Intravenous formulations containing ISTAROXIME for treatment of prestage and cardiac shock

Abstract

The present invention discloses a composition for intravenous infusion of istaroxime in a human patient suffering from a prestage cardiac shock or a cardiac shock. Likewise, the present invention discloses methods of administering istaroxime to an individual exhibiting a pre-cardiac shock or symptom of cardiac shock or having been diagnosed as a pre-cardiac shock or cardiac shock. In particular, disclosed herein is a method of treating and preventing a pre-cardiac shock or a cardiac shock in an individual by administering to the individual a dose regimen of intravenous infusion of istaroxime up to 24 hours.

Description

[0001] CROSS REFERENCE TO RELATED APPLICATIONS

[0002] This application claims the benefit of the filing date of U.S. Provisional Application No. 63 / 332,909, filed on April 20, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] The present invention relates to the field of medicine, and in particular to an intravenous preparation containing istaroxime for treating pre-cardiogenic shock or cardiogenic shock. Background Art

[0004] The prevalence of heart failure (HF) is age-dependent, ranging from less than 2% in persons younger than 60 years to more than 10% in persons older than 75 years [Metra and Teerlink, 2017, Lancet 390:1981-1995]. Most patients with HF have a history of hypertension, coronary artery disease, cardiomyopathy, valvular disease, or a combination of these disorders [Metra and Teerlink, 2017, Lancet 390:1981-1995]. Chronic heart failure (CHF) can be distinguished from individuals presenting with acute heart failure (AHF), which generally refers to the rapid onset or worsening of symptoms and / or signs of HF requiring immediate treatment and / or hospitalization. Individuals with CHF or other preexisting cardiomyopathies may experience a sudden onset of worsening of their condition, resulting in a specific type of AHF known as acute decompensated heart failure (ADHF) [Joseph et al., 2009, Tex. Heart Inst. J. 36:510-520]. Importantly, individuals with CHF have a much worse clinical course and prognostic outcomes following 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].

[0005] One of the most serious acute coronary conditions is cardiogenic shock, which is associated with significant morbidity and mortality, presenting a therapeutic challenge to 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 rates range from 35% to greater than 60% [Singh et al., 2019, Cardio. Rev. 27(4):198-201; Jentzer et al., 2019, JACC 74(17):2117-2127], interventions are clearly needed to prevent deterioration to overt cardiogenic shock. Aside from revascularization of the primary coronary artery in patients presenting with acute myocardial infarction (AMI), no interventions affect short-term survival in patients with cardiogenic shock, and there is no established therapy for patients with non-AMI cardiogenic etiologies [Singh et al., 2019, Cardio. Rev. 27(4):198-201]. However, early interventions that can mitigate the clinical and hemodynamic deterioration of cardiogenic shock may provide a window of opportunity to stabilize and reverse myocardial dysfunction and maintain favorable hemodynamics.

[0006] The period of clinical and hemodynamic deterioration preceding cardiogenic shock is called precardiogenic shock or, according to the Society for Cardiovascular Angiography and Interventions (SCAI) classification system, stage B cardiogenic shock [Jentzer et al., 2019, JACC 74(17):2117-2127]. The primary goal of intervention during precardiogenic shock is to interrupt or reverse the downward hemodynamic spiral that ultimately leads to cardiogenic shock and death. If left unattended, precardiogenic shock can lead to overt cardiogenic shock with refractory hypotension, profound alterations in cellular metabolism, and end-organ failure. This transitional period lacks the clinical and hemodynamic criteria that define cardiogenic shock or SCAI stage C cardiogenic shock; namely, systolic blood pressure (SBP) less than 90 mmHg (or use of vasopressor therapy to maintain SBP above 90 mmHg) and cardiac index (CI) less than 2.2 L / min / m 2 , 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].

[0007] Although AMI remains the most common cause of pre-cardiogenic shock, steady-state hemodynamic deterioration leading to ADHF and reduced ejection fraction (HFrEF) is the most common cause of pre-cardiogenic shock in non-AMI patients [Singh et al., 2019, Cardio. Rev. 27(4):198-201; Savarese and Lund, 2017, Cardiac Failure Rev. 3(1):7-11]. In fact, ADHF may account for up to 30% of all cases of cardiogenic shock [Kar et al., 2011, J. Am Coll. Cardiol. 57(6): 688-696]. These individuals frequently experience a decline in disease stability or are frequently noncompliant with guideline-based therapy, precipitating an acute deterioration in their condition. The management of patients with ADHF and cardiogenic shock or CHF in the setting of cardiogenic shock may differ substantially from that of other types of cardiogenic shock, as the hemodynamic status and neurohormonal milieu are often significantly different. HF patients often have a marked upregulation of vasoconstrictor substances 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].

[0008] Regardless of the underlying etiology, unloading of left ventricular (LV) filling pressures has been reported to significantly reduce LV end-diastolic wall stress and decompress microvasculature, thereby increasing myocardial blood flow to the endocardial layer and maintaining LV systolic function [Kapur et al., 2013, Circulation 128(4):328-336]. Therefore, pharmacological interventions that can stabilize the failing LV and improve myocardial contractility and hemodynamics without increasing workload or myocardial oxygen demand would be ideal for preventing the deterioration of pre-cardiogenic shock to overt cardiogenic shock. Currently, most pharmacological interventions, including inotropes (e.g., dobutamine, milrinone) and vasopressors (e.g., norepinephrine), as well as novel inotropes under development, have not been shown to reduce mortality despite transient improvements in hemodynamic status. Furthermore, the treatment of cardiogenic shock is complicated by the heterogeneity of the underlying pathophysiological mechanisms that lead to the condition, and current medical therapies and interventions fail to properly account for individual patient variability in order to properly tailor the treatment of pre-cardiogenic shock and cardiogenic shock. Therefore, there is an unmet need for agents that treat individuals in pre-cardiogenic shock to prevent the hemodynamic deterioration leading to overt cardiogenic shock without increasing mortality.

[0009] One compound currently under investigation for the treatment of AHF patients is Istaroxime (PST 2744), an androstenedione derivative that is chemically unrelated to cardiac glycosides. Istaroxime may have the potential to overcome many of the problems of previous or existing therapies used to treat AHF patients. Istaroxime works through a dual mechanism of action: 1) inhibiting Na + / K + -ATPase activity, resulting in an increase in intracellular calcium, which increases the contraction (contractility) of cardiomyocytes; and 2) activation of the sarcoplasmic reticulum calcium ATPase isoform (SERCA2a), which improves both myocardial relaxation (relaxation) and contraction and may reduce the risk of arrhythmias.

[0010] A specific clinical study examining the effects of Istaroxime in patients with AHF is outlined in the HORIZON-HF study [see Gheorghiade et al., JACC, 51(23):2276-2285]. This study observed 120 patients hospitalized for ADHF and reduced LV systolic function who were given escalating doses of Istaroxime for 6 hours (i.e., 0.5-1.0-1.5 μg / kg / min). The primary endpoint of the study was the change from baseline in PCWP after 6 hours and 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 hours to 6 hours after the start of the infusion. The results also showed that HR tended to decrease during the 6-hour infusion, while SBP increased slightly in a dose-dependent manner. However, this study did not include patients with ADHF who had persistent hypotension (mean baseline SBP was 116 mmHg, and specifically excluded patients with SBP less than 90) or precardiogenic shock or clinical shock, nor did it show the efficacy of istaroxime in increasing SBP to the extent required to relieve the hypotension associated with ADHF in patients with precardiogenic shock.

[0011] WO 2020 / 180356 A9 discloses another clinical study examining long-term istaroxime infusions in 120 ADHF patients. This study involved two doses of istaroxime (0.5 μg / kg / min and 1.0 μg / kg / min) infused for up to 24 hours. The primary endpoint of this study was the E / Ea ratio and revealed improvements in both treatment groups compared to the placebo group. Contrary to what the results of the Horizon study suggested, long-term Istaroxime infusion showed significant improvements in most diastolic function parameters measured 6 hours after infusion. However, this study only included ADHF patients with an SBP range between 90 mmHg and 120 mmHg, thus excluding patients presenting with pre-cardiogenic shock or cardiogenic shock.

[0012] Therefore, there is a clear but unmet need to treat patients in the pre-cardiogenic shock stage to stabilize the failing LV and prevent the hemodynamic and subsequent global metabolic deterioration that leads to overt cardiogenic shock. Summary of the invention

[0013] Described herein is a pharmaceutical composition containing istaroxime, which is formulated for administration to a subject for use in a treatment method for pre-cardiogenic shock or cardiogenic shock. In a specific embodiment, the administration is performed by intravenous infusion and lasts for up to about 24 hours, thereby improving systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure and other cardiac function parameters in the individual. For example, the improvement in cardiac function can be measured by a change in SBP or the area under the SBP curve (AUC) compared to a baseline at 6 hours and / or 24 hours after the start of infusion. An individual with pre-cardiogenic shock or cardiogenic shock may show improved cardiac function after administering istaroxime (e.g., by intravenous infusion) for a period of up to 24 hours. Surprisingly, it has been found that individuals with pre-cardiogenic shock who administer istaroxime by intravenous infusion show both cardiac index and blood pressure (e.g., systolic blood pressure) while increasing, which is unique and has not been observed when any previous intravenous drugs administered to individuals with pre-cardiogenic shock or cardiogenic shock are used.

[0014] One aspect of the invention describes a pharmaceutical composition for use as a medicament for treating or preventing early cardiogenic shock or cardiogenic shock in an individual. The individual is defined as suffering from acute heart failure and having a systolic blood pressure of less than about 90 mmHg for a first period of at least about 1 hour. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and istaroxime or a pharmaceutically 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.

[0015] In one embodiment, one or more cardiac function parameters, such as blood pressure, are measured in the individual. In another embodiment, the blood pressure is systolic pressure, and the administration of the pharmaceutical composition causes the systolic pressure to increase to above baseline. In other embodiments, one or more cardiac function parameters in the 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 / minute to about 150 beats / minute, or if the individual has been administered a beta-blocker, the heart rate is about 60 bpm to about 150 bpm.

