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Currently, there is insufficient information on the variability in levocetirizine pharmacometrics among individuals, a crucial aspect for establishing its clinical use. The gender differences in pharmacokinetics and the extent of variation in pharmacodynamics have not been definitively identified. The primary goal of this study was to investigate gender differences in levocetirizine pharmacokinetics and quantitatively predict and compare how these gender-related pharmacokinetic differences impact pharmacodynamics, using population pharmacokinetic–pharmacodynamic modeling. Bioequivalence results for levocetirizine (only from the control formulation) were obtained from both healthy Korean men and women. Physiological and biochemical parameters for each individual were utilized as pharmacokinetic comparison and modeling data between genders. Pharmacodynamic modeling was performed using reported data on antihistamine responses following levocetirizine exposure. Gender, weight, body surface area, peripheral distribution volume, albumin, central–peripheral inter-compartmental clearance, and the fifth sequential absorption rate constant were explored as effective covariates. A comparison of the model simulation results showed a higher maximum concentration and faster plasma loss in females than in males, resulting in a faster recovery to baseline of the antihistamine effect; however, the absolute differences between genders in the mean values were not large within 10 ng/mL (for plasma concentrations) or % (wheal and flare size changes). Regarding the pharmacokinetics and pharmacodynamics of levocetirizine, the gender effect may not be significant when applying the usual dosage (5 mg/day). This study will be useful for bridging the knowledge gap in scientific precision medicine by introducing previously unconfirmed information regarding gender differences in levocetirizine pharmacometrics. [ABSTRACT FROM AUTHOR]

This study presents a deep learning-based monitoring system for estimating extrusion angles in the manufacturing process of microcatheter tubes. Given the critical nature of these tubes, which are directly inserted into the human body, strict quality control is imperative. To mitigate potential quality variations stemming from operator actions, a system utilizing a convolutional neural network to precisely measure the extrusion angle—a parameter with profound implications for tube quality—is developed. Until now, there has been no method to estimate the extrusion angle of resin being extruded in real-time. In this study, for the first time, a method using deep learning to estimate the angle was proposed. This innovative system comprises two RGB cameras capturing both front and side perspectives. The acquired images undergo segmentation via a meticulously trained convolutional neural network. Subsequently, the extrusion angle is accurately estimated through the application of principal component analysis on the segmented image. The usefulness of the proposed system was rigorously confirmed through comprehensive validation measures, including mean intersection over union (mIoU), mean absolute angle error (MAE), and inference time, using a real-world dataset. The attained metrics, with an mIoU of 0.8848, MAE of 0.5968, and an inference time of 0.0546, unequivocally affirm the system's suitability for enhancing the catheter tube extrusion process. [ABSTRACT FROM AUTHOR]

Zaltoprofen is a drug used for various pain and inflammatory diseases. Scientific and quantitative dosage regimen studies regarding its clinical application are scarce. This study aimed to discover effective covariates related to interindividual pharmacokinetic variability through population pharmacokinetic modeling for zaltoprofen and to explore dosage regimens. The bioequivalence results of healthy Korean males, biochemical analysis, and CYP2C9 genotyping information were utilized in modeling. The established model has been sufficiently verified through a bootstrap, goodness-of-fit, visual predictive check, and normalized prediction distribution error. External data sets derived from the literature were used for further model validation. The final model could be used to verify the dosage regimen through multiple exposure simulations according to the numerical change of the selected covariates. Zaltoprofen pharmacokinetics could be explained by a two-compartment with a first-order absorption model. Creatinine clearance (CrCL) and albumin were identified as effective covariates related to interindividual zaltoprofen pharmacokinetic variability, and they had positive and negative correlations with clearance (CL/F), respectively. The differences in pharmacokinetics between individuals according to CYP2C9 genetic polymorphisms (*1/*1 and *1/*3) were not significant or valid covariates. The model simulation confirmed that zaltoprofen pharmacokinetics could significantly differ as the CrCL and albumin levels changed within the normal range. Steady-state plasma exposure to zaltoprofen was significantly reduced in the group with CrCL and albumin levels of 130 mL/min and 3.5 g/dL, respectively, suggesting that dose adjustment may be necessary. This study is useful to guide precision medicine of zaltoprofen and provides scientific quantitative judgment data for its clinical applications. [ABSTRACT FROM AUTHOR]

Background: Meloxicam, used for treating inflammatory diseases, shows large differences in metabolism according to CYP2C9 genetic polymorphisms; however, there are few studies on dose regimen setting based on quantitative predictions. Objective: The aim of this study was to determine the appropriate meloxicam dose regimen for each genotype through population pharmacokinetic‐pharmacodynamic modeling of meloxicam by considering CYP2C9 genetic polymorphisms. Methods: For modeling, previously reported pharmacokinetic (plasma concentration)‐pharmacodynamic (inhibition of thromboxane B2 generation) data of meloxicam were collected for CYP2C9 genetic polymorphisms (n = 43). And these data were mainly used in the modeling process. Through simulations of the established models, steady‐state pharmacokinetic‐pharmacodynamic profiles were obtained according to meloxicam multiple exposures for each CYP2C9 genotype, and predictions were made based on dose regimen changes. Results: Genetic polymorphisms of CYP2C9 were identified as key covariates that significantly affected pharmacokinetic variability of meloxicam between individuals. The developed meloxicam population pharmacokinetic‐pharmacodynamic model predicted pharmacokinetic results of the 7.5 mg meloxicam administration groups (n = 26) for CYP2C9*1/*1 and *1/*3 as an external validation. The results of model simulation revealed that the differences were 2.39–5.42 times for steady‐state mean plasma concentrations and 1.21–1.71 times for the degree of inhibition of thromboxane B2 generation following multiple exposures for CYP2C9*1/*1 versus *1/*13, *1/*3, and *3/*3. This suggested that thromboxane B2 inhibition following increased plasma exposure to meloxicam differed significantly according to CYP2C9 genetic polymorphisms. The dose of meloxicam in CYP2C9*1/*13, *1/*3, and *3/*3 was randomly adjusted to 1.6–15 mg to approximate the mean thromboxane B2 inhibition for CYP2C9*1/*1 at steady state, the dose intervals varied from 24 h to 48 h. Conclusions: The results suggested that clinical dose adjustment of meloxicam would be necessary to account for CYP2C9 genetic polymorphisms and reduce side effects. This study suggests a clearer direction for setting up clinical therapy based on personalized medicine and quantitative predictions for meloxicam. [ABSTRACT FROM AUTHOR]

Torsemide is a widely used diuretic in clinical practice. In this study, pharmacokinetic (PK) and pharmacodynamic (PD) simulations of torsemide for various population groups and exposure scenarios were performed through human-scale physiologically-based PK-PD (PBPK-PD) modeling of torsemide. For PBPK-PD modeling of torsemide, invitro and clinical data of torsemide reported previously were used. After exposure to clinical doses of torsemide, observed plasma (or serum) concentration and urine torsemide excretion profiles were used as PK-data, and observed urinary sodium excretion rate was used as PD-data. The model was then extended to take into account physiological and biochemical factors according to different CYP2C9 phenotypes or patient populations. The established model captured various torsemide clinical results well. Differences in torsemide PKs and PDs between patient groups or CYP2C9 genetic polymorphisms were modelologically identified. It was confirmed that degrees of differences in torsemide PKs and PDs by disease groups were greater than those according to different CYP2C9 phenotypes. According to torsemide administration frequency or dose change, it was confirmed that although the difference in plasma PKs between groups (healthy adult and patient groups) could increase to 14.80 times, the difference in PDs was reduced to 1.01 times. Results of this study suggested that it is very important to consider disease groups in the setting of torsemide clinical therapy and that it is difficult to predict PD proportionally with only differences in PKs of torsemide between population groups. The PBPK-PD model established in this study is expected to be utilized for various clinical cases involving torsemide application in the future, enabling optimal drug therapy. [ABSTRACT FROM AUTHOR]

Lornoxicam physiologically based pharmacokinetic (PBPK) models were developed and validated on the basis of clinical pharmacokinetic results obtained by considering CYP2C9 genetic polymorphisms in healthy adult populations. PBPK models were extended to predict lornoxicam pharmacokinetics for patients with cirrhosis by quantitatively examining the pathophysiological information associated with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.12–2.83 times higher in the CYP2C9*1/*3 and *1/*13 groups than in the CYP2C9*1/*1 group of healthy adult populations and patients with cirrhosis. The predicted plasma exposure to lornoxicam was approximately 1.28–3.61 times higher in patients with cirrhosis than in healthy adult populations. If the relationship between lornoxicam exposure in plasma and drug efficacy was proportional, then the proposed adjusted doses of lornoxicam for each group varied from 1.25 mg to 8 mg. As the severity of cirrhosis increased, or when the CYP2C9 genotype was *1 heterozygous, the dose adjustment range of lornoxicam increased. Therefore, the effect of pathophysiological factors (cirrhosis severity) on the pharmacokinetics of lornoxicam might be more important than that of CYP2C9 genetic factors. These results could be useful for broadening the scope of clinical application of lornoxicam by enabling dose selection based on CYP2C9 genotypes and liver cirrhosis degree. [ABSTRACT FROM AUTHOR]

