WO2023205183A1 - Formulation intraveineuse contenant de l'istaroxime pour le traitement d'un pré-choc cardiogénique et d'un choc cardiogénique - Google Patents
Formulation intraveineuse contenant de l'istaroxime pour le traitement d'un pré-choc cardiogénique et d'un choc cardiogénique Download PDFInfo
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- WO2023205183A1 WO2023205183A1 PCT/US2023/018998 US2023018998W WO2023205183A1 WO 2023205183 A1 WO2023205183 A1 WO 2023205183A1 US 2023018998 W US2023018998 W US 2023018998W WO 2023205183 A1 WO2023205183 A1 WO 2023205183A1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Definitions
- the present invention relates to the field of pharmaceutical s, in particular to an istaroxime-containing intravenous formation for use in the treatment of prc-cardiogenic shock or cardiogenic shock.
- HF heart failure
- AH F acute heart failure
- ADHF acute decompensated heart failure
- pre-cardiogenic shock The period of clinical and hemodynamic deterioration that precedes cardiogenic shock is known as pre-cardiogenic shock, or, according to the Society for Cardiovascular Angiography and Intervention (SC Al) classification system, Stage B cardiogenic shock [see Jentzer et al., 2019, JACC 74( 17):2117-2127].
- SC Al Society for Cardiovascular Angiography and Intervention
- the major aim of an intervention in pre-cardiogenic shock is to interrupt or reverse the hemodynamic dow nw ard spiral that ultimately leads to cardiogenic shock and death. Left unattended, pre-cardiogenic shock leads to overt cardiogenic shock with refractory hypotension, profoundly altered cellular metabolism, and end-organ failure.
- This transition period lacks the clinical and hemodynamic criteria that define cardiogenic shock, or SCAI Stage C cardiogenic shock; namely, systolic blood pressure (SBP) below 90 mmHg (or vasopressor therapy to maintain SBP over 90 mmHg), cardiac index (Cl) less than 2.2 L /min/m 2 , pulmonary capillary' w edge pressure (PCWP) over 15 mmHg, and clinical evidence of end-organ hypoperfusion [Hochman et al., 1999, N, Engl. J. Med, 341(9):625-634].
- SBP systolic blood pressure
- Cl cardiac index
- PCWP pulmonary capillary' w edge pressure
- Treatment of patients with ADHF and cardiogenic shock or CHF presenting in cardiogenic shock can differ substant i ally from the treatm ent of other types of cardiogenic shock because the hemodynamic condition and neurohormonal milieu are often strikingly different.
- Patients with HF often have profound upregulation of vasoconstrictor substances, such as angiotensin II, endothelin 1, and norepinephrine (Milo-Cotter et aL, 2011 , Cardiology 1 19:96-105; Shah et al, 2001 , Rev. Cardio vase. Med. 2(supp. 2)S2-S6].
- Istaroxime (PS T 2744), which is an androstenedione derivative and chemically unrelated to cardiac glycosides, Istaroxinie may have potential to overcome may of the issues with prior or existing therapies being used to treat patients with AHF.
- Istaroxime exerts its effects through dual mechanisms of action: 1 ) the inhibition of the Na7K*-ATPase activity, thereby causing an increase in intracellular calcium, which increases cardiomyocyte contractility (inotropy); and 2) the activation of the sarcoplasmic reticulum calcium ATPase isoform (SERCA2a), thus improving both myocardial relaxation (lusitropy) and contractility as well as potentially reducing the risk for arrythmias.
- SERCA2a sarcoplasmic reticulum calcium ATPase isoform
- WO 2020 180356 A9 discloses another clinical study that examined prolonged istaroxime infusion in 120 patients with ADHF.
- This study involved two doses of istaroxime (0.5 pg/kg/min and 1.0 pg'kg'min) infused for up to 24 hours.
- the primary endpoint of this study was E/Ea ratio and revealed an improvement in both treatment groups compared to the placebo groups.
- prolonged infusion with Istaroxime showed significant improvements for most, of the diastolic function parameters measured after 6 hours of infusion.
- compositions containing istaroxime formulated for administration to a subject for use in a treatment method for pre-cardiogenic shock or cardiogenic shock.
- the administration is by intravenous infusion and is for a duration of up to about 24 hours, whereby the systolic blood pressure (SBP), diastolic blood pressure (DBP), mean blood pressure, and other parameters of heart function in the individual are improved.
- SBP systolic blood pressure
- DBP diastolic blood pressure
- mean blood pressure mean blood pressure
- the improvement in heart function can be measured by a change from baseline of SBP or SBP area under the curve (AUC) at 6 hour's and'or 24 hours from the start of infusion.
- One aspect of the invention features a pharmaceutical composition for use as a medicament in the treat ment or prevention of early cardiogenic shock or cardiogenic shock in an individual.
- the individual is defined as having acute heart failure with a systolic blood pressure of less than about 90 mmHg for a first period of time of at least about 1 hour.
- the pharmaceutical composition includes 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 pg/kg/min to about 2.0 pg ⁇ kg/min for a second period of time of at least about 3 hours.
- one or more parameters of heart function in the individual are measured, such ns blood pressure.
- the blood pressure is systolic blood pressure, and the administration of the pharmaceutical composition results in an increase over baseline for the systolic blood pressure.
- the one or more parameters of heart function in the individual additionally includes cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof.
- the acute heart failure is acute decompensated heart failure without evidence of end-organ hypoperfusion or acute coronary syndrome.
- the individual has a heart rate of about 75 beats/minute and about 150 beats /minute or about 60 bpm to about 150 bpm if the individual has been administered a beta blocker.
- the istaroxime or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 pg/kg/mln to about 1.5 pg/kg/mln.
- the first period of lime is at least about 2 hours, or at least about 6 hours, or at least about 24 hours.
- the individual has at least one of dyspnea at rest or minimal exertion, congestion on chest x-ray or lung ultrasound with brain natriuretic peptide of less than about 400 pg/mL or N-terminal pro b- type Natriuretic Peptide of at least 1 ,400 pg/mi, or left ventricular ejection fraction of less than about 40%, or echocardiogram confirming ejection fraction of less than about 40%
- the one or more parameters of heart function birther comprise heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP), systolic blood pressure (SBP), creatine clearance, deceleration slope, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide levels (BNP).
- HR heart rate
- DBP diastolic blood pressure
- SBP systolic blood pressure
- BNP brain natriuretic peptide
- NT-pro-BNP levels troponin levels, venous lactate levels, echocardiographic measurements, left ventricle end diastolic diameter (EDD), left ventricle end systolic diameter (ESD), left ventricle end diastolic volume ( EDV), left ventricle end systolic volume (ESV), left atrium diameter (LAD), left atrium area (LAA), left atrium volume (LAV), E wave, A wave, E wave deceleration time (EDT), E/A ratio. Ea, Aa, E/Ea ratio, left ventricle ejection fraction (LVEF).
- EDD left ventricle end diastolic diameter
- ESD left ventricle end systolic diameter
- EDV left ventricle end diastolic volume
- EV left atrium diameter
- LAA left atrium area
- LAV left atrium volume
- E wave A wave, E wave deceleration time (EDT), E/A ratio.
- the pharmaceutical composition includes one or more further therapeutically active ingredients, such as, but not limited to ACE inhibitors (e.g., Lisinopril or Ramipril), angiotensin receptor blockers (ARBs) (eg., valsartan, candesartan, olmesartan, lelmisartan, or losartan), diuretics (e.g., furosemide, bumetanide, torasemide, metolazone.
- ACE inhibitors e.g., Lisinopril or Ramipril
- ARBs angiotensin receptor blockers
- diuretics e.g., furosemide, bumetanide, torasemide, metolazone.
- the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising the istaroxime admixed with a bulking agent.
- a pharmaceutical composition for use as a medicament in the treatment of pre-cardiogenic shock or cardiogenic shock in an individual.
- the pharmaceutical composition includes a pharmaceutically acceptable carrier and istaroxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof.
- the istaroxime or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated for administration by intra venous infusion at a dose of about 0.2 pg/kg/min to about 2.0 pg/kg/min for at least about 6 hour, whereby blood pressure and cardiac output are improved.
- the istaroxime or pharmaceutically acceptable salt, solvate, or hydrate thereof is formulated for administration by intravenous infusion at a dose of about 1.0 pg/kg/min to about 1.5 pg/kg/min for at least about 24 hours.
- the blood pressure is systolic blood pressure, which can be measured by sphygmomanometer or arterial line.
- the administration of the pharmaceutical composition increasing systolic blood pressure over baseline by 6 hours after start of intravenous infusion.
- the administration of the pharmaceutical composition to the individual results in (a) increased cardia index: (b) decreased left atrial area; (c ) increased stroke volume; (d) decreased left ventricular end-diastolic volume; (e) decreased left ventricular end-diastolic volume; or (f> any combination of (a) ⁇ (e).
- the pharmaceutical composition includes saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising the istaroxime admixed with a bulking agent.
- the individual is undergoing a therapeutic treatment with one or more therapeutically active ingredients, such as, but not limited to ACE inhibitors, ARBs, diuretics, Ca channel blockers, beta-blockers, digitalis, NO donors, vasodilators, SERCA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, activators of the soluble Guanylate Cyclase (sGC), and/or beia-arrestin ligand of Angiotensin 11 receptor.
- 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,
- Another aspect of the invention features a method of treating or preventing early cardiogenic shock or cardiogenic shock in an individual.
