Analysis of Prednisolone-Induced Osteoporosis Using the Japanese Adverse Drug Event Report Database.

PURPOSE: Osteoporosis is an adverse event of prednisolone. This study aimed to assess prednisolone-induced osteoporosis (PIO) profiles and patient backgrounds by analyzing data from the Japanese Adverse Drug Event Report (JADER) database. METHODS: The current study focused only on orally administered prednisolone. PIO was defined using preferred terms from the Medical Dictionary for Regulatory Activities. Reporting odds ratio (ROR) at 95% confidence interval (CI) and the time-to-onset profile of PIO were used to evaluate adverse events. RESULTS: The RORs (95% CI) of the female and male subgroups were 4.73 (4.17-5.38) and 2.49 (2.06-3.00), respectively. The analysis of time-to-onset profiles demonstrated that the median values (interquartile range: 25.0-75.0%) of PIO were 136 (74.0-294.0). The prednisolone treatment duration was significantly longer in the PIO patient group than in the non-PIO patient group. The findings suggest that patients with rheumatoid arthritis, systemic lupus erythematosus, and nephrotic syndrome receiving prednisolone have different age-related PIO profiles. CONCLUSIONS: Our results suggest that longer prednisolone treatment duration and larger cumulative dose might be risk factors of PIO. The potential risk for PIO should not be overlooked, and careful observation is recommended.

Evaluation method regarding the effect of psychotropic drugs on driving performance: A literature review.

Although automobile driving is necessary for many people, including patients with mental disorders, the influence of psychotropic drugs on driving performance remains unclear and requires scientific verification. Therefore, the objective of this study was to conduct a review of the literature in order to aid the development of a valid evaluation method regarding the influence of medication on driving performance. We conducted a literature search using two sets of terms on PubMed. One set was related to psychotropic drugs, and the other to driving tests. We excluded reviews and case studies and added literature found on other sites. A total of 121 relevant reports were found. The experiments were roughly divided into on-the-road tests (ORT) and driving simulators (DS). Although highway driving tests in ORT are most often used to evaluate driving performance, DS are becoming increasingly common because of their safety and low cost. The validity of evaluation methods for alcohol should be verified; however, we found that there were few validated tests, especially for DS. The scenarios and measurement indices of each DS were different, which makes it difficult to compare the results of DS studies directly. No evaluation indices, except for SD of lateral position, were sufficiently validated. Although highway ORT are the gold standard, DS were shown to have an increasing role in evaluating driving performance. The reliability of DS needs to be established, as does their validation with alcohol in order to accumulate more high-quality evidence.

Relationship between the Number of Pharmacists per Pharmacy and the Provision of Home Healthcare Services in Japan.

Home healthcare services provided by community pharmacists are essential for maintaining community care, especially in Japan's aging population. Personnel shortage in pharmacies is occasionally cited as the reason why pharmacies are unable to provide home healthcare services. This study examined the relationship between the number of pharmacists in each pharmacy and the provision of home healthcare services. The number of full-time and part-time pharmacists per pharmacy has a positive impact on the provision of home healthcare services. Moreover, the larger the number of pharmacists per pharmacy, the easier it is for the pharmacy to provide home healthcare services. With regard to pharmacies with one full-time pharmacist, there are more pharmacies that provide home healthcare services when the population density of municipalities where the pharmacy is located is high. However, the impact of the number of pharmacists on population density became obscure when the number of full-time pharmacists per pharmacy was three or more. Taken together, these findings indicate that the provision of home healthcare services by pharmacies is related to the number of pharmacists per pharmacy and the population density of the area. This could have implications for widening regional disparities in home healthcare services.

Identification of Drugs and Patient Profiles at Risk for Severe Skin Injuries Due to Extravasation: Analysis of a Spontaneous Reporting System.

