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- Item1,3-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 Technology2-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.
- Item1,3-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 Technology1,3-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.
- ItemThe 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.
- ItemThe 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 MeasureDue 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.
- ItemAcceptability 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 BoardVaccines 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.
- ItemAddition-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 CorkSynthetically 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.
- ItemAdvances 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 FundRNA-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.
- ItemAdvances 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 ProgrammePeroxide-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.
- ItemAdvancing algorithmic drug product development: Recommendations for machine learning approaches in drug formulation(Elsevier B.V., 2023-09-29) Murray, Jack D.; Lange, Justus J.; Bennett-Lenane, Harriet; Holm, René; Kuentz, Martin; O'Dwyer, Patrick J.; Griffin, Brendan T.; Irish Research Council; Horizon 2020Artificial intelligence is a rapidly expanding area of research, with the disruptive potential to transform traditional approaches in the pharmaceutical industry, from drug discovery and development to clinical practice. Machine learning, a subfield of artificial intelligence, has fundamentally transformed in silico modelling and has the capacity to streamline clinical translation. This paper reviews data-driven modelling methodologies with a focus on drug formulation development. Despite recent advances, there is limited modelling guidance specific to drug product development and a trend towards suboptimal modelling practices, resulting in models that may not give reliable predictions in practice. There is an overwhelming focus on benchtop experimental outcomes obtained for a specific modelling aim, leaving the capabilities of data scraping or the use of combined modelling approaches yet to be fully explored. Moreover, the preference for high accuracy can lead to a reliance on black box methods over interpretable models. This further limits the widespread adoption of machine learning as black boxes yield models that cannot be easily understood for the purposes of enhancing product performance. In this review, recommendations for conducting machine learning research for drug product development to ensure trustworthiness, transparency, and reliability of the models produced are presented. Finally, possible future directions on how research in this area might develop are discussed to aim for models that provide useful and robust guidance to formulators.
- ItemAge-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 MedicineBackground: 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.
- ItemAlkyl 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 RazvojaTwo 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.
- ItemAngiotensin-(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 TecnológicaAngiotensin (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.
- ItemAnisamide-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 IrelandA 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.
- ItemAnisamide-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 CouncilMetastatic 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.
- ItemAnisamide-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 UniversitySmall 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.
- ItemAntimicrobial 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, AoifeBackground: 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.
- ItemApplication 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 ProgrammeBumetanide 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.
- ItemThe application of molecular tethers in controlling axial chirality(Bentham Science Publishers, 2016-06) Reen, Michael; O'Sullivan, Timothy P.Atropisomeric biaryl compounds are an attractive target in organic chemistry due to their abundance in nature and their utility as ligands in catalysis. Among the methods available for their synthesis, the use of chiral tethers offers very high levels of stereocontrol. In this article, we review the application of molecular tethers in controlling axial chirality across a range of different ligands and natural products.
- ItemThe application of percolation threshold theory to predict compaction behaviour of pharmaceutical powder blends(Elsevier, 2019-05-13) Queiroz, Ana Luiza P.; Faisal, Waleed; Devine, Ken; Garvie-Cook, Hazel; Vucen, Sonja; Crean, Abina M.; Science Foundation Ireland; European Regional Development FundPercolation theory provides a statistical model which can be used to predict the behaviour of powder blends based on particle-particle interactions. The aim of this study was to investigate if percolation theory could be used to predict the drug loading concentration of pharmaceutical tablets, and the relative density of a blend, above which tablet tensile strength is reduced, resulting in the production of unsatisfactory products. The model blend studied contained ibuprofen as the API, which exhibits poor flow and compressibility, and microcrystalline cellulose (MCC) as the excipient, which exhibits good flowability and compressibility. Two MCC grades with differing physical properties were investigated, Vivapur® 102 (air streamed dried quality), and Emcocel® 90 (spray dried quality) to test the theory. Blends containing 2.5 to 40% w/w of ibuprofen were compacted at a range of pressures and the values of the powder true density, compaction pressure, tablet envelope density, and tablet tensile strength were used to calculate the percolation thresholds mathematically. The drug loading threshold values predicted with the model (19.08% w/w and 17.76% w/w respectively for Vivapur® 102 and Emcocel® 90) were found to be in good agreement when compared to experimental data and the infinite cluster of drug was visually confirmed on the surface of tablets using Raman imaging. The capability of multivariate analysis to predict the drug loading threshold was also tested. Principal component analysis was unable to identify the threshold, but provided an overview of the changes of the analysed properties as ibuprofen drug loading increased. It was also able to identify differences between blends containing Vivapur® or Emcocel®. In conclusion, percolation theory was able to predict the maximum acceptable drug loading for this binary system of API and excipient. This methodology could be employed for other binary systems to predict maximum drug loading potential without the need for time consuming and expensive tablet production.
- ItemApplication of percolation threshold to disintegration and dissolution of ibuprofen tablets with different microcrystalline cellulose grades(Elsevier, 2020-09-03) Queiroz, Ana Luiza P.; Wood, Barbara; Faisal, Waleed; Farag, Fatma; Garvie-Cook, Hazel; Glennon, Brian; Vucen, Sonja; Crean, Abina M.; Science Foundation Ireland; European Regional Development FundThe study presented was conducted to determine whether a percolation threshold value, previously determined for ibuprofen/microcrystalline cellulose (MCC) blends using percolation theory and compression data (Queiroz et al., 2019), could translate to tablet disintegration and dissolution data. The influence of MCC grade (air stream dried versus spray dried) on tablet disintegration and dissolution was also investigated. Complementary to conventional disintegration and dissolution testing, Raman imaging determined drug distribution within tablets, and in-line particle video microscopy (PVM) and focused-beam reflectance measurement (FBRM) monitored tablet disintegration. Tablets were prepared containing 0–30% w/w ibuprofen. Raman imaging confirmed the percolation threshold by quantifying the number and equivalent circular diameters of ibuprofen domains on tablet surfaces. Across the percolation threshold, a step change in dissolution behaviour occurred, and tablets containing air stream dried MCC showed slower disintegration rates compared to tablets containing spray dried MCC. Dissolution measurements confirmed experimentally a percolation threshold in agreement with that determined using percolation theory and compression data. An increase in drug domains, due to cluster formation, and less efficient tablet disintegration contributed to slower ibuprofen dissolution above the percolation threshold. Slower dissolution was measured for tablets containing air stream dried compared to spray dried MCC.