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Antimicrobial stewardship (AS) Guidelines by the Infectious Diseases Society of America recommend employing prospective audit and feedback (PAF) as an effective intervention in AS programs. Since July 2022, our hospital has implemented PAF for all patients with positive blood cultures, including those with extended-spectrum β -lactamase (ESBL)-producing Escherichia coli (EC) bacteremia. Our study examined the effect of PAF on clinical outcomes in patients with ESBL-EC bacteremia. We enrolled 62 patients diagnosed with ESBL-EC via blood culture who were undergoing antibiotic treatment. The patients were divided into the pre-PAF and post-PAF implementation groups. The rate of antibiotic de-escalation from broad-spectrum antibiotics to narrow-spectrum cefmetazole was significantly higher in the post-PAF group than in the pre-PAF group (80.7% vs. 32.4%, p = 0.0003). The treatment failure rate in the pre-PAF group was higher than that in the post-PAF group (38.7% vs. 12.9%, p = 0.04). The results of this study indicate that the implementation of PAF is advantageous not only in terms of process indicators but also in improved clinical outcomes, including reduced treatment failure rates. We hope that this study will encourage the implementation of PAF in more facilities to instigate a collective effort to reduce the incidence of antimicrobial resistance.

Background: The therapeutic landscape for ulcerative colitis (UC) has recently broadened to include anti-TNFα, anti-integrin, and anti-IL-12/23p40 antibody agents. These biological agents are tailored to individual patient profiles. However, some patients cease biological treatment. This study investigates factors influencing the discontinuation of biological treatment in UC patients., Methods: This retrospective single-cohort study encompasses UC patients who commenced treatment with biological agents like infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab from April 2019 to March 2022. Patients were categorized into continuation and discontinuation groups based on their one-year treatment status. Baseline characteristics were compared between the groups., Results: Of the 116 UC patients, 102 were included in the study. Among these, 74 (72.5%) continued and 28 (27.5%) discontinued biological therapy. Discontinuation rates for infliximab, adalimumab, golimumab, vedolizumab, and ustekinumab were 33.3%, 25.0%, 50.0%, 30.2%, and 15.6%, respectively. The primary discontinuation reason was lack of efficacy (85.7%), followed by adverse events (7.1%), pregnancy (3.6%), and death (3.6%). The discontinuation group had a significantly lower rate of concomitant thiopurine compared to the continuation group (28.6% vs. 56.8%, p = 0.0132). Multivariable analysis revealed that concomitant thiopurine was independently associated with therapy continuation (p = 0.0075)., Conclusion: The study indicates that concomitant thiopurine significantly correlates with the continuation of biological therapies in UC patients, underscoring the importance of concomitant thiopurine in sustaining biological therapy. Further studies are warranted to assess the efficacy of combination therapy., (© 2024. The Author(s).)

Medication adherence is important for the appropriate drug-based treatment in patients with chronic diseases, especially those with cardiovascular diseases (CVDs). The purpose of the present study was to evaluate medication adherence among patients with CVDs using subjective and objective measurements. We enrolled outpatients who visited Fukuoka University Chikushi Hospital from June to December 2022. As a subjective measurement, we used a self-reported questionnaire developed by Ueno et al., which consists of 12 questionnaire items grouped into the following four domains: medication compliance (subjective compliance), collaboration with health care providers (collaboration), willingness to access and use information about medication (willingness), and acceptance to take medication and how taking medication fits a patient's lifestyle (acceptance). The pill counting method was used as an objective measurement to calculate the medication adherence rate; Poor Adherence was defined as a medication adherence rate of <100%. Ninety-four patients were analyzed. No statistically significant differences were observed between the patients in the Good and Poor Adherence groups classified by pill counting, an objective indicator; in the subjective evaluation index Ueno scale scores of subjective compliance, collaboration, willingness, and acceptance domains; and in the total score. A multivariate analysis revealed that obesity (odds ratio, 3.527; 95% confidence interval, 1.387-9.423; p = 0.008) was an independent factor associated with Poor Adherence. In conclusion, we found a discrepancy between subjective and objective measurements for the evaluation of medication adherence. Furthermore, obesity was an independent factor associated with poor medication adherence assessed by the pill counting method; thus, patients with CVD and obesity require a careful follow-up.

