Language：English   Publishing type：Research paper (scientific journal)  

Fluoroquinolones, which are widely used antibiotics, have been linked to aortic disease, which prompted an FDA warning in 2018. Recent reports have challenged the perception that fluoroquinolones pose a significant risk for vascular diseases. This study aimed to investigate whether fluoroquinolones increase the risk of aortic diseases by focusing on the onset of aortic dissection. Levofloxacin (LVFX), a fluoroquinolone, was studied in vitro using cultured vascular cells and in vivo using a mouse model prone to aortic dissection. Risk of adverse drug events was analyzed using VigiBase, a global safety database, and a retrospective cohort analysis was conducted using the JMDC Claims database. LVFX resulted in endothelial cell injury and increased matrix metalloproteinases in vitro. However, in vivo studies showed no significant effect on elastin degradation or aortic dissection incidence. The effect of LVFX on endothelial injury was altered during the onset of dissection, exacerbating injury before onset but inhibiting it afterward. Safety database analysis showed no significant risk signals for aortic dissection associated with fluoroquinolones, which was supported by findings in the receipt database. Inconsistencies were observed in the in vitro and in vivo actions of fluoroquinolones and differences in their effects on aortic dissection and aneurysms. Despite cytotoxicity, the risk of aortic dissection was not significantly increased in clinical scenarios. Based on our findings, concerns regarding aortic diseases do not justify discontinuation of fluoroquinolone use. Further studies are needed to elucidate the conflicting actions of fluoroquinolones, taking into account background pathophysiology such as infection and inflammation.

DOI： 10.1016/j.biopha.2024.117418

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Language：Japanese   Publisher：(一社)医療の質・安全学会  

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

There is a growing concern about the relationship between vancomycin-associated nephrotoxicity (VAN) and concomitant use of nephrotoxins. We examined this relationship by combined retrospective analyses of two real-world databases. Initially, the FDA Adverse Event Reporting System (FAERS) was analyzed for the effects of concomitant use of one or more nephrotoxins on VAN and the types of combinations of nephrotoxins that exacerbate VAN. Next, electronic medical records (EMRs) of patients who received vancomycin (VCM) at Tokushima University Hospital between January 2006 and March 2019 were examined to confirm the FAERS analysis. An elevated reporting odds ratio (ROR) was observed with increases in the number of nephrotoxins administered (VCM + one nephrotoxin, adjusted ROR (95% confidence interval [CI]) 1.67 [1.51-1.85]; VCM + ≥2 nephrotoxins, adjusted ROR [95% CI] 1.54 [1.37-1.73]) in FAERS. EMRs analysis showed that the number of nephrotoxins was associated with higher incidences of VAN [odds ratio: 1.99; 95% CI: 1.42-2.78]. Overall, concomitant use of nephrotoxins was associated with an increased incidence of VAN, especially when at least one of those nephrotoxins was a renal hypoperfusion medication (furosemide, non-steroidal anti-inflammatory drugs, and vasopressors). The concomitant use of multiple nephrotoxins, especially including renal hypoperfusion medication, should be avoided to prevent VAN.

DOI： 10.18926/AMO/66151

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Language：Japanese   Publisher：(一社)医療の質・安全学会  

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Language：Japanese   Publisher：(一社)日本臓器保存生物医学会  

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Language：English   Publishing type：Research paper (scientific journal)  

Aortic dissection is an adverse event of angiogenesis inhibitors; however, the association between the drugs and aortic dissection is unclear. Therefore, we investigated if and how angiogenesis inhibitors increase the onset of aortic dissection using pharmacologically-induced aortic dissection-prone model (LAB) mice, cultured endothelial cells, and real-world databases, which is a novel integrated research approach. Disproportionality analysis was performed and calculated using the reporting odds ratio as a risk signal using a worldwide database of spontaneous adverse events to estimate the risk of adverse events. Angiogenesis inhibitors, but not other hypertension-inducing drugs, showed significant risk signals for aortic aneurysms and dissection. A retrospective cohort analysis using JMDC, a medical receipt database in Japan, showed that the history of atherosclerosis and dyslipidemia, but not hypertension, were significantly associated with the onset of aortic dissection during angiogenesis inhibitor medication administration. For in vivo studies, sunitinib (100 mg/kg/day) was administered to LAB mice. Sunitinib increased systolic blood pressure (182 mmHg vs. 288 mmHg with sunitinib; p＜0.01) and the incidence of aortic dissection (40% vs. 59% with sunitinib; p = 0.34) in mice. In vivo and in vitro studies revealed that sunitinib increased endothelin-1 expression and induced endothelial cell damage evaluated by intracellular- and vascular cell adhesion molecule-1 expressions. The increased risk of developing aortic dissection with angiogenesis inhibitors is associated with the development of drug-specific hypertension via endothelial cell damage and endothelin-1 expression. Our findings are invaluable in establishing safer anticancer therapies and strategies to prevent the development of vascular toxicity in high-risk patients.

DOI： 10.1016/j.biopha.2023.115504

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Although an association has been reported between diuretics and myocarditis, it is unclear whether the risk of immune checkpoint inhibitor (ICI)-induced myocarditis is affected by concomitant diuretics. Thus, the aim of this work was to evaluate the impact of concomitant diuretics on ICI-induced myocarditis. This cross-sectional study used disproportionality analysis and a pharmacovigilance database to assess the risk of myocarditis with various diuretics in patients receiving ICIs via the analysis of data entered into the VigiBase database through December 2022. Multiple logistic regression analysis was performed to identify risk factors for myocarditis in patients who received ICIs. A total of 90 611 patients who received ICIs, including 975 cases of myocarditis, were included as the eligible dataset. A disproportionality in myocarditis was observed for loop diuretic use (reporting odds ratio 1.47, 95% confidence interval [CI] 1.02-2.04, P = .03) and thiazide use (reporting odds ratio 1.76, 95% CI 1.20-2.50, P < .01) in patients who received ICIs. The results of the multiple logistic regression analysis showed that the use of thiazides (odds ratio 1.67, 95% CI 1.15-2.34, P < .01) was associated with an increased risk of myocarditis in patients who received ICIs. Our findings may help to predict the risk of myocarditis in patients receiving ICIs.

DOI： 10.1002/ijc.34616

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BACKGROUND: It is unclear whether use of a proton pump inhibitors (PPIs) increases the risk of rhabdomyolysis. OBJECTIVE: To clarify whether use of PPIs increases the risk of rhabdomyolysis. METHODS: This cross-sectional study analyzed data entered into the Medical Data Vision (MDV) database in Japan and into the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS). The MDV data were analyzed to evaluate the association between use of PPIs and rhabdomyolysis. Then, the FAERS data were analyzed to evaluate whether the risk of rhabdomyolysis was increased further when a statin or fibrate was used concomitantly with a PPI. In both analyses, histamine-2 receptor antagonist was set as a comparator because it is used to treat gastric disease. In the MDV analysis, Fisher's exact test and multiple logistic regression analysis were performed. In the FAERS analysis, a disproportionality analysis using Fisher's exact test and multiple logistic regression analysis were performed. RESULTS: Multiple logistic regression analysis of both databases showed a significant association between use of PPIs and an increased risk of rhabdomyolysis (odds ratio [OR] = 1.74-1.95, P ≤ 0.01). However, use of a histamine-2 receptor antagonist was not significantly associated with increased risk of rhabdomyolysis. In the sub-analysis of the FAERS data, use of a PPI did not increase the risk of rhabdomyolysis in patients receiving a statin. CONCLUSION AND RELEVANCE: The data in 2 separate databases consistently suggest that PPIs may increase the risk of rhabdomyolysis. The evidence for this association should be assessed in further drug safety studies.

DOI： 10.1177/10600280231156270

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BACKGROUND/AIM: Interstitial lung disease (ILD) is a serious adverse event (AE) associated with the use of immune checkpoint inhibitors (ICIs). However, the risk factors for developing ICI-related ILD remain poorly understood. Therefore, this study investigated the effect of concomitant analgesics on developing ICI-related ILD using the Japanese Adverse Drug Event Report (JADER) database. PATIENTS AND METHODS: All the reported AE data were downloaded from the Pharmaceuticals and Medical Devices Agency website, and the JADER data between January 2014 and March 2021 were analysed. The relationship between ICI-related ILD and concomitant use of analgesics was assessed using reporting odds ratio (ROR) and 95% confidence interval. We investigated whether the effect of developing ILD varied according to the type of analgesics used during ICI treatment. RESULTS: Positive signals for ICI-related ILD development were detected for the concomitant use of the narcotic analgesics codeine, fentanyl and oxycodone, but not with morphine. In contrast, there were no positive signals for the concomitant use of the non-narcotic analgesics celecoxib, acetaminophen, loxoprofen and tramadol. An increased ROR for ICI-related ILD in cases with concomitant use of narcotic analgesics was observed in a multivariate logistic analysis adjusted by sex and age. CONCLUSION: These results suggest that the concomitant use of narcotic analgesics is involved in the development of ICI-related ILD.

DOI： 10.21873/invivo.13203

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Myasthenia gravis (MG) is a rare but fatal adverse event of immune checkpoint inhibitors (ICIs). We assessed whether patient characteristics differed between those with ICI-related myasthenia gravis and those with idiopathic myasthenia gravis. Reports from the US Food and Drug Administration Adverse Event Reporting System were analyzed. Multivariate analyses were conducted to evaluate the associations between age, sex, and ICI treatment and the reporting rate of myasthenia gravis. Among 5 464 099 cases between 2011 and 2019, 53 447 were treated with ICIs. Myasthenia gravis was reported more often in ICI users. Multiple logistic regression analyses showed that the reporting rate of ICI-related myasthenia gravis did not differ significantly between men and women; however, it was higher in older people than in younger people (adjusted odds ratio, 2.4 [95%CI, 1.84-3.13]). We also investigated useful signs for the early detection of myositis and myocarditis, which are fatal when overlapping with ICI-related myasthenia gravis. Patients with elevated serum creatine kinase or troponin levels were more likely to have concurrent myositis and myocarditis. Unlike idiopathic myasthenia gravis, there was no sex difference in the development of ICI-related myasthenia gravis, which may be more common in older people. Considering the physiological muscle weakness that occurs in the elderly, it may be necessary to monitor ICI-related myasthenia gravis more closely in older people.

