Intravenous infusion preparations containing istaloxime for the treatment of pre- and post-cardiogenic shock - Patent Application 20070233334

Abstract

Compositions are disclosed for intravenous infusion of istaloxime in human patients suffering from pre-cardiogenic shock or cardiogenic shock. Similarly, methods are disclosed for administering istaloxime to individuals who are symptomatic of or diagnosed with pre-cardiogenic shock or cardiogenic shock. In particular, methods are disclosed herein for treating or preventing pre-cardiogenic shock or cardiogenic shock in individuals by administering a dosing regimen of istaloxime to the individual by intravenous infusion for up to 24 hours.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 332,909, filed April 20, 2022, the entire contents of which are incorporated herein by reference.

[0002] FIELD OF THEINVENTION The present invention relates to the field of medicine, in particular to an intravenous infusion formulation containing istaloxime for use in the treatment of pre-cardiogenic shock or cardiogenic shock. [Background technology]

[0003] background The prevalence of heart failure (HF) is age-dependent, ranging from less than 2% in people under 60 years to more than 10% in people over 75 years of age [Metra & Teerlink, 2017, Lancet 390:1981-1995]. Many HF patients have a history of hypertension, coronary artery disease, cardiomyopathy, valvular disease, or a combination of these diseases [Metra & Teerlink, 2017, Lancet 390:1981-1995]. Chronic heart failure (CHF) can be differentiated from individuals who exhibit acute heart failure (AHF), which generally refers to the sudden onset or worsening of symptoms and / or signs of HF that require immediate treatment and / or hospitalization. Individuals with CHF or other pre-existing cardiomyopathies may experience a sudden deterioration in their condition and develop a specific type of AHF called acute decompensated heart failure (ADHF) [Joseph et al., 2009, Tex. Heart Inst. J. 36:510-520]. Importantly, the clinical course and prognostic outcomes of individuals with CHF are much worse after an episode of AHF or ADHF [Solomon et al., 2007, Circulation 116:1482-1487; Teneggi et al., 2018, Heart Failure Rev. 23:667-691; Joseph et al., 2009, Tex. Heart Inst. J. 36:510-520].

[0004] One of the most severe acute coronary conditions is cardiogenic shock, which is associated with high morbidity and mortality and represents a therapeutic challenge for clinicians [van Diepen et al., 2017, Circulation 136:e232-e268; Hunziker et al., Circ. Cardiovasc. Interv. 12(4):e007293; Berg et al., 2019, Circ. Outcomes 12:e005618]. Given that short-term mortality ranges from 35% to over 60% [Singh et al., 2019, Cardio. Rev. 27(4):198-201; Jentzer et al., 2019, JACC 74(17):2117-2127], interventions to prevent progression to overt cardiogenic shock are clearly needed. Other than coronary revascularization for patients presenting with acute myocardial infarction (AMI), no other interventions impact short-term survival in patients with cardiogenic shock, and no established treatment exists for patients with non-AMI cardiogenic etiology [Singh et al., 2019, Cardio. Rev. 27(4):198-201]. However, early interventions that can mitigate the clinical and hemodynamic deterioration leading to cardiogenic shock may provide an opportunity to stabilize and reverse myocardial dysfunction as well as maintain favorable hemodynamics.

[0005] The period of clinical and hemodynamic deterioration preceding cardiogenic shock is known as precardiogenic shock or, according to the Society for Cardiovascular Angiography and Intervention (SCAI) classification system, stage B cardiogenic shock [see Jentzer et al., 2019, JACC 74(17):2117-2127]. The primary goal of intervention in the precardiogenic shock phase is to arrest or reverse the negative hemodynamic spiral that ultimately leads to cardiogenic shock and death. If left untreated, precardiogenic shock leads to overt cardiogenic shock with refractory hypotension, profound changes in cellular metabolism, and end-organ failure. This transitional phase lacks the clinical and hemodynamic criteria that define cardiogenic shock, or SCAI stage C cardiogenic shock; i.e., a systolic blood pressure (SBP) of less than 90 mmHg (or vasopressor therapy to maintain SBP >90 mmHg), ≥2.2 L / min / m 2 The following criteria are considered to be critical for determining whether or not a cardiac deficiency is present: cardiac index (CI) less than 0.05, pulmonary capillary wedge pressure (PCWP) greater than 15 mmHg, and clinical evidence of end-organ hypoperfusion [Hochman et al., 1999, N. Engl. J. Med. 341(9):625-634].

[0006] Although AMI remains the most common cause of precardiogenic shock, stable hemodynamic deterioration leading to ADHF with reduced ejection fraction (HFrEF) is the most common cause of precardiogenic shock in non-AMI patients [Singh et al., 2019, Cardio. Rev. 27(4):198-201; Savarese & Lund, 2017, Cardiac Failure Rev. 3(1):7-11]. In fact, ADHF may account for up to 30% of all cardiogenic shock cases [Kar et al., 2011, J. Am Coll. Cardiol. 57(6) 688-696]. These individuals often experience a decline in disease stability or poor adherence to guideline-based therapies, triggering acute exacerbations of their condition. Treatment of ADHF and cardiogenic shock, or CHF patients with cardiogenic shock, may differ substantially from treatment of other types of cardiogenic shock, as the hemodynamic status and neurohormonal environment are often significantly different. HF patients often have marked upregulation of vasoconstrictors such as angiotensin II, endothelin 1, and norepinephrine [Milo-Cotter et al., 2011, Cardiology 119:96-105; Shah et al., 2001, Rev. Cardiovasc. Med. 2(supp. 2)S2-S6].

[0007] Regardless of the underlying etiology, it has been reported that unloading left ventricular (LV) filling pressure significantly reduces LV end-diastolic wall stress and decompresses the microvasculature, thereby increasing myocardial blood flow to the endocardial layer and preserving LV systolic function [Kapur et al., 2013, Circulation 128(4):328-336]. Therefore, to prevent deterioration from pre-cardiogenic shock to overt cardiogenic shock, pharmacological interventions that can stabilize the failing LV and improve myocardial contractility and hemodynamics without increasing work or myocardial oxygen demand are most desirable. Currently, most pharmacological interventions, including inotropes (e.g., dobutamine, milrinone) and vasoactive agents (e.g., norepinephrine), as well as new inotropes under development, have not been shown to reduce mortality despite transient improvements in hemodynamics. Furthermore, the treatment of cardiogenic shock is complicated by the heterogeneity of the underlying pathophysiological mechanisms that cause the condition, and current medical treatments and interventions fail to adequately account for pre-cardiogenic shock and cardiogenic shock treatments that properly account for individual patient variability. Thus, there is an unmet need for agents to treat individuals suffering from pre-cardiogenic shock that prevent the hemodynamic deterioration that leads to overt cardiogenic shock without increasing mortality.

[0008] One compound currently being investigated for the treatment of AHF patients is istaroxime (PST 2744), an androstenedione derivative that is chemically unrelated to cardiac glycosides. Istaroxime has the potential to overcome the problems of previous and existing therapies used to treat AHF patients. Istaroxime exerts its effect through a dual mechanism of action: 1) Na + / K + -Inhibition of sarcoplasmic reticulum calcium ATPase activity, thereby increasing intracellular calcium and enhancing the force of contraction of cardiomyocytes (inotropy); and 2) activation of the sarcoplasmic reticulum calcium ATPase isoform (SERCA2a), thereby improving both myocardial relaxation (diastolic function) and contractility and potentially reducing the risk of arrhythmias.

[0009] One particular trial that investigated the effect of istaloxime in patients with AHF was the HORIZON-HF trial [see Gheorghiade et al., JACC, 51(23):2276-2285]. In this study, 120 patients hospitalized with ADHF and reduced LV systolic function were administered istaloxime at increasing doses (i.e., 0.5-1.0-1.5 μg / kg / min) over 6 hours. The primary endpoint of the study was the change from baseline in PCWP at 6 hours, which revealed a dose-dependent improvement in PCWP between treatment cohorts compared to the placebo group. However, this improvement in PCWP plateaued after 3 hours and remained constant from 3 to 6 hours after the start of the infusion. The results also showed a trend toward a decrease in HR during the 6-hour infusion, but a slight dose-dependent increase in SBP. However, this study did not include ADHF patients with persistent hypotension (mean baseline SBP was 116 mmHg; patients with SBP <90 were specifically excluded) or cardiogenic shock or preclinical shock, and did not demonstrate the efficacy of istaloxime in increasing SBP to the degree necessary to alleviate the hypotension associated with ADHF patients with precardiogenic shock.

[0010] WO 2020 / 180356 A9 discloses another clinical trial investigating long-term infusion of istaloxime in 120 patients with ADHF. In this study, two doses of istaloxime (0.5 μg / kg / min and 1.0 μg / kg / min) were infused for up to 24 hours. The primary endpoint of this study was the E / Ea ratio, which was found to improve in both treatment groups compared to the placebo group. In contrast to what the results of the Horizon study suggested, the long-term infusion of istaloxime showed significant improvements in most of the diastolic function parameters measured 6 hours after infusion. However, this study only included ADHF patients with SBP in the range of 90 mmHg to 120 mmHg, thus excluding patients presenting with precardiogenic shock or cardiogenic shock.

[0011] Thus, there is a clear but unmet need to treat pre-cardiogenic shock patients to stabilize the failing LV and prevent the hemodynamic and therefore systemic metabolic deterioration that leads to overt cardiogenic shock. Summary of the Invention

[0012] Summary of the Invention Described herein is a pharmaceutical composition for use in a method for treating pre-cardiogenic shock or cardiogenic shock, comprising istaloxime formulated for administration to a subject.In certain embodiments, administration is by intravenous infusion and for a period of up to about 24 hours, thereby improving the individual's systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure, and other parameters of cardiac function.For example, improvement of cardiac function can be measured by the change in SBP or SBP area under the curve (AUC) from baseline 6 hours and / or 24 hours after initiation of infusion.An individual suffering from pre-cardiogenic shock or cardiogenic shock can show improvement in cardiac function for a period of up to 24 hours after administration of istaloxime (e.g., by intravenous infusion). Surprisingly, it was discovered that individuals suffering from pre-cardiogenic shock administered istaloxime by intravenous infusion exhibited a concomitant increase in both cardiac index and blood pressure (e.g., systolic blood pressure), which is unique and has not been observed with any conventional intravenous infusion administered to individuals suffering from pre-cardiogenic shock or cardiogenic shock.

[0013] One embodiment of the invention features a pharmaceutical composition for use as a medicament in the treatment or prevention of early cardiogenic shock or cardiogenic shock in an individual. The individual is defined as suffering from acute heart failure with a systolic blood pressure of less than about 90 mmHg for a first period of time of at least 1 hour. The pharmaceutical composition includes a pharmaceutical acceptable carrier and istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof. The pharmaceutical composition is formulated for administration by intravenous infusion at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min for a second period of at least about 3 hours.

[0014] In some embodiments, one or more parameters of cardiac function in an individual are measured, such as blood pressure. In another embodiment, the blood pressure is systolic blood pressure, and administration of the pharmaceutical composition increases the systolic blood pressure above baseline. In other embodiments, the one or more parameters of cardiac function in an individual further include cardiac index, left atrial area, stroke volume, left ventricular end systolic volume, left ventricular end diastolic volume, or any combination thereof. In some embodiments, the acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome. In other embodiments, the individual's heart rate is about 75 beats / min to about 150 beats / min, or about 60 bpm to about 150 bpm if the individual is administered a beta blocker.

