Pharmacy - Doctoral Theses
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Item The design of cyclodextrins for delivery of siRNA - a structure-activity relationship(University College Cork, 2024) Kont, Ayse; O'Driscoll, Caitriona M.; Griffin, Brendan T.; Science Foundation Ireland; Jazz Pharmaceuticals; Advanced Materials and Bioengineering ResearchPreviously non-viral delivery of therapeutic nucleic acids (NAs) has been achieved for the treatment of liver disease and in the case of the COVID-19 vaccine. The delivery vector in both applications was a lipid-base nanoparticle (LNP). To expand the therapeutic application of NAs to treat more complex chronic diseases, such as cancer, delivery systems with wider biodistribution capable of going beyond the vaccine and the liver are required. This thesis aims to investigate the potential of modified cyclodextrins (CDs) as alternative biomaterials for siRNA delivery and to identify the optimum functional groups to maximise safety and efficacy. To help reduce the overall cationic charge and the potential for in vivo toxicity a co-formulation approach using a blend of an anionic and cationic amphiphilic CDs was investigated. The co-formulation was characterised and a reduction in the positive charge was achieved. The NPs were evaluated in vitro in HL-60, a leukaemia cell line, and results indicate that endosomal escape was a limiting factor to gene silencing with the siRNA. Structural modification of amphiphilic cationic CDs was investigated as a second approach to enhance the efficacy of CD NPs. The structural changes included varying the terminal amine, the linker, and the CD type, β versus γ. Primary amine proved to be more successful compared to tertiary amine in β- and γ-CDs. However, neither CD type was superior to the other, containing the primary amines. The exhaustive derivatisation of the secondary side of γ-CDs increased charge density and led to better transfection efficiency compared to O2-modified γ-CDs. Finally, the exchange of the linker group from triazole to thiopropyl increased the efficiency further in primary amine O2- and O3-substituted γ-CD. The optimum cellular uptake and gene silencing, in a lung cancer cell line (A549), was achieved with an O2- and O3-substituted γ-CD with a thiopropyl-linked primary amine. Finally, the potential ability of CD polymers to deliver siRNA was studied. Two cationic β-CD-polymers one functionalised with a primary amine and the other with a quaternary ammonium were used to formulate NPs containing siRNA. Both polymers formed NPs with sizes in the range of 150 to 200 nm. The primary amine functionalised polymer was taken up into the cells (A549) and produced 40% gene silencing. In contrast, the quaternary ammonium polymer failed to show any cellular uptake. The superior delivery effect achieved with the primary amine functional group agreed with the previous results from the monomer CD. In conclusion, modulation of the physicochemical characteristics of siRNA-NPs was achieved by changing the chemistry of the incorporated CD. The chemical structure significantly influenced the degree of gene knockdown. The primary amine showed superior efficiency in both monomeric amphiphilic cationic CDs and polymeric cationic CDs. Results indicate that further functionalisation of the CD is possible, and the potential exists to fine-tune the structure to achieve more specific biodistribution.Item Guideline-led prescribing to heart failure patients in Ireland and Egypt(University College Cork, 2019-06) El Hadidi, Seif; Bermingham, Margaret; Byrne, Stephen; Darweesh, Ebtissam; Future University in Egypt; University College CorkIntroduction: Guidelines strongly recommend patients with Heart Failure (HF) be treated with multiple medications proven to improve clinical outcomes, as tolerated. Guideline-led prescribing of HF evidence-based medicines is strongly associated with improved survival, prognosis, and quality of life in HF. The guidelines strongly recommend, and the optimal patient outcomes are achieved with an appropriate prescription of target doses of all HF therapies. The degree to which gaps in medication use and dosing persist in contemporary Irish or Egyptian practices is unclear. Aim: To assess guideline-led prescribing of the evidence-based HF medications in routine clinical practice in Ireland and Egypt and to assess the prevalence of HF-specific potentially inappropriate prescribing in the same Irish and Egyptian clinical settings. Method: Firstly, a narrative literature review was undertaken to determine and compare the available data and gaps in knowledge regarding HF management in Ireland as a developed European country, and Egypt as a developing Middle-Eastern country, with a particular focus on the guideline-directed medical therapies. Secondly, a systematic review was undertaken to identify the objective quantitative tools to assess the quality of HF prescribing practice. Next, a prospective cohort study was conducted on an Irish outpatient population to evaluate the extent of use and dosing of the guideline-directed medical therapies. Then, a multicentre retrospective study was carried out in 14 Long-Term Care (LTC) facilities in Cork County to assess the prevalence of appropriate and potentially inappropriate prescribing practices. In Egypt, a longitudinal observational study was conducted in order to evaluate the prescribing quality and patterns in HF patients in an Egyptian critical care setting at discharge. Finally, a descriptive survey was developed to address the barriers to guideline-led prescribing in a middle-income setting. Results: The literature