- the method includes the steps of providing an individual with acute heart lai Sure, determining that the individual has a systolic blood pressure of less than about 90 mmHg for a first period of time of at least about I hour, and administering to the individual a therapeutically effective amount of a pharmaceutical composition.
- the pharmaceutical composition includes a pharmaceutically acceptable carrier and istaroxime or a pharmaceutically acceptable salt, solvate, or hydrate thereof, which is administered at a dose of about 0.2 ug/kg /min to about 2.0 pg/kg/min by infusion for a second period of time of at least about 3 hours.
- the administering of the pharmaceutical composition results in an increase over baseline for both systolic heart function and cardiac output, the increase measurable by a third period of time following the start of the intravenous infusion, thereby treating or preventing early cardiogenic shock or cardiogenic shock in the indi vidual.
- the method includes the step of measuring one or more parameters of heart function in the individual, such as blood pressure or, preferably, systolic blood pressure.
- the administering of the pharmaceutical composition results in an increase over baseline for the systolic blood pressure, and the third period of time is about 6 hours.
- the blood pressure is measured as systolic blood pressure area under the curve, and administering of the pharmaceutical composition results in an increase over baseline for the systolic blood pressure area under the curve - the third period of time is about 6 hours.
- the one or more parameters of heart function in the individual additionally includes cardiac index, left atrial area, stroke volume.
- the acute heart failure is acute decompensated heart failure wi thout evidence of end-organ hypoperfusion or acute coronary syndrome.
- the method includes the step of determining that the individual has a heart rate of about 75 beatsZminute and about 150 beats/minute, or about 60 bpm to about 150 bpm if the individual has been administered a beta blocker.
- the istaroxime or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered al a dose of about 1.0 pg/kg/min to about 1.5 pg/kg/min.
- the first period of time is at least about 2 hours, or at least about 6 hours, or at least about 24 hours.
- the individual is a human aged at least IS years old.
- the individual has at least one of dyspnea at rest or minimal exertion, congestion on chest x-ray or lung ultrasound with brain natriuretic peptide of less than about 400 pg/mL or N-tenninal pro b-type Natriuretic Peptide of at least 1,400 pg/ml, or left ventricular ejection fraction of less than about 40%, or echocardiogram confirming ejection fraction of less than about 40%.
- the one or more parameters of heart function further comprise heart rate (HR), diastolic relaxation, systolic contraction, dyspnea, chest congestion, diastolic blood pressure (DBP ), systolic blood pressure (SBP), creatine clearance, deceleration slope, mitral inflow velocity, mean arterial pressure, brain natriuretic peptide levels (BNP), NT- pro-BNP levels, troponin levels, venous lactate levels, echocardiographic measurements, left ventricle end diastolic diameter (EDD), left ventricle end systolic diameter (ESD), left ventricle end diastolic volume (EDV), left ventricle end systolic volume (ESV), left atrium diameter (LAD), left atrium area (LAA), left atrium volume (LAV), E wave, A wave, E wave deceleration time (EDT), E/A ratio, Ea, Aa, E Ea ratio, left ventricle
- the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted, from a lyophilized powder comprising the istaroxime admixed with a bulking agent.
- the pharmaceutical composition comprises saline as the pharmaceutically acceptable carrier, and the istaroxime is reconstituted from a lyophilized powder comprising the istaroxime admixed with a bulking agent.
- the invention also features a method of treating pre-cardiogenic shock in an individual that includes the steps of: 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 Fig without end-organ hypoperfusion or myocardial infarction; b) administering to the individual a therapeutically effective amount of a pharmaceutical composi tion compri sing: (i) a pharmaceutically acceptable carrier; and (ii ) istaroxime or a pharmaceutical ly acceptable salt, solvate, or hydrate thereof, wherein the istaroxime or pharmaceutically acceptable salt, solvate, or hydrate thereof is administered at a dose of about 0,2 pg kg min to about 2.0 pg kg min, and wherein the administering comprises intravenous infusion for at least about 6 hours; and c) measuring one or more parameters of heart function in the individual, wherein the one or more parameters of heart function compri ses blood pressure. Further, the administering of the
- the blood pressure is systolic blood pressure
- the administration of the pharmaceutical composition results in an increase over baseline for the systolic blood pressure.
- the blood pressure is measured as systolic blood pressure area under the curve, and the administration of the pharmaceutical composition results in an increase over baseline for the systolic blood pressure area under the curve.
- the one or more parameters of heart function in the indi vidual additionally includes cardiac index, left atrial area, stroke volume, left ventricular end-systolic volume, left ventricular end-diastolic volume, or any combination thereof.
- the administering of the pharmaceutical composition may result in one or more of increased cardiac index, decreased left atrial area, increased stroke volume, decreased Sell ventricular end-diastolic volume, and/or decreased left ventricular end-diastolic volume.
- FIG. 1 is a flowchart of an exemplary study for testing the efficacy of istaroxime for use in the treatment of pre-cardiogenic shock.
- FIG. 2 is a chart showing die change in systolic blood pressure (SBP) for individuals treated with istaroxime (solid area) versus placebo (hatched area) over time.
- SBP systolic blood pressure
- the y-axis presents the change from baseline of SBP (mmHg), whereas the x-axis represents hours from infusion (h),
- FIG. 3 are graphs showing changes in blood pressure (BP) over time for individuals treated with istaroxime (solid line) versus placebo (dashed line).
- Panel A shows the changes in SBP up to 6 hours following infusion
- Panel B shows the changes in SBP up to 24 hours following infusion
- Panel C shows the mean changes in diastolic blood pressure (DBP) up to 96 hours from infusion.
- the y-axis in each represents the change from baseline of BP (mmHg), whereas the x-axis represents hours from infusion.
- FIG. 4 are graphs showing levels of heart and renal function parameters over time.
- Panel A shows changes in MAP for individuals treated with istaroxime (solid line) versus placebo (dashed line).
- Panel B is a graph showing the change in blood levels of eGFR over time between individuals treated with either 1.0 pg/kg/mm (light gray line), 1.5 pg-kg-'min (gray line), or placebo (dashed dark gray line).
- Panel C is a graph showing the change in blood levels of NT- proBNP over time between individuals treated with either 1 .0 pg/kg/min (light gray line), 1.5 pg/kg/min (gray Line), or placebo (dashed dark gray line).
- compositions and methods disclosed herein provide, for the first time, a treatment regimen for individuals with pre-cardiogenic shock or cardiogenic shock.
- individuals with pre-cardiogenic shock that were administered istaroxime exhibited a concomitant increase in both cardiac index and blood pressure (e.g., systolic blood pressure), which is unique and has not been observed with any previous intravenous drugs administered to individuals with pre-cardiogenic shock or cardiogenic shock.
- blood pressure e.g., systolic blood pressure
- 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 more) and exhibit an increase in systolic blood pressure by 6 hours and/or by 24 hours as compared to similarly-situated individuals (i.e., with pre-cardiogenic shock or cardiogenic shock) who were not administered istaroxime or were administered a placebo.
- a period of time e.g., up to about 6 hours, or up to about 24 hours, or more
- Such individuals who are administered istaroxime may exhibit one or more additional cardiac improvements, such as, but not limited to, increased cardiac index, decreased left atrial area, decreased left ventricular end- systolic volume, and decreased left ventricular end-diastolic volume as compared to such individuals prior to administration of istaroxime and or compared to individuals with pre- cardiogenic shock or cardiogenic shock that are not administered istaroxime.
- additional cardiac improvements such as, but not limited to, increased cardiac index, decreased left atrial area, decreased left ventricular end- systolic volume, and decreased left ventricular end-diastolic volume as compared to such individuals prior to administration of istaroxime and or compared to individuals with pre- cardiogenic shock or cardiogenic shock that are not administered istaroxime.
- compositions comprising istaroxime suitable for administration to individuals having pre-cardiogenic shock or cardiogenic shock symptoms.
- istaroxime is administered to these individuals by intravenous infusion for up to 24 hours to increase systolic blood pressure and alleviate symptoms of pre-cardiogenic shock or cardiogenic shock.
- istaroxime is administered by intravenous infusion to an individual presenting with pre-cardiogenic shock without evidence of end-organ hypoperfusion or acute coronary syndrome to treat pre-cardiogenic shock and prevent progression to overt cardiogenic shock.
- compositions and methods disclosed herein will be described in more detail below.
- the term “about” refers to the variation in the numerical value of a measurement, e.g., volume, time, pressure, concentration, etc., due to typical error rates of the device used to obtain that measure. 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.
- cardiogenic shock refers to a condition in an individual, such as a human patient, where the heart cannot pump enough blood and oxygen to the brain, kidneys, and other vital organs leading to end-organ hypoperfusion.
- Overt “cardiogenic shock” or SCAI Stage C “cardiogenic shock” is defined by a systolic blood pressure of less than about 90 mmHg (hypotension), a cardiac index of less than about 2,2 Umin/m 2 , pulmonary capillary wedge pressure of greater than 15 mmHg, and evidence of end-organ hypoperfusion
- Pre-cardiogenic shock SCAI Stage B “pre-cardiogenic shock”
- early cardiogenic shock refer to a condition where the individual has not yet developed overt “cardiogenic shock” and is defined by a systolic blood pressure of less than about 90 mmHg without evidence of end-organ hypoperfusion.
- heart fai lure refers to a clinical syndrome characterized by typical symptoms (e.g.» breathlessness, ankle swelling and fatigue) that may be accompanied by signs (e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema) caused by a structural and/or functional cardiac abnormality, resulting in a reduced cardiac output and/or elevated intracardiac pressures at rest or during stress.
