Istaroxime

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Istaroxime
Istaroxime.svg
Clinical data
Other names(3Z,5α)-3-[(2-Aminoethoxy)imino]androstane-6,17-dione
Legal status
Legal status
  • Investigational
Identifiers
  • (3E,5S,8R,9S,10R,13S,14S)-3-(2-aminoethoxyimino)-10,13-dimethyl-1,2,4,5,7,8,9,11,12,14,15,16-dodecahydrocyclopenta[a]phenanthrene-6,17-dione
PubChem CID
ChemSpider
ChEMBL
Chemical and physical data
Formula C21H32N2O3
Molar mass 360.498 g·mol−1
3D model (JSmol)
  • C[C@]12CCC(=NOCCN)C[C@@H]1C(=O)C[C@@H]3[C@@H]2CC[C@]4([C@H]3CCC4=O)C
  • InChI=1S/C21H32N2O3/c1-20-7-5-13(23-26-10-9-22)11-17(20)18(24)12-14-15-3-4-19(25)21(15,2)8-6-16(14)20/h14-17H,3-12,22H2,1-2H3/t14-,15-,16-,17+,20+,21-/m0/s1
  • Key:MPYLDWFDPHRTEG-IFVNMTGRSA-N

Istaroxime is an investigational drug under development for treatment of acute decompensated heart failure

Contents

Originally patented and developed by Sigma-Tau, it was sold to CVie Therapeutics in July 2012. [1]

Heart failure

Istaroxime is a treatment for both systolic and diastolic heart failure. [2]

Intracellular calcium fluxes regulate both contraction and relaxation. Cardiac muscle cells from patients with heart failure show smaller amounts of peak calcium in their cytoplasm during contraction, and slower removal., [4] [5] 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., [4] [6]

Mechanism of action

Istaroxime is a positive inotropic agent [2] that mediates its action through inhibition of sodium/potassium adenosine triphosphatase (Na+/K+ ATPase). [7] 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., [5] [8]

Additionally, istaroxime increases intracellular calcium by improving the efficacy by which intracellular calcium triggers sarcoplasmic reticulum calcium release, [5] [8] and by accelerating the inactivation state of L-type calcium channels, which allow for calcium influx. [9] Together the changes in calcium handling increase cell contraction.

Istaroxime also enhances the heart's relaxation phase [5] by increasing the rate of intracellular calcium sequestration by Sarco/endoplasmic Reticulum Calcium ATPase, isotype 2a (SERCA2a). [8] SERCa2a is inhibited by phospholamban and higher phospholamban-to-SERCA2a ratios cause SERCA inhibition and impaired relaxation. [5] Istaroxime reduces SERCA2a-phospholamban interaction, [5] [8] and increases SERCA2a affinity for cytosolic calcium. [7] Studies on failing human heart tissue show that istaroxime increases SERCA2a activity up to 67%. [5]

Clinical use

Clinical trials show that istaroxime improves ejection fraction, stroke volume and systolic blood pressure, while also enhancing ventricular filling. [1] The drug also reduces heart rate and ventricular diastolic stiffness. [1] Contrary to available inotropic therapies, istaroxime may permit cytosolic calcium accumulation while avoiding a proarrhythmic state. [5] [9] [10] [11]

Proposed mechanisms for istaroxime's antiarrhythmic effect include a suppression of the transient inward calcium current directly involved in the production of delayed after-depolarizations [5] and improved calcium sequestration due to SERCA2a stimulation. [11] SERCA down-regulation in the failing myocardium [12] might sensitize patients to the detrimental effect of other currently used positive inotropes. Istaroxime's lusitropic effect facilitates its wider margin of safety, as patients can receive higher doses without signs of arrhythmias. [10]

Related Research Articles

Cardiac glycoside

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and increase its rate of contractions by acting on the cellular sodium-potassium ATPase pump. Their beneficial medical uses are as treatments for congestive heart failure and cardiac arrhythmias; however, their relative toxicity prevents them from being widely used. Most commonly found as secondary metabolites in several plants such as foxglove plants, these compounds nevertheless have a diverse range of biochemical effects regarding cardiac cell function and have also been suggested for use in cancer treatment.

Sarcoplasmic reticulum

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the endoplasmic reticulum in other cells. The main function of the SR is to store calcium ions (Ca2+). Calcium ion levels are kept relatively constant, with the concentration of calcium ions within a cell being 10,000 times smaller than the concentration of calcium ions outside the cell. This means that small increases in calcium ions within the cell are easily detected and can bring about important cellular changes (the calcium is said to be a second messenger; see calcium in biology for more details). Calcium is used to make calcium carbonate (found in chalk) and calcium phosphate, two compounds that the body uses to make teeth and bones. This means that too much calcium within the cells can lead to hardening (calcification) of certain intracellular structures, including the mitochondria, leading to cell death. Therefore, it is vital that calcium ion levels are controlled tightly, and can be released into the cell when necessary and then removed from the cell.

