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- Kindmark, Andreas, et al.
(författare)
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Genome-wide pharmacogenetic investigation of a hepatic adverse event without clinical signs of immunopathology suggests an underlying immune pathogenesis
- 2008
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Ingår i: The Pharmacogenomics Journal. - : Springer Science and Business Media LLC. - 1470-269X .- 1473-1150. ; 8:3, s. 186-195
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Tidskriftsartikel (refereegranskat)abstract
- One of the major goals of pharmacogenetics is to elucidate mechanisms and identify patients at increased risk of adverse events (AEs). To date, however, there have been only a few successful examples of this type of approach. In this paper, we describe a retrospective case–control pharmacogenetic study of an AE of unknown mechanism, characterized by elevated levels of serum alanine aminotransferase (ALAT) during long-term treatment with the oral direct thrombin inhibitor ximelagatran. The study was based on 74 cases and 130 treated controls and included both a genome-wide tag single nucleotide polymorphism and large-scale candidate gene analysis. A strong genetic association between elevated ALAT and the MHC alleles DRB1*07 and DQA1*02 was discovered and replicated, suggesting a possible immune pathogenesis. Consistent with this hypothesis, immunological studies suggest that ximelagatran may have the ability to act as a contact sensitizer, and hence be able to stimulate an adaptive immune response.
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- Kvitne, K. E., et al.
(författare)
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Correlations between 4 beta-hydroxycholesterol and hepatic and intestinal CYP3A4: protein expression, microsomal ex vivo activity, and in vivo activity in patients with a wide body weight range
- 2022
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Ingår i: European Journal of Clinical Pharmacology. - : Springer Science and Business Media LLC. - 0031-6970 .- 1432-1041. ; 78:8, s. 1289-1299
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Variability in cytochrome P450 3A4 (CYP3A4) metabolism is mainly caused by non-genetic factors, hence providing a need for accurate phenotype biomarkers. Although 4 beta-hydroxycholesterol (4 beta OHC) is a promising endogenous CYP3A4 biomarker, additional investigations are required to evaluate its ability to predict CYP3A4 activity. This study investigated the correlations between 4 beta OHC concentrations and hepatic and intestinal CYP3A4 protein expression and ex vivo microsomal activity in paired liver and jejunum samples, as well as in vivo CYP3A4 phenotyping (midazolam) in patients with a wide body weight range. Methods The patients (n = 96; 78 with obesity and 18 normal or overweight individuals) were included from the COCKTAIL-study (NCT02386917). Plasma samples for analysis of 4 beta OHC and midazolam concentrations, and liver (n = 56) and jejunal (n = 38) biopsies were obtained. The biopsies for determination of CYP3A4 protein concentration and microsomal activity were obtained during gastric bypass or cholecystectomy. In vivo CYP3A4 phenotyping was performed using semi-simultaneous oral (1.5 mg) and intravenous (1.0 mg) midazolam. Results 4 beta OHC concentrations were positively correlated with hepatic microsomal CYP3A4 activity (rho = 0.53, p < 0.001), and hepatic CYP3A4 concentrations (rho = 0.30, p = 0.027), but not with intestinal CYP3A4 concentrations (rho = 0.18, p = 0.28) or intestinal microsomal CYP3A4 activity (rho = 0.15, p = 0.53). 4 beta OHC concentrations correlated weakly with midazolam absolute bioavailability (rho = - 0.23, p = 0.027) and apparent oral clearance (rho = 0.28, p = 0.008), but not with systemic clearance (rho = - 0.03, p = 0.81). Conclusion These findings suggest that 4 beta OHC concentrations reflect hepatic, but not intestinal, CYP3A4 activity. Further studies should investigate the potential value of 4 beta OHC as an endogenous biomarker for individual dose requirements of intravenously administered CYP3A4 substrate drugs.
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- Kvitne, K. E., et al.
