WO1992020361A1 - New combination of factor viii and an antifibrinolytic - Google Patents
New combination of factor viii and an antifibrinolytic Download PDFInfo
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- WO1992020361A1 WO1992020361A1 PCT/EP1992/000941 EP9200941W WO9220361A1 WO 1992020361 A1 WO1992020361 A1 WO 1992020361A1 EP 9200941 W EP9200941 W EP 9200941W WO 9220361 A1 WO9220361 A1 WO 9220361A1
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- Prior art keywords
- factor viii
- antifibrinolytic
- blood
- substances
- mixture
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- 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
- A61K38/55—Protease inhibitors
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
- A61K38/095—Oxytocins; Vasopressins; Related peptides
-
- 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
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
- A61K38/37—Factors VIII
Definitions
- the present invention relates to a new active ingredient combination of the blood coagulation factor VIII or a substance that increases its concentration in the blood, and an antifibrinolyti um.
- anticoagulants In the treatment of coronary heart diseases and for thrombosis prophylaxis in general, anticoagulants must be administered over a longer period of time. Patients who are treated with such substances are at risk of bleeding to death in the event of injuries because the blood's ability to clot is blocked or at least greatly reduced by the anticoagulants. Substances must therefore be available which are administered to patients treated with anticoagulants in the event of an injury, the need for surgery or in the event of an overdose and which eliminate or block the action of the anticoagulants. A 20 such substance should be available for each anticoagulant.
- Coagulation and fibrinolysis are in dynamic equilibrium in every organism. If a patient is treated with anticoagulants, this balance is shifted in favor of fibrinolysis 5 and blood clotting is impeded.
- Known anticoagulant substances are hirudin, heparin, low molecular weight heparins or synthetic thrombin inhibitors or hirudin derivatives. It has been described that, for example, the APTT-prolonging effect of hirudin can be partially abolished by applying factor VIII or fragments thereof (EP 367 713).
- factor VIII, its fragments or substances which increase its concentration in the blood has the disadvantage, however, that this treatment causes the effects of hirudin only in very high doses and not immediately, but only with a fairly large time Delay and incomplete cancellation because the release of factor VIII reaches its maximum in humans only after 30 to 60 minutes. For acute emergencies, the sole administration of 0 factor VIII for hemostasis is insufficient. It has now been found that the coagulation-promoting effect of blood coagulation factors such as factor VIII or a substance which increases its concentration in the blood can be greatly improved by adding further substances.
- the invention relates to a mixture of a) factor VIII, its active fragments and / or substances which cause the formation of factor VIII in the blood, and b) an antifibrinolytic.
- Factor VIII is a long-known factor of B - coagulation, which is applied prophylactically in patients with haemophilia A or Von Willebrand disease (vascular pseudohemophilia A) and before minor surgical interventions such as tooth extraction (Nature 312, 337 (1984)).
- Peptides whose sequences have homologies to factor VIII and which result from tryptic digestion of factor VIII or can be prepared synthetically and have factor VIII activity are suitable as active fragments of factor VIII.
- Factor VIII can be found in the plasma in a concentration of 1 U / ml. To neutralize the anticoagulant effects which are achieved with the usual doses of anticoagulants, the high dose of 30 to 200 U / kg of body weight is required with factor VIII alone.
- Desmopressin (Merck Index, 11th edition, No. 2904), adrenaline, ⁇ -vasopressin are described as substances which increase the concentration of factor VIII in the blood. However, all of these substances have other effects in the doses releasing factor VIII. For example, Desmopressin releases tPA, thereby increasing fibrinolytic activity. The tPA-releasing effect of desmopressin on humans reaches its maximum after only 20 min, the factor VIII releasing effect, however, only after 40 min (Thromb. Haem. 58, 366 (1987)).
- Desmopressin is used to reduce blood clotting times in the case of prophylactic administration before minor surgical interventions, in order to effectively eliminate acute bleeding risks after anticoagulant therapy, Desmopressin or another antidote that works by increasing blood coagulation factors can be combined with an antifibrinolytic.
