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Vogel J.S.,University of California Retired | Giacomo J.A.,Vitalea Science
Radiocarbon | Year: 2017

Observation of 80 μA/mm2 C- current from a 0.5-mm-diameter sample compared to 20 μA/mm2 from a 1-mm-diameter sample contradicts the long-held surface ionization hypothesis of cesium sputter ion source operation. Resonant ionization occurs in neutral Cs plasma above a sample in a sputtered pit or well. A collision-radiation model of that plasma followed electronic excitation and radiation relaxation up to the Cs(7d) state. The Cs(5d) metastable state dominates plasma in a 1-mm-diameter well, but high electron densities in narrow wells drive a majority to Cs(7d) and higher. Competitive ionization by Al2 dimers from the sample holder reduces Cs(7s,p) states resonant in ionization energy with C-. Al anions from states above Cs(7p) in narrow wells also diminish radiation cascades to the Cs(7s,p), reducing C-. We tested sample wells of non-ionizing Zn to maintain high ionization efficiency for small samples in narrow wells. © 2016 by the Arizona Board of Regents on behalf of the University of Arizona.


Aklamati E.K.,University of California at Davis | Mulenga M.,Ndola Central Hospital | Dueker S.R.,Vitalea Science | Buchholz B.A.,Lawrence Livermore National Laboratory | And 4 more authors.
Journal of Nutrition | Year: 2010

A survey indicated that high-dose vitamin A (HD-VA) supplements had no apparent effect on vitamin A (VA) status, assessed by serum retinol concentrations, of Zambian children < 5 y of age. To explore possible reasons for the lack of response, we quantified absorption, retention, and urinary elimination of either a single HD-VA supplement (209.8 μmol; 60 mg) or a smaller dose of stable isotope (SI)-labeled VA (17.5 μmol; 5 mg), which was used to estimate VA pool size, in 3- to 4-y-old Zambian boys (n = 4 for each VA dose). A tracer dose of [ 14C 2]-labeled VA (0.925 kBq; 25 nCi) was coadministered with the HD-VA supplement or SI-labeled VA, and 24-h stool and urine samples were collected for 3 and 7 consecutive days, respectively, and 24-h urine samples at 4 later time points. Accelerator MS was used to quantify 14C in stool and urine. Estimates of absorption, retention, and the urinary elimination rate (UER) were 83.8 ± 7.1%, 76.3 ± 6.7%, and 1.9 ± 0.6%/d, respectively, for the HD-VA supplement and 76.5 ± 9.5%, 71.1 ± 9.4%, and 1.8 ± 1.2%/d, respectively, for the SI-labeled VA. Mean estimates of absorption, retention, and the UER did not differ by size of the VA dose administered. Estimated absorption and retention were negatively associated with reported fever (r = -0.83; P =0.011). The HD-VA supplement and SI-labeled VA were adequately absorbed, retained, and utilized in apparently healthy Zambian preschool-age boys; absorption and retention may be affected by recent fever. © 2010 American Society for Nutrition.


Ross A.B.,Nestlé | Vuong L.T.,Vitalea Science | Ruckle J.,Covance | Synal H.A.,ETH Zurich | And 14 more authors.
American Journal of Clinical Nutrition | Year: 2011

Background: To our knowledge, there is no direct information on lycopene metabolism in humans. Objective: The objective of this study was to quantify the long-term human bioavailability of lycopene in plasma and skin after a single dose of 14C-lycopene and to profile the metabolites formed. Design: We preselected 2 male subjects as lycopene absorbers and gave them an oral dose of 10 mg synthetic lycopene combined with ≈6 μg [6,6′,7,7′- 14C]lycopene (≈30,000 Bq; 92% trans lycopene). The appearance of 14C in plasma, plasma triacylglycerol-rich lipoprotein (TRL) fraction, urine, expired breath carbon dioxide, and skin biopsies was measured over 42 d. The 14C in lycopene-isomer fractions from plasma and TRL fraction was measured to assess the isomerization of lycopene in vivo. Results: We quantified 14C from 14C-lycopene in plasma, the plasma TRL fraction, expired carbon dioxide, urine, and skin. The time to maximum concentration (tmax) of total 14C-lycopene in plasma was 6 h, and the elimination half-life (t1/2) was 5 d, which were different from the tmax and t1/2 of unlabeled lycopene (0.5 and 48 d, respectively). 14C-Lycopene was extensively isomerized after dosing as a 92% all-trans isomer at dosing but changed to 50% trans, 38% 5 cis, 1%9cis, and 11% other cis isomers after 24 h. A similar pattern of isomerization was seen in plasma TRL fractions. Conclusions: Lycopene was extensively isomerized after dosing and rapidly metabolized into polar metabolites excreted into urine with the rapid peak of 14CO 2 after dosing, which implies that β-oxidation was involved in the lycopene metabolism. Lycopene or its metabolites were detected in skin for up to 42 d. © 2011 American Society for Nutrition.