[0016] In one embodiment, the istaroxime 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. In another embodiment, the first time period is at least about 2 hours or at least about 6 hours or at least about 24 hours. In one 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 and brain natriuretic peptide less than about 400 pg / mL or N-terminal b-type natriuretic peptide precursor of at least 1,400 pg / ml, or left ventricular ejection fraction less than about 40% or echocardiogram confirming an ejection fraction less than about 40%. In yet another embodiment, the one or more cardiac function parameters further include heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine 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 diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume ...ESD), left ventricular end-systolic volume (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (ESD), left ventricular end-diastolic volume (ESD), left ventricular end-systolic 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 plane systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

[0017] In other embodiments, the pharmaceutical composition includes one or more other therapeutically active ingredients, such as, but not limited to, ACE inhibitors (e.g., lisinopril or ramipril), angiotensin receptor blockers (ARBs) (e.g., valsartan, candesartan, olmesartan, telmisartan, or losartan), diuretics (e.g., furosemide, bumetanide, torsemide, metolazone, aldosterone antagonists, or thiazides), Ca channel blockers, beta-blockers (e.g., carvedilol or metoprolol), digitalis, NO donors, vasodilators (e.g., hydralazine, amlodipine, felodipine, diltiazem, and verapamil), SERCA2a stimulators, enkephalinase (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP proteins, soluble guanylate cyclase (sGC) activators, and / or beta-arrestin ligands for the angiotensin II receptor (e.g., sacubitril). In another embodiment, the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent.

[0018] In another aspect of the present invention, a pharmaceutical composition is provided herein for use as a medicament for treating pre-cardiogenic shock or cardiogenic shock in an individual. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof. The istaroxime or a pharmaceutically 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, thereby improving blood pressure and cardiac output. In one embodiment, the istaroxime 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 for at least about 24 hours.

[0019] In another embodiment, the blood pressure is systolic blood pressure, which can be measured by a sphygmomanometer or an arterial catheter. In one embodiment, 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 the 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 one embodiment, the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a volume expander. In another embodiment, the individual is receiving 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, enkephalinase (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, soluble guanylate cyclase (sGC) activators and / or beta-arrestin ligands for the angiotensin II receptor.

[0020] Another aspect of the present invention describes a method for treating or preventing early cardiogenic shock or cardiogenic shock in an individual. The method includes the steps of providing an individual with acute heart failure, determining that the individual has a systolic blood pressure of less than about 90 mmHg in a first time period of at least about 1 hour, and administering a therapeutically effective amount of a pharmaceutical composition to the individual. The pharmaceutical composition comprises a pharmaceutically acceptable carrier and istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, which is administered by infusion at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min for a second time period of at least about 3 hours. In such methods, administration of the pharmaceutical composition results in an increase in both cardiac systolic function and cardiac output above baseline, which is measurable in a third time period after the start of the intravenous infusion, thereby treating or preventing early cardiogenic shock or cardiogenic shock in the individual.

[0021] In one embodiment, the method includes measuring one or more cardiac function parameters such as blood pressure or preferably systolic pressure in the individual. In one embodiment, the administration of the pharmaceutical composition causes the systolic pressure to increase to above baseline, and the third time period is about 6 hours. In another embodiment, the blood pressure is measured as the area under the systolic pressure curve, and the administration of the pharmaceutical composition causes the area under the systolic pressure curve to increase to above baseline, and the third time period is about 6 hours. In yet another embodiment, one or more cardiac function parameters in the individual additionally include cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume or any combination thereof. In other embodiments, the acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome.

[0022] In one embodiment, the method includes the step of determining that the individual's heart rate is about 75 beats / minute to about 150 beats / minute, or if the individual has been administered a beta-blocker, the heart rate is about 60 bpm to about 150 bpm. In one embodiment, the istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof 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 of time is at least about 2 hours or at least about 6 hours or at least about 24 hours. In a specific embodiment, the individual is a human of at least 18 years of age. In another embodiment, the individual has at least one of the following: dyspnea at rest or with minimal exercise, congestion on chest x-ray or lung ultrasound and brain natriuretic peptide less than about 400 pg / mL or N-terminal b-type natriuretic peptide precursor of at least 1,400 pg / ml, or left ventricular ejection fraction less than about 40% or echocardiogram confirms ejection fraction less than about 40%.

[0023] In one embodiment of the method, the one or more cardiac function parameters further include heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine 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 diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume ...ESD), left ventricular end-systolic volume (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-systolic volume (SBP), left ventricular end-diastolic volume (ESD), left ventricular end-systolic volume (ESD), left ventricular end-diastolic volume (EDV), left ventricular end-sys 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 plane 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 therapeutic treatment for pre-cardiogenic shock or cardiogenic shock with one or more other therapeutically active ingredients, such as, but not limited to, ACE inhibitors (e.g., lisinopril or ramipril), ARBs (e.g., valsartan, candesartan, olmesartan, telmisartan, or losartan), diuretics (e.g., furosemide, bumetanide, torsemide, metolazone, aldosterone antagonists, or thiazides), Ca channel blockers. In another embodiment, the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent. In yet another embodiment of the method, the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent. In yet another embodiment of the method, the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent.

[0024] The present invention also describes a method of treating pre-cardiogenic shock in an individual, the method comprising the following steps: a) providing an individual with pre-cardiogenic shock with acute heart failure, wherein the pre-cardiogenic shock comprises a systolic blood pressure of less than about 90 mm Hg without end-organ hypoperfusion or myocardial infarction; b) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier; and (ii) istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the istaroxime or a pharmaceutically 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 wherein the administration comprises an intravenous infusion for at least about 6 hours; and c) measuring one or more cardiac function parameters in the individual, wherein the one or more cardiac function parameters comprise blood pressure. In addition, the administration of the pharmaceutical composition results in an increase in the blood pressure above baseline, the increase being measurable 6 hours after the start of the intravenous infusion, thereby treating pre-cardiogenic shock in the individual.

[0025] In one embodiment of the method, the blood pressure is systolic pressure, and the administration of the pharmaceutical composition causes the systolic pressure to increase above baseline. In another embodiment, the blood pressure is measured as the area under the systolic pressure curve, and the administration of the pharmaceutical composition causes the area under the systolic pressure curve to increase above baseline. In yet another embodiment, one or more cardiac function parameters in the individual further include cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof. For example, the administration of the pharmaceutical composition may result in one or more of the following: an increase in cardiac index, a decrease in left atrial area, an increase in stroke volume, a decrease in left ventricular end-diastolic volume, and / or a decrease in left ventricular end-diastolic volume.

[0026] These and other features and advantages of the present invention will become better understood from the following description, appended claims and accompanying drawings. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a flow chart of an exemplary study testing the efficacy of istaroxime for the treatment of pre-cardiogenic shock.

[0028] Figure 2 is a graph showing the change in systolic blood pressure (SBP) over time in individuals treated with istaroxime (solid area) versus placebo (shaded area). The y-axis represents the change in SBP from baseline (mmHg) and the x-axis represents hours (h) from infusion.

[0029] Figure 3are graphs showing changes in blood pressure (BP) over time in individuals treated with istaroxime (solid line) versus placebo (dashed line). Panel A shows the change in SBP up to 6 hours after infusion, while Panel B shows the change in SBP up to 24 hours after infusion. Panel C shows the mean change in diastolic blood pressure (DBP) up to 96 hours after infusion. The y-axis in each graph represents the change in BP from baseline (mmHg), while the x-axis represents the number of hours from infusion.

[0030] Figure 4 are graphs showing changes in levels of cardiac and renal function parameters over time. Panel A shows changes in MAP in subjects treated with istaroxime (solid line) compared to placebo (dashed line). Panel B is a graph showing changes in blood levels of eGFR over time between subjects treated with 1.0 μg / kg / min (light gray line), 1.5 μg / kg / min (gray line), or placebo (dark gray dashed line). Panel C is a graph showing changes in blood levels of NT-proBNP over time between subjects treated with 1.0 μg / kg / min (light gray line), 1.5 μg / kg / min (gray line), or placebo (dark gray dashed line). DETAILED DESCRIPTION

[0031] 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 who are administered istaroxime show a simultaneous increase in both cardiac index and blood pressure (e.g., systolic pressure), which is unique and has not been observed when any previous intravenous drug administered to individuals with pre-cardiogenic shock or cardiogenic shock is used. In some embodiments, individuals with pre-cardiogenic shock or cardiogenic shock will be administered istaroxime by intravenous infusion for a period of time (e.g., up to about 6 hours or up to about 24 hours or longer), and compared to individuals with similar conditions (i.e., suffering from pre-cardiogenic shock or cardiogenic shock) who are not administered istaroxime or who are administered a placebo, systolic pressure is increased by 6 hours and / or 24 hours. Such individuals administered istaroxime may exhibit one or more additional cardiac improvements, such as, but not limited to, an increase in cardiac index, a decrease in left atrial area, a decrease in left ventricular end-systolic volume, and a decrease in left ventricular end-diastolic volume, compared to such individuals prior to administration of istaroxime and / or compared to individuals with pre-cardiogenic shock or cardiogenic shock who are not administered istaroxime.

[0032] Provided herein are compositions comprising istaroxime suitable for administration to individuals with pre-cardiogenic shock or cardiogenic shock symptoms. In a specific embodiment, istaroxime is administered to these individuals for up to 24 hours by intravenous infusion to increase systolic blood pressure and relieve symptoms of pre-cardiogenic shock or cardiogenic shock. For example, in one embodiment, istaroxime is administered to individuals who exhibit pre-cardiogenic shock but have no evidence of end-organ hypoperfusion or acute coronary syndrome by intravenous infusion to treat pre-cardiogenic shock and prevent progression to overt cardiogenic shock.

[0033] The compositions and methods disclosed herein are described in more detail below.

[0034] definition

[0035] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those of ordinary skill in the art to which the invention belongs. Unless otherwise specified, standard techniques are used. Although methods and materials similar or equivalent to those described herein may be used in the practice or testing of the present disclosure, suitable methods and materials are described below. The materials, methods and examples are merely illustrative and are not intended to be limiting. All publications, patents and other documents mentioned herein are incorporated herein by reference in their entirety.

[0036] As used herein, references without a specific number include plural referents unless the context clearly indicates otherwise.

[0037] 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 one embodiment, the term "about" means within 5% of the reported numerical value, preferably, the term "about" means within 3% of the reported numerical value.

[0038] 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 adequate 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 defined as a systolic blood pressure of less than about 90 mmHg (hypotension) and a cardiac index of less than about 2.2 L / min / m 2 , pulmonary capillary wedge pressure greater than 15 mmHg, and evidence of end-organ hypoperfusion. "Precardiogenic shock," SCAI stage B "precardiogenic shock," or "early cardiogenic shock" refers to a condition in which the individual has not yet progressed to overt "cardiogenic shock," which is defined as a systolic blood pressure less than approximately 90 mmHg and no evidence of end-organ hypoperfusion.

[0039] The term “heart failure” refers to a clinical syndrome characterized by classic symptoms (e.g., shortness of breath, ankle swelling, and fatigue) and may be accompanied by signs caused by structural and / or functional cardiac abnormalities (e.g., increased jugular venous pressure, lung fissures, and peripheral edema) leading to decreased cardiac output and / or increased intracardiac pressure at rest or during stress.

