Pharmacokinetics of l -Arginine in Adults with Moderately Severe Malaria

Abstract

Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] ‫؍‬ 52%) and a volume of distribution of 24 liters (CV ‫؍‬ 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the K m of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.The treatment of severe malaria currently relies on antimalarial drugs and supportive treatments, but the early case fatality rate remains high (8). Adjunctive therapies targeting underlying pathogenic processes early in the treatment of severe malaria may reduce mortality further, but to date none have proven efficacious (10). L-Arginine has been proposed as a potential adjunctive therapy for severe malaria because of its ability to increase nitric oxide (NO) production in endothelial and other cells (16, 34).We have previously described impaired production of NO (1, 34); low plasma concentrations of its precursor, L-arginine (16); and impaired NO-dependent endothelial function in cases of severe malaria (34). Endothelial dysfunction is a measure of endothelial activation and may play a role in the pathogenesis of severe malaria by increasing the adhesion of parasitized erythrocytes to the endothelium and thereby worsening microcirculatory obstruction and oxygen delivery (9). NO downregulates endothelial inflammation (7) and reduces the cytoadherence of parasitized erythrocytes in vitro (20,23). Endothelial NO production is dependent on the intracellular movement of extracellular L-arginine by cationic amino acid transporter protein-1 (CAT-1) (35). Estimates for the halfsaturating concentration (K m ) of extracellular L-arginine for CAT-1 are 100 to 150 mol/liter (32), within the estimated range of the K m of extracellular L-arginine for intracellular NO production (73 to 150 mol/liter) (11, 14). In severe malaria, plasma L-arginine concen...

Malaria-Associatedl-Arginine Deficiency Induces Mast Cell-Associated Disruption to Intestinal Barrier Defenses against Nontyphoidal Salmonella Bacteremia

“…Intravenous infusion of L-arginine has been used to reduce pathology associated with severe malaria, but this application is invasive and expensive and requires medical monitoring (39,68). However, oral supplementation has been used to enhance livestock production (40)(41)(42)(43) and to treat clinical cases of trauma and sepsis (44).…”

L-Arginine Exacerbates Experimental Cerebral Malaria by Enhancing Pro-Inflammatory Responses

“…Tregs inhibit the Th1 response by modifying DC function, producing IL-10, and inducing CD4 + T cell apoptosis (Slade and Langhorne 1989;Zheng et al 2009), which facilitates immune evasion by the parasite (Hisaeda et al 2004). Previous studies have shown that Tregs contributed to determining the incidence and outcome of CM in Pb ANKA-infected mice by altering the balance of pro-(IFN-γ, TNF-α, IL-6, IL-17, and NO) and anti-inflammatory (IL-10) responses (Lopansri et al 2003;Amante et al 2007;Yeo et al 2008b). Therefore, we assessed the effect of L-Arg on the percentage of Tregs and the production of the anti-inflammatory cytokine IL-10.…”

Current Advances in Cerebral Malaria Associated Encephalopathy

“…Indeed, they did find good evidence for the protective role of NO in human CM (Lopansri, Anstey et al 2003;Gramaglia, Sobolewski et al 2006;Weinberg, Lopansri et al 2008). Some investigators proposed that severe malaria is associated with reduced NO production and low blood levels of L-arginine, the substrate for NO synthase (Yeo, Rooslamiati et al 2008). Cell-free hemoglobin produced by hemolysis in falciparum malaria quench NO, disrupt endothelial function, increase adhesion receptor expression and impair www.intechopen.com tissue perfusion (Yeo, Lampah et al 2009).…”

“…Cell-free hemoglobin produced by hemolysis in falciparum malaria quench NO, disrupt endothelial function, increase adhesion receptor expression and impair www.intechopen.com tissue perfusion (Yeo, Lampah et al 2009). Adjunctive agents to improve endothelial NO bioavailability including L-arginine are being extensively tested in human patients (Yeo, Lampah et al 2007;Yeo, Lampah et al 2008;Yeo, Rooslamiati et al 2008;Yeo, Lampah et al 2009) and a safety pharmacokinetics profile has been established (Yeo, Rooslamiati et al 2008).…”