review identified many gaps in knowledge in the Egyptian and Irish literature on HF. For instance, the studies included in the review did not discuss the target dose prescribing. The systematic review identified the widespread use of the Guideline Adherence Index (GAI-3) in 13 studies worldwide in the quantitative assessment of HF prescribing. The Irish HF outpatient study showed room for optimising the prescription of the guideline-directed medical therapies in 34% of ambulatory patients. No patient achieved the 100% target dose of all three evidence-based medications. The prevalence of potentially inappropriate prescribing was 20%. The Irish LTC study showed that patients with HF were older than those without HF (84.8 ± 7.4 vs 83.4 ± 7.9 years, p-value = 0.024). Loop diuretic was the most frequently prescribed HF medication up to 88% of the total population and renin-angiotensin system inhibitors to 24.2% only. The prevalence of potentially inappropriate prescribing in LTC was 24%. On the other hand, the Egyptian longitudinal study showed the moderate adherence level at discharge from the critical care unit but the potential role of clinical pharmacy service in HF drug therapy optimisation via improving beta-blocker prescription rates by from 24% to 38% and reducing digoxin rates from 34% to 23%. However, the service did not improve the overall guideline adherence levels or the prevalence of inappropriate prescribing. The survey explored some new aspects in HF practice, such as the urgent need for locally-drafted guidelines and the more significant implementation of clinical pharmacy service to optimise the implementation of guideline-led prescribing in routine clinical practice. Conclusion: This thesis has made a significant contribution to the knowledge and generated a much needed conceptual understanding of the complexity of HF guideline-led prescribing. This work reflects the moderate adherence levels to guidelines and high prevalence of potentially inappropriate prescribing in the two countries. None of the prescribers either in Ireland or Egypt prescribed at least a renin-angiotensin system inhibitor to all HF patients despite the strong, long-standing evidence.Item Exploring the utility of the pig model for predicting bioavailability in humans(University College Cork, 2020-07-01) Henze, Laura J.; Griffin, Brendan T.; Holm, René; Vertzoni, Maria; Horizon 2020Purpose It has been increasingly recognised that there is a need to reduce costly drug development delays and facilitate earlier access to market for new medicines. Within drug development, there is considerable debate on which preclinical animal model is most appropriate for assessing oral bioavailability in humans. In order to streamline preclinical development, and reduce repeated testing in various animal models, it is necessary to get a better understanding which particular animal model is suitable for a specific drug candidate. In pharmaceutical drug development, preclinical tests in animal models are essential to demonstrate whether the new drug is orally bioavailable and to gain a first insight into in vivo pharmacokinetics (PK) parameters that can subsequently be used to predict human values. Preclinical testing, therefore, provides essential scientific evidence in advance of pivotal clinical testing in humans on the safety and efficacy of new drug candidate. Despite significant advances in development of bio-predictive in vitro models and increasing ethical expectations for reducing the number of animals used for research purposes, there is still a need for appropriately selected preclinical in vivo testing to provide guidance on the decision to progress to testing in humans. The selection of appropriate animal models is essential both to maximise the learning that can be obtained from such experiments and to avoid unnecessary testing in a range of species. Selection of the right species for the various questions and compounds is therefore a critical step. While there has been extensive discussion in the literature on the use of dog and non-human primate models to predict oral bioavailability in humans (Musther et al., 2014), in relation to the pig model there are significant gaps in our understanding. Methods The suitability of the pig as a preclinical model within pharmaceutical research was evaluated using bioenabling formulations of the model drugs fenofibrate and venetoclax. In addition, the ability of predicting food dependent bioavailability was assessed for both compounds. The formulations were evaluated in vivo in landrace (LR) pigs. Followed by a post-mortem assessment of the gastrointestinal (GI) fluids, to assess fasted and fed study protocols. Subsequently the physiological composition of the porcine GI fluids has been characterised in terms of pH, buffer capacity, osmolality, surface tension, as well as the bile salt, phospholipid and free fatty acid content. Based on the findings a porcine biorelevant media (FaSSIFp) was proposed. Porcine GI transit conditions were studied with a telemetric motility capsule (SmartPill®) under fasted and postprandial conditions, by determining pH values, pressure and temperature. The physiological GI knowledge of pigs has been combined in a pig specific absorption model, to predict drug levels prospectively. Results This thesis has firstly demonstrated the suitability of the pig as a preclinical model for predicting oral bioavailability in humans. Moreover, it was the first report in the literature, where the pig model was used successfully capturing clinical reported food dependent bioavailability of the two model drugs fenofibrate and