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WO1998058661A1 - UTILISATION DU FVIIa POUR TRAITER DES HEMORRAGIES CHEZ DES PATIENTS PRESENTANT UNE CASCADE DE COAGULATION SANGUINE NORMALE ET UNE FONCTION PLAQUETTAIRE NORMALE - Google Patents

UTILISATION DU FVIIa POUR TRAITER DES HEMORRAGIES CHEZ DES PATIENTS PRESENTANT UNE CASCADE DE COAGULATION SANGUINE NORMALE ET UNE FONCTION PLAQUETTAIRE NORMALE Download PDF

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Publication number
WO1998058661A1
WO1998058661A1 PCT/DK1998/000272 DK9800272W WO9858661A1 WO 1998058661 A1 WO1998058661 A1 WO 1998058661A1 DK 9800272 W DK9800272 W DK 9800272W WO 9858661 A1 WO9858661 A1 WO 9858661A1
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Prior art keywords
bleeding
use according
normal
fviia
patients
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PCT/DK1998/000272
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English (en)
Inventor
Ulla Hedner
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Novo Nordisk A/S
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.)
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Publication date
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU79073/98A priority Critical patent/AU7907398A/en
Publication of WO1998058661A1 publication Critical patent/WO1998058661A1/fr

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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)
    • A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
    • 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

Definitions

  • FVIIa for the treatment of bleedings in patients with a normal blood clotting cascade and normal platelet function.
  • the present invention relates to the use of FVIIa for the treatment of bleedings in patients having a normal blood clotting cascade and a normal platelet function.
  • the invention further relates to the potentiation or enhancement of the normal haemostatic system in a patient.
  • the present invention is generally directed toward the use of Factor Vila (FVIIa) to achieve haemostasis in certain situations when the haemostatic system including the coagulation cascade and platelets is functioning normally.
  • FVIIa Factor Vila
  • FVIIa may be used to potentiate, or enhance, the normal haemostatic system in situations where bleeding can be foreseen and where prevention or treatment of such bleeding is needed or desirable.
  • FVIIa may be used in such situations as well as when the bleeding is diffuse and poorly responding to current haemostatic techniques and therapies (e.g. haemorrhagic gastritis and profuse uterine bleeding).
  • FVIIa may also be suitable for the treatment of bleedings occurring in organs with limited possibility for mechanical haemostasis such as brain, inner ear region, eyes as well as in association with the process of taking biopsies from various organs and in laparoscopic surgery.
  • Bleeding disorders may be caused by clotting factor deficiencies (haemophilia A and B, deficiency of coagulation factors XI or VII) or clotting factor inhibitors. Excessive bleedings also occur in patients with a normally functioning blood clotting cascade (no clotting factor deficiencies or -inhibitors against any of the coagulation factors) and may be caused by a defective platelet function, thrombocytopenia or von Willebrand's disease.
  • the bleedings may be likened to those bleedings caused by haemophilia because the haemostatic system, as in haemophilia, lacks or has abnormal essential clotting "compounds" (such as platelets or von Willebrand factor protein) which causes major bleedings.
  • desmopressin also increases the fibrinolytic activity which perse may lead to an increased bleeding.
  • Tranexamic acid as well as ⁇ -aminocaproic acid specifically inhibit the fibrinolytic system and may be used as an adjuvant together with haemostatic agents. Due to the low molecular weight of these substances and their rapid clearance they must be given in high concentrations.
  • Achieving satisfactory haemostasis also is a problem when bleedings occur in organs such as the brain, inner ear region and eyes with limited possibility for surgical haemostasis.
  • the same problem may arise in the process of taking biopsies from various organs (liver, lung, tumour tissue, gastrointestinal tract) as well as in laparoscopic surgery. Common for all these situations is the difficulty to provide haemostasis by surgical techniques (sutures, clips, etc.) which also is the case when bleeding is diffuse (haemorrhagic gastritis and profuse uterine bleeding). Acute and profuse bleedings may also occur in patients on anticoagulant therapy in whom a defective haemostasis has been induced by the therapy given.
