Publications
112 results found
Owen DR, Wood DM, Archer JR, et al., 2015, Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects and acute toxicity., Drug and Alcohol Review, Vol: 35, Pages: 591-596, ISSN: 1465-3362
INTRODUCTION AND AIMS: There has been a global increase in the availability and use of novel psychoactive substances (NPS) over the last decade. Phenibut (β-phenyl-γ-aminobutyric acid) is a GABAB agonist that is used as an NPS. Here, we bring together published scientific and grey information sources to further understand the prevalence of use, desired effects and acute toxicity of phenibut. DESIGN AND METHODS: Using European Monitoring Centre for Drugs and Drug Addiction Internet snapshot methodology, we undertook an English language Internet snapshot survey in May 2015 to gather information on the availability and price of phenibut from Internet NPS retailers. To gather information on prevalence of use, desired effects and/or adverse effects, we searched grey literature (online drug discussion forums) and medical literature (PubMed and abstracts from selected International Toxicology conferences). RESULTS: We found 48 unrelated Internet suppliers selling phenibut in amounts ranging from 5 g (US$1.60, £1.01/g) to 1000 kg (US$0.23, £0.14/g). Capsules containing 200-500 mg of phenibut were available in packs of between 6 (US$4.45, £2.80/g) and 360 (US$0.43, £0.27/g). According to the grey literature, phenibut is taken for its anxiolytic and euphoric properties, with tolerance and withdrawal syndromes commonly reported adverse effects. Phenibut is taken orally at an average dose of 2.4 g. Case reports in the medical literature feature users who present to emergency departments heavily sedated or experiencing withdrawal. There have been no reported deaths relating to phenibut use. DISCUSSION AND CONCLUSIONS: Phenibut is readily available in the UK from Internet sites selling NPS. Its desired and adverse effects appear similar to other gamma-aminobutyric acid receptor agonists. [Owen DR, Wood DM, Archer JRH, Dargan PI. Phenibut (4-amino-3-phenyl-butyric acid): Availability, prevalence of use, desired effects
Colasanti A, Guo, Giannetti P, et al., 2015, Hippocampal neuroinflammation, functional connectivity and depressive symptoms in multiple sclerosis, Biological Psychiatry, Vol: 80, Pages: 62-72, ISSN: 1873-2402
BackgroundDepression, a condition commonly comorbid with multiple sclerosis (MS), is associated more generally with elevated inflammatory markers and hippocampal pathology. We hypothesized that neuroinflammation in the hippocampus is responsible for depression associated with MS. We characterized the relationship between depressive symptoms and hippocampal microglial activation in patients with MS using the 18-kDa translocator protein radioligand [18F]PBR111. To evaluate pathophysiologic mechanisms, we explored the relationships between hippocampal neuroinflammation, depressive symptoms, and hippocampal functional connectivities defined by resting-state functional magnetic resonance imaging.MethodsThe Beck Depression Inventory (BDI) was administered to 11 patients with MS and 22 healthy control subjects before scanning with positron emission tomography and functional magnetic resonance imaging. We tested for higher [18F]PBR111 uptake in the hippocampus of patients with MS relative to healthy control subjects and examined the correlations between [18F]PBR111 uptake, BDI scores, and hippocampal functional connectivities in the patients with MS.ResultsPatients with MS had an increased hippocampal [18F]PBR111 distribution volume ratio relative to healthy control subjects (p = .024), and the hippocampal distribution volume ratio was strongly correlated with the BDI score in patients with MS (r = .86, p = .006). Hippocampal functional connectivities to the subgenual cingulate and prefrontal and parietal regions correlated with BDI scores and [18F]PBR111 distribution volume ratio.ConclusionsOur results provide evidence that hippocampal microglial activation in MS impairs the brain functional connectivities in regions contributing to maintenance of a normal affective state. Our results suggest a rationale for the responsiveness of depression in some patients with MS to effective control of brain neuroinflammation. Our findings also lend support to further investigation of t
Owen DR, Guo Q, Rabiner EA, et al., 2015, The impact of the rs6971 polymorphism in TSPO for quantification and study design, Clinical and Translational Imaging, Vol: 3, Pages: 417-422, ISSN: 2281-5872
Second-generation translocator protein (TSPO) radioligands were developed to circumvent the technical short comings of 11C-PK11195, the first TSPO targeting tracer. However, in early clinical positron emission tomography (PET) studies they displayed greater inter- and intra-subject variability than was expected given the promising characteristics they showed in preclinical and in vitro studies. A great deal of this variability, although not all, can be explained by the rs6971 polymorphism in the gene encoding TSPO. This polymorphism causes a single amino acid substitution in the TSPO which, for all second-generation tracers tested in man hitherto, reduces binding affinity in mutants relative to wild type. This has obvious implications for interpretation of data, because inter-subject comparisons in PET studies are predicated on the assumption that binding affinity is consistent across all subjects. In this paper, we discuss the implications of the rs6971 polymorphism on study design, analysis and interpretation of data for clinical PET studies using second-generation TSPO radioligands.
