The patent's inventors are Rajagopalan, Raghavan (
This patent was filed on
From the background information supplied by the inventors, news correspondents obtained the following quote: "As a preliminary note, various publications are referenced throughout this disclosure by Arabic numerals in brackets. A citation corresponding to each reference number is listed following the detailed description.
"Acute renal failure (ARF) is a common ailment in patients admitted to general medical-surgical hospitals. Approximately half of the patients who develop ARF die, and survivors face marked increases in morbidity and prolonged hospitalization . Early diagnosis is generally believed to be important, because renal failure is often asymptomatic and typically requires careful tracking of renal function markers in the blood. Dynamic monitoring of renal functions of patients is desirable in order to minimize the risk of acute renal failure brought about by various clinical, physiological and pathological conditions [2-6]. Such dynamic monitoring tends to be particularly important in the case of critically ill or injured patients, because a large percentage of these patients tend to face risk of multiple organ failure (MOF) potentially resulting in death [7, 8]. MOF is a sequential failure of the lungs, liver and kidneys and is incited by one or more of acute lung injury (ALI), adult respiratory distress syndrome (ARDS), hypermetabolism, hypotension, persistent inflammatory focus and sepsis syndrome. The common histological features of hypotension and shock leading to MOF generally include tissue necrosis, vascular congestion, interstitial and cellular edema, hemorrhage and microthrombi. These changes generally affect the lungs, liver, kidneys, intestine, adrenal glands, brain and pancreas in descending order of frequency . The transition from early stages of trauma to clinical MOF generally corresponds with a particular degree of liver and renal failure as well as a change in mortality risk from about 30% up to about 50% .
"Traditionally, renal function of a patient has been determined using crude measurements of the patient's urine output and plasma creatinine levels [11-13]. These values are frequently misleading because such values are affected by age, state of hydration, renal perfusion, muscle mass, dietary intake, and many other clinical and anthropometric variables. In addition, a single value obtained several hours after sampling may be difficult to correlate with other physiologic events such as blood pressure, cardiac output, state of hydration and other specific clinical events (e.g., hemorrhage, bacteremia, ventilator settings and others).
"With regard to conventional renal monitoring procedures, an approximation of a patient's glomerular filtration rate (GFR) can be made via a 24 hour urine collection procedure that (as the name suggests) typically requires about 24 hours for urine collection, several more hours for analysis, and a meticulous bedside collection technique. Unfortunately, the undesirably late timing and significant duration of this conventional procedure can reduce the likelihood of effectively treating the patient and/or saving the kidney(s). As a further drawback to this type of procedure, repeat data tends to be equally as cumbersome to obtain as the originally acquired data.
"Occasionally, changes in serum creatinine of a patient must be adjusted based on measurement values such as the patient's urinary electrolytes and osmolality as well as derived calculations such as 'renal failure index' and/or 'fractional excretion of sodium.' Such adjustments of serum creatinine undesirably tend to require contemporaneous collection of additional samples of serum and urine and, after some delay, further calculations. Frequently, dosing of medication is adjusted for renal function and thus can be equally as inaccurate, equally delayed, and as difficult to reassess as the measurement values and calculations upon which the dosing is based. Finally, clinical decisions in the critically ill population are often equally as important in their timing as they are in their accuracy.
"It is known that hydrophilic, anionic substances are generally capable of being excreted by the kidneys . Renal clearance typically occurs via two pathways: glomerular filtration and tubular secretion. Tubular secretion may be characterized as an active transport process, and hence, the substances clearing via this pathway typically exhibit specific properties with respect to size, charge and lipophilicity.
"Most of the substances that pass through the kidneys are filtered through the glomerulus (a small intertwined group of capillaries in the malpighian body of the kidney). Examples of exogenous substances capable of clearing the kidney via glomerular filtration (hereinafter referred to as 'GFR agents') are shown in FIG. 1 and include creatinine (1), o-iodohippuran (2), and .sup.99mTc-DTPA (3) [15-17]. Examples of exogenous substances that are capable of undergoing renal clearance via tubular secretion include .sup.99mTc-MAG3 (4) and other substances known in the art [15, 18, 19]. .sup.99mTc-MAG3 (4) is also widely used to assess renal function though gamma scintigraphy as well as through renal blood flow measurement. As one drawback to the substances illustrated in FIG. 1, o-iodohippuran (2), .sup.99mTc-DTPA (3) and .sup.99mTc-MAG3 (4) include radioisotopes to enable the same to be detected. Even if non-radioactive analogs (e.g., such as an analog of o-iodohippuran (2)) or other non-radioactive substances were to be used for renal function monitoring, such monitoring would typically require the use of undesirable ultraviolet radiation for excitation of those substances."
Supplementing the background information on this patent, NewsRx reporters also obtained the inventors' summary information for this patent: "In one regard, the present invention relates to transforming lipophilic fluorescent dyes into hydrophilic molecules. One concept of the present invention relates to molecules whose clearance properties are preferably similar to that of creatinine or o-iodohippuran, and to render such molecules hydrophilic by incorporating appropriate polar functionalities such as hydroxyl, carboxyl, sulfonate, phopshonate and the like into their backbones. Pyrazine dyes of the invention may be characterized by some as being desirable for renal applications because they tend to be cleared from the body via the kidneys, demonstrate absorption and emission/fluorescence in the visible region, and tend to exhibit significant Stokes shifts. These properties allow flexibility in both tuning a molecule to a desired wavelength and introducing a variety of substituents to improve clearance properties.
