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1.
《Drug metabolism and pharmacokinetics》2019,34(5):308-316
LC-MS quantification of drug metabolites is sometimes impeded by the availability of internal standards that often requires customized synthesis and/or extensive purification. Although isotopically labeled internal standards are considered ideal for LC-MS/MS based quantification, de novo synthesis using costly isotope-enriched starting materials makes it impractical for early stage of drug discovery. Therefore, quick access to these isotope-enriched compounds without chemical derivatization and purification will greatly facilitate LC-MS/MS based quantification. Herein, we report a novel 18O-labeling technique using metabolizing enzyme carboxylesterase (CES) and its potential application in metabolites quantification study. Substrates of CES typically undergo a two-step oxygen exchange with H218O in the presence of the enzyme, generating singly- and doubly-18O-labeled carboxylic acids; however, unexpected hydrolytic behavior was observed for three of the test compounds – indomethacin, piperacillin and clopidogrel. These unusual observations led to the discovery of several novel hydrolytic mechanisms. Finally, when used as internal standard for LC-MS/MS based quantification, these in situ labeled compounds generated accurate quantitation comparable to the conventional standard curve method. The preliminary results suggest that this method has potential to eliminate laborious chemical synthesis of isotope-labeled internal standards for carboxylic acid-containing compounds, and can be developed to facilitate quantitative analysis in early-stage drug discovery. 相似文献
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Fast CT-PRESS-based spiral chemical shift imaging at 3 Tesla. 总被引:2,自引:0,他引:2
Dirk Mayer Dong-Hyun Kim Elfar Adalsteinsson Daniel M Spielman 《Magnetic resonance in medicine》2006,55(5):974-978
A new sequence is presented that combines constant-time point-resolved spectroscopy (CT-PRESS) with fast spiral chemical shift imaging. It allows the acquisition of multivoxel spectra without line splitting with a minimum total measurement time of less than 5 min for a field of view of 24 cm and a nominal 1.5x1.5-cm2 in-plane resolution. Measurements were performed with 17 CS encoding steps in t1 (Deltat1=12.8 ms) and an average echo time of 151 ms, which was determined by simulating the CT-PRESS experiment for the spin systems of glutamate (Glu) and myo-inositol (mI). Signals from N-acetyl-aspartate, total creatine, choline-containing compounds (Cho), Glu, and mI were detected in a healthy volunteer with no or only minor baseline distortions within 14 min on a 3 T MR scanner. 相似文献
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The generation of thrombin-like activity from rat, human, bovine and mouse prothrombin by Echis carinatus venom (ECV) treatment was compared using a partially purified system (i.e. whole ECV and isolated prothrombin). A rapid increase in coagulant activity was obtained within 0.5 to 2 min., being constant upon further incubation for 60 min. A large variation in coagulant activity of the ECV generated thrombin from the four species was found, whereas no differences were found for the amidolytic activities. The coagulant activities of the ECV generated thrombin was also low compared with the corresponding thrombin activities obtained by physiological activation. Coagulant activity of the ECV generated thrombin levelled off at increasing concentration of prothrombin in the sample as measured by the one-stage coagulation assay. By measuring amidolytic activity a linear relationship to the concentration of prothrombin was found, however. These findings indicate that ECV converts prothrombin from the four different species to a thrombin-like protein with properties distinct from -thrombin. The lack of linearity in the ECV generated clot activity with increasing concentration of prothrombin could be explained by assuming a dimerization of the thrombin like protein molecules making them less accessible to fibrinogen. The significance of these observations for the quantification of prothrombin from different species is discussed. 相似文献
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This paper presents a method for calculating stage line diagrams, a novel type of reference diagram useful for tracking developmental processes over time. Potential fields of applications include: dentistry (tooth eruption), oncology (tumor grading, cancer staging), virology (HIV infection and disease staging), psychology (stages of cognitive development), human development (pubertal stages) and chronic diseases (stages of dementia). Transition probabilities between successive stages are modeled as smoothly varying functions of age. Age‐conditional references are calculated from the modeled probabilities by the mid‐P value. It is possible to eliminate the influence of age by calculating standard deviation scores (SDS). The method is applied to the empirical data to produce reference charts on secondary sexual maturation. The mean of the empirical SDS in the reference population is close to zero, whereas the variance depends on age. The stage line diagram provides quick insight into both status (in SDS) and tempo (in SDS/year) of development of an individual child. Other measures (e.g. height SDS, body mass index SDS) from the same child can be added to the chart. Diagrams for sexual maturation are available as a web application at http://vps.stefvanbuuren.nl/puberty . The stage line diagram expresses status and tempo of discrete changes on a continuous scale. Wider application of these measures scores opens up new analytic possibilities. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
8.
