Bacterial transmission is the major cause of microbe associated morbidity and mortality in transfusion recipients. In these studies initially the actual clinical impact was assessed and bacterial contamination rate determined in blood components. Until the late 1990 s, no effective intervention had been introduced in the UK to reduce the transmission of bacteria by transfusion. Three strategies were developed: improved donor arm disinfection, diversion of the first 20ml of donated blood and bacterial screen testing of platelet concentrates. These interventions have now been implemented by the National Blood Service (NBS) and other blood services worldwide. Improved donor arm disinfection was shown to be 10 times more efficient than existing practice and reduced bacterial contamination in whole blood by 57% and reduced clinically apparent transmissions by 65% (from 17 to 6 cases per million). Diversion reduced contamination in whole blood by 47% and clinically apparent transmissions from platelet concentrates by 76% (from 21 to 5 cases per million) and 100% in red cell units (previously 0.3 cases per million). BacT/ALERT was adapted for screen testing platelet concentrates and is now used routinely for shelf life extension. Pall eBDS was developed and enhanced by the National Bacteriology Laboratory of the NBS on a collaborative basis for the same purposes. These studies provided data which facilitated Certificate European marking and Food and Drug Administration approval for both systems. Both systems have now been implemented throughout the world and are market leaders. Scansystem (a rapid assay) was investigated, but was not considered suitable for routine use. Screen testing of all NBS platelet concentrates is now under consideration by the service. The studies undertaken have made a significant contribution to knowledge and have helped improve blood transfusion practice worldwide. Practicable and cost effective interventions supported by scientifically robust data have resulted in a marked reduction in transfusion-transmitted bacterial reactions, thereby improving the safety of the blood supply.

Polyfunctional pyrroles are interesting heterocyclic intermediates as they have a range of reactive centres and the chemoselectivity of their reactions under a range of conditions, is therefore, of much interest. Polyfunctionalised heterocycles are relatively difficult to prepare, but the reactions of these substituted pyrroles allow access to a wide variety of new substituted heterocyclic compounds via these intermediates. The aim of this project was to synthesise polyfunctional pyrroles in order to investigate their use in the preparation of libraries and compounds with known biological activity. The synthesis and initial investigation of the regioselectivity of polyfunctional pyrroles, such as 3,5-dichloro-1H-pyrrole-2,4-dicarboxaldehyde, has previously been described; this work investigated only nucleophilic substitutions. We have investigated the chemoselectivity of the reaction of these pyrroles with a range of reagents and a number of pyrrole derivatives were synthesised via selective functional group transformations. All new compounds were fully characterised by spectroscopic and elemental analysis. Another aim of this project was to discover novel agents that inhibit VEGF receptors using structure based drug design. We have identified hit compounds and synthesised them using regioselective reactions of functional groups present on the pyrrole ring. The compounds were tested for anti-proliferative activity against the HaCaT, human keratinocyte cell line, and also against HT29 and CaCo-2, human colon cell lines using the MTT assay.

