Treatment method for modifying blood dynamics

Abstract

The present invention provides methods of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject, optionally having impaired renal function, wherein treatment with administering the AQGV peptide comprises maintaining or improving hemodynamic stability in a human subject, such as a human subject having or suspected of having Clarkson's disease (CLS).

Description

Background Art

[0001] When a human subject has suffered severe trauma, particularly trauma caused by medical intervention such as surgery, for example, when undergoing a major medical intervention such as open heart surgery, the human subject or patient is placed in an intensive care unit (ICU) where vital signs can be closely monitored. The patient receives medical treatment to enable recovery, and if the vital signs are within an acceptable range, the patient can be released from the ICU and transferred to standard in-hospital care. If the patient shows stability under standard care, particularly if sufficient hemodynamic stability is demonstrated, the patient can be released from the hospital and return home. Subsequently, the patient can be readmitted to the hospital if the need arises, for example, if the patient's condition deteriorates. Any improvement in the aforementioned vital signs, that is, any improvement in the patient's health and recovery that affects the length of stay in the ICU, the length of stay under standard care in the hospital, and / or patient readmission, generally results in significant benefits to healthcare and the patient. Therefore, any means and methods for improving the health and recovery (recovery rate) of patients are worthy of attention.

[0002] In the ICU or hospital, patients are often treated with infusions, for example, with an aqueous solution containing salts such as physiological saline (e.g., 0.9% NaCl, also called saline) or any other solution suitable for injection. Sometimes, drugs may be added to such aqueous solutions if determined to be necessary for the patient. Usually, an aqueous solution containing a drug is administered intravenously (i.v.) by continuous (drip) infusion or by intravenous bolus injection. Another route of infusion therapy is intraperitoneal administration by the aforementioned infusion injection or bolus administration. Infusion balance (renal function) is one of the criteria for determining the outcome of patients in the ICU. For example, hypervolemia is a medical condition of having too much body fluid in the body, having excessive water retention or fluid retention, or generally being described as fluid overload. Infusion therapy can result in fluid overload. Fluid overload can occur in human subjects, and its symptoms include, for example, weight gain and edema.

[0003] Fluid overload and the resulting inappropriate blood flow or hemodynamic instability, often recognized as necessitating frequent infusion and / or vasopressor therapy, occur relatively frequently in critically ill patients and are often the result of life-saving emergency measures by intravenous infusion therapy. Despite the common perception of being benign, fluid overload in critically ill patients is independently associated with increased morbidity and mortality. Extravascular leakage of fluid into the interstitial space due to capillary leakage can cause various symptoms ranging from cognitive impairment, cardiac contractile impairment, to tissue edema in the skin and muscles leading to delayed wound healing, pressure ulcers, and wound infections, and can have harmful effects on multiple organ systems. In the lungs, fluid overload causes an increase in extravascular lung water content, accompanied by increased work of breathing leading to hypoxemia and gas exchange impairment. A particularly serious complication of fluid overload is kidney damage. It is known that fluid overload can extend the length of stay in the intensive care unit by up to 60% and the length of stay in the hospital by up to 30%.

[0004] Generally, fluid overload (FO) contributes to delayed recovery in the ICU and prolonged hospital stays, leading to increased healthcare resource use and costs. In a recent US study (Child D et al., Clinicoecon Outcomes Res., 2015;7:1-8), the total hospitalization cost per visit for the FO cohort was estimated to be approximately $15,000 higher than that of the non-FO cohort, averaging over $21,000. The ICU cost for the FO cohort was $5,000 higher than that of the non-FO cohort. FO patients had a 16% higher mortality rate and a 31% longer hospital stay. More importantly, this resulted in a nearly 60% longer stay in the ICU, a significant increase in 30-day readmissions, and increased use of mechanical ventilation compared to the non-FO cohort (all P<0.05). Diuretics are the most commonly used drugs to treat clinically diagnosed fluid overload. However, there is no conclusive evidence that diuretic treatment changes major outcomes such as survival to discharge or length of hospital stay.

[0005] The kidney is a highly vascular encapsulated organ that is exquisitely sensitive to inappropriate (insufficient or excessive) blood flow. The kidney is particularly sensitive to venous congestion, and studies have shown that reduced venous return causes more severe kidney damage than arterial flow deprivation. Intravenous fluid infusion inevitably causes interstitial edema when it exceeds the capacity of lymphatic drainage in the microcirculation. In the kidney, interstitial edema increases subcapsular and intracapsular pressures, leading to a decrease in forward renal artery blood flow, a decrease in venous return, and a decrease in lymphatic drainage, ultimately causing tissue hypoxia and AKI. Inappropriate urine output in AKI can further exacerbate tissue edema, creating a vicious cycle.

[0006] Such acute kidney injury is characterized by a rapid loss of kidney function. Moreover, acute injury often progresses to a chronic state and ultimately leads to end-stage kidney disease. These patients are considered critically ill and in need of dialysis or renal replacement therapy. AKI not only contributes to multiple organ failure in critically ill patients but also has a direct impact on other organs and systems. More than three million patients develop AKI each year, and its mortality rate is up to 70%. AKI is directly related to both short-term and long-term complications in patients, and the condition is associated with a mortality rate of 40 - 70%. The mortality rate among AKI patients is approximately one in four. Currently, the only treatment options for AKI are dialysis and supportive care, which do not address the underlying cause, do not limit further damage, and do not prevent progression. Currently, there are no approved drugs to treat this condition.

Summary of the Invention

Problems to be Solved by the Invention

[0007] In a clinical trial aimed at evaluating the safety, tolerability, and immunomodulatory effect of the AQGV peptide (also referred to as EA-230 in this specification), the peptide was found to be safe. Unexpectedly, however, no immunomodulatory effect was observed when comparing the treated patients to the control group. Although no immunomodulatory effect was observed, the inventors surprisingly discovered from the analysis of the data obtained in the clinical trial that new and highly beneficial properties that had not been previously observed could be attributed to the AQGV peptide. Such properties are clearly independent of the known and observed immunomodulatory effects.

[0008] Surprisingly, although no immunomodulatory effect was observed, the length of stay in the ICU (intensive care unit) and also the overall hospital stay of the patients treated with the AQGV peptide were significantly reduced. From a thorough analysis of the parameters monitored in human subjects during this trial, it was discovered that the use of the AQGV peptide favorably regulates the hemodynamics of the treated patients. Despite the absence of any observed immunomodulatory effect in these patients treated with the AQGV peptide, it was shown that parameters related to renal function in human patients were either significantly improved or maintained at a functional level without deterioration. Parameters related to renal function and / or hemodynamics generally determine the length of stay in either the ICU or the hospital for patients under monitoring. And the use of the AQGV peptide or its functional equivalent favorably improves the parameters monitored in human patients, thereby making it possible to reduce the length of stay in either the ICU or the hospital (see, for example, Figures 5, 10, 15, 16).

[0009] Accordingly, the present invention relates to the use of a peptide, also referred to as the AQGV peptide in this specification, and its analogs (functional equivalents) for improving the clinical parameters of human patients admitted to a hospital and / or intensive care so that the period from admission to discharge from the hospital and / or intensive care can be shortened.

Means for Solving the Problem

[0010] In one embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, the method comprising administering an AQGV peptide to the subject, wherein the AQGV peptide is defined as a peptide comprising at least 50%, more preferably at least 75%, most preferably 100% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P). In a more preferred embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), leucine (L), and proline (P). In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the peptide comprises at least 50%, more preferably at least 75%, most preferably 100% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, most preferably 100% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV.

[0011] In another preferred embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the subject has suffered severe trauma such as surgery. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent (e.g., chemotherapy and / or radiotherapy) or an immunomodulatory agent. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the subject is considered to be suffering from capillary leak syndrome such as that seen in drug adverse reactions. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the human subject has organ dysfunction, particularly renal dysfunction. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the method includes reduced use of vasopressors. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the method includes a reduced water intake. In another embodiment, the present invention provides a method for treating a human subject who is considered to need to reduce harmful vascular permeability, the method including administering to the subject a peptide comprising at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 75%, and most preferably 100% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P).In a more preferred embodiment, the present invention provides a method for treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), leucine (L), and proline (P). In another embodiment, the present invention provides a method for treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV.

[0012] In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the subject has suffered a severe trauma such as surgery involving administering an AQGV peptide to the subject. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent or an immunomodulatory agent. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the subject is considered to be suffering from capillary leak syndrome such as that seen in drug adverse reactions. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the human subject has renal dysfunction. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the method comprises reduced use of a vasopressor. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the method comprises a reduced water intake. In another embodiment, the present invention provides a method of treating a human subject in whom it is considered necessary to reduce harmful body fluid retention, comprising administering to the subject an AQGV peptide comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P).In a more preferred embodiment, the present invention provides a method for treating a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), leucine (L), and proline (P). In another embodiment, the present invention provides a method for treating a human subject who is considered to need to reduce harmful body fluid retention, wherein the peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV.

[0013] In another preferred embodiment, the present invention provides a method for treating a human subject who is considered to need to reduce harmful body fluid retention, wherein the subject has suffered severe trauma such as surgery. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV.

[0014] In another embodiment, the present invention provides a method of treating a human subject who is thought to need to reduce harmful body fluid retention, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent or an immunomodulatory agent. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV.

[0015] In another embodiment, the present invention provides a method of treating a human subject who is believed to need to reduce harmful body fluid retention, wherein the subject is believed to be suffering from a capillary leak syndrome such as that seen in drug adverse reactions. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, and most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV. In another embodiment, the present invention provides a method of treating a human subject who is believed to need to reduce harmful body fluid retention, wherein the human subject has renal dysfunction. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, and most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV. In another embodiment, the present invention provides a method of treating a human subject who is believed to need to reduce harmful body fluid retention, wherein the method comprises reduced use of a vasopressor. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, and most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV, or, for example, its dimer or trimer, tetramer or pentamer. In another embodiment, the present invention provides a method of treating a human subject who is believed to need to reduce harmful body fluid retention, wherein the method comprises a reduced water intake. The AQGV peptide preferably consists of at least 50%, more preferably at least 75%, and most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V).The peptide is preferably AQGV.

[0016] In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is a salt of an organic acid, preferably the organic acid is selected from the group consisting of maleic acid, acetic acid, tartaric acid, and citric acid. In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is a salt of an organic acid, more preferably maleic acid, even more preferably acetic acid, even more preferably tartaric acid, and most preferably citric acid.

[0017] In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful vascular permeability, wherein the AQGV peptide is a salt of an organic acid, preferably the organic acid is selected from the group consisting of maleic acid, acetic acid, tartaric acid, and citric acid. In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful vascular permeability, wherein the AQGV peptide is a salt of an organic acid, more preferably maleic acid, even more preferably acetic acid, even more preferably tartaric acid, and most preferably citric acid.

[0018] In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide is a salt of an organic acid, preferably the organic acid is selected from the group consisting of maleic acid, acetic acid, tartaric acid, and citric acid. In another embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide is a salt of an organic acid, more preferably maleic acid, even more preferably acetic acid, even more preferably tartaric acid, and most preferably citric acid.

[0019] In another embodiment, the present invention is a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate, preferably an aqueous solution, preferably the stock solution comprises or is prepared to contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, most preferably at least 1.8 mol / L of the AQGV peptide - acetate, the AQGV peptide - tartrate, or the AQGV peptide - citrate. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - tartrate or the AQGV peptide - citrate, wherein the concentration of the AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - citrate, wherein the concentration of the AQGV peptide - citrate ranges from 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the peptide - citrate, wherein the concentration of the peptide - citrate ranges from 3 mol / L to 3.5 mol / L.In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate in the range of 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate in the range of 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate of 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0020] In another embodiment, the present invention is a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate, preferably an aqueous solution, preferably the stock solution comprises or is prepared to contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, most preferably at least 1.8 mol / L of the AQGV peptide - acetate, the AQGV peptide - tartrate, or the AQGV peptide - citrate. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - tartrate or the AQGV peptide - citrate, wherein the concentration of the AQGV peptide is in the range of 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - citrate, wherein the concentration of the AQGV peptide - citrate is in the range of 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention is a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the peptide - citrate, wherein the concentration of the peptide - citrate is in the range of 3 mol / L to 3.5 mol / L.In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate in which the concentration of the peptide-citrate is in the range of 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate in which the concentration of the peptide-citrate is in the range of 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate in which the concentration of the peptide-citrate is 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0021] In another embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate, preferably an aqueous solution, preferably the stock solution is prepared to comprise or contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, most preferably at least 1.8 mol / L of the AQGV peptide - acetate, the AQGV peptide - tartrate, or the AQGV peptide - citrate. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - tartrate or the AQGV peptide - citrate, wherein the concentration of the AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - citrate, wherein the concentration of the AQGV peptide - citrate ranges from 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject in whom it is considered necessary to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the peptide - citrate, wherein the concentration of the peptide - citrate ranges from 3 mol / L to 3.5 mol / L.In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate in the range of 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate in the range of 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject who is considered to need to reduce harmful body fluid retention, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a concentration of the peptide-citrate of 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0022] In another embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate, preferably an aqueous solution, preferably the stock solution is prepared to comprise or contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, and most preferably at least 1.8 mol / L of the AQGV peptide - acetate, the AQGV peptide - tartrate, or the AQGV peptide - citrate. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - tartrate or the AQGV peptide - citrate, wherein the concentration of the AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the AQGV peptide - citrate, wherein the concentration of the AQGV peptide - citrate ranges from 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the peptide - citrate, wherein the concentration of the peptide - citrate ranges from 3 mol / L to 3.5 mol / L.In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a peptide-citrate concentration in the range of 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a peptide-citrate concentration in the range of 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a method for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide is provided from a stock solution of the peptide-citrate having a peptide-citrate concentration of 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0023] In another embodiment, the present invention provides an AQGV peptide for use in the treatment of a human subject in need of maintaining or improving hemodynamic stability, wherein the peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R); preferably, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P); preferably, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), leucine (L), and proline (P); or the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). Most preferably, the peptide consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). Preferably, the peptide for use in the treatment of a human subject in need of maintaining or improving hemodynamic stability is AQGV.

