News Column

Researchers Submit Patent Application, "Methods of Treating Cardiovascular Indications", for Approval

August 24, 2014



By a News Reporter-Staff News Editor at Heart Disease Weekly -- From Washington, D.C., NewsRx journalists report that a patent application by the inventor HOLZMEISTER, JOHANNES (ZURICH, CH), filed on January 24, 2014, was made available online on August 7, 2014 (see also Cardiorentis Ltd.).

The patent's assignee is Cardiorentis Ltd.

News editors obtained the following quote from the background information supplied by the inventors: "This application claims priority to U.S. Provisional Application Ser. No. 61/756,692 filed Jan. 25, 2013, the disclosure of which is hereby incorporated by reference.

A family of related peptides has been discovered that works in concert to achieve salt and water homeostasis in the body. These peptides, termed natriuretic peptides for their role in moderating natriuresis and diuresis, have varying amino acid sequences and originate from different tissues within the body. This family of natriuretic peptides consists of atrial natriuretic peptide ('ANP'), brain natriuretic peptide ('BNP'), C-type natriuretic peptide ('CNP'), Dendroaspis natriuretic peptide ('DNP'), and urodilatin ('URO', or ularitide). Their tissue-specific distribution of these peptides is as follows: heart (ANP, BNP, and DNP); brain (ANP, BNP, and CNP); endothelial cells (CNP); plasma (DNP); and kidney (URO). These peptides are constituents of a hormonal system that plays a critical role in maintaining an intricate balance of blood volume/pressure in the human body. For instance, urodilatin, a close analog of ANP secreted by kidney tubular cells, promotes excretion of sodium and water by acting directly on kidney cells in the collecting duct to inhibit sodium and water reabsorption.

"Like other natriuretic peptides, such as ANP and BNP, urodilatin has been studied for use in treating various conditions, including renal failure and cardiovascular conditions such as congestive heart failure (see, e.g., U.S. Pat. Nos. 5,571,789 and 6,831,064; Kentsch et al., Eur. J. Clin. Invest. 1992, 22(10):662-669; Kentsch et al., Eur. J. Clin. Invest. 1995, 25(4):281-283; Elsner et al., Am. Heart J. 1995, 129(4):766-773; and Forssmann et al., Clinical Pharmacology and Therapeutics 1998, 64(3):322-330).

"Cardiovascular diseases are a leading cause of death, regardless of gender or ethnicity. Among these diseases, congestive heart failure ('CHF') is highly prevalent. According to the American Heart Association, the number of hospital discharges and the number of deaths due to CHF both rose roughly 2.5-fold from 1979 to 1999. Currently, about 5 million Americans have been diagnosed with CHF, and about 550,000 new cases occur annually (American Heart Association 2001). This life-threatening condition is accompanied by great financial impact.

"There continues to be a need for new and more effective methods for treating cardiovascular conditions, especially in the area of acute onset of symptoms in an emergency situation.

"All documents referenced herein are hereby incorporated by reference in their entireties for all purposes."

As a supplement to the background information on this patent application, NewsRx correspondents also obtained the inventor's summary information for this patent application: "It is an object of the present invention to provide methods for the treatment of cardiovascular events, e.g., acute onset cardiovascular events.

"The objects are met by the present invention which in certain embodiments is directed to a method of treating a cardiovascular indication comprising administering a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide to a patient in need thereof within 24 hours of clinical assessment of the patient.

"In one embodiment, the methods of the present invention may result in the prevention or minimization of myocardial cell death. The prevention or minimization of this cell death may be in the presence of one or more factors selected from C-reactive protein, TNF-alpha, IL-1.beta., endothelin-1 or galectin-3.

"In another embodiment, the methods of the present invention may result in the prevention or minimization of nitrosylation of myocardial cells. The prevention or minimization of nitrosylation of myocardial cells may be in the presence of one or more factors selected from C-reactive protein, TNF-alpha, IL-1.beta., endothelin-1 or galectin-3

"In certain embodiments, the present invention is directed to a use of a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide for the treatment of a cardiovascular indication on a patient in need thereof within 24 hours of clinical assessment of the patient.

"In certain embodiments, the present invention is directed to a use of a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide in the preparation of a medicament for the treatment of a cardiovascular indication on a patient in need thereof within 24 hours of clinical assessment of the patient.

"In certain embodiments, the present invention is directed to a use of a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide to prevent or minimize myocardial cell death. In one embodiment, the use to prevent or minimize myocardial cell death is in the presence of one or more factors selected from C-reactive protein, TNF-alpha, IL-1.beta., endothelin-1 or galectin-3. In another embodiment, the use to prevent or minimize myocardial cell death is within about 2 hours, within about 4 hours, within about 6 hours, within about 10 hours or within about 24 hours of exposure to the one or more factors.