  • Radical retropubic prostatectomy is a commonly performed procedure for patients with localized prostate cancer. The operation is frequently complicated by sigmificant and sometimes massive blood loss. Over the last years, refinement in technique and greater surgical experience have contributed to lessen the potential bleeding consequences of the procedure, nonetheless radical retropubic prostatectomy remains associated with major blood loss and the frequent need for transfusion of blood and blood products. According to a survey of the recent literature, the perioperative blood loss ranges from 400-1500 ml, and 10-40% of patients require a blood transfusion.
  • Such therapy may include heparin, other forms of proteoglycans, warfarin or other forms of vitamin K-antagonists as well as aspirin and other platelet aggregation inhibitors.
  • TF tissue factor
  • FVII coagulation factor VII
  • the complex between TF and FVIIa is extremely effective in initiating the coagulation cascade, thus activating FX into FXa, and finally providing the first molecules of thrombin.
  • Thrombin converts fibrinogen into fibrin which is insoluble and forms the haemostatic plug.
  • the thrombin molecules also activate the platelets providing the site for further coagulation involving other coagulation factors such as FVIII and FIX important for the maintenance of haemostasis.
  • the initiation of the haemostasis which depends on the complex formation between FVIIa and TF occurs at the site of injury where the FVIIa/TF complex is anchored to the injured vessel wall where TF is exposed.
  • a systemic activation of the coagulation cascade may lead to disseminated intravascular coagulation (DIC), a dreaded complication associated with a high mortality rate.
  • DIC disseminated intravascular coagulation
  • Such complications have not been seen in patients treated with high doses of recombinant FVIIa (around 500 patients with life- and limb-threatening bleeds in patients with antibodies against coagulation factors) confirming the importance of a localised haemostatic process of the kind induced by the complex formation between FVIIa and TF exposed at the site of vessel wall injury.
  • a systemic activation of the coagulation system should be avoided as this could lead to unwanted side effects.
  • the present invention fulfils this need in providing extra FVIIa for complex formation with TF exposed in injured tissue. No systemic activation in the circulating blood has been seen following the administration of surprisingly high amounts of FVIIa confirming that extra exogenous FVIIa enhances normal haemostasis through localised complex formation at the site of injury also in patients basically having a normal haemostatic system.
  • the present invention has a prompt action and should not suffer from the unwanted side effects associated with reversing heparin by protaminsulphate, which is not very efficient in the case of low molecular weight heparins and in addition is associated with the risk of developing haemostatic defects by itself.
  • Reversing vitamin K antagonists requires a time period of 2-3 days following the administration of vitamin K.
  • prothrombin complex concentrates may be administered which, however, means the risk of transferring human viruses.
  • European Patent No. 225.160 (Novo Nordisk) discloses compositions of FVIIa and methods for the treatment of bleeding disorders not caused by clotting factor defects or clotting factor inhibitors.
  • European Patent No. 82.182 (Baxter Travenol Lab.) discloses a composition of factor Vila for use in counteracting deficiencies of blood clotting factors or the effects of inhibitors to blood clotting factors in a patient.
  • FVIIa which is a major initiator of the coagulation cascade may be used to potentiate, or enhance, the normal haemostatic system in patients and thus preventing or treating excessive bleedings in association with tissue damage, for example surgery or trauma, especially in tissues rich in tissue factor (TF).
  • FVIIa may be used in such situations as well as when the bleeding is diffuse and poorly responding to current haemostatic techniques and therapies (e.g. haemorrhagic gastritis and profuse uterine bleeding).
  • FVIIa may also be suitable for the treatment of bleedings occurring in organs with limited possibility for mechanical haemostasis such as brain, inner ear region, eyes as well as in association with the process of taking biopsies from various organs and in laparoscopic surgery.