[0040] The terms "acute heart failure" or "AHF" are used interchangeably herein and generally refer to the rapid onset or worsening of symptoms and / or signs of HF requiring immediate treatment and hospitalization. Current definitions of "acute heart failure" are rather nonspecific and may include a broad spectrum of conditions with several phenotypes, characterized by different clinical presentations, etiologies, precipitating factors, treatments, and prognoses. In addition, a large proportion of human patients have a subacute course, with progressive worsening of signs and symptoms of HF that may precede hospitalization over the course of several days.

[0041] As used herein, the term "acute decompensated heart failure" refers to a sudden worsening of the signs and symptoms of heart failure, which in humans typically include dyspnea (difficulty breathing), swelling in the legs or feet, and fatigue.

[0042] 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).

[0043] The terms "chronic heart failure" or "CHF" are used interchangeably herein and refer to the current clinical classification of chronic HF, which is divided into three categories based on the presence of signs and symptoms of HF and left ventricular ejection fraction (LVEF) in an individual (e.g., a human patient): "heart failure with reduced ejection fraction" or "HFrEF," which is characterized by an LVEF of less than about 40%; "heart failure with intermediate ejection fraction" or "HFmEF" or "HFmrEF," which is characterized by an LVEF of about 40% to about 49%; and "heart failure with preserved ejection fraction" or "HFpEF," which is characterized by an LVEF equal to or greater than about 50%. 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) with evidence of structural and / or functional heart disease (evidence of left ventricular hypertrophy and / or left atrial enlargement and / or diastolic dysfunction).

[0044] As used herein, the term "hypotension" is defined as a systolic blood pressure (SBP) of less than 90 mmHg or a mean arterial pressure (MAP) of less than about 60 mmHg or a decrease of more than 30 mmHg from baseline.

[0045] As used herein, the term "end-organ hypoperfusion" refers to clinical signs such as coldness, limb clamping, low urine output, confusion, elevated lactate, or elevated creatinine.

[0046] The term "treatment" refers to any successful indication of treatment or improvement of a disease or condition in an individual. Treatment may include, for example, lessening or alleviating the severity of one or more symptoms of a disease or condition, or may include reducing the frequency with which an individual (e.g., a human patient) experiences symptoms of a disease, defect, disorder, or adverse condition, etc.

[0047] The term "preventing" refers to preventing a disease or condition, such as precardiogenic shock or cardiogenic shock, in an individual (e.g., a human patient). For example, if an individual at risk for developing precardiogenic shock or cardiogenic shock is treated using the methods of the invention and subsequently does not develop precardiogenic shock or cardiogenic shock, then the disease has been prevented in that individual.

[0048] The terms "treating or preventing" are sometimes used herein to refer to methods that result in some degree of treatment or amelioration of a disease or condition, and contemplate a range of results directed toward this end, including, but not limited to, preventing the condition altogether.

[0049] As used herein, the term "pharmaceutically acceptable" salt, solvate, hydrate or ester refers to a salt, solvate, hydrate or ester form of the active ingredient that is compatible with any other ingredients of the pharmaceutical composition and not deleterious to the subject to which the composition is administered.

[0050] As used herein, the term "pharmaceutically acceptable carrier" means a chemical composition with which an istaroxime compound can be combined and, after combination, can be used to administer the compound to a mammal.

[0051] The term "intravenous infusion" refers to the administration or delivery of a liquid substance directly into a vein of a mammal. A typical "infusion" uses only pressure provided by gravity.

[0052] When used herein to refer to measuring cardiac function, the term "parameter" means any cardiac function observable or measurable using suitable measurement techniques available in the art. A non-limiting list of exemplary "parameters" of cardiac function includes heart rate (HR), blood pressure (BP), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), area under the systolic blood pressure curve (SBP) and heart rate. The following items were used for the analysis: 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 atrial 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 annular plane systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), etc. As will be appreciated by one of ordinary skill in the art, measuring one or more "parameters" of cardiac function can be used to detect cardiac dysfunction compared to average normal parameters, and can also be used to determine whether cardiac function improves after or during treatment.

[0053] The term "therapeutically active" or "active" ingredient or compound refers to a substance that provides a beneficial effect to the individual to which the substance is administered. A "therapeutically effective amount" or "therapeutically effective dose" is an amount of a composition or active ingredient sufficient to provide a beneficial effect to the individual to which the composition or active ingredient is administered.

[0054] describe

[0055] The present invention relates to administering istaroxime to an individual, such as a human patient, to treat or prevent pre-cardiogenic shock or cardiogenic shock. In a preferred embodiment, the route of administration of istaroxime is intravenous infusion. For individuals showing pre-cardiogenic shock symptoms, istaroxime infusion is administered to treat pre-cardiogenic shock (SCAI stage B) and prevent progression to overt cardiogenic shock. In some embodiments, istaroxime infusion can be administered to individuals with overt cardiogenic shock (SCAI stage C) to relieve symptoms and improve cardiac function.

[0056] In one embodiment, the composition and treatment method relieve symptoms associated with pre-cardiogenic shock or cardiogenic shock in individuals with acute decompensated heart failure (ADHF), which is an acute decompensation of underlying chronic systolic heart failure caused by, for example, arterial hypertension, ischemic heart disease, or dilated cardiomyopathy. In some embodiments, the 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 present with persistent hypotension characterized by systolic blood pressure (SBP) below about 90 mmHg, without evidence of acute coronary syndrome and without evidence of end-organ hypoperfusion. Therefore, istaroxime is administered to these individuals by intravenous infusion to increase SBP, thereby alleviating hypotension associated with pre-cardiogenic shock and preventing progression to SCAI stage C overt cardiogenic shock. In other cases, individuals with precardiogenic shock or early cardiogenic shock may present with normotensive, with evidence of end-organ hypoperfusion and without evidence of an acute coronary syndrome.

[0057] In some embodiments, the istaroxime infusion is between about 3 hours and up to 24 hours or longer, such as 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h or more hours. For example, the infusion can be up to 24 hours or longer. In some embodiments, the duration of the 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, for example 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h, 48h, 54h, 60h, 66h, 72h, 78h, 84h, 90h, 96h, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or longer. It should be understood that the infusion of istaroxime provides an improvement in cardiac function, such as an increase in 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 one embodiment, an individual who exhibits pre-cardiogenic shock or cardiogenic shock administered with istaroxime shows an improvement in SBP within 6 hours after the start of the infusion, compared to an individual who exhibits pre-cardiogenic shock or cardiogenic shock administered with a placebo.

[0058] Istaroxime is a positive inotropic compound having the following structural formula (I):

[0059]

[0060] Formula (I).

[0061] Therefore, the object of the present invention is to use istaroxime or its pharmaceutically acceptable salt or ester, hydrate, solvate or polymorph in medicine to treat or prevent pre-cardiogenic shock or cardiogenic shock in an individual. In a preferred embodiment, istaroxime is administered to an individual for the treatment of pre-cardiogenic shock and to prevent the individual's condition from deteriorating to overt cardiogenic shock.

[0062] Also disclosed herein is a pharmaceutical composition comprising istaroxime admixed with at least one pharmaceutically acceptable vehicle and / or excipient. In a preferred embodiment, the pharmaceutical composition is formulated for administration to a subject by infusion, preferably by intravenous infusion.

[0063] The therapeutic effect of the present invention in treating the early stage of cardiogenic shock can be seen in the following Tables 1 and Figure 1 The FDA evaluated the FDA-approved 2-HT-100-L-adrenergic (2-HT-100-L) 100 mg / kg sham treatment in the exemplary clinical studies summarized in Table 2.

[0064] Table 1. Exemplary clinical studies

[0065]

[0066]

[0067]

[0068]

[0069]

[0070]

[0071]

[0072]

[0073]

[0074] In order to determine the efficacy of istaroxime administration in individuals with pre-cardiogenic shock or cardiogenic shock, many cardiac function parameters can be measured to determine whether the condition is improved or prevented. In a preferred embodiment, SBP is measured using standard equipment of the prior art, such as, but not limited to, a sphygmomanometer or an arterial catheter. In a specific embodiment, the cardiac function parameter measured is the area under the SBP curve (SBP AUC), and is determined by multiplying the SBP value or the change in the SBP value within a specific time period. SBP can be monitored / measured using any standard technology of the prior art, such as, but not limited to, a sphygmomanometer or an arterial catheter. Specifically, an arterial catheter is a thin and flexible tube that is inserted into an artery (e.g., a radial artery or ulnar artery at the wrist, a brachial artery at the elbow, a femoral artery in the groin, or a dorsalis pedis artery at the foot), and blood pressure is measured in real time by connection to a pressure sensor. ABP AUC is usually measured from baseline (0 hours) to a specific endpoint, such as 1 h, 2 h, 3 h, 6 h, 12 h, 18 h, or 24 h after the start of istaroxime administration. For example, measuring SBP AUC (0-6)or SBP AUC (0-24) . An improvement in SBP AUC during this period can be considered treating pre-cardiogenic shock or preventing overt cardiogenic shock in the individual. In addition, an increase in the change in SBP 10 min, 20 min, 30 min, 40 min, 50 min, 1 h, 1.5 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 18 h, 24 h or more after an infusion, e.g., after initiation of istaroxime administration, can be considered treating pre-cardiogenic shock or preventing overt cardiogenic shock in the individual.

[0075] In another embodiment, an echocardiogram is performed on the individual according to international standards [see, e.g., 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]. An echocardiogram is within the purview of a skilled physician or sonographer. For example, an echocardiogram can be performed during screening of potential clinical research participants or after an individual is admitted to a health care facility. In other embodiments, the echocardiogram is performed at baseline or 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 31 h, 32 h, 33 h, 34 h, 35 h, 36 h, 37 h, 38 h, 39 h, 40 h, 41 h, 42 h, 43 h, 44 h, 45 h, 46 h, 47 h, 48 h, 72 h, 73 h, 74 h, 75 h, 76 h, 77 h, 78 h, 79 h, 80 h, 81 h, 82 h, 83 h, 84 h In some embodiments, the infusion is performed at 12, 24, 48, 72, 80, 90, 100, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, or 300 days. In one embodiment, the echocardiogram is monitored during the infusion and the values ​​are recorded 24 and 30 hours after the infusion. In other embodiments, the echocardiogram values ​​are recorded 12, 24, 48, 72, and 96 hours after the infusion. Table 2 summarizes exemplary echocardiograms and other cardiac function parameters.

[0076] Table 2. Cardiac function parameters

[0077]

[0078]

[0079] NR = normal range.

