Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria

Tsin Yeo, D LAMPAH, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Donald Granger, J Brice Weinberg, Bert Lopansri, Ric Price, D CELERMAJER, Stephen Duffull, Nicholas Anstey

Research output: Contribution to journalArticleResearchpeer-review

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 (p=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 (ranger: 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 12g 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.
Original languageEnglish
Pages (from-to)-
JournalPLoS One
Volume3
Issue number6
Publication statusPublished - 2008

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Falciparum Malaria
malaria
arginine
Arginine
Safety
signs and symptoms (animals and humans)
Malaria
Blood pressure
hemodynamics
dosage
bicarbonates
dose response
blood pressure
Hemodynamics
Bicarbonates
potassium
Blood Pressure
quinine
Potassium
Arterial Pressure

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Yeo, T., LAMPAH, D., Gitawati, R., Tjitra, E., Kenangalem, E., Granger, D., ... Anstey, N. (2008). Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria. PLoS One, 3(6), -.
Yeo, Tsin ; LAMPAH, D ; Gitawati, Retno ; Tjitra, Emiliana ; Kenangalem, Enny ; Granger, Donald ; Weinberg, J Brice ; Lopansri, Bert ; Price, Ric ; CELERMAJER, D ; Duffull, Stephen ; Anstey, Nicholas. / Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria. In: PLoS One. 2008 ; Vol. 3, No. 6. pp. -.
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Yeo, T, LAMPAH, D, Gitawati, R, Tjitra, E, Kenangalem, E, Granger, D, Weinberg, JB, Lopansri, B, Price, R, CELERMAJER, D, Duffull, S & Anstey, N 2008, 'Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria', PLoS One, vol. 3, no. 6, pp. -.

Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria. / Yeo, Tsin; LAMPAH, D; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; Granger, Donald; Weinberg, J Brice; Lopansri, Bert; Price, Ric; CELERMAJER, D; Duffull, Stephen; Anstey, Nicholas.

In: PLoS One, Vol. 3, No. 6, 2008, p. -.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria

AU - Yeo, Tsin

AU - LAMPAH, D

AU - Gitawati, Retno

AU - Tjitra, Emiliana

AU - Kenangalem, Enny

AU - Granger, Donald

AU - Weinberg, J Brice

AU - Lopansri, Bert

AU - Price, Ric

AU - CELERMAJER, D

AU - Duffull, Stephen

AU - Anstey, Nicholas

PY - 2008

Y1 - 2008

N2 - 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 (p=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 (ranger: 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 12g 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.

AB - 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 (p=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 (ranger: 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 12g 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.

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KW - hyperkalemia

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KW - male

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KW - Blood Pressure

KW - Dose-Response Relationship, Drug

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KW - Hydrogen-Ion Concentration

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Yeo T, LAMPAH D, Gitawati R, Tjitra E, Kenangalem E, Granger D et al. Safety Profile of L-Arginine Infusion in Moderately Severe Falciparum Malaria. PLoS One. 2008;3(6):-.