The steric and electronic properties of N-Heterocyclic carbenes and their use as ligands in asymmetric catalysis are reviewed. Key features of enantioselective palladium-catalysed allylie substitution and copper-catalysed conjugate addition reaction are discussed. A modular design approach was applied to the synthesis of iminoalkyl imidazol-2-ylidenes to enable simple structural modifications and fine-tuning catalytic performance for selected reactions. A range of novel chiral imino alkyl alkylimidazolium salts and imino alkyl arylimidazolium salts have been prepared via the N-alkylation of substituted imidazoles with iminoalkyl bromides in moderate to good yields. The chiral iminoalkyl bromides were synthesised from amino acids using a five-step procedure, involving reduction, N-BOC protection, bromination, N-BOC deprotection and imination. The synthesis of chiral iminoalkyl alkylimidazolium salts derived from glycine, alanine, leucine, valine and phenylalanine and N-methyl-, N-benzyl-, N-phenyl and N-mesitylimidazoles is reported. The preparation of both benzylideneamine- and benzylhydrylideneamine derivatives was achieved. One example of an imidazolin-2-ylidene ligand precursor, derived from a dihydroimidazole is also reported. Silver iminoalkyl imidazol-Z-ylidene complexes were prepared by deprotonation of the corresponding imidazolium salts with silver(I) oxide. An X-ray crystal structure of example is reported; it shows the monodentate co-ordination of the iminoalkyl complexes failed. Nonetheless, the silver complexes were successfully employed as earbene transfer reagents for the generation of imino alkyl imidazol-2-ylidene palladium catalysts for use in asymmetrie allylie substitution. The application and performance of the small library of imino alkyl imidäzol-z-ylidene ligands in asymmetric palladium-catalysed allylie substitution is reported and discussed. Catalytic testing demonstrated that variation of the imidazole substituent had a greater effect on enantioselectivity than changing the alkyl substituent at the stereogenic centre on the ligand backbone. The highest enantiomeric excess obtained for the substitution of 1,3-diphenylprop-3-enyl acetate with dimethyl malonate was 53%. The ligands were also screened for enantioselectivity towards copper catalysed conjugate addition of diethyl zinc to cyclohexenone. Performance for this reaction was poor with a highest enantiomeric excess of 18% being obtained.

The Nicholas reaction is the reaction of a cobalt-stabilised propargyl cation with a nucleophile and the aim of this project was to attempt this reaction with a chiral substrate in an effort to effect an asymmetric Nicholas reaction. A range of contemporary techniques were applied to reach this goal. Initially an attempt was made to reproduce an earlier successful racemic synthesis of a fused carbocyclic compound using a chiral precursor. It was envisaged that this would be approached using a 1,4-conjugate addition to an enone using a chiral ligand to install the C-3 alkenyl group selectively. Although the conjugate addition reactions were successful, using well tried and tested ligands, the enantiomeric excesses were very low and unfortunately a suitable chelating catalyst that prevent fulfil the requirements was not identified at this stage of the investigation. The next approach made use of an asymmetric alkynylation reaction to an aldehyde. This was successfully carried out using a Carreira asymmetric alkynylation reaction to afford optically active propargyl alcohols with good to excellent enantiomeric excess (50%-82% ees). The desired optical active propargyl alcohols were then complexed, with dicobalt octacarbonyl, to afford the corresponding dicobalt hexacarbonyl complexes. These then successfully underwent the corresponding Nicholas cyclisation reaction to afford, after oxidative decomplexation of the cobalt species, a range of optically active chromane and isochromanes with ees of (45%-81%). In a second study a series of optically active benzopyran derivatives were also successfully synthesised, using the same methodology, again with high levels of enantiomeric excess (87% - 94%). In the final phase of this investigations it was explored the use of chiral derivatives of the chiral pool molecule citronellal as well as an achiral analogue in an effort to afford novel chiral aldehydes for propargylation and cyclisation. The new chiral centres were successfully installed using chiral auxiliary technology however unexpectedly difficulties were encountered in the removal of the chiral auxiliary. A lack of time, in order to further explore the removal step, unfortunately meant that this was put on hold for further studies.