As a toxic substance, 4-n-nonylphenol (4-n-NP) or 4-nonylphenol (4-NP) is widely present in the environment. 4-n-NP is a single substance with a linear-alkyl side chain, but 4-NP usually refers to a random mixture containing various branched types. Unfortunately, human risk assessment and/or exposure level analysis for 4-n-NP (or 4-NP) were almost nonexistent, and related research was urgently needed. This study aimed to analyze the various exposures of 4-n-NP (or 4-NP) through development of a physiologically based-pharmacokinetic (PBPK) model considering gender difference in pharmacokinetics of 4-n-NP and its application to human risk assessment studies. A PBPK model was newly developed considering gender differences in 4-n-NP pharmacokinetics and applied to a human risk assessment for each gender. Exposure analysis was performed using a PBPK model that considered gender differences in 4-n-NP (or 4-NP) exposure and high variabilities in several countries. Furthermore, an extended application was attempted as a human risk assessment for random mixture 4-NP, which is difficult to accurately evaluate in reality. External-exposure and margin-of-safety estimated with the same internal exposure amount differed between genders, meaning the need for a differentiated risk assessment considering gender. Exposure analysis based on biomonitoring data confirmed large variability in exposure to 4-n-NP (or 4-NP) by country, group, and period. External-exposures estimated using PBPK model varied widely, ranging from 0.039 to 63.875 mg/kg/day (for 4-n-NP or 4-NP). By country, 4-n-NP (or 4-NP) exposure was higher in females than in males and the margin-of-safety tended to be low. Overall, exposure to 4-n-NP (or 4-NP) in populations was largely not safe, suggesting need for ongoing management and monitoring. Considering low in vivo accumulation confirmed by PBPK model, risk reduction of 4-n-NP is possible by reducing its use. [ABSTRACT FROM AUTHOR]

To date, for the diagnosis of dentofacial dysmorphosis, we have relied almost entirely on reference points, planes, and angles. This is time consuming, and it is also greatly influenced by the skill level of the practitioner. To solve this problem, we wanted to know if deep neural networks could predict postoperative results of orthognathic surgery without relying on reference points, planes, and angles. We use three-dimensional point cloud data of the skull of 269 patients. The proposed method has two main stages for prediction. In step 1, the skull is divided into six parts through the segmentation network. In step 2, three-dimensional transformation parameters are predicted through the alignment network. The ground truth values of transformation parameters are calculated through the iterative closest points (ICP), which align the preoperative part of skull to the corresponding postoperative part of skull. We compare pointnet, pointnet++ and pointconv for the feature extractor of the alignment network. Moreover, we design a new loss function, which considers the distance error of transformed points for a better accuracy. The accuracy, mean intersection over union (mIoU), and dice coefficient (DC) of the first segmentation network, which divides the upper and lower part of skull, are 0.9998, 0.9994, and 0.9998, respectively. For the second segmentation network, which divides the lower part of skull into 5 parts, they were 0.9949, 0.9900, 0.9949, respectively. The mean absolute error of transverse, anterior–posterior, and vertical distance of part 2 (maxilla) are 0.765 mm, 1.455 mm, and 1.392 mm, respectively. For part 3 (mandible), they were 1.069 mm, 1.831 mm, and 1.375 mm, respectively, and for part 4 (chin), they were 1.913 mm, 2.340 mm, and 1.257 mm, respectively. From this study, postoperative results can now be easily predicted by simply entering the point cloud data of computed tomography. [ABSTRACT FROM AUTHOR]

Expanded hemodialysis (HD) equipped with a medium cut-off (MCO) membrane provides superior removal of larger middle molecules. However, there is still little research on the long-term benefits of expanded HD. Over a three-year period, this observational study evaluated the efficacy and safety profile of expanded HD for inflammatory cytokines, including IL-6. We conducted a prospective cohort study to investigate the inflammatory cytokine changes and a retrospective observational cohort study to investigate long-term clinical efficacy and safety over a three-year period. We categorized the patients according to dialyzer used: MCO and high-flux (HF) dialyzer. The inflammatory cytokines, including IFN-γ, IL-1β, IL-6, and TNF-α, were measured annually. The concentrations and changes of the four cytokines over time did not differ between the HF group (n = 15) and MCO group (n = 27). In both prospective and retrospective (HF group, n = 38; MCO group, n = 76) cohorts, there were no significant differences in either death, cardiovascular events, infections, or hospitalizations. Furthermore, the temporal changes in laboratory values, including serum albumin and erythropoietin prescriptions, did not differ significantly between the two groups in either the prospective or retrospective cohorts. In conclusion, clinical efficacy and safety outcomes, as well as inflammatory cytokines, did not differ with expanded HD compared with HF dialysis during a three-year treatment course, although the level of inflammatory cytokine was stable. [ABSTRACT FROM AUTHOR]

Torsemide is a diuretic drug used for several cardiovascular and chronic diseases. With regard to the clinical application of torsemide, studies on individualized pharmacotherapy and modeling that take variability in pharmacokinetics (PKs) within a population into account have been rarely reported. Thus, the objective of this study was to perform population pharmacokinetic (Pop-PK) modeling and to identify effective covariates that could explain the inter-individual variability (IIV) of torsemide PK. Pop-PK modeling for torsemide was performed based on serum concentration data obtained from 112 healthy Korean males and analysis of various genetic and physicochemical parameters. Modeling was performed with nonlinear mixed-effects (NLME) using Phoenix NLME. The finally developed model was fully verified. The model was also reconfirmed using NONMEM software. As a basic model, the PKs of torsemide within the population were well described by a two-compartment model reflecting the lag-time on oral absorption. According to the genetic polymorphisms of OATP1B1 and CYP2C9, significant associations were found in the V/F, CL/F, and CL2/F of torsemide. These were reflected as effective covariates in the final Pop-PK model of torsemide, resulting in an approximately 5–10% improvement in the model parameter IIV values. Considering that torsemide is a substrate for CYP2C9 and OATP1B1, it was important to search for genetic polymorphisms in CYP2C9 and OATP1B1 as covariates to explain the PK diversity of torsemide between individuals. The differences in CL/F and CL2/F between the phenotypes of CYP2C9 were approximately 36.5–51%. The difference in V/F between the phenotypes of OATP1B1 was approximately 41–64.6%. These results suggested that the phenotypes of CYP2C9 and OATP1B1 produced significant differences in torsemide PKs. Considering that CYP2C9 and OATP1B1 phenotypes as covariates affected different PK parameters of torsemide, it could be inferred that torsemide's cell membrane permeation process by OATP1B1 and the metabolic process by CYP2C9 could independently affect each other in vivo without interplay. There was no significant difference in the parameter estimates between modeling software (Phoenix NLME vs. NONMEM). In this study, the torsemide PK variability between individuals was largely explained. In the future, individualized effective drug therapy of torsemide taking individual patient's genotypes into account might become possible. [ABSTRACT FROM AUTHOR]

Di-isodecyl phthalate (DiDP) is a high-molecular-weight phthalate that is mainly used as a plasticizer for plastics. Therefore, exposure to DiDP in the environment has become common with the increasing use of plastics around the world. Environmental regulations and scientific risk management for DiDP, which can be associated with endocrine disruption and various metabolic diseases, are urgently needed. The purpose of this study was to provide useful reference material for future human DiDP risk assessments by conducting toxicokinetic studies on DiDP. Rats were given 100 mg/kg of DiDP orally or intravenously, and plasma, urine, feces, and various tissues were sampled at preset times. DiDP and its major metabolites mono-isodecyl-phthalate (MiDP), mono-hydroxy-isodecyl-phthalate (MHiDP), mono-carboxy-isononyl-phthalate (MCiNP), and mono-oxo-isodecyl-phthalate (MOiDP) were simultaneously quantified from collected biological samples through the application of a newly developed and verified ultrahigh-performance liquid chromatography–electrospray ionization-tandem mass spectrometer (UHPLC–ESI-MS/MS) method. Based on the quantitative results for each analyte, toxicokinetic analyses were performed. DiDP was rapidly and extensively metabolized to MiDP, MHiDP, MCiNP, and MOiDP. The major metabolite excreted in the urine was MCiNP, suggesting that it could be a useful biomarker. The conjugated forms of DiDP and its metabolites have been significantly quantified in the plasma, urine, and feces. DiDP and its major metabolites were also distributed in various tissues in significant quantities. The toxicokinetic properties of DiDP, which have not been clearly reported previously, were identified through this study. This report will serve as a useful reference for future DiDP environmental regulation and scientific human risk assessment studies. [ABSTRACT FROM AUTHOR]

