CA2156990A1 - Pharmaceutical which is suitable for employment as an antidote to blood anticoagulants, and its use - Google Patents
Pharmaceutical which is suitable for employment as an antidote to blood anticoagulants, and its useInfo
- Publication number
- CA2156990A1 CA2156990A1 CA002156990A CA2156990A CA2156990A1 CA 2156990 A1 CA2156990 A1 CA 2156990A1 CA 002156990 A CA002156990 A CA 002156990A CA 2156990 A CA2156990 A CA 2156990A CA 2156990 A1 CA2156990 A1 CA 2156990A1
- Authority
- CA
- Canada
- Prior art keywords
- pharmaceutical
- prothrombin
- blood
- antidote
- anticoagulants
- 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.)
- Abandoned
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4833—Thrombin (3.4.21.5)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/02—Antidotes
-
- 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
-
- 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
- A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
Abstract
A pharmaceutical is disclosed which is used as an anti-dote to blood anticoagulants and which contains prothrombin.
Description
~ 21569g~
I~,e; H~~ . AKT ~ ~N~ T~ C~AFT 1994/BO14--Ma 1040 Dr. Bc/hg Pharmaceutical which is :3uitable f or employment as an antidote to blood anticoagulants, and its use The invention relates to an antidote to blood anticoagulants .
8100d coagulation is a complex process in which plasma proteins and cells are involved. Formation of a wound 10 closure is initiated by rapid adhesion of blood platelets to the damaged surf aces and by proteases and contact factor3 which are activated successively in a cascade-like reaction sequence. This course of events leads to the production of thrombin which, inter alia, catalyzes 15 activation of fibrinogen to form fibrin.
Proteins such as factors VIII and V contribute, as accelerators, to the Pff;~;Pn~y of this system. In addition to the protein C sy~tem, inhibitors of the proteases involved essentially regulate the coagulation 20 processes in such a way that, while wound closure takes place, excessive reactions are avoided. Disturbance of this f inely tuned equilibrium can lead to f ibrin deposition or the formation of thromboses. AS is known, the vessel occlusions which re~ult ~rom this are t~e 25 cause of many pathophysiological processes 3uch as cardiac infarction, Ln particular. This problem assumes particular importance in those patients who are subject to increased risk of thromboYis, which often represents a post-operative complication.
30 Various approaches are taken for preventing these pathophysiological processes. Thus, anticoagulants which intervene in dif f erent ways in the event of coagulation are often used in clinical practice to prevent the formation of a thrombu~ or el~e to support its disso-35 lution (th~ombolysis). In addition to reducing or pre-~ venting t~rombocyte functions ~aggregation, adhesion and 21~990 activation and the synthesis and aecretion of activation produc ts ), inhibitors of participating coagulation proteases, in particular of the thromboplastin/factor VIIa complex, of factor Xa and, in particular, of 5 thrombin (factor IIa) are being investigated and applied.
E~irudin, which was originally isolated from the salivary glands of the leech ~lirudo m~ n;ll;s~ is a particularly specific and potent inhibitor of thrombin. In the interim, a variety of different variants, analogs, 10 fragmellts and mutants of hirudin have become known and are being investigated for their suitability. While hirudill is sulfated in its naturally occurring form, it has been observed that the advantageous biological activity is also retained in the non-sulfated form. As a 15 consequence, hirudin or its derivatives can conveniently be prepared by means of genetic manipulation.
The blood anticoagulants also include heparin, and its fragments and variants, as well as synthetic inhibitors which inhibit the catalytic activity of thrombin and 20 other coagulation proteases, for example factor Xa. These components can also be employed in the prophylaxis and/or therapy of thrombotic or pre-thrombotic complications.
The search for ever more specific and potent anticoagulants and antithrombotic agents reflects the 25 unsatisfactory situation that the ~l;n;r-;~lly established substances such as heparins or vitamin K antagonists are either insuf~;c~;~n~ly effective or else exhibit side effects which are undesirable and in some cases serious.