DOI： 10.1002/jcph.2187

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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Language：Japanese   Publisher：(一社)日本移植学会  

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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AIM: Doxorubicin, an anthracycline anti-tumour agent, is an essential chemotherapeutic drug; however, the adverse events associated with doxorubicin usage, including cardiotoxicity, prevent patients from continuing treatment. Here, we used databases to explore existing approved drugs with potential preventative effects against doxorubicin-induced cardiac events and examined their efficacy and mechanisms. METHODS: The Gene Expression Omnibus (GEO), Library of Integrated Network-based Cellular Signatures (LINCS), and Food and Drug Administration Adverse Events Reporting System (FAERS) databases were used to extract candidate prophylactic drugs. Mouse models of doxorubicin-induced cardiac events were generated by intraperitoneal administration of 20 mg/kg of doxorubicin on Day 1 and oral administration of prophylactic candidate drugs for 6 consecutive days beginning the day before doxorubicin administration. On Day 6, mouse hearts were extracted and examined for mRNA expression of apoptosis-related genes. RESULTS: GEO analysis showed that doxorubicin administration upregulated 490 genes and downregulated 862 genes, and LINCS data identified sirolimus, verapamil, minoxidil, prednisolone, guanabenz, and mosapride as drugs capable of counteracting these genetic alterations. Examination of the effects of these drugs on cardiac toxicity using FAERS identified sirolimus and mosapride as new prophylactic drug candidates. In model mice, mosapride and sirolimus suppressed the Bax/Bcl-2 mRNA ratio, which is elevated in doxorubicin-induced cardiotoxicity. These drugs also suppressed the expression of inflammatory cytokines Il1b and Il6 and markers associated with myocardial fibrosis, including Lgal3 and Timp1. CONCLUSION: These findings suggest that doxorubicin-induced cardiac events are suppressed by the administration of mosapride and sirolimus.

DOI： 10.1016/j.ejphar.2022.175083

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Cisplatin is effective against many types of carcinoma. However, a high rate of renal damage is a clinical problem. Thus, there is a need to establish a method to prevent it. Although various compounds have been reported to be effective against cisplatin-induced renal injury, there are no examples of their clinical application. Therefore, we attempted to search for prophylactic agents with a high potential for clinical application. We used Cascade Eye to identify genes that are altered during cisplatin-induced renal injury, Library of Integrated Network-based Cellular Signatures (LINCS) to identify drugs that inhibit changes in gene expression, and a large database of spontaneous adverse drug reaction reports to identify drugs that could prevent cisplatin-induced kidney injury in clinical practice. In total, 10 candidate drugs were identified. Using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS), we identified drugs that reduce cisplatin-induced kidney injury. Fenofibrate was selected as a candidate drug to prevent cisplatin-induced kidney injury based on the FAERS analysis. A model was used to evaluate the efficacy of fenofibrate against cisplatin-induced renal injury. Studies using HK2 cells and mouse models showed that fenofibrate significantly inhibited cisplatin-induced renal injury but did not inhibit the antitumor effect of cisplatin. Fenofibrate is a candidate prophylactic drug with high clinical applicability for cisplatin-induced renal injury. Analysis of data from multiple big databases will improve the search for novel prophylactic drugs with high clinical applicability. For the practical application of these findings, evaluation in prospective controlled trials is necessary.

DOI： 10.1111/cts.13282

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Language：Japanese   Publisher：(公社)日本薬学会  

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Language：Japanese   Publisher：(一社)日本TDM学会  

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Language：Japanese   Publisher：(公社)日本薬学会  

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BACKGROUND: Drug repositioning is a cost-effective method to identify novel disease indications for approved drugs; it requires a shorter developmental period than conventional drug discovery methods. We aimed to identify prophylactic drugs for oxaliplatin-induced peripheral neuropathy by drug repositioning using data from large-scale medical information and life science information databases. METHODS: Herein, we analyzed the reported data between 2007 and 2017 retrieved from the FDA's database of spontaneous adverse event reports (FAERS) and the LINCS database provided by the National Institute of Health. The efficacy of the drug candidates for oxaliplatin-induced peripheral neuropathy obtained from the database analysis was examined using a rat model of peripheral neuropathy. Additionally, we compared the incidence of peripheral neuropathy in patients who received oxaliplatin at the Tokushima University Hospital, Japan. The effects of statins on the animal model were examined in six-week-old male Sprague-Dawley rats and seven or eight-week-old male BALB/C mice. Retrospective medical chart review included clinical data from Tokushima University Hospital from April 2009 to March 2018. RESULTS: Simvastatin, indicated for dyslipidemia, significantly reduced the severity of peripheral neuropathy and oxaliplatin-induced hyperalgesia. In the nerve tissue of model rats, the mRNA expression of Gstm1 increased with statin administration. A retrospective medical chart review using clinical data revealed that the incidence of peripheral neuropathy decreased with statin use. CONCLUSION AND RELEVANCE: Thus, drug repositioning using data from large-scale basic and clinical databases enables the discovery of new indications for approved drugs with a high probability of success.

DOI： 10.1016/j.biopha.2022.112744

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Language：Japanese   Publisher：(公社)日本化学療法学会  

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In April 2018, the Clinical Trials Act pertaining to investigator-initiated clinical trials was passed in Japan. The purpose of this study was to investigate activity in investigator-initiated clinical studies before and after enforcement of the new Clinical Trials Act. This was done by analysing the records of the Ethics Committee of Tokushima University Hospital, which reviews studies based on the Japanese government's Ethical Guidelines for Medical and Health Research Involving Human Subjects prior to the Clinical Trials Act, and records of the Certified Review Board established at Tokushima University under the Clinical Trials Act in 2018. The number of new applications to these two review boards during fiscal years 2015-2017 (pre-Act) and fiscal years 2018 and 2019 (post-Act) were used as an indicator of activity in investigator-initiated clinical studies. The number of new applications to the Ethics Committee was 303, 261, 316, 303, and 249 in 2015, 2016, 2017, 2018, and 2019, respectively. The data show that the total number of new interventional studies decreased from 50.3 in average in 2015-2017 (pre-Act) to 42 in 2018 and 40 in 2019 (post-Act), respectively. These results suggest that fewer interventional studies were started following enforcement of the new Clinical Trials Act. To confirm this trend and identify contributing factors, further studies are required. In addition, possible way, such as broader contribution of clinical research coordinators, to promote clinical studies in the new Clinical Trials Act era should be examined.

DOI： 10.1248/bpb.b21-00753

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Language：Japanese   Publisher：一般社団法人 日本臨床薬理学会  

【目的】バンコマイシン(VCM)関連腎障害(VAN; VCM-associated nephrotoxicity)は、投与症例の約10～40%に発症する重篤な有害事象である。近年、発症後の腎障害遷延や生命予後の悪化が問題となっているが、転帰に関連する因子は明らかになっていない。今回、VAN発症後の腎障害遷延や生命予後に関連する因子について検討した。

【方法】2つのリアルワールドデータを用いて解析した。まず、世界最大規模の副作用自発報告が集積されているFAERS (FDA Adverse Event Reporting System)を用いてVAN発症と死亡の関係を検討した(1. FAERS解析)。次に、詳細な情報を得られる診療情報データ(EMR: Electronic Medical Records)を用いて、VAN発症後の腎機能遷延および生命予後の悪化に関連する因子を検討した(2. EMR解析)。

(1.FAERS解析) 2004年第1期～2020年第1期に、注射用VCMが投与された10,414例の報告を解析した。VAN発症と死亡の関係は、ロジスティック回帰分析により検討した。

(2. EMR解析) 2006年1月～2019年3月に徳島大学病院において、VCMが初回投与された482例を解析した。VAN発症後の腎障害遷延および生命予後に対する観察期間は、それぞれ7日、1年間とした。VAN発症後の転帰に関連する因子は、Cox比例ハザード分析により検討した。

【結果・考察】FAERS解析におけるVAN発症例の死亡率 (23.3%, 613/2634)は、非発症例 (17.2%, 1338/7780)よりも有意に高かった [調整オッズ比: 1.43, 95%信頼区間(CI): 1.28-1.59]。FAERS解析にてVAN発症後の死亡率上昇が示唆されたため、VAN発症後の予後悪化に関連する因子をEMR解析にて検討した。全482例中、VAN発症は72例(14.9%)、院内死亡は74例(15.4%)に認められた。1年の観察期間における生存は234例 (48.5%)、死亡は136例 (28.2%)、打ち切りは112例 (23.2%)であった。VAN発症後の腎障害遷延は、院内死亡[ハザード比 (HR):4.05, 95%CI: 2.42-6.77]および1年死亡(HR: 3.03, 95% CI: 1.98-4.64]に有意に関連していた。腎障害の改善率は、AKIステージ≧2に進展したVAN発症例で有意に低かった (HR: 0.09; 95% CI: 0.02-0.40)。VAN発症後の生命予後悪化には腎障害の遷延が関連しており、そのリスク因子はAKIステージ≧2への進展であることが示された。

【結論】VCM投与症例の生命予後改善には、VANの発症と重症化を予防することが重要である。

DOI： 10.50993/jsptsuppl.43.0_3-c-o08-3

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Language：Japanese   Publishing type：Research paper (scientific journal)  

