JPS6023084B2 - 代用血液 - Google Patents
代用血液Info
- Publication number
- JPS6023084B2 JPS6023084B2 JP54087910A JP8791079A JPS6023084B2 JP S6023084 B2 JPS6023084 B2 JP S6023084B2 JP 54087910 A JP54087910 A JP 54087910A JP 8791079 A JP8791079 A JP 8791079A JP S6023084 B2 JPS6023084 B2 JP S6023084B2
- Authority
- JP
- Japan
- Prior art keywords
- hemoglobin
- polyethylene glycol
- mol
- moles
- molecular weight
- 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
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
- C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
- C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
- C08G65/32—Polymers modified by chemical after-treatment
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/08—Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/795—Porphyrin- or corrin-ring-containing peptides
- C07K14/805—Haemoglobins; Myoglobins
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
- C08L71/00—Compositions of polyethers obtained by reactions forming an ether link in the main chain; Compositions of derivatives of such polymers
- C08L71/02—Polyalkylene oxides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Description
【発明の詳細な説明】
本発明は、修飾ヘモグロビンを酸素運搬物質として含有
する新規代用血液に関する。
する新規代用血液に関する。
従来、代用血液に使用する酸素運搬物質として膜成分を
含まないヘモグロビンを用いることは公知である(S.
F.Rabine「 et.al、J.Ex.Med.
、126、1142(1967))。
含まないヘモグロビンを用いることは公知である(S.
F.Rabine「 et.al、J.Ex.Med.
、126、1142(1967))。
ところが、ヘモグロビンは血管内に注入されると速やか
に腎臓あるいは肝臓等から代謝されることが知られてい
る。この問題を解決するためにヘモグロビンをグルタル
アルデヒドで相互結合させたもの(持閥昭51−639
20号公報)、ヘモグロビンをデキストラン(特開昭5
2一51016号公報)若し〈はヒドロキシェチル澱粉
(西独公開2616086号)に結合せしめたものに提
案された。しかしこれらのものは例えば前者は酸素親和
性が強すぎるために末梢組織での酸素の受け渡しが行わ
れにくく、また後者は粘度が高いためにヘモグロビン濃
度を上げると好ましくない結果をもたらす場合が多い。