[0024] In another embodiment, the present invention provides an AQGV peptide for use in the treatment of a human subject in which it is considered necessary to reduce harmful vascular permeability, said peptide comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R), said AQGV peptide more preferably comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P), preferably said AQGV peptide comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), leucine (L), and proline (P), or said AQGV peptide comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). Most preferably, said peptide consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). Said peptide is preferably AQGV for use in the treatment of a human subject in which it is considered necessary to maintain or improve hemodynamic stability.

[0025] In another embodiment, the present invention provides a method for treating a human subject in need of reducing harmful body fluid retention with an AQGV peptide, wherein the peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R); more preferably, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P); preferably, the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), leucine (L), and proline (P); or the AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), and valine (V). Most preferably, the peptide consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), and valine (V). The peptide is preferably AQGV for use in the treatment of a human subject in need of reducing harmful body fluid retention.

[0026] In another embodiment, the present invention provides a method for treating a human subject in whom it is considered necessary to reduce harmful body fluid retention, said method comprising administering an AQGV peptide, wherein said peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R); more preferably, said AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P); preferably, said AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), leucine (L), and proline (P); or said AQGV peptide comprises at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), and valine (V). Most preferably, said peptide consists of at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter code A), glutamine (Q), glycine (G), and valine (V). Said peptide is preferably AQGV for use in the treatment of a human subject in whom it is considered necessary to reduce harmful body fluid retention.

[0027] In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the subject has suffered severe trauma such as surgery.

[0028] In another embodiment, the present invention provides a peptide according to the present invention, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent or an immunomodulatory agent. In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the subject is considered to be suffering from capillary leak syndrome such as that seen in drug adverse reactions.

[0029] In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the human subject has renal dysfunction. In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the use includes (results in) a reduced use of antihypertensive agents. In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the use includes (results in) a reduced water intake. In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the peptide is a salt of an organic acid, preferably, the organic acid is selected from the group consisting of maleic acid, acetic acid, tartaric acid, and citric acid. In another embodiment, the present invention provides an AQGV peptide according to the present invention, wherein the AQGV peptide is a salt of an organic acid such as maleic acid, more preferably acetic acid, more preferably tartaric acid, and most preferably citric acid. In another embodiment, the present invention provides a method in which the AQGV peptide is provided from a stock solution of the AQGV peptide (preferably, the AQGV peptide is AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate), preferably an aqueous solution, and preferably, the stock solution comprises or is prepared to contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, and most preferably at least 1.8 mol / L of the AQGV peptide - acetate, the AQGV peptide - tartrate, or the AQGV peptide - citrate. In a more preferred embodiment, the present invention provides a stock solution of the AQGV peptide - tartrate or the AQGV peptide - citrate, wherein the concentration of the AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of the AQGV peptide - citrate, wherein the concentration of the AQGV peptide - citrate ranges from 2.5 mol / L to 3 mol / L.In a more preferred embodiment, the present invention provides a stock solution of the peptide-citrate salt, wherein the concentration of the peptide-citrate salt ranges from 3 mol / L to 3.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of the peptide-citrate salt, wherein the concentration of the peptide-citrate salt ranges from 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of the peptide-citrate salt, wherein the concentration of the peptide-citrate salt ranges from 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of the peptide-citrate salt, wherein the concentration of the peptide-citrate salt is 5.5 mol / L or higher. The stock solution is preferably an aqueous solution.

[0030] In another embodiment, the present invention provides a pharmaceutical preparation comprising the AQGV peptide according to the present invention. In another embodiment, the present invention provides a pharmaceutical preparation according to the present invention and at least one pharmaceutically acceptable additive. Preferably, the preparation is a stock solution of the AQGV peptide. Preferably, a stock solution of AQGV peptide-acetate, AQGV peptide-tartrate, or AQGV peptide-citrate, preferably an aqueous solution, preferably the stock solution comprises, or is prepared to contain, at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, most preferably at least 1.8 mol / L of the AQGV peptide-acetate, the AQGV peptide-tartrate, or the AQGV peptide-citrate. In a more preferred embodiment, the present invention provides a pharmaceutical preparation comprising a stock solution of the AQGV peptide-tartrate or the AQGV peptide-citrate, wherein the concentration of the AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention provides a pharmaceutical preparation comprising a stock solution of the AQGV peptide-citrate, wherein the concentration of the AQGV peptide-citrate ranges from 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention provides a method for treating a human subject who is considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide is provided from a stock solution of the peptide-citrate, wherein the concentration of the peptide-citrate ranges from 3 mol / L to 3.5 mol / L. In a more preferred embodiment, the present invention provides a pharmaceutical preparation comprising a stock solution of the AQGV peptide-citrate, wherein the concentration of the AQGV peptide-citrate ranges from 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a pharmaceutical preparation comprising a stock solution of the AQGV peptide-citrate, wherein the concentration of the AQGV peptide-citrate ranges from 4.5 mol / L to 5.5 mol / L.In a more preferred embodiment, the present invention provides a pharmaceutical preparation comprising a stock solution of the AQGV peptide-citrate salt, wherein the concentration of the AQGV peptide-citrate salt is 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0031] In one embodiment, the use of the AQGV peptide and its analogs is for use in medical treatment for modifying hemodynamics in a human subject, particularly a subject with resulting renal dysfunction. In a further embodiment, the use in a human subject for modifying hemodynamics involves a reduction in undesired fluid retention (i.e., undesired fluid overload) and / or a reduced use of vasopressor / inotropic agents in a human subject, particularly a subject with resulting renal dysfunction. In another embodiment, the use of the AQGV peptide and its analogs is for use in a human subject with capillary leakage, particularly a subject with resulting renal dysfunction.

[0032] In one embodiment, an AQGV peptide or a functional analog thereof is provided for use in the treatment of a human subject, and the use includes a treatment for modifying hemodynamics in the human subject. Hemodynamics involves the dynamics of blood flow, i.e., the physical factors that govern blood flow through the human body. Hemodynamics in a human patient can be monitored, for example, by measuring blood pressure and / or fluid balance. When the blood pressure is low and / or the fluid balance is disrupted in a human patient, vasopressor or inotropic substances can be used and / or administered by infusion, for example, intravenously. Inotropic substances and vasopressors are biologically and clinically important vasoactive agents that are derived from different pharmacological groups and act on some of the most fundamental receptors and signaling systems in the body. More than 20 such agents are commonly used clinically, and there are only a few reviews of their pharmacology in addition to textbooks of physiology and pharmacology. Despite their extensive use in critically ill patients, the understanding of the clinical effects of these drugs in pathology is poor. The harmful effects of vasopressors and inotropic substances depend on the mechanism of action. In drugs with β-stimulating effects, arrhythmia is one of the most common harmful effects that is desired to be reduced.

[0033] The inventor has discovered that the use of the AQGV peptide or a functional analog thereof significantly improves hemodynamics in human patients after trauma, as indicated, for example, by a reduced use of vasopressors and / or an improved fluid balance in human patients. Thus, the use of the AQGV peptide or a functional analog thereof (as defined herein) improves hemodynamic stability in human patients, as described herein. Modification or optimization of hemodynamics in a human subject is important postoperatively or after injury, for example, when the human subject is suffering from trauma and / or blood loss. Accordingly, the AQGV peptide or an analog thereof can be advantageously used in hemodynamic therapy. Hemodynamic therapy, i.e., optimization of hemodynamics in a patient, includes perioperative hemodynamic therapy and / or goal-directed hemodynamic therapy. Such therapies can include fluid management and / or the use of vasopressors in a patient.

[0034] Functional AQGV analogs are defined herein as peptides that, while not necessarily quantitatively the same, have an effect or function similar to that of the AQGV peptides described herein. Based on the present invention, these may be used as single peptides or in combination with other analogs and / or AQGV peptides in any desired ratio to modulate the half-life of the resulting mixture. Functional AQGV analogs may have sequence identity, i.e., they may contain at least a part or all of the AQGV peptide. Preferably, the functional AQGV analogs are structural analogs of the AQGV peptide. A preferred structural analog may be the LQGV peptide. The structural analogs of the AQGV peptide may be selected from peptides containing amino acids selected from the group of amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), and proline (P). A, Q, G, V, and L are preferred. A, Q, G, and V are most preferred in lengths of 4 - 30 amino acids, preferably 4 - 12 amino acids, in any order and ratio relative to the others. In a preferred embodiment, the present invention defines a structural AQGV analog comprising at least 50%, more preferably at least 75%, most preferably 100% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), proline (P), and arginine (R). The ratio between the amino acids may vary, but the peptide must contain at least three different amino acids and Q should be present. Preferably, the structural analog of the AQGV peptide has a length in the range of 4 - 30 amino acids, more preferably 4 - 12 amino acids. Preferably, such structural analogs are linear peptides. Suitable structural analogs of AQGV may have a length of less than 4 amino acids, for example, a length of 3 amino acids, but such lengths may require higher doses of these peptides as their half-life is shorter and thus less preferred. Longer structural analogs, for example, those longer than 30 residues, are less preferred due to the potential immunogenicity of such longer peptides.The structural AQGV analog according to the present invention may be selected from the group consisting of peptides comprising a tetrapeptide selected from the group of AQLP, PLQA, LQGV, LAGV, PQVG, PQVA, VGQL, LQPL, LQVG, LQGA, AQGA, QPLA, PQVP, VGQA, QVGQ, VGQG.

[0035] A pressor is a type of drug that can raise low blood pressure. Some pressors act as vasoconstrictors, other pressors sensitize adrenergic receptors to catecholamine - glucocorticoids, and another type of pressor can increase cardiac output. Whichever pressor is used, the present invention enables a reduction in the use of the pressor. The reduction in the use of the pressor is involved in a reduction in the amount of the pressor used, that is, the pressor use period is reduced and / or the dosage of the pressor is reduced. Examples of pressors are, for example, epinephrine, norepinephrine, phenylephrine, dobutamine, dopamine, and vasopressin. Infusion management in a patient involves, for example, monitoring the oral, enteral, and / or intravenous intake of the infusion, as well as the body fluid output (e.g., urine), and then managing the water intake in case, for example, body fluid retention is observed (i.e., when the water intake exceeds the body fluid output and there is an overload situation). Notably, the use of the AQGV peptide or its analog can reduce body fluid retention (also referred to herein as body fluid overload). Thus, the AQGV peptide or its functional analog can be used in addition to known interventions for improving hemodynamics in a human patient, thereby resulting in a more rapid improvement in hemodynamics compared to the case where the AQGV peptide or its analog is not used.

