WO2010149172A2 - Effet pro-hemostatique systemique de facteurs de coagulation en combinaison avec des sympathicomimetiques a effets agonistiques sur des recepteurs α-adrenergiques et/ou β-adrenergiques du systeme nerveux, associe a une capacite de coagulation amelioree - Google Patents

Effet pro-hemostatique systemique de facteurs de coagulation en combinaison avec des sympathicomimetiques a effets agonistiques sur des recepteurs α-adrenergiques et/ou β-adrenergiques du systeme nerveux, associe a une capacite de coagulation amelioree Download PDF

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WO2010149172A2
WO2010149172A2 PCT/DK2010/050163 DK2010050163W WO2010149172A2 WO 2010149172 A2 WO2010149172 A2 WO 2010149172A2 DK 2010050163 W DK2010050163 W DK 2010050163W WO 2010149172 A2 WO2010149172 A2 WO 2010149172A2
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microgram
hour
clotting factor
adrenaline
adrenergic receptor
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WO2010149172A3 (fr
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Pär JOHANSSON
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Rigshospitalet
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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
    • A61K38/17—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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • 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

  • the present invention relates to a novel use and methods of treatment using the combination of clotting factors and sympathicomimetic / adrenergic receptor agonists with pro-hemostatic activity.
  • Blood coagulation is a process consisting of a complex interaction of various blood components (or factors) that eventually gives rise to a fibrin clot [Roberts et al. 2006].
  • the blood components which participate in what has been referred to as the coagulation "cascade"
  • the coagulation "cascade” are enzymatically inactive proteins (proenzymes or zymogens) that are converted to proteolytic enzymes by the action of an activator (which itself is an activated clotting factor).
  • Coagulation factors that have undergone such a conversion are generally referred to as "active factors”, and are designated by the addition of the letter "a" to the name of the coagulation factor (e.g. Factor Vila).
  • Initiation of the hemostatic process is mediated by the formation of a complex between tissue factor, exposed as a result of injury to the vessel wall, and Factor Vila [Roberts et al. 2006].
  • This complex then converts Factors IX and X to their active forms.
  • Factor Xa converts limited amounts of prothrombin to thrombin on the tissue factor-bearing cell.
  • Thrombin activates platelets and Factors V and VIII into Factors Va and Villa, both cofactors in the further process leading to the full thrombin burst.
  • This process includes generation of Factor Xa by Factor IXa (in complex with factor Villa) and occurs on the surface of activated platelets.
  • Thrombin finally converts fibrinogen to fibrin resulting in formation of a fibrin clot.
  • Factor VII and tissue factor have been found to be the main initiators of blood coagulation.
  • clotting factor deficiencies e.g. hemophilia A and B or deficiency of coagulation Factors Xl or VII
  • clotting factor inhibitors clotting factor inhibitors
  • Such bleeding may, for example, be caused by a defective platelet function, thrombocytopenia or von Willebrand's disease [Brace 2007].
  • Bleeding is also a major problem in connection with surgery and other forms of tissue damage [Vaslev et al. 2002, Hardy et al. 2005].
  • transfusion associated graft versus host reaction TA-GVHD
  • PTP posttransfusions purpura
  • transfusion of allogenic blood products is also associated with immunomodulation and immunosuppression predisposing for the development of postoperative infections as reported in orthopedic, burn and colorectal surgery [Banbury et al. 2006, Jeschke et al. 2007, Milasiene et al. 2007].
  • administration of blood products is independently associated with an increase in development of multiorgan failure [Zallen et al 1999] and mortality [Herbert et al. 1999, Engoren et al.
  • rFVIIa is a genetically engineered protein expressed from cloned human FVII genes in baby hamster kidney cells. No material of human origin is used in either the production process or in the final product. Thus rFVIIa is less likely than human blood products to transmit infectious agents. rFVIIa is currently approved worldwide for the treatment of bleeding in patients with haemophilia A or B with inhibitors to coagulation factors VIII or IX [Hoffman, 2003]. In Europe, the use of rFVIIa is also approved for factor VII deficiency and Glanzmann's thrombasthenia in patients who are refractory to platelet transfusions, but it is not approved as an adjunctive treatment for massive or coagulopathic bleeding in any country.
  • tissue factor In cases of injury, tissue factor (TF) is brought into contact with naturally occurring FVIIa present in minute quantities to initiate the coagulation pathway [Gabriel et al., 2004].
  • FVIIa binds to activated platelets at the site of injury and activate factors IX and X, leading to a thrombin burst [Toschi et al., 1997].
  • platelets are activated only at sites of TF exposure, it is believed that the action of rFVIIa is localised to these sites. Nevertheless, a primary concern of treatment with rFVIIa is the possibility of an increased incidence of thrombotic adverse events from systemic activation of the coagulation pathway or from TF exposure at sites not associated with tissue injury.
  • rFVIIa for off-label exists based upon case reports and small case series and anecdotal experience [Dutton and Stein, 2006; Levy et al., 2006; Kenet et al., 1999; Clark et al., 2004] demonstrating benefit for reducing bleeding in critically ill patients, and that is so although the use of rFVIIa in intractable bleeding is questioned [Johansson 2008]. Routine administration of rFVIIa in non-haemophilic patients to limit or to prevent bleeding and transfusion requirements is not supported by evidence from the reported 17 randomized clinical trials to date [Friederich et al., 2003].
  • vasoconstrictors such as adrenaline and noradrenaline have also been used as a treatment alternative.
  • vasoconstrictors such as adrenaline and noradrenaline have also been used as a treatment alternative.
  • local administration of vasoconstrictors the peripheral blood vessels are constricted whereby blood loss is reduced.
  • systemic effects normally associated with vasoconstrictors are avoided, such as, for example, elevated systemic blood pressure and thus increased blood loss through open vessels.
  • vasoconstrictors as local hemostatic agents.
  • a wound dressing comprising a vasoconstrictive medicinal substance, such as adrenaline, as a ready to use product for local treatment of bleeding wounds.
  • vasoconstrictors such as adrenaline and noradrenaline
  • compositions of intermacromolecular complexes such as, e.g. polyether, polyacids and polyalkylene and methods for making and using such compositions in reducing post-surgical bleeding is described.
  • the application further describes the incorporation of vasoconstrictors in these compositions in order to have a local drug delivery at a surgical site.
  • vasoconstrictors in a method to control gastrointestinal bleeding when injected directly into the peritoneal cavity or intragastrically is described US 4,337,573. By this method, a local effect is obtained without any unwanted systemic effects because the vasoconstrictors are absorbed into the portal system and inactivated before entering systemic circulation.
  • the inventor of the present invention has surprisingly found that systemic administration of the combination of clotting factors such as prothrombin complex concentrate factors or single coagulation factors such as factor FVIIa and sympathicomimetic agonists such as adrenaline and noradrenaline in low doses (10 to a 100 times lower than in the current indications i.e. cardiac arrest, anaphylactic shock), will result in a systemic activation of the coagulation system, while at the same time avoiding the side effects such as elevated blood pressure, and thus increased blood loss through open vessels, that would counteract the benefits of the treatment.
  • clotting factors such as prothrombin complex concentrate factors or single coagulation factors such as factor FVIIa and sympathicomimetic agonists such as adrenaline and noradrenaline in low doses (10 to a 100 times lower than in the current indications i.e. cardiac arrest, anaphylactic shock)
  • clotting factors in combination with low doses of systemic sympathicomimetic agonists, a faster and stronger thrombin generation will take place, which will result in faster clot formation, and a stronger and more durable clot, which is more resistant to shear forces and fibrinolytic enzymes.
  • systemic treatment with clotting factors such as prothrombin complex concentrate factors together with sympathicomimetic agonists such as adrenaline, noradrenaline, dopamine, dobutamine and ephedrine etc. in low doses are contemplated to reduce bleeding and/or risk of bleeding.
  • any clotting factor including prothrombin complex concentrate factors and any sympathicomimetic substance, including adrenaline and noradrenaline, can be used in the present invention.
  • one object of the present invention relates to the effect of a combination of clotting factors and sympathicomimetic agonists, resulting in a faster maximal haemostatic effect, when administered systemically by way of intravenous, intramuscular or subcutaneous, intrapulmonary, intra-alveolarly, oral, sublingual, mucosal, or rectal routes as well as any nucleic acid constructs encoding such clotting factors and agonists, vectors and host cells comprising and expressing the nucleic acids, pharmaceutical compositions, uses and methods of treatment.
  • the present invention relates to novel uses and methods of treatment using the combination of clotting factors and sympathicomimetic agonists with pro-hemostatic activity resulting in a faster maximal haemostatic effect, improved clot strength, as well as nucleic acid constructs encoding such clotting factors and sympathicomimetic agonists, vectors and host cells comprising and expressing the nucleic acids and pharmaceutical compositions.
  • an object of the present invention relates to the combination of a clotting factor and an adrenergic receptor agonist for systemic administration for the treatment and/or prophylaxis of bleeding in a subject.
  • Another object of the present invention relates to novel uses and methods of treatment using a combination of clotting factors and sympathicomimetic agonists with pro- hemostatic activity in combination with compounds capable of blocking or minimizing any adverse effects that may be elicited by administration of the sympathicomimetic agonists.
  • a third object of the present invention relates to novel uses and methods of treatment using the combination of clotting factors and sympathicomimetic agonists with pro- hemostatic activity in combination with potassium in order to maintain serum potassium concentrations upon administration of the combination of clotting factors and sympathicomimetic agonists alone or in combination with the adrenergic receptor blockers.
  • a third object of the present invention thus relates to a composition comprising a clotting factor, an adrenergic receptor agonist, potassium in a pharmaceutically acceptable form and optionally a beta blocker for the treatment or prophylaxis of bleeding in a subject.
  • Figure 1 TEG technology.
  • Figure 2 TEG parameters.
  • FIG 3 Representative TEG profile of healthy volunteers before and after administration of a sympathicomimetics agonist (adrenaline).
  • Figure 4 a, b, and c TEG parameters (4a) R, (4b) Angle and (4c) MA of 30 healthy volunteers after totally 15 minutes of i.v. administration of adrenaline.
  • Figure 5 TEG MA measured before and after i.v. infusion of noradrenaline at 4.8 ⁇ g/kg/h for 15 minutes in 10 healthy volunteers.
  • Figure 7 a, b and c TEG parameters (7a) R, (7b) Angle and (7c) MA from blood samples collected from patients infused with adrenaline prior to prostatectomy.
  • Figure 8 Intra-operative bleeding (in ml) of the patients of figure 7 (receiving adrenaline in the step-wise doses 1 , 2 and 3 ⁇ g/kg/h) and 10 other prostatectomy patients receiving a 15 minutes continuous adrenaline infusion of 3 ⁇ g/kg/h.
  • Figure 9 a and b (9a) A representative example of TEG tracings with tPA induced fibrinolysis before and immediately after infusions of adrenaline. (9b) Statistic comparisons of the lysis AUC (area under the curve).
  • Figure 10 Administration of adrenaline and adrenaline and seloken to 7 healthy volunteers.
  • Figure 11 a, b, c, d, and e The volunteers of figure 10 were monitored haemodynamically at the same time points as described in figure 10: (1 1a) heart rate (HR), (1 1 b) cardiac output (CO), (11 c) stroke volume (SV), (1 1d) invasive blood pressure: mean arterial pressure, MAP) and (11 e) total peripheral resistance (TPR).
  • Figure 12 Administration of adrenaline in stepwise doses followed by Seloken and again adrenaline in stepwise doses to 7 healthy volunteers.
  • Figure 13 Representative TEG profile of a healthy volunteer before and after administration of a clotting factor (rFVIIa).
  • Figure 14 TEG MA in awake volunteers.
  • FIG. 15 TEG MA in prostatectomy patients during surgery.
  • the term "activity" is intended to mean the ability to generate a clot of improved stability as well as an increased initiation, amplification and propagation of the hemostatic system, resulting in a faster formation of a clot of greater mechanical strength and stability together with increased resistance to fibrinolysis as compared to when the agonists are not administered.
  • bleeding disorder used herein will reflect any defect, congenital, acquired or induced, of cellular or molecular origin that is manifested in bleedings.
  • bleeding episodes or “bleeding” is meant to include any episode were bleeding of a magnitude necessitating administration of blood products may occur, including uncontrolled and excessive bleeding both in connection with surgery and other forms of tissue damage in a subject.
  • a “subject” or “patient” includes humans and other mammals, and thus the methods are applicable to both human therapy and veterinary applications, in particular to human therapy.
  • the term “mammal” includes humans, non-human primates (e.g. baboons, orangutans, monkeys), mice, pigs, cows, goats, cats, rabbits, rats, guinea pigs, hamsters, horse, monkeys, sheep or other non-human mammal.
  • Treatment is therefore intended 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 minimizing the bleeding.
  • Prophylactic administration of the variant according to the invention is thus included in the term "treatment”.
  • the term clotting factor as used herein further covers any proenzyme / zymogen or activated clotting factor and thus the term “variant hereof” includes both the zymogen and activated form of a given clotting factor.
  • the terms clotting factor and coagulation are used interchangeably.
  • An "a" at the end of the name of a given clotting factor is intended to the activated version of said factor for example: FVIIa is the activated from of FVII.
  • factor Vila or FVIIa are intended to mean the activated form of clotting factor VII.
  • rFVIIa is intended to mean the recombinant activated form of clotting factor Vl and rhFVIIa is intended to mean the recombinant human activated form of clotting factor VII.
  • NovoSevenTM may be referred to as both rFVIIa and rhFVIIa.
  • variant and analogue is also meant any variant and analogue of a clotting factor according to the invention which are functional equivalents of said clotting factors.
  • functional equivalent of a clotting factor is in the present context meant a molecule which meets the criteria for a variant or a fragment of said clotting factor described above and which is capable of one or more functional activities of said clotting factor or a compound comprising said clotting factor.
  • sympathicomimetics or “sympathicomimetic agonists” or “adrenergic receptor agonist” are used interchangeable herein, includes any pharmaceutical compounds with the same or similar activity as noradrenaline (norepinephrine) and adrenaline (epinephrine). This group of compounds, having predominantly peripheral action, can be divided into:
  • composition indicates that the drugs may be formulated together, or are kept as separate entities and may be administered simultaneously or within a predetermined interval of each other. Examples of how the clotting factors, the sympathicomimetic agonists and/or potassium of the present invention may be administered in combination with each other are given in the below.
  • dose shall mean any concentration of the clotting factors and agonists administered producing a pro-hemostatic effect on the hemostatic system.
  • a dose sufficient to produce the desired effect in relation to the conditions for which it is administered, in particular an amount of a clotting factor and sympathicomimetic agonists that is effective to stop, reduce or prevent the unwanted bleeding shall be described as the "effective dose”, “therapeutically effective dose” or “effective amount”.
  • the dose should be capable of preventing or lessening the severity or spread of the condition or indication being treated.
  • the exact dose will depend on the circumstances, such as the condition being treated, the administration schedule, whether the clotting factor and sympathicomimetic agonists is administered alone or in conjunction with another therapeutic agent or another clotting factor or sympathicomimetic agonists, the plasma half-life of the clotting factor and the sympathicomimetic agonists and the general health of the subject.
  • tachycardia / tachyarrhythmia are intended to mean rapid heart rate, usually defined as greater than 100 beats per minute at rest.
  • the tachycardias include sinus tachycardia, paroxysmal atrial tachycardia (PAT), and ventricular tachycardia..
  • the term "pharmaceutical acceptable” means a carriers or excipients that does not cause any untoward effects in subjects to whom it is administered.
  • Trauma is intended to mean injury to living tissue caused by an extrinsic agent.
  • the inventor of the present invention has surprisingly found that the combination of low doses of clotting factors and sympathicomimetic agonists activate the hemostatic system and improve clot strength and stability.
  • systemic administration of low doses of a combination of clotting factors and sympathicomimetic agonists no significant elevation of the blood pressure is experienced and thereby blood loss due to this effect is absent, whereas the pro-hemostatic effect on the coagulation system is increased.
  • Administration of clotting factors and sympathicomimetic agonists result in a dose- dependent increase in velocity in the initiation phase and in thrombin burst that is more pronounced than what can be achieved with sympathicomimetic agonists alone.
  • thrombosis does not occur more frequently with the agents of the present invention than without administration of the agents. This may in part be due to the fact that the sympathicomimetic agonists such as adrenaline and noradrenaline quickly, as in within minutes, are cleared from the body. Thus, the effects of the sympathicomimetic agonists are halted within minutes of termination of administration, and the hemostatic equilibrium of the particular subject is returned to its usual level. Addition of doses of clotting factors as low as relevant for the present invention also does not increase the risk of thrombosis.