[0080] In one embodiment, a subject with pre-cardiogenic shock or cardiogenic shock is administered istaroxime, and the subject's SBP AUC (0-6) at least about 20 mmHg•h within about 6 hours after the start of istaroxime administration, for example, 20 mmHg•h, 25 mmHg•h, 30 mmHg•h, 35 mmHg•h, 40 mmHg•h, 45 mmHg•h, 50 mmHg•h or more within about 6 hours after the start of istaroxime administration; preferably, the SBP AUC (0-6) more preferably, it increases by at least about 40 mmHg•h or at least about 50 mmHg•h. In another embodiment, an individual with pre-cardiogenic shock or cardiogenic shock is administered istaroxime, and the individual's SBPAUC (0-24) at least about 200 mmHg•h within about 24 hours after the start of istaroxime administration, for example, 200 mmHg•h, 210 mmHg•h, 220 mmHg•h, 230 mmHg•h, 240 mmHg•h, 250 mmHg•h, 260 mmHg•h, 270 mmHg•h, 280 mmHg•h, 290 mmHg•h, 300 mmHg•h or more within about 24 hours after the start of istaroxime administration; preferably, the SBP AUC (0-24) The SBPAUC in subjects with pre-cardiogenic shock or cardiogenic shock who were administered istaroxime by infusion was increased by at least about 220 mmHg•h; more preferably, it was increased by at least about 250 mmHg•h or at least about 280 mmHg•h. When compared to subjects with pre-cardiogenic shock or cardiogenic shock who were not administered istaroxime, the SBPAUC in subjects with pre-cardiogenic shock or cardiogenic shock who were administered istaroxime by infusion was increased by at least about 220 mmHg•h; more preferably, it was increased by at least about 250 mmHg•h or at least about 280 mmHg•h. (0-6) Compared with the mean SBP AUC of subjects not taking istaroxime (0-6)65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 100%, 101%, 102%, 103%, 104%, 105%, 106%, 107%, 108%, 109%, 110%, 111%, 112%, 113%, 114%, 115%, 116%, 117%, 118%, 119%, 120%, 121%, 122%, 123%, 124%, 125%, 126%, 127%, 128%, 129%, 130%, 131%, 132%, 133%, 134%, 135%, 136%, 137%, 138%, 139%, (0-6) Compared with the mean SBPAUC of individuals not taking istaroxime (0-6) More preferably, the individual's SBP AUC (0-6) Compared with the mean SBP AUC of subjects not taking istaroxime (0-6) At least about 50% greater, or greater than the mean AUC in subjects not taking istaroxime (0-6) At least about 60% greater, or greater than the mean AUC in subjects not taking istaroxime (0-6) In another embodiment, the SBP AUC of an individual with pre-cardiogenic shock or cardiogenic shock who is administered istaroxime by infusion is at least about 70% greater. (0-24) Compared with the mean SBP AUC of subjects not taking istaroxime (0-24) 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 more; preferably, the individual's SBP AUC is at least about 10%, for example, ... (0-24) Compared with the mean SBP AUC of subjects not taking istaroxime (0-24) More preferably, the individual's SBP AUC (0-24) Compared with the mean AUC of subjects not taking istaroxime (0-24) At least about 30% greater, or greater than the mean AUC in subjects not taking istaroxime (0-24) At least about 40% larger.

[0081] In another embodiment, the change in SBP is an increase of at least about 1 mmHg within about 1 hour after the start of the infusion, or an increase of at least about 3 mmHg within about 3 hours after the start of the infusion, or an increase of at least about 8 mmHg within about 6 hours after the start of the infusion, or an increase of at least about 10 mmHg within about 24 hours after the start of the infusion. For example, in a specific embodiment, the adjusted increase in SBP at 6 hours after the infusion is at least about 8 mmHg, such as 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, or 15 mmHg; preferably, the adjusted increase in SBP at 6 hours after the infusion is at least about 10 mmHg. In another embodiment, the adjusted increase in SBP 24 hours after infusion 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; preferably the adjusted increase in SBP 24 hours after infusion is at least about 12 mmHg; more preferably, it is at least about 15 mmHg.

[0082] In addition to an increase in SBP, individuals with pre-cardiogenic shock or cardiogenic shock who are administered istaroxime will also demonstrate improvements in one or more additional parameters of cardiac function, including, but not limited to, an increase in cardiac index (CI), a decrease in left atrial area, an increase in stroke volume, a decrease in left ventricular end-systolic volume, and a decrease in left ventricular end-diastolic volume. Interestingly, administration of istaroxime improves CI by increasing stroke rate rather than increasing heart rate. Thus, istaroxime increases cardiac output in these individuals without placing the additional stress of an increased heart rate on the heart.

[0083] In another embodiment, blood is drawn from the individual at various time points, such as during pre-screening, at baseline, and / or after infusion, such as 12, 24, 48, 72, 96 hours, 5 days, 10 days, 30 days after the start of istaroxime administration. The blood can be used for various laboratory tests to assess the individual's body chemistry, hematology, cardiac protein levels, and the pharmacokinetics of istaroxime infusion. Exemplary chemistry includes, but is 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 b-type natriuretic peptide precursor (NT-proBNP), and brain natriuretic peptide (BNP). The levels of each of most of these proteins provide practitioners with information about cardiac function, and the measurement and / or interpretation of these levels are entirely within the purview of professional technicians. For example, in one embodiment, the level of NT-proBNP is reduced within about 6 hours after infusion or within about 24 hours after administration, compared to baseline. The levels of some parameters are not a direct measure of cardiac function, but are used to assess renal function. Although many positive inotropes or vasopressors have been shown to have adverse effects on renal function, individuals administered istaroxime show improvements in cardiac function without adverse effects on renal function. For example, in one embodiment, in individuals with pre-cardiogenic shock or cardiogenic shock who are administered istaroxime for 24 hours, the level of eGFR, which is a measure of renal function, is increased within about 6 hours of infusion or within about 24 hours of infusion, compared to baseline.

[0084] Other cardiac function parameters include chest tightness, which can be measured using chest x-ray, lung ultrasound or other standard equipment in the art, wherein an improvement in the level of chest tightness after infusion of istaroxime indicates treatment or prevention of pre-cardiogenic shock and / or cardiogenic shock. Other parameters include heart rate, mean arterial pressure (MAP), dyspnea or labored breathing, the need for administration of intravenous vasopressors, other positive inotropes and / or mechanical cardiac or renal support, symptoms of worsening heart failure, occurrence of adverse events (AEs) or serious adverse events (SAEs), the need for admission to an intensive care unit, discharge from an intensive care unit, and death. In some embodiments, MAP increases from baseline within about 24 hours of infusion.

[0085] Pharmaceutical composition

[0086] Pharmaceutical compositions and formulations for intravenous infusion comprising istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof in admixture with at least one conventional pharmaceutically acceptable carrier and / or solvent and / or excipient are well known in the art.

[0087] The pharmaceutical compositions and formulations for intravenous infusion may be formulated in any manner and may be administered in a variety of unit dosage forms, depending upon the disorder or disease and the extent of the disorder, the general medical condition of each patient, the preferred method of administration obtained, etc. Details regarding formulations and administration techniques are well described in the scientific and patent literature [see, e.g., the latest edition of Remington's Pharmaceutical Sciences, Mack Publishing Co, Easton PA ("Remington's")].

[0088] The preparation can be conveniently presented in unit dosage form and can be prepared by any method known in the pharmaceutical art. The amount of active ingredient that can be combined with a carrier or solvent material to produce a single dosage form will vary with the subject being treated and the specific mode of administration. The amount of active ingredient that can be combined with a carrier material to produce a single dosage form is generally the amount of the compound that produces a therapeutic effect.

[0089] The pharmaceutical preparations provided herein can be prepared according to any pharmaceutical manufacturing method known in the art. Such preparations may contain additional agents such as preservatives or stabilizers. The preparations may be mixed with non-toxic pharmaceutically acceptable carriers or excipients suitable for manufacture. The preparations may include one or more diluents, emulsifiers, preservatives, buffers, excipients, etc., and may be provided in the form of liquids, powders, emulsions, lyophilized powders, etc.

[0090] Aqueous suspensions can contain a mixture of active agents (e.g., compositions for practicing the purposes and methods provided herein) and excipients suitable for making aqueous suspensions. Such excipients include suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone, tragacanth gum, and gum arabic, and dispersants or wetting agents such as naturally occurring phospholipids (e.g., lecithin), condensation products of alkylene oxides and fatty acids (e.g., polyoxyethylene stearate), condensation products of ethylene oxides and long-chain fatty alcohols (e.g., 17-ethylene oxide cetyl alcohol), condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol (e.g., polyoxyethylene sorbitol monooleate), or condensation products of ethylene oxides and partial esters derived from fatty acids and hexitol anhydrides (e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension can also contain one or more preservatives, such as ethyl p-hydroxybenzoate or n-propyl ester. The osmotic pressure concentration of the preparation can be adjusted.

[0091] According to the present invention, istaroxime is administered by intravenous (IV) administration. These preparations may contain a solution of an active agent dissolved in a pharmaceutically acceptable carrier. Acceptable vehicles and solvents that can be used are water, aqueous dextrose and Ringer's solution (an isotonic sodium chloride). These solutions are sterile and generally do not contain unwanted substances. These preparations can be sterilized by conventional, well-known sterilization techniques. As needed, the preparation may contain pharmaceutically acceptable auxiliary substances to approach physiological conditions, such as pH regulators and buffers, toxicity regulators, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, etc. The concentration of the active agent in these preparations can vary widely and will be selected based on the specific mode of administration selected and the needs of the patient, mainly based on fluid volume, viscosity, body weight, etc. The administration is by push injection or continuous infusion (e.g., introduced into a blood vessel substantially uninterruptedly over a prescribed period of time).

[0092] Istaroxime provided herein can be lyophilized. A stable lyophilized formulation comprising a composition provided herein is provided herein, which can be prepared by lyophilizing a solution comprising a drug provided herein and a bulking agent (e.g., mannitol, trehalose, raffinose, lactose and sucrose or a mixture thereof). There are many other traditional lyophilizers. Among the sugars, lactose is the most commonly used. Citric acid, sodium carbonate, EDTA, benzyl alcohol, glycine, sodium chloride, etc. are also used [see, e.g., Journal of Excipients and Food Chemistry Vol. 1, Issue 1 (2010) pp 41-54; U.S. Patent Application No. 20040028670]. In a preferred embodiment, according to the teachings of CN103315968, istaroxime can be prepared as a lyophilized powder for injection.

