水野 智博

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

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

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

In Japan, use of a report for providing information from pharmacies to medical institutions called as "tracing report (TR)" is not widespread especially in the field of cancer chemotherapy. Identification of the factors related to submission of TRs could enhance the necessity of TRs. The purpose of this study is to clarify the factors related to submission of TRs regarding cancer chemotherapy through a questionnaire survey. A questionnaire survey was conducted at the live web-based seminar regarding cancer chemotherapy held for pharmacists in January 2023. After the questionnaire survey, the participants were divided into those who had submitted at least one TR regarding cancer chemotherapy within one month before the seminar (TR group) and those who had not (non-TR group). The multivariate analysis was conducted to identify factors related to submission of TRs regarding cancer chemotherapy. Of 118 participants, the responses from 93 pharmacy pharmacists involved in dispensing drugs who agreed to participate in this study and fulfilled all questionnaire were analyzed. TR group included 21 participants and non-TR group included 72. As a result of multivariate analysis, "Years of experience in counseling and following-up with patients undergoing cancer chemotherapy (odds ratio: 4.81, p=0.02)" and "Types of workplaces (odds ratio: 3.79, p=0.02)" significantly increased the incidence of submission of TRs regarding cancer chemotherapy. It was revealed that experience of intervention in cancer chemotherapy cases and an environment in which prescriptions for cancer chemotherapy can be handled on a daily basis are important for submission of TRs regarding cancer chemotherapy.

AIM: Multiple risk factors are involved in geriatric syndrome (GS) occurring in older adults. Although drug therapy often contributes to GS, the specific causes among older adults in Japan remain unclear. In this study, we examined the possible prescribing cascade rate among older outpatients eligible for Late-stage Elderly Health Insurance and elucidated the differences between GS and GS associated with medication (GSAM) trends. METHODS: This retrospective study enrolled patients from health insurance claims data in Japan between October 2018 and March 2019; hospitalized patients were excluded. Two groups were identified among the participants with GS: GS (no use of GS-causing medications) and possible-GSAM (p-GSAM; use of GS-causing medications). The collected data were analyzed using the Bell Curve for Excel, and statistical significance was set at P < 0.05. RESULTS: In total, 137 781 outpatients were enrolled. Of the 32 259 outpatients who did not use GS-causing medications, 7342 were classified into the GS group. Among 105 522 outpatients who used GS-causing medications, 8347 were classified as having p-GSAM. The mean number of prescriptions was significantly higher in the p-GSAM group than in the GS group (P < 0.01). Furthermore, all GS symptoms showed significant differences, with impaired appetite being the most prevalent in the p-GSAM group than in the GS group (P < 0.01). A possible prescribing cascade was suspected in 2826 (33.9%) of 8347 outpatients in the p-GSAM group. CONCLUSION: Impaired appetite in patients taking GS-causing medications might lead to prescribing cascades. Further studies are needed to prevent such prescribing cascades. Geriatr Gerontol Int 2024; 24: 61-67.

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

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

Extracellular histones induce endothelial damage, resulting in lung haemorrhage; however, the underlying mechanism remains unclear. Factor XIII, as a Ca2+-dependent cross-linking enzyme in blood, mediates fibrin deposition. As another isozyme, transglutaminase 2 (TG2) has a catalytic activity distributing in most tissues. Herein, we investigated whether TG2 promotes fibrin deposition and mediates the adhesion of platelets to ECs in histone-induced acute lung injury (ALI). We evaluated the lung histology and the adhesion of platelets to endothelial cells (ECs) after injecting histones to wild-type (WT) C57BL/6J and TG2 knockout (TG2-/-) mice, and administered a TG2 inhibitor (NC9) to WT mice. Pulmonary haemorrhage was more severe in TG2-/- mice than that in WT mice. The area of fibrin deposition and the proportion of CD41+CD31+ cells were lower in TG2-/- mice than in WT mice. Pre-treatment of NC9 decreased the area of fibrin deposition and the proportion of CD41+CD31+ cells in WT mice. These results suggest that TG2 prevents from pulmonary haemorrhage in ALI by promoting the adhesion of platelets to ECs and the fibrin deposition.

BACKGROUND: Sodium zirconium cyclosilicate, a non-absorbed non-polymer zirconium silicate, is a new potassium binder for hyperkalemia. A previous report showed that administering sodium zirconium cyclosilicate to patients with hyperkalemia allows a higher continuation rate of renin-angiotensin-aldosterone system inhibitors. However, no studies have compared sodium zirconium cyclosilicate with existing potassium binders for renin-angiotensin-aldosterone system inhibitor continuity. The purpose of this study was to evaluate the effect of sodium zirconium cyclosilicate on angiotensin-converting enzyme inhibitor /angiotensin receptor blocker continuation in patients with hyperkalemia compared to that of calcium polystyrene sulfonate. METHODS: Patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers who were newly prescribed sodium zirconium cyclosilicate or calcium polystyrene sulfonate to treat hyperkalemia at a tertiary referral hospital between August 2020 and April 2022 were enrolled in this single-center, retrospective observational study. The primary outcome measure was angiotensin-converting enzyme inhibitor/angiotensin receptor blocker prescription three months after initiating potassium binders. RESULTS: In total, 174 patients on angiotensin-converting enzyme inhibitors/angiotensin receptor blockers who were newly administered sodium zirconium cyclosilicate (n = 62) or calcium polystyrene sulfonate (n = 112) were analyzed. The prescription rate of angiotensin-converting enzyme inhibitors /angiotensin receptor blockers at 3 months was significantly higher in the sodium zirconium cyclosilicate group than in the calcium polystyrene sulfonate group (89 vs. 72%). Multivariate logistic regression models showed that sodium zirconium cyclosilicate was independently associated with the primary outcome (odds ratio 2.66, 95% confidence interval 1.05-7.43). The propensity score-matched comparison also showed a significant association between sodium zirconium cyclosilicate and the primary outcome. CONCLUSIONS: Our study suggests that administering sodium zirconium cyclosilicate to patients with hyperkalemia allows for a higher continuation rate of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers than calcium polystyrene sulfonate. These findings suggest that sodium zirconium cyclosilicate has potential benefits for patients with chronic kidney disease receiving renin-angiotensin-aldosterone system inhibitors.

