Jp Kühn

Cohort Profile: The Study of Health in Pomerania

Henry Volzke, y Dietrich Alte,1y Carsten Oliver Schmidt, Dorte Radke, Roberto Lorbeer, Nele Friedrich, Nicole Aumann, Katharina Lau, Michael Piontek, Gabriele Born, Christoph Havemann, Till Ittermann, Sabine Schipf, Robin Haring, Sebastian E Baumeister, Henri Wallaschofski, Matthias Nauck, Stephanie Frick, Andreas Arnold, Michael Junger, Julia Mayerle, Matthias Kraft, Markus M Lerch, Marcus Dorr, Thorsten Reffelmann, Klaus Empen, Stephan B Felix, Anne Obst, Beate Koch, Sven Glaser, Ralf Ewert, Ingo Fietze, Thomas Penzel, Martina Doren, Wolfgang Rathmann, Johannes Haerting, Mario Hannemann, Jurgen Ropcke, Ulf Schminke, Clemens Jurgens, Frank Tost, Rainer Rettig, Jan A Kors, Saskia Ungerer, Katrin Hegenscheid, Jens-Peter Kuhn, Julia Kuhn, Norbert Hosten, Ralf Puls, Jorg Henke, Oliver Gloger, Alexander Teumer, Georg Homuth, Uwe Volker, Christian Schwahn, Birte Holtfreter, Ines Polzer, Thomas Kohlmann, Hans J Grabe, Dieter Rosskopf, Heyo K Kroemer, Thomas Kocher, Reiner Biffar,17,y Ulrich John20y and Wolfgang Hoffmann1y

Hepatic Uptake of the Magnetic Resonance Imaging Contrast Agent Gd-EOB-DTPA: Role of Human Organic Anion Transporters

Contrast-enhancing magnetic resonance imaging with the liver-specific agent gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) has been shown to improve the detection rate of focal lesions. There is evidence from preclinical studies that multidrug organic anion transporters are involved in hepatic uptake of Gd-EOB-DTPA. Therefore, we evaluated affinity of the contrast agent to human organic anion-transporting polypeptides (OATP1B1, OATP1B3, OATP2B1) and to the Na+/taurocholate cotransporting polypeptide (NTCP) using stable transfected human embryonic kidney (HEK) 293 cells. In competition assays, Gd-EOB-DTPA inhibited the uptake of bromosulfophthalein (BSP) by OATP1B1 (IC50 = 0.6 mM) and OATP1B3 (IC50 = 0.4 mM). In comparison, the IC50 values for rifampicin were 11.9 (OATP1B1), 1.4 (OATP1B3), and 80.5 μM (OATP2B1), respectively. Uptake of BSP by OATP2B1, uptake of taurocholic acid by NTCP, and viability of all HEK cells were not influenced by Gd-EOB-DTPA in concentrations up to 10 mM. In uptake assays using a new liquid chromatography-tandem mass spectrometry method for quantification, Gd-EOB-DTPA was a substrate for OATP1B1 (Km = 0.7 mM, Vmax = 10.5 pmol/mg × min), OATP1B3 (Km = 4.1 mM, Vmax = 22.7 pmol/mg × min), and NTCP (Km = 0.04 mM, Vmax = 1.4 pmol/mg × min). The uptake by OATP2B1 was not different from the vector control. In conclusion, Gd-EOB-DTPA is a substrate of the liver-specific OATP1B1, OATP1B3, and NTCP.

Whole-body magnetic resonance imaging of healthy volunteers: pilot study results from the population-based SHIP study.

PURPOSE Approximately 4000 volunteers will undergo whole-body magnetic resonance imaging (WB-MRI) within the next 3 years in the population-based Study of Health in Pomerania (SHIP). Here we present a pilot study conducted (a) to determine the feasibility of adding a WB-MRI protocol to a large-scale population-based study, (b) to evaluate the reliability of standardized MRI interpretation, and (c) to establish an approach for handling pathological findings. MATERIALS AND METHODS The institutional review board approved the study, and oral and written informed consent was obtained from each participant. Two hundred healthy volunteers (99 women, 101 men; mean age 48.3 years) underwent a standardized WB-MRI protocol. The protocol was supplemented by contrast-enhanced cardiac MRI and magnetic resonance (MR) angiography in 61 men (60.4%) and cardiac MRI and MR mammography in 44 women (44.4%). MR scans were evaluated independently by two readers. Abnormalities were discussed by an advisory board and classified according to the need for further clinical work-up. RESULTS One hundred ninety-four (97.0%) WB-MRI examinations were successfully completed in a mean scan time per subject of 90 minutes. There were 431 pathological findings in 176 (88%) of the participants. Of those 45 (10.4%) required further clinical work-up and 386 (89.6%) characterized as benign lesions did not. The interobserver agreement for the detection of pathological findings was excellent (kappa = 0.799). CONCLUSION The preliminary results presented here indicate that a large prospective, population-based study using WB-MRI is feasible and that the results of image analysis are reproducible. A variety of positive findings provide valuable information regarding disease prevalence in a general adult population.

