山田 成樹

IMPORTANCE: Hyponatremia is an adverse event associated with antipsychotic use; however, comparative evidence among individual second-generation antipsychotics remains limited. OBJECTIVE: To compare the risk of hyponatremia associated with individual second-generation antipsychotics. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study and disproportionality analysis, data were obtained from the US Food and Drug Administration Adverse Event Reporting System (FAERS; quarter 4 1997 to quarter 3 2023), a dataset provided by the Japan Pharmaceutical Information Center, and a Japanese hospital-based claims database (Medical Data Vision; April 2008 to April 2024). The study adopted a new-user design and included patients routinely prescribed antipsychotics. Patients aged 18 to 69 years with at least 180 days of active medical history preceding the initial antipsychotic prescription, with no history of antipsychotics or hyponatremia during that period, were included. EXPOSURES: Initiation of second-generation antipsychotics. MAIN OUTCOMES AND MEASURES: Hyponatremia associated with individual antipsychotics was compared with that associated with olanzapine. Reporting odds ratios with 95% CIs were calculated for FAERS. The incidence within 180 days of treatment initiation was analyzed for claims database using hazard ratios estimated with stabilized inverse probability of treatment weighting based on propensity scores. RESULTS: In the FAERS database, most antipsychotics showed lower reporting odds ratios for hyponatremia than olanzapine. In a Japanese claims database, among 961 010 patients prescribed antipsychotics, 55 394 were included in the final analysis. The mean (SD) age was 50.4 (14.3) years, and there were 25 839 (46.6%) male and 29 555 (53.4%) female patients. After stabilized inverse probability of treatment weighting, aripiprazole was associated with a significantly lower risk of hyponatremia than olanzapine (adjusted hazard ratio, 0.52; 95% CI, 0.35-0.76), whereas other antipsychotics showed no significant differences. Sensitivity analysis confirmed the robustness of the findings. CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of antipsychotic users, aripiprazole was associated with a lower risk of hyponatremia than was olanzapine. Although residual confounding should be considered, these findings may help inform clinical decision-making for high-risk patients.

AIM: To identify specific pharmacists' practices associated with participation in multidisciplinary team conferences and meetings such as pre-visit conferences, predischarge conferences, and care planning meetings in Japanese home-based care. METHODS: An online survey was conducted for community pharmacists involved in home-based care across Japan in 2023. We compared the implementation of daily pharmacists' practices between those who participated in multidisciplinary team conferences and meetings and those who did not. Multivariable logistic regression analysis was conducted to evaluate the associations of individual pharmacists' practices with participation in multidisciplinary team conferences and meetings. RESULTS: This study included 1151 community pharmacists, with 676 pharmacists (59%) participating in multidisciplinary team conferences and meetings. Daily practice associated with participation in these conferences and meetings included collecting information on how to store and set medications (adjusted odds ratio [aOR], 1.86; 95% confidence interval [CI], 1.34-2.59), confirmation of medication intake (aOR, 1.42; 95% CI, 1.06-1.91), and gathering information on medication prescribed at other medical institutions (aOR, 1.89; 95% CI, 1.42-2.51). CONCLUSION: We identified some daily practices, including collecting medication management information, gathering all prescription details, and confirming medication intake, which were associated with participation in multidisciplinary team conferences for community pharmacists. Facilitating these practices could further enhance interprofessional collaboration, facilitate the standardization of home-based pharmaceutical care practices, and inform the optimization of future medical fees to ensure high-quality patient support.

A variety of medications contribute to the risk of postoperative delirium (POD) in older adults. This multicenter retrospective study aimed to investigate the relationship between the number of delirium-associated medication types and the incidence of POD. Patients aged greater than or equal to 70 years who underwent surgery under general anesthesia were included. Odds ratios (ORs) and 95% confidence intervals were estimated via multivariate logistic regression analysis, using patients not receiving delirium-associated medications as the reference group. Delirium-associated medications were selected from seven medication classes: benzodiazepines, non-benzodiazepines, opioids, antiparkinsonian agents, glucocorticoids, H1-antihistamines, and H2-antihistamines. A total of 4562 patients were included in the analysis. The overall incidence of POD was 7.7% (352/4562) and increased progressively with the number of delirium-associated medication types, from 6.0% among patients receiving none to 31.0% among those receiving four or more types. After adjusting for other delirium-related factors, the ORs of POD were significantly higher in patients receiving delirium-associated medications than in those receiving none and increased with the number of medication types. Sensitivity analyses confirmed the robustness of these findings. Our findings suggest that a higher number of delirium-associated medications is associated with an increased risk of POD in older adults, warranting preoperative medication review.

BACKGROUND: Clozapine is associated with a high risk of central nervous system abnormalities. However, seizure risk related to interactions between clozapine and other antipsychotics remains poorly characterized, and the pharmacological mechanisms underlying these seizures are unclear. OBJECTIVES: We aimed to evaluate safety signals for seizures associated with clozapine augmentation by other antipsychotics and analyze the relationship between these signals and neurotransmitter receptor occupancy profiles. DESIGN: A pharmacovigilance-pharmacodynamic analysis using a spontaneous reporting system. METHODS: This pharmacovigilance study used VigiBase, an adverse drug reaction database maintained by the World Health Organization. Drug-drug interactions (DDIs) between clozapine and other antipsychotics were assessed using the Ω shrinkage measure model. The association between DDI signals and neurotransmitter receptor occupancy was evaluated using linear regression. Robustness was tested using four frequency statistical models: additive, multiplicative, combination risk ratio, and chi-square statistic models. RESULTS: Of 38,758,077 reports in VigiBase between 1990 and 2024, 230,371 involved clozapine. Among antipsychotics classified under ATC code N05A, DDIs with clozapine were detected for amisulpride, chlorpromazine, haloperidol, lurasidone, olanzapine, penfluridol, risperidone, sulpiride, zotepine, and zuclopenthixol. A significant association between dopamine D4 receptor occupancy and the point estimates of signal values was observed in the Ω shrinkage measure model (β = 0.295, 95% confidence interval: 0.119-0.471, p = 0.002) and replicated across all frequency statistical models. CONCLUSIONS: These findings suggest a potential role of dopamine D4 receptor occupancy in seizures associated with clozapine augmentation by other antipsychotics. Further large-scale epidemiological studies are needed to validate these findings.

AIMS: Polypharmacy, hyperpolypharmacy, and potentially inappropriate medication (PIM) in older adults are growing health concerns in the aging population. Older patients with degenerative cervical myelopathy (DCM) often have multiple comorbidities and are prescribed numerous medications. Thus, we investigated the current status of medication use among older patients with DCM, identified the characteristics of those with hyperpolypharmacy, and evaluated its impact on postoperative outcomes. METHODS: This retrospective study included 130 older patients with surgery for DCM. All participants completed the Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire (JOACMEQ) before and 1 year after surgery. RESULTS: Forty-two patients had hyperpolypharmacy (H group), and 88 had non-hyperpolypharmacy (N group). The commonly prescribed PIMs were antidiabetics (24.6%), nonsteroidal anti-inflammatory drugs (21.5%), and hypnotics (20.8%). Hypnotic use was significantly higher in the H group than in the N group (p < 0.001). The H group exhibited significantly more advanced frailty than the N group (p = 0.001). The preoperative JOACMEQ scores for upper extremity, lower extremity, and bladder function were significantly worse in the H group than in the N group (p = 0.020, 0.003, and 0.007, respectively) and remained significant following the multivariable model. Both groups had favorable surgical outcomes, but quality of life improvements were significant in the N group (p = 0.005) but not in the H group (p = 0.900). CONCLUSIONS: Older DCM patients with hyperpolypharmacy had more severe preoperative symptoms. Although surgery is a viable treatment option for this population, thorough preoperative informed consent regarding surgical outcomes is critically important.