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

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

Complement (C) activation occurs via three pathways, namely the classical, lectin, and alternative pathways. Intercommunication occurs between the complement and coagulation systems, which can trigger tissue injury and inflammation. Disseminated intravascular coagulation (DIC) is a life-threatening disease characterized by disordered coagulation and systemic inflammation; here, the intercommunication between the complement and coagulation systems contributes to the development of DIC. Extracellular histones, which are contributors to the damage-associated molecular pattern, induce severe thrombosis. C5 is a key molecule in the intercommunication between the complement and coagulation systems and is associated with the development of lethal histone-induced thrombosis. Heparin and chondroitin sulfate (CS) are negatively charged, allowing them to bind to extracellular histones. As the coagulation system is less affected by CS than heparin, CS shows potential as an effective drug for the treatment of patients with DIC who have a high risk of bleeding. Complement receptor type-1-related gene Y (Crry) inhibits the complement pathway via binding to C3b and C4b. Hence, Crry is a potent inhibitor of the classical and alternative C pathways. The expression of Crry is decreased by the endothelial damage induced by extracellular histones. Crry dysfunction promotes the activation of C on the surface of endothelial cells. The prevention of C3 cleavage on endothelial cells might be a useful therapy targeting acute lung injury.

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

BACKGROUND/AIM: Immune-related adverse events (irAEs) are associated with the efficacy of nivolumab. However, whether the tolerability of second-line chemotherapy is associated with the efficacy of nivolumab monotherapy (third-line chemotherapy) remains unclear. Our study aimed to investigate whether the results of second-line treatment were associated with the efficacy of nivolumab in patients with gastric cancer. PATIENTS AND METHODS: We enrolled Japanese patients aged ≥20 years with gastric cancer who were treated with nivolumab as a third-line chemotherapy at Fujita Health University Hospital from October 2017 to September 2021. Patients with the evaluations of complete response, partial response, and stable disease after third-line chemotherapy were included in the disease control (DC) group, while others were included in the progressive disease (PD) group. RESULTS: A total of 126 patients were enrolled. The population of patients aged over 65 years in the DC group was significantly higher than that in the PD group. The number of patients continuing second-line chemotherapy for >7 months was significantly higher in the DC than in the PD group. Age over 65 years [odds ratio (OR)=2.67], duration of second-line chemotherapy over 7 months (OR=3.10), and the occurrence of irAEs (OR=3.60) were detected as the factors associated with disease control after nivolumab chemotherapy. CONCLUSION: The effect and tolerability of second-line chemotherapy, and age over 65 years are the factors associated with DC after nivolumab chemotherapy. The control of tumour inflammatory status might be important for improving treatment outcomes.

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

Information on immune checkpoint inhibitor-induced vasculitides is limited, and predictors for this condition have not been identified. Therefore, we have examined the frequency of immune checkpoint inhibitor-induced vasculitides by analyzing the data recorded in the Japanese Adverse Drug Event Report database. Data from April 2004 to March 2020 were extracted, and vasculitides as an immune-related adverse event was defined according to the 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Adverse event signals were recognized as significant when the reporting odds ratio estimates and lower limits of the corresponding 95% confidence intervals exceeded 1. The use of nivolumab showed a significant signal for vasculitides. Furthermore, significant signals of polymyalgia rheumatica were found when the patients were treated with nivolumab, pembrolizumab, and ipilimumab. In addition, the frequencies of nivolumab- and pembrolizumab-induced polymyalgia rheumatica were higher in patients aged ≥70 years and female patients, respectively. Polymyalgia rheumatica was reported in 38 patients treated with nivolumab; 31 (82%) of these were either in recovery or in remission. Further, polymyalgia rheumatica was reported in 17 patients treated with pembrolizumab; 13 (76%) of these were in recovery or remission, while three (18%) were not. Polymyalgia rheumatica was reported in 12 patients treated with ipilimumab; seven (58%) of these were in recovery or remission. Our study highlights that careful monitoring for the symptom of PMR (e.g., bilateral pain in shoulder and pelvic girdles) is required when the patients are aged &amp;gt;70 years and have been treated with nivolumab and when the patients are women and have been treated with pembrolizumab.

OBJECTIVES: Favipiravir is an antiviral that is being evaluated for the treatment of COVID-19. Use of favipiravir is associated with elevation of serum uric acid levels. Risk factors for the occurrence of hyperuricemia are unclear. METHODS: Specimens from COVID-19 patients who received 10 days of favipiravir in a previous clinical trial (jRCTs041190120) were used. Serum favipiravir concentrations were measured by LC-MS. Factors associated with the development of hyperuricemia were investigated using logistic regression analysis. Optimal cut-off values for the baseline serum uric acid levels and steady-state serum favipiravir concentrations in predicting the occurrence of hyperuricemia were determined by ROC curve analysis. RESULTS: Among the 66 COVID-19 patients who were treated with favipiravir for 10 days, the steady-state serum favipiravir concentrations were significantly correlated with serum uric acid levels. High baseline serum uric acid levels and steady-state serum favipiravir concentrations during therapy were factors associated with the development of hyperuricemia. The cut‑off baseline serum uric acid level and steady-state serum favipiravir concentration during favipiravir administration determined to predict hyperuricemia were 3.7 mg/dL and 46.14 μg/mL, respectively. CONCLUSIONS: Patients with high baseline serum uric acid levels or who achieved high steady-state serum favipiravir concentrations during therapy were susceptible to hyperuricemia.

