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Although dietary potassium restriction is an acceptable approach to hyperkalemia prevention, it may be insufficient for outpatients with chronic kidney disease (CKD). Most outpatients with CKD use community pharmacies owing to the free access scheme in Japan. The MieYaku-CKD project included a community pharmacist-led nutritional intervention for dietary potassium restriction, with the goal of determining its efficacy for patients' awareness of potassium restriction and serum potassium levels in outpatients with CKD. This was a five-community pharmacy multicenter prospective cohort study with an open-label, before-and-after comparison design. Eligible patients (n = 25) with an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 received nutritional guidance from community pharmacists. The primary outcome was a change in serum potassium levels at 12 weeks post-intervention. The eligible patients' knowledge, awareness, and implementation of potassium restriction were evaluated using a questionnaire. The median value of serum potassium was significantly reduced from 4.7 mEq/L before to 4.4 mEq/L after the intervention [p < 0.001, 95% confidence interval (CI): 0.156–0.500], with no changes in eGFR (p = 0.563, 95% CI: -2.427–2.555) and blood urine nitrogen/serum creatinine ratio (p = 0.904, 95% CI: -1.793–1.214). The value of serum potassium had a tendency of attenuation from 5.3 to 4.6 mEq/L (p = 0.046, 95% CI: 0.272–1.114) in the eGFR < 30 mL/min/1.73 m2 group. A questionnaire revealed that after the intervention, knowledge and attitudes regarding dietary potassium restriction were much greater than before, suggesting that the decrease in serum potassium levels may be related to this nutritional guidance. Our findings indicate that implementing a dietary potassium restriction guidance program in community pharmacies is feasible and may result in lower serum potassium levels in outpatients with CKD. [ABSTRACT FROM AUTHOR]

Postoperative delirium (PD) is an acute brain dysfunction, with a particularly high incidence after cardiovascular surgery. Pharmacist-led interventions show limited evidence in attenuating PD in cardiovascular surgery. In this retrospective cohort study, we aimed to clarify the risk factors of PD for cardiovascular surgery focused on pharmacotherapy and elucidate the effect of pharmacist-led intervention on the PD attenuation rate based on protocol-based pharmaceutical management (PBPM). This study included 142 adult patients who underwent elective valve replacement or valvuloplasty. The risk factors for PD were investigated using multivariate logistic regression analysis. Taking risk factors into consideration, a protocol was developed to discontinue benzodiazepines prescriptions by ward pharmacists, and replace with ramelteon and suvorexant if all the following factors apply: 1) number of medications ≥ 6 drugs, 2) number of doses to take ≥ 4 times, and 3) regular use of benzodiazepines or insomnia. Subsequently, the PD rate was compared during a period of two years and 6 months between the pre-PBPM (n = 39) and post-PBPM (n = 62). The PD rate for elective valve replacement or valvuloplasty was 25% (35/142). The adjusted odds ratio for polypharmacy was 3.3 (95% confidence interval: 1.2–8.9, p = 0.016), suggesting that preoperative risk assessment may be essential for patients with polypharmacy. The PD rate significantly decreased to 13% (8/62) in the post-PBPM group compared with 33% (13/39) in the pre-PBPM group (p = 0.014). There was a significant decrease in benzodiazepines use in post-PBPM compared with pre-PBPM (p = 0.026); however, the rate of ramelteon and orexin receptor antagonists use increased by PBPM introduction (p < 0.001). Although the present PBPM still requires further modification, it is simple and potentially useful for pharmacists to assess the risk of patients undergoing any elective cardiovascular surgery. [ABSTRACT FROM AUTHOR]

