JPH0755905B2 - Liver disease treatment agent - Google Patents
Liver disease treatment agentInfo
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- JPH0755905B2 JPH0755905B2 JP16839686A JP16839686A JPH0755905B2 JP H0755905 B2 JPH0755905 B2 JP H0755905B2 JP 16839686 A JP16839686 A JP 16839686A JP 16839686 A JP16839686 A JP 16839686A JP H0755905 B2 JPH0755905 B2 JP H0755905B2
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- liver
- carbon tetrachloride
- present
- compound
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Description
【発明の詳細な説明】 ＜産業上の利用分野＞ 本発明は肝臓疾患治療剤に関する。DETAILED DESCRIPTION OF THE INVENTION <Industrial field of application> The present invention relates to a therapeutic agent for liver diseases.
更に詳しくは２−フェニル−1,2−ベンズイソセレナゾ
ール−３（2H）−オン（以下、本発明対象化合物と称
す）またはその生理学的に許容されうる塩を含有する肝
臓疾患治療剤に関する。More specifically, it relates to a therapeutic agent for liver diseases containing 2-phenyl-1,2-benzisoselenazol-3 (2H) -one (hereinafter referred to as the compound of the present invention) or a physiologically acceptable salt thereof.
＜従来技術＞ 肝臓は生命の維持には必須の最大臓器であり、その主機
能として解毒作用、糖、蛋白質、脂質の貯蔵および代謝
を営んでいる。<Prior Art> The liver is the largest organ essential for sustaining life, and its main functions are detoxification, storage of sugars, proteins, and lipids and metabolism.
この精密な機能を営む肝臓は常にアルコール、ウィル
ス、薬物（毒物）など種々の障害因子にさらされてお
り、栄養不良などの状況下では急性の肝細胞および機能
障害を惹き起すことがある。また慢性的には脂肪肝、そ
れらの終末像としての肝硬変などの疾患として表われ
る。The liver, which performs this precise function, is constantly exposed to various damaging factors such as alcohol, viruses, drugs (poisonous substances), and may cause acute hepatocyte and dysfunction under conditions such as malnutrition. It is chronically manifested as a disease such as fatty liver and cirrhosis as the terminal image thereof.
従来、臨床試験で効果を確認された主な肝臓疾患治療剤
を大別すると １） 肝水解物・肝抽出液 ２） 含硫化合物製剤 ３） トリテルペン環構造体、ステロイド環構造体 ４） 淡白合成促進剤 ５） その他（アデノシントリフォスフェート、プロト
ポルフィリンナトリウムなど） となる。The major therapeutic agents for liver diseases that have been confirmed to be effective in clinical trials are broadly classified as follows: 1) Liver hydrolyzate / liver extract 2) Sulfur-containing compound preparation 3) Triterpene ring structure, steroid ring structure 4) Light-white synthesis Accelerator 5) Others (adenosine triphosphate, protoporphyrin sodium, etc.).
これらはいずれも優れた肝臓疾患治療剤であり臨床的に
も使用され治療に貢献している。しかしながら、近年、
肝臓疾患の成因および病態解析が進み、それにともない
作用機序の明確度、さらに有用性の高い、すなわち肝細
胞および機能障害の抑制効果が明確であり、かつ副作用
の少ない肝臓疾患治療剤の開発が期待されている。All of these are excellent liver disease therapeutic agents and are clinically used to contribute to the treatment. However, in recent years
As the etiology and pathological state of liver disease progresses, the development of a therapeutic agent for liver disease with a clear degree of action mechanism and higher utility, that is, a clear inhibitory effect on hepatocytes and dysfunction and less side effects, is advanced. Is expected.
＜発明が解決しようとする問題点＞ 本発明者らは新規肝臓疾患治療剤を開発すべく鋭意研究
した結果、本発明の対象化合物が、実験的肝障害モデル
の肝細胞壊死および機能障害を明確に改善し、虚血再潅
流モデルの脂質過酸化の主成亢進を抑制することを認
め、種々の因子による肝臓疾患の予防・治療剤として優
れたものであることを見出し本発明を完成した。<Problems to be Solved by the Invention> As a result of intensive studies conducted by the present inventors to develop a novel therapeutic agent for liver disease, the target compound of the present invention clearly shows hepatocellular necrosis and dysfunction in an experimental liver injury model. The present invention was completed and the present invention was completed, finding that it is an excellent prophylactic / therapeutic agent for liver diseases caused by various factors, while it was confirmed to suppress the main promotion of lipid peroxidation in ischemia-reperfusion model.