- typical symptoms e.g.» breathlessness, ankle swelling and fatigue
- signs e.g., elevated jugular venous pressure, pulmonary crackles and peripheral edema
- AHF acute heart failure
- the terms “acute heart failure” or “AHF” are used interchangeably herein and refer generally to a rapid onset or worsening of symptoms and/or si gns of HF requiring immediate treatment and hospitalization.
- the current definition of “acute heart fai lure” is rather nonspecific and may include a broad spectrum of conditions with several phenotypes characterized by different clinical presentation, etiology, precipitating factors, therapeutic approach, and prognosis.
- a large proportion of human patients have a subacute course of the disease with a progressive worsening of signs and symptoms of HF which could develop days before hospital admission.
- acute decompensated heart failure refers to a sudden worsening of the signs and symptoms of heart failure, which, in humans, typically includes difficulty breathing (dyspnea), leg or feet swelling, and fatigue.
- acute coronary syndrome refers to a sudden reduction or blockage of blood flow to the heart.
- a common example of “acute coronary' syndrome” is a myocardial infarction (heart attack).
- chronic heart failure or “CHF” are used interchangeably herein and refer to the current clinical classification of chronic HF based on the presence of signs and symptoms of HF and left ventricular ejection fraction (LVEF) in an individual, such as a human patient, recognizing three categories: “heart failure with reduced ejection fraction” or “HFrEF,” which is characterized by an LVEF of less than about 40%; “heart failure with mid-range ejection fraction” or “HFmEF” or “HFmrEF,” which is characterized by an LVEF from about 40% to about 49%; and “heart failure with preserved ejection fraction” or “HFpEF,” which is characterized by an LVEF of equal to or greater than about 50%.
- HFrEF left ventricular ejection fraction
- HFmrEF and “HFpEF” include two additional criteria, namely increased natriuretic peptides levels (BNP >35 pg/ml and/or NT-proBNP >125 pg/mL) associated with the evidence of structural and/or functional heart disease (left ventricular hypertrophy and/or left atrium enlargement and/or evidence of diastolic dysfunction).
- hypotension as used herein is defined as systolic blood pressure (SBP) that is less than 90 mmHg or mean arterial blood pressure (MAP) less than about 60 mmHg or greater than 30 mmHg drop from baseline.
- SBP systolic blood pressure
- MAP mean arterial blood pressure
- end-organ hypoperfusion means clinical signs such as cold, clamped extremities, poor urine output, mental confusion, elevated lactate or increased creatinine.
- treating refers to any indicia of success in the treatment or amelioration of the disease or condition in an individual. Treating can include, for example, reducing or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a di sease, defect, disorder, or adverse condition, and the like, are experienced by an individual, such as a human patient.
- preventing refers to the prevention of the disease or condition, e.g., pre- cardiogenic shock or cardiogenic shock, in an individual, such as a human patient. For example, if an individual at risk of developing pre-cardiogenic shock or cardiogenic shock is treated with the methods of the present invention and does not later develop pre-cardiogenic shock or cardiogenic shock, then the disease has been prevented in that individual.
- treat or prevent is sometimes used herein to refer to a method that results in some level of treatment or amelioration of the disease or condition, and contemplates a range of results directed to that end, including but not restricted to prevention of the condition entirely.
- the term “pharmaceutically acceptable” salt, solvate, hydrate, or ester means a salt, solvate, hydrate, or ester form of the active ingredient which is compatible with any other ingredients of the pharmaceutical composition, which is not deleterious to the subj ect to which the composition is to be administered.
- the term “pharmaceutically acceptable carrier’ means a chemical composition with which an istaroxime compound may be combined and which, following the combination, can be used to administer the compound to a mammal.
- intravenous infusion refers to the administration or delivery of liquid substances directly into a vein of a mammal.
- Typical “infusions” use only the pressure supplied by gravity.
- heart rate HR
- BP blood pressure
- DBP diastolic blood pressure
- SBP systolic blood pressure area under the curve
- SBP AUC creatine clearance
- deceleration slope mitral inflow velocity
- mean arterial pressure brain natriuretic peptide levels (BNP), NT-pro-BNP levels, troponin levels, venous lactate levels, echocardiographic measurements, left ventricle end diastolic diameter (EDD), left ventricle end systolic diameter (BSD), left ventricle end diastolic volume (EDV), left ventricle end systolic volume (ESV),
- terapéuticaally active or “active” ingredient or compound refer to a substance that provides a beneficial effect to the individual to whom the substance is administered.
- a “therapeutically effective amount” or “therapeutically effective dose” is the amount of a composition or active ingredient sufficient to provide a beneficial effect to the individual to whom the composition or active ingredient is administered.
- the present invention is directed to administration of istaroxime to individuals, such as human patients, to treat or prevent pre-cardiogenic shock or cardiogenic shock.
- the route of administration of istaroxime is by intravenous infusion.
- istaroxime infusion is administered to treat the pre-cardiogenic shock (SCAI Stage B) and prevent progression to overt cardiogenic shock.
- istaroxime infusion can be administered to individuals presenting with overt cardiogenic shock (SCAI Stage C) to alleviate the symptoms and improve heart function.
- compositions and treatment methods alleviate symptoms associated with pre-cardiogenic shock or cardiogenic shock in individuals with acute decompensated heart failure (ADHF), which is an acute decompensation of an underlying chronic systolic heart failure due to, e.g., arterial hypertension, ischemic heart disease, or dilated cardiomyopathy.
- ADHF acute decompensated heart failure
- the pre-cardiogenic shock or cardiogenic shock is not caused by an acute coronary syndrome, such as a myocardial infarction.
- Individuals with pre- cardiogenic shock or early cardiogenic shock may present with persistent hypotension characterized by a systolic blood pressure (SBP) of less than about 90 mmHg without evidence of an acute coronary syndrome and without evidence of end-organ hypoperfusion.
- SBP systolic blood pressure
- the istaroxime infusion is between about 3 hours and up to 24 hours or more, eg, 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.
- the infusion can be for up to 24 hours, or longer.
- the duration of the infusion is from about 6 hours to about 24 hours, or from about 12 hours to about 24 hours, or about 18 hours to about 24 hours.
- the duration of the infusion is greater than about 24 hours, e.g., 25 h, 26 h, 27 h, 28 h, 29 h, 30 h, 31 h, 32 h, 33 h, 34 h, 35 li, 36 It, 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, 1 1 days 12 days, 13 days, 14 days, or longer.
- the infusion of istaroxime provides an improvement in the heart function of the individual, e.g,, an increase in SBP, within about 24 hours from the start of infusion; preferably, the improvement occurs within about 12 hours from the start of infusion, or within about 6 hours from the start of the infusion, or within about 3 hours from the start of infusion, or within about 1 hour from the start of infusion.
- an individual presenting with pre-cardiogenic shock or cardiogenic shock who is administered istaroxime exhibits an improvement in SBP within 6 hours after the start of infusion as compared to an individual presenting with pre- cardiogenie shock or cardiogenic shock who is administered a placebo.
- Istaroxime is an inotropic compound having the following structural formula (I):
- istaroxime or its pharmaceutically acceptable salt or ester, hydrate, solvate, or polymorphic form in a medicament to treat or prevent pre-cardiogenic shock or cardiogenic shock in an individual
- istaroxime is administered to an individual for the treatment of pre-cardiogenic shock and to prevent the worsening of the individual’s condition to overt cardiogenic shock.
- compositions comprising istaroxime in an admixture with at least one pharmaceutically acceptable vehicle and or excipient.
- the pharmaceutical composition is formulated for administering to an individual by infusion, preferably, it is by intravenous infusion.
- SBP SBP area under the curve
- SBP AUC SBP area under the curve
- an arterial line which is a thin, flexible tube that is inserted into an artery (e.g., in the radial or ulnar artery' of the wrist, brachial artery of the elbow, femoral artery in the groin, or dorsalis pedis artery of the foot) to measure blood pressure in real time via a connection to a pressure transducer.
- ABP AUC is typically measured from baseline (time 0) to a particular endpoint, e.g., 1 h, 2 h, 3 h, 6 h, 12 h, 18 h, or 24 h after the start ofistaroxime administration. For instance, SBP AUCuuj or SBP AUGo-W is measured.
- An improvement in SBP AUC within this time can be considered treating pre-cardiogenic shock or preventing overt cardiogenic shock in an individual.
- an increase in the change in SBP after infusion u.g., 10 min, 20 min, 30 m, 40 min, 50 min, I 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 start of istaroxime administration can be considered treating pre-cardiogenic shock or preventing overt cardiogenic shock in an individual.
- echocardiography is per loaned on individuals according to international standards I'.se'e, for example, Lang et al, 2005, .1. Am. Soc. Echocardiogr.
- Echocardiography is within the purview of skilled physicians or sonographers. For instance, echocardiography can be performed during screening of potential clinical study participants or upon admission of an individual to a health care facility.
- echocardiography is done 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, I 5 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, 96, h, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 11 days.
- echocardiography is monitored during infusion and values are recorded at 24 and 30 hours post-infusion. In other embodiments, echocardiographic values are recorded 12, 24, 48, 72, and 96 hours post-infusion. Table 2 summarizes exemplary echocardiographic and other heart function parameters.
