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- Kvitne, K. E., et al.
(author)
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Digoxin Pharmacokinetics in Patients with Obesity Before and After a Gastric Bypass or a Strict Diet Compared with Normal Weight Individuals
- 2024
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In: Clinical Pharmacokinetics. - 0312-5963. ; 63:1, s. 109-120
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Journal article (peer-reviewed)abstract
- Background and Objective Several drugs on the market are substrates for P-glycoprotein (P-gp), an efflux transporter highly expressed in barrier tissues such as the intestine. Body weight, weight loss, and a Roux-en-Y gastric bypass (RYGB) may influence P-gp expression and activity, leading to variability in the drug response. The objective of this study was therefore to investigate digoxin pharmacokinetics as a measure of the P-gp phenotype in patients with obesity before and after weight loss induced by an RYGB or a strict diet and in normal weight individuals. Methods This study included patients with severe obesity preparing for an RYGB (n = 40) or diet-induced weight loss (n = 40) and mainly normal weight individuals scheduled for a cholecystectomy (n = 18). Both weight loss groups underwent a 3-week low-energy diet (<1200 kcal/day) followed by an additional 6 weeks of <800 kcal/day induced by an RYGB (performed at week 3) or a very-low-energy diet. Follow-up time was 2 years, with four digoxin pharmacokinetic investigations at weeks 0, 3, and 9, and year 2. Hepatic and jejunal P-gp levels were determined in biopsies obtained from the patients undergoing surgery. Results The RYGB group and the diet group had a comparable weight loss in the first 9 weeks (13 +/- 2.3% and 11 +/- 3.6%, respectively). During this period, we observed a minor increase (16%) in the digoxin area under the concentration-time curve from zero to infinity in both groups: RYGB: 2.7 mu g h/L [95% confidence interval (CI) 0.67, 4.7], diet: 2.5 mu g h/L [95% CI 0.49, 4.4]. In the RYGB group, we also observed that the time to reach maximum concentration decreased after surgery: from 1.0 +/- 0.33 hours at week 3 to 0.77 +/- 0.08 hours at week 9 (-0.26 hours [95% CI -0.47, -0.05]), corresponding to a 25% reduction. Area under the concentration-time curve from zero to infinity did not change long term (week 0 to year 2) in either the RYGB (1.1 mu g h/L [-0.94, 3.2]) or the diet group (0.94 mu g h/L [-1.2, 3.0]), despite a considerable difference in weight loss from baseline (RYGB: 30 +/- 7%, diet: 3 +/- 6%). At baseline, the area under the concentration-time curve from zero to infinity was -5.5 mu g h/L [95% CI -8.5, -2.5] (-26%) lower in patients with obesity (RYGB plus diet) than in normal weight individuals scheduled for a cholecystectomy. Further, patients undergoing an RYGB had a 0.05 fmol/mu g [95% CI 0.00, 0.10] (29%) higher hepatic P-gp level than the normal weight individuals. Conclusions Changes in digoxin pharmacokinetics following weight loss induced by a pre-operative low-energy diet and an RYGB or a strict diet (a low-energy diet plus a very-low-energy diet) were minor and unlikely to be clinically relevant. The lower systemic exposure of digoxin in patients with obesity suggests that these patients may have increased biliary excretion of digoxin possibly owing to a higher expression of P-gp in the liver.
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- Kvitne, K. E., et al.