BACKGROUND: Trifluridine/tipiracil (FTD/TPI) plus bevacizumab (BEV) is a standard third-line therapy for unresectable advanced or recurrent colorectal cancer. The standard dosing schedule (5 days of administration followed by 2 days off) is associated with a high incidence of severe neutropenia. Conversely, a biweekly dosing schedule (5 days of administration followed by 9 days off) reportedly reduces this incidence. However, no direct comparison of these regimens has been made. In this study, we retrospectively compared the efficacy and safety of these two dosing schedules. METHODS: We analyzed data from patients who received FTD/TPI + BEV treatment between June 2016 and January 2024 at three hospitals affiliated with Fujita Health University. The effects of the dosing schedules on hematological toxicity, overall survival (OS), and time to treatment failure (TTF) were assessed. RESULTS: Among the 125 patients, 26 and 99 were classified into the standard and biweekly groups, respectively. Grade ≥ 3 neutropenia occurred in 50.0% of patients in the standard group and 29.3% of those in the biweekly group (P = .062), with multivariable analysis confirming the dosing schedule impact (P = .048). Median TTF was 5.4 and 7.0 months, while median OS was 16.4 and 14.5 months (P = .908, 0.947) in the standard and biweekly groups, respectively. CONCLUSION: The biweekly regimen of FTD/TPI + BEV resulted in a lower tendency for severe neutropenia than that in the standard regimen, while maintaining comparable OS and TTF in patients with unresectable advanced or recurrent colorectal cancer.

BACKGROUND: The prevalence of degenerative spine diseases has continued to rise with the aging of the global population. Despite the availability of various aging indices, limited studies have comprehensively investigated degenerative spine diseases from the perspective of aging. This study aimed to evaluate degenerative cervical and lumbar diseases surgically treated using multiple clinical aging indices and elucidate the characteristics of each condition through comparative analysis. METHODS: Clinical data of consecutive patients aged ≥ 65 years who underwent surgery for degenerative cervical and lumbar diseases were retrospectively collected. Frailty was assessed using the 11-point modified frailty index. Locomotive syndrome stage was determined based on the 25-Question Geriatric Locomotive Function Scale. Functional decline was assessed according to the Kihon Checklist. Polypharmacy was defined based on a cutoff of six drugs. A total of 19 categories were considered potentially inappropriate medications. RESULTS: Among the included patients, 313 and 103 had degenerative lumbar (L group) and degenerative cervical (C group) diseases, respectively. The C group had significantly lower serum albumin levels (p = 0.03), a significantly higher frequency of functional decline in both physical function (p = 0.02) and activities of daily living (p = 0.046), and significantly more advanced frailty (p = 0.004) than the L group. Among potentially inappropriate medications, the frequency of diuretic use was significantly higher in the C group than in the L group (p = 0.04). Longitudinal observations showed significant postoperative improvements in locomotive syndrome stages in the L group but not the C group. Cross-sectional observations revealed no significant differences in locomotive syndrome stage distributions between both the groups before surgery (p = 0.402); however, the C group exhibited significantly more advanced locomotive syndrome stages than the L group at 6 months (p < 0.001) and 1 year after surgery (p < 0.001). CONCLUSIONS: Across various indices of aging, patients with degenerative cervical spine disease showed more significant progression than those with lumbar spine disease. Thorough understanding of these characteristics is essential when managing degenerative spine diseases, particularly in the selection of effective treatment approaches for the increasingly aging society in the future.

BACKGROUND/AIM:  Bruton's tyrosine kinase inhibitors (BTKi) are important targeted agents for hematological malignancies. Second-generation BTKi are considered to have fewer off-target enzyme effects than first-generation agents; however, real-world comparative data on adverse events (AEs) remain limited. AEs of special interest with BTKi include bone marrow suppression, infection, hemorrhage, and cardiac-related events. This study aimed to investigate the frequency and severity of AEs of special interest associated with the three BTKi, namely, ibrutinib (IBR), tirabrutinib (TIR), and acalabrutinib (ACB), in real-world clinical practice. METHODS: We retrospectively investigated cytopenia and non-hematologic toxicities, including infections, bleeding, and cardiovascular AEs, for up to one year in patients who received BTKi at Fujita Health University Hospital and an affiliated hospital between March 2016 and March 2025 (IBR, n = 24; TIR, n = 24; ACB, n = 5). Data were collected from electronic medical records and graded according to the Common Terminology Criteria for Adverse Events, version 5.0. RESULTS: In the IBR group, the median age was 76 years (range, 76-81 years). Cytopenia, infections, bleeding, and cardiovascular AEs occurred in 21 (87.5%), nine (37.5%), eight (33.3%), and four (16.6%) patients, respectively. In the TIR group, the median age was 70 years (range, 64-76 years). Cytopenia, infections, and bleeding occurred in 17 (70.8%), seven (29.1%), and six (25.0%) patients, respectively. In the ACB group, the median age was 68 years (range, 52-75 years), and cytopenia was observed in four (80.0%) patients. CONCLUSION: All BTKi agents were associated with bone marrow suppression, infection, and bleeding, whereas cardiac-related AEs occurred only with IBR. Several Grade 3 or higher events were identified, underscoring the need for careful monitoring of patients receiving BTKi in clinical practice.

Recombinant tissue-type plasminogen activators (rtPA) effectively dissolve blood clots and improve symptoms in patients with acute ischemic stroke and myocardial infraction. Although rtPA are used in patients taking antiplatelets or anticoagulants to improve clinical outcomes, combination therapy may increase the risk of hemorrhagic transformation (HT) and intracerebral hemorrhage (ICH). However, few studies have investigated the risk of HT and ICH associated with these combination therapies. This study aimed to investigate the adverse-event and drug-drug interaction signals for HT and ICH under combination therapy with alteplase and various antiplatelets or anticoagulants, using the Japanese Adverse Drug Event Report database. Adverse-event signals were evaluated using the reporting odds ratio and information components, and drug-drug interaction signals were studied using the Ω shrinkage measure, additive, multiplicative, and Chi-square statistics models. We also investigated predictors of HT and ICH, time-to-onset, and outcomes in patients receiving alteplase. HT and/or ICH signals were detected in patients receiving alteplase in combination with aspirin, P2Y₁₂ inhibitors, cilostazol, ozagrel sodium, direct oral anticoagulants, warfarin potassium, heparin group, or argatroban. Hypertension and diabetes mellitus were significant risk factors for alteplase-induced HT. Most HT and ICH events occurred within 1 day after alteplase administration, and more than 60% of affected patients were not in recovery. In conclusion, continued monitoring is required in patients receiving alteplase in combination with any of the eight types of antiplatelets or the aforementioned anticoagulants. Additionally, the occurrence of HT or ICH within 1 day post-alteplase administration should be considered in patients with hypertension or diabetes mellitus. The findings from this study may help in understanding the risk of HT and ICH induced by rtPA in patients taking antiplatelet or anticoagulant medications, as well as in promoting the appropriate use of rtPA. Further prospective observational studies and randomized controlled trials are needed to assess these finding.

OBJECTIVES: Sivelestat sodium hydrate (SSH) may be effective in the early stage of acute respiratory distress syndrome (ARDS) before the neutrophil extracellular trap scaffold structure is complete. Therefore, patients with suppression of fibrinolysis (SF) before the secondary fibrinolytic process might benefit from SSH administration. The primary aim of this study was to determine the effect of the SF state and combination therapy on the effect of SSH administration. METHODS: We retrospectively reviewed the data of patients diagnosed with ARDS at Fujita Health University Hospital between July 2005 and December 2016. Patients with ARDS were stratified into the SF and hyperfibrinolysis (HF) groups. Using the fibrin degradation product (FDP)/D-dimer ratio, cut-off values were set as follows: FDP/D-dimer >2 for the HF group and FDP/D-dimer ≤2 for the SF group. The 28-day mortality was the primary endpoint. RESULTS: In total, 168 patients (71 in the HF group and 97 in the SF group) were included in the analysis. The mortality within 28 days was not different based on SSH administration in either group (HF group: p=0.956, SF group: p=0.957). In the SF group, the mortality rate within 28 days in SSH-treated patients who received antithrombotic drugs was significantly higher than that in patients who received SSH only (p<0.05). However, this finding was not present in the HF group (p=0.786). CONCLUSIONS: Concomitant use of SSH and antithrombotic drugs might worsen the treatment outcome of patients with ADRS in the SF state.

