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  • 1
    Language: English
    In: Nature reviews. Drug discovery, 2015-06, Vol.14 (6), p.387-404
    Description: Drug metabolism can produce metabolites with physicochemical and pharmacological properties that differ substantially from those of the parent drug, and consequently has important implications for both drug safety and efficacy. To reduce the risk of costly clinical-stage attrition due to the metabolic characteristics of drug candidates, there is a need for efficient and reliable ways to predict drug metabolism in vitro, in silico and in vivo. In this Perspective, we provide an overview of the state of the art of experimental and computational approaches for investigating drug metabolism. We highlight the scope and limitations of these methods, and indicate strategies to harvest the synergies that result from combining measurement and prediction of drug metabolism.
    Subject(s): Animals ; Computational biology ; Computational Biology - methods ; Computational Biology - trends ; Drug Design ; Drug Discovery - methods ; Drug Discovery - trends ; Drug metabolism ; Forecasting ; Humans ; Methods ; Pharmaceutical Preparations - metabolism ; Pharmacology, Experimental ; Research
    ISSN: 1474-1776
    E-ISSN: 1474-1784
    Source: Academic Search Ultimate
    Source: Nature Reviews
    Source: Get It Now
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  • 2
    Language: English
    In: IEEE transactions on microwave theory and techniques, 2017-11, Vol.65 (11), p.4294-4306
    Description: An optimization procedure for multitransmitter multiple-input single-output (MISO) wireless power transfer (WPT) systems based on tight semidefinite relaxation (SDR) is presented. This method ensures physical realizability of MISO WPT systems designed via convex optimization-a robust, semianalytical, and intuitive route to optimizing such systems. To that end, the nonconvex constraints requiring that power is fed into rather than drawn from the system via all transmitter ports are incorporated in a convex SDR, which is efficiently and reliably solvable by dedicated algorithms. A test of the solution then confirms that this modified problem is equivalent (tight relaxation) to the original (nonconvex) one and that the true global optimum has been found. This is a clear advantage over global optimization methods (e.g., genetic algorithms), where convergence to the true global optimum cannot be ensured or tested. Discussions of numerical results yielded by both the closed-form expressions and the refined technique illustrate the importance and practicability of the new method. It is shown that this technique offers a rigorous optimization framework for a broad range of current and emerging WPT applications.
    Subject(s): Algorithms ; Computational geometry ; Convex optimization ; Convex programming ; Convexity ; Genetic algorithms ; Global optimization ; Impedance ; Impedance (Electricity) ; Load modeling ; Mathematical optimization ; MISO ; MISO (control systems) ; multiple transmitters ; Optimization ; power transfer efficiency (PTE) ; Realizability ; Receivers ; Research ; Resistance ; Robustness (mathematics) ; semidefinite programming ; semidefinite relaxation (SDR) ; Transmitters ; Usage ; wireless power transfer (WPT) ; Wireless power transmission
    ISSN: 0018-9480
    E-ISSN: 1557-9670
    Source: IEEE Electronic Library (IEL)
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  • 3
    Language: English
    In: Cancer chemotherapy and pharmacology, 2017-11-29, Vol.81 (1), p.195-206
    Description: Purpose To evaluate the mass balance, metabolic disposition, and pharmacokinetics of a single dose of regorafenib in healthy volunteers. In addition, in vitro metabolism of regorafenib in human hepatocytes was investigated. Methods Four healthy male subjects received one 120 mg oral dose of regorafenib containing approximately 100 µCi (3.7 MBq) [ 14 C]regorafenib. Plasma concentrations of parent drug were derived from HPLC–MS/MS analysis and total radioactivity from liquid scintillation counting (LSC). Radiocarbon analyses used HPLC with fraction collection followed by LSC for all urine samples, plasma, and fecal homogenate extracts. For the in vitro study, [ 14 C]regorafenib was incubated with human hepatocytes and analyzed using HPLC–LSC and HPLC–HRMS/MS. Results Regorafenib was the major component in plasma, while metabolite M-2 (pyridine N -oxide) was the most prominent metabolite. Metabolites M-5 (demethylated pyridine N -oxide) and M-7 ( N -glucuronide) were identified as minor plasma components. The mean concentration of total radioactivity in plasma/whole blood appeared to plateau at 1–4 h and again at 6–24 h post-dose. In total, 90.5% of administered radioactivity was recovered in the excreta within a collection interval of 12 days, most of which (71.2%) was eliminated in feces, while excretion via urine accounted for 19.3%. Regorafenib (47.2%) was the most prominent component in feces and was not excreted into urine. Excreted metabolites resulted from oxidative metabolism and glucuronidation. Conclusions Regorafenib was eliminated predominantly in feces as well as by hepatic biotransformation. The multiple biotransformation pathways of regorafenib decrease the risk of pharmacokinetic drug–drug interactions.
