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

Yeo, Tsin W., Lampah, Daniel A., Rooslamiati, Indri, Gitawati, Retno, Tjitra, Emiliana, Kenangalem, Enny, Price, Ric N., Duffull, Stephen B. and Anstey, Nicholas M. (2013). A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria: Preliminary Safety, Efficacy and Pharmacokinetics. PLoS One,8(7):e69587-1-e69587-8.

Document type: Journal Article
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NHMRC Grant No. ICRG ID 283321
505807
496600
Title A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria: Preliminary Safety, Efficacy and Pharmacokinetics
Author Yeo, Tsin W.
Lampah, Daniel A.
Rooslamiati, Indri
Gitawati, Retno
Tjitra, Emiliana
Kenangalem, Enny
Price, Ric N.
Duffull, Stephen B.
Anstey, Nicholas M.
Journal Name PLoS One
Publication Date 2013
Volume Number 8
Issue Number 7
ISSN 1932-6203   (check CDU catalogue open catalogue search in new window)
Scopus ID 2-s2.0-84880802406
Start Page e69587-1
End Page e69587-8
Total Pages 8
Place of Publication United States of America
Publisher Public Library of Science
HERDC Category C1 - Journal Article (DIISR)
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.

DOI http://dx.doi.org/10.1371/journal.pone.0069587   (check subscription with CDU E-Gateway service for CDU Staff and Students  check subscription with CDU E-Gateway in new window)
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Additional Notes This is an Open Access article distributed under the terms of the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Description for Link Link to CC Attribution 4.0 License
URL https://creativecommons.org/licenses/by/4.0/au/legalcode


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