Introduction: The Cancer and Aging Research Group (CARG) prediction tool was designed in the United States to predict grade ≥ 3 chemotherapy-related adverse events (CRAE) in older patients. However, its usefulness among Japanese people, who have different sensitivities to anticancer drugs and life expectancy, remains unknown. We aimed to prospectively evaluate the utility of the CARG tool for predicting severe CRAE in older Japanese patients with cancer., Material and Methods: Patients with solid tumors aged 65 years and older who commenced anticancer drug regimens from April 2018 to October 2020 were divided into three groups (low, medium, and high-risk) based on their CARG risk scores. Toxicity was prospectively observed by a pharmacist. The primary objective was to evaluate the correlation between the incidence of grade ≥ 3 CRAE and the CARG risk score. The secondary objective was to evaluate hematological and non-hematological toxicities. CRAE incidence was compared among the three groups using a closed testing procedure: (1) Cochran-Armitage test for trend and (2) chi-square test for paired comparison., Results: The patients (N = 165) had a median age of 71 years (range: 65-89 years). CRAE in patients divided into low-, medium-, and high-risk groups, based on CARG risk scores, were 39%, 55%, and 82%, respectively (low vs high; p < 0.001, medium vs high; p < 0.01). The incidence of severe hematologic toxicity was 37%, 35%, and 50% in the low-, medium-, and high-risk groups, respectively; the incidence of severe non-hematologic toxicity was 15%, 36%, and 65%, respectively (low vs medium; p < 0.01, low vs high; p < 0.001, and medium vs high; p < 0.01)., Discussion: To our knowledge, this is the first prospective observational study to validate the CARG prediction tool in older Japanese patients with cancer. The CARG risk score may be effective in predicting the development of non-hematologic toxicities. These results should be considered when administering chemotherapy to older Japanese patients with advanced solid tumors., Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest directly relevant to the content of this article., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Hypersensitivity reactions are an adverse effect of anticancer drug therapy. Prophylactic administration of antiallergic drugs and steroids is recommended when administering drugs associated with a high hypersensitivity reaction incidence. First-generation antihistamines are generally used in this setting. These medications, however, induce drowsiness and sedation due to their inhibitory effects on the central nervous system. They are contraindicated in patients with angle-closure glaucoma and prostatic hyperplasia. Second-generation antihistamines are used as alternative drugs for such cases in our hospital. This study investigated the use of second-generation antihistamines at our hospital and examined their efficacy and safety. A total of 7 second-generation antihistamines were used at our hospital. Approximately 90% of the target patients were shifted from first-generation antihistamines to bilastine or desloratadine. The most frequent reasons for changing to second- generation antihistamines were drowsiness(32.3%)and car driving(24.2%). No central inhibitory side effects were observed upon consumption of second-generation antihistamines. Only 2 patients(3.2%)developed hypersensitivity reactions after changing to second-generation antihistamines. Our findings suggest that second-generation antihistamines are effective in preventing hypersensitivity reactions. These medications may be used in patients who have concerns regarding the central inhibitory side effects of first-generation antihistamines or their potential to exacerbate comorbidities. Their use can help improve the safety of anticancer drug therapy.

Pseudomonas aeruginosa bacteremia is associated with a high mortality rate, and meropenem (MEPM) is commonly used to treat it. However, the relationship between the time above the minimum inhibitory concentration ( f T >MIC ) of MEPM and its therapeutic efficacy in P. aeruginosa bacteremia has not been explored. This study aimed to investigate this relationship by defining the target % f T >MIC of MEPM as 75%. The retrospective study spanned 14 years and included hospitalized patients treated with MEPM for P. aeruginosa bacteremia. Monte Carlo simulation was used to calculate the probability of target attainment (PTA) for each patient, and the threshold for a PTA of 75% f T >MIC associated with in-hospital survival was determined using receiver operating characteristic (ROC) curves. The ROC curve-derived PTA associated with improved in-hospital survival was 65.0%, a significant finding in multivariate logistic regression analysis adjusted for patient background factors (odds ratio: 20.49, 95% confidence interval: 3.02-245.23, p = 0.005). This result suggests a dosing regimen that achieves a PTA of at least 65% when the target f T >MIC of MEPM for treating P. aeruginosa bacteremia is defined as 75%.

Background: Immune-checkpoint inhibitors (ICIs) are effective against various cancers; however, immune-related adverse events (irAEs) have been reported and the timing and risk factors are unknown. Therefore, we examined the incidence and timing of irAE occurrence., Methods: Patients who received ICIs at our hospital between 1 April 2016 and 31 March 2020 were enrolled. Patients were classified into an irAE group or non-irAE group. In addition, we examined the onset time and symptoms of irAEs for each ICI type., Results: A total of 80 patients received ICIs, of which 27 (33.8%) developed irAEs. The incidence of irAEs was 35.3% for nivolumab, 35.5% for pembrolizumab, and 28.6% for atezolizumab. The incidence of pneumonitis was 12.5%, 8.8% for dermatologic adverse events, and 6.3% for thyroid dysfunction. The earliest case of onset was after the 1st course, and the latest cases occurred after the 66th course. By the sixth course, 69% of the irAEs occurred. The positive rates for anti-thyroid peroxidase and anti-thyroglobulin antibodies were higher in the irAE group compared to the non-irAE group., Conclusions: Our findings suggest a high probability of irAEs occurring early in ICI treatment, with a diverse range of symptoms. This underscores the need for vigilant monitoring and tailored patient management during the initial courses of ICI therapy.

