WO2017048157A1 - Thérapie combinatoire pour traiter le choc hémorragique et les suites d'une traumatisme craniocérébral - Google Patents

Thérapie combinatoire pour traiter le choc hémorragique et les suites d'une traumatisme craniocérébral Download PDF

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WO2017048157A1
WO2017048157A1 PCT/RU2016/000626 RU2016000626W WO2017048157A1 WO 2017048157 A1 WO2017048157 A1 WO 2017048157A1 RU 2016000626 W RU2016000626 W RU 2016000626W WO 2017048157 A1 WO2017048157 A1 WO 2017048157A1
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activity
combination
serping1
serpingl
substance
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Вероника Николаевна БАДЭ
Владимир Александрович БОБКОВ
Армен Александрович ОВСЕПЯН
Дмитрий Александрович ПОТЕРЯЕВ
Елена Валерьевна БЕЛЯНИНА
Александр Михайлович ШУСТЕР
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Общество С Ограниченной Ответственностью "Международный Биотехнологический Центр "Генериум" (Ооо "Мбц "Генериум")
Вероника Николаевна БАДЭ
Владимир Александрович БОБКОВ
Армен Александрович ОВСЕПЯН
Дмитрий Александрович ПОТЕРЯЕВ
Елена Валерьевна БЕЛЯНИНА
Александр Михайлович ШУСТЕР
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Publication of WO2017048157A1 publication Critical patent/WO2017048157A1/fr

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    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans

Definitions

  • the present invention relates to the field of medicine, namely, to the treatment of the conditions of a mammalian organism accompanied by one or more adverse phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, and may be used in the pharmaceutical industry.
  • TBI traumatic brain injury
  • TBI is usually classified according to severity, anatomical features of trauma and mechanism (causes) (Saatman, Duhaime et al. 2008). TBIs are usually classified as closed and open (Maas, Stocchetti et al. 2008). Closed CCT (CCT) occurs when the brain is not subjected to direct mechanical stress, and brain damage (concussion, edema, hematoma, etc.) can be caused indirectly. An open TBI occurs when there is a violation of the integrity of the skull, the meninges. Despite the different mechanism of damage, the prognosis after head injury is largely dependent on the severity of the injury. With mild injuries, the prognosis is conditionally favorable, in some cases there is a complete recovery without medical assistance.
  • the most common functional impairments after a head injury are motor impairment, the appearance of post-traumatic seizures that require taking anticonvulsants throughout life, decreased cognitive abilities, psychiatric disorders, a vegetative or impaired mental state, memory deficit, epileptic seizures, encephalopathy, paresis and paralysis, speech disorders and other neurological consequences.
  • the restoration of such functions can last for months or years, and sometimes complete restoration of motor or cognitive functions, or mental health does not occur (Hayward, Immonen et al. 2010).
  • cerebral edema is one of the main factors leading to high mortality and complications in patients with head injury. It has been noted that cerebral edema can be responsible for up to half the deaths of all TBI victims (Marmarou 2003).
  • General cerebral edema begins with an increase in the fluid content in the intracranial space, as a result of the flow of water through the walls of blood vessels.
  • the regulation of vascular permeability and the blood-brain barrier can be a way to influence brain edema.
  • Aquaporins, extracellular matrix metalloproteinases and vasoactive agents of inflammation are potential mediators of cerebral edema after head injury.
  • kinins (bradykinins) play an active role in modulating the permeability of the blood-brain barrier after TBI (Donkin and Vink 2010).
  • Hemorrhagic shock occurs when acute blood loss exceeds approximately 20% of the normal blood volume.
  • the main feature of hemorrhagic shock is a decrease in the volume of circulating blood, which leads to hypoperfusion of the main organ systems. Hypoperfusion leads to a lack of nutrients and causes local tissue ischemia, which leads to progressive damage to many organs and their subsequent dysfunction (Keith 1986).
  • resuscitation by replacing the intravascular volume with blood or saline, further damage caused by reperfusion occurs (Keith 1986).
  • hemorrhagic shock and resuscitation the gastrointestinal tract is also severely damaged.
  • Intestinal necrosis occurs, starting with edema of the villi of the small intestine epithelium and subsequent bacterial translocation with the release of endotoxins is observed (Tamion, Richard et al. 1997). This, as a rule, leads to a significant increase in the level of inflammatory cytokines, which can enhance multiple organ dysfunction.
  • Coagulopathy (a pathological condition of the body caused by bleeding disorders) associated with trauma and hemorrhagic shock is diagnosed in one third of patients with traumatic bleeding upon admission to medical institutions. Injured patients with coagulopathy have a significantly higher mortality rate compared to patients with similar injuries without coagulopathy. In case of trauma induced by hemorrhagic shock of coagulopathy, infusion-transfusion therapy is usually used during resuscitation enterprises.
  • Coagulopathy after head injury occurs quite often and is a sign of an adverse outcome and prognosis.
  • the complex pathophysiological mechanisms of coagulopathy in TBI are multifactorial and not fully understood.
  • the current understanding of the development of coagulopathy after head injury is that head injury causes both hypocoagulation and hypercoagulation, the latter often replacing the former, depending on the degree and extent of the injury.
  • Coagulopathy as a result of head injury leads to secondary damage to the central nervous system of varying degrees, through the development of foci of hemorrhage and ischemia.
  • coagulopathy due to TBI includes the release of tissue factor (TF), hyperfibrinolysis, shock and hypoperfusion, which in turn trigger the mechanisms of the Protein C signaling cascade, disseminated intravascular coagulation and platelet dysfunction (Maegeleoel de Ol; 2013; , Neto et al. 2015).
  • Coagulopathy associated with TBI has now been proven to be a poor prognosis for recovery (Rancan, Morganti-Kossmann et al. 2003; Epstein, Mitra et al. 2014; Epstein, Mitra et al. 2014; Joseph, Aziz et al. 2014; Sillesen, Rasmussen et al. 2014; de Oliveira Manoel, Neto et al. 2015; Abdelmalik, Boorman et al. 2016).
  • Fibrinolysis is the process of dissolution of blood clots and blood clots, an integral part of the hemostatic system, always accompanying the process of blood coagulation. Its increase, or hyperfibrinolysis, is a known consequence of trauma with hemorrhagic shock (Nathan J. White, ASH Education Book December 6, 2013 vol. 2013 no. 1 660-663).
  • Fibrinolysis is most severely affected in severe head injury, up to its deep suppression against the background of normal retraction rates (A.V. Usenko et al., Emergency Medicine N ° l (2), 2006).
  • TBI therapy remains an unmet medical need (Diaz-Arrastia, Kochanek et al. 2014).
  • the EMA European Medicines Agency
  • FDA US Food and Drug Administration
  • Numerous drugs for the treatment of TBI showing efficacy and safety in preclinical studies in animals, have not been able to show effectiveness in TBI in clinical trials (Kaufmann and Cardoso 1992). Examples of such drugs are glutamate receptor agonists; steroids; PEG superoxide dismutase; IGF-1 / growth hormone; cannabinoids and their analogues (Narayan, Michel et al. 2002).
  • Mannitol is also used to reduce cerebral edema, although there is no reliable data on its effectiveness in the treatment of head injury. Moreover, the use of mannitol in TBI can be harmful because it enhances the permeability of the blood-brain barrier (BBB) (Kaufmann and Cardoso 1992).
  • BBB blood-brain barrier
  • 1: 1: 1 protocol which is a combination of red blood cells, freshly frozen blood plasma, and platelets, is available only at inpatient facilities such as hospitals.
  • the application of the 1: 1: 1 protocol is limited by the shelf life of the individual components.
  • the recommended shelf life of red blood cells is 8 days, and platelets - 5 days.
  • Tranexamic acid is currently the most effective treatment for hemorrhagic shock for use in conditions where inpatient medical facilities are unavailable.
  • Tranexamic acid significantly reduces overall mortality and death due to bleeding in patients with severe bleeding caused by trauma, especially when administered early after injury (Shakur, Roberts et al. 2010; Roberts, Shakur et al. 2011; Ker, Kiriya et al. 2012; Roberts, Prieto-Merino et al. 2014).
  • Tranexamic acid has antifibrinolytic activity due to reversible binding to plasminogen, preventing its interaction with fibrin and, thus, inhibits lysis of the fibrin clot.
  • the lysine amino acid residues of the fibrin protein molecule mediate the binding of fibrin to lysine-binding sites plasminogen molecules (Ferring Pharmaceuticals Inc. Lysteda (tranexamic acid) tablets: US prescribing information. [Online]. - URL: http://lysteda.com/assets/pdf/PI_FERRING2010.pdf, (Dunn and Goa 1999)).
