ANTI-ADRENOMEDULIN (ADM) ANTIBODY OR ANTI-ADM ANTIBODY FRAGMENT OR ANTI-ADM ASSEMBLY WITHOUT IG FOR USE IN CONGESTION INTERVENTION AND THERAPY IN A PATIENT IN NEED OF IT

Abstract

The present invention relates to an anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to adrenomedullin, for use in congestion therapy in a patient with congestive hypertension; heart failure, in particular acute heart failure; wherein said anti-ADM antibody or anti-ADM fragment binds to the N-terminal portion (aa 1 to 21) of adrenomedullin YRWSMNNFWGLRSFGCRFGTC (SEA ID NO. 22), and wherein said patient is resistant to diuretics or does not respond to diuretic therapy.

Description

ANTI-ADRENOMEDULIN (ADM) ANTIBODY OR ANTI-ADM ANTIBODY FRAGMENT OR SUPERCONTIGO WITHOUT IG ANTI-ADM FOR USE IN CONGESTION INTERVENTION AND THERAPY IN A PATIENT IN NEED OF IT FIELD OF INVENTION The subject matter of this present invention is an anti-Adrenomedullin (ADM) antibody or an anti-Adrenomedullin antibody fragment or an anti-ADM ig-free supercontigo for use in congestion intervention and therapy in a patient in need thereof. BACKGROUND OF THE INVENTION The peptide adrenomedullin (ADM) was first described in 1993 (Kitamura et al., 1993. Biochem Biophys Res Comm 192 (2): 553-56(5) as a novel hypotensive peptide comprising 52 amino acids, isolated from a human eochromocytoma cell line (SEQ ID No.: 20). In the same year, the cDNA encoding a precursor peptide comprising 185 amino acids and the complete amino acid sequence of this precursor peptide were also described. The precursor peptide, comprising, among others, a 21-amino-acid signal sequence at the N-terminus, is termed “pre-proadrenomedullin” (pre-proADM). In the present description, all specified amino acid positions generally relate to pre-proADM, comprising the 185 amino acids. The peptide adrenomedullin (ADM) is a peptide comprising 52 amino acids (SEQ ID No: 20) and comprising amino acids 95 to 146 of pre-proADM, from which it is formed by proteolytic cleavage.To date, substantially only a few of the peptide fragments formed during the cleavage of pre-proADM have been investigated more precisely, in particular the physiologically active peptides ADM and “PAMP,” a peptide comprising 20 amino acids (22–41), which follows the 21 amino acids of the signal peptide in pre-proADM. The discovery and characterization of ADM in 1993 triggered intense research activity, the results of which have been summarized in several review articles, in the context of this description, with particular reference to the articles found in an issue of “Peptides” dedicated to ADM (Takahashi 2001. Peptides 22: 1691; Etto 2001. Peptides 22: 1693–1711). A further review is by Hinson et al. 2000 (Hinson et! al. 2000. Endocrine Reviews 21(2):138-167).Scientific research to date has found, among other things, that ADM can be considered a polyfunctional regulatory peptide. It is released into the circulation in an inactive, glycine-extended form (Kitamura et al. 1998. Biochem Biophys Common 244(2): 551-555). There is also a binding protein (Pió et al. 2001. The Journal of Biological Chemistry 276(15): 12292-12300) that is specific to ADM and likely also modulates its effects. These physiological effects of ADM, as well as those of PAMPs, which are of primary importance in research to date, are the effects that influence blood pressure. Therefore, ADM is an effective vasodilator, and thus it is possible to associate the hypotensive effect with particular peptide segments in the C-terminal portion of ADM. Furthermore, the physiologically active peptide PAMP mentioned above, formed from pre-proADM, has also been found to exhibit a hypotensive effect, even though it appears to have a different mechanism of action. ADM (in addition to the review articles mentioned above Eto et al. 2001 and Hinson et al. 2000 see also Kuwasaki et al. 1997. FEBS Lett 414(1): 105-110; Kuwasaki et al. 1999. Ann. Clin. Biochem. 36: 622-628; Tsuruda et al. 2001 Life Sci. 69(2): 239-245 and EP-A2 0 622 458). Furthermore, ADM concentrations, which can be measured in the circulation and other biological fluids, have been found in a number of pathological states to be significantly higher than the concentrations found in healthy control subjects. Therefore, the ADM level in patients with congestive heart failure, myocardial infarction, kidney disease, hypertensive disorders, diabetes mellitus, in the acute phase of shock, and in sepsis and septic shock increases significantly, although to varying degrees.PAMP concentrations also increase in some of these pathological states, but plasma levels are lower relative to ADM (Eto 2001. Peptides 22: 1693-1711). Unusually high ADM concentrations have been reported in sepsis, and the highest concentrations in septic shock (Eto 2001. Peptides 22: 1693-1711; Hirata et al. Journal of Clinical Endocrinology and Metabolism 81(4): 1449-1453; Ehlenz et al. 1997. Exo Clin Endocrinol Diabetes 105: 156-162; Tomoda et al. 2001. Peptides 22: 1783-1794; Ueda et al. 1999. Am. J. Hespir. Crit. Care Med. 160: 132-136 and Wang et al. 2001. Peptides 22: 1835-1840). Plasma ADM concentrations are elevated in patients with heart failure and correlate with disease severity (Hirayama et al. 1999. J Endocrinol 160:297-303; Yu et al. 2001. Heart 86: 155-160). High plasma ADM is an independent negative prognostic indicator in these subjects (Poyner et al. 2002. Pharmacol Rev 54:233-246). The role of MR-proADM (SEQ ID No.: 33) in heart failure has been tested in several studies. In the BACH study (Maisel et al. 2010. J. Am. Col. Cardiol. 55:2062-2076), MR-proADM was a strong predictor of 90-day mortality, adding prognostic value beyond that of natriuretic peptides. Subsequent data from the PRIDE study (Shah et al. 2012. Eur. Heart J. 33: 2197-2205) further solidified a potential prognostic role for MR-proADM; among patients, MR-proADM had the best area under the curve (AUC) for 1-year mortality. Similarly, MR-proADM levels in patients with chronic heart failure (CHF) were strongly correlated with disease severity, and elevated peptide levels were strongly associated with an increased risk of death at 12 months of follow-up (van Haehíing et al. 2010. European Journal of Heart Failure 12: 484-491; Adlbrecht et al. 2009. European Journal of Heart Failure 11: 361-366). MR-proADM was investigated during treatment in patients with acute decompensated heart failure (Boyer et al. 2012. Congest Heart Fail 18(2):91-97). Patients whose MR-proADM levels tended to increase during acute therapy had findings associated with persistent congestion. In the 12- to 24-hour post-treatment period, patients with elevated MR-proADM had greater peripheral edema. Kaiser et al. measured MR-proADM in patients with univentricular hearts (Kaiser et al. 2014. Europ J Heart Failure 16:1082-1088). Levels in patients with a failed Fontan circuit (showing ascites and peripheral edema) were significantly higher compared to patients without a failed Fontan circuit. Furthermore, Eisenhut speculated whether treatments leading to a reduction in adrenomedullin levels can reduce the severity and extent of alveolar edema. in pneumonia and septicemia (Eisenhut 2006). Grit Care 10:418) The technique also includes a method for identifying adrenomedullin immunoreactivity in biological fluids for diagnostic purposes, particularly within the scope of sepsis diagnosis, cardiac diagnosis, and cancer diagnosis. According to the invention, the mid-proadrenomedullin regional partial peptide (SEQ ID No. 33), containing amino acids (45-92) of the complete preproadrenomedullin, is measured in particular using an immunoassay that operates with at least one labeled antibody that specifically recognizes a mid-proADM sequence (W02004 / 090546). WQ2004 / 097423 describes the use of an antibody against adrenomedullin for the diagnosis, prognosis, and treatment of cardiovascular disorders. The treatment of diseases by blocking the ADM receptor is also described in the technique (e.g., W02006 / 027147, PCT / EP2005 / 012844). These diseases may include sepsis, septic shock, cardiovascular diseases, infections, dermatological diseases, endocrinological diseases, metabolic diseases, gastroenterological diseases, cancer, inflammation, hematological diseases, respiratory diseases, musculoskeletal diseases, neurological diseases, and urological diseases. It is reported that in the early phase of sepsis, ADM improves cardiac function and blood supply to the liver, spleen, kidneys, and small intestine. Neutralizing antibodies against ADM counteract these effects during the early phase of sepsis (Wanq et al. 2001. Peptides 22: 1835-1840). For other diseases, blocking ADM can be beneficial to some extent. However, it could also be harmful if ADM is completely neutralized, as a certain amount of ADM may be required for various physiological functions. Many reports have highlighted that ADM administration can be beneficial in certain diseases. In contrast, other reports have indicated that ADM is potentially fatal when administered under certain conditions. WO2013 / 072510 describes a non-neutralizing anli-ADM antibody for use in the therapy of a severe acute or chronic disease or acute condition of a patient for the reduction of the risk of mortality for said patient. WO2013 / 072511 describes a non-neutralizing anti-ADM antibody for use in therapy of a chronic or acute disease or acute condition of a patient for the prevention or reduction of organ dysfunction or failure. WO2013 / 072512 describes a non-neutralizing anti-ADM antibody that is an ADM-stabilizing antibody that enhances the half-life (mean retention time t1 / 2) of adrenomedullin in serum, blood, and plasma. This ADM-stabilizing antibody blocks ADM bioactivity to less than 80%. WO2013 / 072513 describes a non-neutralizing anti-ADM antibody for use in the therapy of an acute patient disease or condition to stabilize circulation. WO2013 / 072514 describes a non-neutralizing anti-ADM antibody for regulating the balance of fluids in a patient who has a chronic or acute illness or an acute condition. BRIEF DESCRIPTION OF THE FIGURES Fig. 1a: Illustration of Fv and scFv variant antibody formats. Fig. 1b: Illustration of heterologous antibody-fusion and bifunctional antibody formats. Fig. 1c: Illustration of antibody formats - bivalent antibodies and bispecific antibodies. Fig. 2a: Human ADM dose response curve. Peak cAMP stimulation was set at 100% activation. Fig. 2b: Dose / inhibition curve of human ADM 22-52 (ADM receptor antagonist) in the presence of hADM 5.63nM. Fig. 2c: CT-H dose / inhibition curve in the presence of hADM 5.63 nM. Fig. 2d: Dose / inhibition curve of MR-H in the presence of hADM 5.63 nM. Fig. 2e: NT-H dose / inhibition curve in the presence of hADM 5.63 nM. Fig. 2f: Mouse ADM dose response curve. Peak cAMP stimulation was set to 100% activation. Fig. 2g: Dose / inhibition curve of human ADM 22-52 (ADM receptor antagonist) in the presence of mADM 0.67 nM. Fig. 2h: CT-M dose / inhibition curve in the presence of 0.67 nM mADM. Fig. 2i: Dose / inhibition curve of MR-M in the presence of mADM 0.67 nM. Fig. 2j: NT-M dose / inhibition curve in the presence of mADM 0.67 nM. Fig. 2k: Shows the inhibition of ADM by F(ab)2 NT-M and by Fab NT-M. Fig. 2I: Shows the inhibition of ADM by F(ab)2 NT-M and by Fab NT-M. Fig. 3: This figure shows a typical hADM dose / signal curve and a HADM dose / signal curve in the presence of 100 pg / ml NT-H antibody. Fig. 4: This figure shows the stability of hADM in human plasma (citrate) in the absence and presence of NT-H antibody, Fig. 5: Alignment of the Fab with homologous human framework sequences, Fig. 6: Extravascular albumin accumulation 18h after application of CLP and NT-M at different doses. Fig. 7: VEGF expression 18h after application of CLP and NT-M at different doses. Fig. 8: Angiopoietin-1 expression 18 hours after application of CLP and NTM at different doses. Fig. 9: ADM concentration in healthy human subjects after NT-H application at different doses for up to 60 days. Fig. 10: Timeline for treatment and blood sampling in the double mutation pig model. Fig. 11: ADM concentrations of vehicle (squares) and treatment group (points) (SEM mean values) (p~ 0.003 for interaction; t= 7h to 19h, multivariable, Time*Group). Fig. 12: Heart rate of the vehicle group (squares) and treatment group (points) (mean values ​​with SEM), p= 0.097 for interaction (from 1~ 7h to t= 19h, multivariate, Time*Group). Fig. 13: Cardiac performance of the vehicle group (squares) and treatment group (points) (mean values ​​with SEM) (t test: p <0.05 for t= 9, 10, 11 h). Fig. 14: Application / demand of vehicle volume (squares) and treatment group (points) (mean values ​​with SEM) (Test at 17h: p= 0.034; Test at 19h: p= 0.045). Fig. 15: Application / demand of the accumulated volume of the vehicle group (squares) and of treatment (points) (mean values ​​with SEM) (p~0.039 for T test at 19h; p-0.036 for Mann-Whitney at 19h). Fig. 16: Application / demand of noradrenaline from the vehicle group (squares) and treatment group (points) (mean values ​​with SEM). Fig. 17: Requirement for vasopressor support of the vehicle group (squares) and treatment group (dots) (Chi Test) 2 at=19h: p ::: 0.014 for interaction (t=7h-19h, multivariable, Time*Group: 0.019). Fig. 18: Systemic vascular resistance of the vehicle group (squares) and treatment group (points) (mean values ​​with SEM) (t-test: 15h: p=0.069; 17h: p= 0.037; 19h: p=0.066). Figs. 19a and 19b: rADM concentrations in a rat model of LPS-induced endotoxemia. Figs. 20a and 20b: Vascular permeability in a rat model of endotoxemia. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, it has been found that the administration of an anti-ADM antibody or an anti-ADM antibody fragment that binds to ADM or a binding of anti-ADM Ig-free supercontigs to ADM can be used for the intervention and therapy of congestion in patients in need thereof. Throughout the specification, the “antibodies”, or “antibody fragments” or “non-Ig supercontigs” according to the invention are capable of binding to ADM, and are therefore directed against ADM, and may therefore be referred to as “anti-ADM antibodies”, “anti-ADM antibody fragments”, or “anti-ADM non-Ig supercontigs”. The advantage of administering an anti-ADM antibody, an ADM-binding anti-ADM antibody fragment, or a supercontig without ADM-binding anti-ADM Ig, as opposed to administering, for example, diuretics, is its kidney-protective effect. Such an anti-ADM antibody, an ADM-binding anti-ADM antibody fragment, or a supercontig without ADM-binding anti-ADM Ig does not damage the kidneys, and therefore, no kidney-related side effects are expected. According to the invention, the administration of an anti-ADM antibody or anti-ADM antibody fragment binding to ADM or supercontigo without anti-ADM binding Ig is preferably a systematic application. In a specific modality, said anti-ADM antibody or ADM-binding anti-ADM antibody fragment or supercontigo without ADM-binding anti-ADM ig can be administered to a patient with vascular barrier dysfunction or endothelial dysfunction that may result in congestion. Vascular barrier dysfunction, or endothelial dysfunction, is a systemic pathological state of the endothelium (the inner lining of blood vessels) and can be broadly defined as an imbalance between vasodilating and vasoconstricting substances produced by (or acting upon) the endothelium. (Deanfield et al. 2005. J Hypertens 23(1): 7-17). Normal cell functions Endothelial functions include mediation of coagulation, platelet adhesion, immune function, and control of the volume and electrolyte content of the intravascular and extravascular spaces. The endothelium is a cell monolayer that lines the entire cardiovascular system and regulates many processes, including vascular tone, thrombosis, angiogenesis, and inflammation. Endothelial cells have been shown to be phenotypically dynamic and, in response to a variety of local and systemic stimuli, can transition between inactive and activated states (Colombo et al. 2015. Curr Heart Fail Rep. 12(3): 215-222). In recent years, research has shown that endothelial dysfunction is an important contributing factor to cardiovascular diseases such as hypertension, atherosclerosis, and congestive heart failure (Gutierrez et al. 2013. European Heart Journal 34: 3175-3181).The endothelium tightly controls the exchange of fluid from the circulation to the surrounding tissues, and dysfunction of this barrier leads to uncontrolled fluid extravasation, which can result in congestion and / or edema. A common feature of edema (e.g., pulmonary edema) is increased permeability to low-molecular-weight water solutes (Rocker et al. 1987. Thorax 42: 620-23). Endothelial dysfunction can result from and / or contribute to various disease processes, such as hypertension, hypercholesterolemia, diabetes, or septic shock. Endothelial dysfunction is an important pathophysiological mechanism leading to coronary artery disease and other atherosclerotic diseases. From preclinical experiments in sepsis / septic shock models, it is known that administration of the anti-ADM antibody induces an increase in plasma bio-ADM concentration (Example 8, Fig. 9), and that this coincides with an increased survival rate (Struck et al. 2013. Intensive Care Med Exp 1(1):22). The mechanism underlying this effect is thought to be as follows: the antibody, when adapted for intravenous administration, due to its size, cannot cross the endothelial barrier into the interstitium, but remains in the bloodstream. In contrast, ADM, as a small peptide, can diffuse freely across the endothelial barrier.Thus, when the antibody is adapted to be administered in a vast molar excess over endogenous ADM, it binds to virtually all ADM in the plasma and, as a simple consequence of reaching binding equilibrium, leads to the translocation of ADM from the interstitium to the bloodstream. Interstitial ADM can bind to vascular smooth muscle cells and induce relaxation, resulting in vasodilation. This is reduced by antibody administration. On the other hand, plasma ADM binds to endothelial cells and thus stabilizes or even restores vascular integrity. Therefore, this function is enhanced when plasma ADM levels increase as a result of antibody administration, which is a non-neutralizing antibody. Finally, antibody binding to ADM reduces the proteolytic breakdown of ADM. Surprisingly, the PROTECT study (Example 6) and the BIOSTAT study (Example 7) have shown that in patients with heart failure, bio-ADM concentrations increase with the presence and severity of congestion, despite diuretic treatment. Therefore, the increase in bio-ADM in these patients represents the body's counter-regulation of tissue congestion. However, the natural increase is insufficient to effectively achieve this. Contrary regulation. Tissue congestion also occurs in sepsis. Examples 5, 9, and 10 demonstrate that administration of the anti-ADM antibody in septic animal models leads to the restoration of damaged vascular integrity. Due to the parallel mechanism of tissue congestion in both sepsis and heart failure, it is credible to experts in the field that administration of the anti-ADM antibody should be beneficial in the treatment of congestion in heart failure, similar to sepsis / septic shock. In a specific modality, this anti-ADM antibody, or ADM-binding anti-ADM antibody fragment, or ADM-binding anti-ADM Ig supercontig, can be administered to a patient for use in the intervention and therapy of congestion with the aid of a complementary diagnostic method. This complementary diagnostic method is described below. Pro-adrenomedullin or fragments thereof of at least 5 amino acids can be used as an early surrogate marker for congestion and thus to guide congestion therapy or intervention comprising: "Determine the level of pro-adrenomedulin or fragments thereof of at least 5 amino acids in a body fluid obtained from said subject; and a) To correlate said level of Pro-Adrenomedullin or fragments thereof with the degree of congestion in said subject or to diagnose congestion, where an elevated level above a certain threshold is indicative of congestion or the degree of congestion, or b) To correlate said level of Pro-Adrenomedullin or fragments thereof with the need for or success of therapy or intervention and congestion therapy in said subject, where a level below a certain threshold is predictive of success of therapy or intervention and congestion therapy, and where a level above a certain threshold is indicative of the need for therapy or intervention and congestion therapy, or c) Correlate said level of Pro-Adrenomedullin or fragments thereof with a prediction of decongestion or residual congestion after therapy or intervention and congestion therapy, wherein an elevated level above a certain threshold predicts residual congestion after therapy or intervention and congestion therapy, while a level below a certain threshold predicts decongestion after therapy or intervention and congestion therapy, or d) Correlate said level of Pro-Adrenomedullin or fragments thereof with decongestion or residual congestion after therapy or intervention and congestion therapy, where an elevated level above a certain threshold indicates residual congestion after therapy or intervention and congestion therapy, while a level below a certain threshold indicates decongestion after therapy or intervention and congestion therapy, or e) Correlate said level of Pro-Adrenomedullin or fragments thereof with the evaluation of the decision on hospital discharge where a high level above a certain threshold means that the subject should not be discharged and where a level below a certain threshold means that the subject can be discharged, where said Pro-adrenomedullin or fragment is selected from the group comprising Pro-Adrenomedullin according to SEQ ID No. 31 or PAMP according to SEQ ID No. 32 or MR-proADM according to SEQ ID No.: 33 or ADM-NH2 according to SEQ ID No.: 20 or ADM-Gly according to SEQ ID No.: 34 or CT-proADM according to SEQ ID No.: 35. This method is described in detail in European Patent Applications EP16199092 and EP16178725 and is incorporated herein by reference. The therapy and intervention, as mentioned in the diagnostic method above, is the administration of said anti-ADM antibody or ADM-binding anti-ADM antibody fragment or supercontig without ADM-binding anti-ADM Ig. The severity of congestion, the extent of congestion, the degree of congestion, the degree of congestion, and similar terms are used as synonyms in this application. Mature ADM, bio-ADM and ADM-NFfrse are used synonymously in this application and are a molecule according to SEQ ID No.: 20. Pro-adrenomedullin or its fragments are an early, quantitative, and accurate surrogate for congestion in the context of acute heart failure and heart failure, particularly in a subject with acute heart failure and / or a subject with worsening heart failure and / or a subject with symptoms of heart failure or acute heart failure. An early and accurate surrogate for congestion in the context of acute heart failure or heart failure means that its concentration and / or level of immune reactivity reflects the degree of congestion. If said level of Pro-Adrenomedullin or fragments thereof is above a certain threshold level, the anti-ADM antibody or ADM-binding anti-ADM antibody fragment or ADM-binding anti-ADM Ig supercontigo is suitable for administration as congestion therapy or intervention. This means, in a subject matter of the specific modality of the present invention, that said anti-ADM antibody or ADM-binding anti-ADM antibody fragment or ADM-binding anti-ADM Ig supercontigo is for use in the intervention and therapy of congestion in a patient, wherein a sample of body fluid taken from said patients exhibits an elevated level of proADM and / or fragments thereof having at least 5 amino acids above a certain threshold. Therefore, the diagnostic method using said proADM and / or fragments serves as a complementary diagnostic method. In a specific modality of the diagnostic method, said proADM and / or fragments thereof having at least 5 amino acids are selected from the group comprising: SEQ ID No. 31 (proADM): 164 amino acids (22 - 185 from preproADM) ARLDVASEF RKKWNKWALS RGKRELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RVKRYRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGYGRRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL SEQ ID No. 32 (N-20 terminal proadrenomedullin peptide, PAMP): amino acids 22-41 of preproADM ARLDVASEF RKKWNKWALS R SEQ ID No. 33 (mid-region proAdrenomedullin, MR-proADM): amino acids 45-92 of preproADM ELRMSS SYPTGLA.DVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV SEQ ID No. 20 (mature adrenomedullin (mature ADM); amidated ADM; bio-ADM): amino acids 95-146-CONH2 YRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGY - CONH2 SEQ ID No. 34 (Adrenomeduin 1-52-Gly (ADM 1-52-Gly)): amino acids 95-147 of preproADM YRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK iSPQGYG SEQ ID No. 35 (C-terminal proadrenomeduin, CT-proADM): amino acids 148 - 185 of preproADM RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL In a specific modality of the diagnostic method, said proADM and / or fragments thereof having at least 5 amino acids are selected from the group comprising mature ADM-NH2 (SEQ ID No. 20), ADM 1-52-Gly (SEQ ID No. 34), MR-proADM (SEQ ID No. 33) and CT-proADM (SEQ ID No. 35). In a specific modality of the diagnostic method, the level of mature ADM-NH2 (SEQ ID No. 20) and / or ADM 1-52-Gly (SEQ ID No. 34) - immunoreactivity or the level of MR-proADM (SEQ ID No. 33) immunoreactivity or the level of CT-proADM (SEQ ID No. 35) immunoreactivity is determined and correlated with the need of said patient for therapy or intervention, where said patient is identified as having such need if the level of mature ADM-NH2 (SEQ ID No. 20) and / or ADM 1-52-Gly (SEQ ID No. 34) - immunoreactivity or the level of MR-proADM (SEQ ID No. 33) immunoreactivity or the level of CT-proADM (SEQ ID No. 35) immunoreactivity in the body fluid of said subject is above a threshold. In a specific modality of the diagnostic method, the level of proADM and / or its fragments is determined using at least one binder selected from the group: a binder that binds to a region within the following sequence of mature ADM-NH (SEQ ID No. 20) and / or ADM1-52-Gly (SEQ ID No. 34) and a second binder that binds to a region within the sequence of mature ADM-NI (SEQ ID No. 20) and / or ADM 1-52-Gly (SEQ ID No. 34). In a specific modality of the diagnostic method, the level of proADM and / or fragments thereof is determined using at least one binder selected from the group: a binder that binds to a region within the MR-proADM sequence (SEQ ID No. 33) and a second binder that binds to a region within the MR-proADM sequence (SEQ ID No. 33). In a specific modality of the diagnostic method, the level of pro-ADM and / or fragments thereof is determined using at least one binder selected from the group: a binder that binds to a region within the CT-proADM sequence (SEQ ID No. 35) and a second binder that binds to a region within the CT-pro-ADM sequence (SEQ ID No. 35). The subject matter in a particular modality of the present diagnostic method is a method, according to the present invention, in which said fragment can be selected from MR-proADM according to SEQ ID No.: 33 or mature ADM-NH2 according to SEQ ID No.: 20. The subject matter of the present diagnostic method is a method according to the diagnostic method of the invention, wherein the level of Pro-Adrenomedullin or fragments thereof of at least 5 amino acids is determined using a binder for Pro-Adrenomedullin or fragments thereof of at least 5 amino acids. The subject matter of the present diagnostic method is a method, in accordance with the diagnostic method, wherein the binder is selected from the group comprising an antibody, an antibody fragment or a supercontiguous binding without IG to Prc-Adrenomedullin or fragments thereof of at least 5 amino acids. A body fluid according to the present invention is, in one particular embodiment, a blood sample. A blood sample may be selected from the group comprising whole blood, serum, and plasma. In a specific embodiment of the diagnostic method, such a sample is selected from the group comprising human citrate plasma, heparin plasma, and EDTA plasma. In a specific embodiment of the invention, said anti-ADM antibody or ADM-binding anti-ADM antibody fragment or ADM-binding anti-ADM Ig supercontig is for use in congestion intervention and therapy in a patient according to any embodiment of the invention, wherein said patient is resistant to diuretics or does not respond to diuretic therapy. Another specific embodiment of the invention relates to said anti-adrenomedullin antibody or anti-adrenomedullin antibody fragment or anti-ADM Ig-free supercontig for use in congestion intervention and therapy in a patient in need thereof, wherein said anti-ADM antibody or anti-ADM fragment or anti-ADM Ig-free supercontig binds to the N-terminal portion (aa 1-21) of adrenomedullin: YRQSMNNFQGLRSFGCRFGTC (SEQ ID No. 22), and where the patient is resistant to diuretics or does not respond to diuretic therapy. The term “diuretic resistance” is generally defined as the inability to decrease extracellular fluid volume despite liberal use of diuretics (Ravnan et al. 2002. CHF 8:80-85). Epstein et al. defined diuretic resistance as a failure to excrete at least 90 mmol of sodium within 72 hours of an oral furosemide dose of 160 mg adapted to be administered twice daily (Epstein et al. 1977. Curr Ther Res. 21:656-667). Adaptation to diuretic drugs and diuretic resistance can be caused by similar mechanisms. Diuretic adaptations can be classified as those that occur during diuretic action, those that cause short-term sodium retention (causing 'posi-diuretic NaCl retention'), and those that increase sodium retention chronically (the 'braking phenomenon'). The ways in which the kidneys adapt to chronic diuretic treatment are: First, downstream nephron segments from the site of diuretic action increase NaCl reabsorption during diuretic administration because the delivered NaCl load increases. Second, when diuretic concentrations in the tubule decrease, the renal tubules act to retain NaCl until the next diuretic dose is administered.Third, the ability of the diuretic to increase renal excretion of NaCl decreases over time, an effect that results from both depletion of extracellular fluid volume and structural and functional changes in the tubules themselves. renal. All these adaptations increase the rate of NaCl reabsorption and reduce the effectiveness of diuretic therapy. For a review, see Ellison 1999. Semin Nephrol. 19(6):581-97 and De Bruyne 2003. Postgrad Med J 79:268-271. Although difficult to quantify, diuretic resistance is thought to occur in one out of three patients with congestive heart failure. Heart failure represents the most common clinical situation in which diuretic resistance is observed. In mild congestive heart failure, diuretic resistance is not frequently found, provided renal function is maintained. However, in patients with moderate and severe congestive heart failure, diuretic resistance occurs more frequently and often becomes a clinical problem (Brater 1985. Drugs 30:427-443; Taylor 2000 Cardiol Rev. 8:104-114). In a specific embodiment of the diagnostic method, an assay is used to determine the level of proADM and / or fragments thereof that have at least 5 amino acids, wherein the sensitivity of said assay is capable of quantifying mature ADM-NH2 from healthy subjects and is < 70 pg / ml, preferably < 40 pg / ml and more preferably < 10 pg / ml. The concentrations mentioned above may be used as thresholds for the methods according to the present invention. In a specific modality of the diagnostic method, an assay is used to determine the level of proADM and / or fragments thereof that have at least 5 amino acids, where the sensitivity of said assay is capable of quantifying MR-proADM from healthy subjects and is < 0.5 nmol / L, preferably < 0.4 nmol / L and more preferably < 0.2 nmol / L. The concentrations mentioned above may be used as thresholds for the methods according to the present invention. In a specific modality of the diagnostic method, an assay is used to determine the level of proADM and / or fragments thereof that have at least 5 amino acids, where the sensitivity of said assay is capable of quantifying CT-proADM of healthy subjects and is < 100 pmol / L, preferably < 75 pmol / L and more preferably < 50 pmol / L. The concentrations mentioned above may be used as thresholds for the methods according to the present invention. In a specific modality of the diagnostic method, said binder shows a binding affinity to proADM and / or fragments thereof of at least 10 7 M 1 , preferred 10 8 M 1 , the preferred affinity is greater than 10® IVT1 , most preferred greater than 10 10 M 1 An expert in the art knows that a lower affinity can be compensated for by applying a higher dose of compounds, and this measure would not be outside the scope of the invention. To determine the affinity of antibodies to adrenomedullin, the binding kinetics of adrenomedullin to immobilized antibody were determined by unlabeled surface plasmon resonance using a Biacore 2000 system (GE Healthcare Europe GmbH, Freiburg, Germany). Reversible immobilization of the antibodies was performed using a high-density covalently coupled anti-mouse Fe antibody on a CM5 sensor surface according to the manufacturer's instructions (mouse antibody capture kit; GE Healthcare) (Lorenz et al. 2011. Antimicrob Agents). Chemother. 55 (1): 165-1737 In a specific modality of the diagnostic method, said agglutinant is selected from the group comprising an antibody or an antibody fragment or an Ig-free supercluster binding to proADM and / or fragments thereof. In a specific modality of the diagnostic method, an assay is used to determine the level of proADM and / or fragments thereof that have at least 5 amino acids, wherein said assay is an intercalated assay, preferably a fully automated assay. In one embodiment of the invention, there may be a so-called point-of-care (POC) test, which is a testing technology that allows the test to be performed in less than one hour near the patient without requiring a fully automated assay system. An example of this technology is immunochromatographic testing. In one modality of the diagnostic method, such an assay is an intercalating immunoassay that utilizes any type of detection technology, including but not limited to enzyme labeling, chemiluminescence labeling, and electrochemiluminescence labeling, preferably a fully automated assay. In one modality of the diagnostic method, such an assay is an intercalating labeled enzyme assay. Examples of automated or fully automated assays include assays that can be used with one of the following systems: Roche Elecsys®, Abbott Architect®, Siemens Centauer®, Brahms Kryptor®, BioMérieuxVidas®, and Alere Triage®. A variety of immunoassays are known and can be used for the assays and methods of the present invention, including: radioimmunoassays (“RIA”), enzyme-multiplied homogeneous immunoassays (“EMIT”), enzyme-linked immunosorbent assays (“ELISA”), apoenzyme reactivation immunoassay (“ARIS”), dipstick immunoassays, and immunochromatographic assays. In a specific modality of the diagnostic method, at least one of these two binders is marked to be labeled. The subject matter of the present invention is an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig for use in congestion intervention and therapy in a patient where said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease. The subject matter of the present invention is an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM ig-free supercontig for use in congestion intervention and therapy in a patient in which said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema) and heart failure, in particular acute heart failure. Heart failure (HF) is a heart condition that occurs when a problem with the structure or function of the heart affects its ability to supply enough blood flow to to meet the body's needs. This can cause a wide variety of symptoms, especially shortness of breath (SOB) at rest or during exercise, signs of fluid retention such as pulmonary congestion or ankle swelling, and objective evidence of an abnormality in the structure or function of the heart at rest. Heart failure is a clinical syndrome characterized by a constellation of symptoms and signs caused by cardiac dysfunction. It is a leading cause of morbidity and mortality in developed countries, with a prevalence of 1–2%. Heart failure can be grouped into chronic heart failure and acute heart failure. Patients with chronic heart failure can be further grouped into stable chronic heart failure, those with worsening signs and symptoms of chronic heart failure, and those with acute decompensation of chronic heart failure. Acute heart failure (AHF) is defined as a rapid onset of heart failure signs and symptoms resulting in the need for urgent therapy or hospitalization.Acute heart failure can present as de novo acute heart failure (a new onset of acute heart failure in a patient with no prior cardiac dysfunction) or as acute decompensation of chronic heart failure. Acute heart failure is the leading cause of hospitalization in adults over 65 years of age. Despite marked improvements in the prognosis of patients with chronic heart failure, primarily related to therapeutic advances in recent decades, short- and long-term outcomes remain very poor once patients are hospitalized for decompensated heart failure. Nearly 25% of patients hospitalized for acute heart failure require readmission within 30 days of hospital discharge, while fewer than 50% survive more than 5 years after hospitalization.In addition to significantly reducing survival and quality of life for affected patients, the financial burden of acute heart failure on healthcare systems is enormous. The total cost of heart failure care was estimated at $31 billion in the US alone in 2012, with the majority of this cost associated with hospital care. This cost is projected to rise to an unprecedented $70 billion by 2030 due to the aging population. Heart failure encompasses a wide range of patients, from those with a normal left ventricular ejection fraction (LVEF), generally considered to be >50%, also known as heart failure with preserved ejection fraction (HFpEF), to those with reduced LVEF, typically considered to be <40%, also known as heart failure with reduced ejection fraction (HFrEF). Patients with an LVEF in the 40–49% range represent a 'gray area,' defined as heart failure with mid-range ejection fraction (HFmrEF) (Ponikowski et al. 2016. European Heart Journal 1818): 891–975). The primary goal of treatment for acute heart failure in the hospital setting is decongestion (removal of excess intracellular and extracellular fluid) and relief of the symptoms and signs of congestion. Diuretics remain the mainstay of decongestive therapy during the hospital stay for acute heart failure, and almost all hospitalized patients receive this class of drugs. Other classes of medications that increase cardiac output and reduce filling pressure, such as inotropes and vasodilators, are administered in selected patient groups. Ultrafiltration could also be considered in some patients, particularly those who do not respond adequately to diuretic therapy. Although patients generally respond well to diuretic therapy, a significant proportion are discharged from the hospital without achieving an adequate level of decongestion and euvolemic status (i.e., residual congestion). This is primarily related to the fact that current approaches to the clinical assessment of congestion are inadequate. Consistent evidence indicates that the presence of residual congestion at hospital discharge is associated with worse post-discharge outcomes, particularly hospital readmissions. Therefore, there is a significant unmet need for a more accurate and reliable surrogate for congestion that can facilitate objective and optimal decision-making regarding the adequacy of the level of decongestion achieved and the timing of hospital discharge. In one particular aspect of the invention, the subject is a subject with heart failure. In another particular aspect of the invention, the subject is a subject with acute heart failure and / or a subject with heart failure exhibiting signs of worsening and / or a subject with symptoms of heart failure or acute heart failure. In one particular aspect of the invention, the subject has acute heart failure, i.e., acute heart failure of recent onset or acute decompensated heart failure. In another particular aspect of the invention, the subject has acute decompensated chronic heart failure or worsening signs / symptoms of chronic heart failure. In one particular aspect of the invention, the subject has acute heart failure, specifically, newly onset acute heart failure. The term “acute” is used to refer to a rapid onset and to describe exacerbated or decompensated heart failure, referring to episodes in which a patient may be characterized by a change in the signs and symptoms of heart failure that results in a need for urgent therapy or hospitalization. The term “chronic” refers to long duration. Chronic heart failure is a long-term condition, usually kept stable by treating the symptoms (stable chronic heart failure). Stable chronic heart failure is characterized by: 1. The presence of a structural or functional failure of the heart that affects its ability to supply sufficient blood flow to meet the body's needs, 2. the absence of volume overload (manifested by pulmonary and / or systemic congestion) and / or profound depression of cardiac output (manifested by hypotension, renal failure and / or shock syndrome), and while the patient does not need urgent therapy or therapy adjustment and does not require hospitalization. Chronic heart failure with worsening signs and symptoms is characterized by: 1. The presence of a structural or functional failure of the heart that affects its ability to supply sufficient blood flow to meet the body's needs, 2. Volume overload (manifested by pulmonary and / or systemic congestion) and / or profound depression of cardiac output (manifested by hypotension, renal failure and / or shock syndrome), And while the patient does not need urgent treatment and does not require hospitalization, they do need a therapy adjustment. Chronic heart failure can also decompensate (referred to as acute decompensated heart failure or acute decompensated chronic heart failure), which is most commonly the result of an intercurrent illness (such as pneumonia), myocardial infarction, arrhythmias, uncontrolled hypertension, or the patient's failure to adhere to fluid restriction, diet, or medication. Following treatment, patients with acute decompensated chronic heart failure may return to a stable, chronically compensated state (stable chronic heart failure). Acute heart failure of recent onset and acute decompensated chronic heart failure are characterized by: 1. The presence of a structural or functional failure of the heart that affects its ability to supply sufficient blood flow to meet the body's needs, 2. Volume overload (manifested by pulmonary and / or systemic congestion) and / or profound depression of cardiac output (manifested by hypotension, renal failure and / or shock syndrome), and while the patient needs urgent therapy or an adjustment of therapy and requires hospitalization. Acute heart failure Chronic heart failure New-onset acute heart failure Acute decompensated heart failure Acute decompensated chronic heart failure Worsening of symptoms / signs of chronic heart failure Stable chronic heart failure The above definitions of acute heart failure appearing as new-onset acute heart failure or acute decompensated heart failure or acute decompensated chronic heart failure or worsening of signs / symptoms of chronic heart failure are in line with Voors et al., European Journal of Heart Failure (2016), 18, 716-726. Impaired renal function is common in acute and chronic heart failure (HF) settings, which are increasingly described as “cardiorenal syndromes.” Renal congestion (RC) has become more widely recognized as a potential contributor to cardiorenal syndromes, and adequate control of congestion with simultaneous improvement / preservation of renal function has been proposed as a central goal of HF patient management (Aronson 2012. Expert Rev Cardiovasc Ther 10: 177-189). Congestion in heart failure is defined as a ventricular diastolic pressure High left ventricular dysfunction is associated with signs and symptoms of heart failure, such as dyspnea, crackles, and / or edema. These congestion-related signs and symptoms are the primary reasons for heart failure-related hospitalizations. While relieving congestion (and its associated signs and symptoms) and achieving euvolemic status remain the primary goals of acute heart failure therapy in the hospital, there is no standard algorithm or clinical tool for assessing congestion. Current practices for clinical congestion assessment revolve around signs and symptoms. Physical examination findings, such as elevated jugular venous pressure (JVP), peripheral edema, orthopnea, S3 heart sound, and hepatomegaly, or chest X-ray findings, such as cardiomegaly and interstitial / alveolar edema, are used as surrogate markers for congestion. It should be noted that, aside from a carefully performed JVP assessment, the predictive value of these parameters for detecting congestion is modest to moderate. There is a significant unmet need for a reliable and accurate surrogate marker for congestion.There is a high and unmet medical need to determine, predict, evaluate, and / or monitor traffic congestion and decongestion both quantitatively and qualitatively. There is a need to determine, predict, evaluate, and / or monitor the extent of congestion, that is, the degree of congestion. For the present invention, the extent of congestion can also be expressed as the degree of congestion severity and has been determined as described below. However, a person skilled in the art knows that the degree of congestion can be expressed by other scores or substitutes, such as the score used by Ambrosy et al. (Ambrosy et al. 2013. European Heart Journal 34 (11):835-843). As explained previously, congestion can be classified in many different ways. Those skilled in the technique know that the degree of congestion can be expressed using other scoring systems or surrogates. Clinical classification can be based on bedside physical examination to detect the presence of clinical symptoms / signs of congestion (“wet” vs. “dry,” present vs. absent) and / or peripheral hypoperfusion (“cold” vs. “warm,” present vs. absent) (for review, see Ponikowski et al. 2016. Eur Heart J. ehw128). Combining these options identifies four groups: warm and wet (well-perfused and congested): most commonly present; cold and wet (hypoperfused and congested); cold and dry (hypoperfused without congestion); and warm and dry (compensated, well-perfused without congestion). This classification can be useful in guiding therapy in the initial phase and carries prognostic information. Typically, the symptoms and signs of acute heart failure reflect fluid overload (pulmonary congestion and / or peripheral edema) or, less frequently, reduced cardiac output with peripheral hypoperfusion. Chest radiography can be a useful test for diagnosing acute heart failure. Pulmonary venous congestion, pleural effusion, interstitial or alveolar edema, and cardiomegaly are the most specific findings in acute heart failure, although in up to 20% of patients with acute heart failure, the chest radiograph is nearly normal. Symptoms / signs of congestion (left side) are defined as orthopnea, paroxysmal dyspnea Nocturnal sounds, pulmonary crackles (bilateral), peripheral edema (bilateral). Symptoms / signs of congestion (right side) are defined as jugular venous dilation, peripheral edema (bilateral), congested hepatomegaly, hepatojugular reflux, ascites, symptoms of intestinal congestion (for review see table 12.2 in Ponikowski et al. 2016. Eur Heart J. ehw128). Edema is an accumulation of fluid in the intercellular tissue resulting from an abnormal expansion in interstitial fluid volume. The fluid between the interstitial and intravascular spaces is regulated by the capillary hydrostatic pressure gradient and the oncotic pressure gradient across the capillary (Través et al. 2013. Am Fam Physician 88(2):102-110). Fluid accumulation occurs when local or systemic conditions disrupt this balance, leading to increased capillary hydrostatic pressure, increased plasma volume, decreased plasma oncotic pressure (hypoalbuminemia), increased capillary permeability, or lymphatic obstruction. Clinically, edema manifests as swelling: the amount of interstitial fluid is determined by fluid homeostasis, and increased fluid secretion into the interstitium or impaired fluid elimination can cause edema. Increased hydrostatic pressure occurs in heart failure. Causes of edema that are systemic can lead to edema in multiple organs and peripherally. For example, severe heart failure can cause pulmonary edema, pleural effusions, ascites, and peripheral edema. Pulmonary edema is the accumulation of fluid in the air spaces and parenchyma of the lungs. It leads to impaired gas exchange and can cause respiratory failure. It results from either the failure of the left ventricle of the heart to remove blood from the pulmonary circulation (“cardiogenic pulmonary edema”) or injury to the lung parenchyma or pulmonary vasculature (“noncardiogenic pulmonary edema”) (Ware and Matthav 2005. N. Engl. J. Med. 353 (26): 2788-96). Treatment focuses on three aspects: first, improving respiratory function; second, treating the underlying cause; and third, preventing further lung damage. Pulmonary edema, especially acute pulmonary edema, can cause respiratory fatigue or cardiac arrest due to hypoxia. It is a cardinal feature of congestive heart failure. The most prominent symptom of pulmonary edema is shortness of breath, but it can