| 1. |
- Aziz, Mohd Yusmaidie, 1984, et al.
(författare)
-
Inhibition of CYP3A by Antimalarial Piperaquine and Its Metabolites in Human Liver Microsomes With IVIV Extrapolation
- 2018
-
Ingår i: Journal of Pharmaceutical Sciences. - : Elsevier BV. - 0022-3549. ; 107:5, s. 1461-1467
-
Tidskriftsartikel (refereegranskat)abstract
- The potential of the antimalarial piperaquine and its metabolites to inhibit CYP3A was investigated in pooled human liver microsomes. CYP3A activity was measured by liquid chromatography-tandem mass spectrometry as the rate of 1'-hydroxymidazolam formation. Piperaquine was found to be a reversible, potent inhibitor of CYP3A with the following parameter estimates (%CV): IC50 = 0.76 mu M(29), K-i = 0.68 mu M (29). In addition, piperaquine acted as a time-dependent inhibitor with IC50 declining to 0.32 mu M (28) during 30-min pre-incubation. Time-dependent inhibitor estimates were k(inact) = 0.024 min(-1) (30) and K-I = 1.63 mu M(17). Metabolite M2 was a highly potent reversible inhibitor with estimated IC50 and K-i values of 0.057 mu M (17) and 0.043 mu M (3), respectively. M1 and M5 metabolites did not show any inhibitory properties within the limits of assay used. Average (95th percentile) simulated in vivo areas under the curve of midazolam increased 2.2-fold (3.7-fold) on the third which is the last day of piperaquine dosing, whereas for its metabolite M2, areas under the curve of midazolam increased 7.7-fold (13-fold). (C) 2018 American Pharmacists Association (R). Published by Elsevier Inc. All rights reserved.
|
|
| 2. |
- Aziz, Mohd Yusmaidie, 1984, et al.
(författare)
-
LC-MS/MS quantitation of antimalarial drug piperaquine and metabolites in human plasma
- 2017
-
Ingår i: Journal of chromatography. B. - : Elsevier BV. - 1570-0232. ; 1063, s. 253-258
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: This study aimed to develop a sensitive, quantitative assay for the antimalarial piperaquine (PQ) and its metabolites M1 and M2 in human plasma. Results: Analytes were gradiently separated on a C18 column and detected with a Sciex API 4000 MS/MS with an ESI source operated in the positive ion mode with deuterated PQ as internal standard. The response was linear in the range 3.9-2508 nM with a runtime of 7.0 min per sample. The method was applied to clinical samples from healthy volunteers. Conclusion: This LC-MS/MS method for the simultaneous quantitation of PQ and two of its metabolites in plasma may prove helpful for assessment of metabolite safety issues in vivo.
|
|
| 3. |
- Fronzek, Stefan, et al.
(författare)
-
Classifying multi-model wheat yield impact response surfaces showing sensitivity to temperature and precipitation change
- 2018
-
Ingår i: Agricultural Systems. - : Elsevier BV. - 0308-521X. ; 159, s. 209-224
-
Tidskriftsartikel (refereegranskat)abstract
- Crop growth simulation models can differ greatly in their treatment of key processes and hence in their response to environmental conditions. Here, we used an ensemble of 26 process-based wheat models applied at sites across a European transect to compare their sensitivity to changes in temperature (-2 to +9°C) and precipitation (-50 to +50%). Model results were analysed by plotting them as impact response surfaces (IRSs), classifying the IRS patterns of individual model simulations, describing these classes and analysing factors that may explain the major differences in model responses.The model ensemble was used to simulate yields of winter and spring wheat at four sites in Finland, Germany and Spain. Results were plotted as IRSs that show changes in yields relative to the baseline with respect to temperature and precipitation. IRSs of 30-year means and selected extreme years were classified using two approaches describing their pattern.The expert diagnostic approach (EDA) combines two aspects of IRS patterns: location of the maximum yield (nine classes) and strength of the yield response with respect to climate (four classes), resulting in a total of 36 combined classes defined using criteria pre-specified by experts. The statistical diagnostic approach (SDA) groups IRSs by comparing their pattern and magnitude, without attempting to interpret these features. It applies a hierarchical clustering method, grouping response patterns using a distance metric that combines the spatial correlation and Euclidian distance between IRS pairs. The two approaches were used to investigate whether different patterns of yield response could be related to different properties of the crop models, specifically their genealogy, calibration and process description.Although no single model property across a large model ensemble was found to explain the integrated yield response to temperature and precipitation perturbations, the application of the EDA and SDA approaches revealed their capability to distinguish: (i) stronger yield responses to precipitation for winter wheat than spring wheat; (ii) differing strengths of response to climate changes for years with anomalous weather conditions compared to period-average conditions; (iii) the influence of site conditions on yield patterns; (iv) similarities in IRS patterns among models with related genealogy; (v) similarities in IRS patterns for models with simpler process descriptions of root growth and water uptake compared to those with more complex descriptions; and (vi) a closer correspondence of IRS patterns in models using partitioning schemes to represent yield formation than in those using a harvest index.Such results can inform future crop modelling studies that seek to exploit the diversity of multi-model ensembles, by distinguishing ensemble members that span a wide range of responses as well as those that display implausible behaviour or strong mutual similarities.
