Includes bibliographical references / In addition to treating symptomatic patients, malaria prevention and elimination requires giving antimalarial drugs to asymptomatic or uninfected individuals. This shifts the harm-benefit balance and heightens the importance of accurately defining drug safety. Large data sets, including those pooled from multiple sources, are needed to understand uncommon adverse drug reactions. Interpreting individual studies , comparisons between studies and pooled datasets can be compromised, however, by inadequate or varied methods of safety data collection. Specifically, questioning methods may influence participants' reports of medical history, adverse events (AEs) and non-study medications. A Cochrane systematic review synthesised literature on research comparing methods for eliciting AEs from trial participants . A global online survey investigated how antimalarial researchers collect these data, and mixed-methods were used to identify barriers to accurate and complete reporting in South African and Tanzanian antimalarial-antiretroviral drug interaction trials. Focus group discussions were conducted in Ghana, Kenya and Uganda with women in a drugs exposure pregnancy registry to examine barriers to reporting at antenatal clinics, and how they might be overcome. The review included thirty-three studies in various therapeutic areas showing that more specific questioning increases the number of AEs reported by trial participants. Survey responses of 52 antimalarial researchers in 25 countries evidenced a range of methods to obtain AEs, medical histories and non-study drug reports. Qualitative data revealed that the trial context is influential and that detailed questioning facilitated participants' recognition and consideration of what to report. Non-reporting is due to forgetting, not knowing drug names, considering which information is relevant or significant to themselves or trial/healthcare workers, the potential consequences of reporting, and perceiving verbal responses inferior to what blood test results can show. Pregnant women's improved relationship with antenatal staff facilitated information-sharing and registry tools helped overcome problems with recall and naming of medicines. This project provides evidence of the substantial impact of different questioning methods on safety assessments . The results should contribute to developing a framework for researchers when planning globally-relevant, yet context-specific, antimalarial drug safety data collection strategies, and enhance efforts to pool data from multiple sources.

For every 200 births in the UK, one will end in a stillbirth. Stillbirth is classified as a baby born dead after 24 weeks gestation. Mutations in genes that cause ion channelopathies are known to cause sudden cardiac death in adults and children. Prenatal diagnosis of LQT has been possible for decades, creating a disease spectrum where channelopathies may fatally influence pregnancy. We sequenced 35 candidate genes in 70 unexplained stillbirth cases. Thirty-nine cases harboured a predicted damaging protein missense variant. Two novel and two rare variants were observed in the transient receptor potential melastatin 7 (TRPM7) gene and five rare genetic variants were found in A-kinase anchor protein 9 (AKAP9). The aim of this PhD was to perform functional studies of these variants in TRPM7 and AKAP9. TRPM7 is an ion channel indispensable for mouse cardiogenesis. Two TRPM7 variants (p.G179V and p.T860M) showed significantly reduced current compared to wild-type channels. Conversely, cells expressing p.R494Q TRPM7, had a significant increase in current compared to WT channels, but only in CHO-K1 cells. Western blot analyses failed to detect full length TRPM7 in cells transfected with either p.G179V or p.T860M compared to wild-type expressing cells. Proteosomal inhibition using MG132 produced a small but visible band in p.T860M transfected cells. Expression of TRPM7 in iPSC-derived cardiomyocytes increases during cell maturation, and TRPM7-like current was measured in 20-23 day old cardiomyocytes. AKAP9 is required to couple adrenergic stimulation in the heart with faster cardiac repolarisation. Cells expressing WT AKAP9 alongside the KCNQ1/KCNE1 potassium channel responded to β-adrenergic stimulation, however those transfected with p.A3043T AKAP9 did not respond to treatment with forskolin. Our analyses supports two deleterious variants in TRPM7 and one in AKAP9 in unexplained stillbirth cases. These heterozygous variants could lead to haploinsufficiency and may be a cause of stillbirth.

Purpose Two new scales, CORECTS and PUQE-24 are introduced and validated, and the safety and effectiveness of Proctofoam-HC® in pregnancy is demonstrated. Method 315 of Motherisk NVP patients provided information on five clinical parameters as well as PUQE scores. 28 patients visiting a proctologist were graded for the severity of anal conditions by a proctologist before administering CORECTS. Pre and postnatal interviews were conducted with 204 pregnant women prescribed Proctofoam-HC®. Results Strong correlations were found between the following: PUQE-24 scores and parameters of well-being, hospitalization, and multivitamin intake; bleeding and pain components of CORECTS and the proctologist’s grade.There was no significant difference between mean birth weight of Proctofoam-HC® treated and comparison groups. There was a significant reduction in all symptoms of hemorrhoids. Conclusion PUQE-24 and CORECTS are the first validated scales used to assess the severity of NVP and hemorrhoids. Proctofoam-HC® is safe and effective for use in pregnancy.

Purpose Two new scales, CORECTS and PUQE-24 are introduced and validated, and the safety and effectiveness of Proctofoam-HC® in pregnancy is demonstrated. Method 315 of Motherisk NVP patients provided information on five clinical parameters as well as PUQE scores. 28 patients visiting a proctologist were graded for the severity of anal conditions by a proctologist before administering CORECTS. Pre and postnatal interviews were conducted with 204 pregnant women prescribed Proctofoam-HC®. Results Strong correlations were found between the following: PUQE-24 scores and parameters of well-being, hospitalization, and multivitamin intake; bleeding and pain components of CORECTS and the proctologist’s grade.There was no significant difference between mean birth weight of Proctofoam-HC® treated and comparison groups. There was a significant reduction in all symptoms of hemorrhoids. Conclusion PUQE-24 and CORECTS are the first validated scales used to assess the severity of NVP and hemorrhoids. Proctofoam-HC® is safe and effective for use in pregnancy.

This study assessed the separate and combined effects of two important instigators of relapse, alcohol cues and stress, on the salience of alcohol target stimuli and inhibitory control, in 12 male problem drinkers and 16 male controls. Subjects underwent two test sessions where they received alcohol cues (non-alcoholic beer) and/or stress (uncontrollable noise) in a counterbalanced manner. Testing was carried out through validated, computer-based tasks: modified Stroop, gambling-word Shift task; and conventional and modified (Alcohol word) Stop-Signal tasks. Inhibitory control was preferentially impaired to Alcohol stimuli in both groups. Beer and stress in combination increased incentive salience of Alcohol stimuli and moderated self-reported desire for alcohol in problem drinkers but not controls. Results suggest that alcohol cues and stress have interactive effects on subjective motivation, and disinhibit behaviour due to distraction in problem drinkers. Findings from this paradigm may improve understanding and facilitate treatment for relapse prevention in problem drinkers.

This study assessed the separate and combined effects of two important instigators of relapse, alcohol cues and stress, on the salience of alcohol target stimuli and inhibitory control, in 12 male problem drinkers and 16 male controls. Subjects underwent two test sessions where they received alcohol cues (non-alcoholic beer) and/or stress (uncontrollable noise) in a counterbalanced manner. Testing was carried out through validated, computer-based tasks: modified Stroop, gambling-word Shift task; and conventional and modified (Alcohol word) Stop-Signal tasks. Inhibitory control was preferentially impaired to Alcohol stimuli in both groups. Beer and stress in combination increased incentive salience of Alcohol stimuli and moderated self-reported desire for alcohol in problem drinkers but not controls. Results suggest that alcohol cues and stress have interactive effects on subjective motivation, and disinhibit behaviour due to distraction in problem drinkers. Findings from this paradigm may improve understanding and facilitate treatment for relapse prevention in problem drinkers.

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.

Thesis (M.Sc. (Pharmacy)) - Rhodes University, 2006.