Machine Learning Prediction of the Three Main Input Parameters of a Simplified Physiologically Based Pharmacokinetic Model Subsequently Used to Generate Time-Dependent Plasma Concentration Data in Humans after Oral Doses of 212 Disparate Chemicals.

Physiologically based pharmacokinetic (PBPK) modeling has the potential to play significant roles in estimating internal chemical exposures. The three major PBPK model input parameters (i.e., absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearances) were generated in silico for 212 chemicals using machine learning algorithms. These input parameters were calculated based on sets of between 17 and 65 chemical properties that were generated by in silico prediction tools before being processed by machine learning algorithms. The resulting simplified PBPK models were used to estimate plasma concentrations after virtual oral administrations in humans. The estimated absorption rate constants, volumes of the systemic circulation, and hepatic intrinsic clearance values for the 212 test compounds determined traditionally (i.e., based on fitting to measured concentration profiles) and newly estimated had correlation coefficients of 0.65, 0.68, and 0.77 (p < 0.01, n = 212), respectively. When human plasma concentrations were modeled using traditionally determined input parameters and again using in silico estimated input parameters, the two sets of maximum plasma concentrations (r = 0.85, p < 0.01, n = 212) and areas under the curve (r = 0.80, p < 0.01, n = 212) were correlated. Virtual chemical exposure levels in liver and kidney were also estimated using these simplified PBPK models along with human plasma levels. These results indicate that the PBPK model input parameters for humans of a diverse set of compounds can be reliability estimated using chemical descriptors calculated using in silico tools.

An Updated In Silico Prediction Method for Volumes of Systemic Circulation of 323 Disparate Chemicals for Use in Physiologically Based Pharmacokinetic Models to Estimate Plasma and Tissue Concentrations after Oral Doses in Rats.

Updated algorithms for predicting the volumes of systemic circulation (V1), along with absorption rate constants and hepatic intrinsic clearances, as input parameters for physiologically based pharmacokinetic (PBPK) models were established to improve the accuracy of estimated plasma and tissue concentrations of 323 chemicals after virtual oral administrations in rats. Using ridge regression with an enlarged set of chemical descriptors (up to 99), the estimated input V1 values resulted in an improved correlation coefficient (from 246 compounds) with the traditionally determined values. The PBPK model input parameters for rats of diverse compounds can be precisely estimated by increasing the number of descriptors.

In Silico Prediction of Input Parameters for Simplified Physiologically Based Pharmacokinetic Models for Estimating Plasma, Liver, and Kidney Exposures in Rats after Oral Doses of 246 Disparate Chemicals.

Recently developed computational models can estimate plasma, hepatic, and renal concentrations of industrial chemicals in rats. Typically, the input parameter values (i.e., the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance) for simplified physiologically based pharmacokinetic (PBPK) model systems are calculated to give the best fit to measured or reported in vivo blood substance concentration values in animals. The purpose of the present study was to estimate in silico these three input pharmacokinetic parameters using a machine learning algorithm applied to a broad range of chemical properties obtained from several cheminformatics software tools. These in silico estimated parameters were then incorporated into PBPK models for predicting internal exposures in rats. Following this approach, simplified PBPK models were set up for 246 drugs, food components, and industrial chemicals with a broad range of chemical structures. We had previously generated PBPK models for 158 of these substances, whereas 88 for which concentration series data were available in the literature were newly modeled. The values for the absorption rate constant, volume of systemic circulation, and hepatic intrinsic clearance could be generated in silico by equations containing between 14 and 26 physicochemical properties. After virtual oral dosing, the output concentration values of the 246 compounds in plasma, liver, and kidney from rat PBPK models using traditionally determined and in silico estimated input parameters were well correlated (r ≥ 0.83). In summary, by using PBPK models consisting of chemical receptor (gut), metabolizing (liver), excreting (kidney), and central (main) compartments with in silico-derived input parameters, the forward dosimetry of new chemicals could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of hematotoxic, hepatotoxic, or nephrotoxic potential as a part of risk assessment.

[Factors associated with mental health depending on the type of stress related to admission among correspondence course high school students in Japan].