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PURPOSE: Risk for vancomycin-induced nephrotoxicity (VIN) is reportedly reduced by AUC-guided vancomycin dosing. However, it remains unknown whether the increased VIN risk in combination treatment with vancomycin and tazobactam/piperacillin, which is a VIN risk factor, can be diminished by AUC-guided vancomycin dosing (vancomycin-AUC). The aim of this study was to assess whether the evaluation of vancomycin-AUC + tazobactam/piperacillin (VT) combination therapy could prevent VIN. METHODS: The data from patients who received VT or vancomycin + cefepime (VC; the control group) at Tokushima University Hospital (Kuramoto, Japan) between April 2010 and March 2020 were analyzed in this retrospective study. The between-group difference in the prevalence of VIN onset, stratified by AUC, was investigated. The AUC of vancomycin was calculated using the Bayesian method with the blood concentration of vancomycin. The risk factors and probability of VIN onset from the vancomycin exposure-toxicity curve were evaluated using the logistic model. FINDINGS: The prevalences of VIN were 29.5% (18/61) and 7.1% (3/42) in the VT and VC groups, respectively. Multivariate logistic regression analysis of data from all patients revealed concurrent use of tazobactam/piperacillin (odds ratio [OR] = 4.59; P = 0.039) and AUC increase (OR = 1.01; P < 0.01) as risk factors for VIN, but only concurrent use of tazobactam/piperacillin was identified as a risk factor in patients with an AUC of <600 μg · h/mL, the guideline-recommended value (OR = 9.52; P = 0.041). Moreover, the vancomycin exposure-toxicity curve showed that in the guideline-recommended AUC range, VIN probability was consistently higher and the slope of VIN probability was greater in the VT group than in the VC group. IMPLICATIONS: VIN risk was higher with VT than with VC, even when the AUC was controlled to the guideline-recommended range. These results strongly suggest that VIN prevention may be difficult with AUC-guided vancomycin dosing in patients receiving VT.

DOI： 10.1016/j.clinthera.2021.09.007

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Language：Japanese   Publisher：(一社)日本臨床栄養代謝学会  

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Language：Japanese   Publisher：(一社)日本臨床栄養代謝学会  

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Despite the importance and acceptance of research ethics consultation as an entity in many medical research areas, little is known about its status in nursing research. Focusing on inquiries from nurse researchers, we retrospectively analyzed records of integrated clinical research consultation, provided by members of the Clinical Research Center independently of the research ethics committee, at a Japanese university hospital during 2018-2019. Among various consultations in nursing studies (n = 101), 43 were related to research ethics. The main issues in research ethics consultation were compatibility with guidelines (n = 28; 65%) and application of ethics review (n = 12; 28%). Future studies should investigate international settings and address the relevance of research ethics consultation to promote proper nursing studies.

DOI： 10.1177/15562646211036577

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OBJECTIVES: Compared with vancomycin trough concentration (Cmin)-guided dosing, area under the concentration-time curve (AUC)-guided dosing is associated with decreased acute kidney injury (AKI). However, whether Cmin-guided or AUC-guided dosing should be used in patients other than those with serious MRSA infections remains uncertain. The purposes of this multicentre study were to identify risk factors for early- and late-phase vancomycin-induced AKI and to identify candidates for AUC-guided dosing, rather than Cmin-guided dosing, who require a more accurate dose titration to reduce the AKI risk. METHODS: A multivariate logistic regression analysis was applied to identify risk factors for AKI. Additionally, the cut‑off day for AKI onset, cut-off Cmin for AKI, safe Cmin for reduced AKI risk and probability of AKI were calculated. RESULTS: In total, 8.4% (159/1882) of patients developed AKI. AKI occurred within the first 7 days of therapy (early phase) in the vast majority of patients. Significant risk factors for AKI during the early phase were identified as Cmin > 20 mg/L, ICU stay, concurrent diuretic or piperacillin/tazobactam use, and pre-existing renal dysfunction. A temporarily elevated Cmin (>15-20 mg/L) was not associated with a greater risk of AKI. In patients with risk factors, the cut-off Cmin for AKI and the estimated safe Cmin for reduced AKI risk were 18.8-21.0 mg/L and <11.7-13.5 mg/L, respectively. CONCLUSION: Patients with known AKI risk factors require a low target Cmin. The presence of several risk factors for AKI may indicate a need for more accurate dose titration using AUC-guided dosing.

DOI： 10.1016/j.jgar.2021.07.018

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Despite the availability of more than 20 clinical antiepileptic drugs, approximately 30% of patients with epilepsy do not respond to antiepileptic drug treatment. Therefore, it is important to develop antiepileptic products that function via novel mechanisms. In the present study, we evaluated data from one of the largest global databases to identify drugs with antiepileptic effects, and subsequently attempted to understand the effect of the combination of antiepileptic drugs and valacyclovir in epileptic seizures using a kindling model. To induce kindling in mice, pentylenetetrazol at a dose of 40 mg/kg was administered once every 48 h. Valacyclovir was orally administered 30 min before antiepileptic drug injection in kindled mice, and behavioral seizures were monitored for 20 min following pentylenetetrazol administration. Additionally, c-Fos expression in the hippocampal dentate gyrus was measured in kindled mice. Valacyclovir showed inhibitory effects on pentylenetetrazol-induced kindled seizures. In addition, simultaneous use of levetiracetam and valacyclovir caused more potent inhibition of seizure activity, and neither valproic acid nor diazepam augmented the anti-seizure effect in kindled mice. Furthermore, kindled mice showed increased c-Fos levels in the dentate gyrus. The increase in c-Fos expression was significantly inhibited by the simultaneous use of levetiracetam and valacyclovir. The findings of the present study indicate that a combination of levetiracetam and valacyclovir had possible anticonvulsive effects on pentylenetetrazol-induced kindled epileptic seizures. These results suggest that valacyclovir may have an antiseizure effect in patients with epilepsy.

DOI： 10.1016/j.ejphar.2021.174099

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Nausea, vomiting, and renal injury are the common adverse effects associated with cisplatin. Cisplatin is excreted via the multidrug and toxin release (MATE) transporter, and the involvement of the MATE transporter in cisplatin-induced kidney injury has been reported. The MATE transporter is also involved in the excretion of ondansetron, but the effects of 5-HT3 receptor antagonists used clinically for cisplatin-induced renal injury have not been elucidated. Therefore, the aim of this study was to investigate the effects of 5-HT3 receptor antagonists in a mouse model of cisplatin-induced kidney injury and to validate the results using medical big data analysis of more than 1.4 million reports and a survey of 3000 hospital medical records. The concomitant use of a first-generation 5-HT3 receptor antagonist (ondansetron, granisetron, or ramosetron) significantly increased cisplatin accumulation in the kidneys and worsened renal damage. Conversely, the concomitant use of palonosetron had no effect on renal function compared with the use of cisplatin alone. Furthermore, an analysis of data from the US Food and Drug Administration Adverse Event Reporting System and retrospective medical records revealed that the combination treatment of cisplatin and a first-generation 5-HT3 receptor antagonist significantly increased the number of reported renal adverse events compared with the combination treatment of cisplatin and a second-generation 5-HT3 receptor antagonist. These results suggest that compared with the first-generation antagonists, second-generation 5-HT3 receptor antagonists do not worsen cisplatin-induced acute kidney injury. The findings should be validated in a prospective controlled trial before implementation in clinical practice.

DOI： 10.1111/cts.13045

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DOI： 10.1016/j.kint.2021.01.009

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BACKGROUND: Pneumonitis is a serious adverse event in patients treated with immune checkpoint inhibitors (ICIs), with a mortality rate of up to 20%. The risk factors for ICI-related pneumonitis remain unclear due to the scarce data and infrequent event rate of 0-10% for all grades in patients using ICIs. OBJECTIVES: This study evaluated the risk factors for ICI-related pneumonitis using the United States Food and Drug Administration (US FDA) Adverse Event Reporting System (FAERS) database. METHOD: To investigate the association between pneumonitis and ICIs, the FAERS database, which contains spontaneous adverse event reports submitted to the US FDA, was utilized. Data between January 2014 and December 2019 were collected. Univariate logistic regression analysis with covariates, including age, sex, and ICI use, was performed to assess the risk of ICI-related pneumonitis. The relative risk of pneumonitis was estimated using by the odds ratio. RESULTS: We identified 4,248,808 reports, including 51,166 cases of those who received eight different ICIs. Nivolumab was the most common ICI (n = 27,273 of 51,166 [53.3%] patients). Reporting rates of pneumonitis were significantly high in ICI users (odds ratio 29.48; 95% confidence interval [CI], 27.49-31.62). Univariate logistic regression analysis showed that pneumonitis risk was significantly associated with age. Age ≤60 years old was associated with an increase in the reported frequency of pneumonitis. CONCLUSIONS: Our data suggest that the risk of ICI-related pneumonitis may increase in certain populations, including younger age (age <60 years) and ICIs users. These patients require careful monitoring.

DOI： 10.1159/000512633

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BACKGROUND: In patients treated with bevacizumab, hypertension may be a biomarker of therapeutic efficacy. However, it is not clear whether drugs that control blood pressure influence bevacizumab's efficacy. In this study, we investigated drugs that may affect hypertension in bevacizumab-treated patients and examined the impact on the therapeutic effect. PATIENTS AND METHODS: We analyzed 3,724,555 reports from the third quarter of 2010 to the second quarter of 2015. All data were obtained from the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) analysis. In this retrospective cohort study, we investigated a total of 58 patients diagnosed with colorectal cancer and treated for the first time with bevacizumab containing XELOX or mFOLFOX6 at The University of Tokushima Hospital between January 2010 and December 2015. The effect of the treatment was evaluated according to Response Evaluation Criteria in Solid Tumors version 1.0. Thereafter, the effect was confirmed using Gene Expression Omnibus (GEO) and cultured cells. RESULTS: There are few reports in FAERS of hypertension in patients treated with omeprazole on bevacizumab. Based on the chart review, patients who used proton pump inhibitors (PPI) had a lower response to treatment than those who did not (response rate: 25% vs 50%). Furthermore, experiments on GEO and cell lines suggested that induction of vascular endothelial growth factor (VEGF) gene expression by PPIs is the cause of the reduced therapeutic effect. CONCLUSION: PPIs prevent hypertension in bevacizumab-treated patients but may reduce bevacizumab's anti-tumoral effects by inducing VEGF expression.