本発明者は、ヘモグ。
に腎臓あるいは肝臓等から代謝されることが知られてい
る。この問題を解決するためにヘモグロビンをグルタル
アルデヒドで相互結合させたもの(持閥昭51−639
20号公報)、ヘモグロビンをデキストラン(特開昭5
2一51016号公報)若し〈はヒドロキシェチル澱粉
(西独公開2616086号)に結合せしめたものに提
案された。しかしこれらのものは例えば前者は酸素親和
性が強すぎるために末梢組織での酸素の受け渡しが行わ
れにくく、また後者は粘度が高いためにヘモグロビン濃
度を上げると好ましくない結果をもたらす場合が多い。
本発明者は、ヘモグ。
ビンと同程度の酸素運搬能力を有し、その血管内滞留時
間が十分長い代用血液用酸素運搬物質を開発すべく鋭意
検討した結果、ヘモグロビンと、ポリエチレングリコー
ル、ポリプロピレングリコールまたはエチレングリコー
ループロピレングリコール−共重合体との結合物(以下
、「疹節ヘモグロビン」という。)がその目的を達成す
ることを見出し本発明を完成した。前記ポリエチレング
リコール、ポリプロピレングリコールおよびエチレング
リコーループロピレングリコール共重合体は本明細書に
おいてモノメチルエーテル、モノセチルエーテル、モノ
オレイルェーテル等炭素数1乃至16のアルコールによ
るエーテル化物、モノブチルェステル、モノステァリル
ェステル等炭素数2乃至18の脂肪酸類によるェステル
化物、プロピルアミン、ステアリルアミン等炭素数1乃
至18のァミン類による脱水ァミノ化物をも含む。これ
ら重合物を以下単に「本発明に使用する重合体」という
。本発明に使用する修飾ヘモグロビンは、生体内に存す
るヘモグロビンと安全性の高い本発明に使用する重合体
との結合物であるので安全な物質であり、酸素親和性が
へモグ。
間が十分長い代用血液用酸素運搬物質を開発すべく鋭意
検討した結果、ヘモグロビンと、ポリエチレングリコー
ル、ポリプロピレングリコールまたはエチレングリコー
ループロピレングリコール−共重合体との結合物(以下
、「疹節ヘモグロビン」という。)がその目的を達成す
ることを見出し本発明を完成した。前記ポリエチレング
リコール、ポリプロピレングリコールおよびエチレング
リコーループロピレングリコール共重合体は本明細書に
おいてモノメチルエーテル、モノセチルエーテル、モノ
オレイルェーテル等炭素数1乃至16のアルコールによ
るエーテル化物、モノブチルェステル、モノステァリル
ェステル等炭素数2乃至18の脂肪酸類によるェステル
化物、プロピルアミン、ステアリルアミン等炭素数1乃
至18のァミン類による脱水ァミノ化物をも含む。これ
ら重合物を以下単に「本発明に使用する重合体」という
。本発明に使用する修飾ヘモグロビンは、生体内に存す
るヘモグロビンと安全性の高い本発明に使用する重合体
との結合物であるので安全な物質であり、酸素親和性が
へモグ。
ピンと同程度またはやや弱いために体内での酸素の受け
渡し1こは好ましく、また血管内滞留時間もヘモグロビ
ンの2〜4倍にのび、代用血液に用いるのに好ましい化
合物である。特に、ポリエチレングリコールと蛋白との
結合物は蛋白の抗原性を消失させ得ることが知られてお
り(芦原、他、化学の領域、33(1)、44(197
9))、本発明に使用する修飾ヘモグロビンは血管内に
おいて抗原となるおそれのない安全性の高い物質である
。本発明に使用するヘモグロビンはヒト、ウシ、ブタ、
ヒツジ、ウマ、イヌ、サル、ウサギ、ニワトリ等ヘモグ
ロビンを有する動物であればいずれであっても差支えな
い。
渡し1こは好ましく、また血管内滞留時間もヘモグロビ
ンの2〜4倍にのび、代用血液に用いるのに好ましい化
合物である。特に、ポリエチレングリコールと蛋白との
結合物は蛋白の抗原性を消失させ得ることが知られてお
り(芦原、他、化学の領域、33(1)、44(197
