Antihypertensive pharmacotherapy is associated with poor adherence. No validated method exists to establish patients’ likely adherence level. A systematic review and a single, Swedish community pharmacy practice-based pilot study were undertaken investigating blood pressure (BP) optimization from pharmacist-led, community pharmacy based antihypertensive adherence interventions titrated to individual patients. The systematic review showed generic interventions are often used for optimizing BP. Different intervention outcomes vary: positive, negative and no effect has been demonstrated. Pilot study participants (n=153) were categorised into adherence subgroups (A=Adherent, IR=Intentionally non adherent rational, II=Intentionally non-adherent irrational, U=Unintentionally non-adherent) based on responses to questionnaire format adherence screens. Interventions were designed intuitively to optimize adherence for each subgroup: changes in blood pressure and adherence attitudes were assessed. A significant reduction in mean systolic BP (SBP) (3 mmHg, P < 0.05), with no change in mean diastolic BP (DBP) was seen overall. However, outcomes varied with subgroup: adherence was enhanced in the U subgroup (decreased SBP: 3 mmHg; DBP: no change), but indications of a detrimental effect were observed in the II subgroup (SBP: no change; increased DBP: 3 mmHg). It is feasible to assign patients to different adherence subgroups in community pharmacy, which may optimize medicines adherence through personalization of interventions.

Sarcopenia is the age-related loss of skeletal muscle mass and function; inflammation is thought to be one aetiological factor in its development. Adipose tissue accumulates with advancing age and adipose-derived cytokines (adipokines) contribute to inflammaging. Skeletal muscle myogenesis is one adaptaive mechanism by which skeletal muscle mass is sustained throughout the human lifespan. The effect of the adipose inflammatory milieu on such myogenesis is unknown, as is the relative importance of its constituent adipokines to myogenesis. This work demonstrates that conditioned medium generated from obese subcutaneuous adipose tissue has a detrimental effect on in vitro primary human myogenesis. Resistin is shown to be – in part – responsible for this phenomenon and is demonstrated to inhibit myogenesis by activating the classical NFκB pathway. Resistin is further shown to be a metabolic stressor of primary human myotubes, promoting increased oxygen consumption, fatty acid oxidation and lipid accumulation. It is important to identify more avenues for the development of pharmacological interventions in sarcopenia. To that end, this thesis also demonstrates for the first time that the myokine IL-15: 1) is pro-myogenic in primary human cultures; 2) can mitigate the detrimental effects of an inflammatory environment on myogenesis; and 3) supports myogenesis at autocrine concentrations.

The 5-HT₃ receptor is a ligand-gated ion channel that mediates for example fast synaptic neurotransmission in the CNS and PNS. 5-HT₃ receptor antagonists are established anti-emetics in the clinic, they also offer symptomatic relief for patients with irritable bowel syndrome, yet, sometimes serious side-effects limits their use in this indication. The 5-HT₃ receptor is modulated allosterically by various compounds including colchicine, alcohols and volatile anaesthetics but as yet, these modulators either lack potency or selectivity, which hinders investigation. The present study reports a novel 5-HT₃ receptor allosteric modulator that displays relatively high potency and selectivity; 5-chloro-indole (Cl-indole). Cl-indole potentiated 5-HT₃ receptor mediated responses arising from heterologous expression of the h5-HT₃A receptor (assessed by the affinity shift of agonists to compete for the radioligand binding site and by the increase in agonist action upon the h5-HT₃A receptor-mediated increase in [Ca²⁺]i; the latter action was evident with a range of agonists with very low intrinsic activity to full agonists). Cl-indole was also able to modulate allosterically the mouse native 5-HT₃ receptor. Additional studies provided further support for the role of the C-terminus of the h5-HT₃A subunit to promote stability of the arising 5-HT₃ receptor complex and that ligand interaction with the 5-HT₃A receptor impacted cell surface expression. In summary, the study reports the identification of Cl-indole as a positive allosteric modulator of the 5-HT₃ receptor along with extensions to our knowledge concerning a structural component of the 5-HT₃A subunit that promotes stability and the trafficking of the subunit into the cell membrane. These studies increase our understanding of the 5-HT₃ receptor, which may contribute to the design of better drugs targeting this receptor for therapeutic benefit.

The aim of this research was to develop a new work model for hospital pharmacists based on risk assessment of patients using an electronic prescribing and administration system (EPMA). Systematic review was performed to identify risk factors associated with clinical pharmacy intervention. Those factors which can be measured by the EPMA in a UK teaching hospital were subsequently identified. Data was extracted from the EPMA relating to risks in intervention recipients on medical and surgical wards and those patients present concurrently. Univariable and multivariable analysis was performed and a risk score calculated. Receiver operating curves (ROCs) determined predictability of the score. Risk factors for pharmacist intervention were: age, female gender, patient compliance, unavailable stock, prescription of warfarin, number of allergies, comorbidities, regular prescriptions, anti-epileptics, thrombolytics/anticoagulants, central nervous system agents, and chemotherapy / immunosuppressants. The area under the ROC for the risk score was 0.61. Multiple factors were significantly and independently associated, with an increased intervention rate. However, it was not possible to generate a useful model for directing clinical pharmacy services. Inverse relationships were demonstrated between some risk factors usually associated with problems with medicines use.

