Search

BackgroundMental health problems among workers cause enormous losses to companies in Japan. However, workers have been considered to have limited access to psychological support because of time constraints, which makes it difficult for them to engage in face-to-face psychological support interventions. ObjectiveThis study aimed to present an intervention protocol that describes a randomized controlled trial to examine whether brief guided mindfulness meditation (MM) or self-compassion meditation (SCM) provided by a smartphone app is effective for mental health and work-related outcomes among workers. MethodsThis is an open-label, 3-arm randomized controlled trial. The participants will be recruited through an open call on relevant websites with the following inclusion criteria: (1) employees who are working more than 20 hours per week, (2) between the ages of 18 and 54 years, (3) not on a leave of absence, (4) not business owners or students, and (5) not currently diagnosed with a mental disorder and have a Kessler Psychological Distress Scale-6 score below 13 points. We will include 200 participants and randomly assign them to an SCM course (n=67), an MM course (n=67), and a waitlist group (n=66). The intervention groups (SCM and MM) will be instructed to engage in daily guided self-help, self-compassion, and MMs lasting 6-12 minutes per day over 4 weeks. Primary outcomes will include psychological distress and job performance, and secondary outcomes will include somatic symptoms, cognitive flexibility, self-esteem, self-compassion, perceived stress, well-being, emotion regulation, work engagement, anger, psychological safety, and creativity. All procedures were approved by the ethics committee of the University of Tokyo (22-326). All participants will be informed of the study via the websites, and written informed consent will be collected via web-based forms. ResultsThe recruitment of participants began in December 2022, and the intervention began in January 2023. As of September 2023, a total of 375 participants have been enrolled. The intervention and data collection were completed in late October 2023. ConclusionsThis study will contribute to the development of effective self-care intervention content that will improve mental health, work performance, and related outcomes and promote mindful and self-compassionate attitudes when faced with distress. Trial RegistrationUniversity Hospital Medical Information Network Clinical Trials Registry UMIN000049466; https://tinyurl.com/23x8m8nf International Registered Report Identifier (IRRID)DERR1-10.2196/53541

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

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

Abstract Background Although the over-the-counter H1 receptor antagonist diphenhydramine is not a common drug of abuse, it was recently recognized as one of the substances causing acute poisoning in patients attempting suicide that led to admissions to our hospital emergency room. Case presentation Two patients [women aged 21 and 27 years (cases 1 and 2)] were emergently admitted after intentionally taking overdoses of 900 and 1200 mg diphenhydramine, respectively. The plasma diphenhydramine concentrations in case 1 were 977 and 425 ng/mL at 2.5 and 11.5 h after single oral overdose, and those in case 2 were 1320 and 475 ng/mL at 3 and 18 h after administration, respectively. We set up a simplified physiologically based pharmacokinetic (PBPK) model that was established using the reported pharmacokinetic data for a microdose of diphenhydramine. The two virtual plasma concentrations and the area under the curve (AUC) values extrapolated using the PBPK model were consistent with the observed overdose data. This finding implied linearity of pharmacokinetics over a wide dosage range for diphenhydramine. Conclusions The determined plasma concentrations of diphenhydramine of around 1000 ng/mL at ~ 3 h after orally administered overdoses in cases 1 and 2 may not have been high enough to cause hepatic impairment because levels of aspartate aminotransferase and alanine aminotransferase were normal; however, there was an increase in total bilirubin in case 1. Nonetheless, high virtual liver exposures of diphenhydramine were estimated by the current PBPK model. The present results based on drug monitoring data and pharmacokinetic predictions could serve as a useful guide when setting the duration of treatment in cases of diphenhydramine overdose.

