Abstract
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
Highlights
The outcome of adults with severe malaria has improved with use of intravenous artesunate compared to quinine [1,2]
Key mechanisms underlying the pathogenesis of severe and fatal falciparum malaria are microvascular obstruction and impaired organ perfusion resulting from cytoadherence of parasitized red cells to activated endothelial cells, impaired microvascular reactivity and endothelial dysfunction associated with impaired bioavailability of endothelial nitric oxide [3,4,5,6]
Nitric oxide (NO) bioavailability is reduced in both African children with cerebral malaria [7], and Asian and Melanesian adults with severe falciparum malaria [8]
Summary
The outcome of adults with severe malaria has improved with use of intravenous artesunate compared to quinine [1,2]. Key mechanisms underlying the pathogenesis of severe and fatal falciparum malaria are microvascular obstruction and impaired organ perfusion resulting from cytoadherence of parasitized red cells to activated endothelial cells, impaired microvascular reactivity and endothelial dysfunction associated with impaired bioavailability of endothelial nitric oxide [3,4,5,6]. Nitric oxide (NO) bioavailability is reduced in both African children with cerebral malaria [7], and Asian and Melanesian adults with severe falciparum malaria [8]. We have previously shown that infusion of L-arginine in doses of 3 g, 6 g and 12 g over 30 minutes in adults with moderately severe malaria (MSM) increased endothelial and pulmonary NO bioavailability in a dose-dependent manner with minimal adverse effects [8,14]. 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
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