Colasanti A, Guo Q, Giannetti P, et al., 2015, Hippocampal inflammation and depression in multiple sclerosis: integrating evidence from TSPO PET and resting state fMRI, 31st Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis (ECTRIMS), Publisher: SAGE Publications (UK and US), Pages: 492-493, ISSN: 1477-0970
Bloomfield P, Selvaraj S, Bonoldi I, et al., 2015, Translational investigation of microglia and antipsychotic medication, GLIA, Vol: 63, Pages: E315-E315, ISSN: 0894-1491
Owen DRJ, MacAllister R, Sofat R, 2015, Intravenous Furosemide for Acute Decompensated Congestive Heart Failure: What Is the Evidence?, Clinical Pharmacology & Therapeutics, Vol: 98, Pages: 119-121, ISSN: 1532-6535
Use of intravenous furosemide rather than oral administration in acute decompensated congestive cardiac failure is universally recommended in international guidelines. We argue that this recommendation is not supported by the existing evidence, and suggest that trials should be performed to determine whether larger doses of oral furosemide should be prescribed prior to an IV switch. This could reduce length of hospital admissions and allow for more patients to be managed in the primary care setting.
Selvaraj S, Bloomfield P, Veronese M, et al., 2015, Microglial Activity in People at Ultra High Risk of Psychosis and in Schizophrenia: An [11C]PBR28 PET Brain Imaging Study, BIOLOGICAL PSYCHIATRY, Vol: 77, ISSN: 0006-3223
Colasanti A, Guo Q, Giannetti P, et al., 2015, Hippocampal Inflammation and Depressive Symptoms are Associated to the Strength of Hippocampal Functional Connectivity in Multiple Sclerosis: A Study with TSPO-PET and Resting-State fMRI, 70th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry on Stress, Emotion, Neurodevelopment and Psychopathology, Publisher: ELSEVIER SCIENCE INC, Pages: 115S-116S, ISSN: 0006-3223
Michell-Robinson MA, Touil H, Healy LM, et al., 2015, Roles of microglia in brain development, tissue maintenance and repair, Brain, Vol: 138, Pages: 1138-1159, ISSN: 0006-8950
The emerging roles of microglia are currently being investigated in the healthy and diseased brain with a growing interest in their diverse functions. In recent years, it has been demonstrated that microglia are not only immunocentric, but also neurobiological and can impact neural development and the maintenance of neuronal cell function in both healthy and pathological contexts. In the disease context, there is widespread consensus that microglia are dynamic cells with a potential to contribute to both central nervous system damage and repair. Indeed, a number of studies have found that microenvironmental conditions can selectively modify unique microglia phenotypes and functions. One novel mechanism that has garnered interest involves the regulation of microglial function by microRNAs, which has therapeutic implications such as enhancing microglia-mediated suppression of brain injury and promoting repair following inflammatory injury. Furthermore, recently published articles have identified molecular signatures of myeloid cells, suggesting that microglia are a distinct cell population compared to other cells of myeloid lineage that access the central nervous system under pathological conditions. Thus, new opportunities exist to help distinguish microglia in the brain and permit the study of their unique functions in health and disease.
