[Exploration of Risk Factors of the Onset of Antibiotics-induced Acute Kidney Injury and Its Transfer to Chronic Kidney Disease Using the Medical Information Database].

Drug-induced acute kidney injury (AKI) is a serious adverse drug reaction, which results in a significant decline in renal function and is known to progress to chronic kidney disease (CKD). Therefore, appropriate drug therapy is important to avoid the risk of drug-induced AKI and CKD, which are serious concerns in clinical practice. In this study, using the medical information database of Hamamatsu University Hospital, we investigated the risk factors that accelerate the onset of drug-induced AKI or its progression to CKD in patients who received aminoglycoside antibiotics (AGs) or glycopeptide antibiotics (GPs), which are strongly associated with drug-induced AKI and CKD. We performed logistic regression analysis using patients' background, laboratory test results, and concomitant drug use, among other such factors as explanatory variables and drug-induced AKI or CKD onset as objective variables to explore the risk factors for drug-induced AKI and CKD. Our results showed that co-administration of amphotericin B, piperacillin-tazobactam and other AGs and GPs, increased serum creatinine (Scr) and chloride concentrations, serum lactate dehydrogenase activity, and decreased serum albumin concentration were risk factors for drug-induced AKI onset. Moreover, a reduced blood urea nitrogen : Scr ratio at drug-induced AKI onset served as a risk factor for CKD. These results suggest that careful monitoring of the aforementioned factors is important to ensure appropriate usage of these drugs in patients treated with AGs and GPs.

The importance of laparoscopic surgery for young urologists remains unwavering even in the era of robot-assisted surgery.

Robot-assisted surgery (RAS) cannot be achieved without the performance of laparoscopic surgical techniques by a patient-side surgeon (PSS). In many medical institutions in Japan, young urologists often take on the role of a PSS. Participating in RAS as a PSS provides a good opportunity to acquire not only the knowledge necessary for surgery, but also skills in laparoscopic surgical techniques. Learning laparoscopic surgery as a PSS may contribute to improving the quality of RAS. Furthermore, it will lead to skill improvement as an operator in laparoscopic surgery. However, notably, opportunities for young urologists to perform laparoscopic surgery are decreasing in the current era of RAS. Under these circumstances, we believe that cadaver surgical training will become increasingly important in the future. We believe that performance of cadaver surgical training will contribute to increased motivation, enhance the understanding of surgical procedures, and facilitate the acquisition of surgical techniques.

Efficacy of fresh-frozen cadaveric surgical training for arteriovenous fistula in vascular access.

BACKGROUND: Creation of an arteriovenous fistula (AVF) as vascular access is a basic operation that should be learned by all surgeons involved in renal failure treatment. AVF creation is often challenging for inexperienced young surgeons because it requires comprehensive surgical techniques. For such young surgeons, we introduced cadaveric surgical training (CST) for AVF creation using fresh-frozen cadavers (FFCs). This study was performed to identify the differences in AVF surgical techniques between FFCs and living bodies and to examine the impact of CST on young surgeons. METHODS: Twelve CST sessions were performed for AVF creation at the Clinical Anatomy Education and Research Center of Tokushima University Hospital from March 2021 to June 2022. Seven young surgeons (1st- and 2nd-year) performed the operation, and two surgeons (10th- and 11th-year) supervised it. We conducted an anonymous questionnaire survey using a 5-point Likert scale to examine the impact of CST on young surgeons. RESULTS: Twelve CST sessions were performed on nine FFCs. All training sessions allowed completion of AVF creation with a median operative time of 78.5 min. Although veins and arteries were more difficult to identify than in a living body, other surgical operations could be performed in the same way as in a living body. All the respondents stated that it was good for them to experience CST. In addition, 86% of surgeons responded that CST improved their surgical techniques, and 71% of surgeons responded that they were less anxious about AVF creation. CONCLUSIONS: CST for AVF creation is useful for surgical education because it enables learning of surgical techniques that are almost equivalent to those in living bodies. In addition, this study suggested that CST not only contributes to the improvement of surgical skills of young surgeons but also promotes the reduction of anxiety and stress about AVF creation.

