title: Pharmacology of artemether in children with protein energy malnutrition in the Gambia
Creators: name: Sarr Sallah, Mariama
Publisher: name: University of Liverpool Repository
Year: 2015

description: Malaria and malnutrition are causes of high morbidity and mortality in developing countries especially in sub-Saharan Africa and Asia. Malnourished children are at higher risk of developing malaria, a problem compounded by the fact that malnutrition affects the metabolism of different antimalarials including chloroquine and quinine. Emerging resistance to chloroquine, which was the drug of choice, has led to the widespread use of artemisinin combination therapy in the population including children. To date, no studies have been undertaken on the pharmacokinetics of artemisinin compounds in malnourished children. This thesis aims to fill this evidence gap by studying patients with uncomplicated malaria of different nutritional status in The Gambia. Analysis of the nutritional status of 97 children in The Gambia with uncomplicated malaria showed that 30% were both underweight and wasting, while 28% were categorised into stunting. This was much higher than the national average which has been estimated to be 17.4%, 9.5% and 23% for underweight, wasting and stunting, respectively, demonstrating a potential relationship between malaria and Protein energy malnutrition. In-vitro studies showed that although pre-treatment of HL-60 cells with the iron chelator (DFO) did not affect the bioactivation of artesunate, there was a 20% increase in cell viability with IC50 increasing from 7.0 ± 4.3 to 33.3 ± 2.9. This is believed to be as a result of DFO chelating the toxic iron generated as a result of artesunate bioactivation which increased from 0.32 ± 0.6 ng/mol in the control incubations to 0.84 ± 0.1ng/mol at 100 μmol artesunate concentration. In light of the fact that iron was important in the mechanism of action of these compounds, and the fact that iron deficiency is commonly in malnourished children, the effect of both PEM and anaemia on plasma drug levels of artemether and DHA was also studied. LC-MS/MS method was optimised and validated for the simultaneous analysis of artemether and DHA in plasma with ≥80% precision and accuracy. Plasma artemether and DHA concentration analysed 2h post first dose was 138.4 ± 80.9 ng/ml and 58.8 ± 43.7 ng/ml respectively. Severely wasted and wasted children had the highest artemether (156.5 ±69.6 ng/ml) and DHA (84.1 ±62.6) plasma concentrations respectively but values were not statistically significant. Anaemic status of children did not have an influence on drug plasma concentration with anaemic children having artemether and DHA plasma concentration of 138.5 ± 73.7 and 57.9 ± 36.6, respectively, and 138.43 ± 85.3 and 59.3 ± 46.8 for non-anaemic children respectively. However, conclusive results were limited by sample size. In conclusion, this thesis has demonstrated a relationship between malaria and Protein energy malnutrition, and highlighted the possible effects pathophysiological changes as a result of protein energy malnutrition can have on drug pharmacology and therapeutic effects in these children. There is a need for further studies in larger cohorts of children with protein energy malnutrition to determine whether therapeutic efficacy of artemisinin combination therapy is affected in an adverse manner, and whether there is a need for changes in dosing recommendations.