Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-09-13
2003-11-25
Kemmerer, Elizabeth (Department: 1642)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C530S300000, C530S350000
Reexamination Certificate
active
06653287
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This application relates to a method for modulating cardiac function in the treatment of heart disorders.
2. Background of the Invention
Heart failure affects approximately three million Americans, developing in about 400,000 each year. It is currently one of the leading admission diagnoses in the U.S. Recent advances in the management of acute cardiac diseases, including acute myocardial infarction, are resulting in an expanding patient population that will eventually develop chronic heart failure.
Current therapy for heart failure is primarily directed to using angiotensin-converting enzyme (ACE) inhibitors and diuretics. While prolonging survival in the setting of heart failure, ACE inhibitors appear to slow the progression towards end-stage heart failure, and substantial numbers of patients on ACE inhibitors have functional class III heart failure. Moreover, ACE inhibitors consistently appear unable to relieve symptoms in more than 60% of heart failure patients and reduce mortality of heart failure only by approximately 15-20%. Heart transplantation is limited by the availability of donor hearts. Further, with the exception of digoxin, the chronic administration of positive inotropic agents has not resulted in a useful drug without accompanying adverse side effects, such as increased arrhythmogenesis, sudden death, or other deleterious side effects related to survival. These deficiencies in current therapy suggest the need for additional therapeutic approaches.
A large body of data suggests that pathological hypertrophy of cardiac muscle in the setting of heart failure can be deleterious, characterized by dilation of the ventricular chamber, an increase in wall tension/stress, an increase in the length vs. width of cardiac muscle cells, and an accompanying decrease in cardiac performance and function. In fact, the effects of ACE inhibitors have been purported not only to unload the heart, but also to inhibit the pathological hypertrophic response that has been presumed to be linked to the localized renin-angiotensin system within the myocardium.
On a cellular level, the heart functions as a syncytium of myocytes and surrounding support cells, called non-myocytes. While non-myocytes are primarily fibroblast/mesenchymal cells, they also include endothelial and smooth muscle cells. Indeed, although myocytes make up most of the adult myocardial mass, they represent only about 30% of the total cell numbers present in heart. Because of their close relationship with cardiac myocytes in vivo, non-myocytes are capable of influencing myocyte growth and/or development. This interaction may be mediated directly through cell-cell contact or indirectly via production of a paracrine factor. Such association in vivo is important since both non-myocyte numbers and the extracellular matrix with which they interact are increased in myocardial hypertrophy and in response to injury and infarction. These changes are associated with abnormal myocardial function.
Cardiac myocytes are unable to divide shortly after birth. Further growth occurs through hypertrophy of the individual cells. Cell culture models of myocyte hypertrophy have been developed to understand better the mechanisms for cardiac myocyte hypertrophy. Simpson et al.,
Circ. Res
., 51: 787-801 (1982); Chien et al.,
FASEB J
., 5: 3037-3046 (1991). Most studies of heart myocytes in is culture are designed to minimize contamination by non-myocytes. See, for example, Simpson and Savion,
Cir. Cres
., 50: 101-116 (1982); Libby,
J. Mol. Cell. Cardiol
., 16: 803-811 (1984); Iwaki et al.,
J. Biol. Chem
., 265: 13809-13817 (1990).
Hypertrophy of adult cardiac ventricular myocytes is a response to a variety of conditions which lead to chronic overload. This response is characterized by an increase in myocyte cell size and contractile protein content without concomitant cell division, and activation of embryonic genes, including the gene for atrial natriuretic peptide (ANP). Chien et al., supra. Adult myocyte hypertrophy is initially beneficial as a short term response to impaired cardiac function by permitting a decrease in the load on individual muscle fibers. With severe, long-standing overload, however, the hypertrophied cells begin to deteriorate and die. Katz, “Heart failure,” in Katz AM, ed.,
Physiology of the Heart
(New York: Raven Press; 1992) pp. 638-668.
