JPH049334A - Fibrinolytic activity enhancer - Google Patents
Fibrinolytic activity enhancerInfo
- Publication number
- JPH049334A JPH049334A JP2109343A JP10934390A JPH049334A JP H049334 A JPH049334 A JP H049334A JP 2109343 A JP2109343 A JP 2109343A JP 10934390 A JP10934390 A JP 10934390A JP H049334 A JPH049334 A JP H049334A
- Authority
- JP
- Japan
- Prior art keywords
- urokinase
- fibrinolytic activity
- chain urokinase
- chain
- polyoxyethylene
- 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
- 230000003480 fibrinolytic effect Effects 0.000 title claims abstract description 18
- 239000003623 enhancer Substances 0.000 title claims abstract description 6
- 108090000435 Urokinase-type plasminogen activator Proteins 0.000 claims abstract description 72
- 102000003990 Urokinase-type plasminogen activator Human genes 0.000 claims abstract description 72
- 229960005356 urokinase Drugs 0.000 claims abstract description 72
- 229920002503 polyoxyethylene-polyoxypropylene Polymers 0.000 claims abstract description 20
- 239000004480 active ingredient Substances 0.000 claims abstract description 5
- 230000009885 systemic effect Effects 0.000 abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 6
- 230000020764 fibrinolysis Effects 0.000 abstract description 5
- 229920001577 copolymer Polymers 0.000 abstract description 4
- 238000006116 polymerization reaction Methods 0.000 abstract description 2
- 230000002537 thrombolytic effect Effects 0.000 description 16
- 208000007536 Thrombosis Diseases 0.000 description 9
- 230000000694 effects Effects 0.000 description 9
- 238000002474 experimental method Methods 0.000 description 9
- 238000000034 method Methods 0.000 description 9
- 229950003499 fibrin Drugs 0.000 description 8
- 239000003146 anticoagulant agent Substances 0.000 description 7
- 229940012957 plasmin Drugs 0.000 description 6
- 102000009123 Fibrin Human genes 0.000 description 5
- 108010073385 Fibrin Proteins 0.000 description 5
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 5
- 102000013566 Plasminogen Human genes 0.000 description 5
- 108010051456 Plasminogen Proteins 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 229940090044 injection Drugs 0.000 description 4
- 239000007924 injection Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000003995 emulsifying agent Substances 0.000 description 3
- 230000002708 enhancing effect Effects 0.000 description 3
- 238000010353 genetic engineering Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 210000004072 lung Anatomy 0.000 description 3
- 210000002381 plasma Anatomy 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010049003 Fibrinogen Proteins 0.000 description 2
- 102000008946 Fibrinogen Human genes 0.000 description 2
- 206010018910 Haemolysis Diseases 0.000 description 2
- 208000010378 Pulmonary Embolism Diseases 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000003275 alpha amino acid group Chemical group 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 229940012952 fibrinogen Drugs 0.000 description 2
- 239000003527 fibrinolytic agent Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000002504 physiological saline solution Substances 0.000 description 2
- 229920001451 polypropylene glycol Polymers 0.000 description 2
- 239000002243 precursor Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 229960000103 thrombolytic agent Drugs 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- RTECMAMFVYJPCM-NSCUHMNNSA-N 4-[(E)-3-aminoprop-1-enyl]-1-methylcyclohexa-2,4-dien-1-ol Chemical compound CC1(CC=C(/C=C/CN)C=C1)O RTECMAMFVYJPCM-NSCUHMNNSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- 239000004475 Arginine Substances 0.000 description 1
- 206010008132 Cerebral thrombosis Diseases 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 1
- 239000005977 Ethylene Substances 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Chemical compound OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 206010062713 Haemorrhagic diathesis Diseases 0.000 description 1
- 102000008100 Human Serum Albumin Human genes 0.000 description 1
- 108091006905 Human Serum Albumin Proteins 0.000 description 1
- 201000001429 Intracranial Thrombosis Diseases 0.000 description 1
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 101000685667 Mus musculus Bile acyl-CoA synthetase Proteins 0.000 description 1
- 101000715642 Mus musculus Bile salt-activated lipase Proteins 0.000 description 1
- 208000030831 Peripheral arterial occlusive disease Diseases 0.000 description 1
- 206010035226 Plasma cell myeloma Diseases 0.000 description 1
- 102000001938 Plasminogen Activators Human genes 0.000 description 1
- 108010001014 Plasminogen Activators Proteins 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 description 1
- 108010023197 Streptokinase Proteins 0.000 description 1
- 206010058990 Venous occlusion Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 125000000539 amino acid group Chemical group 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 1
