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Pharmacokinetics of L-Arginine in Adults with Moderately Severe Malaria

Yeo, Tsin W., Rooslamiati, Indri, Gitawati, Retno, Tjitra, Emiliana, Lampah, Daniel A., Kenangalem, Enny, McNeil, Yvette R., Price, Richard N., Anstey, Nicholas M. and Duffull, Stephen B. (2008). Pharmacokinetics of L-Arginine in Adults with Moderately Severe Malaria. Antimicrobial Agents and Chemotherapy,52(12):4381-4387.

Document type: Journal Article
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IRMA ID 10247xPUB13
Title Pharmacokinetics of L-Arginine in Adults with Moderately Severe Malaria
Author Yeo, Tsin W.
Rooslamiati, Indri
Gitawati, Retno
Tjitra, Emiliana
Lampah, Daniel A.
Kenangalem, Enny
McNeil, Yvette R.
Price, Richard N.
Anstey, Nicholas M.
Duffull, Stephen B.
Journal Name Antimicrobial Agents and Chemotherapy
Publication Date 2008
Volume Number 52
Issue Number 12
ISSN 0066-4804   (check CDU catalogue open catalogue search in new window)
Start Page 4381
End Page 4387
Total Pages 7
Place of Publication Washington, United States
Publisher American Society for Microbiology
Field of Research 0605 - Microbiology
1108 - Medical Microbiology
HERDC Category C1 - Journal Article (DEST)
Abstract Severe malaria is associated with decreased nitric oxide (NO) production and low plasma concentrations of L-arginine, the substrate for NO synthase. Supplementation with L-arginine has the potential to improve NO bioavailability and outcomes. We developed a pharmacokinetic model for L-arginine in moderately severe malaria to explore the concentration-time profile and identify important covariates. In doses of 3, 6, or 12 g, L-arginine was infused over 30 min to 30 adults with moderately severe malaria, and plasma concentrations were measured at 8 to 11 time points. Patients who had not received L-arginine were also assessed and included in the model. The data were analyzed using a population approach with NONMEM software. A two-compartment linear model with first-order elimination best described the data, with a clearance of 44 liters/h (coefficient of variation [CV] = 52%) and a volume of distribution of 24 liters (CV = 19%). The natural time course of L-arginine recovery was described empirically by a second-order polynomial with a time to half recovery of 26 h. The half-life of exogenous L-arginine was reduced in patients with malaria compared with that for healthy adults. Weight and ethnicity were significant covariates for clearance. MATLAB simulations of dosing schedules for use in future studies predicted that 12 g given over 6, 8, or 12 h will provide concentrations above the Km of endothelial cell CAT-1 transporters in 90%, 75%, and 60% of patients, respectively.
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