[0093] According to the present invention, istaroxime provided herein can be used for preventive and / or therapeutic treatment. In therapeutic applications, the composition is applied to a subject who has suffered from the condition or disease in an amount sufficient to treat, prevent, cure, alleviate or partially prevent the clinical manifestations of the condition or disease and its complications (i.e., a "therapeutically effective amount"). For example, in an optional embodiment, the pharmaceutical composition provided herein is applied in an amount sufficient to treat, prevent or improve the individual value in need. The amount of the pharmaceutical composition sufficient to achieve this goal is defined as a "therapeutically effective dose". The dosage schedule and amount, i.e., "dosage regimen", effective for this purpose will depend on various factors, including the stage of the disease or condition, the severity of the disease or condition, the overall state of the patient's health, the patient's physical condition, age, etc. When calculating the patient's dosage regimen, the mode of administration will also be taken into account.

[0094] The dosage regimen also takes into account pharmacokinetic parameters known in the art, i.e., bioavailability, metabolism, clearance rate, etc. 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, ur. J. Clin. Pharmacol. 24:103-108; latest edition of Remington's, supra]. The prior art allows the clinician to determine the dosage regimen for each individual patient, active agent, and disease or condition being treated. The guidance provided for similar compositions used as pharmaceuticals can be used as a guide to determine whether the dosage regimen (ie, dosing schedule and dosage level) for practicing the methods provided herein is correct and appropriate.

[0095] Depending on the dosage and frequency required for the patient's pre-cardiogenic shock or cardiogenic shock symptoms, a single or multiple administration of the preparation can be provided. The preparation should provide a sufficient amount of active agent to effectively treat or prevent or improve the illness, disease or symptom described herein. By selectively normalizing the biochemical activity reduced behind the symptoms of a subgroup of patients, the correct treatment of the pre-cardiogenic shock or cardiogenic shock may be expected to selectively improve symptoms and reduce the incidence of adverse side effects produced by the available drugs during hospitalization or after discharge. When lung pressure can be continuously monitored using a suitable long-term implantable device (which provides SBP, SBP AUC (e.g., to 6 hours or to 24 hours) or an estimate of other parameters of cardiac function discussed elsewhere herein), the term prevention is applicable.

[0096] In one embodiment, an effective amount of istaroxime or an equivalent amount of a pharmaceutically acceptable salt, solvate or hydrate thereof is administered to an individual with pre-cardiogenic shock or cardiogenic shock symptoms at a dosing schedule, 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, 0.85 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, 1.3 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. For example, in some embodiments, istaroxime is administered by infusion at an effective dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min, or about 0.5 μg / kg / min to about 1.5 μg / kg / min, or about 1.0 μg / kg / min to about 1.5 μg / kg / min. In a specific embodiment, the istaroxime is administered by intravenous infusion at an effective dose of about 1.5 μg / kg / min. Alternatively, the effective dose of istaroxime can be started at about 1.0 μg / kg / min for about 1 to about 2 hours, and then increased to 1.5 μg / kg / min during the remaining infusion time, unless the individual exhibits nausea or other signs of poor or insufficient drug tolerance.In another embodiment, the effective dose of istaroxime may be initiated at about 1.5 μg / kg / min for about 1 to about 2 hours and then increased to 1.0 μg / kg / min for the remainder of the infusion time.

[0097] In one exemplary embodiment, a pharmaceutical composition comprising istaroxime in the form of a lyophilized powder is provided. In another embodiment, the pharmaceutical composition comprises istaroxime and a bulking agent (e.g., lactose) in the form of a lyophilized powder. For example, the composition can be a lyophilized powder comprising about 0.1 to about 0.3 wt% istaroxime and about 0.7 to about 0.9 wt% lactose (e.g., 10 mg istaroxime and 50 mg lactose). The lyophilized powder can be reconstituted with any pharmaceutically acceptable carrier (e.g., saline containing 0.9% NaCl) before intravenous infusion.

[0098] Treatment

[0099] Also provided herein are pharmaceutical compositions for use as drugs for treating pre-cardiogenic shock or cardiogenic shock, and methods for treating individuals with pre-cardiogenic shock or cardiogenic shock. In one embodiment, the individual exhibits symptoms of pre-cardiogenic shock SCAI stage B or has been diagnosed with pre-cardiogenic shock SCAI stage B. In a preferred embodiment, the individual exhibits symptoms of pre-cardiogenic shock SCAI stage B caused by ADHF or has been diagnosed with pre-cardiogenic shock SCAI stage B caused by ADHF. In a more preferred embodiment, the individual exhibits symptoms of pre-cardiogenic shock SCAI stage B caused by ADHF or has been diagnosed with pre-cardiogenic shock SCAI stage B caused by ADHF, but has no evidence of acute coronary syndrome (e.g., myocardial infarction). For example, the individual has dyspnea at rest or with minimal exertion, chest tightness with BNP equal to or greater than about 400 pg / mL or NT-proBNP equal to or greater than about 1,400 pg / mL. Preferably, the individual exhibits persistent hypotension at least 2 hours before screening or treatment begins, characterized by an SBP between about 70 mmHg and about 100 mmHg, or more preferably between about 75 mmHg and about 90 mmHg. In addition, before treatment begins, the SBP in the individual does not drop more than about 7 mmHg. The individual may also have a heart rate in the range of about 65 bpm to about 160 bpm or preferably about 75 bpm to about 150 bpm, or if the individual uses a beta-blocker, the heart rate may be about 60 bpm to about 150 bpm. The individual may also have a history of LVEF less than or greater than about 40%. In another embodiment, the individual has a heart rate less than about 90 mmHg without evidence of end-organ hypoperfusion. Alternatively, in some embodiments, the individual has a heart rate less than about 90 mmHg and has evidence of end-organ hypoperfusion. In another embodiment, the individual exhibits symptoms of or has been diagnosed with SCAI stage C cardiogenic shock. However, in other embodiments, the treatment is directed to treating pre-cardiogenic shock, and the individual will not exhibit symptoms of or be diagnosed with SCAI stage C cardiogenic shock or have evidence of end-organ hypoperfusion. Although the individual can be a non-human animal, in preferred embodiments, the individual is a human patient, such as a human patient exhibiting symptoms of pre-cardiogenic shock.

[0100] In some cases, a measurement step is first performed to determine the baseline cardiac function of the individual. For example, an individual with heart failure may present with persistent hypotension, dyspnea, and reduced LVEF. The measurement step may include measuring one or more parameters of cardiac function or cardiac function impairment, such as, but not limited to, reduced SBP or SBP AUC, reduced left ventricular end-diastolic / end-systolic volume and function (LVEF), increased E / Ea or E / A ratios, reduced Ea ratios, reduced stroke volume, increased heart rate, etc. As will be appreciated by those of ordinary skill in the art, any suitable measurement technique available in the art during the measurement step is suitable for use herein, and the selection of a suitable measurement technique corresponding to the parameter of interest is entirely within the purview of those skilled in the art. A non-limiting list of suitable measurement equipment / techniques includes echocardiography, cardiac catheterization, nuclear stress testing, CAT scans, radionuclide ventriculography scans, stethoscopes, sphygmomanometers, pulmonary capillary wedge pressure (PCWP), etc. For example, the SBP can be measured by a sphygmomanometer or arterial catheter attached to a pressure sensor. In another embodiment, one or more cardiac function parameters are measured, which are selected from heart rate (HR), blood pressure (BP), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), area under the systolic blood pressure curve (SBP) The results of the present study showed that the systolic volume of the left ventricle (LV) was 4.37 mmol / l and 3.34 mmol / l, respectively. The systolic volume of the right ventricle (LV) was 1.34 mmol / l and 1.37 mmol / l, respectively. The systolic volume of the right ventricle (LV) was 1.37 mmol / l and 1.37 mmol / l, respectively. The systolic volume of the right ventricle (LV) was 1.37 mmol / l and 1.37 mmol / l, respectively.

[0101] It may be desirable to establish a clinical study group to examine a cohort of individuals who exhibit cardiac function parameters within a selected range of values. For this study, as will be appreciated by one of ordinary skill in the art, there are certain inclusion and exclusion criteria to determine whether an individual is selected to participate in the study. In one embodiment, individuals with one or more inclusion criteria are selected for treatment. In a preferred embodiment, the inclusion criteria include one or more clinical manifestations of pre-cardiogenic shock with ADHF in SCAI stage B and no evidence of acute coronary syndrome. In another embodiment, additional inclusion criteria include males and females aged 18 to 85 years, dyspnea, chest tightness and BNP equal to or greater than about 400 pg / mL or NT-proBNP equal to or greater than about 1400 pg / mL, LVEF less than or equal to 40%, persistent hypotension (which is defined as SBP less than about 90 mmHg) and / or a heart rate of about 75 bpm to about 150 bpm.

[0102] The methods disclosed herein further comprise administering to the individual a therapeutically effective amount of istaroxime. In a preferred embodiment, the istaroxime is in a pharmaceutical composition, such as any of the combinations discussed above. The istaroxime is administered at a therapeutically effective dose. For example, the istaroxime may be administered by intravenous infusion at a dose ranging from about 0.25 μg / kg / min to about 3.0 μg / kg / min, such as 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, 1.3 μg / kg / min, 1.4 In a preferred embodiment, the dose of istaroxime administered to the individual is in the range of about 0.5 μg / kg / min to about 3.0 μg / kg / min. In a more preferred embodiment, the dose of istaroxime administered to the individual is in the range of about 1.0 μg / kg / min to about 2.0 μg / kg / min or 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 a specific embodiment, the dose of istaroxime administered to the individual is about 1.0 μg / kg / min.

[0103] The time period for infusion can be at least about 1 hour to about 48 hours or longer, for example 1 h, 2h, 3 h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, 25h, 26h, 27h, 28h, 29h, 30h, 31h, 32h, 33h, 34h, 35h, 36h, 37h, 38h, 39h, 40h, 41h, 42h, 43h, 44h, 45h, 46h, 47h or 48h. Preferably, the infusion is performed 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 a specific embodiment, the individual is administered istaroxime by intravenous infusion for about 24 hours. In other embodiments, the time period for infusion can be greater than 24 hours, such as 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 31 h, 32 h, 33 h, 34 h, 35 h, 36 h, 37 h, 38 h, 39 h, 40 h, 41 h, 42 h, 43 h, 44 h, 45 h, 46 h, 47 h, 48 h, 54 h, 60 h, 66 h, 72 h, 78 h, 84 h, 90 h, 96 h, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days, 12 days, 13 days, 14 days or longer. For example, the istaroxime infusion administered by a pump can be performed for a much longer duration.

