Strathclyde Institute of Pharmacy and Biomedical science

Glasgow, United Kingdom

Strathclyde Institute of Pharmacy and Biomedical science

Glasgow, United Kingdom
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Sakata S.,Rutgers University | Sakata S.,Strathclyde Institute of Pharmacy and Biomedical science | Sakata S.,University of Strathclyde | Harris K.D.,Rutgers University | Harris K.D.,Imperial College London
Frontiers in Neural Circuits | Year: 2012

Cortical circuits spontaneously generate coordinated activity even in the absence of external inputs. The character of this activity depends on cortical state. We investigated how state affects the organization of spontaneous activity across layers of rat auditory cortex in vivo, using juxtacellular recording of morphologically identified neurons and large-scale electrophysiological recordings. Superficial pyramidal cells and putative fast-spiking interneurons were consistently suppressed during cortical desynchronization. Pyramidal cells in deep layers showed heterogeneous responses to desynchronization, with some cells showing increased rates, typically large tufted pyramidal cells of high baseline firing rate, but not fast-spiking interneurons. Consistent results were found between desynchronization occurring spontaneously in unanesthetized animals, and desynchronization evoked by electrical stimulation of the pedunculopontine tegmental nucleus under urethane anesthesia. We hypothesize that reduction in superficial layer firing may enhance the brain's extraction of behaviorally relevant signals from noisy brain activity. © 2012 Sakata and Harris.

Furman B.L.,Strathclyde Institute of Pharmacy and Biomedical science
Toxicon | Year: 2012

The development of Byetta (synthetic exendin-4; exenatide) as a treatment of diabetes arose from two, parallel lines of investigation. The development of the 'incretin concept' which hypothesised that hormones from the gut contributed to the insulin secretion in response to meals, led to the identification of glucagon-like peptide 1 (GLP-1) as an important 'incretin' hormone. GLP-1 not only increases insulin secretion but increases β-cell proliferation and survival, suppresses glucagon secretion, delays gastric emptying and suppresses appetite, all of these actions contributing to a potential anti-diabetic effect. However, GLP-1 has a very short half due to its rapid breakdown by dipeptidyl peptidase IV and ectopeptidases. A systematic investigation of the composition and activity of venom from the Gila monster, Heloderma suspectum, led to the isolation of a 39-amino acid peptide, designated exendin-4, showing 53% structural homology with GLP-1(7-36). Exendin-4 mimicked GLP-1 through stimulating the GLP-1 receptor. The much greater stability of exendin-4 led to its experimental and clinical evaluation as an anti-diabetic agent and its introduction to the market in 2005. © 2011 Elsevier Ltd.

Millar D.I.A.,University of Edinburgh | Marshall W.G.,Rutherford Appleton Laboratory | Oswald I.D.H.,Strathclyde Institute of Pharmacy and Biomedical science | Pulham C.R.,University of Edinburgh
Crystallography Reviews | Year: 2010

This article reviews how the advances in the techniques for the collection and analysis of high-pressure X-ray and neutron diffraction data, augmented by spectroscopic data, now permit the accurate determination of the full crystal structure of energetic materials under extreme conditions. Using these methods, the crystal structure of the high-pressure γ-form of RDX (1,3,5-trinitrohexahydro-s-triazine) has been determined-the first case of a high-pressure structure of an energetic material. In addition, the crystal structure of the highly metastable β-form has been determined and, contrary to the previous reports, has been shown to be different from the form obtained at elevated temperatures and pressures. © 2010 Taylor & Francis.

