http://hdl.handle.net/2262/87 Pharmacy and Pharmaceutical Sciences 2013-05-25T23:17:35Z http://hdl.handle.net/2262/64564 Title: Measuring and benchmarking safety culture: application of the safety attitudes questionnaire to an acute medical admissions unit. Author: RYDER, SHEILA ANNE Abstract: Objectives: To assess the safety culture in an acute medical admissions unit (AMAU) of a teaching hospital in order to benchmark results against international data and guide a unit-based, integrated, risk management strategy. Methods: The Safety Attitudes Questionnaire (SAQ), a validated instrument for the measurement of safety culture, was applied to an AMAU. All AMAU healthcare staff (n = 92) were surveyed: doctors, nurses, healthcare assistants (HCAs) and allied healthcare professionals (AHPs). Safety attitude scores for the overall unit and individual caregiver types were assessed across six domains of safety culture. Results: When compared against an international benchmark, the AMAU scored significantly higher for four of the six safety domains: p<0.01 for ‘teamwork climate’, ‘safety climate’ and ‘stress recognition’, and p<0.05 for ‘job satisfaction’. The difference between nurse manager scores and the overall mean for the study group was statistically significant for the domains of ‘teamwork climate’ (p<0.05) and ‘safety climate’ (p<0.01). HCAs scored significantly lower relative to staff overall with regard to ‘working conditions’ (p<0.05) and ‘perceptions of management’ (p<0.01). Conclusions: The SAQ was successfully applied to an AMAU setting giving a valuable insight into staff issues of concern across the safety spectrum: employee and environmental safety, clinical risk management and medication safety. Description: PUBLISHED; PMID: 19437091 2009-01-01T00:00:00Z http://hdl.handle.net/2262/64124 Title: The interrelation of Physicochemical Parameters and Topological Descriptors for a series of Ò-blocking Agents Author: QUIGLEY, MARY JOHN; Naughton, Sarah Abstract: The intercorrelation between a series of physicochemical parameters and topological indices for a set of â-blockers is investigated. Partition coefficients are calculated using the ClogP program, and the results are compared with previous data, both experimental and theoretical. These data are complemented by hydrophilicity and solubility calculations, together with the determination of molecular area and volume. Connectivity indices, of order 1 and 2, including simple, valence, and differential terms, are evaluated. The derivation of a recently proposed topological descriptor, the eccentric adjacency index, from the adjacency and distance matrices, is presented. The corresponding valence term, a novel descriptor, is developed, and other indices related to the distance matrix, the Wiener and Hyper-Wiener terms, are included. A high degree of linear correlation between the connectivity indices is noted. The correlations for first-order terms are slightly superior to the corresponding second-order values. This is particularly true when considering the valence terms compared with the nonvalence terms. The relationship between these terms and reported pharmacological properties are investigated. A decrease in the eccentric adjacency index resulted in an increase in the pharmacological property. Description: PUBLISHED 2002-01-01T00:00:00Z http://hdl.handle.net/2262/64094 Title: Cytoskeletal re-arrangement in TGF-beta1-induced alveolar epithelial-mesenchymal transition studied by atomic force microscopy and high-content analysis Author: DAVIES, ANTHONY; MEDINA MARTIN, CARLOS; EHRHARDT, CARSTEN Abstract: Epithelial-mesenchymal transition (EMT) is closely implicated in the pathogenesis of idiopathic pulmonary fibrosis. Associated with this phenotypic transition is acquisition of an elongated cell morphology and establishment of stress fibres. The extent to which these EMT-associated changes influence cellular mechanics is unclear. We assessed the bio-mechanical properties of alveolar epithelial cells (A549) following exposure to TGF-β1. Using atomic force microscopy, changes in cell stiffness and surface membrane features were determined. Stimulation with TGF-β1 gave rise to a significant increase in stiffness, which was augmented by