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1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with diazoalkanes
(RSC Publishing, 2010-06-21) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
2-Thio-3-chloroacrylamides undergo 1,3-dipolar cycloadditions with diazoalkanes leading to a series of novel pyrazolines and pyrazoles. The mechanistic and synthetic features of the cycloadditions to the 2-thio-3-chloroacrylamides at both the sulfide and sulfoxide levels of oxidation are rationalised on the basis of the nature of the substituents.
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones
(Elsevier, 2010-06-19) Kissane, Marie; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology
1,3-Dipolar cycloadditions of 2-thio-3-chloroacrylamides with nitrile oxides and nitrones is described. A series of novel isoxazolines are isolated from the nitrile oxide cycloadditions, whilst the isoxazolines generated from the nitrone cycloadditions undergo further ring opening to yield piperidines.
The 5-HT1F receptor as the target of ditans in migraine - from bench to bedside
(Springer Nature Ltd., 2023-07-12) Mitsikostas, Dimos D.; Waeber, Christian; Sanchez-del-Rio, Margarita; Raffaelli, Bianca; Ashina, Håkan; Maassen van den Brink, Antoinette; Andreou, Anna; Pozo-Rosich, Patricia; Rapoport, Alan; Ashina, Messoud; Moskowitz, Michael A.
Migraine is a leading cause of disability in more than one billion people worldwide, yet it remains universally underappreciated, even by individuals with the condition. Among other shortcomings, current treatments (often repurposed agents) have limited efficacy and potential adverse effects, leading to low treatment adherence. After the introduction of agents that target the calcitonin gene-related peptide pathway, another new drug class, the ditans — a group of selective serotonin 5-HT1F receptor agonists — has just reached the international market. Here, we review preclinical studies from the late 1990s and more recent clinical research that contributed to the development of the ditans and led to their approval for acute migraine treatment by the US Food and Drug Administration and the European Medicines Agency.
The ability of Listeria monocytogenes to form biofilm on surfaces relevant to the mushroom production environment
(Elsevier, 2019-10-22) Dygico, Lionel Kenneth; Gahan, Cormac G.; Grogan, Helen; Burgess, Catherine M.; Department of Agriculture, Food and the Marine, Ireland; Food Institutional Research Measure
Due to its ubiquitous nature, Listeria monocytogenes is a threat to all fresh fruits and vegetables, including mushrooms, which are Ireland's largest horticultural crop. Although fresh cultivated mushrooms (Agaricus bisporus) have not been previously linked with listeriosis outbreaks, the pathogen still poses a threat to the industry, particularly due to its ability to form biofilms. This threat is highlighted by the multiple recalls of mushroom products caused by L. monocytogenes contamination and by previous studies demonstrating that L. monocytogenes is present in the mushroom production environment. In this study, the biofilm formation potential of L. monocytogenes strains isolated from the mushroom production environment was investigated on materials and at temperatures relevant to mushroom production. A preliminary assessment of biofilm formation of 73 mushroom industry isolates was undertaken using a crystal violet assay on polystyrene microtitre plates. The biofilm formation of a subset (n = 7) of these strains was then assessed on twelve different materials, including materials that are representative of the materials commonly found in the mushroom production environments, using the CDC biofilm reactor. Vertical scanning interferometry was used to determine the surface roughness of the chosen materials. All the strains tested using the CDC biofilm reactor were able to form biofilms on the different surfaces tested but material type was found to be a key determining factor on the levels of biofilm formed. Stainless steel, aluminium, rubber, polypropylene and polycarbonate were all able to support biofilm levels in the range of 4–4.9 log10 CFU/cm2, for seven different L. monocytogenes strains. Mushroom industry-specific materials, including growing nets and tarpaulins, were found to support biofilms levels between 4.7 and 6.7 log10 CFU/cm2. Concrete was found to be of concern as it supported 7.7 log10 CFU/cm2 of biofilm for the same strains; however, sealing the concrete resulted in an approximately 2-log reduction in biofilm levels. The surface roughness of the materials varied greatly between the materials (0.7–3.5 log10 Ra) and was found to have a positive correlation with biofilm formation (rs = 0.573) although marginally significant (P = 0.051). The results of this study indicate that L. monocytogenes can readily form biofilms on mushroom industry relevant surfaces, and additionally identifies surfaces of specific concern, where rigorous cleaning and disinfection is required.