There have been many attempts to formulate a variety of drugs in nano-size formulations. However, biodistribution characteristics of these formulated drugs remain unclear. Information about the pharmacokinetics and distributions of these formulations is essential for future practical use and advanced formulation development. Topotecan is a useful agent for treating a variety of cancers. It exhibits anti-cancer activity by inhibiting topoisomerase. However, oral bioavailability of topotecan was not satisfactory in previous studies. Reversible hydrolysis of its active site according to pH environment was a major limitation in terms of treatment. To improve the bioavailability and retention of topotecan in target organs (such as lung and brain) and increase its delivery to the lymphatic system as a major pathway for cancer metastasis, this study was conducted on topotecan-loaded nanoparticles using poly(lactic- co -glycolic acid) (PLGA). These nanoparticles were prepared by double emulsion solvent evaporation. Formulated topotecan-loaded PLGA nanoparticles were subjected to several in vitro tests to determine various physicochemical properties such as size, zeta potential, encapsulation efficiency, morphology, and release profile. These nanoparticles were also subjected to in vivo studies using rats. Based on in vivo results, pharmacokinetic properties, distribution in the body, and delivery efficiency of these formulated nanoparticles were confirmed. Topotecan-loaded PLGA nanoparticles showed a delayed release pattern in vitro. Their pharmacokinetic profiles and distributions in the body were clearly different from those of free topotecan hydrochloride. Results confirmed that topotecan encapsulated in the PLGA polymer was stable from hydrolysis and present in an active form for a longer time in the body. Biometric imaging revealed in vivo properties of topotecan-loaded PLGA nanoparticles for qualitative confirmation. And oral delivery of topotecan in polymeric nanoparticles to lymph and various body tissues has been identified. Findings of this study indicate that topotecan formulated into nanoparticles (using PLGA) has a better pharmacokinetic profile and a better delivery to lymphoid tissues, lung, and brain than free topotecan hydrochloride, suggesting that these topotecan-loaded PLGA nanoparticles might provide better therapeutic results. [Display omitted] • Pharmacokinetics of topotecan in active lactone and total forms are compared. • PLGA nanoparticles improved stability and bioavailability of topotecan in vivo. • Topotecan-loaded nanoparticles enhanced drug delivery to lymph, lung, and brain. • This presents a quantitative/qualitative approach to study on topotecan nanoparticles. [ABSTRACT FROM AUTHOR]

Di-isobutyl phthalate (DiBP) is a substance used in the production of objects frequently used in human life. Mono-isobutyl phthalate (MiBP), a major in vivo metabolite of DiBP, is a biomarker for DiBP exposure assessment. Therefore, risk assessment studies on DiBP and MiBP, which have not yet been reported in detail, are needed. The aim of this study was to develop and evaluate a physiologically based pharmacokinetic (PBPK) model for DiBP and MiBP in rats and extend this to human risk assessment based on human exposure. Pharmacokinetic studies were performed in male rats following the administration of 5–100 mg/kg DiBP, and these results were used for the development and validation of the PBPK model. In addition, the previous pharmacokinetic results in female rats following DiBP administration and the pharmacokinetic results in both males and females according to multiple exposures to DiBP were used to develop and validate the PBPK model. The metabolism of DiBP to MiBP in the body was very significant and rapid, and the biodistribution of MiBP was broad and major. Furthermore, the amount of MiBP in the body showed a correlation with DiBP exposure, and from this, a PBPK model was developed to evaluate the external exposure of DiBP from the internal exposure of MiBP. The predicted rat plasma, urine, fecal, and tissue concentrations using the developed PBPK model fitted well with the observed values. The established PBPK model for rats was extrapolated to a human PBPK model of DiBP and MiBP based on human physiological parameters and allometric scaling. The reference dose of 0.512 mg/kg/day of DiBP and external doses of 6.14–280.90 μg/kg/day DiBP for human risk assessment were estimated using Korean biomonitoring values. Valuable insight and approaches to assessing human health risks associated with DiBP exposure were provided by this study. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a method for simultaneous analysis of aucubin, catalpol, and geniposide, which are representative iridoid glycoside constituents of Rehmannia glutinosa, in rat plasma, urine, and feces using hydrophilic interaction ultra high‐performance liquid chromatography with tandem mass spectrometry. The three components were separated using 10 mmol/L aqueous ammonium formate containing 0.01% (v/v) formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.2 mL/min, equipped with a Kinetex® HILIC column (50 × 2.1 mm, 2.6 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer employing electrospray ionization and operated in multiple reaction monitoring mode. The chromatograms showed high resolution, sensitivity, and selectivity with no interference with plasma constituents. In all three iridoid glycosides, both the intra‐ and interbatch precisions (coefficient of variation %) were less than 4.81%. The accuracy was 96.56–103.55% for aucubin, 95.23–106.21% for catalpol, and 94.50–104.16% for geniposide. The developed analytical method satisfied the criteria of international guidance and was successfully applied to pharmacokinetic studies including oral bioavailability of aucubin, catalpol, and geniposide, and their urinary and fecal excretion ratios after oral or intravenous administration to rats. The new method was also applied to measure plasma protein binding ratios in vitro. [ABSTRACT FROM AUTHOR]

Diethyl phthalate (DEP) belongs to phthalates with short alkyl chains. It is a substance frequently used to make various products. Thus, humans are widely exposed to DEP from the surrounding environment such as food, soil, air, and water. As previously reported in many studies, DEP is an endocrine disruptor with reproductive toxicity. Monoethyl phthalate (MEP), a major metabolite of DEP in vivo, is a biomarker for DEP exposure assessment. It is also an endocrine disruptor with reproductive toxicity, similar to DEP. However, toxicokinetic studies on both MEP and DEP have not been reported in detail yet. Therefore, the objective of this study was to evaluate and develop physiologically based pharmacokinetic (PBPK) model for both DEP and MEP in rats and extend this to human risk assessment based on human exposure. This study was conducted in vivo after intravenous or oral administration of DEP into female (2 mg/kg dose) and male (0.1–10 mg/kg dose) rats. Biological samples consisted of urine, plasma, and 11 different tissues. These samples were analyzed using UPLC–ESI–MS/MS method. For DEP, the tissue to plasma partition coefficient was the highest in the kidney, followed by that in the liver. For MEP, the tissue to plasma partition coefficient was the highest in the liver. It was less than unity in all other tissues. Plasma, urine, and fecal samples were also obtained after IV administration of MEP (10 mg/kg dose) to male rats. All results were reflected in a model developed in this study, including in vivo conversion from DEP to MEP. Predicted concentrations of DEP and MEP in rat urine, plasma, and tissue samples using the developed PBPK model fitted well with observed values. We then extrapolated the PBPK model in rats to a human PBPK model of DEP and MEP based on human physiological parameters. Reference dose of 0.63 mg/kg/day (or 0.18 mg/kg/day) for DEP and external doses of 0.246 μg/kg/day (pregnant), 0.193 μg/kg/day (fetus), 1.005–1.253 μg/kg/day (adults), 0.356–0.376 μg/kg/day (adolescents), and 0.595–0.603 μg/kg/day (children) for DEP for human risk assessment were estimated using Korean biomonitoring values. Our study provides valuable insight into human health risk assessment regarding DEP exposure. [ABSTRACT FROM AUTHOR]

