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PubMed2006

Pharmacokinetics and metabolic disposition of sirolimus in healthy male volunteers after a single oral dose.

The pharmacokinetics and metabolic disposition of sirolimus (rapamycin, Rapamune), a macrocyclic immunosuppressive agent for the prevention of allograft rejection in organ transplantation, were investigated in 6 healthy male volunteers after a single nominal 40-mg oral dose of the C-radiolabeled drug, with the added aim of assessing the potential role of sirolimus metabolites in the clinical pharmacology of the parent drug. The absorption of parent drug and derived materials was rapid (tmax 1.3 +/- 0.5 hours, mean +/- SD), and the elimination of sirolimus was slow (t(1/2) 60 +/- 10 hours, mean +/- SD) in whole blood. The high whole blood to plasma (B/P) concentration ratio of sirolimus (142 +/- 39) was consistent with its extensive partitioning into formed blood elements. The markedly lower B/P value based on radioactivity (2.7 +/- 0.4) suggested that drug-derived products partitioned into formed blood elements to a much lesser extent. Based on AUC0-144h values, unchanged sirolimus represented an average 35% of total radioactivity in whole blood. Drug-derived products in whole blood were characterized by HPLC, LC/MS, and LC/MS/MS as 41-O-demethyl, 7-O-demethyl, and several hydroxy, dihydroxy, hydroxy-demethyl and didemethyl sirolimus metabolites. The percentage distribution of sirolimus metabolites in whole blood ranged from 3%-10% at 1 hour to 6%-17% at 24 hours after drug administration. Based on their low immunosuppressive activities and relative abundance in whole blood of humans after sirolimus administration, metabolites of sirolimus do not appear to play a major role in the clinical pharmacology of the parent drug. A majority of the administered radioactivity (91.0 +/- 8.0%) was recovered from feces, and only 2.2% +/- 0.9% was renally excreted.

Administration, Oral↗

PubMed1985

Can a sponge fractionate isotopes?

The study has unequivocally demonstrated that siliceous sponges Spirastrella cuspidifera and Prostylyssa foetida from the same microecological niche exhibit a high degree of species specificity, while accumulating a host of heavy metal ions (Ni, Cr, Cd, Sn, Ti, Mo, Zr). S. cuspidifera accumulated, in addition, 60Co and 63Ni, showing discrimination against other radionuclides, 137Cs and 131I, present in the ambient waters receiving controlled low level waste discharges from a B.W.R. nuclear power station. P. foetida, on the other hand, accumulated only 131I and showed discrimination against other radionuclides including 60Co, although the stable iodine concentrations in both the sponges were the same. The specific activity of 60Co (in becquerels per gram of 59Co) in S. cuspidifera and 131I (in becquerels per gram of 127I) in P. foetida were at least two orders of magnitude greater than in the ambient sea water. That of 63Ni (in becquerels per gram of 62Ni) in S. cuspidifera, on the other hand, was lower by two orders of magnitude than in either abiotic matrices from the same environment. Thus, not only did both the species show bioaccumulation of a specific element, but also preferential uptake of isotopes of the same element, though they were equally available for intake. Such differential uptake of isotopes can possibly be explained in terms of two quite different mechanisms operating, each applicable in a particular case. One is that the xenobiotic isotope enters the environment in a physicochemical form or as a complex different from that of its natural counterpart. If equilibration with the latter is slow, so that the organism acquires the xenobiotic in an unfamiliar chemical context, it may treat it as a chemically distinct entity so that its concentration factor differs from that of stable isotope, thus changing the specific activity. Alternatively, if the xenobiotic is present in the same chemical form as the stable isotope, the only way in which specific activities can be modified is by fractionation on the basis of mass of isotope. In view of the remarkable concentration factors observed for stable and radioactive isotopes of the same element and the specific activities reached, it is desirable that species of sponges, especially from the coastal and estuarine environments, be monitored to detect levels of pollution due to anthropogenic substances.

