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Introduction: Pharmacists are needed as members of oncology teams. The Japanese Society of Hospital Pharmacists (JSHP) conducts a nationwide survey annually to analyze the actual situation and generate fundamental information about hospital pharmacy practice in Japan. Using data from this large-scale survey, we described pharmacists' involvement in cancer chemotherapy. We explored the factors related to the acceleration of pharmacists' tasks or involvement in clinical practice, primarily in oncology., Methods: Data were obtained from annual surveys conducted by JSHP from 2015 to 2020. All variables were expressed as categorical variables and tabulated. The Chi-square and Fisher's exact tests were used to compare the categorical variables. The Cochran-Armitage trend test was used to identify significant trends., Results: From 2015 to 2020, 22,362 responses were recorded. After applying the exclusion criteria, 20,906 were analyzed. The proportion of hospitals enrolling pharmacists with oncology-related certifications significantly increased in all hospitals providing cancer care. Multivariable logistic regression analysis indicated that a smaller number of beds per pharmacist significantly correlated with additional fees for outpatient pharmacy services ( p  = 0.0002 for trend)., Conclusion: Hospitals charging increased fees for outpatient oncology pharmacy services were associated with a smaller number of beds per pharmacist, regardless of hospital size. A balance between the number of beds and pharmacists, particularly certified oncology pharmacists, is crucial for safe and high-quality cancer treatment., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Photoinduced single-electron reduction is an efficient method for the mono-selective activation of the C-F bond on a trifluoromethyl group to construct a difluoroalkyl group. We have developed an electron-donor-acceptor (EDA) complex mediated single-electron transfer (EDA-SET) of α,α,α-trifluoromethyl arenes in the presence of lithium salt to give α,α-difluoroalkylarenes. The C-F bond reduction was realized by lithium iodide and triethylamine, two common feedstock reagents. Mechanistic studies revealed the generation of a α,α-difluoromethyl radical by single-electron reduction and defluorination, followed by the radical addition to alkenes. Lithium salt interacted with the fluorine atom to promote the photoinduced reduction mediated by the EDA complex. Computational studies indicated that the lithium-assisted defluorination and the single-electron reduction occurred concertedly. We call this phenomenon fluoride-coupled electron transfer (FCET). FCET is a novel approach to C-F bond activation for the synthesis of organofluorine compounds., (© 2024 Wiley-VCH GmbH.)

1,1'-Binaphthyl-2,2'-diamine (BINAM) is a useful axially chiral compound. The kinetic resolution of BINAM is one of the most crucial methods for synthesizing chiral BINAM. We have developed a chiral calcium phosphate-catalyzed kinetic resolution of BINAM by utilizing an acylation reaction to produce a mono-amide. The kinetic resolution of BINAM derivatives was achieved by using isobutyric anhydride in the presence of chiral calcium phosphate and 4-morpholinopyridine with up to s = 127. 6,6'-Substituted BINAM derivatives were also applicable for this reaction. The resulting mono-acylated BINAM could be transformed into BINAM by hydrolysis under acidic conditions.

