B-beta-15-42 for treating viral endotheliitis

Abstract

The present invention is based on fibrin-derived peptides, which are therapeutic compounds for treating inflammatory complications of virally caused diseases, such as diffuse inflammation of the endothelium, also known as systemic endotheliitis or vasculitis and related disorders. The use of fibrin-derived peptides and analogs of these compounds has resulted in surprisingly effective patient recovery.

Description

[Technical Field]

[0001] This invention is based on fibrin-derived peptides, which are therapeutic compounds for treating inflammatory complications of viral diseases, such as diffuse inflammation of the endothelium, also known as systemic endotheliitis or vasculitis and related disorders. The use of certain fibrin-derived peptides and analogs of these compounds has resulted in remarkably effective patient recovery. [Background technology]

[0002] In December 2019, a cluster of viral pneumonia cases associated with a novel coronavirus called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China.[1] The clinical range of this new disease is varied, with symptoms ranging from asymptomatic infection to a severe, progressive course leading to respiratory failure or even death.[2] Critical patients, who comprise about 2–9% of all infected individuals, progress from pneumonia and hypoxemia to multi-organ failure, with limited options for acute treatment.[3] Gathering and disseminating information on potential experimental treatment options for this novel viral infection, for which no specific therapies proven beyond supportive care are available, is essential to enabling rapid treatment. Currently, many drugs show in vitro activity against different coronaviruses, but there is no clinical evidence to support the efficacy and safety of any drug against any coronavirus in humans, including SARS-CoV-2.[4]

[0003] However, numerous off-label and humanitarian use therapies demonstrating antiviral or anti-inflammatory properties in vitro have been tested worldwide, including chloroquine, hydroxychloroquine, azithromycin, lopinavir, ritonavir, favipiravir, remdesivir, ribavirin, interferon, steroids, and anti-IL-6 inhibitors. Nevertheless, no proven effective therapies have been reported to date.[5,6] Low kinase inhibitors have been proposed for the treatment of SARS-CoV-2-induced acute respiratory distress syndrome.[7] In particular, the increase in angiotensin-converting enzyme 2 (ACE2) associated with low kinase inhibition has been described.[7]

[0004] Therefore, the reuse of drugs that are already available, clinically safe, have been tested for adverse reactions, and are (ideally) approved may be essential for the rapid treatment of COVID-19 and / or other viral diseases, or the inflammatory complications caused by each, in infected patients.

[0005] FX-06 (or "FX06") is a peptide (amino acids 15-42) derived from the naturally occurring Bβ polypeptide chain of human fibrin, which binds to the transmembrane adhesion receptor vascular endothelial (VE) cadherin. Fibrin is an insoluble plasma protein produced by thrombin-mediated proteolytic cleavage from the soluble parent protein fibrinogen, a protein complex composed of three pairs of polypeptide chains: Aα, Bβ, and γ. The proteolytic conversion of fibrinogen to fibrin releases two fibrinopeptides, A and B, derived from the Aα and Bβ polypeptide chains, respectively. Cleavage of fibrinopeptide B from the Bβ chain exposes amino acids 15-42 on the Bβ polypeptide chain of fibrinogen, thereby enabling fibrin and its degradation products to bind to VE cadherin.

[0006] Despite being naturally present in the blood, the Bβ15-42 peptide exhibits lower affinity for VE-cadherin binding compared to the endogenous pro-inflammatory fibrin E1 fragment. However, application of Bβ15-42 at hyperphysiological doses has been demonstrated to reduce leukocyte migration across the endothelial barrier, an effect associated with a reduction in infarct size in animal models of acute myocardial infarction. This finding led to the development of FX-06, which is involved in the administration of Bβ15-42 at hyperphysiological doses. In addition to binding to VE-cadherin, FX-06 induces VE-cadherin-mediated intracellular signaling events in endothelial cells, stabilizing the actin cytoskeleton and adhesion junctions. FX-06-induced VE-cadherin signaling can maintain endothelial barrier function, thereby reducing capillary leakage; therefore, FX-06 is also considered to have potential therapeutic benefits in the treatment of diseases associated with endothelial barrier breakdown. At the time of publication, FX-06 had completed a Phase 2 trial for the prevention of ischemia / reperfusion injury (ClinicalTrials.gov identifier: NCT00326976; FIRE) and was undergoing preclinical evaluation for the treatment of capillary leak syndrome.

[0007] During the 2014 Ebola virus outbreak, FX06 treatment was used empirically as a treatment in patients with severe Ebola virus disease.[8] FX06 binds to endothelial cells and prevents leukocyte migration through endothelial cell gap junctions.[9] It maintains endothelial integrity. FX06 is known for its anti-inflammatory properties[10,11] and has already been investigated in clinical trials, demonstrating a well-tolerated and compelling efficacy with a favorable safety profile.

[12]

[0008] Treatment of dengue shock syndrome induced by the dengue virus with FX06 is described, in which FX06 helps maintain the endothelial barrier

[13] . In particular, FX06 was found to antagonize stress-induced RhoA activation [13,14]. [Overview of the Initiative] [Problems that the invention aims to solve]

[0009] Therefore, in particular with respect to the COVID-19 pandemic, it is an objection to the present invention to reuse drugs that are currently undergoing clinical trials for other related diseases in order to treat inflammatory complications caused by the virus. [Means for solving the problem]

[0010] In general and in a brief description, the main aspects of the present invention can be described as follows:

[0011] In a first embodiment, the present invention relates to a compound used for treating inflammatory disorders of the endothelium in a subject, wherein the compound is fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof, and the treatment comprises the step of administering the compound to the subject in a therapeutically effective amount.

[0012] In a second embodiment, the present invention relates to a compound used for treating inflammatory complications induced by or resulting from viral infections and / or viral diseases in a subject, wherein the compound is fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof, and the treatment comprises the step of administering the compound to the subject in a therapeutically effective amount.

[0013] In a third embodiment, the present invention relates to a method for treating inflammatory disorders of the endothelium in a subject, the treatment comprising administering to the subject a therapeutically effective amount of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof.

[0014] In a fourth embodiment, the present invention relates to a method for treating inflammatory complications induced by or resulting from viral infections and / or viral diseases in a subject, the treatment comprising administering to the subject a therapeutically effective amount of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof.