also include coughing up blood (classically seen as pink, frothy sputum), excessive sweating, anxiety, and pale skin. Shortness of breath may manifest as orthopnea (inability to lie flat due to lack of breath) and / or paroxysmal nocturnal dyspnea (episodes of sudden, severe shortness of breath at night). These are common presenting symptoms of chronic pulmonary edema due to left ventricular failure.The development of pulmonary edema may be associated with symptoms and signs of “fluid overload.” This is a nonspecific term used to describe the manifestations of left ventricular failure in the rest of the body and includes peripheral edema (swelling of the legs, generally of the “pitting” variety, where the skin is slow to return to normal when pressed), increased jugular venous pressure, and hepatomegaly, where the liver is enlarged and may be tender or even pulsatile. Other signs include end-inspiratory crackles (sounds heard at the end of a deep breath) on auscultation and the presence of a third heart sound. As highlighted above, clinical surrogates have a lower predictive value than the optimum for detecting congestion. In the so-called protection study (O'Connor et al. 2012 European Journal of Heart Failure 14: 605-612), three of the strongest clinical surrogates for congestion (i.e., JVP, peripheral edema, and orthopnea) were combined to improve accuracy and developed a composite clinical congestion score (CCS) using the scheme presented below: Parameter 0 1 2 3 Peripheral edema 0 Ankle Below knee Above knee Orthopnea 0 pillow 1 pillow 2 pillows 3 pillows JVP <6cm 6-10cm >10cm The score on each of these three parameters was added together to obtain a composite congestion score, which was in the range between Da 8. The following algorithm was used to classify the severity of the congestion: CCS=0, no clinical congestion CCS 1-3, mild clinical congestion CCS 4-5, moderate clinical congestion CCS >6, severe clinical congestion Conditions that affect the structure and function of the kidney can be considered acute or chronic, depending on their duration (chronic kidney disease (CKD), acute kidney disease (AKD), or acute kidney injury (AKI)). AKD is characterized by structural kidney damage for <3 months and by functional criteria also found in AKI, or a GFR of <60 ml / min per 1.73 m² 2 for <3 months, or a decrease in GFR of >35%, or an increase in serum creatinine (SCr) of >50% for <3 months (Kidney International Supplements, Vol. 2, Issue 1, March 2012, pp. 19-36). AKI is one of several acute kidney diseases and disorders (AKD) and can occur with or without other acute or chronic kidney diseases and disorders. AKI is defined as a reduction in kidney function, including a decrease in glomerular filtration rate (GFR) and kidney failure. The criteria for diagnosing GFR and the stage of AKI severity are based on changes in serum creatinine (SCr) and urine output. Structural criteria are not required in AKI (but may be present), but an increase in serum creatinine (SCr) of 50% over 7 days, or an increase of 0.3 mg / dL (26.5 pmol / L), or oligune, is found. AKI can occur in patients with trauma, stroke, sepsis, systemic inflammatory response syndrome (SIRS), septic shock, acute myocardial infarction (AMI), post-AMI, local and systemic bacterial and viral infections, autoimmune diseases, burn patients, surgical patients, cancer, liver disease, lung disease, as well as in patients receiving nephrotoxins such as cyclosporine, antibiotics including aminoglycosides, and cancer drugs such as cisplatin. Renal failure is a stage of AKI and is defined as a GFR <15 ml / min per 1.73 m 2 of body surface area, or requirement for renal replacement therapy (RRT). CKD is characterized by a glomerular filtration rate (GFR) of <60 ml / min per 1.73 m 2 for > 3 months and for kidney damage for > 3 months (Kidney International Supplements, 2013; Vol. 3: Chronic extracellular volume expansion is one of the most common and traditional disorders comprising the syndrome of end-stage renal disease (ESRD). Mild to moderate volume expansion may go unnoticed in ESRD, but marked fluid overload in these patients is eventually a medical emergency requiring hospitalization and extradialysis. Both pulmonary congestion and congestive heart failure are common in ESRD (Zoccali et al. 2013 Blood Purif 36:184-191). Liver disease (also called hepatic disease) is a type of liver damage or illness. Liver disease can occur through various mechanisms. One common form of liver disease is viral infection, such as that caused by the hepatitis virus. Liver cirrhosis is the formation of fibrous tissue in place of liver cells that have died due to various causes, including viral hepatitis, excessive alcohol consumption, and other forms of liver toxicity that lead to chronic liver failure. Congestive liver disease refers to the spectrum of chronic liver injury attributed to passive hepatic congestion arising in the context of right heart failure or any cause of increased central venous pressure, including severe pulmonary hypertension (Shah and Sass 2015. Liver Res Open J. 1(1): 1-10). Cardiohepatic dysfunction is common in patients with acute decompensated heart failure, and cardiohepatic syndromes share some common pathophysiological mechanisms with cardiorenal syndromes, such as increased venous congestion (Nikolaou et al. 2013. European Heart Journal 34: 742-749). End-stage liver disease results in profound salt and water retention. Although most of this fluid retention manifests in the peritoneal cavity as ascites, peripheral edema can become prominent in later stages, particularly when severe hypoalbuminemia is present (Cha and Atwood 2002).Am J Med. 113:580-586). The congestion intervention or therapy in a patient according to the present invention may be combined with prior art treatments. Prior art congestion therapy or intervention may be selected from the group comprising the administration of diuretics, the administration of inotropes, the administration of vasodilators, and ultrafiltration, particularly diuretics. Furthermore, in one embodiment of the invention, an anti-adrenomedullin (ADM) antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontig is monospecific. A monospecific anti-adrenomedullin (ADM) antibody or monospecific anti-adrenomedullin antibody fragment or monospecific non-IG anti-adrenomedullin supercontig means that said antibody or antibody fragment or non-IG supercontig binds to a specific region that It encompasses at least 5 amino acids within the target ADM. A monospecific anti-adrenomedullin (ADM) antibody, monospecific anti-adrenomedullin antibody fragment, or monospecific IG-free anti-adrenomedullin supercontig is an anti-adrenomedullin (ADM) antibody, anti-adrenomedullin antibody fragment, or IG-free anti-ADM supercontig, all of which have affinity for the same antigen. In another specific and preferred embodiment, the anti-ADM antibody, or anti-ADM antibody fragment, or anti-ADM Ig-free superclone that binds to ADM is a monospecific antibody, antibody fragment, or Ig-free superclone, respectively, wherein monospecific means that said antibody, antibody fragment, or Ig-free superclone binds to a specific region spanning at least four amino acids within the target ADM. The monospecific antibodies, fragments, or Ig-free superclones according to the invention are antibodies, fragments, or Ig-free superclones that all have affinity for the same antigen. Monoclonal antibodies are monospecific, but monospecific antibodies can also be produced by other means that produce them from a common germ cell. Said anti-ADM antibody or antibody fragment that binds to ADM or IG-free supercontigo that binds to ADM may be a non-neutralizing anti-ADM antibody or antibody fragment that binds to ADM or IG-free supercontigo that binds to ADM. In one specific modality, such an anti-ADM antibody, non-neutralizing anti-ADM antibody fragment, or Ig-free anti-ADM supercontig is an antibody, fragment, or supercontig without Ig. A neutralizing anti-ADM antibody, anti-ADM antibody fragment, or Ig-free anti-ADM supercontig would block ADM bioactivity by almost 100%, at least more than 90%, preferably at least more than 95%. In contrast, an anti-ADM antibody, or anti-ADM antibody fragment, or supercontig without anti-ADM Ig blocks ADM bioactivity by less than 100%, preferably less than 95%, preferably less than 90%, more preferably less than 80%, and even more preferably less than 50%. This means that the bioactivity of ADM is reduced to less than 100%, to 95% or less, but no more, to 90% or less, but no more, to 80% or less, but no more, to 50% or less, but no more. This means that the residual bioactivity of ADM bound to the non-neutralizing anti-ADM antibody, or to the anti-ADM antibody fragment, or to the supercontig without anti-ADM Ig would be more than 0%, preferably more than 5%, preferably more than 10%, more preferably more than 20%, and even more preferably more than 50%. In this context, a molecule (or molecules), being an antibody, or an antibody fragment, or an Ig-free supercontig with "non-neutralizing anti-ADM activity," referred to here collectively for simplicity as a "non-neutralizing anti-ADM antibody," an antibody fragment, or an Ig-free supercontig that, for example, blocks ADM bioactivity to less than 80%, is defined as - a molecule or molecules that bind to ADM, which, when added to a culture of a eukaryotic cell line expressing the functional recombinant human ADM receptor composed of CRLR (calcitonin-like receptor) and RAMP3 (receptor activity-modifying protein 3), reduces the amount of cAMP produced by the cell line through the action of the parallel added synthetic human ADM peptide, wherein said added synthetic human ADM is added in an amount which, in the absence of the non-neutralizing antibody to be analyzed, leads to half of the maximum stimulation of cAMP synthesis, wherein the reduction of cAMP by the binding of said molecule(s) to ADM is carried out to a degree that is no more than 80%, even when the non-neutralizing molecule(s) is added to the ADM to be analyzed in an amount that is 10 times greater than the amount needed to obtain the maximum reduction of cAMP synthesis that can be obtained with the non-neutralizing antibody to be analyzed. The same definition applies to the other intervals; 95%, 90%, 50% etc. An antibody or fragment according to the present invention is a protein comprising one or more polypeptides substantially encoded by immunoglobulin genes that bind specifically to an antigen. Recognized immunoglobulin genes include the constant region genes kappa, lambda, alpha (IgA), gamma (IgGi, IgGz, IgGs, IgG-i), delta (IgD), epsilon (IgE), and mu (IgM), as well as the myriad variable region genes of immunoglobulins. Full-length immunoglobulin light chains are generally about 25 kDa or 214 amino acids in length. Full-length immunoglobulin heavy chains are typically around 50 kDa or 446 amino acids long. Light chains are encoded by a variable region gene at the NH₂ terminus (approximately 110 amino acids long) and a constant region gene at the COOH terminus (kappa or lambda). Heavy chains are similarly encoded by a variable region gene (approximately 116 amino acids long) and one of the other constant region genes. The basic structural unit of an antibody is generally a tetramer consisting of two pairs of identical immunoglobulin chains, each pair having a light chain and a heavy chain. In each pair, the variable regions of the light and heavy chains bind to an antigen, and the constant regions mediate selective functions. Immunoglobulins also exist in a variety of other forms including, for example, Fv, Fab, and (Fab')κ, as well as bifunctional hybrid antibodies and single chains (e.g., Lanzavecchia et al. 1987. Eur. J. Immunol. 17:105; Huston et al. 1988. Proc. Nati. Acad. Sei. USA, 85:5879-5883; Bird et al. 1988. Science 242:423-426; Hood et al. 1984, Immunology, Benjamin, NY, 2nd ed.; Hunkapiller and Hood 1986. Nature 323:15-16).A variable region of immunoglobulin light or heavy chain includes a framework region interrupted by three hypervariable regions, also called complementarity-determining regions (CDRs) (see, Sequences of Proteins of Immunological Interest, E. Kabat et al. 1983, US Department of Health and Human Services). As noted above, the CDRs are primarily responsible for binding to an antigen epitope. An immune complex is an antibody, such as a monoclonal antibody, a chimeric antibody, a humanized antibody, or a human antibody, or a functional antibody fragment, specifically bound to an antigen. Chimeric antibodies are antibodies whose light and heavy chain genes have been constructed, usually through genetic engineering, from immunoglobulin variable and constant region genes belonging to different species. For example, the variable segments of a mouse monoclonal antibody gene can be joined to human constant segments, such as kappa and gamma 1 or gamma 3. In one example, a therapeutic chimeric antibody is therefore a hybrid protein composed of the variable or antigen-binding domain of a mouse antibody and the constant or effector domain of a human antibody, although other mammalian species may be used, or the variable region may be produced by molecular techniques. Methods for producing chimeric antibodies are well known in the art; for example, see U.S. Patent No. 5,807,715. A “humanized” immunoglobulin is an immunoglobulin that includes a human structural region and one or more CDRs from a non-human immunoglobulin (such as mouse, rat, or synthetic). The non-human immunoglobulin that provides the CDRs is called a “donor,” and the human immunoglobulin that provides the framework is called an “acceptor.” In one modality, all the CDRs in a humanized immunoglobulin are derived from the donor immunoglobulin.Constant regions need not be present, but if they are, they must be substantially identical to the constant regions of human immunoglobulin, i.e., at least approximately 85–90%, such as approximately 95% or more. Therefore, all parts of a humanized immunoglobulin, except possibly the CDRs, are substantially identical to the corresponding parts of the natural human immunoglobulin sequences. A “humanized antibody” is an antibody comprising a humanized light chain and a humanized heavy chain immunoglobulin. A humanized antibody binds to the same antigen as the donor antibody that provides the CDRs. The acceptor framework of a humanized immunoglobulin or antibody may have a limited number of amino acid substitutions taken from the donor framework.Humanized antibodies or other monoclonal antibodies may have additional conservative amino acid substitutions, which have no substantial effect on antigen binding or other immunoglobulin functions. Exemplary conservative substitutions include gly, ala; val, ile, leu; asp, glu; asn, gln; ser, thr; iys, arg; and phe, tyr. Humanized immunoglobulins may be constructed by genetic engineering (e.g., see U.S. Patent No. 5,585,089). A human antibody is an antibody in which the light and heavy chain genes are of human origin. Human antibodies may be generated using methods known in the art. Human antibodies may be produced by immortalizing a human B cell that secretes the antibody of interest.Immortalization can be achieved, for example, by EBV infection or by fusing a human B cell with a myeloma or hybridoma cell to produce a trioma cell. Human antibodies can also be produced by phage display methods (see, for example, WO91 / 17271; WQ92 / 001047; WO92 / 2Q791), or selected from a collection of human combinatorial monoclonal antibodies (see the Morphosys website). Human antibodies can also be prepared using transgenic animals carrying a human immunoglobulin gene (for example, see WO93 / 12227; WO91 / 10741). Therefore, the anti-ADM antibody can have the forms known in the art. Examples include human antibodies, monoclonal antibodies, humanized antibodies, chimeric antibodies, and antibodies grafted to CDRs. In a preferred embodiment, the antibodies according to the present invention are recombinantly produced antibodies such as, for example, IgG, a typical full-length immunoglobulin, or antibody fragments containing at least the F variable domain of the heavy and / or light chain such as, for example, chemically coupled antibodies (fragment antigen binding) including, among others, Fab fragments including Fab minibodies, single-chain Fab antibody, monovalent Fab antibody with epitope tags, for example Fab-V5Sx2; bivalent Fab (mini-antibody) dimerized with the CH3 domain; bivalent Fab or multivalent Fab, for example formed by multimerization with the help of a heterophobic domain, for example by means of dimerization of the dHLX domains, for example Fab-dHLX-FSx2; F(ab')2- fragments, scFv- fragments, multivalent and / or multispecific multimerized scFv- fragments, bivalent and / or bispecific diabodies, BITE® (bispecific T cell transmitter), trifunctional antibodies, polyvalent antibodies, for example of a class other than G;single-domain antibodies, for example nanobodies derived from immunoglobulins of camelids or fish and many others.; In addition to anti-ADM antibodies, other biopolymer supercontigs are well-known in the technique for complexing a target molecule and have been used to generate highly targeted, specific biopolymers. Examples include aptamers, spiegelmers, anticalins, and conotoxins. For illustrations of antibody formats, please see Fig. 1a, 1b, and 1c. In a preferred embodiment, the anti-ADM antibody format is selected from the group comprising Fv fragment, scFv fragment, Fab fragment, scFab fragment, F(ab)2 fragment, and scFv-Fc fusion protein. In another preferred embodiment, the antibody format is selected from the group comprising scFab fragment, Fab fragment, scFv fragment, and bioavailability-optimized conjugates thereof, such as PEGylated fragments. One of the most preferred formats is the scFab format. Ig-free supercontiges can be protein supercontiges and can be used as antibody mimics, since they are able to bind to ligands or antigens. Ig-free supercontigs may be selected from the group comprising tetranectin-based Ig-free supercontigs (e.g., those described in US 2010 / 0028995), fibronectin-based supercontigs (e.g., those described in EP 1 266 025), lipocalin-based supercontigs (e.g., those described in IVO 2011 / 154420), ubiquitin-based supercontigs (e.g., those described in WO 2011 / 073214), transferrin-based supercontigs (e.g., those described in US 2004 / 0023334), protein A-based supercontigs (e.g., those described in EP 2 231 860), ankyrin repeat-based supercontigs (e.g., those described in WO 2010 / 060748), and microproteins, preferably cysteine-knot-forming microproteins. supercontigs (for example described in EP 2314308).Fyn SH3 domain-based supercontigs (e.g., described in WO 2011 / 023685), EGFR-A domain-based supercontigs (e.g., described in IVO 2005 / 040229), and Kunitz domain-based supercontigs (e.g., described in EP 1 941 867). In one embodiment of the invention, the anti-ADM antibodies according to the present invention can be produced as described in Example 1 by synthesizing ADM fragments as antigens. Afterward, the binder of said fragments is identified using the methods described below or other methods known in the art. The humanization of murine antibodies can be performed according to the following procedure: For the humanization of a murine antibody, the antibody sequence is analyzed to determine the structural interaction of the framework regions (FRs) with the complementary determinant regions (CDRs) and the antigen. Based on structural modeling, an appropriate human FR is selected, and the murine CDR sequences are transplanted into the human FR. Variations in the amino acid sequence of the CDRs or FRs can be introduced to recover structural interactions that were abolished by the species change for the FR sequences. This recovery of structural interactions can be achieved through a random approach using phage display collections or through a targeted approach guided by molecular modeling (Almagro and Fransson 2008. Humanization of antibodies. Front Biosci. 2008 Jan 1;13:1619–33). In a preferred embodiment, the ADM antibody format is selected from the group comprising Fv fragment, scFv fragment, Fab fragment, scFab fragment, F(ab)2 fragment, and scFv-Fc fusion protein. In another preferred embodiment, the antibody format is selected from the group comprising scFab fragment, Fab fragment, scFv fragment, and bioavailability-optimized conjugates thereof, such as PEGylated fragments. One of the most preferred formats is the scFab format. In another preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or anti-ADM Ig-free supercontig is a full-length antibody, an antibody fragment, or an Ig-free supercontig. In a preferred embodiment, the anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontig is targeted and can bind to an epitope of at least 5 amino acids in length contained in ADM, In a more preferred embodiment, the anti-adrenomedullin antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig is targeted and can bind to an epitope of at least 4 amino acids in length contained in ADM, In a specific embodiment of the invention, the anti-adrenomedullin antibody or anti-ADM antibody fragment binding to adrenomedullin or anti-ADM non-Ig supercontig that binds to adrenomedullin is provided for use in therapy or prevention of an acute disease or acute condition of a patient wherein said antibody or fragment or supercontig is not ADM protein-binding 1 (complement factor H). In a specific embodiment of the invention, the anti-adrenomedullin antibody or anti-ADM antibody fragment binding to adrenomedullin or non-Ig anti-ADM supercontig that binds to adrenomedullin is provided for use in the therapy or prevention of an acute disease or acute condition in a patient, wherein said antibody or antibody fragment or non-Ig supercontig binds to a region of at least 4, or at least 5 amino acids within the amino acid sequence 1-42 of mature human ADM: SEQ ID No.: 23 YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA. In a specific embodiment of the invention, the anti-adrenomedullin antibody or anti-adrenomedullin-binding antibody fragment or anti-adrenomedullin-binding supercontig is provided for use in the therapy or prevention of an acute disease or acute condition of a patient wherein said antibody or fragment or supercontig binds to a region of preferably at least 4, or at least 5 amino acids within the amino acid sequence 1-21 of mature human ADM: SEQ ID No.: 22 YRQSMNNFQGLRSGFGCRFGTC. In a preferred embodiment of the present invention, said anti-ADM antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig binds to an ADM region or epitope located in the N-terminal part (aa 1-21) of adrenomedullin. In another preferred embodiment, said anti-ADM antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig recognizes and binds to a region or epitope within amino acids 1-14 (SEQ ID No.: 25) of adrenomedullin; this means the N-terminal portion (aa 1-14) of adrenomedullin. In another preferred embodiment, said anti-ADM antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig recognizes and binds to a region or epitope within amino acids 1-10 of adrenomedullin (SEQ ID No.: 26); this means the N-terminal portion (aa 1-10) of adrenomedullin. aa 1-14 of ADM YRQSMNNFQGLRSF (SEQ ID No.: 25) aa 1-10 of ADM YRQSMNNFQG (SEQ ID No.: 26) In another preferred embodiment, said anti-ADM antibody or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig recognizes and binds to a region or epitope within amino acids 1-6 of adrenomedullin (SEQ ID No.: 27); meaning the N-terminal portion (aa 1-6) of adrenomedullin. As stated above, said region or epitope preferably comprises at least 4 or at least 5 amino acids in length. aa 1-6 of ADM YRQSMN (SEQ ID No.: 27) In another preferred embodiment, the anti-ADM antibody, or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig, recognizes and binds to the N-terminal end (aa1) of adrenomedullin. The N-terminal end refers to amino acid 1, which is "Y" of SEQ ID No. 20, 22, or 23; it is mandatory for antibody binding. The antibody, fragment, or supercontig will not bind to the extended N-terminal, modified N-terminal, or degraded N-terminal adrenomedullin. This means that, in another preferred embodiment, the anti-ADM antibody, or an anti-adrenomedullin antibody fragment or supercontig without anti-ADM Ig, binds only to a region within the mature ADM sequence if the N-terminal end of ADM is free. In this mode, the anti-ADM antibody or the anti-adrenomedullin antibody fragment or supercontig without Ig would not bind to a region within the mature ADM sequence if that sequence is, for example, included within pro-ADM. For clarity, experts in the technique understand that the numbers in parentheses for specific regions of ADM such as “N-terminal part (aa 1-21)” comprise that the N-terminal part of ADM consists of amino acids 1-21 of the mature ADM sequence. In another specific embodiment according to the invention, the present document provides an anti-ADM antibody or an anti-ADM antibody fragment or an anti-ADM Ig-free supercontig that does not bind to the C-terminal