Background: The causative microorganisms of bloodstream infections (BSIs) in patients with inflammatory bowel disease (IBD) and the clinical characteristics of these patients have not yet been fully identified. Therefore, this study investigated IBD patients who developed BSI to determine their clinical characteristics and identify the BSI-causing bacteria., Methods: The subjects were IBD patients who developed bacteremia between 2015 and 2019 at Fukuoka University Chikushi Hospital. The patients were divided into two groups according to IBD type (Crohn's disease (CD) or ulcerative colitis (UC)). The medical records of the patients were reviewed to determine their clinical backgrounds and identify the BSI-causing bacteria., Results: In total 95 patients, 68 CD and 27 UC patients were included in this study. The detection rates of Pseudomonas aeruginosa ( P. aeruginosa ) and Klebsiella pneumoniae ( K. pneumoniae ) were higher in the UC group than in the CD group (18.5% vs. 2.9%, P = 0.021; 11.1% vs. 0%, P = 0.019, respectively). Immunosuppressive drugs use was higher in the CD group than in the UC group (57.4% vs. 11.1%, P = 0.00003). Hospital stay length was longer in the UC group than in the CD group (15 vs. 9 days; P = 0.045)., Conclusions: The causative bacteria of BSI and clinical backgrounds differed between patients with CD and UC. This study showed that P. aeruginosa and K. pneumoniae had higher abundance in UC patients at the onset of BSI. Furthermore, long-term hospitalized patients with UC required antimicrobial therapy against P. aeruginosa and K. pneumoniae., Competing Interests: The authors declare that they have no competing interests., (Copyright 2023, Kamada et al.)

A nucleic acid amplification test (NAAT) is recommended to determine whether or not patients have a Clostridioides difficile infection (CDI) when the glutamate dehydrogenase activity assay is positive and the rapid membrane enzyme immunoassays for toxins is negative. In our hospital, a NAAT was introduced to diagnose CDI precisely in April 2020. This study aimed to investigate the impact of a NAAT on the clinical outcomes in patients with CDI at our hospital. Seventy-one patients diagnosed with CDI between April 2017 and March 2022 were included in our study. Patients with CDI were divided into two groups: before (pre-NAAT) and after (post-NAAT) the introduction of NAAT. The clinical outcome was compared between the two groups. Of the 71 patients with CDI, 41 were sorted into the pre-NAAT group and 30 into the post-NAAT group. The clinical cure rate was significantly higher in the post-NAAT group compared to the pre-NAAT group (76.7% vs. 48.8%, p = 0.018). In the multivariable analysis, the clinical cure was significantly associated with the introduction of NAAT ( p = 0.022). Our findings suggest that the introduction of NAAT can improve the clinical outcomes in CDI patients.

Background and Objectives : Remdesivir (RDV) is the first antiviral agent approved in Japan for the treatment of coronavirus disease 2019 (COVID-19). The aim of our study was to assess the efficacy and safety of RDV treatment in mildly to moderately ill patients with COVID-19. Materials and Methods: A single-center, retrospective study was performed in Fukuoka University Chikushi Hospital. Patients admitted to our hospital from June to October 2021 for RDV treatment against COVID-19 were enrolled. The primary end point was clinical status on days 10 and 14, using a 6-point ordinal scale ranging from death (category 6) to discharge (category 1). Adverse events were assessed and graded using the Japanese version of Common Terminology Criteria for Adverse Events (CTCAE) v5.0. Results : In total, 47 COVID-19 patients receiving RDV treatment were assessed during the study period. Thirty-four (72.3%) out of 47 patients required oxygen therapy. Out of these 34 patients, 30 (88.2%) showed a 2-point clinical improvement on day 14 after RDV was initiated. Serum alanine aminotransferase levels were elevated in three patients (6.4%) (CTCAE Grade 3) and neutropenia was detected in one patient (2.1%) out of the 47 patients. Conclusions : RDV may be highly effective, with good safety profiles, in patients with COVID-19 requiring oxygen therapy.