[0015] In a fifth aspect, the present invention further relates to the use of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative or physiologically acceptable salt thereof in the manufacture of a medicament for treating one of the disorders and / or complications of the first to fourth aspects of the present invention. [Brief explanation of the drawing]

[0016] [Figure 1] This figure shows the norepinephrine dosage for all patients in Example 1 over the first 14 days of hospitalization. [Figure 2] This figure shows the oxygen supply index for all patients in Example 1 over the first 14 days of hospitalization. [Figure 3] This figure shows chest X-rays of Patient 1 in Example 1 on day 3 (left), day 7 (center), and day 14 (right). [Figure 4] This figure shows chest X-rays of Patient 2 in Example 1 on day 1 (left), day 6 (center), and day 14 (right). [Figure 5] This figure shows chest X-rays of Patient 3 in Example 1 on day 1 (left), day 6 (center), and day 10 (right). [Figure 6A-6C] This figure shows inflammatory markers in all patients in Example 1 over a 14-day period from the start of hospitalization; A: c-reactive protein; B: interleukin-6 (IL-6); C: procalcitonin. [Figure 7] This figure shows chest X-rays from day 0 (left), day 4 (center), and day 7 (right) after the first administration of FX06 in Example 2 (Patient 1). [Figure 8] This figure shows the ventilation parameters of patient 1 in Example 2. [Figure 9] This figure shows chest X-rays taken on day 1 (left) and day 4 (right) after the start of the FX06 procedure (Patient 2 in Example 2). [Figure 10] This figure shows the ventilation parameters of patient 2 in Example 2. [Figure 11] This figure shows the serum inflammatory markers of patient 2 in Example 2. [Figure 12] This figure shows the ventilation and oxygen supply parameters for patient 3 in Example 2. [Figure 13] This figure shows the serum inflammatory markers of patient 3 in Example 2. [Figure 14] This figure shows chest X-rays taken on day 2 (left) and day 8 (right) after the first application of FX06 (Patient 3 in Example 2). [Modes for carrying out the invention]

[0017] The elements of the present invention will be described below. These elements are described by specific embodiments; however, it should be understood that additional embodiments can be created by combining them in any manner and in any number. The various examples and preferred embodiments described should not be construed as limiting the invention to only the embodiments expressly describing the invention. This description should be understood as supporting and encompassing embodiments that combine two or more expressly described embodiments or combine one or more of the expressly described embodiments with any number of disclosed and / or preferred elements. Furthermore, any permutations and combinations of all elements described in this application should be considered disclosed by this description unless indicated otherwise in the context.

[0018] In a first embodiment, the present invention relates to a compound used for treating inflammatory disorders of the endothelium in a subject, wherein the compound is fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof, and the treatment comprises the step of administering the compound to the subject in a therapeutically effective amount.

[0019] In one alternative first embodiment, and as further described, defined, claimed or otherwise disclosed herein, the present invention relates to a method for treating an inflammatory disorder of the endothelium in a subject, the method comprising the step of administering to the subject a fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof.

[0020] As described in another related first embodiment, and as further described, defined, claimed or otherwise disclosed herein, the present invention relates to the use of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative or physiologically acceptable salt thereof for the production of a medicament for treating endothelial inflammatory disorders in a subject.

[0021] The terms “subject,” “individual,” “host,” and “patient” are used interchangeably herein to refer to mammals, including but not limited to mice (rats, house mice), cats, non-human primates (e.g., monkeys), humans, dogs, ungulates, etc. In some embodiments, “subject” is a human and may also be referred to as “patient.”

[0022] In this specification, the term "endothelium" refers to the layer of cells that line the inner surface of blood vessels and form capillaries. The term "endothelial cell" refers to the differentiated cells that form the epithelial endothelium and line the inner wall of blood vessels. Therefore, in some embodiments, endothelium refers to one or more endothelial cells of a vascular system. Inflammation of the endothelium, which is systemic or systemic endotheliitis.

[0023] In some preferred embodiments of the present invention, the inflammatory disorder of the endothelium is diffuse inflammation of the endothelium, preferably endotheliitis (or vasculitis).

[0024] In further embodiments, inflammatory complications associated with endothelial inflammatory disorders and / or viral diseases such as COVID-19 may be vasculitis, e.g., systemic vasculitis. The term “vasculitis” refers to inflammation of blood vessels. The outcomes of vasculitis depend on the size, location, and number of vessels involved. When small or medium-sized arteries are involved, infarction of the tissues supplied by the vessels may occur (for example, coronary vasculitis can lead to a heart attack), but when very small vessels such as capillaries are involved, the effects are less severe. An exception is widespread focal vasculitis, such as that occurring in the kidneys, which can lead to glomerulonephritis. The vasculitis of the present invention may include small vessel vasculitis (Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis, Henoch-Schönlein purpura, essential cryoglobulinemia vasculitis), medium vessel vasculitis (cutaneous leukocytoclastic vasculitis), and large vessel vasculitis [polyarteritis nodosa, Kawasaki disease, giant cell (temporal) arteritis, Takayasu's arteritis].

[0025] "Therapeutically effective dose" or "effective dose" means the amount of a compound (such as fibrin-derived peptide B beta 15-42 and / or at least one of its functional derivatives or physiologically acceptable salts thereof) that, when administered to a mammal or other subject to treat the disease, is sufficient to achieve that treatment of the disease. The "therapeutically effective dose" will vary depending on the compound, the disease and its severity, and the age, weight, etc., of the subject being treated.

[0026] In some embodiments, an "effective amount" of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative or physiologically acceptable salt thereof is the amount administered in one or more doses to an individual having an inflammatory disorder of the endothelium, e.g., endotheliitis. For example, in some embodiments, an "effective amount" of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative or physiologically acceptable salt thereof is the amount administered in one or more doses to an individual having an inflammatory disorder of the endothelium, e.g., endotheliitis, and is effective in reducing such inflammation in one or more cells of the endothelium being treated.

