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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
ChEMBL
CompTox Dashboard (EPA)
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

<span class="mw-page-title-main">Cardiac glycoside</span> Class of organic compounds

Cardiac glycosides are a class of organic compounds that increase the output force of the heart and decrease its rate of contractions by inhibiting the cellular sodium-potassium ATPase pump. Their beneficial medical uses include 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 and milkweed 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.

<span class="mw-page-title-main">Sarcoplasmic reticulum</span> Menbrane-bound structure in muscle cells for storing calcium

The sarcoplasmic reticulum (SR) is a membrane-bound structure found within muscle cells that is similar to the smooth 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). 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.

<span class="mw-page-title-main">Frank–Starling law</span> Relationship between stroke volume and end diastolic volume

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 cardiac muscle, 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 or inotropic is a drug or any substance 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 sarcoplasmic/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.

<span class="mw-page-title-main">Phospholamban</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">T-tubule</span> Extensions in cell membrane of muscle fibres

T-tubules are extensions of the cell membrane that penetrate into the center of skeletal and cardiac muscle cells. With membranes that contain large concentrations of ion channels, transporters, and pumps, T-tubules permit rapid transmission of the action potential into the cell, and also play an important role in regulating cellular calcium concentration.

Myocardial contractility represents the innate ability of the heart muscle (cardiac muscle or myocardium) to contract. It is the maximum attainable value for the force of contraction of a given heart. 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.

Urocortin 2 (Ucn2) is an endogenous peptide in the corticotrophin-releasing factor (CRF) family.

<span class="mw-page-title-main">Amrinone</span> Chemical compound

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.

<span class="mw-page-title-main">Catecholaminergic polymorphic ventricular tachycardia</span> 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 or Treppe effect or Staircase Phenomenon, 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.

ATP2A2 also known as sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2) is an ATPase associated with Darier's disease and Acrokeratosis verruciformis.

Lusitropy or lucitropy 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.

<span class="mw-page-title-main">PDE3 inhibitor</span>

A PDE3 inhibitor is a drug which inhibits the action of the phosphodiesterase enzyme PDE3. They are used for the therapy of acute heart failure and cardiogenic shock.

<span class="mw-page-title-main">ATP2A1</span> Protein-coding gene in the species Homo sapiens

Sarcoplasmic/endoplasmic reticulum calcium ATPase 1 (SERCA1) also known as Calcium pump 1, is an enzyme that in humans is encoded by the ATP2A1 gene.

<span class="mw-page-title-main">Sarcolipin</span> Protein-coding gene in the species Homo sapiens

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

<span class="mw-page-title-main">Omecamtiv mecarbil</span> Chemical compound

Omecamtiv mecarbil (INN), previously referred to as CK-1827452, is a cardiac-specific myosin activator. It is an experimental drug 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+.

References

  1. 1 2 3 Shah SJ, Blair JE, Filippatos GS, Macarie C, Ruzyllo W, Korewicki J, et al. (June 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): 1035–41. doi:10.1016/j.ahj.2009.03.007. PMID   19464414.
  2. 1 2 Mattera GG, Lo Giudice P, Loi FM, Vanoli E, Gagnol JP, Borsini F, Carminati P (January 2007). "Istaroxime: a new luso-inotropic agent for heart failure". The American Journal of Cardiology. 99 (2A): 33A–40A. doi:10.1016/j.amjcard.2006.09.004. PMID   17239702.
  3. ↑ Gheorghiade M, Ambrosy AP, Ferrandi M, Ferrari P (August 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): 141–51. PMID   21878191.
  4. 1 2 Davies CH, Davia K, Bennett JG, Pepper JR, Poole-Wilson PA, Harding SE (November 1995). "Reduced contraction and altered frequency response of isolated ventricular myocytes from patients with heart failure". Circulation. 92 (9): 2540–9. doi:10.1161/01.cir.92.9.2540. PMID   7586355.
  5. 1 2 3 4 5 6 7 8 9 Micheletti R, Palazzo F, Barassi P, Giacalone G, Ferrandi M, Schiavone A, et al. (January 2007). "Istaroxime, a stimulator of sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a activity, as a novel therapeutic approach to heart failure". The American Journal of Cardiology. 99 (2A): 24A–32A. doi:10.1016/j.amjcard.2006.09.003. PMID   17239701.
  6. ↑ Lehnart SE, Schillinger W, Pieske B, Prestle J, Just H, Hasenfuss G (September 1998). "Sarcoplasmic reticulum proteins in heart failure". Annals of the New York Academy of Sciences. 853 (1): 220–30. Bibcode:1998NYASA.853..220L. doi:10.1111/j.1749-6632.1998.tb08270.x. PMID   10603950. S2CID   22792584.
  7. 1 2 Rocchetti M, Besana A, Mostacciuolo G, Micheletti R, Ferrari P, Sarkozi S, et al. (April 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]". The Journal of Pharmacology and Experimental Therapeutics. 313 (1): 207–15. doi:10.1124/jpet.104.077933. PMID   15576469. S2CID   19954351.
  8. 1 2 3 4 Rocchetti M, Alemanni M, Mostacciuolo G, Barassi P, Altomare C, Chisci R, et al. (September 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". The Journal of Pharmacology and Experimental Therapeutics. 326 (3): 957–65. doi:10.1124/jpet.108.138701. PMID   18539651. S2CID   2420808.
  9. 1 2 Rocchetti M, Besana A, Mostacciuolo G, Ferrari P, Micheletti R, Zaza A (May 2003). "Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of electrophysiological mechanisms". The Journal of Pharmacology and Experimental Therapeutics. 305 (2): 765–71. doi:10.1124/jpet.102.047696. PMID   12606646. S2CID   116370.
  10. 1 2 Adamson PB, Vanoli E, Mattera GG, Germany R, Gagnol JP, Carminati P, Schwartz PJ (August 2003). "Hemodynamic effects of a new inotropic compound, PST-2744, in dogs with chronic ischemic heart failure". Journal of Cardiovascular Pharmacology. 42 (2): 169–73. doi: 10.1097/00005344-200308000-00003 . PMID   12883318. S2CID   25796174.
  11. 1 2 Alemanni M, Rocchetti M, Re D, Zaza A (May 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): 910–8. doi:10.1016/j.yjmcc.2011.02.008. PMID   21354172.
  12. ↑ Movsesian MA, Karimi M, Green K, Jones LR (August 1994). "Ca(2+)-transporting ATPase, phospholamban, and calsequestrin levels in nonfailing and failing human myocardium". Circulation. 90 (2): 653–7. doi: 10.1161/01.cir.90.2.653 . PMID   8044934.
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