Animals↗

PubMed1974

Studies with radioactive endotoxin. III. Localization of 3H-labelled endotoxin in the formed elements of the blood and detection of endotoxin in calf blood with the Limulus amebocyte lysate.

(3)H-labelled Pseudomonas endotoxin was incubated in vitro with blood from nontolerant and endotoxin tolerant calves. Formed elements were separated from serial samples of the incubated mixtures. The labelled endotoxin became associated with neutrophils, monocytes, lymphocytes, platelets and erythrocytes. Association of (3)H-endotoxin with formed elements of the blood occurred during the first five minutes of incubation and did not significantly change over the course of a three hour incubation period. Tolerance did not result in increased uptake of (3)H-endotoxin by formed elements of the blood. Tolerance of calves to endotoxin is apparently not due to increased uptake of endotoxin by formed elements of the blood. The Limulus amebocyte lysate assay was unreliable for the detection of endotoxin which was present in calf blood in vitro and requires further modification.

Animals↗

PubMed1999

Determinations of subnanomole elemental levels by NAA and their possible impact on human health related issues.

Neutron activation analysis (NAA) is an appropriate tool for the determination of trace elements in biological systems. The virtually blank-free NAA procedures fittingly complement precautions employed in sampling and sample preparation of biological matrices. Results from instrumental NAA procedures used to establish baseline values and time trends for elements in human tissues demonstrate the advantages as well as the limits of these procedures for nanomole and, in a considerable number of instances, subnanomole elemental levels. In addition, subnanomole mass fractions have been determined with extremely low limits of detection by employing NAA with radiochemical separations isolating very low levels of radioactivity from the matrix background. The elements reviewed in this article include Cr, Se, Pt, and others that have been determined by NAA at subnanomole levels in human tissues and body fluids and in biological macromolecules.

Humans↗

PubMed1991

Evidence for regulatory control of iron uptake from ferric maltol across the small intestine of the rat.

1. 59Fe absorption from the novel iron compound, ferric maltol, was studied in rats pretreated twice daily for two weeks with non-radioactive ferric maltol in oral doses containing 7 mg elemental iron. Tissue accumulation of 59Fe 2 h after administration of radioactive ferric maltol into the stomach was significantly lower in iron pretreated animals than in saline-treated controls. 2. 59Fe uptake from ferric maltol into isolated fragments of ileum and of duodenum was of similar magnitude in control animals but in iron-treated animals, duodenal uptake was significantly lower than that of the ileum. 3. Absorption of 59Fe was also investigated in anaesthetized rats after intestinal perfusion with saline (controls) or with 5 mM chenodeoxycholate to render the intestines more permeable. 4. Changes in permeability of the small intestine were monitored by estimating the amount of [14C]-mannitol absorbed and fluid secreted with reference to the non-absorbable [3H]-inulin in the perfusate effluents. 5. Despite the increased permeability of the intestines after bile salt treatment, there was little difference from control in the tissue accumulation of 59Fe from ferric maltol 2 h after intraduodenal administration. However 59Fe absorption from ferrous sulphate was significantly increased after bile salt treatment. 6. Gel filtration profiles of plasma made 5 and 60 min after intraduodenal administration of [59Fe]-ferric [3H]-maltol demonstrated that metal and ligand do not enter the circulation as the complex even when intestinal permeability is increased. 7. Uptake of 59Fe was investigated in isolated fragments of rat small intestine after saline or bile salt perfusion. Although 59Fe uptake from ferric maltol was somewhat greater in the bile salt-treated intestinal fragments, saturable kinetics were still observed. By contrast, "Fe uptake from ferrous sulphate: ascorbate was greatly enhanced by bile salt pretreatment and a very large diffusional component of uptake was evident. 8. It is concluded that iron uptake from ferric maltol may well be under endogenous regulatory control even in damaged intestines, so it is unlikely that this novel iron compound can bring about iron overload when administered orally.