[0015] In some embodiments, istaloxime or a pharma- ceutically acceptable salt, solvate or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min. In other embodiments, the first period is at least about 2 hours, or at least about 6 hours, or at least about 24 hours. In some embodiments, the individual has at least one of the following: dyspnea at rest or with minimal exertion, congestion on chest x-ray or lung ultrasound with brain natriuretic peptide less than about 400 pg / mL or N-terminal pro b-type natriuretic peptide of at least 1,400 pg / mL, or a left ventricular ejection fraction of less than about 40%, or an echocardiogram confirming an ejection fraction of less than about 40%. In yet another embodiment, one or more parameters of cardiac function are selected from the group consisting of cardiac rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatine clearance, deceleration gradient, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide level (BNP), NT-pro-BNP level, troponin level, venous lactate level, echocardiographic measurements, left ventricular end diastolic dimension (EDD), left ventricular end systolic dimension (ESD), left ventricular end diastolic volume (EDV), left ventricular Further comprising: end systolic volume (ESV), left atrial dimension (LAD), left atrial area (LAA), left atrial volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annular systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

[0016] In other embodiments, the pharmaceutical composition is selected from the group consisting of an ACE inhibitor (e.g., lisinopril or ramipril), an angiotensin receptor blocker (ARB) (e.g., valsartan, candesartan, olmesartan, telmisartan or losartan), a diuretic (e.g., furosemide, bumetanide, torasemide, metolazone, an aldosterone antagonist or a thiazide), a Ca channel blocker, a beta blocker (e.g., carvedilol or metoprolol), a digitalis, an NO donor, a vasodilator, In another embodiment, the pharmaceutical composition comprises one or more additional therapeutically active ingredients, such as, but not limited to, an anti-inflammatory agent (e.g., hydralazine, amlodipine, felodipine, diltiazem, and verapamil), a SERCA2a stimulator, a neprilysin (NEP) inhibitor, a myosin filament activator, a recombinant relaxin-2 mediator, a recombinant NP protein, an activator of soluble guanylate cyclase (sGC), and / or a beta arrestin ligand of the angiotensin II receptor (e.g., sacubitril). In another embodiment, the pharmaceutical composition comprises saline as a pharma- ceutical acceptable carrier, and istartroxime is reconstituted from a lyophilized powder comprising istartroxime in admixture with a bulking agent.

[0017] In another aspect of the present invention, provided herein is a pharmaceutical composition for use as a medicament in the treatment of pre-cardiogenic shock or cardiogenic shock in an individual. The pharmaceutical composition comprises a pharmaceutical carrier and istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof. Istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min for at least about 6 hours, and administration improves blood pressure and cardiac output. In some embodiments, istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min for at least about 24 hours.

[0018] In another embodiment, the blood pressure is systolic blood pressure, which can be measured by a sphygmomanometer or an arterial line. In some embodiments, administration of the pharmaceutical composition increases systolic blood pressure above baseline by 6 hours after the start of intravenous infusion. In some embodiments, administration of the pharmaceutical composition to an individual results in (a) an increase in cardiac index; (b) a decrease in left atrial area; (c) an increase in stroke volume; (d) a decrease in left ventricular end diastolic volume; (e) a decrease in left ventricular end diastolic volume; or (f) any combination of (a)-(e). In some embodiments, the pharmaceutical composition includes saline as a pharmacologic acceptable carrier, and istaloxime is reconstituted from a lyophilized powder that includes istaloxime mixed with a bulking agent. In another embodiment, the individual is undergoing therapeutic treatment with one or more therapeutically active ingredients, such as, but not limited to, ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin 2 mediators, recombinant NP protein, activators of soluble guanylate cyclase (sGC), and / or beta arrestin ligands of the angiotensin II receptor.

[0019] Another aspect of the invention features a method of treating or preventing premature cardiogenic shock or cardiogenic shock in an individual. The method includes the steps of subjecting an individual suffering from acute heart failure, determining that the individual's systolic blood pressure is less than about 90 mmHg for a first period of at least about 1 hour, and administering to the individual a therapeutically effective amount of a pharmaceutical composition. The pharmaceutical composition includes a pharma- ceutically acceptable carrier and istaloxime or a pharma- ceutical acceptable salt, solvate or hydrate thereof, and is administered by infusion at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min for a second period of at least about 3 hours. In such a method, administration of the pharmaceutical composition increases both systolic cardiac function and cardiac output above baseline, the increases being measurable by a third period after the start of the intravenous infusion, thereby treating or preventing premature cardiogenic shock or cardiogenic shock in the individual.

[0020] In some embodiments, the method comprises measuring one or more parameters of cardiac function in an individual, such as blood pressure, or preferably systolic blood pressure.In some embodiments, administration of the pharmaceutical composition causes systolic blood pressure to increase above baseline, and the third period is about 6 hours.In another embodiment, blood pressure is measured as the area under the systolic blood pressure curve, and administration of the pharmaceutical composition causes systolic blood pressure area under the curve to increase above baseline--the third period is about 6 hours.In yet another embodiment, the one or more parameters of cardiac function in an individual further comprises cardiac index, left atrial area, stroke volume, left ventricular end systolic volume, left ventricular end diastolic volume, or any combination thereof.In yet another embodiment, acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome.

[0021] In certain embodiments, the method includes determining that the individual's heart rate is about 75 beats / min to about 150 beats / min, or about 60 bpm to about 150 bpm if the individual is administered a beta blocker. In certain embodiments, istaloxime or a pharma- ceutically acceptable salt, solvate or hydrate is administered at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min. In another embodiment, the first period is at least about 2 hours, or at least about 6 hours, or at least about 24 hours. In certain embodiments, the individual is a human being at least 18 years of age. In another embodiment, the individual has at least one of the following: dyspnea at rest or with minimal exertion, congestion on chest x-ray or lung ultrasound with brain natriuretic peptide less than about 400 pg / mL or N-terminal pro b-type natriuretic peptide of at least 1,400 pg / mL, or a left ventricular ejection fraction less than about 40%, or an echocardiogram confirming an ejection fraction less than about 40%.

[0022] In certain embodiments of the method, one or more parameters of cardiac function are selected from the group consisting of cardiac rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatine clearance, deceleration gradient, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide level (BNP), NT-pro-BNP level, troponin level, venous lactate level, echocardiographic measurements, left ventricular end diastolic dimension (EDD), left ventricular end systolic dimension (ESD), left ventricular end diastolic volume (EDV), left ventricular vasoconstriction (V ... Further comprising: end systolic volume (ESV), left atrial dimension (LAD), left atrial area (LAA), left atrial volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annular systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof. In another embodiment, the individual is receiving treatment with an ACE inhibitor (e.g., lisinopril or ramipril), an ARB (e.g., valsartan, candesartan, olmesartan, telmisartan, or losartan), a diuretic (e.g., furosemide, bumetanide, torasemide, metolazone, an aldosterone antagonist, or a thiazide), a Ca channel blocker, a beta blocker (e.g., carvedilol or metoprolol), a digitalis, an NO donor, a vasodilator (e.g., hydralazine, amlodipine, felodipine, , diltiazem, and verapamil), SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin 2 mediators, recombinant NP protein, activators of soluble guanylate cyclase (sGC), and / or beta arrestin ligands of the angiotensin II receptor (e.g., sacubitril). In another embodiment, the pharmaceutical composition comprises saline as a pharmacologic acceptable carrier, and istartroxime is reconstituted from a lyophilized powder comprising istartroxime in admixture with a bulking agent.In yet another embodiment of the method, the pharmaceutical composition comprises saline as a pharma- ceutically acceptable carrier and the isstaroxime is reconstituted from a lyophilized powder comprising isstaroxime in admixture with a bulking agent.

[0023] The invention also features a method of treating pre-cardiogenic shock in an individual, comprising the steps of: a) targeting an individual suffering from pre-cardiogenic shock with acute heart failure, where pre-cardiogenic shock comprises a systolic blood pressure of less than about 90 mmHg without end-organ hypoperfusion or myocardial infarction; b) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising: (i) a pharmaceutical acceptable carrier; and (ii) istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof, where istaloxime or a pharmaceutical acceptable salt, solvate or hydrate thereof is administered at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min, and where the administration comprises an intravenous infusion for at least about 6 hours; and c) measuring one or more parameters of cardiac function in the individual, where the one or more parameters of cardiac function comprise blood pressure. Furthermore, administration of the pharmaceutical composition elevates blood pressure above baseline, the increase being measurable up to 6 hours after the start of the intravenous infusion, thereby treating pre-cardiogenic shock in the individual.

[0024] In some embodiments of the method, blood pressure is systolic blood pressure, and administering the pharmaceutical composition increases systolic blood pressure above baseline.In another embodiment, blood pressure is measured as the area under the systolic blood pressure curve, and administering the pharmaceutical composition increases the area under the systolic blood pressure curve above baseline.In yet another embodiment, the one or more parameters of cardiac function in an individual further comprise cardiac index, left atrial area, stroke volume, left ventricular end systolic volume, left ventricular end diastolic volume, or any combination thereof.For example, administering the pharmaceutical composition can cause one or more of the following: increase in cardiac index, decrease in left atrial area, increase in stroke volume, decrease in left ventricular end diastolic volume, and / or decrease in left ventricular end diastolic volume.

[0025] These and other features and advantages of the present disclosure will become better understood with regard to the following description, appended claims, and accompanying drawings. [Brief description of the drawings]

[0026] [Figure 1] FIG. 1 is a flow chart of an exemplary study to test the effectiveness of istaloxime for use in pre-cardiogenic shock treatment.

[0027] [Diagram 2] 2 is a chart showing the change in systolic blood pressure (SBP) over time for individuals treated with istaloxime (solid area) versus placebo (hatched area). The Y-axis represents the change from baseline in SBP (mmHg) and the X-axis represents time from infusion (hours).

[0028] [Diagram 3] Figure 3 is a graph showing the change in blood pressure (BP) over time in individuals treated with istaloxime (solid line) and placebo (dashed line). Panel A shows the change in SBP from 6 hours post-infusion, and Panel B shows the change in SBP from 24 hours post-infusion. Panel C shows the mean change in diastolic blood pressure (DBP) from 96 hours post-infusion. The Y-axis of each represents the change in BP from baseline (mmHg) and the X-axis represents time since infusion.

[0029] [Figure 4] FIG. 4 is a graph showing the levels of cardiac and renal function parameters over time. Panel A shows the change in MAP for individuals treated with istaloxime (solid line) and placebo (dashed line). Panel B shows the change in blood levels of eGFR over time among individuals treated with either 1.0 μg / kg / min (light gray line), 1.5 μg / kg / min (gray line), or placebo (dark gray dashed line). Panel C shows the change in blood levels of NT-proBNP over time among individuals treated with either 1.0 μg / kg / min (light gray line), 1.5 μg / kg / min (gray line), or placebo (dark gray dashed line). DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0030] detail The compositions and methods disclosed herein provide a treatment regimen for individuals with pre-cardiogenic shock or cardiogenic shock for the first time.Surprisingly, individuals with pre-cardiogenic shock administered with ishtaroxime show a simultaneous increase in both cardiac index and blood pressure (e.g., systolic blood pressure), which is unique and has not been observed with any conventional intravenous infusion drug administered to individuals with pre-cardiogenic shock or cardiogenic shock.In some embodiments, individuals with pre-cardiogenic shock or cardiogenic shock are administered with ishtaroxime by intravenous infusion for a period of time (e.g., up to about 6 hours, or up to about 24 hours, or longer), and show an increase in systolic blood pressure by 6 hours and / or by 24 hours, compared with similar individuals (i.e., individuals with pre-cardiogenic shock or cardiogenic shock) who do not receive ishtaroxime or receive placebo. Such individuals administered istaloxime may exhibit one or more additional cardiac improvements, such as, but not limited to, increased cardiac index, decreased left atrial area, decreased left ventricular end systolic volume, and decreased left ventricular end diastolic volume, compared to such individuals prior to administration of istaloxime and / or compared to individuals prior to or suffering from cardiogenic shock who are not administered istaloxime. Provided herein is a composition comprising istaloxime suitable for administration to individuals with pre-cardiogenic shock or cardiogenic shock symptoms.In certain embodiments, istaloxime is administered to these individuals by intravenous infusion for up to 24 hours to increase systolic blood pressure and alleviate pre-cardiogenic shock or cardiogenic shock symptoms.For example, in some embodiments, istaloxime is administered to individuals who show pre-cardiogenic shock without end-organ hypoperfusion or acute coronary syndrome evidence to treat pre-cardiogenic shock and prevent progression to overt cardiogenic shock.

[0031] The compositions and methods disclosed herein are described in more detail below.

[0032] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art to which this invention belongs. Unless otherwise specified, standard techniques are used. Similar or equivalent methods and materials to those described herein can be used to carry out or test this disclosure, but suitable methods and materials are described below. Materials, methods and examples are illustrative only and are not intended to be limiting. All publications, patents and other materials described herein are incorporated by reference in their entirety.

