JPS63284132A - Agent for reducing side-effect of cisplatin - Google Patents
Agent for reducing side-effect of cisplatinInfo
- Publication number
- JPS63284132A JPS63284132A JP62118678A JP11867887A JPS63284132A JP S63284132 A JPS63284132 A JP S63284132A JP 62118678 A JP62118678 A JP 62118678A JP 11867887 A JP11867887 A JP 11867887A JP S63284132 A JPS63284132 A JP S63284132A
- Authority
- JP
- Japan
- Prior art keywords
- cisplatin
- group
- administration
- agent
- glutathione
- 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.)
- Pending
Links
- DQLATGHUWYMOKM-UHFFFAOYSA-L cisplatin Chemical compound N[Pt](N)(Cl)Cl DQLATGHUWYMOKM-UHFFFAOYSA-L 0.000 title claims abstract description 19
- 229960004316 cisplatin Drugs 0.000 title claims abstract description 19
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 11
- 108010024636 Glutathione Proteins 0.000 claims abstract description 7
- 229960003180 glutathione Drugs 0.000 claims abstract description 7
- 125000000217 alkyl group Chemical group 0.000 claims abstract description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims abstract description 4
- 230000000694 effects Effects 0.000 claims description 21
- 239000004480 active ingredient Substances 0.000 claims description 4
- 125000005907 alkyl ester group Chemical group 0.000 claims description 2
- 239000000126 substance Substances 0.000 claims description 2
- 239000003638 chemical reducing agent Substances 0.000 claims 1
- MVNCPACIPXNJIW-IUCAKERBSA-N (2s)-2-azaniumyl-5-oxo-5-[[(2r)-1-oxo-1-[(2-oxo-2-propan-2-yloxyethyl)amino]-3-sulfanylpropan-2-yl]amino]pentanoate Chemical compound CC(C)OC(=O)CNC(=O)[C@H](CS)NC(=O)CC[C@H](N)C(O)=O MVNCPACIPXNJIW-IUCAKERBSA-N 0.000 abstract description 12
- 108700041175 glutathione monoisopropyl ester Proteins 0.000 abstract description 12
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 abstract description 6
- 150000001875 compounds Chemical class 0.000 abstract description 6
- 239000003795 chemical substances by application Substances 0.000 abstract description 5
- 150000002148 esters Chemical class 0.000 abstract description 4
- 238000002347 injection Methods 0.000 abstract description 4
- 239000007924 injection Substances 0.000 abstract description 4
- 239000000243 solution Substances 0.000 abstract description 3
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000008187 granular material Substances 0.000 abstract description 2
- 239000000843 powder Substances 0.000 abstract description 2
- 238000007911 parenteral administration Methods 0.000 abstract 2
- PNNCWTXUWKENPE-UHFFFAOYSA-N [N].NC(N)=O Chemical compound [N].NC(N)=O PNNCWTXUWKENPE-UHFFFAOYSA-N 0.000 description 7
- 210000002966 serum Anatomy 0.000 description 7
- 241000700159 Rattus Species 0.000 description 5
- 239000002246 antineoplastic agent Substances 0.000 description 5
- 230000000259 anti-tumor effect Effects 0.000 description 4
- -1 organic acid salt Chemical class 0.000 description 4
- 230000004580 weight loss Effects 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 230000037396 body weight Effects 0.000 description 2
- 238000000691 measurement method Methods 0.000 description 2
- 231100000820 toxicity test Toxicity 0.000 description 2
- 230000004584 weight gain Effects 0.000 description 2
- 235000019786 weight gain Nutrition 0.000 description 2
- 125000006218 1-ethylbutyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000005916 2-methylpentyl group Chemical group 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Natural products NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- 230000007059 acute toxicity Effects 0.000 description 1
- 231100000403 acute toxicity Toxicity 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 239000003721 gunpowder Substances 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 125000003187 heptyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 125000004491 isohexyl group Chemical group C(CCC(C)C)* 0.000 description 1
- 239000012669 liquid formulation Substances 0.000 description 1
- 150000002688 maleic acid derivatives Chemical class 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 150000002823 nitrates Chemical class 0.000 description 1
- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000002347 octyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 125000001147 pentyl group Chemical group C(CCCC)* 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 125000003548 sec-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明はシスプラチンの副作用軽減剤に関する。[Detailed description of the invention] (Industrial application field) The present invention relates to an agent for reducing the side effects of cisplatin.