  • FVIIa Factor VII
  • One aspect of the invention is the use of Factor Vila for the manufacture of a pharmaceutical composition for the treatment of bleedings in patients having a normal blood clotting cascade and a normal platelet function which composition comprises factor Vila in an effective haemostatic amount.
  • Another aspect of the invention is the use of Factor Vila for the manufacture of a pharmaceutical composition having a potentiating or enhancing effect on the normal haemostatic system in a patient.
  • Another aspect of the invention is the use of Factor Vila for the manufacture of a pharmaceutical composition for inducing rapid haemostasis in patients having a normal blood clotting cascade and a normal platelet function.
  • Another aspect of the invention is a method for preventing or treating bleedings in patients having a normal blood clotting cascade and a normal platelet function comprising administering to a patient a composition comprising factor Vila in an effective haemostatic amount.
  • Another aspect of the invention is a method of potentiating or enhancing the normal haemostatic system in a patient comprising administering to the patient a composition comprising factor Vila in an effective haemostatic amount.
  • Another aspect of the invention is a method for inducing a rapid haemostasis in a patient comprising administering to the patient a composition comprising factor Vila in an effective haemostatic amount.
  • Another aspect of the invention is a method for reestablishment of normal haemostasis in patient having received anticoagulant therapy, comprising administering to the patient a composition comprising factor Vila in an effective haemostatic amount.
  • the bleeding is associated with severe tissue damage. In another preferred embodiment, the bleeding is associated with severe trauma. In another preferred embodiment, the bleeding is associated with surgery. In another preferred embodiment, the bleeding is associated with laparoscopic surgery. In another preferred embodiment, the bleeding is associated with haemorrhagic gastritis. In another preferred embodiment, the bleeding is profuse uterine bleeding
  • the bleeding is occurring in organs with a limited possibility for mechanical haemostasis. In another preferred embodiment, the bleeding is occurring in the brain, inner ear region or eyes. In another preferred embodiment, the bleeding is associated with the process of taking biopsies. In another preferred embodiment, the bleeding is associated with anticoagulant therapy.
  • the anticoagulant may be a proteoglycan, e.g. heparin or low molecular heparins, or a vitamin K antagonist, e.g. warfarin, or an inhibitor of platelet aggregation and/or platelet adhesion, e.g. aspirin.
  • a proteoglycan e.g. heparin or low molecular heparins
  • a vitamin K antagonist e.g. warfarin
  • an inhibitor of platelet aggregation and/or platelet adhesion e.g. aspirin.
  • tissue rich in tissue factor is designated to mean tissues in which a redundance of TF has been demonstrated to occur, such as brain, vessel walls, etc.
  • the term “Factor Vila”, or FVIIa may be purified from blood or produced by recombinant means. It is evident that the practice of the methods described herein is independent of how the purified factor Vila is derived and, therefore, the present invention is contemplated to cover use of any factor Vila preparation suitable for use herein. Preferred are human FVIIa.
  • normal haemostatic system is designated to mean a normal coagulation cascade with normal levels and function of all the coagulation factors and no induced inhibitors to any of these factors as well as normal platelet function and normal platelet counts.
  • the term "potentiating or enhancing the haemostatic system” is designated to mean enhancement of the FVIIa/TF-dependent coagulation pathway by adding factors normally active in this pathway, such as FVIIa, to overcome the shut-down of this pathway that normally occurs after an initiation of the haemostasis has taken place.
  • treatment is meant to include both prevention of an expected bleeding, such as in surgery, and regulation of an already occurring bleeding, such as in trauma, with the purpose of inhibiting or minimising the bleeding.
  • Prophylactic administration of FVIIa is thus included in the term "treatment”.
  • one unit is defined as the amount of factor VII present in 1 ml of normal plasma, corresponding to about 0.5 ⁇ g protein. After activation 50 units correspond to about 1 ⁇ g protein.
