Istaroxime is an investigational drug under development for treatment of

acute decompensated heart failure Acute decompensated heart failure (ADHF) is a sudden worsening of the signs and symptoms of heart failure, which typically includes difficulty breathing (dyspnea), edema, leg or feet swelling, and Fatigue (medical), fatigue. ADHF is a common and ...

Originally patented and developed by

Sigma-Tau Leadiant Biosciences, formerly known as Sigma-Tau Industrie Farmaceutiche Riunite, was founded in 1957 by research chemist Claudio Cavazza. In 2018 Leadiant Biosciences has come under fire for creating a monopoly for CDCA and unnecessarily in ...

, it was sold to CVie Therapeutics in July 2012.

Heart failure

Istaroxime is a treatment for both systolic and

diastolic heart failure Heart failure with preserved ejection fraction (HFpEF) is a form of heart failure in which the ejection fraction – the percentage of the volume of blood ejected from the left ventricle with each heartbeat divided by the volume of blood when the l ...

. * Systolic heart failure is characterized by impaired ventricular emptying, caused by reduced contractility. * Diastolic dysfunction is defined by defective ventricular filling, caused by the heart's inability to properly relax between beats. Intracellular

calcium Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar to ...

fluxes regulate both contraction and relaxation.

Cardiac muscle cells Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

from patients with heart failure show smaller amounts of peak calcium in their cytoplasm during contraction, and slower removal., The mishandling of intracellular calcium is often due to problems in the cells’ ability to mediate calcium influx, and sequestration of calcium back in the

sarcoplasmic reticulum The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth endoplasmic reticulum in other Cell (biology), cells. The main function of the SR is to store calcium ions (Ca2+). Calcium in bio ...

Mechanism of action

Istaroxime is a positive inotropic agent that mediates its action through inhibition of sodium/potassium adenosine triphosphatase (Na+/K+ ATPase). Na+/K+ ATPase inhibition increases intracellular sodium levels, which reverses the driving force of the sodium/calcium exchanger, inhibiting calcium extrusion and possibly facilitating calcium entry., Additionally, istaroxime increases intracellular calcium by improving the efficacy by which intracellular calcium triggers sarcoplasmic reticulum calcium release, and by accelerating the inactivation state of

L-type calcium channels The L-type calcium channel (also known as the dihydropyridine channel, or DHP channel) is part of the high-voltage activated family of voltage-dependent calcium channel. "L" stands for long-lasting referring to the length of activation. This c ...

, which allow for calcium influx. Together the changes in calcium handling increase cell contraction. Istaroxime also enhances the heart's relaxation phase by increasing the rate of intracellular calcium sequestration by Sarco/endoplasmic Reticulum Calcium ATPase, isotype 2a (SERCA2a). SERCa2a is inhibited by

phospholamban Phospholamban, also known as PLN or PLB, is a micropeptide protein that in humans is encoded by the ''PLN'' gene. Phospholamban is a 52-amino acid integral membrane protein that regulates the calcium (Ca2+) pump in cardiac muscle cells. Funct ...

and higher phospholamban-to-SERCA2a ratios cause

SERCA SERCA, or sarco/endoplasmic reticulum Ca2+-ATPase, or SR Ca2+-ATPase, is a calcium ATPase-type P-ATPase. Its major function is to transport calcium from the cytosol into the sarcoplasmic reticulum. Function SERCA is a P-type ATPase. It resides i ...

inhibition and impaired relaxation. Istaroxime reduces SERCA2a-phospholamban interaction, and increases SERCA2a affinity for cytosolic calcium. Studies on failing human heart tissue show that istaroxime increases SERCA2a activity up to 67%.

Clinical use

Clinical trials show that istaroxime improves

ejection fraction An ejection fraction (EF) is the volumetric fraction (or portion of the total) of fluid (usually blood) ejected from a chamber (usually the heart) with each contraction (or heartbeat). It can refer to the cardiac atrium, ventricle, gall bladder, ...

, stroke volume and

systolic blood pressure Blood pressure (BP) is the pressure of circulating blood against the walls of blood vessels. Most of this pressure results from the heart pumping blood through the circulatory system. When used without qualification, the term "blood pressure" r ...

, while also enhancing ventricular filling. The drug also reduces heart rate and ventricular diastolic stiffness. Contrary to available inotropic therapies, istaroxime may permit cytosolic calcium accumulation while avoiding a proarrhythmic state. Proposed mechanisms for istaroxime's

antiarrhythmic Antiarrhythmic agents, also known as cardiac dysrhythmia medications, are a group of pharmaceuticals that are used to suppress abnormally fast rhythms ( tachycardias), such as atrial fibrillation, supraventricular tachycardia and ventricular tac ...

effect include a suppression of the transient inward calcium current directly involved in the production of delayed after-depolarizations and improved calcium sequestration due to SERCA2a stimulation. SERCA down-regulation in the failing

myocardium Cardiac muscle (also called heart muscle, myocardium, cardiomyocytes and cardiac myocytes) is one of three types of vertebrate muscle tissues, with the other two being skeletal muscle and smooth muscle. It is an involuntary, striated muscle that ...

might sensitize patients to the detrimental effect of other currently used positive inotropes. Istaroxime's

lusitropic Lusitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility (positive inotropic effect), but the myocardial relaxation, or lusitropy, decreases ...

effect facilitates its wider margin of safety, as patients can receive higher doses without signs of arrhythmias.

References

{{Reflist Amines Androstanes Diketones Steroid oximes Ketoximes