Predictors of a Good Diuretic Response and Administration Methods for Carperitide in Patients With Acute Heart Failure.

PURPOSE: In Japan, carperitide has been recommended for the treatment of pulmonary congestion in patients with acute heart failure. Identifying useful indicators to support the decision to administer carperitide and the optimal timing of administration may lead to better improvement of pulmonary congestion. Therefore, we investigated the factors associated with good diuretic response to carperitide in patients with acute heart failure and the optimal timing of carperitide administration. METHODS: This retrospective cohort study investigated 293 hospitalized patients who were diagnosed with acute heart failure and treated with carperitide at the Department of Cardiology, Showa University Fujigaoka Hospital. The primary endpoint was the diuretic response to carperitide. Patients with urine output ≥100 mL/h were defined as the good diuretic response group, and those with a urine output <100 mL/h during the first 6 hours of carperitide administration were defined as the poor diuretic response group. Multivariate analysis was used to examine the predictors of good diuretic response. The relationship between the time from intravenous furosemide to carperitide administration and urine output was also investigated. FINDINGS: The patients' median age was 77 (range: 28-99) years, and 75.5% had New York Heart Association stage IV acute heart failure. The median urine output within 6 hours of carperitide administration was 104.5 (range: 6.6-1571.3) mL/h, and 118 patients (53.6%) showed a good diuretic response. Significant predictors of good diuretic response were age < 75 years [odds ratio (OR) 4.186; 95% confidence interval (CI), 2.129-8.230; P < 0.001], no prior use of loop diuretics (OR 2.155; 95% CI, 1.104-4.207; P = 0.024), blood urea nitrogen <20 mg/dL (OR 2.637; 95% CI, 1.340-5.190; P = 0.005), and white blood cell count <8.6 × 109/L (OR 3.162; 95% CI, 1.628-6.140; P = 0.001). The median urine output in the group with <2 hours between intravenous furosemide and carperitide administration was significantly higher than that in the group with an interval >6 hours [127.3; interquartile range (IQR), 77.6-216.2 mL/h vs. 66.2; IQR. 51.8-114.8 mL/h; P = 0.012). IMPLICATIONS: The 4 predictors (age, no prior use of loop diuretics, blood urea nitrogen, and white blood cell count) of good diuretic response are useful indicators to support decision-making for carperitide administration. Additionally, the administration of carperitide within 2 hours of intravenous furosemide may lead to the improvement of pulmonary congestion.

Bleeding risk factors and real-world antithrombotic therapies in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention: a retrospective study.

BACKGROUND: Bleeding risk factors in elderly patients with atrial fibrillation undergoing percutaneous coronary intervention (PCI) are unclear and data on the use of antithrombotic drugs are lacking. We investigated the bleeding risk factors in elderly patients with atrial fibrillation undergoing PCI to help optimize antithrombotic therapy according to bleeding risk. We also investigated the association between the actual use of antithrombotic therapy and bleeding events. METHODS: A retrospective cohort study was conducted on 134 elderly patients with atrial fibrillation who underwent primary PCI at the Department of Cardiology, Showa University Fujigaoka Hospital. The endpoint was a bleeding event within 1-year. Bleeding risk factors were identified using multivariate analysis. The association between the number of antithrombotics and bleeding events was evaluated using the chi-squared test. RESULTS: The mean age of the patients was 76.0 ± 6.2 years. Bleeding events occurred in 41 (30.6%) patients. Age > 80 years (odds ratio [OR]: 2.54, 95% confidence interval [CI]: 1.10-5.85), multivessel disease (OR: 2.76, 95% CI: 1.22-6.23), and history of surgery (OR: 3.03, 95% CI: 1.14-8.06) were identified as bleeding risk factors. The proportion of patients receiving triple therapy was significantly higher in the bleeding group compared to the non-bleeding group (70.7% vs. 27.5%, p < 0.001). CONCLUSIONS: Age > 80, multivessel disease, and history of surgery were found to be risk factors for bleeding in elderly patients with atrial fibrillation undergoing PCI. In addition, dual therapy after PCI in elderly patients at high risk of bleeding should be considered to avoid bleeding events.