DOI： 10.1002/cam4.3587

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Patients who undergo multiple-day chemotherapy sessions experience hard-to-treat nausea and vomiting. Currently, there is no effective standard treatment for this condition. This study compared the preventive effect of first-generation 5-hydroxytryptamine 3 receptor antagonists (5-HT3 RAs) and second-generation 5-HT3 RAs palonosetron in multiple-day chemotherapy-induced nausea and vomiting. The design of this study was a retrospective case-control study of patients who received a five-day cisplatin-based chemotherapy and were treated with aprepitant, dexamethasone, granisetron, and ramosetron or palonosetron. The patients were divided into two groups: patients given granisetron and ramosetron (the first-generation group), and those given palonosetron (palonosetron group). The percentage of patients with a complete response or total control was assessed. They were divided into three phases: 0-216 h (overall phase), 0-120 h (remedial phase), and 120-216 h (after phase). The remedial phase was further divided into 0-24 h (early phase) and 24-120 h (later phase). Moreover, the nutritional status of each patient was assessed by noting the patients' total calorie-intake per day and total parenteral nutrition. First-generation 5-HT3 RAs and palonosetron were used for treatment in 18 and 28 patients, respectively. The complete response rate and caloric oral intake of the later phase were higher in the palonosetron group than in the first-generation group. We conclude that palonosetron treatment was more effective than first-generation 5-HT3 RAs in controlling multiple-day chemotherapy-induced nausea and vomiting.

DOI： 10.1248/bpb.b20-00609

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Post-exposure prophylaxis (PEP) for healthcare workers is one of the effective strategies for preventing nosocomial outbreaks of influenza. However, PEP adherence in healthcare workers is rarely analysed, and no strategies have been established to improve adherence to PEP for healthcare workers. We aimed to retrospectively analyse adherence to PEP and the factors associated with non-adherence in healthcare workers. A survey of 221 healthcare workers who were eligible for PEP at Tokushima University Hospital in the 2016/2017 season was conducted. Once-daily oseltamivir (75 mg for 10 d) was used as the PEP regimen. Of the 221 healthcare workers, 175 received PEP and were surveyed for adherence using a questionnaire. Of the 130 healthcare workers who responded to the questionnaire, 121 (93.1%) had been vaccinated. In this survey, 82 healthcare workers (63.1%) did not fully complete PEP. Multiple logistic regression analysis revealed that physicians (odds ratio: 4.62, 95% confidence interval [CI]: 2.08-10.25) and non-vaccination (odds ratio: 9.60, 95% CI: 1.12-82.25) were the factors for non-adherence to PEP. Of the 47 healthcare workers who responded to the item regarding reasons for non-adherence, 36 (76.6%) reported forgetting to take oseltamivir or discontinuing it due to a misguided self-decision that continuation of PEP was unnecessary, and 5 (10.6%) reported discontinuing treatment due to adverse effects. In conclusion, healthcare workers, particularly physicians, had low PEP adherence owing to forgetting or stopping to take oseltamivir due to a misguided self-decision. To obtain the maximum preventive effect of PEP, medication education should be provided to endorse PEP compliance.

DOI： 10.1248/bpb.b21-00165

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Language：Japanese   Publisher：Japanese Pharmacological Society  

<b>Background</b>: Cisplatin is widely used as an anti-tumor drug for the treatment of solid tumors. Unfortunately, it causes nephrotoxicity as a critical side effect, limiting its use, given that no preventive drug against cisplatin-induced nephrotoxicity (CIN) is currently available. In the present study, we searched and identified candidate drugs for preventing CIN

Methods: We used a database of medical big data for the screening of candidate drugs for the prevention of CIN. Based on the results of the analysis of medical big data, we evaluated the actual efficacy of DPH via <i>in vitro</i> and <i>in vivo</i> experiments<i> </i>in culture cells and a mouse model.

Results: We identified that a previously developed drug, diphenhydramine (DPH), may provide a novel treatment for CIN by the analysis of medical big data. DPH inhibited cisplatin-induced cell death in renal proximal tubular cells. Mice administered cisplatin developed kidney injury with renal dysfunction, augmented oxidative stress, increased apoptosis, and elevated inflammatory cytokines; however, most of these symptoms were suppressed by treatment with DPH. Additionally, the renal concentration of cisplatin was attenuated in DPH-treated mice. Importantly, DPH did not i interfere with its anti-tumor effect in any of the <i>in vitro</i> or <i>in vivo</i> experiments. Moreover, a retrospective clinical study showed that patients with malignant cancer who had used DPH before cisplatin treatment exhibited less acute kidney injury.

Conclusion: DPH may be a preventive medicine against CIN.

DOI： 10.1254/jpssuppl.94.0_2-o-d3-1

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Language：Japanese   Publisher：一般社団法人 日本臨床薬理学会  

【目的】てんかんおよび双極性障害の維持療法に適応を有するラモトリギンは、副作用として重篤な皮膚障害が現れることがあり、死亡に至った例も報告されたことから2015年に安全性速報で注意喚起がなされた。ラモトリギン誘発皮膚障害は、血中濃度の急激な上昇が関与しており、代謝経路に関与するUDP-グルクロン酸転移酵素（UGT）阻害作用を示すバルプロ酸との併用でリスクが高いことが知られている。しかし、UGT阻害作用を示す薬剤はバルプロ酸の他にも睡眠薬、鎮痛薬、免疫抑制薬など多数存在するにも関わらず、それらの薬剤併用によるラモトリギン誘発皮膚障害への影響は不明である。本研究では、医療ビッグデータ解析を用いてUGT阻害作用を示す薬剤がラモトリギン誘発皮膚障害の報告オッズ比に与える影響を検討した。さらに、徳島大学病院の病院診療情報を用いて、併用薬によるラモトリギンの皮膚障害リスクの変化を検討した。【方法】大規模副作用症例報告データベース（FAERS：FDA Adverse Event Reporting System）を用いて、ラモトリギンとの併用により皮膚障害報告数を上昇させる薬剤を探索した。さらに徳島大学病院診療録より、ラモトリギン服用を開始した患者を対象とし、ラモトリギンの投与量、併用薬、皮膚障害の有無などを調査した。【結果】FAERS解析から、UGT阻害作用を示す医薬品のうち、ラモトリギンとの併用により皮膚障害リスクの上昇が示唆される薬剤として、バルプロ酸（ROR: 2.98, 95%CI: 2.63-3.37）、フルニトラゼパム（ROR: 5.93, 95%CI: 4.33-8.14）およびニトラゼパム（ROR: 2.09, 95%CI: 1.24-3.51）が抽出された。徳島大学病院診療情報を用いた後方視的観察研究の結果、ラモトリギン服用が開始された患者の内、20％程度で皮膚障害が認められ、フルニトラゼパム併用患者では皮膚障害発生頻度が上昇する傾向が認められた。【考察】フルニトラゼパムおよびニトラゼパムは、UGT阻害作用を示す薬剤であることから、ラモトリギンの血中濃度に影響し、ラモトリギンの皮膚障害リスクを上昇させている可能性がある。また、睡眠薬であることから精神科領域で併用する可能性があり、睡眠薬の選択や併用時の副作用モニタリングに注意を要すると考えられる。

DOI： 10.50993/jsptsuppl.42.0_3-p-r-2

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Authorship：Lead author,　Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

Background : Enforcement of the 2018 Clinical Trials Act (CTA) in Japan resulted in strict and complicated regulations surrounding intervention studies. Few Japan-specific measures have been developed to promote intervention studies in Japan despite concerns about CTA's negative influence on such studies. Therefore, this study examined the changes in academic investigators' interest in conducting clinical studies before and after enforcement of the CTA to determine measures to promote specified clinical trials. Methods : We conducted a questionnaire survey with investigators belonging to the Institute of Biomedical Sciences, Tokushima University Graduate School, before and after enforcement of the CTA. Results : Investigators had lesser interest in intervention studies in the post-questionnaire survey (post) group than in the pre-questionnaire survey (pre) group. Their desire for "project management" was significantly higher in the post-group than in the pre-group. Their desire for "support for preparing documents when conducting specified clinical trials" was significantly higher in the group interested in conducting specified clinical trials than that in the not-interested group. Conclusion : We revealed that investigators were highly interested in "project management" and "support for preparing documents when conducting specified clinical trials" after enforcement of the CTA. Measures for these desires may promote specified clinical trials. J. Med. Invest. 68 : 71-75, February, 2021.

