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- Ericsson, Therese, 1984, et al.
(författare)
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The Evaluation of CYP2B6 Inhibition by Artemisinin Antimalarials in Recombinant Enzymes and Human Liver Microsomes. : The Inhibitory Effect of Artemisinin Antimalarials on CYP2B6
- 2012
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Ingår i: Drug metabolism letters. - : Bentham Science Publishers Ltd.. - 1874-0758 .- 1872-3128. ; 6:4, s. 247-57
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Tidskriftsartikel (refereegranskat)abstract
- Artemisinin-based combination therapy (ACT) is the recommended treatment of uncomplicated P.falciparum malaria by the World Health Organisation (WHO). Some artemisinin compounds and anti-retroviral drugs have been shown to be metabolized by CYP2B6. In the African clinical settings, the likelihood of co-administration of ACTs and antiretroviral drugs is higher than elsewhere, posing the risk of drug-drug interactions (DDIs). This study aimed to investigate whether artemisinin compounds inhibit CYP2B6 activity in vitro using recombinant CYP2B6 (rCYP2B6) and human liver microsomes (HLM). Values for IC50 and Ki were determined by kinetic analyses using non-linear regression. In vitro to in vivo extrapolations of the likelihood of DDIs where done using a static [I]/Ki approach. Artemisinin and artemether were shown to inhibit CYP2B6 in vitro through a partial mixed type of inhibition, while dihydroartemisinin did not inhibit the enzymatic activity. IC50 values for artemisinin were 9.5 and 9.1 µM for rCYP2B6 and HLM, respectively, after 30 min of incubation. Corresponding values for artemether were 7.5 and 5.4 µM. Artemisinin did not show any time-dependency or requirement of NADPH in its mechanism, indicating a reversible mode of inhibition. Based on the [I]/Ki approach using rCYP2B6, the risk of DDIs for artemisinin was indicated to be medium to high, while artemether had a low risk. The findings indicate a potential but moderate risk of DDIs in the co-administration of artemisinin or artemether with efavirenz in the co-treatment of malaria and HIV/AIDS.
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- Syvänen, Stina, et al.
(författare)
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PET-evaluated transport of [11C]hydroxyurea across the rat blood-brain barrier - : lack of influence of cyc-losporin and probenecid
- 2007
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Ingår i: Drug Metabolism Letters. - : Bentham Science Publishers Ltd.. - 1872-3128. ; 1:3, s. 189-194
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Tidskriftsartikel (refereegranskat)abstract
- The transport of hydroxyurea, a ribonucleoside reductase inhibitor, over biological membranes is slow and it has therefore been suggested that the substance could interact with an active efflux transporter. The transport of [11C]hydroxyurea into the rat brain was therefore studied after administration of the multidrug resistance protein inhibitor probenecid (50 and 150 mg/kg), the P-glycoprotein inhibitor cyclosporin A (25 mg/kg), hydroxyurea (50, 150 and 450 mg/kg) and mannitol (25%). None of the intervention drugs affected the brain uptake of [11C]hydroxyurea. The brain-toplasma concentration ratios (Kp), with or without intervention drug, were in the range 0.12-0.25 after 60 min of [11C]hydroxyurea infusion. [11C]Verapamil, a P-glycoprotein substrate with low brain penetration, was used to study the ability of hydroxyurea to inhibit P-glycoprotein. Administration of hydroxyurea (150 and 450 mg/kg) did not increase brain concentrations of [11C]verapamil. It is therefore unlikely that hydroxyurea is a substrate for or an inhibitor of Pglycoprotein or a substrate for a probenecid sensitive transport system. The low brain concentrations may instead be the result of slow uptake due to the hydrophilic nature of hydroxyurea.
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- Fallahnejad, Mostafa, et al.
(författare)
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District heating potential in the EU-27 : Evaluating the impacts of heat demand reduction and market share growth
- 2024
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Ingår i: Applied Energy. - Oxford : Elsevier. - 0306-2619 .- 1872-9118. ; 353:Part B
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Tidskriftsartikel (refereegranskat)abstract
- This paper presents a novel approach to modeling the gradual reduction in heat demand and the evolving expansion of district heating (DH) grids for assessing the DH potential in EU member states (MS). It introduces new methodological elements for modeling the impact of connection rates below 100% on heat distribution costs in both dense and sparse areas. The projected heat demand in 2050 is derived from a decarbonization scenario published by the EU, which would lead to a reduction in demand from 3128 TWh in 2020 to 1709 TWh by 2050. The proposed approach yields information on economic DH areas, DH potential, and average heat distribution costs. The results confirm the need to expand DH grids to maintain supply levels in view of decreasing heat demand. The proportion of DH potential from the total demand in the EU-27 rises from 15% in 2020 to 31% in 2050. The analysis of DH areas shows that 39% of the DH potential is in areas with heat distribution costs above 35 EUR/MWh, but most MS have average heat distribution costs between 28 and 32 EUR/MWh. The study reveals that over 40% of the EU's heat demand is in regions with high potential for implementing DH. © 2023 The Author(s)
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