Author Correction: Identification of a binding protein for sesamin and characterization of its roles in plant growth.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Author Correction: Identification of a binding protein for sesamin and characterization of its roles in plant growth.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Evaluating the impact of regulatory action on denosumab-induced hypocalcaemia in Japan.

WHAT IS KNOWN AND OBJECTIVE: Since its introduction in April 2012, denosumab has been administered to approximately 7,300 patients as of August 2012, and 32 cases of serious hypocalcaemia after denosumab administration, including two deaths, have been reported in Japan. A Dear Healthcare Professional Letter of Rapid Safety Communication ('Blue letter') was released to warn about the risks of hypocalcaemia associated with denosumab. The goal of this study therefore was to measure the impact of regulatory action on denosumab-induced hypocalcaemia in Japan by using an electronic medical information database (MID). METHODS: We used two different aggregated data sets based on MIDs (data sets one and two). The patients studied were those who were newly prescribed denosumab or zoledronic acid between April 2012 and September 2014. We assessed four indicators: (a) the proportion of patients with calcium supplementation at the initial denosumab treatment, (b) the proportion of patients who underwent a serum calcium test, (c) the average number of serum calcium tests performed and (d) the prevalence of hypocalcaemia. All indices were aggregated by every 3 months. To evaluate the impact of regulatory action, we used difference in difference (DID) analysis. RESULTS AND DISCUSSION: The proportion of patients with calcium supplementation at the initial denosumab treatment increased year by year in both data sets. The average number of serum calcium tests increased year by year in data set two. There was a significant difference in the prevalence of hypocalcaemia in data set two. This suggests that the estimate of impact of the regulatory action may vary according to the database. In DID analysis, however, significant influences of the regulatory action on combination use with a calcium supplement were detected in both data sets. WHAT IS NEW AND CONCLUSION: There was a significant influence on combination use of denosumab with vitamin D and/or calcium supplement in both data sets. That there was no apparent increase in the prevalence of denosumab-induced hypocalcaemia, suggests that the regulatory action had an impact in the clinical setting studied. Such regulatory actions may play an important role in the promotion of drug safety.

Identification of a binding protein for sesamin and characterization of its roles in plant growth.

Sesamin is a furofuran-type lignan that is found abundantly in seeds of Sesamum indicum (sesame) and has been widely accepted as a dietary supplement with positive effects on human health. The biological activity of sesamin in human cells and organs has been analysed extensively, although comparatively few studies show biological functions for sesamin in planta. Herein we screened sesamin-binding proteins (SBP) from sesame seedling extracts using sesamin-immobilized nano-beads. In subsequent peptide mass fingerprinting analyses, we identified a SBP, Steroleosin B, which is one of the membrane proteins found in oil bodies. In addition, pull-down assays and saturation transfer difference-nuclear magnetic resonance (STD-NMR) experiments demonstrated that sesamin binds directly to recombinant Steroleosin B in vitro. Finally, ectopic accumulations of sesamin and Steroleosin B in transgenic Arabidopsis thaliana plants induced severe growth defects including suppression of leaf expansion and root elongation. Collectively, these results indicate that sesamin influences tissue development in the presence of Steroleosin B.

Identification of risk factors and development of detection algorithm for denosumab-induced hypocalcaemia.