  • Tranexamic acid almost completely blocks the binding of plasminogen or the plasmin heavy chain to fibrin, mainly by binding to the high affinity lysine binding site of plasminogen. Despite the fact that in the presence of a plasminogen activator (for example, a tissue plasminogen activator) plasminogen can still be converted to plasmin, after binding to tranexamic acid, it cannot interact with fibrin and, therefore, cleave it. (Dunn and Goa 1999). Tranexamic acid also blocks the binding of ag-antiplasmin to plasmin and its inactivation by plasmin. In addition to plasmin inhibition, tranexamic acid also competitively inhibits trypsinogen activation by enterokinase, non-competitively inhibits trypsin and weakly inhibits thrombin (Dunn and Goa 1999).
  • a plasminogen activator for example, a tissue plasminogen activator
  • the binding strength of tranexamic acid with plasminogen is about 6 -10 times greater than that of another synthetic lysine derivative, ⁇ -aminocaproic acid, which is also an antifibrinolytic drug (Dunn and Goa 1999).
  • the lysine binding sites of plasminogen are located in different so-called kringle domains, which are a region of the polypeptide chain consisting of beta structures that are stabilized by three disulfide bonds.
  • Both tranexamic and ⁇ -aminocaproic acids interact with the low affinity lysine binding site of the fifth kringle domain, which is likely to be needed for the initial association of plasminogen with fibrin (Dunn and Goa 1999).
  • the high affinity lysine-binding first kringle domain is necessary for binding to the carboxy-terminal lysine residue, which is present in fibrin only after partial hydrolysis of it (Anonick, Vasudevan et al. 1992).
  • Tranexamic acid is currently used as a drug of choice by military doctors in the US and the UK to treat severe war injuries and bleeding.
  • tranexamic acid is also FDA approved for oral use in women with severe menstrual bleeding and intravenously for the prevention of dental bleeding in hemophilia patients.
  • tranexamic acid is often used inappropriately to reduce bleeding caused by various causes, including trauma and surgical interventions.
  • a large randomized, double-blind, placebo-controlled, multinational clinical trial CRASH-2 (Clinical Randomization of an Antifibrinolytic in Significant Hemorrhage 2 - Clinical Randomization of Antifibrinolytic with Significant Bleeding) evaluated the effectiveness of early use of tranexamic acid in Roberts et al. al. 2010). Based on the results of this study, tranexamic acid significantly reduced mortality in all causes within 4 weeks (primary endpoint of the trial) and the risk of death due to bleeding. For all reasons, mortality in the placebo group was 16%, while in the group with tranexamic acid - 14.5%. The mortality due to bleeding in the placebo group was 5.7%, and in the group using tranexamic acid - 4.9%.
  • CRASH-2 analysis focused on the mechanism of action of tranexamic acid in patients with bleeding, concluded that tranexamic acid has the greatest effect on reducing mortality on the first day after an injury. Tranexamic acid, applied in the first 3 hours after injury, reduces overall mortality on the first day and increases subsequent survival by 20%.
  • Aminocaproic and aminomethylbenzoic acids which are synthetic derivatives of the lysine amino acids that share common functional features and a mechanism of action with tranexamic acid, are also currently used as antifibrinolytic agents used for bleeding.
  • Aminomethylbenzoic acid (“Amben”) is close to ⁇ -aminocaproic acid and tranexamic acid by the mechanism of action; inhibits fibrinolysis by competitive inhibition of plasminogen activating enzyme and inhibition of plasmin formation (Langenbach 2006). Compared to ⁇ -aminocaproic acid, aminomethylbenzoic acid more effectively inhibits fibrinolysis, but has half the inhibitory activity than tranexamic acid (Verstraete 1985).
  • SERPINGI also known as C1 or C 1 inhibitor esterase inhibitor
  • C1 or C 1 inhibitor esterase inhibitor is a member of the serine protease inhibitor family.
  • Cls and Clr subcomponents of the C1 complex of the classical activation pathway (Arlaud, Reboul, Sim, & Colomb, 1979; Nilsson, Sjoholm, & Wiman, 1983; Nilsson & Wiman, 1983; RatnoffSchena et al., 1980;, 1969; Sim , Arlaud, & Colomb, 1980)
  • SERPINGI plays a key role in regulating complement system activity.
  • SERPINGI also regulates the kinin-kallikriya new system, inhibits kallikrein, factor X1a and factor HPA (Aasen, Erichsen, Gallimore, & Amundsen, 1980; Cullmann, Kovary, Dick, Czarnetzki, & Echternach-Happle, 1982; Harpel & Cooper, 1975; Harpel, 1970; Ratnoff, 1969; Revak & Cochrane, 1976; Schapira, Scott, & Colman, 1981; van der Graaf, Koedam, & Bouma, 1983).
  • SERPINGI indirectly prevents plasminogen activation through inhibition of kallikrein and factor CIA, and also directly inhibits plasmin in the blood (Beattie, Ogston, Bennett, & Douglas, 1976; Haselager, Goote, & Vreeken, 1976), which, in turn, reduces fibrinolysis (Travis & Salvesen, 1983 ), which is a key feature of coagulopathy in severe, life-threatening hemorrhagic shock, or in brain edema caused by head injury.
  • SERPING1 by inhibiting kallikrein, reduces the plasma concentration of bradykinin (a vasoactive peptide that increases capillary permeability and plasma extravasation).
  • SERPI G1 counteracts edema and reduces edema and also reduces hemorrhagic shock-induced permeability of endothelial tissue (Cheng et al., 2008; Schmidt, Stenzel, Gebhard, Martin, & Schmidt, 1999). Otherwise, the permeability of the endothelium often leads to tissue damage, and in case of violation of the intestinal epithelium to sepsis. Changes in the permeability of the cerebral vascular endothelium lead to a violation of the integrity of the blood-brain barrier (BBB) and, as a result, to brain edema.
  • BBB blood-brain barrier
  • SERPING1 significantly reduced tissue damage in the kidneys, intestines, and lungs in a dose-dependent manner (100 and 250 IU / kg).
  • rhSERPINGl at a dose of 250 IU / kg markedly reduced metabolic acidosis and the level of circulating TNF- ⁇ (Dalle Lucca, Li et al. 2012).
  • SERPING1 significantly reduced motor-motor deficits and, moreover, immunohistochemical analysis showed that 20 minutes after administration, SERPING1 was localized to the endothelial cells of brain vessels in the area of injury (Longhi, Perego et al. 2009).
  • SERPING1 inhibits and / or reduces the pathological permeability of blood vessels, and possibly reduces the BBB permeability, the integrity of the latter is usually impaired in TBI.
  • Activation of the complement system is one of the key points of neuropathology in TBI, and inhibition of the complement system in TBI can lead to neuroprotection.
  • inhibition of the complement system in the central nervous system can have a neuroprotective effect after HRI (Hua, Xi et al. 2000; Xi, Hua et al. 2001; Xi, Hua et al. 2002; Gong, Xi et al. 2005; Yang, Nakamura et al. 2006; Zhang, Lee et al. 2013) (Rancan, Morganti- Kossmann et al. 2003).
  • another inhibitor of the complement system has been described, which in the TBI model in mice improved the recovery of neurological functions (Ruseva, Ramaglia et al. 2015).
  • SERPI G1 The indicated properties of SERPI G1 indicate the possibility of its use in replacement therapy for angioedema (both congenital and acquired), for the prevention and treatment of sepsis, including septic shock, for the prevention and treatment of multiple organ dysfunction, increased permeability syndrome capillaries, including sepsis and / or septic shock, for the prevention and treatment of acute respiratory distress syndrome, for adjuvant therapy for atherosclerotic vascular lesions, for the prevention and treatment of ischemic stroke and its complications, acute cerebrovascular accident, prevention and treatment shock conditions in the surgical and postoperative periods during coronary artery bypass grafting, to prevent and treat shock conditions during transluminal angioplasty, for prophylaxis Ki and treatment of reperfusion syndrome after coronary artery bypass grafting and transluminal angioplasty in combination with direct anticoagulants, for the prevention and treatment of rejection reactions during organ and tissue transplantation (including bone marrow), for the treatment or prevention of systemic rheumatological diseases that occur with activation of the
  • the disadvantages of the known existing treatments for hemorrhagic shock, head injury and related brain edema include insufficient mortality, unresolved long-term effects (neurological deficits, neuropathology, impaired behavior and cognitive functions), lack of effectiveness, undesirable side effects caused by reperfusion when applying standard infusion-transfusion therapy, characterized by early activation of neutrophils and the formation of free radicals (Ioannou, Dalle Lucca et al. 201 one).
