Search

This thesis draws together a series of publications based on work carried out between 2008 and 2018, which examines various aspects of pharmacy regulation as it is reformed in response to changing perspectives on healthcare. The regulated activities of pharmacy include supply of medicines, handling of controlled substances, and maintenance of registration with the General Pharmaceutical Council. The legal underpinnings of each of these activities has undergone significant change in the last ten years. Failing to stay abreast of changes to pharmacy law, or to understanding how these changes affect their practice, can leave pharmacists open to criminal prosecution, civil actions, and fitness to practise proceedings. This regulatory environment can create the potential for moral distress to occur as practitioners are prevented from acting in congruence with their own moral agency. The submission includes thirteen pieces of work discussed under four headings: the three legally regulated activities mentioned above; and a fourth category dealing with moral considerations raised with respect to conscientious objection and moral distress. Initial analysis of the changing legal landscape identifies possible triggers for moral distress, which are subsequently factored into the development of a tool to measure this phenomenon in community pharmacists. The earlier publications included in this thesis have had a significant impact on several aspects of pharmacy regulation, while informing the direction of the later work, which seeks to provide an insight into the incidence of moral distress experienced by community pharmacists and provide researchers with a set of tools with which to extend the scope of the literature in this area.

Nogalamycin is a member of the anthracycline family of antitumour antibiotics. These are potent cytotoxic agents and are routinely used in cancer chemotherapy. Though nogalamycin is clinically insignificant, it does exhibit three distinct types of non-covalent binding to DNA. Since most other anthracyclines bind to DNA by only one or two of these mechanisms, nogalamycin is an excellent model with which to probe the interaction of this class of anti-tumour agents with DNA. Here, we investigate the binding orientation and stoichiometry of nogalamycin in adjacent TpG(CpA) (and CpG(CpG)) intercalation sites using a combination of NMR techniques and NOE-restrained molecular dynamics simulations. These methods are also employed to investigate the structure of GNA hairpin loops, which are considered to have important biological functions, and assess how their structure and stability are influenced by the introduction of nogalamycin at an adjacent site. The effect of nogalamycin on extrahelical thymine bases incorporated onto either face of the intercalation sites is also investigated in this context. Binding of quadruplex-specific antibodies to telomeric DNA in Stylonychia lemnae macronuclei has recently been detected using immunofluorescence, providing direct evidence for the formation of quadruplex DNA structures in vivo. Guanine-rich quadruplex structures have been extensively studied by NMR and x-ray crystallographic methods. Previous structural studies have failed to unambiguously resolve the conformation preferred by less-stable A-tetrads incorporated into DNA quadruplexes. Additionally, little effort has been made to address the exact number of ions bound to these adenine-containing structures. This forms the basis of our study into quadruplex DNA. Finally, we endeavour to investigate the extent of hydration of both duplex and quadruplex structures using rMD methods, and to comapre hydration patterns in the liquid- and solid-state.