| Synthesis, compositions and methods for the measurement of the concentration of stable-isotope labeled compounds in life forms and life form excretory products -> Monitor Keywords |
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Synthesis, compositions and methods for the measurement of the concentration of stable-isotope labeled compounds in life forms and life form excretory productsRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Radionuclide Or Intended Radionuclide Containing; Adjuvant Or Carrier Compositions; Intermediate Or Preparatory CompositionsSynthesis, compositions and methods for the measurement of the concentration of stable-isotope labeled compounds in life forms and life form excretory products description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20060067881, Synthesis, compositions and methods for the measurement of the concentration of stable-isotope labeled compounds in life forms and life form excretory products. Brief Patent Description - Full Patent Description - Patent Application Claims
RELATED APPLICATION [0001] This application claims priority to provisional patent application U.S. Ser. No. 60/266,647, filed Feb. 5, 2001, the contents of which are hereby incorporated by reference in entirety herein. FIELD OF THE INVENTION [0002] The invention relates to methods wherein, by recording the concentration or amount of one or more stable isotopically labeled xenobiotic compound containing an element detectable after neutron activation, this xenobiotic compound may be determined in a living subject in blood, serum, plasma, urine, fecal, biopsy, or other body fluid or composition. BACKGROUND OF THE INVENTION [0003] Neutron activation and stable isotope labeling allows for the detection of low amounts of molecules in biological systems, as shown in chromatographs and gel electrophoretograms (1). For many diagnostic and therapeutic applications, it can be important to detect small amounts of a molecule of interest in a biological sample. Present methods for detecting biological compounds or physiological processes of interest can lack the requisite sensitivity and non-toxicity for in vivo administration. SUMMARY OF THE INVENTION [0004] The invention is based in part on the discovery of highly sensitive stable isotope-containing compositions that allow for detection and measurement of small quantities of a biological molecule in samples taken from a subject. An embodiment of the invention features a composition comprising a compound having a structure X-M, wherein X is a chelator, M is an atom of a stable isotope of an element having a nucleus capable of capturing a neutron and subsequently emitting a photon, M is noncovalently bound to X, X being at a concentration at least as great as that of M, the composition having a counterion and a physiologically acceptable buffer. In general, the atom of the stable isotope M is selected from the group consisting of: .sup.45Sc, .sup.50Cr, .sup.55Mn, .sup.58Fe, .sup.59Co, .sup.63Cu, .sup.103Rh, .sup.113Cd, .sup.114Cd, .sup.113In, .sup.115In, .sup.123Te, .sup.133Cs, .sup.139La, .sup.141Pr, .sup.146Nd, .sup.149Sm, .sup.152Sm, .sup.151Eu, .sup.153Eu, .sup.152Gd, .sup.155Gd, .sup.157Gd, .sup.159Tb, .sup.158Dy, .sup.160Dy, .sup.161Dy, .sup.162Dy, .sup.163Dy, .sup.164Dy, .sup.168Yb, .sup.169Tm, .sup.174Hf, .sup.178Hf, .sup.175Yb, .sup.165Ho, .sup.175Lu, .sup.176Lu, .sup.181Ta, .sup.185Re, .sup.187Re, .sup.190Ir, .sup.193Ir, .sup.196Hg, .sup.202Hg, and .sup.197Au. The counterion is, for example, meglumine (1-deoxy-1-methylamino-D-glucitol antimoniate). The chelator X can be selected from the group consisting of: diethylenetriaminepentaacetic acid (DTPA), diethylenetriamine-pentamethylenephosphonic acid (DTPMP), tetraazacyclododecanetetraacetic acid (DOTA) or a derivative of DOTA, ethylene-diaminetetraacetic acid (EDTA), tetraazacyclododecanetetrakis (methylene phosphonic acid) (DOTP), hydroxypropyl tetraazacylododecanetriacetic acid (HP-DO3A), diethylenetriaminetriacetic acid bismethylamide (DTPA-BMA), and MS-325. The concentration of X is between about 100 micromolar and about 1.5 molar. [0005] In another embodiment, the invention features a method of preparing a pharmaceutical composition of a compound having a structure X-M, the method comprising: providing a solution having X and M, wherein X is a chelator, and M is an atom of a stable isotope of an element noncovalently bound to X and having a nucleus capable of capturing a neutron and subsequently emitting a photon, and the concentration of X is at least as great as that of M, the solution being aqueous and having a physiologically acceptable buffer; and sterilizing the solution. In a related embodiment of the method, M is selected