[0027] This disclosure provides compounds and methods for treating endothelial inflammatory complications associated with viral infections, wherein the viruses are members of the families Filoviridae or Coronaviridae, and the method comprises the step of administering an effective amount of fibrin-derived peptide B beta 15-42 peptide, or a derivative or salt thereof, to an individual (subject) infected with a member of the family Coronaviridae. The family Coronaviridae includes, for example, coronaviruses, such as human coronavirus 229E (HCoV-229E), human coronavirus OC43 (HCoV-OC43), Middle East respiratory (MERS) virus, and SARS-CoV [the causative agent of severe acute respiratory syndrome (SARS)], which cause upper respiratory tract infections, lower respiratory tract infections, and gastroenteritis.

[0028] According to preferred embodiments of the present invention, fibrin-derived peptide B beta 15-42 can be administered as the sole active ingredient or in combination with at least one derivative thereof. Naturally, at least one derivative of fibrin-derived peptide B beta 15-42 can also be administered as the sole active ingredient or in combination with fibrin-derived peptide B beta 15-42.

[0029] Fibrin-derived peptide B beta 15-42 and / or at least one derivative thereof may be administered to subjects in need by any means known to those skilled in the art, including intravenous, subcutaneous, intramuscular, and mucosal administration. Therefore, formulations may be formulated for administration via intravenous, subcutaneous, intramuscular, and mucosal routes. Mucosal routes may include, but are not limited to, pulmonary, nasal, sublingual, or oral routes.

[0030] For intravenous, subcutaneous, or intramuscular administration, the formulation may be provided as a sterile solution, suspension, or emulsion. The formulation may be administered by injection or infusion. For mucosal administration, the formulation may be provided as an aqueous spray and may be applied directly by a spray container or inhaler. Alternatively, the formulation may be administered to the mucous membrane as an aqueous gel.

[0031] Fibrin-derived peptide B beta 15-42 and / or at least one derivative thereof may be provided in liquid or solid dosage form. Both components may also be portions of lyophilized agents (solid dosage form) that can be combined with a buffer or physiological saline before administration to a subject. Alternatively, the components may be portions of a liquid formulation that may include oils, polymers, vitamins, carbohydrates, amino acids, salts, buffers, albumin, surfactants, or fillers. Typical carbohydrates include monosaccharides, disaccharides or polysaccharides, or sugars or sugar alcohols such as water-soluble glucans. Sugars or glucans may include fructose, dextrose, lactose, glucose, mannose, sorbose, xylose, maltose, sucrose, dextran, pullulan, dextrin, alpha and beta cyclodextrin, soluble starch, hydroxyethyl starch, and carboxymethylcellulose, or mixtures thereof. "Sugar alcohols" are defined as C4-C8 hydrocarbons having an -OH group, and include galactitol, inositol, mannitol, xylitol, sorbitol, glycerol, and arabitol. These sugars or sugar alcohols mentioned above may be used individually or in combination. In some embodiments, buffers may be used in the composition to minimize the pH change of the solution before lyophilization or after reconstitution. Any physiological buffer may be used, but in some cases, it may be selected from or a mixture thereof of citrate, phosphoric acid, succinate, and glutamate buffers.

[0032] The compounds of the present invention are effective at doses of 0.001 mg / kg body weight to 500 mg / kg body weight, preferably 0.1 mg / kg to 50 mg / kg.

[0033] In alternative embodiments of fibrin-derived peptide B beta 15-42 and / or at least one derivative thereof, subjects are administered daily doses of 100 mg to 1000 mg, preferably 150 mg to 800 mg, more preferably 200 mg to 600 mg, most preferably 300 mg to 500 mg, and more preferably approximately 300 mg, approximately 400 mg, approximately 500 mg, or approximately 600 mg. Furthermore, in additional or other embodiments, fibrin-derived peptide B beta 15-42 and / or at least one derivative thereof are administered in a single daily dose, or preferably in two separate (preferably equivalent) daily doses within an interval of 1 hour, preferably 30 minutes, most preferably 10 minutes. In some embodiments, administration to subjects may be carried out by intravenous (bolus) injection or by intravenous infusion, for example, by infusion of a therapeutically effective amount over 1 to 6 hours. In another alternative embodiment, the therapeutically effective dose of the compound of the present invention is administered by continuous intravenous infusion over 1 to 10 hours, preferably about 3 to 6 hours.

[0034] The treatment described herein, using the fibrin-derived peptide according to the present invention, or any derivative or salt thereof, is advanced for a sufficient time to reduce endothelial inflammation, or at least for a time to begin normalizing the signs of inflammation, but in a preferred embodiment, the treatment is continued for 1 to 10 days, preferably 3 to 7 days.

[0035] In any one of the embodiments disclosed herein, the individual is a human being approximately 1 month to approximately 6 months old, approximately 6 months to approximately 1 year old, approximately 1 year to approximately 5 years old, approximately 5 years to approximately 12 years old, approximately 13 years to approximately 18 years old, approximately 18 years to approximately 25 years old, approximately 25 years to approximately 50 years old, approximately 50 years to approximately 75 years old, or over 75 years old. In some embodiments, the individual has a chronic lung disease (e.g., emphysema, chronic bronchitis, asthma, cystic fibrosis, bronchiectasis, COPD, or interstitial lung disease), or other risk factors for a poor prognosis such as cardiovascular disease, diabetes, or obesity. In some embodiments, the individual has pneumonia in addition to coronavirus infection, and the pneumonia is caused by a coronavirus (preferably SARS-CoV-2) or bacterial infection. In some embodiments, the human subject is immunocompromised.

[0036] Subjects treated with the fibrin-derived peptide or any derivative or salt thereof according to the present invention are, in some preferred embodiments, distinguished by any one or any combination of the following clinical parameters: Coronavirus infection, preferably SARS-CoV-2, infectious disease; ·PaO2 / F i O2 < 300; and / or • The patient received tracheal intubation and mechanical ventilation within 72 hours prior to initiating the procedure. • LDH (serum) level > 365 U / L • High-sensitivity CRP (serum) value > 40 mg / mL, and / or Lymphocyte count <15%.

[0037] In the context of the present invention, fibrin-derived peptide B beta 15-42 is a peptide preferably derived from the amino acid sequence GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID NO: 1). Such peptides will be referred to in this disclosure as "FX06" or "FX06 peptide".