Alzheimer’s Disease (AD), Parkinson’s Disease (PD) and Lewy Body Disease (LBD) are some of the many neurodegenerative disorders associated with dementia, for which there is no ultimate cure. It is widely accepted that central nervous system (CNS) nicotinic acetylcholine receptors (nAChRs) may be strongly implicated in the pathology of these devastating disorders, and that stimulation of nAChRs can enhance cognitive behaviour in animals and humans. Nicotine and other nicotinic receptor binding compounds have, over many years, been explored as potential therapies for disorders such as AD and PD. This thesis describes the preparation and pharmacological investigation of a series of 3- substituted and 3,5-disubstitued pyridine derivatives as potential novel and selective nictotinic receptor agonists. Chapter Two details the synthesis of targeted compounds using the generation of [(pyridin-3-yl)methyl]lithium and [(5-methylpyridin-3- yl)methyl]lithium, respectively and subsequent reaction with various electrophiles. Unsuccessful attempts at the synthesis of enantiomerically pure 4-substituted arylpyridin-3-yl-ethanol derivatives by reduction of prochiral 4-substituted arylpyridin-3-yl-ethanone derivatives were made using both catalytic and enzymatic approaches; however, a pair of enantiomerically pure alcohols were isolated via the resolution of diastereomeric esters (prepared by reaction with (S)-O-acetyl mandelic acid) and subsequent hydrolysis. iv Chapter Three explores the synthesis of targeted compounds using halogen-lithium exchange reactions of 3-bromopyridine using n-BuLi and ring-opening by the resultant pyridin-3-yllithium of 4-substituted aryl epoxides. As an extension, Sonogashira cross-coupling of 3- bromopyridine and 4-substituted arylacetylenes and subsequent hydration as an approach to 4-substituted pyridin-3-yl-ethanone derivatives is described. A series of indole derivatives were synthesised using identical approaches. Using methodology developed in previous Chapters, Chapter Four describes approaches to symmetrical and asymmetrical 3,5- bis(arylethynyl)pyridine derivatives, the corresponding bis(ketones), alcohols and 3,5-disubstituted keto-alcohol products. Chapter Five details preliminary pharmacological data (binding and functional assays) performed by our collaborators at Institut de Recherches Servier.

This integrative doctoral report describes how I have used my underpinning experience as a practising pharmacist to make a substantial contribution to pharmacy education. Using separate models for undergraduate and postgraduate students I have planned and delivered high quality innovative programmes which prepare undergraduate pharmacy students for practice and postgraduate professional students for advanced practice. Using an action research methodology I have planned and led a team in the development of a suite of M.Sc. programmes (modular master’s degrees) which matches stakeholder requirements (i.e. students and employers). These programmes offer flexible learning opportunities requiring limited contact. With support systems in place, this model allows the busy healthcare professional to work in a full time capacity whilst studying for a postgraduate qualification. Using this model I have developed short courses and led a team to successfully operate them both in the UK and in Hong Kong. Taking an early lead in the development of supplementary and then independent prescribing courses, has allowed our graduates to develop to meet their potential and allow these practitioners to specialise in their chosen clinical fields. My work with the Centre for Excellence in Healthcare Professional Education (CETL4HealthNE) is perhaps one of the most important and major suggested changes to pharmacy undergraduate education for many years. This is the introduction of Inter-Professional Education (IPE) and practice-based learning. I am a firm advocate for IPE and practice-placements being at the heart of, and becoming a substantial component of, undergraduate pharmacy education. This allows clinical patient-focused teaching to be maximised. I believe that this is of critical importance to ensure that new graduates have both underpinning theoretical knowledge and practical application ability. This is all with the same goal: for the safe and effective care of patients. From my own experiences gained from my collaborative research work and CETL4HealthNE, I propose a model where pharmacists work together with other healthcare professionals, both in practice and in IPE, for the benefit of patient care.