Introduction: Atlantoaxial rotatory fixation (AARF) in children presents with an acute onset of neck pain. Almost all cases heal within a few days of onset and are treated conservatively. Because few cases of AARF have been reported, the age distribution or gender ratio of AARF in the child population have not been described enough. In Japan, the social insurance system covers all citizens. Thus, we used insurance claims data to investigate the features of AARF. The aim of this study is to examine the age distribution, compare gender ratio and determine the recurrence proportion of AARF., Methods: We used the JMDC database to search for claims data submitted between January 2005 and June 2017 for cases of AARF in patients aged <20 years., Results: We identified 1949 patients with AARF, of which 1102 (56.5%) were male. The mean age was 98.3 ± 42.2 months and 91.6 ± 38.4 months in males and females, respectively, and males with AARF were significantly older at onset than females with AARF (p < 0.001). In both sexes, the highest frequency of AARF occurred when the patient was 6 years old. There were 121 (6.2%) cases of recurrent AARF (male: 61, 5.5%; female: 60, 7.1%), but the age differences between the sexes in these cases were not statistically significant., Conclusions: This is the first report to describe the characteristics of the study population of AARF. Males were more likely to suffer from AARF than females. Furthermore, age (in months) at AARF onset was significantly higher in males than in females. Recurrence rate was not significant in both sexes., Competing Interests: Declaration of competing interest Y.O. received lecture fees from Daiichi Sankyo Co. Ltd and Asahi Kasei Pharma. K.M. and JMDC Inc. collaborate other project according to the collaborative research agreement. JMDC Inc. did not intervene in data implementation according to the analyzed results of this study. K.M. received honorarium fees for presentations from JMDC Inc. Nippon-Kayaku and Abbvie Inc. K.T. received a research grant from Bayer Yakuhin, Ltd. Department of Hospital Pharmaceutics received budget from Ono with a contract research project according to the collaborative research agreement. As a potential conflict of interest, Hospital Pharmaceutics received a research grant from Daiichi Sankyo, Mochida, Shionogi, Ono, Taiho and Nippon-kayak., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: Since the SARS-CoV-2 Omicron variant became dominant, assessing COVID-19 vaccine effectiveness (VE) against severe disease using hospitalization as an outcome became more challenging due to incidental infections via admission screening and variable admission criteria, resulting in a wide range of estimates. To address this, the World Health Organization (WHO) guidance recommends the use of outcomes that are more specific to severe pneumonia such as oxygen use and mechanical ventilation., Methods: A case-control study was conducted in 24 hospitals in Japan for the Delta-dominant period (August-November 2021; "Delta") and early Omicron (BA.1/BA.2)-dominant period (January-June 2022; "Omicron"). Detailed chart review/interviews were conducted in January-May 2023. VE was measured using various outcomes including disease requiring oxygen therapy, disease requiring invasive mechanical ventilation (IMV), death, outcome restricting to "true" severe COVID-19 (where oxygen requirement is due to COVID-19 rather than another condition(s)), and progression from oxygen use to IMV or death among COVID-19 patients., Results: The analysis included 2125 individuals with respiratory failure (1608 cases [75.7%]; 99.2% of vaccinees received mRNA vaccines). During Delta, 2 doses provided high protection for up to 6 months (oxygen requirement: 95.2% [95% CI:88.7-98.0%] [restricted to "true" severe COVID-19: 95.5% {89.3-98.1%}]; IMV: 99.6% [97.3-99.9%]; fatal: 98.6% [92.3-99.7%]). During Omicron, 3 doses provided high protection for up to 6 months (oxygen requirement: 85.5% [68.8-93.3%] ["true" severe COVID-19: 88.1% {73.6-94.7%}]; IMV: 97.9% [85.9-99.7%]; fatal: 99.6% [95.2-99.97]). There was a trend towards higher VE for more severe and specific outcomes., Conclusion: Multiple outcomes pointed towards high protection of 2 doses during Delta and 3 doses during Omicron. These results demonstrate the importance of using severe and specific outcomes to accurately measure VE against severe COVID-19, as recommended in WHO guidance in settings of intense transmission as seen during Omicron., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Takeshi Arashiro is an unpaid consultant for the World Health Organization. The other authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Hospitals in Japan established the healthcare delivery system from FY 2018 to 2021 by acquiring an additional reimbursement for infection prevention (ARIP) of category 1 or 2. However, research on outcomes of ARIP applications related to the practice of hospital pharmacists is scarce., Methods: This study assessed the activities performed by hospital pharmacists in hospitals with 100 to 299 beds, using ARIP acquirement as an indicator, using data from an annual questionnaire survey conducted in 2020 by the Japanese Society of Hospital Pharmacists on the status of hospital pharmacy departments. Out of the survey items, this study used those related to hospital functions, number of beds, number of pharmacists, whether the hospital is included in the diagnosis procedure combination (DPC) system, average length of stay, and nature of work being performed in the analysis. The relationship between the number of beds per pharmacist and state of implementation of pharmacist services or the average length of hospital stay was considered uncorrelated when the absolute value of the correlation coefficient was within 0-0.2, whereas the relationship was considered to have a weak, moderate, or strong correlation when the absolute value ranged at 0.2-0.4, 0.4-0.7, or 0.7-1, respectively., Results: Responses were received from 3612 (recovery rate: 43.6%) hospitals. Of these, 210 hospitals meeting the criteria for ARIP 1 with 100-299 beds, and 245 hospitals meeting the criteria for ARIP 2 with 100-299 beds, were included in our analysis. There was a significant difference in the number of pharmacists, with a larger number in ARIP 1 hospitals. For the pharmacist services, significant differences were observed, with a more frequency in ARIP 1 hospitals in pharmaceutical management and guidance to pre-hospitalization patients, sterile drug processing of injection drugs and therapeutic drug monitoring. In DPC hospitals with ARIP 1 (173 hospitals) and 2 (105 hospitals), the average number of beds per pharmacist was 21.7 and 24.7, respectively, while the average length of stay was 14.3 and 15.4 d, respectively. Additionally, a weak negative correlation was observed between the number of pharmacist services with "Fairly well" or "Often" and the number of beds per pharmacist for both ARIP 1 (R = -0.207) and ARIP 2 (R = -0.279) DPC hospitals. Furthermore, a weak correlation (R = 0.322) between the average number of beds per pharmacist and the average length of hospital stay was observed for ARIP 2 hospitals., Conclusions: Our results suggest that lower beds per pharmacist might lead to improved pharmacist services in 100-299 beds DPC hospitals with ARIP 1 or 2. The promotion of proactive efforts in hospital pharmacist services and fewer beds per pharmacist may relate to shorter hospital stays especially in small and medium-sized hospitals with ARIP 2 when ARIP acquisition was used as an indicator. These findings may help to accelerate the involvement of hospital pharmacists in infection control in the future., (© 2024. The Author(s).)

Sunflower seed extract, an antioxidant agent registered on the List of Existing Food Additives in Japan, was evaluated using HPLC, and three common constituents were detected. These peaks were identified as monocaffeoylquinic acids (3-O-caffeoylquinic acid, 4-O-caffeoylquinic acid, and 5-O-caffeoylquinic acid [chlorogenic acid]). Upon scrutinizing other components, dicaffeoylquinic acids (isochlorogenic acids; 3,4-di-O-caffeoylquinic, 3,5-di-O-caffeoylquinic, and 4,5-di-O-caffeoylquinic acids) were also identified. Structures of two newly isolated compounds were determined to be 3-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic and 4-O-(3S-2-oxo-3-hydroxy-indole-3-acetyl)-5-O-caffeoylquinic acids. To identify the components that contribute to the antioxidant activity of sunflower seed extract, we fractionated the food additive sample solution and examined the active fractions for 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity. Monocaffeoylquinic and dicaffeoylquinic acids showed high DPPH activity, including their contribution to the antioxidant activity of this food additive. DPPH radical scavenging activity of the new compounds showed almost the same value as that of the positive control, Trolox. Therefore, the contribution of these compounds was also considered.