Acceptability of microneedle-patch vaccines: A qualitative analysis of the opinions of parents
(Elsevier Ltd., 2017-08-02) Marshall, Sarah; Fleming, Aoife; Moore, Anne C.; Sahm, Laura J.; Health Research Board
Vaccines incorporated into microneedle-based patch platforms offer advantages over conventional hypodermic injections. However, the success and clinical utility of these platforms will depend on its acceptance among stakeholders. Minimal focus has been placed on determining parents' acceptability of microneedle-patch vaccines intended for paediatric use. This qualitative study probes the perceived acceptability of microneedle technology for paediatric vaccination in a parent population. Focus groups (n=6) were convened through purposive sampling of Cork city primary schools. Discussions were audio-recorded, transcribed verbatim, anonymised, independently verified and analysed by thematic analysis, with constant comparison method applied throughout. The opinions of 32 parents were included. All participants declared that their children were fully vaccinated. Five core themes were identified and defined as: (i) concern, (ii) suitability for paediatric use, (iii) potential for parental administration, (iv) the role of the healthcare professional and (v) special populations. Drivers for acceptance include; concerns with current vaccines and vaccination programmes; attributes of microneedle-patch (reduced pain, bleeding, fear and increased convenience) and endorsement by a healthcare professional. Barriers to acceptance include; lack of familiarity, concerns regarding feasibility and suitability in paediatrics, allergic potential, inability to confirm delivery and potential reduction in vaccine coverage. This is the first study to explore parental acceptance of microneedle-patch vaccines. Capturing the opinions of parents, the ultimate decision makers in paediatric vaccination, is crucial in the understanding of the eventual uptake of microneedle technology and therefore adds to literature currently available. This study has revealed that even "vaccine-acceptors"; parents who agree with, or do not question vaccination, will question the safety and efficacy of this novel method. Participants in this study remained tentative. However, the study has also revealed that endorsement by healthcare professionals could reduce this tentativeness, thereby identifying the role of healthcare professionals in disseminating information and providing support to parents. An increased awareness of developments in microneedle technology is needed to permit informed decision-making by parents.
Addition-substitution reactions of 2-thio-3-chloroacrylamides with carbon, nitrogen, oxygen, sulfur and selenium nucleophiles
(RSC Publishing, 2011-04-07) Kissane, Marie; Murphy, Maureen; O'Brien, Elisabeth; Chopra, Jay; Murphy, Linda.; Collins, Stuart G.; Lawrence, Simon E.; Maguire, Anita R.; Irish Research Council for Science Engineering and Technology; Forbairt; Merck, United States; University College Cork
Synthetically versatile conjugate addition of a range of carbon, nitrogen, oxygen, sulfur and selenium nucleophiles to the highly functionalised 2-thio-3-chloroacrylamides is described. The stereochemical and synthetic features of this transformation are discussed in detail. In most instances, the nucleophile replaces the chloro substituent with retention of stereochemistry. With the oxygen nucleophiles, a second addition can occur leading to acetals, while with the nitrogen nucleophiles, E-Z isomerism occurs in the resulting enamine derivatives. The ratio of the E/Z isomers can be rationalised on the basis of the substituent and the level of oxidation.
