Intravenous regional guanethidine Bier's block (IVRGBB) is often used to treat complex regional pain syndrome type I (CRPS 1). Guanethidine is taken up via the neuronal norepinephrine transporter (NET) and displaces norepinephrine (NE) from release vesicles. The local anaesthetic agents cocaine, tetracaine, dibucaine, procaine, bupivacaine, prilocaine and lidocaine all inhibited the uptake of [3H]NE (as a surrogate for guanethidine) into both SH-SY5Y human neuroblastoma and HEK293 cells expressing the recombinant human NET (293-hNET) with pIC50 values ranging from 6.81 (cocaine) to 2.89 (lidocaine). Of particular interest was the prilocaine with a pIC50 of 3.72 and 3.19 in SH-SY5Y and 293-hNET cells respectively. As prilocaine is estimated to reach around 1mM in IVRGBB, such values would make a reduction in guanethidine uptake likely. Local anaesthetics were also found to displace the specific NET label [3H]nixosetine in a concentration dependent manner with pKi values ranging from 5.53 (cocaine) to 2.21 (lidocaine). Values for prilocaine were 3.16 and 3.07 in SH-SY5Y and 293-hNET cells respectively. There was a positive correlation between pIC50 (uptake) and pKi (binding) suggesting a link between uptake inhibition and specific uptake site interaction. In ex vivo electrically field stimulated mouse vas deferens, prilocaine (1mM), procaine (300M) and cocaine (30M) reduced the efficacy of guanethidine block by accelerating twitch response recovery. Furthermore, the effects of prilocaine appeared to be competitive as the inhibition was partially overcome by increasing the concentration of guanethidine. Based on the results of this thesis, I would strongly advise that until further clinical research is carried out, guanethidine and local anaesthetic agents should not be coadministered in IVRGBB.

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This present thesis focuses on compounds related to the epidithiodiketopiperazine (ETP) family of natural products, their synthesis and biological effects. The domain of natural products has long been recognized as an invaluable source of lead structures for the discovery and development of novel therapeutic agents, with the motif being one example that has long been recognized for its potent biological effects which are directly related to the disulfide bridge at the central core. The first chapter provides a detailed analysis of the ETP family of natural products with both the monomeric and dimeric family members being described to provide an overview of this diverse family of compounds and their corresponding biological effects. The second section in this chapter highlights the various synthetic strategies adopted by a number of different research groups and attempts to classify these into the varying approaches towards the central core. Finally the section closes with a description of dimeric natural products and their biological effects in relation to the potent activity observed from the dimeric ETP congeners. The results of our own approach towards the ETP core are described in the third chapter which commences with the synthesis of disubstituted ETPs and expands towards our efforts in synthesizing their tri and tetrasubstituted counterparts. Efforts to extend this chemistry towards dimeric ETPs are also described and our successful routes towards these complex compounds are discussed. The following section of this chapter outlines the successful biological evaluation of the ETP compounds that were synthesised with relevance to their effects in a surrogate model of tuberculosis, cancer cells via inhibition of the hypoxia pathway and activity against the feline immunodeficiency virus. The final chapter provides a formal description of the experimental results and procedures with full characterisation of the data for each compound.

Various aspects in the field of chromogens were studied. In a multifaceted approach, investigations into their synthesis, coupling to less common sugars, and screening as substrates for biological activity, together with kinetic studies on the rate of hydrolysis of indoxyl substrates were carried out. A three-step route to synthesise substituted indoxyl chromogens was successfully developed. This method was subsequently used to prepare a number of halogen derivatives to study the effect of halogen type and position of substitution on the reaction yields. Overall yields range between 2 and 27 %. However attempts to make /V-alkyl indoxyl derivatives were unsuccessful. Studies were carried out to extend the range of target glycosidases by coupling indoxyl to a range of less common pentose and hexose sugars. The following sugars were successfully coupled; D- and L-glucose, D- and L-iyxose, D-galactose, L-rhamnose, 2-deoxy-D-ribose and acetyl-D-xylofuranose. The syntheses of indoxyl aminopeptidase substrates were successfully carried out using L- and D-alanine and L-pyroglutamic acid, with overall yields of between 1 and 3%. An ALDOL™ phosphatase substrate was synthesised with an overall yield of 18%. Studies determined that it was potentially suitable as both a fluorogenic and a chromogenic substrate. Agar based testing indicated that Clostridium perfringens could be successfully detected at a concentration 2.5 x 102 CFU/mL. The substrate was also found to fluoresce plastics. An agar method was developed to screen a range of key microorganism targets with indolyl substrates. The optimised method included the use of agar multipoint inoculators with 3mm pins, by inoculating 1.5 x 108 CFU/mL into nutrient agar containing chromogenic substrate (50mg/100mL), and incubating at 37 °C for 24 hours. Using quantitative UV-Vis and HPLC analyses, techniques to monitor the hydrolysis of indoxyl galactosides were developed and used to correlate molecular structure with rates of hydrolysis. Rates were observed to increase in the order unsubstituted<monosubstituted<disubstituted halogen derivatives. 5-Bromo-4-chloro-3-indolyl-(3-galactopyranoside was seen to give the best colouration, rate of hydrolysis and stability.