Bawazeer S.,Strathclyde Institute of Pharmacy and Biomedical science | Sutcliffe O.B.,Manchester Metropolitan University | Euerby M.R.,HiChrom Ltd. | Watson D.G.,Strathclyde Institute of Pharmacy and Biomedical science
Journal of Chromatography A | Year: 2012

The retention properties of a silica gel column and a type C silica (silicon hydride) column for bases, sugars and polar acids were compared in hydrophilic interaction chromatography (HILIC) mode with formic acid or ammonium acetate as aqueous phase modifiers. The type C silica column was much more retentive for a series of model bases than the silica gel column and, surprisingly, retention of bases increased on the type C silica column when, the higher pH, ammonium acetate containing mobile phase was used. The retention of sugars was greater on the type C silica column than on the silica gel column and also increased on the type C silica column with increased pH suggesting either a silanophilic mechanism of retention or some unknown mechanism. Three type C silica based columns, type C silica, cogent diamond hydride and a β-pinene modified column, which it was hoped might exert some additional stereochemical discrimination, were tested for metabolomic profiling of urine. In general the unmodified type C silica column gave the strongest retention of the many polar metabolites in urine and could provide a useful complement to established HILIC methods for metabolomic profiling. © 2012 Elsevier B.V.

Al-Tannak N.F.,Strathclyde Institute of Pharmacy and Biomedical science | Bawazeer S.,Strathclyde Institute of Pharmacy and Biomedical science | Siddiqui T.H.,Strathclyde Institute of Pharmacy and Biomedical science | Watson D.G.,Strathclyde Institute of Pharmacy and Biomedical science
Journal of Chromatography A | Year: 2011

The hydrophilic interaction chromatography (HILIC) like properties of an ACE cyano (CN) HPLC column was studied for the separation of some basic compounds. Good separation of a test mix of basic compounds was obtained with a mobile phase consisting of acetonitrile/water (95:5) containing 3.25mM ammonium acetate. The retention times of the basic compounds decreased with increased ionic strength or with increased water content in the mobile phase. When Trishydroxymethyl aminomethane (Tris) (pKa 8.0), which is a weaker amine than ammonia (pKa 9.3), was used as an additive in the mobile phase retention of the basic compounds was increased. The ACE CN column gave excellent peak shapes for all the basic compounds. The utility of the column for impurity profiling of two basic drugs was tested and some impurities in oxprenolol were characterised by interfacing with Fourier transform mass spectrometry. It was also observed that ACE butyl and ACE phenyl columns retained basic compounds when the columns were eluted with a mobile phase consisting of acetonitrile/water (95:5) containing 3.25mM ammonium acetate. © 2011 Elsevier B.V.

Zhang T.,Strathclyde Institute of Pharmacy and Biomedical science | Creek D.J.,University of Glasgow | Creek D.J.,University of Melbourne | Barrett M.P.,University of Melbourne | And 2 more authors.
Analytical Chemistry | Year: 2012

In this study, we assessed three liquid chromatographic platforms: reversed phase (RP), aqueous normal phase (ANP), and hydrophilic interaction (HILIC) for the analysis of polar metabolite standard mixtures and for their coverage of urinary metabolites. The two zwitterionic HILIC columns showed high-quality chromatographic performance for metabolite standards, improved separation for isomers, and the greatest coverage of polar metabolites in urine. In contrast, on the reversed phase column, most metabolites eluted very rapidly with little or no separation. Using an Exactive Orbitrap mass spectrometer with a HILIC liquid chromatographic platform, approximately 970 metabolite signals with repeatable peak areas (relative standard deviation (RSD) ≤ 25%) could be putatively identified in human urine, by elemental composition assignment within a 3 ppm mass error. The ability of the methodology for the verification of nonmolecular ions, which arise from adduct formation, and the possibility of distinguishing isomers could also be demonstrated. Careful examination of the raw data and the use of masses for predicted metabolites produced an extension of the metabolite list for human urine. © 2012 American Chemical Society.