[0033] As used herein, the singular forms "a," "the," and similar expressions include the plural forms unless the context clearly indicates otherwise.

[0034] The term "about" refers to the variation in the numerical value of a measurement, e.g., volume, time, pressure, concentration, etc., due to the typical error rate of the device used to obtain the measurement. In certain embodiments, the term "about" means within 5% of the reported numerical value, preferably, the term "about" means within 3% of the reported numerical value.

[0035] As used herein, the term "cardiogenic shock" refers to a condition in an individual, such as a human patient, in which the heart is unable to pump enough blood and oxygen to the brain, kidneys and other vital organs, resulting in end-organ hypoperfusion. Overt "cardiogenic shock" or SCAI Stage C "cardiogenic shock" is characterized by a systolic blood pressure of less than about 90 mmHg (hypotension), a systolic blood pressure of less than about 2.2 L / min / m 2"Precardiogenic shock", SCAI stage B "precardiogenic shock", or "early cardiogenic shock" refers to a state in which an individual has not yet developed overt "cardiogenic shock" and is defined by a systolic blood pressure of less than approximately 90 mmHg without evidence of end-organ hypoperfusion.

[0036] The term "heart failure" refers to a clinical syndrome characterized by typical symptoms (e.g., dyspnea, ankle swelling and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by structural and / or functional cardiac abnormalities that result in reduced cardiac output and / or elevated intracardiac pressures at rest or under stress.

[0037] The terms "acute heart failure" or "AHF" are used interchangeably herein and generally refer to the sudden onset or worsening of symptoms and / or signs of HF that require immediate treatment and hospitalization. The current definition of "acute heart failure" is fairly non-specific and may include a broad range of conditions with several phenotypes characterized by different clinical symptoms, etiologies, precipitating factors, therapeutic approaches, and prognosis. Furthermore, the majority of human patients will have a subacute course of the disease with progressive worsening of signs and symptoms of HF that may develop several days prior to hospitalization.

[0038] As used herein, the term "acute decompensated heart failure" refers to a sudden worsening of the signs and symptoms of heart failure in humans, which generally include shortness of breath, swelling of the legs or feet, and fatigue.

[0039] As used herein, the term "acute coronary syndrome" refers to a sudden reduction or blockage of blood flow to the heart. A common example of an "acute coronary syndrome" is a myocardial infarction (heart attack).

[0040] The terms "chronic heart failure" or "CHF" are used interchangeably herein and refer to the current clinical classification of chronic HF based on the presence of signs and symptoms of HF and left ventricular ejection fraction (LVEF) in an individual, such as a human patient, with three recognized categories: "heart failure with reduced ejection fraction" or "HFrEF", characterized by an LVEF of less than about 40%; "heart failure with moderate ejection fraction" or "HFmEF" or "HFmrEF", characterized by an LVEF of about 40% to about 49%; and "heart failure with preserved ejection fraction" or "HFpEF", characterized by an LVEF of about 50% or greater. The terms "HFmrEF" and "HFpEF" include two additional criteria, namely elevated natriuretic peptide levels (BNP>35 pg / mL and / or NT-proBNP>125 pg / mL) associated with evidence of structural and / or functional heart disease (evidence of left ventricular hypertrophy and / or left atrial enlargement and / or diastolic dysfunction).

[0041] As used herein, the term "hypotension" is defined as a systolic blood pressure (SBP) that is less than 90 mmHg or a mean arterial blood pressure (MAP) that is less than about 60 mmHg or a decrease from baseline of more than 30 mmHg.

[0042] As used herein, the term "end-organ hypoperfusion" refers to clinical signs such as chills, contractures of the limbs, decreased urinary output, confusion, elevated lactate or elevated creatinine.

[0043] The term "treatment" refers to any indication of success in treating or improving a disease or condition in an individual. Treating can include, for example, reducing or alleviating the severity of one or more symptoms of a disease or condition, or reducing the frequency with which a symptom, such as a disease, defect, disorder, or adverse condition, is experienced by an individual, such as a human patient.

[0044] The term "prevention" refers to the prevention of a disease or condition, such as pre-cardiogenic shock or cardiogenic shock, in an individual, such as a human patient. For example, if an individual at risk of developing pre-cardiogenic shock or cardiogenic shock is treated with the method of the present invention and does not subsequently develop pre-cardiogenic shock or cardiogenic shock, the disease will be prevented in that individual.

[0045] The term "treatment or prevention" is sometimes used herein to refer to a method that results in some level of treatment or amelioration of a disease or condition, and contemplates a range of outcomes directed to that end, including, but not limited to, complete prevention of the condition.

[0046] As used herein, the term "pharmaceutically acceptable" salts, solvates, hydrates, or esters refers to salts, solvates, hydrates, or ester forms of the active ingredient that are compatible with all other ingredients of the pharmaceutical composition and are not deleterious to the subject to which the composition is to be administered.

[0047] As used herein, the term "pharmaceutical acceptable carrier" refers to a chemical composition with which an istaloxime compound can be combined and which, after combination, can be used to administer the compound to a mammal.

[0048] The term "intravenous infusion" refers to the administration or delivery of a liquid substance directly into a mammalian vein. Typically, the "infusion" uses only pressure supplied by gravity.

[0049] The term "parameter" as used herein to refer to measuring cardiac function refers to any cardiac function that can be observed or measured using suitable measurement techniques available in the art. A non-exhaustive list of "parameters" of cardiac function includes cardiac rate (HR), blood pressure (BP), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), area under the systolic blood pressure curve (SBP AUC), creatine clearance, deceleration slope, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide level (BNP), NT-pro-BNP level, troponin level, venous lactate level, echocardiographic measurements, left ventricular end diastolic dimension (EDD), left ventricular end systolic dimension (ESD), left ventricular end diastolic volume (EDV), left ventricular end systolic volume (ESV), left atrial dimension (LAD), left atrial area (LAA), left atrial volume (LAV ... These include volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annular systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR) and inferior vena cava diameter (IVC), etc. As will be appreciated by those skilled in the art, measuring one or more "parameters" of cardiac function can be used to detect cardiac dysfunction in comparison to average normal parameters, and can also be used to determine whether cardiac function has improved after or during treatment.

[0050] The term "therapeutically active" or "active" ingredient or compound refers to a substance that provides a beneficial effect to an individual to whom it is administered. A "therapeutically effective amount" or "therapeutically effective dose" is the amount of a composition or active ingredient sufficient to provide a beneficial effect to the individual to whom it is administered.

[0051] explanation The present invention is directed to the administration of istaloxime to individuals, such as human patients, to treat or prevent pre-cardiogenic shock or cardiogenic shock. In a preferred embodiment, the route of administration of istaloxime is by intravenous infusion. For individuals exhibiting pre-cardiogenic shock symptoms, istaloxime infusion is administered to treat pre-cardiogenic shock (SCAI stage B) and prevent progression to overt cardiogenic shock. In some embodiments, istaloxime infusion can be administered to individuals exhibiting overt cardiogenic shock (SCAI stage C) to alleviate symptoms and improve cardiac function.

[0052] In some embodiments, the compositions and treatment methods alleviate symptoms associated with pre-cardiogenic shock or cardiogenic shock in individuals with acute decompensated heart failure (ADHF), which is the acute exacerbation of underlying systolic heart failure, for example, due to arterial hypertension, ischemic heart disease or dilated cardiomyopathy.In some embodiments, pre-cardiogenic shock or cardiogenic shock is not caused by acute coronary syndrome, such as myocardial infarction.Individuals with pre-cardiogenic shock or early cardiogenic shock may exhibit persistent hypotension, characterized by a systolic blood pressure (SBP) of less than about 90 mmHg, without evidence of acute coronary syndrome and without evidence of end-organ hypoperfusion.Therefore, administering istaloxime to these individuals by intravenous infusion increases SBP, thereby alleviating the hypotension associated with pre-cardiogenic shock and preventing the progression to overt cardiogenic shock of SCAI stage C. In other cases, individuals with pre-cardiogenic or early cardiogenic shock may present with normotension, with evidence of end-organ hypoperfusion, and without evidence of acute coronary syndrome.

[0053] In some embodiments, istaloxime infusion is about 3 hours to up to 24 hours or more, for example, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, or longer. For example, the infusion can be up to 24 hours or longer. In some embodiments, the duration of infusion is about 6 hours to about 24 hours, or about 12 hours to about 24 hours, or about 18 hours to about 24 hours. In other embodiments, the duration of the infusion is greater than about 24 hours, e.g., 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, 72 hours, 78 hours, 84 hours, 90 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, or more. It is understood that the infusion of istaloxime improves the cardiac function of an individual, for example, increases SBP, within about 24 hours from the start of the infusion; preferably, the improvement occurs within about 12 hours from the start of the infusion, or within about 6 hours from the start of the infusion, or within about 3 hours from the start of the infusion, or within about 1 hour from the start of the infusion.For example, in some embodiments, individuals who are administered istaloxime and are experiencing pre-cardiogenic shock or cardiogenic shock, compared with individuals who are administered placebo and are experiencing pre-cardiogenic shock or cardiogenic shock, show an improvement in SBP within 6 hours from the start of the infusion.

[0054] Istaroxime has the following structural formula (I): [ka] It is an inotropic compound having the formula:

[0055] It is therefore an object of the present invention to utilize isstaroxime, or a pharma- ceutically acceptable salt or ester, hydrate, solvate, or polymorphic form thereof, in a pharmaceutical preparation to treat or prevent pre-cardiogenic shock or cardiogenic shock in an individual. In a preferred embodiment, isstaroxime is administered to an individual to treat pre-cardiogenic shock and to prevent the individual's condition from deteriorating to overt cardiogenic shock.

[0056] Also disclosed herein is a pharmaceutical composition comprising istaloxime in admixture with at least one pharma- ceutically acceptable vehicle and / or excipient. In a preferred embodiment, the pharmaceutical composition is formulated for administration to an individual by injection, preferably, administration is by intravenous injection.

[0057] The effectiveness of the present invention for treatment prior to cardiogenic shock can be evaluated in an exemplary clinical trial summarized in Table 1 and FIG. 1 below. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9]

[0058] To determine the effectiveness of istaloxime administration in individuals suffering from precardiogenic or cardiogenic shock, there are several cardiac function parameters that can be measured to determine whether the condition is improved or prevented. In a preferred embodiment, SBP is measured using standard equipment in the art, such as but not limited to a sphygmomanometer or an arterial line. In certain embodiments, the cardiac function parameter measured is the SBP area under the curve (SBP AUC), which is determined by multiplying the SBP value or the change in SBP value over a specific period of time. SBP can be monitored / measured using any standard technology in the art, such as but not limited to a sphygmomanometer or an arterial line. In particular, an arterial line is a thin, flexible tube that is inserted into an artery (e.g., the radial or ulnar artery in the wrist, the brachial artery in the elbow, the femoral artery in the groin, or the dorsal artery in the foot) and measures blood pressure in real time via connection to a pressure transducer. ABP AUC is generally measured from baseline (time 0) to a particular endpoint, e.g., 1 hour, 2 hours, 3 hours, 6 hours, 12 hours, 18 hours, or 24 hours after initiation of istaloxime administration. For example, SBP AUC (0-6) or SBP AUC (0-24) is measured. Improvement in SBP AUC within this time period can be considered to treat pre-cardiogenic shock or prevent overt cardiogenic shock in an individual. Furthermore, an increase in the change in SBP 10 minutes, 20 minutes, 30 minutes, 40 minutes, 50 minutes, 1 hour, 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 18 hours, 24 hours or more after infusion, e.g., from the start of istaloxime administration, can be considered to treat pre-cardiogenic shock or prevent overt cardiogenic shock in an individual.

