JPH08771B2 - Agents for functional deterioration of organs caused by reduced oxygen supply due to blood circulation inhibition and resupply of oxygen due to reperfusion - Google Patents
Agents for functional deterioration of organs caused by reduced oxygen supply due to blood circulation inhibition and resupply of oxygen due to reperfusionInfo
- Publication number
- JPH08771B2 JPH08771B2 JP63271657A JP27165788A JPH08771B2 JP H08771 B2 JPH08771 B2 JP H08771B2 JP 63271657 A JP63271657 A JP 63271657A JP 27165788 A JP27165788 A JP 27165788A JP H08771 B2 JPH08771 B2 JP H08771B2
- Authority
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- Japan
- Prior art keywords
- blood circulation
- reperfusion
- oxygen
- present
- resupply
- 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 - Lifetime
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- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Description
【発明の詳細な説明】 ［産業上の利用分野］ 本発明は臓器の機能低下改善剤に関するものであり、
更に詳しくは、特定の有機ゲルマニウム化合物を有効成
分とする、血行阻害による酸素の供給低下及び再潅流に
よる酸素の再供給に起因する臓器の機能低下改善剤に関
するものである。DETAILED DESCRIPTION OF THE INVENTION [Industrial field of use] The present invention relates to an agent for improving functional deterioration of organs,
More specifically, the present invention relates to an agent for improving functional deterioration of organs, which contains a specific organic germanium compound as an active ingredient and causes a decrease in oxygen supply due to blood circulation inhibition and a resupply of oxygen due to reperfusion.
［従来の技術］ 生体における全ての臓器にとって、それが要求するだ
けの充分な血液が供給されるということは、当該臓器及
びその機能の維持に必要不可欠であり、従って、何らか
の理由により臓器に対する血行が阻害された場合には、
当然のことながら当該臓器及びその機能に大きな障害が
発生することとなる。[Prior Art] It is indispensable for all organs in a living body to be supplied with sufficient blood as required by the organs, and therefore it is essential to maintain the organs and their functions. If is blocked,
As a matter of course, the organ and its function will be seriously impaired.
臓器に対する血行が阻害される例としては、移植のた
めに特定の臓器を生体から分離した場合を代表的なもの
としてあげることができる。A typical example of the inhibition of blood circulation to an organ is a case where a specific organ is separated from a living body for transplantation.
即ち、特に臓器分離と臓器移植とが地理的に離れた場
所で行なわれる場合には、臓器提供者から分離された臓
器は、特殊な保存容器に収容された状態で運搬され、そ
の後に移植されるので、運搬の間、特殊な溶液中で低温
に保たれるとはいっても、その臓器にとって不可欠な血
行が阻害されることは事実であり、程度の問題は別とし
て、その機能が低下することも容易に推測されるのであ
る。That is, especially when the organ separation and the organ transplant are performed at geographically distant places, the organ separated from the organ donor is transported in a state of being housed in a special storage container and then transplanted. Therefore, even if kept at a low temperature in a special solution during transportation, it is a fact that the blood circulation essential for the organ is inhibited, and its function declines, apart from the degree of problem. It is also easy to guess.
尚、血行阻害による臓器の機能低下は、当該臓器に対
し酸素の供給が停止されることにより、経時的に細胞が
変成していくことによるものであるが、そればかりでな
く、血液再潅流時における細胞障害に起因する側面もあ
る。そして、この血液再潅流時における細胞障害は、当
該臓器に対し酸素の供給が停止されている段階で誘起さ
れているといわれている。The function deterioration of the organ due to blood circulation inhibition is due to the morphology of cells over time due to the supply of oxygen to the organ being stopped. There is also an aspect due to cell damage in. It is said that the cell damage at the time of blood reperfusion is induced at the stage when the supply of oxygen to the organ is stopped.
［発明が解決しようとする問題点］ 然し乍ら、従来は血行阻害或いは再潅流により臓器の
機能が低下したような場合であっても、その原因を除去
して機能の自然回復を待つことが行なわれている程度
で、積極的に機能低下を防止したり、或はその回復を図
ったりする方法は存在しなかったのである。[Problems to be Solved by the Invention] However, conventionally, even when the function of an organ is deteriorated due to blood circulation inhibition or reperfusion, it is necessary to eliminate the cause and wait for the natural recovery of the function. However, there was no method to actively prevent the functional deterioration or to recover it.