Introduction: A rapid membrane enzyme immunoassays (EIA) are frequently used to diagnose Clostridioides difficile infection (CDI). If EIA does not provide a definitive CDI diagnosis, whether treatment with anti-CD agents is to be performed depends on the pathogenesis and severity of the disease. In Japan, "MN criteria" have been proposed for the classification of disease severity. In this study, we investigated the association between disease severity and CDI prognosis when MN criteria are used., Methods: This study included 102 patients diagnosed with CDI between April 2015 and March 2020. The disease serverity classification accorditng to MN criteria was divided into two groups: non-severely ill (mild to moderate) and severely ill (severe to critical) group., Results: Mortality was significantly higher in severely ill patients than non-severely ill patients (46.7% vs. 13.8%, p = 0.0025). Multivariable analysis showed that the mortality of patients with CDI was significantly associated with advanced age (odds ratio [OR] = 1.1; 95% confidence interval [CI] = 1.0-1.2; p = 0.019) and disease severity (OR = 4.2; 95% CI = 1.2-14.8; p = 0.023)., Discussion: The classification of disease severity according to the MN criteria would be particularly useful in predicting the patients' prognoses., (Copyright © 2022 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The substantial increase in the use of expensive anticancer drugs has been accompanied by an increase in the amount of disposing residual liquid from drug preparations. Many Western countries, including the United States, have implemented drug vial optimization (DVO) to prevent the waste of anticancer drugs and have reported the reductions in the total drug costs. This study was designed to estimate the expected reduction in spending on anticancer drugs by Japanese cancer hospitals when DVO was implemented instead of individual preparations and to test the effectiveness of this approach., Methods: We investigated the doses of drugs used and quantity specifications for individually prepared vials for patients who received anticancer drug treatment in December 2017 at the Outpatient Treatment Center of the National Cancer Center Hospital East. Based on these findings, we calculated the total quantity of each drug used on a given day, and the minimum cost for preparation of the number of specified combinations corresponding to the total cost (DVO preparation). Based on the differences in these two costs, we estimated the economic impact of implementing DVO., Results: While the cost for anticancer drugs for the 1-month study period was US$3,305,595 (US$1 = \110) for individual preparations, the estimated cost for DVO preparations was US$3,092,955, equivalent to a reduction of US$212,640., Conclusions: Based on these study results, implementation of DVO-based preparation of injectable anticancer drugs in Japan in 2017 would have resulted in saving approximately US$460 million. This calculation revealed the need for the Japanese government to modify the methods employed to calculate drug costs in the insurance system and develop policies for the proper and optimal use of medical resources.

Background: Polypharmacy (PP) and potentially inappropriate medications (PIMs) cause problematic drug-related issues in elderly patients; however, little is known about the association between medication adherence and PP and PIMs. This study evaluated the association of self-reported medication adherence with PP and PIMs in elderly patients., Methods: A cross-sectional pilot study was conducted using data collected from electronic medical records of 142 self-administering patients aged ≥65 years, excluding emergency hospitalization cases. Self-reported medication adherence was assessed using the visual analogue scale (VAS)., Results: Of the 142 patients, 91 (64.1%) had PP and 80 (56.3%) used at least one PIM. In univariate analysis, patients with a VAS score of 100% had a significantly higher number of female patients and ≥1 PIM use compared to other patients. We found no association between the VAS score and PP. In multivariable analysis, the use of PIMs was significantly associated with a VAS score of 100% (odds ratio = 2.32; 95% confidence interval = 1.16-4.72; p = 0.017)., Conclusions: Use of PIMs by elderly patients is significantly associated with self-reported medication adherence. Pharmacists should pay more attention to prescribed medications of self-administering elderly patients in order to improve their prescribing quality.

Background: Inappropriate dosing of direct oral anticoagulants (DOACs) has been associated with clinical safety and efficacy; however, little is known about clinical data associated with an inappropriate DOAC dosing in Japan. In addition, there is no report in which the appropriateness of DOAC dosing between prescription for inpatients and for outpatients was examined. In this study, we aimed to investigate the prevalence and factors associated in the inappropriate dosing of DOACs in patients with atrial fibrillation (AF)., Methods: The retrospective cohort study was conducted at a single Japanese university hospital. Both inpatients and outpatients, who were diagnosed with AF and for whom treatment with either dabigatran, rivaroxaban, apixaban, or edoxaban was initiated between April 1, 2014 and March 31, 2018, were enrolled in the study. Appropriateness of DOAC dosing was assessed according to the manufacturer's labeling recommendations (dose reduction criteria) of each DOAC. Inappropriate reduced dose, namely, underdosing, was defined as prescription of a reduced dose of DOAC despite the patient not meeting the dose reduction criteria. Inappropriate standard dose, namely, overdosing, was defined as prescription of a standard dose of DOAC despite the patient meeting the dose reduction criteria. Inappropriate DOAC dosing was defined as a deviation of the recommended dose (both underdosing and overdosing)., Results: A total of 316 patients (dabigatran, 28; rivaroxaban, 107; apixaban, 116; and edoxaban, 65) were included, with a median (interquartile range) age of 75 (66-81) years and 62.3% male. DOACs were prescribed at an appropriate standard dose in 39.2% of patients, an appropriate reduced dose in 36.7%, an inappropriate standard dose in 2.5%, and an inappropriate reduced dose in 19.3%. Multivariate analysis revealed that the inappropriate dosing of DOACs was significantly associated with prescriptions for outpatients (vs. inpatients; odds ratio [OR] 2.87, 95% confidence interval [CI] 1.53-5.62, p  < 0.001) and those with higher HAS-BLED scores (OR 1.87, 95% CI 1.42-2.51, p < 0.001)., Conclusions: Our results demonstrated that the inappropriate dosing of DOACs occurred in approximately 20% of AF patients, and was more frequent in outpatients (vs. inpatients) and in those with a higher risk of bleeding. It is recommended that pharmacists play a greater role in assisting in the prescription process to help physicians make better decisions., Competing Interests: Competing interestsThe author(s) declare no competing interests., (© The Author(s). 2020.)

