JPH05213764A - Oxygen radical scavenger - Google Patents
Oxygen radical scavengerInfo
- Publication number
- JPH05213764A JPH05213764A JP1766992A JP1766992A JPH05213764A JP H05213764 A JPH05213764 A JP H05213764A JP 1766992 A JP1766992 A JP 1766992A JP 1766992 A JP1766992 A JP 1766992A JP H05213764 A JPH05213764 A JP H05213764A
- Authority
- JP
- Japan
- Prior art keywords
- glycine
- oxygen radical
- radical scavenger
- solution
- divalent metal
- 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
Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
【０００１】[0001]
【産業上の利用分野】本発明は、生体内で多量に発生し
た有害な酸素ラジカルを捕捉する酸素ラジカル捕捉剤に
関する。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an oxygen radical scavenger which traps harmful oxygen radicals generated in large quantities in the living body.
【０００２】[0002]
【従来の技術およびその問題点】酸素ラジカルは、生体
内組織や臓器への血流が遮断され、組織が低酸素状態と
なった虚血時、および血流が正常に回復した再灌流時に
多量に生成し、このものは組織および臓器に著しい損
傷、即ち虚血時および虚血後組織損傷を与える。有害酸
素ラジカルは、生化学的に異なる２つの起源に発してい
る。2. Description of the Related Art Oxygen radicals are abundant in a large amount during ischemia when the blood flow to tissues and organs in the body is blocked and the tissues become hypoxic, and during reperfusion where blood flow is restored to normal. It produces significant damage to tissues and organs, ie, ischemic and post-ischemic tissue damage. Hazardous oxygen radicals originate from two biochemically different sources.
【０００３】１つはヒポキサンチンからキサンチンへの
キサンチンオキシダーゼによる酵素的変換への副生物と
して、そしてもう１つは、活性化多形核白血球としても
知られる活性化好中球からの代謝産物として多量の酸素
ラジカルが生成する。そこで従来、虚血後組織損傷の治
療剤としてアロプリノールのようなキサンチンオキシダ
ーゼ阻害剤やアプロチニンのような活性化好中球の酸素
ラジカル産生阻害剤が用いられている。[0003] One as a by-product to the enzymatic conversion of hypoxanthine to xanthine by xanthine oxidase, and another as a metabolite from activated neutrophils, also known as activated polymorphonuclear leukocytes. A large amount of oxygen radicals are generated. Therefore, conventionally, xanthine oxidase inhibitors such as allopurinol and oxygen radical production inhibitors of activated neutrophils such as aprotinin have been used as therapeutic agents for post-ischemic tissue damage.
【０００４】しかしながら上述した従来の治療剤は必ず
しも効果が十分ではなく、より有効な治療剤が望まれて
いた。However, the above-mentioned conventional therapeutic agents are not always sufficiently effective, and more effective therapeutic agents have been desired.
【０００５】本発明者等は、生体内で発生する酸素ラジ
カルを捕捉して酸素ラジカルの攻撃から生体組織や臓器
等あるいは体内に投与される医療物質を保護する薬剤を
開発すべく鋭意研究を重ねた結果、本発明を完成したも
のである。The present inventors have earnestly conducted research to develop a drug that traps oxygen radicals generated in the living body and protects medical substances administered to living tissues, organs or the like from the attack of oxygen radicals. As a result, the present invention has been completed.
【０００６】[0006]
【課題を解決するための手段】本発明はグリシン０.１m
M〜１０mMおよび２価金属１nM〜１mMを含む水溶液であ
って、当該水溶液に含まれるグリシンと２価金属とのモ
ル比が１：５×１０-1 0〜１：５０×１０-10である酸素
ラジカル捕捉剤からなる。The present invention provides glycine 0.1 m
An aqueous solution comprising M~10mM and divalent metal 1 nm to 1 mm, the molar ratio of glycine and divalent metal contained in the aqueous solution is 1: 5 × 10 -1 0 ~1 : is 50 × 10 -10 It consists of an oxygen radical scavenger.
【０００７】本発明において、２価金属としては生体に
含まれ、上記の濃度で生理学的に安全なものは全て使用
しうるが、２価のマンガン、銅および亜鉛が特に好適に
使用される。In the present invention, divalent metals contained in the living body and all of which are physiologically safe at the above concentrations can be used, but divalent manganese, copper and zinc are particularly preferably used.
【０００８】本発明においては、水溶液中のグリシンと
２価金属との濃度および両者のモル比が特定の範囲内に
あることが重要である。即ち、グリシンの濃度は、０.