We report herein an enantioselective intermolecular [2 + 2] photocyclization of alkenyl 2-pyrrolyl ketones using the bathochromic shift mediated by a chiral phosphoric acid. This synthetic method provides access to cyclobutanes with up to 98% ee. According to the UV-Vis spectra, the bathochromic effect was observed by mixing alkenyl 2-pyrrolyl ketones and a chiral phosphoric acid. A non-linear correlation was observed between the ee of the catalyst and the ee of the cycloadduct, suggesting that both substrates bind to the chiral phosphoric acid and form a dimer complex before photocycloaddition.

Despite the various biological activities exhibited by water chestnut (the fruit of the Trapa genus), the phenolic compounds present in its extract require comprehensive characterization. Accordingly, we analyzed a 80% methanol extract of commercially available water chestnut and identified a new hydrolyzable tannin dimer termed trapadin A. Additionally, 22 known compounds, including 10 hydrolyzable tannin monomers and 2 dimers, were also detected in the extract. Spectroscopic and chemical methods were used to elucidate the structure of trapadin A, revealing it to be a hydrolyzable tannin dimer formed from units of tellimagrandin II and 1,2,3,6-tetra- O -galloyl-β-d-glucose. Moreover, the 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity assay used to determine the half-maximal effective concentration values for the 23 compounds isolated from water chestnut indicated significant radical scavenging activity associated with hydrolyzable tannins. Notably, trapadin A, the new hydrolyzable tannin dimer, exhibited the highest activity value among the tested compounds.

The hydrosilylation of alkenes is one of the most important methods for the synthesis of organosilicon compounds. In addition to the platinum-catalyzed hydrosilylation, silyl radical addition reactions are notable as economic reactions. An efficient and widely applicable silyl radical addition reaction was developed by using 2-silylated dihydroquinazolinone derivatives under photocatalytic conditions. Electron-deficient alkenes and styrene derivatives underwent hydrosilylation to give addition products in good to high yields. Mechanistic studies indicated that the photocatalyst functioned not as a photoredox catalyst but as an energy transfer catalyst. DFT calculations clarified that the triplet excited state of 2-silylated dihydroquinazolinone derivatives released a silyl radical through the homolytic cleavage of a carbon-silicon bond, and this was followed by the hydrogen atom transfer pathway, not the redox pathway., (© 2023 Wiley-VCH Verlag GmbH.)

Desymmetrization is an essential method for the synthesis of chiral compounds, particularly chiral biaryls. We have developed an enantioselective synthesis of axially chiral biaryls by desymmetrization using C(sp 3 )-H activation catalyzed by chiral palladium phosphate. Mechanistic studies show that C-H activation is the rate- and enantiomer-determining step. To the best of our knowledge, this is the first report of asymmetric desymmetrization of axially chiral compounds by C(sp 3 )-H activation.

Hazelnuts contain biologically active phenolic compounds and are widely used for their nutritional value. In this study, the phenolic compounds contained in hazelnuts were isolated from the kernels of Corylus avellana L. and investigated. Spectral analyses revealed 2 new acetophenone glycosides, characterized as 2',4',6'-trihydroxyacetophenone-4'-O-(2-O-β-d-apiosyl)-β-d-glucoside and 2',4',6'-trihydroxyacetophenone-4'-O-(2-O-β-d-apiosyl-6-O-α-l-arabinosyl)-β-d-glucoside, and 4 known compounds. Four high-molecular-mass condensed tannin fractions were detected in the water-soluble fraction of the extract, characterized as B-type procyanidin consisting of extension and terminal units. Gel permeation chromatography analyses revealed that the average molecular mass, based on the polystyrene standard, was approximately 15 000-113 000. These high-molecular-mass condensed tannin fractions were chemically characterized and exhibited different molecular weights. The fractions of high-molecular-mass condensed tannins were obtained from hazelnuts and tested for 1,1-diphenyl-2-picrylhydrazyl radical scavenging activity. The EC50 values indicated significant activity for all the fractions., (© The Author(s) 2023. Published by Oxford University Press on behalf of Japan Society for Bioscience, Biotechnology, and Agrochemistry.)

We have developed a chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts alkylation reaction between pyrroles and indolylmethanols. Wide substrate scope was observed, and a chiral all-carbon quaternary center was constructed at the 3 position of indoles in high yields with high to excellent enantioselectivities (up to 99% ee).

Electron donor-acceptor (EDA) complex-mediated single-electron transfer (SET) is a crucial method for generating carbon radicals. Hydrogen atom transfer (HAT) enables the direct generation of alkyl radicals. We report a dual-role EDA-SET/HAT photoreaction system for carbon-carbon bond formation using a phenol catalyst and aryl iodide. This system facilitates addition of alkyl radicals generated from ethers, amide, sulfide, and cycloalkane to arenes. Mechanistic studies revealed that EDA complex formation is mediated by halogen bonding between phenoxide and aryl iodide. Irradiation of the EDA complex with visible light generates an aryl radical, which abstracts a hydrogen atom from an sp 3 carbon to form an alkyl radical.