  • the clot is not after formation a permanent feature, the equilibrium between coagulation and fibrinolysis is changed, due to the increased speed of formation and longer durability of the clot following adrenaline administration, but there still is equilibrium between coagulation and fibrinolysis.
  • the advantages of the present invention are several fold: for the individual subject treated less blood is lost and thus less, if any, blood and/or blood products need be administered.
  • a reduced blood loss lessens the stress on the bodily systems of the subject and adverse effects known to medical practitioners and others skilled in the art that may follow from receiving blood and/or blood products are avoided and/or minimized.
  • money is saved and thus the administration of the combination of clotting factors and sympathicomimetic agonists optionally in combination with potassium as stated in the below has an economic incentive as well.
  • the present invention is useful in any situation wherein an individual is bleeding e.g. trauma, or is expected to bleed eg. during surgery.
  • These two situations differ in several respects: during trauma, if it is at all possible to administer anesthesia, there is no time to wait for the full effect before performing the necessary interventions; during elective surgery, which here is defined as any type of non-acute intervention that will or is expected to cause bleeding, the entire situation is under control from the onset, and there is time to wait for the full effect of the anesthesia to set in.
  • the blood pressure generally lowers.
  • the present invention is particularly useful for the treatment of trauma, especially in a pre-hospital setting, where blood loss before entering the hospital is the major determinant of mortality.
  • the term "activity" is intended to mean the ability to generate a clot of improved stability as well as an increased initiation, amplification and propagation of the hemostatic system, resulting in a faster formation of a clot of greater mechanical strength and stability together with increased resistance to fibrinolysis as compared to when the agonists are not administered.
  • systemic administration of a combination of clotting factors and sympathicomimetic agonists will be useful for treatment or prophylaxis of controlled or uncontrolled bleeding episodes in connection with various forms of e.g. trauma, surgery, post partum or due to congenital or acquired bleeding conditions.
  • Administration of the sympathicomimetic agonists of the present invention increases clot strength and stability and may be used to increase the clot strength and stability in a subject with subnormal clot strength and stability or may be used to increase clot strength and stability in a subject with normal clot strength and stability to a higher degree of strength and stability.
  • clot strength and stability is shifted to a more stable level following administration of a combination of clotting factors and sympathicomimetic agonists.
  • the clot strength and stability after administering a combination of the clotting factor(s) and the sympathicomimetic agonist(s) is kept within the normal range of clot strength and stability but is either lifted from a subnormal level to within the normal range of clot strength and stability or is lifted from within the normal range of clot strength and stability towards the upper end of the normal range of clot stability.
  • the clot strength and/or stability by administration of a combination of a clotting factor and a sympathicomimetic agonist is shifted to the upper end of the normal range(s) of clot strength and /or stability. It is an option to further use the combination of a clotting factor and a sympathicomimetic agonist together with a beta blocker in any of the herein cited embodiments.
  • the clot strength and stability and changes herein may be measured as increases in relative clot strength by the TEG (Thrombelastography) measurable parameter MA and clot stability by the TEG derivable parameter Lysis AUC.
  • the maximal amplitude (MA) parameter reflects maximal clot strength i.e. the maximal elastic modus of the clot.
  • the area under the lysis curve, i.e. area under the curve from MA is obtained (Lysis AUC) reflects degree of fibrinolysis (see Figure 2). Both clot strength and stability may be measured, or one parameter only may be followed during a procedure such as either the clot stability or the clot strength.
  • the clot strength measured by the MA increases relative to the MA prior to administration of a sympathicomimetic agonist by 105%, such as by 1 10%, such as by 115%, such as by 120%, such as by 125%, such as by 130%, such as by 135%, such as by 140%, such as by 145%, such as by 150%, such as by 155%, such as by 160%, such as by 165%, such as by 170%, such as by 175%, such as by 180%, such as by 185%, such as by 190%, such as by 195%, such as by 200% or more.
  • the clot stability increases Lysis AUC.
  • This parameter may with a TEG analysis be measured e.g. after addition of tissue plasminogen activator (tPA), and thus it is an object of the present invention that the clot stability measured by the Lysis AUC increases relative to the Lysis AUC prior to administration of a sympathicomimetic agonist by 105%, such as by 1 10%, such as by 115%, such as by 120%, such as by 125%, such as by 130%, such as by 135%, such as by 140%, such as by 145%, such as by 150%, such as by 155%, such as by 160%, such as by 165%, such as by 170%, such as by 175%, such as by 180%, such as by 185%, such as by 190%, such as by 195%, such as by 200% or more.
  • 105% such as by 1 10%, such as by 115%, such as by 120%, such as by 125%, such as by 130%, such as by 135%, such as by 140%, such as by 145%, such as by 150%,
  • Additional values that represent clot formation as determined by TEG are: the R value (or reaction time), the K value, and the angle (and as stated above the MA (maximum amplitude)).
  • the R value represents the speed of clot formation (time until the first evidence of a clot is detected).
  • the K value is the time from the end or R until the clot reaches 20mm and this represents the speed of clot formation.
  • the angle is the tangent of the curve made as the K is reached and offers similar information to K.
  • the R value is of special relevance when administering coagulation factors, as the addition of a coagulation factor decreases the R value as measured by TEG. Therefore it is an object of the present invention that the R value decreases relative to the measurement of the R value prior to administration of one or more coagulation factors optionally in combination with a sympathicomimetic agonist (and optionally further in combination with a beta blocker) by anywhere between 1 and 99% such as by 5%, such as by 10%, such as by 15%, such as by 20%, such as by 25%, such as by 30%, such as by 35%, such as by 40%, such as by 45%, such as by 50%, such as by 55%, such as by 60%, such as by 65%, such as by 70%, such as by 75%, such as by 80%, such as by 85%, such as by 90% such as by 95%, such as by 98%.
  • the Angle value is of special relevance when administering coagulation factors, as the addition of a coagulation factor increases the Angle value as measured by TEG. Therefore it is an object of the present invention that the Angle value increases relative to the measurement of the Angle value prior to administration of one or more coagulation factors optionally in combination with a sympathicomimetic agonist (and optionally further in combination with a beta blocker) 105%, such as by 110%, such as by 1 15%, such as by 120%, such as by 125%, such as by 130%, such as by 135%, such as by 140%, such as by 145%, such as by 150%, such as by 155%, such as by 160%, such as by 165%, such as by 170%, such as by 175%, such as by 180%, such as by 185%, such as by 190%, such as by 195%, such as by 200% or more.
  • bleeding disorder used herein will reflect any defect, congenital, acquired or induced, of cellular or molecular origin that is manifested in bleedings.
  • bleeding episodes or “bleeding” is meant to include any episode were bleeding of a magnitude necessitating administration of blood products may occur, including uncontrolled and excessive bleeding both in connection with surgery and other forms of tissue damage in a subject.
  • a “subject” or “patient” includes humans and other mammals, and thus the methods are applicable to both human therapy and veterinary applications, in particular to human therapy.
  • the term “mammal” includes humans, non-human primates (e.g. baboons, orangutans, monkeys), mice, pigs, cows, goats, cats, rabbits, rats, guinea pigs, hamsters, horse, monkeys, sheep or other non-human mammal.
  • Treatment is therefore intended 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 minimizing the bleeding.
  • Prophylactic administration of the variant according to the invention is thus included in the term "treatment”.
  • Blood coagulation is a process consisting of a complex interaction of various blood components (or factors) that eventually gives rise to a fibrin clot [Roberts et al. 2006].
  • the blood components which participate in what has been referred to as the coagulation "cascade"
  • the coagulation "cascade” are enzymatically inactive proteins (proenzymes or zymogens) that are converted to proteolytic enzymes by the action of an activator (which itself is an activated clotting factor).
  • Clotting factors that have undergone such a conversion are generally referred to as "active factors”, and are designated by the addition of the letter "a" to the name of the clotting factor.
  • the term clotting factor as used herein further covers any proenzyme / zymogen or activated clotting factor and thus the term “variant hereof" includes both the zymogen and activated form of a given clotting factor.
  • An object of the present invention is the use of low doses of clotting factors in combination with low doses of sympathicomimetic agonists for the treatment and/or prophylaxis of bleeding in a subject.
  • a clotting factor for use according to the present invention may be any clotting factor including any variant or analogue with the same or similar activity as activated factor VII (FVIIa), or any pharmaceutical compound containing a clotting factor or variants or analogues.
  • factor VII is intended to encompass, without limitation, polypeptides having the amino acid sequence 1-406 of wild-type human factor VII (as disclosed in U. S. Patent No. 4,784, 950 or NP_000122), as well as wild-type factor Vl I derived from other species, such as, e. g., bovine, porcine, canine, murine, and salmon factor VII, said factor VII derived from blood or plasma, or produced by recombinant means.
  • factor VII It further encompasses natural allelic variations of factor VII that may exist and occur from one individual to another. Also, degree and location of glycosylation or other post-translation modifications may vary depending on the chosen host cells and the nature of the host cellular environment.
  • factor VII is also intended to encompass factor VII polypeptides in their uncleaved (zymogen) form, as well as those that have been proteolytically processed to yield their respective bioactive forms, which may be designated factor Vila. Typically, factor VII is cleaved between residues 152 and 153 to yield factor Vila.
  • Variant of clotting factors relevant to the present invention also include as herein exemplified by variants of FVII and FVIIa genetically modified versions of a clotting factor such as the V158D/E296V/M298Q (NN1731 ) form of FVII or any GIa domain variants of human Factor VII or human Factor Vila, comprising 1-15 amino acid modifications relative to human Factor VII or human Factor Vila, wherein a hydrophobic amino acid residue has been introduced by substitution in position 34; or having an amino acid substitution in position 36 such as disclosed in US 20071 17756. All variants disclosed herein are incorporated by reference.
  • Variants also include conjugates of Factor VII (FVII) and Factor Vila (FVIIA), wherein a conjugate comprises at least one non-polypeptide moiety covalently attached to a polypeptide of FVII or FVIIa as disclosed in US 2009023635 and hereby incorporated by reference.
  • FVII Factor VII
  • FVIIA Factor Vila
  • Non limiting examples of clotting factors according to the present invention include, but are not limited to: clotting factors I (fibrinogen), Il (prothrombin), Tissue factor, Calcium, V (proaccelerin, labile factor), Vl, VII (stable factor), VIII (Anti Hemophilic factor A,), IX (Anti Hemophilic Factor B or Christmas factor, NP_000124 or P00740), X (Stuart- Prower factor, NP_000495 or P00742), Xl (plasma thromboplastin antecedent), XII (Hageman factor), XIII (fibrin-stabilizing factor, A1 polypeptide: NM_000129 or P00488; B polypeptide: NM_001994 or P05160), von Willebrand factor, prekallikrein, high- molecular-weight kininogen (HMWK), and fibronectin, and any activated form of any of the mentioned clotting factors.
  • I fibrinogen
  • a combination of clotting factors may be used as is commercially available in specific concentrates.
  • a clotting factor for use according to the present invention may be a prothrombin complex concentrate factor and/or an activated prothrombin complex concentrate factor.
  • Such concentrates may include FII, FVII , FIX and FX as for example Octaplex and Beriplex as well as preparations comprising the activated factors FIIa, FVIIa , FIa, and FXa, such as FIEBA.
  • recombinant FVIII such as Advate, Nexgene, Kogenate, Refakto and human derived products such as Haemate, and Octanate.
  • Others include recombinant human factor Vila (rhFVIIa) (NovoSeven), a fibrinogen-concentrate (Haemocomplettan), human FXIII (Fibrogammin-P) and recombinant FXIII.
  • a clotting factor for use according to the invention is selected from the group comprising the activated forms of the clotting factors FVIIa, rFVIIa, rhFVIIa, FXIIIa,
  • FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa or a variant or analogue thereof and the group comprising the unactivated form of the clotting factors and FII, FV, FVII, FVIII, FIX, FX, FXII and FXIII, or a variant or analogue thereof.
  • Activated clotting factors are preferred over the non-activated forms.
  • FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof are more preferred.
  • the clotting factor is selected from the group consisting of FVIIa, FXIIIa, FIXa and FXa or a variant or analogue thereof.
  • the clotting factor for use according to the invention is selected from the group comprising FVIIa, rFVIIa, rhFVIIa, FVII, rFVII, or a variant or analogue thereof.
  • the clotting factor for use according to the invention is FVIIa, rFVIIa, rhFVIIa or a variant or analogue thereof.
  • the clotting factors for use according to the invention may be a natural clotting factor and/or a recombinant clotting factor.
  • Recombinant FVIIa (rFVIIa) and human recombinant FVIIa (rhFVIIa) are preferred. Most preferred is NovoSevenTM or any other brand on the market.
  • the clotting factors may also be in combination of two or more, such as three or more, such as four or five or more of any of the clotting factors discussed above.
  • variant and analogue is meant a protein that has a level of amino acid identity with the naturally occurring clotting factor an amino acid sequence which has at least 75% identity with a sequence of a selected clotting factor, such as 76-80% identity, for example 81-85% identity, such as 86-90% identity, for example 91-95% identity, such as 96-99% identity, wherein the identity is defined as a percentage of identical amino acids in said sequence when it is collated with the selected sequence.
  • amino acid sequences may be calculated using well known algorithms such as BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM 55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80, BLOSUM 85, or BLOSUM 90.
  • a variant and analogue according to the invention can be a recombinant or non-recombinant amino acid sequence.
  • variant and analogue is also meant any variant and analogue of a clotting factor according to the invention which are functional equivalents of said clotting factors.
  • functional equivalent of a clotting factor is in the present context meant a molecule which meets the criteria for a variant or a fragment of said clotting factor described above and which is capable of one or more functional activities of said clotting factor or a compound comprising said clotting factor.
  • the functionality of a clotting factor according to the present invention may be assessed in several ways.
  • any clotting factor or compound capable of inducing an activation of the hemostatic system equal to or better than that of 1 to 100 microgram/kg of FVIIa is contemplated to induce a significant pro-hemostatic effect and is thus falls within the scope of the present invention.
  • any clotting factor or compound capable of inducing an activation of the hemostatic system equal to or better than that of between 1 and 10 microgram/kg/hour of adrenaline is contemplated to induce a significant pro-hemostatic effect.
  • any clotting factor or compound capable of inducing an activation of the hemostatic system equal to that of 6 microgram/kg/hour of adrenaline is contemplated to induce a significant pro-hemostatic effect.
  • Any clotting factor able of inducing an activation of the hemostatic system equal to or better than that of 5 microgram/kg of FVIIa and/or 6 microgram/kg/hour of adrenaline is contemplated to induce a significant pro-hemostatic effect.
  • a method for testing the hemostatic efficacy and/or the required dose of a clotting factor comprises the following steps: a) administering to a subject and/or to a blood sample taken from a subject a clotting factor to be tested, b) optionally administering a sympathicomimetic agonist and/or a beta blocker prior to, during or after administering the clotting factor to the subject or to a sample of venous or arterial blood from the subject, c) conducting a TEG analysis on a blood sample from the subject, d) comparing the at least one measured parameter such as but not limited to: R value (clotting time), K value (clot kinetics), Angle or alpha (representing velocity of clot formation), MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or more parameters following the intravenous administration of 5 microgram/kg of FVIIa and
  • the parameter measured is R value (clotting time).
  • a preferred clotting factor is capable of reducing the R value of the blood also when administered in combination with a sympathicomimetic agonist or when administered with both a sympathicomimetic agonist and a beta blocker.
  • a preferred clotting factor is capable of increasing the Angle value of the blood also when administered in combination with a sympathicomimetic agonist or when administered with both a sympathicomimetic agonist and a beta blocker.
  • a most preferred clotting factor is capable of both reducing the R value and increasing the Angle value of the blood also when administered in combination with a sympathicomimetic agonist or when administered with both a sympathicomimetic agonist and a beta blocker.
  • the lowest dosage of clotting factor administered gives a response corresponding to that measured upon the administration of 5 microgram/kg of FVIIa and/or 6 microgram/kg/hour of adrenaline, optionally this response is measured in one of the assays herein disclosed.
  • the lowest dosage of clotting factor administered gives a response corresponding to that measured upon the administration of 6 microgram/kg/hour of adrenaline; preferably, the clotting factor is FVIIa, optionally this response is measured in one of the assays as herein disclosed.
  • a concentration may be 2 microgram/kg, such as 3 microgram/kg/hour, such as 5 microgram/kg, such as 6 microgram/kg/hour, such as 9 microgram/kg/hour, such as 10 microgram/kg, such as 12 microgram/kg/hour, such as 15 microgram/kg, such as 20 microgram/kg, such as 25 microgram/kg, such as 30 microgram/kg, such as 35 microgram/kg, such as 40 microgram/kg, such as 45 microgram/kg, such as 50 microgram/kg, such
  • between 1 microgram/kg/hour of adrenaline and 15 microgram/kg/hour of adrenaline, dependent upon which effect is desired to be achieved by the clotting factor, such a concentration may be 2 microgram/kg/hour, such as 3 microgram/kg/hour, such as 6 microgram/kg/hour, such as 9 microgram/kg/hour, such as 12 microgram/kg/hour, such as 15 microgram/kg/hour of adrenaline.