  • an antifibrinolytic selected from the group consisting of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid, and a substance with SERPING1 activity for the treatment of hemorrhagic shock, head trauma, and accompanying phenomena.
  • the present invention solves the problem of providing highly effective agents (combination, kit, pharmaceutical composition) and a method that can be used both in inpatient care and in the absence of these conditions, to prevent or eliminate blood loss, impaired coagulation (coagulopathy), disorders fibrinolysis systems and the associated edema in brain injury (and associated cerebral edema) and similar phenomena that occur with head injury, hemorrhagic shock, and other pathologists conditions accompanied by the indicated phenomena and violations by eliminating and / or reducing the severity of these phenomena.
  • highly effective agents coagulation, kit, pharmaceutical composition
  • a method that can be used both in inpatient care and in the absence of these conditions, to prevent or eliminate blood loss, impaired coagulation (coagulopathy), disorders fibrinolysis systems and the associated edema in brain injury (and associated cerebral edema) and similar phenomena that occur with head injury, hemorrhagic shock, and other pathologists conditions accompanied by the indicated phenomena and violations by eliminating and / or reducing the severity of these phenomena.
  • the authors first discovered that the combined use of a substance with SERPINGl activity and one or more antifibrinolytics selected from the group consisting of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid or their functional analogs provides a synergistic positive effect when exposed to such pathological phenomena as a violation of fibrinolysis, coagulopathy, edema, massive blood loss, which manifests itself in increased survival mammals in conditions accompanied by these phenomena, in particular, with massive blood loss, hemorrhagic shock and traumatic brain injuries.
  • the authors also first discovered that the specified combined use:
  • the authors of the present invention showed for the first time that the combined use of a substance with SERPING1 activity and an antifibrinolytic selected from tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid or their functional analogue has a significantly stronger protective effect in hemorrhagic shock, acute massive blood loss and cerebral edema caused by TBI than SERPI G1 or one of the mentioned antifibrinolytics, for example, tranexamic acid, used alone.
  • SERPING1 tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid improves survival in hemorrhagic shock by normalizing hemostasis (preventing the development of coagulopathy), by counteracting inflammation, preventing tissue damage, minimizing shock, as well as minimizing hemorrhagic shock-related translocation of bacteria and bacterial endotoxins from the intestines.
  • the authors of the present invention also for the first time showed that the combined use of SERPING1 and tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid improves survival in TBI by reducing brain edema, preventing the development of coagulopathy, by counteracting inflammation, preventing tissue damage, minimizing shock, and minimizing the associated with TBI consequences, such as a decrease in neurological deficits, neuropathologies, impaired behavior and cognitive functions.
  • the object of the present invention is the combination of one or more antifibrinolytics and a substance with activity of SERPING1 for the treatment of a mammal, accompanied by one or more phenomena selected from the following: coagulopathy, fibrinolysis, edema, blood loss, similar phenomena manifested by head trauma and hemorrhagic shock, by eliminating and / or reducing the severity of these phenomena.
  • the specified combination can be used for administration to patients with hemorrhagic shock, for the treatment of bleeding that could potentially lead to hemorrhagic shock; for administration to patients with head injury, head trauma, as well as the phenomena accompanying these state of the body, such as swelling / swelling of the brain, coagulopathy, impaired fibrinolysis.
  • Another object of the present invention is the use of this combination to treat the condition of a mammalian organism, accompanied by one or more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminating and / or reducing the severity of these phenomena.
  • a further object of the present invention is a kit for treating a condition of a mammalian organism comprising one or more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock by eliminating and / or reduce the severity of these phenomena.
  • Another object of the present invention is a kit for treating the condition of a mammalian organism accompanied by one or more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminating and / or reducing the severity these phenomena, including a metered pharmaceutical composition containing, as an active principle, a substance having SERPING1 activity, as well as an instruction in which However, this composition should be used in combination with one or more antifibrinolytics.
  • Another object of the present invention is a kit for treating the condition of a mammalian organism, accompanied by one or more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminating and / or reducing the severity of these phenomena, including a metered pharmaceutical composition containing, as an active principle, one or more antifibrinolytics, as well as an instruction that states or from which it clearly follows that the composition should be used in combination with a substance with activity SERPING1.
  • an object of the present invention is a pharmaceutical composition
  • a pharmaceutical composition comprising a combination of the invention for treating a condition of a mammalian organism accompanied by one or more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminate and / or reduce the severity of these phenomena.
  • the last object of the present invention is a method for treating the condition of a mammalian organism accompanied by one or more phenomena selected from the following: coagulopathy, impairment of fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminating and / or reducing the severity of these phenomena characterized in that it comprises administering to the mammal an effective amount of said combination.
  • the indicated disease may be hemorrhagic shock, massive blood loss or the consequences of a traumatic brain injury.
  • said edema is preferably cerebral edema.
  • the specified mammal can be any mammal, including, without limitation, humans.
  • the antifibrinolytic may be selected from the group consisting of tranexamic, aminomethylbenzoic, ⁇ -aminocaproic acid or a functional analogue thereof.
  • the antifibrinolytic is tranexamic acid.
  • a substance having SERPING1 activity is one of the following: a polypeptide having SERPING1 activity, a fragment of the specified polypeptide having SERPI G1 activity, a recombinant full-size SERPING1, a serpine domain of the specified polypeptide, a mutant of the specified polypeptide, a modified analog of the specified polypeptide with SERPING1 activity with SERPING1 activity, a chemical compound with activity of SERPINGl, a recombinant human SERPINGl polypeptide, or its biologically active mutant, or its chemically modified analogue, or its fusion protein.
  • one or more antifibrinolytic and a substance having SERPINGl activity are preferably used in the method of the invention and are present in combination, kit, pharmaceutical composition of the invention in therapeutically effective amounts.
  • a therapeutically effective amount of a substance having SERPINGl activity is from 10 to 1500 ME / kg body weight.
  • the therapeutically effective amount of antifibrinolytic is from 0.005 to 0.5 g / kg body weight.
  • a therapeutically effective amount of tranexamic acid can be from 0.01 to 0.05 g / kg body weight, and a therapeutically effective amount of a substance having SERPINGl activity is from 50 to 500 ME / kg body weight.
  • the pharmaceutical composition of the invention may be a lyophilisate or solution. If said pharmaceutical composition is in the form of a lyophilisate, then a pharmaceutically acceptable solvent or diluent suitable for reconstitution may be presented in a separate pharmaceutically acceptable container and is preferably selected from the group consisting of water for injection, saline or Ringer's solution.
  • the kit according to the invention may contain only one component of the combination or the entire combination in the form of one, two or more dosage pharmaceutical compositions, which further comprise pharmaceutically acceptable additives. However, if the kit according to the invention includes only one component of the combination according to the invention in the form of one of two or more metered pharmaceutical compositions, then the kit must also contain instructions that indicate or clearly indicate that the composition should be used in combination with another dosage a pharmaceutical composition that contains a component of the combination of the invention that is not in the kit.
  • the components of the combination kit may be contained in different dosage pharmaceutical compositions.
  • both the metered pharmaceutical composition containing one or more antifibrinolytics as an active principle, and the metered pharmaceutical composition containing a substance having SERPINGl activity as an active principle can be independently presented in the form of a solution or lyophilisate, and a kit according to the invention may additionally contain a pharmaceutically acceptable solvent and / or diluent if at least one pharmaceutical composition in the kit is in the form of a lyophilisate.
  • the kit of the invention may contain at least one pharmaceutically acceptable container for containing each dosage pharmaceutical composition.
  • the method according to the invention may include the introduction of the components of the combination either simultaneously or sequentially.
  • the interval between the introduction of the components of the combination is from about 0 to about 60 minutes.
  • the introduction can be carried out, including intravenously.
  • the components of the combination according to the method according to the invention can be entered in the form of at least one dosage pharmaceutical composition, preferably additionally containing pharmaceutically acceptable additives.
  • the pharmaceutical composition should be suitable for intravenous administration.
  • the components of the combination used in the method according to the invention can be administered in the form of two dosage pharmaceutical compositions, each of the compositions in this case may contain only one component of the combination and, in combination with the other pharmaceutical composition containing the other component of the combination, can provide the combination according to the invention .
  • compositions can be used together, following, for example, the instructions attached to at least one of these compositions, and the specified instruction contains an indication of or from which explicitly follows that for the treatment of the condition of a mammalian organism, accompanied by one and more phenomena selected from the following: coagulopathy, impaired fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma and hemorrhagic shock, by eliminating and / or reducing the severity of these phenomena, one or more antifibrinolytics should be used in conjunction with a substance with activity SERPING1.
  • At least one pharmaceutical composition used in the method of the invention is a lyophilisate, it must be reconstituted with a pharmaceutically acceptable diluent and / or solvent selected from the group consisting of preferably water for injection, saline or Ringer's solution before administration.
