No description available.

The endocannabinoid system (ECS) comprises the endocannabinoids (ECs), including anandamide (AEA) and 2-arachidonoyl glycerol (2AG), which interact with the G protein-coupled type-1 and type-2 cannabinoid receptors(CB1 and CB2 respectively). The ECS is thought to have a role in a number of central processes including neuroinflammation, neurogenesis, neuroprotection, learning and memory. Due to its influence on a diverse number of processes, it has been suggested that modifying the ECS may be therapeutically beneficial in Alzheimer's disease (AD). AD is an age-related neurodegenerative disorder characterised by the presence of extracellular amyloid beta (Ab) plaques and intracellular neurofibrillary tangles (NFTs) resulting in impairments in learning in memory. The aim of this thesis was to determine the status of the brain ECS in the APPswe/PS18E9 mouse model of AD and wild type littermates at 4, 6 and 8 months of age and the performance of these animals in a behavioural test battery. The results of this study indicated that APPswe/PS18E9 animals were hyperactive compared to their wildtype counterparts at all ages and that they also displayed deficits in behavioural flexibility. EC levels increased with age in both wild type and APPswe/PS18E9 mice. Cannabinoid receptor coupling was increased in the frontal cortex and striatum of APPswe/PS18E9 mice relative to wildtype. This study concluded that the status of the brain ECS is altered in AD. Modifications to the performance of the ECS were made in the form of chronic administration of a CB1 receptor antagonist (SR141716A1rimonabant) and a CB2 receptor agonist (JWH133). Chronic administration of SR141716A was able to reverse some learning impairments in APPswe/PS18E9 animals. In contrast, chronic administration of JWH133 resulted in impaired memory extinction in both wildtype and APPswe/PS18E9 mice. The results support the potential benefit of modulating the endocannabinoid system in the treatment of memory impairment in AD.

At the height of its popularity, mephedrone was the most common recreationally used cathinone. This is thought to be due to its perceived likeness to MDMA. Therefore the aim of this thesis was to examine mephedrone-induced changes in behaviour, body temperature or neurochemistry in the rat and to compare these changes to those observed following MDMA administration. This was achieved by assessing changes in body temperature following acute mephedrone, MDMA, cathinone or methcathinone administration. Additionally, locomotor activity and cognitive tasks were performed following chronic intermittent administration of mephedrone, MDMA or cathinone. These behaviours, as well as mephedrone-induced changes to body temperature and ‘anxiety-related’ behaviour, were also assessed following either pre-treatment with MDMA or co-administration of caffeine. Finally, locomotor activity, body temperature changes and in vivo striatal dopamine release were assessed following rapid repeated dosing of mephedrone, and the roles of dopamine, 5-HT and noradrenaline in these responses were examined. Post mortem monoamine concentrations from specific brain regions were also assessed following acute, chronic intermittent and rapid repeated dosing of mephedrone. It was found that the neurochemical, behavioural and physiological effects of mephedrone in the rat include hyperactivity, hypothermia, cognitive deficits, anxiety-related behaviour and increased striatal dopamine efflux. Pre-exposure to MDMA, or concomitant caffeine administration, caused an increase in rectal temperature following mephedrone injection while caffeine co-administration prolonged the hyperactive profile of mephedrone. Importantly, unlike MDMA, rapid repeated mephedrone administration (3 x 10 mg kg-1 at 2 h intervals) had no cumulative effect on mephedrone-induced hypothermia or hyperactivity. It is also clear that mephedrone is inducing its effects via noradrenergic, dopaminergic and serotonergic mechanisms. The cathinones and MDMA had varying effects on post mortem tissue levels of the monoamines and their metabolites. Importantly, these effects of mephedrone appear to be occurring by mechanisms that are different, but similar, to MDMA.

No description available.