Background: This study aimed to investigate the trends and antimicrobial resistance profile of extended-spectrum β-lactamase-producing Escherichia coli (ESBL-EC) clinical isolates., Methods: A total of 1,303 E. coli isolates from January 2012 to December 2017 at Fukuoka University Chikushi Hospital, Japan, were analyzed. The rate of resistance to cefmetazole (CMZ), flomoxef (FMOX), imipenem (IPM), meropenem (MEPM), amikacin (AMK), gentamicin (GM), minocycline (MINO), ciprofloxacin (CPFX), and levofloxacin (LVFX) was compared between non-ESBL-producing E. coli (non-ESBL-EC) and ESBL-EC., Results: The proportion of ESBL-EC among all the E. coli isolates was 24.6% (320/1,303), and the proportion remained stable throughout the study period. There was no difference in the rate of resistance to CMZ, FMOX, IPM, MEPM, and AMK between non-ESBL-EC and ESBL-EC; however, the rate of resistance to GM, MINO, CPFX, and LVFX was higher in ESBL-EC than in non-ESBL-EC (17.5% vs. 10.0%, 19.1% vs. 7.7%, 87.5% vs. 24.2%, and 87.5% vs. 23.5%, respectively; P < 0.01). The rate of resistance to CPFX and LVFX in ESBL-EC increased throughout the study course. The rate of E. coli isolates susceptible to all the antibiotics was significantly higher in non-ESBL-EC than in ESBL-EC (68.2% vs. 7.5%; P < 0.01), and this rate decreased significantly from 10.0% in 2012 to 3.8% in 2017 in ESBL-EC (P < 0.01)., Conclusions: Our findings indicate a changing antimicrobial resistance profile of ESBL-EC, particularly to fluoroquinolones. Determination of the prevalence and antimicrobial resistance of ESBL-EC will help physicians in selecting the initial empirical treatment for patients with ESBL-EC infections., Competing Interests: The authors declare that they have no conflict of interest.

Objective: The aim of this study was to examine the association between medication adherence and illness perceptions, and to explore the factors associated with poor medication adherence in atrial fibrillation (AF) patients receiving direct oral anticoagulants (DOACs) in a real-world clinical setting., Methods: An observational cross-sectional pilot study was conducted at a single Japanese university hospital. One hundred and twenty-nine patients who were diagnosed with AF and who were taking DOACs were recruited from outpatients between January 4th and April 25th, 2017. We evaluated medication adherence to DOACs using the Morisky Medication Adherence Scale-8 (MMAS-8) and illness perceptions using the Brief Illness Perception Questionnaire (BIPQ). The patients' characteristics and clinical data were collected from electronic medical records., Results: Ninety-nine (76.7%) patients (male, n = 74; mean age, 71.4±9.8 years) participated in this study. According to the MMAS-8, 21 (21.2%) of the patients were classified into the poor adherence group (MMAS-8 score of <6), and 78 (78.8%) were classified into the good adherence group (MMAS-8 score of 6-8). A multivariate logistic regression analysis revealed that age (per year, odds ratio [OR] 0.912, 95% confidence interval [CI] 0.853-0.965, p = 0.001), a history of warfarin use (OR 0.181, 95% CI 0.033-0.764, p = 0.019), duration of DOAC exposure (per 100 days, OR 1.245, 95% CI 1.084-1.460, p = 0.001), and the BIPQ emotional response score (per 1 point, OR 1.235, 95% CI 1.015-1.527, p = 0.035) were significantly associated with poor medication adherence in AF patients receiving DOACs., Conclusion: Poor medication adherence to DOACs was strongly associated with a stronger emotional response (i.e. stronger feelings of anger, anxiety, and depression), as well as younger age, the absence of a history of warfarin treatment, and longer DOAC exposure. Further evaluation of the factors associated with medication adherence in AF patients and the development and execution of strategies for improving poor adherence are warranted in the real-world clinical setting., Competing Interests: The authors have declared that no competing interests exist.

