Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-01-21
2003-01-21
Witz, Jean C. (Department: 1651)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S002600, C514S021800
Reexamination Certificate
active
06509317
ABSTRACT:
The present invention relates generally to novel therapeutic uses of BPI protein products that involve treatment of chronic cardiac disease including, but not limited to, chronic states such as congestive heart failure and cardiomyopathy.
BACKGROUND OF THE INVENTION
Chronic cardiac disease is a leading cause of mortality and morbidity in the developed world. One type of chronic cardiac disease is cardiomyopathy, which is actually a diverse group of diseases characterized by myocardial dysfunction that is not related to the usual causes of heart disease such as coronary atherosclerosis, valvular dysfunction and hypertension. Cardiomyopathies are categorized hemodynamically into dilated, hypertrophic, restrictive and obliterative cardiomyopathy, and can be of known or idiopathic etiology. Among the etiologies of dilated cardiomyopathy are pregnancy, drugs and toxins, such as alcohol, cocaine and chemotherapeutic agents (including doxorubicin and daunorubicin, dactinomycin, dacarbazine, cyclophosphamide, mitomycin, and anthracycline), and infectious and autoimmune processes. Hypertrophic cardiomyopathy is hereditary in more than 50% of cases and has a distinctive pattern of myocardial hypertrophy (thickening of muscle) usually with a pattern of asymmetrical thickening of the interventricular septum (also called asymmetrical septal hypertrophy). Restrictive cardiomyopathies are usually the product of an infiltrative disease of the myocardium, such as amyloidosis, hemochromatosis or a glycogen storage disease, and may also be seen in certain diabetic patients. Obliterative cardiomyopathy can be caused by endomyocardial fibrosis and hypereosinophilic syndrome. A common complication of all of the cardiomyopathies is progressive congestive heart failure.
Congestive heart failure is often defined as the inability of the heart to deliver a supply of oxygenated blood sufficient to meet the metabolic needs of peripheral tissues at normal filling pressures. Chronic congestive heart failure can result as a consequence of coronary artery disease, cardiomyopathy, myocarditis, aortic stenosis, hypertension, idiopathic asymmetrical septal hypertrophy, coarctation of the aorta, aortic regurgitation, mitral regurgitation, left-to-right shunts, hypertrophied muscle, pericardial tamponade, constrictive pericarditis, mitral stenosis, left atrial mzxoma, left atrial thrombus, cor triatriatum and numerous other conditions. Congestive heart failure is generally distinguished from other causes of inadequate oxygen delivery, such as circulatory collapse from hemorrhage or other causes of severe volume loss, congestion caused by fluid overload and high-output failure caused by increased peripheral demands which occurs in conditions such as thyrotoxicosis, arteriovenous fistula, Paget's disease and anemia. Therapy for congestive heart failure typically focuses on the treating the underlying etiology and the symptoms of fluid overload and heart failure. Chronic congestive heart failure that persists after correction of reversible causes is treated with diuretics (including thiazides such as chlorothiazide and hydrochlorothiazide, loop diuretics such as ethacrynic acid, furosemide, torsemide and bumetanide, potassium sparing agents such as spironolactone, triamterene and amiloride, and others such as metolazone and other quinazoline-sulfonamides), vasodilators (including nitroglycerin, isosorbide dinitrate, hydralazine, sodium nitroprusside, prostacyclin, captopril, enalapril, lisinopril, quinapril and losartan), positive inotropic agents (such as digitalis or digoxin), occasionally beta blockers, or combinations of these measures.
Recent studies indicate that an increase in pro-inflammatory cytokines is seen in diverse cardiac diseases, including congestive heart failure, cardiomyopathy, and myocarditis. Hegewisch S, et al.
Lancet
1990;2:294-295; Levine B, et al.,
N.Engl.Med.
1990;323 (4):236-241; Mann D L, et al.,
Chest
1994;105:897-904; and Givertz M M, et al.,
Lancet
1998;352:34-38 For example, the cytokine tumor necrosis factor-&agr;(TNF) is synthesized by human cardiac myocytes, and the level of TNF expression correlates with the degree of cardiac dysfunction in patients. Torre-Amione G, et al.,
J. Am. Col. Cardiol.
1996;27:1201-1206; Torre-Amione G, R D, et al.