Risk Factors for Thromboembolic and Bleeding Events in Patients After the Fontan Operation (Insights from the National Database of Health Insurance Claims of Japan).

Risk stratification of thromboembolic events (TEs) and bleeding events is important for the appropriate selection of thromboprophylaxis in patients after the Fontan operation. Therefore, we clarified the risk factors for TEs and bleeding events in patients after the Fontan operation using the National Database of Health Insurance Claims and Specific Health Checkups of Japan. We conducted a retrospective cohort study including 2,515 patients who underwent the Fontan operation between June 2011 and September 2019. The end points were TEs and bleeding events within 1 year of the Fontan operation analysis. We analyzed the risk factors for these end points using a multivariate analysis. In total, 1,903 patients were included in the analysis. The median age at the time of the Fontan operation was 3 (1 to 22) years, and 1,067 patients (56%) were male. The incidence rates of TEs and bleeding events were 12% and 11%, respectively. Age (odds ratio [OR] 1.1 per 1 year older, p <0.05) was an independent risk factor for TEs. Thromboprophylaxis with aspirin after the Fontan operation significantly reduced TEs (OR 0.3, p <0.05). A history of postoperative hemorrhage (OR 1.5, p <0.05) and the use of a potassium channel blocker (OR 2.1, p <0.05) were independent risk factors for bleeding events. In conclusion, aspirin was found to reduce the risk of TEs within 1 year of the Fontan operation. The results of this study will be useful in selecting effective and safe thromboprophylaxis in patients after the Fontan operation.

Factors associated with readmission after long-term administration of tolvaptan in patients with congestive heart failure.

Introduction: We investigated the factors associated with readmission in patients with congestive heart failure (HF) receiving long-term administration of tolvaptan (TLV) to support treatment decisions for HF. Methods: This retrospective cohort study included 181 patients with congestive HF who received long-term administration of TLV. Long-term administration of TLV was defined as the administration of TLV for 60 days or longer. The outcome was a readmission event for worsening HF within 1 year after discharge. Significant factors associated with readmission were selected using multivariate analysis. To compare the time to readmission using significant factors extracted in a multivariate analysis, readmission curves were constructed using the Kaplan-Meier method and analysed using the log-rank test. Results: The median age was 78 years (range, 38-96 years), 117 patients (64.6%) were males, and 77 patients (42.5%) had a hospitalisation history of HF. Readmission for worsening HF within 1 year after long-term TLV treatment occurred in 62 patients (34.3%). In the multivariate analysis, estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2 (odds ratio, 3.22; 95% confidence interval, 1.661-6.249; P = 0.001) was an independent significant factor. When eGFR at discharge was divided into two groups (eGFR < 30 vs. eGFR ≥ 30), readmission rates within 1 year were 53.3% vs. 25.4%, respectively (P = 0.001). Conclusion: We revealed that eGFR was strongly associated with readmission in patients with HF who received long-term administration of TLV. Furthermore, we showed that eGFR is an important indicator in guiding treatment of HF in patients receiving TLV.

Development of a model predicting cardiac events in heart failure patients with decreased renal function: a retrospective study.

BACKGROUND: Inappropriate and multiple medications affect the prognosis of patients with acute decompensated heart failure (ADHF). However, in ADHF patients with decreased renal function, there have been no reports on prognostic factors, including medication data, or models for predicting cardiac events. AIM: To develop a model including medication data to predict cardiac events in ADHF patients with decreased renal function. METHOD: This retrospective cohort study included 443 first-time admitted ADHF patients with decreased renal function (estimated glomerular filtration rate < 60 mL/min/1.73 m2 at discharge) in the Showa University Fujigaoka Hospital. The primary outcome was cardiac events within one year after discharge, defined as the composite of HF readmission, HF mortality, and cardiovascular mortality. The model for predicting cardiac events was developed using predictive factors extracted by multivariable analysis. The cardiac events curves were visualized using the Kaplan-Meier method and estimated using a log-rank test. RESULTS: The incidence of cardiac events within one year after discharge was 20.1%. By multivariable analysis, we observed that atrial fibrillation, weight loss < 5%, brain natriuretic peptide ≥ 200 pg/mL, polypharmacy, and beta-blockers use below target dosage were significantly associated with an increased risk of cardiac events. The developed model, the cardiac events rate in the high-risk group was significantly higher than in the low-risk group (41.0 vs. 9.2%, p < 0.001). CONCLUSION: The developed model for predicting cardiac events will be useful in decision-making to support appropriate early management of ADHF patients with decreased renal function.

