Safety profile of L-arginine infusion in moderately severe falciparum malaria

Abstract

Background: L-arginine infusion improves endothelial function in malaria but its safety profile has not been described in detail. We assessed clinical symptoms, hemodynamic status and biochemical parameters before and after a single L-arginine infusion in adults with moderately severe malaria.

Methodology and findings: In an ascending dose study, adjunctive intravenous L-arginine hydrochloride was infused over 30 minutes in doses of 3 g, 6 g and 12 g to three separate groups of 10 adults hospitalized with moderately severe Plasmodium falciparum malaria in addition to standard quinine therapy. Symptoms, vital signs and selected biochemical measurements were assessed before, during, and for 24 hours after infusion. No new or worsening symptoms developed apart from mild discomfort at the intravenous cannula site in two patients. There was a dose-response relationship between increasing mg/kg dose and the maximum decrease in systolic (rho = 0.463; Spearman's, p = 0.02) and diastolic blood pressure (r = 0.42; Pearson's, p = 0.02), and with the maximum increment in blood potassium (r = 0.70, p<0.001) and maximum decrement in bicarbonate concentrations (r = 0.53, p = 0.003) and pH (r = 0.48, p = 0.007). At the highest dose (12 g), changes in blood pressure and electrolytes were not clinically significant, with a mean maximum decrease in mean arterial blood pressure of 6 mmHg (range: 0-11; p<0.001), mean maximal increase in potassium of 0.5 mmol/L (range 0.2-0.7 mmol/L; p<0.001), and mean maximal decrease in bicarbonate of 3 mEq/L (range 1-7; p<0.01) without a significant change in pH. There was no significant dose-response relationship with blood phosphate, lactate, anion gap and glucose concentrations. All patients had an uncomplicated clinical recovery.

Conclusions/significance: Infusion of up to 12 g of intravenous L-arginine hydrochloride over 30 minutes is well tolerated in adults with moderately severe malaria, with no clinically important changes in hemodynamic or biochemical status. Trials of adjunctive L-arginine can be extended to phase 2 studies in severe malaria.

Trial registration: ClinicalTrials.gov NCT00147368.

Conflict of interest statement

Competing Interests: Nicholas Anstey, Don Granger and J Brice Weinberg are named as inventors in a US patent for the use of L-arginine as treatment for severe malaria, but have transferred all their rights to their respective institutional malaria research collaborations. This patent is issued for US rights only and no rights are being sought in other countries.

Figures

Figure 1. Effects of L-arginine hydrochloride infusion on blood pressure.

Figure 1A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal fall in systolic blood pressure at any time during or in the two hours following infusion (n = 30; ρ = −0.463, p = 0.015). Figure 1B: The systolic blood pressure profiles of patients before, during and up to 120 minutes after 30 minute administration of the highest dose of L-arginine (12 g; n = 10). Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM. Figure 1C: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal fall in diastolic blood pressure at any time during or in the two hours following infusion (n = 30; r = −0.42, p = 0.02). Figure 1D: The diastolic blood pressure profiles of patients before, during and up to 120 minutes after 30 minute administration of the highest dose of L-arginine (12 g; n = 10). Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM.

Figure 2. Effects of L-arginine hydrochloride infusion on whole blood potassium concentrations.

Figure 2A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal increase in whole blood potassium concentration at any time during or in the two hours following infusion (n = 30; r = 0.73, p

Figure 3. Effects of L-arginine hydrochloride infusion on venous blood bicarbonate concentrations.

Figure 3A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal decrease in venous blood bicarbonate concentration at any time during or in the two hours following infusion (n = 30; r = −0.53, p = 0.003). Figure 3B: Venous blood bicarbonate concentrations of patients before and after 30 minute administration of the highest dose of L-arginine (12 g; n = 10). Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM.

Figure 4. Effects of L-arginine hydrochloride infusion on venous blood pH.

Figure 4A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal decrease in venous blood pH at any time during or in the two hours following infusion (n = 30; r = −0.48, p = 0.007). Figure 4B: Venous blood pH in patients before and after 30 minute administration of the highest dose of L-arginine (12 g; n = 10). Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM.

Figure 5. Effects of L-arginine hydrochloride infusion on venous blood chloride concentrations.

Figure 5A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal decrease in venous blood chloride at any time during or in the two hours following infusion (n = 30, r = 0.6, p

Figure 6. Effects of L-arginine hydrochloride infusion on venous blood lactate concentrations and anion gap.

Figure 6A: Relationship between dose/weight (mg/kg) of L-arginine and change in venous blood lactate before and 4 hours after infusion (n = 30; ns). Figure 6B: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal change in venous anion gap at any time during or in the two hours following infusion (n = 30; ns).

Figure 7. Effects of L-arginine hydrochloride infusion on plasma phosphate concentrations.

Figure 7A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal decrease in plasma phosphate concentration at any time during or in the two hours following infusion (n = 30; r = −0.06, p = 0.8). Figure 7B: Plasma phosphate concentrations of patients before and after 30 minute administration of the highest dose of L-arginine (12 g; n = 10).. Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM.

Figure 8. Effects of L-arginine hydrochloride infusion on blood glucose concentrations.

Figure 8A: Relationship between dose/weight (mg/kg) of infused L-arginine and the maximal decrease in whole blood glucose concentration at any time during or in the two hours following infusion (n = 30; r = −0.27, p = 0.14). Figure 8B: Whole blood glucose concentrations of patients before and after 30 minute administration of the highest dose of L-arginine (12 g; n = 10). Shaded area indicates time of L-arginine infusion. Dots and bars indicate mean±SEM.