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Issue 6 2007
Issue 6 2007 / 23 November 2007 /
Non-coding RNAs (ncRNAs) consist of a growing heterogeneous class of transcripts defined as RNA molecules that lack any extensive “Open Reading Frame” (ORF) and function as structural, catalytic or regulatory entities rather than serving as templates for protein synthesis. While non-coding sequences make up only a small fraction of the DNA of prokaryotes, among eukaryotes, the proportion of DNA that does not code for protein increases with their complexity, underscoring the likelihood of a “hidden layer” of gene regulation in animal genomes1.
Although previously being classified as “junk”, recent studies strongly indicate that ncRNAs play central roles in regulating gene expression at multiple levels including; transcription, alternative splicing, RNA modification, such as RNA editing, RNA stability and translation and chromatin modification. Still, there is an ongoing debate on whether ncRNAs are important functional contributors to an organism’s complexity or rather represent transcriptional “background” or “noise”2. NcRNAs can be subdivided into two main classes: “housekeeping” RNAs such as transfer RNAs (tRNAs), ribosomal RNAs (rRNAs), small nuclear RNAs (snRNAs) and regulatory RNAs (“riboregulators”), such as small nucleolar RNAs (snoRNAs), and microRNAs (miRNAs), which are expressed at certain stages of organism development or cell differentiation and can modulate expression of other genes on the levels of transcription or translation. In particular, miRNAs represent a class of ncRNAs which has recently attracted major attention within the scientific community. Although information on the function of miRNAs is still sparse, an increasing body of evidence suggests that these molecules play major roles in important biological processes and may contribute to the pathogenesis of human diseases3. Consequently, an increasing number of research scientists who have traditionally worked on proteins, are beginning to move their focus towards studying the world of these tiny RNA molecules. The potential and prospects of miRNAs and other newly discovered ncRNA family members as a new class of therapeutic are reviewed, and the constraints associated with current miRNA target validation approaches are discussed. (more…)
Tagged with: Dr. Jan Weiler, microRNA, Novartis Institutes for BioMedical Research, siRNA Therapeutics
Issue 6 2007 / 23 November 2007 /
Alteration of microRNA (miRNA) expression in a disease compared to a healthy state and/or correlation of miRNA expression with clinical parameters (like disease progression or therapy response), may indicate that miRNAs can serve as clinically relevant biomarkers1-3. An important first step for further functional characterisation is the information about differential miRNA expression in cellular processes such as; differentiation4,5, proliferation or apoptosis6, that may determine which disease causing genes are specifically regulated by miRNAs, or vice versa; which genes regulate miRNA expression.
Whatever the question you would like to address, the precise information about the level of miRNA expression in a specific cell type or tissue is often considered an important first step. A range of methods can be used for the isolation and profiling of miRNAs. Two recent reviews on microRNA7 and qPCR8 in European Pharmaceutical Review addressed both topics individually in great detail, but not their combination. This article aims to provide an insight into the application of quantitative real-time PCR (qPCR) to assay microRNA expression. (more…)
Tagged with: David Ibberson, Dr Vladimir Benes, Dr. Mirco Castoldi, EMBL, Jens Stolte, microRNA, Polymerase Chain Reaction (PCR), Prof. Martina Muckenthaler, qPCR, University of Heidelberg
Issue 6 2007 / 23 November 2007 /
A round table discussion covering the driving forces behind the integration of automated technology within the pharmaceutical industry, the procedures that are followed when implementing new automated techniques, current areas of drug discovery most benefiting from lab automation, how lab automation advanced the drug discovery marketplace over the last five years, the groundbreaking techniques occurring in lab automation, the relationship between vendor companies and their customers and the current limitations within lab automation. (more…)
Tagged with: AstraZeneca, Dr Gary Allenby, Dr Thomas H Keller, Drug discovery, Lab Automation, Mr Kjell Fransson, Neil Benn, Pfizer, Professor Gordon Alton, Ziath
Issue 6 2007 / 23 November 2007 /
High Content Screening (HCS) is becoming increasingly utilised as an early drug-discovery and basic research tool for defining the functions of genes, proteins and other biomolecules in normal and abnormal cellular functions. HCS involves the integration of a number of preparation steps which include; cell-sample preparation, fluorescent labelling, image acquisition, image processing, image analysis, information management and knowledge mining1.
These advanced microscopy and image analysis platforms are proving to be immensely powerful tools for the study of molecular and morphological events in cells. This allows for the first time, a multi-parametric characterisation of gross cellular responses and behaviour of a variety of molecular and cellular targets, including subcellular localisation and redistribution of individual proteins and complex cellular structures. In contrast to the more traditional biochemical or genetic analysis, HCS allows for the detection of physiological responses within the context of the structural and functional networks of cells in both normal and diseased states2. (more…)
Tagged with: Anthony Davies, Drug discovery, HCS (High Content Screening), Trinity College Dublin
Issue 6 2007 / 23 November 2007 /
The determination of accurate thermodynamic data for the interactions of biomolecules has been enhanced over the last decade by the use of isothermal titration calorimetric (ITC) instrumentation. These instruments are now standard kits in many biophysical/structural biochemistry laboratories of pharmaceutical companies. Despite this, there is little evidence for the input of thermodynamic data into the drug development process.