[0036] In another embodiment, the AQGV peptide or a functional analog thereof is provided for use in the treatment of a human subject having renal dysfunction. In a further embodiment, the renal dysfunction is acute kidney injury (AKI). In one embodiment, the AQGV peptide or a functional analog thereof is provided for use in the treatment of a human subject to improve renal function. Renal function can be evaluated, for example, by determining the glomerular filtration rate (GFR) or by assessing the clearance of iohexol from plasma. Renal function can also be evaluated by measuring the plasma level of creatinine and calculating an estimated GFR (eGFR) function, also referred to as the MDRD (Modification of Diet in Renal Disease) formula or equation, from the plasma level taking into account patient characteristics such as gender, age, and race. Renal function can be evaluated based on the GFR measurement (or its estimate based on MDRD) by applying the RIFLE criteria (see Figure 3). Having a RIFLE score that is in the stage of risk, injury, failure, loss, or ESKD can mean renal impairment and / or renal dysfunction. Evaluating renal function in humans (e.g., by determining GFR, creatinine clearance, and / or eGFR / MDRD) is standard clinical practice. Improvement in renal function when compared to not receiving the AQGV peptide can include the progression of the renal function stage evaluated under the RIFLE criteria to a less severe stage (e.g., the patient progressing from having an injury to being at risk or progressing without AKI). Improvement in renal function also includes having an improvement in the GFR or eGFR score. Regardless of which evaluation is made, the use of the AQGV peptide or its analog can improve renal function in humans having renal dysfunction and / or renal impairment in a subject lacking an immunomodulatory effect.

[0037] The use of the AQGV peptide enables improvement of renal function and can also prevent reduction and / or impairment of renal function (see, for example, FIGS. 6, 7, and 8). As a result, it may be possible to prevent AKI. Preferably, for the prevention of human subjects with renal dysfunction, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, and most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, and most preferably for at least 2 hours, but the administration may be longer, such as more than 3 hours. The actual administration time may be determined by a doctor. Thus, in one embodiment, the use of the AQGV peptide or a functional analog thereof enables maintenance of renal function in a human patient. Thus, the use of the AQGV peptide or an analog thereof enables protection of renal function in a human patient. In another embodiment, the use of the AQGV peptide or an analog thereof prevents reduction and / or impairment of renal function in a human patient. For example, a human patient who may be classified as at risk of having no AKI or renal impairment (such as AKI) may maintain that state instead of progressing to renal function deficiency at a higher severity stage if such a patient receives treatment with the AQGV peptide. Thus, for example, a human patient at risk of developing renal impairment due to (induced) trauma may be able to maintain their renal function status as a result of treatment with the AQGV peptide or an analog thereof.

[0038] In another embodiment, the AQGV peptide or a functional analog thereof is provided for use in a human subject having renal dysfunction, the use including modifying hemodynamics in the human subject. Treatment of renal function and treatment of hemodynamic stability can be linked here, and the use of the AQGV peptide or a functional analog thereof according to the invention can be advantageously used to protect and / or improve renal function and modify hemodynamics. Such combined use results in, for example, improved and / or maintained renal function, and a reduction in the use of vasopressors, and / or improved fluid management in a human subject (see, for example, Tables 1, 3, 4, and Figures 14, 18, 19, and 20). Preferably, in the treatment of a human subject having renal dysfunction, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, more preferably for at least 4.5 hours.

[0039] In a further embodiment, the present invention defines a reduced use of a pressor agent. The reduced use of a pressor agent is understood to include reducing the amount of pressor agent used. The use of a pressor agent can be reduced by reducing the period of use of the pressor agent. The use of a pressor agent can be reduced by reducing the amount of the pressor agent (e.g., reducing the amount per dose and / or increasing the time interval between administrations). The use of a pressor agent can be reduced by reducing both the amount of the pressor agent and the period of use of the pressor agent. By reducing the use of a pressor agent, a human subject recovers more rapidly, advantageously, compared to a human subject not receiving an AQGV peptide or an analog thereof. Preferably, in the use in reducing the amount and / or period of use of a pressor agent, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably, at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours (such as 2.5 hours or more). In another embodiment, the use of an AQGV peptide or a functional analog thereof reduces harmful fluid retention in a human subject. Capillary leakiness, fluid retention or fluid overload can occur in a human subject, and the symptoms include, for example, weight gain and edema. Fluid retention (also known as swelling or edema) or capillary leakage is the accumulation of fluid in the body. As fluid leaks out of the bloodstream, blood volume and blood pressure can decrease. This can deprive tissues of the oxygen and nutrients necessary for the organs to function properly in the kidneys, brain, and liver. Such swelling most often develops in the extremities (such as the feet, ankles, and hands), but swelling can also develop in other parts of the body, such as an organ cavity or the abdominal cavity or the brain. The cause of the swelling may be related to a drug, heart disease, liver disease, or kidney failure.Cancer treatments such as radiation therapy or some chemotherapy drugs can cause fluid retention in the body. This form of cancer swelling is most noticeable in the feet, ankles, hands, and face. An increase in the ability of fluid in the capillaries to "leak" to the skin layer causes the swelling, which is due to a vascular reaction. This occurs much less frequently than hives alone. Fluid retention generally causes swelling in the tongue, lips, or eyelids. Swelling of the airways can cause breathing difficulties, airway obstruction, and, in the worst case, death. Brain swelling is often associated with or follows blood-brain barrier dysfunction and post-traumatic edema formation. Traumatic brain injury (TBI) is a major cause of death and long-term physical disability in developing countries, especially in the young and elderly. One of the major clinical problems associated with TBI, like other types of brain injury such as subarachnoid hemorrhage or intracerebral hemorrhage, is the formation of brain edema (a rapid swelling of neural tissue that can lead to death if not controlled).

[0040] Another concern is capillary leak syndrome (also known as capillary leak syndrome (CLS), systemic capillary leak syndrome (SCLS), or Clarkson's disease (CLS)), a disorder characterized by frequent relapses of massive plasma leakage from blood vessels into adjacent body cavities and muscles. This can lead to a rapid drop in blood pressure that can cause organ failure and death if left untreated. Capillary leak syndrome (CLS) is a rare disease associated with profound vascular leakage and is associated with high mortality. The disease can also occur in cancer patients, and effective treatment strategies have not yet been established. CLS can be idiopathic or secondary to autoimmune diseases, hematological malignancies, snake bites, and treatments (such as chemotherapy and therapeutic growth factors). In recent years, it has become increasingly clear that drugs that are harmfully associated with CLS are actually commonly used. Multiple reports have been made about CLS as a harmful effect of anticancer agents and therapies, and the incidence of CLS according to the type of anticancer drug has been systematically evaluated (PMID: 30691103). The majority of studies report the incidence of CLS during interleukin-2 (IL-2) treatment, followed by a large number of studies reporting on anti-surface antigen classification (anti-CD) agents. In addition, the use of anticancer drugs or immunomodulatory agents such as monoclonal antibodies (mAbs) including IL-2 + imatinib mesylate and rituximab has shown a dose-dependent increase in the incidence of CLS as a harmful event of anticancer treatment. Similarly, Clarkson's disease (CLS) is commonly reported as an adverse drug reaction (ADR) in human clinical trials as a very common harmful response to drug trials (experimental or clinical).

[0041] Preferably, in the treatment of a human subject having fluid retention, the AQGV peptide as defined herein is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably, at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours (such as at least 2.5 hours), more preferably, for at least 3.5 hours, more preferably, for at least 4.5 hours. Thus, in one embodiment, the use of the AQGV peptide or an analog thereof enables the treatment of fluid retention in a human subject. Thus, the use of the AQGV peptide or an analog thereof prevents fluid retention in a human subject. In a preferred embodiment, the use of the AQGV peptide or an analog thereof prevents fluid retention such as Clarkson's disease (CLS) in a human patient undergoing cancer treatment such as treatment with an anti-cancer drug or an immunomodulatory agent.

[0042] In another embodiment, the use of the AQGV peptide or an analog thereof prevents fluid retention in a human patient. For the prevention of fluid retention in a human subject, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably, at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours, or for at least 2.5 hours or more. In a preferred embodiment, the use of the AQGV peptide or an analog thereof prevents fluid retention such as capillary leak syndrome (CLS) in a human patient undergoing cancer treatment such as treatment with an anti-cancer drug or an immunomodulatory agent that affects capillary leakage. In another preferred embodiment, the use of the AQGV peptide or an analog thereof prevents fluid retention such as capillary leak syndrome (CLS) in a human patient having a drug adverse reaction such as after (experimental) treatment with a drug that affects capillary leakage, often an anti-cancer drug or an immunomodulatory drug.

[0043] Fluid retention can be a result of decreased renal function and / or impaired hemodynamics. Thus, since the use of the AQGV peptide can affect renal function and / or hemodynamics in a human subject, the use of the AQGV peptide can similarly affect fluid retention. Fluid retention can be a result of leaky capillaries. Thus, the use of the AQGV peptide and / or its analogs can have an effect on capillary leakiness and may reduce the leakage of plasma from the blood vessels into the surrounding tissues and / or organs. Most preferably, edema can be reduced and / or avoided by the use of the AQGV peptide. Edema may also be referred to as harmful fluid retention since it has a harmful effect on the patient. Regardless of the cause of fluid retention, the use of the AQGV peptide and / or its functional analogs can improve fluid retention in a human subject, thereby alleviating symptoms associated with fluid retention such as weight gain and edema, which can result in a reduction in the use of diuretics. Preferably, for use in a human subject having fluid retention, the AQGV peptide as defined herein is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably, at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably, for at least 1.5 hours, most preferably, for at least 2 hours (such as at least 2.5 hours), more preferably, for at least 3.5 hours, more preferably, for at least 4.5 hours.

[0044] In another embodiment, the use of an AQGV peptide or a functional analog thereof according to the present invention is not necessarily limited to patients having renal impairment and / or in need of hemodynamic therapy. The use of an AQGV peptide and / or a functional analog thereof according to the present invention includes the treatment of human patients who are considered to be at risk of having renal impairment and / or are expected to need hemodynamic therapy. Such human patients include patients who are scheduled to be sent to or are expected to be sent to intensive care. Thus, the use of an AQGV peptide or a functional analog thereof includes use for induced trauma such as surgery, as shown, for example, in the examples. Induced trauma includes any physical impairment to the human body and typically can include blood loss and / or injury to the tissues of a human subject. Induced trauma includes, for example, surgery. Thus, in a preferred embodiment, the induced trauma is surgery. The use of an AQGV peptide for induced trauma such as surgery is before, during, and / or after the surgery. The use of an AQGV peptide or an analog thereof may preferably be during the surgery. In particular, the surgery may more preferably require cardiopulmonary bypass. Advantageously, the use of an AQGV peptide as shown in the examples improved GFR, particularly in patients having a long-term cardiopulmonary bypass and thus receiving an AQGV peptide infusion for a long period of time, i.e., for more than 2.5 hours. Thus, in a further embodiment, the use of an AQGV peptide or an analog thereof is during a cardiopulmonary bypass having a length of more than 2.5 hours, where the AQGV peptide or its (functional) analog is administered during the cardiopulmonary bypass. Preferably, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, and most preferably for at least 2 hours.Preferably, the administration of the AQGV peptide is administered at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours or at least 2.5 hours, more preferably for at least 3.5 hours, and more preferably for at least 4.5 hours. Typically, the administration of the AQGV peptide (or a combination thereof) according to the present invention may continue throughout and sometimes also after the intervention procedure. However, it is possible to determine during the intervention whether the administration of the composition or formulation according to the present invention is required to adjust the infusion balance in the subject being treated and to initiate such administration during the intervention. In another or further embodiment, the use of the AQGV peptide or a functional analog thereof for use according to the present invention is for use in a human subject having heart failure. Preferably, for use in a human subject having heart failure, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, and most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is administered at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, and more preferably for at least 4.5 hours.

[0045] In another embodiment, the use of an AQGV peptide or a functional analog thereof according to the present invention is not limited to patients having renal impairment and / or requiring hemodynamic therapy. The present invention includes the use of an AQGV peptide or a functional analog thereof for use in the treatment of human subjects suffering from or at risk of or suffering from fluid overload, said use including modifying the hemodynamics in a human subject. The use of an AQGV peptide or a functional analog thereof according to the present invention includes the treatment of human patients considered to be at risk of having fluid overload and / or expected to require hemodynamic therapy. Such human patients include patients scheduled or expected to be sent to intensive care. Thus, the use of an AQGV peptide or a functional analog thereof includes use for the prevention of induced fluid overload, such as by infusion therapy as shown in the examples. Preferably, for use for the prevention of induced fluid overload, administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably at least 1.5 hours, most preferably at least 2 hours or at least 2.5 hours, more preferably at least 3.5 hours, more preferably at least 4.5 hours.