"In a first aspect, the present invention is directed to pyrazine derivatives of Formula I. With regard to Formula I, X.sup.1 and X.sup.2 may be characterized as electron withdrawing substituents and may be independently chosen from the group consisting of --CN, --CO.sub.2R.sup.1, --CONR.sup.2R.sup.3, --COR.sup.4, --NO.sub.2, --SOR.sup.5, --SO.sub.2R.sup.6, --SO.sub.2OR.sup.7, --PO.sub.3R.sup.8R.sup.9, --CONH(AA), and --CONH(PS). In some embodiments, at least one of X.sup.1 and X.sup.2 is either --CONH(AA) or --CONH(PS). (AA) is a polypeptide chain that includes one or more natural or unnatural .alpha.-amino acids linked together by peptide bonds. (PS) is a sulfated or non-sulfated polysaccharide chain that includes one or more monosaccharide units connected by glycosidic linkages. Y.sup.1 and Y.sup.2 may, at least in some embodiments, be characterized as electron donating substituents and may be independently chosen from the group consisting of --OR.sup.10, --SR.sup.11, --NR.sup.12R.sup.13, --N(R.sup.14)COR.sup.15, --P(R.sup.16).sub.3, --P(OR.sup.17).sub.3, and substituents corresponding to Formula A above. In some embodiments, at least one of Y.sup.1 and Y.sup.2 is either --P(R.sup.16).sub.3 or --P(R.sup.17).sub.3. Z.sup.1 may be a single bond, --CR.sup.18R.sup.19, --O, --NR.sup.20, --NCOR.sup.21, --
"A second aspect of the invention is directed to pyrazine derivatives of Formula II. With regard to Formula II, X.sup.3 and X.sup.4 may be characterized as electron withdrawing substituents and may be independently chosen from the group consisting of --CN, --CO.sub.2R.sup.22, --CONR.sup.23R.sup.24, --COR.sup.25, --NO.sub.2, --SOR.sup.26, --SO.sub.2R.sup.27, --SO.sub.2OR.sup.28, --PO.sub.3R.sup.29R.sup.30, --CONH(AA), and --CONH(PS). In some embodiments, at least one of X.sup.3 and X.sup.4 is either --CONH(AA) or --CONH(PS). (AA) is a polypeptide chain that includes one or more natural or unnatural .alpha.-amino acids linked together by peptide bonds. (PS) is a sulfated or non-sulfated polysaccharide chain that includes one or more monosaccharide units connected by glycosidic linkages. Y.sup.3 and Y.sup.4 may, at least in some embodiments, be characterized as electron donating substituents and may be independently chosen from the group consisting of --OR.sup.31, --SR.sup.32, --NR.sup.33R.sup.34, --N(R.sup.35)COR.sup.36, --P(R.sup.37).sub.3, --P(OR.sup.38).sub.3, and substituents corresponding to Formula B above. In some embodiments, at least one of Y.sup.3 and Y.sup.4 is either --P(R.sup.37).sub.3 or --P(OR.sup.38).sub.3. Z.sup.2 may be a single bond, --CR.sup.39R.sup.40, --O, --NR.sup.41, --NCOR.sup.42, --
"Yet a third aspect of the invention is directed to pharmaceutically acceptable compositions, each of which includes one or more pyrazine derivatives disclosed herein. Incidentally, the phrase 'pharmaceutically acceptable' herein refers substances which are, within the scope of sound medical judgment, suitable for use in contact with relevant tissues of humans and animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. The compositions of this third aspect may include one or more appropriate excipients such as, but not limited to, suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers. One example of a composition of this third aspect may include at least one pyrazine derivative of Formula I and at least one pyrazine derivative of Formula II. Another example of a composition of the third aspect may include one or more pyrazine derivatives of Formula I or one or more pyrazine derivatives of Formula II.
"Still a fourth aspect of the invention is directed to methods of determining renal function using pyrazine derivatives such as those described above with regard to Formulas I and II. In these methods, an effective amount of a pyrazine derivative is administered into the body of a patient (e.g., a mammal such as a human or animal subject). Incidentally, an 'effective amount' herein generally refers to an amount of pyrazine derivative that is sufficient to enable renal clearance to be analyzed. The pyrazine derivative in the body of the patient is exposed to at least one of visible and near infrared light. Due to this exposure of the pyrazine derivative to the visible and/or infrared light, the pyrazine derivative emanates spectral energy that may be detected by appropriate detection equipment. This spectral energy emanating from the pyrazine derivative may be detected using an appropriate detection mechanism such as an invasive or non-invasive optical probe. Herein, 'emanating' or the like refers to spectral energy that is emitted and/or fluoresced from a pyrazine derivative. Renal function can be determined based the spectral energy that is detected. For example, an initial amount of the amount of pyrazine derivative present in the body of a patient may be determined by a magnitude/intensity of light emanated from the pyrazine derivative that is detected (e.g., in the bloodstream). As the pyrazine derivative is cleared from the body, the magnitude/intensity of detected light generally diminishes. Accordingly, a rate at which this magnitude of detected light diminishes may be correlated to a renal clearance rate of the patient. This detection may be done periodically or in substantially real time (providing a substantially continuous monitoring of renal function). Indeed, methods of the present invention enable renal function/clearance to be determined via detecting one or both a change and a rate of change of the detected magnitude of spectral energy (indicative of an amount of the pyrazine derivative that has not been cleared) from the portion of the pyrazine derivative that remains in the body. While this fourth aspect has been described with regard to use of a single pyrazine derivative of the invention, it should be noted that some embodiments of this fourth aspect include the use of compositions of the invention that may include one or more pyrazine derivatives disclosed herein."
For the URL and additional information on this patent, see: Rajagopalan, Raghavan; Dorshow, Richard B.; Neumann,
Keywords for this news article include:
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