WHAT IS KNOWN AND OBJECTIVE: This study used electronic medical records to identify risk factors and establish a detection algorithm for denosumab-induced hypocalcaemia. METHODS: We identified 201 patients with cancer who were initially prescribed denosumab. Hypocalcaemia was defined as an adjusted serum calcium level of ≤2.13 mmol/L. A diagnosis of denosumab-induced hypocalcaemia was confirmed by two physicians after reviewing patient medical records. We evaluated patient characteristics as potential screening factors. Moreover, a retrospective cohort study was conducted to identify risk factors for denosumab-induced hypocalcaemia. Odds ratios (ORs) were estimated using logistic regression analysis. RESULTS: We analysed 164 patients with a low risk of hypocalcaemia. Among these, 29 (17.7%) patients were suspected to have denosumab-induced hypocalcaemia. The times to onset of definitive hypocalcaemia were shorter among these patients than among patients with non-denosumab-induced hypocalcaemia. Based on receiver operating characteristic curve analysis, we used time to onset of hypocalcaemia of ≤90 days as a second screening factor. The positive predictive value of this factor was 87.5%. In the retrospective cohort study, a significant difference was observed among patients with serum alkaline phosphatase (ALP) levels of >5.95 µkat/L before initial prescription (P < 0.01). Patients with higher serum ALP levels had a 6.63 times higher risk of developing hypocalcaemia than those without increased serum ALP levels (OR: 6.63, 95% confidence interval [CI]: 1.79-29.31). The same results were observed in a sensitivity analysis using another database. WHAT IS NEW AND CONCLUSION: We developed a detection algorithm for denosumab-induced hypocalcaemia based on calcium levels and time to onset of hypocalcaemia. We also identified elevated ALP levels as a risk factor for hypocalcaemia. Clinicians should carefully monitor initial serum calcium levels and screen for signs of hypocalcaemia in patients receiving denosumab who demonstrate elevated serum ALP levels.

Insights into the formation mechanism of chloropropanol fatty acid esters under laboratory-scale deodorization conditions.

Chloropropanol fatty acid esters (CPFAEs) are well-known contaminants in refined oils and fats, and several research groups have studied their formation. However, the results obtained in these studies were not satisfactory because the CPFAEs were not analyzed comprehensively. Thus, in the present study, a comprehensive analysis was performed to obtain new details about CPFAE formation. Each lipid (monopalmitin, dipalmitin, tripalmitin, monoolein, diolein, triolein, and crude palm oil) was heated at 250°C for 90 min, and the CPFAEs were analyzed using supercritical fluid chromatography/tandem mass spectrometry. It was found that CP fatty acid monoesters were formed from monoacylglycerols and diacylglycerols after heating in the presence of a chlorine compound. In addition, CP fatty acid diesters were formed from diacylglycerols and triacylglycerols under the same conditions. In the case of crude palm oil, only CP fatty acid diesters were formed. Therefore, these results indicated that CPFAEs in refined palm oil were formed mainly from triacylglycerols.

A detection algorithm for drug-induced liver injury in medical information databases using the Japanese diagnostic scale and its comparison with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method scale.

PURPOSE: Drug-induced liver injury (DILI) is one of the primary targets for pharmacovigilance using medical information databases (MIDs). Because of diagnostic complexity, a standardized method for identifying DILI using MIDs has not yet been established. We applied the Digestive Disease Week Japan 2004 (DDW-J) scale, a Japanese clinical diagnostic criteria for DILI, to a DILI detection algorithm, and compared it with the Council for International Organizations of Medical Sciences/the Roussel Uclaf Causality Assessment Method (CIOMS/RUCAM) scale to confirm its consistency. Characteristics of DILI cases identified by the DDW-J algorithm were examined in two Japanese MIDs. METHODS: Using an MID from the Hamamatsu University Hospital, we constructed a DILI detection algorithm on the basis of the DDW-J scale. We then compared the findings between the DDW-J and CIOMS/RUCAM scales. We examined the characteristics of DILI after antibiotic treatment in the Hamamatsu population and a second population that included data from 124 hospitals, which was derived from an MID from the Medical Data Vision Co., Ltd. We performed a multivariate logistic regression analysis to assess the possible DILI risk factors. RESULTS: The concordance rate was 79.4% between DILI patients identified by the DDW-J and CIOMS/RUCAM; the Spearman rank correlation coefficient was 0.952 (P < 0.0001). Men showed a significantly higher risk for DILI after antibiotic treatments in both MID populations. CONCLUSIONS: The DDW-J and CIOMS/RUCAM algorithms were equivalent for identifying the DILI cases, confirming the utility of our DILI detection method using MIDs. This study provides evidence supporting the use of MID analyses to improve pharmacovigilance.

Changes in compliance with Japanese antiemetic guideline for chemotherapy-induced nausea and vomiting: a nationwide survey using a distributed research network.