  • the method for testing the hemostatic efficacy and/or the required dose of a clotting factor may optionally comprise an additional step relating to from where the blood sample from the subject is collected, namely whether it is collected from an artery or a vein and dependent hereon, the sample(s) on which the reference value(s) is / are based must have been collected from the same arterial or venous source to ensure accuracy.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from arterial blood.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from venous blood.
  • the method for testing the hemostatic efficacy and/or the required dose of a clotting factor may further comprise the following steps: a) administering to a subject and/or to a venous or arterial blood sample taken from a subject a clotting factor to be tested, b) optionally administering a sympathicomimetic agonist and/or a beta blocker prior to, during or after administering the clotting factor to the subject or to a sample of venous or arterial blood from the subject, c) conducting a TEG analysis on a blood sample from the subject, d) comparing the at least one measured parameter such as but not limited to: R value (clotting time), K value (clot kinetics), Angle or alpha (representing velocity of clot formation) MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or more parameters following the administration of 5 microgram/kg of
  • a clotting factor is tested against the values obtained for FVIIa, such as for 5 microgram/kg of FVIIa, 10 microgram/kg of FVIIa or any concentration of FVIIa between 1 and 100 microgram/kg.
  • the compounds including those that give the reference value(s) i.e. FVIIa and/or adrenaline may be administered to a subject prior to or while drawing blood and as a single or repeated bolus or continuous infusion or during or after sampling of the blood where the compound(s) is/are administered to the sample directly.
  • a clotting factor for use according to the present invention is a substance capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the substance is administered such as: lowering the R value (clotting time), lowering the K value (clot kinetics), increasing the Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength), increasing the Lysis AUC (the area under the fibrinolysis curve AUC) and/or increasing the fibrinolysis time (LY).
  • a clotting factor for use according to the present invention is a substance capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the substance is administered such as lowering the R value (clotting time), lowering the K value (clot kinetics), increasing the Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength).
  • a clotting factor for use according to the present invention is a substance capable of altering the lowering the r value (clotting time) and/or increasing the Angle value.
  • the treatment with the combination of clotting factors and sympathicomimetic agonists comprises adrenaline, noradrenaline, dobutamin, ephedrine, dopamine etc, see herein below.
  • the "sympathicomimetics” or “sympathicomimetic agonists” or “adrenergic receptor agonist” as used interchangeably herein includes any pharmaceutical compounds with the same or similar activity as noradrenaline (norepinephrine) and adrenaline (epinephrine). This group of compounds, having predominantly peripheral action, can be divided into:
  • Directly acting sympathicomimetics act upon the adrenergic receptors (adrenoceptors), these comprising the a r , a 2 -, ⁇ i, ⁇ 2 - and ⁇ 3 -subtypes [Goldstein. 2006].
  • Any sympathicomimetic agonist is of relevance for the present invention for use in the treatment and/or prophylaxis of bleeding in a subject.
  • Such sympathicomimetic agonists include but are not limited to agonists that are ligands of any one or more of the abovementioned receptors.
  • Some sympathicomimetic agonists are specific for one or more of the abovementioned receptors; for example a particular agonist may be alpha-1 specific, or be alpha specific indicating that the agonist will bind either of the two known alpha receptors, or may be an agonist capable of interacting with any of the adrenergic receptors; an example hereof is adrenaline.
  • Examples of all of these types of sympathicomimetic of relevance to the present invention include, but are not limited to: Adrenaline (epinephrine), Noradrenaline (norepinephrine), Phenylephrine, Methoxamine, Cirazoline, Xylometazoline, Methylnorepinephrine, Oxymetazoline, Dexmedetomidine, Clonidine, Lofexidine, Xylazine, Tizanidine, Guanfacine, Guanabenz, Guanoxabenz, Guanethidine, Methyldopa, amidephrine, amitraz, anisodamine, apraclonidine, brimonidine, cirazoline, detomidine, dexmedetomidine, ergotamine, etilefrine, indanidine, lofexidine, medetomidine, mephentermine, metaraminol (e.g.
  • Aramine methoxamine, midodrine, mivazerol, naphazoline, norfenefrine, octopamine, oxymetazoline, phenylpropanolamine, rilmenidine, romifidine, synephrine, talipexole and tizanidine, Dopamine (e.g.
  • sympathicomimetic agonists for use according to the invention comprises agonists of the Alpha-1 adrenergic receptor, such as but not limited to: Adrenaline (epinephrine), Noradrenaline (norepinephrine), Phenylephrine, Methoxamine, Cirazoline, Xylometazoline Methylnorepinephrine, and Oxymetazoline; as well as Alpha-2 adrenergic receptor agonists such as, but not limited to: Adrenaline (epinephrine), Noradrenaline (norepinephrine), Dexmedetomidine, Clonidine, Lofexidine, Xylazine, Tizanidine, Guanfacine, Guanabenz, Guanoxabenz,
  • Alpha-1 adrenergic receptor such as but not limited to: Adrenaline (epinephrine), Noradrenaline (norepinephrine), Phenyle
  • Guanethidine, and Methyldopa and agonists that interact with both alpha receptors (and in some instances also the beta receptors), examples of these including, but again not being limited to: Adrenaline (epinephrine), Noradrenaline (norepinephrine), amidephrine, amitraz, anisodamine, apraclonidine, brimonidine, cirazoline, detomidine, dexmedetomidine, ergotamine, etilefrine, indanidine, lofexidine, medetomidine, mephentermine, metaraminol, methoxamine, midodrine, mivazerol, naphazoline, , norfenefrine, octopamine, oxymetazoline, phenylpropanolamine, rilmenidine, romifidine, synephrine, talipexole and tizanidine.
  • Adrenaline epine
  • examples of sympathicomimetic agonists that according to the present invention may be administered for the prevention and/or treatment of bleeding in a subject are agonists that interact with the beta receptors, these include, but are not limited to agonists that bind the Beta 1 adrenergic receptor, such as, but not restricted to: Noradrenaline, Isoprenaline, Dobutamine, Dobutrex, and Isoproterenol ( ⁇ 1 and ⁇ 2); the Beta-2 adrenergic receptor agonists, again including but not limited to: Salbutamol (Albuterol in USA), Bitolterol mesylate, Formoterol, Isoprenaline, Levalbuterol, Metaproterenol, Salmeterol, Terbutaline, Ritodrine, Fenoterol, Isoproterenol ( ⁇ 1 and ⁇ 2), and Clenbuterol; as well as the following non-limiting examples of agonists that bind the Beta-3 adrene
  • the sympathicomimetic agonists for use according to the invention may be any endogenous or exogenous agonistic substance affecting any one or more of the ⁇ i, ⁇ 2 , ⁇ i, ⁇ 2 , ⁇ adrenergic receptors.
  • the agonistic substance may comprise any human, non-human, recombinant or by any other means manufactured agonistic substance affecting any one or more of the ⁇ i, ⁇ 2 , ⁇ i, ⁇ 2 , ⁇ adrenergic receptors of the sympathetic nerve system.
  • sympathicomimetic agonists for the prevention and/or treatment of bleeding in a subject include but are not limited to agonists capable of binding at least one adrenergic receptor subtype.
  • the sympathicomimetic agonists for the prevention and/or treatment of bleeding in a subject include but are not limited to adrenaline, noradrenaline, dobutamin, dobutrex, and dopamine, as well as metabolic products and chemically related synthetic derivates hereof.
  • sympathicomimetic agonists may further include any agonist with an agonistic effect on ⁇ -adrenergic and/or ⁇ -adrenergic receptors, including any subtypes (e.g.
  • a r 0 2 -, ⁇ i, ⁇ 2 - and ⁇ 3 -subtypes
  • the sympathetic nervous system such as but not limited to adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, ephedrine and other known or yet undiscovered chemical or biological substances or compounds where any of the above mentioned are included.
  • the agonistic substance or derivatives hereof may also be in a combination of two or more, such as three or more, four or more and five or more of any of the sympathicomimetics agonist discussed above.
  • the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine. Analogs of these substances may also be useful in the present invention.
  • the sympathicomimetic agonist comprises or is adrenaline (epinephrine).
  • the sympathicomimetic agonist comprises or is noradrenaline (norepinephrine).
  • adrenaline and epinephrine are used interchangeably herein and both denote the compound defined in formula I with IUPAC name: (7?,)-4-(1-hydroxy-2- (methylamino)ethyl)benzene-1 ,2-diol: Formula I:
  • noradrenaline and norepinephrine are used interchangeably herein and both denote the compound defined in formula Il with IUPAC name: 4-(2-Amino-1 - hydroxyethyl)benzene-1 ,2-diol: Formula II:
  • a method for testing the hemostatic efficacy and/or the required dose of a sympathicomimetic agonist comprises the following steps: a) administering to a subject and/or to a blood sample taken from a subject a sympathicomimetic agonist to be tested, b) conducting a TEG analysis on a blood sample from the subject, c) comparing the at least one measured parameter such as but not limited to: r value (clotting time), k value (clot kinetics), Angle or alpha (representing velocity of clot formation) MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or more parameters following the administration of
  • reference value is understood a value that has been obtained after repeated testing of the effects of administering 6 microgram/kg/hour of adrenaline to a statistically relevant number of subjects.
  • the reference value may alternatively be based on the effects of administering another concentration of adrenaline, such as but not limited to: between 1 microgram/kg/hour of adrenaline and 10 microgram/kg/hour of adrenaline, dependent upon which effect is desired to be achieved by the sympathicomimetic agonist.
  • the method for testing the hemostatic efficacy and/or the required dose of a sympathicomimetic agonist may optionally comprise an additional step relating to from where the blood sample from the subject is collected, namely whether it is collected from an artery or a vein and dependent hereon, the sample(s) on which the reference value(s) is / are based must have been collected from the same arterial or venous source to ensure accuracy.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from arterial blood.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from venous blood.
  • the method for testing the hemostatic efficacy and/or the required dose of a sympathicomimetic agonist may further comprise the following steps: a) administering to a subject and/or to a venous or arterial blood sample taken from a subject a sympathicomimetic agonist to be tested, b) conducting a TEG analysis on a blood sample from the subject, c) comparing the at least one measured parameter such as but not limited to: R value (clotting time), K value (clot kinetics), Angle or alpha (representing velocity of clot formation) MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or more parameters following the administration of 6 microgram/kg/hour of adrenaline and/or 5 microgram/kg of
  • FVIIA as measured on a venous or arterial blood sample, the sample being drawn from the same source as in a) wherein the parameters obtained for the 6 microgram/kg/hour of adrenaline and/or 5 microgram/kg of FVIIA may be obtained from the same subject being tested with the sympathicomimetic agonist or a reference value / parameter obtained in advance.
  • a sympathicomimetic agonist for use according to the present invention is a substance capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the substance is administered such as: lowering the R value (clotting time), lowering the K value (clot kinetics), increasing the Angle or alpha
  • a sympathicomimetic agonist for use according to the present invention is a substance capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the substance is administered such as lowering the r value (clotting time), lowering the k value (clot kinetics), increasing the Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength).
  • a sympathicomimetic agonist for use according to the present invention is a substance capable of altering all of the following TEG measurable parameters of the blood of a subject to which the substance is administered by lowering the R value (clotting time), lowering the K value (clot kinetics), and increasing the MA, maximal amplitude, (the maximal physical clot strength).
  • noradrenaline may be administered in the same dose interval as adrenaline, and dopamine at a dose of 10 -100 x higher (for example 30 - 300 microgram/kg/hour) than adrenaline and noradrenaline, and dobutamin may be administered at a dose of 10 -100 x higher (for example 30-300 microgram/kg/hour) than adrenaline and noradrenaline.
  • An aspect of the present invention relates to the administration of a clotting factor in combination with a sympathicomimetic agonist for treatment/and or prophylaxis of bleeding in a subject.
  • Systemic administration of adrenaline results in an earlier increase in platelet count and clot strength (MA), as evaluated by TEG than in coagulation factor activity, which increases progressively secondary to increase in circulating coagulation factors and occurs as evaluated by a reduction in APTT (activated partial thromboplastin time), PT (prothrombin time) and a reduction in R as evaluated by TEG.
  • MA platelet count and clot strength
  • APTT activate partial thromboplastin time
  • PT prothrombin time
  • rFVIIa a single low dose rFVIIa at the start of adrenaline infusion (1-20 ⁇ g/kg) the initiation of the coagulation process including the thrombin burst will occur earlier than when adrenaline is administered alone and this will result in a faster maximal haemostatic effect. Furthermore, by adding rFVIIa a more pronounced initiation and generation of thrombin burst may be achieved than when adrenaline is administered alone, also when the maximal effect of adrenaline on coagulation factors is present.
  • any combination of the clotting factors and sympathicomimetic agonists discussed in the above can be used according to the present invention.
  • the clotting factor for use according to the invention is selected from the group consisting of FII, FV, FVII, FVIII, FIX, FX, FXII, FXIII, and FIIa, FVa, FVIIa, FVIIIa, FIXa, FXa, FXIIa and FXIIIa, rFVIIa and rhFVIIa or a variant or analogue thereof, and the sympathicomimetic agonist for use according to the invention is selected from adrenaline, noradrenaline, dobutamin, dobutrex, and dopamine, as well as metabolic products and chemically related synthetic derivates hereof.
  • the clotting factor for use according to invention is FVIIa, rFVIIa, rhFVIIa or a variant or an analogue hereof and the sympathicomimetic agonist for use according to the invention is adrenaline and or/noradrenaline.
  • clotting factors and sympathicomimetic agonists can comprise one or several clotting factors and/or one or several sympathicomimetic agonists.
  • the combination of clotting factor and sympathicomimetic agonist may be administered as bolus injections, repeated bolus injections or continuous injections and may be administered differently from one another such as by administering the sympathicomimetic agonist by continuous infusion and the clotting factor as a single or repeated bolus injections.
  • the timing may also vary such that the administration of a clotting factor may be done prior to, during or after the administration of the sympathicomimetic agonist.
  • a method for testing the hemostatic efficacy and/or the required dose(s) of a combination of a clotting factor and a sympathicomimetic agonist comprises the following steps: a) administering to a subject and/or to a blood sample taken from a subject independently of each other or simultaneously a combination of a clotting factor and a sympathicomimetic agonist to be tested, b) conducting a TEG analysis on a blood sample from the subject, c) comparing the at least one measured parameter such as but not limited to: R value (clotting time), K value (clot kinetics), Angle or alpha (representing velocity of clot formation) MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or more parameters following the administration of 1 microgram/kg of FVIIa, and/or 6 microgram/kg/hour of adrenaline wherein the parameters obtained for the 5 micro
  • a concentration may be 2 microgram/kg, such as 3 microgram/kg/hour, such as 4 microgram/kg/hour, such as 5 microgram/kg, such as 6 microgram/kg/hour, such as 7 microgram/kg/hour, such as 8 microgram/kg/hour, such as 9 microgram/kg/hour, such as 10 microgram/kg, such as 11 microgram/kg/hour, such as 12 microgram/kg/hour, such as 13 microgram/kg/hour, such as 14 microgram/kg/hour, such as 15 microgram
  • between 1 microgram/kg/hour of adrenaline and 15 microgram/kg/hour of adrenaline, dependent upon which effect is desired to be achieved by the clotting factor, such a concentration may be 2 microgram/kg/hour, such as 3 microgram/kg/hour, such as 6 microgram/kg/hour, such as 9 microgram/kg/hour, such as 12 microgram/kg/hour, such as 15 microgram/kg/hour of adrenaline.
  • the method for testing the hemostatic efficacy and/or the required dose(s) of a combination of a clotting factor and a sympathicomimetic agonist may optionally comprise an additional step relating to from where the blood sample from the subject is collected, namely whether it is collected from an artery or a vein and dependent hereon, the sample(s) on which the reference value(s) is / are based must have been collected from the same arterial or venous source to ensure accuracy.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from arterial blood.
  • the blood sample to be analyzed and the sample or samples (such as those on which a reference value is based) with which it is compared are all drawn from venous blood.