- an individual with pre-cardiogenic shock or cardiogenic shock is administered istaroxime, and the SBP AUCfo- «) of the individual increases by at least about 20 mmHg’h within about 6 hours after the start of administration of istaroxime, 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 within about 6 hours after the start of administration of istaroxime; preferably, the SB P AUC(o-6> increases by at least about 30 mmHg’h; more preferably, it increases by al least about 40 mmHg’h, or at least about 50 mmHg’h.
- an individual with pre- cardiogenic shock or cardiogenic shock is administered istaroxime, and the SBP AUC(o-24> of the individual increases by at least about 200 mmHg’h within about 24 hours after the start of administration of istaroxime, e.g., 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 administration of istaroxime; preferably, the SBP AUCfowj increases by at least about 220 mmHg’h; more preferably, it increases by at least about 250 mmHg’h, or at least about 280 mmHg’h.
- an individual with pre-cardiogenic shock or cardiogenic shock who is administered istaroxime by infusion will have a SBP AUQo-si that is at least about 30% greater, c.g, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%.
- the individual will have a SBP AUC(0-6j that is at least about 40’% greater than the mean SBP AUGy-o) for those individuals who are not administered istaroxime; more preferably, the individual will have a SBP AUG'o-6) that is at least about 50% greater than the mean SBP AUQo-s) for those individuals who are not administered istaroxime, or at least about 60% greater than the mean AUC(o-6> for those individuals who are not administered istaroxime, or at least about 70% greater than the mean AUC(0-6) for those individuals who are not administered istaroxime.
- an individual with pre-cardiogenic shock or cardiogenic shock who is administered istaroxime by infusion will have a SB? AUC(M ⁇ J that is at least about 10% greater, e.g., 10%, 11%, 12%, 13%, 14%, 15%, .16%, 17%, 18%, 19%, 20%, 21 %, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, or more than the mean SBP AUCffw-o for those individuals who are not administered .istaroxime; preferably, the individual will have a SB?
- AUGO-M that is at least about 20% greater than the mean SBP .AUQo.24) for those individuals who are not administered istaroxime; more preferably, the individual will have a SBP AUGo-ci that is at least about 30% greater than the mean SBP AUGo-24) for those individuals who are not administered istaroxime, or at least about 40%) greater than the mean AUC(O-24) for those individuals who are not administered istaroxime.
- the change in SBP increases by at least about 1 mmHg within about 1 hour after the start of infusion, or by at least about 3 mmHg within about 3 hours after the start of infusion, or by at least about 8 mmHg without about 6 hours after the start of infusion, or by at least about 10 mmHg without about 24 hours after the start of infusion.
- the adjusted increase in SBP at 6 hours after infusion is at least about 8 mmHg. eg..
- the adjusted increase in SBP at 6 hours after infusion is at least about 10 mmHg.
- the adjusted increase in SBP at 24 hours after infusion is at least about 10 mmHg, e.g., 10 mmHg.
- istaroxime In addition to the increased SBP, individuals with pre-cardiogenic shock or cardiogenic shock administered istaroxime will exhibit an improvement in one or more additional parameters of cardiac function, inc hiding, but not limited to, increased cardiac index (Cl), decreased left atrial area, increased stroke volume, decreased left ventricular end-systolic volume, and decreased left ventricular end-diastolic volume.
- istaroxime administration improved CI by increasing the stroke rate, but not by increasing the heart rate.
- istaroxime increases cardiac output in these individuals without additional strain of increased heart rate on the heart.
- blood is drawn from the individual e.g., during prescreening, at baseline and or at various timepoints post-infusion, e.g., 12, 24, 48, 72, 96 hours, 5 days, 10 days, 30 days after the start of istaroxime administration.
- This blood can be used for various laboratory testing to assess the individual’s body chemistry, hematology, heart protein levels, and the pharmacokinetics of the 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.
- Exemplar ⁇ ' hematology includes, but is not limited to, complete blood count with differential.
- Suitable heart proteins include cardiac troponin I (cTNI), cardiac troponin T (eTNT), N-terminal pro b-type natriuretic peptide (NT-proBMP), and brain natriuretic peptide (BN P).
- cTNI cardiac troponin I
- eTNT cardiac troponin T
- NT-proBMP N-terminal pro b-type natriuretic peptide
- BN P brain natriuretic peptide
- the levels of each most of these proteins provide information to the practitioner about heart function and the measurement and/or interpretation of these levels is well within the purview of the skilled artisan.
- the level of NT-proBNP is decreased as compared to baseline within about 6 hour of infusion, or within about 24 hours of administration.
- the levels of some of parameters are not a direct measure of heart function, but rather are used to assess kidney function.
- the level of eGFR which is a measure of kidney function, is increased as compared to baseline within about 6 hours of infusion, or within about 24 hours of infusion.
- MAP mean arterial pressure
- AE adverse events
- SAE serious adverse events
- MAP is increased as compared to baseline within about 24 hours of infusion.
- compositions and formulations for intravenous infusion comprising istaroxime or a pharmaceutical ly acceptable salt, solvate, or hydrate thereof in admixture with at least one conventional pharmaceutically acceptable carrier and/or vehicle and or excipient are commonly known in the art.
- compositions and formulations for intravenous infusion can be formulated in any way and can be administered in a variety of unit dosage forms depending upon the condition or disease and the degree of illness, the general medical condition of each patient, the resulting preferred method of admin istration and the like. Details on techn iques for formulation and administration 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”)].
- the formulations may conveniently be presented in unit dosage form and may be prepared by any method known in the art of pharmacy.
- the amount of active ingredient which can be combined with a carrier or vehicle material to produce a single dosage form will vary depending upon the subject being treated and the particular mode of administration.
- the amount of active ingredient that can be combined with a carrier material to produce a single dosage form will generally be the amount of the compound which produces a therapeutic effect.
- compositions as provided herein can be prepared according to any method known to the art for the manufacture of pharmaceuticals. Such formulations can contain additional agents, such as preserving or stabilizing agents.
- a formulation can be admixtured with nontoxic pharmaceutically acceptable carriers or excipients which are suitable for manufacture. Formulations may comprise one or more diluents, emulsifiers, preservatives, buffers, excipients, etc. and may be provided in such forms as liquids, powders, emulsions, lyophilized powders, etc.
- Aqueous suspensions can contain an active agent (e.g, a composition used to practice the uses and methods as provided herein) in an admixture with excipients suitable for the manufacture of aqueous suspensions.
- excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents, such as a naturally-occurring phosphatide (e.g., lecithin), a condensation product o f an alkylene oxide with a fatty acid (e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol (e.g., heptadecaethylene oxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol (e.g.
- islaroxime is given by intravenous (IV) administration.
- IV intravenous
- These formulations can comprise a solution of active agent dissolved in a pharmaceutically acceptable carrier.
- Acceptable vehicles and solvents that can be employed are water, dextrose in water, and Ringer’s solution, an isotonic sodium chloride. These solutions are sterile and generally free of undesirable matter.
- These formulations may be sterilized by conventional, well known sterilization techniques.
- the formulations may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions such as pH adjusting and buffering agents, toxicity adjusting agents, eg, sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate and the like.
- the concentration of active agent in these formulations can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight, and the like, in accordance with the particular mode of administration selected and the patient's needs.
- the administration is by bolus or continuous infusion (e.g., substantially uninterrupted introduction into a blood vessel for a specified period of time).
- Istaroxime as provided herein can be lyophilized.
- a stable lyophilized formulation comprising a composition as provided herein, which can be made by lyophilizing a solution comprising a pharmaceutical as provided herein and a bulking agent, e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof
- a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof
- a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof
- a bulking agent e.g., mannitol, trehalose, raffinose, lactose, and sucrose or mixtures thereof
- lactose is the most common.
- istaroxime as provided herein can be administered for prophylactic and/or therapeutic treatments.
- compositions are administered to a subject already suffering from a condition, or disease in an amount sufficient to treat, prevent, cure, alleviate or partially arrest the clinical manifestations of the condition, or disease and its complications (i.e., a “therapeutically effective amount”).
- pharmaceutical compositions as provided herein are administered in an amount sufficient to treat, prevent or ameliorate in an individual in need thereof.
- the amount of pharmaceutical composition adequate to accomplish this is defined as a “therapeutically effective dose,”
- the dosage schedule and amounts effective for this use, z.e., the “dosing regimen,” will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient's physical status, age and the like, In calculatin g the dosage regimen for a patient, the mode of admini stration also is taken into consideration.
- the dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the active agents’ bioavailability, metabolism, clearance, and the like [see, ⁇ ?.g., Flidalgo-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: 1144-1 146; Rohatagi, 1995, Pharmazie 50:610-613; Brophy, 1983, Eur. J. Clin. Pharmacol. 24:103-108; the latest Remington’s, supra].
- the active agents bioavailability, metabolism, clearance, and the like
- formulations can be given depending on the dosage and frequency as required by the prc-cardiogenic shock or cardiogenic shock symptoms of patient.
- the formulations should provide a sufficient quantity of active agent to effectively treat or prevent or ameliorate a conditions, diseases or symptoms as described herein,
- a correct treatment of pre-cardiogenic shock or cardiogenic shock, by selectively normalizing a depressed biochemical activi ty under lying the symptoms of subset of patients, may be expected to selectively improve the symptoms and to reduce the incidence of unwanted side effects produced by the available drugs either during hospital staying or after discharge.
- the term prevention is applicable when the continuous monitoring of the pulmonary pressure is possible w ith the appropriate chronic implantable devices that furnish and estimation of SBP, SBP AUC (e.g., io 6 hours or to 24 hours) or other parameter of heart function as discussed elsewhere herein.
