Search results for " Preclinical"
showing 10 items of 159 documents
Simultaneous screening and quantification of aminoglycoside antibiotics in honey using mixed-mode liquid chromatography with quadrupole time-of-fligh…
2018
An analytical method based on liquid chromatography with quadrupole time-of-flight mass spectrometry has been developed for the simultaneous determination of six aminoglycoside antibiotics in honey. The sample pretreatment included extraction with aqueous trichloroacetic acid followed by solid-phase extraction on Strata-X polymeric reversed phase cartridges. Liquid chromatography separation was performed on an Obelisc R zwitterionic type mixed-mode column. An ionBooster™ heated electrospray source was used and showed enhanced ionization efficiency in comparison to a conventional electrospray source. The observed signal enhancement ranged from 3- (neomycin) to 16-fold (gentamicin C1). A data…
A new mathematical approach for the estimation of the AUC and its variability under different experimental designs in preclinical studies
2011
The aim of the present work was to develop a new mathematical method for estimating the area under the curve (AUC) and its variability that could be applied in different preclinical experimental designs and amenable to be implemented in standard calculation worksheets. In order to assess the usefulness of the new approach, different experimental scenarios were studied and the results were compared with those obtained with commonly used software: WinNonlin® and Phoenix WinNonlin®. The results do not show statistical differences among the AUC values obtained by both procedures, but the new method appears to be a better estimator of the AUC standard error, measured as the coverage of 95% confi…
Multicellular tumor spheroids: an underestimated tool is catching up again.
2009
The present article highlights the rationale, potential and flexibility of tumor spheroid mono- and cocultures for implementation into state of the art anti-cancer therapy test platforms. Unlike classical monolayer-based models, spheroids strikingly mirror the 3D cellular context and therapeutically relevant pathophysiological gradients of in vivo tumors. Some concepts for standardization and automation of spheroid culturing, monitoring and analysis are discussed, and the challenges to define the most convenient analytical endpoints for therapy testing are outlined. The potential of spheroids to contribute to either the elimination of poor drug candidates at the pre-animal and pre-clinical …
Structure-based engineering of strictosidine synthase: auxiliary for alkaloid libraries.
2007
SummaryThe highly substrate-specific strictosidine synthase (EC 4.3.3.2) catalyzes the biological Pictet-Spengler condensation between tryptamine and secologanin, leading to the synthesis of about 2000 monoterpenoid indole alkaloids in higher plants. The crystal structure of Rauvolfia serpentina strictosidine synthase (STR1) in complex with strictosidine has been elucidated here, allowing the rational site-directed mutation of the active center of STR1 and resulting in modulation of its substrate acceptance. Here, we report on the rational redesign of STR1 by generation of a Val208Ala mutant, further describing the influence on substrate acceptance and the enzyme-catalyzed synthesis of 10-m…
Instruction of haematopoietic lineage choices, evolution of transcriptional landscapes and cancer stem cell hierarchies derived from an AML1-ETO mous…
2013
The t(8;21) chromosomal translocation activates aberrant expression of the AML1-ETO (AE) fusion protein and is commonly associated with core binding factor acute myeloid leukaemia (CBF AML). Combining a conditional mouse model that closely resembles the slow evolution and the mosaic AE expression pattern of human t(8;21) CBF AML with global transcriptome sequencing, we find that disease progression was characterized by two principal pathogenic mechanisms. Initially, AE expression modified the lineage potential of haematopoietic stem cells (HSCs), resulting in the selective expansion of the myeloid compartment at the expense of normal erythro- and lymphopoiesis. This lineage skewing was foll…
Application of Imprinted Synthetic Polymers in Binding Assay Development
2000
The first part of the review describes a method for the synthesis of molecularly imprinted polymers for use in binding assays. The method considers the many factors involved that affect the recognition properties of the materials and describes an approach to screening and optimization of these factors. The second part describes the development of binding assays using such polymers. This includes the use of different labels, the effect of solvent and buffer, the scale of the assay (amount of solid polymer), and how these influence the quality of the assay in terms of sensitivity, selectivity, and speed of analysis.
Luminometric sub-nanoliter droplet-to-droplet array (LUMDA) and its application to drug screening by phase I metabolism enzymes.
2012
Here we show the fabrication of the Luminometric Sub-nanoliter Droplet-to-droplet Array (LUMDA chip) by inkjet printing. The chip is easy to be implemented and allows for a multiplexed multi-step biochemical assay in sub-nanoliter liquid spots. This concept is here applied to the integral membrane enzyme CYP3A4, i.e. the most relevant enzymatic target for phase I drug metabolism, and to some structurally-related inhibitors.
Topical anti-inflammatory potential of quercetin in lipid-based nanosystems: In vivo and in vitro evaluation
2013
Purpose: To develop quercetin-loaded phospholipid vesicles, namely liposomes and PEVs (Penetration Enhancer-containing Vesicles), and to investigate their efficacy on TPA-induced skin inflammation. Methods: Vesicles were made from a mixture of phospholipids, quercetin and polyethylene glycol 400 (PEG), specifically added to increase drug solubility and penetration through the skin. Vesicle morphology and self-assembly were probed by Cryo-Transmission Electron Microscopy and Small/Wide Angle X-ray Scattering, as well as the main physico-chemical features by Light Scattering. The anti-inflammatory efficacy of quercetin nanovesicles was assessed in vivo on TPA-treated mice dorsal skin by the d…
Impact of
2018
Drosophila melanogaster has been for over a century the model of choice of several neurobiologists to decipher the formation and development of the nervous system as well as to mirror the pathophysiological conditions of many human neurodegenerative diseases. The rare disease Friedreich’s ataxia (FRDA) is not an exception. Since the isolation of the responsible gene more than two decades ago, the analysis of the fly orthologue has proven to be an excellent avenue to understand the development and progression of the disease, to unravel pivotal mechanisms underpinning the pathology and to identify genes and molecules that might well be either disease biomarkers or promising targets for therap…