Hiromitsu Imai

Background: Hangovers can impair the ability to drive a car or work in industrial settings, in addition to causing unpleasant symptoms such as headaches and fatigue. As for reducing hangover symptoms, the effect of consuming water between drinks, often referred to as a “chaser,” has been empirically recognized; however, this effect has not been verified to date. The purpose of this study was to clarify whether intermittent drinking of water during alcohol consumption affects the ethanol and acetaldehyde kinetics in the body and whether it alleviates hangover symptoms with the psychomotor function test and subjective symptoms on the following day. Methods: Thirteen healthy Japanese adult males with wild-type aldehyde dehydrogenase (ALDH)2 ( ALDH2 * 1 /* 1 ) were included in this study. The trial design was a randomized, 2×2 crossover study in which subjects drank (1) sake equivalent to 1.3 g/Kg body weight of pure alcohol (Control group) and (2) the same amount of sake and 15 mL/Kg body weight of water (Water group) intermittently, each at a constant pace over 1 hour. Before drinking, immediately after drinking, and at various times up to 15 hours after, we measured ethanol and acetaldehyde concentrations in the expired air, administered the Digit Symbol Substitution Test (DSST), and evaluated the subjective intoxication symptom score (VAS). Breath ethanol and acetaldehyde concentrations were determined by sensor gas chromatography. Differences in breath concentrations and pharmacodynamic indices between the two groups were evaluated using a linear mixed-effects model with fixed effects for the test beverages and the number of administrations, and random effects for the subjects. Results: No differences were observed between the two groups in the kinetics of exhaled ethanol and acetaldehyde. The DSST scores were similar between them. The VAS assessed subjective symptoms of facial flushing, headache, nausea, concentration, sleepiness, and mood elevation, and no differences were found between the two groups. Conclusion: The intermittent addition of drinking water during ethanol consumption did not significantly alter ethanol disposition or pharmacodynamic parameters, suggesting it did not affect hangover symptoms.

In a randomized crossover trial of 20 participants, a cadence-based smartphone app using either fixed or lottery financial incentives showed no significant difference in weekly challenge completions, daily steps, or distance, although fixed incentives may be preferable for their implementation simplicity.

Physiologically based pharmacokinetic (PBPK) modeling is a mathematical method for predicting drug pharmacokinetics based on individual physiological information, and its usefulness has been attracting attention in recent years. This study aimed to investigate and compare the extent to which PBPK models are utilized in drug package inserts in Japan, the United States, and Europe. We searched the official websites of the PMDA, FDA, and EMA to examine the number and content of drugs that mention the use of PBPK modeling as of 2024. Furthermore, we compared the consistency and detail of the descriptions between Japan, the United States, and Europe. As a result, 38 drugs in Japan listed PBPK modeling, many of which were related to drug-drug interactions. Compared with Europe, there were no complete matches and only seven partial matches, while compared with the United States, there were two complete matches and 24 partial matches. A comparison of the details of the 24 partial matches revealed a tendency for Japanese package inserts to be more detailed. PBPK model analysis has become increasingly important in recent drug development, and Japan in particular has a tendency to provide more detailed information on package inserts. This study suggests the potential for further utilization of PBPK models in the field of clinical pharmacology. Graphical Abstract

UNSTRUCTURED In a randomized crossover trial of 20 participants, a cadence-based smartphone app using fixed or lottery financial incentives showed no significant difference in weekly challenge completions, steps, or distance, although fixed incentives may be preferable for their simplicity and user preference.