- Aprotinin, tranexamic acid, ⁇ -aminocaproic acid and 4-aminomethylbenzoic acid are particularly suitable as antifibrinolytics.
- the components a) and b) are incorporated into the mixture in the amounts in which they are normally administered as individual substances. These dosages are usually for
- the mixture is usually administered intravenously.
- the new combination of active ingredients can be used very well as an antidote against anticoagulants in the case of bleeding complications, overdosage of the anticoagulant and in preparation for operations on patients who are treated with anticoagulants. It has the advantage that its effect begins immediately after IV application and that the required doses of blood coagulation factor VIII or of substances which increase the concentration of factor VIII in the blood are considerably lower as a result of the combination.
- synthetic thrombin inhibitors such as hirudin or hirudin derivatives
- warfarin phenprocoumon and acenocoumarol.
- the anti-oagulatory effect of hirudin and polyethylene glycol hirudin is particularly well inhibited.
- rats were administered intravenously with 1 mg / kg of hirudin at the time.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Medicinal Chemistry (AREA)
- Gastroenterology & Hepatology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Hematology (AREA)
- Zoology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Description
NEUE WIRKSTOFFKOMBINATION AUS FAKTOR VIII UND EINEM ANTIFIBRINOLYTIKUMNEW ACTIVE COMBINATION OF FACTOR VIII AND AN ANTIFIBRINOLYTIC
Beschreibungdescription
5 Die vorliegende Erfindung betrifft eine neue Wirkstoffkombination aus dem Blutgerinnungsfaktor VIII bzw. einer Substanz, die dessen Konzentration im Blut erhöht, und einem Antifibrinolyti um.5 The present invention relates to a new active ingredient combination of the blood coagulation factor VIII or a substance that increases its concentration in the blood, and an antifibrinolyti um.
Bei der Behandlung der koronaren Herzerkrankungen und zur 10 Thromboseprophylaxe allgemein müssen Antikoagulantia über einen längeren Zeitraum appliziert werden. Patienten, die mit solchen Substanzen behandelt werden, unterliegen der Gefahr, bei Ver¬ letzungen zu verbluten, weil die Gerinnungsfähigkeit des Blutes durch die Antikoagulantien blockiert oder zumindest stark 15 vermindert ist. Es müssen deshalb Substanzen bereit stehen, die im Fall einer Verletzung, der Notwendigkeit einer Operation oder bei Überdosierung an mit Antikoagulatien behandelte Patienten verabfolgt werden und die die Wirkung der Antikoagulantien beseitigen oder blockieren. Für jedes Antikoagulans sollte eine 20 solche Substanz zur Verfügung stehen.In the treatment of coronary heart diseases and for thrombosis prophylaxis in general, anticoagulants must be administered over a longer period of time. Patients who are treated with such substances are at risk of bleeding to death in the event of injuries because the blood's ability to clot is blocked or at least greatly reduced by the anticoagulants. Substances must therefore be available which are administered to patients treated with anticoagulants in the event of an injury, the need for surgery or in the event of an overdose and which eliminate or block the action of the anticoagulants. A 20 such substance should be available for each anticoagulant.
In jedem Organismus stehen Koagulation und Fibrinolyse in einem dynamischen Gleichgewicht. Wird ein Patient mit Antikoagulantien behandelt, so wird dieses Gleichgewicht zugunsten der Fibrinolyse 5 verschoben und die Blutgerinnung wird behindert.Coagulation and fibrinolysis are in dynamic equilibrium in every organism. If a patient is treated with anticoagulants, this balance is shifted in favor of fibrinolysis 5 and blood clotting is impeded.