  • the method for testing the hemostatic efficacy and/or the required dose of a clotting factor or a combination of a clotting factor and a sympathicomimetic agonist optionally also combined with a beta blocker may further comprise the following steps: a) administering to a subject and/or to a venous or arterial blood sample taken from a subject independently of each other or simultaneously a clotting factor or a combination of a clotting factor and a sympathicomimetic agonist optionally also combined with a beta blocker to be tested, b) conducting a TEG analysis on a blood sample from the subject, c) comparing the at least one measured parameter such as but not limited to: R value (clotting time), K value (clot kinetics), Angle or alpha (representing velocity of clot formation) MA, maximal amplitude, (the maximal physical clot strength), Lysis AUC (the area under the fibrinolysis curve AUC) and/or fibrinolysis time (LY) with the same one or
  • a clotting factor when used in combination with a sympathicomimetic agonist and optionally also a beta blocker according to the present invention is a combination of substances capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the combination is administered such as: lowering the R value (clotting time), lowering the K value (clot kinetics), increasing the Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength), increasing the Lysis AUC (the area under the fibrinolysis curve AUC) and/or increasing the fibrinolysis time (LY).
  • the combination of a clotting factor and a sympathicomimetic agonist and optionally also a beta blocker for use according to the present invention is a combination capable of altering one or more of the TEG measurable parameters of the blood of a subject to which the substance is administered such as lowering the R value (clotting time), lowering the K value (clot kinetics), increasing the Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength).
  • the combination of a clotting factor and a sympathicomimetic agonist and optionally also a beta blocker for use according to the present invention is a combination capable of altering all of the following TEG measurable parameters of the blood of a subject to which the substance is administered by lowering the R value (clotting time), lowering the K value (clot kinetics), and increasing the MA, maximal amplitude, (the maximal physical clot strength) and increasing the Angle or alpha (representing velocity of clot formation).
  • the hemostatic efficacy of the combination of a clotting factor and a sympathicomimetic agonist is higher / better than that of either the clotting factor or the sympathicomimetic agonist alone.
  • the improved effect may be measured as any one or more of the following TEG measurable parameters of the blood of a subject to which the combination is administered by lowering the r value (clotting time), lowering the k value (clot kinetics), and increasing the MA, maximal amplitude, (the maximal physical clot strength) and increasing the Angle or alpha (representing velocity of clot formation).
  • a beta blocker and or potassium may be used in combination with the clotting factor and the sympathicomimetic agonist.
  • a current indication for which adrenaline is used is for the treatment cardiac arrest, anaphylactic shock and other cardiac dysrhythmias resulting in diminished or absent cardiac output.
  • the action of adrenaline is to increase peripheral resistance via ⁇ 1- adrenoceptor vasoconstriction, so that blood is shunted to the body's core, and the ⁇ 1- adrenoceptor response which is increased cardiac rate and output (the speed and pronouncement of heart beats) resulting in amongst others: high blood pressure.
  • the consequence of especially the beta-1 mediated response: increased cardiac rate, cardiac output and high blood pressure, is detrimental to subjects that are bleeding, as this will increase the rate with which blood is being pumped out of the body.
  • clotting factor FVIIa in combination with low doses of adrenaline increases the hemostatic ability of the blood. If dysrhythmias, and especially tachycardia, never the less are sought prevented, an aspect of the present invention comprising the co- administration of a clotting factor and a sympathicomimetic agonist with a beta-1 blocker accommodates this.
  • a clotting factor and a sympathicomimetic agonist with a beta-1 blocker accommodates this.
  • beta adrenergic receptors There are three known types of beta adrenergic receptors and any compound capable of blocking the action of one or more of these is of relevance to the present invention.
  • beta blockers that may be used in combination with a clotting factor and a sympathicomimetic agonist for the prevention and/or treatment of bleeding in a subject include, but are not limited to: Acebutolol, Alprenolol, Amosulalol, Arotinolol, Atenolol, Befunolol, Betaxolol, Bevantolol, Bisoprolol, Bopindolol, Bucindolol, Bunitrolol, Bupranolol, Butaxamine, Carazolol, Carteolol, Carvedilol, Celirolol, Esmolol (Brevibloc), Indenolol, Labetalol, Landiolol, Levobetaxolol, Levobunolol, Mepindolol, Metipranolol, Metoprolol (Seloken), Nadolol,
  • At least one beta blocker of above is used in combination with clotting factors and sympathicomimetic agonists which may include any clotting factor such as but not limited to a prothrombin complex concentrate factor and/or an activated prothrombin complex concentrate factor, and any agonist with an agonistic effect on ⁇ - adrenergic and/or ⁇ -adrenergic receptors, including any subtypes (e.g.
  • a r a 2 -, ⁇ i, ⁇ 2 - and ⁇ 3 -subtypes
  • the sympathetic nervous system such as but not limited to adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, ephedrine and other known or yet undiscovered chemical or biological substances or compounds where any of the above mentioned are included.
  • the clotting factor comprises FVIIa, rFVIIa, rhFVIIa or a variant or analogue thereof and the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine and are administered in combination with at least one beta blocker such as but not limited to a non-selective agent (i.e.
  • beta adrenergic receptor may bind or block the action of more than one beta adrenergic receptor, such as, but not restricted to: Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, and Timolol.
  • beta adrenergic receptor such as, but not restricted to: Alprenolol, Carteolol, Levobunolol, Mepindolol, Metipranolol, Nadolol, Oxprenolol, Penbutolol, Pindolol, Propranolol, Sotalol, and Timolol.
  • the clotting factor comprises FVIIa or a variant or analogue thereof and the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine and are administered in combination with at least one beta blocker such as but not limited to ⁇ 1 -selective agents such as Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol (Seloken), Nebivolol, Amosulalol, Landiolol, and Tilisolol; or ⁇ 2-Selective agents such as Butaxamine; or beta 3 selective agents.
  • ⁇ 1 -selective agents such as Acebutolol, Atenolol, Betaxolol, Bisoprolol, Esmolol, Metoprolol (Seloken), Nebivolol, Amosulalol, Landiolol, and Tilisolol
  • the clotting factor comprises FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine and are administered in combination with at least one beta blocker with a high cardioselectivity (i.e. ⁇ i / ⁇ 2 ratio) and low half life such as but not limited to Seloken, Esmolol and Landiolol.
  • the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine and are administered in combination with at least one beta blocker with a high cardioselectivity (i.e. ⁇ i / ⁇ 2 ratio) and low half life such as but not limited to Seloken, Esmolol and Landiolol.
  • composition indicates that the drugs may be formulated together, or are kept as separate entities and may be administered simultaneously or within a predetermined interval of each other. Examples of how the clotting factors, the sympathicomimetic agonists and beta blockers of the present invention may be administered in combination with each other are given in the below.
  • the beta blocker of the present invention that is used in combination with a clotting factor and sympathicomimetic for the treatment of bleeding in a subject is administered in the pharmaceutically efficient dose of the particular compound.
  • Seloken may be administered in a tablet comprising 50 mg to 200 mg of Seloken and an appropriate dosage of a sympathicomimetic agonist as disclosed above.
  • Seloken may be administered parenterally at doses between 1 mg and 40 mg administered in one or several dosages or intravenously at a rate of 10 to 150 ml/hour (1 mg/ml).
  • Esmolol (tradename Brevibloc) may be administered at 0.1 to 5.0 mg/kg as an i.v.
  • bolus injection such as 0.5 mg/kg and/or as between 0.01 to 1 mg/kg/min i.v., such as 0.05 to 0.3 mg/kg/min as first administration or continued administration.
  • Landiolol may be administered intravenously at dosages between 0.01 to 5 mg/kg/min, such as 0.1 to 0.5 mg/kg/min or as bolus injections of between 1 mg to 20 mg.
  • the dosage of beta blocker may be increased according the necessity thereof.
  • Adrenaline is known to have a lowering effect on serum potassium concentrations.
  • Normal reference values for potassium in plasma is: 3,2 - 4,7 mmol/l and in serum: 3,5 - 5,0 mmol/l.
  • Mild hypokalaemia (low concentration of potassium in the blood) is defined as a plasma potassium concentration >3.0 mmol/L and severe hypokalaemia is when the potassium concentration is ⁇ 3.0 mmol/L.
  • Epinephrine in the doses to be administered for the prevention and/or treatment of bleeding in a subject lowers the potassium concentration to approximately 3.3 mmol/l. and is thus not expected to cause hypokalaemia.
  • an embodiment of the present invention comprises administration of potassium at a concentration of or in an amount corresponding to between 1 mmol/L to 30 mmol/L, or 1.5 mmol/L to 25 mmol/L, or 2 mmol/L to 20 mmol/L, or 2.5 mmol/L to 15 mmol/L, or 3 mmol/L to 10 mmol/L, or 4 mmol/L to 5 mmol/L.
  • potassium is comprised in an amount that counter the effect of the sympathicomimetic compound and thus retains the plasma potassium concentration within the normal range.
  • the "normal range" may be the pharmaceutically / medically accepted range of potassium concentrations found in human beings or may be individualized so the plasma concentration of potassium measured in the individual prior to commencement of treatment may be kept at the measured level.
  • An embodiment of the present invention relates to the administration of a a clotting factor in combination with a sympathicomimetic agonist in a formulation comprising potassium at a concentration betweeni mmol/L and 30 mmol/L for the prevention and/or treatment of bleeding in a subject.
  • the treatment of bleeding in a subject comprises the administration of at least one clotting factor comprising a prothrombin complex concentrate factor and/or an activated prothrombin complex concentrate factor and at least one of the following sympathicomimetic agonists: adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, and ephedrine in combination with potassium at a concentration betweeni mmol/L and 30 mmol/L.
  • sympathicomimetic agonists adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, and ephedrine
  • adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, and ephedrine in combination with potassium at a concentration betweeni mmol/L and 30 mmol/L.
  • FVIIa or a variant or analogue thereof, and adrenaline and/or noradrenaline are administered in combination with potassium at a concentration of betweeni mmol/L and 30
  • another embodiment of the present invention relates to the administration of a clotting factor and a sympathicomimetic agonist in combination with a beta blocker in a formulation further comprising potassium at a concentration between 1 mmol/L and 30 mmol/L for the prevention and/or treatment of bleeding in a subject.
  • the treatment of bleeding in a subject comprises the administration of at least one clotting factor comprising a prothrombin complex concentrate factor and/or an activated prothrombin complex concentrate factor and at least one of the following sympathicomimetic agonists: adrenaline, noradrenaline, dopamine, dobutamin, dobutrex, and ephedrine in combination with a beta blocker, the blocker preferably being a beta 1 receptor specific blocker and further being administered in combination with potassium at a concentration betweeni mmol/L and 30 mmol/L. Most preferably, FVIIa, adrenaline and/or noradreline are administered in combination potassium at a concentration of betweeni mmol/L and 30 mmol/L.
  • the administration of potassium may follow that of the administration of the clotting factor and the sympathicomimetic agonist or be independent hereof.
  • the administration of potassium may precisely follow the administration of e.g. adrenaline or FVIIa such that the administration of potassium starts and/or stops with the administration of adrenaline or FVIIa.
  • potassium may be administered to counter this lowering bringing the concentration of plasma potassium back to normal.
  • the administration of potassium stops at the same time as the administration of the clotting factor and/or the sympathicomimetic agonist and/or beta blocker.
  • Administration of the clotting factors and sympathicomimetic agonists is to be given to a subject resulting in a systemic concentration of the clotting factors and sympathicomimetic agonists.
  • Methods of administration include enteral, such as oral, sublingual, gastric, intraalveolar or rectal and/or parenterally, that is by intravenous, intramuscular, subcutaneous, intranasal, intrapulmonary, intrarectal, intravaginal, intraosseous or intraperitoneal administration.
  • the subcutaneous and intravenous forms of parenteral administration are generally preferred.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • the compounds may also be administered by inhalation that is by intranasal and oral inhalation administration.
  • Appropriate dosage forms for such administration such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.
  • the compounds according to the invention may be administered with at least one other compound.
  • the compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.
  • dose shall mean any concentration of the clotting factors and sympathicomimetic agonists administered producing a pro-hemostatic effect on the hemostatic system.
  • a dose sufficient to produce the desired effect in relation to the conditions for which it is administered, in particular an amount of a clotting factor and sympathicomimetic agonists that is effective to stop, reduce or prevent the unwanted bleeding shall be described as the “effective dose”, “therapeutically effective dose” or “effective amount”.
  • the dose should be capable of preventing or lessening the severity or spread of the condition or indication being treated.
  • the exact dose will depend on the circumstances, such as the condition being treated, the administration schedule, whether the clotting factor and sympathicomimetic agonists is administered alone or in conjunction with another therapeutic agent or another clotting factor or sympathicomimetic agonists, the plasma half-life of the clotting factor and the sympathicomimetic agonists and the general health of the subject.
  • the dose is preferably given by the parenteral administration route, notably the intravenous, intramuscular, intraosseous and/or the subcutaneous, sublingual, trans-mucosal, intrapulmonal and intra-alveolar route.
  • the dosages given in the following is contemplated to be in the same order of magnitude irrespective of the parenteral administration route.
  • the normal dose of FVIIa given is usually in the range of 25-200 microgram/kg. Surprisingly, the inventor has discovered that low doses of up to 20 microgram/kg of the clotting factor FVIIa is most effective.
  • the dose given should preferably induce a appropriate systemic concentration of FVIIa in the range of 0.1 to 10 microgram/kg, such as 0.2 to 8 microgram/kg, for example 0.3 to 7 microgram/kg, such 0.4 to 6 microgram/kg, for example 0.5 to 5 microgram/kg, such as 0.7 to 4 microgram/kg, for example 0.8 to 4 microgram/kg, such as 0.9 to 3 microgram/kg, such as around 1 microgram/kg.
  • the dose administered will for enteral and/or parenteral, notably oral, intravenous, intramuscular and/or subcutaneous routes, single or repeated bolus dose(s) be in the range of from 1 microgram/kg to 20 microgram/kg, 1.5 microgram/kg to 20 microgram/kg, such as 2 microgram/kg to 20 microgram/kg, such as 3 microgram/kg to 20 microgram/kg, such as 4 microgram/kg to 20 microgram/kg, such as 5 microgram/kg to 20 microgram/kg, or any interval therein between.
  • the dose for parenteral administration notably intravenous infusion, will be in the range of from 0,1 microgram/kg to 20 microgram/kg, or 0,5 microgram/kg to 20 microgram/kg, or 1 microgram/kg to 20 microgram/kg, or any interval therein between.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 1 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous routes in a single or repeated bolus dose of about 5 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 10 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 15 microgram/kg. In a still further embodiment the clotting factor FVIIa or rFVIIa, the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 16, 17, 18, or 19 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 20 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 21 , 22, 23, or 24 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 25 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 30 microgram/kg.
  • the dose administered will for intravenous, intramuscular and/or subcutaneous single or repeated bolus dose be about 40 microgram/kg.
  • the bolus injection may be given once, twice or several times, for instance, in keeping with the dosage administered the bolus injection may be given every 5 min (minutes), such as every 10 min, such as every 15 min, such as every 20 min, such as every 25 min, such as every 30 min, such as every 35 min, such as every 40 min, such as every 45 min, such as every 50 min, such as every 55 min, such as every 60 min such as every 70 min, such as every 80 min, such as every 90 min, such as every 100 min, such as every 110 min such as every 120 min or more.
  • the bolus dosage may be administered in the appropriate intervals from the time of trauma to the subject and until a treatment facility such as a hospital or other is reached.
  • the dose for parenteral administration notably intravenous or intraosseous infusion
  • the dose for parenteral administration will be in the range of from 0.1 microgram/kg/hour to 30 microgram/kg/hour, such as 0.5 microgram/kg/hour to 29 microgram/kg/hour, such as 0.7 microgram/kg/hour to 28 microgram/kg/hour, such as 0.8 microgram/kg/hour to 27 microgram/kg/hour, such as 0.9 microgram/kg/hour to 26 microgram/kg/hour, such as 1 microgram/kg/hour to 25 microgram/kg/hour or any interval therein between.
  • the interval may be between 1 microgram/kg/hour to 20 microgram/kg/hour, 1.5 microgram/kg/hour to 19.5 microgram/kg/hour, such as 2 microgram/kg/hour to 19 microgram/kg/hour, such as 2.5 microgram/kg/hour to 18.5 microgram/kg/hour, such as 3 microgram/kg/hour to 18 microgram/kg/hour, such as 3.5 microgram/kg/hour to 17.5 microgram/kg/hour, such as 4 microgram/kg/hour to 17 microgram/kg/hour, such as 4.5 microgram/kg/hour to 16.5 microgram/kg/hour, such as 5 microgram/kg/hour to 16 microgram/kg/hour, such as 5.5 microgram/kg/hour to 15.5 microgram/kg/hour, such as 6 microgram/kg/hour to 15 microgram/kg/hour, such as 6.5 microgram/kg/hour to 14.5 microgram/kg/hour, such as 7 microgram/kg/hour to 14 microgram/kg/hour, such as 7.5 microgram/gram/
  • the dose for parenteral administration notably intravenous or intraosseous infusion, will be in the range of from 1 microgram/kg/hour to 10 microgram/kg/hour, or 1.5 microgram/kg/hour to 9.5 microgram/kg/hour, or 2 microgram/kg/hour to 9 microgram/kg/hour, or 2.5 to 8.5 microgram/kg/hour, or 2.5 microgram/kg/hour to 8.5 microgram/kg/hour, or 3 microgram/kg/hour to 8 microgram/kg/hour, or 3.5 microgram/kg/hour to 7.5 microgram/kg/hour, or 4 microgram/kg/hour to 7 microgram/kg/hour or any interval therein between.