Frank–Starling law

The Frank–Starling law of the heart represents the relationship between stroke volume and end diastolic volume. The law states that the stroke volume of the heart increases in response to an increase in the volume of blood in the ventricles, before contraction, when all other factors remain constant. As a larger volume of blood flows into the ventricle, the blood stretches the cardiac muscle fibers, leading to an increase in the force of contraction. The Frank-Starling mechanism allows the cardiac output to be synchronized with the venous return, arterial blood supply and humoral length, without depending upon external regulation to make alterations. The physiological importance of the mechanism lies mainly in maintaining left and right ventricular output equality.

An inotrope is an agent that alters the force or energy of muscular contractions. Negatively inotropic agents weaken the force of muscular contractions. Positively inotropic agents increase the strength of muscular contraction.

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.

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.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. The ability to produce changes in force during contraction result from incremental degrees of binding between different types of tissue, that is, between filaments of myosin (thick) and actin (thin) tissue. The degree of binding depends upon the concentration of calcium ions in the cell. Within an in vivo intact heart, the action/response of the sympathetic nervous system is driven by precisely timed releases of a catecholamine, which is a process that determines the concentration of calcium ions in the cytosol of cardiac muscle cells. The factors causing an increase in contractility work by causing an increase in intracellular calcium ions (Ca++) during contraction.

Amrinone

Amrinone, also known as inamrinone, and sold as Inocor, is a pyridine phosphodiesterase 3 inhibitor. It is a drug that may improve the prognosis in patients with congestive heart failure. Amrinone has been shown to increase the contractions initiated in the heart by high gain calcium induced calcium release (CICR). The positive inotropic effect of amrinone is mediated by the selective enhancement of high gain CICR which contributes to the contraction of myocytes by phosphorylation through cAMP dependent protein kinase A (PKA) and Ca2+ calmodulin kinase pathways.

Catecholaminergic polymorphic ventricular tachycardia Medical condition

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited genetic disorder that predisposes those affected to potentially life-threatening abnormal heart rhythms or arrhythmias. The arrhythmias seen in CPVT typically occur during exercise or at times of emotional stress, and classically take the form of bidirectional ventricular tachycardia or ventricular fibrillation. Those affected may be asymptomatic, but they may also experience blackouts or even sudden cardiac death.

k-Strophanthidin Chemical compound

k-Strophanthidin is a cardenolide found in species of the genus Strophanthus. It is the aglycone of k-strophanthin, an analogue of ouabain. k-strophanthin is found in the ripe seeds of Strophanthus kombé and in the lily Convallaria.

The Bowditch effect, also known as the Treppe phenomenon and the Treppe effect, is an autoregulation method by which myocardial tension increases with an increase in heart rate. It was first observed by Henry Pickering Bowditch in 1871.

The Anrep effect is an autoregulation method in which myocardial contractility increases with afterload. It was experimentally determined that increasing afterload caused a proportional linear increase in ventricular inotropy. This effect is found in denervated heart preparations, such as the Starling Preparation, and represents an intrinsic autoregulation mechanism.

ATP2A2 is an ATPase associated with Darier's disease and Acrokeratosis verruciformis.

Lusitropy is the rate of myocardial relaxation. The increase in cytosolic calcium of cardiomyocytes via increased uptake leads to increased myocardial contractility, but the myocardial relaxation, or lusitropy, decreases. This should not be confused, however, with catecholamine-induced calcium uptake into the sarcoplasmic reticulum, which increases lusitropy.

ATP2A1

Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 is an enzyme that in humans is encoded by the ATP2A1 gene.

ATP2A3

Sarcoplasmic/endoplasmic reticulum calcium ATPase 3 is an enzyme that in humans is encoded by the ATP2A3 gene.

Sarcolipin

Sarcolipin is a micropeptide protein that in humans is encoded by the SLN gene.

Omecamtiv mecarbil

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is being studied for a potential role in the treatment of left ventricular systolic heart failure.

CXL 1020 is an experimental drug that is being investigated as a treatment for acute decompensated heart failure. CXL 1020 functions as a nitroxyl donor; nitroxyl is the reduced, protonated version of nitric oxide. Nitroxyl is capable of enhancing left ventricular contractility without increasing heart rate by modifying normal Ca2+ cycling through the sarcoplasmic reticulum as well as increasing the sensitivity of cardiac myofilaments to Ca2+.

Mydicar is a genetically targeted enzyme replacement therapy being studied for use in patients with severe heart failure. It is designed to increase the level of SERCA2a, a sarcoplasmic endoplasmic reticulum calcium (Ca2+) ATPase found in the membrane of the sarcoplasmic reticulum (SR). The SERCA2a gene is delivered to the heart via an adeno-associated viral vector. Using the α-myosin heavy chain gene promoter in the cardiac muscle cells, also called cardiomyocytes, Mydicar is able to direct the gene expression only to the heart muscle. Mydicar is being tested in a phase 2 study, in which has been compared to a placebo in 39 advanced heart failure patients. Thus far, patients treated with Mydicar have shown a 52% reduction in the risk of worsening heart failure compared to patients treated with the placebo.