BACKGROUND: The incidence of chemotherapy-induced nausea and vomiting (CINV) when using an oxaliplatin-based regimen may vary according to the cancer type. This study compared the occurrence of CINV in patients with gastric or colorectal cancers. METHODS: This retrospective study included patients who received oxaliplatin-containing regimens for gastric or colorectal cancer. The incidence of CINV during the first treatment course was evaluated. Propensity score matching (PSM) was performed between gastric cancer (GC) and colorectal cancer (CRC) groups to compare the complete response (CR) and total control (TC) rates as indicators of antiemetic efficacy. The impact of primary tumor resection history, surgical procedure, and antiemetic agents was analyzed in the group with a higher incidence of CINV. RESULTS: The GC group included 99 patients and the CRC group included 180 patients, with 60 patients per group, after PSM. The CR rate was significantly lower in the GC group (75.0%) than in the CRC group (95.0%) (P < 0.01). Before PSM, the TC rate varied significantly by resection type in patients with GC (P = 0.012), indicating that tumor resection influenced the TC rate (P = 0.015). In patients with GC who underwent tumor resection, neither dopamine 2 receptor antagonists (P = 0.090) nor neurokinin 1 receptor antagonist (P = 0.66) use was associated with a significant difference in the CR rate. CONCLUSION: Patients with GC have a higher incidence of CINV than those with CRC. In patients with GC, tumor resection significantly influenced the total control rate of CINV.

BACKGROUND/AIM: Trifluridine/tipiracil (TAS-102) is a standard treatment for unresectable advanced or recurrent colorectal cancer. The incidence of grade 3 or higher neutropenia is high with the standard 5-day-on/2-day-off dosing schedule. Previous studies suggest that a 5-day-on/9-day-off (biweekly) schedule is associated with a lower incidence of neutropenia; however, direct comparative evidence is limited. This study aimed to retrospectively evaluate the impact of TAS-102 dosing schedules on safety. PATIENTS AND METHODS: Patients with colorectal cancer who received TAS-102 with/without bevacizumab with either the standard or biweekly schedule at three Fujita Health University-affiliated hospitals between June 2014 and January 2024 were included. The incidence of neutropenia, anemia, and thrombocytopenia based on the dosing schedule and renal function was retrospectively compared. The effect of dosing schedules on grade ≥3 neutropenia was also evaluated. RESULTS: Among 260 patients, 127 received the standard schedule, and 133 the biweekly schedule. Grade ≥3 neutropenia incidence was significantly lower with the biweekly schedule (26.3%) than with the standard schedule (40.2%) (p=0.0247). Multivariate analysis demonstrated that the standard schedule of TAS-102 was associated with a higher incidence of grade ≥3 neutropenia (p<0.01). Grade ≥3 anemia incidence was also lower with the biweekly schedule (13.5% versus 25.2%) (p=0.0187). Grade ≥3 neutropenia showed a trend towards a higher incidence in patients with estimated glomerular filtration rates ≥60 mL/min, at 29.4% compared with 41.0% in those with rates <60 ml/min (p=0.0679). CONCLUSION: The biweekly schedule of TAS-102 with/without bevacizumab was associated with a significantly lower incidence of grade ≥3 neutropenia than the standard schedule. This schedule may help patients - including those with impaired renal function - adhere to planned treatment regimens.

PURPOSE: Tranexamic acid (TXA) is widely used as an antifibrinolytic drug. However, studies to determine the optimal blood concentration of TXA have produced inconsistent results. During cardiac surgery, cardiopulmonary bypass (CPB) has serious effects on drug distribution, elimination, and plasma concentration. Therefore, we aimed to establish a population pharmacokinetics model of TXA in patients undergoing cardiac surgery with CPB that considers renal function as a covariate, thereby facilitating personalized treatment. METHODS: In total, 453 TXA plasma samples were prospectively collected from 77 patients who underwent cardiac surgery with CPB. Plasma concentrations were determined by ultra-performance liquid chromatography-tandem mass spectrometry. The population pharmacokinetic model of TXA was analyzed using nonlinear mixed-effects modeling. RESULTS: The two-compartment-based model with combined errors was determined as the best. The final model included the effect of bodyweight and CLcr may be summarized as V1 (L) = 12.77 × (bodyweight / 61.4)0.911, V2 (L) = 6.857, CL1 (L/h) = 3.263 × [CLcr (L/h) / 61.0]0.752, CL2 (L/h) = 2.859. CONCLUSION: Patients who undergo cardiac surgery with CPB may require an adjusted dose of TXA tailored to CPB due to lower CL1 and increased V1. Our TXA population pharmacokinetic model may be useful for developing individualized dosing designs for TXA in patients who undergo cardiac surgery with CPB.

Background/Objectives: The risk of fractures associated with immune checkpoint inhibitors (ICIs) is increasing; however, the relationship between fracture risk and potential factors, such as osteoporosis and hyperthyroidism, remains unclear. Methods: Using VigiBase, the World Health Organization's global pharmacovigilance database, we investigated the signals for osteoporosis, hyperthyroidism, and fractures associated with ICIs (nivolumab, pembrolizumab, atezolizumab, durvalumab, ipilimumab, and tremelimumab) by calculating information components (ICs) and their 95% confidence intervals (CIs). Furthermore, we estimated the association between the occurrence of fractures in patients receiving ICIs and osteoporosis or hyperthyroidism. Results: Signals of hyperthyroidism (IC = 4.66, 95% CI: 4.58–4.73), but not osteoporosis (IC = −1.79, 95% CI: −2.22 to −1.36) or fractures (IC = −0.21, 95% CI: −0.36 to −0.06), were detected in patients using ICIs. Osteoporosis (odds ratio: 118.00, 95% CI: 61.00–230.00) was associated with an increased reporting frequency of fractures related to ICIs, whereas hyperthyroidism (odds ratio: 0.60, 95% CI: 0.19–1.87) was not associated with such an increase. Conclusions: The VigiBase analysis indicates that the use of ICIs does not increase the reporting frequency of osteoporosis or fractures. Additionally, hyperthyroidism did not increase the reporting frequency of fractures associated with ICIs.

Background: Progression of chronic kidney disease (CKD) increases the risk of complications such as cardiovascular disease; however, knowledge regarding renal function in the general population is low. We aimed to determine factors necessitating CKD education in the general population. Methods: Participants for a health promotion seminar were recruited via the Sugiura Memorial Foundation website and Sugi Pharmacy stores. Those who agreed to participate in the seminar were included in the questionnaire survey after a health seminar. Results: Out of 1548 participants, 1050 answered all questionnaire items, resulting in a valid response rate of 67.83%. Multivariable analysis revealed that sex (OR = 0.611), pharmacy consultations (OR = 0.661), receiving a blood test within 1 year (OR = 0.268), awareness of blood pressure (OR = 0.038), and knowledge of blood glucose level (OR = 0.099) were factors for unawareness of renal function. Conclusions: This study suggests that female individuals unaware of their blood pressure or glucose levels, those who have not had a blood test within 1 year, and those who have not sought health consultations need education on renal function.

BACKGROUND: Although several guidelines provide dosing recommendations for antidepressants based on patients' genetic information, pharmacogenetic testing for antidepressant use is rarely routinely performed in Japan. To clarify the clinical impact of pharmacogenetic testing, this study estimated the potential drug-gene interactions for first-time antidepressant treatment in Japanese patients with major depressive disorder. METHODS: This study retrospectively included Japanese patients who were registered for depressive episodes (F32, International Classification of Diseases, Tenth Revision) and initiated on antidepressants between July 2022 and March 2023. Antidepressant prescription rates were calculated using a nationwide hospital-based database (Medical Data Vision Co., Ltd). The incidence of actionable drug-gene interactions was estimated by multiplying the first-time prescription rate of each relevant antidepressant by the frequency of its corresponding actionable phenotype. RESULTS: A total of 3,197 patients were included in the analysis. Escitalopram was the most frequently prescribed antidepressant (18.7%, n = 597), followed by mirtazapine (17.5%, n = 561), and sertraline (15.4%, n = 493). Of the patients receiving their first treatment of major depressive disorder, 56.5% (n = 1,807) were prescribed a drug with actionable pharmacogenetic implications, and 26.4% (n = 844) were estimated to have required actionable therapeutic recommendations. The highest incidence of actionable drug-gene interactions was observed in escitalopram and CYP2C19 pairs (12.4%, n = 398). For sertraline and CYP2C19 or CYP2B6 pairs, the incidence was 11.0% (n = 352). Among all antidepressants, paroxetine had the highest incidence of actionable drug-gene interactions related to CYP2D6 at 1.8% (n = 56); this interaction was rarely observed with other antidepressants (<1%). CONCLUSIONS: We estimated that one in four Japanese patients with major depressive disorder who were prescribed first-time antidepressants had actionable drug-gene interactions. These results suggest that pre-emptive pharmacogenetic testing in the treatment of major depressive disorder could have important clinical implications.

