AbstractThe pathogenesis of severe Plasmodium falciparum disease is still not clearly understood, however reduction in tissue oxygen delivery and vascular flow due to parasite sequestration in the blood vessels of the microcirculation is thought to play a major role. Sequestration is a result of increased expression of endothelium adhesion receptors during P. falciparum infection which bind to ligands expressed on the surface of parasitized erythrocytes.
Previous clinical studies in malaria have demonstrated a global reduction in nitric oxide production proportional to disease severity, but not at the organ level. Vascular nitric oxide (NO) bioavailability or endothelial function has a major role in physiological homeostasis by reducing vasoconstrictor and inflammatory activity. Reduced endothelial NO bioavailability in malaria may increase adhesion receptor expression and parasite binding. In diseases with increased intravascular haemolysis, increased plasma or cell-free haemoglobin released during erythrocyte rupture, quenches and reduce vascular NO bioavailability. The possible contribution of these two mechanisms in the pathogenesis of severe malaria has not been previously assessed in clinical studies.
We measured endothelial function using a finger plethysmography method in adults in Papua, Indonesia with severe and moderately severe P. falciparum malaria as well as healthy individuals. Endothelial function decreased with increasing disease severity, and was inversely associated with markers of disease severity including blood lactate concentrations, plasma intercellular adhesion molecule-1 (ICAM-1), and parasite biomass. There was also a significant association between markers of haemolysis and endothelial dysfunction, suggesting NO quenching by cell-free haemoglobin.
Decreased plasma levels of L-arginine, the precursor of NO, has been described and hypothesized to impair cellular NO production. We conducted an ascending dose study of up to 12 grams of intravenous L-arginine in adults with moderately severe malaria and demonstrated a significant dose-related increase in endothelial function with no clinically significant adverse effects. Using a population approach, a pharmacokinetic model was developed and used to simulate the concentration time profile for various dose ranges of L-arginine.
Based on the findings detailed in this thesis, a phase 2A study using a continuous infusion of Larginine is being conducted to assess its potential role as an adjunctive agent in adults with severe malaria.
|Date of Award||2008|