3~irudin is currently the most powerful known thrombin 30 inhibitor which does not also interfere wlth the other enzymes of the blood coagulation cascade. To date, hirudin has not been observed to have any appreciable side effects on pulse rate, respiration, blood pressure, thrombocyte count or the content of fibrinogen or 35 hemoglobin. For this reason, hirudin ls a preferred blood anticoagulant .
21~6990 , ~
The u3e o anticoagulants or antithrombotic agents in a patient naturally entails the risk of increasing the tendency to bleed which, in extreme situations, for example in a3sociation with improper use or dosing, can 5 lead to uncontrolled hemorrhages. In order to be able to counteract the undesirable tendency to bleed in such a situation, it is possible rapidly to remove some 3ubstances, whose constitution (molecular weight and structure) p~rmits it, from the blood plasma of the 10 pa~:ient by dialysis. ~owever when this is not possible due to the lack of appropriate apparatus or for other reasons, an antidote must be made available.
Some substances or preparations have already been pro-posed as antidotes. Thus, the thrombins and their blocked 15 variants exhibit a certain hirudin-neutralizing effect;
however, on the one hand, the use of active thrombin in patients who are being treated with blood anticoagulants is contraindicated as a rule and, on the other, it is problematic to prepare inactive thrombin using low 20 molecular weight inhibitors which enter into covalent bonds, owing to the toxicity of these substances. In addition, there is a lack of experience with regard to whether these complexes possibly have an antigenic effect. Owing to their nature, these complexes are not 25 suitable for neutralizing low molecular weight (synthetic) antithrombins or antithrombotic agents. While meizothrombin, an intermediate which arises briefly when prothrombin is activated to form thrombin, possesses a certain antagonistic potency, it can transform rapidly 30 into thrombin in vivo and, as such, is contraindicated as a rule.
Investigation of factor V~I as a hirudin antidote in appropriate models failed to provide satisfactory results. European Patent Application EPA 89.810733.9 35 describe3 the use of factor VIII, or fragments of factor VIII, as antidotes to blood anticoagulants. It is also known that substances, such as, for example, desmopressin . , .. . ~
21S~99~
(Mannucci, P.M., Progress in ~aemostasis and ~hrombosis, 8 (1986), pp. 19-45~, can be used which increase the concentration of factor VIII in the blood.
Eowever, since even these antidotes are not ade~uate for 5 all areas of application, there is still the need to make available antidotes to blood anticoagulants, anti-thrombotic agents and platelet antagonists which are more effective and have fewer side effects.
Within the scope of the present applic~;orl, anti-10 coagulatory or antithrombotic substances are understoodto mean glycosaminoglycans and sulfated polysaccharides, including heparins, in particular unfractionated and low molecular weight (LMW) pentosan polysulfate, heparan sulfate, dermatan sulfate or chondroitin sulfate, and 15 also hirudins and their fragments, for example hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 3561, analogs or mutant~, for example Eirulog~) (W0 92/13952), coupled hirudins, for example PEG-hirudin or hirutonins, natural or synthetic inhibitors of the thrombo-20 plastin/factor VIIa complex, of factor Xa or of thrombin,components of the protein C system, namely activated protein C, protein S and throm`onmo~l-l;n, inhibitor3 of fibrin aggregation or crosslinking, substances from the vitamin ~ antago~ist group, substances which have an 25 effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-l inhibitors, or stimulators of 30 the synthesis and secretion of ~7~ nngen activator inhibitors, and thus have an indirect antithrombotic effect.
It is particularly important to provide a suitable antidote to the said coupled hirudins, for example PEG-35 hirudin, since these coupled hirudins can only be removedfrom the organism with dificulty.
21~699~
It has been found, 3urprisingly, that prothrombin (factor II) is highly effective a3 an antidote to blood anticoagulants .