Objective　This study aimed to determine the factors associated with mental health based on the type of stress related to high school admissions for correspondence courses.Methods　The targeted participants were 3,888 students belonging to 11 campuses of a high school providing correspondence courses. During the homeroom, the teachers in charge distributed and collected questionnaires directly. The questionnaire was designed to collect data concerning demographic characteristics, stresses, mental health, and life skills. Concerning stress, the questions inquired about stress before admission and after admission. Further, they asked about stress related to entry regarding the study, friendship, relationship with teachers, club activities, school events, home environment, health, and work. Kessler 6 was used as an index of mental health.Results　Questionnaires were returned by 2,424 students (response rate of 62.3%). Regarding the change in stress before and after admission, students showed decreases in anxiety after admission in other areas, excluding work. Because of the k-means clustering analysis, based on the scores of the eight areas of stress related to admission, six groups were extracted. Factors related to mental health were extracted from each group. Health stress was strongly associated with the K6 score in all groups. For the study stress group, friendship stress group, family environment, and health stress group, stress related to admission were associated with the K6 score. Furthermore, for the complex school-related stress group, friendship and family environment stress were associated with the K6 score. In the high-stress group, the K6 score was significantly associated with study stress. As for life skills, stress management and decision-making skills were associated with higher mental health.Conclusions　These findings indicate that it is important to understand students' needs and support them in coping with stress and improving their life skills according to their stress type. Support should be developed for high school students enrolled in correspondence courses.

Physiologically Based Pharmacokinetic Models Predicting Renal and Hepatic Concentrations of Industrial Chemicals after Virtual Oral Doses in Rats.

Recently developed high-throughput in vitro assays in combination with computational models could provide alternatives to animal testing. The purpose of the present study was to model the plasma, hepatic, and renal pharmacokinetics of approximately 150 structurally varied types of drugs, food components, and industrial chemicals after virtual external oral dosing in rats and to determine the relationship between the simulated internal concentrations in tissue/plasma and their lowest-observed-effect levels. The model parameters were based on rat plasma data from the literature and empirically determined pharmacokinetics measured after oral administrations to rats carried out to evaluate hepatotoxic or nephrotic potentials. To ensure that the analyzed substances exhibited a broad diversity of chemical structures, their structure-based location in the chemical space underwent projection onto a two-dimensional plane, as reported previously, using generative topographic mapping. A high-throughput in silico one-compartment model and a physiologically based pharmacokinetic (PBPK) model consisting of chemical receptor (gut), metabolizing (liver), central (main), and excreting (kidney) compartments were developed in parallel. For 159 disparate chemicals, the maximum plasma concentrations and the areas under the concentration-time curves obtained by one-compartment models and modified simple PBPK models were closely correlated. However, there were differences between the PBPK modeled and empirically obtained hepatic/renal concentrations and plasma maximal concentrations/areas under the concentration-time curves of the 159 chemicals. For a few compounds, the lowest-observed-effect levels were available for hepatotoxicity and nephrotoxicity in the Hazard Evaluation Support System Integrated Platform in Japan. The areas under the renal or hepatic concentration-time curves estimated using PBPK modeling were inversely associated with these lowest-observed-effect levels. Using PBPK forward dosimetry could provide the plasma/tissue concentrations of drugs and chemicals after oral dosing, thereby facilitating estimates of nephrotoxic or hepatotoxic potential as a part of the risk assessment.

[The development, reliability, and validity of a Japanese version of the MBI-ES].

In this study, we developed a Japanese version of the Maslach Burnout Inventory - Educators Survey (MBI-ES). We also examined the reliability and validity of the scale, based on data from Japanese schoolteachers. Because some items related to depersonalization showed a floor effect, the reliability of the MBI-ES was evaluated using item response theory (IRT), which can evaluate the difficulty of the items. The IRT analysis showed that scores of emotional exhaustion and personal accomplishment had high reliabilities among the wide range of distribution of the latent scores around the means. However, the reliability of the depersonalization items was estimated to be moderate when it was implemented among highly depersonalized teachers, whereas the reliability was lower for relatively healthy teachers. Correlations with the General Health Questionnaire, frequency of emotional labor, and job satisfaction were mostly consistent with previous research and the current theory of burnout, supporting the high validity of the Japanese version of the MBI-ES.

Bilateral atypical femoral fractures treated with compression hip screw and intramedullary nail fixation.