Advances in the design of (nano)formulations for delivery of antisense oligonucleotides and small interfering RNA: Focus on the central nervous system
(American Chemical Society, 2021-03-18) Mendonça, Monique C. P.; Kont, Ayse; Aburto, Maria Rodriguez; Cryan, John F.; O'Driscoll, Caitríona M.; Science Foundation Ireland; European Regional Development Fund
RNA-based therapeutics have emerged as one of the most powerful therapeutic options used for the modulation of gene/protein expression and gene editing with the potential to treat neurodegenerative diseases. However, the delivery of nucleic acids to the central nervous system (CNS), in particular by the systemic route, remains a major hurdle. This review will focus on the strategies for systemic delivery of therapeutic nucleic acids designed to overcome these barriers. Pathways and mechanisms of transport across the blood-brain barrier which could be exploited for delivery are described, focusing in particular on smaller nucleic acids including antisense oligonucleotides (ASOs) and small interfering RNA (siRNA). Approaches used to enhance delivery including chemical modifications, nanocarrier systems, and target selection (cell-specific delivery) are critically analyzed. Learnings achieved from a comparison of the successes and failures reported for CNS delivery of ASOs versus siRNA will help identify opportunities for a wider range of nucleic acids and accelerate the clinical translation of these innovative therapies.
Advances in the synthesis of acyclic peroxides
(Royal Society of Chemistry, 2017-03-31) O'Sullivan, Timothy P.; Gandhi, Hirenkumar; O'Reilly, Kate; Gupta, Manoj K.; Horgan, Conor C.; O'Leary, Eileen M.; Irish Research Council; European Commission; Seventh Framework Programme
Peroxide-containing compounds are an attractive synthetic target, given their widespread abundance in nature, with many displaying potent antimalarial and antimicrobial properties. This review summarises the many developments in the synthesis of acyclic peroxides, with a particular focus on the past 20 years, and seeks to update organic chemists about these new approaches. The synthetic methodologies have been subdivided into metal-catalysed reactions, organocatalytic reactions, direct oxidation reactions, miscellaneous reactions and enzymatic routes to acyclic peroxides.
Age-dependent differences in pulmonary host responses in ARDS: A prospective observational cohort study
(Springer Open, 2019-05-14) Schouten, Laura R.; van Kaam, Anton H.; Kohse, Franziska; Veltkamp, Floor; Bos, Lieuwe D.; de Beer, Friso M.; van Hooijdonk, Roosmarijn T.; Horn, Janneke; Straat, Marleen; Witteveen, Esther; Glas, Gerie J.; Wieske, Luuk; van Vught, Lonneke A.; Wiewel, Maryse A.; Ingelse, Sarah A.; Cortjens, Bart; van Woensel, Job B.; Bos, Albert P.; Walther, Thomas; Schultz, Marcus J.; Wösten-van Asperen, Roelie M.; Center for Translational Molecular Medicine
Background: Results from preclinical studies suggest that age-dependent differences in host defense and the pulmonary renin–angiotensin system (RAS) are responsible for observed differences in epidemiology of acute respiratory distress syndrome (ARDS) between children and adults. The present study compares biomarkers of host defense and RAS in bronchoalveolar lavage (BAL) fluid from neonates, children, adults, and older adults with ARDS. Methods: In this prospective observational study, we enrolled mechanical ventilated ARDS patients categorized into four age groups: 20 neonates (< 28 days corrected postnatal age), 29 children (28 days–18 years), 26 adults (18–65 years), and 17 older adults (> 65 years of age). All patients underwent a nondirected BAL within 72 h after intubation. Activities of the two main enzymes of RAS, angiotensin converting enzyme (ACE) and ACE2, and levels of biomarkers of inflammation, endothelial activation, and epithelial damage were determined in BAL fluid. Results: Levels of myeloperoxidase, interleukin (IL)-6, IL-10, and p-selectin were higher with increasing age, whereas intercellular adhesion molecule-1 was higher in neonates. No differences in activity of ACE and ACE2 were seen between the four age groups. Conclusions: Age-dependent differences in the levels of biomarkers in lungs of ARDS patients are present. Especially, higher levels of markers involved in the neutrophil response were found with increasing age. In contrast to preclinical studies, age is not associated with changes in the pulmonary RAS.