|
|
| 4. |
- Petrovic, Dusan, et al.
(författare)
-
Shuffling Active Site Substate Populations Affects Catalytic Activity : The Case of Glucose Oxidase
- 2017
-
Ingår i: ACS Catalysis. - : AMER CHEMICAL SOC. - 2155-5435. ; 7:9, s. 6188-6197
-
Tidskriftsartikel (refereegranskat)abstract
- Glucose oxidase has wide applications in the pharmaceutical, chemical, and food industries. Many recent studies have enhanced key properties of this enzyme using directed evolution, yet without being able to reveal why these mutations are actually beneficial. This work presents a synergistic combination of experimental and computational methods, indicating how mutations, even when distant from the active site, positively affect glucose oxidase catalysis. We have determined the crystal structures of glucose oxidase mutants containing molecular oxygen in the active site. The catalytically important His516 residue has been previously shown to be flexible in the wild-type enzyme. The molecular dynamics simulations performed in this work allow us to quantify this floppiness, revealing that His516 exists in two states: catalytic and noncatalytic. The relative populations of these two substates are almost identical in the wild-type enzyme, with His516 readily shuffling between them. In the glucose oxidase mutants, on the other hand, the mutations enrich the catalytic His516 conformation and reduce the flexibility of this residue, leading to an enhancement in their catalytic efficiency. This study stresses the benefit of active site preorganization with respect to enzyme conversion rates by reducing molecular reorientation needs. We further suggest that the computational approach based on Hamiltonian replica exchange molecular dynamics, used in this study, may be a general approach to screening in silico for improved enzyme variants involving flexible catalytic residues.
|
|
| 5. |
- Rodríguez, A., et al.
(författare)
-
Implications of crop model ensemble size and composition for estimates of adaptation effects and agreement of recommendations
- 2019
-
Ingår i: Agricultural and Forest Meteorology. - : Elsevier BV. - 0168-1923 .- 1873-2240. ; 264, s. 351-362
-
Tidskriftsartikel (refereegranskat)abstract
- Climate change is expected to severely affect cropping systems and food production in many parts of the world unless local adaptation can ameliorate these impacts. Ensembles of crop simulation models can be useful tools for assessing if proposed adaptation options are capable of achieving target yields, whilst also quantifying the share of uncertainty in the simulated crop impact resulting from the crop models themselves. Although some studies have analysed the influence of ensemble size on model outcomes, the effect of ensemble composition has not yet been properly appraised. Moreover, results and derived recommendations typically rely on averaged ensemble simulation results without accounting sufficiently for the spread of model outcomes. Therefore, we developed an Ensemble Outcome Agreement (EOA) index, which analyses the effect of changes in composition and size of a multi-model ensemble (MME) to evaluate the level of agreement between MME outcomes with respect to a given hypothesis (e.g. that adaptation measures result in positive crop responses). We analysed the recommendations of a previous study performed with an ensemble of 17 crop models and testing 54 adaptation options for rainfed winter wheat (Triticum aestivum L.) at Lleida (NE Spain) under perturbed conditions of temperature, precipitation and atmospheric CO2 concentration. Our results confirmed that most adaptations recommended in the previous study have a positive effect. However, we also showed that some options did not remain recommendable in specific conditions if different ensembles were considered. Using EOA, we were able to identify the adaptation options for which there is high confidence in their effectiveness at enhancing yields, even under severe climate perturbations. These include substituting spring wheat for winter wheat combined with earlier sowing dates and standard or longer duration cultivars, or introducing supplementary irrigation, the latter increasing EOA values in all cases. There is low confidence in recovering yields to baseline levels, although this target could be attained for some adaptation options under moderate climate perturbations. Recommendations derived from such robust results may provide crucial information for stakeholders seeking to implement adaptation measures.