DOI： 10.2152/jmi.68.71

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Language：Japanese   Publisher：ライフサイエンス出版(株)  

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BACKGROUND: With the global proliferation of the novel COVID-19 disease, conventionally conducting institutional review board (IRB) meetings has become a difficult task. Amid concerns about the suspension of drug development due to delays within IRBs, it has been suggested that IRB meetings should be temporarily conducted via the internet. OBJECTIVE: This study aimed to elucidate the current status of IRB meetings conducted through web conference systems. METHODS: A survey on conducting IRB meetings through web conference systems was administered to Japanese national university hospitals. Respondents were in charge of operating IRB offices at different universities. This study was not a randomized controlled trial. RESULTS: The survey was performed at 42 facilities between the end of May and early June, 2020, immediately after the state of emergency was lifted in Japan. The survey yielded a response rate of 74% (31/42). Additionally, while 68% (21/31) of facilities introduced web conference systems for IRB meetings, 13% (4/31) of the surveyed facilities postponed IRB meetings. Therefore, we conducted a further survey of 21 facilities that implemented web conference systems for IRB meetings. According to 71% (15/21) of the respondents, there was no financial burden for implementing these systems, as they were free of charge. In 90% (19/21) of the facilities, IRB meetings through web conference systems were already being conducted with personal electronic devices. Furthermore, in 48% (10/21) of facilities, a web conference system was used in conjunction with face-to-face meetings. CONCLUSIONS: Due to the COVID-19 pandemic, the number of reviews in clinical trial core hospitals has decreased. This suggests that the development of pharmaceuticals has stagnated because of COVID-19. According to 71% (15/21) of the respondents who conducted IRB meetings through web conference systems, the cost of introducing such meetings was US $0, showing a negligible financial burden. Moreover, it was shown that online deliberations could be carried out in the same manner as face-to-face meetings, as 86% (18/21) of facilities stated that the number of comments made by board members did not change. To improve the quality of IRB meetings conducted through web conference systems, it is necessary to further examine camera use and the content displayed on members' screens during meetings. Further examination of all members who use web conference systems is required. Our measures for addressing the requests and problems identified in our study could potentially be considered protocols for future IRB meetings, when the COVID-19 pandemic has passed and face-to-face meetings are possible again. This study also highlights the importance of developing web conference systems for IRB meetings to respond to future unforeseen pandemics.

DOI： 10.2196/22302

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Publishing type：Research paper (scientific journal)   Publisher：Springer Science and Business Media LLC  

<title>Abstract</title>
The role of research ethics consultants in biomedical research has increased to the point that they have an advisory capacity at all research institutes. For such professionals, we have established an educational system, which includes teaching materials, training methods, and nationwide educational workshops. These workshops have served to examine the developed system’s usefulness and to provide realistic training for consultant candidates. In addition, we have used the current workshop to encourage clinical research investigators (and related personnel) to participate. Subsequently, we examined its usefulness as an opportunity to provide exposure to research ethics. In October 2019, we held a 1-day pilot workshop in Tokushima, Japan, which included a basic lecture in research ethics. During the lecture, two sets of materials were used for case discussion: case 1, covering issues related to a clinical trial, and case 2, covering issues related to human biological specimens. At the end of the workshop, a 30-item self-reporting anonymous questionnaire was provided. Of the 13 total participants, 9 (70%) were clinical research investigators and related personnel, while 6 (46%) had no direct intention to act as consultants. Respondents indicated that case 2 was more difficult than case 1. However, both cases were generally accepted as educational materials; thus, satisfaction was expressed in relation to both. As the evaluations of the cases were generally positive, we will further examine the usefulness of participation in the workshop in the cultivation of research ethics in the investigator community.

DOI： 10.1007/s40889-020-00107-x

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Other Link： http://link.springer.com/article/10.1007/s40889-020-00107-x/fulltext.html

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Atherosclerosis-related acute aortic syndromes, such as aortic aneurysms or aortic dissection are life-threatening diseases. Since they develop suddenly and progress rapidly, the establishment of preventive strategies is urgently needed. Quercetin, a flavonoid abundant in various vegetables and fruits, is suggested to reduce the risk of cardiovascular disease. Therefore, in this study, the preventive effect of quercetin was evaluated using a mouse model of aortic aneurysm and dissection. The model was established by administering angiotensin II (Ang II) and β-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, to mice to induce hypertension and degeneration of the elastic lamina, which would eventually result in the onset of an aortic aneurysm. Ang II, BAPN, and a nitric oxide synthase inhibitor was administered to induce aortic dissection via endothelial dysfunction. Quercetin (60 mg/kg/day) was administered 2 weeks before inducing aortic diseases by the end of the experiments (8 weeks in the aneurysm model, 6 weeks in the dissection model). It was found to reduce the incidence of aneurysm (from 72 to 45%), dissection (from 17 to 10%), and rupture (from 33 to 15%) in mice. Elastin degradation was ameliorated in the quercetin-treated mice compared to that in the mice without quercetin treatment (degradation score 2.9 ± 0.3 vs 2.2 ± 0.2). Furthermore, quercetin suppressed the expression of vascular cell adhesion molecule-1, macrophage infiltration, and pro-matrix metalloproteinase-9 activity. Our results suggest that quercetin might prevent the onset of atherosclerosis-related acute aortic syndromes through its anti-inflammatory and endothelial cell-protective effects.

DOI： 10.3390/ijms21197226

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Immune checkpoint inhibitors (ICIs) elicit antitumour effects by activating the host immunity and cause immune-related adverse events (irAEs). ICI-related interstitial lung disease (ICI-ILD) is a fatal irAE that is difficult to treat; moreover, its incidence is relatively higher in patients with lung cancer. Therefore, early ICI-ILD detection and intervention are important for patient safety. However, a risk assessment method for ICI-ILD has not been established and the prediction of ICI-ILD occurrence is difficult. The aim of our study was to identify the risk factors associated with ICI-ILD. To this end, we retrospectively analysed 102 patients with lung cancer who first received ICI and completed the treatment between April 2016 and December 2019 at Tokushima University Hospital. Nineteen patients had all grades of ICI-ILD and 10 had grade ≥ 3 ICI-ILD. The 30-day mortality rate of patients with grade ≥ 3 ICI-ILD was the highest among all patients (P < 0.01). The multivariate logistic analysis indicated that the performance status ≥ 2 alone and both performance status ≥ 2 and ≥ 50 pack-year were independent risk factors of ICI-ILD of grade ≥ 3 and all grades, respectively. Overall, our study provides insights to predict ICI-ILD occurrence.

DOI： 10.1038/s41598-020-70743-2

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Authorship：Lead author,　Corresponding author   Language：English  

Cystatin C-guided vancomycin (VCM) dosing is useful in critically ill patients. Its usefulness in septic patients with bacterial meningitis remains unknown, as there are no published reports. In this study, we sought to clarify its benefit. Cystatin C was used to guide VCM dosing in a septic bacterial meningitis patient with normal kidney function, according to therapeutic drug monitoring (TDM). Using cystatin C, the Bayesian method-based TDM made optimal VCM dosing possible, and decreased the predicted error (4.85 mg/L) compared to serum creatinine (16.83 mg/L). We concluded TDM of VCM using cystatin C can be considered in sepsis patients with bacterial meningitis with normal kidney function.

DOI： 10.18926/AMO/60376

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The roles of cancer-associated fibroblasts (CAFs) have been studied in the tumor progression, and CAFs are expected to become the new targets for cancer pharmacotherapies. CAFs contribute to tumor cell survival and proliferation, tumor angiogenesis, immune suppression, tumor inflammation, tumor cell invasion and metastasis, and extracellular matrix remodeling. However, detailed mechanisms of how CAFs function in the living system remain unclear. CAFs include α-smooth muscle actin, expressing activated fibroblasts similar to myofibroblasts, and are highly capable of producing collagen. Several reports have demonstrated the contributions of extracellular-signal-regulated kinase 5 (ERK5) in fibroblasts to the fibrotic processes; however, the roles of CAF-derived ERK5 remain unclear. To investigate the roles of CAF-derived ERK5 in the tumor progression, we created mice lacking the ERK5 gene specifically in fibroblasts. Colon-26 mouse colon cancer cells were implanted into the mice subcutaneously, and the histological analyses of the tumor tissue were performed after 2 weeks. Immunofluorescence analyses showed that recipient-derived fibroblasts existed within the tumor tissue. The present study demonstrated that fibroblast-specific ERK5 deficiency exacerbated tumor progression and it was accompanied with thicker tumor vessel formation and the increase in the number of activated fibroblasts. We combined the results of The Cancer Genome Atlas (TCGA) database analysis with our animal studies, and indicated that regulating ERK5 activity in CAFs or CAF invasion into the tumor tissue can be important strategies for the development of new targets in cancer pharmacotherapies.

DOI： 10.1007/s00210-020-01859-5

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Language：Japanese   Publisher：(一社)日本病院薬剤師会  

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2020&ichushi_jid=J04451&link_issn=&doc_id=20200710240010&doc_link_id=%2Fdg4hppha%2F2020%2F005607%2F010%2F0803-0808%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fdg4hppha%2F2020%2F005607%2F010%2F0803-0808%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Language：Japanese   Publisher：(一社)日本臨床薬理学会  

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Authorship：Corresponding author   Language：English   Publishing type：Research paper (scientific journal)  

BACKGROUND: Arbekacin (ABK) is used to treat infections caused by methicillin-resistant Staphylococcus aureus and is used widely for the treatment of febrile neutropenia (FN). As ABK has a narrow therapeutic concentration window, the dosage must be adjusted via therapeutic drug monitoring. However, the influence of the physiology of patients with FN on the pharmacokinetic (PK) parameters of ABK remains unclear. Therefore, we examined this influence on ABK PK parameters. METHOD: We performed a retrospective cohort study using data from patients with a hematologic malignancy who were ≥18 years and had been administered ABK. We excluded patients who did not receive therapeutic drug monitoring and had an estimated glomerular filtration rate (eGFR) of <30 mL/min, because clinically sufficient data would not be available. RESULT: Of the 99 enrolled patients, 25 did not have FN and 74 had FN. Arbekacin clearance (CLabk) was shown to correlate with eGFR in patients with FN (r = 0.32, P = 0.0062) and without FN (r = 0.50, P = 0.01). CLabk was higher in patients with FN than in those without FN. In addition, in the eGFR of <100 mL/min group (normal renal function), CLabk and CLabk/eGFR were also higher in patients with FN than in those without FN. CONCLUSIONS: CLabk was increased in patients with FN and normal renal function; therefore, we propose an increased ABK dose for patients with FN and normal renal function.

