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.
Ghali
Jalal K
JK
Louisiana State University Health Sciences Center, Shreveport, Louisiana, USA.
Smith
William B
WB
Torre-Amione
Guillermo
G
Haynos
William
W
Rayburn
Barry K
BK
Amato
Antonino
A
Zhang
Dan
D
Cowart
Doug
D
Valentini
Giovanni
G
Carminati
Paolo
P
Gheorghiade
Mihai
M
D000328:Adult; D000368:Aged; D001794:Blood Pressure / Q000187:drug effects; D002307:Cardiography, Impedance / Q000187:drug effects; D002316:Cardiotonic Agents / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D005043:Etiocholanolone / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006207:Half-Life; D006333:Heart Failure / Q000188:drug therapy*; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009200:Myocardial Contraction / Q000187:drug effects
D002316:Cardiotonic Agents; D005043:Etiocholanolone; C468128:Istaroxime