The present invention therefore relates to a pharma-5 ceutical which contains prothrombin for antagonizingblood anticoagulants, it being possible for these blood anticoagulants to be selected from the group consisting of glycosaminoglycans and sulfated polysaccharides, and also hirudins, and their fragments, analogs or mutants, lO natural and synthetic inhibitors of the thromboplastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S and thrombomodulin, inhibitors of fibrin aggregation or crossllnking, sub-15 stances from the vitamin K antagonist group, substanceswhich have an ef fect on platelet activation and/or platelet aggregation and also platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for 20 fibrinolysis, such as, in particular, PAI-I inhibitors or stimulators of the synthesis and secretion o~ plasminogen activator inhibitors.
Within the scope of the present invention, prothrombin is also understood to mean active ~r~ ~ L8 or variants 25 which can be prepared conventionally or, in particular, by genetic manipulation.
In the pharmaceutical according to the invention, prothrombin is employed in a concentration of from I to 2000 international units (I~ per kilogram of the 30 bodyweight of the patient to be treated, with concen-trations of from lO to lO00 IU~kg being particularly pref erred .
The invention also relates to the use of prothrombin as an antidote to blood anticoagulants.
~, 21~69~0 The invention fur~h. -= relateR to a proces~ for preparing a pharmaceutical which contain3 prothrombin for antagonlzing blood anticoagulantR.
The pre3ent invention i8 illustrated further by the 5 f ollowing example .
E~xample Standard human plasma (S~P) to which 20 llg/ml hirudin were added was investigated in the aPTT te3t for the antagonizing effect of prothrombin (F II). The coagu-10 lation times shown in the table verify the effectivenes~of prothrombin.
Ta`ole aPTT ( 3ec Control >2 0 0 0 . 0 2 IU factor II 258 . 7 2 IU factor ~r >2000.0 2 IU ~Eactor VI~ >2000 . O
2 IU factor VIII >2000.0 2 IU factor IX >2000 . 0 2 IU factor X . >2000 . 0
I~,e; H~~ . AKT ~ ~N~ T~ C~AFT 1994/BO14--Ma 1040 Dr. Bc/hg Pharmaceutical which is :3uitable f or employment as an antidote to blood anticoagulants, and its use The invention relates to an antidote to blood anticoagulants .
8100d coagulation is a complex process in which plasma proteins and cells are involved. Formation of a wound 10 closure is initiated by rapid adhesion of blood platelets to the damaged surf aces and by proteases and contact factor3 which are activated successively in a cascade-like reaction sequence. This course of events leads to the production of thrombin which, inter alia, catalyzes 15 activation of fibrinogen to form fibrin.
Proteins such as factors VIII and V contribute, as accelerators, to the Pff;~;Pn~y of this system. In addition to the protein C sy~tem, inhibitors of the proteases involved essentially regulate the coagulation 20 processes in such a way that, while wound closure takes place, excessive reactions are avoided. Disturbance of this f inely tuned equilibrium can lead to f ibrin deposition or the formation of thromboses. AS is known, the vessel occlusions which re~ult ~rom this are t~e 25 cause of many pathophysiological processes 3uch as cardiac infarction, Ln particular. This problem assumes particular importance in those patients who are subject to increased risk of thromboYis, which often represents a post-operative complication.
30 Various approaches are taken for preventing these pathophysiological processes. Thus, anticoagulants which intervene in dif f erent ways in the event of coagulation are often used in clinical practice to prevent the formation of a thrombu~ or el~e to support its disso-35 lution (th~ombolysis). In addition to reducing or pre-~ venting t~rombocyte functions ~aggregation, adhesion and 21~990 activation and the synthesis and aecretion of activation produc ts ), inhibitors of participating coagulation proteases, in particular of the thromboplastin/factor VIIa complex, of factor Xa and, in particular, of 5 thrombin (factor IIa) are being investigated and applied.
E~irudin, which was originally isolated from the salivary glands of the leech ~lirudo m~ n;ll;s~ is a particularly specific and potent inhibitor of thrombin. In the interim, a variety of different variants, analogs, 10 fragmellts and mutants of hirudin have become known and are being investigated for their suitability. While hirudill is sulfated in its naturally occurring form, it has been observed that the advantageous biological activity is also retained in the non-sulfated form. As a 15 consequence, hirudin or its derivatives can conveniently be prepared by means of genetic manipulation.
