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- Kloprogge, F., et al.
(författare)
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Artemether-lumefantrine dosing for malaria treatment in young children and pregnant women: A pharmacokinetic-pharmacodynamic meta-analysis
- 2018
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Ingår i: Plos Medicine. - : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 15:6
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Tidskriftsartikel (refereegranskat)abstract
- Background The fixed dose combination of artemether-lumefantrine (AL) is the most widely used treatment for uncomplicated Plasmodium falciparum malaria. Relatively lower cure rates and lumefantrine levels have been reported in young children and in pregnant women during their second and third trimester. The aim of this study was to investigate the pharmacokinetic and pharmacodynamic properties of lumefantrine and the pharmacokinetic properties of its metabolite, desbutyl-lumefantrine, in order to inform optimal dosing regimens in all patient populations. A search in PubMed, Embase, ClinicalTrials. gov, Google Scholar, conference proceedings, and the WorldWide Antimalarial Resistance Network (WWARN) pharmacology database identified 31 relevant clinical studies published between 1 January 1990 and 31 December 2012, with 4,546 patients in whom lumefantrine concentrations were measured. Under the auspices of WWARN, relevant individual concentration-time data, clinical covariates, and outcome data from 4,122 patients were made available and pooled for the meta-analysis. The developed lumefantrine population pharmacokinetic model was used for dose optimisation through in silico simulations. Venous plasma lumefantrine concentrations 7 days after starting standard AL treatment were 24.2% and 13.4% lower in children weighing < 15 kg and 15-25 kg, respectively, and 20.2% lower in pregnant women compared with non-pregnant adults. Lumefantrine exposure decreased with increasing pre-treatment parasitaemia, and the dose limitation on absorption of lumefantrine was substantial. Simulations using the lumefantrine pharmacokinetic model suggest that, in young children and pregnant women beyond the first trimester, lengthening the dose regimen (twice daily for 5 days) and, to a lesser extent, intensifying the frequency of dosing (3 times daily for 3 days) would be more efficacious than using higher individual doses in the current standard treatment regimen (twice daily for 3 days). The model was developed using venous plasma data from patients receiving intact tablets with fat, and evaluations of alternative dosing regimens were consequently only representative for venous plasma after administration of intact tablets with fat. The absence of artemether-dihydroartemisinin data limited the prediction of parasite killing rates and recrudescent infections. Thus, the suggested optimised dosing schedule was based on the pharmacokinetic endpoint of lumefantrine plasma exposure at day 7. Our findings suggest that revised AL dosing regimens for young children and pregnant women would improve drug exposure but would require longer or more complex schedules. These dosing regimens should be evaluated in prospective clinical studies to determine whether they would improve cure rates, demonstrate adequate safety, and thereby prolong the useful therapeutic life of this valuable antimalarial treatment.
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- Palmroth, M., et al.
(författare)
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Magnetosheath jet properties and evolution as determined by a global hybrid-Vlasov simulation
- 2018
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Ingår i: Annales Geophysicae. - : Copernicus GmbH. - 0992-7689 .- 1432-0576. ; 36:5, s. 1171-1182
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Tidskriftsartikel (refereegranskat)abstract
- We use a global hybrid-Vlasov simulation for the magnetosphere, Vlasiator, to investigate magnetosheath high-speed jets. Unlike many other hybrid-kinetic simulations, Vlasiator includes an unscaled geomagnetic dipole, indicating that the simulation spatial and temporal dimensions can be given in SI units without scaling. Thus, for the first time, this allows investigating the magnetosheath jet properties and comparing them directly with the observed jets within the Earth's magnetosheath. In the run shown in this paper, the interplanetary magnetic field (IMF) cone angle is 30°, and a foreshock develops upstream of the quasi-parallel magnetosheath. We visually detect a structure with high dynamic pressure propagating from the bow shock through the magnetosheath. The structure is confirmed as a jet using three different criteria, which have been adopted in previous observational studies. We compare these criteria against the simulation results. We find that the magnetosheath jet is an elongated structure extending earthward from the bow shock by ∼ 2.6 RE, while its size perpendicular to the direction of propagation is ∼ 0.5R/E. We also investigate the jet evolution and find that the jet originates due to the interaction of the bow shock with a high-dynamic-pressure structure that reproduces observational features associated with a short, large-amplitude magnetic structure (SLAMS). The simulation shows that magnetosheath jets can develop also under steady IMF, as inferred by observational studies. To our knowledge, this paper therefore shows the first global kinetic simulation of a magnetosheath jet, which is in accordance with three observational jet criteria and is caused by a SLAMS advecting towards the bow shock.
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