9))、本発明に使用する修飾ヘモグロビンは血管内に
おいて抗原となるおそれのない安全性の高い物質である
。本発明に使用するヘモグロビンはヒト、ウシ、ブタ、
ヒツジ、ウマ、イヌ、サル、ウサギ、ニワトリ等ヘモグ
ロビンを有する動物であればいずれであっても差支えな
い。
ヘモグロビンに結合する本発明に使用する重合体の分子
量は300〜20000、性能および粘度の点で好まし
くは750〜5000である。
量は300〜20000、性能および粘度の点で好まし
くは750〜5000である。
ヘモグロビンと本発明に使用する重合体とはどのような
方法により結合させてもよく、例えば臭化シアン等の縮
合剤を用いて直接に結合させたり、あるいは塩化シアヌ
ル、2・2′ージクロロベンジジン、P・P′−ジフル
オローm・m′−ジニトロジフエニルスルフオン、2・
4−ジクロロニトロベンゼン等の化学結合剤により結合
させればよい。
方法により結合させてもよく、例えば臭化シアン等の縮
合剤を用いて直接に結合させたり、あるいは塩化シアヌ
ル、2・2′ージクロロベンジジン、P・P′−ジフル
オローm・m′−ジニトロジフエニルスルフオン、2・
4−ジクロロニトロベンゼン等の化学結合剤により結合
させればよい。
ヘモグロビン1分子当り、本発明に使用する重合体は4
〜15び分子程度が結合している。
〜15び分子程度が結合している。
本発明に使用する修飾ヘモグロビンは、例えば次の如く
して調製することができる。{1} ポリエチレングリ
コールと2〜5倍モル好ましくは3倍モルの臭化シアン
とをpH9〜10で反応させた後ゲル猿週、透析等の方
法により臭化シアンを除去する。
して調製することができる。{1} ポリエチレングリ
コールと2〜5倍モル好ましくは3倍モルの臭化シアン
とをpH9〜10で反応させた後ゲル猿週、透析等の方
法により臭化シアンを除去する。
得られた物質にpH7〜9好まし〈は7.5〜8で水溶
液中1/I0〜1/50の音好ましくは1/10ぴ音モ
ル程度のヘモグロビンとを反応せしめる。‘21 過剰
の炭酸ソーダを含むベンゼンにポリエチレングリコール
を加え、これと2〜5倍モル好ましくは3〜4倍モルの
塩化シアヌルとを反応させ生成したポリエチレングリコ
ール−4・6−ジクロル−S−トIJァジンを分離する
。
液中1/I0〜1/50の音好ましくは1/10ぴ音モ
ル程度のヘモグロビンとを反応せしめる。‘21 過剰
の炭酸ソーダを含むベンゼンにポリエチレングリコール
を加え、これと2〜5倍モル好ましくは3〜4倍モルの
塩化シアヌルとを反応させ生成したポリエチレングリコ
ール−4・6−ジクロル−S−トIJァジンを分離する
。
pH8〜9.5の緩衝液中ポリエチレングリコールー4
・6−ジクロル−S−トリアジンと1〜1/50の音モ
ル好ましくは1/10〜1/10M音モルのヘモグロビ
ンとを反応せしめる。上記調製法は、ポリエチレングリ
コールに代えてポリプロピレングリコールまたはエチレ
ングリコーループロピレングリコール共重合体を用いて
も、同様に実施することが可能である。
・6−ジクロル−S−トリアジンと1〜1/50の音モ
ル好ましくは1/10〜1/10M音モルのヘモグロビ
ンとを反応せしめる。上記調製法は、ポリエチレングリ
コールに代えてポリプロピレングリコールまたはエチレ
ングリコーループロピレングリコール共重合体を用いて
も、同様に実施することが可能である。
以下実施例により本発明を詳細に説明する。
実施例 1ポリエチレングリコ−ルモノメチルエーテル
(平均分子量750)2.5夕(0.003モル)を4
0の‘の水に溶解し、これに5の‘のジキオサンに溶解
した1夕(0.0095モル)の臭化シアンを氷冷化滴
下した。州NaOHによりPH9〜10に保ちつつ1時
間縄拝を続けた。INHCIによりpH7.5に調製し
たのち分子量50瓜阻止のメンブランにより限外濠週を
行った。20の‘まで濃縮したのちpH7.5のリン酸