from the group consisting of: .sup.45Sc, .sup.50Cr, .sup.55Mn, .sup.58Fe, .sup.59Co, .sup.63Cu, .sup.103Rh, .sup.113Cd, .sup.114Cd, .sup.113In, .sup.115In, .sup.123Te, .sup.133CS, .sup.139La, .sup.141Pr, .sup.141Nd, .sup.149Sm, .sup.152Sm, .sup.151Eu, .sup.153Eu, .sup.152Gd, .sup.155Gd, .sup.157Gd, .sup.159Tb, .sup.158Dy, .sup.160Dy, .sup.161Dy, .sup.162Dy, .sup.163Dy, .sup.164Dy, .sup.168Yb, .sup.169Tm, .sup.174Hf, .sup.178Hf, .sup.175Yb, .sup.165Ho, .sup.175Lu, .sup.176Lu, .sup.181Ta, .sup.185Re, .sup.187Re, .sup.190Ir, .sup.193Ir, .sup.196Hg, .sup.202Hg, and .sup.197Au. [0006] In yet another embodiment, the invention provides a method for quantifying by neutron activation an amount of a complex having a structure X-M, the method comprising: exposing each of the X-M complex and a standard to a neutron source, wherein X is a chelator and M is an atom of a stable isotope of an element having a nucleus capable of capturing a neutron and subsequently emitting a photon, and wherein the standard has a predetermined quantity of M, X-M and the standard being exposed to the neutron source at the same time, such that M emits a photon after capture of a neutron; detecting an emitted photon from each of X-M and the standard; and comparing an amount of photonic emissions from each of the X-M and the standard, thereby quantifying the amount of the complex having the structure X-M. [0007] The invention in another embodiment features a method of determining the glomerular filtration rate (GFR) of a subject, comprising: administering a known quantity of a test substance to the subject, the test substance having at least one atom of a stable isotope of an element with a nucleus capable of capturing of a neutron and subsequently emitting a photon, the test substance being filtered by the kidneys and detectable by neutron activation analysis in a sample of a bodily fluid; obtaining at least one sample of a bodily fluid from the subject at least one predetermined time interval following administering the test substance; determining the amount of test substance in a volume of the at least one sample of the bodily fluid by neutron flux activation; and calculating the GFR from the amount of photon emission by the activated element, thereby determining the GFR of the subject. [0008] In a related embodiment of this method, determining the amount of the test substance further involves comparing photon emission of the activated element in the sample of the bodily fluid to photon emission from a standard that includes the same stable isotope and is exposed to the same neutron flux. Another related embodiment of this method further comprises, prior to administering the compound to the subject, obtaining a sample from the subject of at least one bodily fluid for determining a baseline of concentration of the element. In other various related embodiments of the method, the test substance is selected, for example, from the group consisting of Sm-DTPA, La-DTPA, Lu-DTPA, Sm-DOTA, La-DOTA, and Lu-DOTA; the test substance is, for example, an iodinated contrast agent; the agent comprises iohexol or iothalamate; a dose of the test compound administered to the subject is about one .mu.mol to about 0.5 mmol per kg body weight of the subject; the test compound is administered, for example, intravenously; the time interval can be about 10 to about 60 minutes; calculating the GFR an further involve using a computerized program; and obtaining a sample from the subject further comprises catheterizing the urethra of the subject. [0009] The invention features in yet another embodiment a kit for measuring glomerular filtration rate in a subject, comprising: at least one vial of a test composition, the test composition having: a compound of structure X-M, wherein X is a chelator and M is an atom of a stable isotope of an element having a nucleus capable of capturing a neutron and subsequently emitting a photon, M being noncovalently bound to the X, and a counterion, the compound being dissolved in a physiologically compatible solution; at least one sample container to collect a bodily fluid; and instructions for use. The kit in a related embodiment further comprising a data recording system. The kit can further comprise an internal standard monitor distributed into each of the sample containers. [0010] In another embodiment, the invention provides a composition comprising at least one compound .OMEGA..sub.i-X.sub.j-M.sub.k and a counterion, wherein: each .OMEGA..sub.i is an organic compound having a molecular weight greater than about 50; each X.sub.j is at least one chelator covalently bound to each .OMEGA..sub.i; and each M.sub.k is noncovalently bound to X and has a nucleus capable of capturing a