    Subject(s): Administration, Oral ; Adult ; Analysis ; Antineoplastic Agents - administration & dosage ; Antineoplastic Agents - adverse effects ; Antineoplastic Agents - blood ; Antineoplastic Agents - pharmacokinetics ; Biotransformation ; Cancer Research ; Chromatography, High Pressure Liquid - methods ; Collection ; Drug dosages ; Excretion ; Feces ; Feces - chemistry ; Healthy Volunteers ; Hepatocytes ; Hepatocytes - metabolism ; High-performance liquid chromatography ; Human ; Humans ; Liquid chromatography ; Liver - metabolism ; Male ; Medicine ; Medicine & Public Health ; Metabolism ; Metabolites ; Middle Aged ; Oncology ; Original ; Original Article ; Oxidative metabolism ; Pharmacokinetics ; Pharmacology ; Pharmacology/Toxicology ; Phase I ; Phenylurea Compounds - administration & dosage ; Phenylurea Compounds - adverse effects ; Phenylurea Compounds - blood ; Phenylurea Compounds - pharmacokinetics ; Plasma ; Pyridine ; Pyridines ; Pyridines - administration & dosage ; Pyridines - adverse effects ; Pyridines - blood ; Pyridines - pharmacokinetics ; Radioactivity ; Regorafenib ; Risk reduction ; Scintillation counters ; Scintillation Counting ; Tandem Mass Spectrometry - methods ; Urinalysis - methods ; Urine
    ISSN: 0344-5704
    E-ISSN: 1432-0843
    Source: Alma/SFX Local Collection
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  • 4
    Language: English
    In: IEEE transactions on antennas and propagation, 2019-06, Vol.67 (6), p.3974-3986
    Description: A new approach for the computation of electromagnetic field derivatives, up to any order, with respect to the material and geometric parameters of a given geometry, in a single finite-difference time-domain (FDTD) simulation is introduced. The proposed method is based on embedding the complex-step derivative (CSD) approximation into the standard FDTD update equations. Being finite-difference free, CSD provides accurate derivative approximations even for very small perturbations of the design parameters, unlike finite-difference approximations that are prone to subtractive cancellation errors. The availability of accurate approximations of field derivatives with respect to design parameters enables studies such as sensitivity analysis of multiple objective functions (as derivatives of those can be derived from field derivatives via the chain rule), uncertainty quantification, as well as multiparametric modeling and optimization of electromagnetic structures. The theory, FDTD implementation, and applications of this technique are presented.