[0038] In the context of the inventions disclosed herein, a “derivative” of FX06 is preferably a peptide having at most three, preferably two, and more preferably at most one amino acid substitutions, deletions, and / or additions compared to the amino acid sequence shown in SEQ ID NO: 1, wherein such substitutions, deletions, and / or additions do not affect the positions of the first four amino acids in SEQ ID NO: 1.

[0039] Other derivatives of FX06 that are considered to be included in this disclosure are the derivatives and analogues of FX06 specifically disclosed in WO2019 / 011879. A description of such derivative analogues is provided below:

[0040] The "derivatives" of fibrin-derived peptide B beta 15-42 may contain one or more amino acid changes compared to the wild-type peptide. Preferably, the first four amino acid residues of the derivative are identical to those of the wild-type peptide. The N-terminus of the derivative is preferably a free amino group, but the C-terminus may be modified by the addition of an organic group such as polyethylene glycol (PEG). The derivatives of the present invention may contain 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 amino acid exchanges compared to the wild-type peptide. The derivatives may be monomers, dimers, trimers, or tetramers of the modified or wild-type fibrin-derived peptide B beta 15-42, so that the monomers of the above-mentioned multimers are linked to each other by disulfide bonds of cysteine ​​residues, for example, or other chemical moieties that form bridges between monomers. The derivatives of the present invention exhibit properties that inhibit, treat, and / or prevent inflammatory disorders of the endothelium and / or inflammatory complications associated with viral diseases such as COVID-19.

[0041] In further and some preferred embodiments, derivatives of fibrin-derived peptide B beta 15-42 are known to those skilled in the art. For example, WO2019 / 011879, WO2007 / 095659, WO2007 / 095660, WO2007 / 095661, WO2009 / 137850, WO2009 / 137851 and WO2009 / 137852 disclose derivatives of fibrin-derived peptide B beta 15-42, and such derivatives can be used for the medical applications of the present invention.

[0042] According to a further preferred embodiment of the present invention, the fibrin-derived peptide B beta 15-42 derivative is: H2N-GHRP X1X2X3X4X5X6X7X8PX9X 10 X 11 PX 12 PPPX 13 X <000​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​(Sequence ID 6), H2N-GHRPX1X2X3X4X5X6X7X8PX9X 10 X 11 PX 12 PPPX 13 X 14 X 15 X 16 B(1)B(2)B(3)-X 17 (V) (Sequence ID 7) and H2N-GHRPX 20 X 21 X 22 -pright 23 X 24 X 25 X 26 X 27 X 28 X 29 -X 17 (VI), (Sequence 8) It has a general formula selected from the group consisting of, X1, X2, X3, X4, X5, X6, X7, X8, X9, X 10 , X 11 , X 12 , X 13 , X 14 , X 15 and X 16 These are independently selected from a group of amino acid residues, X 17 teeth, a) OR1 [wherein R1 is hydrogen or C1~C] 10 It is an alkyl group, or b) NR2R3[wherein R2 and R3 are independently hydrogen, C1~C 10 It is an alkyl group, or c) Residue-PEG 5-60K [In the formula, the PEG- residue is linked to the N atom via a spacer], or d) Residue NH-Y1-Z-PEG 5-60K [In the formula, Y1 is a chemical bond or an amino acid residue selected from the group consisting of S, C, K, and R, and Z is a spacer through which a polyethylene glycol (PEG) residue is linked] or X 18 teeth, a) OR1 [wherein R1 is hydrogen or C1~C] 10 It is an alkyl group, or b) NR2R3[wherein R2 and R3 are independently hydrogen, C1~C 10 It is an alkyl group, or c) Residue-PEG 5-60K [In the formula, the PEG- residue is linked to the N atom via a spacer], or d) Residue NH-Y1-Z-PEG 5-60K [In the formula, Y1 is a chemical bond or an amino acid residue selected from the group consisting of S, C, K, and R, and Z is a spacer through which a polyethylene glycol (PEG) residue is linked], or e) Residue-PEG 5-60K -CO-NR4R5[wherein R4 and R5 are independently hydrogen or C1~C 10 It is an alkyl group, or f) Residue NH-CH(CONH2)-(CH2)4-NH-CO-Y2-PEG 5-60K [In the formula, Y2 is either an oxygen atom or an NH group] X 19 It is either OH or NH2. X 20 , X 21 , X 22 , X 23 , X 24 , X 25 and X 26 Each of these is independently selected from a group composed of amino acid residues, X 27 , X 28 and X 29 These are independently selected from a group composed of amino acid residues, or are independently single bonds. B is -CO-(CH2) bonded to the ε-amino group of amino acid residue K via a CO group. m -Y3-(CH2) m -CO, where m is an integer from 1 to 4, and Y3 is -N-CO-(CH2) n-NH-CO-Z-PEG 5-60K and, or, n is an integer from 1 to 4, and Z is either NH or O. B(1) is a chemical bond or G, B(2) is a chemical bond or Y, B(3) is a chemical bond or R, β is an amino acid residue or peptide mimetic element, and the amino acid residues are L-proline, D-proline, L-hydroxyproline, D-hydroxyproline, L-(O-benzyl)hydroxyproline, D-(O-benzyl)hydroxyproline, L-(O-tert-butyl)hydroxyproline, 4-(O-2-naphthyl)hydroxyproline, 4-(O-2-naphthylmethyl)hydroxyproline, 4-(O-phenyl)hydroxyproline, 4-(4-phenylbenzyl)proline, cis-3-phenylproline, cis-4- Selected from the group consisting of phenylproline, trans-4-phenylproline, cis-5-phenylproline, trans-5-phenylproline, 4-benzylproline, 4-bromobenzylproline, 4-cyclohexylproline, 4-fluorinated proline, L-tetrahydroisoquinoline-2-carboxylic acid (L-Tic), all diastereomers of octahydroindole-2-carboxylic acid (Oic), and all diastereomers of 1-azabicyclo[3,3,0]octane-2carboxylic acid, and the peptide mimetic element is cis- 2-aminocyclopentanecarboxylic acid (cis-Acpc), (1R,2R)-(2-aminocyclopentanecarboxylic acid ((1R,2R)-Acpc), (1S,2S)-2-aminocyclopentanecarboxylic acid ((1S,2S)-Acpc), 1-aminomethylcyclohexaneacetic acid (1-Achc), 3-amino-1-carboxymethylpyridine-2-one (Acpo), 1-aminocyclobutanecarboxylic acid (1-Acbc), 1-aminocyclohexanecarboxylic acid (1-Achc), cis-4-aminocyclohexaneacetic acid (4-Acha), (1R, 2R)-2-aminocyclohexanecarboxylic acid ((1R,2R)-Ache), (1R,2S)-2-aminocyclohexanecarboxylic acid ((1R,2S)-Ache), (1S,2R)-2-aminocyclohexanecarboxylic acid ((1S,2R)-Achc), (1S,2S)-2-aminocyclohexanecarboxylic acid ((1S,2S)-Ache), 1-aminocyclopentanecarboxylic acid (1-Acpec), 1-aminocyclopropanecarboxylic acid (1-Acprc), 4-(2-aminoethyl)-6-dibenzofuranpropionic acid (Aedfp), (R,(S)-1-aminoindan-1-carboxylic acid (1-Aic), 2-aminoindan-2-carboxylic acid (2-Aic), 2'-(aminomethyl)-biphenyl-2-carboxylic acid (Ambc), 2-aminomethylphenylacetic acid (Ampa), 3-amino-2-naphthoic acid (Anc), 4-aminotetrahydropyran-4-carboxylic acid (Atpc), (R,S)-2-aminotetralin-2-carboxylic acid (2-Atc), (2S,6S,9S)-6-amino-2-carboxymethyl-3,8-diazabicyclo-[4,3,0]-nonane-1,4-dione (A (cdn), (R)-3-amino-5-carboxymethyl-2,3-dihydro-1,5-benzothiazepine-4(5H)-one (Acbt), (S)-3-amino-5-carboxymethyl-2,3-dihydro-1,5-benzoxazepine-4(5H)-one (Acbo), (R,S)-3-amino-1-carboxymethyl-2,3,4,5-tetrahydro-1H-[1]-benzazepine-2-one (1-Acmb), (S)-4-amino-2-carboxymethyl-1,3,4,5-tetrahydro-2H-[2]-benzazepine-3-one (2-Acm b) (R,S)-3-amino-1-carboxymethylvalerolactam (Acmv), 3-(2-aminoethyl)-1-carboxymethylquinazoline-2,4-dione (Acq), (2S,5S)-5-amino-1,2,4,5,6,7-hexahydroazepino[3,2,1-hi]-indole-4-one-2-carboxylic acid (Haic), (R,S)-3-amino-N-1-carboxymethyl-2-oxo-5-cyclohexyl-1,4-benzodiazepine (Accb), (R,S)-3-amino-N-1-carboxymethyl-2-oxo-5-fu Phenyl-1,4-benzodiazepine (Acpb), (2S,11aS))-2-amino-10-carboxymethyl-1,2,3,11a-tetrahydro-10H-pyrrolo[2,1-c][1,4]-benzodiazepine-5,11-dione (PBD), (2S,3S)-2-(4'-(3'-benzyl-2'-oxopiperazin-1-yl))-3-phenylpropionic acid (Bppp), 3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decane-4-one (Cptd), (R,S)-3-amino-9-Boc-1,2,3,The following are selected from the group consisting of 4-tetrahydrocarbazole-3-carboxylic acid (The), 3-exo-aminobicyclo[2.2.1]heptane-2-exo-carboxylic acid (Abhc), (3S)-3-amino-1-carboxymethylcaprolactam (Accl), (S,S)-(ProLeu)spirolactamPhe (PLSP), and 2-oxo-3-amino-7-thia-1-azabicyclo[4.3.0]nonane-9-carboxylic acid (BTD).