Polypharmacy in older adults causes problems such as increased adverse drug reactions, overdose or duplication, and poor medication adherence. We have established a "medication review team" organized by pharmacists. This prospective and retrospective observational study evaluated the effectiveness of the pharmacist-led team-based approach for reducing polypharmacy as compared to the individual pharmacist approach. Data on the individual pharmacist approach were collected retrospectively, but prospectively for the pharmacist-led team approach. The study included patients who were admitted to the nephrology, orthopedic surgery, and psychiatry wards. Characteristics for patient included in each study group were adjusted using the propensity score method. The pharmacist-led team approach had a significantly higher medication change rate compared to that of the individual pharmacist approach (odds ratio (OR), 2.28; 95% confidence interval (CI), 1.21 to 4.46; p = 0.009). The rate of patients with two or more medication discontinuations and the rate of patients with intervention by young clinical pharmacist were also significantly higher in the pharmacist-led team approach (OR, 2.19; 95% CI, 1.06 to 4.74; p = 0.03 and OR, 5.67; 95% CI, 1.22 to 53.15; p = 0.02, respectively). The rate of patients with discontinuation of potentially inappropriate medications was not significantly different between the two groups (OR, 2.07; 95% CI, 0.86 to 5.33; p = 0.11). Our results suggest that it is possible to improve the quality of medication review by conducting team conferences even with only pharmacists.

BACKGROUND: The number of patients aged 80 years or older with diffuse large B-cell lymphoma (DLBCL) is increasing, and the incidence rate of the disease in this population group reaches up to 20%. The risk of infection is higher in older patients than in other patients. Although hypnotic drugs are frequently detected as potentially inappropriate medications, it is unclear whether hypnotic drugs affect the occurrence of infection during chemotherapy. Here, we investigated whether the use of hypnotic drugs is associated with infection during first-line chemotherapy in patients with diffuse large B-cell lymphoma (DLBCL) aged 80 years or older. METHODS: Japanese patients aged 80 years or older with diffuse large B-cell lymphoma who had received first-line chemotherapy at Fujita Health University Hospital from January 2005 to March 2020 were enrolled in this retrospective cohort study. The primary study outcome was the identification of the risk factor for infection during first-line chemotherapy. RESULTS: This study included 65 patients received first-line chemotherapy. The proportion of patients with National Comprehensive Cancer Network-international prognostic index ≥ 6 was higher in the infection group than in the non-infection group. The relative dose intensity of each anticancer drug (cyclophosphamide, adriamycin, and vincristine) and dose of prednisolone did not significantly differ between the two groups. Multivariate analysis showed that the use of benzodiazepines was a risk factor for infection (odds ratio, 4.131 [95% confidence interval: 1.225-13.94], P = 0.022). CONCLUSION: DLBCL patients using benzodiazepines should be monitored for infection symptoms during chemotherapy.

Acute lung injury (ALI) occurs in patients with severe sepsis and has a mortality rate of 40%-60%. Severe sepsis promotes the release of histones from dying cells, which can induce platelet aggregation, activate coagulation and cause endothelial cell (EC) death. We previously reported that the expression of membrane complement receptor type 1-related gene Y (Crry)/p65, which plays a principal role in defence against abnormal activation of complement in the blood, is reduced in response to peritoneal mesothelial cell injury, and we hence hypothesized that a similar mechanism occurs in pulmonary ECs. In this study, we examined the role of Crry/p65 in histone-mediated ALI using an experimental animal model. In ALI model mice, exposure to extracellular histones induces lung injury and results in a decrease in Crry/p65 expression. The levels of lactic acid dehydrogenase (LDH), a marker of cell damage, were significantly increased in the serum of ALI model compared with vehicle mice. The significant inverse correlation between the expression of Crry/p65 and LDH levels in plasma revealed an association between Crry/p65 expression and cell damage. The levels of complement component 3a (C3a) were also significantly increased in the serum of the ALI model compared with vehicle mice. Notably, a C3a receptor antagonist ameliorated lung injury induced by histones. We hypothesize that extracellular histones induce complement activation via down-regulation of Crry/p65 and that C3a might serve as a therapeutic target for the treatment of ALI.

BACKGROUND: Early detection and prediction of cisplatin-induced acute kidney injury (Cis-AKI) are essential for the management of patients on chemotherapy with cisplatin. This study aimed to evaluate the performance of a prediction model for Cis-AKI. METHODS: Japanese patients, who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital, were enrolled in the study. The main metrics for evaluating the machine learning model were the area under the curve (AUC), accuracy, precision, recall, and F-measure. In addition, the rank of contribution as a predictive factor of Cis-AKI was determined by machine learning. RESULTS: A total of 1,014 and 226 patients were assigned to the development and validation data groups, respectively. The current prediction model showed the highest performance in patients 65 years old and above (AUC: 0.78, accuracy: 0.77, precision: 0.38, recall: 0.70, F-measure: 0.49). The maximum daily cisplatin dose and serum albumin levels contributed the most to the prediction of Cis-AKI. CONCLUSION: Our prediction model for Cis-AKI performed effectively in older patients.

BACKGROUND/AIM: The aim of this study was to evaluate the effect of drug-induced interstitial lung disease (DILD) on treatment outcomes by comparing the mortality of patients with DILD induced by different pharmacological types of anticancer drugs. PATIENTS AND METHODS: Japanese patients with lung cancer who had received chemotherapy at Fujita Health University Hospital were enrolled. The primary outcome was the short-term mortality rate from the administration of chemotherapy that might have caused DILD. RESULTS: Eleven, 16, and 20 patients with DILD were assigned to the kinase inhibitor (KI), immune-checkpoint inhibitor (ICI), and cytotoxic anticancer drug groups, respectively. The 90-day mortality rate after the DILD event in the group treated with cytotoxic anticancer drugs was significantly higher than in the KI and ICI groups. CONCLUSION: Patients with DILD induced by cytotoxic anticancer drugs have poorer prognoses than those with DILD induced by KIs or ICIs.

