US 2015 0011643A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0011643 A1 DiLisa et al. (43) Pub. Date: Jan. 8, 2015 (54) TREATMENT OF HEART FAILURE AND (60) Provisional application No. 61/038,230, filed on Mar. ASSOCATED CONDITIONS BY 20, 2008, provisional application No. 61/155,704, ADMINISTRATION OF MONOAMINE filed on Feb. 26, 2009. OXIDASE INHIBITORS (71) Applicants:Nazareno Paolocci, Baltimore, MD Publication Classification (US); Univeristy of Padua, Padova (IT) (51) Int. Cl. (72) Inventors: Fabio DiLisa, Padova (IT): Ning Feng, A63L/38 (2006.01) Baltimore, MD (US); Nina Kaludercic, (52) U.S. Cl. Baltimore, MD (US); Nazareno CPC ..... ... A61 K31/138 (2013.01) Paolocci, Baltimore, MD (US) USPC .......................................................... S14/651 (21) Appl. No.: 14/332,234 (22) Filed: Jul. 15, 2014 (57) ABSTRACT Related U.S. Application Data Administration of monoamine oxidase inhibitors is useful in (63) Continuation of application No. 12/407,739, filed on the prevention and treatment of heart failure and incipient Mar. 19, 2009, now abandoned. heart failure. Patent Application Publication Jan. 8, 2015 Sheet 1 of 2 US 201S/0011643 A1 Figure 1 Sial 8. Sws-L) Cleaved Š Caspase-3 ) Figure . Prevention of caspase-3 productief) fron cardiomyocytes Lapoi) reatment with clorgyi Be. Patent Application Publication Jan. 8, 2015 Sheet 2 of 2 US 201S/0011643 A1 Figure 2 8:38:8 ::::::::8: US 2015/0011643 A1 Jan. 8, 2015 TREATMENT OF HEART FAILURE AND in the art is a variety of MAO inhibitors and their pharmaceu ASSOCATED CONDITIONS BY tically acceptable compositions for administration, in accor ADMINISTRATION OF MONOAMINE dance with the present invention, to mammals including, but OXIDASE INHIBITORS not limited to, humans. CROSS-REFERENCE TO RELATED PATENT BRIEF DESCRIPTION OF THE DRAWINGS APPLICATIONS 0010 FIG. 1. Prevention of caspase-3 production from 0001. This application claims the benefit of U.S. Provi cardiomyocytes upon treatment with clorgyline. sional Application Ser. No. 61/038.230 filed 20 Mar. 2008, 0011 FIG. 2. Interaction of MAO-A and MAO-B iso and U.S. Provisional Application Ser. No. 61/155,704 filed 26 forms with neurotransmitters/dietary amines in the central Feb. 2009, both of which applications are incorporated herein and peripheral nervous system. by reference in their entirety. DETAILED DESCRIPTION OF THE INVENTION STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH ORDEVELOPMENT 0012. The detailed description of the various aspects and embodiments of the invention is divided into the following 0002 This invention was made with government support sections beginning with a definition of certain terms used under National Heart, Lung, and Blood Institute grant no. herein. R01 HL075265-01A2. The government has certain rights in the invention. Definitions BACKGROUND OF THE INVENTION 0013 The following definitions are provided to assist the reader. Unless otherwise defined, all terms of art, notations 0003 1. Field of the Invention and other scientific or medical terms or terminology used 0004. The present invention relates generally to the field of herein are intended to have the meanings commonly under medicine, pharmaceutical chemistry, biology and in particu stood by those of skill in the chemical and medical arts. In lar to methods for treating and inhibiting heart failure and Some cases, terms with commonly understood meanings are incipient heart failure. defined herein for clarity and/or for ready reference, and the 0005 2. State of the Art inclusion of such definitions herein should not necessarily be 0006. In spite of various known treatment and preventive construed to represent a substantial difference over the defi methods, heart failure continues to remain a major cause of nition of the term as generally understood in the art. As used worldwide mortality. There is a strong need for new effective herein, certain terms may have the following defined mean methods of therapy for prevention and treatment of heart ings. failure and incipient heart failure. The present invention pro 0014. As used herein, the singular form “a” “an and “the vides methods for preventing and treating heart failure and include singular and plural references unless the context incipient heart failure by administering monoamine oxidase clearly dictates otherwise. (MAO) inhibitors. 