DOI： 10.1097/FTD.0000000000000678

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Proton pump inhibitors (PPIs) have been used worldwide to treat gastrointestinal disorders. A recent study showed that long-term use of PPIs caused iron deficiency; however, it is unclear whether PPIs affect iron metabolism directly. We investigated the effect of PPIs on the peptide hepcidin, an important iron regulatory hormone. First, we used the FDA Adverse Event Reporting System database and analyzed the influence of PPIs. We found that PPIs, as well as H2 blockers, increased the odds ratio of iron-deficient anemia. Next, HepG2 cells were used to examine the action of PPIs and H2 blockers on hepcidin. PPIs augmented hepcidin expression, while H2 blockers did not. In fact, the PPI omeprazole increased hepcidin secretion, and omeprazole-induced hepcidin upregulation was inhibited by gene silencing or the pharmacological inhibition of the aryl hydrocarbon receptor. In mouse experiments, omeprazole also increased hepatic hepcidin mRNA expression and blood hepcidin levels. In mice treated with omeprazole, protein levels of duodenal and splenic ferroportin decreased. Taken together, PPIs directly affect iron metabolism by suppressing iron absorption through the inhibition of duodenal ferroportin via hepcidin upregulation. These findings provide a new insight into the molecular mechanism of PPI-induced iron deficiency.

DOI： 10.1016/j.toxlet.2019.10.016

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Society of Clinical Pharmacology and Therapeutics  

DOI： 10.3999/JSCPT.51.77

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Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Appropriate use of vancomycin (VCM) is important in preventing acute kidney injury (AKI). Because of the high frequency of VCM use for febrile neutropenia and concomitant use of other nephrotoxic drugs, haematologic patients have a different nephrotoxic background compared with patients with other diseases. Therefore, it is unclear whether the risk factors of VCM-induced AKI identified in other patient groups are also applicable to haematologic patients. Herein, we performed a single-centre retrospective analysis to identify the factors associated with VCM-induced AKI in haematologic patients. METHODS: We retrospectively analysed 150 haematologic patients to whom VCM was administered between April 2010 and March 2018 at Tokushima University Hospital. VCM-induced AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) criteria. Multivariate logistic regression analyses were performed to identify risk factors for VCM-induced AKI. RESULTS: Seventeen patients had VCM-induced AKI. Multivariate analysis revealed that the risk factors of VCM-induced AKI were an initial VCM trough concentration of > 15 mg/L and concomitant use of tazobactam/piperacillin (TAZ/PIPC) and liposomal amphotericin B (L-AMB). Patients with an initial VCM trough concentration of < 10 mg/L showed significantly lower efficacy in febrile neutropenia. Interestingly, concomitant L-AMB use increased the incidence of VCM-induced AKI in a VCM concentration-dependent manner, whereas concomitant TAZ/PIPC increased the incidence in a VCM concentration-independent manner. CONCLUSIONS: The optimal initial VCM trough concentration was 10-15 mg/L in haematologic patients, considering safety and effectiveness. There were differences in the effect of VCM-induced AKI between nephrotoxic drugs.

DOI： 10.1007/s00228-019-02756-4

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PURPOSE: Epirubicin and cyclophosphamide (EC) therapy, a major chemotherapy for patients with early-stage breast cancer, has a low risk (< 10%) of febrile neutropenia (FN). However, data used in reports on the incidence rate of FN were derived primarily from non-Asian populations. In this study, we investigated the FN incidence rate using EC therapy among Japanese patients with breast cancer and evaluated the significance of prophylactic administration of granulocyte colony-stimulating factor (G-CSF). METHODS: We evaluated medical records of patients with early-stage breast cancer who had been treated with EC therapy as neoadjuvant or adjuvant therapy between November 2014 and July 2018. RESULTS: The incidence rate of FN was 23.9%. In patients who received G-CSF as primary prophylaxis, FN expression was completely suppressed. The incidence rate of severe leucopenia/neutropenia, emergency hospitalization, and the use of antimicrobial agents were low in patients receiving primary prophylaxis with G-CSF compared with those not receiving G-CSF (27.3% vs. 64.8%, 9.1% vs. 27.3%, and 27.3% vs. 71.6%, respectively). Furthermore, in all patients who received primary prophylaxis with G-CSF, a relative dose intensity > 85% using EC therapy was maintained. CONCLUSION: The incidence of FN in EC therapy among Japanese patients was higher than expected, EC therapy appears to be a high-risk chemotherapy for FN, and prophylactic administration of G-CSF is recommended. Maintaining high therapeutic intensity is associated with a positive prognosis for patients with early breast cancer, and prophylactic administration of G-CSF is likely to be beneficial in treatment involving EC therapy.

DOI： 10.1007/s00280-019-03948-6

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Authorship：Lead author,　Corresponding author   Language：English  

DOI： 10.1007/s00228-019-02728-8

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Authorship：Lead author   Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: It is important to accurately estimate accurate vancomycin (VCM) clearance (CLvcm) for appropriate VCM dosing in the treatment of patients with sepsis. However, the pathophysiology of sepsis can make CLvcm prediction less accurate. Clearance of hydrophilic antibiotics is disturbed by organ dysfunction, and hemoglobin levels are negatively correlated with sequential organ function assessment scores. We investigated whether hemoglobin levels are associated with CLvcm in sepsis patients. METHODS: We performed a retrospective cohort study of patients treated with VCM in the Emergency and Critical Care Center of Nihon University Itabashi Hospital between 2005 and 2015. We enrolled 72 patients after exclusion of patients who received renal replacement therapy or surgery, had a change in hemoglobin levels more than 2 g/dL or received an erythrocyte infusion during the interval between initial VCM administration and measurement of initial trough levels, had a serum baseline creatinine level of ≥ 2 mg/dL, or were under 18 years old. RESULTS: Enrolled patients consisted of 13 non-sepsis patients and 59 sepsis patients. In sepsis patients, although CLvcm was correlated with CrCl in HGB ≥ 9 group as well as in non-sepsis patients, its correlation was not observed in HGB < 9 group. Hemoglobin levels were correlated with CLvcm in sepsis patients but not in non-sepsis patient. Multiple linear regression analysis also indicated that lower CLvcm was associated with lower hemoglobin and CrCl. CONCLUSION: Lower hemoglobin levels influence a relationship between CLvcm and CrCl in sepsis patients. We propose that VCM dosing should be adjusted for hemoglobin levels in sepsis patients.

DOI： 10.1007/s00228-019-02661-w

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Language：English   Publishing type：Research paper (scientific journal)  

OBJECTIVE: In Japan, under the new Clinical Trials Act pertaining to investigator-initiated clinical trials that came into effect on 1 April 2018, review boards should review proposed clinical trials while considering written opinions from specialists. Additionally, involvement of non-specialists is mandatory, and attention is being placed on their effective contributions. This study was performed to determine representative key issues with which to promote these contributions. METHODS: This qualitative study was conducted in 2018 using a focus group interview of six non-specialists regarding perspectives on clinical research itself and research ethics committees. RESULTS: For perspectives on clinical research itself, 33 codes were established and sorted into 2 categories and 6 subcategories relating to ambivalence toward clinical research. For perspectives on research ethics committees, 54 codes were established and sorted into 3 categories and 10 subcategories relating to the theme "knowledge and an environment that promotes non-specialist members' participation." One notable result was the willingness of participants to obtain details about a study should they be selected. CONCLUSIONS: The results suggest that detailed explanation of a particular study would encourage non-specialist members to participate in a clinical research review committee. Education aimed at non-specialist participation should therefore be considered in future studies.

DOI： 10.1177/0300060518823941

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PURPOSE: SN-38, an active metabolite of irinotecan, is reabsorbed by the intestinal tract during excretion, causing diarrhoea and neutropenia. In addition, the association between blood levels of SN-38 and neutropenia has been reported previously, and the rapid excretion of SN-38 from the intestinal tract is considered to prevent neutropenia. Oral alkalization drugs are used as prophylactic agents for suppressing SN-38 reabsorption. The relationship between oral alkalization drugs and neutropenia, however, has not been well studied. The aim of this study was to investigate the relationship between oral alkalization drugs and neutropenia in irinotecan-treated patients. METHODS AND RESULTS: Patients with cervical or ovarian cancer were administered irinotecan and investigated by medical chart reviews to determine whether oral alkalization drugs were effective at ameliorating irinotecan-induced neutropenia. The drug combination in the oral alkalization drugs-ursodeoxycholic acid, magnesium oxide, and sodium hydrogen carbonate-significantly improved neutrophil counts and reduced dose intensity compared with those of non-users. In the large-scale Japanese Adverse Drug Event Report database, the reporting odds ratio of irinotecan-induced neutropenia was significantly lower when irinotecan had been given in combination with oral alkalization drugs. CONCLUSIONS: These data indicate that oral alkalization drugs may reduce the frequency of neutropenia caused by irinotecan administration, making it possible to increase the dose safely.

