Asahikawa Medical University (旭川医科大学, Asahikawa Ika Daigaku), Kyokui (旭医), or AMU, is a national university and medical school in Asahikawa, Hokkaido, Japan. Established in 1973, the university has one faculty, Faculty of Medicine, consisting of Department of Medicine and Department of Nursing. The affiliated Asahikawa Medical University Hospital was established in 1976.
Diphenidine (DPD) is a dissociative novel psychoactive substance (NPS) structurally related to phencyclidine and ketamine. Although DPD is legally regulated in Japan and several other countries, analogues sharing the core scaffold are not comprehensively regulated. Therefore, it is possible that analogues with minor scaffold modifications may continue to emerge. This study examined the effects of methoxy or hydroxy substitution at the 4-position of DPD on its blood–brain barrier (BBB) penetration and dopamine release in the synaptic cleft. Using in vivo brain microdialysis in freely moving unanesthetized rats, DPD, 4-methoxydiphenidine (4MeO-DPD), and 4-hydroxydiphenidine (4OH-DPD) (20 mg/kg, i.p. each) were administered, and concentrations in the nucleus accumbens and plasma were quantified by liquid chromatography–mass spectrometry. Extracellular dopamine levels were determined by high-performance liquid chromatography with electrochemical detection. To investigate carrier-mediated BBB transport, verapamil (P-glycoprotein, P-gp, inhibitor) or diphenhydramine (organic cation transporter, OCT, inhibitor) was administered 1 h prior to each compound. DPD and its analogues showed distinct BBB penetration profiles, among which 4OH-DPD showed the highest brain concentrations and dopamine release. Verapamil but not diphenhydramine pretreatment significantly increased brain extracellular concentrations and prolonged elimination half-lives of all compounds, particularly 4MeO-DPD. P-gp inhibition elevated brain-to-plasma concentration ratios, indicating restricted BBB penetration by P-gp. The dopamine concentration profile was consistent with those observed for DPD and its analogues. This study demonstrates that 4MeO-DPD and 4OH-DPD strongly elicit dopamine release compared with DPD. These findings show that P-gp regulates BBB penetration, offering important insights for the toxicological risk assessment for newly emerging NPS.
OBJECTIVES:Enfortumab vedotin (EV) is the standard treatment for locally advanced or metastatic urothelial carcinoma (la/mUC), though skin toxicities are problematic. We evaluated whether prophylactic corticosteroid premedication is associated with reduced toxicity and survival outcomes. METHODS:We retrospectively analyzed 157 patients with la/mUC receiving EV monotherapy, stratified by prophylactic intravenous dexamethasone (6.6 mg) premedication (pre-EV steroid, n = 20) or not (no pre-EV steroid, n = 137). Endpoints included the incidence of EV-related adverse events (AEs), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Inverse probability of treatment weighting (IPTW) was used to adjust for baseline imbalances. RESULTS:Corticosteroid premedication was associated with a significantly lower incidence of skin AEs (10% vs. 62.7%, p < 0.001) and a reduced number of cumulative AEs (median 1 vs. 2, p = 0.018). The ORR were comparable. However, patients with steroid premedication showed inferior OS compared to those without (median OS 10.3 vs. 17.4 months, p = 0.008), while PFS showed no significant difference. Multivariable analysis confirmed corticosteroid premedication as an independent predictor of reduced skin AEs (OR 0.08, p = 0.001); however, it was associated with worse OS (HR 1.91, p = 0.048), with no significant impact on PFS. In the IPTW-adjusted analysis, corticosteroid premedication remained significantly associated with worse OS. CONCLUSIONS:Corticosteroid premedication reduces skin toxicities during EV monotherapy, but its impact on survival remains uncertain and requires validation in larger studies.