Moore CS, Cui Q-L, Warsi NM, et al., 2015, Direct and Indirect Effects of Immune and Central Nervous System-Resident Cells on Human Oligodendrocyte Progenitor Cell Differentiation, JOURNAL OF IMMUNOLOGY, Vol: 194, Pages: 761-772, ISSN: 0022-1767
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- Citations: 70
Colasanti A, Guo Q, Muhlert N, et al., 2014, In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with <SUP>18</SUP>F-PBR111 PET, JOURNAL OF NUCLEAR MEDICINE, Vol: 55, Pages: 1112-1118, ISSN: 0161-5505
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- Citations: 78
Guo Q, Owen DR, Rabiner EA, et al., 2014, A graphical method to compare the <i>in vivo</i> binding potential of PET radioligands in the absence of a reference region: application to [<SUP>11</SUP>C]PBR28 and [<SUP>18</SUP>F]PBR111 for TSPO imaging, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 34, Pages: 1162-1168, ISSN: 0271-678X
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- Citations: 31
Owen DR, Guo Q, Kalk NJ, et al., 2014, Determination of [<SUP>11</SUP>C]PBR28 binding potential <i>in vivo:</i> a first human TSPO blocking study, JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, Vol: 34, Pages: 989-994, ISSN: 0271-678X
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- Citations: 97
Kalk NJ, Guo Q, Owen DR, et al., 2014, HIPPOCAMPAL MICROGLIAL DYSFUNCTION IN ALCOHOL DEPENDENCE: A [C-11]PBR28 POSITRON EMISSION TOMOGRAPHY (PET) STUDY, 37th Annual Scientific Meeting of the Research-Society-on-Alcoholism (RSA) / 17th Congress of the International-Society-for-Biomedical-Research-on-Alcoholism (ISBRA), Publisher: WILEY-BLACKWELL, Pages: 23A-23A, ISSN: 0145-6008
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- Citations: 1
Colasanti A, Guo Q, Giannetti P, et al., 2014, TSPO-targeted PET Imaging Suggests Increased Microglia Activation in Multiple Sclerosis Hippocampus is Correlated to Depressive Symptomatology, 69th Annual Scientific Convention and Meeting of the Society-of-Biological-Psychiatry, Publisher: ELSEVIER SCIENCE INC, Pages: 94S-95S, ISSN: 0006-3223
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- Citations: 1
Owen DR, Guo Q, Kalk NJ, et al., 2014, Eratum: Determination of [ 11 C]PBR28 binding potential in vivo: A first human TSPO blocking study (Journal of Cerebral Blood Flow and Metabolism (2014) 34 (1256)), Journal of Cerebral Blood Flow and Metabolism, Vol: 34, ISSN: 0271-678X
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- Citations: 3
Kalk NJ, Owen DR, Tyacke RJ, et al., 2013, Are Prescribed Benzodiazepines Likely to Affect the Availability of the 18 kDa Translocator Protein (TSPO) in PET Studies?, SYNAPSE, Vol: 67, Pages: 909-912, ISSN: 0887-4476
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- Citations: 16
Shalhoub J, Oskrochi Y, Davies AH, et al., 2013, Clinical Assessment of Carotid Atherosclerosis Inflammation by Positron Emission Tomography, CURRENT MOLECULAR MEDICINE, Vol: 13, Pages: 1646-1652, ISSN: 1566-5240
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- Citations: 7
Colasanti A, Owen DR, Grozeva D, et al., 2013, Bipolar Disorder is associated with the rs6971 polymorphism in the gene encoding 18 kDa Translocator Protein (TSPO), PSYCHONEUROENDOCRINOLOGY, Vol: 38, Pages: 2826-2829, ISSN: 0306-4530
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- Citations: 41
Colasanti A, Guo Q, Mulhert N, et al., 2013, [18F]PBR111 binding in lesional and peri-lesional multiple sclerosis white matter, 29th Congress of the European-Committee-for-Treatment-and-Research-in-Multiple-Sclerosis / 18th Annual Conference of Rehabilitation in MS, Publisher: SAGE PUBLICATIONS LTD, Pages: 68-69, ISSN: 1352-4585