  • the combination is used in a therapeutically effective amount, which may be such an amount that contains a substance having SERPING1 activity in an amount of from 10 to 1500 ME / kg body weight and antifibrinolytic in an amount of from 0.005 to 0.5 g / kg body weight.
  • the antifibrinolytic may be tranexamic acid
  • the substance having SERPING1 activity may be a polypeptide with the indicated activity
  • the amount of tranexamic acid being the therapeutically effective amount of the combination is from 0.01 to 0.05 g / kg body weight
  • the amount of the polypeptide having SERPING1 activity in the therapeutically effective amount of the combination is from 50 to 500 ME / kg body weight.
  • the combination as a substance having SERPING1 activity may comprise a recombinant human SERPING1 polypeptide, or a biologically active mutant thereof, or a chemically modified analogue thereof, or a fusion protein thereof.
  • the method of the invention may further include re-administering a substance having SERPING1 activity after administration of the combination.
  • a metered pharmaceutical composition containing one or more antifibrinolytics as an active principle which is in the form of a solution
  • a metered pharmaceutical composition containing, as an active principle, a substance having SERPI Gl activity which is presented in the form of a solution or in the form of a solution reconstituted from the lyophilisate before administration.
  • Dosage pharmaceutical compositions used in the method of the invention may additionally contain pharmaceutically acceptable additives. Moreover, each pharmaceutical composition used in the method according to the invention may, if necessary, be contained in a separate pharmaceutically acceptable container for containing each dosage pharmaceutical composition.
  • FIG. 1 Thromboelastogram of activated normal human blood plasma.
  • A Clot formation in activated plasma (control)
  • B Clot lysis caused by the addition of tissue plasminogen activator (t- ⁇ / ⁇ - ⁇ ).
  • B The addition of tranexamic acid to the activated human blood plasma does not change the coagulation parameters (clot formation) in the activated plasma.
  • FIG. 2 Thromboelastogram of activated normal human blood plasma with the addition of t-PA and rhSERP! NGl.
  • rhSERPINGl alone does not affect in vitro induced t-PA fibrinolysis.
  • TXA tranexamic acid
  • B Inhibition of transexamic acid by clot lysis induced by t-PA is potentiated by the addition of rhSERPINGl.
  • FIG. 3 The truncated amino terminus of rhSERPINGl (rhCHNHi 2 o-5oo), which retains the serpin domain, also has the ability to enhance the antifibrinolytic effect of tranexamic acid.
  • FIG. 4 Quantification of thromboelastograms. The time of clot lysis is shown, from R (reaction time of the beginning of clot formation) to complete lysis of the clot.
  • FIG. 5 Effect of rhSERPlNGl on the release of inflammatory cytokines in an ex vivo / in vitro model on whole blood.
  • the histogram shows the total amount (AUC, pg / ml in 24 hours) of IL-6 (A) or IL-1 ⁇ (B), ejected 24 hours after induction with LPS (LPS - bacterial polysaccharides); rhClI H 2 3-500 - mature full-sized rhSERPlNGl, amino acid residues 23-500; C IINH120-500 — truncated at the amino terminus of rhSERPlNGl containing a serpine domain, amino acid residues 120-500; rhCHNH 2 3-i 2 2 - truncated at the carboxy-terminus of rhSERPlNGl, without serpin domain, amino acid residues 23-122; rhClINH465ARTVKV - rhSERPlNGl with
  • FIG. 6 Reduction of mouse paw edema induced by carrageenan by rhSERPlNGl. Capillary blood flow at the site of edema was measured by laser Doppler flowmetry. Y axis - 100% normal blood flow in a healthy paw.
  • FIG. 7 Kaplan- Mayer survival chart for each experimental group: control - hemorrhagic shock without intervention (without infusion therapy); Ringer's solution - infusion therapy with Ringer's solution to compensate for hypovolemia; C1INH - rhSERPlNGl (168 IU / kg); TXA - tranexamic acid (0.15 g / kg). All rats that lived 14 hours after hemorrhagic shock were alive by 72 hours after hemorrhagic shock (euthanasia time).
  • FIG. 8. A histogram of the survival of animals in each of the experimental groups of hemorrhagic shock (groups are shown as shown in Fig. 7) 72 hours after hemorrhagic shock.
  • C Survival of animals 72 hours after hemorrhagic shock, which was administered a combination of rhSERPlNGl (C1INH) and tranexamic acid, depends on the dose of rhSERPING.
  • FIG. 9 Typical micrographs of sections of the jejunum stained with hematoxylin and eosin. Arrows indicate goblet cells, tips - on the Grunhagen cavity, which are signs of villi degeneration.
  • A is a control showing normal intestinal epithelium.
  • B A group with hemorrhagic shock during resuscitation with Ringer's solution.
  • FIG. 10 A quantitative assessment of damage to the intestinal epithelium in animals with hemorrhagic shock and various treatment options.
  • A Damage to the epithelium of the mucous membrane according to the Chiu / Park scale.
  • B The number of goblet cells in a villus section. The experimental groups are indicated as in FIG. 7.
  • FIG. 11 The effect of the combined use of rhSERPINGl and tranexamic acid on the size of cerebral edema after CCT.
  • A Pictures of MRI diffusion maps 24 hours after CTL, cerebral edema is indicated by arrows.
  • B Dynamics of the development of edema over time after MST in the control (infusion therapy with Ringer's solution) and experimental groups of animals treated 30 minutes after MST: rhClINH - rhSERPINGl (500 IU / kg); TXA - tranexamic acid (178 mg / kg); TCA (178 mg / kg) and rhClINH (500 IU / kg). Data on edema volume are presented in mm 3 (M ⁇ STD).
  • FIG. 12 Dynamics of restoration of neurological functions (reduction of neurological deficit) of mice on days 1, 3, 5, 7, and 9 in the post-traumatic period, scores (M ⁇ SEM) were calculated according to all criteria of the NSS scale on each day of testing in all animals. Groups of animals are shown as shown in FIG. eleven.
  • FIG. 13 An analysis of the reactions of vertical motor activity (V DA) on the 10th day of the post-traumatic period, reflecting tentative research behavior.
  • V DA vertical motor activity
  • A Duration (time) of the VDA reactions.
  • B The number of manifested VDA reactions. Groups of animals are shown as shown in FIG. 11. Background - animals before CCW.
  • FIG. 14 Recovery of horizontal locomotor activity (G YES) of mice 10 days after CCTV.
  • G YES horizontal locomotor activity
  • A The total distance traveled by the animals in the “open field” test for 5 minutes to 10 days of the post-traumatic period.
  • B The rate of locomotor activity of animals on the 10th day of the post-traumatic period. Groups of animals are shown as shown in FIG. 11. Background - animals before CCW.
  • FIG. 15 The development of a passive strategy of behavior in animals after CCI.
  • the fading reaction was evaluated 10 days after the injury. Groups of animals are shown as shown in FIG. 11. Background - animals before CCW.
  • FIG. 16 Violation of animal memory functions in animals on the 10th day after CCI. The functions of memory and learning were evaluated by the latent time of transition to the dark compartment of the camera (conditional reaction of passive avoidance) before the injury and on the 10th day of the post-traumatic period. Groups of animals are shown as shown in FIG. 1 1. Background - animals that have not been trained.
  • a disease in the framework of the present invention is any disease that is accompanied by adverse events such as coagulopathy, fibrinolysis disorders, massive blood loss, edema, similar phenomena that occur with head trauma and hemorrhagic shock.
  • adverse events such as coagulopathy, fibrinolysis disorders, massive blood loss, edema, similar phenomena that occur with head trauma and hemorrhagic shock.
  • the disease is hemorrhagic shock, massive blood loss or the effects of traumatic brain injury.
  • edema in the framework of the present invention is meant any edema that occurs due to the same or essentially the same mechanisms that lead to coagulopathy, impaired fibrinolysis, massive blood loss and other adverse events accompanying head trauma, massive blood loss and hemorrhagic shock.
  • Said edema in case of head injury is preferably cerebral edema.
  • the specified functional analogue of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid is any substance that exhibits antifibrinolytic properties that reduce the fibrinolytic activity of blood, as well as tissues and help to stop bleeding associated with increased fibrinolysis.
  • the specified functional analogue can be either a synthetic drug or a drug of animal origin (trasilol, etc.).
  • the functional analog of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid is a synthetic analog of lysine (amino acid), which is capable of saturating the lysine-binding sites of plasminogen.