    Subject(s): Antennas ; Approximation ; Computation ; Computer simulation ; Derivatives ; Design parameters ; Electromagnetic fields ; Electromagnetic simulation ; Electromagnetism ; Engineering ; Engineering, Electrical & Electronic ; Finite difference methods ; Finite difference time domain method ; finite-difference time-domain (FDTD) ; Multiple objective analysis ; Optimization ; Parameter sensitivity ; Perturbation methods ; Science & Technology ; Sensitivity ; Sensitivity analysis ; Standards ; Technology ; Telecommunications ; Time-domain analysis
    ISSN: 0018-926X
    E-ISSN: 1558-2221
    Source: IEEE Electronic Library (IEL)
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  • 5
    Language: English
    In: Sensors (Basel, Switzerland), 2015-08-18, Vol.15 (8), p.20305-20315
    Description: In this paper we present and discuss two innovative liquid-free SOI sensors for pressure measurements in harsh environments. The sensors are capable of measuring pressures at high temperatures. In both concepts media separation is realized using a steel membrane. The two concepts represent two different strategies for packaging of devices for use in harsh environments and at high temperatures. The first one is a "one-sensor-one-packaging_technology" concept. The second one uses a standard flip-chip bonding technique. The first sensor is a "floating-concept", capable of measuring pressures at temperatures up to 400 °C (constant load) with an accuracy of 0.25% Full Scale Output (FSO). A push rod (mounted onto the steel membrane) transfers the applied pressure directly to the center-boss membrane of the SOI-chip, which is placed on a ceramic carrier. The chip membrane is realized by Deep Reactive Ion Etching (DRIE or Bosch Process). A novel propertied chip housing employing a sliding sensor chip that is fixed during packaging by mechanical preloading via the push rod is used, thereby avoiding chip movement, and ensuring optimal push rod load transmission. The second sensor can be used up to 350 °C. The SOI chips consists of a beam with an integrated centre-boss with was realized using KOH structuring and DRIE. The SOI chip is not "floating" but bonded by using flip-chip technology. The fabricated SOI sensor chip has a bridge resistance of 3250 Ω. The realized sensor chip has a sensitivity of 18 mV/µm measured using a bridge current of 1 mA.
    Subject(s): Electricity ; Electronics - instrumentation ; Environment ; Finite Element Analysis ; MEMS ; Pressure ; sensors for harsh environment ; sensors for high temperature ; Signal Processing, Computer-Assisted ; Silicon - chemistry ; SOI-based sensors ; Temperature
    ISSN: 1424-8220
    E-ISSN: 1424-8220
    Source: Academic Search Ultimate
    Source: PubMed Central
    Source: Alma/SFX Local Collection
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  • 6
    Language: English
    In: Drug metabolism and disposition, 2018-11, Vol.46 (11), p.1546-1555
    Description: Mass balance and biotransformation of finerenone, a nonsteroidal mineralocorticoid receptor antagonist, were investigated in four healthy male volunteers following a single oral administration of 10 mg (78 Ci) of [ C]finerenone and compared with data from studies in dogs and rats. The total recovery of the administered radioactivity was 101% in humans, 94.7% in dogs, and 95.2% in rats. In humans, radioactivity was mainly excreted renally (80%); in rats, it was primarily the biliary/fecal route (76%); and in dogs, excretion was more balanced. Finerenone was extensively metabolized in all species by oxidative biotransformation, with minor amounts of unchanged drug in excreta (humans: 1%; dogs, rats: 〈9%). In vitro studies suggested cytochrome P450 3A4 was the predominant enzyme involved in finerenone metabolism in humans. Primary metabolic transformation involved aromatization of the dihydronaphthyridine moiety of metabolite M1 as a major clearance pathway with a second oxidative pathway leading to M4. These were both prone to further oxidative biotransformation reactions. Naphthyridine metabolites (M1-M3) were the dominant metabolites identified in human plasma, with no on-target pharmacological activity. In dog plasma, finerenone and metabolite M2 constituted the major components; finerenone accounted almost exclusively for drug-related material in rat plasma. For metabolites M1-M3, axial chirality was observed, represented by two atropisomers (e.g., M1a and M1b). Analysis of plasma and excreta showed one atropisomer (a-series, 〉79%) of each metabolite predominated in all three species. In summary, the present study demonstrates that finerenone is cleared by oxidative biotransformation, mainly via naphthyridine derivatives.