[0046] In another embodiment, the use of an AQGV peptide or a functional analog thereof according to the present invention is not limited to patients having renal impairment and / or requiring hemodynamic therapy. The present invention includes the use of an AQGV peptide or a functional analog thereof for use in the treatment of human subjects for whom pressor / inotropic treatment is considered necessary, said use including modifying the hemodynamics in a human subject. The use of an AQGV peptide or a functional analog thereof according to the present invention includes the treatment of human patients who are considered at risk for treatment with a pressor or inotropic agent and / or are expected to require hemodynamic therapy. Such human patients include patients who are scheduled or expected to be sent to intensive care. Thus, the use of an AQGV peptide or a functional analog thereof includes use for the treatment of human patients who are considered at risk for treatment resulting from the use of a pressor or inotropic agent, such as treatment with a drug selected from the group consisting of dopamine, dobutamine, adrenaline, noradrenaline, phenylephrine, vasopressin, and milrinone, as shown, for example, in the examples. Preferably, for use in the treatment of human patients who are considered at risk for treatment resulting from the use of a pressor or inotropic agent, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, more preferably for at least 4.5 hours.

[0047] In another embodiment, the use of an AQGV peptide or a functional analog thereof according to the present invention is not necessarily limited to patients having renal impairment and / or in need of hemodynamic therapy. The present invention includes the use of an AQGV peptide or a functional analog thereof for the treatment of a human subject for improving the length of stay of the subject in the ICU and further for shortening the length of stay of the subject in the ICU, said use including modifying the hemodynamics in the human subject. The use of an AQGV peptide or a functional analog thereof according to the present invention includes the treatment of human patients who are considered to be at risk due to treatment with vasopressors or inotropic agents and / or who are expected to require hemodynamic therapy by infusion therapy. Such human patients include patients who are sent or scheduled to be sent or expected to be sent to intensive care, and for this purpose, a shortening of the length of stay in the ICU is expected. Thus, the use of an AQGV peptide or a functional analog thereof includes use for the treatment of human patients who are considered to be at risk due to treatment with vasopressors or inotropic agents and / or by infusion therapy, as shown, for example, in the examples. Preferably, for use in shortening the length of stay of a subject in the ICU in human patients who are considered to be at risk, particularly during ICU admission, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, more preferably for at least 4.5 hours.

[0048] In another embodiment, the use of the AQGV peptide or a functional analog thereof according to the present invention is not limited to patients having renal impairment and / or requiring hemodynamic therapy. The present invention includes the use of the AQGV peptide or a functional analog thereof for the treatment of human subjects for improving (i.e., reducing) the length of stay of the subject in the hospital, which use includes modifying the hemodynamics in the human subject. The use of the AQGV peptide or a functional analog thereof according to the present invention includes the treatment of human patients who are considered to be at risk due to treatment with vasopressor or inotropic agents and / or are expected to require vasopressor or inotropic agents and / or are expected to require hemodynamic therapy by infusion therapy. Such human patients include patients who are in intensive care or are being sent or are expected to be sent to the hospital, for which a shortened length of stay in the hospital is expected. Thus, the use of the AQGV peptide or a functional analog thereof includes use for the treatment of human patients who are considered to be at risk due to treatment with vasopressor or inotropic agents and / or by infusion therapy, as shown, for example, in the examples. Preferably, for use in shortening the length of stay of the subject in the ICU in human patients who are considered to be at risk, particularly during ICU admission, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, more preferably for at least 4.5 hours.

[0049] The present invention also provides an AQGV peptide for use in the treatment of human subjects who are considered to need to maintain or improve hemodynamic stability, wherein the AQGV peptide comprises at least 50% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 60%, most preferably at least 70% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L), which have been found to have the best autophagy-inhibiting properties. In a more preferred embodiment, the AQGV peptide comprises at most 30%, more preferably at most 20%, most preferably at most 10% amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R), and the inclusion of these amino acids is desirable to confer proteolytic sensitivity to the AQGV peptide if necessary. In one embodiment, the AQGV peptide preferably consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). To improve solubility, the AQGV peptide is preferably a salt selected from the group of AQGV peptide - acetates, more preferably the group of AQGV peptide - tartrates, and most preferably the group of AQGV peptide - citrates. The AQGV peptides vary in length from 4 to 30 amino acids.

[0050] The present invention also provides an AQGV peptide for use in the treatment of a human subject in which it is considered necessary to reduce harmful vascular permeability, said AQGV peptide comprising at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, said AQGV peptide comprises at least 50%, more preferably at least 60%, most preferably at least 70% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L), which have been found to have the best autophagy-inhibiting properties. In a more preferred embodiment, said AQGV peptide comprises at most 30%, more preferably at most 20%, most preferably at most 10% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R), the inclusion of these amino acids being desirable to confer proteolytic sensitivity to the AQGV peptide as required. In one embodiment, the AQGV peptide preferably consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). To improve solubility, said AQGV peptide is preferably a salt selected from the group of AQGV peptide - acetates, more preferably from the group of AQGV peptide - tartrates, most preferably from the group of AQGV peptide - citrates. The AQGV peptide varies in length from 4 to 30 amino acids.

[0051] The present invention also provides an AQGV peptide for use in the treatment of a human subject who is considered to need to reduce harmful body fluids, wherein the AQGV peptide comprises at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 60%, and most preferably at least 70% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L), which have been found to have the best autophagy-inhibiting properties. In a more preferred embodiment, the AQGV peptide comprises at most 30%, more preferably at most 20%, and most preferably at most 10% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R), and the inclusion of these amino acids is desirable to confer proteolytic sensitivity to the AQGV peptide as needed. In one embodiment, the AQGV peptide preferably consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). To improve solubility, the AQGV peptide is preferably a salt selected from the group of AQGV peptide - acetate salts, more preferably from the group of AQGV peptide - tartrate salts, and most preferably from the group of AQGV peptide - citrate salts. The AQGV peptide varies in length from 4 to 30 amino acids.

[0052] The present invention also provides an AQGV peptide for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), wherein the AQGV peptide comprises at least 50% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide comprises at least 50%, more preferably at least 60%, most preferably at least 70% amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L), which have been found to have the best autophagy-inhibiting properties. In a more preferred embodiment, the AQGV peptide comprises at most 30%, more preferably at most 20%, most preferably at most 10% amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R), and the inclusion of these amino acids is desirable to confer proteolytic sensitivity to the AQGV peptide as needed. In one embodiment, the AQGV peptide preferably consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V). To improve solubility, the AQGV peptide is preferably a salt selected from the group of AQGV peptide - acetates, more preferably the group of AQGV peptide - tartrates, and most preferably the group of AQGV peptide - citrates. The AQGV peptide varies in length from 4 to 30 amino acids.

[0053] The present invention also provides a pharmaceutical preparation according to the present invention, which contains at least two different AQGV peptides each containing at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R). In a preferred embodiment, the AQGV peptide contains at least 50%, more preferably at least 60%, and most preferably at least 70% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L), which have been found to have the best autophagy-inhibiting properties. In a more preferred embodiment, the AQGV peptide contains at most 30%, more preferably at most 20%, and most preferably at most 10% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R), and the inclusion of these amino acids is desirable to confer proteolytic sensitivity to the AQGV peptide as needed. In one embodiment, the AQGV peptide preferably consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), and valine (V). To improve solubility, the AQGV peptide is preferably a salt selected from the group of AQGV peptide - acetates, more preferably the group of AQGV peptide - tartrates, and most preferably the group of AQGV peptide - citrates. The AQGV peptides vary in length from 4 to 30 amino acids. Further, the pharmaceutical preparation preferably contains at least 0.85 mol / L of one or more of the AQGV peptides. In another embodiment, the pharmaceutical preparation contains at least one pharmaceutically acceptable additive. An example of such a preparation is a stock solution of the AQGV peptide as provided herein.

[0054] The present invention also provides the use of a formulation or solution according to the present invention for use in a method of treating a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), in a method of treating a human subject in whom it is considered necessary to maintain or improve hemodynamic stability, in a method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, and in a method of treating a human subject in whom it is considered necessary to reduce harmful fluid retention.

[0055] Preferably, the use of an AQGV peptide or a functional analog thereof according to the present invention as described above involves administration of the peptide into the bloodstream. Administration into the bloodstream is understood to include, for example, intravenous or intra-arterial administration. For example, a constant supply of an AQGV peptide or an analog thereof via an infusion in which the AQGV peptide or an analog thereof is contained in a physiologically acceptable solution is preferred. Suitable physiologically acceptable solutions may include a physiological saline solution (e.g., 0.9% NaCl), or any other suitable solution for injection and / or infusion. Such physiological solutions may contain additional compounds (e.g., glucose, etc.) that may provide additional benefits to the human subject, and may also contain other pharmaceutical compounds (e.g., vasopressors, typically at a reduced rate).

[0056] Preferably, the AQGV peptide is administered at a rate of at least 50 mg / kg patient body weight per hour (mg / kg / hour). Preferably, this administration rate is at least 60 mg, at least 70, at least 80, or most preferably at least 90 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 70 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours (such as at least 2.5 hours), more preferably for at least 3.5 hours, more preferably for at least 4.5 hours. Preferably, the administration is carried out during surgery. More preferably, the administration is carried out throughout the entire duration of the surgery.

[0057] As shown in the examples, the mean arterial maximum concentration (mean Cmax) determined in vivo in humans for EA-230 in a Phase II clinical trial was 30,500 ng / ml in the range of 12,500 to 57,500 ng / ml. The mean venous Cmax was 68,400 ng / ml in the range of 19,600 to 113,000 ng / ml. Thus, whatever means and methods are used for the administration of EA-230 (or AQGV), preferably, means and methods are contemplated that enable obtaining an arterial Cmax in the range of 10,000 to 60,000 ng / ml and / or a venous Cmax in the range of 15,000 to 120,000 ng / ml. Therefore, the route of administration need not necessarily be limited to intravenous administration and may include other routes of administration that result in similar venous and / or arterial Cmax concentrations.

[0058] In another embodiment, the AQGV peptide or a functional analog thereof is provided for any use according to the present invention described above, where the human subject is sent to intensive care, and the use improves a measured parameter of the human subject, and the parameter of the human subject is determined to evaluate whether to stay in intensive care. As described above, the parameters evaluated when a human patient is in intensive care include parameters related to renal function and hemodynamics. In any case, the use of the AQGV peptide or an analog thereof is for improving such parameters, thereby reducing the length of stay in the intensive care unit. The use of the AQGV peptide or an analog thereof not only reduces the length of stay in intensive care, but the effect of the use of the AQGV peptide or an analog thereof also reduces the length of stay in the hospital and also reduces readmission to the hospital.

[0059] In any case, the use of the AQGV peptide or a functional analog thereof has a significant effect on renal function and / or hemodynamics in a human subject, thereby advantageously assisting the human subject, for example, when suffering from an induced trauma, such as when undergoing cardiac surgery and being under a cardiopulmonary bypass pump. Thus, in one embodiment, the use of the AQGV peptide or a functional analog thereof is for use in cardiac surgery. In another embodiment, the use of the AQGV peptide or a functional analog thereof is for use in a human patient under a cardiopulmonary bypass pump.

[0060] Without being bound by theory, the effect of the AQGV peptide or a functional analog thereof may have an effect on vasoconstriction. Vasoconstriction is involved in the narrowing of blood vessels resulting from the contraction of the muscular layer of the blood vessels. Thus, in one embodiment, the use of the AQGV peptide or a functional analog thereof according to the present invention is involved in inducing vasoconstriction. In particular, the use of the AQGV peptide or an analog thereof may induce peripheral vasoconstriction and / or vasoconstriction in the efferent arterioles within the kidney. Peripheral vasoconstriction may improve hemodynamics, while vasoconstriction in the efferent arterioles may improve renal function.

Brief Description of the Drawings

[0061]

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Mode for Carrying Out the Invention

[0062] (Peptide Synthesis) The AQGV peptide is synthesized, for example, using classical solid-phase synthesis or other methods known in the art. The purity of the peptide is confirmed by high-performance liquid chromatography and / or fast atom bombardment mass spectrometry. Typically, a peptide is defined as a molecule consisting of between 2 and 50 amino acids, while a protein is composed of 50 or more amino acids. Also, peptides tend to have a less well-defined structure compared to proteins, which can adopt complex three-dimensional structures known as secondary, tertiary, and quaternary structures. There may also be a functional distinction between peptides and proteins. In fact, most researchers, as well as this application, use the term "peptide" to specifically refer to a peptide or, alternatively, a relatively short amino acid of up to 50 amino acids, while the term "polypeptide" is used to describe a protein or a chain of 50 or more or much more amino acids.

[0063] (Peptide administration) As shown in the clinical trial protocol (Groenendael et al., JMIR Res Protoc, February 2019; 8(2): e11441), the test agent, the EA-230 formulation, is dissolved in water for injection at a final concentration of 300 mg / mL with an osmolality of 800 to 1000 mOsm / kg and filled and provided in sterile 5 mL glass vials with a content of 1500 mg / vial. The placebo formulation consists of sodium chloride diluted with water for injection in the same sterile 5 mL glass vial with a content of 29 mg / mL to result in a solution having the same osmolality. EA-230 and the placebo are prepared for intravenous infusion at an osmolality of less than 400 mOsm / kg by adding an appropriate amount of EA-230 or placebo to 1000 mL of normal saline under aseptic conditions.