A fully automatic three-step liver segmentation method on LDA-based probability maps for multiple contrast MR images

Automatic 3D liver segmentation in magnetic resonance (MR) data sets has proven to be a very challenging task in the domain of medical image analysis. There exist numerous approaches for automatic 3D liver segmentation on computer tomography data sets that have influenced the segmentation of MR images. In contrast to previous approaches to liver segmentation in MR data sets, we use all available MR channel information of different weightings and formulate liver tissue and position probabilities in a probabilistic framework. We apply multiclass linear discriminant analysis as a fast and efficient dimensionality reduction technique and generate probability maps then used for segmentation. We develop a fully automatic three-step 3D segmentation approach based upon a modified region growing approach and a further threshold technique. Finally, we incorporate characteristic prior knowledge to improve the segmentation results. This novel 3D segmentation approach is modularized and can be applied for normal and fat accumulated liver tissue properties.

Percutaneous biliary drainage in patients with nondilated intrahepatic bile ducts compared with patients with dilated intrahepatic bile ducts.

OBJECTIVE The purpose of this article is to compare the technical success and guidance of percutaneous transhepatic biliary drainage (PTBD) in patients with nondilated and dilated bile duct systems using different techniques to supplement the conventional approach. MATERIALS AND METHODS Between 2006 and 2008, 71 patients (mean age, 66.6 years) underwent PTBD with 97 interventions. According to sonographic evaluation of bile duct morphology, patients were divided into two groups: 50 patients with dilated and 21 patients with nondilated bile ducts. In a retrospective analysis, both groups were compared for technical success, fluoroscopy time, complications, and medical indications. The use of interventional guidance (deviations from the standard protocol) in patients with nondilated bile ducts was recorded. RESULTS The technical success rate was 90% in patients with dilated bile ducts versus 81% in patients with nondilated ducts, with no significant difference (p = 0.36). The greater complexity of the intervention in patients with nondilated bile ducts resulted in longer fluoroscopy times (p = 0.04). Complication rates were not different between the two groups. The main indication for PTBD was relief of a compressed biliary system in patients with dilated ducts and postoperative management of complications or prevention of tumor-associated bile duct obstruction in patients with nondilated ducts. T-drainage, additional CT-guided puncture, and temporary gallbladder drainage were performed in 16 of 21 interventions for patients with nondilated bile ducts, resulting in a 100% success rate, versus a success rate of 60% in the five PTBDs of nondilated ducts performed in the conventional manner. CONCLUSION T-drainage, additional CT-guided puncture, and temporary gallbladder drainage improve the technical success of PTBD when used in patients with nondilated bile ducts. With these measures, technical success and complication rates in patients with nondilated ducts are comparable to those for PTBD of dilated bile ducts.

Characterization of the intestinal and hepatic uptake/efflux transport of the magnetic resonance imaging contrast agent gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid.