    Subject(s): Administration, Oral ; Aged ; Animals ; Bile - metabolism ; Biotransformation ; Biotransformation - physiology ; Blood plasma ; Carbon 14 ; Chirality ; Cytochrome ; Cytochrome P-450 CYP3A - metabolism ; Cytochrome P450 ; Cytochromes P450 ; Data recovery ; Dogs ; Excretion ; Feces - chemistry ; Female ; Humans ; Male ; Mass balance ; Metabolism ; Metabolites ; Middle Aged ; Mineralocorticoid Receptor Antagonists - metabolism ; Naphthyridines - metabolism ; Oral administration ; Oxidation-Reduction ; Pharmacology ; Plasma ; Radioactivity ; Rats ; Rats, Wistar ; Transformation
    ISSN: 0090-9556
    E-ISSN: 1521-009X
    Source: Alma/SFX Local Collection
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  • 7
    Language: English
    In: IEEE transactions on microwave theory and techniques, 2016-08, Vol.64 (8), p.2511-2518
    Description: Due to manufacturing requirements, surface finishes have become a necessity in printed circuit board design. These finishes have significant effects on the RF performance of the transmission lines. In this paper, a filament modeling approach is used to model skin, proximity, and surface roughness effects in transmission lines with surface finishes up to 70 GHz. The approach shows a high accuracy compared with measurements. The model also gives an insight into how the current distributes itself by showing the frequency dependent proportion of the current that flows in each surface finish layer. In the case of NiP-Au or Ni-Au surface finishes, current migrates increasingly into gold at high frequencies and reaches a maximum in the Ni or NiP at around 3.5 GHz, and then declines. The distribution of the current in different materials can also be explained as the decay of an electromagnetic wave at the surface of the conductor. This approach shows that the evanescent wave in the cross section of the conductor can be analyzed as analog to a transmission- reflection problem, what we will call the surface finish effect. This effect brings into question the accuracy of the traditional skin-depth value, δ, and the models that depend on it, such as most surface roughness correction factors, for structures where different metals are layered in thicknesses that are not much larger than δ.
    Subject(s): Accuracy ; Boards ; Circuit boards ; Circuit printing ; Computer simulation ; Computer-generated environments ; Conductors ; Conductors (devices) ; Filament model ; Modelling ; partial element equivalent circuit (PEEC) method ; Printed circuits ; Product design ; proximity effect ; Research ; Rough surfaces ; Skin ; skin effect ; Surface finish ; Surface resistance ; Surface roughness ; surface roughness effect ; Surface waves ; Transmission line measurements ; Transmission lines ; Usage
    ISSN: 0018-9480
    E-ISSN: 1557-9670
    Source: IEEE Electronic Library (IEL)
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  • 8
    Language: English
    In: Microsystem technologies : sensors, actuators, systems integration, 2019-03-02, Vol.25 (4), p.1137-1149
    Description: A cost effective and reliable technology for the fabrication of electrochemical test-cell arrays for battery materials research, based on batch-fabricated glass micro packages was developed and tested. Jet dispensing was investigated for the first time as a process for fabricating battery electrode arrays and separators and compared to micro dispense printing. The process shows the reproducibility over the whole range of investigated materials and battery cell structures that is required for battery materials research. Such setup gives rise to a significantly improved reliability and reproducibility of electrochemical experiments. Cost-effective fabrication of our test chips by batch processing allows for their single-use in electrochemical experiments, thereby preventing contamination issues due to repeated use as in conventional laboratory test cells. In addition, the integration of micro pseudo reference electrodes is demonstrated. Thus, the test cell array together with the developed electrode/electrolyte deposition technology provide a highly efficient tool for speedy combinatorial and high throughput testing of battery materials on a system level (full cell tests). Experimental results are shown for the microfabrication of lithium-ion test cells with help of several electrode and binder materials. The influence of jetting parameters on electrode lateral dimensions and thickness, reproducibility of the electrode mass as well as the use of integrated micro-reference electrodes for impedance spectroscopy and cyclic voltammetry measurements in micro cells are presented in detail.
