+

WO1992020361A1 - New combination of factor viii and an antifibrinolytic - Google Patents

New combination of factor viii and an antifibrinolytic Download PDF

Info

Publication number
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
Authority
WO
WIPO (PCT)
Prior art keywords
factor viii
antifibrinolytic
blood
substances
mixture
Prior art date
Application number
PCT/EP1992/000941
Other languages
German (de)
French (fr)
Inventor
Verena Baldinger
Original Assignee
Knoll Aktiengesellschaft
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Knoll Aktiengesellschaft filed Critical Knoll Aktiengesellschaft
Publication of WO1992020361A1 publication Critical patent/WO1992020361A1/en

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
    • A61K38/55—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.

Landscapes

  • 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

A mixture of (a) factor VIII, its active fragments and/or substances that cause the release or the formation of factor VIII in blood, and of (b) an antifibrinolytic is useful as an antidote for anticoagulants.

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.
Figure imgf000007_0002
Figure imgf000007_0002
Figure imgf000007_0004
Figure imgf000007_0004
Figure imgf000007_0003
Figure imgf000007_0001
Figure imgf000007_0003
Figure imgf000007_0001

Claims

Patentansprüche Claims
1. Mischung aus a) Faktor VIII, dessen aktiven Fragmenten und/oder Substanzen, die die Freisetzung bzw. Bildung von Faktor VIII im Blut bewirken, und b) einem Antifibrinolytikum.1. Mixture of a) factor VIII, its active fragments and / or substances which cause the release or formation of factor VIII in the blood, and b) an antifibrinolytic.
2. Lösung enthaltend eine Mischung gemäß Anspruch 1.2. Solution containing a mixture according to claim 1.
3. Verfahren zur Herstellung einer Lösung enthaltend eine Mischung aus a) Faktor VIII, dessen aktiven Fragmenten und/oder Substanzen, die die Freisetzung bzw. Bildung von Faktor VIII im Blut bewirken, und b) einem Antifibrinolytikum, dadurch gekennzeichnet, daß man die Mischungsbestandteile in Wasser löst und die Lösung mit einem physiologisch verträglichen Salz blutisotonisch einstellt und sterilisiert. 3. A process for the preparation of a solution comprising a mixture of a) factor VIII, its active fragments and / or substances which cause the release or formation of factor VIII in the blood, and b) an antifibrinolytic, characterized in that the mixture components dissolves in water and the solution is adjusted to blood isotonic with a physiologically acceptable salt and sterilized.
PCT/EP1992/000941 1991-05-11 1992-04-30 New combination of factor viii and an antifibrinolytic WO1992020361A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE4115453A DE4115453A1 (en) 1991-05-11 1991-05-11 NEW ACTIVE COMPOUND
DEP4115453.3 1991-05-11

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 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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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
ES2254092T3 (en) * 2000-09-22 2006-06-16 Perlei Medical Produkte Gmbh USE OF ANTIFIBRINOLITIC AGENTS FOR PREPARATION OF STAMPS, COMPRESSES AND APOSITOS.

Citations (1)

* Cited by examiner, † Cited by third party
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

Patent Citations (1)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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)

* Cited by examiner, † Cited by third party
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 vWF-containing concentrates as combination therapy for therapy with antithrombotics and fibrinolytics
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

Similar Documents

Publication Publication Date Title
DE3887875T2 (en) METHOD FOR PREVENTING Vascular Thrombosis Dependent on Platelets.
DE69130289T2 (en) THERAPEUTIC USE OF ACTIN BINDING COMPOUNDS
DE68911068T2 (en) EGF for the prevention of tissue damage after ischemia.
AT408720B (en) PARENTERAL PHARMACEUTICAL FORMULATION OF A HUMAN INSULIN ANALOG COMPLEX
DE69713485T2 (en) Medicines for the treatment or prevention of thrombocytopenia
EP0065747B1 (en) Nonapeptide for the treatment of symptoms caused by the withdrawal of drugs
DE60024415T2 (en) GLYCIN BETAIN FOR ANTITROMOMBOTIC USE
EP0876140A2 (en) Improved concentrated injection and infusion solutions for intravenous administration
EP0430200B1 (en) Drug for s.c. or i.m. application containing polypeptides
WO1987001591A2 (en) Novel use of tauroline
DE60029340T2 (en) PHARMACEUTICAL COMPOSITIONS CONTAINING A P2T RECEPTOR ANTAGONIST AND MELAGATRANE
LU84546A1 (en) USE OF PEPTIDES AS MEDICINE
EP1226829A2 (en) Stabilised liquid preparations of the protease or its proenzyme which activitate the blood coagulation factor VII
AU696954B2 (en) Antithrombotic and non-hemorrhagic heparin-based compositions, process for their preparation and therapeutic applications
DE68904264T2 (en) FRAGMENTS AND FRACTIONS OF HEPARIN WITH EFFECT AGAINST HIV.
EP0625908B1 (en) Antidote for hirudin and synthetic thrombin inhibitors
EP0328957B1 (en) Mixture of a thrombolytically acting and an antithrombolytically acting substance
WO1992020361A1 (en) New combination of factor viii and an antifibrinolytic
DE69832066T2 (en) USE OF AN OLIGOSACCHARIDE FOR PREVENTING BLOOD CLIMBING IN EXTRACORPOREAL CIRCUITS
DE2528460A1 (en) 1-Carbamoyl 2-cyano aziridine as immunostimulant - for therapy of bacterial and viral infections
DE69527205T2 (en) MEDICINE AGAINST ENDOTOXIN SHOCK AND MULTIPLE ORGAN FAILURE THAT CAUSED
AT408719B (en) AGENT FOR TREATING HEPATITIS C
DE60220084T2 (en) THE USE OF A SPECIFIC DOSE OF FONDAPARINUX SODIUM FOR THE TREATMENT OF ACUTE CORONARY SYNDROME
DE69128465T2 (en) HEPARIN NEUTRALIZATION THROUGH BLOOD PLATE FACTOR
AT405905B (en) NEW USE OF ANTITHROMBIN III

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): CA JP US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
NENP Non-entry into the national phase

Ref country code: CA

点击 这是indexloc提供的php浏览器服务，不要输入任何密码和下载