[0104] In another embodiment, the individual is administered a lower dose of istaroxime over an initial period of time to determine whether the individual exhibits signs of poor drug tolerance, such as nausea, pain at the infusion site, etc. For example, the individual may be administered istaroxime by intravenous infusion at a dose of about 1.0 μg / kg / min over the first 1-2 hours, and if the individual does not exhibit signs of drug intolerance, the dose may be increased to 1.5 μg / kg / min over the remaining infusion time (e.g., 24 hours). Similarly, the individual may be administered a higher dose of istaroxime initially, and if the individual exhibits signs of drug intolerance, the dose may be reduced. For example, the individual may be administered istaroxime by intravenous infusion at a dose of about 1.5 μg / kg / min over the first 1-2 hours, and if the individual does exhibit signs of drug intolerance, such as nausea, the dose may be reduced to 1.0 μg / kg / min over the remaining infusion time (e.g., 24 hours). In some embodiments, as an alternative to adjusting the istaroxime infusion dose, the individual may be co-administered an antiemetic (eg, ondansetron) to relieve nausea.

[0105] After the individual istaroxime is administered, the method may include one or more measuring steps performed regularly during and / or after a period of time. The measuring step may include measuring one or more cardiac function parameters as described above before starting the infusion, at the start of the infusion administration, and / or at one or more time points during and after the infusion, such as 15 m, 30 m, 45 m, 1 h, 1.25 h, 1.5 h, 1.75 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h, 13 h, 14 h, 15 h, 16 h, 17 h, 18 h, 19 h, 20 h, 21 h, 22 h, 23 h, 24 h, 48 h, 72 h, 96 h, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 14 days, 21 days, 28 days, 30 days or more after starting the infusion. For example, for individuals who are administered istaroxime by intravenous infusion for up to 24 hours, one or more cardiac function parameters may be measured before, during, and 12 h, 24 h, 48 h, 72 h, 96 h, and 30 days after the start of the infusion. As will be appreciated by those of ordinary skill in the art, the one or more cardiac function parameters are indicative of the efficacy of istaroxime treatment. In some embodiments, the SPB increases by at least about 8 mmHg, such as 8 mmHg, 9 mmHg, 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg or 15 mmHg 6 hours after the administration of istaroxime, indicating the treatment of the pre-cardiogenic shock or the prevention of cardiogenic shock; or the SPB increases by at least about 10 mmHg, such as 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 the administration of istaroxime, indicating the treatment of the pre-cardiogenic shock or the prevention of cardiogenic shock. In other embodiments, within about 6 hours after the start of istaroxime administration, the SPB AUC (0-6) An increase from baseline of at least about 20 mmHg•h, e.g., 20 mmHg•h, 25 mmHg•h, 30 mmHg•h, 35 mmHg•h, 40 mmHg•h, 45 mmHg•h, 50 mmHg•h or more, is indicated for treatment of pre-cardiogenic shock or prevention of cardiogenic shock. In addition, within about 24 hours after initiation of istaroxime administration, the SPB AUC (0-24)An increase from baseline of at least about 200 mmHg•h, such as 200 mmHg•h, 210 mmHg•h, 220 mmHg•h, 230 mmHg•h, 240 mmHg•h, 250 mmHg•h, 260 mmHg•h, 270 mmHg•h, 280 mmHg•h, 290 mmHg•h, 300 mmHg•h or more, indicates treatment of pre-cardiogenic shock or prevention of cardiogenic shock. In some embodiments, improvement in SBP is accompanied by one or more additional indicators of improved cardiac function, such as, but not limited to, increased CI, decreased left ventricular size (e.g., decreased left ventricular end-systolic volume and / or decreased left ventricular end-diastolic volume), and / or decreased left atrial size (e.g., decreased left atrial area). In other embodiments, a decrease in NT-proBNP levels or an increase in eGFP levels indicates treatment of pre-cardiogenic shock or prevention of cardiogenic shock.

[0106] In an alternative embodiment, when evaluating the efficacy of a treatment, treatment regimen, or a specific dose or determining whether a therapeutic dose or maintenance dose should be given, individuals, such as patients affected by precardiogenic shock or cardiogenic shock, are screened regularly to check for the presence and extent of organ and tissue involvement or damage, such as heart (ventricular dilatation, third heart sound myocardial hypertrophy), fatigue, tiredness, decreased exercise tolerance, prolonged recovery time after exercise, kidney (renal insufficiency, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, shortness of breath), ankle swelling, increased jugular venous pressure. In the treatment of cardiovascular disease, especially ADHF with precardiogenic shock or cardiogenic shock, a thorough physical examination should be performed at intervals selected by the expert, which will focus on cardiac, pulmonary and peripheral circulatory function. Thus, in an alternative embodiment, therapy with istaroxime disclosed herein or an equivalent thereof of a pharmaceutically acceptable salt, solvate or hydrate is initiated as early as possible, preferably in the emergency department, to prevent rapid progression of symptoms (e.g., progression from pre-cardiogenic shock to overt cardiogenic shock), and continued for several years after the patient is discharged from the hospital, preferably throughout the patient's life or at least for a period of time consistent with the use of other drugs in heart failure.

[0107] According to the present invention, the uses and methods provided herein may further include co-administration with other drugs or agents. In fact, the present invention selectively corrects reduced cardiac biochemical function (i.e., SERCA2a activity). This undoubtedly helps to alleviate the existing clinical symptoms of pre-cardiogenic shock or cardiogenic shock and ADHF, with fewer unwanted side effects than existing therapies (simply because of the above-mentioned selectivity). However, since pre-cardiogenic shock and cardiogenic shock are complex clinical syndromes, the present invention may be associated 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, enkephalinase (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP proteins, soluble guanosine b) Specific 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 with pre-cardiogenic shock or cardiogenic shock who are treated with the above drugs and receive regular clinical monitoring (e.g., continuous monitoring of their pulmonary blood pressure using an implanted probe) can be protected to predict the onset of ADHF or cardiogenic shock that may be prevented by istaroxime infusion according to the present invention.

[0108] Istaroxime, used as a therapeutic agent for treating pre-cardiogenic shock or cardiogenic shock, disclosed in the present invention, can be combined or co-administered with other therapeutic agents for treating the same disease and / or underlying HF. Exemplary other therapeutic agents are diuretics such as furosemide, bumetanide and torsemide; metolazone; aldosterone antagonists such as spironolactone or eplerenone; thiazide diuretics such as hydrochlorothiazide, metolazone and chlorthalidone. Other agents are ACE inhibitors such as lisinopril and ramipril. ARBs such as valsartan, candesartan and losartan may also be considered. Angiotensin receptor / neprilysin inhibitors (ARNIs) such as sacubitril are included. Other agents may be selected from beta-blockers, such as carvedilol and metoprolol, or vasodilators such as hydralazine, optionally in combination with isosorbide dinitrate, nitrates such as nitroglycerin, amlodipine and felodipine; non-dihydropyridine drugs, such as diltiazem or verapamil. If desired, the compounds of the invention may also be combined with digoxin. Other drugs, such as ivabradine and other anticoagulants, may be considered.

[0109] The compounds of the present invention can be combined with other therapeutic agents, in particular agents that can be used to treat cardiovascular diseases, more particularly in the combination therapy of pre-cardiogenic shock or cardiogenic shock with ADHF. The combined active ingredients can be administered according to different schemes determined by the doctor. According to one embodiment of the present invention, the combination therapy can be performed by administering istaroxime and one or more other therapeutic active ingredients simultaneously or at different times. In the case of concomitant administration, the compound of the present invention and one or more other active ingredients can each be formulated into a corresponding pharmaceutical composition or the same single dosage form. In the former case, the present invention provides a drug kit, in particular a drug kit for treating pre-cardiogenic shock or cardiogenic shock, which contains separate pharmaceutical compositions containing a compound of the present invention and the one or more other active ingredients, respectively. In another embodiment, the present invention provides a drug unit dosage kit, in particular a drug kit for treating pre-cardiogenic shock or cardiogenic shock, which contains a compound of the present invention and the one or more other active ingredients in the same unit dosage form. In addition to or synergistically in combination with the well-known therapeutic effects of the other active agents disclosed herein, combination therapy according to the present invention provides advantageous treatment for pre-cardiogenic shock or cardiogenic shock due to the positive inotropic-relaxant effects of istaroxime disclosed herein.

[0110] Also provided are nanoparticles, nanolipid particles, vesicles and liposome membranes, which contain compounds for practicing the uses and methods provided herein, for example, to deliver to subjects in need thereof the pharmaceutically active compounds and compositions provided herein: istaroxime or its equivalents of pharmaceutically acceptable salts, solvates or hydrates, and optionally in combination with other therapeutically active agents disclosed above. In an optional embodiment, these compositions are designed to target specific molecules, including biomolecules such as polypeptides, including cell surface polypeptides, for example, for targeting desired cell types such as muscle cells or cardiac cells, endothelial cells, etc. The slow release of istaroxime can provide sufficient compound to selectively increase the plasma level of metabolites, so that the plasma level of istaroxime is maintained in a very low range.

[0111] Provided are multilamellar liposomes comprising compounds for practicing the methods provided herein, for example as described in U.S. Application No. 20070082042. The multilamellar liposomes can be prepared using a mixture of oil phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithin to have a particle size of about 200 to 5000 nm to encapsulate the compositions for practicing the uses and methods provided herein.

[0112] Liposomes can be prepared using any method, such as described in U.S. Pat. No. 4,534,899 or U.S. Application No. 20070042031, including a method for producing liposomes by encapsulating an active agent (or a 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 with the organic lipid solution in a first mixing zone to produce a liposome solution, wherein the organic lipid solution mixes with the aqueous solution to essentially instantaneously produce liposomes encapsulating the active agent; and then immediately mixing the liposome solution with a buffer solution to produce a diluted liposome solution.

[0113] In one embodiment, the liposome composition for practicing the uses and methods provided herein comprises a substituted ammonium and / or polyanion for, for example, targeted delivery of istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof for practicing the methods provided herein to a desired cell type as described in U.S. Application No. 20070110798.

[0114] Nanoparticles comprising compounds according to the invention are provided for practicing the uses and methods provided herein, which take the form of nanoparticles (e.g., secondary nanoparticles) containing active agents, as described in U.S. Application No. 20070077286. In one embodiment, nanoparticles are provided comprising a lipid-soluble active agent or a fat-soluble, water-soluble active agent that acts with a divalent or trivalent metal salt for practicing the uses and methods provided herein.

[0115] In one embodiment, solid lipid suspensions can be used to formulate and deliver compositions for practicing the uses and methods provided herein to mammalian cells in vivo, in vitro or ex vivo, as described in US Application No. 20050136121.

[0116] Compositions and preparations for practicing the purposes and methods provided herein can be delivered by using liposomes or nanoliposomes. By using liposomes, especially when carrying target cell-specific ligands on the surface of liposomes or otherwise preferentially targeting specific organs, people can centrally deliver the active agent to target cells in vivo [see, for example, U.S. Patent Nos. 6063400, 6007839; 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 present invention also provides Eur J Pharm Biopharm. 2011; 79 (2): 285-93 disclosed in the liposomal preparation of istaroxime.