[0059] In another embodiment, echocardiography is performed on an individual according to international standards (see, for example, Lang et al., 2005, J. Am. Soc. Echocardiogr. 18(12):1440-1463; Negueh et al., 2009, Eur. J. Echocardiogr. 10(2):165-193; Evangelista et al., 2008, Eur. J. Echocardiogr. 9(4):438-448). Echocardiography is within the competence of a skilled physician or sonographer. For example, echocardiography can be performed during screening of potential participants or when an individual is admitted to a medical facility. In other embodiments, echocardiography is performed at baseline or 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours after the start of the infusion. After 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 72 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days, 15 days, 16 days, 17 days, 18 days, 19 days, 20 days, 21 days, 22 days, 23 days, 24 days, 25 days, 26 days, 27 days, 28 days, 29 days, or 30 days. In some embodiments, echocardiography is monitored during the infusion and values ​​are recorded 24 hours and 30 hours after the infusion. In other embodiments, echocardiographic values ​​are recorded 12, 24, 48, 72, and 96 hours after injection. Table 2 summarizes exemplary echocardiographic and other cardiac function parameters. [Table 2-1] [Table 2-2] [Table 2-3]

[0060] In one embodiment, an individual pre- or suffering from cardiogenic shock is administered istaloxime, and the individual's SBP AUC (0-6) increases by at least about 20 mmHg·hr within about 6 hours after initiation of administration of istaroxime, e.g., increases by 20 mmHg·hr, 25 mmHg·hr, 30 mmHg·hr, 35 mmHg·hr, 40 mmHg·hr, 45 mmHg·hr, 50 mmHg·hr or more within about 6 hours after initiation of administration of istaroxime; preferably, SBP AUC (0-6) is elevated by at least about 30 mmHg·hour; more preferably, it is elevated by at least about 40 mmHg·hour or at least about 50 mmHg·hour. In another embodiment, an individual prior to or suffering from cardiogenic shock is administered istaloxime, and the individual's SBP AUC (0-24) rises by at least about 200 mmHg·hr within about 24 hours after initiation of administration of istaroxime, e.g., rises by 200 mmHg·hr, 210 mmHg·hr, 220 mmHg·hr, 230 mmHg·hr, 240 mmHg·hr, 250 mmHg·hr, 260 mmHg·hr, 270 mmHg·hr, 280 mmHg·hr, 290 mmHg·hr, 300 mmHg·hr or more within about 24 hours after initiation of administration of istaroxime; preferably, SBP AUC (0-24) is elevated by at least about 220 mmHg·hour; more preferably, it is elevated by at least about 250 mmHg·hour or at least about 280 mmHg·hour. Individuals in pre-cardiogenic shock or in cardiogenic shock who receive istaroxime by infusion have a lower mean SBP AUC (0-6)at least about 30% greater, e.g., 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70% or greater, than (0-6) and preferably, the individual has a mean SBP AUC (0-6) SBP AUC at least 40% greater than (0-6) and more preferably, the individual has a mean SBP AUC (0-6) SBP AUC at least 50% greater than (0-6) Mean AUC for individuals with or without istaloxime (0-6) SBP AUC at least 60% greater than (0-6) Mean AUC for individuals with or without istaloxime (0-6) SBP AUC at least 70% greater than (0-6) In another embodiment, individuals pre- or suffering from cardiogenic shock who are administered istaroxime by infusion have a mean SBP AUC (0-24) at least about 10% greater, e.g., 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40% or greater than the SBP AUC (0-24) and preferably, the individual has a mean SBP AUC (0-24) SBP AUC at least 20% greater than (0-24) and more preferably, the individual has a mean SBP AUC (0-24)SBP AUC at least 30% greater than (0-6) Mean AUC for individuals with or without istaloxime (0-24) SBP AUC at least 40% greater than (0-6) has.

[0061] In another embodiment, the change in SBP is at least about 1 mmHg increase within about 1 hour after infusion starts, or at least about 3 mmHg increase within about 3 hours after infusion starts, or at least about 8 mmHg increase within about 6 hours after infusion starts, or at least about 10 mmHg increase within about 24 hours after infusion starts.For example, in certain embodiments, the adjusted increase in SBP 6 hours after infusion is at least about 8 mmHg, for example, 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg or 15 mmHg; preferably, the adjusted increase in SBP is at least about 10 mmHg 6 hours after infusion starts. In another embodiment, the adjusted increase in SBP is at least about 10 mmHg, e.g., 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, or 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg, 24 hours after infusion; preferably, the adjusted increase in SBP is at least about 12 mmHg, 24 hours after infusion; more preferably, it is at least about 15 mmHg.

[0062] In addition to the increase in SBP, individuals with pre-cardiogenic shock or cardiogenic shock who receive estaloxime show improvement in one or more additional parameters of cardiac function, including but not limited to increased cardiac index (CI), decreased left atrial area, increased stroke volume, decreased left ventricular end systolic volume and decreased left ventricular end diastolic volume.Interestingly, estaloxime administration improves by increasing stroke rate, not by increasing heart rate.Thus, estaloxime increases cardiac output in these individuals without additional stress on the heart due to increased cardiac rate.

[0063] In another embodiment, blood is collected from an individual, for example during prescreening, at baseline and / or at various time points after infusion, for example 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 5 days, 10 days, 30 days after the start of istaloxime administration. This blood can be used for various laboratory tests to evaluate the individual's body chemistry, hematology, cardiac protein values, and pharmacokinetics of istaloxime infusion. Exemplary chemistries include, but are not limited to, electrolytes, liver function tests, lipids, creatinine (and estimated glomerular filtration rate (eGFR)), urea, blood urea nitrogen (BUN), glucose, albumin, and protein. Exemplary hematology includes, but is not limited to, complete blood count with differential. Suitable cardiac proteins include cardiac troponin I (cTNI), cardiac troponin T (cTNT), N-terminal pro-b-type natriuretic peptide (NT-proBNP), and brain natriuretic peptide (BNP). The respective values ​​of most of these proteins provide the practitioner with information regarding cardiac function, and the measurement and / or interpretation of these values ​​is well within the skill of the art. For example, in one embodiment, within about 6 hours after infusion or within about 24 hours after administration, the value of NT-proBNP is reduced compared to baseline. The values ​​of some parameters are not a direct measure of cardiac function, but are used to assess renal function. While many inotropic or vasopressor agents have been shown to adversely affect renal function, individuals administered istaloxime show improved cardiac function without adverse effects on renal function. For example, in one embodiment, in individuals before or with cardiogenic shock who are administered istaloxime for 24 hours, the value of eGFR, an indicator of renal function, is increased within about 6 hours after infusion or within about 24 hours after infusion compared to baseline.

[0064] Further cardiac function parameters include chest congestion, which can be measured by chest X-ray, lung ultrasound, or other standard equipment in the art, and improvement in the level of chest congestion after istaloxime infusion indicates pre-cardiogenic shock and / or treatment or prevention of cardiogenic shock.Furthermore, cardiac nights, mean arterial pressure (MAP), dyspnea or labored breathing, need for intravenous vasopressor administration, other inotropic administration and / or mechanical cardiac or renal support, symptoms of worsening heart failure, occurrence of adverse events (AE) or serious adverse events (SAE), need for intensive care unit admission, discharge from intensive care unit, and death.In some embodiments, within about 24 hours of infusion, MAP is elevated compared to baseline.

[0065] Pharmaceutical Compositions Pharmaceutical compositions and formulations for intravenous infusion comprising istaloxime or a pharma- ceutically acceptable salt, solvate or hydrate thereof in admixture with at least one conventional pharma- ceutically acceptable carrier and / or vehicle and / or excipient are generally known in the art.

[0066] The pharmaceutical compositions and preparations for intravenous infusion can be formulated in any manner and can be administered in various unit dosage forms depending on the condition or disease and the extent of the disease, the general health of each patient, the resulting preferred method of administration, etc. Details regarding formulation and administration techniques are well described in the scientific and patent literature [see, for example, the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA (“Remington's”)].

[0067] The preparation can be conveniently provided in unit dosage form and can be manufactured by any method known in the art of pharmacy.The amount of active ingredient that can be combined with carrier or medium material to produce single dosage form varies according to the subject to be treated and specific mode of administration.The amount of active ingredient that can be combined with carrier material to produce single dosage form is generally the amount of compound that produces therapeutic effect.

[0068] The pharmaceutical preparations as provided herein can be manufactured according to any method known in the art for the manufacture of pharmaceuticals.Such preparations can contain additional agents such as preservatives or stabilizers.The preparations can be mixed with non-toxic pharmaceutically acceptable carriers or additives suitable for manufacture.The preparations can contain one or more diluents, emulsifiers, preservatives, buffers, additives, etc., and can be provided in the form of liquid, powder, emulsion, lyophilized powder, etc.

[0069] Aqueous suspensions may contain an activator (e.g., a composition used to practice the uses and methods provided herein) in admixture with additives suitable for the manufacture of aqueous suspensions. Such additives include suspending agents, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth, and gum acacia, and dispersing or wetting agents, such as naturally occurring phosphatides (e.g., lecithin), condensation products of alkylene oxides with fatty acids (e.g., polyoxyethylene stearates), condensation products of ethylene oxide with long chain aliphatic alcohols (e.g., heptadecaethyleneoxycetanol), condensation products of ethylene oxide with partial esters derived from fatty acids and hexitols (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). Aqueous suspensions may also contain one or more preservatives, such as ethyl or n-propyl p-hydroxybenzoate. Preparations may be adjusted for osmolarity.

[0070] According to the present invention, istaloxime is administered by intravenous (IV) administration. These formulations may include a solution of the active agent dissolved in a pharma- ceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water, dextrose in water, and Ringer's solution, isotonic sodium chloride. These solutions are sterile and generally free of undesirable substances. These formulations may be sterilized by conventional, well-known sterilization techniques. The formulations may include pharma- ceutically acceptable auxiliary substances such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, necessary to approximate physiological conditions, e.g., sodium acetate, sodium chloride, potassium chloride, calcium chloride, and sodium lactate. The concentration of the active agent in these formulations may vary widely and is selected primarily based on fluid volumes, viscosities, body weight, and the like, depending on the particular mode of administration selected and the needs of the patient. Administration is by bolus or continuous infusion (e.g., substantially uninterrupted introduction into the blood vessels over a specified period of time).

[0071] The istaloxime provided herein can be lyophilized. Provided herein is a stable lyophilized formulation comprising the composition provided herein, which can be produced by lyophilizing a solution comprising the pharmaceutical agent provided herein and a bulking agent, such as mannitol, trehalose, raffinose, lactose and sucrose, or a mixture thereof. There are many other conventional lyophilizing agents. Among sugars, lactose is the most common. Also used are citric acid, sodium carbonate, EDTA, benzyl alcohol, glycine, sodium chloride, etc. [see, for example, Journal of Excipients and Food Chemistry Vol. 1, Issue 1 (2010) pp 41-54; US patent app. no. 20040028670]. In a preferred embodiment, istaloxime can be produced as a lyophilized powder for injection, following the teachings of CN103315968.

[0072] According to the present invention, istaloxime provided herein can be administered for preventive and / or therapeutic treatment. In therapeutic applications, the composition is administered to a subject already suffering from a condition or disease in an amount sufficient to treat, prevent, cure, alleviate or partially arrest the clinical symptoms of the condition or disease and its complications (i.e., a "therapeutically effective amount"). For example, in another embodiment, the pharmaceutical composition provided herein is administered in an amount sufficient to treat, prevent or ameliorate in an individual in need thereof. The amount of pharmaceutical composition sufficient to achieve this is defined as a "therapeutically effective dose". The administration schedule and amount, i.e., "administration regimen", effective for this use depends on various factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient's physical condition, age, etc. The mode of administration is also taken into consideration when calculating the administration regimen for a patient.

[0073] The dosing regimen will also take into account pharmacokinetic parameters well known in the art, such as bioavailability, metabolism and clearance of the active agent (see, e.g., Hidalgo-Aragones, 1996, Steroid Biochem. Mol. Biol. 58:611-617; Groning, 1996, Pharmazie 51:337-341; Fotherby, 1996, Contraception 54:59-69; Johnson, 1995, J. Pharm. Sci. 84:1144-1146; Rohatagi, 1995, Pharmazie 50:610-613; Brophy, 1983, Eur. J. Clin. Pharmacol. 24:103-108; the latest Remington's, supra). The state of the art allows the clinician to determine the dosage regimen according to the individual patient, the active agent and the disease or condition to be treated. Guidelines provided for similar compositions used as pharmaceuticals can be used as a guide to determine whether the dosage regimen, i.e., the dosage schedule and dosage level, administered when practicing the methods as provided herein is correct and appropriate.