Population Pharmacokinetic Model and Dosing Simulation of Meropenem Using Measured Creatinine Clearance for Patients with Sepsis.

PURPOSE: Creatinine clearance (CCr) and pharmacokinetic parameters are markedly affected by pathophysiological changes in patients with sepsis. However, only a few reports have assessed renal function in patients with sepsis using the measured CCr. Furthermore, the administration regimen has not been sufficiently evaluated using a population PK (PPK) model across renal function broad ranges. Therefore, this study was performed to construct a meropenem PPK model for patients with sepsis using the measured CCr and evaluate the optimized meropenem dosing regimen based on the CCr. METHODS: Patients with sepsis who received intravenous meropenem at the Showa University Hospital were enrolled in this prospective observational study. The PPK model was constructed using blood samples and clinical information of patients. The probability of target attainment (PTA) indicates the likelihood of achieving 50% time above the minimum inhibitory concentration (% T > MIC) based on 10,000 virtual patients using Monte Carlo simulations. The PTA for each meropenem regimen was 50% T > MIC based on different renal functions using the Monte Carlo simulation. RESULTS: One hundred samples were collected from 31 patients. The final PPK model incorporating the measured CCr as a covariate in CL displayed the best fit. The recommended dosing regimen to achieve a PTA of 50% T > MIC of 4 mcg/mL was 1 g every 8 hours as a 3-hour prolonged infusion for patients with CCr 85-130 mL/min and 1 g every 8 hours as an 8-hour continuous infusion for patients with CCr ≥ 130 mL/min. CONCLUSIONS: This model precisely predicted meropenem concentrations in patients with sepsis by accurately evaluating renal function using the measured CCr. Extended dosing was demonstrated to be necessary to achieve a PTA of 50% T > MIC for patients with CCr ≥ 85 mL/min. Meropenem effectiveness can be maximized in patients with sepsis by selecting the appropriate dosing regimen based on renal function and the MIC.

Predictive Factors of Febrile Neutropenia After Primary Prophylactic Pegfilgrastim With DCF Chemotherapy for Esophageal Cancer.

BACKGROUND/AIM: We investigated the predictive factors of febrile neutropenia (FN) after the administration of pegfilgrastim as primary prophylaxis in patients with esophageal cancer who received neoadjuvant chemotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF) to support the appropriate management of FN. We evaluated changes in neutrophil counts and relative dose intensity (RDI) after the incidence of FN. PATIENTS AND METHODS: This retrospective study involved 122 patients with esophageal cancer who were treated with DCF and pegfilgrastim at Showa University Hospital, Japan, between April 2016 and August 2021. The primary outcome was FN incidence after cycle 1 of DCF chemotherapy. The significant independent factors associated with FN incidence were selected using the multivariate analysis. Changes in neutrophil counts and RDI were compared between the FN and non-FN groups. RESULTS: One-hundred patients were included in the analysis. The incidence of FN in cycle 1 was 21%. In the multivariate analysis, geriatric nutritional risk index (GNRI) <92 [odds ratio (OR)=13.162, p<0.001] and combination of platelet and neutrophil-to-lymphocyte ratio (COP-NLR) score of 0 (OR=4.619, p=0.012) were independent predictors of FN. The neutrophil count on day 7-10 and RDI in the FN group were lower than those in the non-FN group (all p<0.05). CONCLUSION: GNRI <92 and COP-NLR score of 0 are important indicators to predict patients at high risk of DCF chemotherapy-induced FN. Furthermore, FN incidence after pegfilgrastim administration had a strong effect on delayed neutrophil recovery and reduced RDI.

Prognostic model for overall survival that includes the combination of platelet count and neutrophil-lymphocyte ratio within the first six weeks of sunitinib treatment for metastatic renal cell carcinoma.