This study aimed to identify risk factors and combinations thereof that are associated with severe skin injuries due to the extravasation of injectable drugs. A cross-sectional study using the Japanese Adverse Drug Event Report database was conducted according to the RECORD-PE checklist. Adverse event reports related to necrosis, ulcers, or erosions due to extravasation were considered "with severe skin injury," and others were considered "without severe skin injury." Approximately 255 cases "with" and 260 cases "without" severe skin injury were identified. The relationship between the incidence of severe skin injury and age, sex, drugs, and primary disease was evaluated using the χ2 test. Association rule mining was used to evaluate the correlation between each combination of factors and skin injury. Nine factors were identified as independent risk factors for severe skin injury, including age (<10 or ≥70 years), peripheral parenteral nutrition use, and mental disorders. The association rule mining results suggested that a combination of specific patient backgrounds and drug use was associated with the incidence of necrosis or ulcers. The findings of this study reiterate that nurses might consider closely observing patients with the risk factors identified in this study for the prevention and early detection of extravasation-related skin injuries.

Survey of community and hospital pharmacist involvement in outpatient chemotherapy using Japanese health information data.

In this study, information on injectable anticancer drug use and additional fee for enhanced collaboration (AEC) and additional fee for specific drug management guidance 2 (ASD2) claims from the NDB Open Data Japan (NODJ) dataset and the number of patients with cancer according to sex and age from the National Cancer Registry (NCR) dataset were integrated and evaluated to determine the current status and challenges in pharmacist interventions for patients receiving cancer treatment. The NODJ data, including receipt data billed from 2020 to 2021, were obtained from the Ministry of Health, Labour and Welfare website. The use of injectable anticancer drugs decreased relative to the number of cancer patients aged ≥ 75 years compared to those aged < 75 years. Regarding injectable anticancer drug use, the number of AEC claims was similar between men and women, but the number of ASD2 claims was lower in men than in women. The number of times community pharmacists claimed their ASD2 was approximately 5% of the number of times hospital pharmacists claimed their AEC. This study revealed that several patients did not receive sufficient guidance from community pharmacists compared to hospital pharmacists, suggesting a potential insufficiency in the collaboration between the two groups.

Analysis of drug-induced interstitial lung disease caused by herbal medicine using the Japanese Adverse Drug Event Report database.

BACKGROUND: Drug-induced interstitial lung disease (DIILD) is a severe adverse event leading to morbidity and mortality. This study evaluated the adverse event indicators of DIILD and time-to-onset profiles following the daily intake of herbal drugs (Scutellariae radix ["ogon" in Japanese], Bupleuri radix ["saiko" in Japanese], and Pinelliae tuber ["hange" in Japanese]) using the Japanese Adverse Drug Event Report database. DIILD was defined in accordance with the Medical Dictionary for Regulatory Activities. METHODS: The Japanese Adverse Drug Event Report database contained 830,079 reports published between April 2004 and April 2023. The association between herbal medicines and DILLD was evaluated using the pharmacovigilance index as the reporting odds ratio (ROR), logistic regression models, propensity score-matching techniques, and Weibull shape parameters. RESULTS: The adjusted RORs using multivariate logistic regression models for Scutellariae radix (daily intake), Pinelliae tuber (daily intake), sex (male), age (≥ 60 years), Scutellariae radix (daily intake)*age (≥ 60 years), and Scutellariae radix (daily intake)* Pinelliae tuber (daily intake) were 1.47 (1.36 - 1.59), 1.05 (1.01 - 1.10), 1.45 (1.34 - 1.57), 1.92 (1.74 - 2.11), 3.35 (3.12 - 3.60), and 1.49 (1.46 - 1.53), respectively. DIILD onset profiles were evaluated using the Weibull shape parameter. A logistic plot of daily intake and onset of DIILD was drawn. ROR signals were detected in 32 of 54 herbal medicines, including Scutellariae radix, Bupleuri radix, and Pinelliae tuber. The median duration (days) (interquartile range) to DIILD onset was 36.0 (27.0-63.0) for Saikokaryukotsuboreito, 35.0 (21.0-55.0) for Saireito, and 31.0 (13.5-67.5) for Shosaikoto. The Weibull shape parameter beta (95% confidence interval) values for Saikokaryukotsuboreito, Saireito, and Shosaikoto were 1.36 (1.08-1.67), 1.36 (1.20-1.52), and 1.31 (0.98-1.68), respectively. CONCLUSIONS: DIILD demonstrated a dose-dependent to crude drugs. Clinicians should strive for the early detection of DIILD and avoid the inadvertent administration of herbal medicines.

