Lawrence Livermore National Laboratory



New Grants

September 22, 2014

Awarded 1R21GM111242 from NIH/NIGMS - Development of laser spectroscopic methods for quantification of 14C

This proposal seeks to develop a table-top sized spectroscopic method to quantify 14C in milligram sized biological samples at levels down to the natural isotopic abundance, using a technique called Cavity Ring Down Spectroscopy. This system will be much cheaper to acquire and to operate, and could eventually replace the current state of the art technology -- accelerator mass spectrometry. This approach will lead to a new paradigm for 14C analysis in allowing studies to be carried out on the metabolism, disposition, fate and mass balance of 14C-labeled therapeutic entities for drug development, potential toxicants for risk assessment, and analysis of biomarkers for personalized medicine. Given the expected cost and simplicity of operation, this new technique will enable much greater access to high sensitivity 14C analysis than now currently available as any biomedical or biochemistry laboratory could afford to operate such an instrument.

Press Releases

Oct. 14, 2016

Pharmacokinetics of polycyclic aromatic hydrocarbons in human volunteers

The National Institute of Environmental Health Sciences Superfund Research Program (SRP) chose a paper authored by researchers from Oregon State University and Lawrence Livermore and Pacific Northwest national laboratories as its "Hot Publication" for October. Metabolism is a key health risk factor following exposures to pro-carcinogenic polycyclic aromatic hydrocarbons (PAHs). However, little data is available on the metabolism and pharmacokinetics in humans of high-molecular-weight PAHs, such as dibenzo[def,p]chrysene (DBC). In this study, detailed in a Chemical Research in Toxicology paper, researchers used a novel "moving wire" interface between ultraperformance liquid chromatography and accelerator mass spectrometry to detect and quantify parent DBC and its major metabolites in human volunteers who were orally administered a microdose of DBC. The major product identified in plasma from the subjects was unmetabolized DBC. They also identified major and minor metabolites in blood and urine. The SRP, in naming this its "Hot Publication," noted that the study provides the first data set to assess metabolite profiles and associated pharmacokinetics of a carcinogenic PAH in human volunteers at an environmentally relevant dose, providing data to translate high-dose animal models to humans to improve environmental health risk assessment.

[E. P. Madeen, T. J. Ognibene, R. A. Corley, T. J. McQuistan, M. C. Henderson, W. M. Baird, G. Bench, K. W. Turteltaub, and D. E. Williams, Human Microdosing with Carcinogenic Polycyclic Aromatic Hydrocarbons: In Vivo Pharmacokinetics of Dibenzo[def,p]chrysene and Metabolites by UPLC Accelerator Mass Spectrometry, Chem. Res. Toxicol., available online on August 5, 2016, DOI: 10.1021/acs.chemrestox.6b00169.]


Jun. 17, 2016

BioAMS Research Resource team receives "best poster" award at USA Medical Defense Bioscience Review Meeting
Biomedical researchers Michael Malfatti, Heather Enright, Edward Kuhn, Felice Lightstone, and Carlos Valdez received a best poster award for a "US Non-DOD scientist" at the 20th Biennial USA Medical Defense Bioscience Review Meeting, held in Aberdeen, MD June 6–9, 2016. The poster, entitled Quantifying the Pharmacokinetics of an Oxime Acetylcholinesterase Reactivator Using Accelerator Mass Spectrometry in Guinea Pigs, describes the work the team performed to quantify the pharmacokinetics of a compound recently developed to treat organophosphorus nerve-agent poisoning. Using accelerator mass spectrometry, they found that the compound was distributed mainly to the kidney and liver in their guinea pig model. They also found evidence that the compound crossed the blood–brain barrier, suggesting that it should be further developed as a potential treatment for nerve agent poisoning.


Mar. 2, 2016

LLNL BioAMS Article makes Editor's List for Editorial Board of Chemical Research in Toxicology favorite CRT Article.
Every year at the fall ACS meeting, the Editorial Board of Chemical Research in Toxicology meets to enjoy a social hour and dinner. At the 2015 meeting in Boston, the Editorial Advisory Board members were asked to pick their favorite paper published in CRT in the past two years; these would be collected in a virtual issue. 16 papers were highlighted and chosen. This paper was one of the 16: Human in Vivo Pharmacokinetics of [14C]Dibenzo[def,p]chrysene by Accelerator Mass Spectrometry Following Oral Microdosing Erin Madeen, Richard A. Corley, Susan Crowell, Kenneth Turteltaub, Ted Ognibene, Mike Malfatti, Tammie J. McQuistan, Mary Garrard, Dan Sudakin, and David E. Williams
 Chem. Res. Toxicol., 2015, 28 (1), pp 126–134 DOI: 10.1021/tx5003996 .


Jan. 6, 2015

A paper using AMS to provide data to make better models of human pharmacokinetics is marked as one of three "papers of note" for the NIH National Institute of Environmental Health Sciences (NIEHS) for January ( http://www.niehs.nih.gov/news/newsletter/2015/1/science-noted/index.htm.




October 2014

Resource staff, in conjunction with LLNL Industrial Partnerships Office presented a webinar to the business community, titled Biomedical Accelerator Mass Spectrometry: Measurement at incredibly small concentrations  by Ted Ognibene, LLNL, Center for Accelerator Mass Spectrometry (CAMS).

Publications

Bomb-pulse dating of collagen extracted from cerebral aneurysms showed that the structural proteins of aneurysms are unlike cerebral arteries and that the carbon in the collagen is less than 4 years old. Subjects with the risk factors of hypertension, smoking or history of cocaine use experienced carbon turnover less than 2 years. The work was featured on the June 2014 cover of Stroke.

N. Etminan, R. Dreier, B.A. Buchholz, K. Beseoglu. P. Bruckner, C. Matzennaur, J.C. Torner, R.D. Brown, H.J. Steiger, D. Hänggi, R.L. Macdonald. The Age of Collagen in Intracranial Saccular Aneurysms. Stroke 45 (2014) 1757-1763.

 

Identification of the GABAA receptor target of tetramethylenedisulfotetramine was reported using 14C-AMS competitive binding assays and mathematical modeling in collaboration with John Casida at UC Berkeley and Bruce Hammock at UC Davis. Identifying the receptor site is helpful in designing antidotes to GABA channel toxins.

C. Zhao, S.H. Hwang, B.A.Buchholz, T.S.Carpenter, F. Lightstone, J. Yang, B.D. Hammock, J.E. Casida. GABAA receptor target of tetramethylenedisulfotetramine. PNAS 111 (2014) 8607-8612.

 

Assessing the PKs of a novel antimicrobial preclinical drug candidate (GP-4) in rats was reported as a step toward human micro dosing studies.

Use of Microdosing and Accelerator Mass Spectrometry To Evaluate the Pharmacokinetic Linearity of a Novel Tricyclic GyrB/ParE Inhibitor in Rats. Malfatti MA, Lao V, Ramos CL, Ong VS, Turteltaub KW. Antimicrob Agents Chemother. 2014 Nov; 58(11):6477-83. doi: 10.1128/AAC.03300-14. Epub 2014 Aug 18. PMID: 25136019