Bekannte antikoagulatorisch wirkende Substanzen sind Hirudin, Heparin, niedermolekulare Heparine oder synthetische Thrombininhibitoren bzw. Hirudinabkömmlinge. Es ist beschrieben, 0 daß man z.B. die APTT-verlängernde Wirkung von Hirudin durch Applikation von Faktor VIII oder Fragmenten davon teilweise aufheben kann (EP 367 713). Die Anwendung von Faktor VIII, dessen Fragmenten oder Substanzen, die dessen Konzentration im Blut er¬ höhen, hat jedoch den Nachteil, daß durch diese Behandlung die 5 Wirkung von Hirudin erst in sehr hohen Dosen und nicht sofort, sondern nur mit einer ziemlich großen zeitlichen Verzögerung und unvollständig aufgehoben wird, da die Freisetzung von Faktor VIII ihr Maximum beim Menschen erst nach 30 bis 60 Minuten erreicht. Für den akuten Notfall ist daher die alleinige Gabe von 0 Faktor VIII zur Blutungsstillung unzureichend. Es wurde nun gefunden, daß man die gerinnungsfördernde Wirkung von Blutgerinnungsfaktoren wie Faktor VIII bzw. einer Substanz, die dessen Konzentration im Blut erhöht, durch Zusatz weiterer Substanzen stark verbessern kann.Known anticoagulant substances are hirudin, heparin, low molecular weight heparins or synthetic thrombin inhibitors or hirudin derivatives. It has been described that, for example, the APTT-prolonging effect of hirudin can be partially abolished by applying factor VIII or fragments thereof (EP 367 713). The use of factor VIII, its fragments or substances which increase its concentration in the blood has the disadvantage, however, that this treatment causes the effects of hirudin only in very high doses and not immediately, but only with a fairly large time Delay and incomplete cancellation because the release of factor VIII reaches its maximum in humans only after 30 to 60 minutes. For acute emergencies, the sole administration of 0 factor VIII for hemostasis is insufficient. It has now been found that the coagulation-promoting effect of blood coagulation factors such as factor VIII or a substance which increases its concentration in the blood can be greatly improved by adding further substances.
Gegenstand der Erfindung ist eine Mischung aus a) Faktor VIII, dessen aktiven Fragmenten und/oder Substanzen, die die Bildung von Faktor VIII im Blut bewirken, und b) einem Antifibrinolytikum.The invention relates to a mixture of a) factor VIII, its active fragments and / or substances which cause the formation of factor VIII in the blood, and b) an antifibrinolytic.
Faktor VIII ist ein seit langem bekannter Faktor der B -- gerinnung, der prophylaktisch bei Patienten mit Hämophiiie A oder Von Willebrand-Krankheit (vaskuläre Pseudohämophilie A) sowie vor kleineren chirurgischen Eingriffen wie Zahnextraktionen applϊziert wird (Nature 312, 337 (1984)). Als aktive Fragmente des Faktors VIII kommen Peptide in Betracht, deren Sequenzen Homologien zu Faktor VIII aufweisen und die durch tryptische Verdauung von Faktor VIII entstehen oder synthetisch hergestellt werden können und Faktor VIII-Aktivität besitzen. Faktor VIII ist im Plasma in einer Konzentration von 1 U/ml zu finden. Zur Neutralisierung von antikoagulatorischen Effekten, die mit üblichen Dosen an Antikoagulantien erzielt werden, ist mit Faktor VIII alleine die hohe Dosis von 30 bis 200 U/kg Körper¬ gewicht erforderlich.Factor VIII is a long-known factor of B - coagulation, which is applied prophylactically in patients with haemophilia A or Von Willebrand disease (vascular pseudohemophilia A) and before minor surgical interventions such as tooth extraction (Nature 312, 337 (1984)). Peptides whose sequences have homologies to factor VIII and which result from tryptic digestion of factor VIII or can be prepared synthetically and have factor VIII activity are suitable as active fragments of factor VIII. Factor VIII can be found in the plasma in a concentration of 1 U / ml. To neutralize the anticoagulant effects which are achieved with the usual doses of anticoagulants, the high dose of 30 to 200 U / kg of body weight is required with factor VIII alone.