a collagen I matrix. Additionally, TGF-β1-treated cells exhibited a rougher surface profile with notable protrusions. Simultaneous quantitative examination of the morphological attributes of stimulated cells using an image-based high-content analysis system revealed dramatic alterations in cell shape, F-actin content and distribution. Together, these investigations point to a strong correlation between the cytoskeletal-associated cellular architecture and the mechanical dynamics of alveolar epithelial cells undergoing EMT. Description: PUBLISHED 2012-01-01T00:00:00Z http://hdl.handle.net/2262/64030 Title: Approaches to the safety assessment of engineered nanomaterials (ENM) in food Author: RADOMSKI, MAREK Abstract: A systematic, tiered approach to assess the safety of engineered nanomaterials (ENMs) in foods is presented. The ENM is first compared to its non-nano form counterpart to determine if ENM-specific assessment is required. Of highest concern from a toxicological perspective are ENMs which have potential for systemic translocation, are insoluble or only partially soluble over time or are particulate and bio- persistent. Where ENM-specific assessment is triggered, Tier 1 screening considers the potential for translocation across biological barriers, cytotoxicity, generation of reactive oxygen species, inflammatory response, genotoxicity and general toxicity. In silico and in vitro studies, together with a sub-acute repeat-dose rodent study,could be considered for this phase. Tier 2 hazard characterisation is based on a sentinel 90-day rodent study with an extended range of endpoints, additional parameters being investigated case-by-case. Physicochemical characterisation should be performed in a range of food and biological matrices. A default assumption of 100% bioavailability of the ENM provides a ‘worst case’ exposure scenario, which could be refined as additional data become available. The safety testing strategy is considered applicable to variations in ENM size within the nanoscale and to new generations of ENM. Description: PUBLISHED 2011-01-01T00:00:00Z http://hdl.handle.net/2262/63992 Title: In-vivo impact of prodrug isosorbide-5-nicotinate-2-aspirinate on lipids and prostaglandin D2: is this a new immediate-release therapeutic option for niacin? Author: GILMER, JOHN FRANCIS; HARMON, SHONA; Jones, Michael Abstract: Objectives: To evaluate the pharmacokinetics and effects of the first immediate-release (IR) niacin-aspirin prodrug (ST0702) on lipid, prostaglandin and thromboxane levels in non-human primates (NHPs). Methods: We compared 28 mg/kg crystalline IR niacin, equimolar doses of crystalline IR ST0702 and control (daily oral gavage) on low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides (Tg) in NHPs (6 per group) over 48 hours. In addition, we compared IR niacin and ST0702 effects on prostaglandin (PG)D2, ex-vivo thromboxane B2 (TXB2) levels and plasma pharmacokinetics. Results: ST0702 is metabolised in-vivo to aspirin, niacin and salicylic acid with Tmax values of 30, 45 and 95 minutes respectively using a non-compartmental model. ST0702 resulted in 38% and 40% reductions in LDL-C and ApoB levels compared to control over the 48 hour period (p = 0.027 and p = 0.012 respectively). Corresponding values were 32% and 25% for niacin (both p = NS vs control). ST0702, but not niacin, decreased Tg levels (p = 0.017 for between group difference). Post prandial glycaemia was attenuated vs baseline in the ST0702 group only. Ex-vivo serum TXB2 generation was suppressed at 15 minutes and complete suppression of TXB2 was sustained at 24 hours (p < 0.01 vs niacin). ST0702 suppressed PGD2 exposure eightfold (p = 0.012) compared to niacin over the first 24 hours Conclusions: This two-dose study in NHPs suggests that ST0702 is more effective than IR niacin on lipid profiles, while suppressing TXB2 and PGD2 increases and preventing post-prandial glycaemia. ST0702 shows promise as a new IR therapeutic option for niacin Description: IN_PRESS 2012-01-01T00:00:00Z http://hdl.handle.net/2262/63920 Title: The potential of metabolic fingerprinting as a tool for the modernisation of TCM preparations Author: SHERIDAN, HELEN Abstract: A vast majority Chinese Herbal Medicines (CHM) are