Alkyl polyglucoside vs. ethoxylated surfactant-based microemulsions as vehicles for two poorly water-soluble drugs: physicochemical characterization and in vivo skin performance
(De Gruyter Open, 2017) Pajic, Natasa Z. Bubic; Todosijevic, Marija N.; Vuleta, Gordana M.; Cekic, Nebojsa D.; Dobricic, Vladimir D.; Vucen, Sonja R.; Calija, Bojan R.; Lukic, Milica Z.; Ilic, Tanja M.; Savic, Snezana D.; Ministarstvo Prosvete, Nauke i Tehnološkog Razvoja
Two types of biocompatible surfactants were evaluated for their capability to formulate skin-friendly/non-irritant microemulsions as vehicles for two poorly water-soluble model drugs differing in properties and concentrations: alkyl polyglucosides (decyl glucoside and caprylyl/capryl glucoside) and ethoxylated surfactants (glycereth-7-caprylate/caprate and polysorbate 80). Phase behavior, structural inversion and microemulsion solubilization potential for sertaconazole nitrate and adapalene were found to be highly dependent on the surfactants structure and HLB value. Performed characterization (polarized light microscopy, pH, electrical conductivity, rheological, FTIR and DSC measurements) indicated a formulation containing glycereth-7-caprylate/caprate as suitable for incorporation of both drugs, whereas alkyl polyglucoside-based systems did not exhibit satisfying solubilization capacity for sertaconazole nitrate. Further, monitored parameters were strongly affected by sertaconazole nitrate incorporation, while they remained almost unchanged in adapalene-loaded vehicles. In addition, results of the in vivo skin performance study supported acceptable tolerability for all investigated formulations, suggesting selected microemulsions as promising carriers worth exploring further for effective skin delivery of model drugs.
Analysis of service-users attending Matt Talbot Services (MTS) from 2007-2010.
(Springer Netherlands; European Society of Clinical Pharmacy (ESCP), 2012-10-29) Murphy, Kevin D.; Byrne, Stephen; Lambert, Sharon; Sahm, Laura J.
An analysis of the pharmacist workforce capacity in Ireland over the past 15 years
(University College Cork, 2018) McMahon, Tara; Bermingham, Margaret; Griffin, Brendan T.
Background: The FIP 2018 global pharmacy workforce report identified that the pharmacy workforce is facing increasing capacity challenges and predicted that globally, the pharmacy workforce would grow by 40% over the next 15 years. The purpose of this report was to specifically examine the pharmacist workforce in Ireland over the last 15 years with reference to a number of developments that have both directly and indirectly affected the capacity of the pharmacy sector. A second objective was to benchmark the pharmacy workforce capacity in Ireland against other countries of similar demographic and economic standing in order to assess how Ireland compares. Methods: Data was collected from PSI Annual Reports, Eurostat, OECD, PHARMINE Reports, UCAS, CSO Census Reports, WHO and FIP Global Pharmacy Workforce Reports regarding the pharmacy workforce in Ireland and selected comparison countries. Comparison countries were chosen based on population, GDP/capita, healthcare expenditure and HDI values. The data was analysed and presented using graphs and tables. Results: The number of pharmacists in Ireland has increased by 90% over the last 15 years. Despite two new Schools of Pharmacy opening in 2002 (RCSI) & 2003 (UCC), 57% of new registrants to the PSI over the last 15 years qualified via the EU route, predominately from the UK. Since the first graduates from RCSI and UCC qualified, PSI registrants via the national route range between 27-56% of total additions annually. Ireland’s output of pharmacy graduates per population is 40% lower than the UK and the number of pharmacy graduates per school of pharmacy in the UK is over twice that of Ireland. Ireland has the second highest number of pharmacies per 100,000 population out of 10 comparator countries. Ireland also has the joint highest number of pharmacists per 100,000, based on the total number of pharmacists registered with the PSI. This includes 5.5 % of PSI registrants who are in non-patient facing roles, 2.5% who are not-practicing/other and 21.5% of registrants who do not state their area of practice, with only 70.5% of registrants declaring as ‘patient-facing’. Conclusions: The pharmacy workforce in Ireland is highly dependent on new registrants applying via the EU mutual recognition route, predominantly from the UK. Any interruption to mutual recognition of pharmacists between the EU and UK, as a result of Brexit, would significantly affect the capacity of pharmacy services in Ireland. Compared to similar EU countries, pharmacists/pharmacies per head of population is relatively high. However, estimates of pharmacy workforce in Ireland based on all pharmacists registered with the PSI may overestimate capacity in Ireland. In order to meet global trends of the increasing number of patients needing access to pharmacy related services and diversification of pharmacist roles, ongoing review of capacity in pharmacy is essential.