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

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

The octanol/water partition coefficient, P (logP), is a hydrophobicity index and is one of the determining factors of the pharmacokinetics of chemical compounds. LogP values obtained from in silico software, open chemistry databases, and in vitro liquid chromatography retention factors may vary. Some chemicals (boscalid, etoxazole, and permethrin) have up to four-order-magnitude differences in in silico/in vitro P values. This study aimed to evaluate the effects of logP values of these three compounds, along with bisphenol A, 1,2-dibromobenzene, tetrabromobisphenol A, trazodone, and triazolam, on the input parameters and output plasma/hepatic concentration–time profiles of simple physiologically based pharmacokinetic (PBPK) models. Although the blood-to-plasma concentration ratios (~0.9–0.6) were slightly affected by variations in logP values, logarithmic plasma unbound fraction values and liver-to-plasma partition coefficients (Kp,h) were, respectively, inversely and linearly correlated with logP values (Kp,h was stable at ~6.7 for logP > 4). LogP was among the input parameters for previously established machine learning systems; consequently, the resulting logarithmic intrinsic clearance values were correlated with logP values in the range 2–8. However, the bioavailability, absorption rate constants, and volumes of distribution were not affected. PBPK-modeled plasma and hepatic maximum concentrations and areas under the concentration–time curves after virtual oral doses were mostly within ~0.5- to ~2-fold ranges, except for substances with low in vitro logP values, e.g., etoxazole and permethrin. These results suggest that in silico logP values are generally suitable for pharmacokinetic modeling; nevertheless, caution is needed for compounds with low in vitro logP values of ~2. [ABSTRACT FROM AUTHOR]

The octanol/water partition coefficient P (logP) is a hydrophobicity index and is one of the determining factors for the pharmacokinetics of orally administered substances because it influences membrane permeability. To illustrate the wide-ranging variety of compounds in the chemical space, a two-dimensional data plot consisting of 25 blocks was previously proposed based on a substance’s in silico chemical descriptors. The logP values of approximately 200 diverse chemicals (test plus reference compounds covering all 25 blocks of the chemical space) were estimated experimentally using retention times in reverse-phase liquid chromatography; these values were compared with those of authentic reference compounds with established logP values (available for 17 of 60 reference substances in the Organization for Economic Co-operation and Development Test Guideline 117). The logP values of 140 of 165 chemicals successfully estimated using four different mobile phase conditions (pH 2, 4, 7, and 10 for molecular forms) correlated significantly with those calculated using the in silico packages ChemDraw and ACD/Percepta (r > 0.72). Although substances that neighbored authentic compounds in the chemical space had precisely correlated logP values estimated experimentally and in silico, some compounds that were more distant from authentic substances showed lower logP values than those estimated in silico. These results indicate that additional authentic reference materials with wider ranging chemical diversity and their logP values from reverse-phase liquid chromatography should be included in the international test guidance to promote simple and reliable estimation of octanol/water partition coefficients, which are important determinant factors for the pharmacokinetics of general chemicals. [ABSTRACT FROM AUTHOR]

Physiologically based pharmacokinetic (PBPK) modeling has the potential to estimate internal chemical exposures. Algorithms for predicting the input parameters for PBPK modeling, such as absorption rate constants (ka), were previously reported for 323 chemicals in rats. In this study, a currently updated system for estimating the fraction absorbed x intestinal availability of compounds, along with a modified estimation system that generates ka values, is reported, based on the previously analyzed 323 primary compounds, 10 secondary compounds, and 39 additional substances. The in silico estimation of input parameters for PBPK models (i.e., fraction absorbed x intestinal availability and ka) was adapted for an updated panel of 372 chemicals using machine learning algorithms based on between 16 and 18 in silico- calculated chemical properties. Simplified human PBPK models were then used to calculate virtual areas under the plasma concentration-time curve (AUC) based on two sets of input parameters, i.e., traditionally derived values from in vivo data and those calculated in silico using the current updated machine learning systems. The AUC data sets were well correlated; the current correlation coefficient increased from 0.61 to 0.82 (p < 0.01, n = 372). Therefore, the above-described computational methods constitute a new alternative approach that could contribute to chemical safety evaluations. [ABSTRACT FROM AUTHOR]