  • haemostatic effect or “haemostatic amount” is defined as the substantial cessation of bleeding within 15 minutes after administration of about 250-1000 units per kg body weight of pure factor Vila.
  • TF tissue factor TF tissue factor
  • FVII factor VII in its single-chain, unactivated form FVIIa factor VII in its activated form
  • tissue factor-FVIIa tissue factor-FVIIa complex
  • the tissue factor-FVIIa complex is able to either directly or indirectly (via factor IX/VIII) activate factor X, which subsequently converts prothrombin into thrombin.
  • factor IX/VIII factor IX/VIII
  • rFVIIa recombinant activated factor Vila
  • the administration of rFVIIa was shown to offer a rapid and highly effective pro-haemostatic response in haemophilic patients with bleeding, that could not be treated with coagulation factor products due to antibody formation. Also bleeding patients with a factor VII deficiency could be treated successfully with FVIIa.
  • FVIIa may be used in such situations as well as when the bleeding is diffuse and poorly responding to current haemostatic techniques and therapies (e.g. haemorrhagic gastritis and profuse uterine bleeding). FVIIa may also be suitable for the treatment of bleedings occurring in organs with limited possibility for mechanical haemostasis such as brain, inner ear region, eyes as well as in association with the process of taking biopsies from various organs and in laparoscopic surgery.
  • haemostatic techniques and therapies e.g. haemorrhagic gastritis and profuse uterine bleeding.
  • FVIIa may also be suitable for the treatment of bleedings occurring in organs with limited possibility for mechanical haemostasis such as brain, inner ear region, eyes as well as in association with the process of taking biopsies from various organs and in laparoscopic surgery.
  • Human purified factor Vila suitable for use in the present invention is preferably made by DNA recombinant technology, e.g. as described by Hagen et al., Proc.Natl.Acad.Sci. USA 83: 2412- 2416, 1986 or as described in European Patent No. 200.421 (ZymoGenetics).
  • Factor Vila produced by recombinant technology may be authentic factor Vila or a more or less modified factor Vila provided that such factor Vila has substantially the same biological activity for blood coagulation as authentic factor Vila.
  • modified factor Vila may be produced by modifying the nucleic acid sequence encoding factor VII either by altering the amino acid codons or by removal of some of the amino acid codons in the nucleic acid encoding the natural FVII by known means, e.g. by site-specific mutagenesis.
  • Factor VII may also be produced by the methods described by Broze and Majerus, J.Biol.Chem. 255 (4): 1242-1247, 1980 and Hedner and Kisiel, J.CIin.lnvest. 71 : 1836-1841 , 1983. These methods yield factor VII without detectable amounts of other blood coagulation factors. An even further purified factor VII preparation may be obtained by including an additional gel filtration as the final purification step. Factor VII is then converted into activated FVIIa by known means, e.g. by several different plasma proteins, such as factor Xlla, IX a or Xa. Alternatively, as described by Bjoern et al. (Research Disclosure, 269 September 1986, pp. 564-565), factor VII may be activated by passing it through an ion-exchange chromatography column, such as Mono Q® (Pharmacia fine Chemicals) or the like.
  • Mono Q® Phharmacia fine Chemicals
  • the regimen for any patient to be treated with FVIIa as mentioned herein should be de- termined by those skilled in the art.
  • the daily dose to be administered in therapy can be determined by a physician and will depend on the particular compound employed, on the route of administration and on the weight and the condition of the patient.
  • a convenient daily dosage is suitably from about 5 ⁇ g/kg/day to about 500 ⁇ g/kg/day, preferably from about 10 ⁇ g/kg/day to 300 ⁇ g/kg/day, more preferred from about 15 ⁇ g/kg/day to 200 ⁇ g/kg/day, most preferred from about 20 ⁇ g/kg/day to 100 ⁇ g/kg/day.