Serum magnesium (Mg) monitoring in patients with heart failure (HF) receiving magnesium oxide (MgO) is not adequately performed. Furthermore, the relationship between left ventricular function (LVF) and hypermagnesemia in HF is unknown. Here, we investigated the efficacy of serum Mg monitoring by protocol‐based pharmaceutical management (PBPM) and the effect of LVF on hypermagnesemia. This protocol is for patients with an estimated glomerular filtration rate of <45 mL/min, receiving MgO, and admitted to the cardiology unit. The pharmacist includes the measurement of Mg when a blood test is ordered for a patient by their physician. Rates of serum Mg measurement and hypermagnesemia detection were compared at 2 years pre‐PBPM (n = 88) and at 2 years post‐PBPM (n = 55). LVF parameters and reported factors for hypermagnesemia were selected as explanatory factors on multivariate logistic regression. The measurement rate of serum Mg concentration significantly increased from 19.3% pre‐PBPM to 80.0% post‐PBPM (P <.001). The detection rate of hypermagnesemia also increased from 3.4% to 27.3%, respectively (P <.001). Our results suggest that serum Mg monitoring by PBPM may contribute to the early detection of hypermagnesemia and prevent its progression in HF. According to logistic regression, the adjusted odds ratio for hypermagnesemia with an exacerbation of HF was 9.57 (95% confidence interval: 1.594–57.477, P =.014), and the E/e' > 15, an index of reduced left ventricular diastolic capacity, was 6.46 (95% confidence interval: 1.291–32.364, P =.023). We propose that serum Mg monitoring should be performed during exacerbations of HF in patients with left ventricular diastolic dysfunction, with a pharmacist's assistance. [ABSTRACT FROM AUTHOR]

Valproic acid (VPA) is well‐known as a histone deacetylase (HDAC) inhibitor. It has been reported that HDAC inhibitors enhance basal and aryl hydrocarbon receptor (AhR) ligand‐induced aryl hydrocarbon receptor‐responsive gene expression. Other studies suggested that HDAC inhibition might significantly activate the NF‐E2‐related factor‐2 (Nrf2). Moreover, VPA activates mitogen‐activated protein kinases (MAPKs). MAPK pathways regulate Nrf2 transactivation domain activity. Uridine 5′‐diphospho‐glucuronosyltransferase (UGT) 1A6 is one of the important isoforms to affect drug pharmacokinetics. UGT1A6 gene is regulated transcriptionally by AhR and Nrf2. The present study aimed to investigate whether UGT1A6 expression was changed by VPA and to elucidate the mechanism of the alteration. Following VPA treatment for 72 h in Caco‐2 cells, UGT1A6 mRNA was increased by 7.9‐fold. Moreover, UGT1A6 mRNA was increased by other HDAC inhibitors, suggesting that HDAC inhibition caused the UGT1A6 mRNA induction. AhR and Nrf2 proteins in the nucleus of Caco‐2 cells were increased by 1.5‐ and 1.7‐fold, respectively, following the VPA treatment. However, VPA treatment did not activate the extracellular signal‐regulated kinase (ERK) and c‐Jun N‐terminal kinase (JNK) pathways in Caco‐2 cells. In conclusion, we observed that VPA induced UGT1A6 mRNA expression via AhR and Nrf2 pathways, but not via the ERK or JNK pathways. [ABSTRACT FROM AUTHOR]

Drug-induced thrombocytopenia (DITP) can be triggered by antibiotics; however, the details remain unclear. Here, we evaluated the expression profiles of DITP using the Japanese Adverse Drug Event Report (JADER) database. We analyzed reports of DITP between April 2004 and January 2021 from the JADER database. The reporting odds ratio (ROR) and 95% confidence interval (CI) were used to detect DITP signals. Factors thought to affect DITP, such as male sex and an age of at least 60 years, were added as covariates. We evaluated the time-to-onset profile and hazard type using the Weibull shape parameter. The JADER database contained 1,048,576 reports. Twelve of 60 antibiotics showed signals for DITP; the RORs (95% CIs) for ampicillin/sulbactam, ceftazidime, cefozopran, ciprofloxacin, fluconazole, fos-fluconazole, linezolid, pazufloxacin, piperacillin/tazobactam, teicoplanin, trimethoprim/sulfamethoxazole, and voriconazole were 1.75 (1.41-2.16), 1.77 (1.42-2.18), 1.35 (1.06-1.72), 2.56 (2.19-2.98), 1.93 (1.67-2.23), 2.08 (1.76-2.46), 5.29 (2.73-9.60), 1.92 (1.51-2.41), 1.54 (1.05-2.19), 1.47 (1.16-1.84), 1.92 (1.73-2.14), and 2.32 (1.59-3.30), respectively. In multiple logistic regression analysis, 7 and 6 antibiotics were detected for the factors age and male sex, respectively. The median times-to-onset of DITP for ciprofloxacin (oral treatment), fluconazole, linezolid, piperacillin/tazobactam, and trimethoprim/sulfamethoxazole were 91, 91, 11.5, 10, and 9 days, respectively. Furthermore, the 95% CI of the Weibull shape parameter β for these antibiotics was above and excluded 1, indicating that the antibiotics were the wear out failure type. We revealed the expression profiles of DITP following treatment with 12 antibiotics. [ABSTRACT FROM AUTHOR]