In general, the intraventricular administration of cytotoxic antitumor drugs provides a high drug concentration in the cerebrospinal fluid with a reduced risk of systemic adverse reactions. Methotrexate (MTX) high-dose therapy requires close monitoring when performed in combination with trimethoprim-sulfamethoxazole (ST) therapy and proton pump inhibitor (PPI) and nonsteroidal anti-inflammatory drug administration for excretion delay and toxicity enhancement. While the frequency of systemic side effects is thought to be low with intrathecal administration, such effects do rarely but occasionally occur. We must consider drug interactions with combination therapy as a potential factor inducing such effects. We examined the patients who received MTX intrathecal administration at Fukuoka University Hospital from January 2013 to December 2014 with respect to the onset of side effects and combination therapy. MTX intrathecal administration was performed a total of 79 times in 27 patients. In five of these 27 patients, MTX intrathecal administration was performed twice a week, and hematotoxicity and non-hematotoxicity developed in two patients in whom ST was also administered. On the other hand, even if ST and/or PPI was administered, no side effects were observed in the patients administered levofolinate.

Warfarin (WF) shows a number of interactions with other drugs, which alter its anticoagulant effects. The albumin binding interaction is one such pharmacokinetic mechanism of drug interaction with WF, which induces a rise in the free WF concentration and thus increases the risk of WF toxicity. Teicoplanin (TEIC) is an anti-methicillin-resistant Staphylococcus aureus drug, which also binds strongly to albumin in the plasma. Therefore, co-administration of TEIC may displace WF from the albumin binding site, and possibly result in a toxicity. The present study was performed to investigate the drug-drug interaction between WF and TEIC in comparison with controls treated with vancomycin (VCM), which has the same spectrum of activity as TEIC but a lower albumin binding ratio.The records of 49 patients treated with WF and TEIC or VCM at Fukuoka University Hospital between 2010 and 2015 were retrospectively reviewed. These 49 patients consisted of 18 treated with TEIC in combination with WF, while 31 received VCM in combination with WF. Prothrombin time-international normalized ratio (PT-INR) showed a significant increase of 80.9 (52.0-155.3) % after co-administration of TEIC with WF. In contrast, the rate of PT-INR elevation associated with VCM plus WF was 30.6 (4.5-44.1) %. These observations suggested that TEIC can cause a rise in free WF concentration by albumin binding interaction. Therefore, careful monitoring of PT-INR elevation is necessary in patients receiving WF plus TEIC.

BACKGROUND Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a potentially life-threatening syndrome comprising severe skin eruption, fever, eosinophilia, lymphadenopathy, and involvement of internal organs. Here, we describe a case of DRESS syndrome caused by cross-reactivity between vancomycin and subsequent teicoplanin administration. CASE REPORT A 79-year-old male was admitted to our hospital for the treatment of injuries incurred in a traffic accident. Eosinophilia and lung dysfunction appeared after vancomycin administration. These symptoms were improved temporarily by withdrawal of vancomycin and administration of corticosteroid, but exacerbated by subsequent teicoplanin administration. These symptoms disappeared after discontinuation of teicoplanin. Based on comprehensive assessment of the overall clinical course, we judged that DRESS syndrome was induced by cross-reactivity between vancomycin and subsequent teicoplanin administration. Using the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scoring system, we categorized DRESS syndrome related to vancomycin and teicoplanin as "probable." We describe, for the first time, DRESS syndrome (defined using the RegiSCAR scoring system) caused by cross-reactivity between vancomycin and subsequent teicoplanin administration. CONCLUSIONS Clinicians should be aware that DRESS syndrome can be induced by cross-reactivity between vancomycin and teicoplanin.

We have developed a fluorous affinity-based extraction method for measurement of protein kinase activity. In this method, a fluorescent peptide substrate was phosphorylated by a protein kinase, and the obtained phosphopeptide was selectively captured with Fe(III)-immobilized perfluoroalkyliminodiacetic acid reagent via a metal chelate affinity technique. Next, the captured phosphopeptide was selectively extracted into a fluorous solvent mixture, tetradecafluorohexane and 1H,1H,2H,2H-tridecafluoro-1-n-octanol (3:1, v/v), using the specificity of fluorous affinity (fluorophilicity). In contrast, the remained substrate peptide in the aqueous (non-fluorous) phase was easily measured fluorimetrically. Finally, the enzyme activity could be assayed by measuring the decrease in fluorescence. The feasibility of this method was demonstrated by applying the method for measurement of the activity of cAMP-dependent protein kinase (PKA) using its substrate peptide (kemptide) pre-labeled with carboxytetramethylrhodamine (TAMRA)., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background Target trough concentrations are recommended for teicoplanin (TEIC) to minimize its adverse effects and to maximize efficacy in sepsis caused by grampositive cocci, including methicillin-resistant Staphylococcus aureus infection. However, optimal doses to attain proper trough values in patients with sepsis have not yet been well established for TEIC. Objective This study investigated whether the systemic inflammatory response syndrome (SIRS) score could predict the pharmacokinetics of TEIC in patients with sepsis. Setting This study was conducted at Fukuoka University Hospital in Japan. Methods We retrospectively reviewed the records of patients using TEIC between April 2012 and March 2015. SIRS positive was defined as infection with a SIRS score ≥2. Estimates of pharmacokinetic parameters were calculated using a Bayesian method. Creatinine clearance rates were estimated by the Cockcroft-Gault formula (eCcr). Main outcome measure Change of TEIC loading dose requirement for incremental increases of SIRS score. Results In total, 133 patients were enrolled: 50 non-SIRS patients and 83 patients with SIRS. The TEIC plasma trough concentration was significantly lower in SIRS than non-SIRS patients (15.7 ± 7.1 vs. 20.1 ± 8.6 μg/mL; P < 0.01), although there was no significant difference in the loading dose administered. Moreover, SIRS scores were increasingly predictive of eCcr and TEIC clearance in a stepwise manner. To achieve the target trough concentration (15-30 μg/mL), the optimal doses required in non-SIRS versus SIRS patients were 12-24 versus 18-30 mg/kg/day, respectively, during the first 48 h. Conclusions These findings suggest that the pharmacokinetics of TEIC are altered in SIRS patients, who required higher doses than non-SIRS patients to achieve the target trough concentration. We suggest that the SIRS score can become a new modality to determine the initial TEIC loading dose.