なお、本発明対象化合物は、グルタチオンペルオキシダ
ーゼ様作用抗酸化および抗炎症作用を呈することが知ら
れている。The compound of the present invention is known to exhibit glutathione peroxidase-like action, antioxidant action and anti-inflammatory action.
〔バイオケミカル ファーマコロジーVol.33 No.20 P32
41−3245.（1984），〕 しかしながら、これらの作用は肝臓疾患治療および予防
に直接結びつくものではない。[Biochemical Pharmacology Vol.33 No.20 P32
41-3245. (1984),] However, these effects are not directly linked to the treatment and prevention of liver diseases.
＜発明の構成＞ 本発明対象化合物の有用性は下記の試験方法により確認
した。<Structure of Invention> The usefulness of the compound of the present invention was confirmed by the following test methods.
マウス四塩化炭素急性肝障害モデルに対する作用 四塩化炭素は肝細胞の広範な壊死、機能の障害を惹起す
る代表的な化合物であり、肝障害発症機序の研究および
薬物の効果判定に最も繁用されており、肝薬物代謝酵素
によりトリクロロラジカル（CCl3ラジカル）に変化し肝
障害を惹き起すと言われる。Effect on mouse carbon tetrachloride acute liver injury model Carbon tetrachloride is a typical compound that causes widespread necrosis and functional impairment of hepatocytes, and is most frequently used for studying the mechanism of liver injury and determining the effect of drugs. It is said that it is converted into trichloro radical (CCl 3 radical) by hepatic drug-metabolizing enzyme and causes liver damage.
本発明の対象化合物を四塩化炭素急性肝障害マウスに経
口投与した場合、四塩化炭素による肝細胞壊死の指標で
あるGOT（グルタミック、オキザルアセテック、トラン
スアミネース）およびGPT（グラタミック、ピルビッ
ク、トランスアミネース）値の上昇を明確に抑制した。When the target compound of the present invention is orally administered to carbon tetrachloride acute liver injury mice, it is an indicator of hepatocyte necrosis due to carbon tetrachloride, GOT (glutamic, oxal acetec, transaminase) and GPT (glatamic, pyruvic, trans). Aminase) value increase was clearly suppressed.
ラットガラクトサミン肝炎モデルに対する作用 ガラクトサミンはヒトの慢性肝炎の病体に似た炎症性反
応をともなった散在性の壊死を惹き起す化合物であり、
肝炎モデルとして良く用いられ、ウリジンの合成阻害、
エンドトキセミアなどがその発症に関係すると考えられ
ている。Effect on rat galactosamine hepatitis model Galactosamine is a compound that causes disseminated necrosis with an inflammatory response similar to that of human chronic hepatitis.
Often used as a hepatitis model, it inhibits uridine synthesis,
It is thought that endotoxemia and the like are involved in the onset.
本発明の対象化合物をガラクトサミン肝炎ラットに経口
投与した場合、ガラクトサミンによる肝細胞崩死の指標
であるGOTおよびGPT値の上昇を著明に抑制した。When the subject compound of the present invention was orally administered to galactosamine hepatitis rats, the increase in GOT and GPT values, which are indicators of hepatocellular necrosis due to galactosamine, was significantly suppressed.
ラット四塩化炭素慢性肝障害モデルに対する作用 四塩化炭素による急性肝障害についてはすでに述べた
が、この化合物は反復投与することによって慢性肝障害
モデルの作成が可能であり、慢性肝障害モデルに対する
効果をしらべるのに用いられる。Action on rat carbon tetrachloride chronic liver injury model Although the acute liver injury caused by carbon tetrachloride has already been described, this compound can produce a chronic liver injury model by repeated administration, and its effect on the chronic liver injury model is shown. It is used for searching.
本発明の対象化合物を、四塩化炭素の反復投与により作
成した慢性肝障害モデルに経口投与した場合、肝細胞壊
死の指標であるGOT値の上昇、胆道系障害の指標であるA
LP（アルカリンフォスファターゼ）値の上昇、LDH（ラ
クテイトデヒドロゲナーゼ）活性の上昇、コレステロー
ル合成の低下に対していずれも明確な改善を示した。When the subject compound of the present invention is orally administered to a chronic liver injury model prepared by repeated administration of carbon tetrachloride, an increase in GOT value, which is an index of hepatocyte necrosis, is an index of biliary tract disorder.