Background: Hydroxychloroquine (HCQ) has been positioned as an anchor drug for systemic lupus erythematosus (SLE). There is evidence supporting the benefits of HCQ; however, the effect of additional HCQ in maintenance therapy remains unclear. Methods: Thirty patients with SLE who visited Juntendo University Hospital were receiving maintenance therapy before HCQ treatment and were able to complete more than 104 weeks of HCQ treatment were analyzed. Anti-DNA antibody titers, IgG and CH50 levels, the maintenance dose of corticosteroids, the SLE disease activity index (SLEDAI), and the achievement of the Lupus Low Disease Activity State (LLDAS) were evaluated at baseline and at 12, 24, 52, and 104 weeks after HCQ initiation. Results: We observed improvements in the anti-DNA antibody titers, IgG and CH50 levels, maintenance dose of corticosteroids, and SLEDAI at week 104 relative to baseline. Moreover, the LLDAS achievement rate increased over time from 10% at baseline to 43% and 80% at week 52 and week 104, respectively. Conclusion: Two years of continuous HCQ treatment led to improvements in SLE disease activity and corticosteroid dose and an increase in LLDAS achievement, thereby demonstrating the significance of the maintenance dose of HCQ for the management of SLE. [ABSTRACT FROM AUTHOR]

In metal-based single-electron devices (SEDs), charge-offset drift has been observed, which is a time-dependent instability caused by charge noise. This instability is an issue in the application of new information processing devices, such as neural network devices, quantum computing devices (charge sensing), and reservoir computing devices. Therefore, the charge-offset drift in metal-based SEDs needs to be suppressed. However, the charge-offset stability of metal-based SEDs has not been investigated in depth, except in the case of Al and Al2O3 SEDs. In this work, Fe-based SEDs formed by single-layer Fe nanodot arrays embedded in MgF2 were studied with regard to their charge-offset stability. Using devices that produce simple current oscillations, the charge-offset drift (ΔQ0) of Fe-based SEDs was evaluated by focusing on peak shifts of the simple current oscillation over time, despite the use of a multi-dot system. This drift (ΔQ0 ≈ 0.3e) was shown to be much lower than in SEDs with Al-dots and Al2O3 tunnel junctions. Notably, the charge-offset drift in the metal-based SEDs was suppressed using the Fe–MgF2 system. The excellent stability of these devices was attributed to the material properties of the Fe–MgF2 system. Finally, as the Fe nanodot array contained numerous dots, the effect of satellite dots acting as traps on the charge-offset instability was discussed. The findings of this study will be important in future applications of metal-based SEDs in new information processing devices. [ABSTRACT FROM AUTHOR]

The tunnel magnetocapacitance (TMC) effect in two-dimensional single nanogranular layered Fe / MgF 2 films is investigated both experimentally and theoretically. We measured the frequency dependence of TMC ratios in a frequency range of 20 Hz–1 MHz and discovered that TMC ratios strongly depend on the frequency, reaching a peak value at a specific frequency. We observe that the largest TMC ratios occur at lower frequencies and that TMC values steadily reduce with increasing frequency. Notably, we achieved a maximum TMC ratio of 1.45%, which is the largest low-field TMC ever reported for granular films. A combination of the Debye–Fröhlich (DF) model and the Julliere formula is used to fit the experimental data to theory, and an excellent agreement between the calculated values and the experimental data is obtained. To perfectly fit the experimental data, the conventional DF model is extended to a composite model in which three capacitors (with three different relaxation times) are introduced. Our findings will give further insights into the exact mechanism of the TMC effect in nanogranular films and will open broader opportunities for device applications, such as magnetic sensors and impedance tunable devices. [ABSTRACT FROM AUTHOR]

