istaroxime and Acute-Disease

Acute heart failure (AHF) is a frequent medical condition associated with a poor prognosis. Based on systolic blood pressure at presentation, patients with AHF can be classified into 5 clinical profiles enabling a more targeted use of standard medications including diuretics, vasodilators and inotropes. The most recent guidelines underline the importance of a rapid management and the favorable impact of heart failure programs, which reduce morbidity and mortality after an admission for AHF. New therapeutic perspectives include ultrafiltration, vasopressin and adenosine antagonists, relaxin and new inotropes such as istaroxime.

Topics: Acute Disease; Adenosine; Algorithms; Cardiotonic Agents; Diuretics; Drug Therapy, Combination; Etiocholanolone; Heart Failure; Hemodiafiltration; Humans; Oxygen Inhalation Therapy; Practice Guidelines as Topic; Prognosis; Relaxin; Risk Factors; Treatment Outcome; Vasoconstrictor Agents; Vasodilator Agents; Vasopressins

Acute heart failure syndromes (AHFS) are associated with the rapid onset of heart failure (HF) signs and symptoms. Hospitalizations for AHFS continue to rise and are associated with significant mortality and morbidity. Several pharmacological agents are currently approved for the treatment of AHFS, but their use is associated with an increase in short-term mortality. There is a need for new agents that can be given in the acute setting with increased efficacy and safety. Istaroxime is a unique agent with both inotropic and lusitropic properties which is currently being studied for the treatment of AHFS. Istaroxime inhibits the sodium-potassium adenosine triphosphatase (ATPase) and stimulates the sarcoplasmic reticulum calcium ATPase isoform 2 (SERCA-2) thereby improving contractility and diastolic relaxation. Early data from human studies reveal that istaroxime decreases pulmonary capillary wedge pressure (PCWP) and possibly improves diastolic function without causing a significant change in heart rate (HR), blood pressure, ischemic or arrhythmic events. Most commonly reported side effects were related to gastrointestinal intolerance and were dose related. In conclusion, istaroxime is a novel agent being investigated for the treatment of AHFS whose mechanism of action and cellular targets make it a promising therapy. Further studies with longer infusion times in patients with hypotension are required to confirm its efficacy and safety.

Topics: Acute Disease; Animals; Cardiotonic Agents; Dobutamine; Etiocholanolone; Heart Failure; Hemodynamics; Humans; Pulmonary Wedge Pressure; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sodium-Potassium-Exchanging ATPase

Treatment with inotropic agents is one of the most controversial topics in heart failure. Initial enthusiasm, based on strong pathophysiological rationale and apparent empirical efficacy, has been progressively limited by results of controlled trials and registries showing poorer outcomes of the patients on inotropic therapy. The use of these agents remains, however, potentially indicated in a significant proportion of patients with low cardiac output, peripheral hypoperfusion and end-organ dysfunction caused by heart failure. Limitations of inotropic therapy seem to be mainly related to their mechanisms of action entailing arrhythmogenesis, peripheral vasodilation, myocardial ischemia and damage, and possibly due to their use in patients without a clear indication, rather than to the general principle of inotropic therapy itself. This review will discuss the characteristics of the patients with a potential indication for inotropic therapy, the main data from registries and controlled trials, the mechanism of the untoward effects of these agents on outcomes and, lastly, perspectives with new agents with novel mechanisms of action.

Topics: Acute Disease; Cardiotonic Agents; Digoxin; Dobutamine; Etiocholanolone; Exercise Test; Heart Failure; Hemodynamics; Hospitals, Group Practice; Humans; Hydrazones; Prognosis; Pyrazines; Pyridazines; Quinolines; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Treatment Outcome; Urea; Vasodilator Agents

Sigma-Tau Ind Farm Riunite SpA and Debiopharm SA are developing istaroxime, the lead in a series of Na(+)/K(+)-ATPase inhibitors, for the potential treatment of cardiac failure. By September 2005, phase I/II trials of istaroxime were ongoing.

Topics: Acute Disease; Animals; Cardiotonic Agents; Enzyme Inhibitors; Etiocholanolone; Heart Failure; Humans; Molecular Structure; Patents as Topic; Sodium-Potassium-Exchanging ATPase; Structure-Activity Relationship; Treatment Outcome

Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of the Na+/K+ adenosine triphosphatase and stimulation of sarcoplasmic reticulum calcium adenosine triphosphatase activity. We analyzed data from HORIZON-HF, a randomized, controlled trial evaluating the short-term effects of istaroxime in patients hospitalized with heart failure and left ventricular ejection fraction < or = 35% to test the hypothesis that istaroxime improves diastolic stiffness in acute heart failure syndrome.. One hundred twenty patients were randomized 3:1 (istaroxime/placebo) to a continuous 6-hour infusion of 1 of 3 doses of istaroxime or placebo. All patients underwent pulmonary artery catheterization and comprehensive 2-dimensional/Doppler and tissue Doppler echocardiography at baseline and at the end of the 6-hour infusion. We quantified diastolic stiffness using pressure-volume analysis and tissue Doppler imaging of the lateral mitral annulus (E').. Baseline characteristics were similar among all groups, with mean age 55 +/- 11 years, 88% men, left ventricular ejection fraction 27% +/- 7%, systolic blood pressure (SBP) 116 +/- 13 mm Hg, and pulmonary capillary wedge pressure (PCWP) 25 +/- 5 mm Hg. Istaroxime administration resulted in an increase in E' velocities, whereas there was a decrease in E' in the placebo group (P = .048 between groups). On pressure-volume analysis, istaroxime decreased end-diastolic elastance (P = .0001). On multivariate analysis, increasing doses of istaroxime increased E' velocity (P = .043) and E-wave deceleration time (P = .001), and decreased E/E' ratio (P = .047), after controlling for age, sex, baseline ejection fraction, change in PCWP, and change in SBP.. Istaroxime decreases PCWP, increases SBP, and decreases diastolic stiffness in patients with acute heart failure syndrome.

Topics: Acute Disease; Aged; Cardiovascular Agents; Diastole; Etiocholanolone; Female; Heart; Heart Failure; Hospitalization; Humans; Male; Middle Aged; Sodium-Potassium-Exchanging ATPase; Stroke Volume

We examined the hemodynamic, echocardiographic, and neurohormonal effects of intravenous istaroxime in patients hospitalized with heart failure (HF).. Istaroxime is a novel intravenous agent with inotropic and lusitropic properties related to inhibition of Na/K adenosine triphosphatase (ATPase) and stimulation of sarcoplasmic reticulum calcium ATPase.. One hundred twenty patients admitted with HF and reduced systolic function were instrumented with a pulmonary artery catheter within 48 h of admission. Three sequential cohorts of 40 patients each were randomized 3:1 istaroxime:placebo to a continuous 6-h infusion. The first cohort received 0.5 microg/kg/min, the second 1.0 microg/kg/min, and the third 1.5 microg/kg/min istaroxime or placebo.. All doses of istaroxime lowered pulmonary capillary wedge pressure (PCWP), the primary end point (mean +/- SD: -3.2 +/- 6.8 mm Hg, -3.3 +/- 5.5 mm Hg, and -4.7 +/- 5.9 mm Hg compared with 0.0 +/- 3.6 mm Hg with placebo; p < 0.05 for all doses). Istaroxime significantly decreased heart rate (HR) and increased systolic blood pressure (SBP). Cardiac index increased and left ventricular end-diastolic volume decreased significantly only with 1.5 microg/kg/min. On echocardiography, left ventricular end diastolic volume and deceleration time improved with 1.5 microg/kg/min. There were no changes in neurohormones, renal function, or troponin I. Adverse events were not life threatening and were dose related.. In patients hospitalized with HF, istaroxime improved PCWP and possibly diastolic function. In contrast to available inotropes, istaroxime increased SBP and decreased HR. (A Phase II Trial to Assess Hemodynamic Effects of Istaroxime in Pts With Worsening HF and Reduced LV Systolic Function [HORIZON-HF]; NCT00616161).

Topics: Acute Disease; Adolescent; Adult; Aged; Aged, 80 and over; Cardiotonic Agents; Diastole; Etiocholanolone; Female; Heart Failure; Heart Rate; Hemodynamics; Hospitalization; Humans; Infusions, Intravenous; Male; Middle Aged; Sodium-Potassium-Exchanging ATPase; Stroke Volume; Systole; Ultrasonography

Acute heart failure represents an increasingly common cause of hospitalization, and may require the use of inotropic drugs in patients with low cardiac output and evidence of organ hypoperfusion. However, currently available therapies may have deleterious effects and increase mortality. An ideal inotropic drug should restore effective tissue perfusion by enhancing myocardial contractility without causing adverse effects. Such a drug is not available yet. New agents with different biological targets are under clinical development. In particular, istaroxime seems to dissociate the inotropic effect exerted by digitalis (inhibition of the membrane sodium/potassium adenosine triphosphatase) from the arrhythmic effect and to ameliorate diastolic dysfunction (via sarcoendoplasmic reticulum calcium adenosine triphosphatase activation). Additionally, the myosin activator omecamtiv mecarbil appears to have promising characteristics, while genetic therapy has been explored in animal studies only. Further investigations are needed to confirm and expand the effectiveness and safety of these agents in patients with acute heart failure and low cardiac output.

Topics: Acute Disease; Animals; Cardiac Output; Cardiotonic Agents; Clinical Trials as Topic; Digoxin; Dobutamine; Etiocholanolone; Genetic Therapy; Heart Failure; Humans; Hydrazones; Pyridazines; Ryanodine Receptor Calcium Release Channel; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Simendan; Sodium-Potassium-Exchanging ATPase; Urea

Topics: Acute Disease; Cardiotonic Agents; Etiocholanolone; Heart Failure; Heart Rate; Humans; Stroke Volume