本発明は上述した従来技術を背景として、血行阻害及
び再潅流による臓器の機能低下に対する効果的な措置を
可能とする薬剤を提供することを目的としてなされた。The present invention has been made in view of the background of the above-mentioned conventional art, and an object thereof is to provide a drug that enables effective measures against functional deterioration of organs due to blood circulation inhibition and reperfusion.
又、本発明の他の目的は、血行阻害の発生した生体の
状態に鑑み、毒性や副作用のない血行阻害及び再潅流に
よる臓器の機能低下改善剤を提供することにある。Another object of the present invention is to provide an agent for improving the function deterioration of organs due to blood flow inhibition and reperfusion, which is free from toxicity and side effects, in view of the state of the body where blood flow inhibition has occurred.
［問題点を解決するための手段］ 上記目的を達成すめために本発明が採用した構成は、
式 （Ge−CH2−CH2−COOH）2O3 ……（１） で表わされる有機ゲルマニウム化合物を有効成分とする
ことを特徴とするものである。[Means for Solving Problems] The configuration adopted by the present invention in order to achieve the above object is as follows.
It is characterized in that the organogermanium compound represented by the formula (Ge-CH 2 -CH 2 -COOH ) 2 O 3 ...... (1) as an active ingredient.
以下に本発明を詳細に説明する。 The present invention will be described in detail below.
本発明の血行阻害及び再潅流による臓器の機能低下改
善剤は上記式（１）で表わされる特定の有機ゲルマニウ
ム化合物を有効成分としているので、まずこの化合物に
ついて説明すると、これはプロピオン酸とゲルマニウム
原子とが結合したゲルミルプロピオン酸を基本骨格と
し、当該基本骨格におけるゲルマニウム原子と酸素原子
とが2:3の割合で結合したものである。Since the agent for improving the function deterioration of organs by blood circulation inhibition and reperfusion of the present invention contains a specific organic germanium compound represented by the above formula (1) as an active ingredient, first, this compound will be explained by referring to propionic acid and germanium atom. The basic skeleton is formed of germanylpropionic acid in which and are bonded, and germanium atoms and oxygen atoms in the basic skeleton are bonded at a ratio of 2: 3.
而して、上記構造の有機ゲルマニウム化合物は様々な
方法により製造することができる。Thus, the organic germanium compound having the above structure can be produced by various methods.
即ち、例えば、下記式反応式に示すように、トリクロ
ルゲルミルプロピオン酸（２）を加水分解すれば良いの
である。That is, for example, as shown in the following reaction formula, trichlorogermylpropionic acid (2) may be hydrolyzed.
上記のようにして得られた有機ゲルマニウム化合物に
ついての核磁気共鳴吸収（NMR）スペクトルや赤外線吸
収（IR）スペクトル等の機器分析の結果は、上記の化合
物が式（１）で示されるものであることを良く支持して
いる 尚、上記の有機ゲルマニウム化合物は、 （Ge−CH2−CH2−COOH）2nO3n 或いは、 ｛（Ge−CH2−CH2−COOH）2O3｝ｎ のように表現することもある。又、水中においては、 のような構造をとるものである。 The results of instrumental analysis such as nuclear magnetic resonance absorption (NMR) spectrum and infrared absorption (IR) spectrum of the organogermanium compound obtained as described above show that the above compound is represented by the formula (1). Note is well supported that, organogermanium compounds described above, (Ge-CH 2 -CH 2 -COOH) 2n O 3n or, {(Ge-CH 2 -CH 2 -COOH) 2 O 3} n of Sometimes expressed as follows. Also, in water, It has a structure like.
本発明の血行阻害及び再潅流による臓器の機能低下改
善剤は、上記のように合成した有機ゲルマニウム化合物
を有効成分としたものであり、その投与形態は経口でも
非経口でも差し支えなく、経口の場合は錠剤や散剤、顆
粒剤等に製剤して投与し、非経口の場合は注射液等とし
て用いれば良い。The agent for improving function deterioration of organs by blood circulation inhibition and reperfusion of the present invention is an organic germanium compound synthesized as described above as an active ingredient, and its administration form may be oral or parenteral, and in the case of oral administration May be formulated into tablets, powders, granules, etc. and administered. When parenteral, it may be used as an injection solution or the like.