- an effective amount of istaroxime or equivalent of a pharmaceutically acceptable salt, solvate, or hydrate thereof is administered to an individual with pre-cardiogenic or cardiogenic shock symptoms at a dosing schedule, e.g., from about 0.1 pg/kg/min to about 3.0 pg/kg/min, e.g., 0.1 pg/kg/min, 0.15 pg/kg/min, 0.2 pg/kg/min, 0.25 pg/kg/min, 0,3 pg/kg/min, 0.35 pg/kg/min, 0.4 pg/kg/min, 0.45 pg/kg/min, 0,5 pg/kg/min, 0.55 pg/kg/min, 0.6 ug-kg-'min, 0.7 pg ; kg/min, 0.75 pg/kg/min, 0.8 pg ?
- istaroxime is administered by infusion at an effective dose from about 0.2 pg kg min to about 2.0 pg kg /min, or from about 0.5 pg/kg/min to about 1 .5 pg/kg/min, or from about 1 ,0 pg/kg/min to about 1 .5 pg/kg/min.
- the istaroxime is administered by intravenous infusion at an effective dose of about 1 ,5 pg'kg'min.
- the effective dose of istaroxime can be initiated at about 1,0 pg/kg/min for about 1 to about 2 hours, which is then increased to 1.5 pg/kg/min for the remaining infusion time unless the individual exhibits nausea or other signs of poor or insufficient drug tolerance.
- the effective dose of istaroxime can be initiated at about 1.5 pg/kg/min for about I to about 2 hours, which is then increased to 1.0 pg/kg/min for the remaining infusion time.
- a pharmaceutical composition comprising istaroxime in lyophilized power form.
- the pharmaceutical composition comprises istaroxime and a bulking agent (e.g., lactose) in lyophilized powder form.
- the composition may 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, such as saline with 0.9% NaCl) prior to intravenous infusion.
- compositions for use as a medicament in the treatment of pre-cardiogenic shock or cardiogenic shock as well as methods of treating an individual with pre-cardiogenic shock or cardiogenic shock.
- the individual exhibits symptoms of, or has been diagnosed with pre-cardiogenic shock SCAI Stage B.
- the individual exhibits symptoms of, or has been diagnosed with SCAI Stage B pre-cardiogenic shock caused by AD HF.
- the individual exhibits symptoms of, or has been diagnosed with SCAI Stage B pre-cardiogenic shock caused by ADHF without evidence for an acute coronary syndrome (e.g., myocardial infarction).
- the individual have dyspnea at rest or with minimal exertion, chest congestion with BNP equal to or greater than about 400 pg/ml. or NT-proBNP equal to or greater than about .1,400 pg ml...
- the individual will exhibit persistent hypotension characterized by an SBP for between about 70 mmHg and about 100 mmHg or, more preferably between about 75 mmHg and about 90 mmHg for at least 2 hours prior to screening or initiation of treatment. Further, the SBP in this individual does not decrease by greater than about 7 mmHg before initiation of treatment.
- the individual may also have a heart rate in the range from about 65 bpm to about 160 bpm or, preferably about 75 bpm to about 150 bpm or, if the individual is on a beta-blocker, the heart rate might be from about 60 bpm to about 150 bpm.
- the individual may also have a history of LVEF less than or greater to about. 40%.
- the individual has a heart rate of less than about 90 mmHg without evidence of end-organ hypoperfusion.
- the individual has a heart rate of less than about 90 mmHg with evidence of end-organ hypoperfusion.
- the individual exhibits symptoms or, or has been diagnosed with SCA.I Stage C cardiogenic shock.
- 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.
- the individual can be a non-human animal, in a preferred embodiment, the individual is a human patient, such as a human patient exhibiting pre-cardiogenic shock symptoms.
- a measuring step is first carried out to determine the baseline heart function of the individual. For instance, an individual with heart failure may present with persistent hypotension, dyspnea, and reduced LVEF.
- the measuring step may include measuring one or more parameters o f heart function or heart function impairment, such as, but not limited to, decreased SBP or SBP AUC, reduced left ventricular end-diastolic/systolic volume and function (LVEF), or increased E/Ea or E/A ratios, reduced Ea ratio decreased stroke volume, elevated heart rate, and others.
- parameters o f heart function or heart function impairment such as, but not limited to, decreased SBP or SBP AUC, reduced left ventricular end-diastolic/systolic volume and function (LVEF), or increased E/Ea or E/A ratios, reduced Ea ratio decreased stroke volume, elevated heart rate, and others.
- a non-limiting list of suitable measuring equipment techniques includes echocardiogram, cardiac catheterization, nuclear stress test, CAT scan, radionuclide ventriculography scan, stethoscope, sphygmomanometer, pulmonary capillary wedge pressure (PCWP), and the like.
- the SBP can be measured by sphygmomanometer or arterial line attached to a pressure transducer.
- the one or more parameters of heart function are measured and selected from the group consisting of heart rate (HR), blood pressure (BP).
- diastolic relaxation systolic contraction, dyspnea, chest congestion
- diastolic blood pressure BDF
- systolic blood pressure SBP
- systolic blood pressure area under the curve SBP AUC
- creatine clearance deceleration slope
- mitral inflow' velocity mean arterial pressure
- brain natriuretic peptide levels BNP
- NT- pro-BNP levels troponin levels
- venous lactate levels echocardiographic measurements, left ventricle end diastolic diameter (EDD), left ventricle end systolic diameter (BSD), left ventricle end diastolic volume (EDV), left ventricle end systolic volume (ESV), left atrium diameter (LAD), left atrium area (LAA), left atrium volume (LAV), E wave, A wave, E wave deceleration time (EDT), E/A ratio, Ea.
- EDD left ventricle end diastolic diameter
- LVEF left ventricle ejection fraction
- Sa stroke volume
- CO cardiac output
- SVI stroke volume index
- CI cardiac index
- PASP pulmonary' arterial systolic pressure
- TAPSE tricuspid annular plane systolic excursion
- MR mitral regurgitation
- IVC inferior vena cava diameter
- an individual is selected for treatment having one or more inclusion criteria.
- the inclusion criteria includes one or more of clinical presentation with SC Al Stage B pre-cardiogenic shock with ADHF and no evidence of acute coronary syndrome.
- additional inclusion criteria include males and females that are 18 to 85 years of age, dyspnea, chest congestion with BNP equal to or greater than about 400 pg/mL or NT-proBNP equal to or greater than about 1 ,400 pg/mL, LVEF of less than or equal to 40%, persisting hypotension defined as an SBP of less than about 90 mmHg, and/or heart rate of about 75 bpm to about 150 bpm.
- the methods disclosed herein also include administering to the individual a therapeutically effective amount of istaroxime.
- the istaroxime is in a pharmaceutical composition, such as any of the combinations discussed above.
- the istaroxime is administered in a therapeutically effective dose.
- the istaroxime can be administered to the individual via intravenous infusion with a dose in the range from about 0.25 pg/kg/min to about 3.0 pg/kg/min, e.g., 0.25 pg/kg/min, 0.3 pg/kg/min, 0.35 pg/kg/min, 0,4 pg/kg/min, 0.45 pg/kg/min, 0.5 pg/kg/min, 0.55 pg-'kg'min, 0.6 pg/kg/min, 0.65 pg/kg/min, 0.7 pg/kg/min, 0.75 pgkg/min, 0.8 pg/kg/min, 0.85 pg/kg/min, 0.9 pg/kg/min, 0.95 ug/kg/min, 1,0 pg/kg/min, 1.1 pg/kg/min, 1.2 pg'kg'min, 1,3 pg/kg/min, 1.4 pg/kg/min,
- the dose of istaroxime administered to the individual is in the range from about 0.5 pg/kg/min to about 3.0 pg/kg/min.
- the dose of istaroxime administered to the individual is in the range from about 1.0 pg/kg/min to about 2.0 pg/kg/'min, or about 1.0 pg/kg/min to about 1.5 pg/kg/min, or about 1 .0 pg/kg/min, or about 1.5 pg/kg/min. In one particular embodiment, the dose of istaroxime administered to the individual is about 1.0 pg/kg/min.
- the time period for the infusion may be at least about 1 hour to about 48 hours, or more, e.g., 1 h. 2 h. 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, I I 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.
- the infusion is carried out from about 3 hours to about 24 hours, or from about 6 hours to about 24 hours, or from about 12 hours to about 24 hours.
- the individual is administered istaroxime by intravenous infusion for about 24 hours.
- the time period for infusion may be greater than 24 hours, ag., 25 h, 26 h, 27 h, 28 h, 29 h, 30 h.
- the individual is administered a lower dose of istaroxime for an initial period of time to determine whether that indi vidual exhibits signs for poor drug tolerance, such as nausea, infusion site pain, etc.
- the individual can be administered istaroxime by intravenous infusion at a dose of about 1.0 ug kg min for an initial 1-2 hours, which dose can be increased to 1 .5 jig/kg/min for die remaining infusion time (e.g. , 24 hours) if the individual does not exhibit signs of drug intolerance.
- the individual can be administered a higher dose of istaroxime initially, which can be lowered if the individual exhibits signs of drug intolerance.
- the individual can be administered istaroxime by intravenous infusion at a dose of about 1.5 pg/kg/min for an initial 1-2 hours, which dose can be decreased to 1 .0 p.g/kg/min for the remaining infusion time (e.g., 24 hours) if the individual does exhibits signs of drug intolerance, such as nausea.
- the individual can be co-administered an antienietic (e.g., ondansetron) to alleviate nausea as an alternative to adjusting the infusion dose of istaroxime.