BACKGROUND/AIM: Opioid-induced constipation (OIC) is a common adverse drug event in patients undergoing chronic pain therapy. Naldemedine is an oral, peripherally acting μ-opioid receptor antagonist that improves bowel movement without affecting opioid pain relief. In palliative wards, many patients experience malnutrition caused by cachexia and systemic inflammation because of cancer progression. We investigated whether the C-reactive protein-to-albumin ratio (CAR) affects the continuation of naldemedine therapy in a palliative ward. PATIENTS AND METHODS: We included Japanese patients in the palliative ward of Fujita Health University Hospital between April 2020 and August 2023 in this retrospective observational study. The log-rank test was used to compare the continuation rates of naldemedine over 14 days. Cox proportional hazards analysis was performed using the terms morphine-equivalent daily dose <30 mg and CAR ≥0.888. RESULTS: Eighty patients were divided into continuation (n=58) and discontinuation (n=22) groups. The proportion of patients with a CAR ≥0.888 was significantly higher in the discontinuation group than in the continuation group (p =0.020). Cox proportional hazards analysis showed that morphine-equivalent daily dose <30 mg was not a factor for discontinuation of naldemedine therapy (hazard ratio=1.040, p=0.929) but CAR ≥0.888 was (hazard ratio=3.251, p=0.035). CONCLUSION: A high CAR (≥0.888) was a risk factor for the discontinuation of naldemedine therapy in a palliative ward. Our results suggest that physicians and pharmacists should monitor CAR as a marker of malnutrition and systemic inflammation before initiating naldemedine therapy.

INTRODUCTION: Hip fractures, which result in a high rate of complications and mortality, are a major public health concern in aging societies. Physical restraint for older patients with hip fractures may be employed to ensure safety, continue medical treatment, and minimize the risk of harm to oneself or others. This study aimed to investigate the current practices of physical restraint use among hip fracture patients across 2 acute-care hospitals, as well as uncover factors associated with physical restraint in patients with hip fracture. METHODS: We retrospectively reviewed all patients aged ≥65 years who underwent surgery for hip fractures at two institutions. Physical restraint was applied in accordance with institutional guidelines, following thorough assessments by physicians and nurses and obtaining informed consent from the patient or their family. When we examined the independent associations of physical restraint during hospitalization, the Poisson regression models were used to estimate the relative risks (RRs) and 95% confidence intervals (CIs). RESULTS: In total, 463 older patients with hip fractures were assessed. Among the included patients, 118 (25.5%) were subjected to physical restraint. Multivariable analysis revealed that 85 years or older (RR, 1.8; CI: 1.1-3.0), a BMI below 18.5 (RR, 1.8; CI: 1.4-2.5), dementia (RR, 2.3; CI: 1.7-3.1), stroke (RR, 1.5; CI: 1.1-2.0), impairment in physical function (RR, 3.1; CI: 1.2-8.3), and administration of antipsychotics (RR, 1.6; CI: 1.0-2.4) were significantly associated with the implementation of physical restraint. CONCLUSIONS: This retrospective study provided real-world data regarding the use of physical restraint in older patients with hip fractures. Patients with older age, low BMI, dementia, stroke, impaired physical function, and administration of antipsychotics may be at high risk for the use of physical restraints. To minimize the use of physical restraints, future research for further data collection will be essential.

BACKGROUND/AIM: Effective monitoring of antibiotic use is essential for antimicrobial stewardship. While Days of Therapy (DOT) is commonly used to assess antibiotic consumption, it does not fully capture changes in antimicrobial spectrum during de-escalation. To address this, the Days of Antibiotic Spectrum Coverage (DASC) metric-calculated using a spectrum score weighted by antimicrobial breadth-was developed. This study aimed to evaluate the utility of DASC in identifying trends in antibiotic de-escalation across hospital wards and to determine whether it can serve as a reliable metric for assessing the appropriateness of antibiotic use at the departmental level. PATIENTS AND METHODS: This single-center retrospective study was conducted at an acute care community hospital in Japan, which has 21 clinical departments and 250 inpatient beds, including four intensive care unit beds. We retrospectively analyzed trends in inpatient antimicrobial use from May 2019 to March 2023 using DASC to assess the effectiveness of a newly instituted antimicrobial stewardship program. RESULTS: DASC/DOT in the Otolaryngology and respiratory medicine wards showed a significant decreasing trend, but a significant increase was observed in both the surgery and general practice wards. We observed no significant trends in the other wards. In the surgery and respiratory medicine wards, broad-spectrum antimicrobials such as carbapenems were frequently used. CONCLUSION: DASC highlighted differences in the trends of antimicrobial de-escalation at the ward level and identified targets for antimicrobial stewardship intervention.

BACKGROUND: Immune checkpoint inhibitors (ICIs) play a central role in cancer immunotherapy. However, the occurrence of immune-related adverse events, especially ICI-induced interstitial lung disease (ICI-ILD), is life-threatening and affects the effectiveness of ICI treatment. This study aimed to explore potential drugs to mitigate ICI-ILD occurrence using data from the Japanese Adverse Drug Event Report (JADER) and the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS [JAPIC AERS]). RESEARCH DESIGN AND METHODS: We investigated concomitant drugs that reduce ILD associated with four ICIs - nivolumab, pembrolizumab, atezolizumab, and durvalumab - across the JADER and FAERS databases. Subsequently, the identified common concomitant drugs that reduce the occurrence of ICI-ILD were detected and analyzed. RESULTS: We found omega-3 fatty acids, loperamide, and amlodipine as common concomitant drugs that reduced ICI-ILD occurrence in both the JADER and FAERS databases. Omega-3 fatty acids reportedly have many effects in animal models of drug-induced ILD, including their association with ILD in humans and anti-inflammatory effects against ICI-ILD. However, loperamide and amlodipine reportedly have minimal effects against ILD, thereby necessitating further evaluation. CONCLUSION: Omega-3 fatty acids have emerged as potential agents for reducing ICI-ILD occurrence, as evidenced by findings from two different pharmacovigilance databases.

OBJECTIVE: This pharmacovigilance study evaluated the profile of clozapine-related adverse events by region using the Food and Drug Administration Adverse Event Reporting System (FAERS). METHODS: We categorized each case into five regions (America, Europe/West Asia, Oceania, Asia, and Africa) based on the reporting country information in the FAERS database. The number of clozapine-related adverse events reported in each region was aggregated according to the preferred term (PT) and the Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ). RESULTS: A total of 101,872 clozapine-related adverse events were registered in the FAERS database. In America and Europe, leukocyte or neutrophil count abnormalities accounted for half of the top 10 PTs by relative reporting rate. However, Asia had higher relative reporting rates of pyrexia and salivary hypersecretion (13.91% and 10.85%, respectively). Regarding the SMQ, the relative reporting rates of infective pneumonia, convulsions, extrapyramidal syndrome, gastrointestinal obstruction, and hyperglycaemia/new onset diabetes mellitus were higher in Asia than in other regions (5.26%, 9.72%, 12.65%, 5.13%, and 8.26%, respectively), with significant differences even after adjusting for confounding factors using multivariate logistic regression analysis. CONCLUSION: Spontaneous reports of adverse events associated with clozapine show regional disparities, particularly in Asia, where concentration-dependent adverse events are more frequently reported. However, the spontaneous reporting system has several limitations, requiring further research for validation.