Ondansetron-Induced Anaphylactic Shock: An In-Depth Analysis of a Rare Adverse Event.

Ondansetron, a drug predominantly employed in most general anesthesia cases, is critical for mitigating postoperative nausea and vomiting prompted by anesthetics. Although infrequent side effects such as serotonin syndrome are recognized, the drug is generally acknowledged for its safety. Nonetheless, some reports showed cases of anaphylactic shock associated with ondansetron. In this context, we have meticulously analyzed an anaphylactic case triggered by ondansetron that we encountered. Our deep-dive investigation suggests that the reaction might not be a traditional type I allergic reaction, typically associated with the drug. Instead, we present the possibility that the response could be mediated through Mas-related G protein-coupled receptor X2 (MRGPRX2), a divergent pathway leading to comparatively milder symptoms of anaphylaxis. In addition to the crucial role of adrenaline in unstable hemodynamics, our case highlights the effective use of antihistamines in rapidly managing such reactions. This finding suggests a need to further examine the safety profiles of common drugs like ondansetron and the potential involvement of MRGPRX2 in drug-induced hypersensitivity reactions.

Study of Factors to Increase the Usage Rate of Generic Drugs in Platelet Aggregation Inhibitors.

To reduce pharmacy-related medical expenses, it is necessary to reduce drug costs. One way to achieve this is by increasing the usage rate of generic drugs. The purpose of this study was to identify platelet aggregation inhibitors (PAIs) that contribute to high drug costs and are sold as brand-name drugs in order to increase the usage rate of generic drugs, and to analyze the factors that affect the usage rate of generic drug. We conducted a cross-sectional study based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan (NODJ) of the Ministry of Health, Labor and Welfare and datasets containing related medical information from official statistical surveys such as the Basic Survey on Wage Structure. Monthly personal income in each prefecture were negatively correlated with outpatient out-of-hospital and outpatient in-hospital prescriptions of the PAIs clopidogrel (75 mg), cilostazol (50 mg), cilostazol (100 mg), and ticlopidine (100 mg), but not between monthly personal income and outpatient out-of-hospital prescription of ticlopidine (100 mg). For outpatient out-of-hospital prescriptions and outpatient in-hospital prescriptions, negative correlation was generally observed between the usage rate of generic drug and monthly personal income, except for ticlopidine (100 mg), which has the lowest price among the brand-name drugs. The usage rate of generic PAIs is negatively correlated with monthly personal income. Promoting the use of generic drugs among high-income earners might be necessary to further increase the usage rate of generic drug.

Promoting generic drug usage in Japan: correlation between generic drug usage and monthly personal income.

BACKGROUND: To reduce pharmacy-related medical expenses, it is necessary to cut drug costs, potentially by increasing generic drug usage. This study analyzes the correlation between generic drug usage and monthly personal income by examining prescriptions for individual drugs. METHODS: We conducted a cross-sectional study based on the data set from the National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan and the Basic Survey on Wage Structure. We calculated the correlation coefficient between the usage rate of generic drugs in each prefecture of Japan and monthly personal incomes. We then analyzed the correlation coefficients based on the therapeutic categories of medicinal drugs; the contingency table was visualized as a mosaic plot. To compare the proportions between multiple categories, the chi-squared test was applied as a statistical significance test that was used in the analysis of n × m contingency tables. We worked with the null hypothesis that there were no differences between classes in the population. RESULTS: Regarding the correlation coefficient between the usage rate of generic drugs and monthly personal incomes, the proportion of negative correlation coefficients for outpatient out-of-hospital and outpatient in-hospital prescriptions was over 70%, while that for inpatient prescriptions was 46.9%. The proportion of medicinal drugs exhibiting a negative correlation between the rates of generic drug usage and monthly personal incomes for outpatient out-of-hospital prescriptions and outpatient in-hospital prescriptions was higher than that of inpatient prescriptions. The proportion of statistically correlated medicinal drugs among inpatient prescriptions was lower than that among outpatient out-of-hospital and outpatient in-hospital prescriptions. The proportions of significant negative correlations for outpatient out-of-hospital, outpatient in-hospital, and inpatient prescriptions were 30.6%, 22.7%, and 3.5%, respectively. It was also observed that the rate of generic prescription usage for outpatient out-of-hospital and in-hospital prescriptions increased as monthly personal incomes decreased. In outpatients, the therapeutic categories with strong negative correlations were vasodilators and hyperlipidemia drugs. CONCLUSIONS: Our results may help to increase the usage rate of generic drugs in different prefectures by providing useful information for promoting them throughout Japan.

