投与後は
７．２ｍｇ／ｄｌとなり、薬剤投与により有意に（ｐ＜
０．０１）減黄効果が認められた。また、ＰＴＢＤ処置
を行っていた６名については、薬剤投与前５日間におけ
る胆汁***量の１日平均値が４１３．５ｍｌであったの
に対して、薬剤投与後５日間では７６３．３ｍｌとな
り、薬剤投与により有意に（ｐ＜０．０５）胆汁***量
の増加が認められた。2. Results In 9 patients, the mean serum total bilirubin before drug administration was 13.8 mg / dl, whereas after drug administration was 7.2 mg / dl, which was significantly (p <
0.01) A yellowing effect was recognized. For the 6 patients who were treated with PTBD, the daily bile excretion amount during the 5 days before the drug administration was 413.5 ml, whereas it was 763.3 ml during the 5 days after the drug administration. A significant (p <0.05) increase in biliary excretion was observed after drug administration.
【００２２】［安全性］ロイコボリンが医薬として用い
た場合に十分に安全な薬剤であることは既に知られてい
る。具体的には、マウスに対するＬＤ50値が経口投与で
５０００ｍｇ／ｋｇ以上、静脈内投与で５００〜８００
ｍｇ／ｋｇである。[Safety] It is already known that leucovorin is a sufficiently safe drug when used as a drug. Specifically, the LD 50 value for mice is 5000 mg / kg or more by oral administration and 500-800 by intravenous administration.
mg / kg.
【００２３】［製剤例］１バイアル中にｄｌ−ロイコボ
リン２５ｍｇを粉末のまま充填する。用時、蒸留水約３
〜４ｍｌを添加して注射剤とする。[Formulation Example] One vial is filled with 25 mg of dl-leucovorin as powder. When using, about 3 distilled water
Add ~ 4 ml to make an injection.
【００２４】[0024]
【発明の効果】以上の薬理試験結果から明らかなとお
り、ロイコボリンは閉塞性黄疸に対して極めて有効であ
ることが確認された。したがって、本発明の閉塞性黄疸
治療剤は、従来から行われている外科的ＰＴＢＤ処置に
代わる内科的処置として、現実の臨床の場で極めて有用
である。As is clear from the above pharmacological test results, it was confirmed that leucovorin is extremely effective against obstructive jaundice. Therefore, the therapeutic agent for obstructive jaundice of the present invention is extremely useful in actual clinical situations as a medical treatment in place of the conventional surgical PTBD treatment.
【図１】 ［薬理試験］ＩＩに記載した、ヒトにおける
減黄効果を示すグラフである。FIG. 1 is a graph showing the yellowing effect in humans described in [Pharmacological test] II.
Claims (1)
閉塞性黄疸治療剤1. A therapeutic agent for obstructive jaundice containing leucovorin as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11018694A JPH07291864A (en) | 1994-04-27 | 1994-04-27 | Therapeutic agent for obstructive jaundice |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP11018694A JPH07291864A (en) | 1994-04-27 | 1994-04-27 | Therapeutic agent for obstructive jaundice |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH07291864A true JPH07291864A (en) | 1995-11-07 |
Family
ID=14529231
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP11018694A Ceased JPH07291864A (en) | 1994-04-27 | 1994-04-27 | Therapeutic agent for obstructive jaundice |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH07291864A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6808725B2 (en) | 1996-01-31 | 2004-10-26 | South Alabama Medical Science Foundation | Preparations containing folic acid and a natural isomer of a reduced folate |
| WO2023078435A1 (en) * | 2021-11-05 | 2023-05-11 | 广州市妇女儿童医疗中心 | Application of folic acid in prevention, diagnosis, and treatment of hereditary, infectious, or allergic diseases |
-
1994
- 1994-04-27 JP JP11018694A patent/JPH07291864A/en not_active Ceased
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6808725B2 (en) | 1996-01-31 | 2004-10-26 | South Alabama Medical Science Foundation | Preparations containing folic acid and a natural isomer of a reduced folate |
| US7172778B2 (en) | 1996-01-31 | 2007-02-06 | South Alabama Medical Science Foundation | Food and vitamin preparations containing the natural isomer of reduced folates |
| US7674490B2 (en) | 1996-01-31 | 2010-03-09 | South Alabama Medical Science Foundation | Food and vitamin preparations containing the natural isomer of reduced folates |
| WO2023078435A1 (en) * | 2021-11-05 | 2023-05-11 | 广州市妇女儿童医疗中心 | Application of folic acid in prevention, diagnosis, and treatment of hereditary, infectious, or allergic diseases |
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