Recently, hydroxypropyl methylcellulose (HPMC) has been made available as an alternative to gelatin for the manufacture of two-piece hard capsules. Hard Capsules manufactured from HPMC with carrageenan as a gelling agent have demonstrated rapid and comparable in-vivo disintegration times to gelatin and overcome some of the disadvantages gelatin capsules present. Gelatin becomes brittle when stored at low humidity and shell dehydration may occur with hygroscopic fillings. In addition, the presence of aldehyde groups in the filling material can reduce the solubility of the gelatin capsule shell by crosslinking. HPMC capsule shells demonstrate lack of brittleness even at moisture levels below 2%, no cross-linking and improved chemical stability, however there is a lack of information relating to the physico- chemical properties of HPMC capsule shells and their dissolution behaviour. The aims of this work were to develop and use different techniques to investigate the physicochemical properties of HPMC and gelatin hard capsule shells and to study the possible interactions between the capsule shell (after different storage conditions) and dissolution media (composition, pH and ionic strength) with and without filling materials. Thermal analysis was undertaken using MDSC to determine and compare the glass transition temperatures of gelatin and three batches of HPMC, which gave an insight into their fundamental physico-chemical properties. Rheological studies were undertaken using DMA, which is a novel method that has not been used previously on capsule shells, to investigate and compare the different viscoelastic properties of the capsules. These included: static scans to study the elastic modulus, linear creep to determine the behaviour of the capsule shells under stress, and dynamic scans to determine the storage modulus and viscosity. The influence of storage RH and time (35% and 53% RH for 24 hours and 3 days), dissolution media composition, ionic strength and pH on the shell dissolution time, and drug release properties of the capsules (using theophylline as the model drug) was also investigated. The findings show that the gelatin capsules became brittle at low moisture content and show some degree of aging upon storage, this was not seen for HPMC. Capsules made form HPMC were more elastic than gelatin and gelatin/Polyethylene glycol, with a greater degree of recovery to an applied stress (e.g. the Young’s Modulus for New HPMC and gelatin capsules was 0.728 MPa vs 1.092 MPa respectively after storage at 53%RH/3 days, and % JR for both capsules was 99.26% vs 98.47% respectively after storage at 35%RH/24 hr). It was also found that storage conditions showed no significant effect on the capsule shell dissolution time, and pH had minimal effect on shell dissolution time of the HPMC capsules. The Changes seen with change in pH were attributed to dissolution media composition, salt concentration and ionic strength of the different dissolution media. For HPMC shells, dissolution time in Sörensen phosphate buffer decreased by 13 – 22 % as pH increased from 5 to 8, however, in citro-phosphate buffer there was a 19 – 36 % increase in dissolution time from pH 5 to 7, In acetate buffer, HPMC shells did not dissolve in pH 6, whereas gelatin dissolution time increased from 2.0 to 3.5 mins as pH increased. Drug dissolution rate was highest from HPMC capsules in all 0.1 M 3 dissolution media compared with gelatin and was affected by the presence of high concentrations of K+ and Na+ ions, whereas gelatin capsules were influenced mostly by the presence of Na+ ions. For example in 0.1 M potassium phosphate buffer (KPB) 100% drug release from HPMC capsules occurred after 35 mins, however, this occurred after 180 mins for gelatin capsules, and in 0.1 M sodium phosphate buffer (NaPB) 100% drug release from HPMC and gelatin capsules occurred after 27 mins and 120 mins respectively. After 5 hours, < 4 % and 10 % drug release was obtained in 0.5 M KPB and NaPB respectively. The mechanism of drug release from gelatin capsules was found to be different in both basic and acidic media. This was constant for the HPMC capsules, showing that the change in pH did not affect the release mechanism. These investigations support work that has been previously reported concerning the properties of the HPMC capsules, and provide new information In terms of their viscoelasticity, interactions with various ions present in different dissolution media, drug dissolution behaviour before and after storage for prolonged periods, and the mechanisms of drug release.

Psoriasis is a chronic inflammatory skin disorder that affects around two percent of the population. There are many treatments available for the management of psoriasis including topical therapy, systemic agents and phototherapy. Despite the number of treatments available, however, there are still problems in the management of psoriasis. It is suggested here that the thioredoxin enzyme system may play a role in the pathology of psoriasis. Using specific molecular modelling techniques, a lead compound, RDP00060, was identified as a potential inhibitor of thioredoxin reductase, a key enzyme in the thioredoxin system. In vitro RDP00060 showed moderate inhibitory activity against the thioredoxin enzyme system with an IC50 value of 1.4 mM. RDP00060 also showed powerful activity in an MTT assay using a human papilloma virus immortalized keratinocyte (HPV-16) cell line. To increase the inhibitory activity towards thioredoxin reductase, molecular modelling techniques were used to identify analogues of RDP00060 with a high binding affinity for thioredoxin reductase. Several novel compounds were then synthesized, characterized and evaluated for inhibitory activity towards the thioredoxin system. One of the compounds, N-(3,4-bis-(toluene-4- sulfonylamino)phenyl)-2-furamide (33f) showed good inhibitory activity against the thioredoxin enzyme with an IC50 value of 37 μM. It is anticipated that N-(3,4- bis-(toluene-4-sulfonylamino)phenyl)-2-furamide (33f) binds to thioredoxin reductase irreversibly through a 1,4-conjugate addition mechanism. This compound also showed powerful activity in the MTT assay using an HPV-16 immortalized keratinocyte cell line. Further testing revealed that N-(3,4-bis-(toluene-4-sulfonylamino)phenyl)-2- furamide (33f) also showed apoptotic and antiproliferative properties in human Tcells. As a result of this work, N-(3,4-bis-(toluene-4-sulfonylamino)phenyl)-2- furamide (33f) has been selected for further investigation as a potential antipsoriatic agent.