Atypical femoral fractures (AFF) are more difficult to treat than typical femoral fractures; they require strong fixation and good reduction. Intramedullary (IM) nailing is the first option for the treatment of complete AFF; however, there are few reports comparing IM nailing and extramedullary fixation. Moreover, there are no reports on the outcomes of bilateral atypical subtrochanteric femoral fractures treated with an IM nail on one side and a compression hip screw (CHS) on the other. We report the case of a 69-year-old woman who had been on risedronate sodium once a month since she was 58 years old. She reportedly felt pain in both her thighs due to an undiagnosed cause. Six months later, she fell and was diagnosed with bilateral complete atypical femoral subtrochanteric fractures (right side: Seinsheimer type IIC; left side: Seinsheimer type IIA). Four days later, she underwent CHS on the right side and IM nailing after open reduction surgery on the left. The reduction was successful. The left side healed 6 months after surgery, but the right side healed only after 14 months, despite assistance with low-intensity pulsed ultrasound. In atypical femoral subtrochanteric fractures, good reduction is important for healing, but, in this case, the CHS side healed slowly despite achievement of good reduction because of the difference in the fixation force between IM nailing and CHS, in addition to a probable occurrence of severely suppressed bone turnover (SSBT). Furthermore, reaming was not done on the CHS side, which may have contributed to the delay in bony union. IM nailing is the first option for atypical femoral subtrochanteric fractures because of faster union and lower reoperation rate than extramedullary fixation. Based on our findings, we recommend IM nailing as the first option for atypical femoral subtrochanteric fractures when good reduction can be achieved.

Total femur fixation using the "nail-plate docking technique" for ipsilateral femur shaft fracture.

In an aging society, the number of femoral fractures is increasing, as well as the incidence of periprosthetic fractures. These secondary fractures are often difficult to fixate stably because of the osteoporotic bone and the existence of the former implant. Herein, we present two cases of secondary femoral shaft fractures after osteosyntheses for distal femur fractures with polyaxial locking plates (Non-Contact-Bridging Distal Femur, NCB-DF®, ZimmerBIOMET, Winterthur, Switzerland). Antegrade intramedullary nails (Natural Nail®-GT Femoral, ZimmerBIOMET, Winterthur, Switzerland) were utilized without removal of the NCB-DFs. In these osteosyntheses, proximal locking screws of NCB-DFs were inserted and locked into the distal inter-locking holes of Natural Nails. This "nail-plate docking technique" could allow for more stable fixation of the whole femur with minimally invasive surgical intervention while preserving the existing implant. Although there are a few surgical technical knacks and pitfalls in inserting the screw, further fractures of the femur could also be prevented with this technique.

Delayed hematoma in gluteus medius caused by Gamma nail protrusion over the greater trochanter.

Aside from cases of mechanical complications or infection short femoral nails (SFNs) are not removed after open reduction and internal fixation (ORIF) because femoral trochanteric fractures often occur in older osteoporotic females. Occasionally, SFN removal is performed because of severe chronic hip and thigh pain after surgery. However, cases of large hematoma formation in the gluteus medius with associated severe pain have not been reported in patients after ORIF. A 58-year-old healthy woman fell and incurred a femoral trochanteric fracture at work. ORIF was performed using Gamma nail for the fracture, which was classified as AO31-1.2 according to the AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification. The bone healed sufficiently. The patient reported chronic hip and thigh pain after ORIF, but the SFN was not removed because of concerns about further fractures. After 1 year and 8 months, she suddenly experienced severe hip and thigh pain with hip swelling, but without prior trauma. Magnetic resonance imaging (MRI) showed a large hematoma in the gluteus medius near the greater trochanter. Under general anesthesia, SFN removal was performed because of the persistent pain. After SFN removal, the chronic pain resolved without any complications, such as a femoral neck fracture. In this case, chronic hip and thigh pain and delayed hematoma may have been caused by SFN protrusion over the greater trochanter, damaging soft tissues around the gluteus medius. Thus, soft tissue injury and hematoma are possible in patients with chronic hip and thigh pain after ORIF using SFN. In using SFN for femoral trochanteric fractures, it is important to prevent protrusion of SFN over the greater trochanter. Further careful follow-up with MRI and/or ultrasonography is needed to study delayed hematoma after ORIF using SFN.

Rapid Destructive Arthropathy of the Knee in Parkinson's Disease with Pisa Syndrome: A Case of Knee-Spine Syndrome.