Background: Information sharing among medical professionals is important for providing quality medical care. The purpose of the present study was to elucidate the actual status of information sharing between hospitals and other healthcare delivery facilities by surveying information sharing among the pharmaceutical departments of Japanese hospitals in 2020 conducted by the Japanese Society of Hospital Pharmacists., Methods: Responses were received from 3612 (43.6%) of the 8278 target medical institutions between May 2020 and August 2020., Results: The proportions of hospitals that shared information with community pharmacies, other hospitals, and long-term nursing homes were 40.6%, 36.4%, and 27.3%, respectively. While tracing reports were the most common tool used by hospitals for information sharing with community pharmacies (54.3%), drug summaries were used for sharing information with other hospitals and long-term nursing homes (77.4% and 78.0%, respectively). The proportion of hospitals sharing information with community pharmacies and other hospitals showed a tendency to increase as the number of hospital beds increased. No relationship could be established between the number of hospital beds and the proportion of hospitals sharing information with long-term nursing homes., Conclusion: Information between hospitals and community pharmacies was shared primarily using tracing reports, whereas information between hospitals and other hospitals and long-term nursing homes was primarily shared via drug summaries., (© 2022. The Author(s).)

What Is Known and Objective: Adverse drug reactions (ADRs) are one of the primary reasons for hospitalization. The spontaneous reporting of ADRs by healthcare professionals is important for issuing post-marketing drug safety measures. The Japanese Society of Hospital Pharmacists (JSHP) conducts a nationwide survey annually. Using data from this large-scale survey, we identified the characteristics of hospitals that reported ADRs to regulatory authorities and pharmaceutical companies., Methods: Data were obtained from annual surveys conducted by JSHP from 2015 to 2020. All variables were expressed as categorical variables and tabulated. The Chi-square test was used to compare the categorical variables. The Cochran-Armitage trend test was used to identify significant trends in the proportion of hospitals reporting ADRs., Results and Discussion: From 2015 to 2020, 22,362 responses were recorded. There was a significant increase in the proportion of hospitals that reported ADRs with an increase in number of beds and pharmacists (p < 0.0001). The proportion of hospitals reporting ADRs to regulatory authorities was also significantly higher in those charging an additional fee for pharmacist-performed ward operations and in those with an ADR data management section than in hospitals without these attributes (p < 0.0001)., What Is New and Conclusion: Hospitals that submitted ADR reports to the regulatory authorities and pharmaceutical companies charged an additional fee for pharmacist-performed ward operations, had a central ADR data management section, and had fewer beds per pharmacist. This trend was similar, regardless of the size of the hospital., (© 2022 John Wiley & Sons Ltd.)

Developed herein is an enantioselective Friedel-Crafts alkylation reaction of N -unprotected alkynyl trifluoromethyl ketimines with pyrroles catalyzed by chiral phosphoric acid to furnish chiral primary α-trifluoromethyl-α-(2-pyrrolyl)propargylamines with high enantioselectivity. Transformation of the alkynyl group of the adducts afforded optically active α-trifluoromethylated amines bearing various substituents such as alkyl, alkenyl, enyne, and triazole without loss of optical purity.

This study aimed to identify the components of proton pump inhibitors (PPIs) or potassium-competitive acid blocker (PCAB) that lead to cardiovascular events in individuals of working age. We analyzed large claims data of individuals who were administered PPIs or PCAB. We enrolled working-age individuals administered PPI or PCAB without cardiovascular history with a 12-month screening and 12-month observation period and determined the proportion of cardiovascular events and the predictive factors of cardiovascular events in this population. Among the eligible individuals, 0.5% (456/91098) had cardiovascular events during the 12-month observation period. Predictive factors for cardiovascular events were age for +1 year (p < 0.0001), male sex (p < 0.0001), hypertension (p = 0.0056), and diabetes mellitus (p < 0.0001). The cardiovascular disease risk was higher in working-age individuals administered lansoprazole than in those administered other drugs (vs. rabeprazole; p = 0.0002, vs. omeprazole; p = 0.0046, vs. vonoprazan; p < 0.0001, and vs. esomeprazole; p < 0.0001). We identified the risk for cardiovascular events in individuals being treated with lansoprazole. Lansoprazole is known for its higher CYP2C19 inhibition activity compared with other PPIs or PCAB. A possible mechanism by which lansoprazole may lead to cardiovascular events is inhibiting the generation of epoxyeicosatrienoic acids from arachidonic acids, an intrinsic cardioprotective activator via CYP2C19 inhibition. Thus, we recommend avoiding administering lansoprazole to working-age individuals require PPIs or PCAB.

The number of working-age individuals undergoing cancer treatment has been increasing. In these patients, transdermal fentanyl is the preferred treatment. However, it is known to have (1) pharmacodynamic interactions with benzodiazepines and (2) fever-induced pharmacokinetic variations. The aim of this study is to clarify the frequency of co-administration of benzodiazepine and the predictors for fever among working-age patients with cancer using transdermal fentanyl. We used a large claims data source including over 3.6 million patients. Finally, 759 working-age patients aged 20 to 60 years undergoing cancer treatment, in whom transdermal fentanyl was initiated, were analyzed. The proportion of patients receiving co-administration of benzodiazepines with the first administration of transdermal fentanyl was 16.5% (n = 125). This increased to 39.3% (n = 298) within 30 days. Predictive factors for fever using patients' baseline characteristics were male sex, gastrointestinal cancer, hematological cancer, and renal disease. To provide adequate pharmacotherapy to working-age patients undergoing cancer treatment with transdermal fentanyl, medical staff should pay attention to (1) avoid adding benzodiazepines easily and (2) monitor patients having predictors for fever to avoid fentanyl-related adverse events.