4- tert -octylphenol (4- tert -OP) is a potentially harmful substance, which is found widely in the environment. Nevertheless, information on the in vivo toxicokinetics of 4- tert -OP is lacking, and quantitative risk assessment studies are urgently needed. Therefore, we aimed to quantitatively identify differences in the toxicokinetics of 4- tert -OP and its distribution among tissues between sexes. To this end, following exposure of male and female rats to 10 or 50 mg/kg 4- tert -OP orally and 4 or 8 mg/kg 4- tert -OP intravenously, we conducted a quantitative analysis of samples using ultra-high performance liquid chromatography-tandem mass spectrometry. The results revealed that the 4- tert -OP plasma concentration profiles differed between sexes; however, systemic absorption of 4- tert -OP through the gastrointestinal tract occurred within 0.5 h of exposure in both sexes. Although small, the excretion percentage of 4- tert -OP in urine and feces was lower in males than females (0.06–0.08% vs. 0.82–1.11% of exposure). Significant sex differences were also confirmed in the tissue distribution patterns of 4- tert -OP, and overall, the average tissue distribution in males was lower than that in females. The distribution of 4- tert -OP to liver, adipose, spleen, kidney, brain, and lung in both sexes was predominant. A covariate exploration modeling approach revealed that sex explained the differences in 4- tert -OP toxicokinetics between sexes. These significant differences in the toxicokinetics and tissue distribution of 4- tert -OP between sexes will be important for the scientific precision human risk assessment of 4- tert -OP. [Display omitted] • The difference in 4- tert -OP toxicokinetics between genders was significant. • The biodistribution of 4- tert -OP was greater in females than in males. • The in vivo clearance of 4- tert -OP is higher in males than in females. • Gender as a valid covariate in the 4- tert -OP toxicokinetic compartmental model. [ABSTRACT FROM AUTHOR]

The aim of this study was to newly identify and investigate the gender differences in pharmacokinetics (PKs) and tissue distribution of 4-n-nonylphenol (4-n-NP) in both male and female Sprague–Dawley rats. For this study, a UPLC–ESI–MS/MS system for 4-n-NP was developed as a sensitive and rapid analysis method and validated according to the accepted criteria of the international guidelines. The method was finally applied to the analysis of plasma, urine, feces, and nine different tissue samples of rats. PK parameters were calculated after single oral or intravenous administration of 4-n-NP at a dose of 10 or 50 mg/kg. Mean half-life of 4-n-NP in female rats was shorter and its clearance was larger for all doses than those in male rats. There were statistically significant differences in excretion patterns of urine and feces between male and female rats. Distribution of nine different tissues for 4-n-NP was greater in male than in female, and 4-n-NP was highly distributed in the liver or kidney. It was also specific that the distribution of 4-n-NP into brain was considerable. These results suggest that there are gender differences in the PKs of 4-n-NP in rats. Although, 4-n-NP is known to be a reproductive toxicant, reports on its PKs, excretion pattern, tissue distribution, and gender difference are limited. Therefore, our results will be useful data for gender differences as well as toxicokinetic information for 4-n-NP. In addition, it is expected to be very important for future risk assessment and PBPK model establishment of 4-n-NP. [ABSTRACT FROM AUTHOR]

• UPLC–MS/MS method for simultaneous analysis of DEP and MEP in rat biological samples. • Successfully applied to characterize PK, tissue distribution and metabolism of DEP in rats. • The first study for simultaneous analysis of DEP and MEP in rat biological samples. • Useful for developing PBPK models for DEP and its metabolite in future exposure study. This study describes the development of a novel and sensitive UPLC-MS/MS method for simultaneous determination of diethyl phthalate (DEP) and its major metabolite, monoethyl phthalate (MEP), in rat plasma, urine, and 11 different tissues collected from a toxicokinetic study. Analytes were separated using 0.1% (v/v) aqueous formic acid and acetonitrile containing 0.1% (v/v) formic acid as a mobile phase by gradient elution at a flow rate of 0.25 mL/min with a KINETEX core-shell C 18 column (50 × 2.1 mm, 1.7 μm). Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operated in multiple reaction monitoring. The assay achieved lower limit of quantification for 0.04 ng/mL of DEP and 0.1 ng/mL of MEP in plasma, urine, and all tissues. The disposition of DEP was characterized by short half-life (1.30–1.34 h) and a high clearance (11.76 ± 0.08 L/h/kg). It was rapidly metabolized to MEP. Its levels consistently exceeded DEP levels. The tissue distribution of DEP and MEP of liver, kidney, gastro-intestinal tract, spleen, testis, lung, brain, muscle, thymus, heart, and adipose was determined at 24 h after drug administration. For DEP, the tissue to plasma partition coefficient was the highest in the kidney (16.72), followed by that in the liver (10.04), spleen (1.35), and adipose (1.18). For MEP, the tissue to plasma partition coefficient was the highest in the liver (2.18). It was less than unity for all other tissues. The developed analytical method satisfied the criteria of international guidance. It could be successfully applied to toxicokinetic studies of DEP after oral and intravenous administration of DEP to rats. In addition, findings of this study may be useful to evaluate exposure and toxic potential of DEP and its metabolite in risk assessment. [ABSTRACT FROM AUTHOR]

P-glycoprotein (P-gp) is a widely membrane-expressed multi-drug transporter. It is unclear whether the pharmacokinetic diversity of P-gp substrates is highly dependent on ABCB1 polymorphisms encoding P-gp. The purpose of this study is to analyze the mechanistic function of P-gp through in silico molecular modeling and to approach the resolution of controversy over pharmacokinetic differences according to ABCB1 polymorphisms. P-gp conformations of apo, ligand-docked, and outward-facing states can be modeled based on structural information of human P-gp. And polymorphic P-gp structures were constructed through homology modeling. ABCB1 c.2677G > T/A (Ala893Ser/Thr), did not correspond to P-gp's nucleotide-binding-domain (NBD) or drug-binding-pocket (DBP) or involve mechanical conformational changes. Although amino acid substitution by ABCB1 c.2677G > T/A caused a 30 % increased strain in an α -helix hinge between the NBD and DBP in P-gp's internal tunnel, there were no overall structural changes compared to wild-type. ABCB1 c.2677G > T/A may increase torsional energy, impacting conformational change rate, but this does not significantly affect P-gp's general functioning. Fexofenadine docking into P-gp's DBP explained the substrate interaction, but no effect by ABCB1 c.2677G > T/A was confirmed. Our findings provide additional insights useful in resolving the debate about the influence of ABCB1 polymorphisms on the interindividual pharmacokinetic variability of P-gp substrates. • A structure-based mechanism of P-glycoprotein (P-gp) through molecular modeling • ABCB1 c.2677G > T/A gene polymorphism was not major for functional changes in P-gp. • Ala893Ser/Thr is unlikely to be related to substrate pharmacokinetic variability. • Resolving the current the P-gp genetic polymorphism controversy • 3 steps for pharmacokinetic variability molecular anlaysis of P-gp substrates [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a method for simultaneous analysis of schizandrin, ephedrine, paeoniflorin, and cinnamic acid as constituents of Socheongryong-tang tablet in human plasma using UPLC-MS/MS. These four components were separated using water containing 0.01% formic acid and methanol as a mobile phase by gradient elution at a flow rate of 0.3 mL/min with a HALO-C 18 column (2.1 mm × 100 mm, 2.7 μm particle size). Quantitation was performed on a triple quadrupole mass spectrometer employing electrospray ionization technique operated in multiple reaction monitoring mode. Mass transitions were m / z 432.9 → 384.1 for schizandrin, 165.8 → 148.1 for ephedrine, 525.0 → 449.2 for paeoniflorin, 146.8 → 102.9 for cinnamic acid, and 340.0 → 324.0 for papaverine as internal standard. Liquid-liquid extraction and protein precipitation with ethyl acetate-methanol (1:2, v/v) were used to obtain these four components. Chromatograms showed high resolution, sensitivity, and selectivity without interference by plasma constituents. Calibration curves of schizandrin, ephedrine, paeoniflorin, and cinnamic acid in human plasma ranged from 0.02 to 8 ng/mL, 0.5 to 200 ng/mL, 0.2 to 80 ng/mL, and 1 to 400 ng/mL, respectively. Calibration curves of each analyte displayed excellent linearity, with correlation coefficients > 0.99. For all four components, both intra- and inter-day precisions (CV%) were <5.99%. The accuracy was 99.35–103.30% for schizandrin, 98.48–104.38% for ephedrine, 97.06–103.34% for paeoniflorin, and 99.97–104.36% for cinnamic acid. This analytical method developed in this study satisfied the criteria of international guidance. It could be successfully applied to pharmacokinetic studies of schizandrin, ephedrine, paeoniflorin, and cinnamic acid after oral administration of Socheongryong-tang tablet to humans. [ABSTRACT FROM AUTHOR]

In this research, a new layout optimization method is developed to consider high cycle fatigue constraints which occur due to variable amplitude mechanical loading. Although fatigue is a very important property in terms of safety when designing mechanical components, it has rarely been considered in topology optimization with the lack of concept and the difficulty of sensitivity analysis for fatigue constraints calculated from multiaxial cycle counting. For the topology optimization for fatigue constraint, we use transient stress analysis to extract effective stress cycles and Miner's cumulative damage rule to calculate total damage at every spatial element. Because the calculation of the exact sensitivities of a transient system is complex and time consuming for the topology optimization application, this research proposes to use the pseudo-sensitivities of fatigue constraints calculated by applying equivalent static load approach. In addition, as an aggregated fatigue constraint is very sensitive to the changes in stress value which causes some unstable convergences in optimization process, a new scaling approach of the aggregated fatigue damage constraint is developed. To validate the usefulness of the developed approaches, we solved some benchmark topology optimization problems and found that the present method provides physically appropriate layouts with stable optimization convergence. [ABSTRACT FROM AUTHOR]