No description available.

Despite having been described by the then (2003) Chief Pharmaceutical Officer for England as ·probably the biggest untapped resource for health improvement", the development of the public health function of community pharmacists has been limited. However, devolution of healthcare budgets has led 10 differential rates of development of the public health function in each administration of the UK (England, Scotland, Wales and Northern Ireland). This is measured and reflected upon in this thesis. Two large-scale surveys were conducted, one of key strategic personnel (Directors of Public Health and Chief Pharmacists) in Primary Care Organisations (PCOs) and one of practicing community pharmacists. This research highlights the fact that community pharmacists have developed an individualistic, service-based approach to their engagement with public health that is contrary to the more collective approach adopted by the wider public health movement. The study measures the scope and level of health-improving services through community pharmacy across the UK and shows that the nature of the pharmacy contractor (independent, multiple etc.) may impact on the range and nature of services provided. Survey data also suggest that attitudes towards pharmacy involvement in the public health agenda vary markedly between Directors of Public Health, PCO Chief Pharmacists, and community pharmacists. Furthermore, within the community pharmacist population, attitudes are affected by a wide range of factors including the nature of employment (owner, employee, self-employed) and the type of employing pharmacy (independent, multiple etc.). Implications for policy and areas for further research aimed at maximising the public health function of community pharmacists are suggested.

There have been numerous studies reporting that cannabinoids, both exogenous and endogenous, have a potential beneficial function during incidences of neurological damage. Using gene knockout mice and cannabinoid-selective agents, this study demonstrates the diverse actions of cannabinoids with a particular focus on experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. The results presented here report on the action of stimulators of cannabinoid receptors in the nervous system (CNS) on; immune function, as a mechanism of suppressing autoimmune attack of the central nervous system, as agents to suppress neurodegenerative events leading to disease progression and as agents that can control signs of disease that occur as the consequences of autoimmune neurodegeneration such as spasticity. Tetrahydrocannabinol the psychoactive component in cannabis and the CB1 cannabinoid receptor appears to be central to many of the therapeutic actions of cannabis but also to the side-effect potential of cannabinoid drugs. This study reports on methods to avoid psychoactive side-effects of conventional brain-penetrant CB1 receptor agonists whilst exploiting the therapeutic potential of the cannabinoid system in order to control spasticity. This was achieved by targeting mechanisms of endocannabinoid degradation, particularly using fatty acid amide hydrolase inhibitors. Furthermore, this study also reports the development of novel cannabinoid compounds that are excluded from the brain and inhibit spasticity and also demonstrates the mechanism of exclusion of CNS-excluded cannabinoid CB1 receptor agonists. This study provides further evidence for the efficacy of cannabinoid compounds during an ongoing CNS disease and also their efficacy for treating the consequences of CNS autoimmune disease, which hopefully, will give additional impetus for further clinical investigations of cannabinoid agents in not only multiple sclerosis but also other neurodegenerative diseases of the CNS.

The endogenous cannabinoids (endocannabinoids) arachidonoyl ethanolamide (AEA) and 2-arachidonoyl glycerol (2-AG) regulate neurotransmission and inflammation by activating the CB1 cannabinoid receptors in the central nervous system and the CB2 cannabinoid receptors on immune cells. Endocannabinoids are inactivated via a 2-step process: firstly undergoing reuptake into the cell and then hydrolysis by fatty acid amide hydrolase (FAAH) for AEA or by monoacylglycerol lipase (MAGL) for 2-AG. Inhibition of FAAH is an effective treatment for inflammatory pain and is a target for the development of novel analgesics. FAAH and MAGL produce arachidonic acid by hydrolysis of endocannabinoids. In inflammation arachidonic acid is oxidised by cyclooxygenase 2 (COX-2) to synthesise the prostaglandins. Both FAAH and MAGL inhibition were showed to indirectly suppress prostaglandin E2 synthesis in activated macrophages. This effect was found to be dependent on the amount of lipopolysaccharide used to activate the macrophages. The FAAH substrates, AEA, oleoyl ethanolamide (OEA) and palmitoyl ethanolamide (PEA), were measured in samples from an in vivo model of inflammatory pain to screen various FAAH inhibitors to prove their mechanism of action. Liquid chromatography-tandem mass spectrometry methods were developed and validated for the measurement of these three substrates in brain and whole blood. Blood OEA and PEA concentrations were found to be indicative of brain FAAH activity and brain AEA concentrations. FAAH is capable of conjugating arachidonic acid to paracetamol to form the active metabolite AM404, an inhibitor of AEA reuptake. It was shown that FAAH can also conjugate oleic acid and palmitic acid to paracetamol, producing novel metabolites. A clinical trial was conducted to comprehensively investigate the pharmacokinetics, metabolism and mechanism of action of intravenous paracetamol in cerebrospinal fluid and plasma. Paracetamol, its major metabolites, AM404, prostaglandin E2, leukotriene B4, serotonin and the FAAH substrates were measured. For the first time AM404 was demonstrated to be formed by humans and be present in the cerebrospinal fluid.