(author)
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Impact of type 2 diabetes on in vivo activities and protein expressions of cytochrome P450 in patients with obesity
- 2022
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In: Clinical and Translational Science. - : Wiley. - 1752-8054 .- 1752-8062. ; 15:11, s. 2685-2696
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Journal article (peer-reviewed)abstract
- Previous studies have not accounted for the close link between type 2 diabetes mellitus (T2DM) and obesity when investigating the impact of T2DM on cytochrome P450 (CYP) activities. The aim was to investigate the effect of T2DM on in vivo activities and protein expressions of CYP2C19, CYP3A, CYP1A2, and CYP2C9 in patients with obesity. A total of 99 patients from the COCKTAIL study (NCT02386917) were included in this cross-sectional analysis; 29 with T2DM and obesity (T2DM-obesity), 53 with obesity without T2DM (obesity), and 17 controls without T2DM and obesity (controls). CYP activities were assessed after the administration of a cocktail of probe drugs including omeprazole (CYP2C19), midazolam (CYP3A), caffeine (CYP1A2), and losartan (CYP2C9). Jejunal and liver biopsies were also obtained to determine protein concentrations of the respective CYPs. CYP2C19 activity and jejunal CYP2C19 concentration were 63% (−0.39 [95% CI: −0.82, −0.09]) and 40% (−0.09 fmol/μg protein [95% CI: −0.18, −0.003]) lower in T2DM-obesity compared with the obesity group, respectively. By contrast, there were no differences in the in vivo activities and protein concentrations of CYP3A, CYP1A2, and CYP2C9. Multivariable regression analyses also indicated that T2DM was associated with interindividual variability in CYP2C19 activity, but not CYP3A, CYP1A2, and CYP2C9 activities. The findings indicate that T2DM has a significant downregulating impact on CYP2C19 activity, but not on CYP3A, CYP1A2, and CYP2C9 activities and protein concentrations in patients with obesity. Hence, the effect of T2DM seems to be isoform-specific. © 2022 The Authors. Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.
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- Agren Bolmsjö, I, et al.
(author)
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From cure to palliation: agreement, timing, and decision making within the staff
- 2007
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In: The American journal of hospice & palliative care. - : SAGE Publications. - 1049-9091 .- 1938-2715. ; 24:5, s. 366-70
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Journal article (peer-reviewed)abstract
- Important issues in the transition From curative treatment to palliative care are agreement, timing, and decision making. A survey oF 309 nurses and 415 physicians in Sweden showed that 61% oF the nurses and 83% oF the physicians thought agreement was current practice. None said that the decisions were made too early, but 19% oF the nurses and 14% oF the physicians thought that they oFten were made too late. Very Few respondents stated that such decisions are changed, 0% and 1%, respectively. More than halF oF the inFormants made detailed comments on such transitions indicating that awareness and Flexibility are desirable to make well-inFormed decisions. Three themes that emerged From the analysis concerning the decision to stop curative treatment and Focus on palliative care were that the staFF members should (iF possible) make such decisions in agreement and should sometimes make the decisions earlier and that well-based reasons are required to make changes.
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- Handin, Niklas, et al.
(author)
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Proteome deconvolution of liver biopsies reveals hepatic cell composition as an important marker of fibrosis
- 2023
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In: Computational and Structural Biotechnology Journal. - : Elsevier. - 2001-0370. ; 21, s. 4361-4369
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Journal article (peer-reviewed)abstract
- Human liver tissue is composed of heterogeneous mixtures of different cell types and their cellular stoichiometry can provide information on hepatic physiology and disease progression. Deconvolution algorithms for the identification of cell types and their proportions have recently been developed for transcriptomic data. However, no method for the deconvolution of bulk proteomics data has been presented to date. Here, we show that proteomes, which usually contain less data than transcriptomes, can provide useful information for cell type deconvolution using different algorithms. We demonstrate that proteomes from defined mixtures of cell lines, isolated primary liver cells, and human liver biopsies can be deconvoluted with high accuracy. In contrast to transcriptome-based deconvolution, liver tissue proteomes also provided information about extracellular compartments. Using deconvolution of proteomics data from liver biopsies of 56 patients undergoing Roux-en-Y gastric bypass surgery we show that proportions of immune and stellate cells correlate with inflammatory markers and altered composition of extracellular matrix proteins characteristic of early-stage fibrosis. Our results thus demonstrate that proteome deconvolution can be used as a molecular microscope for investigations of the composition of cell types, extracellular compartments, and for exploring cell-type specific pathological events. We anticipate that these findings will allow the refinement of retrospective analyses of the growing number of proteome datasets from various liver disease states and pave the way for AI-supported clinical and preclinical diagnostics.
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- Jansson-Löfmark, R, et al.
