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Aims: This study evaluated drug–drug interactions between the CYP3A4 inhibitor carotegrast methyl and the other CYP3A4 substrates, midazolam, atorvastatin and prednisolone. Methods: A total of 88 healthy volunteers orally received carotegrast methyl 960 mg 3 times daily for 14 days. A single oral (5 mg) or intravenous (0.017 mg kg−1) midazolam, oral (5 mg) prednisolone or oral (10 mg) atorvastatin was administered before, with and after carotegrast methyl treatment. When the 90% confidence interval (CI) for the geometric mean ratios of the pharmacokinetic (PK) parameters with coadministration with carotegrast methyl (Day 14) to those before carotegrast methyl administration was between 0.80 and 1.25, no PK interaction were deemed. Results: The Cmax and AUC0‐t of oral midazolam before administration of carotegrast methyl were 30.9 ± 9.8 ng mL−1 and 74.5 ± 21.9 ng h mL−1, respectively. The geometric mean ratio of the Cmax and AUC0‐t of midazolam on Day 14 to those on Day −1 was 1.86 (90% CI, 1.64–2.11) and 3.07 (90% CI, 2.81–3.35), which did not fall within the range of 0.80–1.25, suggesting that carotegrast methyl had a PK interaction with midazolam. Similar PK interactions were found for intravenous midazolam and atorvastatin, but not for prednisolone. The inhibitory effect of carotegrast methyl on CYP3A4‐mediated metabolism of midazolam and atorvastatin had almost disappeared by 14 days after the end of administration. Conclusion: Carotegrast methyl was classified as a moderate CYP3A4 inhibitor in humans. Carotegrast methyl might enhance the action of drugs that are metabolized by CYP3A4. [ABSTRACT FROM AUTHOR]

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&#95;view.cgi?recptno=R000057420., (©Kosuke Hayashi, Hiromitsu Imai, Ichiro Oikawa, Yugo Ishihara, Hirokazu Wakuda, Iori Miura, Shingo Uenohara, Asuka Kuwae, Megumi Kai, Ken'ichi Furuya, Naoto Uemura. Originally published in JMIR Formative Research (https://formative.jmir.org), 24.10.2024.)

We report a case comparing the measured half-life of flecainide with the half-life stated on the label. An 84-year-old woman presented with symptoms of anorexia and exertional dyspnea. She had undergone mitral and aortic valve replacements and excision of the membranous septum in the atrium for mitral and aortic stenosis and cor triatriatum. She was regularly administered 100 mg/day flecainide for paroxysmal atrial fibrillation. A previous electrocardiogram (ECG) showed a regular sinus rhythm. However, upon admission, the ECG revealed a heart rate of 94 bpm and an accelerated idioventricular rhythm originating from the left ventricle. Flecainide toxicity was suspected, leading to the discontinuation of flecainide treatment. The following day, the serum flecainide concentration was 1,348 ng/mL, exceeding the therapeutic window of 200-1,000 ng/mL. After discontinuing flecainide, the accelerated idioventricular rhythm ceased, and a regular sinus rhythm temporarily returned. We measured blood drug concentrations several times; our calculated half-life was 56.8 h, approximately five times longer than the half-life of 11.0 h stated on the package insert. To ensure safe and effective therapy with antiarrhythmic drugs, prioritizing therapeutic drug monitoring and carefully monitoring pharmacokinetics is important, particularly during the elimination phase., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Otani et al.)