Itraconazole is a triazole antifungal used in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF) and for the prevention of invasive fungal infections in paediatric patients undergoing bone marrow transplants (BMT). The pharmacokinetic (PK) properties of this drug and its active metabolite have been described before; however, there is only sparse information available of the PK properties of this drug in the general paediatric population and CF patients in particular. Even though the target concentrations to obtain treatment success from this drug in ABPA have not been established, therapeutic drug monitoring has been shown to be necessary due to a high interpatient variability and low concentrations reported in these patient groups. The general aim of this thesis was to use modelling approaches to provide a better understanding of the PK of itraconazole, in particular to investigate the relative bioavailability of the two commercial formulations (capsule and oral solution), and to attempt to evaluate relationships between patient characteristics and parameters to enable better individualised therapy to maximise the benefits of this drug. The first study was a paediatric population PK (popPK) investigation of itraconazole and its active metabolite hydroxy-itraconazole in CF and BMT patients. All paediatric CF or BMT patients taking oral itraconazole for therapeutic reasons were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. Itraconazole and hydroxy-itraconazole plasma concentrations were measured by a newly developed and validated high-performance liquid chromatography. A nonlinear mixed-effects modelling approach (NONMEM 5.1.1) was used to describe the PK of itraconazole and hydroxy-itraconazole simultaneously. A 1-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order conversion to hydroxy-itraconazole. For itraconazole, the apparent clearance and volume of distribution was 35.5 L/h and 672 L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h¯¹ and for the oral solution formulation it was 0.959 h¯&sup1. The relative bioavailability for the capsules was 0.55. Of several screened covariates, only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. High inter-patient variability confirmed previous data in CF, leukaemia and BMT patients. From the population model, simulations were performed to develop more adequate dosage regimens to achieve target therapeutic trough plasma concentration of 0.5 mg/L. Higher doses of itraconazole than presently used are needed in these patients, particularly when it is prescribed as capsules. To further support the aims of the thesis, a popPK study with oral itraconazole and its active metabolite in adult patients with CF for capsule and oral solution was performed. A D-optimal study design was developed in MATLAB using POPT v. 2.0, B, which was based on the administration of solution and capsules to 30 patients in a cross-over design. Eight blood samples were taken on two occasions as per the optimal sampling design and assayed by HPLC. NONMEM (5.1.1) was used for the popPK analysis. A total of 241 blood samples were collected, of which 94% were taken within the defined optimal sampling window. A 2-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order formation for metabolism to the hydroxy-metabolite. Absorption rate constants for capsule and solution were 0.0315 h¯¹ and 0.125 h¯¹, respectively. The comparative bioavailability of the capsule to solution was 0.82 in this study. There was no evidence of nonlinearity in the PK of itraconazole and no screened covariate significantly improved the fit to the data. There was high inter-patient variability confirmed previous results in CF. The optimal design performed well for estimation of model parameters from a complex parent-metabolite popPK model. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but at times that were “near-optimal” for estimating the popPK parameters. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily would provide a trough target concentration at steady state in only 35% of patients when administered as the solution, and 31% when administered as the capsules. The optimal dosing schedule was 500 mg b.d. for both formulations. Since the therapeutic target for itraconazole, is still unresolved, the potential risks of these dosing schedules need to be assessed on an individual basis. This thesis provides information on several methods and their applications to sparse sampling population pharmacokinetic studies and offers results and future directions to maximize the benefits of itraconazole therapy. The population modelling approach has been successfully applied to both clinical studies.