No description available.

The diterpenoid natural product Taxol, first discovered in the late 1960’s, is one of the most important current drugs for the treatment of several cancers including breast and ovarian cancers. Although tremendous efforts towards its synthesis have been made in the last two decades, resulting in six elegant total syntheses, Taxol still constitutes a remarkable challenge for organic chemists due to its unique structural framework. The high level of interest has spilled over to our laboratory, the purpose of this thesis was to develop an approach for the construction of medium-ring fused polycarbocyclic systems, which would then be applied to the synthesis of the sterically hindered eight-membered ring of the tricyclic core system of Taxol. Described herein is the continuation of efforts focused towards the access of fused medium-ring carbocycles by tandem catalytic oxonium ylide generation and rearrangement. The novel method in which intramolecular reaction of metal carbenoids with α-vinyl ethers and subsequent [2,3]-rearrangement of the cyclic oxonium ylide intermediates has been used as a powerful strategy to produce linearly fused bicyclic and tricyclic systems. Following the success of our methodology, a key diazoketone intermediate was chosen to establish the viability of our strategy, before embarking on the total synthesis of Taxol. The efficient synthesis of the required diazoketone is discussed in detail, after the exploration of many different approaches. Finally, studies concerning the catalytic decomposition of the diazoketone towards the tricyclic core system of Taxol are presented.

The present study was conducted to investigate the phannacokinetics (PK) and phannacodynamics (PD) of some nonsteroidal antiinflammatory drugs (NSAIDs), including phenylbutazone (PBZ, in sheep, goats and donkeys), flunixin meglumine (FM, in sheep and donkeys), carprofen and its enantiomers (CPF, in sheep), paracetamol (PRT, in goats and camels) and NG-nitro-L-arginine methyl ester (L-NAME, in sheep).

LL-Z1640-2 (5Z-7-Oxo-zeaenol) was first isolated in 1978 from a culture broth. Although LL-Z1640-2 was initially classified as an anti-protazoan agent, it was not until 1999 that it’s cytokine release inhibiting activity was discovered. More recently LL-Z1640-2 has been reported to selectively inhibit the kinase activity of TAK1. TAK1 (transforming growth factor β-activated protein kinase 1) is a major member of the mitogen activated protein kinase kinase kinase (MAPKKK) family. TAK1 is responsible for the activation and control of at least three signalling pathways that play crucial roles in the inflammatory response. Hence, TAK1 has emerged as a prime target for the treatment and regulation of chronic inflammatory diseases such as rheumatoid arthritis, psoriasis and inflammatory bowel disease. LL-Z1640-2 is structurally related to other 14 membered resorcylic lactones such as 7-oxo-zeaenol, zeaenol and radicicol. Although there has been a significant amount of work dedicated to the synthesis of radicicol, the efforts towards LLZ1640-2 have been rather limited. At the outset of the research contained within this thesis, only two total syntheses of LL-Z1640-2 had been published. They were both lengthy (>20 steps) making them impractical for lead development. The work described in this thesis illustrates the attempted flexible and convergent synthesis of LL-Z1640-2 from the simple, commercially available, starting materials 2-deoxy-D-ribose and methyl 2,4,6-trihydroxybenzoate.