  • the term “substance having SEPRING1 activity” refers to proteins or fragments thereof that function as serine protease inhibitors and protease inhibitors associated with the complement system, preferably C1g and C Is proteases, and proteases MASP-1 and MASP-2 associated with the kallikrein-kinin system, preferably plasma kallikrein and HPA factor, and proteases associated with the blood coagulation system, preferably factor X1a.
  • the indicated substance having SERPINGl activity in various embodiments of the present invention, can be a polypeptide having SERPINGl activity, a fragment of said polypeptide having SERPINGl activity, a recombinant full-length SERPINGl, a serpine domain of said polypeptide, a mutant of said polypeptide, a modified analogue of said polypeptide, with SERPINGl activity; aptamer with SERPINGl activity; chemical compound with SERPINGl activity.
  • the substance having SERPINGl activity is the recombinant human SERPINGl polypeptide, or its biologically active mutant, or its chemically modified analogue, or its fusion protein.
  • SEPRING1 may be modified to improve bioavailability and / or half-life, to improve efficacy and / or reduce potential side effects.
  • modifications can be made by recombinant methods, chemical conjugation, or other methods known to the person skilled in the art. Examples of such modifications are glycosylation, a hybrid (chimeric) protein, where SEPRING1 is fused to another protein or polypeptide, such as, for example, albumin or an immunoglobulin Fc fragment. That is, we are talking about such derivatives that retain activity at the level of the original protein. Examples of possible modifications are described, for example, in EP 1984503, US 20130108629.
  • SERPINGl can be carried out in various ways. Obtaining pdSERPlNGl (plasma SERPINGl) by sequential purification from human blood plasma is described in detail, for example, in international application WO2001046219 or patent RU2256464. Also described is the production of recombinant human SERPINGl (rhSERPINGl) from the milk of transgenic animals (van Veen, Coeter et al. 2012) (patent US7067713). In addition, recombinant SERPINGl can be produced in eukaryotic cell cultures (as described, for example, in WO201 1 116291) or in prokaryotes using currently accepted genetic engineering methods.
  • the C 1 inhibitor can be used both in the native form and in the form of an active fragment obtained by recombinant or other means and preserving functional abilities, as well as in the form of mutant forms, for example, such as those proposed in WO2010002453.
  • the antifibrinolytic and a substance having SERPINGl activity are used in the method of the invention and are present in the combination of the invention, the pharmaceutical composition of the invention or in the kit of the invention in therapeutically effective amounts.
  • therapeutically effective amount means the total amount of each active component of the combination that is sufficient to show a significant benefit to the patient, for example, amelioration of symptoms, recovery or increase the speed of recovery.
  • the term refers to combined amounts of active ingredients that lead to a therapeutic effect, whether they are administered in combination, serially or simultaneously.
  • a therapeutically effective amount of a combination of the invention is an amount that contains an effective amount of a substance having SERPING1 activity and a therapeutically effective amount of an antifibrinolytic.
  • an effective amount of an antifibrinolytic and a substance having SERPING1 activity based on known rules and patterns, including without limitation: age and weight of patients, frequency of administration, severity of condition, preliminary treatment of a patient, characteristics of the patient’s body, etc. d.
  • the attending physician based on personal experience and practice, can decide on the amount of antifibrinolytic and substances with SERPING1 activity, which it is advisable to treat each patient individually.
  • the attending physician can introduce small doses of these substances and, according to the patient’s response, adjust their quantity.
  • a therapeutically effective amount of SERPING1 includes a dosage of from about 10 to about 1,500 IU / kg body weight of a mammal, and most preferably from about 50 to about 500 IU per kg body weight.
  • a therapeutically effective amount of an antifibrinolytic or a combination thereof is from about 0.005 to 0.5 g / kg body weight of a mammal, and most preferably from about 0.01 g to 0.05 g / kg body weight.
  • the combination according to the invention can be presented in the form of one or more dosage pharmaceutical compositions.
  • the combination may be in the form of two dosage or more pharmaceutical compositions.
  • the pharmaceutical compositions comprise various combination components.
  • compositions may contain, in addition to the active components, pharmaceutically acceptable additives, such as fillers, carriers, stabilizers, preservatives, buffers, antioxidants, solubilizers, diluents or other additives known to specialists in this field and disclosed, for example, in ((Handbook of Pharmaceutical Excipients " (Rowe, Sheskey et al. 2012).
  • pharmaceutically acceptable additives such as fillers, carriers, stabilizers, preservatives, buffers, antioxidants, solubilizers, diluents or other additives known to specialists in this field and disclosed, for example, in ((Handbook of Pharmaceutical Excipients " (Rowe, Sheskey et al. 2012).
  • the term "pharmaceutically acceptable” means a non-toxic material that does not reduce the effectiveness of the biological activity of the active (s) ingredient (s).
  • compositions of the invention are formulated, dosed and administered in accordance with the principles of good medical practice.
  • pharmaceutical compositions comprising a combination of the invention, or used in kits and methods of the invention can be prepared by methods known to those skilled in the art. Standard pharmaceutical formulation methods are known to those skilled in the art (Remington 1995).
  • compositions comprising the combination of the invention, or used in the kits and methods of the invention, can be formulated as liposome compositions in which amphipathic agents, such as lipids, which exist in aggregated form in the form of micelles, are used in addition to pharmaceutically acceptable carriers insoluble monolayers, liquid crystals or lamellar layers in an aqueous solution.
  • amphipathic agents such as lipids, which exist in aggregated form in the form of micelles
  • Suitable lipids for the preparation of a liposome preparation include, but are not limited to, monoglycerides, diglycerides, sulfatides, lysolecithin, phospholipids, saponin, bile acids, etc.
  • the preparation of such liposome preparations is disclosed, in particular, in US Pat. No. 4,235,871, US Pat. No. 4,501,728, US Pat. No. 4,837,028 and US Pat. No. 4,737,323, which are incorporated herein by reference in their entirety.
  • compositions may be presented in the form of solutions or lyophilisates for the preparation of solutions. Moreover, it is preferable that each pharmaceutical composition that contains a combination of the present invention or which is used in the methods and / or kits of the present invention, is made in a form suitable for intravenous administration.
  • compositions may contain additives such as mannitol, starch, glucose, lactose, sucrose, sodium stearate, glycerol monostearate, sodium chloride, glycerin, propylene, glycol, water, ethanol and the like.
  • additives such as mannitol, starch, glucose, lactose, sucrose, sodium stearate, glycerol monostearate, sodium chloride, glycerin, propylene, glycol, water, ethanol and the like.
  • pH stabilizing buffer agents such compositions may contain, for example, sodium citrate or phosphate.
  • humectants and emulsifiers such compositions may contain, for example, polysorbate or pluronic.
  • stabilizers such compositions may contain, for example, histidine, arginine.
  • preservatives such compositions may contain, for example, benzyl alcohol.
  • compositions may contain, for example, ascorbic acid or alpha-tocopherol. Also, such compositions may contain technological auxiliaries, colorants, diluents, such as saline (0.9% sodium chloride) and other known additives.
  • an osmolarity regulator for example, sodium chloride
  • mannitol as a stabilizer.
  • the resulting solution can be filtered using, for example, a 0.22 micron filter to remove impurities and contaminants.
  • the resulting solution can be used as such or lyophilized using standard methods.
  • the combination of the invention is in the form of a pharmaceutical composition
  • a pharmaceutical composition comprising a C 1 inhibitor lyophilisate mixed with tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid powder and the necessary pharmaceutically acceptable additives.
  • tranexamic acid is most preferred.
  • Forms containing lyophilisate are preferred for use in difficult field conditions, as potentially have a maximum shelf life in comparison with the combination in the form of a solution / solutions for administration, which, despite its greater ease of use, usually requires more stringent storage conditions.
  • a lyophilisate of a C 1 inhibitor can be a lyophilisate of a solution consisting of the following components: 20-40 mg / ml C 1 inhibitor; 40-60 mg / ml trehalose; 2-10 mg / ml NaCl; 1.78 mg / ml Na 2 HP0 4 ; 1.38 mg / ml NaH 2 P0 4 , pH 6.8.
  • Water for injection can be used as a solvent for said lyophilisate, and 0.9% sodium chloride solution or Ringer's solution can be used as a diluent for said lyophilisate.
  • the combination of the invention can be formulated as a single pharmaceutical composition by mixing solutions of tranexamic and / or aminomethylbenzoic and / or ⁇ -aminocaproic acid and SERPING1 at a suitable pH with physiologically acceptable carriers.
  • the pH of the composition may vary from about 6 to about 8.
  • the combination is a dosed pharmaceutical composition in the form of an intravenous solution containing therapeutically effective amounts of SERPI G1 and aminomethylbenzoic and / or ⁇ -aminocaproic acid.