[0074] Single or multiple administrations of the formulation may be made depending on the dosage and frequency required by the patient's pre-cardiogenic shock or cardiogenic shock symptoms. The formulation should provide a sufficient amount of active agent to effectively treat or prevent or ameliorate the condition, disease or symptoms described herein. Correct treatment of pre-cardiogenic shock or cardiogenic shock may be expected to selectively improve symptoms and reduce the incidence of undesirable side effects caused by drugs available during hospitalization or after discharge by selectively normalizing the reduced biochemical activity underlying some patients' symptoms. The term prophylaxis is applicable when continuous monitoring of pulmonary pressure is possible with a suitable chronically implantable device that provides estimates of SBP, SBP AUC (e.g., up to 6 hours or up to 24 hours) or other cardiac function parameters described elsewhere herein.

[0075] In certain embodiments, an effective amount of istaloxime, or a pharma- ceutically acceptable salt, solvate, or hydrate equivalent thereof, is administered to an individual suffering from a precardiogenic or cardiogenic shock condition on a dosing schedule of, for example, about 0.1 μg / kg / min to about 3.0 μg / kg / min, for example, 0.1 μg / kg / min, 0.15 μg / kg / min, 0.2 μg / kg / min, 0.25 μg / kg / min, 0.3 μg / kg / min, 0.35 μg / kg / min, 0.4 μg / kg / min, 0.45 μg / kg / min, 0.5 μg / kg / min, 0.55 μg / kg / min, 0.6 μg / kg / min, 0.7 μg / kg / min, 0.75 μg / kg / min, 0.8 μg / kg / min, 0.85μg / kg / min, 0.9μg / kg / min, 0.95μg / kg / min, 1.0μg / kg / min, 1.1μg / kg / min, 1.2μg / kg / min, 1.3μg / kg / min, 1.4μg / kg / min, 1.5μg / kg / min, 1.6μg / kg / min, 1.7μg / kg / min, 1.8μg / kg / min, 1. 9μg / kg / min, 2.0μg / kg / min, 2.1μg / kg / min, 2.2μg / kg / min, 2.3μg / kg / min, 2.4μg / kg / min, 2.5μg / kg / min, 2.6μg / kg / min, 2.7μg / kg / min, 2.8μg / kg / min, 2.9μg / kg / min, or 3.0μg / kg / min. For example, in some embodiments, istaloxime is administered by infusion at an effective dose of about 0.2μg / kg / min to about 2.0μg / kg / min, or about 0.5μg / kg / min to about 1.5μg / kg / min, or about 1.0μg / kg / min to about 1.5μg / kg / min. In certain embodiments, istaloxime is administered by intravenous infusion at an effective dose of about 1.5μg / kg / min. Alternatively, an effective dose of istaloxime may be initiated at about 1.0 μg / kg / min for about 1 to about 2 hours, which is then increased to 1.5 μg / kg / min for the remainder of the infusion unless the individual exhibits nausea or other signs of poor or inadequate drug tolerance. In another embodiment, an effective dose of istaloxime may be initiated at about 1.5 μg / kg / min for about 1 to about 2 hours, which is then increased to 1.0 μg / kg / min for the remainder of the infusion.

[0076] In one exemplary embodiment, a pharmaceutical composition is provided that includes istaloxime in lyophilized powder form. In another embodiment, the pharmaceutical composition includes istaloxime and a bulking agent (e.g., lactose) in lyophilized powder form. For example, the composition can be a lyophilized powder that includes about 0.1 to about 0.3 wt% istaloxime and about 0.7 to about 0.9 wt% lactose (e.g., 10 mg istaloxime and 50 mg lactose). The lyophilized powder can be reconstituted with any pharma- ceutically acceptable carrier, such as saline containing 0.9% NaCl, prior to intravenous infusion.

[0077] Treatment Also provided herein are pharmaceutical compositions for use as medicaments in the treatment of pre-cardiogenic shock or cardiogenic shock, as well as methods for treating individuals suffering from pre-cardiogenic shock or cardiogenic shock. In some embodiments, the individual shows symptoms of or is diagnosed with pre-cardiogenic shock SCAI stage B. In a preferred embodiment, the individual shows symptoms of or is diagnosed with pre-cardiogenic shock SCAI stage B. In a more ... Preferably, the individual exhibits persistent hypotension characterized by an SBP of about 70 mmHg to about 100 mmHg, or more preferably about 75 mmHg to about 90 mmHg, for at least 2 hours prior to screening or treatment initiation. Furthermore, the individual's SBP does not fall by more than about 7 mmHg prior to treatment initiation. The individual may also have a cardiac rhythm in the range of about 65 bpm to about 160 bpm, or preferably in the range of about 75 bpm to about 150 bpm, or if the individual is taking a beta-blocker, the cardiac rhythm may be in the range of about 60 bpm to about 150 bpm. The individual may also have a history of LVEF of less than about 40% or greater. In another embodiment, the individual has a cardiac rhythm of less than about 90 mmHg without evidence of end-organ hypoperfusion. Alternatively, in some embodiments, the individual has a cardiac rhythm of less than about 90 mmHg with evidence of end-organ hypoperfusion. In another embodiment, the individual is symptomatic or diagnosed with SCAI stage C cardiogenic shock. However, in other embodiments, treatment is directed to treating pre-cardiogenic shock and does not exhibit symptoms or be diagnosed with SCAI stage C cardiogenic shock or have no evidence of end-organ hypoperfusion. Although the individual may be a non-human animal, in a preferred embodiment, the individual is a human patient, such as a human patient exhibiting pre-cardiogenic shock symptoms.

[0078] In some cases, a measuring step is first performed to determine the baseline cardiac function of an individual. For example, an individual suffering from heart failure may exhibit persistent hypotension, dyspnea, and decreased LVEF. The measuring step may include measuring one or more parameters of cardiac function or cardiac dysfunction, such as, but not limited to, decreased SBP or SBP AUC, decreased left ventricular end-diastolic / end-systolic volume and function (LVEF), or increased E / Ea or E / A ratio, decreased Ea ratio, decreased stroke volume, and increased cardiac rate. As will be understood by those skilled in the art, at the time of the measuring step, any suitable measuring technique available in the art is suitable for use herein, and it is well within the scope of such a person skilled in the art to select the appropriate measuring technique corresponding to the parameter of interest. A non-limiting list of suitable measuring equipment / techniques includes echocardiogram, cardiac catheterization, nuclear stress test, CAT scan, radionuclide ventriculography scan, stethoscope, sphygmomanometer, and pulmonary capillary wedge pressure (PCWP), etc. For example, SBP can be measured by an arterial line attached to a sphygmomanometer or pressure transducer. In another embodiment, one or more parameters of cardiac function are measured, including cardiac rate (HR), blood pressure (BP), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), area under the systolic blood pressure curve (SBP AUC), creatine clearance, deceleration slope, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide level (BNP), NT-pro-BNP level, troponin level, venous lactate level, echocardiographic measurements, left ventricular end diastolic dimension (EDD), left ventricular end systolic dimension (ESD), left ventricular end diastolic volume (EDV), left ventricular end systolic volume (ESV), left atrial dimension (LAD), left atrial area (LAA), left atrial volume ( LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annular systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR) and inferior vena cava diameter (IVC).

[0079] It may be desirable to develop a clinical trial group to examine a cohort of individuals who exhibit cardiac function parameters within a selected range of values. For such studies, as those skilled in the art will understand, there are certain inclusion and exclusion criteria to determine whether an individual is selected to participate in the study. In some embodiments, individuals who meet one or more inclusion criteria are selected for treatment. In a preferred embodiment, the inclusion criteria include one or more of the clinical symptoms of SCAI stage B precardiogenic shock with ADHF and no evidence of acute coronary syndrome. In another embodiment, further inclusion criteria include males and females aged 18-85 years, dyspnea, chest congestion with BNP of about 400 pg / mL or more or NT-proBNP of about 1,400 pg / mL or more, LVEF of 40% or less, persistent hypotension defined as SBP of less than about 90 mmHg and / or heart rate of about 75 bpm to about 150 bpm.

[0080] The methods disclosed herein also include administering a therapeutically effective amount of istaloxime to an individual. In a preferred embodiment, istaloxime is present in a pharmaceutical composition, such as a pharmaceutical composition of any of the combinations described above. Istaloxime is administered in a therapeutically effective dose. For example, istaloxime is administered at a dose within the range of about 0.25 μg / kg / min to about 3.0 μg / kg / min, for example, 0.25 μg / kg / min, 0.3 μg / kg / min, 0.35 μg / kg / min, 0.4 μg / kg / min, 0.45 μg / kg / min, 0.5 μg / kg / min, 0.55 μg / kg / min, 0.6 μg / kg / min, 0.65 μg / kg / min, 0.7 μg / kg / min, 0.75 μg / kg / min, 0.8 μg / kg / min, 0.85 μg / kg / min, 0.9 μg / kg / min, 0.95 μg / kg / min, 1.0 μg / kg / min, 1.1 μg / kg / min, 1.2 μg / kg / min, 1.4 μg / kg / min, 1.5 μg / kg / min, 1.6 μg / kg / min, 1.7 μg / kg / min, 1.8 μg / kg / min, 1.9 ...

[0043] The compound may be administered to an individual via intravenous infusion at 1.2 μg / kg / min, 1.3 μg / kg / min, 1.4 μg / kg / min, 1.5 μg / kg / min, 1.6 μg / kg / min, 1.7 μg / kg / min, 1.8 μg / kg / min, 1.9 μg / kg / min, 2.0 μg / kg / min, 2.1 μg / kg / min, 2.2 μg / kg / min, 2.3 μg / kg / min, 2.4 μg / kg / min, 2.5 μg / kg / min, 2.6 μg / kg / min, 2.7 μg / kg / min, 2.8 μg / kg / min, 2.9 μg / kg / min or 3.0 μg / kg / min. In a preferred embodiment, the dose of istaloxime administered to an individual is within the range of about 0.5 μg / kg / min to about 3.0 μg / kg / min. In a more preferred embodiment, the dose of istaloxime administered to an individual is within the range of about 1.0 μg / kg / min to about 2.0 μg / kg / min, or within the range of about 1.0 μg / kg / min to about 1.5 μg / kg / min, or about 1.0 μg / kg / min, or about 1.5 μg / kg / min. In certain embodiments, the dose of istaloxime administered to an individual is about 1.0 μg / kg / min.

[0081] The duration of the infusion can be at least about 1 hour to about 48 hours, or longer, e.g., 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, or 48 hours. Preferably, the infusion is administered for about 3 hours to about 24 hours, or about 6 hours to about 24 hours, or about 12 hours to about 24 hours. In certain embodiments, an individual is administered istaloxime by intravenous infusion for about 24 hours. In other embodiments, the duration of the infusion can be longer than 24 hours, for example, 25 hours, 26 hours, 27 hours, 28 hours, 29 hours, 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, 37 hours, 38 hours, 39 hours, 40 hours, 41 hours, 42 hours, 43 hours, 44 hours, 45 hours, 46 hours, 47 hours, 48 ​​hours, 54 hours, 60 hours, 66 hours, 72 hours, 78 hours, 84 hours, 90 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or more. For example, istaloxime infusion administered by pump can be performed for a longer period of time.

[0082] In another embodiment, an individual is administered a low dose of istaloxime for an initial period to determine whether the individual shows signs of poor drug tolerance, such as nausea, pain at the injection site, etc. For example, an individual can be administered intravenous istaloxime at a dose of about 1.0 μg / kg / min for the first 1-2 hours, which can be increased to 1.5 μg / kg / min for the remainder of the infusion time (e.g., 24 hours) if the individual does not show signs of drug intolerance. Similarly, an individual can be administered a high dose of istaloxime initially, and the dose can be lowered if the individual shows signs of drug intolerance. For example, an individual can be administered intravenous istaloxime at a dose of about 1.5 μg / kg / min for the first 1-2 hours, which can be decreased to 1.0 μg / kg / min for the remainder of the infusion time (e.g., 24 hours) if the individual does not show signs of drug intolerance, such as nausea. In some embodiments, the individual can be co-administered with an antiemetic (eg, ondansetron) to alleviate nausea instead of adjusting the infusion rate of istaloxime.