OBJECTIVE: Prophylaxis of chemotherapy (CT)-induced nausea and vomiting (CINV) is important for patient's quality of life and adherence to CT. Neurokinin receptor antagonist (NK1 antagonist) was marketed in Japan in December 2009 and the first guideline for antiemetics for CINV was released in May 2010 from Japan Society of Clinical Oncology (JSCO). We assessed changes in compliance with the JSCO guideline during the first 18 months from the launch of NK1 antagonist in Japan. METHODS: Patient-level data was extracted locally using a nationwide distributed research network consisting of 39 hospitals. Monthly compliance rates for acute (day of CT) and delayed (days 2-5) phases were summarized according to the emetic risks. RESULTS: In total, 81,739 CTs for 9,978 patients were analyzed. Prescription of oral NK1 antagonist was started in 31/39 hospitals during the study period. The compliance in acute phase for high emetic risk (HER) CTs gradually improved up to 39.3% whereas it reached only to 10-15% in delayed phase. The extra use of antiemetics decreased inversely to the increased compliance. Better compliance for HER CTs was associated with opioid use, younger age, second or later cycles, and CT regimens. Compliance in acute phase was better in inpatient whereas that in delayed phase was better in outpatients. CONCLUSIONS: A multi-hospital survey revealed that more than half of the HER CTs remained without accompanying the standard antiemetic therapies. Association with the compliance and CINV outcomes would be also interesting to explore.

High-Throughput Analysis of Sucrose Fatty Acid Esters by Supercritical Fluid Chromatography/Tandem Mass Spectrometry.

Supercritical fluid chromatography (SFC) coupled with triple quadrupole mass spectrometry was applied to the profiling of sucrose fatty acid esters (SEs). The SFC conditions (column and modifier gradient) were optimized for the effective separation of SEs. In the column test, a silica gel reversed-phase column was selected. Then, the method was used for the detailed characterization of commercial SEs and the successful analysis of SEs containing different fatty acids. The present method allowed for fast and high-resolution separation of monoesters to tetra-esters within a shorter time (15 min) as compared to the conventional high-performance liquid chromatography. The applicability of our method for the analysis of SEs was thus demonstrated.

Interindividual variations in aprepitant plasma pharmacokinetics in cancer patients receiving cisplatin-based chemotherapy for the first time.

The pharmacokinetics of aprepitant, a neurokinin-1 receptor antagonist, have not been fully evaluated in clinical settings. The aim of this study was to characterize the plasma pharmacokinetics of aprepitant and reveal their influence of laboratory tests and cytochrome P450 (CYP) 3A5 gene polymorphisms in cancer patients. Forty-four Japanese cancer patients receiving cisplatin-based chemotherapy for the first time following oral aprepitant (125 mg on day 1 and 80 mg on days 2 and 3) were enrolled. The patients did not have gastrointestinal disease and the clinical laboratory values were within their normal reference levels. The plasma concentrations of aprepitant 24 (day 2 predose), 72, and 120 h after the first aprepitant administration were determined using LC-MS/MS. The relationships between plasma exposure to aprepitant and body weight, clinical laboratory values, age, gender, or CYP3A5*3 were investigated. The median and interquartile ranges of the 120-h area under the plasma concentration time curve (AUC)(0-120) of aprepitant were 73215 and 55518-91121 ng h/mL. The coefficient of variation value for aprepitant AUC(0-120) was 53%. The AUC(0-120) of aprepitant was correlated with the levels of total bilirubin and serum albumin, respectively (r=0.454, p<0.01 and r=0.287, p=0.06), but not with other non-genetic factors and CYP3A5 genetic variants in a univariate analysis. The AUC(0-120) of aprepitant was significantly correlated with the level of total bilirubin (adjusted R(2)=0.187, p<0.01) in a multivariate analysis. In conclusion, the plasma pharmacokinetics of aprepitant varied markedly in cancer patients receiving cisplatin-based chemotherapy for the first time and were correlated with the level of total bilirubin.

High-throughput and sensitive analysis of 3-monochloropropane-1,2-diol fatty acid esters in edible oils by supercritical fluid chromatography/tandem mass spectrometry.