Als Substanzen, die die Konzentration von Faktor VIII im Blut erhöhen, sind z.B. Desmopressin (Merck-Index, 11. Auflage, Nr. 2904), Adrenalin, α-Vasopressin beschrieben. Alle diese Substanzen haben jedoch in den den Faktor VIII freisetzenden Dosen noch andere Wirkungen. So setzt beispielsweise Desmopressin tPA frei und erhöht dadurch gleichzeitig die fibrinolytische Aktivität. Die tPA-fre setzende Wirkung von Desmopressin am Menschen erreicht bereits nach 20 min ihr Maximum, die den Faktor VIII freisetzende Wirkung dagegen erst nach 40 min (Thromb. Haem. 58, 366 (1987)). Desmopressin wird zur Verkürzung von Blutgerinnungszeiten bei prophylaktischer Gabe vor kleineren chirurgischen Eingriffen verwendet, um akute Blutungsgefahren nach einer Antikoagulans-Therapie wirksam aufzuheben, kann Desmopressin bzw. ein anderes über die Erhöhung von Blut- gerinnungsfaktoren wirkendes Antidot mit einem Antifibrinolytikum kombiniert werden. Als Antifibrinolytika eignen sich insbesondere Aprotinin, Tranexamsäure, ε-Aminocapronsäure und 4-Aminomethylbenzoesäure.Desmopressin (Merck Index, 11th edition, No. 2904), adrenaline, α-vasopressin are described as substances which increase the concentration of factor VIII in the blood. However, all of these substances have other effects in the doses releasing factor VIII. For example, Desmopressin releases tPA, thereby increasing fibrinolytic activity. The tPA-releasing effect of desmopressin on humans reaches its maximum after only 20 min, the factor VIII releasing effect, however, only after 40 min (Thromb. Haem. 58, 366 (1987)). Desmopressin is used to reduce blood clotting times in the case of prophylactic administration before minor surgical interventions, in order to effectively eliminate acute bleeding risks after anticoagulant therapy, Desmopressin or another antidote that works by increasing blood coagulation factors can be combined with an antifibrinolytic. Aprotinin, tranexamic acid, ε-aminocaproic acid and 4-aminomethylbenzoic acid are particularly suitable as antifibrinolytics.
In die Mischung werden die Bestandteile a) und b) in den Mengen eingearbeitet, in denen sie normalerweise als Einzelsubstanzen verabfolgt werden. Diese Dosierungen betragen in der Regel fürThe components a) and b) are incorporated into the mixture in the amounts in which they are normally administered as individual substances. These dosages are usually for
Faktor VIII: 10-200 U/kg Desmopressin: 0, 1-0, 8 μg/kg Aprotinin: 500-50.000 U/kg Tranexamsäure: 1-100 mg/kg ε-Aminocapronsäure: 5-150 mg/kg 4-Aminomethylbenzoesäure: 0,5-5,0 mg/kgFactor VIII: 10-200 U / kg desmopressin: 0.1-0.8 μg / kg aprotinin: 500-50,000 U / kg tranexamic acid: 1-100 mg / kg ε-aminocaproic acid: 5-150 mg / kg 4-aminomethylbenzoic acid : 0.5-5.0 mg / kg
Die Mischung wird in der Regel intravenös verabfolgt.The mixture is usually administered intravenously.
Die Lösungen für die Mischung werden in bekannter Weise hergestellt (vgl. H. Sucker et al., Pharmazeutische Technologie, Thie e-Verlag, Stuttgart 1978).The solutions for the mixture are prepared in a known manner (cf. H. Sucker et al., Pharmaceutical Technology, Thie e-Verlag, Stuttgart 1978).
Die neue Wirkstoffkombination läßt sich sehr gut als Antidot gegen Antikoagulantien bei Blutungskomplikationen, Überdosierung des Antikoagulans und zur Vorbereitung von Operationen an Patienten einsetzen, die mit Antikoagulantien behandelt werden. Sie hat den Vorteil, daß ihre Wirkung sofort nach der i .v.-Applikation einsetzt und daß die erforderlichen Dosen an Blutgerinnungsfaktor VIII bzw. an Substanzen, die die Konzentration von Faktor VIII im Blut erhöhen, durch die Kombination erheblich geringer sind.The new combination of active ingredients can be used very well as an antidote against anticoagulants in the case of bleeding complications, overdosage of the anticoagulant and in preparation for operations on patients who are treated with anticoagulants. It has the advantage that its effect begins immediately after IV application and that the required doses of blood coagulation factor VIII or of substances which increase the concentration of factor VIII in the blood are considerably lower as a result of the combination.