Harnett W.,Strathclyde Institute of Pharmacy and Biomedical science | Rzepecka J.,Strathclyde Institute of Pharmacy and Biomedical science | Houston K.M.,Strathclyde Institute of Pharmacy and Biomedical science
Trends in Parasitology | Year: 2010

An unusual aspect of the biology of nematodes is the attachment of phosphorylcholine (PC) to carbohydrate. The attachment appears to play an important role in nematode development and, in some parasitic species, in immunomodulation. This article considers the nature of the biosynthetic pathway of nematode PC-containing glycoconjugates and, in particular, the identity of the final component in the pathway - the enzyme that transfers PC to carbohydrate (the 'PC transferase'). We offer the opinion that the PC transferase could be a member of the fukutin family (fukutin refers to the mutated gene product that causes Fukuyama congenital muscular dystrophy), a group of enzymes with apparent phosphoryl-ligand transferase activity that are found in organisms ranging from bacteria to humans. © 2009 Elsevier Ltd. All rights reserved.

Wilson C.G.,Strathclyde Institute of Pharmacy and Biomedical science
International Journal of Pharmaceutics | Year: 2010

Colonic transit is a subject of great relevance when considering in vivo/. in vitro relationships for oral controlled release dosage forms. Our knowledge of colonic motility has first come from the clinic, where measurement of the whole gut transit of different excreted markers was used as a method of discriminating pathologies. X-ray contrast, although widely available, was used sparing due to the accumulating dosimetry associated with each exposure. Although such methods were used for swallowing studies, gamma scintigraphy allowed physicians to measure colon function with a more moderate radiation burden. The ability to label meal and dosage form separately and to measure dispersion with more certainty, prompted the use in pharmaceutical sciences; finally, the relationship between blood concentrations and transit of different sized dosage began to be understood. This mini-review considers the development of colon transit measurements and how different designs of clinical assessment assist in elucidating size and shape influence on colon transit in man. © 2010 Elsevier B.V.

Goodwin R.J.A.,University of Glasgow | Scullion P.,Schering | MacIntyre L.,Strathclyde Institute of Pharmacy and Biomedical science | Watson D.G.,Strathclyde Institute of Pharmacy and Biomedical science | Pitt A.R.,University of Glasgow
Analytical Chemistry | Year: 2010

A dry matrix application for matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) was used to profile the distribution of 4-bromophenyl-1,4-diazabicyclo(3.2.2)nonane-4-carboxylate, monohydrochloride (BDNC, SSR180711) in rat brain tissue sections. Matrix application involved applying layers of finely ground dry α-cyano-4-hydroxycinnamic acid (CHCA) to the surface of tissue sections thaw mounted onto MALDI targets. It was not possible to detect the drug when applying matrix in a standard aqueous-organic solvent solution. The drug was detected at higher concentrations in specific regions of the brain, particularly the white matter of the cerebellum. Pseudomultiple reaction monitoring imaging was used to validate that the observed distribution was the target compound. The semiquantitative data obtained from signal intensities in the imaging was confirmed by laser microdissection of specific regions of the brain directed by the imaging, followed by hydrophilic interaction chromatography in combination with a quantitative high-resolution mass spectrometry method. This study illustrates that a dry matrix coating is a valuable and complementary matrix application method for analysis of small polar drugs and metabolites that can be used for semiquantitative analysis. © 2010 American Chemical Society.

Watson D.G.,Strathclyde Institute of Pharmacy and Biomedical science
Computational and Structural Biotechnology Journal | Year: 2013

Compound identification in mass spectrometry based metabolomics can be a problem but sometimes the problem seems to be presented in an over complicated way. The current review focuses on metazoans where the range of metabolites is more restricted than for example in plants. The focus is on liquid chromatography with high resolution mass spectrometry where it is proposed that most of the problems in compound identification relate to structural isomers rather than to isobaric compounds. Thus many of the problems faced relate to separation of isomers, which is usually required even if fragmentation is used to support structural identification. Many papers report the use of MS/MS or MS2 as an adjunct to the identification of known metabolites but there a few examples in metabolomics studies of metazoans of complete structure elucidation of novel metabolites or metabolites where no authentic standards are available for comparison.

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