Angiotensin-(1-7) counteracts the transforming effects triggered by angiotensin II in breast cancer cells
(Impact Journals, 2017) Cambados, Nadia; Walther, Thomas; Nahmod, Karen; Tocci, Johanna M.; Rubinstein, Natalia; Boehme, Ilka; Simian, Marina; Sampayo, Rocio; Del Valle Suberbordes, Melisa; Kordon, Edith C.; Schere-Levy, Carolina; Deutsche Forschungsgemeinschaft; Ministerio de Ciencia, Tecnología e Innovación Productiva; National Cancer Institute; Consejo Nacional de Investigaciones Científicas y Técnicas; Agencia Nacional de Promoción Científica y Tecnológica
Angiotensin (Ang) II, the main effector peptide of the renin-angiotensin system, has been implicated in multiple aspects of cancer progression such as proliferation, migration, invasion, angiogenesis and metastasis. Ang-(1-7), is a biologically active heptapeptide, generated predominantly from AngII by the enzymatic activity of angiotensin converting enzyme 2. Previous studies have shown that Ang-(1-7) counterbalances AngII actions in different pathophysiological settings. In this study, we have analysed the impact of Ang( 1-7) on AngII-induced pro-tumorigenic features on normal murine mammary epithelial cells NMuMG and breast cancer cells MDA-MB-231. AngII stimulated the activation of the survival factor AKT in NMuMG cells mainly through the AT1 receptor. This PI3K/AKT pathway activation also promoted epithelial-mesenchymal transition (EMT). Concomitant treatment of NMuMG cells with AngII and Ang-(1-7) completely abolished EMT features induced by AngII. Furthermore, Ang-(1-7) abrogated AngII induced migration and invasion of the MDA-MB-231 cells as well as pro-angiogenic events such as the stimulation of MMP-9 activity and VEGF expression. Together, these results demonstrate for the first time that Ang-(1-7) counteracts tumor aggressive signals stimulated by AngII in breast cancer cells emerging the peptide as a potential therapy to prevent breast cancer progression.
Anisamide-targeted cyclodextrin nanoparticles for siRNA delivery to prostate tumours in mice
(Elsevier, 2012-11) Guo, Jianfeng; Ogier, Julien R.; Desgranges, Stephane; O'Driscoll, Caitríona M.; Darcy, Raphael; Irish Research Council for Science Engineering and Technology; Science Foundation Ireland; Enterprise Ireland
A hepta-guanidino-β-cyclodextrin (G-CD), its hepta-PEG conjugate (G-CD-PEG), and the corresponding anisamide-terminated PEG conjugate (G-CD-PEG-AA) have been synthesised and compared as delivery vectors for siRNA to prostate cancer cells and tumours in vivo. The G-CD-PEG-AA.siRNA formulations (in which anisamide targets the sigma receptor), but not the non-targeted formulations, induced prostate cell-specific internalisation of siRNA resulting in approximately 80% knockdown in vitro of the reporter gene, luciferase. Following intravenous administration of the anisamide-targeted formulation in a mouse prostate tumour model significant tumour inactivation with corresponding reductions in the level of vascular endothelial growth factor (VEGF) mRNA were achieved, without demonstrating enhanced toxicity. This data imply significant potential for anisamide-conjugated cyclodextrin vectors for targeted delivery of therapeutic siRNAs in the treatment of prostate cancer.