- 239000002473 artificial blood Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000012228 culture supernatant Substances 0.000 description 1
- ATDGTVJJHBUTRL-UHFFFAOYSA-N cyanogen bromide Chemical compound BrC#N ATDGTVJJHBUTRL-UHFFFAOYSA-N 0.000 description 1
- 230000009089 cytolysis Effects 0.000 description 1
- 238000012217 deletion Methods 0.000 description 1
- 230000037430 deletion Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 1
- 229910000397 disodium phosphate Inorganic materials 0.000 description 1
- 235000019800 disodium phosphate Nutrition 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 239000008151 electrolyte solution Substances 0.000 description 1
- 229940088598 enzyme Drugs 0.000 description 1
- 210000003743 erythrocyte Anatomy 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 229940093181 glucose injection Drugs 0.000 description 1
- 239000003102 growth factor Substances 0.000 description 1
- 239000001963 growth medium Substances 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 208000031169 hemorrhagic disease Diseases 0.000 description 1
- 229940106780 human fibrinogen Drugs 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- 230000016784 immunoglobulin production Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 210000003292 kidney cell Anatomy 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002101 lytic effect Effects 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 1
- 235000019799 monosodium phosphate Nutrition 0.000 description 1
- 201000000050 myeloid neoplasm Diseases 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 239000003002 pH adjusting agent Substances 0.000 description 1
- 229950008618 perfluamine Drugs 0.000 description 1
- 229950011087 perflunafene Drugs 0.000 description 1
- MRQNKLRMROXHTI-UHFFFAOYSA-N perfluoro-N-methyldecahydroisoquinoline Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)C2(F)C(F)(F)N(C(F)(F)F)C(F)(F)C(F)(F)C21F MRQNKLRMROXHTI-UHFFFAOYSA-N 0.000 description 1
- UWEYRJFJVCLAGH-IJWZVTFUSA-N perfluorodecalin Chemical compound FC1(F)C(F)(F)C(F)(F)C(F)(F)[C@@]2(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)[C@@]21F UWEYRJFJVCLAGH-IJWZVTFUSA-N 0.000 description 1
- JAJLKEVKNDUJBG-UHFFFAOYSA-N perfluorotripropylamine Chemical compound FC(F)(F)C(F)(F)C(F)(F)N(C(F)(F)C(F)(F)C(F)(F)F)C(F)(F)C(F)(F)C(F)(F)F JAJLKEVKNDUJBG-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229940127126 plasminogen activator Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- -1 polyoxypropylene copolymer Polymers 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 239000004017 serum-free culture medium Substances 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 description 1
- 210000004989 spleen cell Anatomy 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008223 sterile water Substances 0.000 description 1
- 229960005202 streptokinase Drugs 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- TXEYQDLBPFQVAA-UHFFFAOYSA-N tetrafluoromethane Chemical class FC(F)(F)F TXEYQDLBPFQVAA-UHFFFAOYSA-N 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229960003766 thrombin (human) Drugs 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、ポリオキノエチレン−ポリオキシプロピレン
共重合体を有効成分とする一本鎖ウロキナーゼの線溶活
性の増強剤に関する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Field of Application] The present invention relates to an agent for enhancing the fibrinolytic activity of single-chain urokinase, which contains a polyquinoethylene-polyoxypropylene copolymer as an active ingredient.
（従来技術・発明が解決しようとする課題〕現在、スト
レプトキナーゼやウロキナーゼが、血栓？容解剤として
脳血栓症、末梢動脈閉塞症、末梢静脈閉塞症、象性心筋
梗塞等の血栓、閉塞性疾患の治療に広く使用されるよう
になっている。(Prior art/problem to be solved by the invention) Currently, streptokinase and urokinase are used as thrombus dissolving agents for thrombosis and occlusive diseases such as cerebral thrombosis, peripheral artery occlusion, peripheral venous occlusion, and myocardial infarction. It has become widely used in the treatment of
しかし、これらの薬剤の使用においては、副作用として
、循環フィブリノゲンの減少や出血傾向が指摘されてき
た。このような理由から、より安全で、しかもより効果
的な、フィブリンに特異的な血栓溶解剤の開発の試みが
なされてきた。However, when using these drugs, reduction in circulating fibrinogen and bleeding tendency have been pointed out as side effects. For these reasons, attempts have been made to develop safer and more effective fibrin-specific thrombolytic agents.
−末鎖ウロキナーゼはフィブリンに特異的な血栓溶解剤
の一つである。この−末鎖ウロキナーゼはプラスミン処
理により、−本鎖構造が切れて一木鎖型のウロキナーゼ
（従来から知られているいわゆるウロキナーゼであり、
以下二本鎖ウロキナゼともいう）に変換する。- End-chain urokinase is one of the fibrin-specific thrombolytic agents. When this terminal chain urokinase is treated with plasmin, its main chain structure is broken and it becomes a single-chain type urokinase (a conventionally known so-called urokinase).
(hereinafter also referred to as double-stranded urokinase).
ウロキナーゼのようなプラスミノゲンアクチヘーター（
ＰＡ）は、血中を循環するプラスミノゲンを活性化し、
プラスミンに変えることにより血栓を溶解する。しかし
、血栓溶解に重要な意味を持つのは血栓中に存在するプ
ラスミノゲンの活性化に基づく血栓溶解作用である。Plasminogen activators such as urokinase (
PA) activates plasminogen circulating in the blood,
Dissolves blood clots by converting them to plasmin. However, what is important for thrombolysis is the thrombolytic action based on the activation of plasminogen present in the thrombus.
