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A post-marketing study was performed on all patients who had started treatment with iguratimod, a conventional synthetic disease-modifying antirheumatic drug approved in Japan. During the study period, various safety measures were implemented to reduce risks. We investigated the frequency of adverse drug reactions before and after implementation of each safety measure to examine the preventive effect of these measures. Post-hoc analysis was performed using data from all-case surveillance of iguratimod. The subjects were all of the patients receiving iguratimod for whom safety information was obtained. To identify the time after starting administration when adverse drug reactions were most likely to occur, a generalized linear mixed-effect model was applied for the period from initiation of administration until occurrence of reactions in each patient. The mean incidence of adverse drug reactions per patient was compared before and after the implementation of safety measures by using generalized estimating equations based on a two-sided test, 95% confidence interval, and 5% significance level. The number of patients treated with iguratimod was not related to changes in the number of patients with adverse drug reactions. After implementing precautions regarding co-administration with warfarin and liver dysfunction, the estimated mean incidence rate of adverse drug reactions (95% confidence interval) decreased significantly to 0.73 (0.59–0.90) and 0.72 (0.55–0.94), respectively. Accordingly, some of the implementation of safety measures significantly reduced adverse drug reactions. The effectiveness of safety measures implemented during the all-case surveillance of iguratimod was evaluated, revealing that early implementation of safety measures decreased the incidence of adverse drug reactions.

Background and objective A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind. Methods Insomnia patients ( n  = 550) administered LEM (5–10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient’s complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters. Results A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment. Conclusion Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful.

Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

BackgroundLenvatinib demonstrated a treatment effect on overall survival by the statistical confirmation of non-inferiority to sorafenib for the first-line treatment of uHCC. The objective of this study was to evaluate the cost-effectiveness of lenvatinib compared with sorafenib for patients with uHCC in Japan.MethodsA partitioned-survival model was developed to estimate the cost-effectiveness of lenvatinib versus sorafenib when treating uHCC patients over a lifetime horizon and considering total public healthcare expenditure. Efficacy and safety data were extracted from the REFLECT trial. Utility values were derived from the European Quality-of-Life 5-Dimension Questionnaire, conducted with patients enrolled in the REFLECT trial. Direct medical costs, such as primary drug therapy, outpatient visits, diagnostic tests, hospitalization, post-progression therapy, and adverse-event treatments, were included. Cost parameters unavailable in the clinical trial or publications were obtained based on the consolidated clinical standards from a Delphi panel of four Japanese medical experts.ResultsFor lenvatinib versus sorafenib, the incremental cost was − 406,307 Japanese Yen (JPY), and the incremental life years and quality-adjusted life years (QALYs) were 0.27 and 0.23, respectively. Thus, lenvatinib dominated sorafenib, due to the mean incremental cost-effectiveness ratio falling in the fourth quadrant, conferring more benefit at lower costs compared with sorafenib. The probabilistic sensitivity analysis showed that 81.3% of the simulations were favorable to lenvatinib compared with sorafenib, with a payer’s willingness-to-pay-per-QALY of 5 million JPY.ConclusionsLenvatinib was cost-effective compared with sorafenib for the first-line treatment of uHCC in Japan.

Purpose This study aimed to investigate the molecular mechanisms associated with chromosome segregation errors caused by intrinsic oxidative stress during in vitro oocyte maturation (IVM) using oocytes from Sod1‐deficient (Sod1KO) mice. Methods Ovulated or in vitro matured cumulus‐cells oocyte complexes (COCs) were collected from wild‐type (WT) and Sod1KO mice and evaluated chromosome alignment, chromosome segregation, meiotic progression, and BUBR1 and REC8 protein expression levels. Results In 21% O2 IVM, the Sod1KO had significantly higher frequencies of chromosome misalignment and segregation errors compared to the WT, and they also reached Germinal Vesicle Break Down (GVBD) and M I stages peak earlier and showed a shorter M I stage residence time compared to the WT. These changes were associated with a decrease in the recruitment of BUBR1 to kinetochores at M I stage, but there were no differences in the expression of REC8 between the two genotypes. Furthermore, the addition of L‐ascorbic acid (AsA) or N‐acetyl‐L‐cysteine (NAC) during IVM reduced the frequency of chromosome segregation errors in Sod1KO oocytes. Conclusions Oxidative stress caused by Sod1 deficiency during IVM impairs the spindle assembly checkpoint function due to a decrease in the recruitment of BUBR1 to M I stage kinetochores, leading to abnormalities in meiotic progression and chromosome segregation. Intrinsic oxidative stress caused by a Sod1 deficiency during oocyte maturation induces meiotic chromosome segregation errors by reducing its function as a spindle assembly checkpoint as the result of a decreased recruitment of BUBR1 to kinetochores at metaphase I.