"In certain embodiments, the present invention is directed to a use of a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide to prevent or minimize nitrosylation of myocardial cells. In one embodiment, the use to prevent or minimize nitrosylation of myocardial cells is in the presence of one or more factors selected from C-reactive protein, TNF-alpha, IL-1.beta., endothelin-1, or galectin-3. In another embodiment, the use to prevent or minimize nitrosylation of myocardial cells is within about 2 hours, within about 4 hours, within about 6 hours, within about 10 hours or within about 24 hours of exposure to the one or more factors.

"In certain embodiments, the present invention is directed to a kit comprising a natriuretic peptide, a diuretic peptide and/or a vasodilatory peptide and instructions for use in the treatment of a cardiovascular indication on a patient in need thereof within 24 hours of clinical assessment of the patient.

"In certain embodiments, the natriuretic peptide utilized in the present invention is ularitide or neseritide.

"As used herein, the term 'cardiovascular indication' encompasses all types of cardiovascular conditions that, regardless of their cause, are generally recognized by a physician as heart failure, which include but are not limited to, acute heart failure, chronic heart failure, congestive heart failure (CHF), and particularly acute decompensated heart failure (which is a separate and distinct disease state than CHF). In this application, the terms acute decompensated heart failure ('ADHF') and decompensated heart failure ('DHF') are used interchangeably. These conditions typically involve weakened heart function combined with a build-up of body fluid and may be the result of either a sudden event, such as myocardial infarction or the rupture of a heart valve, or a chronic and slowly progressing process, such as the gradual weakening of heart muscles due to cardiomyopathy from infections or alcohol/drug abuse, and other pre-existing medical conditions such as hypertension, coronary artery disease, valve disease, thyroid disease, kidney disease, diabetes, or congenital heart defects. Also encompassed by the term 'heart failure' are any heart conditions relating to fluid build-up in the heart, such as myocardial edema.

"The term 'administrate' or 'administration,' as used herein, encompasses various methods of delivering a composition containing a natriuretic peptide to a patient. Modes of administration may include, but are not limited to, methods that involve delivering the composition intravenously, intraperitoneally, intranasally, transdermally, topically, subcutaneously, parentally, intramuscularly, orally, or systemically, and via injection, ingestion, inhalation, implantation, or adsorption by any other means. The preferred means of administering a composition comprising a natriuretic peptide (e.g., ularitide) is intravenous injection, where the composition is formulated as a sterile solution. Another route of administration is oral ingestion, where the natriuretic peptide can be formulated as a pharmaceutical composition in the form of a syrup, an elixir, a suspension, a powder, a granule, a tablet, a capsule, a lozenge, a troche, an aqueous solution, a cream, an ointment, a lotion, a gel or an emulsion. In some embodiments, the pharmaceutical composition for oral ingestion is formulated for sustained release over a period of at least 24 hours. Furthermore, administration of a natriuretic peptide can be achieved by subcutaneous injection of a natriuretic peptide-containing composition, which is prepared as a sustained release system comprising microspheres or biodegradable polymers, such that the natriuretic peptide can be released into a patient's body at a controlled rate over a period of time, e.g., at least 24 hours or 48 hours.

"An 'effective amount' refers to the amount of an active ingredient, e.g., urodilatin, in a pharmaceutical composition that is sufficient to produce a beneficial or desired effect at a level that is readily detectable by a method commonly used for detection of such an effect. In some embodiments, such an effect results in a change of at least 10% from the value of a basal level where the active ingredient is not administered. In other embodiments, the change is at least 20%, 50%, 80%, or an even higher percentage from the basal level. As will be described below, the effective amount of an active ingredient may vary from subject to subject, depending on age, general condition of the subject, the severity of the condition being treated, and the particular biologically active agent administered and the like. An appropriate 'effective' amount in any individual case may be determined by one of ordinary skill in the art by reference to the pertinent texts and literature and/or by using routine experimentation.

"The term 'natriuretic peptide' refers to a peptide that has the biological activity of promoting natriuresis, diuresis and vasodilation. Assays for testing such activity are known in the art, e.g., as described in U.S. Pat. Nos. 4,751,284 and 5,449,751. Examples of natriuretic peptides include, but are not limited to, atrial natriuretic peptide (ANP(99-126)), brain natriuretic peptide (BNP), C-type natriuretic peptide (CNP), Dendroaspis natriuretic peptide (DNP), urodilatin (URO, or ularitide), and any fragments of the prohormone ANP(1-126) or BNP precursor polypeptide that retains the vasodilating, natriuretic or diuretic activity. For further description of exemplary natriuretic peptides and their use or preparation, see, e.g., U.S. Pat. Nos. 4,751,284, 4,782,044, 4,895,932, 5,449,751, 5,461,142, 5,571,789, and 5,767,239. See also, Ha et al., Regul. Pept. 133(1-3):13-19, 2006. The invention can also be practiced with peptides and proteins which may cause a diuresis or vasodilation effect such as relaxin.