末鎖型ウロキナーゼは、活性型であるため、主として血
中プラスミン処理を活性化し、血栓を溶解する。従って
、循環中プラスミンによるフィブリノゲンの分解など全
身ｖＡ溶も引き起こす。それに対し一本鎖ウロキナーゼ
は、二本鎖型ウロキナーゼに比して、プラスミノゲンの
活性化能が著しく弱い、たとえ循環中プラスミノゲンを
活性化し、プラスミンが微量生成したとしても、既時型
の強力なプラスミン阻害因子であるα、ＰＩによって阻
害されるので循環中プラスミノゲンをほとんど活性化し
ない。フィブリンへの親和性が高いことから主として血
栓中のプラスミノゲンを活性化することによって血栓溶
解を引き起こし、全身線溶は生しない。Since terminal chain urokinase is an active type, it mainly activates blood plasmin processing and dissolves thrombi. Therefore, it also causes systemic vA lysis, such as the breakdown of fibrinogen by circulating plasmin. On the other hand, single-chain urokinase has a significantly weaker ability to activate plasminogen than double-chain urokinase. Since it is inhibited by the inhibitory factors α and PI, it hardly activates circulating plasminogen. Because it has a high affinity for fibrin, it causes thrombolysis mainly by activating plasminogen in the thrombus and does not cause systemic fibrinolysis.
一方、ポリオキシエチレン−ポリオキシプロピレン共重
合体は、商品名プルロニックとしてよく知られた非イオ
ン系界面活性剤であるが、溶血防止作用、赤血球凝集抑
制作用、血小板凝集抑制作用を有しており、人工心肺を
用いる関心術時の溶血を防止する目的で体外循環用回路
充填液に添加して用いられ、その有効性が認められてい
る。On the other hand, polyoxyethylene-polyoxypropylene copolymer, which is a nonionic surfactant well known under the trade name Pluronic, has hemolysis-preventing effects, red blood cell aggregation-inhibiting effects, and platelet aggregation-inhibiting effects. It is used by adding it to the extracorporeal circulation circuit filling fluid for the purpose of preventing hemolysis during surgical procedures using a heart-lung machine, and its effectiveness has been recognized.
ポリオキシエチレン−ポリオキシプロピレン共重合体は
、それ自身でも弱い血栓溶解作用を持ち、これまでに、
二本鎖型ウロキナーゼとポリオキシエチレン−ポリオキ
シプロピレン共重合体とを併用することにより、ｖＡ溶
活性を増強させることが試みられている（特表千１−５
００５９２号公報）。Polyoxyethylene-polyoxypropylene copolymer itself has a weak thrombolytic effect, and so far,
Attempts have been made to enhance vA lytic activity by using double-stranded urokinase and polyoxyethylene-polyoxypropylene copolymer (Featured Japanese Patent Publication No. 11-5
00592).
しかし、二本鎖型ウロキナーゼとポリオキンエチレン−
ポリオキシプロピレン共重合体の併用においても、前述
の理由により、二本鎖型ウロキナーゼが副作用として全
身線？容をひきおこすという問題があった。However, double-stranded urokinase and polyoxine ethylene
Even when using polyoxypropylene copolymer in combination, double-stranded urokinase may cause systemic radiation as a side effect due to the reasons mentioned above. There was the problem of causing discomfort.
そこで、本発明の目的は全身線溶をおこさない一本鎖ウ
ロキナーゼの線溶活性の増強剤を提供することである。Therefore, an object of the present invention is to provide an agent for enhancing the fibrinolytic activity of single-chain urokinase that does not cause systemic fibrinolysis.
〔課題を解決するための手段］
このような目的を達成すべく、本発明者らは種々研究を
重ねた結果、−末鎖ウロキナーゼとポリオキシエチレン
−ポリオキシプロピレン共重合体とを併用することによ
って、−末鎖ウロキナーゼの線溶活性が増強されること
、さらに全身線溶の回避ができることを見出した。[Means for Solving the Problems] In order to achieve such an object, the present inventors have conducted various studies and found that -terminal chain urokinase and polyoxyethylene-polyoxypropylene copolymer are used together. We have found that the fibrinolytic activity of -terminal chain urokinase is enhanced by this method, and that systemic fibrinolysis can be avoided.
本発明はかかる新知見に基づいて完成されたものであり
、ポリオキシエチレン−ポリオキシプロピレン共重合体
を有効成分とする一本鎖ウロキナーゼの線溶活性の増強
剤を提供するものである。The present invention was completed based on this new knowledge, and provides an agent for enhancing the fibrinolytic activity of single-chain urokinase, which contains a polyoxyethylene-polyoxypropylene copolymer as an active ingredient.
以下、本発明を詳述する。The present invention will be explained in detail below.
（１）−末鎖ウロキナーゼ
本発明で使用される一本鎖ウロキナーゼは、そのままで
はほとんど、％Ｉ ？８活性を有しないが、プラスミン
等の酵素処理により、二本鎖ウロキナーゼに変換されて
線溶活性を示すものである。また、フィブリン存在下で
も若干の線溶活性を示すものである。(1) - End-chain urokinase The single-chain urokinase used in the present invention has almost no %I? Although it does not have 8 activity, it is converted to double-stranded urokinase by treatment with an enzyme such as plasmin and exhibits fibrinolytic activity. It also shows some fibrinolytic activity even in the presence of fibrin.
