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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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- Venkatesan, M, et al.
(författare)
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Erratum
- 2019
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Ingår i: The American journal of tropical medicine and hygiene. - : American Society of Tropical Medicine and Hygiene. - 1476-1645 .- 0002-9637. ; 100:3, s. 766-766
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Tidskriftsartikel (refereegranskat)
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- Faucher, Sebastien P., et al.
(författare)
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Toxoflavin secreted by Pseudomonas alcaliphila inhibits the growth of Legionella pneumophila and Vermamoeba vermiformis
- 2022
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Ingår i: Water Research. - : Elsevier. - 0043-1354 .- 1879-2448. ; 216
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Tidskriftsartikel (refereegranskat)abstract
- Legionella pneumophila is a natural inhabitant of water systems. From there, it can be transmitted to humans by aerosolization resulting in severe pneumonia. Most large outbreaks are caused by cooling towers colonized with L. pneumophila. The resident microbiota of the cooling tower is a key determinant for the colonization and growth of L. pneumophila. In our preceding study, the genus Pseudomonas correlated negatively with the presence of L. pneumophila in cooling towers, but it was not clear which species was responsible. Therefore, we identified the Pseudomonas species inhabiting 14 cooling towers using a Pseudomonas-specific 16S rRNA amplicon sequencing strategy. We found that cooling towers that are free of L. pneumophila contained a high relative abundance of members from the Pseudomonas alcaliphila/oleovorans phylogenetic cluster. P. alcaliphila JCM 10630 inhibited the growth of L. pneumophila on agar plates. Analysis of the P. alcaliphila genome revealed the presence of a gene cluster predicted to produce toxoflavin. L. pneumophila growth was inhibited by pure toxoflavin and by extracts from P. alcaliphila culture found to contain toxoflavin by liquid chromatography coupled with mass spectrometry. In addition, toxoflavin inhibits the growth of Vermameoba vermiformis, a host cell of L. pneumophila. Our study indicates that P. alcaliphila may be important to restrict growth of L. pneumophila in water systems through the production of toxoflavin. A sufficiently high concentration of toxoflavin is likely not achieved in the bulk water but might have a local inhibitory effect such as near or in biofilms.
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- Hernandez, Svea, et al.
(författare)
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First Cospatial Comparison of Stellar, Neutral-gas, and Ionized-gas Metallicities in a Metal-rich Galaxy : M83
- 2021
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 908:2
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Tidskriftsartikel (refereegranskat)abstract
- We carry out a comparative analysis of the metallicities from the stellar, neutral-gas, and ionized-gas components in the metal-rich spiral galaxy M83. We analyze spectroscopic observations taken with the Hubble Space Telescope, the Large Binocular Telescope, and the Very Large Telescope. We detect a clear depletion of the H i gas, as observed from the H i column densities in the nuclear region of this spiral galaxy. We find column densities of log[N(H i) cm−2] < 20.0 at galactocentric distances of <0.18 kpc, in contrast to column densities of log[N(H i) cm−2] ~ 21.0 in the galactic disk, a trend observed in other nearby spiral galaxies. We measure a metallicity gradient of −0.03 ± 0.01 dex kpc−1 for the ionized gas, comparable to the metallicity gradient of a local benchmark of 49 nearby star-forming galaxies of −0.026 ± 0.002 dex kpc−1. Our cospatial metallicity comparison of the multiphase gas and stellar populations shows excellent agreement outside of the nucleus of the galaxy, hinting at a scenario where the mixing of newly synthesized metals from the most massive stars in the star clusters takes longer than their lifetimes (~10 Myr). Finally, our work shows that caution must be taken when studying the metallicity gradient of the neutral-gas component in star-forming galaxies, since this can be strongly biased, as these environments can be dominated by molecular gas. In these regions the typical metallicity tracers can provide inaccurate abundances, as they may trace both the neutral- and molecular-gas components.
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