RESUMO
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.
Assuntos
Cardiotônicos/uso terapêutico , Inibidores Enzimáticos/uso terapêutico , Etiocolanolona/análogos & derivados , Insuficiência Cardíaca/tratamento farmacológico , ATPase Trocadora de Sódio-Potássio/antagonistas & inibidores , Doença Aguda , Animais , Cardiotônicos/efeitos adversos , Cardiotônicos/química , Cardiotônicos/farmacocinética , Cardiotônicos/farmacologia , Cardiotônicos/toxicidade , Inibidores Enzimáticos/efeitos adversos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/toxicidade , Etiocolanolona/efeitos adversos , Etiocolanolona/química , Etiocolanolona/farmacocinética , Etiocolanolona/farmacologia , Etiocolanolona/uso terapêutico , Etiocolanolona/toxicidade , Insuficiência Cardíaca/enzimologia , Humanos , Estrutura Molecular , Patentes como Assunto , ATPase Trocadora de Sódio-Potássio/metabolismo , Relação Estrutura-Atividade , Resultado do TratamentoRESUMO
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.