本発明で使用される一本鎖ウロキナーゼのまず第１の代
表例は、分子量５００００〜５５０００で、−末鎖のペ
プチド結合構造を有するものである。The first representative example of the single-chain urokinase used in the present invention has a molecular weight of 50,000 to 55,000 and a -terminal peptide bond structure.
このような−末鎖ウロキナーゼとしては、たとえば構成
アミノ酸４１１個（アミノ酸配列は後記実施例・実験例
における一本鎖ウロキナーゼの調製の項参照）のものが
挙げられる（特開昭６０６２９８１号公報参照）。Examples of such -terminal chain urokinase include one having 411 constituent amino acids (for the amino acid sequence, see the section on the preparation of single-chain urokinase in Examples and Experimental Examples below) (see JP-A-6062981). .
上記−末鎖ウロキナーゼの由来には特に制限はなく、た
とえば、細胞培養法、遺伝子工学法などにより調製され
たものが例示される。細胞培養法は特開昭６０−６２９
８１号公報等に、遺伝子工学法は特開昭６０−１８０５
９１号公報等に開示されている。The origin of the above-mentioned -terminal chain urokinase is not particularly limited, and examples thereof include those prepared by cell culture methods, genetic engineering methods, etc. Cell culture method is JP-A-60-629
The genetic engineering method is described in Japanese Patent Application Laid-open No. 1805-1981, etc.
This is disclosed in Publication No. 91 and the like.
本発明でいう一本鎖ウロキナーゼは上記のものに限定さ
れず、その誘導体をも包合する概念である。かかる誘導
体としては一本鎖ウロキナーゼのエビダーマルグロース
ファクタートメインの全領域もしくはその一部を欠失、
または該全領域もしくはその一部を他のアミノ酸残基で
置換されている蛋白質分子等が挙げられる。従って、特
に言及しない限り、本願明細書において一本鎖ウロキナ
ーゼとは一本鎖ウロキナーゼ自体および上記のごとき一
本鎖ウロキナーゼ誘導体を意味するものである。The single-chain urokinase referred to in the present invention is not limited to the above-mentioned ones, but also includes derivatives thereof. Such derivatives include deletion of the entire region or part of the Evidermal Growth Factor domain of single-chain urokinase;
Alternatively, examples include protein molecules in which the entire region or a portion thereof is replaced with other amino acid residues. Therefore, unless otherwise specified, single chain urokinase as used herein refers to single chain urokinase itself and single chain urokinase derivatives as described above.
この−末鎖ウロキナーゼ誘導体は、通常分子量４万〜５
万程度で一本鎖ウロキナーゼ自体と同様に一本鎖のペプ
チド結合構造を有する。また、その線溶活性の発現様式
も上記−末鎖ウロキナーゼ自体と同しである。This -terminal chain urokinase derivative usually has a molecular weight of 40,000 to 50,000
It has a single-chain peptide bond structure similar to single-chain urokinase itself. Furthermore, the expression mode of its fibrinolytic activity is the same as that of the above-mentioned -terminal chain urokinase itself.
この誘導体は、たとえば遺伝子工学的な手法により調製
される（特開昭６３−１４６７８９号公報、特願平１−
１２６４３３号公報または特願平１−１２６４３４号公
報）。This derivative is prepared, for example, by genetic engineering techniques (Japanese Patent Application Laid-open No. 146789/1989, Japanese Patent Application No.
126433 or Japanese Patent Application No. 126434).
一本鎖ウロキナーゼの比活性としては、合成基質法〔森
田等、 Ｊ、 Ｂｉｏｃｈｅｍ、 ８２．１４９５−１
４９８（１９７７）；笠井等、 Ｊ、 Ｒｉａｌ、 Ｃ
ｈｅｎ、 ２６０．１２３７７−１２３８［１９８５）
）で測定した場合にそのままでは活性を示さず、フィ
ブリン存在下で１００〜１００ＯＵＫ単位／■程度、プ
ラスミン処理時に８万〜２０万ＵＫ単位／■程度が例示
される。The specific activity of single-chain urokinase can be determined using the synthetic substrate method [Morita et al., J. Biochem, 82.1495-1.
498 (1977); Kasai et al., J., Rial, C.
hen, 260.12377-1238 [1985)
), it does not show any activity as it is, and examples include about 100 to 100 OUK units/■ in the presence of fibrin, and about 80,000 to 200,000 UK units/■ when treated with plasmin.
（ｉｉ ）ポリオキシエチレン−ポリオキシプロピレン
共重合体
本発明で使用されるポリオキシエチレン−ポリオキシプ
ロピレン共重合体は、一般式
％式％）
（式中、重合度係数はそれぞれ、ａ＋ｃ−１３２〜１６
６ 、ｂ ＝２８〜３４である）で表される分子量７，
６００〜９．１００の水に易溶解性の化合物である。(ii) Polyoxyethylene-polyoxypropylene copolymer The polyoxyethylene-polyoxypropylene copolymer used in the present invention has the general formula % (%) (wherein, the degree of polymerization coefficient is a+c-132, respectively) ~16
6, b = 28 to 34) with a molecular weight of 7,
It is a compound that is easily soluble in water with a molecular weight of 600 to 9.100.