  • the combination is a dosed pharmaceutical composition in the form of an intravenous solution containing therapeutically effective amounts of SERPING1 of aminomethylbenzoic and / or ⁇ -aminocaproic acid and / or tranexamic acid.
  • the combination is a dosed pharmaceutical composition in the form of an intravenous solution administration containing therapeutically effective amounts of SERPING1 and tranexamic acid.
  • the combination of the invention contains one or more pharmaceutical combinations in the form of a solution and one or more pharmaceutical combinations in the form of a lyophilisate.
  • the metered pharmaceutical composition containing one or more antifibrinolytics as an active principle is in the form of a solution
  • the pharmaceutical composition containing the SERPING1 active substance as an active principle is in the form of a lyophilisate
  • the composition in the lyophilisate form is supplemented with a pharmaceutically acceptable solvent placed in a separate pharmaceutically acceptable container.
  • the combination according to the invention contains one or more pharmaceutical compositions in the form of a lyophilisate, it may further comprise a pharmaceutically acceptable solvent or diluent in a separate pharmaceutically acceptable container. It is preferred that said pharmaceutically acceptable solvent or diluent be selected from the group consisting of water for injection, saline or Ringer's solution.
  • the combination is a kit consisting of a pharmaceutical composition comprising a C 1 inhibitor lyophilisate complete with a solution of tranexamic, aminomethylbenzoic and / or ⁇ -amino caproic acid, where both components of the kit may also contain pharmaceutically acceptable additives.
  • a C 1 inhibitor lyophilisate can be obtained by any standard method from a solution containing 20-40 mg / ml C 1 inhibitor; 40-60 mg / ml trehalose; 2-10 mg / ml NaCl; 15-30 mM Na 3 P0 4 , pH 6.8.
  • An amino acid such as tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic, can be used as a solution in water for injection with a concentration of from 10 to 150 mg / ml. Preferably, 50-100 mg / ml.
  • the composition can be further diluted with a 0.9% sodium chloride solution or Ringer's solution.
  • the combination can also be presented in the form of a kit that includes a dosage pharmaceutical composition containing, as an active principle, one or more antifibrinolytics, presented in the form of a solution, and a dosage pharmaceutical composition containing, as an active principle, a substance having SERPINGl activity also presented as a solution.
  • Each pharmaceutical composition that contains a combination of the present invention is preferably presented in at least one pharmaceutically acceptable container, such as, for example, an ampoule or vial.
  • a pharmaceutical composition for the manufacture of a holiday product may be 6 is packaged in a variety of different ways, depending on whether it is intended for emergency events on an outpatient or field basis.
  • a holiday product includes a kit containing a container containing one or more pharmaceutical compositions with the combination of the invention in a suitable form, instructions for use, and, if necessary, a container with a solvent.
  • Suitable containers are known to those skilled in the art and include vials (plastic and glass), ampoules, and the like.
  • the container may also have a device resistant to external influences to prevent careless access to the contents of the package.
  • the container has a label attached to it that describes the contents of the container. The label may also contain appropriate warnings.
  • the product for dispensing includes a kit for sequential administration containing a vial with a solution of tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid and a vial with a solution of C 1 inhibitor, and instructions for use containing an indication of consistent use.
  • the treatment method of the invention provides for both separate and co-administration of the components of the combination of the invention.
  • the interval between the introduction of the components of the combination according to the invention can be 0-60 minutes, i.e. sequential administration of the components of the combination for a short period of time within 1 hour is permissible.
  • the interval between the introduction of the components of the combination is 0-30 minutes.
  • the method of the invention comprises the simultaneous administration of SERPING1 and an antifibrinolytic, preferably tranexamic acid, in the form of an injection.
  • either the attending physician, or the patient as prescribed by the attending physician, or the representative of the junior medical staff as prescribed by the attending physician of the patient administer to the patient the combination according to the invention, following the instructions attached either to the dosage pharmaceutical composition containing one or more antifibrinolytics, or a dosed pharmaceutical composition containing a substance having SERPI G1 activity, either to each of these dosage compositions, or to a dosed pharmaceutical composition a cell containing both a substance having SERPING1 activity and one or more antifibrinolytics, either to a kit containing one or more antifibrinolytics, or to a dosed pharmaceutical composition containing a substance having SERPING1 activity.
  • the specified instruction may explicitly contain or from it may explicitly follow for the specialist that for the treatment of the condition of the body of a mammal, accompanied by one or more phenomena selected from the following: coagulopathy, disorders of fibrinolysis, edema, blood loss, similar phenomena manifested in head trauma, massive blood loss and hemorrhagic shock, one or more antifibrinolytics should be used in conjunction with a substance with SERPING1 activity.
  • said instruction provided it is applied to a pharmaceutical composition comprising a polypeptide with human SERPING1 activity and / or tranexamic acid, may indicate that the polypeptide with human SERPING1 activity and tranexamic acid should be used in combination for treatment of hemorrhagic shock and / or consequences of traumatic brain injury.
  • Factors considered include the specific disorder and clinical condition of the individual patient, the cause of the disorder, route of administration, route of administration, and other factors known to practicing physicians.
  • administration can be carried out by intravenous administration by transfusion, together with crystalloid solutions during standard therapy, as well as by a bolus method by intravenous injection.
  • a substance having the activity of SERPING1 or its analogues or derivatives, such as chimeric or fused proteins, or a functionally active fragment thereof, in combination with an antifibrinolytic selected from tranexamic, aminomethylbenzoic and / or ⁇ -aminocaproic acid or their analogue is administered to patients after the onset of symptoms (edema / swelling of the brain, coagulopathy, impaired fibrinolysis, bleeding) associated with hemorrhagic shock, head injury or other disease accompanied by the onset these symptoms.
  • the duration of therapy using the combination of the present invention varies depending on the severity of the disease to be treated and the condition, and also depending on the potential response of each individual patient. It is assumed that the duration of therapy is determined by the severity of the symptoms. Ultimately, the attending physician decides on the appropriate duration of therapy using the combination of the present invention.
  • the method of treatment of the present invention when applied to hemorrhagic shock, can reduce the risk of death, and preferably includes administering to the mammal (animal or human) experiencing shock a combination of therapeutically effective amounts of SERPING1 and tranexamic acid.
  • a shock-treated mammal is administered a combination of therapeutically effective amounts of SERPING1 and aminomethylbenzoic and / or ⁇ -aminocaproic acid.
  • the present invention is illustrated by the following examples.
  • the authors in the experiment showed that the claimed combination is significantly more effective in increasing the survival of experimental animals in the model of acute blood loss (hemorrhagic shock), in the model of closed head injury, than standard infusion therapy with crystalloids or each of the active components of the combination separately.
  • one of the possible mechanisms of action of the claimed combination may be the suppression of coagulopathy-related hyperfibrinolysis in an in vitro model of secondary fibrinolysis.
  • the claimed combination effectively counteracts the development of cerebral edema, and, as a result, reduces the delayed effects of TBI, such as neuropathology, impaired behavior and cognitive functions.
  • EXAMPLE 1 Obtaining recombinant human SERPING1 (rhSERPINGl) and its variants
  • the expression of recombinant human SERPI G1 (rhSERPINGl) and its modified forms (see Table 1) was carried out by introducing an expression plasmid containing the DNA sequence encoding the human SERPING1 and / or part thereof under the control of a strong promoter into a bacterial or eukaryotic host line, by transfection of cells. Electroporation was used as a transfection method. As a result, the introduced sequence can be stably integrated into the host genome, or can be a transiently expressing host line.
  • the expression plasmid also carried the gene for resistance to puromycin, ampicillin and ensured the resistance of the transfected cell line to a selective marker.
  • rhSERPINGl protein or its variants a eukaryotic cell line or bacterial shamm producer expressing rhSERPINGl or its variants was used.
  • various chromatography and filtration methods were used.
  • compositions were used for further experiments and administration to animals.
  • SERPING1 or its fragments The specific activity of SERPING1 or its fragments is the inhibition of serine proteases, and in particular proteases, which play a key role in the complement system (C1g and C Is). The presence of this activity confirms the functionality of SERPING1 or its fragments, and, as a result, participation in the control of the blood coagulation system, kalekreinovoy system and fibrinolysis.
  • a standard chromogenic analysis technique was used. For the experiment, the TECHNOCHROM C1-INH kit, # 5345003 (Technoclone Gmbh) was used.
  • This method is based on the inhibition of an excess of the resulting complex of C 1 esterase with a C1 esterase inhibitor, followed by hydrolysis of the chromogenic substrate with an excess of C 1 esterase.
  • the amount of paranitroaniline released during hydrolysis, and measured at a wavelength of 405 nm, is inversely proportional to the activity of the C 1 inhibitor present in the reaction medium.