neutron and subsequently emitting a photon and is an atom of a stable isotope of an element selected from the group consisting of .sup.45Sc, .sup.50Cr, .sup.55Mn, .sup.58Fe, .sup.59Co, .sup.63Cu, .sup.113Cd, .sup.114Cd, .sup.113In, .sup.115In, .sup.123Te, .sup.133Cs, .sup.139La, .sup.141Pr, .sup.146Nd, .sup.149Sm, .sup.152Sm, .sup.151Eu, .sup.153Eu, .sup.152Gd, .sup.155Gd, .sup.157Gd, .sup.159Tb, .sup.158Dy, .sup.160Dy, .sup.161Dy, .sup.162Dy, .sup.163Dy, .sup.164Dy, .sup.168Yb, .sup.169Tm, .sup.174Hf, .sup.178Hf, .sup.175Yb, .sup.165Ho, .sup.175Lu .sup.176Lu, .sup.181 Ta .sup.185Re, .sup.187Re, .sup.190Ir, .sup.193Ir, .sup.196Hg, .sup.202Hg, and .sup.197Au, wherein each M.sub.k is distinct in identity; i, j, and k each being a number from 1 to 8, wherein i is at least equal to k. [0011] In another embodiment, the invention provides a composition comprising at least one compound .OMEGA..sub.i-X.sub.j-M.sub.k, at least one compound .PSI.-N, and a cationic counterion, wherein: each .OMEGA. is an organic compound having a molecular weight greater than about 50; each X is at least one chelator covalently bound to .OMEGA. and noncovalently bound to M; T is a chelator noncovalently bound to N; N is different from M, N and M each being an atom of a stable isotope of an element selected from the group consisting of .sup.45Sc, .sup.50Cr, .sup.55Mn, .sup.58Fe, .sup.59Co, .sup.63Cu, .sup.103Rh, .sup.113Cd, .sup.114Cd, 1131n, .sup.115In, .sup.123Te, .sup.133Cs, .sup.139La, .sup.141Pr, .sup.146Nd, .sup.149Sm, .sup.152Sm, .sup.151Eu, .sup.153Eu, .sup.152Gd, .sup.155Gd, .sup.157Gd, .sup.159Tb, .sup.158Dy, .sup.160Dy, .sup.161Dy, .sup.162Dy, .sup.163Dy, .sup.164Dy, .sup.168Yb, .sup.169Tm, .sup.174Hf, .sup.178Hf, .sup.175Yb, .sup.165Ho, .sup.175Lu, .sup.176Lu, .sup.181Ta, .sup.185Re, .sup.187Re, .sup.190Ir, .sup.193Ir, .sup.196Hg, .sup.202Hg, and .sup.197Au, each M and N, independently, having a nucleus capable of capturing a neutron and subsequently emitting a photon; and i, j and k are independently each a number from 1 to about 8. [0012] In another embodiment, the invention provides a composition comprising: a compound .OMEGA..sub.i-M and a cationic counterion, wherein: each .OMEGA. is an organic compound having a molecular weight greater than about 50, i being a number from 1 to about 8; and M is an atom of a stable isotope of an element selected from the group of elements consisting of .sup.36S, .sup.74Se, .sup.79Br, .sup.81Br, .sup.107Ag, .sup.109Ag, .sup.127I, .sup.197Au, .sup.190Pt, and .sup.196Hg, wherein M is covalently bound to .OMEGA. and has a nucleus capable of capturing of a neutron and subsequently emitting a photon. In various related embodiments of this composition, the at least one .OMEGA..sub.i-X-M.sub.i compound differs in molecular weight range from the other compounds, the .OMEGA..sub.i-X-M.sub.i compounds having the same net charge; the .OMEGA..sub.i-X-M.sub.i compounds have different net charges and about the same molecular weight; and .OMEGA..sub.i is a polymer. [0013] In various additional related embodiments of this composition, the polymer is selected from the group consisting of a polysaccharide, a polypeptide, and a polynucleotide; the polysaccharide is a ficoll, a dextran, a pullulan, a starch, or a hydroxyethylstarch; the polypeptide is covalently attached to a polyethylene glycol polymer; and the non-covalently bound chelator is a bile acid compound. In various additional related embodiments of this composition, the bile acid compound is selected from the group consisting of cholic acid, cholic acid taurine, chenodeoxycholic, deoxycholic acid, homocholic acid taurine, and lithocholic acid; the bile acid compound is a synthetic derivative of a bile acid; the non-covalently bound chelator is a drug or a drug metabolite; .OMEGA..sub.i is selected from the group consisting of a hormone and a hormone antagonist; .OMEGA..sub.i is a steroid hormone; and the non-covalently bound chelator is selected from the group consisting of an antibiotic, a tranquilizer, a vitamin, a narcotic, a cannabinoid, a barbiturate, and an alkaloid. [0014] An embodiment of the invention also provides a composition comprising a plurality of colloids having the structure Y--O.sub.u-M.sub.t and a cation counterion, the composition being suspended in a physiologically compatible buffer, wherein: Y is a polymer having a molecular weight greater than about 1000; O is oxygen and u is a number between zero and about 200; and each M is an atom selected from the group of stable isotopes capable of capturing a neutron, thereby becoming unstable and emitting a photon having a characteristic energy spectrum, the photon being selected from the group consisting of a gamma photon, an x-ray