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Bundling arrows: improving translational CNS drug development by integrated PK/PD-metabolomics

Diseases of the Central Nervous System (CNS) affect millions of people worldwide, with the number of people affected quickly growing. Unfortunately, the successful development of CNS-acting drugs is less than 10%, and this is attributed to the complexity of the CNS, unexpected side effects, difficulties in penetrating the blood-brain barrier and lack of biomarkers. Areas covered: Herein, the authors first review how pharmacokinetic/pharmacodynamic (PK/PD) models are designed to predict the dose-dependent time course of effect, and how they are used to translate drug effects from animal to man. Then, the authors discuss how pharmacometabolomics gives insight into system-wide pharmacological effects and why it is a promising method to study interspecies differences. Finally, the authors advocate the application of PK/PD-metabolomics modeling to advance translational CNS drug development by discussing its opportunities and challenges. Expert opinion: It is envisioned that PK/PD-metabolomics will increase our understanding of CNS drug effects and improve translational CNS drug development, thereby increasing success rates. The successful future development of this concept will require multi-level and longitudinal biomarker evaluation over a large dose range, multi-tissue biomarker evaluation, and the generation of a proof of principle by application to multiple CNS drugs in multiple species. INTRODUCTIONArticle / Letter to editorLeiden Academic Centre for Drug Researc

Immobilized-Enzyme Reactors Integrated into Analytical Platforms: Recent Advances and Challenges

Immobilized-enzyme reactors (IMERs) are flow-through devices containing enzymes that are physically confined or localized with retention of their catalytic activities. IMERs can be used repeatedly and continuously and have been applied for (bio)polymer degradation, proteomics, biomarker discovery, inhibitor screening, and detection. Online integration of IMERs with analytical instrumentation, such as high-performance liquid chromatography (HPLC) systems, reduces the time needed for multi-step workflows, reduces the need for sample handling, and enables automation. However, online integration can also be challenging, as reaching its full potential requires complex instrumental setups and experienced users. This review aims to provide an assessment of recent advances and challenges in online IMER-based (analytical) LC platforms, covering publications from 2014-2021. A critical discussion of challenges often encountered in IMER fabrication, sample preparation, integration into the analytical workflow, long-term usage, and of potential ways to overcome these is provided. Finally, the obstacles preventing the proliferation of IMERs as efficient tools for high-throughput pharmacological, industrial, and biological studies are discussed

Next-generation capillary electrophoresis-mass spectrometry approaches in metabolomics

Capillary electrophoresis-mass spectrometry has shown considerable potential for profiling polar ionogenic compounds in metabolomics. Hyphenation of capillary electrophoresis to mass spectrometry is generally performed via a sheath-liquid interface. However, the electrophoretic effluent is significantly diluted in this configuration thereby limiting the utility of this method for highly sensitive metabolomics studies. Moreover, in this set-up the intrinsically low-flow property of capillary electrophoresis is not effectively utilized in combination with electrospray ionization. Here, advancements that significantly improved the performance of capillary electrophoresis-mass spectrometry are considered, with a special emphasis on the sheathless porous tip interface. Attention is also devoted to various technical aspects that still need to be addressed to make capillary electrophoresis-mass spectrometry a robust approach for probing the polar metabolome.Analytical BioScience

Electroextraction and electromembrane extraction: Advances in hyphenation to analytical techniques.

Electroextraction (EE) and electromembrane extraction (EME) are sample preparation techniques that both require an electric field that is applied over a liquid-liquid system, which enables the migration of charged analytes. Furthermore, both techniques are often used to pre-concentrate analytes prior to analysis. In this review an overview is provided of the body of literature spanning April 2012-November 2015 concerning EE and EME, focused on hyphenation to analytical techniques. First, the theoretical aspects of concentration enhancement in EE and EME are discussed to explain extraction recovery and enrichment factor. Next, overviews are provided of the techniques based on their hyphenation to LC, GC, CE, and direct detection. These overviews cover the compounds and matrices, experimental aspects (i.e. donor volume, acceptor volume, extraction time, extraction voltage, and separation time) and the analytical aspects (i.e. limit of detection, enrichment factor, and extraction recovery). Techniques that were either hyphenated online to analytical techniques or show high potential with respect to online hyphenation are highlighted. Finally, the potential future directions of EE and EME are discussed.Analytical BioScience