We have established a high-throughput and sensitive analytical method based on supercritical fluid chromatography (SFC) coupled with triple quadrupole mass spectrometry (QqQ MS) for 3-monochloropropane-1,2-diol (3-MCPD) fatty acid esters in edible oils. All analytes were successfully separated within 9 min without sample purification. The system was precise and sensitive, with a limit of detection less than 0.063 mg/kg. The recovery rate of 3-MCPD fatty acid esters spiked into oil samples was in the range of 62.68-115.23%. Furthermore, several edible oils were tested for analyzing 3-MCPD fatty acid ester profiles. This is the first report on the analysis of 3-MCPD fatty acid esters by SFC/QqQ MS. The developed method will be a powerful tool for investigating 3-MCPD fatty acid esters in edible oils.

[Comparison of 1 mg/body and 3 mg/body of intravenous granisetron for the prevention of chemotherapy-induced nausea and vomiting and adverse events in hematological malignancy patients].

Granisetron is a selective 5-hydroxy tryptamine3 receptor antagonist and widely used for chemotherapy-induced nausea and vomiting (CINV). Recommended dose of intravenous granisetron in the USA and Europe has been set at 0.01 mg/kg (1 mg/body) in the antiemetic treatment guidelines established by the American Society of Clinical Oncology and National Comprehension Cancer Network. In contrast, the approved dose in Japan is 0.04 mg/kg (3 mg/body). Randomized controlled trials (RCTs) which compared 1 mg/body with 3 mg/body of intravenous granisetron for CINV had been reported in Japan. In these RCTs, however, hematological malignancy patients were excluded. We performed observational retrospective study to compare 1 mg/body with 3 mg/body of intravenous granisetron for the prevention of CINV and adverse events in hematological malignancy patients. Number of the patients and chemotherapy courses were 15 and 30 in the 1 mg/body group, and 15 and 27 in the 3 mg/body group, respectively. No nausea rates in the 1 and 3 mg/body group were 83% and 89% of courses, respectively. No vomiting rates in the 1 and 3 mg/body group were 97% and 100% of courses, respectively. The incidences of constipation in the 1 and 3 mg/body group were 34% and 45% of courses, respectively. Anaphylaxis and headache did not occur in both groups. Our findings suggested that 1 mg/body of intravenous granisetron can prevent from CINV in hematological malignancy patients, as well as 3 mg/body.

Detection of fluoroquinolone-induced tendon disorders using a hospital database in Japan.

PURPOSE: Tendinitis and tendon rupture are well-known side effects of fluoroquinolones (FQs) in Western countries. In Japan, some case reports have been reported; however, the incidence of FQ-induced tendon disorders has not been investigated. The aims of this study were to measure the occurrence of tendon disorders associated with FQs in Japanese patients and to compare the observed risk with that of previous reports. Moreover, the observed risk in FQ-prescribed patients was compared with that in cephalosporin-prescribed patients. METHODS: The Hamamatsu University Hospital database was examined to determine the risk of tendon disorders that occurred in all inpatients and outpatients between the first day of prescription of an oral FQ or cephalosporins to the calculated end date plus 30 days. The risk of tendon disorders, the risk ratio, and their 95% confidence intervals (CIs) were evaluated. RESULTS: From April 1996 to December 2009, FQs were prescribed to 17 147 patients, 14 of whom had tendon disorders (risk: 0.082%, 95%CI: 0.049-0.137). The risk of a tendon disorder in FQ-prescribed patients was significantly higher than that in cephalosporin-prescribed patients (five tendon disorders in 38 517 patients, risk: 0.013%, 95%CI: 0.006-0.030, and p < 0.001). The risk ratio of a tendon disorder in FQ-prescribed patients in relation to cephalosporin-prescribed patients was 6.29 (95%CI: 2.27-17.46). A large discrepancy in the risk of tendon disorders was not observed between our findings and previous reports. CONCLUSION: A hospital database search revealed that the risk of tendon disorders in Japanese patients administered with FQs was higher than in those administered with cephalosporins.

The cost of antiemetic therapy for chemotherapy-induced nausea and vomiting in patients receiving platinum-containing regimens in daily practice in Japan: a retrospective study.