Profiles and Outcomes of Skin Injuries Caused by Injectable Drug Extravasation: An Analysis of the Japanese Adverse Drug Event Report Database.

Extravasation occurs when injectable drugs leak out of the blood vessels, damaging the surrounding tissues and causing a variety of skin injuries. This study aimed to comprehensively analyze extravasation risk, skin injury profiles, and outcomes for suspect drugs from the Japanese Adverse Drug Event Report (JADER) database. Adverse events were defined according to the Medical Dictionary for Regulatory Activities/Japanese version; the term extravasation (Standardized MedDRA Query Code: 20000136) was used in this analysis. The names of adverse events were entered as unified preferred terms and redefined to evaluate skin injury profiles. In addition, skin injury outcomes were divided into 2 broad categories: "improvement" and "no improvement." Reporting odds ratios were used to detect signals for adverse events. A total of 656 cases of extravasation-related adverse events were reported between April 2004 and January 2022. Signals for extravasation-related adverse events were detected from 11 drugs. Then, their respective skin injury profiles and outcomes were determined. These results suggest a relationship between adverse events associated with extravasation and 11 drugs and identify the characteristics of each skin injury and their outcomes. These findings will contribute to improving the quality of infusion management in clinical practice.

Double-stranded oligonucleotides containing 5-aminomethyl-2'-deoxyuridine form thermostable anti-parallel triplexes with single-stranded DNA or RNA.

This Letter describes the synthesis and properties of double-stranded antisense oligonucleotides connected with a pentaerythritol linker. We found that double-stranded antisense oligonucleotides with aminomethyl residues have high affinity for single-stranded DNA or RNA in buffer solutions with and without MgCl(2). Thus, these oligonucleotides would be useful as antisense oligonucleotides for targeting single-stranded RNA through triplex formation.

Residual effects of zopiclone on driving performance using a standardized driving simulator among healthy volunteers.

RATIONALE: The effects of hypnotics on automobile driving have been attracting increasing attention. However, few driving simulators (DSs) have been confirmed to have acceptable reliability and validity for assessing the next-day residual effects of zopiclone as a positive control on driving performance. OBJECTIVE: To investigate whether a new DS could permit detection of the next-day residual effects of zopiclone on driving performance. METHODS: In this double-blind, randomized, placebo-controlled crossover trial, 28 healthy males received zopiclone 7.5 mg at bedtime on days 1 and 8 and placebo on the other days over a period of 16 days. The participants took part in three driving tasks-road-tracking, car-following, and harsh-braking-using a DS on days 2 and 9 at 9-h post-dosing. Scores on the Karolinska Sleepiness Scale and Profile of Mood States-Second Edition were then assessed, as was the serum concentration of zopiclone. RESULTS: The estimated differences in the standard deviation of lateral position (cm) in the road-tracking task between the zopiclone and placebo groups on days 2 and 9 were 3.75 cm (90% confidence interval (CI): 1.71-5.79) and 4.07 cm (90% CI: 2.02-6.11), respectively. The estimated differences in the distance coefficient of variation in the car-following task and in the brake reaction time in the harsh-braking task between the zopiclone and placebo groups on day 2 were 4.31 (90% CI: 1.94-6.69) and 24.6 ms (90% CI: 12.7-36.4), respectively. CONCLUSIONS: The DS used in this study has sufficient sensitivity to detect the next-day residual effects of zopiclone on driving performance.

