| 1. |
- Lilja, Mats, et al.
(författare)
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High-doses of anti-inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults.
- 2018
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 222:2
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: This study tested the hypothesis that high doses of anti-inflammatory drugs would attenuate the adaptive response to resistance training compared with low doses.METHODS: Healthy men and women (aged 18-35 years) were randomly assigned to daily consumption of ibuprofen (IBU; 1200 mg; n=15) or acetylsalicylic acid (ASA; 75 mg; n=16) for 8 weeks. During this period, subjects completed supervised knee-extensor resistance training where one leg was subjected to training with maximal volitional effort in each repetition using a flywheel ergometer (FW), while the other leg performed conventional (work-matched across groups) weight-stack training (WS). Before and after training, muscle volume (MRI) and strength were assessed, and muscle biopsies were analysed for gene and protein expression of muscle growth regulators.RESULTS: The increase in m. quadriceps volume was similar between FW and WS, yet was (averaged across legs) greater in ASA (7.5%) compared with IBU (3.7%, group difference 34 cm(3) ; P=0.029). In the WS leg, muscle strength improved similarly (11-20%) across groups. In the FW leg, increases (10-23%) in muscle strength were evident in both groups yet they were generally greater (interaction effects P<0.05) for ASA compared with IBU. While our molecular analysis revealed several training effects, the only group interaction (P<0.0001) arose from a down-regulated mRNA expression of IL-6 in IBU.CONCLUSION: Maximal over-the-counter doses of ibuprofen attenuate strength and muscle hypertrophic adaptations to 8 weeks of resistance training in young adults. Thus, young individuals using resistance training to maximise muscle growth or strength should avoid excessive intake of anti-inflammatory drugs. This article is protected by copyright. All rights reserved.
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| 2. |
- Norgren, Jakob, et al.
(författare)
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Capillary blood tests may overestimate ketosis : triangulation between three different measures of beta-hydroxybutyrate
- 2020
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Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 318:2, s. e184-E188
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Tidskriftsartikel (refereegranskat)abstract
- The ketone body beta-hydroxybutyrate (BHB), assessed by a point-of-care meter in venous whole blood (BHBv), was used as the main outcome in a study on nutritional ketosis in healthy older adults. Two other BHB measures were also used in the study for validation and exploratory purposes, and here we report findings on correlation and agreement between those three methods. Ketosis in the range of 0-1.5 mmol/L was induced in 15 healthy volunteers by intake of medium-chain fatty acids after a 12-h fast. BHBv was assessed at 12 time points for 4 h. The same point-of-care meter was also used to test capillary blood (BHBc) at three time points, and a laboratory test determined total ketones (TK) in plasma (BHBp + acetoacetate) at four time points. A total of 180 cases included simultaneous data on BHBv, BHBc, BHBp, and TK. TK correlated with BHBp (Pearson's r = 0.99), BHBv (r = 0.91), and BHBc (r = 0.91), all P < 0.0001. BHBv and BHBp had good agreement in absolute values. However, the slope between BHBc and BHBv, measured with the same device, was in the range of 0.64-0.78 in different regression models, indicating substantially higher BHB concentrations in capillary versus venous blood. We conclude that all three methods are valid to detect relative changes in ketosis, but our results highlight the importance of method considerations and the possible need to adjust cutoffs, e.g., in the management of ketoacidosis and in the evaluation and comparison of dietary interventions.
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| 3. |
- Norgren, Jakob, et al.