（ｉｉｉ ）用法・用量
本発明において、−本領ウロキナーゼは、それ自体で、
または担体、安定化剤（例えば、アルブミン、クエン酸
ナトリウム、アルギニン、デキストラン等）、賦形剤、
ｐＨ調整剤（例えば、リン酸水素ナトリウム、リン酸二
水素ナトリウム等〕、その他の添加剤等とともに、通常
注射剤、点滴剤等として調製される。当該製剤は、通常
江射用仄留水、生理食塩液、ブドウ糖注射液等に溶解、
分散して製造される。(iii) Dosage/Dosage In the present invention, - the main urokinase itself,
or carriers, stabilizers (e.g. albumin, sodium citrate, arginine, dextran, etc.), excipients,
It is usually prepared as an injection, a drip, etc. together with a pH adjusting agent (e.g., sodium hydrogen phosphate, sodium dihydrogen phosphate, etc.) and other additives. Dissolved in physiological saline, glucose injection, etc.
Manufactured in a distributed manner.
一本鎖ウロキナーゼの投与ルートとしては、たとえば静
注、点滴静注または冠動脈的投与が挙げられる。Administration routes for single-chain urokinase include, for example, intravenous injection, intravenous drip injection, or coronary administration.
一本鎖ウロキナーゼの投与量は、患者の体重、性別、症
状等により異なるが、例えば成人−回当たり、１〜１０
００万ＵＫ単位（ウロキナーゼ変換時）程度である。The dosage of single-chain urokinase varies depending on the patient's weight, sex, symptoms, etc., but for example, for adults, 1 to 10
It is approximately 1,000,000 UK units (when converted to urokinase).
本発明において、ポリオキシエチレン−ポリオキシプロ
ピレン共重合体は、それ自体で、または水、乳化剤、亜
硫酸水素ナトリウム等とともに、通常注射剤等として調
製される。当該製剤は、たとえば水性溶媒（たとえば、
注射用蒸留水、無菌水、糖液、電解室液等）に溶解する
ことによって、またリン脂質等の乳化剤等を使用して自
体既知の手段にて乳化剤とすることによって、またさら
にパーフルオロデカリン、パーフルオロトリプロピルア
ミン、パーフルオロ−Ｎ−メチルデカハイドロイソキノ
リン等のパーフルオロカーボン化合物と共に乳剤として
もよい。In the present invention, the polyoxyethylene-polyoxypropylene copolymer is usually prepared as an injection by itself or together with water, an emulsifier, sodium bisulfite, etc. The formulation may be prepared, for example, in an aqueous solvent (e.g.
Perfluorodecalin can be prepared by dissolving it in water (distilled water for injection, sterile water, sugar solution, electrolyte solution, etc.), or by making it into an emulsifier using an emulsifier such as phospholipid by a known method. , perfluorotripropylamine, perfluoro-N-methyldecahydroisoquinoline, and other perfluorocarbon compounds.
ポリオキシエチレン−ポリオキシプロピレン共重合体の
具体的製剤としては、たとえばフルオシ−ルーＤＡ（商
品名、ミドリ十字社）、エキソコルボール（商品名、ミ
ドリ十字社） 、Ｒｈｅｏｔｈ ＲＸ（Ｃｙｔ ＲＸ社
）、プルロニンクＦ６８、ポロクサマ−１８８（−船名
）等が例示される。なお、エキソコルポールは１０％Ｗ
／Ｗ、フルオシ−ルーＯＡは２．７％Ｗ ／ Ｗのポリ
オキシエチレン−ポリオキシプロピレン共重合体を含有
する。Specific formulations of polyoxyethylene-polyoxypropylene copolymers include, for example, Fluocyl-DA (trade name, Midori Juji Co., Ltd.), Exocorbol (trade name, Midori Juji Co., Ltd.), and Rheoth RX (Cyt RX Co., Ltd.). , Pluronink F68, Poloxama-188 (-ship name), etc. In addition, Exocolpol is 10%W
/W, Fluocyl-OA contains 2.7% W/W polyoxyethylene-polyoxypropylene copolymer.
ポリオキシエチレン−ポリオキシプロピレン共重合体の
投与ルートとしては、たとえば静注または冠動脈的投与
が例示される。Examples of the administration route for the polyoxyethylene-polyoxypropylene copolymer include intravenous injection and coronary administration.
ポリオキシエチレン−ポリオキシプロピレン共重合体の
投与量は、患者の体重、性別、症状に応じて異なるが、
例えば成人−回当たり０．１〜１０ｇ程度である。The dosage of polyoxyethylene-polyoxypropylene copolymer varies depending on the patient's weight, gender, and symptoms;
For example, it is about 0.1 to 10 g per serving for adults.
一本鎖ウロキナーゼとポリオキンエチレンーポリオキシ
ブロビレン共重合体は、別々または同時ニー、同一ルー
トまたは別個のルートによって投与される。別々に投与
する場合、どちらを先に投与してもよい。投与方法とし
てはたとえば下記のような例が挙げられる。The single chain urokinase and the polyoxine ethylene-polyoxybrobylene copolymer are administered separately or simultaneously, by the same route or by separate routes. If administered separately, either may be administered first. Examples of the administration method include the following.
