A randomized pilot study of L-arginine infusion in severe falciparum malaria: preliminary safety, efficacy and pharmacokinetics

Abstract

Background: Decreased 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.

Methods: In 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.

Results: Six 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.

Conclusion: In 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 registration: ClinicalTrials.gov NCT00616304.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow diagram of patients screened and enrolled for the ARGISM-1 study.

Figure 2

a. Profile of the systolic blood pressure of patients before, during and one hour after receiving L-arginine. Dotted lines indicate patients who received saline. L-arginine was infused between zero and eight hours. b. Profile of the diastolic blood pressure of patients before, during and one hour after receiving L-arginine. Dotted lines indicate patients who received saline.

Figure 3

a. Profile of the venous potassium concentration of patients before, during and three hours after receiving L-arginine. Broken lines indicate patients with acute renal failure and dotted lines indicate patients who received saline. L-arginine was infused between zero and eight hours. b. Profile of the venous bicarbonate concentrations of patients before, during and three hours after receiving L-arginine. Broken lines indicate patients with acute renal failure and dotted lines indicate patients who received saline. c. Profile of the venous blood glucose concentrations of patients before, during and three hours after receiving L-arginine. Broken lines indicate patients with acute renal failure and dotted lines indicate patients who received saline. d. Profile of the venous blood chloride concentrations of patients before, during and three hours after receiving L-arginine. Broken lines indicate patients with acute renal failure and dotted lines indicate patients who received saline.

Figure 4. RH-PAT index profile pre-infusion, one hour and eight hours after infusion of L-arginine.

Dotted lines indicate patients who received saline.

Figure 5. Time-concentration curves for plasma L-arginine concentrations before and after infusion of 12 g L-arginine (solid line) or saline (broken line) for patients 1 to 5.

X-axis = time in hours, y-axis = L-arginine concentration in mg/L.