Endothelial cells, smooth muscle cells and fibroblast/mesenchymal cells exist in close contact with myocytes in the heart. Nag,
Cytobios
., 28: 41-61 (1980). In vito studies have indicated that paracrine factors produced by these “non-myocyte” supporting cells may be involved in the development of hypertrophy. The identification of such factors remains a major pursuit in cardiac biology and medicine. Chien et al.,
Science
, 260: 916-917 (1993). See also Chien et al.,
Annu. Rev. Physiol
., S5: 77-95 (1993), regarding the use of an in vitro assay system for myocardial cell hypertrophy to isolate and characterize novel activities that might mediate this important physiological response.
Cell culture models have been developed to study hypertrophy and its causes. Thus, for example, totipotent mouse embryonic stem cells differentiate into multicellular, cystic embryoid bodies when cultured in the absence of a fibroblast feeder layer or with the removal of leukemia inhibitory factor (LIF).
Robbins et al.,
J. Biol. Chem
., 265: 11905-11909 (1990). Since these embryoid bodies spontaneously beat and display cardiac-specific markers (Robbins et al., supra; Doetschman et al.,
J. Embryol. Exp. Morphol
., 87: 27-45 (19851; Miller-Hance et al.,
J. Biol. Chem
., 268: 25244-25252 [19931), they might serve as a valuable source of factors that can induce a hypertrophic response in vitro. Chien,
Science
, supra; Miller-Hance et al., supra.
Further, Long et al.,
Cell Reg
., 2: 1081-1095 (1991), discovered that cultured neonatal rat cardiac non-myocytes, which were primarily fibroblast-like cells, produced an unidentified protein that also induced hypertrophy of cardiac myocytes in vitro. This factor bound to heparin-sepharose, failed to stimulate phosphoinositol hydrolysis, and had an apparent molecular weight of 45 to 50 kD. Experiments with neutralizing antisera to platelet-derived growth factor, tumor necrosis factor alpha, acidic and basic fibroblast growth factors and transforming growth factor beta 1, eliminated these growth factors as possible candidates.
Endothelin has been shown to affect the cells in the heart both in vivo and in vitro. In vivo endothelin is present in both atrial and ventricular myocardium in healthy and failing hearts and enhances myocardial inotropic activity, vascular smooth muscle proliferation and coronary vasoconstriction. Wei et al.,
Circulation
, 89: 1580-1586 (1994). In vitro endothelin stimulates a multiple cell-signalling pathways in cultured adult cardiac myocytes. Hilal-Dandan et al.,
Mol. Pharm
., 45: 1183-1190 (1994); Jones et al.,
Am. J. Physiol
. (
Heart Circ. Physiol
. 32) 263: H1447-H1454 [1992). Several investigators have shown that endothelin-1, which is known to be produced in endothelial cells, induces hypertrophy of cardiac myocytes in vitro. Shubeita et al.,
J. Biol. Chem
., 265: 20555-20562 (1990); Ito et al.,
Circ Res
., 69: 209-215 (1991); Suzuki et al.,
J. Cardiovasc. Pharmacol
., 17 Suppl 7: S182-S186 (1991). See also U.S. Pat. No. 5,344,644 issued Sep. 6, 1994.
LIF, also known as leukocyte inhibitory factor, differentiation-inducing factor (DIF, D-factor), hepatocyte-stimulating factor (HSF-II HSF-III), and melanoma-derived LPL inhibitor (MLPLI), depending on its particular activity or effect (Hilton et al.,
J. Cell. Biochem
., 46: 21-26 [1991]), has also been identified as the cholinergic neuronal differentiation factor (CDF) from rat neonatal heart cell cultures with both myocytes and non-myocytes. Yammamori et al.,
Science
, 246: 1412-1416 (1989). Additionally, LIF has been found to be useful for the protection, inhibition, and prevention of the d
Ferrara Napoleone
King Kathleen
Luis Elizabeth
Mather Jennie P.
Paoni Nicholas F.
Conley Deirdre L.
Genentech Inc.
Kemmerer Elizabeth
Li Ruixiang
LandOfFree
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