（従来の技術およびその問題点）
従来、数多くの抗腫瘍剤が開発され臨床的に使用されて
きた。これらの抗腫瘍剤においては一般に抗腫瘍作用の
強力なものは副作用も強（。(Prior art and its problems) Conventionally, many antitumor agents have been developed and used clinically. Among these antitumor drugs, those with strong antitumor effects generally also have strong side effects.
また副作用の軽度のものは抗腫瘍作用も劣るという傾向
にあり、確実に抗腫瘍効果を期待しうる抗腫瘍剤はどう
しても副作用を度外視できなかった。このため、各種抗
腫瘍剤の副作用軽減は、抗腫瘍剤を適用するに際し重要
な課題であった。Furthermore, those with mild side effects tend to have poor antitumor effects, so it has been impossible to ignore the side effects of antitumor agents that can be expected to have a reliable antitumor effect. Therefore, reducing the side effects of various antitumor agents has been an important issue when applying antitumor agents.
たとえば、シスプラチン（シスージアミンジクロロプラ
チヌム）は、すぐれた抗腫瘍作用を示す反面、激しい吐
き気・嘔吐を主体とする消化器障害、腎機能障害、造血
障害等の副作用が知られており、これに起因する体重減
少や血清中尿素窒素の増加が報告されている。このよう
有効であることが報告されている（特開昭６１−１２６
０２１号および６０−２８９２８号公報）。For example, although cisplatin (cissudiamindichloroplatinum) exhibits excellent antitumor effects, it is known to have side effects such as gastrointestinal disorders, mainly severe nausea and vomiting, renal dysfunction, and hematopoietic disorders. Elevated weight loss and increased serum urea nitrogen have been reported. It has been reported that it is effective in this way (Japanese Unexamined Patent Publication No. 61-126
021 and 60-28928).
本発明者等は、これらの化合物と化学構造を全く異にす
るグルタチオン モノ アルキルエステル 就中グルタ
チオンモノ イソプロピルエステルがシスプラチンの副
作用軽減に極めて有用であることを見出し本発明を完成
した。The present inventors have completed the present invention by discovering that glutathione mono-alkyl ester, especially glutathione mono-isopropyl ester, which has a completely different chemical structure from these compounds, is extremely useful in reducing the side effects of cisplatin.
グルタチオン モノ アルキルエステルは。Glutathione monoalkyl ester.
グルタチオン（ｒ−Ｌ−グルタミル−し−システイニル
グリシン）のグリシンカルボキシル基におけるモノアル
キルエステルであって、この化合物にシスプラチンの副
作用軽減効果を認めたことは予想外である。This compound is a monoalkyl ester of the glycine carboxyl group of glutathione (r-L-glutamyl-cysteinylglycine), and it was unexpected that this compound was found to be effective in reducing the side effects of cisplatin.
（問題点を解決するための手段）
すなわち本発明は一般式（１）
％式％
（式中Ｒは、アルキル基を意味する゛）で示されるグル
タチオン モノ アルキルエステル又はその塩を有効成
分とするシスプラチンの副作用軽減剤である。(Means for Solving the Problems) That is, the present invention uses as an active ingredient a glutathione monoalkyl ester or a salt thereof represented by the general formula (1) %formula% (wherein R means an alkyl group) It is an agent that reduces the side effects of cisplatin.
ここにＲで示されるアルキル基は炭素数１乃至１０個の
直鎖又は分枝状のものであり、具体的には２例えばメチ
ル基、エチル基、プロピル基、イソプロピル基、ブチル
基、インブチル基。The alkyl group represented by R here is a linear or branched one having 1 to 10 carbon atoms, and specifically includes 2 such as methyl group, ethyl group, propyl group, isopropyl group, butyl group, and inbutyl group. .
ｔｅｒｔ−ブチル基、ペンチル基、インペンチル基。tert-butyl group, pentyl group, impentyl group.
ネオペンチル基、１−メチルブチル基、ヘキシル基、イ
ソヘキシル基、２−メチルペンチル基。Neopentyl group, 1-methylbutyl group, hexyl group, isohexyl group, 2-methylpentyl group.
１−エチルブチル基、ヘプチル基、オクチル基、ノニル
基、デシル基等である。また、その塩としては塩酸塩、
硝酸塩、硫酸塩等の無機塩、あるいは。These include 1-ethylbutyl group, heptyl group, octyl group, nonyl group, and decyl group. In addition, its salts include hydrochloride,
Inorganic salts such as nitrates and sulfates, or.
