JP2770175B2 - Kidney protective liquid - Google Patents
Kidney protective liquidInfo
- Publication number
- JP2770175B2 JP2770175B2 JP63239697A JP23969788A JP2770175B2 JP 2770175 B2 JP2770175 B2 JP 2770175B2 JP 63239697 A JP63239697 A JP 63239697A JP 23969788 A JP23969788 A JP 23969788A JP 2770175 B2 JP2770175 B2 JP 2770175B2
- Authority
- JP
- Japan
- Prior art keywords
- kidney
- solution
- renal
- phosphoenolpyruvate
- protective liquid
- 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 - Fee Related
Links
Description
【発明の詳細な説明】 （産業上の利用分野） 本発明は阻血状態にある腎臓の壊死を防ぐ腎臓の庇護
液に関する。Description: FIELD OF THE INVENTION The present invention relates to a kidney protection solution for preventing necrosis of an ischemic kidney.
（従来の技術及び解決すべき課題） 近年、腎臓疾患患者に対して人工透析による治療法以
外に腎臓移植或は腎手術の問題がクローズアップされて
きている。腎臓移植或は腎手術の際に最も重要な問題の
一つは、長時間の阻血状態における腎臓の組織、細胞の
庇護である。すなわち、酸素の供給が停止した状態の腎
臓を壊死させることなく、移植手術が完了したときや再
び血液を循環したとき、腎臓が正常な働きを行なうよう
にすることである。(Prior Art and Problems to Be Solved) In recent years, problems of kidney transplantation or renal surgery other than a treatment method using artificial dialysis for a kidney disease patient have been highlighted. One of the most important problems in kidney transplantation or renal surgery is the protection of kidney tissues and cells during prolonged ischemia. That is, without necrosis of the kidney in a state where the supply of oxygen is stopped, the kidney performs a normal operation when the transplant operation is completed or when blood is circulated again.
このように、出来るだけ阻血時間を長くしても、再び
正常な働きを行なうようにするためには、阻血状態前に
腎臓に十分にエネルギーを供給して賦活しておくことが
考えられる。そのため、腎臓細胞の膜を透過する高エネ
ルギー物質を腎臓に与えていることが肝要である。Thus, even if the ischemia time is made as long as possible, it is conceivable that sufficient energy is supplied to the kidney and activated before the ischemic state in order to perform the normal operation again. Therefore, it is important to provide the kidney with a high-energy substance that penetrates the membrane of kidney cells.
従来、このような目的としてリン酸やブドウ糖が用い
られているが、高エネルギー物質としては不十分であ
る。他方、細胞の生存に必要なアデノシン−５′−トリ
フォスフェート（ATP）は、腎臓細胞膜を透過しないた
め、これを直接腎臓に与えて細胞を賦活することはでき
ない。この点を改良する目的で、ATPにホスホエノール
ピルビン酸塩を添加した組成物として与えることは知ら
れている（特表明58−502208号公報参照） ところで、本発明者は先に、虚血状態による酸素不足
のために惹起される心筋梗塞や腎不全の治療にATPの生
合成前駆体であるホスホエノールピルビン酸（PEP）が
有効であることを見出したが（特願昭61−64744号参
照）、更に研究の結果、PEPを含有する晶質液にて腎臓
を灌流し、この液を腎臓内に満たした状態でおくと、そ
の後の阻血状態の腎に対して庇護効果を有することを見
出し、本発明を完成するに至ったもので、本発明の目的
は、腎臓の庇護液を提供するにある。Conventionally, phosphoric acid and glucose have been used for such a purpose, but are insufficient as high energy substances. On the other hand, adenosine-5'-triphosphate (ATP), which is necessary for cell survival, does not penetrate the kidney cell membrane, and thus cannot be directly supplied to the kidney to activate the cells. For the purpose of improving this point, it is known to give ATP a composition obtained by adding phosphoenolpyruvate (see Japanese Patent Publication No. 58-502208). ATP biosynthesis precursor phosphoenolpyruvate (PEP) was found to be effective in the treatment of myocardial infarction and renal failure caused by oxygen deficiency caused by oxygen (see Japanese Patent Application No. 61-64744). ) And further studies have shown that perfusing the kidney with a crystalline fluid containing PEP and filling the kidney with this fluid has a protective effect on subsequent ischemic kidneys. The present invention has been completed, and an object of the present invention is to provide a protective liquid for kidney.
（課題を解決するための手段） 本発明は、高エネルギー化合物としてホスホエノール
ピルビン酸の生理学的に許容しうる水溶性塩のみを含有
する晶質液よりなる腎臓の庇護液である。(Means for Solving the Problems) The present invention is a kidney protecting solution comprising a crystalline liquid containing only a physiologically acceptable water-soluble salt of phosphoenolpyruvate as a high energy compound.
本発明の腎臓の庇護液とは腎手術等における体内で阻
血状態にある腎臓の組織、細胞を保護するに止まらず、
腎移植のために摘出されて腎臓を保存するために使用す
る薬液を言うのである。The kidney protective solution of the present invention is not limited to protecting kidney tissues and cells that are ischemic in the body during renal surgery or the like,
It is a drug solution that is removed for kidney transplantation and used to preserve the kidney.
