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


RESULTS
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
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.


BACKGROUND
ClinicalTrials.gov NCT00147368.
International Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
Tsin W
TW
Yeo
Daniel A
DA
Lampah
Retno
R
Gitawati
Emiliana
E
Tjitra
Enny
E
Kenangalem
Donald L
DL
Granger
J Brice
JB
Weinberg
Bert K
BK
Lopansri
Ric N
RN
Price
David S
DS
Celermajer
Stephen B
SB
Duffull
Nicholas M
NM
Anstey
D000328:Adult; D001120:Arginine / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001786:Blood Glucose / Q000032:analysis; D001794:Blood Pressure / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004573:Electrolytes / Q000032:analysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007262:Infusions, Intravenous; D016778:Malaria, Falciparum / Q000188:drug therapy*
D001786:Blood Glucose; D004573:Electrolytes; D001120:Arginine