緩衝液300の‘を加え再度20Mまで濃縮した。
(平均分子量750)2.5夕(0.003モル)を4
0の‘の水に溶解し、これに5の‘のジキオサンに溶解
した1夕(0.0095モル)の臭化シアンを氷冷化滴
下した。州NaOHによりPH9〜10に保ちつつ1時
間縄拝を続けた。INHCIによりpH7.5に調製し
たのち分子量50瓜阻止のメンブランにより限外濠週を
行った。20の‘まで濃縮したのちpH7.5のリン酸
緩衝液300の‘を加え再度20Mまで濃縮した。
氷冷下縄拝しつつ10%ヘモグロビン溶液20の上を加
え4℃に一夜放置した。pH6.0に平衡化したCMー
セフアデックス樹脂に反応液を通してヘモグロビンおよ
び生成物を吸着させた後pH6.8のリン酸緩衝液によ
り溶麹する画分を分離した。分子量5方阻止のメンブラ
ンにより限外櫨過を行い脱塩、濃縮後0.4&メンブラ
ンにより猿過し、乾燥後、ポリエチレングリコ−ルモノ
メチルェーテルが結合したヘモグロビン3.5夕を得た
。ポリエチレングリコ‐ルモノメチルエーテルの置換度
は約10であった。
え4℃に一夜放置した。pH6.0に平衡化したCMー
セフアデックス樹脂に反応液を通してヘモグロビンおよ
び生成物を吸着させた後pH6.8のリン酸緩衝液によ
り溶麹する画分を分離した。分子量5方阻止のメンブラ
ンにより限外櫨過を行い脱塩、濃縮後0.4&メンブラ
ンにより猿過し、乾燥後、ポリエチレングリコ−ルモノ
メチルェーテルが結合したヘモグロビン3.5夕を得た
。ポリエチレングリコ‐ルモノメチルエーテルの置換度
は約10であった。
実施例 2
ポリエチレングリコ一ルモノメチルエーテル(平均分子
量750)7.5夕(0.01モル)を500の‘のベ
ンゼンに溶解し、炭酸ソーダ10夕を加えた。
量750)7.5夕(0.01モル)を500の‘のベ
ンゼンに溶解し、炭酸ソーダ10夕を加えた。
氷冷下、激しく鷹拝しつつ塩化シアヌル5.5夕(0.
03モル)を加えた後、室温にて一夜縄拝した。炭酸ソ
ーダを猿過後、石油エーテル(沸点30〜70qo)1
そを加えると2−○ーメトキシポリェチレングリコール
−4・6ージクロロ−S−トリアジン(活性化ポリエチ
レングリコール)が沈澱した。この結晶を石油エーテル
でよく洗った後乾燥した(11.5夕)。ヘモグロビン
0.5夕(0.0077ミリモル)を100泌のホゥ酸
緩衝液(pH9.2)に溶解した溶液に氷冷下上記活性
化ポリエチレングリコール1.7夕(1.8ミリモル)
を加えた。1時間氷冷下礎洋した後分子量10方阻止メ
ンプランにより限外渡過を繰返し未反応ヘモグロビンお
よび活性化ポリエチレングリコ、一ルを猿別後乾燥する
ことにより修飾ヘモグロビン2.6夕を得た。
03モル)を加えた後、室温にて一夜縄拝した。炭酸ソ
ーダを猿過後、石油エーテル(沸点30〜70qo)1
そを加えると2−○ーメトキシポリェチレングリコール
−4・6ージクロロ−S−トリアジン(活性化ポリエチ
レングリコール)が沈澱した。この結晶を石油エーテル
でよく洗った後乾燥した(11.5夕)。ヘモグロビン
0.5夕(0.0077ミリモル)を100泌のホゥ酸
緩衝液(pH9.2)に溶解した溶液に氷冷下上記活性
化ポリエチレングリコール1.7夕(1.8ミリモル)
を加えた。1時間氷冷下礎洋した後分子量10方阻止メ
ンプランにより限外渡過を繰返し未反応ヘモグロビンお
よび活性化ポリエチレングリコ、一ルを猿別後乾燥する
ことにより修飾ヘモグロビン2.6夕を得た。
置換度:約50。実施例 3ポリエチレングリコ−ルモ
ノメチルエーテル(平均分子量1900)19夕(0.
01モル)、400Mのベンゼン、炭酸ソーダ10夕お
よび塩化シアヌル5.5夕(0.03モル)を用いて、
実施例2と同機の反応、処理を行い活性化ポリエチレン
グリコール24夕を得た。
ノメチルエーテル(平均分子量1900)19夕(0.