Circulation
1995;92:1487-1493; and Torre-Amione G, et al.,
Circulation
1996;93:704-711 In animals, synthesis of TNF by the heart is itself sufficient to cause cardiomyopathy and lethal cardiac failure. Bryant D, et al.,
Circ.
1998;97:175-183 and Kubota T, et al.
J.Am.Col.Cardiol.
1997;346A(Abstract) Furthermore, early human trials have demonstrated that antagonism of TNF improves cardiac failure in humans with NYHA Class III heart failure or idiopathic dilated cardiomyopathy. Deswal et al.,
Circulation
96: I-323 (1997); and Sliwa et al.,
Lancet
351: 1091-1093 (1998) However, the primary stimulus for cytokine secretion remains unknown.
Bacterial endotoxin, or lipopolysaccharide (LPS), is a primary inducer of TNF production during sepsis. With respect to cardiac diseases, the role of endotoxin has been examined primarily in the context of cardiopulmonary bypass, driven by the hypothesis that endotoxin may be present in the extracorporeal circuit, or may be translocated across the intestine secondary to non-pulsatile, low flow perfusion. Riddington D W, et al.
JAMA
1996;275:1007-1012 and Wan S, et al.,
Chest
1997;112:676-692 These studies have demonstrated only transient low-level endotoxemia during cardiopulmonary bypass, with rapid resolution following completion of cardiopulmonary bypass in the majority of patients. Nilsson L,
J Thorac Cardiovasc Surg
1990;100:777-780; Casey W F,
Crit.Care Med.
1992;20 (8):1090-1096; Khabar K S, et al.,
Clin Immunol Immunopathol
1997;85:97-103; Jansen N J,
Ann Thorac Surg
1992;54:744-747. Bennett-Guerrero E et al.,
JAMA
1997;277:646-650 reported that lower levels of anti-endotoxin antibodies pre-operatively were associated with an increased risk of post-operative complications and hypothesized that this difference was
Investigators have thus far failed to demonstrate, or failed to attempt to demonstrate, persistent endotoxemia in a majority of patients with cardiac disease Nilsson L,
J Thorac Cardiovasc Surg
1990; 100:777-780; Casey W F,
Crit. Care Med.
1992
;
20
(8): 1090-1096; Khabar K S, et al.,
Clin Immunol Immunopathol
1 997;85:97-103; Jansen N J,
Ann Thorac Surg
1992;54:744-747. See also Niebauer J,
Eur. Heart J.
1998;19:174, which reported elevated levels of plasma endotoxin in adults with edemetous chronic congestive heart failure that was not associated with elevated levels of LBP or anti-endotoxin antibodies (indicators of long-term endotoxin exposure).
BPI is a protein isolated from the granules of mammalian polymorphonuclear leukocytes (PMNs or neutrophils), which are blood cells essential in the defense against invading microorganisms. Human BPI protein has been isolated from PMNs by acid extraction combined with either ion exchange chromatography [Elsbach,
J. Biol. Chem.,
254:11000 (1979)] or
E. coli
affinity chromatography [Weiss, et al.,
Blood,
69:652 (1987)]. BPI obtained in such a manner is referred to herein as natural BPI and has been shown to have potent bactericidal activity against a broad spectrum of gram-negative bacteria. The molecular weight of human BPI is approximately 55,000 daltons (55 kD). The amino acid sequence of the entire human BPI protein and the nucleic acid sequence of DNA encoding the protein have been reported in
FIG. 1
of Gray et al.,
J Biol. Chem.,
264:9505 (1989), incorporated herein by reference. The Gray et al. amino acid sequence is set out in SEQ ID NO: 1 hereto. U.S. Pat. No. 5,198,541 discloses recombinant genes encoding and methods for expression of BPI proteins, including BPI holoprotein and fragments of BPI.
BPI is a strongly cationic protein. The N-terminal half of BPI accounts for the high net positive charge; the C-terminal half of the molecule has a net charge of −3.
Giroir Brett P.
Scannon Patrick J.
Board of Regents the University of Texas System
Marshall Gerstein & Borun
Witz Jean C.
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