■ポリオキンエチレンーポリオキンブロビレン共重合体
を静注または冠動脈内投与後、ある程度時間を経てから
（１分〜数十分後）−本領ウロキナーゼを静注または冠
動脈的投与する方法。(2) A method in which the original urokinase is administered intravenously or intracoronarily after a certain period of time (1 minute to several tens of minutes) after polyoquine ethylene-polyoquine brobylene copolymer is intravenously or intracoronarily administered.
■−一本鎖ロキナーゼを静注または冠動脈内投与後、あ
る程度時間を経てから（１分〜数十分後）ポリオキシエ
チレン−ポリオキシプロピレン共重合体を静注または冠
動脈的投与する方法。(2) A method in which a polyoxyethylene-polyoxypropylene copolymer is intravenously or intracoronarily administered after a certain period of time (1 minute to several tens of minutes) after intravenously or intracoronarily administering single-chain rokinase.
■ポリオキシエチレンーポリオキシプロピレン共重合体
を静注または冠動脈内投与後、−本鎖ウロキナーゼを点
滴静注する方法。■A method in which polyoxyethylene-polyoxypropylene copolymer is injected intravenously or intracoronarily, followed by intravenous infusion of -main-chain urokinase.
■−一本鎖ロキナーゼを点滴静注している間にポリオキ
シエチレン−ポリオキシプロピレン共重合体を１回〜数
回静注または冠動脈内投与する方法。(2) A method in which polyoxyethylene-polyoxypropylene copolymer is intravenously injected or intracoronarily administered once to several times during intravenous infusion of single-chain rokinase.
〔作用・効果］
一本鎖ウロキナーゼとポリオキシエチレン−ポリオキシ
プロピレン共重合体とを併用することにより、−本領ウ
ロキナーゼによるｗＡ溶活性の異常亢進（全身線溶）を
来すことなく、−末鎖ウロキナーゼの線溶活性を増強す
ることができる。[Action/Effect] By using single-chain urokinase and polyoxyethylene-polyoxypropylene copolymer together, the The fibrinolytic activity of chain urokinase can be enhanced.
従って、本発明の線溶活性の増強剤を使用することによ
って、−本領ウロキナーゼの投与量の軽減をはかること
ができ、ひいては副作用である全身線溶が軽減される。Therefore, by using the fibrinolytic activity enhancer of the present invention, it is possible to reduce the dose of the main urokinase, and as a result, systemic fibrinolysis, which is a side effect, is reduced.
以上のことから、本発明に係わる一本鎖ウロキナーゼの
線溶活性の増強剤の使用は、−本領ウロキナーゼによる
血栓溶解療法にとって極めて有用と考えられる。From the above, the use of the fibrinolytic activity enhancer of single-chain urokinase according to the present invention is considered to be extremely useful for thrombolytic therapy using the original urokinase.
本発明をより詳細に説明するために実験例を挙げて説明
するが、本発明はこれらによって何ら限定されるもので
はない。EXAMPLES Experimental examples will be given to explain the present invention in more detail, but the present invention is not limited to these in any way.
なお、実験方法は以下のようにした。The experimental method was as follows.
（実験方法）
人工血詮皇訓エ
ヒト血漿１−当たりに＋２′Ｉ標識ヒトフイブリノゲン
２μＣｉを添加し、十分に混和した。この１２５Ｉ標識
ヒトフィブリノゲン添加ヒト血％ ０．２ ｍｌにＣａ
Ｃｌ ２およびヒトトロンビンをそれぞれ終濃度が２５
１および１０Ｕ＃になるように添加し混和した。この混
液を３７゛Ｃで３０分間放置し凝固させた。その後、生
成した血栓を取り出し、生理食塩液で十分に洗浄し、血
栓溶解実験に供した。(Experimental Method) 2 μCi of +2'I-labeled human fibrinogen was added to 1 liter of artificial blood plasma and thoroughly mixed. Add Ca to this 125I-labeled human fibrinogen-added human blood% 0.2 ml.
Cl2 and human thrombin each at a final concentration of 25
1 and 10 U# were added and mixed. This mixed solution was allowed to stand at 37°C for 30 minutes to solidify. Thereafter, the generated thrombus was removed, thoroughly washed with physiological saline, and subjected to a thrombolytic experiment.
ニ第１゛ウロキ −ゼのｆＬＬ！
培養人腎細胞を０．１％ヒト血清アルブミン添加無血清
培養液に３日間培養し、培養液を遠心分離し、その上清
を凍結して保存した。プールした培養上清をｐ）１５．
５に調製した後、ＣＭ−３ｅｐｈａｄｅｘ Ｃ−５０に
接触した。０．１６ Ｍリン酸緩衝液（ｐＨ５，５）で
カラムを洗浄した後、０．１６ Ｍリン酸緩衝液（ｐＨ
８，５）で吸着していた一本鎖ウロキナーゼを溶出させ
た。2nd 1st ``FLL''! Cultured human kidney cells were cultured for 3 days in a serum-free culture medium supplemented with 0.1% human serum albumin, the culture medium was centrifuged, and the supernatant was frozen and stored. The pooled culture supernatant was p)15.
