Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-06-29
2003-07-08
Jones, Dwayne (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
Reexamination Certificate
active
06589938
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to the use of angiotensin I derivatives, including des-Aspartate angiotensin I in the treatment and/or prevention of infarction-related cardiac injuries and disorders. More particularly, the present invention contemplates a method for the treatment and/or prevention of myocardial infarction, heart failure and/or related conditions. The present invention further contemplates compositions for use in the treatment and/or prophylaxis of infarction-related cardiac injuries and disorders such as but not limited to myocardial infarction and heart failure.
BACKGROUND OF THE INVENTION
Infarction or necrosis of part of the heart muscle can lead to various conditions including ischemia of cardiac tissue, angina, arrhythmia, cardiac hypertrophy, and heart failure. Extensive infarction or enlargement of infarction may result in cardiac arrest and death. Cardiac or myocardial infarction and related injuries and disorders contribute to significant morbidity and mortality in patients affected by such conditions.
Des-Aspartate angiotensin I (des-Asp-angiotensin I) is a nonapeptide produced from a decapeptide by the action of an aminopeptidase. The nonapeptide is produced from angiotensin I by enzymatic NH
2
-terminal degradation (1). Des-Asp-angiotensin I is a substrate for plasma and pulmonary angiotensin converting enzyme (2). U.S. Pat. No. 5,773,415 discloses the attenuating effect of des-Asp-angiotensin I on experimentally induced non-infarction-related cardiac hypertrophy in rat. In U.S. Pat. No. 6,100,237, the use of des-Asp-angiotensin I as an anti-neointima and anti-arteriosclerotic agent is disclosed. It appears des-Asp-angiotensin I act on a specific indomethacin and losartan-sensitive subtype of angiotensin receptor AT
1
(3) to antagonize the pressor (4) and hypertrophic (5, 6) actions of angiotensin II. AT
1
is one of the two specific angiotensin receptors, the activation of which is related to the effect of angiotensin II on cardiac tissue (7).
The level of angiotensin II has been shown to increase after moycardial infarction (7). However, the precise role of angiotensin II in the pathology of myocardial infarction remains to be elucidated.
SUMMARY OF THE INVENTION
It has now been found surprisingly that angiotensin I derivatives, including des-Asp-angiotensin I is effective in the treatment and/or prevention of infarction-related cardiac injuries and disorders.
One aspect of the present invention therefore relates to a method for the treatment or prevention of an infarction-related cardiac injury or disorder, the method comprising administering an effective amount of a derivative of angiotensin I to a subject in need of such treatment or prevention. In one embodiment, the derivative of angiotensin I is des-Asp-angiotensin I.
Another aspect of the invention relates to use of a derivative of angiotensin I to treat or prevent an infarction-related cardiac injury or disorder. In another aspect, the invention relates to use of a derivative of angiotensin I in the manufacture of medicament for the treatment or prevention of an infarction-related cardiac injury or disorder. Still a further aspect of the present invention provides a composition comprising a derivative of angiotensin I and a pharmaceutically acceptable carrier for use in the treatment or prevention of an infarction-related cardiac injury or disorder. In another aspect, the present invention relates to a combination comprising a container, a derivative of angiotensin I or a pharmaceutical composition containing the same, and instructions for use of the derivative of angiotensin I or the composition containing the same for the treatment or prevention of an infarction-related cardiac injury or disorder. A kit is also provided which comprises a derivative of angiotensin I and instructions for use of the derivative of angiotensin I for the treatment or prevention of an infarction-related cardiac injury or disorder. In specific embodiments according to these aspects of the invention, the angiotensin I derivative is des-Asp-angiotensin I.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The effect of des-Asp-angiotensin I on the infarct size and transmurality in the left ventricle of a rat following experimental myocardial infarction was determined and the present invention is predicated in part on the determination that a derivative of angiotensin I prevents or otherwise attenuates or decreases the infarct size and transmurality. Animal models for studying infarction-induced injuries and disorders, including small animals such as the rat are well accepted in the art (8). The inventors have therefore determined, surprisingly that a derivative of angiotensin I such as des-Asp-angiotensin I is capable of preventing or otherwise ameliorating infarction-related cardiac injuries and disorders.
Accordingly, one aspect of the present invention provides a method for the treatment and/or prevention of infarction-related injuries and disorders, the method comprising administering an effective amount of a derivative of angiotensin I.
An “effective amount” refers to an amount effective, at dosages and for periods of time necessary to achieve the desired therapeutic result, such as to prevent, inhibit or delay the onset of infarction-related injuries and disorders or ameliorate the symptoms of infarction related injuries and disorders. While the effective amount may vary according to various factors such as the disease state, age, sex, and weight of the individual in the case of a human patient, in one embodiment, the effective amount is about 1.8 mg/kg/day.
The term “infarction-related injuries and disorders” is used herein in its broadest sense and includes myocardial infarction and any and all injuries, disorders or conditions, induced by, following, or related to myocardial infarction, including, ischemia of cardiac tissue, angina, arrhythmia, remodeling cardiac hypertrophy, congestive heart failure, and cardiac arrest. Following infarction, unaffected heart cells will compensate for heart cells that have died by realigning (remodelling) and growing bigger in size (hypertrophy). Remodeling cardiac hypertrophy as that term is used is therefore intended to describe infarction-related hypertrophy and is to be distinguished from non-infarction-related hypertrophy. Persons skilled in the art will also appreciate that treatment of infarction related cardiac hypertrophy differs from the treatment of non-infarction-related cardiac hypertrophy. The former is treated mainly with angiotensin converting enzyme inhibitors such as captopril and angiotensin receptor blockers such as losartan, while any drug that lowers blood pressure may be used to treat non-infarction-related cardiac hypertrophy.
A “derivative of angiotensin I” refers to any mutant, fragment, part or portion of angiotensin I, including molecules comprising single or multiple amino acid substitutions, deletions and/or insertions to angiotensin I and which inhibits, reduces or otherwise interferes with the activity or function of angiotensin II, or homologue, analogue or chemical equivalent thereof which is functionally equivalent in that it inhibits, reduces or otherwise interferes with the activity or functioning of angiotensin II.
Insertional amino acid sequence derivatives are those which include an addition of one or more amino acid residues. The addition may be introduced into a predetermined site or by random insertion with suitable screening of the resulting products. An amino acid insertional derivative of angiotensin I may include amino and/or carboxyl terminal fusions as well as intra-sequence insertions of single or multiple amino acids. Deletional derivatives are characterized by the removal of one or more amino acids from the sequence. Substitutional amino acid derivatives are those in which at least one residue in the sequence has been removed and a different residue inserted in its place.
A homologue of an angiotensin I derivative includes functionally, structurally or stereochemically similar polypeptides, for exa
Jones Dwayne
Klarquist & Sparkman, LLP
National University of Singapore
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