(författare)
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Ketosis After Intake of Coconut Oil and Caprylic Acid-With and Without Glucose : A Cross-Over Study in Healthy Older Adults
- 2020
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Ingår i: Frontiers in Nutrition. - : Frontiers Media SA. - 2296-861X. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Medium-chain-triglycerides (MCT), formed by fatty acids with a length of 6-12 carbon atoms (C6-C12), constitute about two thirds of coconut oil (Coc). MCT have specific metabolic properties which has led them to be described as ketogenic even in the absence of carbohydrate restriction. This effect has mainly been demonstrated for caprylic acid (C8), which constitutes about 6-8% of coconut oil. Our aim was to quantify ketosis and blood glucose after intake of Coc and C8, with and without glucose intake. Sunflower oil (Suf) was used as control, expected to not break fasting ketosis, nor induce supply-driven ketosis. Method: In a 6-arm cross-over design, 15 healthy volunteers-age 65-73, 53% women-were tested once a week. After a 12-h fast, ketones were measured during 4 h after intake of coffee with cream, in combination with each of the intervention arms in a randomized order: 1. Suf (30 g); 2. C8 (20 g) + Suf (10 g); 3. C8 (20 g) + Suf (10 g) + Glucose (50 g); 4. Coc (30 g); 5. Coc (30 g) + Glucose (50 g); 6. C8 (20 g) + Coc (30 g). The primary outcome was absolute blood levels of the ketone beta-hydroxybutyrate, area under the curve (AUC). ANOVA for repeated measures was performed to compare arms. Results: beta-hydroxybutyrate, AUC/time (mean +/- SD), for arms were 1: 0.18 +/- 0.11; 2: 0.45 +/- 0.19; 3: 0.28 +/- 0.12; 4: 0.22 +/- 0.12; 5: 0.08 +/- 0.04; 6: 0.45 +/- 0.20 (mmol/L). Differences were significant (all p <= 0.02), except for arm 2 vs. 6, and 4 vs. 1 & 3. Blood glucose was stable in arm 1, 2, 4, & 6, at levels slightly below baseline (p <= 0.05) at all timepoints hours 1-4 after intake. Conclusions: C8 had a higher ketogenic effect than the other components. Coc was not significantly different from Suf, or C8 with glucose. In addition, we report that a 16-h non-carbohydrate window contributed to a mild ketosis, while blood glucose remained stable. Our results suggest that time-restricted feeding regarding carbohydrates may optimize ketosis from intake of MCT.
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| 4. |
- Norgren, Jakob, et al.
(författare)
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Serum proBDNF Is Associated With Changes in the Ketone Body β-Hydroxybutyrate and Shows Superior Repeatability Over Mature BDNF : Secondary Outcomes From a Cross-Over Trial in Healthy Older Adults
- 2021
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Ingår i: Frontiers in Aging Neuroscience. - : Frontiers Media SA. - 1663-4365. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: β-hydroxybutyrate (BHB) can upregulate brain-derived neurotrophic factor (BDNF) in mice, but little is known about the associations between BHB and BDNF in humans. The primary aim here was to investigate whether ketosis (i.e., raised BHB levels), induced by a ketogenic supplement, influences serum levels of mature BDNF (mBDNF) and its precursor proBDNF in healthy older adults. A secondary aim was to determine the intra-individual stability (repeatability) of those biomarkers, measured as intra-class correlation coefficients (ICC).Method: Three of the arms in a 6-arm randomized cross-over trial were used for the current sub-study. Fifteen healthy volunteers, 65–75 y, 53% women, were tested once a week. Test oils, mixed in coffee and cream, were ingested after a 12-h fast. Labeled by their level of ketosis, the arms provided: sunflower oil (lowK); coconut oil (midK); caprylic acid + coconut oil (highK). Repeated blood samples were collected for 4 h after ingestion. Serum BDNF levels were analyzed for changes from baseline to 1, 2 and 4 h to compare the arms. Individual associations between BHB and BDNF were analyzed cross-sectionally and for a delayed response (changes in BHB 0–2 h to changes in BDNF at 0–4 h). ICC estimates were calculated from baseline levels from the three study days.Results: proBDNF increased more in highK vs. lowK between 0 and 4 h (z-score: β = 0.25, 95% CI 0.07–0.44; p = 0.007). Individual change in BHB 0–2 h, predicted change in proBDNF 0–4 h, (β = 0.40, CI 0.12–0.67; p = 0.006). Change in mBDNF was lower in highK vs. lowK at 0–2 h (β = −0.88, CI −1.37 to −0.40; p < 0.001) and cumulatively 0–4 h (β = −1.01, CI −1.75 to −0.27; p = 0.01), but this could not be predicted by BHB levels. ICC was 0.96 (95% CI 0.92–0.99) for proBDNF, and 0.72 (CI 0.47–0.89) for mBDNF.Conclusions: The findings support a link between changes in peripheral BHB and proBDNF in healthy older adults. For mBDNF, changes differed between arms but independent to BHB levels. Replication is warranted due to the small sample. Excellent repeatability encourages future investigations on proBDNF as a predictor of brain health.Clinical Trial Registration: ClinicalTrials.gov, NCT03904433.