Analysis of drug-induced hand-foot syndrome using a spontaneous reporting system database.

Purpose: The aim of our study was to assess the clinical features of hand-foot syndrome (HFS) associated with certain systemic chemotherapeutic drugs in a real-world setting using the Japanese Adverse Drug Event Report (JADER) database. Methods: HFS was defined using the preferred terms from the Medical Dictionary for Regulatory Activities. We used several indices, such as the reporting odds ratios (RORs) at 95% confidence interval (CI), the time-to-onset profile of HFS, and cluster analysis. Results: Of 646,779 reports (submission period: April 2004 to September 2020), 1814 reported HFS events. The RORs (95% CI) for axitinib, capecitabine, lapatinib, regorafenib, sorafenib, and sunitinib were 14.9 (11.1-20.1), 54.6 (49.2-60.6), 130.4 (110.7-153.6), 63.3 (55.2-72.6), 29.0 (25.8-32.7), and 13.9 (11.7-16.5), respectively. The analysis of time-to-onset profiles revealed that the median values (interquartile range: 25.0-75.0%) of drug-induced HFS caused by capecitabine, cisplatin, docetaxel, everolimus, regorafenib, sorafenib, and trastuzumab were 21.0 (13.0-42.0), 15.0 (10.0-82.0), 6.0 (3.0-25.0), 86.5 (67.0-90.5), 9.0 (6.0-14.0), 9.0 (6.0-14.0), and 70.0 (15.0-189.0) days, respectively. The number of clusters was set to 4. Among these, one cluster, which included capecitabine, regorafenib, and lapatinib, exhibited a higher reporting ratio and ROR of drug-induced HFS than other drugs. Conclusions: The RORs and results of time-to-onset analysis obtained in this study indicated the potential risk of HFS associated with chemotherapeutic drugs. Our results suggest that health care professionals must be aware of the potential onset of drug-induced HFS with docetaxel, regorafenib, and sorafenib for at least 4 weeks; therefore, careful observation is recommended. Plain Language Summary: Elucidation of the relationship between cancer drugs and risk of hand-foot syndrome: Purpose: Hand-foot syndrome (HFS) is an adverse effect of some cancer drugs, which is characterized by symptoms such as redness, swelling, blistering, and pain in the area of palms and soles. HFS reduces the quality of life of patients and can sometimes interfere with anticancer treatment plans. It is important to understand the clinical manifestations of HFS and gain knowledge that will allow for early intervention by clinicians.Methods: In this study, we used a large-scale side effect database of real-world cases for a comprehensive investigation of anticancer-drug-induced HFS. The database contained 646,779 adverse event reports from April 2004 to September 2020; among which, we identified 1814 HFS events. Using these data, we could obtain information on the relationship between 19 types of anticancer drugs and HFS, and the onset time of HFS and HFS prognosis related to each anticancer drug. Results: Our results suggest that clinicians should monitor the risk of HFS with docetaxel, regorafenib, and sorafenib for at least the first 4 weeks after drug administration. Conclusion: These findings are crucial for improving the management of the adverse effects caused by anticancer drugs.

Gentamicin-induced hearing loss: A retrospective study using the Food and Drug Administration Adverse Event Reporting System and a toxicological study using drug-gene network analysis.