BACKGROUND/AIM: The aim of this study was to investigate the impact of drug-induced interstitial lung disease (DILD) on the mortality of patients with lung cancer. PATIENTS AND METHODS: Japanese patients with lung cancer who had received chemotherapy in Fujita Health University Hospital from January 2017 to December 2018 were enrolled in this study. The primary outcome was to identify independent factors associated with patient mortality. The secondary outcome was to identify the risk factor of DILD. RESULTS: Four hundred and fifty-seven patients were assigned to the current study. The multivariable analysis revealed that being aged 75 years or older, small cell lung carcinoma, cancer stage IV, and DILD event were risk factors of mortality. Male sex was identified as a risk factor of DILD. CONCLUSION: DILD event has the same degree of risk for mortality as age 75 years or older in lung cancer patients.

WHAT IS KNOWN AND OBJECTIVE: Hypertension (HTN) and chronic kidney disease (CKD) are recognized as silent killers because they are asymptomatic conditions that contribute to the burden of multiple comorbidities. The achievement of a blood pressure (BP) goal can dramatically reduce the risks of CKD. In this study, we aimed to assess the effectiveness of pharmacist intervention on BP control in patients with CKD and evaluate the usefulness of home-based BP telemonitoring. METHODS: The terms "chronic kidney disease," "pharmacist," "BP" and "randomized controlled trial (RCT)" were used five databases to search for information regarding pharmacist intervention on BP control in patients with CKD. The inclusion criteria were as follows: (a) studies for adult patients with uncontrolled HTN and (b) studies with adequate data for meta-analysis. The primary outcome was an evaluation of achievement of BP goal in patients with CKD. The secondary outcome was usefulness of home-based BP telemonitoring by pharmacists in patients with CKD. RESULTS AND DISCUSSION: Six RCTs were identified and included in the meta-analysis with a total of 2573 patients (mean age 66.0 years and 63.9% male). Pharmacist interventions resulted in significantly better BP control vs usual care (OR = 1.53, 95% CI = 1.15-2.04, P < .01). Pharmacist interventions using home-based BP telemonitoring were significantly superior to control/usual care (OR = 2.03, 95% CI = 1.49-2.77, P < .01), whereas pharmacist interventions without home-based BP telemonitoring did not significantly improve BP control compared to that with control/usual care (OR = 1.30, 95% CI = 0.97-1.75, P = .08). Home-based BP telemonitoring supported team-based care for HTN in these studies. In addition, patient self-monitoring with telemedicine devices might enhance patients' abilities to manage their condition by pharmacist instruction. WHAT IS NEW AND CONCLUSION: The findings of this meta-analysis showed that pharmacist interventions with home-based BP telemonitoring improve BP control among adult patients with CKD.

Renal anemia in chronic kidney disease is treated with recombinant human erythropoietin (rhEPO). However, some patients with anemia do not respond well to rhEPO, emphasizing the need for a more biocompatible EPO. Differentiation protocols for hepatic lineages have been modified to enable production from human induced pluripotent stem cell (hiPSC)-derived EPO-producing cells (EPO cells). However, markers for hiPSC-EPO cells are lacking, making it difficult to purify hiPSC-EPO cells and therefore to optimize EPO production and cell counts for transplantation. To address these issues, we investigated whether CD140b and CD73 could be used as markers for hiPSC-EPO cells. We measured the expression of EPO, CD140b, and CD73 in hiPSC-EPO cells and the EPO concentration in the cell supernatant by immunohistochemistry and enzyme-linked immunosorbent assays on culture day 13, revealing that expression levels of CD140b and CD73 are correlated with the level of EPO. In addition, rates of CD140b+ CD73+ cells were observed to be correlated with the concentration of EPO. Thus, our results suggest that CD140b and CD73 may be markers for hiPSC-EPO cells.

A common renal disease, immunoglobulin A (IgA) nephropathy (IgAN), is associated with glomerular deposition of IgA1-containing immune complexes. IgA1 hinge region (HR) has up to six clustered O-glycans consisting of Ser/Thr-linked N-acetylgalactosamine with β1,3-linked galactose and variable sialylation. IgA1 glycoforms with some galactose-deficient (Gd) HR O-glycans play a key role in IgAN pathogenesis. The clustered and variable O-glycans make the IgA1 glycomic analysis challenging and better approaches are needed. Here, we report a comprehensive analytical workflow for IgA1 HR O-glycoform analysis. We combined an automated quantitative analysis of the HR O-glycopeptide profiles with sequential deglycosylation to remove all but Gd O-glycans from the HR. The workflow was tested using serum IgA1 from healthy subjects. Twelve variants of glycopeptides corresponding to the HR with three to six O-glycans were detected; nine glycopeptides carried up to three Gd O-glycans. Sites with Gd O-glycans were unambiguously identified by electron-transfer/higher-energy collision dissociation tandem mass spectrometry. Extracted ion chromatograms of isomeric glycoforms enabled quantitative assignment of Gd sites. The most frequent Gd site was T236, followed by S230, T233, T228, and S232. The new workflow for quantitative profiling of IgA1 HR O-glycoforms with site-specific resolution will enable identification of pathogenic IgA1 HR O-glycoforms in IgAN.

AIM: To analyze the impact of clinical medication reviews (CMR) on reducing unplanned hospitalizations owing to polypharmacy among older adults using an intervention. METHODS: Our meta-analysis complied with PRISMA guidelines. The literature review comprised a search for articles published between January 1972 and March 2017 on MEDLINE and Google Scholar. We identified randomized controlled trials focusing on CMR that evaluated unplanned hospitalization and re-hospitalization among older adults as a primary outcome. The keywords used were "CMR" or "medication review" in their titles, and the phrases "elderly" or "older adults" or "geriatric" and "polypharmacy." The randomized controlled trials selected were divided according to the three types of CMR to analyze the characteristics of each review. RESULTS: We included nine randomized controlled trials that examined the impact of CMR of polypharmacy in older patients. Five trials corresponded to CMR type I (prescription only review) or II (adherence review), whereas four corresponded to type III (comprehensive clinical evaluation for disease management). Type I/II increased the number of unplanned hospitalizations (RR 1.22, 95% CI 1.07-1.38, P = 0.002), whereas type III decreased hospital admissions (RR 0.86, 95% CI 0.79-0.95, P = 0.001). CONCLUSIONS: The present findings show the need for an intervention standardization for CMR, particularly for type III in older adults with polypharmacy, to decrease hospitalizations. Geriatr Gerontol Int 2019; 19: 1275-1281.