BACKGROUND: Chemotherapy-induced thrombocytopenia is often a use-limiting adverse reaction to gemcitabine and cisplatin (GC) combination chemotherapy, reducing therapeutic intensity, and, in some cases, requiring platelet transfusion. OBJECTIVE: A retrospective cohort study was conducted on patients with urothelial cancer at the initiation of GC combination therapy and the objective was to develop a prediction model for the incidence of severe thrombocytopenia using machine learning. METHODS: We performed receiver operating characteristic analysis to determine the cut-off values of the associated factors. Multivariate analyses were conducted to identify risk factors associated with the occurrence of severe thrombocytopenia. The prediction model was constructed from an ensemble model and gradient-boosted decision trees to estimate the risk of an outcome using the risk factors associated with the occurrence of severe thrombocytopenia. RESULTS: Of 186 patients included in this study, 46 (25%) experienced severe thrombocytopenia induced by GC therapy. Multivariate analyses revealed that platelet count ≤ 21.4 (×104/µL) [odds ratio 7.19, p < 0.01], hemoglobin ≤ 12.1 (g/dL) [odds ratio 2.41, p = 0.03], lymphocyte count ≤ 1.458 (×103/µL) [odds ratio 2.47, p = 0.02], and dose of gemcitabine ≥ 775.245 (mg/m2) [odds ratio 4.00, p < 0.01] were risk factors of severe thrombocytopenia. The performance of the prediction model using these associated factors was high (area under the curve 0.76, accuracy 0.82, precision 0.68, recall 0.50, and F-measure 0.58). CONCLUSIONS: Platelet count, hemoglobin level, lymphocyte count, and gemcitabine dose contributed to the development of a novel prediction model to identify the incidence of GC-induced severe thrombocytopenia.

Acute lung injury (ALI), which occurs in association with sepsis, trauma, and coronavirus disease 2019 (COVID-19), is a serious clinical condition with high mortality. Excessive platelet-leukocyte aggregate (PLA) formation promotes neutrophil extracellular trap (NET) release and thrombosis, which are involved in various diseases, including ALI. Macrophage-1 antigen (Mac-1, CD11b/CD18), which is expressed on the surface of leukocytes, is known to promote NET formation. This study aimed to elucidate the role of Mac-1 in extracellular histone-induced ALI. Exogenous histones were administered to Mac-1-deficient mice and wild-type (WT) mice with or without neutrophil or platelet depletion, and several parameters were investigated 1 h after histone injection. Depletion of neutrophils or platelets improved survival time and macroscopic and microscopic properties of lung tissues, and decreased platelet-leukocyte formation and plasma myeloperoxidase levels. These improvements were also observed in Mac-1-/- mice. NET formation in Mac-1-/- bone marrow neutrophils (BMNs) was significantly lower than that in WT BMNs. In conclusion, our findings suggest that Mac-1 is associated with exacerbation of histone-induced ALI and the promotion of NET formation in the presence of activated platelets.

Hypertension is a major cause of cardiovascular diseases. Several recent studies reported that pharmacists' remote follow-up reduced hypertension patients' blood pressure (BP). This meta-analysis aims to verify whether remote follow-up by pharmacists improves BP levels and reveal the factors that make the intervention effective. The search, conducted using PubMed/Medline, Embase, and Cochrane Library from June to July 2023, targeted articles published between October 1982 and June 2023, using terms including "pharmacist", "hypertension", and "randomized controlled trial (RCT)". The inclusion criteria were: (a) RCTs involving hypertension patients with or without comorbidities, (b) pharmacists using remote communication tools to conduct follow-up encounter during the intervention period, (c) reporting systolic blood pressure (SBP) at baseline and during intervention. SBP was the primary outcome for the meta-analysis. Thirteen studies (3969 participants) were included in this meta-analysis. The mean difference of SBP between intervention group and control group was - 7.35 mmHg (P < 0.0001). Subgroup analyses showed the greater reduction of SBP in the "regularly scheduled follow-up cohort" (- 8.89 mmHg) compared with the "as needed follow-up cohort" (- 3.23 mmHg, P < 0.0001). The results revealed that remote follow-up by pharmacists reduced SBP levels in hypertension patients and scheduled remote follow-up may contribute to the effectiveness.

BACKGROUND/AIM: This study aimed to determine the effectiveness of online team-based learning (TBL) and the factors influencing dropouts from online TBL for pharmacists on how to conduct clinical medication reviews for older adults. PARTICIPANTS AND METHODS: All participants were randomly assigned to the TBL or non-TBL group by using a random number sequence table matched by their years of experience working as a pharmacist. The primary outcome was whether the score on the team readiness assurance test (TRAT) in the TBL group differed from that on the second individual readiness assurance test (IRAT) in the non-TBL group. The secondary outcome was to identify factors contributing to dropouts from the online TBL program. RESULTS: The TRAT score in the TBL group was significantly higher than the second IRAT score in the non-TBL group during the first session (p=0.010). There were no differences in TRAT and IRAT scores between groups in two subsequent sessions. Logistic regression analysis revealed that less than 10 years of pharmacy experience was a contributor to dropouts (p=0.039), whereas experience in home-based care prevented dropouts (p=0.026) in our online TBL program. CONCLUSION: This study revealed the short-term usefulness of online TBL on medication reviews for older adults and elucidated the factors related to dropouts. Although instructors should provide positive feedback to participants with insufficient experience in pharmacy practice and home-based care, online TBL has the potential to improve educational effectiveness for community pharmacists during the COVID-19 pandemic.

BACKGROUND/AIM: Patients with malignant lymphoma, in a latent state of weakened immune function, are at risk of chemotherapy-induced immunosuppression and cytomegalovirus (CMV) infection. Concomitant therapy with bendamustine and rituximab or obinutuzumab intensifies immunosuppression, potentially affecting CMV onset. This study aimed to assess CMV onset differences between bendamustine monotherapy and combination therapy with rituximab or obinutuzumab using the Japanese Adverse Drug Event Report database (JADER). PATIENTS AND METHODS: A JADER analysis dataset (April 2004 to September 2022) defined CMV infection using 31 preferred term (PT) words from MedDRA 25.1J HLT "Cytomegalovirus infection (10011827)". Reporting odds ratios (ROR) calculated CMV infection signals for bendamustine monotherapy, rituximab, obinutuzumab, bendamustine+rituximab (BR), and bendamustine+obinutuzumab (GB). ROR confidence intervals exceeding 1 indicated a CMV signal. Days of CMV infection were calculated based on adverse event onset and administration start. RESULTS: CMV signals were confirmed for monotherapy and combination therapies. CMV infection durations (median, interquartile range) were 41.0 days (23.5-69.5) for bendamustine monotherapy, 63.5 days (35.2-95.0) for BR, and 61.0 days (33.0-102.5) for GB, with cases exceeding 200 days. CONCLUSION: JADER analysis detected significant CMV signals for rituximab, obinutuzumab, and bendamustine. Caution may be warranted 7-9 months post-bendamustine administration, necessitating further investigation, including cell-mediated immunity suppression assessment.

BACKGROUND/AIM: Renal dysfunction necessitates S-1 dose reduction. However, decreased dihydropyrimidine dehydrogenase (DPD) activity may lead to adverse events due to 5-FU. The guidelines provided by pharmaceutical companies state that total bilirubin (T-Bil) should be ≤upper limit of normal (ULN)×1.5 as a reference value for safely taking S-1. Nevertheless, the relationship between the degree of liver dysfunction and S-1 dose reduction has not been clearly established. PATIENTS AND METHODS: This study focused on patients who received S-1 monotherapy for various types of cancer. The primary outcome was defined as the variation between blood sampling results on the test day and the subsequent test. The variation data were categorized based on the difference in T-Bil: Low T-Bil group (≤2.25) and High T-Bil group (>2.25). RESULTS: The number of patients that underwent S-1 monotherapy was 883 and the running number was 7,511; Low T-Bil group included 7,245 and High T-Bil group included 266. Examination of the effect of the T-Bil Group on clinical outcomes revealed a correlation with red blood cell (RBC) count, platelet (PLT) count, and T-Bil level. When the impact of the interaction between the T-Bil Group and any of the clinical outcomes, such as the RBC count, PLT count, and T-Bil level, was determined, each outcome showed a significant decrease in the High T-Bil group compared with the Low T-Bil group. CONCLUSION: S-1 administration in patients with liver dysfunction accompanied by elevated T-Bil levels may cause thrombocytopenia.