DOI： 10.1007/s00520-018-4367-y

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BACKGROUND: Several reports from basic researches and clinical studies have suggested that xanthine oxidase (XO) inhibitors have suppressive effects on cardiovascular diseases. However, the roles of a XO inhibitor, febuxostat (FEB), in the pathogenesis of vascular remodeling and hypertension independent of the serum uric acid level remain unclear. METHODS: To induce vascular remodeling in mice, angiotensin II (Ang II) was infused for 2 weeks with a subcutaneously implanted osmotic minipump. FEB was administered every day during Ang II infusion. Aortic fibrosis was assessed by elastica van Gieson staining. Mouse macrophage RAW264.7 cells (RAW) and mouse embryonic fibroblasts were used for in vitro studies. RESULTS: FEB suppressed Ang II-induced blood pressure elevation and aortic fibrosis. Immunostaining showed that Ang II-induced macrophage infiltration in the aorta tended to be suppressed by FEB, and XO was mainly colocalized in macrophages, not in fibroblasts. Transforming growth factor-β1 (TGF-β1) mRNA expression was induced in the aorta in the Ang II alone group, but not in the Ang II + FEB group. Ang II induced α-smooth muscle actin-positive fibroblasts in the aortic wall, but FEB suppressed them. XO expression and activity were induced by Ang II stimulation alone but not by Ang II + FEB in RAW. FEB suppressed Ang II-induced TGF-β1 mRNA expression in RAW. CONCLUSIONS: Our results suggested that FEB ameliorates Ang II-induced aortic fibrosis via suppressing macrophage-derived TGF-β1 expression.

DOI： 10.1093/ajh/hpy157

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Breakpoint cluster region-Abelson murine leukemia (BCR-ABL) inhibitors markedly improve the prognosis of chronic myeloid leukemia. However, high treatment adherence is necessary for successful treatment with BCR-ABL inhibitors. Therefore, an adequate understanding of the adverse event profiles of BCR-ABL inhibitors is essential. Although many adverse events are observed in trials, an accurate identification of adverse events based only on clinical trial results is difficult because of strict entry criteria or limited follow-up durations. In particular, BCR-ABL inhibitor-induced impaired glucose metabolism remains controversial. Pharmacovigilance evaluations using spontaneous reporting systems are useful for analyzing drug-related adverse events in clinical settings. Therefore, we conducted signal detection analyses for BCR-ABL inhibitor-induced impaired glucose metabolism by using the FDA Adverse Event Reporting System (FAERS) and Japanese Adverse Drug Event Report (JADER) database. Signals for an increased reporting rate of impaired glucose metabolism were detected only for nilotinib use, whereas these signals were not detected for other BCR-ABL inhibitors. Subgroup analyses showed a clearly increased nilotinib-associated reporting rate of impaired glucose metabolism in male and younger patients. Although FAERS- and JADER-based signal detection analyses cannot determine causality perfectly, our study suggests the effects on glucose metabolism are different between BCR-ABL inhibitors and provides useful information for the selection of appropriate BCR-ABL inhibitors.

DOI： 10.1002/cam4.1920

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PURPOSE: Nivolumab, an anti-programmed death 1 antibody, produces antitumor effects by activating host immunity, which also causes immune-related adverse events (irAEs). The aim of this study was to analyze the association between antitumor effect and irAEs induced by nivolumab in patients with melanoma. METHODS: Fifteen patients with melanoma who had received nivolumab at Tokushima University Hospital or Ehime University Hospital between January 2015 and December 2016 were enrolled in this study. Patients who had and did not have irAEs during nivolumab treatment were classified into an irAEs-positive group (n = 8) and an irAEs-negative group (n = 7), respectively. We compared the disease control rate (DCR) and overall survival (OS) between the 2 groups. Data on blood cell counts were also analyzed. FINDINGS: After a median of 4 cycles of nivolumab treatment, irAEs occurred. The DCRs were 75% and 14% in the irAEs-positive and irAEs-negative groups, respectively (p < 0.05). OS in the irAEs-positive group was higher than that in the irAEs-negative group (p < 0.05). Multivariable Cox proportional hazards regression analysis revealed that irAE occurrence affected OS with nivolumab treatment. Moreover, the increase in baseline peripheral lymphocyte count at the time of onset of irAEs was significantly greater in the irAEs-positive group than in the irAEs-negative group after 4 cycles of nivolumab treatment (p < 0.05). IMPLICATIONS: Our study indicated that clinical response with nivolumab treatment improves with irAE occurrence in patients with melanoma. Moreover, the early increase in peripheral lymphocyte count may act as a biomarker for predicting the occurrence of irAEs induced by nivolumab.

DOI： 10.1016/j.clinthera.2018.11.004

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The survival rate of cardiac arrest patients is less than 10%; therefore, development of a therapeutic strategy that improves their prognosis is necessary. Herein, we searched data collected from medical facilities throughout Japan for drugs that improve the survival rate of cardiac arrest patients. Candidate drugs, which could improve the prognosis of cardiac arrest patients, were extracted using "TargetMine," a drug discovery tool. We investigated whether the candidate drugs were among the drugs administered within 1 month after cardiac arrest in data of cardiac arrest cases obtained from the Japan Medical Data Center. Logistic regression analysis was performed, with the explanatory variables being the presence or absence of the administration of those candidate drugs that were administered to ≥10 patients and the objective variable being the "survival discharge." Adjusted odds ratios for survival discharge were calculated using propensity scores for drugs that significantly improved the proportion of survival discharge; the influence of covariates, such as patient background, medical history, and treatment factors, was excluded by the inverse probability-of-treatment weighted method. Using the search strategy, we extracted 165 drugs with vasodilator activity as candidate drugs. Drugs not approved in Japan, oral medicines, and external medicines were excluded. Then, we investigated whether the candidate drugs were administered to the 2,227 cardiac arrest patients included in this study. The results of the logistic regression analysis showed that three (isosorbide dinitrate, nitroglycerin, and nicardipine) of seven drugs that were administered to ≥10 patients showed significant association with improvement in the proportion of survival discharge. Further analyses using propensity scores revealed that the adjusted odds ratios for survival discharge for patients administered isosorbide dinitrate, nitroglycerin, and nicardipine were 3.35, 5.44, and 4.58, respectively. Thus, it can be suggested that isosorbide dinitrate, nitroglycerin, and nicardipine could be novel therapeutic agents for improving the prognosis of cardiac arrest patients.

DOI： 10.3389/fphar.2019.01257

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Language：Japanese   Publisher：Japanese Pharmacological Society  

OBJECTIVE: Cisplatin (CDDP)-induced acute kidney injury (AKI) is highly expressed. Forced hydration and diuresis may partially prevent nephrotoxicity, but it is still difficult to completely prevent kidney injury, so establishment of a new preventive method is required. Therefore, in this study, we elected to candidates for preventive drugs of CDDP-induced AKI using big data analysis, and to verify the effectiveness of the drugs.

METHODS: Using FAERS (FDA Adverse Event Reporting System), existing drugs that may reduce CDDP-induced AKI were extracted. C57BL/6 mice were intraperitoneally administered with CDDP. Renal function was evaluated by serum creatinine and blood urea nitrogen. Histological damage in the cortex of kidney sections was scored. The effect of preventive drugs for CDDP-induced nephropathy was evaluated.

Results: The drug X was extracted a candidate drug suggesting the protective effect of CDDP-induced AKI by FAERS analysis. It was revealed that administration of the drug X significantly suppressed CDDP-induced AKI.

Conclusions: From the results of this study, it was suggested that existing pharmaceutical products elected by FAERS could be a preventive drug for CDDP-induced AKI.

DOI： 10.1254/jpssuppl.92.0_3-p-076

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Language：Japanese   Publisher：Japanese Pharmacological Society  

Treatment outcomes of cancer patients have improved with progress in oncology medication therapy, but side effects caused by anticancer agents are becoming widespread. Side effects caused by anticancer drugs not only significantly lower the patient's QOL but also often lead to dose reduction or discontinuation of the anticancer drugs. Addressing these side effects is important for improving patient prognosis. Therefore, improvement of the quality of cancer therapy through the development of preventive drugs against anticancer drug-induced side effects is an urgent goal. In recent years, clinical research has been carried out in Japan using large-scale medical information sources such as disease/side effect databases, in order to accurately evaluate the effects of drug used in clinical practice. Research utilizing such a large-scale medical information database can cover various patient parameters and a wide range of observation areas. Therefore, this approach is suitable for conducting clinical research on rare diseases and low-frequency side effects. In this symposium, we will introduce research conducted using drug discovery tools and cell/animal experiments based on a large-scale medical information database to search for preventive agents against anticancer drug-induced side effects, as well as consider future prospects for this approach.

DOI： 10.1254/jpssuppl.92.0_2-as1-3

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PURPOSE: Drug side effects often lead to serious outcomes. Administration of second-generation antipsychotics has resulted in diabetic ketoacidosis and diabetic coma leading to death. Therefore, pharmacists are required to collect information on clinical test values, determine the appropriate test timing, and coordinate with doctors for further clinical laboratory orders, all of which are labor-intensive and time-intensive tasks. In this study, we developed a side effect-monitoring tool and aimed to clarify the influence and efficiency of monitoring side effects by using the tool in patients taking atypical antipsychotics in whom it is necessary to check clinical test values such as blood sugar levels. METHODS: We extracted clinical test values for patients treated with second-generation antipsychotics from electronic medical records. The test values are automatically displayed in the side effect grade classification specified by CTCAE ver. 4.0. A database was constructed using scripts to provide alerts for the timing of clinical testing. The pharmacist used this tool to confirm clinical test values for patients taking medication and requested the physician to inspect orders based on the appropriate test timings. RESULTS: The management tool reduced the pharmacists' effort in collecting information on patients' prescription status and test values. It enabled patients to undergo tests at the appropriate time according to the progression of glucose metabolism and allowed for easy monitoring of side effects. CONCLUSIONS: The results suggested that regardless of pharmacists' experience or skill, the introduction of this tool enables centralization of side effect monitoring and can contribute to proper drug use.