Drug substitution is mainly economically not medically-driven; it can benefit healthcare services but does not directly benefit individual patients. Many healthcare providers have been promoting drug substitution in an attempt to contain their costs. This practice has been approved and supported on the basis of the presumption that the cheaper drug is not inferior to the more expensive one and the premise that any saving that does not compromise the quality of care is essentially appropriate. However, substitutions become problematic when the cheaper drug is known to have different effects and side effects, or even when there is just uncertainty about such effects. This thesis explores issues surrounding generic and therapeutic substitution from the ethical, patients’ and physicians’ point of view and from the potential differences in formulations between the branded and generic medicines. A series of studies such as a review of the ethical issues in drug substitution, multicentre surveys to explore patients’ and physicians’ views on drug substitution and other in-vitro and in-vivo comparisons between the actual formulations of the branded medicines and their generic counterparts were included in this thesis. The main objective was to encourage safe and effective generic and therapeutic substitution by validating the appropriateness and the potential impact of these substitutions on patients’ clinical outcomes and thus to promote high quality strategic logistic planning and effective management of drug formularies in hospitals. It was confirmed in this thesis that promoting generic and therapeutic substitution on economic grounds alone is unethical because it can be potentially harmful to patients and is incompatible with patient-centred medicine. As a consequence, multicentre surveys were conducted to assess patients’ views on generic substitution in hospital settings. A total of 163 renal transplant patients were surveyed using 36 multiple-choice questions at Barts and The London Renal Transplant Clinic, in the UK. This group of patients was specified because they may be particularly affected by drug substitution. Any small changes in the medicinal effect of this group of patients can negatively impact their clinical outcome. It was revealed in this survey that 84% of participating patients felt that generic medicines were not equivalent or only equivalent sometimes and they were uncertain that generics had the same quality as branded medicines. In addition, many patients admitted that they would refuse the generic substitution of ciclosporin when it became available in the UK. Another multicentre survey in the United Arab Emirates (UAE) using 188 renal patients revealed that 68% of participating patients felt that generics were not equivalent or only equivalent sometimes, and they were uncertain that generics had the same quality as branded medicines. Therefore, many patients admitted that they would refuse the generic substitution of ciclosporin when become available. These beliefs were highly marked in patients with less education, less communication with healthcare professionals and who suspected that the cheaper drug substitution was implemented only to save costs. In another prescription based survey in the UAE, a random sampling of 1000 written prescriptions was analysed to determine physicians’ attitudes towards generic medicines and prescribing. It was explored in this study that prescribers were not yet ready to promote appropriate generic substitution. They were still prescribing generic medicines on occasions where health complications may occur as well as increase healthcare expenditure. As a result, improving awareness and education among physicians is compulsory to implement appropriate generic prescribing and substitution. In-vitro dissolution study was also conducted in this thesis to detect any potential differences in dissolution behaviour between the branded medicines and their generic counterparts. A total of 37 medicines (13 innovator medicines and 24 generic counterparts) were collected locally and internationally and tested according to the British Pharmacopeia, European Pharmacopeia and the US Pharmacopeia with the rate of dissolution determined by ultra-violet Spectrophotometer. It was marked in this study that some generic medicines showed significant differences in dissolution rate at 60 and 120 minutes compared to their branded counterparts. Other generics violated the EMA and the FDA guidelines for industry when they failed to achieve 85% dissolution at 60 minutes and to keep the same dosage form as their branded counterparts. Moreover, a bioequivalence study was carried out in this thesis using 24 healthy volunteers under fasting conditions to compare Resclar 500 mg (Neopharma, UAE) with its branded Klacid® 500 mg (Abbott Laboratories Ltd, England), both are macrolide antibiotics contain 500 mg clarithromycin per tablet. It was confirmed in this study that Resclar 500 mg met the regulatory definition of bioequivalence with Klacid® 500 mg as the innovator product based on a single dose comparative bioavailability study under fasting conditions in the selected healthy volunteers. Therefore, Resclar 500 mg could provide an acceptable prescribable alternative to Klacic® 500 mg. In conclusion, the results presented in this thesis suggested that randomly and economically-driven drug substitution can be potentially deleterious to patients and should not be promoted. Factors such as physicians and patients education, monitoring, severity of the disease and efficacy of generic medicines are essential to promote safe and effective drug substitution. Thus, to achieve excellent strategic logistic planning and effective management of drug formularies in hospitals, generic and therapeutic substitution should be solely based on providing patients with the best possible care and quality medicines.