5 and then contacted with CM-3ephadex C-50. After washing the column with 0.16 M phosphate buffer (pH 5,5), 0.16 M phosphate buffer (pH 5,5) was added.
8,5), the adsorbed single-chain urokinase was eluted.
一方、−本領ウロキナーゼで予め免疫しておいたマウス
Ｂ Ａ Ｌ Ｂ ／ ｃの牌臓細胞とマウスミエローマ
細胞をポリエチレングリコールにより融合させたハイブ
リドーマのうち、−本領ウロキナーゼに対する抗体産生
の高いクローンを選択した。この融合細胞の培養液から
、−末鎖ウロキナーゼモノクローナル抗体を回収した。On the other hand, - Among the hybridomas obtained by fusing mouse BAL B/c spleen cells and mouse myeloma cells, which had been immunized with the original urokinase, using polyethylene glycol, - clones with high antibody production against the original urokinase were selected. . A -terminal chain urokinase monoclonal antibody was recovered from the culture solution of this fused cell.
このモノクローナル抗体をＢｒＣＮ活性化５ｅｐｈａｒ
ｏｓｅ ４ Ｂ （Ｐｈａｒ閣ａｃｉａ社）に固定した
。This monoclonal antibody was activated by BrCN.
ose 4 B (Pharmacia).
このモノクローナル抗体カラムを０．４ Ｍ ＮａＣ１
含有０．１ Ｍリン酸緩衝液（ｐＨ７，０）で平衡化し
、これに前記の一本鎖ウロキナーゼ前駆体を含有する溶
出液を接触した。０．４ Ｍ Ｎａ（：ｌ含有０．１
Ｍリン酸緩衝液（ｐＨ７，０）でカラムを洗浄した後、
吸着していたウロキナーゼ前駆体を０．５ Ｍ ＮａＣ
１含有０．１Ｍグリシン−ＨＣｌＣｌ水液８液Ｈ２，５
）で溶出させた。溶出液を除菌ｉ１過した後、凍結乾燥
し比活性が１５０．０００ＵＫ単位／ｍｇ（ウロキナー
ゼ変換時）の高度精製−本領ウロキナーゼを得た。この
−本領ウロキナーゼのアミノ酸配列は後記第３表に示す
通りである。This monoclonal antibody column was diluted with 0.4 M NaCl.
The solution was equilibrated with a 0.1 M phosphate buffer (pH 7.0), and the eluate containing the single-chain urokinase precursor was contacted therewith. 0.4 M Na (:l containing 0.1
After washing the column with M phosphate buffer (pH 7,0),
The adsorbed urokinase precursor was dissolved in 0.5 M NaC.
1 containing 0.1M glycine-HClCl aqueous solution 8 solutions H2.5
) was eluted. After the eluate was sterilized and filtered, it was lyophilized to obtain highly purified authentic urokinase with a specific activity of 150,000 UK units/mg (when converted to urokinase). The amino acid sequence of this main urokinase is shown in Table 3 below.
ｉ夕」コに亙１ぼし匹外足
Ｇｌｔ４１ｙ−Ａｒｇ−ＭＣＡ（ｐ−メチルクマリルア
ミド）を用いた合成基質法によって測定した。It was measured by a synthetic substrate method using Glt41y-Arg-MCA (p-methylcoumarylamide) in the external paw of one animal every day.
実験例１
血栓存在下で一本鎖ウロキナーゼもしくは二本類型ウロ
キナーゼとエキソコルポールを併用したときの線溶活性
をｉｎ ｖｉｔｒｏで検討した。Experimental Example 1 Fibrinolytic activity was investigated in vitro when exocolpol was used in combination with single-chain urokinase or two-chain urokinase in the presence of thrombus.
（実験方法）
１．７５ｄのヒト血漿に調製した人工血栓を加え、エキ
ソコルポール２５０μゼを終濃度が１２５ μ！／ｌｄ
となるよう添加した。その後、−本領ウロキナーゼ、二
本類型ウロキナーゼをそれぞれ２００μｌ添Ｈし、３７
℃でインキュベートした。添加後０〜５時間まで１時間
ごとに上記溶液を採取し、放射活性を測定した。なお、
血栓溶解率は開始時の人工血栓中の放射活性から各時間
の血漿中に漏出した放射活性を滅じることによって算出
した。(Experimental method) The prepared artificial thrombus was added to 1.75 d of human plasma, and the final concentration of exocorpol 250μ was 125μ! /ld
It was added so that Then, add 200 μl each of the original urokinase and the two-type urokinase, and
Incubated at ℃. The solution was sampled every hour from 0 to 5 hours after addition, and radioactivity was measured. In addition,
The thrombolysis rate was calculated by subtracting the radioactivity leaked into the plasma at each time from the radioactivity in the artificial thrombus at the start.
その結果を第１図に示す。The results are shown in FIG.