BACKGROUND: The association between the combination of platelet count and neutrophil-lymphocyte ratio (COP-NLR) at the time of adverse events during sunitinib treatment and prognosis is unclear, and prognostic models combining the prognostic factors of sunitinib have not been well studied. Thus, we developed a prognostic model that includes the COP-NLR to predict the prognosis of patients with metastatic renal cell carcinoma (mRCC) treated with sunitinib. METHODS: We performed a retrospective cohort study of 102 patients treated with sunitinib for mRCC between 2008 and 2020 in three hospitals associated with Showa University, Japan. The primary outcome was overall survival (OS). The collected data included baseline patient characteristics, adverse events, laboratory values, and COP-NLR scores within the first 6 weeks of sunitinib treatment. Prognostic factors of OS were analyzed using the Cox proportional hazards model. The integer score was derived from the beta-coefficient (ß) of these factors and was divided into three groups. The survival curves were visualized using the Kaplan-Meier method and estimated using a log-rank test. RESULTS: The median OS was 32.3 months. Multivariable analysis showed that the number of metastatic sites, Memorial Sloan Kettering Cancer Center risk group, number of metastases, non-hypertension, modified Glasgow Prognostic Score, and 6-week COP-NLR were significantly associated with OS. A higher 6-week COP-NLR was significantly associated with a shorter OS (p < 0.001). The ß values of the five factors for OS were scored (non-hypertension, mGPS, and 6-week COP-NLR = 1 point; number of metastatic sites = 2 points; MSKCC risk group = 3 points) and patients divided into three groups (≤ 1, 2-3, and ≥ 4). The low-risk (≤ 1) group had significantly longer OS than the high-risk (≥ 4) group (median OS: 99.0 vs. 6.2 months, p < 0.001). CONCLUSIONS: This study showed that the COP-NLR within the first 6 weeks of sunitinib treatment had a greater impact on OS than the COP-NLR at the start of sunitinib treatment. The developed prognostic model for OS, including the 6-week COP-NLR, will be useful in decision-making to continue sunitinib in the early treatment stage of patients with mRCC.

Predictors of Opioid Resistance: An Investigation in Cancer Pain.

Appropriate use of opioid analgesics according to the World Health Organization pain relief ladder has provided pain relief to many patients with cancer pain. However, a proportion of patients fail to achieve sufficient pain relief and develop opioid resistance. Individual risk factors may relate to opioid resistance. Therefore, we conducted a historical cohort study to identify risk factors for opioid resistance and to construct an index to predict it. We investigated salient factors at the time of opioid initiation in the medical records of 233 patients. The outcome was the achievement of stable pain at 14 days after opioid introduction. We identified factors contributing to opioid resistance by multivariate analysis (p < 0.05). We created a resistance score from the regression equation of the identified factors to predict opioid resistance. Forty-nine (21.0%) patients were opioid resistant without achieving the outcome. Age, neuropathic pain, and alkaline phosphatase were extracted as significant factors for opioid resistance (p < 0.05). A resistance score was created from these factors and classified into binary values, the sensitivity was 80.6% and the negative predictive value was 91.6%. The findings suggest that the resistance score could be a sensitive predictor of opioid resistance before opioid initiation.

Identification of factors associated with the efficacy of atomoxetine in adult attention-deficit/hyperactivity disorder.

AIM: Atomoxetine (ATX) is a non-central stimulant and a standard treatment for adult attention-deficit/hyperactivity disorder (ADHD). The long-term efficacy of Atomoxetine is about 40% at 6 months. The variability in efficacy between individuals is thought to be related to patient-specific factors, but no detailed research has been conducted. In this retrospective cohort study, we aimed to identify the factors associated with Atomoxetine efficacy. METHODS: A total of 147 patients with attention-deficit/hyperactivity disorder aged ≥18 years who were using Atomoxetine for the first time were included in this study. The outcome was treatment success (treatment maintained for at least 6 months and improvement in symptoms). Symptom assessment was based on the overall improvement in symptoms judged by an expert physician. RESULTS: Of the patient sample, 103 (70.1%) achieved the outcome. Logistic regression analysis identified "the maximum dose of ATX" and "gambling habit" as factors associated with efficacy ( P  < 0.05). In the process of Atomoxetine titration, the larger the maximum dose, the higher the efficacy was shown to be. Gambling habits may be indicative of impulsivity, which is among the core symptoms of attention-deficit/hyperactivity disorder. Thus, a gambling habit may be considered a surrogate marker for impulsivity. CONCLUSIONS: Knowledge of these factors will help healthcare professionals to predict the likely efficacy of Atomoxetine in a given patient before subscribing it, facilitating individualized pharmacotherapy for adult attention-deficit/hyperactivity disorder.