Postmarketing surveillance is useful to collect safety data in real‐world clinical settings. In this study, we applied postmarketing real‐world data on a mechanistic model analysis for neutropenic profiles of eribulin in patients with recurrent or metastatic breast cancer. Demographic and safety data were collected using an active surveillance method from eribulin‐treated recurrent or metastatic breast cancer patients. Changes in neutrophil counts over time were analyzed using a mechanistic pharmacodynamic model. Pathophysiological factors that might affect the severity of neutropenia were investigated, and neutropenic patterns were simulated for different treatment schedules. Clinical and laboratory data were collected from 401 patients (5199 neutrophil count measurements) who had not received granulocyte colony‐stimulating factor and were eligible for pharmacodynamic analysis. The estimated mean parameters were as follows: mean transit time = 104.5 h, neutrophil proliferation rate constant = 0.0377 h−1, neutrophil elimination rate constant = 0.0295 h−1, and linear coefficient of drug effect = 0.0413 mL/ng. Low serum albumin levels and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted to be 69%, 27%, and 27% for patients on standard, biweekly, and triweekly treatment scenarios, respectively, based on virtual simulations using the developed pharmacodynamic model. In conclusion, this is the first application of postmarketing surveillance data to a model‐based safety analysis. This analysis of safety data reflecting authentic clinical settings will provide useful information on the safe use and potential risk factors of eribulin. This article reports the first application of postmarketing real‐world data on a mechanistic pharmacodynamic model for neutropenic profiles by eribulin. Low serum albumin and low baseline neutrophil counts were associated with severe neutropenia. The probability of grade ≥3 neutropenia was predicted in different dosing schedules, based on virtual simulations using the developed pharmacodynamic model.

Recent studies have demonstrated that large language models exhibit exceptional performance in medical examinations. However, there is a lack of reports assessing their capabilities in specific domains or their application in practical data analysis using code interpreters. Furthermore, comparative analyses across different large language models have not been extensively conducted. The purpose of this study was to evaluate whether advanced artificial intelligence (AI) models can analyze data from template-based input and demonstrate basic knowledge of reproductive medicine. Four AI models (GPT-4, GPT-4o, Claude 3.5 Sonnet, and Gemini Pro 1.5) were evaluated for their data analytical capabilities through numerical calculations and graph rendering. Their knowledge of infertility treatment was assessed using 10 examination questions developed by experts. First, we uploaded data to the AI models and furnished instruction templates using the chat interface. The study investigated whether the AI models could perform pregnancy rate analysis and graph rendering, based on blastocyst grades according to Gardner criteria. Second, we assessed model diagnostic capabilities based on specialized knowledge. This evaluation used 10 questions derived from the Japanese Fertility Specialist Examination and the Embryologist Certification Exam, along with chromosome imaging. These materials were curated under the supervision of certified embryologists and fertility specialists. All procedures were repeated 10 times per AI model. GPT-4o achieved grade A output (defined as achieving the objective with a single output attempt) in 9 out of 10 trials, outperforming GPT-4, which achieved grade A in 7 out of 10. The average processing times for data analysis were 26.8 (SD 3.7) seconds for GPT-4o and 36.7 (SD 3) seconds for GPT-4, whereas Claude failed in all 10 attempts. Gemini achieved an average processing time of 23 (SD 3) seconds and received grade A in 6 out of 10 trials, though occasional manual corrections were needed. Embryologists required an average of 358.3 (SD 9.7) seconds for the same tasks. In the knowledge-based assessment, GPT-4o, Claude, and Gemini achieved perfect scores (9/9) on multiple-choice questions, while GPT-4 showed a 60% (6/10) success rate on 1 question. None of the AI models could reliably diagnose chromosomal abnormalities from karyotype images, with the highest image diagnostic accuracy being 70% (7/10) for Claude and Gemini. This rapid processing demonstrates the potential for these AI models to significantly expedite data-intensive tasks in clinical settings. This performance underscores their potential utility as educational tools or decision support systems in reproductive medicine. However, none of the models were able to accurately interpret and diagnose using medical images.

Background To understand the extent to which a large-scale healthcare claims database (DB) captures the safety profile of eribulin mesylate (Halaven ® , Eisai Co., Ltd., Japan), we compared patient characteristics, drug use, and adverse events (AEs) between data for patients treated with eribulin retrieved from a DB and data for metastatic breast cancer patients from a conventional prospective post-marketing surveillance (PMS). Methods We descriptively summarized patient characteristics and AEs of 551 and 951 patients retrieved from DB and PMS, respectively, during 2011‒2013. Using 2814 patient data from the DB during 2011‒2016, the drug use and AE incidence over time were assessed. Results In both datasets, 99.8% were females, and the mean age was 57.8 ± 10.7 years. The mean number of eribulin administration was 11.1 ± 10.9 and 10.1 ± 7.8 in DB and PMS, respectively. Although, overall, the difference in AE incidence between the two datasets was moderate, gaps were larger for nausea (DB: 73.32% vs. PMS: 15.77%), neutropenia (20.87% vs. 66.67%), stomatitis (37.39% vs. 10.94%), and alopecia (0.36% vs. 12.09%). During 2011‒2016, the observed incidence of anemia or pyrexia significantly decreased (trend test, p  = 0.0009 for both). Conclusion Generally, patient characteristics, drug use, and AE incidence between the DB and PMS were comparable; however, AEs such as neutropenia may require defining based on the laboratory data to achieve more comparable results in DBs. Besides the usefulness of healthcare claims DBs for long-term assessments, they may also serve as a good complementary to PMS in the pharmacovigilance of eribulin.