The objectives of the study were to evaluate the relationship between gentamicin (GEN) and hearing loss using the Food and Drug Administration Adverse Event Reporting system (FAERS) database and elucidate the potential toxicological mechanism of GEN-induced hearing loss through a drug-gene network analysis. Using the preferred terms and standardized queries from the Medical Dictionary for Regulatory Activities, we calculated the reporting odds ratios (RORs). We extracted GEN-associated genes (seed genes) and analyzed drug-gene interactions using the ClueGO plug-in in the Cytoscape software and the DIseAse MOdule Detection (DIAMOnD) algorithm. The lower limit of the 95% confidence interval (CI) of the ROR for aminoglycosides (AG) antibacterials was over 1, and the ROR was 5.5 (5.1-6.0). We retrieved 17 seed genes related to GEN from the PharmGKB and Drug Gene Interaction databases. In total, 1018 human genes interacting with GEN were investigated using ClueGO. Through Molecular Complex Detection (MCODE) analysis, we identified 17 local gene clusters. The nodes and edges of the highest-ranked local gene cluster named "Cluster 1" were 30 and 433, respectively. According to the ClueGO analysis using the Kyoto Encyclopedia of Genes and Genomes (KEGG), Cluster 1 genes were highly enriched in "oxidative phosphorylation." According to the ClueGO analysis using ClinVar, Cluster 1 genes were highly enriched in "mitochondrial diseases," "mitochondrial complex I deficiency," "hereditary hearing loss and deafness," and "Leigh syndrome." We identified 60 GEN-associated genes using the DIAMOnD algorithm. Several GEN-associated genes in the DIAMOnD algorithm were highly enriched in "PI3K-Akt signaling pathway," "Ras signaling pathway," "focal adhesion," "MAPK signaling pathway," "regulation of actin cytoskeleton," "oxidative phosphorylation," and "ECM-receptor interaction." Our analysis demonstrated an association between several AGs and hearing loss using the FAERS database. Drug-gene network analysis demonstrated that GEN may be associated with oxidative phosphorylation-associated genes and integrin genes, which may be associated with hearing loss.

Validity and reliability of a driving simulator for evaluating the influence of medicinal drugs on driving performance.

RATIONALE: Although driving simulators (DS) are receiving increasing attention due to concern over traffic accidents under the influences of drugs, few DS are recognized for their reliability and validity. Therefore, the development of an evaluation system using DS for driving performance is urgently needed. OBJECTIVES: To investigate whether the standard deviation of lateral position (SDLP) increases with blood alcohol concentration (BAC) using a DS with reliability and calculate the SDLP threshold from the difference between BAC levels of 0 and 0.05%. METHODS: Twenty healthy Japanese men performed the DS tasks up to 60 min in Study 1 and DS tasks twice at 1-week intervals in Study 2. Twenty-six healthy men conducted the same DS tasks under BAC level (0, 0.025, 0.05, and 0.09%) in double-blind, randomized, crossover trial in Study 3. The primary outcome was SDLP in a road-tracking test. The test-retest reliability of DS data was assessed, and the estimated difference in SDLP between BAC levels of 0 and 0.05% was calculated using a linear regression model. RESULTS: The cumulative SDLP values at 5-min intervals were stable, and the intraclass correlation coefficient for its values was 0.93. SDLP increased with BAC in a concentration-dependent manner. The predicted ΔSDLP value for the difference between BAC levels of 0 and 0.05% was 9.23 cm. No participants dropped out because of simulator sickness. CONCLUSIONS: The new DS used in these studies has reliability, validity, and tolerability and is considered suitable for evaluating the influence of drugs on driving performance.

Development of Liquid-Chromatography Tandem-Mass-Spectrometry Method for Determining Environmental Contamination by Powdered Medicinal Drugs in Pharmacies.

The environment and personnel are both exposed to powdered pharmaceuticals inside pharmacies. This makes developing new methods for rapidly determining such contaminants an important objective. In this study, we developed a liquid-chromatography tandem-mass-spectrometry (LC-MS/MS) method for the simultaneous qualitative and quantitative determination of powdered medicinal drugs, such as famotidine, risperidone, lansoprazole, olanzapine, haloperidol, clarithromycin, promethazine, levomepromazine, and chlorpromazine. The method involves the use of acetaminophen as the internal standard, an LC-MS/MS method with a core-shell column, and a 10 mM ammonium formate/acetonitrile gradient mobile phase. The analytes were separated within 14 min, and MS with an electrospray ionization source in positive-ion mode was used. The limits of detection for the 9 drugs were .1-8.4 ng/mL. Linear calibration curves in the 10-50 000 ng/mL range were constructed, and inter-day accuracies of 92.6-113.8% were determined for the 9 drugs. The coefficients of variation were less than 14.6%. These data suggest that the proposed method is applicable for the routine assaying of powdered-medicine contamination in pharmacies.