Animals↗

PubMed2002

Diffusion studies in non-oxide ceramics: analytical aspects of the use of ion implanted stable tracers and SIMS.

The physical and chemical properties of complex non-oxide ceramic materials require advanced methods of diffusivity determination. In this study, we present a method based on the high-dose ion implantation of stable tracers in combination with secondary ion mass spectroscopy for depth profiling. The analytical basics, advantages and problems of the method are discussed for two examples of complex materials, the Si-B-C-N precursor ceramics and the Ti-based transition metal diborides. We demonstrate that is possible to measure the temperature dependence of diffusivities, especially for ceramic systems with low diffusivities, for systems that contain elements for which no suitable radioactive tracers exist for extended measurements.

Ceramics↗

PubMed2005

Renal tubulointerstitial changes after internal irradiation with alpha-particle-emitting actinium daughters.

The effect of external gamma irradiation on the kidneys is well described. However, the mechanisms of radiation nephropathy as a consequence of targeted radionuclide therapies are poorly understood. The functional and morphologic changes were studied chronologically (from 10 to 40 wk) in mouse kidneys after injection with an actinium-225 (225Ac) nanogenerator, a molecular-sized, antibody-targeted, in vivo generator of alpha-particle-emitting elements. Renal irradiation from free, radioactive daughters of 225Ac led to time-dependent reduction in renal function manifesting as increase in blood urea nitrogen. The histopathologic changes corresponded with the decline in renal function. Glomerular, tubular, and endothelial cell nuclear pleomorphism and focal tubular cell injury, lysis, and karyorrhexis were observed as early as 10 wk. Progressive thinning of the cortex as a result of widespread tubulolysis, collapsed tubules, glomerular crowding, decrease in glomerular cellularity, interstitial inflammation, and an elevated juxtaglomerular cell count were noted at 20 to 30 wk after treatment. By 35 to 40 wk, regeneration of simplified tubules with tubular atrophy and loss with focal, mild interstitial fibrosis had occurred. A lower juxtaglomerular cell count with focal cytoplasmic vacuolization, suggesting increased degranulation, was also observed in this period. A focal increase in tubular and interstitial cell TGF-beta1 expression starting at 20 wk, peaking at 25 wk, and later declining in intensity with mild increase in the extracellular matrix deposition was noticed. These findings suggest that internally delivered alpha-particle irradiation-induced loss of tubular epithelial cells triggers a chain of adaptive changes that result in progressive renal parenchymal damage accompanied by a loss of renal function. These findings are dissimilar to those seen after gamma or beta irradiation of kidneys.

Actinium↗

PubMed2002

Correlation between serum cholesterols and trace element uptake in liver, kidney, and blood of hypercholesterolemic mice.

The radioactive multitracer technique was applied to the simultaneous determination of the uptake of 17 trace elements (Be, Na, Sc, V, Cr, Mn, Fe, Co, Zn, As, Se, Rb, Sr, Y, Zr, Nb, and Ru) in the liver, kidney, and blood of hypercholesterolemic model mice. The uptakes of Be, Sc, V, Cr, Fe, As, Rb, Y, Zr, Nb, and Ru in liver increased with an increasing feeding period of a cholesterol-rich diet, whereas the uptakes of Zn and Se decreased. Feeding of the diet resulted in a marked increase in serum total cholesterol, triglycerides, and low-density lipoprotein cholesterol. The metabolism of trace elements between cholesterolemic and normal mice was compared with respect to their serum cholesterol levels. A significant positive correlation was found between the concentration of serum triglycerides and liver uptakes of Cr, Fe, and As and a negative correlation for the uptake of Zn. A significant positive correlation was found between the concentrations of serum high- and low-density lipoprotein cholesterols and kidney uptakes of Cr and Rb. A negative correlation was found between the uptake of Be in the blood and the concentration of serum triglycerides. These results suggest that cholesterolemia have some specific effects on the metabolism of some elements.

