Istaroxime: A New Luso-Inotropic Agent for Heart Failure
Section snippets
Materials and Methods
All experiments were conducted according to international guidelines and approved by the Italian Ministry of Health. Animals were routinely monitored by a veterinarian.
Clinical signs and behavior
Dogs did not show signs of intolerance or discomfort during administration of vehicle or 1 μg/kg per min istaroxime for 24 hours and presented regurgitation of food within 4–5 hours only at an infusion rate of 3 μg/kg per min.
Effects on hemodynamics
Istaroxime-induced hemodynamic effects were independent of treatment sequence (F(2,17) = 1.34, p = 0.38). Istaroxime dose dependently increased (F(2,17) = 11.80, p <0.004) cardiac inotropism (LV +dP/dtmax), which reached a peak after 8–10 hours and remained constant
Discussion
This study, which was conducted in conscious animals with LV dysfunction, shows that both short-term (24-hour infusion) and long-term (oral) istaroxime administration have powerful beneficial effects on cardiac performance and survival, without inducing relevant side effects. The combined mechanisms of action by sodium-potassium ATPase activity inhibition and SERCA2a stimulation in the same molecule may explain these findings.
Compared with digoxin, istaroxime induced positive inotropic effects
Conclusion
Istaroxime is a powerful luso-inotropic agent that, in animal models of HF, does not enhance the risk of arrhythmia. The lusitropic effect of the compound could be of interest in patients with diastolic dysfunction. The experiment in cardiomyopathic hamsters suggests that long-term oral treatment with istaroxime may interfere with critical mechanisms associated with disease progression and may ultimately result in improved survival. Very recent investigations documented that istaroxime does not
References (17)
- et al.
Readmission after hospitalization for congestive heart failure among Medicare beneficiaries
Arch Intern Med
(1997) - et al.
Milrinone therapy in catecholamine-dependent critically ill patients with heart failure
Acta Anaesthesiol Scand
(2000) - et al.
Effect of neseritide versus dobutamine on short-term outcomes in the treatment of patients with acutely decompensated heart failure
J Am Coll Cardiol
(2002) - et al.
Pharmacological profile of the novel inotropic agent (E,Z)-3-((2-aminoethoxy)imino)androstane-6,17-dione hydrochloride (PST2744)
J Pharmacol Exp Ther
(2002) - et al.
Structure-based design and synthesis of novel potent Na+/K+ ATPase inhibitors derived from a 5α,14α-androstane scaffold as positive inotropic compounds
J Med Chem
(2003) - et al.
Diverse toxicity associated with cardiac Na+/K+ pump inhibition: evaluation of electrophysiological mechanisms
J Pharmacol Exp Ther
(2003) - et al.
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]
J Pharmacol Exp Ther
(2005)
Cited by (36)
Calcium dysregulation in heart diseases: Targeting calcium channels to achieve a correct calcium homeostasis
2022, Pharmacological ResearchPositive Inotropic Drugs for Treating Heart Failure
2022, Comprehensive PharmacologyNatural cardenolides suppress coronaviral replication by downregulating JAK1 via a Na<sup>+</sup>/K<sup>+</sup>-ATPase independent proteolysise
2020, Biochemical PharmacologyCitation Excerpt :However, in addition to Na+/K+-ATPase, there are several other potential pharmacological targets of cardenolides, e.g. steroid receptors [1,2]. Also, ouabain and digoxin are both antagonists of estrogen receptor (ER) that could be useful in the development of breast cancer drugs [1]; ouabagenin, the hydrolysis product of ouabain, is a novel ligand for the liver X receptor (LXR)[2]; and innovative derivatives of cardiotonic steroids (cardenolides and bufadienolides) that target Na+/K+-ATPase are under development for the optimization of their cardio therapeutic effects [3–6]. Janus kinase 1 (JAK1) is a member of the JAK family of intracellular, nonreceptor tyrosine kinases; essential for signaling certain type I and type II cytokines or interferons [7,8].
Istaroxime, a positive inotropic agent devoid of proarrhythmic properties in sensitive chronic atrioventricular block dogs
2018, Pharmacological ResearchCitation Excerpt :In addition, no afterdepolarizations or afterdepolarization-dependent ventricular arrhythmias occurred, respectively, in control ventricular cardiomyocytes and dogs exposed to istaroxime. This absent proarrhythmic effect of istaroxime under unremodelled conditions, consistent with existing cellular [3,4,25], animal [3,6,7,9], and clinical data [10–12], was associated with low STV values of APD in vitro and ARI in vivo, which otherwise often increase prior to occurrence of EADs and TdP, respectively [16]. In CAVB dogs [13], while the inhibition of Na+/K+-ATPase using ouabain generally results in DAD-dependent ventricular tachycardias under conscious and anesthetized conditions [14,15], the lack of significant proarrhythmic events elicited upon istaroxime administration confirms its low proarrhythmic profile.
Development and physico-chemical characterization of a liposomal formulation of istaroxime
2011, European Journal of Pharmaceutics and BiopharmaceuticsCitation Excerpt :By exerting both inotropic and lusitropic activities, istaroxime targets defective Ca2+ cycling without compromising cardiac efficiency, representing an effective and safe treatment of both acute and chronic HF [10]. Animal models have shown that istaroxime promotes both muscle contraction and relaxation and prevents the cytosolic calcium overload and arrhythmia associated with digoxin [9]. The compound demonstrated good tolerability in a phase I/II safety study.