Analysis of drug adverse events in elderly patients based on the Japanese Adverse Drug Event Report Database.

WHAT IS KNOWN AND OBJECTIVE: Compared with the general adult population, pharmacokinetics and changes in drug responsiveness occur to a greater extent in the elderly. Interactions may occur between drugs used in combination to treat various diseases and may cause adverse events (AEs). We conducted a cross-sectional risk assessment of AEs in elderly patients based on information gathered from Japanese medical practices with the goal of obtaining information that will contribute to optimizing pharmacotherapy. METHODS: The Japanese Adverse Drug Event Report database was used to determine the incidence of AEs in elderly patients (aged 80 years or older) compared with patients aged less than 80 years old by evaluating the reporting odds ratio using the data obtained from reports. RESULTS AND DISCUSSION: Hypnotics and anxiolytics, as well as anticoagulants and theophylline, were identified as groups of drugs that warrant special attention in the elderly. Hypnotics and anxiolytics, especially those that are short-acting, tend to cause delirium and geriatric syndromes including falls and fractures. With respect to anticoagulants, no increase in the risk of bleeding was evident and the dose was believed to be properly adjusted; however, there was an increased risk of anemia. Theophylline toxicity tended to occur more frequently in the elderly, suggesting the need for drug monitoring. WHAT IS NEW AND CONCLUSION: Based on these cross-sectional studies, the evaluation of the risk of AEs for drugs commonly used in the elderly based on near real-world information was achieved.

Terahertz intersublevel transitions in single self-assembled InAs quantum dots with variable electron numbers.

We propose a method for performing terahertz spectroscopy on nanometer (nm)-scale systems by using metal nanogap electrodes. Intersublevel transition spectra of single self-assembled InAs quantum dots (QDs) have been measured with high signal/noise ratios by using a single electron transistor geometry that consists of a QD and nanogap metal electrodes as a terahertz detector. Photocurrent distribution with respect to the Coulomb diamonds indicates that there are two mechanisms for the photocurrent generation. When the p shell was fully occupied, we observed rather simple photocurrent spectra induced by the p → d transitions. However, when the p shell was half-filled, the photocurrent spectra exhibited a markedly different behavior, which we attribute to the fluctuation in electron configuration when the empty p state is filled back from the electrodes.

Waveguide coupled air-slot photonic crystal nanocavity for optomechanics.

We investigate a structure consisting of two parallel GaAs thin membranes with an air-slot type photonic crystal (PhC) nanocavity, which is designed to achieve highly efficient optomechanical coupling. The structure shows a large theoretical optomechanical coupling factor of ~990 GHz/nm. We designed, fabricated, and performed optical characterization of a system consisting of a grating coupler, a PhC waveguide, and a PhC nanocavity, which achieves highly efficient vertical emission using the band folding technique. The experimentally obtained overall efficiency is about 0.3% for a microscope objective lens with a moderate numerical aperture of 0.65. This waveguide coupled air-slot PhC nanocavity with efficient vertical light coupling can be useful for on-chip cavity optomechanical systems.

Co-Development of Oncology Drugs and Companion Diagnostics: Analyses of Approval Lags and Drug Development Periods in Recently Approved Cases in Japan.

BACKGROUND: The utilization of biomarkers has become increasingly active to enhance efficiency of clinical development. This study evaluated the current situation and quantitative impact of co-development of companion diagnostics (CDx) on the oncology drug development in Japan. METHODS: Based on publicly available information about the oncology drugs and CDx approved in Japan in 2010-2020, we evaluated the approval lag time between drugs and CDx, and the duration between the pivotal study start date and the new drug application submission date (the time to application). Influences of multiple factors including the use of CDx on the time to application were also analyzed. RESULTS: A diagnostic test was mostly used from an early development phase such as phase1/2 study, and the median approval lag has tended to decrease when approved CDx were used (- 507 vs. - 25 days for newly developed CDx). The shorter median times to application were observed in Drugs with CDx (1204 days) compared to Targeted therapies without CDx (1423 days) or Other drugs without CDx (1853 days), although both the cancer types and the implementation of multi-regional clinical trials have a larger impact on the time to application compared to the use of CDx. CONCLUSIONS: The use of CDx from the early development phase and the global development strategy could have a positive contribution on the development period of oncology drugs, which will facilitate patients' earlier access to the optimal treatment.

Incidence of stroke, systemic embolism and bleeding events in patients without anticoagulation based on real-world data in Japan: a retrospective cohort study.