  • polypeptides with a preserved serpin domain does not differ from plasma proteins (Berinert®, CSL Behring), which indicates the functional activity of these polypeptides.
  • EXAMPLE 3 The synergistic effect of the combination of rhSERPINGl and tranexamic acid in relation to fibrinolysis in vitro.
  • FIG. 1A shows a typical thromboelastogram of clot formation in activated human plasma.
  • t-PA tissue plasminogen activator
  • rhSERPING rhCHNH 2 3-5oo
  • rhSERPINGl (CI INH 120 -500) truncated at the amino terminus comprising serpinovy domain effectively potentiates the antifibrinolytic effect of tranexamic acid.
  • EXAMPLE 4 Inhibition of inflammatory cytokines in an ex vivo septic shock model.
  • cytokines in frozen plasma was determined by ELISA (Quantikine SixPak, R&D Systems).
  • concentrations of the following cytokines were determined: TNF-alpha, HH-lp / HJl-lF2, IL-6.
  • rhCHNH 2 3-5oo or CHNHno-soo was added to whole blood significantly reduced the LPS-induced release of IL-6 (Fig. 5).
  • the addition of 23 rhCHNH -5oo or variants thereof that retain functional activity inhibits the release of certain inflammatory cytokines, namely IL-6 and IL- ⁇ , which attract neutrophils to the site of infection and inflammation, causing a further increase in inflammation.
  • the proinflammatory cytokines listed above play an important role in the development of inflammation caused by cerebral edema, as well as in the development of septic shock, which is often a consequence of hemorrhagic shock.
  • EXAMPLE 5 Model of carrageenan-induced hind paw edema of the mouse.
  • the inflammatory response is usually determined by the increase in the size of the hind paw (edema) into which the carrageenan was introduced.
  • Maximum edema develops within 10 minutes after the introduction of carrageenan and at the same time there is a release of specific molecules characteristic of the inflammatory cascade.
  • the degree of edema can also be assessed by measuring capillary blood flow in the paw - the stronger the swelling, the weaker the blood flow.
  • edema was induced by subcutaneous injection of 100 ⁇ l of 1% carrageenan ( ⁇ -carrageenan type IV, Sigma) in saline into the right hind paw. The left hind paw was used as a control.
  • rhSERPINGl 500 IU / kg
  • pdSERPINGl 500 IU / kg
  • diclofenac 3 mg / kg, manufactured by Hemofarm AD, Serbia
  • Ringer's solution was administered intravenously .
  • the dynamics of capillary blood flow in the paw for 3 hours was measured using the laser-Doppler method.
  • the level of the pro-inflammatory cytokine IL-6 was measured.
  • EXAMPLE 6 Pharmaceutical combination of SERPING1 and tranexamic acid.
  • compositions for administration were prepared as follows. A. Solution for administration Prepare the following composition:
  • Component Composition 1 Composition 2 Composition 3
  • NaH 2 P0 4 1.38 mg / ml 1.38 mg / ml 1.38 mg / ml trehalose 56.7 mg / ml 56.7 mg / ml 56.7 mg / ml
  • the calculated amount of trehalose and sodium chloride is weighed and dissolved with stirring in the required amount of 20 mm sodium phosphate buffer with a pH of 6.8. Then, the calculated amount of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid powder is added to the solution, mixed and the pH is checked. If necessary, the pH is adjusted to a value of 6.8 using a solution of 1M NaOH or 1M HC1. To the resulting solution add the required amount of rhSERPINGl obtained in Example 1, and mix gently. The solution was adjusted to a certain volume with water for injection, filtered through a 0.22 micron membrane filter and collected in a container under sterile conditions.
  • the resulting liquid composition can be administered by any means intravenously: in a jet, drip, or bolus; the composition may be diluted with Ringer's solution and other crystalloids.
  • subsequent administration can be carried out either in parallel with infusion therapy (dropper), or independently of infusion therapy.
  • a solution of the preparation is prepared by the method described in section A, but without the addition of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid, placed in sterile vials and sealed.
  • a solution of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid is prepared separately at a concentration of 50 mg / ml.
  • the drug is administered intravenously, sequentially (before or after) or simultaneously with the intravenous administration of a solution of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid, or a combination thereof.
  • the intravenous solution obtained in section A is lyophilized using the following method:
  • the solution is reconstituted at room temperature by adding the necessary amount of water for injection, physiological saline or Ringer's solution to the vial and shaking thoroughly until the contents of the vial are completely dissolved. Further administration to the patient is carried out as described in section A. G. Solvent kit
  • a solution of the preparation is prepared by the method described in section A, but without the addition of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid, and its lyophilization is carried out under the conditions described in section B.
  • the finished lyophilisate is placed in sterile vials and sealed.
  • a solution of tranexamic, aminomethylbenzoic or ⁇ -aminocaproic acid with a concentration of 10-100 mg / ml is prepared by dissolving the powder of the corresponding acid in water for injection with stirring. The resulting solution is filtered through a sterile filter and poured into vials.
  • a solution of the corresponding acid is drawn with a syringe, injected into a vial with a lyophilisate and gently mixed until the contents of the vial are completely dissolved.
  • the prepared rhSERPINGl solution with an amino acid can be additionally diluted with 0.9% sodium chloride solution or Ringer's solution to the desired concentration.
  • EXAMPLE 7 Evaluation of the effectiveness of the claimed composition on a rat model of hemorrhagic shock.
  • Rats were anesthetized and caused hemorrhagic shock by incision of the femoral artery.
  • the volume of blood loss lasting 20-25 minutes was 50% of the estimated total circulating blood volume (BCC).
  • BCC for rats was calculated by the equation:
  • EXAMPLE 8 The effectiveness of the claimed combination in reducing damage to the intestinal epithelium in a model of hemorrhagic shock in rats.
  • the excised segments of the small intestine were embedded in paraffin, sliced (5 ⁇ m), and stained with hematoxylin-eosin. Sections were analyzed using a light microscope.
  • Goblet cells secrete mucus, which forms the intestinal barrier.
  • the intestines from group 2 showed the most serious damage (Medium 4 ⁇ 1.2) (Fig. 9), with frequent complete exposure or loss of villi, increased cellularization or decay of lamina intestinal; a decrease in the number or complete loss of goblet cells.
  • tranexamic acid intestinal damage was significantly reduced (average degree 1, 9 ⁇ 0.7).
  • the use of rhSERPINGl also reduced intestinal damage, to approximately the same degree (average degree 1.7 ⁇ 0.5).
  • the villi in the rhSERPINGl therapy group were noticeably shorter and thinner than in the control group without hemorrhagic shock or in the group with tranexamic acid therapy.
  • mucosal damage was least pronounced among groups with hemorrhagic shock (average degree 0.4 ⁇ 0.7). (Fig. 9, 10). In this case, villus edema was not observed and the number of goblet cells almost did not change.
  • EXAMPLE 10 rhSERPINGl, tranexamic acid or a combination thereof reduces cerebral edema caused by traumatic brain injury.
  • CCT craniocerebral trauma
  • Installation for applying closed CCT is a steel rack mounted on a metal platform.
  • Two metal rods are attached to the rack using a hinge system located in parallel planes and used to fix a sterile polypropylene pipe with an inner diameter of 12 mm.
  • the sterile polypropylene pipe was secured with a hinge system so that its height and angle with respect to the lower platform and the metal stand could change. Through this polypropylene pipe, a load was dropped to deliver a focal blow to a given area of the head.
  • mice were anesthetized with 1.5% isoflurane anesthesia. Mice breathed on their own, their tracheas were not intubated. The surgical stage of anesthesia was determined by the absence of a corneal reflex in animals. Anesthetized animals were fixed in a stereotactic setup for mice "Narishige” (Japan). The animal’s head was pressed against a steel plate to prevent fracture of the jaw and achieve a horizontal arrangement of the cranial vault to the end portion of the load, as well as to reduce the dispersion of impact energy.
  • a longitudinal longitudinal incision (1 cm) was made on the scalp free of hair and treated with an aseptic solution, the coronal and sagittal sutures of the skull were found and the site of the left-sided focal injury was determined (bregma 2 mm, 2 mm lateral from the midline).
  • the load was a steel cylinder weighing 270 g with a blunt impact surface with a silicone tip with a diameter of 4 mm, which protects from penetrating fracture of the bones of the skull at the site of application of the focal injuries.
  • the load rose to a height of 5 cm and was dropped through a polypropylene pipe, striking a given area. After injury, the bones of the skulls of mice were examined for fractures.
  • mice with skull fractures or severe hemorrhage were excluded from further research.
  • the skin of animals was tightly sutured with surgical thread (0.2 mm), the suture was treated with an antiseptic solution.