portion of ADM, i.e., to aa 43-52 of ADM (SEQ ID No.: 24) PRSKISPQGY-NH2 In a specific embodiment, it is preferred to use an anti-ADM antibody or an anti-adrenomedullin antibody fragment or supercontigo without Ig anti-ADM according to the present invention, wherein said anti-adrenomedullin antibody or said anti-adrenomedullin antibody fragment or supercontigo without Ig leads to an increase in the level of ADM or ADM immunoreactivity in serum, blood, plasma of at least 10%, preferably at least 50%, more preferably > 50%, more preferably > 100%. In a specific embodiment, it is preferred to use an anti-ADM antibody or an anti-adrenomedullin antibody fragment or Ig-free anti-ADM supercontig according to the present invention, wherein said anti-adrenomedullin antibody or said anti-adrenomedullin antibody fragment or Ig-free supercontig is an ADM-stabilizing antibody or an adrenomedullin-stabilizing antibody fragment or an Ig-free adrenomedullin-stabilizing supercontig that improves the half-life (ti / z; mean retention time) of adrenomedullin in serum, blood, plasma by at least 10%, preferably at least 50%, more preferably > 50%, most preferably > 100%. The half-life (mean retention time) of ADM can be determined in human serum, blood, or plasma in the absence and presence of an ADM-stabilizing antibody or an adrenomedullin-stabilizing antibody fragment or an adrenomedullin-stabilizing Ig-free supercontig, respectively, using an immunoassay for ADM quantification. The following stages can be carried out: - ADM can be diluted in human citrate plasma in the absence and presence of an ADM-stabilizing antibody or an adrenomedullin-stabilizing antibody fragment or an adrenomedullin-stabilizing Ig-free supercontigo, respectively, and can be incubated at 24°C. - Aliquots are taken at selected time points (e.g., within 24 hours) and the degradation of ADM can be stopped in these aliquots by freezing at -20°C. The amount of ADM can be determined directly by an hADM immunoassay if the assay is not influenced by the stabilizing antibody. Alternatively, the aliquot can be treated with denaturing agents (such as HCl) and, after sample removal (e.g., by centrifugation), the pH can be neutralized and the ADM quantified by an ADM immunoassay. Alternatively, non-immunoassay technologies (e.g., RP-HPLC) can be used for ADM quantification. - The half-life of ADM is calculated for ADM incubated in the absence and presence of an antibody ADM stabilizer or an adrenomedullin-stabilizing antibody fragment or Ig-free adrenomedullin-stabilizing supercontigo, respectively. - The half-life improvement is calculated for stabilized ADM compared to ADM that has been incubated in the absence of an ADM-stabilizing antibody or an adrenomedullin-stabilizing antibody fragment or an adrenomedullin-stabilizing Ig-free supercontig. A twofold increase in the half-life of ADM is a 100% half-life improvement. The half-life (average retention time) is defined as the period during which it takes for the concentration of a specific chemical or drug to fall to half its reference concentration in the specified fluid or blood. Example 3 describes an assay that can be used to determine the half-life (mean retention time) of adrenomedullin in serum, blood, and plasma. In a preferred embodiment, such a non-neutralizing anti-ADM antibody, anti-ADM antibody fragment, or super-tig without anti-ADM Ig is an antibody, fragment, or super-tig. A neutralizing anti-ADM antibody, anti-ADM antibody fragment, or super-tig without anti-ADM Ig would block ADM activity to nearly 100%, to at least more than 90%, preferably to at least more than 95%. In other words, this means that the non-neutralizing anti-ADM antibody, anti-ADM antibody fragment, or super-tig without anti-ADM Ig blocks ADM activity to less than 100%, preferably less than 95%, preferably less than 90%.In another modality where such an anti-ADM antibody without neutralization, anti-ADM antibody fragment, or supercontig without anti-ADM Ig blocks ADM activity to less than 95%, an anti-ADM antibody, anti-ADM antibody fragment, or supercontig without anti-ADM Ig that would block ADM bioactivity to more than 95% would be outside the scope of that modality. This means that in a modality, bioactivity is reduced to 95% or less but not more, preferably to 90% or less, more preferably to 80% or less, and more preferably to 50% or less but not more. In one embodiment of the invention, the antibody is a non-neutralizing antibody that binds to a region of at least 5 amino acids within the aa 1-42 sequence of mature human ADM (SEQ ID No.: 23), preferably within the aa 1-32 sequence of mature human ADM (SEQ ID No.: 28), or an antibody that binds to a region of at least 5 amino acids within the aa 1-40 sequence of mature murine ADM (SEQ ID No.: 29), preferably within the aa 1-31 sequence of mature murine ADM (SEQ ID No.: 30). In another preferred embodiment of the invention, the non-neutralizing antibody is an antibody that binds to a region of at least 4 amino acids within the aa 1-42 sequence of mature human ADM (SEQ ID No.: 23), preferably within the aa 1-32 sequence of mature human ADM (SEQ ID No.: 28), or an antibody that binds to a region of at least 4 amino acids within the aa 1-40 sequence of mature murine ADM (SEQ ID No.: 29), preferably within the aa 1-31 sequence of mature murine ADM (SEQ ID No.: 30). aa 1-32 ADM human mature human YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQ (SEQ ID No.: 28) aa 1-40 ADM murine human YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGMA (SEQ ID No.: 29) aa 1-31 ADM murine human YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQL (SEQ ID No.: 30) In a specific embodiment according to the present invention, an anti-ADM antibody without neutralization, or an adrenomedullin antibody fragment, or an Ig-free ADM supercluster is used, wherein said anti-ADM antibody or anti-adrenomedullin antibody fragment blocks the bioactivity of ADM to less than 80%, preferably less than 50% (of the reference values). It is understood that said limited blockade of the bioactivity (i.e., reduction of bioactivity) of ADM occurs even at an excess concentration of the antibody, fragment, or supercluster, meaning an excess of the antibody, fragment, or supercluster relative to ADM. This limited blockade is an intrinsic property of the ADM binder itself in said specific embodiment. This means that said antibody, fragment, or supercluster has a maximum inhibition of 80% or 50%, respectively.In a preferred embodiment, the anti-ADM antibody, anti-ADM antibody fragment, or supercontig without anti-ADM Ig would block or reduce the bioactivity of anti-ADM to at least 5%. This means that approximately 20%, 50%, or even 95% of the residual ADM bioactivity would remain, respectively. Therefore, according to the present invention, the anti-ADM antibodies, anti-ADM antibody fragments, and non-provided anti-ADM supercontigs do not neutralize the respective ADM bioactivity. Bioactivity is defined as the effect a substance exerts on a living organism, tissue, organ, or functional unit in vivo or in vitro (e.g., in an assay) following its interaction. In the case of ADM bioactivity, this could be the effect of ADM in a functional cAMP assay of the recombinant human adrenomedullin receptor. Thus, according to the present invention, bioactivity is defined by a functional cAMP assay of the adrenomedullin receptor. The following steps can be performed to determine the bioactivity of ADM in such an assay: - Dose response curves are performed with ADM in said functional assay of recombinant human adrenomedullin receptor cAMP. - The ADM concentration can be calculated from the maximum mean cAMP stimulation. - At constant semi-maximal cAMP-stimulating ADM concentrations, dose response curves (up to 100 pg / ml final concentration) are performed by an ADM-stabilizing antibody or an adrenomedullin-stabilizing antibody fragment or an adrenomedullin-stabilizing Ig-free supercontig, respectively A maximum inhibition of 50% in said ADM bioassay means that said anti-ADM antibody, or said anti-adrenomedullin antibody fragment, or said Ig-free anti-adrenomedullin supercontig, respectively, blocks ADM bioactivity to 50% of the reference values. A maximum inhibition of 80% in said ADM bioassay means that said anti-ADM antibody, or said anti-adrenomedullin antibody fragment, or said Ig-free anti-adrenomedullin supercontig, respectively, blocks ADM bioactivity to 80%. This is in the sense of blocking ADM bioactivity to no more than 80%. This means that approximately 20% of the residual ADM bioactivity remains. present. However, according to the present description and in the above context, the expression “blocks ADM bioactivity” in relation to the anti-ADM antibodies described herein, the anti-ADM antibody fragments and the Ig-free anti-ADM supercontigs should be understood as merely decreasing ADM bioactivity from 100% to 20% of the remaining ADM bioactivity at most, preferably decreasing ADM bioactivity from 100% to 50% of the remaining ADM bioactivity; but in any case, there remains ADM bioactivity that can be determined as detailed above. The bioactivity of ADM can be determined in a recombinant human adrenomedullin receptor cAMP functional assay (adrenomedullin bioassay) according to Example 2. In a preferred embodiment, a modulating antibody or a modulating anti-adrenomedullin antibody fragment or an Ig-nonmodulating anti-adrenomedullin supercontig is used in therapy or prevention of a chronic or acute disease or acute condition in a patient to stabilize circulation, particularly by stabilizing systemic circulation. A "modulating" anti-ADM antibody, modulating anti-adrenomedullin antibody fragment, or non-Ig modulating anti-adrenomedullin supercontig is an antibody, anti-adrenomedullin antibody fragment, or non-Ig supercontig that enhances the half-life (ti / 2 mean retention time) of adrenomedullin in serum, blood, or plasma by at least 10%, preferably at least 50%, more preferably > 50%, and more preferably > 100%, and blocks ADM bioactivity to less than 80%, preferably less than 50%. Such an anti-ADM antibody, anti-ADM antibody fragment, or non-Ig anti-ADM supercontig would block ADM activity to at least 5%. These values ​​relating to half-life and bioactivity blockade should be understood in relation to the assays mentioned above for determining these values. This is in the sense of blocking the bioactivity of ADM by no more than 80% or no more than 50%, respectively. Such a modulating anti-adrenomedullin antibody, or a modulating anti-adrenomedullin antibody fragment, or an Ig-free modulating anti-adrenomedullin supergroup, offers the advantage of simplified dosing. The combination of partially blocking or partially reduced adrenomedullin bioactivity and increased in vivo half-life (by increasing adrenomedullin bioactivity) leads to the beneficial simplicity of dosing anti-adrenomedullin antibodies, anti-adrenomedullin antibody fragments, or Ig-free anti-adrenomedullin supergroups. In situations of excess endogenous adrenomedullin (maximal stimulation, late sepsis phase, shock, hypodynamic phase), the activity-reducing effect of the antibody, fragment, or supergroup is the greatest impact, limiting the (negative) effect of adrenomedullin.In cases of low or normal endogenous adrenomedullin concentrations, the biological effect of anti-adrenomedullin antibodies, anti-adrenomedullin antibody fragments, or supercontiges without anti-ADM Ig is a combination of reduction (through partial blockade) and enhancement by increasing the adrenomedullin half-life. Therefore, modulating, non-neutralizing anti-adrenomedullin antibodies, anti-adrenomedullin antibody fragments, or supercontiges without anti-adrenomedullin Ig act as a buffer solution for ADM bioactivity, maintaining ADM bioactivity within a certain physiological range. In one specific embodiment of the invention, the antibody is a monoclonal antibody or a fragment thereof. In one embodiment of the invention, the anti-ADM antibody or anti-ADM antibody fragment is a human or humanized antibody or a derivative thereof. In one specific embodiment, one or more (murine) CDRs are grafted onto a human antibody or antibody fragment. The subject matter of the present invention, in one aspect, is an antibody grafted onto a human CDR or antibody fragment thereof that binds to ADM, wherein the antibody grafted onto a human CDR or antibody fragment thereof comprises an antibody heavy chain (H chain) comprising: SEQ ID No.:1 GYTFSRYW SEQ ID No.: 2 ILPGSGST I SEQ ID No.: 3 TEGYEYDGFDY and / or further comprising an antibody light chain (L chain) comprising: SEQ ID No.: 4 QSIVYSNGNTY “RVS” SEQUENCE (not part of the sequence list): RVS I SEQ ID No.: 5 FQGSHIPYT. In a specific embodiment of the invention, the subject matter of the present invention is a human monoclonal antibody that binds to ADM or an antibody fragment thereof that binds to ADM, wherein the heavy chain comprises at least one CDR selected from the group comprising: SEQ ID No.: 1 GYTFSRYW SEQ ID No.: 2 ILPGSGST SEQ. ID No.: 3 TEGYEYDGFDY and wherein the light chain comprises at least one CDR selected from the group consisting of: SEQ ID No.: 4 QSIVYSNGNTY “RVS” SEQUENCE (not part of the sequence list): RVS SEQ ID No.: 5 FQGSHIPYT. In a more specific embodiment of the invention, the subject matter of the invention is a human monoclonal antibody that binds to ADM or an antibody fragment thereof that binds to ADM wherein the heavy chain comprises the sequences: SEQ ID No.: 1 GYTFSRYW SEQ ID No.: 2 ILPGSGST SEQ ID No.: 3 TEGYEYDGFDY and where the light chain comprises the sequences: SEQ ID No.: 4 QSIVYSNGNTY “RVS” SEQUENCE (not part of the sequence list): RVS SEQ ID No.: 5 FQGSHIPYT. In a very specific modality, the anti-ADM antibody has a selected sequence from the group comprising: SEQ ID No. 6, 7, 8, 9, 10, 11, 12, and 13. The anti-ADM antibody or anti-medullin antibody fragment or supercell without anti-ADM Ig according to the present invention exhibits an affinity for human ADM such that the affinity constant is greater than 10⁻⁶ 7 M, preferably 10' 8 M, the preferred affinity is greater than 10' 9 M, the most preferred, greater than 10~ w M, A person skilled in the art knows that a lower affinity can be compensated for by applying a higher dose of compounds, and this measure would not be outside the scope of the invention. The affinity constants can be determined according to the method described in Example 1. The subject matter of the present invention is a human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof for use in the intervention and therapy of congestion in a patient according to the present invention, wherein said antibody or fragment comprises a sequence selected from the group comprising: SEQ ID NO: 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFK GKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPPKHHHHHH SEQ ID NO: 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYiCN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ¡D NO: 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC SEQ ID NO: 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRUYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID NO: 13 (AM-VL2-E40) DWMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC The subject matter of the present invention is a pharmaceutical formulation for use in intervention and therapy of congestion in a patient comprising an antibody or fragment or supercontig according to the present invention. The subject matter of the present invention is a pharmaceutical formulation for use in the intervention and therapy of congestion in a patient comprising an antibody or fragment or supercontig according to the present invention, wherein said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling, or retention of water (edema), heart failure, particularly acute heart failure, kidney or liver disease. The subject matter of the present invention is a pharmaceutical formulation for use in intervention and therapy of congestion in a patient, wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution. The subject matter of the present invention is a pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to the present invention, wherein said pharmaceutical formulation is in a lyophilized state. The subject matter of the present invention is a pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to the present invention, wherein said pharmaceutical formulation is adapted to be administered intramuscularly. The subject matter of the present invention is a pharmaceutical formulation for use in intervention and therapy of congestion in a patient according to the present invention, wherein said pharmaceutical formulation is adapted to be administered intravascularly. The subject matter of the present invention is a pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to the present invention, wherein said pharmaceutical formulation is adapted to be administered by infusion. The subject matter of the present invention is a pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to the present invention, wherein said pharmaceutical formulation must be administered systemically. The following embodiments are the subject of the present invention: 1. Anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontigo without anti-ADM Ig for use in congestion intervention and therapy in a patient in need thereof. 2. Anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontigo without anti-ADM Ig for use in congestion intervention and therapy in a patient according to point 1, wherein said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease. 3. Anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontigo without anti-ADM Ig for use in the intervention and therapy of congestion in a patient according to points 1 or 2 wherein said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema), and heart failure, in particular acute heart failure. 4. Anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to adrenomedullin or an anti-ADM Ig-free supercontig that binds to adrenomedullin for use in congestion intervention and therapy in a patient according to any of points 1 to 3, wherein said antibody or antibody fragment or Ig-free supercontig is monospecific. 5. Anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that is binds to adrenomedullin or a supercontig without anti-ADM ig that binds to adrenomedullin for use in the intervention and therapy of congestion in a patient according to any of points 1 to 4, wherein said antibody or fragment or supercontig exhibits an ADM binding affinity of at least 10 7 M. 6. Anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment binding to adrenomedullin or an anti-ADM Ig-free supercontig binds to adrenomedullin for use in the intervention and therapy of congestion in a patient according to any of points 1 to 5, wherein said antibody or antibody fragment or Ig-free supercontig binds to a region of preferably at least 4, or at least 5 amino acids within the amino acid sequence 1-42 of mature human ADM: YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA (SEQ ID No.: 23). 7. Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM ig-free supercontig for use in congestion intervention and therapy in a patient according to any of points 1 to 6 wherein said antibody or fragment or supercontig binds to the N-terminate portion (aa 1-21) of adrenomedullin: YRQSMNNFQGLRSGFGCRFGTC (SEQ ID No. 22). 8. Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontig for use in the intervention and therapy of congestion in a patient according to any of points 1 to 7, wherein said antibody or fragment or supercontig recognizes and binds to the N-terminal end (aa 1) of adrenomedullin. 9. An anti-adrenomedullin (ADM) antibody or an anti-ADM antibody fragment that binds to adrenomedullin or an anti-ADM Ig-free supercontig that binds to adrenomedullin for use in congestion intervention and therapy in a patient according to any of points 1 to 8, characterized in that said antibody, antibody fragment or Ig-free supercontig does not bind to the C-terminal portion of ADM, filling the aa sequence 43-52 of ADM PRSKISPQGY-NH2 (SEQ ID NO: 24). 10. Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontig for use in the intervention and therapy of congestion in a patient according to any of points 1 to 9, wherein said antibody or fragment or supercontig blocks ADM blockaactivity by not more than 80%, preferably not more than 50%. 11. Anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontigo for use in congestion intervention and therapy in a patient according to any of points 1 to 10, wherein said patient is an ICU patient. 12. Anti-ADM antibody or an anti-adrenomedullin antibody fragment for use in the intervention and therapy of congestion in a patient according to any of points 1 to 11, wherein said antibody or fragment is a human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof wherein the heavy chain comprises the sequences: SEQ ID NO: 1 GYTFSRYW SEQ ID NO: 2 ILPGSGST SEQ ID NO: 3 TEGYEYDGFDY and where the light chain comprises the sequences: SEQ ID NO: 4 QSIVYSNGNTY “RVS” SEQUENCE (not part of the sequence list): RVS SEQ ID NO: 5 FQGSHIPYT. 13. A human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof for use in the intervention and therapy of congestion in a patient according to point 12, wherein said antibody or fragment comprises a sequence selected from the group comprising: SEQ ID NO: 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFK GKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYÍCN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC SEQ ID NO: 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASiSCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID NO: 13 (AM-VL2-E40) DWMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSI-ilPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC 14. Anti-ADM antibody or ADM-binding anti-ADM antibody fragment or ADM-binding anti-ADM Ig supercontigo for use in congestion intervention and therapy in a patient according to any of points 1-13, wherein a body fluid sample taken from such patients exhibits an elevated level of proADM and / or fragments thereof having at least 5 amino acids above a certain threshold. 15. Anti-ADM antibody or ADM-binding anti-ADM antibody fragment or ADM-binding anti-ADM Ig supercontigo for use in congestion intervention and therapy in a patient according to any of points 1-14, wherein said patient is resistant to diuretics or does not respond to diuretic therapy. 16. Pharmaceutical formulation for use in intervention and therapy of congestion in a patient comprising an antibody or fragment or supercontig according to any of points 1 to 15. 17. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient comprising an antibody or fragment or supercontig according to any of points 1 to 16, wherein the patient has a selected disease or condition from the group comprising: congestive hypertension, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease. 18. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to point 16 or 17, wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution. 19. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to point 18, wherein said pharmaceutical formulation is in a lyophilized state. 20. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to any of points 18 to 19, wherein said pharmaceutical formulation is adapted to be administered by intramuscular route. 21. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to any of points 18 to 19, wherein said pharmaceutical formulation is adapted to be administered intravenously. 22. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to point 21, wherein said pharmaceutical formulation is adapted to be administered by infusion. 