OBJECTIVES: To examine the incidence of stroke or systemic embolic events (SSEs) and bleeding events in untreated patients with non-valvular atrial fibrillation (NVAF) after widespread use of direct oral anticoagulant agents (DOACs). DESIGN: Multicentre, non-interventional, observational, retrospective cohort study using real-world data in Japan (2016-2018). SETTING: The Mie, Musashino University study of NVAF, which used the Mie-Life Innovation Promotion Center Database. This is a regional clinical database involving one university hospital and eight general hospitals in Mie Prefecture in Japan. PARTICIPANTS: Japanese patients with NVAF (n=7001). PRIMARY AND SECONDARY OUTCOME: The incidence of SSEs and bleeding events. RESULTS: A total of 7001 patients with NAVF were registered, and 53.0% were treated with DOACs, 10.6% were treated with warfarin and 36.4% had no treatment. Additionally, 29.5% of patients with a CHADS2 (congestive heart failure, hypertension, age≥75 years, diabetes, previous stroke or transient ischemic attack) score of 3-6 were untreated. In the no treatment group, the SSE rates by the CHADS2 score (0, 1, 2 and 3-6) were 1.4%, 1.4%, 3.2% and 8.0%, respectively. The rates of bleeding events by the CHADS2 score (0, 1, 2 and 3-6) in the no treatment group were 0.7%, 1.0%, 1.2% and 2.9%, respectively. A multivariate analysis of SSEs in components of the CHADS2 showed that the adjusted HRs were 2.32 for heart failure, 1.66 for an age ≥75 years, 1.81 for diabetes mellitus and 5.84 for prior stroke or transient ischaemic attack. CONCLUSIONS: Approximately one-third of the patients do not receive any anticoagulation in the modern DOAC era in Japan. The SSE rate increases by the CHADS2 score. The SSE rate is low in patients with a CHADS2 score <1, supporting no indication of anticoagulation in current guidelines. In patients with a CHADS2 score >1, the use of anticoagulant drug therapy is recommended because of a higher risk of stroke.

Model-based approach to sampling optimization in studies of antibacterial drugs for infants and young children.

Clinical trials for pediatric indications and new pediatric drugs face challenges, including the limited blood volume due to the patients' small bodies. In Japan, the Evaluation Committee on Unapproved or Off-labeled Drugs with High Medical Needs has discussed the necessity of pediatric indications against the background of a lack of Japanese pediatric data. The limited treatment options regarding antibiotics for pediatric patients are associated with the emergence of antibiotic-resistant bacteria. Regulatory guidelines promote the use of model-based drug development to reduce practical and ethical constraints for pediatric patients. Sampling optimization is one of the key study designs for pediatric drug development. In this simulation study, we evaluated the precision of the empirical Bayes estimates of pharmacokinetic (PK) parameters based on the sampling times optimized by published pediatric population PK models. We selected three previous PK studies of cefepime and ciprofloxacin in infants and young children as paradigms. The number of sampling times was reduced from original full sampling times to two to four sampling times based on the Fisher information matrix. We observed that the precision of empirical Bayes estimates of the key PK parameters and the predicted efficacy based on the reduced sampling times were generally comparable to those based on the original full sampling times. The model-based approach to sampling optimization provided a maximization of PK information with a minimum burden on infants and young children for the future development of pediatric drugs.

Classification of drugs for evaluating drug interaction in drug development and clinical management.

During new drug development, clinical drug interaction studies are carried out in accordance with the mechanism of potential drug interactions evaluated by in vitro studies. The obtained information should be provided efficiently to medical experts through package inserts and various information materials after the drug's launch. A recently updated Japanese guideline presents general procedures that are considered scientifically valid at the present moment. In this review, we aim to highlight the viewpoints of the Japanese guideline and enumerate drugs that were involved or are anticipated to be involved in evident pharmacokinetic drug interactions and classify them by their clearance pathway and potential intensity based on systematic reviews of the literature. The classification would be informative for designing clinical studies during the development stage, and the appropriate management of drug interactions in clinical practice.

Development of a new Japanese guideline on drug interaction for drug development and appropriate provision of information.

Drug interactions, in particular with concomitant drugs having a narrow therapeutic range, sometimes cause serious adverse drug reactions or attenuation of the therapeutic effect. Therefore, evaluation of the characteristics and severities of possible drug interactions in drug development is essential to understand such interactions to help prevent any potential risk for patients. In Japan, a regulatory document which was notified in 2001 to outline the basic principles of drug interaction studies during drug development was revised as a new guideline after 17 years to present general procedures that are currently considered scientifically valid. This article aims to present an overview of development process of the new Japanese guideline for investigating drug interactions and show the impact of implementating this guideline on drug interaction evaluations, thereby providing future perspectives of regulatory activities on drug interactions.

COVID-19 Pandemic Challenges and Lessons Learned by Pharmacy Educators Around the Globe.