Anisamide-targeted gold nanoparticles for siRNA delivery in prostate cancer - synthesis, physicochemical characterisation and in vitro evaluation
(Royal Society of Chemistry, 2016-03-08) Fitzgerald, Kathleen A.; Rahme, Kamil; Guo, Jianfeng; Holmes, Justin D.; O'Driscoll, Caitríona M.; Irish Cancer Society; Science Foundation Ireland; Irish Research Council
Metastatic prostate cancer is a leading cause of cancer-related death in men and current chemotherapies are largely inadequate in terms of efficacy and toxicity. Hence improved treatments are required. The application of siRNA as a cancer therapeutic holds great promise. However, translation of siRNA into the clinic is dependent on the availability of an effective delivery system. Gold nanoparticles (AuNPs) are known to be effective and non-toxic siRNA delivery agents. In this study, a stable gold nanosphere coated with poly(ethylenimine) (PEI) was prepared to yield PEI capped AuNPs (Au-PEI). The PEI was further conjugated with the targeting ligand anisamide (AA, is known to bind to the sigma receptor overexpressed on the surface of prostate cancer cells) to produce an anisamide-targeted nanoparticle (Au-PEI-AA). The resulting untargeted and targeted nanoparticles (Au-PEI and Au-PEI-AA respectively) were positively charged and efficiently complexed siRNA. Au-PEI-AA mediated siRNA uptake into PC3 prostate cancer cells via binding to the sigma receptor. In addition, the Au-PEI-AA·siRNA complexes resulted in highly efficient knockdown of the RelA gene (∼70%) when cells were transfected in serum-free medium. In contrast, no knockdown was observed in the presence of serum, suggesting that adsorption of serum proteins inhibits the binding of the anisamide moiety to the sigma receptor. This study provides (for the first time) proof of principle that anisamide-labelled gold nanoparticles can target the sigma receptor. Further optimisation of the formulation to increase serum stability will enhance its potential to treat prostate cancer.
Anisamide-targeted PEGylated gold nanoparticles designed to target prostate cancer mediate: enhanced systemic exposure of siRNA, tumour growth suppression and a synergistic therapeutic response in combination with paclitaxel in mice
(Elsevier, 2019-02-16) Luan, Xue; Rahme, Kamil; Cong, Zhongcheng; Wang, Limei; Zou, Yifang; He, Yan; Yang, Hao; Holmes, Justin D.; O'Driscoll, Caitríona M.; Guo, Jianfeng; Department of Science and Technology of Jilin Province; Jilin University
Small interfering RNA (siRNA) has recently illustrated therapeutic potential for malignant disorders. However, the clinical application of siRNA-based therapeutics is significantly retarded by the paucity of successful delivery systems. Recently, multifunctional gold nanoparticles (AuNPs) as non-viral delivery carriers have shown promise for transporting chemotherapeutics, proteins/peptides, and genes. In this study, AuNPs capped with polyethylenimine (PEI) and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of positively charged anisamide-targeted PEGylated AuNPs (namely Au-PEI-PEG-AA). The anisamide-targeted AuNPs effectively complexed siRNA via electrostatic interaction, and the resultant complex (Au110-PEI-PEG5000-AA.siRNA) illustrated favourable physicochemical characteristics, including particle size, surface charge, and stability. In vitro, anisamide-targeted AuNPs selectively bound to human prostate cancer PC-3 cells, inducing efficient endosomal escape of siRNA, and effective downregulation of the RelA gene. In vivo, prolonged systemic exposure of siRNA was achieved by anisamide-targeted AuNPs resulting in significant tumour growth suppression in a PC3 xenograft mouse model without an increase in toxicity. In addition, a combination of siRNA-mediated NF-κB knockdown using anisamide-targeted AuNPs with Paclitaxel produced a synergistic therapeutic response, thus providing a promising therapeutic strategy for the treatment of prostate cancer.