01モル)、400Mのベンゼン、炭酸ソーダ10夕お
よび塩化シアヌル5.5夕(0.03モル)を用いて、
実施例2と同機の反応、処理を行い活性化ポリエチレン
グリコール24夕を得た。
ヘモグロビン2夕(0.031ミリモル)、20物‘の
ホウ酸緩衝液(pH9.2)および活性化ポリエチレン
グリコール6.4夕(3.1ミリモル)を用いて実施例
2と同様の反応、精製操作を行し、疹節ヘモグロビンを
7.6タ得た。置換度:約80。実施例 4ポリエチレ
ングリコ一ルモノメチルエーテル(平均分子量5000
)50夕(0.01モル)、500の‘のベンゼン、1
0夕の炭酸ソーダおよび5.5夕(0.03モル)の塩
化シアヌルを用いて実施例2と同様の反応、処理を行い
活性化ポリエチレングリコール53夕を得た。
ホウ酸緩衝液(pH9.2)および活性化ポリエチレン
グリコール6.4夕(3.1ミリモル)を用いて実施例
2と同様の反応、精製操作を行し、疹節ヘモグロビンを
7.6タ得た。置換度:約80。実施例 4ポリエチレ
ングリコ一ルモノメチルエーテル(平均分子量5000
)50夕(0.01モル)、500の‘のベンゼン、1
0夕の炭酸ソーダおよび5.5夕(0.03モル)の塩
化シアヌルを用いて実施例2と同様の反応、処理を行い
活性化ポリエチレングリコール53夕を得た。
10%ヘモグロビン溶液20舷、450の‘のホウ酸緩
衝液(pH9.2)および40夕の活性化ポリJエチレ
ングリコールを用いて実施例2と同様の反応、精製操作
を行い修飾ヘモグロビン34夕を得た。
衝液(pH9.2)および40夕の活性化ポリJエチレ
ングリコールを用いて実施例2と同様の反応、精製操作
を行い修飾ヘモグロビン34夕を得た。
置換度:105。実施例 5
ポリエチレングリコール(平均分子量20000)Z4
M(0.002モル)、ベンゼン1夕、炭酸ソーダ10
夕および塩化シアヌル1.1夕(0.006モル)を加
え、室温にて一夜楓拝した。
M(0.002モル)、ベンゼン1夕、炭酸ソーダ10
夕および塩化シアヌル1.1夕(0.006モル)を加
え、室温にて一夜楓拝した。
石油エーテル1夕を加えて生じた沈澱を用いて実施例2
と同様の反応、処理を行い活性化ポリエチレングリコー
ル392夕が得られた。400の【のホウ酸緩衝液(p
H9.2)に10%ヘモグロビン溶液20の‘(0.0
0003モル)を加えて氷冷下上記活性化ポリエチレン
グリコール10夕(0.0005モル)を加え1時間損
拝を行った。
と同様の反応、処理を行い活性化ポリエチレングリコー
ル392夕が得られた。400の【のホウ酸緩衝液(p
H9.2)に10%ヘモグロビン溶液20の‘(0.0
0003モル)を加えて氷冷下上記活性化ポリエチレン
グリコール10夕(0.0005モル)を加え1時間損
拝を行った。
分子量10万阻止のメンブランで限外猿過し濃縮後pH
6.0のリン酸緩衝液で平衡化したCM−セフアデック
スに吸着させた後、pH6.3のリン酸緩衝液で溶離す
る分画を捨て、次にpH6.8のリン酸緩衝液で漆離す
る分画を分離した。この分画を分子量10万阻止のメン
ブランで濃縮して修飾ヘモグロビン3夕を得た。置換度
:約4。実施例 6 ポリエチレングリコールモノステアリルエステル(平均
分子量2500)12.5夕(0.005モル)、40
0の‘のベンゼン、炭酸ソーダ5夕および塩化シアヌル
2.75夕(0.015モル)を用いて実施例2と同様
の反応、処理を行い活性化ポリエチレングリコール13
.5夕を得た。
6.0のリン酸緩衝液で平衡化したCM−セフアデック
スに吸着させた後、pH6.3のリン酸緩衝液で溶離す
る分画を捨て、次にpH6.8のリン酸緩衝液で漆離す
る分画を分離した。この分画を分子量10万阻止のメン
ブランで濃縮して修飾ヘモグロビン3夕を得た。置換度
:約4。実施例 6 ポリエチレングリコールモノステアリルエステル(平均
分子量2500)12.5夕(0.005モル)、40
0の‘のベンゼン、炭酸ソーダ5夕および塩化シアヌル
2.75夕(0.015モル)を用いて実施例2と同様
の反応、処理を行い活性化ポリエチレングリコール13
.5夕を得た。
10%ヘモグロビン溶液25の【(0.04ミリモル)
、900の【ホウ酸緩衝液(pH9.2)および上記活
性化ポリエチレングリコール10.5夕(0.004モ
