Disposition of oral and intravenous pravastatin in MRP2-deficient TR- rats.

The aim of this study was to characterize the role of the efflux transporter Mrp2 (Abcc2) in the pharmacokinetics of orally and intravenously administered pravastatin in rats. Eight Mrp2-deficient TR- rats and eight wild-type rats were given an oral dose of 20 mg/kg pravastatin. Four TR- animals and four wild-type animals were studied after intravenous administration of pravastatin (5 mg/kg). The TR(-) rats showed a 6.1-fold higher mean area under the plasma concentration-time curve (AUC) of pravastatin (p < 0.001) after oral administration and a 4.7-fold higher AUC (p < 0.01) after intravenous administration of pravastatin as compared with the wild-type animals. The mean systemic (total) clearance of pravastatin was 4.6-fold higher (39.2 versus 8.50 l/h/kg, p < 0.001) and the mean V 4.3-fold higher (14.1 versus 3.29 l/kg, p < 0.01) in the wild-type rats. The mean renal clearance of pravastatin in the TR(-) rats was 16.5-fold increased as compared with the wild-type animals (0.695 versus 0.042 l/h/kg, p < 0.05). The increased systemic exposure to oral pravastatin in the TR- rats was associated with a greater inhibitory effect on 3-hydroxy-3-methylglutaryl CoA reductase, as shown by smaller lathosterol to cholesterol concentration ratios. These results suggest that the reduced biliary pravastatin excretion in the Mrp2-deficient TR- rats is partly compensated for by increased urinary excretion of pravastatin. Furthermore, intestinal Mrp2 does not appear to play a major role in the oral absorption of pravastatin in normal rats.     

Astrocytic induction of matrix metalloproteinase-9 and edema in brain hemorrhage.

We tested the hypothesis that astrocytic matrix metalloproteinase-9 (MMP-9) mediates hemorrhagic brain edema. In a clinical case of hemorrhagic stroke, MMP-9 co-localized with astrocytes and neurons in peri-hematoma areas. In a mouse model where blood was injected into striatum, MMP-9 was colocalized with astrocytes surrounding the hemorrhagic lesion. Because MMP-9 is present in blood as well as brain, we compared four groups of wild type (WT) and MMP-9 knockout (KO) mice: WT blood injected into WT brain, KO blood into KO brain, WT blood into KO brain, and KO blood into WT brain. Gel zymography showed that MMP-9 was elevated in WT hemorrhagic brain tissue but absent from KO hemorrhagic brain tissue. Edematous water content was elevated when WT blood was injected into WT brain. However, edema was ameliorated when MMP-9 was absent in either blood or brain or both. To further assess the mechanisms involved in astrocytic induction of MMP-9, we next examined primary mouse astrocyte cultures. Exposure to hemoglobin rapidly upregulated MMP-9 in conditioned media within 1 to 24 h. Hemoglobin-induced MMP-9 was reduced by the free radical scavenger U83836E. Taken together, these data suggest that although there are large amounts of MMP-9 in blood, hemoglobin-induced oxidative stress can trigger MMP-9 in astrocytes and these parenchymal sources of matrix degradation may also be an important factor in the pathogenesis of hemorrhagic brain edema.     

Verifikation und Anwendungen des voxelbasierten Monte-Carlo-(VMC++-)Elektronen-Dosismoduls von Oncentra™ MasterPlan

PURPOSE, MATERIAL AND METHODS: The dose calculation accuracy of the voxel-based Monte Carlo (VMC++) electron dose module of Oncentra MasterPlan (Nucletron B.V., Veenendaal, The Netherlands) was verified by measurements in homogeneous water phantoms. RESULTS: Measured and calculated dose maxima on the central beam axis (calculations with 10,000-20,000 incident electron histories per cm(2)) agree well using standard applicator configurations as well as individually shaped inserts. Profile scans with higher electron energies (>/= 15 MeV) reveal differences up to 5% especially in the penumbra region. Depth dose curves agree best in the vicinity of maximum depths. In the buildup region energy-dependent differences up to 5% in both directions could be observed. In the decay region of depth dose curves calculated doses were up to 10% higher than measured values. CONCLUSION: Good VMC++ accuracy combined with moderate computing times of 1-15 min per beam satisfy all clinical needs. VMC++ allows, for the first time, accurate routine dose evaluations of radiation therapy with electrons. Adequate positioning of the dose reference point is essential. Even small displacements may significantly influence the calculation of monitor units.     

Computer-assisted LISS plate osteosynthesis of proximal tibia fractures: feasibility study and first clinical results.

Fluoroscopy is the most common tool for the intraoperative control of long-bone fracture reduction. Limitations of this technology include high radiation exposure for the patient and the surgical team, limited visual field, distorted images, and cumbersome verification of image updating. Fluoroscopy-based navigation systems partially address these limitations by allowing fluoroscopic images to be used for real-time surgical localization and instrument tracking. Existing fluoroscopy-based navigation systems are still limited as far as the virtual representation of true surgical reality is concerned. This article, for the first time, presents a reality-enhanced virtual fluoroscopy with radiation-free updates of in situ surgical fluoroscopic images to control metaphyseal fracture reduction. A virtual fluoroscopy is created using the projection properties of the fluoroscope; it allows the display of detailed three-dimensional (3D) geometric models of surgical tools and implants superimposed on the X-ray images. Starting from multiple registered fluoroscopy images, a virtual 3D cylinder model for each principal bone fragment is constructed. This spatial cylinder model not only supplies a 3D image of the fracture, but also allows effective fragment projection recovery from the fluoroscopic images and enables radiation-free updates of in situ surgical fluoroscopic images by non-linear interpolation and warping algorithms. Initial clinical experience was gained during four tibia fracture fixations that were treated by LISS (Less Invasive Stabilization System) osteosynthesis. In the cases operated on, after primary image acquisition, the image intensifier was replaced by the virtual reality system. In all cases, the procedure including fracture reduction and LISS osteosynthesis was performed entirely in virtual reality. A significant disadvantage was the unfamiliar operation of this prototype software and the need for an additional operator for the navigation system.