Impact of variability of in silico and in vitro octanol/water partition coefficients of compounds on the input parameters and results of simplified human physiologically based pharmacokinetic models after virtual oral administrations.

The octanol/water partition coefficient, P (logP), is a hydrophobicity index and is one of the determining factors of the pharmacokinetics of chemical compounds. LogP values obtained from in silico software, open chemistry databases, and in vitro liquid chromatography retention factors may vary. Some chemicals (boscalid, etoxazole, and permethrin) have up to four-order-magnitude differences in in silico/in vitro P values.

Effects of an online mindfulness-based intervention on brain haemodynamics: a pilot randomized controlled trial using functional near-infrared spectroscopy.

Although many neuroimaging studies have evaluated changes in the prefrontal cortex during mindfulness-based interventions, most of these studies were cross-sectional studies of skilled participants or involved pre-post comparisons before and after a single session. While functional near-infrared spectroscopy is a useful tool to capture changes in the hemodynamic response of the prefrontal cortex during continuous mindfulness-based intervention, its ability to detect the accumulated effects of continuous mindfulness-based intervention is currently unclear. We investigated whether a 12-wk online mindfulness-based intervention changed the hemodynamic response of the prefrontal cortex during a verbal fluency task.

Mindful Self-Compassion Smartphone Intervention for Worker Mental Health in Japan: Protocol for a Randomized Controlled Trial.

Background: Mental health problems among workers cause enormous losses to companies in Japan. However, workers have been considered to have limited access to psychological support because of time constraints, which makes it difficult for them to engage in face-to-face psychological support interventions.

Objective: This study aimed to present an intervention protocol that describes a randomized controlled trial to examine whether brief guided mindfulness meditation (MM) or self-compassion meditation (SCM) provided by a smartphone app is effective for mental health and work-related outcomes among workers.

Modeled Hepatic/Plasma Exposures of Omeprazole Prescribed Alone in Cytochrome P450 2C19 Poor Metabolizers Are Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Omeprazole, a gastric acid pump inhibitor, is repeatedly administered and is oxidatively metabolized mainly by polymorphic cytochrome P450 2C19. The prescribed dosage of omeprazole was discontinued or reduced in 47 of the 135 patients who received omeprazole alone in this survey, as recorded in the Japanese Adverse Drug Event Report database. The days to onset of omeprazole-related disorders were 3-4 d (median) and 16 d for intravenous 20-40 mg and oral 20 mg daily doses, respectively, in 34 patients for whom relevant data were available.

Modeled Hepatic/Plasma Exposures of Fluvastatin Prescribed Alone in Subjects with Impaired Cytochrome P450 2C9*3 as One of Possible Determinant Factors Likely Associated with Hepatic Toxicity Reported in a Japanese Adverse Event Database.

Fluvastatin is a 3-hydroxy-3-methylglutaryl CoA reductase inhibitor that competitively inhibits human cytochrome P450 (P450) 2C9 in vitro. Drug interactions between a variety of P450 2C9 substrates/inhibitors and fluvastatin can increase the incidence of fluvastatin-related hepatic or skeletal muscle toxicity in vivo. In this survey, the prescribed dosage of fluvastatin was reduced or discontinued in 133 of 164 patients receiving fluvastatin alone, as recorded in the Japanese Adverse Drug Event Report database of spontaneously reported events.

A decreasing plasma concentration of a toxicologically active metabolite 9-carboxymethoxymethylguanine after dialysis - A potential new clinical biomarker for improving encephalopathy in patients treated with acyclovir.

Although acyclovir is a key drug for the treatment of herpes infections, a consciousness disorder known as "acyclovir encephalopathy" is among its side effects. We encountered a patient with encephalopathy and measured the plasma and cerebrospinal fluid concentrations of acyclovir and its toxicologically active metabolite 9-carboxymethoxymethylguanine (CMMG). Before dialysis, cerebrospinal fluid concentrations of acyclovir and CMMG in this patient with a consciousness disorder were approximately 10% and 1%, respectively, of their plasma concentrations.