|
|
| 6. |
- Sundell, Jesper, et al.
(författare)
-
Simultaneous quantification of four first line antitubercular drugs and metabolites in human plasma by hydrophilic interaction chromatography and tandem mass spectrometry
- 2019
-
Ingår i: Journal of Chromatography B: Analytical Technologies in the Biomedical and Life Sciences. - : Elsevier BV. - 1570-0232. ; 1105, s. 129-135
-
Tidskriftsartikel (refereegranskat)abstract
- Co-infection of tuberculosis in HIV-patients is a major health concern worldwide and especially so in Sub-Saharan Africa. To enhance the study of potential drug-drug interactions when simultaneously treating the two infections, a liquid chromatography tandem mass spectrometry method was developed for the quantitation of the four first line anti-tuberculosis drugs isoniazid, rifampicin, pyrazinamide, ethambutol and four of their major metabolites in human plasma. Analytes were extracted from 200 μL of plasma using a sequential liquid-liquid extraction with ethyl acetate at neutral and acidic pH. The combined extracts were analyzed by liquid chromatography with mass spectrometric detection in a multiple reaction monitoring mode. The chromatographic separation was performed on a hydrophilic interaction column using a stepwise gradient with two mobile phases consisting of water with 0.3% formic acid and methanol with 0.3% formic acid, respectively. The total run time of each analysis was 4 min. The lower limit of quantification applied was 40 ng/mL for ethambutol, acetylisoniazid and 25-desacetylrifampicin, 60 ng/mL for 5-hydroxypyrazinamide, 80 ng/mL for isoniazid and isonicotinic acid, 200 ng/mL for rifampicin and 320 ng/mL for pyrazinamide. The method was validated according to US Food and Drug Administration guidance. The method exhibited adequate accuracy (87.1–114.9%), precision (CV < 12.8%) and specificity. Recovery and matrix effect were consistent (CV < 11.9%). The extracted samples were stable in the autosampler at 8 °C for up to 24 h as well as after three freeze-thaw cycles (recovery > 86.3%). The method has been shown to be robust for the analysis of the stated drugs and metabolites in human plasma obtained from 73 patients receiving these four first line anti-tuberculosis drugs. © 2018 Elsevier B.V.
|
|
| 7. |
- Varmuza, Kurt, et al.
(författare)
-
Significance of variables for discrimination : Applied to the search of organic ions in mass spectra measured on cometary particles
- 2018
-
Ingår i: Journal of Chemometrics. - : Wiley. - 0886-9383 .- 1099-128X. ; 32:4
-
Tidskriftsartikel (refereegranskat)abstract
- The instrument Cometary Secondary Ion Mass Analyzer (COSIMA) on board of the European Space Agency mission Rosetta to the comet 67P/Churyumov-Gerasimenko is a secondary ion mass spectrometer with a time-of-flight mass analyzer. It collected near the comet several thousand particles, imaged them, and analyzed the elemental and chemical compositions of their surfaces. In this study, variables have been generated from the spectral data covering the mass ranges of potential C-, H-, N-, and O-containing ions. The variable importance in binary discriminations between spectra measured on cometary particles and those measured on the target background has been estimated by the univariate t test and the multivariate methods discriminant partial least squares, random forest, and a robust method based on the log ratios of all variable pairs. The results confirm the presence of organic substances in cometary matter-probably a complex macromolecular mixture.
|
|
| 8. |
- Aad, G, et al.
(författare)
-
- 2015
-
swepub:Mat__t
|
|