Levodropropizine is a non-narcotic, non-centrally acting antitussive that inhibits the cough reflex triggered by neuropeptides. Despite the active clinical application of levodropropizine, the exploration of its inter-individual pharmacokinetic diversity and of factors that can interpret it is lacking. The purpose of this study was to explore effective covariates associated with variation in the pharmacokinetics of levodropropizine within the population and to perform an interpretation of covariate correlations from a therapeutic perspective. The results of a levodropropizine clinical trial conducted on 40 healthy Korean men were used in this pharmacokinetic analysis, and the calculated pharmacokinetic and physiochemical parameters were screened for effective correlations between factors through heatmap and linear regression analysis. Along with basic compartmental modeling, a correlation analysis was performed between the model-estimated parameter values and the discovered effective candidate covariates for levodropropizine, and the degree of toxicity and safety during the clinical trial of levodropropizine was quantitatively monitored, targeting the hepatotoxicity screening panel. As a result, eosinophil level and body surface area (BSA) were explored as significant (p-value < 0.05) physiochemical parameters associated with the pharmacokinetic diversity of levodropropizine. Specifically, it was confirmed that as eosinophil level and BSA increased, levodropropizine plasma exposure increased and decreased, respectively. Interestingly, changes in an individual's plasma exposure to levodropropizine depending on eosinophil levels could be interpreted as a therapeutic advantage based on pharmacokinetic benefits linked to the clinical indications for levodropropizine. This study presents effective candidate covariates that can explain the inter-individual pharmacokinetic variability of levodropropizine and provides a useful perspective on the first-line choice of levodropropizine in the treatment of inflammatory respiratory diseases. [ABSTRACT FROM AUTHOR]

We developed a new layout optimization method that incorporates dynamic fatigue and static failure criteria under constant and proportional mechanical loads. Although fatigue failure is one of the most important design considerations to ensure the safety of a mechanical structure, it has rarely been considered in terms of topology optimization due to several major theoretical and numerical difficulties. In addition to the numerical and theoretical issues associated with static failure criteria, we found that the local mode issue and the non-differentiability of the fatigue failure criteria needed to be addressed prior to performing fatigue constraint topology optimization. By resolving the inherent and newly-found issues associated with fatigue criteria, we were able to perform successful topology optimization with dynamic fatigue criteria under constant and proportional mechanical loads. [ABSTRACT FROM AUTHOR]

Abstract: This research develops a new interpolation scheme, a separable stress interpolation (SSI) which allows stress-based topology optimization with multiple materials (STOMM). In common material interpolation function such as extended solid isotropic material with penalization (SIMP) for multiple materials, Young's modulus is interpolated from those of several solids to a smaller value with respect to design variables whose number is same as the number of considered materials. When the same interpolated Young's modulus is used for stress evaluation, it is found that the calculated stress norm becomes a small value when ones are assigned to the design variables of each element causing physically unacceptable layouts. In order to resolve this ill-posed issue for STOMM, we present the SSI scheme which computes the stress constraints of stacked elements separately. For a stable topology optimization process, the computational issues of the p-norm stress measure, the number of stress evaluation points inside an element, and the correction parameter for the approximated stress measure are addressed for STOMM. Furthermore, we present a new regional constraint method based on the sorting algorithm. The applicability and limitations of the newly developed framework are discussed in the context of its application to several stress-based topology optimizations with multiple materials. [Copyright &y& Elsevier]

Highlights: [•] A phase field based method for local stress topology optimization is developed. [•] The Augmented Lagrange multiplier method is developed in the phase field. [•] The locality helps to solve difficult structural optimization problems. [•] The topological derivatives of the local stress constraints are derived. [ABSTRACT FROM AUTHOR]

Abstract: In this work, a novel computational approach is developed for the gradient-based stress-based topology optimization method, where the volume is minimized according to locally defined stress constraints of static failure criteria in the framework of tailored finite element (FE) software without direct access to an internal finite element information database. Tailored finite element codes that require substantial understanding and modification (reprogramming) or do not directly provide internal finite element information have rarely been used for stress-based topology optimization with solid isotropic material with penalization (SIMP) methods. Therefore, much research has been confined to two-dimensional problems with rectilinear basic finite elements, as complex three-dimensional geometries with advanced finite element formulations are not supported. To overcome this problem, we developed a new computational procedure for sensitivity analysis without direct access to an internal information database, a task that has previously been regarded as almost impossible. Since the calculation of linear strain–displacement matrices is required in the sensitivity analysis, the present procedure includes a node selection algorithm to efficiently calculate the matrices of irregular-shaped finite elements by displacement perturbations. The benefits of the present approach are that well-established powerful finite element codes, i.e., commercial or sophisticated public FE codes, can be easily incorporated for linear stress-based topology optimization, and any type of finite element formulation can be readily employed. In contrast to classical sensitivity analysis, small computations are used for sensitivity analysis in this work. To demonstrate the validity and efficiency of the present procedure and approach, several topology optimization problems with 3D and shell elements are solved. [Copyright &y& Elsevier]

Abstract: This research develops a stress-based topology optimization method (STOM) that considers various static failure criteria, including those from the maximum shear stress theory, the distortion energy theory, the ductile Coulomb–Mohr theory, the brittle Coulomb–Mohr theory, and the modified Mohr theory for ductile and brittle materials. Due to some theoretical and numerical challenges, the above static failure theories have not been implemented in topology optimization. By substituting failure formulas that are non-differentiable with respect to the stress components and design variables with differentiable approximation formulas, it is possible to utilize these failure criteria to design mechanical structures that minimize mass. [Copyright &y& Elsevier]

Due to the use of di-isobutyl-phthalate (DiBP) in the production of soft-polyvinyl chloride articles, it is currently a hazardous substance prevalent in human daily life. However, reports on DiBP's toxicokinetics are still very scarce. And no studies have been reported on gender differences in DiBP toxicokinetics. Therefore, this study was conducted in accordance with these research needs. DiBP of 100 mg/kg has been exposed to male and female rats single or multiple times. DiBP and its major metabolite, mono-isobutyl-phthalate (MiBP), were quantified from various biological samples obtained from rats administered with DiBP. Based on these results, several toxicokinetic parameters were estimated. Toxicokinetic results between genders were compared, and from this, existence and extent of gender differences in DiBP's toxicokinetics were explored. Investigation of presence and extent of subacute toxicity in male and female rats following multiple exposures to DiBP were also conducted. This study provided comprehensive information on DiBP toxicity and gender differences that have not been reported in detail. Results of these studies imply that subacute toxicity in liver, kidney, lung, and testis of rats at 100 mg/kg of DiBP is modest and that there is little difference in toxicokinetics between genders. And in both male and female rats, the metabolism of DiBP (to MiBP) was significant, and excretion of MiBP into urine was a major indicator of DiBP exposure. [Display omitted] • Following oral or intravenous dose to rats, DiBP is predominantly metabolized to MiBP. • DiBP is degraded to MiBP mainly by ester cleavage by carboxyl esterases. • MiBP plasma levels are higher following oral dosing as compared to intravenous dose. • No toxicokinetic differences by gender after single or multiple oral dosing of DiBP. [ABSTRACT FROM AUTHOR]

The purpose of this study was to identify and explore the differences in pharmacokinetics between different nanoformulations. This was done by comparing the pharmacokinetics of methotrexate-loaded nanoparticles [poly(lactic-co-glycolic acid); size of 163.70 ± 10.25 nm] and nanoemulsions (olive oil and Labrasol; size of 173.77 ± 5.76 nm), which represent hard- and soft-type nanoformulations, respectively. In addition, the population pharmacokinetic modeling approach as a useful tool for the comparison of pharmacokinetics between nanoformulations was newly proposed through this study. Significant pharmacokinetic differences were identified between nanoformulations through the new population pharmacokinetic modeling approach. As a result, the formulation type was explored as a significant covariate. The clearance and bioavailability of methotrexate-loaded nanoemulsions tended to decrease by 99% and increase by 19%, respectively, compared to those of the nanoparticles. The exploration of significant pharmacokinetic differences between drug formulations and their correlations presented in this study provide new perspectives on the development of nanoformulations. [ABSTRACT FROM AUTHOR]