[0117] delivery vehicle

[0118] In an optional embodiment, any delivery vehicle can be used to practice the purposes and methods provided herein, for example, to deliver the compounds provided herein to a subject in need thereof. For example, a delivery vehicle comprising a polycation, a cationic polymer and / or a cationic peptide (e.g., a polyethyleneimine derivative) can be used, such as described in U.S. Application No. 20060083737.

[0119] In one embodiment, a dried polypeptide-surfactant complex is used to formulate a composition for practicing the uses and methods provided herein, such as described in US Application No. 20040151766.

[0120] In one embodiment, the compositions for practicing the purposes and methods provided herein can be applied to cells using a vehicle with a cell membrane penetrating peptide conjugate, such as described in U.S. Patent Nos. 7,306,783 and 6,589,503. In one aspect, the composition to be delivered is coupled to a cell membrane penetrating peptide. In one embodiment, the composition to be delivered and / or the delivery vehicle is coupled to a peptide that mediates transport, such as described in U.S. Patent No. 5,846,743, which describes a peptide that mediates transport that is highly alkaline and binds to polyphosphoinositide.

[0121] In one embodiment, electropermeabilization is used as the primary or auxiliary means of delivering the composition to the cells, for example using any of the electroporation systems described in US Pat. Nos. 7,109,034, 6,261,815, 5,874,268.

[0122] The following examples further illustrate the present invention.

[0123] Example 1 - 24-hour istaroxime infusion therapy in patients hospitalized for pre-cardiogenic shock: a randomized, double-blind, placebo-controlled, parallel-group study

[0124] To evaluate the safety and efficacy of istaroxime in patients with pre-cardiogenic shock, 60 patients with AHF and presenting with pre-cardiogenic shock (pre-CS) without acute myocardial infarction were randomized to 24-hour istaroxime 1.0-1.5 mg / kg / min or placebo. Pre-CS was defined as systolic blood pressure (SBP) <90 mmHg, without hypoperfusion, intravenous lactate >2 mmol / L, and / or mechanical or inotropic support. Inclusion criteria included AHF-related SCAI stage B pre-CS, 18-85 years of age, hospitalization for AHF, left ventricular ejection fraction <40%, persistent hypotension (SBP between 75 and 90 mmHg), heart rate 75-150 bpm, and no need for mechanical support or intravenous therapy to increase BR after 6 h at screening or planned. Patients with the following clinical signs were excluded according to the stage B SCAI classification: peripheral hypoperfusion, venous lactate >2 mmol / L, and / or receiving mechanical support or treatment with intravenous vasodilators, inotropes, or vasopressors. Other exclusion criteria were concurrent or planned treatment with oral digoxin (randomization was allowed if digoxin plasma concentration was <0.5 ng / ml at screening); acute coronary syndrome or stroke in the past 3 months; coronary artery bypass grafting or percutaneous coronary intervention in the past month or planned within the next month; life-threatening ventricular arrhythmia or implantable cardioverter-defibrillator shock in the past month; sustained ventricular tachycardia or uncontrolled arrhythmia in the past 3 months; fever >38°C; estimated glomerular filtration rate (eGFR) <30 ml / min / m 2 ; serum potassium >5.3 or <3.5 mmol / L; stroke or transient ischemic event within the past 3 months; and acute respiratory distress syndrome.

[0125] Patients were centrally randomized in a 1:1 ratio to receive istaroxime or placebo using an interactive response technique. Study medication was provided in uniquely numbered kits containing identical vials of lyophilized powder (istaroxime plus lactose) to be reconstituted by adding 5 ml of normal saline to the vial. Istaroxime was administered as a continuous infusion of 1.0 µg / kg / min for 24 h. The infusion rate could be reduced at the investigator's discretion based on tolerability issues (e.g., nausea), severe bradycardia, or greater than expected increases in BP. The original protocol had a target and maximum infusion dose of 1.5 µg / kg / min; however, after 26 of 60 patients had been enrolled, the sponsor and executive steering committee amended the protocol to limit the dose of istaroxime to 1.0 µg / kg / min, after which all patients would receive a target and maximum dose of 1.0 µg / kg / min of istaroxime.

[0126] The primary efficacy endpoint was the area under the curve representing the change from baseline in SBP from the start of study drug infusion until 6 h (SBP AUC). Secondary end points included SBP AUC up to 24 h; changes from baseline in SBP (particularly at 6 and 24 h), diastolic blood pressure (DBP), and mean arterial pressure (MAP); change from baseline in heart rate (HR); treatment failure score (based on death, mechanical circulatory, respiratory, or renal support or intravenous inotropic or vasopressor therapy, and change in SBP); treatment failure, defined as death or the need for mechanical circulatory, respiratory, or renal support or intravenous inotropic or vasopressor therapy; an increase in SBP of >5% and / or >10 mm Hg from baseline; change in quality of life as measured by the EuroQol 5 dimensions 5 levels (EQ-5D-5L); changes from baseline to 24 h in echocardiographic parameters; changes in troponin and N-terminal pro-B-type natriuretic peptide (NT-proBNP); readmission for heart failure and any reason before day 30; worsening of heart failure during hospitalization by day 5; and length of hospital stay. Worsening of heart failure during hospitalization was defined as worsening of signs and / or symptoms of heart failure since the last assessment, requiring intensification of intravenous therapy for heart failure or mechanical ventilatory, renal, or circulatory support. Safety endpoints were assessed throughout the study and included the incidence of adverse events; changes in vital signs and 12-lead electrocardiographic (ECG) parameters; the incidence of clinically or hemodynamically significant supraventricular or ventricular arrhythmic episodes detected by continuous ECG monitoring; standard laboratory parameters; measures of renal function; cardiac troponin I or T; and mortality through day 30. The studies are summarized in Tables 1 and Figure 1 middle.

[0127] Statistical analysis

[0128] The primary efficacy analysis population was the modified intention-to-treat (mITT) population, defined as subjects who received study treatment (any istaroxime or placebo infused into the patient) and had at least one post-baseline BP assessment. Supportive efficacy analyses were performed in the ITT population (including all randomized patients) and the per-protocol population (including subjects who received study drug infusion and did not violate the exclusion protocol). Safety analyses included all patients who received any study drug. Since all randomized patients received study treatment and had at least one post-baseline BP assessment, the mITT, ITT, and safety populations were identical. Since the dosing regimen was changed after the trial was underway, patients in the active drug group were categorized according to the maximum istaroxime dose received (all <1.0 vs. any >1.0 µg / kg / min), and additional pairwise comparisons were performed.

[0129] Unadjusted results for continuous variables are presented as means and standard deviations, while adjusted changes are presented as least square mean changes and corresponding standard errors (SEs). Frequencies for categorical variables are presented. Sites that enrolled fewer than six patients were combined and treated as one site to adjust for combined sites. Frequencies for categorical variables and binary clinical end points are reported.

[0130] The primary end point (i.e., SBP AUC up to 6 hours) was calculated by the trapezoidal rule. Treatment groups were compared with the use of ANCOVA, using baseline values, pooled sites, and treatment in the model. Changes in creatinine clearance, heart rate, MAP, natriuretic peptides, and troponins were compared between treatment groups with mixed models for repeated measures, using baseline values, treatment, pooled study sites, time, and treatment-by-time interactions. Changes from baseline to 96 hours and 30 days on the EuroQol visual analog scale and changes in echocardiographic measures at 24 and 30 hours were compared between treatment groups at each time point with the use of ANCOVA, using baseline values, treatment, and pooled study sites in the model. Treatment failure scores (up to 24 hours), length of hospital stay, length of stay in the intensive care unit or coronary care unit (ICU / CCU), survival to hospital discharge, and survival out of the critical care unit to day 30 were compared between groups with the use of the Van Elteren test, stratified by pooled study center. The proportions of subjects with persistent treatment failure, any rehospitalization within 30 days, or an increase in SBP from baseline of >5% and >10 mmHg at a time point between 4 and 6 h after dosing were compared using the Cochran-Mantel-Haenszel (CMH) test controlling for combined sites. A two-sided p < 0.05 was considered statistically significant. No adjustment for multiple testing was performed. Analyses were performed using SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA).

[0131] result

[0132] The primary endpoint was AUC, representing the change in SBP from the start of the infusion to hour 6. Figure 2-4 The results of this analysis are summarized in Table 1. The adjusted mean 6-h AUC was 53.1 (SE 6.88) mmHg•h in patients treated with istaroxime compared with 30.9 (SE 6.76) mmHg•h in the placebo group (p=0.017), an increase of 72% (see Table 1. Figure 2 In addition, the adjusted mean 24-h SBP AUC was 291.2 (SE 27.5) mmHg•h in the istaroxime group compared with 208.7 (SE 27.0) mmHg•h in the placebo group (p=0.025), an increase of 40% (data not shown). Figure 3 As shown in Figure A, the adjusted SBP increase at 6 h was 12.3 (SE 1.71) mmHg in the istaroxime treatment group compared with 7.5 (SE 1.64) mmHg in the placebo group (p = 0.045). Figure 3As shown in B, the corresponding adjusted SBP change at 24 h was 17.1 (SE 2.36) mmHg in the istaroxime group compared with 15.1 (SE 2.25) mmHg in the placebo group (p = 0.543). In addition, DBP (see Figure 3 C) and MAP (see Figure 4 A) and the latter two persisted 24 hours after study drug administration. Figure 4 Changes in laboratory values ​​of eGFR and NT-proBNP between istaroxime- and placebo-treated patients are shown in B and 4C, respectively.

[0133] Echocardiographic changes during the first 24 h of the study are presented in Table 3. Of the echocardiographic measures assessed, some were significantly improved in istaroxime-treated patients compared with placebo-treated patients at 24 h after adjustment, including cardiac index (+0.16 + 0.1 vs -0.06 + 0.1 L / min / m 2 ; p = 0.016), left atrial area (-1.8 + 0.5 vs 0.0 + 0.5 cm 2 ; 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).

[0134] Table 3. Echocardiographic changes during the first 24 hours

[0135]

[0136]

[0137] As shown above, istaroxime treatment resulted in an increase in SBP from the start of treatment to 24 h, based on AUC at 6 h and 24 h. Notably, this study is the first to show a beneficial effect on BP in patients with CS using a non-adrenergic agent, thus having no effect on pulse. Several improvements in echocardiographic measures were observed, including an increase in cardiac index and a decrease in left ventricular and atrial dimensions. These findings suggest that istaroxime improves cardiac function in this patient population. The simultaneous increase in cardiac index and BP is unique and has not been observed previously when any intravenous agent is administered to patients with CS. This improvement may allow patients with CS to stabilize more quickly and initiate other life-saving therapies earlier.