DOI： 10.1002/pds.4656

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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Other Link： https://search-tp.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J03405&link_issn=&doc_id=20190117410007&doc_link_id=%2Fda2jjsem%2F2018%2F002106%2F007%2F0735-0739%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fda2jjsem%2F2018%2F002106%2F007%2F0735-0739%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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OBJECTIVE: Research ethics consultation is an advisory activity that differs from ethics committees, and its role is not yet widely known in Japan. Research ethics consultations were started in 2012 by members of the Clinical Trial Center of Tokushima University Hospital, a support section for clinical trials. We analyzed the research ethics consultation records from Tokushima University Hospital during the 5-year period of 2012-2016 to examine the Japanese context of research ethics consultation. RESULTS: During the study period, 125 research ethics consultations were carried out, 115 (91%) before starting studies. All but one request were from investigators at Tokushima University. The main issue was compatibility with guidance and regulations (n = 74, 67.2%), such as ethical handling of human biological specimens and information utilized in research; only 6 (4.8%) requests involved research ethics issues that investigators face in their research. Therefore, it is necessary to expand the consultation function, with a nationwide system of consultant education and data sharing. Moreover, standardization of consultation should be considered.

DOI： 10.1186/s13104-018-3772-0

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DOI： 10.1002/pds.4656

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BACKGROUND: Appropriate initial dosing of vancomycin (VCM) is important in improving survival and in preventing nephrotoxicity in critically ill patients, but the potential relationship between initial VCM trough levels and early-onset nephrotoxicity remains unclear. We examined the relationship between initial VCM trough levels and early-onset VCM-associated nephrotoxicity. METHODS: We performed a retrospective study of patients who had therapeutic drug monitoring of VCM with initial trough levels within 4 days after the beginning of VCM administration. We excluded patients who received renal replacement therapy from 2 days before to 7 days after the beginning of VCM administration, were younger than 18 years, or had renal dysfunction before the beginning of VCM administration. Early-onset VCM-associated nephrotoxicity was defined as an increase in serum creatinine level of ≥0.5 mg/dL (44.2 μmol/L) or 50% above baseline for 2 or more consecutive days within 7 days after the beginning of VCM administration. RESULTS: Among 109 enrolled patients, 13 patients had early-onset VCM-associated nephrotoxicity. Its incidence rate was 31.3% in patients with initial trough levels of ≥20g/mL, which was significantly higher than 6.3% in patients with initial trough levels of <10 mg/L. Multiple logistic regression analysis demonstrated that early-onset VCM-associated nephrotoxicity was associated with initial trough levels of ≥20 mg/L (odds ratio, 5.0; 95% confidence interval, 1.3-19.1) and with vasopressor use (odds ratio, 5.0; 95% confidence interval, 1.3-19.1). Kaplan-Meier analysis showed that the probability of nonnephrotoxicity for patients with initial VCM trough levels of ≥20 mg/L was lower compared with patients with trough levels of <15 mg/L. CONCLUSIONS: Initial trough levels of ≥20 mg/L but not ≥15 mg/L were associated with early-onset VCM-associated nephrotoxicity in critically ill patients. Future prospective studies are needed to examine outcomes in critically ill patients achieving initial VCM trough levels of 15-20 mg/L.

DOI： 10.1097/FTD.0000000000000459

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DOI： 10.1691/ph.2018.8711

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Other Link： http://orcid.org/0000-0002-5755-283X

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BACKGROUND/AIMS: We have reported that nitrosonifedipine (NO-NIF), a photodegradation product of nifedipine, has strong antioxidant and endothelial protective effects, and can suppress several cardiovascular diseases in animal models. The objective of the present study was to investigate the effects of NO-NIF on aortic aneurysm formation. METHODS: The mice were infused with β-aminopropionitrile for 2 weeks and angiotensin II for 6 weeks to induce aortic aneurysm formation. The oxidative stress was measured by dihydroethidium staining and nitrotyrosine staining. The expressions of inflammation-related genes were assessed by quantitative real-time PCR and immunohistochemical staining. To clarify the mechanisms of how NO-NIF suppresses vascular cell adhesion molecule (VCAM)-1, endothelial cells were used in in vitro system. RESULTS: NO-NIF suppressed pharmacologically induced the aortic aneurysm formation and aortic expansion without blood pressure changes. NO-NIF suppressed elastin degradation and matrix metalloproteinase-2 mRNA expression. NO-NIF suppressed the reactive oxygen species-cyclophilin A positive feedback loop. Upregulated mRNA expressions of inflammation-related genes and endothelial VCAM-1 were suppressed by NO-NIF co-treatment in aortae. CONCLUSION: NO-NIF has the potential to be a new, nifedipine-derived therapeutic drug for suppressing aortic aneurysm formation by directly improving aortic structure with its strong ability to reduce oxidative stress and inflammation.

DOI： 10.1159/000492577

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PURPOSE: Although the 2016 Japanese guidelines for the management of sepsis recommend de-escalation of treatment after identification of the causative pathogen, adherence to this practice remain unknown. The objective of this study was to evaluate the benefits of de-escalating treatment for sepsis patients at an advanced critical care and emergency medical centre. METHODS: Based on electronic patient information, 85 patients who were transported to the centre by ambulance, and diagnosed with sepsis between January 2008 and September 2013 were enrolled and evaluated. Patients were divided into two groups with and without de-escalation, and comparisons were conducted for several variables, including length of hospital stay, and length of antibiotic administration. Two types of subgroup analysis were conducted between patients with septic shock or positive blood cultures. Statistical analysis was conducted using chi-square and Mann-Whitney U tests. RESULTS: The length of hospital stay after diagnosis was significantly shorter for the de-escalation group than for the non-de-escalation group. In the subgroup analysis, de-escalation for blood culture-positive patients was beneficial in terms of the length of hospital stay and length of antibiotic administration. CONCLUSIONS: The findings of this study suggest that sepsis treatment de-escalation is beneficial for treatment efficacy and appropriate use of antibiotics. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page.

DOI： 10.18433/jpps29737

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DOI： 10.1038/s41598-017-13073-0

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DOI： 10.1016/j.clinthera.2016.10.009

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Language：Japanese   Publisher：(一社)日本臨床救急医学会  

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DOI： 10.1248/bpb.35.582

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Language：Japanese   Publisher：一般社団法人日本医療薬学会  

DOI： 10.5649/jjphcs.36.347

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Language：Japanese   Publisher：(一社)日本TDM学会  

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Language：English   Publishing type：Rapid communication, short report, research note, etc. (scientific journal)  

DOI： 10.1016/j.kint.2021.01.009

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Language：Japanese   Publisher：日本病院薬剤師会  

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Other Link： https://search.jamas.or.jp/link/ui/2021004714

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Language：Japanese   Publisher：日本腎臓病薬物療法学会  

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Language：Japanese   Publisher：Japanese Society for Emergency Medicine  

&lt;b&gt;目的&lt;/b&gt;：救急認定薬剤師の現状と今後の課題を把握するために，救急認定薬剤師の業務実態と展望を調査した。&lt;b&gt;方法&lt;/b&gt;：2014年4月1日時点で日本臨床救急医学会により認定を受けた救急認定薬剤師に択一選択および自由記述の調査用紙を郵送した。&lt;b&gt;結果&lt;/b&gt;：調査用紙の回収率は75%，所属施設の病床数は平均649床，救急・集中治療業務への従事率は77%であった。現在の業務内容として，処方提案，注射薬の監査，麻薬等の管理，投与速度の算出，治療薬物モニタリング（therapeutic drug monitoring; TDM），持参薬の確認については80%以上が行っており，救急認定薬剤師が精通している領域は，救急医療が最も多かった。今後実施したいと考えている業務は初療が60%，今後の展望として，業務のガイドライン作成が73%と最も多かった。&lt;b&gt;考察&lt;/b&gt;：救急認定薬剤師が大小さまざまな施設で救急・集中治療に従事しており，今後は初療に関与してゆくことが課題であり，早急に業務ガイドラインの作成を行う必要があると考える。

DOI： 10.11240/jsem.19.46

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&amp;nbsp;&amp;nbsp;As a part of the antimicrobial stewardship program (ASP), our hospital has held regular &amp;ldquo;conferences for appropriate use of anti-methicillin-resistant &lt;i&gt;Staphylococcus aureus&lt;/i&gt; (MRSA) agents&amp;rdquo; since 2006. The conferences include multiple disciplines including physicians, pharmacists, microbiological technicians, and nurses, and conduct evaluation of the status of use and feedback. All patients who receive anti&amp;ndash;MRSA agents are evaluated. Based on the medical records and bacteriological test results, correct use is defined as &amp;ldquo;infection necessitating administration of anti&amp;ndash;MRSA agents,&amp;rdquo; &amp;ldquo;high probability of such infection,&amp;rdquo; &amp;ldquo;administration necessary from clinical viewpoint,&amp;rdquo; and &amp;ldquo;febrile neutropenia.&amp;rdquo; In cases evaluated as &amp;ldquo;unevaluable&amp;rdquo; because no sample has been submitted for culture, or &amp;ldquo;administration not needed&amp;rdquo; because bacterial infection was considered to result from colonization or contamination, the purpose of administration was confirmed with the attending physician and intervention conducted if necessary. As indices for the efficacy of ASP, the trend of use of anti&amp;ndash;MRSA agents and the trend of &lt;i&gt;S. aureus&lt;/i&gt; sensitivity were investigated. As a result of active intervention, the number of cases of &amp;ldquo;correct use&amp;rdquo; in 2012 increased over that in 2006 (82.3% vs. 65.3%; p&lt;0.01), although no marked changes in the number of patients using anti&amp;ndash;MRSA agents and the trend of use were observed. Similarly, the rates of de-escalation therapy in 2012 increased over that in 2006 (85% vs. 33%; p&lt;0.01). The rates of sensitivity of MRSA to vancomycin, teicoplanin, arbekacin, and linezolid were well maintained. This study indicates that holding multidisciplinary conferences and feedback of the evaluation results promote correct use of anti&amp;ndash;MRSA agents and are effective in reducing the incidence of MRSA detection.&lt;br&gt;

DOI： 10.4058/jsei.30.56

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