Antimicrobial stewardship in Ireland, with a focus on long term care facilities
(University College Cork, 2015) Fleming, Aoife; Byrne, Stephen; Health Research Board
Background: Antimicrobial resistance is a major public health concern, and its increasing incidence in the Long Term Care Facility (LTCF) setting warrants attention (1). The prescribing of antimicrobials in this setting is often inappropriate and higher in Ireland than the European average (2). The aim of the study was to generate an evidence base for the factors influencing antimicrobial prescribing in LTCFs and to investigate Antimicrobial Stewardship (AMS) strategies for LTCFs. Methods: An initial qualitative study was conducted to determine the factors influencing antimicrobial prescribing in Irish LTCFs. This allowed for the informed implementation of an AMS feasibility study in LTCFs in the greater Cork region. Hospital AMS was also investigated by means of a national survey. A study of LTCF urine sample antimicrobial resistance rates was conducted in order to collate information for incorporation into future LTCF AMS initiatives. Results: The qualitative interviews determined that there are a multitude of factors, unique to the LTCF setting, which influence antimicrobial prescribing. There was a positive response from the doctors and nurses involved in the feasibility study as they welcomed the opportunity to engage with AMS and audit and feedback activities. While the results did not indicate a significant change in antimicrobial prescribing over the study period, important trends and patterns of use were detected. The antimicrobial susceptibility of LTCF urine samples compared to GPs samples found that there was a higher level of antimicrobial resistance in LTCFs. Conclusion: This study has made an important contribution to the development of AMS in LTCFs. The complexity of care and healthcare organisation, and the factors unique to LTCFs must be borne in mind when developing quality improvement strategies.
Antimicrobial use and antimicrobial resistance in Enterobacterales and Enterococcus faecium: a time series analysis
(Elsevier, 2022-01-01) O'Riordan, Frank; Shiely, Frances; Byrne, Stephen; O'Brien, Deirdre; Ronayne, Aoife; Fleming, Aoife
Background: Irish and European antimicrobial resistance (AMR) surveillance data have highlighted increasing AMR in Enterobacterales and vancomycin resistance in Enterococcus faecium (VRE). Antimicrobial consumption (AC) in Irish hospital settings is also increasing. Methods: A retrospective time series analysis (TSA) was conducted to evaluate the trends and possible relationship between AC of selected antimicrobials and AMR in Enterobacterales and vancomycin resistance in E. faecium, from January 2017 to December 2020. Results: Increased AC was seen with ceftriaxone (P = 0.0006), piperacillin/tazobactam (P = 0.03) and meropenem (P = 0.054), while ciprofloxacin and gentamicin use trended downwards. AMR rates in Escherichia coli, Klebsiella pneumoniae and other Enterobacterales were largely stable or decreasing, an increase in ertapenem resistance in the latter from 0.58% in 2017 to 5.19% in 2020 (P = 0.003) being the main concern. The proportion of E. faecium that was VRE did not changed significantly (64% in 2017; 53% in 2020, P = 0.1). TSA identified a correlation between piperacillin/tazobactam use and the decreasing rate of ceftriaxone resistance in E. coli. Conclusion: Our data suggest that the hospital antimicrobial stewardship programme is largely containing, but not reducing AMR in key nosocomial pathogens. An increase in AC following the COVID-19 pandemic appears as yet to have had no impact on AMR rates.
Application of a physiologically-based pharmacokinetic model for the prediction of bumetanide plasma and brain concentrations in the neonate
(Wiley, 2018-01-10) Donovan, Maria D.; Abduljalil, Khaled; Cryan, John F.; Boylan, Geraldine B.; Griffin, Brendan T.; Irish Research Council for Science, Engineering and Technology; Health Research Board; Science Foundation Ireland; Seventh Framework Programme
Bumetanide is a loop diuretic that is proposed to possess a beneficial effect on disorders of the central nervous system, including neonatal seizures. Therefore, prediction of unbound bumetanide concentrations in the brain is relevant from a pharmacological prospective. A physiologically‐based pharmacokinetic (PBPK) model was developed for the prediction of bumetanide disposition in plasma and brain in adult and paediatric populations. A compound file was built for bumetanide integrating physicochemical data and in vitro data. Bumetanide concentration profiles were simulated in both plasma and brain using the Simcyp PBPK model. Simulations of plasma bumetanide concentrations were compared against plasma levels published in the literature. The model performance was verified with data from adult studies before predictions in the paediatric population were undertaken. The adult and paediatric intravenous models predicted pharmacokinetic factors, namely area under the concentration–time curve, maximum concentration in plasma and time to maximum plasma concentration, within two‐fold of observed values. However, predictions of plasma concentrations within the neonatal intravenous model did not produce a good fit with the observed values. The PBPK approach used in this study produced reasonable predictions of plasma concentrations of bumetanide, except in the critically ill neonatal population. This PBPK model requires more information regarding metabolic intrinsic clearance and transport parameters prior to further validation of drug disposition predictions in the neonatal population. Given the lack of information surrounding certain parameters in this special population, the model is not appropriately robust to support the recommendation of a suitable dose of bumetanide for use as an adjunct antiepileptic in neonates.