(författare)
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Short- and long-term effects of body weight, calorie restriction and gastric bypass on CYP1A2, CYP2C19 and CYP2C9 activity
- 2022
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Ingår i: British Journal of Clinical Pharmacology. - : Wiley. - 0306-5251 .- 1365-2125. ; 88:9, s. 4121-4133
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Tidskriftsartikel (refereegranskat)abstract
- Aim Roux-en-Y gastric bypass (RYGB) may influence drug disposition due to surgery-induced gastrointestinal alterations and/or subsequent weight loss. The objective was to compare short- and long-term effects of RYGB and diet on the metabolic ratios of paraxanthine/caffeine (cytochrome P450 [CYP] 1A2 activity), 5-hydroxyomeprazole/omeprazole (CYP2C19 activity) and losartan/losartan carboxylic acid (CYP2C9 activity), and cross-sectionally compare these CYP-activities with normal-to-overweight controls. Methods This trial included patients with severe obesity preparing for RYGB (n = 40) or diet-induced (n = 41) weight loss, and controls (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day, weeks 0-3) followed by a 6-week very-low-energy diet or RYGB (both <800 kcal/day, weeks 3-9). Follow-up time was 2 years, with four pharmacokinetic investigations. Results Mean +/- SD weight loss from baseline was similar in the RYGB-group (13 +/- 2.4%) and the diet group (10.5 +/- 3.9%) at week 9, but differed at year 2 (RYGB -30 +/- 6.9%, diet -3.1 +/- 6.3%). From weeks 0 to 3, mean (95% confidence interval [CI]) CYP2C19 activity similarly increased in both groups (RYGB 43% [16, 55], diet 48% [22, 60]). Mean CYP2C19 activity increased by 30% (2.6, 43) after RYGB (weeks 3-9), but not in the diet-group (between-group difference -0.30 [-0.63, 0.03]). CYP2C19 activity remained elevated in the RYGB group at year 2. Baseline CYP2C19 activity was 2.7-fold higher in controls compared with patients with obesity, whereas no difference was observed in CYP1A2 and CYP2C9 activities. Conclusion Our findings suggest that CYP2C19 activity is lower in patients with obesity and increases following weight loss. This may be clinically relevant for drug dosing. No clinically significant effect on CYP1A2 and CYP2C9 activities was observed.
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| 5. |
- Kvitne, K. E., et al.
(författare)
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Short- and long-term effects of body weight loss following calorie restriction and gastric bypass on CYP3A-activity - a non-randomized three-armed controlled trial
- 2022
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Ingår i: Cts-Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:1, s. 221-233
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Tidskriftsartikel (refereegranskat)abstract
- It remains uncertain whether pharmacokinetic changes following Roux-en-Y gastric bypass (RYGB) can be attributed to surgery-induced gastrointestinal alterations per se and/or the subsequent weight loss. The aim was to compare short- and long-term effects of RYGB and calorie restriction on CYP3A-activity, and cross-sectionally compare CYP3A-activity with normal weight to overweight controls using midazolam as probe drug. This three-armed controlled trial included patients with severe obesity preparing for RYGB (n = 41) or diet-induced (n = 41) weight-loss, and controls (n = 18). Both weight-loss groups underwent a 3-week low-energy-diet (<1200 kcal/day) followed by a 6-week very-low-energy-diet or RYGB (both <800 kcal/day). Patients were followed for 2 years, with four pharmacokinetic investigations using semisimultaneous oral and intravenous dosing to determine changes in midazolam absolute bioavailability and clearance, within and between groups. The RYGB and diet groups showed similar weight-loss at week 9 (13 +/- 2.4% vs. 11 +/- 3.6%), but differed substantially after 2 years (-30 +/- 7.0% vs. -3.1 +/- 6.3%). At baseline, mean absolute bioavailability and clearance of midazolam were similar in the RYGB and diet groups, but higher compared with controls. On average, absolute bioavailability was unaltered at week 9, but decreased by 40 +/- 7.5% in the RYGB group and 32 +/- 6.1% in the diet group at year 2 compared with baseline, with no between-group difference. No difference in clearance was observed over time, nor between groups. In conclusion, neither RYGB per se nor weight loss impacted absolute bioavailability or clearance of midazolam short term. Long term, absolute bioavailability was similarly decreased in both groups despite different weight loss, suggesting that the recovered CYP3A-activity is not only dependent on weight-loss through RYGB.
