Browsing by Author "Smythe, Wynand Anton"

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    Characterising the role of actin and PI (3) kinases in endocytosis in the malaria parasite Plasmodium falciparum
    (2007) Smythe, Wynand Anton; Hoppe, Heinrich C
    By contrast to mammalian cells, very little is known about endocytosis in the malaria parasite. However, endocytosis via the cytostome is required by the parasite to ingest haemoglobin from its host cytosol which it transports within double membrane vesicles to the digestive vacuole, where digestion occurs and metabolites are used mostly for nutritional purposes. To gain a deeper understanding of the molecular basis and mechanisms of this vital process, a panel of inhibitors was used to inhibit the actin cytoskeleton and PI (3) kinases in the parasite. In this study Cytochalasin D and Latrunculin A, which depolymerise and prevent actin fimalment formation, Jasplakinolide, which stabilises actin filaments, and Wormannin and LY294002, which inhibit PI 93) kinase, were used to study actin disrupting and PI (3) kinase inhibiting drug effects on haemoglobin endocytosis and transport vesicle trafficking within the malaria parasite Plasmodium falciparum.
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    Characterizing population pharmacokinetic/pharmacodynamic relationships in pulmonary tuberculosis infected adults using nonlinear mixed effects modelling
    (2016) Smythe, Wynand Anton; McIlleron, Helen; Denti, Paolo
    This pharmacokinetic sub-study was nested within the phase-III OFLOTUB study investigating the shortening of tuberculosis treatment. A total of 343 adults enrolled in Benin, Guinea, Senegal, and South Africa were randomized to receive rifampicin, isoniazid, pyrazinamide, and ethambutol in the standard 6-month control regimen or the 4-month test regimen where gatifloxacin replaced ethambutol. The pharmacokinetics of all drugs was described at first dose and steady-state using nonlinear mixed-effects modelling, and individual exposures were summarised as area under the concentration-time curve (AUC0-24) and peak concentration. Autoinduction of rifampicin metabolism was characterized with a semi-mechanistic enzyme turn-over model. Gatifloxacin dose was evaluated using Monte Carlo simulations. Lastly, Classification & Regression Tree (CART) analysis techniques were used to identify factors predictive of 2-month culture conversion or 24-month long-term composite outcome. Consistent with literature findings, approximately 73.0, 43.0, 0.3, 6.0 and 0.0% of patients failed to achieve previously reported target concentrations for rifampicin, isoniazid, pyrazinamide, ethambutol, and gatifloxacin, respectively.