Application of mesoporous silica for the oral delivery of poorly water-soluble drugs
(University College Cork, 2014) Ahern, Robert J.; Crean, Abina M.; Ryan, Katie B.; Science Foundation Ireland
The objective of this thesis was to improve the dissolution rate of the poorly waters-soluble drug, fenofibrate by processing it with a high surface area carrier, mesoporous silica. The subsequent properties of the drug – silica composite were studied in terms of drug distribution within the silica matrix, solid state and release properties. Prior to commencing any experimental work, the properties of unprocessed mesoporous silica and fenofibrate were characterised (chapter 3), this allowed for comparison with the processed samples studied in later chapters. Fenofibrate was a highly stable, crystalline drug that did not adsorb moisture, even under long term accelerated storage conditions. It maintained its crystallinity even after SC-CO2 processing. Its dissolution rate was limited and dependent on the characteristics of the particular in vitro media studied. Mesoporous silica had a large surface area and mesopore volume and readily picked up moisture when stored under long term accelerated storage conditions (75% RH, 40 oC). It maintained its mesopore character after SC-CO2 processing. A variety of methods were employed to process fenofibrate with mesoporous silica including physical mixing, melt method, solvent impregnation and novel methods such as liquid and supercritical carbon dioxide (SC-CO2) (chapter 4). It was found that it was important to break down the fenofibrate particulate structure to a molecular state to enable drug molecules enter into the silica mesopores. While all processing methods led to some increase in fenofibrate release properties; the impregnation, liquid and SC-CO2 methods produced the most rapid release rates. SC-CO2 processing was further studied with a view to optimising the processing parameters to achieve the highest drug-loading efficiency possible (chapter 5). In this thesis, it was that SC-CO2 processing pressure had a bearing on drug-loading efficiency. Neither pressure, duration or depressurisation rate affected drug solid state or release properties. The amount of drug that could be loaded onto to the mesoporous silica successfully was also investigated at different ratios of drug mass to silica surface area under constant SC-CO2 conditions; as the drug – silica ratio increased, the drug-loading efficiency decreased, while there was no effect on drug solid state or release properties. The influence of the number of drug-loading steps was investigated (chapter 6) with a view to increasing the drug-loading efficiency. This multiple step approach did not yield an increase in drug-loading efficiency compared to the single step approach. It was also an objective in this chapter to understand how much drug could be loaded into silica mesopores; a method based on the known volume of the mesopores and true density of drug was investigated. However, this approach led to serious repercussions in terms of the subsequent solid state nature of the drug and its release performance; there was significant drug crystallinity and reduced release extent. The impact of in vitro release media on fenofibrate release was also studied (chapter 6). Here it was seen that media containing HCl led to reduced drug release over time compared to equivalent media not containing HCl. The key findings of this thesis are discussed in chapter 7 and included: 1. Drug – silica processing method strongly influenced drug distribution within the silica matrix, drug solid state and release. 2. The silica surface area and mesopore volume also influenced how much drug could be loaded. It was shown that SC-CO2 processing variables such as processing pressure (13.79 – 41.37 MPa), duration time (4 – 24 h) and depressurisation rate (rapid or controlled) did not influence the drug distribution within the SBA- 15 matrix, drug solid state form or release. Possible avenues of research to be considered going forward include the development and application of high resolution imaging techniques to visualise drug molecules within the silica mesopores. Also, the issues surrounding SBA-15 usage in a pharmaceutical manufacturing environment should be addressed.

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