0015. As used herein, "compensated hypertrophy' refers to abnormal chamber function or enlargement of the heart SUMMARY OF THE INVENTION coincident with an increase in muscle mass. For example, in 0007. This invention is directed towards novel methods for cardiac disease, the compensation for the inefficiency of the preventing and treating heart failure, incipient heart failure, heart's pump action is by enlisting the various reserves of the and associated conditions, symptoms, signs, and disorders. In heart such as hypertrophy, enlargement, or increase in rate so one aspect, the invention provides a method of treating heart as to maintain circulatory equilibrium and prevent the appear failure in a mammal in need thereof, which method comprises ance of the signs of congestive heart failure. administering to said mammal diagnosed with heart failure a 0016. As used herein, the term “comprising is intended to therapeutically effective amount of an MAO inhibitor. In mean that the compositions and methods include the recited another aspect, the invention provides a method of preventing elements, but not excluding others. “Consisting essentially heart failure in a mammal in need thereof, which method of when used to define compositions and methods, shall comprises administering to said mammal diagnosed with a mean excluding other elements of any essential significance susceptibility to heart failure a therapeutically effective to the composition or method. “Consisting of shall mean amount of a MAO inhibitor. excluding more than trace elements of other ingredients for 0008. In another aspect, the invention provides a method claimed compositions and Substantial method steps. Embodi of inhibiting incipient heart failure in a mammal in need ments defined by each of these transition terms are within the thereof, which method comprises administering to said mam Scope of this invention. Accordingly, it is intended that the mal diagnosed with incipient heart failure a therapeutically methods and compositions can include additional steps and effective amount of a MAO inhibitor. In another aspect, the components (comprising) or alternatively including steps and invention provides a method of treating incipient heart failure compositions of no significance (consisting essentially of) or in a mammal in need thereof, which method comprises alternatively, intending only the Stated method steps or com administering to said mammal diagnosed with incipient heart positions (consisting of). failure atherapeutically effective amount of a MAO inhibitor. 0017. As used herein, “cardiomyocytes' or “cardiac myo 0009. A variety of well known methods are useful for cytes' are specialized muscle cells which form the myocar diagnosing heart failure or incipient heart failure, their signs dium of the heart. Cardiomyocytes have five major compo and symptoms, and mammalian Subject Susceptible to Such nents: cell membrane (sarcolemma) and T-tubules for conditions. A variety of MAO inhibitors are useful for prac impulse conduction; sarcoplasmic reticulum for contraction; ticing the methods of the present invention. Also well known contractile elements; mitochondria; and a nucleus. US 2015/0011643 A1 Jan. 8, 2015 0018. As used herein, “heart failure (HF) or “congestive 0023. As used herein, “mammals” include, but are not heart failure (CHF), refers to a condition in which the heart limited to, murines, rats, simians, humans, farm animals, can not pump enough blood to the body's other organs due to, sport animals and pets. for example, heart muscle malfunction, weakening of the 0024. As used herein, "monoamine oxidases” are heart muscle called cardiomyopathy, and other heart muscle enzymes that catalyze the oxidation of monoamines. Two related reasons. Congestive heart failure (CHF) is character monoamine oxidase (MAO) isoenzymes, MAO-A and MAO ized, among other effects, by left ventricle (LV) chamber B, are closely linked in opposite orientation on the X chro dilation, decreased LV contractility and elevated levels of mosome and are expressed in the outer mitochondrial mem circulating catecholamines. In another aspect, congestive brane. In vivo, MAO-A and MAO-B oxidize monoamine heart failure occurs due to ischemic and other reperfusion, neurotransmitters and dietary monoamines, the regulation of and other non-ischemic factors. Heart failure includes, but is which is important in maintaining normal mental states. not limited to, the following symptoms or signs: cardiac rep MAO-A prefers serotonin, norepinephrine, and dopamine as erfusion injury, compensated hypertrophy, human end stage substrates, whereas MAO-B prefers phenylethylamine and heart failure, hypertensive cardiomyopathy, left ventricular trace amines. These proteins have been sequenced and char hypertension, left or right ventricular dilation, left or right acterized, see for example, the National Center for Biotech Ventricular failure, maladaptive hypertrophy, myocardial nology Information (NCBI) GenBank Accession Nos. for structural disarrangement (apoptosis and loss of cardiomyo MAO-A gi572841 14|emb|CAI43.120.1||57284.114): cyte) and myocardial dysfunction (loss in contraction and/or