Xu X.,Bristol Myers Squibb | Dueker S.R.,Vitalea Science | Christopher L.J.,Bristol Myers Squibb | Lohstroh P.N.,Vitalea Science | And 8 more authors.
Bioanalysis | Year: 2012

Background: An absolute bioavailability study that utilized an intravenous [14C]microdose was conducted for saxagliptin (Onglyza®), a marketed drug product for the treatment of Type 2 diabetes mellitus. Concentrations of [14C]saxagliptin were determined by accelerator MS (AMS) after protein precipitation, chromatographic separation by UPLC and analyte fraction collection. A series of investigative experiments were conducted to maximize the release of the drug from high-affinity receptors and nonspecific adsorption, and to determine a suitable quantitation range. Results: A technique-appropriate validation demonstrated the accuracy, precision, specificity, stability and recovery of the AMS methodology across the concentration range of 0.025 to 15.0 dpm/ml (disintegration per minute per milliliter), the equivalent of 1.91-1144 pg/ml. Based on the study sample analysis, the mean absolute bioavailability of saxagliptin was 50% in the eight subjects with a CV of 6.6%. Incurred sample reanalysis data fell well within acceptable limits. Conclusion: This study demonstrated that the optimized sample pretreatment and chromatographic separation procedures were critical for the successful implementation of an UPLC plus AMS method for [14C] saxagliptin. The use of multiple-point standards are useful, particularly during method development and validation, to evaluate and correct for concentration-dependent recovery, if observed, and to monitor and control process loss and operational variations. © 2012 Future Science Ltd.


Gordi T.,Rosa and Co LLC | Baillie R.,Rosa and Co LLC | Vuong L.T.,Vitalea Science | Abidi S.,Vitalea Science | And 6 more authors.
Journal of Clinical Pharmacology | Year: 2014

Pharmacokinetic studies in the neonatal population are often limited by the small volume of blood that can be collected. The high sensitivity of 14C-accelerator mass spectrometry (AMS) enables pharmacokinetic studies to be conducted with greatly reduced sample volumes. We demonstrated the utility of AMS in infants by studying the plasma pharmacokinetic behavior of nanogram doses of 14C-ursodiol administered as a non-perturbing microdose or as a microtracer with therapeutic doses of non-labeled ursodiol in infants. Five non-cholestatic infants were administered 3 consecutive oral microdoses of 14C-ursodiol: 8ng (1.0nCi), 26ng (3.3nCi), and 80ng (10nCi) 48hours apart. Three additional infants with cholestasis were administered a single 80ng (10.0nCi) oral dose of 14C-ursodiol together with a therapeutic dose of 40mg/kg of non-labeled ursodiol. A pharmacokinetic model describing ursodiol concentrations was developed using nonlinear mixed-effects modeling. The pharmacokinetics of ursodiol in this pilot study were best described by a two-compartment model with first-order elimination. This study demonstrates the feasibility and utility of microdose and microtrace methodology in pediatric research. © 2014, The American College of Clinical Pharmacology.