The aims of this study were: (1) to perform population pharmacokinetic analysis of cefaclor in healthy Korean subjects, and (2) to investigate possible effects of various covariates on pharmacokinetic parameters of cefaclor. Although cefaclor belongs to the cephalosporin family antibiotic that has been used in various indications, there have been very few population studies on factors affecting its pharmacokinetics. Therefore, this study is very important in that effective therapy could be possible through a population pharmacokinetic study that explores effective covariates related to cefaclor pharmacokinetic diversity between individuals. Pharmacokinetic results of 48 subjects with physical and biochemical parameters were used for the population pharmacokinetic analysis of cefaclor. A one-compartment with lag-time and first-order absorption/elimination was constructed as a base model and extended to include covariates that could influence between-subject variability. Creatinine clearance and body weight significantly influenced systemic clearance and distribution volume of cefaclor. Cefaclor's final population pharmacokinetic model was validated and some of the population's pharmacokinetic diversity could be explained. Herein, we first describe the establishment of a population pharmacokinetic model of cefaclor for healthy Koreans that might be useful for customizing cefaclor or exploring additional covariates in patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to investigate the pharmacokinetic properties of ephedrine, paeoniflorin, and cinnamic acid after single or multiple doses of Socheongryong-tang (SCRT) were administered to rats, and to present an example of the pharmacokinetic changes following multiple doses of an herbal medicine. SCRT is a traditional herbal medicine that has been used clinically for a long time, and its main ingredients include ephedrine, paeoniflorin, and cinnamic acid. However, studies on the pharmacokinetic properties of SCRT are insufficient, and particularly, no pharmacokinetic information has been reported for multiple doses. In this study, SCRT was administered orally to rats once or multiple times, and plasma sampled at different times was quantitatively analyzed for ephedrine, paeoniflorin, and cinnamic acid using ultra-high-performance liquid chromatography-tandem mass spectrometry. There was a difference between the pharmacokinetic parameter values of each component (especially in paeoniflorin and cinnamic acid) obtained after single or multiple doses of SCRT. The actual observed values of each component obtained after multiple doses of SCRT were clearly different from the predicted results of multiple-dose simulations based on the pharmacokinetic profiles obtained after a single dose. The results confirmed that the plasma concentrations and, thus, exposures to paeoniflorin and cinnamic acid were significantly increased when SCRT was administered multiple times, whereas that of ephedrine was not. The results of this study are expected to provide useful pharmacokinetic data for the safety and efficacy evaluation of SCRT in the future and demonstrate the necessity of pharmacokinetic comparison studies according to single or multiple oral administrations of herbal medicines. [ABSTRACT FROM AUTHOR]

The aim of this study was to reveal cranio-spinal differences between skeletal classification using convolutional neural networks (CNNs). Transverse and longitudinal cephalometric images of 832 patients were used for training and testing of CNNs (365 males and 467 females). Labeling was performed such that the jawbone was sufficiently masked, while the parts other than the jawbone were minimally masked. DenseNet was used as the feature extractor. Five random sampling crossvalidations were performed for two datasets. The average and maximum accuracy of the five crossvalidations were 90.43% and 92.54% for test 1 (evaluation of the entire posterior–anterior (PA) and lateral cephalometric images) and 88.17% and 88.70% for test 2 (evaluation of the PA and lateral cephalometric images obscuring the mandible). In this study, we found that even when jawbones of class I (normal mandible), class II (retrognathism), and class III (prognathism) are masked, their identification is possible through deep learning applied only in the cranio-spinal area. This suggests that cranio-spinal differences between each class exist. [ABSTRACT FROM AUTHOR]

• First report of clinical pharmacokinetic study of Banhahoobak-tang tablets. • First report of in vitro analysis for 18 main components of Banhahoobak-tang. • Provide scientific evidence for clinical use of Banhahoobak-tang. • Serve as a basis for designing dosage forms of Banhahoobak-tang tablets. • Useful for effectiveness, safety, and quality evaluation of Banhahoobak-tang tablets. Banhahoobak-tang is the most prescribed herbal drug in East Asia when individuals experience sudden symptoms such as sore throat or neurological symptoms. The low toxicity and high in-vivo safety of this herbal medicine has made it more attractive to patients, and it has recently been formulated as tablets. In addition, Banhahoobak-tang tablets are registered as health insurance drugs in South Korea, and clinical prescriptions and demand are increasing. However, there are very few clinical trial data as well as very little accurate content analysis and results for Banhahoobak-tang tablets. The purpose of this study was to perform in-vitro and in-vivo studies on Banhahoobak-tang tablets, including content analysis, pharmacokinetics in humans, and plasma protein binding. For this study, a UPLC-ESI-MS/MS method with polarity switching was developed for simultaneous analysis of 18 components of Banhahoobak-tang. To separate the analytes, a C 8 reverse-phase column was used as the stationary phase, 0.1 % aqueous formic acid and acetonitrile as the mobile phase, and ionization and multiple reaction monitoring for quantification. The developed method was able to isolate and quantify the 18 components with good sensitivity and selectivity and was fully validated according to international analytical standards. Stability tests were also conducted on the analytes. Finally, the method was applied to in-vitro and in-vivo studies of Banhahoobak-tang tablets, and the tablet components were 52.49 ng/g to 91.00 μg/g on average. The detected components showed rapid oral absorption in humans as well as high plasma protein binding ratio overall. These results and methods can be useful not only for effectiveness and safety evaluation but also for quality control of Banhahoobak-tang tablets. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the toxicokinetics of diisobutyl-phthalate (DiBP) and its major metabolite, monoisobutyl-phthalate (MiBP), by developing a UPLC-ESI-MS/MS method for simultaneously measuring DiBP and MiBP in rat plasma, urine, feces, and 11 different tissues. For the experiment, 0.1% (v/v) aqueous formic acid and acetonitrile mobile phase by gradient elution at a flow rate of 0.3 mL/min, equipped with a KINETEX core-shell C 18 -column (50 × 2.1 mm, 1.7 μm), was used to completely separate analytes. The mass transitions were m/z 279.1 → 149.0 for DiBP, 221.0 → 77.0 for MiBP, and 283.2 → 153.0 for DiBP-d 4 as an internal standard. The developed assay had lower limits of quantification of 0.01 ng/mL for DiBP and 0.1 ng/mL for MiBP at all biological matrices. Toxicokinetics of DiBP were characterized by extensive distribution, short half-life, and high clearance. DiBP was rapidly metabolized to MiBP, with MiBP levels consistently exceeding the DiBP levels. Distribution of MiBP to tissues was considerable. The developed analytical method satisfied international criteria and was successfully applied to toxicokinetic studies after oral and intravenous administration of DiBP to rats. Findings of this study may be useful for evaluating the external exposure and toxic potential of DiBP and its metabolite in risk assessment. Image 1 • The first study for simultaneous analysis of DiBP and MiBP in rat biological samples. • UPLC-ESI-MS/MS development and validation for DiBP and MiBP in rat biological samples. • Well applied to in vivo toxicokinetic and tissue distribution of DiBP and MiBP. • Rapid in vivo metabolism of DiBP and considerable tissue distribution of MiBP. • Useful for developing PBPK model for DiBP and its metabolite in future exposure study. [ABSTRACT FROM AUTHOR]

Methotrexate, which is widely used in the treatment of cancer and immune-related diseases, has limitations in use because of its low bioavailability, short half-life, and tissue toxicity. Thus, in this study, a nano-sized water-in-oil-in-water (W/O/W) double emulsion containing methotrexate was prepared to enhance its lymphatic delivery and bioavailability. Based on the results from solubility testing and a pseudo-ternary diagram study, olive oil as the oil, Labrasol as a surfactant, and ethanol as a co-surfactant, were selected as the optimal components for the nanoemulsion. The prepared nanoemulsion was evaluated for size, zeta potential, encapsulation efficiency, pH, morphology, and in vitro release profiles. Furthermore, pharmacokinetics and lymphatic targeting efficiency were assessed after oral and intravenous administration of methotrexate-loaded nanoemulsion to rats. Mean droplet size, zeta potential, encapsulation efficiency, and pH of formulated nanoemulsion were 173.77 ± 5.76 nm, −35.63 ± 0.78 mV, 90.37 ± 0.96%, and 4.07 ± 0.03, respectively. In vitro release profile of the formulation indicated a higher dissolution and faster rate of methotrexate than that of free drug. The prepared nanoemulsion showed significant increases in maximum plasma concentration, area under the plasma concentration-time curve, half-life, oral bioavailability, and lymphatic targeting efficiency in both oral and intravenous administration. Therefore, our research proposes a methotrexate-loaded nanoemulsion as a good candidate for enhancing targeted lymphatic delivery of methotrexate. [ABSTRACT FROM AUTHOR]