[0046] According to a preferred embodiment of the present invention, X in equation (I) 15 or X 16 This is an amino acid selected from the group consisting of C and K, and this amino acid is connected to the residue Z-PEG via a heteroatom in the side chain. 5-60K It is connected to, X in equation (I) 17 teeth, a) OR1 [wherein R1 is hydrogen or C1~C] 10 It is an alkyl group, or b) NR2R3[wherein R2 and R3 are independently hydrogen or C1~C 10 It is an alkyl group.

[0047] According to another preferred embodiment of the present invention, X1, X9, X 10 , X 14 , X 20 and X 23 These are L, I, S, M, or A, respectively, X2, X6, X7 and X 21 These are independently either E or D, X3, X4, X5X 11 and X 22 These are R or K, independently of each other. X8X 12 , X 24 , X 25 and X 26 These are A, G, S, or L, respectively, X 13 is I, L, or V, X in equations (IIa) and (IIb)15 and X 16 is each independently G, A, S or C, X 27 is G, A or L, X 28 is Y, F, H or a single chemical bond, X 29 is R, K or a single chemical bond.

[0048] According to a preferred embodiment of the present invention, the compound of formula I is preferably selected from the group consisting of GHRPLDKKREEAPSLRPAPPPISGGGYR-NH2 (SEQ ID NO: 9), GHRPLDKKREEAPSLRPAPPPISGGGYRC-(S-CH2-CO-NH-PEG 20K )-OH (SEQ ID NO: 10), GHRPLDKKREEAPSLRPAPPPISGGGYRC(S-CH2-CO-NH-PEG 20K )-amide (SEQ ID NO: 11), and GHRPLDKKREEAPSLRPAPPPISGC(S-CH2-CO-NH-PEG 20K )-GYR-amide (SEQ ID NO: 12).

[0049] According to another preferred embodiment of the present invention, the compound of formula IIa is preferably (GHRPLDKKREEAPSLRPAPPPISGCGYR)2, a Cys25-Cys25 homodimer cysteine peptide (SEQ ID NO: 13).

[0050] According to another preferred embodiment of the present invention, the compound of formula IIb is (GHRPLDKKREEAPSLRPAPPPISCGGYR)2, a Cys24-Cys24 homodimer cysteine peptide (SEQ ID NO: 14).

[0051] According to a further preferred embodiment of the present invention, the compound of formula III is:

[0052]

Chemical formula

[0053] [ka] (Sequence ID 16) That is the case.