Transdermal patches containing rotigotine, a dopamine agonist (DA) for treatment of Parkinson disease, continuously exert stable effects when applied once daily. Therefore, they are expected to reduce the patient burdens due to complications such as wearing-off and dysphagia. However, dosing is occasionally reduced or discontinued after application because of several reasons such as skin reactions or unsatisfactory efficacy. To identify the risk factors involved in the reduced or discontinued use of rotigotine patches, a retrospective study was conducted with reference to the medical records of patients with Parkinson disease who received rotigotine patches in our hospital. 85 patients were involved in this study. Dosing of rotigotine was reduced or discontinued in 53 patients during the study period. The factors associated with charges in treatment included combination therapy with clonazepam and oral administration of another DA before the application of rotigotine. The reduction or discontinuation rate of rotigotine patches in patients who reduced the equivalent dose of DA on the introduction of rotigotine patches was 94.7%, showing a significantly higher rate compared with 61.3% in the increased dose group. To improve adherence to rotigotine patch therapy, physicians need to carefully consider concomitant drugs and total dose of DAs. (Received December 7, 2015; Accepted February 22, 2016; Published June 1, 2016).

Adult T-cell leukemia/lymphoma (ATL), an aggressive T-cell malignancy that develops after long-term infection with human T-cell leukemia virus (HTLV-1), requires new treatments. Drug repositioning, reuse of a drug previously approved for the treatment of another condition to treat ATL, offers the possibility of reduced time and risk. Among clinically available angiotensin II receptor blockers, telmisartan is well known for its unique ability to activate peroxisome proliferator-activated receptor-γ, which plays various roles in lipid metabolism, cellular differentiation, and apoptosis. Here, telmisartan reduced cell viability and enhanced apoptotic cells via caspase activation in ex vivo peripheral blood monocytes from asymptomatic HTLV-1 carriers (ACs) or via caspase-independent cell death in acute-type ATL, which has a poor prognosis. Telmisartan also induced significant growth inhibition and apoptosis in leukemia cell lines via caspase activation, whereas other angiotensin II receptor blockers did not induce cell death. Interestingly, telmisartan increased the LC3-II-enriched protein fraction, indicating autophagosome accumulation and autophagy. Thus, telmisartan simultaneously caused caspase activation and autophagy. A hypertension medication with antiproliferation effects on primary and leukemia cells is intriguing. Patients with an early diagnosis of ATL are generally monitored until the disease progresses; thus, suppression of progression from AC and indolent ATL to acute ATL is important. Our results suggest that telmisartan is highly effective against primary cells and leukemia cell lines in caspase-dependent and -independent manners, and its clinical use may suppress acute transformation and improve prognosis of patients with this mortal disease. This is the first report demonstrating a cell growth-inhibitory effect of telmisartan in fresh peripheral blood mononuclear cells from leukemia patients.