- an antienietic e.g., ondansetron
- the method can include one or more measuring steps carried out periodically during the treatment and/or for a period of time posttreatment.
- the measuring steps may include measuring one or more parameters of heart function as described above prior to beginning infusion, at the initiation of infusion administration, and/or at one or more time points during and after infusion, e.g., 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, lO h, I I 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
- one or more parameters of heart function can be measured before, during, and 12 h, 24 li , 48, 11, 72 11, 96 h, and 30 days following initiation of infusion.
- the one or more parameters of heart function indicate the efficacy of istaroxime treatment.
- an increase in SPB by at least about 8 mmHg, e.g., 8 mmHg, 9 mmHg, 1.0 mmHg, I l mmHg, 12 mmHg, 13 mmHg, 14 mmHg, or 15 mmHg after 6 hours of istaroxime administration indicates treatment of pre-cardiogenic shock or prevention of cardiogenic shock; or an increase in SPB by at least about 10 mmHg, eg., 10 mmHg, 11 mmHg, 12 mmHg, 13 mmHg, 14 mmHg, or 15 mmHg, 16 mmHg, 17 mmHg, 18 mmHg, 19 mmHg, or 20 mmHg after 24 hours of istaroxime administration indicates treatment of pre-cardiogenic shock or prevention of cardiogen ic shock.
- the improvement of SBP is accompanied by one or more additional indicators of heart function impro vement, such as, but not limited to, increased CI, decreased left ventricular dimensions (e.g., decreased left ventricular end-systolic volume and/or decreased left ventricular end-diastolic volume), and/or decreased left atrial dimensions (e.g., decreased left atrial area).
- a decrease in the level of NT-proBNP or an increase in the level of cGFP indicates treatment of pre-cardiogenic shock or prevention of cardiogenic shock.
- individuals in evaluating the efficacy of a treatment, a treatment regimen or a particular dosage, or to determine if a treatment versus a maintenance dosage should be given, are subject to regular periodic screening for the presence and extent of organ and tissue involvement or damage, e.g., heart (ventricle dilatation, third heart sound cardiac hypertrophy), fatigue, tiredness, reduced exercise tolerance, increased time to recover after exercise, kidney (renal insufficiency, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, tachypnea), ankle swelling, elevated jugular venous pressure.
- heart ventricle dilatation, third heart sound cardiac hypertrophy
- fatigue e.g., tiredness, reduced exercise tolerance
- increased time to recover after exercise e.g., kidney (renal insufficiency, oliguria), lung (orthopnea, paroxysmal nocturnal dyspnea, tachypnea), ankle swelling, elevated ju
- ADHF Alzheimer's disease
- therapy with istaroxime or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof as disclosed herein, is instituted as early as possible, preferably in emergency, to prevent the rapid evolution of symptoms (e.g. f progression from pre-cardiogenic shock to overt cardiogenic shock) and continued after patient’s discharge for years, preferably during the whole life of the patient or at least a period consistent with the way other drags are used in heart failure.
- uses and methods as provided herein can further comprise co-administration with other drugs or pharmaceuticals.
- the present invention selectively corrects a depressed cardiac biochemical function (namely the SERCA2a activity). This certainly contributes to relieving the existing pre-cardiogenic shock or cardiogenic shock and ADHF clinical symptoms, with less unwanted side effects than those of the available therapies (just because the selectivity mentioned above).
- the present invention is potentially associable to 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, SER.CA2a stimulators, neprilysin (NEP) inhibitors, myosin filament activators, recombinant relaxin-2 mediators, recombinant NP protein, activators of the soluble Guanylate Cyclase (sGC), beta-anestin ligand of Angiotensin II receptor; b) specific drags: hydrochlorothyzide, furosemide, verapamil, diltiazem, carvedilol, metoprolol, hydralazine, eplerenone, spironolactone, lisinopril, rami
- drug classes such as, ACE inhibitors, angiotens
- Istaroxime as disclosed in the present invention can he combined or co-admiiistered with other therapeutic agents used in the treatment of the same disease and/or the underlying HF.
- therapeutic agents are diuretics, for example furosemide, bumetanide, and torasemide.
- Metolazone an aldosterone antagonist, such as spironolactone or eplerenone; thiazide diuretics, such as Hydrochlorothiazide, metolazone, and chlorthalidone.
- Other agents are ACE inhibitors, for example Lisinopril and Ramipril.
- ARBs such as valsartan, candesartan and losartan can be taken into consideration.
- Angiotensin receptor/neprilysin inhibitor (ARM), sacubitril for example, are comprised.
- Other agents can be selected from Beta-blockers, such as carvedilol and metoprolol for example, or Vasodilators, for example Hydralazine, optionally combined with isosorbide dinitrate, Nitrates, as nitroglycerin, amlodipine and felodipine: non- dihydropyridines such as diltiazem or verapamil.
- the compounds of the present invention can also be combined with Digoxin, if needed. Other drags, as Ivabradine and other Anticoagulant may be considered.
- the compounds of die present invention can be combined with other therapeutic agents, in particular agents useful for treating cardiovascular diseases, more in particular in the combination therapy of pre-cardiogenic shock or cardiogenic shock with ADHF,
- the combined active ingredients can be administered according to different protocols, decided by the medical doctor.
- combination therapy can be carried out by administering istaroxime both at the same time or at different time of the further therapeutically active ingredient or ingredients.
- the compound of the present invention and the further active ingredient or ingredients can be each formulated In a respective pharmaceutical composition or in the same unitary dosage form.
- the present invention provides a kit, in particular for the treatment ofpre- cardiogenic shock or cardiogenic shock, comprising separate pharmaceutical compositions containing the compound of the present invention and the further active ingredient or ingredients, respectively.
- the present invention provides a pharmaceutical unit dosage form kit, in particular for the treatment ofpre-cardiogenic shock or cardiogenic shock, comprising compound of the present invention and the further active ingredient or ingredients in the same unit dosage form.
- Combination therapy according to the present invention provides advantageous treatment ofpre-cardiogenic shock or cardiogenic shock due to the inotropic* lusi tropic effect of istaroxime herein disclosed in addition to or synergically combined with the well-known therapeutic effect of the additional active agents herein disclosed.
- nanoparticles, nanolipoparticles, vesicles and liposomal membranes comprising compounds used to practice the uses and methods as provided herein, e.g., to deliver pharmaceutically active compounds and compositions as provided herein: istaroxime or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof, optionally combined with a further therapeutical ly active agent as disclosed above to a subject in need thereof.
- these compositions are designed to target specific molecules, including biologic molecules, such as polypeptides, including cell surface polypeptides, e.g., for targeting a desired cell type, eg,, a myocyte or heart cell, an endothelial cell, and the like.
- a slow release of Istaroxime may provide a sufficient compound to selectively increase the plasma levels of the metabolite leaving the plasma levels of Istaroxime within very low ranges.
- multilayered liposomes comprising compounds used to practice methods as provided herein, e.g., as described in U.S, application No. 20070082042.
- the multilayered liposomes can be prepared using a mixture of oil -phase components comprising squalane, sterols, ceramides, neutral lipids or oils, fatty acids and lecithins, to about 200 to 5000 nm in particle size, to entrap a composition used to practice uses and methods as provided herein.
- Liposomes can be made using any method, e.g. t as described in U.S. Patent No.4,534,899; or U.S. application No. 20070042031, including method of producing a liposome by encapsulating an active agent according to the present invention (or a combination of active agents), 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 region to produce a liposome solution, where the organic lipid solution mixes with the aqueous solution to substantially instantaneously produce a liposome encapsulating the active agent; and immediately then mixing the liposome solution with a buffer solution to produce a diluted liposome solution.
- liposome compositions used to practice uses and methods as provided herein comprise a substituted ammonium and/or polyanions, e.g., for targeting delivery of istaroxime or an equivalent of a pharmaceutically acceptable salt, solvate or hydrate thereof used to practice methods as provided herein to a desired cell type, as described, e.g. , in U.S. application No. 200701 10798.
- nanoparticles comprising compounds according to the present invention used to practice uses and methods as provided herein in the form of active agent-containing nanoparticles (e.g., a secondary nanoparticle), as described, e.g., in U.S. application No, 20070077286.
- active agent-containing nanoparticles e.g., a secondary nanoparticle
- nanoparticles comprising a fat-soluble active agent used to practice a use and method as provided herein or a fat-solubilized water-soluble active agent to act with a bivalent or trivalent metal salt.
- solid lipid suspensions can be used to formulate and to deliver compositions used to practice uses and methods as provided herein to mammalian cells fo vivo, in vitro or ex vivo, as described, e.g., in U.S. application No. 20050136121 .
- compositions and formulations used to practice the uses and methods as provided herein can be delivered by the use of liposomes or nanoliposomes.
- liposomes particularly where the liposome surface carries ligands specific for target cells, or are otherwise preferentially directed to a specific organ, one can focus the delivery of the active agent into target cells in vivo [.see. e.g., U.S. Patents Nos. 6,063,400; 6,007,839; Al-Muhammed, 1996, MicroencapsuL 13:293-306; Chonn, 1995, Curr. Opin. Biotechnol. 6:698-708; Ostro, 1989, Am. J. Hosp. Pharm. 46: 1576-1587.]
- a liposome formulation of istaroxime as disclosed in Eur J Pharm Biopharm, 201 1;79(21:285-93 is also provided in the present invention.