Itraconazole is a triazole antifungal used in the treatment of allergic bronchopulmonary aspergillosis (ABPA) in patients with cystic fibrosis (CF) and for the prevention of invasive fungal infections in paediatric patients undergoing bone marrow transplants (BMT). The pharmacokinetic (PK) properties of this drug and its active metabolite have been described before; however, there is only sparse information available of the PK properties of this drug in the general paediatric population and CF patients in particular. Even though the target concentrations to obtain treatment success from this drug in ABPA have not been established, therapeutic drug monitoring has been shown to be necessary due to a high interpatient variability and low concentrations reported in these patient groups. The general aim of this thesis was to use modelling approaches to provide a better understanding of the PK of itraconazole, in particular to investigate the relative bioavailability of the two commercial formulations (capsule and oral solution), and to attempt to evaluate relationships between patient characteristics and parameters to enable better individualised therapy to maximise the benefits of this drug. The first study was a paediatric population PK (popPK) investigation of itraconazole and its active metabolite hydroxy-itraconazole in CF and BMT patients. All paediatric CF or BMT patients taking oral itraconazole for therapeutic reasons were eligible for the study. A minimum of two blood samples were drawn after the capsules and also after switching to oral solution, or vice versa. Itraconazole and hydroxy-itraconazole plasma concentrations were measured by a newly developed and validated high-performance liquid chromatography. A nonlinear mixed-effects modelling approach (NONMEM 5.1.1) was used to describe the PK of itraconazole and hydroxy-itraconazole simultaneously. A 1-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order conversion to hydroxy-itraconazole. For itraconazole, the apparent clearance and volume of distribution was 35.5 L/h and 672 L, respectively; the absorption rate constant for the capsule formulation was 0.0901 h¯¹ and for the oral solution formulation it was 0.959 h¯&sup1. The relative bioavailability for the capsules was 0.55. Of several screened covariates, only allometrically scaled total body weight significantly improved the fit to the data. No difference between the two populations was found. High inter-patient variability confirmed previous data in CF, leukaemia and BMT patients. From the population model, simulations were performed to develop more adequate dosage regimens to achieve target therapeutic trough plasma concentration of 0.5 mg/L. Higher doses of itraconazole than presently used are needed in these patients, particularly when it is prescribed as capsules. To further support the aims of the thesis, a popPK study with oral itraconazole and its active metabolite in adult patients with CF for capsule and oral solution was performed. A D-optimal study design was developed in MATLAB using POPT v. 2.0, B, which was based on the administration of solution and capsules to 30 patients in a cross-over design. Eight blood samples were taken on two occasions as per the optimal sampling design and assayed by HPLC. NONMEM (5.1.1) was used for the popPK analysis. A total of 241 blood samples were collected, of which 94% were taken within the defined optimal sampling window. A 2-compartment model with first order absorption and elimination best described itraconazole kinetics, with first order formation for metabolism to the hydroxy-metabolite. Absorption rate constants for capsule and solution were 0.0315 h¯¹ and 0.125 h¯¹, respectively. The comparative bioavailability of the capsule to solution was 0.82 in this study. There was no evidence of nonlinearity in the PK of itraconazole and no screened covariate significantly improved the fit to the data. There was high inter-patient variability confirmed previous results in CF. The optimal design performed well for estimation of model parameters from a complex parent-metabolite popPK model. Due to the sampling windows, most of the samples could be collected within the daily hospital routine, but at times that were “near-optimal” for estimating the popPK parameters. Simulations from the final model showed that the current dosing regimen of 200 mg twice daily would provide a trough target concentration at steady state in only 35% of patients when administered as the solution, and 31% when administered as the capsules. The optimal dosing schedule was 500 mg b.d. for both formulations. Since the therapeutic target for itraconazole, is still unresolved, the potential risks of these dosing schedules need to be assessed on an individual basis. This thesis provides information on several methods and their applications to sparse sampling population pharmacokinetic studies and offers results and future directions to maximize the benefits of itraconazole therapy. The population modelling approach has been successfully applied to both clinical studies.

The treatment of menopausal symptoms by combined hormone replacement therapy (HRT) utilises drug formulations whereby a progestii1 is added to the oestrogen component to decrease the risk of endometrial carcinoma prnduced by the oestrogen. However, administration of large doses of progestins can increase low density lipid cholesterol, as well as reduce some of the beneficial effects of oestrogens. Local administration of progestins to the uterus may allow a much smaller dose to be used reducing the antagonism produced by progestins on desired oestrogenic effects. The simplest way to administer drugs to the uterus is by inserting a device through the cervix, however, this procedure may be associated with bacterial contamination of the uterus leading to pelvic infection. This study has therefore set out to develop a device for the delivery of antimicrobial agents to the uterus to reduce microbial contamination associated with transcervical insertion, and also the delivery of progestins which could be used as an adjunct to oestrogen HRT by targeting the progestin locally to the endometrium.

No description available.

No description available.

Osteoarthritis is common with radiographic features practically universal in at least some joints in people aged over 60 years. One of the main therapeutic interventions used in the management of osteoarthritis is the injection of corticosteroid and hyaluronan (Gossec 2006). However, there exist few studies that seek to explore possible factors that influence outcome following injection. This study examined the factors that may influence the outcomes following injection of either corticosteroid or hyaluronan in the management of osteoarthritis of the knee.