Sulfotransferase (SULT) has been found in the brain; however, the details of its function remain unclear. The present study aimed to elucidate the regional differences in the expression of SULT1 and SULT2 mRNA and SULT activities in the eight functional regions of the rat brain (cerebellum, cortex, hippocampus, medulla oblongata, midbrain, olfactory bulb, striatum, and thalamus). All SULT1 isoforms were detected in the medulla oblongata and thalamus. SULT2A1 mRNA was not observed in any of the eight regions, whereas SULT2B1a and SULT2B1b were found in all regions. The SULT2B1b mRNA expression level in the medulla oblongata was 1.7-fold higher than that in the liver. The sulfonation of p-nitrophenol and pregnenolone was detected in all regions. The kinetics of p-nitrophenol sulfonation in the cerebellum fitted to the substrate inhibition model (Km = 37.6 nM, Vmax = 2.72 pmol/min/mg, Vinh = 1.60 pmol/min/mg, and Ki = 0.87 μM). The pregnenolone sulfonation also exhibited substrate inhibition kinetics (Km = 0.99 μM, Vmax = 1.53 pmol/min/mg, and Ki = 54.67 μM). We clarified that SULT1 and SULT2 were expressed and had metabolizing capacities in the rat brain, suggesting that brain SULTs may be involved in metabolism of endogenous compounds and drugs. [ABSTRACT FROM AUTHOR]

Abstract: Single‐walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH‐P‐ and SO‐SWCNTs) on human CYP activity. In addition, other nano‐sized carbon materials, such as carbon black, fullerene‐C60, and fullerene‐C70 were also evaluated to compare their effects on CYP activities. Ten CYP substrates (phenacetin, coumarin, bupropion, paclitaxel, tolbutamide, S‐mephenytoin, dextromethorphan, chlorzoxazone, midazolam, and testosterone) were used. Testosterone 6β‐hydroxylation and midazolam 1′‐hydroxylation, which are catalysed by both CYP3A4 and CYP3A5 in liver microsomes, were decreased by 25% and 45%, respectively, in the presence of 0.1 mg/ml SO‐SWCNT. Dextromethorphan O‐demethylation, which is catalysed mainly by CYP2D6, was decreased by 40% in the presence of SO‐SWCNT. Other CYP activities, however, were not attenuated by SO‐SWCNT. FH‐P‐SWCNT, carbon black, fullerene‐C60, and fullerene‐C70 at 0.1 mg/ml had no effect on CYP activities. The Ki values for testosterone 6β‐hydroxylation, midazolam 1′‐hydroxylation, and dextromethorphan O‐demethylation in liver microsomes were 136, 34, and 56 μg/ml, respectively. SO‐SWCNT was determined to be a competitive inhibitor of CYP3A4, CYP3A5, and CYP2D6. These results suggest that the effect of SO‐SWCNT differs among CYP isoforms, and that the inhibition potency depends on the physicochemical properties of the nanocarbons. [ABSTRACT FROM AUTHOR]

UDP-glucuronosyltransferase (UGT) is an enzyme that catalyses a major phase II reaction in drug metabolism. Glucuronidation occurs mainly in the liver, but UGTs are also expressed in extrahepatic tissues, where they play an important role in local metabolism. UGT1A isoforms catalyse the glucuronidation of several drugs, neurotransmitters and neurosteroids that exert pharmacological and physiological effects on the brain. The aim of the current study was to determine UGT1A mRNA expression levels and glucuronidation activities in different regions of the rat brain (namely the cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, olfactory bulb, striatum and thalamus). It was found that all UGT1A isoforms were expressed in all the nine regions, but their expression levels differed between the regions. The difference between the regions of the brain where the mRNA levels were highest and those where they were lowest ranged between 2.1- to 7.8-fold. Glucuronidation activities were measured using the UGT substrates such as mycophenolic acid, p-nitrophenol and umbelliferone. Glucuronidation activity was detected in all nine regions of the brain. Activity levels differed between the regions, and were highest in the cerebellum, medulla oblongata and olfactory bulb. Differences in glucuronidation activity between regions with the highest rates and those with the lowest rates ranged from 5.3- to 10.1-fold. These results will contribute to our current understanding of the physiological and pharmacokinetic roles of drug-metabolizing enzymes in the brain. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: The 2-MeV electron radiation damage of silicon–carbon source/drain (S/D) n-type metal oxide semiconductor field effect transistors with different carbon (C) concentrations is studied. Before irradiation, an enhancement of the electron mobility with C concentration of the S/D stressors is clearly observed. On the other hand, after electron irradiation, both the threshold voltage shift and the maximum electron mobility degradation are independent on the C concentration for all electron fluences studied. These results indicate that the strain induced electron mobility enhancement due to the C doping is retained after irradiation in the studied devices. [Copyright &y& Elsevier]