Factors associated with a reduction in the quality of life of patients with chronic hepatitis C treated by ledipasvir/sofosbuvir therapy.

OBJECTIVE: We investigated factors associated with a reduction in the quality of life and their OR of patients with chronic hepatitis C who underwent ledipasvir/sofosbuvir therapy. METHODS: The subjects were 141 outpatients who had undergone ledipasvir/sofosbuvir therapy under a diagnosis of genotype I chronic hepatitis C or Child-Pugh A compensated cirrhosis at Hitachi General Hospital. The patient background before ledipasvir/sofosbuvir therapy, laboratory data and the Chronic Liver Disease Questionnaire scores during ledipasvir/sofosbuvir therapy were investigated. The Chronic Liver Disease Questionnaire consists of 29 questions, and the mean value is calculated as the overall score through a 7-step assessment by patients. Using two divisions: a Chronic Liver Disease Questionnaire score of <7 (symptoms are present) and that of 7 (no symptoms), as objective variables, patients with a Chronic Liver Disease Questionnaire score of <7 were defined as having a reduced quality of life. Independent factors significantly associated with a reduction in the quality of life were extracted using logistic regression analysis. RESULTS: Based on the multivariate analysis, an alanine aminotransferase level of ≥23 U/L (OR: 4.380, 95% CI: 1.394 to 13.756) was extracted as an independent factor associated with a reduction in the quality of life (p<0.05). CONCLUSION: An increase in the baseline level of alanine aminotransferase was found to play a role in the reduction in the quality of life of patients with chronic hepatitis C who had undergone ledipasvir/sofosbuvir therapy.

Scoring Model to Predict a Low Disease Activity in Elderly Rheumatoid Arthritis Patients Initially Treated with Biological Disease-modifying Antirheumatic Drugs.

Objective We aimed to develop a scoring model to predict a low disease activity (LDA) in elderly rheumatoid arthritis (RA) patients initially treated with biological disease-modifying antirheumatic drugs (bDMARDs). Methods This retrospective cohort study included 82 elderly RA patients who initially received bDMARDs. The outcome was an LDA after bDMARDs initiation. We developed a predictive formula for an LDA using a multivariate analysis, the accuracy of which was assessed by the area under the curve (AUC) of the receiver operating characteristic curves; the scoring model was developed using the formula. For each factor, approximate odds ratios were scored as an integer, divided into three groups based on the distribution of these scores. In addition, the scoring model accuracy was assessed. Results The mean age was 73.5±6.0 years old, and 86.6% were women. An LDA was achieved in 43 patients (52.4%). The predictive formula for an LDA was prepared using six factors selected for the multivariable analysis: the neutrophil-to-lymphocyte ratio (NLR), anemia, the 28-joint disease activity score with erythrocyte sedimentation rate (DAS28-ESR), serum level of matrix metalloproteinase-3 (MMP-3), diabetes mellitus (DM), and rheumatoid factor (RF). The AUC for the formula was 0.829 (95% confidence interval, 0.729-0.930). The odds ratios of the six factors were scored (DAS28-ESR and serum MMP-3=1 point, NLR, anemia, DM, and RF=2 points) and divided into three groups (≤4, 5-7, and ≥8). The high-score group (≥8) achieved a positive predictive value of 83%. Conclusion The scoring model accurately predicted an LDA in elderly RA patients initially treated with bDMARDs.

Factors predicting addition of disease-modifying antirheumatic drugs after initial methotrexate monotherapy in patients with rheumatoid arthritis.