Extracellular histones induce lethal thrombosis by promoting platelet aggregation, neutrophil migration, and cell injuries. Heparin, which has negative charges, can bind to extracellular histones; however, heparin strongly inhibits the activation of coagulation. Since chondroitin sulfate (CS) shows less effect on the coagulation system than heparin does, CS has the potential to become an effective drug for lethal thrombosis with high risk of bleeding. To elucidate the therapeutic mechanisms of CS in lethal thrombosis, we investigated the interaction between CS and extracellular histones. Mouse vascular endothelial cells were incubated with histones in the presence of heparin or CS, and the expression of caspase-3/7 was measured. The interactions between histones and heparin or CS were measured by surface plasmon resonance analysis. Vascular permeability, platelet counts, liver and renal functions, and coagulation times were evaluated in an in vivo assay. The apoptosis induced by histones was inhibited by treatment with heparin or CS. Heparin and CS showed strong binding to histones and inhibited vascular hyperpermeability. The platelet counts as well as liver and renal functions were not decreased by the treatment with heparin or CS. Moreover, CS showed less effect on the coagulation system than heparin did. These results suggested that CS can be a novel agent for lethal thrombosis with the risk for hemorrhage. Since vascular endothelial cell injuries occur at an early stage of lethal thrombosis, administration of CS might be a useful approach.

3年次生物学応用実習(薬理学)において、1人1台でインストラクタソフトウェア(LLEAP)搭載PCを用いて演習プログラムを実施した。LLEAPを起動した後、急性喘息発作の症例を選択し、1日目のエピネフリン急速静脈内投与と2日目のエピネフリン、ノルエピネフリン、イソプレナリン持続点滴静脈内投与のシミュレーション演習を実施した。3日目の課題1はニフェジピン、リシノプリル、プロプラノロールの経口投与による循環器に対する作用、課題2はプロプラノロール経口投与による喘息患者における喘息発作増悪作用のシミュレーション演習を行った。全問題、知識関連、演習関連、降圧薬関連のポストテストの正答率はプレテストと比較してすべて有意に上昇した。学生の49%は喘息患者に禁忌であることを演習レポートに記述した。「喘息発作を悪化させる」と記述した学生は32%、「心不全・徐脈」を禁忌として記述した学生は15%であった。「喘息に禁忌・喘息を悪化」と「心不全・徐脈」を記述した学生は10%であった。プロプラノロールの降圧作用の機序として心拍数の低下や心拍出量の低下を演習レポートに記述した学生は40%であった。

AIM: Polypharmacy is an extremely important problem, because it increases the risk of adverse drug reactions. The aim of the current study was to create a clinical medication review tool to detect inappropriate medication use, and assess this new method with elderly Japanese patients. METHODS: The new method involves optimizing prescription drugs from indications, based on the chronic disease-anatomical therapeutic class code list. The present study investigated the prevalence of potentially inappropriate medications in 5667 Japanese patients aged ≥65 years with polypharmacy (≥5 drugs) in comparison with the Beers criteria 2012. RESULTS: We propose a new method called the Mapping Approach for Pharmacotherapeutic Classifications: (i) identify the chronic disease-anatomical therapeutic class code assigned to the prescription drugs; (ii) identify the chronic disease-anatomical therapeutic class code corresponding to the patient's chronic disease; (iii) compare the prescription drug and patient's chronic disease chronic disease-anatomical therapeutic class codes; and (iv) identify the appropriateness of medication use based on the comparison (appropriate use is defined as matching codes). The mean number of potentially inappropriate medications detected was significantly different between the mapping approach and Beers criteria 2012 (3.1 ± 2.6 vs 0.6 ± 0.8 drugs, respectively; P < 0.001). CONCLUSIONS: The Mapping Approach for Pharmacotherapeutic Classifications is highly dependent on the chronic condition. Pharmacists should confirm the chronic condition with the treating physician before reducing a patient's medications. We hope this process will further influence prescribing patterns, and decrease the inappropriate use of medications and associated adverse drug reactions in older adults. Geriatr Gerontol Int 2017; 17: 2025-2033.

Extracellular histones promote platelet aggregation and thrombosis; this is followed by induction of coagulation disorder, which results in exhaustion of coagulation factors. Complement component 5 (C5) is known to be associated with platelet aggregation and coagulation system activation. To date, the pathological mechanism underlying liver injury has remained unclear. Here, we investigated whether C5 promotes liver injury associated with histone-induced lethal thrombosis. C5-sufficient and C5-deficient mice received single tail vein injections of purified, unfractionated histones obtained from calf thymus (45-75 μg/g). Subsequently, the mice were monitored for survival for up to 72 h. Based on the survival data, the 45 μg/g dose was used for analysis of blood cell count, liver function, blood coagulation ability, and promotion of platelet aggregation and platelet/leukocyte aggregate (PLA) production by extracellular histones. C5-deficient mice were protected from lethal thrombosis and had milder thrombocytopenia, consumptive coagulopathy, and liver injury with embolism and lower PLA production than C5-sufficient mice. These results indicate that C5 is associated with coagulation disorders, PLA production, and embolism-induced liver injury. In conclusion, C5 promotes liver injury associated with histone-induced lethal thrombosis.

We previously started pharmacist blood pressure (BP) management programs using telemonitoring systems for monitoring side effects of antihypertensive drugs in a community pharmacy. The present case demonstrates that pharmacist BP management programs using telemonitoring systems are useful for monitoring side effects of antihypertensive drugs in a community pharmacy.