In utero exposure to a low concentration of diesel exhaust affects spontaneous locomotor activity and monoaminergic system in male mice.

BACKGROUND: Epidemiological studies have suggested that suspended particulate matter (SPM) causes detrimental health effects such as respiratory and cardiovascular diseases, and that diesel exhaust particles from automobiles is a major contributor to SPM. It has been reported that neonatal and adult exposure to diesel exhaust damages the central nervous system (CNS) and induces behavioral alteration. Recently, we have focused on the effects of prenatal exposure to diesel exhaust on the CNS. In this study, we examined the effects of prenatal exposure to low concentration of diesel exhaust on behaviour and the monoaminergic neuron system. Spontaneous locomotor activity (SLA) and monoamine levels in the CNS were assessed. METHODS: Mice were exposed prenatally to a low concentration of diesel exhaust (171 microg DEP/m(3)) for 8 hours/day on gestational days 2-16. SLA was assessed for 3 days in 4-week-old mice by analysis of the release of temperature-associated infrared rays. At 5 weeks of age, the mice were sacrificed and the brains were used for analysis by high-performance liquid chromatography (HPLC). RESULTS AND DISCUSSION: Mice exposed to a low concentration of diesel exhaust showed decreased SLA in the first 60 minutes of exposure. Over the entire test period, the mice exposed prenatally to diesel exhaust showed decreased daily SLA compared to that in control mice, and the SLA in each 3 hour period was decreased when the lights were turned on. Neurotransmitter levels, including dopamine and noradrenaline, were increased in the prefrontal cortex (PFC) in the exposure group compared to the control group. The metabolites of dopamine and noradrenaline also increased in the PFC. Neurotransmitter turnover, an index of neuronal activity, of dopamine and noradrenaline was decreased in various regions of the CNS, including the striatum, in the exposure group. The serum corticosterone level was not different between groups. The data suggest that decreased SLA in mice exposed prenatally to diesel exhaust is due to facilitated release of dopamine in the PFC. CONCLUSIONS: These results indicate that exposure of mice in utero to a low concentration of diesel exhaust decreases SLA and alters the neurochemical monoamine metabolism of several regions of the brain.

Development and validation of a driving simulator for evaluating the residual effects of drugs on driving performance - sensitivity analysis using zopiclone as a positive control: Study Protocol Clinical Trial (SPIRIT Compliant).

INTRODUCTION: Drugs acting on the central nervous system (CNS), especially hypnotics, can impair driving. The US Food and Drug Administration started requiring pharmaceutical companies to evaluate the residual influence of CNS agents on driving performance to review their recommended doses. Although it is important for physicians to discuss automobile driving while on medication with patients to promote traffic safety, the package inserts of most CNS agents in Japan uniformly prohibit patients from driving. Although more evidence-based information regarding the effects of drugs on driving performance is needed, the current evaluation methods for driving performance abroad cannot be applied directly to Japanese drivers because of differences in traffic environments, laws, and constitutions. Therefore, we plan to establish a new driving simulator (DS) that would enable the next-day residual effects of drugs on driving performance to be examined. METHODS: In this double-blind, randomized, placebo-controlled, crossover trial, we plan to recruit 26 healthy Japanese males aged 21 to 64 years through advertisements. During the test periods, which will take place twice every other week, the participants will undergo a DS evaluation in the hospital for 2 days/1 night after the first and last doses of the study drug following 8 days of administration. The participants in the study drug group will take zopiclone 7.5 mg at bedtime on the first and eighth days in the hospital, and placebo on the other days. The DS evaluation consists of road tracking, car following, and harsh braking tests. The primary outcome is the standard deviation of lateral position (SDLP), which is a gold standard evaluation item, in the 60-min road-tracking test. The exploratory outcomes are other evaluation items in the DS tests, in the Karolinska Sleepiness Scale sleep questionnaire, and the Profile of Mood States Second Edition rating scale. The estimated difference in the SDLP between the zopiclone and placebo groups will then be calculated. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov NCT04108351, on September 30, 2019. Ethics approval was obtained from the Ethics Committee at Hakata Clinic and the Nagoya University Medical School Hospital Bioethics Review Committee.