BACKGROUND/AIM: Capecitabine plus oxaliplatin (CapeOX) therapy is used as an adjuvant chemotherapy regimen for patients with colorectal cancer (CRC). Although oxaliplatin induces thrombocytopenia, the risk factors for thrombocytopenia in oxaliplatin-treated patients with CRC are not well established. We aimed to investigate the risk factors for thrombocytopenia in CapeOX-treated patients with CRC. In addition, we evaluated platelet counts and non-invasive liver fibrosis indices, specifically the aspartate aminotransferase-to-platelet ratio index (APRI) and the fibrosis-4 index (FIB-4), during CapeOX therapy in these patients. PATIENTS AND METHODS: Between July 2017 and June 2020, we enrolled CapeOX-treated patients with high-risk stage II or stage III CRC at seven hospitals collaborating with the Division of Oncology, Aichi Prefectural Society of Hospital Pharmacists (Aichi prefecture, Japan). In this retrospective study, we investigated patients' backgrounds, laboratory data, concomitant medications, number of cycles of CapeOX and oxaliplatin, cumulative dose of oxaliplatin, and administration period. The cut-off values were calculated using receiver operating characteristic analysis of platelet counts and APRI and FIB-4 scores. RESULTS: Fifty-five patients without thrombocytopenia and 44 patients with thrombocytopenia were enrolled. During CapeOX therapy, the thrombocytopenia group showed a significant decrease in platelet count and a significant increase in APRI and FIB-4 scores compared to the non-thrombocytopenia group. Baseline albumin level ≤3.5 g/dl and platelet count ≤238×103/μl were independently associated with ≥grade 2 thrombocytopenia in CapeOX-treated patients. CONCLUSION: Baseline albumin level and platelet count may be useful for predicting thrombocytopenia in CapeOX-treated patients with high-risk stage II or stage III CRC.

OBJECTIVE: Several medications are associated with delirium; however, studies with adequate statistical power are limited, and it is difficult to determine the effects of the various concomitant medications used in clinical practice. Therefore, in this study, we aimed to comprehensively evaluate the safety signals of delirium-associated drugs using a spontaneous adverse event reporting system. METHOD: The JAPIC AERS (Food and Drug Administration Adverse Event Reporting System pre-processed by the Japan Pharmaceutical Information Center) was used for the analysis in this pharmacovigilance study. The reporting odds ratio (ROR) for delirium was adjusted for using multivariate logistic regression analysis with sex, age, indication, and melatonin receptor agonist use, and 22 drug categories were targeted as covariates. RESULTS: After excluding patients with missing information, 7,527,568 patients were included in the study. Delirium signals were detected even after adjusting for covariates in 17 drug categories, including benzodiazepines (adjusted ROR, 1.76; 95% confidence interval [CI], 1.64-1.89), opioids (adjusted ROR, 4.42; 95% CI, 4.21-4.64), and tricyclic antidepressants (adjusted ROR, 2.44; 95% CI, 2.20-2.71). CONCLUSIONS: These findings suggest that many drug classes, such as benzodiazepines, are independent risk factors for delirium and strengthen the evidence of an association between delirium and medications.

BACKGROUND/AIM: The frequency rate of injection site reactions (ISR) due to fosaprepitant meglumine (Fos APR) has been shown to vary depending on the types of combined anticancer drug. This study aimed to elucidate the impact of Fos APR on ISR in patients receiving paclitaxel and carboplatin, with and without bevacizumab therapy (TC±Bev). PATIENTS AND METHODS: This study focused on patients with gynecologic cancer (n=93) who received TC±Bev administration at Fujita Health University Hospital from March 2016 to February 2020, and monitored up to six cycles. The patients were randomly assigned to the Fos APR group (n=47) and the Aprepitant (APR) group (n=46). Using Visual Infusion Phlebitis (VIP) scores, ISR was evaluated by comparing the VIP scores of all cycles using a linear mixed model. The risk factors that contribute to the occurrence of vascular pain throughout all cycles were also examined. RESULTS: The VIP scores of all cycles showed a near significant intergroup difference (p=0.071). Factors that affected the development of vascular pain included Fos APR and age (p=0.027 and 0.049, respectively). Regarding age, patients aged <65 years had a higher risk. Four patients underwent a switch from the originally assigned neurokinin-1 receptor antagonist; in all of these cases, Fos APR was changed to APR for vascular pain. CONCLUSION: Fos APR may increase the risk for ISR associated with TC±Bev therapy for gynecological cancer.

Naldemedine is structurally designed to prevent passage across the blood–brain barrier (BBB), resulting in the attenuation of opioid-induced constipation without interfering with the analgesic effects of opioids. However, the influence of brain metastasis (BM), as one indicator of BBB disruption, on the analgesic effects of opioids in patients treated with naldemedine remains unclear. To examine whether the analgesic effects of opioids following naldemedine treatment are lower in patients with BM than in those without BM, we surveyed inpatients with lung and breast cancers treated with naldemedine at Fujita Health University Hospital between April 2017 and March 2022. Changes in the numeric rating scale (NRS) scores, morphine milligram equivalents (MMEs), and the number of rescues were assessed as analgesia-related outcomes during the first 7 days of naldemedine treatment in patients with or without BM, matched by the propensity score. In total, 172 patients were enrolled. After propensity-score matching, 30 patients with BM and 60 patients without BM were included in the analysis. Changes in NRS scores, MMEs, and the number of rescues did not differ between patients with and without BM. In the linear mixed-effects model, the coefficient of interaction between patients with or without BM and the days for each outcome was not statistically significant. BM does not influence the analgesic effect of opioids in patients with lung and breast cancers treated with naldemedine. Naldemedine may be useful for treating BM.

BACKGROUND: Clozapine is the only antipsychotic medication with proven efficacy against treatment-resistant schizophrenia. This multicenter retrospective cohort study aimed to evaluate the impact of a delay in clozapine initiation on long-term outcomes. METHODS: Patients who initiated clozapine treatment between July 2009 and December 2018 were included in this study. According to the length of time from the diagnosis of schizophrenia to clozapine initiation, the patients were categorized into one of three groups: early (≤ 9 years), intermediate (10-19 years), and late (≥ 20 years) initiation. The endpoints were psychiatric rehospitalization and all-cause clozapine discontinuation within 3 years. Hazard ratios (HR) and 95% confidence interval (CI) were estimated using the Fine and Gray method or the Cox proportional hazards model. RESULTS: The incidence rates of rehospitalization within three years, according to the cumulative incidence function, were 32.3% for early, 29.7% for intermediate, and 62.2% for late initiation, respectively. Late initiation had a significantly higher risk of psychiatric rehospitalization than early initiation (HR, 2.94; 95% CI, 1.01- 8.55; P = 0.016 by the Gray's test). The risk of psychiatric rehospitalization was not significantly different between the early and intermediate initiation groups. The incidence rate of all-cause clozapine discontinuation within three years using the Kaplan-Meier method was 13.0% for early, 10.6% for intermediate, and 20.1% for late initiation. The risk of all-cause clozapine discontinuation was not significantly among the groups. The late initiation group had more patients discontinuing because of death due to physical diseases than the other groups. CONCLUSIONS: The study suggests that clozapine should be initiated promptly in patients with treatment-resistant schizophrenia to prevent psychiatric rehospitalization during long-term treatment. Further prospective studies with appropriate consideration of confounding factors and large sample sizes are needed to strengthen the evidence.