photon or a prompt photon, t being an integer from 1 to about 10. In a related embodiment, each colloid among the plurality has a distinct molecular weight and is uniquely associated with a distinct M. [0015] An embodiment of the invention provides a method for quantifying by neutron activation an amount of at least one compound .OMEGA..sub.i-X.sub.j-M.sub.k, wherein each .OMEGA..sub.i is a unique organic compound having a molecular weight greater than about 50; each X.sub.j is at least one chelator covalently bound to .OMEGA..sub.i; and each M.sub.k is an atom of a stable isotope of an element and is distinct in identity and has a nucleus capable of capturing neutrons and thereby emitting photons, and i, j, and k are each numbers from 1 to 8, i being at least as great as k, the method comprising: exposing a first container having .OMEGA..sub.i-X.sub.j-M.sub.k and a second container having a standard known quantity of M.sub.k to a neutron source using the same neutron field, such that .OMEGA..sub.i-X.sub.i-M.sub.k and the M.sub.k standard capture neutrons and emit photons, wherein each M.sub.k is selected from the group consisting of .sup.45Sc, .sup.50Cr, .sup.55Mn, .sup.58Fe, .sup.59Co, .sup.63Cu, .sup.103Rh, .sup.113Cd, .sup.114Cd, .sup.113In, .sup.115In, .sup.123Te, .sup.133Cs, .sup.139La, .sup.141Pr, .sup.146Nd, .sup.149Sm, .sup.152Sm, .sup.151Eu, .sup.153Eu, .sup.152Gd, .sup.155Gd, .sup.157Gd, .sup.159 Tb, .sup.158Dy, .sup.160Dy, .sup.161Dy, .sup.162Dy, .sup.163Dy, .sup.164Dy, .sup.168Yb, .sup.169Tm, .sup.174Hf, .sup.178Hf, .sup.175Yb, .sup.165Ho, .sup.175Lu, .sup.176Lu, .sup.1Ta, .sup.185Re, .sup.187Re, .sup.190Ir, .sup.193Ir, .sup.196Hg, .sup.202Hg, and .sup.197Au; detecting resulting photon emissions; and comparing photon emissions of .OMEGA..sub.i-X.sub.i-M.sub.k with photon emissions of the standard, thereby quantifying the amount of at least one compound .OMEGA..sub.i-X.sub.i-M.sub.k. [0016] An embodiment of the invention provides a method of evaluating the rate of at least one physiological process in a subject, the method comprising: administering at least one test composition to a subject, wherein each test composition is differently labeled with one of the group of stable isotopes of one or more elements; obtaining a plurality of samples of a bodily fluid from the subject, the samples being obtained at different times after administering the composition; determining by neutron activation the amount of the at least one test composition in a volume of the samples; and calculating the rate of change of concentration over time of the composition in the bodily fluid, thereby evaluating the rate of the physiological process in the subject. In a related embodiment of this method, the rate of the physiological process is the glomerular filtration rate. [0017] In various additional related embodiments of the method, the physiological process is the glomerular integrity rate; the rate of the at least one physiological process is a glomerular filtration rate and a glomerular integrity rate; the rate of change of concentration of the at least one test composition is glomerular selectivity according to size of the test composition; the rate of change of concentration of the at least one test composition is glomerular selectivity according to charge of the test composition; the physiological process is at least one hepatic function; the physiological process is at least one gastrointestinal function; and the rate of the physiological process is evaluating absorption of a bile acid compound. [0018] In related embodiments of the method, evaluating the rate of the physiological process is evaluating cirrhosis; further, evaluating the rate of change of the physiological process is evaluating liver function after liver transplantation. [0019] A featured embodiment of the invention provides a kit for measuring glomerular integrity rate, comprising: a test composition X-M and a counterion in a physiologically compatible solution wherein X is a chelator noncovalently bound to M, and M is an atom of a stable isotope of an element having a nucleus capable of capturing a neutron and subsequently emitting a photon; at least one sample container to collect at least one samples of a bodily fluid; instructions for use; and a data recording system. [0020] An embodiment of the invention provides a composition for lot labeling a plurality of sample containers, the composition comprising at least one stable isotope of an element and a binding agent, wherein the binding agent maintains the stable isotope in the container, the stable isotope having a nucleus capable of capturing a neutron and subsequently emitting a photon. 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