traditionally administered as individually prepared water decoctions (tang) which are rather complicated in practice and their dry extracts show technological problems that hamper straight production of more convenient application forms. Modernised extraction procedures may overcome these difficulties but there is lack of clinical evidence supporting their therapeutic equivalence to traditional decoctions and their quality can often not solely be attributed to the single marker compounds that are usually used for chemical extract optimisation. As demonstrated by the example of the rather simple traditional TCM formula Danggui Buxue Tang, both the chemical composition and the biological activity of extracts resulting from traditional water decoction are influenced by details of the extraction procedure and especially involve pharmacokinetic synergism based on co-extraction. Hence, a more detailed knowledge about the traditional extracts’ chemical profiles and their impact on biological activity is desirable in order to allow the development of modernised extracts that factually contain the whole range of compounds relevant for the efficacy of the traditional application. We propose that these compounds can be identified by metabolomics based on comprehensive fingerprint analysis of different extracts with known biological activity. TCM offers a huge variety of traditional products of the same botanical origin but with distinct therapeutic properties, like differantially processed drugs and special daodi qualities. Through this variety, TCM gives an ideal field for the application of metabolomic techniques aiming at the identification of active constituents. Description: IN_PRESS 2012-01-01T00:00:00Z http://hdl.handle.net/2262/63819 Title: Transport of the fluorescent organic cation 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) in human respiratory epithelial cells Author: EHRHARDT, CARSTEN; SALOMON, JOHANNA Abstract: Organic cation/carnitine transporters (OCT/N) mediate uptake of positively charged molecules. Their role in lung epithelium, however, is not well understood. OCT/N expression and activity was studied in cell lines of human alveolar (A549), bronchial (16HBE14o- and Calu-3) and intestinal (Caco-2) epithelium. Protein levels were largely comparable for all OCT/Ns in the respiratory epithelial cell lines studied, however, OCT2 was exclusively observed in A549 cells. OCT1 and -2 were present at significantly higher levels in Caco-2 cells, compared with the pulmonary epithelial cell types. OCTN1 and -2 were also more abundant in Caco-2. Only OCT3 was expressed evenly across all cell lines investigated. Uptake of 4-(4-(dimethylamino)styryl)-N-methylpyridinium iodide (ASP+) was dependent on concentration, temperature, membrane potential and pH. In 16HBE14o-, Calu-3 and Caco-2 monolayers substrate saturation of ASP+ uptake was not reached. Alveolar A549 cells showed saturable ASP+ uptake via two transporter sites with Km values of 12.5±4.0 μM and 456.9±164.5 μM, respectively. This uptake was sensitive to organic cations, but insensitive to carnitine and lysine. We conclude that uptake of organic cations is facilitated by distinct pathways in different regions of lung mucosa. Luminally localised OCT2 appears to be exclusively involved in the alveolar epithelium, whereas basolateral localised OCT3 might play a role in alveolar as well as in bronchial epithelial cells. Description: PUBLISHED 2012-01-01T00:00:00Z http://hdl.handle.net/2262/62536 Title: Mechanisms of aggregation inhibition by aspirin and nitrate-aspirin prodrugs in human platelets Author: SANTOS-MARTINEZ, MARIA JOSE; RADOMSKI, MAREK Abstract: OBJECTIVES: Aspirin is the mainstay of anti-platelet therapy in the secondary prevention of cardiovascular disease. However, problems with aspirin safety and resistance demand clinical strategies based on multiple pharmacological approaches. Prodrugs of aspirin may offer beneficial effects in terms of gastro-intestinal safety and multiple pharmacological approaches. However, the pharmacological profile of aspirin prodrugs in human platelets has not been completed yet. We aimed to compare the effects of aspirin and prodrugs of aspirin (1-5) on human platelet aggregation stimulated