All of them showed clear improvement in the increase of LP (alkaline phosphatase) level, the increase of LDH (lactate dehydrogenase) activity and the decrease of cholesterol synthesis.
各肝障害モデルにおける病理組織学的検査 肝障害モデルに対する効果をしらべるには先に述べたGO
T,ALP値、コレステロール量などの血清生化学的項目の
検査とともに病理組織学的検査も重要である。Histopathological examination in each liver injury model To examine the effect on the liver injury model, the GO described above was used.
Histopathological examination is important as well as examination of serum biochemical items such as T, ALP level and cholesterol level.
四塩化炭素急性肝障害モデルの小葉中心性の肝細胞壊
死、ガラクトサミン肝炎ラットの炎症をともなった散在
性の肝細胞壊死および四塩化炭素慢性肝障害ラットの肝
細胞壊死、脂肪変性の所見に対し、本発明の対象化合物
を経口投与した場合、部位的に限局され、かつ程度も軽
減されており、病理組織学的な改善像を観察した。For the findings of centrilobular hepatocyte necrosis in a carbon tetrachloride acute liver injury model, disseminated hepatocyte necrosis with inflammation in galactosamine hepatitis rats, and hepatocyte necrosis and steatosis in carbon tetrachloride chronic liver injury rats, When the subject compound of the present invention was orally administered, it was locally localized and the degree was reduced, and the histopathological improvement image was observed.
ラット肝虚血・再潅流モデルの脂質過酸化の生成亢
進に対する作用 肝臓に限らず、脂質過酸化の生成亢進は各臓器障害に引
きがねまたは障害の増悪因子として注目されており、脂
質過酸化の抑制または除去剤の研究が進められている。Effect of rat liver ischemia / reperfusion model on the promotion of lipid peroxidation Not only in the liver, the promotion of lipid peroxidation has been attracting attention as a factor that causes or damages various organ damages. Studies on the inhibitor or scavenger are underway.
本発明の対象化合物を、肝虚血・再潅流ラットに経口投
与した場合、脂質過酸化の指標である肝マロンジアルデ
ハイドの生成亢進を抑制した。When the subject compound of the present invention was orally administered to rats with hepatic ischemia / reperfusion, it inhibited the increase in hepatic malondialdehyde formation, which is an index of lipid peroxidation.
毒性 本発明の対象化合物の毒性は、マウスおよびラットに経
口および腹腔内投与で検討した結果、後記LD50（mg/k
g）値で示されている通り極めて低毒性のものであり、
又高用量投与時の所見として、副作用的に問題となるも
のは認められなかった。Toxicity The toxicity of the target compound of the present invention was examined by oral and intraperitoneal administration in mice and rats, and as a result, LD 50 (mg / k
g) It has extremely low toxicity as indicated by the value,
As for the findings at the time of high dose administration, no side effects were found.
本発明の対象化合物を肝臓疾患治療のために投与するに
際しての投与量は経口投与の場合成人１日量として通常
約100〜600mg程度と実験成績から考えられる。It is considered from experimental results that the dose of the subject compound of the present invention to be administered for the treatment of liver disease is usually about 100 to 600 mg as an adult daily dose in the case of oral administration.
また非経口投与の場合は成人１日量として30〜120mgが
好ましいと考えられる。In the case of parenteral administration, the daily dose for adults is considered to be preferably 30 to 120 mg.
投与に際しては公知の製剤法により任意の剤型、例え
ば、カプセル剤、錠剤、散剤ならびにシロップ、アンプ
ル剤等に加工して使用することが可能である。Upon administration, it can be processed into any dosage form by a known formulation method, for example, capsules, tablets, powders, syrups, ampoules and the like for use.
又、本剤の薬理特性を活かすには症状にあった他剤との
併用が可能であり、他剤との併用により相加、相乗の効
果が期待できる。Further, in order to take advantage of the pharmacological properties of this drug, it can be used in combination with other drugs depending on the condition, and by using it together with other drugs, additive and synergistic effects can be expected.