  • the intravenous infusion of the clotting factor FVIIa will be about 0,1 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 1 microgram/kg/hour. In a specific embodiment the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 2 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 3 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 4 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 5 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 6 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 7 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 8 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 9 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 10 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 1 1 , 12, 13 or 14 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 15 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 16, 17, 18 or 19 microgram/kg/hour. In a still further embodiment the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 20 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 21 , 22, 23 or 24 microgram/kg/hour.
  • the intravenous infusion of the clotting factor FVIIa or rFVIIa will be about 25 microgram/kg/hour.
  • the infusion may be of any duration necessary such as from 1 minute (min) to several hours if required.
  • the dosage can, due to the rapid turnover of FVIIa or rFVIIa and similar compounds be administered continuously without risk of accumulation.
  • a subject for the prophylaxis or treatment of bleeding for more than 1 min such as 5 min, such as 10 min, such as 15 min, such as 20 min, such as 25 min, such as 30 min, such as 35 min, such as 40 min, such as 45 min, such as 50 min, such as 55 min, such as 60 min, such as 65 min, such as 70 min, such as 75 min, such as 80 min, such as 85 min, such as 90 min, such as 95 min, such as 100 min, such as 105 min, such as 110 min, such as 120 min, such as 130 min, such as 140 min, such as 150 min, such as 160 min, such as 170 min, such as 180 min, such as 190 min, such as 200 min, such as 210 min, such as 220
  • the dose administered should have an effect corresponding to in the range of 1 to 30 minutes of intravenous infusion, such as 2 minutes to 27 minutes, for example 5 minutes to 25 minutes, such as 7 minutes to 23 minutes, for example 10 minutes to 20 minutes such as 15 minutes of intravenous infusion of in the range of from 0.1 microgram/kg/hour to about 50 microgram/kg/hour in fully awake, non-anesthetized patients, such as in the range of from 1 microgram/kg/hour to 10 microgram/kg/hour, or 1.5 microgram/kg/hour to 9.5 microgram/kg/hour, or 2 microgram/kg/hour to 9 microgram/kg/hour, or 2.5 microgram/kg/hour to 8.5 microgram/kg/hour, or 3 microgram/kg/hour to 8 microgram/kg/hour, or 3.5 microgram/kg/hour to 7.5 microgram/kg/hour, or 4 microgram/kg/hour to 7 microgram/kg/hour or any interval therein between,
  • the dose of the sympathicomimetic agonists adrenaline or noradrenaline administered to individuals being treated for trauma should correspond to the effect of administering to fully awake, non-anesthetized patients by intravenous infusion 6 microgram/kg/hour of the sympathicomimetic agonists adrenaline for 15 minutes.
  • the dose of sympathicomimetic agonists adrenaline and noradrenaline administered should have an effect corresponding to in the range of 1 to 30 minutes of intravenous infusion, such as 2 minutes to 27 minutes, for example 5 minutes to 25 minutes, such as 7 minutes to 23 minutes, for example 10 minutes to 20 minutes such as 15 minutes of intravenous infusion of in the range of from 0.1 microgram/kg/hour to about 50 microgram/kg/hour, such as in the range of from 0.5 microgram/kg/hour to 10 microgram/kg/hour, or 1.0 microgram/kg/hour to 9.5 microgram/kg/hour, or 1.5 microgram/kg/hour to 9 microgram/kg/hour, or 2.0 microgram/kg/hour to 8.5 microgram/kg/hour, or 2.5 microgram/kg/hour to 8 microgram/kg/hour, such as around 3 - 3.5 microgram/kg/hour.
  • the dose of the sympathicomimetic agonists adrenaline or noradrenaline administered to individuals undergoing elective surgery should correspond to the effect of administering to anesthetized patients by intravenous infusion 3 - 3.5 microgram/kg/hour for 15 minutes of the sympathicomimetic agonists adrenaline.
  • the dose administered will for enteral and/or parenteral, notably oral, intravenous, intraosseous, intramuscular and/or subcutaneous routes, single or repeated bolus dose(s) be in the range of from 0.1 ⁇ g/kg to about 50 ⁇ g/kg, such as, e.g., from about 0.5 ⁇ g/kg to about 50 ⁇ g/kg, from about 1 microgram/kg to 50 microgram/kg, such as e.g.
  • microgram/kg to 20 microgram/kg 2.5 microgram/kg to 15 microgram/kg, 3 microgram/kg to 14 microgram/kg or 3.5 microgram/kg to 13 microgram/kg, or 4 microgram/kg to 12 microgram/kg, or 4.5 microgram/kg to 11 microgram/kg, or 5 microgram/kg to 10 microgram/kg, or 5.5 microgram/kg to 9 microgram/kg, or 6 microgram/kg to 8 microgram/kg.
  • the parenteral, notably intravenous, intramuscular, intraosseous, and/or subcutaneous routes, single or repeated bolus dose(s) are in the range of from 0.01 microgram/kg to 100 microgram/kg, such as 0.02 microgram/kg to 90 microgram/kg, such as 0.03 microgram/kg to 80 microgram/kg, such as 0.04 microgram/kg to 70 microgram/kg, such as 0.05 microgram/kg to 60 microgram/kg, such as 0.06 microgram/kg to 50 microgram/kg, such as 0.07 microgram/kg to 40 microgram/kg, such as 0.08 microgram/kg to 30 microgram/kg, such as 0.09 microgram/kg to 27.5 microgram/kg, such as 0.1 microgram/kg to 25 microgram/kg, such as 0.2 microgram/kg to 24 microgram/kg, such as 0.2 microgram/kg to 23 microgram/kg such as 0.3 microgram/kg to 22 microgram/kg, such as 0.4 microgram/kg to 21 microgram/kg, such as 0.1
  • the interval may be between 1 microgram/kg to 20 microgram/kg, 1.5 microgram/kg to 19.5 microgram/kg, such as 2 microgram/kg to 19 microgram/kg, such as 2.5 microgram/kg to 18.5 microgram/kg, such as 3 microgram/kg to 18 microgram/kg, such as 3.5 microgram/kg to 17.5 microgram/kg, such as 4 microgram/kg to 17 microgram/kg, such as 4.5 microgram/kg to 16.5 microgram/kg, such as 5 microgram/kg to 16 microgram/kg, such as 5.5 microgram/kg to 15.5 microgram/kg, such as 6 microgram/kg to 15 microgram/kg, such as 6.5 microgram/kg to 14.5 microgram/kg, such as 7 microgram/kg to 14 microgram/kg, such as 7.5 microgram/kg to 13.5 microgram/kg, such as 8 microgram/kg to 13 microgram/kg, such as 8.5 microgram/kg to 12.5 microgram/kg, such as 9 microgram/kg to 12 microgram/kg, such
  • the dose for parenteral administration notably intravenous infusion, will be in the range of from 1 microgram/kg to 10 microgram/kg, or 1.5 microgram/kg to 9.5 microgram/kg, or 2 microgram/kg to 9 microgram/kg, or 2.5 to 8.5 microgram/kg, or 2.5 microgram/kg to 8.5 microgram/kg, or 3 microgram/kg to 8 microgram/kg, or 3.5 microgram/kg to 7.5 microgram/kg, or 4 microgram/kg to 7 microgram/kg or any interval therein between.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 1 microgram/kg.
  • the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 2 microgram/kg. In a specific embodiment the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 2.5 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 3 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 3.5 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 4 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 4.5 microgram/kg.
  • the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 5 microgram/kg. In a specific embodiment the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 5.5 microgram/kg.
  • the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 6 microgram/kg.
  • the sympathicomimetic agonists adrenaline and noradrenaline the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 6.5 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 7 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous routes in a single or repeated bolus dose of about 7.5 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 8 microgram/kg.
  • the dose administered will for intravenous, intramuscular, intraosseous, and/or subcutaneous single or repeated bolus dose is about 9 microgram/kg.
  • the bolus injection may be given once, twice or several times, for instance, in keeping with the dosage administered the bolus injection may be given every 5 min (minutes), such as every 10 min, such as every 15 min, such as every 20 min, such as every 25 min, such as every 30 min, such as every 35 min, such as every 40 min, such as every 45 min, such as every 50 min, such as every 55 min, such as every 60 min such as every 70 min, such as every 80 min, such as every 90 min, such as every 100 min, such as every 110 min such as every 120 min or more.
  • the bolus dosage may be administered in the appropriate intervals from the time of trauma to the subject and until a treatment facility such as a hospital or other is reached.
  • the dose for parenteral administration notably intravenous infusion, will be in the range of from 0.01 microgram/kg/hour to 100 microgram/kg/hour, such as 0.02 microgram/kg/hour to 90 microgram/kg/hour, such as 0.03 microgram/kg/hour to 80 microgram/kg/hour, such as 0.04 microgram/kg/hour to 70 microgram/kg/hour, such as 0.05 microgram/kg/hour to 60 microgram/kg/hour, such as 0.06 microgram/kg/hour to 50 microgram/kg/hour, such as 0.07 microgram/kg/hour to 40 microgram/kg/hour, such as 0.08 microgram/kg/hour to 30 microgram/kg/hour, such as 0.09 microgram/kg/hour to 27.5 microgram/kg/kg/
  • the interval may be between 1 microgram/kg/hour to 20 microgram/kg/hour, 1.5 microgram/kg/hour to 19.5 microgram/kg/hour, such as 2 microgram/kg/hour to 19 microgram/kg/hour, such as 2.5 microgram/kg/hour to 18.5 microgram/kg/hour, such as 3 microgram/kg/hour to 18 microgram/kg/hour, such as 3.5 microgram/kg/hour to 17.5 microgram/kg/hour, such as 4 microgram/kg/hour to 17 microgram/kg/hour, such as 4.5 microgram/kg/hour to 16.5 microgram/kg/hour, such as 5 microgram/kg/hour to 16 microgram/kg/hour, such as 5.5 microgram/kg/hour to 15.5 microgram/kg/hour, such as 6 microgram/kg/hour to 15 microgram/kg/hour, such as 6.5 microgram/kg/hour to 14.5 microgram/kg/hour, such as 7 microgram/kg/hour to 14 microgram/kg/hour, such as 7.5 microgram/gram/
  • the dose for parenteral administration notably intravenous infusion, will be in the range of from 1 microgram/kg/hour to 10 microgram/kg/hour, or 1.5 microgram/kg/hour to 9.5 microgram/kg/hour, or 2 microgram/kg/hour to 9 microgram/kg/hour, or 2.5 to 8.5 microgram/kg/hour, or 2.5 microgram/kg/hour to 8.5 microgram/kg/hour, or 3 microgram/kg/hour to 8 microgram/kg/hour, or 3.5 microgram/kg/hour to 7.5 microgram/kg/hour, or 4 microgram/kg/hour to 7 microgram/kg/hour or any interval therein between.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 1 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 2 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 3 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 3.5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 4 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 4.5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 5.5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 6 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 6.5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 7 microgram/kg/hour. In a further embodiment the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 7.5 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 8 microgram/kg/hour.
  • the intravenous infusion of the sympathicomimetic agonists adrenaline and noradrenaline will be about 9 microgram/kg/hour.
  • the infusion may be of any duration necessary such as from 1 minute (min) to several hours if required.
  • the dosage can, due to the rapid turnover of adrenaline and similar compounds be administered continuously without risk of accumulation.
  • Any sympathicomimetic able of inducing an activation of the hemostatic system equal to the above mentioned dose of adrenaline and noradrenaline i.e. dopamine at a dose of 10-100 x higher (30-300 microgram/kg/hour) than adrenaline and noradrenaline and dobutamin at a dose of 10-100 x higher in (30-300 microgram/kg/hour) adrenaline and noradrenaline. Based on this information it is contemplated that a person skilled in the art can choose a proper dosage.
  • clotting factor is administered as a bolus dose which is followed by a continuous dose of sympathicomimetic agonists.
  • the clotting factor, sympathicomimetic agonist and the beta blocker may be co- administered optionally in combination with potassium as soon as the subject is asleep and the administration may be stopped after last suture.
  • the combination of clotting factor and sympathicomimetic agonist and beta blocker acts instantaneously with regard to development of the pro-hemostatic response, and development of tachycardia/tachyarrhythmia is prevented by an initial loading dose of the beta blocker starting prior to the administration of the sympathicomimetic agonist followed by a continuous infusion.
  • an initial loading dose of the beta blocker starting prior to the administration of the sympathicomimetic agonist followed by a continuous infusion.
  • the potassium may be administered such that the blocker is administered for a number of minutes (between 1 and 5 minutes) prior to administration of the sympathicomimetic agonist and likewise towards the end of the treatment, the administration of the blocker is discontinued first, for example 5 to 20 minutes before stopping the administration of the sympathicomimetic agonist.
  • the potassium may be co-administered with the sympathicomimetic agonist.
  • the pro-hemostatic effect of the sympathicomimetic agonist / beta blocker is abated within a well defined time after discontinuation of the infusion and the administration of the blocker will therefore be adjusted so the blockage of the cardiac beta receptors is reversed when the haemodynamic effect of the sympathicomimetic agonist is abated. It will therefore be possible to discontinue the infusion of the sympathicomimetic agonist / beta blocker, well before the surgical procedure is finalized and bleeding has been controlled and the pro-hemostatic effect of the product will not be measurable by TEG MA 30-60 min postoperatively.
  • compositions containing the clotting factor and the sympathicomimetic agonist of the invention are administered to a subject susceptible to or otherwise at risk of a disease state or injury to enhance the subject's own hemostatic capability. Such an amount is defined to be a "prophylactically effective dose.”
  • prophylactic applications the precise amounts once again depend on the subject's state of health and weight, and it is anticipated that the dose generally will be as specified above.
  • beta blockers of the present invention may be administered in the dosages recommended by the manufacturers or as are known to be efficient to those skilled in the art, i.e. medical practitioners.
  • compositions of the invention and its use
  • the present invention also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising one or more clotting factors and and/or one or more sympathicomimetic agonists and optionally potassium and one or more pharmaceutically acceptable carriers or excipients.
  • Such pharmaceutically acceptable carriers or excipients as well as suitable pharmaceutical formulation methods are well known in the art (see for example Remington: The Science and Practice of Pharmacy 1995, edited by E. W. Martin, Mack Publishing Company, 19th edition, Easton, Pa.
  • the sympathicomimetic agonist and the clotting factor are prepared in a parenteral composition.
  • compositions Such methods for preparing parenterally administrable compositions will also be known or apparent to those skilled in the art and are described in more detail in, for example, Remington's Pharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa (1990).
  • pharmaceutical acceptable means a carriers or excipients that does not cause any untoward effects in subjects to whom it is administered.
  • compositions of the instant compounds, where they can be prepared are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases.
  • compositions are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.
  • the compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.
  • Examples of pharmaceutically acceptable acid addition salts for use in the present inventive pharmaceutical composition include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic acids, and arylsulphonic, for example.
  • mineral acids such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids
  • organic acids such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic acids, and arylsulphonic, for example.
  • compositions for parenteral administration comprise the clotting factor of the invention and/or the sympathicomimetic agonist of the invention in combination with, preferably dissolved in, a pharmaceutically acceptable carrier, preferably an aqueous carrier.
  • a pharmaceutically acceptable carrier preferably an aqueous carrier.
  • aqueous carriers such as water, buffered water, lactated Ringer's solution, saline, e.g. such as 0.7%, 0.8%, 0.9% or 1%, glycine such as 0.2%, 0.3%, 0.4% or 0.5% and the like.
  • aqueous carriers such as water, buffered water, lactated Ringer's solution, saline, e.g. such as 0.7%, 0.8%, 0.9% or 1%, glycine such as 0.2%, 0.3%, 0.4% or 0.5% and the like.
  • the composition has an osmotic pressure corresponding to a 0.9% w/w sodium chloride solution in water.
  • pH may be adjusted within suitable ranges centered around pH 7.4.
  • the compositions may be sterilized by conventional, well-known sterilization techniques.
  • the resulting aqueous solutions may be packaged for use or filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with a sterile aqueous solution prior to administration.
  • the compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative.
  • the compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol.
  • oily or non-aqueous carriers, diluents, solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents.
  • the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.
  • Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts
  • suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta. -aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
  • the parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile-lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile-lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the clotting factor and/or sympathicomimetic agonist and/or beta blocker and/or potassium may be formulated so it can be stored at room temperature in preformed bags or syringes containing the solution with the clotting factor and/or sympathicomimetic agonist and/or potassium.
  • the bag may be compartmentalized enabling an initial loading dose of the beta blocker before infusion of the sympathicomimetic agonist and/or clotting factor and/or potassium commence.
  • the syringe may be for single or dual injections and optionally allowing premixing of sympathicomimetic agonist, clotting factor and optionally beta blocker.
  • the concentration of the clotting factor, sympathicomimetic agonist and optionally beta blocker is predefined enabling immediate dosing based on the patients weight regardless of age and gender.
  • the preformed bag may be a 1 liter or a 500 ml or any other conventionally sized bag formulated to tolerate light and be stable at room temperature.
  • the syringe may be a 50 ml syringe, or a syringe of any conventional size such as between 10 ml and 100 ml.
  • the pharmaceutical composition may also be formulated in other forms e.g. as a gel, liquid, or as compressed solid.
  • the preferred form will depend upon the particular indication being treated and will be apparent to one skilled in the art.
  • compositions may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as pH adjusting and buffering agents, stabilizing agents, preservatives, non-ionic surfactants or detergents, antioxidants, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
  • auxiliary substances such as pH adjusting and buffering agents, stabilizing agents, preservatives, non-ionic surfactants or detergents, antioxidants, tonicity adjusting agents and the like, for example, sodium acetate, sodium lactate, sodium chloride, potassium chloride, calcium chloride, etc.
  • the sympathicomimetic agonists may also be in a salt form thereof.
  • Suitable salts include, but are not limited to, salts with alkali metals or earth metals, such as sodium, potassium, calcium and magnesium as well as e.g. zinc salts. These salts or complexes may be present as a crystalline and/or amorphous structure.
  • Administration of the clotting factors and the sympathicomimetic agonists for the treatment of bleeding episodes may either be the sole treatment or in any combination with other therapeutic agents such as red blood cells, and /or plasma and /or platelets and/or other procoagulants such as any of the coagulation factors alone or in combination and/or antifibrinolytics such as aprotinin, tranexamic acid amnio caproic acid, and or vasocontrictors.
  • other therapeutic agents such as red blood cells, and /or plasma and /or platelets and/or other procoagulants such as any of the coagulation factors alone or in combination and/or antifibrinolytics such as aprotinin, tranexamic acid amnio caproic acid, and or vasocontrictors.
  • Administration of the clotting factors and the sympathicomimetic agonists for the treatment of bleeding episodes may also be in combination with vitamin K.
  • agents may be incorporated as part of the same pharmaceutical composition or may be administered separately from the clotting factor and sympathicomimetic agonists, either concurrently or in accordance with another treatment schedule.
  • the clotting factors and sympathicomimetic agonists are primarily intended for parenteral administration for prophylactic and/or therapeutic treatment.
  • the clotting factors and the sympathicomimetic agonists are administered parenterally, i.e., intravenously, subcutaneously, intraosseously or intramuscularly, sublingual, mucosaaplication, intrapulmonary and it may be administered by continuous or pulsatile infusion.
  • the clotting factors and sympathcomimetic agonists can be administered separately or in any combination both for therapeutic or prophylactic use.
  • clot strength is better correlated with postoperative coagulopathic bleeding in subjects than conventional coagulation analysis including prothrombin time (PT), activated partial thromboplastin time (APTT), platelet count and fibrinogen levels undergoing cardiac surgery (Welsby et al. 2006).
  • the clot strength can be approached by use of e.g. thrombelastography (TEG), as will be explained in details in the examples herein.
  • TEG thrombelastography
  • Adhering to a transfusion algorithm aiming at a normal TEG clot strength reduces bleeding and postoperative transfusion requirements in cardiac surgery, liver transplantation and in critically ill patients as shown by Shore-Lesserson et al. (1999), Kang (1995) and Johansson et al. (2007).
  • the compounds of the present invention may be formulated in a wide variety of oral administration dosage forms.
  • the pharmaceutical compositions and dosage forms may comprise the compounds of the invention or its pharmaceutically acceptable salt or a crystal form thereof as the active component.
  • the pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.
  • the composition will be about 0.5% to 75% by weight of a compound or compounds of the invention, with the remainder consisting of suitable pharmaceutical excipients.
  • suitable pharmaceutical excipients include pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the carrier is a finely divided solid which is a mixture with the finely divided active component.
  • the active component is mixed with the carrier having the necessary binding capacity in suitable proportions and compacted in the shape and size desired.
  • the powders and tablets preferably containing from one to about seventy percent of the active compound(s).
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • preparation is intended to include the formulation of the active compound(s) with encapsulating material as carrier providing a capsule in which the active component, with or without carriers, is surrounded by a carrier, which is in association with it.
  • carrier which is in association with it.
  • cachets and lozenges are included. Tablets, powders, capsules, pills, cachets, and lozenges can be as solid forms suitable for oral / sublingual administration.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Sympathicomimetic agonist and/or clotting factor (as free compound(s) or salt(s)thereof)
  • Colloidal silicon dioxide (Aerosil) Cellulose, microcryst. (Avicel) Modified cellulose gum (Ac-Di-SoI) Magnesium stearate
  • beta blocker and/or potassium may also be included in the formulation.
  • Drops according to the present invention may comprise sterile or non-sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • a suitable aqueous solution optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent.
  • the resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100 degree C for half an hour.
  • the solution may be sterilized by filtration and transferred to the container aseptically.
  • bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate (0.002%), benzalkonium chloride (0.01%) and chlorhexidine acetate (0.01 %).
  • Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.
  • solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration.
  • liquid forms include solutions, suspensions, and emulsions.
  • These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • liquid form preparations including emulsions, syrups, elixirs, aqueous solutions, aqueous suspensions, toothpaste, gel dentrifrice, chewing gum, or solid form preparations which are intended to be converted shortly before use to liquid form preparations.
  • Emulsions may be prepared in solutions in aqueous propylene glycol solutions or may contain emulsifying agents such as lecithin, sorbitan monooleate, or acacia.
  • Aqueous solutions can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizing and thickening agents.
  • Aqueous suspensions can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well known suspending agents.
  • Solid form preparations include solutions, suspensions, and emulsions, and may contain, in addition to the active component, colorants, flavors, stabilizers, buffers, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.
  • the compounds of the present invention may also be formulated for sublingual administration.
  • Sublingual administration is particularly suitable for administration to patients with swallowing difficulties, for paediatric use or trauma patients. Patients may have difficulty in swallowing because of a throat disorder or injury and the presently claimed formulation is particularly beneficial in these cases. Patients may also not have a large quantity of saliva so that a larger tablet may not be completely and rapidly dissolved if at all. Passage of an undissolved dosage form from the mouth into the throat is thus undesirable and is avoided using the formulations of the invention. It is therefore to minimise the size of the dosage form and dosage forms in accordance with this invention preferably have a minimum size, eg 6 mm diameter and corresponding weight whilst maintaining the dosage.
  • the total tablet weight does not exceed 100 mg, and more preferably it is less than 70 mg. Rapid dissolution of the dosage form which is necessary to facilitate sublingual absorption may be achieved by selection of an appropriate method of tablet manufacture.
  • Use of direct compression or dry granulation has been found to be less suitable than wet granulation, due to the high bulk density and electrostatic properties of morphine salts, for example morphine sulphate, and excipients.
  • a method of manufacture of a pharmaceutical solid dosage form of a clotting factor and a sympathicomimetic agonist and optionally a beta blocker and/or potassium comprises the steps of:
  • clotting factor and a sympathicomimetic agonist and optionally a beta blocker and/or potassium with one or more excipients selected from saccharides, disintegrants and binders;
  • all of the saccharide or mixture saccharides is granulated together with the compounds of the present invention and a proportion of the disintegrant, the dried, sieved granulate being combined with the remainder of the disintegrant and lubricant and compressed into tablets.
  • This method provides better homogeneity of granulate than if a proportion of the saccharide is added after granulation.
  • Granulation may be carried out using water or an aqueous solvent mixture.
  • the average particle size is not more than 0.3 mm to facilitate tableting into a stable formulation.
  • the mesh size used in the granulation step should preferably be less than 0.70 mm in order to obtain the advantageous particle size distribution.
  • Tablets of the present invention preferably comprise compacted granulates together with an extra-granular disintegrant and a minimal quantity of an extra-granular lubricant.
  • a minimum number of excipients is preferred in order to enhance the sublingual absorption.
  • a preferred formulation includes only the salt of compounds of the present invention, the filler (preferably mannitol, lactose, xylitol and mixtures thereof), the binder (preferably gelatin), and the disintegrant.
  • the compounds of the present invention may be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the pharmaceutical carrier Illustrative solid carriers include lactose, terra alba, sucrose, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and the like.
  • a solid carrier can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents; it can also be an encapsulating material.
  • the carrier is a finely divided solid which is in admixture with the finely divided active ingredient.
  • the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions, and compacted in the shape and size desired.
  • the powders and tablets preferably contain up to 99% of the active ingredient.
  • suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatine, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
  • Illustrative liquid carriers include syrup, peanut oil, olive oil, water, etc. Liquid carriers are used in preparing solutions, suspensions, emulsions, syrups, elixirs and pressurized compositions.
  • the active ingredient can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fats.
  • the liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators.
  • liquid carriers for oral and parenteral administration include water (partially containing additives as above, e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols, e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil).
  • the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate.
  • Sterile liquid carders are useful in sterile liquid form compositions for parenteral administration.
  • the liquid carrier for pressurized compositions can be halogenated hydrocarbon or other pharmaceutically acceptable propellant.
  • Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal, intraosseous or subcutaneous injection. Sterile solutions can also be administered intravenously. The compound can also be administered orally either in liquid or solid composition form.
  • a clotting factor and a sympathicomimetic agonist and/or a beta blocker and/or potassium would be of benefit to a bleeding subject.
  • One is in the hospital / clinic or other similarly well supervised conditions where the subject either will be undergoing planned surgery or is admitted in a state that requires surgery.
  • an embodiment of the present invention comprising a clotting factor and a sympathicomimetic agonist and/or a beta blocker and/or potassium in a pre-prepared and ready to use solution such as in an infusion bag or pre-prepared syringe will be preferable.
  • the pre-prepared solution may then be administered prior to, during or after surgery.
  • a specially preferred embodiment of this aspect of the present invention comprises a pre-prepared formulation of a clotting factor, a sympathicomimetic agonist, and a beta blocker and/or potassium that may be stored at ambient temperature, i.e. room temperature, and which also is unaltered (i.e. the compounds do not degrade / breakdown become metabolized or otherwise loose their activity) if exposed to light. Furthermore it is preferred if the formulation is such that it may be administered in the correct dosage immediately,
  • a pre-prepared formulation may be of a clotting agent a sympathicomimetic agonist and/or a beta blocker and/or potassium, preferably just a clotting factor and a sympathicomimetic agonist in a form that allows immediate administration i.e. in a pre-prepared syringe (for i.e. intra muscular, intravenous or subcutaneous administration) or tablet or other mucosal application form.
  • This formulation may be administered to the subject at the scene, in an ambulance or helicopter, ie. in a pre-hospital setting.
  • An embodiment of the invention thus relates to a pre-prepared syringe with a content befitting the average adult or child human being.
  • the average adult or child human weight after which the amount of clotting factor and sympathicomimetic agonist is calculated may be adapted to suit specific circumstances such as children of different age groups (they are expected to increase in weight with age) or different nationalities, as different countries have different mean weights of their inhabitants.
  • the same amount of FVIIa or any clotting factor and adrenaline or noradrenaline or any sympathicomimetic may correspondingly be pressed into a tablet.
  • a pre- prepared syringe may be made for the specific purpose of having a duration of 5 min, 10 min, 15 min, 30 min, or 60 min or anything therein between.
  • Clotting factor and sympathicomimetic agonists and/or beta blockers and/or potassium combinations are particularly suitable for the treatment and/or prophylaxis of bleeding, including uncontrolled and excessive bleeding episodes in connection with surgery and other forms of tissue damage.
  • clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium combinations are envisaged to be beneficial in controlling or preventing bleedings, due to their above-described systemic hemostatic properties.
  • the present invention is useful in any situation wherein an individual is bleeding e.g. trauma, or is expected to bleed eg. during surgery.
  • These two situations differ in several respects: during trauma, if it is at all possible to administer anesthesia, there is no time to wait for the full effect before performing the necessary interventions; during elective surgery, which here is defined as any type of non-acute intervention that will or is expected to cause bleeding, the entire situation is under control from the onset, and there is time to wait for the full effect of the anesthesia to set in.
  • the blood pressure generally lowers.
  • the normal hemostatic mechanism may be overwhelmed by the demand of immediate hemostasis and they may develop bleeding in spite of a normal hemostatic mechanism. It is envisaged that in any form of trauma, systemic administration of clotting factors and sympathicomimetic agonists may be beneficial to the subject.
  • the term "trauma” is intended to mean injury to living tissue caused by an extrinsic agent.
  • Hemorrhage as a result of trauma can start a cascade of problems. For example physiological compensation mechanisms are initiated with the initial peripheral mesenteric vasoconstriction to shunt blood to the central circulation. If circulation is not restored, hypovolaemic shock ensures (multiple organ failure due to inadequate perfusion.) Trauma patients may develop hypothermia due to environmental conditions at the scene, inadequate protection, intravenous fluid and blood product administration and ongoing blood loss. Deficiencies in coagulation factors and platelets can result from blood loss, dilution, consumption or transfusions. Meanwhile acidosis and hypothermia interfere with normal blood clotting mechanisms. Thus coagulophathy develops which may mask surgical bleeding sites and hamper control of mechanical bleeding. Hypothermia, coagulophathy and acidosis are often characterized as the "lethal triad" as these conditions often lead to uncontrollable blood loss, multiple organ failure and death typically in an intensive care unit.
  • shock may also develop as a result of activation of the inflammatory pathways, resulting in a hypocoagulant state.
  • This subset of trauma patients has particularly high mortality.
  • the trauma may be any type of trauma such as blunt trauma and penetrating trauma; the invention is particularly well suited for treating bleeding following penetrating trauma.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma in a subject, comprising administering to said subject a clotting factor and a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards the head and/or neck including but not limited to the brain, eye(s), ear(s), nose, mouth, esophagus, trachea, soft tissues, muscles, bones and / or vessel(s) in a subject, comprising administering to said subject a clotting factor a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards the thoracic region including but not limited to the heart, lungs, oesophagus, soft tissues, muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards the abdomen including but not limited to the liver, pancreas, spleen, ventricle, gall-bladder, intestines, or retroperitoneal tissue, soft tissues, muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards the pelvis including but not limited to prostate, urinary bladder, uterus, ovarii, bones i.e. pelvic ring, hip, femur, soft tissues, muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards the long bones of the extremities including but not limited to humerus, ulnae, radii and/or bones of the hand, femur, tibia, fibula and/or bones of the foot, the columnae, scapulae, costae, clavicle or in any combination hereof in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards any combination of the above in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by trauma towards any combination of the above in a subject, comprising administering to said subject a clotting factor such as FVIIa in a dose of about 20 microgram/kg, a sympathicomimetic agonist such as adrenalin in a dose of about 6 microgram/kg and/or potassium.
  • a clotting factor such as FVIIa in a dose of about 20 microgram/kg
  • a sympathicomimetic agonist such as adrenalin in a dose of about 6 microgram/kg and/or potassium.
  • the invention in another embodiment, relates to a method for the treatment of subjects suffering from shock as a result of blood loss after trauma comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in connection with any of the indications discussed above.
  • the invention relates a clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in connection with any of the indications discussed above.
  • Intracerebral hemorrhage is the most deadly form of stroke. In addition to high short-term mortality rates, ICH also results in very high rates of severe mental and physical disability among survivors.
  • the causes of ICH are numerous and can include head trauma, traumatic brain injury (TBI), hypertensive hemorrhage, transformation of prior ischemic infarction (ischemic stroke), metastatic brain tumor, coagulophathy, drug induced ICH, arteriovenous malformation, aneurysm, amyloid angiopathy, cavernous angioma, dural arteriosvenous fistula and capillary telaniectasias.
  • a further embodiment of this aspect of the invention relates to methods for the treatment of primary intracerebral bleeding (ICH) in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • ICH primary intracerebral bleeding
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in connection with any of the ICH-related causes of a subject as discussed above.
  • the invention relates a clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in connection with any of the ICH-related causes of a subject as discussed above.
  • the surgery may be either a scheduled or acute procedure, and may be any type of surgery on any part of the body.