Objective: High plasma levels of mono- N -desethylamiodarone (MDEA), an active amiodarone metabolite, may be associated with tissue toxicity in heart failure (patients with heart rhythm disturbances); therefore, a tool that can identify patients for whom therapeutic drug monitoring (TDM) of MDEA is required. This multicenter study aimed to develop a decision tree (DT) model that can identify patients with heart rhythm disturbances at high MDEA concentrations., Materials and Methods: A multicenter retrospective cohort study was conducted, including 157 adult patients with heart failure who received oral amiodarone treatment. A χ 2 automatic interaction-detection algorithm was used to construct a DT model. In the DT analysis, the dependent variable was set as an MDEA trough plasma concentration of ≥ 0.6 μg/mL during the steady-state period. Explanatory variables were selected as factors with p < 0.05 in multivariate logistic regression analysis., Results: The adjusted odds ratios for the daily dose of amiodarone and body mass index were 1.01 (95% coefficient interval: 1.008 - 1.021, p < 0.001) and 0.91 (95% confidence interval: 0.834 - 0.988, p = 0.025), respectively. For DT analysis, the risk of reaching plasma MDEA concentrations ≥ 0.6 μg/mL was relatively high, combined with a daily dose of amiodarone > 100 mg and body mass index ≤ 22.3 kg/m 2 at 69.0% (20/29), and its trend was also detected in the sensitivity analysis., Conclusion: Patients taking a daily amiodarone dose > 100 mg and with a body mass index ≤ 22.3 kg/m 2 warrant TDM implementation for MDEA to minimize the risk of MDEA-induced tissue toxicity.

Background: Piperacillin/tazobactam (PIPC/TAZ), which is a combination of a beta-lactam/beta-lactamase inhibitor, often causes liver enzyme abnormalities. The albumin-bilirubin (ALBI) score is a simple index that uses the serum albumin and total bilirubin levels for estimating hepatic functional reserve. Although patients with low hepatic reserve may be at high risk for drug-induced liver enzyme abnormalities, the relationship between PIPC/TAZ-induced abnormal liver enzymes levels and the ALBI score remains unknown., Objective: This study aimed to elucidate the relationship between PIPC/TAZ-induced abnormal liver enzyme levels and the ALBI score., Methods: This single-center retrospective case-control study included 335 patients. The primary outcome was PIPC/TAZ-induced abnormal liver enzyme levels. We performed COX regression analysis with male gender, age (≥75 years), alanine aminotransferase level (≥20 IU/L), and ALBI score (≥-2.00) as explanatory factors. To investigate the influence of the ALBI score on the development of abnormal liver enzyme levels, 1:1 propensity score matching between the ≤-2.00 and ≥-2.00 ALBI score groups was performed using the risk factors for drug-induced abnormal liver enzyme levels., Results: The incidence of abnormal liver enzyme levels was 14.0% (47/335). COX regression analysis revealed that an ALBI score ≥-2.00 was an independent risk factor for PIPC/TAZ-induced abnormal liver enzyme levels (adjusted hazard ratio: 3.08, 95% coefficient interval: 1.207-7.835, P = 0.019). After 1:1 propensity score matching, the Kaplan-Meier curve revealed that the cumulative risk for PIPC/TAZ-induced abnormal liver enzyme levels was significantly higher in the ALBI score ≥-2.00 group (n = 76) than in the <-2.00 group (n = 76) ( P = 0.033)., Conclusion and Relevance: An ALBI score ≥-2.00 may predict the development of PIPC/TAZ-induced abnormal liver enzyme levels. Therefore, frequent monitoring of liver enzymes should be conducted to minimize the risk of severe PIPC/TAZ-induced abnormal liver enzyme levels in patients with low hepatic functional reserve., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

A 43-year-old man developed headache, dizziness, abdominal pain, and vomiting. His blood pressure was 203/121 mmHg, heart rate 122 beats/min, body temperature 39.1°C, and respiratory rate 24/min. He had elevated levels of creatinine at 2.95 mg/dL and lipase at 1,364 U/L as well as an extremely low calcium level at 5.2 mg/dL. Hypertriglyceridemia and hyperglycemia were seen. Chest and abdominal computed tomography showed interstitial pneumonia, severe pancreatitis, and a right adrenal tumor. The patient also developed vertebral artery dissection and medullary infarction. After right adrenalectomy, the patient was diagnosed with pheochromocytoma multisystem crisis (PMC). Acute pancreatitis might augment numerous life-threatening manifestations of PMC.