Prescribing of psychoactive medications for older residents in nursing homes has been a cause for concern and such medications have been described as ‘chemical restraints’. One factor which may influence the prescribing of these medicines is treatment culture, defined as the way in which prescribing of psychoactive medication is undertaken. Nursing homes have been defined as resident-centred (least likely to use psychoactive medication), traditional (most likely to use psychoactive medication) or ambiguous (a combination of the two) in terms of treatment culture. The overall aim of the research presented in this thesis was to explore and understand treatment culture in nursing homes for older people with dementia in respect of the prescribing of psychoactive medication, and to produce a resource package to assist in decision-making regarding the prescribing of these medications. Qualitative methods were used in Studies 1&2 (Chapters 2&3) to explore and analyse treatment culture in nursing homes. These studies led to the work detailed in Chapter 4 which involved a literature search on culture change in nursing homes, alongside a mapping exercise linking the results from the literature with the findings from Studies 1&2. The outcome of this exercise was to inform the content of an educational resource which was developed during the fourth study (Chapter 5) to promote person-centred care and assist with decision-making on psychoactive medication in nursing homes. The examination of treatment culture in the first and second studies revealed traits that were indicative of the treatment culture category to which each home was assigned. Four contextual themes arose simultaneously throughout the first and second studies; Characteristics of the Setting, Characteristics of the Individual, Relationships, and Decision-making. These themes were linked and each one depicted the differences between the three treatment cultures examined. Traditional homes showed strict routine, little interaction between staff and residents and the administration of psychoactive drugs without a non-pharmacological treatment being tried first. However, in the ambiguous and resident-centred homes, there was a greater focus on resident choice, individualised care and interaction between staff and residents, with more emphasis on non-pharmacological treatments such as distraction and one-on-one attention. The third study confirmed that these contextual elements relating to treatment culture were consistent throughout the existing international literature on culture change. Thus, the content of the educational resource to promote person-centred care and assist with decision-making on psychoactive medication in nursing homes was based upon these four elements. An initial evaluation of the educational resource by nurses working within the nursing home setting, a pharmacist and two Patient and Public Involvement participants revealed that the resource was viewed positively and may be of use to the nursing home sector. Further refinement and pilot-testing of the resource is required. The work of this thesis has confirmed the existence of different treatment cultures among nursing homes in respect of psychoactive prescribing. The traits displayed by each home, were, on the whole, in accordance with the treatment culture category previously assigned to them, and demonstrated how these differences affect the prescribing and administration of psychoactive medications in nursing homes. Assessing and exploring the treatment culture of nursing homes and promoting resident-centred culture in line with current policy should form the focus of future work in this area.

Extremophilic microorganisms, including both halotolerant and halophilic bacteria and archaea, are a potentially untapped source for antimicrobial discovery. Hypersaline environments are receiving increasing interest in the search for novel antimicrobials. One such environment under investigation for its microbial biodiversity and potential antimicrobial diversity is Kilroot salt mine, Ireland’s only salt mine. The overall aim of this research was to explore its microbial biodiversity, through microbial isolation and identification, and to investigate these microbes as producers of antimicrobials with activity against the ESKAPE pathogens. In total 40 culturable isolates were obtained, two-thirds of which were halophilic, and one-third were halotolerant. Six halophilic isolates were proposed as a potential novel species, three of them were chosen for further investigation and extensive characterisation and are here reported as novel species of the Genus Salinisphaera. Following whole genome sequencing, genome mining results obtained from interrogation of the genomes using the antiSmash, and the RAST pipeline revealed the presence of various genes encoded in their genomes, including antibacterial peptide production, ectoine, siderophores, terpenes, and arylpolyenes production. Although culture based activity screening did not reveal antimicrobial activity, further investigations perhaps involving activation of silent gene clusters may yield novel and interesting antimicrobial activities. Isolate AB-7 from the genus Bacillus, exhibited antimicrobial activity against all ESKAPE strains. The Preliminary identification of the active compound indicated that it is non-proteinaceous, and could withstand heating up to 100°C. The structural elucidation of the purified compound identified it as indole. In the second isolate AC-12 from the genus Halovibrio, exhibited antimicrobial activity against all ESKAPE pathogens except P. aeruginosa. The preliminary identification of the active compound indicated that it is in part proteinaceous, and heat stable. This revealed that organisms from the hypersaline environments, are potential source for antimicrobials production.

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