  • the FVIIa should be administered in one single dose, preferably at the start of the bleeding, but it can also be given in multiple doses preferably with intervals of 4-6-12 hours depending on the dose given and the condition of the patient.
  • the FVIIa may be administered intravenously or it may be administered by continuous or pulsatile infusion.
  • FVIIa is preferably administered by intraveneous injections and in an amount of about 100-100,000 units per kg body weight, and preferably in an amount of about 250 - 25,000 units per kg body weight corresponding to about 5-500 ⁇ g/kg, a dose that may have to be repeated 2-4 times per 24 hours.
  • compositions Conventional techniques for preparing pharmaceutical compositions which can be used according to the present invention are, for example, described in Remington's Pharmaceutical Sciences. 1985.
  • compositions used according to this invention are prepared by methods known per se by the skilled art worker.
  • compositions suitable for use according to the present invention is made by mixing FVIIa, preferably in purified form, with suitable adjuvants and a suitable carrier or diluent.
  • suitable physiological acceptable carriers or diluents include sterile water and saline.
  • Suitable adjuvants include calcium, proteins (e.g. albumins), or other inert peptides (e.g. glycylglycine) or amino acids (e.g. glycine, or histidine) to stabilise the purified factor Vila.
  • Other physiological acceptable adjuvants are non-reducing sugars, polyalcohols (e.g.
  • the adjuvants are generally present in a concentration of from 0.001 to 4% w/v.
  • the pharmaceutical preparation may also contain protease inhibitors, e.g. apronitin, and preserving agents.
  • the preparations may be sterilised by, for example, filtration through a bacteria-retaining filter, by incorporating sterilising agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile medium suitable for injection prior to or immediately before use.
  • the test substance, heparin or placebo is administered and the endothelium of the vessel wall was injured in a controlled way by the application of a vessel clamp for 10 minutes. The clamps are then removed and the cyclic flow pattern is registered for 60 minutes. Thereafter rFVIIa is administered and again the cyclic flow pattern is studied. After 30 minutes the rabbits are sacrificed. The same "basic cyclic flow pattern" was found in both the placebo- and the heparin groups (1-7 cycles during the 30 minutes period). In the placebo group the number of cycles during the following 60 minutes period varied between 1-13 cycles and in the heparin group one out of 4 rabbits showed 3 cycles, the other 0 cycles. Following, the administration of rFVIIa restored the cycle pattern in the heparin group to 3-7 cycles (all animals having cycles) and were basically maintained in the placebo group (4-8 cycles).
  • the present experiment demonstrates the immediate effect of rFVIIa in restoring the haemostatic function in an animal anti-coagulated with heparin.
  • a vitamin K antagonist, acenocoumol was given to normal healthy individuals in a dose resulting in a prolonged INR (international normalized ratio expressing the patient's prothrombin time related to the mean prothrombin time) of around 2 which is the ratio considered optimal in vitamin K antagonist therapy. These individuals were then given rFVIIa in doses of 5, 10, 20, 40, 80, 120, 160, 240 and 320 ⁇ g/kg as single doses.
  • the study will be performed as a randomized, double-blind, placebo-controlled, dose- escalation trial comparing the single administration of rFVIIa and placebo.
  • rFVIIa as a single bolus i.v. or saline at an equal volume.
  • the study agent will be administered after the collection of lymphnode biopsies (in case of radical prostatectomy) or after the placement of guiding sutures (in case of Millin prostatectomy). Further treatment of the patient will be completely according to standard care, including the post-operative administration (starting at day 1 post-operatively) of low molecular weight heparin at a prophylactic dose (Fraxiparin once daily 7500 U s.c).
  • Red cell transfusion will be performed if the haemoglobin is less than 5.5 mmol/l, or if the condition of the patients requires transfusion (in that case a haemoglobin value must be known).
  • the administration of other blood components (such as plasma or platelets) will be at the discretion of the attending physician.