＜発明の効果＞ 本発明対象化合物は動物実験により肝臓障害改善に関わ
る種々の薬理作用を有し、安全性、副作用の面で優れる
ことが判明した。<Effects of the Invention> The compound of the present invention has been proved by animal experiments to have various pharmacological actions relating to the improvement of liver damage and to be excellent in safety and side effects.
すなわち、本発明対象化合物は各種肝障害モデルにおけ
る肝細胞壊死、肝機能障害、脂質過酸化に対する改善効
果から、種々の原因によって生ずるヒトの急性または慢
性の肝炎、脂肪肝および肝硬変の予防および治療剤とし
て有用である。That is, the compound of the present invention is a preventive and / or therapeutic agent for human acute or chronic hepatitis, fatty liver and cirrhosis caused by various causes from hepatocyte necrosis in various liver injury models, liver dysfunction, and improving effect on lipid peroxidation. Is useful as
実施例 1.マウス四塩化炭素急性肝障害モデルの血清GOTおよびG
PT値に対する作用 実験方法 体重30〜35gのSlc−ddy系雄性マウスを用いた。四塩化
炭素はオリーブ油混液（1:99）とし、四塩化炭素量とし
て200μ/kg皮下投与（0.2ml/10g）した。本発明対象
化合物は0.5％カルボキシメチルセルロースナトリウム
水溶液に懸濁して、四塩化炭素投与前１時間に経口投与
（0.2ml/10g）した。四塩化炭素投与後24時間にエーテ
ル麻酔下に下大静脈から採血し、3000rpmで15分間血清
を遠心分離した。肝細胞壊死の指標として血清GOTおよ
びGPT値を生化学分析装置（ギルフォードIMPACT400）を
用いて測定した。数値は各群（１群７匹）における個々
の動物値の平均値±標準誤差で表示した。Example 1. Serum GOT and G in a mouse carbon tetrachloride acute liver injury model
Effect on PT value Experimental method Slc-ddy male mice weighing 30 to 35 g were used. Carbon tetrachloride was mixed with olive oil (1:99), and the amount of carbon tetrachloride was 200 μ / kg subcutaneously administered (0.2 ml / 10 g). The compound of the present invention was suspended in a 0.5% sodium carboxymethylcellulose aqueous solution and orally administered (0.2 ml / 10 g) 1 hour before the administration of carbon tetrachloride. Twenty-four hours after the administration of carbon tetrachloride, blood was collected from the inferior vena cava under ether anesthesia, and the serum was centrifuged at 3000 rpm for 15 minutes. Serum GOT and GPT levels were measured using a biochemical analyzer (Gilford IMPACT400) as indicators of hepatocyte necrosis. The numerical values are expressed as the average value ± standard error of the individual animal values in each group (7 animals per group).
実験成績 2.ラットガラクトサミン肝炎モデルの血清GOTおよびGPT
値に対する作用 実験方法 体重160〜180gのSlc:SD系雄性ラットを用いた。ガラク
トサミンは生理食塩液に溶解して、800mg/kg皮下投与
（0.5ml/100g）した。本発明対象化合物は0.5％カルボ
キシメチルセルロースソデウム水溶液に懸濁して、ガラ
クトサミン投与前１時間に経口投与（0.5ml/100g）。ガ
ラクトサミン投与後48時間にエーテル麻酔下に下大静脈
から採血し、3000rpmで15分間血清を遠心分離した。肝
細胞壊死の指標として血清GOTおよびGPT値を生化学分解
装置（ギルフォードIMPACT400）を用いて測定した。数
値は各群（１群６匹）における個々の動物値の平均値±
標準誤差で表示した。Experimental results 2. Serum GOT and GPT of rat galactosamine hepatitis model
Effect on Value Experimental method Male Slc: SD rats with a body weight of 160 to 180 g were used. Galactosamine was dissolved in physiological saline and subcutaneously administered at 800 mg / kg (0.5 ml / 100 g). The compound of the present invention is suspended in a 0.5% aqueous carboxymethylcellulose sodium solution and orally administered (0.5 ml / 100 g) 1 hour before the administration of galactosamine. Forty-eight hours after the administration of galactosamine, blood was collected from the inferior vena cava under ether anesthesia, and the serum was centrifuged at 3000 rpm for 15 minutes. Serum GOT and GPT levels were measured using a biochemical digester (Gilford IMPACT400) as an index of hepatocyte necrosis. Values are mean ± of individual animal values in each group (6 animals per group)
Displayed with standard error.