BACKGROUND AND AIMS: Cisplatin-induced nephrotoxicity primarily occurs in the proximal tubules, and tubular injuries reduce glomerular filtration rates. Lower blood pressure causes renal hypoperfusion, which promotes ischemic acute kidney injury (AKI). Our study examined the relationship between lower blood pressure-induced renal hypoperfusion and cisplatin-induced nephrotoxicity. METHODS: The relationship between cisplatin use and hypoalbuminemia is not clear. This study consisted of Japanese patients who received cisplatin as the first-line chemotherapy at Fujita Health University Hospital from April 2006 to December 2012. Hypoalbuminemia was defined as serum albumin levels ≤3.5 mg/dl. RESULTS: Patients who experienced lower blood pressure during chemotherapy were included in the lower blood pressure group (n = 229), and those who did not were included in the normal blood pressure group (n = 743). Total cisplatin dose in the normal blood pressure and lower blood pressure groups was 58.9 ± 23.8 and 55.0 ± 20.4 mg/m2, respectively. The rate of severe nephrotoxicity was higher and overall survival was shorter in the lower blood pressure group than in the normal blood pressure group. In a multivariable analysis, lower blood pressure significantly correlated with hypoalbuminemia. CONCLUSIONS: To prevent ischemic AKI, nutrition and cachexia controlling are important parts of cancer treatment.

Anti-endothelial cell antibodies (AECA) are frequently detected in patients with systemic lupus erythematosus (SLE), but their pathological role remains unclear. We recently developed a solubilized cell surface protein capture enzyme-linked immunosorbent assay (CSP-ELISA) to detect antibodies against membrane proteins involved in autoimmune reactions. In this study, sera from 51 patients with biopsy-proven lupus nephritis (LN), 25 with SLE without renal involvement (non-LN SLE), 42 disease control (DC) subjects, and 80 healthy control (HC) subjects were tested for IgG- and IgA-AECA for human umbilical vein endothelial cells (HUVEC) and human glomerular EC (HGEC) by using CSP-ELISA. IgG- and IgA-AECA titers were significantly higher in LN and non-LN SLE patients than in the DC or HC (P < 0.001) groups. IgG- and IgA-AECA titers for HUVEC corresponded well with those for HGEC. The IgA-AECA level correlated with the SLE disease activity index and with histological evidence of active lesions (cellular proliferations, hyaline thrombi and wire loops, leukocytic infiltration, and fibrinoid necrosis) in LN patients (P < 0.001). The sensitivity of IgA-AECA as a diagnostic test for histological evidence of active lesions in LN patients was 0.92, with a specificity of 0.70. The significant correlation of IgA-AECA with glomerular hypercellularity indicates that IgA-AECA are associated with endothelial damage in LN.

ヒト型高機能患者シミュレーター(SimMan 3G)を用い、交感神経系に作用する薬物による循環器バイタルサインの変動について検討した。エピネフリンを急速静注でSimMan 3Gに投与し、心拍数、血圧は投与量依存的に上昇し、心拍出量は用量依存性を認めなかった。瞳孔散大、発汗も投与量依存的に効果発現までの時間が短縮され、持続時間が延長した。エピネフリンの急速静注に比べ皮下・筋肉内投与では心拍数、血圧の増加量は半分となり、心拍出量も最大値到達に2〜3倍を要し、瞳孔散大、発汗も作用発現までの時間延長、持続時間の短縮を認めた。イソプレナリンの点滴では著明な心拍数、血圧の増加を認め、ノルエピネフリンで瞳孔散大を認めた。ドブタミンの点滴では心拍数、心拍出量の増加を認めた。SimMan 3Gの多人数での演習効果は、演習後に全項目で席次上位群と下位群に、知識項目で上、中、下位群に、演習項目で上位、下位群に有意な増加を認めた。

The use of antimicrobial agents has increased in recent years as treatments have diversified and resistant bacteria have appeared. With increased use of antimicrobial agents, elderly patients are prone to adverse drug reactions (ADRs) as a result of factors such as drug-drug interactions, polypharmacy, long-term use, and over- or under-dosage. In particular, elderly patients using antimicrobials are at increased risk to develop drug-induced acute kidney injury (AKI), which is the most common severe ADR in such patients. AKI is a serious problem that is associated with mortality amongst hospitalized patients. Antimicrobial-induced AKI can be classified into three different types: acute tubular necrosis (ATN), acute interstitial nephritis (AIN), and renal tubule lumen obstruction. AKI can generally be prevented by proper maintenance of fluid balance. To design dosage regimens that ensure efficient drug excretion via the kidney, it is necessary to accurately estimate renal function; however, the kidney undergoes age-dependent structural and functional alterations over time. Therefore, proper management of antimicrobial agents by an antimicrobial stewardship team may lead to decreased incidence of AKI. This article reviews antimicrobial-induced AKI and discusses potential strategies for increasing awareness of AKI and mitigating its clinical effects.

Comparative studies of the potency of long- and short-acting erythropoiesis-stimulating agents (L-ESAs and S-ESAs) on erythropoietic activity in patients with chronic kidney disease without dialysis have not been performed, although L-ESAs are used in many countries. We performed a retrospective analysis of non-dialysis (ND) patients who had received L-ESA or S-ESA. More days were needed for the S-ESA-treated group (368 d) to reach the haemoglobin (Hb) reference range than for the L-ESA-treated group (126 d). Therefore, we investigated risk factors that influence the period until the Hb level reaches the reference range. Patients were classified into two groups by the period until the Hb level was stabilised within the reference range: the short- and long-term group. Two risk factors for delayed Hb stabilisation were identified: age ≥60 years; and administration of an S-ESA for initial treatment. These findings suggest that the Hb level should be carefully monitored during ESA therapy in elderly ND patients, and that the ESA dose should be increased or L-ESA therapy should be utilised to treat renal anaemia.