ObjectivesThe objectives of the study were to measure the pharmacokinetics and liver enhancement of gadoxetate (gadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid [Gd-EOB-DTPA], Eovist, Primovist) after oral and intravenous administration in wild-type and (multidrug resistance–associated protein 2) Mrp2-deficient rats and to evaluate the in vitro transport of the contrast agent via intestinal and hepatic transporter proteins. Materials and MethodsGadolinium-ethoxylbenzyl-diethylenetriamine-pentaacetic acid–enhanced magnetic resonance imaging and pharmacokinetics of Gd-EOB-DTPA after intravenous and oral administration were evaluated in wild-type and Mrp2-deficient rats using T1-weighted magnetic resonance imaging and a validated liquid chromatography–mass spectrometry method, respectively. Cellular uptake of Gd-EOB-DTPA was measured in stably transfected human embrionic kidney 293-cells expressing oragnic anion-transporting polypeptide 1A2 or organic cation transporter 3 and Madin Darby canine kidney 2-cells expressing apical sodium dependent bile acid transporter. The affinity to MRP2 and multidrug resistance–associated protein 3 was measured using inside-out vesicles. ResultsIn vitro, Gd-EOB-DTPA was demonstrated to be a substrate for OATP1A2 (mean [SD] of the Michaelis-Menten constant [Km], 1.0 [0.4] mmol/L; mean [SD] of the maximal uptake rate [Vmax], 101.3 [21.1] pmol/mg per minute), MRP2 (Km, 1.0 [0.5] mmol/L; Vmax, 86.8 [31.1] pmol/mg per minute), and multidrug resistance–associated protein 3 (Km, 1.8 [0.3] mmol/L; Vmax, 116 [15.9] pmol/mg per minute) but not for the apical sodium-dependent bile acid transporter and organic cation transporter 3. After the oral administration to the wild-type animals, Gd-EOB-DTPA was considerably absorbed from the small intestine (bioavailability, approximately 17%) and predominately eliminated via feces after intravenous dosing (approximately 96%). In the Mrp2-deficient rats, oral bioavailability increased to approximately 21% and Gd-EOB-DTPA was exclusively excreted into urine. Magnetic resonance enhancement of the liver was significantly prolonged in the Mrp2-deficient rats compared with the wild-type rats (mean [SD] area under the curve0-90, 36.4 [8.5] vs 14.8 [10.3] arbitary units per minute; P = 0.003; time to maximum plasma concentration, 48.6 [23.8] vs 6.0 [3.1] minutes; P = 0.001). ConclusionsThe nonmetabolized Gd-EOB-DTPA may have some potentials to be used as a probe-contrast agent to evaluate transporter-mediated mechanisms along the enterohepatic absorption route for drugs by functional visualization in vivo.

Gastric Emptying and Small Bowel Water Content after Administration of Grapefruit Juice Compared to Water and Isocaloric Solutions of Glucose and Fructose: A Four-Way Crossover MRI Pilot Study in Healthy Subjects

Grapefruit juice (GFJ) is known to affect the bioavailability of drugs in different ways. Despite the influence on gastrointestinal enzymes and transporters, the influence on gastrointestinal fluid kinetics is regarded to be relevant for the absorption of several drugs. Thus, it was the aim of this pilot study to investigate the gastric and intestinal volumes after intake of GFJ compared to isocaloric fructose and glucose solutions and water. The gastric and small intestinal volume kinetics after intake of 240 mL of GFJ, 10.6% fructose solution, 10.6% glucose solution, and water were investigated with magnetic resonance imaging in a four-way crossover study in six healthy human volunteers. The carbohydrate content of the administered beverages was quantified by high-performance liquid chromatography. Even with the small sample size of this pilot study, the gastric emptying of GFJ and the glucose solution was significantly slower than that of water. The fructose solution had only a slightly delayed gastric emptying. Small bowel water content was increased by administration of GFJ and fructose solution, whereas it was decreased by glucose compared to the administration of pure water. At 80 min the small bowel water content after GFJ was twice as high as the small bowel water content after administration of water. The observed influence of GFJ on gastrointestinal fluid kinetics may explain certain phenomena in drugs pharmacokinetics. The effect is double edged, as the slower gastric emptying and increased intestinal filling can lead to enhanced or altered absorption. Due to the comparability of fruit juices, a general effect of fruit juices on gastrointestinal volumes is likely.

[Characteristics of necrosis after laser-induced thermotherapy in contrast-enhanced MRI and implications for treatment success].

AIM This article reports on the use of magnetic resonance imaging to access the post-interventional necrosis volume of liver metastases immediately after and 48 hours after LITT. MATERIAL AND METHODS In this prospective study, 56 liver metastases from 39 patients (16 females, 23 males, mean age 60.4 years) underwent LITT. The 56 metastases were divided into 4 groups according to the ablation strategy (dependent on multi-applicator technique and laser duration). Groups I and II were treated with an applicator and a time of ablation greater than 15 minutes and 20 minutes, respectively. In groups III and IV the multi-applicator technology with 3 or 4 applicators and a constant ablation time of 20 minutes were used. With the help of heightened contrast MRI of the liver, the portrayal of the post-interventional necrosis was conducted immediately after LITT and 48 hours after LITT. The post-interventional controls after 48 hours were performed during the inpatient stay. The protocol was complemented by an outpatient long-term control after more than 3 months. RESULTS The local tumor control rate was initially 96.4%. After 3 months it decreased to 92.1%. The mean necrosis volume directly after LITT was: Group I (n = 11; 1 applicator, 30 watt, 10-15 minutes) 6.69 cm(3); Group II (n = 13; 1 applicator, 30 watt, 20 minutes) 10.95 cm(3); Group III (n = 28; 2 applicator, 30 watt, 10-15 minutes) 21.47 cm(3); Group IV (n = 4; 3 applicator, 30 watt, 20 minutes) 40.20 cm(3). In comparison, the necrosis volume after 48 hours increased: Group I 10.56 cm(3); Group II 15.11 cm(3); Group III 31.33 cm(3), Group IV 55.73 cm(3)). CONCLUSION After 48 hours a progressive increase of post-interventional necrosis volumes compared to volumes directly after LITT was able to be observed. An MRI control after 48 hours, as opposed to an MRI control directly after intervention, is a better indicator for post-interventional success after LITT.

