Class of 2005 Abstract / Objectives: Doses of vancomycin are frequently estimated using various predictor formulas aiming for trough concentrations between 5 and 15 mg/L and peak concentrations between 25 and 40 mg/L.1 There is however, some controversy about the relationship between vancomycin concentrations and therapeutic response. This project compares the ability of several methods to estimate serum concentrations of vancomycin. Methods: This project was a retrospective look at 243 patient records, the patients were given vancomycin and later had at least one concentration measured. Data collected while the patient was being treated was used in the nine predictor models to determine which model would best predict actual concentrations. The methods compared were Moellering, Matzke, Lake-Peterson, Rodvold, Abbott, Birt, Burton, Ambrose, and Bauer. Results: There were 188 patients included in the analysis, 97 males and 91 women. The method with the least bias (+ 1.0) was the Rodvold method using the actual body weight. None of the models were very precise, with most around 10 (high of 12.83, and a low of 9.35). The r- values for all the models were also low, none of the models had an r- value greater than 0.5. The Lake-Peterson method predicted within 20% and 50% the most often; the Ambrose method the least often within 50%, and both Ambrose and Bauer the least often within 20%. The Lake-Peterson method predicted concentrations within plus or minus 2.5 and 5.0 mg/L of measured concentrations most frequently. The Ambrose method predicted concentrations within plus or minus 2.5 mg/L of measured the least often; Burton and Rodvold the least often within 5.0 mg/L of measured. Implications: With the best model only accurate (defined as ± 20%) less than 25 percent of the time, there is too much error to make a good decision on dose and interval without the feedback of measured serum concentrations. The models may be a good starting point as which dose and interval to choose, but they are not a substitute for measuring steady state concentrations.

Artemisinins are known for their low aqueous solubility and resultant poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate, to low bibavailability. Enzymatic degradation and physiological barriers are also amongst the challenges which must be overcome to ensure effective delivery. Artemisininbased monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives, their antimalarial activity/efficacy was evaluated in vitro and in vivo in the presence and absence of Pheroid™ technology. Pheroid™ technology is a patented drug delivery system which has the ability to capture, transport and deliver pharmacologically active compounds. Pharmacokinetic models were also constructed for artemis one and artemiside, both in the presence and absence of Pheroid™ technology. Results obtained with the jn vitro antimalarial activity evaluation indicated that artemiside was slightly more potent than artemisone and much more potent than artesunate. Artemiside had IC50 values of 0.54 ± 0.03 nM (reference) and 0.10 ± 0.05 nM (Pheroid™) (p = 0.009) while artemisone had values of 0.94 ± 0.04 nM (reference) and 0.21 ± 0.04 nM (Pheroid™) (p = 0.0001). Artesunate had IC50 values of 29.65 ± 0.05 nM (reference) and 10.20 ± 0.04 nM (Pheroid™) (p < 0.0001). Results obtained with the in vivo antimalarial activity evaluation indicated that artemisone led to more favourable treatment outcomes than artemiside. The Peters' 4-day suppressive test was used as a basis model. With artemisone treatment recrudescence occured at 16 days post infection at a dose of 20.0 mg/kg bodyweight and at 12 days post infection at 2.5 mg/kg bodyweight. With artemiside recrudescence occurred at 8 days post infection with both the 10.0 mg/kg and 2.5 mg/kg bodyweight treatment regimens. When comparing the antimalarial effect of the drugs with and without Pheroid™ technology there was no significant difference in terms of parasite reduction or in the achieved treatment outcomes of either compounds. The pharmacokinetic parameters were evaluated in a mouse model where C57 BL6 mice were used. The compounds were administered at a dose of 50.0 mg/kg bodyweight via an oral gavage tube at a volume of 200 µl. Blood samples were collected by means of tail bleeding. Sensitive and selective LC/MS/MS methods were developed to analyze the drug concentrations in the plasma samples. The relative bioavailability of artemisone was RA = 1.0 (reference) and RA = 4.57 (Pheroid™) (p < 0.001). The absolute bioavailability was calculated as F = 0.10 (reference) and F = 0.48(Pheroid™) (p < 0.001). The boiavailability of artemiside was not dramatically enhanced by the Pheroid™ delivery system. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

