Inka Ceremony for Koen Vermeulen

On March 9, 2013, at the Warsaw Zen Center, Koen Vermeulen received Inka from Zen Master Wu Bon

Physiology-based IVIVE predictions of tramadol from in vitro metabolism data

To predict the tramadol in vivo pharmacokinetics in adults by using in vitro metabolism data and an in vitro-in vivo extrapolation (IVIVE)-linked physiologically-based pharmacokinetic (PBPK) modeling and simulation approach (SimcypA (R)). Tramadol metabolism data was gathered using metabolite formation in human liver microsomes (HLM) and recombinant enzyme systems (rCYP). Hepatic intrinsic clearance (CLint(H)) was (i) estimated from HLM corrected for specific CYP450 contributions from a chemical inhibition assay (model 1); (ii) obtained in rCYP and corrected for specific CYP450 contributions by study-specific intersystem extrapolation factor (ISEF) values (model 2); and (iii) scaled back from in vivo observed clearance values (model 3). The model-predicted clearances of these three models were evaluated against observed clearance values in terms of relative difference of their geometric means, the fold difference of their coefficients of variation, and relative CYP2D6 contribution. Model 1 underpredicted, while model 2 overpredicted the total tramadol clearance by -27 and +22%, respectively. The CYP2D6 contribution was underestimated in both models 1 and 2. Also, the variability on the clearance of those models was slightly underpredicted. Additionally, blood-to-plasma ratio and hepatic uptake factor were identified as most influential factors in the prediction of the hepatic clearance using a sensitivity analysis. IVIVE-PBPK proved to be a useful tool in combining tramadol's low turnover in vitro metabolism data with system-specific physiological information to come up with reliable PK predictions in adults

Mode-field matching design, 3D fabrication and characterization of down-tapers on single-mode optical fiber tips for coupling to photonic integrated circuits

Photonic Integrated Circuits have made it possible to decrease the footprint of traditionally bulky optical systems and they create opportunities for various new and fascinating applications. One of the limiting factors for the widespread adaption of PICs is their connection to the outside world. As the mode field diameter of optical modes in waveguides tends to be an order of magnitude smaller than in their fiber counterparts, creating an efficient, robust and alignmenttolerant fiber-to-chip interface remains a challenge. In this work, we investigate the optimization of the fiber-side of the optical interface, whereas the chip itself remains untouched and makes use of spot-size convertors. Optical fiber tips can be functionalized using two-photon polymerization-based 3D nanoprinting technology, which offers full 3D design freedom and sub-micrometer resolution. We present a down-taper design strategy to match the mode-field diameter of single-mode optical fibers to the modefield diameter of waveguides with spot-size converters on PICs. The 3D printed down-tapers are characterized towards their geometry and mode shape, and we experimentally demonstrate their use for coupling towards a Silicon-On-Insulator chip with spot-size convertors. Furthermore, the performance of these down-tapered fibers is compared to conventional lensed fibers in terms of optical coupling efficiency

Vapor nanobubble is the more reliable photothermal mechanism for inducing endosomal escape of siRNA without disturbing cell homeostasis

Strategies for controlled delivery of therapeutic siRNA into living cells are in high demand as endosomal escape remains the most prominent bottleneck at the intracellular level. Photothermal properties of gold nanoparticles (AuNP) can be used to overcome the endosomal membrane barrier upon laser irradiation by two mechanisms: endosomal rupture by mechanical energy from water vapor nanobubbles (VNBs), or permeabilization of the endosomal membrane by heat diffusion. Here we evaluated how both mechanisms influence cargo release, transfection efficiency, acute cytotoxicity and cell homeostasis. Using a siRNA/AuNP drug delivery system we found that the in vitro release of siRNA from the AuNP carrier occurs equally efficiently by VNB formation or heat generation. Heat-mediated endosomal escape happened more efficiently in cells that had more particles per endosome, resulting in variable siRNA-induced downregulation (20-50%). VNB-mediated endosomal escape did not dependent on the number of AuNP per endosome, yielding high downregulations (50-60%) independent of the cell type. Effects on cell homeostasis by whole transcriptome analysis, showed a quick recover after 24 h or 48 h for either of both photothermal mechanisms. We conclude that VNBs are more consistent to induce efficient endosomal escape and gene silencing independent of the cell type without long lasting effects on cell homeostasis

Inhibition of CYP2D6 with low dose (5 mg) paroxetine in patients with high 10-hydroxynortriptyline serum levels-A prospective pharmacokinetic study

The antidepressant nortriptyline is metabolized by cytochrome P450 2D6 (CYP2D6) to the less active and more cardiotoxic drug metabolite, 10-hydroxynortriptyline. High serum levels of this metabolite (>200 μg/L) may lead to withdrawal of nortriptyline therapy. Adding CYP2D6 inhibitors reduce the metabolic activity of CYP2D6 (phenoconversion) and so decrease the forming of hydroxynortriptyline. In this study, 5 mg paroxetine is administered to patients with high hydroxynortriptyline concentrations (>200 μg/L). The shift in number of patients to therapeutic nortriptyline (50-150 μg/L) and safe hydroxynortriptyline (<200 μg/L) concentrations, and the degree of phenoconversion, expressed as the change in ratio nortriptyline/hydroxynortriptyline concentrations before and after paroxetine addition, are prospectively observed and described. After paroxetine addition, 12 patients (80%) had therapeutic nortriptyline and safe hydroxynortriptyline concentrations. Hydroxynortriptyline concentrations decreased in all patients. The average nortriptyline/hydroxynortriptyline concentrations ratio increased from 0.32 to 0.59. This study shows that 5 mg paroxetine addition is able to lower high hydroxynortriptyline serum levels to safe ranges

Assessing the importance of audio/video synchronization for simultaneous translation of video sequences

Lip synchronization is considered a key parameter during interactive communication. In the case of video conferencing and television broadcasting, the differential delay between audio and video should remain below certain thresholds, as recommended by several standardization bodies. However, further research has also shown that these thresholds can be relaxed, depending on the targeted application and use case. In this article, we investigate the influence of lip sync on the ability to perform real-time language interpretation during video conferencing. Furthermore, we are also interested in determining proper lip sync visibility thresholds applicable to this use case. Therefore, we conducted a subjective experiment using expert interpreters, which were required to perform a simultaneous translation, and non-experts. Our results show that significant differences are obtained when conducting subjective experiments with expert interpreters. As interpreters are primarily focused on performing the simultaneous translation, lip sync detectability thresholds are higher compared with existing recommended thresholds. As such, primary focus and the targeted application and use case are important factors to be considered when selecting proper lip sync acceptability thresholds