  • the study will be performed in 3 groups of 10 patients, that will receive rFVIIa at a dose in ascending order: dose level 1 : 20 ⁇ g rFVIIa/kg bodyweight dose level 2: 40 ⁇ g rFVIIa/kg bodyweight dose level 3: 80 ⁇ g rFVIIa/kg bodyweight
  • a- volume of perioperative blood loss up to 24 hrs after surgery
  • b- red cell transfusion requirements number of units transfused and percentage of patients that need any transfusion
  • c- transfusion requirement of other blood components up to the first 48 hrs after surgery and during the admission.
  • d- post-operative haemoglobin level (as related to pre-operative level), measured directly and 24 hrs after surgery e- duration of operation f- a subjective judgement of the surgeon on the quality of the haemostasis during surgery (on a scale from 1-5)
  • g- coagulation studies measurement of PTT and factor Vila before the administration of the study agent, and at 1 , 2 and 4 hrs hereafter.
  • a- the occurrence of post-operative venous thromboembolism
  • Patients will be carefully monitored for signs and symptoms of venous thromboembolism by daily history and physical examination. If a clinical suspicion of venous thrombosis arises, ultrasound and
  • venography (if necessary) venography will be performed.
  • ventilation/perfusion scanning and (if necessary) pulmonary angiography will be performed.
  • an ultrasound examination of the leg veins will be performed in all patients, b- any other post-operative complication, in particular cardiovascular events, up to 7 days post-operatively; these complications will be monitored by daily history and physical examination, as well as daily electrocardiogram measurement.
  • the volume of perioperative blood loss and the number of units transfused will be compared with the Mann Whitney U-test and Student t-test.
  • the rate of patients requiring a transfusion and the occurrence of postoperative complications in the two treatment groups will be compared with the Chi-square test.

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Abstract

La présente invention concerne, de manière générale, l'utilisation du facteur VIIa (FVIIa) pour réaliser une hémostase dans certaines situations où le système hémostatique, y compris la cascade et les plaquettes de coagulation, fonctionne normalement. Ainsi, le FVIIa peut s'utiliser pour renforcer ou améliorer le système hémostatique normal dans des situations où une hémorragie peut être prédite et où il est nécessaire ou souhaitable de prévenir ou de traiter cette hémorragie. Malgré un système hémostatique normal, des hémorragies généralisées peuvent survenir en association avec une intervention chirurgicale ou avec d'autres types de détérioration tissulaire telle qu'un trauma sévère, par exemple. Le FVIIa peut s'utiliser également lorsque l'hémorragie est diffuse et peu réactive aux techniques et thérapies hémostatiques courantes (cas d'une gastrite hémorragique ou d'une hémorragie utérine abondante, par exemple). Le FVIIa convient également pour le traitement d'hémorragies survenant dans des organes doués de facultés limitées d'hémostase mécanique, tels que le cerveau, la région de l'oreille interne, les yeux. Il peut aussi s'associer à un procédé de réalisation de biopsies à partir de divers organes ou s'utiliser dans une intervention chirurgicale par laparoscopie. Selon l'invention, le FVIIa s'utilise également pour traiter des hémorragies chez des patients qui ont subi un traitement anticoagulant ou chez qui le rétablissement d'une hémostase normale (inversion de l'effet anticoagulant) s'avère nécessaire.