Keck B.D.,Procter and Gamble | Keck B.D.,Vitalea Science | Ognibene T.,Lawrence Livermore National Laboratory | Vogel J.S.,Vitalea Science | Vogel J.S.,Lawrence Livermore National Laboratory
Bioanalysis | Year: 2010

The validation parameters for pharmaceutical analyses were examined for the accelerator mass spectrometry measurement of 14C/C ratio, independent of chemical separation procedures. The isotope ratio measurement was specific (owing to the 14C label), stable across samples storage conditions for at least 1 year, linear over four orders of magnitude with an analytical range from 0.1 Modern to at least 2000 Modern (instrument specific). Furthermore, accuracy was excellent (between 1 and 3%), while precision expressed as coefficient of variation was between 1 and 6% determined primarily by radiocarbon content and the time spent analyzing a sample. Sensitivity, expressed as LOD and LLOQ was 1 and 10 attomoles of 14C, respectively (which can be expressed as compound equivalents) and for a typical small molecule labeled at 10% incorporated with 14C corresponds to 30 fg equivalents. Accelerator mass spectrometry provides a sensitive, accurate and precise method of measuring drug compounds in biological matrices. © 2010 Future Science Ltd.


Schulze-Konig T.,Paul Scherrer Institute | Dueker S.R.,Vitalea Science | Giacomo J.,Vitalea Science | Suter M.,Paul Scherrer Institute | And 2 more authors.
Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms | Year: 2010

The next generation Accelerator Mass Spectrometer system specifically designed to address the needs of the growing pharmaceutical science market has passed validation testing. The system dubbed BioMICADAS is based on a previously developed compact carbon dating instrument, the MICADAS. Like its predecessor, it has an overall footprint of only 2.5 × 3 m2 and uses a 200 kV high voltage platform for tandem based ion acceleration. The ion source can accommodate samples as graphite or gaseous CO2. It is equipped with two independently operating vacuum locks, allowing continuous measurement sequence and providing a capacity of ∼20,000 samples per annum. A barcoded cathode tracking system allows data capture into Laboratory Information Management System (LIMS) for Good Laboratory Practices (GLP) regulated work. It can be housed in research laboratories alongside other complementary bioanalytical equipment and operated by general laboratory staff as the system is designed to be robust and user-friendly. The system has undergone rigorous validation over the range from 0.1 to 100 Modern Carbon, including accuracy, linearity, robustness, and precision experiments over the course of 7 months. It has been shipped and installed at the site of our collaborative partner, Vitalea Science in Davis, California. The installation process took ∼2 weeks from boxes to beam. The feasibility of the system to determine the absolute specific activity of biogenic samples was also shown by using the method of isotopic dilution. © 2009 Elsevier B.V. All rights reserved.


Vogel J.S.,Vitalea Science | Giacomo J.A.,Vitalea Science | Dueker S.R.,Vitalea Science
Nuclear Instruments and Methods in Physics Research, Section B: Beam Interactions with Materials and Atoms | Year: 2013

Our AMS produced a ratio of instrument transmissions for 14C and 13C equal to 13/14 to 0.22 ± 0.06% accuracy at a specific charge-changing energy of 235 keV and giving absolute isotope ratios with that mass correction. The ratio for 13C and 12C transmissions was 12/13 at 215 keV. A differential equation model of energetic ion and atom transport through the gas collision cell was constructed with functions representing experimental cross-sections for all collision effects. This model showed cation yield dependencies that were linear with energy for the monoenergetic isotopic ions at the energies that we measured, explaining the inverse mass dependence. The model predicted multiple lower energies that have this dependence and, more importantly, two low energies at which cation yields were equal for pairs of isotopes, presaging potential absolute isotope ratio measurements at low MS energies. © 2012 Elsevier B.V. All rights reserved.


PubMed | Vitalea Science
Type: Journal Article | Journal: Bioanalysis | Year: 2012

Accelerator MS (AMS) provides a novel method for obtaining and analyzing pharmacokinetics and pharmacodynamics in children. This paper reviews the scientific and ethical rationale for AMS in pediatric trials, the regulatory framework and general considerations with some specific examples of pediatric clinical trials using AMS. Microdosing in the context of this article refers to studies using a negligible amount (nanocuries) of (14)C as tracer, and AMS as a quantitative technique. The technology is by no means a panacea for the deficiency in pediatric clinical research; however, it lessens the challenges and provides the most quantitative tool for pediatric pharmacology studies.

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