OBJECTIVES: To investigate the subjective assessments of an antipsychotic treatment with brexpiprazole. METHODS: This was a 14-week prospective observational study. Nineteen patients participated in the study between February 2019 and January 2020. RESULTS: Patients had a mean age of 40.6±14.2 years and a Clinical Global Impressions-Severity of Illness scale (CGI-S) score of 4.6±1.2 at the initiation of brexpiprazole treatment. The Subjective Well-being under Neuroleptic drug treatment Short form, Japanese version (SWNS-J) total score significantly improved from 68.1±22.3 in week 2 to 79.5±21.0 in week 14 (p=0.0084). The SWNS-J subscales of self-control and social integration status also significantly improved from 14.0±4.7 and 13.9±6.0 in week 2 to 17.0±4.7 and 16.0±5.1 in week 14, respectively (p=0.0053 and 0.012, respectively). No significant improvements were observed in any other SWNS-J subscales or the Drug Attitude Inventory-10 (DAI-10) in the 14-week observation period. Moreover, the SWNS-J total score did not correlate with the DAI-10 (r=0.31, p=0.19), or CGI-S (r=-0.18, p=0.47) scores. CONCLUSIONS: The present results suggest that brexpiprazole might improve subjective well-being, although this may not necessarily reflect psychopathological improvements. To enhance medication adherence, it is important to perform subjective assessments on patients over time.

OBJECTIVES: Patients with cancer, especially those with lung cancer, are at high risk of developing thrombosis. Intralipos® infusion 20% is contraindicated for thrombosis, and there is no consensus on whether it can be safely used in cases of advanced cancer. We conducted a retrospective observational study to elucidate the impact of fat emulsion administration on blood coagulation in patients with terminal lung cancer. METHODS: The subjects were patients with terminal lung cancer in the Department of Surgery and Palliative Medicine, Fujita Health University Nanakuri Memorial Hospital between January 2016 and December 2019. We compared changes in their blood coagulation profile before hospitalization and one month later. RESULTS: There were a total of 213 patients with lung cancer-139 who were administered fat emulsion and 74 who were not-with no significant differences in baseline characteristics. In the fat emulsion administration group (n=27), the prothrombin time-international normalized ratio (PT-INR) and activated partial thromboplastin time (APTT), respectively, were 1.17±0.26 (mean±standard deviation) and 30.5±5.0 s at hospitalization and 1.16±0.12 and 31.2±4.2 s one month later with no significant differences. In the non-administration group (n=6), the PT-INR and APTT, respectively, were 1.44±0.43 and 30.6±5.2 s before hospitalization and 1.28±0.18 and 33.0±7.5 s one month later with no significant differences. CONCLUSIONS: We did not identify any changes in PT-INR and APTT after fat emulsion administration in patients with terminal lung cancer. There were also no new cases of thrombosis, suggesting that fat emulsions were administered safely in patients with terminal lung cancer.

PURPOSE: Clozapine is more effective than other antipsychotics and is the only antipsychotic approved for treatment-resistant schizophrenia. The objective of this study is to reveal the effect of clozapine on employment using a bidirectional mirror-image model. PATIENTS AND METHODS: This design was a retrospective observational study that investigated the employment status of patients with treatment-resistant schizophrenia based on medical records. The bidirectional mirror-image model consisted of 1) switching from other antipsychotics to clozapine and 2) switching from clozapine to other antipsychotics. The observation period was 1 year for each pre- and post-clozapine initiation and discontinuation. RESULTS: We included 36 patients in the bidirectional mirror-image model. The regular employment plus employment support rate was significantly higher in the clozapine phase than in the other antipsychotic phase in the bidirectional mirror-image model (30.6% vs 11.1%, P = 0.039). The days of regular employment plus employment support were also significantly longer in the clozapine phase (61.3 ± 106.2 vs 24.7 ± 82.7 days, P = 0.032). As per the unidirectional mirror-image model, switching to clozapine resulted in significantly higher regular employment plus employment support rates in the clozapine phase than those in the other antipsychotic phase (33.3% vs 10.0%, P = 0.039). Switching from clozapine to other antipsychotics did not exhibit significant differences in any outcomes. CONCLUSION: The results suggest that clozapine is superior to other antipsychotics with respect to achieving employment in patients with treatment-resistant schizophrenia. However, biases specific to the mirror-image model need to be considered.

Purpose: An intraocular hemorrhage is an adverse event that can lead to visual acuity impairment. Antithrombotic therapy with antiplatelet agents and anticoagulants may increase intraocular hemorrhage. However, since their frequency is low, studies on the risk of intraocular hemorrhage with these drugs, especially under combination therapy, are limited. This study aimed to investigate the occurrence of intraocular hemorrhages under monotherapy and combination therapy with antiplatelets and anticoagulants by analyzing a large pharmacovigilance database. Methods: Intraocular hemorrhage signals with oral antiplatelets and anticoagulants were evaluated by calculating reporting odds ratios and information components using the Japan Adverse Drug Reactions Report database from April 2004 to March 2022. In addition, differences in signals between younger and elderly patients, affecting factors, and time-to-onset from initial antiplatelet and anticoagulant treatments were analyzed. Results: Aspirin, clopidogrel, warfarin, apixaban, and rivaroxaban, but not ticagrelor, ticlopidine, prasugrel, dabigatran, and edoxaban showed intraocular hemorrhage signals under monotherapy. In combination therapy, dual therapy (aspirin + P2Y12 inhibitors, warfarin, direct oral anticoagulants, and P2Y12 inhibitors + warfarin) and triple therapy (aspirin + P2Y12 inhibitors + warfarin) resulted in intraocular hemorrhage signals. Intraocular hemorrhage signals were observed in younger patients receiving monotherapy with aspirin and in elderly patients receiving monotherapy and combination therapy with warfarin. Affecting factors were diabetes mellitus in patients with prasugrel, use of medications for intravitreal injections, and posterior sub-Tenon injections with some antiplatelets and anticoagulants. The median period of intraocular hemorrhage occurrence after starting monotherapy with aspirin, clopidogrel, warfarin, or rivaroxaban was within 90 days. Conclusion: In addition to monotherapy with several antiplatelets and anticoagulants, combination therapy using aspirin, P2Y12 inhibitors, and warfarin has the potential risk of intraocular hemorrhage. Particular attention should be paid to the occurrence of intraocular hemorrhages in younger patients taking aspirin, in elderly patients taking warfarin, and within the first 90 days of antiplatelet and anticoagulant use.

Among antipsychotics, clozapine is associated with a high risk of seizures. This study aimed to generate novel hypotheses regarding trends in the onset of clozapine-induced seizures using the JADER (Japanese Adverse Drug Event Report) database. Seizures were defined according to the Standardized MedDRA Queries (SMQ) for convulsions (SMQ20000079). Trends in the onset of clozapine-induced seizures were assessed using multivariate logistic regression analysis with covariates of sex, age, clozapine dose, antipsychotic polypharmacy, concomitant medications, and history of convulsive disorder. In addition, we assessed the time-to-onset of clozapine-induced seizures using the median time, interquartile range, and Weibull shape parameter. The JADER database registered 2,745 cases of adverse events with clozapine, and 1,784 cases were included in the analysis after excluding cases for which clinical information was not available. Medium (200-400 mg) and high (> 400 mg) doses of clozapine had a significantly higher reporting rate of seizures than low doses (< 200 mg) (adjusted reporting odds ratio [aROR] = 3.05, 95% confidence interval [CI]: 1.86-4.99 and aROR = 9.81, 95% CI: 6.06-15.89, respectively). Younger age, antipsychotic polypharmacy, and concomitant use of lithium were also significantly associated with reports of seizures. The time-to-onset analysis of 222 cases of clozapine-induced seizures showed that the median time was 134 (interquartile range, 72-295) days. The 95% CI of the WSP β-value for clozapine-induced seizures included 1 and was classified as a random failure type. In conclusion, the results suggest that clozapine-induced seizures are dose-dependent adverse events that should be monitored with consideration of the effects of age and concomitant medications. Further epidemiological research is needed to strengthen and validate our hypotheses.

