Clinical doses of atomoxetine significantly occupy both norepinephrine and serotonin transports: Implications on treatment of depression and ADHD.

BACKGROUND: Atomoxetine (ATX), a drug for treatment of depression and ADHD, has a high affinity for the norepinephrine transporter (NET); however, our previous study showed it had a blocking effect similar to fluoxetine on binding of [(11)C]DASB, a selective serotonin transporter (SERT) ligand. Whether the therapeutic effects of ATX are due to inhibition of either or both transporters is not known. Here we report our comparative PET imaging studies with [(11)C]MRB (a NET ligand) and [(11)C]AFM (a SERT ligand) to evaluate in vivo IC50 values of ATX in monkeys. METHODS: Rhesus monkeys were scanned up to four times with each tracer with up to four doses of ATX. ATX or saline (placebo) infusion began 2h before each PET scan, lasting until the end of the 2-h scan. The final infusion rates were 0.01-0.12mg/kg/h and 0.045-1.054mg/kg/h for the NET and SERT studies, respectively. ATX plasma levels and metabolite-corrected arterial input functions were measured. Distribution volumes (VT) and IC50 values were estimated. RESULTS: ATX displayed dose-dependent occupancy on both NET and SERT, with a higher occupancy on NET: IC50 of 31±10 and 99±21ng/mL plasma for NET and SERT, respectively. At a clinically relevant dose (1.0-1.8mg/kg, approx. 300-600ng/mL plasma), ATX would occupy >90% of NET and >85% of SERT. This extrapolation assumes comparable free fraction of ATX in humans and non-human primates. CONCLUSION: Our data suggests that ATX at clinically relevant doses greatly occupies both NET and SERT. Thus, therapeutic modes of ATX action for treatment of depression and ADHD may be more complex than selective blockade of NET.

3D Imaging System for Visualizing and Monitoring Patients.

Three-dimensional (3D) visualization or 3D monitoring of patients or infected animals is useful in actual clinical environment. We propose a 3D imaging system with a single camera and multiple mirrors. The camera is located directly above the object and the multiple mirrors are placed surrounding the object. The single captured image includes multiple viewpoint images: the object captured directly and the same objects reflected by the mirrors. After a simple calibration of the measurement, the 3D volume data are reconstructed with the visual hull based method. Texture mapping is also performed to enhance the reality. A living object was observed in usual environment using this system. The results have demonstrated effectiveness of the system.

Practical Consideration about Cost Functions of Spatial Independent Component Analysis in Medical Image Processing.

Independent component analysis (ICA) is widely used for signal separation in various fields. However, low signal to noise ratio (SNR) of data sometimes causes failures in component estimation. We have proposed a spatial ICA-based method for extracting a blood-related component from medical images measured with positron emission tomography (PET) to omit arterial blood sampling, in which a cost function was designed in consideration of statistical properties of components. In this study, spatial ICA with the proposed cost function or kurtosis, a conventional cost function, was applied to real PET images measured with three kinds of radiopharmaceuticals, and the estimation results were compared. The proposed cost function fails to estimate components from the PET data with low SNR because it is sensitive to outliers. Experimental results suggest that a cost function should be selected depending on SNR of data.

Changes in bradykinin and prostaglandins plasma levels during dextran-sulfate low-density-lipoprotein apheresis.

The negative charges of dextran-sulfate (DS) used for low-density-lipoprotein (LDL) apheresis initiate the intrinsic coagulation pathway in which plasma kallikrein acts on the high-molecular-weight kininogen to produce large amounts of bradykinin. This study was undertaken to assess whether bradykinin generated during DS LDL apheresis has any physiologic effects in vivo. The plasma levels of bradykinin, prostaglandins and cyclic guanosine monophosphate (cGMP) were compared. when either of two anticoagulants, heparin or nafamostat mesilate (NM), was used during DS LDL apheresis. Although anticoagulative action by NM depends on the inhibition of thrombin activity this substance also inhibits the activity of plasma kallikrein. During apheresis using heparin, the plasma levels of prostaglandin E2 (PGE2) increased significantly (5.6 +/- 1.2 (mean +/- SE, n = 4) pg/ml before apheresis and 33.4 +/- 13.2 after apheresis, p < 0.05) in association with an increase in bradykinin levels (17.9 +/- 2.6 pg/ml before apheresis and 470 +/- 135 after apheresis, p < 0.01). Interestingly, these changes were suppressed during apheresis using NM. There were no appreciable changes in cGMP during DS LDL apheresis with either of the anticoagulants. This finding suggests that bradykinin generated during apheresis has some pathophysiological effects via activation of the prostaglandin system. Our results support the view that in patients taking angiotensin-converting-enzyme inhibitors, the anaphylactoid reaction occurring during apheresis may be caused by an excessive rise in the bradykinin levels.

Changes in the levels of rat interleukin 8/CINC and gelatinase in the exudate of carrageenin-induced inflammation in rats.

A sensitive enzyme-linked immunosorbent assay (ELISA) for rat interleukin 8/cytokine-induced neutrophil chemoattractant (CINC) has been established by using biotin-conjugated anti-CINC rabbit IgG. The biotin-streptavidin sandwich ELISA detected CINC at concentrations from 3 pg/ml up to 30 ng/ml. The concentration of CINC in the pouch fluid (exudate) of rat carrageenin-induced inflammation was measured by the ELISA. After a time lag of about 2 h, neutrophils steadily accumulated in the carrageenin/air-pouch until 8 h. Similarly, the CINC level of exudate increased after about a 2-h lag, and reached a maximum (134 ng/ml) at 8 h, and thereafter decreased to a negligible concentration at 24 h after carrageenin injection. In association with the rise in CINC level, the concentration of exudate 96-kDa gelatinase corresponding to neutrophil gelatinase/type IV collagenase increased with time. The results suggest that CINC contributes, at least in part, to the neutrophil migration into the inflammatory lesion of the carrageenin-induced inflammation in rats.