PURPOSE: The objective of this study was to estimate the cost of antiemetic therapy for chemotherapy-induced nausea and vomiting (CINV) in daily practice in Japan. METHODS: This was a retrospective observational study using medical records. Eligible patients were those with bladder or testicular cancer receiving platinum-containing highly emetogenic chemotherapy. The incidence of CINV on days 1-5 in single-day chemotherapy and on days 1-9 in multiple-day chemotherapy, and the costs of antiemetic therapy directly associated with the administration of antiemetics were estimated. The analysis of costs was performed from a hospital perspective. RESULTS: A total of 54 patients or 169 chemotherapy courses were included. In all chemotherapy courses 5-HT(3) receptor antagonists were used on the day(s) that platinum-containing agents were administered and frequently used on subsequent days. In contrast, the use of corticosteroids was infrequent. Acute CINV in single-day chemotherapy was well controlled, but the incidences of delayed CINV in single-day chemotherapy and CINV in multiple-day chemotherapy were relatively high. The costs for antiemetic therapy were $484.65 in courses with CINV and $318.56 in courses without CINV, and the difference was approximately $170 per chemotherapy course, which was considered to be mainly imputable to the prevalence of CINV. CONCLUSIONS: The cost of antiemetic therapy for CINV is substantial in Japan as well as in other countries, and it is suggested that the onset of CINV is a possible cost driver. The improvements in antiemetic therapy may contribute not only to improved patient well-being but also to a reduction of economic burden.

[Method for the evaluation of the stability and usability after opening packages of orally disintegrating tablets: case of amlodipine besilate products].

Orally disintegrating (OD) tablets are widely used in clinical practice. However, drug information on the choice and dispensing based on their stability after opening packages and usability in patients and dispensaries is not sufficient. The aim of this study was to investigate possible evaluation methods of the stability and usability of amlodipine OD tablets. Additives of the brand were changed in April 2009, and therefore the previous and current forms and two generics, current and newly marketed (in November 2009) products of different firms, were used. OD tablets were stored at 25 degrees C and 75% relative humidity for 3 months after opening the packages, and their physicochemical properties were evaluated. Their weight, diameter, thickness, and color difference increased slightly from the initial state. The extent of the change in their hardness, disintegration time, and friability was different among products. These physicochemical changes were acceptable in dispensary practice. Storage after opening the packages did not affect their dissolution rate. The dissolution rate at the initial state of the current brand was slower than that of the previous one. All products used were able to be dispensed by an automatic tablet-packing machine and applied to the so-called simple suspension method for intubational administration. Sensory evaluation tests revealed no major difference in the oral disintegration time, taste, impression, and preference among products. In conclusion, the stability and usability of amlodipine OD tablets used in this study were examined using several methods, and they can be used equivalently from the stability and usability viewpoints.

Surveillance of workplace contamination and occupational exposure to antineoplastic agents in a hospital setting: establishment of a monitoring method using Doxorubicin.

An academic subcommittee of Japanese Society of Hospital Pharmacists formulated the guideline for the sterile preparation of antineoplastic agents in 2008. The practical methods to monitor a workplace contamination and occupational exposure to antineoplastic agents have not been introduced into a hospital setting yet. The aims of this study were to develop a monitoring method using doxorubicin for workplace contamination and occupational exposure to antineoplastic agents and to apply it to surveillance in a hospital setting. The surface contamination of workplace was wiped with non-woven fabric containing 70% 2-propanol. The occupational exposure was evaluated by spot urine sampling during 24 hours. Chromatographic separation was achieved by a reverse phase HPLC. Doxorubicin and fluorescein (internal standard) were detected at an excitation and emission wavelength of 470 and 550 nm, respectively. The monitoring method was applied to survey the workplace contamination and occupational exposure to antineoplastic agents in Hamamatsu University Hospital. The calibration curves for doxorubicin were linear over concentration ranges of 1.5-729 ng/100 cm(2) for surface contamination and 1.0-486 ng/ml for the urine. The run time was 10 min. The intra- and interassay precisions were within 8.5%. As the surveillance in a hospital setting, the flow line adhering to the guideline kept the exposure to low level. In addition, the occupational exposure in the workers was not observed. In conclusion, this study developed the monitoring method using doxorubicin for the workplace contamination and occupational exposure to antineoplastic agents. This method can be utilized to survey in a hospital setting.