Modeled Rat Hepatic and Plasma Concentrations of Chemicals after Virtual Administrations Using Two Sets of in Silico Liver-to-Plasma Partition Coefficients.

The hepatic elimination of chemical substances in pharmacokinetic models requires hepatic intrinsic clearance (CL) parameters for unbound drug in the liver, and these are regulated by the liver-to-plasma partition coefficients (K). Both Poulin and Theil and Rodgers and Rowland have proposed in silico expressions for K for a variety of chemicals. In this study, two sets of in silico K values for 14 model substances were assessed using experimentally reported in vivo steady-state K data and time-dependent virtual internal exposures in the liver and plasma modeled by forward dosimetry in rats.

Liver and Plasma Concentrations of Food Chemicals after Virtual Oral Doses Extrapolated Using in Silico Estimated Input Pharmacokinetic Parameters to Confirm Reported Liver Toxicity in Rats.

The estimation of health risks of chemical substances was historically investigated using animal studies; however, current research focuses on reducing the number of animal experiments. The toxicity of chemicals in fish screening systems is reportedly correlated with their hydrophobicity. The inverse relationship between absorption rates (intestinal cell permeability) and virtual hepatic/plasma pharmacokinetics of diverse chemicals has been previously evaluated by modeling oral administration in rats.

Plasma and Hepatic Exposures of Celecoxib and Diclofenac Prescribed Alone in Patients with Cytochrome P450 2C9*3 Modeled after Virtual Oral Administrations and Likely Associated with Adverse Drug Events Reported in a Japanese Database.

The impacts of polymorphic cytochrome P450 (P450 or CYP) 2C9 on drug interactions and the pharmacokinetics of cyclooxygenase inhibitors have attracted considerable attention. In this survey, the prescribed dosage was reduced or discontinued in 150 and 56 patients, respectively, receiving celecoxib and diclofenac prescribed alone, as recorded in a Japanese database of adverse drug events. Among the factors underlying adverse events, intrinsic drug clearance rates may be a contributing factor.

High hepatic and plasma exposures of atorvastatin in subjects harboring impaired cytochrome P450 3A4∗16 modeled after virtual administrations and possibly associated with statin intolerance found in the Japanese adverse drug event report database.

Drug interactions between atorvastatin and cytochrome P450 (P450) 3A substrates/inhibitors lead to an increased incidence of skeletal muscle or hepatic toxicity. However, in this survey, among 483 Japanese subjects administered atorvastatin alone, more than half (258) experienced statin intolerance and were unable to continue using the drug. Although many factors underly atorvastatin toxicity, the intrinsic clearance rate might be a contributing causal factor.

Updated in silico prediction methods for fractions absorbed and absorption rate constants of 372 disparate chemicals for use in physiologically based pharmacokinetic models for estimating internal concentrations in rats.

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), were previously reported for 323 chemicals in rats. In this study, a currently updated system for estimating the fraction absorbed × intestinal availability of compounds, along with a modified estimation system that generates k values, is reported, based on the previously analyzed 323 primary compounds, 10 secondary compounds, and 39 additional substances.

Updated in Silico Prediction Methods for Fractions Absorbed and Key Input Parameters of 355 Disparate Chemicals for Physiologically Based Pharmacokinetic Models for Time-Dependent Plasma Concentrations after Virtual Oral Doses in Humans.

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.

Human biofluid concentrations of mono(2-ethylhexyl)phthalate extrapolated from pharmacokinetics in chimeric mice with humanized liver administered with di(2-ethylhexyl)phthalate and physiologically based pharmacokinetic modeling.

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.

100-Gbps CMOS transceiver for multilane optical backplane system with a 1.3 cm2 footprint.

A compact 4 × 25 Gbps optical transceiver has been fabricated for an optical backplane system, which consists of a 4 × 25 Gbps DFB-LD array, a 4 × 25 Gbps PIN-PD array, and a CMOS transceiver chip. These are directly mounted on 9 × 14 mm(2) multi-layer ceramic package with an electromagnetic shield structure to suppress inner-channel crosstalk effectively. The transceiver includes an analog front-end as well as an electrical interface function to interface with the switch LSI or CPU.