Protocol for the development and validation of a driving simulator for evaluating the influence of drugs on driving performance.

INTRODUCTION: Although automobile driving is often necessary in daily life, most package inserts for psychotropic drugs in Japan prohibit patients from driving under the influence of medication. This may be partially because no system to evaluate the influence of drugs on driving performance has been established. Standardized evaluation methods have been established in the Netherlands and the United States, but these cannot be implemented in Japan because of differences in road situations, traffic laws, and ethnicities. Therefore, to establish a method to evaluate the influence of drugs on driving performance in Japan, we planned a validation study using alcohol and a driving simulator (DS) and set a clinically meaningful threshold involving the standard deviation of lateral position (SDLP), which is a criterion standard evaluation item. METHODS: This study was designed as a double-blind, placebo-controlled, randomized, 4-way, fourth-order crossover trial (Williams design). Twenty-four healthy Japanese men aged 21 to 64 years will be recruited through advertisements. The participants will be required to drive daily for over 3 years and to carry the active-type aldehyde dehydrogenase (ALDH) gene polymorphism (ALDH 2*1/*1). Participants will be randomly assigned to 4 groups based on blood alcohol concentration (BAC): 0% (placebo), 0.025%, 0.05%, and 0.09%. The amount of alcohol intake will be calculated based on Widmark formula using a beverage that is a mixture of 40% vodka and orange juice. After a practice period, each examination period will be set with 6-day intervals. The primary outcome is SDLP in a 60-minute road-tracking test using the DS. The secondary outcomes are other evaluation items in the DS tasks and DS sickness and sleepiness according to questionnaire responses. The estimated difference in SDLP between BAC levels of 0.05% and 0% will be calculated using a linear model. ETHICS AND DISSEMINATION: Ethics approval was obtained from the Ethics Committee at Hakata Clinic and the Nagoya University Medical School Hospital Bioethics Review Committee. The trial results will be disseminated through peer-reviewed publications and international conferences. TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov NCT 03572985 on June 28, 2018.

Exposure to diesel exhaust during fetal period affects behavior and neurotransmitters in male offspring mice.

Exposure to ambient particulate matter (PM) has been associated with the onset of cardiovascular and respiratory diseases. Diesel exhaust particles (DEP) are major components of ambient PM. We first reported DEP in the central nervous system of offspring utilizing maternal inhalation to diesel exhaust (DE). In addition, we found that the effects of maternal exposure to DE reduced spontaneous motor activity. However, it is still unknown whether maternal exposure to DE affects higher order behavioral function. Therefore, the aim of the present study was to examine the effects of fetal exposure to DE on motor coordination, impulsive behavior and monoaminergic systems in various brain regions. The results of the rotating rod test showed that DE-exposed mice displayed decreased time on the rota rod compared to control mice. However, no changes were detected between the two groups in the hanging test. Furthermore, the cliff avoidance test revealed that DE-exposed mice spent more time in the corner and fell off an inverted glass beaker compared to control mice. High performance liquid chromatography analysis revealed that noradrenaline turnover in the cerebellum was decreased by prenatal exposure to DE, and was significantly increased in the hypothalamus. Dopamine and serotonin levels in various brain regions were also changed by prenatal exposure to DE. Our study found that prenatal exposure to DE alters motor coordination, impulsive behavior and related monoamine levels. Therefore, the present study underscores the role of behavioral changes related to monoamine in response to maternal inhalation of DE.