Antimicrobial resistance is a major health concern. A primary cause is the inappropriate use of antimicrobials, particularly by patients with upper respiratory tract infection. However, baseline information for antibiotic use for common cold before being applied the National Action Plan on Antimicrobial Resistance in Japan is lacking. Here, we analyzed the inappropriate use of antibiotics in the working-age workers. We used large claims data from an annual health check-up for at least 5 consecutive years. Among 201,223 participants, we included 18,659 working-age workers who were diagnosed with common cold at a clinic/hospital. We calculated the proportion of patients with common cold who were prescribed antibiotics and analyzed predictive factors associated with antibiotics prescription. Antibiotics were prescribed to 49.2% (n = 9180) of patients diagnosed with common cold. In the logistic regression analysis, the group taking antibiotics was predominantly younger, male, without chronic diseases, and diagnosed at a small hospital/clinic (where the number of beds was 0-19). Cephems accounted for the highest proportion of prescribed antibiotics, with 40-45% of patients being prescribed antibiotics. Our data may be applied to prioritize resources such as medical staff-intervention or education of working-age people without chronic diseases who visit clinics for common cold to avoid the potential inappropriate use of antibiotics and prevent antimicrobial resistance acceleration., (© 2021. The Author(s).)

There are many reports that pharmacotherapy has been optimized to ensure collaboration between physicians and pharmacists. Various scales assess the relationship between physicians and pharmacists as well as medical students and pharmacy students. The Scale of Attitudes Toward Physician-Pharmacist Collaboration (SATP 2 C) can be applied not only to the physician-pharmacist relationship but also to the medical-pharmacy student relationship. As there is no Japanese version of the SATP 2 C, we developed one and examined its psychometric properties. SATP 2 C scores were measured before and after interprofessional education (IPE) to verify responsiveness. The scale showed confirmed reliability: Cronbach's alphas were 0.79 for Responsibility and Accountability, 0.68 for Shared Authority, and 0.67 for Interdisciplinary Education. Pre and post-IPE, each mean subscale score increased: Responsibility and Accountability, 0.7 ± 0.4; Shared Authority, 0.2 ± 0.3; and Interdisciplinary Education, 0.3 ± 0.2. Although the total score increased (1.2 ± 0.7), this was non-significant. The Japanese version of the SATP 2 C can be considered, at least initially, to have reached an acceptable level of reliability and validity. The new measure is currently the only scale in Japan that can evaluate attitudes toward physician-pharmacist collaboration regarding IPE. Further studies are needed to confirm responsiveness pre- and post-IPE.

Developed herein is a visible-light-driven synthesis of sulfides by an electron donor-acceptor/single electron transfer and hydrogen atom transfer combined system without transition metals and strong oxidants. This reaction proceeds through the excitation of an electron donor-acceptor complex between a thiolate and an aryl halide, followed by the hydrogen atom transfer from an alkane to the generated aryl radical., Competing Interests: The authors declare no competing financial interest., (© 2021 The Authors. Published by American Chemical Society.)

In September 2015, "the Act on the Protection of Personal Information" was amended. Accordingly, "the Ethical Guidelines for Medical Research Involving Human Subjects" were also amended. "The Act on Anonymized Medical Data That Are Meant to Contribute to Research and Development in the Medical Field," which came into effect in May 2018, aims to collect and utilize medical information of each patient from medical institutions for the purpose of research and development in the medical field. Thus, the rules of personal information that need to be followed are changing considerably in the balance between importance of protection and utilization for medical development. Therefore, health care professionals and researchers are required to fully understand the current situation and the future.

The hydroalkylation and hydroacylation of electron-deficient alkenes proceeded smoothly by using benzothiazoline derivatives as radical-transfer reagents under thermal conditions without light irradiation or any additive. Both benzyl and benzoyl moieties were transferred efficiently.

The trifluoromethylation of iodoarenes was accomplished by use of a 2-trifluoromethylbenzimidazoline derivative as the trifluoromethylating reagent and a catalytic amount of Cu(I) in the presence of 2,2'-bipyridyl as the ligand. Through a mechanistic study, we found that the oxidative addition of the iodoarene to the Cu(I)-CF 3 species is the rate-determining step., (Copyright © 2020, Uchikura et al.; licensee Beilstein-Institut.)

Supramolecular photocatalysis via charge-transfer excitation of a host-guest complex was developed by use of the macrocyclic boronic ester [2+2] BTH-F containing highly electron-deficient difluorobenzothiadiazole moieties. In the presence of a catalytic amount of [2+2] BTH-F , the triplet excited state of anthracene was generated from the charge-transfer excited state of anthracene@[2+2] BTH-F by visible-light irradiation, and cycloaddition of the excited anthracene with several dienes and alkenes proceeded in a [4+2] manner in high yields., (© 2020 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The chiral indole is an important structure in organic chemistry. We have developed an enantioselective hydrogen transfer reaction of indolylmethanol, which is characterized by the combined use of benzothiazoline and a newly synthesized chiral phosphoric acid. The reaction furnished indoles bearing a chiral tertiary carbon center at the 3-position in high to excellent yields and with excellent enantioselectivities, most of which are greater than 95% ee. The chiral indole was converted into an inhibitor of leukotriene production while retaining excellent ee.

