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Clinical Mass Spectrometry (Del Mar,... Sep 2019Therapeutic drug monitoring (TDM) uses drug concentrations, primarily from plasma, to optimize drug dosing. Optimisation of drug dosing may improve treatment outcomes,... (Review)
Review
Therapeutic drug monitoring (TDM) uses drug concentrations, primarily from plasma, to optimize drug dosing. Optimisation of drug dosing may improve treatment outcomes, reduce toxicity and reduce the risk of acquired drug resistance. The aim of this narrative review is to outline and discuss the challenges of developing multi-analyte assays for anti-tuberculosis (TB) drugs using liquid chromatography-tandem mass spectrometry (LC-MS/MS) by reviewing the existing literature in the field. Compared to other analytical methods, LC-MS/MS offers higher sensitivity and selectivity while requiring relatively low sample volumes. Additionally, multi-analyte assays are easier to perform since adequate separation and short run times are possible even when non-selective sample preparation techniques are used. However, challenges still exist, especially when optimizing LC separation techniques for assays that include analytes with differing chemical properties. Here, we have identified seven multi-analyte assays for first-line anti-TB drugs that use various solvents for sample preparation and mobile phase separation. Only two multi-analyte assays for second-line anti-TB drugs were identified (including either nine or 20 analytes), with each using different protein precipitation methods, mobile phases and columns. The 20 analyte assay did not include bedaquiline, delamanid, meropenem or imipenem. For these drugs, other assays with similar methodologies were identified that could be incorporated in the development of a future comprehensive multi-analyte assay. TDM is a powerful methodology for monitoring patient's individual treatments in TB programmes, but its implementation will require different approaches depending on available resources. Since TB is most-prevalent in low- and middle-income countries where resources are scarce, a patient-centred approach using sampling methods other than large volume blood draws, such as dried blood spots or saliva collection, could facilitate its adoption and use. Regardless of the methodology of collection and analysis, it will be critical that laboratory proficiency programmes are in place to ensure adequate quality control. It is our intent that the information contained in this review will contribute to the process of assembling comprehensive multiplexed assays for the dynamic monitoring of anti-TB drug treatment in affected individuals.
PubMed: 34934812
DOI: 10.1016/j.clinms.2018.10.002 -
Diagnostics (Basel, Switzerland) Mar 2022Liquid biopsy is a promising technique for clinical management of oncological patients. The diversity of analytes circulating in the blood useable for liquid biopsy... (Review)
Review
Liquid biopsy is a promising technique for clinical management of oncological patients. The diversity of analytes circulating in the blood useable for liquid biopsy testing is enormous. Circulating tumor cells (CTCs), cell-free DNA (cfDNA) and extracellular vesicles (EVs), as well as blood cells and other soluble components in the plasma, were shown as liquid biopsy analytes. A few studies directly comparing two liquid biopsy analytes showed a benefit of one analyte over the other, while most authors concluded the benefit of the additional analyte. Only three years ago, the first studies to examine the value of a characterization of more than two liquid biopsy analytes from the same sample were conducted. We attempt to reflect on the recent development of multimodal liquid biopsy testing in this review. Although the analytes and clinical purposes of the published multimodal studies differed significantly, the additive value of the analytes was concluded in almost all projects. Thus, the blood components, as liquid biopsy reservoirs, are complementary rather than competitive, and orthogonal data sets were even shown to harbor synergistic effects. The unmistakable potential of multimodal liquid biopsy testing, however, is dampened by its clinical utility, which is yet to be proven, the lack of methodical standardization and insufficiently mature reimbursement, logistics and data handling.
PubMed: 35453918
DOI: 10.3390/diagnostics12040870 -
Proton-Gradient-Driven Sensitivity Enhancement of Liposome-Encapsulated Supramolecular Chemosensors.Angewandte Chemie (International Ed. in... Aug 2022An overarching challenge in the development of supramolecular sensor systems is to enhance their sensitivity, which commonly involves the synthesis of refined receptors...
An overarching challenge in the development of supramolecular sensor systems is to enhance their sensitivity, which commonly involves the synthesis of refined receptors with increased affinity to the analyte. We show that a dramatic sensitivity increase by 1-2 orders of magnitude can be achieved by encapsulating supramolecular chemosensors inside liposomes and exposing them to a pH gradient across the lipid bilayer membrane. This causes an imbalance of the influx and efflux rates of basic and acidic analytes leading to a significantly increased concentration of the analyte in the liposome interior. The utility of our liposome-enhanced sensors was demonstrated with various host-dye reporter pairs and sensing mechanisms, and we could easily increase the sensitivity towards multiple biologically relevant analytes, including the neurotransmitters serotonin and tryptamine.
