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Human metabolic profiles for substances such as toxic food-derived compounds are usually allometrically extrapolated from traditionally determined in vivo rat concentration profiles. To evaluate internal exposures in humans without any reference to experimental data, physiologically based pharmacokinetic (PBPK) modeling could be used if the model input parameters could be estimated in silico. This approach would simplify the use of PBPK models for forward dosimetry after oral doses. In this study, the in silico estimation of input parameters for PBPK models (i.e., fraction absorbed × intestinal availability, absorption rate constants, and volumes of the systemic circulation) was updated for an panel of 355 chemicals (212 previously analyzed and 143 additional substances) using a light gradient boosting machine learning algorithms (LightGBM) based on between 11 and 29 in silico-calculated chemical descriptors. Simplified human PBPK models were then used to calculate virtual maximum plasma concentrations (C

Physiologically based pharmacokinetic (PBPK) modeling has the potential to estimate internal chemical exposures. Algorithms for predicting the input parameters for PBPK modeling, such as absorption rate constants (k

Background The anticoagulant edoxaban is used clinically at doses of 30–60 mg/day; however, we experienced a patient who had taken an overdose of edoxaban of 750 mg. We investigated the pharmacokinetics of edoxaban in this patient by using liquid chromatography–tandem spectrometry to estimate the follow-up period in emergency clinical practice with this medicine. Case presentation The patient was a 57-year-old woman (body weight, 69 kg) who had taken a single oral dose of 750 mg of edoxaban in a suicide attempt. She was emergently admitted to Kyoto Medical Center. The patient’s edoxaban plasma concentrations during ambulance transport (8 h after oral administration) were ~ 4900 ng/ml, and the concentration gradually decreased to ~ 10 ng/mL and to detectable but unmeasurable levels of ~ 1.0 ng/mL at 60 h and 100 h, respectively. The linear range of the relationship between the dose and plasma concentration was assumed to have been exceeded during the first 8 h; however, the measured elimination rate of edoxaban was similar to that visualized curves predicted by a simplified physiologically based pharmacokinetic model previously established. Conclusion Simplified physiologically based pharmacokinetic models for creating visualized curves have proven to be useful not only during drug discovery or chemical risk assessment but also in cases of medical poisoning. We used a physiologically based pharmacokinetic model previously established for edoxaban to predict the pharmacokinetics in the current case. It is hoped that the results of this study, which encompass drug monitoring data in the patient and visualized pharmacokinetic prediction, will serve as an index when setting the treatment and follow-up period in cases of drug overdose for medicines such as edoxaban in emergency clinical practice.

Background Caffeine (0.1 g) is used as a central nervous system stimulant and as a nontoxic phenotyping probe for cytochrome P450 1A2. However, an increasing number of suicide attempts by caffeine overdose have been recently reported. Case presentation A 25-year-old woman (body weight, 43 kg) who intentionally took an overdose of 5.9 g caffeine as a suicide attempt was emergently admitted to Kyoto Medical Center. The plasma concentrations of caffeine and its primary metabolite, N-demethylated paraxanthine, in the current case were 100 and 7.3 μg/mL, 81 and 9.9 μg/mL, 63 and 12 μg/mL, and 21 and 14 μg/mL, at 12, 20, 30, and 56 h after oral overdose, respectively. The observed apparent terminal elimination half-life of caffeine during days 1 and 2 of hospitalization was 27 h, which is several times longer than the reported normal value. This finding implied nonlinearity of caffeine pharmacokinetics over such a wide dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic model founded on a normal dose of 100 mg. Low serum potassium levels (2.9 and 3.5 mM) on days 1 and 2 may have been caused by the caffeine overdose in the current case. Conclusions The patient underwent infusion with bicarbonate Ringer’s solution and potassium chloride and was discharged on the third day of hospitalization despite taking a potentially lethal dose of caffeine. The virtual plasma exposures of caffeine estimated using the current simplified PBPK model were higher than the measured values. The present results based on drug monitoring data and additional pharmacokinetic predictions could serve as a useful guide in cases of caffeine overdose.