Competing Interests: The authors have no conflicts of interest to declare.

Novel radical transfer reagents under photoirradiation conditions were developed by the use of benzothiazoline derivatives. These reagents enabled both hydroalkylation and hydroacylation of alkenes under neutral conditions at ambient temperature without any toxic reagents or an excess amount of metals. A mechanistic study was carried out to elucidate the radical process.

Background: We conducted an economic assessment using test data from the phase III TRIPLE study, which examined the efficacy of a 5-hydroxytryptamine 3 receptor antagonist as part of a standard triplet antiemetic regimen including aprepitant and dexamethasone in preventing chemotherapy-induced nausea and vomiting in patients receiving cisplatin-based highly emetogenic chemotherapy (HEC)., Methods: We retrospectively investigated all medicines prescribed for antiemetic purposes within 120 h after the initiation of cisplatin administration during hospitalization. In the TRIPLE study, patients were assigned to treatment with granisetron (GRA) 1 mg ( n  = 413) or palonosetron (PALO) 0.75 mg ( n  = 414). The evaluation measure was the cost-effectiveness ratio (CER) assessed as the cost per complete response (CR; no vomiting/retching and no rescue medication). The analysis was conducted from the public healthcare payer's perspective., Results: The CR rates were 59.1% in the GRA group and 65.7% in the PALO group ( P  = 0.0539), and the total frequencies of rescue medication use for these groups were 717 (153/413 patients) and 573 (123/414 patients), respectively. In both groups, drugs with antidopaminergic effects were chosen as rescue medication in 86% of patients. The costs of including GRA and PALO in the standard triplet antiemetic regimen were 15,342.8 and 27,863.8 Japanese yen (JPY), respectively. In addition, the total costs of rescue medication use were 73,883.8 (range, 71,106.4-79,017.1) JPY for the GRA group and 59,292.7 (range, 57,707.5-60,972.8) JPY for the PALO group. The CERs (JPY/CR) were 26,263.4 and 42,628.6 for the GRA and PALO groups, respectively, and the incremental cost-effectiveness ratio (ICER) between the groups was 189,171.6 (189,044.8-189,215.5) JPY/CR., Conclusions: We found that PALO was more expensive than GRA in patients who received a cisplatin-based HEC regimen., Competing Interests: HS, RPh.: Pharmacist at Showa University Hospital; KS, RPh. Ph.D.: Pharmacist at Cancer Institute Hospital, Japanese Foundation for Cancer Research; TU, RPh. Ph.D.: Pharmacist at Showa University Hospital; DT, Ph.D.: Pharmacist at School of Pharmaceutical Sciences, University of Shizuoka; TY, M.D. Ph.D.: Statistician at Yokohama City University; HH, RPh.: Pharmacist at National Cancer Center Hospital; KG, M.D. Ph.D.: Doctor at National Cancer Center Hospital East; RM, RPh.: Pharmacist at National Cancer Center Hospital East; NS, M.D. Ph.D.: Doctor at Teikyo University School of Medicine; T Shimada, RPh.: Pharmacist at Teikyo University Hospital; SI, M.D. Ph.D.: Doctor at International University of Health and Welfare; NI, M.D. Ph.D.: Doctor at St Luke’s International University; TH, RPh. Ph.D.: Pharmacist at Cancer Institute Hospital, Japanese Foundation for Cancer Research; NY, M.D. Ph.D.: Doctor at Wakayama Medical University; T Sasaki, RPh. Ph.D.: Pharmacist at Showa University Hospital.Not applicable.Not applicable.The authors have no conflicts of interest directly relevant to the content of this article.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

A new phenolic compound, 2- O -β-laminaribiosyl-4-hydroxyacetophenone ( 1 ), was isolated from Cynanchi Wilfordii Radix (CWR, the root of Cynanchum wilfordii Hemsley), along with 10 known aromatic compounds, including cynandione A ( 2 ), bungeisides-C ( 7 ) and -D ( 8 ), p -hydroxyacetophenone ( 9 ), 2',5'-dihydroxyacetophenone ( 10 ), and 2',4'-dihydroxyacetophenone ( 11 ). The structure of the new compound ( 1 ) was elucidated using spectroscopic methods and chemical methods. The structure of cynandione A ( 2 ), including a linkage mode of the biphenyl parts that remained uncertain, was unambiguously confirmed using the 2D 13 C- 13 C incredible natural abundance double quantum transfer experiment (INADEQUATE) spectrum. Additionally, health issues related to the use of Cynanchi Auriculati Radix (CAR, the root of Cynanchum auriculatum Royle ex Wight) instead of CWR have emerged. Therefore, constituents present in methanolic extracts of commercially available CWRs and CARs were examined using UV-sensitive high-performance liquid chromatography (HPLC), resulting in common detection of three major peaks ascribed to cynandione A ( 2 ), p -hydroxyacetophenone ( 9 ), and 2',4'-dihydroxyacetophenone ( 11 ). Thus, to distinguish between these ingredients, a thin-layer chromatography (TLC) method, combined with only UV irradiation detection, focusing on wilfosides C1N ( 12 ) and K1N ( 13 ) as marker compounds characteristic of CAR, was performed. Furthermore, we propose this method as a simple and convenient strategy for the preliminary distinction of CWR and CAR to ensure the quality and safety of their crude drugs., Competing Interests: The authors declare no conflict of interest.