The blood anticoagulants also include heparin, and its fragments and variants, as well as synthetic inhibitors which inhibit the catalytic activity of thrombin and 20 other coagulation proteases, for example factor Xa. These components can also be employed in the prophylaxis and/or therapy of thrombotic or pre-thrombotic complications.
The search for ever more specific and potent anticoagulants and antithrombotic agents reflects the 25 unsatisfactory situation that the ~l;n;r-;~lly established substances such as heparins or vitamin K antagonists are either insuf~;c~;~n~ly effective or else exhibit side effects which are undesirable and in some cases serious.
3~irudin is currently the most powerful known thrombin 30 inhibitor which does not also interfere wlth the other enzymes of the blood coagulation cascade. To date, hirudin has not been observed to have any appreciable side effects on pulse rate, respiration, blood pressure, thrombocyte count or the content of fibrinogen or 35 hemoglobin. For this reason, hirudin ls a preferred blood anticoagulant .
21~6990 , ~
The u3e o anticoagulants or antithrombotic agents in a patient naturally entails the risk of increasing the tendency to bleed which, in extreme situations, for example in a3sociation with improper use or dosing, can 5 lead to uncontrolled hemorrhages. In order to be able to counteract the undesirable tendency to bleed in such a situation, it is possible rapidly to remove some 3ubstances, whose constitution (molecular weight and structure) p~rmits it, from the blood plasma of the 10 pa~:ient by dialysis. ~owever when this is not possible due to the lack of appropriate apparatus or for other reasons, an antidote must be made available.
Some substances or preparations have already been pro-posed as antidotes. Thus, the thrombins and their blocked 15 variants exhibit a certain hirudin-neutralizing effect;
however, on the one hand, the use of active thrombin in patients who are being treated with blood anticoagulants is contraindicated as a rule and, on the other, it is problematic to prepare inactive thrombin using low 20 molecular weight inhibitors which enter into covalent bonds, owing to the toxicity of these substances. In addition, there is a lack of experience with regard to whether these complexes possibly have an antigenic effect. Owing to their nature, these complexes are not 25 suitable for neutralizing low molecular weight (synthetic) antithrombins or antithrombotic agents. While meizothrombin, an intermediate which arises briefly when prothrombin is activated to form thrombin, possesses a certain antagonistic potency, it can transform rapidly 30 into thrombin in vivo and, as such, is contraindicated as a rule.
Investigation of factor V~I as a hirudin antidote in appropriate models failed to provide satisfactory results. European Patent Application EPA 89.810733.9 35 describe3 the use of factor VIII, or fragments of factor VIII, as antidotes to blood anticoagulants. It is also known that substances, such as, for example, desmopressin . , .. . ~
21S~99~
(Mannucci, P.M., Progress in ~aemostasis and ~hrombosis, 8 (1986), pp. 19-45~, can be used which increase the concentration of factor VIII in the blood.
Eowever, since even these antidotes are not ade~uate for 5 all areas of application, there is still the need to make available antidotes to blood anticoagulants, anti-thrombotic agents and platelet antagonists which are more effective and have fewer side effects.
Within the scope of the present applic~;orl, anti-10 coagulatory or antithrombotic substances are understoodto mean glycosaminoglycans and sulfated polysaccharides, including heparins, in particular unfractionated and low molecular weight (LMW) pentosan polysulfate, heparan sulfate, dermatan sulfate or chondroitin sulfate, and 15 also hirudins and their fragments, for example hirugen (J. Biol. Chem. 265 (1990), 13484-13487; EP-A-0 333 3561, analogs or mutant~, for example Eirulog~) (W0 92/13952), coupled hirudins, for example PEG-hirudin or hirutonins, natural or synthetic inhibitors of the thrombo-20 plastin/factor VIIa complex, of factor Xa or of thrombin,components of the protein C system, namely activated protein C, protein S and throm`onmo~l-l;n, inhibitor3 of fibrin aggregation or crosslinking, substances from the vitamin ~ antago~ist group, substances which have an 25 effect on platelet activation and/or platelet aggregation or else platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for fibrinolysis, such as, in particular, PAI-l inhibitors, or stimulators of 30 the synthesis and secretion of ~7~ nngen activator inhibitors, and thus have an indirect antithrombotic effect.