Introduction: Immune-checkpoint inhibitors are effective in various advanced cancers. Type 1 diabetes mellitus induced by them (ICI-T1DM) is a serious complication requiring prompt insulin treatment, but the immunological mechanism behind it is unclear., Methods: We examined amino acid polymorphisms in human histocompatibility leukocyte antigen (HLA) molecules and investigated proinsulin epitope binding affinities to HLA molecules., Results and Discussion: Twelve patients with ICI-T1DM and 35 patients in a control group without ICI-T1DM were enrolled in the study. Allele and haplotype frequencies of HLA -DRB1*04:05, DQB1*04:01 , and most importantly DPB1*05:01 were significantly increased in patients with ICI-T1DM. In addition, novel amino acid polymorphisms in HLA-DR (4 polymorphisms), in DQ (12 polymorphisms), and in DP molecules (9 polymorphisms) were identified. These amino acid polymorphisms might be associated with the development of ICI-T1DM. Moreover, novel human proinsulin epitope clusters in insulin A and B chains were discovered in silico and in vitro peptide binding assays to HLA-DP5. In conclusion, significant amino acid polymorphisms in HLA-class II molecules, and conformational alterations in the peptide-binding groove of the HLA-DP molecules were considered likely to influence the immunogenicity of proinsulin epitopes in ICI-T1DM. These amino acid polymorphisms and HLA-DP5 may be predictive genetic factors for ICI-T1DM., Competing Interests: Author YO was employed by GenoDive Pharma Inc. Author HN was employed by Biospecimen Laboratories, Inc. Author SIw has received personal fees from Ono Pharmaceutical Co. Ltd., Bristol-Myers Squibb, Chugai Pharmaceutical Co., Ltd. and MSD K.K. outside of this study. Author HA received grants from Ono Pharmaceutical Co., Ltd., MSD K.K., and Chugai Pharmaceutical Co., Ltd., and personal fees from Ono Pharmaceutical Co., Ltd., Bristol– Myers Squibb and MSD K.K. outside of this study. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Inaba, Morita, Kosugi, Asai, Kaido, Ito, Hirobata, Inoue, Yamamoto, Jinnin, Kimura, Ota, Okudaira, Nakatani, Kobayashi, Iwama, Arima and Matsuoka.)

Digoxin toxicity (plasma digoxin concentration ≥0.9 ng/mL) is associated with worsening heart failure (HF). Decision tree (DT) analysis, a machine learning method, has a flowchart-like model where users can easily predict the risk of adverse drug reactions. The present study aimed to construct a flowchart using DT analysis that can be used by medical staff to predict digoxin toxicity. We conducted a multicenter retrospective study involving 333 adult patients with HF who received oral digoxin treatment. In this study, we employed a chi-squared automatic interaction detection algorithm to construct DT models. The dependent variable was set as the plasma digoxin concentration (≥ 0.9 ng/mL) in the trough during the steady state, and factors with p < 0.2 in the univariate analysis were set as the explanatory variables. Multivariate logistic regression analysis was conducted to validate the DT model. The accuracy and misclassification rates of the model were evaluated. In the DT analysis, patients with creatinine clearance <32 mL/min, daily digoxin dose ≥1.6 µg/kg, and left ventricular ejection fraction ≥50% showed a high incidence of digoxin toxicity (91.8%; 45/49). Multivariate logistic regression analysis revealed that creatinine clearance <32 mL/min and daily digoxin dose ≥1.6 µg/kg were independent risk factors. The accuracy and misclassification rates of the DT model were 88.2 and 46.2 ± 2.7%, respectively. Although the flowchart created in this study needs further validation, it is straightforward and potentially useful for medical staff in determining the initial dose of digoxin in patients with HF.

The albumin-bilirubin (ALBI) score is an index of hepatic functional reserve and is calculated from serum albumin and total bilirubin levels. However, the relationship between ceftriaxone (CTRX)-induced liver injury and ALBI score remains unknown. Therefore, we aimed to elucidate the risk of CTRX-induced liver injury based on the ALBI scores and CTRX dosage. This was a single-center, retrospective, case-control study of 490 patients and the primary outcome was CTRX-induced liver injury. We performed a COX regression analysis using age ≥75 years, male sex, alanine aminotransferase levels, ALBI score, and CTRX dosage regimen (4 ≥2 or 1 g/d) as explanatory factors. We also performed 1 : 1 propensity score matching between non-liver injury and liver injury groups. The incidence of liver injury was 10.0% (49/490). In COX regression analysis, CTRX 4 g/d was an independent risk factor for liver injury (95% coefficient interval: 1.05-6.96, p = 0.04). Meanwhile, ALBI score ≥-1.61 was an independent factor for liver injury (95% coefficient interval: 1.03-3.22, p = 0.04) with the explanatory factor of ≥2 and 1 g/d. The Kaplan-Meier curve indicated that the cumulative risk for CTRX-induced liver injury was significantly higher in the ALBI score ≥-1.61 group than in the ALBI score <-1.61 group before propensity score matching (p = 0.032); however, no significant differences were observed after propensity score matching (p = 0.791). These findings suggest that in patients treated with CTRX with ALBI score ≥-1.61, frequent liver function monitoring should be considered.