This thesis considers the role of individual members and groups of the Religious Society of Friends (Quakers) in the development of therapeutic communities and other types of therapy that consider social environments. The thesis focuses on the history of one specific therapeutic community (anonymised in the research) established and governed by a group of Quakers. The study also provides a contextual history of therapeutic environments, particularly those involving Quakers. The thesis then considers attitudes towards dealing with conflict, and how this topic has been explored in notions of 'youth' and 'adolescence', in therapeutic environments, and in Quakerism. This work was initiated as the first studentship to be supported collaboratively by the University of Birmingham and the Institute for the History and Work of Therapeutic Environments. The thesis is just one part of a process of encouraging multidisciplinary discussion of this topic among historians, archivists, practitioners and policy makers.

Prescribing of medicines is a major healthcare cost, subject to multiple influences. This study uses the lens of a Donabedian Structure-Process-Outcome model, to model those influences. The thesis examines the existing literature on the influences on Primary Care Organisation prescribing and assesses the utility of the Donabedian model when applied to prescribing. Using profiles developed for all Primary Care Organisations in England, differences in prescribing were examined over 3 years to test the utility of this model as a framework to understand prescribing influences. The prescribing of long acting insulin analogues and Glucagon-like-peptide 1 receptor (GLP-1) agonists, were profiled within Primary Care Organisations using the Donabedian model for data for three years from 2011/12 to 2013/14. This study is the first to apply the Donabedian model to influences on prescribing. This model provided a good fit for all known influences on prescribing, providing an overview of how prescribing habits of an organisation are balanced against other clinical targets in a disease area. Using the Donabedian model could enable organisations to evaluate the effect of changing an influence on prescribing behaviour.

Electronic prescribing systems (EPS) may be considered to enhance safe prescribing compared to paper-based prescribing systems. This thesis examined EPS safety, including in non-medical prescribers, in three studies. Firstly, a systematic review and meta-analysis examined the impact of EPS on the incidence of prescribing errors in hospital settings. EPS was associated with a reduction in prescribing errors based on a random effects model odds ratio (OR=0.26, 95% CI, 0.14 to 0.42, p˂0.00001). Secondly, prescribing errors detected and reported in hospital pharmacist interventions were examined. Errors were identified in 1.1% (95% CI 1.1 to 1.2%) of prescribed items. Most errors were considered significant (68.5%). Over half (56%) of errors occurred at the admission stage. Finally, a qualitative examination of semi-structured interviews was conducted with 23 medical and non–medical prescribers in a hospital. Prescribers described multiple contributory factors to electronic prescribing errors, including human factors and human-computer interactions. Prescribers’ perceptions of the benefits of EPS were clear, although concerns about overreliance on EPS and system complexity remained. Prescribers had useful suggestions to increase prescribing safety. In combination, the three branches of this thesis show EPS is an effective tool, and provides insights that can potentially optimise safe prescribing, including tailoring to end-user requirements.