23. Pharmaceutical formulation for use in the intervention and therapy of congestion in a patient according to any of points 18 to 22, wherein said pharmaceutical formulation is to be administered systemically. EXAMPLES It should be emphasized that the antibodies, antibody fragments, and non-IG supercontiges of the example part according to the invention bind to ADM, and should thus be considered as anti-ADM antibodies / antibody fragments / non-IG supercontiges. Example 1 Antibody generation and determination of their affinity constants Several human and murine antibodies were produced and their affinity constants were determined (see Tables 1 and 2). Peptides / conjugates for immunization: The peptides for immunization were synthesized (see Table 1) (JPT Technologies, Berlin, Germany) with an additional N-terminal cysteine ​​residue (if no cisterna is present within the selected ADM sequence) for conjugation of the peptides to bovine serum albumin (BSA). The peptides were covalently linked to BSA using a sulfoiink coupling gel (Perbio-science, Bonn, Germany). The coupling procedure was performed according to the Perbio manual. Murine antibodies were generated according to the following method: A Balb / c mouse was immunized with 100 pg of peptide-BSA conjugate on days 0 and 14 (emulsified in 100 ml of Freund's complete adjuvant) and 50 pg on days 21 and 28 (in 100 ml of Freund's incomplete adjuvant). Three days before the fusion experiment, the animal received 50 pg of the conjugate dissolved in 100 ml of saline solution, adapted for administration as an intraperitoneal injection and a venous injection. Immunized mouse splenocytes and SP2 / 0 myeloma cell line cells were fused with 1 ml of 50% polyethylene glycol for 30 s at 37°C. After washing, the cells were seeded in 96-well cell culture plates. Hybrid clones were selected by growing them in HAT medium [RPMI 1640 culture medium supplemented with 20% fetal calf serum and supplement of HAT], After two weeks, the HAT medium is replaced with HT Medium in three consecutive steps returning to normal cell culture medium. Cell culture supernatants were primarily screened for antigen-specific IgG antibodies three weeks post-fusion. Positive microcultures were transferred to 24-well plates for propagation. After retesting, selected cultures were cloned and re-cloned using the limit dilution technique and isotypes were determined (see also Lane, RD 1985. J. Immunol. Meth. 81: 223-228; Ziegler et al. 1996. Horm. Metab. Res. 28: 11-15). Production of mouse monoclonal antibody! The antibodies were produced through standard antibody production methods (Marx et al., 1997. Monoclonal Antibody Production, ATLA 25, 121) and purified by means of Protein A. The antibody purities were > 95% based on SDS gel electrophoresis analysis. Human antibodies: Human antibodies were produced by displaying phages according to the following procedure: Naive human antibody gene pools HAL7 / 8 were used to isolate single-stranded recombinant F variable domains (scFvs) against the adrenomedullin peptide. The antibody gene pools were selected using a displacement strategy involving peptides containing a biotin tag linked to the adrenomedullin peptide sequence via two different spacers. A screening mix using non-specifically bound antigen and streptavidin-bound antigen was used to minimize the background of non-specific binders. Phages eluted from the third screening round were used to generate monoclonal scFvs expressing E. coli strains. The supernatant from the culture of these clonal strains has been used directly for an antigen ELISA test (see also Hust et al. 2011. Journal of Biotechnology 152. 159-170: Schütte et al. 2009. PLoS One 4, e6625). Positive clones were selected based on a positive ELISA signal for the antigen and a negative signal for streptavidin-coated microtiter plates. For further characterization, the open reading frame scFv was cloned into the expression plasmid pOPE107 (Hust et al., J. Biotech n. 2011), captured from the culture supernatant by immobilized metal-ion affinity chromatography and purified by size exclusion chromatography. Affinity constants: To determine the affinity of antibodies to adrenomedullin, the binding kinetics of adrenomedullin to immobilized antibody were determined by unlabeled surface plasmon resonance using a Biacore 2000 system (GE Healthcare Europe GmbH, Freiburg, Germany). Reversible immobilization of the antibodies was performed using a high-density covalently coupled anti-mouse Fe antibody on a CM5 sensor surface according to the manufacturer's instructions (mouse antibody capture kit; GE Healthcare). (Lorenz et al. 2011. Antimicrob Agents Chemother. 55(1): 165-173). Monoclonal antibodies were generated against the ADM regions shown below for human and murine ADM, respectively. The following table represents a selection of the antibodies obtained and used in further experiments. The selection was based on the target region: Table 1: Sequence number Antigen / immunogen ADM region Designation Affinity constants Kd (M) SEQ ID: 14 ​​YRQSMNNFQGLRSFGCRFGTC 1-21 NT-H 5.9x10 9 SEQ ID: 15 CTVQKLAHQIYQ 21-32 MR-H 2x10 9 SEQ ID: 16 CAPRSKISPQGY-NH2 C-42-52 CT-H 1.1 x 10-® SEQ ID: 17 YRQSMNQGSRSNGCRFGTC 1-19 NT-M 3.9 x 10 9 SEQ ID: 18 CTFQKLAHQIYQ 19-31 MR-M 4.5x10 10 SEQ ID: 19 CAPRNKISPQGY-NH2 C-40-50 CT-M 9x10 2 The following is a list of other monoclonal antibodies obtained: Table 2: Target Source Clone Number Affinity (M) Max. Inhibition Bioassay (%) (see example 2) NT-M Mouse A.DM / 63 5.8x10 9 45 ADM / 364 Mouse 2.2x10 8 48 ADM / 365 Mouse 3.0x10" s ADM / 366 Mouse 1.7x10-® ADM / 367 Mouse 1.3x10- 8 ADM / 368 Mouse 1.9x10" ADM / 369 Mouse 2.0 x10" ADM / 370 Mouse 1.6 x10 8 ADM / 371 2.0x10 Mouse 8ADM / 372 Mouse 2.5x10 - ADM / 373 Mouse 1.8x10 - ADM / 377 Mouse 1.5x10 8 ADM / 378 2.2 x10 Mouse 8 ADM / 379 Mouse 1.6 x 10" ADM / 380 Mouse 1.8 x 10" ADM / 381 Mouse 2.4 x 10" 8 ADM / 382 Mouse 1.6x10- 8 ADM / 383 Mouse 1.8x10' 8 ADM / 384 1.7x10 Mouse 8 ADM / 385 1.7x10 Mouse 8 ADM / 403 1.2x10 Mouse 8 ADM / 395 Mouse 1.2 x10' 8 ADM / 396 3.0x10 Mouse 8 ADM / 397 Mouse 1.5x10' 8 MR-M Mouse ADM / 38 4.5x10 10 68 MR-M Mouse ADM / 39 5.9x10'® 72 CT-M Mouse ADM / 65 9.0x10® 100 CT-M Mouse ADM / 66 1.6x10 8 100 NT-H Mouse ADM / 33 5.9x10 8 38 NT-H Mouse ADM / 34 1.6x10 8 22 MR-H Mouse ADM / 41 1.2x10' 8 67 MR-H Mouse ADM / 42 <1x10-» MR-H Mouse ADM / 43 2.0x10-® 73 MR-H Mouse ADM / 44 <1x10 8 CT-H Mouse ADM / 15 <1x10 8 CT-H Mouse ADM / 16 1.1x10-9 100 CT-H Mouse ADM / 17 3.7x10- 9 100 CT-H Mouse ADM / 18 <1x10" 8hADM Phage Display ADM / A7 <1x10 8 Phage display ADM / B7 <1x10' 8 Phage display ADM / C7 <1x10 8 Phage display ADM / G3 <1x10- 8 Phage display ADM / B6 <1x10 8 ADM / B11 phage display <1x10' 8 ADM / D8 phage display <1x10' 8 ADM / D11 phage display <1x10- 8 ADM / G12 phage display <1x10 8 Generation of antibody fragments by enzymatic digestion: The generation of Fab and F(ab) fragments was carried out by enzymatic digestion of the full-length murine antibody NT-M. The NT-M antibody was digested using a) the pepsin-based F(ab) preparation kit (Pierce 44988) and b) the papain-based Fab preparation kit (Pierce 44985). The fragmentation procedures were performed according to the instructions provided by the supplier. Digestion was carried out for 8 hours at 37°C for F(ab)2 fragmentation. Digestion with Fab fragmentation was carried out for 16 hours. Procedure for the Generation and Purification of Fab: Immobilized papain was equilibrated by washing the resin with 0.5 mL of digestion buffer and centrifuging the column at 5000 x g for 1 minute. The buffer was then discarded. The desalination column was prepared by removing the storage solution and washing it with digestion buffer, centrifuging it each time at 1000 x g for 2 minutes. 0.5 mL of the prepared IgG sample was added to the column tube containing the immobilized papain. The digestion reaction was incubated for 16 h on a benchtop balancer at 37°C. The column was centrifuged at 5000 x g for 1 minute to separate the digestion from the immobilized papain. Subsequently, the resin was washed with 0.5 mL of PBS and centrifuged at 5000 x g for 1 minute. The wash fraction was added to the digested antibody and the total sample volume was 1.0 ml.The NAb protein A column was equilibrated with PBS and IgG elution buffer at room temperature. The column was centrifuged for 1 minute to remove the storage solution (containing 0.02% sodium azide) and equilibrated by adding 2 mL of PBS. It was centrifuged again for 1 minute, and the flow was discarded. The sample was applied to the column and resuspended by inversion. Incubation was performed at room temperature with end-to-end mixing for 10 minutes. The column was centrifuged for 1 minute, saving the flow containing the Fab fragments. (References: Coulter and Harris 1983. J. Immunol. Meth. 59, 199-203.: Lindner et al. 2010. Cancer fies. 70, 277-87: Kaufmann et ai. 2010. PNAS. 107, 18950-5.: Chen et al. 2010. PNAS. 107, 14727-32: Jvsal et al. 2009 J. Exp. Med. 206, 449-62: Thomas et al. 2009. J. Exp. Med. 206, 1913-27: Kong et al. 2009 J. Cell Biol. 185, 1275-840). Procedure for the generation and purification of Ffab'k: Immobilized pepsin was equilibrated by washing the resin with 0.5 mL of digestion buffer and centrifuging the column at 5000 x g for 1 minute. The buffer was then discarded. The desalination column was prepared by removing the storage solution and washing it with digestion buffer, centrifuging it each time at 1000 x g for 2 minutes. 0.5 mL of the prepared IgG sample was added to the column tube containing equilibrated immobilized pepsin. The digestion reaction was incubated for 16 h on a benchtop balancer at 37°C. The column was centrifuged at 5000 x g for 1 minute to separate the digestion from the immobilized papain. Subsequently, the resin was washed with 0.5 mL of PBS and centrifuged at 5000 x g for 1 minute. The wash fraction was added to the digested antibody and the total sample volume was 1.0 ml.The NAb protein A column was equilibrated with PBS and IgG elution buffer at room temperature. The column was centrifuged for 1 minute to remove the storage solution (containing 0.02% sodium azide) and equilibrated by adding 2 mL of PBS. It was centrifuged again for 1 minute, and the flow was discarded. The sample was applied to the column and resuspended by inversion. Incubation was performed at room temperature with end-to-end mixing for 10 minutes. The column was centrifuged for 1 minute, saving the flow containing the Fab fragments. (References: Mariani et al. 1991. Mol. Immunol. 28: 69-77; Beale 1987. Exp Comp Immuno! 11:287-96: Ellerson et al. 1972. FEBS Letters 24(3):318-22: Kerbel and Elliot 1983. Meth Enzymol 93:113-147; Kulkarni et al. 1985. Cancer Immunol Immunotherapy 19:211-4; Rousseaux et al. 1980. Moi Immunol 17:469-82; Rousseaux et al. 1983. J Immunol Meth 64:141-6; Wilson et al. 1991. J Immunol Meth 138:111-9). Humanization of the NT-H antibody fragment: The antibody fragment was humanized by the CDR grafting method (Jones et al. 1986. Nature 321. 522-525). The following steps were taken to achieve the humanized sequence: Total RNA extraction: Total RNA was extracted from NT-H hybridomas using the Qiagen kit. First-round RT-PCR: The QIAGEN® OneStep RT-PCR kit (Cat No. 210210) was used. RT-PCR was performed with primer sets specific to the heavy and light chains. For each RNA sample, 12 individual heavy-chain and 11 individual light-chain RT-PCR reactions were set up using mixtures of degenerate forward primers covering the leading sequences of the variable regions. Reverse primers were positioned in the constant regions of the heavy and light chains. No restriction sites were designed into the primers. Reaction setup: 5x QIAGEN® OneStep RT-PCR buffer solution 5.0 pl, dNTP mix (containing 10 mM of each dNTP) 0.8 pl, Established primer 0.5 pl, QIAGEN® OneStep RT-PCR enzyme mix 0.8 pl, Template RNA 2.0 pl, RNase-free water to 20.0 pl, Total volume 20.0 pl. PCR conditions: Reverse transcription: 50°C, 30 min; Initial PCR activation: 95°C, 15 min. Cycling: 20 cycles of 94°C, 25 sec; 54°C, 30 sec; 72°C, 30 sec; Final amplification: 72°C, 10 min. Second-round semi-amplified PCR: The RT-PCR products from the first-round reactions were further amplified in the second-round PCR. Twelve single heavy chain RT-PCR reactions and eleven light chain RT-PCR reactions were set up using semi-nested primer sets specific for variable antibody regions. Reaction setup: 2x PCR mix 10 pl; primer set 2 pl; first round PCR product 8 pl; Total volume 20 pl; Hybridoma antibody donation report PCR condition: Initial denaturation 5 min at 95°C; 25 cycles of 95°C for 25 sec, 57°C for 30 sec, 68°C for 30 sec; final extension is 10 min 68°C. Once the PCR was complete, PCR reaction samples were run on agarose gel to visualize the amplified DNA fragments. After sequencing more than 15 cloned DNA fragments amplified by nested RT-PCR, several mouse antibody heavy and light chains were cloned and appeared to be correct. Protein sequence alignment and CDR analysis identified one heavy chain and one light chain. After alignment with homologous human scaffold sequences, the resulting humanized sequence for the variable heavy chain is as follows: see Fig. 5. The amino acids at positions 26, 40, and 55 in the heavy chain are shown. The variable and amino acids at position 40 in the variable lumen are critical for binding properties; they can be reverted to the original murine. The resulting candidates are shown below (Padian 1991. Mol. Immunol. 28, 489-498; Harris and Baiorath. 1995. Protein Sci. 4, 306-3101). Annotation for antibody fragment sequences (SEQ ID No.: 7-14): bold and underlined are CDRs 1, 2, 3 in chronological order; italics are constant regions; hinge regions are highlighted with bold letters and the histidine tag with bold and italic letters; the workframe point mutation has a gray letter background. SEQ ID No.: 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWlEWVKQRPGHGLEWIGEiLPGSGSTNYNEKFK GKATITADTSSA / 7A YMQLSSL TSEDSA VYYCTEG YEYDGFDYWGQG TTL TVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRiLPGSGSTNYAQK FQGRVT\TADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAAL GCL VKD YFPEP VTVSWNSGAL TSG VHTFPA VLQSSGL YSLSSVVTVPSSSLGTQ TYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWlEWVRQAPGQGLEWMGRjLPGSGSTNYAQK FQGRVTVTADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCL. VKDYFPEPVTVSWNSGALTSG VHTFPA VLQSSGL YSLSSVVTVPSSSLGTQTYiCN VNHKPSNTKVDKR VEPKHHHHHH SEQ ID No.: 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRWnTADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCL VKDYFPEPVTVSWNSGALTSG VHTFPA VLQSSGL YSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTiTADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSiVYSNGhITYLEWYLQKPGQSPKLLlYRVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC SEQ ID No.: 12 (AM-VL1) DWMTQSPLSLPVTTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEiKRTVAAPSVFIFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID No.: 13 (AM-VL2-E40) DWMTQSPLSLPVTTLGQPASiSCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC Example 2 Effect of anti-aging effects on~ADM also selects the bioactividad artti-ADM The effect of selected ADM antibodies on ADM bioactivity was tested in a functional cAMP assay with recombinant human adrenomedullin receptor (adrenomedullin bioassay). Antibody tests targeting human or mouse adrenomedullin in the recombinant human adrenomedullin receptor cAMP functional assay (adrenomedullin bioassay) Materials: Cell line: CHO-K1 Receptor: Adrenomedullin (CRLR + RAMP3) Cell line receiver access number: CRLR; U17473; RAMP3: AJ001016 CHO-K1 cells expressing the recombinant human adrenomedullin receptor (FAST-027C) cultured prior to the assay in antibiotic-free medium were separated by gentle rinsing with PBS-EDTA (5 mM EDTA), recovered by centrifugation, and resuspended in an assay buffer solution (KRH: 5 mM KCl, 1.25 mM MgSCU, 124 mM NaCl, 25 mM HEPES, 13.3 mM Glucose, 1.25 mM KH2PO4, 1.45 mM CaCl2, 0.5 g / l BSA). Dose response curves were performed in parallel with reference agonists (hADM or mADM). Antagonistic test (96 pocilium): For antagonist testing, 6 µl of the reference agonist (human (5.63 nM) or mouse (0.67 nM) adrenomedullin) were mixed with 6 µl of the test samples at different antagonist dilutions; or with 6 µl of buffer solution. After incubation for 60 minutes at room temperature, 12 µl of cells (2,500 cells / well) were added. The plates were incubated for 30 minutes at room temperature. After adding the lysis buffer solution, the percentage of DeltaF was calculated according to the manufacturer's specifications. The Cis-Bio International HTRF kit (cat. no. 62AM2 PEB) was used with hADM 22-52 as the reference antagonist. cAMP-HTRF antibody test assay Anti-h-ADM antibodies (NT-H, MR-H, CT-H) were analyzed to determine their antagonistic activity in the functional cAMP assay (FAST-027C) of the recombinant human adrenomedullin receptor in the presence of 5.63 nM human ADM 1-52, at the following final concentrations of antibodies: 100 pg / ml, 20 pg / ml, 4 pg / ml, 0.8 pg / ml, 0.16 pg / ml. Anti-m-ADM antibodies (NT-M, MR-M, CT-M) were analyzed for their antagonistic activity in the recombinant human adrenomedullin receptor functional cAMP assay (FAST-027C) in the presence of 0.67 nM mouse ADM 1-50, at the following final antibody concentrations: 100 pg / ml, 20 pg / ml, 4 pg / ml, 0.8 pg / ml, and 0.16 pg / ml. Data were plotted against antagonist concentrations (see Figs. 2a to 2I). The maximum inhibition by individual antibodies is given in Table 3. Table 3: Antibody Maximum inhibition of ADM biological activity (ADM-Biological Assay) (%) NT-H 38 MR-H 73 CT-H 100 NT-M FAB 26 NT-M FAB2 28 NT-M 45 MR-M 66 CT-M 100 Non-specific mouse IgG 0 Example 3 Data for the stabilization of hADM by the anti-ADM antibody The stabilizing effect of human ADM by human ADM antibodies was tested using an hADM immunoassay. immunoassay for the quantification of human adrenomedullin The technology used was an intercalated coated tube luminescence immunoassay, based on the ester with acridinium ester. Labeled compound (tracer): 100 pg (100 pl) CT-H (1 mg / ml in PBS, pH 7.4, AdrenoMed AG Germany) were mixed with 10 pl of acridinium-NHS ester (1 mg / ml in acetonitrile, InVent GmbH, Germany) (EP 0353971) and incubated for 20 min at room temperature. Labeled CT-H was purified by HPLC gel filtration on Bio-Sil® SEC 4G0-5 (Bio-Rad Laboratories, Inc., USA). The purified CT-H was diluted in (300 mmol / L potassium phosphate, 100 mmol / L NaCl, 10 mmol / L Na-EDTA, 5 g / L bovine serum albumin, pH 7.0). The final concentration was approximately 800,000 relative light units (RLU) of the labeled compound (approximately 20 ng of labeled antibody) per 200 pL. The chemiluminescence of acridinium ester was measured using an AutoLumat LB 953 (Berthold Technologies GmbH & Co. KG). Solid phase: Polystyrene tubes (Greiner Bio-One International AG, Austria) were coated (18h at room temperature) with MR-H (AdrenoMed AG, Germany) (1.5 pg MR-H / 0.3 mL 100 mmol / L NaCi, 50 mmol / L TRIS / HCl, pH 7.8). After blocking with 5% bovine serum albumin, the tubes were washed with PBS, pH 7.4 and vacuum dried. Calibration: The assay was calibrated using dilutions of hADM (BACHEM AG, Switzerland) in 250 mmol / L NaCi, 2 g / L Triton X-100, 50 g / L bovine serum albumin, 20 tabs / L protease inhibitor cocktail (Roche Diagnostics AG, Switzerland). hADM immunoassay: 50 pl of sample (or calibrator) were pipetted into coated tubes, after adding labeled CT-H (200 pl), the tubes were incubated for 4 hours at 4°C. Unbound tracer was removed by washing 5 times (every 1 ml) with wash solution (20mM PBS, pH 7.4, 0.1% Triton X-100). Tube-bound chemiluminescence was measured using LB 953: Figure 3 shows a typical hADM dose-signal curve and a HADM dose-signal curve in the presence of 100 pg / ml NT-H antibody. NT-H did not affect the described hADM immunoassay. Stability of human adrenomeduin: Human ADM was diluted in human citrate plasma (final concentration 10 nM) and incubated at 24°C. At selected time points, hADM degradation was arrested by freezing at -20°C. Incubation was performed in the absence and presence of NT-H (100 pg / mL). The remaining hADM was quantified using the hADM immunoassay described above. Figure 4 shows the stability of hADM in human plasma (citrate) in the absence and presence of NT-H antibody. The half-life of hADM alone was 7.8 h; in the presence of NT-H, the half-life was 18.3 h (2.3 times higher than the stability). Example 4 In vivo determination of the side effects of the NT-M antibody Male C57BI / 6 mice aged 12–15 weeks (Charles River Laboratories, Germany) were used for the study. Six mice were treated with NT-M (10 pl / g body weight), 0.2 mg / ml. As a control, six mice were treated with PBS (10 pl / g body weight). Survival and physical condition were monitored for 14 days. Mortality was zero in both groups, and there were no differences in physical condition between the NT-M and control groups. Example 5 Dose dependence of NT-H efficacy The dose dependence of NT-H efficacy was examined in a mouse model of CLP based on renal barrier dysfunction determined by immunochemical staining of the kidney. Male C57BI / 6 mice aged 12–15 weeks were used (Charles River Laboratories, Germany; 6 / group, 4 groups) for the study. Peritonitis was surgically induced under light isoflurane anesthesia (and Rimadyl 0.5 mg / kg subcutaneously with surgery). Incisions were made in the upper quadrant The cecum was exposed in the left peritoneal cavity (normal location of the cecum). A tight ligature was placed around the cecum with sutures distal to the small bowel insertion. A puncture wound was made in the cecum with a 24-gauge needle, and small amounts of cecal contents were expressed through the wound. The cecum was replaced in the peritoneal cavity, and the laparotomy site was closed. Finally, the animals were returned to their cages with free access to food and water. 500 ml of subcutaneous saline was administered as fluid replacement. Eighteen hours after the laparotomy and application of the test item, the animals were euthanized, and the kidneys were removed. Mice were treated with vehicle and compound at different concentrations. The sponsor supplied the vehicles and compounds as ready-to-use solutions in tubes labeled A, B, C, and D. A single intravenous injection was administered 5 minutes before CLP at a dose of 0.1 / 2 / 20 mg / kg body weight in a volume of 5 pl / g body weight via injection into the tail vein. The vehicle was 20 mM His / HCl, pH 6.0. Terminal bleeding was performed on survivors after 18 hours. 500 ml of blood were obtained 6 h after CLP from 3 additional individuals per group via terminal bleeding. EDTA plasma samples were last frozen 1 h after sampling. Kidney processing for immunohistochemistry: The mice were sacrificed by exsanguination, so the kidney was not filled with blood and was removed immediately. After dissection, the kidney was cut in a sagittal section, producing two complete halves. The two kidney halves were placed in a minimum volume of 1 QX of 10% formalin (4% buffered neutral formaldehyde: Fischer 639 3113). The two halves, separately (not joined), were placed in a 5 ml cup filled with 10% formalin and (so that samples could be sent to us during fixation) fixed for 6 days at room temperature (dehydration and overnight paraffin: washing with dH2Q for 2 hours, 40% ethanol for 1 hour, 70% ethanol for 1 hour twice, 80% ethanol for 1 hour, 90% ethanol for 1 hour, 100% ethanol for 1 hour twice, xylene at 40°C for 1.5 hours, xylene at 45°C for 1.5 hours, paraffin at 60 QC 1 hour 3 times, embedded in cassette). The left kidney was dissected immediately upon receipt, fixed with formalin for 6 days, and embedded in paraffin. The 5 pm sections were deparaffinized, exposed to HIER, 10% goat or donkey serum, 1 !> of antibodies (VEGF, Alb, Ang1) 2 o Anti-rabbit antibodies or goat IgG AP were followed by Dako REAL chromium staining and alternately stained with hematoxylin. Slides were analyzed using Axio Vision software (version 4.8) (Zeiss, Jena, Germany) and are represented as red sum of densitometry mean. Densitometry assessment of the stained kidneys with respect to albumin showed significantly lower extravascular albumin accumulation across the three doses analyzed, with a slightly smaller effect at the 20 mg / kg dose (Fig. 6). VEGF is known to increase endothelial vascular permeability and thus acts as a supportive biomarker for renal barrier function. As shown in Fig. 7, VEGF expression was significantly lower at all doses tested, with no dose dependence. Angiopoietin 1 is known to protect against this VEGF-induced plasma leakage and, therefore, Therefore, it must be reciprocally related to the level of VEGF expression. This is shown in Fig. 8 and is relevant for all doses tested. In this study, the efficacy of three different doses of NT-H, adapted for intravenous administration 5 minutes before surgery, was evaluated in a mouse model of CLP-induced peritonitis. NT-H significantly improved renal vascular integrity in septic mice compared to the placebo group at all doses tested. NT-H exhibited a beneficial effect across a broad dose range, with a slight trend toward lesser effect at 20 mg / kg. Furthermore, the results of this study indicate that the application of the NT-H antibody has a positive effect by decreasing endothelial vascular permeability and, therefore, prevents or protects against extravasation of vascular fluid and, ultimately, congestion and / or edema. Example 6 PROTECT Studio Population study and measures The details of this study have been published (Massie et al. 2010. N Engl J Med. 363:1419-1428; Weatherlev et al. 2010. J Card Fail. 16:25-35; Voors et al. 2011. J Am Coll Cardiol. 