[0083] Once istaloxime has been administered to the individual, the method can include one or more measurement steps performed periodically during and / or for a period of time following treatment. The measuring step may include measuring one or more of the cardiac function parameters listed above before the start of the infusion, at the start of the infusion administration and / or at one or more time points during and after the infusion, for example, after 15 minutes, 30 minutes, 45 minutes, 1 hour, 1.25 hours, 1.5 hours, 1.75 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days or more after the start of the infusion. For example, for an individual administered istaloxime by intravenous infusion for up to 24 hours, one or more parameters of cardiac function can be measured before the start of the infusion, during the infusion, and 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, and 30 days after the start of the infusion. As one of ordinary skill in the art will appreciate, one or more parameters of cardiac function indicate the effectiveness of istaloxime treatment. In some embodiments, an increase in SPB of at least about 8 mmHg 6 hours after administration of istaroxime, e.g., an increase in SPB of 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg or 15 mmHg, indicates pre-treatment of cardiogenic shock or prevention of cardiogenic shock; or an increase in SPB of at least about 10 mmHg 24 hours after administration of istaroxime, e.g., an increase in SPB of 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg or 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg or 20 mmHg, indicates pre-treatment of cardiogenic shock or prevention of cardiogenic shock.In other embodiments, an SPB AUC from baseline of at least about 20 mmHg·hr, e.g., 20 mmHg·hr, 25 mmHg·hr, 30 mmHg·hr, 35 mmHg·hr, 40 mmHg·hr, 45 mmHg·hr, 50 mmHg·hr or greater, within about 6 hours after initiation of administration of istaroxime. (0-6) In addition, an increase in SBP AUC from baseline of at least about 200 mmHg·hr, e.g., 200 mmHg·hr, 210 mmHg·hr, 220 mmHg·hr, 230 mmHg·hr, 240 mmHg·hr, 250 mmHg·hr, 260 mmHg·hr, 270 mmHg·hr, 280 mmHg·hr, 290 mmHg·hr, 300 mmHg·hr or greater, within about 24 hours of initiating administration of istaloxime. (0-24) The increase in SBP indicates pre-treatment or prevention of cardiogenic shock.In some embodiments, the improvement of SBP is accompanied by one or more additional indicators of improved cardiac function, including but not limited to the increase in CI, the decrease in left ventricular dimension (e.g., the decrease in left ventricular end systolic volume and / or the decrease in left ventricular end diastolic volume) and / or the decrease in left atrial dimension (e.g., the decrease in left atrial area).In other embodiments, the decrease in NT-proBNP value or the increase in eGFP value indicates pre-treatment or prevention of cardiogenic shock.

[0084] In another embodiment, when evaluating the effectiveness of a treatment, treatment regimen or specific dosage, or to determine whether to give a treatment dosage or a maintenance dosage, an individual, such as a patient before or after cardiogenic shock, is subject to regular screening for the presence and extent of organ and tissue damage or injury, such as heart (ventricular dilation, third heart sound hypertrophy), fatigue, malaise, reduced exercise tolerance, increased recovery time after exercise, kidney (renal failure, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, tachypnea), ankle swelling, and elevated jugular venous pressure.A thorough physical examination should be performed by a specialist in cardiovascular disease, particularly in the treatment of ADHF before or with cardiogenic shock, at selected time intervals focusing on heart, lung and peripheral circulatory function. Thus, in another embodiment, treatment with istaloxime or a pharma- ceutically acceptable salt, solvate or hydrate equivalent thereof disclosed herein is initiated as early as possible, preferably in an emergency setting, to prevent rapid progression of symptoms (e.g., progression from pre-cardiogenic shock to overt cardiogenic shock), and is continued after the patient is discharged from the hospital, preferably for the patient's entire life or at least for the same period as other drugs used in heart failure.

[0085] According to the present invention, the uses and methods provided herein may further include co-administration with other drugs or medicines. Indeed, the present invention selectively corrects the reduced cardiac biochemical function (i.e., SERCA2a activity). This certainly contributes to alleviating the existing pre-cardiogenic shock or cardiogenic shock and clinical symptoms of ADHF with less unwanted side effects than available treatments (simply due to the selectivity mentioned above). However, since pre-cardiogenic shock and cardiogenic shock are complex clinical syndromes, the present invention provides a novel therapeutic approach that can be used in combination with existing and future drug classes and / or specific drugs, such as: a) drug classes, such as ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, Ca channel blockers, beta blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin 2 mediators, recombinant NP proteins, activators of soluble guanylate cyclase (sGC), angiotensin II receptor beta arrestin ligands; b) certain drugs: hydrochlorothiazide, furosemide, verapamil, diltiazem, carvedilol, metoprolol, hydralazine, eplerenone, spironolactone, lisinopril, ramipril, nitroglycerin, nitrates, digoxin, valsartan, olmesartan, telmisartan, candesartan, losartan, entresto, omecamtiv, sacubitril, serelaxin, ularitide, levosimendan, cinaciguat. Subjects who are pre-cardiogenic shock or in cardiogenic shock treated with the above drugs and undergo regular clinical monitoring, for example subjects who are continuously monitoring pulmonary blood pressure with an implanted probe, may be monitored to predict episodes of ADHF or cardiogenic shock that may be prevented by infusion of istaloxime.

[0086] When the istaloxime disclosed in the present invention is used as a therapeutic agent for treating pre-cardiogenic shock or cardiogenic shock, it can be combined or co-administered with other therapeutic agents used in the treatment of the same disease and / or underlying HF.Exemplary other therapeutic agents are diuretics, such as furosemide, bumetanide and torasemide; aldosterone antagonists metolazone, such as spironolactone or eplerenone; thiazide diuretics, such as hydrochlorothiazide, metolazone and chlorthalidone.Other drugs are ACE inhibitors, such as lisinopril and ramipril.Also, ARBs, such as valsartan, candesartan and losartan, can be considered.Included are angiotensin receptor / neprilysin inhibitors (ARNI), such as sacubitril. Other drugs can be selected from beta blockers, such as carvedilol and metoprolol, or vasodilators, such as hydralazine, and can be optionally combined with isosorbide dinitrate, nitrates such as nitroglycerin, amlodipine and felodipine; non-dihydropyridines, such as diltiazem or verapamil. The compounds of the present invention can also be combined with digoxin if necessary. Other drugs, such as ivabradine and other anticoagulants, can also be considered.

[0087] The compounds of the present invention may be combined with other therapeutic agents, particularly those useful in the treatment of cardiovascular disease, and more particularly those useful in combination therapy of pre-cardiogenic shock or cardiogenic shock associated with ADHF. The combined active ingredients may be administered according to various protocols determined by the physician. According to one embodiment of the present invention, combination therapy may be performed by administering istaloxime at the same time or at different times with the additional therapeutic active ingredient or ingredient. In the case of concomitant administration, the compounds of the present invention and the additional active ingredient or ingredient may each be formulated in their own pharmaceutical composition or in the same unit dosage form. In the former case, the present invention provides a kit, particularly for the treatment of pre-cardiogenic shock or cardiogenic shock, comprising separate pharmaceutical compositions each comprising the compounds of the present invention and the additional active ingredient or ingredient. In another embodiment, the present invention provides a pharmaceutical unit dosage form kit, particularly for the treatment of pre-cardiogenic shock or cardiogenic shock, comprising the compounds of the present invention and the additional active ingredient or ingredient in the same unit dosage form. Combination therapy according to the present invention provides advantageous treatment of pre- or cardiogenic shock due to the inotropic-lusotropic effects of istaloxime disclosed herein in addition to or in synergistic combination with the known therapeutic effects of the additional active agents disclosed herein.

[0088] Also provided are nanoparticles, nanolipoparticles, vesicles and liposomal membranes containing compounds used to carry out the uses and methods provided herein, such as compounds used to deliver the pharma- ceutical active compounds and compositions provided herein, which are combinations of istaloxime or its pharma- ceutical acceptable salt, solvate or hydrate equivalent, optionally with additional therapeutically active agents as disclosed above, for subjects in need thereof. In another embodiment, these compositions are designed to target specific molecules, including biological molecules such as polypeptides, including cell surface polypeptides, for example, to target desired cell types, such as muscle or cardiac cells, endothelial cells, etc. The sustained release of istaloxime may provide sufficient compound to selectively increase the plasma levels of metabolites while keeping the plasma levels of istaloxime in a very low range.

[0089] Multilamellar liposomes containing compounds are provided for use in practicing the methods provided herein, such as those described in U.S. Application No. 20070082042. The multilamellar liposomes can be prepared with a particle size of about 200-5000 nm using a mixture of oil phase components including squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithin to encapsulate the compositions used to practice the uses and methods provided herein.

[0090] Liposomes can be prepared using any method, such as the method described in U.S. Pat. No. 4,534,899; or the method described in U.S. Application No. 20070042031, including a method of preparing liposomes by encapsulating an active agent (or combination of active agents) according to the present invention, the method comprising providing an aqueous solution in a first reservoir; providing an organic lipid solution in a second reservoir, and then mixing the aqueous solution and the organic lipid solution in a first mixing area to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously produce liposomes encapsulating the active agent; and then immediately mixing the liposome solution with a buffer to produce a dilute liposome solution.

[0091] In certain embodiments, the liposome compositions used to practice the uses and methods provided herein comprise substituted ammonium and / or polyaniline for targeted delivery of istaloxime, or a pharma- ceutically acceptable salt, solvate or hydrate equivalent thereof, used to practice the methods provided herein, to a desired cell type, e.g., as described in U.S. Application No. 20070110798.

[0092] Nanoparticles comprising compounds according to the invention are provided for use in practicing the uses and methods provided herein in the form of nanoparticles (e.g., secondary nanoparticles) comprising an active agent, such as those described in U.S. Application No. 20070077286. In some embodiments, nanoparticles are provided for use in practicing the uses and methods provided herein, comprising a lipid-soluble active agent, or a water-soluble active agent lipid-solubilized for interaction with a divalent or trivalent metal salt.

[0093] In certain embodiments, solid lipid suspensions can be used to formulate and deliver compositions used to practice the uses and methods provided herein to mammalian cells in vivo, in vitro or ex vivo, such as described in U.S. Application No. 20050136121.

[0094] The compositions and formulations used to carry out the uses and methods provided herein can be delivered by using liposomes or nanoliposomes.By using liposomes, the delivery of active agents can be focused to target cells in vivo, especially when the liposome surface carries a ligand specific to the target cells or is otherwise preferentially directed to a specific organ (see, for example, U.S. Patent No. 6,063,400; U.S. Patent No. 6,007,839; Al-Muhammed, 1996, Microencapsul. 13:293-306; Chonn, 1995, Curr. Opin. Biotechnol. 6:698-708; Ostro, 1989, Am. J. Hosp. Pharm. 46:1576-1587).The liposomal formulation of istaloxime disclosed in Eur J Pharm Biopharm. 2011;79(2):285-93 is also provided in the present invention.

[0095] delivery vehicle In another embodiment, any delivery vehicle can be used to carry out the uses and methods provided herein, for example, to deliver the compounds provided herein to the subject in need thereof.For example, the delivery vehicle comprising polycations such as polyethyleneimine derivatives, cationic polymers and / or cationic peptides can be used, for example, as described in US Application No. 20060083737.

[0096] In certain embodiments, the dry polypeptide-surfactant complex is used to formulate compositions used to practice the uses and methods provided herein, such as those described in U.S. Application No. 20040151766.

[0097] In some embodiments, the composition used to carry out the use and method provided herein can be applied to cells using a medium with cell membrane permeable peptide conjugate, for example, as described in U.S. Patent No. 7,306,783; U.S. Patent No. 6,589,503.In some embodiments, the composition to be delivered is conjugated to cell membrane permeable peptide.In some embodiments, the composition to be delivered and / or delivery medium is conjugated to transport mediating peptide, for example, the highly basic and polyphosphoinositide binding transport mediating peptide described in U.S. Patent No. 5,846,743.