The panacea of being able to correlate thermodynamic parameters with structural perturbation on going from the free state to the target-drug complex is proving difficult to obtain, and as such the value of calorimetric data has been largely disregarded. As a result it is important to ask whether thermodynamic data can provide added value to the drug development process, and if so at what stage can this input be made? In this article the calorimetric method is introduced and evaluated as a platform technology for drug development. The potential to input thermodynamic data in the drug development pipeline is assessed. The conclusion is that these data add significantly to the decision making process at the lead selection and optimisation stage. (more…)
Tagged with: Professor John E. Ladbury, Thermal Analysis, University College London
Issue 6 2007 / 23 November 2007 /
In order to meet the challenges demanded by the requirements of Process Analytical Technology (PAT), the modern microbiological laboratory needs to become more innovative in microbial detection, identification and enumeration. Technology is becoming available that will speed up microbiological analysis, potentially allowing pharmaceutical microbiology tests to get as close as is possible to the concepts of PAT. Following on from the article by Bob Johnson1, this article explores the future technologies in greater detail.
The technical requirements for any rapid microbiology method (RMM) include a combination of the following: significantly reduced time-to-result when compared with conventional microbiological methods; automated, miniaturised and high-throughput technology platforms; increased sensitivity, accuracy, precision and reproducibility; detection of a single, viable micro-organism without the requirement for cellular growth; capable of testing for total counts and specified objectionable simultaneously; enhanced detection of stressed organisms. Business requirements include: significant reduction of testing time to release products more rapidly; lower inventories (raw material, in-process material and finished product); reduction of repeat testing, deviations, OOS investigations and product rejection. Furthermore, the system should be portable and user-friendly. (more…)
Tagged with: Andrew Middleton, BioMicroElectroMechanical Systems (BioMEMS), Biosensors, GlaxoSmithKline, Microbiology, Polymerase Chain Reaction (PCR)
Issue 6 2007 / 23 November 2007 /
ASTM Committee E55 formed in April of 2003 as a result of FDA’s GMPs for the 21st Century Initiative and the subsequent Guidance, “PAT – a framework for innovative pharmaceutical manufacturing and quality assurance.” Focusing on process understanding and flexible manufacturing, FDA encouraged the pharmaceutical industry to utilise the consensus standards approach to enable implementation of PAT principles into their manufacturing processes.
The initial structure of E55 included three main subcommittees: E55.01, PAT System Management; E55.02, PAT System Implementation and Practice; and E55.91, Terminology. These three subcommittees focused on technical guidance documents, application standards and terminology, with the ultimate objective of standards to facilitate continuous quality assurance and real-time release. In December of 2005, subcommittee E55.03 was added, developing general pharmaceutical standards, which would facilitate PAT, and be broadly applicable beyond PAT. A detailed description of the initial structure, organisation and purpose of ASTM E55 can be found in the article, “Committee E55 – an update,” (see Reference 1). (more…)
Tagged with: PAT, Steve Simmons, Wyeth Pharmaceuticals
Issue 6 2007 / 23 November 2007 /
Proper and compliant HVAC systems are fundamental to the pharma industry as we use high air change rates to secure a low viable and particle contamination. HVAC is energy consuming and therefore the HVAC accounts for a large proportion of the energy used in pharma facilities. In the past the energy savings issue was not widely acknowledged; managers wanted to see good compliance and high levels of production and spending time to save money; push for greater sustainability was not really welcomed. Now things have changed and there is a readiness to look at these issues, especially when it is proven that GMP and sustainability are not contradicting and on occasions, can go beautifully hand in hand.
When designing facilities with sustainability in mind, we are often met with the assumptions that it means larger investments. But while a sustainability perspective on design in some cases causes increased investments, it can be proven that this perspective can in some areas actually reduce investment costs. In this article, implemented and planned energy savings on a Novo Nordisk aseptic filling plant will be described. Special attention will be given to sub-projects, demonstrating unison in GMP and energy considerations and showing how sustainable design can also mean cheaper design. (more…)
Tagged with: Cleanrooms, Novo Nordisk, Ulla Thomsen
Issue 6 2007 / 23 November 2007 /
For many years Applied Biosystems has continued to provide robust, reliable tools to analyse DNA and RNA, small molecules, and proteins, in order to make scientific discoveries, develop new pharmaceuticals and conduct standardised testing. Applied Biosystems has developed and introduced dozens of technologies that have catalysed the genomic and proteomics revolutions and are now essential to life science research and applied fields. The company’s biggest contribution has almost certainly been in the development and commercialisation of robust and reliable DNA sequencer technology, and the provision of quality reagents and consumables needed to ensure effective and comparable experimental data. Through the years, our DNA sequencers have remained the gold standard. The first automated DNA sequencer, introduced in 1986, could run 16 samples in a 12-hour cycle, analysing approximately 4,800 base pairs of DNA per day.
By 2002, with the release of the 3730xl DNA Analyzer, we brought high throughput, high quality data and low cost per sample to genetic analysis, with capacity reaching up to two million base pairs of DNA in one 24-hour period. This step up in capabilities was just one example of our continuous stream of development over the following years, which has more recently included products such as the BigDye XTerminator™ Purification Kit that more quickly produces higher quality DNA sequence data and requires less work for purification. Alongside this, new Variant Reporter™ software has been developed for accelerating and streamlining the analysis process for sequence data. (more…)
Tagged with: Applied Biosystems, Proteomics, Sue Ann Molero
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