57:1899-1907). In summary, 2,033 patients with acute heart failure and renal impairment (estimated creatinine clearance between 20 and 80 mL / min using the Cockcroft-Gault formula) were randomly assigned to rolofiliin or placebo. The PROTECT study protocol was approved by the ethics committee at each participating center, and written informed consent was obtained from all participants. Bio-ADM was measured from plasma collected during baseline assessment in 1572 hospitalized patients with acute heart failure enrolled in the PROTECT trial (all available reference samples). PROTECT (short for “Randomized, placebo-controlled study of the adenosine A1 receptor antagonist rolofiiina for hospitalized patients with acute decompensated heart failure and volume overload to evaluate the treatment effect on congestion and renal function”) was a multicenter, randomized, double-blind trial comparing rolofiiina with placebo in 2033 patients hospitalized for acute heart failure. Study results As highlighted previously, clinical surrogates have suboptimal predictive value for congestion detection. In this analysis, we combined three of the strongest clinical surrogates for congestion (i.e., JVP, peripheral edema, and orthopnea) to improve accuracy and developed a composite clinical congestion score (CCS) using the scheme presented below: Parameter 0 1 2 3 Peripheral edema 0 ankle Below knee Above knee Orthopnea 0 pillow 1 pillow 2 pillows 3 pillows JVP <6cm 6-10cm >10cm - The score for each of these three parameters was then added to obtain a composite congestion score that ranged from 0 to 8. Previously, a similar scheme was used by Ambrosy et al. (Ambrosy et al. 2013. European Heart Journal 34 (11): 835-843). The following algorithm was used to classify the severity of the congestion: CCS=0, no clinical congestion CCS 1-3, mild clinical congestion CCS 4-5, moderate clinical congestion CCS >6, severe clinical congestion The diuretic response was defined as weight loss on day 4 per 40 mg diuretic dose. Hemoconcentration was coded as 0 (if there is a decrease or no change in hemoglobin levels on day 4 compared to the baseline value) or 1 (if there is an increase in hemoglobin levels on day 4 compared to the baseline value). Significant residual congestion was defined as a CCS >2 based on assessments of JVP, orthopnea, and edema before day 7. Statistical analysis Clinical characteristics at baseline and biological markers, including bio-ADMs, were summarized by clinical congestion severity at baseline (scheme presented above). Reference factors independently associated with clinical congestion severity at baseline were determined using a multivariable logistic regression model (the CCS variable was recoded as a binary outcome with two levels: 0 = mild / moderate (CCS < 6) and 1 = severe (CCS > 6)). The association between bio-ADM reference values ​​and diuretic response (a continuous variable) was assessed using linear regression analysis. For hemoconcentration and significant residual congestion outcomes, binary logistic regression analysis was performed. Multivariable models were used to evaluate adjusted associations between bio-ADM levels and these outcomes. Results Table 4 shows that bio-ADM concentrations increase with the severity of congestion Table 4: Clinical variables of reference value and biological markers according to the severity of clinical congestion at the reference value Mild clinical congestion N~212 Moderate clinical congestion N=528 Severe clinical congestion P- trend Male sex,% (N) 65.6 (139) 68.4 (361) 65.4 (436) 0.656 Age (years) 71.5*11.7 71.1*11.3 70.8*10.7 0.427 BM! (Kg / m 2 ) 26.5+4.4 27.8*5.3 29.9+6.4 <0.001 LVEF(%) 32.1*13.4 33 2*13.4 32.2+13.4 0.808 SBP (mmHg) 124.2*17.9 125.2*17.4 124.3*17.3 0.773 DBP (mmHg) 72.9*12.2 73 3+11.4 74.1+11.6 0.118 Heart rate (bpm) 77.6*13.6 79.1+15.4 81*15.9 0.002 Respiratory rate (per 20 [18-22] 20 [18-24] 21 [18-24] 0.001 min) Orthopnea,% (N) None 17.9 (38) 4 (21) 0 (0) ref. One pillow (10 cm) 36.8 (78) 14.8 (78) 2.5 (17) <0.001 Two pillows (20 cm) 33.0 (70) 56.6 (299) 31.8 (212) <0.001 > 30 degrees 12 3 (26) 24.6 (130) 65.7 (438) <0.001 Pulmonary crackles. % (N) < 1 / 3 25.5 (54) 33 5 (177) 28.9 (193) ref. 1 / 3 - 2 / 3 57.1 (121) 51.5(272) 48.9 (326) 0.333 > 2 / 3 17.5 (37) 15 (79) 22.2 (148) 0.101 Edema,% (N) 0 56.6 (120) 15.3 (81) 0 (0) ref. 1 + 29.2 (62) 33 1 (175) 5 7 (38) <0.001 2+ 13.2 (28) 43.2 (228) 47.2 (315) <0.001 3+ 0.9 (2) 8.3 (44) 47.1 (314) <0.001 JVP,% (N) <6 cm 42.5 (90) 12.3 (65) 2.4 (16) ref. 6 -10 cm 52.4(111) 62.3 (329) 34.9 (233) <0.001 > 10 cm 5.2 (11) 25.4 (134) 62.7 (418) <0.001 NYHA,% (N) i 0.9 (2) 1.5(8) 0.7 (5) 0.784 II 24.1 (51) 15 (79) 14.4 (96) 0.779 II! 50.5 (107) 50.4 (266) 47.4 (316) 0.668 IV 14.6 (31) 28 6 (151) 34.6 (231) 0.494 Medical History COPD,% (N) 15.1 (32) 20.1 (106) 22 (146) 0.039 Cardiac Arrest,% (MI) 8 (17) 8.3 (44) 10.9 (73) 0.111 Peripheral Vascular Disease,% (N) 12.3 (26) 11.6 (61) 9.3 (62) 0.145 Hypertension,?» (N) 78.8 (167) 77.7 (410) 82.6 (551) 0.075 Diabetes mellitus,% (N) 38.7 (82) 44.1 (233) 48.1 (321) 0.013 Hypercholesterolemia,% 58 (123) 50 (264) 51.1 (340) 0.189 (N) Myocardial infarction,. 0 / » 52.8 (112) 50.1 (264) 49.4 (328) 0.424 (N) Angina,% (N) 20.8 (44) 20.7(109) 24 (160) 0.187 Ischemic disease 68.9 (146) 70.4 (371) 71.4 (475) 0.468 tie! heart, 0 / » (N) Atrial fibrillation,% {N} 44.3 (94) 53.0 (279) 59.8 (396) <0.001 Previous hospitalization for HF,% (N) 41.5 (88) 47.2 (249) 53.4 (356) 0.001 PCI,% (N) 34.0 (71) 26.5 (139) 23.3 (154) 0.003 CABG,% (N) 26.3 (55) 20.6 (108) 22.5 (149) 0.514 Pacemaker,% (N) 9.9 (21) 11 (58) 11.4 (76) 0.556 Medication during hospital admission ACEI / ARB,% (N) 78.3 (166) 75.7 (399) 75.6 (504) 0.492 Beta biologic,% {N} 82.1 (174) 75.1 (396) 75.1 (501) 0.089 MRA,% (N) 41.5 (88) 44.8 (236) 47.5 (317) 0.110 Digoxin,% (N) 20.3 (43) 30.6 (161) 31.3 (209) 0.009 Biological markers Albumin (g / dL) 4.0 3.9 [3.6-4.2] 3.8 [3.5-4.2] <8.00 ALT (U / L) 20 21 [15-4.2] 21 [15-4.2] 20 21 [15-4.2] 20 21 [15-4.2] 20 21 [15-4.2] 30 3.9 [3.6-4.2] 3.9 [3.6-4.2] 3.9 [3.6-4.3] 4.2] 4.1] ALT (U / L) 20 21 [15-4.2] 21 [15-4.2] 3.9 [3.6-4.3] 4.2 ... 0.299 [14-32] 32] 30] AST (U / L) 23 24 [19- 25 [20- 0210 [17-31] 33] 33] Bicarbonate (mEq / L) 23.6+3.4 24.2+3.6 24+3.9 0.485 BUN (mg / dL) 29 28 [21-40] 31 0.057 [22-42] [22-42] Chloride (mEq / L) 102 101 [98- 101 [98- 0.085 [99-105] 104] 104] Creatinine (mg / dL) 1.4 1.4 [1.1- 1.4 [1.1- 0.59 [1.1-1.8] 1.8] 1.8] Total cholesterol (mg / dL) 154.5 146.5 134 <0.001 [122-183.5] [123-173.8] [110-164] Glucose {mg / dL} 126 126 128 0 663 [104.5-155] [101-168] [103-162] Hemoglobin (g / dL) 12.6+1.8 12.5+1.8 12.5+1.9 0.716 Platelet count 221 218 211 0.020 ('W. A 9 / I) [180-278] [170-268] [168-260] Potassium (mmofl / L) 4.3+06 4.3*0.6 4.3+0.6 0 723 RBC Count (^10^9 / 1) 4.2+0.6 4.2+0.6 4.2+0.6 0.200 Sodium (rrmwl / L) 140 140 140 0.139 [137-142] [138-142] [137-142] Triglycerides (mmoi / L) 96 89 83 0.003 [66-132.5] [65-130] [64-112] Uric acid (mg / dL) 8.5+2.5 8.8+2.6 9.1+2.5 0.003 WBC (*10 A 9 / l 7.9 7.3 7 3 0.003 [6.5-10] 16.2-9.1] [5.9-9] Hemaiocrit (%) 39.5+5.4 39.4+5.6 40.1+5.9 0.09 BNP (pg / mf) 406.8 437.4 [247 9- 487.9 0.002 [255.8-648.2) 797.11 [274.8-874] cTni (pg / mL) 12.0 9.8 10.8 0.046 [5.8-38.2] [5.2-20.11 [5.8-22.7] bio-ADM (pg / fflL.) 30.0 37.4 55.4 <e.ssi [20.2-46.1] [22.5-66.8] [31.4-102.6] Furthermore, multivariable logistic regression demonstrated that bio-ADM is an independent predictor of congestion severity and the strongest among all other available variables (Table 5). Table 5: Reference value factors independently associated with clinical congestion severity in a multivariable logistic regression model (severe vs. mild / moderate) Variable Likelihood Ratio [95% CI] P-value Previous hospitalization for 1.40 [1.11-1.75] 0.004 CI BMI 1.06 [1.04-1.08] <0.001 Serum albumin 0.56 [0.43-0.74] <0.001 bio-ADM, log 1.58 [1.38-1.82] <0.001 MMKMQQOmOWWOOeOOOOOOOOOOOOOOOOOOeOOOOOOOOOWWWWgeOQQOOOOWeWOOOOOOOOOOOOOOOOMOOOOOOOWOOOOOOWMWgMQWOOOWWOOOOOOOOOOOODOOOOOOOOMOOOOOOWWOWWWMOQOOOOWWWO» The area under the curve (AUC) of the whole model was 0.69, individual AUCs: bio-ADM= 0.66, BMI 0.61, serum albumin 0.58, previous hospitalization for heart failure 0.54. There are very few reference clinical variables or biological markers associated with clinical congestion severity at the reference value, and bio-ADM appears to be by far the strongest. In addition, we analyzed whether bio-ADM could predict decongestion. Table 6 shows that bio-ADM is an independent predictor of significant residual congestion on day 7. Table 6: Association between bio-ADM reference value levels and decongestion markers. Decongestion marker Unadjusted Adjusted Estimated [95% Cl] P-value Estimated [95% Cl] P-value Significant residual congestion on day 7* 1.98 [1.70-2.32] <0.001 1.30 [1.10-1.60]** 0.009 Diuretic response on day 4 0.02 [-0.02-0.06] 0.350 - Hemoconcentration on day 4 0.82 [0.71-0.94] 0.004 0.90 [0.78-1.04]# 0.160 'defined as composite congestion score >2 on day 7 "Adjusted for reference value variables including orthopnea, JVP, peripheral edema, PCI history, pacemaker, ACEI / ARB use, BMI, DBP, BUN, hematocrit, and BNP ^Adjusted for reference clinical congestion score (NB: there is -30% missing data on hemoconcentration) Bio-ADM baseline levels independently predict significant residual congestion on day 7, as expected for a congestion marker; bio-ADM concentrations were higher the more diuretics were used for treatment (Tables 7 and 8). Table 7: Total intravenous diuretic dose up to day 7 or discharge (if earlier) in fertile women at bio-ADM reference value levels; PROTECT Tercii 1 Terci! 2 Third! 3 Trend P Total druretrsa dose IV until day 7 or thrush (if earlier), mg 200.0 [92.8-302.8] 200.0 [135.5-494.4] 400.0 POO-832] <0.001 Not adjusted Adjusted* Sise) Wafer p S (so) p-value bio-ADM 3.4 (0.3) <0.001 2.2 (0.3) <0.001 Table 8: Unadjusted and adjusted association between baseline bio-ADM levels and total IV diuretic dose to day 7 or discharge if earlier; linear regression analysis; PROTECT * adjusted for age, systolic blood pressure, creatinine, blood urea nitrogen (BUN), albumin, sodium, previous hospitalization for HF, baseline composite congestion score (CCS), and BNP; note that the association was stronger for bio-ADM, baseline CCS, and renal function in this model. MR-proADM was also determined in the same set of samples. The characteristics of f Reference values ​​by tertiles of MR-proADM are shown in Table 9: Similar to bio-ADM, increasing MR-proADM levels was associated with greater extent of edema. Table 9: Reference value characteristics by tertiles of MR-proADM Variable Tertile 1 Tertile 2 Tertile 3 Trend PN=516 N=515 N=516 MR-proADM (nmol / l) 0.24 [0.14-0.29] 0.55 [0.47-0.67] 1.25 [0.94-1.88] Sex 65.9 (340) 64.3 (331) 69.4 (358) 0.235 Age (yrs) 70.1+11.1 71.3+10.9 71.3+11.4 0.073 BMI (Kg / m2) 28+5.5 28.9+5.9 29.5+6.5 <0.001 LVEF(%) 32.9+13.4 33.5±12.3 31.3±13.8 0.178 SBP (mmHg) 126.3+17.5 125.9+17.1 122.2+17.4 <0.001 DBP (mmHg) 74.1+12.1 74.3±11.6 72.6±11.7 0.033 Heart rate (bpm) 78.7+14.4 79.8±15.4 81.2±16.5 0.008 Respiratory rate (per min) 20 [18-24] 20 [18-24] 22 [18.8-24] 0.698 Orthopnea None 3.5 (18) 4.3 (22) 3.3 (17) One pillow 12.8 (66) 10.5 (54) 13.2 (68) 0.819 Two pillows 43.4 (224) 43.3 (223) 34.5 (178) 0.619 >30 degrees 39.1 (202) 41.2 (212) 48.1 (248) 0.439 Death rattles None 8.3 (43) 7.6 (39) 11.2 (58) I laughed. <1 / 3 24.6 (127) 29.1 (150) 32.6 (168) 0.849 1 / 3-2 / 3 58.3 (301) 53 (273) 45.7 (236) 0.012 >2 / 3 8.5 (44) 10.3 (53) 10.3 (53) 0.622 Edema 0 16.3 (84) 14.8 (76) 12.2 (63) ref. 1 + 24.8 (128) 17.5 (90) 15.3 (79) 0.324 2+ 39.7 (205) 40 (206) 40.5 (209) 0.112 3+ 19.2 (99) 27.8 (143) 31.8 (164) <0.001 JVP <6 cm 11 (57) 9.3 (48) 12.6 (65) ref. 6-10 cm 45.3 (234) 42.3 (218) 40.3 (208) 0.22 >10 cm 34.7 (179) 37.7 (194) 37.4 (193) 0.755 NYHA I 1.7 (9) 0.8 (4) 0.6 (3) 0.024 II 17.4 (90) 17.5 (90) 13.8 (71) 0.062 m 50.6 (261) 49.3 (254) 44.8 (231) 0.07 IV 25.6 (132) 29.1 (150) 33.7 (174) 0.114 COPD 18.6 (96) 19.2 (99) 21.9 (113) 0.185 Stoppage 8.7 (45) 8 (41) 11.2 (58) 0.164 Peripheral vascular disease 10.1 (52) 11.9 (61) 11.9 (61) 0.37 Hypertension 79.1 (408) 83.3 (429) 78.7 (406) 0.876 Diabetes mellitus 44.6 (230) 46 (237) 47.5 (245) 0.349 Hypercholesterolemia 53.8 (277) 52.6 (271) 46.9 (242) 0.027 Myocardial infarction 49.2 (252) 50.5 (260) 50.4 (260) 0.708 Angina 22.5 (116) 21.2 (109) 23.9 (123) 0.59 Ischemic heart disease 69.2 (355) 72.8 (375) 69.6 (359) 0.898 Atrial fibrillation 48 (246) 56.5 (290) 58.8 (302) 0.001 Previous hospitalization for HF 44.8 (231) 48.9 (252) 53.3 (275) 0.006 PCI 27.5 (140) 25.6 (131) 24.9 (127) 0.344 CABG 21.4 (109) 21.9 (112) 23.2 (119) 0.472 Pacemaker 8 (41) 13.4 (69) 13 (67) 0.012 ACEI / ARB 77.7 (401) 78.6 (404) 71.5 (369) 0.02 Beta blocker 79.1 (408) 74.5 (383) 72.5 (374) 0.014 MRA 44.6 (230) 45.9 (236) 45 (232) 0.901 Digoxin 28.7 (148) 30.7 (158) 27.3 (141) 0.631 . Standard laboratory parameters Albumin (g / dL) 3.9 [3.6-4.2] 3.9 [3.6-4.2] 3.8 [3.5-4] I <0.001 ALT(U / L) 21 [15-30] 20 [15-31] 21 [15-34] i 0.003 AST (U / L) 24 [18-31] 25 [19-32.8] 26 [19-37] | 0.003 Bicarbonate (mEq / L) 24.5+3.6 24.4+3.7 23.3+3.8 | <0.001 BUN (mg / dL) 25 [19-33] 29 [22-38.2] 38 [28-51] | <0.001 Chloride (mEq / L) 101 [99-104] 101 [99-104] 101 [97-104] | 0.023 Creatinine (mg / dL) 1.2 [1-1.5] 1.4 [1.1-1.7] 1.6 [1.3-2.1] I <0.001 Total Cholesterol (mg / dL) 151 [126-181.2] 146 [119-174] 129 [107.5-159.5] I <0.601 Glucose (mg / dL) 129.5 [104-171.5] 126 [103-164] 128 [101-155] I 0.013 Hemoglobin (g / dL) 12.8+1.9 12.6±1.7 12.2+1.9 | <0.001 Platelet Count (*10 A 9 / l) 227 [180-277] 214.5 [172-266.5] 207 [161.5-263] | 0.011 Potassium (mmol / L 4.3+0.6 4.2+0.6 4.3+0.6 I 0.22 RBC Count (*10 A9 / l) 4.3±0.6 4.2±0.6 4.1±0.6 I <0.001 Sodium (mmol / L) 140 [138-142] 140 [138-143] 139 [136-142] I <0.001 Triglycerides (mmol / L) 101 [71-138.5] . 83 [63-118] 81 [61-107] | <0.001 Uric acid (mg / dL) 8.3±2.4 8.9+2.4 9.7+2.8 I <0.001 WBC (*10 A 9 / l 7.7 [6.3-9.2] 7.3 [6.1-9.1] 7.2 [5.9-9.3] i 0.591 Hematocrit (%) 40.4+5.8 40+5.5 38.9+5.9 | <6.001 Biological markers IL-6 (pg / ml) 9.1 [5.3-16.5] 10.8 [6.4-19.9] 14.3 [8.8-26] 10.037 CRP (ng / ml) 12566.3 [6334.9- 25975.8] 13306.5 [7168.3- 27844.1] 16044.9 [8412.3- 29966.3] | 0.015 Dimer D (ng / ml) 134 [90.6-301] 155.5 [90.6-340.8] 180.3 [90.6-374.7] | 0.017 PIGR (ng / ml) 292.2 [197.5- 500.4] 363 [263.5- 531.6] 578.8 [371.4- 999] | <0.001 Pentraxin-3 (ng / ml) 3.4 [2.2-6] 3.9 [2.8-6] 5.5 [3.6-8.9] i <0.001 GDF-15 (ng / ml) 3.6 [2.5-5.8] 4 [3-6.1] 6.3 [4.3-6.3] <0.001 RAGE (ng / ml) 4.7 [3.4-6.5] 4.9 [3.6-6.4] 5.4 [4-7.4] <0.001 TNF-R1a (ng / ml) 2.6 [1.7-4] 2.9 [2.2-3.9] 4.4 [3.2-5.9] <0.001 PCT (pg / ml) 14 [8-31] 20 [11-41] 35.5 [18-78] <0.001 Myeloperoxidase (ng / ml) 33.9 [17.7-78.5] 30.9 [18.7-60] 32.8 [17-66.2] 0.209 Syndecan-1 (ng / ml) 7.7 [6.4-9.5] 8.1 [6.9-9.4] 9.6 [8.1-11.6] <0.001 Periostin (ng / ml) 4 [2.3-6.8] 5.8 [3.5-8.8] 7.3 [4.3-11.2] <0.001 Galectin-3 (ng / ml) 32 [25.2-43.1] 34 [26.5-44.1] 42.7 [32.5-55.9] <0.001 Osteopontin (ng / ml) 98.3 [66.3-149.9] 106.4 [74.2- 150.3] 133.8 [100.7- 190.8] <0.001 ET1 (pg / ml) 5.7 [4.2-7.6] 6.7 [5.1-9] 7.9 [6.1-11] <0.001 BNP (pg / ml) 310.8 [189.8- 548.6] 477.2 [262.6- 783.3] 630.1 [341.3- 1063] <0.001 NT-proCNP (pg / ml) 34 [22-48] 42 [31-58] 53 [38-74.2] <0.001 ST-2 (ng / ml) 1.8 [0.9-5.6] 2.8 [1-5.7] 6.1 [2.7-10.9] <0.001 VEGFR (ng / ml) 0.3 [0.2-0.4] 0.4 [0.2-0.5] 0.5 [0.3-0.8] <0.001 Anglogenin (ng / ml) 1940 [1229.1- 2950.6] 1979.3 [1388.1- 3093.5] 1675.8 [1178.7- 2552.6] 0.007 Mesothelin (ng / ml) 81.6 [65.6-97] 83.6 [73.6-94.2] 94.5 [83.7-108.1] <0.001 Neurophilin SAND (ng / ml) 10.6 [6.6-15.8] 11.6 [8.1-16.8] 14.8 [10.8-20.4] <0.001 Troy (pg / ml) 72 [49-110] 84 [64-115] 114 [83-153] <0.001 bio-ADM 28 [17.2-53.5] 42.9 [27.1-74.2] 70.9 [40.3-120.3] <0.001 LTBR (ng / ml) 0.3 [0.2-0.5] 0.4 [0.3-0.5] 0.5 [0.4-0.7] <0.001 ESAM (ng / ml) 59.2 [53.4-68] 60.2 [55.6-65.8] 66.3 [60.5-71.7] <0.001 KI M-1 (pg / ml) 273.4 [169.1- 484.6] 296 [181.3- 480.4] 316.8 [199.3- 492.9] 0.485 NGAL(ngZml) 64.8 [44.2-98.6] 81.8 [54.2-123] 107.2 [70.4- 175.2] <0.001 PSAP-B(ng / rnl) 34 [25.3-49.7] 36.9 [27.9-47.8] 45.4 [34.1-61.1] <0.001 WAP4C(ng / ml) 18.2 [8.7-38.8] 22.6 [13.9-38.5] 45.8 [26.9-67.8] <0.001 cTnl(pg / ml) 9.3 [5.1-19.5] 10.9 [5.6-21.2] 12.5 [6.3-27.2] 0.078 . Example 7 Biostat Studio Additional analyses were performed in the BIOSTAT study (Biology Study for Intensive Treatment in Chronic Heart Failure). The study has been described in detail in ( WWW.BIOSTAT-CHF.EU(Voors et al. 2016. Eur J Heart Fail. Jun;18(6):716-26). The Biology Study for Intensive Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and / or symptoms of heart failure in 11 European countries who were considered to be on suboptimal medical treatment. An additional 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. Most patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and / or symptoms of heart failure in outpatient settings. Approximately half of the patients were in New York Heart Association class III, and 7% versus 34% of patients in the index versus validation cohort had heart failure with preserved ejection fraction.According to the study design, all patients used diuretics, but due to the inclusion criteria of both cohorts, the patients were not on evidence-based optimal medical therapy. During the follow-up phase, titration up to the recommended doses according to the guidelines was encouraged. Study population The patients met the following inclusion criteria: » age >18 years with new onset or worsening symptoms of heart failure, ® have objective evidence of documented cardiac dysfunction, either by, » left ventricular ejection fraction of <40% or, »plasma concentrations of pro-brain natriuretic peptide BNP and / or N-terminal pro-BNP (NT-proBNP) >400 pg / mL or >2000 pg / ml, respectively, ® are treated with oral or intravenous furosemide >40 mg / day or equivalent at the time of inclusion, ® not previously treated with evidence-based therapies [angiotensin-converting enzyme (ACE) inhibitors / angiotensin receptor blockers (ARBs) and beta-blockers] or receiving <50% of the target doses of these drugs at the time of enrollment, ® be anticipated, initiated or updated with ACE inhibitors / ARBs and / or beta blockers by the treating physician. Patients were enrolled as inpatients or outpatients. Approximately two-thirds were inpatients and one-third were outpatients. A subset of patients comprising all types of patients included in the trial (n = 1806), for whom biomarker measurements were available at the start of the study, was analyzed in the present invention. Similar to the PROTECT study (example 6), in the BIOSTAT study, increasing levels of bio-ADM were also correlated with increased edema severity (Table 10). Table 10: Clinical variables with reference values ​​and standard biological biomarkers by severity of peripheral edema; BIOSTAT None N = 734 Ankle N = 532 Below the knee N = 408 Above the knee N = 132 Trend P Age (years) 68 [59.7-76.2] 70.7 [62.6-78.6] 72.4 [64.2-78.8] 74.3 [64.6-80.4] <0.001 BIWI (Kg / m 2) 26.5 [23.9-29.4] 27.1 [23.9-30.4] 28.7 [24.8-33.8] 30.5 [26.2-34.9] <0.001 LVEF(%) 30 [25-35] 30 [25-37] 30 [23-38] 35 [25-43.8] 0.002 DBP (mmHg) 75.8±12.9 74.2+12.8 74.3+14.6 72.5+13 0.004 Heart rate (bpm) 75 [65-85] 78.5 [68.2-90] 80 [70-92] 80 [70-92.2] <0.001 Orthopnea 21.5 (158) 40.4 (215) 50.7 (207) 61.4 (81) <0.001 Crackles >1 / 3 5.6 (41) 10.7 (57) 16.4 (67) 28.8 (38) <0.001 lung fields JVP elevated 11.2 (82) 29.7 (158) 38 (155) 47 (62) <0.001 NYHA I 2.7 (20) 0.8 (4) 1 (4) 15.2 (20) laugh. II 48.2 (354) 31 (165) 14.7 (60) 57.6 (76) 0.402 III 39.2 (288) 53.2 (283) 62.7 (256) 21.2 (28) <0.001 IV 8.2 (60) 13.5 (72) 18.1 (74) 6.1 (NA) <0.001 Hepatomegaiia 8 (59) 16.2(86) 22.3 (91) 27.3 (36) <0.001 Medical history Diabetes mellitus 27.1 (199) 32.7 (174) 43.6 (178) 36.4 (48) <0.001 Atrial fibrillation 38.6 (283) 49.1 (261) 56.4 (230) 55.3 (73) <0.001 ACEI / ARB 73.8 (542) 74.6 (397) 66.7 (272) 57.6 (76) <0.001 Beta Bio-Analyzers 86.8 (637) 83.1 (442) 78.2 (319) 75 (99) <0.001 Biological markers ALBUMIN1 (g / L) 33 [28-39] 32 [27-37.5] 31 [26-35] 30 [24.2-33.8] <0.001 AST (U / L) 24 [19-32] 26 [19-36] 28 [21-37] 29 [24-40.8] 0.003 Gamma-GT (U / L) 39.7 61 69 98 5 <0.001 [24-79.5] [30-107.8] [40-142.3] [55-174.5] BUN (mmol / L) 10.1 12.0 11.9 11.3 0.001 [7.1-16.5] [7.8-19.3] [8.3-19.9] [7.4-18.4] Total Cholesterol 4.4 [3.7-5.2] 4 [3.3-4.9] 3.8 [3.1-4.5] 3.1 [2.8-3.7] <0.001 (mmol / L) Hemoglobin (g / dL) 13.5±1.8 13+1.9 13.1+1.9 12.4+2.1 <0.001 Triglycerides (mmol / L) 1.3 [1-1.8] 1.2 [0.9-1.5] 1.1 [0.9-1.5] 0.9 [0.8-1.2] <0.001 Hematocrit (%} 40.6+5.1 39.7+5 4 39.8+5.6 38.3+5.8 <0.001 BMP (pg / ml) 489.1 6S3.8 792.5 759.0 0.02 [225-812] [322-1192] [487-1471] [557-2023] bio-ADM (pg / mL) 2S.1 36.7 52.8 82.8 <0.001 [19.2-37.8] [24.6-54.4] [34.4-86.7] [49.4-141.2] . MR-proADM was also determined in the same set of samples. The characteristics of the reference range by tertiles of MR-proADM are shown in Table 11: Similar to bio-ADM, recent MR-proADM levels were associated with a greater extent of edema. Table 11: Reference value characteristics by tertiles of MR-proADM Variable TT= Tertile 1 704 Tertile 2 703 Tertile 3 703 Trend P MR-proADM (nmoi / L) 0.3 [0.2-0.3] 0.5 [0.4-0.6] 1 [0.8-1.5] <0.001 Male sex 74.6 (525) 72.1 (507) 73 (513) 0.498 Age (years) 65.3 [57-73.8] 71.2 [62.9-78.4] 74.3 [65.2-80.4] <0.001 BMI (Kg / m 2) 26.8 [23.9–30.4] 27.3 [24.2–30.9] 27.1 [24.1–30.7] 0.051 LVEF (%) 30 [25–35] 30 [25–37.2] 30 [25–38] 0.297 SBP (mmHg) 126.3+20.8 125.8+23.4 121.2±21.1 <0.001 DBF (mmHg) 76.4±13.3 75.2+13.3 72.3±13 <0.001 Heart rate (bpm) 75 [65-86] 77 [68-90] 77 [67-90] 0.015 Orthopnea present 23 (162) 35.8 (252) 45.1 (317) <0.001 Stertors>1 / 3 lung fields 6.4 (45) 11.9 (84) 12.9 (91) 0.074 Edema 0 45 (317) 32.9 (231) 23.2 (163); ref. 1 + 20.5 (144) 26.3 (185) 26.5 (186) <0.001 2+ 11.9 (84) 17.2 (121) 27.0 (190) <0.001 3+ 2.1 (15) 4.8 (34) 11.0 (77) <0.001 Elevated JVP 14.9 (105) 20.9 (147) 32.4 (228) <0.001 NYHA i 2.7(19) 2.6 (18) 1 (7) ref. II 46 (324) 37.7 (265) 21.5 (151) 0.751 in 40.1 (282) 48.1 (338) 55.3 (389) 0.002 IV 7.8 (55) 9.7 (68) 18.8 (132) <0.001 Hepatomegaly 9.7 (68) 12.8 (90) 19.8 (139) < 0.001 S3 9.7 (68) 9.7 (68) 9.5 (67) 0.935 Medical History COPD 15.1 (106) 17.4 (122) 18.9 (133) 0.054 Para 7.1 (50) 10 (70) 11.5 (81) 0.005 Peripheral vascular disease 8.5 (60) 12.5 (88) 12.5 (88) 0.017 Hypertension 60.8 (428) 64.3 (452) 61.3 (431) 0.842 Diabetes mellitus 25.6 (180) 35.3 (248) 36.7 (258) <0.001 Myocardial infarction 29.7 (209) 39.5 (278) 42.1 (296) <0.001 Atrial fibrillation 37.1 (261) 46.4 (326) 53.5 (376) <0.001 Previous hospitalization for HF 27.8 (196) 30.4 (214) 34.3 (241) 0.009 PCI 17 (120) 21.2 (149) 23.6 (166) 0.002 CABG 12.2 (86) 17.8 (125) 21.8 (153) <0.001 ACEI / ARB 75.7 (533) 73.1 (514) 66.4 (467) <0.001 Beta blocker 84.9 (598) 83.5 (587) 80.1 (563) 0.016 Standard laboratory parameters Albumin (g / L) 34 [29-39] 33 [27-37] 30 [24-36] <0.001 ALT(U / L) 27 [18-40] 25 [17-39] 23 [15-35] 0.452 AST (U / L) 24 [20-33] 25.9 [18-35] 27 [20-36] 0.087 Gamma-GT (U / L) 40.8 [25-84] 52 [28-99] 76 [32.5-132.4] <0.001 Alkaline phosphatase (ug / L) 80 [63-114.8] 83 [65-111] 91 [69-123.5] 0.087 BUN (mmol / L) 8.9 [6.4-13.3] 11 [7.4-16.2] 15 [9.5-25] <0.001 Creatinine (mg / dL) 89.3 [75.8- 106.1] 100 [84.6-123.4] 124.6 [98-167] 0.61 Total cholesterol (mmol / L) 4.5 [3.8-5.5] 4.2 [3.4-4.9] 3.6 [3-4.5] <0.001 Glucose (mg / dL) 6 [5.3-7.5] 6.4 [5.4-8.5] 6.5 [5.4-7.9] 0.22 Hemoglobin (g / dL) 13.7±1.7 13.3±1.8 12.5±1.9 <0.001 Platelet count (*10. A 9 / l) 221 [183-264] 220 [173-263] 208 [161-258] 0.001 Potassium (mmol / L 4.3 [4-4.6] 4.2 [3.9-4.5] 4.2 [3.8-4 6] 0.003 RBC count (*10 A12 / l) 4.6 [4.2-5] 4.5 [4.1-4.9] 4.2 [3.8-4.7] <0.001 Sodium (mmol / L) 140 [138-142] 140 [137-142] 139 [136-141] <0.001 Triglycerides (mmol / L) 1.3 [1-1.7] 1.3 [0.9-1.8] 1.1 [0.9-1.5] <0.001 WBC (*10^9 / 1 7.7 [6.6-9.2] 8 [6.5-9.8] 7.7 [6.3-9.7] 0.529 Hematocrit (%) 41.3+4.9 40.2±5.2 38.2+5.4 <0.001 Biological markers IL-6 (pg / ml) 3.7 [2-6.8] 5.1 [2.8-8.9] 8.2 [4.5-16.5] <0.001 CRP (ng / ml) 11872.9 [4810.7- 25356.7] 12266.6 [5506.4- 25955.3] 16350.1 [7718.9- 29386.1] 0.004 Dimer D (ng / ml) 0.032 PIGR (ng / ml) 71.5 [44-106.5] 123.6 [89.8- 177.3] 216.3 [153.8- 311.2] <0.001 Pentraxin-3 (ng / ml) 1.3 [0.8-2.1] 2 [1.4-3.1] 3.3 [2.1–5.2] <0.001 GDF-15 (ng / ml) 2.6 [2.2–3.1] 3.4 [3–4] 4.4 [3.8–5.3] <0.001 RAGE (ng / ml) 2 [1.4–2.7] 2.9 [2.1–4] 3.8 [2.8–5] <0.001 TNF-R1a (ng / ml) 0.6 [0.3–0.8] 1 [0.8–1.4] 1.9 [1.3–2.7] < 0.001 PCT (pg / ml) 6.2 [3.7–16.1] 16 [8.2–31.6] 36.6 [18.9–82.2] < 0.001 Myeloperoxidase (ng / ml); 24.3 [20.6–30.2] 28.4 [24.1-34.8] 31.1 [26.6-38.9] <0.001 Syndecan-1 (ng / ml) 1.2 [0.6-2.1] 2.2 [1.4-3.5] 3.9 [2.5-6.1] <0.001 Periostin (ng / ml) 3.9 [2.3-6.5] 6.2 [4-9.5] 9.2 [5.9-14.9] <0.001 Galectin-3 (ng / ml) 17.6 [13.2-24.7] 20.3 [15.4-27] 26.8 [19.1-37.7] <0.001 Osteopontin (ng / ml) 176.3 [147.2- 206.4] 215.4 [187.2- 247] 260.2 [227.7- 298.8] <0.001 ET1 (pg / ml) 4.4 [3.5-5.9] 5.3 [4-6.7] 6.6 [5.1-9.1] <0.001 BNP (pg / ml) 515 [219.9- 957.5] 598.3 [260.7- 1162] 1032 [639- 1641.5] 0.004 NT-proCNP (pg / ml) 5.2 [5.2-5.2] 5.3 [5.2-11.2] 14.7 [6.2-27.4] <0.001 ST-2 (ng / ml) 4.2 [2.3-9.1] 8.3 [4.5-15.6] 20.4 [10.1-36.1] <0.001 VEGFR (ng / ml) 0.1 [0.1-0.1] 0.1 [0.1-0.2] 0.2 [0.1-0.4] <0.001 . Angiogenin(ng / mL) 6202.1 [4115.9- 9654.5] 4484.4 [3193- 6378.8] 3672 [2629- 5151.6] <0.001 Mesóte lina (ng / ml) 47.7] 5 [4.21.7]-5. [48.7–59.5] 60.4 [54.2–68.8] <0.001 Neuropilin SAND (ng / ml) 17 [13.5–20.8] 21.3 [17.5–25.5] 26.6 [21.4–31.1] Troy <0.0.0 (p [0.1–0.2] 0.3 [0.2–0.4] 0.4 [0.3–0.7] <0.001 LTBR (ng / ml) 0.1 [0.1–0.1] 0.2 [0.1–0.2] 0.2 [0.2–0.3] <0.0.1 ng (57.1 m ES [51.6-62.2] 64.2 [59.2-69.1] 71 [65.8-78] <0.001 NGAL(ngZml) 45.6 [30.7-72.4] 59 [37.5-87.6] 82.7

