BackgroundDecreased nitric oxide (NO) and hypoargininemia are associated with severe falciparum malaria and may contribute to severe disease. Intravenous L-arginine increases endothelial NO in moderately-severe malaria (MSM) without adverse effects. The safety, efficacy and pharmacokinetics of L-arginine or other agents to improve NO bioavailability in severe malaria have not been assessed.MethodsIn an open-label pilot study of L-arginine in adults with severe malaria (ARGISM-1 Study), patients were randomized to 12 g L-arginine hydrochloride or saline over 8 hours together with intravenous artesunate. Vital signs, selected biochemical measures (including blood lactate and L-arginine) and endothelial NO bioavailability (using reactive hyperemia peripheral arterial tonometry [RH-PAT]) were assessed serially. Pharmacokinetic analyses of L-arginine concentrations were performed using NONMEM.ResultsSix patients received L-arginine and two saline infusions. There were no deaths in either group. There were no changes in mean systolic (SBP) and diastolic blood pressure (DBP) or other vital signs with L-arginine, although a transient but clinically unimportant mean maximal decrease in SBP of 14 mmHg was noted. No significant changes in mean potassium, glucose, bicarbonate, or pH were seen, with transient mean maximal increases in plasma potassium of 0.3 mmol/L, and mean maximal decreases in blood glucose of 0.8 mmol/L and bicarbonate of 2.3 mEq/L following L-arginine administration. There was no effect on lactate clearance or RH-PAT index. Pharmacokinetic modelling (n = 4) showed L-arginine concentrations 40% lower than predicted from models developed in MSM.ConclusionIn the first clinical trial of an adjunctive treatment aimed at increasing NO bioavailability in severe malaria, L-arginine infused at 12 g over 8 hours was safe, but did not improve lactate clearance or endothelial NO bioavailability. Future studies may require increased doses of L-arginine.Trial RegistrationClinicalTrials.gov NTC00616304

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...

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