Background Loxoprofen is a propionic acid derivative and is the most widely prescribed non-steroidal anti-inflammatory drug in Japan. Loxoprofen is generally considered to be relatively nontoxic. Case presentation A 33-year-old man (body weight, 55 kg) who intentionally took an overdose of 100 tablets of loxoprofen (6000 mg) as a suicide attempt was emergently admitted to Kyoto Medical Center. On arrival, the patient was suffering disorders of consciousness. His plasma concentrations of loxoprofen and its reduced trans-alcohol metabolite were 52 and 24 μg/mL, 3.7 and 2.3 μg/mL, 0.81 and 0.54 μg/mL, and 0.015 and 0.011 μg/mL, respectively, at 4, 26, 50, and 121 h after the oral overdose. The observed apparent terminal elimination half-life of loxoprofen during days 1 and 2 of hospitalization was in the range 6–12 h, which is several times longer than the reported normal value. This finding implied nonlinearity of loxoprofen pharmacokinetics over the current 100-fold dose range, which could affect the accuracy of values simulated by a simplified physiologically based pharmacokinetic (PBPK) model founded on data from a normal dose of 60 mg. The reasons for the delayed eliminations from plasma of loxoprofen and its trans-alcohol metabolite in this case are uncertain, but slight renal impairment (low eGFR values) developed on the second and third hospital days and could be a causal factor. Conclusions Because the patient’s level of consciousness had gradually improved, he was discharged on the fourth day of hospitalization. The virtual plasma exposures of loxoprofen and its reduced trans-alcohol metabolite estimated using the current simplified PBPK model were lower than the measured values in the overdose case. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide in cases of loxoprofen overdose.

A lumped-electrode-type EA-DFB with a short-length modulator packaged by using an ultra-short wiring technique achieved bandwidth over 60-GHz in a wide-temperature range, and 100-Gbaud NRZ eye opening up to 80°C was demonstrated for the first time.

Background Combinations of antidepressant duloxetine (at doses of 40–60 mg/day) and other antipsychotics are frequently used in clinical treatment; however, several fatal and nonfatal cases of duloxetine overdose have been documented. We experienced a patient who had taken an overdose of duloxetine (780 mg) in combination with other drugs in a suicide attempt. Case presentation The patient was a 37-year-old man (body weight, 64 kg) with a history of gender identity disorder and depression. He intentionally took an overdose of duloxetine in combination with three other antipsychotic drugs (18 mg flunitrazepam, 850 mg quetiapine, and 1100 mg trazodone) and was emergently admitted to Kyoto Medical Center. The patient’s plasma concentration of duloxetine during ambulance transport was 57 ng/ml, and the level was still as high as 126 ng/mL at 32 h after administration. Duloxetine disappeared most slowly from plasma, in contrast to quetiapine, which was the fastest to clear among the four medicines determined in this patient. The observed concentrations of duloxetine in this overdose patient were generally within the 95% confidence intervals of the plasma concentration curves predicted using a physiologically based pharmacokinetic (PBPK) model. Conclusion Even if more than 1 h (the generally recommended period) has passed after administration of duloxetine in such overdose cases, gastric lavage and/or administration of activated charcoal may be effective in clinical practice up to 6 h because of the typically slow elimination behavior illustrated by the PBPK model. Pharmacokinetic profiles visualized using PBPK modeling can inform treatment decisions in cases of drug overdose for medicines such as duloxetine in emergency clinical practice.

To deeply understand interrupting phenomena in high-voltage circuit breakers, it is important to measure the electrical characteristics of switching arcs in high-speed gas flow at current zero. A ring-shaped capacitive probe is proposed to measure a spatial arc voltage distribution. The configuration of the probe is decided by considering the effects of arc position and arc radius. The difference between arc voltage distributions is distinguished for an interrupting current of 12 and 30 kA on interrupting tests using the circuit breaker model.

53-Gbaud-PAM4 differential drive of a conventional EA/DFB was demonstrated. Almost the same waveform as single-ended drive was confirmed with outer ER of 4.1 dB and TDECQ of 1.63 dB by differential drive with 0.57 V pp /lane.