一本鎖ウロキナーゼ５０ Ｔ Ｕ／ｄにエキソコルボー
ルを１２５μｅ ／ ｄ併用すると適用後２時間を過ぎ
てより血栓溶解率が上昇し始め、適用後５時間では６３
％の血栓溶解率を示した。これに対して、−本領ウロキ
ナーゼ５０１ Ｕ／ｄ単独適用での血栓溶解率は適用後
５時間で１３．５％であり、エキソコルポール１２５μ
ｌ／Ｍ１併用により血栓溶解率が４．７倍に増幅された
ことを示す。When single-chain urokinase 50 T U/d was combined with exocorbol at 125 μe/d, the thrombolytic rate began to increase after 2 hours after application, and by 5 hours after application, the thrombolysis rate was 63 μe/d.
% thrombolysis rate. On the other hand, the thrombolysis rate when applying urokinase 501 U/d alone was 13.5% at 5 hours after application, and when exocolpol 125μ
This shows that the combined use of l/M1 amplified the thrombolytic rate by 4.7 times.
実験例２
ラット肺栓塞モデルで一本鎖ウロキナーゼとエキソコル
ボールを併用したときの線溶活性を検討した。Experimental Example 2 Fibrinolytic activity was investigated when single-chain urokinase and exocorbol were used together in a rat pulmonary embolism model.
（実験方法）
ＩＺＪ−フィブリンクロットを液体窒素冷却下で粉砕し
て調製した＋２５１−フィブリンサスペンションをラッ
トに静脈内投与し、その後各薬削を２５分間持続静脈内
投与した。薬剤投与を終了して３０分後ラットを層殺し
、その肺放射活性を測定した。血栓溶解率は実験終了時
の肺放射活性残存率を１２５１−フィブリンサスペンシ
ョン投与直後に層殺したラットの肺放射活性残存率で除
することにより求めた。その結果を第１表に示す。(Experimental Method) A +251-fibrin suspension prepared by crushing an IZJ-fibrin clot under liquid nitrogen cooling was intravenously administered to rats, and then each drug shaving was continuously intravenously administered for 25 minutes. Thirty minutes after drug administration, the rats were sacrificed and their lung radioactivity was measured. The thrombolysis rate was determined by dividing the residual rate of lung radioactivity at the end of the experiment by the residual rate of lung radioactivity of rats sacrificed immediately after administration of the 1251-fibrin suspension. The results are shown in Table 1.
一本鎖ウロキナーゼ１０万ＩＯ／ｋｇ単独でば血栓溶解
率は３８．０％であったが、エキソコルボール６０ｍ１
／ｋｇを併用することにより６２．９％ニ向上した。Single-chain urokinase alone at 100,000 IO/kg had a thrombolytic rate of 38.0%, but 60 mL of exocorbol
/kg improved by 62.9%.
実験例３
ラット肺栓塞モデルで一本鎖ウロキナーゼとフルオシ−
ルーＤＡを併用したときの線溶活性を検討した。Experimental Example 3 Single-chain urokinase and fluocycin in a rat pulmonary embolism model
Fibrinolytic activity was investigated when RuDA was used in combination.
（実験方法）
薬剤にフルオシ−ルーＤＡを用いて実験例２と同様の方
法で行なった。その結果を第２表に示す。(Experimental Method) The experiment was conducted in the same manner as in Experimental Example 2 using Fluocyl-DA as the drug. The results are shown in Table 2.
（以下余白〕
−末鎖ウロキナーゼ１０万ＩＵ／ｋｇ単独では血栓溶解
率は４９．６％であったが、フルオゾールＤＡ６０ｄ／
ｋｇを併用することにより７２．８％に向上した。以上
の結果から、ｉｎ ｖｉｖｏにおいてもポリオキシエ
チレン−ポリオキシプロピレン共重合体と併用すること
により、−末鎖ウロキナーゼの線溶活性が増強されるこ
とが証明された。(Margins below) - Thrombolytic rate was 49.6% with terminal chain urokinase 100,000 IU/kg alone, but with fluozol DA60d/kg
By using kg together, the improvement was increased to 72.8%. From the above results, it was proved that the fibrinolytic activity of -terminal chain urokinase is enhanced by using it in combination with polyoxyethylene-polyoxypropylene copolymer also in vivo.
［以下余白］[Margin below]
第１図は、−末鎖ウロキナーゼもしくは二本鎖型ウロキ
ナーゼとエキソコルボールを併用したときの血栓溶解率
の経時的変化を示す。FIG. 1 shows the time course of the thrombolytic rate when exocorbol is used in combination with -terminal chain urokinase or double-chain urokinase.
Claims (1)
有効成分とする一本鎖ウロキナーゼの線溶活性の増強剤
。An enhancer for fibrinolytic activity of single-chain urokinase containing a polyoxyethylene-polyoxypropylene copolymer as an active ingredient.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2109343A JPH049334A (en) | 1990-04-24 | 1990-04-24 | Fibrinolytic activity enhancer |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2109343A JPH049334A (en) | 1990-04-24 | 1990-04-24 | Fibrinolytic activity enhancer |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| JPH049334A true JPH049334A (en) | 1992-01-14 |
Family
ID=14507820
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP2109343A Pending JPH049334A (en) | 1990-04-24 | 1990-04-24 | Fibrinolytic activity enhancer |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH049334A (en) |
-
1990
- 1990-04-24 JP JP2109343A patent/JPH049334A/en active Pending
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