It is particularly important to provide a suitable antidote to the said coupled hirudins, for example PEG-35 hirudin, since these coupled hirudins can only be removedfrom the organism with dificulty.
21~699~
It has been found, 3urprisingly, that prothrombin (factor II) is highly effective a3 an antidote to blood anticoagulants .
The present invention therefore relates to a pharma-5 ceutical which contains prothrombin for antagonizingblood anticoagulants, it being possible for these blood anticoagulants to be selected from the group consisting of glycosaminoglycans and sulfated polysaccharides, and also hirudins, and their fragments, analogs or mutants, lO natural and synthetic inhibitors of the thromboplastin/factor VIIa complex, of factor Xa or of thrombin, components of the protein C system, namely activated protein C, protein S and thrombomodulin, inhibitors of fibrin aggregation or crossllnking, sub-15 stances from the vitamin K antagonist group, substanceswhich have an ef fect on platelet activation and/or platelet aggregation and also platelet adhesion, such as, in particular, fibrinogen receptor antagonists, or which are able to increase the endogenous capacity for 20 fibrinolysis, such as, in particular, PAI-I inhibitors or stimulators of the synthesis and secretion o~ plasminogen activator inhibitors.
Within the scope of the present invention, prothrombin is also understood to mean active ~r~ ~ L8 or variants 25 which can be prepared conventionally or, in particular, by genetic manipulation.
In the pharmaceutical according to the invention, prothrombin is employed in a concentration of from I to 2000 international units (I~ per kilogram of the 30 bodyweight of the patient to be treated, with concen-trations of from lO to lO00 IU~kg being particularly pref erred .
The invention also relates to the use of prothrombin as an antidote to blood anticoagulants.
~, 21~69~0 The invention fur~h. -= relateR to a proces~ for preparing a pharmaceutical which contain3 prothrombin for antagonlzing blood anticoagulantR.
The pre3ent invention i8 illustrated further by the 5 f ollowing example .
E~xample Standard human plasma (S~P) to which 20 llg/ml hirudin were added was investigated in the aPTT te3t for the antagonizing effect of prothrombin (F II). The coagu-10 lation times shown in the table verify the effectivenes~of prothrombin.
Ta`ole aPTT ( 3ec Control >2 0 0 0 . 0 2 IU factor II 258 . 7 2 IU factor ~r >2000.0 2 IU ~Eactor VI~ >2000 . O
2 IU factor VIII >2000.0 2 IU factor IX >2000 . 0 2 IU factor X . >2000 . 0
Claims (5)
1. A pharmaceutical which contains prothrombin for antagonizing blood anticoagulants.
2. A pharmaceutical as claimed in claim 1, where prothrombin means active fragments or variants of prothrombin which are prepared either conventionally or by genetic manipulation.
3. A pharmaceutical as claimed in claim 1, which con-tains prothrombin in a concentration of from 1 to 2000 international units (IU) per kilogram of the bodyweight of the patient to be treated.
4. A pharmaceutical as claimed in claim 3, in which the prothrombin concentration is from 10 to 1000 IU/kg of the bodyweight of the patient to be treated.