Sphingosine kinase 1 (SK1) catalyses the synthesis of the important bioactive sphingolipid sphingosine-1-phosphate (S1P), that has an important role in vascular tone regulation and cardioprotection against ischaemia/reperfusion injury. The work presented in this thesis describes the influence of short periods of hypoxia on expression of SK1 in vascular endothelium and how this may regulate vascular function. The aims were achieved by using wire myography to study vascular function and confocal microscopy for the studies of expression and distribution of SK1 under normoxic and hypoxic conditions. In the first study, it was found that exposure of isolated rat coronary artery to a short period of hypoxia increases SK1 expression and ser225 phosphorylation. It was also demonstrated that the hypoxia-induced increase in SK1 expression was reduced by pre-treatment with cycloheximide, a protein synthesis inhibitor, SKi, a non-selective SK inhibitor and PF543, a selective SK1 inhibitor. However, pre-treatment with proteasomal and/or lysosomal inhibitors did not increase SK1 expression under normoxia or hypoxia. Similarity, SK1 expression was also increased in aortic endothelium following exposure to short-term hypoxia and this effect was also inhibited by cycloheximide, SKi and PF543. Collectively, these data suggest that hypoxia increases SK1 synthesis in coronary and aortic endothelium. Moreover, the SKi-induced reduction in SK1 expression in coronary endothelium was reversed by proteasomal and/or lysosomal inhibitors, indicating that SKi stimulates both proteasomal and lysosomal degradation of SK1 under normoxia and hypoxia. In chapter two, it was demonstrated that S1P and CYM5541, an S1P3 agonist, induced dose-dependent relaxation in endothelium-intact aortic rings, whereas the S1P1 agonist SEW2871 was without effect. The S1P stimulated relaxation was significantly enhanced in endothelium-intact aortic rings subjected to short-term hypoxia and this effect was entirely endothelium-dependent. Interestingly, the vasorelaxation response to S1P was inhibited by pre-treatment with SKi and PF543 but not ROMe, a selective SK2 inhibitor under both normoxia and hypoxia. A nitric oxide synthase inhibitor also inhibited the S1P-induced relaxation in aortic rings. Moreover, the enhanced relaxation response to S1P due to hypoxia was maintained in aortae obtained from spontaneously hypertensive Wistar Kyoto rats. These findings suggest that the vasorelaxation response to S1P under normoxia and the enhanced response under hypoxia are mediated by SK1 and NO. In chapter five, it was found that hypoxia did not change the SK1b expression in HUVECs and pre-treatment with SKi or cycloheximide exerted no effect under both normoxia and hypoxia. However, proteasomal and/or lysosomal inhibitors increased SK1 expression under hypoxic conditions. In heart tissue, no significant difference was seen in expression of SK1 following exposure to hypoxia. However, SK1 expression was reduced by pre-treatment with SK inhibitors and cycloheximide under normoxia but not hypoxia. SK1a was identified in heart tissue, which is more sensitive to the degradation-induced by SK inhibitors than SK1b. In summary, the results of this study imply that short-term hypoxia induces an increase in SK1 expression in coronary and aortic vascular endothelium. The increased SK1 induced by hypoxia appears to mediate the enhanced vasorelaxation response to S1P in endothelium-intact aortae. In HUVECs and heart tissue, it is likely that hypoxia induces resistance of SK1 to SK inhibitor-induced downregulation through a compensatory increase in SK1 expression.

Nucleoside analogues are an important class of antimetabolites, used both as anticancer and antiviral agents for their resemblance to endogenous nucleosides, and their capacity to inhibit metabolic pathways in which these substrates are involved, leading to therapeutic potential. The need for both new anticancer and antiviral cures is significant, and often caused by the emergence of resistance to the available therapies. In the case of therapies with nucleoside analogues, the delivery of a nucleoside monophosphate prodrug inside the cell has potential to overcome resistance to treatment, and proved successful especially with the application of the ProTide approach. This strategy led to the progression into clinical trials of numerous antiviral and anticancer agents. This work focused on the synthesis of novel ProTide prodrugs to different nucleoside analogues that are involved in clinical trials, such as purine and pyrimidine nucleosides with modifications in the base and sugar regions. This strategy was also applied to nucleoside analogues where in vitro evaluation has never been reported. The synthetic strategies to prepare each nucleoside analogue are also reported. The in vitro evaluation of novel nucleotide prodrugs as anticancer and antiviral agents is described and discussed. Moreover the mechanism of activation of the ProTides is supported by studying their bioactivation to the corresponding monophosphate forms, through enzymatic NMR studies and molecular modeling simulations. Modifications on the scaffold of the two most promising families of ProTides were also performed, leading to the introduction of groups on the nucleobase or alteration of the sugar moiety. Moreover, the phosphosphate group was also modified, with the application of alternative phosphorodiamidate and phosphonoamidate prodrug approaches, with the aim of improving the biological profile. Selected analogues from two families were submitted to numerous preclinical assessments, retaining better potency compared to the parent nucleosides. Moreover these analogues were stable in human plasma, serum and liver microsomes. Further investigations on these potential new drugs are currently ongoing.

Pharmacists have been identified to address the increasing workload in United Kingdom (UK) general practice. A pilot has been commissioned by National Health Service England (NHSE) to upskill pharmacists for this purpose. Evaluation is underway and early reports indicate that there have been integration issues. The value of pharmacists working in general practice and the level of training required for the role are not fully understood. The research reported in this thesis was started before the NHSE pilot. It was conducted to understand the background of Clinical Commissioning Group (CCG) practice pharmacists (PPs), and their interactions with stakeholders. The rationale was to provide an insight into their working relationships and to generate recommendations to support the integration of pharmacists into general practice. The project was conducted in four CCGs in the West Midlands in 2014 using an interpretive/collective case study approach incorporating mixed methods for data collection. Quantitative data was collected on the background, employment and activities of PPs. Qualitative data was collected on stakeholders’ views of the CCG PP role from commissioners, general practitioners (GPs), and patients. Different commissioning models for PPs were studied to provide a deeper understanding of PPs’ interactions. The workload problems in general practice subsequently modified the focus of this thesis to determine the value of PPs to general practice, the level of training required and to propose a model for the integration of pharmacists into UK general practice. The thesis study identified some determinants of integration found in previously published studies but also discovered new areas specific to the integration of pharmacists into UK general practice. These areas can be grouped into three elements - the pharmacist’s skills and attributes, practice level facilitation and national level support. They are presented as a unique Model for the Successful Integration of Pharmacists into General Practice Teams.