１mM〜１０mM、好ましくは０.５〜２mMである。２価金
属の濃度は、金属の種類にもよるがおよそ１nM〜１mM、
好ましくは１.０〜５.０nMである。そしてグリシンと２
価金属とのモル比はグリシン１に対して２価金属５〜５
０×１０-10、好ましくは１０〜３０×１０-10である。In the present invention, it is important that the concentration of glycine and the divalent metal in the aqueous solution and the molar ratio of both are within a specific range. That is, the concentration of glycine is 0.
It is 1 mM to 10 mM, preferably 0.5 to 2 mM. The concentration of divalent metal depends on the type of metal, but it is approximately 1 nM to 1 mM,
It is preferably 1.0 to 5.0 nM. And 2 with glycine
The molar ratio of the valent metal to the glycine is 5 to 5 divalent metals.
It is 0 × 10 −10 , preferably 10 to 30 × 10 −10 .
【０００９】本発明の溶媒としてはpH値が６.８〜７.２
である生理的溶媒が好ましく、燐酸緩衝液、生理食塩
液、リンゲル液、輸液等が好適に使用される。The solvent of the present invention has a pH value of 6.8 to 7.2.
The physiological solvent is preferably phosphate buffer solution, physiological saline solution, Ringer's solution, infusion solution and the like.
【００１０】本発明の酸素ラジカル捕捉剤は上記の溶媒
に所定の濃度となるようにグリシンおよび２価金属を加
えて均一に混合溶解させることによって製造される。２
価金属は、硫酸塩あるいは塩化物のような水溶性の化合
物の形態で使用される。The oxygen radical scavenger of the present invention is produced by adding glycine and a divalent metal to the above-mentioned solvent to a predetermined concentration and uniformly mixing and dissolving them. Two
The valent metal is used in the form of a water-soluble compound such as sulfate or chloride.
【００１１】本発明の酸素ラジカル捕捉剤は、虚血時お
よび虚血後組織損傷が原因となる種々の疾病の予防およ
び治療に有用である。上記の疾病の例としては、腸、心
筋、脳の虚血および循環系ショック、凍瘡および臓器移
植等が挙げられる。The oxygen radical scavenger of the present invention is useful for the prevention and treatment of various diseases caused by tissue damage during and after ischemia. Examples of the above-mentioned diseases include ischemia of the intestine, myocardium, cerebral ischemia and circulatory shock, frostbite and organ transplantation.
【００１２】本発明の酸素ラジカル捕捉剤をヒトまたは
動物に投与するに際しては、成人１日当たり１００〜１
０００mlの量で静脈内注射により投与される。When the oxygen radical scavenger of the present invention is administered to humans or animals, it is 100 to 1 per day for an adult.
It is administered by intravenous injection in a volume of 000 ml.
【００１３】本発明の酸素ラジカル捕捉剤は、上記の疾
病の予防および治療に使用される他に、酸素ラジカルの
攻撃から保護することが望まれる医療物質、例えば人工
赤血球等の保護液としても使用される。人工赤血球の保
護は、本発明の酸素ラジカル捕捉剤の存在下で赤血球を
マイクロカプセル化することなどによって達成される。The oxygen radical scavenger of the present invention is used not only for the prevention and treatment of the above-mentioned diseases but also as a protective solution for medical substances desired to be protected from the attack of oxygen radicals such as artificial red blood cells. To be done. The protection of artificial red blood cells is achieved by microencapsulating red blood cells in the presence of the oxygen radical scavenger of the present invention.
【００１４】[0014]
【作用】本発明の酸素ラジカル捕捉剤が有害酸素ラジカ
ルを捕捉するメカニズムは明らかではないが、水溶液中
でグリシンと２価金属とで錯体が形成され、グリシンと
２価金属との間の電子の授受の過程で周囲に存在する酸
素ラジカルが捕捉され、消費されるものと推定される。The mechanism by which the oxygen radical scavenger of the present invention traps harmful oxygen radicals is not clear, but a complex is formed between glycine and a divalent metal in an aqueous solution, and an electron between the glycine and the divalent metal is formed. It is presumed that oxygen radicals existing in the surroundings are captured and consumed in the process of transfer.
【００１５】[0015]
【実施例】次に実施例をあげて本発明をさらに具体的に
説明する。 実施例１ 酸素ラジカル捕捉剤の調製 グリシン（ナカライ社製）１.５mgを秤量し、リン酸緩
衝液（pH６.８）に溶解し４mMグリシン液を調製する。
塩化マンガン（ナカライ社製）９９mgを秤量し、リン酸
緩衝液（pH６.８）に溶解、希釈を繰り返して１０nM塩
化マンガン溶液を調製する。４mMグリシン液と１０nM塩
化マンガン液を等量混合し、２nMグリシン−５nMマンガ
ン液を調製する。用時倍希釈とする。EXAMPLES Next, the present invention will be described more specifically with reference to examples. Example 1 Preparation of oxygen radical scavenger 1.5 mg of glycine (manufactured by Nakarai Co., Ltd.) was weighed and dissolved in a phosphate buffer (pH 6.8) to prepare a 4 mM glycine solution.
