Johns Hopkins University

University of California

The United States of America, As Represented by the Secretary, Department of Health and Human Services

Louisiana State University and Agricultural & Mechanical College

Vanderbilt University

Temple University

Universita Di Napoli Federico Ii

Nazareno Paolocci

David A Wink

David A Kass

Katrina M Miranda

Martin Feelisch

Jon M Fukuto

Ning Feng

Tatsuo Katori

Bruce Ralph Carter

Walter J Koch

Carlo G Tocchetti

Pasquale Pagliaro

Alessandro Cannavo

Giuseppe Rengo

Cyrus Takahashi

The present invention relates to compositions and methods for the treatment of heart failure.

Methods for treating heart failure with a TRKB agonist

The present invention provides 75 kD transmembrane neurotrophin receptor (p75) antagonists and their use in prevention and treatment of loss of function, and adverse remodeling, in cardiac tissues subject to acute or chronic hemodynamic stress. Uses of the antagonists with or without additional cardiotropic agents for improving contractility and for treatment of congestive heart failure are also provided.

P75antagonists and treatment of acute and chronic cardiac disease

Nitroxyl donating compounds are administered prior to the onset of ischemia for the prevention and/or reduction of ischemia/reperfusion injury in subjects at risk for ischemia. Nitroxyl donors also are administered to organs to be transplanted for the prevention and/or reduction of ischemia/reperfusion injury upon reperfusion in a recipient. Nitroxyl donors include any nitroxyl donating compound. In particular cases the nitroxyl donor is a nitroxyl-donating diazeniumdiolate, such as Angeli's salt or IPA/NO.

Method of treating ischemia/reperfusion injury with nitroxyl donors

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure. Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO(Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent. Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy.

Nitroxyl progenitors in the treatment of heart failure

Administration of an HNO/NOdonating compound, such as Angeli's salt, increases myocardial contractility while concomitantly lowering left ventricular preload in subjects experiencing heart failure Moreover, administration of the HNO/NOdonating compound isopropylamine (IPA)/NO (Na(CH)CHNHN(O)NO) surprisingly exhibited positive inotropic effects in subjects experiencing heart failure that were superior to those caused by the HNO/NOdonating compound Angeli's salt. Additionally, in contrast to the effects observed with NOdonors, administration of an HNO/NOdonor in combination with a positive inotropic agent did not impair the positive inotropic effect of the positive inotropic agent Further, HNO/NOexerts its positive inotropic effect independent of the adrenergic system, increasing contractility even in subjects receiving beta-antagonist therapy

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Baltimore, MD, United States of America

Nazareno Paolocci