INTRODUCTION: We investigated factors predicting the addition of disease-modifying antirheumatic drugs (DMARDs) after an initial methotrexate (MTX) monotherapy in rheumatoid arthritis (RA) patients to support an early decision on the DMARDs addition. METHODS: This retrospective cohort study included 311 patients who were diagnosed with RA and started on MTX monotherapy at Showa University Hospital, Japan. The outcome was addition of DMARDs after an initial MTX monotherapy at 6 months. Baseline patient characteristics were compared between the DMARDs addition and MTX monotherapy continuation groups, and significant independent predictive factors for the addition of DMARDs were selected using multivariate analysis. RESULTS: The median age of patients was 62 years (range 24-90), 170 patients (73%) were women, the median swollen 28-joint count (SJC28) was 3 (0-28), and the median tender 28-joint count (TJC28) was 5 (0-28). DMARDs were added in 65 (27.9%) patients. In the univariate analysis, higher TJC28 and SJC28, concomitant use of nonsteroidal anti-inflammatory drugs, and intra-articular glucocorticoid (GC) injection history were significantly associated with the DMARDs addition. In the multivariate analysis, by adding covariates to the variables identified in the univariate analysis, SJC28 (odds ratio [OR] 1.390 per 5 joints increase; 95% confidence interval [CI], 1.036-1.866) and intra-articular GC injection history (OR 3.678; 95% CI, 1.170-11.557) were independent predictors of DMARDs addition. CONCLUSION: A higher SJC28 and intra-articular GC injection history may be useful predictors of DMARDs addition after the initial MTX monotherapy. We expect that using these predictors will enable an earlier shift to a more aggressive treatment. Key Points ・We performed a retrospective cohort study with the addition of DMARDs as the outcome in patients with RA who were started on MTX monotherapy. ・A higher SJC28 (OR 1.390; 95% CI, 1.036-1.866) and an intra-articular GC injection history (OR 3.678; 95% CI, 1.170-11.557) may be useful predictors for the addition of DMARDs of initiating MTX monotherapy at 6 months. ・The use of such indicators may support an early decision on the addition of DMARDs after the initial MTX monotherapy.

Predictive Factors of Opioid-Induced Nausea in Cancer Patients.

Approximately 30% of patients experience nausea after initiation of opioid therapy, which can lead to poor quality of life. We aimed to identify risk factors for opioid-induced nausea at the initiation of opioid therapy by conducting a retrospective review of medical records of patients diagnosed by palliative care specialists with solid cancer and pain at the lesion site at Showa University Hospital between June 2005 and June 2011. The primary endpoint was the development of nausea grade ≥1 according to the Common Terminology Criteria for Adverse Events version 4.0 within 48 hours of initiation of opioid therapy. The median age of the 134 enrolled patients was 67.7 (range 28-95) years. Fifty-three percent were male and 44% had gastrointestinal cancer. Furthermore, 22.4% had opioid-induced nausea. Age (odds ratio (OR) 1.74; 95% confidence interval (CI), 1.13-2.69), edema (OR 5.83; 95% CI, 1.22-28.19), and gastrointestinal cancer (OR 2.61, 95% CI 1.07-6.36) were significantly associated with opioid-induced nausea. Prophylactic antiemetics were found to be ineffective.

[Rubric Assessment for Pharmacotherapy in Spiral Curriculum: Development and Usefulness Evaluation].

A requirement, which students must satisfy, for a diploma at the Showa University School of Pharmacy is the ability to "plan, practice, and assess pharmacotherapy". To continuously assess the ability of students to meet this requirement and to provide patients with proper pharmacotherapy during student clinical rotations, we formulated the "Rubric assessment for pharmacotherapy" and evaluated its usefulness in tutorial learning classes. Clinical pharmacy faculty members created the rubric based on the Subjective, Objective, Assessment, and Plan (SOAP) note guidelines of the university. Third- (2016) and fourth-year students (2017) were required to self-assess their SOAP notes to analyze six clinical cases using the rubric. The rubric consists of three domains: (1) Evaluation of patient condition, (2) Proposal of pharmacotherapy, and (3) Plan for an assessment of pharmacotherapy. The rubric comprises 31 subdomains and is evaluated according to four levels of performance. In this study, 978 rubric sheets that were used by students to evaluate their own SOAP notes were analyzed. We found that the students were able to continuously self-assess their performance using the rubric while continuously improving their achievement level (p<0.05). The results of this study suggest that rubric assessments may be used as a tool for supporting students to plan, practice, and assess pharmacotherapy.