In this study, we developed a novel direct tandem mass spectrometric method for rapid and accurate analysis of amino acids utilizing a fluorous derivatization and purification technique. Amino acids were perfluoroalkylated with 2H,2H,3H,3H-perfluoroundecan-1-al in the presence of 2-picoline borane via reductive amination. The derivatives were purified by perfluoroalkyl-modified silica-based monolithic solid-phase extraction (monolithic F-SPE), and directly analyzed by tandem mass spectrometry using electrospray ionization without liquid chromatographic separation. The perfluoroalkyl derivatives could be sufficiently distinguished from non-fluorous compounds, i.e. the biological matrix, due to their fluorous interaction. Thus, rapid and accurate determination of amino acids was accomplished. The method was validated with human plasma samples and applied to the analysis of amino acids in the plasma of mice with maple syrup urine disease or phenylketonuria., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A liquid chromatographic (LC) method with improved selectivity for the simultaneous determination of 5-hydroxyindoles (5-HIs; 5-hydroxytryptophan, 5-hydroxytryptamine, N-acetyl-5-hydroxytryptamine, 5-hydroxyindole-3-acetic acid, and 5-hydroxytryptophol) is described. This method involves precolumn derivatization with 4-(3',3',4',4',5',5',6',6',7',7',8',8',9',9',10',10',10'-heptadecafluorodecyl)benzylamine (HFBA) and separation of the derivatives using a fluorous LC column. In this study, stable benzoxazole derivatives of 5-HIs with HFBA have been obtained by a simple derivatization procedure; their fluorescent properties enabled highly sensitive detection. In addition, only the HFBA derivatives of 5-HIs has been selectively retained on the fluorous LC column via fluorous interaction whereby perfluoroalkyl compounds show affinities with each other, while the non-fluorous compounds did not. The HFBA derivatives were separated within 30 min and the detection limits for 5-HIs in a 20-μL injection volume were 1.2-14 fmol (S/N=3). Furthermore, this method was applied to the analysis of 5-HIs in the human plasma from healthy subjects., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The acquirement of basic knowledge of clinical trials and professional attitude in their practices is a general instructional objective in the Model Core Curriculum for Pharmaceutical Education. Unfortunately, the previous program of clinical trial education was not effective in the acquirement of a professional attitude in their practices. Then, we developed the new clinical trial education program using protocol through small group discussion (SGD) and roll-playing. Our program consists of 7 steps of practical training. In step 1, the students find some problems after presentation of the protocol including case and prescription. In step 2, they analyse the extracted problems and share the information obtained in SGD. In steps 3 and 5, five clinical case scenarios are presented to the students and they discuss which case is suitable for entry to the clinical trial or which case corresponds to the discontinuance criteria in the present designed protocol. In steps 4 and 6, the roll-playing is performed by teachers and students as doctors and clinical research coordinators (CRC) respectively. Further, we conducted a trial practice based on this program for the students. In the student's self-evaluation into five grades, the average score of the skill acquisition level in each step was 3.8-4.7 grade. Our clinical trial education program could be effective in educating the candidates for CRC or clinical pharmacists.

Aims: The present study aimed to evaluate the associations between medication use and falls and to identify high risk medications that acted as a trigger for the onset of falls in an acute care hospital setting., Methods: We applied a case-crossover design wherein cases served as their own controls and comparisons were made within each participant. The 3-day period (days 0 to -2) and the 3-day periods (days -6 to -8, days -9 to -11 and days -12 to -14) before the fall event were defined as the case period and the control periods, respectively. Exposures to medications were compared between the case and control periods. Odds ratios (OR) and 95% confidence intervals (CI) for the onset of falls with respect to medication use were computed using conditional logistic regression analyses., Results: A total of 349 inpatients who fell during their hospitalization were recorded on incident report forms between March 2003 and August 2005. The initial use of antihypertensive, antiparkinsonian, anti-anxiety and hypnotic agents as medication classes was significantly associated with an increased risk of falls, and these ORs (95% CI) were 8.42 (3.12, 22.72), 4.18 (1.75, 10.02), 3.25 (1.62, 6.50) and 2.44 (1.32, 4.51), respectively. The initial use of candesartan, etizolam, biperiden and zopiclone was also identified as a potential risk factor for falls., Conclusions: Medical professionals should be aware of the possibility that starting a new medication such as an antihypertensive agent, including candesartan, and antiparkinsonian, anti-anxiety and hypnotic agents, may act as a trigger for the onset of a fall.

A method for the determination of acetylcholine (ACh) has been developed using liquid chromatography with chemiluminescence detection. This method is based on the pre-column alkaline cleavage of ACh to form trimethylamine (TMA) and the post-column tris(2,2'-bipyridyl)ruthenium(III) chemiluminescence detection of TMA. ACh was converted to TMA with high yield at 180 degrees C in the presence of lithium hydroxide, and the produced TMA was separated on a cation-exchange/reversed-phase dual-functional column using a mixture of 0.2 M potassium phosphate buffer (pH 5.9) and acetonitrile (20:1, v/v) as the mobile phase. The eluate was online mixed with acidic tris(2,2'-bipyridyl)ruthenium(III) solution, and the generated chemiluminescence was detected. The detection limit (signal-to-noise ratio = 3) for ACh was 0.80 nmol/mL, which corresponded to 1.1 pmol TMA per injection volume of 5 microL. This is simple and robust method that does not need an expensive device and unstable enzymes, and was applied to the determination of ACh in pharmaceutical formulations.