Facial photographs of the subjects are often used in the diagnosis process of orthognathic surgery. The aim of this study was to determine whether convolutional neural networks (CNNs) can judge soft tissue profiles requiring orthognathic surgery using facial photographs alone. 822 subjects with dentofacial dysmorphosis and / or malocclusion were included. Facial photographs of front and right side were taken from all patients. Subjects who did not need orthognathic surgery were classified as Group I (411 subjects). Group II (411 subjects) was set up for cases requiring surgery. CNNs of VGG19 was used for machine learning. 366 of the total 410 data were correctly classified, yielding 89.3% accuracy. The values of accuracy, precision, recall, and F1 scores were 0.893, 0.912, 0.867, and 0.889, respectively. As a result of this study, it was found that CNNs can judge soft tissue profiles requiring orthognathic surgery relatively accurately with the photographs alone. [ABSTRACT FROM AUTHOR]

Topotecan is actively used in clinic, with its primary use being in treatment of various types of cancer. The approved administration routes are oral and intravenous. The purpose of this study was to investigate and identify pharmacokinetic profiles of different administration routes. We conducted pharmacokinetic studies on three different routes of administration in rats. Five rats in each group received a single dose of 4 mg/kg of topotecan hydrochloride intravenously, orally, or subcutaneously, and the concentrations of lactone and total forms of the drug in plasma, urine, and feces were quantified. Various pharmacokinetic parameters were compared statistically. Plasma concentrations of both the lactone and total forms at elimination phase following subcutaneous administration, were two times higher than was seen with oral administration and 10 times higher than with intravenous administration. Subcutaneous administration of topotecan showed pharmacokinetic profiles similar to sustained release. In addition, subcutaneous administration showed bioavailability from 88.05% (for lactone form) to 99.75% (for total form), and these values were four–five times greater than those of oral administration. The results of this non-clinical study will not only provide greater understanding of the in vivo pharmacokinetics of topotecan, but also be useful for development of additional formulations and/or administration routes. [ABSTRACT FROM AUTHOR]

The purpose of this study was to perform population pharmacokinetic (PPK) analysis of tiropramide in healthy Korean subjects, as well as to investigate the possible effects of various covariates on pharmacokinetic (PK) parameters of tiropramide. Although tiropramide is commonly used in digestive system-related diseases as an antispasmodic, PPK reporting and factors affecting PKs are not clearly reported. Thus, this study for healthy subjects is very significant because it could find new covariates in patients that had not been reported before or predict PPK for patients in the clinic by establishing PPK in healthy adults. By using Phoenix NLME, PK, demographic, and genetic data (collected to explain PK diversity of tiropramide in population) analyses were performed. As a basic model, a one-compartment with first-order absorption and lag-time was established and extended to include covariates that influenced the inter-subject variability. The total protein significantly influenced the distribution volume and systemic clearance of tiropramide, but genetic factors such as ABCB1 (1236C>T, 2677G>T/A, and 3435C>T), CYP2D6 (*1 and *10), OCT2 (808G>T), and PEPT1 (1287G>C) genes did not show any significant association with PK parameters of tiropramide. The final PPK model of tiropramide was validated, and suggested that some of the PK diversity in the population could be explained. Herein, we first describe the establishment of the PPK model of tiropramide for healthy Korean subjects, which may be useful as a dosing algorithm for the diseased population. [ABSTRACT FROM AUTHOR]

The purpose of the study was to develop two new methods, HPLC-UV and UPLC-MS/MS, for quantifying epinastine in human plasma and to compare pharmacokinetic (PK) parameters obtained using them. Even in the same sample, there may be a difference in the quantitative value of drug depending on the assay, so that minor changes in PK parameter values may affect drug dose and usage settings. Therefore, selection and establishment of analytical methods are very important in PK studies of drugs, and a comparison of PK parameters according to analytical methods will be vital. For this study of PK parameter change, we newly developed two methods, HPLC-UV and UPLC-MS/MS, which are most commonly used to quantify epinastine concentrations in human plasma. All developed methods satisfied the international guidelines and criteria for successful application to PK study of 20 mg epinastine hydrochloride tablets after oral administration to twenty-six humans. A comparison of these two methods for in vivo analysis of epinastine was performed for the first time. This comparison study confirmed that different dose and usage settings might be possible based on PK parameters calculated using other analyses. Such changes in calculated PK parameters according to analytical methods would be crucial in the clinic. [ABSTRACT FROM AUTHOR]

Background: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Objectives: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Method: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Results: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Conclusion: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Clinical trial registration: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004.Graphical abstract: Loxoprofen has been actively used clinically to relieve musculoskeletal pain and inflammatory symptoms. However, there are few reports on quantitative pharmacokinetic (PK) prediction tools and diversity analyzes for loxoprofen within populations.The aim of this study was to identify effective covariates associated with explaining inter-individual PK variability through a population pharmacokinetic (Pop-PK) modeling approach for loxoprofen, and to provide a starting point for establishing scientific dosing regimens.The bioequivalence PK results of loxoprofen performed on 52 healthy Korean men and the physiological and biochemical parameters derived from each individual were used as base data for the development of a Pop-PK model of loxoprofen. In order to simultaneously predict the PKs of the active form according to loxoprofen exposure, previously reported PK results of trans-alcohol loxoprofen, an active metabolite of loxoprofen, were used to expand the model.The Pop-PK profiles of loxoprofen were described in terms of the basic structure of a non-sequential two absorption with 2-disposition compartment, and for inter-individual PK variations, peripheral compartment volume of distribution could be correlated with body surface area (BSA), and central compartment clearance with creatinine clearance (CrCL) and albumin levels. As a result of the model simulation, the concentrations of loxoprofen and its alcoholic metabolites in plasma significantly decreased as CrCL and albumin levels increased and decreased, respectively. On the other hand, it was confirmed that the higher the BSA, the greater the distribution of loxoprofen to the periphery, and the minimum concentrations of loxoprofen and alcoholic metabolites in plasma in steady-state increased by approximately 1.78–2 times, while the fluctuation between maximum and minimum concentrations decreased. The results suggest that patients with large BSA, impaired renal function, and high serum albumin levels may have significantly higher plasma exposure to loxoprofen and trans-alcohol loxoprofen. It was also suggested that the potential side effects in the gastrointestinal system and various tissues and the level of exposure in plasma due to long-term application of loxoprofen in this patient group could be causally explained.This study provides a very useful starting point for a scientific precision medicine approach to loxoprofen by discovering effective covariates and establishing a quantitative model that can explain the diversity of loxoprofen PKs within the population.The clinical study protocol used in this study was thoroughly reviewed and approved by the Institutional Review Board of the Institute of Bioequivalence and Bridging Study, Chonnam National University, Gwangju, Republic of Korea. The bioequivalence study permit numbers are as follows: 041113; 10.15.2004. [ABSTRACT FROM AUTHOR]

Cefprozil, one of cephalosporin antibiotics, has been used extensively in clinics. However, pharmacokinetic (PK) information on cefprozil is still very limited. There have been no reports of population pharmacokinetics (PPKs). A PPK model for cefprozil will be a great advantage for clinical use. Thus, the aim of this study was to develop a PPK model for cefprozil for healthy male Koreans. Clinical PK and demographic data of healthy Korean males receiving cefprozil at a dose of 1000 mg were analyzed using Phoenix® NLME™. A one-compartment model with first-order absorption with lag-time was constructed as a base model. The model was extended to include covariates that influenced between-subject variability. Creatinine clearance significantly influenced systemic clearance of cefprozil. The final PPK model for cis-, trans-, and total cefprozil was established and validated. PPK parameter values of cis- and total cefprozil were similar to each other, but different from those of trans-isomer. Herein, we describe the establishment of accurate PPK models of cis-, trans-, and total cefprozil for healthy male Koreans for the first time. It may be useful as a dosing algorithm for the general population. These results might also contribute to the development of stereoisomeric cefprozil. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a method for simultaneous analysis of fourteen major active components in Gumiganghwal-tang tablet widely prescribed for cold related diseases using UPLC-ESI-MS/MS. Twelve of these 14 components were separated using 0.1% formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.3 mL/min equipped with a KINETEX C 18 column (2.1 × 50 mm, 1.7 μm). The remaining two components were separated using 10 mM aqueous ammonium formate containing 0.01% formic acid and acetonitrile as a mobile phase by gradient elution at a flow rate of 0.2 mL/min equipped with an Inertsil C 8 –3 column (2.1 × 100 mm, 2.0 μm). Quantitation of this analysis was performed on a triple quadrupole mass spectrometer using electrospray ionization technique operating in multiple reaction monitoring mode. Full validation of the analysis method was carried out, including its linearity, selectivity, sensitivity, precision, accuracy, recovery, and stability. Chromatograms showed high resolution, sensitivity, and selectivity without interference by impurities. Calibration curves of all 14 components ranged from 0.5 to 1000 ng/mL, displaying excellent linearity (correlation coefficients >0.99). The relative standard deviations (RSD) of intra- and inter-day were <11.75%. Recoveries were within the range 95.41–103.24% (RSD value of 1.62–9.09%). These results demonstrate that the developed method is simple, rapid, reliable, specific, accurate, and sensitive for the quantification of bioactive components of Gumiganghwal-tang. The developed method was successfully applied to the analysis of Gumiganghwal-tang tablet. The developed UPLC-ESI-MS/MS method could be useful not only for quality control, but also for effectiveness and safety evaluation of Gumiganghwal-tang tablet. • UPLC-ESI-MS/MS method for Gumiganghwal-tang was newly developed and fully validated. • Chromatograms show good resolution for 14 components in Gumiganghwal-tang sample. • Simultaneous determination of 14 major active components in Gumiganghwal-tang tablet. • Our method is expected to be a useful tool for quality control and formulation evaluation. [ABSTRACT FROM AUTHOR]