シュ’７酸塩、ｐｌルエンスルホン酸塩、マレイン酸塩
等の有機酸塩との塩である。It is a salt with an organic acid salt such as a heptacid salt, a pl-luenesulfonate salt, or a maleate salt.
本発明の有効成分の副作用軽減効果および毒性試験等を
以下に説明する。尚、下記実験例で使用したグルタチオ
ン モノ イソプロピル エステル（イソプロピル ｒ
−Ｌ−グルタミル−し−システイニルグリシネート）硫
酸塩は本発明者等の出願に係る特開昭６２−８９６９５
号に記載の方法で製造したものを使用した。The effect of reducing side effects and toxicity tests of the active ingredient of the present invention will be explained below. In addition, glutathione monoisopropyl ester (isopropyl r
-L-glutamyl-cysteinylglycinate) sulfate is disclosed in Japanese Patent Application Laid-Open No. 62-89695 filed by the present inventors.
The product manufactured by the method described in No. 1 was used.
（１） 副作用軽減効果
シスプラチンを投与した場合における体重減少および血
清中尿素窒素の増加の抑制効果を測定方法とともに示す
。(1) Effect of reducing side effects The effect of suppressing weight loss and increase in serum urea nitrogen when cisplatin is administered will be shown together with the measurement method.
（測定方法）
雄のスプラグ−ドーリ−ラット（６週令）にシスプラチ
ン、５１Ｑｇ／ｋｇを腹腔内投与した。投与後４日間の
ラットの体重を測定し、４日目にラットをエーテル麻酔
し工大静脈より採血し、血清尿素窒素値を測定した。(Measurement method) Cisplatin, 51 Qg/kg, was intraperitoneally administered to male Sprague-Dawley rats (6 weeks old). The body weight of the rat was measured for 4 days after administration, and on the 4th day, the rat was anesthetized with ether, blood was collected from the vena cava, and the serum urea nitrogen level was measured.
グルタチオンモノ イソプロピルエステル硫酸塩は３０
０ｍｇ／ｋｇをシスブチン投与当日に投与の３０分前お
よび２時間後の２回、および投与後２−４日に各日１回
腹腔内投与した。Glutathione mono isopropyl ester sulfate is 30
0 mg/kg was intraperitoneally administered twice on the day of cisbutin administration, 30 minutes before and 2 hours after administration, and once each day 2-4 days after administration.
なお、シスプラチンのみを同様に投与し、グルタチオン
モノ イソプロピルエステル硫酸塩を投与しないもの（
対照群）およびシスプラチンおよびグルタチオンモノイ
ソプロピルエステル硫酸塩を共に投与しないもの（正常
群）についても同様に測定した。In addition, cisplatin alone was administered in the same manner, but glutathione monoisopropyl ester sulfate was not administered (
Measurements were made in the same manner for the control group) and the group to which cisplatin and glutathione monoisopropyl ester sulfate were not administered together (normal group).
（結 果）
シスブチンの投与によりラットの体重増加の減少が認め
られた。これに対するグルタチオンモノ イソプロピル
エステルの改善効果を第１図に示す。また、シスプラチ
ン投与による血清尿素窒素値の上昇に対するグルタチオ
ンモノ イソプロピルエステルの改善効果を第２図に示
す。(Results) Administration of cisbutin reduced the weight gain of rats. The improvement effect of glutathione monoisopropyl ester on this is shown in Figure 1. Furthermore, Fig. 2 shows the improving effect of glutathione monoisopropyl ester on the increase in serum urea nitrogen level caused by administration of cisplatin.
この結果グルタチオンモノ イソプロピルエステルは、
シスブチンによる体重抑制及び、血清尿素窒素上昇を顕
著に軽減することが判明した。As a result, glutathione monoisopropyl ester is
It was found that cisbutin-induced body weight suppression and increase in serum urea nitrogen were significantly reduced.
（２）毒性試験
本発明の化合物ＣＩ）またはその塩の急性毒性（ｔ’Ｄ
ｓｏ）は、たとえばイソプロピルエステルの場合、マウ
ス腹腔内注射で、 ５．３ｇ／ｋｇ程度である。(2) Toxicity test Acute toxicity (t'D
For example, in the case of isopropyl ester, the amount is about 5.3 g/kg when intraperitoneally injected into a mouse.
（発明の効果）
上記試験結果から本発明の一般式（Ｉ）で示される化合
物又はその塩を有効成分とする薬剤は。(Effects of the Invention) From the above test results, the drug containing the compound represented by the general formula (I) or a salt thereof of the present invention as an active ingredient.