PCT/DK1998/000272 1997-06-23 1998-06-22 UTILISATION DU FVIIa POUR TRAITER DES HEMORRAGIES CHEZ DES PATIENTS PRESENTANT UNE CASCADE DE COAGULATION SANGUINE NORMALE ET UNE FONCTION PLAQUETTAIRE NORMALE WO1998058661A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU79073/98A AU7907398A (en) 1997-06-23 1998-06-22 Use of fviia for the treatment of bleedings in patients with a normal blood clotting cascade and normal platelet function

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK0736/97 1997-06-23
DK73697 1997-06-23
US5008297P 1997-06-26 1997-06-26
US60/050,082 1997-06-26

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Cited By (23)

* Cited by examiner, † Cited by third party
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WO2001085199A1 (fr) * 2000-05-10 2001-11-15 Novo Nordisk A/S COMPOSITION PHARMACEUTIQUE COMPRENANT UN FACTEUR VIIa ET UN INHIBITEUR DE TFPI
EP1216709A1 (fr) * 2000-12-21 2002-06-26 Boehringer Ingelheim Pharma KG Application du facteur de coagulation VII activé pour le traitement de saignements majeurs induits par thérapie fibrinolytique
WO2003039589A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides alpha2-antiplasmines
WO2003039582A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant un poylpeptide de facteur vii et un acide epsilon-aminocapronique
WO2003039586A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de thrombomoduline
WO2003039581A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides du facteur vii et de l'acide tranexamique
WO2003039584A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de facteur v
WO2003039588A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique renfermant des polypeptides de facteur vii et des inhibiteurs du plasminogene tissulaire
WO2003039587A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Preparation pharmaceutique contenant des polypeptides facteur vii et des inhibiteurs de la proteine s
WO2003039580A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de pai-1
WO2003039579A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant un polypeptide de facteur vii et un polypeptide tafi
WO2005107795A1 (fr) * 2004-05-11 2005-11-17 Novo Nordisk Health Care Ag Utilisation du facteur viia dans le traitement de traumas par brulures
WO2005123118A1 (fr) * 2004-06-21 2005-12-29 Novo Nordisk Health Care Ag Utilisation du factor viia ou d'equivalents du facteur viia pour la prevention ou l'attenuation d'une evolution hemorragique et/ou de la formation d'oedeme apres une hemorragie intracerebrale (hic)
US7015194B2 (en) 2000-05-10 2006-03-21 Novo Nordisk A/S Pharmaceutical composition comprising factor VIIa and anti-TFPI
US7078479B2 (en) 2001-11-09 2006-07-18 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and alpha2-antiplasmin polypeptides
US7125846B2 (en) 2001-11-09 2006-10-24 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and factor V polypeptides
US7291587B2 (en) 2001-11-09 2007-11-06 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and TAFI polypeptides
WO2009045412A2 (fr) * 2007-10-01 2009-04-09 American Diagnostica, Inc. Méthodes de traitement utilisant des molécules de type 1 modifiées inhibitrices des activateurs du plasminogène
US7829529B2 (en) 1999-07-14 2010-11-09 Novo Nordisk Health Care A/G Use of factor VIIa or a tissue factor antagonist for regulating gene expression and cell migration or chemotaxis
US8138317B2 (en) 2007-07-17 2012-03-20 Hoffmann-La Roche Inc. Purification of pegylated polypeptides
US8354377B2 (en) 2008-01-18 2013-01-15 Novo Nordisk Health Care Ag Use of factor VIIa or factor VIIa equivalents for preventing or attenuating haemorrhage growth, and/or oedema generation following intracerebral haemorrhage (ICH) in a selected subpopulation of ICH patients
US8674074B2 (en) 2003-09-09 2014-03-18 Novo Nordisk Healthcare Ag Coagulation factor VII polypeptides
US8795533B2 (en) 2007-07-17 2014-08-05 Hoffmann-La Roche Inc. Chromatographic methods

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US7829529B2 (en) 1999-07-14 2010-11-09 Novo Nordisk Health Care A/G Use of factor VIIa or a tissue factor antagonist for regulating gene expression and cell migration or chemotaxis