[QOL Assessment in Chronic Hepatitis C Patients Receiving Ledipasvir/ Sofosbuvir or Simeprevir/Peginterferon/Ribavirin in Clinical Practice].

Recently, a clinical study using a Chronic Liver Disease Questionnaire (CLDQ) showed that ledipasvir/sofosbuvir (LDV/SOF)-treated patients' QOL was more favorable than that of IFN/ribavirin (RBV)-treated patients. However, no study has reported QOL assessment in clinical practice. In this study, we compared the QOL between patients treated with LDV/SOF and those treated with simeprevir (SMV)/peginterferon (Peg-IFN)/RBV to provide QOL information in clinical practice. The subjects were 169 patients with type I chronic hepatitis C or compensated cirrhosis C (Child-Pugh Grade A) who were treated with SMV/Peg-IFN/RBV or LDV/SOF in Hitachi General Hospital. The QOL was assessed ≥2 weeks after the start of administration using the Japanese version of the CLDQ (Kida et al., 2008 version). The total CLDQ score in the LDV/SOF group was significantly higher than in the SMV/Peg-IFN/RBV group (6.59 vs. 6.38, respectively, p=0.007). In particular, the scores for 4 domains (abdominal symptoms, systemic symptoms, activity, and emotional function) in the former were significantly higher than in the latter (p<0.05). Furthermore, the rates of patients scoring 7 (no symptom) on 8 items in the former were significantly higher than in the latter (p<0.05). In clinical practice, LDV/SOF-treated patients' QOL was more favorable than that of those receiving conventional treatment with IFN and RBV. This study may make it possible for health care professionals to provide clinical QOL information on LDV/SOF therapy to patients. Furthermore, QOL information may promote decision-making for treatment, leading to effective treatment.

[Analysis of the Risk Factors Associated with Minor Bleeding in Patients with Venous Thromboembolism during Treatment with Direct Oral Anticoagulants].

Direct oral anticoagulants (DOACs) are safe and efficacious when compared to warfarin for patients with venous thromboembolism (VTE). However, bleeding is a major side effect of anticoagulant therapy in VTE patients. Discontinuation of the DOACs associated to adverse events such as bleeding. The HAS-BLED score predicts warfarin-associated hemorrhage. However, little is known about risk factors for DOAC-associated minor bleeding in VTE patients. We aimed to identify risk factors for minor bleeding in VTE patients that were treated with edoxaban, rivaroxaban, or apixaban. We retrospectively evaluated the data of 212 VTE patients who received treatment with a DOAC. The study endpoint was defined as the occurrence of minor bleeding. Logistic regression analysis was used to determine risk factors that were significantly associated with minor bleeding. A total of 36 (17.0%) patients experienced minor bleeding, with rates of 15.7%, 0%, and 21.3% for edoxaban, rivaroxaban, and apixaban, respectively. In the multivariate analysis, bleeding history or predisposition [odds ratio (OR) 6.083, 95% confidence interval (CI) 2.131-17.364, p=0.001] and cancer (OR 6.397, 95% CI 2.858-14.317, p<0.001) were significantly associated with minor bleeding. Bleeding history or predisposition and cancer were the most important risk factors for DOAC-induced minor bleeding in VTE patients in this study. To continue anticoagulant therapy of the DOACs, further management systems by minor bleeding risk factors for patients with VTE will be required.

[A Cost-effectiveness Analysis of Sunitinib vs. Interferon-alpha in Patient with Advanced Renal Cell Carcinoma in Japan].