そして、ホスホエノールピルビン酸とは、下記の構造
式を有する化合物である。And phosphoenolpyruvate is a compound having the following structural formula.
式中、R1は水素原子又は炭素数１〜12個を有するアル
キル基を表わし、R2及びR3はそれぞれ独立に水素原子、
アルカリ金属又は炭素数１〜12個を有するアルキル基を
表わす。具体的には、R1はメチル基、ｎ−プロピル基、
イソプロピル基、ｎ・ブチル基、イソブチル基、sec・
ブチル基等である。又、R2又はR3がアルカリ金属である
場合、具体的にはナトリウム又はカリウム等である。 In the formula, R 1 represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms, R 2 and R 3 each independently represent a hydrogen atom,
Represents an alkali metal or an alkyl group having 1 to 12 carbon atoms. Specifically, R 1 is a methyl group, an n-propyl group,
Isopropyl group, n-butyl group, isobutyl group, sec.
And a butyl group. When R 2 or R 3 is an alkali metal, it is specifically sodium or potassium.
しかしながら、ホスホエノールピルビン酸は通常、ホ
スホエノールピルビン酸ナトリウム又はカリウム水和物
として入手できるので、ナトリウム又はカリウム塩水和
物を用いるのが好ましい。However, phosphoenolpyruvate is usually available as sodium or potassium phosphoenolpyruvate, so it is preferred to use sodium or potassium salt hydrate.
ホスホエノールピルビン酸を添加する晶質液としては
生理食塩水、リンゲル液などであり、リンゲル液として
は、乳酸リンゲル液などが好ましい。Crystalline liquids to which phosphoenolpyruvate is added include physiological saline and Ringer's solution, and Ringer's liquid is preferably lactated Ringer's solution.
晶質液中に添加するホスホエノールピルビン酸の濃度
としては、0.01〜10％であり、好ましくは、0.2〜４％
である。10％以上では、賦活状態が通常の場合より極め
て高い状態となるために好ましくなく、また、0.001％
以下では、その効果が認められない。そして、ホスホエ
ノールピルビン酸を添加した晶質液よりなる庇護液は約
5.5〜８のpHを有する。The concentration of phosphoenolpyruvate added to the crystalline liquid is 0.01 to 10%, preferably 0.2 to 4%.
It is. If it is 10% or more, the activation state becomes extremely higher than usual, which is not preferable, and 0.001%
Below, the effect is not recognized. And the protective liquid consisting of crystalline liquid to which phosphoenolpyruvate is added is about
It has a pH of 5.5-8.
本発明に係る庇護液には、更にマニトールなど二単糖
やグリセロールを添加してもよい。The protective liquid according to the present invention may further contain a disaccharide such as mannitol or glycerol.
次に実施例をもって、本発明を具体的に説明する。 Next, the present invention will be specifically described with reference to examples.
実施例１ 下記の組成を有する庇護液を製造する。Example 1 A protective liquid having the following composition is produced.
PEP−Na塩を１％になるように乳酸リンゲル液（市販
品）にとかす。この庇護液100mlで腎を灌流する。この
庇護液を持って腎臓の阻血状態にある腎機能を正常の腎
機能とを比較する。Dissolve PEP-Na salt in Ringer's lactate solution (commercially available) to 1%. The kidney is perfused with 100 ml of this protective liquid. With this protective liquid, renal function in the ischemic state of the kidney is compared with normal renal function.
方法としては、雑種成犬５匹を用い、右腎はその儘と
し、左腎に90分間の温阻血を加えた。すなわち、最初の
10分間は左腎動脈に挿入したカテーテルから37℃の上記
組成を有する庇護液を灌流液として腎臓を灌流し、残り
の80分間は左腎動脈の遮断を行い、腎内に灌流液を満た
した状態とした。また、他の雑種成犬５匹を用い、同様
の温阻血を加えた後、灌流液として乳酸リンゲル液を使
用した場合を比較例とした。虚血前と一週間後の分腎機
能をイヌリンクリアランス及びパラアミノ馬尿酸クリア
ランスを比較し、その結果を図示すると第１図及び第２
図のようになる。また、イヌリンクリアランス及びパラ
アミノ馬尿酸クリアランスの阻血前後の変化率を示すと
第１表及び第２表のようになる。As a method, five mongrel dogs were used, the right kidney was left as it was, and the left kidney was subjected to warm ischemia for 90 minutes. That is, the first
For 10 minutes, the kidney was perfused from a catheter inserted into the left renal artery with a protective solution having the above composition at 37 ° C. as a perfusate, and for the remaining 80 minutes, the left renal artery was blocked, and the renal perfusion was filled with renal fluid State. In addition, a comparative example was obtained in which five other mongrel dogs were subjected to the same warm ischemia, and Ringer's lactate solution was used as a perfusate. Comparison between inulin clearance and paraaminohippurate clearance before and after one week of ischemia, and the results are shown in FIG. 1 and FIG.