Single-walled carbon nanotubes (SWCNTs) are made from rolled single graphene sheets with a diameter in the nanometer range and are potential carriers for drug delivery systems. However, their effects on uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A activities remain unclear. The present study aimed to investigate the effect of two kinds of SWCNTs (EC1.5-P- and FH-P-SWCNTs) and other nanocarbons on human UGT1A activity due to the proposed application of SWCNTs in drug and gene delivery. β-Estradiol 3-glucuronidation, which is catalyzed mainly by UGT1A1, was inhibited by 99 and 76% in the presence of 0.1 mg/mL EC1.5-P- and FH-P-SWCNTs in human liver microsomes, respectively. The observed decrease of free UGT1A1 protein in the enzyme reaction mixture suggests a higher interaction with SWCNTs, and indicates the inhibition of β-estradiol 3-glucuronidation. Imipramine N-glucuronidation, which is formed mainly by UGT1A4, was also decreased by SWCNTs. Serotonin glucuronidation, which is mainly responsible for UGT1A6, was only influenced by specific nanocarbons in human liver microsomes. The attenuation of free UGT1A6 protein was observed with SWCNTs and carbon black, indicating that UGT1A6 activity was not influenced by the direct interaction of SWCNTs. We also observed a 127% increase by FH-P-SWCNTs for propofol glucuronidation in human liver microsomes, which is catalyzed mainly by UGT1A9. The values of maximum velocity and intrinsic clearance for propofol glucuronidation in the presence of FH-P-SWCNT were 1.8- and 2.0-fold higher than those of the control in human liver microsomes. These results suggest that the effects of SWCNTs on UGT1A are different among isoforms.

Uridine 5'-diphosphate-glucuronosyltransferase (UGT) is expressed in the liver and extrahepatic tissues. One of the major metabolic pathways of β-estradiol (E2) is glucuronidation at the 17-hydroxy position by UGTs. This study was performed to determine E2 17-glucuronidation kinetics in human and rodent liver, small intestine, and kidney microsomes and to clarify the species and tissue differences. In the human liver and small intestine, Eadie-Hofstee plots exhibited biphasic kinetics, suggesting that E2 17-glucuronide (E17G) formation was catalyzed by more than two UGT isoforms in both tissues. The K m values for E17G formation by the high-affinity enzymes in the human liver and small intestine were 1.79 and 1.12 µM, respectively, and corresponding values for the low-affinity enzymes were 3.72 and 11.36 µM, respectively. Meanwhile, E17G formation in the human kidney was fitted to the Hill equation (S 50 =1.73 µM, n=1.63), implying that the UGT isoform catalyzing E17G formation in the kidney differed from that in the liver and small intestine. The maximum clearance for E17G formation in the human kidney was higher than the intrinsic clearance in the liver. E17G formation in the rat liver and kidney exhibited biphasic kinetics, whereas that in the small intestine was fitted to the Hill equation. In mice, all 3 tissues exhibited biphasic kinetics. In conclusion, we reported species and tissue differences in E2 17-glucuronidation, which occurred not only in the human liver but also in the extrahepatic tissues particularly the kidney.