本発明の有効成分である有機ゲルマニウム化合物は、
毒性が極めて低く、且つ、副作用がほとんど無いことを
特徴としているため、投与量は広い範囲に及ぶものであ
るが、１〜200mg/kg/dayという範囲を例示することがで
きる。The organic germanium compound which is the active ingredient of the present invention,
Since the toxicity is extremely low and there are almost no side effects, the dose is in a wide range, and the range of 1 to 200 mg / kg / day can be exemplified.
［発明の作用及び効果］ 以上説明した本発明剤は、血行阻害による急性腎不全
等、血行阻害及び再潅流による臓器の機能低下を迅速且
つ効果的に改善することができるものであり、マウスを
人工的に温阻血性急性腎不全として投与してみると、腎
機能の迅速な回復が認められたのである。[Operations and Effects of the Invention] The agent of the present invention described above is capable of rapidly and effectively ameliorating the function deterioration of organs due to blood circulation inhibition and reperfusion, such as acute renal failure due to blood circulation inhibition. When artificially administered as warm ischemic acute renal failure, rapid recovery of renal function was observed.
而して、血行が阻害された状態では、各種代謝産物の
供給および除去も阻害されるが、上記本発明の効果は、
血行が阻害され、各種代謝産物の供給および除去も阻害
された状態では、当該臓器を通常状態にきわめて近い状
態に維持し得ることをも意味するものといえる。Thus, in the state where blood circulation is inhibited, supply and removal of various metabolites are also inhibited, but the effect of the present invention is
It can be said that in a state where blood circulation is inhibited and supply and removal of various metabolites are also inhibited, the organ can be maintained in a state very close to a normal state.
又、本発明剤の投与タイミングを種々変化させてみる
と、人工的に温阻血性急性腎不全としたマウスに対し、
血流再開前に投与した場合が最も効果的であることが判
明しており、従って、本発明剤は、一旦分離され、阻血
状態（酸素欠乏状態）にある臓器を移植する際、阻血に
よる臓器組織のダメージと、血流再開によって当該臓器
に与えられる負担乃至はダメージを低下させる作用を有
するものでもあるということができる。In addition, when the administration timing of the agent of the present invention was variously changed, it was found that the artificially warm ischemic acute renal failure was observed in mice.
It has been found that it is most effective when administered before resumption of blood flow. Therefore, the agent of the present invention is isolated once, and when transplanting an organ in ischemic state (oxygen deficient state), It can be said that it also has an effect of reducing the damage to the tissue and the burden or damage given to the organ by resumption of blood flow.
［実施例］ 以下に本発明を実施例により説明する。[Examples] The present invention will be described below with reference to Examples.
実施例１ （１）方 法 雄のSDラット（280〜320g）をネンブタールにより麻
酔し、正中開腹した後、左側の腎の動脈を45分間クラン
プして血流を止めることにより、可逆性の温阻血性急性
腎不全を作成し、同時に右側の腎臓を摘出した。Example 1 (1) Method Male SD rats (280 to 320 g) were anesthetized with Nembutal, and after performing a midline laparotomy, the left renal artery was clamped for 45 minutes to stop the blood flow, thereby reversing the temperature. We created ischemic acute renal failure and simultaneously removed the right kidney.
一方、本発明剤としての化合物（１）30mgを含む溶液
を、クランプ直前及びクランプ解除直前に静脈内に投与
し、これに対し生理食塩水0.5mlのみを静脈内に投与し
たものをコントロールとした。On the other hand, a solution containing 30 mg of the compound (1) as the agent of the present invention was intravenously administered immediately before clamping and immediately before unclamping, whereas 0.5 ml of physiological saline was intravenously administered as a control. .
そして、クランプ解除後24時間目から48時間目にか
け、更に72時間目から96時間目にかけて、ラットを代謝
ケージに入れ、24時間にわたり採尿を行なった。Then, from 24 hours to 48 hours after unclamping, and from 72 hours to 96 hours, the rat was placed in a metabolic cage and urine was collected for 24 hours.
又、クランプ解除後24,48,72時間目に採血を行い、96
時間後に屠殺した。Blood was collected at 24, 48 and 72 hours after unclamping and 96
It was slaughtered after hours.
