Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-02-18
2001-12-11
Henley, III, Raymond (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S222200, C514S231200, C514S249000, C514S255030, C514S315000
Reexamination Certificate
active
06329342
ABSTRACT:
Congestive heart failure (CHF; cardiac failure) is a condition in which weakened heart function exists together with a build-up of body fluid. Cardiac failure often occurs when cardiac output is insufficient to meet metabolic demands of the body, or when the heart cannot meet the demands of operating at increased levels of filling/diastolic pressure.
Congestive heart failure may be caused by many forms of heart disease. Common causes of congestive heart failure include: narrowing of the arteries supplying blood to the heart muscle (coronary heart disease); prior heart attack (myocardial infarction) resulting in scar tissue large enough to interfere with normal function of the heart; high blood pressure; heart valve disease due to past rheumatic fever or an abnormality present at birth; primary disease of the heart muscle itself (cardiomyopathy); defects in the heart present at birth (congenital heart disease) and infection of the heart valves and/or muscle itself (endocarditis and/or myocarditis). Each of these disease processes can lead to congestive heart failure by reducing the strength of the heart muscle contraction, by limiting the ability of the heart's pumping chambers to fill with blood due to mechanical problems or impaired diastolic relaxation, or by filling the heart's chambers with too much blood.
Numerous compounds are known in the art to be useful for the prevention and treatment of congestive heart failure, including &agr;-adrenergic antagonists, angiotensin II antagonists, angiotensin-converting enzyme (ACE) inhibitors, &bgr;-adrenergic antagonists, antihypertensives, calcium channel blockers, diuretics, potassium channel opening vasodilators, renin inhibitors, and serotonin antagonists.
Growth hormone, which is secreted from the pituitary gland, stimulates growth of all tissues of the body that are capable of growing. In addition, growth hormone is known to have the following basic effects on the metabolic processes of the body: (1) increased rate of protein synthesis in all cells of the body; (2) decreased rate of carbohydrate utilization in cells of the body; and (3) increased mobilization of free fatty acids and use of fatty acids for energy. The cardiac effects of growth hormone have been reviewed, and it is suggested that growth hormone plays a role in the modulation of cardiac performance and the maintenance of normal cardiac structure and performance. The effects of growth hormone on heart function is discussed in Sacca, et al.,
Endocrine Rev.
15: 555-573, 1994. Further, dramatic effects of growth hormone on heart failure have been observed clinically (Fazio et al.,
New England Journal of Medicine,
334: 809-14, 1996).
A deficiency in growth hormone secretion can result in various medical disorders, depending on the age of onset. In children, the syndrome is characterized by short stature, with normal body proportions and reduced growth rate, also known as dwarfism. A deficiency in growth hormone secretion later in life may be characterized by excessive adiposity, reduced muscle mass, impaired exercise capacity, reduced body water, decreased bone mineral density, and psychological disorders. For example, a deficiency in growth hormone may result in myocardial dysfunction, in particular left ventricular diastolic dysfunction. Shahj, et al.,
Br. Heart J.,
67, 92-96 (1992). A deficiency in growth hormone also has been suggested to be a factor in increased mortality from cardiovascular disease of adults with growth-hormone deficiency. Rosen,
Lancet,
336, 285-288 (1990).
Supplemental growth hormone administered for a four month period to growth hormone-deficient adults was reported to have no significant effect on left ventricular mass. Jorgenson, et al.,
Lancet,
1221-1225 (1989); Shajh, et al.,
Br. Heart J.,
67, 92-96 (1992). However, when administered to growth-hormone deficient adults over a six month period, supplemental growth hormone increased left ventricular mass, and provided favorable cardiovascular effects including increased cardiac output and glomerular filtration rate and reduced peripheral vascular resistance. Caldahl, et al.,
Clinical Endocrinology,
40, 393-400 (1994). In a patient suffering from growth hormone deficiency and poor cardiac function, supplemental growth hormone resulted in improvement in myocardial contractility and cardiac output. Cuneo et al.,
Lancet,
1, 838-839 (1989). Supplemental growth hormone therapy in growth hormone deficient adults was found to improve resting and exercise cardiac function, but at the expense of ventricular hypertrophy. Fort, et al.,
Circulation,
90, (4, Part 2) pg. I-610, abs. 3290 (1994). However, the effects of growth hormone in human heart failure patients without growth hormone deficiency have not been reported.