5. A process for preparing a pharmaceutical as claimed in claim 1 for antagonizing blood anticoagulants.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4430204.5 | 1994-08-26 | ||
| DE4430204A DE4430204A1 (en) | 1994-08-26 | 1994-08-26 | Medicament, which is suitable as an antidote for blood anticoagulants and its use |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2156990A1 true CA2156990A1 (en) | 1996-02-27 |
Family
ID=6526563
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002156990A Abandoned CA2156990A1 (en) | 1994-08-26 | 1995-08-25 | Pharmaceutical which is suitable for employment as an antidote to blood anticoagulants, and its use |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0700682A3 (en) |
| JP (1) | JP3838680B2 (en) |
| KR (1) | KR960006920A (en) |
| AU (1) | AU708409B2 (en) |
| CA (1) | CA2156990A1 (en) |
| DE (1) | DE4430204A1 (en) |
| IL (1) | IL115057A0 (en) |
| ZA (1) | ZA957140B (en) |
Families Citing this family (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE19625642A1 (en) * | 1996-06-26 | 1998-01-08 | Max Planck Gesellschaft | A process for preparing an antidote precursor for natural and synthetic thrombin inhibitors |
| KR20030031380A (en) * | 2001-10-13 | 2003-04-21 | 이우진 | Skateboard |
| WO2003099324A1 (en) * | 2002-05-23 | 2003-12-04 | Chugai Seiyaku Kabushiki Kaisha | Agent neutralizint tissue factor inhibitor and agent neutralizing activated blood coagulation factor viii preparation |
| KR20040046045A (en) * | 2002-11-26 | 2004-06-05 | 김재영 | Paduk board and chess board that use copper material and maunfacturing method thereof |
| GB0324044D0 (en) | 2003-10-14 | 2003-11-19 | Astrazeneca Ab | Protein |
| EP1874928A1 (en) | 2005-04-13 | 2008-01-09 | AstraZeneca AB | A host cell comprising a vector for production of proteins requiring gamma-carboxylation |
| US8206967B2 (en) | 2007-07-06 | 2012-06-26 | Medimmune Limited | Method for production of recombinant human thrombin |
| KR20130136988A (en) * | 2010-10-06 | 2013-12-13 | 메디뮨 리미티드 | Factor ii and fibrinogen for treatment of haemostatic disorders |
Family Cites Families (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5850202B2 (en) * | 1977-11-10 | 1983-11-09 | 第一製薬株式会社 | Production method of prothrompin |
| DE3043857A1 (en) * | 1980-11-21 | 1982-07-08 | Behringwerke Ag, 3550 Marburg | METHOD FOR THE PRODUCTION OF BLOOD coagulation FACTORS AND THE PREPARATION OF FACTORS II AND VII THEREFORE PRODUCED |
| DD251078A1 (en) * | 1986-07-17 | 1987-11-04 | Bezirksinstitut Fuer Blutspend | PROCESS FOR THE PREPARATION OF PROTHROMBIN CONCENTRATES |
| GB8729822D0 (en) * | 1987-12-22 | 1988-02-03 | Central Blood Lab Authority | Chemical process |
| AU3098289A (en) | 1988-03-04 | 1989-09-07 | Biogen, Inc. | Hirudin peptides |
| JPH0219400A (en) * | 1988-07-07 | 1990-01-23 | Green Cross Corp:The | Production of thrombin or prothronbin |
| US5240913A (en) | 1989-08-18 | 1993-08-31 | Biogen, Inc. | Inhibitors of thrombin |
| JP2549224B2 (en) * | 1990-01-26 | 1996-10-30 | イムノ・アクチェンゲゼルシャフト | Recombinantly produced blood factor, method for expressing the blood factor, and vaccinia virus recombinant used in the method |
| DE4203965A1 (en) * | 1992-02-11 | 1993-08-12 | Max Planck Gesellschaft | ANTIDOT FOR HIRUDIN AND SYNTHETIC THROMBIN INHIBITORS |
| AT397391B (en) * | 1992-05-15 | 1994-03-25 | Immuno Ag | USE OF PROTHROMIN FRAGMENTS |
-
1994
- 1994-08-26 DE DE4430204A patent/DE4430204A1/en not_active Withdrawn
-
1995
- 1995-08-10 EP EP95112569A patent/EP0700682A3/en not_active Withdrawn
- 1995-08-24 IL IL11505795A patent/IL115057A0/en unknown
- 1995-08-24 AU AU30256/95A patent/AU708409B2/en not_active Ceased