Growing volume of data transmission in data centers requires large capacity optical communication networks. High-speed optical devices and their packaging technology have become important not only in realizing high speed optical communication but also from the view point of size and cost reduction. In this presentation, our high-speed optical devices and our approach to their packaging technology are reported.

A cost-effective optical sub-assembly (OSA) for high-speed optical interconnections using lens-integrated surface-emitting lasers (LISELs) is demonstrated. Two concepts of the OSA, one based on a direct-modulation (DM)-LISEL and the other based on a continuous-wave (CW)-LISEL for a silicon-photonics (SiP) platform, are proposed. The design parameters of the integrated lens that enable low fiber-coupling loss and the SiP platform are described. Coupling losses, as low as 4.9 dB for the single mode fiber and 4 dB for the SiP platform, were experimentally confirmed. Furthermore, theoretical and experimental evidence that demonstrates the OSA does not require an optical isolator (i.e., it is “isolator-free”) is presented. A DFB laser used for the LISEL had a low relative intensity noise (less than −140 dB/Hz), even with a back reflection of more than −20 dB. For non-Hermetic packaging, 500 h, 85°C/85% relative humidity storage tests experimentally demonstrated no degradation in the lasing characteristics.

Technologies for high-density integration of optical and electrical components are indispensable for next-generation optical transceivers whose capacity will exceed 400 Gbps. 3-D vertical integration technology with high optical coupling efficiency between a single mode fiber (SMF) array and lens-integrated surface emitting laser (LISEL) array using micro electro mechanical system (MEMS)-based movable micro-mirrors can meet this requirement. Light emitted from the LISEL is reflected at the micro-mirror and coupled to the SMF. Since the micro-mirror can steer the beam emitted from the LISEL to the SMF, the coupling efficiency that depends on the alignment accuracy between the LISEL and SMF is adjustable. After the alignment is completed, the position of the micro-mirror is fixed to keep high coupling efficiency. An optical sub-assembly (OSA) incorporating the LISEL, micro-mirror, and SMF array was fabricated using surface mount technology. All optical components were passively aligned, and the positions of micro-mirrors were adjusted to make a precise optical coupling to the SMFs as a post alignment. To confirm the effectiveness of this post-alignment system, the characteristics of the optical coupling to the SMF array were measured. It was found that the position of the reflected beam could be controlled to sub-micro-meter accuracy.

Di(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant in male rodents. The aim of the current study was to extrapolate the pharmacokinetics and toxicokinetics of mono(2-ethylhexyl)phthalate (MEHP, a primary metabolite of DEHP) in humans by using data from oral administration of DEHP to chimeric mice transplanted with human hepatocytes. MEHP and its glucuronide were detected in plasma from control mice and chimeric mice after single oral doses of 250mg DEHP/kg body weight. Biphasic plasma concentration-time curves of MEHP and its glucuronide were seen only in control mice. MEHP and its glucuronide were extensively excreted in urine within 24h in mice with humanized liver. In contrast, fecal excretion levels of MEHP glucuronide were high in control mice compared with those with humanized liver. Adjusted animal biomonitoring equivalents from chimeric mice studies were scaled to human biomonitoring equivalents using known species allometric scaling factors and in vitro metabolic clearance data with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urine MEHP concentrations in humans were consistent with reported concentrations. This research illustrates how chimeric mice transplanted with human hepatocytes in combination with a simple PBPK model can assist evaluations of pharmacokinetics or toxicokinetics of the primary or secondary metabolites of DEHP.

As a solution to provide a small-size and low-cost 100-Gb/s optical module, direct optical coupling between a lens-integrated surface-emitting DFB laser (LISEL) array and a single-mode fiber (SMF) array is demonstrated. A very-small far-field angle ( $\sim 2$ °) was obtained by monolithic integration of an InP lens with a laser chip. As a result, each channel of the LISEL array can directly couple to an SMF without any additional external optical components. The measured misalignment tolerance between the LISEL array and an SMF array was sufficiently large, namely, $\pm 5.5~\mu \text{m}$ , at excess loss of 1 dB over all four channels with the maximum coupling efficiency of 8.4 dB. These measurement results are in good agreement with a theoretical calculation based on Gaussian optics. These results demonstrate that high coupling efficiency (−3 dB) can be achieved while large misalignment tolerance ( $\pm 4.5~\mu \text{m}$ ) at excess loss of only 1 dB is maintained.