シスプラチン投与による体重減少及び血清中尿素窒素の
増加を顕著に改善する。従って本発明化合物（Ｉ）は、
シスプラチンにみられる副作用を軽減させることで医療
上極めて有用である。Significantly improves weight loss and increase in serum urea nitrogen caused by cisplatin administration. Therefore, the compound (I) of the present invention is
It is extremely useful medically by reducing the side effects seen with cisplatin.
本発明のグルタチオン モノ アルキルエステル（Ｉ）
又はその塩は７通常用いられる製剤用担体、賦形剤その
他の添加剤を用いて１錠剤、散剤、細粒剤、顆粒剤、カ
プセル剤、火剤、液剤。Glutathione mono alkyl ester (I) of the present invention
or its salt can be prepared into a single tablet, powder, fine granule, granule, capsule, gunpowder, or liquid formulation using commonly used pharmaceutical carriers, excipients, and other additives.
注射剤等に調製され、経口的または非経口的に投与され
る。投与量は、投与ルート、患者の体重１年令、症状等
により適宜調整されるが２通常成人１日当り、経口で１
００ｍｇ乃至１０００ｍｇ、静注で１０ｍ１ｉ乃至数１
００１１１７が適当である。It is prepared into an injection or the like and administered orally or parenterally. The dosage may be adjusted as appropriate depending on the administration route, patient's weight, age, symptoms, etc.2 The usual adult dose is 1 orally per day.
00mg to 1000mg, 10ml to several 1 by intravenous injection
001117 is appropriate.
これを、シスプラチン投与と同時および前後数回に分け
て投与する。以下に注射剤の処方例を示す。This will be administered at the same time as cisplatin administration and in several divided doses before and after administration. Examples of prescriptions for injections are shown below.
（注射剤の処方例）
グルタチオン モノ イソプロピルエステル硫酸塩を４
５ ｍｇ／ｍｌの濃度で精製水に懸濁させ、５００以下
に冷却する。エステル硫酸塩に対し、約２倍モルの炭酸
水素ナトリウムを加えて、エステル硫酸塩を溶解し、溶
液をｐＨ４に調整したのち、＠度を４０ｆｆ！ｇ／ｍＺ
とし、無菌濾過する。バイアル瓶に各２５ｍ７の溶液を
入れ凍結乾燥する。(Example of prescription for injection) Glutathione mono isopropyl ester sulfate 4
Suspend in purified water at a concentration of 5 mg/ml and cool to below 500 ml. Add approximately twice the mole of sodium hydrogen carbonate to the ester sulfate to dissolve the ester sulfate, adjust the solution to pH 4, and then adjust the pH to 40ff! g/mZ
and sterile filter. Pour 25 m7 of each solution into vials and freeze-dry.
第１図は、シスプラチン投与によるラットの体重増加の
減少に対するグルタチオン モノ イソプロピルエステ
ルの軽減効果を示す。
第２図は、シスプラチン投与によるラット血清尿素窒素
上昇に対するグルタチオンモノ イソプロピルエステル
の軽減効果を示す。FIG. 1 shows the alleviating effect of glutathione mono-isopropyl ester on the reduction in weight gain in rats induced by cisplatin administration. FIG. 2 shows the alleviating effect of glutathione monoisopropyl ester on the increase in rat serum urea nitrogen caused by administration of cisplatin.
Claims (3)
オン モノ アルキルエステルまたはその塩を有効成分
とするシスプラチンの副作用軽減剤。(1) A side effect reducing agent for cisplatin whose active ingredient is glutathione mono alkyl ester or its salt represented by the general formula ▲ Numerical formula, chemical formula, table, etc. ▼ (in the formula, R means an alkyl group).
）項記載の軽減剤。(2) Claim No. 1 in which R is a lower alkyl group
).
）項記載の軽減剤。(3) Claim No. 2 in which R is an isopropyl group
).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62118678A JPS63284132A (en) | 1987-05-14 | 1987-05-14 | Agent for reducing side-effect of cisplatin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62118678A JPS63284132A (en) | 1987-05-14 | 1987-05-14 | Agent for reducing side-effect of cisplatin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPS63284132A true JPS63284132A (en) | 1988-11-21 |
Family
ID=14742497
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP62118678A Pending JPS63284132A (en) | 1987-05-14 | 1987-05-14 | Agent for reducing side-effect of cisplatin |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPS63284132A (en) |
-
1987
- 1987-05-14 JP JP62118678A patent/JPS63284132A/en active Pending
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