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- Kvitne, Kine Eide, et al.
(författare)
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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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Ingår i: Clinical Pharmacokinetics. - : Springer. - 0312-5963 .- 1179-1926. ; 63:1, s. 109-120
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Tidskriftsartikel (refereegranskat)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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- Ottesen, Anett Hellebø, et al.
(författare)
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Glycosylated Chromogranin A in Heart Failure : Implications for Processing and Cardiomyocyte Calcium Homeostasis
- 2017
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Ingår i: Circulation Heart Failure. - 1941-3289 .- 1941-3297. ; 10:2
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Chromogranin A (CgA) levels have previously been found to predict mortality in heart failure (HF), but currently no information is available regarding CgA processing in HF and whether the CgA fragment catestatin (CST) may directly influence cardiomyocyte function.METHODS AND RESULTS: CgA processing was characterized in postinfarction HF mice and in patients with acute HF, and the functional role of CST was explored in experimental models. Myocardial biopsies from HF, but not sham-operated mice, demonstrated high molecular weight CgA bands. Deglycosylation treatment attenuated high molecular weight bands, induced a mobility shift, and increased shorter CgA fragments. Adjusting for established risk indices and biomarkers, circulating CgA levels were found to be associated with mortality in patients with acute HF, but not in patients with acute exacerbation of chronic obstructive pulmonary disease. Low CgA-to-CST conversion was also associated with increased mortality in acute HF, thus, supporting functional relevance of impaired CgA processing in cardiovascular disease. CST was identified as a direct inhibitor of CaMKIIδ (Ca(2+)/calmodulin-dependent protein kinase IIδ) activity, and CST reduced CaMKIIδ-dependent phosphorylation of phospholamban and the ryanodine receptor 2. In line with CaMKIIδ inhibition, CST reduced Ca(2+) spark and wave frequency, reduced Ca(2+) spark dimensions, increased sarcoplasmic reticulum Ca(2+) content, and augmented the magnitude and kinetics of cardiomyocyte Ca(2+) transients and contractions.CONCLUSIONS: CgA-to-CST conversion in HF is impaired because of hyperglycosylation, which is associated with clinical outcomes in acute HF. The mechanism for increased mortality may be dysregulated cardiomyocyte Ca(2+) handling because of reduced CaMKIIδ inhibition.
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- Sandbu, Rune
(författare)
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A Laparoscopic Approach in Gastro-Oesophageal Surgery : Experimental and Epidemiological Studies
- 2001
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The extension of laparoscopic procedures into the chest may induce specific pathophysiologic effects.In pigs, we have demonstrated how devastating a combined thoraco-laparoscopic approach can be for gas exchange. Furthermore, the transmission of elevated pressure intra-cranially is a potential danger. The application of positive end-expiratory pressure (PEEP) was found to improve gas exchange and, more importantly, hypoxemia could be avoided. The application of PEEP did not increase intra-cranial pressure further; nor did it adversely affect cerebral circulation.Even before the introduction of the laparoscopic technique, there was a substantial increase in the annual number of antireflux procedures. Therefore, the threefold increase of the incidence of antireflux surgery recorded during the past decade cannot solely be explained by the introduction of minimal access surgery. However, a clear shift in the preferred methodology took place. This change was not scientifically supported at the time of the transition and, surprisingly, it is still not supported today. In comparison with open surgery, patients do not seem to derive significant long-term benefits from having the antireflux procedure done laparoscopically. As was demonstrated, laparoscopy might even be an inferior approach in some patients. Nevertheless, it is reasonable to assume that laparoscopy can yield equally good results as open surgery despite our failure to confirm that in our studies. Determination of the effectiveness of minimal access surgery in the treatment of GORD is critical, before minimal access techniques become the standard for antireflux surgery in the community.
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- Sandbu, Rune, et al.
(författare)
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Nationwide survey of long-term results of laparoscopic antireflux surgery in Sweden
- 2010
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Ingår i: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 45:1, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- Objective. Excellent results after laparoscopic antireflux surgery (LARS) have been reported from specialized clinics. These good results were not confirmed in a nationwide survey that studied procedures carried out in 1995-96 in Sweden. Critics pointed out that this study included the learning curve of laparoscopy. Therefore, we have repeated the survey after >5000 LARS procedures have been performed. Material and methods. A random sample of 236 patients operated on in 2000 was identified (Group I) and compared to the population operated on in 1995-96 (Group II). Both groups received a disease-specific questionnaire 4 years after surgery. Results. In Group I, 6.8% of patients had had a second procedure, 16.4% used antireflux medications regularly and 14.9% were dissatisfied. The results for Group II were 6.0%, 19.5% and 15.0%, respectively. Patients reporting any of these three conditions were classified as treatment failures. Treatment failure occurred in 25.4% and 29.0% of patients in Groups I and II, respectively. Conclusions. The nationwide long-term outcome after LARS in Sweden demonstrates that approximately a quarter of patients experience some sort of treatment failure. The results seem to be consistent, even though the surgical technique ought to be well implemented after >8years of common use.
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