Animals↗

PubMedDate not supplied

Application of tracer packet technique for multielemental uptake studies on the inorganic ion exchanger zirconium vanadate.

The conception of tracer packet was first started with the irradiation of a thick cobalt target with 16O, 7Li and 12C beams, consecutively. This produced carrier-free radiotracers of Mn, Cu, Zn, Ga, Ge, As and Se. These elements are adjacent members in the periodic table and are of nutritional importance. Another 'tracer packet', which was subsequently designed, was of heavy and toxic metals. A gold target irradiated with medium energy 7Li and 12C produced 197Hg, 200Tl, 200Pb, 204Bi, 204Po. The uptake of these elements has been studied using two different ion exchangers, one of inorganic origin and the other of chelating type.

Hydrogen-Ion Concentration↗

PubMed1996

The assessment of doses and effects from intakes of radioactive particles.

The behaviour of radionuclides after entry into the body and the radiation doses received by individual tissues depend on the chemical nature of the element, the physicochemical form of the intake, the radioactive half-life of the isotope and the type and energy of the emissions. Ingestion of radionuclides in insoluble particles will result in radiation doses being delivered to tissues of the gastrointestinal (GI) tract; other tissues will also be irradiated by nuclides with penetrating photons emissions (gamma) but doses may be largely confined to the GI tract for charged particle emissions (alpha, beta). Ingestion of more soluble forms will lead to greater absorption to blood and deposition in other tissues and therefore may result in greater doses to other tissues. Similar considerations apply to inhaled material and to the entry of radionuclides through cuts or wounds. For ingested materials, including particles, more information is needed on uptake and retention in intestinal tissues and consequent doses to sensitive cells, particularly for alpha emitters. There has been concern that the pattern of distribution of activity throughout irradiated tissues may influence the extent of damage, particularly for alpha emitters because of the localised deposition of energy and their greater relative biological effectiveness compared with beta/gamma emitters. Aggregation of activity has the potential to result in greater acute tissue damage and has been shown, for example, to result in focalised pneumonitis and fibrosis in the lung and ulceration of the skin. The main long-term effect of irradiation of tissues is the induction of malignant change, although hereditary disease may also be of concern following irradiation of the gonads. There are only limited data available to compare the effect on cancer induction of heterogeneous and homogeneous irradiation of tissues. However, the available information, for irradiation of the lung, skin or liver, indicates that in general nonuniform alpha irradiation from radioactive particles is no more hazardous, and may be less hazardous, than if the same activity is uniformly distributed.

Administration, Oral↗

PubMed2000

The excretion of biotrace elements using the multitracer technique in tumour-bearing mice.

A radioactive multitracer solution obtained from the nuclear reaction of selenium with 25 MeV/nucleon 40Ar ions was used for investigation of trace element excretion into the faeces and urine of cancerous mice. The excretion rates of 22 elements (Na, K, Rb, Mg, Ca, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Mo, Nb, Tc, Ru, Ag and In) were simultaneously measured under strictly identical experimental conditions, in order to clarify the excretion behavior of these elements in cancerous mice. The faecal and urinary excretion rates of Mg, Sr, Ga, As, Sc, V, Cr, Mn, Co, Fe, Y, Zr, Nb, Ru and Mo in cancerous mice, showed the in highest value at 0-8 hours. The accumulative excretion of Ca, Mo, Y and Zr was decreased and Na, Fe, Mn and Co increased in tumour-bearing mice, when compared to normal mice.

Animals↗

PubMed1994

Analysis of scintigrams by singular value decomposition (SVD) technique.

The singular value decomposition (SVD) method is presented as a potential tool for analyzing gamma camera images. Mathematically image analysis is a study of matrixes as the standard scintigram is a digitized matrix presentation of the recorded photon fluence from radioactivity of the object. Each matrix element (pixel) consists of a number, which equals the detected counts of the object position. The analysis of images can be reduced to the analysis of the singular values of the matrix decomposition. In the present study the clinical usefulness of SVD was tested by analyzing two different kinds of scintigrams: brain images by single photon emission tomography (SPET), and liver and spleen planar images. It is concluded that SVD can be applied to the analysis of gamma camera images, and that it provides an objective method for interpretation of clinically relevant information contained in the images. In image filtering, SVD provides results comparable to conventional filtering. In addition, the study of singular values can be used for semiquantitation of radionuclide images as exemplified by brain SPET studies and liver-spleen planar studies.