実験成績 3.ラット四塩化炭素慢性肝障害モデルの血清GOT,ALP
値、LDH活性およびコレステロール合成に対する作用 実験方法 体重200〜230gのslc:SD系雄性ラットを用いた。四塩化
炭素はオリーブ油混液（1:1）とし、四塩化炭素量とし
て1.5ml/kgを背部皮下に週２回２週間（計４回）投与
（0.3ml/100g）した。本発明対象化合物は0.5％カルボ
キシメチルセルロースソデウム（CMC）水溶液に懸濁し
て、四塩化炭素投与前日から12日間（日曜日は除く）経
口投与（0.5ml/100g）し、対照群には0.5CMC水溶液を投
与した。本発明対象化合物の最終投与後48時間にエーテ
ル麻酔下に下大静脈から採血し、3000rpmで15分間血清
を遠心分離した。肝細胞壊死の指標として血清GOT値、
胆管障害の指標としてのALP値およびLDH活性、コレステ
ロール量を生化学分析装置（ギルフォードIMPACT400）
を用いて測定した。数値は各群（１群８匹）における個
々の動物値の平均値±標準誤差で表示した。Experimental results 3. Serum GOT, ALP of rat carbon tetrachloride chronic liver injury model
Value, Action on LDH activity and cholesterol synthesis Experimental method Male slc: SD rats weighing 200 to 230 g were used. Carbon tetrachloride was mixed with olive oil (1: 1), and 1.5 ml / kg of carbon tetrachloride was subcutaneously administered to the back twice a week for 2 weeks (four times in total) (0.3 ml / 100 g). The compound of the present invention was suspended in 0.5% carboxymethylcellulose sodium (CMC) aqueous solution and orally administered (0.5 ml / 100 g) for 12 days (excluding Sunday) from the day before carbon tetrachloride administration, and 0.5 CMC aqueous solution was used for the control group. Was administered. Forty-eight hours after the final administration of the compound of the present invention, blood was collected from the inferior vena cava under ether anesthesia, and serum was centrifuged at 3000 rpm for 15 minutes. Serum GOT level as an indicator of hepatocyte necrosis,
Biochemical analyzer (Gilford IMPACT400) for ALP level, LDH activity and cholesterol level as indicators of bile duct disorders
Was measured using. The numerical values are expressed as the average value ± standard error of the individual animal values in each group (8 animals per group).
実験成績 4.各肝障害モデルにおける病理組織学的所見に対する作
用 実験方法 各肝障害動物をエーテル麻酔下に採血後、肝臓を摘出し
て10％リン酸緩衝ホルマリン溶液に浸し固定した。固定
後肝臓の一部分を切り出し、パラフィン包装、薄切標本
を作成した。ヘマトキシリン、エオジン（H.E.）染色を
施し、鏡検した。Experimental results 4. Effect on histopathological findings in each hepatic disorder model Experimental method Each hepatic disorder animal was subjected to blood sampling under ether anesthesia, and the liver was excised and immersed in a 10% phosphate buffered formalin solution and fixed. After fixation, a part of the liver was cut out, wrapped in paraffin, and a thin section sample was prepared. Hematoxylin and eosin (HE) staining was performed and microscopic examination was performed.
実験成績 四塩化炭素急性肝障害マウスでは小葉中心性の肝細胞壊
死を認めるが、本発明の対象化合物を経口投与（30およ
び100mg/kg）した場合、部位的に限局され、かつその程
度も軽減されていた。Experimental results: Carbon tetrachloride acute hepatic injury mice show centrilobular hepatocyte necrosis, but when the target compound of the present invention is orally administered (30 and 100 mg / kg), it is locally localized and its degree is also reduced. It had been.
ガラクトサミン肝炎ラットでは、炎症をともなった散在
性の肝細胞浸潤および壊死を認めるが、本発明の対象化
合物を経口投与（30および100mg/kg）した場合、炎症の
程度は軽減され、肝細胞の壊死もほとんど認めなかっ
た。In galactosamine hepatitis rats, scattered hepatocyte infiltration and necrosis with inflammation are observed, but when the target compound of the present invention is orally administered (30 and 100 mg / kg), the degree of inflammation is reduced and hepatocyte necrosis. Was hardly admitted.