Topics: Hydrogen-Ion Concentration; Liposomes; Protons
PubMed: 35687027
DOI: 10.1002/anie.202207950 -
Pharmaceutical Research Aug 2022The use of Disease progression models (DPMs) in Drug Development has been widely adopted across therapeutic areas as a method for integrating previously obtained disease... (Review)
Review
The use of Disease progression models (DPMs) in Drug Development has been widely adopted across therapeutic areas as a method for integrating previously obtained disease knowledge to elucidate the impact of novel therapeutics or vaccines on disease course, thus quantifying the potential clinical benefit at different stages of drug development programs. This paper provides a brief overview of DPMs and the evolution in data types, analytic methods, and applications that have occurred in their use by Quantitive Clinical Pharmacologists. It also provides examples of how these models have informed decisions and clinical trial design across several therapeutic areas and at various stages of development. It briefly describes potential new applications of DPMs utilizing emerging data sources, and utilizing new analytic techniques, and discuss new challenges faced such as requiring description of multiple endpoints, rapid model development, application of machine learning-based analytics, and use of high dimensional and real-world data. Considerations for the continued evolution future of DPMs to serve as community-maintained expert systems are also provided.
Topics: Clinical Trials as Topic; Disease Progression; Drug Development; Humans; Research Design
PubMed: 35411507
DOI: 10.1007/s11095-022-03257-3 -
Angewandte Chemie (International Ed. in... Sep 2021Electrochemical sensors are indispensable in clinical diagnosis, biochemical detection and environmental monitoring, thanks to their ability to detect analytes in...
Electrochemical sensors are indispensable in clinical diagnosis, biochemical detection and environmental monitoring, thanks to their ability to detect analytes in real-time with direct electronic readout. However, electrochemical sensors are challenged by sensitivity-the need to detect low concentrations, and selectivity-to detect specific analytes in multicomponent systems. Herein, a porphyrinic metal-organic framework (PP-MOF), Mn-PCN-222 is deposited on a conductive indium tin oxide (ITO) surface. It affords Mn-PCN-222/ITO, a versatile voltammetric sensor able to detect redox-active analytes such as inorganic ions, organic hazardous substances and pollutants, including nitroaromatics, phenolic and quinone-hydroquinone toxins, heavy metal ions, biological species, as well as azo dyes. As a working electrode, the high surface area of Mn-PCN-222/ITO enables high currents, and therefore leverages highly sensitive analysis. The metalloporphyrin centre facilitates analyte-specific redox catalysis to simultaneously detect more than one analyte in binary and ternary systems allowing for detection of a wide array of trace pollutants under real-world conditions, most with high sensitivity.
Topics: Biosensing Techniques; Electrochemical Techniques; Environmental Pollutants; Manganese; Metal-Organic Frameworks; Particle Size; Porphyrins; Surface Properties; Trace Elements
PubMed: 34260128
DOI: 10.1002/anie.202107860 -
Analytical Chemistry Aug 2022Large datasets of chromatographic retention times are relatively easy to collect. This statement is particularly true when mixtures of compounds are analyzed under a...
Large datasets of chromatographic retention times are relatively easy to collect. This statement is particularly true when mixtures of compounds are analyzed under a series of gradient conditions using chromatographic techniques coupled with mass spectrometry detection. Such datasets carry much information about chromatographic retention that, if extracted, can provide useful predictive information. In this work, we proposed a mechanistic model that jointly explains the relationship between pH, organic modifier type, temperature, gradient duration, and analyte retention based on liquid chromatography retention data collected for 187 small molecules. The model was built utilizing a Bayesian multilevel framework. The model assumes (i) a deterministic Neue equation that describes the relationship between retention time and analyte-specific and instrument-specific parameters, (ii) the relationship between analyte-specific descriptors (log , p, and functional groups) and analyte-specific chromatographic parameters, and (iii) stochastic components of between-analyte and residual variability. The model utilizes prior knowledge about model parameters to regularize predictions which is important as there is ample information about the retention behavior of analytes in various stationary phases in the literature. The usefulness of the proposed model in providing interpretable summaries of complex data and in decision making is discussed.
Topics: Bayes Theorem; Chromatography, High Pressure Liquid; Chromatography, Liquid; Mass Spectrometry
PubMed: 35903961
DOI: 10.1021/acs.analchem.2c02034 -
Sensors (Basel, Switzerland) Apr 2021This perspective presents an overview of approaches to the preparation of molecular recognition agents for chemical sensing. These approaches include chemical synthesis,...