（２）結 果 第１図に示すように、45分間の温阻血により血清クレ
アチニン値は大きく上昇し、腎機能の著しい低下が認め
られ、24〜48時間後にピークをむかえた。(2) Results As shown in FIG. 1, serum creatinine level was significantly increased by warm ischemia for 45 minutes, and renal function was markedly decreased, and peaked after 24-48 hours.
この腎機能の低下は７日後には温阻血前の値に復して
おり、可逆性の急性腎不全であることが判る。This decrease in renal function returned to the value before warm ischemia after 7 days, which indicates reversible acute renal failure.
そして、第２図に示すように、本発明剤を投与した群
においては、BUN（尿素窒素）、Ｓ・CRTN（血清クレア
チニン）及びFENa（ナトリウム再吸収率）がいずれも対
象群に比較して有意に低下しており、又、Ｃ・CRTN（ク
レアチニンクリアランス）は対象群に比較して有意に上
昇しており、いずれも本発明剤の投与により腎機能の悪
化が軽減されていることが認められたのである。Then, as shown in FIG. 2, in the group administered with the agent of the present invention, BUN (urea nitrogen), S.CRTN (serum creatinine) and FENa (sodium reabsorption rate) were all compared to the control group. Significantly decreased, and C / CRTN (creatinine clearance) was significantly increased compared to the control group, and it was confirmed that administration of the agent of the present invention alleviated deterioration of renal function. It was done.
実施例２ （１）方法 実施例１の方法と同様とし、唯、本発明剤をクランプ
直前及びクランプ解除直前の２回にわたって投与するの
ではなく、一回投与とし、クランプ直前に投与する群と
クランプ解除直前に投与する群とに分けた。Example 2 (1) Method Same as in the method of Example 1, except that the agent of the present invention was administered once instead of twice before the clamping and immediately before the unclamping, and was administered immediately before the clamping. It was divided into a group to be administered immediately before unclamping.
（２）結果 第３図に示すように、クランプ直前に投与した群では
96時間経過後にBUN,S・CRTが対照群に比較して有意に低
下したが、クランプ解除直前に投与した群では48時間経
過後からBUN,S・CRTが対象群に比較して有意に低下し
た。(2) Results As shown in Fig. 3, in the group administered immediately before the clamp,
BUN, S, CRT decreased significantly after 96 hours compared to the control group, but BUN, S, CRT decreased significantly after 48 hours in the group administered immediately before unclamping compared to the control group did.
又、Ｃ・CRTは、対照群及びクランプ直前投与群に比
較して、クランプ解除直前投与群が有意に上昇した。Further, C / CRT was significantly increased in the administration group immediately before unclamping, as compared with the control group and the administration group immediately before the clamp.
実施例３ （１）方法 10Kg前後の雑種成犬を全身麻酔下で開腹し、左腎を遊
離した後、化合物（１）の1mg/Kgを含む本発明剤と、ヘ
パリンカルシウム100IU/Kgとを同時に静注し、その後に
腎動脈を30分間クランプすることにより、当該腎に対し
温阻血を与えた。Example 3 (1) Method A mixed-breed dog of about 10 kg was subjected to laparotomy under general anesthesia to release the left kidney, and then the agent of the present invention containing 1 mg / Kg of the compound (1) and 100 IU / Kg of heparin calcium. At the same time, intravenous infusion was performed, and then the renal artery was clamped for 30 minutes to give warm ischemia to the kidney.
その後、当該腎を摘出し、ただちに、マンニトール、
ヘパリン、リドカイン及びフロセミドを含むユーロコリ
ンズ液（商品名）で落差灌硫し、48時間及び72時間保存
し、左大腿部に自家移植した。Then, the kidney was removed and immediately mannitol,
It was subjected to head drop vulcanization with a Eurocollins solution (trade name) containing heparin, lidocaine and furosemide, preserved for 48 hours and 72 hours, and autologously transplanted to the left thigh.
一方、対側健腎は、１週間後に摘出し、その後２−３
日間隔で採血して、経過を看た。On the other hand, the contralateral healthy kidney was removed one week later and then 2-3
Blood was collected at daily intervals to monitor the progress.