四塩化炭素慢性肝障害ラットでは肝細胞の水種様性変性
細胞壊死および脂肪変性を認めるが、本発明の対象化合
物を経口投与（100および300mg/kg）した場合、これら
の変化は部位的に限られたものとなり、かつそれらの程
度は軽減されていた。Water-like degenerative cellular necrosis of hepatocytes and steatosis are observed in rats with carbon tetrachloride chronic liver injury, but when the target compound of the present invention is orally administered (100 and 300 mg / kg), these changes are localized. They were limited and their degree was reduced.
5.ラット肝虚血・再潅流モデルの脂質過酸化の生成に対
する作用 実験方法 体重250〜350gのslc:SD系雄性ラットをイナクチン（80m
g/kg）腹腔内投与で麻酔して使用した。肝の外側左葉お
よび中間葉への門脈枝および肝動脈枝を１時間結紮して
肝虚血状態を惹起した。結紮１時間後に結紮を解除して
虚血肝を再潅流し、再潅流２時間後に肝臓を摘出、脂質
過酸化の指標として肝組織中のマロンジアルデハイド量
を測定した。マロンジアルデハイドはチオバルビツール
酸との縮合物を比色定量した。DR−3305は0.5％カルボ
キシメチルセルロースソデウム水溶液に懸濁して、結紮
前１時間に経口投与した。数値は各群における個々の肝
臓のマロンアルジハイド値の平均値±標準誤差で表示し
た。5. Effect of rat liver ischemia / reperfusion model on the production of lipid peroxidation Experimental method Male slc: SD rats weighing 250-350 g were treated with inactin (80 m
g / kg) Anesthetized by intraperitoneal administration before use. The portal vein branch and hepatic artery branch to the lateral left lobe and middle lobe of the liver were ligated for 1 hour to induce hepatic ischemia. The ligation was released 1 hour after the ligation, and the ischemic liver was reperfused, and the liver was removed 2 hours after the reperfusion, and the amount of malondialdehyde in the liver tissue was measured as an index of lipid peroxidation. Malondialdehyde was determined by colorimetric determination of its condensate with thiobarbituric acid. DR-3305 was suspended in a 0.5% aqueous carboxymethylcellulose sodium solution and orally administered 1 hour before ligation. Numerical values were expressed as the average value ± standard error of the malon aldihydrate value of individual livers in each group.
実験成績 6.急性毒性 動物種 投与経路 LD50（mg/kg） マウス p.o. ＞6810 i.p. 740 ラット p.o. ＞6810 i.p. 580Experimental results 6. Acute toxicity Animal species Route of administration LD 50 (mg / kg) Mouse po ＞ 6810 ip 740 Rat po ＞ 6810 ip 580
Claims (1)
ール−３（2H）−オンまたはその生理学的に許容されう
る塩を含有する肝臓疾患治療剤1. A therapeutic agent for liver diseases containing 2-phenyl-1,2-benzisoselenazol-3 (2H) -one or a physiologically acceptable salt thereof.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16839686A JPH0755905B2 (en) | 1986-07-17 | 1986-07-17 | Liver disease treatment agent |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP16839686A JPH0755905B2 (en) | 1986-07-17 | 1986-07-17 | Liver disease treatment agent |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPS6327431A JPS6327431A (en) | 1988-02-05 |
| JPH0755905B2 true JPH0755905B2 (en) | 1995-06-14 |
Family
ID=15867340
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP16839686A Expired - Fee Related JPH0755905B2 (en) | 1986-07-17 | 1986-07-17 | Liver disease treatment agent |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0755905B2 (en) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2553434B2 (en) * | 1992-04-28 | 1996-11-13 | 第一製薬株式会社 | Granular formulation |
| ES2145065T3 (en) | 1993-10-27 | 2000-07-01 | Daiichi Seiyaku Co | GRANULAR PREPARATION. |
| AU3457300A (en) | 1999-03-31 | 2000-10-16 | Daiichi Pharmaceutical Co., Ltd. | Substrates for thioredoxin reductase |
| US10058542B1 (en) | 2014-09-12 | 2018-08-28 | Thioredoxin Systems Ab | Composition comprising selenazol or thiazolone derivatives and silver and method of treatment therewith |
-
1986
- 1986-07-17 JP JP16839686A patent/JPH0755905B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPS6327431A (en) | 1988-02-05 |
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|---|---|---|---|
| LAPS | Cancellation because of no payment of annual fees |