ル)を用いて実施例2と同様の反応、精製操作を行い修
飾ヘモグロビン8夕を得た。
、900の【ホウ酸緩衝液(pH9.2)および上記活
性化ポリエチレングリコール10.5夕(0.004モ
ル)を用いて実施例2と同様の反応、精製操作を行い修
飾ヘモグロビン8夕を得た。
置換度:約90。実施例 7
ポリエチレングリコ一ルモノオレイエーテル(平均分子
量1000)5夕(0.005モル)、400叫のベン
ゼン、炭酸ソーダ5夕および塩化シアヌル2.75夕(
0.015モル)を用いて実施例2と同様の反応、処理
を行い活性化ポリェチレソグIJコール6夕を得た。
量1000)5夕(0.005モル)、400叫のベン
ゼン、炭酸ソーダ5夕および塩化シアヌル2.75夕(
0.015モル)を用いて実施例2と同様の反応、処理
を行い活性化ポリェチレソグIJコール6夕を得た。
牛ヘモグロビン(シグマ社製)1.3夕(0.02ミリ
モル)、450の‘ホゥ酸緩衝液(pH9.2)および
上記活性化ポリエチレングリコール5.3夕(0.00
2モル)を用いて実施例2と同様の反応、精製操作を行
い修飾ヘモグロビン4.2夕を得た。置換度:約8を実
施例 8 ポリプロピレングリコール(平均分子量4000)12
夕(0.003モル)を水120舷に溶解し、これに実
施例1と同様の操作により臭化シアン(0.0095モ
ル)を反応、濃縮を行った。
モル)、450の‘ホゥ酸緩衝液(pH9.2)および
上記活性化ポリエチレングリコール5.3夕(0.00
2モル)を用いて実施例2と同様の反応、精製操作を行
い修飾ヘモグロビン4.2夕を得た。置換度:約8を実
施例 8 ポリプロピレングリコール(平均分子量4000)12
夕(0.003モル)を水120舷に溶解し、これに実
施例1と同様の操作により臭化シアン(0.0095モ
ル)を反応、濃縮を行った。
豚ヘモグロビン(シグマ社製)2夕を実施例1と同様の
操作で反応させた後、分離、精製を行い修飾へモグ。ピ
ン7夕を得た。ポリプロピレングリコールの置換度は約
30であった。本発明で得られる化合物、修飾ヘモグロ
ビンについて血管内滞留時間および酸素新和力を調べた
。
操作で反応させた後、分離、精製を行い修飾へモグ。ピ
ン7夕を得た。ポリプロピレングリコールの置換度は約
30であった。本発明で得られる化合物、修飾ヘモグロ
ビンについて血管内滞留時間および酸素新和力を調べた
。
一試料につきラット(平均体重:350夕)二匹を用い
、ラットの体重に対し5の【/k9の4〜6%修飾ヘモ
グロビンを静柱後5分、IC分、18分、30分、6ひ
分、90分、120分経過時に0.5の‘ずつ採血し、
遠心処理後血数中の修飾ヘモグロビン量をシアンメトヘ
モグロビン法により比色定草した。
、ラットの体重に対し5の【/k9の4〜6%修飾ヘモ
グロビンを静柱後5分、IC分、18分、30分、6ひ
分、90分、120分経過時に0.5の‘ずつ採血し、
遠心処理後血数中の修飾ヘモグロビン量をシアンメトヘ
モグロビン法により比色定草した。
そのグラフから注入した修飾ヘモグロビンの血鰍中での
半減期を計算した。結果を表1に示す。表1 十 実施例1〜4の方法により調製した修飾ヘモグロビン溶
液(0.1M NaCI溶液、pH7.40)をAmi
mo社製Hem−○−Scan装置を用い、酸素平衡曲
線を描き、それから50%酸素解離圧(P50値)を求
めた。
半減期を計算した。結果を表1に示す。表1 十 実施例1〜4の方法により調製した修飾ヘモグロビン溶
液(0.1M NaCI溶液、pH7.40)をAmi
mo社製Hem−○−Scan装置を用い、酸素平衡曲
線を描き、それから50%酸素解離圧(P50値)を求
めた。
結果を表2に示す。表2
Claims (1)
- 1 酸素運搬物質を含有する代用血液において、酸素運
搬物質がヘモグロビンと、ポリエチレングリコール、ポ
リプロピレングリコールまたはエチレングリコール−プ
ロピレングリコール共重合体との結合物であることを特
徴とする代用血液。
Priority Applications (6)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP54087910A JPS6023084B2 (ja) | 1979-07-11 | 1979-07-11 | 代用血液 |