Ductal Mucus Obstruction and Reduced Fluid Secretion Are Early Defects in Chronic Pancreatitis

Objective: Defective mucus production in the pancreas may be an important factor in the initiation and progression of chronic pancreatitis (CP), therefore we aimed to (i) investigate the qualitative and quantitative changes of mucus both in human CP and in an experimental pancreatitis model and (ii) to correlate the mucus phenotype with epithelial ion transport function. Design: Utilizing human tissue samples and a murine model of cerulein induced CP we measured pancreatic ductal mucus content by morphometric analysis and the relative expression of different mucins in health and disease. Pancreatic fluid secretion in CP model was measured in vivo by magnetic resonance cholangiopancreatography (MRCP) and in vitro on cultured pancreatic ducts. Time-changes of ductal secretory function were correlated to those of the mucin production. Results: We demonstrate increased mucus content in the small pancreatic ducts in CP. Secretory mucins MUC6 and MUC5B were upregulated in human, Muc6 in mouse CP. In vivo and in vitro fluid secretion was decreased in cerulein-induced CP. Analysis of time-course changes showed that impaired ductal ion transport is paralleled by increased Muc6 expression. Conclusion: Mucus accumulation in the small ducts is a combined effect of mucus hypersecretion and epithelial fluid secretion defect, which may lead to ductal obstruction. These results suggest that imbalance of mucus homeostasis may have an important role in the early-phase development of CP, which may have novel diagnostic and therapeutic implications.

Low dose caffeine as a salivary tracer for the determination of gastric water emptying in fed and fasted state: A MRI validation study

Graphical abstract Figure. No caption available. &NA; Improving our knowledge about human gastrointestinal physiology and its impact on oral drug delivery is crucial for the development of new therapies and effective drug delivery systems. The aim of this study was to develop an in vivo tool to determine gastric emptying of water by administration of a caffeine as a tracer substance followed by subsequent saliva caffeine analysis. For this purpose, 35 mg of caffeine were given to six healthy volunteers after a 10 h overnight together with 240 mL of tap water either on a fasted stomach or 30 min after the high‐caloric, high‐fat breakfast recommended for bioavailability/bioequivalence (BA/BE) studies. Caffeine was administered in form of an ice capsule in order to omit the contamination of the oral cavity with caffeine. Parallel to saliva sampling, magnetic resonance imaging (MRI) was applied in order to validate this novel approach. After administration of the ice capsule, MRI measurements were performed every 2 min for the first 20 min followed by further measurements after 25, 30, 35, 40, 50 and 60 min. Saliva samples were collected always 1 min after the MRI measurement in supine position in the MRI scanner and continued for further 240 min. The caffeine concentration in saliva was quantified after liquid‐liquid extraction by a validated HPLC/MS‐MS method. The obtained MRI data revealed a fast emptying of the co‐administered water within 10 to 50 min in the fasted state and likewise in the fed state. Salivary caffeine kinetics showed a Cmax from 150 to 400 ng/mL with a tmax from 20 to 90 min. MRI data were normalized by setting the maximum emptied volume to 100% and the salivary caffeine kinetics were normalized by setting Cmax to 100%. In order to compare the results obtained by the MRI and the saliva method, the normalized data for each volunteer was correlated based on a linear regression. In the fasted state the mean slope for six comparisons was 0.9114 ± 0.1500 and the mean correlation coefficient was 0.912 ± 0.055. In the fed state, a mean slope of 0.8326 ± 0.1630 and a mean correlation coefficient of 0.887 ± 0.047 were obtained. Based on these results, we could show that salivary caffeine concentrations are suitable to describe the emptying of water as a non‐caloric liquid from the fasted and the fed stomach. The presented technique provides a straight‐forward, inexpensive and noninvasive method to assess gastric emptying of hydrophilic liquids, which can be broadly used in oral biopharmaceutics. Possible applications are the characterization of real‐life conditions, specific populations (e.g. elderly people) and the better understanding of the contribution of gastric emptying to pharmacokinetic profiles of orally administered drugs.