The changes occurring in knee osteoarthritis often cause alterations in the spinal loading condition, which further lead to degenerative changes. This close relationship of the knee and spine has been reported as knee-spine syndrome. A 60-year-old woman with Parkinson's disease (PD; Hoehn-Yahr stage IV) had severe knee pain with moderate lateral osteoarthritis of the knee (Kellgren-Lawrence classification grade II). Conservative therapy had no effect at all, and the knee developed destructive osteoarthritis rapidly without any traumatic episodes. The radiographic findings progressed to Kellgren-Lawrence grade IV within a month. Magnetic resonance imaging revealed partial depression of the joint surface, including shredded ossicles and substantial amounts of synovial fluid. The imaging findings were considered to be caused by a subchondral insufficiency fracture (SIF). Total knee arthroplasty was performed using a semiconstrained prosthesis. The alignment of her lower extremity improved, and the patient could walk without knee pain. The patient had Pisa syndrome, a lateral flexion of the trunk, which is a postural deformity of the trunk secondary to long-standing PD. The postural deformity in PD is not based on spinal deformity itself but on the loss of postural reflexes and the imbalance of muscle tonus. Her left knee pain appeared 1 month after L1-L4 posterior lumbar interbody fusion (PLIF) as the Pisa syndrome to her left side worsened. The more the trunk tilts to the lateral side, the center of the gravity axis will shift and pass through more lateral points of the knee and result in higher knee load. The stress concentration from the spine to the lateral joint of the knee caused lateral knee osteoarthritis, namely, knee-spine syndrome. When patients undergo correction surgery for adult spinal disorder with impairment of postural reflexes, they need to be followed up carefully regarding not only the spinal alignment but also the lower extremities.

Prediction of permeability across intestinal cell monolayers for 219 disparate chemicals using in vitro experimental coefficients in a pH gradient system and in silico analyses by trivariate linear regressions and machine learning.

For medicines, the apparent membrane permeability coefficients (Papp) across human colorectal carcinoma cell line (Caco-2) monolayers under a pH gradient generally correlate with the fraction absorbed after oral intake. Furthermore, the in vitro Papp values of 29 industrial chemicals were found to have an inverse association with their reported no-observed effect levels for hepatotoxicity in rats. In the current study, we expanded our influx permeability predictions for the 90 previously investigated chemicals to both influx and efflux permeability predictions for 207 diverse primary compounds, along with those for 23 secondary compounds. Trivariate linear regression analysis found that the observed influx and efflux logPapp values determined by in vitro experiments significantly correlated with molecular weights and the octanol-water distribution coefficients at apical and basal pH levels (pH 6.0 and 7.4, respectively) (apical to basal, r = 0.76, n = 198; and basal to apical, r = 0.77, n = 202); the distribution coefficients were estimated in silico. Further, prediction accuracy was enhanced by applying a light gradient boosting machine learning system (LightGBM) to estimate influx and efflux logPapp values that incorporated 17 and 19 in silico chemical descriptors (r = 0.83-0.84, p < 0.001). The determination in vitro and/or prediction in silico of permeability coefficients across intestinal cell monolayers of a diverse range of industrial chemicals/food components/medicines could contribute to the safety evaluations of oral intakes of general chemicals in humans. Such new alternative methods could also reduce the need for animal testing during toxicity assessment.

Blood concentrations of acrylonitrile in humans after oral administration extrapolated from in vivo rat pharmacokinetics, in vitro human metabolism, and physiologically based pharmacokinetic modeling.

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for acrylonitrile in humans based on in vitro metabolic parameters determined using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and a prior previously developed PBPK model in rats. The model basically consists of a chemical absorption compartment, a metabolizing compartment, and a central compartment for acrylonitrile. Evaluation of a previous rat model was performed by comparisons with experimental pharmacokinetic values from blood and urine obtained from rats in vivo after oral treatment with acrylonitrile (30 mg/kg, a no-observed-adverse-effect level) for 14 days. Elimination rates of acrylonitrile in vitro were established using data from rat liver microsomes and from pooled human liver microsomes. Acrylonitrile was expected to be absorbed and cleared rapidly from the body in silico, as was the case for rats confirmed experimentally in vivo with repeated low-dose treatments. These results indicate that the simplified PBPK model for acrylonitrile is useful for a forward dosimetry approach in humans. This model may also be useful for simulating blood concentrations of other related compounds resulting from exposure to low chemical doses.