The coronavirus identified in 2019 (COVID-19) has affected peoples' lives worldwide. This pandemic forced both pharmacy faculty members and students to adapt to a new teaching and learning environment not only in the United States but around the globe. Pharmacy educators faced challenges and opportunities to convert classroom learning and experiences, as well as student assessments, to a remote or online format. The unique approaches taken to overcome difficulties in various countries showed pharmacy faculty members' resilience in the face of adversity and their determination to continue providing education to students. The pandemic also shed light on areas needing improvement for pharmacy educators to work on in the future.

Evaporative electron cooling in asymmetric double barrier semiconductor heterostructures.

Rapid progress in high-speed, densely packed electronic/photonic devices has brought unprecedented benefits to our society. However, this technology trend has in reverse led to a tremendous increase in heat dissipation, which degrades device performance and lifetimes. The scientific and technological challenge henceforth lies in efficient cooling of such high-performance devices. Here, we report on evaporative electron cooling in asymmetric Aluminum Gallium Arsenide/Gallium Arsenide (AlGaAs/GaAs) double barrier heterostructures. Electron temperature, Te, in the quantum well (QW) and that in the electrodes are determined from photoluminescence measurements. At 300 K, Te in the QW is gradually decreased down to 250 K as the bias voltage is increased up to the maximum resonant tunneling condition, whereas Te in the electrode remains unchanged. This behavior is explained in term of the evaporative cooling process and is quantitatively described by the quantum transport theory.

Relationship Between the Review Time and Various PMDA Consultations in Recent New Drug Approval Cases in Japan.

BACKGROUND: It is considered important that the applicants and reviewers communicate well from the development stage and that both mutually understand the development strategy and application contents in conducting the review efficiently after the application is submitted. Therefore, we focus on Pharmaceuticals and Medical Devices Agency (PMDA) consultations from the viewpoint of communication before the application and clarify the issues to consider in the challenge to reduce the review time in terms of the relationship between the review time and various PMDA consultations. METHODS: We investigated the relationship between the review time and various PMDA consultations for the drugs with new active ingredients approved in Japan using public information from the PMDA. RESULTS: Review times tended to be shorter as more PMDA consultations were conducted. In standard review products, statistically significant differences were noted in the review times (median). When looking at the results of the cases of each category of PMDA consultations, variations in the review times were greater as the consultations were conducted in the later stages of clinical development. Review times tended to be shorter when prior assessment consultations were conducted. In standard review products, significant reductions were noted with the review time (median). CONCLUSIONS: It was suggested that conducting more PMDA consultations might lead to shorter review times. Regarding the review times, variations from the standard review time could possibly be smaller by conducting PMDA consultations from the early stage of clinical development in Japan. It was suggested that review times could possibly be further reduced by conducting prior assessment consultations.

Single-electron charge sensing in self-assembled quantum dots.

Measuring single-electron charge is one of the most fundamental quantum technologies. Charge sensing, which is an ingredient for the measurement of single spins or single photons, has been already developed for semiconductor gate-defined quantum dots, leading to intensive studies on the physics and the applications of single-electron charge, single-electron spin and photon-electron quantum interface. However, the technology has not yet been realized for self-assembled quantum dots despite their fascinating transport phenomena and outstanding optical functionalities. In this paper, we report charge sensing experiments in self-assembled quantum dots. We choose two adjacent dots, and fabricate source and drain electrodes on each dot, in which either dot works as a charge sensor for the other target dot. The sensor dot current significantly changes when the number of electrons in the target dot changes by one, demonstrating single-electron charge sensing. We have also demonstrated real-time detection of single-electron tunnelling events. This charge sensing technique will be an important step towards combining efficient electrical readout of single-electron with intriguing quantum transport physics or advanced optical and photonic technologies developed for self-assembled quantum dots.

Drug interaction studies on new drug applications: current situations and regulatory views in Japan.

Drug interaction studies on new drug applications (NDAs) for new molecular entities (NMEs) approved in Japan between 1997 and 2008 are examined in the Pharmaceuticals and Medical Devices Agency (PMDA). The situations of drug interaction studies in NDAs have changed over the past 12 years, especially in metabolizing enzyme and transporter-based drug interactions. Materials and approaches to study drug-metabolizing enzyme-based drug interactions have improved, and become more rational based on mechanistic theory and new technologies. On the basis of incremental evidence of transporter roles in human pharmacokinetics, transporter-based drug interactions have been increasingly studied during drug development and submitted in recent NDAs. Some recently approved NMEs include transporter-based drug interaction information in their package inserts (PIs). The regulatory document "Methods of Drug Interaction Studies," in addition to recent advances in science and technology, has also contributed to plan and evaluation of drug interaction studies in recent new drug development. This review summarizes current situations and further discussion points on drug interaction studies in NDAs in Japan.