β-Estradiol is conjugated by uridine 5'-diphosphate-glucuronosyltransferase (UGT) 1A to 3-glucuronide in the human liver. UGT1A has been found in the brain; therefore, UGT1A may be involved in β-estradiol 3-glucuronidation in the brain. In the present study, we aimed to characterize the β-estradiol 3-glucuronidation reaction in the rat brain. β-Estradiol 3-glucuronidation was detected in eight rat brain regions (cerebellum, frontal cortex, parietal cortex, piriform cortex, hippocampus, medulla oblongata, striatum, and thalamus). β-Estradiol 3-glucuronidation in the cerebellum was fitted to the Hill equation (S 50 =8.0 µM, n=1.1). In inhibition experiments, β-estradiol 3-glucuronidation was inhibited to 73.6% in the cerebellum by 50 µM bilirubin, whereas it was reduced to 20.5% with 5 µM bilirubin in the liver. Unlike in the liver, Ugt1a1 may not be the main isoform catalyzing this glucuronidation in the brain. Serotonin and acetaminophen at 10 mM inhibited glucuronidation to 1.17 and 25.5%, respectively, in the cerebellum. In induction experiments, the administration of β-naphthoflavone, carbamazepine, and phenobarbital did not increase β-estradiol 3-glucuronidation in the brain except for phenobarbital in the striatum. In addition, β-estradiol 3-glucuronidation was not correlated with serotonin or acetaminophen glucuronidation in the brain, suggesting that Ugt1a6 and Ugt1a7 are not major isoforms of β-estradiol 3-glucuronidation in the rat brain. In the present study, although we were unable to identify the isoform responsible for β-estradiol 3-glucuronidation, we confirmed that β-estradiol could be metabolized to glucuronide in the brain under a different metabolic profile from that in the liver.

We investigated the effects of homogeneous electron beam (EB) irradiation and thermal annealing treatments on the structural, optical, and transport properties of bismuth telluride thin films. Bismuth telluride thin films were prepared by an RF magnetron sputtering method at room temperature. After deposition, the films were treated with homogeneous EB irradiation, thermal annealing, or a combination of both the treatments (two-step treatment). We employed Williamson-Hall analysis for separating the strain contribution from the crystallite domain contribution in the x-ray diffraction data of the films. We found that strain was induced in the thin films by EB irradiation and was relieved by thermal annealing. The crystal orientation along c-axis was significantly enhanced by the two-step treatment. Scanning electron microscopy indicated the melting and aggregation of nano-sized grains on the film surface by the two-step treatment. Optical analysis indicated that the interband transition of all the thin films was possibly of the indirect type, and that thermal annealing and two-step treatment methods increased the band gap of the films due to relaxation of the strain. Thermoelectric performance was significantly improved by the two-step treatment. The power factor reached a value of 17.2 μW (cm(-1) K(-2)), approximately 10 times higher than that of the as-deposited thin films. We conclude that improving the crystal orientation and relaxing the strain resulted in enhanced thermoelectric performance.

Purpose: To examine the inhibitory effects of topically instilled bunazosin hydrochloride (bunazosin), a selective alpha1-adrenoceptor antagonist, on the retinal artery constrictions induced by intravitreous phenylephrine hydrochloride (phenylephrine) and endothelin (ET)-1 in rabbits., Methods: Phenylephrine or ET-1 (20 microL) was injected into the central part of the vitreous in both eyes in pigmented rabbits. Color fundus photographs were taken at 5 minutes before and 60 minutes after the injection. The average diameter of the major retinal arteries at the rim of the optic nerve head (ONH) was normalized with respect to ONH diameter. Bunazosin was instilled into one eye (chosen randomly) and vehicle into the fellow eye at 60 minutes before the intravitreous injection. To examine any interaction between the alpha1-adrenoceptor and ET receptor, phenylephrine and ET-1 were co-injected at individually ineffective doses. In addition, ET-1-induced vasoconstriction was examined after unilateral superior cervical ganglionectomy. The binding affinities of bunazosin for ETA and ETB receptors were also evaluated. The series of experiments was performed as masked tests., Results: Retinal arteries were dose-dependently constricted by both intravitreous phenylephrine and intravitreous ET-1. Topically instilled bunazosin at 0.01% partly inhibited both of these vasoconstrictions on the ipsilateral side, but not on the contralateral side. Bunazosin did not bind to ET receptors. Co-injection of phenylephrine and ET-1 at individually ineffective doses constricted retinal arteries significantly. An adrenergic supersensitivity in retinal arteries was observed after superior cervical ganglionectomy only on the ganglionectomized eye. The ET-1-induced vasoconstriction was significantly weaker in cervical ganglionectomized eyes than in sham-surgery eyes., Conclusions: The present findings suggest that topically instilled bunazosin reaches the posterior retina by local penetration at concentrations sufficient to attenuate the phenylephrine- or ET-1-induced constriction of retinal arteries in normal rabbit eyes, and that the inhibitory effect of bunazosin on the ET-1-induced vasoconstriction in this tissue may be partly attributable to an interaction between the alpha1-adrenoceptor and ET receptor.