Kalk NJ, Guo Q, Owen DR, et al., 2013, Using Positron Emission Tomography to investigate microglial activation in alcohol dependence: preliminary findings, EUROPEAN NEUROPSYCHOPHARMACOLOGY, Vol: 23, Pages: S122-S122, ISSN: 0924-977X
Guo Q, Colasanti A, Owen DR, et al., 2013, Quantification of the Specific Translocator Protein Signal of18F-PBR111 in Healthy Humans: A Genetic PolymorphismEffect on In Vivo Binding, Journal of Nuclear Medicine, Vol: 54, Pages: 1-9
PET is used to image active inflammatory processes by targetingthe translocator protein (TSPO). In vitro, second-generation TSPOradioligands, such as PBR111, have been shown to bind to humantissue samples with either high affinity (high-affinity binders, HABs),low affinity (low-affinity binders, LABs), or an intermediate, mixedaffinity (mixed-affinity binders, MABs). We previously explainedthese differences in affinity in human tissue via the rs6971 polymorphismin the TSPO gene and predicted that the specific signalfrom PET ligands in vivo would vary accordingly. In silico modelingpredicted that 18F-PBR111 would have a moderate to high specificto-nonspecific ratio in the normal human brain. To test these predictions,we present here the analysis and modeling of 18F-PBR111data in healthy humans. Methods: Twenty-one subjects (9 HABs, 8MABs, and 4 LABs), 28–62 y old, genotyped for the rs6971 polymorphism,underwent 120-min PET scans with arterial samplingafter a bolus injection of 18F-PBR111. Compartmental models andLogan graphical methods enabled estimation of the total volume ofdistribution (VT) in regions of interest (ROIs). To evaluate the specificsignal, we developed 2 methods to estimate the nondisplaceablevolume of distribution (VND): the first assumed that the in vitro affinityratio of 18F-PBR111 in HABs relative to LABs (4-fold) is preserved invivo; the second modeled the difference in the HAB and MAB signalsin the context of an occupancy plot. Results: A 2-tissue-compartmentmodel described the data well, and a significant differencewas found between the VT of HABs, MABs, and LABs across allROIs examined (P , 0.05). We also found a significant correlationbetween VT and age for both HABs and MABs in most ROIs. Theaverage VND estimated by the 2 methods was 1.18 6 0.35 (methodI: VND 5 0.93, method II: VND 5 1.42), implying that the 18F-PBR111BPND was 2.78 6 0.46 in HABs, 1.48 6 0.28 in MABs, and 0.51 60.17 in LABs and that the in vivo affinity ratio was simil
Owen DR, Rupprecht R, Nutt DJ, 2013, Stratified medicine in psychiatry: a worrying example or new opportunity in the treatment of anxiety?, JOURNAL OF PSYCHOPHARMACOLOGY, Vol: 27, Pages: 119-122, ISSN: 0269-8811
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- Citations: 13
Gaemperli O, Shalhoub J, Owen DRJ, et al., 2012, Imaging intraplaque inflammation in carotid atherosclerosis with <SUP>11</SUP>C-PK11195 positron emission tomography/computed tomography, EUROPEAN HEART JOURNAL, Vol: 33, Pages: 1902-1910, ISSN: 0195-668X
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- Citations: 189
Kalk NJ, Owen D, Reynolds R, et al., 2012, Affinity of commonly-prescribed benzodiazepines for the 18 kDa translocator protein (TSPO): implications for imaging studies, 9th International Symposium on Functional Neuroreceptor Mapping of the Living Brain (NRM), Publisher: NATURE PUBLISHING GROUP, Pages: S52-S53, ISSN: 0271-678X
Zepper P, Owen D, Kostikov A, et al., 2012, Evaluation of a new 18F radiotracer for microglia imaging in stroke, Publisher: SOC NUCLEAR MEDICINE INC, ISSN: 0161-5505
Owen DR, Yeo AJ, Gunn RN, et al., 2012, An 18-kDa translocator protein (TSPO) polymorphism explains differences in binding affinity of the PET radioligand PBR28, J Cereb Blood Flow Metab, Vol: 32, Pages: 1-5, ISSN: 1559-7016