Claims

1. A pharmaceutical composition for use as a medicament for treating or preventing early cardiogenic shock or cardiogenic shock in an individual, the individual being defined as suffering from acute heart failure with a systolic blood pressure of less than about 90 mmHg for a first period of at least about 1 hour, the pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier; and (ii) istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the istaroxime or a pharmaceutically 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 a second period of at least about 3 hours.

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

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

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

5. A pharmaceutical composition for use according to any one of claims 2-4, wherein the one or more cardiac function parameters in the 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 for use according to claim 1, wherein the acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome.

7. The pharmaceutical composition for use according to any one of claims 1 to 6, wherein the subject has a heart rate of about 75 beats / minute to about 150 beats / minute, or if the subject has been administered a beta-blocker, a heart rate of about 60 bpm to about 150 bpm.

8. The pharmaceutical composition for use according to any one of claims 1-7, wherein the istaroxime 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 for use according to any one of claims 1-8, wherein the first period of time is at least about 2 hours.

10. The pharmaceutical composition for use according to any one of claims 1-9, wherein the second period of time is at least about 6 hours.

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

12. The pharmaceutical composition for use according to any one of claims 1-11, wherein the subject has at least one of the following: dyspnea at rest or with minimal exertion, congestion on chest x-ray or lung ultrasound and 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 left ventricular ejection fraction less than about 40% or echocardiographically confirmed ejection fraction less than about 40%.

13. The pharmaceutical composition for use according to any one of claims 2 to 12, wherein the one or more cardiac function parameters further include heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine 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 diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV ), left ventricular end-systolic volume (ESV), left atrial 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 annular plane systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

14. A pharmaceutical composition for use according to any one of claims 1 to 13, comprising one or more other therapeutically active ingredients.

15. The pharmaceutical composition for use according to claim 14, wherein the other therapeutically active ingredients are selected from ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, angiotensin receptor / neprilysin inhibitors (ARNI), myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, soluble guanylate cyclase (sGC) activators and beta-arrestin ligands of angiotensin II receptors.

16. The pharmaceutical composition for use according to claim 15, wherein: (a) the diuretic is selected from furosemide, bumetanide, torsemide, metolazone, aldosterone antagonists and thiazides; or (b) the ACE inhibitor is lisinopril or ramipril; or (c) the angiotensin II receptor blocker is selected from valsartan, candesartan, olmesartan, telmisartan and losartan; or (d) the ARNI is saccubitril; 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.

17. A pharmaceutical composition for use according to any one of claims 1 to 16, wherein the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and wherein the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent.

18. A pharmaceutical composition for use as a medicament for treating pre-cardiogenic shock or cardiogenic shock in an individual, the pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier; and (ii) istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof is formulated for administration by intravenous infusion over at least about 6 hours at a dose of about 0.2 μg / kg / min to about 2.0 μg / kg / min, thereby improving blood pressure and cardiac output.

19. The pharmaceutical composition of claim 18, wherein the istaroxime 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 for at least about 24 hours.

20. A pharmaceutical composition according to claim 18 or claim 19, wherein the blood pressure is systolic blood pressure.

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

22. The pharmaceutical composition of any one of claims 18-21, wherein administration of the pharmaceutical composition increases systolic blood pressure above baseline by 6 hours after initiation of intravenous infusion.

23. The pharmaceutical composition of any one of claims 18-22, wherein administration of the pharmaceutical composition to the 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).

24. The pharmaceutical composition according to any one of claims 18-23, further comprising saline as the pharmaceutically acceptable carrier, and wherein the istaroxime is reconstituted from a lyophilized powder comprising istaroxime mixed with a bulking agent.

25. The pharmaceutical composition according to any one of claims 18-24, wherein the individual is receiving therapeutic treatment with one or more therapeutically active ingredients.

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

27. The pharmaceutical composition according to claim 26, wherein: (a) the diuretic is selected from furosemide, bumetanide, torsemide, metolazone, aldosterone antagonists and thiazides; or (b) the ACE inhibitor is lisinopril or ramipril; or (c) the angiotensin II receptor blocker is selected from valsartan, candesartan, olmesartan, telmisartan and losartan; or (d) the ARNI is saccubitril; 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.

28. A method of treating or preventing early cardiogenic shock or cardiogenic shock in an individual, the method comprising: a) provide individuals with acute heart failure; b) determining that the individual has a systolic blood pressure of less than about 90 mmHg for a first time period of at least about 1 hour; and c) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier; and (ii) istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the istaroxime or a pharmaceutically 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 wherein the administering comprises an intravenous infusion for a second period of at least about 3 hours; and wherein administration of the pharmaceutical composition results in an increase above baseline in both cardiac systolic function and cardiac output, said increase being measurable up to a third time period after initiation of said intravenous infusion, thereby treating or preventing early cardiogenic shock or cardiogenic shock in said individual.

29. The method of claim 28, further comprising measuring one or more cardiac function parameters in the individual, wherein the one or more cardiac function parameters include blood pressure.

30. The method of claim 29, wherein the blood pressure is systolic blood pressure.

31. The method of claim 29 or claim 30, wherein administration of the pharmaceutical composition results in an increase in the systolic blood pressure above baseline, and wherein the third period of time is about 6 hours.

32. The method of claim 29 or claim 30, wherein the 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, and wherein the third time period is about 6 hours.

33. The method of any one of claims 29-32, wherein the one or more cardiac function parameters in the 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 method of claim 28, wherein the acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome.

35. The method of any one of claims 28-34, further comprising determining the individual's heart rate to be between about 75 beats / minute and about 150 beats / minute, or if the individual has been administered a beta blocker, a heart rate of between about 60 bpm and about 150 bpm.

36. The method of any one of claims 28-35, wherein the istaroxime, or a pharmaceutically acceptable salt, solvate, or hydrate thereof, is administered at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min.

37. The method of any one of claims 28-36, wherein the first period of time is at least about 2 hours.

38. The method of any one of claims 28-37, wherein the second period of time is at least about 6 hours.

39. The method of claim 38, wherein the second period of time is at least about 24 hours.

40. The method of any one of claims 28-39, wherein the individual is a human who is at least 18 years old.

41. The method of any one of claims 28-40, wherein the subject has at least one of: dyspnea at rest or with minimal exertion, congestion on chest x-ray or lung ultrasound and 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 left ventricular ejection fraction less than about 40% or an ejection fraction less than about 40% confirmed by echocardiography.

42. The method according to any one of claims 29-41, wherein the one or more cardiac function parameters further include heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine 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 diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), Left ventricular end-systolic volume (ESV), left atrial 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 annular plane systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

43. The method of any one of claims 28-42, wherein the individual is receiving therapeutic treatment for pre-cardiogenic shock or cardiogenic shock with one or more other therapeutically active ingredients.

44. The method of claim 43, wherein the other therapeutically active ingredients are selected from ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, angiotensin receptor / neprilysin inhibitors (ARNI), myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, soluble guanylate cyclase (sGC) activators and beta-arrestin ligands of the angiotensin II receptor.

45. The method of claim 44, wherein: (a) the diuretic is selected from furosemide, bumetanide, torsemide, metolazone, aldosterone antagonists and thiazides; or (b) the ACE inhibitor is lisinopril or ramipril; or (c) the angiotensin II receptor blocker is selected from valsartan, candesartan, olmesartan, telmisartan and losartan; or (d) the ARNI is saccubitril; 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.

46. ​​The method of any one of claims 28-45, wherein the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and wherein the istaroxime is reconstituted from a lyophilized powder comprising istaroxime admixed with a bulking agent.

47. A method of treating pre-cardiogenic shock in an individual, the method comprising: a) providing an individual with pre-cardiogenic shock with acute heart failure, wherein the pre-cardiogenic shock includes systolic blood pressure less than about 90 mm Hg without end-organ hypoperfusion or myocardial infarction; b) administering to the individual a therapeutically effective amount of a pharmaceutical composition comprising: (i) a pharmaceutically acceptable carrier; and (ii) istaroxime or a pharmaceutically acceptable salt, solvate or hydrate thereof, wherein the istaroxime or a pharmaceutically 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 wherein the administration comprises intravenous infusion for at least about 6 hours; and c) measuring one or more cardiac function parameters in the individual, wherein the one or more cardiac function parameters include blood pressure; wherein administration of said pharmaceutical composition results in an increase in said blood pressure above baseline, said increase being measurable up to 6 hours after initiation of said intravenous infusion, thereby treating a pre-cardiogenic shock phase in said individual.

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

49. The method of claim 47, wherein the 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 method of any one of claims 47-49, wherein the one or more cardiac function parameters in the 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 method of claim 50, wherein administration of the pharmaceutical composition results in: (a) Increased cardiac index; or (b) decreased left atrial area; or (c) an increase in stroke volume; or (d) decreased left ventricular end-diastolic volume; or (e) decreased left ventricular end-diastolic volume; or (f) Any combination of (a)-(e).

52. The method of any one of claims 47-51, wherein the acute heart failure is acute decompensated heart failure.

53. The method of any one of claims 47-52, further comprising determining the individual's heart rate to be between about 75 beats / minute and about 150 beats / minute, or if the individual has been administered a beta blocker, a heart rate of between about 60 bpm and about 150 bpm.

54. The method of any one of claims 47-53, wherein the istaroxime, or a pharmaceutically acceptable salt, solvate or hydrate thereof, is administered at a dose of about 1.0 μg / kg / min to about 1.5 μg / kg / min.

55. The method of any one of claims 47-54, wherein the administering comprises intravenous infusion for at least about 24 hours.

56. The method according to any one of claims 47-55, wherein the one or more cardiac function parameters further include heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest tightness, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatinine 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 diameter (EDD), left ventricular end-systolic diameter (ESD), left ventricular end-diastolic volume (EDV), Left ventricular end-systolic volume (ESV), left atrial 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 annular plane systolic excursion (TAPSE), right ventricular Sa, mitral regurgitation (MR), inferior vena cava diameter (IVC), or any combination thereof.

57. The method of any one of claims 47-56, wherein the individual is receiving therapeutic treatment for pre-cardiogenic shock or cardiogenic shock with one or more other therapeutically active ingredients.

58. The method of claim 57, wherein the other therapeutically active ingredients are selected from ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, angiotensin receptor / neprilysin inhibitors (ARNI), myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, soluble guanylate cyclase (sGC) activators, and beta-arrestin ligands of the angiotensin II receptor.

59. The method of any one of claims 47-58, wherein the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and wherein the istaroxime is reconstituted from a lyophilized powder comprising istaroxime admixed with a bulking agent.

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