  • the temperature of the animals was maintained at 36.5 - 37.5 ° C using an electric heating pad. After simulating CCTV, the mice were left to recover from anesthesia, then returned to the living cells. The animals were provided with postoperative care and free access to water and food.
  • Preparations and a 0.9% NaCl solution in the negative control group were administered intravenously, once 30 minutes after the simulation of CCI.
  • the volume of injection solutions was 0.2 ml.
  • Brain edema indices were determined from images of diffusion magnetic resonance imaging (MRI) maps obtained using the high-field MRI method on an Agilent Technologies DD2-400 9.4 T (400 MHz) tomograph with a volume coil M2M (HI), T2-weighted images with a pulse sequence MGEMS (multi gradient echo multi slice). The magnitude of cerebral edema was evaluated in all animals after 4 hours, 8 hours, 24 hours, 48 hours, 72 hours, 96 hours after head injury.
  • MRI diffusion magnetic resonance imaging
  • the repetition time was 1000 ms
  • the number of accumulations was 4
  • the number of slices was 15, the projection of the slices was axial
  • the thickness of one slice was 1 mm
  • the field of view - 20x20 mm2 matrix size - 128x128.
  • Diffusion parameters amplitude - 23.50 G / cm
  • the pulse duration was 6 ms
  • the time between pulses was 12 ms
  • the b factor was chosen to be 1500 s / mm2
  • the diffusion type was slice.
  • the total duration of the sequence was 17 min 34 sec.
  • the calculation of the volume of edema (in mm 3 ) with a closed head injury was performed using the ImageJ program.
  • a region with a hyper-intensive signal corresponding to tissue edema
  • a comparative analysis was performed with a map of the diffusion coefficient to specify the size of the focus (the same region on the map is characterized by a hypo-intense signal).
  • the use of the rhSERPINGl monopreparation in the post-traumatic period significantly reduces or prevents cerebral edema within 4 hours after CCT, and continues to reduce edema after 2-3 days.
  • tranexamic acid monotherapy in the post-traumatic period (Group 3) significantly reduces or prevents cerebral edema within 4 hours after CCT, is almost 2 times more effective than rhSERPINGl monotherapy and continues to reduce swelling after 2 to 3 days.
  • rhSERPI Gl and tranexamic acid preparations (Group 4) also effectively reduces or prevents edema at the 4th hour of the post-traumatic period, as in the case of tranexamic acid or rhSERPINGl monopreparations, however, the edema volume reduction curve is more pronounced. So, by 4 days of the post-traumatic period, when using combination therapy, the edema reaches the same size as monotherapy with tranexamic acid, with large volumes of the edematous region at 4 hours of observation.
  • rhSERPINGl is able to enhance the therapeutic effect of tranexamic acid in the late stages of development of the effects of closed traumatic brain injury in the form of cerebral edema.
  • EXAMPLE 11 The therapeutic effect of hSERPINGl, tranexamic acid, or a combination thereof, on the restoration of neurological functions after head injury.
  • the magnitude of the neurological deficit was estimated 1, 3, 5, 7, and 9 days after the CCT according to all the criteria of the NSS scale (Buresh Y., Bureshova O., Houston J.P. Materials and basic experiments on the study of the brain and behavior. M .: Higher School, 1991. - 397 s, Chen, Constantini et al. 1996) on each day of testing in all animals.
  • mice treated with rhSERPINGl, tranexamic acid or a combination of rhSERPINGl and tranexamic acid (Groups 2, 3 and 4, respectively), in contrast to the control group (Group 1), there was a significant decrease in neurological deficit relative to 1 days (Table 6 and Fig. 12).
  • EXAMPLE 12 The therapeutic effect of hSERPINGl, tranexamic acid or a combination thereof on the restoration of behavioral functions after head injury
  • Modeling of moderate CCST disturbed the structure of the reflex behavior of animals, significantly reducing the orientational research and motor activity of animals.
  • the duration of the VDA reactions also significantly decreased relative to the initial value in all experimental groups, except for the group of mice with the combined therapeutic use of rhSERPlNGl and tranexamic acid preparations (Table 7 and Fig.13).
  • the duration of the research behavior reactions was significantly longer than in the groups with rhSERPlNGl or tranexamic acid monotherapy, which indicates a more pronounced therapeutic effect of the drugs when used together.
  • the duration of the VDA reactions in the groups with rhSERPlNGl monotherapy or tranexamic acid did not statistically significantly differ from this indicator in the control group, which may be due to the presence of paresis of the limbs in animals and, as a consequence, impaired functions of maintaining equilibrium and coordination of movements.
  • the duration of the acts of tentative research behavior in the group with the administration of the drug rhSERPlNGl after modeling of CCI was significantly higher than the duration of the reactions in the group with monotherapy with tranexamic acid.
  • EXAMPLE 13 The therapeutic effect of hSERPINGl, tranexamic acid or a combination thereof on memory function after head injury
  • the latent time of transition to the dark compartment of the camera when reproducing the conditioned passive avoidance reflex (passive avoidance reaction) on the 10th day of the post-traumatic period did not differ from the transition time during training (Table 10 and Fig. 16), that is, the long-term memory function was impaired.
  • the latent time spent by the mice in the light compartment of the chamber during reproduction of passive avoidance reaction was significantly longer than during training, as well as the indicator of the control group, which indicates the preservation of the memorial trail in animals and the ability to reproduce it.
  • the latent time of transition to the dark compartment of the chamber was statistically significantly longer compared to the same indicator in the group with monotherapy with tranexamic acid, which indicates the ability of rhSERPINGl to enhance the optimizing effect of tranexamic acid on the restoration of mnestic processes with traumatic brain damage.
  • CCT leads to the development of cerebral edema at the site of damage, impaired neurological functions, research and locomotor activity of animals, as well as impaired memory functions in the post-traumatic period.
  • the combined therapeutic administration of rhSERPINGl and tranexamic acid normalizes memory processes, contributing to the actualization of traces of long-term memory when reproducing a conditioned reflex acquired before traumatic brain damage.
  • the combined use of rhSERPINGl and tranexamic acid drugs mutually enhances or complements the therapeutic effect of each of the drugs on reducing edema, neurological, behavioral and mnestic dysfunctions of the central nervous system resulting from CCI.
  • the present invention can be used in medicine for the treatment of diseases accompanied by blood loss, impaired fibrinolysis, coagulopathy, edema, in particular, the consequences of head injury or hemorrhagic shock.
  • the present invention can be used to treat other diseases accompanied by blood loss, impaired fibrinolysis, coagulopathy, and edema.
  • the present invention can also be used in the pharmaceutical industry to obtain pharmaceutical compositions, finished dosage forms and kits containing a combination according to the invention, for the treatment of diseases accompanied by blood loss, impaired fibrinolysis, coagulopathy, edema, in particular, consequences of head injury or hemorrhagic shock.
  • SEQ ID N2I is a full-length rhSERPlNGl sequence with cleavable leader peptide (amino acid residues 1-22).
  • SEQ ID N ° 2 is the sequence of rhC HNH 2 3-i22 truncated at the carboxy terminus of rhSERPlNGl, without a serpin domain, with a cleavable leader peptide (amino acid residues 1-22).
  • SEQ ID j ⁇ ° 4 is the sequence of rhCHNH465ART vKV, variant rhSERPlNGl with mutations in the active center (amino acid residues 465-467 of Ala-Arg-Thr replaced by Val-Lys-Val) with cleavable leader peptide (amino acid residues 1-22).

Abstract

L'invention concerne la médecine et peut être utilisée en industrie pharmaceutique et se rapporte à une utilisation combinée d'un anti-fibrinolytique et d'une substance présentant une activité SERPING1 pour traiter l'état d'un mammifère qui est accompagné d'une ou plusieurs manifestations défavorables suivantes : coagulopathie, perturbation de la fibrinolyse, embolie, perte de sang, phénomènes analogues se manifestant lors d'un traumatisme crânien et d'un choc hémorragique, par l'élimination et/ou une expression moindre des phénomènes indiqués ici. On peut utiliser en tant que fibrinolytique l'acide tranexamique, benzoïque ou aminocaproïque ainsi que son analogue fonctionnel. L'invention permet de réduire sensiblement la mortalité provoquée par un choc hémorragique, une perte de sang ou réduire l'œdème du cerveau, diminuer ou éliminer les états neurologiques, des troubles cognitifs ou comportementaux qui peuvent survenir suite à un traumatisme crânien.
PCT/RU2016/000626 2015-09-18 2016-09-15 Thérapie combinatoire pour traiter le choc hémorragique et les suites d'une traumatisme craniocérébral WO2017048157A1 (fr)

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