    Subject(s): Arrays ; Batch processing ; Batteries ; Chip formation ; Combinatorial analysis ; Electrodes ; Electrolytic cells ; Electronics and Microelectronics ; Engineering ; Engineering, Electrical & Electronic ; Flight tests ; Instrumentation ; Laboratory tests ; Lithium ; Lithium ions ; Materials Science ; Materials Science, Multidisciplinary ; Materials testing ; Mechanical Engineering ; Nanoscience & Nanotechnology ; Nanotechnology ; Physical Sciences ; Physics ; Physics, Applied ; Reproducibility ; Science & Technology ; Science & Technology - Other Topics ; Separators ; Technical Paper ; Technology
    ISSN: 0946-7076
    E-ISSN: 1432-1858
    Source: Web of Science - Science Citation Index Expanded - 2019〈img src="http://exlibris-pub.s3.amazonaws.com/fromwos-v2.jpg" /〉
    Source: Alma/SFX Local Collection
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  • 9
    Language: English
    In: Cancer chemotherapy and pharmacology, 2017-07-11, Vol.80 (3), p.535-544
    Description: Purpose To determine the pharmacokinetics of radiolabeled copanlisib (BAY 80-6946) in healthy male volunteers and to investigate the disposition and biotransformation of copanlisib. Methods A single dose of 12 mg copanlisib containing 2.76 MBq [ 14 C]copanlisib was administered as a 1-h intravenous infusion to 6 volunteers with subsequent sampling up to 34 days. Blood, plasma, urine and feces were collected to monitor total radioactivity, parent compound and metabolites. Results Copanlisib treatment was well tolerated. Copanlisib was rapidly distributed throughout the body with a volume distribution of 1870 L and an elimination half-life of 52.1-h (range 40.4–67.5-h). Copanlisib was the predominant component in human plasma (84% of total radioactivity AUC) and the morpholinone metabolite M1 was the only circulating metabolite (about 5%). Excretion of drug-derived radioactivity based on all 6 subjects was 86% of the dose within a collection interval of 20–34 days with 64% excreted into feces as major route of elimination and 22% into urine. Unchanged copanlisib was the main component excreted into urine (15% of dose) and feces (30% of dose). Excreted metabolites (41% of dose) of copanlisib resulted from oxidative biotransformation. Conclusions Copanlisib was eliminated predominantly in the feces compared to urine as well as by hepatic biotransformation, suggesting that the clearance of copanlisib would more likely be affected by hepatic impairment than by renal dysfunction. The dual mode of elimination via unchanged excretion of copanlisib and oxidative metabolism decreases the risk of clinically relevant PK-related drug–drug interactions.
    Subject(s): 1-Phosphatidylinositol 3-kinase ; ADME ; Administration, Intravenous ; BAY 80-9646 ; Biotransformation ; Blood plasma ; Cancer Research ; Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors ; Class I Phosphatidylinositol 3-Kinases - pharmacokinetics ; Class I Phosphatidylinositol 3-Kinases - therapeutic use ; Copanlisib ; Drug dosages ; Excretion ; Feces ; Half-life ; Healthy Volunteers ; Human ; Humans ; Intravenous administration ; Intravenous infusion ; Kidney transplantation ; Male ; Mass balance ; Medicine ; Medicine & Public Health ; Metabolism ; Metabolites ; Middle Aged ; Oncology ; Original ; Original Article ; Oxidative metabolism ; Pharmacokinetics ; Pharmacology ; Pharmacology/Toxicology ; Pyrimidines - administration & dosage ; Pyrimidines - pharmacokinetics ; Pyrimidines - therapeutic use ; Quinazolines - administration & dosage ; Quinazolines - pharmacokinetics ; Quinazolines - therapeutic use ; Radioactive half-life ; Radioactivity ; Renal function ; Urine
    ISSN: 0344-5704
    E-ISSN: 1432-0843
    Source: Alma/SFX Local Collection
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  • 10
    Language: English
    In: IEEE transactions on antennas and propagation, 2014-09, Vol.62 (9), p.4623-4636
    Description: Wireless power transfer systems with multiple transmitters promise advantages of higher transfer efficiencies and focusing effects over single-transmitter systems. From the standard formulation, straightforward maximization of the power transfer efficiency is not trivial. By reformulating the problem, a convex optimization problem emerges, which can be solved efficiently. Further, using Lagrangian duality theory, analytical results are found for the achievable maximum power transfer efficiency and all parameters involved. With these closed-form results, planar and coaxial wireless power transfer setups are investigated.
    Subject(s): Antennas ; Capacitors ; Computational efficiency ; Computing time ; Convex functions ; Convex optimization ; Electric power systems ; Impedance ; Innovations ; Lagrangian functions ; Mathematical analysis ; Mathematical optimization ; Maximization ; maximum transfer efficiency ; multiple transmitters ; Optimization ; Power transfer ; Receivers ; Transmitters ; Usage ; Vectors ; wireless power transfer
    ISSN: 0018-926X
    E-ISSN: 1558-2221
    Source: IEEE Electronic Library (IEL)
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