A conceptually new method for the catalytic electrophilic activation of aromatic carbonyl substrates, by utilizing donor-acceptor interactions between an electron-deficient macrocyclic boronic ester host ([2+2] BTH-F ) and an aromatic carbonyl guest substrate, was realized. In the presence of a catalytic amount of [2+2] BTH-F , dramatic acceleration of the nucleophilic addition of a ketene silyl acetal towards either electron-rich aromatic aldehydes or ketones was achieved. Several control experiments confirmed that inclusion of the aromatic substrates within [2+2] BTH-F , through efficient donor-acceptor interactions, is essential for the acceleration of the reaction., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Polygala Root (the root of Polygala tenuifolia WILLDENOW; Japanese name "Onji"), a well-known crude drug, traditionally used as an expectorant and sedative, has been attracting increased interest in recent years owing to its newly found pharmacological effect related to neuroprotection. However, there is no specific method for identifying and estimating the quality of this crude drug in the Japanese Pharmacopoeia, 17th edition. Therefore, in order to develop a TLC-based simple and convenient identification method using characteristic chemical marker(s) for the drug and its extract products, UV-sensitive constituents of Polygala Root were first investigated. A total of 23 aromatic compounds were isolated and characterized. Two new compounds, namely, polygalaonjisides A (1) and B (2), were characterized as syringic acid 4-O-(2'-O-β-D-apiosyl)-β-D-glucoside and 2-O-(β-D-glucosyl)-3'-O-benzoylsucrose, respectively. Based on these phytochemical results, a TLC method focusing on three marker spots with Rf value of approximately 0.4-0.5 due to tenuifolisides A and B and 3,6'-di-O-sinapoylsucrose was proposed as a simple and convenient test to identify Polygala Root or its single-extract products on the market. The data presented in this paper could be useful in stipulating a confirmation test to identify Polygala Root.

The dosage and frequency of lamotrigine administration for each patient must be prescribed carefully according to the disease, age, concomitant medications, and administration period. According to Pharmaceuticals and Medical Devices Agency (PMDA) reports, either the number of patients with adverse events caused by the inappropriate use of lamotrigine or the ratio of the patients who have benefited from the Relief System for Adverse Drug Reactions did not change even after the revision of the package insert in 2015. The procedure for auditing lamotrigine prescriptions was standardized to improve patient safety in our hospitals. The efficacy of standardization was evaluated by investigating the patients' records and prescriptions. A total of 77 patients treated with lamotrigine were examined to evaluate the appropriateness of the dosage and frequency of administration as well as the number of prescription enquiries made by pharmacists retrospectively. In addition, the presence of adverse events such as skin rash was examined using medical records. The number of inappropriate cases found and the prescription questions asked by pharmacists during the 24-month period before and after standardization were compared. The rate of inappropriate prescriptions after standardization was significantly lower than that before (12.1 vs. 29%; p<0.05). The rate of prescription questions raised after standardization was significantly higher than that before (37.0 vs. 1.7%; p<0.05). Moreover, there was no adverse event after standardization. Our standardization practice was effective to easily identify inappropriate prescriptions and provide physicians with the appropriate dosage or frequency of administration for the patients.

Control of the reversibility during boronic ester formation from boronic acids and diols was found to be possible by choosing an appropriate solvent. As an example, ferrocene dimers and trimers were constructed by using tetrol 1 with an indacene framework, 1,1'-ferrocenediboronic acid 2, and ferrocenemonoboronic acid 4. When equimolar amounts of 1 and 2 were mixed in methanol under equilibrating conditions, two kinds of stacked ferrocene dimers homo- and hetero-3 were selectively obtained depending on the reaction time and both structures were determined by X-ray crystallographic analysis. On the other hand, the ferrocene trimer 7 was successfully constructed by stepwise assembly in the presence of anhydrous magnesium sulfate in acetone where the equilibration of boronic esters was suppressed, while no formation of ferrocene trimer 7 was detected when all components 1, 2 and 4 (2 : 1 : 2 ratio) for trimer 7 were mixed at a time in methanol under equilibrating conditions.

Cynanchi Wilfordii Radix (CWR) is used in Korea as a substitute for Polygoni Multiflori Radix (PMR), which is a crude drug traditionally used in East Asian countries. Recently, the use of Cynanchi Auriculati Radix (CAR) in place of PMR and CWR has emerged a major concern in the Korean market. In Japan, PMR is permitted to be distributed as a pharmaceutical regulated by the Japanese Pharmacopoeia 17th edition (JP17). Although CWR and CAR have not traditionally been used as medicines, CWR was recently introduced as a health food. The distribution of unfamiliar CWR-containing products could lead to the misuse of original species for PMR and CWR like in Korea. To prevent this situation, the original species of plant products distributed as PMR, CWR, and CAR in the Korean and Chinese markets were surveyed and identified by their genes and components. The results revealed that all two PMR in the Korean market were misapplied as CAR, and that CAR was incorrectly used in eight of thirteen products distributed as CWR in both markets. As PMR is strictly controlled by JP17, the risk of mistaking PMR for CWR and CAR would be low in Japan. In contrast, the less stringent regulation of health food products and the present situation of misidentification of CWR in the Korean and Chinese markets could lead to unexpected health hazards. To ensure the quality and safety of crude drugs, it is important to use the information about the genes and components of these crude drugs.

