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Objectives: Although previous studies suggest that dietary texture-driven masticatory activity is correlated with stress tolerance, the underlying mechanisms, including neurotransmitter dynamics, remain unclear. This study investigated the effects of dietary texture-driven masticatory activity on stress tolerance in mice., Methods: Behavioral responses to stress were assessed using the repeated social defeat stress (R-SDS) and social interaction test (SIT) model. Neurotransmitter levels in stress-related brain regions were analyzed in mice fed a solid diet (promoting masticatory activity) or a powdered diet (decreasing masticatory activity)., Results: Mice fed the powdered diet exhibited reduced stress tolerance compared with those fed the solid diet. Following the R-SDS, the powdered diet group displayed elevated gamma-aminobutyric acid (GABA) and norepinephrine levels in the prefrontal cortex. Before stress treatment, glutamic acid levels increased and those of choline decreased in the amygdala, whereas dopamine levels decreased in the powdered diet group after the R-SDS. In the locus coeruleus, mice on the powdered diet showed decreased glutamic acid and adenosine levels, alongside increased GABA levels. Serotonin levels decreased in the powdered diet group after the R-SDS, with no changes observed after the SIT. In the ventral hippocampus, GABA levels increased in the powdered diet group but decreased after the SIT., Conclusions: This study demonstrates a correlation between masticatory activity and stress tolerance, evidenced by both behavioral and neurotransmitter changes. These findings suggest that reduced masticatory activity due to dietary texture contributes to decreased stress resilience., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests related to this study., (Copyright © 2025. Published by Elsevier B.V.)

Pizuglanstat is a novel hematopoietic prostaglandin D synthase inhibitor and investigational treatment for Duchenne muscular dystrophy. This Phase 1 mass balance study aimed to characterize the absorption, metabolism, and excretion of carbon-14 ( 14 C)-labeled pizuglanstat in healthy adults (ClinicalTrials.gov, NCT04825431). After administering a single oral dose of [ 14 C]pizuglanstat solution containing 400 mg of pizuglanstat and 1 megabecquerel of radioactivity to 6 healthy men (median age, 26 years), pizuglanstat in plasma reached a maximal concentration after a median of 0.5 hour and declined with a geometric mean half-life of 7.7 hours. Pizuglanstat and its metabolites were primarily excreted via the fecal route; on average, 66.1% of administered radioactivity was excreted in feces after 168 hours, compared with 32.2% excreted in urine. Pizuglanstat was mostly present as the unchanged parent molecule in plasma, urine, and feces, while the sulfate conjugate of hydroxyl pizuglanstat was the major metabolite in each sample type. Two adverse drug reactions of urticaria were reported in 2 participants (33.3%); both events were nonsevere and manageable with treatment, and no other clinically significant safety events were observed. Overall, this study provides important pharmacokinetic, mass balance, and safety data to support the development of pizuglanstat as a new treatment for Duchenne muscular dystrophy., (© 2025 The Author(s). Clinical Pharmacology in Drug Development published by Wiley Periodicals LLC on behalf of American College of Clinical Pharmacology.)

Aims: Bronchiectasis patients face an unmet need for treatment options that reduce inflammation. Cathepsin C inhibition is expected to achieve this by reducing the activation of neutrophil-derived serine proteases. Here, we present safety and pharmacokinetic (PK) data from a Phase I trial evaluating the novel cathepsin C inhibitor BI 1291583 in healthy Japanese male subjects., Methods: This randomized, double-blind, placebo-controlled, parallel-group study investigated BI 1291583 in healthy Japanese male subjects (jRCT2071210111) and consisted of a single-rising-dose (SRD) part and a multiple-dose (MD) part. The primary endpoint was the percentage of subjects with drug-related treatment-emergent adverse events (AEs). Secondary PK endpoints (SRD: AUC 0-∞ and C max ; MD: AUC τ,1 and C max,1 after first dose and AUC τ,ss and C max,ss after last dose), as well as further safety and PK endpoints, were also assessed., Results: Overall, 36 subjects (n = 24 for SRD part; n = 12 for MD part) entered this Phase I trial. BI 1291583 was safe and well tolerated across the doses tested. All AEs were of mild intensity, with no drug-related treatment-emergent AEs, deaths, serious AEs or AEs of special interest reported in either part of the trial. Following both SRD and MD administration, BI 1291583 was readily absorbed, and PK was supraproportional over the doses assessed., Conclusion: The results show that BI 1291583 has an appropriate benefit-risk ratio for Japanese patients, with no safety or exposure concerns at the doses studied. Japanese patients with bronchiectasis can be safely integrated into future global clinical trials of BI 1291583, with no dose adjustment required., (© 2024 The Author(s). British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)