[0064] (Need for a stock solution containing a high concentration of the active substance) Vials containing the EA-230 formulation (stock solution) used in the clinical trials referenced herein contained 1.5 grams of EA-230, and each vial contained 5 ml at 300 mg / ml [(300 g / L = 0.8 mol / L, AQGV has a molecular weight of 373 g / mol)]. In the above trials, the best practice of treatment was established when the infusion of the active substance lasted at least 1.5 hours, preferably at least 2.5 hours, preferably at least 3.5 hours, more preferably at least 4.5 hours, at 90 mg / kg per hour. As a result, and also depending on body weight, generally more than 12 - 17 vials were required to continue effective treatment, but it was an administration requirement that was very (too much) laborious in the operating room or ICU for the care required. These drawbacks of treatment with too weak an amount of the stock of the EA-230 formulation have revealed the need to provide a more concentrated stock solution that is more and better than what is available.

[0065] (Determination of the aggregation point) It is recognized herein that many drug-like molecules can self-aggregate in aqueous media, and aggregates have physicochemical properties that distort experimental results and clinical judgment. Aggregation of peptide drugs is one of the most common and troublesome processes encountered in almost all phases of biological drug development. Aggregation can take multiple different forms, but this term is used to describe a number of different processes during which peptide molecules associate to form larger species consisting of multiple polypeptide chains. Aggregates can be amorphous or highly structured, e.g., amyloid fibers, and can form on surfaces or in solution by absorption. Aggregates can result from non-covalent association of polypeptide chains or from covalent bonding of the chains. In some cases, aggregation is reversible, and in other cases it is virtually irreversible. In either case, aggregation reduces the physical stability of the peptide in question and leads not only to loss of activity but also to other critical problems such as toxicity and immunogenicity.

[0066] Salts have complex effects on the physical stability of biomolecules, which affects both the conformational stability and the colloidal stability. These effects vary frequently according to the surface charge on the peptide, and the overall effect of a given salt on physical stability is a balance of multiple different mechanisms by which the salt interacts with water and the biomolecule. Different salts can affect physical stability by changing the properties of the peptide-solvent system (the Hofmeister effect) or by changing electrostatic interactions (the Debye-Hückel effect).

[0067] We aimed to investigate the solubility of seven different salts in the prototype autophagy-inhibiting peptide AQGV using a modified flask-shaking method. First, AQGV-acetate was converted to the free base, extracted with an organic solvent, and concentrated in vacuo. Subsequently, citrate, maleate, sulfate (KHSO4), adenosine monophosphate, adenosine salt, acetate, and tartrate were prepared and then screened for their solubility.

[0068] (Results) (Conversion to free base) It was found that extraction of AQGV-acetate with an organic solvent from the neutralized solution (pH = 6 - 7) was not possible. Therefore, an aqueous solution of AQGV-acetate was applied to an ion-exchange column (Amberlite, ca. 100 mL; IR120, H resin). The column was flushed with deionized water and then with 1 N ammonia solution. The first three basic fractions were concentrated, and 4.7 g of the free base AQGV was obtained (1H-NMR).

[0069] (Solubility measurement) As a first attempt, the solution of the free base was mixed with an acid to obtain a concentrated DMSO solution of the salt, which was then diluted with water to determine the solubility. However, the salts tried (adenosine and citrate) were completely insoluble in DMSO. In fact, the mixture became clear after the addition of a small amount of water. Therefore, the solubility of the required salt was determined by diluting a known amount of the (insoluble) salt until a clear solution was obtained.

[0070] For citric acid, 1 mmol of AQGV and 1 mmol of citric acid were mixed in 0.5 mL of 0.9% NaCl. As a result, a clear solution was obtained. More materials of both AQGV and citric acid were added (in amounts of 0.5 and 0.25 mmol), and as a result, a total of 2.75 mmol was dissolved in 0.5 mL of 0.9% NaCl. The mixture remained clear but was extremely thick / viscous. The remaining experiments were conducted in different ways. 1 or 0.5 mmol of salt was weighed in a 4 mL vial, and a small amount of 0.9% NaCl was added until a clear solution was obtained, and the solution remained clear for more than one week. In the case of adenosine and adenosine monophosphate, a clear solution was not obtained.

[0071] Based on the results shown in Table 1, the concentration (coagulation point, see Table 2) of the neutral and autophagy-inhibiting peptide salts screened for which the aggregation peptide salts are less and are more soluble was determined. It can be concluded that changing the anion significantly affects the solubility of AQGV. Compared with AQGV-acetic acid (2 mol / L), higher solubility (solubility in 0.9% NaCl), and, along with it, a higher coagulation point were observed for the salts of AQGV-citric acid (AQGV-citrate, >5.5 mol / L) and AQGV-tartaric acid (AQGV-tartrate), while the maleate and KHSO4 salts showed lower solubility. Using adenosine monophosphate or adenosine did not result in solubility. Citric acid seems to be a special case. The highly concentrated solution did not crystallize or aggregate but was likely to form a highly viscous solution.

[0072] Taking into account the risk of aggregation, vials containing stock solutions of AQGV peptides for use in clinical trials hitherto contained at most (0.8 mol / L) active substrate in solution. According to the present invention, such stock solutions of AQGV salts of organic acids, in particular stock solutions of AQGV peptide - maleate, AQGV peptide - acetate, AQGV peptide - tartrate, or AQGV peptide - citrate (excluding those of adenosine or adenosine monophosphate), are prepared to comprise or contain at least 0.85 mol / L, more preferably at least 0.9 mol / L, more preferably at least 1 mol / L, more preferably at least 1.2 mol / L, more preferably at least 1.4 mol / L, more preferably at least 1.6 mol / L, most preferably at least 1.8 mol / L of said AQGV peptide - acetate, said AQGV peptide - tartrate, or said AQGV peptide - citrate. In a more preferred embodiment, the present invention provides a stock solution of said AQGV peptide - tartrate or said AQGV peptide - citrate in which the concentration of said AQGV peptide ranges from 2 mol / L to 2.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of said AQGV peptide - citrate in which the concentration of said AQGV peptide - citrate ranges from 2.5 mol / L to 3 mol / L. In a more preferred embodiment, the present invention provides a stock solution of said peptide - citrate in which the concentration of said peptide - citrate ranges from 3 mol / L to 3.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of said peptide - citrate in which the concentration of said peptide - citrate ranges from 3.5 mol / L to 4.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of said peptide - citrate in which the concentration of said peptide - citrate ranges from 4.5 mol / L to 5.5 mol / L. In a more preferred embodiment, the present invention provides a stock solution of said peptide - citrate in which the concentration of said peptide - citrate is 5.5 mol / L or more. The stock solution is preferably an aqueous solution.

[0073] When describing the composition, structure, and function of proteins or peptides in this specification, amino acids are referred to. In this specification, amino acid residues are referred to using the abbreviations described below. Also, unless otherwise specified, the amino acid sequences of peptides and proteins are identified from the N-terminus to the C-terminus, from the left end to the right end, where the N-terminus is taken as the first residue. Ala: alanine residue, Asp: aspartic acid residue, Glu: glutamic acid residue, Phe: phenylalanine residue, Gly: glycine residue, His: histidine residue, Ile: isoleucine residue, Lys: lysine residue, Leu: leucine residue, Met: methionine residue, Asn: asparagine residue, Pro: proline residue, Gln: glutamine residue, Arg: arginine residue, Ser: serine residue, Thr: threonine residue, Val: valine residue, Trp: tryptophan residue, Tyr: tyrosine residue, Cys: cysteine residue. Amino acids may also be referred to by their conventional single-letter notations. A = Ala, T = Thr, V = Val, C = Cys, L = Leu, Y = Tyr, I = Ile, N = Asn, P = Pro, Q = Gln, F = Phe, D = Asp, W = Trp, E = Glu, M = Met, K = Lys, G = Gly, R = Arg, S = Ser, and H = His.

[0074] (Inhibition of autophagy by selected amino acids) Autophagy is a degradation pathway that delivers extracellular and intracellular substances to lysosomes via double-membrane vesicles called autophagosomes. Cytoplasmic components are captured into autophagosomes, which then fuse with lysosomes where the cargo is degraded. Extracellular substances are taken up by endocytosis or phagocytosis and then also fuse with lysosomes where the cargo is degraded. Autophagy is an important mechanism involved in many aspects of cell functions including cell metabolism and energy balance, and changes in autophagy have been linked to various pathological processes in humans. Autophagy is a natural mechanism by which cells remove and degrade cell components by autolysosomes.

[0075] As described in a recent review (Cell., July 2019; 8(7)) that relatively well describes the role of autophagy in maintaining tissue homeostasis, it has only recently become possible to evaluate its role during tissue repair and regeneration. The present invention provides that the AQGV peptide, i.e., a peptide enhanced by characteristic amino acids or combinations thereof, results in better control of the balance between proteogenesis (mTOR kinase activity) on the one hand and proteolysis (autophagy) on the other, and at the same time identifies a peptide enhanced with autophagy-inhibiting amino acids as a better enhancer of proteogenesis underlying tissue repair compared to other peptides not enhanced with such amino acids. The mammalian target of rapamycin complex 1 (mTORC1) is a central regulator of cell and organism growth, and this pathway has been associated with the etiology of many human diseases. mTORC1 promotes cell and tissue growth in response to the availability of nutrients such as amino acids, and nutrients drive mTORC1 to the lysosomal surface, its activation site. Recent and prior data identify leucine (L), valine (V), isoleucine (I), alanine (A), glutamine (Q), arginine (R), glycine (G), proline (P), alone or in combination, as more potent mTOR activators or autophagy inhibitors compared to other amino acids, such as glutamic acid (E), threonine (T), serine (S), lysine (K), threonine (T), phenylalanine (F), tyrosine (Y), and methionine (M), for which no effect or an opposite effect has been reported. Thus, as provided herein for inclusion in the AQGV peptide of the present invention, peptides enhanced by leucine (L), valine (V), isoleucine (I), alanine (A), glutamine (Q), arginine (R), glycine (G), proline (P), alone or (preferably) in combination, are the most preferred mTOR activators or autophagy inhibitors for use in human cells with respect to packaging and targeting to cells.The AQGV peptide preferably contains at least 50%, more preferably at least 75%, and most preferably 100% amino acids selected from the group consisting of A, Q, G, V, L, P, I, and R. Preferably, the AQGV peptide provided herein has a length in the range of 4 - 12 amino acids, more preferably 4 - 8 amino acids. Preferably, such AQGV peptides are linear peptides. The functional AQGV peptide analogs according to the present invention may more preferably be selected from the group consisting of peptides containing a dipeptide sequence selected from the group consisting of AQ, LQ, PQ, VQ, GQ. The functional AQGV peptides according to the present invention may more preferably be selected from the group consisting of peptides containing a tripeptide sequence selected from the group consisting of AQL, LQL, PQL, VQL, GQL, PLQ, LQG, PQV, VGQ, LQP, LQV, AQG, QPL, PQV, VGQ, GQG. Amino acids such as leucine (L), alanine (A), glutamine (Q), and proline (P) have been reported to have the most excellent mTOR-related autophagy inhibitory effect on human cells (AJ Meijer et al., Amino Acids, 2015, 47, 2037 - 2063). Glycine (G; Zhong Z, Wheeler MD, Li X, Froh M, Schemmer P, Yin M, Bunzendaul H, Bradford B, Lemasters JJ. l-Glycine: a novel antiinflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metab Care 6:229) improves the amino acid-stimulated mammalian target of rapamycin (mTOR) complex 1 activation. Thus, leucine (L), alanine (A), glutamine (Q), glycine (G), and proline (P), either alone or (preferably) in combination, as provided herein for inclusion in the AQGV peptides according to the present invention, are preferred mTOR activators or autophagy inhibitors for use in human cells.The AQGV peptide preferably contains at least 50%, more preferably at least 75%, and most preferably 100% of the amino acids selected from the group of A, Q, G, V, L, and P. In a more preferred embodiment, the AQGV peptide contains at least 75%, most preferably 100% of the amino acids selected from the group of A, Q, G, and V.

[0076] In the most preferred embodiment, the AQGV peptide according to the present invention is a tetrapeptide containing 100% of the amino acids selected from the group of A, Q, G, and V. Typical preferred examples of such preferred tetrapeptides are AQGV, LQGV, VGQA, VGQL, AQVG, and LQVG. The most typical and preferred one is AQGV, which is the subject of human clinical trials as provided below.

