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Mass spectrometry - Articles and news items
Practical considerations in analysing biologically active peptides by Electrospray Ionisation (ESI) Mass Spectrometry
Neuromodulators such as calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) act as biomarkers for pain assessment (pre-clinical). These markers can be detected at low concentrations by Electrospray Ionisation (ESI) Mass Spectrometry (MS). Currently, little is known about the factors affecting responsiveness in the ESI process though the response of peptide ions depends heavily on analyte basicity in solution, pKb, sampling and instrumental conditions. Other factors may be equally important, however, not enough is known about the link between peptide characteristics and selectivity in the ESI process. Here, we review our findings on these links to improve the analyte signal and allow robust quantitation of these important peptide biomarkers.
Corticosteroids and mass spectrometry; latest applications using LC/MS3.
Multi-analyte LC-MS/MS assays for the quantification of endogenous compounds during the development of drugs and companion diagnostics.
The average cost to a major pharmaceutical company of developing a new drug is over USD 6 billion1. Herper1 observes that the pharmaceutical industry is gripped by rising failure rates and costs, and suggests that the cost of new drugs will be reduced by new technologies and deeper understanding of biology. While the objectives of drug discovery don’t change, the methods and techniques by which pharmaceutical companies, biotechs and academia discover new drugs are evolving at a significant pace – and they need to.
Drug discovery scientists are all aiming to identify compounds and candidate drugs with ‘good’ properties that are safe and efficacious, as quickly and cheaply as possible. The standard approach of the last 20 years has been to identify a single molecule disease target, and then to identify a compound that interacts with and modulates this target with high specificity. However, there is now a growing realisation that this ‘one target – one drug’ approach doesn’t work well, and that screening huge libraries of compounds against one particular property of an isolated target is an inefficient way to discover potential drugs. Much of the innovation currently seen in drug discovery methodologies seeks to access and integrate more information – about targets, compounds, and disease phenotypes – to enable a more comprehensive and holistic approach to discovering ‘good’ drug candidates. This article does not try to crystal ball-gaze deep into the future, but rather to identify those trends in the adoption of new technologies and approaches that are gaining traction now, and that can be expected to become more prevalent in the next two to three years.
MS-based methods for detection, quantitation and localisation of pharmaceuticals and metabolites in biological samples
Chromatography, Issue 6 2012 / 18 December 2012 / Tyler Greer, Department of Chemistry, University of Wisconsin-Madison and Lingjun Li, Department of Chemistry & School of Pharmacy, University of Wisconsin-Madison
Mass spectrometry is a powerful, multi-faceted technique capable of analysing pharmaceuticals and their metabolites in biological matrices. Although it is more commonly applied to proteins, peptides and lipids, an increasing number of studies use mass spectrometry based techniques to detect, quantitate and localise pharmaceuticals and their metabolites. The availability of functionally unique ionisation methods and preparative separation options coupled with the specificity and sensitivity of a mass analyser make mass spectrometry an attractive option in pharmaceutical studies involving biofluids and tissue. This review aims to provide a general description of the primary mass spectrometric and preparative steps used to analyse pharmaceuticals in biological systems.
A leading concern in drug discovery is the potential reactivity of metabolites, which can be biologically transformed from stable pharma – ceutical products. Drug metabolites are often considered to be potentially toxic because of their ability to covalently modify proteins and DNA. For this reason, pharmaceutical developers create methods to assess the propensity of new drugs to degrade into reactive metabolites and gauge the effects these metabolites have1. Another area of study, pharmaceutical meta – bolomics, typically compares the endogenous metabolites of control specimens with drugadministered specimens2. Mass spectrometry has emerged as a useful tool in these two areas because of its throughput, sensitivity and ability to identify multiple molecules in biological media.
Chromatography, Issue 2 2012, Supplements / 25 April 2012 / Ana Rita Angelino, Min Yang, Tasso Miliotis, Constanze Hilgendorf, Anthony Bristow, George McLeod, Detlev Hochmuth, Alessandro Baldi, Gary Harland
Mass spectrometry in drug discovery – Proteomics, small molecules and metablomics.
Quantification of membrane drug transporters and application in drug discovery and development.
Mass spectrometry leaders roundtable.
Liquid Chromatography Mass Spectrometry (LCMS) is a powerful technique that has recently undergone exponential growth in its application to pharmaceutical synthesis. This perspective will outline the general principles of LCMS, detail some recent approaches and the benefits to be derived from its use at an early stage of process development.
Identification of the components in a mixture is the primary function of analytical chemistry and there are a range of techniques available. When the solution to this problem requires some structural identity, LCMS is the instrument of choice.
Liquid Chromatography Mass Spectrometry is defined as the use of the separating properties of liquid chromatography combined with a detector capable of mass analysis (mass spectrometer: single quadrupole, triple quadrupole, ion trap, Time Of Flight, Q-TOF etc.). This combination may be configured in many ways, for a general scheme.