Sunitinib has been shown to offer clinical benefits during the treatment of advanced renal cell carcinoma. However, molecular targeting drugs are expensive and can have a significant impact on medical expenses. The purpose of this study was to assess the cost-effectiveness of sunitinib as a first-line therapy compared with interferon-alpha (IFN-α) in metastatic renal cell carcinoma patients. A Markov model was used to show the clinical courses of patients with metastatic renal cell carcinoma who received sunitinib or IFN-α. The transition probabilities and utilities employed in this Markov model were derived from two sources. This study focused on the perspective of public healthcare payer, as only direct medical costs were estimated from the treatment schedule for metastatic renal cell cancer. In the cost-effectiveness analysis, outcomes were valued in terms of life years (LYs) and quality-adjusted life years (QALYs). We calculated the incremental cost-effectiveness ratio (ICER) during the cost-effectiveness analysis. The results were tested using Monte Carlo simulations. Sunitinib and IFN-α treatment resulted in LYs of 2.40 years and 2.03 years, QALYs of 1.58 and 1.25, and expected costs of 13,572,629 yen and 6,083,002 yen, respectively. As a result, the ICER associated with replacing IFN-α with sunitinib was 22,695,839 yen/QALYs. Our results suggest that compared with IFN-α, sunitinib prolongs LYs and QALYs, but the increases in quality achieved by sunitinib are more expensive than those produced by IFN-α.

The exploration of population pharmacokinetic model for meropenem in augmented renal clearance and investigation of optimum setting of dose.

In recent years, augmented renal clearance (ARC), in which renal function is excessively enhanced, has been reported, and its influence on ß-lactam antibiotics has been investigated. In this study, we aimed to determine the optimum population pharmacokinetic model of meropenem in patients with sepsis with ARC, and evaluated dosing regimens based on renal function. Seventeen subjects (6 with ARC and 11 without) were enrolled in this study. Predicted meropenem concentrations were evaluated for bias and precision using the Bland-Altman method. To examine the dosing regimen, Monte Carlo simulation was performed to calculate the cumulative fraction of response (CFR). In patients with ARC, the bias (average of the predicted value and measured value residuals) of models constructed by Crandon et al. (2011), Roberts et al. (2009), and Jaruratanasirikul et al. (2015) were 5.96 µg/mL, 10.91 µg/mL, and 4.41 µg/mL, respectively. Following 2 g meropenem every 8 h (180 min infusion), CFR ≥ 90%, a criterion of success for empirical therapy, was achieved, even with creatinine clearance of 130-250 mL/min. For patients with sepsis and ARC, the model of Jaruratanasirikul et al. showed the highest degree of accuracy and precision and confirmed the efficacy of the meropenem dosing regimen in this patient population.

Effects of riluzole on spinal seizure-like activity in the brainstem-spinal cord preparation of newborn rat.

Riluzole blocks persistent Na+ current, inhibits generation of neuronal bursts and decreases glutamate-induced excitotoxicity. In previous studies of respiratory activity, riluzole suppressed inspiratory-related burst generation activity in rat slice or en bloc preparations. We examined riluzole's effects on inspiratory burst generation and drug-induced seizure-like activity in newborn rat en bloc preparations. Medulla-spinal cord preparations from postnatal day 0-3 Wistar rats were isolated under deep isoflurane anesthesia and were superfused with artificial cerebrospinal fluid equilibrated with 95% O2 and 5% CO2, pH 7.4, at 25-26°C. Inspiratory activity was monitored from the fourth cervical ventral root. Seizure-like activity was induced by application of 20µM DL-threo-ß-benzyloxyasparatate (TBOA, a glutamate uptake blocker preferentially acting on astrocytes) or coadministration of GABAA antagonist bicuculline (10µM) and glycine antagonist strychnine (10µM). Pretreatment and co-application with 10µM riluzole abolished the seizure-like burst activity induced by TBOA or bicuculline/strychnine. N-methyl-d-aspartic acid receptor antagonist MK801 (10µM) also depressed this activity. Riluzole may attenuate excessive glutamate action involved in pathological hyperexcitability of motor neurons with no major effect on generation of respiratory activity. Riluzole at the optimal dose could be a potential treatment to protect drug-induced epileptic brain tissue from excitotoxic damage without inducing respiratory suppression.