venetoclax. It was further shown that established study protocols, achieved fasted state conditions in pigs. Secondly a porcine biorelevant medium was proposed and has shown the advantage to predict luminal solubility in pigs more accurately in comparison to human biorelevant media. Thirdly an improved porcine physiologically based absorption model was used to prospectively simulate the impact of food on the bioavailability of venetoclax. By using porcine biorelevant media in combination with an in silico pig specific absorption model, it was possible to correctly predict the observed pig plasma concentration profile and food effect. Conclusion The thesis demonstrated that pigs are a suitable model in preclinical research to predict drug product performance and oral bioavailability in humans, including challenging compounds and different formulation strategies. The established porcine physiologically based pharmacokinetic (PBPK) model in combination with the proposed porcine biorelevant medium, can lead to more efficient preclinical processes and provide for more informed decision making on the formulation properties, as summarized in a species specific development guide. Establishing reliable and appropriate in vitro models to reflect preclinical conditions, can lead to reduction and replacement of animal experiments in preclinical development processes. Overall, the impact of this thesis is that the range of application of the pig model can be extended, to address parallel goals in in vivo animal studies, by evaluating optimal formulation strategies to improve drug absorption, as well as predicting impact of food on oral drug product performance early in the product lifecycle.Item Patient safety culture in Irish healthcare: a mixed-methods investigation(University College Cork, 2020-10) Gleeson, Laura; Byrne, Stephen; O'Mahony, DenisIntroduction: Medical error is a leading cause of preventable harm worldwide. Patient safety culture has been described as the way in which members of a healthcare organisation think about and prioritise safety. The patient safety culture in a healthcare organisation can be affected by numerous factors including staff perceptions of teamwork, patient safety, working conditions and support from management in their clinical area. A positive patient safety culture has been reported to have a positive impact on patient safety. Various instruments have been used to measure patient safety culture in healthcare organisations around the world over the past two decades, however there is a lack of research on the patient safety culture in Irish healthcare organisations. Over the past decade, the Irish healthcare system has suffered from the after effects of the global financial crisis and historic underfunding, which has led to understaffing and overcrowding in hospitals. The aim of this thesis was to investigate the patient safety culture in Ireland and to explore methods to improve patient safety in Irish healthcare organisations. Methods: A mixed-methods approach was adopted throughout this thesis. First, a mixed-methods survey study using the Safety Attitudes Questionnaire was carried out to investigate the safety culture in a number of healthcare organisations in the south-west of Ireland. The study involved quantitative analysis of survey results as well as qualitative analysis of data gathered in the comments section of the survey. The results of this mixed methods study informed the development of the topic guide for a qualitative interview study, which aimed to further explore staff perceptions of the safety culture in a large Irish teaching hospital. The results of the survey and interview studies led to the conduction of two systematic reviews: 1) a quantitative systematic review on interventions to improve medication error reporting in hospitals, and 2) a qualitative systematic review on healthcare professionals’ experiences of interprofessional communication. Results: The mixed methods survey study and qualitative interview study found that Irish healthcare professionals generally have positive attitudes towards the patient safety culture in their clinical area. A number of potential areas for improvement were identified including working conditions, interprofessional communication, education, support from management and medication error reporting. The quantitative systematic review on medication incident reporting identified a lack of intervention studies of strong methodological quality. Anonymity, reporting system format, education and a non-punitive culture were identified as important factors to consider when designing an intervention to improve medication error reporting. The qualitative systematic review on interprofessional communication found that personal factors, such as strong working relationships and an interprofessional ethos can act as facilitators, while organisational factors such as hierarchy and stressful working conditions can act as barriers to interprofessional communication. Conclusions: This thesis has made a significant contribution to patient safety research and to the knowledge available regarding patient safety culture in Irish healthcare. This thesis makes three novel contributions to the literature on patient safety: 1) An insight into safety culture in Irish healthcare organisations, 2) A novel systematic review of interventions to improve medication incident reporting and 3) A novel systematic review of healthcare professionals’ experiences of interprofessional communication. This thesis therefore lays the groundwork for two future studies to improve patient safety in Irish healthcare