[0077] The present invention includes the use of an AQGV peptide or a functional analog thereof for the treatment of a human subject for improving the length of stay of the subject in the ICU, and further for shortening the length of stay of the subject in the ICU. One way this may be achieved is by modifying fluid retention in the human subject. The use of an AQGV peptide or a functional analog thereof according to the present invention includes the treatment of human patients who are considered to be at risk due to treatment with vasopressors or inotropic agents and / or who are expected to require hemodynamic therapy by infusion therapy. Such human patients include patients who are sent or scheduled to be sent or expected to be sent to intensive care, and for this reason, a shortened length of stay in the ICU is expected. Accordingly, the use of an AQGV peptide or a functional analog thereof includes use for the treatment of human patients who are considered to be at risk due to treatment with vasopressors or inotropic agents and / or infusion therapy, as shown, for example, in the examples, or for whom such treatment is expected to be necessary. Preferably, for use in shortening the length of stay of a subject in the ICU in a human patient considered to be at risk, the AQGV peptide is administered at a rate of at least 10 mg / kg patient body weight (mg / kg / hour) per hour. Preferably, this administration rate is at least 20 mg, at least 30, at least 40, or most preferably at least 50 mg / kg / hour. Preferably, the AQGV peptide is administered for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours. Preferably, the administration of the AQGV peptide is at a rate of at least 20 mg / kg / hour for at least 1 hour, more preferably for at least 1.5 hours, most preferably for at least 2 hours or at least 2.5 hours, etc., more preferably for at least 3.5 hours, more preferably for at least 4.5 hours.

[0078] Embodiment 1: An AQGV peptide or a functional analog thereof for use in the treatment of a human subject, wherein the use comprises modifying the hemodynamics in the human subject. Embodiment 2: An AQGV peptide or a functional analog thereof for use in the treatment of a human subject suffering from or at risk of developing fluid overload, wherein the use comprises modifying the hemodynamics in the human subject, the AQGV peptide or a functional analog thereof. Embodiment 3: An AQGV peptide or a functional analog thereof for use in the treatment of a human subject suffering from or at risk of developing excessive use of pressors / inotropes, wherein the use comprises modifying the hemodynamics in the human subject, the AQGV peptide or a functional analog thereof. Embodiment 4: An AQGV peptide or a functional analog thereof for use in the treatment of a human subject who has suffered an induced trauma, wherein the use comprises modifying the hemodynamics in the human subject, the AQGV peptide or a functional analog thereof. Embodiment 5: An AQGV peptide or a functional analog thereof for use in the treatment of a human subject with renal dysfunction, wherein the use comprises modifying the hemodynamics in the human subject, the AQGV peptide or a functional analog thereof. Embodiment 6: The AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-5, wherein the use reduces fluid retention in the human subject. Embodiment 7: The AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-6, wherein the use comprises a reduced use of pressors. Embodiment 8: The AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-7, wherein the use comprises a reduced fluid intake. Embodiment 9: The AQGV peptide or a functional analog thereof for use according to Embodiment 7, wherein the reduced use of pressors comprises a reduced period of pressor use. Embodiment 10: The AQGV peptide or a functional analog thereof for use according to any one of Embodiments 6-9, wherein the subject has suffered an induced trauma. Embodiment 11: The use is for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 6-10, which improves renal function in the human subject. Embodiment 12: The improved renal function involves an improved GFR rate, for an AQGV peptide or a functional analog thereof for the use according to Embodiment 11. Embodiment 13: The human subject has a renal dysfunction which is AKI, for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 6-12. Embodiment 14: The use is for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 1-13, which reduces the leakage of plasma from the blood to surrounding tissues and / or organs. Embodiment 15: The use is for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 1-14, which is in a human subject suffering from or at risk of heart failure. Embodiment 16: The use is for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 1-15, which is in a human subject at risk of having edema. Embodiment 17: The human subject has suffered an induced trauma which is surgery, for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 4-16. Embodiment 18: The surgery requires cardiopulmonary bypass, for an AQGV peptide or a functional analog thereof for the use according to Embodiment 17. Embodiment 19: The peptide is administered into the bloodstream, for an AQGV peptide or a functional analog thereof for the use according to any one of Embodiments 1-18. Embodiment 20: The peptide is administered at a rate of at least 70 mg / kg body weight / hour, for an AQGV peptide or a functional analog thereof for the use according to Embodiment 19. Embodiment 21: The peptide is administered for at least 1 hour, for an AQGV peptide or a functional analog thereof for the use according to Embodiment 19 or 20. Embodiment 22: An AQGV peptide or a functional analog thereof for use according to any one of Embodiments 17-21, wherein the administration is during surgery. Embodiment 23: An AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-22, wherein the administration is during cancer treatment. Embodiment 24: An AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-23, wherein the administration is during a drug adverse reaction. Embodiment 25: The human subject is sent to intensive care, the use improves a measured parameter of the human subject, and the parameter of the human subject is determined to evaluate whether to stay in intensive care. An AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-24. Embodiment 26: An AQGV peptide or a functional analog thereof for use according to Embodiment 25, wherein the improvement of the parameter results in a reduced length of stay in intensive care. Embodiment 27: An AQGV peptide or a functional analog thereof for use according to any one of Embodiments 1-26, wherein the use induces vasoconstriction. Embodiment 28: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject in need of maintaining hemodynamic stability. Embodiment 29: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject in need of improving hemodynamic stability. Embodiment 30: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject having renal dysfunction, wherein the treatment of administering the AQGV peptide comprises maintaining or improving hemodynamic stability in the human subject. Embodiment 31: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject in need of improving a drug adverse reaction. Embodiment 32: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject having or suspected of having Clarkson's disease (CLS). Embodiment 33: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject having or suspected of having a drug adverse reaction that affects capillary leakage. Embodiment 34: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject in need of maintaining hemodynamic stability. Embodiment 35: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject in need of improving hemodynamic stability. Embodiment 36: A method of treatment comprising administering an AQGV peptide or a functional analog thereof to a human subject having renal dysfunction, wherein said treatment with administration of the AQGV peptide comprises maintaining or improving hemodynamic stability in said human subject.

[0079] (Example) A Phase 2 clinical trial was designed to test EA-230 (tetrapeptide AQGV) in cardiac surgery (CABG) patients who often develop hemodynamic imbalances leading to organ failure. The trial was completed in 2019, and the results showed significantly improved renal function after treatment with EA-230, with a highly statistically significant reduction in LOS (length of stay in the ICU and hospital) and a reduction in readmissions. These beneficial effects of EA-230 led to a more significantly favorable recovery of open-heart surgery patients treated with EA-230, resulting in a clear economic benefit. The positive outcome probably resulted from the unexpectedly shown very beneficial effect of EA-230 on the hemodynamic stability of intensive care patients during this Phase 2 trial, which led to a reduction in fluid overload, a reduction in the use of vasopressors, and an improvement in kidney function.

[0080] During cardiac surgery, 180 patients (double-blind, placebo-controlled, randomized) received EA-230 or placebo at 90 mg / kg / hour. The primary endpoint was safety. Efficacy was evaluated by immunomodulation (plasma interleukin (IL)-6 concentration), renal function (glomerular filtration rate (GFR iohexol, eGFR MDRD) using iohexol and creatinine, and incidence of acute kidney injury (AKI, RIFLE criteria)), cardiovascular effects (fluid balance, vasoactive agents), and general outcome (length of stay).

[0081] The median [IQR] age was 68 [62 - 74] years and 158 / 180 were male. There were no safety concerns. EA-230 did not modulate IL-6 (area under the curve, 2730 [1968 - 3760] vs 2680 [2090 - 3570] pg / ml*hour for EA-230 and placebo groups respectively, p = 0.80). GFR increased postoperatively (meanΔ±SEM GFR iohexol was 19±2 vs 16±2 ml / min / 1.73m2, p = 0.13, eGFR MDRD was 6±1 vs 2±1 ml / min / 1.73m2, p = 0.01). EA-230 trended towards preventing AKI (stage injury: 7% vs 18%, p = 0.07). Patients in the EA-230 group required less fluid than placebo-treated patients (217±108 vs 605±103 ml respectively, p = 0.01), but vasoactive agent use was similar in both groups (p = 0.39). The length of hospital stay was shorter in the EA-230 treatment group (8 [7 - 11] vs 10 [8 - 12] days, p = 0.001).

[0082] (Safety of EA-230) The final analysis of the EASI trial demonstrated a favorable safety profile for treatment with EA-230. A continuous infusion of EA-230 at 90 mg / kg / hour for up to 4 hours was well tolerated by patients undergoing elective CABG surgery. Pharmacokinetic studies indicate that EA-230 is rapidly cleared from the circulation (within 5 - 10 minutes) upon completion of the infusion. Patients receiving EA-230 appeared to experience fewer (severe) adverse events and fewer major clinical adverse events. In conclusion, the safety profile of EA-230 in patients undergoing elective CABG surgery was comparable, if not superior, to the safety profile of patients receiving a continuous placebo infusion.

[0083] (Efficacy of EA-230) A continuous infusion of EA-230 at 90 mg / kg / hour for up to 4 hours in patients undergoing elective CABG surgery demonstrated an unexpected but clear clinical benefit of treatment with EA-230. Most notably, treatment with EA-230 (n = 90) resulted in a highly significant reduction in the total postoperative length of stay of approximately 3 days. No effect on the CABG-induced cytokine response (as measured by the primary endpoint IL-6) was seen, but treatment with EA-230 clearly caused an overall and significant improvement in hemodynamic stability based on the reduced need for blood pressure (vasopressor / inotropic) agents and the reduced need for fluid therapy, and at the same time, prevented postoperative fluid overload. Also, a significant overall improvement in renal function was seen. As detailed herein, long-term treatment with EA-230 during surgery results in increased clinical benefit in the postoperative patient recovery rate. These results also show the beneficial effect of long-term (long = longer than the median) treatment with EA-230 on renal function, as measured by glomerular filtration rate (GFR), compared to patients treated for a shorter period than the median treatment. Our findings (Figure 17) show a highly significant statistical improvement in postoperative renal function due to long-term treatment of patients with EA-230 during elective CABG surgery. Similarly, postoperative postoperative hemodynamic stability (measured as the need for vasopressors / inotropes and / or fluid therapy, Figure 18) benefits significantly from the long-term use of EA-230 during surgery.

[0084] (Summary of the effects of EA-230) Early administration led us to notice new and highly beneficial effects of EA-230 on hemodynamics, renal function, length of stay in the ICU and hospital, related to improved hemodynamic stability. Treatment of patients with EA-230 during surgery significantly reduced the need for postoperative hemodynamic therapy (combined infusion therapy and blood pressure medications) (p = 0.006). In addition to these improved hemodynamics, EA-230 significantly improved renal function (determined by its effect on glomerular filtration rate) and plasma levels of creatinine, a renal function biomarker (p = 0.003). EA-230 also significantly shortened the postoperative recovery stay in the ICU and significantly reduced the length of stay in the hospital (Figure 1). On average, patients treated with EA-230 required approximately 8 days of in-hospital care, while placebo-treated patients required approximately 10 days. Also, fewer EA-230-treated patients required readmission compared to placebo-treated patients.

[0085] (Effects of EA-230 in human patients) A prospective randomized double-blind placebo-controlled trial was conducted, and 180 elective patients undergoing on-pump or off-pump coronary artery bypass surgery with or without concomitant valve surgery were enrolled. Patients were randomly assigned in a 1:1 ratio to receive either EA-230 (90 mg / kg / hour) or placebo. These were infused from the start of surgery until the end of cardiopulmonary bypass use. The main focus in this first-in-patient trial was the safety and tolerability of EA-230. The primary efficacy endpoint was the modulation of the inflammatory response by EA-230, quantified as the change in postoperative interleukin-6 plasma concentration. The primary secondary endpoint was the effect of EA-230 on renal function.

[0086] (Design and setting) This was a single-site, prospective, randomized, double-blind, placebo-controlled, single-dose, Phase II trial. It had an adaptive design to evaluate the safety and immunomodulatory effects of EA-230 in patients undergoing on-pump cardiac surgery for coronary artery bypass grafting (CABG) with or without concomitant valve surgery. 180 eligible patients were enrolled and randomly assigned in a 1:1 ratio to receive either the active drug or placebo treatment. This was a first-in-patient safety and tolerability trial, but the primary efficacy objective was to evaluate the immunomodulatory effect of EA-230. The primary and secondary efficacy endpoints were the effect of EA-230 on renal function. This trial was described according to the Standard Protocol Items: Recommendations for Interventional Trial (SPIRIT) and registered on the clinicaltrials.gov website with the number NCT03145220.

