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| 2. |
- Arvidsson, Björn, et al.
(författare)
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Online capillary solid phase extraction and liquid chromatographic separation with quantitative tandem mass spectrometric detection (SPE-LC-MS/MS) of ximelagatran and its metabolites in a complex matrix.
- 2009
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Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232 .- 1873-376X. ; 877:3, s. 291-297
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Tidskriftsartikel (refereegranskat)abstract
- This work presents the development and validation of a fully automated quantitative analysis method of melagatran, its prodrug ximelagatran, and its major metabolites for the study of drug behavior in biofluids. The method involves online sample clean-up and enrichment on a C4 capillary column followed by separation on a capillary C18 column. Electrospray ionization tandem mass spectrometric detection in positive ion mode was performed with multiple reactions monitoring of eight different transients, divided into two time segments with four transients each. The structural similarity, the complexity of the matrix (pig liver extract) and the formation of isobaric fragment ions, made efficient chromatographic separation necessary. The analysis method provides valid accuracy (<9%; RSD%), precision (<8%; RSD%), linearity (<1.2 nM–1 μM; R2 > 0.999), limit of quantitation (<3.6 nM), retention repeatability (<1.2%; RSD%), selectivity, as well as analyte and column stabilities over a wide concentration range.
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| 3. |
- Folkersen, Lasse, et al.
(författare)
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Genomic and drug target evaluation of 90 cardiovascular proteins in 30,931 individuals.
- 2020
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:10, s. 1135-1148
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Tidskriftsartikel (refereegranskat)abstract
- Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. Here, we map and replicate protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, resulting in 451 pQTLs for 85 proteins. For each protein, we further perform pathway mapping to obtain trans-pQTL gene and regulatory designations. We substantiate these regulatory findings with orthogonal evidence for trans-pQTLs using mouse knockdown experiments (ABCA1 and TRIB1) and clinical trial results (chemokine receptors CCR2 and CCR5), with consistent regulation. Finally, we evaluate known drug targets, and suggest new target candidates or repositioning opportunities using Mendelian randomization. This identifies 11 proteins with causal evidence of involvement in human disease that have not previously been targeted, including EGF, IL-16, PAPPA, SPON1, F3, ADM, CASP-8, CHI3L1, CXCL16, GDF15 and MMP-12. Taken together, these findings demonstrate the utility of large-scale mapping of the genetics of the proteome and provide a resource for future precision studies of circulating proteins in human health.
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| 4. |
- Fors, Erik, et al.
(författare)
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Development of an H-TDMA for long-term unattended measurement of the hygroscopic properties of atmospheric aerosol particles
- 2009
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; 2:1, s. 313-318
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Tidskriftsartikel (refereegranskat)abstract
- A new hygroscopic tandem differential mobility analyzer (H-TDMA) has been constructed at Lund University within the frameworks of the EU FP6 Infrastructure Project EUSAAR (www.eusaar.org). The aim of this coordinated H-TDMA development is to design and evaluate a new generation of H-TDMAs that are capable of conducting long term measurements of the hygroscopic growth and state of mixing of sub-micrometer atmospheric aerosol particles at the EUSAAR aerosol super-sites across Europe. The H-TDMA constructed for this project has been validated with respect to hygroscopic growth factor, stability of relative humidity (RH), temperature stability and its ability to operate unattended for longer periods of time. When measuring growth factors of ammonium sulphate, the new H-TDMA system was found to measure within a growth factor deviation of +/- 0.05 compared to previously recorded data by Tang et al. (1994). The long term RH of the system has been found stable at 90.0% with a standard deviation of +/- 0.23% and an average temperature variability of the second DMA less than +/- 0.1 K. Daily automated ammonium sulphate measurements have validated the ambient measurements. The instrument is operated at the EMEP/EUSAAR background station Vavihill in the southern part of Sweden.
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| 6. |
- Rissler, Jenny, et al.
(författare)
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Effective Density and Mixing State of Aerosol Particles in a Near-Traffic Urban Environment.
- 2014
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Ingår i: Environmental Science & Technology. - : American Chemical Society (ACS). - 1520-5851 .- 0013-936X. ; 48:11, s. 6300-6308
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Tidskriftsartikel (refereegranskat)abstract
- In urban environments, airborne particles are continuously emitted, followed by atmospheric aging. Also, particles emitted elsewhere, transported by winds, contribute to the urban aerosol. We studied the effective density (mass-mobility relationship) and mixing state with respect to the density of particles in central Copenhagen, in wintertime. The results are related to particle origin, morphology, and aging. Using a differential mobility analyzer-aerosol particle mass analyzer (DMA-APM), we determined that particles in the diameter range of 50-400 nm were of two groups: porous soot aggregates and more dense particles. Both groups were present at each size in varying proportions. Two types of temporal variability in the relative number fraction of the two groups were found: soot correlated with intense traffic in a diel pattern and dense particles increased during episodes with long-range transport from polluted continental areas. The effective density of each group was relatively stable over time, especially of the soot aggregates, which had effective densities similar to those observed in laboratory studies of fresh diesel exhaust emissions. When heated to 300 °C, the soot aggregate volatile mass fraction was ∼10%. For the dense particles, the volatile mass fraction varied from ∼80% to nearly 100%.
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| 9. |
- Sjögren, Erik, et al.
(författare)
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Hepatic disposition of ximelagatran and its metabolites in pig; prediction of the impact of membrane transporters through a simple disposition model
- 2010
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Ingår i: Pharmaceutical research. - : Springer Science and Business Media LLC. - 0724-8741 .- 1573-904X. ; 27:4, s. 597-607
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Tidskriftsartikel (refereegranskat)abstract
- Purpose: The double prodrug ximelagatran is bioconverted, via the intermediates ethylmelagatran and N-hydroxymelagatran, to the direct thrombin inhibitor melagatran. The aims of this study were 1) to investigate the hepatic metabolism and disposition of ximelagatran and the intermediates in pig; and 2) to test a simple in vitro methodology for quantitative investigations of membrane transporters impact on the disposition of metabolized drugs. Methods: Porcine S1 (supernatant fraction obtained by centrifuging at 1000g for 10 min) liver fractions and hepatocytes were incubated in absence and presence of known membrane transporter inhibitors. The in vitro kinetics and disposition were determined by simultaneously fitting of the disappearance of ximelagatran and appearance of ethylmelagatran, N-hydroxymelagatran and melagatran. Results: In S1 liver fractions, the metabolism was significant inhibited by co-incubation of verapamil and ketoconazole but not by erythromycin, quinine and quinidine. The disposition of ximelagatran and the intermediate metabolites in hepatocytes were influenced, to various degrees, by carrier-mediated distribution processes. Conclusion: This work demonstrates that it is possible to obtain profound information of the general mechanisms important in the drug liver disposition with the combination of common in vitro systems and the simple disposition model proposed in this study.
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