- any delivery vehicle can be used to practice the uses and methods as provided herein, e.g., to deliver the compounds provided herein to a subject in need thereof.
- delivery vehicles comprising polycations, cationic polymers and/or cationic peptides, such as polyethyleneimine derivatives, can be used e.g. as described, e.g., in U.S. application No. 20060083737.
- a dried polypepti de-surfactant complex is used to formulate a composition used to practice a use and method as provided herein, e.g., as described in U.S. application No. 20040151766.
- a composition used to practice uses and methods as provided herein can be applied to cells using vehicles with cell membrane-permeant peptide conjugates, e.g., as described in U.S. Patents No. 7,306,783; 6,589,503,
- the composition to be delivered is conjugated to a cell membrane-permeant peptide.
- the composition to be delivered and/or the delivery vehicle are conjugated to a transport-mediating peptide, e.g., as described in U.S. Patent No. 5,846,743, describing transport-mediating peptides that are highly basic and bind io poly-phosphoinositides.
- eleclro-penneabilization is used as a primary or adjunctive means to deliver the composition to a cell, e.g., using any electroporation system as described e.g. in U.S. Patents No. 7,109,034; 6,26.1 ,815; 5,874,268.
- Example 1 Treatment with 24 hour istaroxime infusion in patients hospitalized for pre- cardiogenic shock: a randomized, double-blind, placebo-controlled parallel group study
- pre-CS pre-cardiogenic shock
- stage B SCAI classification patients with clinical signs of peripheral hypoperfusion, venous lactate >2 mmol/L and/or on mechanical support or treatment with intravenous vasodilators, inotropes or vasopressors were excluded.
- exclusion criteria were concomitant or planned treatment with oral digoxin (could be randomized if the plasma concentration of digoxin at screening was ⁇ 0.5 ng /ml); acute coronary syndrome or stroke within the past 3 months; coronary artery bypass graft or percutaneous coronary intervention within the past month or planned in the next month; life-threatening ventricular arrhythmia or implantable cardioverter defibrillator shock within the past month; sustained ventricular tachycardia in the last 3 months or uncontrolled arrhythmia; fever >38°C; estimated glomerular filtration rate (eGFR) ⁇ 30 ml/min/m2; serum potassium >5.3 or ⁇ 3.5 mmol/L; stroke or transient ischaemic accident within the past 3 months; and acute respiratory distress syndrome.
- eGFR estimated glomerular filtration rate
- the patients were randomized centrally, using an interactive response technology, to receive istaroxime or placebo at a ratio of 1 : 1 .
- Study medication was supplied in uniquely- numbered kits containing identical vials of lyophilized powder (i staroxime plus lactose ), reconstituted by adding 5 ml saline to the vial. Istaroxime was administered as a continuous infusion 1.0 pg/kg/min for 24 h. The infusion rate could be decreased at the discretion of the investigator based on the development of tolerability issues (such as nausea), significant bradycardia, or greater than desired BP elevation.
- the original protocol had a target and maximum dose infusion of 1.5 however, after 26 of the 60 patients were recruited, the sponsor and executive steering committee amended tlie protocol to limit the dose of istaroxime to 1.0 pg (kg/min, after which all patients were to recei ve a target and maximum dose of 1.0 pg/kg/min of istaroxime.
- the primary efficacy endpoint was the area under the curve representing the change in SBP from baseline, start of study drug infusion, through 6 h (SBP AUC).
- the secondary endpoints included SBP AUC through 24 h; changes from baseline in SBP (particularly at 6 and 24 h), diastolic blood pressure (DBP) and mean arterial pressure (MAP); changes from baseline in heart rate (HR); treatment failure score (based on death, circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment, and changes in SBP); treatment failure defined as death or need for circulatory, respiratory, or renal mechanical support or intravenous inotrope or vasopressor treatment; increase from baseline in SBP >5% and or >10 mmHg; changes in quality of life measured by the EuroQol 5 Dimension 5 Level (EQ-5D-5L); change from baseline to 24 h in echocardiography parameters; changes in troponin and N-temiinal pro-B-type natriuretic peptide (NT-proBNP); hospital
- In-hospital worsening heart failure was defined as worsening signs and/or symptoms of heart failure since the previous assessment that required an intensification of intra venous therapy for heart failure or mechanical ventilatory, renal, or circulatory' support.
- the safety endpoints were assessed throughout the study and included the incidence of adverse events; changes in vital signs and in 12-lead electrocardiogram (ECG) parameters; incidence of clinically or haeniodynamically significant episodes of supraventricular or ventricular arrhythmias detected by continuous ECG monitoring; standard laboratory parameters; renal function measures; cardiac troponin I or T; and mortality through day 30, The study is summarized in Table 1 and FIG, I .
- the primary efficacy analysis population was a modified intention-to-treat (mITT) population defined as subjects who received study treatment (any istaroxime or placebo infused to patient) and had at least one post-baseline BP assessment.
- mITT intention-to-treat
- Supportive efficacy analyses were conducted in an ITT population including all randomized patients, and a per-protocol population including subjects who received study drug infusion without an excluding protocol violation.
- Safety analyses included all patients who received any study medication. As all patients who were randomized received study treatment and had at least one post-baseline BP assessment, the mfTT, ITT, and safety populations were the same. Because the dosing regimen was changed after the trial was underway, patients in the active group were classified by the maximum istaroxime dose received (all ⁇ 1.0 vs. any >1.0 pg/kg/'min), and additional pairwise comparisons were made.
- Treatment groups were compared using ANCOVA with baseline value, pooled site, and treatment in the model. Changes in creatinine clearance, heart rate, MAP, natriuretic peptides, and troponin were compared between treatment groups using mixed model repeated measures with baseline value, treatment, pooled study site, lime, and treatment by time interaction in the models. Changes in EuroQol visual analogue scale from baseline to 96h and 30 days, and changes in echocardiographic measures at 24 and 30 h were compared between treatment groups at each time point using ANCOV A with baseline value, treatment, and pooled study site in the models.
- Van Elteren test stratified by pooled study centre was used to compare groups regarding treatment failure score (through 24 h), length of hospital stay, stay in intensive care or coronary care units (ICU/CCU), days alive out of the hospital, and days alive out of acute care through day 30, The proportion of subjects who sustained treatment failure, with any hospital readmission through day 30, or with increases from baseline in SBP >5% and >10 mmHg at a timepoint between 4 and 6 h after dosing, were compared using the Cochran-Mantel-Haenszel (CMH) test controlling for pooled sites. Two-sided p ⁇ 0.05 was considered statistically significant. No adjustments for multiple testing were made, SAS version 9.4 (SAS Institute, Inc., Cary, NC, USA) was used for analyses.
- SAS version 9.4 SAS Institute, Inc., Cary, NC, USA
- the primary endpoint was the AUC representing the change in SBP from time of infusion start to hour 6,
- FIGS. 2-4 summarize the results of this analysis.
- Echocardiographic changes during the first 24 h of the study are presented in Table 3.
- Table 3 Echocardiographic changes during the first 24 h.
Abstract
Sont divulgués des compositions de perfusion intraveineuse d'istaroxime chez des patients humains souffrant de pré-choc cardiogénique ou de choc cardiogénique. Sont également divulgués des procédés d'administration d'istaroxime à des personnes faisant preuve de symptômes, ou ayant été diagnostiquées avec un pré-choc cardiogénique ou un choc cardiogénique. En particulier, l'invention concerne un procédé de traitement ou de prévention d'un choc pré-cardiogénique ou d'un choc cardiogénique chez une personne par l'administration à la personne d'un régime posologique d'istaroxime par perfusion intraveineuse allant jusqu'à 24 heures.