Background: In the construction of pharmacoeoconomic models, simplicity is desirable for transparency (people can see how the model is built), ease of analysis, validation (how well the model reproduces reality), and description. Few reports have described concrete methods for constructing simpler models. Therefore we focused on the value of additional states and uncertainty in disease models with multiple complications., Objectives: The objective of this study was to examine the possibility of ranking additional states in disease models with multiple complications using a method for evaluating the quantification and uncertainty of additional states., Methods: The expected value of additional states (EVAS) was formulated to calculate the value of additional states from the variation between analytic models using the net benefit method, and uncertainty was subtracted from the variation. We also verified the usefulness and availability of this method in grade I hypertension as a verification of the disease model. We assumed that stroke was recognized as an associated complication of hypertension in the basic model. In addition, stroke recurrence, coronary heart disease (CHD), and end-stage renal disease (ESRD) were assumed to represent other complications of hypertension. Ten thousand Monte Carlo simulations were performed, and the probability distribution was assumed to be the beta distribution in clinical parameters. The ranges of clinical parameters were ±6.25%, 12.5%, 25%, and 50% of the standard deviation from the mean value., Results: The EVAS in complications of CHD showed the greatest uncertainty. In contrast, the EVAS of ESRD differed from stroke recurrence in the value ranking by uncertainty., Conclusions: The EVAS has the potential to determine the ranking of additional states based on the quantitative value and uncertainty in disease models with multiple complications.

The effectiveness and safety of angiotensin-converting enzyme (ACE) inhibitors for the treatment of hypertension have been confirmed during long-term use. Therefore, ACE inhibitors were selected as one candidate for the switch from ethical drugs to over-the-counter (OTC) medications. The objective of this study was to perform a cost-effectiveness analysis if ACE inhibitors were switched to OTC medications and used by grade I hypertension patients in Japan. We conducted a cost-effectiveness analysis from a social perspective over a lifetime horizon using a Markov Model in 50-year-old men and women with grade I hypertension. They were divided into 3 groups: 1) untreated group; 2) consultation group visiting a clinic and receiving prescriptions for ACE inhibitors; and 3) OTC group purchasing OTC ACE inhibitors. The cost of OTC medications was estimated based on a previous study of willingness to pay (¥7,237/month). Average life expectancies in both the OTC and consultation groups were 20.20 for men and 22.63 for women, while in the untreated group it was 19.97 for men and 22.47 for women. Incremental costs per expected life-year (ICER) were ¥1,743,557 for men and ¥8,647,069 for women in the OTC group and ¥3,819,861 for men and ¥9,639,844 for women in the consultation group. These results suggest that longer life expectancies can be achieved with ACE inhibitors, and the total cost is decreased using OTC ACE inhibitors compared with ethical drugs. OTC ACE inhibitors therefore appear be a useful alternative for patients who do not have time to visit a clinic regularly.

Drug selection for the treatment of non-steroidal anti-inflammatory drug (NSAID)-induced gastric ulcer was analyzed pharmacoeconomically. Two patterns consisting of continuation of an NSAID plus administration of the prostaglandin (PG) preparation misoprostol (PG model) for 8 weeks and continuation of an NSAID plus administration of the proton-pump inhibitors omeprazole and lansoprazole (PPI model) for 8 weeks were examined. Decision analysis models were created on the basis of reports of clinical studies and epidemiologic studies relating to the drugs and gastric ulcer, and cost-comparative analyses were conducted based on the number of persons who had ulcer healing as health outcomes. Costs were estimated with respect to health expenditures from the third-party payer (public) perspective. In the case of continuation of an NSAID plus administration of the proton-pump inhibitor omeprazole for 8 weeks, the health outcomes improved and costs were reduced in comparison with continuation of an NSAID plus administration of misoprostol, thus making the administration of omeprazole the dominant choice. With continuation of an NSAID plus administration of lansoprazole for 8 weeks, the cost-savings of lansoprazole were inferior to those of misoprostol. The generic omeprazole product was the most cost-saving among the four drugs (misoprostol, original omeprazole product, generic omeprazole product, and lansoprazole) examined.

The aim of this study was to assess whether Marrie's critical pathway is an effective approach to reduce the duration of antibiotic intravenous therapy and drug cost in patients with community-acquired pneumonia (CAP) in Japan. We conducted a retrospective cohort study in patients with CAP who were admitted to a community hospital or a university hospital. We collected clinical and economic data from medical records and medical fee receipts and estimated drug cost for switching the dosage form using Marrie's critical pathway. Outcomes of this study were change in duration of intravenous therapy and drug cost. Fifty patients with CAP were selected from two hospitals. Actual days of antibiotic intravenous therapy were 9.5+/-4.2 days; in contrast, estimated days were 1.2+/-3.0 days (p<0.001). Actual drug cost was 37148+/-28791 yen; in contrast, estimated drug cost was 8364+/-18356 yen (p<0.001). Average reduction of days of therapy and drug cost were 8.3 days and 28704 yen, respectively. This study suggests that the implementation of Marrie's critical pathway may be an effective approach to reduce medical resources used for CAP treatment in Japan.