[0054] In another preferred embodiment of the present invention, the compound of formula IV is GHRPLAPSLRPAPPPISGGGYR-OH (SEQ ID NO: 17), GHRPLAPSLRPAPPPISGGGYR-NH2 (SEQ ID NO: 18), and GHRPLAPSLRPAPPPISGGGYRC (S-succinimide PEG 20K )-OH (SEQ ID NO: 19) and GHRPLAPSLRPAPPPISGGGYRC-(S-succinimide PEG 20K Selected from the group consisting of )-amides (SEQ ID NO: 20).

[0055] In another preferred embodiment of the present invention, the compound of formula V is selected from the group consisting of GHRPLDKKREEAPSLRPAPPPISGG-OH (SEQ ID NO: 21), GHRPLDKKREEAPSLRPAPPPISGG-NH2 (SEQ ID NO: 22), GHRPLDKKREEAPSLRPAPPPISGGG-OH (SEQ ID NO: 23), and GHRPLDKKREEAPSLRPAPPPISGGG-NH2 (SEQ ID NO: 24).

[0056] In a further preferred embodiment of the present invention, the compound of formula VI is selected from the group consisting of GHRPLDK-(1S,2R)Achc-ISGGGYR (SEQ ID NO: 25), GHRPLDK-Acdn-ISGGGYR (SEQ ID NO: 26), GHRPLDK(cis-4-Acha)-ISGGGGYR (SEQ ID NO: 27), and GHRPLDK-Haic-ISGGGGYR (SEQ ID NO: 28).

[0057] In a second embodiment, the present invention relates to a compound used for treating inflammatory complications induced by or resulting from viral infections and / or viral diseases in a subject, wherein the compound is fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof, and the treatment comprises the step of administering the compound to the subject in a therapeutically effective amount.

[0058] The above disclosures, descriptions, definitions, and embodiments apply equally to the second aspect as they may be.

[0059] As used in the context of the inventions disclosed herein, the term “inflammatory complications induced by or resulting from viral infections and / or viral diseases” refers to secondary disorders, complications, or side effects resulting from viral infections. Such complications treatable by the inventions disclosed herein are of an inflammatory nature and preferably include or are associated with diffuse inflammation of the endothelium (see above). Preferably, complications treatable by the invention are endotheliitis or vasculitis as described elsewhere herein.

[0060] In a third embodiment, the present invention relates to a method for treating inflammatory disorders of the endothelium in a subject, the treatment comprising administering to the subject a therapeutically effective amount of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof.

[0061] The above disclosures, descriptions, definitions, and embodiments apply equally to the third aspect as they may be.

[0062] In a fourth embodiment, the present invention relates to a method for treating inflammatory complications induced by or resulting from viral infections and / or viral diseases in a subject, the treatment comprising administering to the subject a therapeutically effective amount of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof.

[0063] The above disclosures, descriptions, definitions, and embodiments apply equally to the fourth aspect as they may be.

[0064] In a fifth aspect, the present invention further relates to the use of fibrin-derived peptide B beta 15-42 and / or at least one functional derivative or physiologically acceptable salt thereof in the manufacture of a medicament for treating one of the disorders and / or complications of the first to fourth aspects of the present invention.

[0065] The above disclosures, descriptions, definitions, and embodiments apply equally to the fifth aspect as they may be.

[0066] In this specification, terms such as “of the present invention,” “in accordance with the present invention,” and “according to the present invention” are intended to refer to all aspects and embodiments of the present invention described and / or claimed herein.

[0067] In this specification, the term “comprising” is to be interpreted as encompassing both “including” and “consisting of,” both meanings being particularly intended and therefore the embodiments disclosed individually in this invention. As used herein, “and / or” is to be considered a specific disclosure that includes or excludes the other of two designated features or components. For example, “A and / or B” is to be considered a specific disclosure of (i) A, (ii) B, and (iii) A and B, as each of which is simply described individually in this specification. In the context of this invention, the terms “about” and “approximately” indicate intervals of precision that a person skilled in the art would understand in order to further ascertain the technical effect of the feature in question. The terms generally indicate deviations of ±20%, ±15%, ±10%, for example, ±5% from the numerical value shown. Such a particular deviation from the numerical value of a given technical effect would be determined by the nature of the technical effect, as would be recognized by a person of ordinary skill. For example, natural or biological technological effects can generally have greater deviations than artificial or engineered technological effects. Such a particular deviation from the numerical value of a given technological effect will depend on the nature of the technological effect, as would be recognized by an ordinary engineer. For example, natural or biological technological effects can generally have greater deviations than artificial or engineered technological effects. When an indefinite or definite article, e.g., "a," "an," or "the," is used when referring to a singular noun, this includes the plural form of that noun unless otherwise specified.

[0068] It should be understood that the application of the teachings of the present invention to specific problems or environments, and the inclusion of variations of the present invention or additional features therein (such as further aspects and embodiments), will be within the capabilities of those skilled in the art in light of the teachings contained herein.

[0069] Unless otherwise indicated by the context, the descriptions and definitions of the features set forth above are not limited to any particular aspect or embodiment of the present invention, but apply equally to all aspects and embodiments described herein.

[0070] All references, patents, and publications cited herein are incorporated herein by reference in their entirety. [Examples]

[0071] Specific aspects and embodiments of the present invention are illustrated below by reference to the description, figures, and tables set forth herein. Such examples of the methods, uses, and other aspects of the present invention are merely representative and should not be construed as limiting the scope of the invention to such representative examples alone.

[0072] Therefore, in the examples disclosed herein, FX06 is investigated as a therapeutic agent in a case series involving critically ill patients with COVID-19-related hypoxemia and multiple organ failure at tertiary care facilities of two universities in Germany.

[0073] Examples include: [Examples]

[0074] Critically ill patients with COVID-19 infection at primary university treatment facilities. Case study All patients were diagnosed as SARS-CoV-2 positive by using nasopharyngeal and oropharyngeal swab samples and amplifying the beta-coronavirus E gene and the specific SARS-CoV-2 RdRp gene by PCR.

[0075] Table 1 shows the demographic and clinical characteristics of the patients at the time of admission and treatment. Figure 6 shows the progression of inflammatory markers. Upon admission to the intensive care unit, all patients received mechanical ventilation and emergency treatment as proposed by Poston et al.