WO2001085199A1 (fr) * 2000-05-10 2001-11-15 Novo Nordisk A/S COMPOSITION PHARMACEUTIQUE COMPRENANT UN FACTEUR VIIa ET UN INHIBITEUR DE TFPI
US7015194B2 (en) 2000-05-10 2006-03-21 Novo Nordisk A/S Pharmaceutical composition comprising factor VIIa and anti-TFPI
EP1216709A1 (fr) * 2000-12-21 2002-06-26 Boehringer Ingelheim Pharma KG Application du facteur de coagulation VII activé pour le traitement de saignements majeurs induits par thérapie fibrinolytique
WO2002049665A2 (fr) * 2000-12-21 2002-06-27 Boehringer Ingelheim Pharma Gmbh & Co. Kg Utilisation du facteur vii de coagulation active pour traiter des hemorragies importantes causees par une therapie thrombolytique
WO2002049665A3 (fr) * 2000-12-21 2002-09-26 Boehringer Ingelheim Pharma Utilisation du facteur vii de coagulation active pour traiter des hemorragies importantes causees par une therapie thrombolytique
CZ300670B6 (cs) * 2000-12-21 2009-07-15 Boehringer Ingelheim Pharma Gmbh & Co. Kg Farmaceutický prostredek pro lécbu krvácení
WO2003039582A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant un poylpeptide de facteur vii et un acide epsilon-aminocapronique
WO2003039581A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides du facteur vii et de l'acide tranexamique
WO2003039588A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique renfermant des polypeptides de facteur vii et des inhibiteurs du plasminogene tissulaire
WO2003039587A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Preparation pharmaceutique contenant des polypeptides facteur vii et des inhibiteurs de la proteine s
WO2003039580A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de pai-1
WO2003039579A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant un polypeptide de facteur vii et un polypeptide tafi
WO2003039589A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides alpha2-antiplasmines
WO2003039584A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de facteur v
WO2003039586A1 (fr) * 2001-11-09 2003-05-15 Novo Nordisk Health Care Ag Composition pharmaceutique comprenant des polypeptides de facteur vii et des polypeptides de thrombomoduline
US7078479B2 (en) 2001-11-09 2006-07-18 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and alpha2-antiplasmin polypeptides
US7125846B2 (en) 2001-11-09 2006-10-24 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and factor V polypeptides
US7291587B2 (en) 2001-11-09 2007-11-06 Novo Nordisk Healthcare A/G Pharmaceutical composition comprising factor VII polypeptides and TAFI polypeptides
US8674074B2 (en) 2003-09-09 2014-03-18 Novo Nordisk Healthcare Ag Coagulation factor VII polypeptides
WO2005107795A1 (fr) * 2004-05-11 2005-11-17 Novo Nordisk Health Care Ag Utilisation du facteur viia dans le traitement de traumas par brulures
WO2005123118A1 (fr) * 2004-06-21 2005-12-29 Novo Nordisk Health Care Ag Utilisation du factor viia ou d'equivalents du facteur viia pour la prevention ou l'attenuation d'une evolution hemorragique et/ou de la formation d'oedeme apres une hemorragie intracerebrale (hic)
US8138317B2 (en) 2007-07-17 2012-03-20 Hoffmann-La Roche Inc. Purification of pegylated polypeptides
US8795533B2 (en) 2007-07-17 2014-08-05 Hoffmann-La Roche Inc. Chromatographic methods
US8889837B2 (en) 2007-07-17 2014-11-18 Hoffman-La Roche Inc. Purification of pegylated polypeptides
WO2009045412A3 (fr) * 2007-10-01 2010-01-21 American Diagnostica, Inc. Méthodes de traitement utilisant des molécules de type 1 modifiées inhibitrices des activateurs du plasminogène
WO2009045412A2 (fr) * 2007-10-01 2009-04-09 American Diagnostica, Inc. Méthodes de traitement utilisant des molécules de type 1 modifiées inhibitrices des activateurs du plasminogène
US8354377B2 (en) 2008-01-18 2013-01-15 Novo Nordisk Health Care Ag Use of factor VIIa or factor VIIa equivalents for preventing or attenuating haemorrhage growth, and/or oedema generation following intracerebral haemorrhage (ICH) in a selected subpopulation of ICH patients

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