Certain compounds have been developed which stimulate the release of endogenous growth hormone. These compounds are also called growth hormone secretagogues. Growth hormone releasing peptides GHRP-6 and GHRP-1 (GRP-1 and GRP-6) are described in U.S. Pat. No. 4,411,890 and PCT Patent Publications WO 89/07110 and WO 89/07111. Growth hormone releasing peptide GHRP-2 (GRP-2) is described in PCT Patent Publication WO 93/04081, and hexarelin is described in
J. Endocrinol. Invest.,
15 (Suppl 4), 45 (1992). Growth hormone releasing peptides (GHRPs) are also described in Bowers et al.,
Endocrinology
114: 1537-45 1984. In addition, small organic molecules having growth hormone secretagogue activity have also been described in Jacks et al.,
Endocrinology
137: 5284-9, 1996.
Other compounds with growth hormone secretagogue activity are discussed in U.S. Pat. Nos. 3,239,345; 4,036,979; 4,411,890; 5,206,235; 5,248,841; 5,310,737; 5,310,017; European Patent Publication 144,230; European Patent Publication 513,974; Patent Cooperation Treaty Patent Publication WO 94/07486; Patent Cooperation Treaty Patent Publication WO 94/08583; Patent Cooperation Treaty Patent Publication WO 94/13696;
Science,
260:1640-1643 (1993),
Ann. Rep. Med. Chem.,
28, 177-186 (1993);
Bioorg. Med. Chem. Ltrs.,
4 (22), 2709-2714 (1994);
PNAS
92, 7001-7005 (July 1995); British Patent Application GB 2308064A, U.S. Ser. No. 08/704,494, filed Aug. 20, 1996, and U.S. Ser. No. 08/700,206, filed Aug. 20, 1996. Additional compounds with growth hormone secretagogue activity are described herein.
Recent advances in heart failure therapy have demonstrated it is possible not only to alter the progression of heart failure, but also, in the case of antiadrenergic therapy with &bgr;-blockers, to partially reverse systolic dysfunction and ventricular remodeling of the failed myocardium (Eichhorn and Bristow,
Circulation
94: 2285-96, 1996. In the case of Carvedilol®, these effects upon heart failure appear to result in dramatic reductions in mortality in patients (Packer et al.,
New England Journal of Medicine
334: 1349-55, 1996). Improved biological function of the cardiomyocyte appears to play an important role in the beneficial effects of &bgr;-blockade in experimental heart failure (Tsutsui et al.,
J. Clin. Invest.
93: 2639-2648, 1994). These observations indicate the reversible nature of congestive heart failure.
Although &bgr;-blockers and ACE inhibitors represent significant cornerstones for the treatment of heart failure, important medical issues remain concerning quality of life and survival. Thus, novel therapeutic approaches to congestive heart failure that improve survival rate as well as the indices of quality of life, and that are also convenient for both patient and physician remain an important unmet medical need.
Thus, it would be a significant contribution to the art to provide compounds and methods of using same that promote the secretion of growth hormone for use in the prevention, inhibition, or treatment of congestive heart failure as indicated herein.
The instant invention relates to methods for the modulation of cardiac function which comprise the administration of a compound having growth hormone secretagogue activity.
The present invention yet further relates to methods for th
Kauffman Raymond F.
Palkowitz Alan D.
Boudreaux William R.
Eli Lilly and Company
Henley III Raymond
McNeil Scott A.
Strode Janelle D.
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