A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria

Preliminary Safety, Efficacy and Pharmacokinetics

Tsin Yeo, Daniel Lampah, I Rooslamiati, Retno Gitawati, Emiliana Tjitra, Enny Kenangalem, Ric Price, Stephen Duffull, Nicholas Anstey

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    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.
    Original languageEnglish
    Article numbere69587
    Pages (from-to)1-8
    Number of pages8
    JournalPLoS One
    Volume8
    Issue number7
    DOIs
    Publication statusPublished - 2013

    Fingerprint

    Pharmacokinetics
    Falciparum Malaria
    malaria
    pharmacokinetics
    arginine
    Arginine
    Safety
    nitric oxide
    Nitric Oxide
    Malaria
    bioavailability
    Biological Availability
    lactates
    Lactic Acid
    Vital Signs
    Hyperemia
    Manometry
    bicarbonates
    Bicarbonates
    Potassium

    Cite this

    Yeo, Tsin ; Lampah, Daniel ; Rooslamiati, I ; Gitawati, Retno ; Tjitra, Emiliana ; Kenangalem, Enny ; Price, Ric ; Duffull, Stephen ; Anstey, Nicholas. / A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria : Preliminary Safety, Efficacy and Pharmacokinetics. In: PLoS One. 2013 ; Vol. 8, No. 7. pp. 1-8.
    @article{fb46c9ee6eaa407c9ad1602ae13a64b6,
    title = "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.",
    keywords = "antibiotic agent, arginine, artesunate, bicarbonate, electrolyte, glucose, lactic acid, methemoglobin, placebo, potassium, sodium chloride, adult, article, clinical article, controlled study, diastolic blood pressure, disease severity, drug efficacy, drug safety, female, heart rhythm, human, hyperemia, lactate blood level, malaria falciparum, male, open study, pH, pilot study, randomized controlled trial, systolic blood pressure, tonometry, vital sign, Adolescent, Adult, Arginine, Female, Humans, Infusions, Intravenous, Malaria, Falciparum, Male, Middle Aged, Young Adult",
    author = "Tsin Yeo and Daniel Lampah and I Rooslamiati and Retno Gitawati and Emiliana Tjitra and Enny Kenangalem and Ric Price and Stephen Duffull and Nicholas Anstey",
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    year = "2013",
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    language = "English",
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    pages = "1--8",
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    A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria : Preliminary Safety, Efficacy and Pharmacokinetics. / Yeo, Tsin; Lampah, Daniel; Rooslamiati, I; Gitawati, Retno; Tjitra, Emiliana; Kenangalem, Enny; Price, Ric; Duffull, Stephen; Anstey, Nicholas.

    In: PLoS One, Vol. 8, No. 7, e69587, 2013, p. 1-8.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - A Randomized Pilot Study of L-Arginine Infusion in Severe Falciparum Malaria

    T2 - Preliminary Safety, Efficacy and Pharmacokinetics

    AU - Yeo, Tsin

    AU - Lampah, Daniel

    AU - Rooslamiati, I

    AU - Gitawati, Retno

    AU - Tjitra, Emiliana

    AU - Kenangalem, Enny

    AU - Price, Ric

    AU - Duffull, Stephen

    AU - Anstey, Nicholas

    N1 - NHMRC Grant No.: ICRG ID 283321, 505807, 496600.

    PY - 2013

    Y1 - 2013

    N2 - 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.

    AB - 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.

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    KW - lactic acid

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    KW - article

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    KW - Adolescent

    KW - Adult

    KW - Arginine

    KW - Female

    KW - Humans

    KW - Infusions, Intravenous

    KW - Malaria, Falciparum

    KW - Male

    KW - Middle Aged

    KW - Young Adult

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