Blood Platelets↗

PubMed1984

Mineral metabolism and in vivo uptake of [67 Ga]citrate.

The uptake of [67 Ga]citrate by normal rats of different ages has been compared with the mineral composition of the assayed tissues. Very young animals take up much more 67 Ga than the adults and there seems to be a correlation between the mineral composition (calcium, magnesium and iron) and the radioactivity uptake. The role of those elements and of cellular proliferation in this phenomenon is discussed.

Animals↗

PubMed1975

Contaminants in food: analytical problems and achievements.

In evaluating the toxicological significance of such contaminants as trace metals, polynuclear aromatic hydrocarbons, mycotoxins, pesticides and nitrosamines, analytical chemistry plays an important role. The detection and identification of these in various foods at the mg/kg or mug/kg levels has posed some difficult analytical problems. Considerable progress has been made in this field in the past decade, however, an opportunity is taken to review the achievements in terms of specificity and sensitivity for each class of contaminant.

Anti-Bacterial Agents↗

PubMed2003

Deposition and distribution of Chernobyl fallout fission products and actinides in a Russian soil profile.

In this article the distribution of fission products and actinides in a soil profile from Novo Bobovicky in Russia, which was contaminated due to the Chernobyl nuclear power plant accident, is described. The ground deposition of long-lived fission products determined by gamma-spectrometry was (recalculated to 26 April 1986) 1600 kBq (137)Cs/m(2), 900 kBq (134)Cs/m(2) and 60 kBq (125)Sb/m(2). Of these radionuclides (137)Cs shows the dominating activity at the present time. After 6.5 years 90% of the Cs and Sb activity was contained in the upper 4 cm. A (239,240)Pu ground deposition of 77.4+/-8.0 Bq/m(2) was determined by alpha-spectrometry. The (238)Pu/(239,240)Pu activity ratio of 0.30+/-0.03 and (241)Pu/(239,240)Pu activity ratio of 115+/-14 (in 1986) measured in the soil profile, indicates that the analysed Pu originates mainly from the Chernobyl accident. The average (234)U/(238)U activity ratio of 1.06+/-0.29 indicates that the uranium in this soil is dominated by naturally occurring uranium. The alpha- and beta-autoradiography revealed that the activity is mainly present in particulate form. It could further be observed that the spots containing alpha- or beta-activity originated from different particles. A comparison of alpha-autoradiography with the bulk Pu and Am activity showed that 92% of the alpha-activity was present as clearly detectable alpha-spots. The beta-active particles, located by beta-autoradiography were correlated with gamma-spectrometric measurements and contained only (137)Cs. These hot spots ranged from 0.02 to 0.15 Bq.It could be concluded that the vertical transport of (137)Cs and fuel fragments occurs mainly by movement of particles through the soil. It could also be concluded that the fuel fragments found, in this soil were depleted in respect to Cs, Sb and Eu. Comparison of the analysed (238)Pu/(239,240)Pu, (241)Pu/(239,240)Pu and (241)Am/(239,240)Pu ratios with the ratios calculated with ORIGEN-S code gave an estimate of the average burn-up of the fuel particles to be in the range of 11-12 GWd/tU. The results presented in this article are valid for this single soil profile and should not be generalised unless validated in a more rigorous study of a larger number of soil profiles.

Actinoid Series Elements↗

PubMed2002

Simultaneous separation and detection of actinides in acidic solutions using an extractive scintillating resin.