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Citations (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1079807A (en) | 1912-09-25 | 1913-11-25 | Jonathan S Snyder | Coat-closure. |
US2867004A (en) | 1953-12-31 | 1959-01-06 | Onderzoekings Inst Res | Production of polyamide bars in continuous process |
US4534899A (en) | 1981-07-20 | 1985-08-13 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US5846743A (en) | 1995-02-22 | 1998-12-08 | Brigham And Women's Hospital, Inc. | Polyphoshoinositide binding peptides for intracellular drug delivery |
US5874268A (en) | 1996-09-23 | 1999-02-23 | Duke University | Method of introducing exogenous compounds into cells by electroporation and apparatus for same |
US6007839A (en) | 1996-02-16 | 1999-12-28 | The Liposome Company, Inc. | Preparation of pharmaceutical compositions containing etherlipid-containing multiple lipid liposomes |
US6063400A (en) | 1997-07-02 | 2000-05-16 | Sdg, Inc. | Targeted liposomal constructs for diagnostic and therapeutic uses |
US6589503B1 (en) | 1998-06-20 | 2003-07-08 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
US20040151766A1 (en) | 2003-01-30 | 2004-08-05 | Monahan Sean D. | Protein and peptide delivery to mammalian cells in vitro |
US20050136121A1 (en) | 2003-12-22 | 2005-06-23 | Shear/Kershman Laboratories, Inc. | Oral peptide delivery system with improved bioavailability |
US20060083737A1 (en) | 2004-10-18 | 2006-04-20 | Kenjiro Minomi | Intracellular peptide delivery |
US7109034B2 (en) | 1997-11-06 | 2006-09-19 | Cellectricon Ab | Method for electro-permeabilization of individual cellular and organellar structures and use thereof |
US20070042031A1 (en) | 2005-07-27 | 2007-02-22 | Protiva Biotherapeutics, Inc. | Systems and methods for manufacturing liposomes |
US20070077286A1 (en) | 2003-12-24 | 2007-04-05 | Tsutomu Ishihara | Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle |
US20070082042A1 (en) | 2004-08-06 | 2007-04-12 | Deok-Hoon Park | Multiple-layered liposome and preparation method thereof |
CN103315968A (zh) | 2013-06-26 | 2013-09-25 | 中国生命药物治疗有限公司 | 一种注射用粉针剂及其制备方法 |
WO2020180356A9 (fr) | 2019-03-05 | 2020-11-12 | Windtree Therapeutics, Inc. | Préparation intraveineuse contenant de l'istaroxime pour le traitement de l'insuffisance cardiaque aiguë (ica) |
-
2023
- 2023-04-18 WO PCT/US2023/018998 patent/WO2023205183A1/fr unknown
Patent Citations (19)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US1079807A (en) | 1912-09-25 | 1913-11-25 | Jonathan S Snyder | Coat-closure. |
US2867004A (en) | 1953-12-31 | 1959-01-06 | Onderzoekings Inst Res | Production of polyamide bars in continuous process |
US4534899A (en) | 1981-07-20 | 1985-08-13 | Lipid Specialties, Inc. | Synthetic phospholipid compounds |
US5846743A (en) | 1995-02-22 | 1998-12-08 | Brigham And Women's Hospital, Inc. | Polyphoshoinositide binding peptides for intracellular drug delivery |
US6007839A (en) | 1996-02-16 | 1999-12-28 | The Liposome Company, Inc. | Preparation of pharmaceutical compositions containing etherlipid-containing multiple lipid liposomes |
US5874268A (en) | 1996-09-23 | 1999-02-23 | Duke University | Method of introducing exogenous compounds into cells by electroporation and apparatus for same |
US6261815B1 (en) | 1996-09-23 | 2001-07-17 | Duke University | Method of introducing exogenous compounds into cells by electroporation and apparatus for same |
US6063400A (en) | 1997-07-02 | 2000-05-16 | Sdg, Inc. | Targeted liposomal constructs for diagnostic and therapeutic uses |
US7109034B2 (en) | 1997-11-06 | 2006-09-19 | Cellectricon Ab | Method for electro-permeabilization of individual cellular and organellar structures and use thereof |
US6589503B1 (en) | 1998-06-20 | 2003-07-08 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
US7306783B2 (en) | 1998-06-20 | 2007-12-11 | Washington University | Membrane-permeant peptide complexes for medical imaging, diagnostics, and pharmaceutical therapy |
US20040151766A1 (en) | 2003-01-30 | 2004-08-05 | Monahan Sean D. | Protein and peptide delivery to mammalian cells in vitro |
US20050136121A1 (en) | 2003-12-22 | 2005-06-23 | Shear/Kershman Laboratories, Inc. | Oral peptide delivery system with improved bioavailability |
US20070077286A1 (en) | 2003-12-24 | 2007-04-05 | Tsutomu Ishihara | Drug-containing nanoparticle, process for producing the same and parenterally administered preparation from the nanoparticle |
US20070082042A1 (en) | 2004-08-06 | 2007-04-12 | Deok-Hoon Park | Multiple-layered liposome and preparation method thereof |
US20060083737A1 (en) | 2004-10-18 | 2006-04-20 | Kenjiro Minomi | Intracellular peptide delivery |
US20070042031A1 (en) | 2005-07-27 | 2007-02-22 | Protiva Biotherapeutics, Inc. | Systems and methods for manufacturing liposomes |
CN103315968A (zh) | 2013-06-26 | 2013-09-25 | 中国生命药物治疗有限公司 | 一种注射用粉针剂及其制备方法 |
WO2020180356A9 (fr) | 2019-03-05 | 2020-11-12 | Windtree Therapeutics, Inc. | Préparation intraveineuse contenant de l'istaroxime pour le traitement de l'insuffisance cardiaque aiguë (ica) |
Non-Patent Citations (35)
Title |
---|
AL-MUHAMMED, MICROENCAPSUL, vol. 13, 1996, pages 293 - 306 |
ANONYMOUS: "The Safety and Efficacy of Istaroxime for Pre-Cardiogenic Shock (SEISMiC)", 30 June 2021 (2021-06-30), XP093062788, Retrieved from the Internet <URL:https%3A%2F%2Fclinicaltrials.gov%2Fstudy%2FNCT04325035%3Ftab%3Dtable> [retrieved on 20230711] * |
BERG ET AL., CIRC. OUTCOMES, vol. 12, 2019, pages e005618J |
BROPHY, EUR. J. CLIN. PHARMACOL., vol. 24, 1983, pages 103 - 108 |
CARUBELLI VALENTINA ET AL: "Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial", EUROPEAN JOURNAL OF HEART FAILURE, vol. 22, no. 9, 23 September 2020 (2020-09-23), NL, pages 1684 - 1693, XP093063176, ISSN: 1388-9842, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ejhf.1743> DOI: 10.1002/ejhf.1743 * |
CHIONCEL OVIDIU ET AL: "Istaroxime in acute heart failure: the holy grail is at HORIZON?", EUROPEAN JOURNAL OF HEART FAILURE, vol. 22, no. 9, 6 May 2020 (2020-05-06), NL, pages 1694 - 1697, XP093062800, ISSN: 1388-9842, Retrieved from the Internet <URL:https://onlinelibrary.wiley.com/doi/full-xml/10.1002/ejhf.1843> DOI: 10.1002/ejhf.1843 * |
CHONN, CURR. OPIN. BIOTECHNOL., vol. 6, 1995, pages 698 - 708 |
DUTTON GAIL: "Dual-Action Therapy Boosts Heart Function : Windtree Therapeutics' istaroxime enhances contractions in systole and relaxes muscle in diastole", GENETIC ENGINEERING & BIOTECHNOLOGY NEWS, vol. 42, no. 1, 1 January 2022 (2022-01-01), US, pages 12 - 13, XP093063194, ISSN: 1935-472X, DOI: 10.1089/gen.42.01.04 * |
EUR J PHARM BIOPHARM., vol. 79, no. 2, 2011, pages 285 - 93 |
EVANGELISTA ET AL., EUR. J. ECHOCARDIOGR., vol. 9, no. 4, 2008, pages 438 - 448 |
FOTHERBY, CONTRACEPTION, vol. 54, 1996, pages 59 - 69 |
GHCORGHIADE ET AL., JACC, vol. 51, no. 23, pages 2276 - 2285 |
GRONING, PHARMAZIE, vol. 51, 1996, pages 337 - 341 |
HIDALGO-ARAGONES, STEROID BIOCHEM. MOL. BIOL., vol. 58, 1996, pages 611 - 617 |
HOCHMAN ET AL., N. ENGL. J. MED., vol. 341, no. 9, 1999, pages 625 - 634 |
HUNZIKER ET AL., CIRC. CARDIOVASC. INTERV., vol. 12, no. 4, pages e007293 |
JENTZER ET AL., JACC, vol. 74, no. 17, 2019, pages 2117 - 2127 |
JOHNSON, J. PHARM. SCI., vol. 84, 1995, pages 1144 - 1146 |
JOSEPH ET AL., TEX. HEART INST. J., vol. 36, 2009, pages 510 - 520 |
JOURNAL OF EXCIPIENTS AND FOOD CHEMISTRY, vol. 1, 2010, pages 41 - 54 |
KAPUR ET AL., CIRCULATION, vol. 128, no. 4, 2013, pages 328 - 336 |
KAR ET AL., J. AM COLL. CARDIOL., vol. 57, no. 6, 2011, pages 688 - 696 |
LANG ET AL., J. AM. SOC. ECHOCARDIOGR., vol. 18, no. 12, 2005, pages 1440 - 1463 |
METRATEERLINK, LANCET, vol. 390, 2017, pages 1981 - 1995 |
MILO-COTTER ET AL., CARDIOLOGY, vol. 119, 2011, pages 96 - 105 |
NEGUEH ET AL., EUR. J. ECHOCARDIOGR., vol. 10, no. 2, 2009, pages 165 - 193 |
OSTRO, AM. J. HOSP. PHARM., vol. 46, 1989, pages 1576 - 1587 |
ROHATAGI, PHARMAZIE, vol. 50, 1995, pages 610 - 613 |
SAVARESELUND, CARDIAC FAILURE REV, vol. 3, no. 1, 2017, pages 7 - 11 |
SHAH ET AL., REV. CARDIOVASC. MED., vol. 2, 2001, pages S2 - S6 |
SINGH ET AL., CARDIO. REV., vol. 27, no. 4, 2019, pages 198 - 201 |
SOLOMON ET AL., CIRCULATION, vol. 116, 2007, pages 1482 - 1487 |
TENEGGI ET AL., HEART FAILURE REV., vol. 23, 2018, pages 667 - 691 |
VAN DIEPEN ET AL., CIRCULATION, vol. 136, 2017, pages e232 - c268 |
WINDTREE THERAPEUTICS: "Research Finds U.S. Cardiogenic Shock Patients Have High", 21 November 2021 (2021-11-21), XP093062801, Retrieved from the Internet <URL:https%3A%2F%2Fwww.globenewswire.com%2Fen%2Fnews-release%2F2021%2F11%2F22%2F2338935%2F0%2Fen%2FResearch-Finds-U-S-Cardiogenic-Shock-Patients-Have-High-Hospital-Inpatient-Mortality-and-Long-Length-of-Stay-Adding-to-Previously-Reported-Need-for-New-Pharmacologic-Innovation.html> [retrieved on 20230711] * |
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