  • One embodiment of this aspect of the invention thus relates to methods for the treatment of a subject in connection with surgical inventions, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for the treatment of bleeding in connection with surgery as discussed above.
  • One general aspect of the invention therefore relates to methods of treatment of bleeding in patients suffering from / undergoing various forms of surgery.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in the head and/or neck including but not limited to the brain, eye(s), ear(s), nose, mouth, esophagus, trachea, bones, soft tissue, muscles and vessel(s) in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in the thoracic region including but not limited to the heart, lungs, oesophagus, soft tissue, muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in the abdomen including but not limited to the liver, pancreas, spleen, kidney, adrenal glands, ventricle, gall-bladder, intestines, retroperitoneal tissue, soft tissue, muscles or any vessel or vessels in a subject, comprising administering to said subject a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in the pelvis including but not limited to prostate, urinary bladder, uterus, ovarii, bones i.e. pelvic ring, hip, femur, soft tissue, muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery of the long bones of the extremities including but not limited to humerus, ulnae, radii and/or bones of the hand, femur, tibia, fibula and/or bones of the foot, the columnae, scapulae, costae, clavicle, soft tissue, muscles or in any combination hereof in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by surgery in any combination of the above in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for the treatment of bleeding in connection with surgery as discussed above.
  • the invention relates a clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in connection with surgery as discussed above.
  • Bleeding secondary to vascular defects may arise due to congenital or acquired defects of the vascular system resulting in aneurysms of arteries and or veins, arterioveinuous malformations or rupture of atherosclerotic plaques. These bleedings may be severe or life-threatening depending on localization i.e. intracerebral and/or the size of vessel(s) affected, exemplified by ruptured aortic lesions.
  • One embodiment of this aspect of the invention thus relates to methods for the treatment of a subject in connection with vascular defects, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for the treatment of bleeding in connection with vascular defects as discussed above.
  • One general aspect of the invention therefore relates to methods of treatment of bleeding in patients suffering from various forms of vascular defects.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in the head and/or neck region including, but not limited to the brain, eye(s), ear(s), nose, mouth, esophagus, trachea, soft tissue or muscles in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in the thoracic region including but not limited to the heart, lungs, esophagus, soft tissue or muscles or any other vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in the abdomen including but not limited to the liver, pancreas, spleen, kidney, adrenal glands, ventricle, gall-bladder, intestines, retroperitoneal tissue, soft tissue or muscles or any other vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in the pelvis including but not limited to prostate, urinary bladder, uterus, ovarii, bones i.e. pelvic ring, hip, femur, soft tissue or muscles or any vessel or vessels in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in the soft tissue and /or muscles surrounding of the long bones of the extremities including but not limited to humerus, ulnae, radii and/or bones of the hand, femur, tibia, fibula and/or bones of the foot, the columnae, scapulae, costae, clavicle, soft tissue or muscles or in any combination hereof in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention thus relates to a method for the treatment of bleeding caused by vascular defects in any combination of the above in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for the treatment of bleeding in connection with various forms of vascular defects discussed above.
  • the invention relates a clotting factor, a sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in connection with various forms of vascular defects discussed above.
  • a further aspect of the invention relates to methods of treatment of bleeding in subject undergoing biopsies from various organs (brain, heart, liver, lung, pancreas, spleen, lymphoid tissue, intestines, adrenal glands, tumors, soft tissue, muscles, gastrointestinal tract) as well as in laparoscopic surgery.
  • the invention thus relates to a method for the treatment of bleeding in subjects undergoing biopsies, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention in another embodiment, relates to a method for the treatment of bleeding in subjects undergoing laparoscopic surgery, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to the use of clotting factors, sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding as a in a subject undergoing biopsies as discussed above or undergoing laparoscopic surgery.
  • Uncontrolled and/or excessive bleeding may occur in subjects having a normal coagulation system and subjects having coagulation or bleeding disorders. Excessive bleedings may also occur in subjects with a normally functioning blood clotting cascade (no clotting factor deficiencies or -inhibitors against any of the coagulation factors).
  • Bleeding secondary to coagulopathy i.e. coagulation factor dilution with crystalloids and or colloids and/or blood products and/or consumption such as but not limited to infection, sepsis, DIC (disseminated intravascular coagulation), haematological disorders and malignancies, graft vs. host disease, inhibitors against coagulation factors.
  • the invention relates to a method for the treatment of bleeding in a coagulopathic subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factors, and sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in a coagulopathic subject.
  • the invention clotting factors, and sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in a coagulopathic subject.
  • the invention does not relate to use of clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in a subject with haemophilia.
  • Bleeding also acute and/or profuse may also occur in subjects on anticoagulant therapy in whom a defective hemostasis has been induced by the therapy given. Such subjects may need surgical interventions in case the anticoagulant effect has to be counteracted rapidly. Another situation that may cause problems in the case of unsatisfactory hemostasis is when subjects with a normal hemostatic mechanism are given anticoagulant therapy to prevent thromboembolic disease.
  • Such therapy may include heparin both unfractionated and low molecular weight, other forms of proteoglycans, activated protein C, antithrombin, tissue factor pathway inhibitor, warfarin or other forms of vitamin K-antagonists as well as aspirin, dipyrimidol, , NSAID, GPIIb/llla inhibitors, Flolan (prostacyclin) ADP receptor inhibitors, direct thrombin inhibitors, hirudin, citrate, and other platelet activation/aggregation inhibitors.
  • a further general aspect of the invention therefore relates to methods of treatment of bleeding in connection with anticoagulant therapy.
  • the invention thus relates to a method for treatment of bleeding in a subject receiving an anticoagulant and antithrombotic drug, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding complication due to anticoagulant treatment in a subject.
  • the invention relates to clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding complication due to anticoagulant treatment in a subject.
  • thrombocytopenic subjects are characterized by a reduced blood platelet (thrombocyte) count resulting from a reduced platelet production and/or an increased loss of platelets.
  • thrombocytopenia such as decreased bone marrow production of megakaryocytes (e.g. due to marrow infiltration with tumor or fibrosis, or marrow failure induced by e.g. aplasia, hypoplastic anemias, or chemotherapy or other drugs), splenic sequestration of circulating platelets (e.g. splenic enlargement due to tumor infiltration or plenic congestion due to portal hypertension), increased destruction of circulating platelets (e.g.
  • vascular prosthese due to vascular prosthese, cardiac valves, disseminated intravascular coagulation (DIC), sepsis, vasculitis, autoantibodies to platelets, drug-associated antibodies, or circulating immune complexes induced by systemic lupus erythematosis, viral agents, bacterial sepsis or idiopathic thrombocytopenic pupora (ITP), platelet disorders, von Willebrands disease, Bernhard-Soulier syndrome, Glanzmann's thrombasthenia, decreased cyclooxygenase activity (drug induced or congeniital), granule storage pool defects (acquired or congenital), uremia, platelet coating (e.g.
  • liver disease due to penicillin or paraproteins
  • defective platelet coagulant activity Scott's syndrome, or thrombocytopenia associated with liver disease such as caused by hepatitis C or hepatitis B, or caused by IFN-alpha treatment of hepatitis C or hepatitis B as well as secondary to hypersplenism
  • Another general aspect of the invention thus relates to treatment of bleeding in connection with thrombocytopenia caused by e.g. any of the conditions discussed above.
  • the invention thus relates to a method for treatment of bleeding in connection with thrombocytopenia in a subject, comprising administering to said subject clotting factor, a a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in connection with thrombocytopenia caused by e.g. any of the conditions discussed above.
  • Another aspect of the invention relates to the treatment of bleeding in a subject caused by a combination of coagulopathy (coagulation factor deficiency) and thrombocytopenia (low platelet count) or due to low platelet function
  • the invention thus relates to a method for treatment of bleeding in connection with a combination of coagulopathy (acquired or congenital) and thrombocytopenia (acquired or congenital) in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to the use of clotting factors and sympathicomimetic agonists for the preparation of a medicament for treatment of bleeding in connection with coagulopathy (acquired or congenital) and thrombocytopenia (acquired or congenital) caused by e.g. any of the conditions discussed above.
  • the invention relates to clotting factors and sympathicomimetic agonists use in the treatment of bleeding in connection with coagulopathy (acquired or congenital) and thrombocytopenia (acquired or congenital) caused by e.g. any of the conditions discussed above.
  • Patients undergoing transplantation of solid organs such as but not limited to liver, heart, lungs, pancreas, kidneys and/or intestines are at high risk of developing bleeding due to the surgically induced bleeding.
  • patients undergoing hematopoietic stem cell or bone marrow transplantation are at risk of bleeding due to the conditioning of the patients with body irradiation and chemotherapy eradicating the patients hematopoietic system and hence severely deficient of platelets and red blood cells.
  • these patients are at risk of developing graft vs. host disease, which may result in bleedings from the liver, gastrointestinal and urogenital system as well as from the bronchioalveolar system.
  • the invention thus relates to a method for treatment of bleeding in connection with solid organ or hematopoietic system transplantation in a subject, comprising administering to said subject a clotting factor, a sympathicomimetic agonist and/or a beta blocker and/or potassium.
  • the invention relates to use of clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for the preparation of a medicament for treatment of bleeding in connection with solid organ or hematopoietic system transplantation caused by e.g. any of the conditions discussed above.
  • the invention relates to clotting factors and sympathicomimetic agonists and/or beta blockers and/or potassium for use in the treatment of bleeding in connection with solid organ or hematopoietic system transplantation caused by e.g. any of the conditions discussed above.
  • the clotting factor comprises FVIIa or a variant or analogue thereof and the sympathicomimetic agonists comprise adrenaline and/or noradrenaline and/or dobutamine and the beta blocker is Seloken and/or
  • the adrenaline and/or noradrenaline and/or dobutamine and Seloken and/or Esmolol and/or Landiolol are administered to prevent or treat bleeding in a subject.
  • the clotting factor comprises or is FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is adrenaline and is administered in combination with Seloken.
  • the clotting factor comprises or is FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is adrenaline and is administered in combination with Landiolol.
  • the clotting factor comprises or is FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is adrenaline and is administered in combination with Esmolol.
  • the clotting factor comprises or is FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is noradrenaline and is administered in combination with Seloken.
  • the clotting factor comprises or is FVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is noradrenaline and is administered in combination with Landiolol.
  • the clotting factor comprises or is FVIIa, rFVIIa or a variant or analogue thereof and the sympathicomimetic agonist comprises or is noradrenaline and is administered in combination with Esmolol.
  • Another embodiment of the invention relates to a composition
  • a composition comprising a clotting factor, an adrenergic receptor agonist and a beta blocker for the treatment or prophylaxis of bleeding in a subject.
  • the adrenergic receptor agonist is any of adrenaline, noradrenaline, dobutamine, dopamine, dobutrex and ephedrine.
  • the adrenergic receptor agonist is adrenaline.
  • the adrenergic receptor agonist is noradrenaline.
  • the clotting factor is any of FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof, and FII, FV, FVII, FVIII, FIX, FX, FXII and FXII or a variant or analogue thereof.
  • the clotting factor is FVIIa, rFVIIa, rhFVIIa, FVII, rFVII, or a variant or analogue thereof.
  • the beta blocker has a high cardioselectivity.
  • the beta blocker is any of Seloken, Esmolol and Landiolol.
  • the beta blocker is Seloken.
  • the beta blocker is Esmolol.
  • the beta blocker is Landiolol.
  • composition according is for systemic administration.
  • the adrenergic receptor agonist increases a subjects hemostatic ability by altering one or more of the TEG measurable parameters of the blood of a subject to which substance is administered such as: lowering the r value (clotting time), lowering the k value (clot kinetics), increasing the TEG measurable parameters of the blood of a subject to which substance is administered such as: lowering the r value (clotting time), lowering the k value (clot kinetics), increasing the
  • Angle or alpha (representing velocity of clot formation), and/or increasing the MA, maximal amplitude, (the maximal physical clot strength).
  • the dose of the adrenergic receptor agonist administered is in the range 0.1 to 100 microgram/kg, or 1 microgram/kg to 50 microgram/kg, such as e.g. 2 microgram/kg to 20 microgram/kg, 2.5 microgram/kg to 15 microgram/kg, 3 microgram/kg to 10 microgram/kg or 3.5 microgram/kg 5 microgram/kg.
  • the dose of the adrenergic receptor agonist administered is in the range of 1 to 10 microgram/kg.
  • the dose of the adrenergic receptor agonist is about 2 microgram/kg or more, such as e.g. about 3 microgram/kg or more, or about 4 microgram/kg or more, or about 5 microgram/kg or more, or about 6 microgram/kg or more or about 7 microgram/kg or more.
  • the dose of the clotting factor administered is in the range of 1 to 30 microgram/kg.
  • the composition is administered enterally and/or parenterally.
  • the enteral administration is oral, gastric or rectal.
  • the parenteral administration is intravenous, intraarterial, subcutaneous, intramuscular, intrapulmonary via the alveoli, intracardiac, intradermal, transdermal, transmucosal, intrathecal, intraperitoneal, intraosseous and/or intravesical or by other means whereby an appropriate systemic concentration is obtained.
  • the parenteral administration is subcutaneous, intramuscular, intraosseous and/or intravenous.
  • the dose is administered as a single bolus dose or as repeated doses.
  • the dose is administered continuously.
  • the clotting factor, the agonistic substance and the beta blocker are administered simultaneously or separately.
  • the dose of the adrenergic receptor agonist is in the range 0.1 microgram/kg/hour to 25 microgram/kg/hour, such as e.g. 1 microgram/kg/hour to 20 microgram/kg/hour, 2 microgram/kg/hour to 15 microgram/kg/hour, 2.5 microgram/kg/hour to 10 microgram/kg/hour or 3 microgram/kg/hour to 5 microgram/kg/hour.
  • the dose of the adrenergic receptor agonist is about 3 microgram/kg/hour, such as e.g. about 2 microgram/kg/hour or about 4 microgram/kg/hour or about 5 microgram/kg/hour or more, or about 6 microgram/kg/hour or more or about 7 microgram/kg/hour or more.
  • the dose of the clotting factor is in the range 0.1 microgram/kg/hour to 30 microgram/kg/hour.
  • the composition if for the treatment or prophylaxis of bleedings associated with vascular defects, biopsies and laparoscopic surgery and transplantation, or in connection with bleedings in the brain or central nervous system, or bleedings caused by trauma, surgery and coagulopathy, or as a consequence of treatment with anticoagulants, or due to congenital or acquired conditions.
  • Yet another embodiment of the invention relates to a method for the treatment or prophylaxis of bleeding of a subject in need of such a treatment, the method comprises administration of an effective dose of a composition described herein above for the treatment or prophylaxis of bleeding in a subject.
  • composition described herein above comprises at least one of adrenaline, noradrenaline and dobutamine.
  • the composition comprises at least one of FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof and the group comprising the unactivated form of the clotting factors and FII, FV, FVII, FVIII, FIX, FX, FXII and FXIII, or a variant or analogue thereof.
  • Yet another embodiment of the invention relates to a composition for use in a method according described herein, comprising an adrenergic receptor agonist affecting any of the ⁇ i, ⁇ 2 , ⁇ i, ⁇ 2 receptors of the sympathetic nerve system and a pharmaceutically acceptable excipient.
  • the composition is for use in a method described above, comprising any of adrenaline, noradrenaline and dobutamine.
  • the composition is for use in a method described above, comprising any of FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof and the group comprising the unactivated form of the clotting factors and FII, FV, FVII, FVIII, FIX, FX, FXII and FXIII, or a variant or analogue thereof.
  • kits for use in a method described herein comprising i) an adrenergic receptor agonist, ii) a clotting factor iii) a beta blocker iv) optionally an aqueous medium to dissolve the adrenergic receptor agonist and/or the clotting factor, and v) instructions for use.
  • kits for use in a method described herein comprising
  • adrenergic receptor agonist i)an adrenergic receptor agonist, i) a clotting factor ii) a beta blocker iii) an aqueous medium to dissolve the adrenergic receptor agonist, and iv) optionally, instructions for use.
  • kits for use in a method described herein comprising an adrenergic receptor agonist such adrenaline, noradrenaline and/or dobutamine, a clotting factor such as FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof and the group comprising the unactivated form of the clotting factors and FII, FV, FVII, FVIII, FIX, FX, FXII and FXIII, or a variant or analogue thereof, and a beta blocker such as Seloken, Esmolol and/or Landiolol.
  • an adrenergic receptor agonist such adrenaline, noradrenaline and/or dobutamine
  • a clotting factor such as FVIIa, rFVIIa, rhFVIIa, FXIIIa, FI
  • compositions comprising a clotting factor, an adrenergic receptor agonist, potassium in a pharmaceutically acceptable form and optionally a beta blocker for the treatment or prophylaxis of bleeding in a subject.