It looks like the figure. Tables 1 and 2 show the rates of change in inulin clearance and paraaminohippuric acid clearance before and after ischemia.
これらの結果より、PEPを含む乳酸リンゲル液で左腎
を灌流した雑犬群では、左腎のクレアチニンクリアラン
ス値及びパラアミノ馬尿酸クリアランス値の機能低下は
有意的に抑制され、左腎の機能低下に伴って起る右腎の
代償性機能亢進の程度は小さい。これに対し、PEPを含
まない乳酸リンゲル液を灌流した雑犬群では、左腎の機
能低下が著しく、それに伴って右腎の代償性機能亢進が
著しい。 From these results, in the dog group in which the left kidney was perfused with Lactated Ringer's solution containing PEP, the decline in creatinine clearance and paraaminohippurate clearance in the left kidney was significantly suppressed, and with the decline in the function of the left kidney The degree of compensatory hyperactivity of the right kidney that occurs is small. In contrast, in the dog group perfused with Ringer's lactate solution containing no PEP, the function of the left kidney was markedly reduced, and the compensatory function of the right kidney was markedly increased.
又、FENa及びFEkの値を調べた結果を第３表及び第４
表に示す。Tables 3 and 4 show the results of examining the values of FENa and FEk.
It is shown in the table.
以上の結果より、PEP含有乳酸リンゲル液を灌流液と
して使用した雑犬群は単に乳酸リンゲル液を灌流液を使
用した雑犬群に比してFENa及びFEkの値の増加は大幅に
抑制され、腎機能の劣化を有意義的に抑制されることが
理解できる。即ち、PEP含有乳酸リンゲル液は腎阻血に
対して明らかに腎庇護作用をもっている。 From the above results, the increase in the values of FENa and FEk was significantly suppressed in the dog group using PEP-containing lactated Ringer's solution as a perfusate compared to the dog group using Lactated Ringer's solution alone as the perfusate, and renal function It can be understood that the deterioration of is significantly suppressed. That is, PEP-containing lactated Ringer's solution clearly has a renal protective effect on renal ischemia.
（効果） 以上述べたように、晶質液中にPEPを添加した液を灌
流液とすることによって腎機能低下が有意に制御され
た。結論としては、PEPを添加した晶質液によって、虚
血性腎障害に庇護効果を持つ事が明らかになった。(Effects) As described above, renal function decline was significantly controlled by using a solution obtained by adding PEP to the crystalline fluid as the perfusate. In conclusion, it has been clarified that the crystalline fluid containing PEP has a protective effect on ischemic renal injury.
第１図及び第２図は本発明に係る庇護液を灌流液として
使用した場合、温阻血前後のイヌリンクリアランス及び
パラアミノ馬尿酸クリアランス血クリアランスの変化を
乳酸リンゲル液を灌流液として使用した場合と比較して
示す。各図におけるａは本発明に係る庇護液の場合、ｂ
は乳酸リンゲル液の場合である。FIGS. 1 and 2 show changes in inulin clearance and blood clearance of paraaminohippurate before and after warm ischemia when the protective liquid according to the present invention was used as a perfusion solution and when blood lactate Ringer's solution was used as a perfusion solution. Shown. A in each figure is the case of the protective liquid according to the present invention, b
Is the case of Ringer's lactate solution.
Claims (3)
ピルビン酸の生理学的に許容しうる水溶性塩のみを含有
する晶質液よりなる腎臓の庇護液。1. A kidney protecting solution comprising a crystalline liquid containing only a physiologically acceptable water-soluble salt of phosphoenolpyruvate as a high energy compound.
項記載の腎臓の庇護液。2. The method according to claim 1, wherein the crystalline liquid is Ringer's lactate.
The protective liquid for kidney according to the item.
度が0.01〜10％の範囲である請求項第１項記載の腎臓の
庇護液。3. The renal protective solution according to claim 1, wherein the concentration of the water-soluble salt of phosphoenolpyruvate is in the range of 0.01 to 10%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63239697A JP2770175B2 (en) | 1988-09-27 | 1988-09-27 | Kidney protective liquid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63239697A JP2770175B2 (en) | 1988-09-27 | 1988-09-27 | Kidney protective liquid |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH0288501A JPH0288501A (en) | 1990-03-28 |
| JP2770175B2 true JP2770175B2 (en) | 1998-06-25 |
Family
ID=17048575
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP63239697A Expired - Fee Related JP2770175B2 (en) | 1988-09-27 | 1988-09-27 | Kidney protective liquid |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JP2770175B2 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB9624188D0 (en) * | 1996-11-21 | 1997-01-08 | Itc Research Limited | Pharmaceutical formulations |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE8200252L (en) * | 1982-01-18 | 1983-07-19 | Pharmacia Ab | PHARMACEUTICAL COMPOSITION |
-
1988
- 1988-09-27 JP JP63239697A patent/JP2770175B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0288501A (en) | 1990-03-28 |
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