[0076] [Table 1] JPEG0007855526000007.jpg19146

[0077] Patient 1 presented to the emergency department with typical symptoms of COVID-19 (fever, cough, and dyspnea). A chest CT scan showed multiple bilateral ground-glass opacities with peripheral lung and subpleural distribution in both the superior and inferior lobes. Due to severe respiratory failure and hypoxemia, mechanical ventilation was initiated immediately after admission. Furthermore, due to refractory hypoxemia, venous ECMO therapy was initiated on day 2 of hospitalization. The patient was treated with FX06 for 7 days from the date of admission. Radiographic findings showed regression of pulmonary sclerosis over the following 7 days, and the patient's clinical symptoms significantly improved (Figures 1-3). On day 14 of hospitalization, the patient was extubated from ECMO. The patient remains in the intensive care unit.

[0078] Similar to patient 1, patient 2 presented to the emergency department with cough, fever, and dyspnea and experienced rapid respiratory deterioration. Mechanical ventilation was initiated two hours after admission. Radiographic findings revealed features typical of COVID-19 infection. The patient received FX06 treatment for seven days from the date of admission. Initially, clinical symptoms improved with increased oxygen supply and reduced vasopressor therapy (Figures 1-2), but radiographic findings revealed worsening pulmonary infiltration (Figure 4). Microbiological analysis identified co-infection with Aspergillus fumigatus and Serratia marcescens, which were treated with corresponding antibacterial and antifungal agents. The patient showed continuous improvement in symptoms and underwent percutaneous tracheostomy on day 18 of hospitalization. On day 23 of hospitalization, the patient developed fulminant septic shock and, within 24 hours, progressed to severe multiple organ failure and death.

[0079] Patient 3 was transferred from a secondary care hospital to a university tertiary care hospital on day 8 of the illness due to worsening clinical symptoms. Mechanical ventilation was required due to severe hypoxemia, and ECMO and FX06 therapy were initiated on day 2 of hospitalization. Radiographic diagnosis demonstrated acute lung injury and nearly "white lung" (Figure 5). Significant improvement in pulmonary infiltration was observed within one week of FX06 treatment. Inflammatory markers continued to decrease, and oxygen supply improved over time, but weaning from ECMO has not been successful to date (day 12 of hospitalization). The patient remains in the intensive care unit.

[0080] conclusion The results of Example 1 report the successful administration of FX06 to three critically ill patients with severe COVID-19-related ARDS. Significant improvement was observed in all patients after FX06 administration. If the fulminant sepsis adverse event observed in patient 3 is a typical complication in critically ill patients, then it is not related to FX06 therapy. Therefore, this example demonstrates the use of FX06 in severe COVID-19-related ARDS as an effective therapy for improving the course of the disease, particularly for mitigating inflammatory complications associated with COVID-19. [Examples]

[0081] A critically ill patient suffering from COVID-19 at a secondary university treatment facility. To date, three patients have been treated in individualized treatment trials using FX06 at the second university medical facility. Patient 1 was a 51-year-old woman with obesity, arterial hypertension, and a history of rheumatoid arthritis with immunosuppressive therapy. Patient 2 was a 71-year-old man with a history of type 2 diabetes. Patient 3 was a 55-year-old man with a history of arterial hypertension and obesity.

[0082] All three patients were diagnosed with SARS-CoV-2 pneumonia causing severe acute respiratory distress syndrome (ARDS) and required extracorporeal membrane oxygenation (ECMO) therapy during or early in their treatment at our facility. All patients were referred to our hospital from their primary care providers due to the severity of their symptoms. All patients required ECMO therapy during FX06 treatment.

[0083] FX06 400mg was administered once daily after informed consent was obtained from a close relative.

[0084] [Table 2]

[0085] Patient 1 presented with near-complete pulmonary failure four days after admission, with a remaining tidal volume of only 40 mL. Six days after the first dose of FX06, pulmonary infiltration began to significantly regress (Figure 7). Consequently, ventilation parameters also improved, accompanied by an increase in the oxygen supply index (Horovitz,s Figure 8). Although COVID-19-induced ARDS significantly improved after the FX06 treatment period, the patient unfortunately developed multiple organ failure and died a few days later from acute liver failure.

[0086] Patient 2 did not require mechanical ventilation within the first eight days of admission, compared to Patients 1 and 3, and the onset of respiratory failure was not as rapid. After initiation of FX06 treatment, pulmonary infiltration also began to decrease, as shown in Figure 9. In addition, ventilation improved (Figure 10), and serum inflammatory markers decreased in relation to FX06 treatment (Figure 11). Patient 2 is currently still being treated in the intensive care unit.

[0087] Patient 3 showed a similar response to treatment with FX06 as Patient 2. Ventilation and oxygen supply improved after the intervention (Figure 12), and serum inflammatory markers slowly regressed (Figure 13). Also, as with both other patients, chest X-ray showed a reduction in pulmonary infiltration (Figure 14). Patient 3 remains in intensive care.

[0088] Therefore, Example 2 demonstrates the success of administering FX06 to three critically ill patients with severe COVID-19-related ARDS. In all three patients, the substantial features of the complex syndrome improved during and several days after treatment. There is likely no association between the administration of FX06 and the death of patient 1, but it is rather thought to be attributable to the patient's immunosuppressive therapy for pre-existing symptoms and the severity of the underlying symptoms. Based on the data from the three patients, FX06 is shown to be safe to use in severe ARDS and has the ability to improve the intrinsic features of the disease, particularly inflammatory complications such as endotheliitis.