（２）結果 30分間の温阻血を与えられた後にユーロコリンズ液中
で48時間保存され、移植された群では、５頭中の２頭が
共に尿毒症により１週間以内に死亡した。(2) Results After being given warm ischemia for 30 minutes and preserved in Euro-Collins solution for 48 hours, in the transplanted group, 2 out of 5 dogs both died within 1 week due to uremia.
一方、化合物（１）を含む本発明剤と、ヘパリンカル
シウムとを同時に静注した後に30分間の温阻血を与えら
れ、ユーロコリンズ液中で48時間保存されて移植された
群では、10週間後でも５頭中の５頭が生存し、又、同様
にユーロコリンズ液中で72時間保存されて移植された群
では、10週間後でも２頭中の２頭が生存した。On the other hand, in the group transplanted after being intravenously infused at the same time with the agent of the present invention containing the compound (1) and heparin calcium for 30 minutes in warm ischemia, and preserved in Euro-Collins solution for 48 hours, and transplanted, However, 5 out of 5 animals survived, and similarly, in the group transplanted after being preserved for 72 hours in Euro-Collins solution, 2 out of 2 animals survived even after 10 weeks.
又、化合物（１）を含む本発明剤と、ヘパリンカルシ
ウムとを同時に静注した群においては、Ｓ・CRTN（血清
クレアチニン）の値も低値であった。Moreover, in the group in which the agent of the present invention containing the compound (1) and heparin calcium were simultaneously intravenously injected, the value of S.CRTN (serum creatinine) was also low.
本発明は以上のとおりであるから、血行阻害及び再潅
流による臓器の機能低下改善に有効なものということが
できる。Since the present invention is as described above, it can be said that the present invention is effective for improving the functional deterioration of organs due to blood circulation inhibition and reperfusion.
第１図は温阻血により腎機能が低下する様子を示すグラ
フ、第２図は本発明剤の投与により腎機能の悪化が改善
される様子を示すグラフ、第３図は本発明剤の投与タイ
ミングとそれによる効果との関係を示すグラフである。FIG. 1 is a graph showing that renal function is decreased by warm ischemia, FIG. 2 is a graph showing that deterioration of renal function is improved by administration of the agent of the present invention, and FIG. 3 is timing of administration of the agent of the present invention. It is a graph which shows the relationship between it and the effect by it.
Claims (1)
ことを特徴とする血行阻害による酸素の供給低下及び再
潅流による酸素の再供給に起因する臓器の機能低下改善
剤。1. A decrease in oxygen supply and a re-supply of oxygen due to blood circulation inhibition, which comprises an organic germanium compound represented by the formula (Ge—CH 2 —CH 2 —COOH) 2 O 3 (1) as an active ingredient. An agent for improving functional deterioration of organs caused by resupply of oxygen by perfusion.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63271657A JPH08771B2 (en) | 1987-10-29 | 1988-10-27 | Agents for functional deterioration of organs caused by reduced oxygen supply due to blood circulation inhibition and resupply of oxygen due to reperfusion |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP62-273747 | 1987-10-29 | ||
| JP27374787 | 1987-10-29 | ||
| JP63271657A JPH08771B2 (en) | 1987-10-29 | 1988-10-27 | Agents for functional deterioration of organs caused by reduced oxygen supply due to blood circulation inhibition and resupply of oxygen due to reperfusion |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH01193218A JPH01193218A (en) | 1989-08-03 |
| JPH08771B2 true JPH08771B2 (en) | 1996-01-10 |
Family
ID=26549819
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63271657A Expired - Lifetime JPH08771B2 (en) | 1987-10-29 | 1988-10-27 | Agents for functional deterioration of organs caused by reduced oxygen supply due to blood circulation inhibition and resupply of oxygen due to reperfusion |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH08771B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP5405701B2 (en) * | 2000-05-09 | 2014-02-05 | 株式会社浅井ゲルマニウム研究所 | Oral administration or injection for improving red blood cell deformability |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5936998B2 (en) * | 1981-11-16 | 1984-09-06 | 隆一 佐藤 | organic germanium polymer |
| JPH0662407B2 (en) * | 1984-12-25 | 1994-08-17 | 株式会社三和化学研究所 | Immunomodulator containing stabilized 3-oxygermylpropionic acid polymer as an active ingredient |
-
1988
- 1988-10-27 JP JP63271657A patent/JPH08771B2/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| JPH01193218A (en) | 1989-08-03 |
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