by ADP and collagen and associated receptor expression (GPIIb/IIIa and P-selectin) in platelet-rich plasma (PRP) and washed platelets (WP). METHODS: As aspirin is released from prodrugs following esterase hydrolysis we studied the expression and activity of butyrylcholineterase (BuChE) and carboxyesterase (CE) in plasma and platelets. The mechanism of prodrug-induced platelet aggregation inhibition was explored by studying the effects of plasma and purified human BuChE on aggregation. Finally, the relative contribution of nitric oxide (NO) bioactivity to nitrate-containing prodrugs of aspirin-induced inhibition of aggregation was determined using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ,) a selective inhibitor of the soluble guanylyl cyclase. KEY FINDINGS: ST0702, 2, a nicotinic acid-aspirin codrug was equipotent with aspirin with respect to inhibition of collagen-induced platelet aggregation. Compound 4, a NO releasing aspirin was the most potent inhibitor of ADP-induced platelet aggregation, an effect partially reversed by ODQ. The platelet inhibitory effects of aspirin prodrugs were time-dependent as the maximal inhibitory effects against collagen-induced aggregation were achieved by aspirin at 2 min, 1 at 5 min and ST0702 at 15 min. The aspirin prodrugs were significantly less potent in WP than in PRP and the reverse was true of aspirin. In the presence of complete BuChE inhibition in PRP, there was almost complete loss of aspirin prodrug, but not aspirin anti-aggregatory activity. Interestingly, CE activity was observed in WP and platelet lysate with pNPA substrate. Accordingly, 1 and ST0702 retained 50% and 100% anti-aggregatory activity at maximal concentrations in WP, which was attenuated in the presence of esterase inhibitor phenylmethylsulphonyl fluoride. CONCLUSIONS: The inhibitory effect of aspirin prodrugs in PRP is due to prodrug activation by BuChE. In contrast, the platelet-inhibitory effects of aspirin prodrugs in WP may be mediated through the activity of platelet CE. Compound 4, a NO-containing aspirin prodrug, may exert dual inhibitory effects in platelets. Thus, aspirin prodrugs effectively inhibit human platelet aggregation and as such may be an alternative to conventional aspirin. Description: PUBLISHED 2012-01-01T00:00:00Z http://hdl.handle.net/2262/62421 Title: The PSD-95/nNOS Complex: New Drugs for Depression? Author: DEV, KUMLESH; HARKIN, ANDREW; DOUCET, MARIKA Abstract: Drug treatment of major depressive disorder is currently limited to the use of agents which influence monoaminergic neuronal transmission including inhibitors of presynaptic transporters and monoamine oxidase. Typically improvement in depressive symptoms only emerges after several weeks of treatment, suggesting that downstream neuronal adaptations rather than the elevation in synaptic monoamine levels are responsible for antidepressant effects. In recent years, the NMDA receptor has emerged as a promising target for treating CNS disorders including stroke, pain and depression. In this review, we outline the molecular mechanisms underlying NMDA receptor signaling in neurons and in particular provide an overview of the role of the NMDAR/PSD-95/nNOS complex in CNS disorders. We discuss novel drug developments made that suggest the NMDAR/PSD-95/nNOS complex as a potential target for the treatment of depression. The review also provides examples of how PDZ-based protein-protein interactions can be exploited as novel drug targets for disease. Description: PUBLISHED 2012-01-01T00:00:00Z http://hdl.handle.net/2262/61641 Title: A novel toxic alkaloid from poison hemlock (Conium maculatum L., Apiaceae): identification, synthesis and antinociceptive activity Author: BOYLAN, FABIO Abstract: 2-Pentylpiperidine, named conmaculatin, a novel volatile alkaloid related to coniine was identified from the renowned toxic weed Conium maculatum L. (Apiaceae). The structure of conmaculatin was corroborated by synthesis (8 steps starting from cyclohexanol, overall yield 12%). Conmaculatin’s strong peripheral and central antinociceptive activity in mice was observed in a narrow dose range (10-20 mg/kg). It was found to be lethal in doses higher than 20 mg/kg. Description: PUBLISHED 2012-01-01T00:00:00Z