- 1995-08-25 KR KR1019950026511A patent/KR960006920A/en not_active Application Discontinuation
- 1995-08-25 ZA ZA957140A patent/ZA957140B/en unknown
- 1995-08-25 CA CA002156990A patent/CA2156990A1/en not_active Abandoned
- 1995-08-25 JP JP21683995A patent/JP3838680B2/en not_active Expired - Fee Related
Also Published As
| Publication number | Publication date |
|---|---|
| EP0700682A3 (en) | 1996-05-29 |
| JPH0859505A (en) | 1996-03-05 |
| KR960006920A (en) | 1996-03-22 |
| DE4430204A1 (en) | 1996-02-29 |
| JP3838680B2 (en) | 2006-10-25 |
| ZA957140B (en) | 1996-03-26 |
| AU3025695A (en) | 1996-03-07 |
| EP0700682A2 (en) | 1996-03-13 |
| IL115057A0 (en) | 1995-12-08 |
| AU708409B2 (en) | 1999-08-05 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Cronberg et al. | Suppressive effect of dextran on platelet adhesiveness | |
| Lijnen et al. | Heparin binding properties of human histidine-rich glycoprotein. Mechanism and role in the neutralization of heparin in plasma. | |
| Ohman et al. | Use of aortic counterpulsation to improve sustained coronary artery patency during acute myocardial infarction. Results of a randomized trial. The Randomized IABP Study Group. | |
| Agnelli et al. | The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits | |
| Macintyre et al. | The haemostatic effects of hydroxyethyl starch (HES) used as a volume expander | |
| Thomas et al. | A low molecular weight heparin compared with unfractionated heparin | |
| JP3859176B2 (en) | Compositions suitable for use as antidote to anticoagulants and their use | |
| CA2186390A1 (en) | Combinations of thrombolytically active proteins and anticoagulants, and uses thereof | |
| CZ298552B6 (en) | Pharmaceutical composition and use thereof for preparation of a medicament | |
| CA2156990A1 (en) | Pharmaceutical which is suitable for employment as an antidote to blood anticoagulants, and its use | |
| EP0372670A3 (en) | Hirudin peptides for inhibiting platelet aggregation | |
| US5464615A (en) | Use of transglutaminases as immunosuppressants | |
| US5817309A (en) | Antidote for hirudin and synthetic thrombin inhibitors and method of use | |
| Rebello et al. | Antithrombotic efficacy of a novel factor Xa inhibitor, FXV673, in a canine model of coronary artery thrombolysis | |
| JPH02108633A (en) | Use of plasminogen activating factor inhibitor (pai-2) as immune inhibitor | |
| Schenk et al. | A recombinant hirudin (IK-HIR02) in healthy volunteers | |
| de Prost et al. | Pentosane polysulfate: The effect on hemostasis of a continuous 3‐day infusion | |
| Rübsamen et al. | Prevention of early reocclusion after thrombolysis of copper coil-induced thrombi in the canine carotid artery: comparison of PEG-hirudin and unfractionated heparin | |
| De Prost | Heparin fractions and analogues: a new therapeutic possibility for thrombosis | |
| AU3799199A (en) | Compositions which are suitable for employment as antidotes to blood anticoagulants, and their use | |
| Rebello et al. | Antithrombotic efficacy of single subcutaneous administration of a recombinant nematode anticoagulant peptide (rNAP5) in a canine model of coronary artery thrombolysis | |
| Frisch | Influence of Brinase on Fibrinogen: Fibrin Transition in in vitro and in vivo Studies | |
| Tapparelli et al. | Antithrombotic activity in vivo of SDZ 217-766, a low-molecular weight thrombin inhibitor in comparison to heparin | |
| Uziel et al. | Extracorporeal circulation. Problems and answers | |
| Matos et al. | Reversing the detrimental effect of adriamycin on skin grafts in rats |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| FZDE | Discontinued |