BACKGROUND:Quantifying the burden of respiratory syncytial virus (RSV) in adults is challenging compared to influenza, and data among older adults remain scarce in Japan. Country-specific evidence is essential to support RSV vaccination policy. METHODS:This prospective, multicenter study (APSG-J2) targeted hospitalized adults with community-acquired pneumonia (CAP) and other acute respiratory infections (ARI) in seven community hospitals across four catchment areas in Japan between September 2022 and August 2024. Respiratory samples were analyzed using a multiplex polymerase chain reaction (PCR) kit to detect RSV and influenza. Incidence rates of RSV- and influenza-associated hospitalizations were estimated using study data and national statistics, stratified by age and region. RESULTS:Among 3047 hospitalized patients with CAP/ARI, 1499 (49.2%) underwent multiplex PCR testing. RSV and influenza were detected in 2.8% and 3.3% of tested patients, respectively. The incidences of RSV-associated CAP/ARI hospitalizations among adults aged ≥ 65 years were 29 and 36 per 100,000 person-years in the first and second years, respectively, with higher incidences among those aged ≥ 85 years (150 and 131 per 100,000 person-years). Influenza incidence increased markedly in the second year (from 11 to 71 per 100,000 person-years for adults age ≥ 65 years), possibly reflecting post-COVID-19 transmission changes. CONCLUSIONS:In this multicenter study, we estimated the incidence of RSV- and influenza-associated hospitalizations among adults in Japan. The findings indicated that the incidence increased with age, and influenza-associated hospitalizations increased in the second year. Continued surveillance is essential to accurately assess RSV burden in the adult population.
Background:Adjuvant nivolumab has shown efficacy in randomized trials for high-risk urothelial carcinoma after radical surgery, but its real-world outcomes remain unclear. Objective:To evaluate the association between adjuvant nivolumab and oncological outcomes in real-world practice. Design setting and participants:This retrospective, multicenter study analyzed 366 patients with high-risk bladder cancer or upper tract urothelial carcinoma who underwent radical surgery between 2016 and 2025 at 18 institutions in the Japanese AGEHA database. Patients were classified into an adjuvant nivolumab group (n = 126) and a composite control group (n = 240), consisting of adjuvant chemotherapy (n = 59) or observation alone (n = 181). Outcome measurements and statistical analysis:The primary analysis compared adjuvant nivolumab with observation alone using propensity score matching (PSM). Secondary analyses included PSM comparisons between adjuvant nivolumab, adjuvant chemotherapy, and exploratory subgroup analyses. Results:In the primary PSM cohort (97 matched pairs), adjuvant nivolumab was associated with improved disease-free survival (DFS; hazard ratio [HR] = 0.56, 95% confidence interval [CI] = 0.35-0.88) and overall survival (OS; HR = 0.40, 95% CI = 0.19-0.81) compared with observation alone. In secondary analyses, DFS and OS appeared similar between adjuvant nivolumab and adjuvant chemotherapy. Site-specific analyses demonstrated consistent benefits in patients with muscle-invasive bladder cancer, whereas adequate covariate balance could not be achieved for patients with upper tract urothelial carcinoma. Conclusions:In this multicenter real-world cohort, adjuvant nivolumab was associated with improved DFS and OS compared with observation after radical surgery; however, these findings require confirmation in future studies designed to minimize residual confounding.
INTRODUCTION:Haemoglobin vesicles (HbVs) (product name, NMU-HbVs [Nara Medical University-Haemoglobin Vesicles]), which contain purified human haemoglobin encapsulated within liposomes, have been developed as a potential alternative to blood transfusions in emergency situations. A previous phase I study examined doses up to 100 mL in 11 healthy volunteers. Here, we describe the protocol for a phase Ib study, wherein we will evaluate the safety and pharmacokinetics of NMU-HbV in healthy Japanese adults. METHODS AND ANALYSIS:This single-centre, open-label, dose-escalation study will enrol 16 healthy volunteers divided into four cohorts. Planned doses are 100 mL for cohorts 1 and 2, 200 mL for cohort 3 and 400 mL for cohort 4, with infusion rates gradually increasing to a maximum of 5.0 mL/min. The primary endpoint will be safety, which will be assessed as the incidence of adverse events within 14 days and significant clinical changes within 72 hours after administration. Safety evaluations will include subjective symptoms, vital signs, electrocardiograms and laboratory test results compared with the baseline. The secondary endpoint will be pharmacokinetics, which will be assessed as changes in NMU-HbV concentration immediately after infusion until day 4 to determine the maximum blood concentration, time to reach the maximum blood concentration, area under the blood concentration-time curve and elimination half-life. This study will provide data on the safety and pharmacokinetic profiles of NMU-HbV at doses up to 400 mL. The findings are expected to support the further development of NMU-HbV as a viable alternative to emergency transfusions. ETHICS AND DISSEMINATION:The study protocol was approved by the Institutional Review Board of Nara Medical University on 10 December 2024. Dissemination plans include publishing in peer-reviewed scientific journals and presentation at international conferences. TRIAL REGISTRATION NUMBER:Japan Registry of Clinical Trials (jRCT2051240249). Registered on 27 January 2025 (https://jrct.mhlw.go.jp/en-latest-detail/jRCT2051240249).