99 mg of manganese chloride (manufactured by Nakarai Co., Ltd.) is weighed, dissolved in a phosphate buffer (pH 6.8) and diluted repeatedly to prepare a 10 nM manganese chloride solution. Equal amounts of 4 mM glycine solution and 10 nM manganese chloride solution are mixed to prepare 2 nM glycine-5 nM manganese solution. Dilute twice before use.
【００１６】試験例１ イヌ頚静脈より採血し、赤血球と好中球を分離した。赤
血球を１００％酸素でバブリングした後、好中球と合し
た。赤血球４５×１０7／mlおよび好中球２×１０6／ml
を含むリン酸緩衝溶液を調製し、これに１mMグリシンお
よび２.５nMマンガンを加えて検体を作成し、グリシン
およびマンガンを加えないものを対照とした。両者を３
７℃で１５分間加温し、それぞれに好中球活性化物質と
してＰＭＡ（ホルボールミリステートアセテート）６０
ng／mlを加え、０、１５、３０、４５および６０分間、
３７℃で加温し、ジギトニンを加えて反応を停止させ、
産生したメトヘモグロビンをシアンメトヘモグロビン法
によって測定し、得られた値からヘモグロビンのメト化
率を算出した。その結果を図１に示す。図１に示すよう
にグリシンおよびマンガンを加えたものは対照に比して
８０％以上のメト化抑制を示した。これはＰＭＡで活性
化された好中球が産生する過酸化水素をマンガン−グリ
シンが還元することによってヘモグロビンがメトヘモグ
ロビンに変化するのを防止したためである。Test Example 1 Blood was collected from the jugular vein of a dog to separate red blood cells and neutrophils. Red blood cells were bubbled with 100% oxygen and then combined with neutrophils. Red blood cells 45 × 10 7 / ml and neutrophils 2 × 10 6 / ml
Was prepared, and 1 mM glycine and 2.5 nM manganese were added thereto to prepare a sample, and a sample to which glycine and manganese were not added was used as a control. Both 3
PMA (phorbol myristate acetate) 60 was added as a neutrophil activator by heating at 7 ° C for 15 minutes.
ng / ml for 0, 15, 30, 45 and 60 minutes,
Heat at 37 ° C, add digitonin to stop the reaction,
The methemoglobin produced was measured by the cyan methemoglobin method, and the methemoglobin conversion rate was calculated from the obtained values. The result is shown in FIG. As shown in FIG. 1, those to which glycine and manganese were added showed 80% or more inhibition of methemoglobin as compared with the control. This is because manganese-glycine reduced the hydrogen peroxide produced by PMA-activated neutrophils, thereby preventing hemoglobin from being converted to methemoglobin.
【００１７】試験例２ グリシン濃度を１００mM、１０mM、１.０mMまたは０.１
mMとする以外は、試験例１と全く同様にして本発明の酸
素ラジカル捕捉剤による赤血球のメト化率を測定した。
結果を図２に示す。図２から、グリシンの使用濃度は１
０mM〜０.１mMが好ましく、１００mM以上の濃度では逆
にヘモグロビンのメト化を促進することがわかる。Test Example 2 Glycine concentration was 100 mM, 10 mM, 1.0 mM or 0.1
Except for mM, the rate of erythrocyte methation by the oxygen radical scavenger of the present invention was measured in exactly the same manner as in Test Example 1.
The results are shown in Figure 2. From Figure 2, the concentration of glycine used is 1
It is understood that 0 mM to 0.1 mM is preferable, and that a concentration of 100 mM or more conversely promotes the methemoglobin formation.
【００１８】[0018]
【発明の効果】本発明の酸素ラジカル捕捉剤は、生体内
で多量に発生した酸素ラジカルを捕捉し、生体組織や臓
器あるいは体内に投与される医療物質（例えば人工赤血
球）を酸素ラジカルの攻撃から保護する。従って虚血時
虚血後組織損傷の予防または治療剤として、および人工
赤血球の保護液として有用である。Industrial Applicability The oxygen radical scavenger of the present invention traps a large amount of oxygen radicals generated in a living body and attacks a medical substance (for example, artificial red blood cell) administered to a living tissue, an organ or the body from the attack of the oxygen radicals. Protect. Therefore, it is useful as a preventive or therapeutic agent for post-ischemic tissue damage during ischemia and as a protective solution for artificial red blood cells.
