Newer inotropes in pediatric heart failure.

In the cardiac setting in pediatrics, inotropic support is often employed based on the extrapolation from adult studies, the underlying pathophysiology, pharmacodynamics of inotropes, and anecdotal experience. Large pediatric critical care studies involving inotropic support are rare. Levosimendan, a calcium-sensitizing agent with inotropic and lusitropic properties, is a pyridazole dinitrate derivative with linear pharmacokinetics and a relatively short half life, although an active metabolite, namely, OR-1876, has a half life of 70-80 hours accounting for a prolonged effect. Albeit few, pediatric studies involving levosimendan suggest similar pharmacokinetics to adults with heart failure, an efficacy at least equal to that of milrinone, favorable myocardial oxygen effects, and an ability to decrease concomitant catecholamine dosing. Levosimendan may be a promising new agent in pediatrics, but further experience and study are warranted. Finally, istaroxime, a calcium cycling agent that is in the beginning of adult study, may be another inotrope with lusitropic properties that might be applicable to pediatric patients.

The uPA(+/+)-SCID mouse with humanized liver as a model for in vivo metabolism of 4-androstene-3,17-dione.

The metabolism in primary human hepatocyte cultures often deviates from that in clinical studies, which in turn are hampered by ethical constraints. Here the use of urokinase-type plasminogen activator-severe combined immunodeficiency [uPA(+/+)-SCID] mice transplanted with human hepatocytes was investigated as a model for in vivo metabolic studies. The urinary excretion profile after oral administration of 4-androstene-3,17-dione (AD) in chimeric mice was investigated by using gas chromatography-mass spectrometry detection and was compared with previously reported metabolites of AD in humans and cell cultures. Chimeric mice exhibited an AD metabolic profile similar to that of humans, showing androsterone and etiocholanolone as major metabolites. Several hydroxylated steroids were detected as minor metabolites in the chimeric mice compared with hepatocyte cultures. A significant correlation between the extent of liver replacement and the relative abundances of human-type metabolites was established. The results for AD showed that humanized liver uPA-SCID mice can serve as an alternative model for in vivo metabolism studies in humans. In the future, this model could possibly be used for other steroids or pharmaceutical compounds.

Istaroxime, a novel luso-inotropic agent for the treatment of acute heart failure.

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.

A phase 1-2 dose-escalating study evaluating the safety and tolerability of istaroxime and specific effects on electrocardiographic and hemodynamic parameters in patients with chronic heart failure with reduced systolic function.

Istaroxime (PST2744) is a luso-inotrope that stimulates the sarcoplasmic reticulum calcium adenosine triphosphatase isoform 2a without chronotropic effects. Additionally, it has beneficial effects on myocardial energetics. This phase 1-2 clinical trial in patients with chronic stable heart failure (HF) is the first evaluation of istaroxime in humans. Three cohorts of 6 patients each were exposed to 4 sequentially increasing 1-hour infusions with a random placebo. Doses were 0.005-5.0 micro/kg per min. Safety and hemodynamics were evaluated by impedance cardiography, digital Holter recorder, and electrocardiography. Pharmacokinetic data were obtained for 1 hour during treatment and for 6 hours after dosing. The mean age was 53+/-7 years, and the mean left ventricular ejection fraction was 0.27+/-0.08. Impedance cardiography demonstrated enhanced contractility as measured by the acceleration index, left cardiac work index, cardiac index, and pulse pressure at doses>or=1 micro/kg per min, with evidence of activity at doses of 0.5 micro/kg per min. Istaroxime shortened QTc. After infusion, the hemodynamic effect rapidly dissipated over 1-2 hours. Istaroxime was pharmacologically active and well tolerated at doses up to 3.33 micro/kg per min. Side effects were related to gastrointestinal symptoms and injection site pain at higher doses, which dissipated within minutes after the infusion ended. Ventricular ectopy was not altered. This study suggests that istaroxime is potentially useful in the treatment of HF and may offer a unique treatment for systolic and/or diastolic dysfunction. Additional studies are under way to further define its utility in acute HF.