Methotrexate (MTX) is a folic acid antagonist used as an effective drug to treat various kinds of cancers. However, MTX has limited use in cancer chemotherapy due to its adverse effects such as poor bioavailability, low specificity, drug resistance, and dose-dependent side effects. To improve lymphatic delivery and reduce toxicity of MTX, MTX-loaded nanoparticles (NPs) were prepared in the present study. NPs were prepared with double emulsion solvent evaporation method using poly(lactide-co-glycolide) (PLGA). NPs were assessed for size, encapsulation efficiency, morphology, Fourier-transform infrared spectroscopy, X-ray diffraction, and thermal characterization. In vitro release profiles and cytotoxicity of these NPs were also evaluated. Prepared NPs and free MTX were administered orally or intravenously (5 mg/kg as MTX) to rats to evaluate their pharmacokinetic characteristics and lymphatic delivery effects. Mean particle size and encapsulation efficiency of NPs were 163.7 ± 10.25 nm and 93.3 ± 0.5%, respectively. Prepared NPs showed a sustained release profile of MTX in vitro and may be effective to cancer cells. Area under the blood concentration-time curve, total clearance, half-life, and lymphatic targeting efficiency were significantly different (p < 0.05) between prepared NPs and free MTX. These results demonstrate that MTX-loaded PLGA NPs are good candidates for targeted delivery of MTX to the lymphatic system. [ABSTRACT FROM AUTHOR]

This paper proposes an algorithm that improves ship detection accuracy using preprocessing and post-processing. To achieve this, high-resolution electro-optical satellite images with a wide range of shape and texture information were considered. The developed algorithms display the problem of unreliable detection of ships owing to clouds, large waves, weather influences, and shadows from large terrains. False detections in land areas with image information similar to that of ships are observed frequently. Therefore, this study involves three algorithms: global feature enhancement pre-processing (GFEP), multiclass ship detector (MSD), and false detected ship exclusion by sea land segmentation image (FDSESI). First, GFEP enhances the image contrast of high-resolution electro-optical satellite images. Second, the MSD extracts many primary ship candidates. Third, falsely detected ships in the land region are excluded using the mask image that divides the sea and land. A series of experiments was performed using the proposed method on a database of 1984 images. The database includes five ship classes. Therefore, a method focused on improving the accuracy of various ships is proposed. The results show a mean average precision (mAP) improvement from 50.55% to 63.39% compared with other deep learning-based detection algorithms. [ABSTRACT FROM AUTHOR]

This research develops a new topological optimization (TO) method to assess dynamic fatigue failure in the frequency domain for random excitation forces. Besides static failure, fatigue life (or fatigue failure) is an important design criterion for the safety of mechanical and building structures. Therefore, many assessment theories and computational approaches have been proposed, and they can be divided into two categories: time domain and frequency domain. Although both approaches have been successfully applied for engineering purposes, they are rarely considered in structural TO. To consider fatigue failure caused by stochastic mechanical loads in structural TO, this research adopts fatigue assessment approaches in the frequency domain, such as narrow band solution, the Wirsching and Light method, the Ortiz and Chen method, and Dirlik method. For TO, we perform an adjoint sensitivity analysis with those fatigue assessment methods. We consider some two-dimensional benchmark problems and show that the present design method successfully constrains fatigue. [ABSTRACT FROM AUTHOR]

Highlights: [•] Topology optimization under stress and heat conduction constraints. [•] Multi-physics problem involving linear elasticity and heat conduction. [•] Thermal expansion effect included in the optimization. [•] Optimal solution satisfying stress and heat conduction constraints. [•] Different optima obtained for different thermal conditions. [Copyright &y& Elsevier]

• Excessive cytokine storms can be controlled through Hsp90. • Be01 has anti-inflammatory effects by decreasing surface molecules and cytokines in DCs and macrophages. • Inhibiting Hsp90 via Be01 highly decreased inflammation in vivo DTH and ALI models. The surplus cytokines remaining after use in the early stages of the inflammatory response stimulate immune cells even after the response is over, causing a secondary inflammatory response and ultimately damaging the host, which is called a cytokine storm. Inhibiting heat shock protein 90 (Hsp90), which has recently been shown to play an important role in regulating inflammation in various cell types, may help control excessive inflammatory responses and cytokine storms. We discovered an anti-inflammatory compound by measuring the inhibitory effect of CD86 expression on spleen DCs (sDCs) using the chemical compounds library of Hsp90 inhibitors. Subsequently, to select the hit compound, the production of cytokines and expression of surface molecules were measured on the bone marrow-derived DCs (BMDCs) and peritoneal macrophages. Then, we analyzed the response of antigen-specific Th1 cells. Finally, we confirmed the effect of the compound using acute lung injury (ALI) and delayed-type hypersensitivity (DTH) models. We identified Be01 as the hit compound, which reduced CD86 expression the most in sDCs. Treatment with Be01 decreased the production of pro-inflammatory cytokines (IL-6, TNF-α, and IL-1β) in BMDC and peritoneal macrophages stimulated by LPS. Under the DTH model, Be01 treatment reduced ear swelling and pro-inflammatory cytokines in the spleen. Similarly, Be01 treatment in the ALI model decreased neutrophil infiltration and lower levels of secreted cytokines (IL-6, TNF-α). Reduction of CD80 and CD86 expression on DCs by Be01 indicates reduced secondary inflammatory response by Th1 cells, and reduced release of pro-inflammatory cytokines by peritoneal macrophages may initially control the cytokine storm. [ABSTRACT FROM AUTHOR]

This paper proposes a convolutional neural network (CNN)-based deep learning model for predicting the difficulty of extracting a mandibular third molar using a panoramic radiographic image. The applied dataset includes a total of 1053 mandibular third molars from 600 preoperative panoramic radiographic images. The extraction difficulty was evaluated based on the consensus of three human observers using the Pederson difficulty score (PDS). The classification model used a ResNet-34 pretrained on the ImageNet dataset. The correlation between the PDS values determined by the proposed model and those measured by the experts was calculated. The prediction accuracies for C1 (depth), C2 (ramal relationship), and C3 (angulation) were 78.91%, 82.03%, and 90.23%, respectively. The results confirm that the proposed CNN-based deep learning model could be used to predict the difficulty of extracting a mandibular third molar using a panoramic radiographic image. [ABSTRACT FROM AUTHOR]

The purpose of this study was to determine whether convolutional neural networks (CNNs) can predict paresthesia of the inferior alveolar nerve using panoramic radiographic images before extraction of the mandibular third molar. The dataset consisted of a total of 300 preoperative panoramic radiographic images of patients who had planned mandibular third molar extraction. A total of 100 images taken of patients who had paresthesia after tooth extraction were classified as Group 1, and 200 images taken of patients without paresthesia were classified as Group 2. The dataset was randomly divided into a training and validation set (n = 150 [50%]), and a test set (n = 150 [50%]). CNNs of SSD300 and ResNet-18 were used for deep learning. The average accuracy, sensitivity, specificity, and area under the curve were 0.827, 0.84, 0.82, and 0.917, respectively. This study revealed that CNNs can assist in the prediction of paresthesia of the inferior alveolar nerve after third molar extraction using panoramic radiographic images. [ABSTRACT FROM AUTHOR]