[0087] (Randomization and Stratification) On the morning of surgery, patients were randomized to receive either the active drug or placebo treatment by an unblinded independent trial staff. In this process, the trial staff used data management software (Castor EDC, Amsterdam, the Netherlands) approved by Good Clinical Practice (GCP). The Castor system applied stratified randomization to ensure an equal distribution between the active drug and placebo treatments for patients with known risk factors for adverse outcomes. The three strata included: 1) CABG surgery with or without concomitant valve surgery, 2) preoperative renal function with an estimated GFR of ≤30, 31 - 90, and >90 ml / min / 1.73 m2, and 3) EuroSCORE II <4 or ≥4 (Nashef et al., Eur. J. Cardiothora. Surg., April 2012; 41(4): 734 - 44).

[0088] (Blinding) The double-blind conditions were maintained for all patients, all blinded medical trial team members involved in the trial procedures, data collection, and / or data analysis, and the attending physicians. Unblinded trial personnel not involved in other trial procedures prepared the investigational drug. The infusion systems and solutions for the active drug and placebo treatments were identical in appearance and texture. Unblinding was permitted by the sponsor after completion of the trial, performance of the blinded data review, and database lock.

[0089] (Study Intervention) Intravenous infusion of EA-230 (90 mg / kg / hour) or placebo was initiated at the time of the first surgical incision using an automated infusion pump. The infusion rate was set at 250 ml / hour and the infusion was continued until either interruption of CPB or the first occurrence of a 4-hour continuous infusion elapsed.

[0090] The EA-230 formulation was dissolved in water for injection at a final concentration of 300 mg / ml with a weight molar osmotic concentration of 800 to 1000 mOsm / kg and filled into sterile 5-ml glass vials with a content of 1500 mg / vial. The placebo formulation consisted of sodium chloride diluted with water for injection at a content of 29 mg / ml to result in a solution with the same weight molar osmotic concentration. EA-230 and placebo were prepared for continuous intravenous infusion at a weight molar osmotic concentration of less than 400 mOsm / kg by adding an appropriate amount of EA-230 or placebo to 1000 mL of normal saline under aseptic conditions. The placebo and active drug treatment vials were manufactured by HALIX BV (Leiden, the Netherlands).

[0091] (Adverse Event (AE)) Severity (mild, moderate, or severe) and the perceived relatedness of these to the investigational medicinal product (relatedness is definite, probable, possible, or not / improbable) were determined by the investigator based on the Common Terminology Criteria for Adverse Events guidelines 4.030. SAEs and SUSARs include death, life-threatening diseases, long-term and / or significant disability and / or incapacity, and hospitalizations and / or prolongation of hospitalization.

[0092] (Ethical Considerations, Data Quality Assurance, and Patient and Public Involvement) This trial was conducted in accordance with the ethical principles of the Declaration of Helsinki (ICH E6(R1)), the Medical Research Involving Human Subjects Act, the GCP guidelines, and the European Directive (2001 / 20 / CE). Informed consent was obtained before any trial-specific procedures were performed. Data were handled confidentially and anonymously, and GCP standards were applied. The handling of patient data in this trial was in accordance with the Dutch Personal Data Protection Act (in Dutch: Wet Bescherming Persoonsgegevens, WBP). Patients and the public were not involved in the design and / or conduct of this trial protocol. Trial outcomes were sent individually to all trial participants. The burden of the intervention was evaluated by the CMO and CCMO, independent ethical committees, which include lay members.

[0093] (Results) When evaluating the data obtained in the clinical trial, it was notable that no significant differences in plasma levels were observed between the EA-230 group and the placebo group for IL-8, IL-10, IL-1RA, IL-17, MCP-1, and ICAM, as well as for other cytokines assayed. Thus, neither an immunomodulatory effect nor an anti-inflammatory effect was clearly observed. This also applied to the IL-6 plasma level (see Figure 12), which is the primary evaluation item of this trial, and to IL-18, KIM1, NGAL, L-FABP, and NAG (see Figure 22), which are inflammatory kidney injury markers. Notably, it was found that patients suffering from fluid retention were significantly fewer in the EA-230 treatment group (see Table 1). Various parameters were further analyzed, and hemodynamic parameters (use of vasopressors and / or fluid balance) and / or kidney parameters were favorably affected by the use of EA-230 compared to placebo.

[0094] Table 1: Adverse Events (AE) in the EASI Trial Adverse events (AE), serious adverse events (SAE), and suspected unexpected serious adverse reactions (SUSAR) involving differences between treatment groups are listed here. In the EA-230 treatment group (217 patients), significantly fewer (chi-square P < 0.05) AEs were seen compared to the placebo treatment group (283 patients). In the EA-230 treatment group (n = 2), it was found that patients suffering from fluid retention were significantly fewer (chi-square P < 0.05) compared to the placebo treatment group (n = 11) (p < 0.05).

Table 1

[0095] Table 2: Mean Patient On-Pump Duration of All Patients (Q1 - Q4) Divided into and Assayed for Quartiles Q1, Q2, Q3, and Q4 of the Pump Duration and, Consequently, the Treatment Duration, Along with the Mean Patient Age

Table 2

[0096] (Hemodynamic stability in the EASI test) In Figure 2, the use of vasopressors is shown. Generally, the use of vasopressors was decreased in the group treated with EA-230. Patients were divided into quartiles based on the treatment period. Table 3 shows the descriptive frequencies of two variables: the number of days receiving vasopressin and the net fluid balance on days 0 - 2 (the first 72 hours). The groups were divided into patients without treatment (placebo) and patients with treatment by EA-230 (active drug), and also into patients without acute kidney injury (AKI) and patients with AKI. EA-230 decreased the net fluid balance in both patients with AKI and patients without AKI. EA-230 decreased the need for vasopressors in patients with AKI.

Table 3

[0097] (Regulation of fluid balance and use of vasopressors by treatment with EA-230) The effect of EA-230 compared to placebo was tested in univariate and multivariate models (see Table 4). The input / independent variable was the treatment group (EA-230 or placebo). The output / dependent variables were evaluation items such as the fluid balance in the first 72 hours, the number of days receiving vasopressin, or the vasopressor score (area under the curve). The effect of EA-230 compared to placebo was tested for two combined variables in Model A (fluid balance in the first 72 hours + number of days receiving vasopressin) and Model B (fluid balance in the first 72 hours + vasopressor score AUC). The results of the tests in both multivariate models showed a significant improvement in hemodynamic parameters in patients receiving EA-230. This was observed in Model A (fluid balance in the first 72 hours + number of days receiving vasopressin) (p = 0.006) and Model B (fluid balance in the first 72 hours + vasopressor score AUC) (p = 0.008). In the group of patients who did not show AKI, the hemodynamic effect of EA-230 was also significantly better, indicating that the improvement in hemodynamics can occur independently of renal insufficiency.

[0098] Table 4: Goal-directed hemodynamic therapy with EA-230 Analysis for Model A is shown for the overall group and subgroups of renal dysfunction divided according to the RIFLE criteria (no AKI (placebo n = 42, EA-230 n = 50), Risk (placebo n = 31, EA-230 n = 34), and Injury (placebo n = 16, EA-230 n = 6)). The corresponding p-values are listed. [Table 4]

[0099] Taken together, these results indicate that the use of EA-230 can improve and / or maintain hemodynamics in human patients, as evaluated by affecting the duration of vasopressor use, the amount of vasopressor administered, and / or the fluid balance. In particular, EA-230 improves hemodynamic stability after open heart surgery in humans. Permeability governs the amount of body fluid leaking from blood vessels. The administration of fluid therapy generally increases leakage. Based on the Phase II patient observations, we found a significant decrease in harmful body fluid retention (body fluid leakage due to fluid overload) in patients treated with EA-230 (p = 0.03). Also, contractility governs tension. This is often regulated by the administration of blood pressure agents, but such agents can exhibit major adverse side effects. Based on the Phase II patient observations, we found a significant decrease in the use of blood pressure agents required in half of the patients treated with EA-230 for the longest time (>156 minutes, p = 0.093). Also, we determined the mean maximum concentration (mean Cmax) determined in vivo in humans for EA-230 in the Phase II clinical trial. The mean arterial Cmax was found to be 30500 ng / ml (range 12500 to 57500 ng / ml). The mean venous Cmax was found to be 68400 ng / ml (range 19600 to 113000 ng / ml).

[0100] (EA-230 has beneficial effects on renal function) The effect of EA-230 on the regulation of the incidence of acute kidney injury (AKI) at different stages was determined based on the RIFLE criteria (RIFLE: classification into risk, injury, failure, loss of kidney function, and end-stage kidney disease, Clin. Kidney J., February 2013; 6(1): 8-14). In the EA-230 group, while the number of patients without AKI increased, the number of patients in the injury category of the RIFLE criteria decreased (see Figure 3). Furthermore, the use of EA-230 significantly improved the postoperative GFR (Figure 4). Creatinine clearance, as a biomarker of renal function, was significantly improved postoperatively in patients treated with EA-230 (Figure 5). When preoperative renal function was considered, creatinine clearance was significantly improved when EA-230 was used and preoperative renal function was less than 60 ml / min (Figure 6, left). When preoperative renal function was more than 60 ml / min, no difference was observed (Figure 6, right). Similar observations were made based on the GFR parameter (Figure 7). Treatment with EA-230 significantly improved the postoperative estimated GFR compared to the preoperative estimated GFR, but treatment with placebo did not. When renal function was more than 60 ml / min / 1.73 m2, no difference was observed between the groups. Also, when the patient had a long-term cardiopulmonary bypass, treatment with EA-230 significantly improved the postoperative GFR compared to the preoperative GFR (Figure 8, treatment length > 156 minutes, p = 0.001). Taken together, these results indicate that the use of EA-230 can improve and / or maintain renal function in human patients.

[0101] (ICU, hospital stay, and readmission) In this study, the length of stay of patients in the ICU and the length of stay in the hospital (inpatient treatment) were investigated (see Figure 10). Treatment with EA-230 resulted in a significant reduction in the length of stay (LOS) in the ICU and the hospital. The length of stay in the ICU and the hospital decreased in the EA-230 group. Patients treated with EA-230 also showed a significant (p = 0.09) reduction in the number of readmissions up to 90 days after surgery (see Table 5).

[0102] Table 5: Number of readmissions in the EASI trial (CABG trial). Number of patients who had to be readmitted to the hospital due to clinical illness during the postoperative period. Readmissions were scored for the total 90-day period after surgery, for the 28-day period after surgery, and for the period ranging from 29 - 90 days after surgery. Readmissions decreased in the treatment group of patients receiving EA-230.

Table 5

[0103] Furthermore, in the group of patients treated with AQGV, the number of patients suffering from AKI disorder decreased. However, when patients suffered from AKI disorder, these patients did not require as long a length of stay as observed in the placebo group, and the length of stay was similar to that of patients without AKI or at risk of AKI (see Figure 11).

[0104] At the same time, treatment with EA-230 showed a strong and beneficial effect on recovery. EA-230-treated patients required significantly less hemodynamic therapy, recovered renal function significantly more rapidly after surgery, and stayed in the intensive care unit (ICU) and the hospital for a shorter period compared to the placebo-treated group.

[0105] These new hemodynamic effects of EA-230 appeared to be independent of its anti-inflammatory effect. In short, the marked improvement in hemodynamic stability, renal function, and postoperative recovery in EA-230-treated patients was associated with the new effects of EA-230 on vascular permeability and vasoconstriction. EA-230 administered during surgery showed a marked improvement in postoperative patient recovery over placebo patients. EA-230-treated patients were released more rapidly from intensive care (p = 0.0232) and the hospital (p = 0.0015). EA-230 improved hemodynamic stability (p = 0.006) and renal function (p = 0.003). Although the reduction in the primary outcome of short-term inflammatory cytokine (IL-6) was lost, long-term patient recovery was significantly improved by EA-230. EA-230 was shown to be safe and well tolerated throughout the surgery. In conclusion, EA-230 administered during surgery significantly improved postoperative recovery.

[0106] A significant improvement in hemodynamic stability (reducing fluid therapy and blood pressure medications, p = 0.006) was found, which was accompanied by a significant improvement in renal function (improved glomerular filtration rate reducing plasma creatinine, p = 0.003), a significant decrease in patients suffering from harmful fluid retention during recovery (2 for EA-230 vs. 9 for placebo, p = 0.03), and a considerable decrease in hospital readmission at 90 days post-surgery (4 for EA-230 vs. 10 for placebo, p = 0.09).

[0107] (Additional analysis biomarkers related to vasoconstriction and / or vasodilation) In view of the effects observed on hemodynamics and renal function, plasma samples were further analyzed for selected biomarkers. Plasma samples from control patients and patients receiving EA-230 were analyzed for biomarkers such as endothelin-1, VEGF, angiotensin II, and cAMP, as well as natriuretic peptides. The assays described below were used to determine the levels of the biomarkers.