Artemisinins are known for their low aqueous solubility and resultant poor and erratic absorption upon oral administration. The poor solubility and erratic absorption usually translate, to low bibavailability. Enzymatic degradation and physiological barriers are also amongst the challenges which must be overcome to ensure effective delivery. Artemisininbased monotherapy and combination therapies are essential for the management and treatment of uncomplicated as well as cerebral malaria. Artemisone and artemiside are novel artemisinin derivatives, their antimalarial activity/efficacy was evaluated in vitro and in vivo in the presence and absence of Pheroid™ technology. Pheroid™ technology is a patented drug delivery system which has the ability to capture, transport and deliver pharmacologically active compounds. Pharmacokinetic models were also constructed for artemis one and artemiside, both in the presence and absence of Pheroid™ technology. Results obtained with the jn vitro antimalarial activity evaluation indicated that artemiside was slightly more potent than artemisone and much more potent than artesunate. Artemiside had IC50 values of 0.54 ± 0.03 nM (reference) and 0.10 ± 0.05 nM (Pheroid™) (p = 0.009) while artemisone had values of 0.94 ± 0.04 nM (reference) and 0.21 ± 0.04 nM (Pheroid™) (p = 0.0001). Artesunate had IC50 values of 29.65 ± 0.05 nM (reference) and 10.20 ± 0.04 nM (Pheroid™) (p < 0.0001). Results obtained with the in vivo antimalarial activity evaluation indicated that artemisone led to more favourable treatment outcomes than artemiside. The Peters' 4-day suppressive test was used as a basis model. With artemisone treatment recrudescence occured at 16 days post infection at a dose of 20.0 mg/kg bodyweight and at 12 days post infection at 2.5 mg/kg bodyweight. With artemiside recrudescence occurred at 8 days post infection with both the 10.0 mg/kg and 2.5 mg/kg bodyweight treatment regimens. When comparing the antimalarial effect of the drugs with and without Pheroid™ technology there was no significant difference in terms of parasite reduction or in the achieved treatment outcomes of either compounds. The pharmacokinetic parameters were evaluated in a mouse model where C57 BL6 mice were used. The compounds were administered at a dose of 50.0 mg/kg bodyweight via an oral gavage tube at a volume of 200 µl. Blood samples were collected by means of tail bleeding. Sensitive and selective LC/MS/MS methods were developed to analyze the drug concentrations in the plasma samples. The relative bioavailability of artemisone was RA = 1.0 (reference) and RA = 4.57 (Pheroid™) (p < 0.001). The absolute bioavailability was calculated as F = 0.10 (reference) and F = 0.48(Pheroid™) (p < 0.001). The boiavailability of artemiside was not dramatically enhanced by the Pheroid™ delivery system. / Thesis (Ph.D. (Pharmaceutics))--North-West University, Potchefstroom Campus, 2010.

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Ce doctorat porte sur l’étude de l’activité antipaludique de la cépharanthine. Deux méthodes écologiques d’extraction, utilisant des micro-ondes et ultrasons, ont été proposées. L'activité antiplasmodiale a été évaluée par le calcul de la concentration qui inhibe 50 % de la croissance parasitaire. Les cibles potentielles ont été évaluées par l’étude de la variation d’expression des gènes. Au niveau microscopique, la cépharanthine a semblé inhiber le développement parasitaire et bloquer les parasites au stade anneau. Au niveau transcriptomique, la cépharanthine semble avoir un impact sur le transport de protéines plasmodiales à la surface du globule rouge ; sur des organelles nécessaires à la survie du parasite, et sur les interactions entre le globule rouge parasité et l’endothélium ou les globules rouges sains. Des études de combinaisons thérapeutiques ont montré que la cépharanthine semble potentialiser certains antipaludiques. Une analyse quantitative de la cépharathine plasmatique a permis d’effectuer une étude pharmacocinétique. La cépharanthine pourrait être un chef de file intéressant pour le développement de nouveaux antipaludiques. / This PhD focuses on the study of the antimalarial activity of cepharanthine. Two green extraction methods, using microwave and ultrasound, have been proposed. The antiplasmodial activity was evaluated by calculating the concentration inhibiting 50 % of parasite growth. Potential targets were evaluated by studying the variation of gene expression. At the microscopic level, cepharanthine seemed to inhibit the parasite growth and to block parasite at the ring stages. The transcriptomic assay showed that cepharanthine seems to have an impact on the transport of Plasmodium proteins to the red blood cell surface, on organellar functions necessary for the survival of the parasite, and on the interactions between infected red blood cells and the endothelium or healthy red blood cells. The study of combination therapies showed that cepharanthine appears to potentiate some antimalarial compounds. A quantitative analysis of cepharathine in mouse plasma allowed performing a pharmacokinetic study. Cepharanthine could be an interesting lead to the development of new antimalarial drugs.