  • the beta blocker has a high cardioselectivity.
  • beta blocker is any of Seloken, Esmolol and Landiolol.
  • beta blocker is Seloken.
  • the beta blocker is Esmolol.
  • beta blocker is Landiolol.
  • kits for use in a method according to any of claims 99 to 104 comprising an adrenergic receptor agonist such adrenaline, noradrenaline and/or dobutamine, a clotting factor such as FVIIa, rFVIIa, rhFVIIa, FXIIIa, FIXa, FXa, FIIa, FVa, FVIIIa and FXIIa, or a variant or analogue thereof and the group comprising the unactivated form of the clotting factors and FII, FV, FVII, FVIII, FIX, FX, FXII and FXIII, or a variant or analogue thereof, and a beta blocker such as Seloken, Esmolol and/or Landiolol.
  • an adrenergic receptor agonist such adrenaline, noradrenaline and/or dobutamine
  • a clotting factor such as FVIIa, rFVIIa, rhFVIIa, F
  • FIG. 1 TEG technology. See Example 1 for explanation.
  • TEG parameters The following parameters are derived from a TEG tracing; R, the time from start of analysis until initial clot formation (at 2 mm amplitude); Angle, representing velocity of clot formation; MA, maximal amplitude, the maximal physical clot strength; Lysis AUC, the area under the fibrinolysis curve calculated from MA (hatched area).
  • FIG. 3 Representative TEG profile of healthy volunteers before and after administration of adrenaline.
  • Whole blood was drawn in 1/10 citrate from an arterial catheter.
  • the citrated whole blood sample rested exactly 30 minutes at room temperature before TEG analysis on the Thrombelastograph Hemostasis Analyser, series 5000 (Haemoscope Corp., Skokie, IL):
  • a kaolin vial Haemoscope Corp.
  • a plain TEG cup preloaded with 20 ⁇ l of 0.2 M CaCI 2 and the analysis started immediately.
  • FIG. 5 TEG MA measured before and after i.v. infusion of noradrenaline at 4.8 ⁇ g/kg/h for 15 minutes in 10 healthy volunteers, mean with 95% Cl. MA before and after noradrenaline was compared by a paired t-test with a p-value ⁇ 0.05 considered statistically significant.
  • FIG. 7 TEG parameters (a) R, (b) Angle and (c) MA measured as described in figure 3 and example 1 on blood samples collected from patients infused with adrenaline prior to prostatectomy. Ten patients were anesthetized by propofol and haldid and infused with adrenaline i.v. in the doses 1 , 2 and 3 ⁇ g/kg/h each for 5 minutes prior to skin incision. Hereafter the patients were prostatectomised according to local protocol. Blood samples were collected from an arterial catheter before adrenaline administration and immediately after each infusion dose (1 , 2 and 3 ⁇ g/kg/h) and again 1 hour after discontinuation of adrenaline infusion.
  • Figure 8 Perioperative bleeding (in ml) of the 10 patients described in figure 7 (receiving adrenaline in the step-wise doses 1 , 2 and 3 ⁇ g/kg/h) and 10 other prostatectomy patients receiving a 15 minutes continuous adrenaline infusion of 3 ⁇ g/kg/h.
  • the 2 intervention groups were compared to 40 controls also undergoing prostatectomy, whereof 20 underwent surgery prior to the interventions and the last 20 after the intervention. All values including median for each group is depicted.
  • TEG tissue plasminogen activator
  • tPA tissue plasminogen activator
  • Figure 11 The healthy subjects described in figure 10 were monitored haemodynamically at the same time points as described in figure 10.
  • HR heart rate
  • CO cardiac output
  • SV stroke volume
  • invasive blood pressure mean arterial pressure
  • MAP mean arterial pressure
  • TPR total peripheral resistance
  • Figure 12 Three healthy volunteers received 5 doses of adrenaline infusion lasting for 5 minutes each in the following step-wise increasing doses 1 , 3, 5, 7, and 9 ⁇ g/kg/h. After resting 1 hour, the subjects received Seloken i.v. 0.20 ⁇ g/kg for 10 minutes and rested again 30 minutes before repeating the step-wise adrenaline infusions. Blood samples were obtained from an arterial catheter at baseline (0.0 ⁇ g/kg/h)), after each of the first adrenaline doses, at baseline after Seloken administration and rest and after each of the subsequent adrenaline infusions. The blood was analyzed with TEG as described in figure 3 and Example 1. TEG MA values are presented as mean with 95% Cl.
  • FIG 13 The effect of rFVIIa in a patient with a normal haemostatic competence as evaluated by TEG is depicted herein and demonstrates that the initiation phase of the haemostatic process is accelerated (reduced R) and that the thrombin burst (Angle) is increased, whereas no effect is noticed on the maximal clot strength.
  • Figure 14 TEG MA in awake volunteers. Six healthy volunteers (four males and two females) received intravenous infusion of adrenaline at a dose of 6 microgram/kg/h for 15 minutes. Blood samples for TEG analysis was obtained before start of adrenaline infusion, and 30 min after discontinuation of adrenaline infusion. The blood was analyzed with TEG as described in figure 3 and Example 1. TEG MA values are presented as mean with 95% Cl.
  • FIG. 15 TEG MA in prostatectomy patients during surgery.
  • TEG MA measured as described in figure 3 and example 1 on blood samples collected from patients infused with adrenaline prior to prostatectomy.
  • Ten patients were anesthetized by propofol and haldid and infused with adrenaline i.v. in the doses 1 , 2 and 3 ⁇ g/kg/h each for 5 minutes prior to skin incision.
  • the patients were prostatectomised according to local protocol. Blood samples were collected from an arterial catheter before adrenaline administration and immediately after each infusion dose (1 , 2 and 3 ⁇ g/kg/h) and again 1 hour after discontinuation of adrenaline infusion.
  • the TEG in vitro assay is suitable for determining important parameters in the hemostatic process including clot strength.
  • the TEG system's approach to monitoring patient hemostasis is based on the premise that the end result of the hemostatic process is the clot.
  • the clot's physical properties determine whether the patient will have normal hemostasis, or will be at increased risk for haemorrhage or thrombosis [Salooja et al. 2001].
  • the TEG analyzer uses a small whole blood sample in a rotating cup and a pin suspended in the blood by a torsion wire, which is monitored for motion.
  • the torque of the rotating cup is transmitted to the immersed pin only after fibrin and/or fibrin-platelet bonding has linked the cup and pin together ( Figure 1 ).
  • the strength and rate of these bonds affect the magnitude of the pin motion such that strong clots move the pin more than less strong clots.
  • the TEG technology documents the interaction of platelets with the protein coagulation cascade from the time of placing the blood in the analyzer until initial fibrin formation, clot rate strengthening and fibrin-platelet bonding via GPIIb/llla, through eventual clot lysis ( Figure 2).
  • the TEG R parameter reflects the initiation phase, reaction time, from start of coagulation until the first fibrin band is formed; the Angle ( ⁇ ) represents the increase in clot strength, clot kinetics, correlating with the thrombin generation.
  • the maximal amplitude (MA) parameter reflects maximal clot strength i.e. the maximal elastic modus of the clot.
  • the area under the lysis curve, i.e. area under curve from MA is obtained (Lysis AUC) reflects degree of fibrinolyis.
  • TEG -guided transfusion therapy aiming at normalizing clot strength (MA) has resulted in a reduction in the use of blood products, a reduction in the rate of re-exploration, prediction of bleeding in cardiac surgery and it is approved by the FDA for the monitoring of patients with heart assist devices.
  • MA normalizing clot strength
  • FIG 3 illustrates TEG profiles from a representative volunteer before and after receiving intravenous infusion of adrenaline 3 ⁇ g/kg/h for 15 minutes.
  • Adrenaline was mixed with 0.9% NaCI and infused intravenously.
  • a whole blood sample for TEG analysis was drawn into a tube containing citrate (9 volumes of blood into 1 volume of 0.129 M citrate; Vacutainer system, BD Biosciences, Madison, UK) and rested for exactly 30 minutes before analysis: Coagulation was initiated by kaolin and re-calcified according to the instructions of the manufacturer: Citrated whole blood was added to a kaolin vial and mixed by gently inversion 5 times before transfer to the TEG cup containing calcium chloride (20 ⁇ l of 0.2 M CaCI 2 ) , which was preloaded into the TEG ® cup as published previously [Johansson et al. 2008]. The hemostatic process was recorded by use of a TEG ® coagulation analyzer (5000 series, Haemoscope Corporation).
  • the infusion of adrenaline results in a faster initiation of the coagulation process (R shorter), increased amplification and propagation of the coagulation process, i.e. increased thrombin generation (Angle increased) and a clot with an increased mechanical strength (MA increased).
  • Example 2 We have identified a pro-hemostatic effect of administration of sympathicomimetics, as exemplified by adrenaline infusion in 30 healthy subjects (figure 3 and 4), patients prior to surgery (figure 7), as well as after noradrenaline administration in 10 healthy subjects (figure 5).
  • intravenous administration of adrenaline resulted in a significant reduction in perioperative blood loss.
  • Blood loss of the 10 patients described in example 2 and 10 additional prostatectomy patients receiving a 15 minutes continuous adrenaline infusion of 3 ⁇ g/kg/h before skin incision were compared to 40 control patients, not receiving adrenaline, whereof 20 were operated before the interventions and the last 20 subsequently after the intervention (figure 8).
  • Intravenous administration of adrenaline reduced perioperative blood loss significantly.
  • the Lysis AUC obtained by TEG is a measure of the clot's resistance against fibrinolysis.
  • the fibrinolysis activator tPA American Diagnostica
  • adrenaline improves the resistance against fibrinolysis by increasing the Lysis AUC significantly (154 %). This effect was abrogated 30 minutes after discontinuation of adrenaline infusion.
  • This clot stabilizing effect described above has not been observed when administering coagulation factors concentrates (activated or non-activated) or recombinant factor Vila.
  • Example 7 TEG MA in relation to combination of adrenergic receptor agonist and antagonists.
  • An antagonist directed at the known adrenergic receptors could potentially abrogate the sympathicomimetic induced pro-hemostatic effect as evaluated by TEG MA.
  • Example 8 Hemodynamic effects in relation to administration of a combination of adrenergic receptor agonist and antagonists.
  • Adrenaline affects the heart and hemodynamic system, primarily through the ⁇ -1 receptors. In connection with surgery an increased stress response is seen due to pain, intubation etc. leading to tachycardia and an increased risk of arrhythmias during surgical procedures. Additional anesthetics and/or pain relief and/or ⁇ -receptor blocking agents are used to reduce these side effects.
  • FIG. 11 depict the hemodynamic changes in response to adrenaline before and after administration of the ⁇ -1 receptor antagonist Seloken.
  • Adrenaline alone increased HR significantly, whereas this effect was practically abrogated/normalized when Seloken was infused ( Figure 1 1a) and as the effect of treatment nearly showed significance (p ⁇ 0.052) post hoc separate Bonferroni adjusted paired t-test was completed showing significant differences in HR at the adrenaline doses 5.0 and 6.0 before and after Seloken.
  • the increase in CO in response to adrenaline infusions (figure 11 b) was significantly lower in all adrenaline concentrations when Seloken was administered.
  • infusion of a ⁇ -1 receptor blocker almost normalizes the increase in HR, reduces the increase in CO and reduces the decrease in TPR, seen in response to adrenaline infusion.
  • Plasma K+ concentrations where followed before and after administration of both adrenaline and Seloken (beta blocker). As can be seen from Table 1 , the plasma potassium concentrations fell following adrenaline administration. The drop in plasma potassium concentration was less when Seloken was administered prior to the administration of adrenaline.
  • Plasma concentration of K + Plasma potassium (K + ) was measured in the healthy subjects described in figure 12 before and after adrenaline infusion with 9.0 ⁇ g/kg/h before and after Seloken administration.
  • the combined effect of adrenaline and rFVIIa is evaluated by intravenous administration of adrenaline in dose of 6 ⁇ g/kg/h for 30 minutes and obtain sequential blood samples from an arterial i.v. line at baseline and every 10 min during the adrenaline infusion.
  • the blood samples will be spiked with rFVIIa and analyzed by TEG.
  • the samples are analyzed by TEG after initiation of coagulation with innovin diluted 1 :42500 after spiking according to the following setup, where tPA is added to a final concentration of 2.4 nM: 1.
  • TEG parameters are recorded: R, Angle, MA, Ly30 and LyAUC.
  • conventional coagulation analyses are obtained on the whole blood samples: APTT, PT, INR, and platelet count.
  • healthy volunteers are included in an in vivo cross over study.
  • the healthy volunteers are instrumented, rest for 30 minutes and thereafter a baseline blood sample is obtained.
  • the subjects are randomized to receive one of two treatments a) or b), after which they rest for 3 hours, where after new blood samples are obtained. Then the subjects receive the other treatment (a or b), rest for another 3 hours subsequent to which final blood samples are obtained.
  • Half of the study subjects receive treatment a) first and then b) and the rest of the subjects receive b) before a).
  • Adrenaline at a concentration of 6 ug/kg/h is infused and blood samples are obtained every 10 min for 30 min, after which the infusion is discontinued.
  • Adrenaline at a concentration of 6 ug/kg/h is infused and rFVIIa at a dose of 1 , 3, 5, 10, 15, or 20 ug/kg is administered as a bolus and blood samples are obtained every 10 min for 30 min, after which the infusion is discontinued.
  • Adrenaline at a dose ranging from 3 to 15 ⁇ g/kg is administered as a continuous infusion into patients undergoing surgery and rFVIIa is administered to half of the patients as a single bolus (1 to 20 ⁇ g/kg) dose immediately the adrenaline infusion is commenced. Intraoperative blood loss is compared between groups receiving adrenaline only and adrenaline and rFVIIa in combination.
  • Adrenaline at a dose ranging from 3-15 ⁇ g/kg/h is administered as a continuous infusion into healthy volunteers or patients and rFVIIa is administered as a single bolus (1-20 ⁇ g/kg) dose immediately the adrenaline infusion is commenced.
  • Sequential blood samples are taken every 5 minutes during the first 30 min of adrenaline infusion.
  • the blood samples will be spiked with the rFVIIa in doses ranging from 1-20 ⁇ g/kg and evaluated by TEG.
  • the following TEG parameters are recorded: R, Angle, MA, Ly30 (amplitude of the TEG tracing 30 min after maximum amplitude (MA) and LyAUC.
  • the following conventional coagulation analyses are obtained: APTT (activated partial thromboplastin time), PT (prothrombin time), INR (international normalized ratio), and platelet count.
  • Johansson Pl. Off-label use of recombinant factor Vila for treatment of haemorrhage: results from randomised clinical trials. Vox Sang. 2008;95:1-7.
  • Engoren MC Habib RH, Zacharias A, Schwann TA, Riordan CJ, Durham SJ. Effect of blood transfusion on long-term survival after cardiac operation. Ann Thorac Surg. 2002 Oct;74(4):1 180-6.
  • Goldstein DS Adrenaline and the inner world. Johns Hopkins university Press 2006. Cannon WB, Mendenhall WL. Factors influencing the coagulation of blood. IV The hastening of blood coagulation in pain and emotional excitement. Am J Physiol 1914;34:251-261.
  • McCrath DJ Cerboni E, Frumento RJ, Hirsh AL, Bennett-Guerrero E. Thromboelastography maximum amplitude predicts postoperative thrombotic complications including myocardial infarction. Anesth Analg. 2005;100:1576-83.

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Abstract

La présente invention concerne une nouvelle utilisation et de nouveaux procédés de traitement mettant en œuvre la combinaison de facteurs de coagulation et d'agonistes des récepteurs sympathicomimétiques/adrénergiques avec une activité pro-hémostatique. L'administration d'une combinaison de facteurs de coagulation et d'agonistes des récepteurs sympathicomimétiques/adrénergiques accroît la capacité de coagulation du sang telle que visualisée par des analyses TEG. Les composés selon l'invention sont particulièrement utiles dans le traitement de patients atteints de traumatismes.
PCT/DK2010/050163 2009-06-24 2010-06-24 Effet pro-hemostatique systemique de facteurs de coagulation en combinaison avec des sympathicomimetiques a effets agonistiques sur des recepteurs α-adrenergiques et/ou β-adrenergiques du systeme nerveux, associe a une capacite de coagulation amelioree Ceased WO2010149172A2 (fr)

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WO2015066700A3 (fr) * 2013-11-04 2015-07-16 The Regents Of The University Of California Thérapie pour le traitement ou la prévention d'états associés au saignement ou à l'hypocoagulation
US10407488B2 (en) 2013-11-04 2019-09-10 The Regents Of The University Of California Therapy for treatment or prevention of conditions associated with bleeding or hypocoagulation

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