References

  1. 1 2 3 Shah, S.J., MD, Blair, J.E.A., Filippatos, G.S., Macarie, C., Ruzyllo, W., Korewicki, J., Bubenek-Turconi, S.I., Ceracchi, M., Bianchetti, M., Carminati, P., Kremastinos, D., Grzybowski, J., Valentini, G., Sabbah, H.N., Gheorghiade, M. 2009. Effects of istaroxime on diastolic stiffness in acute heart failure syndromes: Results from the Hemodynamic, Echocardiographic, and Neurohormonal Effects of Istaroxime, a Novel Intravenous Inotropic and Lusitropic Agent: a Randomized Controlled Trial in Patients Hospitalized with Heart Failure (HORIZON-HF) trial. American Heart Journal, 157 (6): 1035-1041.
  2. 1 2 Mattera, G.G., Giudice, P.L., Loi, F.M.P., Vanoli, E., Gagnol, J.P., Borsini, F., and Carminati, P. 2007. Istaroxime: A New Luso-Inotropic Agent for Heart Failure. American Journal of Cardiology, 99(2A): 33A-40A.
  3. ↑ Gheorghiade, M., Ambrosy, A.P., Ferrandi, M., Ferrari, P. 2011. Combining SERCA2a activation and Na-K ATPase inhibition: a promising new approach to managing acute heart failure syndromes with low cardiac output. Discovery medicine, 12 (63):141-151.
  4. 1 2 Davies, C.H., Davia, K., Bennett, J.G., Pepper, J.R., Poole-Wilson, P.A., Harding, S.E. 1995. Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure. Circulation, 92: 2540 –2549.
  5. 1 2 3 4 5 6 7 8 9 Micheletti, R., Palazzo, F., Barassi, P., Giacalone, G., Ferrandi, M., Schiavone, A., Moro, B., Parodi, O., Ferrari, P., and Bianchi, G. 2007. Istaroxime, a Stimulator of Sarcoplasmic Reticulum Calcium Adenosine Triphosphatase Isoform 2a Activity, as a Novel Therapeutic Approach to Heart Failure. American Journal of Cardiology, 99: 24-32.
  6. ↑ Lehnart, S. E., Schillinger, W., Pieske, B., Prestle, J., Just, H., Hasenfuss, G. 1998. Sarcoplasmic Reticulum Proteins in Heart Failure. Annals of the New York Academy of Sciences, 853: 220-30.
  7. 1 2 Rocchetti, M., Besana, A., Mostacciuolo, G., Micheletti, R., Ferrari, P., Sarkozi, S., Szegedi, C., Jona, I., and Zaza, A. 2005. Modulation of sarcoplasmic reticulum function by Na+/K+ pump inhibitors with different toxicity: digoxin and PST2744 [(E,Z)-3-((2- aminoethoxy)imino)androstane-6,17-dione hydrochloride]. Journal of Pharmacology and Experimental Therapeutics, 313: 207–215.
  8. 1 2 3 4 Rocchetti, M., Alemanni, M., Mostacciuolo, G., Barassi, P., Altomare, C., Chisci, R., Micheletti, R., Ferrari, P., and Zaza. A. 2008. Modulation of Sarcoplasmic Reticulum Function by PST2744 [Istaroxime; (E,Z)-3-((2-Aminoethoxy)imino) Androstane-6,17- dione Hydrochloride)] in a Pressure-Overload Heart Failure Model. Journal of Pharmacology and Experimental Therapeutics, 326: 957-965.
  9. 1 2 Rocchetti, M., Besana, A., Mostacciuolo, G., Ferrari, P., Micheletti, R., and Zaza, A. 2003. Diverse Toxicity Associated with Cardiac Na+/K+ Pump Inhibition: Evaluation of Electrophysiological Mechanisms. Journal of Pharmacology and Experimental Therapeutics, 305: 765-771.
  10. 1 2 Adamson, P.B., Vanoli, E., Mattera, G.G., Germany, R., Gagnol, J., Carminati, P., and Schwartz, P.J. 2003. Hemodynamic Effects of a New Inotropic Compound, PST-2744, in Dogs With Chronic Ischemic Heart Failure. Journal of Cardiovascular Pharmacology, 42: 169–173.
  11. 1 2 Alemanni, M., Rocchetti, M., Re, D., Zaza, A. 2011. Role and Mechanism of Subcellular Ca2+ Distribution in the Action of Two Inotropic Agents with Different Toxicity. Journal of Molecular and Cellular Cardiology, 50.5: 910-918.
  12. ↑ Movsesian, M.A., Karimi, M., Green, K., and Jones, L.R. 1994. Ca(2+)-transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium. Circulation, 90: 653-657.
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