Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Reexamination Certificate
2001-09-04
2002-10-08
Nguyen, Bao-Thuy L. (Department: 1641)
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
C422S067000, C422S067000, C435S007930, C435S007940, C435S969000, C435S970000, C435S973000, C435S975000, C436S514000, C436S518000, C436S528000, C436S530000, C436S807000, C436S808000, C436S810000
Reexamination Certificate
active
06461828
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the concept of conjunctive utilization of biological markers expressed in response to abnormal pressure, volume change and stress to a particular organ (e.g. N-terminal ANP (pro-ANP) in heart tissue) along with the expression of biological markers that are indicative of tissue damage (e.g. cardiac Troponin I (cTnI), or fibrosis markers for heart tissue) as a diagnostic tool to accurately and rapidly diagnose the condition of the ailing organ. Although this concept is applicable to numerous organ and organ systems, this application will particularly illustrate the concept of conjunctive marker utilization with respect to the heart, specifically with respect to congestive heart failure. The invention particularly relates to the conjunctive utilization of cardiac Troponin I (cTnI) and natriuretic peptides, e.g. brain natriuretic peptide (BNP), N-terminai BNP (pro-BNP)), c-type natriuretic peptide (CNP), atrial natriuretic peptide (ANP), and N-terminal ANP (pro-ANP) as a retrospective tool for diagnosing the underlying mechanism of heart failure and as a prospective analytical device for monitoring disease progression and efficacy of therapeutic agents.
BACKGROUND OF THE INVENTION
Congestive heart failure (CHF) effects approximately 4.8 million Americans. About 400,000 new cases are diagnosed annually and the condition is responsible for approximately 200,000 deaths per year. These statistics, in conjunction with the approximately;1 million hospitalizations annually attributable to CHF, result in an annual expenditure on the order of $10 billion.
CHF represents a condition which occurs when heart function becomes insufficient to meet the needs of the vital systems and tissues of the body. The inability of the heart to pump sufficiently is correlated to the measured ejection fraction, which is the percent of the blood pumped out during each heartbeat. An ejection fraction of between 50% and 75% is considered normal. This inability can be caused by failure of one or more sides of the heart, typically the left but also the right side; such failure can result from systolic or diastolic dysfunction, and may be represented by an ejection fraction of less than 50% and a resultant backup of fluid and accumulation of fluid in the lungs. Although less common, right-sided heart failure will result in fluid backup that manifests in a swelling of the veins and surrounding body tissues, inadequate tissue perfusion, fatigue and poor exercise tolerance. In addition, heart failure can result from diastolic dysfunction. This can result from disorders such as hypertension, valvular disease, transient ischemia, infiltrative disorders or congenital conditions such as hypertrophic cardiomyopathy. Although there are cases of pure diastolic dysfunction from infiltrative disorders such as amyloidosis or fibrosis, heart failure patients often have a combination of both systolic and diastolic dysfunction contributing to CHF.
The underlying reasons for this failure in heart functionality are varied. Thinning and weakening of the ventricle walls leads to dilation and a loss of pumping ability (systolic dysfunction). Alternatively, loss of elasticity results in a stiffening, which may result in a diminished volume of the heart's chambers and loss of pumping capacity (diastolic dysfunction) and cardiac output. Additionally, abnormalities in the functioning of the heart's valves can lead to insufficient cardiac output, for which the body attempts to compensate by causing the heart to increase its heart rate, hypertrophy and/or dilate. The compensation mechanisms utilized by the body may lead to architectural changes in the form of remodeling (especially after MI) or adaptation of the heart muscle, ultimately leading to irrevocable loss of function. Related causes of cardiac failure may be one or more conditions such as coronary artery disease, ischemic heart damage, e.g. damage resulting from a heart attack, uncontrolled hypertension, the direct and/or indirect effects of diabetes on the heart, valvular heart disease, cardiomyopathy, autoimmune response, disease and abuse by external agents such as alcohol, tobacco, anabolic steroids, and the like.
Historically, the preliminary diagnosis of CHF requires a history and a physical examination during which the condition is often characterized by various signs and symptoms of intra-vascular and interstitial volume overload, including shortness of breath, irregular heart rate, abnormal heart rate and signs of edema. To determine the severity and prognosis of CHF and to more clearly characterize a particular patient's condition, further diagnostic tests are usually needed.
Tests which further illustrate the mechanical condition of the heart are often useful, such tests include, but are not limited to, exercise stress testing, electrocardiogram, radionucleidangiography, echocardiography, chest X-ray and angiography. Echocardiography is presently considered an important diagnostic test for CHF. By using ultrasound to provide real time imagery of the beating heart, valve. function and blood flow through the heart can be readily ascertained. Systolic function and diastolic function or some combination thereof is determinable through echocardiography.
Laboratory tests including but not limited to blood and urine testing are often helpful. These may indicate abnormalities in liver function, kidney function, cholesterol levels; blood sugar levels, hemoglobin levels, thyroid hormone levels and ANP, BNP, pro ANP, pro-BNP.
The diagnostic methods for diagnosing and distinguishing CHF, as outlined above, require numerous steps, expensive technology, and trained personnel for their performance and subsequent analysis. Patients may also be exposed to risk of radiation from nuclear studies or invasive procedures, i.e. heart catheterization. If a method and device could be provided for distinguishing and diagnosing CHF via a simplified body fluid test, the results of which could be interpreted by a lay person, a long felt need would be satisfied.
DESCRIPTION OF THE PRIOR ART
It is well documented in the literature that several peptides exist in the atrium of the human heart which possess the ability to regulate normal extra-cellular fluid parameters including volume and pressure of liquid in blood vessels. These peptides are referred to as Atrial Natriuretic Peptides (ANP). Brain natriuretic peptide or BNP is a peptide isolated initially from pig brain and hence the name BNP (Sudoh et al., Nature, 332:78-81, 1988). In humans, this peptide is synthesized by the brain and myocardial cells and circulates in the bloodstream exerting profound influences on the heart and kidneys. BNP is structurally related to the ANP family of peptides and is present in significantly lower quantities in circulation. The appearance of pro-BNP has been correlated with the progression of heart failure. However, the active molecule is BNP which has been found to be beneficial to the failing heart. It is conceivable that the damage to heart muscle may result in an inefficient processing of the inactive pro-BNP to active BNP (which accounts for the observed increase in pro-BNP). However, due to the inability of the cardiac tissues to process the pro-BNP to BNP, there is no beneficial effect unless the active molecule (BNP) is administered externally.
In addition to changes in pro-BNP/BNP during heart failure, an increase in cardiac Troponin I correlates well with cardiac tissue damage and appears to be a good predictor of death due to cardiac failure. During cardiac cell damage and death, cellular contents are released into the blood stream. Cardiac Troponin I has been shown to be a specific diagnostic marker of cardiac cell damage (Circulation 83, 902-912(1991); Clin. Chem. 40, 1291-1295(1994); Clin. Chem. 41, 312-317 (1995)).
U.S. Pat. No. 6,162,902 entitled “Human BNP-Specific Antibodies” provides reagents and assays for the quantification of hBNP in biological fluid samples such as plasma or serum.
U.S. Pat. No. 5,795,725 entitled “Methods for
Jackowski George
Stanton Eric B.
McHale & Slavin P.A.
Nguyen Bao-Thuy L.
Syn X Pharma
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