A movable micro-mirror array is proposed for high-density multi-channel single-mode optical sub-assembly. Adjustable optical-coupling loss of over 2dB was confirmed from experiments of 4-ch array optical-coupling between DFB lasers and single-mode fibers using the micro-mirrors.

Technologies for creating cost-effective light-emission optical sub-assemblies (OSAs) are discussed from the point of view of laser diodes. A lens-integrated surface-emitting laser (LISEL), consisting of a DFB laser, integrated mirror, and integrated convex lens, has the potential to achieve light-emission OSAs. An OSA based on the LISEL is proposed, and the capabilities of direct and passively aligned optical coupling, isolator-free operation, non-hermetic packaging, and on-wafer testing are introduced.

Two multichannel 1.3-μ m lens integrated surface-emitting laser arrays for massive data links were fabricated. The basic structure of the lasers consists of a short InGaAlAs multiple-quantum-well distributed-feedback (DFB) active-stripe array monolithically integrated with both a 45° total reflection mirror and an aspheric collimation lens. One of them, a four-channel laser array based on this structure, exhibited clear 25-Gb/s eye openings up to 50°C over all four channels and achieved a total output of 100 Gb/s. The other laser, a multiple-wavelength array for wavelength-division-multiplexing applications, produces multiple-wavelength emission thanks to precisely modified DFB gratings by electron beam lithography. It exhibited nine-wavelength stable single-mode operation (side-mode suppression ratio >; 40 dB) between 1260 and 1290 nm at 3.7-nm intervals, and a clear 25-Gb/s eye opening for each wavelength. These two surface-emitting laser arrays have demonstrated their suitability for next-generation multichannel data links (including 100-Gb Ethernet and optical interconnects).

High-speed 1.3-μm directly modulated lasers (DMLs) have been developed to support sharply rising optical communications traffic. The most crucial requirement for these lasers is the ability to operate over a wide temperature range with no power-consuming electric cooler. Due to poor temperature characteristics resulting from its poor electron confinement in the multiquantum well, DMLs with InGaAsP material systems have been replaced by DMLs with InGaAlAs material systems, which have stronger electron confinement. In this paper, progress in uncooled 25-Gb/s 1.3-μm InGaAlAs DMLs is summarized. A 160-μm-long ridge-waveguide-type laser showed a lower threshold current Ith of 14.9 mA at high temperatures up to 95 °C, and a small signal-frequency-response bandwidth f3dB of 14 GHz was achieved at a bias current of 60 mA at 95 °C. Using this laser, clear 25-Gb/s operation was obtained at 95 °C. In addition, stable operation was achieved for up to 4000 h at 85 °C, indicating the basic applicability of the device to next-generation 25-Gb/s data communication systems. Furthermore, the developed technology was applied to a novel uncooled 25-Gb/s 1.3-μm surface-emitting laser for optical interconnects, in which a 45° mirror and a lens were integrated monolithically.

A 25 Gb/s laser diode (LD) driver has been developed on the basis of standard 65 nm CMOS technology for optical interconnects. The LD driver consists of a main driver capable of providing an average current of 30 mA and a predriver providing a gain of 20 dB. The main driver uses mutually coupled inductors to adjust the inductive peaking to improve eye patterns under various packaging conditions. The predriver uses CMOS active feedback to achieve a wide bandwidth and high gain, despite its small size and low power consumption. The fabricated circuit achieves data rates of 25 Gb/s, consumes 156 mW (6.3 mW/Gb/s) and occupies an area of 0.011 mm2 .

We fabricated a p-i-n photodiode (PD) with an integrated microlens, and demonstrated its high performance capabilities including high speed (35GHz), high responsivity (0.8A/W), and large misalignment tolerance (26µm), and an error-free 25-Gbit/s 10-km single-mode fiber transmission by using a 100-Gbit/s Ethernet quadplexer receiver module with the PDs.