A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria: Preliminary Safety, Efficacy and Pharmacokinetics

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

Decreased Rate of Plasma Arginine Appearance in Murine Malaria May Explain Hypoargininemia in Children With Cerebral Malaria

“…Our metabolic flux data demonstrate that >95% of plasma citrulline is used for plasma arginine synthesis. Taken together, these results suggest that citrulline supplementation could simultaneously improve arginine availability and restore citrulline as a secondary NOS substrate pool [2,6]. Our data suggest that ornithine depletion is largely driven by decreased arginine appearance from nonarginine sources, such as glutamate or proline.…”

“…Decreased endothelial nitric oxide (NO) signaling has been implicated in the pathophysiology of severe malaria and may contribute to impaired vasodilation [2] and microcirculatory abnormalities [3]. L-arginine, the substrate for endogenous NO synthesis, is depleted in patients with severe falciparum malaria [2,4,5], and L-arginine supplementation is currently undergoing early stage clinical trials as a strategy to restore endothelial NO signaling [2,6].…”

Pharmacokinetic-Pharmacodynamic Model for the Effect of l -Arginine on Endothelial Function in Patients with Moderately Severe Falciparum Malaria

“…We expect, therefore, that in administering L-arginine to the eventual target group, patients with severe malaria, continuous infusions of L-arginine will also be required. The safety of 8-h infusion of 12 g of L-arginine has now been demonstrated in a small pilot study with adults with severe malaria (32); however, the volume of distribution and clearance of L-arginine appeared to be greater in severe malaria than in moderately severe malaria. Trials of larger doses than used in this pilot study will be needed, again as a continuous infusion.…”

Pathophysiological Mechanisms in Gaseous Therapies for Severe Malaria

“…Infusion of L-arginine improved NO bioavailability without significant adverse effects on vital signs (26). Despite these encouraging results, in patients with severe falciparum malaria infusion of L-arginine at low doses over 8 h failed to change lactate clearance time and RH-PAT (78). However, this was a small pilot study, and as such lacked sufficient power to show beneficial effects.…”