Since its introduction in the field of biomedical imaging over 10 years ago1, matrixassisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) has played an ever increasing role in drug discovery and development and is now utilised in laboratories of many leading pharmaceutical companies and collaborating academic institutions.
The need for mass spectrometry imaging in drug discovery is founded on the shortcomings of current technologies. Traditional methods of spatially mapping the distribution of compounds in tissue involved a combination approach of autoradiography (WBA) with metabolite information obtained from LC/MS analysis of tissue homogenate2. Autoradio – graphy methods only monitor the radiolabel and therefore are not able to distinguish the parent drug from its metabolites. The addition of LC/MS allows for conclusive determination of metabolites. However, this only produces spatial information at the whole organ level and not the spatial detail that can be routinely achieved using MSI.
This is the fourth in a series of articles on rapid microbiological methods that will appear in European Pharmaceutical Review during 2011. Previously, we discussed a number of cellular-component rapid microbiological methods (RMMs), such as ATP bioluminescence, fatty acid analysis, MALDI and SELDI time of flight mass spectrometry, Fourier transform-infrared (FT-IR) spectrometry and technologies that rapidly detect the presence of endotoxins. In the current article, we will review a relatively new set of rapid methods that are based on optical spectroscopy. These technologies are quite exciting, as they do not rely on microbial growth for a response and the time to result can be instantaneous.
Optical spectroscopy is an analytical tool that measures the interactions between light and the material being studied. Light scattering is a phenomenon in which the propagation of light is disturbed by its interaction with particles. There are a number of light scattering principles that may be utilised in rapid method technologies; therefore, it is appropriate to quickly review some of these principles in order to understand the scientific basis for the RMMs that will be discussed later in this article.
Evolution and revolution in time-of-flight mass spectrometry and its impact on research within the pharmaceutical industry
Time of flight mass spectrometry (TOF-MS) has been an attractive choice of instrument for many years due to its potentially unlimited m/z range, high-speed acquisition, accurate mass measurement capability and sensitivity. Originally commercialised in the late 1950’s by the Bendix Corporation1, several physical and technical issues of the early TOF instruments limited both mass resolving power and mass accuracy2. From the early 1970’s to the early 1990’s, these limitations were overcome. Initially the advent of reflectron TOF-MS overcame the ion energy spread, hence increasing mass resolution3. The later combination with orthogonal acceleration (oa) can be seen as the catalyst for the vast range of TOF instrumentation that is available today, with greatly improved mass resolving power and mass accuracy4,5.
Chromatography, Issue 5 2010 / 29 October 2010 / Brian Flatley Dept of Chemistry, University of Reading, Reading and Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Peter Malone Harold Hopkins Dept of Urology, Royal Berkshire NHS Foundation Trust Hospital, Reading and Rainer Cramer Dept of Chemistry, University of Reading, Reading
Each year, approximately 10,000 men in the UK die as a result of prostate cancer (PCa) making it the third most common cancer behind lung and breast cancer. Worldwide, more than 670,000 men are diagnosed every year with the disease1. Current methods of diagnosis of PCa mainly rely on the detection of elevated prostate-specific antigen (PSA) levels in serum and/or physical examination by a doctor for the detection of an abnormal prostate. PSA is a glycoprotein produced almost exclusively by the epithelial cells of the prostate gland2. Its role is not fully understood, although it is known that it forms part of the ejaculate and its function is to solubilise the sperm to give them the mobility to swim. Raised PSA levels in serum are thought to be due to both an increased production of PSA from the proliferated prostate cells, and a diminished architecture of affected cells, allowing an easier distribution of PSA into the wider circulatory system.
Recent years have seen great upward leaps in the development of mass spectrometry applied to the field of proteomics. Today it is possible to take a complex biological sample such as organelles, cells, tissue or a biofluid, perturbed or stimulated in some way, and identify and quantitate up to several thousand proteins and determine the level of relative change caused by the perturbation or stimulus. The current challenge is not to identify or quantitate proteins in a limited set of samples, but to profile large series (clinical samples, time-course, sub-cellular compartments) at sufficient depth, and to interpret and make biological sense of the data.
Testing cleaning validation samples requires a validated method. The extent of validation is dependent upon the type of method employed, the capabilities of the method, the scientific and regulatory needs of the resulting data and the anticipated outcome of the testing. A number of test method options are reviewed for their analytical capabilities, along with their method validation parameters.
ABB Analytical Measurement Analytik Jena AG Azbil BioVigilant, Inc. B&W Tek, Inc. bioMérieux BMG LABTECH GmbH Bruker Daltonik GmbH CAMO Software AS Catalent Pharma Solutions Chemspec Europe Ltd CI Precision Dow Chemical Company Ltd EUROGENTEC FOSS NIRSystems, Inc. GE Analytical Instruments Gerresheimer Group I Holland Limited IDBS IONICON Analytik GmbH LI-COR Biosciences Lonza Natoli Engineering Company, Inc. Pall Life Sciences Patheon Inc PhyNexus, Inc. ReAgent Roche Sirius Analytical Instruments Ltd Vala Sciences Veltek Associates Inc. Waters Corporation