Background: High levels of physical activity are key to improving health outcomes, yet many people fail to take action. Using pedometers to target steps per day and providing financial incentives is a simple and scalable approach to promoting public health. However, conventional pedometers do not account for “intensity” and “duration,” making it challenging to efficiently increase people’s moderate-to-vigorous physical activity (MVPA), which is expected to improve health outcomes. Based on these rationales, we developed a smartphone app that sets step cadence as a goal (defined as a daily challenge of walking more than 1500 steps in 15 minutes twice a day, which is a heuristic threshold for moderate physical activity) and provides financial incentive when the challenge is met. Objective: This study aimed to evaluate the feasibility of our novel app and explore whether its use can increase users’ daily MVPA. Methods: A single-arm pre-post study evaluated the feasibility and efficacy of the app. A total of 15 participants used app 1 (an app without financial incentives) for the first period (4 weeks) and then switched to app 2 (an app with financial incentives) for the second period (4 weeks). The primary outcome was the difference between the first and second periods in the number of successful challenge attempts per week. Secondary outcomes were differences between the first and second periods in daily steps and distance walked. Exploratory outcomes included the difference between the first and second periods in daily “heart points” as measured by Google Fit, a publicly available app that measures users’ daily MVPA. Results: The number of successful challenge attempts per week increased significantly compared to the first period (5.6 times per week vs 0.7 times per week; P<.001). Although not statistically significant, there was a trend toward an increase in the mean steps per day and distance walked per day (6586 steps per day vs 5950 steps per day; P=.19; and 4.69 km per day vs 3.85 km per day; P=.09, respectively). An exploratory end point examining daily MVPA by “heart points” collected from Google Fit also showed a significant increase compared to the first period (22.7 points per day vs 12.8 points per day; P=.02). Conclusions: Our app using step cadence as a goal and providing financial incentives seemed feasible and could be an effective app to increase users’ daily MVPA. Based on the results of this study, we are motivated to conduct a confirmatory study with a broader and larger number of participants. Trial Registration: UMIN 000050518; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000057420

BACKGROUND High levels of physical activity are key to improving health outcomes, yet many people fail to take action. Using pedometers to target steps per day and providing financial incentives is a simple and scalable approach to promoting public health. However, conventional pedometers do not account for “intensity” and “duration,” making it challenging to efficiently increase people’s moderate-to-vigorous physical activity (MVPA), which is expected to improve health outcomes. Based on these rationales, we developed a smartphone app that sets step cadence as a goal (defined as a daily challenge of walking more than 1500 steps in 15 minutes twice a day, which is a heuristic threshold for moderate physical activity) and provides financial incentive when the challenge is met. OBJECTIVE This study aimed to evaluate the feasibility of our novel app and explore whether its use can increase users’ daily MVPA. METHODS A single-arm pre-post study evaluated the feasibility and efficacy of the app. A total of 15 participants used app 1 (an app without financial incentives) for the first period (4 weeks) and then switched to app 2 (an app with financial incentives) for the second period (4 weeks). The primary outcome was the difference between the first and second periods in the number of successful challenge attempts per week. Secondary outcomes were differences between the first and second periods in daily steps and distance walked. Exploratory outcomes included the difference between the first and second periods in daily “heart points” as measured by Google Fit, a publicly available app that measures users’ daily MVPA. RESULTS The number of successful challenge attempts per week increased significantly compared to the first period (5.6 times per week vs 0.7 times per week; P<.001). Although not statistically significant, there was a trend toward an increase in the mean steps per day and distance walked per day (6586 steps per day vs 5950 steps per day; P=.19; and 4.69 km per day vs 3.85 km per day; P=.09, respectively). An exploratory end point examining daily MVPA by “heart points” collected from Google Fit also showed a significant increase compared to the first period (22.7 points per day vs 12.8 points per day; P=.02). CONCLUSIONS Our app using step cadence as a goal and providing financial incentives seemed feasible and could be an effective app to increase users’ daily MVPA. Based on the results of this study, we are motivated to conduct a confirmatory study with a broader and larger number of participants. CLINICALTRIAL UMIN 000050518; https://center6.umin.ac.jp/cgi-open-bin/ctr/ctr_view.cgi?recptno=R000057420