[0098] In some embodiments, electroosmosis is used as a primary or secondary means to deliver compositions to cells, e.g., using any of the electroporation systems described in U.S. Pat. Nos. 7,109,034; 6,261,815; and 5,874,268.

[0099] The following examples further illustrate the invention. EXAMPLES

[0100] Example 1 - Treatment of hospitalized patients with precardiogenic shock with a 24-hour istaloxime infusion: a randomized, double-blind, placebo-controlled, parallel-group study

[0101] To evaluate the safety and efficacy of istaloxime in the treatment of precardiogenic shock patients, 60 AHF patients presenting with precardiogenic shock without acute myocardial infarction (preCS) were randomized to treatment with istaloxime 1.0-1.5 mg / kg / min for 24 hours or placebo for 24 hours. PreCS was defined as hypoperfusion, venous lactate >2 mmol / L and / or systolic blood pressure (SBP) <90 mmHg without mechanical or inotropic support. Inclusion criteria included AHF-associated SCAI stage B preCS, age 18-85 years, ongoing hospitalization for AHF, left ventricular ejection fraction <40%, persistent hypotension (SBP 75-90 mmHg), cardiac rate 75-150 bpm and no need for mechanical support or intravenous therapy to increase BR at screening or planned for its use for the next 6 hours.

[0102] According to stage B SCAI classification, patients with clinical signs of peripheral hypoperfusion, venous lactate >2 mmol / L and / or patients receiving mechanical support or treatment with intravenous vasodilators, inotropes or vasopressors were excluded. Other exclusion criteria were: concurrent or planned treatment with oral digoxin (randomization was possible if digoxin plasma concentration at screening was <0.5 ng / ml); acute coronary syndrome or stroke within the past 3 months; coronary artery bypass surgery or percutaneous coronary intervention within the past month or planned within the next month; life-threatening ventricular arrhythmia or implantable cardioverter-defibrillator shock within the past month; sustained ventricular tachycardia or uncontrolled arrhythmia within the past 3 months; fever >38°C; estimated glomerular filtration rate (eGFR) <30 ml / min / m2; serum potassium >5.3 mmol / L or <3.5 mmol / L; stroke or transient ischemic attack within the past 3 months; and acute respiratory distress syndrome.

[0103] Patients were centrally randomized in a 1:1 ratio to receive istaloxime or placebo using interactive response technology. Study medication was supplied in uniquely numbered kits containing identical vials of lyophilized powder (istaloxime plus lactose) that was reconstituted by adding 5 ml of saline to the vial. Istaroxime was administered as a continuous infusion at 1.0 μg / kg / min for 24 hours. The infusion rate could be reduced at the investigator's discretion based on the occurrence of tolerability problems (e.g., nausea), significant bradycardia, or greater than desired BP elevation. The original protocol had a target and maximum dose of 1.5 μg / kg / min, but after 26 of 60 patients had been recruited, the sponsor and steering committee amended the protocol to limit istaloxime administration to 1.0 μg / kg / min, and all patients subsequently received a target and maximum dose of 1.0 μg / kg / min of istaloxime.

[0104] The primary efficacy outcome was the area under the curve (SBP AUC), which represents the change in SBP from baseline to 6 hours after the start of study drug infusion. Secondary outcomes included 24-h SBP area under curve; change from baseline in SBP (specifically at 6 and 24 h), diastolic blood pressure (DBP), and mean arterial pressure (MAP); change from baseline in cardiac rate (HR); treatment failure score (based on death, circulatory, respiratory, or renal mechanical support, or intravenous inotropic or vasopressor treatment, and change in SBP); treatment failure defined as death or need for circulatory, respiratory, or renal mechanical support, or intravenous inotropic or vasopressor treatment; increase from baseline in SBP >5% and / or >10 mmHg; change in quality of life measured by the EuroQol 5 Dimension 5 Level (EQ-5D-5L); change from baseline to 24 h in echocardiographic parameters; change in troponin and N-terminal pro B-type natriuretic peptide (NT-proBNP); readmission for heart failure and readmission for any cause through day 30; in-hospital worsening of heart failure through day 5; and length of hospital stay. In-hospital worsening of heart failure was defined as worsening signs and / or symptoms of heart failure since the last evaluation requiring intravenous therapy for heart failure or increased mechanical ventilation, renal, or circulatory support.Safety outcomes were assessed throughout the study period and included incidence of adverse events; changes in vital signs and 12-lead electrocardiogram (ECG) parameters; incidence of episodes of clinically or hemodynamically significant supraventricular or ventricular arrhythmias detected by continuous ECG monitoring; standard clinical laboratory parameters; renal function measures; cardiac troponin I or T; and mortality through 30 days.The study is summarized in Table 1 and Figure 1.

[0105] statistical analysis The primary efficacy analysis population was the modified intention-to-treat (mITT) population, defined as subjects who received study treatment (patients were infused with either istaloxime or placebo) and had at least one postbaseline BP assessment. Ancillary efficacy analyses were performed in the ITT population, including all randomized patients, and the per-protocol population, including subjects who received study drug infusions without protocol violation exclusions. Safety analyses included all patients who received either study drug. The mITT, ITT, and safety populations were the same, as all randomized patients received study treatment and had at least one postbaseline BP assessment. Because dosing regimens were changed after study progression, patients in the active group were stratified by maximum istaloxime dose (all <1.0 vs. any >1.0 μg / kg / min) and further pairwise comparisons were performed.

[0106] Unadjusted results for continuous variables are presented as means and standard deviations, and adjusted changes are presented as least-squares mean changes and corresponding standard errors (SE). Frequencies are presented for categorical variables. Centers enrolling fewer than six patients were combined and treated as one center for the combined center adjustment. Frequencies are reported for categorical variables and dichotomous clinical outcomes.

[0107] The primary outcome, SBP AUC to 6 hours, was calculated by the trapezoidal rule. Treatment groups were compared using ANCOVA modeling baseline value, combined center, and treatment. Changes in creatinine clearance, cardiac rate, MAP, natriuretic peptides, and troponin were compared between treatment groups using mixed-model repeated measures with baseline value, treatment, combined center, time, and treatment by time interactions as models. Changes in EuroQol visual analogue scale from baseline to 96 hours and 30 days, and changes in echocardiographic measurements at 24 hours and 30 hours were compared between treatment groups at each time point using ANCOVA modeling baseline value, treatment, and combined center. Van Elteren tests stratified by combined center were used to compare between groups for treatment failure scores (up to 24 hours), length of hospital stay, length of stay in intensive care or coronary care unit (ICU / CCU), days out of hospital, and days out of acute care to 30 days. The proportion of subjects who experienced any readmission by day 30 or sustained treatment failure with an SBP increase from baseline of >5% and >10 mmHg at 4–6 hours post-dose were compared using the Cochran-Mantel-Haenszel (CMH) test, controlling for pooled centers. A two-sided p<0.05 was considered statistically significant. No adjustment for multiple testing was made. Analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).

[0108] result The primary outcome measure was the area under the curve (AUC), which represents the change in SBP from the start of the infusion to the 6th hour. Figures 2–4 summarize the results of this analysis. The adjusted mean 6-hour AUC was 53.1 (SE 6.88) mmHg·hour in istaroxime-treated patients compared with 30.9 (SE 6.76) mmHg·hour in the placebo group (p = 0.017), a 72% increase (see Figure 2). In addition, the adjusted mean 24-hour SBP AUC was 291.2 (SE 27.5) mmHg·hour in the istaroxime group compared with 208.7 (SE 27.0) mmHg·hour in the placebo group (p = 0.025), a 40% increase (data not shown). As shown in Figure 3A, the adjusted SBP increase after 6 hours was 7.5 (SE 1.64) mmHg in the placebo group versus 12.3 (SE 1.71) mmHg in the istaloxime-treated group (p=0.045). As shown in Figure 3B, the corresponding adjusted change in SBP after 24 hours was 17.1 (SE 2.36) mmHg and 15.1 (SE 2.25) mmHg (p=0.543) in the istaloxime versus placebo groups. In addition, there was an increase in DBP (see Figure 3C) and MAP (see Figure 4A), the latter two of which persisted beyond 24 hours of study drug administration. Laboratory changes between istaloxime- and placebo-treated patients for eGFR and NT-proBNP are shown in Figures 4B and 4C, respectively.

[0109] Echocardiographic changes during the first 24 hours of the study are presented in Table 3. Among the echocardiographic indices evaluated, there was a significant improvement in istaloxime-treated patients compared with placebo-treated patients after 24 hours in several adjusted indices, including cardiac index (+0.16+0.1 vs. -0.06+0.1 L / min / m2; p=0.016), left atrial area (-1.8+0.5 vs. 0.0+0.5 cm2; p=0.008), left ventricular end-systolic volume (-8.7+4.2 vs. 3.3+4.2 ml; p=0.034), and left ventricular end-diastolic volume (-6.5+4.9 vs. 5.6+4.8 ml; p=0.061). [Table 3-1] [Table 3-2] [Table 3-3]

[0110] As noted above, istaloxime treatment increased SBP from the start of dosing through 24 hours, both at 6 and 24 hour AUCs. Notably, this study is the first to show a beneficial effect on BP in CS patients using a non-adrenergic agonist, and therefore without affecting pulse rate. Several improvements were noted in echocardiographic measurements, including an increase in cardiac index and a decrease in left ventricular and atrial dimensions. These findings suggest that istaloxime improved cardiac function in this patient population. The simultaneous increase in both cardiac index and BP is unique and has not been observed with any conventional intravenous infusion administered to CS patients. This improvement may allow for earlier stabilization of CS patients and earlier initiation of other life-saving therapies.

Claims

1. A pharmaceutical composition for the treatment or prevention of early cardiogenic shock or cardiogenic shock in an individual, An individual is defined as having acute heart failure with a systolic blood pressure of less than approximately 90 mmHg for at least one hour during the first period. (i) a pharmaceutically acceptable carrier; and (ii) istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which is formulated for intravenous infusion at a dose of approximately 0.2 μg / kg / min to approximately 2.0 μg / kg / min over a second period of at least approximately 3 hours. The aforementioned pharmaceutical composition.

2. The pharmaceutical composition according to claim 1, wherein one or more parameters of cardiac function in an individual are measurable, and one or more parameters of cardiac function include blood pressure.

3. The pharmaceutical composition according to claim 2, wherein blood pressure is systolic blood pressure.

4. The pharmaceutical composition according to claim 2, wherein administration of the pharmaceutical composition results in an increase in systolic blood pressure above baseline.

5. The pharmaceutical composition according to claim 2, wherein one or more parameters of cardiac function in an individual further include cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof.

6. The pharmaceutical composition according to claim 1, wherein the acute heart failure is acute decompensated heart failure without evidence of peripheral organ hypoperfusion or acute coronary syndrome.

7. The pharmaceutical composition according to claim 1, wherein the individual has a heart rate of approximately 75 beats / min to approximately 150 beats / min, or if the individual has been administered a beta-blocker, the individual has a heart rate of approximately 60 bpm to approximately 150 bpm.

8. The pharmaceutical composition according to claim 1, wherein istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min.

9. The pharmaceutical composition according to claim 1, wherein the first period is at least about two hours.

10. The pharmaceutical composition according to claim 1, wherein the second period is at least about 6 hours.

11. The pharmaceutical composition according to claim 10, wherein the second period is at least about 24 hours.

12. The pharmaceutical composition according to claim 1, wherein the individual has at least one of the following: dyspnea at rest or minimal exertion, congestion on chest X-ray or lung ultrasound with brain natriuretic peptide of less than approximately 400 pg / mL or N-terminal pro b-type natriuretic peptide of at least 1,400 pg / mL, or a left ventricular ejection fraction of less than approximately 40%, or an echocardiogram confirming an ejection fraction of less than approximately 40%.

13. One or more parameters of cardiac function are considered to be: heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine clearance, deceleration gradient, mitral valve inflow velocity, mean arterial pressure, brain natriuretic peptide (BNP), NT-pro-BNP, troponin, venous lactate, echocardiographic measurements, left ventricular end-diastolic diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), left atrium The pharmaceutical composition according to claim 2, further comprising diameter (LAD), left atrial area (LAA), left atrial volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annulus systolic displacement (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

14. The pharmaceutical composition according to claim 1, comprising one or more further therapeutically active ingredients.