"As used in this application, the term 'urodilatin' refers to a 32-amino acid peptide hormone that is described by U.S. Pat. No. 5,449,751 and has the amino acid sequence set forth in GenBank Accession No. 1506430A. Urodilatin, the 95-126 fragment of atrial natriuretic peptide (ANP), is also referred to as ANP(95-126). The term 'atrial natriuretic peptide' or 'ANP(99-126)' refers to a 28-amino acid peptide hormone, which is transcribed from the same gene and derived from the same polypeptide precursor, ANP(1-126), as urodilatin but without the first four amino acids at the N-terminus. For a detailed description of the prohormone, see, e.g., Oikawa et al. (Nature 1984; 309:724-726), Nakayama et al. (Nature 1984; 310:699-701), Greenberg et al. (Nature 1984; 312:656-658), Seidman et al. (Hypertension 1985; 7:31-34) and GenBank Accession Nos. 1007205A, 1009248A, 1101403A and AAA35529.

"Conventionally, the term urodilatin (URO) is more often used to refer to the naturally occurring peptide, whereas the term ularitide is often used to refer to the recombinantly produced or chemically synthesized peptide. In this application, the term 'urodilatin' and 'ularitide' are used interchangeably to broadly encompass both a naturally occurring peptide and a recombinant or synthetic peptide. The terms also encompass any peptide of the above-cited amino acid sequence containing chemical modification (e.g., deamination, phosphorylation, PEGylation, etc.) at one or more residues or substitution by the corresponding D-isomer(s), so long as the peptide retains the biological activity as a natriuretic peptide. Furthermore, a chemically modified urodilatin or ularitide may contain one or two amino acid substitutions for the purpose of facilitating the desired chemical modification (e.g., to provide a reactive group for conjugation). 'Urodilatin' or 'ularitide' of this application, regardless of whether it contains chemical modifications, retains a substantial portion, i.e., at least 50%, preferably at least 80%, and more preferably at least 90%, of the biological activity of the naturally-occurring wild-type urodilatin or ANP(95-126).

"The term 'cardiac medicine' refers to a therapeutic agent that is useful for treating a cardiac condition. A 'cardiac medicine' includes but is not limited to natriuretic peptides, ACE inhibitors ('ACEIs'), beta-adrenergic blocking agents ('beta-blockers'), vasodilators, diuretics, digitalis preparations (e.g., digoxin), dopamine, dobutamine, levosimendan, nesiritide, blood thinners, angiotensin II receptor blockers, calcium channel blockers, nitrates and potassium.

"The term 'pharmaceutically acceptable excipient or carrier' refers to any inert ingredient in a composition that may act, for example, to stabilize the active ingredient. A pharmaceutically acceptable excipient can include, but is not limited to, carbohydrates (such as glucose, sucrose, or dextrans), antioxidants (such as ascorbic acid or glutathione), chelating agents, low-molecular weight proteins, high-molecular weight polymers, gel-forming agents or other stabilizers and additives. Other examples of a pharmaceutically acceptable carrier include wetting agents, emulsifying agents, dispersing agents or preservatives, which are particularly useful for preventing the growth or action of microorganisms. Various preservatives are well known and include, for example, phenol and ascorbic acid. Examples of carriers, stabilizers or adjuvants can be found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 17th ed. (1985).

"As used herein, a 'patient' refers to a human or a non-human mammal.

BRIEF DESCRIPTION OF THE FIGURES

"FIG. 1 depicts the percent of myocardial cell death according to the assays of Example 2.

"FIG. 2 depicts the nitrosylation of myocardial cells according to the assays of Example 2.

"FIG. 3 depicts the results of a lactate dehydrogenase assay of Example 2."

For additional information on this patent application, see: HOLZMEISTER, JOHANNES. Methods of Treating Cardiovascular Indications. Filed January 24, 2014 and posted August 7, 2014. Patent URL: http://appft.uspto.gov/netacgi/nph-Parser?Sect1=PTO2&Sect2=HITOFF&u=%2Fnetahtml%2FPTO%2Fsearch-adv.html&r=2153&p=44&f=G&l=50&d=PG01&S1=20140731.PD.&OS=PD/20140731&RS=PD/20140731

Keywords for this news article include: Albumins, Cardiology, Immunology, Proteomics, Amino Acids, Endothelins, Hemodynamics, Vasodilation, Heart Disease, Immunoproteins, Peptide Hormones, Cardiorentis Ltd., C Reactive Protein, C-Reactive Protein, Acute-Phase Proteins, Cardiovascular Diseases, Brain Natriuretic Peptide, C-Type Natriuretic Peptide.

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Source: Heart Disease Weekly


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