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| 9. |
- Sarlus, Zmar, 1984-, et al.
(författare)
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Timing and origin of the host rocks to the Malmberget iron oxide-apatite deposit, Sweden
- 2020
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Ingår i: Precambrian Research. - : Elsevier. - 0301-9268 .- 1872-7433. ; 342
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Tidskriftsartikel (refereegranskat)abstract
- The northern Norrbotten region in Sweden hosts abundant iron-oxide apatite (IOA) deposits including Kiirunavaara, the type locality for Kiruna-type deposits, and Malmberget. Felsic and intermediate metavolcanic rocks hosting the Malmberget IOA deposit contain oscillatory zoned zircon which yield magmatic U-Pb SIMS ages of 1885±6 Ma and 1881±6 Ma, respectively. Metamorphic rims on zircon from these rocks yield 1797±7 Ma and 1775±6 Ma, respectively, and record the age of the latest Svecofennian regional metamorphic event in the Gällivare area, tentatively interpreted as regional contact metamorphism. Two granite dikes that cut the ore yield U-Pb zircon emplacement ages of 1790±6 Ma and 1791±7 Ma, respectively, overlapping with the metamorphic overgrowths, and set a lower age limit for ore formation in the Malmberget IOA deposit. Rocks hosting the Malmberget IOA deposit have an alkalic to alkali-calcic affinity with a geochemical signature that favors a continental-arc, transitional to extensional setting. These rocks are suggested to have been generated in a back-arc region, in response to subduction beneath the craton margin retreating to the SW or W. The obtained ages and geochemical signatures of these rocks coincide well with the regionally defined Kiirunavaara group rocks, hosting several other IOA deposits in northern Sweden.
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| 10. |
- Sarlus, Zmar, et al.
(författare)
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Timing of plutonism in the Gällivare area : mplications for Proterozoic crustal development in the northern Norrbotten ore district, Sweden
- 2018
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Ingår i: Geological Magazine. - : Cambridge University Press. - 0016-7568 .- 1469-5081. ; 155:6, s. 1351-1376
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Tidskriftsartikel (refereegranskat)abstract
- Zircon ion probe (secondary-ion mass spectrometry or SIMS) data from a set of intrusive rocks emplaced in the vicinity of major ore bodies, as well as from large igneous intrusions in the Gällivare area, gave the following results: (1) the Dundret ultramafic–mafic layered complex (1883±5 Ma), the Aitik granite (1883±5 Ma), the Nautanen diorite (1870±12 Ma), the Vassaravaara ultramafic–mafic layered complex (1798±4 Ma), the Aitik dolerite (1813±9 Ma), the Bergmästergruvan and Sikträsk syenites (1795±4 Ma and 1801±3 Ma, respectively) and the Naalojärvi granite (1782±5 Ma). These data broadly fall within the ranges 1.89–1.87 Ga (early Svecofennian) and 1.80–1.78 Ga (late Svecofennian), but geochronologically allow further subdivision into pulses at 1885–1880, 1875–1870, 1800 and 1780 Ma. During these events, large layered ultramafic–mafic and felsic plutonic rocks were generated with distinct overlap in time suggesting coeval felsic–mafic magmatism. Results also indicate the presence of inherited c. 1.87 Ga zircon crystals in the plutonic rocks at 1.78 Ga, supporting reworking of the previous crust. These data indicate the importance of mantle-derived mafic underplating in the process of crustal magma generation in the region. The c. 1.88 Ga event that generated ultramafic–mafic layered complexes is tentatively suggested to have played an important role in the formation of the Aitik Cu–Au porphyry system. The later event at c. 1.80 Ga, generating voluminous mafic–felsic units, is suggested to be coupled to the regional iron-oxide-copper-gold (IOCG) overprint.
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