Als Antikoagulantien, nach deren Gabe die neue Kombination ein¬ gesetzt werden kann, sind besonders zu nennen: Heparin, nieder¬ molekulares Heparin (= LMWH), synthetische Thrombininhibitoren wie Hirudin bzw. Hirudinderivate sowie Warfarin, Phenprocoumon und Acenocoumarol. Ganz besonders gut wird die anti oagulato- rische Wirkung von Hirudin und Polyethylenglykolhirudin (vgl. WO 91/08229) gehemmt.As anticoagulants, after the administration of which the new combination can be used, particular mention should be made of: heparin, low molecular weight heparin (= LMWH), synthetic thrombin inhibitors such as hirudin or hirudin derivatives, and warfarin, phenprocoumon and acenocoumarol. The anti-oagulatory effect of hirudin and polyethylene glycol hirudin (cf. WO 91/08229) is particularly well inhibited.
Die gute Wirkung der Kombination zeigt folgender Versuch: Ratten wurde zum Zeitpunkt 0 1 mg/kg Hirudin intravenös appliziert.The following experiment shows the good effect of the combination: rats were administered intravenously with 1 mg / kg of hirudin at the time.
3 min danach wurde den Tieren Desmopressin bzw. Desmopressin plus Aprotinin infundiert. 10 min später wurde den Tieren die Schwanz¬ spitze entfernt (4 mm) und die subaquale Blutungszeit bestimmt. Die Ergebnisse sind in der Tabelle wiedergegeben. Sie zeigen eine klare Überlegenheit der Kombination gegenüber Desmopressin alleine.3 minutes later, the animals were given Desmopressin and Desmopressin plus Aprotinin infused. 10 min later, the tail tip was removed from the animals (4 mm) and the subaqual bleeding time was determined. The results are shown in the table. They show a clear superiority of the combination over desmopressin alone.
Lösungen zur intravenösen Applikation werden wie folgt hergestellt:Solutions for intravenous administration are made as follows:
1. 25 μg Desmopressin werden in 50 ml physiologischer Kochsalz¬ lösung aufgenommen. Dazu wird eine Lösung von 5 g Tranexam¬ säure in 100 ml physiologischer Kochsalzlösung gegeben. Die Mischung wird steril filtriert und in einen Infusionsbeutel gefüllt.1. 25 μg desmopressin are taken up in 50 ml physiological saline. A solution of 5 g of tranexamic acid in 100 ml of physiological saline is added. The mixture is sterile filtered and placed in an infusion bag.
2. 25 μg Desmopressin werden in 50 ml physiologischer Kochsalz¬ lösung aufgenommen. Dazu wird eine Lösung von 500 000 KIE Aprotinin in 50 ml physiologischer Kochsalzlösung gegeben. Die Mischung wird steril filtriert und in eine Ampulle gefüllt. 2. 25 μg desmopressin are taken up in 50 ml physiological saline solution. A solution of 500,000 KIE aprotinin in 50 ml of physiological saline is added. The mixture is sterile filtered and filled into an ampoule.