PURPOSE: Several nationwide population-based studies have reported that patients with psychiatric disorders are at higher risk of developing chronic kidney disease, chronic liver disease, and metabolic syndrome than the general population; however, there are insufficient studies in the Japanese population. Thus, we aimed to clarify the influence of psychiatric disorders on clinical laboratory data in the Japanese population. PATIENTS AND METHODS: This cross-sectional study was based on medical records from the Department of Psychiatry at Fujita Health University Hospital and the 6th National Database of Health Insurance Claims and Specific Health Checkups of Japan Open Data Japan (specific health checkups in 2018) in the Ministry of Health, Labor and Welfare. The primary endpoint was the incidence of clinical laboratory abnormalities in patients with psychiatric disorders and the general Japanese population. RESULTS: Compared to the general Japanese population, patients with psychiatric disorders had significantly higher rates of the following clinical laboratory abnormalities: estimated glomerular filtration rate, alanine transaminase, aspartate aminotransferase (AST), body mass index (BMI), high-density lipoprotein cholesterol (HDL-C), triglycerides, and hemoglobin A1c (HbA1c). In the age-specific analysis, AST, BMI, HDL-C, and HbA1c levels were more frequently abnormal in patients with psychiatric disorders only in the 40-49 and 50-59 age groups. CONCLUSION: Our results showed that patients with psychiatric disorders have higher rates of various clinical laboratory abnormalities than the general Japanese population, with stronger influences in the middle-aged group. These data suggest the importance of monitoring and preventing chronic diseases in patients with psychiatric disorders in Japan.

We evaluated the impact of carbapenem shortage on antimicrobial practice and patient outcome at a tertiary care center. During the shortage, hospital antimicrobial practice could be safely managed through additional antimicrobial stewardship measures including treatment guidance and mandatory preauthorization. Antimicrobial shortage may present a unique opportunity for promoting antimicrobial stewardship.

BACKGROUND/AIM: Sepsis is a life-threatening biological condition that induces systemic tissue and organ dysfunction and confers a high mortality risk. Although the use of hydrocortisone in combination with ascorbic acid and thiamine (HAT therapy) significantly reduced mortality from sepsis or septic shock in a previous study, it did not improve mortality in subsequent randomized controlled trials (RCTs). Therefore, no definitive conclusion has been established on the benefits of HAT therapy for sepsis or septic shock. We performed a meta-analysis to assess the treatment outcomes of HAT therapy in patients with sepsis or septic shock. PATIENTS AND METHODS: We searched databases (PubMed/MEDLINE, Embase, Scopus and Cochrane Library) for RCTs using the terms "ascorbic acid", "thiamine", "sepsis", "septic shock", and "RCT". The primary outcome of this meta-analysis was the mortality rate, and the secondary outcomes were the incidence of new-onset acute renal injury (AKI), intensive care unit (ICU) length of stay (ICU-LOS), change in the Sequential Organ Failure Assessment (SOFA) score within 72 hours, and duration of vasopressor use. RESULTS: Nine RCTs were identified and included in the outcome evaluation. HAT therapy did not improve the 28-day and ICU mortality, new-onset AKI, ICU-LOS, or SOFA scores. However, HAT therapy significantly shortened the duration of vasopressor use. CONCLUSION: HAT therapy did not improve mortality, the SOFA score, renal injury, or ICU-LOS. Further studies are needed to confirm whether it shortens the duration of vasopressor use.

Purpose: Coronavirus disease 2019 (COVID-19) mRNA vaccines are used worldwide to prevent severe symptoms of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. IgA nephropathy (IgAN) is the most common form of glomerular injury after COVID-19 vaccination; however, because of the low frequency of such events, only a few reports have been published. A large pharmacovigilance database of real-world spontaneous adverse event (AE) reports is essential for evaluating the drug-associated safety signals regarding rare AEs. Herein, we aimed to investigate the frequency of IgAN after the COVID-19 vaccination, using the Japanese Adverse Drug Event Report (JADER) database. Methods: Data on drug-associated AEs reported between April 2004 and May 2022 were obtained from the JADER database on the Pharmaceuticals and Medical Devices Agency website. To evaluate the safety signals for the targeted AEs, reporting odds ratios (RORs), information components (ICs), and their 95% confidence intervals (CIs) were calculated using two-by-two contingency tables. Results: A total of 697,885 cases were included in the analysis. Safety signals were detected for IgAN (ROR: 6.49, 95% CI: 4.38-9.61; IC: 2.27, 95% CI: 1.70-2.83). Of 30 cases for IgAN associated with COVID-19 mRNA vaccines, 16 had information available on time to onset. Of the 16 cases, 11 occurred ≤2 days after vaccination, and two occurred >28 days after vaccination. Conclusion: These results suggest that, compared with other drugs, COVID-19 vaccination is associated with a higher frequency of IgAN. Monitoring of gross hematuria following COVID-19 vaccination should be needed.

BACKGROUND/AIM: This study aimed to determine whether a high neutrophil-lymphocyte ratio (NLR) was associated with the occurrence of febrile neutropenia (FN). PATIENTS AND METHODS: Japanese patients with esophageal cancer who had been treated with first-line 5-fluorouracil and cisplatin therapy at Fujita Health University from April 2016 to March 2021 were enrolled in this retrospective cohort study. The primary outcome was the identification of independent risk factors for FN. RESULTS: One hundred and fourteen patients were enrolled. Advanced cancer (hazard ratios (HR)=6.731) and an NLR ≥3 (HR=4.849) were identified as risk factors for FN. Furthermore, FN occurred earlier in patients with high NLR than in patients with low NLR. CONCLUSION: Advanced cancer and a high NLR might be predictors of the occurrence of severe neutropenia and FN in patients treated with 5-fluorouracil and cisplatin therapy.

BACKGROUND/AIM: The systemic administration of anticancer drugs may cause ocular adverse reactions (OARs). However, such adverse events are generally rare and occur with an unknown frequency. This study aimed to investigate the tendency of occurrence of OARs induced by systemic anticancer drugs using a large spontaneous pharmacovigilance database in Japan. PATIENTS AND METHODS: The safety signals for eight OARs (periorbital and eyelid, conjunctival, corneal, scleral, lacrimal, lens, retinal, and optic nerve disorders) and their associations with anticancer drugs were evaluated by analyzing reporting odds ratios (RORs) and information components (ICs) based on data from the Japanese Adverse Drug Event Report (JADER). RESULTS: Safety signals associated with anticancer drugs were detected for periorbital and eyelid disorders (imatinib), conjunctival disorders (imatinib and lapatinib), corneal disorders (S-1, erlotinib, capecitabine, cetuximab, gefitinib, vandetanib, trastuzumab emtansine, lapatinib), lacrimal disorders (S-1, pembrolizumab), lens disorders (lenalidomide, pomalidomide, elotuzumab, tamoxifen, bexarotene, venetoclax), retinal disorders (encorafenib, binimetinib, tamoxifen, nab-paclitaxel, trametinib, dabrafenib), and optic nerve disorders (tamoxifen and blinatumomab). Some anticancer drugs showed differences in safety signals based on sex and age. CONCLUSION: Safety signals indicative of the risk of occurrence of OARs were observed for several anticancer drugs, and several hitherto unreported ocular adverse events requiring caution were also detected. Our results will help predict the occurrence of OARs by oncologists, ophthalmologists, pharmacists, and other healthcare professionals.

2019年9月から2021年8月までに、藤田医科大学病院、桶狭間病院藤田こころケアセンターで統合失調症と診断され、ブロナンセリン(BNS)貼付剤4週間以上の使用経験がある20歳以上の患者32名(入院患者22名、外来患者10名)に効果の実感度、副作用等が患者の満足度や薬剤の継続意思に及ぼす影響について検討した。23名(男性10名、女性13名、平均年齢52.6±12.6歳)から質問紙への調査協力を得た。罹病期間は平均26.0±16.0年であり、DAI-10の合計スコアは平均5.7±3.9であった。BNS貼付剤の投与量は40mgが7名、80mgが16名であった。BNS貼付剤の投与は前薬からの切り替えが15名、前薬への上乗せ処方が8名であった。BNS貼付剤の効果については「大変効果がある」6名、「大体効果がある」12名との回答で、78.3%の対象者が効果を感じていた。皮膚症状や使用方法の負担を強く感じている場合でも、薬剤の効果を実感している患者は使用満足度が高いことが示唆された。