(author)
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Enantiospecific Reassessment of the Pharmacokinetics and Pharmacodynamics of Oral Eflornithine against Late-Stage Trypanosoma brucei gambiense Sleeping Sickness
- 2015
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In: Antimicrobial Agents and Chemotherapy. - 0066-4804 .- 1098-6596. ; 59:2, s. 1299-1307
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Journal article (peer-reviewed)abstract
- This study aimed to characterize the stereoselective pharmacokinetics of oral eflornithine in 25 patients with late-stage Trypanosoma brucei gambiense sleeping sickness. A secondary aim was to determine the concentrations of l- and d-eflornithine required in plasma or cerebrospinal fluid (CSF) for an efficient eradication of the T. brucei gambiense parasites. Patients were randomly allocated to receive either 100 (group I, n = 12) or 125 (group II, n = 13) mg/kg of body weight of drug every 6 h for 14 days. The concentrations of l- and d-eflornithine in the plasma and CSF samples were measured using a stereospecific liquid chromatographic method. Nonlinear mixed-effects modeling was used to characterize the plasma pharmacokinetics. The plasma concentrations of l-eflornithine were on average 52% (95% confidence interval [CI], 51, 54%; n = 321) of the d-enantiomer concentrations. The typical oral clearances of l- and d-eflornithine were 17.4 (95% CI, 15.5, 19.3) and 8.23 (95% CI, 7.36, 9.10) liters/h, respectively. These differences were likely due to stereoselective intestinal absorption. The distributions of eflornithine enantiomers to the CSF were not stereoselective. A correlation was found between the probability of cure and plasma drug exposure, although it was not more pronounced for the l-enantiomer than for that of total eflornithine. This study may explain why oral treatment for late-stage human African trypanosomiasis (HAT) patients with racemic eflornithine has previously failed; the more potent l-enantiomer is present at much lower concentrations in both plasma and CSF than those of the d-enantiomer. Eflornithine stereoselective pharmacokinetics needs to be considered if an oral dosage regimen is to be explored further.
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- Lynoe, Niels, et al.
(author)
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Teaching medical ethics: what is the impact of role models? Some experiences from Swedish medical schools
- 2008
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In: Journal of Medical Ethics. - : BMJ. - 1473-4257 .- 0306-6800. ; 34:4, s. 315-316
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Journal article (peer-reviewed)abstract
- The goal of the present study was to elucidate what influences medical students' attitudes and interests in medical ethics. At the end of their first, fifth and last terms, 409 medical students from all six medical schools in Sweden participated in an attitude survey. The questions focused on the students' experience of good and poor role models, attitudes towards medical ethics in general and perceived effects of the teaching of medical ethics. Despite a low response rate at some schools, this study indicates that increased interest in medical ethics was related to encountering good physician role models, and decreased interest, to encountering poor role models. Physicians involved in the education of medical students seem to teach medical ethics as role models even when ethics is not on the schedule. The low response rate prevents us from drawing definite conclusions, but the results could be used as hypotheses to be further scrutinised.
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- Löfmark, R, et al.
(author)
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Conditions and consequences of medical futility - from a literature review to a clinical model
- 2002
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In: Journal of Medical Ethics. - : BMJ. - 1473-4257 .- 0306-6800. ; 28:2, s. 115-119
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Journal article (peer-reviewed)abstract
- Objectives: To present an analysis of futility that is useful in the clinical setting. Design: Literature review. Material and methods: According to Medline more than 750 articles have been published about medical futility. Three criteria (language, time period, and the authors expressed their own opinions) singled out 43 of them. The authors opinions about futility were analysed using the scheme: If certain conditions are satisfied, then a particular measure is futile and If a particular measure is futile, then certain moral consequences are implied. Results: Regarding conditions, most authors stated that judgments about futility should be made by physicians. The measure was usually some kind of medical treatment, and the goals related to quality of life, physiological improvement, or prolongation of life. The probability of success in reaching the goal was in most cases described in semiquantitative terms. Regarding consequences, the authors stated that health care professionals may (sometimes ought or should) withhold or withdraw a futile measure, most often after a dialogue with the patient (29 articles), but sometimes without informing the patient (nine articles), or with one-way information (four articles). Over time more and more articles recommend that the patient should be involved in joint decision making. Based on this literature review a clinical model was developed. Conclusions: The model, requiring that conditions and consequences should be made explicit, may, in futility situations, facilitate both the collection of the necessary information and make the moral implications visible. It also makes communication about measures considered to be futile possible without using such ambiguous terms as futile.
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