Sustained exposure to acetaldehyde, the major metabolite of ethanol, may influence psychomotor performance even after the breath ethanol level significantly drops several hours following ethanol consumption. We examined the relationship between psychomotor function and changes in exhaled ethanol and acetaldehyde concentrations after consuming a low dose (0.33 g/kg) of barley shochu, a traditional Japanese distilled alcohol beverage, at the point when the exhaled ethanol concentrations dropped below 78,000 parts per billion (0.15 mg/L), the standard threshold for driving under the influence of alcohol in Japan. We assessed how the genetic polymorphisms of rs671 G/G homozygous (*1/*1) and G/A heterozygous (*1/*2) of ALDH2 influenced the kinetics of ethanol and acetaldehyde in exhaled air and psychomotor dynamics using the Digit Symbol Substitution Test (DSST), Critical Flicker Fusion Test (CFFT), and visual analogue scale (VAS) up to 12 h after shochu or water intake. There was no significant difference in DSST and CFFT scores depending on genotype; however, the time required for the DSST to attain the level prior to drinking was longer in the ALDH2 *1/*2 group than in the *1/*1 group. In the VAS test, facial flushing and mood elevation tended to be higher in the *1/*2 group after shochu consumption. VAS scores for mood elevation and facial flushing correlated with acetaldehyde concentration in exhaled breath. These results indicate that DSST recovery tends to be slower and mood elevation higher in the ALDH2 *1/*2 group even when exposed to a low dose of alcohol.

Drug disposition after topical application to the skin has not been fully elucidated, especially after repeated application. We conducted a clinical trial to evaluate the pharmacokinetics in the stratum corneum of healthy adults after repeated application of lanoconazole cream as a model drug. We applied 25 mg of 1% lanoconazole cream onto the pre-specified areas on the participants' back once daily for 5 days. The stratum corneum was sampled twice on each study day using a standardized tape-stripping method, and the amount of lanoconazole contained in the samples was quantified using the tandem mass spectrometry method. The obtained data were used to evaluate lanoconazole pharmacokinetics in the stratum corneum. The amount of lanoconazole in the stratum corneum after once daily repeated administration reached a steady state on day 3, and it was eliminated from the stratum corneum with a half-life of approximately 11 h after discontinuing application.

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among all infants worldwide and remains a significant cause of morbidity and mortality. To address this unmet medical need, MK‐1654, a half‐life extended RSV neutralizing monoclonal antibody, is in clinical development for the prevention of RSV disease in infants. This was a phase I, randomized, placebo‐controlled, single‐site, double‐blind trial of MK‐1654 in 44 healthy Japanese adults. The safety, tolerability, pharmacokinetics, antidrug antibodies (ADAs), and serum neutralizing antibody (SNA) titers against RSV were evaluated for 1 year after a single intramuscular (i.m.) or intravenous (i.v.) dose of MK‐1654 or placebo in five groups (100 mg i.m., 300 mg i.m., 300 mg i.v., 1000 mg i.v., or placebo). MK‐1654 was generally well‐tolerated in Japanese adults. There were no serious drug‐related adverse events (AEs) reported in any MK‐1654 recipient and no discontinuations due to any AEs in the study. The half‐life of MK‐1654 ranged from 76 to 91 days across dosing groups. Estimated bioavailability was 86% for 100 mg i.m. and 77% for 300 mg i.m. One participant out of 33 (3.0%) developed detectable ADA with no apparent associated AEs. The RSV SNA titers increased in a dose‐dependent manner among participants who received MK‐1654. These data support the development of MK‐1654 for use in Japanese infants.

Although cases of research misconduct in sponsored clinical trials have been sporadically reported, no systematic reviews or national surveys on this topic have been conducted in Japan. Thus, this study aimed to: 1) systemically review publicly available information on scientific misconduct reported through sponsored clinical trials, and 2) carry out a national survey to examine incidents of scientific misconduct using the following three approaches. First, a systematic review of publicly available information on scientific misconduct using Google search, Japan Medical Abstracts Society database, and PubMed.gov; second, a survey of sponsors using an anonymous web questionnaire; and third, a national survey of clinical research coordinators (CRCs) using an anonymous web survey by snowballing sampling. The systematic review identified five cases of misconduct; however, all five cases were already well-recognized in the public domain. In the survey of sponsors, five of the 12 sponsors responded that they had reported other cases to PMDA. In the national survey of CRCs, 22 of 164 (13.4%) responders reported being aware of at least one instance of “fabrication or falsification” in the past three years. These data suggest that not all instances of misconduct in sponsored clinical trials in Japan had been reported to PMDA and that not all instances reported to PMDA had been disclosed to the public. The publicized cases represent only the “tip of the iceberg.” A centralized process for reporting instances of scientific misconduct to Japanese regulatory authorities with pertinent public disclosure may improve the quality of clinical trials.