15. The pharmaceutical composition according to claim 14, wherein the further therapeutic active ingredient is selected from the group consisting of ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulants, angiotensin receptor / neprilysin inhibitors (ARNIs), myosin filament activators, recombinant relaxin 2 mediators, recombinant NP proteins, soluble guanylate cyclase (sGC) activators, and beta-arrestin ligands for the angiotensin II receptor.

16. (a) The diuretic is selected from the group consisting of furosemide, bumetanide, torasemide, metrazone, aldosterone antagonists and thiazides; or (b) The ACE inhibitor is lisinopril or ramipril; or (c) An angiotensin II receptor blocker selected from the group consisting of valsartan, candesartan, olmesartan, telmisartan, and losartan; or (d) ARNI is a sacbitril; or (e) The beta-blocker is carvedilol or metoprolol; or (f) The vasodilator is selected from the group consisting of hydralazine, amlodipine, felodipine, diltiazem, and verapamil. The pharmaceutical composition according to claim 15.

17. The pharmaceutical composition contains saline solution as a pharmaceutically acceptable carrier. Istaroxime is reconstituted from a lyophilized powder containing isstaroxime mixed with a volume extender. A pharmaceutical composition according to any one of claims 1 to 16.

18. A pharmaceutical composition for the treatment of pre-cardiogenic shock or cardiogenic shock in an individual, (i) a pharmaceutically acceptable carrier; and (ii) istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which is formulated for intravenous administration at a dose of approximately 0.2 μg / kg / min to approximately 2.0 μg / kg / min over at least approximately 6 hours, thereby improving blood pressure and cardiac output. The aforementioned pharmaceutical composition.

19. The pharmaceutical composition according to claim 18, wherein istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min over at least about 24 hours.

20. The pharmaceutical composition according to claim 18, wherein blood pressure is systolic blood pressure.

21. The pharmaceutical composition according to claim 20, wherein the systolic blood pressure is measured by a blood pressure monitor or an arterial line.

22. The pharmaceutical composition according to claim 18, wherein, upon administration of the pharmaceutical composition, systolic blood pressure rises above baseline within 6 hours after the start of intravenous infusion.

23. The pharmaceutical composition according to claim 18, wherein administration of the pharmaceutical composition to an individual results in (a) an increase in cardiac index; (b) a decrease in left atrial area; (c) an increase in stroke volume; (d) a decrease in left ventricular end-diastolic volume; or (e) any combination of (a) to (d).

24. The pharmaceutical composition further contains saline solution as a pharmaceutically acceptable carrier. Istaroxime is reconstituted from a lyophilized powder containing isstaroxime mixed with a volume extender. The pharmaceutical composition according to claim 18.

25. The pharmaceutical composition according to any one of claims 18 to 24, wherein an individual is treated with one or more therapeutically active ingredients.

26. The pharmaceutical composition according to claim 25, wherein one or more therapeutic active ingredients are selected from the group consisting of ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulants, angiotensin receptor / neprilysin inhibitors (ARNIs), myosin filament activators, recombinant relaxin 2 mediators, recombinant NP proteins, soluble guanylate cyclase (sGC) activators, and beta-arrestin ligands for the angiotensin II receptor.

27. (a) The diuretic is selected from the group consisting of furosemide, bumetanide, torasemide, metrazone, aldosterone antagonists and thiazides; or (b) The ACE inhibitor is lisinopril or ramipril; or (c) An angiotensin II receptor blocker selected from the group consisting of valsartan, candesartan, olmesartan, telmisartan, and losartan; or (d) ARNI is a sacbitril; or (e) The beta-blocker is carvedilol or metoprolol; or (f) The vasodilator is selected from the group consisting of hydralazine, amlodipine, felodipine, diltiazem, and verapamil. The pharmaceutical composition according to claim 26.

28. A pharmaceutical composition for treating or preventing early cardiogenic shock or cardiogenic shock in an individual, a) The individual suffers from acute heart failure; b) The individual has a systolic blood pressure of less than approximately 90 mmHg for at least one hour during the first period; and c) The pharmaceutical composition comprises (i) a pharmaceutically acceptable carrier; and (ii) istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the individual at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min, wherein the administration comprises intravenous infusion over a second period of at least about 3 hours; and Administration of the pharmaceutical composition to the individual results in an increase in both systolic cardiac function and cardiac output above baseline, the increase being measurable within the third period after the start of intravenous infusion, thereby treating or preventing early cardiogenic shock or cardiogenic shock in the individual. The aforementioned pharmaceutical composition.

29. The pharmaceutical composition according to claim 28, wherein one or more parameters of cardiac function in an individual are measurable, and one or more parameters of cardiac function include blood pressure.

30. The pharmaceutical composition according to claim 29, wherein blood pressure is systolic blood pressure.

31. The pharmaceutical composition according to claim 29, wherein administration of the pharmaceutical composition to the individual results in an increase in systolic blood pressure above baseline, where the third period is approximately 6 hours.

32. The pharmaceutical composition according to claim 29, wherein blood pressure is measured as the area under the systolic blood pressure curve, and administration of the pharmaceutical composition results in an increase in the area under the systolic blood pressure curve above baseline, where the third period is approximately 6 hours.

33. The pharmaceutical composition according to claim 29, wherein one or more parameters of cardiac function in an individual further include cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof.

34. The pharmaceutical composition according to claim 28, wherein the acute heart failure is acute decompensated heart failure without evidence of peripheral organ hypoperfusion or acute coronary syndrome.

35. The pharmaceutical composition according to claim 28, further comprising determining that the individual has a heart rate of about 75 beats / min to about 150 beats / min, or, if the individual has been administered a beta-blocker, a heart rate of about 60 bpm to about 150 bpm.

36. The pharmaceutical composition according to claim 28, wherein istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the individual at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min.

37. The pharmaceutical composition according to claim 28, wherein the first period is at least about two hours.

38. The pharmaceutical composition according to claim 28, wherein the second period is at least about 6 hours.

39. The pharmaceutical composition according to claim 38, wherein the second period is at least about 24 hours.

40. The pharmaceutical composition according to claim 28, wherein the individual is a human being at least 18 years of age.

41. The pharmaceutical composition according to claim 28, wherein the individual has dyspnea at rest or minimal exertion, congestion on chest X-ray or lung ultrasound with brain natriuretic peptide of less than approximately 400 pg / mL or N-terminal pro b-type natriuretic peptide of at least 1,400 pg / mL, or a left ventricular ejection fraction of less than approximately 40%, or at least one echocardiogram confirming an ejection fraction of less than approximately 40%.

42. One or more parameters of cardiac function are considered to be: heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine clearance, deceleration gradient, mitral valve inflow velocity, mean arterial pressure, brain natriuretic peptide (BNP), NT-pro-BNP, troponin, venous lactate, echocardiographic measurements, left ventricular end-diastolic diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), left atrium The pharmaceutical composition according to claim 29, further comprising diameter (LAD), left atrial area (LAA), left atrial volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annulus systolic displacement (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

43. The pharmaceutical composition according to claim 28, wherein the individual is receiving treatment for pre-cardiogenic shock or for cardiogenic shock using one or more further therapeutic active ingredients.

44. The pharmaceutical composition according to claim 43, wherein one or more further therapeutic active ingredients are selected from the group consisting of ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulants, angiotensin receptor / neprilysin inhibitors (ARNIs), myosin filament activators, recombinant relaxin 2 mediators, recombinant NP proteins, soluble guanylate cyclase (sGC) activators, and beta-arrestin ligands for the angiotensin II receptor.

45. (a) The diuretic is selected from the group consisting of furosemide, bumetanide, torasemide, metrazone, aldosterone antagonists and thiazides; or (b) The ACE inhibitor is lisinopril or ramipril; or (c) An angiotensin II receptor blocker selected from the group consisting of valsartan, candesartan, olmesartan, telmisartan, and losartan; or (d) ARNI is a sacbitril; or (e) The beta-blocker is carvedilol or metoprolol; or (f) The vasodilator is selected from the group consisting of hydralazine, amlodipine, felodipine, diltiazem, and verapamil. The pharmaceutical composition according to claim 44.

46. The pharmaceutical composition contains saline solution as a pharmaceutically acceptable carrier. Istaroxime is reconstituted from a lyophilized powder containing isstaroxime mixed with a volume extender. A pharmaceutical composition according to any one of claims 28 to 45.

47. A pharmaceutical composition for treating the pre-cardiogenic shock stage in an individual, a) The individual is suffering from pre-cardiogenic shock with acute heart failure, where pre-cardiogenic shock includes a systolic blood pressure of less than approximately 90 mmHg without peripheral organ hypoperfusion or myocardial infarction; b) The pharmaceutical composition comprises (i) a pharmaceutically acceptable carrier; and (ii) istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof, wherein the istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to the individual at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min, and the administration comprises intravenous infusion over at least about 6 hours; and c) One or more parameters of cardiac function in an individual are measurable, wherein one or more parameters of cardiac function include blood pressure; Administration of the pharmaceutical composition to the individual results in an increase in blood pressure above baseline, the increase is measurable within 6 hours after the start of intravenous infusion, thereby treating the pre-cardiogenic shock in the individual. The aforementioned pharmaceutical composition.

48. The pharmaceutical composition according to claim 47, wherein the blood pressure is systolic blood pressure, and administration of the pharmaceutical composition to the individual results in an increase in systolic blood pressure above baseline.

49. The pharmaceutical composition according to claim 47, wherein blood pressure is measured as the area under the systolic blood pressure curve, and administration of the pharmaceutical composition results in an increase in the area under the systolic blood pressure curve above baseline.

50. The pharmaceutical composition according to claim 47, wherein one or more parameters of cardiac function in an individual further include cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof.

51. The administration of the pharmaceutical composition (a) Increase in cardiac index; or (b) Reduction in left atrial area; or (c) Increase in stroke volume; or (d) Decreased left ventricular end-diastolic volume; or (e) The pharmaceutical composition according to claim 50, which yields any combination of (a) to (d).

52. The pharmaceutical composition according to claim 47, wherein the acute heart failure is acute decompensated heart failure.

53. The pharmaceutical composition according to claim 47, further comprising determining that the individual has a heart rate of approximately 75 beats / min to approximately 150 beats / min, or, if the individual has been administered a beta-blocker, a heart rate of approximately 60 bpm to approximately 150 bpm.

54. The pharmaceutical composition according to claim 47, wherein istaloxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered in a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min.

55. The pharmaceutical composition according to claim 47, wherein the administration comprises intravenous infusion over a period of at least about 24 hours.

56. One or more parameters of cardiac function are considered to be: heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine clearance, deceleration gradient, mitral valve inflow velocity, mean arterial pressure, brain natriuretic peptide (BNP), NT-pro-BNP, troponin, venous lactate, echocardiographic measurements, left ventricular end-diastolic diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESV), left atrium The pharmaceutical composition according to claim 47, further comprising diameter (LAD), left atrial area (LAA), left atrial volume (LAV), E wave, A wave, E wave deceleration time (EDT), E / A ratio, Ea, Aa, E / Ea ratio, left ventricular ejection fraction (LVEF), Sa, stroke volume (SV), cardiac output (CO), stroke volume index (SVI), cardiac index (CI), pulmonary artery systolic pressure (PASP), tricuspid annulus systolic displacement (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

57. The pharmaceutical composition according to claim 47, wherein the individual is being treated for pre-cardiogenic shock or for cardiogenic shock using one or more further therapeutic active ingredients.

58. The pharmaceutical composition according to claim 57, wherein the further therapeutic active ingredient is selected from the group consisting of ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulants, angiotensin receptor / neprilysin inhibitors (ARNIs), myosin filament activators, recombinant relaxin 2 mediators, recombinant NP proteins, soluble guanylate cyclase (sGC) activators, and beta-arrestin ligands for the angiotensin II receptor.

59. The pharmaceutical composition contains saline solution as a pharmaceutically acceptable carrier. Istaroxime is reconstituted from a lyophilized powder containing isstaroxime mixed with a volume extender. A pharmaceutical composition according to any one of claims 47 to 58.

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