[0108] (In vitro effects of EA-230 and AQGV analogs) In an in vitro Transwell assay, the effects of the AQGV peptide (EA-230) and its analogs were tested on human vascular endothelial cells. Briefly, vascular endothelial cells were cultured in Transwell culture dishes and the medium was supplemented with the AQGV peptide and its analogs, or a control compound known to affect endothelial layer permeability, vasoconstriction, and / or vasodilation. Suitable human vascular endothelial cells are, for example, HUVEC (Park et al., Stem Cell Rev., 2(2):93-102, 2006; Jimenez et al., Cytotechnology 65, 1-14, 2012) and HMEC-1 (Ades EW et al., J. Invest. Dermatol., 99(6):683-690, 1992). The permeability of the endothelial layer is determined by measuring the passage of macromolecules. Furthermore, the levels of biomarkers are also determined in the medium. The experiments are performed in a manner as outlined, for example, by Cox et al. (Shock, 43(4):322-6; 2015). In the HUVEC permeability test, established human umbilical vein endothelial cells (HUVEC) with the ability to line blood vessels were expanded by cell culture on sieves in multiple test formats (i.e., n = 5), enabling the determination of leakage according to various test concentrations of the EA-230 peptide or placebo control used, and pharmacological parameters of the effect of the EA-230 peptide on permeability in human cells were established.

[0109] In addition, Bravo et al. (J. Pharmacol. Toxicol. Methods, January - February 2018; 89:47 - 53) developed an impedance - based contraction assay using the xCELLigence RTCA MP system. This technique uses a special 96 - well E - plate in which an array of gold microelectrodes is printed in individual wells to monitor cell adhesion by recording electrical impedance in real time. The impedance change (percentage relative to the control) can be used as a readout for cell contraction. Established human aortic smooth muscle cells (HaSMC) that have the ability to contract blood vessels were expanded by cell culture on gold electrodes (i.e., n = 3) in multiple test formats, enabling the determination of the electrical impedance of endothelin - 1 - induced smooth muscle cell contraction according to various test concentrations of the EA - 230 peptide or placebo control used, and establishing the pharmacological parameters of the effect of the EA - 230 peptide on contractility in human cells. In addition, isolated human aortic smooth muscle cells from aneurysm (n = 3) / control (n = 3) patients (APaSMC) that have the ability to differentially contract blood vessels were expanded by cell culture on gold electrodes in multiple test formats, enabling the determination of the electrical impedance of ionomycin - induced smooth muscle contraction of patient - versus - control cells according to various test concentrations of the EA - 230 peptide or placebo control used, and detecting the effect of EA - 230 in patient cells.

[0110] [Appendix] [Appendix 1] A method of treating a human subject who is considered to need to maintain or improve hemodynamic stability, the method comprising administering to the subject a peptide comprising at least 50% amino acids selected from the group of autophagy - inhibiting amino acids consisting of alanine (one - letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0111] [Appendix 2] A method for treating a human subject who is considered to need to reduce harmful vascular permeability, the method comprising administering to the subject a peptide comprising at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0112] [Appendix 3] A method for treating a human subject who is considered to need to reduce harmful body fluid retention, the method comprising administering to the subject a peptide comprising at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0113] [Appendix 4] The method for treatment according to any one of Appendices 1 to 3, wherein the peptide comprises at least 75% of amino acids selected from the group of autophagy-inhibiting amino acids.

[0114] [Appendix 5] The method for treatment according to any one of Appendices 1 to 4, wherein the peptide consists of amino acids selected from the group of autophagy-inhibiting amino acids.

[0115] [Appendix 6] The method for treatment according to any one of Appendices 1 to 5, wherein the peptide comprises at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L).

[0116] [Appendix 7] The method for treatment according to any one of Appendices 1 to 6, wherein the peptide comprises at most 30% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R).

[0117] [Appendix 8] Administering to the subject at least two different peptides each containing at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R), the treatment method according to any one of Appendices 1 to 7.

[0118] [Appendix 9] The method according to any one of Appendices 1 to 8, wherein one or more of the peptides have a length in the range of 4 - 30 amino acids.

[0119] [Appendix 10] The treatment method according to any one of Appendices 1 to 9, wherein the subject has suffered severe trauma such as surgery.

[0120] [Appendix 11] The treatment method according to any one of Appendices 1 to 9, wherein the subject is receiving cancer treatment such as treatment with an anti-cancer agent or an immunomodulatory agent.

[0121] [Appendix 12] The treatment method according to any one of Appendices 1 to 9, wherein the subject is considered to be suffering from capillary leak syndrome seen in drug adverse reactions.

[0122] [Appendix 13] The method according to any one of Appendices 1 to 12, wherein the human subject has renal dysfunction.

[0123] [Appendix 14] The method according to any one of Appendices 1 to 13, wherein the method includes reduced use of vasopressors.

[0124] [Appendix 15] The method according to any one of Appendices 1 to 14, wherein the method includes a reduced water intake.

[0125] [Appendix 16] The method according to any one of Appendices 1 to 15, wherein the peptide contains at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation: A), glutamine (Q), glycine (G), and valine (V).

[0126] [Appendix 17] The method according to any one of Appendices 1 to 15, wherein the peptide consists of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation: A), glutamine (Q), glycine (G), and valine (V).

[0127] [Appendix 18] The method according to any one of Appendices 1 to 17, wherein the peptide is a salt selected from the group of peptide-organic acids.

[0128] [Appendix 19] A peptide for use in the treatment of a human subject in whom it is considered necessary to maintain or improve hemodynamic stability, wherein the peptide contains at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation: A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0129] [Appendix 20] A peptide for use in the treatment of a human subject in whom it is considered necessary to reduce harmful vascular permeability, wherein the peptide contains at least 50% of amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation: A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0130] [Appendix 21] A peptide for use in the treatment of a human subject where it is considered necessary to reduce harmful moisture, said peptide comprising at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0131] [Appendix 22] The peptide according to any one of Appendices 19 to 21, wherein the subject has suffered severe trauma such as surgery.

[0132] [Appendix 23] The peptide according to any one of Appendices 19 to 21, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent or an immunomodulatory agent.

[0133] [Appendix 24] The peptide according to any one of Appendices 19 to 21, wherein the subject is considered to be suffering from capillary leak syndrome seen in drug adverse reactions.

[0134] [Appendix 25] The peptide according to any one of Appendices 19 to 24, wherein the human subject has renal dysfunction.

[0135] [Appendix 26] The peptide according to any one of Appendices 19 to 25, wherein the use includes a reduced use of vasopressors.

[0136] [Appendix 27] The peptide according to any one of Appendices 19 to 26, wherein the use includes a reduced water intake.

[0137] [Appendix 28] The peptide according to any one of Appendices 19 to 27, wherein the peptide comprises at least 50% of the amino acids selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation A), glutamine (Q), glycine (G), and valine (V).

[0138] [Appendix 29] The peptide is the peptide according to Appendix 28, which consists of an amino acid selected from the group of autophagy-inhibiting amino acids consisting of alanine (one-letter notation: A), glutamine (Q), glycine (G), and valine (V).

[0139] [Appendix 30] The peptide is the peptide according to Appendix 29, which is a salt selected from the group of peptide - acetate, peptide - tartrate, or peptide - citrate.

[0140] [Appendix 31] A pharmaceutical preparation containing the peptide according to any one of Appendices 19 to 30.

[0141] [Appendix 32] The pharmaceutical preparation according to Appendix 31, wherein the peptide contains at least 75% of the amino acids selected from the group of the autophagy-inhibiting amino acids.

[0142] [Appendix 33] The pharmaceutical preparation according to Appendix 31 or 32, wherein the peptide consists of 100% of the amino acids selected from the group of the autophagy-inhibiting amino acids.

[0143] [Appendix 34] The pharmaceutical preparation according to any one of Appendices 31 to 33, wherein the peptide contains at least 50% of the amino acids selected from the group of the autophagy-inhibiting amino acids consisting of alanine (A), glutamine (Q), and leucine (L).

[0144] [Appendix 35] The pharmaceutical preparation according to any one of Appendices 31 to 34, wherein the peptide contains at most 30% of the amino acids selected from the group of the autophagy-inhibiting amino acids consisting of glycine (G), valine (V), isoleucine (I), proline (P), and arginine (R).

[0145] [Appendix 36] A pharmaceutical preparation according to any one of Appendices 31 to 35, comprising at least two different peptides each containing at least 50% of an amino acid selected from the group of autophagy-inhibiting amino acids consisting of alanine (single-letter notation A), glutamine (Q), glycine (G), valine (V), leucine (L), isoleucine (I), proline (P), and arginine (R).

[0146] [Appendix 37] A pharmaceutical preparation according to any one of Appendices 31 to 36, wherein one or more of the peptides are 4 - 30 amino acids in length and differ in length.

[0147] [Appendix 38] A pharmaceutical preparation according to any one of Appendices 31 to 37, comprising at least 0.85 mol / L of one or more of the peptides.

[0148] [Appendix 39] A pharmaceutical preparation according to any one of Appendices 31 to 38, comprising at least one pharmaceutically acceptable additive.

[0149] [Appendix 40] A stock solution comprising a pharmaceutical preparation according to any one of Appendices 31 to 39.

[0150] [Appendix 41] A preparation or solution according to any one of Appendices 31 to 40 for use in the treatment of a human subject considered to need to maintain or improve hemodynamic stability.

[0151] [Appendix 42] A preparation or solution according to any one of Appendices 31 to 40 for use in the treatment of a human subject considered to need to reduce harmful vascular permeability.

[0152] [Appendix 43] A preparation or solution according to any one of Appendices 31 to 40 for use in the treatment of a human subject considered to need to reduce harmful body fluid retention.

[0153] [Appendix 44] The preparation or solution according to any one of Appendices 31 to 40 for use in the treatment of a human subject suffering from or suspected of suffering from Clarkson's disease (CLS).

[0154] [Appendix 45] A method of treating a human subject in whom it is considered necessary to maintain or improve hemodynamic stability, the method comprising administering to the subject a preparation or solution according to any one of Appendices 31 to 40.

[0155] [Appendix 46] A method of treating a human subject in whom it is considered necessary to reduce harmful vascular permeability, the method comprising administering to the subject a preparation or solution according to any one of Appendices 31 to 40.

[0156] [Appendix 47] A method of treating a human subject in whom it is considered necessary to reduce harmful fluid retention, the method comprising administering to the subject a preparation or solution according to any one of Appendices 31 to 40.

[0157] [Appendix 48] A method of treating a human subject suffering from or suspected of suffering from Clarkson's disease (CLS), the method comprising administering to the subject a preparation or solution according to any one of Appendices 31 to 40.

Claims

1. A pharmaceutical preparation for maintaining or improving hemodynamic stability in a human subject who is considered to be at risk of fluid overload or suffering from fluid overload and who needs to maintain or improve hemodynamic stability, said pharmaceutical preparation comprising a tetrapeptide consisting of the amino acid sequence of AQGV.

2. A pharmaceutical preparation for reducing harmful vascular permeability in a human subject who is considered to be at risk of fluid overload or suffering from fluid overload and who needs to reduce harmful vascular permeability, said pharmaceutical preparation comprising a tetrapeptide consisting of the amino acid sequence of AQGV.

3. A pharmaceutical preparation for reducing harmful water in a human subject who is considered to be at risk of fluid overload or suffering from fluid overload and who needs to reduce harmful water, said pharmaceutical preparation comprising a tetrapeptide consisting of the amino acid sequence of AQGV.

4. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the subject has suffered severe trauma such as surgery.

5. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the subject is undergoing cancer treatment such as treatment with an anti-cancer agent or an immunomodulator.

6. The pharmaceutical preparation according to any one of claims 1 to 3, wherein the subject is considered to be suffering from capillary leak syndrome seen in drug adverse reactions.

7. The pharmaceutical preparation according to any one of claims 1 to 6, wherein the human subject has renal dysfunction.

8. The pharmaceutical preparation according to any one of claims 1 to 7, for use comprising reduced use of vasopressors.

9. The pharmaceutical preparation according to any one of claims 1 to 8, for use comprising reduced water intake.

10. The pharmaceutical preparation according to any one of claims 1 to 9, wherein the peptide is a salt selected from the group of peptide - organic acids.

11. The pharmaceutical preparation according to claim 10, wherein the peptide is a salt selected from the group of peptide - acetate, peptide - tartrate, or peptide - citrate.

12. The pharmaceutical preparation according to any one of claims 1 to 11, comprising at least 0.85 mol / L of said peptide.

13. The pharmaceutical preparation according to claim 12, comprising at least one pharmaceutically acceptable additive.

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