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41.
Mia Sandberg Inger Johansson Magnus Christensen Anders Rane Erik Eliasson 《Drug metabolism and disposition》2004,32(5):484-489
CYP2C9-dependent drug metabolism is subject to large interindividual variation. To some extent, this is explained by genetic polymorphism with expression of enzyme variants that differ in catalytic activity. The aim of this study was to characterize the variation in CYP2C9 phenotype in relation to genotype, with further analysis of the CYP2C9 gene in metabolic outliers. A study population of 126 healthy white subjects were recruited and genotyped for the variant alleles, CYP2C9*1-3. In CYP2C9 phenotyping with losartan, three subpopulations were distinguished that differed in the number of CYP2C9*3 alleles (0, 1, or 2). A three-fold higher metabolic ratio (MR; urinary losartan/carboxymetabolite) was found comparing CYP2C9*1/*3 (n = 20) to CYP2C9*1/*1 (n = 81), but there was considerable variation within each genotype. Subjects genotyped as CYP2C9*1/*1, but with an unexpectedly slow oxidation of losartan, were selected for DNA-sequencing analysis of the CYP2C9 gene. Interestingly, single nucleotide polymorphisms (SNPs) could not be identified either in the 5'-flanking region, the nine exons, or exon-intron boundaries. However, sequencing of the CYP2C9 gene was also carried out in patients genotyped as CYP2C9*1/*1 but with an exceptionally low steady-state clearance of S-warfarin. Here, five different SNPs were identified. In further analysis of the healthy volunteers, it became evident that women on oral contraceptives (OCs) had slower oxidation of losartan (MR of losartan: 1.7) than women without OCs (MR of losartan: 0.86). This novel finding was not explained by a different frequency of variant alleles. In summary, CYP2C9 genotype and oral contraceptives both contribute to a large interindividual variation in CYP2C9 activity. 相似文献
42.
Staffan Eksborg Magnus Andersson Lennart Domellöf Ulla Lönroth 《Medical oncology (Northwood, London, England)》1986,3(2):105-110
The plasma pharmacokinetics of adriamycin and 4′epi-adriamycin were studied in patients with malignant tumors of the liver after simultaneous regional administration of equal amounts of the two anthracyclines by the arterial route. The use of a highly selective liquid chromatographic analytical method permitted quantification of plasma concentrations of the two drugs as well as their corresponding 13-hydroxy metabolites. The plasma concentrations of each drug followed a three-compartment open model. On average the area under the plasma concentration time curve (AUC) and the maximum plasma concentration (C max) were 2.1 and 1.7 times larger for adriamycin than for 4′epi-adriamycin, respectively. 4′Epi-adriamycin was eliminated faster than adriamycin, the terminal half-life time being on the average 1.5 times higher for adriamycin. These findings are in agreement with what has previously been observed after intravenous administration. The plasma concentrations of the 13-hydroxy metabolites did not exceed 30 ng ml?1. The AUC values of these metabolites were on average 20% of the AUC values of the intact drugs. 相似文献
43.
Lisa Windisch Stefan Linke Magnus Jütte Julian Baasch Arno Kwade Enrico Stoll Carsten Schilde 《Materials》2022,15(23)
The return to the Moon is an important short-term goal of NASA and other international space agencies. To minimize mission risks, technologies, such as rovers or regolith processing systems, must be developed and tested on Earth using lunar regolith simulants that closely resemble the properties of real lunar soil. So far, no singular lunar simulant can cover the multitude of use cases that lunar regolith involves, and most available materials are poorly characterized. To overcome this major gap, a unique modular system for flexible adaptable novel lunar regolith simulants was developed and chemically characterized in earlier works. To supplement this, the present study provides comprehensive investigations regarding geotechnical properties of the three base regolith simulant systems: TUBS-M, TUBS-T, and TUBS-I. To evaluate the engineering and flow properties of these heterogeneous materials under various conditions, shear tests, particle size analyses, scanning electron microscope observations, and density investigations were conducted. It was shown that small grains <25 µm (lunar dust) are highly compressive and cohesive even at low external stress. They are particularly important as a large amount of fine dust is present in lunar regolith and simulants (x50 = 76.7 to 96.0 µm). Further, ring shear and densification tests revealed correlations with damage mechanisms caused by local stress peaks for grains in the mm range. In addition, an explanation for the occurrence of considerable differences in the literature-based data for particle sizes was established by comparing various measurement procedures. The present study shows detailed geotechnical investigations of novel lunar regolith simulants, which can be used for the development of equipment for future lunar exploration missions and in situ resource utilization under realistic conditions. The results also provide evidence about possible correlations and causes of known soil-induced mission risks that so far have mostly been described phenomenologically. 相似文献
44.