No description available.

No description available.

Chronic lymphocytic leukaemia (CLL) is the most common leukaemia in the western world, and continues to have very low cure rates. The bulk of the tumour cells are non-cycling peripheral cells that accumulate from a minority of dividing cells within proliferation centres (PCs), located the lymph nodes (LN) and spleen. The PCs are rich in activated T helper (TH) cells that express CD40L and secrete IL-4. Like normal B cells, CLL cells interact with TH via their expression of CD40 and receive signals from IL4. This stimulation provides the signal for B cells to divide, as well as protecting them from apoptotic stimuli. Consequently, many current therapies are unable to sufficiently target the cells in the PC, resulting in therapy resistance, residual disease (RD) and relapse. In addition, most therapies have associated toxicities, restricting their use to younger, fitter patients. Thus, there is an urgent need for new therapies with low toxicity, especially for older patients. New drug discovery is time consuming and expensive. Redeployment of existing drugs is one way to potentially combat this issue. The lipid lowering drug Bezafibrate (BEZ) and the sex steroid, medroxyprogesterone acetate (MPA) have been shown to have anti-leukaemic properties in other settings. In this study the in vitro efficacy of BEZ and MPA on resting CLL cells (representing resting cells in the periphery) and when stimulated to proliferate by CD40L (representing cells in the PCs) have been investigated. Both BEZ and MPA exerted pro-apoptotic actions against resting CLL cells and reduced CD40L stimulated proliferation. These actions were increased when both agents were combined and demonstrated selectivity against CLL cells compared to normal peripheral blood mononuclear cells. Combined BEZ+MPA, was as effective as the commonly used chemotherapeutic chlorambucil, with the combination of all 3 agents exerting the greatest effects. However none of the combinations induced apoptosis of CLL cells protected by CD40L. Investigations into the possible mechanisms of drug action revealed that MPA was unlikely to be working either by steroid receptors or by inhibition of the enzyme AKR1C3 and the mechanism remains unknown. BEZ alone and in the presence of MPA induced the production of prostaglandin D2 (PGD2) and exogenously applied PGD2 was found to exert apoptosis in a similar manner to BEZ. Both BEZ and MPA generated reactive oxygen species (ROS) in both culture settings and the combination was more effective than either drug alone. In the absence of CD40L, mitochondrial superoxide (MSO) was also produced but not in CD40L stimulated cells. This finding suggested that CD40L is able to prevent or protect against MSO production and, consequently, apoptosis. Attempts at overcoming this effect revealed that the plant derived compound lycorine exerted minimal effects alone but, when combined with BEZ+MPA, reinstated the induction of MSO and recapitulated BEZ+MPA induced apoptosis despite the continual presence of CD40L. In contrast, the reported ability of dasatinib to overcome CD40L mediated fluadarabine resistance was discovered to be to be unfounded.