GB8022583A GB2055868B (en) | 1979-07-11 | 1980-07-10 | Blood substitute containing hemoglobin |
US06/167,360 US4301144A (en) | 1979-07-11 | 1980-07-10 | Blood substitute containing modified hemoglobin |
FR8015568A FR2460674A1 (fr) | 1979-07-11 | 1980-07-11 | Succedane du sang contenant de l'hemoglobine modifiee |
DE19803026398 DE3026398A1 (de) | 1979-07-11 | 1980-07-11 | Modifiziertes haemoglobin enthaltender blutersatz |
CA000356067A CA1146858A (en) | 1979-07-11 | 1980-07-11 | Blood substitute containing modified hemoglobin |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP54087910A JPS6023084B2 (ja) | 1979-07-11 | 1979-07-11 | 代用血液 |
Publications (2)
Publication Number | Publication Date |
---|---|
JPS5612308A JPS5612308A (en) | 1981-02-06 |
JPS6023084B2 true JPS6023084B2 (ja) | 1985-06-05 |
Family
ID=13928063
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP54087910A Expired JPS6023084B2 (ja) | 1979-07-11 | 1979-07-11 | 代用血液 |
Country Status (6)
Country | Link |
---|---|
US (1) | US4301144A (ja) |
JP (1) | JPS6023084B2 (ja) |
CA (1) | CA1146858A (ja) |
DE (1) | DE3026398A1 (ja) |
FR (1) | FR2460674A1 (ja) |
GB (1) | GB2055868B (ja) |
Families Citing this family (845)
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US4001401A (en) * | 1975-02-02 | 1977-01-04 | Alza Corporation | Blood substitute and blood plasma expander comprising polyhemoglobin |
CA1055932A (en) * | 1975-10-22 | 1979-06-05 | Hematech Inc. | Blood substitute based on hemoglobin |
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CA1146858A (en) | 1983-05-24 |
JPS5612308A (en) | 1981-02-06 |
DE3026398A1 (de) | 1981-03-26 |
GB2055868B (en) | 1983-04-07 |
GB2055868A (en) | 1981-03-11 |
FR2460674B1 (ja) | 1983-06-24 |
US4301144A (en) | 1981-11-17 |
DE3026398C2 (ja) | 1990-09-13 |
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