organisations, and should therefore be used as a guide for future patient safety research.Item Oral dosage form modifications for older adults: a mixed methods investigation(University College Cork, 2018) McGillicuddy, Aoife; Sahm, Laura; Crean, Abina; Irish Research Council; University College CorkIntroduction: Oral dosage forms (ODFs), particularly solid ODFs, are the most popular and most commonly prescribed of all medication formulations. Older adults are the highest consumers of prescription medication. However, age-related pharmacokinetic, pharmacodynamic and physiological changes can complicate the administration of oral medicines to older adults and may result in these ODFs being modified (e.g. tablets crushed or split, or capsules opened) in order to facilitate administration of the appropriate dose or to overcome swallowing difficulties. These modifications may impact on the safety and/or efficacy of the medication, which could have clinical consequences for patients. In addition, many of these modifications represent an off-licence use of the medication, which has subsequent legal implications for healthcare professionals. Despite guidelines advocating that the modification of ODFs should be avoided, it appears to be common practice. Therefore, there is a need to gain a greater understanding of ODF modifications for older adults. Aim: The overall aim of this research was to investigate ODF modifications for older adults in an Irish setting and to gain an understanding of the factors influencing this practice. Methods: A mixed methods approach, using both quantitative and qualitative research methods, was used. Initially, a quantitative systematic review was conducted to identify the available evidence on the prevalence of difficulty swallowing ODFs and the modification of ODFs to overcome swallowing difficulties amongst the older cohort. Secondly, a qualitative systematic review was undertaken to determine the knowledge, attitudes and beliefs of patients, healthcare professionals and carers about ODF modifications. The findings of these reviews served to guide the generation of research questions for the empirical, primary research studies. A retrospective audit of drug charts in one aged care facility (ACF) in Ireland was completed to provide preliminary data on ODF modifications in an Irish setting. Following this, a qualitative, semi-structured interview study was conducted with nurses working in acute and long-term care settings, to elucidate their knowledge, attitudes and beliefs about ODF modification and administration for older adults. Based on the findings of these studies, a direct observation of medication administration to older adults in five ACFs was conducted to provide more in-depth information on ODF modifications. Finally, the views and experiences of community-dwelling older adults and their carers around ODF modifications were explored using qualitative, semi-structured interviews. Results: The quantitative systematic review highlighted the paucity of studies investigating ODF modifications, with only three studies describing modifications in care settings, which when combined with the limitations of the data collection methods used, demonstrated the requirement for further research investigating this issue. The qualitative systematic review provided useful insights into the factors that influence the knowledge, attitudes and beliefs of healthcare professionals and patients about ODF modifications; highlighting that (i) the variability of individual patient’s requirements, (ii) poor communication practices and (iii) lack of knowledge about modifications, when combined with (iv) the complex healthcare environment, complicate decision-making regarding ODF modification. Results from the retrospective audit emphasised that modifications were commonly required to ensure patients’ needs could be met, particularly for fractional dosing. Whilst there was a lack of evidence-based information to support decision making around modifications, in many cases no suitable alternatives were available. This was echoed in the nurse interview study, with modifications seen to be a routine and necessary occurrence in older patient care. The nurses’ role as patient advocate however, helps to optimise formulation suitability within current limitations. The direct observation study once again demonstrated the ubiquity of ODF modifications, providing detailed insights into ODF modification practices in an Irish setting but also highlighting the challenges encountered when administering oral medicines to older adults. Finally, the challenges encountered in the community-setting were elucidated, and there is a clear need for greater engagement with the issue of ODF suitability for community-dwelling older adults. Conclusions: This thesis has made a significant contribution to understanding ODF modifications for older adults. It is clear that ODFs are not meeting the needs of the older cohort. Modifications are common and necessary, due to age-related changes combined with limitations of currently available formulations. This thesis has provided important information about current practices, but has also highlighted the complex factors that give rise to the need to modify ODFs for older adults. There is a need to prioritise engaging with this issue in order to optimise ODF suitability for older adults. This will necessitate input from a wide variety of key stakeholders, including healthcare professionals, industry and regulatory bodies, as well as patients and carers. The findings of this thesis provide direction and important insights that will guide this process.