The online version of this article (doi:10.1186/1475-2875-11-132) contains supplementary material, which is available to authorized users.
The authors declare that they have no competing interests.
PBK, PJ D, CO and CM contributed to the design and conduct of the study. PBK, M L, JM and LN participated in recruitment of participants and data collection. WH and NL performed the bioanalytical assays. PBK, JT and NL analysed and interpreted the data. HMK, EK, NP, PJ D, and CM, participated in training the study staff and provided scientific support. PBK drafted the first version and all authors reviewed and approved the manuscript for submission.
Severe malaria is a medical emergency with high mortality. Prompt achievement of therapeutic concentrations of highly effective anti-malarial drugs reduces the risk of death. The aim of this study was to assess the pharmacokinetics and pharmacodynamics of intravenous artesunate in Ugandan adults with severe malaria.
Fourteen adults with severe falciparum malaria requiring parenteral therapy were treated with 2.4 mg/kg intravenous artesunate. Blood samples were collected after the initial dose and plasma concentrations of artesunate and dihydroartemisinin measured by solid-phase extraction and liquid chromatography-tandem mass spectrometry. The study was approved by the Makerere University Faculty of Medicine Research and Ethics Committee (Ref2010-015) and Uganda National Council of Science and Technology (HS605) and registered with ClinicalTrials.gov (NCT01122134).
All study participants achieved prompt resolution of symptoms and complete parasite clearance with median (range) parasite clearance time of 17 (8–24) hours. Median (range) maximal artesunate concentration (Cmax) was 3260 (1020–164000) ng/mL, terminal elimination half-life (T1/2) was 0.25 (0.1-1.8) hours and total artesunate exposure (AUC) was 727 (290–111256) ng·h/mL. Median (range) dihydroartemisinin Cmax was 3140 (1670–9530) ng/mL, with Tmax of 0.14 (0.6 – 6.07) hours and T1/2 of 1.31 (0.8–2.8) hours. Dihydroartemisinin AUC was 3492 (2183–6338) ng·h/mL. None of the participants reported adverse events.
Plasma concentrations of artesunate and dihydroartemisinin were achieved rapidly with rapid and complete symptom resolution and parasite clearance with no adverse events.
Authors’ original file for figure 112936_2011_2454_MOESM1_ESM.pdf
Authors’ original file for figure 212936_2011_2454_MOESM2_ESM.pdf
Authors’ original file for figure 312936_2011_2454_MOESM3_ESM.doc
Authors’ original file for figure 412936_2011_2454_MOESM4_ESM.doc
Authors’ original file for figure 512936_2011_2454_MOESM5_ESM.doc
WHO: Guidelines for the treatment of malaria. 2010, Geneva: WHO
Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K, Kivaya E, Agbenyega T, Nguah SB, Evans J, Gesase S, Kahabuka C, Mtove G, Nadjm B, Deen J, Mwanga-Amumpaire J, Nansumba M, Karema C, Umulisa N, Uwimana A, Mokuolu OA, Adedoyin OT, Johnson WB, Tshefu AK, Onyamboko MA, Sakulthaew T, Ngum WP, Silamut K, Stepniewska K, Woodrow CJ, Bethell D, Wills B, Oneko M, Peto TE, von Seidlein L, Day NP, White NJ, AQUAMAT group: Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet. 2010, 376: 1647-1657. 10.1016/S0140-6736(10)61924-1. PubMedCentralCrossRefPubMed
Sinclair D, Donegan S, Lalloo DG: Artesunate versus quinine for treating severe malaria. Cochrane Database Syst Rev. 2011, 3: CD005967- PubMed
Krudsood S, Wilairatana P, Vannaphan S, Treeprasertsuk S, Silachamroon U, Phomrattanaprapin W, Gourdeuk VR, Brittenham GM, Looareesuwan S: Clinical experience with intravenous quinine, intramuscular artemether and intravenous artesunate for the treatment of severe malaria in Thailand. Southeast Asian J Trop Med Public Health. 2003, 34: 54-61. PubMedCentralPubMed
Batty KT, Le AT, Ilett KF, Nguyen PT, Powell SM, Nguyen CH, Truong XM, Vuong VC, Huynh VT, Tran QB: A pharmacokinetic and pharmacodynamic study of artesunate for vivax malaria. Am J Trop Med Hyg. 1998, 59: 823-827. PubMed
Batty KT, Ashton M, Ilett KF, Edwards G, Davis TM: The pharmacokinetics of artemisinin (ART) and artesunate (ARTS) in healthy volunteers. Am J Trop Med Hyg. 1998, 58: 125-126. PubMed
Timothy M, Davis E, Hoang Lan Phuong, Kenneth Fl, Nguyen CH, Kevin TB, Vu Duong BP, Shane MP, Huynh Van a Thien, Binh TQ: Pharmacokinetics and Pharmacodynamics of Intravenous Artesunate in Severe Falciparum Malaria. Antimicrob Agents Chemother. 2001, 45: 181-186. 10.1128/AAC.45.1.181-186.2001. CrossRef
Qigui Li, Louis RC, Kevin JL, George AS, Scott Miller R, Victor M, Weina PJ: Pharmacokinetic profiles of artesunate after single intravenous doses at 0.5, 1, 2, 4, and 8 mg/kg in healthy volunteers: a phase I study. Am J Trop Med Hyg. 2009, 81: 615-621. 10.4269/ajtmh.2009.09-0150. CrossRef
Benakis A, Paris M, Loutan L, Plessas CT, Plessas ST: Pharmacokinetics of artemisinin and artesunate after oral administration in healthy volunteers. Am J Trop Med Hyg. 1997, 56: 17-23. PubMed
Teja-Isavadharm P, Watt G, Eamsila C, Jongsakul K, Li Q, Keeratithakul G, Sirisopana N, Luesutthiviboon L, Brewer TG, Kyle DE: Comparative pharmacokinetics and effect kinetics of orally administered artesunate in healthy volunteers and patients with uncomplicated falciparum malaria. Am J Trop Med Hyg. 2001, 65: 717-721. PubMed
Hanpithakpong W, Kamanikom B, Dondorp AM, Singhasivanon P, White NJ, Day NPJ, Lindegardh N: A liquid chromatographic-tandem mass spectrometric method for determination of artesunate and its metabolite dihydroartemisinin in human plasma. J Chromatography B. 2008, 876: 61-68. 10.1016/j.jchromb.2008.10.018. CrossRef
Singh NB, Bhagyabati DS, Singh TB, Singh MA: Artemether vs quinine therapy in Plasmodium falciparum malaria in Manipur--a preliminary report. J Commun Dis. 2001, 33: 83-87. PubMed
- Pharmacokinetics and pharmacodynamics of intravenous artesunate during severe malaria treatment in Ugandan adults
Peter J de Vries
- BioMed Central
Neu im Fachgebiet Innere Medizin
Meistgelesene Bücher aus der Inneren Medizin
Mail Icon II