Gergana Mincheva Carla GimenezGarzo Paula IzquierdoAltarejos Mar MartinezGarcia Magnus Doverskog Thomas P. Blackburn Anneli Hllgren Torbjrn Bckstrm Marta Llansola Vicente Felipo 《CNS Neuroscience & Therapeutics》2022,28(11):1861
AimsHyperammonemic rats show peripheral inflammation, increased GABAergic neurotransmission and neuroinflammation in cerebellum and hippocampus which induce motor incoordination and cognitive impairment. Neuroinflammation enhances GABAergic neurotransmission in cerebellum by enhancing the TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways. Golexanolone reduces GABAA receptors potentiation by allopregnanolone. This work aimed to assess if treatment of hyperammonemic rats with golexanolone reduces peripheral inflammation and neuroinflammation and restores cognitive and motor function and to analyze underlying mechanisms.MethodsRats were treated with golexanolone and effects on peripheral inflammation, neuroinflammation, TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways, and cognitive and motor function were analyzed.ResultsHyperammonemic rats show increased TNFα and reduced IL‐10 in plasma, microglia and astrocytes activation in cerebellum and hippocampus, and impaired motor coordination and spatial and short‐term memories. Treating hyperammonemic rats with golexanolone reversed changes in peripheral inflammation, microglia and astrocytes activation and restored motor coordination and spatial and short‐term memory. This was associated with reversal of the hyperammonemia‐enhanced activation in cerebellum of the TNFR1‐glutaminase‐GAT3 and TNFR1‐CCL2‐TrkB‐KCC2 pathways.ConclusionReducing GABAA receptors activation with golexanolone reduces peripheral inflammation and neuroinflammation and improves cognitive and motor function in hyperammonemic rats. The effects identified would also occur in patients with hepatic encephalopathy and, likely, in other pathologies associated with neuroinflammation. 相似文献
45.
Pierre Carmona Christian von Corswant Magnus Rding Aila Srkk Eva Olsson Niklas Lorn 《RSC advances》2022,12(40):26078
Porous phase-separated ethylcellulose/hydroxypropylcellulose (EC/HPC) films are used to control drug transport out of pharmaceutical pellets. The films are applied on the pellets using fluidized bed spraying. The drug transport rate is determined by the structure of the porous films that are formed as the water-soluble HPC leaches out. However, a detailed understanding of the evolution of the phase-separated structure during production is lacking. Here, we have investigated EC/HPC films produced by spin-coating, which mimics the industrial manufacturing process. This work aimed to understand the structure formation and film shrinkage during solvent evaporation. The cross-sectional structure evolution was characterized using confocal laser scanning microscopy (CLSM), profilometry and image analysis. The effect of the EC/HPC ratio on the cross-sectional structure evolution was investigated. During shrinkage of the film, the phase-separated structure undergoes a transition from 3D to nearly 2D structure evolution along the surface. This transition appears when the typical length scale of the phase-separated structure is on the order of the thickness of the film. This was particularly pronounced for the bicontinuous systems. The shrinkage rate was found to be independent of the EC/HPC ratio, while the initial and final film thickness increased with increasing HPC fraction. A new method to estimate part of the binodal curve in the ternary phase diagram for EC/HPC in ethanol has been developed. The findings of this work provide a good understanding of the mechanisms responsible for the morphology development and allow tailoring of thin EC/HPC films structure for controlled drug release.The EC/HPC/EtOH phase diagram could be estimated from the CLSM monitoring of the cross-sectional in situ phase separation. The findings of this work provide a good understanding of the structure evolution. 相似文献
46.
Sonja Pleininger Alexander Indra Daniel Golparian Florian Heger Stefanie Schindler Susanne Jacobsson Stefan Heidler Magnus Unemo 《Euro surveillance : bulletin européen sur les maladies transmissibles = European communicable disease bulletin》2022,27(24)
We describe a gonorrhoea case with ceftriaxone plus high-level azithromycin resistance. In April 2022, an Austrian heterosexual male was diagnosed with gonorrhoea after sexual intercourse with a female sex worker in Cambodia. Recommended treatment with ceftriaxone (1 g) plus azithromycin (1.5 g) possibly failed. Worryingly, this is the second strain in an Asian Neisseria gonorrhoeae genomic sublineage including high-level azithromycin-resistant strains that developed ceftriaxone resistance by acquisition of mosaic penA-60.001. Enhanced resistance surveillance and actions are imperative to prevent spread. 相似文献
47.
Sofie Stampe Magnus Leth-Mller Eva Greibe Elke Hoffmann-Lücke Michael Pedersen Per Ovesen 《Nutrients》2022,14(13)
Artificial sweeteners (ASs) are calorie-free chemical substances used instead of sugar to sweeten foods and drinks. Pregnant women with obesity or diabetes are often recommended to substitute sugary products with ASs to prevent an increase in body weight. However, some recent controversy surrounding ASs relates to concerns about the risk of obesity caused by a variety of metabolic changes, both in the mother and the offspring. This study addressed these concerns and investigated the biodistribution of ASs in plasma and breast milk of lactating women to clarify whether ASs can transfer from mother to offspring through breast milk. We recruited 49 lactating women who were provided with a beverage containing four different ASs (acesulfame-potassium, saccharin, cyclamate, and sucralose). Blood and breast milk samples were collected before and up to six hours after consumption. The women were categorized: BMI < 25 (n = 20), BMI > 27 (n = 21) and type 1 diabetes (n = 8). We found that all four ASs were present in maternal plasma and breast milk. The time-to-peak was 30–120 min in plasma and 240–300 min in breast milk. Area under the curve (AUC) ratios in breast milk were 88.9% for acesulfame-potassium, 38.9% for saccharin, and 1.9% for cyclamate. We observed no differences in ASs distributions between the groups. 相似文献
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