[(11)C]PBR28 binds the 18-kDa Translocator Protein (TSPO) and is used in positron emission tomography (PET) to detect microglial activation. However, quantitative interpretations of signal are confounded by large interindividual variability in binding affinity, which displays a trimodal distribution compatible with a codominant genetic trait. Here, we tested directly for an underlying genetic mechanism to explain this. Binding affinity of PBR28 was measured in platelets isolated from 41 human subjects and tested for association with polymorphisms in TSPO and genes encoding other proteins in the TSPO complex. Complete agreement was observed between the TSPO Ala147Thr genotype and PBR28 binding affinity phenotype (P value=3.1 x 10(-13)). The TSPO Ala147Thr polymorphism predicts PBR28 binding affinity in human platelets. As all second-generation TSPO PET radioligands tested hitherto display a trimodal distribution in binding affinity analogous to PBR28, testing for this polymorphism may allow quantitative interpretation of TSPO PET studies with these radioligands.
Guo Q, Owen DR, Rabiner EA, et al., 2012, Identifying improved TSPO PET imaging probes through biomathematics: the impact of multiple TSPO binding sites in vivo, Neuroimage, Vol: 60, Pages: 902-910, ISSN: 1095-9572
To date, (1)(1)C-(R)-PK11195 has been the most widely used TSPO PET imaging probe, although it suffers from high non-specific binding and low signal to noise. A significant number of 2nd generation TSPO radioligands have been developed with higher affinity and/or lower non-specific binding, however there is substantial inter-subject variation in their affinity for the TSPO. TSPO from human tissue samples binds 2nd generation TSPO radioligands with either high affinity (high affinity binders, HABs), or low affinity (LABs) or expresses both HAB and LAB binding sites (mixed affinity binders, MABs). The expression of these different TSPO binding sites in human is encoded by the rs6971 polymorphism in the TSPO gene. Here, we use a predictive biomathematical model to estimate the in vivo performances of three of these 2nd generation radioligands ((1)(8)F-PBR111, (1)(1)C-PBR28, (1)(1)C-DPA713) and (1)(1)C-(R)-PK11195 in humans. The biomathematical model only relies on in silico, in vitro and genetic data (polymorphism frequencies in different ethnic groups) to predict the radioactivity time course in vivo. In particular, we provide estimates of the performances of these ligands in within-subject (e.g. longitudinal studies) and between-subject (e.g. disease characterisation) PET studies, with and without knowledge of the TSPO binding class. This enables an assessment of the different radioligands prior to radiolabelling or acquisition of any in vivo data. The within-subject performance was characterised in terms of the reproducibility of the in vivo binding potential (%COV[BP(ND)]) for each separate TSPO binding class in normal and diseased states (50% to 400% increase in TSPO density), whilst the between-subject performance was characterised in terms of the number of subjects required to distinguish between different populations. The results indicated that the within-subject variability for (1)(8)F-PBR111, (1)(1)C-PBR28 and (1)(1)C-DPA713 (0.9% to 2.2%) was significantly l
Shalhoub J, Monaco C, Owen DRJ, et al., 2011, Late-Phase Contrast-Enhanced Ultrasound Reflects Biological Features of Instability in Human Carotid Atherosclerosis, STROKE, Vol: 42, Pages: 3634-3636, ISSN: 0039-2499
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- Citations: 32
Newbould RD, Owen DRJ, Shalhoub J, et al., 2011, Motion-Sensitized Driven Equilibrium for Blood-Suppressed T2*Mapping, JOURNAL OF MAGNETIC RESONANCE IMAGING, Vol: 34, Pages: 702-709, ISSN: 1053-1807
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- Citations: 9
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