Drug – bio-affecting and body treating compositions – In vivo diagnosis or in vivo testing – Diagnostic or test agent produces in vivo fluorescence
Reexamination Certificate
2000-08-02
2002-08-27
Hartley, Michael G. (Department: 1619)
Drug, bio-affecting and body treating compositions
In vivo diagnosis or in vivo testing
Diagnostic or test agent produces in vivo fluorescence
Reexamination Certificate
active
06440389
ABSTRACT:
FIELD OF THE INVENTION
This invention pertains to fluorescent agents, instruments, and techniques for measurement of organ function, and, more specifically, for real-time measurement of organ function.
BACKGROUND OF THE INVENTION
Acute renal failure (ARF), as a complication of multiple surgical, medical and obstetrical conditions, represents an important individual and public health problem. Early identification of patients at risk, with prompt elimination of potential insults, is a golden rule that has saved many lives. Unfortunately, despite close implementation of this rule, the disease still accounts for a large morbidity and mortality, with a survival rate of about 50%, a figure which has not substantially improved since 1950 (Butkus, D.,
Arch. Intern. Med
., 143: 209-212, 1983). This poor outcome contrasts with the almost unique ability of the kidney to undergo virtually complete recovery of function following an episode of transient ischemia or toxin-induced cellular destruction. This discrepancy between mortality and the potential for reversibility emphasizes the need for a reconsideration of current diagnostic and therapeutic options with the goal of assuring complete recovery of organ function after an episode of ARF.
Because the clinical condition of patients with ARF is determined largely by prior health status and the nature of the specific insult that led to renal failure, any therapeutic approach used to treat ARF should be simultaneously oriented toward correcting the precipitating cause and the impaired organ function. Hypoperfusion of the kidney is the most frequently recognized single insult leading to ARF in the setting of trauma, surgery, hemorrhage, or dehydration (Kellen, M., S. Aronson, et al.,
Anesth. Analg
., 78: 134-142, 1994; Hou, S., D. Bushinsky, et al.,
Am. J. Med
., 74: 243-248, 1983). Continuous and precise monitoring of cardiopulmonary function in such acute settings has been available for many years and has undoubtedly helped to restore normal circulatory status in the critically ill patient. At the present time, however, monitoring of renal function is done with crude measurements such as urine output and plasma creatinine. Unfortunately, because of their lengthy resolution time (the time required to obtain a single measurement of renal function), none of these parameters can be used for real-time monitoring of renal function. For example, creatinine clearance measurements have a resolution of about 12 hours. By the time a patient's ARF was recognized by this technique, it would be too late to treat the patient and have any hope of saving the kidney. The inadequacy of standard techniques for monitoring renal function during critical care is the most salient limitation for prevention of ARF and for the determination of an appropriate therapy to correct organ failure.
Measurements of glomerular filtration rate (GFR) can be made directly by micropuncture or indirectly by clearance methods. Although direct techniques have produced major contributions in our understanding of the production and regulation of the glomerular ultrafiltrate in laboratory animals, the invasive nature of the procedures renders them of questionable value in humans. Clearance techniques, on the other hand, are normally used to measure renal function in humans. However, because the techniques have such lengthy resolution times, it is quite difficult to detect rapid changes in GFR that may occur under different physiological and pathological conditions. For instance, GFR changes during exercise (Barclay, J., W. Cooke, et al.,
J. Physiol
. (
London
), 104: 14, 1946), with orthostatic hypotension (Papper, E. and S. Ngai,
Ann. Rev. Med
., 7: 213-224, 1956), and with changes in posture (Werko, L., H. Bucht, et al.,
Scand. J. Clin. Lab. Invest
., 1: 321, 1949). The changes in GFR during exercise were only detected when the exercise level was very intense and the changes in cardiopulmonary function were quite persistent (Selkur, E.,
Handbook of Physiology: Circulation
, J. Field, Ed. Washington, DC: Am. Physiol. Soc.,. Vol. 2, pp. 1457-1516, 1963). These results suggested that changes in GFR at low levels of exercise may have gone undetected due to the poor resolution time of the clearance techniques. In order to fully understand this important limitation of clearance techniques, one should ask how fast the changes in GFR might occur under an ideal experimental condition emulating a hypoperfusion event of the kidney. Studies performed in the isolated, perfused dog kidney indicate that sudden changes (within seconds) in perfusion pressure are very closely followed (also within a few seconds) by changes in GFR (Harvey, R.,
Circulation Res
., 15: 178-182, 1964). Clearance techniques, on the other hand, have a totally different resolution time. It was recognized very early that a considerable interval (more than 30 minutes) is required for a sudden change in GFR to be initially detected in the composition of urine (Smith, H.,
The Kidney: Structure and Function in Health and Disease
, New York: Oxford University Press, 1951). This time most likely represents the time required for the ultrafiltrate to pass down the tubules, collecting ducts, and ureters before it reaches and equilibrates with the urine already contained in the urinary bladder. Since at least two samples are needed to determine that the measurement is done at equilibrium, the minimal ideal resolution time for this procedure will be about 1 hour. This, plus the usual delay in measuring the concentration of an agent in urine and blood samples, represents a significant limitation in the use of this procedure for bedside, real-time, monitoring of renal function in patients with ARF.
Renal function has traditionally been measured by creatinine clearance. It is now recognized, however, that in addition to the technical problems with creatinine measurement and with urine collection, creatinine clearance is not an accurate measure of GFR (Carrie, B., H. Golbertz, et al.,
Am. J. Med
., 69: 177-182, 1980; Price, M.,
J. Urol
., 107: 339-340, 1972). Quantitative methods for measuring renal glomerular and tubular function with clearance techniques have been available for many years. The nonendogenously produced substance inulin probably meets the requirements of an ideal GFR agent (Smith, 1951). Although it has remained the “gold standard” , the chemical methods of measurement are unfortunately too cumbersome for routine use. In addition to seeking a substance that fulfills the requirements of a GFR agent, researchers have also sought to overcome the other major source of error in clearance measurements, namely, incomplete urine collection. Two approaches have been found to be successful. The most accurate, but technically difficult, is the constant infusion of a substance until an equilibrium is reached, at which point the plasma level is steady. The rate of infusion is then equal to the rate of loss in the urine and no urine collection is necessary (Earle, D. and R. Berliner,
Proc. Soc. Exp. Biol. Med
., 62: 262-264, 1946). Alternatively, the rate of plasma disappearance of a substance after a single intravenous injection is determined, enabling calculation of GFR (Sapirstein, L., D. Vidt, et al.,
Am. J. Physiol
., 181: 330-336, 1955; Chantler, C. and T. Barratt,
Archs. Dis. Child
., 47: 613-617, 1972). The disappearance of the tracer is determined by taking multiple blood samples over a period of 3 to 4 hours and then measuring the radioactivity of the samples. In addition to the requirements that a GFR agent must be freely filtered by the glomerulus, four other basic criteria must apply if a substance is to be used to measure clearance without urine collection:
a. it must not be metabolized;
b. it must be cleared exclusively by glomerular filtration (no other route of excretion other than renal);
c. it must not be bound to plasma protein or extracellular components; and
d. it must not be reabsorbed by the nephron.
51
Cr-EDTA,
99m
Tc-DTPA, and
125
I-sodium iothalamate meet these requirements and are the acc
Choate Hall & Stewart
Hartley Michael G.
Rosen Valarie B.
The General Hospital Corporation
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