An extractive scintillating resin was evaluated for the simultaneous separation and detection of actinides in acidic solutions. The transuranic extractive scintillating (TRU-ES) resin is composed of an inert macroporous polystyrene core impregnated with organic fluors (diphenyloxazole and 1,4-bis-(4-methyl-5-phenyl-2-oxazolyl)benzene) and an extractant (octyl(phenyl)-N,N-diisobutylcarbamoylmethylphosphine oxide in tributyl phosphate). The TRU-ES resin was packed into FEP Teflon tubing to produce a flow cell (0.2-mL free column volume), which is placed into a scintillation detection system to obtain pulse height spectra and time series data during loading and elution of actinides onto/from the resin. The alpha-particle absolute detection efficiencies ranged from 77% to 96.5%, depending on the alpha energy and quench. In addition to the on-line analyses, off-line analyses of the effluent can be conducted using conventional detection methods. The TRU-ES resin was applied to the quantification of a mixed radionuclide solution and two actual waste samples. The on-line characterization of the mixed radionuclide solution was within 10% of the reported activities whereas the agreement with the waste samples was not as good due to sorption onto the sample container walls and the oxidation state of plutonium. Agreement between the on-line and off-line analyses was within 35% of one another for both waste samples.

Acids↗

PubMed1981

Disposition of anagrelide, an inhibitor of platelet aggregation.

A single dose of 14C-anagrelide (6,7-dichloro-1,5-dihydroimidazo [2,1-b] quinazoline-2(3H)-one monohydrochloride) equivalent to 1 mg free base and containing 100 muCi radioactivity, was taken by five healthy, fasting men. Blood, plasma, urine, and feces were analyzed for total radioactivity. Plasma and urine concentrations of anagrelide were determined, and the urinary metabolite profile was established by high-performance liquid chromatography (HPLC). The drug was rapidly absorbed with peak plasma levels of radioactivity equivalent to 50 ng anagrelide per milliliter at about 1 hr. These levels decreased to less than 10% of peak in 24 hr. Plasma levels of anagrelide peaked at 5 ng/ml at about 1 hr, decreased rapidly during the first 6 to 8 hr, and then declined more slowly, with an estimated terminal elimination half-life of about 3 days. No significant quantities of radioactivity were associated with the cellular elements of blood. Anagrelide was extensively metabolized before elimination in urine. Means of 68% and 72% of the dose were excreted in urine as metabolites in 24 and 144 hr, and 10% of the dose recovered in the feces. Several urinary metabolites were detected by HPLC.

Adult↗

PubMed2003

Assessing skull burdens of actinides using a mathematical phantom: a Monte Carlo approach.

In vivo monitoring techniques are needed to estimate the amount of an actinide in the skeleton in addition to that in the lungs and liver. Skull counting with external detectors has been a standard procedure for this purpose. Realistic skull phantoms are normally used to calibrate the counting systems. However, the fabrication of realistic phantoms is extremely difficult and expensive. Therefore, a theoretical approach based on Monte Carlo methods in conjunction with a Cristy mathematical phantom has been examined for assessing skull burdens of actinides. A computer program that generates surface sources of actinides on the skull and simulates low-energy photon transport in the heterogeneous media of the head region of the Cristy phantom was developed for this purpose. The program determines the observable pulse height spectrum of the detector and the corresponding calibration factors for different counting geometries. The computer program was used to generate the pulse height spectra and the corresponding calibration factors of 20 cm and 15 cm diameter phoswich detectors, each positioned on the left and right sides and on the top of the head region of the Cristy phantom, whose skull surfaces were assumed to have a uniform distribution of 241Am. The computed calibration factor for a counting geometry consisting of three phoswich detectors (15 cm diameter each) surrounding the phantom's skull was found to be in excellent agreement with the experimental results obtained for the same geometry using a realistic physical skull phantom. This provided a validation of the realistic design of the skull in the Cristy phantom, implying that the results reported in this paper could be used for in vivo measurements of skull burdens of 241Am for the stated counting geometry.

Actinoid Series Elements↗