Stephan E. Maier Harvey E. Cline Ferenc A. Jolesz 《Magnetic resonance in medicine》1995,34(5):706-712
Three dimensional (3D) phase contrast angiograms contain velocity data, which is discarded after the reconstruction of the projections. In extension to earlier work on velocity quantification with ungated 2D phase data, this paper shows that a useful estimate of the average velocity and flow rate can be extracted from ungated 3D phase contrast angiograms. Simulations and experiments in a phantom and in vivo were performed. For pulsatile flow and strong spin saturation, an over-estimation of the flow rate at the net in-flow end of the imaging volume and underestimation at the net out-flow end was observed. Imaging at lower RF tip angles yielded flow rates close to the correct value within the entire imaging volume. In contrast to ungated 2D experiments, the flow rates determined by repeated 3D experiments showed no variation. 相似文献
9.
Ivan Tkác Pierre-Gilles Henry Peter Andersen C Dirk Keene Walter C Low Rolf Gruetter 《Magnetic resonance in medicine》2004,52(3):478-484
An efficient shim system and an optimized localization sequence were used to measure in vivo 1H NMR spectra from cerebral cortex, hippocampus, striatum, and cerebellum of C57BL/6 mice at 9.4 T. The combination of automatic first- and second-order shimming (FASTMAP) with strong custom-designed second-order shim coils (shim strength up to 0.04 mT/cm2) was crucial to achieve high spectral resolution (water line width of 11-14 Hz). Requirements for second-order shim strengths to compensate field inhomogeneities in the mouse brain at 9.4 T were assessed. The achieved spectral quality (resolution, S/N, water suppression, localization performance) allowed reliable quantification of 16 brain metabolites (LCModel analysis) from 5-10-microL brain volumes. Significant regional differences (up to 2-fold, P < 0.05) were found for all quantified metabolites but Asp, Glc, and Gln. In contrast, 1H NMR spectra measured from the striatum of C57BL/6, CBA, and CBA/BL6 mice revealed only small (<13%, P < 0.05) interstrain differences in Gln, Glu, Ins, Lac, NAAG, and PE. It is concluded that 1H NMR spectroscopy at 9.4 T can provide precise biochemical information from distinct regions of the mouse brain noninvasively that can be used for monitoring of disease progression and treatment as well as phenotyping in transgenic mice models. 相似文献
10.
Martin Zeier Jolanta Perz Reinhold P Linke Ugo Donini Rüdiger Waldherr Konrad Andrassy Anthony D Ho Hartmut Goldschmidt 《Nephrology, dialysis, transplantation》2003,18(12):2644-2647
BACKGROUND: High-dose chemotherapy followed by autologous blood stem cell transplantation induces remission of plasma cell dyscrasia in patients with AL amyloidosis. The impact of this treatment on the glomerular amyloid mass is still unknown. METHODS: In the present study, the quantity of the renal amyloid mass before and more than 3 years after high-dose melphalan treatment and autologous blood stem cell transplantation was assessed in two patients. At the time of the second renal biopsy, both patients were in complete remission without detectable serum and urinary monoclonal IgA-lambda and a normal percentage of plasma cells in the bone marrow. RESULTS: In both patients with biopsy-proven AL amyloidosis, urinary protein excretion decreased from 7 g/24 h to <2 g/24 h more than 3 years after autologous blood stem cell transplantation. In contrast, glomerular amyloid deposits persisted, as shown in the second biopsy. CONCLUSION: Despite complete remission of the plasma cell dyscrasia and improvement of glomerular permeability, the amount of glomerular amyloid mass did not regress. 相似文献