Claims
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DEP4115453.3 | 1991-05-11 | ||
| DE4115453A DE4115453A1 (en) | 1991-05-11 | 1991-05-11 | NEW ACTIVE COMPOUND |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO1992020361A1 true WO1992020361A1 (en) | 1992-11-26 |
Family
ID=6431488
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/EP1992/000941 Ceased WO1992020361A1 (en) | 1991-05-11 | 1992-04-30 | New combination of factor viii and an antifibrinolytic |
Country Status (2)
| Country | Link |
|---|---|
| DE (1) | DE4115453A1 (en) |
| WO (1) | WO1992020361A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0713881A2 (en) | 1994-10-20 | 1996-05-29 | BEHRINGWERKE Aktiengesellschaft | Use of vWF containing concentrate as combination therapy with antithrombotics and fibrinolytics |
| WO1998024474A1 (en) * | 1996-12-06 | 1998-06-11 | Fonden Til Fremme Af Eksperimentel Cancerforskning | Inhibition of invasive remodelling |
| US10980757B2 (en) | 2018-09-06 | 2021-04-20 | RTU Pharma SA | Ready-to-use tranexamic acid intravenous solution |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE4317282A1 (en) * | 1993-05-25 | 1994-12-01 | Behringwerke Ag | Medicines for the treatment of sepsis and septic shock |
| AT409335B (en) * | 1998-11-10 | 2002-07-25 | Immuno Ag | PHARMACEUTICAL PREPARATION CONTAINING A RECEPTOR ANTAGONIST FOR THE TREATMENT OF BLOOD COagulation disorders |
| EP1190724B8 (en) * | 2000-09-22 | 2006-05-03 | Perlei Medical Produkte GmbH | Use of antifibrinolytic agents for preparing sponges, compresses or dressings |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2085729A (en) * | 1980-10-17 | 1982-05-06 | Dainippon Pharmaceutical Co | Pharmaceutical composition for oral administration containing coagulation factor VIII |
-
1991
- 1991-05-11 DE DE4115453A patent/DE4115453A1/en not_active Withdrawn
-
1992
- 1992-04-30 WO PCT/EP1992/000941 patent/WO1992020361A1/en not_active Ceased
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2085729A (en) * | 1980-10-17 | 1982-05-06 | Dainippon Pharmaceutical Co | Pharmaceutical composition for oral administration containing coagulation factor VIII |
Non-Patent Citations (4)
| Title |
|---|
| Biological Abstracts, Band 68, Nr. 4, 1992, (Philadelphia, PA, US), I.M. NILSSON et al.: "Factor VIII concentrate prepared from DDAVP stimulated blood donor plasma", siehe Zusammenfassung Nr. 19931, & SCAND. J. HAEMATOL. 221(1), 42-46, 1979, siehe Zusammenfassung * |
| Biological Abstracts, Band 81, Nr. 6, 1986, (Philadelphia, PA, US), A.K. BURROUGHS et al.: "Desmopressin and bleeding time in patients with cirrhosis", siehe Seite AB-751, Zusammenfassung Nr. 55563, & BR. MED. J. 291(6506), 1377-1381, 1985, siehe Zusammenfassung * |
| Biological Abstracts, Band 83, Nr. 9, 1987, (Philadelphia, PA, US), S. SCHULMAN et al.: "DDAVP-induced correction of prolonged bleeding time in patients with congenital platelet function defects", siehe Seite AB-871, Zusammenfassung Nr. 89480, & THROMB. RES. 45(2), 165-174, 1987, siehe Zusammenfassung * |
| Dialog Embase, Dialog Nr. 1451927, Embase Nr. 79222355, I.M. NILSSON et al.: "DDAVP factor VIII concentrate and its properties in vivo and in vitro", & THROMB. RES. (USA), 1979, 15/1-2, 263-271, siehe Zusammenfassung * |
Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0713881A2 (en) | 1994-10-20 | 1996-05-29 | BEHRINGWERKE Aktiengesellschaft | Use of vWF containing concentrate as combination therapy with antithrombotics and fibrinolytics |
| EP0713881A3 (en) * | 1994-10-20 | 1996-08-21 | Behringwerke Ag | Use of concentration containing vWF with antithrombotic and fibrinolytic agents in combination therapy |
| US5571784A (en) * | 1994-10-20 | 1996-11-05 | Behringwerke Aktiengesellschaft | Use of VWF-containing concentrates as a therapy which is employed in combination with antithrombotic and fibrinolytic therapy |
| WO1998024474A1 (en) * | 1996-12-06 | 1998-06-11 | Fonden Til Fremme Af Eksperimentel Cancerforskning | Inhibition of invasive remodelling |
| US10980757B2 (en) | 2018-09-06 | 2021-04-20 | RTU Pharma SA | Ready-to-use tranexamic acid intravenous solution |
| US11696905B2 (en) | 2018-09-06 | 2023-07-11 | RTU Pharma SA | Ready-to-use tranexamic acid intravenous solution |
Also Published As
| Publication number | Publication date |
|---|---|
| DE4115453A1 (en) | 1992-11-12 |
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