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| 5. |
- Rosenborg, Staffan
(författare)
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CYP2C-dependent drug metabolism in vivo : influence of genetics and drug interactions
- 2010
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cytochrome P450 enzymes (CYPs) are responsible for the metabolism of the majority of therapeutic drugs. This thesis focuses on one of the CYP subfamilies, CYP2C, especially CYP2C9 and CYP2C19, which are responsible for the metabolism of 15– 20% of all drugs. All CYP2C enzymes are polymorphic, i.e. there are genetic variants, which have functional consequences for drug metabolism. Individuals can be classified according to their CYP2C metabolic capacity in extensive (EMs), intermediate (IMs) and poor metabolisers (PMs). Recently, a novel variant of the CYP2C19 gene was described in individuals with high metabolic capacity. This allele, CYP2C19*17, has been claimed to cause ultrarapid metabolism (UM) of CYP2C19 substrates. The aim of this thesis is to explore some of the aspects underlying varying metabolic capacity between, and within, individuals with the focus on genetics and drug–drug interactions. The thesis is based on five published papers. In Paper I we explored the influence of the genetic variant CYP2C9*3 on the CYP2C9 dependent metabolism of the anti-inflammatory and analgesic drug celecoxib. We found a seven-fold higher median exposure at steady-state in homozygous carriers of the CYP2C9*3 allele compared to homozygous wild-type subjects. This might be one factor behind the increased risk of cardiovascular events that has been observed in long-term users of celecoxib in a dose-dependent fashion. Paper II and III focused on the CYP2C19*17 allele that has been associated with extensive metabolism of CYP2C19 substrates. We showed a 52% lower exposure of omeprazole in homozygous *17 carriers compared to homozygous wild-type subjects after a single dose of 40 mg. Regarding steady-state levels of escitalopram (5 mg twice daily for a week), we noted a trend towards a 21% lower exposure in CYP2C19*17 homozygous individuals. However, this did not reach statistical significance in this study that was powered for a 40% difference. The clinical impact (or lack of impact) of this allele for various clinically important CYP2C19 substrates will be discussed in the thesis. A clinical consultation was the starting point for Paper IV in which we described eight cases of increased anticoagulant effect of warfarin in connection with concomitant use of noscapine; a cough medicine available over-the-counter. These cases were reported to the Swedish adverse drug reactions (ADR) register and we could show that they yielded a statistically significant signal worthy of further investigation. In vitro experiments were performed, showing that noscapine strongly inhibited CYP2C9 and CYP3A4, the key enzymes in warfarin metabolism. Besides noscapine, another OTC drug, glucosamine, has attracted interest for suspected interaction with warfarin. In Paper V we addressed the pharmacokinetic aspect of these interactions by giving a cocktail of four probe drugs before and during noscapine or glucosamine. Compared to baseline phenotyping, significant inhibition of both CYP2C9 (4.9-fold increase in the urinary losartan/E3174 ratio; 95% CI 2.8 - 8.4) and CYP2C19 (3.6-fold increase in the plasma omeprazole/5-hydroxyomeprazole ratio; 95% CI 2.6 - 4.8) was seen during noscapine treatment. This is likely to explain the observed interaction with warfarin. No enzyme inhibition was seen with glucosamine and a metabolic interaction between warfarin and glucosamine seems highly unlikely.
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| 6. |
- Zhao, Chenyan, et al.
(författare)
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Population pharmacokinetics of apramycin from first-in-human plasma and urine data to support prediction of efficacious dose
- 2022
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Ingår i: Journal of Antimicrobial Chemotherapy. - : Oxford University Press (OUP). - 0305-7453 .- 1460-2091. ; 77:10, s. 2718-2728
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Tidskriftsartikel (refereegranskat)abstract
- Background Apramycin is under development for human use as EBL-1003, a crystalline free base of apramycin, in face of increasing incidence of multidrug-resistant bacteria. Both toxicity and cross-resistance, commonly seen for other aminoglycosides, appear relatively low owing to its distinct chemical structure. Objectives To perform a population pharmacokinetic (PPK) analysis and predict an efficacious dose based on data from a first-in-human Phase I trial. Methods The drug was administered intravenously over 30 min in five ascending-dose groups ranging from 0.3 to 30 mg/kg. Plasma and urine samples were collected from 30 healthy volunteers. PPK model development was performed stepwise and the final model was used for PTA analysis. Results A mammillary four-compartment PPK model, with linear elimination and a renal fractional excretion of 90%, described the data. Apramycin clearance was proportional to the absolute estimated glomerular filtration rate (eGFR). All fixed effect parameters were allometrically scaled to total body weight (TBW). Clearance and steady-state volume of distribution were estimated to 5.5 L/h and 16 L, respectively, for a typical individual with absolute eGFR of 124 mL/min and TBW of 70 kg. PTA analyses demonstrated that the anticipated efficacious dose (30 mg/kg daily, 30 min intravenous infusion) reaches a probability of 96.4% for a free AUC/MIC target of 40, given an MIC of 8 mg/L, in a virtual Phase II patient population with an absolute eGFR extrapolated to 80 mL/min. Conclusions The results support further Phase II clinical trials with apramycin at an anticipated efficacious dose of 30 mg/kg once daily.
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