This perspective presents an overview of approaches to the preparation of molecular recognition agents for chemical sensing. These approaches include chemical synthesis, using catalysts from biological systems, partitioning, aptamers, antibodies and molecularly imprinted polymers. The latter three approaches are general in that they can be applied with a large number of analytes, both proteins and smaller molecules like drugs and hormones. Aptamers and antibodies bind analytes rapidly while molecularly imprinted polymers bind much more slowly. Most molecularly imprinted polymers, formed by polymerizing in the presence of a template, contain a high level of covalent crosslinker that causes the polymer to form a separate phase. This results in a material that is rigid with low affinity for analyte and slow binding kinetics. Our approach to templating is to use predominantly or exclusively noncovalent crosslinks. This results in soluble templated polymers that bind analyte rapidly with high affinity. The biggest challenge of this approach is that the chains are tangled when the templated polymer is dissolved in water, blocking access to binding sites.
Topics: Binding Sites; Catalysis; Molecular Imprinting; Polymers; Proteins
PubMed: 33919700
DOI: 10.3390/s21082757 -
Molecules (Basel, Switzerland) May 2021Ternary quantum dots (QDs) are novel nanomaterials that can be used in chemical analysis due their unique physicochemical and spectroscopic properties. These properties... (Review)
Review
Ternary quantum dots (QDs) are novel nanomaterials that can be used in chemical analysis due their unique physicochemical and spectroscopic properties. These properties are size-dependent and can be adjusted in the synthetic protocol modifying the reaction medium, time, source of heat, and the ligand used for stabilization. In the last decade, several spectroscopic methods have been developed for the analysis of organic and inorganic analytes in biological, drug, environmental, and food samples, in which different sensing schemes have been applied using ternary quantum dots. This review addresses the different synthetic approaches of ternary quantum dots, the sensing mechanisms involved in the analyte detection, and the predominant areas in which these nanomaterials are used.
PubMed: 34066652
DOI: 10.3390/molecules26092764 -
Frontiers in Bioengineering and... 2023The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR associated) system has proven to be a powerful tool for nucleic acid detection due to... (Review)
Review
The CRISPR (clustered regularly interspaced short palindromic repeats)/Cas (CRISPR associated) system has proven to be a powerful tool for nucleic acid detection due to its inherent advantages of effective nucleic acid identification and editing capabilities, and is therefore known as the next-generation of molecular diagnostic technology. However, the detection technologies based on CRISPR/Cas systems require preamplification of target analytes; that is, target gene amplification steps through isothermal amplification or PCR before detection to increase target analyte concentrations. This creates a number of testing limitations, such as extended testing time and the need for more sophisticated testing instruments. To overcome the above limitations, various amplification-free assay strategies based on CRISPR/Cas systems have been explored as alternatives, which omit the preamplification step to increase the concentrations of the target analytes. Nanozymes play a pivotal role in enhancing the sensitivity of CRISPR-based detection, enabling visual and rapid CRISPR assays. The utilization of nanozyme exceptional enzyme-like catalytic activity holds great promise for signal amplification in both electrochemical and optical domains, encompassing strategies for electrochemical signal sensors and colorimetric signal sensors. Rather than relying on converting a single detection target analyte into multiple analytes, these methods focus on signal amplification, the main mechanism of which involves the ability to form a large number of reporter molecules or to improve the performance of the sensor. This exploitation of nanozymes for signal amplification results in the heightened sensitivity and accuracy of detection outcomes. In addition to the strategies that improve sensor performance through the application of nanozymes, additional methods are needed to achieve visual signal amplification strategies without preamplification processes. Herein, we review the strategies for improving CRISPR/Cas systems that do not require preamplification, providing a simple, intuitive and preamplification-free CRISPR/Cas system detection platform by improving in-system one-step amplification programs, or enhancing nanozyme-mediated signal amplification strategies.
PubMed: 38249803
DOI: 10.3389/fbioe.2023.1327498 -
Sensors (Basel, Switzerland) Oct 2022Sweat analysis offers non-invasive real-time on-body measurement for wearable sensors. However, there are still gaps in current developed sweat-sensing devices (SSDs)... (Review)
Review
Sweat analysis offers non-invasive real-time on-body measurement for wearable sensors. However, there are still gaps in current developed sweat-sensing devices (SSDs) regarding the concerns of mixing fresh and old sweat and real-time measurement, which are the requirements to ensure accurate the measurement of wearable devices. This review paper discusses these limitations by aiding model designs, features, performance, and the device operation for exploring the SSDs used in different sweat collection tools, focusing on continuous and non-continuous flow sweat analysis. In addition, the paper also comprehensively presents various sweat biomarkers that have been explored by earlier works in order to broaden the use of non-invasive sweat samples in healthcare and related applications. This work also discusses the target analyte's response mechanism for different sweat compositions, categories of sweat collection devices, and recent advances in SSDs regarding optimal design, functionality, and performance.
Topics: Biomarkers; Biosensing Techniques; Monitoring, Physiologic; Sweat; Wearable Electronic Devices
PubMed: 36236769
DOI: 10.3390/s22197670