[51] (ZZml) <m0.135. 25.5 [17.2–33] 31.6 [24.4–37.4] 37 [29.4–43.1] <0.001 WAP4C(ngZml) 0.7 [0.5–1.2] 1.4 [0.9–2.3] 3.5 c [6 / 2ml)00]p [5–23.5] 12.6 [7.2–27] 16.5 [9.5–35.9] 0.098 Example 8 Administration of NT-H in healthy humans The study was conducted in healthy male subjects as a randomized, double-blind, placebo-controlled, single-dose escalating study of NT-H antibodies adapted to be administered as an intravenous (iv) infusion in 3 sequential groups of 8 healthy male subjects each (1st group 0.5 mg / kg, 2nd group 2 mg / kg, 3rd group 8 mg / kg) of healthy male subjects (n= 6 active, n^ 2 placebo for each group). The main inclusion criteria were written informed consent, age 18 to 35 years, agreement to use a reliable contraceptive method, and a BMI between 18 and 30 kg / m² 2 . The subjects received a single IV dose of NT-H antibody (0.5 mg / kg; 2 mg / kg; 8 mg / g) or placebo by slow infusion over a period of 1 hour in a research unit. The reference ADM values ​​in the 4 groups did not differ. The median ADM values ​​were 7.1 pg / mL in the placebo group, 6.8 pg / mL in the first treatment group (0.5 mg / kg), 5.5 pg / mL in the second treatment group (2 mg / kg), and 7.1 pg / mL in the third treatment group (8 mg / mL). The results show that ADM values ​​increased rapidly in the first 1.5 hours after NT-H antibody administration in healthy human individuals, then reached a plateau and slowly declined (Fig. 9). Example 9 NT-H antibody administration in septic pigs, two-hit model A two-shock septic shock model established in pigs (Simon TP et al., Crit Care. 2D 12 Jan 25:16(1)^16) was used to induce heart failure and to study the influence of the NT-H antibody on hemodynamic and clinical parameters including cardiac function. Sixteen German Landrace pigs (n = 16; mean ± standard deviation (SD) 33 ± 1.5 kg body weight (BW)) were anesthetized and ventilated, and standard procedures for the care of laboratory animals were followed. This study was approved by the institutional and local committee on the care and use of animals (Landesamt für Natur, Umwelt und Verbraucherschutz Nordrhein-Westfalen, Germany, 84-02.04.2015.A037). The animals were premedicated with azaperone (1–2 mg / kg body weight) and ketamine (10 mg / kg body weight), and general anesthesia was induced by intravenous injection of propofol (1–2 mg / kg body weight). The animals were intubated orally and placed in a supine position. General anesthesia was maintained with infusions of propofol and fentanyl. Pressure-controlled ventilation was selected to ventilate the animals with an inspiratory oxygen fraction of 0.5, an inspiratory-to-expiratory ratio of 1:1.5, PEEP set at 5 cm H₂O, and a tidal volume of 8–10 mL / kg body weight. The respiratory rate was set to maintain a PaCO₂ of 3.5–4.5 kPa. Core body temperature was maintained above 37.5°C using a warming blanket. Two central venous catheters were inserted into the external jugular vein and the femoral vein, and an arterial PICCO catheter was inserted into the femoral artery via transcutaneous puncture. At the end of the study, the animals were euthanized in the presence of a veterinarian with a lethal dose of Narcan® (Merial, Hallbergmoos, Germany) while still under deep narcosis. In this model, we used a clot loaded with E. coli with 7-9x10 11 colony-taking units (CFUs) per kg / BW to induce septic shock. Hemodynamic measurements: All intravascular pressure measurements were referenced to the mid-thoracic level, and values ​​were obtained at end-expiration. Heart rate, mean arterial pressure (MAP), central venous pressure (CVP), and stroke volume variation (SW) were continuously recorded. Cardiac output (CO) was measured using transpulmonary thermodilution (PICCO, Pulsion Medical Systems, Feldkirchen, Germany). Extravascular lung water (EVLW), intrathoracic blood volume (ITBV), and global end-diastolic volume (GEDV) were calculated using a standard formula. Experimental protocol: During catheterization, the animals received 10 mL / kg BW / h of a balanced crystalloid solution. Hemorrhagic shock was induced by bleeding the animals through the femoral vein catheter. The animals were bled until half of the baseline mean arterial pressure (MAP) was reached. Hemorrhagic shock was maintained for 45 minutes, followed by fluid resuscitation with a balanced crystalloid solution to restore baseline mean arterial pressure. Two hours after hemorrhagic shock, the blood collected during the shock was re-transfused. As a second shock, sepsis was induced using an E. coli-laden clot placed in the abdominal cavity six hours after hemorrhagic shock. The animals were randomly assigned to receive either the adrenomedullin antibody or the vehicle solution. Therapy with either the antibody or the vehicle solution began immediately after sepsis induction.The antibody / vehicle solution was infused at a dose of 2 mg / kg of body weight over a period of 30 minutes. 4 hours later. Once sepsis was induced, septic shock therapy was initiated using balanced crystalloids and norepinephrine as needed. Volume replacement and vasopressor therapy were titrated to maintain a central venous pressure of 8 to 12 mmHg, a mean arterial pressure above 65 mmHg, and a central venous oxygen saturation of 70%, as recommended by the Sepsis Survival Campaign. Sepsis therapy continued for an additional 8 hours. EDTA-plasma and serum samples were obtained for various measurements before hemorrhagic shock, before sepsis induction, and 1, 2, 3, 4, 6, 8, 10, and 12 hours post-induction of sepsis, and stored at -8°C until measurement.Hemorrhagic and septic shock were not performed on the SHAM group animals, but otherwise, they received the same treatment, including the entire intravascular catheter, midline laparotomy, and blind application of the antibody / vehicle solution. Blood samples were drawn as in the septic animals. The schedule for treatment and blood sampling is shown in Fig. 10. As expected, plasma ADM concentrations began to increase after sepsis induction in both groups. This increase was accelerated by NT-H antibody administration concurrent with sepsis induction. Although the vehicle group showed an increase of approximately 30 pg / mL one hour after sepsis induction, the treatment group showed 265 pg / mL at the same time point. The treatment group reached a steady state of approximately 1,100 pg / mL three hours after NT-H antibody administration, while the vehicle group showed a steady increase in ADM concentration to 700 pg / mL by the end of the experiment (Fig. 11). NT-H antibody administration also induced an increase in plasma ADM in the sham control animals. This is analogous to the results observed in healthy humans (Example 8). The heart rate (HR) increased at the point of blood collection for hemorrhagic shock to compensate for volume loss and returned to baseline values ​​after volume replacement with crystalloid solution and blood. After the induction of sepsis, the heart rate remained constant at 60–65 bpm. 1 during the first hour and then began to increase, where the rate of increase was higher in the vehicle group compared to the antibody treatment group with final values ​​at 125 min 1 (vehicle) compared to 98 mim 1 (treatment) (Fig. 12). Cardiac output (CO) describes the volume of blood pumped by the heart, specifically by a left or right ventricle, per unit of time. CO values ​​can be expressed using many physical units, such as L / min. Cardiac output in this study was significantly lower in the NT-H antibody-treated group compared to the vehicle group (Fig. 13). Fluid requirements (Figs. 14 and 15) and norepinephrine requirements (Fig. 16) to maintain a constant mean arterial pressure were considerably lower in the NT-H antibody treatment group compared to the vehicle group. Importantly, only one-third of the NT-H-treated animals experienced shock (i.e., required vasopressor support to maintain target MAP), whereas all vehicle controls required vasopressors (Fig. 17). Urine output did not differ between the NT-H antibody treatment group and the vehicle group. The reduced fluid requirements following NT-H antibody administration, especially Also considering the reduced noradrenaline requirement, it shows that less fluid had escaped from the bloodstream and, therefore, less congestion had occurred in the NT-H antibody treatment group. Vascular resistance refers to the resistance to blood flow offered by the entire systemic vasculature, excluding the pulmonary vasculature. Systemic vascular resistance (SVR) is used in calculations of blood pressure, blood flow, and cardiac function. SVR, in units of dyn.s.crrr 5 It was calculated from other measurements using the following formula: SVR = 80 x (MAP~CVP) / CO. SVR increases to tighten the arterial vascular circuit in an attempt to maintain blood pressure. As shown in Fig. 18, systemic vascular resistance in this animal model was higher in the NT-H-treated group compared to the vehicle group. Example 10 NT-H administration in LPS-induced endotoxemia in rats The aim of this study was to examine the effect of HAM8101 on vascular permeability in the liver and kidney after LPS-induced endotoxemia in rats. Doses of 0.02, 0.1, 0.5, and 2.5 mg of HAM81D1 / kg body weight or PBS were administered intravenously (single bolus injection) to male Wistar rats (n = 8 / group) (see Table 12). Five minutes later, 2.5 or 5 mg LPS / kg body weight were administered to induce endotoxemia (the 2.5 mg LPS / kg group was used only to test the appropriate LPS dose and was not further evaluated). Blood samples were collected 3, 6, and 24 hours after the administration of LPS and HAM81D1. Twenty-four hours after application of the LPS solution, Evans Blue was slowly administered via injection into the tail vein. The animals were sacrificed 15 minutes later and perfused with heparinized saline (50 IU / ml). The kidneys and liver were removed, weighed, and sectioned. After further manipulation, the concentration of Evans Blue in the tissue was determined (spectroscopic absorbance at 620 nm), indicating vascular permeability. Additionally, urine was collected from the bladder prior to perfusion. Table 12 Experimental Groups and Doses Group Dose HAM8101 [mg / kg] Dose [mg / kg] LPS NA (Control) NaCI NaCI 8 B (Placebo; only tests NaCI 2.5 6 for appropriate LPS dose, without further evaluation) C (Placebo) NaCI 5 8 D 2.5 5 8 E 0.5 5 8 F 0.1 5 8 G 0.02 5 8 The time course of rADM plasma concentrations for the placebo group (NaCI + LPS) showed an increase during the first 6 hours after LPS application to a peak plasma concentration of 140 pg / mL with a subsequent decrease to 64 pg / mL at 24 hours. Total rADM levels increased further with HAM8101 treatment in a dose-dependent manner, with peak rADM concentrations of 550 pg / mL for 2.5 mg / kg and 270 pg / mL for 0.5 mg / kg achieved 3 hours after LPS and HAM8101 administration. Lower doses of 0.1 and 0.02 mg / kg showed no additional increase compared to the LPS-induced increase in rADM (19A). When total rADM levels were normalized to those achieved in the placebo group at the respective time points, peak levels increased by a factor of 5.3 and 2.7 in the 2.5 mg / kg and 0.5 mg / kg groups, respectively. This increase in total plasma ADM concentration compared to baseline is greater than in healthy animals (factor 3 for 2.5 mg / kg) and septic mice (factor 2). The lower doses of 0.1 and 0.02 mg / kg showed no increase in total rADM levels exceeding the levels achieved by LPS alone (19B). Rats were treated with NaCl (healthy, green) or LPS at 5 mg / kg body weight (placebo, red); rats were further treated with NaCl (placebo, red) or HAM8101 (blue) at different doses by single IV bolus injection 5 minutes before LPS administration. rADM levels were determined 3, 6, and 24 hours after LPS administration and are presented as (A) mean ± SEM values ​​or (B) as induction x times compared with the placebo group at the respective time point. Vascular permeability increased significantly after LPS challenge. There was a clear and significant reduction in vascular permeability with HAM8101 treatment at doses of 0.1 to 2.5 mg / kg in the kidneys (see Fig. 20A). At a dose of 0.1 mg / kg, the restoration of permeability to a normal state was significantly more effective compared to doses of 0.5 and even 2.5 mg / kg (p < 0.05). Whether this effect is reliable should be validated in further studies. In contrast, almost no beneficial effect on vascular permeability was observed at 0.02 mg / kg. Vascular permeability data in the liver showed a comparable trend, but were not statistically significant (see Fig. 20B). Rats were treated with NaCl (control, green) or LPS at 5 mg / kg body weight (placebo, red). Rats were further treated with NaCl (placebo, red) or HAM8101 (blue) at different doses via a single IV bolus injection 5 minutes before LPS administration. Vascular permeability was measured by determining the concentration of Evans Blue in (A) kidney and (B) liver tissue 24 hours after challenge and LPS treatment. Values ​​are given as mean ± SEM; p-values ​​<0.05 were considered statistically significant. In conclusion, in this rat endotoxemia model, treatment with HAM8101 at doses starting at 0.1 mg / kg led to a significant restoration of vascular integrity in the kidney. A comparable effect was observed in the liver, which, however, was not statistically significant. It is unclear whether this is a real effect or due to the detection method used. A significant increase in total plasma rADM levels was observed at HAM8101 doses above 0.1 mg / kg. INFORMATION ABOUT THE SEQUENCE LIST SEQ ID No.: 1 GYTFSRYW SEQ ID No.: 2 ILPGSGST SEQ ID No.: 3 TEGYEYDGFDY SEQ ID No.: 4 QSIVYSNGNTY SEQUENCE “RVS” (not part of the sequence listing): RVS SEQ ID No.: 5 FQGSHIPYT SEQ ID No.: 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFK GKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID No.: 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC SEQ ¡D No.: 12 (AM-VL1) DWMTQSPLSLPVTLGQPASiSCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID No.: 13 (AM-VL2-E40) DWMTQSPLSLPVTTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKÍSRVEAEDVGVYYCFQGSHiPYTFGQGTKLEÍKRTVAAPSVFiFPPSDEQLKSGTAS WCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID No.: 14 (ADM humana 1-21) YRQSMNNFQGLRSFGCRFGTC SEQ ID No.: 15 (ADM humana 21-32) CTVQKLAHQIYQ SEQ ID No.: 16 (ADM humana C-42-52) CAPRSKISPQGY-CONHz SEQ ID No.: 17 (ADM marina 1-19) YRQSMNQGSRSNGCRFGTC SEQ ID No.: 18 (ADM marina 19-31) CTFQKLAHQIYQ SEQ ID No.: 19 (ADM marina C-40-50) CAPRNKISPQGY-CONHz SEQ ID No.: 20 (Adrenomedulina humana madura (ADM madura); ADM amid: blo-ADM): aminoácidos 1-52 o aminoácidos 95-146 de pro-ADM YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVAPRSKISPQGY-CONHz SEQ ID No.: 21 (ADM marina 1-50) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGMAPRNKISPQGY-CONH2 SEQ ID No.: 22 (1-21 de ADM humana): YRQSMNNFQGLRSFGCRFGTC SEQ ID No.: 23 (1-42 de ADM humana): YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQFTDKDKDNVA SEQ ID No.: 24 (aa 43 - 52 de ADM humana) PRSKISPQGY-NH2 SEQ ID No.: 25 (aa 1-14 de ADM humana) YRQSMNNFQGLRSF SEQ ID No.: 26 (aa 1-10 de ADM humana) YRQSMNNFQG SEQ ID No.: 27 (aa 1-6 de ADM humana) YRQSMN SEQ ID No.: 28 (aa 1-32 de ADM humana) YRQSMNNFQGLRSFGCRFGTCTVQKLAHQIYQ SEQ ID No.: 29 (aa 1-40 ADM murina) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQLTDKDKDGMA SEQ ID No.: 30 (aa 1-31 ADM murina) YRQSMNQGSRSNGCRFGTCTFQKLAHQIYQL SEQ ID No.: 31 (proADM: 164 amino acids (22 -- 185 de preproADM)) ARLDWASEF RKKWNKWALS RGKRELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RVKRYRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGYGRRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL SEQ ID No.: 32 (terminal N-20 peptide proadrenomedullin, PAMP: amino acids 22 - 41 of preproADM) ARLDVASEF RKKWNKWALS R SEQ ID No.: 33 (mid-region proAdrenomedullin, MR-proADM: amino acids 45 - 92 of preproADM) ELRMSS SYPTGLADVK AGPAQTLIRP QDMKGASRSP EDSSPDAARI RV SEQ ID No.: 34 (Adrenomedullin 1-52-Gly (ADM 1-52-Gly): amino acids 95- 147 of preproADM) YRQSMN NFQGLRSFGC RFGTCTVQKL AHQIYQFTDK DKDNVAPRSK ISPQGYG SEQ ID No.: 35 (proAdrenomedullin C-terminus, CT-proADM: amino acids 148 - 185 of preproADM) RRR RRSLPEAGPG RTLVSSKPQA HGAPAPPSGS APHFL