Determination and prediction of permeability across intestinal epithelial cell monolayer of a diverse range of industrial chemicals/drugs for estimation of oral absorption as a putative marker of hepatotoxicity.

Apparent permeability coefficients (P app) across a human intestinal epithelial Caco-2 cell monolayer were measured for a range of industrial/drug chemicals. A predictive equation for determining in vitro P app values of fifty-six substances was set up using multivariate regression analysis based on in silico-estimated physicochemical properties (molecular weights and water distribution coefficients for apical and basal pH environments) (r = 0.77, p <  0.01). Predicted logP app values of a secondary set of 34 compounds were correlated with the measured values. Under the medicinal logP app values associated with their reported fraction absorbed, a significant inverse non-linear correlation was found between the logarithmic transformed values of observed P app values and reported hepatic no-observed-effect levels of industrial chemicals (r = -0.55, p <  0.01, n = 29). In vitro determination and/or in silico prediction of permeability across intestinal cells could be effective for estimating oral absorption as a putative indicator for hepatotoxicity.

High-speed screening of human ATP-binding cassette transporter function and genetic polymorphisms: new strategies in pharmacogenomics.

Drug transporters represent an important mechanism in cellular uptake and efflux of drugs and their metabolites. Hitherto a variety of drug transporter genes have been cloned and classified into either solute carriers or ATP-binding cassette (ABC) transporters. Such drug transporters are expressed in various tissues such as the intestine, brain, liver, kidney, and, importantly, cancer cells, where they play critical roles in the absorption, distribution, and excretion of drugs. We developed high-speed functional screening and quantitative structure-activity relationship analysis methods to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide powerful and practical tools for screening synthetic and natural compounds, and the deduced data can be applied to the molecular design of new drugs. Furthermore, we demonstrate a new "SNP array" method to detect genetic polymorphisms of ABC transporters in human samples.

Human blood concentrations of cotinine, a biomonitoring marker for tobacco smoke, extrapolated from nicotine metabolism in rats and humans and physiologically based pharmacokinetic modeling.

The present study defined a simplified physiologically based pharmacokinetic (PBPK) model for nicotine and its primary metabolite cotinine in humans, based on metabolic parameters determined in vitro using relevant liver microsomes, coefficients derived in silico, physiological parameters derived from the literature, and an established rat PBPK model. The model consists of an absorption compartment, a metabolizing compartment, and a central compartment for nicotine and three equivalent compartments for cotinine. Evaluation of a rat model was performed by making comparisons with predicted concentrations in blood and in vivo experimental pharmacokinetic values obtained from rats after oral treatment with nicotine (1.0 mg/kg, a no-observed-adverseeffect level) for 14 days. Elimination rates of nicotine in vitro were established from data from rat liver microsomes and from human pooled liver microsomes. Human biomonitoring data (17 ng nicotine and 150 ng cotinine per mL plasma 1 h after smoking) from pooled five male Japanese smokers (daily intake of 43 mg nicotine by smoking) revealed that these blood concentrations could be calculated using a human PBPK model. These results indicate that a simplified PBPK model for nicotine/cotinine is useful for a forward dosimetry approach in humans and for estimating blood concentrations of other related compounds resulting from exposure to low chemical doses.

High-speed screening and QSAR analysis of human ATP-binding cassette transporter ABCB11 (bile salt export pump) to predict drug-induced intrahepatic cholestasis.

Human ATP-binding cassette transporter ABCB11 (SPGP/BSEP) mediates the elimination of bile salts from liver cells and thereby plays a critical role in the generation of bile flow. In the present study, we have developed in vitro high-speed screening and quantitative structure-activity relationship (QSAR) analysis methods to investigate the interaction of ABCB11 with a variety of drugs. Plasma membrane vesicles prepared from insect cells overexpressing human ABCB11 were used to measure the ATP-dependent transport of [14C]taurocholate. Over 40 different drugs and natural compounds were tested to evaluate their interaction with ABCB11-mediated taurocholate transport. On the basis of the extent of inhibition, we have analyzed the QSAR to identify one set of chemical fragmentation codes closely associated with the inhibition of ABCB11. This approach can be used to predict compounds with a potential risk of drug-induced intrahepatic cholestasis.