BACKGROUND/AIM: To elucidate the mechanism responsible for developing acute kidney injury in patients with diabetes mellitus, we also evaluated the issue of whether advanced glycation endproducts (AGEs) influence the expressions of multi antimicrobial extrusion protein (MATE1/SLC47A1) in tubular cells. MATERIALS AND METHODS: To detect changing expression of MATE1/SLC47A1 in dose- and time-dependent manners, human proximal tubular epithelial cells were incubated with AGE-aggregated-human serum albumin. As a function assay for MATE1/SLC47A1, human proximal tubular epithelial cells were incubated with cisplatin or carboplatin. RESULTS: On incubation with AGEs, the expressions of MATE1/SLC47A1 were decreased in tubular cells. In addition, the toxicities of cisplatin were increased in tubular cells that had been pretreated with AGEs. However, the toxicities of carboplatin were smaller than that of cisplatin in proximal tubular epithelial cells. CONCLUSION: The expression of the MATE1/SLC47A1 is decreased by AGEs, which increases the risk for proximal tubular injury.

BACKGROUND: Patients with end-stage renal disease (ESRD) have symptoms related to severe anemia, edema, and heart failure. Although dialysis improves ESRD syndromes, the optimum timing for initiation of dialysis is unclear. Recent observational studies have suggested that early commencement of dialysis can be harmful. Given that early dialysis may increase the risk of death, avoiding an early start to dialysis is recommended. Patients with diabetic nephropathy (DN) may have risk factors for early dialysis. However, the risk factors for early dialysis are unclear in ESRD patients with DN. The aim of this study was to elucidate the risk factors for early initiation of dialysis in patients with DN and ESRD. METHODS: From April 2009 to December 2012, we identified Japanese DN patients with an estimated glomerular filtration rate of less than 15 mL/minute/1.73 m(2). The patients were divided into late or early dialysis groups based on the timing of start of dialysis. RESULTS: We evaluated 52 patients who commenced dialysis during the observation period, including 33 in the late dialysis group and 19 in the early dialysis group. There was a significant association between early dialysis and age ≥65 years (odds ratio 4.59). The incidence of pneumonia before starting dialysis was significantly higher in elderly patients than in nonelderly patients. CONCLUSION: Our findings suggest that elderly patients with DN and ESRD have an increased risk of early initiation of dialysis, and occurrence of pneumonia is also associated with early dialysis. To avoid early commencement of dialysis, booster pneumococcal vaccination could be useful in elderly DN patients with ESRD.

Blood pressure (BP) telemonitoring systems and pharmacist management programs were introduced into Haruka Community Pharmacy. A 22-year-old healthy male came to the community pharmacy, although he was not in a diseased state, he had been informed previously that he had a moderately high BP during a routine examination. He continued home BP telemonitoring for 28 days. A pharmacist intervention was conducted at 2 week intervals. His average nighttime systolic BP was higher than the daytime systolic BP. The pharmacist consulted a doctor based on the BP telemonitoring results, and ambulatory blood pressure monitoring (ABPM) was initiated. The doctor detected nocturnal hypertension based on the results of ABPM monitoring. BP telemonitoring systems have been introduced into a small percentage of pharmacies in Japan, and this is the first case report for the usefulness of these systems in a community pharmacy.

BACKGROUND: Maintenance of low serum urate levels is important for the management of gout. Achieving the recommended serum urate levels of less than 6.0 mg/dL is difficult in elderly (65 years of age or older) patients with renal impairment. Xanthine oxidase inhibitors allopurinol and febuxostat are used for this purpose. Although febuxostat had been shown to be efficacious in elderly patients, its safety and efficacy in elderly female patients with hyperuricemia remain unclear. OBJECTIVE: The aim of this study was to assess the efficacy and safety of febuxostat in elderly female patients. METHODS: We studied a retrospective cohort study. The study included elderly Japanese patients (65 years of age or older) who were treated with febuxostat at Fujita Health University Hospital from January 2012 to December 2013. The treatment goal was defined as achievement of serum urate levels of 6.0 mg/dL or lower within 16 weeks; this was the primary endpoint in the present study. Adverse events of febuxostat were defined as more than twofold increases in Common Terminology Criteria for adverse events scores from baseline. RESULTS: We evaluated 82 patients treated with febuxostat during the observation period and classified them into male (n=53) and female (n=29) groups. The mean time to achievement of the treatment goal was significantly shorter in the female group (53 days) than in the male group (71 days). There were no significant differences in adverse events between the 2 groups. CONCLUSION: Our findings suggest that the efficacy of febuxostat in elderly female patients is superior to that in elderly male patients and that the safety is equivalent.

In peritoneal dialysis (PD) therapy, physical stresses such as exposure to peritoneal dialysate, catheter trauma, and peritonitis may induce peritoneal injury that can prevent continued long-term PD therapy. Therefore, protection of the peritoneum is an important target to enable long-term PD therapy in patients with end-stage renal disease. We previously showed that neutralization of the membrane complement regulators (CRegs) Crry and CD59 in rat peritoneum provokes development of acute peritoneal injury due to uncontrolled complement activation. C5a is a key effecter molecule of the complement system released during acute inflammation. Control of C5a has been proposed as a strategy to suppress inflammatory reactions and, because peritoneal injury is accompanied by inflammation, we hypothesized that C5a targeted therapy might be an effective way to suppress peritoneal injury. In the present study we used an established acute peritonitis model induced by neutralization of CRegs to investigate the effects on acute peritoneal injury of inhibiting C5a. Intravenous administration of an anti-C5a complementary peptide (AcPepA) up to 4 h after induction of injury significantly and dose-dependently prevented accumulation of inflammatory cells and reduced tissue damage in the model, accompanied by decreased C3b deposition. We show that C5a contributed to the development of peritoneal injury. Our results suggest that C5a is a target for preventing or treating peritoneal injury in patients undergoing prolonged PD therapy or with infectious complications.