Claims

CLAIMS 1. An anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontig without anti-ADM Ig, for use in congestion intervention and therapy in a patient in need thereof, wherein said anti-ADM antibody or anti-ADM fragment or supercontig without anti-ADM Ig binds to the N-terminal portion (aa 1-21) of adrenomedullin: YRQSMNNFQGLRSFGCRFGTC (SEQ ID No. 22), and where the patient is resistant to diuretics or does not respond to diuretic therapy.

2. The anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontigo without anti-ADM Ig for use in congestion intervention and therapy in a patient according to claim 1, wherein said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease.

3. The anti-adrenomedullin (ADM) antibody or an adrenomedullin antibody fragment or supercontigo without anti-ADM Ig for use in congestion intervention and therapy in a patient according to claim 1 or 2, wherein said patient has a disease or condition selected from the group comprising: congestive hypertension, swelling or water retention (edema) and heart failure, in particular acute heart failure.

4. The anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment that binds to adrenomedullin or anti-ADM Ig-free supercontig that binds to adrenomedullin for use in congestion intervention and therapy in a patient according to any of claims 1 to 3, wherein said antibody or antibody fragment or Ig-free supercontig is monospecific.

5. The anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment binding to adrenomedullin or anti-ADM Ig supercontigue binding to adrenomedullin for use in congestion intervention and therapy in a patient according to any of claims 1 to 4, wherein said antibody or fragment or supercontigue exhibits an ADM binding affinity of at least 10⁻⁴ 7 M.

6. The anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontig for use in congestion intervention and therapy in a patient according to any of claims 1 to 5, wherein said antibody, fragment or supercontig recognizes and binds to the N-terminal end (aa 1) of adrenomedullin.

7. The anti-adrenomedullin (ADM) antibody or anti-ADM antibody fragment binding to adrenomedullin or non-Ig anti-ADM supercontigue binding to adrenomedullin for use in congestion intervention and therapy in a patient according to any one of claims 1 to 6, wherein said antibody, antibody fragment or non-Ig supercontigue does not bind to the C-terminal portion of ADM, ADM having the aa sequence 43-52 PRSKISPQGY-NH2 (SEQ ID NO: 24).

8. The anti-ADM antibody or an anti-adrenomedullin antibody fragment or a supercontig without anti-ADM lg for use in congestion intervention and therapy in a patient in accordance with any of claims 1 to 7, wherein said antibody or fragment or superantigen blocks the bioactivity of ADM by not more than 80%, preferably not more than 50%.

9. The anti-ADM antibody or an anti-adrenomedullin antibody fragment or an anti-ADM Ig-free supercontigo for use in congestion intervention and therapy in a patient according to any of claims 1 to 8, wherein said patient is an ICU patient.

10. The anti-ADM antibody or an anti-adrenomedullin antibody fragment for use in congestion intervention and therapy in a patient according to any of claims 1 to 9, wherein said antibody or fragment is a human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof, wherein the heavy chain comprises the sequences: SEQ ID NO: 1 GYTFSRYW SEQ ID NO: 2 ILPGSGST SEQ ID NO: 3 TEGYEYDGFDY and where the light chain comprises the sequences: SEQ ID NO: 4 QSIVYSNGNTY SEQUENCE: RVS SEQ ID NO: 5 FQGSHIPYT.

11. The human monoclonal antibody or fragment that binds to ADM or an antibody fragment thereof for use in congestion intervention and therapy in a patient according to claim 10, wherein said antibody or fragment comprises a sequence selected from the group consisting of: SEQ ID NO: 6 (AM-VH-C) QVQLQQSGAELMKPGASVKISCKATGYTFSRYWIEWVKQRPGHGLEWIGEILPGSGSTNYNEKFK GKATITADTSSNTAYMQLSSLTSEDSAVYYCTEGYEYDGFDYWGQGTTLTVSSASTKGPSVFPLAPSSK STSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVN HKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 7 (AM-VH1) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWISWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 8 (AM-VH2-E40) QVQLVQSGAEVKKPGSSVKVSCKASGYTFSRYWIEWVRQAPGQGLEWMGRILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 9 (AM-VH3-T26-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWISWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 10 (AM-VH4-T26-E40-E55) QVQLVQSGAEVKKPGSSVKVSCKATGYTFSRYWIEWVRQAPGQGLEWMGEILPGSGSTNYAQK FQGRVTITADESTSTAYMELSSLRSEDTAVYYCTEGYEYDGFDYWGQGTTVTVSSASTKGPSVFPLAPS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICN VNHKPSNTKVDKRVEPKHHHHHH SEQ ID NO: 11 (AM-VL-C) DVLLSQTPLSLPVSLGDQATISCRSSQSIVYSNGNTYLEWYLQKPGQSPKLLIYRVSNRFSGVPDR FSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHIPYTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASV VCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGL SSPVTKSFNRGEC SEQ ID NO: 12 (AM-VL1) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLNWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC SEQ ID NO: 13 (AM-VL2-E40) DVVMTQSPLSLPVTLGQPASISCRSSQSIVYSNGNTYLEWFQQRPGQSPRRLIYRVSNRDSGVPD RFSGSGSGTDFTLKISRVEAEDVGVYYCFQGSHIPYTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTAS VVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQ GLSSPVTKSFNRGEC 12. The anti-ADM antibody or anti-ADM antibody fragment binding to ADM or supercontigo without anti-ADM Ig binding to ADM for use in congestion intervention and therapy in a patient according to any of claims 1 to 11, wherein a sample of body fluid taken from said patients exhibits an elevated level of proADM and / or fragments thereof having at least 5 amino acids above a certain threshold.

13. A pharmaceutical formulation for use in congestion intervention and therapy in a patient comprising an antibody or fragment or supercontig according to any of claims 1 to 12.

14. The pharmaceutical formulation for use in intervention and therapy of congestion in a patient comprising an antibody or fragment or supercontig according to any of claims 1 to 13, wherein said patient has a disease or condition selected from group that includes: congestive hypertension, swelling or water retention (edema), heart failure in particular acute heart failure, kidney or liver disease.

15. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to claim 13 or 14, wherein said pharmaceutical formulation is a solution, preferably a ready-to-use solution.

16. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to claim 15, wherein said pharmaceutical formulation is in a lyophilized state.

17. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to any of claims 15 to 16, wherein said pharmaceutical formulation is adapted to be administered intramuscularly.

18. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to any of claims 15 to 16, wherein said pharmaceutical formulation is adapted to be administered intravascularly.

19. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to claim 18, wherein said pharmaceutical formulation is adapted to be administered by infusion.

20. The pharmaceutical formulation for use in congestion intervention and therapy in a patient according to any of claims 15 to 19, wherein said pharmaceutical formulation is adapted to be systemically administered.