【図１】試験例１におけるヘモグロビンのメト化率を経
時的に示したグラフである。FIG. 1 is a graph showing the hemoglobin metation rate in Test Example 1 over time.
【図２】試験例２におけるヘモグロビンのメト化率を経
時的に示したグラフである。FIG. 2 is a graph showing the hemoglobin metation rate in Test Example 2 over time.
Claims (1)
属１nM〜１mMを含む水溶液であって、当該水溶液に含ま
れるグリシンと２価金属とのモル比が１：５×１０-10
〜１：５０×１０-10であることを特徴とする酸素ラジ
カル捕捉剤。1. An aqueous solution containing 0.1 mM to 10 mM of glycine and 1 nM to 1 mM of a divalent metal, wherein the molar ratio of glycine to the divalent metal contained in the aqueous solution is 1: 5 × 10 −10.
˜1: 50 × 10 −10 Oxygen radical scavenger characterized by the above-mentioned.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1766992A JPH05213764A (en) | 1992-02-03 | 1992-02-03 | Oxygen radical scavenger |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1766992A JPH05213764A (en) | 1992-02-03 | 1992-02-03 | Oxygen radical scavenger |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH05213764A true JPH05213764A (en) | 1993-08-24 |
Family
ID=11950265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1766992A Pending JPH05213764A (en) | 1992-02-03 | 1992-02-03 | Oxygen radical scavenger |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH05213764A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021526550A (en) * | 2018-05-25 | 2021-10-07 | オニール・パテル | Methods and compositions for inhibiting harmful injuries |
-
1992
- 1992-02-03 JP JP1766992A patent/JPH05213764A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2021526550A (en) * | 2018-05-25 | 2021-10-07 | オニール・パテル | Methods and compositions for inhibiting harmful injuries |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chevion | Protection against free radical-induced and transition metal-mediated damage: the use of “pull” and “push” mechanisms | |
| Ambrosio et al. | Evidence for a reversible oxygen radical-mediated component of reperfusion injury: reduction by recombinant human superoxide dismutase administered at the time of reflow. | |
| Eagle et al. | Clinical uses of 2, 3—dimercaptopropanol (BAL). I. The systemic treatment of experimental arsenic poisoning (mapharsen, lewisite, phenyl arsenoxide) with BAL | |
| US3930000A (en) | Silver-zinc allantoinate compositions and method of killing bacteria and fungi therewith | |
| WO1998034626A1 (en) | Compounds for reducing ischemia/reperfusion injury | |
| JPS61502893A (en) | absorption enhancer | |
| US6100297A (en) | Intravenous magnesium gluconate for treatment of conditions caused by excessive oxidative stress due to free radical distribution | |
| EP1301181A2 (en) | Therapeutic and prophylactic use of reduced forms of pharmaceutical compounds | |
| US4426372A (en) | Inhibition of undesired effects of platinum(II) compounds | |
| US4594238A (en) | Inhibition of undesired effect of platinum compounds | |
| US4978668A (en) | Treatment to reduce ischemic tissue injury | |
| AU735055B2 (en) | Induction of a cellular stress response with heavy metal salts | |
| Toet et al. | Mercury kinetics in a case of severe mercuric chloride poisoning treated with dimercapto-1-propane sulphonate (DMPS) | |
| US4581224A (en) | Inhibition of undesired effect of platinum compounds | |
| DE10223013A1 (en) | Use of meloxicam for the relief of organ injuries during organ surgery or transplantation | |
| US4107331A (en) | Zinc chelating fungicidal composition | |
| Nagler et al. | Hydrogen cyanide poisoning: treatment with cobalt EDTA | |
| JP4459303B2 (en) | Method of treating disease in mammals resulting from inflammatory reaction and composition thereof | |
| JPH05213764A (en) | Oxygen radical scavenger | |
| JP2008518017A (en) | Method for producing and using synergistic multifunctional composition | |
| JP2515119B2 (en) | Pharmaceutical composition containing a piperazine derivative, which has an active oxygen production suppressing effect and an active oxygen removing effect | |
| Perrin | Medicinal chemistry | |
| Hom et al. | The effects of conjugated deferoxamine in porcine skin flaps | |
| UA58565C2 (en) | Cytoflavin injectional drug possessing cytoprotective properties | |
| MXPA97000967A (en) | Therapeutic use of acetazolamide for the treatment of edema cereb |