[0089] References 1. Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X: Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. The lancet 2020; 395: 497-506 2. Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X: Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. The lancet 2020 3. Xu Z, Shi L, Wang Y, Zhang J, Huang L, Zhang C, Liu S, Zhao P, Liu H, Zhu L: Pathological findings of COVID-19 associated with acute respiratory distress syndrome. The Lancet respiratory medicine 2020; 8: 420-422 4. Kalil AC: Treating COVID-19-Off-Label Drug Use, Compassionate Use, and Randomized Clinical Trials During Pandemics. JAMA 2020 5. Magagnoli J, Narendran S, Pereira F, Cummings T, Hardin JW, Sutton SS, Ambati J: Outcomes of hydroxychloroquine usage in United States veterans hospitalized with Covid-19. medRxiv 2020: 2020.04.16.20065920 6. Horby P, Cao B, Wang Y, Wang C: Evaluation of the Efficacy and Safety of Intravenous Remdesivir in Adult Patients with Severe Pneumonia caused by COVID-19 virus Infection: study protocol for a Phase 3 Randomized, Double-blind, Placebo-controlled, Multicentre trial. 2020 7. Calo L A, Bertoldi G: Rho kinase inhibitors for SARS-CoV-2 induced acute respiratory distress syndrome: Support from Bartter's and Gitelman's syndrome patients. Pharmacological Research 2020; 158; 104903 8. Wolf T, Kann G, Becker S, Stephan C, Brodt H-R, de Leuw P, Grunewald T, Vogl T, Kempf VA, Keppler OT: Severe Ebola virus disease with vascular leakage and multiorgan failure: treatment of a patient in intensive care. The Lancet 2015; 385: 1428-1435 9. Bergt S, Gruenewald M, Beltschany C, Grub A, Neumann T, Albrecht M, Vollmar B, Zacharowski K, Roesner JP, Meybohm P: The fibrin-derived peptide Bβ15-42 (FX06) ameliorates vascular leakage and improves survival and neurocognitive recovery: implications from two animal models of cardiopulmonary resuscitation. Critical care medicine 2016; 44: e988-e995 10. Ahrens I, Peter K: FX-06, a fibrin-derived Bβ. Current Opinion in Investigational Drugs 2009; 10 11. Henning R, Zacharowski K, Petzelbauer P: FX06 (fibrin-derived peptide Bbeta15-42)-A potential candidate for myocardial reperfusion therapy. Drugs of the Future 2006; 31: 811-818 12. Atar D, Petzelbauer P, Schwitter J, Huber K, Rensing B, Kasprzak JD, Butter C, Grip L, Hansen PR, Suselbeck T: Effect of intravenous FX06 as an adjunct to primary percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: results of the FIRE (Efficacy of FX06 in the Prevention of Myocardial Reperfusion Injury) trial. Journal of the American College of Cardiology 2009; 53: 720-729 13. Groger M, Pasteiner W, Ignatyev G, Matt U, Knapp S, Atrasheuskaya A, Bukin E, Friedl P, Zinkl D, Hofer-Warbinek R, Zacharowski K, Petzelbauer P, Reingruber S: Peptide Bs 15-42 Preserves Endothelial Barrier Function in Shock. PLOS One 2008; 4 (4): e5391 14. Matt U, Warszawaska J M, Bauer M, Dietl W, Mesteri I, Doninger B, Haslinger I, Schabbauer G, Perkmann T, Binder C J, Reingruber S, Petzelbauer P, Knapp S: Bs 15-42Protects against Acid-induced Acute Lung Injury and Secondary Pseudomonas Pneumonia In Vivo. American Journal of Respiratory and Critical Care Medicine 2009; 180 (12): 1208-1217 15. Poston JT, Patel BK, Davis AM: Management of critically ill adults with COVID-19. Jama 2020

Claims

1. A composition for use in the treatment of inflammatory endothelial disorders and / or complications resulting from a viral infection in a subject, wherein the composition comprises fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof, the treatment comprising the step of administering the composition to the subject in a therapeutically effective amount, the viral infection in the subject being caused by a virus of the family Coronavirus, the functional derivative being a peptide having at most three amino acid substitutions, deletions and / or additions compared to the amino acid sequence of SEQ ID NO: 1, and the fibrin-derived peptide B beta 15-42 comprising the amino acid sequence GHRPLDKKREEAPSLRPAPPPISGGGYR (SEQ ID NO: 1).

2. The composition for use according to claim 1, wherein the functional derivative is a peptide having at most two or at most one amino acid substitutions, deletions, and / or additions compared to the amino acid sequence of SEQ ID NO: 1, and the substitutions, deletions, and / or additions do not affect the positions of the first four amino acids of SEQ ID NO:

1.

3. The composition for use according to claim 1 or 2, wherein the viral infection is caused by a virus that infects endothelial cells.

4. The composition for use according to any one of claims 1 to 3, wherein the inflammatory impairment of the endothelium is related to the accumulation of inflammatory cells associated with the endothelium in the subject.

5. The composition for use according to any one of claims 1 to 4, wherein the subject suffers from one or more disorders that increase the risk of a poor prognosis, selected from the group consisting of immunosuppression, chronic lung disease, hypertension, obesity, and diabetes.

6. The composition for use according to claim 5, wherein the chronic lung disease is asthma, chronic obstructive pulmonary disease, cystic fibrosis, interstitial lung disease, bronchitis, sarcoidosis, idiopathic pulmonary fibrosis, bronchiectasis, acute respiratory distress syndrome, or acute lung injury.

7. A composition for use according to any one of claims 1 to 6, wherein the viral infection is caused by HCoV-229E, HCoV-OC43 (HCoV-OC43), Middle East Respiratory Syndrome-related Coronavirus (MERS)-CoV, Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV), or SARS-CoV-2.

8. A composition for use according to any one of claims 1 to 7, wherein the fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof is administered to a subject in a daily dose of 100 mg to 1000 mg, 150 mg to 800 mg, 200 mg to 600 mg, 300 mg to 500 mg, 300 mg, 400 mg, 500 mg, or 600 mg.

9. The composition for use according to any one of claims 1 to 8, wherein the composition is administered to the subject by intravenous (bolus) injection or intravenous drip infusion.

10. The composition for use according to any one of claims 1 to 9, wherein the treatment comprises a therapy lasting 1 to 10 days or 3 to 7 days.

11. A composition for use according to any one of claims 1 to 10, wherein the fibrin-derived peptide B beta 15-42 and / or at least one functional derivative thereof or a physiologically acceptable salt thereof is administered in doses of 0.1 mg / kg body weight to 50 mg / kg body weight, 0.5 to 20 mg / kg body weight, or 0.7 to 17.5 mg / kg body weight.

12. The composition for use according to any one of claims 1 to 11, wherein the composition is formulated as a pharmaceutical composition together with a pharmaceutically acceptable carrier and / or excipient.

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