Peritoneal fibrosis (PF) causes ultrafiltration failure (UFF) and is a complicating factor in long-term peritoneal dialysis. Lymphatic reabsorption also may contribute to UFF, but little is known about lymphangiogenesis in patients with UFF and peritonitis. We studied the role of the lymphangiogenesis mediator vascular endothelial growth factor-C (VEGF-C) in human dialysate effluents, peritoneal tissues, and peritoneal mesothelial cells (HPMCs). Dialysate VEGF-C concentration correlated positively with the dialysate-to-plasma ratio of creatinine (D/P Cr) and the dialysate TGF-β1 concentration. Peritoneal tissue from patients with UFF expressed higher levels of VEGF-C, lymphatic endothelial hyaluronan receptor-1 (LYVE-1), and podoplanin mRNA and contained more lymphatic vessels than tissue from patients without UFF. Furthermore, mesothelial cell and macrophage expression of VEGF-C increased in the peritoneal membranes of patients with UFF and peritonitis. In cultured mesothelial cells, TGF-β1 upregulated the expression of VEGF-C mRNA and protein, and this upregulation was suppressed by a TGF-β type I receptor (TGFβR-I) inhibitor. TGF-β1-induced upregulation of VEGF-C mRNA expression in cultured HPMCs correlated with the D/P Cr of the patient from whom the HPMCs were derived (P<0.001). Moreover, treatment with a TGFβR-I inhibitor suppressed the enhanced lymphangiogenesis and VEGF-C expression associated with fibrosis in a rat model of PF. These results suggest that lymphangiogenesis associates with fibrosis through the TGF-β-VEGF-C pathway.

児童期における医学・薬学教育の推進を目的として、小学生を対象とした「くすりと安全に安心して付き合うための出前くすり実験授業」を開催している。参加した児童の「くすりの知識」が向上したか評価するため、体験授業前・後にアンケート調査を行い、265名から回答を得た。授業前の「くすりの知識」については1〜3年生と4〜6年生で有意差が認められた。体験授業後の「くすりの知識」は肯定的な回答(はい、わかった)の割合が有意に高くなっていた。「くすりの実験」については90%以上の児童から肯定的な回答が得られた。「薬剤師を知っていた」と回答した1〜3年生は30.0%、4〜6年生は77.9%と有意差が認められた。

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) infections are associated with significant mortality and health care costs. To improve treatment outcomes for MRSA, a better understanding of the pharmacokinetic/pharmacodynamic parameters of vancomycin is required to develop optimal dosing strategies, particularly in elderly patients (≥75 years of age) with limited renal function. The purpose of this study was to determine whether pharmacokinetic indices for vancomycin are associated with mortality from MRSA hospital-acquired pneumonia in elderly patients. METHODS: We conducted a retrospective observational study with 28-day mortality as the primary outcome for 94 patients with MRSA hospital-acquired pneumonia who had been treated with vancomycin from January 2006 through December 2012. Our most recent sampling of MRSA isolates had a minimum inhibitory concentration (MIC) for vancomycin of 1 μg/mL (86%), indicating that the area under the curve (AUC) was equal to the AUC/MIC in these isolates. The primary data from 28-day survivors and nonsurvivors were compared. RESULTS: Among 94 elderly patients, the mean age was 82 (75-99) years. Multivariate analyses revealed that, among the factors examined, only the nonoptimal AUC (<250, >450 μg*h/mL) was an independent predictor of 28-day mortality in elderly patients (odds ratio 23.156, 95% confidence interval 6.814-78.687, P < 0.001). We detected a significant difference for increasing nephrotoxicity in nonsurvivors (nine of 32 patients [28%]) compared with survivors (three of 62 patients [4.8%], P = 0.003). CONCLUSION: This finding indicates that patients with potentially poor renal function are likely to have increased AUC values and a poor prognosis. Consideration of the pharmacokinetics/pharmacodynamics of vancomycin and targeting an AUC/MIC value of 250-450 μg*h/mL may result in improved treatment outcomes for elderly patients with MRSA hospital-acquired pneumonia.

BACKGROUND: Vancomycin (VCM) treatment outcomes depend on the characteristics of the patient, and it is well known that hypoalbuminemia is a risk factor for poor treatment outcomes, as reported in a previous study. However, the reason that severe hypoalbuminemia has an influence on the treatment outcome of VCM remains unknown. OBJECTIVE: To elucidate the association between severe hypoalbuminemia and VCM treatment outcomes, we examined pharmacokinetic/pharmacodynamic (PK/PD) parameters in elderly patients with severe hypoalbuminemia. METHODS: We conducted a retrospective observational study of 94 patients with methicillin-resistant Staphylococcus aureus (MRSA) hospital-acquired pneumonia who had been treated with VCM between January 2006 and December 2012. The 94 patients were divided into severe hypoalbuminemia and non-severe hypoalbuminemia groups. The PK/PD parameters and treatment outcomes of VCM were compared between the two groups. RESULTS: The half-life of VCM in the severe hypoalbuminemia group was significantly longer than in the non-severe hypoalbuminemia group (33.2 + 5.4 vs 24.9 + 1.6; P = 0.049). Area under the concentration curve (AUC)/minimum inhibitory concentration (MIC) values of 250-450 and >450 μg × h/mL were significantly associated with 28-day mortality in the severe hypoalbuminemia group (P < 0.001), whereas AUC/MIC values of <250 μg × h/mL were not associated. We also detected a significant difference in the increased percentage of nephrotoxicity in the severe hypoalbuminemia group (6 of 23 patients [26%]) compared with the non-severe hypoalbuminemia group (6 of 71 patients [8%]; P < 0.001). CONCLUSION: These findings indicate that severe hypoalbuminemia influences the half-life of VCM and treatment outcomes in elderly patients (≥75 years of age). To establish a more effective and safer treatment protocol, the issue of malnutrition in elderly patients needs to be addressed and improved.